Derivatives benzanilide, the method of production thereof and pharmaceutical composition exhibiting antagonism to 5-htidreceptors

 

(57) Abstract:

Usage: for the treatment or prevention of depression and other CNS disorders. Product: N-(4-chloro-3-(4-methyl-1-piperazinil)phenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1,1'-biphenyl)-4-carboxamid28H28ClN5O20,4 C2H6O. TLC, dichloromethane: ethanol: 0.88 ammonia. Rf0,56. 2 c. and 16 C.p. f-crystals.

The invention relates to new benzanilide derivatives, processes for their preparation and the pharmaceutical compositions.

In accordance with our invention are compounds of General formula (I):

< / BR>
or their physiologically acceptable salt or solvate (e.g. hydrate),

where R1represents a hydrogen atom, a halogen atom or a group selected from C1-C6-alkyl or C1-C6-alkoxygroup;

R2represents phenyl substituted by a group selected from:

< / BR>
and may, optionally substituted by one or two substituents selected from halogen atoms, WITH1-C6-alkoxygroup, hydroxyl and C1-C6-alkyl;

R3represents a group of the formula:

< / BR>
R4and R5may be the same or different, each follows the group and1-C6-alkyl;

R6represents a hydrogen atom or a group selected from-NR9R10and C1-C6-alkyl, possibly substituted by one or two substituents selected from C1-C6-alkoxygroup, hydroxyl, C1-C6-alloctype and-SO2R11;

R7, R8and R9may be the same or different, each independently represents a hydrogen atom or a C1-C6-alkyl;

R10represents a hydrogen atom or a group selected from C1-C6-alkyl, C1-C6-acyl, benzoyl and-SO2R11;

R11represents an oxygen atom or a group selected from NR8and S(O)k;

k is 0, 1 or 2.

The present invention is directed to all geometric and optical isomers of compounds of General formula (I) and their mixtures, including racemic mixtures.

Physiologically acceptable salts of the compounds of General formula (I) include salts with acids, formed with inorganic or organic acids (for example, hydrochloride, hydrobromide, sulfates, phosphates, benzoate, naphthoate, hydroxynaphthoate, p-toluensulfonate, methanesulfonate, sulfamate, ascorbate, tartratami, citrates, ATA).

In the compounds of General formula (I), the terms "1-C6-alkyl" or "C1-C6-alkoxygroup" as a group or part of a group means that the group has normal or ISO-structure and contains 1-6 carbon atoms. Examples of acceptable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl. Examples of acceptable alkoxygroup include methoxy, ethoxy-, n-propoxy, isopropoxy, h-butoxy-, second -, butoxy - and tert-butoxypropan. The term "halogen" in the definition of R2means fluorine, chlorine, bromine or iodine.

In the compounds of General formula (I), the term "acyl" as a group or part of a group means alkanoyl, such as acetyl or pivaloyl.

Featured group of the compounds of General formula (I) include compounds in which Deputy formula:

< / BR>
in the above definition in the phenyl group, R2attached in the meta - or para-position relative to the connection with the phenyl cycle And in the General formula (I).

A more preferred group of compounds of General formula (I) include compounds in which Deputy formula:

,

in the phenyl group, R2attached in the para-position relative to the connection with the phenyl cycle And a total x R2optionally substituted by one or two substituents selected from halogen atoms, WITH1-C6-alkoxygroup, hydroxyl and C1-C6-alkyl and is attached in ortho-position to the connection with the phenyl cycle And in the General formula (I).

To a more preferred group of compounds of General formula (I) include compounds in which R2represents phenyl, substituted Deputy formula:

< / BR>
and may, optionally substituted by one or two substituents selected from halogen atoms, WITH1-C6-alkoxygroup, hydroxyl and C1-C6-alkyl.

Recommended for those compounds of General formula (I) in which R1represents a hydrogen atom or a C1-C6-alkyl, especially methyl.

Another featured group of compounds of General formula (I) include compounds in which Z represents an oxygen atom.

A more preferred group of compounds of General formula (I) in which R6is1-C6-alkyl, in particular methyl, possibly substituted C1-C6-alkoxygroup, in particular a methoxy group.

We also recommend that group of compounds of General formula (I), in which the PA compounds of General formula (I) includes compounds in which R4halogen atom, especially a fluorine atom or chlorine, or hydroxyl, or C1-C6-alkoxygroup, in particular the methoxy group.

A more preferred group of compounds of General formula (I) in which R5the hydrogen atom.

And even more preferred group of compounds of General formula (I) in which R7C1-C3-alkyl, in particular methyl.

Especially recommended compound of General formula (I) is:

N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl] -4-carboxamide and its physiologically acceptable salt and solvate.

Other recommended compounds of General formula (I) include:

N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl-2'-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)[1,1'-biphenyl]-4-carboxamid,

N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)[1,1'-biphenyl]-4-carboxamid,

N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-5'-(5-methyl-1,3,4-oxadiazol-2-yl)[1,1'-biphenyl]-4-carboxamid,

N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -[4'-] 5-(methoxymethyl) -1,2,4-oxadiazol-3-yl] -2'-methyl] [1,1'-biphenyl] -4-carboxamide, N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -2-methyl-4'-(5-metapontino featured compounds of General formula (I) include:< / BR>
4'-[3-(dimethylamino)-1,2,4-oxadiazol-5-yl] -N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl]-2'-methyl-[1,1'-biphenyl]-4-carboxamid,

N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -4'-(5-methyl-1,2,4-oxadiazol-3-yl)[-1,1'-biphenyl]-4-carboxamid,

N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl]-4'-(1-methyl-1H-1,2,3-triazole-4-yl)[1,1'-biphenyl]-4-carboxamid,

N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4' -[[5-(methylsulphonyl)methyl]-1,2,4-oxadiazol-3-yl][1,1'-biphenyl] -4-carboxamid,

N-[(4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4' -(5-methyl-1,3,4-thiadiazole-2-yl)[1-1'-biphenyl] -4-carboxamide, 4'-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]-N-[4-methoxy-3 -(4-methyl-1-piperazinil)phenyl]-2'-methyl[1,1'-biphenyl]-4-carboxamid

and their physiologically acceptable salt and solvate.

Especially recommended compounds of General formula (I) include:

N-[4-chloro-3-(4-methyl-1-piperazinil] phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamid,

N-[4-methoxy-3-(4-methyl-1-piperazinil] -2'-methyl-4'-(3-methyl-1,2,4-thiadiazole-5-yl)[1,1'-biphenyl]-4-carboxamid,

2'-chloro-N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -4' -(5-methyl-1,3,4-oxadiazol-2-yl)[1,1'-biphenyl]-4-carboxamid,

N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4' -(1,2,3-thiadiazole-4-yl)[1,1'-biphenyl]-4-carboxy,

4'-(1,5-dimethyl-1H-1,2,4-triazole-3-yl)-N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl][-2'-methyl[1,1'-biphenyl]-4-carboxamid,

2-chloro-N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -4'-(5-methyl-1,2,4-oxadiazol-3-yl[1,1'-biphenyl]-4-carboxamid,

N-[2-fluoro-4-methoxy-5-(4-methyl-1-piperazinil)phenyl] -2-methyl -4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamid,

N-[4-chloro-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4' -(5-methyl-1,3,4-oxadiazol-2-yl)[1,1'-biphenyl]-4-carboxamid,

N-[4-bromo-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4' -(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamid,

N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4' -(1,3,4-oxadiazol-2-yl)[1,1'-biphenyl]-4-carboxamid

and their pharmaceutically acceptable salt and solvate.

5-Hydroxytryptamine (serotonin is a neurotransmitter widely distributed in the Central nervous system (CNS), platelets and gastrointestinal tract. Changes in the transmission serotoninergicheskih pathways in the Central nervous system, as is known, changes, for example, mood, psychomotor activity, appetite, memory and blood pressure. Selection 5-hydroxytryptamine of platelets can lead to vascular spasm; change the content of free 5-hydroxyvitamin can alter the secretion and Perov 5-hydroxytryptamine different types, summing basis at the molecular level for a wide range of its validity. These receptors are classified as 5-HT1, 5-HT2and 5-HT3and receptors 5-HT1form a 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1Dand 5-HT1D(like) receptors. The identification of these classes and subclasses of receptors is based mainly on the study of the radiological binding.

Connection providing selective antagonistic effect on 5-HT1Dreceptor, type disclosed by the present invention can provide a beneficial effect on subjects suffering from a disorder of the Central nervous system.

Accordingly, another aspect of the present invention is a method of treating a patient suffering from a CNS disorder. The method consists in the introduction to the patient an effective amount of 5-1T1Dantagonist. Ill preferably is the man.

In the present description 5-HT1Dantagonist is not found in nature (synthetic) connection that is specific and selective is antagonism to 5-HT1D-receptors, i.e., blocks a specific step 5-hydroxytryptamine passed 5-HT1D-a receptor. Podobn is ivania with the cortex of the human brain and the striped body of the Guinea pig (Hoyer and others //Nevroscience Letters, 1988, 85, R. 357-362). Activity against 5-1T1Dreceptors can be confirmed in vivo using the model with rotation of Guinea pigs (Higgins, S. A. and other //Br. J. Pharmacol. 1991, 102, R. 305-310).

Intended for use in the treatment method of the present invention, the 5-HT1Dantagonists must be selective with respect to 5-HT1D-receptors. In the present description means that the 5-HT1Dantagonist must be 30 or more times more selective for 5-HT1D-receptors than in relation to 5-HT1A, 5-HT1Cor 5-HT2-receptors.

According to the above definition, the affinity of the compound with 5-HT1A, 5-HT1Cand/or 5-HT2receptors determine the in vitro tests described in the following publications: 5-HT1A: Gozlan, etc. //Natvre, 1983, 305, R. 140-142; 5-HT1C: Pazos, etc. //Evr. J. Pharmacol, 1988, 106, R. 531-538; 5-HT2: Humphrey, etc. //Br. J. Pharmacol, 1988, 94, R. 1123-1132 (model of the aorta of the rabbit).

So, for example, shows that the compounds of the present invention inhibit the called 5-hydroxytryptamine reduction of isolated saphenous vein of the leg of the dog and show antagonism to the called 5-hydroxytryptamine inhibition of neurotransmission in the Central and peripheral may be used to treat disorders of the Central nervous system, such as: mood disorder, including depression, seasonal effective state and dysthymia; anxiety, including the General state of fear, panic condition, agoraphobia, social phobia, obsessive compulsive condition, posttraumatic stress; memory disorders, including dementia, memory disorders, senile memory impairment and disturbances in eating, including anorexia hervosa and bulimia nervosa. Other Central nervous system disorders include Parkinson's disease, dementia in Parkinson's disease, neuroleptic caused parkinsonism and late dyskinesia, as well as other mental disorders.

5-HT1Dantagonists, in particular compounds of the present invention can also find use for the treatment of endocrine disorders such as hyperprolactinaemia, treatment of vasospasm (particularly of the brain) and high blood pressure and disturbances in the gastrointestinal tract, associated with changes in motility and secretion. Connections can also be used to treat sexual disorders.

Thus, in accordance with the second aspect of our invention provides a compound of General formula (I) or its fiziologicheskogo of our invention provides a compound of General formula (I) or a physiologically acceptable salt, or a solvate for use in the treatment of the aforementioned disorders.

According to another aspect of the present invention given us the use of compounds of General formula (I) or a physiologically acceptable salt, or MES for production of therapeutic agents for the treatment of the aforementioned disorders.

According to an additional aspect of our invention provides a method of treating the above disorders, which consists in the introduction of an effective amount of compounds of General formula (I) or a physiologically acceptable salt, or MES in need of such treatment a patient.

In particular, according to another aspect of our invention provides a compound of General formula (I) or a physiologically acceptable salt, or MES for use in the treatment or prevention of depression.

You must specify that the compounds of the invention can be applied with success in combination with one or more other therapeutic agents, such as various antidepressants, such as tricyclic antidepressants (e.g. amitriptyline, dothiepin, dothiepin, trimipramine, butriptyline, clomipramine, desipramine, imipramine, iprindole, intermin, nortriptyline or proteiform excessive absorption of 5-HT (for example, fluvoxamine, sertraline, floxetine or paroxetine), and/or anti-parkinsonism, such as dopaminergic anti-parkinsonism (e.g., ldopa, preferably in combination with a peripheral decarboxylase inhibitor, such as benserazide or carbidopa, or a dopamine agonist, such as bromocriptine, lisuride or pergolid). It must be emphasized that the present invention encompasses the use of compounds of General formula (I) or a physiologically acceptable salt or MES in combination with one or more other therapeutic agents.

