Derivatives of five-membered heterocycles, their preparing and using as medicinal agents

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

 

The present invention relates to certain compounds of General formula (I), described later, to these compounds as medicines, as well as to use them to produce a medicinal product intended for the inhibition of monoamine oxidase (MAO), and/or lipid peroxidation, and/or to act as modulators of sodium channels.

The compounds mentioned above, usually have 2 or 3 types of activities listed above, which makes them useful pharmacological properties.

Indeed, play an important role in fisiopatologia MAO and ROS (reactive oxygen upon the occurrence of lipid peroxidation), new derivatives described by the General formula (I)may be useful or beneficial effects in the treatment of pathologies involving these enzymes and/or these kinds of radicals.

In particular:

- disorders of the Central or peripheral nervous system, such as, for example, neurological diseases, among which may be specified Parkinson's disease, traumatic brain or spinal cord injury, ischemic stroke, subarachnoid hemorrhage, epilepsy, aging, senile dementia, Alzheimer's disease, Huntington Hantington, amyotrophic lateral sclerosis, peripheral neuropathy, pain;

- sizofrenik is, depression, psychosis;

- memory disorders and mood;

pathology, such as, for example, migraine;

behavioral disorders, bulimia and anorexia;

- autoimmune and viral diseases, such as lupus, AIDS, parasitic and viral infections, diabetes and its complications, multiple sclerosis;

- addiction to toxic substances;

inflammatory and proliferative diseases;

and, more generally, all pathology characterized by excessive production of ROS and/or participation MAO.

For all these pathologies, there is experimental evidence for the involvement of ROS (Free It. Blol. Med. (1996) 20, 675-705; Antioxid. Health. Dis. (1997) 4 (Handbook of Synthetic Antioxidants), 1-52), as well as participation MAO (Goodman & Oilman''s: The pharmacological basis of therapeutics, 9th edition, 1995, 431-519).

The value of the combination of MAO-inhibitory activity and inhibitory activity against lipid peroxidation, for example, is well illustrated in Parkinson's disease. This disease is characterized by loss of dopaminergic neurons nigrostriatal the way, the reason of which is partly linked to oxidative stress due to ROS. To maintain sufficient levels of dopamine is used in the treatment of exogenous dopamine, based on L-DOPA. In order to avoid metabolic degradation of L-DOPA, with him also apply MAO inhibitors, but theynot effect on ROS. Therefore, compounds acting as MAO and ROS, have certain advantages.

In addition, the ability to modulate sodium channels is very effective for these therapeutic indications, such as:

- the treatment or prevention of pain, in particular:

- postoperative pain,

- migraine,

- neuropathic pain such as trigeminal neuralgia, post herpetic pain, diabetic neuropathy, neuralgia glossopharyngeal nerve, secondary radiculopathy and neuropathy associated with metastatic infiltrations, morbid obesity, and pain associated with burns,

- pain of Central origin, as a result of cerebrovascular events, thalamic lesions and multiple sclerosis, and

- pain in chronic inflammatory diseases or pain associated with cancer;

- the treatment of epilepsy;

- the treatment of disorders associated with neurodegeneration and, in particular:

with vascular brain damage

with brain injury and

- with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis;

treatment of bipolar disorders and irritable bowel syndrome.

Thus, the specific advantage of having a connection, at least one of these activities is clear from Viseu asanoha.

In European patent application EP 432740 described derivatives hydroxyphenyltriazine that can be used in the treatment of inflammatory diseases such as rheumatic diseases. These derivatives hydroxyphenyltriazine have the property of trapping free radicals and properties of inhibition of arachidonic acid metabolism (they inhibit lipoxygenase and cyclooxygenase).

Other derivatives hydroxyphenyltriazine or hydroxyphenylacetate described in the patent application PCT WO 99/09829. The latter possess analgesic properties.

Some imidazole derivatives with structures similar or identical to the structures of the compounds corresponding to General formula (I) according to this invention, also described by the applicant in the patent application PCT WO 99/64401 as agonists or antagonists of somatostatin. However, these imidazole derivatives have therapeutic properties in the area, other than specified above (in particular, the suppression of growth hormone and treatment of acromegaly, the treatment of restenosis, inhibition of the secretion of stomach acid and prevention of gastrointestinal bleeding).

Further, in the patent application PCT WO 96/16040 were described compounds of General formula (A1)

where

R1 is one of the aryl radicals, heteroaryl, aralkyl and the and cycloalkyl, optionally substituted from one to three substituents, independently selected from a halogen atom, CF3, CN, OH, alkyl or alkoxy, radical SO2R9, where R9 represents NH2or NHCH3;

X represents NR2, R2 represents H or alkyl;

Y represents N or CR3;

Z represents CR3 or N;

provided, however, that Y and Z are not simultaneously represent CR3 or N;

R3 represents H, alkyl, halogen, hydroxyalkyl or phenyl, optionally substituted by 1-3 substituents selected from H, CF3CN, SO2NH2, OH, alkyl or alkoxy;

m is 0, 1 or 2;

R4 represents H or alkyl;

when Z represents CR3, then R3 and R4 together may also represent -(CH2)n1-where n1 is an integer from 2 to 4, or R2 and R4 together can also be a

-(CH2)n2-where n2 is an integer from 2 to 4;

R5 and R6 independently represent H, alkyl, alkoxy, aryl or aralkyl;

NR5R6 together can also represent (in particular): optionally substituted 2-(1,2,3,4-tetrahydroquinolin) radical,

radical, where R7 is one of the radicals phenyl, benzyl or phenethyl, where the phenyl ring may be substituted;

radical, where p is an integer from 1 to 3,

W p is ecstasy a N and R8 represents H, CF3one of the radicals phenyl, pyridyl or pyrimidinyl, optionally substituted by 1-2 radicals selected from halogen, OH, alkyl or alkoxy, or

W represents CH, and R8 is an optionally substituted phenyl or aralkyl, optionally substituted in the aryl group;

as partial agonists or antagonists dopamine subreceptors brain or as proletarienne forms of these partial agonists or antagonists. Thus, these compounds could have useful properties for the diagnosis and treatment of affective disorders such as schizophrenia and depression, as well as certain movement disorders such as Parkinson's disease.

Also in the patent application WO 98/27108 were described some amides of the General formula (A2)

where

R1, in particular, represents an optionally substituted alkyl radical, phenyl or optionally substituted heterocyclic radical aryl;

R2 represents H or phenylalkyl;

R4 represents H, hinely, 3-4-methylenedioxyphenyl or one of the radicals phenyl or pyridyl, optionally substituted by one or more radicals chosen in particular from alkyl, alkoxy, alkylthio, optionally protected hydroxy, amino, alkylamino, dialkyl the Ino;

R5 represents H or a radical imidazolyl, phenyl, nitrophenyl, phenylalkyl, or the radical-CO-N(R7)(R8), where R7 and R8 independently represent H, phenyl, phenylalkyl, alkyl or alkoxy;

or R4 and R5 in combination form a group of formula-CH=CH-CH=CH-;

Y represents a phenylene radical substituted by a radical of the phenyl, phenoxy or funeralcare, or a group of the formula-CH(R3)-where R3 represents H or a radical of the formula -(CH2)n-where R6 represents an optionally protected hydroxy radical, acyl, carboxy, acylamino, alkoxy, funeralcare, alkylthio, optionally substituted phenyl, optionally substituted pyridyl, pyrazinyl, pyrimidinyl, furyl, imidazolyl, naphthyl, N-acylinder or 3,4-methylenedioxyphenyl, and n is an integer from 0 to 3;

R2 and R3, taken together with carrying their carbon atom, may form a phenyl group;

X represents S or NR9;

R9 represents H, an alkyl radical or cycloalkyl, or a benzyl radical, optional one-deputizing in his phenyl part H, alkyl or alkoxy;

which are inhibitors of NO synthase and can be effective in the treatment of diseases, which include, in particular, cardiovascular ischemia or ischemia of the brain, bleeding in the brain, Central nervous system disorders, disease Alzheimer, scattered with Leros, diabetes, hepatitis, migraine, rheumatoid arthritis and osteoporosis.

On the other hand, prior to this by the applicants in patent publication PCT WO 98/58934 were described derivatives of amidine with the ability to inhibit NO synthase and/or lipid peroxidation.

Recently in the patent application PCT/FROO/02805 by the applicant have been described, some of the intermediate products from the first stage of synthesis of amidine described in the patent application PCT WO 98/58934, and, in General, some derivatives of five-membered heterocycles, i.e. the product of General formula (I)defined below, having at least one of the three properties selected from the following properties (and even more often two of these three properties, and sometimes all three at once):

- properties of inhibition of MAO;

- properties of inhibition of lipid peroxidation; and

- properties of modulating sodium channels.

These useful properties capable of numerous applications of such compounds, in particular, in the treatment of neurodegenerative diseases and, in particular, those specified previously, pain or epilepsy.

In accordance with the patent application WO 01/26656 compounds corresponding to General formula (I)

in racemic, enantiomeric form or as a combination of these forms, where Het is with the battle of the 5-membered heterocycle, containing 2 heteroatoms, and in the form of General formula (I), correspond to only one of the following subformulas:

where

A represents

or radical

where R3represents a hydrogen atom, an OH group or a radical of the alkoxy or alkyl,

or radical

where R4, R5, R6, R7and R8independently represent a hydrogen atom, a halogen, an OH group or a radical of the alkyl, alkoxy, cyano, nitro or NR10R11,

R10and R11independently represent a hydrogen atom, an alkyl radical or a group-COR12or R10and R11form together with the nitrogen atom optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, said heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

R12represents a hydrogen atom or an alkyl radical, alkoxy or NR13R14,

R13and R14independently represent a hydrogen atom or an alkyl radical, or R13and R14together with the atom is m nitrogen form an optionally substituted heterocycle, containing from 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, said heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

R9represents a hydrogen atom, an alkyl radical or a group-COR15,

R15represent a hydrogen atom or an alkyl radical, alkoxy or NR16R17,

R16and R17independently represent a hydrogen atom or an alkyl radical, or R16and R17form together with the nitrogen atom optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms independently selected from the group comprising atoms of O, N and S, said heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

and W is absent or represents a bond, or-O-, -S - or-NR18-where R18represents a hydrogen atom or an alkyl radical;

or

radical, where Q represents a H radical OR22, -SR22,

-NR23R24, phenyl, optionally substituted by one or more substituents, independently you the security of a halogen atom, the OH radical, cyano, nitro, alkyl, alkoxy or-NR10R11and a group of two substituents together represent a radical of methylendioxy or Ethylenedioxy, or Q represents a radical-COPh, -SO2Ph or-CH2Ph specified radical-COPh, -SO2Ph or-CH2Ph, optionally substituted in its aromatic part by one or more substituents, independently selected from radicals of the alkyl or alkoxy and halogen atom,

R10and R11independently represent a hydrogen atom, an alkyl radical or a group-COR12or R10and R11form together with the nitrogen atom optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, said heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

R12represents a hydrogen atom, alkyl, or alkoxy, or a radical NR13R14,

R13and R14independently represent a hydrogen atom or an alkyl radical, or R13and R14together with the nitrogen atom form an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, and add to the performance communications heteroatoms, independently selected from the group comprising atoms of O, N and S, said heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

R22represents a hydrogen atom, an alkyl radical or aryl, optionally substituted by one or more substituents selected from the radicals alkyl, OH, halogen, nitro and alkoxy,

R23and R24independently represent a hydrogen atom, an alkyl radical or the radical-CO-R25,

R25represents an alkyl radical,

and R19, R20and R21independently represent hydrogen, halogen, an OH group or SR26or an alkyl radical, cycloalkyl, alkenyl, alkoxy, cyano, nitro, -SO2Other49, -CONHR55, -S(O)qR56,

-NH(CO)R57, -CF3, -OCF3or NR27R28,

R26represents a hydrogen atom or an alkyl radical,

R27and R28independently represent a hydrogen atom, an alkyl radical or a group-COR29or R27and R28form together with the nitrogen atom optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, said heterocycle may be, for example, azetidine, PIR is alidina, the piperidine, piperazine, morpholine or thiomorpholine,

R49and R55independently represent, whenever they are enabled, a hydrogen atom or an alkyl radical or alkylsulphonyl,

q is an integer from 0 to 2,

R56and R57independently represent, whenever they are enabled, a hydrogen atom or an alkyl radical or alkoxy,

R29represents a hydrogen atom, alkyl radical, alkoxy or-NR30R31,

R30and R31independently represent a hydrogen atom or an alkyl radical, or R30and R31form together with the nitrogen atom optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, said heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

or

radical, where R32represents a hydrogen atom or an alkyl radical, and T represents the radical -(CH2)m-where m = 1 or 2

or, finally,

radical, where R33represents a hydrogen atom or an alkyl radical, -Σ-NR34R35or -Σ-CHR36R37,

: represents a linear or branched radical of alkylene containing from 1 to 6 carbon atoms,

R34and R35independently represent a hydrogen atom or an alkyl radical,

R36and R37independently represent a hydrogen atom or a radical carbocyclic or heterocyclic aryl, optionally substituted by one or more substituents selected from the radicals alkyl, OH, halogen, nitro, alkoxy or NR10R11,

R10and R11independently represent a hydrogen atom, an alkyl radical or a group-COR12or R10and R11together with the nitrogen atom form an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, said heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

R12represents a hydrogen atom or alkyl, alkoxy or a radical NR13R14,

R13and R14independently represent a hydrogen atom or an alkyl radical, or R13and R14together with the nitrogen atom form an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing at the m of nitrogen, additional heteroatoms, independently selected from the group comprising atoms of O, N and S, said heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, and T is a radical

-(CH2)m-where m = 1 or 2

or A represents a radical alkyl, cycloalkyl or cycloalkenyl;

X represents S or NR38,

R38represents a hydrogen atom or an alkyl radical, cianelli, aralkyl, alkylaryl or aralkylamines,

Y represents O or S;

R1represents a hydrogen atom, an alkyl radical, aminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, triptorelin, alkenyl, alltel, alltracel, quinil, cianelli, -(CH2)g-Z1R39, -(CH2)g-COR40, -(CH2)g-NHCOR70, aryl, aralkyl, arylcarbamoyl, heteroaromatic or aralkylamines, where the aryl group of the aryl radicals, aralkyl, arylcarbamoyl, heteroaromatic or aralkylamines, in turn, optionally substituted by one or more substituents selected from the group comprising the radicals alkyl, halogen, alkoxy, nitro, cyano, cianelli, amino, alkylamino, dialkylamino, -(CH2)k-Z2R39or -(CH2)k-COR40,

Z1and Z2provide the amount of the bond, -O-, -NR41- or-S-,

R39and R41independently represent, whenever they are enabled, a hydrogen atom or an alkyl radical, alkenyl, quinil or cianelli,

R40independently represents, every time it is switched on, a hydrogen atom or an alkyl radical, alltel, alltracel, alkenyl, quinil, cianelli, alkoxy or NR42R43,

R42and R43independently represent, whenever they are enabled, a hydrogen atom or an alkyl radical, alltel, alltracel, alkenyl, quinil or cianelli,

and R2represents a hydrogen atom, an alkyl radical, aminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, triptorelin or -(CH2)g-NHCOR71or one of the radicals aralkyl or heteroaromatic optionally substituted in the aryl or heteroaryl group by one or more groups independently selected from the group consisting of a halogen atom and a radical alkyl radical, alkoxy, hydroxy, cyano, nitro, amino, alkylamino or dialkylamino,

R70and R71independently represent an alkyl radical or alkoxy;

or R1and R2taken together with carrying their carbon atom, form carbocycle with 3-7 members;

Represents a hydrogen atom, an alkyl radical, a radical -(CH2)g-Z3R44or carbocyclic the ski aryl radical, optionally substituted with 1-3 radicals selected from the group consisting of a halogen atom, a linear or branched alkyl or alkoxy radical containing from 1 to 6 carbon atoms, a hydroxy radical, a cyano or nitro, amino, alkylamino or dialkylamino radical and a carbocyclic aryl radical,

Z3represents a bond, -O-, -NR45- or-S-,

R44and R45independently represent a hydrogen atom or an alkyl radical, alkenyl, quinil, alltel, alltracel or cianelli;

Ω represents one of the radicals NR46R47or or48where:

R46and R47independently represent a hydrogen atom or an alkyl radical, cycloalkyl, cycloalkenyl, alkenyl, quinil, alltel, alltracel, cianelli, -(CH2)g-Z4R50, -(CH2)k-COR51,

-(CH2)k-COOR51, -(CH2)k-CONHR51or-SO2R51or also a radical chosen from aryl radicals, aralkyl, aryloxyalkyl, arylcarbamoyl, arylimino, aralkylamines, heteroaryl and, in particular, the radicals pyridinyl, pyridinylmethyl or pyridylcarbonyl, where aryl or heteroaryl group mentioned radicals aryl, aralkyl, aryloxyalkyl, arylcarbamoyl, arylimino, aralkylamines, heteroaryl, pyridinylmethyl or pyridylcarbonyl neobyazatelnostyu one or more substituents, independently selected from halogen, alkyl, alkoxy, hydroxy, nitro, cyano, cyanoalanine, amino, alkylamino, dialkylamino, -(CH2)kZ5R50, -(CH2)k-COR51and -(CH2)k-COOR51,

Z4and Z5represent a bond, -O-, -NR52- or-S-,

or R46and R47taken together with the nitrogen atom, form the non-aromatic heterocycle with 4 to 8 members, the elements of the chain are selected from the group consisting of-CH(R53)-, -NR54-, -O-, -S - and-CO-, said heterocycle may be, for example, azetidine, piperazine, homopiperazine, 3,5-dioxopiperazinyl, piperidine, pyrrolidine, morpholine or thiomorpholine,

R50and R52independently represent, whenever they are enabled, a hydrogen atom or an alkyl radical, alkenyl, quinil, alltel, alltracel or cianelli,

R51independently represents, whenever it is enabled, the hydrogen atom, one of the radicals cycloalkyl or cycloalkenyl where cycloalkyl radical contains from 3 to 7 carbon atoms, a linear or branched alkyl radical containing from 1 to 8 carbon atoms, a radical of alkenyl, quinil, alltel, alltracel, cianelli, alkoxyalkyl or NR58R59or aryl radical or aralkyl, where the specified radicals aryl or aralkyl may be substituted by one or more mixing what italiani, independently selected from a halogen atom and alkyl radical or alkoxy,

R58and R59independently represent a hydrogen atom or an alkyl radical, alkenyl, quinil, alltel, alltracel or cianelli,

R53and R54independently represent a hydrogen atom or the radical -(CH2)k-Z7R60or -(CH2)k-COR61,

Z7represents a bond, -O-, -NR62- or-S-,

R60and R62independently represent a hydrogen atom or an alkyl radical, alkenyl, alltel, alltracel, quinil, cianelli, aryl, aralkyl, arylcarbamoyl, aralkylamines, pyridinyl, pyridinylmethyl or pyridylcarbonyl, where aryl or pyridinoline group of radical aryl, aralkyl, arylcarbamoyl, aralkylamines, pyridinyl, pyridinylmethyl or pyridylcarbonyl optionally substituted by one or more substituents selected from the group consisting of alkyl radicals, halogen, nitro, alkoxy, cyano, cianelli, -(CH2)k-Z8R63and -(CH2)k-COR64,

R61represents a hydrogen atom, an alkyl radical, alltel, alltracel, alkenyl, quinil, cianelli, alkoxy or NR65R66,

R65and R66independently represent a hydrogen atom or an alkyl radical, alltel, alltracel, alkenyl, quinil or qi is noelker,

Z8represents a bond, -O-, -NR67- or-S-,

R63and R67independently represent a hydrogen atom, an alkyl radical, alltel, alltracel, alkenyl, quinil or cianelli,

R64represents a hydrogen atom, an alkyl radical, alltracel, alkenyl, alkenyl, quinil, cianelli, alkoxy or NR68R69,

R68and R69independently represent a hydrogen atom or an alkyl radical, alltel, alltracel, alkenyl, quinil or cianelli,

and R48represents a hydrogen atom or an alkyl radical, quinil or cianelli;

g and p, whenever they are enabled independently is an integer from 1 to 6, and k and n each time they are activated, independently is an integer from 0 to 6;

it is clear that when Het is such that the compound of General formula (I) corresponds to the overall Podgornoe (I)4then:

A represents a radical 4-hydroxy-2,3-di-tert-butylphenyl;

B, R1and R2all represent H; and finally,

Ω represents OH;

or pharmaceutically acceptable salts of the compounds of General formula (I);

can be used with obtaining drugs having at least one of the following three types of activity:

- monoamine oxidase inhibition, in particular, monoamine oxidase B,

- inhibition of peroxidation is about lipid oxidation,

- the expression modulating activity against sodium channels.

This allows the compounds of General formula (I) to be effective in the treatment of the above diseases associated with MAO, lipid peroxidation and sodium channels.

Under alkyl, unless otherwise stated, mean linear or branched alkyl radical containing from 1 to 6 carbon atoms. Under cycloalkyl, unless otherwise specified, mean monocyclic carbon system containing from 3 to 7 carbon atoms. Under alkenyl, unless otherwise specified, mean linear or branched alkyl radical containing from 1 to 6 carbon atoms and having at least one unsaturation (double bond). Under quinil, unless otherwise specified, mean linear or branched alkyl radical containing from 1 to 6 carbon atoms, and having at least one double unsaturation (triple bond). Under allenina mean the radical-CH=C=CH2. Under carbocyclic or heterocyclic aryl mean carbocyclic system (in particular, the phenyl radical, which may be indicated by the abbreviation Ph) or heterocyclic system containing at least one aromatic ring, heterocyclic system is, when at least one of the rings contained therein, with the holding heteroatom (O, N or S). Under the heterocycle mean mono - or polycyclic system, where the system includes at least one heteroatom selected from O, N and S, and is a saturated, partially or fully unsaturated or aromatic. Under heteroaryl imply a heterocycle, as defined above, where at least one of its component rings is aromatic. Under halogenation mean an alkyl radical, at least one (and optionally all) of the hydrogen atoms of which are substituted by a halogen atom.

Moreover, unless otherwise stated, under optionally substituted radical is meant a radical containing one or more substituents independently selected from the group consisting of halogen atom and alkyl radicals and alkoxy.

Under radicals, alkylthio, alkoxy, halogenated, alkoxyalkyl, triptorelin, cycloalkenyl, halogenoalkane, aminoalkyl, alkenyl, quinil, alltracel, cianelli and aralkyl mean, respectively, radicals, alkylthio, alkoxy, halogenated, alkoxyalkyl, triptorelin, cycloalkenyl, halogenoalkane, aminoalkyl, alkenyl, quinil, alltracel, cianelli and aralkyl, in which the alkyl radical (alkyl radicals) is(are) the value(s)shown(s) above.

Under the heterocycle implies, in particular, radicals thiophene, PIP is ridin, piperazine, quinoline, indoline and indole. Under linear or branched alkyl containing from 1 to 6 carbon atoms, implies, in particular, the radicals methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl. Finally, under the halogen is meant fluorine atoms, chlorine, bromine or iodine.

