Derivatives of 2-(iminomethyl)aminophenyl, the method of production thereof, pharmaceutical compositions on their basis and intermediate substances

 

(57) Abstract:

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3

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The object of the present invention is new derivatives of 2-(iminomethyl) AMINOPHENYL possessing inhibitory activity against the enzyme NO-synthase, producing nitrogen monoxide NO and/or catching activity against reactive oxygen species (ROS), "reactive Opodepe species"). More specifically, the invention relates to derivatives of General formula (I) defined below, methods for their production, pharmaceutical preparations on their basis and their use for therapeutic purposes, particularly as an inhibitor of NO-synthase and as traps, selective or non-selective, reactive oxygen species.

Given the potential role of NO and ROS in fisiopatologia, new derivatives that meet the General formula (I), can be useful or beneficial effect in the treatment of pathologies involving these chemicals. Namely:

- cardiovascular and cerebrovascular disorders, FarCry and myocardial ischemic brain of origin or as a result of hemorrhage, ischemia and thrombosis;

- disorders of the Central or peripheral nervous system, such as neurodegenerative diseases, which include, in particular, the infarctions of the brain, subarachnoid hemorrhage, aging, senile dementia, including Alzheimer's disease, Huntington Huntington, Parkinson's disease, spastic pseudosclerosis of Creutzfeld-Jakob disease and a prions, amyotrophic lateral sclerosis, pain, brain or spinal cord, dependence on drugs, alcohol and substances, leading to excessive addiction, erectile dysfunction and functions of reproducibility, disorder of consciousness, encephalopathy, encephalopathy, viral or toxic origin.< / BR>
- disorders of skeletal muscle and neuromuscular connections (myopathy, myositis), and skin diseases;

- proliferative and inflammatory disorders such as atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis, inflammation of the gastro-intestinal system (colitis, Crohn's disease) or pulmonary system and the respiratory tract (asthma, sinusitis, rhinitis);

- organ transplantation;no, multiple sclerosis;

cancer;

- neurological diseases associated with intoxication (poisoning by cadmium inhalation of n-hexane, pesticide, herbicide), with treatment (radiotherapy) or disorders of genetic origin (Wilson's disease);

- all pathologies characterized by excessive production or dysfunction of NO and/or ROS.

The experiments show clearly the fact that in all these pathologies involved NO or ROS (J. Med.Chem. (1995) 38. 4343-4362; Free It.Biol.Med. (1996) 20, 675-705; The Neuroscientist (1997) 3, 327-333).

In addition, inhibitors of NO-synthase, their use and combination of these inhibitors with foods with antioxidant or radical scavenging properties described in earlier patents (U.S. patents 5,081,148; 5,360,925 and unpublished patent application).

The object of the present invention are derivatives of 2-(iminomethyl) AMINOPHENYL, obtaining them and their use in therapy.

Compounds according to the invention correspond to General formula (I):

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in which And means:

or the radical:

< / BR>
in which R1and R2signify, independently from each other, a hydrogen atom, halogen, a group HE, linear or branched al the military alkyl, having from 1 to 6 carbon atoms, or the radical COR4where

R4means a linear or branched alkyl with 1-6 carbon atoms,

or the radical:

< / BR>
in which R3has the meaning indicated above, or a radical:

< / BR>
in which R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means linear or branched alkyl with 1-6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 links, containing from 1 to 4 heteroatoms selected from O, S, N, and in particular, thiophene, furan, pirola or thiazole, and the aryl radical optionally substituted by one or more groups selected from linear or branched alkyl radicals, alkenyl or alkoxy having from 1 to 6 carbon atoms;< / BR>
X is-Z-, -Z1-CO-, -CH= CH-CO, -Z1-NR3-CO-, -Z1-NR3-CS-, -Z1-NR3-SO2or a simple bond;

Y represents a radical chosen from the radicals Z2-Q, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, -NR3-Z2-Q-, -NR3-CO-Z2-Q-, -NR3-NH-CO-Z2-, -NH-NH-Z2, -NR3-O-Z2-, -NR3-SQ2-, NR3<>-, R3-N-Z3- or-S-Z3-;

Z1, Z2and Z3mean independently from each other a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is a whole number equal to from 0 to 6;

R6means a hydrogen atom or a group of IT;

or are their salts.

Compounds of General formula (I) containing an asymmetric center, have isomeric forms. The racemates and enantiomers of these compounds are also part of this invention.

Compounds according to the invention can be in the form of bases or addition salts, namely, in the form of salts with organic or inorganic acids or bases, and in particular, in the form of hydrates, chlorhydrate, diclorhidrato, fumarate or Poluboyarinov.

Under linear or branched alkyl with 1-6 carbon atoms implies, in particular, the radicals methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl. Under linear or branched alkoxy radicals with 1-6 carbon atoms involve radicals, alkyl which has videocasette, the object of the present invention, are described in the examples, the following compounds of General formula (I) (some are in salt form):

-3,5-bis(1,1-dimethylethyl) -4-hydroxy-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-benzamide;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

-4-acetoxy-3,5-dimethoxy-N-{ 4-[[(2-thienyl(imino)methyl)amino] phenyl]methyl}-benzamide;

-3,5-dimethoxy-4-hydroxy-N-{ 4-[[(2-thienyl(imino)methyl)amino] phenyl]methyl}-benzamide;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;

-4-acetoxy-3,5-dimethoxy-N-{ 4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl] ethyl}-benzamide;

-3,5-dimethoxy-4-hydroxy-N-{ 4-[2-[(2-thienyl-(imino)methyl)amino] phenyl] ethyl}-benzamide;

3,4,5-trihydroxy-N-{ 4-[2-[(2-thienyl(imino)methyl)-amino] phenyl] ethyl}-benzamide;

-N-{ 4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinil]-phenyl}-2-thiophenecarboxylate;

-N-{ 4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl] -1-piperazinil]-phenyl}-2-thiophenecarboxylate;

-N-{ 4-[4-[3,5-dimethoxy-4-hydroxybenzoyl] -1-piperazinil]-phenyl)-2-thiophenecarboxylate;

-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carbox the l} -2-thiophenecarboxylate;

-N-{ 4-[4-[(5-methoxy-1H-indol-3-yl)methylcarbamoyl]-1 - piperazinil]phenyl} -2 - thiophenecarboxylate;

-N-[4-[4-[{ 3-[3,5-bis-1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-piperazinil]phenyl]]-2-thiophenecarboxylate;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N - {3-[[(2-thienyl-(imino)methyl)amino] phenyl]methyl}-benzamide;

-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N'-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;

-N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl} amino]-2-hydroxyphenyl]-2-thiophenecarboxylate;

-N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl} amino]-4-hydroxyphenyl]-2 - thiophenecarboxylate;

-N-{4-[4-[3,4,5-trihydroxybenzoic]-1-piperazinil]-phenyl}-2-thiophenecarboxylate;

-N-[3,5-bis-[1,1-dimethylethyl)-4-hydroxyphenyl)-N'-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbylamine}-urea;

-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N'-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thiourea;

-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl} -N'-{ 2-{ 4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-urea;

-N'-(4-{ 4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil}-phenyl)-2 - thiophenecarboxylate;

-N-[4-{ 4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-the-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil)phenyl}-2 - thiophenecarboxylate;

-(S)-N-{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil)phenyl}-2-thiophenecarboxylate;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;

N-{ 4-[4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-ethyl]-1-piperazinil)phenyl}-2-thiophenecarboxylate;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-benzoate 2-{4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-benzoate 2-{3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-benzoate 2-{2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl;

and also their salts, in particular their chlorhydrate, dichlorhydrate, fumarate or profumata.

Preferred compounds are compounds of General formula (I), in which

- X means a linear or branched alkylene with 1-6 carbon atoms, and Y represents piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, NR3-Z2-Q-, -NR3-NH-CO-Z2, -NH-NH-Z2or-NR3-O-Z2-; or

- X means Z1-CO - or-CH=CH-CO - and Y represents piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, NR3-Z2-Q-, -NR3-NH-CO-Z1
-NR3-CO - and Y represents-Z2-Q-, -NH-Z2-Q-,

-NH-CO-Z2-Q"- Q"= O-Z3-, R3-N-Z3- or S-Z3- or Y represents-NR3-SO2-NR3-Z2or-O-Z2-Q-;

or

- X means Z1-NH-CO - and Y represents piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine,

-NR3-Z2-Q-, -NR3-NH-CO-Z2, -NH-NH-Z2or-NR3-O-Z2-;

or

- X means Z1-NR3-SO2and Y means Z2-Q - c Q"=O-Z3, R3-N-Z3- or S-Z3- or Y represents-NR3-Z2-Q-;

or

- X means Z1and Y represents-O-CO-Z2-Q-;

or

- X means Z1-NR3-CS, and Y represents-NH-Z2-Q - or piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, -NR3-Z2-Q-, -NH-NH-Z2- or-NR3-O-Z2;

or

- X represents a bond, a Y means O-Z2-NH-, -S-Z2-NH-.

Group X-Y is preferably selected from the following radicals:

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where T means a simple link, the radical-NR3or the radical-CO-NR3-,

or

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or

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in which Rpmeans a hydrogen atom or methyl,

or

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in
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or

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or

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or

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or

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moreover, the radicals Z1-, Z2and Z3have the values specified above.

The most preferred compounds according to the invention are compounds selected from the following;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;

-3,4,5-trihydroxy-N-{ 4-[2-[(2-thienyl(imino)methyl)-amino] phenyl]ethyl}-benzamide;

-N-{ 4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinil]-phenyl}-2-thiophenecarboxylate;

-N-{ 4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl] -piperazinyl] -phenyl}-2-thiophenecarboxylate;

-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;

-N-{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

-N-{ 4-[4-[(5-methoxy-1H-indol-3-yl)methylcarbamoyl] -1-piperazinil]phenyl} -2-thiophenecarboxylate;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl-(imino)methyl)amino]phenyl]methyl}-benzamide;

-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N'-{{4-[(2-thienyl(imino)methyl)amino)phenyl}methyl}-urea;

-N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyben Setenil)-1-oxo-2-propenyl} amino]-4-hydroxyphenyl]-2-thiophenecarboxylate;

-N-{4-[4-[(3,4,5-trihydroxybenzoic]-1-piperazinyl}-2-thiophenecarboxylate;

-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-N'-{ { 4-[(2-thienyl (imino)methyl)amino]phenyl}carbylamine}-urea;

or salt of one of these compounds, in particular the hydrochloride, dichlorhydrate, fumarate or profumata one of these compounds.

Other preferred compounds according to the invention are the following:

-4-acetoxy-3,5-dimethoxy-N-{ 4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl] ethyl}-benzamide;

-3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)

-amino]phenyl]ethyl}-benzamide;

or salt of one of them, in particular the hydrochloride, dichlorhydrate, fumarate or profumata one of these compounds.

Preferred compounds according to the invention are the following:

-N-{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2 - thiophenecarboxylate;

-(R)-N-{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2 - thiophenecarboxylate;

- (S)-N-{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

or salt of one who P CLASS="ptx2">

Finally, the present invention is especially preferred are compounds of General formula (I), which have the following characteristics:

or:

And means

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or

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X is-CO - or-NH-CO-;

a Y means the radical-NH-Z2-Q - or piperazine, Q means a simple bond or a radical Of-R3, R3-N-Z3or S-Z3a Z2and Z3signify, independently from each other, the bond or linear or branched alkylene having from 1 to 6 carbon atoms, and3means a hydrogen atom or a linear or branched alkyl with 1-6 carbon atoms.

or: R6group IT.

The object of the present invention are also medicines which are used in the above compounds of General formula (I) and their pharmaceutically acceptable salts. The invention relates also to pharmaceutical compositions containing these compounds as the active agent or its pharmaceutically acceptable salts, and to the use of these compounds or their pharmaceutically acceptable salts for the manufacture of medicinal products intended for the inhibition of neuronal NO-synthase or inducible NO-synthase, inhibition of p is retinova oxidation of lipids.

Under a pharmaceutically acceptable salt imply in particular, the additive salts of inorganic acids such as hydrochloride, sulfate, diphosphate, bromohydrin and nitrate, or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, paratoluenesulfonyl, pamoate, oxalate and stearate. In the scope of the present invention also includes salts formed with bases such as sodium hydroxide or potassium. As other examples of pharmaceutically acceptable salts can be used those specified in the document "Pharmaceutical salts", J. Pharm. Sci. 66:1 (1977).

Pharmaceutical compositions comprising compounds according to the invention may be in solid form, for example, in the form of powder, granules, tablets, gelatin capsules, liposomes or suppositories. Appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidine and wax.

Pharmaceutical compositions comprising compounds according to the invention can also be in liquid form, for example, they may be in the form of solutions, emulsions, aspen is such as glycerol or glycols, as well as their mixtures in water in different proportions.

The drug according to the invention can be introduced by topical, oral, parenteral, by intramuscular injection, etc.

Offer injected dose of the medicinal product according to the invention is from 0.1 mg to 10 g depending on the type of active compounds.

The invention relates also to new industrial products, which are compounds, which are intermediates for the synthesis of compounds of General formula (I), namely, to compounds of General formula (II):

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in which W stands for the radical of amino, or nitro,

And means:

or the radical:

< / BR>
in which R1and R2signify, independently from each other, a hydrogen atom, halogen, a group HE, a linear or branched alkyl or alkoxy with 1-6 carbon atoms,

R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4,

R4means a linear or branched alkyl with 1-6 carbon atoms,

or the radical:

< / BR>
in which R3has the above value,

or the radical:

< / BR>
in which R5means and the 1-, -Z1-CO-, -CH= CH-CO-, -Z1, -NR3-CO-, -Z1-NR3-CS-, -Z1-NR3-SO2or a simple bond;

Y represents a radical chosen from the radicals Z2-Q-, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, -NR3-Z2-Q-, -NR3-CO-Z2-Q-, -NR3-NH-CO-Z2-, -NH-NH-Z2-, -NR3-O-Z2-, -NR3-SO2-NR3-Z2-, -O-Z2-Q-, -O-CO2-Z2-Q - or-S-Z2-Q-,

in which Q means a simple bond, -O-Z3-, R3-N-Z3- or-S-Z3-;

Z1, Z2and Z3signify, independently from each other, a simple bond or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is a whole number equal to from 0 to 6;

R6means a hydrogen atom or a group of IT;

except 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide;

or salts of these compounds.

The invention relates to new industrial products, which are, in particular, the following compounds, which is an intermediate in the synthesis of compounds of General formula (I):

-3,5-bis(1,1-dimethylethyl)-4-hydroc-(1,1-dimethylethyl)-4-hydroxy-N-[(4-AMINOPHENYL)methyl]-benzamide;

-4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide;

-4-acetoxy-3,5-dimethoxy-N-[(4-AMINOPHENYL)methyl]-benzamide;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-AMINOPHENYL)ethyl]-benzamide;

-4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

-4-acetoxy-3,5-dimethoxy-N-[2-(4-AMINOPHENYL)ethyl]-benzamide;

-3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

-3,4,5-trihydroxy-N-[2-(4-AMINOPHENYL)ethyl]-benzamide;

-2,6-bis(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinil]-carbonyl} -phenol;

-2,6-bis(1,1-dimethylethyl)-4-{ [4-(4-AMINOPHENYL)-1 - piperazinil]-carbonyl}-phenol;

-2,6-bis(1,1-dimethylethyl)-4-{ [4-(4-nitrophenyl)-1 - piperazinil]-methyl} -phenol;

-2,6-bis(1,1-dimethylethyl)-4-{ [4-(4-AMINOPHENYL)-1-piperazinil]-methyl}-phenol;

-2,6-dimethoxy-4-{[4-(4-nitrophenyl)-1-piperazinil]-carbonyl}-phenol;

-2,6-dimethoxy-4-{[4-{4-AMINOPHENYL)-1-piperazinil]-carbonyl}-phenol;

-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl} - 2H-1-benzopyran-2-carboxamide;

-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-AMINOPHENYL} -2H-1-benzopyran-2-carboxamide;

-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-nitrophenyl} -1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol;

-3,4-DL-3-yl)methylcarbamoyl]-4-(4-nitrophenyl)-piperazine;

-1-[(5-methoxy-1H-indol-3-yl)methylcarbamoyl]-4-(4-AMINOPHENYL)-piperazine;

-2,6-bis(1,1-dimethylethyl)-4-{ 3-[4-(4-nitrophenyl)-1-piperazinil] -3-oxo-2-propenyl}-phenol;

-2,6-bis(1,1-dimethylethyl)-4-{ 3-[4-(4-AMINOPHENYL)-1-piperazinil] -3-oxo-2-propenyl}-phenol;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[(3-AMINOPHENYL)methyl]-benzamide;

-N-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -N'-[(4-nitrophenyl)methyl] -urea;

-N-[(4-AMINOPHENYL)methyl] -N'-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -urea;

-3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl] -N-(4-hydroxy-3-nitrophenyl)-2-propenamide;

-3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl] -N-(4-hydroxy-3-AMINOPHENYL)-2-propenamide;

-3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -N-(2-hydroxy-5-nitrophenyl)-2-propenamide;

-3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl] -N - (2-hydroxy-5-AMINOPHENYL)-2-propenamide;

-5-{[4-(4-nitrophenyl)-1-piperazinil]carbonyl}-benzene-1,2,3-triol;

-5-{[4-(4-AMINOPHENYL)-1-piperazinil]carbonyl}-benzene-1,2,3-triol;

-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N'-[(4-nitrophenyl)carbylamine]-urea;

-N-[(4-AMINOPHENYL] carbylamine] -N'-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;

-N-[3,5-bis(1,1-di is ethyl)-4-hydroxyphenyl] -thiourea;

-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -N'-[(4-nitrophenyl)ethyl] -urea;

N-[2-(4-AMINOPHENYL)ethyl]-N'-[3,5-bis(1,1-dimethylethyl)-4 - hydroxyphenyl] -urea;

-1-{ [3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl] carbonyl}-4-(4-nitrophenyl)piperazine;

-1-{ [3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl] carbonyl}-4-(4-AMINOPHENYL)piperazine;

-hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepin;

-1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl] carbonyl}hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepin;

-1-(4-AMINOPHENYL)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8 - tetramethyl-2H-1-benzopyran-2-yl]carbonyl}hexahydro-1H-1,4-diazepin;

-hydrochloride N-[4-{ 4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl] -1H-1,4-diazepin-1-yl} -phenyl]-2-thiophenecarboxaldehyde;

-(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-nitrophenyl)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol;

-(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-AMINOPHENYL)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol;

-(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-nitrophenyl)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol;

-(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-AMINOPHENYL)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol;

-3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-nitro is eilati)-4-hydroxybenzoate 2-(4-nitrophenyl) ethyl;

-3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoate 2-(4-nitrophenyl)ethyl;

or their salts.

