New derivatives of benzimidazole containing these compounds in pharmaceutical compositions

 

(57) Abstract:

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where R represents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, R represents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5-membered monocyclic heterocyclic group which contains in its structure one or more than one heteroatom, representing groups, consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and R represents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted acyl. The invention also relates to a method of treatment and pharmaceutical compositions for the modulation of GABAAND-receptor complex on the basis of these compounds. The technical result is to provide new compounds and farmaceuticas the status. 3 S. and 13 C.p. f-crystals, 10 PL.

The present invention relates to new derivatives of benzimidazole, pharmaceutical compositions containing these compounds and methods of treatment using them.

Compounds according to the invention are useful in treating diseases and disorders of the Central nervous system, which are sensitive to modulation of GABAAND-receptor complex, and, in particular, for the induction and maintenance of anaesthesia, sedation and muscle relaxation, as well as to suppress febrile convulsions.

Compounds according to the invention can also be used by veterinarians.

BACKGROUND OF THE INVENTION

Agents that bind or interact with modulatory sites GABAANDreceptor complex, such as, for example, benzodiazepine receptor, can have a synergistic effect on the action of GABA, i.e. to show a positive modulatory effect on the receptor (agonists, partial agonists), a debilitating effect on the action of GABA, to realize the negative modulation of receptor inverse agonists, partial inverse agonists), or they can block the effect of both agonists and inverserelationship, hypnotic, sedative, anxiolytic and/or anticonvulsant action, while inverse agonists have prostorage, protivoblastomna entries or action. Compounds which possess anxiolytic effect, but have reduced muscle-relaxing, hypnotic and sedative effect or not have it at all, are characterized as partial agonists. Partial inverse agonists are useful as stimulants of cognition".

Full agonist at the benzodiazepine receptor are useful as anesthetics. However, many of the pharmaceuticals currently available as anesthetics and especially preanesthetic have greater residual effect, and long Wake-up time, which requires careful monitoring of the patient. Anesthetics with a long half-life can also create difficulties in cases of overdose, such as prolonged respiratory depression. In addition, some widely used drugs cannot be used for anestesiologia children, as there have been reports of deaths in children after long-term use of propofol (Propofol). A number of anesthetic is P>

A well-known anesthetic propofol injected into a mixture of soy oil, glycerin and purified egg fosfatados that can support the growth of bacteria. It was noted [Wiklund et al. The New England Journal of Medicine 1997, 337 (16), 1132-1141], introduction bacterial contaminated propofol caused sepsis and death. Further, compounds with long half-life in vivo create problems associated with their accumulation during and after long-term treatment, for example with the introduction of the patient connected to the ventilator. A short elimination half-life, when compounds are metabolized to inactive metabolites, make it possible to predict the correlation of dose and duration of pharmacological effect.

Ideally anesthetic action should occur soon after bolus injection or infusion connection. Rapid onset of action reduces the period of anxiety and distress experienced by the patients before surgery.

Patients suffering from severe and prolonged epileptic seizures, which currently treat large quantities of sedatives, such as benzodiazepines, will benefit the treatment SS="ptx2">The preferred route of administration is intravenous injection or infusion. Anesthetic compounds are preferably water-soluble.

EP 616807 describes benzimidazole compounds for use as ligands of the benzodiazepine receptor.

WO 96/33194, WO 96/33191 and WO 96/33192 describe benzimidazole compounds having affinity to the GABA-receptor complex.

WO 98/34923 describes derivatives of phenylbenzimidazol as ligands of the GABAA receptor complex.

WO 98/17651 describes benzimidazole compounds for applications, such as anesthetics. However, as described in this application connections exceed the previously described connections.

SUMMARY OF THE INVENTION

The objective of the invention is to provide new compounds which are useful as anesthetics and/or preanesthetic, sedatives, muscle relaxants, as well as for the treatment of febrile convulsions in children, epileptic status, for use in patient connected to the ventilator, as well as for veterinary use.

In the first aspect of the invention proposed benzimidazole derivative represented on predstavljaet a group of formula -(ALK)q-R1,

where

(Ala) is an alkyl, alkenyl or quinil,

q is 0 or 1,

R1represents a group of formula-CO2R2where

R2represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, toolboxitem, alkyl-heterocycle, or-alkyl-NR3R4,

where

"heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl and a group of the formula -(alkyl)p-SP, -(alkyl)p-aryl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-R5,

moreover, in these formulas, R, s and t independently of each other 0 or 1,

"heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl, the si or a group of the formula-NR6R7or-O-alkyl-NR6R7,

moreover, in these formulas

R6and R7independently of one another represent hydrogen, alkyl, cycloalkyl or mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl, or

R6and R7together with the nitrogen to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl; and

R3and R4independently of one another represent hydrogen, alkyl or cycloalkyl, or

R3and R4together with the nitrogen to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl; or

Is,

R12represents hydrogen, alkyl, alkoxy or hydroxyalkyl, and

R13represents hydrogen, hydroxy, alkyl, alkoxy or hydroxyalkyl; or

R1represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl and a group of the formula -(alkyl)p-aryl, -(alkyl)p"heterocycle", -(alkyl)p-SP or -(alkyl-CO2)s-(alkyl)t-R5,

moreover, in these formulas

R, s and t independently of each other 0 or 1,

"heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl,

R5represents a hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl, thiolcarbamate or a group of the formula-NR6R7or-O-alkyl-NR6R7,

moreover, in these formulas

R6and R7clichesque group, which is possibly substituted by one or more than one substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl, or

R6and R7together with the nitrogen atom to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl; and

R" represents -(alkyl)o"heterocycle" or -(alkyl)about-CO2-(alkyl)u"heterocycle",

where o and u independently from each other 0 or 1, and

"heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl and a group of the formula -(alkyl)p-SP, -(alkyl)p-aryl, -(alkyl)p-aralkyl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p-CO2-aryl, -(alkyl)p-CO2-aralkyl, -(alkyl)UP>5,

moreover, in these formulas

R, s and t independently of each other 0 or 1,

"heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl,

R5represents hydrogen, hydroxy, alkyl, alkoxy, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyl, toolboxitem, thiolcarbamate or a group of the formula-NR6R7or-O-alkyl-NR6R7,

moreover, in these formulas

R6and R7independently of one another represent hydrogen, alkyl, cycloalkyl or mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl, or

R6and R7together with the nitrogen to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than adaxially, carboxyl and acyl; or

R represents -(alkyl)m-CO2R8,

where

m is 0 or 1, and

R8represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, toolboxitem or a group of the formula -(alkyl)p-NR9R10,

where

p is 0 or 1, and

R9and R10independently of one another represent hydrogen, alkyl, cycloalkyl or mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl, or

R9and R10together with the nitrogen atom to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl.

In the second aspect of the invention proposed pharmaceutical composition comprising a therapeutically effective amount of the benzimidazole derivative according to the invention and the known carrier, excipient or diluent.

In the third aspect of the invention the application of the benzimidazole derivative according to the invention for the manufacture of medicinal products for the treatment, prevention or relief of a disease or disorder, or condition that is sensitive to modulation of GABA-a receptor complex, in a mammal, including humans.

In the fourth aspect of the invention, a method for treating, preventing or alleviating disease or disorder, or condition that is sensitive to modulation of GABA-a receptor complex, the animal, including human, in which such animal if necessary, enter a therapeutically effective amount of the benzimidazole derivative according to the invention.

Other objects of the invention will be obvious to a person skilled from the following detailed description and working examples.

DETAILED DESCRIPTION OF THE INVENTION

Derivatives of benzimidazole

In the first aspect of the invention proposed new derivatives of benzimidazole. Derivatives of benzimidazole according to the invention represented by the General formula (I)

or their pharmaceutically acceptable salts,

Gda alkyl, alkenyl or quinil,

q is 0 or 1,

R1represents a group of formula-CO2R2where

R2represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, toolboxitem, alkyl-heterocycle, or-alkyl-NR3R4,

where

"heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl and a group of the formula -(alkyl)p-SP, -(alkyl)p-aryl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl),-R5,

moreover, in these formulas

R, s and t independently of each other 0 or 1,

"heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl,

R5represents a hydroxy, alkoxy, hydroxy>,

moreover, in these formulas

R6and R7independently of one another represent hydrogen, alkyl, cycloalkyl or mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl, or

R6and R7together with the nitrogen to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl; and

R3and R4independently of one another represent hydrogen, alkyl or cycloalkyl, or

R3and R4together with the nitrogen to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl; or

R1is groupcard, alkyl, alkoxy or hydroxyalkyl, and

R13represents hydrogen, hydroxy, alkyl, alkoxy or hydroxyalkyl, or

R1represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl and a group of the formula -(alkyl)p-aryl, -(alkyl)p"heterocycle", -(alkyl)p-SP or -(alkyl-CO2)s-(alkyl),-R5,

moreover, in these formulas

R, s and t independently of each other 0 or 1,

"heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl,

R5represents a hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl, thiolcarbamate or a group of the formula-NR6R7or-O-alkyl-NR6R7,

moreover, in these formulas

R6and R7independently of one another represent hydrogen, alkyl, who than once substituents, selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl, or

R6and R7together with the nitrogen to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl; and

R represents -(alkyl)about"heterocycle" or -(alkyl)about-CO2-(alkyl)u"heterocycle",

where o and u independently from each other 0 or 1, and "heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl and a group of the formula -(alkyl)p-SP, -(alkyl)p-aryl, -(alkyl)p-aralkyl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p-CO2-aryl, -(alkyl)p-CO2-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s

"heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl,

R5represents hydrogen, hydroxy, alkyl, alkoxy, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyl, toolboxitem, thiolcarbamate or a group of the formula-NR6R7or-O-alkyl-NR6R7,

moreover, in these formulas

R6and R7independently of one another represent hydrogen, alkyl, cycloalkyl, mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl, or

R6and R7together with the nitrogen to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyl

where m is 0 or 1, and

R8represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, toolboxitem or a group of the formula -(alkyl)p-NR9R10,

where

p is 0 or 1, and

R9and R10independently of one another represent hydrogen, alkyl, cycloalkyl or mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl, or

R9and R10together with the nitrogen to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl.

In the preferred embodiment of the benzimidazole derivative according to the invention is represented by formula I, where R represents

2-(4-acetylpiperidine-1-yl)-ethoxy-carbonyl;

pyridine-2-yl-methoxy-carbonyl;

1-methyl-2-pyrrolidyl-methoxy-carbonyl or

3,5-di is Azola is a

2-(1-acetyl-4-piperazinil)-ethyl 3-(5-(3-furanyl)-1-benzimidazolyl)-benzoate;

1-methyl-2-pyrrolidinyl 3-(5-(3-furanyl)-1-benzimidazolyl)-benzoate

or their pharmaceutically acceptable salt.

In another preferred embodiment of the benzimidazole derivative according to the invention is a compound of formula I, where

R1represents a group of formula-CO2R2where

R2represents alkyl, hydroxyalkyl, alkoxyalkyl, toolboxitem, alkyl-N(alkyl)2; or

R1represents a group of the formula

where R12represents alkyl, and

R13represents a hydroxy or alkoxy; or

R1represents fornillo group, pyrazolidine group, isoxazolyl group, oxazolidinyl group, oxadiazolyl group.

In a more preferred embodiment of the

R1represents a group of formula-COOH, -CO2-CH3, -CO2-C2H5, -CO2-CH2-CH(OH), -CO2(CH2)2OCH3, -CO2(CH2)2S3, -CO2(CH2)2SC2H5or-CO2(CH2<>2represents methyl or ethyl, and

R13represents hydroxy, methoxy or ethoxy; or

R1represents a 2 - or 3-fornillo group.

In the most preferred embodiment of the benzimidazole derivative is a

2-(3,5-dimethyl-1-piperazinil)-ethyl 3-(5-acetylbenzoate-1-yl)-benzoyloxy; or

2-(2-pyridyl)-methyl 3-(5-acetylbenzoate-1-yl)-benzoyloxy; or their pharmaceutically acceptable salt.

In another preferred embodiment of the benzimidazole derivative according to the invention is represented by formula I, where

R represents a group of formula -(alkyl)about"heterocycle", where o is 0 or 1, and

"heterocycle" represents fornillo group, 2H-fornillo group, 4H-fornillo group, thienyl group, pyrrolidino group, 2H-pyrrolidino (pyrrolidino) group, 4H-pyrrolidino (pyrrolidinyloxy) group, imidazolidinyl group, oxazolidinyl group, 2H-oxazolidine (oxazolidinone) group, 4H-oxazolidine (oxazolidinyl) group, isoxazolyl group, 2H-isoxazolidine (isoxazolyl) group, 4H-isoxazolidine (isoxazolidinone) group, oxadiazolyl g is molinillo group, thiomorpholine group, pyridinyl group, piperidinyl group, pieperazinove group, homopiperazine group or tetrazolyl group, and these heterocyclic groups may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, oxo, acyl, alkyl-CO2H, alkyl-CO2-alkyl, -(alkyl)p-CO2-aryl, -(alkyl)p-CO2-aralkyl and alkyl-CO2-alkyl-CONR6R7,

where R6and R7independently from each other represent hydrogen or alkyl.

In a more preferred embodiment of the

"heterocycle" represents pyrrolidin-1-yl, piperazine-1-yl, homopiperazin-1-yl, imidazol-1-yl, pyridine-4-yl, 4H-pyridin-4-yl, in particular 1,2,5,6-tetrahydro-pyridin-4-yl, piperidine-4-yl, 2H-isoxazol-3-yl, in particular 4,5-dihydro-isoxazol-3-yl.

In another preferred embodiment of the benzimidazole derivative according to the invention is represented by formula I, where R

4-etoxycarbonyl-1-imidazolyl;

4-methoxycarbonyl-1-imidazolyl;

5-((N,N-diethylcarbamoyl)-methoxy-carbonyl-methyl)-4,5-dihydroisoxazole-3-yl;

5-((N,N-dimethylcarbamoyl)-methoxy-carbonyl-methyl/P>

1-ethyl-1,2,5,6-tetrahydropyridine-4-yl;

4-(2-oxazolidinone-5-yl)-methyl)-1-piperazinil;

4-(5-metronidazol-3-yl)-methyl)-1-piperazinil;

4-(3,5-dimethylisoxazol-4-yl)-methyl)-1-piperazinil;

4-(2-oxo-tetrahydrofuran-3-yl)-1-piperazinil;

4-(2-chloro-5-thienyl)-methyl-1-piperazinil; or

(1-methyl-2-pyrrolidyl)-methyl-carbonyl.

In the most preferred embodiment of the benzimidazole derivative according to the invention is a

2-methoxyethyl 1-(3-(4-methoxycarbonyl-1-imidazolyl)-phenyl)-benzimidazole-5-carboxylate;

(N,N-diethylcarbamoyl)methyl 2-(3-[3-(5-etoxycarbonyl-1-benzimidazolyl)-phenyl]-4,5-dihydroxysuccinic-5-yl)-acetate;

methyl 1-(3-(1-imidazolidinyl)-phenyl)-benzimidazole-5-carboxylate;

2-(methylthio)-ethyl 1-(3-(1-imidazolidinyl)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-(1-methyl-5-tetrazolyl)methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(1-ethyl-1,2,5,6-tetrahydropyridine-4-yl)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-(2-oxazolidinone-5-yl)-methyl)-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-(5-metaloxide the azole-4-yl)-methyl)-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-(2-oxo-tetrahydrofuran-3-yl)-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-(2-chloro-5-thienyl)-methyl)-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

5-(3-furanyl)-1-(3-(4-methoxycarbonyl-1-imidazolyl)-phenyl)-benzimidazole;

or

N,N-diethylcarbamoyl 2-(3-(3-(5-(3-furanyl)-1-benzimidazolyl)-phenyl)-4,5-dihydroisoxazole-5-yl)-acetate;

or their pharmaceutically acceptable salt.