The present invention relates to the selected series of compounds of General formula (I)above, namely the following connections:

- 2,6-di-tert-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol (hereafter compound 1);

- 2,6-di-tert-butyl-4-[4-(hydroxymethyl)-1,3-oxazol-2-yl]phenol (hereafter compound 2);

- 2,6-di-tert-butyl-4-{2-[1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol (hereafter compound 3);

- 2,6-di-tert-butyl-4-[2-(methoxymethyl)-1,3-thiazol-4-yl]phenol (hereafter compound 4);

- 2,6-di-tert-butyl-4-{4-[(methylamino)methyl]-1,3-oxazol-2-yl}phenol (hereafter compound 5);

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide (hereinafter compound 6);

- ethyl [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylcarbamate (hereinafter compound 7);

- 2,6-di-tert-butyl-4-[2-(morpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol (hereafter compound 8);

- 2,6-di-tert-butyl-4-[2-(thiomorpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol (hereafter compound 9);

- 4-[2-(anilinomethyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol (Yes is its connection 10);

- 2,6-di-tert-butyl-4-(2-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}-1,3-thiazol-4-yl)phenol (hereafter compound 11);

- 2,6-di-tert-butyl-4-{5-methyl-2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 12);

- 1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methanamine (hereinafter compound 13);

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-methylacetamide (hereinafter compound 14);

- 1-[4-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-2-yl]-N-methylmethanamine (hereinafter compound 15);

- 2,6-di-tert-butyl-4-{2-[(ethylamino)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 16);

- 2,6-di-tert-butyl-4-{2-[(4-phenylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 17);

- 2,6-di-tert-butyl-4-{2-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 18);

- N-{1-[4-(4-anilinophenol)-1,3-thiazol-2-yl]ethyl}-N-methylamine (hereinafter compound 19);

- 2,6-di-tert-butyl-4-{2-[(isopropylamino)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 20);

- 2,6-di-tert-butyl-4-{2-[(cyclohexylamino)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 21);

- 2,6-di-tert-butyl-4-{2-[(4-isopropylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 22);

- N-methyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]ethanamine (hereinafter compound 23);

- 2,6-di-tert-butyl-4-{2-[(4-ethylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 24);

- N-{[4-(4-anilinophenol)-1,3-thiazol-2-yl]methyl}-N-atrami is at (hereinafter compound 25);

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}ethanamine (hereinafter compound 26);

- 2,6-di-tert-butyl-4-(2-{[4-(dimethylamino)piperidine-1-yl]methyl}-1,3-thiazol-4-yl)phenol (hereafter compound 27);

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-Olu (hereinafter compound 28);

- 4-methylpentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 29);

- 3,3-dimethylbutyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 30);

- isopentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 31);

- hexyl 2-[4-(4'-bromo-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 32);

- benzil-2-[4-(4-tert-butylphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 33);

- 3,3-dimethylbutyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 34);

- hexyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 35);

- hexyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 37);

- 3,3-dimethylbutyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 38);

- 3,3-dimethylbutyl 2-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 39);

- benzil-2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 40);

- benzil-2-[4-(4-p is Raiden-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 41);

- 2-phenylethyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 42);

- butyl 2-[4-(4'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 43);

- butyl 2-[4-(1,1'-biphenyl-4-yl)-5-methyl-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 44);

- butyl 2-[4-(4'-methyl-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 45);

- butyl 2-[4-(4'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 46);

- butyl 2-[4-(2'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 47);

- butyl 2-[4-(2',4'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 49);

- 2,6-di-tert-butyl-4-{2-[(propylamino)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 50);

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}-N-Propylamine (hereinafter compound 51);

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}butane-1-amine (the compound 52);

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pentane-1-amine (the compound 53);

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-3-Olu (hereinafter compound 54);

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-Olu (hereinafter compound 55);

- [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methanol (hereinafter compound 56);

- N,N-dimethyl-N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}amine (hereinafter compound 57);

- 2-{2-[(4-methylpiperid the Zin-1-yl)methyl]-1,3-thiazol-4-yl}-10H-phenothiazines (hereinafter compound 58);

- 2-[2-(piperidine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-phenothiazines (hereinafter compound 59);

- 2-[2-(piperazine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-phenothiazines (hereinafter compound 60);

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}azetidin-3-Olu (hereinafter compound 61);

- 2-[2-(morpholine-4-ylmethyl)-1,3-thiazol-4-yl]-10H-phenothiazines (hereinafter compound 62);

- 2-[2-(thiomorpholine-4-ylmethyl)-1,3-thiazol-4-yl]-10H-phenothiazines (hereinafter compound 63);

- 2-{2-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-thiazol-4-yl}-10H-phenothiazines (hereinafter compound 64);

- (3R)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-Olu (hereinafter compound 65);

- (3S)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-Olu (hereinafter compound 66);

- 2,6-di-tert-butyl-4-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]phenol (hereafter compound 67);

- 2,6-di-tert-butyl-4-{2-[(butylamino)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 68);

- 2-{2-[(4-ethylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}-10H-phenothiazines (hereinafter compound 69);

- N-methyl-N-{[4-(10H-phenothiazines-2-yl)-1H-imidazol-2-yl]methyl}amine (hereinafter compound 70);- methyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate (hereinafter compound 71);

- butyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate (hereinafter compound 72);

- N-neopentyl-N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}amine (hereinafter compound 73);

- 1-{[4-(10H-phenothiazines-2-yl)-1,-thiazol-2-yl]methyl}piperidine-4-Olu (hereinafter compound 74);

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide (hereinafter compound 75);

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}butanamide (hereinafter compound 76);

- 2,6-di-tert-butyl-4-{2-[(4-propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 77);

- 2,6-di-tert-butyl-4-{2-[2-methyl-1-(methylamino)propyl]-1,3-thiazol-4-yl}phenol (hereafter compound 78);

- N,2-dimethyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]propan-1-amine (the compound 79);

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}hexanamide (hereinafter compound 80);

- (3R)-1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-Olu (hereinafter compound 81);

- (3S)-1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-Olu (hereinafter compound 82);

- 1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}azetidin-3-Olu (hereinafter compound 83);

- 2-{2-[(4-propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-phenothiazines (hereinafter compound 84);

- 2-{2-[(4-acetylpiperidine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-phenothiazines (hereinafter compound 85);

- 2-{2-[(4-butylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-phenothiazines (hereinafter compound 86);

- methyl 4-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate (hereinafter compound 87);

- 4-[2-(aminomethyl)-1H-imidazol-4-yl]-2,6-di-tert-butylphenol (hereinafter compound 88);

- 4-{2-[(benzylamino)methyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol (hereinafter compound 89);

- 4-{2-[(4-acetyle erasin-1-yl)methyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol (hereinafter the compound 90);

- N-methyl-N-{[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]methyl}amine (hereinafter compound 91);

- 4-[2-(azetidin-1-ylmethyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol (hereinafter the compound 92);

- 2,6-di-tert-butyl-4-{2-[(4-butylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol (hereafter compound 93);

- butyl 2-[4-(3'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 94);

- butyl 2-[4-(3'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 95);

-butyl 2-[4-(4-isobutylphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 96);

- benzil-2-[4-(4-isobutylphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 97);

- butyl 2-[4-(3'-chloro-4'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 98);

- butyl 2-[4-(3',4'-dichloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 99);

- butyl 2-[4-(4-propylphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 100);

- butyl 2-[4-(4-ethylphenyl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 101);

- butyl 2-[4-(4'-cyano-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 102);

- butyl 2-[4-(1,1'-biphenyl-4-yl)-5-ethyl-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 104);

- butyl 2-[4-(2'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 105);

- butyl 2-[4-(2',3'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 106);

- butyl 2-[4-(2'-the rum-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 107);

- butyl 2-[4-(3',5'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 108);

- butyl 2-[4-(2'-methoxy-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 109);

- butyl 2-[4-(3'-nitro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 110);

- butyl 2-[4-(2',5'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 111);

- butyl 2-[4-(3'-methoxy-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate (hereinafter compound 112);

- methyl 4-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate (hereinafter compound 113);

- methyl [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylcarbamate (hereinafter compound 114);

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}benzamide (hereinafter compound 115);

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-2-phenylacetamide (hereinafter compound 116);

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}propanamide (hereinafter compound 117);

- acetate 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-DRS (hereinafter compound 118);

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3,4-diolo (hereinafter compound 119);

and salts of the latter.

In particular, this invention relates to compounds 1-112 and their salts and, in particular, to compounds 1-49 and their salts.

In accordance with the laws the AI with a preferred variant of the invention, these compounds have at least two types of activity mentioned above. In particular, they inhibit MAO, and catch ROS, or they have antagonistic activity against sodium channels, and activity capture ROS. In some cases, compounds of General formula (I) combine three types of activity.

In accordance with a particular variant of the invention, when the compounds of this invention have mainly inhibitory activity against MAO and/or ROS, they are preferably chosen from compounds 1-28, 50-93 and 113-119, and salts of these compounds (particularly compounds 1-28 and 50-93 and salts of these compounds and, in particular, compounds 1-28 and salts of these compounds).

More preferably, the compounds according to this invention, when they possess inhibitory activity against MAO and/or ROS, selected from compounds 1, 3, 6-8, 12, 13, 15, 16, 18-20, 22-28, 50-62, 64-71, 73-86, 89, 91-93 and 119 and salts of these compounds (particularly compounds 1, 3, 6-8, 12, 13, 15, 16, 18-20, 22-28, 50-62, 64-71, 73-86, 89 and 91-93 and salts of these compounds and, in particular, from compounds 1, 3, 6-8, 12, 13, 15, 16, 18-20 and 22-28 and salts of these compounds).

Even more preferably, the compounds according to this invention, when they possess inhibitory activity against MAO and/or ROS, selected from compounds 1, 3, 6-8, 12, 13, 15, 16, 18-20, 22-24, 26, 28, 50-52, 54, 55, 57, 58, 61, 62, 65-69, 73, 75, 77-82, 86, 89, 91, 92 and 119 and the lei of these compounds (in particular, of compounds 1, 3, 6-8, 12, 13, 15, 16, 18-20, 22-24, 26, 28, 50-52, 54, 55, 57, 58, 61, 62, 65-69, 73, 75, 77-82, 86, 89, 91 and 92, and salts of these compounds and, in particular, compounds 1, 3, 6-8, 12, 13, 15, 16, 18-20, 22-24, 26 and 28, and salts of these compounds).

In particular, the compounds according to this invention, when they possess inhibitory activity against MAO and/or ROS, selected from compounds 1, 3, 6, 15, 16, 18, 20, 23, 24, 26, 28, 50, 52, 55, 61, 65-69, 77, 78, 79, 81, 86, 89, 91, 92 and 119 and salts of these compounds (particularly compounds 1, 3, 6, 15, 16, 18, 20, 23, 24, 26, 28, 50, 52, 55, 61, 65-69, 77, 78, 79, 81, 86, 89, 91 and 92 and salts of these compounds and, in particular, of the compounds 1, 3, 6, 15, 16, 18, 20, 23, 24, 26 and 28 and salts of these compounds).

More preferably, the compounds according to this invention, when they possess inhibitory activity against MAO and/or ROS, selected from compounds 3, 15, 16, 20, 23, 26, 28, 50, 55, 61, 65-68, 78, 79, 91 and 92, and salts of these compounds (particularly compounds 3, 15, 16, 20, 23, 26 and 28 and salts of these compounds).

Even more preferably, the compounds according to this invention, when they possess inhibitory activity against MAO and/or ROS, selected from compounds 3, 15, 16, 28, 55, 61, 65, 66 and 79, and salts of these compounds (in particular, compounds 3, 15, 16, and 28 and salts of these compounds).

In accordance with another variant of the invention, when the compounds according to this invention basically have modulatory activity against sodium channels, they pre is respectfully, selected from the compounds 1, 3, 5, 12, 15, 16, 29-35, 37-47, 49, 94-102 and 104-112 and salts of these compounds (particularly compounds 1, 3, 5, 12, 15, 16, 29-35, 37-47 and 49 and salts of these compounds).

More preferably, the compounds of this invention having modulating activity against sodium channels, selected from compounds 3, 15, 16, 29-35, 37-47, 49, 94-102 and 104-112 and salts of these compounds (particularly compounds 1, 3, 5, 12, 15, 16, 29-35, 37-47 and 49 and salts of these compounds).

Even more preferably, compounds of General formula (I)having modulating activity against sodium channels, selected from compounds 30, 37, 42, 44-46, 48, 49, 106, 108, 109 and 112 and salts of these compounds (in particular, compounds 30, 37, 42, 44-46, 48 and 49 and salts of these compounds).

Further, compounds, mainly possessing inhibitory activity against lipid peroxidation, preferably selected from compounds 1-28, 37, 38, 40, 50-93 and 113-119, and salts of these compounds (particularly compounds 1-28, 37, 38, 40 and 50-93 and salts of these compounds and, in particular, compounds 1-28, 37, 38 and 40, and salts of these compounds).

More preferably, compounds, mainly possessing inhibitory activity against lipid peroxidation, preferably selected from compounds 1-28, 50-62, 64-93 and 113-119, and salts of these compounds (particularly compounds 1-28, 50-62 and 64-93 and salts of these compounds and, particularly, of the compounds 1-28 and salts of these compounds).

Even more preferably, compounds, mainly possessing inhibitory activity against lipid peroxidation, preferably selected from compounds 13, 18, 19, 22-27, 51-53, 55-60, 62, 64, 69, 73-76, 79, 81-86, 91 and salts of these compounds (in particular, compounds 13, 18, 19, 22-27, and salts of these compounds).

In particular, compounds, mainly possessing inhibitory activity against lipid peroxidation, preferably selected from the compounds 13, 23, 58, 64, 81, 82 and 91 and salts of these compounds (in particular, compounds 13 and 23 and the salts of these compounds).

Further, the invention relates to the selected compounds mentioned above, and their pharmaceutically acceptable salts as a drug. The invention also relates to compositions containing as active ingredient at least one selected from the compounds listed above, or a pharmaceutical salt of one of these compounds.

The purpose of this invention is also the use of one of the selected compounds mentioned above, or a pharmaceutically acceptable salt of one of these compounds, with taking drugs having at least one of the following three types of activity:

- monoamine oxidase inhibition, in particular monoamine oxidase B,

in euromania lipid peroxidation,

- the expression modulating activity against sodium channels.

In particular, the present invention relates to the use of one of the selected compounds mentioned above, or a pharmaceutically acceptable salt of one of these compounds, with taking drugs designed for treatment of one of the following disorders or diseases: Parkinson's disease, senile dementia, Alzheimer's disease, horei of Hantington, amyotrophic lateral sclerosis, schizophrenia, depression, psychosis, migraine or pain, in particular neuropathic pain.

The invention also relates to compounds of General formula (I'), the General formula is identical to General formula (I), except that:

(a) either A is replaced by a radical'

where Q' represents a phenyl radical, optionally substituted by one or more substituents, independently selected from a halogen atom, an OH radical, cyano, nitro, alkyl, halogenoalkane, alkoxy, alkylthio or-NR10'R11'and a group of two substituents together represent a radical of methylendioxy or Ethylenedioxy,

R10'and R11'independently represent a hydrogen atom, an alkyl radical or a group-COR12'or R10'and R11'form together with the nitrogen atom optionally substituted gets recycl, containing from 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, where the heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

R12'represents a hydrogen atom, alkyl, or alkoxy, or a radical NR13'R14',

R13'and R14'independently represent a hydrogen atom or an alkyl radical, or R13'and R14'form together with the nitrogen atom optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, where the heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

and R19', R20'and R21'independently represent hydrogen, halogen, OH or group SR26'or an alkyl radical, cycloalkyl, alkenyl, alkoxy, alkylthio, cyano, nitro, -SO2Other49', -CONHR55', -S(O)qR56', -NH(CO)R57', -CF3, -OCF3or NR27'R28',

R26'represents a hydrogen atom or an alkyl radical,

R27'and R28'independently represent a hydrogen atom which, the alkyl radical or the group-COR29'or R27'and R28'together with the nitrogen atom form an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, where the heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

R49'and R55'independently represent, whenever they are enabled, a hydrogen atom, or an alkyl radical, or alkylaryl,

q is an integer from 0 to 2,

R56'and R57'independently represent, whenever they are enabled, a hydrogen atom, or an alkyl radical, or alkoxy,

R29'represents a hydrogen atom, alkyl radical, alkoxy or-NR30'R31',

R30'and R31'independently represent a hydrogen atom or an alkyl radical, R30'and R31'together with the nitrogen atom form an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, where the heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or t is morpholino,

R51moreover, replaced by the radical R51'specified the radical R51'represents one of the radicals specified for R51in the General formula (I), or a radical halogenated,

it is clear that either Q' represents a phenyl radical substituted at least one halogenosilanes radical or at least one of Q', R19', R20'and R21'represents a radical of alkylthio;

(b) either Ω replaced by radical Ω', where the specified radicals Ω' represents a radical NR46R47where one of R46'and R47'is a radical-COOR51'and the other represents a hydrogen atom, R51'represents a radical halogenated;

and salts of such compounds.

In particular, this aspect of the invention relates to the compound of General formula (I'), the General formula is identical to General formula (I), except that:

(a) either A is replaced by a radical'

where Q' represents a phenyl radical, optionally substituted by one or more substituents, independently selected from a halogen atom, an OH radical, cyano, nitro, alkyl, alkoxy, alkylthio or-NR10'R11'and two of the substituents represents together a radical of methylendioxy or Ethylenedioxy,

R10'and R11'the independent is about represent a hydrogen atom, the alkyl radical or the group-COR12'or R10'and R11'together with the nitrogen atom form an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, where the heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

R12'represents a hydrogen atom, alkyl radical or alkoxy, or NR13'R14',

R13'and R14'independently represent a hydrogen atom or an alkyl radical, or R13'and R14'together with the nitrogen atom form an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, where the heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

and R19', R20'and R21'independently represent hydrogen, halogen, OH or group SR26'or an alkyl radical, cycloalkyl, alkenyl, alkoxy, alkylthio, cyano, nitro, -SO2Other49', -CONHR55', -S(O)qR56', -NH(CO)R57', -CF3, -OCF3or NR27'R28',

26'represents a hydrogen atom or an alkyl radical,

R27'and R28'independently represent a hydrogen atom, an alkyl radical or a group-COR29'or R27'and R28'together with the nitrogen atom form an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group comprising atoms of O, N and S, where the heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

R49'and R55'independently represent, whenever they are enabled, a hydrogen atom, or an alkyl radical, or alkylaryl,

q is an integer from 0 to 2,

R56'and R57'independently represent, whenever they are enabled, a hydrogen atom, or an alkyl radical, or alkoxy,

R29'represents a hydrogen atom, alkyl, alkoxy or the radical-NR30'R31',

R30'and R31'independently represent a hydrogen atom or an alkyl radical, R30'and R31'together with the nitrogen atom form an optionally substituted heterocycle containing 4 to 7 members and 1 to 3 heteroatoms, including existing nitrogen atom, the additional heteroatoms, independently selected from the group including the nd atoms O, N and S, where the heterocycle may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,

R51moreover, substituted by the radical R51'specified the radical R51'represents one of the radicals defined in R51in the General formula (I), or a radical halogenated,

it is clear that at least one Q', R19', R20'and R21'represents a radical of alkylthio;

(b) either Ω replaced by radical Ω', where the specified radicals Ω' represents a radical NR46R47where one of R46'and R47'is a radical-COOR51'and the other represents a hydrogen atom, R51'represents a radical halogenated;

and salts of such compounds.

In the case of (a) compounds of General formula (I') is preferably such that n is 0 or 1, and Ω is a radical NR46R47(when n = 1, then one of R46and R47preferably represents the radical COOR51). Similarly, R1and R2preferably independently selected from the group consisting of hydrogen atom and alkyl radical or cycloalkyl (and, preferably, a methyl radical). More preferably, in the case of (a) compounds of General formula (I') correspond to compounds of the General podhorany (I)1or (I)2X PR is doctitle represents S or NH, and more preferably, NH. In addition, the radical of alkylthio preferably represents a radical of ethylthio or methylthio, more preferably a methylthio radical.

In case (b) compounds of General formula (I') is preferably such that n is 0 or 1 (preferably 1). Similarly, R1and R2preferably represent hydrogen atoms. Moreover, more preferably, in the case of (b) radical halogenated preferably represents a radical, substituted exclusively by one or more fluorine atoms (for example, radical 4,4,4-trifloromethyl). Also preferably, in the case of (b)that the compounds of General formula (I') correspond to compounds of the General podhorany (I)1or (I)2X preferably represents S or NH, and, more preferably, NH.

This invention, therefore, also, in particular, relates to the following compounds of General formula (I'):

- butyl 2-{4-[4'-(methylthio)-1,1'-biphenyl-4-yl]-1H-imidazol-2-yl}ethylcarbamate;

- 4,4,4-tripcomputer 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-{4-[4'-(trifluoromethyl)-1,1'-biphenyl-4-yl]-1H-imidazol-2-yl}ethylcarbamate;

and the salts of these compounds;

and in particular:

- butyl 2-{4-[4'-(methylthio)-1,1'-biphenyl-4-yl]-1H-imidazol-2-yl}ethylcarbamate;

- 4,4,4-tripcomputer 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]e is ylcarbamate;

and salts of such compounds.

In addition, the invention relates to compounds of General formula (I')defined above, and their pharmaceutically acceptable salts as a drug. The invention also relates to compositions containing as active ingredient at least one compound of General formula (I')defined above, or pharmaceutically acceptable salt of one of these compounds.

The object of this invention is also the use of one of the compounds of General formula (I')defined above, or pharmaceutically acceptable salt of one of these compounds, with taking drugs having at least one of the following three types of activity:

- monoamine oxidase inhibition, in particular monoamine oxidase B,

the inhibition of lipid peroxidation,

- manifestation of moduliruemoi activity against sodium channels.

In particular, the present invention relates to the use of one of the compounds of General formula (I')above, or a pharmaceutically acceptable salt of one of these compounds, with taking drugs designed for treatment of one of the following disorders or diseases: Parkinson's disease, senile dementia, Alzheimer's disease, horei of Hantington, side amitr is pichiciego sclerosis, schizophrenia, depression, psychosis, migraine or pain, in particular neuropathic pain.

In some cases, compounds of the present invention may contain asymmetric carbon atoms. Therefore, compounds of the present invention can be in two possible enantiomeric forms, i.e. in the "R" and "S" configurations. The present invention includes two enantiomeric forms and all combinations of these forms, including the "RS" razemicescuu mixture. For simplicity, unless a specific configuration in the structural formulas and names of compounds, it is clear that presents two enantiomeric forms and mixtures thereof.

The invention also relates to the compounds mentioned above, or their pharmaceutically acceptable salts as a drug. Similarly, it refers to pharmaceutically acceptable compositions containing as active ingredient the above compounds or their pharmaceutically acceptable salts, as well as to the use of these compounds and their pharmaceutically acceptable salts with reception of medicines intended for the inhibition of monoamine oxidase, in particular monoamine oxidase B, for the inhibition of lipid peroxidation, having modulating activity against sodium channels, or with two of three or three of the above activities.

In particular, the compounds of this invention can be used for obtaining a medicinal product intended to treat one of the following disorders or diseases: Parkinson's disease, senile dementia, Alzheimer's disease, horei of Hantington, amyotrophic lateral sclerosis, schizophrenia, depression, psychosis, migraine or pain, in particular neuropathic pain. More specifically, compounds represented as inhibiting MAO and/or ROS, can be used to treat one of the following disorders or diseases: Parkinson's disease, senile dementia, Alzheimer's disease, horei of Hantington, amyotrophic lateral sclerosis, schizophrenia, depression, psychosis; and compounds represented as having modulating activity against sodium channels, can be used to treat the following disorders or diseases: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, migraine or pain, in particular neuropathic pain.

Under the salt in this application implies, in particular, salts of adding inorganic or organic acids, and salts formed with bases.

Under a pharmaceutically acceptable salt implies, in particular, salts of addition of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, diphosphate and nitrate or organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, pamoate and stearate. Also in the scope of the present invention are salts formed with bases, such as sodium hydroxide or potassium when they can be used. Reference to other examples of pharmaceutically acceptable salts can be given in "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

The pharmaceutical composition may be in the form of a solid, for example powders, granules, tablets, gelatin capsules, liposomes or suppositories. Appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax. Pharmaceutical compositions containing a compound according to this invention, can also be presented in liquid form such as solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, and mixtures thereof in various proportions in water.