The invention relates also to methods of preparing compounds of General formula (I), which consist, for example, in the interaction in a lower alcohol, such as methanol, ethanol, isopropyl alcohol or tert. butanol, preferably, isopropyl alcohol, at a temperature of from 20 to 90oWith, for example, at the 50oWith, and within 48 hours, preferably for 15 to 24 hours, optionally in the presence of DMF, compounds of General formula (III) above, with the compound of General formula (IV)

< / BR>
the named compound of formula (IV) can be optionally converted into a salt with mineral acid G, and b has the above value, a L means delete the group, in particular, alkoxy, thioalkyl, group, sulphonic acid, halide, kilowog alcohol or Totila (remove other group, well known to the specialist, and that, if necessary, can be used according to the invention described in the following literature: Advanced Organic Chemistry, J. March, 3rdEdition (1985), Me Graw-Hill, p.315). Preferably, G means the Hcl, HBr or HI.

Other ways to get considered, for example, in "The Chemistry of amidines and about to get way described below.

Obtaining compounds of General formula (I):

Compounds of General formula (I) can be obtained from the intermediates of General formula (II) according to scheme 1 (see the end of the description).

The restoration of the nitro group of intermediate compounds of General formula (II) is usually carried out by catalytic hydrogenation in ethanol in the presence of Pd/C (palladium on coal), except when X=-CH=CH-CO - or Y= -O-CH2- selectively the nitrogroup restore using, for example, SnCl2(J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedon Letters(1984), 25, (8), 839-842). Then the reaction carried out by heating the mixture at a temperature of approximately 70oC for at least three hours in ethyl acetate, to which, if necessary, add ethanol.

Derivatives of aniline of General formula (III) thus obtained can be condensed with a derivative of General formula (II), for example, derivatives of type O-alkylthiomethyl or S-alkylthiomethyl to obtain the final compounds of General formula (I) (see scheme 1). For example, for V=thiophene, you can condense derivatives of General formula (III) with Edgerton 3-methylthiosemicarbazone obtained by the method described in the literature (Ann. Chim. (1962) is necessary, in the presence of DMF at a temperature of, preferably 50-100oWith in a period of time, usually from several hours to one night.

The intermediate compounds of General formula (II):

Intermediate compounds of General formula (II) can be obtained in different ways depending on the functional groups; amines, carboxamide, urea, thiourea, sulfonamide, aminosulfonyl, sulfonamides, carbamates, ethers, esters, thioethers, allodapini and so on:

If X = a linear or branched alkylene with 1-6 carbon atoms, a Y = piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, -NR3-Z2-Q-, -NR3-NH-CO-Z2-, -NH-NH-Z2-, -NR3-O-Z2-.

Amines of General formula (II), scheme 2 (see the end of the description), in which A, X, Y, and R6defined above, can be obtained by nucleophilic substitution of halogenated derivatives of General formula (VI) with the amine of General formula (VII). The reaction is carried out, for example, in DMF in the presence of K2CO3at 20oC. Halogenated derivatives of General formula (VI) are available, they can be obtained, for example, as a result, the synthesized primary alcohols aimi, can be obtained according to the procedures described in the literature (Tetrahedron Lett. (1983), 24, (24), 2495-2496).

Amines of General formula (VII) in which Y means homopiperazin, 2,5-dimethylpiperazine, 4-aminopiperidine or, as a rule, -NR3-Z2-NR3- are synthesized in three steps from the corresponding commercial diamines. The diamines selectively mono - protect in the form of carbamates (Synthesis(1984), (12), 1032-1033; Synth. Commun(1990), 20, (16), 2559-2564) before interaction by nucleophilic substitution on fornaro-benzene, in particular, 4-peritrabecular. Amines, previously protected, released in the last step, according to the procedures described in the literature (T. W. Greene et P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991) to obtain the intermediate compounds of General formula (VII).

If X = -Z1-CO-, -CH=CH-CO-, a Y = piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, -NR3-Z2-Q-, -NR3-NH-CO-Z2-, -NH-NH-Z2-, -NR3-O-Z2-.

Carboxamide General formula (II), scheme 3 (see end of description) in which A, X, Y, and R6defined above, are obtained by condensing commercial carboxylic acids of General formula(VIII), if X = Z1-CO - and the General formula (IX), if X = is the logical, which are described in the literature (J. Org.Chem. (1974), 39(2) 219-222; J. Amer.Chem. Soc. (1957), 79, 5019-5023, et CHIMIA(1991), 45 (4), 121-123, if a represents the radical 6-alkoxy-2,5,7,8-tetramethylchroman. Amines of General formula (VII) in which Y means homopiperazin, 2,5-dimethylpiperazine, 4-aminopiperidine, or, as a rule, NR3-Z2-NR3- receive according to the procedures similar to those described in the preceding paragraph. Carboxamide bonds are formed in the classical conditions of peptide synthesis (M. Bodanszky et A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984) in THF, dichloromethane or DMF in the presence of a blending agent such as dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CBI) (J. Med.Chem. (1991), 35 (23), 4464-4472) or the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)).

If X = -Z1-NR3-CO-, a Y = -Z2-Q-.

Carboxamide General formula (II) in which A, X, Y, and R6defined above, can be also obtained (scheme 4, see the end of the description) by peptide condensation of an amine of General formula (X) with a commercial acid of General formula (XI). If X=-NR3-CO and R3=H, the compounds of General formula (X) are anilines, which are obtained by hydrogenation in the presence of katal is parallel in accordance with the method described in the literature (J. Org. Chem. (1968), 33(1), 223-226). If X is-NR3-CO-, a R3- linear or branched alkyl with 1-6 carbon atoms, monoalkylamines can be obtained according to the method described in U.S. patents.

3,208,859 and 2,962,531. Non-commercial carboxylic acids of General formula (XI) can be obtained according to the procedures described in the literature: Acta Chem. Scand. (1983), 37, 911-916; Synth.Cononun. (1986), 16 (4), 479-483; Phophorus, Sulfur Silicon Relat. Elem. (1991), 62, 269-273).

If X = -Z1-NR3-CO-, a Y = -NH-Z2-Q-, -NH-CO-Z2-Q-, Q = O-Z3-, R3-N-Z3or S-Z3-.

Urea of General formula (II), scheme 5 (see the end of the description), in which A, X, Y, and R6defined above, is obtained by attaching an amine of General formula (X) to the isocyanate of General formula (XII), (XIII) or (XIV) in a solvent such as chloroform at 20oC. Synthesis of non-commercial isocyanates of General formula (XII) are described in the literature (J. Med.Chem. (1992), 35, (21), 3745-3754). Intermediate halogenated urea (XV) and (XVII) is then replaced by a derivative of General formula (XVI), in which Q denotes O-Z3-, R3-N-Z3- or S-Z3- in the presence of a base, such as, FOR example, a2CO3or NaH, in an aprotic solvent such as THF or DMF, with Poluchenie-methylpiperazin, 2,5-dimethylpiperazine, 4-aminopiperidine, -NR3-Z2-Q-, -NR3-NH-CO-Z2-, -NH-NH-Z2-, -NR3-O-Z2-.

Urea of General formula (II), scheme 6 (see end of description) in which A, X, Y, and R6defined above, is obtained by attaching an amine of General formula (VII) described above, the isocyanate of General formula (XVIII) in the presence of a base, such as diisopropylethylamine.

The isocyanates of General formula (XVIII) are synthesized from primary amines of General formula (X) described above, triphosgene and tertiary amine (J. Org.Chem. (1994), 59 (7), 1937-1938).

Amines of General formula (VII) in which Y is-NH-O-, receive according to the method described in literature (J. Org.Chem. (1984), 49 (8), 1348-1352).

If X = -Z1-NR3-CO-and Y = -NR3-SO2-NR3-Z2-.

Aminosulphonylphenyl General formula (II), scheme 7 (see the end of the description), in which A, X, Y, and Re are defined above, is obtained by joining the amines of General formula (X) described above, to chlorosulfonylisocyanate (J. Med. Chem. (1996), 39 (6), 1243-1252). Intermediate chlorotriphenylmethane (XIX) is then condensed with amines of General formula (VII) described above, obtaining aminosulphonylphenyl General formula (II), which, if necessary, can be alkilirovanny General formula (II).

If X = -Z1-NR3-SO2-, a Y = -Z2-Q-with Q = O-Z3-, R3-N-Z3- or S-Z3-.

Sulfonamides of General formula (II), scheme 8 (see end of description) in which A, X, Y, and R6defined above, is obtained by joining the amines of General formula (X) described above, the chlorides halogenallylacetic General formula (XX). Halogenated.sulphonated General formula (XXI) is obtained at an intermediate stage, then condense with alcohol, amine or thiol of General formula (XVI) in the presence of a base, such as2CO3or NaH, in a polar solvent such as acetonitrile or DMF.

If X = -Z1-NR3-SO2-, a Y = -NR3-Z2-Q-.

The sulfonamides of General formula (II), scheme 9 (see at the end of the description), in which A, X, Y, and R6defined above, get in three stages of the amines of General formula (X) and chlorosulfonylisocyanate. The interaction of alcohol, such as tBuOH, with isocyanate function chlorosulfonylisocyanate (Tetrahedron Lett. (1991,), 32 (45), 6545-6546) leads to the intermediate connection type chlorosulfonylisocyanate, which is subjected to interaction with the amine of General formula (X) to obtain the derived type carboxylamide General formula (XXII). Processing XIII). The alkylation of compounds of General formula (XXIII) with halogenated derivatives of General formula (XXIV) in the presence of a base, such as for example NaH, in an aprotic polar solvent allows to obtain a sulfa derivative of General formula (II).

If X = -Z1-NR3-CO-, a Y = -O-Z2-Q-.

Carbamates of General formula (II), scheme 10 (see end of description) in which A, X, Y, and R6defined above, is produced by the interaction of amines of General formula (X) described above, with chloroformate derivatives of General formula (XXV) obtained according to the method described in literature (Tetrahedron Lett. (1993), 34 (44), 7129-7132).

If X = -Z1-CO-, -CH=CH-CO-, and Y = -O-Z2-Q-.

Esters of General formula (II), scheme 11 (see end of description) in which A, X, Y, and R6defined above, is produced by the interaction of acids of General formula (VIII) or (IX) and alcohols of General formula (XXVI) in the presence of dicyclohexylcarbodiimide and catalytic amounts of 4-dimethylaminopyridine in such a solvent, such as THF or DMF at 20oC.

If X = -Z1-, a Y = -O-CO-Z2-Q-.

Esters of General formula (II), scheme 12 (see end of description) in which A, X, Y, and R6defined formula (V) above.

If X = -Z1-NR3-CS-, a Y = -NH-Z2-Q-, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, -NR3-Z2-Q-, -NH-NH-Z2, NR3-O-Z2-.

Thiourea of General formula (II) in which A, X, Y, and R6defined above, derived from urea, described above, using Lawesson reagent, according to the experimental Protocol described in the literature (J. Med.Chem. (1995), 38 (18), 3558-3565).

If X denotes a single bond, a Y = -O-Z2-Q-, -S-Z2-Q-, and Q = -HN-.

Ferocity or diapirically General formula (II), scheme 13 (see end of description) in which A, X, Y, and R6described above, is obtained from dihydrothieno General formula (XXVII) (J. Chem. Soc., Perkin Trans I, (1981), 303-306) or thiophenols General formula (XXVIII) (Bio.Med.Chem. Letters. (1993), 3 (12), 2827-2830) and electrophilic agent (E+), such as bromoacetonitrile or 4 nitrophenylacetylene, in the presence of K2CO3(J. Heterocyclic Chem., (1994), 31, 1439-1443). NITRILES should be restored (lithium hydride or catalytic hydrogenation) to obtain the intermediate compounds of General formula (XXIX) or (XXX). Opening nitrophenylacetylene obtained by reacting the corresponding nitroanilines with chlorine is eposredstvenno to compounds of General formula (XXIX) or (XXX), which then condense with peritrabecular to obtain the intermediate compounds of General formula (II):

If X means Z1-CO - or-CH=CH-CO-, Y = -NR3-CO-Q-, and Q = R3-N-Z3.

Allodapini General formula (II), scheme 14 (see end of description) in which A, X, Y, and R6described above, are obtained by condensation of the acids of General formula (VIII) or (IX), scheme 3, and ureas of General formula (XXXI) in the presence of the agent combinations, traditionally used in the synthesis of peptides, as described above, in a solvent such as dichloromethane or DMF. Urea of General formula (XXXI) is obtained from isocyanates of General formula (XII), scheme 5, in accordance with the method described in the literature (J. Chem.Soc., Perkin Trans I.(1985), (1), 75-79).

If not given otherwise defined, all technical and scientific terms used herein have the common values that are understandable to the average specialist in the area belongs to this invention. All these are publications, patent applications, patents, and other reference materials included in the reference literature.

The following are examples that illustrate the processes described above and which should not be construed as limiting obaino)methyl)amino]phenyl}-benzamide: 1

1.1) 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-Besame

In a flask with a capacity of 250 ml containing 20 ml of tetrahydrofuran, enter to 1.38 g (10 mmol) 4-nitroaniline, 2.5 g (10 mmol) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, and 2.26 g (11 mmol) of dicyclohexylcarbodiimide. The reaction mixture is stirred for 15 hours at room temperature, pop the precipitate filtered and washed with ethyl acetate. After concentration under reduced pressure the residue was diluted with 20 ml of ethyl acetate, and the insoluble substance is filtered off. The solvent is removed under vacuum and the residue is precipitated in diethyl ether. The solid is extracted by filtration, rinsed in diethyl ether to obtain a white powder with a yield of 65%. Melting point: 277-278oC.

NMR1H (100 MHz, DMSO-d6, ): of 10.72 (s, 1H, CONH); 8,30 (m, 4H, ); 7,80 (s, 2H, Ph) and 1.60 (s, N, 2tBu).

1.2) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide:

In the vessel Parra capacity of 250 ml is dissolved 2.4 g (6.5 mmol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide in 50 ml of a mixture of absolute ethanol/dichloromethane (1/1) in the presence of 10% palladium on coal (Pd/C). The mixture was stirred at a hydrogen pressure of 20 PSI, 30ooC.

NMR1H (100 MHz, DMSO-d6, ): 9,80 (s, 1H, CONH); for 7.78 (s, 2H, ); 7,05 (m, 4H, ); 5,02 (s, 2H, HE) and 1.60 (s, N, 2 x tBu).

1.3) Hydrochloride 3,5-bis-(1,1-disutility)-4-hydroxy-N-{4-[-2-thienyl-(imino)methyl)amino]phenyl}-benzamide: 1

In a flask with a capacity of 100 ml, containing a solution of 1.05 g (is 3.08 mmol) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL) -benzamide in 20 ml of 2-propanol, add 880 mg (is 3.08 mmol) oggidata S-methyl-2-titaniumoxide (Ann. Chim. (1962), 7, 303-337). After heating at 50oC for 15 hours, the reaction mixture is concentrated to dryness in vacuo. The residue is treated with 50 ml of ethyl acetate and 50 ml of a saturated solution of sodium carbonate. After decanting, the organic phase is washed successively with 50 ml saturated RA is evaporated under reduced pressure. The obtained crystals treated with diethyl ether, filtered and washed successively with ethyl acetate and acetone. Get 0,77 g with a yield of 58%.

Hydrochloride get out of 0.77 g (1,71 mmol), dissolved in 60 ml of methanol and converted into a salt in the presence of 3.42 ml (3,42 mmol) molar solution of Hcl in anhydrous diethyl ether. After stirring for half an hour at room temperature the solvent is evaporated in vacuum and the residue is precipitated in the presence of diethyl ether. The resulting crystals are filtered and washed with a large amount of diethyl ether to obtain after drying, 0.65 g (43%) of pale yellow powder. Melting point: 290-291oC.

NMR1H (400 MHz, DMSO-d6, ): for 11.55 (s, 1H, NH+); the 10.40 (s, 1H, CONH); 9,83 (s, 1H, NH+); cent to 8.85 (s, 1H, NH+); 8,21 (m, 2H, thiophene); of 7.70 (s, 2H, Ph); to 7.67 (m, 4H, ); of 7.60 (s, 1H, HE); 7,40 (m, 1H, thiophene); of 1.42 (s, N, 2 x tBu).

IR:OH: 3624 cm-1, 3430 cm-1;C=O(amide): 1653 cm-1;C=N(amidon): 1587 cm-1.

Example 2: hydrochloride 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl-(imino)methyl)amino]phenyl)methyl}-benzamide: 2

2.1) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl) methyl] -benzamide:

In Kolb mmol) 3,5-di-tert-butyl-4-hydroxybenzoic acid, to 1.38 g (10 mmol) of triethylamine and 2.26 g (11 mmol) of dicyclohexylcarbodiimide. The reaction mixture is stirred for 15 hours at room temperature, pop the precipitate is filtered and washed with a minimal amount of ethyl acetate. After concentration under reduced pressure the residue is precipitated in a mixture of ethyl acetate/diethyl ether (1/4) and filtered. The crystals are rinsed in diethyl ether, to obtain a final white powder with a yield of 74% (2.85 g). Melting point: 230-231oC.

NMR1H (100 MHz, CDCl3): a 7.85 (m, 4H, Ph-NO2); of 7.69 (s, 2H, ); PC 6.82 (m, 1H, NHCO); 5,67 (s, 1H, OH); at 4.75 (d, 2H, CH2-NHCO, J=6.5 Hz); for 1.49 (s, N, 2 x tBu).

2.2) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N- [(4-AMINOPHENYL) methyl]-benzamide:

In the vessel Parra capacity of 250 ml dissolve 2.85 g (7.4 mmol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide in 30 ml of a mixture of absolute ethanol alcohol/dichloromethane (1/1) in the presence of 10% palladium on coal. The mixture was stirred at a hydrogen pressure of 20 PSI, 30oWith in one hour. After filtering celite the filtrate was concentrated in vacuo. The product evaporate spontaneously crystallizes. Leave it overnight, filtered, the crystals washed with a mixture of diet the ptx2">

NMR1H (100 MHz, CDC13, ): a 7.62 (s, 2H, Ph); to 6.95 (m, 4H, ); of 6.20 (m, 1H, NHCO); to 5.58 (s, 1H, HE); 4,50 (d, 2H, J=6.5 Hz); 3,70 (s, broad, 2H, NH2); to 1.47 (s, N, 2 x tBu).

