Derivatives of 1-(arylalkylamine) imidazole or their pharmaceutically acceptable salts, method of production thereof, pharmaceutical composition and method of treatment

 

(57) Abstract:

The invention relates to imidazole derivatives of the formula 1 and their pharmaceutically acceptable salts, where R1, R2and R3independently from each other hydrogen, halogen, alkoxy, phenoxy, phenyl, alkoxycarbonyl, - NR13R14, halogenated alkoxy, halogenated alkyl, benzyloxy, hydroxy, hydroxyalkyl, (C2-6-alkoxycarbonyl) vinyl, S(O)nR7carbamoylethyl, alkoxycarbonylmethyl, -CONR11R12or R1and R2together with the phenyl ring are dattilografare, R4and R5are independent from each other hydrogen, alkyl, phenyl or together with the carbon atom represents a C3-6-cycloalkyl represents hydrogen, alkyl or - hydroxyalkyl, A represents a C2-5-alkylen, R8represents hydrogen, alkyl, halogen, alkoxy, hydroxyalkyl, benzyl or phenyl, R9and R10are independent from each other hydrogen, alkyl, halogen, alkoxy, phenyl, hydroxyalkyl, alkoxycarbonyl, nitro, NR30R31alkanoyloxy or aminomethyl, which are anti-inflammatory and antiallergic agents. OPI is ptx2">

The present invention relates to new compounds 1-(aryl-acylaminoalkyl)imidazole, which has a medicinal effect and used to treat conditions associated with inflammation or allergic effect, therapeutic compositions containing these new compounds, and methods of obtaining these new compounds.

It is believed that in response to causing inflammation stimuli activates phospholipase enzymes associated with the release of arachidonic acid from phospholipids. The existing non-steroidal anti-inflammatory drugs (NSPs) called first, as I believe, the conversion lock this eye-catching arachidonic acid into prostaglandins through ziklooksigenazny path switching arachidonic acid. Most of the existing tools of this type (NSPs) unacceptable for the treatment of asthma. The authors found a series of compounds that block the allocation of arachidonic acid from phospholipids. These compounds can be used as anti-inflammatory agents with potentially broader spectrum of activity than the existing NSPs and potentially significantly less side effects for the gastrointestinal tract. Additionally, these sadisto, having inhibitory action on platelet aggregation in vitro

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Compound B represented as a chemical intermediate product in the European patent application 0230035. About the pharmacological activity of this compound has not been reported.

In the patent UK

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In the United Kingdom patent 2088888 described compositions for developers with reduced sensitivity containing imidazoles of the formula C

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in which

R1represents a hydrogen atom, a C1-20-alkyla or C6-20-allograph, R2represents a hydrogen atom, a C1-20-allilohreos, C6-20-allograph, an amino group or a C1-20-allylthiourea, R3and R4that may be the same or different, each represents a hydrogen atom, a C1-4-allilohreos or C6-20-allograph and R1, R2, R3and R4can be substituted. The patent describes 1-(6-benzamidophenyl)-2-Mei. About the pharmacological activity of this compound has not been reported.

More distantly related compounds of formula D

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in which the ring containing N, and Z is dialkylamino, morpholine or piperidine described in Indian Journal of Pharmacology is rvnoy system. N-(2-(4-morpholino)propyl/ --ethyl-3,4-dichloraniline, they claim, has anti-inflammatory activity, but has a whole range of undesirable side effects.

The present invention relates to new compounds of the formula I

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and their pharmaceutically acceptable salts, wherein R1, R2and R3independently of one another represent hydrogen, halogen, C1-6-allilohreos, C1-6-alkoxygroup, phenoxy (optionally substituted C1-4-allilohreos, C1-4-alkoxygroup or halogen), phenyl (optionally substituted C1-4-allilohreos, C1-4-alkoxygroup or halogen), C2-6-alkoxycarbonyl group, the amino group of the formula-NR13R14(in which R13and R14are independent from each other hydrogen or C1-4-allilohreos or R13and R14together with connected with them by a nitrogen atom represent a pyrolidine ring, morpholine ring or piperidine ring), halogenated C1-4-alkoxygroup, halogenated C1-4group, halogenated C1-4-accelgroup, benzyloxy (optionally substituted C1-4-accelgroup, C1-4-Alcock the PU formula S(O)nR7(in which R7represents a C1-4-accelgroup and n is the integer 0, 1 or 2), C2-4-carbamoylethyl, C2-6-alkoxycarbonyl C1-2-accelgroup, a group of carbamoyl formula-CONR11R12(in which R11and R12are independently hydrogen or C1-6-alkyl), or R1and R2together with the phenyl ring to which they are attached, represent a naphthyl, R4and R5independently represent hydrogen, C1-4-accelgroup, phenyl (optionally substituted C1-4-allilohreos, halogen or C1-4-alkoxygroup) or R4and R5together with the United with them the carbon atom represents a C3-6-cycloalkyl group.

R6represents hydrogen, C1-4-altergroup or hydroxy-C1-4-allilohreos,

A represents a C2-9-alkylene, which may be straight chain or branched,

R8represents hydrogen, C1-6-alkyl, halogen, C1-4-alkoxy-C1-4-hydroxyalkyl, phenyl (optionally substituted C1-4-alkyl, halogen or C1-4-alkoxygroup) or benzyl (optionally substituted C1-4-alkyl, halagu>1-6-allilohreos, halogen, C1-4-alkoxygroup, phenyl (optionally substituted C1-4-alkyl, halogen or C1-4-alkoxygroup), or R4and R5together with connected with them carbon atom represents a C3-6-cycloalkyl,

R6represents hydrogen, C1-4-alkyl or hydroxy-C1-4-alkyl,

A represents a C2-9-alkylene, straight or branched chain,

R8represents hydrogen, C1-6-alkyl, halogen, C1-4-alkoxygroup, C1-4-hydroxyalkyl, phenyl (optionally substituted C1-4-alkyl, halogen or C1-4-alkoxygroup) or benzyl (optionally substituted C1-4-alkyl, halogen or C1-4-alkoxygroup),

R9and R10are independently hydrogen, C1-6-alkyl, halogen, C1-4-alkoxygroup, phenyl (optionally substituted C1-4-alkyl, halogen or C1-4-alkoxygroup), C1-4-hydroxyalkyl group, a C2-6-alkoxycarbonyl group, nitro, an amino group of the formula NR30R31(in which R30and R31independently from each other represent hydrogen or C1-4-allilohreos), C1-6-alkanoyloxy C1-43, R4, R5, R6, R8, R9and R10represent hydrogen, R1is not hydrogen or 4-chlorine and that if A is a (CH2)5and R1, R2, R3, R4, R5, R6, R9and R10represent hydrogen, R8is not the stands.

It is obvious that the group containing a chain of 3 or more carbon atoms may be straight or branched, for example propyl, may include n-propyl and isopropyl, and butyl, respectively, is n-butyl, sec.-butyl, isobutyl or tert.-butyl.

In a preferred group of compounds of the formula I R1, R2and R3independently of one another represent hydrogen, halogen, such as bromine, chlorine or bromine, C1-4-allilohreos (for example, methyl, ethyl, propyl or butyl), C1-4-alkoxygroup (for example, methoxy, ethoxy, propoxy or butoxy), phenoxy, phenyl, C2-6-alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl or phenoxycarbonyl), the amino group of the formula-NR13R14in which R13and R14independently from each other represent hydrogen or C1-2B>-alkoxygroup (for example, triptoreline or pentaborate), polygalae C1-2is an alkyl group (for example, trifluoromethyl or pentafluoroethyl), benzyloxy, hydroxy, (C2-6-alkoxycarbonyl)-minilogue, C2-6-alkoxycarbonyl-C1-2is an alkyl group, or R1and R2together with the United with them the phenyl ring are dattilografare,

R4and R5independently of one another represent hydrogen, C1-4is an alkyl group (e.g. methyl, ethyl, propyl or butyl), phenyl, or R4and R5together with connected with them carbon atom represents a C3-6-cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl),

R6represents hydrogen or C1-4is an alkyl group (e.g. methyl, ethyl, propyl or butyl),

A represents a C2-7-accelerograph, which may be straight or branched (for example, ethylene, trimethylene, tetramethylene, 1,1-dimethylethylene, 2,2-dimethylethylene or heptamethine),

R8represents hydrogen, C1-4-allilohreos (for example, methyl, ethyl, propyl or butyl), phenyl (optionally substituted C1-4-allilohreos, halogen or C1-4
R9and R10independently of one another represent hydrogen, C1-4-allilohreos (for example, methyl, ethyl, propyl or butyl), halogen (e.g. bromine, chlorine or fluorine), C1-4-hydroxyalkyl group, for example, hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl), C2-6-alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl or butoxycarbonyl), nitro, or C1-6-alkanoyloxy C1-2is an alkyl group (for example, formyloxyethyl, acetoxymethyl, propenolatomethyl or butanonoxime).

The group of more preferred compounds of formula I, corresponding to the formula II

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and their pharmaceutically acceptable salts, characterized in that R1represents halogen, C1-4-allilohreos, C2-4-alkoxygroup, phenoxy, phenyl, C2-4-alkoxycarbonyl group, paraloid-C1-2-alkoxygroup, perhalocarbon C1-2-allilohreos, benzyloxy, amino group of the formula NR13R14(in which R13and R14independently from each other represent hydrogen or C1-4is an alkyl group), (C2-4-alkoxycarbonyl)vinyl group, a C2-6-alkoxycarbonyl-C1-2is an alkyl group, or R4independently of one another represent hydrogen, halogen, C1-4is an alkyl group, a C1-4-alkoxygroup, perhalocarbon C1-2is an alkyl group or hydroxy, R4and R5represent independently from each other hydrogen, C1-4is an alkyl group, phenyl, or R4and R5together with connected with them carbon atom represents a C3-6-cycloalkyl group

R6represents hydrogen or C1-3is an alkyl group, A represents an ethylene, trimethylene, tetramethylene, 1,1-dimethylethylene or heptamethine,

R8represents hydrogen, C1-4is an alkyl group, phenyl or benzyl,

R9and R10independently of one another represent hydrogen, C1-4is an alkyl group, halogen, C1-4-hydroxyalkyl group, a C2-6-alkoxycarbonyl group, nitro or C1-6-alkanoyloxy C1-2is an alkyl group.

In a preferred group of compounds of formula II, R1represents bromine, chlorine, methyl, ethyl, tert.-butyl, butoxy, phenoxy, phenyl, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, dimethylamino, triptoreline, trifluoromethyl, benzyloxy, 2-ethoxycarbonylphenyl or R11represents bromine, chlorine, tert.-butyl, butoxy, phenoxy, phenyl, methoxycarbonyl, propoxycarbonyl, triptoreline, trifluoromethyl, benzyloxy, 2-ethoxycarbonylphenyl or R1and R2together with the phenyl ring to which they are attached, represent dattilografare. If the preferred option is, when R1represents bromine or chlorine.

In a preferred group of compounds of formula II, R2represents hydrogen, 3-chloro, 2-chloro, 3-fluoro, 2-methyl, 3-methyl, 2-methoxy, 2-ethoxy, 2-hydroxy or 3-trifluoromethyl and R3represents a 2-chloro or 3-chloro. More preferably, if R2represents hydrogen, 3-chloro, 2-chloro-3-fluoro, 2-methyl, 3-methyl, 2-ethoxy, 2-hydroxy or 3-trifluoromethyl and R3represents hydrogen. Even more preferably, when R2represents hydrogen or 2-chloro and R3represents hydrogen.

In a preferred group of compounds of formula II, R4and R5represent independently from each other hydrogen, methyl, ethyl, or R4and R5together with the carbon atom to which they are joined represent cyclopropenone. More preferably, when RB>4
and R5are the stands.

In a preferred group of compounds of formula II, R6represents hydrogen or methyl. More preferably, if R6is hydrogen.

In a preferred group of compounds of formula II, A is ethylene, trimethylene or tetramethylene. More preferably, when A is an ethylene or trimethylene.

In a preferred group of compounds of formula II, R8represents hydrogen, methyl, ethyl, isopropyl, phenyl or benzyl. More preferred is an option when R8represents hydrogen or methyl.

In a preferred group of compounds of formula II, R9and R10independently of one another represent hydrogen, methyl, chloro, hydroxymethyl, etoxycarbonyl, nitro or acetoxymethyl. More preferably, when R9and R10independently of one another represent hydrogen, methyl, chlorine, acetoxymethyl or etoxycarbonyl. Even more preferably, when R9and R10independently of one another represent hydrogen or methyl.

The second group of more preferred compounds of formula I, expressed by formula II, differs are the ethyl, R6represents hydrogen, A is ethylene, R8represents hydrogen or C1-4-alkyl and R9and R10- independent from each other hydrogen, methyl, hydroxymethyl or acetoxymethyl.

The third group of preferred compounds of formula I, expressed by formula II, characterized in that R1represents chlorine, R2is hydrogen or 3-chloro, R3represents hydrogen, R4, R5and R6represents hydrogen, A is ethylene, R8represents hydrogen or methyl and R9and R10independently of one another represent hydrogen or methyl.

Specific compounds of formula I are:

-/1-(4-chlorophenyl)ethyl/-3-(imidazol-1-yl)Propylamine,

-/1-(2,4-dichlorophenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(3,4-dichlorophenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(4-forfinal)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(4-benzyloxyphenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(4-dimethylaminophenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(3-chlorophenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(2-chlorophenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(4-chloro-3-triptoreline)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(4-chloro-3-f is-were)ethyl/-3-(imidazol-yl)Propylamine,

-/1-(2,3,4-trichlorophenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(4-bromophenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(2,5-dichlorophenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

3-(imidazol-1-yl)- -/1-(4-phenoxyphenyl)ethyl/Propylamine,

-/1-(4-chloro-2-methoxyphenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(4-chloro-2-ethoxyphenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(4-tert.-butylphenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

ethyl 4-/1-/3-(imidazol-1-yl)propylamino/ethyl/benzoate,

-/1-(4-ethylphenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(4-butoxyphenyl)ethyl/-3-(imidazol-1-yl)-Propylamine,

3-(imidazol-1-yl)- -/1-(4-trifloromethyl)ethyl-/Propylamine,

-/-(4-chlorophenyl)ethyl/-3-(4,5-dimethylimidazole-1-yl)-Propylamine,

-/1-(4-chlorophenyl)ethyl/-3-(2-phenylimidazol-1-yl)-Propylamine,

-/1-(4-chlorophenyl)ethyl/-4-(imidazol-1-yl)butylamine,

-/1-(4-chlorophenyl)ethyl/-3-(2-Mei-1-yl)-Propylamine,

-/ -(4-chlorophenyl)benzyl/-3-(imidazol-1-yl)Propylamine,

5-chloro-2-/1-/3-(imidazol-1-yl)propylamino/ethyl/phenol,

-/1-(4-chlorophenyl)propyl/-3-(imidazol-1-yl/-Propylamine,

-/1-(4-chlorophenyl)ethyl/-3-(2,4-dimethylimidazole-1-yl)Propylamine,

3-(2-benzyl-4-Mei-1-yl)- -/1-(4-chlorophenyl)ethyl/- Propylamine,

3-/2-benzyl-5-Mei-1-yl)--/1-(4-what phenyl)ethyl/-3-(5-methyl-2-phenyl-imidazol-1-yl/- Propylamine,

