1-phenyl-benzimidazole compounds, pharmaceutical composition and method of treating disorders or diseases that are sensitive to modulation of gabaand-receptor complex of the central nervous system

 

(57) Abstract:

The invention relates to novel benzimidazole compounds represented by the General formula I

< / BR>
where denotes the number 0, 1, 2 or 3; R1represents an alkyl group, phenyl group or a monocyclic heterocyclic group containing as the heteroatom N or O, and these groups may be substituted once or more than once, by substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyano, amino and nitro; or R1represents cyano or a group of formula-alkyl-CO2R2alkenyl-CO2R2, -CO-R2, -CO2(CH2)mR2or-C(R3)=N-OR2where m denotes the number 0, 1, 2 or 3; R2represents hydrogen, alkyl, phenyl, benzyl, 5 - or 6-membered heterocyclic group, which 5 - or 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R2may represent a group of the formula -(CH2)q-NR4R5, -(CH2)q-CON(R4R5), -(CH2)q-CO2R4or-alkyl-CO2R4where R4and R5independently before the R11represents a group of General formula-CO2-R9where R9represents an alkyl or R9can represent a 6-membered heterocyclic group, and this 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R9represents a group of General formula-alkyl-N(R10R12), where R10and R12independently represent hydrogen or alkyl; or R11represents a group of General formula II

< / BR>
where n denotes the number 0, 1, 2 or 3; R' and R" together with the N atom to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member, one oxygen atom and/or one additional nitrogen atom; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed by R' and R", may be substituted once or more than once by a group of the formula -(CH2)px, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, hydroxyl, alkyl or alkenyl, and these alkyl and alkenyl can be substituted once or more than once by a group of the formula-CO2R6; R7independently represent hydrogen or alkyl; or R11may represent a group of General formula III

< / BR>
where n denotes the number 1; R' represents hydrogen or alkyl; R'" and R" 'together with the atoms to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member one chain-CH=CH-; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed R'" and R"", may be substituted once or more than once by a group of the formula -(CH2)pX, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, alkyl; or its pharmaceutically acceptable salt; provided that if R11is morpholinyl, R1may not represent tert-butyl; pharmaceutical compositions having the properties of the modulator of the GABAANDreceptors and the treatment of disorders and diseases of the living organism, and it is a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous system. 3 S. and 11 C.p. f-crystals, 7 PL.

THE SCOPE OF THE INVENTION

The present invention relates to the deposits with their help and the method of obtaining such benzimidazole compounds. These new compounds according to this invention are useful in treating diseases and disorders of the Central nervous system that are affected by modulation of GABAA-receptor complex, such as anxiety, sleep disorders, anesthesia, memory disorders, epilepsy or other convulsive syndromes.

BACKGROUND OF THE INVENTION

GABAAND-receptors-aminobutyric acid (GABA) are the most abundant receptor inhibition in the mammalian brain. GABAANDreceptors structurally represent macromolecular heteropentameric complexes (combinations, and / protein subunits). Using the techniques of modern molecular biology are several subtypes of GABAA-receptors.

Every GABAA-receptor complex includes a channel for chloride ions, which controls the flow of chloride ions across the neuronal membrane, and many sites recognition small modulatory molecules such as benzodiazepines, barbiturates, picrotoxin and certain steroids. When GABA interacts with its receptor, this ion channel is open, the flow of chloride ions increases, the membrane hyperpolarizes, and clickaway various agents, including agents that interact with the receptor or site of recognition for benzodiazepines.

Agents that bind or interact with modulatory sites GABAA-receptor complex, such as, for example, the receptor benzodiazepines can have either synergistic effect on the action of GABA, it has a positive modulatory action of the receptor (agonists, partial agonists), or debilitating effect on the action of GABA, i.e. negative modulation of receptor inverse agonists, partial inverse agonists), or they can block the action of agonists and inverse agonists through competitive block (antagonists or ligands that do not have their own activity).

Agonists usually relaxes muscles and produce hypnotic, sedative, anxiolytic and/or anticonvulsant action, whereas inverse agonists produce prostorage, protivoblastomna entries and action. Compounds with anxiolytic action, but with reduced or absent relaxing muscles, hypnotic and sedative action characterized as partial agonists. Partial inverse agonists are useful in kacey belonging to different chemical series connection, having an affinity for the benzodiazepine receptors. However, although the sites of the receptors to benzodiazepines are still considered attractive biological sites to influence the Central nervous system to treat various disorders and diseases, first of all synthesized compounds acting on these receptor sites, failed in clinical development due to unacceptable side effects.

Benzimidazole compounds for use in the treatment of disorders of the Central nervous system is known (ER); imidazole compounds as calcium channel blockers known (EP 563001).

THE INVENTION

The present invention is to provide new derivatives of benzimidazole and their pharmaceutically acceptable salts obtained by joining acids, which are useful in the treatment of disorders, diseases or ailments of the Central nervous system is sensitive to modulation of GABAA-receptor complex, and have favorable pharmacodynamic and pharmacokinetic properties.

The task of the invention was also to provide a pharmaceutical composition containing the new benzimidazole compounds according to the invention.

In C the compounds according to this invention.

To solve this problem proposed chemical compound represented by the General formula (I):

< / BR>
moreover, in the formula (I)

o denotes the number 0, 1, 2 or 3;

R1represents an alkyl group, phenyl group or a monocyclic heterocyclic group containing as the heteroatom N or O, and these groups may be substituted once or more than once, by substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyano, amino and nitro;

or R1represents cyano or a group of formula-alkyl-CO2R2alkenyl-CO2R2, -CO-R2, -CO2(CH2)mR2or-C(R3)=N-OR2and , in these formulas

m denotes the number 0, 1, 2 or 3,

R2represents hydrogen, alkyl, phenyl, benzyl, 5 - or 6-membered heterocyclic group, which 5 - or 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy;

or R2may represent a group of the formula -(CH2)q-NR4R5, -(CH2)q-CON(R4R5), -(CH2)q-CO2R4or alkyl-CO2R4and in these formula 3;

R3represents hydrogen or alkyl;

R11represents a group of General formula-CO2-R9where

R9represents alkyl;

or R9can represent a 6-membered heterocyclic group, and this 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy;

or R9represents a group of General formula-alkyl-N(R10R12), and in this formula

R10and R12independently represent hydrogen or alkyl;

or R11represents a group of General formula (II):

< / BR>
in this formula (II)

n denotes the number 0,1,2 or 3;

R' and R" together with the N atom to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member, one oxygen atom and/or one additional nitrogen atom;

and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed by R' and R" may be substituted once or more than once by a group of the formula -(CH2)pX, where

R denotes the number 0, 1, 2 or 3;

X predstavljaju more than once by a group of the formula-CO2R6;

or X represents a group of formula-CO-R6, -CO2-R6or-CON-R6R7moreover, in these formulas

R6, R7independently represent hydrogen or alkyl;

or R11may represent a group of General formula (III):

< / BR>
in this formula (III)

n denotes the number 1;

R' represents hydrogen or alkyl;

R'" and R" ' together with the atoms to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member one chain-CH=CH-;

and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed R'" and R"" may be substituted once or more than once by a group of the formula -(CH2)pX, where

R denotes the number 0, 1, 2 or 3;

X represents hydrogen, alkyl;

or its pharmaceutically acceptable salt;

provided that if R11is morpholinyl, R1may not represent tert-butyl.

In the preferred embodiment the chemical compound according to this invention is characterized by the General formula (I):

< / BR>
moreover, the GRF is the group or monocyclic heterocyclic group, containing as the heteroatom N or O, and these groups can be someseni one or more than one substituents selected from C1-8of alkyl, C3-7cycloalkyl;

or R1represents cyano or a group of the formula C1-8alkyl-CO2R2C2-6alkenyl-CO2R2, -CO-R2, -CO2(CH2)mR2or-C(R3)=N-OR2and , in these formulas

m denotes the number 0 or 1;

R2represents hydrogen, C1-8alkyl, C3-7cycloalkyl, benzyl, 5 - or 6-membered heterocyclic group, which 5 - or 6-membered heterocyclic group may be substituted once or more than once WITH1-8by alkyl;

or R2can independently represent a group of the formula -(CH2)q-NR4R5, -(CH2)q-CON(R4R5), -(CH2)q-CO2R4or alkyl-CO2R4and , in these formulas

R4and R5independently represent a1-8alkyl; and

q denotes the number 0, 1, 2 or 3;

R3represents hydrogen or alkyl;

R11represents a group of General formula-CO2-R9where

R9performance, and this 6-membered heterocyclic group may be substituted once or more than once WITH1-8of alkyl;

or R9represents a group of General formula-alkyl-N(R10R12), and in this formula

R10and R12independently represent a1-8alkyl or C3-7cycloalkyl;

or R11represents a group of General formula (II):

< / BR>
in this formula (II)

n denotes the number 0, 1 or 2;

R' and R" together with the N atom to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member, one oxygen atom and/or one additional nitrogen atom;

and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed by R' and R" may be substituted once or more than once by a group of the formula -(CH2)pX, where

R denotes the number 0, 1, or 2;

X represents hydrogen, hydroxy, C1-8alkyl or C2-6alkenyl, and those WITH1-8alkyl, C3-7cycloalkyl and C2-6alkenyl can be substituted once or more than once by a group of the formula-CO2R6;

or X represents a group of formula-CO2-R6or-CON-R6R7and , in these formulasor R11may represent a group of General formula (III):

< / BR>
in this formula (III)

n denotes the number 1;

R' represents a C1-8alkyl;

R'" and R" ' together with the atoms to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member one chain-CH=CH-;

and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed R'" and R"" may be substituted once or more than once by a group of the formula -(CH2)pX, where

R denotes the number 0 or 1;

X represents hydrogen or C1-8alkyl;

or its pharmaceutically acceptable salt.

Preferred is a chemical compound according to the invention, as defined above, in the present invention, where

of mean 0, and

R1represents cyano, phenyl group, fornillo group, tetrahydrofuranyl group, isoxazolyl group or oxadiazolyl group;

or R1represents a C1-4alkenylphenol group, substituted CO2-C1-4by alkyl;

or R1is a group Fori-C3-5-cyclo-C1-4alkyl group, benzyl group, picollo group, and these groups may be substituted WITH1-3alkyl group;

or R2may represent a group of the formula -(CH2)q-NR4R5or -(CH2)q-CO-NR4R5and , in these formulas

q means the number 0, 1 or 2;

R4and R5each independently represents hydrogen or C1-4alkyl group;

or R1may represent a group of the formula-C(R3)=N-OR2moreover, in this formula

R3and R2each independently represents hydrogen or C1-4alkyl group;

or R1represents a group of formula-C(R3)=N-OR4Aand in this formula

R3represents hydrogen or C1-4alkyl group;

and R4Arepresents hydrogen, C1-4alkyl group or a C1-4alkyl-CO2-C1-4alkyl group.

Also preferred is a compound of formula (I) as defined above, where

on means the number 1, and

R1represents a group of formula-CO2R4and in this formula

R4represents a
of mean 0, and

R1is a 3-furanyl, 3-tetrahydro-furanyl, 5-isoxazolyl, 3-cyclopropyl-1,2,4-oxadiazol-5-yl, -CHNOH, -C(CH3)MON, -C(CH3)NR-CH3- (CH3NO-C2H5- (CH3)NO-isopropyl, -C(CH3)NO-tert-butyl, -C(CH3)NR-CH2CO2CH3- (CH3)NR-CH2CO2WITH2H5THE SRPA-C(CH3)2CO2CH3- (CH3)NR-C(CH3)2CO2CH3- (CH3)NR-C(CH3)2CO2WITH2H5, -CO2CH3, -CO2WITH2H5,

-CO2CH(CH3)2, -CO2(CH2)2N(CH3)2, -CO2-CH2-cyclopropyl or (N,N-diethylcarbamyl)-methyl-oxycarbonyl.

Also preferred is a chemical compound according to the invention of formula (I) as defined above, where

on means the number 1, and

R1represents-CO2CH3, -CO2C2H5.

Especially preferred is a chemical compound of the formula (I) as defined above, where

R11represents a C1-8alkyl-oxycarbonyl group, N,N-di-(C1-4alkyl)-amino-C1-4al is denilou group, pyrrolidinyl-C1-3alkyl group, piperazinilnom group, morpholinyl group, homopiperazine group, tetrahydropyranyloxy group, picolyl-oxycarbonyl group, and these groups may be substituted once or more than once, by substituents selected from C1-4of alkyl, C1-4alkyl-oxycarbonyl,1-4alkyl-oxycarbonyl-C1-4of alkyl, acetyl or N,N-di-C1-4alkyl-carboxamido-C1-4the alkyl.

Also, the preferred embodiment of the present invention is a chemical compound of the formula (I) as defined immediately above, where

R11is a 1-piperidinyl, 1-pyrrolidinyl, 4-methyl-1-piperazinil, 1-methyl-3-piperidinyl, (1-methyl-4-piperidinyl)oxycarbonyl, (1-methyl-3-piperidinyl)-oxycarbonyl, 2-picolyl-oxycarbonyl, 3-picolyl-oxycarbonyl, 4-morpholinyl, 1-acetyl-4-piperazinil, 4-(2-hydroxyethyl)-piperazine-1-yl, (1-pyrrolidinyl)methyl, 4-methylhomopiperazine-1-yl, 1-methyl-1,2,3,6-tetrahydropyran-5-yl, 4-(N,N-diethyl-carboxamidates)-piperazine-1-yl, 4-(methoxycarbonylmethyl)-1-piperazinyl, 4-(ethoxycarbonylmethyl)-1-piperazinil, 4-(diethylcarbamoyl)piperazine-1-yl, 4-(2,2-bis(etoxycarbonyl)ethynyl)piperazine-1-yl, 4-(2-ptx2">

In the preferred embodiment the chemical compound of this invention is a

5-cyano-1-(3-(1-piperidyl)phenyl)benzimidazole (compound 3A);

5-cyano-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 3A2);

5-cyano-1-(3-(4-methyl-1-piperazinil)phenyl)benzimidazole (compound 3A3);

5-cyano-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole (compound 3A4);

5-cyano-1-(3-(4-morpholinyl)phenylbenzimidazol (compound 3a5);

the reaction of 5-formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole (compound 3b1);

the reaction of 5-formyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 3b2);

the reaction of 5-formyl-1-(3-(4-methyl-1-piperazinil)phenyl)benzimidazole (compound 3b3);

the reaction of 5-formyl-1-(3-(1-methyl-3-piperidinyl)phenyl)-benzimidazole (compound 3b4);

On-isopropoxy 5-formyl-1-(3-(1-piperidinyl)phenyl)-benzimidazole (compound 3b);

On-methyloxime 5-formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole (compound 3G);

the reaction of 5-acetyl-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (compound 3D1);

the reaction of 5-acetyl-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)-phenylbenzimidazol (compound 3D2);

On-acyloxy 5-acetyl-1-(3-(4-(2-Gerasin-1-yl)phenyl) benzimidazole (compound 3E2);

On-acyloxy 5-acetyl-1-(3-(1-pyrrolidinyl)phenyl)-benzimidazole (compound 3E3);

On-acyloxy 5-acetyl-1-(3-(4-methylhomopiperazine-1-yl)benzimidazole (compound 3E4);

On-acyloxy 5-acetyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 3e5);

On-acyloxy 5-acetyl-1-(3-(1-piperidinyl)phenyl)benzimidazole (compound 3E6);