In another preferred embodiment of the benzimidazole derivative according to the invention is represented by formula I, where

R represents a group of formula-CO2(alkyl)o"heterocycle",

where o is 0 or 1, and

"heterocycle" represents pyrrolidino group, 2H-pyrrolidino (pyrrolidino) group, 4H-pyrrolidino (pyrrolidinyloxy) group, imidazolidinyl group, oxazolidinyl group, isoxazolyl group, 2H-isoxazolidine (isoxazolyl) group, 4H-isoxazolidine (isoxazolidinone) group, oxadiazolyl group, pyridyloxy group, piperidinyl group, pieperazinove group or homopiperazine group, and these heterocyclic groups may be substituted by one or Bo the 2the alkyl and alkyl-CO2-alkyl-NR6R7where

R6and R7independently from each other represent hydrogen or alkyl.

In a more preferred embodiment of the benzimidazole derivative according to the invention is represented by formula I, where

R represents a group of the formula

in which o is 0 or 1,

n is 0, 1 or 2,

X represents N or CH,

Y represents O, NR11or CHR11,

where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl, or a group of the formula -(alkyl)p-SP, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-R5,

where R, s and t independently of each other 0 or 1,

"heterocycle" represents a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl, hydroxy, oxo, cyano, hydroxyalkyl, alkoxyalkyl, carboxyl and acyl,

R5or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas

R6and R7independently of one another represent hydrogen, alkyl, cycloalkyl or mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of alkyl and acyl, or

R6and R7together with the nitrogen to which they are attached, form a mono - or polycyclic heterocyclic group which may be substituted once or more than once, by substituents selected from the group consisting of alkyl and acyl, and

R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or

R represents a group of formula-CO2R8,

where R8represents an alkyl-NR9R10where

R9and R10together with the nitrogen to which they are attached, form a pyrolidine or pieperazinove group which may be substituted once or more than once, by substituents selected from the group consisting of alkyl and acyl.

In a more preferred embodiment is produced in ronil-methyl-3,5-dimethyl-1-piperazinil;

4-etoxycarbonyl-methyl-3,5-dimethyl-1-piperazinil;

4-methyl-3,5-dimethyl-1-piperazinil;

4-ethyl-3,5-dimethyl-1-piperazinil; or

3,5-dimethyl-1-piperazinil.

In the most preferred embodiment of the benzimidazole derivative according to the invention is a

2-methoxyethyl 1-(3-(4-ethoxycarbonylmethyl-3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methyl 1-(3-(4-ethoxycarbonylmethyl-3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-ethyl-3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate; or

2-(3,5-dimethyl-1-piperazinil)-ethyl 3-(5-acetylbenzoate-1-yl)-benzoyloxy;

or their pharmaceutically acceptable salt.

In yet another preferred embodiment of the benzimidazole derivative according to the invention is represented by formula I, where

R represents a group of the formula

in which o is 0 or 1,

n is 0, 1 or 2,

X substitutes a N or CH, and

Y represents NR11or CHR11where

R11PR is UB>p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl),-R5or -(alkyl)t-R5,

where R and t independently of each other 0 or 1, and

R5represents a hydroxy, alkoxy, NH2, NH(alkyl) or N(alkyl)2.

In a more preferred embodiment of the

R represents

4-(methoxy-carbonyl)-1-piperazinylmethyl;

4-(ethoxy-carbonyl)-1-piperazinylmethyl;

4-(methoxy-carbonyl-methyl)-1-piperazinil;

4-(ethoxy-carbonyl-methyl)-1-piperazinil;

4-(methoxy-carbonyl-methyl)-1-piperazinylmethyl;

4-(ethoxy-carbonyl-methyl)-1-piperazinylmethyl;

1-piperazinil;

1-piperazinil-methyl;

4-acetyl-1-piperazinil;

4-methyl-1-piperazinil;

4-ethyl-1-piperazinil;

1-methyl-4-piperidinyl;

1-acetyl-4-piperidinyl;

1-methyl-4-piperidyl;

1-acetyl-4-piperidyl;

4-tert-butoxycarbonylmethyl-1-piperazinil;

4-isopropoxycarbonyl-1-piperazinil;

4-carboxymethyl-1-piperazinil;

4-benzyl-1-piperazinil;

4-cyanomethyl-1-piperazinil;

4-benzyloxy-ethyl-1-pipemeter-1-piperazinil;

4-dimethylcarbamoyl-1-piperazinil; or

4-diethylcarbamoyl-1-piperazinil.

In the most preferred embodiment of the benzimidazole derivative according to the invention is a

2-methoxyethyl 1-(3-(4-ethoxy-carbonyl)-1-piperazinylmethyl)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-ethoxy-carbonyl-methyl)-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-carboxymethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-acetyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(1-methyl-4-piperidyl)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(1-acetyl-4-piperidyl)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-tert-butoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-ISO-propoxycarbonyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-[4-(3-(5-methoxycarbonylamino-1-yl)-phenyl)-1-piperazinil]-acetic acid;

2-(methylthio)-ethyl 1-(3-(4-methyl-1-piperazinil)-Hairdryer shall imidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-benzyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

methyl 1-(3-(4-cyanomethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-cyanomethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

methyl 1-(3-(4-benzyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-benzyloxyethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-ethyl-1-homopiperazine)-phenyl)-benzimidazole-5-carboxylate;

2-methyl 1-(3-(4-ethyl-1-homopiperazine)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-ethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl 1-(3-(4-(2-hydroxyethyl)-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

methyl 1-(3-(1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl 1-(3-(4-methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl 1-(3-(4-methoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl 1-(3-(4-ethoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-LASS="ptx2">2-methoxyethyl 1-(3-(4-methoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl 1-(3-(4-carbamoylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl 1-(3-(4-carbamoylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl 1-(3-(4-diethylcarbamoyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl 1-(3-(4-carboxymethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

5-(3-furanyl)-1-(3-((4-etoxycarbonyl-1-piperazinil)-methyl)-phenyl)-benzimidazole;

5-(3-furanyl)-1-(3-(1-ethoxy-carbonyl-methyl)-4-piperazinil)-phenyl)-benzimidazole;

5-(3-furanyl)-1-(3-(4-tert-butoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole;

5-(3-furanyl)-1-(3-(1-ethoxycarbonylmethyl-4-piperazinylmethyl)-phenyl)-benzimidazole;

5-(3-furanyl)-1-(3-(1-ethoxycarbonylmethyl-4-piperidyl)-phenyl)-benzimidazole;

5-(3-furanyl)-1-(3-(4-ethoxycarbonylphenyl-1-ylmethyl)-phenyl)-benzimidazole; or

5-(3-furanyl)-1-(3-(1-etoxycarbonyl-4-piperazinil)-phenyl)-benzimidazole;

or their pharmaceutically acceptable salt.

The definition of the substituents

In the context of the present invention is supplemented flax group refers to a monovalent saturated, a straight or branched hydrocarbon chain. The hydrocarbon chain preferably consists of one to eight carbon atoms (C1-8-alkyl), more preferably from one to six carbon atoms (C1-6-alkyl), including pentyl, isopentyl, neopentyl, tertiary of pentyl, hexyl and isohexyl. In the preferred embodiment, the alkyl is a1-4is an alkyl group, including butyl, isobutyl, secondary butyl and tertiary butyl. In the preferred embodiment of this invention, the alkyl is a1-3-alkyl group, which in particular may be the stands, ethyl, propylene or isopropyl.

In the context of this invention cycloalkyl group refers to a cyclic alkyl group, preferably containing from three to seven carbon atoms (C3-7-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of this invention Alchemilla group denotes a carbon chain containing one or more than one double bond, including dieny, triene and a polyene. In the preferred embodiment Alchemilla group according to the invention contains from two to six carbon atoms (C2-6alkenyl) and includes SEB is, s is atenilol, 1,2 - or 2,3-propanolol, or 1,2-, 2,3 - or 3,4-butanolom.

In the context of this invention Alchemilla group denotes a carbon chain containing one or more than one triple bond, including dieny, triinu and Polyany. In the preferred embodiment Alchemilla group according to the invention contains from two to six carbon atoms (C2-6-quinil) and includes at least one triple bond. In the preferred embodiment Alchemilla group according to the invention is atenilol, 1,2 - or 2,3-PROPYNYL, 1,2-, 2,3 - or 3,4-butanolom.

In the context of this invention alkoxyalkyl group refers to the group "alkyl-O-alkyl -, where the alkyl such as defined above.

In the context of this invention dialkoxybenzene group refers to the group "alkyl-S-alkyl, where alkyl such as defined above.

In the context of this invention alkoxyalkyl group refers to the group "alkyl-O-alkyl, where alkyl such as defined above.

In the context of this invention dialkoxybenzene group denotes an O-alkyl-S-alkyl, where alkyl such as defined above.

In the context of this invention the acyl group denotes a carboxyl group is such as defined above. Examples of preferred acyl groups of the invention include carboxy, acetyl and propionyl.

In the context of this invention, the aryl group denotes a monocyclic or polycyclic aromatic hydrocarbon group. Examples of preferred aryl groups of the invention include phenyl, naphthyl and anthracene.

In the context of this invention kalkilya group denotes a mono - or polycyclic aryl group as defined above which is attached to the alkyl group, also defined above. Examples of preferred Uralkalij groups according to the invention include benzyl and phenethyl.

In the context of this invention "heterocycle" denotes a mono - or polycyclic heterocyclic group, which is mono - or polycyclic group, and which contains in its ring structure, one or more than one heteroatom. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulfur (S). One or more than one ring structure may, in particular, to be aromatic (i.e. heteroaryl), saturated or partially saturated. Preferred monocyclic heterocyclic groupingcollection group according to the invention are bicyclic heterocyclic groups.

Examples of preferred aromatic heterocyclic 5-membered monocyclic groups of the invention include

furan, in particular 2 - or 3-furanyl;

thiophene, in particular 2 - or 3-thienyl;

pyrrole (azole), in particular 1-, 2 - or 3-pyrrolyl;

oxazol, in particular oxazol-(2-, 4 - or 5-)yl;

the thiazole, in particular thiazol-(2-, 4 - or 5-)yl;

imidazol, in particular imidazole-(1-, 2-, 4- or 5-)yl;

pyrazole, in particular a pyrazole-(1-, 3-, 4- or 5-)yl;

isoxazol, in particular isoxazol-(3-, 4 - or 5-)yl;

isothiazol, in particular isothiazol-(3-, 4 - or 5-)yl;

1,2,3-oxadiazole, in particular 1,2,3-oxadiazol-(4 - or 5-)yl;

1,2,4-oxadiazol, in particular 1,2,4-oxadiazol-(3 - or 5-)yl;

1,2,5-oxadiazol, in particular 1,2,5-oxadiazol-(3 - or 4-)yl;

1,2,3-triazole, in particular 1,2,3-triazole-(1-, 4 - or 5-)yl;

1,2,4-thiadiazole, in particular 1,2,4-thiadiazole-(3 - or 5-)yl;

1,2,5-thiadiazole, in particular 1,2,5-thiadiazole-(3 - or 4-)yl and

1,3,4-thiadiazole, in particular 1,3,4-thiadiazole-(2 - or 5-)yl.

Examples of preferred saturated or partially saturated monocyclic heterocyclic 5-membered groups of the invention flucanazole-(1-, 2-, 3-, 4 - or 5-)yl;

2-imidazolin, in particular 2-imidazolin-(1-, 2-, 4- or 5-)yl;

3-imidazolin, in particular 3-imidazolin-(1-, 2-, 4- or 5-)yl;

4-imidazolin, in particular 4-imidazolin-(1-, 2-, 4- or 5-)yl;

2H-oxazol (oxazoline), in particular 2N-oxazol-(2-, 4 - or 5-)yl;

41-1-oxazol (oxazolidine), in particular 4H-oxazol-(2-, 4 - or 5-)yl;

1,2,3-oxadiazolyl, in particular 1,2,3-oxadiazol-(4 - or 5-)yl;

1,2,4-oxadiazolyl, in particular 1,2,4-oxadiazol-(3 - or 5-)yl;

1,2,5-oxadiazolyl, in particular 1,2,5-oxadiazol-(3 - or 4-)yl;

1,2,3-oxadiazolyl, in particular 1,2,3-oxadiazol-(4 - or 5-)yl;

1,2,4-oxadiazolidine, in particular 1,2,4-oxadiazol-(3 - or 5-)yl;

1,2,5-oxadiazolidine, in particular 1,2,5-oxadiazol-(3 - or 4-)yl;

2H-pyrrole (pyrrolin), in particular, 2H-pyrrole(1-, 2 - or 3-)yl;

4H-pyrrole (pyrrolidin), in particular 4H-pyrrol-(1-, 2 - or 3-)yl;

pyrazolidine, in particular pyrazolidine-(1-, 2-, 3-, 4- or 5-)yl;

2-pyrazolin, in particular 2-pyrazolin-(1-, 3-, 4- or 5-)yl and

3-pyrazolin, in particular 3-pyrazolin-(1-, 3-, 4- or 5-)yl.

Examples of preferred aromatic heterocyclic 6-membered monocyclic groups of the invention is asin-(3 - or 4-)yl;

the pyrimidine, in particular pyrimidine-(2-, 4 - or 5-)yl;

piratin, in particular pyrazin-(2-, 3-, 5- or 6-)yl;

1,3,5-triazine, in particular 1,3,5-triazine-(2-, 4 -, or 6-)yl and

Pashinin, in particular fastenin-(2-, 3 - or 4-)yl.

Examples of preferred saturated or partially saturated heterocyclic monocyclic 6-membered groups of the invention include

1,4-dioxolane, in particular 1,4-dioxolane-(2 - or 3-)yl;

1,4-dition, in particular 1,4-dition-(2 - or 3-)yl;

morpholine, in particular morpholine-(2-, 3 - or 4-)yl;

1,4-oxazin, in particular 1,4-oxazin-(2-)yl;

oxadiazon, in particular oxadiazine-(2-, 3 - or 5-)yl;

piperidine, in particular piperidine-(1-, 2-, 3- or 4-)yl;

piperazine, in particular piperazine-(1-, 2-, 3-or 4-)yl;

2H-Piran, in particular 2H-Piran-(2-, 3 - or 4-)yl;

4H-Piran, in particular 4H-Piran-(2-, 3 - or 4-)yl;

thiomorpholine, in particular thiomorpholine-(2-, 3 - or 4-)yl and

1,3,5-trician, in particular 1,3,5-trician-(2-)Il.