-benzhydryl-3-(imidazol-1-yl)Propylamine,

-(3,4-dichlorobenzyl)-3-(imidazol-1-yl)Propylamine,

-(4-bromobenzyl)-3-(imidazol-1-yl)Propylamine,

3-(imidazol-1-yl)- -(4-trifloromethyl)Propylamine,

3-(imidazol-1-yl)- -(4-phenoxybenzyl)Propylamine,

-(4-chloro-2-methylbenzyl)-3-(imidazol-1-yl)Propylamine,

-(2,4-dichlorobenzyl)-3-(imidazol-1-yl)Propylamine,

-(4-Chlorobenzyl)-3-(2-Mei-1-yl)Propylamine,

-(4-Chlorobenzyl)-3-(4-Mei-1-yl)Propylamine,

-(4-Chlorobenzyl)-3-(5-Mei-1-yl)Propylamine,

-(4-Chlorobenzyl)-3-(4,5-dimethylimidazole-1-yl)Propylamine,

-(4-Chlorobenzyl)-4-(imidazol-1-yl)butylamine,

-(4-Chlorobenzyl)-3-(5-methyl-2-phenylimidazol-1-yl)Propylamine,

-(4-Chlorobenzyl)-3-(4-methyl-2-phenylimidazol-1-yl)Propylamine,

Methyl-4-/3-(2-Mei-1-yl)propylaminoethyl/benzoate,

3-(imidazol-1-yl)- -(4-methoxy-2,6-dimethylbenzyl)Propylamine,

Ethyl 4-/3-(2-Mei-1-yl)propylaminoethyl/cinnamal,

(-) -/1-(4-chlorophenyl)ethyl/-3-(imidazol-1-yl)Propylamine,

-/1-(4-chlorophenyl)ethyl and 3-(2-ethylimidazole-1-yl)Propylamine,

-/1-(4-chlorophenyl)ethyl/-3-(4-Mei-1-yl)Propylamine,

-/1-(4-chlorophenyl)ethyl/-3-(5-methylimidazol-1-yl)Propylamine,

-/1-(4-chlorophenyl)ethyl/-5-(imidazol-1-yl)pentylaniline,

-/1-(4-chlorophenyl)-1-methylethyl/-3-(imidazol-1-yl)Propylamine,

-/1-(4-chlorophenyl)-1-methylethyl)-3-(2-Mei-1-yl/Propylamine,

-(4-Chlorobenzyl)-3-(imidazol-1-yl)-2,2-dimethylpropylene,

-(1-chlorophenyl)-1-methylethyl/-8-(imidazol-1-yl)octylamine,

-(4-Chlorobenzyl)-3-(4,5-dichloroimidazole-1-yl/-Propylamine,

-/1-(4-chlorophenyl)ethyl/-3-(2-isopropylimidazole-1-yl)-Propylamine,

-/1-(4-chlorophenyl)ethyl/-3-(2,4,5-trimethylimidazo-1-yl)-Propylamine,

-/1-(4-chlorophenyl)ethyl/-3-(4,5-dichloroimidazole-1-yl)Propylamine,

-/1-(4-chlorophenyl)-1-methylethyl/3-(4-methyl-imidazol-1-yl/-Propylamine,

-/1-(4-chlorophenyl)-1-methylethyl/-3-(5-Mei-1-yl)-Propylamine,

-/1-(4-chlorophenyl)-1-methylethyl/-3-(4,5-dimethylimidazole-1-yl)Propylamine

-/4-Chlorobenzyl)-3-(2-isopropylimidazole-1-yl)Propylamine,

-(4-Chlorobenzyl)-3-(2-arylamidase-1-yl)Propylamine,

3-(2-Mei-1-yl)- -(1-methyl-1-(p-tolyl)ethylpropylamine,

-/1-(4-chlorophenyl)-1-methylethyl/-3-(4-nitroimidazol-1-yl/-Propylamine,

3-(imidazol-1-yl)--/1-methyl-1-(p-tolyl)ethyl/Propylamine,

1-(4-chlorophenyl)-1-ethyl-3'-(imidazol-1-yl/-dipropylamine,

1-/3-/1-(4-chlorophenyl)-1-methylethylamine/propyl/imidazol-4-ylmethanol,

-(1-ethyl-1-phenylpropyl)-3-(imidazol-1-yl)Propylamine,

Ethyl-4-/1-/3-(imidazol-1-yl)propylamino/-1-yl/-3-(imidazol-1-yl/Propylamine,

Ethyl 1-/3-/1-(4-chlorophenyl)-1-methylethylamine/propyl/-4-Mei - 5-carboxylate,

-/1-(2-(naphthyl)-1-methylethyl)-3-(imidazol-1-yl)Propylamine,

1-/3-/1-(3,4-dichlorophenyl)-1-methylethylamine/propyl/imidazol-5-ylmethanol,

1-/3-/1-(4-chlorophenyl)-1-methylethylamine/propyl/imidazol-5-yl-methanol,

1-/3-/1-(4-biphenylyl)-1-methylethylamine/propyl/-imidazol-4-ylmethanol,

1-/3-(1-ethyl-1-phenylpropylamine)propyl/imidazol-4-ylmethanol,

-/1-(4-benzyloxyphenyl)-1-methylethyl/-3-(imidazol-1-yl)-Propylamine,

-/1-(4-chlorophenyl)-1-methylethyl/-4-(imidazol-1-yl)butylamine,

-/1-(4-chlorophenolate)-3-(imidazol-1-yl) - a-methyl-Propylamine,

-/1-(4-chlorophenyl)propyl/-3-(imidazol-1-yl)- -methylpropylamine,

-/4-chlorbenzyl/-3-(2,4-dimethylimidazole-1-yl)Propylamine,

3-(2-benzyl-4-Mei-1-yl)- -(4-chlorbenzyl)Propylamine,

3-(2-benzyl-5-Mei-1-yl)- -(4-chlorbenzyl)Propylamine,

-/1-(4-chlorophenyl)-1-methylethyl-5-(imidazol-1-yl)-pentylamine,

Propyl-4-/3-(2-Mei-1-yl)propylaminoethyl/-benzoate,

-/4-chlorbenzyl/-5-(2-Mei-1-yl)pentylamine,

-/1-(4-chlorophenyl)-1-methylethyl/-3-(imidazol-1-yl)- - methylpropylamine,

-/4-Chlorobenzyl)-N-methyl-3-(2-Mei-1-yl)Propylamine,

-1-/4-chlorophenyl)-1-methylethyl/-3-(2-isopropylimidazole-1-yl/- plateline/propyl-5-Mei-4 - ilmatieteen and

2-/4-(1-3-imidazol-1-yl)propylamino)-1-methylethyl/phenylethanol

and their pharmaceutically acceptable salts in the form of individual enantiomers, racemates, or other mixtures of enantiomers.

The compounds of formula I can form organic and inorganic salts; for example, the compounds of formula I can form salts of the acid products of accession with inorganic or organic acids, such as hydrochloric, Hydrobromic, fumaric, tartaric, citric, sulfuric, uudistoodetena, phosphoric, acetic, maleic, benzoic, succinic, Panova, palmitic, dodekanisa and acidic amino acids, for example, glutamic acid. Some compounds of formula I may form salts with alkali metals such as sodium hydroxide, or with amino acids, such as lysine or arginine. It is believed that salt only if they are pharmaceutically acceptable, may be used for the purposes of treatment instead of the corresponding compounds of formula I. Such salts are obtained when the interaction of the compounds of formula I suitable for this purpose, acids or bases according to traditional methods. Such salts may also exist in the form of solutions (e.g., hydrates).

is introw. Thus the compounds of formula I in which R4and R5not the same, contain a chiral center. Some of the substituents R1, R2, R3, R4, R5, R6, R8, R9and R10may also contain at least one chiral center, for example, if R1, R2, R3, R4, R5, R6, R8, R9or R10represent Deut.-butyl.

If the compound of formula I contains one chiral center, it may exist in two enantiomeric forms. The present invention applies both to individual enantiomers, and mixtures of these enantiomers. These enantiomers can be obtained by known special techniques. Such methods typically include separation by formation of diastereoisomeric salts or complexes which can be divided, for example, by crystallization; separation by formation of diastereoisomeric derivatives or complexes which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective interaction of a single enantiomer-specific enantiomer reagent, for example enzymatic esterification, oxidation or vosstanovlenie liquid chromatography in a chiral environment, for example, chiral media, such as silicon dioxide, associated with the chiral ligand or in the presence of a chiral solvent. It is established that when the desired enantiomer is converted into another chemical structural unit using one of the above methods of separation, at the next stage, you must consistently produce cleavage of the desired enantiomeric form. In another case, specific enantiomers can be synthesized by the method of asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another method of asymmetric transformation.

When the compound of formula I contains more than one chiral center, it may exist in diastereoisomeric forms. Diastereomer pairs can be separated using well-known to every expert methods, for example, by chromatography or crystallization and the individual enantiomers of each pair can be divided in accordance with the techniques described above. The present invention includes each diastereoisomer of compounds of formula I or II or mixtures thereof.

Certain compounds of formula I introduced each crystal form and mixtures thereof. Certain compounds of formula I may exist, for example in the form of solutions, for example in the form of hydrates, and the invention also applies to each solution or mixtures thereof.

The present invention also includes pharmaceutical compositions containing an effective treatment for a number of compounds of formula I together with a pharmaceutically acceptable diluent or excipient. Such pharmaceutical compositions can be used to treat inflammation and/or allergic diseases.

As used below, the term "active compound" is a 1-(arylalkylamine)imidazole-derived formula I. For therapeutic purposes, the active connection, you can enter the oral, rectal, parenteral, locally, in the form of eye means an ear of funds funds applied through the nose, through the vagina or transbukkalno, while providing a local or systemic effect. The active compound can be administered as a preventive measure. Thus the present invention, therapeutic compositions can be prepared in the form of the known pharmaceutical forms for such purposes of use. The compositions can be prepared according to known special is from the dosage form, for example, rapid or controlled allocation of the present invention compounds. Pharmaceutically acceptable excipients and carriers used for such purposes are well known in the pharmaceutical industry. Present invention the compositions contain from 0.1 to 90% of the active substance by weight. Considered in the compositions of the invention is usually prepared in single dose form.

Compositions for oral (by mouth) use represent preferred compositions, appropriate subject matter, and have traditional pharmaceutical form, i.e., can be prepared in the form of tablets, capsules, granules, syrups, aqueous or oil suspensions. The fillers used for obtaining such compositions are well known to specialists in this field.

Tablets can be prepared from a mixture of active substances with extenders, for example, lactose or calcium phosphate decomposing means, for example, corn starch, and lubricating means, for example, magnesium stearate, binders such as microcrystalline cellulose or polyvinylpyrrolidone, and other ingredients that allow tableting mixtures by known who for this purpose, includes floor, decaying in the intestine, can be used, for example, hydroxypropylmethylcellulose.

Tablets can be obtained by conventional technologies, providing controlled and confirm allocation of the present invention compounds. Optionally, such tablets can be provided with "enteric coating" by known methods, for example, through the use of azettftalat pulp.

Similarly capsules, for example hard or soft gelatin capsules, containing the active substance, with the addition of filler or without it, it is possible to obtain using traditional methods, optionally coated, putrefying in the intestines by known methods. The contents of the capsules can be prepared by known methods for the controlled release of active substances. Present invention compositions with such coatings may be useful depending on the nature of the active compounds. Tablets and capsules usually contain from 1 to 1000 mg of active substance each (for example, 10 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg) of the active substance. Other compositions for oral administration include, for example, aqueous suspensions of societally, and oily suspensions containing a compound represented by the invention, suitable for this purpose vegetable oil, such as sunflower.

The active substance can be prepared in granules with the addition of filler or without him. The patient can swallow themselves granules, or it can be added in suitable for this purpose, the liquid carrier (e.g. water) before swallowing. Granules can contain disintegrating supplements (e.g., pharmaceutically acceptable effervescent couple, which include the acid and the carbonate or bicarbonate salt) providing a dispersion in a liquid medium.

Present invention the compositions for rectal use are well known pharmaceutical forms that have a specified purpose, such as lighted candles, solid fat content, as well as on the basis of semi-synthetic glycerides or polyethylene glycols.

Relevant to the subject matter of the invention, the compositions for parenteral application are also well known in the pharmaceutical industry and are well-known form for this purpose, for example, sterilnye suspension in water or an oil medium or sterile RA is th matrix in which the dispersed active substance that can maintain direct contact with the skin for direct administration of the active substance transdermal method. Or active substance may be dispersed in a cream, gel or ointment base, or be applied in aerosol form. Present invention compounds having inhalant use, i.e., inserted through the mouth or nose and mouth at the same time, are also well known pharmaceutical forms and can be prepared, for example, in the form of aerosol, sprayable solutions or powders.

You can also use strictly metered metered system, well known to every expert.

Formulations acceptable for hominids applications include soluble tablets, lozenges, chewing gum, gels, powders, means for mouthwash or rinsing the mouth.

Submitted by invention compounds can be administered by continuous infusion or in the form of external administration from an external source, for example, intravenous infusion, or from a source placed in the patient's body. Internal sources of nutrients include implanted reservoirs, code of osmolite, or implants, which can be a liquid, such as oil solutions or suspensions of the compounds to be limited, for example, in the form of very economical water-soluble derivatives, such as dodecanoate salt or (b) a solid substance in the form of implanted fastening means, for example, synthetic resin or plastic material for the highlighting of the connection. As the carrier can be a single object that contains all the connection entirely, or several such objects containing the connection part is released by diffusion.

In some formulations it may be useful to use the present invention compounds in the form of particles of different size, for example, the resulting liquid grinding.

In the present invention the compositions of the active substance can be optionally connected with other pharmaceutically acceptable and physiologically compatible ingredients such as, for example, (a) pain reliever (for example, for the treatment of rheumatoid arthritis); b) 2 agonist (for example, in the treatment of asthma) and C) nesecarily antihistamine (for example, in the treatment of other allergic zabolevayemost to be used for the treatment of inflammation and/or allergic compounds, when introduced into the body. When such treatment an amount of the compounds of formula I, entered in the day, ranges from 0.1 to 3000 mg of Specific compounds that can be administered simultaneously with the present invention compounds are new compounds mentioned above.

therapeutic efficacy of the compounds of the formula I was demonstrated during the experimental tests on a standard laboratory animals. Such studies include, for example, oral introduction of compounds to rats, which caused inflammation. Therefore, the compounds of formula I can be used for the treatment of inflammatory diseases in mammals. While the updated number of active connections, be inserted in the body depends on many factors, such as age of patient, severity of the disease and the history of the disease and should always be determined by common sense of the attending physician, the appropriate doses for enteral introduction of mammals, including humans, is usually from 0.01 to 80 mg/kg/day, usually from 0.2 to 40 mg/kg/day, which is injected in the form of a single or divided into smaller doses. For parenteral application priemlemii divided into smaller doses, forms or by continuous infusion. Oral administration is preferred.

The compounds of formula I and their pharmaceutically acceptable salts are indicated for the treatment of inflammation and/or allergic disorders of skeletal muscle, such as, for example, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, muscle injury, gout, ankylosing spondylitis, tatalina and bursitis, respiratory diseases such as asthma and rhinitis, diseases of the gastrointestinal tract, such as gastritis, granulomatous disease (Crohn's disease), ulcerative colitis and other inflammatory disorders in the intestine, diseases associated with changes in the condition of the mouth, such as gum disease and gingivitis, a disease of the skin, for example, psoriasis, urticaria, allergic skin diseases, burns, inflammation of the eyes, IIIT. The compounds of formula I and their salts can be used as analgesics and/or antipyretics.

On the other hand present invention also includes a method of treating inflammatory diseases and/or allergic complications, including the introduction of effective treatment amount of compound of formula I.

As the exact mechanism is oznachaet results from the ability of these compounds to inhibit the secretion of arachidonic acid from phospholipids. Further, as a preferred aspect of the present invention is the method of treating inflammation and/or allergic reactions, consisting in the introduction of an effective amount of an inhibitor of the formula I, affecting the allocation of arachidonic acid.

Further, as another aspect of the present invention are the use of compounds of formula I in the manufacture of a medicine for the treatment of inflammatory diseases and/or allergic reactions.

Describes how to obtain the compounds of formula I. These methods are also included in the subject matter.

The compounds of formula I in which R5and R6represent hydrogen, can be obtained by restoring the imine of formula III.

< / BR>
in which

R1, R2, R3, R4, R8, R9, R10and A have the above meaning, when using sodium borohydride in the presence of an inert organic liquid which is preferably a solvent for the compounds of formula III, for example, ethanol, at temperatures from 0 to 150oC at atmospheric pressure.

The compounds of formula III can be obtained by condensation of the ur from 0 to 200oC, preferably from 15 to 150oC optionally in the presence of an inert organic liquid, which in the preferred embodiment is a solvent for the reactants.

The compounds of formula I can be obtained by two-stage method in the same container by the reaction of compounds of formula IV with the compound of the formula V by heating at a temperature of from 0 to 200oC, followed by reduction of the resulting intermediate product, for example, using sodium borohydride, in the presence of an inert organic liquid, which in the preferred embodiment is a solvent for the reactants, for example, ethanol, at temperatures from 0 to 150oC at atmospheric pressure.

The compounds of formula I can also be obtained by one-step method by reaction of compounds of formula IV with the compound of the formula V in the presence of a reducing agent, for example, cyanoborohydride sodium in the presence of an inert organic liquid, preferably a solvent for the reactants, for example, ethanol, at temperatures from 0 to 150oC at atmospheric pressure.

The compounds of formula I in which R6represents hydrogen, can be obtained by restoring the imine of formula VI
oC at atmospheric pressure.

The compounds of formula VI can be obtained by condensation of compounds of formula VII

< / BR>
in which

R6represents hydrogen, with a compound of formula VIII

< / BR>
for example, by heating the two compounds at a temperature of from 0 to 200oC, preferably from 15 to 150oC optionally in the presence of an inert organic liquid which is preferably a solvent for the reactants, for example, alcohol at atmospheric pressure.

The compounds of formula I can be obtained by two-stage method in the same container by reacting the compounds of formula VII, in which R6represents hydrogen, with a compound of formula VIII, for example by heating the two compounds at a temperature of from 0 to 200oC, preferably from 15 to 150oC, optionally in the presence of an inert organic liquid which is preferably a solvent for the reactants, for example, alcohol, with the immediate and subsequent reduction of the obtained intermediate product by reaction with a reducing agent, e.g. sodium borohydride, in the presence of inert the tion at a temperature of from 0 to 150oC.

The compounds of formula I can be obtained by one-step method as a result of interaction of the compounds of formula VII, in which R6represents hydrogen, with a compound of formula VIII in the presence of a reducing agent, for example, laborgerate sodium, in the presence of an inert organic liquid, which is, in the preferred embodiment, the solvent for the reactants, for example, ethanol, at temperatures from 0 to 150oC at atmospheric pressure.

The compounds of formula I can be obtained by reacting the compounds of formula IX

< / BR>
with regenerating agent, for example, boron or sociallyengaged, optionally in the presence of an inert organic solvent, which in the preferred embodiment is a solvent for the compounds of formula IX, for example, ether, at temperatures from 0 to 200oC, more preferably from 15 to 150oC at atmospheric pressure.

The compounds of formula I in which R4and R5represent hydrogen, can be obtained by reaction of compounds of formula X

< / BR>
with a reducing agent, for example, boron or sociallyengaged, optionally in the presence of an inert organic liquid, which is the GRE from 0 to 200oC, mainly from 15 to 150oC.

The compounds of formula I can be obtained by reaction of compounds of formula XI

< / BR>
in which

R16represents hydrogen, with a compound of formula XII

< / BR>
in which

Z represents tsepliaeva group, for example chlorine or bromine, optionally in the presence of a base, such as triethylamine, in the presence of an inert organic liquid, which is primarily a solvent for the reactants, at a temperature of from 0 to 200oC.

The compounds of formula I in which R6represents hydrogen, can be obtained by reaction of compounds of formula XI in which R16represents a hydrolyzable acyl group (for example, formyl or acyl) with the compound of the formula XII, optionally in the presence of a strong base such as sodium hydride, followed by hydrolysis.

The compounds of formula I in which R6represent hydrogen, can be obtained by removing protection from compounds of formula XIII,

< / BR>
in which

PG represents a protecting the amino group.

Examples of acceptable for protecting groups for amines and methods for their introduction and removal can be found in the textbook "Protect the health of the formula I, in which R5is not hydrogen, can be obtained by reaction of compounds of formula R5MgX or R5Li, in which R5represents a C1-4is an alkyl group or a phenyl group (optionally substituted C1-4is an alkyl group, halogen or C1-4-alkoxygroup) and X is a halogen.

The compounds of formula I in which R6represents a C1-4is an alkyl group, can be obtained by alkylation of the corresponding compounds of formula I in which R6represents hydrogen, for example, using reductive alkylation using an aldehyde or ketone in the presence of a reducing agent, e.g. sodium borohydride.