On-acyloxy 5-acetyl-1-(3-(1-methyl-3-piperidinyl)phenyl)-benzimidazole (compound 3E7);

On-acyloxy 5-acetyl-1-(3-(1-methyl-1,2,3,6-tetrahydropyran-5-yl)-phenyl)benzimidazole (compound 3E8);

On-isopropoxy 5-acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl) benzimidazole (compound g1);

On-isopropoxy 5-acetyl-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)-phenyl)benzimidazole (compound g2);

On-isopropoxy 5-acetyl-1-(3-(4-acetylpiperidine-1-yl)phenyl) benzimidazole (compound g3);

O-tert-butyloctyl 5-acetyl-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)-phenyl)benzimidazole (compound 33);

5-(3-furanyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 3i1);

5-(3-furanyl)-1-(3-(1 -methylpiperidin-3-yl)phenyl)benzimidazole (compound 3i2);

5-(3-furanyl)-1-(3-(4-(2-hydroxyethyl)piperazin)-phenyl)benzimidazole (compound 3i4);

5-phenyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 3K1);

5-phenyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 3K2);

5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (compound 3);

5-tert-butyl-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (compound 3M);

5-(etoxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl) benzimidazole (compound 4a1);

5-(etoxycarbonyl)-1-(3-(4-methylpiperazin-3-yl)phenyl)benzimidazole (compound 4a2);

5-(etoxycarbonyl)-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)phenyl) benzimidazole (compound 4A3);

5-(etoxycarbonyl)-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (compound 4A4);

5-(etoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)-phenyl)benzimidazole (compound 4A5);

5-(etoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)-phenyl)benzimidazole (compound 4A6);

5-(2-(etoxycarbonyl)ethynyl)-1-(3-(1-piperidyl)phenyl)benzimidazole (compound 4B1);

5-(2-(etoxycarbonyl)ethynyl)-1-(3-(4-methylpiperazin-1-yl)phenyl) benzimidazole (compound 4B2);

5-(2-(toxicarol)ethynyl)-1-(3-(4-morpholinyl)phenyl)benzimidazole (SUB>);

5-(2-(methoxycarbonyl)ethynyl)-1-(3-(4-morpholinyl)phenyl) benzimidazole (compound 4B2);

5-(methoxycarbonyl)-1-(3-(1 -acetylpiperidine-3-yl)phenyl) benzimidazole (compound 4G1);

5-(methoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4G2)

4-(methoxycarbonyl)-1-(3-(4-methoxycarbonylmethyl)piperazine-1-yl)-benzimidazole (compound 4G3);

5-(methoxycarbonyl)-1-(3-(4-(diethylcarbamoyl)piperazine-1-yl)-phenyl)benzimidazole (compound 4G4);

5-(methoxycarbonyl)-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound 4G5);

5-(ISO-propylenecarbonate)-1-(3-(1-piperidinyl)phenyl)benzimidazole (compound 4D1);

5-(ISO-propylenecarbonate)-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 4D2);

5-(ISO-propylenecarbonate)-1-(3-(4-methylpiperazin-1-yl)phenyl) benzimidazole (compound 4D3);

5-(ISO-propylenecarbonate)-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound 4D4);

5-(cyclopropanecarbonyl)-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (compound 4E);

5-(benzyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl) benzimidazole (compound g);

5-(3-ecolological)-1-(3-(1-methylpiperidin-3-yl)phenyl)-imidazol (compound 4I);

5-((2-(dimethylamino)ethyl)oxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)-piperazine-1-yl)phenyl)benzimidazole (compound 4K);

5-((N, N-diethylcarbamyl)methyloxycarbonyl)-1-(3-(4-ethoxycarbonylmethyl)-piperazine-1-yl)phenyl)benzimidazole (compound 4 l1);

5-((N, N-diethylcarbamyl)-methyloxycarbonyl)-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (compound 4 l2);

5-(methoxycarbonylmethyl)-1-(3-(4-methylpiperazin-1-yl)phenyl) benzimidazole (compound 4m1);

5-(ethoxycarbonylmethyl)-1 -(3-(4-methylpiperazin-1-yl)phenyl) benzimidazole (compound 4m2);

5-(methoxycarbonyl)-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound 4m3);

5-(etoxycarbonyl)-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound 4m4);

5-((1-methylpyrrolidine-2-yl)methoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)-piperazine-1-yl)phenyl)benzimidazole (compound 4h);

On-isopropoxy 5-acetyl-1-(3-(1-methyl-4-piperidinylcarbonyl)-phenyl)benzimidazole (compound 5a1);

O-ISO-propyloxy 5-acetyl-1-(3-(1-methyl-3-piperidinylcarbonyl)-phenyl)benzimidazole (compound 5A2);

O-ISO-propyloxy 5-acetyl-1-(3-(2-ecolological)phenyl)-benzimidazole (compound 5A3);

O-(ethoxycarbonylmethyl)the reaction of 5-acetyl-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (compound 5B2);

O-(methoxycarbonyl-(dimethyl)methyl)oxime 5-acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 5B3);

O-(methoxy-carbonylmethyl)the reaction of 5-acetyl-1-(3-(4-(2-hydroxyethyl)-piperazine-1-yl)phenyl)benzimidazole (compound 5B1);

O-(ethoxy-carbonylmethyl)the reaction of 5-acetyl-1-(3-(4-(2-hydroxyethyl)-piperazine-1-yl)phenyl)benzimidazole (compound 5B2);

O-(ethoxy-carbonyl(dimethyl)methyl)oxime 5-acetyl-1 -(3-(4-(2-hydroxyethyl)piperazine-1-yl)phenyl)benzimidazole (compound 5B3);

the reaction of 5-acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)phenyl) benzimidazole (compound 5g1);

On-acyloxy 5-acetyl-1 -(3-(4-(ethoxycarbonylmethyl)-piperazine-1-yl)-phenyl)benzimidazole (compound 5g2);

O-(methoxycarbonyl-(dimethyl)methyl)oxime 5-acetyl-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (compound 5D1);

O-(methoxycarbonyl-methyl)oxime 5-acetyl-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (compound 5D2);

O-(methoxycarbonylmethyl)the reaction of 5-acetyl-1-(3-(4-morpholinyl)phenyl)-benzimidazole (compound 5D3);

O-ISO-propyloxy 5-acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)phenyl)benzimidazole (compound 5e1);

O-ISO-prophylaxe-(methoxycarbonyl-(dimethyl)methyl)oxime 5-formyl-1 -(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound g1);

O-(methoxycarbonyl)dimethyl)-methyl)oxime 5-formyl-1 -(3-(4-morpholinyl)phenyl)benzimidazole (compound g2);

5-(5-isoxazolyl)-1-(3-(methoxycarbonyl)phenyl)benzimidazole (compound 6a1);

5-(5-isoxazolyl)-1-(3-(etoxycarbonyl) phenyl) benzimidazole (compound 6A3);

1-(3-etoxycarbonyl)phenyl-5-phenylbenzimidazole (compound 6b1);

5-phenyl-1-(3-(4-ethoxycarbonylmethyl)piperazine-1-yl)phenyl) benzimidazole (compound 6b2);

5-phenyl-1-(3-(2-ecolological)phenyl)benzimidazole (compound 6b3);

5-phenyl-1-(3-(3-ecolological)phenyl)benzimidazole (compound 6b4);

5-phenyl-1-(3-(1-methylpiperid-3-jocstarbunny) phenyl)benzimidazole (compound 6b5);

5-phenyl-1-(3-((1-methylpiperid-4-yl)oxycarbonyl)phenyl) benzimidazole (compound 6b6);

5-(3-furanyl)-1-(3-(etoxycarbonyl)phenyl)benzimidazole (compound 6b1);

5-(3-tetrahydrofuranyl)-1-(3-(etoxycarbonyl)phenyl)benzimidazole (compound 6b2);

5-(3-furanyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)phenyl) benzimidazole (compound 6b3);

5-(3-furanyl)-1-(3-(4-(tert-butoxycarbonyl)piperazine-1-yl)phenyl) benzimidazole (compound 6b4);

5-(3-furanyl)-1-(3-(4-(oxycarbonyl)ethynyl)piperazine-1-yl)-phenyl)benzimidazole (compound 6b6);

5-(3-furanyl)-1-(3-(4-(2-(methoxycarbonyl)ethynyl)piperazine-1-yl)-phenyl)benzimidazole (compound 6b7);

5-(3-furanyl)-1-(3-(2-(dimethylamino)ethoxycarbonyl)phenyl) benzimidazole (compound 6b8);

5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyran-5-yl)phenyl] -benzimidazole (compound 7) or

5-acetyl-1-[3-(1-methylpiperidin-3-yl)phenyl] -benzimidazole (compound 9)

or its pharmaceutically acceptable salt.

In accordance with another aspect of the present invention proposed a pharmaceutical composition having the property of a modulator of the GABAANDreceptors containing an effective amount of a chemical compound according to the invention, as defined above, and pharmaceutically acceptable excipient, carrier or diluent.

In addition, in accordance with the invention proposed a chemical compound according to the invention, as defined above, used for the preparation of drugs for the treatment of a disorder or disease of a living animal body, including a human, with a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous system.

According to another aspect of predlozhenie to positive modulation of GABAAND-receptor complex of the Central nervous system.

Preferred is a chemical compound according to the invention, as defined above, where the disorder or disease is a anxiety, sleep disorders, anesthesia, memory disorders, epilepsy or any other convulsive disorder.

In accordance with another aspect of the present invention, a method of treatment of a disorder or disease of a living animal body, including a human, with a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous system, which is administered a therapeutically effective amount of a chemical compound according to the invention, as defined above.

The definition of the substituents

In the context of this invention, halogen represents fluorine, chlorine, bromine or iodine.

In the context of this invention alkyl means a straight chain or branched chain, containing from one to eight carbon atoms (C1-8alkyl, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl but not limited to, or cyclic alkyl, containing from three to with the l, but not limited to. In the preferred embodiment of this invention, alkyl is a1-C4alkyl, preferably1-C3alkyl, most preferred methyl, ethyl, propyl, isopropyl or tert-butyl.

In the context of this invention alkenyl means a group containing from two to six carbon atoms (C2-C6alkenyl) and including at least one double bond. This chain can be straight or branched. In the preferred embodiment alkenylphenol group is ethynyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl or 3-butenyl.

In the context of this invention quinil means a group containing from two to six carbon atoms (C2-C6quinil) and including at least one triple bond. This chain can be straight or branched. In the preferred embodiment alkenylphenol group is ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl or 3-butynyl.

In the context of this invention, amino represents NH2, NH-alkyl or N-(alkyl)2where alkyl is defined above.

In the context of this invention cycloalkyl-alkyl means cycloalkyl, as defined above, which Priseltsi, which is formed of R' and R" or R" and R'" include piperidinyl, tetrahydropyridine, tetrahydropyrimidines, hexahydropyridine, pyrrolidinyl, homopiperazine, morpholine, isoxazolidine, oxazolidine, piperazinil, peligrosamente and perhydroxyl, but are not limited to.

In the context of this invention, the aryl means an aromatic hydrocarbon, such as phenyl or naphthyl.

In the context of this invention monocyclic heteroaryl means 5 - or 6-membered monocyclic heterocyclic group. Preferred monocyclic heteroaryl groups include oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazole - 3-yl, 1,2,5-thiadiazole-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 pirimidil, 4 pirimidil, 5 pirimidil, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl.

In the context of this Isobel, pyrrolyl, pyrrolidyl, imidazolyl, oxadiazolyl, pyridyl, trienyl, isooxazolyl, pyrimidyl, pyrazole, but is not limited to them.

In the context of this invention alkyl-hydroxy (alkoxy means alkyl-O-, where alkyl is defined above.

In the context of this invention alkyl-oxycarbonyl (alkoxycarbonyl) means alkyl-O-CO-, where alkyl is defined above.

Steric isomers

Some chemical compounds of this invention exist in (+)- and (-)-forms, as well as in racemic forms.

The racemic forms can be split into the optical antipodes by known methods, for example by separation of the diastereomeric salts with optically active acid and allocation of optically-active amine compound by treatment with base. Another method of separation of racemates on the optical antipodes based on chromatography on optically-active matrix. Thus, the racemic compounds of the present invention can be divided into their optical antipodes, for example by fractional crystallization of d - or I-salts (tartratami, mandelate or camphorsulfonate).

Chemical compounds of the present invention can also be split by education diast the th activated carboxylic acid, such as acid, derived from (+)- or ( - ) phenylalanine, (+)- or ( - ) phenylglycine, (+)- or (-)-camphoric acid, or the formation of diastereomeric carbamates by reacting a chemical compound according to the present invention with an optically-active chloroformate or the like.

Known additional methods of separation of optical isomers {Jaques J, Collet A, & Wilen's in."Enantiomers, Racemates and Resolutions". John Wiley and Sons, New York (1981)).

Moreover, as oximes, chemical compounds in this invention can exist in two forms, SYN - and antiforms (Z - and E-form), depending on the location of the substituents relative to the double bond-C=N-. Thus, a chemical compound according to the present invention can be SYN - or antiformal (Z - or E-form), or it may be their mix.

Pharmaceutically acceptable salt

New benzimidazole derivatives according to this invention can be supplied in any form appropriate to the routes of administration for which they are intended. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts.

Examples of pharmaceutically acceptable salts of joining include salts obtained presidentat, citrate, lactate, tartrate, malate, fumarate, mandelate, benzoate, ascorbate, cinnamate, bansilalpet, methanesulfonate, stearate, succinate, glutamate, glycolate, toluene-p-sulfonate, formate, malonate, naphthalene-2-sulfonate, salicylate and acetate. Such salts are obtained by well known methods.

Other acids, such as oxalic acid, although are not in themselves pharmaceutically acceptable, may be useful in obtaining salts useful as intermediates in obtaining chemical compounds according to this invention and its pharmaceutically acceptable salts formed by the addition of acid.

Salt chemical compounds according to this invention with metals include alkali metal salts such as sodium salt chemical compounds according to this invention containing a carboxyl group.

Chemical compound according to this invention can be supplied in diluted or dissolved form, together with pharmaceutically acceptable solvents such as water, ethanol and the like. In General, for the purposes of the present invention dissolved or dissolved form are equivalent.

Pharmaceutical compositions

In the preferred embodiment, the invention provides pharmaceutical compositions containing the chemical compound of this invention or its pharmaceutically acceptable salt or a derivative thereof together with one or more pharmaceutically acceptable, carrier(s) for him and, perhaps, other therapeutic and/or prophylactic ingredients. This(and) the carrier(s) must(must) be acceptable(and)" in the sense of compatibility with other ingredients of this preparation and safety for its recipient.

Pharmaceutical compositions are compositions suitable for oral, rectal, nasal, local (including transbukkalno and sublingual), vaginal or parenteral (including intramuscular, subcutaneous or intravenous) administration, or compositions in a form suitable for webmaste with a conventional adjuvant, the carrier or diluent can be present in the form of pharmaceutical compositions and their standard doses, and in this form be used in solid form, such as tablets or filled capsules, or in liquid form such as solutions, suspensions, emulsions, elixirs, or filled their capsules - all for oral use, or in the form of suppositories for rectal administration, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and their standard dosage forms may contain conventional ingredients in conventional proportions, with the presence or absence of additional active compounds or started, and such a standard dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dose range to be used. Accordingly, acceptable typical standard dosage forms are compositions containing ten (10) milligrams of active ingredient or, more broadly, from 0.1 to 100 milligrams per tablet.