The administration of a medicinal product according to this invention may occur local, oral, couple tarannum by, by intramuscular injection and the like.

Enter the dose prescribed for medicines in this invention is from 0.1 mg to 10 g, depending on the type of active connections.

In accordance with this invention, compounds of General formula (I) can be obtained using the methods described below.

Obtaining the compounds according to the invention

General information

Obtain the compounds according to this invention, where Ω represents OH, carried out by methods similar to those described in the patent application PCT WO 99/09829 and in European patent application EP 432740.

As for the compounds of this invention where Het is an imidazole ring, a specialist in this area could usefully refer to the patent application PCT WO 99/64401.

Other compounds according to this invention is carried out by methods similar to those described in the patent application PCT WO 98/58934 (see, in particular, pages 39-45 of this document, the synthesis of intermediate compounds of formulae (XXV) and (XXVIII)or corresponds to the methods described below.

Furthermore, compounds of General formula (I') was obtained in a manner analogous to the method of obtaining compounds of General formula (I); analysis of the description that follows of the compounds of the General formula (I)can in General be extended to the synthesis of the compounds the deposits of the General formula (I').

Obtaining compounds of General formula (I)

Compounds of General formula (I) can be obtained 8 synthetic routes are illustrated below (figure 1) from the intermediate compounds of General formulas (IV), (V), (VI), (VII), (VIII), (IX), (X) and (I)a, where A, B, Ω, R1, R2, Het and n are such as defined above, L represents a removable group, such as, for example, halogen, Alk represents an alkyl radical, Gp represents a protective group for the amine functional group, for example group 2-(trimethylsilyl)ethoxymethyl (SEM), and Gp' represents a protective group for an alcohol functional group, such as group type benzyl, acetate or silyl, such as tert-butyldimethylsilyl, and, finally, Λ represents a bond or a radical -(CH2)X-, -CO-(CH2)X-, -(CH2)y-O - or-C(=NH)-. Of course, the person skilled in the art may choose to use other protective group Gp and Gp' known groups and, in particular, from those specified in: Protective groups in organic synthesis, 2nd edition, (John Wiley & Sons Inc., 1991).

Chart 1

Path 1: Het is an imidazole, and Ω represents NR46R47but not radical urethane type

Amines and carboxamide General formula (I), chart 2, where A, B, R1, R2, R46, R47, Het and n are such as defined above, receive by removing the protection, in the case where Gp represents the SEM, using fluoride tert-butylamine (TBAF) in THF, the amine of General formula (IV) to release the amine in the heterocycle compounds of General formula (I). Protected amines of General formula (IV) can be obtained in General by the synthesis described in Biorg. and Med. Chem. Lett., 1993, 3, 915 and Tetrahedron Lett., 1993, 34, 1901, and, more preferably, in the patent application PCT WO 98/58934.

Chart 2

Path 2: Het is an imidazole, oxazole or thiazole, and Ω represents NR46R47

Amines and carboxamide General formula (I), chart 3, where A, B, R1, R2, R46, Het, g, k and n are such as defined above, Δ is an alkyl radical, cycloalkyl, arylalkyl, aryl, alltel, alltracel, alkenyl, quinil, cianelli or hydroxyalkyl, and Δ' represents an alkyl radical, cycloalkyl, arylalkyl or aryl, when g or k are not 0, or Δ' represents an alkyl radical, cycloalkyl, arylalkyl radical or aryl, preferably deactivated (i.e. radical substituted aryl group, attracts electrons, such as for example, nitro or cyano), when g or k is equal to 0, is obtained by condensation of the amines of General formula (V) with carboxylic acids (or the corresponding acid chlorides) General the formula (XIII) standard for peptide synthesis, with aldehydes of General formula (XII) in the presence of a reducing agent, such as triacetoxyborohydride sodium or sodium borohydride, in a lower aliphatic alcohol, such as methanol, optionally in the presence of molecular sieves, or halogenated derivatives (Hal = halogen atom) of General formula (XI). In particular, when Δ is a radical alltel, alltracel, alkenyl, quinil, cianelli or hydroxyalkyl, compounds of General formula (V) is converted into the corresponding compounds of General formula (I) by reacting with a halogenated derivative of General formula (XI) in a solvent such as acetonitrile, dichloromethane or acetone and in the presence of a base, such as, for example, triethylamine or potassium carbonate, at a temperature in the range from room temperature to the boiling point of the solvent under reflux.

Derivatives of General formula (V) can be obtained, in particular, shared by the synthesis described in Biorg. and Med. Chem. Lett., 1993, 3, 915 and Tetrahedron Lett., 1993, 34, 1901, and, more preferably, in the patent application WO 98/58934. When R46= H, the compounds of General formula (V) can be obtained, for example, in accordance with the method described in patent application WO 98/58934 (instead of using N-Boc-sarcosinate the corresponding amino acid).

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Chart 3

In particular, when R47represents a radical cycloalkyl, amines of General formula (I), figure 3a, where A, B, R1, R2, R46, Het and n are such as defined above, and i is an integer from 0 to 4, obtained by condensation of the amines of General formula (V) with cycloalkylcarbonyl General formula (XIV) in the presence of a reducing agent, such as triacetoxyborohydride sodium or sodium borohydride, in a lower aliphatic alcohol, such as methanol, optionally in the presence of molecular sieves at room temperature.

Chart 3A

Sulfonamides of General formula (I), figure 3b, where A, B, R1, R2, R46, Het and n are such as defined above, R47represents a radical-SO2-Δ, and Δ is an alkyl radical, cycloalkyl, cycloalkenyl or arylalkyl, obtained by condensation of the amines of General formula (V) with sulfochloride General formula (XV) under standard conditions, for example, in a solvent such as dimethylformamide, at room temperature.

Chart 3b

Urease General formula (I), figure 3c, where A, B, R1, R2, R46, Het and n are such as defined above, R47represents a radical-CO-NH-Δ, and Δ represents the t of a radical alkyl, cycloalkyl, cycloalkenyl or arylalkyl produced by the interaction of amines of General formula (V) with isocyanates of General formula (XVI) in an inert solvent such as dichloromethane or 1,2-dichloroethane.

Chart 3c

Path 3: Het represents oxazole or thiazole, R1and R2both represent H, and Ω represents OH.

Derivatives of alcohols of General formula (I), chart 4, where A, B, Het and n are such as defined above, and R1and R2represent hydrogen atoms, are obtained by recovery of the acids or esters of General formula (VI) (received overall by the synthesis described in J. Med Chem., 1996, 39, 237-245, and in the patent application PCT WO 99/09829). This recovery is possible, for example, by exposure to boron or socialogical, or also diisobutylaluminium, in an aprotic polar solvent such as tetrahydrofuran.

Chart 4

Path 4: Het represents oxazole or thiazole, and Ω represents NR46R47

Amines of General formula (I), chart 5, where A, B, R1, R2, R46, R47, Het and n are such as defined above, are obtained by condensation of primary or secondary amines of General formula R46-Other47with compounds of General formula (VII) (where L preferably represents the volume of Hal is halogen, but it can also represent a group mesilate or tosylate) in accordance with the General by the synthesis described in J. Med. Chem., 1996, 39, 237-245, and the patent application PCT WO 99/09829 or in U.S. patent 4123529. This way of synthesis, in particular, can be used when R46and R47taken together with the nitrogen atom to which they are attached, form a non-aromatic 4-to 8-membered heterocycle. Communication is usually carried out in an anhydrous solvent (e.g. dimethylformamide, dichloromethane, tetrahydrofuran or acetone) in the presence of a base (for example, Na2CO3or2CO3in the presence of triethylamine) and, preferably, by heat.

Chart 5

Path 5: Het is an imidazole, and Ω is a radical urethane type

When Ω is a radical urethane type, acids of General formula (VIII) can be cyklinowanie in the form of the imidazole derivatives of General formula (I), chart 6, by adding cesium carbonate, followed by condensation with α-halogenatom formula A-CO-CH(B)-[Br,Cl] and further by adding a large excess of ammonium acetate (for example, 15 or 20 equivalents per equivalent of the acid of General formula (VIII)). This interaction is, preferably, carried out in a mixture of xylene and heated (if appropriate, also can is about at the same time to remove the water, formed during the interaction).

Chart 6

Path 6: Het is an imidazole, oxazole or thiazole, and Ω represents NR46R47

When Ω is a radical NR46R47where R47represents a radical containing aminophenylamino, alkylamidoamines or dialkylaminomethyl end group, compounds of General formula (I), where A, B, Het, n, R1, R2and R46such as defined above, and Λ represents a bond or a radical -(CH2)X-, -CO-(CH2)X-, -(CH2)y-O - or-C(=NH)-, x and y are integers from 0 to 6, can be obtained, diagram 7, by restoring the compounds of General formula (IX), for example, under the action of hydrogen in the presence of a catalyst of the type palladium on coal in a solvent such as, for example, methanol, ethanol, dichloromethane or tetrahydrofuran. Restoration of functional nitro group can also be carried out, for example, by heating the product in an appropriate solvent, such as ethyl acetate, a small amount of ethanol in the presence of SnCl2(J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842), or in the presence of SnCl2/Zn (Synthesis (1996), 9.1076-1078), using NaBH4-BiCl3, (Synth. Com. (1995) 25 (23), 3799-3803) in a solvent such as ethanol, Il is then, using Raney Ni, to which was added hydrazinehydrate (Monatshefte für Chemie, (1995), 126, 725-732), or using indium in a mixture of ethanol and ammonium chloride by boiling under reflux (Synlett(1998) 9, 1028).

When R47represents a radical aminophenylthio, alkylamidoamines or dialkylaminoalkyl type (Alk and Alk' are the same or different alkyl radicals), the compound of General formula (IX) restore obtaining aniline derivative of General formula (I) and exercise optionally mono - or dialkylamino in accordance with standard reactions known to the person skilled in the art. Monoalkylamines carried out by reductive amination with aldehyde or by nucleophilic substitution by interacting with the equivalent of halogenoalkane Alk-Hal. Then optionally it is possible to conduct the second alkylation by halogenoalkane Alk'-Hal.

Chart 7

In particular, when Alk = Alk' = -CH3and when Λ is not-CH2-, nitro-derivatives of General formula (IX) is treated with appropriate amounts of paraformaldehyde in a stream of hydrogen in a solvent such as ethanol, in the presence of a catalyst of the type palladium on coal" (figure 7a).

Chart 7a

This path can be used when Ω represents OH. In contrast to the path 3, R1and R2cannot be hydrogen atoms. In this case, compounds of General formula (I) can be obtained, figure 8, by removing the protection from the protected alcohol of General formula (X).

When Gp' represents a protective group, silyl type, delete, protection may be, for example, by adding fluoride Tetra-tert-butylamine to the solvent, such as tetrahydrofuran. When Gp' represents a protective group of the benzyl type, the destruction carried out by hydrogenation in a solvent such as, for example, methanol, dichloromethane or tetrahydrofuran. When Gp' represents a protective group of the acetate type, remove protectors, for example, using sodium carbonate or potassium hydroxide in an alcohol solvent such as methanol. Otherwise, the person skilled in the art can refer to the following document: Protective groups in organic synthesis, 2nd edition (John Wiley & Sons Inc., 1991).

Chart 8

Path 8: Het is an imidazole, oxazole or thiazole, and Q is a OR48where R48≠ N. Compounds of General formula (I), where Ω is a radical OR48 where R48≠ N receive, for example, figure 9, of the alcohols of General formula (I), a (which are compounds of General formula (I)as defined above, where Ω represents OH) by reacting the latter with a halide of General formula R48-Hal (Hal = Br, Cl or I) in a solvent such as dichloromethane, acetonitrile, anhydrous or anhydrous tetrahydrofuran simple ether and in the presence of a base such as potassium carbonate or sodium, sodium hydride or triethylamine.

In the case where the radicals A, B, R1and R2contain a functional group of an alcohol, phenol, amine or aniline, it may be necessary to add stages protect/delete protect these functional groups in accordance with standard methods known to experts in the field (stage not shown on diagram 9).

Chart 9

The intermediate compounds

Getting imidazoles and thiazolo General formula (V)

General chart

Commercially available derivative of the ketone of General formula (V.i) or (V.i)2where A and b are such as defined in the General formula (I), transform, chart 3.1, the corresponding α-Bratton General formula (V.ii) or (V.ii)2by interacting with brainwashin agent such as CuBr2(J. Org. Chem. (1964), 29, 3459), bromine (J. Het. Chem. (1988), 25, 337), -bromosuccinimide (J. Amer. Chem. Soc. (1980), 102, 2838) in the presence of acetic acid in a solvent such as ethyl acetate or dichloromethane, HBr or Br2in simple ether, ethanol or acetic acid (Biorg. Med. Chem. Lett. (1996), 6(3), 253-258; J. Med. Chem. (1988), 31(10), 1910-1918; J. Am. Chem. Soc. (1999), 121, 24), or using commercially available brominated polymer (J. Macromol. Sci. Chem. (1977), A11, (3) 507-514). In the particular case when A is a radical p-dimethylaminophenyl, you can use a working method, schematically presented in Tetrahedron Lett., 1998, 39 (28), 4987. Then, in accordance with the methods presented below in chart 3.2 (imidazoles) and 3.3 (thiazole), receive amine of General formula (V).

Chart 3.1

Alternatively, synthesis, shown in figure 3.1, a specialist in this area may not need to use α-chlorcon instead of α-brometea.

Getting imidazoles of General formula (V)

The acid of General formula (V.iii), where Gp represents a protective group for the functional amino groups, for example the protective group of the urethane type, process, chart 3.2, using Cs2CO3in a solvent such as methanol or ethanol. To the recovered cesium salt was added α-halogenation General formula (V.ii) in an inert solvent, such as dimethylformamide. Intermediate ketoester was cyclically using CIPAC the deposits under reflux in xylene (mixture of isomers) in the presence of a large excess of ammonium acetate (for example, 15 or 20 equivalents) to give the imidazole derivative of General formula (V.iv) (during the reaction water formed is not necessarily removed).

In the case when R38is not H, the functional amino group, imidazole ring compounds of General formula (V.iv) was replaced by interaction with the halogenated derivative of R38-Hal (Hal = halogen atom); then with protected functional amino group was removed protection under standard conditions (for example: triperoxonane acid or HCl in an organic solvent, if it is a protective group of the urethane type, or by hydrogenation in the presence of palladium on coal, when the protective group is a carbamate of the benzyl).

Chart 3.2

Getting thiazolo General formula (V), designed to obtain the compounds of General formula (I)1or (I)2:

Thiocarboxamide General formula (V.v), where Gp represents a protective group for the functional amino groups, for example, the protective group of the urethane type obtained, for example, by reacting the corresponding carboxamide with reagent Lawesson (Lawesson) or C (P2S5)2were subjected to interaction, figure 3.3, with α-bromoketones General formula (V.ii) or (V.ii)2in accordance with a method described in literature (J. Org. Chem., (1995), 60, 5638-642). Then have a protected functional amino group was removed protection under standard conditions in the environment of a strong acid (for example: triperoxonane acid or HCl in an organic solvent, when the group is a protective group of the urethane type), releasing the amine of General formula (V).

Chart 3.3

Getting thiazolo General formula (V), designed to obtain the compounds of General formula (I)3:

These connections receive in accordance with the method shown in figure 3.4 below. First handle carboxamid General formula (VII.ii), for example, the reagent Lawesson or (P2S5)2then by communicating with a halogenated derivative of General formula (V.vii) get thiocarboxamide General formula (VII.iii) (see Biorg. Med. Chem, Lett, (1996), 6(3), 253-258; J. Med. Chem. (1988), 31(10), 1910-1918; Tetrahedron Lett., (1993), 34(28), 4481-4484; or J. Med. Chem. (1974), 17, 369-371; or Bull Acd. Sci. USSR Div. Chem. Sci. (Engl Transl) (1980) 29, 1830-1833). Then the thus obtained protected amine of General formula (V.viii) remove the protection under standard conditions known to the person skilled in the art (for example: triperoxonane acid or HCl in an organic solvent, when Gp represents a protective group of the urethane type).

Chart 3.4

Getting oksazolov General formula (V), the purpose is the R to obtain the compounds of General formula (I) 3:

These connections receive in accordance with the method shown in figure 3.5 below. Carboxamid General formula (VII.ii) were first subjected to interaction with the halogenated derivative of General formula (V.vii). Then the thus obtained protected amine of General formula (V.ix) remove the protection under standard conditions known to the person skilled in the art, to obtain the compounds of General formula (V) (for example: triperoxonane acid or HCl in an organic solvent, when Gp represents a protective group of the urethane type).

Chart 3.5

Deriving ketone of General formula (V.i) and specific derivatives α-brometea General formula (V.ii), (V.ii)2or (V.vii)

Commercially available derivative of the ketone of General formula (V.i) or α-bracketology homologues can be obtained by methods described in the literature, or similar means, adapted by the person skilled in the art. In particular:

when A represents a radical indolinyl or tetrahydroquinolin, compounds of General formula (V.i) can be obtained by methods described in the literature, such as, for example, in J. Med. Chem. (1986), 29, (6), 1009-1015 or J. Chem. Soc., Perkin Trans. 1(1992), 24, 3401-3406.

Alternatively, compounds of General formula (V.ii), where A represents a radical indolinyl or tetr hydrochinone, where R33represents H, can be synthesized in accordance with the method described in J. Chem. Soc., Perkin Trans 1 (1992), 24, 3401-3406, which is slightly modified. This method is presented in figure 3.6 below.

Chart 3.6

Indolin or tetrahydroquinolin (T represents a-CH2- or -(CH2)2-) defended using chlorocatechol, to obtain the compounds of General formula (XVII), which was subjected to reaction Friedel-(substituted chlorocatechol General formula (XVIII), where a has the meaning indicated above, in a solvent such as carbon disulphide, in the presence of aluminium chloride) to obtain the compounds of General formula (XIX). Then the compound of General formula (XIX) is hydrolyzed in the presence of acid, for example a mixture of acetic acid/HCl, to obtain the compounds of General formula (V.ii) in the form of a mixture of meta - and para-isomers. These isomers can be separated by fractional crystallization in a solvent such as glacial acetic acid.

The person skilled in the art can adapt the methods of synthesis described above for the case when A is a radical indolinyl or tetrahydroquinolin, where R33is not H, for example when R33represents an alkyl radical or aralkyl, the stage of protection and removal of protection are unnecessary.

p> when A represents a radical of the type 4-(4-hydroxyphenyl)phenyl, the compounds of General formula (V.i) can be obtained by methods described in the literature, such as, for example, in J. Org. Chem., (1994), 59(16), 4482-4489.

Alternatively, compounds of General formula (V.i) and (V.ii), where A represents the radical of 4-(4-hydroxyphenyl)phenyl, can be obtained, for example, by the methods illustrated in the figure 3.7 below.

Chart 3.7

Compounds of General formula (V.i) or (V.ii), where S1, S2, S3and S4independently selected from a hydrogen atom and an OH, cyano, nitro, alkyl, alkoxy or-NR10R11as defined for General formula (I)receive, figure 3.7, from esters of General formula (XX) (see, in particular, Chem. Lett. (1998), 9, 931-932 and Synthesis (1993), 8, 788-790). Of course, the presence of functional groups of the phenol or aniline, due to the nature of the substituents R19, R20, R21, S1, S2, S3and S4may induce a specialist in this area to add to the stages in the diagram 3.7 protection phase (and, subsequently, in the synthesis of compounds of General formula (I), remove the protection) of these functional groups so that they do not affect the rest of the chemical synthesis. Esters of General formula (XX) is hydrolyzed to obtain the acid of General formula (XXI). The latter was then subjected is eacli joining with N,O-dimethylhydroxylamine (Syn. Commun. (1995), 25(8), 1255; Tetrahedron Lett. (1999), 40(3), 411-414) in a solvent such as dimethylformamide or dichloromethane, in the presence of a base, such as triethylamine, with dicyclohexylcarbodiimide or the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and hydroxybenzotriazole, to obtain the intermediate compounds of General formula (XXII). Compounds of General formula (V.i) are obtained from compounds of General formula (XXII) by substitution reaction with MeLi (J. Med. Chem. (1992), 35(13), 2392). Bromoacetophenone General formula (V.ii) can then be obtained from acetophenone of General formula (V.i) in the previously described conditions.

When A represents a radical carbazolyl, compounds of General formula (V.i) can be obtained by methods described in the literature, such as, for example, in J. Org. Chem., (1951), 16, 1198 or Tetrahedron (1980), 36, 3017.

Alternatively, compounds of General formula (V.ii), where A represents the radical carbazolyl, where R9represents H, can be synthesized according to a slightly modified method described for the case when A = carbazolyl, Tetrahedron (1980), 36, 3017. This method is presented in chart 3.8 below:

Chart 3.8

Carbazole General formula (XXIII) defended using acetic anhydride, to obtain the compounds of General formula (XXIV), which was subjected to reaction Friedel-(substituted chlorine is ethyl chloride of General formula (XVIII), as defined above, in a solvent such as carbon disulphide, in the presence of aluminium chloride) to obtain the compounds of General formula (XXV). Then acyl group, protecting the functional amino group that is hydrolyzed in the presence of acid, for example, a mixture of AcOH/HCl, to obtain the compounds of General formula (V.ii). When A represents a radical carbazolyl, where R9represents alkyl or the group-COR15(this case is not represented in the figure 3.8), the initial stage of acylation is not needed, and compounds of General formula (V.ii) can be obtained from the last two stages on the chart 3.8. Of course, the presence of functional groups of the phenol or aniline, due to the nature of the substituents R4, R5, R6, R7and R8may induce a specialist in this area to add to the stages shown in figure 3.8, the stage protection (and subsequently, during the synthesis of compounds of General formula (I), remove the protection) of these functional groups so that they do not affect the rest of the chemical synthesis.

When A represents phenothiazinyl radical, intermediate compounds of General formula (V.i) and (V.ii) can be obtained by methods described in the literature: J. Heterocyclic. Chem. (1978), 15, 175-176 and Arzneimittel Forschung (1962), 12, 48.

Alternatively, intermediate compounds of General formula (V.ii), where A is the battle phenothiazinyl radical, can be obtained in accordance with a slightly modified method described for phenothiazinyl radical in Arzneimittel Forschung (1962), 12, 48, which is represented on the chart 3.9 below (see also examples). Phenothiazines General formula (XXVI) defended using chlorocatechol obtaining compounds of General formula (XXVII), which is then subjected to reaction Friedel-(a compound of General formula (XVIII) in a solvent such as disulfate carbon in the presence of aluminium chloride) to obtain the compounds of General formula (XXVIII). During the last stage of the process, along with halogen exchange carry out the hydrolysis with HCl/acetic acid, which made possible to obtain chloretone General formula (V.ii). Of course, the presence of functional groups of the phenol or aniline, due to the nature of the substituents R4, R5, R6and R8may induce a specialist in this area to add to the stages shown in figure 3.9, the stage protection (and subsequently, during the synthesis of compounds of General formula (I), remove the protection) of these functional groups so that they do not affect the rest of the chemical synthesis.

Chart 3.9

when A represents a radical phenylaminopropyl, compounds of General formula (V.i) can be obtained by methods described in the literature, such as the, for example, Chem. Commun., (1998), 15, (6) 1509-1510 or Chem Ber., (1986), 119, 3165-3197, or similar methods, adapted specialist in this field.