2.3) hydrochloride 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl-(imino)methyl)amino]phenyl]methyl}-benzamide: 2

Work similar to that described for compound 1 and using 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-amino-phenyl) methyl] -benzamide instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. After salt formation with a molar solution of Hcl in anhydrous diethyl ether, receive a white powder with a yield of 56%. Melting point: 218-219oC.

NMR1H (400 MHz, DMSO-d6, ): 11,60 (s, 1H, NH+); 9,83 (s, 1H, NH+); of 9.02 (s, 1H, CONH); 8,90 (c, 1H, NH+); 8,18 (m, 2H, thiophene); of 7.70 (s, 2H, Ph); 7,42 (m, 6N, thiophene, HE); 4,50 (d, 2H, CH2-NHCO, J=5.7 Hz); of 1.40 (s, N, 2 x tBu).

IR;OH: 3624 cm-1, 3424 cm-1;C=O(amide): 1644 cm-1;C=N(amidon): 1568 cm-1.

Example 3: 4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino) methyl)amino] phenyl]methyl}-benzamide: 3

3.1) 4-acetoxy-3,5-dimethoxy-benzoic acid:

In a vessel with a capacity of 100 ml, in a nitrogen atmosphere, dissolved 1.50 g (EUR 7.57 mmol) purple acid in 15 ml of dry pyridine. Add the Pyridine is evaporated under reduced pressure, the residue is treated with 25 ml of dichloromethane and washed with 10 ml of a molar solution of Hcl, then with 2 to 10 ml of water. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuum. Get 1,72 g (95%) of a beige powder. Melting point: 181-183oC.

NMR1H (100 MHz, l3, ): 8,15 (s, 1H, CO2N); 7,40 (s, 2H, Ph); 3,90 (s, 6N, ON3); is 2.40 (s, 3H, CH3).

3.2) 4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide:

Work the same as when obtaining an intermediate product of 2.1, using 4-acetoxy-3,5-dimethoxy-benzoic acid instead of 3,5-di - tert-butyl-4-hydroxy-benzoic acid. Receive a colorless oil with a yield of 28%.

NMR1H (100 MHz, DMSO-d6, ): 9,26 (t, 1H, NHCO, J=6.0 Hz); to $ 7.91 (m, 4H, Ph-NO2); 7,31 (s, 2H, Ph); the 4.65 (d, 2H, CH2, J=6.0 Hz); a 3.83 (s, 6N, ON3); of 2.28 (s, 3H, CH3).

3.3) 4-acetoxy-3,5-dimethoxy-N-[(4-AMINOPHENYL)methyl]-benzamide

Work the same as when obtaining an intermediate product 2.2, and using 4 - acetoxy - 3,5 - dimethoxy-N-[(4 - nitrophenyl)methyl]-benzamide instead of 3,5-bis(1,1-dimethylethyl)-4 - hydroxy-N-[(4-nitrophenyl)methyl] -benzamide. Receive a colorless oil with a yield of 82%. The product is used directly is)amino]phenyl] methyl}-benzamide: 3

Work as and when the connection is 1, and using 4-acetoxy-3,5-dimethoxy-N-[(4-AMINOPHENYL)methyl] -benzamide instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. Get the base 3 in the form of a beige powder with a yield of 65%. Temperature: 47-48oC.

NMR1H (400 MHz, DMSO-d6, ): the remaining 9.08 (broad, 1H, CONH); to 7.75 (m, 1H, thiophene); a 7.62 (m, 1H, thiophene); 7,30 (s, 2H, PH); 7,10 (m, 1H, thiophene); 7,07 (m, 4H, Ph-N); 6.48 in (broad, 2H, NH2); 4,50 (d, 2H, CH2, J=4.6 Hz); of 3.80 (s, 6N, ON3); is 2.30 (s, 3H, CH3).

IR:C=O(ether): 1760 cm-1,C=O(amide): 1630 cm-1; C=N(amidon): 1540 cm-1.

Example 4: 3,5-dimethoxy-4-hydroxy-N-(4-[[(2-thienyl(imino) methyl)amino] phenyl]methyl}-benzamide: 4

In a flask with a capacity of 50 ml, add one drop of 1 ml (2 mol) of 2N hydrochloric acid in a solution of 0.59 g (1 mol) of the compound 3 in 5 ml of ethanol. The reaction mixture is stirred for 18 hours at 50oC. the Solvent is evaporated to dryness, the residue treated with dichloromethane (5 ml) and washed molar solution of alkali sodium (35 ml). After drying the organic phase, filtering and concentrating to dryness, the resulting oil purified by chromatography on silica gel (elwira a mixture of dichloromethane/methanol: 9/1). Clean 55-58oC.

NMR1H (400 MHz, DMSO-d6, ): of 8.92 (s, 1H, HE); 8,84 (m, 1H, CONH); to 7.75 (m, 1H, thiophene); 7,63 (m, 1H, thiophene); 7,26 (s, 2H, Ph); 7,10 (m, 1H, thiophene), 7,05 (m, 4H, Ph-N); 6,50 (s, 2H, NH2); of 4.45 (d, 2H, CH2, J=5.7 Hz); 3,81 (s, 6N, 2 och3).

IR:OH: 3600 cm-1;C=O(amide): 1630 cm-1;C=N(amidon): 1590 cm-1.

Example 5: iggeret 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide: 5

5.1) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl) ethyl] -benzamide:

In a flask with a capacity of 100 ml, containing 20 ml of tetrahydrofuran, enter 2,02 g (10 mmol) of the hydrochloride of 4-nitrophenylamino, 2.5 g (10 mmol) of 3,5-di-tert-butyl-4-hydroxy-benzoic acid, to 1.38 g (10 mmol) of triethylamine and 2.26 g (11 mmol) of dicyclohexylcarbodiimide. The reaction mixture is stirred for 15 hours at room temperature, pop the precipitate is filtered and washed in ethyl acetate. After concentration of the filtrate under reduced pressure the residue is precipitated in diethyl ether. The solid is recovered by filtration and washed in diethyl ether. Get white powder with a yield of 73%. Melting point: 204-206oC.

NMR1H (100 MHz, CDCl3, ): 7,52 (s, 2H, Ph); 6,85 (m, 4H, Ph-NO2the l) ethyl]-benzamide:

Work the same as when obtaining an intermediate compound of 2.2, and using 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)methyl] -benzamide. Get white powder with a yield of 76%. Melting point: 193-195oC.

NMR1H (100 MHz, CDC13, ): 7,80 (m, 4H, Ph-NH2); at 7.55 (s, 2H, Ph); 6,10 (m, 1H, NHCO); of 5.55 (s, 1H, HE); of 3.75 (m, 2H, ); 3,10 (m, 2H, ); 1,50 (s, N, 2 x tBu).

5.3) iggeret 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{ 4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide: 5

In a flask with a capacity of 50 ml, containing 1.01 g (2,74 mmol) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-AMINOPHENYL)ethyl] -benzamide are dissolved in 20 ml of 2-propanol, add 0,78 g (2,74 mmol) oggidata 3-methyl-2-thiophene-thiocarboxamide (Ann.Chim. (1962), 7, 303-337). The reaction mixture is heated at 40oC for 4 hours. The solvent is evaporated in vacuum and the residue is precipitated in the presence of 50 ml of a mixture of water/ethyl acetate (1/1). Formed crystals are filtered and washed successively with ethyl acetate and diethyl ether. After drying receive light yellow powder with a yield of 68%. Melting point: 185-186oC.

NMR1H (400 MHz, DMSO-d6, ): 9,80 (s, 1H, NH+); 8,88 (s, 1H, NH8, 2 x tBu).

IR:OH: 3624 cm-1, 3423 cm-1;C=O(amide): 1636 cm-1;C=N(amidon): 1569 cm-1.

Example 6: fumarate 4-acetoxy-3,5-dimethoxy-N-{ 4-[2-[(2-thienyl- (imino)methyl)-amino]phenyl]ethyl}-benzamide:

6.1) 4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide:

Work the same as when receiving the intermediate 5.1, and using 4-acetoxy-3,5-dimethoxy-benzoic acid (intermediate compound 3.1) instead of 3,5-di-tert-butyl-4-hydroxy-benzoic acid. Receive a colorless oil with a yield of 70%. The product is used directly in the next step.

6.2) 4-acetoxy-3,5-dimethoxy-N-[2-(4-AMINOPHENYL)ethyl]-benzamide:

Work the same as when obtaining an intermediate product 2.2, and using 4 - acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl) ethyl]-benzamide instead of 3,5-bis-(1,1-dimethyl-ethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl] -benzamide. Receive a colorless oil in quantitative yield. The product is used directly in the next step without additional purification.

6.3) fumarate, 4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl- (imino)methyl)amino)phenyl]ethyl}-benzamide: 6

To obtain a free base function as when receiving soil)-4-hydroxy-N-(4-AMINOPHENYL) -benzamide. The resulting reaction product is transformed into a salt in the presence of equimolar amount of fumaric acid in ethanol under reflux. Get connection 6 in the form of a beige powder with a yield of 74%. Melting point: 178-180oC.

NMR 1H (400 MHz, DMSO-d6, ): at 8.60 (m, 1H, CONH); to 7.75 (m, 1H, thiophene); to 7.64 (d, 1H, thiophene, J=5.0 Hz); 7,20 (s, 2H, Ph); 7,11 (t, 2H, thiophene, J=9.0 Hz); 7,02 (m, 4H, Ph-N); is 6.61 (s, 2H, CH=CH fumarate); 3,81 (s, 6N, 2 och3); 3,50 (kV, 2H, CH2-N, J=6.5 Hz); 2,82 (t, CH2-Ph, J=7,0 Hz); 2,27 (C, H, CH3).

IR:C=O(ester): 1750 cm-1,C=O(amide): 1640 cm-1;C=N(amidon): 1550 cm-1.

Example 7: hydrochloride 3,5-dibutoxy-4-hydroxy-N-{ 4-[2-[(2-thienyl-(imino)methyl)-amino)phenyl]ethyl}-benzamide:

In a flask with a capacity of 50 ml, add one drop of 1.40 ml (2.80 mmol) of 2N hydrochloric acid in a solution of 0.64 g (1.37 mmol) of compound 6 in the form of the free base in 5 ml of ethanol. The reaction mixture is stirred for 18 hours at 50oC. the Solvent is evaporated to dryness and the product precipitated by evaporation in a mixture of 5 ml of 2N caustic soda solution of sodium hydroxide and 10 ml of dichloromethane. After filtration, the solid product is treated with in hydrochloric ethanol (4N). Remove easy wasp is the idea of the hydrochloride with a yield of 58%.

Melting point: 164-boC.

NMR1H (400 MHz, DMSO-d6, ): 9,80 (s, 1H, NH+); of 8.90 (s, 2H, NH+HE); 8,54 (m, 1H, CONH); 8,18 (s, 1H, thiophene); is 8.16 (s, 1H, thiophene); 7,40 (m, 4H, Ph-N); 7,21 (s, 2H, Ph); 7,11 (m, 1H, thiophene); 3,81 (s, 6N, ON3); 3,51 (kV, 2H, CH2-N, J=7,0 Hz); 2,92 (t, 3H, J=7,0 Hz).

IR: OH: 3300 cm-1;C=O(amide): 1620 cm-1;C=N(amidon): 1560 cm-1.

Example 8: profumata 3,4,5-trihydroxy-N-{4-[2-[(2-thienyl- (imino)methyl)-amino]phenyl]ethyl}-benzamide: 8

8.1) 3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide:

In a flask with a capacity of 100 ml, containing 30 ml of anhydrous dimethylformamide, enter 2 g (11.5 mmol) of Gallic acid, 2.5 g (11.5 mmol) of the hydrochloride of 4-nitrophenylamino, 1.8 g (11.5 mmol) of hydrated 1-hydroxybenzotriazole, 2.25 g (11.5 mmol) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 3.3 ml (23 mmole) of triethylamine. The resulting orange solution stirred at 20oC for 20 hours and diluted in a mixture of dichloromethane (50 ml) and water (30 ml). After decanting, the organic phase is washed with a molar solution of hydrochloric acid (20 ml) and water (3 20 ml) to a neutral state. After drying the organic phase over magnesium sulfate, filtration and concentration in vacuumlike the product as a colourless oil with a yield of 42% (of 1.57 g).

NMR1H (100 MHz, DMSO-d6, ): 8,95 (m, 3H, 3 HE); a 7.85 (m, 4H, Ph-NO2); to 6.80 (s, 2H, Ph); to 3.36 (m, 2H, CH2N); of 2.97 (t, 2H, J=6.0 Hz).

8.2) 3,4,5-trihydroxy-N-[2-(4-AMINOPHENYL)ethyl]-benzamide:

Work the same as when obtaining an intermediate product 2.2, and using 3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl] -benzamide. Get a beige powder with a yield of 89%. The melting point; 167-169oC.

NMR1H (100 MHz, DMSO-d6, ): 8,80 (m, 3H, HE); 8,07 (t, 1H, NHCO, J=5.0 Hz); for 6.81 (s, 2H, Ph); of 6.68 (m, 4H, Ph-NH2); or 3.28 (m, 2H, CH2N); 2,60 (t, 2H, J=7,0 Hz).

8.3) profumata 3,4,5-trihydroxy-N-{4-[2-[(2-thienyl- (imino)methyl)amino)-phenyl]ethyl}-benzamide: 8

Work the same as when the connection is 1, and use the 3,4,5-trihydroxy-N-[2-(4-AMINOPHENYL)ethyl] -benzamide instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. Get the base 8 in the form of a powder, which turned into salt by heating under reflux at the boiling temperature of ethanol, in the presence of an equivalent of fumaric acid. Salt spontaneously crystallizes in the 20oC. After filtration and washing with ethanol target product in the form of beige on the, 3); to 8.14 (t, 1H, NHCO, J= 5.0 Hz); 7,73 (s, 1H, thiophene); of 7.60 (d, 1H, thiophene, J=5.0 Hz); 7,16 (s, 2H, Ph): to 7.09 (t, 1H, thiophene, J=4.0 Hz); to 6.80 (m, 4H, Ph-N); 6,59 (broad, 2H, 1/2-CH= CH, NH); to 3.41 (m, 3H, CH2-N+NH); was 2.76 (t, 2H, CH2, J=7.5 Hz).

IR:OH: 3300 cm-1;C=O(amide): 1620 cm-1;C=N(amidon): 1590 cm-1.

Example 9: hydrochloride-N-{ 4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinil]-phenyl}-2 - thiophenecarboxylate: 9.

9.1) 2,6-bis(1,1-dimethylethyl)-4-{ [4-(4-nitrophenyl)-1-piperazinil] -carbonyl}-phenol:

In a flask with a capacity of 100 ml, containing 25 ml of DMF, enter 2,07 g (10 mmol) of 1-(4-nitrophenyl)piperazine, 2.5 g (10 mmol) of 3,5-di-tert-butyl-4-hydroxy-benzoic acid and 2.26 g (11 mmol) of dicyclohexylcarbodiimide. The reaction mixture is stirred for 15 hours at room temperature, pop the precipitate is filtered and washed in ethyl acetate. After concentration of the filtrate under reduced pressure, the residue is dissolved in 20 ml of ethyl acetate and new insoluble product is removed by filtration. The solvent is evaporated in vacuo, and the residue is precipitated in diethyl ether. The solid is filtered, washed with 220 ml of ethyl acetate, to obtain a yellow powder with a yield of 89%. Melting point: 15 piperazine); 3,55 (m, 4H, piperazine); of 1.46 (s, N, 2 x tBu).

9.2) 2,6-bis(1,1-dimethylethyl)-4-{[4-(4-AMINOPHENYL)-1-piperazinil]-carbonyl}-phenol:

In the vessel Parra capacity of 250 ml dissolve 2,19 g (5.0 mmol) of intermediate product 9.1 in 50 ml of absolute ethyl alcohol in the presence of 10% palladium on coal (Pd/C). The mixture was stirred at a hydrogen pressure of 20 PSI at 30oWith in one hour. After filtering celite the filtrate was concentrated in vacuo. Product evaporation is treated with 25 ml diethyl ether, filtered and washed with 220 ml of diethyl ether. Get a pale pink powder with a yield of 82%. Melting point: 221-222oC.

NMR1H (100 MHz, CDCl3, ): 7,30 (s, 2H, Ph); to 6.75 (m, 4H, Ph-NH2); the 5.45 (s, 1H, HE); of 3.80 (m, 4H, piperazine); 3,10 (m, 4H, piperazine); for 1.49 (s, N, 2 x tBu).

9.3) hydrochloride-N-{4-[4-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl] -1-piperazinil]-phenyl}-2-thiophene-carboxamidine: 9

Work as and when the connection is 1, and the use of 2,6-bis-(1,1-dimethylethyl)-4-{ [4-(4-AMINOPHENYL)-1-piperazinil] -carbonyl} -phenol instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. After processing molar solution of Hcl in anhydrous diethyl ether get a beige powder with vyhoda (s, 1H, NH+); 9,78 (s, 1H, NH+); is 8.75 (s, 1H, NH+); 8,19 (m, 2H, thiophene); 7,29 (m, 5H, Ph-N, thiophene); 7,10 (s, 2H, Ph); the ceiling of 5.60 (broad, 1H, OH); 3,70 (m, 4H, piperazine); 3,30 (m, 4H, piperazine); of 1.40 (s, N, 2 x tBu).

IR:OH: 3633 cm-1, 3433 cm-1;C=O(amide): 1617 cm-1;C=N(amidon): 1590 cm-1.

Example 10: hydrochloride-N-{4-[4-[(3,5-bis-(1,1-dimethyl-ethyl)-4-hydroxybenzyl]-1-piperazinil]-phenyl}-2-thiophenecarboxaldehyde: 10

10.1) 2,6-bis(1,1-dimethylethyl)-4-bromomethylphenyl:

In a three-neck flask with a capacity of 250 ml in a nitrogen atmosphere dissolve of 2.36 g (10 mmol) of 3,5-di-tert-butyl-4-hydroxybenzoato alcohol in 25 ml of anhydrous tetrahydrofuran. The solution is cooled with an ice bath, and then added dropwise to 0.95 ml (10 moles) of tribromide phosphorus, diluted with 25 ml anhydrous THF. After stirring for 15 minutes at 0oThe solution was diluted with 100 ml dichloromethane and washed with 330 ml of water, then 30 ml of brine. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo to obtain a dark brown oil which is used directly in the next step.