Chemical compound according to the present invention can be introduced in a very goudie dosage forms may contain as an active ingredient or chemical compound according to this invention, or a pharmaceutically acceptable salt of a chemical compound according to this invention.

For preparing pharmaceutical compositions from a chemical compound according to the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Drugs in solid form include powders, tablets, pills, capsules, pills, suppositories, and dispersible granules. Solid carriers can be one or more than one substance(s) can(can) act as diluents, corrigentov, soljubilizatory, lubricants, suspendresume tools, binders, preservatives, loosening agents for tablets or encapsulating material.

In powders, the carrier is a finely pulverized solid material, which is mixed with finely pulverized active ingredient.

In tablets, the active component is mixed in suitable proportions with the carrier having the necessary binding capacity, and pressed to the desired shape and size.

Such powders and tablets preferably contain from five or ten to about seventy percent of the active compounds. Suitable carriers are the cellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. It is implied that the term "drug" includes the preparation of the active compound with encapsulating material as a carrier, creating a capsule in which the active component with the media or no media is surrounded by carrier, which thus is in Association with him. Likewise enabled wafers and cakes. Tablets, powders, capsules, pills, wafers and cakes can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, first melt the low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, and by stirring the dispersed active component to its homogeneity. Then, this molten homogeneous mixture is then poured into forms convenient size and allow to cool and thereby solidify.

Compositions suitable for vaginal administration, can be represented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient and even the media, which is known for its suitability for this purpose.

Liquid preparations include races is you for parenteral administration can be in the form of solutions in an aqueous solution of polyethylene glycol.

Thus, a chemical compound according to the present invention can be manufactured in the form of a preparation for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in a standard dosage form in ampoules, pre-filled syringes, containers for infusion of small volumes or mnogochasovykh containers with an added preservative. These compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous fillers, and may contain agents for the preparation of drugs, such as suspendida, stabilizing and/or dispersing agents. On the other hand, the active ingredient may be in powder form, obtained by aseptic allocation of sterile solid or by lyophilization from solution, for alignment before use with a suitable filler, such as sterile pyrogen-free water.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizers and thickeners, as desired.

Aqueous suspensions omponent in water, containing a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other well-known suspendresume agents.

Also included are solid form preparations which are intended to shortly before use they were made in the preparations in liquid form for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, corrigentov, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents and the like.

For local injection into the epidermis chemical compound according to this invention can be manufactured as a drug in the form of ointments, creams or lotions, or as a cutaneous patch. Ointments and creams may, for example, be prepared in the form of the drug with an aqueous or oily base with the addition of suitable thickeners and/or gelling agents. Lotions can be made with water or oil based, and they usually contain one or more than one emulsifier, a stabilizing agent, a dispersing agent, suspendat the pellet, which contain the active agent in the basis with the addition of corrigenda, normally sucrose and gum Arabic or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerol or sucrose and gum Arabic; rinse containing the active ingredient in a suitable liquid carrier.

The solutions or suspensions are injected directly into the nasal cavity by conventional means, for example by using a dropper or pipette, or injection. These compositions can be presented in a single dose or mnogochasovoj form. In the latter case in combination with the use of a dropper or pipette, the patient can achieve this by introducing an appropriate, pre-determined amount of solution or suspension. When injection this can be achieved, for example, by measuring the spray.

Introduction to the respiratory tract can be accomplished through an aerosol formulation in which the active ingredient is in the package under pressure with a suitable propellant, such as chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other acceptable gas. This aerosol can traditionally contain also surfaces the ptx2">

On the other hand, the active ingredients can be present in the form of a dry powder, such as powder mixtures of such compounds in a suitable powder base such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidone (PVP). Convenient to the nasal cavity, the powder carrier formed gel. The powder composition can be provided in standard dosage forms, for example, capsules or cartridges, for example, from gelatin or blister packs from which the powder can be entered using the inhaler.

In compositions intended for administration to the respiratory tract, including intranasal composition, the particle size of such a connection is typically small, for example about 5 μm or less. This particle size can be obtained by known methods, for example by micronization.

If you prefer to use a composition adapted to provide delayed release of the active ingredient.

Preferably, these pharmaceutical preparations were in standard dosage forms. In such form the preparation is divided into standard doses containing appropriate quantities of skretny quantity of the drug, such as packaged tablets, capsules, and powders in vials or ampoules. Standard dosage form can be a capsule, tablet, wafer or bread or the appropriate number in Packed form.

The preferred compositions are tablets or capsules for oral administration and liquids for intravenous administration.

Biological activity and methods of treatment

4-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter, which, as shown, operates throughout the Central and peripheral nervous system. Currently, there are two types of receptors for GABA, the GABAAand GABAIN-receptors. Recent molecular biological studies have shown that GABAAreceptors can be divided into many subreceptors consistent with selective and/or partial pharmacological effects observed with certain ligands of the benzodiazepine receptor in contrast to non-selective effects that are observed with the classical ligands of the benzodiazepine receptor, such as diazepam.

Activation of GABA receptors leads to changes in membrane potential (Gedney channel for chloride ions, whereas activation of GABAINreceptors indirectly alters potassium and sodium channels, and modifies production of second messengers. The recognition sites of the GABAAcan be activated using, for example, GABA, muscimol and isoguvacine, but not GABAIN-agonists, such as baclofen. Modulatory site recognition GABAAsites benzodiazepine receptors can be selectively labeled with radioactive isotope 3H-flunitrazepam.

Thus, the affinity of different potential ligands to the sites benzodiazepine receptors can be assessed by determining the ability of test compounds to replace3H-flunitrazepam.

Compounds of the present invention may be useful for treating disorders or disease of a living animal body through their modulatory effect on website recognition benzodiazepines GABAA-receptor complex. This property makes the connection according to this invention is extremely useful as muscle relaxants in the treatment of convulsions, anxiety, sleep disorders, anesthesia, memory disorders, and other disorders sensitive to modelirovaniye, including man, in need of treatment, mitigation or elimination of disorders or diseases associated with GABAA-receptors. They include, in particular, convulsions, anxiety, sleep disorders, anesthesia and memory disorders.

Currently, it is assumed that a suitable range of dosages will be between about 0.01 to about 100 mg per day, more preferably from about 0.1 to about 50 mg per day, most preferably from about 0.1 to about 30 mg per day, which depends, however, on what route of administration and the form for entering, what are the indications for administration, who make the introduction, what is its weight and, further, from the preference and experience of the attending physician or veterinarian.

Ways to get

New benzimidazole derivatives according to this invention can be obtained by using common methods of chemical synthesis, for example those described in the working examples. Starting materials for the methods described in this application are known or can be easily prepared with conventional methods from commercially available chemicals.

The final products described herein reactions can be distinguished using conventional techniques, the invention is illustrated further by reference to the following examples, which are not intended to in any way limit the scope of this invention as it is claimed.

The compounds of this invention represented by the following General formula

< / BR>
prepared as described in scheme 1.

Raw materials (1 and 2), were used for this synthesis are listed in table. 1, 2.

Example 1

Preparative example

4-Fluoro-3-nitroacetophenone (1B): Concentrated sulfuric acid (200 ml) is cooled to 5oC. Add 4-peracetate (20 ml; 0.16 mol), maintaining the temperature below 10oC. the mixture is cooled to 0-5oAnd the portions within 2 hours add the potassium nitrate (25 g; 0.25 mol), maintaining the temperature in the same range. After the addition the mixture is stirred in the cold for another 2 hours. This mixture was poured into ice (600 g) and the crude product is filtered off. Column chromatography on silica gel using a mixture of ethylacetate and petroleum ether (1:9) as eluent gives pure 1 (18.2 g; 60%). So pl. 48-49oC.

Example 2

Preparative example

Ethyl ester of 4-chloro-3-nitrobenzoic acid (1B): 4-Chloro-3-nitrobenzoic acid (40,0 g; 0.2 mol) was boiled under reflux and thionyl chloride (150 dobavlyali absolute ethanol (500 ml) and the resulting mixture was boiled under reflux overnight. The excess ethanol was removed under reduced pressure. Was led product adding aqueous sodium bicarbonate (1 M). Output: 42.5 g (93%).

Example 3

Preparative example

4-Fluoro-1-iodine-3-nitrobenzene (1G): Intensively stirred suspension of 4-fluoro-3-nitroaniline (25 g, 0.16 mol) in conc. hydrochloric acid (125 ml) was cooled to -15oC. was added dropwise a solution of sodium nitrite (12.1 g; 0.18 mol) in water (25 ml), maintaining the temperature of -15oC. After addition the mixture was stirred 15 min, then for 45 min was added a solution of potassium iodide (33,4 g; 0.2 mol) in water (65 ml). At the end of the addition the mixture was additionally stirred for 30 min at ambient temperature. Removal of iodine was added aqueous sodium sulfite (1M) and the resulting mixture was extracted three times with diethyl ether. The combined extracts are then washed with cooled in ice water, sodium hydroxide (1M) and brine solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was cleaned by using column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:9 vol/vol) as the eluent, to give the desired product (30,3 g; 71%) as relevatory), potassium carbonate (38,8 g, 281 mmol), 1,3-propane diol cases (33.8 ml, 468 mmol) and tetrakis(triphenylphosphine)-palladium (0) (0.5 g) in a mixture of 1,2-dimethoxyethane, passing through Al2O3removal of peroxides (100 ml) and water (50 ml) was heated for 1 hour under nitrogen to boiling under reflux. The course of the reaction was checked by thin-layer chromatography (TLC) using as mobile phase a mixture of ethyl acetate and petroleum ether (1:9 vol/vol). This mixture was poured into ice water (500 ml). The precipitate was filtered, washed with water and dissolved in ethyl acetate (200 ml). This solution was washed with cold 1M HCl (g ml) and saline solution. The organic phase was dried over Na2SO4and was evaporated to dryness to obtain a residue, representing the crude product (100%). The crude product was dissolved in a mixture of dichloromethane and petroleum ether (1: 1 vol/vol) and filtered through a short column (1.5 g of silica gel per gram of the crude product). This column was washed above mixture (20 ml per gram of the crude product). The solvent was removed under reduced pressure and the residue was recrystallized (60oWith --> 0o(C) from propanol-2 (4 ml per gram of residue).

Yield: 80%. So pl. 74,3 P CLASS="ptx2">

4-Fluoro-3-nitrobiphenyl (1D) was prepared similarly from 1G and phenylboronic acid.

Example 4

Preparative example

4-Fluoro-3-nitro-tert-butylbenzoyl (1E): To a cold (5o(C) suspension of 4-tert-butylaniline in a mixture of conc, hydrochloric acid (25 ml) and water (25 ml) was added a solution of sodium nitrite (7.6 g; 0.11 mol) in water (10 ml), keeping the temperature at the level of 5-7oC. at the end of the addition the mixture was stirred for another 15 min, then was added dropwise a solution of tetrafluoroborate sodium (15,4 g; 0.14 mol) in water (30 ml), maintaining the temperature at 5-8oC. After a further 15 min at 5oWith salt, page was filtered, dried by suction and washed with diethyl ether (yield 21 g). Salt the page subjected to decomposition by careful heating to 120oC in an oil bath. Product drove and collected with getting 1E (yield 11.2 g; 73,5%).

Example 5

Preparative example

3-(1-piperidyl)aniline (2A): a Mixture of 3-peritrabecular (10.0 g; for 70.9 mmol) and piperidine (14 ml, 141 mmol) was stirred at 110oWith in three days. After cooling, was added water (200 ml) and was extracted with the mixture dichloromethane (I ml). The combined organic extracts were washed with saturated aqueous carb is it a 1-(3-nitrophenyl)piperidine (13,7 g; 93%). This oil was dissolved in ethanol (150 ml) and was first made at ambient pressure using palladium on charcoal as catalyst, to obtain 2A (11,7 g; 100%) as oil.

Similarly received the following connections:

3-(1-pyrrolidinyl)aniline (2B)

3-(4-methyl-1-piperazinil)aniline (2B) and

3-(4-morpholinyl)aniline (2P).

Example 6

Preparative example

3-(1-acetylpiperidine-4-yl)aniline (2 g): a Mixture of 3 - peritrabecular (10,7 ml; 0.1 mol) and piperazine (43 g; 0.5 mol) in anhydrous N-methyl-2-pyrrolidone was heated to 115oWith in 2 days. After cooling the mixture was poured into water (200 ml) and was extracted with ethyl acetate (CH ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was cleaned by using column chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 vol./about./about.) as the eluent, to obtain 1-(3-nitrophenyl)piperazine (17,2 g; 83%). This intermediate compound was azetilirovanie acetic anhydride (yield 90%) and was first made in methanol at ambient pressure using Pd (5% on charcoal) in calironia 1-(3-nitrophenyl)piperazine ethyl ester, 2-bromoxynil acid, N. N-diethylformamide, 2-bromoethanol, methyl ester 2-bromoxynil acid, diethyl ether of ethoxymethylenemalonic acid and methylpropionate with subsequent hydrogenation was possible to obtain, respectively:

ethyl ester of 2-(4-(3-AMINOPHENYL)piperazine-1-yl) acetic acid (2D);

N, N-diethyl-2-(4-(3-nitrophenyl)piperazine-1-yl)-ndimethylacetamide (2nd);

3-(4-(2-hydroxyethyl)piperazine-1-yl) -aniline (2l);

methyl ester of 2-(4-(3-AMINOPHENYL)-piperazine-1-yl)-acetic acid (2m);

diethyl ether (4-(3-AMINOPHENYL)piperazine-1-yl)-metromanila acid (2n) and

methyl ester of 2-(4-(3-AMINOPHENYL)piperazine-1-yl)-acrylic acid (2).

Example 7

Preparative example

3-(1-(tert-butoxycarbonyl)piperazine-4-yl)-aniline (2ZH): a Mixture of tert-butyl methyl ether 1-piperazinecarboxamide acid (4 g; 21.5 mmol) and 3-peritrabecular (2,3 ml, 21.5 mmol) in anhydrous N-methyl-2-pyrrolidone (5 ml) was heated to 120oWith in 3 days. After cooling, was added water (25 ml) and was extracted with a mixture of ethyl acetate (2x10 ml). The organic extract was dried over sodium sulfate and solvent was removed under reduced pressure. The residue was cleaned by using column chromatography, consistently using petroleum ether and trienyl)-1-piperazinecarboxamide acid: 1,34 g (20%). This intermediate compound quantitatively was first made to 2ZH in ethanol at ambient pressure using Pd (5% on activated carbon) as the catalyst.

Similarly got the following link:

3-(1-methyl-4-homopiperazine)aniline (2H).

Example 8

Preparative example

3-((1-pyrrolidinyl)methyl)aniline (2i): To a solution of 3-nitrobenzylamine (3 g; a 13.9 mmol) in anhydrous tetrahydrofuran (30 ml) dropwise with stirring solution was added pyrrolidine (2,3 ml, 27.8 mmol) in anhydrous tetrahydrofuran (10 ml). After the addition the mixture was stirred over night at ambient temperature. This reaction mixture was filtered. The filter cake was washed with small volume of anhydrous tetrahydrofuran and the filtrate was concentrated to a residue in the form of oil, which represents an intermediate compound, 1-(3-nitrobenzyl)pyrrolidin. This oil was dissolved in methanol (50 ml) and added three equivalents of ammonium chloride and UN-hydrated sodium sulfide. This mixture was heated to boiling under reflux for 2 hours. After cooling, the mixture was filtered. The filter cake was washed with methanol and the filtrate was concentrated under reduced of storytale quantitatively remained 2i in the form of yellow crystals.

