Derivatives benzimidazolone, mixtures of their isomers or their acid additive salt as a receptor antagonist 5 - ht*00i*00a and 5-ht*002

 

(57) Abstract:

The object of the invention are derivatives of benzimidazolone General formula (I) described in the claims, where R1and R2the same or different and mean a hydrogen atom, halogen atom, trifluoromethyl, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms, hydroxy, nitro group or amino group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, acylamino with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, cyano, aralkylamines with 1-6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, or aminosulfonyl group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms; R3is a hydrogen atom, alkyl with 1 to 6 carbon atoms, alkenyl with 2-6 carbon atoms or quinil with 2-6 carbon atoms; a group-CO - or-CONH-, or a is absent; B is an unbranched or branched, UB>4is phenyl, naphthyl or benzodioxan, unsubstituted or substituted by at least one Deputy from the group comprising halogen atom, trifluoromethyl, cyano, alkoxy with 1 to 3 carbon atoms and alkyl with 1 to 4 carbon atoms, mixtures of their isomers or individual isomers and their acid additive salts, which possess biological activity, in particular can be used as a receptor antagonist 5 - HT1Aand 5-HT2. 2 S. and 2 C.p. f-crystals, 3 tables.

The invention relates to new derivatives of benzimidazolone, possessing valuable pharmacological properties, in particular derivatives benzimidazolone General formula

< / BR>
where R1and R2the same or different and mean a hydrogen atom, halogen atom, trifluoromethyl, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms, hydroxy, nitro group or amino group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, acylamino with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, cyano, alcalali disubstituted by alkyl with 1 to 4 carbon atoms, or aminosulfonyl group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms;

R3a hydrogen atom, alkyl with 1 to 6 carbon atoms, alkenyl with 2-6 carbon atoms or quinil with 2-6 carbon atoms;

And the group-CO - or-CONH-, or a is absent;

In an unbranched or branched, saturated or unsaturated alkyl with 2 to 6 carbon atoms;

m and n independently of one another denote an integer of 1 to 3;

R4phenyl, naphthyl or benzodioxan, unsubstituted or substituted by at least one Deputy from the group comprising halogen atom, trifluoromethyl, cyano, alkoxy with 1 to 3 carbon atoms and alkyl with 1 to 4 carbon atoms,

mixtures of their isomers or individual isomers and their acid additive salts.

For pharmaceutical use, the compound of General formula (I) can be applied or as such or in the form of the tautomers or physiologically-tolerated acid additive salts. Under acid additive salts means salts with inorganic or organic acids. As physiologically portable organic acids that can be used in the form of a salt, can be called, for example, maleic acid, lemon the strong acid, gluconic acid, izational acid, glycine acid, lactic acid, malic acid, Mukanova acid, glutamic acid, sulfamic acid and ascorbic acid, as well as suitable inorganic acids can be called hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.

Some of the compounds of General formula (I) contain chiral or probiralsya centers and therefore may exist in different stereoisomeric forms, including (+)- and (-)-enantiomers and their mixtures. The present invention relates to the individual isomers and their mixtures.

In the case of mixtures of optical isomers may be divided by a known method on the basis of their different physical and chemical properties, for example, by fractional crystallization of their acid additive salts suitable optically active acid or by chromatography using a suitable solvent mixture.

Preferred within the invention are those compounds in which a is absent, means an unbranched saturated alkyl with 2 to 4 carbon atoms, m and n mean 2, and R4means substituted penisa formula (I) can be obtained by the following methods.

a) Compound of General formula

< / BR>
in which G has the meaning of the radical R3or is the failure of the protective group, for example alkoxycarbonyl, aryloxyalkyl, arylalkyl, alkylaryl, preferably etoxycarbonyl, alpha methylvinyl, alpha fineliner,

And no,

R1, R2, R3and have the above values,

X removable group, for example halogen atom, methanesulfonate or 4-methylbenzenesulfonate,

subjected to interaction with the compound of General formula

< / BR>
in which R4, m and n have the above significance.

The interaction is preferably carried out in an environment of a solvent, such as alcohol, ketone, benzene, ethyl acetate, acetonitrile, dioxane, chloroform or di-methylformamide, at temperatures from 0 to 150oC, preferably at the 5oC, or at the boiling point of the used solvent. If necessary, you can use an acid acceptor, for example sodium carbonate, triethylamine or similar In the case when G is alkoxycarbonyl or aryloxyalkyl as a protective group, it is advisable to take during interaction or by further processing of the aqueous alkali, Lucae, if G means arylalkyl or alkylaryl, then it can be removed by subsequent treatment with acid, for example aqueous hydrochloric acid or sulfuric acid. In any of these cases get a connection General formula (I) in which R3means a hydrogen atom.