The compounds of formula I in which R6represent hydrogen, can be obtained by reacting the compounds of formula XXIX

< / BR>
with the compound of the formula XXX

< / BR>
in which

R30is a group of magnesium or litigated formula MgX, in the presence of an organic liquid, preferably a solvent for the reactants, for example, ether, at a temperature of from 50 to 150oC.

The compounds of formula I can be obtained by reaction of compounds formally V, for example, when heated in the presence of an organic liquid which is preferably a solvent for the reactants, at a temperature of from 0 to 150oC. Optionally the compounds of formula V can be modified before the interaction with the compound XXXI, to stimulate monoalkylamines, for example, by protecting with a subsequent removal of the protection after the reaction in accordance with methods well known to every expert.

The compounds of formula I in which R1, R2, R3, R6, R8, R9and R10represent a hydroxyalkyl group, can be obtained by restoring the compounds of formula I in which R1, R2, R3, R6, R8, R9or R10respectively represent alkoxycarbonyl or alkoxycarbonylmethyl group, by methods known to every expert, for example, when using borane.

The compounds of formula IV can be purchased or obtained by methods known in the art, for example in accordance with data described in Comprehensive Organic Chemistry I. 1 (edited by D. F. Stoddart) and published by Pergamon Press, 1979.

The compounds of formula V can be obtained PU is acid or by reaction of compounds of formula XIV with hydrazine.

The compounds of formula VII can be purchased or obtained by methods known in the art, described, in particular, in Comprehensive Organic Chemistry, so 2 (edited by Acting Sutherland), published by Pergamon Press, 1979. Preferred compounds of formula VII, in which R6represents hydrogen, you can get ptemperature amide of formula XXV

< / BR>
the mechanism Hofmann.

Or the compounds of formula VII, in which R6represents hydrogen, can be obtained by reaction of compounds of formula XXVI

< / BR>
with a reducing agent, e.g. hydrogen in the presence of a catalyst or iron in the presence of acid.

The compounds of formula VIII, in which A represents -(CH2)2can be obtained by interaction of acrolein with the compound of the formula YH, in which Y represents a group of formula XXVII

< / BR>
not necessarily in the presence of a catalyst, for example, acetic acid.

The compounds of formula IX can be obtained by reaction of compounds of formula XV

< / BR>
in which

Z represents useplease group, for example halogen, preferably bromine or chlorine, with a compound of formula YH or M+Y-where M

The compounds of formula IX, in which A represents -(CH2)2- can be obtained by reaction of compounds of formula XVI

< / BR>
with the compound of the formula YH, in which Y represents a group of formula XXVII, which has the above meaning, in the presence of a catalyst (for example, -benzyltrimethylammonium) and optionally in the presence of an organic liquid which is preferably a solvent for the starting materials, for example, pyridine or 1,4-dioxane at a temperature of from 50 to 200oC, preferably from 80 to 150oC.

The compounds of formula IX can be obtained by reaction of compounds of formula XVII

< / BR>
with the compound of the formula NC-A-Y, in which Y represents a group of formula XXVII, for example, in the presence of a strong acid, such as sulfuric acid. The compounds of formula NC-A-Y can be obtained by methods known in the art.

The compounds of formula IX can be obtained by reaction of compounds of formula VII with the compound of the formula X. CO.A.Y, in which X represents useplease group, for example, chlorine, and Y represents a group of formula XXVII, n is accordance with the methods known to every expert in this field.

The compounds of formula X mono be obtained by reaction of compounds of formula XVIII

< / BR>
in which Z represents useplease group, for example, halogen, preferably chlorine, with a compound of formula R6-NH-CH2-A-Y-, which is obtained from compounds of formula V by methods known in the art.

Compounds of formulas XI and XII can be obtained also known in the art methods.

The compounds of formula XIII can be obtained by reacting the compounds of formula XIX

< / BR>
in which

Z represents useplease group (e.g. halogen) with the compound of the formula YH or formula M+Y-with the above values, for example by heating.

The compounds of formula XIII can be obtained by reaction of compounds of formula XX

< / BR>
in which

R17represents hydrogen or formyl, imidazolinium a synthon, as described, for example, in Advances in Heterocyclic Chemistry, I. 12, 103 (1970), published Academic Press.

The compounds of formula XIII, in which R4or R5represent a group other than hydrogen, can be obtained by reaction of compounds of formula XIII, in cumidin) and R4or R5represent hydrogen, respectively, with a reagent of formula R4-Z or R5-Z, in which Z represents useplease group (e.g. halogen) in the presence of a base, for example, n-utility or butylacrylate.

The compounds of formula XIII, in which R4and R5represent a group other than hydrogen, and have different meanings, can be obtained by the sequential reaction of compounds of formula XIII, in which PG represents an activating protecting group (for example, blocked acyl group or formamide) and both radical R4and R5represent hydrogen, with a reagent of formula R4-Z and then with a reagent of formula R5-Z or Vice versa in the presence of a base, for example n-utillity.

The compounds of formula XIII, in which R4and R5have the same value and are not hydrogen, can be obtained by reaction of compounds of formula XIII, in which PG represents a protecting an activating group (e.g., blocked acyl group), and R4and R5are both hydrogen, with a compound of formula R4-Z in the presence of a base, for example, n-utility or guide is soedineniya formula XIII can be obtained by reaction of compounds of formula XXIII

< / BR>
with the compound of the formula X-CH2-A-Y, in which X represents useplease group, for example, halogen, and Y represents a group of formula XXVII. The compounds of formula XIII can be obtained by reacting the compounds of formula XXIII with a compound of the formula X-CO-A-Y with subsequent recovery. The compounds of formula X-CH2-A-Y and X-CO-A-Y can be obtained by methods known in the art.

The compounds of formula XIV can be obtained by reaction of compounds of formula XXI

< / BR>
in which

Z represents useplease group, for example, halogen, preferably chlorine or bromine, with a compound of formula YH or formula M+Y-.

The compounds of formula XV can be obtained by reaction of compounds of formula VII with acylhalides formula X. CO.A.Z, in which Z represents useplease group, for example, halogen, preferably chlorine, and X is useplease group, for example, halogen, in the presence of a base, such as triethylamine.

The compounds of formula XVI can be obtained by reaction of compounds of formula VII with the compound of the formula XXII

< / BR>
in which

Z represents useplease group, for example, halogen, preferably chlorine.

The compounds of formula XIX can be obtained by reaction of compounds of formula XXIII with a compound of the formula X-CO-A-Z with subsequent recovery. The compounds of formula X-CO-A-Z, in which X and Z are, for example, halogen as tsepliaeva group, can be obtained by methods known to experts.

The compounds of formula XX, in which R17is a formula that can be obtained from compounds of formula XX, in which R17represents hydrogen, by methods known in the art.

The compounds of formula XX, in which R17represents hydrogen, can be obtained by hydrolysis of compounds of formula XXIV,

< / BR>
in accordance with methods known in the art.

The compounds of formula XXIII can be obtained from compounds of formula VII, in which R6represents hydrogen, also known in the art methods.

The compounds of formula XXIV can be obtained from the compounds of formula XXIII by apothem hydrolysis of compounds of formula XXVIII

< / BR>
for example, a) when using acid, or b) if the Foundation is not necessary in the presence of an oxidant, e.g. hydrogen peroxide.

The compounds of formula XXVI in which R4or R5represent a group other than hydrogen, can be obtained by reaction of compounds of formula XXVI in which R4or R5represent hydrogen, respectively, with a reagent of formula R4-Z or R5-Z, in which Z represents useplease group (e.g. halogen) in the presence of a base, for example, n-utility or sodium hydride.

The compounds of formula XXVI in which R4and R5represent a group other than hydrogen, and have different meanings, can be obtained by the sequential reaction of compounds of formula XXVI in which R4and R5represent hydrogen, with a reagent of formula R4-Z and then with a reagent of formula R5-Z or Vice versa, in the presence of a base, for example, n-utility or sodium hydride.

The compounds of formula XXVI in which R4and R5have the same value and are not hydrogen, can be obtained by reaction of compounds of formula XXVI in which R4and R5both presided sodium. It is preferable to use at least two moles of R4-Z and grounds.

The compounds of formula YH, in which Y represents a group of formula XXVII can be purchased or obtained by methods known to experts.

The compounds of formula XXVIII in which either R4or R5represents a group which is not hydrogen, can be obtained by reaction of compounds of formula XXVIII in which R4or R5represent hydrogen, respectively, with a reagent of formula R4-Z or R5-Z, in which Z represents useplease group (e.g. halogen) in the presence of a base, for example, n-utility or nutrigenie.

The compounds of formula XXVIII in which R4and R5represent a group other than hydrogen, can be obtained by sequential interactions of the compounds of formula XXVIII in which R4and R5represent hydrogen, with a reagent of formula R4-Z and then with a reagent of formula R5-Z or Vice versa, in the presence of a base, for example, n-utility or nutrigenie.

The compounds of formula XXVIII in which R4and R5have the same value and are not hydrogen, orod, with the compound of the formula R4-Z in the presence of a base, for example, n-utility or sodium hydride. It is preferable to use at least two mole R4-Z and base.

The compounds of formula XXIX can be obtained by reaction of compounds of formula V with a compound of formula XXXII.

< / BR>
by methods known in the art, for example, by heating optionally in the presence of an organic liquid which is preferably a solvent for the reactants at a temperature from 0 to 150oC, preferably in the presence of means for removing water, such as a desiccant or liquid, forming an azeotropic compound with water.

Compounds of formula XV, XVII, XVIII, XXI, XXII and XXXI can be obtained by methods known in the art.

Some compounds of formulas IV, V, VI, VII and VIII are known, but each specialist clear that new connections can be obtained by similar methods of obtaining the known compounds of the above formulas.

Some intermediate products, i.e., compounds of formulas III, IV, V, VI, VIII, IX, X, XI, XII and XIII consider new connections. Everything described here, the new compounds are also included in the subject matter.

The compounds of formula I asstandard laboratory animals. Therapeutic activity of compounds of the formula I was demonstrated during one or two tests A and/or B.

A pilot test of A series carried out as follows.

Inhibition of the release of arachidonic acid from macrophages stimulated simhasanam

Female mice MPI (weighing 20 to 25 g) score when using high concentrations of CO2. Mice are placed on the back and abdomen of the animals wipe with 70% alcohol. Pulling the skin, revealing peritonealnuu wall. Environment A (5 ml) (see below) was injected into the abdominal cavity of each mouse, and then using a syringe (20 ml) and needle 21G x 40 mm injected with approximately 1 ml of air to form a suspension macrophagic cells. The resulting suspension is taken into a sterile jar and store on ice. Combine the extracts from all animals and this combined cell suspension cheated when using counter Cultura, then brought to a final value of 1-1,3106cells/ml before tagging them (3H) arachidonic acid. Typically, five mice is sufficient to obtain the required number of cells for each mesh plate.

Enough (3H)-arachidonic acid in ethanol needed to get to the Ute arachidonic acid in 1 or 2 ml of cell suspension, which is then mixed with the remaining cell suspension in the centrifuge bottle. Labeled cell suspension was poured into a sterile plastic 96-flat bottom porous plates (250 μl per cell) and stored over night at 37oC in a humid atmosphere of 5% CO295% of the air.

The next day nescience cells removed by three washings with sterile saline with the addition of a phosphate buffer (FSB). Sticky peritoneal macrophages store in the next 24 hours in the presence or in the absence of drugs in the environment (B) (see below) at 37oC in an atmosphere of 5% CO2to measure the actions of drugs on the spontaneous secretion of arachidonic acid in the absence of the stimulus. After this storage, the supernatant layer is removed with a receiving environment 1 and stored in sealed mesh plates at 4oC to conduct scintillation counting. A drug that enhances spontaneous allocation of arachidonic acid, as will Paul, is toxic at the concentration at which this phenomenon occurs. The supernatant layer is replaced with fresh medium C, consisting of a fresh preparation and stimulus. Test three drug proposesto, consisting of a positive control tools (e.g., dexamethasone), medium (B), and the environment C.

Then incubated for another 5 hours, the supernatant layer is collected with the receiving environment and sticky cells are washed with saline phosphate buffer. The cells are then subjected to lysis using 100 μl of 0.1% Triton X100 in 0.1% solution of albumin bovine serum in 0.9% saline solution and mechanically sever, receiving the lysates of the cells. These supernatant layers (medium 2) and cell lysates (cells) store in a sealed mesh plates at 4oC to conduct scintillation counting. 200 μl portions of the environment or 100 μl portions cells use to calculate using 2 ml OPTIPHAZE "Hihg Safe" (trade mark LKB) as scintillant.

The calculation results

The percentage of released arachidonic acid is calculated from the average value for each group (4 cell) by the following equation:

< / BR>
cpm is the number of counts per minute.

Values, reflecting the allocation of arachidonic acid in the absence of stimulus (spontaneous, cpm environment 2) from cells that are not exposed to irritation or action of the drug, is subtracted from all equivalent.marijuana selection. The percentage inhibition of the release of arachidonic acid, caused by the action of the drug is calculated from the following equation:

< / BR>
The compounds of formula I have at six concentrations (100, 50, 20, 5 and 1 μm) and calculate the IC50-is. Connection with IC50less than 100 microns is considered active. Promising compounds are IC50less than 50 μm.

Environment A (for lavage of the abdominal cavity)

In a sterile 100 ml measuring cylinder injected: 40 ml TS with salts Earl (ten-fold concentrate) (TMC), 4 ml of inactivated by heating serum pigs (IMC), 10 ml of sodium bicarbonate (7.5% in sterile water), 0.4 ml of an antibiotic solution (60 mg/ml benzyl penicillin + 100 mg/ml streptomycin) and 0.72 ml of heparin (5000 u/ml). The resulting mixture is transferred into a sterile container and brought to 400 ml of sterile water.

Environment B (for cell culture)

In a sterile 250 ml measuring cylinder injected: 65 ml of TC 199 (ten-fold concentrate) salt Earl (IMC), and 6.5 ml of inactivated by heating serum pigs, 16,25 ml of sodium bicarbonate (7.5% in sterile water), 0,65 ml of an antibiotic solution (7 above composition) and 65 ml glutamine. The mixture is transferred into a sterile container/glass/ and lead up to 650 ml sterilisator as follows: zymosan (200 mg) (manufactured by Sigma) is added to a saline phosphate buffer (20 ml). The mixture is boiled for 30 minutes, and then restore the volume to 20 ml with water. Zymosan collected by centrifugation at 500 Xg for 5 minutes, washed twice by re-suspension in the SWF and stored in 1 ml portions at -20oC. 650 ml of medium B containing 15 ml zymosan = 12.5 particles (cell receive and store in 3 ml portions in the refrigerator).

Test B is carried out as follows.

Test for swelling of the feet, caused by carrageenan

Female rats weighing from 125 to 159 g closed at night. One of the hind paws of each animal labeled line connection cuboid bones of the metatarsus of the foot (navicular bone as well as heel bone) and the talus of the foot. The group of six rats orally administered dose of 10 ml/kg in an arbitrary order (specified dose of the compounds is introduced in the form of a solution or suspension in 10% (wt./about.) an aqueous solution of gum.

One hour after injection of 0.1 ml of 1% (wt/V) sterile carrageenan in normal saline solution is injected deep into the plantar surface of the marking line of the rear legs of each animal. The amount of legs (up to the marking line) measured directly after injection when using the readings of the water displaced. Three characene, calculated above.

The increase in the feet (i.e., the degree of swelling) in animals treated with medications, in comparison with the control group, who didn't take such treatment, is considered as the degree of inhibition of swelling under the influence of drugs.

In this test, the compounds are considered active if they give 20% or more inhibition of edema metatarsus of legs, at least two or three tests after oral administration of 100 mg/kg Statistical significance evaluated using test Student for single dose studies and Dunnet test for multiple dose studies. More promising compounds show activity in both tests A and B. (see tab. 1).

The most promising compounds of formula I show activity in tests A and B and subsequent tests. Caused by carrageenan pleurisy in rats examined in the test for the present invention the drug, as described by Ackerman and researcher. in J. Pharmacol. Exp. Therap. 1980, 215, 588-595. "Migratory" leukocytes collected by washing the chest cavity 72 hours after injection of 0.3 ml of 1% carrageenan in sterile isotonic saline. The compounds administered orally during the administration of substances and through active in these three tests, and in "the plateau phase" of the next test. Early and late stage bronchostenosis in Guinea pigs after administration of the antigen is determined according to the method described by Hutson and researcher. Am. Rev. Resper. Des. 1988, 137, 548-557. Guinea pigs sensibiliser by single intraperitoneal injection of 10 μg of ovalbumin and after 15 to 17 days to introduce the antigen in the aerosol (4%) within 5 minutes after pre-treatment with mepyramine to prevent anaphylaxis. The compounds administered orally for 24 hours and 2 hours prior to injection.

The invention is illustrated by the following unlimited examples, which are compositions of mixed solvents in the form of volumetric ratios. The new compounds are characterized by using one or more methods of analysis, namely: elementary analysis, a method of nuclear magnetic resonance, infrared and mass spectroscopy. The temperature data are given in degrees Celsius. Abbreviation HPIC refers to high performance liquid chromatography, THF is tetrahydrofuran, DMF is dimethylformamide, Amt - the amount Vol - volume, Temp, temperature, Ex - example, IM (technical methylated alcohol c is the concentration in grams of sample per 100 ml of solution s - singlet, d - doublet, t - triple the Il/imidazole (12.5 g) is heated at a temperature of 110oC for 16 hours in a nitrogen atmosphere, then cooled to room temperature.

b) the Reaction mixture is dissolved in absolute ethanol (250 ml), add sodium borohydride (7.6 g) and the mixture refluxed for 7 hours.

b) the Solvent is evaporated and the resulting residue is dissolved in water (220 ml). The aqueous mixture is extracted with ether and the combined extract is extracted with 5M hydrochloric acid. The combined extract hydrochloric acid is alkalinized with an aqueous solution of sodium hydroxide and then extracted with ether. The combined ether extract is washed with water, dried and filtered to obtain after evaporation of the filtrate oily product. The oil is dissolved in ether and treated with ethereal hydrogen chloride. Hygroscopic solid is collected in the filtering process. The obtained solid is suspended in ether and incubated until complete evaporation of the solvent. The resulting solid is dried in vacuum at 40oC, while receiving -/1-/4-chlorophenyl/ethyl/-3-/imidazol-1-yl/ propilenglikolem with so pl. 182 - 183oC.