Examples of preferred saturated or partially saturated monocyclic heterocyclic 7-membered groups of the invention include

homopiperazin, in particular impactfully aromatic bicyclic heterocyclic groups of the invention include

endolysin, in particular indolizine-(1-, 2-, 3-, 5-, 6-, 7- or 8-)yl;

indole, in particular indole-(1-, 2-, 3-, 4-, 5-, 6- or 7-)yl;

the isoindole, in particular the isoindole-(1-, 2-, 3-, 4-, 5-, 6- or 7-)yl;

benzo[b]furan (benzofuran), in particular benzo[b]furan-(2-, 3-, 4-, 5-, 6- or 7-)yl;

benzo[C]furan (isobenzofuran), in particular isobenzo[C]furan-(1-, 3-, 4-, 5-, 6- or 7-)yl;

benzo[b]thiophene (benzothiophen), in particular benzo[b]thiophene-(2-, 3-, 4-, 5-, 6- or 7-)yl;

benzo[C]thiophene (isobenzofuran), in particular benzo[C]thiophene-(1-, 3-, 4-, 5-, 6- or 7-)yl;

the benzimidazole, in particular benzimidazole-(1-, 2-, 4-, 5-, 6- or 7-)yl;

benzthiazole, in particular benzthiazole-(2-, 4-, 5-, 6- or 7-)yl;

purine, in particular purine-(2-, 6 - or 8-)yl;

the quinoline, in particular the quinoline-(2-, 3-, 4-, 5-, 6-, 7 or 8-)yl;

isoquinoline, in particular isoquinoline-(1-, 3-, 4-, 5-, 6-, 7 or 8-)yl;

cinnolin, in particular cinnolin-(3-, 4-, 5-, 6-, 7 or 8-)yl;

phthalazine, in particular phthalazine-(1-, 4-, 5-, 6-, 7 or 8-)yl;

hinzelin, in particular hinzelin-(2-, 4-, 5-, 6-, 7 or 8-)yl;

cinoxacin, in particular cinoxacin-(2-, 3-, 5-, 6-, 7 or 8-)yl;

1,8-naphthiridine, in particular 1,8-naphthiridine-(2-, 3-, 4-, 5-, 6- or 7-)yl and pteridine, in particular per the PP according to the invention include

carbazole, in particular carbazole-(1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)Il;

acridine, in particular the acridine-(1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)Il;

fenesin, in particular fenesin-(1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-)Il;

phenothiazines, particularly phenothiazines-(1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-)silt, and

phenoxazin, in particular phenoxazin-(1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-)Il.

Examples of preferred saturated or partially saturated bicyclic heterocyclic groups of the invention include indolin, in particular of indolin-(1-, 2-, 3-, 4-, 5-, 6- or 7-)yl;

3H-indole, in particular 3H-indole-(2-, 3-, 4-, 5-, 6- or 7-)yl;

1H-indazol, in particular 1H-indazol-(3-, 4-, 5-, 6- or 7-)yl;

4H-hemolysin, in particular 4H-hemolysin-(1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-)Il;

Hinkley, in particular Hinkley-(2-, 3-, 4-, 5-, 6-, 7- or 8-)yl;

ethanologen, in particular ethanologen-(1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-) yl;

tropan, in particular tropan-(1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-)or

nortropane, in particular nortropane-(1-, 2-, 3-, 4-, 5-, 6- or 7-)yl.

Pharmaceutically acceptable salt

Chemical compound according to the invention can be prepared in any form suitable for the intended administration. Suitable forms of chemical compounds according to the invention.

Examples of pharmaceutically acceptable salts of joining include without limitation non-toxic salt accession of inorganic and organic acids, such as hydrochloride, derived hydrochloric acid, hydrobromide, derived Hydrobromic acid, nitrate, derived nitric acid, perchlorate, derived perchloro acid, a phosphate, a derivative of phosphoric acid, a sulfate, a derivative of sulfuric acid, the formate-derived formic acid, acetate, a derivative of acetic acid, aconet derived amanitowoc acid, the ascorbate derived ascorbic acid, bansilalpet derived benzosulfimide acid, the benzoate derived benzoic acid, cinnamic, a derivative of cinnamic acid, the citrate, derived citric acid, embonate derived monowai acid, enanthate, derived enanthic acid, the fumarate derived fumaric acid, the glutamate derived glutamic acid, the glycolate derived glycolic acid, the lactate derived lactic acid, the maleate derived maleic acid, malonate, a derivative of malonic acid, mandelate derived almond acid, methanesulfonate, derived methanesulfonic acid, NAT, derivative of salicylic acid, sorbate derived sorbic acid, stearate, derived stearic acid, a succinate, a derivative of succinic acid, tartrate, a derivative of tartaric acid, paratoluenesulfonyl derived paratoluenesulfonyl acid, and the like. Such salts can be obtained by using the described and well known in the prior art methods.

Other acids, such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in obtaining salts which are useful as intermediates for the production of chemical compounds according to the invention and its pharmaceutically acceptable salts accession acid.

Metal salts chemical compounds according to the invention include alkali metal salts such as sodium salt chemical compounds according to the invention containing a carboxy group.

In the context of this invention "onevia salt" N-containing compounds are also considered as pharmaceutically acceptable salts. Preferred "onevia salts" include alcyoniidae salt, cycloalkanes salt and cycloalkylation salt.

Chemical compound according to image what varicellae, such as water, ethanol and the like. Soluble forms may also include hydrated forms, such as the monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like. In General, soluble forms are considered equivalent for the purposes of this invention is insoluble forms.

Spatial isomers

Chemical compounds of the present invention may exist in (+) and (-) forms as well as in racemic forms. The racemates of these isomers themselves and individual isomers are included in the scope of the present invention.

The racemic forms can be divided into the optical antipodes by known methods and techniques. One of the ways the separation of the diastereomeric salts is to use optically active acid and separation of the optically active amine compounds by interaction with the substrate. Another method for the separation of racemates on the optical antipodes is based on chromatography on optically active matrix. Racemic compounds of the present invention can be divided into their optical antipodes by fractional crystallization of d - or I-salts (such as tartratami, mandelate or camphorsulfonate).

Chemical modifications is of chemical compounds of the present invention with an optically active activated carboxylic acid, such as a derivative (+) or (-) phenylalanine derivative (+) or (-) phenylglycine-derived (+) or (-) campanulas acid, or through the formation of diastereomeric carbamates by the interaction of the chemical compounds of the present invention with an optically active chloroformate and the like.

Additional methods for the separation of optical isomers is well known from the prior art. Such methods include the methods described Jaques J, Collet A, & Wilen S "Enantiomers. Racemates. and Resolutions". John Wiley and Sons, New York (1981).

Optically active compounds can also be obtained from optically active starting materials.

In addition, some chemical compounds according to the invention can exist in two forms, CIS - and TRANS-Farmah (Z - and E-form), depending on the location of the substituents at the double-C=C - bond. Thus, the chemical compound of the present invention may be CIS - or TRANS-form (Z - and E-form) or may be mixtures thereof.

Ways to get

Derivatives of benzimidazole according to the invention can be obtained by ordinary methods of chemical synthesis, for example by the methods described in the working examples. Source materials for the methods described in the present is="ptx2">Also one connection according to the invention can be converted into another compound of the invention using conventional methods.

The final products described herein reactions can be distinguished using conventional techniques such as extraction, crystallization, distillation, chromatography and so on.

The pharmaceutical composition

In another aspect of the invention proposed new pharmaceutical compositions containing a therapeutically effective amount of the benzimidazole derivative according to the invention.

As a chemical compound according to the invention for use in therapy can be introduced in the form of the raw chemical compound, it is preferred to introduce the active ingredient, possibly in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more than one adjuvant, excipient, carrier, buffer, diluent and/or other customary pharmaceutical auxiliary means.

In the preferred embodiment of the invention offers a pharmaceutical composition comprising a chemical compound according to the invention or its pharmaceutically acceptable salt or a derivative thereof, together with one or more than one the customers. The carrier (s) must be "acceptable" in the sense of compatibility with other ingredients of the drug and safety for its recipient.

The pharmaceutical compositions according to the invention can be of a composition suitable for oral, rectal, bronchial, intranasal, local (including transbukkalno and sublingual administration), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, vnutricherepnuyu, vnutriglaznae injection or infusion) injections, or compositions in a form suitable for administration by inhalation or insufflation, including powders and the introduction of liquid aerosols, or by using systems with continuous release. Suitable examples of systems with continuous release include semi-permeable matrices of solid hydrophobic polymers containing a compound according to the invention, which may be in the form of shaped articles, e.g. films, or microcapsules.

Chemical compound according to the invention together with a conventional adjuvant, carrier or diluent can, thus, be represented in the form of pharmaceutical compositions and their standke, pellets and liquids, in particular aqueous or nonaqueous solutions, suspensions, emulsions, elixirs and filled them capsules used for all oral administration, suppositories for rectal administration and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and their standard dosage forms may contain conventional ingredients in conventional proportions, with an additional active compounds or active basis or without them, and such a standard dosage forms may contain any suitable effective amount of the active ingredient commensurate with the size of the planned daily dose.

Chemical compound according to the present invention can be introduced in the composition of a wide variety of oral and parenteral dosage forms. For the person skilled in the art it is obvious that the dosage form can contain as an active ingredient or chemical compound according to the invention, or pharmaceutically acceptable salt of a chemical compound according to the invention.

To prepare the pharmaceutical compositions of the chemical compounds of the present invention pharmaceutically acceptable socialpay, pills, suppositories, and dispersible granules. A solid carrier can be one or more than one substance, which may also act as a diluent, the corrective agent, solubilizers agent, a lubricating substance, suspendisse agent, binder, preservative, loosening tablet agent or encapsulating material.

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

In tablets, the active component is mixed in suitable proportions with the media, always having binding ability, and arranged in a desired shape and size.

The powders and tablets preferably contain from 5-10% to about 70% of the active compounds. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like. The term "preparation" includes the preparation of the active compound with encapsulating material as a carrier to receive the capsule, in which AK is eacii with him. Similarly receive a wafer and pellet. Tablets, powders, capsules, pills, wafers and cakes can be used as solid dosage forms suitable for oral administration.

For preparing suppositories low-melting wax such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed therein under stirring until a homogeneous state. The molten homogeneous mixture is then poured into a suitable size, shape and leave to cool and harden.

Compositions suitable for vaginal administration, can be represented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient carriers, known from the prior art as suitable.

Liquid preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, liquid preparations for parenteral injection can be prepared as solutions in water polietilenglikolja solution.

Thus, the chemical compound of the present invention can be prepared in the form of a preparation for parenteral administration (in particular, by injecti the capsules pre-filled syringes, small volume infusion or in mnogochasovykh containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous fillers, and may contain technological agents, such as suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic selection of sterile solid or by lyophilization from solution, for reconstitution before use with a suitable filler, such as sterile pyrogen-free water.

Aqueous solutions suitable for oral use can be obtained by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be obtained by dispersing finely pulverized active ingredient in water containing a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose or other well-known suspendresume before use, in 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, dispersants, thickeners, solubilizing agents and the like.

For the local introduction of the epidermis connection according to the invention can be prepared in the form of ointments, creams or lotions, or as a transdermal patch. Ointments and creams, for example, can be prepared in an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions can be prepared in water or oil-based, and in General they contain one or more than one emulsifying agent, stabilizing agent, dispersing agent, suspendisse agent, thickening agent, or coloring agent.

Compositions suitable for local injection in the mouth include pellet containing the active agent in a corrective basis, usually sucrose and Arabian gum or tragakant, lozenges, containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and Arabian gum, and poloskaniya directly into the nasal cavity by conventional means, for example, using a dropper, pipette or spray. The compositions may be presented in single or mnogochasovoj form. In the latter case, the patient may carry out the introduction with the help of a dropper or pipette the appropriate, predetermined volume of solution or suspension. In the case of spray this can be accomplished, for example, using a spray gun.

Introduction to the respiratory tract can also be performed using aerosol formulation in which the active ingredient is in the package under pressure with a suitable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. The aerosol can well as for facilities to contain a surfactant such as lecithin. Medication dose may be controlled by metering valve.

Alternatively, the active ingredient may be in the form of a dry powder, for example in the form of a powder mixture of the compounds with a suitable powder base such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidone (PVP). For convenience andartes dosage form, for example in the form of capsules or cartridges, for example, from gelatin or blister packs from which the powder can be entered using the inhaler.

In compositions intended for introduction into the respiratory tract, including intranasal compositions connection in General should have a small particle size, for example of the order of 5 microns or less. This particle size can be obtained by known methods, for example by micronisation.

If you prefer to use a composition adapted for continuous release of the active ingredient.

The pharmaceutical preparations are preferably in a standard dosage forms. In such form the preparation is subdivided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Standard dosage form may be in the form of capsules, tablets, wafers or cakes by itself, or it may represent an appropriate number of any of these in packaged form.

Tablets are preferred compositions.

Additional details of methods for the preparation and introduction can be found in the latest edition of the Remingtons Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

A therapeutically effective dose refers to that amount of active ingredient that improves the symptoms or condition. Therapeutic efficacy and toxicity, such as ED50and LD50can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The ratio of the dose between therapeutic and toxic effects is therapeutic index and it can be expressed by the ratio LD50/ED50. Preferred are compositions which exhibit large pharmaceutical indexes.

Enter the dose should, of course, be carefully chosen depending on the age, weight and condition of the individual subject treatment, and route of administration, dosage form and regimen and the desired result. The exact dose will, of course, must be determined by a medical practitioner.

The actual dosage depends on the nature and severity of the disease to be treated, the route of administration and remain at the discretion of the physician, and may vary by tetricus considered what farmatsevticheskii composition containing from about 0.1 to about 500 mg of the active ingredient on the individual dose, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10 mg, suitable for therapeutic treatment.

The active ingredient, you can enter one or more doses per day. A satisfactory result can be obtained in some cases when the dose is 0.1 mg/kg I.V. and 1 mcg/kg orally. The upper limit of the interval dosing is now considered to be equal to about 10 mg/kg I.V. and 100 mg/kg orally. The preferred spacing is from about 0.1 μg/kg to about 10 mg/kg / day intravenously and from about 1 μg/kg to about 100 mg/kg / day orally.

The preferred route of administration is intravenous and infusion intervals doses comprise from 0.01 μg/kg / hour to about 10 mg/kg per hour.

Biological activity

In the present invention was to create compounds able to modulate GABAA-receptor complex, and this problem was solved with new benzimidazole derivatives of formula I.

Derivatives of benzimidazole according to the invention p is este sedatives, as muscle relaxants, as well as for suppression of febrile convulsions in children, epileptic status, for use in patient connected to the ventilator.

Derivatives of benzimidazole according to the invention exhibit a short duration of action, they are soluble in water in therapeutically appropriate dose and, in particular, are well suited for intravenous administration.

Compounds according to the invention can also be used in veterinary medicine.

As shown in the working examples, benzimidazole derivatives according to the invention show affinity from high to moderate to the benzodiazepine receptor, as measured by the replacement of3N flunitrazepam in vitro and in vivo. The most preferred compounds are full agonists, that is, they exhibit high maximum effect in the test capture, as described in the application.

Preferred compounds are full agonists GABAA-receptor complex, for example, as measured by anticonvulsant activity in PT test described in example 14, and give a 2-5 fold increase in tolerated dose PT. The most preferred compounds are those, knew demonstrate the elimination half-life of less than 30 minutes, that means a short duration of action. The preferred elimination half-life ranged from about 30 seconds to about 20 minutes. The most preferred elimination half-life ranged from about 2 to about 5 minutes.

Preferred compounds induce rapid onset of anesthesia, less than 1-2 minutes. Most preferred is the onset of anesthesia is less than 1 minute.

Awakening from anesthesia after bolus injection (centuries) or after overlapping infusion should occur within a short period of time, i.e. within the range from about 5 to about 30 minutes, preferably from about 5 to about 10 minutes, after which the patient should quickly return to its normal condition, that is, less than 40 minutes, preferably less than 20 minutes, as measured by the awakening.