Example 9

Preparative example

3-(1-methyl-3-piperidinyl)aniline (2K): a Mixture of 3-nitrophenylarsonic acid (50 g, 0.3 mol), 3-bromopyridine (48 ml, 0.5 mol), potassium carbonate (207 g; 1.5 mol), 1,3-propane diol (107 ml, 1.5 mol) and tetrakis(triphenylphosphine)palladium (0) (0.5 g) in a mixture of water (200 ml) and dimethoxyethane (400 ml) was stirred for 3 hours in a nitrogen atmosphere at 80oC. After cooling was removed dimethoxyethane under reduced pressure and the residue was stirred with an additional 200 ml of water during the night. The precipitate was filtered and was extracted with aqueous hydrochloric acid (4M; 300 ml). This extract was made alkaline by adding aqueous sodium hydroxide (12M). The product was filtered, washed with water and dried by suction to obtain 3-(3-nitrophenyl)pyridine (50.6 g; 84%).

3-(3-nitrophenyl)pyridine (50 g, 0.25 mol) in portions under stirring were added to dimethylsulfate (125 ml). This mixture was stirred at ambient temperature for 24 hours, and during this time additionally contributed dimethylsulfate (g ml). At the end of the reaction was added diethyl ether (400 ml) and the mixture was stirred in the cold for 2 hours. The precipitate was filtered and repeatedly washed with diethyl ether. Finally, the precipitate was stirred E. 30 min, then the product was filtered off, washed with diethyl ether and dried to obtain methyl sulfate 1-methyl-3-(3-nitrophenyl)pyridinium (66.6 g; 82%).

The above salt (66 g; 0.2 mol) was dissolved in methanol (750 ml) and portions were added thereto sodium borohydride (11.4 g; 0.3 mol). At the end of the addition the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was distributed between water and diethyl ether. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. This concentrate was dissolved in ethanol (500 ml) and was first made at ambient pressure using Pd (5% Pd on activated carbon) as the catalyst. Output 2: 24.2 g (64%).

3-(3-Pyridyl)aniline (2P): a Mixture of diethyl ether 3-pyridylamino acid (16.3 g, 0.11 mol), 3-bromoaniline (12,2 ml; 0.11 mol), potassium carbonate (48,5 g; 0.33 mol) and tetrakis(triphenylphosphine)palladium (0) (80 mg) in a mixture of water (40 ml) and dimethoxyethane (80 ml) was heated overnight to 80oWith in a stream of nitrogen. After cooling, the mixture was diluted with water and ethyl acetate and filtered through fluted filter paper. Shared layers. The aqueous layer once were extracted with ethyl acetate. The combined organic phases were dried over saravali the mixture to dryness. The residue was led with rubbing with ice water. The crystals were collected, dried and washed with petroleum ether to obtain pure 2P (16.3 g; 87%). So pl. 75-76oC.

Example 10

5-cyano-1-(3-(1-piperidyl)phenyl)benzyl)benzimidazole (3a1): A mixture of 4-chloro-3-nitrobenzonitrile (5.0 g; a 27.4 mmol), 2A (4.8 g; 27.7 mmol) and triethylamine (3.8 ml; 27,4 ml) in anhydrous N-methyl-2-pyrrolidone (5 ml) was heated overnight to 120oWith stirring in a stream of nitrogen. After cooling the mixture was poured into water (50 ml). The crude product was filtered, washed with water and dried by suction. Treatment with activated charcoal in boiling in a flask with reflux ethanol gave pure N-(3-(1-piperidyl)-phenyl)-4-cyano-2-nitroaniline (6,24 g, 71%).

This intermediate product (6,17 g; of 19.1 mmol) was first made in ethanol at ambient pressure using Pd (5% on activated carbon) as the catalyst, to obtain the corresponding diamine (5.6 g; 100%), which within hours was treated with formic acid (25 ml) at 80oC. After cooling, the mixture was poured into water (100 ml) and podslushivaet the addition of saturated aqueous sodium carbonate. The product was filtered and cleaned by the processing activerow the Yu on silica gel, using a mixture of ethyl acetate and petroleum ether (1:1, volume/volume) as eluent Exit 3a1: 4.4 g (70%). So pl. 106-108oWITH,

Similarly received the following connections:

5-cyano-1 -(3-(1-pyrrolidinyl)phenyl)benzimidazole (3A2), so pl. 171-172oC;

5-cyano-1-(3-(4-methyl-1-piperazinil)phenyl)benzimidazole (3A3), so pl. 177-179oC;

hydrochloride-5-cyano-1-(3-(4-methyl-3-piperidinyl)phenyl)benzimidazole (3A4), so pl. 158-160oAnd

5-cyano-1-(3-(4-morpholinyl)phenylbenzimidazol (3a5), so pl. 163-165oC.

Example 11

The reaction of 5-formyl-1-(3-(1-piperidinyl) phenyl) benzimidazole (3b1): To a solution of 3A1(3,83 g; 12.9 mmol) in a mixture of formic acid (45 ml) and water (15 ml) was added Raney Nickel (2.14 g; slurry in water). This mixture was boiled under reflux with stirring for 3 hours. After cooling, the mixture was filtered through celite and the filtrate was evaporated to dryness. Spent the distribution of the residue between ethyl acetate and aqueous sodium bicarbonate (1M), the Organic phase was dried over sodium sulfate and concentrated under reduced pressure. The concentrate was suirable through a short column of silica gel using ethyl acetate. After evaporation of the solution is present in the flask with reflux ethanol (15 ml). Added hydroxylamine hydrochloride (2.64 g; 30.0 mmol) and triethylamine (1.70 ml) and continued boiling for 5 hours, the Cooled mixture was podslushivaet the addition of triethylamine. Added water and the precipitate was filtered, washed with water and dried to obtain 3b1(2,89 g; 70%). So pl. 213-214oC.

Similarly, using appropriate hydroxylamine, prepared the following compounds:

the reaction of 5-formyl-1 -(3-(1-pyrrolidinyl)phenyl)benzimidazole (3b2), so pl. 242-244oC;

the reaction of 5-formyl-1-(3-(4-methyl-piperazinil)phenyl)benzimidazole (3b3), so pl. 224-227oC;

the reaction of 5-formyl-1-(3-(4-methyl-1-piperidinyl)phenyl)benzimidazole (3b4), so pl. 241-218oC;

On-isopropoxy 5-formyl-1 -(3-(1-piperidinyl)phenyl)- benzimidazole (3V), so pl. 127-128oWith; and

On-methyloxime 5-formyl-1-((1-piperidinyl)phenyl)benzimidazole (3G), so pl. 107-108oC.

Example 12

The reaction of 5-acetyl-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (3D1): A mixture of 1B (0.75 g; 4.1 mmol) and 2D (0.9 g; 4.1 mmol) in anhydrous N-methyl-2-pyrrolidone (2 ml) was heated to 80oWith overnight in a stream of nitrogen. After cooling, was added water (20 ml) and this mixture is extracted with dichloromethane. The organic extract was dried is cromatografia on silica gel, using ethyl acetate as eluent to obtain 4-acetyl-N-(3-(1-acetylpiperidine-4-yl)-phenyl)-2-nitroaniline in the form of butter.

This oil was dissolved in ethanol (25 ml) and was first made at ambient pressure using Pd (5% on activated carbon) as the catalyst. The resulting mixture was filtered through celite and solvent was removed under reduced pressure. To the residue was added formic acid (5 ml) and the mixture was heated up to 80oC for 1 hour. After cooling, was added water and the product was extracted with ethyl acetate. Processing using column chromatography on silica gel using mixtures of ethyl acetate and methanol (9:1) as eluent received 5-acetyl-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (0,53 g; 36%). So pl. 112-114oC.

This product was treated with hydroxylamine hydrochloride in ethanol as described in example 11, to obtain 3D1(90%). So pl. 240-242oC.

In a similar manner were prepared the following compounds:

the reaction of 5-acetyl-1-(3-(4-(2-hydroxyethyl)-piperazine-1-yl)phenylbenzimidazol (3D2); so pl. 193-195oC;

On-acyloxy 5-acetyl-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)phenylbenzimidazol (3e1),1H-NMR (Dl3, 500 MHz): 1.44 is(d, 1H), 7.86 ppm, (d, 1H), 8.15 memorial plaques (s, 1H), 8.20 memorial plaques (s, 1H);

hydrochloride O-atylosia -5 acetyl-1-(3-(4-methylpiperazin-1-yl)-phenyl)benzimidazole (3E2), so pl. 62-63o(Oily crystals);

hydrochloride On-atylosia 5-acetyl-1-(3-(1-pyrrolidinyl)-phenyl)benzimidazole (3E3), t square 158-162oC;

hydrochloride On-atylosia 5-acetyl-1-(3-(4-methylhomopiperazine-1-yl)-benzimidazole (3E4) so pl. 147-151oC;

On-acyloxy 5-acetyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (3E5), so pl. 118-120oC;

On-acyloxy 5-acetyl-1-(3-(1-piperidinyl)phenyl)benzimidazole (3E6), so pl. 88-89oC;

hydrochloride On-atylosia 5-acetyl-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (3E1), t square 112-114oC;

hydrochloride On-Isopropylamine 5-acetyl-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (j1), t, pl. 48-55oC,1H-NMR (CDCl3, 500 MHz): 1.37 ppm (d, 6H), 1.75 M. D. (qd, 1H), 2.08 M. D. (d, 1H), 2,23, M. D. (d, 1H), 2.34 ppm (s, 3H), 2.54 M. D. (m, 1H), 2.80 M. D. (m, 1H), 2.87 memorial plaques (s+m, 4H), 3.64 memorial plaques (t, 2H), 3.80 M. D. (m, 1H), 4.50 M. D. (hept, 1H), 7.43 M. D. (d, 2H), 7,51 m d (m, 3H), 7.61 m DV (t, 1H), 7.86 M. D. (d, 1H), 8.13 memorial plaques (s, 1H), of 8.47 M. D. (broad, 1H);

hydrochloride On-Isopropylamine 5-acetyl-1 -(3-(4-(2-hydroxyethyl)-piperazine-1-yl)phenyl)benzimidazole (j2), so pl. 165 to 169oC;
S, and O-tert-butyloctyl 5-acetyl-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)-phenyl)benzimidazole (3C),1H-NMR (Dl3, 500 MHz): 1.34 memorial plaques (s, 9H), 2.25 M. D. (s, 3H), 2.86 M. D. (broad, 2H), 2.98 M. D. (broad, 4H), 3.47 M. D. (broad, 4H), 3.82 (broad, 2H), 6.97 M. D. (m, 3H), 7.44 M. D. (m, 2H), 7.77 M. D. (d, 1H), 8.06 memorial plaques (s, 2H).

Example 12 and

On-Acyloxy 5-acetyl-1 -[3-[1-methyl-1,2.3.6-tetrahydropyran-5-yl)- phenyl]benzimidazole (3E8):

4-Acetyl-N-(3-(3-pyridyl)phenyl-2-nitroaniline: a Mixture of 1B from Example 1 (5 g; 27,3 mmol) and 2P from Example 9a (4,62 g; for 27.2 mmol) in dry N-methyl-2-pyrrolidone (10 ml) was stirred at 40-50oWith during the night. The resulting solid reaction mixture was suspended in ice water and podslushivaet the addition of an aqueous sodium carbonate (1M). The product was filtered, washed with water and dried to obtain 7.68 g 4 (85%). So pl. 112-113oC.

The methyl sulfate 4-acetyl-N-[3-(1-methylpiperid-3-Eli)phenyl]-2 - nitroaniline (5):

< / BR>
4-Acetyl-N-[3-(3-pyridyl)phenyl] -2-nitroaniline (4) (3,68 g, 11.05 mmol) in dimethylsulfate (7.5 ml) was stirred at ambient temperature for 15 minutes was Added diethyl ether and stirred the mixture for another 30 minutes, the Product was filtered and dried to obtain methyl sulfate 4-acetyl-N-[3-(1-methylpiperid-3-or] -2-nitroaniline (6):

< / BR>
To a suspension of methyl sulfate 4-acetyl-N-[3-(1-methylpiperid-3-Eli)phenyl]-2-nitroaniline (5) (4.9 g; of 10.7 mmol) in methanol (50 ml) was added in portions with stirring, sodium borohydride (0.6 g; 16 mmol). The resulting solution was stirred 1 h, then solvent was removed by evaporation. Spent the distribution of the residue between water and etiracetam. The organic phase was dried over sodium sulfate, concentrated under reduced pressure and cleaned using column chromatography on silica gel using a mixture of dichloromethane, methanol and acetone (4:1:1 vol./about.) as eluent. Yield: 2.1 g (56%).

5-Acetyl-1 -[3-(1-methyl-1,2,3,6-tetrahydropyran-5-yl)phenyl] -benzimidazole (7):

< / BR>
A mixture of 4-acetyl-N-[3-(1-methyl-1,2,3,6-tetrahydropyran-5-yl)phenyl] -2-nitroaniline (5) (1 g; 3 mmol), nonahydrate of sodium sulfide (4,32 g, 18 mmol) and ammonium chloride (0.96 g, 18 mmol) in methanol (50 ml) overnight was heated to boiling under reflux. The solvent was removed under reduced pressure and perform the distribution of the residue between ethyl acetate and water. The organic phase was dried over sodium sulfate and concentrated to obtain oil (m/e: 321), which was stirred in formic acid (10 ml) at 80oC for 4 hours. Received the Wali, adding solid sodium carbonate, and extragonadal with ethyl acetate. The extract was dried over sodium sulfate. The solvent was evaporated to obtain a residue, which represents a 5-acetyl-1 -[3-(1-methyl-1,2,3,6-tetrahydropyran-5-yl)phenyl] benzimidazole (7) in the form of oil. Yield: 0.5 g (50%), m/e 331. A small sample of this oil was dissolved in ethanol and precipitated as the hydrochloride by addition of hydrogen chloride in diethyl ether, So pl. 227-233oC.

O-Acyloxy 5-acetyl-1-(3-(1-methyl-1,2,3,6-tetrahydropyran-5-yl)-phenyl)benzimidazole (3E8):

< / BR>
To a solution of 5-acetyl-1 -[3-(1-methyl-1,2,3,6-tetrahydropyran-5-yl)-phenyl] -benzimidazole (7) (the above free base) in ethanol was added the hydrochloride of O-ethylhydroxylamine. This mixture was heated to boiling under reflux for 1.5 hours, after which the solvent was removed under reduced pressure. The residue was pereirae with a mixture of diethyl ether and ethanol to obtain On-atylosia 5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyran-5-yl)phenyl]benzimidazole (3E8in the form of hygroscopic crystals.

So pl. 138-143, m/e 374.

Example 12B

5-Acetyl-1 [3-(1-methylpiperidin-3-yl)phenyl]benzimidazole (9):

< / BR>
To a solution of 4-acetyl-N-[3-(1-methyl-1,2,3,6-tertia coal and the mixture was first made during the night when the ambient pressure. This reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. To this concentrate was added formic acid (10 ml) and the resulting solution was stirred at 80oWith during the night. The excess formic acid was removed by evaporation. The residue was dissolved in water and podslushivaet by adding solid sodium carbonate. Extraction with ethyl acetate and the treatment of the extract with activated charcoal in ethanol was allowed to get 5-acetyl-1 -[3-(1-methylpiperidin-3-yl)phenyl]-benzimidazole (9) (0.5 g; 50%) as oil. M/e 333.