Examples 2 through 23

According to the method described in example 1, the compound of formula I poluchaetsya (Amin in table A) and (b) by heating the product in ethanol under reflux with sodium borohydride (see the following table (A) (example 1 included in the table for comparison). The substituents in the compound of formula IV R1, R2, R3if there is no special reservations are hydrogen.

The compounds of formula I, obtained in examples 2 to 6, are:

Example 2. -/1-/2,4-dichlorophenyl/ethyl/-3-/imidazol - 1-yl/Propylamine, so Kip. 155 - 165oC (0.01 mm Hg).

Example 3. -/1-/3,4-dichlorophenyl/ethyl/-3-/imidazol - 1-yl/Propylamine, so Kip. 180oC (0.05 mm Hg).

Example 4. -/1-/4-forfinal/ethyl/-3-/imidazol-1-yl/Propylamine, so Kip. 160oC (0.05 mm Hg).

Example 5. -/1-/4-benzyloxyphenyl/ethyl/-3-/imidazol-1 - yl/Propylamine, so Kip. 200oC (0.04 mm Hg). The oil is triturated with ether to obtain a solid substance with so pl. 45 - 51oC.

Example 6. -/1-/4-dimethylaminophenyl/ethyl/-3-/imidazol-1 - yl/Propylamine, so Kip. 155 - 160oC (0.05 mm Hg).

For further info, see table A.

Notes to table:

(1) the Reaction mixture is extracted with dichloromethane. The resulting residue is dissolved in ether, treated with charcoal, filtered and after evaporation of the filtrate get oily product.

(2) According to the method described Ei use for this purpose of sodium hydroxide. The obtained oily product is further purified by distillation.

(3) as solvent for extraction using dichloromethane. The residue obtained after removal of dichloromethane, is distilled in vacuum.

(4) Reaction (C) is carried out at room temperature with stirring, after which the mixture was kept at this temperature for 64 hours.

(5) the Residue obtained after evaporation of the solvent from the extraction (ethyl acetate), dissolved in diethyl ether and treated with ethereal oxalic acid until the mixture acquires a sour character. Precipitated solid product is collected in the filter and dried.

(7) After removal of ethanol add water (75 ml) and concentrated solution of sodium hydroxide (10 ml, 20 moles). The product is extracted with ethyl acetate. After evaporation of the combined extracts get oily product (3.9 g) which is dissolved in ether (20 ml) and add citric acid (1.9 g) in absolute alcohol (50 ml). The mixture is heated at 95oC for 5 minutes, then cooled and scraped. The liquid above the settled layer merge with semi-solid substances. Semi-solid substance is triturated with ether and filtered. The remainder of srolution hygroscopic solid product.

The compounds of formula I, obtained in examples 7-23, are the following substances:

Example 7: -/1-/3-chlorophenyl/ethyl/-3-/imidazol-1-ID/Propylamine, so Kip. 180-185oC (0,45 mm Hg).

Example 8: -/1-/2-chlorophenyl/ethyl/-3-/imidazol-1-yl/Propylamine, so Kip. 130-140oC (0.02 mm Hg).

Example 9: -/1-/4-chloro-3-triptoreline/ethyl/-3-/imidazol-1-yl/Propylamine, so Kip. 142-146oC (0.02 mm Hg).

Case 10: -/1-/4-chloro-3-forfinal/ethyl/-3-imidazol-1-yl/propilenglikolem, so pl. 199-201oC, after recrystallization from ethanol

Example 11: 3-/imidazol-1-yl/- - /4-triptoreline/-ethyl/Propylamine, oily product, which is not distilled.

Example 12: -/1-/4-chloro-3-were/ethyl/-3-imidazol-1-yl/ Propylamine, oily product, which is not distilled.

Example 13: -/1-2,3,4-trichlorophenyl/ethyl/-3-imidazol-1-yl/ propilenglikolem, so pl. 211-214oC after trituration with hot propan-2-I.

Example 14: -/1-/4-bromophenyl/ethyl/-3-(imidazol-1-yl)-Propylamine, so Kip. 153-158oC (0.01 mm Hg).

Example 15: -/1-/2,5-dichlorophenyl/ethyl/-3-/imidazol-1-yl)- Propylamine, so Kip. 170-175oC (0.5 mm Hg).

Example 16: 3-/imageconsumer/ethyl/-3-imidazol-1-yl/-Propylamine, so Kip. 180oC (0.4 mm Hg).

Case 18: -/1-/4-chloro-2-ethoxyphenyl/ethyl/-3-imidazol-1-yl/ Propylamine, so Kip. 185oC (0.5 mm Hg).

Case 19: -/1-/4-tert.-butylphenyl/ethyl/-3-/imidazol-1-yl/ Propylamine, so Kip. 130-140oC (0.01 mm Hg).

Example 20 ethyl 4-/1-/3-/imidazol-1-yl/propylamino/ethyl/-benzoate, so Kip. 180oC (0.1 mm Hg).

Example 21: -/1-/4-ethylphenyl/ethyl/-3-/imidazol-1-yl/-propyleneglycol, so pl. 201-202oC.

Example 22: -/1-/4-butoxyphenyl/ethyl/-3-/imidazol-1-yl/- propilengikolya, so pl. 114-116oC.

Example 23: 3-/imidazol-1-yl/- -/1-/4-trifloromethyl/-ethyl/propylaminosulfonyl, so pl. 143-149oC.

According to the method similar to that described in example 1, amines of the formula Y, in which a represents a group of the formula (CH2)ninteract with 4'-chloroacetophenone (ketone), as shown in table C. the Substituents in the compound of the formula Y, R8R9R10represent hydrogen, because of other indications in the table In there. Values of "n" are shown in table C.

The compounds of formula I, obtained in examples 24-27 represent the following substances.

Example 24: propane-2-I and ether.

Example 25: -/1-/4-chlorophenyl/ethyl/-3-/2-phenylimidazol-1-yl/ propylenglykolether, so pl. <100 oC (hygroscopic).

Example 26: -/1-/4-chlorophenyl/ethyl/-4-imidazol-1-yl/butylamine, so Kip. 180-185oC (0.4 mm Hg).

Example 27: -/1-/4-chlorophenyl/ethyl/-3-2-Mei-1-yl/- propilenglikolem, so pl. 239-241oC.

Example 28

According to the method similar to that described in example 1, a mixture of 4-chlorobenzophenone (8.0 g) and 1-(3-aminopropyl/imidazole (4.6 g) is heated at 130oC for 12 hours. Then the mixture is cooled, dissolved in absolute alcohol (100 ml), treated with sodium borohydride (2.8 g) and refluxed for 8 hours. Obtained after processing the oil when using dichloromethane as solvent at the extraction is distilled to obtain -( - (4-chlorophenyl)benzyl)-3-(imidazol-1-yl)Propylamine with so Kip. 240oC (0.3 mm Hg).

Example 29

a) Concentrated sulfuric acid (5 drops) is carefully added under stirring to a mixture of 3-chlorophenol (74 g) and acetic anhydride (64,6 g) at room temperature. Then the mixture was incubated for 18 hours and added to water (300 ml). The mixture is extracted with dichloromethane and obyrne oil is distilled under vacuum, getting the 3-chlorophenylacetic with so Kip. 116-118oC (2 mm Hg).

b) the Acetate of (a) from (74 g) is mixed with anhydrous aluminium chloride (85 g) and heated at 150oC for 2 hours. The mixture is cooled, and then cooled with a mixture of ice and 5M hydrochloric acid and vapors distilled. The distillate is extracted with diethyl ether to obtain 4'-chloro-2-hydroxyacetophenone in the form of an oily product, which is immediately used in part c).

c) Acetophenone (3.3 grams) of paragraph b) and 1-/3-aminopropyl/imidazole (7,1 g) dissolved in methanol (30 ml). Saturated methanol hydrogen chloride (3 ml) is added to the resulting solution followed by the addition of laborgerate (0.84 g). The resulting mixture was stirred at room temperature for 48 hours and then incubated for 64 hours. Concentrated hydrochloric acid (6 ml) and water (30 ml) is added to the mixture, and then stirred for 10 minutes. The mixture is diluted with water, washed with dichloromethane, alkalinized 5M solution of sodium hydroxide, and then extracted with dichloromethane. The combined extract is dried and evaporated to obtain an oily product, which was dissolved in diethyl ether and acidified with ethereal hydrogen chloride. The obtained solid PR is nondihydropyridine with so pl. >300oC.

Example 30

According to the method similar to that described in example 1, a mixture of 4'-chloropyridine (8.4 g) and 1-(3-aminopropyl)-imidazole (6.3 g) is heated at 120oC for 9 hours. The cooled mixture was dissolved in absolute ethanol (100 ml), treated with sodium borohydride (3,9 g) and refluxed for 16 hours. Obtained after processing, the oil is dissolved in ether and treated with ethereal oxalic acid until the mixture acquires a sour character. The solid product is filtered off and recrystallized from ethanol to obtain -/1-/4-chlorophenyl/propyl/-3-/imidazol-1-yl/- propylenoxide with so pl. 189-190oC.

Example 31

According to the method similar to that described in example 1, a mixture of 4'-chloroacetophenone (4.0 g) and 1-(3-aminopropyl)-2,4-dimethylimidazole (4.0 g) is heated at a temperature of 115-120oC for 7 hours, and then restore the sodium borohydride (2.0 g) in ethanol (70 ml) over 18 hours. The obtained solid product is triturated with propan-2-I and filtered to obtain -/1-/4-chlorophenyl/ethyl/-3-2,4-dimethylimidazole-1-yl/- propilengikolya, so pl. 218-220oC.

Example 32

According to the method similar to that described in example 3, a mixture of 4'-chloroacetophenone (7.9 g) is nalivajut by sodium borohydride (2.0 g) in IMC (200 ml) for 16 hours. The resulting product is a 3/2-benzyl-4-Mei-1-yl/- -/1-/4-chlorophenyl/ethyl/Propylamine, so Kip. 185 - 195oC (0.04 mm Hg). The product contains a 12.7% 3-/2-benzyl-5-Mei-1-yl/- -/1/-4-chlorophenyl/ethyl/ Propylamine/ according to gas-liquid chromatography (GLC).

Example 33

A mixture of 3-/4-methyl-2-phenylimidazol-1-yl/Propylamine (5.3g) and 4'-chloroacetophenone (3.8 g) is heated at 120 - 125oC for 7 hours. When the cooling oil is dissolved in absolute ethanol (70 ml) and after addition of sodium borohydride (7.0 g) and the mixture refluxed for 16 hours. After processing in accordance with example 3 to obtain an oily product, which was distilled at 185 - 205oC (0.06 mm Hg). The main fraction is re-distilled to obtain -/1-/4-chlorophenyl/ethyl/-3-/4-methyl-2 - phenylimidazol-1-yl)-Propylamine, so Kip. 205oC (0.04 mm Hg). GC indicates the presence of 14% -/1-/4-chlorophenyl-ethyl/-3-/5-methyl-2-phenylimidazol-1-yl/Propylamine.

Example 34

According to the method similar to that described in example 1, the reaction of benzophenone (10.0 g) and 1-(3-aminopropyl/--imidazole (6,9 g) receive-benzhydryl-3-/imidazol-1-yl/propilenglikolem. So pl. 243 - 244oC.

is (of 8.75 g) in absolute alcohol (100 ml) at room temperature under nitrogen atmosphere and stirred the mixture for 6 hours.

b) Add sodium borohydride (1.9 g) and the mixture refluxed for 16 hours. The mixture is evaporated to dryness under reduced pressure and the resulting residue is dissolved in water (about 100 ml). The solution is extracted with ethyl acetate (CH ml) and the combined extract was washed with 5M hydrochloric acid (g ml). United leaching acid alkalinized 10 M sodium hydroxide under ice cooling, and the product extracted with ethyl acetate (CH ml). The combined extract was washed with water (100 ml), dried over magnesium sulfate and evaporated to obtain -(3,4-dichlorobenzyl)-3-(imidazol-1-yl/Propylamine in the form of an oily product, which is not distilled.

Examples 36 - 41

The products of examples 36 and 41 receive the procedure described in example 35, by reaction of compounds of formula IV in which R4represents hydrogen, 3-(imidazol-1-yl)Propylamine (Amin), are shown in table C. R1R2R3represents hydrogen, as there is no special reservations on this score (see table C).

Example 36

-/4-bromobenzyl/-3-/imidazol-1-yl/Propylamine, so Kip. 185 - 200oC (0.075 mm Hg).

Example 37

3-(imidazol-1-yl)- -/4-triptoreline)profilereminder.exe, so pl. 160 - 163oC.

Example 39

3-/imidazol-1-yl/- -/4-phenoxybenzyl/Propylamine, so Kip. 190oC (0.02 mm Hg).

Example 40

-/4-chloro-2-methylbenzyl)-3-(imidazol-1-yl)propilenglikolem, so pl. 212 - 214oC

Example 41

-/2,4-dichlorobenzyl/-3-(imidazol-1-yl/Propylamine, so Kip. 140 - 150oC (0.02 mm Hg).

Example 42

According to the method similar to that described in example 35, a mixture of 4-chlorobenzaldehyde (3.8 g) and 1-(3-aminopropyl)-2,4-dimethylimidazole (4, 1 g) in ethanol (70 ml) is stirred and then restore the sodium borohydride (2.0 g).

Cleaners containing hydrochloride salt is triturated with propan-2-I, filtered, and the residue is washed with ether, then dried under vacuum at 45oC obtaining -/4-Chlorobenzyl)-3-(2,4-dimethylimidazole-1-yl/propilengikolya, so pl. 208 - 210oC.

Examples 43 - 46

According to the method similar to that described in example 35, the amine of the formula Y, in which A represents (CH2)n, interacting with 4-chlorobenzaldehyde (aldehyde) to obtain the compounds of formula I, as shown in table D. R8R9R10represents hydrogen, if there is no special reservations on this score in table D.

Soedinenii/-3-/2-Mei-1-yl/-Propylamine, so Kip. 150 - 155oC (0.02 mm Hg).

Example 44

-/4-chlorbenzyl/-3-/4-Mei-1-yl/propilenglikolem, so pl. 186 - 188oC (from ethanol).

Example 45

-/4-Chlorobenzyl)-3-/4,5-dimethylimidazole-1-yl/propilenglikolem, so pl. 212 - 214oC.

Example 46

-/4-Chlorobenzyl)-4-(imidazol-1-yl)butylaminoethyl, so pl. 162 - 165oC (propane-2-ol).

Example 47

According to the method similar to that described in example 35, a mixture of 4-chlorobenzaldehyde (5.6 g) and 1-(3-aminopropyl)-2-benzyl-4-methylimidazole (9.2 grams) in ethanol (100 ml) is stirred and then restore the sodium borohydride (1.6 g) with 3-(2-benzyl-4-Mei-1-yl/- -/4-chlorbenzyl/Propylamine, so Kip. 190 - 200oC (0.04 mm Hg), GLC and1H-NMR indicated that the product contains 21% 3-/2-benzyl-5-Mei-1-yl/- -/4-chlorbenzyl/Propylamine.

Example 48

3-/4-methyl-2-phenylimidazol-1-yl/Propylamine (5.5 g) and 4-chlorobenzaldehyde (3.6 g) was stirred in absolute ethanol (70 ml) for 16 hours. Add sodium borohydride (2.0 g) and the mixture refluxed for 7 hours. The mixture is treated according to the method described in example 42, with receipt -/4-chlorbenzyl/-3-/4-methyl-2-phenylimidazol-1 and is-/5-methyl-2-phenylimidazol-1-yl/Propylamine.

Example 49.

According to the method similar to that described in example 35 in the interaction of methyl-4-formylbenzoate (8,2 g) and 1-(3-aminopropyl/-2-methylimidazole (5.9 g) receive a 4-/3-/2-Mei-1-yl/propylaminoethyl/benzoate in the form of oil, which is not distilled.

Example 50

According to the method similar to that described in example 37, the interaction of molar equivalents of 4-methoxy-2,6-dimethylbenzaldehyde 1-(3-aminopropyl)-imidazole receive 3-(imidazol-1-yl)- -(4-methoxy-2,6-dimethylbenzyl/propilenglikolem, so pl. 212-213oC (from aqueous propan 2-ol).

Example 51

4-formulario acid (1,76 g) and (1-(3-aminopropyl)-2-Mei (2,78 g) is stirred in methanol (100 ml) for 5 hours at room temperature. Add sodium borohydride (1,14 g) and continue to stir the mixture for 2 days at room temperature. The reaction mixture is evaporated to dryness. The residue is dissolved in water (60 ml) and washed with dichloromethane. The aqueous solution is neutralized with 5M hydrochloric acid, then washed with dichloromethane. The aqueous layer is evaporated to dryness to obtain crude 4-(3-(2-Mei-1-yl)-propylaminoethyl/cinnamic acid, which is refluxed in absolute ethanol (50 and the resulting residue is dissolved in water, alkalinized 2M sodium hydroxide and extracted with ethyl acetate to obtain an oily product, which was dissolved in ether and treated with ethereal solution of hydrogen chloride. The solid product is filtered off and recrystallized from propan-2-ol to obtain ethyl 4-/3-/2-Mei-1-yl/propylaminoethyl/cinnamaldehyde, so pl. 109-110,5oC.