Compounds according to this invention can be used in conjunction with analgesics, such as Remifentanil, fentanyl, or other opiates.

The methods of treatment

In another aspect of the invention, a method for treating, preventing or alleviating sensitive to modulation of GABA-a receptor complex Zab including humans, introducing an effective amount of the benzimidazole derivative according to the invention.

In a more preferred embodiment of the invention, a method of inducing or maintaining anesthesia or preanesthesia, muscle relaxation or sedation or treatment, prevention or relief of small seizures or epileptic status.

Now suppose that the appropriate rate of infusion are in the range of from about 0.01 to about 100 mg/kg per hour, more preferably from about 0.1 to about 15 mg/kg per hour, depending on the specific way of introduction, input forms, indications, which is the introduction, the subject of the patient and body mass of the subject is the patient, and, in addition, the preference and experience of the physician or veterinarian.

EXAMPLES

The invention is additionally illustrated by the following examples which are in no way intended to limit the scope of this invention.

Example 1

All benzimidazole, are presented in Table 1, was obtained by the above scheme, as illustrated below for compound 1A.

2-methoxyethyl 1-(3-(4-ethoxy-carbonyl)-1-piperazinylmethyl)-phenyl)-benzoni the TBA paratoluenesulfonyl acid in tetrahydrofuran (10 ml) was heated under reflux for 30 minutes. The cooled mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium hydroxide (1M). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using ethyl acetate as eluent. The product was besieged in the form of a hydrochloride by adding to the eluate ethereal hydrogen chloride. Yield 0.4 g (64%). Tpl.171-173°C.

The following compounds were obtained analogously to compound 1A:

2-Methoxyethyl 1-(3-(4-ethoxy-carbonyl-methyl)-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1b) of 2b. As eluent was used a mixture of ethyl acetate and acetone (4:1 o/o). Tpl.161-163°C.

2-Methoxyethyl 1-(3-(4-methoxycarbonyl-1-imidazolyl)-phenyl)-benzimidazole-5-carboxylate (1C) of 2C. Tpl.132-134°C.

2-Methoxyethyl 1-(3-(4-carboxymethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1d) 2d. Tpl.105-110°C. as eluent to purification using column chromatography was used a mixture of acetonitrile, acetic acid and water (8:1:1 o/o/o). Hydrogen chloride was added.

2-Methoxyethyl 1-(3-(4-methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1E) of the 2nd. Tpl.136-137°C. Vyd the l 1-(3-(4-acetyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1f) (2f). Tpl.157-164°C. as eluent was used a mixture of ethyl acetate and acetone (4:1 o/o).

2-Methoxyethyl 1-(3-(1-methyl-4-piperidyl)-phenyl)-benzimidazole-5-carboxylate (1g) (2g). Tpl.123-125°C. as eluent was used a mixture of ethyl acetate and acetone (4:1 o/o).

2-Methoxyethyl 1-(3-(1-acetyl-4-piperidyl)-phenyl)-benzimidazole-5-carboxylate (1h) (2h). Tpl.139-140°C. as eluent to purification using column chromatography was used acetone.

2-Methoxyethyl 1-(3-(4-tert-butoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1i), (2I). Tpl.218-224°C.

2-Methoxyethyl 1-(3-(4-ISO-propoxycarbonyl-1-piperazinil)-Phenyl)-benzimidazole-5-carboxylate (1j) (2j). Tpl.155-159°C.

(N,N-diethylcarbamoyl)-methyl 2-(3-[3-(5-etoxycarbonyl-1-benzimidazolyl)-phenyl]-4,5-dihydroxysuccinic-5-yl)-acetate (1k) 2k. Tpl.157-159°C.

Methyl 1-(3-(1-imidazolidinyl)-phenyl)-benzimidazole-5-carboxylate (1l) of 2l. Tpl.241-244°C. as eluent was used a mixture of dichloromethane and methanol (9:1 o/o).

2-[4-(3-(5-Methoxycarbonylamino-1-yl)-phenyl)-1-piperazinil]-acetic acid (1m) 2m. Tpl.210-220°C. the Product was twice subjected to chromatography the thio)-etil-(3-(1-imidazolidinyl)-phenyl)-benzimidazole-5-carboxylate (1n) 2n. Tpl.71-75°C. as eluent was used a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 o/o/o). Allocated in the form of free base.

2-(Methylthio)-ethyl 1-(3-(4-methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1B) of 2O. Tpl.121-122°C.

2-(N,N-dimethylamino)-ethyl 1-(3-(1-carboxymethyl-4-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1P) 2P. Tpl.47°C (decomposition). As eluent was used a mixture of acetonitrile, acetic acid, pyridine and water (7:1:1:1 o/o/o/o).

2-Methoxyethyl 1-(3-(1-isopropoxycarbonyl-4-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1q) from 2q. Tpl.155-159°C.

2-Methoxyethyl 1-(3-(4-benzyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1r) 2r. Tpl.172-177°C

Methyl 1-(3-(4-cyanomethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1s) 2s. Tpl.160-162°C. the Product is isolated in the form of a free base.

2-Methoxyethyl 1-(3-(4-cyanomethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1t) 2t. Tpl.91-93°C. the Product is isolated in the form of a free base.

Methyl 1-(3-(4-benzyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1u) of 2u. Tpl.153-163°C.

2-Methoxyethyl 1-(3-(4-benzyl 1-(3-(4-(1-methyl-5-tetrazolyl)methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1w) of 2w. Tpl.196-198°C

2-Methoxyethyl 1-(3-(4-ethyl-1-homopiperazine)-phenyl)-benzimidazole-5-carboxylate (1x) 2. Melting point not determined. As eluent was used a mixture of dichloromethane and methanol (9:1 o/o).

2-Methyl 1-(3-(4-ethyl-1-homopiperazine)-phenyl)-benzimidazole-5-carboxylate (1U) of 2U. Melting point not determined. As eluent was used a mixture of dichloromethane and methanol (9:1 o/o).

2-Methoxyethyl 1-(3-(4-ethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1z) of 2z. Tpl.166-168°C.

2-Methoxyethyl 1-(3-(4-ethoxycarbonylmethyl-3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1A) 2A. Tpl.90-94°C.

2-Methyl 1-(3-(4-ethoxycarbonylmethyl-3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1bb) of 2bb. Tpl.168-181°C.

2-Hydroxyethyl 1-(3-(4-(2-hydroxyethyl)-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (s) from SS. Tpl.182-192°C. as eluent was used a mixture of ethyl acetate and methanol (1:1 o/o).

2-Methoxyethyl 1-(3-(4-ethyl-3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1dd) from 2dd. Tpl.202-208°C. as eluent was used a mixture of ethyl acetate and methanol (1:1 o/o).

2-S="ptx2">2-Methoxyethyl 1-(3-(4-(2-oxazolidinone-5-yl)methyl)1-piperazinyl-phenyl)-benzimidazole-5-carboxylate (1ff) 2ff. Allocated in the form of oil.

2-Methoxyethyl 1-(3-(4-(5-metronidazol-3-yl)methyl)1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1gg) from 2gg. Allocated in the form of oil.

Methyl 1-(3-(1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1hh) from 2hh. Tpl.179-202°C. After ring closure of the BOC-group was removed by treatment triperoxonane acid in dichloromethane.

2-Methoxyethyl 1-(3-(1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1ii) 2ii. Tpl.191-205°C. After ring closure of the BOC-group was removed by treatment triperoxonane acid in dichloromethane.

2-Methoxyethyl 1-(3-(3,5-dimethylisoxazol-4-yl)-methyl)1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1jj) received from 2ii by alkylation with 4-chloromethyl-3,5-dimethylisoxazole. Tpl.219-223°C.

2-Methoxyethyl 1-(3-(3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1kk) from 2kk. Tpl.215-231°C. After ring closure of the BOC-group was removed by treatment triperoxonane acid in dichloromethane.

2-Methoxyethyl 1-(3-(4-(2-oxo-tetrahydrofuran-3-yl)-1-piperazinil)-phenyl)-benzimidazole-5-carbox the imidazole-5-carboxylate (1mm) was obtained from 1ii by alkylation with 2-chloromethyl-5-chlorothiophenol. Tpl.185-186°C.

2-Hydroxyethyl 1 -(3-(4-methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1nn) from 2nn. Tpl.As eluent was used a mixture of ethyl acetate and methanol (1:1 o/o).

2-Hydroxyethyl 1-(3-(4-methoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (OO) from OO. Tpl.As eluent was used a mixture of ethyl acetate and methanol (9:1 o/o).

2-Hydroxyethyl 1-(3-(4-ethoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (RR) from RR. Tpl.As eluent was used a mixture of ethyl acetate and methanol (9:1 o/o).

2-Methoxyethyl 1-(3-(4-diethylcarbamoyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1qq) from 2qq. Tpl.202-204°C. as eluent was used a mixture of ethyl acetate and methanol (9:1 o/o).

2-Methoxyethyl 1-(3-(4-methoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1rr) of 2rr. Tpl.161-164°C. as eluent was used a mixture of ethyl acetate and methanol (9:1 o/o).

2-Methoxyethyl -(3-(4-carbamoylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1ss) 2ss. Tpl.211-212°C. as eluent was used a mixture of ethyl acetate and methanol (9:1 o/o).

2-Hydroxyethyl 1-(3-(4-carbamoylmethyl-1-Pipa is racette and methanol (9:1 o/o).

2-Hydroxyethyl 1-(3-(4-diethylcarbamoyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1uu) from 2uu. Tpl.149-154°C. as eluent was used a mixture of ethyl acetate and methanol (9:1 o/o).

2-Hydroxyethyl 1-(3-(4-carboxymethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate (1vv) from 2vv. The solvent DMF was used, and as eluent a mixture of acetonitrile, water and acetic acid (8:1:1 o/o).

Example 2

All the diamines shown in Table 2, obtained with a quantitative yield by hydrogenation of the corresponding nitroanilines (3) in the above scheme, as illustrated below for compounds 2A.

2-Methoxyethyl 3-amino-4-(3-((1-etoxycarbonyl-4-piperazinil)-methyl)-phenylamino)-benzoate (2A). 3A (0.75 g; 1.54 mmol) suspended in tetrahydrofuran. Added palladium catalyst (50 mg, 5% on activated carbon) and the mixture was first made when the ambient pressure up until did not stop the absorption of hydrogen. The mixture was filtered through celite, and the filtrate was evaporated to dryness to obtain 2A with a quantitative yield.

The following compounds were obtained analogously to obtain compounds 2A:

2-Methoxyethyl 3-the but-4-(3-(4-methoxycarbonyl-1-imidazolyl)-phenylamino)-benzoate (2C) of 3C.

2-Methoxyethyl 3-amino-4-(3-(1-methyl-4-piperazinil)-phenylamino)-benzoate (2E) of 3E.

2-Methoxyethyl 3-amino-4-(3-(1-acetyl-4-piperazinil)-phenylamino)-benzoate (2f) of 3f.

2-Methoxyethyl 3-amino-4-(3-(1-methyl-4-piperidyl)-phenylamino)-benzoate (2g) 3g.

2-Methoxyethyl 3-amino-4-(3-(1-methyl-4-piperidyl)-phenylamino)benzoate (2h) of 3h.

2-Methoxyethyl 3-amino-4-(3-(1-tert-butoxycarbonylmethyl-4-piperazinil)-phenylamino)-benzoate (2i) from 3i.

2-Methoxyethyl 3-amino-4-(3-(1-ISO-propoxycarbonyl-4-piperazinil)-phenylamino)-benzoate (2j) of 3j.

(N,N-Diethylcarbamoyl)-methyl 2-[3-(3-((2-amino-4-ethoxycarbonylphenyl)amino)-phenyl)-4,5-dihydroisoxazole-5-yl)-acetate (2K) 3K.

Methyl 3-amino-4-(3-((1-imidazolyl)-methyl)-phenylamino)-benzoate (21) 31.

2-(Methylthio)-ethyl 3-amino-4-(3-(1-imidazolidinyl)-phenylamino)-benzoate (2n) 3n, using Raney Nickel as a catalyst.

2-(Methylthio)-ethyl 3-amino-4-(3-(4-methyl-1-piperazinil)-phenylamino)-benzoate (2) of 3O.

2-Methoxyethyl 3-amino-4-(3-(1-benzyl-4-piperazinil)-phenylamino)-benzoate (2r) of 3r. As the catalyst used PtO2.

Methyl 3-amino-4-(3-(1-cyanomethyl-4-piperazinil)-phenylamino)-benzoate (2s) 3s.

2-Methox>.

Methyl 3-amino-4-(3-(1-benzyl-4-piperazinil)-phenylamino)-benzoate (2u) of 3u. As the catalyst used tO2.

2-Methoxyethyl-amino-4-(3-(1-(2-benzyloxyethyl)-4-piperazinil)-phenylamino)-benzoate (2v) of 3v. As the catalyst used tO2.

2-Methoxyethyl 3-amino-4-(3-(1-((1-methyl-5-tetrazolyl)-methyl)-4-piperazinil)-phenylamino)-benzoate (2w) from 3w. As the catalyst used tO2.

2-Methoxyethyl 3-amino-4-(3-(1-ethyl-4-homopiperazine)-phenylamino)-benzoate(2) 3.

Methyl 3-amino-4-(3-(1-ethyl-4-homopiperazine)-phenylamino)-benzoate (2U) of 3U.

2-Methoxyethyl 3-amino-4-(3-(1-ethyl-4-piperazinil)-phenylamino)-benzoate(2z) 3z.

2-Methoxyethyl 3-amino-4-(3-((1-(ethoxy-carbonyl-methyl)-2,6-dimethyl)-4-piperazinylmethyl)-phenylamino)-benzoate (2A) of AA.

Methyl 3-amino-4-(3-((1-(ethoxy-carbonyl-methyl)-2,6-dimethyl)-4-piperazinylmethyl)-phenylamino)-benzoate(2bb) of 3bb.

2-Hydroxyethyl 3-amino-4-(3-(1-(2-hydroxyethyl)-4-piperazinil)-phenylamino)-benzoate (s) from SS.

2-Methoxyethyl 3-amino-4-(3-((1-ethyl-2,6-dimethyl)-4-piperazinylmethyl)-phenylamino)-benzoate (2dd) of 3dd.

2-Methoxyethyl 3-amino-4-(3-(1-(2-oxazoline-5-yl)methyl-4-piperazinil)-phenylamino)-Bezout (2gg) from 3gg. As the catalyst used PtO2.

Methyl 3-amino-4-(3-(1-b-4-piperazinil)-phenylamino)-benzoate (2hh) from 3hh.

2-Methoxyethyl 3-amino-4-(3-(1-b-4-piperazinil)-phenylamino)-benzoate (2ii) 3ii.

2-Methoxyethyl 3-amino-4-(3-(1-b-2,6-dimethyl-4-piperazinil)-phenylamino)-benzoate (CC) from CC.

2-Methoxyethyl 3-amino-4-(3-(1-(2-oxitetraciclina-3-yl)-4-piperazinil)-phenylamino)-benzoate (2II) 3II.

2-Hydroxyethyl 3-amino-4-(3-(4-methyl-1-piperazinil)-phenylamino)-benzoate (2nn) from 3nn.

2-Hydroxyethyl 3-amino-4-(3-(4-methoxycarbonylmethyl-1-piperazinil)-phenylamino)-benzoate (OO) from OO.