Thus, in an additional or alternative aspect of the present invention provides a compound of General formula (I) or a physiologically acceptable salt, or MES and antidepressant agent in combination with each other in the body of a human or animal for the treatment of the aforementioned disorders.

A special aspect of the present invention provides a compound of General formula (I) or a physiologically acceptable salt, or MES and anti-parkinsonism, such as dopaminergic agent against Parkinson's disease such as levodopa and a peripheral decarboxylase inhibitor, for example, is another in the body of a human or animal to treat Parkinson's disease, dementia with parkinsonism, neuroleptic called parkinsonism and tardive dyskinesia.

When using compounds of General formula (I) or a physiologically acceptable salt, or MES, and one or more therapeutic agents may be preferred application of the active components in the form of separate pharmaceutical compositions. However, you may be used and joint strength, while in this joint composition of active ingredients, of course, must be stable and compatible with each other.

Obviously, to enter the active components of human or animal simultaneously, separately or sequentially. The separate introduction of the delayed introduction of the second active component should not be too large in order not to lose the advantageous effect of the combination of active ingredients.

Although it is possible the introduction of compounds of General formula (I) in the form of the raw chemical, it is advisable to have an active component in the form of a pharmaceutical composition.

Compounds of General formula (I) and their physiologically acceptable salt or solvate can be prepared in the form of a composition for administration in any convenient way, and izobreteniya General formula (I) or a physiologically acceptable salt, or MES. Such compositions may be presented for use in the usual manner in a mixture with one or more physiologically acceptable carriers or excipients.

The carrier(s) must be acceptable in the sense of compatibility with other components of the composition and do not adversely impact on the recipient.

Thus, compositions of the invention can be made in the form of compositions for oral, duckling, parenteral or rectal injection or in a form suitable for administration by inhalation or insufflation. Recommended oral composition.

Tablets and capsules for oral administration may contain conventional excipients such as binders such as syrup, gum acacia, gelatin, sorbitol, tragakant, starch glue or polyvinylpyrrolidone; fillers, for example lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol; lubricants, for example magnesium stearate, stearic acid, talc, polyethylene glycol or silica; strukturator, for example potato starch, or nitroglycol starch or wetting agents such as nutriceuticals. On the tablets of the measures aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product, mixed with water or other acceptable media before use. Such liquid preparations may contain conventional additives such as suspendresume means, for example, sorbitol syrup, methylcellulose, glucose syrup/sugar, gelatin, hypromellose, carboxymethylcellulose, aluminum stearate in the form of a gel or hydrogenated edible fats; emulsifying agents, for example lecithin, monooleate sorbitol or gum acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, fatty acid esters, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl ester of n-hydroxybenzoic acid, or sorbic acid. The composition can also be prepared in the form of suppositories containing, for example, a typical candlestick bases such as cocoa butter or other glycerides.

For buccal administration of composition may be in the form of tablets or lozenges prepared in the usual way.

The composition of the invention can be prepared in the form of a composition for parenteral weezyaveli form in ampoules or in the form of a container with many doses with the addition of preservative. The composition can be in the form of suspensions, solutions or emulsions in oily or aqueous carriers can contain a part tools such as suspendida, stabilizing and/or dispersing the funds. Or the active ingredient may be in powder form, designed for mixing before use, with an acceptable carrier, such as sterile, free of pyrogens water.

For administration by inhalation or ingestion, or through the nasal compositions of the invention are typically supplied in the form of an aerosol spray composition under pressure in the container in a mixture with acceptable propellant, such as DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or any other appropriate gas, or composition comes from nebulizador. In the case of a pressurized aerosol the dosage unit may be provided for the valve that supplies a certain amount of spray.

For administration by inhalation, the compositions of the invention can be in the form of a dry powder composition, for example a powder mix of the compound and acceptable powder base, such as lactose or starch. The powder composition may be PR Packed bubbles, from which the powder may be introduced using an inhaler or insufflator.

The pharmaceutical compositions of the invention may also contain other active ingredients such as antimicrobial agents and preservatives.

Compositions of the invention can be prepared by mixing the various components in the usual way.

Obviously, the amount of compounds of General formula (I) required for the treatment will vary not only depending on the choice of a particular compound, but also on the route of administration, the nature of the subject to treatment of symptoms, age and condition of the patient, which is quite within the competence of the attending physician or veterinarian. However, in General, the proposed dose of the compounds of the invention for receiving a person is 0.5-1000 mg, preferably 1-200 mg of the active component in a unit dose which could be administered, for example, 1-4 times a day.

Compounds of the invention can be synthesized in various ways, which are listed below. When describing the methods that can be applied to obtain the compounds of General formula (I) or suitable for the synthesis of intermediate compounds, the values of RI-PII, Z and k in different formulas are the same as the producing compounds of General formula (I) at certain stages of the reaction may be necessary to protect the various reactive substituents in the original products of a particular reaction and subsequent removal of the protective group. Such protection and subsequent release can be especially relevant when R7, R8, R9and/or R10in the intermediate compounds used in the synthesis of compounds of General formula (I), is represented by hydrogen. Can be used standard methods of protection and release, such as education phthalimide (in the case of primary amine), benzyl, trailing, benzyloxycarbonyl or trichlorocarbanilide derivatives. Subsequent removal of the protective group (release) can be carried out in the usual manner. So, talimena group can be removed by treatment with hydrazine or a primary amine such as methylamine. Benzyl or benzyloxycarbonyl group can be removed by hydrogenolysis in the presence of a catalyst, for example palladium, and trichlorocarbanilide group can be removed by treatment with zinc dust. Triteleia group can be removed in an acidic medium by standard methods.

In some cases it may be necessary to protect the carboxylic acid group (for example, in the form of ester), aldehyde or catography (such as acyclic or cyclic acetals or ketals or thioacetamide esters can be removed under conditions of acid or alkaline hydrolysis, benzyl esters can be removed by hydrogenolysis in the presence of a catalyst, for example palladium. Acyclic or cyclic acetals or ketals can be removed under conditions of acid hydrolysis, and thioacetal or thioketal can be removed using salts of mercury.

Hydroxyl groups may also require protection, and hydroxyl may be protected under appropriate conditions in the form of its esters or trialkylsilyl, tetrahydropyranyl or benzyl ethers. Such derivatives can be released by conventional methods.

According to one of the common ways (I) compounds of General formula (I) can be synthesized by the reaction of carbosilane involving aniline (II):

,

where R3, R4and R5take the values stated for the General formula (I), and gaoidheilge derivative (III):

,

where Y represents a halogen atom such as bromine or iodine, or a group-OSO2CF3, a R1and R2take the values stated for the General formula (I).

The reaction is carried out, for example, in the presence of carbon monoxide and a palladium salt as a catalyst. The reaction is carried out in the presence of reasonable grounds, naprimer dimethylformamide or nitril, for example acetonitrile, in the temperature range from -10oC to +150oC.

Acceptable for the reaction of salts include palladium salts triarylphosphine (II), for example bis(triphenylphosphine)palladium(II)chloride.

According to another General process (2) compounds of General formula (I) can be obtained by treating compounds of formula (IV):

< / BR>
aminosalila formula (V):

R7N(CH2CH2HaI)2(V)

where HaI, a chlorine atom, bromine or iodine.

The reaction is conveniently carried out in the presence of a polar solvent, such as alcohol (e.g. n-butanol) or a nitrile (e.g. acetonitrile), possibly in the presence of a base such as a carbonate of an alkali metal such as sodium carbonate or potassium carbonate, or in a non-polar solvent (e.g. chlorobenzene) and without reason. The reaction is conveniently carried out at elevated temperature, for example by boiling.

According to another General process (3) compounds of General formula (I) can be obtained by the reaction of aniline of the formula (II) with activated carboxylic acid derivative of the formula (VI):

,

where L outgoing group.

Acceptable activated derivative of carboxylic acid represented former, mixed anhydride with formic acid). These activated derivatives can be formed from the corresponding acid of formula (VII):

< / BR>
known methods. For example, the anhydrides can be obtained by reaction with pentachloride phosphorus, thionyl chloride or oxalylamino, and anhydrides of acids may be obtained by reaction with the appropriate acid anhydride (for example, anhydride triperoxonane acid), acid chloride (for example, acetylchloride), alkyl - or aralkylamines (for example, ethyl - or benzylchloride) or methanesulfonanilide. Activated carboxylic acid derivatives of the formula (VI) can also be obtained in situ by reaction of the corresponding acids of formula (VII) with a linking reagent, such as carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphinic.

The conditions in which get activated derivative of carboxylic acid of the formula (VI) and then carry out the reaction with aniline formula (II), depend on the nature of the activated derivative. However, as a rule, the reaction between the compounds of formulae (II) and (VI) can be carried out in non-aqueous medium such as, for example, dimethylformamide, tetrahydrofuran, acetonitrile or a halogenated at the reaction in the presence of a base, such as triethylamine or pyridine, and the base can be also used as the reaction solvent.

When using acid chlorides, the reaction may be carried out by the method of Schotten's-Bauman in the presence of a base, for example aqueous sodium hydroxide, typically at a temperature of 0-100oC, for example at room temperature.

According to another General process (4A) compounds of General formula (I) can be obtained by treating compounds of formula (VIII):

,

where Y represents a bromine atom or iodine, or a group-OSO2CF3,

compound of formula (IXa):

R2B(OH)2(IXa)

or a complex ester, or anhydride.

Or according to the General method (4B) compounds of General formula (I) can be obtained by treating compounds of formula (VIIIb):

< / BR>
or a complex ester, or anhydride compound of the formula (IXo):

R2-Y (IXo)

where Y represents a bromine atom or iodine, or a group-OSO2CF3.

Both reactions may be carried out in the presence as catalyst of a transition metal, such as (PH3P)4Pd (where Ph represents phenyl) in an acceptable solvent such as a simple ether (for example, 1,2-d is emer, benzene). The reaction is recommended in the presence of a base such as a carbonate of alkali or alkaline-earth metal (e.g. sodium carbonate) and within an acceptable temperature range, up to the boiling point.

Compounds of General formula (I) in which R2, R4and R5take specific values, can be converted into another compound of the invention by standard methods of interconversion.

For example, if R2contains hydroxyl or alkoxygroup and/or if R4and/or R5represents hydroxyl or alkoxygroup, such groups can be vzaimozatmeniya standard methods O-alkylation or O-dealkylation. For example, the compound in which R4is hydroxyl, can be obtained by treating the corresponding compounds in which R4represents a methoxy group, the reaction system is capable of removing a methyl group, for example, mercaptides, such as ethylmercaptan sodium in a solvent such as dimethylformamide, lithium iodide in collidine, tribromide boron in galoidovodorodami solvent, for example methylene chloride or molten pyridine hydrochloride.

Prematurely with the compound of the formula (XI):

< / BR>
in the presence of acetic anhydride, followed by reduction of the resulting intermediate diketopiperazine using, for example, borane. The reaction can be carried out in the temperature interval from 50oC to the boiling temperature and, possibly, in a solvent such as simple ether, for example tetrahydrofuran, or toluene. The nitrogroup then by a standard method can be converted into amine.

Or intermediate compounds of formula (II) in which R4located next to R3and R5represents hydrogen, can be obtained by nitration of compounds of formula (XII):

< / BR>
with acceptable system nitration, such as sulfuric acid and potassium nitrate or tetrafluoroborate nitronium, in the presence of a solvent, for example acetonitrile, or, if R7is not hydrogen, nitrotyrosine using, for example, sodium nitrite and acceptable acids, such as sulfuric acid, in a solvent, for example water, followed in each case by the restoration of the standard methods nitro - or nitrosopropane.

Intermediate compounds of formula (IV) can be obtained by reduction of the corresponding nitro-derivatives of the formula (XIII):

Intermediate compounds of formula (XIII) can be obtained by condensation of compounds of formula (VI) with the compound of the formula (X) in the General method (3).

Of course, optionally halogen Deputy can be turned into carboxyl using standard techniques. For example, the intermediate compound of formula (VII) can be obtained from the intermediate compounds of formula (II) treatment by a compound of lithium, for example n-butyllithium, and then adding carbon dioxide.

Intermediate compounds of formulae (VIIIa) and (VIIIb) can be obtained by reaction of compounds of formula (II), respectively, with a compound of formula (XIVa) and (XVIb):

< / BR>
in accordance with the method of General process (3).

Intermediate derivatives of boranova acid of formula (VIIIb), (IXa) and (XIVb) or their esters or anhydrides can be used in situ under the conditions described above for the General method (4).