The compound of General formula (II) used as starting compound in carrying out the above method, can be obtained by reacting compounds of General formula

< / BR>
in which R1, R2and G have the abovementioned meaning,

with alkalihalide or haloalkane in the presence of a strong base such as sodium hydride, in an environment aprotic solvent, such as tetrahydrofuran or dimethylformamide, or solid potassium hydroxide in an environment dimethyl-formamide at a temperature of from 20 to 100oC, or in the presence of aqueous alkali, such as sodium hydroxide or potassium, in an environment of organic solvent, insoluble in water, such as methylene chloride, benzene or toluene, and in the presence of catalytic amounts of a catalyst of transition phases, such as Quaternary ammonium salts, at a temperature of 20oC to the boiling point of the used solvent. In fact with what sulfonylurea or 4-methylbenzenesulfonamide transferred to the methanesulfonate or 4-methylbenzenesulfonate to obtain compounds of General formula (III). Compounds of General formula (IV) can be put m the methods known from the literature, for example J. Org.Chem. N 38, S. 3498-3502, 1973,

or

b) the compound of General formula

< / BR>
in which R1, R2, R4And, B, m and n have the abovementioned meaning,

subjected to interaction with the derived carbonyl General formula

< / BR>
in which Y and Y' are the same or different deleted group, for example halogen atom, halogenoalkane, alkoxy, aryloxy, or a heterocycle, preferably a chlorine atom, trichlormethane, methoxy, ethoxy or imidazolyl.

Interaction can be done in an environment aprotic solvent, such as tetrahydrofuran, methylene chloride, chloroform, acetone, acetonitrile, benzene, toluene, ethyl acetate, carbon tetrachloride or dimethylformamide, if necessary in the presence of an acid acceptor, such as triethylamine, pyridine or sodium carbonate or potassium at a temperature of from 0 to 100oC, preferably at room temperature.

The compound of General formula (V) used as starting compounds for carrying out the above method, can be obtained by restoring the compounds of General formula

< / BR>
< / BR>
with a compound of General formula

< / BR>
in which R1, R2, R4In, m, n have the abovementioned meaning and Hal means a group to delete, for example atom galactosides, for example, butanol, isopropanol, ethanol, etc. or without a solvent at a temperature of from 50 to 200oC.

Compounds of General formula (IX) it is expedient to obtain, for example, by restoring the corresponding nitrile of General formula

< / BR>
in which R4, m and n have the abovementioned meaning,

In contains one carbon atom less than according to the above value.

Interaction is advisable to carry out by catalytic hydrogenation in an environment of ammonia or acids, for example hydrochloric acid, in the presence of a catalyst, such as Raney Nickel, platinum dioxide or etc., Or NITRILES of General formula (X) can be recovered with the metal hydride, for example lithium aluminum hydride, or sodium borohydride.

In case a represents a carbonyl group, CO, compounds of General formula (VII) can be obtained by reacting compounds of the formula

< / BR>
with a compound of General formula

< / BR>
in which R1, R2, R3, B, m, n and Hal have the above values,

A represents a carbonyl group.

The interaction is carried out in the environment aprotic solvent, such as tetrahydrofuran, acetonitrile, chlorine is lots preferably in the environment of pyridine at a temperature of from 20 to 100oC, preferably at temperatures from 20 to 80oC. the Compound of General formula (XII) can be obtained by well-known specialist methods. In that case, if a means carboxamido group-CONH-, the compound of General formula (VII) can be obtained by reacting compounds of General formula

< / BR>
in which R1and R2have the above meaning,

with a compound of General formula (IX).

Interaction is advisable to carry out in the environment aprotic solvent, such as tetrahydrofuran, chloroform, toluene, benzene or cyclohexane, at a temperature of from 0 to 80oC, preferably from 5 to 30oC.

To obtain compounds of General formula (I) in which a is absent or a represents a carbonyl group, the compound of General formula

< / BR>
in which R1, R2and R3have the above meaning,

M indicates a metal atom, for example an atom of sodium, potassium or lithium, preferably sodium,

subjected to interaction with the compound of General formula

< / BR>
in which Hal, A, m, n, A and R4have the above values.

The interaction of the preferred implementation is at a temperature of from 0 to 100oC, preferably at room temperature.

The compound of formula (XIV) are obtained in situ from the corresponding hydrogen-containing compounds using sodium, potassium, hydride, or hydroxide of sodium or potassium tert.the butyl potassium, utility or diisopropylamide lithium, preferably sodium hydride. In the case of using sodium hydroxide or potassium hydroxide in a concentrated aqueous solution interaction, it is advisable to carry out in the environment inorganic solvent that is not miscible with water, such as methylene chloride, in the presence of a catalyst of transition phases, such as the corresponding Quaternary ammonium salt at a temperature of from 20 to 50oC. the Compound of General formula (XV) in which a is absent or a represents a carbonyl group, can be obtained from suitable starting compounds put m well-known specialist methods.

g) To obtain compounds of General formula (I) in which a represents a group-CONH-, the compound of General formula

< / BR>
in which R1, R2and R3have a specified value,

L means removable group, for example halogen atom or alkoxy, preferably a chlorine atom, methoxy or ethoxy,

subjected to interaction with connected is an example of tetrahydrofuran, of methylene chloride, ethyl acetate, acetonitrile, acetone or benzene, if necessary in the presence of acceptor organic or inorganic acid, such as triethylamine, pyridine, or sodium carbonate or potassium at a temperature of from -10oC to the boiling point of the used solvent, preferably at room temperature. Compounds of General formula (XVI) can be obtained from suitable starting compounds by known methods.