For example, intermediate compounds of General formula (V.i)a and (V.ii)a, where A is a radical phenylalaninol (which corresponds to the respective functional aniline group of compounds of General formula (V.i) and (V.ii), which was azetilirovanna), can be obtained in accordance with a slightly modified method described for radical Veniaminovna in Chem Ber. (1986), 119, 3165-3197. This method is presented in figure 3.10 below.

Chart 3.10

In case (presented in the chart 3.10), when the radical R9the synthesized compounds of General formula (I) represents a hydrogen atom or acetyl group, diphenylamine of the General formula (XXIX), formed by reaction of accession in the presence of CuI, protected by acetylation using, for example, acetic anhydride to obtain compounds of General formula (V.i)a. If (not represented in the figure 3.10), when R9radical synthesized compounds of General formula (I) is not a hydrogen atom or an acetyl radical, stage acetylation was replaced by the stage of substitution on the aniline in accordance with standard methods known to the person skilled in the art, with getting soo the appropriate compounds of General formula (V.i). The compound of General formula (V.i)a (or (V.i), in case that are not represented on the chart 3.10) is then subjected to the reaction of synthesized using commercially available brominated polymer, the polymer PVPHP (polyvinylpyridine the hydrobromide of perbromide), described in J. Macromol. Sci. Chem. (1977), All, (3), 507-514, to obtain the compounds of General formula (V.ii)and (or (V.ii), if not represented in the figure 3.10). Of course, the presence of functional groups of the phenol or aniline, due to the nature of the substituents R4, R5, R6, R7and R8may induce a specialist in this area to the stages shown in figure 3.10, to add protection phase (and subsequently, during the synthesis of compounds of General formula (I), remove the protection) of these functional groups so that they do not affect the rest of the chemical synthesis. Remove protection acetylated functional aniline group is essentially carried out during the last stage of the synthesis of compounds of General formula (I).

When A represents a radical benzopyran or benzofuran, such as defined in the General formula (I), where R32represents a hydrogen atom, intermediate compounds of General formula (V.i) and (V.ii) can be obtained by methods illustrated in chart 3.11 below.

Chart 3.11

Compounds of General formula (V.i) and (V.ii), figure 3.11, where the T is, as defined above, and Gp = protective group, is obtained from the acids of General formula (XXX). Acids of General formula (XXX) was subjected to reaction accession with N,O-dimethylhydroxylamine (Syn. Commun. (1995), 25, (8), 1255; Tetrahedron Lett. (1999), 40, (3), 411-414) in a solvent such as dimethylformamide or dichloromethane, in the presence of a base, such as triethylamine, with dicyclohexylcarbodiimide or the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and hydroxybenzotriazole, to obtain the intermediate compounds of General formula (XXXI). Then protect functional phenolic group in the form of Antilibanus or tert-butyldimethylsilyl derivative or other protective groups (Gp), known to the person skilled in the art, to obtain the compounds of General formula (XXXII). Compounds of General formula (V.i) are obtained from compounds of General formula (XXXII) by substitution reactions with Grignard reagents, MeMgCl (J. Het. Chem. (1990), 27, 1709-1712) or with MeLi (J. Med. Chem. (1992), 35, 13). Bromoacetophenone General formula (V.ii) can then be obtained from acetophenone of General formula (V.i) under the conditions described above.

Alternatively, the compound of General formula (V.ii), where R32represents a hydrogen atom or an alkyl radical, can be obtained in accordance with the method only in stage 3 (see chart 3.12 - also see examples). In this way bromination of compounds of obatala (V.i) at the last stage of obtaining compounds of General formula (V.ii) is preferably carried out in accordance with J. Am. Chem. Soc. (1999), 121, 24.

Chart 3.12

when A represents a radical substituted biphenyl, an intermediate ketones of General formula (V.i), in particular, can be obtained through synthesis Suzuki (Suzuki) (see Baroni et al., J.Org. Chem. 1997, 62, 7170-7173; also see example 44 this proposal, stage 44.1).

When A represents a radical of substituted phenol, it may be necessary to use the intermediate compounds of General formula (V.ii), as described above, the functional phenolic group which was azetilirovanna (below referred to as compounds of General formula (V.ii) (b). In particular:

when A represents a radical 4-hydroxy-3,5-diisopropylphenyl homologous α-bracketology derivatives functional phenolic group of compounds of General formula (V.ii), which is substituted by an acetyl radical, can be obtained as shown in figure 3.13 below.

Chart 3.13

2,6-Diisopropylphenol has azetilirovanie in accordance with methods known to the person skilled in the art, for example, by reacting with acetic acid in the presence of anhydride triperoxonane acid or acetylchloride in the presence of a base, such as, For example, a3CO3. Acetylated homologue 2,6-diisopropylphenol then subjected to a rearrangement of the fry (ries) in the presence of aluminium chloride in a solvent, such as nitrobenzene, obtaining the compounds of formula (V.i). Then the compound of formula (V.i) azetilirovanie with obtaining the compounds of formula (V.i)b. Then carry out the bromination with CuBr2as described above, to obtain compounds of formula (V.ii)b. Then, in the synthesis of compounds of General formula (I) conducted the stage of removing protection from the release of functional phenolic groups (during which the person skilled in the art considers most appropriate).

When A represents a radical dimethoxyphenol type, compounds of General formula (V.ii)b can be obtained in a manner analogous to the method of synthesis described for the compounds of formula (V.ii)b obtained from 2,6-diisopropylphenol, optionally, with minor changes in the framework of specialist knowledge in this area. For example, when A represents a radical of 3,5-dimethoxy-4-hydroxyphenyl, appropriate α-bracketname derivative of the formula (V.ii)b can be obtained from commercially available compounds of formula (XXXV), for example, as shown in figure 3.13:.

Chart 3.14

Compounds of General formula (V.ii)2where A and b are such as defined above, can be obtained in accordance with the method shown in figure 3.15 below.

Chart 3.15

Acid total HUF the uly (XXXVI) was subjected to reaction accession with N,O-dimethylhydroxylamine (Syn. Commun. (1995), 25, (8), 1255; Tetrahedron Lett. (1999), 40, (3), 411-414) in a solvent such as dimethylformamide or dichloromethane, in the presence of a base, such as triethylamine, with dicyclohexylcarbodiimide or the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and hydroxybenzotriazole, to obtain the intermediate compounds of General formula (XXXVII). Compounds of General formula (V.i)2obtained from compounds of General formula (XXXVII) by substitution reactions of derivatives of lithium or magnesium General formula B-M, where M is Li or MgHal (Hal = I, Br or Cl), in solvents such as simple ether or anhydrous tetrahydrofuran. α-Bromo - or α-chloretone General formula (V.ii)2further can be obtained from ketones of General formula (V.i)2in the conditions described above.

In addition, commercially available α-halogenosilanes derivatives of General formula (V.vii) can be obtained using the methods described in the literature. In particular, they can be obtained in accordance with the method shown in figure 3.16.

Chart 3.16

Substituted amino acids of General formula (XXXVIII) is obtained by protecting the amino group of the urethane type, in accordance with methods known to the person skilled in the art. Then the acid of General formula (XXXVIII) was subjected to a reaction process the organisations with N,O-dimethylhydroxylamine (Syn. Commun. (1995), 25, (8), 1255; Tetrahedron Lett. (1999), 40, (3), 411-414) in a solvent such as dimethylformamide or dichloromethane, in the presence of a base, such as triethylamine, with dicyclohexylcarbodiimide or the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and hydroxybenzotriazole, to obtain the intermediate compounds of General formula (XXXIX). Compounds of General formula (XLI) are obtained from compounds of General formula (XXXIX) by substitution reactions with derivatives of lithium or magnesium General formula (XL) (Hal = I, Br or Cl), in solvents such as simple ether or anhydrous tetrahydrofuran. Bromine or chloracetophenone General formula (V.vii) can then be obtained from acetophenone of General formula (XLI) in the conditions described above.

Alternatively, a person skilled in the art may also use or adapt the syntheses described in Angew. Chem. Int. (1998), 37 (10), 411-414, Liebigs Ann. Chem. (1995), 1217 or Chem. Pharm. Bull (1981), 29(11), 3249-3255.

Obtaining derivatives of acids of General formula (V.iii)

Derivatives of acids of General formula (V.iii) can be directly obtained, figure 3.17, by reacting commercially available amino acids of General formula (V.vi) with compounds of the type (ar)alkylphosphonate or di(ar)allylcarbamate (Δ is a radical alkyl or benzyl) under standard conditions well-known specialist in this field.

Chart 3.17

Obtaining compounds of General formula (V.v)

Thiocarboxamide General formula (V.v) can be obtained in three stages from compounds of General formula (V.vi), as shown in figure 3.18 below. Functional amino group of the amino acids of General formula (V.vi) first protected under standard conditions using tBu-O-CO-Cl or (tBu-O-CO)2O (or other protective groups known to the person skilled in the art), then the resulting intermediate compound is converted into its corresponding amide by the methods described in the literature (see, for example, J. Chem. Soc., Perkin Trans. 1, (1998), 20, 3479-3484 or patent application PCT WO 99/09829). Finally, carboxamid transform in thiocarboxamide General formula (V.v), for example, by reacting with a reagent of Lawesson in a solvent such as dioxane or tetrahydrofuran at a temperature, preferably in the range from room temperature to the boiling point of the mixture under reflux, or also using (P2S5)2in standard conditions, well-known specialist in this field.

Chart 3.18

Alternatively, thiocarboxamide General formula (V.v) can also be obtained, figure 3.19, by adding H2S to the corresponding cyanoderivatives General formula (V.x) under standard conditions known to the specialist given in the second field.

Chart 3.19

Receiving acids of General formula (VI)

Receiving acids, derivatives of thiazolo General formula (VI)

Acids of General formula (VI), derivatives of thiazolo, can be obtained in accordance with the methods shown in figure 4.1 below.

Chart 4.1

Carboxamide General formula (VII.ii) is treated under standard conditions with obtaining thiocarboxamide General formula (VII.iii), for example, by using a reagent Lawesson or using also (P2S5)2under standard conditions known to the person skilled in the art. Alternatively, the acid of General formula (VII.i) activated by the action of 1,1'-carbonyldiimidazole, then treated with methylamine in an aprotic polar solvent such as, for example, tetrahydrofuran. The obtained intermediate carboxamide transform in thiocarboxamide General formula (VI.i) under standard conditions, for example, using a reagent of Lawesson or using also (P2S5)2under standard conditions known to the person skilled in the art. Then thiocarboxamide General formula (VII.iii) or (VI.i) were subjected to interaction with the compound of General formula (VI.ii), for example, by boiling under reflux in a solvent such as benzene, dioxane or dimethylformamide. Obtained with whom you esters of General formula (VI.iii) can then be hydrolyzed under the influence of a base, such as, for example, potassium carbonate in an alcoholic medium or LiOH in tetrahydrofuran, to obtain the acid of General formula (VI).

Receiving acids, derivatives oxazole, the General formula (VI)

Acids of General formula (VI)derived oksazolov, can be obtained in accordance with the method shown in figure 4.2 below.

Chart 4.2

Carboxamide General formula (VII.ii) were subjected to interaction with the compound of General formula (VI.ii) when heated, for example, by boiling under reflux, with or without solvent, such as dimethylformamide. The obtained ester of General formula (VI.iv) can then be gidrirovanny under the action of a base, such as potassium carbonate in an alcoholic medium or LiOH in tetrahydrofuran, to obtain the acid of General formula (VI).

Receiving acids, derivatives of oxazolines, the General formula (VI)

Acid, isoxazolines derivatives, of General formula (VI), which are used to obtain compounds of General formula (I)4can be obtained in accordance with the method shown in figure 4.3 below.

Chart 4.3

Acids of General formula (VI), isoxazolines derivatives can be obtained as follows: commercially available aldehydes of General formula (VI.v) was subjected cooperation is to work with hydroxylamine hydrochloride. The resulting oxime of General formula (VI.vi) was activated in the form of chloride oxime of General formula (VI.vii) by reacting N-chlorosuccinimide in DMF, was then subjected to interaction with esters of General formula (VI.viii) (where Alk represents an alkyl radical with getting isoxazoline derivatives in accordance with the method described in literature (Tetrahedron Lett., 1996, 37 (26), 4455; J. Med. Chem., 1997, 40, 50-60 and 2064-2084). Then there was the hydrolysis of isoxazolines General formula (VI.ix) in a standard way (for example, by the action of KOH in ethanol solvent or LiOH in a solvent such as tetrahydrofuran) to give the acid derivative of General formula (VI).

Commercially available unsaturated esters of General formula (VI.x) can be obtained in accordance with the methods described in the literature (J. Med. Chem., 1987, 30, 193; J. Org. Chem., 1980, 45, 5017).

Getting thiazolo and oksazolov General formula (VII)

General chart

Acids of General formula (VII.i), figure 5.1, is converted into the corresponding carboxamide General formula (VII.ii) by the methods described in the literature (see, for example, J. Chem. Soc., Perkin Trans. 1, (1998), 20, 3479-3484 or patent application PCT WO 99/09829). Then the compounds of General formula (VII) can be obtained in a standard way in accordance with the methods presented in figure 5.2 and 5.3 (thiazole) and figure 5.4 (oksazolov) below.

<> This way of synthesis is then used to obtain compounds of the General Podgornoe (I)1and (I)3.

Chart 5.1

Getting thiazolo General formula (VII)

When R1and R2both represent H, thiazole General formula (VII)intended to obtain compounds of General formula (I)3can be obtained in accordance with the method shown in figure 5.2. Carboxamid General formula (VII.ii) is converted into the corresponding thiocarboxamide General formula (VII.iii) in the presence of the reagent of Lawesson in a solvent such as dioxane or benzene, at a temperature preferably in the range from room temperature to the boiling point of the mixture under reflux. Thiocarboxamide General formula (VII.iii) then treated α-halogenation General formula (VII.iv), where Alk represents an alkyl radical (e.g. methyl, ethyl or tert-butyl), with a complex ester of General formula (VII.v), which is reduced to the corresponding alcohol of General formula (VII.vi), for example, the effects of lithium aluminum hydride or diisobutylaluminium hydride in a solvent such as tetrahydrofuran. The latter could then be converted to halogenated derivative of General formula (VII) in accordance with methods known specifications the sheet in this area, for example, in the case of the brominated derivative (L = Br), by interacting with CBr4in the presence of triphenylphosphine in dichloromethane at room temperature.

Chart 5.2

Thiazole General formula (VII)intended to obtain compounds of General formula (I)1can be obtained in accordance with the method presented in chart 5.3. Cyanoderivatives General formula (VII.vii), where Gp' represents a protective group for an alcohol functional group (for example, benzyl or-CO-ρ group ρ represents alkyl, for example methyl or tert-butyl), is converted into the corresponding thiocarboxamide General formula (VII.viii) under the action of H2S in a solvent such as ethanol, in the presence of triethanolamine at a temperature preferably in the range from room temperature to the boiling point of the mixture under reflux. Thiocarboxamide General formula (VII.viii) then treated α-halogenation General formula (VII.x) to obtain the compounds of General formula (VII.xi), which was removed protection to obtain the corresponding alcohol of General formula (VII.xi) in accordance with methods known to the person skilled in the art (for example, when Gp' represents a protective group of the acetate type, the latter were extracted in situ using the same solution of sodium carbonate). The latter can then be converted to halogenated derivative of General formula (VII) in accordance with methods known to the person skilled in the art, for example, in the case of the brominated derivative (L = Br), by interacting with CBr4in the presence of triphenylphosphine in dichloromethane at room temperature.

Chart 5.3

Getting oksazolov General formula (VII)

When R1and R2both represent H, oksazolov General formula (VII)intended to obtain the compounds of General formula (I)3can be obtained in accordance with the method shown in figure 5.4. Carboxamid General formula (VII.ii) handle α-halogeometricum General formula (VII.iv), where Alk represents an alkyl radical (e.g. methyl, ethyl or tert-butyl) obtaining of ester/acid of General formula (VII.xii). Last restored in the corresponding alcohol of General formula (VII.xiii), for example, under the action of socialogical or diisobutylaluminium hydride in a solvent such as tetrahydrofuran, if the original product was ester, or under the influence of DIBORANE in tetrahydrofuran, if the original product was acid. The latter can then be converted to halogenated derivative of General formula (VII) in accordance with the method, from the local specialist in this field, for example, in the case of the brominated derivative (L = Br) by interacting with CBr4in the presence of triphenylphosphine in dichloromethane at room temperature.

Chart 5.4

Receiving acids of General formula (VII.i)

Commercially available acid of General formula (VII.i) can be obtained by methods from the literature. In particular:- when A represents fenotiazinas radical, the acid of General formula (VII.i) can be obtained by methods described in the literature, for example, in J. Med. Chem. (1992), 35, 716-724, J. Med. Chem. (1998), 41, 148 -156; Synthesis (1988) 215-217; or J. Chem. Soc. Perkin. Trans. 1 (1998), 351-354;

when A represents a radical indolinyl, acids of General formula (VII.i) can be obtained by methods described in the literature, for example, in J. Het. Chem. (1993), 30, 1133-1136 or Tetrahedron(1967), 23, 3823;

when A represents a radical phenylaminopropyl, acids of General formula (VII.i) can be obtained by methods described in the literature, for example, in J. Amer. Chem Soc. (1940), 62, 3208; Zh. Obshch. Khim. (1953), 23, 121-122 or J. Org. Chem. (1974), 1239-1243;

when A represents a radical carbazolyl, acids of General formula (VII.i) can be obtained by methods described in the literature, for example, in J. Amer. Chem Soc., (1941), 63, 1553-1555; J. Chem. Soc. (1934), 1142-1144; J. Chem. Soc. (1945), 945-956; or Can. J. Chem. Soc. (1982), 945-956; and

when A represents a radical of the type 4-(4-hydroxyphenyl)is Anil, reference may be made, for example, the following publications: Synthesis, (1993) 788-790.

Obtaining compounds of General formula (VIII)

When R1and R2both represent H, a protected amino acids of General formula (VIII) are either commercially available or obtained by way of security commercially available amino acids using the urethane groups of the type in accordance with methods known to the expert in this field.

When at least one of R1and R2is not H, and n = 0, protected amino acids of General formula (VIII) are obtained in one stage, chart 6.1, by alkylation in a solvent such as tetrahydrofuran, and at a low temperature of commercially available compounds of General formula (VIII.i), using 3 equivalents of utility and approximately one equivalent of the halogenated derivative of General formula (VIII.ii), where R1represents a radical of the type alkyl, cycloalkyl, cycloalkenyl or arylalkyl, and Hal represents a halogen atom. In accordance with this case, the second alkylation (not shown on diagram 6.1) can be carried out in a similar way, making it possible to obtain compounds of General formula (VIII), where either R1or R2are not H.

Chart 6.1

Getting imidazoles, thiazolo and oksazolov obatala (IX)

The intermediate compounds of General formula (IX) described in patent application WO 98/58934 (see, in particular, page 10-50 and examples in this document) or it is done similarly, using commercially available starting products.

Getting alcohols of General formula (X)

Obtaining compounds of General formula (X), derivatives of imidazoles

The acid of General formula (X.i) consistently treated, chart 8.1, Cs2CO3, a compound of General formula (V.ii) and NH4OAc, to obtain the compounds of General formula (X). Reaction conditions similar to those described above for this type of synthesis.

Chart 8.1

Obtaining compounds of General formula (X), derived thiazolo

Cyanoderivatives General formula (X.ii) process, chart 8.2, using H2S with obtaining thiocarboxamide General formula (H), which are condensed with the compound of General formula (V.ii), making it possible to obtain compounds of General formula (X). Reaction conditions similar to the conditions described above (figure 5.3) for this type of synthesis.

Chart 8.2

Receiving acids of General formula (XXXVI)

Commercially available acid of General formula (XXXVI) can be obtained by methods described in the literature or similar means, adapted specialist in this field the tee. In particular:

when A represents fenotiazinas radical, the acid of General formula (XXXVI) can be obtained by methods described in the literature, for example, J. Org. Chem., (1956), 21, 1006; Chem. Abstr., 89, 180029 and Arzneimittel Forschung (1969), 19, 1193.

When A represents a radical diphenylamine, acids of General formula (XXXVI) can be obtained by methods described in the literature, for example, in Chem Ber., (1986), 119, 3165-3197; J. Heterocyclic. Chem. (1982), 15, 1557-1559; Chem. Abstr., (1968), 68, 68730x; or adapting these methods, a specialist in the field;

when A represents a radical of the type 4-(4-hydroxyphenyl)phenyl, acids of General formula (XXXVI) can be obtained by methods described in the literature, for example, in Tetrahedron Lett. (1968), 4739, or J. Chem. Soc. (1961), 2898.

When A represents a radical carbazolyl, acids of General formula (XXXVI) can be obtained by methods described in the literature, for example, in J. Amer. Chem., (1946), 68, 2104 or J. Het. Chem (1975), 12, 547-549.

When A represents a radical of the type benzopyran or benzofuran, acids of General formula (XXXVI) can be obtained by methods described in the literature, for example, in Syn. Commun. (1982), 12(8), 57-66; J. Med. Chem. (1995), 38(15), 2880-2886; or Helv. Chim. Acta. (1978), 61, 837-843.

When A represents a radical indolinyl or tetrahydroquinolin, acids of General formula (XXXVI) can be obtained by methods described in the literature, such as the R, in J. Med. Chem. (1997), 40, (7), 1049-1062; Bioorg. Med. Chem. Lett. (1997), 1519-1524; Chem. Abstr. (1968), 69, 43814k; or Chem. Abstr. (1966), 66, s.

Of course, the presence of functional groups of the phenol, amino or aniline, due to the nature of the substituents on the radicals And compounds of General formula (XXXVI)may induce a specialist in this area to add to the described stages stage protect/delete protect these functional groups so that they do not affect the rest of the chemical synthesis.

If not stated otherwise, all technical and scientific terms used herein have the same meaning and values, usually understandable to an ordinary specialist in the field to which this invention. Similarly, all publications, patent applications, all patents and other references mentioned herein are shown as a reference.

The following examples are given to illustrate the above methods and in any case should not be construed as limiting the scope of this invention.

Examples

Example 1: the Hydrochloride of 2,6-di-tert-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol:

1.1) Tert-butyl 2-cyanoethyl(methyl)carbamate:

In dichloromethane (100 ml)containing of 20.9 ml (0.12 mol) of diisopropylethylamine, was dissolved in 0.1 mol N-methyl-β-alaninemia. The mixture was cooled to 0°C, then by parts) was added Boc-O-Boc (26,2 g; 0.12 mol)and the mixture was stirred overnight during which the temperature of the environment. Then the reaction mixture was poured into ice water and was extracted with dichloromethane. The organic phase is successively washed with 10% aqueous sodium bicarbonate solution and water, and finally with a saturated solution of sodium chloride. Then the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. In this form, obtained a brown-red oil was used in the next stage.

1.2) Tert-butyl 3-amino-3-tioxaprofen(methyl)carbamate:

In ethanol (40 ml)containing triethylamine (6,1 ml), was dissolved to 43.4 mmol intermediate 1.1. Next, the mixture barbotirovany H2S for 3 hours, then the solvent was evaporated to dryness. The expected product is obtained after chromatography on a column of silica gel (eluent: 50% ethyl acetate in heptane) as a light orange oil. Crystallization of this oil from diisopropyl ether gave a white solid product with a yield of 15%. Melting point: 104°C.

1.3) 4-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-[(1,1-dimethylmethoxy)carbonyl]-N-methyl-2-thiazolidinones:

Intermediate 1.2 (2,11 mmol) and bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)alanon (6,9 g; 2,11 mmol) was dissolved in toluene (75 ml) in an argon atmosphere, then the mixture was stirred at ambient temperature for 12 hours. Reaction medium was boiled under reflux for 4 hours. PEFC is the evaporation of the solvents the residue was diluted with dichloromethane and washed with saturated solution of NaCl. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuum. The expected product crystallized in the form of a white solid product. Melting point: 204°C.