Intermediate compounds of formula (VII) can be obtained by the reaction of the l, by the method of General process (4).

Intermediate compounds of formula (II) can also be obtained from the corresponding carboxylic acids by conventional methods (for example, rearrangement of Curtius).

Intermediate compounds of formula (V), (X), (XI), (XII), (XIVa) and (XIYb) are either known compounds or can be synthesized by standard methods, or these methods.

Intermediate compounds containing the group R2can be obtained from these methods and the application of well known techniques (see for example: D. Barton and Ollis, W. D. General organic chemistry. So 4. Oxford: Pergamon Press, 1979; special attention to be paid to C. 1020-1050 related to the five-membered cyclic systems with mixed heteroatoms; Katritzky, A. P. and Rees C. W. General chemistry of heterocycles. So 6. Oxford: Pergamon Press, 1984, S. 365-577).

Physiologically acceptable salts with acids of compounds of General formula (I) can be obtained by treating the free base of the appropriate acid in the usual manner. For example, in General, a convenient way of obtaining salts with acids consists in mixing the appropriate quantity of free base and acid in an acceptable solvent, Napoli (I) can also turned well-known methods in other physiologically acceptable salts of the compounds of General formula (I).

The invention is illustrated by, but is not limited to the following examples, in which the temperature is given inoC. Thin-layer chromatography (TLC) carried out on plates of silicon oxide.

Use the following abbreviations:

DMF dimethylformamide,

Of the tea triethylamine,

THF tetrahydrofuran,

MCX methansulfonate,

BTP bis(triphenylphosphine)palladium(II)chloride,

DMA dimethylamine,

PMS industrial methylated spirits,

GMFA of hexamethylphosphoramide,

HCC chromatography on short columns held if there are no other indications on silica (Merck 7747),

Water pressure column chromatography carried out on silica (Merck 9385).

"Dried' refers to drying over sodium sulfate or magnesium sulfate, unless otherwise indicated.

Use the following solvent system: system a - dichloromethane-ethanol-0.88 ammonia; the System In dichloromethane-methanol-0.88 ammonia.

The intermediate connection 1

3-(4-Bromo-3-were)-5-methyl-1,2,4-oxadiazol

To a solution of hydroxylamine hydrochloride (2,48 g) in methanol (30 ml) dropwise over 10 minutes, add a solution of sodium methoxide (1,93 g) in methanol, the mixture is stirred for the RC. Evaporation of the solvent get the grey matter, part of which (2.2 g) is dissolved in acetic anhydride (6 ml) and heated for 18 hours at 80oC. the Reaction mixture is cooled and transferred into water (100 ml). The solid product is separated, collected and recrystallization from isopropanol (20 ml) receive 896 mg of the title compound as colourless microcrystals with so pl. 78oC.

Intermediate compound 2

5-(4-Bromo-3-were)-3-methyl-1,2,4-oxadiazol

To a suspension of molecular sieves (4A) in absolute ethanol (30) in a nitrogen atmosphere at 20oC add sodium metal (602 mg), and after 15 minutes add N-hydroxyethylamide (1,94 g). The mixture is stirred for 1 hour, then add the intermediate compound 8 (1 g). The mixture is boiled for 1.5 hours, filtered, and the filtrate evaporated to dryness. The residue is dissolved in water (75 ml) and extracted with ethyl acetate (2 x 75 ml). Evaporation of the dried extracts are derived 856 mg of the title compound as a colourless substance with so pl. 75-77oC.

Intermediate compound 3

Hydrochloride methyl ester 4-methoxy-3-(4-methyl-1-piperazinil)benzoic acid

A suspension of 2-chloro-N-(2-chloroethyl)-N-methylethanamine, hydrochloride (1.92 g) and methyl ester of 3-amino-4-methox the,54 g), and continue boiling for another 8.5 hours. Subsequent evaporation of the solvent receive oil, which is transferred into water (50 ml) and 2 N. hydrochloric acid (50 ml) and extracted with ethyl acetate (2 x 50 ml). Acid solution is alkalinized with sodium bicarbonate and again extracted with ethyl acetate (3 x 50 ml). The extracts are dried and concentrated to obtain a liquid substance (2, 47), which absorb from system A (200:8:1) (5 ml) at kieselgel (100 g). By elution with the same solvent to get the original product and a small amount of impurities of the main character. Further elution with system A (200:8:1) (450 ml) receive first a small amount of impurities, and in subsequent fractions obtain the target compound in the form of free base (resin of 0.48 g). The resulting resin is transferred to a methanol (5 ml), filtered and treated with ethereal hydrogen chloride, and diluted to 25 ml with ethyl acetate. The cream-colored substance was separated by filtration, and recrystallization of the product (0,586 g) from methanol-ethyl acetate to obtain the title compound, so pl. 202-204oC.

Intermediate compound 4

The hydrazide of 4-methoxy-3-(4-methyl-1-piperazinil)benzoic acid.

Intermediate compound 3 in the form of the free base (2 g) in IU the balance adsorb from ethanol on silica gel (Merck, Art. 7734, 5 g). Cleaning HCC with elution system A (91:9:0,9) get 0,764 g of the title compound in the form of a snow-white solid. TLC system A (90:10:0,1) Rf0,2.

The intermediate compound 5

4-Methoxy-3-(4-methyl-1-piperazinil)Benjamin.

A solution of intermediate compound 4 (0.73 g) in water (30 ml) is mixed with concentrated hydrochloric acid (0.6 ml), the solution is cooled to 0-5oC, and then within 5 minutes, add a solution of sodium nitrite (0,219 g) in water (10 ml). The solution is stirred for 20 minutes at 0-5oC, then 1 hour at 23oC and treated with a mixture of concentrated hydrochloric acid (40 ml) and acetic acid (40 ml). The mixture is boiled for 2 hours, cooled and transferred into 5 N. aqueous sodium hydroxide (260 ml). The mixture is extracted with ethyl acetate (3 x 500 ml), evaporation of the dried combined extracts are derived in the form of resin to 0.19 g of the title compound. TLC system A (95:5:0.5) with Rf0,2.

The intermediate compound 5, in addition, obtained in an alternative two-step reaction as follows.

a) 1-Methyl-4-(2-methoxy-5-nitrophenyl)piperazine

1-(2-Methoxyphenyl)-4-methylpiperazine (are 5.36 g), acidified with 5 N. sulfuric acid, and the excess water is evaporated in a vacuum. Add concentri the dark mix the solution at room temperature for ten portions with an interval of about 5 minutes add the potassium nitrate (of 3.07 g). The mixture is stirred for 4 hours at room temperature, then transferred onto ice (500 ml) and slightly alkalinized anhydrous sodium carbonate. The alkaline mixture is extracted with ethyl acetate (4 x 150 ml) and the combined extracts dried. After 1 hour the mixture is filtered, and the filtrate is evaporated to dryness in a vacuum. Dark red residue was diluted with ether (200 ml), solid (0.51 g) is filtered off and discarded. The filtrate is evaporated to dryness, the oily residue with ether (300 ml) and the suspension filtered. Evaporation of the filtrate to dryness receive a red resin, which slowly solidifies in the title compound (0.45 g). TLC system A (150:8:1) Rf0,45.

(b) 4-Methoxy-3-(4-methyl-1-piperazinil)Benjamin

To a solution of the product of stage (a) (5,07 g) in ethanol (70 ml) add paste of Raney Nickel in water (2 g). The hot suspension with constant stirring for 20 minutes, added dropwise hydrazinehydrate (5 ml) with periodic heating. Upon termination, boiling the suspension is heated for 15 minutes and then filtered in a nitrogen atmosphere with the addition of ethanol. The remainder of the humid washed with ethanol and the combined filtrate and wash solutions are evaporated to dryness with the addition of ethanol. The dark residue is again Hispaania get 2,365 g of the title compound as a solid substance. TLC, the system And (70:8:1) Rf0,25.

The intermediate compound 6

4-Bromo-N-(4-methoxy-3-(4-methyl-1-piperazinil)phenyl/benzamid.

A solution of intermediate compound (5 has 0.168 g) in pyridine (3 ml) is treated with 4-bromobenzylcyanide (0.25 g) and stirred for 5 hours in nitrogen atmosphere at 110oC. Add sodium bicarbonate (20 ml, 8%), and the mixture evaporated. The remainder of the pre-adsorb on silica gel (Merck, Art. 7734, approximately 5 g) and purified HCC with elution system A (97:3:0.3 to) obtaining 0,237 g of the title compound as a beige substance so pl. 158,5-159,5oC.

Intermediate compound 7

4-{ [4-Methoxy-3-(4-methyl-1-piperazinil)phenyl(amino)carbonyl]phenyl}- Baranova acid.

To a stirred solution of intermediate compound 6 (404 mg) and triisopropylsilane (2,77 ml) in dry THF over 45 minutes in a nitrogen atmosphere at -90 -100oC added dropwise n-utility (7.5 ml, 1.6 M solution in hexane), and the stirring is continued for 1.5 h at -90 -103oC. After incubation for 3 h at -78oWith the cooling bath removed and the mixture is stirred for 11 hours at +23oC. Add 4 ml of water, and after 1 hour, the mixture is evaporated. The remainder adsorb from system A (50:45:5) on silica gel (Merck 7734, 10 ml) and Ocimum the title compound as a cream foam (280 mg). TLC system A (50:45:5) Rf0,04.

Intermediate compound 8

Methyl ester of 4-bromo-3-methylbenzoic acid

In 50 ml of methanol containing concentrated sulfuric acid (2 ml) suspended 4-bromo-3-methylbenzoic acid (10 g) and the mixture is boiled for 18 hours. Once added to the cooled reaction mixture 8% NaHCO3(100 ml) the resulting precipitate is filtered off. Drying in vacuum at 40-45oTo get the title compound in the form of liquid, zakristallizuetsya cooling (of 10.25 g), so pl. 39,5-40,5oC.

Intermediate compound 9

The hydrazide of 4-bromo-3-methylbenzoic acid

A solution of intermediate 8 (2 g) in methanol (20 ml) containing hydrazinehydrate (1.1 ml), boiled for 18 hours. After cooling, the crystallized precipitate, filtration which and washing with ether gain of 1.81 g of the title compound as colourless needles with so pl. 164-166oC.

Intermediate compound 10

2-(4-Bromo-3-were)-5-methyl-1,3,4-oxadiazol

Intermediate compound 9 (1 g) in 1,1-triethoxysilane boil for 18 hours. The mixture is then allowed to cool, and collected by filtration the title compound (816 mg) as colorless powder with so pl. 135-137oC.

Intermediate compound 12

3-(4-Bromo-3-were)-5-(methoxymethyl)-1,2,4-oxadiazol

To a solution of hydroxylamine hydrochloride (950 mg) in methanol (15 ml) added dropwise a solution of sodium methoxide (740 mg) in methanol (10 ml), the mixture is stirred for 1 hour at 20oC and then filtered. To the filtrate add 2,68 g of 4-bromo-3-methylbenzonitrile, and the mixture is boiled for 18 hours. Subsequent evaporation of the solvent receive a grey solid (3.5 t), sample (1 g) dissolved in dry pyridine (5 ml) and treated with adding dropwise methoxyacetanilide (0.8 ml). The resulting mixture was boiled for 0.5 hour. The cooled mixture is transferred into the water and leave for 1 week in the refrigerator. The formed precipitate is filtered off, and recrystallization from isopropanol (2 ml) receive 300 mg of the title compound in the form of snow-white microcrystals with so pl. 52-53,5o.

Sub is soyou acid (a 4.86 g) in excess thionyl chloride (25 ml) is boiled for 1 hour. The excess thionyl chloride is then removed by distillation and evaporation. The obtained acid chloride was added to a mixture solution of intermediate compound 5 (5 g) in THF (25 ml) and sodium hydroxide (1.8 g) in water (30 ml). After stirring for about a day at room temperature and under nitrogen atmosphere, the solvent is evaporated, water is added (40 ml), the mixture is extracted with dichloromethane (I ml) and dried, after evaporation receive orange-brown sticky foam cleaning which WSU with elution system B (970:20:10) to obtain the title compound (5.73 g). TLC, the system In (970:20:10) Rf0,11.

Intermediate compound 14

4-{ [4-methoxy-3-(4-methyl-1-piperazinil)phenyl(amino)carbonyl] -2-were}boranova acid

The processing of intermediate compound 13 (5,77 g) by the method of obtaining an intermediate compound 7 produce the title compound (1,87 g) as pale yellow foam. TLC, the system In (890:100:10) Rf0,07.