10.2) 2,6-bis(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinil]-methyl)-phenol:

In a flask with a capacity of 100 ml, containing process is carbonate potassium and 2.07 g (10 mmol) of 1-(4-nitrophenyl)piperazine. After two hours stirring at ambient temperature the reaction mixture is diluted with 150 ml dichloromethane and washed sequentially in x ml of water, then 40 ml of brine. The organic solution is dried over sodium sulfate, filtered and

concentrate under reduced pressure. The obtained dark brown residue is purified by chromatography on silica gel (elwira with a mixture of petroleum ether (b 40-70o)/ethyl acetate: 8/2). After concentration of the pure fractions get 2,31 g (54%) of a dark brown powder.

Melting point: 177,5-178,5oC.

NMR1H (100 MHz, Dl3, ): 7,50 (m, 4H, Ph-NO2); for 7.12 (s, 2H, Ph); 5,19 (s, 1H, HE); 3,50 (s, 2H, CH2-Ph); 3,40 (m, 4H, piperazine); 2,60 (m, 4H, piperazine); for 1.49 (s, N, 2tBu).

10.3) 2,6-bis(1,1-dimethylethyl)-4-{[4-(4-AMINOPHENYL)-1-piperazinil]-methyl)-phenol:

Work as well as when obtaining an intermediate product of 9.2, and use of 2,6-bis-(1,1-dimethylethyl)-4-{[[4-(4-nitrophenyl)-1-piperazinil]-carbonyl] -methyl} -phenol instead of 2,6-bis- (1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinil] -carbonyl} -phenol. Get a light pink powder with a yield of 75%. Melting point: 152-154oC.

10.4) hydrochloride-N-{4-[4-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl] -1-piperazinediones 10.3 in 20 ml of 2-propanol, type of 0.43 g (1.5 mmole) of oggidata S-methyl-2-thiophene-thiocarboxamide (Ann. Chim. (1962), 7, 303-337). After heating under reflux for 15 hours, the reaction mixture was concentrated to dryness in vacuo. The residue is purified by chromatography on silica gel (elwira with a mixture of dichloromethane/ethanol: 90/10). Pure fractions concentrated in vacuo and the product evaporation transformed into a salt in the presence of a molar solution of Hcl in anhydrous diethyl ether. Get the powder of light yellow color with a yield of 40%. Melting point: 234-236oC.

NMR1H (400 MHz, DMSO-d6, ): 11,60 (s, 1H, NH+); 11,40 (s, 1H, NH+); of 9.75 (s, 1H, NH+); to 8.70 (s, 1H, NH+); 8,17 (m, 2H, thiophene); 7,39 (s, 2H, PH); 7,38 (m, 1H, thiophene); from 7.24 (m, 5H, Ph-N, IT); 4.26 deaths (d, 2H, CH2-Ph, J= 4.6 Hz), 3,90 (m, 2H, piperazine); to 3.35 (m, 4H, piperazine); 3.15 in (m, 2H, piperazine); of 1.40 (s, N, 2tBu).

IR:OH: 3624 cm-1, 3418 cm-1;C=N(amidon): 1610 cm-1.

Example 11: hydrochloride-N-{4-[4-[(3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinil]-phenyl}-2-thiophenecarboxaldehyde: 11

11.1) 2,6-dimethoxy-4-{[4-(4-nitrophenyl)-1-piperazinil]-carbonyl}-phenol:

In vitro capacity of 100 ml dissolve 0,99 g (5 mmol) purple acid, 0.74 g (5.5 mmol) of hydroxybenzotriazole, 1.10 g (ivania at room temperature the mixture is filtered and the precipitate washed with 20 ml DMF, then 100 ml of chloroform. Receive 2 g of yellow powder, which contains approximately 20% of dicyclohexylamine. The product is used as such in the next step.

NMR1H (100 MHz, DMSO-d6, ): of 7.69 (m, 4H, Ph-NO2); to 6.88 (s, 2H, Ph); 5,72 (m, 1H, HE); 3,91 (s, 6N, ON3); of 3.75 (m, 4H, piperazine); to 3.49 (m, 4H, piperazine).

11.2) 2,6-dimethoxy-4-{[4-(4-AMINOPHENYL)-1-piperazinil]-carbonyl}-phenol:

In the vessel Parra capacity of 250 ml dissolve 2 g of the intermediate product 11.1 in 4 ml of absolute ethanol DMSO (1/3) in the presence of 10% palladium on coal (Pd/C). The mixture is stirred under hydrogen pressure of 20 PSI, 25oWith over 15 hours. After filtering celite the filtrate was concentrated in vacuo. Light brown product evaporation is treated with 50 ml of ethyl acetate, the precipitate is removed by filtration, washed with 20 ml of ethyl acetate and the filtrate is extracted with 225 ml of a molar solution of Hcl. The aqueous phase is alkalinized by adding sodium carbonate powder and extracted with 250 ml ethyl acetate. The organic solution is dried over sodium sulfate, filtered and concentrated in vacuo. The resulting powder was treated with 20 ml of diethyl ether containing 3 ml of methanol, filtered and washed the tion: 182-183oC.

NMR1H (100 MHz, DMSO-d6, ): to 6.80 (s, 2H, Ph); 6,74 (m, 4H, Ph-NH2); 4,80 (m, 2H, NH2); 3,91 (s, 6N, ON3); of 3.77 (m, 4H, piperazine); is 3.08 (m, 4H, piperazine).

11.3) hydrochloride-N-{ 4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinil]-phenyl} -2-thiophenecarboxaldehyde: 11

In a flask with a capacity of 100 ml, containing a solution of 0.4 g (1,13 mmole) of intermediate compounds of 11.2 in 10 ml of 2-propanol, added 0.32 g (1,13 mmole) of oggidata S-methyl-2-thiophene-thiocarboxamide (Ann.Chim. (1962), 7, 303-337). After heating at 50oC for 15 hours, the reaction mixture is concentrated to dryness in vacuo. The product is evaporated, treated with 100 ml of a mixture of ethyl acetate/saturated sodium carbonate solution (1/1). Appearing precipitate filtered and washed successively with 20 ml water, 20 ml of ethyl acetate and 50 ml of ether. The resulting basis is turned into salt in the presence of a molar solution of Hcl in anhydrous diethyl ether. After filtration, washing with 10 ml of acetone and drying obtain 0.12 g (20%) of light yellow powder. Melting point: 184-185oC.

NMR1H (400 MHz, DMSO-d6, ): 11,47 (s, 1H, NH+); 9,78 (s, 1H, NH+); 8,76 (s, 1H, NH+); 8,18 (m, 2H, thiophene); 7,37 (m, 1H, thiophene); 7,28 (m, 4H, Ph-N); 6,74 (s, 2H, Ph); 4,27 (broad, 1H, OH); of 3.80 (s, 6N, ON3)>=N(amidon): 1587 cm-1.

Example 12: hydrochloride 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl-(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide: 12

12.1) 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide:

In a flask with a capacity of 100 ml type of 1.62 g (10 mmol) of 1,1'-carbonyldiimidazole in a solution of 2.5 g (10 mmol) Troloxin 25 ml of THF. After one hour stirring at room temperature, add drop by drop a solution of 4-nitro-aniline in 20 ml of THF. Stirring is continued for 15 hours and the solution is evaporated in vacuum. The residue is dissolved in 50 ml of dichloromethane and washed successively with 25 ml of molar solution of hydrochloric acid, 25 ml of water and 25 ml brine. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil purified by chromatography on silica gel (elwira with a mixture of petroleum ether (b 40-70oWith/ethyl acetate: 7/3). After concentration of the pure fractions receive light yellow powder with a yield of 77%. Melting point: 150-151oC.

NMR 1H (100 MHz, CDCl3, ): 8,68 (s, 1H, CONH); to $ 7.91 (m, 4H, Ph); 4,59 (s, 1H, HE); 2,95-0.87 (m, N, Trolox).

12.2) 3,4-dihydro-6-hydroxy-2,5,7,8-Ter the unity 9.2, with the use of 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide instead of 2,6-bis-(1,1-dimethylethyl)-4-{ [4-(4-nitrophenyl)-1-piperazinil]-carbonyl}-phenol. The reaction product is purified by chromatography on silica gel (elwira with a mixture of petroleum ether (b 40-70oC)/ethyl acetate: 6/4). Pure fractions are collected, after evaporation of the solvent in vacuo receive a colorless oil with a yield of 45%.

NMR1H (100 MHz, CDCl3, ): 8,19 (s, 1H, CONH); 7,00 (m, 4H, Ph); 4,59 (s, 1H, HE); the 3.65 (broad, 2H, NH2); 2,95-0.87 (m, N, Trolox).

12.3) hydrochloride 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[2-thienyl-(iminomethyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide: 12

Work the same as when the connection is 1, and using 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-AMINOPHENYL)-2H-1-benzopyran-2-carboxamide instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. Melting point: 279-280oC.

NMR1H (400 MHz, DMSO-d6, ): 9,80 (s, 1H, NH+); 9,50 (s, 1H, NH+); 8,73 (s, 1H, NHCO); 8,18 (m, 2H, thiophene); 7,60 (m, 1H, HE); to 7.59 (m, 4H, Ph); of 7.36 (m, 1H, thiophene); 2,60-of 1.57 (m, N, Trolox).

IR:OH: 3236 cm-1;C=O(amide): 1683 cm-1;C=N(amidon): 1577 cm-1.
13.1) 3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol:

In a flask with a capacity of 100 ml type of 1.62 g (10 mmol) of 1,1'-carbonyldiimidazole in a solution of 2.5 g (10 mmol) Troloxin 25 ml of THF. After one hour of stirring at room temperature, add drop by drop a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMF. Stirring is continued for 15 hours, then the reaction mixture was concentrated in vacuo. Product evaporation is dissolved in 50 ml of dichloromethane and washed successively 325 ml of water and 25 ml brine. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The oil obtained is precipitated in 30 ml of a mixture (95/5) ethyl acetate/ethanol, the solid is filtered and washed with 220 ml of ethyl acetate. Get a light-yellow powder with a yield of 79%. Melting point 199-200oC.

NMR1H (100 MHz, CDCl3, ): was 7.45 (m, 4H, Ph); to 4.41-to 3.35 (m, 8H, piperazine); 2,95-1,25 (m, N, Trolox).

13.2) 3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-AMINOPHENYL)-1-piperazinyl] -carbonyl)-2H-1-benzopyran-6-ol:

Work the same as when receiving the intermediate 2.2, and using 3,4-dihydro-2,5,7,8-tetramethyl-2-{4-nitrophenyl)-1-piperazinil]-carbonyl} -2H-1-t by chromatography on silica gel (elwira with a mixture of dichloromethane/methanol: 9/1). Pure fractions are collected, so that after evaporation of the solvent in vacuo to obtain a brown oil with a yield of 66%.

NMR1H (100 MHz, CDCl3, ): 6,70 (m, 4H, Ph); 4,15-of 2.97 (m, 8H, piperazine); 2,80-of 0.90 (m, N, Trolox).

13.3) hydrochloride-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl] -1-piperazinil] -phenyl} -2-thiophenecarboxaldehyde: 13

Work same as for connection 1, and using 3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-AMINOPHENYL)-1-piperazinil]-carbonyl} -2H-1-benzopyran-6-ol instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. But the reaction is slower and requires 15 hours of heating. The base obtained after extraction, purified by chromatography on silica gel (elwira with a mixture of petroleum ether (So Kip.40-70oWith/ethyl acetate: 3/7). Pure fractions concentrated in vacuo and the product evaporation transformed into a salt in the presence of a molar solution of Hcl in anhydrous diethyl ether. Get a pale yellow powder with a yield of 40%. Melting point: 210-211oC.

NMR1H (400 MHz, DMSO-d6, ): 11,50 (s, 1H, NH+); 9,79 (s, 1H, NH+); 8,69 (s, 1H, NH+); 8,19 (m, 2H, thiophene); 7,38 (m, 1H, thiophene); 7,20 (m, 4H, Ph); 4,58 (broad, 1H, WHOM B>OH: 3410 cm-1;C=O(amide): 1642 cm-1;C=N(amidon): 1613 cm-1.

Example 14: N-{4-[4-[(5-methoxy-1H-indol-3-yl)methyl-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate: 14

14.1) 1-[(5-methoxy-1H-indol-3-yl)methylcarbamoyl] -4-(4-nitrophenyl)-piperazine:

In a flask with a capacity of 100 ml type of 1.62 g (10 mmol) of 1,1'- carbonyl-diimidazole in a solution of 2.05 g (10 mmol) 5-methoxyindol-3-acetic acid in 10 ml of THF. After one hour stirring at room temperature, add drop by drop a solution of 1-(4-nitrophenyl)-piperazine in 10 ml of DMF. Stirring is continued for 15 hours. Then the reaction mixture was concentrated in vacuo, and the product precipitated by evaporation to 50 ml of a mixture of ethyl acetate/water (1/1). After filtration, the solid is washed successively with 50 ml water, 50 ml of ethyl acetate and 50 ml of dichloromethane. Receives a yellow powder after drying in vacuum to yield 91%. Melting point: 239-240oC.

NMR1H (100 MHz, DMSO-d6, ): 10,90 (m, 1H, NH); 7,63 (m, 4H, Ph-NO2); 7,40-to 7.15 (m, 3H), indole); 6.87 in (DD, 1H, indole, Jortho=8,7 Hz, Jmetaand 2.8 Hz); 3,90 (s, 2H, CH2-CO); 3,88 (s, 3H, och3); with 3.79 (m, 4H, piperazine); 3,50 (m, 4H, piperazine).

14.2) 1-[(5-methoxy-1H-indol-3-yl)methylcarbamoyl] -4-(4-AMINOPHENYL)-parisuddhi 10% palladium on coal (Pd/C). The mixture is stirred under hydrogen pressure of 20 PSI, 25oWith over 7 hours. After filtering celite the filtrate was concentrated in vacuo. Product evaporation is dissolved in 50 ml ethyl acetate and washed with 350 ml of water. The organic phase is then extracted with 225 ml of a molar solution of Hcl. After washing the acidic solution with 225 ml of ethyl acetate, it is alkalinized with sodium carbonate in powder form. After repeated extraction with 250 ml of ethyl acetate, the organic solution is dried over sodium sulfate, filtered, and the solvent is evaporated in vacuum. The residue is purified by chromatography on silica gel (elwira with a mixture of dichloromethane/methanol: 98/2). Pure fractions are collected and after evaporation of the solvent under reduced pressure to obtain 0.39 g of pale yellow powder with a yield of 46%. Melting point: 119-120oC.

NMR1H (100 MHz, CDCl3, ): 8,32 (s, 1H, indole); 7,27-to 6.80 (m, 4H, indole); 6,69 (m, 4H, Ph-NH2); is 3.82 (s, 3H, och3); of 3.80 (s, 2H, CH2-CO); of 3.80 (s, 2H, piperazine); 3,62 (m, 2H, piperazine); of 3.48 (s, 2H, NH2); 2,90 (m, 4H, piperazine).

14.3) -N-{ 4-[4-[(5 methoxy-1H-indol-3-yl)methylcarbamoyl]-1-piperazinil] phenyl}-2-thiophenecarboxylate: 14

Work the same as if the,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. The target product is isolated in the form of the free base with a yield of 20% (pale yellow powder). Melting point: 221-222oC.

NMR1H (400 MHz, DMSO-d6, ): 10,78 (s, 1H, NH indole); 7,72 (m, 1H, thiophene); to 7.59 (m, 1H, thiophene); 7,22 (d, 1H, indole, J=8.7 Hz); 7,19 (m, 1H, thiophene); to 7.09 (m, 2H, indole); PC 6.82 (m, 4H, Ph); 6,72 (m, 1H, indole); 6,35 (s, 2H, NH2); of 3.80 (s, 2H, CH2); 3,62 (m, 4H, piperazine), 2,95 (m, 4H, piperazine).

IR:OH: 3414 cm-1;C=O(amide): 1628 cm-1;C=N(amidon): 1590 cm-1.

Example 15: fumarate-N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-1-piperazinil]phenyl]]-2-thiophenecarboxaldehyde: 15

15.1) 2,6-bis(1,1-dimethylethyl)-4-{3-[4-(4-nitrophenyl)-1-piperazinil]-3-oxo-2-propenyl}-phenol:

Work the same as when obtaining an intermediate compound of 11.1, and using 3,5-di-tert-butyl-hydroxy-cinnamic acid instead of purple acid. Get the oil yield 60%.

NMR1H (100 MHz, CDCl3, ): 7,71 (d, 1H, C=CH, J=15,0 Hz); 7,51 (m, 4H, Ph-NR2); 7,38 (s, 2H, Ph); 6,69 (d, 1H, HC=C, J=15,0 Hz); of 5.50 (s, 1H, HE); 3,88 (m, 4H, piperazine); of 3.53 (m, 4H, piperazine); 1,47 (s, N, 2tBu).

15.2) 2,6-bis(1,1-dimethylethyl)-4-{3-[4-(4-AMINOPHENYL)-1-piperazinil]-3-oxo-2-propenyl}-phenol:

In the flask with a capacity of 50 ml, sleep, acid and 5 ml of absolute ethyl alcohol. Cool the mixture to 0oAnd add a couple of servings 1,69 g (7.5 mmol) digidratirovannogo chloride of tin. At the end of the addition the reaction medium is heated under reflux for 30 minutes. Then evaporate the solvent in vacuo, the residue is treated with 15 ml of water, neutralize 2N potassium sodium and diluted with 20 ml dichloromethane. The precipitate is filtered on celite and the filtrate is decanted. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 0.3 g (67%) of a yellow oil.

NMR1H (100 MHz, CDCl3, ): 7,66 (d, 1H, C=CH, J=15,0 Hz); 7,37 (s, 2H, Ph); to 6.75 (m, 4H, Ph-NH2); 6,30 (D, 1H, HC=C, J=15,0 Hz); 5,46 (s, 1H, HE); of 3.80 (m, 4H, piperazine); a 3.06 (m, 4H, piperazine); of 1.46 (s, N, 2tBu).

15.3) fumarate-N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl] -1-oxo-2-propenyl}-1-piperazinil]phenyl]]-2 - thiophenecarboxaldehyde: 15

Work the same as when the connection is 1, and the use of 2,6-bis(1,1-dimethylethyl)-4-{ 3-[4-(4-AMINOPHENYL)-1-piperazinil] -3-oxo-2-propenyl} -phenol instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide.

The reaction product is transformed into a salt in the presence of equimolar amount of fumaric acid in ethanol with reverse, chilling the x2">

NMR1H (400 MHz, DMSO-d6, ): to 7.77 (s, 1H, thiophene); to 7.67 (d, 1H, thiophene, J=5.0 Hz); of 7.48 (d, 1H, C=CH, J=15,0 Hz); 7,39 (s, 2H, Ph); 7,34 (broad, 1H, OH); 7,13 (t, 1H, thiophene, J=4.0 Hz); 7,05 (d, 1 H, HC=C, J=15,0 Hz); 6,92 (m, 4H, Ph-N); 6,60 (s, 2H, CH=CH fumarate); of 3.78 (m, 4H, piperazine); of 3.13 (m, 4H, piperazine); of 1.41 (s, N, 2tBu).