Example 13

5-(3-Furanyl)-1 -(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (3i1):

A mixture of 1G (1.4 g; 5.2 mmol) and 2B (1.0 g; 5.2 mmol) in anhydrous N-methyl-2-pyrrolidone (5 ml) over night warmed up to 80oWith in a stream of nitrogen. This mixture was poured into ice water (50 ml) and podslushivaet the addition of saturated aqueous sodium carbonate. The precipitate was filtered and cleaned by using column chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 vol./about./about.) as eluent. Output 4-iodine-2-nitro-N-(3-(4-methylpiperazin-1-yl)phenyl)aniline: 1.32 g (58%).

To a solution of the above product (1.3 g; of 2.97 mmol) in a mixture of dimethoxyethane (20 is Ivanishin)palladium (0) (70 mg) and 1,3-propandiol (1.07 ml; of 14.8 mmol). The resulting mixture was stirred in a stream of nitrogen at 80oC for 6 hours. After cooling, the mixture was filtered. The filtrate was diluted with water (50 ml) and was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to dryness to obtain a residue, a 4-(3-furanyl)-2-nitro-N-3-(4-methylpiperazin-1-yl)phenyl)aniline (0.95 g; 85%) as a red oil.

This oil was first made when the ambient pressure in ethanol, using Pd (5% on activated carbon) as the catalyst to obtain 2-amino-4-(3-furanyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-aniline (0.6 g; 69%), which in the hour-long process of boiling in a flask with reflux condenser formic acid (5 ml). After cooling the solution was poured into ice water (25 ml) was added aqueous sodium hydroxide (10 M) to obtain an alkaline reaction. Extraction with ethyl acetate followed by chromatographic processing on silica gel using a mixture of ethyl acetate and methanol (9: 1 volume/volume) as eluent gave pure 3i1(0,23 g; 41%). So pl. 129-130oC.

In a similar manner were prepared the following compounds:

5-(3-furanyl)-1-(3-(1-Metzen-1-yl)phenyl)-benzimidazole (3i3), so pl. 137-140oC;

5-(3-furanyl)-1-(3-(4-(N, N-diethylcarbamoyl)-piperazine-1-yl)-phenyl)benzimidazole (3i4), so pl. 107-109oC;

5-phenyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (3K1), so pl. 131-132oWith 5-phenyl-1 -(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (3K2), so PL 42-44oC.

If 3K1and 3K2used phenylboronic acid.

Example 14

Hydrochloride 5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1 -(3-(1 methylpiperidin-3-yl)phenyl)benzimidazole (3l): To a solution of sodium (0.1 g; 4 mmol) in anhydrous ethanol (10 ml) was added 4A1(see Example 16) (0.36 g; 1 mmol) and the reaction cyclopropanecarboxamide and this mixture over night were heated to boiling in a flask with reflux condenser. After solvent removal was performed distribution of the residue between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The product is precipitated with a solution of anhydrous hydrogen chloride in diethyl ether. Output 3 liter: 0.2 g (46%). T, PL, 184-190oC.

Example 15

Hydrochloride 5-tert-butyl-1 -(3-(1-methylpiperidin-3-yl)phenyl)-benzimidazole (3M): a Mixture of 1E (1.26 g; 6,9 mmol) and 2K (1.22 g; 6.4 mmol) in anhydrous N-methyl-2-pyrrolidon the sodium carbonate and the resulting mixture was extracted with ethyl acetate. The organic phase was concentrated and cleaned using column chromatography on silica gel using a mixture of ethyl acetate and methanol (9:1 volume/volume) as eluent. Output 4-tert-butyl-N-(3-(1-methylpiperidin-3-yl)phenyl)- 2-nitroaniline in the form of oil was 0.32 g (14%). This oil was dissolved in ethanol (15 ml) and was first made at ambient pressure using Pd (5% on activated carbon) as the catalyst, with quantitative obtain the corresponding phenylenediamine. To a solution of 2-amino-4-tert-butyl-N-(3-(1-methylpiperidin-3-yl)phenyl)aniline in tetrahydrofuran (5 ml) was added triethylorthoformate (3.0 ml; 1.8 mmol) and a catalytic amount of pTSA. The resulting mixture during the night, they were heated to boiling in a flask with reflux condenser. To the cooled solution was added aqueous sodium carbonate (1M) and the mixture was extracted with ethyl acetate. The organic extract was dried over sodium sulfate and evaporated to dryness. The residue was treated with a solution of anhydrous hydrogen chloride in diethyl ether to obtain 3M (0.21 g; 63%) as a hygroscopic solid. So pl. approximately 200oWith (at 70oWith decomposed), m/e: 347.

Example 16

Hydrochloride 5-(etoxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl) - Rev. ke nitrogen to 70oC. the resulting melt was stirred at 70oWith during the night. Spent the distribution of this reaction mixture between water and ethyl acetate and the organic phase is extracted with diluted hydrochloric acid (4M). The aqueous phase was podslushivaet the addition of an aqueous sodium hydroxide (4M) and was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and solvent was removed under reduced pressure, resulting remained ethyl ester 4-(3-(1-methylpiperidin-3-yl)phenylamino)-3-nitrobenzoic acid (7.5 g; 98%) as oil.

The above oil was dissolved in ethanol (150 ml) and was first made at ambient pressure, using as catalyst Pd (5% on charcoal). Received phenylenediamine was treated with formic acid (25 ml) at 80oC for 4 hours. After that, the excess formic acid was removed by evaporation. Spent the distribution of the balance between aqueous sodium hydroxide (1M) and ethyl acetate. The organic phase was concentrated and cleaned using column chromatography on silica gel using a mixture of dichloromethane, methanol and acetone (4:1:1 vol./about./about.) as eluent. In the evaporation of the solvent and treatment of the residue with a solution of tipepidine-3-yl)phenyl)benzimidazole (2.8 g; 35%) as a hygroscopic solid.1H-NMR (DMSO-d6, 500 MHz): 1.43 memorial plaques (t, 3H), 1.47 M. D. (m, 1H), 1.83 M. D. (m, 2H), 2.00 M. D. (m, 2H), 2.06 m DV (t, 1H), 2.34 memorial plaques (s, 3H), 2.98 M. D. (m, 3H), 4.40 M. D. (q, 3H), 7.37 M. D. (m, 3H), 7.50 M. D. (m, 2H), 8.05 M. D. (d, 1H), 8.17 memorial plaques (s, 1H), 8.58 memorial plaques (s, 1H).

In a similar manner were prepared the following compounds:

5-(etoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (4A2), so pl. 86-87oC;

hydrochloride 5-(etoxycarbonyl)-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)-phenyl)benzimidazole (4A3), so pl. 233-236oC;

5-(etoxycarbonyl)-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (4A4), so pl. 155-156oC;

hydrochloride 5-(etoxycarbonyl)-1-(3-(4-(methoxycarbonylmethyl)-piperazine-1-yl)phenyl)benzimidazole (4a5), so pl. 185-186oAnd

hydrochloride 5(etoxycarbonyl)-1-(3-(4-ethoxycarbonylmethyl)-piperazine-1-yl)phenyl)benzimidazole (4A6), so pl. 196-200oC.

Example 17

5-(2-(etoxycarbonyl)ethynyl)-1-(3-(1-piperidyl)phenyl)benzimidazole (4B1): To a suspension of sodium hydride (70 mg, 60% dispersion in mineral oil) in anhydrous toluene (5 ml) was added triethylphosphite (0.33 ml; of 1.64 mmol), maintaining the temperature at 30-35oC. After the addition was continued premisesfor 5-formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole (0.5 g; of 1.64 mmol; prepared as described in Example 11) in anhydrous toluene. After the addition the mixture was stirred 15 minutes at ambient temperature and then for another 15 min at 60-65oC. Stirring is continued overnight at ambient temperature. This reaction mixture decantation, leaving retinopathy residue, which was extracted several times with toluene. United decantate washed with water, dried over sodium sulfate and evaporated to dryness. The residue was pereirae with petroleum ether to obtain 4B1(0,38 g; 61%). So pl. 85-87oC.

Similarly received the following connections:

5-(2-(etoxycarbonyl)ethynyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)-benzimidazole (4B2), so pl. 133-134oC;

5-(2-(etoxycarbonyl)ethynyl)-1-(3-(4-morpholinyl)phenyl)benzimidazole (4B3), so pl. 197-200oC;

5-(2-(methoxycarbonyl)ethynyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)-benzimidazole (4V1), so pl. 138-140oAnd

5-(2-(methoxycarbonyl)ethynyl)-1-(3-(4-morpholinyl)phenyl)-benzimidazole (4V2), so pl. 137-139oC.

For the latter two drugs used metiltiofosfonata.

Example 18

5-(Methoxycarbonyl)-1-(3-(1-acetylpiperidine-3-yl)phenyl)benim the l-2-pyrrolidone (5 ml) was added 2 g (2,03 g; 9.28 are mmol) and triethylamine (1.3 ml; 9.28 are mmol). This mixture over night was heated under stirring to 80oC. the Cooled solution was poured into ice water (50 ml) and the resulting mixture was extracted with ethyl acetate (3x10 ml). The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residue was pereirae with petroleum ether to obtain methyl ester of 4-(3-(1-acetylpiperidine-4-yl)-aniline)-3-nitrobenzoic acid (3,14 g; 85%) as red crystals.

This intermediate product was dissolved in methanol (50 ml) and was first made at ambient pressure using Pd (5% on activated carbon) as the catalyst, to obtain the corresponding diamino compound (2.8 g; 96%).

To a solution of the diamine in tetrahydrofuran (50 ml) was added triethylorthoformate (2.5 ml, and 15.2 mmol) and a catalytic amount of pTSA. This mixture was heated to boiling in a flask under reflux for one hour. After cooling, the solvent was removed by evaporation and spent the distribution of the balance between aqueous sodium carbonate (1M) and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was cleaned with the help of Kent. Exit 4G1: 5,52 (53%). So pl. 189-191oC.

Similarly received the following connections:

5-(methoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (4G2): so pl. 119-121oC;

4-(methoxycarbonyl)-1-(3-(4-methoxycarbonylmethyl)piperazine-1-yl)- benzimidazole (4G3),1H-NMR (Dl3, 500 MHz): 2.90 M. D. (broad, 4H), 3.35 M. D. (wide, 6N), 3.70 M. D. (s, 3H), 3,90 m DV (s, 3H), 6,91 M. D. (m, 2H), 6.95 M. D. (d, 1H), 7.39 m DV (t, 1H), 7.48 M. D. (d, 1H), 7 99 M. D. (d, 1H), 8,11 memorial plaques (s, 1H), 8.51 memorial plaques (s, 1H);

5-(methoxycarbonyl)-1-(3-(4-(N, N-diethylcarbamoyl)piperazine-1-yl)phenyl)-benzimidazole (4G4),1H-NMR (CDCl3, 500 MHz): 1.18 memorial plaques (t, 3H), 1.26 ppm, (t, 3H), 2.90 (broad, 4H), 3.42 M. D. (m, 1H), 3.99 MD. (s, 3H), 6.98 M. D. (supersaloon d+s, 2H), 7.04 M. D. (d, 1H), 7,56 M. D. (d, 1H), 8.07 M. D. (d, 1H), 8.20 memorial plaques (s, 1 H), 8.60 memorial plaques (s, 1H), and

5-(methoxycarbonyl)-1-(3-(4-morpholinyl)phenyl)benzimidazole (4G5), so pl. 150-152oC.

Example 19

5-(ISO-propylenecarbonate)-1-(3-(1-piperidinyl)phenyl)benzimidazole (4D1): To a mixture of isopropyl ether 4-chloro-3-nitrobenzoic acid (3.0 g; 12.3 mmol) and 2A (2.16 g; 12.3 mmol) in anhydrous N-methyl-2-pyrrolidone (5 ml) was added triethylamine (1,71 g; 12.3 mmol) and during the night stirred the mixture in a stream of nitrogen at 80oC. Conducted Noi hydrochloric acid (4M). The aqueous extract was podslushivaet by adding aqueous sodium hydroxide (12M), and was extracted with ethyl acetate. This organic extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographically on silica gel using a mixture of ethyl acetate and petroleum ether (1:1 volume/volume) as eluent, to obtain the isopropyl ester of 3-nitro-4-(3-(1-piperidinyl)-aniline)benzoic acid (2.55 g; 54%) as a red oil. This intermediate product was dissolved in ethanol (50 ml) and was first made when the ambient pressure. The resulting diamine was treated with formic acid (25 ml) at 80oC for one hour. The reaction mixture was poured into water (100 ml) and podslushivaet by adding aqueous sodium hydroxide (10 M). The crude product was filtered, washed with water and dried. Purification was carried out by treatment with activated charcoal in boiling in a flask with reflux condenser propane-2-Ola with subsequent grinding with diethyl ether. Output 4D1: 1.27 g (53%). So pl. 160-161oC.

In a similar manner were prepared the following compounds:

5-(ISO-propylenecarbonate)-1-(3-(1-pyrrolidinyl)phenyl)-benzimidazole (4D2), so pl. 170-172oC;

5-(ISO-propyloxy bonil)-1-(3-(4-morpholinyl)phenyl)benzimidazole (4D4), so pl. 173-174oC.

Example 20

5-(Cyclopropanecarbonyl)-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (4E): To a solution of 4a1(1.5 g, 3.8 mmol) in ethanol (10 ml) was added aqueous potassium hydroxide (10 ml, 2M) and heated the mixture to boiling in a flask under reflux for 2 hours. The ethanol was removed under reduced pressure and the residue was neutralized by adding acetic acid. The resulting amino acid was filtered and dried. This product has suspensively in toluene (100 ml). Added thionyl chloride (3 ml) and heated the mixture to 80oC for 4 hours. The cooled mixture was evaporated to dryness and the residue suspended in anhydrous tetrahydrofuran (60 ml).

Part of the above suspension (20 ml) was added cyclopropylmethanol (0.8 ml; 10 mmol) and the mixture was stirred at room temperature for 5 days. The solvent was removed by evaporation and spent the distribution of the balance between aqueous sodium hydroxide (1M) and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was pereirae with petroleum ether to obtain 4E (30 mg; 7%). So pl. 111-113oC.

In a similar manner were prepared the following compounds:

hydrochloride 5-(benzyloxycarbonyl)-1 -(3-(1-methylpiperidin-3-yl)-phenyl)-benzimidazole (s),1H-NMR (Dl3, 500 MHz): 1.45 M. D. (m, 1H), 1.8 M. D. (broad, 2H), 2.1 M. D. (broad, 3H), 2.4 M. D. (broad, 3H), 3.0.m.D. (wide,

2H), 5.36 memorial plaques (s, 2H), 7.3 ppm (several signals, 4H), 7.45 memorial plaques (t, 2H), 7.77 M. D. (d, 1H), 8.01 M. D. (d, 1H), 8.12 memorial plaques (s, 1H), 8.55 M. D. (d, 1H), 8.57 memorial plaques (s, 1H), 8.69 memorial plaques (s, 1H).