Intermediate compound 15

1-(2-Chloro-5-nitrophenyl)-4-methylpiperazin

A mixture of 2-chloro-5-nitrobenzamide (of 7.95 g) of the hydrochloride of 2-chloro-N-(2-chloroethyl)-N-methylethanamine (8,86 g) in chlorobenzene (40 ml) was boiled for 3 days under nitrogen atmosphere, then cooled and diluted with dichloromethane (60 ml). The reaction mixture extrana (4 x 400 ml). Concentration in vacuum the combined dried extracts get a dark brown oil (of 7.82 g), treatment of which WSS with elution with ether get a dark brown oil that crystallized in the state. The product is dissolved in ethanol (40 ml) and boiled with 300 mg of activated charcoal. Hot ethanol, the suspension is filtered and after concentration in vacuo get a 5.25 g of the title compound as a yellow oil that crystallized upon standing, so pl. 63-64oC.

The intermediate connection 16

4-Chloro-3-(4-methyl-1-piperazinil)benzolamide

A solution of intermediate 15 (of 5.06 g) in ethanol (60 ml) and water (10 ml) is treated with Raney Nickel (2 g of sediment in the water) in a nitrogen atmosphere. The mixture is cooled to 18oC and treated with dropwise addition over 15 minutes of hydrazine hydrate is added (4 ml). The resulting mixture was stirred for 2 hours at room temperature and then filtered. Concentration of the filtrate in vacuo receive oil that crystallized upon cooling. Drying pale brown crystalline substance in the vacuum get the title compound as a brown substance (4,36 g) including square 96-97oC.

Intermediate compound 17

4-{[4-Chloro-3-(4-methyl-1-Pipera (4-carboxyphenyl)boranova acid (166 mg) in dry pyridine (5 ml) is added an excess of thionyl chloride (0,08 ml), the mixture is stirred for 30 minutes, then add the intermediate compound 16 (225 mg). The stirring is continued for another 18 hours at 20o. Add water (40 ml) and the mixture is washed with ethyl acetate (2 x 40 ml). Formed in the aqueous layer of the precipitate is collected and dried obtain the title compound (196 mg). TLC, the system (10:8:1) Rf0,1.

Intermediate compound 18

5-(4-Bromo-3-were)-3-methyl-1,2,4-thiadiazole

A solution of 4-bromo-3-methylbenzeneboronic (1.2 g) in dimethylacetal dimethylacetamide (2 ml) and dichloromethane (30 ml) is stirred for 7 hours at room temperature in a nitrogen atmosphere. Evaporation of the solvent in vacuo get a dark brown oil, which add hydroxylamine-o-sulfonic acid (0.88 g), methanol (20 ml) and pyridine (0,83 ml), and the mixture is stirred for 16 hours at room temperature in a nitrogen atmosphere. After evaporation of the added aqueous potassium carbonate and the mixture extracted with dichloromethane. The combined extracts are dried and evaporation receive a brown residue, which was purified column chromatography on silica with elution by the mixture hexane-ethyl acetate (4:1) and obtaining the title compound (0.8 g) as an orange solid. TLC, hexane-etelaat the amine

To a stirred solution of 4-bromo-3-methylbenzoic acid (500 mg) in dry acetonitrile (5 ml) containing tea (of 0.48 ml) in nitrogen atmosphere are added dropwise 0.33 ml of ethylchloride. The mixture is stirred for 30 minutes, and then add the hydrochloride of N,N-dimethyl-N-hydroxyguanidine (486 mg), and stirring is continued for 18 hours at 20oC. Add 2 n sodium carbonate and the mixture extracted with ethyl acetate (2 x 30 ml). Evaporation of the dried extracts are derived pale yellow solid residue by chromatography on which silica with elution with system A (200:8:1) receive 400 mg of colorless solid. The obtained intermediate compound (200 mg) is dissolved in absolute methanol (5 ml) and treated with sodium methoxide (38 mg). The mixture is boiled for 2 hours and then filtered to remove inorganic impurities. Subsequent evaporation of the solvent receive solid cream color, chromatography on the silica gel with elution by the mixture hexane-dichloromethane (1:2) to obtain 62 mg of the title compound in the form of a snow-white solid. TLC system A (100:8:1) Rf0,58.

Intermediate compound 20

2-Chloro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol

A mixture of hydrazide 3-chloro-4-hydroxybenzoic actionnow mixture of the crystalline precipitate is filtered off, thoroughly washed with ethyl acetate and, after drying obtain 1.8 g of the title compound. TLC, ethanol, Rf0,65.

The intermediate connection 21

2-Chloro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol, ether with triftormetilfullerenov acid

To a solution of intermediate 20 (1 g) and pyridine (0.75 ml) in dichloromethane (19 ml) under nitrogen atmosphere at 0oWith added dropwise to the anhydride triftormetilfullerenov acid (0.95 ml) and the resulting mixture is stirred for 2 hours at room temperature. Add a further quantity of anhydride triftormetilfullerenov acid (0.1 ml), and stirring is continued for another 1 hour. The solution is transferred into a 1 N. hydrochloric acid (100 ml), the mixture is extracted with dichloromethane (3 x 100 ml), and evaporation of the dried extracts obtain 1.85 g of the title compound as a pale orange solid.

Analysis, found: C 34,70; H 1,8; N, 8.2% OF

Calculated for C10H6N2O4ClF3: C 35,05; H 1,8; N, 8.2% OF

Intermediate compound 22

4-(4-Bromo-3-were)-1,2,3-thiadiazole

A mixture of 1-(4-bromo-3-were)ethanol (500 mg) and hydrazide 4-methylbenzenesulfonate (437 mg), boiled for 5 hours in ethanol (15 ml) containing a small amount of 4A molecular sieves. is rasona dissolved in thionyl chloride (2 ml) and stirred for 5 hours at 20oC. the Mixture is neutralized 2 N. sodium carbonate (40 ml) and extracted with ethyl acetate (2 x 30 ml). Evaporation of the dried extracts receives a yellow solid, chromatography which on silica with elution with a mixture of dichloromethane-hexane (1:1) obtain 167 mg of the title compound as a pale yellow solid. TLC, ethyl acetate-hexane (1:4) Rf0,52.

Intermediate compound 23

1-(2-Methyl-5-nitrophenyl)-4-methyl-2,6-piperazinyl

A suspension of N-methyliminodiacetic acid (2 g) in acetic anhydride (10 ml) is stirred for 10 minutes at room temperature and then 1 hour and heated at 150oC, during this time the solution becomes dark brown in color. The solution was concentrated in vacuo with a selection of 10 ml of distillate. The obtained brown resin was then treated with 2-methyl-5-nitrobenzylamine (2,60 g) suspended in toluene (20 ml). The resulting mixture is heated for 60 minutes at 100oC, cooled for about a day, and the formed precipitate is filtered off, washed with cold toluene (3 x 10 ml) and dried in air for 2 minutes. The obtained solid product is transferred into a flask with 15 ml of acetic anhydride and heated for 20 minutes at 140oC with the complete dissolution of the solids. The mixture is left Revival, washed with ether, and recrystallization from methanol (20 ml) to obtain 1.78 g of the title compound in the form of a crystalline powder brown substance with so pl. 157-158oC.

Intermediate compound 24

1-(5-Amino-2-were)-4-methyl-2,6-piperazinyl

A suspension of intermediate 23 (1.7 g) in a mixture of ethanol-water (5:2, 50 ml) is added under vacuum to a suspension of 10% palladium on charcoal in the form of a 50% paste (600 mg) in a mixture of ethanol-water (5:2, 20 ml). The resulting suspension is stirred in hydrogen atmosphere for 10 minutes at room temperature, filtered through hyflo, concentrated in vacuo, the residue is dissolved in dichloromethane, dried, filtered, and concentrated in vacuo get 1,49 g of the title compound in the form of a cream-colored foam. TLC system A (150:8:1) Rf0,41.

Intermediate compound 25

4-Methyl-3-(4-methyl-1-piperazinil)benzolamide

A solution of intermediate 24 (1.48 g) in dry THF (60 ml) is boiled under nitrogen atmosphere and then treated with dropwise addition of a complex of borane-THF (1 M solution of 25.5 ml). The resulting mixture was boiled for 22 hours in a nitrogen atmosphere, cooled and treated very slow addition of 2 N. hydrochloric acid (10 ml). Then see what izbavlyayut 2 N. sodium carbonate (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined dried extracts are dried in vacuum and water after cleaning with elution system A (150:8:1) receive 922 mg of the title compound as pale yellow crystals with so pl. 83-84oC.

Analysis, found: C to 70.2; H 9,5; N 20,3%

Calculated for C12H19N3: C TO 70.2; H 9,3; N 20,5%

The intermediate connection 25, in addition, obtained in an alternative two-step reaction as follows.

(a) 1-Methyl-4-(2-methyl-5-nitrophenyl)piperazine

A suspension of 2-methyl-5-nitrobenzamide (the 5.25 g) in chlorobenzene (40 ml) is treated in nitrogen atmosphere hydrochloride 2-chloro-N-(2-chloroethyl)-N-methylamine (6,64 g). The resulting mixture is boiled with stirring for 20 hours, cooled to room temperature and diluted with dichloromethane (40 ml). The organic layer is extracted with weakly acidified water (2 x 150 ml), the combined aqueous extracts alkalinized 2 N. sodium hydroxide and then extracted with dichloromethane (3 x 250 ml). Concentration in vacuum the combined dried extracts get a dark brown oil, purification of which is using WSS with elution system A (250:8:1) to obtain the title compound (4.59 g) as yellow crystals g) in ethanol is added under vacuum to pre-saturated with hydrogen suspension of palladium on charcoal (10% Ro, 50% paste in water, 1.4 g) in a mixture of ethanol-water (5:2, 50 ml). The suspension is stirred for 2 hours in hydrogen atmosphere at room temperature. The suspension is filtered through a layer hyflo, layer, thoroughly washed with a mixture of ethanol-water (4: 1, 200 ml), and evaporation of the combined filtrates in vacuo get a resinous substance that is dissolved in dichloromethane, dried, and after concentration in vacuum to get the title compound (4,052 g) as pale green crystals with so pl. 82-83oC.

Analysis, found: C to 70.2; H 9,5; N 20,4%

Calculated for C12H19N3: C TO 70.2; H 9,3; N 20,5%

The intermediate connection 26

4-Bromo-N-[4-methyl-3-(4-methyl-1-piperazinil)phenyl]benzamide

To a stirred solution of intermediate 25 (915 mg) in THF (15 ml) in water (10 ml) containing 350 mg of sodium hydroxide, add rator 4-bromobenzonitrile (1.47 g) in THF (5 ml). The mixture is stirred for 2.5 hours at room temperature in a nitrogen atmosphere, and then add water (50 ml) and extracted with dichloromethane (3 x 50 ml). The combined extracts dried and concentrated in vacuum to obtain a pale yellow foam. The foam was dissolved in dichloromethane (5 ml) to obtain the solidified yellow solution. Excess dichloromethane is removed in vacuo, theC obtain the title compound (1,464 g in the form of snow-white matter with so pl. 208-209oC.

Intermediate compound 27

Methyl ester of 4'-{[[4-methoxy-3-(4-methyl-1-piperazinil)-phenyl]amino]carbonyl}-2-methyl-(1,1'-biphenyl)-4-carboxylic acid

A mixture of intermediate compound 7 (1.1 g), intermediate 8 (0.68 g), tetrakis(triphenylphosphine)palladium(0) (50 mg) and 2 n sodium carbonate (10 ml) in DME (10 ml) is treated according to the method of example 10, and receive the title compound (1,15 g) as pale yellow foam. TLC system A (100:8:1) Rf0,36.

The intermediate connection 28

4-Bromo-3-methyl-N-hydroxybenzamide

A solution of 4-bromo-3-methylbenzonitrile (20 g) in methanol (100 ml) is treated with 6 hours of hydroxylamine hydrochloride (4 x 2,08 g) and tert-piperonyl potassium (4 x 3.25 g) and the resulting mixture is boiled for 18 hours. After cooling, the reaction mixture is transferred into water (800 ml), the suspension is stirred for 30 minutes, a white precipitate is filtered off and dried after 30 minutes, a white precipitate is filtered off and after drying in vacuum to get the title compound (21.2 g).

Analysis, found: C 41,9; H 3,9; N 12,2%

Calculated for C8H9B> > N2O: C 42,0; H 4,0; N 12,2%

Intermediate compound 29
oC.