It should be noted that compounds of General formula (I) containing a group R1, R2, R3and R4that can be translated to a different group, R1, R2, R3and R4included in the above list of values that represent a valuable new intermediate compounds. Some changes in the values of the radicals in the above list can also be subjected to intermediate compounds used to obtain compounds of General formula (I).

As examples of such changes can result, for example,

1) the Nitrogroup through recovery can be converted to the amino group.

2) the Amino group by acylation with a suitable carboxylic acid derivative can be converted to alluminare with sennou by alkyl with 1 to 4 carbon atoms.

4) the Amino group by reacting with a corresponding reactive derivative of complex monoether alkalicarbonate acid with 1 to 6 carbon atoms in the alkyl part can be translated in alkoxycarbonyl group with 1 to 6 carbon atoms in the CNS part.

5) Carboxyl by reacting a corresponding reactive carboxylic acid derivative with the corresponding alcohols and amines can be converted to alkoxycarbonyl with 1 to 6 carbon atoms in the CNS or in carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms.

6) Carbarnoyl by dehydration can be converted to the cyano.

7) Alkylthiols with 1 to 6 carbon atoms by oxidation can be translated in alkylsulfonyl with 1 to 6 carbon atoms, and alkylsulfonyl with 1 to 6 carbon atoms by oxidation can be translated in alkylsulfonyl with 1 to 6 carbon atoms.

8) Hydrogen by nitration can be converted to the nitro-group.

9) Hydrogen by halogenation can be converted to halogen.

10) the Compound of General formula (I) in which R3means a hydrogen atom, by alkylation with a suitable alkylhalides in the presence of strong is Italia, such as dimethylformamide or tetrahydrofuran, at a temperature of from 20 to 100oC can be converted into a compound of General formula (I) in which R3means alkyl with 1 to 6 carbon atoms, alkenyl with 2-6 carbon atoms or quinil with 2-6 carbon atoms. In the case of a concentrated aqueous solution of sodium hydroxide or potassium reaction, it is advisable osushestvljaem in the environment is not miscible with water, an organic solvent, such as methylene-chloride in the presence of a catalyst of transition phases, such as suitable Quaternary ammonium salts, at a temperature of from 20 to 50oC.

11) Tertiary amino group by reacting with a suitable alkylation agent, such as methyl or methyliodide, can be converted to Quaternary ammonium derivative.

These reactions are widely known to experts.

Compounds of General formula (I) obtained according to these methods, if necessary, by a known method using inorganic or organic acids can be converted to non-toxic, physiologically tolerated acid additive salts, for example, by reacting compounds as the base with a solution sootvetstvo-additive salts are salts with hydrochloric acid, nitric acid, sulfuric acid, maleic acid, fumaric acid, citric acid, tartaric acid, methanesulfonate, acetic acid, benzoic acid, succinic acid, gluconic acid, lactic acid, glycine acid, malic acid, Mukanova acid, glutamic acid, italianboy acid, phosphoric acid, ascorbic acid or sulfamic acid. Particularly preferred are hydrochloric acid, maleic acid and fumaric acid.

Especially preferred amongst the compounds are the following:

1-[2-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)ethyl] -2,3-dihydro-1H-Benzema-Gasol-2-on (compound 3)

1-[4-(4-(3-chloro-phenyl)piperazine-1-yl)butyl] - 2,3-dihydro-1H-benzimidazole-2-on (compound 4)

1- [4-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)butyl] -2,3-dihydro-1H - benzimidazole-2-on (compound 8)

1-[4-(4-(3-trifluoromethyl-phenyl)Petersen-1-yl)butyl]-3-methyl-2,3-dihydro-1H-benzimidazole-2-on (compound 9)

1-[4-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)butyl]-3 - isopropyl-2,3-dihydro-1H-benzimidazole - 2-on (compound 15)

1-[3-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)propyl] -2,3-dihydro-1H-benzimidazole-2-on (compound 18)<
1-[4-(4-(1-naphthyl)piperazine-1-yl)butyl]-2,3-dihydro-1H-benzimidazole-2-on (compound 30).

We offer new compounds of General formula (I) have valuable pharmacological properties, related to their activity in relation to serotonin receptors in the Central nervous system, in particular receptor subtypes 5-HT1Aand 5-HT2. Thanks to this new connection can be used in economic scale for the prevention and treatment of diseases in which the role played by changes in the functioning of the receptors 5-HT1Aand 5-HT2.

Biochemical and pharmacological properties of the proposed compounds was assessed by determining their ability to bind with the receptors of the 5-HT1Aand 5-HT2their effectiveness was investigated by inducing a known defect in behavior by excitation of the receptors 5-HT1Aand by assessing the antagonism relatively defect in behavior caused by hypusine, stimulating the receptors 5-HT2.

Experiments on binding to receptors.

To determine the binding capacity of the studied compounds was performed experiments on binding to receptors of the 5-HT1Aand 5-HT2.

Receptor 5-HToC for 10 minutes

Experience in linking.

Experiments were performed by incubation 980 μl of the product of homogenization in the presence of 1.0 to 1.5 nmol (10 μl) [3H]-8-OH-DPAT and different concentrations of the investigated compounds dissolved in 10 μl of buffer at a temperature of 30oC for 15 min (final volume 1 ml).