1.4) of the Hydrochloride of 2,6-di-tert-butyl-4-{2-[2-(methylamino)-ethyl]-1,3-thiazol-4-yl}phenol

In ethyl acetate (20 ml) was dissolved 1,95 mmol intermediate 1.3. The solution was cooled to 0°C, then barbotirovany gaseous HCl for 10 minutes. The mixture was allowed to warm to ambient temperature with stirring. After filtering and drying in vacuum, the expected product was isolated as white crystals, which were washed with ether. Quantitative output. Melting point: 206-208°C.

Example 2: 2,6-Di-tert-butyl-4-[4-(hydroxymethyl)-1,3-oxazol-2-yl]phenol:

This compound can be obtained according to a manner analogous to that described for intermediate product 1.C in the PCT application WO 99/09829, where 4-chloroacetoacetate replace ethylbromide, and selected intermediate ester then restore using DIBAL in dichloromethane at 0°C. Then the reaction mixture is treated with an aqueous solution of NH4Cl and filtered on celite, followed by extraction 50/50 mixture of dichloromethane and ethyl acetate. After decanting, drying over magnesium sulfate, filtration and evaporation of the filtrate, crystallization from ethanol did applicatio is by obtaining the expected product in the form of a white powder. Melting point: 167-168 °C.

Example 3: the Hydrochloride of 2,6-di-tert-butyl-4-{2-[1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol:

3.1) N'-(Tert-butoxycarbonyl)-N'-methylalanine:

In dimethoxyethane was dissolved 12 mmol Boc-N-Me-DL-Ala-OH. Was added dropwise N-methylmorpholine, then isobutylparaben. After stirring the mixture for 15 minutes at -15°C barbotirovany ammonia (NH3), then the mixture was continuously stirred at this temperature overnight. The precipitate was filtered. After drying, the product is used as it is in the next stage.

3.2) Tert-butyl 2-amino-1-methyl-2-tixati(methyl)-carbamate:

This compound is produced by the interaction of c P2S5under the conditions described in example 12 for the stage 12.2.

3.3) Tert-butyl 1-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]ethyl(methyl)carbamate:

The intermediate product 3.2 and bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)Etalon are condensed in accordance with the method similar to the method described for stage 1.3.

3.4) of the Hydrochloride of 2,6-di-tert-butyl-4-{2-[1-(methylamino)-ethyl]-1,3-thiazol-4-yl}phenol:

Method experiment similar to that described for stage 1.4 of example 1, substituting intermediate product 1.3 intermediate product 3.3. The expected product is obtained in the form of a white powder. Melting point: 236-237°C.

Example 4: 2,6-Dit-rebute the-4-[2-(methoxymethyl)-1,3-thiazol-4-yl]phenol;

4.1) Pivalate [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl:

The intermediate product 4.1 receive in accordance with a method identical to the method described in example 1, step 1.3 by replacing intermediate 1.2 2-(tert-BUTYLCARBAMATE)thioacetamide and replacing the benzene to toluene. The expected compound obtained as white solid with a yield of 100%. Melting point: 114,6-116,0°C.

4.2) 2,6-Di-tert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol:

The intermediate product 4.1 (1.25 mmol) was dissolved in methanol (20 ml). The solution was cooled using an ice bath, and then was added dropwise 1 n NaOH solution. The mixture was allowed to warm to ambient temperature with stirring. After evaporation to dryness and dilute the residue with water, the solution was neutralized using citric acid and was extracted with dichloromethane. Before drying over magnesium sulfate the organic phase is washed with saturated aqueous sodium chloride, then filtered and concentrated in vacuum. The white solid product is obtained with a yield of 88%. Melting point: 126,4-127,4 °C.

4.3) 2,6-Di-tert-butyl-4-[2-(methoxymethyl)-1,3-thiazol-4-yl]phenol:

The intermediate product is 4.2 (1 equivalent) was metilirovanie through the interaction of a c 1,1 equivalent yodmetilat in the presence of 2 equivalents of triethylamine, the reaction is carried out in tetrahydrof is ane. Get dark cream-colored powder. Melting point: 115, 8mm-117°C.

Example 5: the Hydrochloride of 2,6-di-tert-butyl-4-{4-[(methylamino)-methyl]-1,3-oxazol-2-yl}phenol:

5.1) 2,6-Di-tert-butyl-4-[4-(methyl bromide)-1,3-oxazol-2-yl]phenol:

The compound of example 2 (4,70 mmol) was dissolved in dichloromethane (30 ml). After adding CBr4(2,02 g; 6,10 mmol) the reaction mixture was cooled to 0°C. In parts) was added PPh3(1.48 g; 5,63 mmol), then the mixture was left to warm to ambient temperature. Then the reaction medium was poured into ice water and was extracted with dichloromethane. The organic phase is washed with salt water, was filtered and was concentrated in vacuo, then dried over magnesium sulfate. The resulting crude oil is pure enough to be directly used in the next stage.

5.2) of the Hydrochloride of 2,6-di-tert-butyl-4-{4-[(methylamino)-methyl]-1,3-oxazol-2-yl}phenol:

In acetonitrile (50 ml) was dissolved 33 mmol of methylamine (2 M solution in THF). When 0°C was added 5,48 mmol intermediate product 5.1 dissolved in acetonitrile (50 ml), then the mixture was stirred at ambient temperature for 3 hours. The solvent was evaporated, then the residue was distributed between ethyl acetate and 10% aqueous solution of NaHCO3. The organic phase is washed with salt water, was filtered and was concentrated in vacuo, then the sewed over magnesium sulfate. Then, dissolving the base in a simple ether and adding ether 1.2 ml of 1 n HCl solution, get a hydrochloride. After filtration and washing with ether, the obtained solid product get a dark orange powder. Melting point: decomposes at 150°C.

Example 6: N-{[4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide:

6.1) Benzyl {4-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-thiazol-2-yl}methylcarbamate:

This connection receive in accordance with the method described in patent application WO 98/58934 (see intermediate products 26.1 and 26.2), using Z-Gly-NH2instead of N-Boc of sarcosinate. The expected compound obtained as a pale yellow oil with a yield of 99%. MH+ = 453,20

6.2) 4-[2-(Aminomethyl)-1,3-thiazol-4-yl]-2,6-di(tert-butyl)phenol:

To a solution of 0,106 g (1.1 mmol) of the intermediate product 6.1 in 10 ml of methanol was added dropwise to 0.1 ml of 40% potassium hydroxide solution. After stirring overnight while boiling under reflux the reaction mixture was concentrated in vacuo, and the residue was diluted with dichloromethane and washed with 1 N. HCl solution, and then 50 ml of a saturated solution of NaCl. The organic phase was separated and dried over magnesium sulfate, filtered and concentrated in vacuum. The expected product is obtained after chromatography on a column of silica gel (eluent: 5% ethanol in dichloromethane) as a brown foam which with the yield 76%. MH+ = 319,29.

6.3) N-{[4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide:

The intermediate product 6.2 (2 mmol) was dissolved in dichloromethane (20 ml). Was added triethylamine (3 mmol) and the mixture was cooled to 0°C. Then was added dropwise acetylchloride (3 mmol). After complete addition, the mixture was allowed to warm to ambient temperature and was stirred overnight at this temperature and then poured into ice-cold water. The aqueous phase was extracted with dichloromethane, and the organic phase is washed with salt water, then dried over magnesium sulfate. After filtration and evaporation of solvents and further chromatography on a column of silica gel (eluent: 3% ethanol in dichloromethane) to obtain the expected product with a yield of 79%. Dark creamy foam. MH+ = 361,2.

Example 7 Ethyl [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylcarbamate:

The solution containing the intermediate product 6.2 above (5 mmol)and 5 ml of 1 n sodium hydroxide solution, cooled to 10°C. were Simultaneously added ethylchloride (5 mmol) and 2.5 ml of 2 n sodium hydroxide solution. After stirring for 16 hours at 23°C) to establish the values of pH of 4-5 was added about 0.5 ml of concentrated hydrochloric acid (approximately 11 BC). The resulting oil was extracted with ethyl acetate (2x5 ml), washed with water is th, then was dried over magnesium sulfate. The solvent was evaporated and the expected product was obtained as white crystals. MH+ =391,2.

Example 8: 2,6-Di-tert-butyl-4-[2-(morpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol;

8.1) 4-[2-(methyl bromide)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol:

In dichloromethane (30 ml) was dissolved 1.5 g (4,70 mmol) of the intermediate product 4.2, (2,6-di-tert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol. After adding CBr4(2,02 g; 6,10 mmol), the reaction medium was cooled to 0°C. was Added in parts PPh3(1.48 g; 5,63 mmol), then the mixture was left to warm to ambient temperature. Then the reaction medium was poured into ice water and was extracted with dichloromethane. The organic phase is washed with salt water, was filtered and was concentrated in vacuo, then dried over magnesium sulfate. The expected product is obtained after chromatography on a column of silica gel (eluent: 30% ethyl acetate in heptane) emitting a brown oil with a yield of 92%. This product was sufficiently pure to use directly in the next stage. MH+ = 382,20.

8.2) 2,6-Di-tert-butyl-4-[2-(morpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol:

In dimethylformamide (15 ml) was dissolved 1.57 mmol of the research and 0.4 ml (2,62 mmol) of triethylamine. Added 0.400 g (1.05 mmol) of the intermediate product 8.1, dissolved in dimethylformamide (5 ml), then the mixture was stirred p. and ambient temperature for 18 hours. Then the reaction medium was poured into ice water and was extracted with ethyl acetate. The organic phase is washed with salt water, was filtered and was concentrated in vacuo, then dried over magnesium sulfate. The expected product is obtained after chromatography on a column of silica gel (eluent: 50% ethyl acetate in heptane) to give an orange oil with a yield of 92%. Get pale cream crystals. Melting point: 136,7 is 137.2°C.

Example 9: 2,6-Di-tert-butyl-4-[2-(thiomorpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol:

The method used is similar to that described in example 8, substituting in the second stage morpholine on thiomorpholine. The expected product is obtained in the form of a light orange solid product. Melting point: 153,4-154, 6mm°C.

Example 10: 4-[2-(Anilinomethyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;

The method used is the same as the method described in example 8, substituting in the second stage of morpholine on aniline. The expected product was obtained as brown crystals. Melting point: to 147.2-148,0°C.

Example 11: 2,6-Di-tert-butyl-4-(2-{[[2-(dimethylamino)ethyl]-(methyl)amino]methyl}-1,3-thiazol-4-yl)phenol:

11.1) Hydrochloride 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolidinone:

This compound was obtained by using a method identical to the method stages 14.1-14.4 example 14 (see below).

11.2) 2,6-Di-tert-butyl-4-2-{[[2-(dimethylamino)ethyl]-(methyl)amino]methyl}-1,3-thiazol-4-yl)phenol:

To a solution of 1 mmol of intermediate product 11.1 in 20 ml of dimethylformamide was added dropwise 5 mmol of triethylamine and a slight excess (1.2 mmol) of N-dimethyl-N-(2-chloroethyl)amine at ambient temperature in an argon atmosphere. After stirring for 24 hours at 80°C the reaction mixture was poured into ice water, then extracted with ethyl acetate, washed with saturated NaCl solution, dried over magnesium sulfate and the solution was concentrated. After chromatography on a column of silica gel (eluent:dichloromethane containing 5% ethanol with traces of ammonia) to obtain the expected product. After evaporation of pure fractions gave a brown viscous oil. MH+ = 404,26.

Example 12: the Hydrochloride of 2,6-di-tert-butyl-4-{5-methyl-2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenol:

12.1) N-Boc-sarcosine:

In dichloromethane containing 46.2 ml (0,265 mol) of diisopropylethylamine, was dissolved 15.0 g (0,120 mol) of sarkainmerkeilla (N-Me-Gly-NH2•HCl). The mixture was cooled to 0°C, then by parts) was added Boc-O-Boc (28.8 g; 0,132 mol)and the mixture was stirred over night at ambient temperature. Then the reaction medium was poured into ice water and was extracted with dichloromethane. The organic phase was washed sequentially with 10% aqueous sodium bicarbonate solution and water, then, in the end, a saturated solution of sodium chloride. Then the organic phase sushi is over magnesium sulfate, was filtered and concentrated in vacuum. The obtained product was purified by crystallization from diisopropyl ether to obtain a white solid product with a yield of 72%. Melting point: 103°C.

12.2) 2-{[(1,1-Dimethylmethoxy)carbonyl]methyl}amino attentioned:

In dimethoxyethane (500 ml) was dissolved 16.0 g (of 0.085 mol) of the intermediate product 12.1, and the resulting solution was cooled to 5°C. Then in small portions was added sodium bicarbonate (28.5 g; 0.34 mol) and (P2S5)2(38,76 g; to 0.17 mol). The reaction mixture was allowed to warm to ambient temperature with stirring for 24 hours. After evaporation of the solvents in vacuo the residue was added 10% aqueous sodium bicarbonate solution, and the solution was extracted using ethyl acetate. The organic phase is successively washed with 10% aqueous sodium bicarbonate solution and water, then, in the end, a saturated solution of sodium chloride. Then the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The obtained product was purified by crystallization from ether to obtain white solid product with a yield of 65%. Melting point: 150-151°C.

12.3) Bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)propane-1-he:

This connection will receive a simple way by reacting 1-(3,5-di-tert-butyl-4-hydroxyphenyl)propane-1-the on (derived from 2,6-di-tert-butylphenol according to Russ. J. Org. Chem. (1997), 33, 1409-1416) with bromine in acetic acid, or in accordance with the method described in one of the following links: Biorg. Med. Chem. Lett.(1996), 6(3), 253-258; J. Med. Chem. (1988), 31(10), 1910-1918; J. Am. Chem. Soc. (1999), 121, 24.

12.4) 5-Methyl-4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-[(1,1-dimethylmethoxy)carbonyl]-N-methyl-2-thiazolidinones:

The intermediate product 12.2 (4.3 g; 2,11 mmol) and intermediate product 12.3 (2,11 mmol) was dissolved in toluene (75 ml) in an argon atmosphere, then the mixture was stirred at ambient temperature for 12 hours. Reaction medium was boiled under reflux for 4 hours. After evaporation of the solvents the residue was diluted with ethyl acetate and washed with 10% solution of NaHCO3then a saturated solution of NaCl. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuum. The expected product is obtained after chromatography on a column of silica gel (eluent: 30% ethyl acetate in heptane). The resulting oil was used in this form in the next stage.

12.5) of the Hydrochloride of 2,6-di-tert-butyl-4-{5-methyl-2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenol:

This compound is obtained as white powder in accordance with the method of the experiment, similar to the way the stage 1.4 of example 1. Melting point: 140-142°C.

Example 13: the Hydrochloride of 1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methanamine:

13.1) 2 the EOS-1-(10H-phenothiazines-2-yl)alanon:

2-Chloro-1-[10-(chloroacetyl)-10H-phenothiazines-2-yl)Etalon get from fenotiazina in accordance with the method described in the literature (J. Heterocyclic. Chem. (1978), 15, 175 and Arzneimittel Forschung, (1962), 12, 48), and then reaction of the removal of protection in acidic conditions (acetic acid and hydrochloric acid) chloroceryle group (which serves to protect the position 10 fenotiazina in the reaction Friedel -).

13.2) Benzyl 2-amino-2-taxationa:

In dimethoxyethane was dissolved 85 mmol of Z-Gly-NH2(500 ml)and the resulting solution was cooled to 5°C. Then in small portions was added sodium bicarbonate (28.5 g; 0.34 mol) and (P2S5)2(38,76 g; to 0.17 mol). The reaction mixture was allowed to warm to ambient temperature with stirring for 24 hours. After evaporation of the solvents in vacuo the residue was added 10% aqueous sodium bicarbonate solution, and the solution was extracted using ethyl acetate. The organic phase is successively washed with 10% aqueous sodium bicarbonate solution and water, then, in the end, a saturated solution of sodium chloride. Then the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. Then the obtained product was purified by crystallization from a simple ether.

13.3) Benzyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate:

Carry out the reaction accession intermediate the products 13.1 and 13.2 in accordance with the method, similar to the method described for stage 1.3 of example 1.

13.4) Hydrochloride 1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methanamine

The method used is similar to the method described for stage 1.4 of example 1, substituting intermediate product 1.3 intermediate product 13.3. After drying in vacuum, the expected product is obtained in the form of a dark green powder. Melting point:> 275°C.

Example 14: N-{[4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-methylacetamide:

14.1) N-Boc-sarcosine:

Obtaining this compound has already been described for stage 12.1 example 12.

14.2) 2-{[(1,1-Dimethylmethoxy)carbonyl]methyl}-aminoadenine:

This connection was described for stage 12.2 example 12.

14.3) 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-[(1,1-dimethylmethoxy)carbonyl]-N-methyl-2-thiazoleethanol:

The intermediate product 14.2 (4.3 g; 2,11 mmol) and bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)alanon (6,9 g; 2,11 mmol) was dissolved in benzene (75 ml) in an argon atmosphere, then the mixture was stirred at ambient temperature for 12 hours. Reaction medium was boiled under reflux for 4 hours. After evaporation of the solvents the residue was diluted with dichloromethane and washed with saturated solution of NaCl. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuum. Expected about the SPS obtained after chromatography on a column of silica gel (eluent: 20% ethyl acetate in heptane) in the form of oil, which slowly crystallized in the refrigerator with the release of 28%. Melting point: 126,5-RUB 127.3°C.

14.4) Hydrochloride 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolidinone:

In ethyl acetate (20 ml) was dissolved 1,95 mmol intermediate 14.3. The solution was cooled to 0°C, then barbotirovany gaseous HCl for 10 minutes. The mixture was left to warm to ambient temperature with stirring. After filtering and drying in vacuum received the expected product (quantitative yield).

14.5) N-{[4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-methylacetamide:

This connection receive in accordance with a method identical to the method described for stage 6.3 example 6, substituting intermediate product 6.2 intermediate product 14.5. White crystals. Melting point: 132,3-133,1°C.

Example 15: the Hydrochloride of 1-[4-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-2-yl]-N-methylmethanamine:

15.1) 4-[3,5-Bis(1,1-dimethylethyl)-4-methoxyphenyl]-N-[(1,1-dimethylmethoxy)carbonyl]-N-methyl-2-thiazoleethanol:

The intermediate product was 14.3 metilirovanie by the interaction of methyliodide in the presence of NaH in tetrahydrofuran to obtain the expected product. The obtained brown oil in this form is used in the next stage.

15.2) Hydrochloride 1-[4-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-2-yl]-N-metime is adamina

The method is similar to method stage 14.4 example 14, substituting intermediate product 14.3 intermediate product 15.1 and ethyl acetate, replaced with a mixture of ethyl acetate and ether. The expected product is obtained in the form of a pale cream crystals. Melting point: 218,4-219,6°C.

Example 16: the Hydrochloride of 2,6-di-tert-butyl-4-{2-[(ethylamino)methyl]-1,3-thiazol-4-yl}phenol:

Method identical to the method used in the stages 14.1-14.4 example 14, substituting in the first stage N-sarcosinate N-ethylglycine (J. Med. Chem. (1995), 38(21), 4244-4256). White crystals. Melting point: 232,4-234,6°C.

Example 17: the Hydrochloride of 2,6-di-tert-butyl-4-{2-[(4-phenylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol:

The method used is similar to the method described in example 8, substituting in the second stage morpholine 4-phenylpiperazin. Pale cream crystals. Melting point: 225,3-226,9°C.

Example 18: the Hydrochloride of 2,6-di-tert-butyl-4-{2-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-thiazol-4-yl}phenol:

The method used is similar to the method described in example 8, substituting in the second stage morpholine N-methylhomopiperazine. White crystals. Melting point: 222,1-225,4°C.

Example 19: Hydrochloride of N-{1-[4-(4-anilinophenol)-13-thiazol-2-yl]ethyl}-N-methylamine:

19.1) 7-(4-Anilinophenol)alanon

In dimethylformamide (75 ml) was dissolved 4-aminoacetophenone (4,87 g; 36,0 mmol). Added 15 g (to 0.108 mol) of potassium carbonate (p is evritania dried at 170° C in argon atmosphere), 7,236 g (36,0 mmol) yogashala, 0.4 g of copper powder and a catalytic amount of copper iodide. The reaction mixture is boiled under reflux for 12 hours. Then the reaction medium was allowed to warm to ambient temperature, the powder of copper iodide was filtered on celite and poured into ice-cold water. After extraction with ethyl acetate the organic phase is washed with water and dried over magnesium sulfate, filtered and concentrated in vacuum. The obtained product was purified by crystallization from heptane to obtain a yellow solid product with a yield of 53.4 per cent. Melting point: 105°C.

19.2) N-(4-acetylphenyl)-N-phenylacetamide:

This connection receive in accordance with the method proposed in Tetrahedron (1980), 36, 3017-3019. The intermediate product 19.1 (60 mmol) suspended in 150 ml of acetic anhydride. Added 70% perchloro acid (0.5 ml). After heating for 15 minutes at 70°C the mixture was poured into ice and the precipitate was filtered. After drying in vacuum, re-dissolved in dichloromethane and treatment with activated charcoal suspension was filtered on celite, and the solvent was evaporated. After crystallization from heptane was obtained yellow solid product with access to 54.2%. Melting point: 118-120°C (literature data: 122-123°C).

19.3) N-[4-(bromoacetyl)phenyl]-N-phenylacetamide

Sub the full product 19.2 (0,633 g; 2.5 mmol) was dissolved in methanol (20 ml) was added 1 g (2.0 mmol) of the brominated polymer PVPHP (J. Macromol. Sci. Chem. (1977), A11 (3), 507-514). After stirring in an argon atmosphere for 4 hours resinous products were filtered off and washed with methanol. After evaporation of the filtered solvent and crystallization from methanol to obtain a white solid product with a yield of 59%. Melting point: 152-153°C.

19.4) Tert-butyl (4-{4-[acetyl(phenyl)amino]phenyl}-1,3-thiazol-2-yl)methyl(methyl)carbamate:

The intermediate product 19.3 (2,11 mmol) and intermediate 3.2 (2,11 mmol) was dissolved in toluene (75 ml) in an argon atmosphere, then the mixture was stirred at ambient temperature for 12 hours. Reaction medium was boiled under reflux for 4 hours. After evaporation of the solvents the residue was diluted with dichloromethane and washed with saturated solution of NaCl. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuum. Get the expected product and used in the next stage.

19.5) of the Hydrochloride of N-{1-[4-(4-anilinophenol)-1,3-thiazol-2-yl]ethyl}-N-methylamine

The intermediate product 19.4 (1.5 mmol) is treated with concentrated HCl (15 ml) and acetic acid (30 ml). After boiling under reflux for 24 hours and evaporation of the solvents the residue was treated with toluene is m, the solvent was again evaporated, and then the product was led from a small amount of water. Get a grey powder. Melting point: > 250°C.

Example 20: the Hydrochloride of 2,6-di-tert-butyl-4-{2-[(isopropylamino)methyl]-1,3-thiazol-4-yl}phenol:

The intermediate product 6.2 (2 mmol), in solution in methanol (20 ml) was subjected to interaction with acetone (2.2 mmol), NaBH4(2.2 mmol) in the presence of molecular sieves. Then the reaction product is converted into the hydrochloride in accordance with the method similar to the method stage 1.4 of example 1. White crystals. Melting point: 197,1-198,8°C

Example 21: the Hydrochloride of 2,6-di-tert-butyl-4-{2-[(cyclohexylamino)methyl]-1,3-thiazol-4-yl]phenol:

The method used is similar to the method described in example 20, substituting acetone for cyclohexanone. White crystals. Melting point: 202,1-203,4°C.