The intermediate connection 30

2-Acetylhydrazine-4-bromo-3-methylbenzoic acid

A mixture of intermediate compound 9 (1 g) in ethanol (20 ml) containing acetic anhydride (0,61 ml) and tea (of 0.91 ml), boiled for 2 hours. The mixture is then allowed to cool and transferred into water (150 ml). The result is a very fine precipitate, which is collected and after drying receive 991 mg of the title compound, so pl. 186-187oC.

The intermediate connection 31

2-(4-Bromo-3-were)-5-methyl-1,3,4-thiadiazole

A mixture of intermediate 30 (450 mg) and 2,4-bis-(2-methoxyphenyl)-1,3,2,4-dithiophosphate-2,4-disulfide (reagent Lassen, 840 mg) boil 1 hour in toluene (15 ml) and under nitrogen atmosphere. After cooling, the mixture was partitioned between 2 N. sodium carbonate (60 ml) and ethyl acetate (2 x 40 ml). Evaporation of the dried extracts are derived pale yellow oil. Rinse the oil is eaten title compound (382 mg) as colorless crystals. TLC, ethyl acetate-hexane (1:2) Rf0,3.

The intermediate connection 32

3-(4-Bromo-3-were)-1,2,4-oxadiazol-5-methanol

A solution of intermediate 28 (250 mg) in methanol (5 ml) is heated to boiling and treated by simultaneous dropwise addition of sodium methoxide (30% in methanol, 0.5 ml) and methylhydroxylamine (0,31 ml), both diluted in methanol (3 ml). The mixture is heated for 18 hours, then allowed to cool and transferred into water (75 ml). Sediment cream color picked, and after drying in a vacuum get the title compound (241 mg), so pl. 111-112oC.

The intermediate connection 33

3-(4-Bromo-3-were)-5-methyl-1H-1,2,4-triazole

A mixture of intermediate compound 9 (742 mg), and hydrochloride of ethylacetamide (600 mg) in ethanol (20 ml) containing tea (1.35 ml), boiled for 18 hours under nitrogen atmosphere. The solvent is evaporated, and purification of the residue of the water with algorovania system (300:8:1) to obtain the title compound (450 mg) as colorless solids. TLC system A (100:8:1) Rf0,55.

The intermediate connection 34

3-(4-Bromo-3-were)-1,5-dimethyl-1H-1,2,4-thiazole

To a stirred solution of intermediate 33 (300 mg) in dry, TMPA (3 ml) under nitrogen atmosphere add the hydride NMEs stirred for 1 hour at 20oC, then add water (20 ml), and stirring is continued for another 1 hour. The precipitation is collected and after drying in a vacuum get the title compound (214 mg). TLC system A (200: 8:1) Rf0,41.

The intermediate connection 35

4-fluoro-2-methoxybenzylamine

A solution of 5-fluoro-2-NITROPHENOL (10 g) in dry acetone (40 ml) under nitrogen atmosphere is treated with potassium carbonate (8,9 g). In the mixture formed dark red thick precipitate. Slowly added methyl iodide (5 ml, 11.4 g), the mixture is stirred for about a day and then 3 hours at 60oC. Add another portion of methyl iodide (3 ml, at 6.84 g), and the mixture is stirred for 3 hours at 60oC. By this time dark-red color disappears, the mixture (orange) is transferred into water (50 ml) and sodium hydroxide (2 N. 40 ml) and extracted with dichloromethane (I ml). The concentration of the combined dried extracts in vacuo receives a yellow oil that crystallized upon cooling in pale yellow crystals of 4-fluoro-2-methoxy-1-nitrobenzene (10,88 g). A solution of the obtained product in a mixture of ethanol-water (200 ml, 6:2) is added under vacuum to pre-saturated with hydrogen suspension of palladium (10% on charcoal, 50% paste, 2.5 g) in a mixture of ethanol-water (80 ml, 6:2). The suspension is stirred 2 cha water. The combined filtrates concentrated in vacuo, and the moist residue re-evaporated with ethanol. Purple oily residue is dissolved in dichloromethane (200 ml), dried, and after concentration in vacuo get 7,73 g of the title compound as a dark purple liquid.

Analysis, found: C to 59.8; H 6,1; N 9,8%

Calculated for C7H8FNO: C TO 59.6; H TO 5.7; N, 9.9% OF

Intermediate compound 36

1-(4-fluoro-2-methoxyphenyl)-4-methylpiperazin

A mixture of intermediate 35 (7.7 g) and hydrochloride of 2-chloro-N-(2-chlorethyl)-N-methylethanamine (11,7 g) in chlorobenzene (60 ml) is boiled with stirring for 5 hours, then cooled to room temperature and stirred for 60 hours. Again down the heat source and boil for 5 hours, cooled to room temperature, diluted with dichloromethane (100 ml) and extracted with water (3 x 100 ml). The solution is slightly acidified with 2 N. hydrochloric acid, the aqueous extract is then alkalinized (pH 8-9) 2 N. sodium hydroxide and extracted with dichloromethane (4 x 75 ml). Concentration in vacuum the combined dried extracts get the dark brown oily residue, which is purified water with elution system A (300:8:1), and after drying in a vacuum get the title compound (1,312 g) 1-(4-fluoro-2-methoxy-5-nitrophenyl)-4-methylpiperazin

In concentrated sulfuric acid (4 ml) added dropwise intermediate compound 36 (1,25 d). The mixture is stirred until complete dissolution of the product, and then portions added potassium nitrate (0,712 g), keeping the temperature 25oC c using a water bath. The resulting mixture was stirred for 2 hours at room temperature and then transferred onto ice (20 g). Then the aqueous solution is neutralized to 0.88 aqueous ammonia and alkalinized (pH 8) 2 n sodium carbonate. The alkaline solution with a resinous precipitate is extracted with dichloromethane (4 x 10 ml), and concentrated in vacuum the combined dried extracts obtain the title compound (1,349 g) as a dark orange oil that crystallized upon standing.

NMR (DCl3) : is 2.37 (3H, s), 2,61 (4H, sh.t), to 3.09 (4H, sh.t), of 3.97 (3H, s), 6,7 (1H, d), a 7.62 (1H, d).

Intermediate compound 38

2-Fluoro-4-methoxy-5-(4-methyl-1-piperazinil)benzolamide

A solution of intermediate 37 (1.3 g) in a mixture of ethanol-water (7:2, 45 ml) is added under vacuum to pre-saturated with hydrogen suspension of palladium on charcoal (10% Ro, 50% paste, 480 mg) in a mixture of ethanol-water (7:2, 18 ml) and the resulting suspension is stirred for 3 hours in hydrogen atmosphere. Then the suspension is filtered is uume, the residue is dissolved in dichloromethane, dried, filtered, and after concentration in vacuum to get the title compound (1,065 g) as a brown with purple tinge solid.

NMR (CDCl3d: 2,35 (3H, c.), of 2.6 (4H, m), 3,01 (4H, m), 3,4 (2H, sh.with. ), with 3.79 (3H, s), to 6.43 (1H, d), and 6.6 (1H, d).

The intermediate connection 39

4-Bromo-N - [2-fluoro-4-methoxy-5-(4-methyl-1-piperazinil)phenyl] -3-methylbenzamide

A suspension of 4-bromo-3-methylbenzoic acid (606 mg) in thionyl chloride (3 ml) is boiled for 2 hours in nitrogen atmosphere. The excess thionyl chloride is removed in vacuo and the resulting oily residue (acid chloride) was dissolved in THF (5 ml) is slowly added to a stirred solution of intermediate 38 (657 mg) in THF (30 ml) and 2 N. sodium hydroxide (3 ml). The mixture is stirred for 4 hours at room temperature, then transferred into water (100 ml), extracted with dichloromethane (3 x 100 ml). Concentration in vacuum the combined dried extracts receive 940 mg of the title compound as a brown foam.

NMR (CDCl3d: a 2.36 (3H, c.), 2,48 (3H, c.), 2,62 (4H, m), and 3.1 (4H, m ), 3,85 (3H, s), 6,7 (1H, d), 7,52 (1H, DV. D.), the 7.65 (1H, d), 7,78 (2H, m), to 7.99 (1H, d).

The intermediate connection 40

[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]boranova acid<82 g), cool in an atmosphere of nitrogen to -100oC and carefully treated with tert-butyllithium (8,82 ml, 1.7 M solution). During the addition the temperature of the support from -90oC to -105oC. Upon completion of addition, the mixture is stirred for 20 minutes at -100oC and then allowed to warm to -30oC. the Mixture is treated with slow addition of water (5 ml) and left to warm to room temperature, then add 2 n sodium hydroxide (50 ml), and the alkaline aqueous layer washed with dichloromethane (2 x 50 ml). The aqueous layer was acidified with 2 N. hydrochloric acid (60 ml) and extracted with dichloromethane (4 x 50 ml, containing 20% methanol). Concentration in vacuum the combined dried extracts obtain the title compound (500 mg) as a pale yellow substance with so pl. 266-268oC.

The intermediate connection 41

2'-Methyl-4'-(2-methyl-1,3,4-oxadiazol-5-yl)[1,1'-biphenyl] -4-carboxylic acid

A mixture of intermediate compound 10 (610 mg) and 2 n sodium carbonate (3 ml) in DME (10 ml) is treated in an atmosphere of nitrogen, tetrakis(triphenylphosphine)palladium(0) (20 mg), stirred for 10 minutes and add 4-(carboxyphenyl)boranova acid (400 mg). The resulting mixture was heated to boiling and stirred for 24 hours, then cooled to room is sleuth. An acidic aqueous phase is extracted with a mixture of dichloromethane-methanol (5:1, h ml), the combined extracts dried and concentrated in vacuum to obtain the title compound (684 mg) as a white powder with so pl. 224-225oC.

The intermediate connection 42

2'-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl] -4-carboxylic acid

A mixture of 4-(carboxyphenyl)boranova acid (150 mg), intermediate 1 (228 mg), sodium carbonate (412 mg) and tetrakis(triphenylphosphine)palladium(0) (21 mg) in aqueous DME (1:1, 20 ml) is boiled for 18 hours under nitrogen atmosphere. The mixture is allowed to cool, acidified with 2 N. hydrochloric acid and then extracted with ethyl acetate (2 x 40 ml). Evaporation of the dried extracts are derived solid cream color (285 mg), recrystallization from isopropanol (5 ml) to obtain the title compound (165 mg) as a yellowish-brown substance with so pl. 229-231oC.

The intermediate connection 43

N-Methyl-4-(2-bromo-5-nitrophenyl)piperazine

A suspension of 2-bromo-5-nitrobenzylamine (26 g), and hydrochloride of 2-chloro-N-(2-chloroethyl)-N-methylethanamine (23 g) in chlorobenzene (150) is treated according to the method of obtaining the intermediate connection 36. Cleaning water with elution system A (300: 8: 1 gradient to 20 the internal connection 44

4-Bromo-3-(4-methyl-1-piperazinil)benzolamide

A suspension of intermediate 43 (8,68 g) in ethanol (80 ml) and water (20 ml) under nitrogen atmosphere is treated with Raney Nickel (3 g of sediment in the water). Then the suspension is cooled to 17oC, and the temperature is kept lower than the 28oC during slow addition over 20 minutes of hydrazine hydrate is added (6 ml). Then the cooled mixture is stirred for 2 hours in nitrogen atmosphere and filtered through hyflo. The filter cake is thoroughly washed with a mixture of ethanol-water (280 ml, 6: 1) and concentration in vacuo of the combined filtrates get a resinous substance that is dissolved in dichloromethane, dried and concentrated in vacuo to obtain a dark-grey (brown) solids. The resulting product is kept for about a day in a mixture of hexane:ether (1:1, 50 ml). The solid is filtered off and after drying obtain the title compound (3.28 g) as a solid. Additional product is obtained by concentration of the filtrate in vacuo. Purification of the obtained orange solid residue WSU with elution system A (300:8:1) to obtain the title compound (3,38 g) as a yellow substance with so pl. 120-121,5oC.

The intermediate connection 45

the s (300 mg) and thionyl chloride (2 ml) is treated with DMF (1 drop) and boiled for 1 hour. The thionyl chloride is evaporated in vacuo, the residue suspended in THF (2 ml) and one portion is added to a mixture of intermediate compound 5 (385 mg) in THF (2 ml) and 2 N. aqueous sodium hydroxide (4 ml). The mixture is stirred for 1 hour, diluted with water (25 ml) and washed with dichloromethane (2 x 100 ml). The aqueous phase is neutralized 2 N. hydrochloric acid and extracted with dichloromethane (3 x 75 ml). The dried extract is evaporated, and purification of the residue of the water with elution system B (240:10:1), then (190: 10:1) to obtain the title compound (140 mg) as an orange foam. TLC, the system In (90:10:1) Rf0,4.