Example 21

5-(2-((Dimethylamino)ethyl)oxycarbonyl)-1-(3-(1-acetylpiperidine-4-yl)-phenyl)benzimidazole (4I): To a solution of 2-(dimethylamino)-ethyl ester 4-chloro-3-nitrobenzoic acid (2.5 g; 9.1 mmol) and 2G (2.0 g; 9.1 mmol) in anhydrous N-methyl-2-pyrrolidone (5 ml) was added triethylamine (1.3 ml; 9.1 mmol) and the mixture was stirred at 80oC for 4 hours. The cooled mixture was poured into ice water (100 ml) and was extracted with ethyl acetate (4x20 ml). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was cleaned by using column chromatography on silica gel using a mixture of dichloromethane and methanol (9: 1 vol/vol) as eluent to obtain 2-(dimethylamino)-ethyl ester 3-nitro-4-(3-)1-acetylpiperidine-4-yl)-aniline)-benzoic acid (1 g; 24%). This intermediate product was dissolved in ethanol (50 ml) and quantitatively was first made at ambient pressure using Pd (5% on activiautonomous (0.7 ml; 4.2 mol) together with a catalytic amount of pTSA. This mixture was heated to boiling in a flask under reflux for one hour. The solvent was removed under reduced pressure and perform the distribution of the balance between aqueous sodium carbonate (1M) and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure and was chromatographically the residue on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (volume ratio 90:10:1) as eluent. Isolated from the eluate product was treated with activated charcoal in boiling in a flask with reflux ethanol and the resulting product was pereirae with petroleum ether to obtain 4 (0.18 g; 20%). So pl. 101-103oC.

Similarly got the following link:

5-(2-((dimethylamino)-ethyl)-oxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)-piperazine-1-yl)-phenyl)-Beneamata (4K),1H-NMR (CDCI3, 500 MHz): 1.29 m DV (t, 3H), 2.44 M. D. (s, 6H), 2.77 m DV (t, 4H), 2.88 m DV (t, 2H), 3.28 memorial plaques (s, 2H), 3.33 m DV (t, 4H), 4.21 M. D. (q, 2H), 4.54 m DV (t, 2H), 6.94 M. D. (d, 1H), 6.96 memorial plaques (s, 1H), 7.02 M. D. (d, 1H), 7.44 m DV (t, 1H), 7.55 M. D. (d, 1H), 8.06 M. D. (d, 1H), 8.17 memorial plaques (s, 1H), 8.58 memorial plaques (s, 1H).

Example 22

5-((N, N-Diethylcarbamyl)-methyloxycarbonyl)-1-(3-(4-the addition of 1-(3-(1-acetylpiperidine-4-yl)-phenyl)-benzimidazole (4 l2). These compounds were prepared from (N,N-diethylcarbamyl)-methyl ether 4-chloro-3-benzoic acid (1Z) and 2D and 2E, respectively, as described in example 21.

1H was prepared as follows: To a solution of 4-chloro-3-nitrobenzoic acid (5.0 g; for 24.8 mmol) in anhydrous dimethylformamide (25 ml) was added sodium iodide (0,37 g; 2.5 mmol), triethylamine (6.9 ml; of 49.6 mmol) and 2-chloro-N,N-diethylacetamide (3.4 ml; for 24.8 mmol). The resulting mixture was stirred at room temperature overnight. This mixture was poured into ice water (100 ml) and the oily precipitate was filtered and re-dissolved in ethyl acetate. This solution was dried over sodium sulfate and evaporated to dryness to obtain 1Z (7,46 g; 96%) as a yellow oil.

Example 23

4-Fluoro-3-nitrophenylarsonic acid (1i): a Suspension of 4-florfenicol acid (10.0 g; 64,9 mmol) in concentrated sulfuric acid (100 ml) was cooled to 0oC. was added dropwise concentrated nitric acid (4.5 ml; 65 mol), maintaining the temperature between 0-5oC. at the end of the addition the mixture was poured into ice water (400 ml). The precipitate was filtered, thoroughly washed with water and dried by suction to obtain 1i (9,11 g; 70%).

Example 24

Hydrochloride 5-(methodname N-methyl-2-pyrrolidone (2 ml) was added 2V (2,88 g; 15.1 mmol) and triethylamine (2.1 ml, 30.2 mmol). This mixture over night was stirred at 80oWith in a stream of nitrogen. This cooled mixture was poured into a mixture of diethyl ether and petroleum ether (100 ml, 1:1 volume/volume), which led to the separation of the lower oily phase. The mixture decantation, and the oil was dissolved in dichloromethane and was suirable through silica gel with a mixture of dichloromethane and methanol (4:1 volume/volume) to give 3-nitro-4-(3-(4-metapopulation-1-yl)-phenylamino)-phenylacetic acid (1.63 g, 29%). This acid (0.64 g; of 1.73 mmol) was dissolved in methanol and was added concentrated hydrochloric acid (0.2 ml). This mixture was heated to boiling in a flask under reflux for 4 days. The solvent was removed under reduced pressure and the residue was cleaned by using column chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (volume ratio 90:10:1) as eluent, to obtain the ester (0,47 g; 71%) as a red oil. This oil was first made in methanol at ambient pressure using Pd (5% on activated carbon) as the catalyst, to obtain the corresponding diamine (0,38 g). This diamine for 30 min at 80oWith treated triethylorthoformate (0.35 ml, 2.14 mmol) and Catala between aqueous sodium hydroxide (1M) and ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and suirable through a column of silica gel with a mixture of dichloromethane, methanol and aqueous ammonia (volume ratio 90:10:1). The product was besieged in the form of a hydrochloride by adding in the eluate solution of anhydrous hydrogen chloride in diethyl ether. Output 4m1: 0.2 g (41%). So pl. 140-142oC.

In a similar manner were prepared the following compounds:

hydrochloride 5-(ethoxycarbonylmethyl)-1-(3-(4-methylpiperazin-1-yl)-phenyl)-benzimidazole (4 mg), so pl. 180-182oC;

hydrochloride 5-(methoxycarbonyl)-1-(3-(4-morpholinyl)-phenyl)-benzimidazole (4m3), so pl. 164-165oWith made from 1i and 2s, and

hydrochloride 5-(etoxycarbonyl)-1-(3-(4-morpholinyl)-phenyl) benzimidazole (4m4); so pl. 168-169oWith made from 1i and 2s.

Example 25

5-((1-Methylpyrrolidine-2-yl)-methoxycarbonyl)-1-(3-(4-(etoxycarbonyl)-piperazine-1-yl)-phenyl)-benzimidazole (4h) was prepared as in Example 21 from (1 methylpyrrolidine-2-yl)-methyl ether 4-chloro-3-nitrobenzoic acid and 2D.1H-NMR (CDCl3, 500 MHz): 1.10 m DV (t, 3H), 1.66 M. D. (broad, 2H), 1.78 M. D. (broad, 1H), 1.94 M. D. (broad, 1H), 2,29, M. D. (broad, 1H), 2.43 memorial plaques (s, 3H), 2.60 m DV (t, 4H), 2.70 M. D. (broad, 1H), 3.10 M. D. (supersaloon s, 2H and wide.D. (d, 1H), 7.98 memorial plaques (s, 1H), 8.38 memorial plaques (s,1H).

Example 26

On-Isopropoxy 5-acetyl-1 -(3-(1-methyl-4-piperidinylcarbonyl)-phenyl)-benzimidazole (5a1): A mixture of 1B (11,0 g; 60,2 mol), ethyl ester of 3-aminobenzoic acid (9,9 g; 6.2 mmol) and triethylamine (8.34 per ml; a 60.2 mmol) in anhydrous N-methyl-2-pyrrolidone (5 ml) was heated to 130oC for 4 hours in a stream of nitrogen with stirring. The cooled mixture was poured into ice water (100 ml). Was added ethanol (10 ml) and the mixture was stirred until complete crystallization. The precipitate was filtered, washed with water and dried to obtain ethyl ester of 4-(acetyl-2-nitrophenyl)- aminobenzoic acid (19.1 g; 97%). This ether quantitatively was first made in a mixture of ethanol (400 ml) and dichloromethane using Pd (5% on activated carbon) as the catalyst. The resulting diamine was heated under reflux in formic acid (100 ml) for 1 hour. The cooled mixture was poured into ice water (400 ml) and the precipitate was filtered, washed with water and dried to obtain 5-acetyl-1-(3-etoxycarbonyl)-phenylbenzimidazol (16.4 g; 91%).

The above ester (10 g, 32.5 mmol) was dissolved in dimethoxyethane (200 ml) was added aqueous sodium hydroxide (100 ml). This mixture was heated up to 80oWith ice water (100 ml) and the mixture was neutralized by addition of glacial acetic acid. The precipitate was filtered, washed with water and dried to obtain 5-acetyl-1-(3-carboxyphenyl)-benzimidazole (7,56 g; 83%).

This acid (4,66 g; 16,64 mmol) suspended in anhydrous does not contain peroxides tetrahydrofuran (50 ml) and was heated to boiling in a flask with reflux condenser. Portions over 3 hours was added carbonyldiimidazole (5,4 g; 33,28 mmol). Boiling under reflux was continued overnight. The solvent was removed under reduced pressure and the residue was pereirae with diethyl ether to obtain crude 5-acetyl-1-(3-carboxyamide)-phenylbenzimidazol (6,9 g) mixed with imidazole and carbonyldiimidazole.

To a solution of 1-methyl-4-hydroxypiperidine (of 1.06 ml, 9.1 mmol) in a mixture of anhydrous tetrahydrofuran (5 ml) and anhydrous dimethylformamide (5 ml) was added at ambient temperature sodium hydride (0.36 g of 60% dispersion in mineral oil, 9.1 mmol). When the evolution of hydrogen had ceased, was added to the above crude imidazole (1.5 g) and the mixture throughout the night warmed up to the 40oC. to This cooled mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate, combined with the washings, was diluted with water and extracted with ethyl acetate. Granitovo column chromatography, using a mixture of dichloromethane, methanol and aqueous ammonia (volume ratio 90: 10:1) as eluent. This procedure allowed to obtain 5-acetyl-1-(3-(1-methyl)-4-piperidinylcarbonyl)-phenyl)-benzimidazole (0.56 g; 33%), which was treated with the hydrochloride of O-ISO-propilgidroksibenzoat (0.17 g; of 1.52 mmol) in boiling in a flask with reflux ethanol (5 ml) over night. After evaporation of the solvent left crude product, which when conducting chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (volume ratio 90: 10: 1) as eluent gave pure 5a1(80 mg). So pl. 106-107oC.

In a similar manner were prepared the following compounds:

O-ISO-propyloxy-5-acetyl-1-(3-(1-methyl-3-piperidinylcarbonyl)-phenyl)-benzimidazole (5A2), so pl. 83-84oWith, and

O-ISO-propyloxy 5-acetyl-1-(3-(2-ecolological)-phenyl)benzimidazole (5A3), so pl. 104-106oC.

Example 27

5-Acetyl-1-(3-(1-methylpiperidin-3-yl)-phenyl)-benzimidazole was prepared as described in Example 12. From this ketone by treatment of the appropriate O-alkylated hydroxylamine under standard conditions was prepared following the O-alkylated oximes:

hydrochlooC;

O-(methoxycarbonylmethyl)-oxime 5-acetyl-1-(3-(1-methylpiperidin-3-yl)-phenyl)-benzimidazole (5B2), so pl. 104-106oWith, and

O-(methoxycarbonyl-(dimethyl)-methyl)-oxime-5-acetyl-1-(3-(1-methylpiperidin-3-yl)-phenyl)-benzimidazole (5B3), so pl. 113-115oC.

Example 28

5-Acetyl-1-(3-(4-(2-hydroxyethyl)-piperazine-1-yl)-phenyl)-benzimidazole was prepared as described in example 12. From this ketone by treatment of the appropriate O-alkylated hydroxylamine under standard conditions was prepared following the O-alkylated oximes:

O-(methoxycarbonylmethyl)-oxime 5-acetyl-1-(3-(4-(2-hydroxyethyl)-piperazine-1-yl)-phenyl)-benzimidazole (5 V1), so pl. 117-119oC;

hydrochloride, O-(ethoxycarbonylmethyl)-oxime 5-acetyl-1-(3-(4-(2-hydroxyethyl)-piperazine-1-yl)-phenyl)-benzimidazole (5 V2),1H-NMR (D1, 500 MHz) 1.23 m DV (t, 3H), 2.36 ppm (s, 3H), 2.66 m DV (t, 2H), 2.74 M. D. (broad, 4H), 3.30 m DV (t, 4H), to 3.67 ppm, (t, 2H), 4,17 M. D. (q, 2H), 4.70 M. D. (s, 2H), 6.92 M. D. (m, 3H), 7.37 m DV (t, 1H), 7,43 M. D. (d, 1H), 7.67 M. D. (d, 1H), 8.01 memorial plaques (s, 1H), 8.05 memorial plaques (s, 1H), and

hydrochloride, O-(etoxycarbonyl-(dimethyl)-methyl)-oxime 5-acetyl-1 -(3-(4-(2-hydroxyethyl)-piperazine-1-yl)-phenyl)-benzimidazole (5 V3),1H-NMR (Dl3, 500 MHz) 1.16 ppm, (t, 3H), 1,52 m DV (s, 6H), 2.32 M. D. (s, 3H), 3.11 (m, 4H), 3.33 m DV (t,D. 08 PM (s, 1H), 9.73 memorial plaques (s, 1H), 11.0 M. D. (broad, 1H).

Example 29

The reaction of 5-acetyl-1-(3-(4-ethoxycarbonylmethyl)piperazine-1-yl)phenyl)- benzimidazole (5g1) was prepared from 1B and 2D conditions described in Example 12, so pl. 154-146oC and

On-acyloxy 5-acetyl-1-(3-(4-(ethoxycarbonylmethyl)-piperidine-1-yl)-phenyl)-benzimidazole (5g2), so pl. 119-120oC, was prepared in the same way.

Example 30

5-Acetyl-1 -(3-(1-acetylpiperidine)4-yl)piperazine-1-yl)phenyl)-benzimidazole and 5-acetyl-1-(3-(4-morpholinyl)-phenyl)-benzimidazole was prepared as described in Example 12. Of these ketones by treatment of the appropriate O-alkylhydroxylamines under standard conditions was prepared following the O-alkylated oximes:

O-(methoxycarbonyl-(dimethyl)methyl)-oxime 5-acetyl-1-(3-[1 - acetylpiperidine-4-yl)-phenyl)-benzimidazole (5D1), so pl. 119-120oC;

O-(methoxycarbonylmethyl)-oxime 5-acetyl-1-(3-(1-acetylpiperidine-4-yl)-phenyl)-benzimidazole (5D2). So pl. 137-139oWith, and

O-(methoxycarbonylmethyl)-oxime 5-acetyl-1-(3-(4-morpholine)-phenyl)-benzimidazole (5D3), so pl. 149-150oC.