IR:OH: 3619 cm-1, 3300 cm-1;C=O(amide): 1640 cm-1;C=C1600 cm-1;C=N(amidon): 1570 cm-1.

Example 16: hydrochloride 3,5-bis-(1,1-dimethylethyl) -4-hydroxy-N- { 3- [[(2-thienyl-imino)methyl) amino]phenyl]methyl}-benzamide: 16

16.1) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N- [(3-nitrophenyl) methyl]-benzamide:

Work the same as with the intermediate connection of 2.1, and use of the hydrochloride of 3-nitrobenzylamine hydrochloride instead of 4-nitrobenzylamine. Get white powder with a yield of 63%. Melting point: 210-211oC.

NMR1H (100 MHz, DMSO-d6, ): 9,12 (m, 1H, NH); of 8.25 (m, 2H, Ph-NO2); 7,80 (m, 4H, ); 7,60 (broad, 1H, OH); and 4.68 (d, 2H, CH2, J=6 Hz); of 1.55 (s, N, 2tBu).

16.2) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N- [(3-AMINOPHENYL) methyl]-benzamide:

In the vessel Parra capacity of 250 ml dissolve 2,40 g (6.2 mmol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide in 45 ml of a mixture absolutnogo 20 PSI, when 30oWith over three hours. After filtering celite the filtrate is concentrated to dryness and the residue is purified by chromatography on silica gel (elwira mixture: heptane/ethyl acetate; 60/40). Pure fractions are collected and concentrated under reduced pressure to obtain 0,94 g (45%) of white powder. Melting point: 171-172oC.

NMR1H (100 MHz, CDCl3, ): 7,20 (m, 2H, Ph-NH2); 6,70 (m, 4H, ); 6,34 (m, 1H, NH); of 5.55 (s, 1H, HE); 4,56 (d, 2H, CH2, J=6 Hz); 3,70 (broad, 2H, NH2); for 1.49 (s, N, 2tBu).

16.3) hydrochloride 3,5-bis-(1,1-dimethylethyl)-4-hydroxy - N-{3-[[(2-thienyl-(imino)methyl)amino]phenyl]methyl}-benzamide: 16

Work the same as when the connection is 1, and using 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-amino-phenyl)methyl] -benzamide instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. After transformation into a salt with a molar solution of Hcl in a mixture of acetone/anhydrous methanol, get pale yellow powder with a yield of 50%. Melting point: 226-227 of theoC.

NMR1H (400 MHz, DMSO-d6, ): 11,71 (s, 1H, NH+); to 9.93 (s, 1H, NH+); 9,10 (s, 1H, CONH); 9,00 (s, 1H, NH+); 8,18 (m, 2H, thiophene); of 7.70 (s, 2H, Ph); 7,42 (m, 6N, thiophene, Ph-NH, OH); 4,50 (d, 2H, CH2-NHCO, J=5.4 Hz); of 1.40 (s, N, 2tBu).

IR:OH-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N'-{ {4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea: 17

17.1) 4-amino-2,6-bis(1,1-dimethylethyl)-phenol:

In the vessel Parra capacity of 250 ml dissolve 3.6 g (14 mmol) of 4-nitro-2,6-bis(1,1-dimethylethyl)-phenol (J. Org.Chem. (1968), 33 (1), 223-226) in 60 ml of a mixture (2/1) of ethanol and dichloromethane in the presence of catalytic amount of 10% Pd/C. the Mixture is stirred for 2 hours at 20oC under hydrogen pressure of 20 PSI. After filtering celite the filtrate is concentrated to dryness under reduced pressure. The obtained gray powder suspended in heptane (30 ml), filtered and washed with the same volume of heptane. The expected product is obtained in the form of a powder Orangevale pink color with the release of 50% (1/56 g).

Melting point: 123-124oC.

NMR 1H (100 MHz, CDCl3, ): 6,60 (s, 2H, Ph); the 4.65 (broad, 1H, OH); 3,15 (broad, 2H, NH2); to 1.42 (s, N, 2tBu).

17.2) chloride 4-nitrophenylarsonic acid:

In a solution of 0.9 g (5 mmol) 4-nitrophenylarsonic acid in a mixture consisting of 10 ml of dichloromethane and 0.5 ml of DMF, added at 20oWith 3.75 ml (7.5 mmol) of a 2M solution of oxalicacid in dichloromethane. After 30 minutes of stirring the solution was concentrated in vacuo. The obtained yellow oil used without further purification in the next step.

17.3) 4-nitrobenzylidene:

To aq is ssnoi acid, dissolved in dry acetone (7.5 ml). The mixing environment is maintained for one hour after adding 0-5oC. Then the reaction mixture is diluted with 30 ml of chloroform, decanted, and the organic phase washed with water (20 ml) and then saturated sodium chloride solution (20 ml). After drying over sodium sulfate the organic solution is filtered and concentrated partially (20 ml) in vacuo. This solution utilised in chloroform is heated under reflux for one hour. The resulting isocyanate is used directly in the solution in the next step.

17.4) -N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -N'-[(4-nitrophenyl)methyl]-urea:

To a solution of isocyanate (intermediate compound 17.3) (theoretical 5 mmol) in 20 ml of chloroform added at one time 1.1 g (5 mmol) 4-amino-2,6-bis(1,1-dimethylethyl)-phenol. After 2 hours stirring at 20oWith the appearance of the precipitate is filtered and washed with chloroform (220 ml). Receives a yellow powder with a yield of 73%. Melting point: 240-241oC.

NMR1H (100 MHz, DMSO-d6, ): at 8.60 (s, 1H ); 8,01 (m, 4H, Ph-NR2); 7,30 (s, 2H, ); 6,77 (m, 1H ); of 6.71 (s, 1H, HE); to 4.52 (d, 2H, CH2, J=5.5 Hz); for 1.49 (s, N, 2tBu).

17.5) N-[(4-nitrophenyl)methyl] -N'-[3, the IP-(1,1-dimethylethyl)-4-hydroxyphenyl]-N'-[(4-nitrophenyl)methyl]-urea mixture (2/1) ethanol and ethyl acetate, in the presence of 10% Pd/C. After 1 hour and 30 minutes hydrogenation at 20oWith under a hydrogen pressure of 20 PSI, the mixture is filtered on celite and concentrate the filtrate in vacuo. The evaporation residue is dissolved in 20 ml of diethyl ether and the expected product spontaneously crystallizes. The crystals are filtered and washed with 20 ml of diethyl ether. Get white powder with a yield of 60% (0.31 g). Melting point: 194-195oC.

NMR1H (100 MHz, CDCl3, ): was 7.08 (s, 2H, Ph-OH); 6.87 in (m, 4H, ); 6.15 (s, 1H ); 5,14 (s, 1H, HE); 4,89 (m, 1H, NH-CH2); to 4.41 (d, 2H, CH2, J=5.5 Hz); the 3.65 (broad, 2H, -NH2); for 1.49 (s, N, 2tBu).

17.6) of the hydrochloride of N-[3,5-bis(1,1-dimethylethyl)-4 - hydroxyphenyl]-N'-{{ 4-[(2-thienyl(imino)methyl)amino) phenyl}methyl}-urea: 17

Work the same as when the connection 1 and using N-[(4-AMINOPHENYL)methyl] -N'-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -urea instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. After salt formation with a molar solution of Hcl in anhydrous diethyl ether to obtain a white powder with a yield of 45%. Melting point: 236-237oC.

NMR1H (400 MHz, DMSO-d6, ): 11,42 (broad, 1H, NH<19 (, 2H, Ph); 6,70 (m, 1H ); 6,60 (s, 1H, HE); of 4.35 (d, 2H, CH2, J=5.5 Hz); of 1.34 (s, N, 2tBu).

IR:OH: 3624 cm-1; C=O(urea): 1644 cm-1;C=N(amidon): 1569 cm-1.

Example 18: N hydrochloride-[5-[{3-(3,5-bis-(1,1-dimethylethyl) -4-hydroxyphenyl)-1-oxo-2-propenyl} amino] -2-hydroxyphenyl] -2 - thiophenecarboxaldehyde: 18

18.1) 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-N-(4-hydroxy-3-nitrophenyl)-2-propenamide:

In a flask with a capacity of 50 ml containing 10 ml of THF, enter 1.78 g (6.4 mmol) of 3,5-di-tert-butyl-4-hydroxyanisol acid, 0,99 g (6.4 mmol) of 4-amino-2-NITROPHENOL, pre-dissolved in 10 ml of DMF, 0,86 g (6.4 mmol) of hydroxybenzotriazole and of 1.32 g (6.4 mmol) of dicyclohexylcarbodiimide. The reaction mixture is stirred for 15 hours at room temperature, the obtained residue was filtered and washed with ethyl acetate. After concentration under reduced pressure, the residue is dissolved in 20 ml of ethyl acetate and the insoluble substance is again filtered. The filtrate is washed with 20 ml saturated sodium carbonate solution. After drying over sodium sulfate the organic solution is filtered and concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel (eluant: heptane/ethylacetate-orange powder. Melting point: 231-232oC.

NMR1H (100 MHz, CDCl3, ): 10,45 (s, 1H, NH); to 8.45 (d, 1H, Ph-NO2, J=l, 7 Hz ); 7,98 (DD, 1H, Ph-NO2, J=1.7 Hz and J=6.8 Hz); for 7.78 (d, 1H, -CH=CH-, J= 10.5 Hz); of 7.75 (s, 1H, HE); 7,40 (s, 2H, ); then 7.20 (d, 1H, Ph-NO2); 6.48 in (d, 1H, -CH=CH-); the 5.51 (s, 1H, HE); 1,50 (s, N, 2tBu).

18.2) 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)]-N-(4-hydroxy-3-AMINOPHENYL)-2-propenamide:

In a vessel with a capacity of 100 ml with fridge dissolve 0.9 g (2.18 mmol) of 3-[(3,5-bis-(1,1 dimethylethyl)-hydroxy-phenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide in 20 ml of ethyl acetate, add 2,46 g (10.9 mmol) of tin chloride (dihydrate), and the mixture is heated at 70oC for 3 hours. After returning to room temperature, the reaction medium is then poured into stirred solution of sodium bicarbonate (0.1 M), a precipitate, which is removed by filtration on celite. The filtrate is decanted and the aqueous phase is extracted with 20 ml ethyl acetate. The organic phases are grouped together and washed with 20 ml of water, then 20 ml of a saturated solution of sodium chloride. After drying over sodium sulfate and filtration, the organic solution concentrated to dryness in a partial vacuum. The evaporation residue is suspended in a mixture of heptane/ethyl acetate (1/1) and filtered to obtain yellow is 3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboxaldehyde: 18

Work the same as when the connection 1 and using 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)] -N-(4-hydroxy-3-AMINOPHENYL)-2-propenamide instead of 3,5-bis(1,1-dimethylethyl) -4-hydroxy-N-(4-AMINOPHENYL)-benzamide. The free base is purified by chromatography on silica gel (elwira mixture: heptane/ethyl acetate: 35/65). Pure fractions are collected and concentrated under reduced pressure. The evaporation residue is dissolved in 10 ml of acetone and converted into salt in a molar solution of Hcl in anhydrous ether, as described above. Get the final product weighing 0.35 g of a yellow powder with a yield of 62%. Melting point 199-200oC.

NMR1H (400 MHz, DMSO-d6, ): of 11.11 (s, 1H, NH+); 10,29 (s, 1H, NH+); 10,17 (c, 1H, NH+); 9,71 (c, 1H, CONH); 8,61 (broad, 1H, HE), 8,14 (m, 2H, thiophene); 7,79 (s, 1H, Ph-N); 7,53 (m, 1H, Ph-N); of 7.48 (d, 1H, -CH=CH-, J= 14,7 Hz); 7,37 (m, 4H, Ph-tBu+N, Ph-N); 7,05 (m, 1H, thiophene); of 6.68 (d, 1H,-CH=CH-); of 1.41 (s, N, 2tBu).

IR:OH: 3624 cm-1, 3415 cm-1; C=O(amide): 1656 cm-1;C=C: 1616 cm-1;C=N(amidon): 1587 cm-1.

Example 19: N hydrochloride-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl)amino]-4-hydroxyphenyl]-2-thiophenecarboxaldehyde: 19

19.1) 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)]-N-(2-g is eaten using 2-amino-4-NITROPHENOL instead of 4-amino-2-NITROPHENOL. Get a light-yellow powder with a yield of 25%. Melting point: 256-257oC.

NMR1H (400 MHz, DMSO, ): to 11.79 (broad, 1H, OH); 9,59 (s, 1H, NH); of 9.21 ( broad, 1H, Ph-NO2); of 7.90 (DD mA rsolu), 1H, Ph-NO2); CONH); 8,61 (broad, 1H, OH); to 8.14 (m, 2H, thiophene); 7,79 (s, 1H, Ph-N; J=8,l Hz); 7,52 (d, 1H, -CH=CH-, J==15,5 Hz); 7,47 (s, 1H, HE); 7,42 (s, 2H, Ph-NO2); to 7.15 (d, 1H, -CH=CH -);? 7.04 baby mortality (d, 1H, Ph-NO2); to 1.42 (s, N, 2tBu).

19.2) 3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)] -N-(2-hydroxy-5-AMINOPHENYL)-2-propenamide:

Work the same as when receiving the intermediate 18,2, and using 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)]-N-(2-hydroxy-5-nitrophenyl)-2-propenamide instead of 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)] -N-(4-hydroxy-2-nitrophenyl)-2-propenamide. Receives a yellow powder with a yield of 74%. The product is used without further purification in the next step.

19.3) hydrochloride N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-4-hydroxyphenyl]-2-thiophenecarboxaldehyde: 19

Work the same as when the connection 1 and using 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)] -N-(2-hydroxy-5-AMINOPHENYL)-2-propenamide instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)benzamide. After the formation of satura melting point: 256-257oC.

NMR1H (400 MHz, DMSO-d6, ): made 11.32 (s, 1H, NH+); 10,67 (s, NH+); RS 9.69 (s, 1H, NH+); of 9.55 (s, 1H, CONH); to 8.70 (broad, 1H, OH); 8,19 (m, 2H, thiophene); of 7.48 (d, 1H, -CH=CH-, J=15,5 Hz); 7,40 (s, 2H, Ph-tBu); 7,37 (m, 2H, Ph-N); 7,34 (s, 1H, HE); 7,13 (d, 1H, -CH=CH-); 7,10 (m, 1H, Ph-N); 6,99 (m, 1H, thiophene); of 1.41 (s, N, 2tBu).

IR:OH: 3623 cm-1, 3410 cm-1;C=O(amide): 1652 cm-1;C=C1616 cm-1;C=N(amidon): 1587 cm-1.

Example 20: N hydrochloride-{4-[4-[3,4,5-trihydroxybenzoic)-1-piperazinil] phenyl}-2-thiophenecarboxylate: 20

20.1) 5-{[4-(4-nitrophenyl)-1-piperazinil]carbonyl]-Benzen-1,2,3-triol:

Work the same as when receiving the intermediate 8.1, and using 1-(4-nitrophenyl)piperazine instead of 4-nitrophenylamino. Receives a yellow powder, which contains even traces of impurities with the release of 43%.

NMR1H (100 MHz, DMSO, ): 9,17 (broad, 2H, 2 OH); 8,55 (broad, 1H, -OH); EUR 7.57 (m, 4H, Ph-NO2); 6,40 (s, 2H, ); 3,59 (m mal resolu, 8H, piperazine).

20.2) 5-{[4-(4-AMINOPHENYL)-1-piperazinil]carbonyl]-Benzen-1,2,3-triol:

Work the same as when receiving the intermediate 2.2, and using 5-{ [4-(4-nitrophenyl)-1-piperazinil]carbonyl]-Benzen-1,2,3-triol instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[(4-neki in the next step.

NMR1H (100 MHz, DMSO, ): 9,12 (broad, 2H, 2 OH); 8,55 (broad, 1H, -OH); is 6.61 (m, 4H, Ph-NH2); 6,34 (s, 2H, ); 3,59 (m, 4H, piperazine); 2,89 (m, 4H, piperazine).

20.3) hydrochloride N-{4-[4-[3,4,5-trihydroxybenzoic]-1-piperazinil)phenyl} -2-thiophenecarboxaldehyde: 20

Work the same as when the connection 1 and using 5-{ [4-(4-AMINOPHENYL)-1-piperazinil] carbonyl]-Benzen-1,2,3-triol instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)benzamide. After processing molar solution of Hcl in anhydrous diethyl ether, get a dark brown powder with a yield of 25%. Melting point: 198-205oC.

NMR1H (400 MHz, DMSO-d6, ): 11,38 (s, 1H, NH+); of 9.75 (s, 1H, NH+); 9,00 (broad, 1H, OH); is 8.75 (s, 1H, NH+); 8,15 (m, 2H, thiophene); 7,39 (m, 1H, thiophene); 7,22 (m, 4H, ); 6,40 (s, 2H, Ph); 5,11 (broad, 2H, hon); the 3.65 (m, 4H, piperazine); 3,29 (m, 4H, piperazine).

IR:OH: 3399 cm-1;C=O(amide): 1696 cm-1;C=N(amidon): 1588 cm-1.

Example 21: hydrochloride of N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-N'{{ 4-[(2-thienyl(imino)methyl)amino]phenyl} carbylamine}-urea: 21

21.1) N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-N'-[{ 4-nitrophenyl)carbylamine]-urea:

In a three-neck flask with a capacity of 50 ml, the mass add drop by drop in the course of one hour a solution of 0.44 g (2 mmole) of 4-amino-2,6-bis(1,1-dimethylethyl)-phenol (intermediate compound 17.1) and 0.38 ml (2.2 mmole) of diisopropylethylamine in 7 ml of anhydrous dichloromethane. Five minutes after you add at one time add a solution of 0.36 g (2 mmole) 4-nitrobenzoyl and 0.38 ml (2.2 mmole) of diisopropylethylamine in 4 ml of anhydrous DMF. After 4 hours stirring at 20oWith the reaction mixture is concentrated to dryness under reduced pressure. The evaporation residue is dissolved in 40 ml of ethyl acetate and the organic solution washed successively 3 times with 20 ml of water and 20 ml of saturated solution of sodium chloride. After drying over sodium sulfate the organic solution is filtered and the filtrate is concentrated to dryness under reduced pressure. The resulting residue is suspended in heptane, stirred and filtered to obtain a yellow powder with a yield of 86%. Melting point: 163-164oC.