Nonspecific binding was determined in the presence of 100 µmol (10 ál) 5-HT. The Department of [3H]-8-OH-DPAT-free number, which is associated with the receptor, carried out by filtration using filters GF/B Whatman company. Radioactivity was measured put m liquid scintillation spectrometry.

Analysis of the obtained data.

Data binding (Kiindividual compounds have been widely known by regression analysis. The data specified on the basis of availability of radio on the receptors according to the equation KiKT50/(1 + [C]/KD), where CT stands for the oxygen>]-8-OH-DPAT) (dissociation constant).

Receptor 5-HT2.

Preparation of tissue.

Used rats (males breed Sprague Dawley weighing 200-250 g). The cortex of these animals homogenized in 10 containers of ice 0,32 molar sucrose. Product homogenization was centrifuged (1000g for 15 min), and then re-centrifuged supernatant at 48000g within 15 minutes of Centrifugal suspended in 10 vol. 50 mmol of TRIS buffer with a pH equal to 7.4, incubated at temperature 37oC for 10 min and again centrifuged at 48000g within 15 minutes

The residue is then suspended in about 10. 50 mmol TRIS-buffer value (pH = 7,4.

Experience in linking.

The fabric was diluted in 50 mmol TRIS-buffer (pH = 7.4 in the ratio of 1 (by weight) to 100 (vol.), in the result, received a final protein concentration of approximately 200 mg/ml

Experiments on the displacement carried out by incubation 980 μl of a homogeneous mass in the presence of 0.5 and 1.0 nmol (10 μl) [3H]-Ketanserina and different concentrations of the investigated compounds dissolved in 10 μl of buffer at a temperature of 30oC for 10 min (final volume: 1 µl).

Nonspecific binding plrs-D-liargovas acid). The Department of [3H]-Ketanserina-free number, which is associated with the receptor, carried out by filtration using filters GF/B Whatman company. Radioactivity was measured by liquid scintillation spectrometry.

Analysis of the obtained data.

Data binding (Kiindividual compounds have been widely known by regression analysis. The data specified on the basis of availability of radio on the receptors according to the equation KiCT50/(1 + [C]/KD), where CT stands for the coefficient of braking, [C] concentration, and KDfor the constant replacement of used radioligand ([3H]-Ketanserina) (dissociation constant).

The results of some of the proposed compounds for binding to the receptors 5-HT1Aand 5 - HT2are given in table. 1. As comparative compounds used 1-[2-[4-(3-triptoreline-phenyl)-piperazine-1-yl]-ethyl] -3-methyl-benzimidazole-2-it is described in the application GB N 2023594.

Experiments on animals.

The defect in behavior.

This defect is caused by excitation of 5-HT1Areceptors and described Good-win and Green (1985), is in a flat position, course prednisonum the compounds and registering the presence of the above symptoms for 50 min, the symptoms considered. The results of the experiments are expressed in number of symptoms in one rat (see table. 2).

Data represent the average number of deviations from four rats.

The antagonism caused by hypusine convulsive movements of the head.

Convulsive movements of the head are caused by excitation of 5-HT2receptors (see Goodwin and Green, 1985). The experiments consisted in giving the compounds of animals, which before gave hepsin, and reading the number of convulsive movements of the head for 20 min (see table. 3).

The compound of formula (I) or its physiologically tolerable salt of the acid can be used as an active substance in the known pharmaceutical preparations.

Preferably the drugs get in the units corresponding to one dose, i.e., each unit has one dose of the active substance. Thus, each unit contains between 0.01 to 100 mg, preferably from 0.1 to 50 mg of active substance.

Example 1. 1-[4-(4-(2-methoxy-phenyl)piperazine-1-yl)butyl]-2,3-dihydro-1H-benzimidazole-2-on (compound 1).

A mixture of 2 g of 1-(4-chlorobutyl)-2,3-dihydro-1H-benzimidazole-2-she and 2.03 g of the hydrochloride of 1-(2-methoxyphenyl)piperazine with 1.88 g carbonolites salt is filtered off and the solvent evaporated, then the residue is dissolved in dilute hydrochloric acid and washed with ethyl acetate. The aqueous phase is strongly alkalinized put m adding 30% sodium hydroxide, and the resulting product is extracted with ethyl acetate. Subjected to dehydration, after which the solvent is removed in vacuum. The result is a white solid, which process is simple diethyl ether, filtered and recrystallized from isopropanol. Yield: 2.1 g of the target product. Melting point: 160 -161oC.

Analysis:

C22H28N4O2< / BR>
Found, C 69,00; H 7,44; N 14,15

Calculated C 69,45; H 7,42; N 14,73

1H NMR (CDCl3): 9,82 (s, 1H), 7,1-6,7 (8H), 3,93 (t, 2H), of 3.84 (s, 3H), OF 3.1 AND 2.9 (4H), 2,8-2,5 (4H), a 2.45 (t, 2H), 1,9-1,4 (4N)

The following compounds receive according to the method described in example 1 from the corresponding derivatives of benzimidazole-2-it, arylpiperazine.