Example 22: the Hydrochloride of 2,6-di-tert-butyl-4-{2-[(4-isopropylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol:

The method used is similar to the method described in example 8, substituting in the second stage morpholine N-isopropylpiperazine. White crystals. Melting point: 238,4-239,7°C.

Example 23: Hydrochloride of N-methyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]ethanamine:

The method used is similar to the method described for stage 19.4 example 19, substituting intermediate product 19.3 intermediate product 13.1, this stage should the duty to regulate by stage, similar stage 1.4 of example 1 to obtain a hydrochloride. Dark green powder. Melting point: > 250°C.

Example 24: the Hydrochloride of 2,6-di-tert-butyl-4-{2-[(4-ethylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol:

The method used is similar to the method described in example 8, substituting in the second stage morpholine N-ethylpiperazin. White crystals. Melting point: 247,0-248,8°C.

Example 25: the Hydrochloride of N-{[4-(4-anilinophenol)-1,3-thiazol-2-yl]methyl}-N-ethylamine:

The method used is similar to the method described for stages a 14.1-14.4 example 14, substituting sarcosine N-ethyl-glycinamide (J. Med. Chem. (1995), 38(21), 4244-56) and substituting bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)Etalon intermediate product 19.3. Dark green powder. Melting point: > 250°C.

Example 26: Hydrochloride of N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}ethanamine:

The method used is similar to the method described for stages 14.1 - 14.4 example 14, substituting sarcosine N-ethyl-glycinamide (J. Med. Chem. (1995), 38(21), 4244-56), and replacing bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)Etalon intermediate product 13.1. Dark green powder. Melting point: > 250°C.

Example 27: the Hydrochloride of 2,6-di-tert-butyl-4-(2-{[4-(dimethylamino)piperidine-1-yl]methyl}-1,3-thiazol-4-yl)phenol:

The method used is similar to the method described in example 8, replacing the morpholine in the second stage 4-dimetilan epipedon (J. Med. Chem. (1983), 26, 1218-1223 or J. Chem. Soc. (1957), 3165-3172). Dark green powder. Melting point: level 113.0-to 113.4°C.

Example 28: Hydrochloride of 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-ol:

28.1) 1-{[4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-ol

The method used is similar to the method described in example 8, substituting morpholine for piperidine-4-one hydrochloride (J. Org. Chem. (1949), 14, 530-535), and 2 additional equivalent of triethylamine was used in the second stage. Received the product in this form was used in the next stage.

28.2) of the Hydrochloride of 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-ol:

The intermediate product 28.1 reduced to alcohol by interacting with NaBH4in methanol. After completion of the reaction medium were added dichloromethane and salt water. The aqueous phase was extracted with dichloromethane and washed with salt water. The combined organic phases were dried over magnesium sulfate and the solvent was evaporated. The resulting product was pre-dissolved in ethyl acetate, and the solution was cooled to 0°C. was Slowly added a 1 n solution of HCl in ether (3 equivalent), adding the temperature of the mixture was maintained equal to 0°C, then left to warm to ambient temperature, stirred for 12 hours. Get the expected product in the de white solid product. Melting point: 215,4-218,2°C.

Example 29: 4-Methylpentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

29.1) N-{[(4-Methylpentyl)oxy]carbonyl}-β-alanine:

In a solution containing 4-methyl-1-pentanol (5 g; 0,049 mol) in 80 ml dichloromethane, was added triphosgene at 23°C (5,3 g; 0.019 mol). The mixture was cooled to 0°C, then was added dropwise pyridine (3.8 g; 0,049 mol). The mixture is brought up to 23°C and was stirred for 2 hours. The solvent was evaporated using a rotary evaporator. After trituration in ether, the obtained white solid product was filtered on a Frit. The filtered ether was evaporated. A mixture containing β-alanine (4.4 g, 0,049 mol) and 50 ml of 1 n sodium hydroxide solution, cooled to 10°C. Simultaneously to the mixture β-alanine and sodium hydroxide obtained above, was added prior fresh chloride of 4-methylpentanoate and 50 ml of 1 n sodium hydroxide solution at 5°C. After stirring for 16 hours at 23°C, to determine the pH to 4-5, was added to about 80 ml of hydrochloric acid (approximately 1 N.) to obtain the bright white precipitate. The reaction mixture was extracted with ethyl acetate (2 x 50 ml), and the extract was washed with water, then dried over magnesium sulfate. Get colorless oil (7.2 g; yield 68%).

NMR H1(δ ppm, DMSO): 0,85 (DQC, 6H); to 1.15 (m, 2H); 1,49-of 1.53 (m, 3H); 2,35 (t, 2H); 3,14-3,9 (m, 2H); 3,88-3,91 (m, 2H);? 7.04 baby mortality (CE, 1H); 12 (CE, 1H)

29.2) 4-Methylpentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

A mixture of intermediate product 29.1 (4.52 g; 0,021 mol) and cesium carbonate (3.4 g; 0,0105 mol) in 35 ml of methanol was stirred at 23°C for 1 hour. The methanol was removed by evaporation under reduced pressure in a rotary evaporator. The resulting mixture was dissolved in 70 ml of dimethylformamide was then added 2-bromo-4-phenylacetophenone (5.7 g; 0,021 mol). After stirring for 16 hours the solvent was evaporated under reduced pressure. The resulting mixture was treated with ethyl acetate, then was filtered bromide cesium. The ethyl acetate from the filtrate was evaporated, and the reaction oil was treated with a mixture of xylenes (300 ml) and ammonium acetate; 0.42 mol). The reaction mixture was boiled under reflux for about one and a half hours, water was removed using the apparatus of the Dean-stark, then, after cooling, a mixture of ice water and ethyl acetate was poured into the reaction medium. After decanting, the organic phase is washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, then evaporated in vacuum. After purification on a column of silica gel (eluent: ethyl acetate-heptane/5-5 - 10-0) will receive a white powder (yield 10%). Melting point: 128,3°C. MH+ = 392,3.

The compounds of examples 30 to 43 receive in accordance with the methods, similar to CNAME ways, described in example 29 or higher, in part, entitled "Obtaining compounds of General formula (I).

Example 30: 3,3-Dimethylbutyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 119,2°C. MH+ = 385,3.

Example 31: Isopentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 128-130°C. MH+ = 378,3.

Example 32: Hexyl 2-[4-(4'-bromo-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 138-140°C. MH+ = 470,2.

Example 33: Benzyl 2-[4-(4-tert-butylphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 173°C. MH+ = 378,2.

Example 34: 3,3-Dimethylbutyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 98,4°C. MH+ = 392,15.

Example 35: Hexyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 110-114°C. MH+ = 385,3.

Example 36: 4,4,4-Tripcomputer 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 148,3°C. MH+ = 411,3.

Example 37: Hexyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 197,4°C. MH+ = 444,4.

Example 38: 3,3-Dimethylbutyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 118-120°C. MH+ = 441,3.

Example 39: 3,3-Dimethylbutyl 2-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 116,8°C. MH+ = 346,2.

Example 40: Benzyl 2-[4-(3,5-di-tert-butyl-4-g is PROXIFIER)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 177,5°C. MH+ = 450,3.

Example 41: Benzyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 122,4°C. MH+ = 391,2.

Example 42: 2-Phenylethyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 142-143°C. MH+ = 412,2.

Example 43: Butyl 2-[4-(4'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 149,3°C. MH+ = 382,2.

Example 44: Butyl 2-[4-(1,1'-biphenyl-4-yl)-5-methyl-1H-imidazol-2-yl]ethylcarbamate:

44.1) 1-(1,1'-biphenyl-4-yl)propan-1-he:

A mixture containing phenylboric acid (6,1 g; 50 mmol), 4'-bromopropiophenone (10,65 g; 50 mmol), sodium carbonate (5.3 g; 50 mmol) and palladium chloride (500 mg, 2.8 mmol) in 300 ml of water was boiled under reflux for 4 hours. Then added boric acid (1 g; 0.8 mmol) followed by heating for another 30 minutes. When the temperature of the mixture was decreased to 23°C, was added 250 ml of ethyl acetate, then filtered on a Frit, then on paper GFA. The filtrate decantation, the organic phase, before drying over MgSO4off , washed with a saturated solution of NaCl and concentrated using a rotary evaporator. The precipitate was stirred for 30 minutes in 100 ml of isopentane and 5 ml dichloromethane. After filtration on a Frit solid product was washed with isopentane. Received a cream coloured powder (8.7 g; 83%). Melting point: 98-99°C. MH+ = 211,1

44.2) 1-(1,1'-Biphenyl-4-the l)-2-bromopropane-1-he:

Pre-obtained intermediate product 43.1 mixed with brominated polymer PVPHP (30 g; 2 mmol Br3/g) in 120 ml of toluene for 3 hours at a temperature of approximately 5°C. was Added approximately 15 g of the brominated polymer, and then continued to stir for an additional 3 hours at 23°C. the Newly added approximately 15 g of the polymer, and then the mixture was stirred for 16 hours. The polymer obtained by filtration on a Frit, followed by washing with toluene, then with dichloromethane. The filtrate was concentrated to dryness and the resulting residue was stirred in isopropylacetate for 30 minutes, then filtered on a Frit and washed with isopentane. Get a cream coloured powder (9,58 g; 87%). Melting point: 102-104°C. MH+ = 398,2.

44.3) N-(Butoxycarbonyl)-β-alanine:

The solution containing β-alanine (8,9 g; 0.1 mol) and 100 ml of 1 n sodium hydroxide solution, cooled to 10°C. were Added simultaneously N-butylchloroformate (13,66 g; 0.1 mol) and 50 ml of 2 n sodium hydroxide solution. After stirring for 16 hours at 23°C) to establish the level of pH of 4-5 was added about 10 ml of concentrated hydrochloric acid (approximately 11 BC). The resulting oil was extracted with ethyl acetate (2 x 50 ml), washed with water, then dried over magnesium sulfate. Product crystallizes the Lee of isopentane in the form of a white powder (yield 68%). Melting point: 50,5°C.

44.4) Butyl 2-[4-(1,1'-biphenyl-4-yl)-5-methyl-1H-imidazol-2-yl]ethylcarbamate:

A mixture of N-(butoxycarbonyl)-β-alanine (obtained at the stage 44.3; 3,27 g; 0,0173 mol) and cesium carbonate (2,81 g; 0,0087 mol) in 50 ml of methanol was stirred at 23°C for 1 hour. The methanol was removed by evaporation under reduced pressure in a rotary evaporator. The resulting mixture was dissolved in 50 ml of dimethylformamide was then added to the intermediate product 44.2 (5 g; 0,0173 mol). After stirring for 16 hours the solvent was evaporated under reduced pressure. The resulting mixture was treated with ethyl acetate, then the cesium bromide was filtered. The ethyl acetate from the filtrate was evaporated, and the reaction oil was treated with a mixture of xylene (80 ml) and ammonium acetate (26,6 g; 0.35 mol). The reaction mixture is boiled under reflux for about one and a half hours with removal of water using the apparatus of the Dean-stark, then, after cooling, a mixture of ice water and ethyl acetate was poured into the reaction medium. After decanting, the organic phase is washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, then evaporated in vacuum. After purification on a column of silica gel (eluent: CH2Cl2-ethanol/9-1) to obtain a colorless oil, which was led from a mixture of isopentane and isopropyl ether. After filtrat and and drying to produce a powder of white colour (of 3.31 g, yield 50%). Melting point: 143-144°C. MH+ = 378,2.

The compounds of examples 45 to 49 receive in accordance with methods similar to the methods described in example 44 or higher in the part entitled "Obtaining the compounds of General formula (I).

Example 45: Butyl 2-[4-(4'-methyl-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 168,4°C. MH+ = 378,2.

Example 46: Butyl 2-[4-(4'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 164,2°C. MH+ = 398,2.

Example 47: Butyl 2-[4-(2'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 113,8 °C. MH+ = 382,2.

Example 48: Butyl 2-{4-[4'-(methylthio)-1,1'-biphenyl-4-yl]-1H-imidazol-2-yl}ethylcarbamate:

Melting point: 167,9°C. MH+ = 410,3.

Example 49: Butyl 2-[4-(2',4'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 105,7°C. MH+ = 430,2.

Example 50: Hydrochloride of 2,6-di-tert-butyl-4-{2-[(propylamino)methyl]-1,3-thiazol-4-yl}phenol:

50.1) 2,6-Di-tert-butyl-4-{2-[(propylamino)methyl]-1,3-thiazol-4-yl}phenol:

Into a flask containing 20 ml of anhydrous MeOH, successively added 0,636 g (2.0 mmol) of the intermediate product 6.2, 0.16 ml (2.2 mmol) of Propionaldehyde and 1 g pre-activated powdered 4 Å molecular sieves, in an atmosphere of inert gas. The reaction mixture was intensively stirred for 18 hours and then added, in portions, 0.083 g (2.2 mmol) NaBH4 . Was stirred for another 4 hours, then added 5 ml of water. After a quarter of an hour the sieve was filtered and the reaction mixture was twice extracted with 100 ml of CH2Cl2. The organic phase is washed successively with 50 ml water and 50 ml of salt water, then dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified on a column of silica gel (eluent: 30% ethyl acetate in heptane). The obtained yellow oil was used in this form in the next stage.

50.2) of the Hydrochloride of 2,6-di-tert-butyl-4-{2-[(propylamino)-methyl]-1,3-thiazol-4-yl}phenol:

The intermediate product 50.1 was dissolved in anhydrous ether (15 ml). The solution was cooled to 0°C, then was added dropwise an excess of 1 n HCl in ether (0.6 ml). The mixture was left to warm to ambient temperature with stirring. After filtration, was washed with ether, then with isopentane and dried in vacuum to obtain a white-gray solid product with a yield of 4%. MH+ = 361,2.

Example 51: Hydrochloride of N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}-N-Propylamine:

The method used is similar to the method described for stage 50.1 example 50, substituting the compound of example 13 for the intermediate product 6.2. Get a yellow-green solid product with a yield of 32%. MH+ = 354,2.

Example 52: N-{[4-(10H-Phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}butane-1-amine:

The method used EN the logical way described in example 8, substituting at the stage 8.2 morpholine on butylamine. The yellow solid product is obtained with a yield of 25.6%. Melting point: 139,0-141,0°C.

Example 53: Hydrochloride of N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pentane-1-amine:

The method used is similar to the method described for stage 50.1 example 50, substituting intermediate product 6.2 and Propionaldehyde connection example 13 and valeraldehyde respectively. Get a solid dark color with 38%. MH+ = 382,2.

Example 54: Hydrochloride of (R,S)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-3-ol:

The method used is similar to the method described in example 8, substituting at the stage 8.2 morpholine (R,S)-3-hydroxypiperidine. Received in the base product was transferred into the salt according to the method described for stage 50.2 obtaining light cream solid product with a yield of 81%. Melting point: 126,9-to 130.1°C.

Example 55: Hydrochloride of (R,S)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol:

The method used is similar to the method described in example 8, substituting at the stage 8.2 morpholine (R,S)-3-hydroxypyrrolidine. Received in the base product was transferred into the salt according to the method described for stage 50.2 obtaining light cream solid product with a yield of 93%. Point PLA is ing: 79,8-83,3° C.

Example 56: [4-(10H-Phenothiazines-2-yl)-1,3-thiazol-2-yl]methanol:

56.1) [4-(10H-Phenothiazines-2-yl)-1,3-thiazol-2-yl]metreweli:

This connection receive in accordance with a method identical to the method described for stage 1.3 of example 1, using 2-(tert-BUTYLCARBAMATE)thioacetamide 2-bromo-1-[10-(chloroacetyl)-10H-phenothiazines-2-yl)Etalon instead of, respectively, the intermediate product 1.2 and bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone. The expected compound obtained as a greenish solid product with a yield of 63.2%. Melting point: 120,0-122,0°C.

56.2) [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methanol:

This compound is obtained from an intermediate product 56.1 in accordance with a method identical to the method described for stage 4.2 example 4. The expected compound obtained as a greenish solid product with a yield of 61%. Melting point: 145,0-147,0°C.

Example 57: N,N-dimethyl-N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}amine:

57.1) 2-[2-(methyl bromide)-1,3-thiazol-4-yl]-10H-phenothiazines:

This connection receive in accordance with a method identical to the method described for stage 8.1 example 8, using the intermediate product 56.2 instead of the intermediate product 4.2. The expected compound obtained as a bright, bright Golden yellow-green crystals with a yield of 42%. Melting point: 165-170°C (Razlog.).

57.2) N,N-Dimethyl-N-{[4-(10H-is initiatin-2-yl)-1,3-thiazol-2-yl]methyl}amine:

This connection receive in accordance with a method identical to the method described for stage 8.2 example 8, using the intermediate product 57.1 and N,N-dimethylamine, respectively, instead of the intermediate product 8.1 and research. The expected compound obtained as yellow solid with a yield of 41.8%. Melting point: 155,0-157,0°Spamer 58: Hydrochloride, 2-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl)-10H-phenothiazines:

The method used is similar to the method described in example 8, substituting intermediate product 8.1 and morpholine in stage 8.2, respectively, to the intermediate product and 57.1 N-methylpiperazin. Received in the base product was transferred into the salt according to the method described for stage 50.2 obtaining gray solid product with a yield of 67%. Melting point: 210,0-212,0°C.

Example 59: 2-[2-(piperidine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-phenothiazines;

The used experimental technique similar to the method described in example 8, substituting intermediate product 8.1 and morpholine in stage 8.2, respectively, to the intermediate product 57.1 and piperidine. The obtained product was besieged in accordance with the method described for stage 50.2 obtaining gray-yellow solid product with a yield of 67%. Melting point: of 186.0-188,0°C.

Example 60: Hydrochloride of 2-[2-(piperazine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-feet the azina:

60.1) Tert-butyl 4-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate:

This connection receive in accordance with a method identical to the method described in example 8, using the intermediate product 57.1 and N-tert-butoxycarbonylmethyl, respectively, instead of the intermediate product 8.1 and research. The expected compound is obtained in output 81,2%. MH+ = 481,2.

60.2) of the Hydrochloride of 2-[2-(piperazine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina:

This connection receive in accordance with a method identical to the method described for stage 1.4 example 1, substituting intermediate product 1.3 intermediate product 60.1. The expected compound obtained as a gray-green solid product with a yield of 78.9 per cent. Melting point: 210,0-215,0°C.

Example 61: Hydrochloride of 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}azetidin-3-ol:

61.1) Hydrochloride 1-(diphenylmethyl)-3-hydroxyazetidine:

Aminodiphenylamine (55 g; 0.3 mol) and epichlorohydrin (23,5 ml; 0.3 mol) were mixed in methanol (200 ml). The mixture was subjected to boiling under reflux for 5 days. Then the methanol was evaporated to obtain a beige solid product. This product was filtered and washed with ether to obtain a white solid product with a yield of 45%. Melting point: of 186.0-186,4°C.

61.2) Azetidin-3-ol:

The intermediate product 61.1 was dissolved in sm is si ethanol/THF (7:3), to which was added water to achieve good dissolution. Before placing the mixture in an atmosphere of hydrogen under a pressure of 3 bar at ambient temperature, the mixture was purged with argon, then hydrogen. After filtration and washing with ethanol, the solvent was evaporated, and the pasty residue was treated with ether. The obtained solid product was filtered and washed with ether to obtain a white solid product (yield 86%). Melting point: 74,0-76,8°C.

61.3) of the Hydrochloride of 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}azetidin-3-ol:

This connection receive in accordance with a method identical to the method described in example 8, replacing the morpholine in stage 8.2 intermediate product 61.2. Received in the base product was transferred into the salt according to the method described for stage 50.2 obtaining light cream solid product with a yield of 74%. Melting point: 124,2-126,5°C.

Example 62: 2-[2-(Morpholine-4-ylmethyl)-1,3-thiazol-4-yl]-10H-phenothiazines:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2 intermediate product 8.1 intermediate product 57.1 obtaining not quite white solid product with the release of 86,0%. Melting point: 203,0-205,0°C.

Example 63: 2-[2-(Thiomorpholine-4-ylmethyl)-1,3-thiazol-4-yl]-10H-phenothiazines:

This with the Association receive in accordance with the method, identical to the method described in example 8, substituting at the stage 8.2, respectively, the intermediate product 8.1 and morpholine intermediate product 57.1 and thiomorpholine. The expected product is obtained in the form of a yellow solid product with access to 80.8%. Melting point: 229,0-231,0°C.

Example 64: 2-{2-[(4-Methyl-1,4-diazepan-1-yl)methyl]-1,3-thiazol-4-yl}-10H-phenothiazines:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2, respectively, the intermediate product 8.1 and morpholine intermediate product 57.1 and homopiperazin. The expected product is obtained in the form of a yellow solid product with the release of 27.0%. Melting point: 135-137°C.

Example 65: Hydrochloride, (3R)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2 morpholine (R)-3-pyrrolidino. Received in the base product was transferred into the salt according to the method described in stage 50.2 obtaining a white solid product with a yield of 93%. Melting point: 162,0-164,6°C.

Example 66: Hydrochloride, (3S)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol:

This connection receive in accordance with a method identical to the method described in example 8, replacing the Yaya on stage 8.2 morpholine (S)-3-pyrrolidino. Received in the base product was transferred into the salt according to the method described for stage 50.2 obtaining a white solid product with a yield of 93%. Melting point: 162,8-165,9°C.

Example 67: Hydrochloride of 2,6-di-tert-butyl-4-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]phenol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2 morpholine to pyrrolidine. Received in the base product was transferred into the salt according to the method described for stage 50.2 obtaining not quite white solid product with a yield of 73%. Melting point: 188,0-195,0°C.

Example 68: Hydrochloride of 2,6-di-tert-butyl-4-{2-(butylamino)-methyl]-1,3-thiazol-4-yl}phenol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2 morpholine on butylamine. Received in the base product was transferred into the salt according to the method described for stage 50.2, obtaining not quite white solid product with a yield of 72%. Melting point: to $ 179.7-180,2°C.

Example 69: 2-{2-[(4-Ethylpiperazin-1-yl)methyl-1,3-thiazol-4-yl}-10H-phenothiazines:

This connection receive in accordance with a method identical to the method described in example 8, replacing, respectively, the intermediate stage 8.2 8.1 product and morpholine split timing on the th product 57.1 and N-ethylpiperazine. The expected product is obtained in the form of a white solid product with a yield of 57.7%. Melting point: 182,0-184,0°C.

Example 70: Hydrochloride of N-methyl-N-{[4-(10H-phenothiazines-2-yl)-1H-imidazol-2-yl]methyl}amine:

70.1) Tert-butylmethyl{[4-(10H-phenothiazines-2-yl)-1H-imidazol-2-yl]methyl}carbamate:

This connection receive in accordance with a method identical to the method described for stage 44.4 example 44, substituting, respectively, N-(butoxycarbonyl)-β-alanine and intermediate product 44.2 on Boc-Sar-OH and 2-chloro-1-[10-(chloroacetyl)-10H-phenothiazines-2-yl)alanon (cf stage 13.1 example 13) when replacing this stage 44.4 ethanol for methanol. The expected product is obtained with a yield of 81.6% and used in this form in the next stage.

70.2) of the Hydrochloride of N-methyl-N-{[4-(10H-phenothiazines-2-yl)-1H-imidazol-2-yl]methyl}amine:

Before conversion into a hydrochloride in the intermediate product 70.1 remove protective groups in accordance with a method similar to the method used in stage 1.4 of example 1. The expected product is obtained in the form of a brown powder with a yield of 53.7%. Melting point: 190,0-195,0°C.