NMR1H (100 MHz, DMSO-d6, ): 10,65 (broad, 1H, NH amide); 8,72 (s, 1H ); scored 8.38 (m, 4H, Ph-NO2); to 8.20 (s, 1H ); of 7.36 (s, 2H, ); is 6.78 (s, 1H, CH); 1,50 (s, N, 2tBu).

21.2) N-[(4-AMINOPHENYL)carbylamine)-N'-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-urea:

In a Parr flask with a capacity of 250 ml dissolve 0,72 g (1.68 mmol) of N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-N'-[(4-nitrophenyl) carbylamine] -urea in 30 ml of absolute ethanol in the presence of 10% Pd/C. the Mixture is stirred under hydrogen pressure of 20 PSI PR is of suspended in diethyl ether (20 ml), stirred and filtered to obtain a pale yellow powder with a yield of 75%. Melting point: 245-246oC.

NMR1H (100 MHz, DMSO-d6, ): 9,84 (broad, 1H, NH amide); 8,56 (s, 1H, ); a 7.85 (m, 2H, ); 7,74 (s, 1H, ); 7,38 (s, 2H, ); is 6.78 (s, 1H, HE); 6,60 (m, 2H, ); 5,80 (broad, 2H, NH2); 1,50 (s, N, 2tBu).

21.3) of the hydrochloride of N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-N'-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbylamine}-urea: 21

Work the same as when the connection 1 and using N-[(4-AMINOPHENYL)carbylamine]-N'-[3,5-,b-(1,1-dimethylethyl)-4-hydroxyphenyl] -urea instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. The free base is purified by chromatography on silica gel (elwira mixture: heptane/ethyl acetate: 1/1). Pure fractions are collected and concentrated under reduced pressure. The evaporation residue is dissolved in 15 ml of acetone and converted into the salt with a molar solution of Hcl in anhydrous ether, as described above. Obtain 0.40 g (58%) of yellow powder. Melting point: 254-255oC.

NMR1H (400 MHz, DMSO, ): 1,68 (broad, 1H, NH+); 10,32 (s, 1H, NH amide); 9,94 (broad, 1H, NH+); 9,13 (broad, 1H, NH+); 9,13 (broad, 1H, NH+); 8,68 (s, 1H, NH-CO); 8,18 (m, 2H, thiophene); 8,07 (m, 3H, ); 7,5 (amide),C=O(urea): 1654 cm-1; 1602 cm-1;C=N(amidon): 1559 cm-1.

Example 22: the hydrochloride of N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-N'-{ (4-[(2-thienyl(imino)methyl)amino]phenyl)methyl}-thiourea: 22

22.1) N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-N'-{ { 4-nitrophenyl)methyl]-thiourea:

Connection 22.1 treated with Lawesson reagent intermediate 17.4 in accordance with the method described in the literature (J. Med. Chem. (1995), 38 (18), 3558-3565). Get a light-yellow powder with a yield of 80%. Melting point: 218-220oC.

NMR1H (100 MHz, CDCl3, ); a 7.85 (m, 4H, Ph-NO2); of 7.70 (s, 1H ); 7,05 (s, 2H, Ph-OH); 6,21 (m, 1H, NH-CH2); to 5.40 (s, 1H, HE); 5,00 (d, 2H, CH2, J=6.5 Hz); of 1.41 (s, N, 2tBu).

22.2) N-[(4-AMINOPHENYL)methyl] -N'-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-thiourea:

Work the same as when receiving the intermediate 18.2, and use intermediate connection 22.1 instead of 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-N-(4-hydroxy-3-nitrophenyl)-2-propenamide. Get white powder with a yield of 70%. Melting point: 167-169oC.

NMR1H (100 MHz, CDCl3, ): of 7.48 (broad, 1H ); to 6.95 (s, 2H, ); for 6.81 (m, 4H, ); 5,98 (m, 1H ); 5,28 (s, 1H, HE); 4,69 (d, 2H, CH2, J=5.5 Hz); 3,62 (with a wide,Ino)methyl)amino]phenyl}methyl}-thiourea: 22

Work the same as when receiving the intermediate 17,6, and use intermediate connection 22.2 instead of N-[(4-AMINOPHENYL) methyl] -N'-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -urea. Get a pale yellow powder with a yield of 15%. Melting point: 203-205oC.

NMR1H (400 MHz, DMSO-d6, ): to 11.52 (broad, 1H, NH+); 9,86 (broad, 1H, NH+); 8,98 (broad, 1H, NH+); 8,39 (s, 1H ); 8,16 (m, 2H, thiophene); 7,46 (m, 6N, thiophene, ); to 7.18 (s, 2H, Ph); 6,92 (s, 1H, HE); 4,80 (broad, 2H, CH2); to 1.35 (s, N, 2tBu).

IR:OH: 3630 cm-1;C=O(urea): 1649 cm-1;C=N(amidon): 1600 cm-1.

Example 23: hydrochloride of N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-N'-{ 2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-urea: 23

23.1) N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-N'-[2-(4-nitrophenyl)ethyl]-urea:

Work the same as when receiving the intermediate 21.1, and use 4-nitrophenylamino instead of 4-nitrobenzoyl-hydrazide. Get a beige powder with a yield of 80%. Melting point: 185-187oC.

NMR1H (100 MHz, CDCl3, ): to 7.75 (m, 4H, Ph-NO2); 7,00 (s, 2H, Ph-OH); 6,05 (s, 1H, HE); by 5.18 (s, 1H, NH); and 4.68 (m, 1H ); 3,50 (m, 2H, NH-CH2); 2,92 (m, 2H, CH2); of 1.40 (s, N, 2tBu).

oC.

NMR1H (100 MHz, DMSO-d6, ): of 8.25 (broad, 1H, Ph-NH-CO); 7,22 (s, 2H, ); 6,79 (m, 4H, ); of 6.65 (s, 1H, HE); of 5.92 (m, 1H ); to 4.98 (broad, 2H, -NH2); and 3.31 (m, 2H, ); to 2.65 (m, 2H, CH2); to 1.48 (s, N, 2tBu).

23.3) of the hydrochloride of N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-N'-{2-{ 4-[(2-thienyl (imino)methyl)AMINOPHENYL}ethyl}-urea: 23

Work the same as when the connection is 1, and use intermediate connection of 23.2 instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. The free base is purified by chromatography on silica gel (elwira mixture: heptane/ethyl acetate: 1/1). Pure fractions are collected and concentrated under reduced pressure. The evaporation residue is dissolved in 15 ml of acetone and converted into the salt with a molar solution of Hcl in anhydrous ether, as described above. Obtain 0.25 g (24%) of pale yellow powder. Melting point: 207-210oC.

NMR1H (400 MHz, DMSO-d6, ): 11,48 (broad, 1H, NH+); 9,83 (broad, 1H, NH+); 8,95 (broad, 1H, NH+); and 8.50 (s, 1H, NH-CO); 8,18 (m, 2 the ptx2">

IR:OH: 3631 cm-1;C=O(urea): 1654 cm-1; 1600 cm-1;C=N(amidon): 1560 cm-1.

Example 24: N hydrochloride-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl] -1-piperazinil]phenyl) -2-thiophenecarboxaldehyde: 24

24.1) 1-{ [3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-4-(4-nitrophenyl) piperazine:

Work the same as when receiving the intermediate 13.1, pricedisplay()-3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-carboxylic acid (obtained according CHIMIA(1991), 45 (4), 121-3) instead of ()-Trolox. Receives a yellow powder.

NMR1H (100 MHz, CDCl3, ): was 7.45 (m, 4H, Ph); of 3.60 (s, 3, CH3O); 3,40 (m, 4H, piperazine); 3,00 (m, 4H, piperazine); 2,50-to 1.60 (m, N, Trolox).

24.2) 1-{ [3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-4-(4-AMINOPHENYL)piperazine:

Work the same as when receiving the intermediate 13,2, and use intermediate connection 24.1 instead of 3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-nitrophenyl)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol. Receive the oil which is used directly in the next step.

NMR1H (100 MHz, CDCl3, ):1,60 (m, N, Trolox).

24.3) hydrochloride N-(4-{ 4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl] -1-piperazinil] phenyl)-2-thiophenecarboxaldehyde: 24

Work the same as when the connection 13, and use intermediate connection 24.2 instead of 3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-AMINOPHENYL)-1-piperazinil] -carbonyl} -2H-1-benzopyran-6-ol. Get a pale yellow powder. Melting point: 190-195oC.

NMR1H (400 MHz, DMSO, ): 11,35 (broad, 1H, NH+); to 9.70 (broad, 1H, NH+); to 8.70 (broad, 1H, NH+); 8,15 (broad, 2H, thiophene); to 7.35 (broad, 1H, thiophene); 7,17 (m, 4H, Ph); 3,90 (d broad, 4H, piperazine); 3,50 (s, 3H, CH3O) a 3.15 (m, 4H, piperazine); 2,55-of 1.55 (m, N, Trolox).

IR:C=O(amide): 1642 cm-1;C=N(amidon): 1618 cm-1.

Example 25: N hydrochloride-(4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboxaldehyde: 25

25.1) hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepin:

To a solution of 2.44 g (12.2 mmol) of hexahydro-lH-l,4-diazepin-1-carboxylate (1,1-dimethyl)ethyl in 50 ml of DMF add 3,37 g (24.4 mmol) of potassium carbonate and 1.89 g (13.4 mmol) of 4-nitrofluoranthene. The reaction mixture is heated p is decanted, and the aqueous phase is extracted with 350 ml of ethyl acetate. The organic phases are combined and washed with 50 ml of brine, dried over sodium sulfate, filtered and concentrated in vacuo. Obtain 3.7 g of a solid substance bright yellow with access 95%. This solid is dissolved in 100 ml of solvent mixture (dichloromethane/ethyl acetate 1:1), to which is added drop by drop, at 0oWith 20 ml of an aqueous solution (6N) hydrochloric acid. After strong stirring at 20oC for 1 hour, the reaction mixture is decanted. The aqueous phase is alkalinized to pH 11 using 4N alkali sodium and extracted with 350 ml of dichloromethane. The combined organic phases are washed with 50 ml water, then 50 ml of brine, dried over sodium sulfate and, finally, filtered and concentrated in vacuo. Obtain 1.78 g of a bright yellow powder with a yield of 66%. The product is used directly in the next step without additional purification.

NMR1H (100 MHz, Dl3, ): 8,10 (m, 2H, PH); of 6.65 (m, 2H, Ph); 3,70 (kV, 4H, CH2N, J=5,2 Hz); 3,10 (t, 2H, CH2N); to 2.85 (t, 2H, CH2N); 1,95 (kV, 2H, C-CH2-C); 1,65 (broad, 1H, NH).

25.2) 1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepin

Into the flask emkostnoe THF. After stirring for 1 hour at 20oTo add drop by drop a solution of 0.95 g (4.3 mmol) of the intermediate 25.1 in 4 ml of DMF. The reaction mixture is stirred for 16 hours at 20oC. After evaporation of the solvents in vacuo the residue is treated with 30 ml of a solvent mixture (dichloromethane/water 1:2). After decanting, the organic phase is washed with 2x20 ml of water, dried over sodium sulfate and concentrated in vacuo. Get a pale yellow powder with a yield of crude product is 97%. The product is used directly in the next step without further purification.

NMR1H (100 MHz, CDCl3, ): 8,10 (m, 2H, Ph); 6,60 (m, 2H, PH); however, 4.40 (broad, 1H, OH); 3,50 (m, 8H, CH2N); 2,50-1,50 (m, N, Trolox+ CH2).

25.3) 1-(4-AMINOPHENYL)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]hexahydro-1H-1,4-diazepin

Work the same as when receiving the intermediate 13,2, and use intermediate connection 25.2 instead of 3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-nitrophenyl)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol. The resulting product was then purified by chromatography on silica gel (elwira mixture ethylacetophenone ether 3:2). Get the oil yield 57%.

25.4) hlog carboxamidine: 25

A mixture of 0.52 g (1,22 mmole) of intermediate compound 25.3 and 0.35 g (1,22 mmole) of oggidata S-methyl-2-thiophene-dicarboximide in 4 ml of isopropanol is heated under 50oWith over 40 hours. The reaction mixture was then filtered and the resulting solid is treated with 4 ml of a saturated aqueous solution of sodium carbonate and 4 ml of ethyl acetate. The resulting mixture is heated at 50oC for 30 minutes, then decanted. The organic phase is washed with 2x10 ml of water, then 10 ml of brine. The combined organic phases, dried on sodium sulfate, filtered and concentrated under reduced pressure. The obtained solid is purified by chromatography on silica gel (elwira mixture:ethyl acetate/petroleum ether 5:1). Obtain 0.5 g of product with a yield of 77%. 0.15 g (0,29 mmole) of the product is then dissolved in 2 ml of acetone. Add drop by drop from 0.84 ml (from 0.84 mmole) lN hydrochloric acid solution in anhydrous ethyl ether. The contents stirred at room temperature for 30 minutes. Formed yellow precipitate, which is filtered. The precipitate triturated and washed sequentially with 35 ml of ethyl ether and 5 ml of acetone. Dark yellow powder is dried in vacuum at 70oWith in 48 hours. Receive product with a yield of 80%. Melting point: 180-185+); 8,10 (broad, 2H, thiophene); to 7.35 (broad, 1H, thiophene); 7,02 (m, 4H, Ph); 4,80 (broad, 1H, OH); 3,70 (m, 8H, CH2N); 2,50-of 1.40 (m, N, Trolox+ CH2).

IR:OH: 3412 cm-1;C=O(amide): 1613 cm-1;C=N(amidon): 1613 cm-1.

Example 26: hydrochloride (R) N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxaldehyde: 26

< / BR>
26.1) (R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4- [(4-nitrophenyl)-1-piperazinil]-carbonyl} -2H-1-benzopyran-6-ol:

Work the same as when the connection is 13.1, and using (R)-Troloxinstead of ()-Trolox. Get a bright yellow powder with a yield of 98%. Melting point: 102-105oC.

26.2) (R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-AMINOPHENYL) -1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol:

Work the same as when receiving the intermediate 2,2, and use intermediate connection 26.1 instead of 3,5-bis (1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl) methyl]-benzamide. Get a pink powder with a yield of 75%. The product is used as such in the next step. Melting point: 103-105oC.

26.3) hydrochloride (R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-funeral connection 13, using an intermediate connection 26.2 instead of 3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-AMINOPHENYL)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol. The product is obtained in the form of a pale yellow powder, which is hydrated in the air. Melting point: 195-197oC.

Analyses by NMR and IR identical analyses for compounds 13.

[]20D= -43,5(C=0,11; DMSO)

Example 27: dichlorhydrate (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl] -1-piperazinil]phenyl}-2-thiophenecarboxaldehyde: 27

< / BR>
27.1 (S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-nitrophenyl)-1-piperazinil]-carbonyl}-2H-1-benzopyran-6-ol:

Work the same as when the connection 13,1, using (S)-Troloxinstead of ()-Trolox. Receives a yellow powder with a yield of 73%. Melting point: 110-111oC.

27.2) (S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-AMINOPHENYL)-1-piperazinil]-carbonyl}-2H-1-benzopyran-6-ol:

Work the same as when receiving the intermediate 2,2, while use intermediate connection 27.1 instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl] -benzamide. After purification by chromatography on silica gel (elwira mixture: heptane/ethyl acetate: which means: 109-111oC.

27.3) dichlorhydrate (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl] -1-piperazinil]phenyl}-2-thiophenecarboxaldehyde: 27

Work the same as when the connection 13, with use intermediate connection 27.2 instead of 3,4-dihydro-2,5,7, 8-tetramethyl-2-{4-[(4-AMINOPHENYL)-1-piperazinil]-carbonyl}-2H-1-benzopyran-6-ol. The product is obtained in the form of a pale yellow powder, which is hydrated in the air. Melting point: 210,6-211,8oC.

Analyses by NMR and IR identical analyses for compounds 13.

[]20D= -43,5(C=0,11; DMSO)

Alternatively, the connection 27 can be obtained according to the following Protocol:

27.4) 2-thiophene methylcarbamate:

In a conical flask with a capacity of 250 ml, purged with argon, is injected 10,91 g (0.1 mole) of 2-thiophenecarbonitrile, 100 ml of anhydrous ethyl ether and 4.5 ml of 0.11 mol) of methanol. The solution is cooled to 0oWith using an ice bath, and saturated with anhydrous Hcl gas stream within 45 minutes. The reaction mixture is stirred one hour at 0oAnd one night at 20oC. the Formed precipitate was filtered, washed with ethyl ether and dried. The resulting hydrochloride is administered portions in a mixture of Stacie and separation, the organic phase is washed successively 230 ml of water and 30 ml brine. After drying over magnesium sulfate the organic solution is filtered and concentrated in vacuo. Receive a colorless oil with a yield of 66%.

NMR1H (400 MHz, Dl3, ): 7,58 (broad, 1H, =N-H); 7,42 (m, 1H, thiophene); 7,37 (m, 1H, thiophene); 7,01 (m, 1H, thiophene); 3,86 (s, 3H, och3).

IR:C=N(carboximide); 1630 cm-1.

27.5) dichlorhydrate (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1 - piperazinil]phenyl} -2-thiophenecarboxaldehyde: 27

In a conical flask with a capacity of 150 ml under a stream of argon, dissolved of 8.2 g (20 mmol) of (S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-AMINOPHENYL)-1-piperazinil]-carbonyl}-2H-1-benzopyran-6-ol, obtained as an intermediate connection 13.2, but from (S)-Troloxin 60 ml of methanol and added to 4.2 g (30 mmol) 2-thiophenecarboxylate. The reaction mixture is heated for 18 hours under reflux. The methanol is evaporated in vacuum and the brown oily residue purified by chromatography on silica gel (elwira with a mixture of dichloromethane/ethanol: 95/5). Pure fractions are collected and concentrated in vacuo to obtain a brown oil with a yield of 68%. This oil is treated with 22 ml hour at 0oC. the precipitate is filtered and washed successively with acetone and ethyl ether. After drying receive dichlorhydrate in the form of a pale yellow powder with a yield of 53%.

Example 28: hydrochloride 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{ 2-[3-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide: 28

28.1) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{ 2-(3-nitrophenyl)ethyl} -benzamide:

Work the same as when receiving the intermediate 5.1, using 3-nitrophenylamino (J. Med. Chem. (1968), 11 (1), 21-26) instead of 4-nitrophenylamino. Get white powder with a yield of 50%. Melting point: 195-197oC.