1-[4-(3-(3-chlorophenyl)piperazine-1-yl)propyl] - 2,3-dihydro-1H-benzimidazole-2-he

(compound 2)

The dihydrochloride (from isopropanol)

Melting point: 165 170oC

Analysis:

C20H23ClN4O 2HCl

Found, C 53,48; H 5,71; N KZT 12.39

Calculated C 54,13; H of 5.68; N BR12.62

1H NMR(DMCO-d6/CDCl 5: 2): 11,09 ( 1H), DRO-1H-benzimidazole-2-he

(compound 3)

Hydrochloride (from isopropanol)

Melting point: 230 231oC

Analysis:

C20H21F3N4HCl

Found, C 56,37; H 5,20; N 13,12

Calculated C 56,27; H 5,20; N 13,13

1H NMR(DMCO-d6/CDCl 5: 2): 11,09 (d, 1H), 11,04 (c, 1H), 7,5-6,9 (8H), 4,36 (t, 2H), 4,1-3,1 (10H)

1-[4-(4-(3-chlorophenyl)piperazine-1-yl)butyl] -2,3-dihydro - 1H-benzimidazole-2-he

(compound 4)

The dihydrochloride (from isopropanol)

Melting point: 217 220oC

Analysis:

C21H25ClN4O2HCl

Found, C 54,87; H by 5.87; N 12,34

Calculated C 55,09; H 5,94; N 12,24

1H NMR (DMSO-d6/CDCl35:2): br11.01 (d, 1H), 10,92 (s, 1H), and 7.3 to 6.8 (8H), 4,42 (d, 1H), 4,0 to 3.8 (4H), 3,50 (d, 2H) 3,3-3,0 (6N), 1,9-1,6 (4H)

1-[2-(4-(3-chlorophenyl)piperazine-1-yl)ethyl] -2,3-dihydro-1H-benzimidazole-2-he

(compound 5)

The dihydrochloride (from isopropanol)

Melting point: 230 231oC

Analysis:

C19H21ClN4O2HCl

Found, C 53,39; H 5,64; N 13,06

Calculated C 53,10; H 5,39; N 13,04

1H NMR (DMSO-d6): 11,10 (d, 2H), 7,35 (m, 1H), 7,26 (m, 1H), 7,1-a 7.0 (4H), 6,97 (d, 1H), 6.87 in (d, 1H), 4,32 (t, 2H), 4,1 TO 3.0 (10H).

1-[2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl]- 2,3-dihydro-1H-benzimidazole-2-he

(compound 6)

The dihydrochloride (from isopropanol)

The point of the melt is Calculated, C 56,47; H 6,16; N 13,17

1H NMR(DMSO-d6/CDCl35:2): 11,0 ( d, 1H), 10,97 (c, 1H), 7,4-6,7 (9H), 4,35 (t, 2H), 3,82 (c, 3H), of 4.0 and 2.9 (10H).

1-[4-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)butyl]-2,3-dihydro-1H-benzimidazole-2-he

(compound 7)

Melting point: 114 115oC

Analysis:

C22H25F3N4O

Found, C 62,99; H 6,18; N 13,41

Calculated C 63,15; H of 6.02; N 13,39

1H NMR (CDCl3): 10,16 (s, 1H), 7,34 (m, H), a 7.2 to 7.0 (7H), of 3.94 (t, 2H), 3,30 (m, 4H), to 2.74 (m, 4H), 2,61 (t, 2H), 2.0 to 1,6 (4H).

1-[4-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)butyl]-3-methyl-2,3-dihydro-1H-benzimidazole-2-he

(compound 8)

Hydrochloride (from isopropanol)

Melting point: 215 216oC

Analysis:

C23H27F3N4OHCl

Found, C 59,19; H 6,20; N 12,14

Calculated C 58,91; H of 6.02; N 11,95

1NMR(DMSO-d6/CDCl35:2): 10,81 (d, 1H), 7,5-6,9 (8H), 3,90 (m, 2H), on 3.36 (s, 3H), 4,1 TO 3.0 (10H), A 2.0-1,6 (4H).

1-[3-(4-(2-methoxyphenyl)piperazine-1-yl)propyl]-2,3-dihydro-1H-benzimidazole-2-he

(compound 9)

The dihydrochloride (from isopropanol)

Melting point: 200 204oC

Analysis:

C21H26N4O22HCl

Found, C 56,93; H 6,50; N 12,57

Calculated C 57,41; H 6.42 per; N WAS 12.75

1H NMR(DMSO-d6/CDCl35:2): 11,12 (�]-2,3-dihydro-1H-benzimidazole-2-he

(compound 10)

The dihydrochloride (from isopropanol)

Melting point: 255 259oC

Analysis:

C21H26N4O2HCl

Found, C 59,32; H 6,69; N 12,99

Calculated C 59,57; H 6,67; N 13,23

1H NMR (DMSO-d6/CDCl35:2): to 11.11 ( d, 1H), was 10.82 (s, 1H), 9,10 (s, 1H + HDO), 7,4-6,7 (9H), 4,0-3,1 (12H), and 1.9 to 1.7 (4H).