Example 52.

a) a Mixture of 4'-chloroacetophenone (103,3 g), formamide (98%, 123 g) and formic acid (97%, and 8.3 ml) is stirred under heating at 180oC. Formed during the reaction water is removed by distillation together with a small number of source acetophenone, which is then separated and returned to the reaction vessel. Formic acid (70 ml) just add in small portions over 8 hours. The reaction mixture is cooled and completely extracted with toluene. The combined toluene extract is washed with water, dried, filtered and the filtrate is evaporated. Add concentrated hydrochloric acid (70 ml) for forming the residue and the resulting mixture was refluxed for 1 hour. Then the mixture is cooled, extracted with toluene and the resulting aqueous layer was alkalinized with an aqueous solution of hydroxide hydroxide is stragiht with ethyl acetate. United an ethyl acetate extract is dried, filtered, and then produce evaporation of the filtrate. Get oily product, which was distilled to obtain (+)-1-/4-chlorophenyl/-ethylamine, so Kip. 120-122oC (19 mm Hg). A small number of distillate dissolved in dry ether and adding an equivalent amount (volume) of a saturated ethereal solution of hydrogen chloride. The formed solid is filtered off and dried to obtain (+)-1-(4-chlorophenyl)etilamingidrokhlorida, so pl. 186-189oC.

b) a Solution of 3-chloropropionitrile (32.7 g) in methylene chloride (20 ml) is added dropwise with stirring a solution of (+)-1-/4-chlorophenyl/ethylamine (40 g) in dichloromethane (260 ml) with triethylamine (28.4 g) for 45 minutes at 0-5oC. the Temperature was raised to 25oC and the mixture is stirred for another 2 hours. The cooled reaction mixture is washed with saturated aqueous sodium bicarbonate solution (260 ml). The organic layer is separated, dried and filtered, the filtrate is evaporated. The residue is triturated with benzene, filtered and recrystallized from ethyl acetate to obtain 3-chloro - a -(1-(4-chlorophenyl)-ethyl)propionamide, so pl. 86-91oC. the resulting product is a mixture of C -/1-/4-harfe the et reaction and it is removed for further processing in the next stage.

c) a Solution of 2-methylimidazole (2.64 g) in dry tetrahydrofuran (THF) (40 ml) added dropwise within 1 minute under stirring suspension of sodium hydride (1.54 g, 60% dispersion in oil) in tetrahydrofuran (65 ml) in a dry nitrogen atmosphere. The mixture is stirred at room temperature for 1 hour, then refluxed and leave to cool. Add a solution of 3-chloro- -/1-/4-chlorophenyl/ethyl/-propionamide (5.7 g) in tetrahydrofuran (25 ml) and the mixture is stirred at the boil under reflux for 16 hours. After that, the mixture is cooled and added in several portions of water (100 ml) under stirring, and then ethyl acetate (200 ml). The acid layer is separated and extracted with ethyl acetate. United an ethyl acetate extract is extracted with hydrochloric acid (5M). The combined acid extract is alkalinized with concentrated sodium hydroxide solution and extracted with ethyl acetate to obtain oil. The oily product is triturated with ether and filtered to obtain -/1-/4-chlorophenyl)ethyl)-3-(2-Mei-1-yl)propionamide, so pl. 135-137oC.

d) a Mixture of borane and tetrahydrofuran (1 M, 55 ml) is added during 5 minutes while stirring to a suspension of amide obtained in paragraph (C//3,21 g dry Tetra is aces at room temperature. The solvent is removed by evaporation and the resulting residue is boiled in a nitrogen atmosphere at 100oC for 1 hour. Add hydrochloric acid and the mixture continued to heat for 1.5 hours. The reaction mixture was alkalinized with an aqueous solution of sodium hydroxide (5M) and extracted with ethyl acetate to obtain N-/1-/4-chlorophenyl/ethyl/3-/2-Mei-1-yl/Propylamine in the form of an oily product.

Examples 53-57

a) According to the method similar to that described in example 52b formed on the intermediate stage amides of formula XV, in which R1= 4-chloro, R2, R3, R5and R6represent hydrogen, R4= CH3, A = (CH2)nand Z represents chlorine, used in the examples 55-57, obtained by reaction of compounds of formula VII, in which R1= 4-chloro, R2, R3, R5and R6= H and R4= CH3with the appropriate acylchlorides presented in table E. (Example 52b concluded in table E for comparison).

b) According to the method similar to that described in example 52c, the compounds of formula IX in which R1= 4-chloro, R2, R3, R5and R6= H and R4= CH3, A = (CH2)nand n represents a value of ukazanno>, R2, R3, R4, R5, R6and A have the above meaning, with the sodium salt of the formula Na+Y-formed by the reaction YH, in which Y represents a group of formula XXVII with sodium hydride in table F (example 52c shown for comparison).

Notes to table F)

(1) a Solid product obtained after evaporation of an ethyl acetate filtrate, used without further purification.

(2) the Ether wash liquid after grinding is evaporated to obtain a pale yellow oily product, which is used without further purification.

(3) After boiling under reflux, the reaction mixture was hot filtered through silica as a filtration media. The residue is washed with hot tetrahydrofuran, and then ether. The combined filtrate is washed with water and the water is re-extracted with ether to obtain an oily residue.

Oily residue elute with a mixture of methanol and dichloromethane (1:9) as mobile phase at processing on a column with a packing of silica. The silica is washed with methanol to obtain an oily substance, which is used without further PTS is held by the solid washed with hot tetrahydrofuran. The combined filtrate and wash water is evaporated to obtain an oily residue. The remainder elute through the column with silica using a mixture of methanol: dichloromethane (1: 9) as mobile phase. The obtained solid is used without further purification.

(5) By analogy with p. (4), but without the use of columns with silicon dioxide, fraction Rf0,30 evaporated to obtain a solid substance, so pl. 126 - 128oC.

(c) By the procedure similar to that described in example 52 d, the compounds of formula I are obtained by recovery of amides of the formula IX obtained in paragraph (b), in which A represents (CH2)nand the other substituents have the above meaning, see item b) with borane in table G (example 52 (d) are shown for comparison).

Notes.

(1) the Residue is distilled at 160oC (0.1 mm Hg), dissolved in ether and treated with ethereal solution of hydrogen chloride. The obtained solid is triturated with ether and dissolved in a minimum amount of hot ethanol. The solution is cooled, precipitated with ether and then cooled to 0oC obtaining oily resin. The latter is dried and rubbed some time with ether recip is Alba) to give a colorless oil.

(3) Transparent oily product is dissolved in ether and acidified with ethereal solution of hydrogen chloride. Ether defend and solid resinous substance re-dissolved in ether. The ether is then evaporated to obtain an oily material, which emit in the form of a free base by treatment with 5M sodium hydroxide and extracted with ether to obtain an oily substance. The oil is dissolved in ether and acidified with ethereal solution of oxalic acid. The resulting solid is collected by filtration and recrystallized from TMC to obtain a solid salt.

(4) Oily product is distilled at 135oC (0.1 mm Hg), dissolved in ether and acidified with ethereal solution of hydrogen chloride. The resulting solid product is filtered off and suspended in the air. The ether is evaporated to obtain solid, which is recrystallized from propan-1-ol.

(5) the Oily product is dissolved in ether and acidified with ethereal solution of hydrogen chloride. The resulting solid is filtered off and suspended in the air. Then produce evaporation of ether to obtain solid, which is recrystallized from propan-2-ol.

< / BR> -/1-/4-chlorophenyl/ethyl/-3-/2-ethylimidazole-1-yl/propilenglikolem, so pl. 112 - 113oC.

Example 54

-/1-/4-chlorophenyl/ethyl/-3-/4-/5-Mei-1-yl/Propylamine, so Kip. 190oC (0.1 mm Hg).

Example 55

-/1-/4-chlorophenyl/ethyl/-5-imidazol-1-yl/intramedical, so pl. 93 - 94oC.

Example 56

(+)- -/1-/4-chlorophenyl/ethyl/-3-/imidazol-1-yl/Propylamine, dihydrochloride, so pl. 122 - 123oC, chiral high performance liquid chromatography shows the enantiomeric purity of the product was 98.2%.

(L)22= + 21,9o(c = 0,9 EtOH).

Example 57

(-) -(1-(4-chlorophenyl)ethyl/-3-(imidazol-1-yl)propilenglikolem, so pl. 180oC (coherent with the appearance of bubbles at 124 - 127oC). Chiral high performance liquid chromatography shows santomero product purity and 86.8%.

(L)22= of-21.5o(c = 0,9 EtOH).

Example 58

(a) a Solution of 3-chloro-2,2-dimethylpropanamide (7.0 g) in dichloromethane (50 ml) is added dropwise with stirring a solution of 1-(4-chlorophenyl)ethylamine (7.0 g) and triethylamine (6.3 ml) in dichloromethane (100 ml) at 0 - 5oC in nitrogen atmosphere. After the addition the mixture was stirred at 0oC for 0.5 hours, and then Get and evaporated. The residue is recrystallized from petroleum ether (so Kip. 60 - 80oC) with 3-chloro-N-/1-(4-chlorophenyl)ethyl) - /-2,2-dimethylpropanamide, so pl. 95 - 96oC.

(b) a Mixture of 3-chloro- -/1-/4-chlorophenyl/ethyl/-2,2-dimethylpropanamide (5.0 g) and imidazole (6, 2 g) is heated with stirring at a temperature of 125oC for 6 hours. An excess of imidazole is removed by azeotropic distillation with toluene under reduced pressure. The residue is dissolved in 5M hydrochloric acid and washed with dichloromethane. The acid layer is alkalinized 5M solution of sodium hydroxide and extracted with dichloromethane. The combined extract was washed with water, dried and evaporated to obtain -/1-/4-chlorophenyl/ethyl/-3-imidazol-1-yl/-2,2-dimethylpropanamide, which is used directly in paragraph (C).

(c) By the procedure similar to that described in example 52 (d), -/1-/4-chlorophenyl/ethyl/-3-imidazol-1-yl/-2.2-dimethylpropionic (4.0 g) in tetrahydrofuran (100 ml) is treated with BH3/THF (52.1 ml, 1M) to obtain an oily product, which is distilled at a temperature of 165oC (0.05 mm Hg) and low-boiling fraction is re-crystallized to obtain -/1-/4-chlorophenyl/ethyl/-3-/imidazol-1-yl/-2,2-dimethylpropylene, so Kip. 160oC (0.03mm tutorialdownload (20,0 g) reacts with 3-chloropropionitrile (12.3 g) in dichloromethane (250 ml), containing triethylamine (27,0 ml). After alkalizing saturated solution of sodium bicarbonate, the product is extracted with dichloromethane to obtain a mixture of 3-chloro-N-/1-/4-chlorophenyl/1-methylethyl/propionamide (26%) and -/1-/4-chlorophenyl/1-methylethyl/acrylamide (74%), which is then used in paragraph (b).

b) According to the method similar to that described in example 52 c, a mixture of imidazole (1,05 g) and sodium hydride (0,63 g, 60% dispersion) in tetrahydrofuran (35 ml) was treated with 3-chloro-N-/1-/4-chlorophenyl/1-methylethyl/propionamide (4.0 g) in tetrahydrofuran (15 ml) to give N-/1-/4-chlorophenyl/-1-methylethyl/-3-/imidazol-1-yl/propionamide, which is used directly in part (c).

c) Propionamide obtained in paragraph b (see above) (3.2 g) in tetrahydrofuran (100 ml) is treated with BH3/THF /43,8 ml, 1M/ according to the method described in example 52d), with -/1-/4-chlorophenyl/-1-methylethyl-3-/imidazol-1-yl/Propylamine, so Kip. 180oC (0.05 mm Hg).

Example 60

a) According to the method similar to that described in example 52c, a mixture of 2-methylimidazole (1.3 g) and sodium hydride (0,63 g, 60% dispersion) in tetrahydrofuran (35 ml) is treated with a mixture of 3-chloro - a -(1-/4-chlorophenyl/-1-methylethyl)propionamide (4.0 g) in tetrahydrofuran (15 ml) to obtain -/1-/4-/chlorophenyl/-1-methylethyl/-3-/2-Mitilini Propionamide of p. a) (of 1.9 g) in tetrahydrofuran (10 ml) is added dropwise with stirring to a suspension of aluminum hydride (of 8.27 mmol) in tetrahydrofuran (18 ml) at 0-5oC in nitrogen atmosphere. The mixture was stirred at 0oC for 1 hour and then at room temperature for 2 hours. The mixture is thoroughly cooled mixture of tetrahydrofuran and water (1:1) (25 ml). After alkalizing 5M sodium hydroxide and extraction with dichloromethane the product obtained still contains a small amount of starting material. The mixture was dissolved in tetrahydrofuran (5 ml) and added to a suspension of sociallyengaged (0.25 g) in tetrahydrofuran (5 ml) under stirring in nitrogen atmosphere. The mixture is refluxed for 4 hours, then cooled and stew with ethyl acetate and then with water. The mixture is filtered and the filtrate is extracted with ethyl acetate. The combined extract is dried and evaporated. The residue is distilled to obtain N-/1-/4-chlorophenyl/-1-methylethyl/-3-/2-Mei-1-yl/Propylamine, so Kip. 160oC (0.05 mm RT. column)

Example 61

a) According to the method similar to that described in example 52b, 3-chloro-2,2-dimethylpropionic (27.4 g) in dichloromethane (100 ml) is added 4-chlorobenzylamino (25,0 g) and triethylamine (24.6 ml) in dichloromethane (400 ml) to obtain the range with imidazole (10,5 g) by the method described in example 52c obtaining -/4-/Chlorobenzyl)-3-(imidazol-1-yl)-2,2-dimethylpropanamide, which is used directly in paragraph (c).

c) Propionamide (2.0 g) of paragraph b) is treated with a mixture BH3/tetrahydrofuran (27.4 ml, 1 M) according to the method described in example 52d, obtaining -(4-Chlorobenzyl)-3-(imidazol-1-yl)-2,2-dimethylpropylene, so Kip. 180oC (0.4 mm Hg).

Example 62

a) 1-(4-chlorophenyl)-1-methylaminopropane (4.0 g) interacts with the 5-carpenterworm (3.0 g) in dichloromethane (15 ml) containing triethylamine (8.1 ml) using the procedure described in example 52b, to obtain 5-chloro- -/1-/4-chlorophenyl/-1-methylethyl/pentanolide.

b) Chloramide of p. a) (6.0 g) and imidazole (7,1 g) is heated at 125oC under stirring for 6 hours. The mixture is diluted with dichloromethane and extracted with 5 M hydrochloric acid. The acid extracts are combined alkalinized 5 M solution of sodium hydroxide and extracted the product with dichloromethane. The combined organic extract was washed with water, dried and evaporated to obtain -/1-4-chlorophenyl/-1-methylethyl/-5-/imidazol-1-yl/pentamid, which is used directly in stage c).

c) According to the method similar to that described in example 52d, the solution SUB>3
/THF (63.7 ml of 1 M solution) to obtain -/1-/4-chlorophenyl/-1-methylethyl/-5-/imidazol-1-yl/pentylamine in the form of an oily product with so Kip. 195oC (0.05 mm Hg).

Example 63

a) a Mixture of 8-bromooctanoate acid (26,4 g), thionyl chloride (40 ml) and acetonitrile (40 ml) is heated at 95oC for 3 hours. The solvent is removed by distillation under vacuum and the resulting residue purified by the method of azeotropic distillation using acetonitrile to obtain 8-bromooctanoate.

b) 1-/4-Chlorophenyl)-1-methylethylenediamine (4.0 g) is reacted with 8-bromooctanoate (4.0 g) in dichloromethane (50 ml) containing triethylamine (8.1 ml) using the procedure described in example 52b to obtain 8-bromo- -/1-/4-chlorophenyl/-1-methylethyl/octanamide, which is used directly in paragraph (c).

c) According to the method similar to that described in example 62b, the mixture bromamide of p. b/ (8,1 g) and imidazole (7.9 g) reacts with receipt -/1-4-chlorophenyl/-1-methylethyl/-8-/imidazol-1-yl/octanamide, which is used directly in paragraph (d).

d) According to the method similar to that described in example 52d, solution -/1-4-chlorophenyl/-1-methylethyl/-8-/imidazol-1-yl/octanamide (5.9 g) in tetrahydrofuran (130 ml) restore mix BH3/THF is tochnogo post).

Example 64

a) a Mixture -/4-chlorbenzyl/acrylamide (example V) (3,9 g), 4,5-dichloroimidazole (2.7 g), benzyltrimethylammonium (Triton B) (0,20 ml of 40% solution in methanol) and pyridine (13 ml) is refluxed for 8 hours. The mixture is evaporated under reduced pressure and the residue is dissolved in dichloromethane (100 ml). The solution was washed with water (I ml) and then extracted with 5 M hydrochloric acid (g ml). The combined acid extract is alkalinized 5 M of sodium hydroxide, after which the product is extracted with dichloromethane to obtain a yellow oily substance, which was triturated with hot petroleum ether (so Kip. 60-80oC) receive -(4-Chlorobenzyl-3-/4,5)-dichloroimidazole-1-yl/propylamide, which, according to1H-NMR spectroscopic analysis, is sufficiently pure for use in part ii. b).

b) Material of p. a) (4,2 g) dissolved in dry tetrahydrofuran (70 ml) under nitrogen atmosphere and add a complex compound with borane-tetrahydrofuran (51 ml, 1 M solution) at a time at room temperature. The mixture is refluxed for 2.5 hours and then evaporated to dryness under reduced pressure. The residue is heated at 95oC in nitrogen atmosphere in those who SUP>C for 1.5 hours. Upon cooling, the mixture is alkalinized with concentrated solution of sodium hydroxide (12 M) and extracted with ethyl acetate. The combined organic extract is extracted with 5 M hydrochloric acid and the combined acid extract is alkalinized 5 M sodium hydroxide. The product is extracted with ethyl acetate to obtain oil, which contains a small amount of solids. The oily product is dissolved in ether and filtered in order to remove this solid. The filtrate is evaporated to obtain an oil which is treated with an ethereal solution of hydrogen chloride, thus obtaining -/4-chlorbenzyl/-3-/4,5-dichloroimidazole-1-yl/propilenglikolem, so pl. 185-187oC.

Example 68a

(Alternative method)

Mix -/1-/4-chlorophenyl/-1-methylethyl/acrylamide (200 g), imidazole (60,9 g), Triton B (20 ml) and 1,4-dioxane (1600 ml) is stirred and refluxed for 20 hours. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane (2000 ml). The mixture is extracted with 2 M hydrochloric acid. The combined aqueous extract is alkalinized 2 M solution of sodium hydroxide and extracted with dichloromethane to obtain N-/1-4-hartely XVI, in which R1, R2, R3, R4and R5have the values listed in tables H1 and H2, and represent hydrogen, interact with compounds of the formula YH, where Y represents imidazolium formula XXVII in which R8, R9and R10have table values H1 and H2, according to the method described in the examples 64a and 68a (alternative method) (see tables H1 and H2) to produce compounds of formula IX, in which A represents (CH2)2and R1- R6have the above values. In cases when there is a mixture of two spatial isomers, the components of the mixture are separated and their structures determined according to the1H-NMR and/or13C-NMR spectra by comparing the chemical shifts and coupling constants with known substituted imidazoles. Products restore following the procedure described in example 64b (see table 1), to obtain compounds of formula I. In examples 79, 84, 85, 86, and 88 carry out the restoration and other functional groups.