NMR1H (100 MHz, Dl3): 7,86 (m, 4H, Ph-NO2); to 7.50 (s, 2H, Ph); 6,10 (m, 1H, NHCO); 5,54 (s, 1H, HE); of 3.75 (m, 2H, ); is 3.08 (m, 2H, ); of 1.42 (s, N, 2tBu).

28.2) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-AMINOPHENYL) ethyl]-benzamide:

Work the same as when receiving the intermediate 5.2, using the intermediate connection 28.1 instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl] -benzamide. Get white powder with a yield of 40%, pure enough to be used in the next step.

28.3) hydrochloride 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl-(imino)methyl)amino]phenyl] the tick connection 28.2 instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. Get a pale yellow powder with a yield of 35%. Melting point: 205-207oC.

NMR1H (400 MHz, DMSO-d6, ): 11,59 (broad, 1H, NH+); of 9.89 (s, 1H, NH+); of 8.95 (s, 1H, NH+); 8,46 (s, 1H, CONH); 8,17 (m, 2H, thiophene); 7,54 (s, 2H, ); 7,39 (m, 6N, thiophene, HE); 3,51 (m, 2H, CH2-NHCO); 2,89 (m, 2H, CH2-Ph-NH); to 1.38 (s, N, 2tBu).

IR:OH: 3624 cm-1;C=O(amide): 1631 cm-1;C=N(amidon): 1577 cm-1.

Example 29: N hydrochloride-{4-(4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-piperazinil)phenyl} -2-thiophenecarboxaldehyde: 29

Work the same as when obtaining the compound (9), using 3,5-di-tert-butyl-4-hydroxyphenylarsonic acid instead of 3,5-di-tert-butyl-4-hydroxybenzoic acid in the first stage of the synthesis. Receives a yellow powder. Melting point: 176-180oC.

NMR1H (400 MHz, DMSO-d6, ): 11,30 (broad, 1H, NH+); to 9.70 (s, broad, 1H, NH+); 8,65 (s, broad, 1H, NH+); 8,10 (with a wide, N, thiophene); to 7.35 (broad, 1H, thiophene); for 7.12 (m, 4H, Ph-N); to 6.95 (s, 2H, ); to 6.80 (broad, 1H, OH); of 3.60 (broad, 6N, piperazine, CH2CO); 3,10 (m, 4H, piperazine); to 1.35 (s, N, 2tBu).

IR:OH: 3620 cm-1;C=O((ester): 1638 cm-1;C=N(amidon): 1612 cm-1.

NMR1H (100 MHz, CDCl3, ): a 7.85 (m, 4H, Ph-NO2); 7,80 (s, 2H, ); 5,70 (s, 1H, HE); 4,50 (m, 2H, O-CH2); 3,20 (m, 2H, O-CH2); 3,20 (m, 2H, CH2); of 1.40 (s, N, 2tBu).

30.2) 3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoate 2-(4-AMINOPHENYL)ethyl:

Work the same as when receiving the intermediate 2,2, while use intermediate connection 30.1 instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)-methyl]-benzamide. Get the white powder is m, 4H, Ph-N); the 4.90 (broad, 1H, OH); of 4.25 (m, 2H, O-CH2); 3,30 (broad, 2H, NH2); 2,80 (m, 2H, CH2); of 1.40 (s, N, 2tBu).

30.3) hydrochloride 3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoate 2-{4-[(2-thienyl-(imino)methyl)amino]phenyl}ethyl: 30

Work the same as when receiving the intermediate 1.3, using the intermediate connection 30.2 instead of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-(4-AMINOPHENYL)-benzamide. Get a white solid with a yield of 26%. Melting point: 145-150oC.

NMR1H (400 MHz, DMSO-d6, ): 11,50 (broad, 1H, NH+); 9,80 (broad, 1H, NH+); 8,90 (broad, 1H, NH+); a 7.85 (s, 1H, HE); of 7.75 (s, 2H, Ph-OH); 7,47 (s, 5H, Ph-N, thiophene); to 4.41 (m, 2H, O-CH2); is 3.08 (m, 2H, CH2); of 1.40 (s, N, 2tBu).

IR:C=O((ester): 1700 cm-1;C=N(amidon): 1592 cm-1.

Example 31: hydrochloride 3,5-bis(1,1-dimethylethyl)- 4-hydroxybenzoate 2-{ 3-[(2-thienyl-(imino)methyl) amino]phenyl}ethyl: 31

Work the same as when the connection 30, using 3-nitrobenzene-ethanol instead of 4-nitrobenzene-ethanol in the first stage of the synthesis. Get a pale yellow powder. Melting point: 145-148oC.

NMR 1H (400 MHz, DMSO-d6, ): 11,50 (broad, 1H, NH+);EN); to 4.41 (m, 2H, O-CH2); is 3.08 (m, 2H, CH2); to 1.38 (s, N, 2tBu).

IR:OH: 3620 cm-1;C=O((ester): 1707 cm-1;C=N(amidon): 1654 cm-1.

Example 32: hydrochloride 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoat 2-{ 2-[(2-thienyl-(imino)methyl)amino]phenyl}ethyl: 32

Work the same as when the connection 30, using 2-nitrobenzene-ethanol instead of 4-nitrobenzene-ethanol in the first stage of the synthesis. Get a beige powder. Melting point: 139-145oC.

NMR1H (400 MHz, DMSO-d6, ): 11,50 (broad, 1H, NH+); 9,80 (broad, 1H, NH+); 8,65 (broad, 1H, NH+); 8,15 (m, 2H, thiophene); 7,80 (s, 1H, HE); of 7.70 (s, 2H, Ph-ON); of 7.60 (m, 1H, Ph); was 7.45 (m, 3H, Ph); to 7.35 (s, 1H, thiophene); and 4.40 (m, 2H, O-CH2); 3,00 (m, 2H, CH2); to 1.35 (s, N, 2tBu).

IR:C=O((ester): 1728 cm-1;C=N(amidon): 1649 cm-1.

Example 33: Hydrochloride of 2-Hydroxy-5-methoxy-N-{2-[4-[(2-thienyl(imino)-methyl)amino]phenyl]ethyl}benzamide:

< / BR>
33.1.) 2-hydroxy-5-methoxy-N-{2-(4-nitrophenyl)ethyl}benzamide:

Hydrochloride 4-nitrophenylamino (1,81 g; 8.9 mmol), triethylamine (2.8 ml; 20 mmol), hydroxybenzotriazole (1.45 g; 10,7 mol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.75 g; 19,62 mmol) gebaut overnight at 25oC. the Mixture is diluted with 40 ml of water and stirred for 10 minutes, then the product is extracted with dichloromethane. The organic solution is dried over sodium sulfate, filtered and concentrated in vacuo and obtained after evaporation the residue is purified on a column of silica (eluent=ethyl acetate/heptane; 50/50) to obtain white solids, the output of which is 64%. Melting point: 200oC.

NMR1H (DMSO-d6, 400 MHz ): 3,00 (m, 2H, CH2); of 3.60 (m, 2H, CH2); 3,70 (S, 3H, -OCH3); to 6.80 (d, arene., J=8,8 Hz); 7,00 (d, 1H, arene., J=8,8 Hz); to 7.35 (s, 1H, arene.); to 7.50 (d, 2H, arene., J=7.8 Hz); 8,10 (d, 2H, arene., J= 7,6 Hz); of 8.90 (broad s, 1H, CO-NH); 11,90 (broad s, 1H, HE).

33.2) 2-hydroxy-5-methoxy-N-{2-(4-AMINOPHENYL)-ethyl}benzamide:

2.10 g of the intermediate product 33.1 (6,64 mmol) dissolved in a mixture of ethanol (40 ml) and dichloromethane (60 ml) and add 0.3 g of palladium on carbon (10%). The reaction medium is placed in an atmosphere of hydrogen at a pressure of 4 bar. The catalyst is filtered off and the solvent is evaporated under reduced pressure. Obtained after evaporation the residue is purified on a column of silica (eluent: ethyl acetate/heptane; 50/50) to obtain the whitish-cream solid. Melting point: N, -OCH3); THE 4.90 (S, 2H, NH2), 6,50 (d, arene., J=7.8 Hz); PC 6.82 (d, 1H, arene., J=8,8 Hz); 6.90 to (d, 2H, arene., J=8.7 Hz); 7,00 (d, 1H, arene. , J= 8,8 Hz); 7,39 (S, 1H, arene.); 8,87 (broad s, 1H, CO-NH); 12,09 (broad s, 1H, HE).

33.3) of the Hydrochloride of 2-hydroxy-5-methoxy-N-{2-[4-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}benzamide:

The intermediate product 33.2 (0.6 g; 2.1 mmol) dissolved in 2-propanol (10 ml), add 0,896 g hydroiodide S-methyl-2-titaniumoxide (3.14 mmol) (Ann.Chim.(1962), 7, 303-337).

After heating at 50oC for 15 hours, the reaction mixture was concentrated under vacuum to dryness. The residue is absorbed in ethyl acetate and a saturated solution of sodium carbonate. After decanting, the organic phase is successively washed with 50 ml saturated sodium carbonate solution, water and saturated salt solution. The organic solution is dried over sodium sulfate, filtered and evaporated under reduced pressure. Obtained after evaporation the residue is purified on a column of silica (eluent: ethanol/dichloromethane, 5/95). Get 0,523 g of free base. The hydrochloride is obtained from 0,523 g (1,32 mmol) dissolved in 20 ml of acetone, and form a salt in the presence of 2.0 ml (2.0 mmol) molar solution of Hcl in anhydrous diethyl ether. g (yield 64%) of the desired product in the form of a white solid. Melting point: 242oC.

NMR1H (DMSO-d6, 400 MHz ): to 2.94 (t, 2H, CH2, J=7.2 Hz); to 3.58 (m, 2H, CH2); to 3.73 (s, 3H, -OSS); 6,85 (d, 1H, arene., J=9.0 Hz); 7,01 (d, 1H, arene. , J= 8,8 Hz); 7,20-of 7.70 (m, 6N, arene.); is 8.16 (m, 2H, thiophene); 8,88 (broad s, 1H, NH+); 9,11 (broad t, 1H, CO-NH, J=5,15 Hz); 9,83 (broad s, 1H, NH+); 11,54 (broad s, 1H, NH+), 12,10 (s, 1H, HE).

IR:C=N(amidon): 1645 cm-1;C=O(amide): 1645 cm-1.

Example 34: N Hydrochloride-{4-[2-({2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]ethyl}amino)ethyl]phenyl}-2-thiophenecarboxaldehyde:

< / BR>
34.1) 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]acetic acid:

3.6 ml (46 mmol) triperoxonane acid are added to a solution of 1.56 g (with 4.64 mmol) of tert-butyl 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy] acetate (obtained according to J. Heterocycl.Chem. (1994) 31, 1439-1443) in 20 ml of dichloromethane. The reaction mixture is stirred for 1 hour, concentrated in vacuo and the residue is dissolved in 5.0 ml Et2O. the Organic solution was twice extracted with 25 ml of saturated solution Panso3then the aqueous phase is washed with 25 ml Et2O. the Aqueous basic solution is then podkalyvayut at 0oWith a saturated solution of KHSO4and then the expected product is extracted with the use of obtaining a white powdery product with a yield of 70%. Melting point: 172-173oC.

34.2) 2,6-di(tert-butyl)-4-{2-[(4-nitrophenyl)-amino]-ethoxy}phenol:

1.92 g (4.5 mmol) of 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]-N-(4-nitrophenacyl)ndimethylacetamide (obtained as an intermediate product using the procedure of example 1 for the intermediate product 34,1) was injected into the flask containing 80 ml of anhydrous THF in an argon atmosphere. To the reaction mixture add a solution 13,45 ml (13,45 mmol) NR3in THF and the mixture is stirred while heating at the boiling point under reflux for 4 hours and 30 minutes. At the end of the reaction, add 10 ml of the Meon and the heating continued for another 30 minutes. Then the reaction mixture was concentrated in vacuo, the residue is absorbed in 30 ml of 3 N mixture Meon/Hcl (2/1) and the mixture refluxed for another hour. The reaction mixture is allowed to cool to 22oC, diluted with 50 ml of CH2Cl2and added 2 M aqueous sodium hydroxide solution to obtain an alkaline pH. After decanting, the organic phase is successively washed with 20 ml water and 20 ml saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuo. The expected product is purified by means of chromatography on a column of silica (elwen who yl)-4-hydroxyphenoxy] -ethyl(4-nitrophenyl)carbamate:

1.27 g (3 mmol) of the intermediate product 34.2 dissolved in a mixture of 15 ml of CH2Cl2and of 0.53 ml (3 mmol) of N,N-diisopropylethylamine. The mixture is cooled using an ice bath before the addition of 0.67 g (3 mmol) (BOC)2About one piece. The reaction mixture is stirred for 5 hours at 23oC. After concentration under vacuum, the residue is absorbed in 50 ml of ethyl acetate and poured into a mixture of ice water. The organic phase is decanted, washed sequentially with 20 ml water and 20 ml saturated salt solution. After drying over sodium sulfate, filtration and concentration in vacuum polycast solid yellow with a quantitative yield.

34.4) tert-Butyl 4-aminophenethyl { 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]ethyl}carbamate:

1.7 g (3 mmol) of the intermediate product and 34.3 0.8 ml (15 mmol) of hydrazine hydrate is added dissolved in 50 ml of absolute ethanol before adding 0.2 g of Raney Nickel. The reaction mixture is heated to boiling point under reflux until complete disappearance of the original product (4 hours 30 minutes). After cooling the flask is added a small amount of silicon dioxide and then the solvent is removed under vacuum. The obtained powdery substance placed the bar is the Expected product is obtained in the form of an orange oil with a yield of 83%.

34.5) tert-Butyl 4-{ [amino(2-thienyl)methylidene]amino}-phenethyl{2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]ethyl}carbamate:

0,93 g (1.9 mmol) of the intermediate product and 34.4 of 0.60 g (2.1 mmol) of hydroiodide S-methyl-2-titaniumoxide (Ann. Chim. (1962) 7, 303-337) dissolved in 50 ml of isopropanol. The reaction mixture is stirred for 15 hours at 60oC. After evaporation of the solvent in vacuo the residue is absorbed in 60 ml of AcOEt and 40 ml of a saturated solution of PA2CO3. The mixture is intensively stirred and then decanted. The organic phase is successively washed with 20 ml water, 20 ml of saturated saline, dried over sodium sulfate, filtered and concentrated in vacuo. The product obtained is used directly in the next stage without additional purification.

34.6) N-{ 4-[2-({ 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy] -ethyl} amino)ethyl]phenyl}-2-thiophenecarboxylate:

0.8 g (1.3 mmol) of the intermediate product 34.5 dissolved in 20 ml of ethanol and add 7 ml of 3N hydrochloric acid. The mixture is stirred for 1 hour at 23oC. After cooling with ice bath, the solution is alkalinized by adding PA2CO3in powder form and the mixture is then diluted with 50 ml of AcOEt. After intensive is lifecom sodium, filter and concentrate to dryness. The residue is purified on a column of silica (eluent: t /heptane/NH4HE: 12,5/12,5/0,5).

34.7) Hydrochloride N-{4-[2-({2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]-ethyl}amino)ethyl]phenyl}-2-thiophenecarboxaldehyde:

The intermediate product 34.6 (0,29 g, 0.6 mmol) dissolved in 30 ml of absolute ethanol, the mixture is cooled using an ice bath, then add 2.4 ml (2.4 mmol) lN solution of Hcl in anhydrous ether. After stirring for 30 minutes at 23oThe solvent is evaporated in vacuum to obtain solid hot pink color. Melting point: 151-153oC.

Example 35 (E)-N-(4-{[amino(2-thienyl)methylidene]amino}-phenethyl)-3-(2-hydroxyphenyl)-2-propenamide:

< / BR>
To a solution of 8.9 mmol 2-oksikorichnye acid in dichloromethane (80 ml) was added the hydrochloride of 4-nitrophenylamino (8.9 mmol), triethylamine (20 mmol), hydroxybenzotriazole (10,7 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (19,62 mol). The reaction medium is stirred overnight at 25 ° C, the mixture is diluted with 40 ml of water and stirred for 10 minutes, then the product is extracted with dichloromethane. The organic solution is dried over sodium sulfate, filtered and concentrated in vtan; 50/50) to obtain the desired intermediate product.

3,59 g (16 mmol) SnCl2, 2H2O is introduced into a solution of the intermediate product obtained in the previous phase (3,18 mmol) in 50 ml of a mixture of ethyl acetate/ethanol/acetone (2/1/2). The reaction mixture is heated to boiling point under reflux for 5 hours and then, after cooling, concentrated in vacuo to half volume. Obtained after evaporation the residue is then poured into 50 ml of a saturated solution of cold Panso3and extracted with 100 ml of ethyl acetate. The mixture is filtered on celite and the filtrate is decanted. Organismal phase is successively washed with 50 ml water and 50 ml saturated salt solution. After drying over magnesium sulfate and filtration, the organic solution was concentrated in vacuo. Get the expected intermediate product, which is used in the next stage.

The intermediate product obtained in the previous phase (2.1 mmol), dissolved in 2-propanol (10 ml) and add there 3.14 mmol of hydroiodide 5-methyl-2-titaniumoxide (Ann.Chim. (1962), 7, 303-337). After heating for 15 hours at 50oTo the reaction mixture was concentrated in vacuo to dryness. The residue is absorbed in ethyl acetate and nasyshennye sodium carbonate, water and saturated salt solution. The organic solution is dried over sodium sulfate, filtered and evaporated under reduced pressure. Obtained after evaporation the residue is purified on a column of silica (eluent: ethanol/dichloromethane, 5/95). The product is obtained in free base form, which is converted into the hydrochloride in the following way: 1,32 mmol base, dissolved in 20 ml of acetone, add 2.0 ml (2.0 mmol) molar solution of Hcl in anhydrous diethyl ether. The resulting crystals are filtered and washed in diethyl ether to obtain after drying, the desired product in the form of a solid white color. Melting point: 145-155oC.

Example 36: (E)-N-(4-{[amino(2-thienyl)methylidene]amino}-phenethyl)-3-(3,4-dihydroxyphenyl)-2-propenamide:

< / BR>
This connection receive in accordance with the experimental Protocol similar to that described for compound 35. A yellow oil. MN+: 408,08.

Example 37 (E)-N-(4-{[amino(2-thienyl)methylidene]amino}-phenethyl)-3-(4-hydroxy-3,5-acid)-2-propenamide:

< / BR>
This connection receive in accordance with the experimental Protocol similar to that described for compound 35. Solid pale yellow color. Stemetil]amino}benzoylbutyric

< / BR>
38.1) 2-amino-4-methoxyphenol

Used an experimental Protocol is the same as described for intermediate 33.2, thus instead of 2-hydroxy-5-methoxy-N-{2-(4-nitrophenyl)ethyl}benzamide using 4-methoxy-2-NITROPHENOL.