1-[6-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)hexyl]-2,3-dihydro-1H-benzimidazole-2-he

(compound 11)

Hydrochloride (from isopropanol)

Melting point: 118 120oC

Analysis:

C24H29F3N4OHCl

Found, C 57,21; H 6,28; N 11,00

Calculated C 55,54; H 6,44; N 11,18

1H NMR (DMSO-d6/CDCl35:2): 10,89 ( d, 1H), of 10.76 (s, 1H), 7,6-6,9 (8H), 4,1-3,0 (N), A 2.0 A 1.2 (8H).

1-[6-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)hexyl]-3-ethyl-2,3-dihydro-1H-benzimidazole-2-he

(compound 12)

Hydrochloride (from isopropanol)

Melting point: 138 139oC

Analysis:

C26H33F3N4OHCl

Found, C 61,21; H 6,64; N 10,67

Calculated C 61,11; H of 6.71; N 10,96

1H NMR (CDCl3): 12,91 ( d, 1H), AND 7.4 TO 6.8 (8H), 4,1-2,8 (14H), of 1.33 (t, 3H), 2,2-1,2 (8H)

1-[4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl] -3-allyl-2,3 - dihydro-1H - benzimidazole-2-he

(compound 13)

The dihydrochloride (isopropanol 61,35; H TO 7.09; N 11,18

Calculated C 60,85; H 6,94; N 11,35

1H NMR (DMSO-d6/CDCl35:2): 11,07 ( d, 1H), 8,04 (s, 1H + HDO), a 7.2 to 6.8 (8H), 5,90 (m, 1H), 5,2 to 5.0 (2H), 4,48 (d, 2H), 3,92 (t, 2H), 3,82 (s, 3H), 3,7-3,0 (10H), A 2.0 A 1.7 (4H).

1-[4-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)butyl] -3-isopropyl-2,3-dihydro-H-benzimidazole-2-he

(compound 14)

Hydrochloride (from isopropanol)

The melting point: 181 184oC

Analysis:

C25H31F3N4OHCl

Found, C 60,01; H 6,51; N 11,24

Calculated C 60,42; H of 6.49; N 11,27

1H NMR (CDCl3): 12,85 ( d, 1H), 7,4-6,9 (8H), 4,70 (m, 1H), 3,92 (t, 2H), 4,0 IS 2.8 (10H), 2,2-1,8 (4H), 1.53 (d, 6N).

1-[4-(4-(3-chlorophenyl)piperazine-1-yl)butyl] -3-n-hexyl-2,3-dihydro-1H-benzimidazole-2-he

(compound 15)

Hydrochloride (from isopropanol)

Melting point: 107 111oC

Analysis:

C27H37ClN4OHCl

Found, C 64,57; H 7,53; N 11,10

Calculated C 64,15; H 7,58; N 11,08

1H NMR (CDCl3): 12,80 ( d, 1H), 7,2-6,5 (8H), 3,9-2,7 (14N), 2,3-1,2 (12H), 0.87 (m, 3H).

1-[4-(4-(3-chlorophenyl)piperazine-1-yl)butyl] -3-methyl-2,3-dihydro-1H-benzimidazole-2-he

(compound 16)

Hydrochloride (from isopropanol)

Melting point: 214 216oC

Analysis:

C22H27ClN4OHCl

Found, C 60,88; H to 6.58; N 12,86

Russ is">

1-[3-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)propyl] -2,3-dihydro-1H-benzimidazole-2-he

(compound 17)

The dihydrochloride (from isopropanol)

Melting point: 160 162oC

Analysis:

C21H23F3N4OHCl

Found, C of 52.84; H of 5.29; N 11,77

Calculated C of 52.84; H 5,28; N 11,74

1H NMR (DMSO-d6/CDCl35:2): 11,14 ( d, 1H), 10,87 (s, 1H), 7,6-6,9 (8H), only 6.64 (s, 1H + HDO), 3,93 (t, 2H), 4,1 TO 3.0 (10H), of 2.21 (m, 2H).

1-[4-(4-)2-chlorophenyl)piperazine-1-yl)butyl] -2,3-dihydro-1H-benzimidazole-2-he

(compound 18)

Hydrochloride (from ethanol)

Melting point: 247 250oC

Analysis:

C21H25ClN4OHCl

Found, C 59,36; H 6,34; N 12,96

Calculated C 59,86; H 6,22; N 13,30

1H NMR (DMSO-d6/CDCl35:2): 10,81 ( d, 1H), 10,80 (s, 1H), 7,4-6,9 (8H), 3,86 (t, 2H), 3,7-3,1 (10H), A 2.0 A 1.7 (4H).

1-[4-(4-(3-methoxyphenyl)piperazine-1-yl)butyl] - 2,3-dihydro-1H-benzimidazole-2-he

(compound 19)

The dihydrochloride (from ethanol)

Melting point: 190 192oC

Analysis:

C21H28ClN4O2HCl

Found, C 65,49; H of 6.31; N 12,58

Calculated C 65,67; H 6,20; N 12,76

1H NMR (DMSO-d6/CDCl35:2): 10,97 (s, 1H), 10,63 ( d,1H), 7,9-7,0 (10H), 4,37 (t, 2H), of 3.94 (s, 3H), 4,1 TO 3.2 (10H).