Next, see tables H1 and H2.

Notes to tables H1 and H2

(1) 2,4,5-trimethylimidazo receive in accordance with the data given in Chem., Ber., 86, 96 (1953)

(2) the Residue is recrystallized from atilol processing of the mixture, carried out in accordance with example 62a, the mixture is separated by means of flash chromatography with silica gel, elwira a mixture of ethyl acetate and triethylamine (9:1) as mobile phase. The first fraction contains ethyl 1-/ -/4-chlorophenyl/-1-methylethyl/-2-carbamoylethyl/-4-Mei-5 - carboxylate as an oily substance, which is not distilled (example 78(a).

The column is washed with methanol to obtain ethyl 1-/ -/1-/4-chlorophenyl/-1-methylethyl/-2-carbamoylethyl/-5-Mei-4 - carboxylate, in the form of oil, which is not distilled. The obtained product is used as starting material in example 98.

(4) the Reaction mixture was kept at room temperature for 18 hours, the solid is separated by filtration and recrystallized twice from ethyl acetate to obtain -/1-/4-chlorophenyl/-1-methylethyl/-3-/formylindole-1-yl/propionamide, so pl. 151-153oC (79a), which is used in example 79b.

The mother liquor from the recrystallization of the combined and evaporated to dryness. To the resulting residue, water is added and the resulting mixture extracted with dichloromethane. The dichloromethane extract is extracted with 5M hydrochloric acid. The acid extracts are combined and alkalinized aka isomer. The filtrate is evaporated and the residue is treated on a chromatographic column with silica, elwira a mixture of ethyl acetate (triethylamine (9: 1) as mobile phase to obtain N-(1-(4-chlorophenyl)-1-methyl-3-/5-formylindole-1-yl/propionamide, so pl. 127-129oC (example 88a), which is used later in the example 88b.

(5) the Mixture is cooled on ice, incubated at room temperature, the solid product is filtered off and recrystallized from ethyl acetate to obtain -/1-/3,4-dichlorophenyl/-1-methylethyl/-3-/4-formylindole-1-yl/ propionamide, so pl. 161-163oC. the dioxane Filtrate is evaporated to dryness and the residue is divided between water and dichloromethane. The combined dichloromethane extract is extracted with 5M hydrochloric acid. The combined acid extract is alkalinized with concentrated solution of sodium hydroxide and extracted with dichloromethane to obtain the residue, which is triturated with ethyl acetate and filtered. The obtained solid product is dissolved in ethyl acetate and treated on a chromatographic column with silica, elwira with ethyl acetate as mobile phase. Get N-/1-/3,4-dichlorophenyl/-1-1-methylethyl/-3-/5-formylindole-1-yl/ propionamide, so pl. 180oC, which is

(1) the Product (free base) is extracted with dichloromethane. Received dihydrochloride salt, which is an extremely hygroscopic product, convert back to the free base by treatment with 12M of sodium hydroxide. The selected base is extracted with dichloromethane, the extracts are combined and evaporated to obtain the product.

(2) the Product is extracted with dichloromethane after alkalizing, and then redistilled.

(3) the oil Obtained after processing purify using flash chromatography with silica, elwira a mixture of ethyl acetate and triethylamine (99:1) as mobile phase.

The compounds (see table H) represent the following substances:

Example 65a

-/1-/4-chlorophenyl/ethyl/-3-/2-isopropylimidazole-1-yl/- propionamide, in the form of oil, which is not distilled.

Example 66a

-/4-chlorophenyl/ethyl/-3-/2,4,5-trimethyl-imidazol-1-yl/- propionamide, so pl. 141-143oC.

Example 67a

N -/1-/4-chlorophenyl/ethyl/-3-/4,5-dichloroimidazole-1-yl/- propionamide in the form of oil, which is not distilled.

Example 68a

-/1-/4-chlorophenyl/-1-methylethyl/-3-/imidazol-1-yl/ propionamide, so pl. 154-155oC (after recrystallization from ethyl acetate).


Example 70a

-/1-/4-chlorophenyl/-1-methylethyl/-3-/4,5-dimethylimidazole-1-yl/ propionamide

Example 71a

-/4-chlorbenzyl/-3-/2-isopropylimidazole-1-yl/propionamide (oil).

Example 72a

-/4-chlorbenzyl/-3-/2-ethylimidazole-1-yl/propionamide (oil).

Example 73a

3-/2-Mei-1-yl/- -/1-methyl-1-/p-tolyl/ethyl/- propionamide, so pl. 133-135oC.

Example 74a

N -/1-/4-chlorophenyl/-1-methylethyl/-3-/4-nitroimidazol-1-yl/ propionamide, so pl. 165-166oC.

Example 75a

3-/imidazol-1-yl/- -/1-methyl-1-/p-tolyl/ethyl/-propionamide, so pl. 120-121oC.

Example 76a

-/1-/4-chlorophenyl/-1-ethylpropyl/-3-/imidazol-1-yl/- propionamide in the form of butter.

Example 77a

Ethyl /1-/3-imidazol-1-yl/propionamido/-1-methylethyl/benzoate, T. pl. 118 - 119oC.

Example 78a

Ethyl 1-/ -/1-/4-chlorophenyl/-1-methylethyl/-2-carbamoylethyl/- 4-Mei-5-carboxylate in the form of oil, which is not distilled.

Example 79a

-/1-/4-chlorophenyl/-1-methylethyl/-3-/4-formylindole-1-yl/- propionamide, so pl. 151 - 153oC.

Example 80a

-/1-ethyl-1-phenylpropyl-3-/imidazol-1-yl/propionamide in the form of butter.

Example 81a

-/1-4-biphenylyl/-1-methylethyl/-3-/imidazol-1-yl/propionamide in the form of butter.

Example 83a

3-/imidazol-1-yl/- -/1-methyl-1-/2-naphthyl/ethyl/propionamide

Example 84a

N-1-/3,4-dichlorophenyl/-1-methylethyl/-3-/5-formylindole-1-yl/propionamide, so pl. 180 - 181,5oC (see table H2, note 5).

Example 85a

N-/1-/4-biphenyl - /-1-methylethyl/-3-/4-formimidoyl-1-yl/- propionamide, so pl. 171 - 172oC.

Example 86a

N-/1-ethyl-1-phenylpropyl/-3-/4-formylindole-1-yl/-propionamide, so pl. 142 - 143,5oC.

Example 87a

N-/1-/4-benzyloxyphenyl/-1-methylethyl/-3-/imidazol-1-yl/- propionamide, so pl. 187 - 189oC.

Compounds shown in table I, are the following substances:

Example 65b

N-/1-/4-chlorophenyl/ethyl/-3-/2-isopropyl-imidazol-1-yl/- Propylamine, in the form of oil, which is not distilled.

Example 66b

N-/1-/4-chlorophenyl/ethyl/-3-/2,4,5-trimethylimidazo-1-yl - Propylamine in the form of oil, which is not distilled.

Example 67b

N-/1-/4-chlorophenyl-ethyl/-3-/4,5-dichloroimidazole-1-yl/- propylaminosulfonyl, so pl. 248 - 250oC (decomposition).

Example 68b

N-/1-/4-chlorophenyl/-1-/methylethyl/-3-/imidazol-1-yl-Propylamine in the form of oil, so Kip. 180oC (0.05 mm Hg). The sample obtained oil is dissolved in ether and adding ethereal solution of chloride vedaranyam N-/1-/4-chlorophenyl/-1-methylethyl/-3-/imidazol-1 - yl/propilengikolya, so pl. 216 - 218oC (example 68(2)).

Example 69b

Mix -/1-/4-chlorophenyl/-1-methylethyl/-3-/4-Mei-1 - yl/Propylamine and -/1-/4-chlorophenyl/-1-methylethyl/-3-/5 - Mei-1-yl/Propylamine, representing the oil, so Kip. 160 - 170oC (0.1 mm Hg).

13C-NMR spectroscopic analysis shows that the ratio of 4-methyl-isomer: methyl 5-isomer is 2:1

Example 70b

-/1-/4-chlorophenyl/-1-methylethyl/-3-/4,5-dimethylimidazole-1 - yl/Propylamine, so Kip. 165oC (0.05 mm Hg).

Example 71b

-/4-chlorbenzyl/-3-/2-isopropylimidazole-1 - yl/propilenglikolem, so pl. 189 - 192oC.

Example 72b

-/4-Chlorobenzyl)-3-(2-ethylimidazole-1-yl)-Propylamine, so pl. 155 - 165oC (0.1 mm Hg)

Example 73b

3-/2-Mei-1-yl/- -/1-methyl-1-/p-tolyl/ethyl/- propilenglikolem, so pl. 255oC (decomposition).

Example 74b

-/1-/4-chlorophenyl/-1-methylethyl/-3-/4-nitroimidazol-1-yl - Propylamine in the form of oil, which is not distilled. The product was then purified using flash chromatography with silica, elwira a mixture of ethyl acetate/methanol as mobile phase.

Example 75b

3-/imidazol-1-yl/- -/1-methyl-1-/p - tolyl/ethyl/propilendiamindioksimom, so pl. 208 - 211oC.

Example 77b

Ethyl 4-/1-/3-imidazol-1-yl/propylamino-1-methylethyl/-benzoate in the form of oil, which is not distilled

Example 78b

Ethyl 1-/3-/1-/4-chlorophenyl/-1 methylethylamine/propyl/-4 - Mei-5-carboxylate in the form of oil, which is not distilled.

Example 79b

1-/3-/1-/4-chlorophenyl/-1 methylethylamine/-propyl/imidazol-4 - yl-methanol, so pl. 103 - 104oC.

Example 80b

-/1-ethyl-1-phenylpropyl/-3-/imidazol-1-yl/Propylamine, so Kip. 140 - 150oC (0.02 mm Hg)

Example 81b

-1/1-/4-biphenyl - /-1-methylethyl/-3-/imidazol-1 - yl/propilenglikolem, so pl. 222 - 226oC.

Example 82b

-/1-/4-chlorophenyl/cycloprop-1-yl/-3-/imidazol-1 - yl/propilenglikolem, so pl. 188 - 189oC.

Example 83b

-/1-/2-naphthyl/-1-methylethyl/-3-/imidazol-1 - yl/propilenglikolstearat, so pl. 219 - 222oC

Example 84b

1-/3-/4-/3,4-dichlorophenyl/-1 methylethylamine/propyl/imidazol - 5-ylmethanol, so pl. 117 - 118oC

Example 85b

The obtained residue after processing is recrystallized from a mixture of cyclohexane and ethyl acetate (5:7) to obtain the 1-/3-/1- /4-biphenylyl/-1 methylethylamine/propyl/imidazol-4-ylmethanol, so pl. 128 - 129oC

Example 86b

Polucheniyami-4-ylmethanol, so pl. 82 - 84oC.

Example 87b

-/1-/4-benzyloxyphenyl/-1-methylethyl/-3-/imidazol-1 - yl/propilenglikolem, so pl. 186 - 187oC

Example 88b

1-/3-/1-/4-chlorophenyl/-1 methylethylamine/propyl/imidazol-5 - immunologically, so pl. 165 - 169oC.

Example 89

a) According to the method similar to that described in example 52b, 1-/4-chlorophenyl/-1-methylaminopropane (2.5 g) is treated with 4-chlorobutyronitrile (1.7 g) in dichloromethane (30 ml) containing triethylamine (3.4 ml) to obtain 4-chloro- -/1-/4-chlorophenyl/-1 - methylethyl/butylamide, which is used directly in stage b).

b) Chloroethylamide (3.1 g) from stage a) and imidazole (3.8 g) is heated at 125oC for 6 hours. The mixture is cooled, dissolved in 5M hydrochloric acid, then washed with dichloromethane. The aqueous phase is alkalinized 5M sodium hydroxide, and then extracted with dichloromethane. The combined extract is dried and evaporated to obtain -/1-/4-chlorophenyl/-1-methylethyl/-4 - imidazol-1-yl/butyramide, which is used directly in stage c).

c) Butyramide (2.9 g) of paragraph b) restore a mixture of borane with tetrahydrofuran (37.1 ml, 1M) according to the method described in example 52d, receipt/1-/4-chlorophenyl-1-methylethyl/-4-(initimidate-1-yl/propilenglikolem (1.7 g, obtained in example 1) is added by portions in formic acid (1.2 g, 97%) at 0oC. Formaldehyde (0.96 g, 37%) is added to the resulting mixture, and then heated at 95oC for 6 hours. After cooling, add concentrated hydrochloric acid (0.6 ml) and the solution is evaporated to dryness under reduced pressure. The residue is dissolved in water, alkalinized 5M solution of sodium hydroxide and extracted the product with ether. The combined extract is dried and evaporated. The resulting oil is dissolved in ether and treated with ethereal solution of hydrogen chloride. Formed cleaners containing hydrochloride salt, which represents a hygroscopic product, alkalinized 5M sodium hydroxide to obtain -/-1-/4-chlorophenyl/ethyl/-3-/imidazol-1-yl/- - methylpropylamine in the form of oil, which is not distilled.

Example 91

-/1-/4-chlorophenyl/propyl/-3-/imidazol-1-yl/Propylamine (13,9 g, free base from example 30) are added in portions in formic acid (11,75 g, 98 - 100%) at 0oC. Add formaldehyde (9.6 g, 37%) and the mixture is heated at 95oC for 6 hours. After processing in accordance with example data, 90 get -/1-/4-chlorophenyl/propyl/-3-/imidazol-1-yl/- -methylpropylamine in the form of oil, motorolafree in example 1, in ethanol (10 ml), mixed with solution D /-/-tartaric acid (3.0 g) in ethanol (50 ml) and refluxed with stirring until a precipitate colorless substance. The mixture is cooled, the solid product is filtered off, washed them with obtaining /-/-N-/1-/4-chlorophenyl-ethyl-3-/imidazol-1 - yl/Propylamine/-/-ditartrate, so pl. 180 - 183oC (decomposition). According to chiral HPLC purity of the enantiomer is 98,1%.

Example 93

a) a Mixture of ()-N-/1-/4-chlorophenyl/ethyl/-3-imidazol-1-yl) - Propylamine (15,8 g), obtained as in example 1, TMC (50 ml) is mixed with solution 1(+)-tartaric acid (9.0 g) in TMS (100 ml). The mixture is brought to a volume of 300 ml with TMS and refluxed with careful stirring, until then, until you precipitate a solid. The mixture is cooled, the solid product filtered off, washed with TMS and recrystallized twice from TMS to obtain (+)-N-/1-/4-chlorophenyl/ethyl/-3-/imidazol-1-yl/Propylamine- /+/ditartrate, so pl. 181 - 183oC (decomposition). According to chiral HPLC, the enantiomeric purity is 94,1%.

Example 94

The product from example 49 (4.0 g), propane-1-ol (50 ml) and collected under reduced pressure and the residue is dissolved in water (50 ml) and alkalinized 5M solution of sodium hydroxide. The product is extracted with ethyl acetate. After distillation propyl 4-/3-/2-Mei-1-yl/propylaminoethyl/benzoate, T. pl. 185 - 195oC (0.05 mm Hg).

Example 95

According to the method similar to that described in example 70, 5-chloro-N-/4-chlorbenzyl/valeramide (10.3 g, obtained from 4-chlorobenzylamino and 5-chlorovaleronitrile) and 2-methylimidazole (6.5 g) reacts with receipt -/4-chlorbenzyl/-5-/2-Mei-1 - yl/valeramide (6.5 g), so pl. 72 - 75oC, which restores a mixture of borane with tetrahydrofuran (86 ml, 1M) to obtain -/4 - Chlorobenzyl)-5-(2-Mei-1-yl)pentylamine, so Kip. 170 - 185oC (0.1 mm Hg).

Example 96

In analogy to example 90, -/1-/4-chlorophenyl/-1-methylethyl/-3- /imidazol-1-yl/Propylamine is reacted with formaldehyde and formic acid to obtain -/1-/4-chlorophenyl/-1-methylethyl/-3-/imidazol-1-yl/- -methylpropylamine, so pl. 170oC (0.03 mm Hg)

Example 97

In analogy to example 90, -/4-chlorbenzyl/-3-/2-Mei - 1-yl/Propylamine treated with formaldehyde and formic acid to obtain -/4-chlorbenzyl/- -methyl-3-/2-Mei-1-yl/ Propylamine, so Kip. 160 - 166oC (0.2 mm Hg).

Example 98

a) According to the method similar measure 78) interacting with a mixture of borane with tetrahydrofuran (303,4 ml, 400 ml of THF), 1.0 M solution give 1-/3-/1-/4-chlorophenyl/-1 methylethylamine/propyl/-5-Mei-4-ylmethanol, so pl. 97 - 99oC.

b) a Solution of acetylchloride (8.7 g) in dichloromethane (35,5 ml) is added dropwise with stirring a solution 1-/3-/1-/4- chlorophenyl/-1 methylethylamine/propyl/-5-Mei-4-ylmethanol (3.55 g) in dichloromethane (88,8 ml) containing triethylamine (11.1 g) at 0oC. the Mixture was stirred at 0oC for 30 min and then at room temperature for another 2 hours. The mixture is diluted with dichloromethane, washed with 5M solution of sodium hydroxide, dried and evaporated. The resulting residue is dissolved in ether and acidified with ethereal solution of hydrogen chloride. The solid product is filtered off and recrystallized from aqueous propan-1-ol with obtaining 1-/3-/1-/4-chlorophenyl/-1 methylethylamine/propyl/-5-Mei-4 - ilmatieteenlaitos.fi, so pl. 188 - 189oC.

Example 99

-/1-/4-chlorophenyl/-1-methylethyl/-3-/imidazol-1-yl/Propylamine (1,25 g) and citric acid (0.95 g) was dissolved in warm TMS (10 ml) and leave to cool. After keeping involving episodic soccermania, leads to crystallization of the salt. The resulting salt is filtered off, triturated with a mixture of ethyl acetate/methanol (1:1), SN isC.