2-Hydroxyethyl 3-amino-4-(3-(4-ethoxycarbonylmethyl-1-piperazinil)-phenylamino)-benzoate (RR) from RR.

2-Methoxyethyl 3-amino-4-(3-(4-(N,N-diethyl-carbarnoyl)methyl-1-piperazinil)-phenylamino)-benzoate (2qq) from 3qq.

2-Methoxyethyl 3-amino-4-(3-(4-methoxycarbonylmethyl-1-piperazinil)-phenylamino)-benzoate (2rr) of the 3rr.

2-Methoxyethyl 3-amino-4-(3-(4-carbamoylmethyl-1-piperazinil)-phenylamino)-benzoate (2ss) of 3ss.

2-Hydroxyethyl 3-amino-4-(3-(4-carbamoylmethyl-1-piperazinil)-phenylamino)-benzoate (2tt) from 3tt.

2-Hydroxyethyl 3-amino-4-(3-(4-(N,N-diethyl-carbarnoyl)-methyl-1-piperazinil)-phenylamino)-benta is enylamine)-benzoate (2d). To a solution of 2-methoxyethyl-3-nitro-4-(3-(4-(benzyloxy-carbonyl-methyl)-1-piperazinil)-phenylamino)-benzoate (3d) (3.5 g; 6.4 mmol) in a mixture of tetrahydrofuran (50 ml) and DMF (5 ml) was added palladium catalyst (0.9 g, 5% on activated carbon) and ammonium formate (0.8 g; 12.6 mmol), the mixture was heated under reflux for 2 hours. The cooled mixture was filtered through celite, and the solvent was removed under reduced pressure to obtain 2q with a quantitative yield.

The following compounds were obtained analogously to obtain compound 2d:

Methyl 3-amino-4-(3-(1-carboxymethyl-4-piperazinil)-phenylamino)-benzoate (2m) 3m.

2-(Dimethylamino)-ethyl 3-amino-4-(3-(1-carboxymethyl-4-piperazinil)-phenylamino)-benzoate (2p) 3P.

2-Hydroxyethyl 3-amino-4-(3-(1-carboxymethyl-4-piperazinil)-phenylamino)-benzoate (2vv) from 3vv.

Example 2b

2-Methoxyethyl 3-amino-4-(3-(1-ethyl-1.2.5.6-tetrahydropyridine-4-yl)-phenylamino)-benzoate (2ee) from EE. The mixture EE (0.97 g; 1.9 mmol), deviations of sodium sulfide (1,37 g; 5,71 mmol) and ammonium chloride (0.3 g; 5,61 mmol) in a mixture of THF (5 ml) and 2-methoxyethanol (5 ml) was heated at 80°C for 2 hours. The cooled mixture was poured into ice water and was extracted with etilize column, using as eluent a mixture of ethyl acetate and methanol (9:1 o/o). Output: 0,21,

Example 3

Nitroaniline presented in Table 3, were obtained by reacting 4-chloro-3-nitrobenzoate 5 with substituted aniline (4) in accordance with the above scheme, as illustrated below for compound 3A.

2-Methoxyethyl 3-nitro-4-(3-(1-etoxycarbonyl-4-piperazinylmethyl)-phenylamino)-benzoate (3A). A mixture of 5a (0,94 g; 3.62 mmol), 4A (1.0 g; a 3.83 mmol) and triethylamine (of 0.53 ml; of 3.80 mmol) in NMP (N-organic (10 ml) was heated at 110°C during the night. The cooled mixture was distributed between water and ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and petroleum ether (1:1 o/o). Yield: 0.75 g (43%).

The following compounds were obtained analogously to obtain compounds 3A:

2-Methoxyethyl 3-nitro-4-(3-N-(ethoxy-carbonyl-methyl)-4-piperazinylmethyl)-phenylamino)-benzoate(2b) of 4b and 5a.

2-Methoxyethyl 3 nits is siloxy-carbonyl-methyl)-4-piperazinil)-phenylamino)-benzoate (3d) 4d and 5A.

2-Methoxyethyl 3-nitro-4-(3-(1-methyl-4-piperazinil)-phenylamino)-benzoate (3E) of 4E and 5A.

2-Methoxyethyl 3-nitro-4-(3-(1-acetyl-4-piperazinil)-phenylamino)-benzoate (3f) 4f and 5A.

2-Methoxyethyl 3-nitro-4-(3-(1-methyl-4-piperidyl)-phenylamino)-benzoate (3g) 4g and 5A.

2-Methoxyethyl 3-nitro-4-(3-(1-acetyl-4-piperidyl)-phenylamino)-benzoate (3h) of 4h and 5A.

2-Methoxyethyl 3-nitro-4-(3-(1-tert-butoxy-carbonyl-methyl)-4-piperazinil)-phenylamino)-benzoate(3i) of 4i and 5A.

2-Methoxyethyl 3-nitro-4-(3-(1-ISO-propoxy-carbonyl-methyl)-4-piperazinil)-phenylamino)-benzoate (3j) of 4j and 5A.

(N,N-Diethylcarbamoyl)-methyl 2-(3-(3-[N-(4-etoxycarbonyl-3-nitrophenyl)-amino]-phenyl)-4,5-dihydroisoxazole-5-yl)-acetate (3K) of 4K and 5b.

Methyl 3-nitro-4-(3-(1-imidazolidinyl)-phenylamino)-benzoate (3l) of 4l and 5C.

2-(Methylthio)-ethyl 3-nitro-4-(3-(1-imidazolidinyl)-phenylamino)-benzoate (3n) of 4l and 5d.

2-(Methylthio)-ethyl 3-nitro-4-(3-(4-methyl-1-piperazinil)-phenylamino)-benzoate(3O)of 4l and 5d.

2-Methoxyethyl 3-nitro-4-(3-(4-benzyl-1-piperazinil)-phenylamino)-benzoate (3r) of the 4s and 5A.

Methyl 3-nitro-4-(3-(4-(cyanomethyl)-1-piperazinil)-phenylamino)-benzoate (3s) of 4t and 5C.

2-Methoxyethyl 3-nitro-4-(3-(4-(cyanomethyl)-1-piperazinil)-f 5C.

2-Methoxyethyl 3-nitro-4-(3-(4-((1-methyl-5-tetrazolyl)-methyl)-1-piperazinil)-phenylamino)-benzoate (3w) from 4u and 5A.

2-Methoxyethyl 3-nitro-4-(3-(4-ethyl-1-homopiperazine)-phenylamino)-benzoate (3) of 4v and 5A.

Methyl 3-nitro-4-(3-(4-ethyl-1-homopiperazine)-phenylamino)-benzoate (3U) of 4v and 5C.

2-Methoxyethyl 3-nitro-4-(3-(4-ethyl-1-piperazinil)-phenylamino)-benzoate (3z) of 4v and 5A.

2-Methoxyethyl 3-nitro-4-(3-(4-(ethoxycarbonylmethyl)-3,5-dimethyl-1-piperazinil)-phenylamino)-benzoate (AA) of 4U and 5A.

2-Methyl-3-nitro-4-(3-(4-(ethoxycarbonylmethyl)-3,5-dimethyl-1-piperazinil)-phenylamino)-benzoate(3bb) of 4U and 5C.

2-Hydroxyethyl 3-nitro-4-(3-(4-ethyl-3,5-dimethyl-1-piperazinil)-phenylamino)-benzoate (3dd) of 4 AA and 5A.

2-Methoxyethyl 3-nitro-4-(3-(1-ethyl-1,2,5,6-tetrahydropyridine-4-yl)-phenylamino)-benzoate (EE) from 4bb and 5A.

2-Methoxyethyl 3-nitro-4-(3-(2-oxo-oxazolidin-5-yl)methyl)-phenylamino)-benzoate (3ff) from SS and 5A.

2-Methoxyethyl 3-nitro-4-(3-(4-((5-methyl-3-oxadiazolyl)methyl)-1-piperazinil)-phenylamino)-benzoate(3gg) from 4dd and 5A.

Methyl 3-nitro-4-(3-(4-b-piperazine-1-yl)-phenylamino)-benzoate (3hh) from EE and 5C.

2-Methoxyethyl 3-nitro-4-(3-(4-b-piperazine-1-yl)-phenylamino)-benzoate (3ii) from EE and 5A.

2 Marks the ro-4-(3-(4-(2-oxitetraciclina-3-yl)-1-piperazinil)-phenylamino)-benzoate(3ll) 4gg and 5A.

2-hydroxyethyl 3-nitro-4-(3-(4-methyl-1-piperazinil)-phenylamino)-benzoate (3nn) of 4F and 5f.

2-Hydroxyethyl 3-nitro-4-(3-(4-methoxycarbonylmethyl-1-piperazinil)-phenylamino)-benzoate (OO) of methyl-3-nitro-4-chlorobenzoate and 5f.

2-Hydroxyethyl 3-nitro-4-(3-(4-ethoxycarbonylmethyl-1-piperazinil)-phenylamino)-benzoate (RR) of 4b and 5f.

2-Methoxyethyl 3-nitro-4-(3-(4-(N,N-diethylcarbamoyl)-piperazine-1-yl)-phenylamino)-benzoate (3qq) 4ii and 5A.

2-Methoxyethyl 3-nitro-4-(3-(4-methoxycarbonylmethyl-1-piperazinil)-phenylamino)-benzoate (3rr) of methyl-3-nitro-4-chlorobenzoate and 5A.

2-Methoxyethyl 3-nitro-4-(3-(4-carbamoylmethyl)-piperazine-1-yl)-phenylamino)-benzoate (3ss) from 4jj and 5A.

2-Hydroxyethyl 3-nitro-4-(3-(4-(carbamoylmethyl)-piperazine-1-yl)-phenylamino)-benzoate (3tt) from 4jj and 5f.

2-Hydroxyethyl 3-nitro-4-(3-(4-(N,N-diethylcarbamoyl)-piperazine-1-yl)-phenylamino)-benzoate (3uu) 4ii and 5f.

Example 4

Substituted anilines, are presented in Table 4, were obtained by hydrogenation of the corresponding nitro compounds (6), as illustrated below for compounds 4A.

1-Etoxycarbonyl 4-(3-aminobenzyl)-piperazine 4A. To a solution of 6A (2.2 g; 7.5 mmol) in absolute ethanol AI environment as long until stopped absorption of hydrogen. By filtration through celite and evaporation of solvent received 4A with a quantitative yield.

The following compounds were obtained analogously to compound 4A:

Ethyl 2-(4-(3-AMINOPHENYL)-1-piperazinil)-acetate (4b) of 6b.

Methyl 1 -(3-AMINOPHENYL)-4-imidazolecarboxamide (4C) of 6s.

Benzyl 2-(4-(3-AMINOPHENYL)-1-piperazinil)-acetate (4d) of 6d. As the catalyst used tO2.

3-(4-Methyl-1-piperazinil)-aniline (4E) 6E.

3-(4-Acetyl-1-piperazinil)-aniline (4f) of 6f.

3-(1-Methyl-4-piperidyl)-aniline (4g) of 6g.

3-(1-Acetyl-4-piperidyl)-aniline (4h) from 6h.

Tert-butyl 2-(4-(3-AMINOPHENYL)-1-piperazinil)-acetate (4i) from 6i.

ISO-propyl 2-(4-(3-AMINOPHENYL)-1-piperazinil)-acetate (4j) from 6j.

(N,N-Diethylcarbamoyl)-methyl 2-(3-(3-AMINOPHENYL)-4,5-dihydroisoxazole-5-yl)-acetate (4K) of 6K.

1-[(3-AMINOPHENYL)-methyl]-imidazole (4I) from 6I.

Ethyl 2-(4-[(3-AMINOPHENYL)-methyl]-1-piperazinil)-acetate (4m) of 6m.

Ethyl 2-(4-(3-AMINOPHENYL)-1-piperidyl)-acetate (4n) of 6n.

Ethyl 2-(4-(3-AMINOPHENYL)-methyl)-1-piperidyl)-acetate (a) of 6o.

Ethyl 2-(4-(3-AMINOPHENYL)-1-piperazinil)-acetate (4P) 6.

2-(4-shall religiotis 3-aminobenzoate (4r) of the 6r. The solvent THF was used.

3-(4-Benzyl-1-piperazinil)-aniline (4s) from 6s. As the catalyst used PtO2.

2-(4-(3-AMINOPHENYL)-1-piperazinil)-acetonitrile (4t) of 6t.

3-(4-((1-Methyltetrazol-5-yl)methyl)-1-piperazinil)-aniline (4u) of 6u. As the catalyst used tO2.

3-(4-Ethyl-1-homopiperazine)-aniline (4v) of 6v. 3-(4-Ethyl-1-piperazinil)-aniline (4) of 6x. 3-(4-Ethoxycarbonylmethyl-3,5-dimethyl-1-piperazinil)-aniline (4y) from 6y.

3-(4-(2-Hydroxyethyl)-1-piperazinil)-aniline (4z) of 6z. 3-(4-Ethyl-3,5-dimethyl-1-piperazinyl-aniline (4 AA) from AA. 3-(4-(2-Oxo-oxazolidin-5-yl)methyl)-1-piperazinil)-aniline (s) from SS.

3-(4-(5-Metronidazol-3-yl)methyl)-1-piperazinil)-aniline (4dd) from 6dd.

3-(4-Boc-1-piperazinil)-aniline (EE) from EE. 3-(4-BOC-3,5-dimethyl-1-piperazinil)-aniline (4ff) from 6ff. 3-(4-(2-Oxitetraciclina-3-yl)-1-piperazinil)-aniline (4gg) 6gg.

3-(4-Methoxycarbonylmethyl-1-piperazinil)-aniline (4hh), as described in WO 98/17651.

3-(4-((N,N-Diethylcarbamoyl)-methyl)-1-piperazinil)-aniline (4ii) 6ii.

3-(4-Carbamoylmethyl)-1-piperazinil)-aniline (4jj) from 6jj.

Example 4A

3-(4-(1-Ethyl-1,2,5,6-tetrahydropyridine-4-yl)-1-piperazinil)-aniline (4bb). The mixture 6bb (example 6g) (0.85 grams; 3, the l) was heated under reflux for 4 hours. The cooled mixture was poured into ice water and was extracted with dichloromethane. The extract was dried over magnesium sulfate, filtered and evaporated to obtain 4 bb. The output of 0.60 g (81%).

Example 5

2-Methoxyethyl 4-chloro-3-nitrobenzoate 5A. A mixture of 4-chloro-3-nitrobenzoic acid (10 g; of 49.6 mmol) and thionyl chloride (50 ml) was heated under reflux overnight. The excess thionyl chloride was removed by evaporation and then added methoxyethanol (50 ml). The resulting mixture was stirred at 80°C for 4 hours. The cooled solution was diluted with water (500 ml) and was extracted with ethyl acetate (2×100 ml). The organic extract was dried over magnesium sulfate and concentrated under reduced davlenie. In the trituration of the residue with petroleum ether got 5A (8.0 g; 62%), low-melting solid (Tpl.33-35°C).

The following compounds were obtained analogously to compound 5A:

ethyl 4-chloro-3-nitrobenzoate (5b);

methyl 4-chloro-3-nitrobenzoate (5C);

2-(methylthio)ethyl 4-chloro-3-nitrobenzoate (5d);

2-(N,N-dimethylamino)ethyl 4-chloro-3-nitrobenzoate (5e) and

2-hydroxyethyl-chloro-3-nitrobenzoate (5f).