Example 1.

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)/1,1'-biphenyl]-4-carboxamid

A mixture of intermediate compound I (200 mg) and intermediate 7 (291 mg) in aqueous DME (1:1,20 ml) containing sodium carbonate (276 mg) and tetrakis(triphenylphosphine)palladium(0) (18 mg) is boiled under nitrogen atmosphere for 18 hours. The mixture is allowed to cool, add silica gel (5 g), the solvent evaporated and chromatography of the residue on silica gel with elution with system A (200: 8: 1) to obtain the title compound (224 mg) as a cream-colored foam. TLC system A (100:8:1) Rf0,58.

Analysis, found: C 68,25; H 6,1; N 13,35%

Calculated for C<>.

A similar methodology is received:

Example 2

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(3-methyl,2, - 4-oxadiazol-5-yl)[1,1'-biphenyl] -4-carboxamide in the form of a pale yellow foam. TLC system A (150:8:1) Rf0,26.

Found: C 68,40; H equal to 6.05; N 13,65%

Calculated for C29H31N5O30,45 H2O: C 68,85; N 6.35MM; N 13,85%

Determination of water: 1,59% wt./wt. of 0.45 mol. H2O.

From a mixture of intermediate compound 2 (200 mg) and intermediate 7 (291 mg) in aqueous DME (1:1, 20 ml) containing sodium carbonate (276 mg) and tetrakis(triphenylphosphine)palladium(0) (18 mg).

Example 3

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)[1,1'-biphenyl] -4-carboxamide in the form of a colourless foam (136 mg). TLC system A (100:8:1) Rf0,44.

NMR (CDCl3d: and 2,35 2,38 (6N, 2 x C), to 2.65 (7H, m+), 3,15 (4H, m ), with 3.89 (3H, s), to 6.88 (1H, d), 7,25 (1H, m), and 7.3 (1H, DV. D.), was 7.36 (1H, d), 7,46 (2N, 1/2 W BB'), and 7.8 (1H, m s;), 7,88 shed 8.01 (4H, m).

From a mixture of intermediate compound 10 (149 mg) and intermediate 7 (218 mg) in aqueous DME (1:1, 20 ml) containing sodium carbonate (206 mg) and tetrakis(triphenylphosphine)palladium(0) (14 mg).

Example 4

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-5'-(5-me,4.

Analysis, found: C 67,55; H 6,35; N, 13.2% OF

Calculated for C29H31N5O30,3 H2O 0,4 C2H6O0,1 CH2Cl2: C 67,75; H 6,50; N, 13.2% OF

Determination of water: 1,08% wt./wt. 0.3 mmol of N2O.

From a mixture of intermediate compound 11 (200 mg) and intermediate 7 (291 mg) in aqueous DME (1:1, 20 ml) containing sodium carbonate (276 mg) and tetrakis(triphenylphosphine)palladium(0) (18 mg).

Example 5

4'-[5-(Methoxymethyl)-1,2,4-oxadiazol-3-yl] -N-[4-methoxy-3-(4 - methyl-1-piperazinil)phenyl] -2'-methyl[1,1'-biphenyl]-4-carboxamide in the form of a colourless foam (200 mg). TLC system A (100:8:1) Rf0,42.

Analysis, found: C 67,2; H equal to 6.05; N, 12.7% OF

Calculated for C30H33N5O40,35 H2O: C OF 67.5; H 6,35; N 13,1%

Determination of water: 1,16% wt./wt. 0,35 mol. H2O.

From a mixture of intermediate 12 (200 mg) and intermediate 7 (261 mg) in aqueous DME (1:1, 20 ml) containing sodium carbonate (247 mg) and tetrakis(triphenylphosphine)palladium(0) (16 mg).

Example 6

N-[-4-Methoxy-3-(4-methyl-1-piperazinil)phenyl] -2-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl] -4-carboxamide in the form of a colourless foam (100 mg). TLC system A (100:8:1) Rf0,4.

Analysis found: C, 68.75 kilopascals; H of 6.25; N, 13.3% OF

the 1,2,4-oxadiazole (100 mg) and intermediate 14 (160 mg) in aqueous DME (1:1, 20 ml) containing sodium carbonate (146 mg) and tetrakis(triphenylphosphine)Palladia(0) (10 mg).

Example 7

N-[4-Chloro-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(5-methyl,2,4-o - xavator-3-yl)[1,1'-biphenyl]-4-carboxamide in the form of a brown foam (122 mg). TLC system A (100:8:1) Rf0,56.

Analysis, found: C 64,9; H the 5.65; N, 12.9% OF

Calculated for C28H28ClN5O20,4 C2H6O: C WAS 65.3; H 6,00; N, 13.2% OF

From a mixture of intermediate compound 1 1 (131 mg) and intermediate 17 (194 mg) in aqueous DME (1:1, 20 ml) containing sodium carbonate (181 mg) and tetrakis(triphenylphosphine)palladium(0) (12 mg).

Example 8

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl] -2 methyl-4'-(3-methyl-1,2,4-thiadiazole-5-yl)[1,1'-biphenyl] -4-carboxamide in the form of a pale yellow foam (65 mg). TLC system A (100:8:1) Rf0,42.

Analysis, found: C 66,15; H 6,0; N, 12.8% OF

Calculated for C29H31N5O2S0,75 H2O: C 66,06; H 6,2; N, 13.3% OF

From a mixture of intermediate 18 (142 mg) and intermediate compound 7 (300 mg) in aqueous DME (1:1, 20 ml) containing sodium carbonate (185 mg) and tetrakis(triphenylphosphine)palladium(0) (12 mg).

Example 9

4'-[3-(Dimethylamino)-1,2,4-oxadiazol-5-yl] -N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl[1,1'-b is Geno: C 66,65; H 6,50; N 14,95%

Calculated for C30H34N6O3H2O: C 66,15; H OF 6.65; N 15,45%

From a mixture of intermediate 19 (50 mg) and intermediate 7 (103 mg) in aqueous DME (1:1, 10 ml) containing sodium carbonate (63 mg) and tetrakis(triphenylphosphine)palladium(0) (4 mg).

Example 10

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl]-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamide.

A mixture of intermediate compound 7 (0.75 g), 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazol (0,49 g), tetrakis(triphenylphosphine)palladium(0) (50 mg) and 2 n sodium carbonate (10 ml) in DME (10 ml), boiled for 3 hours. After cooling, the solution was diluted with 2 N. sodium carbonate (20 ml), extracted with ethyl acetate (3 x 50 ml) and the combined extracts dried. The mixture is filtered, and the filtrate is vacuum evaporated to dryness. The residue is purified pressure column chromatography with elution system A (100:8:1) and obtaining the title compound (0,49 g) as a white substance with so pl. 135-137oC. TLC system A (100:8:1) Rf0,52.

Example 11

2'-Chloro-N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -4'-(5-methyl,3,4- -oxadiazol-2-yl)[1,1'-biphenyl]-4-carboxamid

From a mixture of intermediate compound 7 (300 mg), intermediate 21 (55 mg) and carbonate on the od. Then add tetrakis(triphenylphosphine)palladium(0) (19 mg) and the reaction mixture is boiled under nitrogen atmosphere for 17 hours. Then the reaction mixture was diluted with water (10 ml) and extracted with dichloromethane (3 x 15 ml). The combined extracts are dried and evaporation in vacuo get a brown solid residue. Cleaning column chromatography on silica with elution with system A (200:8:1) to obtain a pale yellow solid product (130 mg), which is transferred into dichloromethane and ethanol, filtered and after evaporation in vacuo obtain the title compound (91 mg) as a yellow substance with so pl. 225-229oC. TLC system A (50:8:1) Rf0,74.

Example 12

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl] -4'-(1-methyl-1H-1,2,3-triazole-4-yl)[1,1'-biphenyl]-4-carboxamid

A mixture of intermediate compound 7 (334 mg), 4-(4-bromophenyl)-1-methyl-1H-1,2,3-triazole (140 mg), tetrakis(triphenylphosphine)palladium(0) (20 mg), 2 N. aqueous sodium carbonate (2 ml) and DME (8 ml) is boiled for 5 hours in nitrogen atmosphere. The mixture is then treated with water (50 ml) and extracted with dichloromethane (3 x 50 ml). Evaporation of the dried extract prepared brown solid product, which is then rinsed with a mixture of ether-dichloromethane (2:1, 30) and purified water with elution system B (240:10:1), then (190:f 0,4.

NMR (D4CH3OD) d: is 2.37 (3H, c.), of 2.66 (4H, sh.m.), of 3.12 (4H, sh.m). 3,86 (3H, s), 4,18 (3H, s), 6,97 (1H, d), 7,33-the 7.43 (2H, m), 7,44-7,88 (4H, 2 x 1/2 AA'BB'), 7,95 (2H, 1/2 AA'BB'), 8,03 (2H, 1/2 AA'BB'), to 8.34 (1H, c.).

Example 13

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(1,2,3-thiadiazole-4-yl)[1,1'-biphenyl]-4-carboxamid

A mixture of intermediate 22 (121 mg), intermediate 7 (270 mg), palladium acetate (5 mg) and three(o-tolyl)phosphine (15 mg) was dissolved in DMF (2 ml) and tea (1 ml) and heated in a nitrogen atmosphere for 18 hours at 100oC. the Mixture is allowed to cool and then partitioned between water (50 ml) and ethyl acetate (2 x 30 ml). Evaporation of the dried extracts receive a bright yellow oil, which chromatographic on silica gel with elution with system A (200: 8: 1) and obtaining the title compound (86 mg) as a yellow foam. TLC system A (100:8:1) Rf0,4.

Analysis, found: C 66,55; H 5,95; N 12,50%

Calculated for C28H29N5O2S0,5 H2O: C 66,10; H 5,95; N OF 13.75%

Example 14

2'-Methyl-N-[4-methyl-3-(4-methyl-1-piperazinil)phenyl] -4'-(5-methyl-1,3,4-oxadiazol-2-yl)[1,1'-biphenyl]-4-carboxamid

A solution of intermediate 26 (926 mg) in dry THF (15 ml) is cooled to -75oC and treated in a nitrogen atmosphere by adding in those treated with dropwise addition of triisopropylsilane (2 ml, 1.63 g). The reaction mixture was left to warm to room temperature, then treated with water (3 ml) and evaporated in vacuo to remove excess solvent. The aqueous residue containing resin cream color, thoroughly washed with ethyl acetate and then neutralized 2 N. hydrochloric acid. When scratching the resin is curing. The suspension is left for 72 hours, the formed precipitate is filtered off and washed with water (2 x 2 ml). Drying of the solid product in vacuum at 60oC receive intermediate derived boranova acid as a white solid (245 mg), used without further purification.

A solution of the obtained product (240 mg) in DME (8 ml) containing 2 n sodium carbonate (2 ml) and tetrakis(triphenylphosphine)palladium(0) (20 mg) in a nitrogen atmosphere is treated with an intermediate compound 10 (150 mg). The mixture is boiled for 18 hours, then cooled to room temperature, add water (50 ml) and the mixture extracted with dichloromethane (2 x 50 ml) and then ethyl acetate (50 ml). The combined dried extracts was concentrated in vacuo, and purification of the residue pressure column chromatography with elution with a gradient system And(450: 8:1-300:8:1) get the title compound (195 mg) in the form of b is UB>2O: C 71,0; H 6,5; N 14,3%

NMR (DCl3d: 2,28 (3H, c.), of 2.36 (6H, 2 x c.), of 2.6 (4H, m), of 2.64 (3H, s ), 3 (4H, m), 7,18 (1H, d), 7,25 to 7.4 3H, m), 7,46 (2H, d), 7,81 (1H, s), to $ 7.91 (1H, DV. D.), 8 (1H, s).

Example 15

4'-(3-Amino-1,2,4-oxadiazol-5-yl)-N-[4-methoxy-3-(4-methyl-1 - piperazinil)phenyl]-2'-methyl-[1,1'-biphenyl]-4-carboxamid

In absolute ethanol (10 ml) dissolved sodium (0.24 g) in a nitrogen atmosphere, add sulfate hydroxyguanidine (2:1), salt (0.95 g), stirred for 40 minutes, and add the intermediate compound 27 (1 g). The mixture is boiled for 20 hours, and after cooling, the solvent is evaporated in vacuum. The residue is purified water with elution system A (100:8:1) and evaporation of the eluate to dryness obtain the title compound (22 mg) as a pale yellow substance with so pl. 169-171oC. TLC system A (100:8:1) Rf0,26.