Example 100

-/1-/4-chlorophenyl/-1-methylethyl/-3-/imidazol-1-yl/Propylamine (to 2.57 g) and L-/+/-tartaric acid (1.39 g) was dissolved in warm TMS (10 ml) and leave to cool. When soccermania get vykristallizovalsya salt. The salt is filtered off and recrystallized from TMS to obtain -/1-/4-chlorophenyl/-1 - methylethyl/-3-/imidazol-1-yl/Propylamine/+/tetradehydro, so pl. 76 - 78oC.

Example 101

a) According to the method similar to that described in example 68a (alternative), the mixture -/1-/4-chlorophenyl/-1-methylethyl/acrylamide (6.7 g) 2-isopropylimidazole (3.3 grams), 1,4-dioxane (100 ml) and benzyltrimethylammonium (Triton B) (5 ml, 40% solution in methanol) gives -/1-/4-chlorophenyl/- 1-methylethyl/-3-/2-isopropylimidazole-1-yl/propionamide in the form of oil, which is not distilled.

b) using the procedure similar to the one mentioned in example 65b, a mixture of amide of (a) from (5.8 g) and with borane-tetrahydrofuran (70 ml, 1M solution) gives -/1-4-chlorophenyl/-1-methylethyl/-3-/2-isopropylimidazole-1 - yl/propilenglikolem, so pl. 156oC.

Example 102

a) Sodium (26.7 g) was dissolved in methanol ( 600 ml) and cool the solution to -45oC. is Added dropwise bromine under vigorous stirring, until the temperature is set at the level of -45oC. Ccsne (257 ml) and methanol (350 ml). Adding produce for 20 minutes at -45oC. the Mixture is left to warm slowly to 20oC, followed by a release of heat and the temperature rises to 50oC. Exothermic process control using external cooling. The mixture is then refluxed for 4.5 hours, and the solvent is removed under reduced pressure. The residue is diluted with 5M sodium hydroxide solution and extracted with ether to obtain -/1-methyl-1-/p-tolyl/ethyl/carbamate, so pl. 42 - 43oC.

b) a Mixture of the carbamate of (a) (4.0 g), -bromosuccinimide (3.8 g), carbon tetrachloride (80 ml) and azobisisobutyronitrile (0.12 g) is refluxed for 18 hours. The mixture is cooled, washed with water, dried, filtered, and the solvent is removed by distillation under reduced pressure to obtain N -/1-/4-bromomethylphenyl-1-methylethyl/carbamate, so pl. 74 - 76oC.

c) a Solution of potassium cyanide (24.4 g) in water (70 ml) is added dropwise within 20 minutes at 50oC in a mixture of the product from paragraph b) (60,0 g) in acetonitrile (500 ml). The mixture is refluxed for 1 hour, then the solvent is removed under reduced pressure. The residue is diluted with water and extracted with ether with p the doctrine N -/1-/4 - cyanomethylene/-1-methylethyl/carbamate, so pl. 88 - 90oC.

d) Trimethylsilylmethyl (24,0 g) added over 5 minutes a solution of the product from p. c) (28,0 g) in chloroform (200 ml) under stirring in nitrogen atmosphere at room temperature. The mixture continued to stir at 60oC for 2.5 hours, then cooling the mixture with ice water, stew saturated methanolic solution of hydrogen chloride (20 ml) and stirred at ambient temperature for 1 hour. The solvent is removed under reduced pressure and the residue diluted with ether (250 ml) and stirred at the same temperature for 64 hours. The mixture is filtered to obtain 4-/1-amino-1-methylethyl/phenylacetonitrile.

e) the Product from paragraph d) (8.0 g) and 6M hydrochloric acid (100 ml) is refluxed for 6 hours. The resulting sedimentation of the upper layer of fluid is drained from the insoluble product and evaporated under reduced pressure. The remainder is stored under vacuum over pjatiokisi phosphorus for 16 hours. The residue is refluxed in propane-1-Ola (300 ml) containing concentrated sulfuric acid (5 ml) at 95oC for 64 hours. The solvent is removed under reduced pressure and the residue diluted with water and promycelium propyl-4-/1-amino-1-methylethyl/phenylacetate in the form of an oily product.

f) a Solution of akriloilkhlorida (1.7 g) in dichloromethane (15 ml) is added dropwise to a mixture of the product from p. e) (4,32 g), triethylamine (2.6 ml) and dichloromethane (50 ml) under stirring in nitrogen atmosphere. The mixture was stirred at 0oC for 30 minutes and then at room temperature for 2.5 hours. The mixture is diluted with dichloromethane, washed with water and the organic layer dried and evaporated to obtain an oily residue. The resulting residue is purified using flash chromatography on silica, elwira petroleum ether, so Kip. 60-80oC/ethyl acetate (2: 1) as mobile phase to obtain propyl-4-/1-acrylamide-1-methylethyl/phenylacetate, so pl. 71-72oC.

g) a Mixture of the product from paragraph (f) (1.7 g), imidazole (0.4 g), benzyltrimethylammonium (Triton B) (4,9 mg 40% solution in methanol) and 1,4-dioxane (20 ml) is heated at 95oC for 18 hours. After the treatment described in example 68a (alternative), but using ethyl acetate as the extracting means get drunk 4/1-/3-/imidazol-1-yl/propionamido/-1-methylethyl/-phenylacetate in the form of an oily product. The structure of the product is confirmed according to the1H NMR spectroscopy.

h) the Product of paragraph (g) (460 mg), a mixture of borane and oritel removed under reduced pressure and added propane-1-ol (20 ml), saturated with gaseous hydrogen chloride. The mixture is heated at 95oC for 1 hour, the solvent is removed under reduced pressure. The residue is added water and the solution washed with ethyl acetate. The aqueous acidic layer is separated, then alkalinized 5M solution of sodium hydroxide and the product extracted with ethyl acetate to obtain oil. The oil is purified using flash chromatography with Dukakis silicon, elwira mixture of methanol and ethyl acetate (1: 1) as mobile phase, to obtain propyl 4-/1-/3-/imidazol-1-yl/propylamino/-1-methylethyl/phenyl-acetate in the form of an oily product.

1H NMR (250 MHz) (CDCl3), of 0.91 (3H, t), of 1.42 (6H, s), 1,5 (1H, s W), of 1.65 (2H, sextet) and 1.83 (2H, pentablet), 2,32 (2H, t), 3,61 (2H, s), 3,98 (2H, t), 6,83 (1H, s), 7,02 (1H, s) and 7.2 was 7.45 (5H, m).

Example 103

The solution acetylchloride (of 0.24 ml) in dichloromethane (6 ml) is added dropwise to a solution of 1-(3-(1-ethyl-1-phenylpropylamine)-propyl/imidazol - 4-ylmethanol (10 g, from example 86b) in dichloromethane (18 ml) containing triethylamine (0,46 ml) under stirring at a temperature of 0oC. the Mixture continued to stir at the same temperature for 30 minutes, then at room temperature for another 2 hours. After the treatment described in example 98b way, but without treatment essential RA is East of the product.

Example 104

To obtain a product in the form of capsules 10 parts by weight of the active compounds and 240 parts by weight of lactose together and mix. The mixture is filled into hard gelatin capsules, each capsule contains 10 mg of active substance.

Example 105

Tablets produced from the following ingredients (parts by weight):

Active substance - 10

Lactose - 190

Corn starch - 22

Polyvinylpyrrolidone - 10

Magnesium stearate - 3

The active substance, lactose and some of the starch are combined, stirred and the resulting mixture granularit with a solution of methanol in ethanol. The dry granules are mixed with magnesium stearate and the rest of the starch. The mixture is pressed in teletrauma machine to obtain tablets containing 10 mg of active substance.

Example 106

Tablets receive in accordance with the method described in the previous example. Tablets involve coating soluble in the intestine by the traditional method using a solution of 20% azettftalat cellulose and 3% diethylphthalate in a mixture of ethanol and dichloromethane (1:1).

Example 107

To obtain the dosage form, representing candles, 100 parts by weight of axles processed in supposely, containing 100 mg of active ingredient.

Example 108

To obtain capsules 50 parts by weight of the active substance 300 parts of lactose and 3 parts by weight of magnesium stearate are combined together and mixed. The mixture is put into hard gelatin capsules, each containing 50 mg of active ingredient.

Example 109

An active connection is put on the basis of the method of homogenization will not occur until a uniform distribution of medicines. Ointment Packed in 10 g darkened jars with screw cap.

The active ingredient is 0.1 g

white soft paraffin 10 g

Obtaining initial substances

Used in the examples, the starting materials are commercially available, i.e., always available, or may be obtained through the Fine Chemicals Directory (fine Chemicals directory).

2,4-dimethylimidazole and 2-benzyl-4/5/-Mei receive from the firm Polyorganic incorporan MA.

A/5/-methyl-2-phenylimidazol is the product of the firm TCI (Tokyo Kazei Kogyo Corporation, Ltd.).

4-formylindole get from Muybridge chemical Corporation, Ltd.). In accordance with the described methods in the literature were obtained following substances: 4,5-dimeth which measures A

a) a Solution of imidazole (13,6 g) in dry dimethylformamide (50 ml) is added dropwise with stirring to a suspension of sodium hydride (8.0 g 60% dispersion in oil) in dry DMF (250 ml) at room temperature under nitrogen atmosphere for 2.5 hours. Suspension/4-bromobutyl/phtalimide (53,6 g) in dry DMF (80 ml) is added to the resulting mixture, after which the resulting mass is heated at 95oC for 16 hours. The solvent is evaporated under vacuum and the residue is extracted with hot toluene. The combined toluene extract is evaporated to dryness and the resulting residue triturated with ether and dried to obtain -(4-imidazol-1-yl/butyl/phtalimide, so pl. 76 - 79oC.

b) a Mixture of phthalimide (19.5 g) and hydrochloric acid (6M, 226 ml) is refluxed for 8 hours, then incubated at room temperature for 18 hours. The mixture is cooled to 0oC for 2 hours and the resulting solid is filtered off. The filtrate is evaporated to dryness and the residue is divided into two portions between ethyl acetate and water. The aqueous layer was alkalinized with concentrated solution of sodium hydroxide and extracted with dichloromethane. The combined dichloromethane extract is dried, filtered and the filtrate is evaporated to obtain 4-is (a).

Example B.

a) a Solution of 2-phenylimidazole (14.4 g) in dry dimethylformamide (25 ml) is added dropwise with stirring to a suspension of sodium hydride (4.0 g, 60% dispersion in oil) in dry DMF (125 ml) at room temperature under nitrogen atmosphere for 2 hours. Suspension -/3-bromopropyl/phtalimide (25,5 g) in dry DMF (40 ml) is added dropwise to the resulting mixture and the resulting mass is heated at 100oC for 16 hours. The solvent is evaporated and the resulting residue is extracted with hot toluene. The combined toluene extract is evaporated to dryness and the residue triturated with ether and dried to obtain -/3-/2-phenylimidazol-1-yl/propyl/-phthalimide, so pl. 109 - 110oC.

b) a Mixture -/3-/2-phenylimidazol-1-yl/-propyl/phtalimide (17.0 g), sodium hydroxide (1.1 g) and water (5,4 g) is heated at 95oC for 48 hours. When cooled add the mixture of concentrated hydrochloric acid (66 ml) and water (13 ml) and boil the mixture under reflux for 6 hours. After keeping at room temperature for 16 hours the mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is treated with water (16 ml), then cooled and added sodium hydroxide (24 g) servings. The solution shall comply with getting oily product, which is distilled under reduced pressure to obtain 3-/2-phenylimidazol-1-yl/Propylamine, so Kip. 128oC (0.05 mm Hg).

Example C

A solution of 4'-chloro-2'-hydroxyacetophenone (1.0 g) in dry DMF (5 ml) is added under stirring to a mixture of sodium hydride (0,235 g, 60% dispersion) in dry DMF (5 ml) and 5oC in nitrogen atmosphere. After the addition the mixture was stirred at 0oC for 15 minutes and then at room temperature for 1 hour. The solution iodomethane (0,92 g) in dry DMF (5 ml) is added dropwise to the resulting mixture, keeping the temperature below 10oC. the Reaction mixture was stirred at room temperature for 5 hours, and then incubated for 16 hours. For alkalizing mixture add a solution of potassium carbonate and extracted the product with dichloromethane. The combined extract is dried and evaporated. The residue is dissolved in ether, washed with water, then dried and evaporated to obtain 4'-(chloro-2'-methoxyacetophenone, methoxyacetophenone, which is pure enough to be used for synthetic purposes in example 17.

Example D

According to the method similar to that described in example C, 4'-chloro-2'-hydroxyacetophenone (1.0 g) is treated with a hydride is. pl. 92 - 93oC) after recrystallization from petroleum ether, so Kip. 60 - 80oC).

Example E

A solution of n-utility in hexane (30,4 ml, 2.5 M) is added dropwise under stirring in nitrogen atmosphere to a solution of N,N,N-trimethylethylenediamine (7.9 g) in dry tetrahydrofuran (150 ml) at -15 ° to -20oC. After addition the mixture was stirred at -23oC for 15 minutes and then at a temperature of minus 15 - 20oC is added dropwise 4-chlorobenzaldehyde (10.0 g). After the addition the mixture was stirred at -23oC for 15 minutes and then added dropwise n-utility in hexane (85,4 ml, 2.5 M) at -15oC. the Mixture continued to stir at -23oC for 3 hours, cooled to -40oC and add iodomethane (60,6 g) at -40 to -20oC. After the addition the mixture is stirred at -40oC for 5 minutes, then allowed to warm to room temperature and stirred at this temperature for 30 minutes. The mixture is carefully poured onto cooled with ice to 10% hydrochloric acid (2 l) and incubated for 64 hours. The mixture is extracted with diethyl ether to obtain an oily product, which is twice distilled under vacuum to obtain 4-chloro-2-methylbenzaldehyde, so Kip. so in example 40.

Example F

1) According to the method similar to that described in example A mixture of 2,4-dimethylimidazole (24,0 g) is added to a suspension of sodium hydride (10.0 g, 60% dispersion) in dimethylformamide (300 ml). After stirring for 1.5 hours, add dimethylformamide (80 ml), and then the suspension -(3-bromopropyl/phtalimide (63,8 g) in dimethylformamide (100 ml). After the reaction mixture is treated as described in example A, and the residue triturated with petroleum ether, so Kip. 60-80oC, and then with ether. The remainder precrystallizer from ethyl acetate to obtain -/3-dimethylimidazole-1-yl/propyl/phtalimide, so pl. 191-192oC. According to the1H-NMR spectroscopy shows the presence of about 10% -/3-/2.5-dimethylimidazole-1-yl/propyl/phtalimide.

2) Phthalimide from p. 1) dissolved in TMC (600 ml) and treated with hydrazinehydrate (19.3 g) at room temperature under stirring. After stirring for 3 days the mixture is filtered and the residue washed with TMC. The combined filtrate and wash water is evaporated to dryness. The residue is treated with 10M sodium hydroxide and the mixture extracted with dichloromethane. The combined organic extract washed with brine, dried and evaporated to obtain 3-/2,4-dimethylimidazole-1-yl/Propylamine in VI

Examples G - J

According to the method similar to that described in example F (1), the compounds of formula XXI, in which A represents (CH2)2and Z represents a bromine interact with imidazoles of the formula YH, in which Y represents a group of formula XXVII in which R8, R9and R10have the following value, to obtain the compounds of formula XIV (see table 1). The compounds of formula XIV is treated in further hydrazinehydrate according to the method described in example F(2) to obtain the compounds of formula Y, in which A represents -(CH2)2(see table K).

Compounds derived and presented in table J:

Example G(1):

-/3-/2-Mei-1-yl/propyl/phthalimid, so pl. 119-121oC.

Example H(1):

-/3-/4,5-dimethylimidazole-1-yl/propyl/phthalimid, so pl. 119-121oC after recrystallization from ethyl acetate

Example I(1):

-/3-/4-Mei-1-yl/propyl/phthalimid, so pl. 82-90oC.

Example J(1):

-/3-/2-benzyl-4-Mei-1-yl/propylmalonic in the form of butter.

Compounds derived and are presented in table K:

Example G (2):

3-Mei-1-yl/Propylamine in the form of oil, which is not distilled.


3-/4-Mei-1-yl/Propylamine in the form of oil, which is not distilled.

According to the1H-NMR spectroscopy revealed the presence of approximately 33% for 3-/5-Mei-1-yl/Propylamine.

Example J/2/:

3-/2-benzyl-4-Mei-1-yl/Propylamine, so Kip. 160-165oC at 0.35 mm Hg. According to analysis by gas chromatography revealed the presence of about 20% 3-/2-benzyl-5-Mei-1-yl/Propylamine.

Example K

(and) (+)-1-/4-chlorophenyl/ethylamine receive, as described in example 52a.

(+) Enantiomer (the original product for example 56) are obtained by the traditional method, described below. A mixture of (+) -/4-chlorophenyl/ethylamine (73 g) and D/-/tartaric acid (70 g) in technical methylated alcohol (TMC) (4.2 l) was kept at room temperature for 2 days. The resulting solid product is filtered off, washed with TMC and recrystallized from TMC to obtain (+) 1-/4-chlorophenyl/-ethylamine (-)-tartrate, so pl. 195-199oC. the Salt is suspended in water and alkalinized with an aqueous solution of ammonia (specific gravity 0.88 to). The mixture is extracted with diethyl alcohol to obtain (+)-4/-chlorophenyl/-ethylamine, which is distilled under 120-125oC (30 mm Hg). Chiral vysokoeffektivnaya for example 57) are obtained by the traditional method, described below. A warm solution of ()-1-/4-chlorophenyl/ethylamine (101 g) and L (+) tartaric acid (97,3 g) in TMC (7 l) is slowly cooled and incubated at room temperature for 3 days. The solid is filtered off, washed with TMC and recrystallized twice from TMC to obtain (-) 1-/4-chlorophenyl/ethylamine (+) tartrate, so pl. 195-196oC. the Salt is suspended in water and alkalinized with an aqueous solution of ammonia (specific gravity 0.88 to). The mixture is extracted with diethyl ether to obtain (-) 1-/4-chlorophenyl/-ethylamine/free base), which is distilled under 122-124oC (28 mm Hg). Chiral high performance liquid chromatography shows the enantiomeric purity of the product 96,8%.