Example 31

O-ISO-propyloxy 5-acetyl-1-(3-(4-(methoxycarbonylmethyl)-piperazine-1-yl)-phenyl)-benzimidazole (5e1): To a solution of 5-acetyl-1-(3-(1-AC is hydroxide sodium (70 ml, 1M) and the mixture throughout the night warmed up to 80oC. the Organic solvent was removed under reduced pressure and the residue was diluted with water and was extracted with dichloromethane. The organic phase was concentrated and cleaned using column chromatography on silicagel using a mixture of dichloromethane, methanol and aqueous ammonia (volume ratio 90: 10: 1) as eluent. The concentrated eluate was pereirae with diethyl ether to obtain 5-acetyl-1-(3-(piperazine-1-yl)-phenyl)-benzimidazole (4,81 g; 65%) as red crystals. This product (2.0 g; and 6.25 mmol) was dissolved in a boiling flask with reflux ethanol (20 ml). Added the hydrochloride of O-isopropylacrylamide (0.7 g; and 6.25 mmol) and kept boiling under reflux for 5 hours. This reaction mixture was evaporated to dryness and perform the distribution of the balance between aqueous sodium hydroxide (1M) and dichloromethane. The organic phase was dried, concentrated and suirable through silica gel with a mixture of dichloromethane, methanol and aqueous ammonia (volume ratio 90:10: 1) to obtain the O-ISO-propyloxy 5-acetyl-1-(3-(1-piperazine)-phenyl)-benzimidazole (1.75 g, 74%). This product alkilirovanie methylbromide in anhydrous dimethylformamide in prisutstvie the regulation diethyl ether ethoxymethylenemalonic acid was allowed to obtain O-ISO-propyloxy 5-acetyl-1-(3-(4-(2,2-bis(etoxycarbonyl)ethinyl)-piperazine-1-yl)-phenyl)-benzimidazole (5e2) So pl. 128-129oC.

Example 32

5-Formyl-1-(3-(4-matlinpatterson-1-yl)-phenyl)- benzimidazole and 5-formyl-1-(3-(4-morpholinyl)-phenyl)-benzimidazole was prepared as described in example 11. These aldehydes are condensed with O-(methoxycarbonyl-(dimethyl)-methyl)-hydroxylamine under standard conditions and received:

hydrochloride, O-(methoxycarbonyl-(dimethyl)-methyl)-oxime 5-formyl-1-(3-(4-methylpiperazin-1-yl)-phenyl)-benzimidazole (j1), so pl. 199-201oWith, and

hydrochloride, O-(methoxycarbonyl-(dimethyl)-methyl)-oxime 5-formyl-1-(3-(4-morpholinyl)-phenyl)-benzimidazole (j2), so pl. 175-177oC.

Example 33

5-(5-Isoxazolyl)-1-(3-(methoxycarbonyl)-phenyl)-benzimidazole (6a1): To a suspension of 5-acetyl-1 -(3-(methoxycarbonyl)-phenyl)-benzimidazole (prepared by analogy with Example 26) (0.6 g; 2.04 mmol) was added dimethylacetal of methylformamidine (of 0.43 ml, 3.24 mmol) and the mixture was heated overnight in a stream of nitrogen up to 120oC. to This cooled mixture was poured into ice water (25 ml), the precipitate was filtered and cleaned it using column chromatography on silica gel using a mixture of ethyl acetate and methanol (9: 1 vol/vol) as the eluent to obtain 5-(3-dimethylaminopropyl)-1-(3-(amoxicillinbuy in methanol (10 ml) was added hydroxylamine hydrochloride (0.21 g; 3 mmol). This mixture for 2 hours, heated to boiling in a flask with reflux condenser. The cooled mixture was poured into ice water. The precipitate was filtered, washed with water and dried. This crude product was chromatographically on silica gel, using acetate as the eluent, to obtain 6a1(0.2 g; 52%). So pl. 190-191oC.

In a similar manner were prepared the following link:

5-(5-isoxazolyl)-1-(3-(etoxycarbonyl)-phenyl)-benzimidazole (6A2), so pl. 156-157oC.

Example 34

1-(3-Etoxycarbonyl)-phenyl-5-(phenylbenzimidazol (6b1): To a suspension 1D (8.0 g; 36,9 mmol) and ethyl ester of 3-aminobenzoic acid (6,1 g, 36,9 mmol) in anhydrous N-methyl-2-pyrrolidone (5 ml) was added triethylamine (5.1 ml, 36,9 mmol) and this mixture over night was stirred at 140oC in nitrogen atmosphere. The cooled reaction mixture was diluted with water (50 ml) and was extracted with ethyl acetate (3h20 ml). The organic extracts were dried over sodium sulfate and concentrated under reduced pressure. From a balance besieged product grinding with a mixture of diethyl ether and petroleum ether (1:1). The output of the ethyl ester of N-(3-nitrobiphenyl-4-yl)-aminobenzoic acid: 7,46 g (56%).

This ether Colisee catalyst. The resulting diamine for 1 hour, treated with 80oWith formic acid (50 ml). The cooled reaction mixture was poured into ice water (200 ml) and made alkaline by adding aqueous sodium hydroxide (10M). This mixture was extracted with ethyl acetate, the extract was dried over sodium sulfate and evaporated to dryness. The residue was pereirae with a mixture of petroleum ether and diethyl ether (1: 1) and the remainder received 6b1(5.8 g; 85%). So pl. 122-123oC.

Similarly from 1D and 2D were prepared following link:

5-phenyl-1-(3-(4-ethoxycarbonylmethyl)-piperazine-1-yl)-phenyl)-benzimidazole (6b2). So pl. 121-122oC.

Example 35

5-Phenyl-1-(3-(2-ecolological)-phenyl)-benzimidazole (6b3): To a solution of 6b1(5.30 g; a 15.5 mmol) in dimethoxyethane (100 ml) was added aqueous sodium hydroxide (50 ml, 1M) and the mixture was heated for 2 hours to 40oC. the Organic solvent was removed by evaporation. The residue was diluted with an equal volume of water and acidified by the addition of glacial acetic acid. The precipitate was filtered, washed with water and dried to obtain 5-phenyl-1-(3-carboxyphenyl)-benzimidazole (4.26 deaths / g; 88%). So pl. 289-291oC.

This acid for two hours handled the business with ether and quantitatively received the corresponding carboxylic acid chloride.

To a suspension of the above carboxylic acid chloride (1.0 g; 3 mmol) in anhydrous tetrahydrofuran (10 ml) was added 2-pyridylcarbinol (0,29 ml; 3 mmol) and this mixture over night was stirred in nitrogen atmosphere at 40oC. the Solvent was removed under reduced pressure and the residue was stirred in aqueous sodium bicarbonate (1M). The precipitate was filtered, washed with water and dried. Column chromatography on silica gel using mixtures of ethyl acetate and methanol (9:1 vol/vol) was allowed to get BS (0,29 g; 24%). So pl. 149-150oC.

Similarly received the following connections:

hydrochloride 5-phenyl-1-(3-(3-ecolological)-FNL)-benzimidazole (6b4), so pl. 195-197oC;

hydrochloride 5-phenyl-1-(3-(1-methylpiperid-3-jocstarbunny)-phenyl)-benzimidazole (6b6), so pl. 180-191oWith, and

hydrochloride-5-phenyl-1-(3-((1-methylpiperid-4-yl)-oxycarbonyl)-phenyl)-benzimidazole (6b6), so pl. 187-188oC.

Example 36

5-(3-Furanyl)-1-(3-(etoxycarbonyl)-phenyl)-benzimidazole (6V1): To a solution of 1 g (2,07 g; 10 mmol) in N-methyl-2-pyrrolidone (2 ml) was added ethyl ester of 3-aminobenzoic acid (1,82 g; 11 mmol) and triethylamine and heated the mixture overnight in a nitrogen atmosphere to 1101(0.66 g; 56%). So pl. 87-89oC.

Some compounds were selected following a by-product:

hydrochloride-5-(3-tetrahydrofuranyl)-1-(3-(etoxycarbonyl)-phenyl)-benzimidazole (6V2), so pl. 168-171oC.

Similarly from 1D and 2D, 2ZH, 2m, 2n, 2O and 2-(dimethylamino)-ethyl ester 3-aminobenzoic acid, respectively, were prepared the following compounds:

5-(3-furanyl)-1-(3-(4-(ethoxycarbonylmethyl)-piperazine-1-yl)-phenyl)-benzimidazole (6V3), so pl. 110-112oC;

5-(3-furanyl)-1-(3-(4-(tert-butoxycarbonyl)-piperazine-1-yl)-phenyl)- benzimidazole (6V4), ), so pl. 124-125oC;

5-(3-furanyl)-1-(3-(4-(2,2-bis(etoxycarbonyl)-ethynyl)-piperazine-1-yl)-phenyl)-benzimidazole (6V6), so pl. 97-102oC;

5-(3-furanyl)-1-(3-(4-(2-(methoxycarbonyl)-ethynyl)-piperazine-1-yl)-phenyl)-benzimidazole (6V7), so pl. 131-133oWith, and

hydrochloride-5-(3-furanyl)-1-(3-(2-(dimethylamino)-ethoxycarbonyl)-phenyl)-benzimidazole (6V8), so pl. 168-171oC.

Example 37

Biological activity

Preparation of tissue: the Preparation is carried out at 0-4oC, unless otherwise agreed.

The cerebral cortex of male Wistar rats (Wistar) (150-200 g) homogenized for 5-10 s in 20 ml of Tris-Hcl (30 mm, pH 7.4) using a homogenizer (Ultra-Turrax. The resulting suspension is centrifuged at 27000 g for 15 minutes. The precipitate washed three times with buffer (centrifuged at 27000 g for 10 minutes). The washed precipitate homogenized in 20 ml of buffer and incubated in a water bath (37oC) for 30 min to remove endogenous GABA, and then centrifuged 10 min at 27000 g. Then the sediment homogenized in buffer and centrifuged 10 minutes at 27000 g. The final precipitate resuspension in 30 ml of buffer and this drug is frozen and stored at -20oC.

Analysis: Preparation of membranes thawed and Antigua homogenizer (Ultra-Turrax, and centrifuged 10 min at 27000 g. The final precipitate resuspended in 50 mm Tris-citrate, pH 7,1 (500 ml buffer per 1 g of original tissue) and then used to determine binding. Aliquots of 0.5 ml of tissue preparation is added to 25 μl of test solution and 25 μl of3H-FNM (final concentration 1 nm), mixed and incubated for 40 minutes with 2oC. non-specific binding determine using clonazepam (final concentration 1 μm). After incubation the sample add 5 ml ice buffer and immediately pour them on under suction fiberglass filters Whatman GF/C and immediately washed them with 5 ml ice buffer. Radioactivity on the filters quantitatively determined by conventional liquid scintillation counting. Specific binding is the total binding minus nonspecific binding.

The test result is calculated as IR50(concentration in nm, at which the test compound inhibits specific binding3H-FNM 50%).

The test results obtained with selected compounds of the present invention, readily available from the table. 7.

Penilesecrets (PTZ, Sigma) renderation cramping is a sign of drugs, effective against different forms of epilepsy. The compound of the present invention in small doses inhibit convulsions, which the reserve calls in mice.

Example 38

Biological activity

Inhibition of binding3H-flunitrazepam ([3N]FNM) in vivo

[3N]FNM can be used for research tagging receptors in vivo in mice. The accumulation associated with [3H]FNA occurs throughout the brain, because GABAANDreceptors present in him widely. Specific binding of [3H] -FNA can be partially or completely prevent the simultaneous or prior the introduction of pharmacologically active benzodiazepines or some benzodiazepine-like compounds.

Method: All the tested substances are solutions prepared in 10% Tween 80. In groups of three female NMRI mice (25 g) animals injected intravenously through the tail vein of 5.0 MCI of [3H]-FNM in 0.2 ml of saline. 15 minutes after the introduction of [3H]-FNM intravenously injecting the test substance. 20 minutes after the introduction of [3H] -FNM mice slaughtered by decapitation, large cerebral hemispheres quickly cut and using the Ohm 1 ml immediately filtered through glass fiber filters GF/C and washed twice with portions of 5 ml ice buffer.

Radioactivity on the filters and 200 ml of homogenate quantify the conventional scintillation counting. The group is not exposed to mice serve as a control.

To determine nonspecific binding groups of mice for 10 minutes prior to the introduction of [3H] -FNM intravenous clonazepam (25 mg/kg) intraperitoneally. Specific binding is binding in the control minus binding in mice receiving clonazepam.

Results: On the basis of the curves of binding dose-dependent gain values of the ED50. These results show that the compounds of the present invention possess very favorable kinetic properties.

1. Chemical compound represented by the General formula I

< / BR>
where denotes the number 0, 1, 2 or 3;

R1represents an alkyl group, phenyl group or a monocyclic heterocyclic group containing as the heteroatom N or O, and these groups may be substituted once or more than once, by substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyano, amino and nitro; or R1represents cyano or a group of formula-ALK is= N-OR2where m denotes the number 0, 1, 2 or 3; R2represents hydrogen, alkyl, phenyl, benzyl, 5 - or 6-membered heterocyclic group, which 5 - or 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R2may represent a group of the formula -(CH2)q-NR4R5, -(CH2)q-CON(R4R5), -(CH2)q-CO2R4or-alkyl-CO2R4where R4and R5independently represent hydrogen or alkyl, and q represents the number 0, 1, 2 or 3;

R3represents hydrogen or alkyl;

R11represents a group of General formula-CO2-R9where R9represents alkyl; or R9can represent a 6-membered heterocyclic group, and this 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R9represents a group of General formula-alkyl-N(R10R12), where R10and R12independently represent hydrogen or alkyl; or R11represents a group of General formula II

< / BR>
where n denotes the number 0, 1, 2 or 3;

R' and R" together with the atom is licencee ring can contain as a ring member, one oxygen atom and/or one additional nitrogen atom; heterocyclic ring with the number of members from 5 to 7, formed by R' and R" may be substituted once or more than once by a group of the formula -(CH2)pX, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, hydroxyl, alkyl or alkenyl, and these alkyl and alkenyl can be substituted once or more than once by a group of the formula-CO2R6; or X represents a group of formula-CO-R6, -CO2-R6or-CON-R6R7where R6and R7independently represent hydrogen or alkyl;

or R11may represent a group of General formula III

< / BR>
where n denotes the number 1;

R' represents hydrogen or alkyl;

R' "and R" 'together with the atoms to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member one chain-CH= CH-; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed R' "and R" " may be substituted once or more than once by a group of the formula -(CH2)pX, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, alkyl,

or farmaceuticas who manage a tert-butyl.

2. Chemical compound under item 1, represented by the General formula I

< / BR>
where denotes the number 0, 1, 2 or 3;

R1represents a C3-7cycloalkyl, phenyl group or a monocyclic heterocyclic group containing as the heteroatom N or O, and these groups may be substituted once or more than once, by substituents selected from C1-8of alkyl, C3-7cycloalkyl; or R1represents cyano or a group of the formula-C1-8alkyl-CO2R2WITH2-6alkenyl-CO2R2, -CO-R2, -CO2(CH2)mR2or-C(R3)= N-OR2where m denotes the number 0 or 1; R2represents hydrogen, C1-8alkyl, C3-7cycloalkyl, benzyl, 5-or 6-membered heterocyclic group, which 5 - or 6-membered heterocyclic group may be substituted once or more than once C1-8by alkyl; or R2can independently represent a group of the formula -(CH2)q-NR4R5, -(CH2)q-CON(R4R5), -(CH2)q-CO2R4or-C1-8alkyl-CO2R4where R4and R5independently represent a1-8alkyl; and q denotes the number of the soup of the formula-CO2-R9where R9represents a C1-8alkyl, or R9can represent a 6-membered heterocyclic group, and this 6-membered heterocyclic group may be substituted once or more than once C1-8the alkyl, or R9represents a group of General formula-alkyl-N(R10R12), where R10and R12independently represents a C1-8alkyl or C3-7cycloalkyl;

or R11represents a group of General formula II

< / BR>
where n represents the number 0, 1 or 2;

R' and R" together with the N atom to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member, one oxygen atom and/or one additional nitrogen atom; and a heterocyclic ring with the number of members from 5 to 7, formed by R' and R" may be substituted once or more than once by a group of the formula -(CH2)pX, where p denotes the number 0, 1 or 2; X represents hydrogen, hydroxy, C1-8alkyl or C2-6alkenyl, and these C1-8alkyl, C3-7cycloalkyl and C2-6alkenyl can be possibly substituted by one or more than one RA is P>R7where R6and R7independently represent hydrogen or C1-8alkyl, C3-7cycloalkyl;

or R11may represent a group of General formula III

< / BR>
where n denotes the number 1;

R' represents a C1-8alkyl;

R' "and R" 'together with the atoms to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member one chain-CH= CH-; and a heterocyclic ring with the number of members from 5 to 7, formed R' "and R" " may be substituted once or more than once by a group of the formula -(CH2)pX, where p denotes the number 0 or 1; X represents a hydrogen or C1-8alkyl;

or its pharmaceutically acceptable salt.