Example 16

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl]-2'-methyl-4'-{[5- (methylsulphonyl)methyl]-1,2,4-oxadiazol-3-yl}[1,1'-biphenyl]-carboxamid

A mixture of intermediate 29 (123 mg) and intermediate 7 (189 mg), tea (1 ml) and DMF (2 ml) containing palladium acetate (5 mg) and tri-o-tolylphosphino (15 mg), treated by the method of example 13, and obtain 68 mg of the title compound in the form of a powder color buff skin with so pl. 146-148oC. TLC system A (100:8:1) R<2-yl)[1,1'-biphenyl]-4-carboxamid

A mixture of intermediate 31 (150 mg), intermediate 7 (about 30% purity, 754 mg) and tetrakis(triphenylphosphine)palladium(0) (20 mg) in aqueous DME (1: 1, 20 ml) is treated according to the method of example 1, and receive the title compound (183 mg) as a pale yellow foam. TLC system A (100:8:1) Rf0,38.

Analysis, found: C 64,95; H x 6.15; N, 12.5% OF

Calculated for C29H31N5O20,8 C2H6O0,75 H2O: C 65,15; H OF 6.65; N, 12.4% OF

Example 18

4'-(5-Hydroxymethyl)-1,2,4-oxadiazol-3-yl-N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl]-2'-methyl[1,1'-biphenyl]-4-carboxamid

A mixture of intermediate compound 7 (258 mg), intermediate 32 (130 mg) and tetrakis(triphenylphosphine)palladium(0) (10 mg) in aqueous DME (1:1, 20 ml) is treated according to the method of example 1, and obtain 205 mg of the title compound as a colourless powder with so pl. 175-178oC. TLC system A (100:8:1) Rf0,12.

Example 19

4'-(1,5-Dimethyl-1H-1,2,4-triazole-3-yl)-N-[4-methoxy-3-(4-methyl-1 - piperazinil)phenyl]-2'-methyl[1,1'-biphenyl]-4-carboxamid

A mixture of intermediate 34 (144 mg) and intermediate compound 7 (200 mg) is heated to boiling in an aqueous DME (1:1, 20 ml) containing sodium carbonate (189 mg) and tetrakis(triphenylphosphine)palladium(0) (12 mg),system A (100:8:1) Rf0,2.

Analysis, found: C 68,1; H 6,6; N 15,35%

Calculated for C30H34N6O20,3 CH2Cl2: C TO 67.9; H, 6.5; THE N 15,65%

Example 20

N-[4-Hydroxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamid

A mixture of the product of example 1 (91 mg) and pyridine hydrochloride (2 g) is heated 8 hours at 180-190oC. Add sodium bicarbonate (8%, 30 ml) and the mixture extracted with dichloromethane (2 x 25 ml). Evaporation of the dried extracts get a dark oil, which chromatographic on silica gel (Merck 7729, 10 g) with elution system A (200:8:1) and obtaining the title compound (27 mg) as colorless foam. TLC system A (100:8:1) Rf0,4.

Analysis, found: C 68,15; H 6,00; N 13,8%

Calculated for C28H29N5O30.5 H2O: C 68,25; H X 6.15; N, 14.2% OF

Example 21

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(5-methyl-1H-1 - 2,4-triazole-3-yl)[1,1'-biphenyl]-4-carboxamid

Intermediate compound 27 (300 mg) dissolved in methanol (10 ml), boiled for 2 days with hydrazinehydrate (of 0.44 ml), the mixture is cooled and transferred into water (75 ml). The formed precipitate is filtered off and dried, then dissolved in ethanol (5 ml) and boiled for 18 hours in the presence of hydrochloride this is) get the title compound (83 mg) as colorless foam. TLC system A (50:8:1) Rf0,63.

Analysis, found: C 66,75; H 6,70; N 15,65%

Calculated for C29H32N6O20,4 C2H6O H2O: C 67,15; H OF 6.65; N OF 15.75%

Example 22

2-Chloro-N-[4-methoxy-3-(4-methyl-1-piperazinil)phenyl] -4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamid

To a solution of intermediate 45 (130 mg) and pyridine (50 mg) in dichloromethane (2 ml) was added dropwise to the anhydride triftormetilfullerenov acid (110 mg). The solution is stirred for 1 hour and evaporated. The residue is treated intermediate compound 40 (102 mg), potassium phosphate (rejonowy) (212 mg), dioxane (3 ml) and heated in a nitrogen atmosphere for 16 hours. The cooled mixture was added to 2 N. aqueous sodium carbonate (10 ml) and extracted with dichloromethane (3 x 20 ml). The dried extract is evaporated, and purification of the residue of the water with elution system (190:10:1) receives a yellow resin, the treatment of which with ether and evaporation obtain the title compound (35 mg) as a yellow substance with so pl. 93-95oC. TLC, the system In (90:10:1) Rf0,5.

Example 23

N-[2-Fluoro-4-methoxy-5-(4-methyl-1-piperazinil)phenyl]-2-methyl-4' -(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamid

A mixture of intermediate 39 (438 mg) and 2 M sodium carbonate (is 5 minutes add the intermediate connection 40 (186 mg). The mixture is boiled with stirring for 24 hours. Add a further quantity of catalyst (20 mg), aqueous sodium carbonate (0.5 ml) and intermediate 40 (45 mg) and the mixture is boiled for a further 8 hours. The mixture is cooled to room temperature and transferred into a 1 n sodium carbonate (50 ml). The aqueous layer was extracted with dichloromethane (2 x 50 ml), and concentrated in vacuum the combined dried extracts get a brown foam, which is purified water with elution system A (200:8:1) and receiving a pale pink oil that crystallized upon standing. Drying the solid product 8 hours in vacuum at 60oC obtain the title compound (385 mg) as pale pink crystals with so pl. 192-193oC.

Analysis, found: C and 63.9; H 6,3; N 11,8%

Calculated for C29H30FN5O30,8 C2H6O 1,2 H2O: C 64,0; H 6,5; N 12,2%

Example 24

N-[4-Chloro-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(5-methyl,2,4-o - xavator-3-yl)[1,1'-biphenyl]-4-carboxamid (alternative production method)

To a stirred solution of intermediate 42 (400 mg) in dry pyridine (10 ml) was added dropwise thionyl chloride (0,11 ml). The mixture is stirred for 1 hour at 20oC, then add a solution of intermediate carbonator sodium (50 ml) and ethyl acetate (2 x 70 ml). Evaporation of the dried extract receives a yellow oil, cleaning which WSU with elution system A (200:8:1) to obtain the title compound (500 mg) in the form of snow-white foam. TLC system A (100:8:1) Rf0,56.

Analysis, found: C 66,2; H 5,70; N 13,55%

Calculated for C28H28ClN5O20,6 C2H61,5 H2O: C 65,10; H OF 6.65; N 13,0%

Example 28

N-[4-Methoxy-3-(4-methyl-1-piperazinil)phenyl] -2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamid

(a) Hydrochloride

A suspension of compound of example 1 (of 4.05 g) in isopropanol (73 ml) is heated under nitrogen atmosphere to 70oC in order to dissolve the solids. Add a further quantity of isopropanol (8 ml), and heating continued 76oC obtaining a transparent pale yellow solution. Add concentrated hydrochloric acid (0,77 ml) and the solution with stirring, allowed to cool to 40oC. After the beginning of crystallization, the solution is cooled with stirring in a bath with ice for 3 hours. The precipitate is filtered off, washed with isopropanol (2 × 12 ml), and after drying in a vacuum obtain hydrochloride of the title compound (4,37 g) in the form of crystals pale cream color with so pl. 256oC (approximately).

3H8O: C 62,65; H 6,5; N 12,1; Cl 6,15%

(b) Methanesulfonate

A suspension of compound of example 1 (3.98 g) in PMS (60 mg) is heated in a nitrogen atmosphere to 70oC in order to dissolve the solid product. The heating is stopped, and when 65oC add a solution methanesulfonic acid (0,67 ml) in PMS (4 ml). The solution with stirring, allowed to cool to 35oC and then to initiate crystallization tatrallyay. Then the solution is stirred for further 1.5 hours in the bath with ice. The precipitate is filtered off, washed with PMS (2 x 12 ml), and after drying in a vacuum get methanesulfonate title compound (4,37 g) as a white substance with so pl. 256oC.

Analysis, found: C to 59.4; H 6,1; N 11,40; S 5,2%

Calculated for C29H31N5O3CH4O3H2O: C OF 58.9; H 6,1; N OF 11.45; S 5,2%

(c) Sulphate

A suspension of compound of example 1 (4.12 g) in PMS (62 ml) is treated according to the method of example 28(a) solution of concentrated sulfuric acid (0.5 ml) in PMS (4 ml), and receive sulfate title compound (4.5 g) as a white substance with so pl. 207-218oC (decomp.).

Analysis, found: C to 58.2; H 5,7; 11,4 N; S 5,1%

Calculated for C29H31N5O30,9 H2SO40.1 C2H6O4: C 58,6; H 5,6; N 11,7; S 5,4%

(d) sforno acid (of 0.62 ml) in PMS (4 ml), and get the phosphate capital of the connection (to 4.41 g) in the form of a white substance with so pl. 206oC.

Analysis, found: C 57,3; H 5,8; N 11,4; P 5,3%

Calculated for C29H31N5O3H3O4P 0,75 H2O: C 57,2; H 5,9; N IS 11.5; P 5,1%

The following examples illustrate pharmaceutical compositions of the invention. The term "active component" refers to a compound of formula (I).

Pharmaceutical example 1

Oral tablets AND

Active component 700 mg

Nitroglycol starch 10 mg

Microcrystalline cellulose 50 mg

Magnesium stearate 4 mg

The active ingredient and microcrystalline cellulose sieved through a sieve of 40 mesh. and mixed in a suitable mixer. Nitroglycol starch and magnesium stearate is sifted through a sieve of 60 mesh. add powder to the mixture and mixed until a homogeneous composition. Pressed by using the appropriate stamp in automatic tabletirujut press. Tablets can be coated with a thin polymer coating using methods of coating film, a well-known specialist. In film coating can be injected dye.

Pharmaceutical example 2

Oral tablets

Active Nicolet starch 10 mg

Magnesium stearate 4 mg

Weight pills 667 mg

The active ingredient, lactose and corn starch is sifted through a sieve of 40 mesh. and the powders are mixed in a suitable mixer. Receive an aqueous solution of polyvinylpyrrolidone (5-10 wt./vol.). Add the resulting solution to the mixed powder and mixed to form granules. Sieved granules through a sieve to 12 mesh. and dried in an acceptable furnace or fluidized bed dryer. Sift the remaining components through a sieve of 60 mesh. and mixed with the dried granules. Pressed by using appropriate tools in automatic tabletirujut press.

Tablets can be coated with a thin polymer film by applying a film coating, a well-known specialist. In film coating can be injected dye.

Pharmaceutical example 3

Cartridges for inhalation

Active ingredient 1 mg

Lactose 24 mg

The active component, the particles of which is reduced to a very small size (mean weight diameter of about 5 μm), mixed with lactose in acceptable powder mixer, powder mixture filled hard gelatin capsules No. 3.

The contents of the cartridges can be videntity component 1

Water for injection C. R. to 100

To make the solution of the tone can be added to sodium chloride, and the use of dilute acid or alkali or by adding acceptable buffer salts can be set to pH for maximum stability or promote the dissolution of the active component. Can also be added antioxidants and hepatoblastoma salt.

The solution was prepared, lighten and filled into ampoules required size, being sealed by melting the glass. The injectable composition is sterilized by heating in an autoclave using one of the acceptable cycles. Or the solution may be sterilized by filtration and filled into sterile ampoules under aseptic conditions. The solution can be packaged in an inert atmosphere of nitrogen.

1. Derivatives benzanilide General formula I

< / BR>
or its physiologically acceptable salt or MES,

where R1is a hydrogen atom or halogen atom or a group selected from C1WITH6-alkyl and C1WITH6-alkoxygroup;

R2phenyl substituted by a group selected from

< / BR>
< / BR>
and maybe (optional) optionally substituted by one or two substituents, selected the3group

< / BR>
R4and R5that may be the same or different, each independently a hydrogen atom or halogen atom or a group selected from hydroxyl, C1WITH6-alkoxygroup and C1- C6-alkyl;

R6a hydrogen atom or a group selected from-NR9R10and C1WITH6-alkyl, possibly substituted by one or two substituents selected from C1- C6-alkoxygroup, hydroxyl, C1WITH6-alloctype and SO2-R11;

R7, R8and R9that may be the same or different, each independently a hydrogen atom or a C1WITH6-alkyl;

R10a hydrogen atom or a group selected from C1- C6-alkyl, C1WITH6-acyl, benzoyl and SO2R11;

R11WITH1WITH6-alkyl or phenyl;

Z is an oxygen atom or a group selected from NR8and S(O)k;

k is 0, 1 or 2.