Example 6A

1-Taxicab what about the drops) was added piperazine-1-carboxylate. By the end of the addition the temperature reached 35°C. Then was added triethylamine (1.39 ml), resulting in the temperature rose to 40°C. the Mixture was additionally stirred for 30 minutes and then diluted with diethyl ether (25 ml). The mixture was filtered, the filtrate washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate is suspended in diethyl ether and filtered. The filtrate was diluted with ethyl acetate and was extracted with diluted hydrochloric acid. The aqueous phase was podslushivaet by adding aqueous saturated sodium bicarbonate solution and was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to dryness to obtain 6A (1,72 g; 59%).

Example 6b

1-(3-Nitrophenyl)-piperazine. A suspension of 3-peritrabecular (23 ml, 0.21 mol) and piperazine (55,5 g; 0.64 mol) in anhydrous NMP (30 ml) was heated at 70°C for 5 days. The cooled mixture was diluted with water (250 ml) and was extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, elwira successively with mixtures of ethyl acetate and methane-nitrophenyl)-1-piperazinil)-acetate (6b). To a solution of 1-(3-nitrophenyl)piperazine (12.0 g; 58 mmol) in DMF (60 ml) in portions over 30 minutes was added sodium hydride (2.55 g; 64 mmol, 60% dispersion in mineral oil). The mixture was kept under nitrogen. Was added ethyl-2-bromoacetate (7,1 ml, 64 mmol), the mixture was stirred at ambient temperature for 1 hour and then poured into water (250 ml). The oily precipitate was filtered, pererestorani in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate and evaporated to dryness obtaining 6b (11,0 g; 65%).

The following compounds were obtained analogously to compound 6b:

Isopropyl 2-(4-(3-nitrophenyl)-1-piperazinil)-acetate (6j) of 1-(3-nitrophenyl)-piperazine and isopropyl-2-bromoacetate,

Tert-butyl 2-(4-(3-nitrophenyl)-1-piperazinil)-acetate (6i) of 1-(3-nitrophenyl)-piperazine and tert-butyl-2-bromoacetate.

1-(3-Nitrophenyl)-4-benzylpiperazine (6s) of 1-(3-nitrophenyl)piperazine and benzylchloride.

2-(1-(3-Nitrophenyl)-4-piperazinil)-acetonitrile (6t) of 1-(3-nitrophenyl)piperazine and 2-bromoacetonitrile.

1-(3-Nitrophenyl)-4-acylhomoserine (6v) of 1-(3-nitrophenyl)homopiperazine (obtained analogously to 1-(3-nitrophenyl)piperazine) and iodata.

1-(3-Nitrophenyl)-4-methylpiperazine (6x) (6y) from 1-(3-nitrophenyl)-2,6-dimethylpiperazine (obtained analogously to 1-(3-nitrophenyl)piperazine) and ethyl-2-bromoacetate.

1-(3-Nitrophenyl)-4-(2-hydroxyethyl)-piperazine (6z) of 1-(3-nitrophenyl)piperazine and 2-bromoethanol.

1-(3-Nitrophenyl)-4-ethyl-3,5-dimethylpyrazine (AA) of 1-(3-nitrophenyl)-2,6-dimethylpiperazine (obtained analogously to 1-(3-nitrophenyl)piperazine) and iodata.

1-(3-Nitrophenyl)-4-((2-oxo-oxazolidin-5-yl)-methyl)-piperazine (SS) of 1-(3-nitrophenyl)-piperazine and 5-chloromethyl-2-oxazolidinone.

1-(3-Nitrophenyl)-4-((5-metronidazol-3-yl)-methyl)-piperazine (6dd) of 1-(3-nitrophenyl)-piperazine and 3-chloromethyl-5-metronidazole.

1-(3-Nitrophenyl)-4-b-piperazine (EE) of 1-(3-nitrophenyl)piperazine and b-anhydride.

1-(3-Nitrophenyl)-4-b-3,5-dimethylpiperazine (6ff) of 1-(3-nitrophenyl)-2,6-dimethylpiperazine (obtained analogously to 1-(3-nitrophenyl)piperazine) and b-anhydride.

1-(3-Nitrophenyl)-4-(2-oxitetraciclina-3-yl)-piperazine (6gg) of 1-(3-nitrophenyl)-piperazine and-bromobutyrate.

1-(3-Nitrophenyl)-4-((N,N-diethylcarbamoyl)-methyl)-piperazine (6ii) of 1-(3-nitrophenyl)-piperazine and 2-chloro-N,N-diethylacetamide.

1-(3-Nitrophenyl)-4-(carbamoylmethyl)-piperazine (6jj) of 1-(3-nitrophenyl)-piperazine and 2-chloracetamide.

Example 6C

Methyl 1-(3-nitrophenyl)-imidazole-4-carboxylate (6C). When P was heated at 120°C overnight under nitrogen atmosphere. The cooled mixture was poured into water (100 ml), the precipitate was filtered, washed with water and dried to obtain 6s (2.38 g; 58%).

Example 6d

Benzyl 2-(4-(3-nitrophenyl)-1-piperazinil)-acetate (6d). To a solution of 1-(3-nitrophenyl)piperazine (example 6A) (10.0 g; to 48.3 mmol) in anhydrous DMF (50 ml) in small portions was added sodium hydride (2,12 g, 60% dispersion in mineral oil; 53,1 mmol). The mixture was stirred and added 2-bromoacetate. The process of adding very ectothermic. The reaction mixture was allowed to mix at ambient temperature over night. The mixture was poured into water (200 ml) and was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, using ethyl acetate as eluent, to obtain the 6s (14.4 g; 84%).

Example 6E

1-(3-Nitrophenyl)-4-methylpiperazine (6E). A mixture of 3-peritrabecular (20 ml to 0.19 mol) and 1-methylpiperazine (40 ml; 0.36 mol) was heated at 120°C for weeks. The cooled mixture was purified by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and methanol (9:1 o/1). Yield 33 g (79%).

Example 6g

4-(3-Nitrophenyl)-pyridine. A mixture of 4-bromopyridine hydrochloride (8,03 g; a 41.3 mmol), 3-nitrophenylarsonic acid (6.85 g; 41,0 mmol), potassium carbonate (34,2 g; 0.25 mol), 1,3-propane diol (14.9 ml; 0.21 mol), tetrakis(triphenylphosphine) palladium (0.2 g) in a mixture of dimethoxyethane (80 ml) and water (40 ml) was stirred at 80°C in nitrogen atmosphere overnight. The cooled mixture was diluted with ethyl acetate and filtered through celite. The filtrate was evaporated to dryness and to the residue was added water. Intensive mixing caused loss of product in the sediment. The product was filtered, washed with water, dried and then washed with petroleum ether. Output: 8,15 g (99%).

1-Methyl-4-(3-nitrophenyl)-pyridinium monomethyl-sulfate. A mixture of 4-(3-nitrophenyl)pyridine (4.0 g; 20 mmol) and dimethylsulfate (10 ml) was heated at 100°C for 5 days. The cooled mixture was diluted with diethyl ether (50 ml) and carefully moving the m ether and once with ethanol to obtain a crystalline product (2.9 g; 47%).

1-Methyl-4-(3-nitrophenyl)-1,2,5,6-tetrahydropyridine (6g). To a suspension of 1-methyl-4-(3-nitrophenyl)of pyridinium monomethylaniline (2.8 g; 9,03 mmol) in methanol (50 ml) in portions over 30 minutes was added borohydride sodium (0.68 g; 18.0 mmol). After that, the mixture was stirred at ambient temperature overnight. The mixture was diluted with water (200 ml) and was extracted with ethyl acetate (2×100 ml). The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to dryness. In the trituration of the residue with diethyl ether there was obtained crystalline product (1.7 g; 86%).

1-Ethyl-4-(3-nitrophenyl)-1,2,5,6-tetrahydropyridine (6dd) was obtained similarly, by alkylation with iodatum.

Example 6h

1-Acetyl-4-(3-nitrophenyl)-1,2,5,6-tetrahydropyridine (6h). To a mixture of 4-(3-nitrophenyl)pyridine (example 6g) (4.0 g; 20.0 mmol) and acetic anhydride (20 ml) in glacial acetic acid (30 ml) in portions over 1 hour was added borohydride sodium (1.51 g; 40.0 mmol). The resulting mixture was stirred at ambient temperature for five days and then poured into ice-cold water. The mixture was extracted with ethyl acetate, the organic phase is washed with water, dried over magnesium sulfate and concentrated under ponr 6k

3-nitrobenzaldehyde (6K2). To a solution of 3-nitrobenzaldehyde (5.0 g; 33,1 mmol) in absolute ethanol (40 ml) was added hydroxylamine hydrochloride (3,45 g; of 49.6 mmol) and the resulting suspension was heated under reflux overnight. The cooled mixture was poured into water (100 ml), the product was filtered and dried. Output (4.5 g; 82%).

2-(3-(3-Nitrophenyl)-4.5-dihydroisoxazole-5-yl)-acetic acid. To a solution 6K2(3.1 g; 18,8 mmol) in THF (30 ml) was added vinyloxy acid (3,41 ml; of 56.4 mmol). Dropwise, maintaining the temperature in the range of 25-30°C, was added aqueous sodium hypochlorite solution (47 ml; 0.2 M). After the addition the mixture was stirred at ambient temperature overnight. The pH was brought to 4 by addition of aqueous citric acid and the mixture was extracted three times with diethyl ether. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and methanol (9:1 o/o). Yield 4.7 g (98%).

N,N-Diethylcarbamoyl 2-(3-(3-nitrophenyl)-4,5-dihydroisoxazole-5-yl)-acetate (6K). The mixture 6K2(4.6 g; 18.4 mmol), 2-PI the I in anhydrous DMF (25 ml) was stirred at ambient temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue was distributed between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure.

Example 6l

1-(3-Nitrobenzyl)-imidazole (6K). A mixture of 3-nitrobenzylamine (10 g; and 46.3 mmol) and imidazole (6.3 g; of 92.5 mmol) in NMP (10 ml) was stirred at 80°C for the night. The cooled mixture was poured into ice water and was podslushivaet by adding aqueous sodium hydroxide (4M). The precipitate was filtered, washed with water and dried to obtain 61 (6,9 g; 73%).

Example 6m

1-Acetyl-4-(3-nitrobenzyl)-piperazine (6m2). To a solution of 1-acetylpiperidine (5.0 g; 39,0 mmol) in THF (50 ml) was added triethylamine (5.6 ml; 39,0 mmol) and 3-nitrobenzylamine (8,4 g; 39,0 mmol). The mixture was stirred at ambient temperature for 1 hour and the solvent was removed by evaporation. The residue was distributed between water and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated under reduced pressure to obtain with quantitative yield 6m2.

1-(3-Nitrobenzyl)-piperazine (6m1). To a solution of 6m2(10.2 g; 39,0 mmol) in dimethoxyethane (100 ml) was added to dryness and the residue was extracted with a mixture of ethanol and dichloromethane (2:1 o/o). The extract evaporated to dryness to obtain 6m1(6,1 g; 71%).

Ethyl-2-(4-(3-nitrobenzyl)-1-piperazinil)-acetate (6m). To a solution of 6m1(2.5 g; 11.3 mmol) in anhydrous DMF (20 ml) was added sodium hydride (to 13.6 mmol; 0.54 g, 60% dispersion in mineral oil) and ethyl-2-bromoacetate (1.25 ml; 11.3 mmol). The exothermic reaction was over within 15 minutes. The mixture was poured into ice water and was extracted with ethyl acetate. The organic extract was dried over sodium sulfate and evaporated to dryness to obtain with a quantitative yield of 6m.

Example 6n

1-(Ethoxy-carbonyl-methyl)-4-(3-nitrophenyl)-pyridineboronic (6n1).

A mixture of 4-(3-nitrophenyl)pyridine (2.25 g; 11.3 mmol) and ethyl-2-bromoacetate (1.5 ml; 13.5 mmol) in THF (10 ml) was heated under reflux overnight. The cooled mixture was filtered and the crystalline product is washed with THF and dried to obtain 6n1(3,49 g; 84%).

1-(Ethoxy-carbonyl-methyl)-4-(3-nitrophenyl)-1,2,5,6-tetrahydropyridine (6n). To a suspension 6n1(2,90 g; 7,88 mmol) in absolute ethanol (50 ml) in portions over 1 hour was added borohydride sodium (0.6 g; 15.9 mmol). The mixture was stirred at ambient temperature for 2 days, poured into ice water and EXT the ü-ethyl acetate to obtain 6n (1.65 g; 72%).

Example 6o

Ethyl 1-(3-nitrophenyl)-piperidine-4-carboxylate (6o). To a solution of 3-nitrobenzaldehyde (2.0 g; 11.7 mmol) and triethylamine (1.65 ml; 11.7 mmol) in NMP (3 ml) was added isonipecotate (1.8 ml; 11.7 mmol). The mixture was heated at 80°C for the night. The cooled mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate and evaporated to dryness to obtain 6o with a quantitative yield.

Example 6

1-Etoxycarbonyl-4-(3-nitrophenyl)-piperazine (6R). To a solution of 3-fluoro-1-nitrobenzene (3,37 ml; of 31.6 mmol) in NMP (5 ml) was added triethylamine (of 4.38 ml; of 31.6 mmol), ethyl-1-piperidinecarboxylate (4,63 ml; of 31.6 mmol) and the mixture was heated at 120°C for 5 days. The cooled mixture was poured into ice water and added a small amount of ethanol. Intensive mixing caused loss of product in the sediment. The product was filtered, washed with petroleum ether and dried to obtain 6 (3,34 g; 38%).

Example 6q

1-Acetyl-4-(2-hydroxyethyl)-piperazine (6q1). To a solution of 1-(2-hydroxyethyl)piperazine (5.5 ml; of 42.3 mmol) in toluene (50 ml) was added acetic anhydride (4.0 ml; 42,4 mmol). The mixture was heated at 80°C in the first of ether and petroleum ether (1:1 o/a) obtaining 6q1in the form of an oil (5.2 g; 72%).

2-(1-Acetyl-4-piperazinil)-ethyl 3-nitrobenzoate (6q). To a solution of 3-nitrobenzotrifluoride (2.5 g; 13.5 mmol) in a mixture of THF (25 ml) and DMF (5 ml) was added triethylamine (1,87 ml; 13.5 mmol), catalytic amount of 4-(N,N-dimethylamino)pyridine and 6q1(2,32 g; 13.5 mmol). The mixture was heated at 80°C for 2 hours, after which the solvent was removed under reduced pressure. The remainder of pererestorani in dichloromethane and was extracted with diluted hydrochloric acid (4 M). The aqueous phase was podslushivaet by adding aqueous sodium hydroxide (4 M) and was extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel, using as eluent a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 o/o/o). Yield: 1.0 g (23%).

Example 6r

(1-Methyl-2-pyrrolidyl)-methyl 3-nitrobenzoate (6r). To a solution of 3-nitrobenzotrifluoride (2.5 g; 13.5 mmol) in THF (25 ml) was added triethylamine (1,87 ml; 13.5 mmol), catalytic amount of 4-(N,N-dimethylamino)pyridine and (S)-(-)-1-methyl-2-pyrrolidineethanol (1,61 ml; 13.5 mmol). The mixture was heated under reflux for 1.5 hours and left ATOC was distributed between dichloromethane and dilute hydrochloric acid (4 M). The aqueous phase was podslushivaet by adding aqueous sodium hydroxide (4 M) and was extracted with dichloromethane. The organic extract was dried over sodium sulfate and evaporated to obtain 6r (2.8 g; 78%).