Example 71: Methyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate:

The compound of example 13 (0,622 g; 2.0 mmol) was dissolved in dioxane (100 ml), cooled to 0°C. was Added triethylamine and then, dropwise, methylchloroform (2.5 mmol). Then the reaction mixture was stirred for hours at ambient temperature and was poured into ice water and was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The expected product was purified on a column of silica gel (eluent: 10% acetone in dichloromethane). Pure fractions were collected and the solvent was evaporated to obtain not just the white solid product with access to 46.0%. Melting point: 151-153°C.

Example 72: Butyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate:

This connection receive in accordance with a method identical to the method described in example 71, using n-butylchloroformate instead of methylchloroform. The expected product is obtained in the form of a yellow solid product with the release of 61,0%. Melting point: of 186.0-188,0°C.

Example 73: N-Neopentyl-N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}amine:

This connection receive in accordance with a method identical to the method described for stage 50.1 example 50, substituting, respectively, the intermediate product 6.2 and Propionaldehyde connection example 13 and pivilege. The expected product is obtained in the form of not quite white solid product with a yield of 40.6%. Melting point: 172,0-174,0°C.

Example 74: 1-{[4-(10H-Phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}piperidine-4-ol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2, respectively, the intermediate product 8.1 and morpholine in Prohm is filling product and 57.1 4-hydroxypiperidine. The expected product is obtained in the form of a white solid product with a yield of 52.5%. Melting point: 205,0-207,0°C.

Example 75 N-{[4-(10H-Phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide:

This connection receive in accordance with a method identical to the method described in example 6, substituting at the stage 6.3 intermediate product 6.2 connection of example 13. The expected product is obtained in the form of a yellow solid with a yield of 25.0%. Melting point: 219,0-221,0°C.

Example 76 N-{[4-(10H-Phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}butanamide:

This connection receive in accordance with a method identical to the method described in example 6, substituting at the stage 6.3, respectively, the intermediate product 6.2 and acetylchloride connection example 13 and butanolate. The expected product is obtained in the form of a yellow solid product with access to 47.2%. Melting point: 218,0-220,0°C.

Example 77: 2,6-Di-tert-butyl-4-{2-[(4-propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol:

77.1) Hydrochloride tert-butyl 4-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate:

This connection receive in accordance with a method identical to the method described in example 8, replacing the morpholine in stage 8.2 N-Boc-piperazine. Get a pale orange solid product with a yield of 64%. Melting point: 108-109°C.

77.2) of the Hydrochloride of 2,6-di-tert-butyl-4-[2-(piperaz the n-1-ylmethyl)-1,3-thiazol-4-yl]phenol:

This connection receive in accordance with a method identical to the method described for stage 1.4, replacing intermediate product 1.3 intermediate product 77.1. Get white solid product with a yield of 86%. Melting point: 255,4-257,7°C.

77.3) 2,6-Di-tert-butyl-4-{2-[(4-propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol:

This connection receive in accordance with a method identical to the method described for stage 50.1 example 50, substituting intermediate product 6.2 intermediate product 77.2, and adding first an excess of triethylamine to convert the intermediate product 77.2 in the corresponding base. The expected product is obtained in the form of not quite white solid product with a yield of 45%. Melting point: 236,5-238,2°C.

Example 78: Hydrochloride of 2,6-di-tert-butyl-4-{2-[2-methyl-1-(methylamino)propyl]-1,3-thiazol-4-yl}phenol:

78.1) N-(Tert-butoxycarbonyl)-N-methylvaline:

N-methyl-D,L-valine (10.0 g; 0,0763 mol) was dissolved in a mixture of dioxane-water (9:1) (100 ml)containing triethylamine (13 ml). The mixture was cooled to 0°C, then portions were added Boc-O-Boc (18,32 g; 0,0763 mol)and the mixture was kept under stirring overnight at ambient temperature. Then the reaction medium was poured into ice water and was extracted with ethyl acetate. The organic phase was washed sequentially with 10% aqueous sodium bicarbonate solution and water, then, at the end, a saturated solution of sodium chloride. Then the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to obtain an oily product, which was led from petroleum ether. Get the expected product with a yield of 67% and used in this form in the next stage. Melting point: 83-85°C.

78.2) N2-(Tert-butoxycarbonyl)-N2-methylvaleramide:

Consistently hydrochloride was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (9,777 g; 0,051 mol) and hydroxybenzotriazole (7,8 g; 0,051 mol) of the intermediate product 78.1 (11,8 g; 0,051 mol) in dichloromethane (200 ml). Then dropwise added triethylamine (13 ml) and the mixture was stirred for 12 hours at ambient temperature. Then the reaction mixture was poured into 10% aqueous sodium bicarbonate solution. After decanting, the organic phase is washed with water, then saturated sodium chloride solution. Then the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was treated with methanol, previously saturated with gaseous ammonia (150 ml). The mixture was placed in an autoclave oven at 50°C and was stirred for 4 days at this temperature. The methanol was evaporated, and the product was treated with dichloromethane and washed with a saturated solution of sodium chloride. The organic phase was dried on the magnesium sulfate, was filtered and concentrated in vacuum. The product was purified by rubbing in the air to obtain a white solid product with a yield of 23.5%. Melting point: 181-183°C.

78.3) Tert-butyl 1-(iminocarbonothioyl)-2-methylpropyl-(methyl)carbamate:

This compound is produced by the interaction of the intermediate product with 78.2 P2S5under the conditions described in example 12, step 12.2. The expected product was purified by chromatography on a column of silica gel (eluent = 5% methanol in dichloromethane) to give the not quite white solid product with a yield of 32.5%. Melting point: 199,0-201,0°C.

78.4) of the Hydrochloride of 2,6-di-tert-butyl-4-{2-[2-methyl-1-(methylamino)propyl]-1,3-thiazol-4-yl}phenol:

This connection receive in accordance with a method identical to the method described for stage 1.3 of example 1, the intermediate product 78.3 replaces the intermediate product 1.2. The resulting intermediate compounds were removed protective group using the Hydrobromic acid formed in situ, to obtain the expected product in the form of free base, which was purified by chromatography on a column of silica gel (eluent: 30% ethyl acetate in heptane). Then the free base was transferred into the salt by dissolution in ethyl acetate, through which was passed a stream of gaseous HCl for 10 minutes. After stirring the mixture for one hour the UE shall rival to dryness and the residue was treated with ether. After filtration get a pale pink solid product with a yield of 92%. Melting point: 248,6-250,0°C.

Example 79: Hydrochloride of N,2-dimethyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]propan-1-amine:

79.1) Tert-butyl methyl{2-methyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]propyl}carbamate:

Intermediate products and 78.3 13.1 subjected interaction in accordance with the method similar to the method described for stage 1.3 of example 1. The expected connection receive in the form of oil, which was purified by chromatography on a column of silica gel (eluent:pure dichloromethane). The expected product is obtained in the form of a white solid product with access to 72.4%. In this form it was used in the next stage.

79.2) Hydrochloride, N,2-dimethyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]propan-1-amine:

This connection receive in accordance with a method identical to the method described for stage 1.4 of example 1, substituting intermediate product 1.3 intermediate product 79.1. After washing with ether and isopentane it was dried and got the expected compound in the form of a dark-green powder with a yield of 62%. MH+ = 368,1.

Example 80 N-{[4-(10H-Phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}hexanamide;

This connection receive in accordance with a method identical to the method described in example 6, substituting at the stage 6.3, respectively, the intermediate product 6.2 and acetylchloride on with the unity of example 13 and hexanoate. The expected product is obtained in the form of a brown solid product with a yield of 40.7%. Melting point: 192,0-194,0°C.

Example 81: (3R)-1-{[4-(10H-Phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2, respectively, the intermediate product 8.1 and morpholine intermediate product 57.1 and (R)-3-pyrrolidino. The expected product is obtained in the form of a white solid product with a yield of 49.5%. Melting point: 180,0-182,0°C.

Example 82: (3S)-1-{[4-(10H-Phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2, respectively, the intermediate product 8.1 and morpholine intermediate product 57.1 and (S)-3-pyrrolidino. The expected product is obtained in the form of a white solid product with a yield of 49.5%. Melting point: 178,0-180,0°C.

Example 83: 1-{[4-(10H-Phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}azetidin-3-ol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2, respectively, the intermediate product 8.1 and morpholine intermediate product 57.1, azetidin-3-ol (intermediate product 61.2). The expected product is obtained in the form of not quite white solid product with a yield of 20.4%. That is ka melting point: 240,0-242,0° C.

Example 84: 2-{2-[(4-Propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-phenothiazines:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2, respectively, the intermediate product 8.1 and morpholine intermediate product 57.1 and N-propylpiperazine. The expected product is obtained in the form of a white solid product with a yield of 42.6%. Melting point: 189,0-190,0°C.

Example 85: 2-{2-[(4-Acetylpiperidine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-phenothiazines:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2, respectively, the intermediate product 8.1 and morpholine intermediate product 57.1 and N-acetylpiperidine. The expected product is obtained in the form of not quite white solid product with a yield of 53.5%. Melting point: 218,0-220,0°C.

Example 86: 2-{2-[(4-Butylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-phenothiazines:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2, respectively, the intermediate product 8.1 and morpholine intermediate product 57.1 and N-butylpiperazine. The expected product is obtained in the form of a white solid product with a yield of 69.3%. Melting point: 188,0-190,0°C.

Example 87: Methyl 4-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate:

Prohm is filling product 60.2 (0,380 g; 1 mmol) was dissolved in THF. To the thus obtained solution was added triethylamine (1 ml), then was added dropwise methylchloroform (0.1 ml). When the reaction was completed, the reaction mixture was poured into ice water and was extracted with ethyl acetate. The separated organic phase was filtered, and the solvent was evaporated. After crystallization from isopropanol, the expected product is obtained in the form of a white solid product with a yield of 66.1%. Melting point: 180,0-182,0°C.

Example 88: Hydrochloride 4-[2-(aminomethyl)-1H-imidazol-4-yl]-2,6-di-tert-butylphenol:

88.1) Benzyl [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]methylcarbamate

This connection receive in accordance with a method identical to the method described for stage 44.4 example 44, substituting, respectively, N-(butoxycarbonyl)-β-alanine and intermediate product 44.2 to carbobenzoxy and bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)Etalon. The expected product is obtained with a yield of 55%. Melting point: 212,1-213,4°C.

88.2) Hydrochloride 4-[2-(aminomethyl)-1H-imidazol-4-yl]-2,6-di-tert-butylphenol:

The intermediate product 88.1 (2.2 g; of 5.05 mmol) was dissolved in a 50/50 mixture of ethanol and THF (70 ml). Added 0.7 g of palladium on coal (10 %) and the mixture was placed in an atmosphere of hydrogen (pressure 3.5 bar). The catalyst was filtered, then the solvent was evaporated under reduced pressure. The resulting basis is their was dissolved in ether and receive hydrochloride by adding 1N. HCl solution in ether (20 ml). After filtration and drying under vacuum to obtain the expected product in the form of a solid color from white to light gray, which was washed with ether, then with isopentane (yield 56%). Melting point: 225-228,3°C.

Example 89: Hydrochloride 4-{2-[(benzylamino)methyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2 morpholine to benzylamine. The expected product is obtained in the form of a white solid product with a yield of 62%. Melting point: 166,4-167,8°C.

Example 90: Hydrochloride 4-{2-[(4-acetylpiperidine-1-yl)methyl-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2 morpholine N-acetylpiperidine. The expected product is obtained in the form of a white solid product with a yield of 64%. Melting point: 199,0-200,4°C.

Example 91: Hydrochloride of N-methyl-N-{[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]methyl}amine:

This connection receive in accordance with a method identical to the method described in example 12, substituting bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)propane-1-it 2-chloro-1-(10H-phenoxazin-2-yl)alanon (2-chloro-1-(10H-phenoxazine-2-yl)Etalon received the same method used to obtain the intermediate product is and 13.1-see J. Org. Chem. (1960), 25, 747-753). The expected product was obtained after the interaction, and remove protection and transformed to a salt in the form of a green solid product. Melting point: 218-220°C.

Example 92: Hydrochloride 4-[2-(azetidin-1-ylmethyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol:

This connection receive in accordance with a method identical to the method described in example 8, azetidin replaces the morpholine in stage 8.2. The expected product is obtained in the form of a white solid product with a yield of 90%. Melting point: 141,7-144,2°C.

Example 93: Hydrochloride of 2,6-di-tert-butyl-4-{2-[(4-butylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2 morpholine N-butyl-piperazine. The expected product is obtained in the form of not quite white solid product with a yield of 68%. Melting point: 229,9-of 230.5°C.

Compounds of examples 94 and 112 receive in accordance with methods similar to the methods described in example 29 or higher in the part entitled "Obtaining the compounds of General formula (I).

Example 94: Butyl 2-[4-(3'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 142,6°C. MH+ = 398,3.

Example 95: Butyl 2-[4-(3'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 141,5°C. MH+ = 381,2.

Example 96: Butyl 2-[4-(4-isobutylphenyl)1H-imidazol-2-yl]ethylcarbamate:

Melting point: 95,5°C. MH+ = 344,2.

Example 97: Benzyl 2-[4-(4-isobutylphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 125,2°C. MH+ = 378,4.

Example 98: Butyl 2-[4-(3'-chloro-4'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 132,4°C. MH+ = 416,3.

Example 99: Butyl 2-[4-(3',4'-dichloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 137,5°C. MH+ = 432,2.

Example 100: Butyl 2-[4-(4-propylphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 83,2°C. MH+ = 330,4.

Example 101: Butyl 2-[4-(4-ethylphenyl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 92,4°C. MH+ = 316,3.

Example 102: Butyl 2-[4-(4'-cyano-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 147°C. MH+ = 389,2.

Example 103: Butyl 2-{4-[4'-(trifluoromethyl)-1,1'-biphenyl-4-yl]-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 168,5°C. MH+ = 432,3.

Example 104: Butyl 2-[4-(1,1'-biphenyl-4-yl)-5-ethyl-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 127-128°C. MH+ = 392,2.

Example 105: Butyl 2-[4-(2'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 99,7°C. MH+ = 398,1.

Example 106: Butyl 2-[4-(2',3'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 90°C. MH+ = 400,1.

Example 107: Butyl 2-[4-(2'-bromo-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 109,6 °C. MH+ = 442,1.

Example 108: Butyl 2-[4-(3',5'-debtor-1,1'-biphenyl-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 111,1°C. MH+ = 400,2.

Example 109: Butyl 2-[4-(2'-methoxy-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 116-121 °C. MH+ = 394,3.

Example 110: Butyl 2-[4-(3'-nitro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 100,5 is 101.5°C. MH+ = 409,2.

Example 111: Butyl 2-[4-(2',5'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 109,5 °C. MH+ = 400,2.

Example 112: Butyl 2-[4-(3'-methoxy-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate:

Melting point: 112-113°C. MH+ = 394,2.

Example 113: Hydrochloride of methyl 4-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2 morpholine on methyl ether piperazine-1-carboxylic acid. The expected product is obtained in the form of white crystals with a yield of 51%. Melting point: 240,6-241.4 M.°C.

Example 114: Methyl [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylcarbamate:

This connection receive in accordance with a method identical to the method described in example 71, substituting the compound of example 13, the intermediate product 6.2. The expected product is obtained in the form of a crystalline white solid product with a yield of 18%. Melting point: 94,0-95,9°C.

Example 115 N-{[4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3-thiazo the-2-yl]methyl}benzamide:

This connection receive in accordance with a method identical to the method described in example 71, substituting the compound of example 13 for the intermediate product 6.2, and replacing methylchloroform on benzoyl chloride. The expected product is obtained in the form of a crystalline white solid product with a yield of 84%. Melting point: 200,4-201,2°C.

Example 116 N-{[4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-2-phenylacetamide:

This connection receive in accordance with a method identical to the method described in example 71, substituting the compound of example 13 for the intermediate product 6.2, and replacing methylchloroform on phenylacetylene. The expected product is obtained in the form of a crystalline white solid product with a yield of 45%. Melting point: 123,5-125,4°C.

Example 117 N-{[4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}propanamide:

This connection receive in accordance with a method identical to the method described in example 71, substituting the compound of example 13 for the intermediate product 6.2, and replacing methylchloroform on propionate. The expected product is obtained in the form of a crystalline white solid product with a yield of 45%. Melting point: 82,0-83,5°C.

Example 118: Acetate 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-Il:

This connection receive in accordance with the method, the IDA is a more pragmatic way, described in example 8, substituting at the stage 8.2 morpholine by 1-acetyl-piperazine. The expected product is obtained in the form of a crystalline orange solid product with a yield of 50%. Melting point: 160,3-160,6°C.

Example 119: 1-{[4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3,4-diol:

This connection receive in accordance with a method identical to the method described in example 8, substituting at the stage 8.2 morpholine 3.4-dihydroxypyrrolidine. The expected product is obtained in the form of a brown foam with a yield of 29%. MH+ = 405,20. Pharmacological study of the products of this invention

The study of the effects on binding of specific ligand MAO-B, [3H]Ro 19-6327

Inhibitory activity of the products according to this invention were determined by measuring their actions by binding of a specific ligand MAO-B, [3H]Ro 19-6327.

a) Obtain the mitochondrial fraction from the cerebral cortex of the rat

Getting mitochondrial fractions from cortex of the rat brain was carried out according to the method described Cesura A.M., Galva M.D., Imhof R. and Da Prada, M., J. Neurochem. 48 (1987)0, 170-176. Rats were decapitated and the cerebral cortex was removed, homogenized in 9 volumes of 0.32 M sucrose buffer, safereating at a pH of 7.4 with 5 mm HEPES, and then centrifuged at 800 g for 20 minutes. Supernatant was removed and the residue twice about ivali of 0.32 M sucrose buffer, described above. Supernatant collected by centrifugation at 10000 g for 20 minutes. The obtained precipitates suspended in Tris buffer (50 mm Tris, 130 mm NaCl, 5 mm KCl, 0.5 mm EGTA, 1 mm MgCl2, a pH of 7.4) and centrifuged at 10,000 g for 20 minutes. This step was repeated twice and the final residue corresponding mitochondrial fractions were stored at -80°C in Tris buffer. The protein content in the sample was determined by the method of Lowry.

b) Binding of [3H]Ro 19-6327

The Eppendorf tube was incubated with 100 ál of mitochondrial sample (2 mg protein/ml) for 1 hour at 37°C in the presence of 100 μl of [3H]Ro 19-6327 (33 nm, final concentration) and 100 μl of Tris buffer containing or not containing inhibitors. The reaction was stopped by adding to each tube 1 ml of unlabeled Tris buffer, then the samples were centrifuged for 2 minutes at 12000 g. Supernatant was aspirated and the precipitation was washed with 1 ml Tris buffer. Precipitates were then dissolved in 200 μl of sodium dodecyl sulfate (20% weight/volume) for 2 hours at 70°C. Radioactivity was determined using gidrostimulyatsionnye processing of samples.

c) Results

The compounds of examples 1, 3, 5, 11 and 18, described above, have the IC50less than or equal to 10 microns.

The study of the effects on lipid peroxidation of brain cortex of rats

Inhibitory activity of the products on this izaberete the s was determined by measuring their effect on the degree of lipid peroxidation, defined as the concentration of malondialdehyde (MDA). MDA formed during peroxide oxidation of unsaturated fatty acids, is a good indicator of lipid peroxidation (H. Esterbauer and K.H. Cheeseman, Meth. Enzymol. (1990) 186: 407-421). Male rats Sprag-douli, weighing 200 to 250 g (Charles River) were killed by decapitation. The cerebral cortex was removed, and then homogenized using a homogenizer Thomas in 20 mm Tris-HCl buffer, pH = 7,4. The homogenate was centrifuged twice at 50000 g for 10 minutes at 4°C. the Precipitate was stored at -80°C. on the day of the experiment, the sediment was transferred into a suspension with a concentration of 1 g/15 ml and centrifuged at 515 g for 10 minutes at 4°C. the Supernatant was immediately used for determination of lipid peroxidation. The homogenate of cerebral cortex of rats (500 μl) were incubated at 37°C for 15 minutes in the presence of the tested compound or solvent (10 ml). Reaction of lipid peroxidation was initiated by adding 50 μl of FeCl21 mm, EDTA 1 mm) and ascorbic acid and 4 mm. After incubation for 30 minutes at 37°C the reaction was stopped by adding 50 μl of solution gidrauxilirovannogo di-tert-butyltoluene (BHT, 0.2 percent). MDA was quantitatively evaluated using the colorimetric test, by interaction of a chromogenic reagent (R), N-methyl-2-phenylindole (650 ml) with 200 μl of the homogenate for 1 cha is and at 45° C. Condensation MDA molecule with two molecules of reagent R gave a stable chromophore with maximal absorption wavelength equal to 586 nm. (Caldwell et al. European J. Pharmacol. (1995) 285, 203-206). The value of the IC50compounds of examples 1, 3-28, 50-62, 64-86, 88-93 and 114-118, above, below or equal to 10 microns.

Test bind against sodium channels in brain cortex of rats

The test consists in measuring the impact of compounds on the binding titiraupenga of batrachotoxin with valittaviksi sodium channels in accordance with the method described by Brown (J. Neurosci. (1986), 6, 2064-2070).

Getting homogenates of the cortex of rat brain

Removed the cerebral cortex of rats Sprag-douli, weighing 230-250 g (Charles River, France)were weighed and homogenized using a Potter homogenizer equipped with a Teflon piston (10 strokes) in 10 volumes of buffer to allocate the following composition (sucrose 0,32 M, K2HPO45 mm, pH 7,4). The homogenate was first subjected to centrifugation at 1000 g for 10 minutes. The supernatant was removed and centrifuged at 20000 g for 15 minutes. The precipitate was placed in the buffer to allocate and was centrifuged at 20000 g for 15 minutes. The precipitate is again suspended in the buffer for incubation (HEPES 50 mm, KCl 5.4 mm MgSO40.8 mm, glucose 5.5 mm, 130 mm choline chloride, pH 7,4), then divided into aliquots and stored at -80°C until the day of the experts who ment. The final concentration of protein ranged from 4 to 8 mg/ml of the protein Analysis is performed with the use of a set produced by BioRad (France).

Measurement of binding titiraupenga of batrachotoxin

The binding reaction is carried out by incubation for 1 hour 30 minutes at 25°C 100 µl of homogenate cortex of rats containing 75 μg of protein, 100 ál of [3H] benzoate of batrachotoxin-A-20-alpha (37,5 Kyu/mmol, NEN) at 5 nm (final concentration), 200 μl of tetrodotoxin at 1 μm (final concentration) and Scorpion venom at 40 μg/ml (final concentration) and 100 μl of buffer for incubation, with or without investigational products in various concentrations. Nonspecific binding was determined in the presence of 300 μm veratridine, and the value of this nonspecific binding subtracted from all other values. The samples were then filtered using a Brandel (Gaithersburg, Maryland, USA), using Unifilter GF/C plates for preincubation with 0.1% polyethylenimine (20 μl/cell) and washed twice with 2 ml of buffer for filtering (HEPES 5 mm, CaCl21.8 mm, MgSO40.8 mm, 130 mm choline chloride, BSA in 0.01%, pH of 7.4). After adding 20 μl of Microscint 0 ®, radioactivity was counted using gidrostimulyatsionnye counter (Topcount, Packard). The measurement is carried out repeatedly. The results are expressed as % specific binding titiraupenga of batrachotoxin on the compared to control.

Results

The value of the IC50all of the compounds of examples 1, 3, 5, 12, 15, 16, 18, 20, 28-47, 49, 52, 61, 65-69, 89 and 94-112, described above, was less than or equal to 1 micron.