1-[4-(4-(5-benzodioxan)piperazine melting point: 186 188oC

Analysis:

C23H28N4O32HCl

Found, C 56,96; H to 6.57; N 11,83

Calculated C 57,38; H 6,28; N 11,64

1H NMR (DMSO-d6): of 10.93 (s, 1H), 10,9 ( d, 1H), 7,15 (m, 1H), 7,1-6,9 (3H), 6,76 (m, 1H), 6,6-6,5 (2N), a 4.53 (s, 1H + HDO), 4,24 (s, 4H), 3,83 (t, 2H), 3,6-3,4 (4H), 3,3-3,0 (6N), 1,9-1,6 (4H).

1-[4-(4-(1-naphthyl)piperazine-1-yl)butyl] -2,3-dihydro-1H - benzimidazole-2-he

(compound 22)

The dihydrochloride (from isopropanol)

Melting point: 264 267oC

Analysis:

C25H28N4O2 HCl

Found, C 63,66; H 6,59; N 11,99

Calculated C 63,42; H to 6.39; N 11,83

1H NMR (DMSO-d6): 10,86 (s, 1H), 10,51 ( d, 1H), 8,12 (m, 1H), 7,89 (m, 1H), to 7.64 (d, 1H), 7,6-7,5 (2N), 7,42 (d, 1H), 7,2-7,0 (5H), to 3.89 (t, 2H), 3,7-3,2 (10H), A 2.0 A 1.7 (4H).

1-[2-(4-(3-trifluoromethyl-phenyl)hexahydro-1H-1,4-diazepin-1-yl)ethyl] -2,3-dihydro-1H-benzimidazole-2-he

(compound 23)

Hydrochloride (from a mixture of ethyl acetate and simple diethyl ether)

Melting point: 128 130oC

Analysis:

C21H23F3N4O HCl

Found, C 55,81; H 5,56; N 12,19

Calculated C 57,21; H 5,49; N 12,71

1H NMR (CDCl3): 12,77 ( d, 1H), 9,86 ( d, 1H), 7.5 to 6.8 cm (8H), of 4.44 ( d, 2H), 4,2-2,0 (10H), 2.40 a (m, 2H).

1-[2-(4-phenyl-piperazine-1-yl)ethyl]-2,3 - dihydro-1H-benzimidazole-2-he

(compound 24)

Hydrochlor the SUB>4OHCl

Found, C 62,84; H 6,46; N 15,43

Calculated C 63,59; H 6,46; N 15,61

1H NMR (DMSO-d6/CDCl35:2): 11,0 ( d, 1H), 10,97 (s, 1H), 7,4-6,7 (N), 4,34 (t, 2H), 4.0 TO ABOUT 3.1 (10H).

1-[3-(3-phenylimidazoline-1-yl)butyl]-2,3-dihydro-1H-benzimidazole-2-he

(compound 25)

Example 2. 6-methoxy-1-[2-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)ethyl] -2,3-dihydro-1H-benzimidazole-2-on (compound 26).

6 g complex ethyl ester 5-methoxy-3-(2-bromacil)-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid are suspended in a mixture of 60 ml of ethanol and 20 ml of dry dimethylformamide in the presence of 0.23 g of sodium carbonate. To the resulting suspension at room temperature and under stirring drops add 0.33 ml 3-triftormetilfullerenov, and then the reaction mixture is heated under reflux for 14 hours, the Solvent is removed in vacuo and the resulting crude product is purified by column chromatography on silica gel using as eluent a mixture of methylenechloride, methanol and 32-tion of ammonium hydroxide in the ratio 98:2: 0.2 to. The target product is further purified by crystallization from 50 aqueous ethanol. Output: 0,1 g of the Hydrochloride is obtained adding the stoichiometric amount of water chlorestol the>< / BR>
Analysis:

C21H23F3N4O2HCl

Found, C 61,55; H for 6.81; N 12,70

Calculated C 61,80; H 6,99; N 12,53

1H NMR (DMSO-d6/CDCl 5:2): 10,96 (d, 1H), 10,61 (s, 1H), 7,2-6,6 (6H), 6,53 (m, 1H), 3,81 (s, 3H), of 3.77 (s, 3H), 3.9 TO 3,0 (N), 1,9-1,6 (4H).

6-methoxy-1-[4-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)butyl]-2,3-dihydro-1H-benzimidazole-2-he

(compound 28)

Hydrochloride (from ethanol)

Melting point: 122 124oC

Analysis:

C23H27F3N4O22HCl

Found, C 50,19; H ceiling of 5.60; N 10,52

Calculated C 50,59; H of 5.40; N OF 10.73

1H NMR (DMSO-d6/CDCl35:2): 11,16 (s, 1H), 10,75 ( d, 1H), 7,42 (s, 1H), 7,13 (s, 1H), 7,2-6,7 (5H), 3,82 (s, 3), 4,0-3,0 (N), 2,1-1,6 (4H),

6-methyl-1-[4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl] -2,3-dihydro-1H-benzimidazole-2-he

(compound 32)

The dihydrochloride (from isopropanol)

Melting point: 210 -213oC

Analysis:

C23H30N4O22HCl

Found, C 59,53; H 7,19; N 11,68

Calculated C 59,10; H 6,90; N 11,99

1H NMR (DMSO-d6/CDCl35: 2): 10,98 ( d, 1H), 10,66 (s, 1H), was 7.08 ( d, 1H), 7,1-6,7 (7H), 3,82 (s, 3H), 3.9 TO 3,0 (N), to 2.35 (s, 3H), OF 2.1 AND 1.7 (4H).