The concentrate was purified by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and petroleum ether (9:1 o/o). Yield: 2.6 g (38%).

Example 6u

1-(3-Nitrophenyl)-4-((1-methyl-5-tetrazolyl)-methyl)-piperazine (6u). The solution 6t (2,40 g; 10.0 mmol), sodium azide (1,43 g; 22,0 mmol) and ammonium chloride (0.64 g; to 12.0 mmol) in DMF (25 ml) was heated at 120°C for the night. The cooled mixture was poured into ice water and the precipitate was filtered, washed with water and subjected to air drying to obtain tetrazol (2,03 g).

This intermediate product is suspended in DMF (25 ml) under nitrogen atmosphere was added sodium hydride (0.28 g; 7.0 mmol). After the evolution of hydrogen had ceased, was added itmean (of 0.44 ml, 7.1 mmol) and the mixture was stirred at ambient temperature for 4 hours. The mixture was diluted with four volumes of water and was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. The residue is triturated with a mixture of diethyl ether and petroleum is benzimidazole, presented in Table 5, were obtained by the above scheme, as illustrated below for compound 7a.

5-(3-Furanyl)-1-(3-((4-etoxycarbonyl-1-piperazinil)-methyl)-phenyl)-benzimidazole (7a). To a solution of 8A (0,13 g; 0.31 mmol) in THF was added triethylorthoformate (0.1 ml; of 0.62 mmol) and a catalytic amount paratoluenesulfonyl acid. The mixture was heated at 80°C for 30 minutes. The cooled mixture was diluted with ethyl acetate and washed with aqueous sodium hydroxide and water successively. The organic phase was dried over sodium sulfate and concentrated to small volume. Adding ethereal hydrogen chloride, the product precipitated as hydrochloride. The result of the filter received the product in quantitative yield. TPL248-250°C.

The following compounds were obtained analogously to compound 7a:

5-(3-Furanyl)-1-(3-(1-ethoxy-carbonyl-methyl)-4-piperazinil)-phenyl)-benzimidazole (7b) 8b. The product was purified on silica gel using a mixture of ethyl acetate and ethanol (9:1 o/o), and were isolated as the free base. TPL113-114,5°C.

5-(3-Furanyl)-1-(3-(4-methoxycarbonyl-1-imidazolyl)-phenyl)-benzimidazole (7C) of 8C. TPL221-223°C.

5-(3-Furanyl)-1-(3-(4-trecastle eluent ethyl acetate and was isolated as free base. TPL131-132°C.

N,N-Diethylcarbamoyl 2-(3-(3-(5-(3-furanyl)-1-benzimidazolyl)-phenyl)-4,5-dihydroisoxazole-5-yl)-acetate (7E) of 8E. The product was purified on silica gel, using as eluent ethyl acetate and was isolated as free base.

5-(3-Furanyl)-1-(3-(1-ethoxycarbonylmethyl-4-piperazinylmethyl)-phenyl)-benzimidazole (7f) of 8f. The product was purified on silica gel, using as eluent a mixture of ethyl acetate and ethanol (9:1 o/o), and were isolated as the free base.

5-(3-Furanyl)-1-(3-(1-ethoxycarbonylmethyl-4-piperidyl)-phenyl)-benzimidazole (7g) of 8g. The product was purified on silica gel, using as eluent ethyl acetate and was isolated as free base. TPLOf 114.5-115°C.

5-(3-Furanyl)-1-(3-(4-ethoxycarbonylphenyl-1-ylmethyl)-phenyl)-benzimidazole (7h) of 8h. The product was purified on silica gel, using as eluent a mixture of ethyl acetate and ethanol (9:1 o/o), and were isolated as the free base.

5-(3-Furanyl)-1-(3-(1-etoxycarbonyl-4-piperazinil)-phenyl)-benzimidazole (7i) from 8i. The product was purified on silica gel, using as eluent ethyl acetate and was isolated as free base. TPL131-132°C.

2-(1-Acetyl-dimethyl 3-(5-(3-furanyl)-1-benzimidazolyl)-benzoate (7K) of 8K. TPL198-200°C.

Example 8

All furnishedin phenylendiamine presented in Table 6, were obtained with a quantitative yield by hydrogenation of the corresponding nitro compounds (9), as illustrated below for compound 8A.

2-Amino-4-(3-furanyl)-N-(3-(1-etoxycarbonyl-4-piperazinylmethyl)-phenyl)-aniline (8A). To a suspension of 9a (0,37 g; 0.82 mmol) in ethanol (10 ml) was added Pd catalyst (5% Pd on activated carbon) and the mixture was first made until such time as not to stop the absorption of hydrogen. The mixture was filtered through celite and the solvent was removed by evaporation to give the desired product in quantitative yield.

The following compounds were obtained analogously to compound 8A:

2-Amino-4-(3-furanyl)-N-(3-(1-ethoxycarbonylmethyl-4-piperazinil)-phenyl)-aniline (8b) 9b.

2-Amino-4-(3-furanyl)-N-(3-(4-methoxycarbonyl-1-imidazolyl)-phenyl)-aniline (8C) of 9c, using ethanol as solvent.

2-Amino-4-(3-furanyl)-N-(3-(1-tert-butoxycarbonyl-4-piperazinil)-phenyl)-aniline (8d) of 9d, using THF as solvent.

N,N-Diethylcarbamoyl 2-(3-(3-(2-amino-4-(3-furanyl)-phenylamino)-phenyl)-4,5-dihydroisoxazole-5-Tyl-4-piperazinylmethyl)-phenyl)-aniline (8f) of the 9f.

2-Amino-4-(3-furanyl)-N-(3-(1-etoxycarbonyl-4-piperidyl)-phenyl)-aniline (8g) of 9g.

2-Amino-4-(3-furanyl)-N-(3-(4-etoxycarbonyl-1-piperidinyl)-phenyl)-aniline (8h) of 9h.

2-Amino-4-(3-furanyl)-N-(3-(4-etoxycarbonyl-1-piperazinil)-phenyl)-aniline (8i) from 9i.

2-(4-Acetyl-1-piperazinil)ethyl 3-(N-(2-amino-4-(3-furanyl)-phenyl)-amino)-benzoate (8j) 9j, using THF as solvent.

1-Methyl-2-pyrrolidinyl 3-(N-(2-amino-4-(3-furanyl)-phenyl)-amino)-benzoate (8k) of 9k, using THF as solvent.

Example 9

All furnishedin nitroaniline presented in Table 7 were obtained by the interaction 10 (obtained as described in WO 96/33194) with substituted aniline 4 (see example 4), as described below for compound 9a.

2-Nitro-4-(3-furanyl)-N-(3-(1-etoxycarbonyl-4-piperazinylmethyl)phenyl)-aniline (9a). To a solution of 10 (0.75 g; 3.61 mmol) in NMP (5 ml) was added triethylamine (of 0.53 ml, 3.61 mmol) and 4A (1.0 g; a 3.83 mmol). The mixture was heated at 110°C for 2 days, then poured into water and was extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by means of colonic yhod: 23%.

The following compounds were obtained analogously to compound 9a:

2-Nitro-4-(3-furanyl)-N-(3-(1-ethoxycarbonylmethyl-4-piperazinil)-phenyl)-aniline (9b) of 10 and 4b.

2-Nitro-4-(3-furanyl)-N-(3-(4-methoxycarbonyl-1-imidazolyl)-phenyl)-aniline (9c) of 10 and 4C. As eluent ethyl acetate was used.

2-nitro-4-(3-furanyl)-N-(3-(1-tert-butoxycarbonyl-4-piperazinil)-phenyl)-aniline (9d) of 10 and 4i.

N,N-Diethylcarbamoyl 2-(3-(3-(N-(2-nitro-4-(3-furanyl)-phenyl)-amino)-(phenyl)-4,5-dihydroisoxazole-5-yl)-acetate (9F) out of 10 and 4k. As eluent was used a mixture of ethyl acetate and petroleum ether (9:1 o/o).

2-Nitro-4-(3-furanyl)-N-(3-(1-ethoxycarbonylmethyl-4-piperazinylmethyl)-phenyl)-aniline (9f) out of 10 and 4m.

2-Nitro-4-(3-furanyl)-N-(3-(1-etoxycarbonyl-4-piperidyl)-phenyl)-aniline (9g) of 10 and 4n. As eluent was used acetate

2-Nitro-4-(3-furanyl)-N-(3-(4-etoxycarbonyl-1-piperidinyl)-phenyl)-aniline (9h) 10 and a.

2-Nitro-4-(3-furanyl)-N-(3-(4-etoxycarbonyl-1-piperazinil)-phenyl)-aniline (9i) of 10 and 4P.

2-(4-Acetyl-1-piperazinil)ethyl-3-(N-(2-nitro-4-(3-furanyl)-phenyl)-amino)-benzoate (9j) of 10 and 4q. As eluent was used acetate

1-Methyl-2-pyrrolidinyl 3-(N-(2-nitro-4-(3-furanyl)-f�90:10:1).

Example 10

5-(3-Furanyl)-1-(3-(1-(3-methyl-5-oxadiazolyl)-4-piperazine)-phenyl)-benzimidazole (11). To a solution of sodium (0.12 g; 5.2 mmol) in absolute ethanol (10 ml) was added molecular sieves (0.5 g), ndimethylacetamide-oxime (0,19 g; 2.57 mmol) and 7b (1.0 g; 2.32 mmol). The mixture was heated under reflux overnight. The cooled suspension was diluted with dichloromethane (50 ml) and stirred until then, until the organic material is not dissolved. Molecular sieves were filtered off and the filtrate was washed with water and brine, dried over sodium sulfate and evaporated to dryness. The residue was dissolved in toluene and was added a catalytic amount paratoluenesulfonyl acid. The mixture was heated at 100°C overnight, then cooled mixture is washed with aqueous sodium carbonate, dried over sodium sulfate and evaporated to dryness. The residue is triturated with diethyl ether to obtain 11 (0,47 g; 46%). TPL129-130°C.

Example 11

Ethyl (E)-3-(1-(3-(4-methyl-1-piperazinil)-phenyl)-benzimidazole-5-yl)-propenoate (12). To a suspension of sodium hydride (40 mg, 60% dispersion in mineral oil, 1.0 mmol), kept in an inert atmosphere, was added triethylphosphite (0.2 ml; 1.0 mmol). The mixture premesis is 13 (0.33 g; to 0.94 mmol) in anhydrous toluene (5 ml). Stirring was continued for 15 minutes at room temperature, after which the temperature was raised to 60-65°C for the night. The solvents were removed under reduced pressure and the residue was distributed between water and ethyl acetate. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated. The concentrate was purified by column chromatography on silica gel, using as eluent a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 o/o/o). Fractions containing the product were evaporated to dryness, pererestorani in absolute ethanol and precipitated the product as hydrochloride by adding ethereal hydrogen chloride. Yield: 0.28 g (68%). TPL129-130°C (decomposition).

5-Acetyl-1-(3-(4-methyl-1-piperazinil)-phenyl)-benzimidazole (13). To a solution of 14 (0.75 g; 2.34 mmol) in anhydrous DMF (10 ml) was added sodium hydride (0.1 g, 60% dispersion in mineral oil). The mixture was stirred for 30 minutes and added itmean (0.15 ml; 2.34 mmol). After one hour the mixture was poured into ice water and was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced consistently mixture of ethyl acetate and methanol (9:1 o/o 1:1 o/o). Yield: 0.34 g (41%).

5-Acetyl-1-(3-(1-piperazinil)-phenyl)-benzimidazole (14). To a solution of 15 (8,3 g; 23,0 mmol) in dimethoxyethane (140 ml) was added aqueous sodium hydroxide (70 ml; 1 M) and the mixture was heated under reflux overnight. Volatile solvent was removed and the aqueous suspension was extracted with dichloromethane. The extract was dried over sodium sulfate, concentrated and suirable through silicagel column with a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 o/o/o). Yield: 4.8 g (65%).

5-Acetyl-1-(3-(1-acetyl-4-piperazinil)-phenyl)-benzimidazole (15). 16 (17,7 g, 50.3 mmol) was treated with triethylorthoformate as described in example 1. The product was purified by column chromatography on silica gel, using as eluent a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 o/o/o). Yield: 16.0 g (88%).

2-(3,5-Dimethyl-1-piperazinil)ethyl 3-(5-acetylbenzoate-1-yl)-benzoate was obtained similarly to obtain 15. The compound was treated with hydroxylamine hydrochloride in absolute ethanol to obtain 2-(3,5-dimethyl-1-piperazinil)ethyl 3-(5-acetylbenzoate-1-yl)-benzoyloxy (15a). TPL255-260°C

2-(2-Pyridyl)methyl 3-(5-acetylbenzoate-1-yl)-benzoate was obtained analogues of the 2-(2-pyridyl)methyl 3-(5-acetylbenzoate-1-yl)-benzoyloxy (15b). TPL162-163°C.

N-(4-Acetyl-2-AMINOPHENYL)-3-(1-acetyl-4-piperazinil)-aniline (16). 17 (45 g; 93,6 mmol) was first made as described in example 2, and with a quantitative yield was obtained 16.

N-(4-Acetyl-2-nitrophenyl)-3-(1-acetyl-4-piperazinil)-aniline (17). To a solution of 18 (17.1 g; 93,6 mmol) (obtained as previously described in WO 96/33191) and triethylamine (13 ml; 93,6 mmol) in anhydrous NMP (50 ml) was added 4f and the mixture was heated at 80°C for 4 hours. The cooled mixture was poured into ice water and was extracted three times with ethyl acetate. The organic extract was dried over sodium sulfate and evaporated to dryness to obtain 17 with a quantitative yield.

Example 12

Ethyl 1-(3-(4-acetyl-1-piperazinil)-phenyl)-6-forbesides-5-carboxylate (19) were obtained from 20 analogously to example 1. As eluent was used a mixture of ethyl acetate and ethanol (9:1 o/o). Yield: 55%. The melting temperature is not defined.

Ethyl 3-amino-4-(3-(4-amatil-1-piperazinil)-phenyl)-amino-6-perbenzoate (20) were obtained from 21 analogously to example 2. As a solvent used absolute ethanol. The quantitative output.

Ethyl 4-(3-(4-acetyl-1-piperazinil)-phenyl)-amino-6-fluoro-3-nitrobenzoate (21). The mixture is 0 ml) was heated at 80°C for 1 hour. The cooled mixture was poured into water and was extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, concentrated under reduced pressure and was purified by column chromatography on silica gel, using as eluent ethyl acetate. Output: 1,53 g (82%).

Ethyl 2,4-debtor-5-nitrobenzoate (22). To a cooled (-5-0°C) a solution of ethyl-2,4-differentiate (3.4 g; and 18.3 mmol) in concentrated sulfuric acid (6 ml) was added in small portions during 1 hour potassium nitrate (1,94 g; 19.2 mmol), keeping the temperature between -5°C. After the addition the temperature was allowed to rise for about 4.5 hours up to 20°C. the Mixture was poured into ice water with vigorous stirring. The product was filtered, washed with water and subjected to air drying. Yield: 3.2 g (76%).

Example 13

Binding activity in vitro and in vivo

Website recognition GABA and benzodiazepine modulatory unit can selectively mark3H-muscimol and3H-flunitrazepam, respectively.