1. A compound selected from the following compounds:

- 2,6-di-tert-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-[4-(hydroxymethyl)-1,3-oxazol-2-yl]phenol;

- 2,6-di-tert-butyl-4-{2-[1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-[2-(methoxymethyl)-1,3-thiazol-4-yl]phenol;

- 2,6-di-tert-butyl-4-{4-[(methylamino)methyl]-1,3-oxazol-2-yl]phenol;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide;

- ethyl [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylcarbamate;

- 2,6-di-tert-butyl-4-[2-(morpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol;

- 2,6-di-tert-butyl-4-[2-(thiomorpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol;

- 4-[2-(anilinomethyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;

- 2,6-di-tert-butyl-4-(2-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}-1,3-thiazol-4-yl)phenol;

- 2,6-di-tert-butyl-4-{5-methyl-2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methanamine;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-methylacetamide;

- 1-[4-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-2-yl]-N-methylmethanamine;

- 2,6-di-tre the-butyl-4-{2-[(ethylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[(4-phenylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- N-{1-[4-(4-anilinophenol)-1,3-thiazol-2-yl]ethyl}-N-methylamine;

- 2,6-di-tert-butyl-4-{2-[(isopropylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[(cyclohexylamino)methyl]-1,3-thiazol-4-yl} phenol;

- 2,6-di-tert-butyl-4-{2-[(4-isopropylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- N-methyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]ethanamine;

- 2,6-di-tert-butyl-4-{2-[(4-ethylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- N-{[4-(4-anilinophenol)-1,3-thiazol-2-yl]methyl}-N-ethylamine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}of ethanamine;

- 2,6-di-tert-butyl-4-(2-{[4-(dimethylamino)piperidine-1-yl]methyl}-1,3-thiazol-4-yl)phenol;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-ol;

- 4-methylpentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

3,3-dimethylbutyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- isopentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- hexyl 2-[4-(4'-bromo-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(4-tert-butylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 3,3-dimethylbutyl 2-[4-(1,1'-biphenyl-4-yl)-1H-and idazole-2-yl]ethylcarbamate;

- hexyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- hexyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 3,3-dimethylbutyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 3,3-dimethylbutyl 2-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 2-phenylethyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(1,1'-biphenyl-4-yl)-5-methyl-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-methyl-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

butyl 2-[4-(2',4'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate,

or pharmaceutically acceptable salt of one of the foregoing compounds.

2. A compound selected from the following compounds:

- 2,6-di-tert-butyl-4-{2-[(propylamino)methyl]-1,3-thiazol-4-yl}phenol;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}-N-Propylamine;

- N-{[4-(10H-phenothiazines--yl)-1,3-thiazol-2-yl]methyl}butane-1-amine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pentane-1-amine;

1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-3-ol;

1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methanol;

- N,N-dimethyl-N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}amine;

- 2-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- 2-[2-(piperidine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 2-[2-(piperazine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}azetidin-3-ol;

- 2-[2-(morpholine-4-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 2-[2-(thiomorpholine-4-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 2-{2-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- (3R)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl} pyrrolidin-3-ol;

- (3S)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl} pyrrolidin-3-ol;

- 2,6-di-tert-butyl-4-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]phenol;

-2,6-di-tert-butyl-4-{2-[(butylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 2-{2-[(4-ethylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- N-methyl-N-{[4-(10H-phenothiazines-2-yl)-1H-imidazol-2-yl]methyl}amine;

- ethyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate;

- butyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate;

- N-neopentyl-N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}amine;

- 1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}piperidine-4-ol;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}butanamide;

- 2,6-di-tert-butyl-4-{2-[(4-propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[2-methyl-1-(methylamino)propyl]-1,3-thiazol-4-yl}phenol;

- N,2-dimethyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]propan-1-amine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}hexanamide;

- (3R)-1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- (3S)-1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- 1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}azetidin-3-ol;

- 2-{2-[(4-propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- 2-{2-[(4-acetylpiperidine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- 2-{2-[(4-butylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- methyl 4-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate;

- 4-[2-(aminomethyl)-1H-imidazol-4-yl]-2,6-di-tert-butylphenol;

- 4-{2-[(benzylamino)methyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;

- 4-{2-[(4-acetyle the Razin-1-yl)methyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;

- N-methyl-N-{[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]methyl}amine;

- 4-[2-(azetidin-1-ylmethyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;

- 2,6-di-tert-butyl-4-{2-[(4-butylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- butyl 2-[4-(3'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4-isobutylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(4-isobutylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3'-chloro-4'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3',4'-dichloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4-propylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4-ethylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-cyano-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(1,1'-biphenyl-4-yl)-5-ethyl-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2',3'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-bromo-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3',5'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-methoxy-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

p num="1076"> - butyl 2-[4-(3'-nitro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2',5'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3'-methoxy-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate,

or pharmaceutically acceptable salt of one of the foregoing compounds.

3. A compound selected from the following compounds:

- methyl 4-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate;

- methyl [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylcarbamate;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl} benzamide;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-2-phenylacetamide;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}propanamide;

- acetate 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-yl;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3,4-diol,

or pharmaceutically acceptable salt of one of the foregoing compounds.

4. The compound according to claim 1 or pharmaceutically acceptable salt as drugs having at least one of the following activities:

monoamine oxidase inhibition, in particular monoamine oxidase;

inhibition of peroxidation Oka is of lipids;

the expression modulating activity against sodium channels.

5. The compound according to claim 2 or pharmaceutically acceptable salt as drugs having at least one of the following activities:

monoamine oxidase inhibition, in particular monoamine oxidase;

inhibition of lipid peroxidation;

the expression modulating activity against sodium channels.

6. The compound according to claim 3 or pharmaceutically acceptable salt as drugs having at least one of the following activities:

monoamine oxidase inhibition, in particular, monoamine oxidase;

inhibition of lipid peroxidation;

the expression modulating activity against sodium channels.

7. The use of compounds selected from the following compounds:

- 2,6-di-tert-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-[4-(hydroxymethyl)-1,3-oxazol-2-yl]phenol;

- 2,6-di-tert-butyl-4-{2-[1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-[2-(methoxymethyl)-1,3-thiazol-4-yl]phenol;

- 2,6-di-tert-butyl-4-{4-[(methylamino)methyl]-1,3-oxazol-2-yl]phenol;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide;

- the Teal[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylcarbamate;

- 2,6-di-tert-butyl-4-[2-(morpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol;

- 2,6-di-tert-butyl-4-[2-(thiomorpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol;

- 4-[2-(anilinomethyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;

- 2,6-di-tert-butyl-4-(2-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}-1,3-thiazol-4-yl)phenol;

- 2,6-di-tert-butyl-4-{5-methyl-2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methanamine;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-methylacetamide;

- 1-[4-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-2-yl]-N-methylmethanamine;

- 2,6-di-tert-butyl-4-{2-[(ethylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[(4-phenylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- N-{1-[4-(4-anilinophenol)-1,3-thiazol-2-yl]ethyl}-M-methylamine;

- 2,6-di-tert-butyl-4-{2-[(isopropylamino)methyl]-1,3-thiazol-4-yl} phenol;

- 2,6-di-tert-butyl-4-{2-[(cyclohexylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[(4-isopropylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- N-methyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]ethanamine;

- 2,6-di-tert-butyl-4-{2-[(4-ethylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- N-{[4-(4-anilinophenol)-1,3-thiazol-2-the l]methyl}-N-ethylamine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}of ethanamine;

- 2,6-di-tert-butyl-4-(2-{[4-(dimethylamino)piperidine-1-yl]methyl}-1,3-thiazol-4-yl)phenol;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-ol;

- 4-methylpentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- 3,3-dimethylbutyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- isopentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- hexyl 2-[4-(4'-bromo-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(4-tert-butylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 3,3-dimethylbutyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- hexyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- hexyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 3,3-dimethylbutyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 3,3-dimethylbutyl 2-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 2-phenylethyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]Amilcar the Amata;

- butyl 2-[4-(1,1'-biphenyl-4-yl)-5-methyl-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-methyl-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2',4'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate,

or pharmaceutically acceptable salt of one of the above compounds to obtain drugs having at least one of the following three types of activities:

monoamine oxidase inhibition, in particular, monoamine oxidase B,

inhibition of lipid peroxidation,

the expression modulating activity against sodium channels.

8. The use of compounds selected from the following compounds:

- 2,6-di-tert-butyl-4-{2-[(propylamino)methyl]-1,3-thiazol-4-yl}phenol;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}-N-Propylamine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}butane-1-amine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pentane-1-amine;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-3-ol;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- [4-(10H-phenothiazines--yl)-1,3-thiazol-2-yl]methanol;

- N,N-dimethyl-N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}amine;

- 2-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- 2-[2-(piperidine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 2-[2-(piperazine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}azetidin-3-ol;

- 2-[2-(morpholine-4-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 2-[2-(thiomorpholine-4-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 2-{2-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- (3R)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- (3S)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- 2,6-di-tert-butyl-4-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]phenol;

- 2,6-di-tert-butyl-4-{2-[(butylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 2-{2-[(4-ethylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- N-methyl-N-{[4-(10H-phenothiazines-2-yl)-1H-imidazol-2-yl]methyl}amine;

- methyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate;

- butyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate;

- N-neopentyl-N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}amine;

- 1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}piperidine-4-ol;

- N-{[4-(10H-phenothiazines-yl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}butanamide;

- 2,6-di-tert-butyl-4-{2-[(4-propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[2-methyl-1-(methylamino)propyl]-1,3-thiazol-4-yl}phenol;

- N,2-dimethyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]propan-1-amine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}hexanamide;

- (3R)-1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- (3S)-1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- 1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}azetidin-3-ol;

- 2-{2-[(4-propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- 2-{2-[(4-acetylpiperidine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- 2-{2-[(4-butylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- methyl 4-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate;

- 4-[2-(aminomethyl)-1H-imidazol-4-yl]-2,6-di-tert-butylphenol;

- 4-{2-[(benzylamino)methyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;

- 4-{2-[(4-acetylpiperidine-1-yl)methyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;

- N-methyl-N-{[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]methyl}amine;

- 4-[2-(azetidin-1-ylmethyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;

- 2,6-di-tert-butyl-4-{2-[(4-butylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl)phenol;

- butyl 2-[4-(3'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4-isobutylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(4-isobutylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3'-chloro-4'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3',4'-dichloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4-propylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4-ethylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-cyano-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(1,1'-biphenyl-4-yl)-5-ethyl-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2',3'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-bromo-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3',5'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-methoxy-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3 '-nitro-1,1 '-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2',5'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3'-methoxy-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate,

or pharmaceutically acceptable salt of one of the above compounds to obtain drugs having at least one of the following three types of activities:

monoamine oxidase inhibition, in particular, monoamine oxidase B,

inhibition of lipid peroxidation,

the expression modulating activity against sodium channels.

9. The use of compounds selected from the following compounds:

- methyl 4-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate;

- methyl [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylcarbamate;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}benzamide;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-2-phenylacetamide;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}propanamide;

acetate 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-yl;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3,4-diol,

or pharmaceutically acceptable salt of one of the above compounds to obtain drugs having at least one of the following three types of activities:

monoamine oxidase inhibition, cast the STI, monoamine oxidase B,

inhibition of lipid peroxidation,

the expression modulating activity against sodium channels.

10. The use according to claim 7, characterized in that the drug is intended to treat one of the following disorders or diseases: Parkinson's disease, senile dementia, Alzheimer's disease, horei of Hantington, amyotrophic lateral sclerosis, schizophrenia, depression, psychosis, migraine or pain, in particular neuropathic pain.

11. The use of claim 8, characterized in that the drug is intended to treat one of the following disorders or diseases: Parkinson's disease, senile dementia, Alzheimer's disease, horei of Hantington, amyotrophic lateral sclerosis, schizophrenia, depression, psychosis, migraine or pain, in particular neuropathic pain.

12. The use according to claim 9, characterized in that the drug is intended to treat one of the following disorders or diseases: Parkinson's disease, senile dementia, Alzheimer's disease, horei of Hantington, amyotrophic lateral sclerosis, schizophrenia, depression, psychosis, migraine or pain, in particular neuropathic pain.

13. Use one of the following compounds is the second

- 2,6-di-tert-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-[4-(hydroxymethyl)-1,3-oxazol-2-yl]phenol;

- 2,6-di-tert-butyl-4-{2-[1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-[2-(methoxymethyl)-1,3-thiazol-4-yl]phenol;

- 2,6-di-tert-butyl-4-{4-[(methylamino)methyl]-1,3-oxazol-2-yl]phenol;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide;

- ethyl [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylcarbamate;

- 2,6-di-tert-butyl-4-[2-(morpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol;

- 2,6-di-tert-butyl-4-[2-(thiomorpholine-4-ylmethyl)-1,3-thiazol-4-yl]phenol;

- 4-[2-(anilinomethyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;

- 2,6-di-tert-butyl-4-(2-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}-1,3-thiazol-4-yl)phenol;

- 2,6-di-tert-butyl-4-{5-methyl-2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methanamine;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-N-methylacetamide;

- 1-[4-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-2-yl]-N-methylmethanamine;

- 2,6-di-tert-butyl-4-{2-[(ethylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[(4-phenylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-eazol-4-yl}phenol;

- N-{1-[4-(4-anilinophenol)-1,3-thiazol-2-yl]ethyl}-N-methylamine;

- 2,6-di-tert-butyl-4-{2-[(isopropylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[(cyclohexylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[(4-isopropylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- N-methyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]ethanamine;

- 2,6-di-tert-butyl-4-{2-[(4-ethylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- N-{[4-(4-anilinophenol)-1,3-thiazol-2-yl]methyl}-N-ethylamine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}of ethanamine;

- 2,6-di-tert-butyl-4-(2-{[4-(dimethylamino)piperidine-1-yl]methyl}-1,3-thiazol-4-yl)phenol;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-ol,

or pharmaceutically acceptable salt of one of the above compounds to obtain drugs for inhibition of monoamine oxidase and/or for the inhibition of lipid peroxidation.

14. Use one of the following connections:

- 2,6-di-tert-butyl-4-{2-[(propylamino)methyl]-1,3-thiazol-4-yl}phenol;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}-N-Propylamine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}butane-1-amine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pentane-1-amine;

- 1-{[4-(3,5-di-tert-butyl-4-hydroc iphenyl)-1,3-thiazol-2-yl]methyl}piperidine-3-ol;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methanol;

- N,N-dimethyl-N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}amine;

- 2-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- 2-[2-(piperidine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 2-[2-(piperazine-1-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}azetidin-3-ol;

- 2-[2-(morpholine-4-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 2-[2-(thiomorpholine-4-ylmethyl)-1,3-thiazol-4-yl]-10H-fenotiazina;

- 2-{2-[(4-methyl-1,4-diazepan-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- (3R)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- (3S)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- 2,6-di-tert-butyl-4-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]phenol;

- 2,6-di-tert-butyl-4-{2-[(butylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 2-{2-[(4-ethylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- N-methyl-N-{[4-(10H-phenothiazines-2-yl)-1H-imidazol-2-yl]methyl}amine;

- methyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate;

- butyl [4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methylcarbamate;

- N-neopentyl-N-{[4-(10H-f is notizen-2-yl)-1,3-thiazol-2-yl]methyl}amine;

- 1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}piperidine-4-ol;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}ndimethylacetamide;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}butanamide;

- 2,6-di-tert-butyl-4-{2-[(4-propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[2-methyl-1-(methylamino)propyl]-1,3-thiazol-4-yl}phenol;

- N,2-dimethyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]propan-1-amine;

- N-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}hexanamide;

- (3R)-1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- (3S)-1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- 1-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}azetidin-3-ol;

- 2-{2-[(4-propylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- 2-{2-[(4-acetylpiperidine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- 2-{2-[(4-butylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}-10H-fenotiazina;

- methyl 4-{[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate;

- 4-[2-(aminomethyl)-1H-imidazol-4-yl]-2,6-di-tert-butylphenol;

- 4-{2-[(benzylamino)methyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;

- 4-{2-[(4-acetylpiperidine-1-yl)methyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;

- N-methyl-N-{[4-(10H-phenoxazin-2-yl)-1,3-thiazol-2-yl]methyl}amine;

- 4-[2-(azetidin the-1-ylmethyl)-1,3-thiazol-4-yl]-2,6-di-tert-butylphenol;

- 2,6-di-tert-butyl-4-{2-[(4-butylpiperazine-1-yl)methyl]-1,3-thiazol-4-yl}phenol,

or pharmaceutically acceptable salt of one of the above compounds to obtain drugs for inhibition of monoamine oxidase and/or for the inhibition of lipid peroxidation.

15. Use one of the following connections:

- methyl 4-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate;

- methyl [4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylcarbamate;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}benzamide;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}-2-phenylacetamide;

- N-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}propanamide;

- acetate 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperidine-4-yl;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3,4-diol,

or pharmaceutically acceptable salt of one of the above compounds to obtain drugs for inhibition of monoamine oxidase and/or for the inhibition of lipid peroxidation.

16. The application of clause 15, wherein the compound is selected from the following compounds:

- 1-[4-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-2-yl]METI the}-N-methylmethanamine;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- 1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}azetidin-3-ol;

- (3R)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- (3S)-1-{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}pyrrolidin-3-ol;

- N,2-dimethyl-1-[4-(10H-phenothiazines-2-yl)-1,3-thiazol-2-yl]propan-1-amine,

and pharmaceutically acceptable salts of the above compounds.

17. Use item 13, characterized in that the drug is intended for treatment of the following disorders and diseases: Parkinson's disease, senile dementia, Alzheimer's disease, horei of Hantington, amyotrophic lateral sclerosis, schizophrenia, depression, psychosis.

18. The application 14, characterized in that the drug is intended for treatment of the following disorders and diseases: Parkinson's disease, senile dementia, Alzheimer's disease, horei of Hantington, amyotrophic lateral sclerosis, schizophrenia, depression, psychosis.

19. The application of clause 15 or 16, characterized in that the drug is intended for treatment of the following disorders and diseases: Parkinson's disease, senile dementia, Alzheimer's disease, horei of Gantin the tone, amyotrophic lateral sclerosis, schizophrenia, depression, psychosis.

20. Use one of the following connections:

- 2,6-di-tert-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{2-[1-(methylamino)ethyl]-1,3-thiazol-4-yl}phenol;

- 2,6-di-tert-butyl-4-{4-[(methylamino)methyl]-1,3-oxazol-2-yl]phenol;

- 2,6-di-tert-butyl-4-{5-methyl-2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 1-[4-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-2-yl]-N-methylmethanamine;

- 2,6-di-tert-butyl-4-{2-[(ethylamino)methyl]-1,3-thiazol-4-yl}phenol;

- 4-methylpentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- 3,3-dimethylbutyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- isopentyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- hexyl 2-[4-(4'-bromo-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(4-tert-butylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 3,3-dimethylbutyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- hexyl 2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- hexyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 3,3-dimethylbutyl 2-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]this is carbamate;

- benzil-2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- 2-phenylethyl 2-[4-(1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(1,1'-biphenyl-4-yl)-5-methyl-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-methyl-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2',4'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate,

or pharmaceutically acceptable salt of one of the above compounds for obtaining a medicinal product intended for modulation of sodium channels.

21. Use one of the following connections:

- butyl 2-[4-(3'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4-isobutylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- benzil-2-[4-(4-isobutylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3'-chloro-4'-fluoro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3',4'-dichloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4-propylphenyl)-1H-imidazol-2-reticent;

- butyl 2-[4-(4-ethylphenyl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(4'-cyano-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(1,1'-biphenyl-4-yl)-5-ethyl-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-chloro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2',3'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-bromo-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3',5'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2'-methoxy-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3'-nitro-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(2',5'-debtor-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

- butyl 2-[4-(3'-methoxy-1,1'-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate;

or pharmaceutically acceptable salt of one of the above compounds for obtaining a medicinal product intended for modulation of sodium channels.

22. The application of claim 20, characterized in that the drug is intended for treatment of the following disorders or diseases: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, migraine or pain, in particular neuropathic pain.

23. Use item 21, is great for the different themes, that received the drug is intended for treatment of the following disorders or diseases: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, migraine or pain, in particular neuropathic pain.



 

Same patents:

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

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

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

EFFECT: improved method for treatment, valuable medicinal properties of compounds and composition.

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of the formula: and to its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition inhibiting activity of protein-tyrosine kinases and comprising the indicated compound, a method for treatment of disorders associated with protein-tyrosine kinases, such as an immune disorder, and oncology disease, and a method for cancer treatment.

EFFECT: valuable biochemical and medicinal properties of compounds and composition.

5 cl, 2 tbl, 581 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 2-cycloalkylimino-5-(4-nitrophenyl)-1,3,4-thiadiazines of the general formula (I): wherein the group represents: piperidino-, pyrrolidino-, methylpiperazino-, hexamethyleneimino-group that possess the biological activity against smallpox virus. Invention provides preparing novel biological active compounds possessing an antiviral effect, in particular, against smallpox virus.

EFFECT: valuable biological and medicinal properties of compounds.

1 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to derivatives of dihydronaphthalene represented by the formula (I):

wherein radical values are determined in the description and to its nontoxic salts. The proposed compound is a regulator of receptors activated by a peroxisome proliferator (PPAR) of α- and γ-type. The agent can be useful as a hypoglycemic agent, hypolipidemic agent, agent for prophylaxis and/or treatment of diseases associated with metabolic disturbances, agent increasing the content of HDL-cholesterol and reducing the content of LDL-cholesterol and/or VLDL-cholesterol and agent for weakening diabetes mellitus factor risk, and/or X-syndrome. Also, invention claims derivative of dihydronaphthalene representing 3-{5-{2-[2-(4-methylphenyl)-5-methyloxazol-4-yl]ethoxy}-3,4-dihydronaphthalen-1-yl}propanoic acid.

EFFECT: valuable medicinal properties of compounds and agent.

21 cl, 15 tbl, 14 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new derivatives of 2-arylimino-2,3-dihydrothiazoles of the general formula (I): wherein radical values R1, R2, R3 and R4 are given in the claim invention. New compounds are useful in treatment of pathological states or diseases wherein one or some somatostatin receptors are implicated, for example, acromegaly, hypophysis adenomas or gastroenteropancreatic endocrine tumors with carcinoid syndrome and gastroenteric bleedings.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

14 cl, 2825 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine N-oxides of the general formula (I) and their pharmaceutically acceptable acid-additive salts wherein R means hydrogen atom, lower alkyl or halogen atom; R1 means hydrogen atom; R2 and R2' mean independently of one another hydrogen, halogen atom, trifluoromethyl group, (lower)-alkoxy-group; or R2 and R2' can mean in common the group -CH=CH-CH=CH- optionally substituted with one or two substitutes taken among lower alkyl or (lower)-alkoxy-group; R3 and R3' mean independently of one another hydrogen atom, lower alkyl; R4 and R4' mean independently of one another -(CH2)mOR6 or lower alkyl; or R4 and R4' form in common with N-atom to which they are bound substituted R5-cyclic tertiary amine representing pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-dioxomorpholine-4-yl; R5 means hydrogen atom, hydroxyl, -COOR3, -N(R3)CO-lower alkyl or -C(O)R3; R6 means hydrogen atom, lower alkyl; X means -C(O)N(R6)-, -N(R6)C(O)-; n = 0, 1, 2, 3 or 4; m = 1, 2 or 3. Also, invention describes a medicinal agent comprising these compounds. Compounds can be used as drugs in treatment or prophylaxis of diseases associated with antagonists of NK-1 receptor.

EFFECT: valuable medicinal properties of agent.

6 cl, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

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