Example L

a) a Solution of 4-chlorophenylacetyl (70 g) in dry tetrahydrofuran (50 ml) is added under stirring to a suspension of sodium hydride (39,7 g, 60% dispersion) in boiling tetrahydrofuran (100 ml) under reflux in nitrogen atmosphere with such speed, that boiling occurred without heating capacity. After the addition the mixture is refluxed for 2 hours. Add THF (100 ml) and cool the mixture to 10oC. the Solution iodomethane (139 g) in tetrahydrofuran (50 ml) is added dropwise to the mixture round for 18 hours, the temperature was then lowered to below 10oC, adding dropwise methanol (30 ml) and then water (150 ml). After that, the mixture is heated to room temperature, then concentrated under reduced pressure to remove tetrahydrofuran. The residue is diluted with water and extracted with dichloromethane. The combined extract is dried and evaporated to obtain an oil which is distilled under vacuum to obtain 2-/4-chlorophenyl-2-methylpropionitrile, so Kip. 90-94oC (0.5 mm Hg).

b) a Solution of propionitrile (10 g) of paragraph a) TMS (30 ml) is treated with a solution of sodium hydroxide (0,67 g) in water (3.3 ml). The mixture is heated at 50oC and added dropwise with stirring, hydrogen peroxide (14 ml, 60% vol/weight). The mixture is then stirred at room temperature for 3 hours, then evaporated to dryness under reduced pressure. The remainder is divided into portions between ethyl acetate and water. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer is washed, dried and evaporated to obtain 2-/4-chlorophenyl/-2-methylpropionamide, so pl. 125oC.

C) Boiling a solution of the amide from p. in) (68,3 g) in acetonitrile (500 ml) is added in one portion to a warm suspension (approximately the 50o

Formed the remainder add in hot water (150 ml) to give a suspension, which is alkalinized solid hyprocisy sodium with external cooling. The mixture is extracted with diethyl ether and the combined extract is dried over magnesium sulfate and filtered. The filtrate is acidified with ethereal solution of hydrogen chloride and the resulting solid is filtered off and precrystallizer from aqueous acetonitrile to obtain 1-/4-chlorophenyl/-1-methylethylenediamine, so pl. 246oC.

d) Akriloilkhlorida (0.88 g) is added dropwise with stirring to a solution of 1-(4-chlorophenyl)-1-methylethylenediamine (2.0 g) and triethylamine (2,07 ml) in dichloromethane (10 ml) at -15 ° to -20oC in nitrogen atmosphere. After the addition the mixture is stirred at room temperature for 2.5 hours. The mixture is diluted with 5M sodium hydroxide solution, and methadone.sq. 122-123oafter recrystallization).

, - dialkylamino benzylamine used as starting materials in table H, get on methods similar to those described in tables L-O summarizing stages a, b, c and d of example 1, respectively.

In table 1 the compounds of formula XXVII in which R4and R5represent hydrogen, alkylate with obtaining compounds of formula XXVIII in which R4= R5. In table M the compounds of formula XXVIII is converted into the compounds of formula XXV.

In the table N the compounds of formula XXV is converted into the compounds of formula XVII, in which R6represents hydrogen.

In the table O the compounds of formula VII, in which R6represents hydrogen, is converted into the compounds of formula XVI in which R6represents hydrogen.

Example S, stage c.

Bromine is added dropwise with stirring (139 g) in 3-regular solution of sodium hydroxide (1712 ml) at 0oC. When dissolved all the bromine add portions of 2-(3,4-dichlorophenyl)-2-methyl-propionamide (201 g) at 0oC. the Mixture is stirred at the same temperature for 5 hours and then maintained at the same temperature for 18 hours. The mixture is heated at 95oacid, until you fall a solid residue. The solid product is filtered to obtain 2-(3,4-dichlorophenyl)-2-methylpropionitrile, so pl. 238-239oC.

Example A. stage b

2-/4-chlorophenyl/-2-ethylbutyrate (104,9 g) is added dropwise to the boiling solution of potassium hydroxide (40,3 g) in pentane-1-Ola (450 ml) under stirring. The mixture is refluxed for 24 hours. Then the mixture is cooled and poured into same amount of water. The mixture is washed with ether and the aqueous layer was extracted with dichloromethane to obtain the oil, which during curing is converted into a solid substance. The solid is triturated with cyclohexane and filtered to obtain 2-/4-chlorophenyl/-2-/ethylbutylamine, so pl. 107-109oC.

Example O, stage b

a) a Mixture of methyl-4-/1-cyan-1-methylethyl/benzoate (1.0 g), sodium hydroxide (0.4 g), water (2 ml) and technical methylated alcohol (5 ml) is heated to 50oC under stirring. Added dropwise hydrogen peroxide (60% weight/about/, 1.23 ml) and stirred the reaction mixture at 50oC for 1 hour and then at room temperature for 3 hours. The reaction mixture is evaporated to dryness under reduced pressure. To the resulting precipitate add water (10 ml) and heat the mixture at 95oC for 1 h is of 4-/carbarnoyl-1-methylethyl/benzoic acid, so pl. 218-219oC.

b) Acid from (a) (0,70 g), absolute ethanol (7 ml) and concentrated sulfuric acid (2 drops) and refluxed for 4 hours. Under reduced pressure to remove the ethanol and to the resulting residue water is added. After extraction with dichloromethane obtain ethyl 4-/1-carbarnoyl-1-methylethyl/benzoate, T. pl. 104-109oC. (gas-Liquid chromatography shows about 10% of the content of ethyl 4-/1-etoxycarbonyl-1-methylethyl/benzoate.

Example V

a) Akriloilkhlorida (86,9 g) is added dropwise with stirring to a solution of 4-chlorobenzylamino (br135.8 g) and triethylamine (138, 8 ml) in dichloromethane (500 ml) at 15 to -20oC in nitrogen atmosphere. After the addition the mixture is stirred at room temperature for 2.5 hours. The mixture is washed with diluted aqueous hydrogen peroxide solution, and then water. The dichloromethane solution is dried and evaporated under reduced pressure. The solid residue is recrystallized from ethyl acetate to obtain /4-chlorbenzyl/acrylamide, T. pl. 103-104oC.

Example W

a) According to the method similar to that described in example 62a, a mixture of akriloilkhlorida with (58.2 g) added 1-/4-chlorophenyl/-ethylamine (100 g) and triethylamine (65,2 g) in dichloromethane (400 ml) Cneu described in example A, 4/5/-methyl-2-phenylimidazole (25,0 g) reacts with sodium hydride (6.3 g, 60% dispersion) in dimethylformamide and then with -/3-bromopropyl/phthalimido (40,4 g) obtaining-/3-/4-/5-methyl-2-propylimidazol-1-yl/propyl/-phthalimide, which is used directly in paragraph (b).

b) phthalimide (50.0 g) of p. a) is treated with hydrazinehydrate (4/7 g) technical methylated alcohol (1400 ml) using the procedure described in example F, with 3-/4-methyl-2-phenylimidazol-1-yl/Propylamine in the form of oil, so Kip. 156 to 160oC (0.4 mm Hg), which is purified by converting cleaners containing hydrochloride salt using ethereal solution of hydrogen chloride, and then turning back to the free base using 5M sodium hydroxide. According to gas chromatography, the product contains about 12% 3-/5-methyl-2-phenylimidazol-1-yl)-Propylamine.

1. Derivatives of 1-(arylalkylamine) imidazole of the General formula I

< / BR>
or their pharmaceutically acceptable salt,

in which R1, R2and R3independently from each other represent hydrogen, halogen, C1-4-alkyl, C1-4-alkoxygroup, phenoxy, phenyl C2-6-alkoxycarbonyl group, the amino group of the formula-NR13R14in new C1-2-alkoxygroup, halogenated C1-2-accelgroup, benzyloxy, hydroxy, C1-4-hydroxyalkyl, (C2-6-alkoxycarbonyl)vinyl, C2-6-alkoxycarbonyl C1-2-alkyl, or R1and R2together with the phenyl ring to which they are attached, represent naphthyl;

R4and R5independently from each other, represent hydrogen, C1-4-alkyl, phenyl, or R4and R5together with the carbon atom to which they are attached, are C3-6-cycloalkyl;

R6is hydrogen or C1-4-alkyl;

A - C2-7-alkylene, which may be straight or branched;

R8is hydrogen, C1-4-alkyl, phenyl, optionally substituted C1-4-alkyl, halogen or C1-4-alkoxygroup, or benzyl, optionally substituted C1-4-alkyl, halogen or C1-4-alkoxygroup;

R9and R10independently from each other, represent hydrogen, C1-3-alkyl, halogen, C1-4-hydroxyalkyl, C2-6-alkoxycarbonyl, nitro -, or C1-6-alkanoyloxy C1-2-alkyl, provided that when A is (CH2)2and R2, R3, R4, R5, R6, R8, R9and R10presented the UB>)5and R1, R2, R3, R4, R5, R6, R9and R10represent hydrogen, then R8is not the stands.

2. Connection on p. 1, corresponding to formula II,

< / BR>
or their pharmaceutically acceptable salt,

in which R1- halogen, C1-4is an alkyl group, a C2-4-alkoxygroup, phenoxy, phenyl, C2-4-alkoxycarbonyl group, halogenated C1-2-alkoxygroup, halogenated C1-2is an alkyl group, benzyloxy, amino group of the formula NR13R14in which R13and R14represent, independently from each other, hydrogen or C1-2is an alkyl group, (C2-4-alkoxycarbonyl) vinyl group, a C2-6-alkoxycarbonyl C1-2is an alkyl group, or R1and R2together with the phenyl ring to which they are attached, represent naphthyl;

R2and R3- independent from each other and represent hydrogen, halogen, C1-4-alkyl, C1-4-alkoxygroup, halogenated C1-2is an alkyl group or hydroxy;

R4and R5- independent from each other and represent hydrogen, C1-4alkyl group, phenyl, or R4and R5together with compounds which SUB>1-3
is an alkyl group;

A - ethylene, trimethylene, tetramethylene, 1,1-dimethylethylene or heptamethine;

R8is hydrogen, C1-4is an alkyl group, phenyl or benzyl;

R9and R10- independent from each other and represent hydrogen, C1-4-alkyl, halogen, C1-4-hydroxyalkyl group, a C2-6-alkoxycarbonyl group, nitro -, or C1-6-alkanoyloxy C1-2is an alkyl group.

3. Connection on p. 2, where R1represents bromine, chlorine, methyl, ethyl, tert. butyl, butoxy, phenoxy, phenyl, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, dimethylamino, triptoreline, trifluoromethyl, benzyloxy, 2-ethoxycarbonylphenyl or R1and R2together with the phenyl ring to which they are attached, represent a naphthyl.

4. Connection on p. 2 or 3, where R2represents hydrogen, 3-chloro, 2-chloro, 3-fluoro, 2-methyl, 3-methyl, 2-methoxy, 2-ethoxy, 2-hydroxy or 3-trifluoromethyl and R3represents hydrogen, 2-chloro or 3-chloro.

5. Connection at one PM.2, 3, or 4, where R4and R5independently from each other, represent hydrogen, methyl, ethyl, or R4and R5together with the carbon atom to which they are connec the battle hydrogen or methyl.

7. Join one of the PP.2 - 6, where A represents ethylene, trimethylene or tetramethylene.

8. Join one of the PP.2 - 7, where R8represents hydrogen, methyl, ethyl, isopropyl, phenyl or benzyl.

9. Connection PP.2 - 8, where R9and R10are independent from each other, and represent hydrogen, methyl, chloro, hydroxymethyl, etoxycarbonyl, nitro or acetoxymethyl.

10. The compounds of formula I on p. 2, where R1, R2and R3represent hydrogen, R4and R5are ethyl, R6represents hydrogen, A is ethylene, R8represents hydrogen or C1-4-alkyl and R9and R10are independently hydrogen, methyl, hydroxymethyl or acetoxymethyl.

11. The compounds of formula I on p. 2, where R1represents chlorine, R2represents hydrogen or 3-chloro, R3represents hydrogen, R4, R5and R6each represents hydrogen, A is ethylene, R8represents hydrogen or methyl and R9and R10independently of one another represent hydrogen or methyl.

12. Connection foretel]-3-(imidazol-1-yl)-Propylamine,

N-[1-(3-chlorophenyl) ethyl]-3-(imidazol-1-yl)-Propylamine,

N-[1-(4-bromophenyl)ethyl]-3-(imidazol-1-yl)-Propylamine,

N-[1-(4-chlorophenyl)ethyl]-4-(imidazol-1-yl)-butylamine,

N-[1-(4-chlorophenyl)propyl]-3-(imidazol-1-yl)-Propylamine,

N-(3,4-dichlorobenzyl)-3-(imidazol-1-yl)-Propylamine,

N-(4-Chlorobenzyl)-3-(2-methylimidazol-1-yl)-Propylamine,

N-[1-(4-chlorophenyl)-ethyl]-3-(4-methylimidazol-1-yl)-Propylamine,

N-[1-(4-chlorophenyl)ethyl]-3-(5-methylimidazol-1-yl)-Propylamine,

N-[1-(4-chlorophenyl)ethyl]-5-(imidazol-1-yl)-pentylamine,

N-[1-(4-chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)-Propylamine,

N-(1-ethyl-1-phenylpropyl)-3-(imidazol-1-yl)-Propylamine,

N-[1-(4-chlorophenyl)-1-methylethyl]-4-(imidazol-1-yl)-butylamine,

N-[1-(4-chlorophenyl)propyl]-3-(imidazol-1-yl)-N-methyl-Propylamine,

or their pharmaceutically acceptable salts.

13. Pharmaceutical composition having anti-inflammatory and/or anti-allergic activity, including an active ingredient and a pharmaceutically acceptable diluent or carrier, characterized in that it contains as the active compounds are effective amount of the compounds of formula I according to any one of paragraphs.1 - 12.

14. The compounds of formula I on PP.1 - 12 exhibiting anti-inflammatory, protricity diseases in mammals, in need of such treatment, wherein introducing an effective treatment for a number of compounds of formula I on PP.1 - 12.

16. The method of obtaining compounds of formula I, as defined in paragraph 1, characterized in that carry out the reaction of the compound of formula IX

< / BR>
where the values of R1- R6and R8- R10given in paragraph 1,

with a reducing agent optionally in the presence of an inert organic liquid, preferably a solvent for the compounds of formula IX, at atmospheric pressure, a temperature of 0 - 200oC at atmospheric pressure.

 

Same patents:

The invention relates to new substituted phenylimidazoline, to a method for their production and to their use in pharmaceutical compositions

The invention relates to new derivatives of pyrazolo/4,3-d/pyrimidine-7-it formula I, where R1- H, CH3C2H5, R2- CH3CH2OH, CH2OCH3or n - C3H7, R3- C2H5CH2= CH - CH2, R4together with the nitrogen atom to which it is attached is 4-(R5)-piperidino - or 4-N (R6)-piperazino group, R5- H, N(CH3)2, CONH2, R6- H, CH3i - C3H7CH2CH2OH, CSNH2C(NH)NHCH3or C(NH)S CH3and their pharmaceutically acceptable salts, pharmaceutical compositions showing inhibitory activity against cyclic guanosin-31,51-monophosphatase (CGMP), which contains 1-400 mg per single dose of the compounds of formula (I) in a mixture with a pharmaceutically acceptable diluent or carrier; the method of treatment or prevention of conditions caused by the activity of CGMP, the essence of which consists in assigning to the person an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or above compositions
The invention relates to the field of veterinary medicine, namely to helminthology

The invention relates to medicine

The invention relates to the creation of new chemical compounds with anticonvulsant, antihypoxic and antioxidant activity and belonging to a new class of anticonvulsants

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: veterinary science.

SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.

EFFECT: higher efficiency of therapy.

4 cl,262 ex, 12 tbl

FIELD: medicine, gynecology, anesthesiology.

SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.

EFFECT: improved assistance method.

7 tbl, 4 ex

FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an antifungal gel pharmaceutical composition based on ketoconazole and clotrimazole that are derivatives of imidazole. The composition comprises ketoconazole or clotrimazole as an active component, polyethylene glycol-400 (PEG-400) as a solvent, carboxyvinyl polymer as a gel-forming agent, polyethylene glycol as a gel stabilizing agent, organic amine or inorganic bas as a regulator of pH and water taken in the definite ratio of components. The composition is prepared by dissolving active component in PEG-400, dispersing carboxyvinyl polymer in water, successive addition to dispersion propylene glycol as a stabilizing agent and regulator of pH and combination of prepared solution and gel followed by stirring the mixture up to preparing the gel composition with pH 5-7. Invention provides preparing antifungal composition with reduced adverse effect.

EFFECT: improved preparing method, valuable medicinal properties of composition.

2 cl, 1 tbl, 11 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with applying selector as a selenium-containing organic preparation to be introduced for cows and calves monthly intramuscularly at the dosage of 10 mcg/kg body weight. The method provides decreased fodder expenses for the synthesis of the production obtained.

EFFECT: higher productivity in cattle.

2 ex, 7 tbl

FIELD: organic chemistry, medicine, allergology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for treatment of patient suffering with allergic disease. Method involves administration to patient the therapeutically effective dose of pharmaceutical composition comprising compound of the formula (I)

. The compound elicits high effectiveness in treatment of allergy and shows low toxicity also.

EFFECT: improved method for treatment.

9 cl, 2 tbl, 2 dwg, 40 ex

FIELD: veterinary science.

SUBSTANCE: one should apply a selenium-containing preparation named selecor: it should be introduced on the 80-90th d of swine gestation twice at 10-15-d-long interval parenterally at the dosage of 20 mg/kg animal body weight. Application of low-toxic antioxidant as selecor enables to improve functional properties of cell membranes of placental system and endometrium and increase inspecific immune resistance in sows. It, also, enables to increase fertility in sows, values of uncomplicated deliveries and puerperal period.

EFFECT: higher viability of off-spring.

2 ex, 3 tbl

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

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