3. Chemical compound on PP. 1 and 2, where o denotes 0,1represents cyano, phenyl group, fornillo group, tetrahydrofuranyl group, isoxazolyl group or oxadiazolyl group, or R1represents a C1-4alkenylphenol group, substituted CO2-C1-4the alkyl, or R1represents a group of formula-CO2R2and in this formula, R1-3alkyl group; or R2may represent a group of the formula -(CH2)q-NR4R5or -(CH2)q-CO-NR4R5and , in these formulas, q means the number 0, 1 or 2; R4and R5each independently represents hydrogen or C1-4alkyl group; or R1may represent a group of the formula-C(R3)= N-OR2and in this formula, R3and R4each independently represents hydrogen or C1-4alkyl group; or R1represents a group of formula-C(R3)= N-OR4aand in this formula, R3represents hydrogen or C1-4alkyl group, and R4arepresents hydrogen, C1-4alkyl group or a C1-4alkyl-CO2-C1-4alkyl group.

4. Chemical compound on PP. 1 and 2, where denotes the number 1 and R1represents a group of formula-CO2R4and in this formula, R4represents a C1-4alkyl group.

5. Chemical compound under item 3, where denotes the number 0 and1is a 3-furanyl, 3-tetrahydro-furanyl, 5-isoxazolyl, 3-cycloprop>)NO-isopropyl, -C(CH3)NO-tert-butyl, -C(CH3)NR-CH2CO2CH3- (CH3)NR-CH2CO2WITH2H5THE SRPA-C(CH3)2CO2CH3- (CH3)NR-C(CH3)2CO2CH3,

- (CH3)NR-C(CH3)2CO2WITH2H5, -CO2CH3, -CO2WITH2H5, -CO2CH(CH3)2,

-CO2(CH2)2N(CH3)2, -CO2-CH2-cyclopropyl or (N, N-diethyl-carboxamido)-methyloxycarbonyl.

6. Chemical compound under item 4, where the means of the number 1 and1represents-CO2CH3, -CO2WITH2H5.

7. Chemical compound according to any one of paragraphs. 1-6, where R11represents a C1-4alkyl-oxycarbonyl group, N, N-di-(C1-4alkyl)-amino-C1-4alkyl-oxycarbonyl group, or piperidinyl group, piperidinyl-oxycarbonyl group, pyrrolidinyl group, pyrrolidinyl-C1-3alkyl group, piperazinilnom group, morpholinyl group, homopiperazine group, tetrahydropyranyloxy group, picolyl-oxycarbonyl group, and these groups may be substituted one or bol is dicarbonyl-C1-4of alkyl, acetyl or N, N-di-C1-4alkyl-carboxamido-C1-4the alkyl.

8. Chemical compound under item 7, where R11is a 1-piperidinyl, 1-pyrrolidinyl, 4-methyl-1-piperazinil, 1-methyl-3-piperidinyl, (1-methyl-4-piperidinyl)oxycarbonyl, (1-methyl-3-piperidinyl)oxycarbonyl, 2-picolyl-oxycarbonyl, 3-picolyl-oxycarbonyl, 4-morpholinyl, 1-acetyl-4-piperazinil, 4-(2-hydroxyethyl)-piperazine-1-yl, (1-pyrrolidinyl)methyl, 4-methylhomopiperazine-1-yl, 1-methyl-1,2,3,6-tetrahydropyran-5-yl, 4-(N, N-diethyl-carboxamidates)-piperazine-1-yl, 4-(methoxycarbonylmethyl)-1-piperazinil, 4-(ethoxy-carbonylmethyl)-1-piperazinil, 4-(diethylcarbamyl-methyl)-piperazine-1-yl, 4-(2,2-bis(etoxycarbonyl)ethynyl)piperazine-1-yl, 4-(2-methoxycarbonyl-ethynyl)piperazine-1-yl, methoxycarbonyl, etoxycarbonyl or 2-(N, N-dimethylamino)etoxycarbonyl.

9. Chemical compound under item 1, which is a

5-cyano-1-(3-(1-piperidyl)phenyl)benzimidazole (compound 3A);

5-cyano-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 3A2);

5-cyano-1-(3-(4-methyl-1-piperazinil)phenyl)benzimidazole (compound 3A3);

5-cyano-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole (compound 3A4);

5-cyano-1-(3-(4-m is (compound 3b1);

the reaction of 5-formyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 3b2);

the reaction of 5-formyl-1-(3-(4-methyl-1-piperazinil)phenyl)benzimidazole (compound 3b3);

the reaction of 5-formyl-1-(3-(1-methyl-3-piperidinyl)phenyl)benzimidazole (compound 3b4);

On-isopropoxy 5-formyl-1-(3-(1-piperidinyl)phenyl)-benzimidazole (compound 3b);

On-methyloxime 5-formyl-1-(3-(1-piperidinyl)phenyl)benzimidazole (compound 3G);

the reaction of 5-acetyl-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (compound 3D1);

the reaction of 5-acetyl-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)phenylbenzimidazol (compound 3D2);

On-acyloxy 5-acetyl-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)phenylbenzimidazol (compound 3e1);

On-acyloxy 5-acetyl-1-(3-(4-methylpiperazin-1-yl)phenyl) benzimidazole (compound 3E2);

On-acyloxy 5-acetyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 3E3);

On-acyloxy 5-acetyl-1-(3-(4-methylhomopiperazine-1-yl)benzimidazole (compound 3E4);

On-acyloxy 5-acetyl-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 3E5);

On-acyloxy 5-acetyl-1-(3-(1-piperidinyl)phenyl)benzimidazole (compound 3E6);

On-acyloxy 5-acetyl-1-(3 is rehydrated-5-yl)-phenyl)benzimidazole (compound 3E8);

On-isopropoxy 5-acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound g1);

On-isopropoxy 5-acetyl-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)-phenyl)benzimidazole (compound g2);

On-isopropoxy 5-acetyl-1-(3-(4-acetylpiperidine-1-yl)phenyl)benzimidazole (compound g3);

O-tert-butyloctyl 5-acetyl-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)-phenyl)benzimidazole (compound 3C);

5-(3-furanyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 3i1);

5-(3-furanyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 3i2);

5-(3-furanyl)-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)phenyl)benzimidazole (compound 3i3);

5-(3-furanyl)-1-(3-(4-(diethylcarbamoyl)piperazine-1-yl)-phenyl)benzimidazole (compound 3i4);

5-phenyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 3K1);

5-phenyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 3K2);

5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (compound 3);

5-tert-butyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 3M);

5-(etoxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (soy is R>
5-(etoxycarbonyl)-1-(3-(4-(2-hydroxyethyl)piperazine-1-yl)phenyl)benzimidazole (compound 4A3);

5-(etoxycarbonyl)-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (compound 4A4);

5-(etoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)-phenyl)benzimidazole (compound 4A5);

5-(etoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)-phenyl)benzimidazole (compound 4A6);

5-(2-(etoxycarbonyl)ethynyl)-1-(3-(1-piperidyl)phenyl)benzimidazole (compound 4B1);

5-(2-(etoxycarbonyl)ethynyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4B2);

5-(2-(etoxycarbonyl)ethynyl)-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound 4B3);

5-(2-(methoxycarbonyl)ethynyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4B1);

5-(2-(methoxycarbonyl)ethynyl)-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound 4B2);

5-(methoxycarbonyl)-1-(3-(1-acetylpiperidine-3-yl)phenyl)benzimidazole (compound 4G1);

5-(methoxycarbonyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4G2);

4-(methoxycarbonyl)-1-(3-(4-methoxycarbonylmethyl)piperazine-1-yl)benzimidazole (compound 4G3);

5-(methoxycarbonyl)-1-(3-(4-(deathline)phenyl)benzimidazole (compound 4G5);

5-(ISO-propylenecarbonate)-1-(3-(1-piperidinyl)phenyl)benzimidazole (compound 4D1);

5-(ISO-propylenecarbonate)-1-(3-(1-pyrrolidinyl)phenyl)benzimidazole (compound 4D2);

5-(ISO-propylenecarbonate)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound 4D3);

5-(ISO-propylenecarbonate)-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound 4D4);

5-(cyclopropanecarbonyl)-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (compound 4E);

5-(benzyloxycarbonyl)-1-(3-(1-methylpiperidin-3-yl)phenyl) benzimidazole (compound g);

5-(3-ecolological)-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound s);

5-(2-((dimethylamino)ethyl)oxycarbonyl)-1-(3-(1-acetylpiperidine-4-yl)-phenyl)benzimidazole (compound 4I);

5-((2-(dimethylamino)ethyl)oxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)-piperazine-1-yl)phenyl)benzimidazole (compound 4K);

5-((N, N-diethylcarbamyl)methyloxycarbonyl)-1-(3-(4-ethoxycarbonylmethyl)-piperazine-1-yl)phenyl)benzimidazole (compound 4 l1);

5-((N, N-diethylcarbamyl)-methyloxycarbonyl)-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (compound 4 l2);

5-(methoxycarbonylmethyl)-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (with>);

5-(methoxycarbonyl)-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound 4m3);

5-(etoxycarbonyl)-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound 4m4);

5-((1-methylpyrrolidine-2-yl)methoxycarbonyl)-1-(3-(4-(ethoxycarbonylmethyl)-piperazine-1-yl)phenyl)benzimidazole (compound 4h);

On-isopropoxy 5-acetyl-1-(3-(1-methyl-4-piperidinylcarbonyl)-phenyl)benzimidazole (compound 5a1);

O-isopropoxy 5-acetyl-1-(3-(1-methyl-3-piperidinylcarbonyl)-phenyl)benzimidazole (compound 5A2);

On-isopropoxy 5-acetyl-1-(3-(2-ecolological)phenyl)benzimidazole (compound 5A3);

O-(etoxycarbonyl-methyl)-oxime 5-acetyl-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (compound 5B1);

O-(methoxycarbonylmethyl)-oxime 5-acetyl-1-(3-(1-methylpiperidin-3-yl)-phenyl)benzimidazole (compound 5B2);

O-(methoxycarbonyl-(dimethyl)methyl)-oxime 5-acetyl-1-(3-(1-methylpiperidin-3-yl)phenyl)benzimidazole (compound 5B3);

O-(methoxycarbonylmethyl)-oxime 5-acetyl-1-(3-(4-(2-hydroxyethyl)-piperazine-1-yl)phenyl)benzimidazole (compound 5B1);

O-(ethoxycarbonylmethyl)-oxime 5-acetyl-1-(3-(4-(2-hydroxyethyl)-piperazine-1-yl)phenyl)benzimidazole (compound 5 is idazole (connection 5V3);

the reaction of 5-acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)phenyl)benzimidazole (compound 5g1);

On-acyloxy 5-acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperidine-1-yl)-phenyl)benzimidazole (compound 5g2);

O-(methoxycarbonyl-(dimethyl)methyl)-oxime 5-acetyl-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (compound 5D1);

O-(methoxycarbonyl-methyl)-oxime 5-acetyl-1-(3-(1-acetylpiperidine-4-yl)phenyl)benzimidazole (compound 5D2);

O-(methoxycarbonylmethyl)-oxime 5-acetyl-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound 5D3);

On-isopropoxy 5-acetyl-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)phenyl)benzimidazole (compound 5e1);

On-isopropoxy 5-acetyl-1-(3-(4-(2,2-bis(etoxycarbonyl)ethynyl)-piperazine-1-yl)phenyl)benzimidazole (compound 5e2);

O-(methoxycarbonyl-(dimethyl)methyl)-oxime 5-formyl-1-(3-(4-methylpiperazin-1-yl)phenyl)benzimidazole (compound g1);

O-(methoxycarbonyl-(dimethyl)methyl)-oxime 5-formyl-1-(3-(4-morpholinyl)phenyl)benzimidazole (compound g2);

5-(5-isoxazolyl)-1-(3-(methoxycarbonyl)phenyl)benzimidazole (compound 6a1);

5-(5-isoxazolyl)-1-(3-(etoxycarbonyl)phenyl)benzimidazole (compound 6ais ylmethyl)piperazine-1-yl)phenyl)benzimidazole (compound 6b2);

5-phenyl-(3-(2-ecolological)phenyl)benzimidazole (compound 6b3);

5-phenyl-1-(3-(3-ecolological)phenyl)benzimidazole (compound 6b4);

5-phenyl-1-(3-(1-methylpiperid-3-jocstarbunny)phenyl)benzimidazole (compound 6b5);

5-phenyl-1-(3-((1-methylpiperid-4-yl)oxycarbonyl)phenyl)benzimidazole (compound 6b6);

5-(3-furanyl)-1-(3-(etoxycarbonyl)phenyl)benzimidazole (compound 6b1);

5-(3-tetrahydrofuranyl)-1-(3-(etoxycarbonyl)phenyl)benzimidazole (compound 6b2);

5-(3-furanyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)phenyl)benzimidazole (compound 6b3);

5-(3-furanyl)-1-(3-(4-(tert-butoxycarbonyl)piperazine-1-yl)phenyl)benzimidazole (compound 6b4);

5-(3-furanyl)-1-(3-(4-(ethoxycarbonylmethyl)piperazine-1-yl)phenyl)benzimidazole (compound 6b5);

5-(3-furanyl)-1-(3-(4-(2,2-bis(etoxycarbonyl)ethynyl)piperazine-1-yl)-phenyl)benzimidazole (compound 6b6);

5-(3-furanyl)-1-(3-(4-(2-(methoxycarbonyl)ethynyl)piperazine-1-yl)-phenyl)benzimidazole (compound 6b7);

5-(3-furanyl)-1-(3-(2-(dimethylamino)ethoxycarbonyl)phenyl)benzimidazole (compound 6b8);

5-acetyl-1-[3-(1-methyl-1,2,3,6-tetrahydropyran-5-yl)phenyl] benzimidazo is almost acceptable salt.

10. Pharmaceutical composition having the property modulator of GABAANDreceptors containing an effective amount of a chemical compound according to any one of paragraphs. 1-9 or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient, carrier or diluent.

11. Chemical compound according to any one of paragraphs. 1-9 used for preparation of drugs for the treatment of a disorder or disease of a living animal body, including a human, with a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous system.

12. Chemical compound on p. 11, which disorder or disease is sensitive to positive modulation of GABAAND-receptor complex of the Central nervous system.

13. Chemical compound on p. 11, which disorder or disease is a anxiety, sleep disorders, anesthesia, memory disorders, epilepsy or any other convulsive disorder.

14. The method of treatment of a disorder or disease of a living animal body, including a human, with a disorder or disease responsive to modulation of GABAAND-receptor complex C is I according to any one of paragraphs. 1-8.

 

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