38.2) N-(2-hydroxy-5-methoxy)-4-nitrobenzophenone

Used an experimental Protocol is the same as described for intermediate connection 33.1, however instead of 5-methoxysalicylaldehyde acid using 4-(4-nitrophenyl)butane acid and instead of the hydrochloride of 4-nitrophenylamino using 2-amino-4-methoxyphenol.

38.3) N-(2-hydroxy-5-methoxy)-4-aminobenzophenone

Used an experimental Protocol is the same as described for intermediate 33.2, thus instead of 2-hydroxy-5-methoxy-N-{2-(4-nitrophenyl)ethyl} benzamide using N-(2-hydroxy-5-methoxy)-4-nitrobenzophenone.

38.4) of the Hydrochloride of N-(2-hydroxy-5-methoxy)-4-{ [2-thienyl-(imino)methyl] amino}benzoylbutyric.

Used an experimental Protocol is the same as described for intermediate 33, thus instead of 2-hydroxy-5-methoxy-N-{2-(4-AMINOPHENYL)ethyl} benzamide using N-(2-hydroxy-5-methoxy)-4-aminobenzophenone. Temperature is>; 2,70 (m, 2H, CH2); to 3.64 (s, 3H, -och3); 6,51-6,9 (m, 2H, arene.); of 7.36 (m, 6N, arene. ); 8,17 (m, 2H, thiophene); 8,88 (broad s, 1H, NH+); 9,38 (s, 2H, -HE & CONH); 9,81 (broad s, 1H, NH+); to 11.52 (broad s, 1H, NH+).

IR:C=N(amidon): 1662 cm-1;C=O(amide): 1693 cm-1.

Example 39: N-(2-hydroxy-5-methoxy)-4-{ [2-thienyl(imino)-methyl]amino} benzoylpropionic

< / BR>
39.1) N-(2-hydroxy-5-methoxy)-4-N-BOC-benzoylpropionic.

Used an experimental Protocol is the same as described for intermediate connection 38.2, thus instead of 4-(4-nitrophenyl)butane acid using 3-(4-tert-butoxycarbonyl-amino)phenylpropane acid.

39.2 N-(2-hydroxy-5-methoxy)-4-aminobenzophenone.

Concentrated hydrochloric acid (0.6 ml) are added to a solution 3,86 mmol intermediate 39.1 in methanol (30 ml). The reaction medium is stirred overnight at 25oC. the Solvent is evaporated and the residue is washed subsequently with 340 ml of water and then 40 ml of a saturated salt solution. The organic solution is dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown oil which is sufficiently pure for IP is-(imino)methylamino}benzoylpropionic.

Used an experimental Protocol is the same as described for intermediate connection 38, thus instead of N-(2-hydroxy-5-methoxy)-4-aminobenzenesulfonamide using N-(2-hydroxy-5-methoxy)-4-aminobenzophenone.

Melting point: 197,6-197,8oC.

NMR1H (DMSO-d6, 400 MHz ): 2,49 (m, 2H, CH2); 2,70 (m, 2H, CH2); 3,61 (s, 3H, -och3); 6,50-7,0 (m, 2H, arene.); 7,40 (m, 6N, arene.); of 8.90 (broad s, 1H, NH+); 9,40 (s, 2H, -HE & CONH); for 9.90 (broad s, 1H, NH+); 11,60 (broad s, 1H, NH+).

IR:C=N(amidon): 1660 cm-1; C=O(amide): 1685 cm-1.

Test the viability of the cell line macrophages of mice J774-A1

Cell line

Cell line macrophages of mice J 774 A1 received from ATS and maintained at 37oWith 5% CO2in the modified Dulbecco minimum basic medium (DMEM)/10% serum fetal cow (FBS).

Treatment of cells

Cells were collected after centrifugation, washed and suspended in DMEM/10% FBS. Cells (5104cells per well) were cultured in 96-well tablets in 24 hours, and then for 18 hours in the presence of the test compounds at concentrations of 10, 30, 50, or 100 microns. Ispytyvaemoj cultivation was carried out in DMEM. The final concentration of DMSO or ethanol had no effect on the morphology of the cells or cell viability.

Assessment of cell viability.

Analysis using blue dye (Alamar blue) was performed according to the manufacturer's instructions (Interchim). Briefly, after extraction of the environment, the Alamar Blue solution, diluted 1/10 in DMEM without phenol red/ 10% FBS was added for 3 hours at 37oWITH 5% CO2). Colorimetric detection was performed at 570 nm and 620 nm on a tablet reader. The percentage inhibition of metabolic activity in response to test compounds compared to untreated cells was calculated by the formula:

< / BR>
The value of CI50is the concentration that reduces the % cell viability by 50% and obtained by extrapolation of the graph of the relationship dose-response.

Pharmacological study of the compounds according to the invention

Studying the effects on neural constitutive NO-synthase of rat cerebellum.

Inhibitory activity of the compounds according to the invention is determined by measuring their effects on the transformation via NO synthase [3H]-arginine to [3H] L-citrulline under zavlekayut, open at 4oC and homogenized in a volume of extraction buffer (HEPES 50 mm, EDTA 1 mM, pH 7.4, pepstatin And 10 mg/ml, lambertin 10 mg/ml). Then the homogenates centrifuged at a speed of 21,000 g for 15 minutes at 4oC. the Analysis is carried out in a glass tube, into which distribute 100 ál of incubation buffer containing 100 mm HEPES (pH 7.4), 2 mm EDTA, 2.5 mm CaCl2, 2 mm dithiothreitol, 2 mm restored NADPH and 10 μg/ml of calmoduline. Add 25 ál of a solution containing 100 nm of [3H]L-arginine (specific activity: 56.4 Ci/mmol, Amesrsham) and 40 μm non-radioactive L-arginine. The reaction is initiated by adding 50 μl of homogenate, and the final volume is 200 ál (missing 25 ál is either water, or test the connection). After 15 minutes the reaction is stopped with 2 ml of buffer solution (20 mm HEPES, pH 5.5, 2 mm EDTA). After transferring the samples to 1 mm-th column of resin DOWEX determine the amount of radioactivity using a spectrometer with a liquid Scintilla. The compounds of examples 6, 7, 13 and 14, described above, have CI50less than 3.5 microns.

The study of the effect on lipid peroxidation of the cerebral cortex of the rat.

Inhibitory activity of the compounds according to the invention determines the measurement is MDA). The malondialdehyde produced during peroxide oxidation of unsaturated fatty acids, is an indicator of lipid peroxidation (Esterbauer H and KH Cheese-man, Meth. Enzymol. (1990) 186: 407-421). Male rats breed Sprague Dawley weighing 200 to 250 g (Charles River) were euthanized by decapitation. The cerebral cortex was removed, and then homogenized in a homogenizer Thomas in buffer solution Tris-HCl 20 mm, pH 7.4. The homogenate was centrifuged 2 times at a speed of 50000 g for 10 minutes at 4oC. the Precipitate was stored at -80oC. on the day of the experiment the sediment again suspended to a concentration of 1 g/15 ml and centrifuged at a speed of 515 g for 10 minutes at 4oC. Emergent part immediately used for determination of lipid peroxidation. The homogenate of cerebral cortex of rats (500 μl) were incubated at 37oC for 15 minutes in the presence of test compounds or solvent (10 ml). Reaction of lipid peroxidation was initiated by adding 50 μl of FeCl2(1 mm), EDTA (1 mm) and ascorbic acid (4 mm). After 30 minutes incubation at 37oThe reaction was stopped by adding 50 μl of solution gidrauxilirovannogo tert. butyltoluene (BHT, 0.2 percent). The amount of MDA was determined using a colorimeter is Uchenie 1 hour at 45oC. Condensation of one molecule of MDA with two molecules of reagent R forms a stable chromophore, in which the wavelength of maximum absorption is equal to 586 nm. (Caldwell et coll. European J. Pharmacol. (1995) 285, 203-206). Connection examples 5,8,9,10,12,13,14,16,17,18,19,20,21,26 and 27 described above, all have CI50less than 30 μm. The results farmakologicheski tests are presented in the table.

1. Derivatives of 2-(iminomethyl)aminobenzene, the General formula (I)

< / BR>
in which And means:

or radical

< / BR>
in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms;

R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4;

R4means a linear or branched alkyl with 1-6 carbon atoms,

or radical

< / BR>
in which R3has the meaning specified above,

or radical

< / BR>
in which R5means a hydrogen atom, a group HE or linear or branched alkyl, or alkoxy with 1-6 carbon atoms;

In the mean thienyl;

X means Z1-, -Z1-CO-, -Z1-NR3-CO-, -CH=CH-CO-, or a simple bond;

Y oznacza-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3-, -N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is a whole number equal to from 0 to 6;

R6means a hydrogen atom or a group of IT;

or pharmaceutically acceptable salt of the compounds of General formula (I), except for compounds of the following formula:

< / BR>
2. Connection on p. 1, representing one of the following connections:

3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl-(imino)methyl)amino] phenyl}-benzamide;

3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{4-{[(2-thienyl-(imino)methyl)amino]phenyl]methyl}-benzamide;

4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl} -benzamide;

3,5-dimethoxy-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl} -benzamide;

3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;

4-acetoxy-3,5-dimethoxy-N-{ 4-[2-[(2-thienyl(imino)methyl)amino] phenyl] ethyl}-benzamide;

3,5-dimethoxy-4-hydroxy-N-{ 4-[2-[(2-thienyl(imino)methyl)amino] phenyl] ethyl}-benzamide;

3,4,5-trihydroxy-N-{ arsenil]-phenyl}-2-thiophenecarboxylate;

N-{ 4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl] -1-piperazinil] -phenyl}-2-thiophenecarboxylate;

N-{ 4-[4-[3,5-dimethoxy-4-hydroxybenzoyl] -1-piperazinil]-phenyl}-2-thiophenecarboxylate;

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;

N-{ 4-[4-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

N-{ 4-[4-[(5-methoxy-1H-indol-3-yl)methylcarbamoyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

N-[4-[4-[{ 3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-1-piperazinil]phenyl]]-2-thiophenecarboxylate;

3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{ 3[[2-thienyl-(imino)methyl)amino] phenyl]methyl}-benzamide;

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N'-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;

N-[5-[{ 3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl} amino]-2-hydroxyphenyl]-2-thiophenecarboxylate;

-N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl} amino]-4-hydroxyphenyl]-2-thiophenecarboxylate;

N-{4-[4-[3,4,5-trihydroxybenzoic]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N'-{{4-[(2-thienyl(imino)methyl)amino]fail}methyl}-thiourea;

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] -N'-{ 2-{ 4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-urea;

N(4-{ 4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil}phenyl)-2-thiophenecarboxylate;

N-[4-{ 4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboxylate;

(R)-N-{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

(S)-N{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;

N-{ 4-(4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxoethyl] -1-piperazinil)phenyl}-2-thiophenecarboxylate;

3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoate-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl;

3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoate-{3-[(2-thienyl(imino)methyl)amino]phenyl}ethyl;

3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoate-{2-[(2-thienyl(imino)methyl)amino]phenyl}ethyl

or one of the salts of one of these compounds, in particular the hydrochloride, dichlorhydrate, fumarate or profumata one of these compounds.

3-O-Z2; or X is-Z1-CO - or-CH=CH-and Y WITH means piperazinil, homopiperazine, -NR3-Z2-Q-, -NR3-O-Z2-, -O-Z2-Q-, or X means Z1-NR3-CO - and Y represents-Z2-Q-, -NH-CO-Z2-Q"- Q"=O-Z3-, -NR3-Z3or Y represents-O-Z2-Q-; or X is-Z1-NH-CO - and Y represents piperazinil, homopiperazine or NR3-O-Z2; or Y means Z2-Q" Q"=O-Z3, -NR3-Z3- or X means piperazinil, homopiperazine, -NR3-O-Z2-; or X represents a bond.

4. Connection PP.1, 2 or 3, characterized in that means

< / BR>
or

< / BR>
X represents-CO - or-NR3-CO-; Y means piperazinil, and Q means a bond, O-Z3and Z3means bond or a linear or branched alkylene with 1-6 carbon atoms, and R3means a hydrogen atom or a linear or branched alkyl with 1-6 carbon atoms.

5. Connection under item 1 or 2, which represents one of the following connections:

3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;

3,4,5-trihydroxy-N-{ 4-[2-[(2-thienyl-(imino)methyl)-amino] phenyl]ethyl}-Bentham is 4-[4-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzyl] -1-piperazinil]phenyl}-2-thiophenecarboxylate;

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)-amino]phenyl}-2H-1-benzopyran-2-carboxamide;

N-{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

N-{ 4-[4-[(5-methoxy-1H-indol-3-yl)methylcarbamoyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl-(imino)methyl)amino]phenyl]methyl}-benzamide;

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N'-{{4-[(2-thienyl(imino)methyl)amino]phenyl}-methyl}-urea;

N-[5-[{ 3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl} amino]-2-hydroxyphenyl]-2-thiophenecarboxylate;

N-[3-[{ 3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl} amino]-2-hydroxyphenyl]-2-thiophenecarboxylate;

N-[4-[4-[3,4,5-trihydroxybenzoic]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N'-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbylamine}-urea;

(R)-N-{ 4-[4-[3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

(S)-N-{ 4-[4-[3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

or salt odnoi.

6. Connection under item 1 or 2, which is a 4-acetoxy-3,5-dimethoxy-N-{4-[2-[2-thienyl-(iminomethyl)-amino]phenyl]ethyl}-benzamide; 3,5-dimethoxy-4-hydroxy-N-{ 4-[2-[2-thienyl-(iminomethyl)-amino] phenyl]ethyl}-benzamide; or a salt of one of these compounds, in particular the hydrochloride, dichlorhydrate, fumarate or profumata one of these compounds.

7. Connection under item 1 or 2, which is N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate; or a salt of this compound, in particular the hydrochloride, dichlorhydrate, fumarate or profumata this connection.

8. Connection under item 1 or 2, which represents one of the following connections:

N-{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

(R)-N-{ 4-[4[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

(S)-N-{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate;

or salt of one of these compounds, in particular the hydrochloride, dichlorhydrate, fumarate or profumata one of these compounds.

-yl)-carbonyl]-1-piperazinil] phenyl} -2-thiophenecarboxylate or its salt, in particular the hydrochloride, dichlorhydrate, fumarate or profumata.

10. Intermediate compounds of General formula (II)AND

< / BR>
in which W stands for amino, or nitro;

And means:

or radical

< / BR>
in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy with 1-6 carbon atoms;

R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4;

R4means a linear or branched alkyl with 1-6 carbon atoms,

or radical

< / BR>
in which R3has the meaning specified above,

or radical

< / BR>
in which R5means alkoxy c 1 to 6 carbon atoms;

X means Z1-, -Z1-CO-, -Z1-NR3-CO-, -CH=CH-CO-, or a simple bond;

Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2-Q-; in which Q means a simple bond, -O-Z3-; -N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, and Z1, Z2and Z3mean the or group IT;

except 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide;

or salt compounds of General formula (II)And, with the exception of the compounds corresponding to the following formula:

< / BR>
< / BR>
11. Intermediate compounds of General formula (II)And selected from the group including

1-{ [3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl] carbonyl}-4-(4-nitrophenyl)piperazine;

1-{ [3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl] carbonyl}-4-(4-AMINOPHENYL)piperazine;

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepin;

1-(4-AMINOPHENYL)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-1H-1,4-diazepin;

(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-nitrophenyl)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol;

(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-AMINOPHENYL)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol;

(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-nitrophenyl)-1-piperazinil] carbonyl}-2H-1-benzopyran-6-ol;

(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{ 4-[(4-AMINOPHENYL)-1-piperazinil] -carbonyl}-2H-1-benzopyran-6-ol;

3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-nitrophenyl)-ethyl]-benzamide;

3,5-bis(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-and eilati)-4-hydroxybenzoate-(4-AMINOPHENYL)ethyl;

or salt of one of these compounds.

12. A method of obtaining a compound according to any one of paragraphs.1-9, characterized in that the compound of General formula (III)

< / BR>
in which And means:

or radical

< / BR>
where R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl with 1-6 carbon atoms, linear or branched alkoxy with 1-6 carbon atoms;

R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4;

R4means a linear or branched alkyl with 1-6 carbon atoms,

or radical

< / BR>
in which R3has the meaning specified above,

or radical

< / BR>
in which R5means alkoxy with 1-6 carbon atoms;

X means Z1-, -Z1, -CO-, -Z1, -NR3-CO-, -CH=CH-CO-, or a bond;

Y means Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2-Q; where Q=bond, -O-Z3-; -N(R3)-Z3-, Z1, Z2and Z3means independently a bond or a linear or branched alkylene with 1-6 carbon atoms;

R6means a hydrogen atom or a group of HE,

enter into inter is sopapilla alcohol, with a compound of General formula (IV)

< / BR>
which means thienyl;

L means delete the group, in particular thioalkyl, a sulfonic acid radical, triftormetilfullerenov acid or tosyl, halide or phenoxy, or salt of the compounds of formula (IV) with a mineral acid G, preferably Hcl, NVG or HI.

13. The compound of General formula (I) according to any one of paragraphs.1-9, or a pharmaceutically acceptable salt of this compound with inhibitory activity against the enzyme NO-synthase and/or catching activity against reactive forms of oxygen.

14. Pharmaceutical composition having inhibitory activity against the enzyme NO-synthase and/or catching activity against reactive forms of oxygen, containing as active principle at least one connection on p. 13.

15. The pharmaceutical composition according to p. 14, in which the active principle is an (S)-N-{ 4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinil]phenyl}-2-thiophenecarboxylate or its pharmaceutically acceptable salt.

16. The compound of General formula (I) according to any one of paragraphs.1-9, or a pharmaceutically acceptable salt of this with the SS="ptx2">

17. The compound of General formula (I) according to any one of paragraphs.1-9, or a pharmaceutically acceptable salt of this compound, to obtain a medicinal product intended for the inhibition of the inducible NO-synthase.

18. The compound of General formula (I) according to any one of paragraphs.1-9, or a pharmaceutically acceptable salt of this compound, to obtain a medicinal product intended for the inhibition of lipid peroxidation.

19. The compound of General formula (I) according to any one of paragraphs.1-9, or a pharmaceutically acceptable salt of this compound, to obtain medications simultaneously possessing inhibitory activity against NO-synthase in relation to lipid peroxidation.

 

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< / BR>
< / BR>
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