13A: Inhibition of binding3H-flunitrazepam (3H-FNM) in vitro

Obtaining tissue

The drugs were given at 0-4°C, unless otherwise noted. The cerebral cortex chloride) (30 mm, pH 7.4) using a homogenizer (Ultra-Turrax. The suspension is centrifuged at 27000×g for 15 minutes and the precipitate washed three times with buffer (cetrifugation when 27000×g for 10 minutes). The washed precipitate homogenized in 20 ml of buffer and incubated in a water bath (37°C) for 30 minutes to remove endogenous GABA, and then centrifuged for 10 minutes at HD. The precipitate is then homogenized in buffer and centrifuged for 10 minutes at 27000×g. The final precipitate resuspended in 30 ml of buffer, the product is frozen and stored at -20°C.

Analysis

The membrane preparation is thawed and centrifuged at 2°C for 10 minutes at 27000×g. The precipitate washed twice with 20 ml of 50 mm Tris-citrate (pH of 7.1) using a homogenizer (Ultra-Turrax and centrifuged for 10 minutes at 27000×g. The final precipitate resuspended in 50 mm Tris-citrate pH of 7.1 (500 ml buffer per 1 g of original tissue) and then used in the analysis of binding. Aliquots of 0.5 ml of tissue added to 25 μl of the solution for analysis and 25 ál3H-FNM (final concentration 1 nm), mixed and incubated for 40 minutes at 2°C. non-specific binding determine using clonazepam (final concentration 1 μm). After incubation the samples dobavleniem and immediately washed with 5 ml chilled on ice buffer. The amount of radioactivity on the filters was determined by conventional liquid scintillation counter. Specific binding represents the total binding minus nonspecific binding.

Results

Before the calculation of the IC50must be received 25-75% inhibition of specific binding.

The value of the analysis are as IC50(the concentration (μm) of the analyte, which inhibits the specific binding3H-FNM 50%).

IC50=(used concentration of the analyte, μm) ×

where

WITH0specific binding in control analysis; and

WITHxspecific binding in the experimental analysis.

(Calculations assume normal kinetics of mass action).

The results of these experiments are shown in Table 8 below.

13B: Inhibition of binding3H-flunitrazepam (3H-FNM) in vivo

Introduction

Research associate in vitro showed that benzodiazepine [3H]FNM binds selectively and with high affinity complex with GABAAthe receptor - ion channel. [< binding will occur throughout the brain, because GABAAreceptors are widely distributed. Specific binding of [3H]FNM can be partially or completely prevented by simultaneous or prior administration of pharmacologically active benzodiazepines or other benzodiazepine compounds.

Way

All of the analyte used in the form of solutions prepared in 10% TWEEN 80 (TWEEN 80). Groups of 3 female NMRI mice (25 g) is injected intravenously through the tail vein of 5.0 µci of [3H]FNM in 0.2 ml of saline. 15 minutes after injection of [3H]FNM injected an analyte. 20 minutes after injection of [3H]FNM mice killed by decapitation, the front brain rapidly removed and homogenized in 12 ml of chilled on ice in 50 mm Tris-citrate pH of 7.1, using a homogenizer (Ultra-Turrax. Three aliquots of 1 ml immediately filtered through glass fiber filters GF/C and washed with chilled on ice buffer (2×5 ml). The amount of radioactivity on the filters and 200 μl of the homogenate was determined by conventional liquid scintillation counting. Groups of untreated mice served as control. To determine nonspecific binding, groups of represents the number of binding in the controls minus the amount of binding of the treated clonazepam mice.

Results

The value of the ED50define the curves of dose-response. If you enter only one dose of the analyte, then the value of the ED50calculated as follows, assuming that the inhibition of specific binding is within the interval 25-75%.

ED50=(input dose (mg/kg) ×

where Caboutspecific binding in the controls, andx- specific binding in mice treated with the analyzed substance.

The results of these experiments are presented in Table 8 below.

Example 14

Clonic convulsions induced PT

The purpose of this test is to show the antagonism clonic seizures induced by pentylenetetrazole (PT). PT induced clonic seizures in mice after intravenous infusion. The antagonism induced PT cramps is a measure of agonistic nature of the ligands for the benzodiazepine recognition.

Procedure

Female NMRI mice (Bomholdtgaard, Ry), 20 g, 6 mice in each group, injected carrier or an analyte. After 5 minutes, carry out intravenous infusion solution PDO occurrence of clonic seizures.

Dose PT required for the induction of seizures in each mouse count as PT/kg of body weight. Calculate average values±standard deviation () for each experimental group of 6 mice. ED100calculated by linear regression expressions doses increasing the threshold PT to 100 mg PT/kg

The threshold value controls treated with the carrier is in the range of 37-39 mg PT/kg as a control in each experiment the reserve is administered by infusion of six mice treated with media.

The results of these experiments are presented in Table 9 below.

Example 15

Evaluation of effectiveness

Selected compounds showing promising profile in the above analyses, evaluated for effectiveness and duration of action and compared with the prior art as follows.

Aqueous solutions of the analyzed substances (50 mg/ml of isotonic glucose) was administered to pigs (25-30 kg) as a bolus injection. The actual dose of each substance included in the table below. Pigs were observed for the time of induction of anesthesia, cont is found in Table 10, are presented below. This table also contains comparative data for the compounds of the prior art (WO 98/17651).

From the table it can be concluded that the compounds of the present invention have a very favorable profile with respect to time of induction, duration of action and recovery time. Compared with the compounds of the prior art that show or too weak anesthetic action, or too long cooldown, the compounds of the present invention meet the criteria for promising anesthetics.

The example of the pharmaceutical composition

Tablet containing compound 1b, mg:

Compound 1b 200

Potato starch 50

Milk sugar 45

Talc 5

Total 300

The composition obtained by dry mixing the compound of Example 2, milk sugar and part of the starch, moistening the mixture of starch paste, granulation of the mass, drying the granules, dusting and subsequent pressing of the tablets.

1. A derivative of benzimidazole represented by the General formula I

or its pharmaceutically acceptable yet an alkyl, alkenyl or quinil,

q is 0 or 1,

R1represents a group of formula-CO2R2where

R2represents a hydroxy-alkyl, alkoxy-alkyl or dialkoxy-alkyl,

R represents a group of the formula

where o is 0 or 1;

n is 0, 1 or 2;

X represents N or CH;

Y represents O, NR11or CHR11,

where R11represents hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-SP, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5,

moreover, in these formulas, R, s and t independently of each other 0 or 1,

"heterocycle" represents a 5-membered monocyclic heterocyclic group which contains in its structure one or more than one heteroatom, representing nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5hydroxy, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7,

moreover, in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and

R14and R15independently of one another represent hydrogen, alkyl, hydroxy-alkyl, alkoxy-alkyl, carboxyl or acyl;

or where R represents a group of formula -(ALK)q-R1where

(Ala) is an alkyl, alkenyl or quinil,

q is 0 or 1,

R1represents fornillo group; and

R represents -(alkyl)m-CO2R8,

where m is 0 or 1, and

R8represents a group of formula -(alkyl)p-NR9R10,

where p is equal to 0 or 1, and

R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted acyl.

2. A derivative of benzimidazole under item 1, where R represents a 2-(4-acetylpiperidine-1-yl)-ethoxy-carbonyl.

3. A derivative of benzimidazole under item 2, which is 2-(1-acetyl-4-piperazinil)-ethyl-3-(5-(3-furanyl)-1-benzimidazolyl)-benzoate the ILIT a group of the formula-CO2-CH2-CH(OH), -CO2(CH2)2OCH3, -CO2(CH2)2S3or-CO2(CH2)2SC2H5.

5. A derivative of benzimidazole under item 1, where R represents a 4-(1-methyl-5-tetrazolyl)-methyl-1-piperazinil;

4-(2-oxazolidinone-5-yl)-methyl-1-piperazinil;

4-(5-metronidazol-3-yl)-methyl-1-piperazinil;

4-(3,5-dimethylisoxazol-4-yl)-methyl-1-piperazinil;

4-(2-oxo-tetrahydrofuran-3-yl)-1-piperazinil; or

4-(2-chloro-5-thienyl)-methyl-1-piperazinil.

6. A derivative of benzimidazole under item 5, which is a

2-methoxyethyl-1-(3-(4-(1-methyl-5-tetrazolyl)methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-(5-metronidazol-3-yl)-methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-(3,5-dimethylisoxazol-4-yl)-methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-(2-oxo-tetrahydrofuran-3-yl)-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-(2-chloro-5-thienyl)-methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

or their pharmaceutically acceptable salt.

7. "ptx2">4-etoxycarbonyl-methyl-3,5-dimethyl-1-piperazinil;

4-methyl-3,5-dimethyl-1-piperazinil;

4-ethyl-3,5-dimethyl-1-piperazinil; or

3,5-dimethyl-1-piperazinil.

8. Connection on p. 7, which is a

2-methoxyethyl-1-(3-(4-ethoxycarbonylmethyl-3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-ethyl-3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(3,5-dimethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

or their pharmaceutically acceptable salt.

9. A derivative of benzimidazole under item 1, where

R represents a group of the formula

in which o is 0 or 1;

n is 0, 1 or 2;

X represents N or CH, and

Y represents NR11or CHR11where

R11represents hydrogen, alkyl, hydroxy alkyl, carboxy, acyl or a group of the formula -(alkyl)p-SP, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl or -(alkyl)t-FULFILLS I TS COR5,

where R and t independently of each other 0 or 1, and R5represents a hydroxy, alkoxy, NH2, NH(alkyl) and the and-carbonyl)-1-piperazinylmethyl;

4-(ethoxy-carbonyl)-1-piperazinylmethyl;

4-(methoxy-carbonyl-methyl)-1-piperazinil;

4-(ethoxy-carbonyl-methyl)-1-piperazinil;

4-(methoxy-carbonyl-methyl)-1-piperazinylmethyl;

4-(ethoxy-carbonyl-methyl)-1-piperazinylmethyl;

1-piperazinil;

1-piperazinil-methyl;

4-acetyl-1-piperazinil;

4-methyl-1-piperazinil;

4-ethyl-1-piperazinil;

1-methyl-4-piperidinyl;

1-acetyl-4-piperidinyl;

1-methyl-4-piperidyl;

1-acetyl-4-piperidyl;

4-tert-butoxycarbonylmethyl-1-piperazinil;

4-isopropoxycarbonyl-1-piperazinil;

4-carboxymethyl-1-piperazinil;

4-benzyl-1-piperazinil;

4-cyanomethyl-1-piperazinil;

4-benzyloxy-ethyl-1-piperazinil;

4-ethyl-1-homopiperazine;

4-(2-hydroxy-ethyl)-1-piperazinil;

4-carbamoylmethyl-1-piperazinil;

4-dimethylcarbamoyl-1-piperazinil; or

4-diethylcarbamoyl-1-piperazinil.

11. Connection on p. 10, which represents

2-methoxyethyl-1-(3-(4-etoxycarbonyl-1-piperazinylmethyl)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-acetyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(1-methyl-4-piperidyl)phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(1-acetyl-4-piperidyl)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-tert-butoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-ISO-propoxycarbonyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-(methylthio)-ethyl-1-(3-(4-methyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-benzyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-cyanomethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-benzyloxyethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-ethyl-1-homopiperazine)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-ethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl-1-(3-(4-(2-hydroxyethyl)-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(1-piperazin-5-carboxylate;

2-hydroxyethyl-1-(3-(4-methoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl-1-(3-(4-ethoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-diethylcarbamoyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-methoxycarbonylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-methoxyethyl-1-(3-(4-carbamoylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl-1-(3-(4-carbamoylmethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl-1-(3-(4-diethylcarbamoyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

2-hydroxyethyl-1-(3-(4-carboxymethyl-1-piperazinil)-phenyl)-benzimidazole-5-carboxylate;

or their pharmaceutically acceptable salt.

12. Pharmaceutical composition for modulation of GABAAND-a receptor complex containing a therapeutically effective amount of the benzimidazole derivative according to any one of paragraphs.1-11 or its pharmaceutically acceptable salt accession, together with at least one pharmaceutically acceptable carrier, excipient or diluent.

13.egenia disease, or disorder, or condition that is sensitive to modulation of GABA-a receptor complex, in a mammal, including humans.

14. A derivative of benzimidazole according to any one of paragraphs.1-11 for the production of medicines intended for the induction of anesthesia, pre-anesthesia, muscle relaxation or sedation, or for treatment, prevention or relief of small seizures or epileptic status.

15. A method of treating, preventing or alleviating disease or disorder, or condition that is sensitive to modulation of GABA-a receptor complex, the animal, including man, comprising a stage on which such needy in this animal is administered a therapeutically effective amount of the benzimidazole derivative according to any one of paragraphs.1-11.

16. The method according to p. 15 for the induction or maintenance of anesthesia or pre-anesthesia, muscle relaxation or sedation, or for treatment, prevention or relief of small seizures or epileptic status.



 

Same patents:

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to chemistry and medicine, in particular relates to new chemical compounds - derivatives of 3,4-bis(furazan-3-yl)furoxan General formula I:

where R = R1= HE, NH2N3lowest alkoxy or a group of the General formula NR2R3where R2= R3= N or R2and R3together with the nitrogen atom form piperidinyl cycle, or R = NH2and R1- (lower alkanoyl)amino group, provided that R and R1not represent methoxy, possessing pharmacological activity

The invention relates to organic chemistry and pharmacology, and relates new connection - 1-(1,1-dissociator-3)-2-morpholinobenzenediazonium hydrochloride, increasing resistance to acute hypoxia with hypercapnia

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to the field of chemistry, particularly the proton pump inhibitors

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to new imidazole-cyclic acetals of the formula I, where R1- optionally substituted 4-pyridyl or optionally substituted 4-pyrimidinyl; R2is phenyl, substituted with halogen; R3is hydrogen; R4refers to a group - L3-R14; R5is hydrogen, alkyl or hydroxyalkyl; or R4and R5when attached to the same carbon atom, may form with the specified carbon atom kernel cycloalkyl or the group C=CH2; R6is hydrogen or alkyl and m=1; L3and R14have the meanings specified in the description, and pharmaceutically acceptable salts and solvate (for example, hydrates), which have inhibitory activity against TNF-alpha, as well as to intermediate compounds, pharmaceutical compositions and method of treatment

The invention relates to new derivatives of 2-aminopyridine F.-ly (1) where denotes unsubstituted or substituted phenyl, pyridyl, thienyl, thiazolyl, hinely, cinoxacin-2-yl or Antonelliana derivatives; D is unsubstituted or substituted phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, hinely, triazolyl, oxazolyl, isoxazolyl or Antonelliana derivatives, provided that C and D are not simultaneously have the following values: S - phenyl, and D is phenyl, S - phenyl, and D - pyridyl, With - pyridyl and D - phenyl, - pyridyl and D - pyridyl; R1- R4- hydrogen, NO2or NH2

The invention relates to a derivative copernicia and their pharmaceutically acceptable salts of General formula I

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where R1represents a methyl group, R2represents a methyl group, R4represents a hydroxy-group and X represents a methylene group; R1represents a methyl group, R2represents a hydrogen atom, R4represents a hydroxy-group and X represents a methylene group; R1represents a methyl group, R2represents a methyl group, R4represents a hydrogen atom and X represents a methylene group; R1represents a hydrogen atom, R2represents a hydrogen atom, R4represents a hydroxy-group and X represents a methylene group; or R1represents a methyl group, R2represents a methyl group, R4represents a hydroxy-group and X represents a sulfur atom
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