2. The compound of General formula II under item 1

< / BR>
or its physiologically acceptable salt or MES,

wherein R1a hydrogen atom or halogen atom or a group selected from C1WITH6-alkyl or C1-sustained fashion substituted by one or two substituents, selected from halogen atoms, WITH1WITH6-alkoxygroup, hydroxyl and C1WITH6-alkyl;

R3group

< / BR>
R4and R5that may be the same or different, each independently a hydrogen atom or halogen atom or a group selected from hydroxyl, C1WITH6-alkoxygroup and C1- C6-alkyl;

R6a hydrogen atom or a group selected from-NR9R10and C1WITH6-alkyl, possibly substituted by one or two substituents selected from C1- C6-alkoxygroup, hydroxyl and C1WITH6-acyloxy;

R7, R8, R9that may be the same or different, each independently a hydrogen atom or a C1WITH6-alkyl;

R10a hydrogen atom or a group selected from C1- C6-alkyl, C1WITH6-acyl, benzoyl and-SO2R11;

R11WITH1WITH6-alkyl or phenyl;

Z is an oxygen atom or a group selected from NR8and S(O)k;

k 0,1 or 2.

3. Connection under item 1 or 2, characterized in that the Deputy formula

< / BR>
where the phenyl group, R2attached in the meta or parabolize the phenyl cycle As in General formula I.

4. The compound according to any one of paragraphs.1 to 3, characterized in that R2optionally substituted by one or two substituents selected from halogen atoms, WITH1WITH6-alkoxygroup, hydroxyl and C1- C6-alkyl, and Deputy or deputies joined in anthopology in relation to communication with the phenyl cycle As in General formula I.

5. The compound according to any one of paragraphs.1 to 4, characterized in that R2is phenyl, substituted Deputy

< / BR>
and maybe optionally substituted by one or two substituents selected from halogen atoms, WITH1WITH6-alkoxygroup, hydroxyl and C1WITH6-alkyl.

6. The compound according to any one of paragraphs.1 to 5, characterized in that R1is a hydrogen atom or a C1WITH6-alkyl, in particular methyl.

7. The compound according to any one of paragraphs.1 to 6, characterized in that Z is an oxygen atom.

8. The compound according to any one of paragraphs. 1 to 7, wherein R6- C1WITH6-alkyl, in particular methyl, possibly substituted C1WITH6-alkoxygroup, in particular a methoxy group.

9. The compound according to any one of paragraphs.1 to 8, wherein R4attached paraprotein relative to the amide bond.

1WITH6-alkoxygroup, in particular the methoxy group.

11. The compound according to any one of paragraphs.1 to 10, wherein R5- the hydrogen atom.

12. The compound according to any one of paragraphs. 1 to 11, characterized in that R7- C1WITH3-alkyl, in particular methyl.

13. The compound of General formula (I) under item 1, or a physiologically acceptable salt or MES, wherein R1a hydrogen atom or halogen atom, or WITH1WITH6-alkyl; R2phenyl substituted by a group selected from

< / BR>
and maybe optionally substituted by one or two substituents selected from halogen atoms and C1WITH6-alkyl;

R3group

< / BR>
R4and R5that may be the same or different, each independently a hydrogen atom or halogen atom or a group selected from hydroxyl, C1WITH6-alkoxygroup and C1- C6-alkyl;

R6a hydrogen atom or a group selected from-NR9R10and C1WITH6-alkyl, possibly substituted by one or two substituents selected from C1- C6-alkoxygroup, hydroxyl and SO2R11;

R7, R8and R
R10hydrogen or C1WITH6-alkyl;

R11WITH1WITH6-alkyl;

Z is a group selected from-0-; NR8and-S-.

14. Connection PP. 1 to 13, characterized in that a represents N-(4-methoxy-3- (4-methyl-1-piperazinil)phenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)(1,1'-biphenyl)-4-carboxamide and its physiologically acceptable salt and solvate.

15. The compound according to any one of paragraphs.1 to 13, characterized in that selected from the group comprising N-/4-methoxy-3-(4-methyl-1-piperazinil)phenyl/-2'-methyl-4'- (3-methyl-1,2,4-oxadiazol-5-yl)/1,1'-biphenyl - /-4-carboxamide; N-/4-methoxy-3-(4-methyl-1-piperazinil)phenyl-2'-methyl-4'-( 5-methyl-1,3,4-oxadiazol-2 - yl)/1,1'-biphenyl - /-4-carboxamide; N-/4-methoxy-3-(4-methyl-1-piperazinil) phenyl-2'-methyl-5'-(5-methyl-1,2,4-oxadiazol-2-yl) /1,1'-biphenyl - /4-carboxamide; N-/4-methoxy-3-(4-methyl-1-piperazinil) phenyl/-4'-[ 5'-(methoxymethyl)-1,2,4-oxadiazol-3-yl] -2'-methyl/ 1,1'-biphenyl - /-4-carboxamide; N-/4-methoxy-3-(4-methyl-1 - piperazinil)phenyl/-2-methyl-4'-(5-methyl-1,2,4-oxadiazol-3 - yl)/1,1'-biphenyl - /-4-carboxamide; 4'-/3-(dimethylamino)-1,2,4 - oxadiazol-5-yl/-N-/4-methoxy-3-(4-methyl-1 - piperazinil)-phenyl/-2'- methyl/1,1'-biphenyl - /-4 - carboxamide; N-/4-methoxy-3-(4-methyl-1 - piperazinil)phenyl/-4'-(5-methyl-1,2,4-oxadiazol-3-yl)/1,1'-biphenyl - / - 4-carboxamide;ethyl-1-piperazinil)phenyl/-2'- methyl-4'-// 5-(methylsulphonyl)methyl/-1,2,4-oxadiazol-3-yl/1,1' -biphenyl - /-4-carboxamide; N-/4-methoxy-3-(4-methyl-1-piperazinil)phenyl/-2' -methyl-4'-(5-methyl-1,3,4-thiadiazole-2-yl)/1,1'-biphenyl - /- 4-carboxamide; 4'/5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl/-N- /4-methoxy-3-(4-methyl-1-piperazinil)phenyl/-2'-methyl/ 1,1'-biphenyl - /-4-carboxamide; N-/4-chloro-3-(4-methyl-1 - piperazinil)phenyl/-2'-methyl-4'(5-methyl-1,2,4-oxadiazol-3-yl)/1,1'-biphenyl - /-4-carboxamide; N-/4-methoxy-3-(4-methyl-1-piperazinil )phenyl/-2'- methyl-4'- (3-methyl-1,2,4-thiadiazole-5-yl)/ 1,1'-biphenyl - /-4-carboxamide; 2'-chloro-N-/4-methoxy - 3-(4-methyl-1-piperazinil)phenyl/-4'-(5-methyl-1,3,4-oxadiazol-2-yl)/1,1'- biphenyl - /-4-carboxamide; N-/4-methoxy-3-(4-methyl-1-piperazinil)phenyl/- 2'-methyl-4'-(1,2,3 - thiadiazole-4-yl)/1,1-biphenyl - /-4-carboxamide; 2'-methyl-N /-4-methyl-3-(4-methyl-1 - piperazinil)phenyl/-4'-(5-methyl-1,3,4-oxadiazol-2-yl)/1,1'- biphenyl - /-4-carboxamide; 4'-(1,5-dimethyl-1H-1,2,4-triazole-3-yl)-N-/4-methoxy-3-(4 - methyl-1-piperazinil)phenyl/-2'-methyl/- 1,1'-biphenyl - /-4-carboxamide-2-chloro-N-/4-methoxy-3-(4-methyl-1 - piperazinil)phenyl/-4'-(5-methyl-1,2,4-oxadiazol-3 - yl)/1,1'-biphenyl - /-4-carboxamide; N-/2-fluoro-4-methoxy-5-(4-methyl-1-piperazinil) phenyl/-2-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)/1,1'-biphenyl - /-4-carboxamide; N-/4-chloro-3-(4-methyl-1-piperazinil)phenyl/-2' -methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)/1,1'-biphenyl - /- 4-carboxamide; N-/4-bromo-3-(4-methyl-1 - piperazinil)phenyl/-2'-methyl'-(5-methyl-1,2,4-oxadiazol-3 - yl)/1,1 is ID, and their physiologically acceptable salt and solvate.

16. A method of obtaining a compound according to any one of paragraphs.1 15, or its physiologically acceptable salt, or MES, characterized in that the compound of formula VIII

< / BR>
is treated with a compound of the formula R2Rxwhere one of Ryand Rxa bromine atom, or iodine, or a group-OSO2CF3and the other of Ryand Rxgroup B(OH)2followed, if necessary, removing any protective groups, if present, and/or, if desired, convert the compound obtained of General formula I or its salt in its physiologically acceptable salt or MES.

17. The pharmaceutical composition exhibiting antagonism to 5-HTIDreceptors containing the active ingredient and a carrier, wherein the active component contains 0.5 to 1000 mg per single dose of the compound of General formula 1 according to any one of items 1 to 15, or its physiologically acceptable salt or MES.

18. The compound of General formula I according to any one of paragraphs.1 15, or its physiologically acceptable salt or MES with antagonism to 5-HTIDthe receptors.

Priority signs

12.03.92 R2phenyl, substituted the

 

Same patents:

The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

< / BR>
aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

The invention relates to new heterocyclic derivatives of substituted 2-acylamino-5-thiazolo exhibiting affinity to the receptor cholecystokinin and gastrin to a method for producing such compounds and to pharmaceutical compositions based on

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to new aminoven derivatives, processes for their production and insecticide containing as selective compounds listed derivatives

Derivative amide // 2037493

The invention relates to new derivatives substituted benzoylbenzene-, biphenyl - 2-oxazolidinone acid, which has inhibitory activity against lipoxygenase, phospholipase A2and which are leukotriene antagonists; derivatives, which are suitable for use as anti-inflammatory, antiallergic agents, but also as protectors

The invention relates to clinical immunology and can be used for pharmacological correction of disorders of neutrophils

The invention relates to medicine, namely to radiology, and can be used for the prevention of early postradiation diarrhea in medicine and veterinary medicine

The invention relates to veterinary medicine, in particular to the use of known chemical compounds [2-oxo-2(antipyrine-4-ylamino)-ethyl]pyridinylamino (cap) as a substance exhibiting a catalytic effect on the motor function of the thin intestine in animals

The invention relates to new chemical compound is 4-bromoaniline N-allyl-N-(adamantyl-1' ) Anthranilic acid of the formula I

exhibiting anti-inflammatory and analgesic activity

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to pharmaceutical composition comprising atenolol as an active component and additives - starch, magnesium basic carbonate, polyvinylpyrrolidone and/or starch glycolate sodium salt, gelatin and stearate; or starch, polyvinylpyrrolidone, stearate, aerosil and microcrystalline cellulose. Composition shows improved physical-mechanical properties.

EFFECT: improved pharmaceutical properties of composition.

14 cl, 1 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of N-desacetylthiocolchicine of the formula (I):

wherein n represents a whole number from 0 to 8; Y represents group CH2 or if n = 1 then can mean group NH also. These compounds elicit an anti-proliferative activity. Also, invention describes pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable medicinal properties of derivatives.

4 cl, 1 tbl, 4 ex

FIELD: neurological diseases.

SUBSTANCE: composition contains therapeutically effective amount of anticonvulsant agent dissolved or dispersed in aqueous carrier containing 10-80 vol % aliphatic alcohol, 10-80 vol % ethylene glycol, and 0.1-5 vol % bile acid salt or lecithin. Indicated carrier ensures increased access of anticonvulsant agent (such as benzodiazepin, in particular diazepam, clonazepam, phoenitoin, mephoenitoin, ethotoin, phenobarbital, carbamazepin, ethosuccinamide, valproic acid, gabapentine, trimethadion, lamotrigin) into blood and rapid pharmacological response when using nasal administration.

EFFECT: accelerated anticonvulsant effect.

11 cl, 9 dwg, 10 tbl, 13 ex

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