Example 4. 1- [4-(4-(3-chlorophenyl)piperazine-1-yl)butyl]-3-methyl-2,3-dihydro-1H-benzimidazole-2-on (compound 16).

To a suspension of 1 g of 80% of the ion mixture is stirred at room temperature for one hour, then add a solution of 6 g of 4-(3-chlorophenyl)-1-chlorobutyl-piperazine in 15 ml of dimethylformamide. The reaction mixture is allowed to react at a temperature of 60oC for 10 h, then allowed to cool, water is added and the product extracted with ethyl acetate. The crude product is purified by column chromatography on silica gel using as eluent a mixture of CH2Cl2and MeOH in a ratio of 95 to 5. Yield: 5 g of the target product.

Hydrochloride (from isopropanol).

Melting point: 213 -216oC.

Analysis:

C22H27ClN4HCl

Found, C 60,65; H 6,53; N 12,34.

Calculated C 60,69; H 6,48; N 12,87

1H NMR (CDCl3): 12,84 ( d, 1H), AND 7.3 AND 6.7 (8H), 3,93 (t, 2H), 3,42 (s, 3H), OF 4.0 AND 2.9 (10H), 2,1-1,8 (4H).

A similar method receive the following connections:

1-[4-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)butyl]-3-methyl - 1,3-dihydro - 1H-benzimidazole-2-on (compound 8);

Hydrochloride (from isopropanol).

Melting point: 215 216oC.

Analysis:

C23H27F3N4OHCl

Found, C 58,74; H Between 6.08; N A 12.03.

Calculated C 58,91; H of 6.02; N 11,95

1H NMR (DMSO-d6/CDCl35:2): 10,81 ( d, 1H), 7,5-6,9 (8H), 3,90 (m, 2H), on 3.36 (s, 3H), 4,1 TO 3.0 (10H), 2,1-1,6 (4H).

1-[6-(4-(3-Chlorid (from isopropanol).

Melting point: 136 139oC.

Analysis:

C26H33F3N4OHCl

Found, C 60,89; H 6,51; N 11,03.

Calculated C 61,11; H Of 6.71; N 10,96.

1H NMR (CDCl3): 12,91 ( d, 1H), and 7.4 to 6.8 (8H), 4,1-2,8 (14H), of 1.33 (t, 3H), 2,2-1,2 (8H).

1-[4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl] -3-allyl-2,3-dihydro-1H-benzimidazole-2-on(compound 13).

The dihydrochloride (from isopropanol).

Melting point: 201 204oC.

Analysis:

C25H32N4O22HCl

Found, C Of 60.50; H 6,59; N 11,53.

Calculated C 60,85; H 6,94; N 11,35.

1H NMR (DMSO-d3/CDCl35:2): 11,07 ( d, 1H), 8,04 (s, 1H + HDO), a 7.2 to 6.8 (8H), 5,90 (m, 1H), 5,90 (m, 1H), 5,2-5,0 (2N), 4,48 (doctor 2H), 3,92 (t, 2H), 3,82 (s, 3H), 3,7-3,0 (10H), A 2.0 A 1.7 (4H).

1-[4-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)butyl] -3-isopropyl-2,3-dihydro-1H-benzimidazole-2-on (compound 14).

Hydrochloride (from isopropanol).

Melting point: 181 184oC.

Analysis:

C25H31F3N2O2HCl

Found, C 60,00; H 6,69; N Br11.01.

Calculated C 60,42; H Of 6.49; N 11,27.

1H NMR (CDCl3): 12,84( d, 1H), 7,4-6,9 (8H), 4,70 (m, 1H), 3,92 (t, 2H), 4,0 IS 2.8 (10H), 2,0-1,8 (4H), 1,53 (d, 6N).

1-[4-(4-(3-chlorophenyl)piperazine-1-yl)butyl] -3-n-hexyl-2,3-Digi the 7 111oC.

Analysis:

C27H37ClN4OHCl

Found, C 63,87; H 7,37; N 11,27.

Calculated C 64,15; H 7,58; N 11,08.

1H NMR (CDCl3): 12,80 ( d, 1H), 7,2-6,5 (8H), 3,9-2,7 (14H), 2,3-1,2 (12H), 0.87 (m, 3H).

Example 5. N-[2-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (compound 33).

A mixture of 1 g of 1-chlorocarbonyl-benzimidazole-2-it is obtained as described in the application EP 3094423 method, and 3.2 g of 4-(3-trifluoromethyl-phenyl)-1-(2-amino-ethyl)-piperazine with of 1.57 g of sodium carbonate in 50 ml of anhydrous dimethylformamide with stirring is heated at a temperature of 100oC for 4 h Then the reaction mixture is cooled, diluted with water and extracted with ethyl acetate. After removal of residual solvent TV Joe substance is transferred into the corresponding hydrochloride by adding anhydrous hydrogen chloride to a solution of the base in isopropanol. Yield: 1.3 g of the target product.

Hydrochloride (from isopropanol).

Melting point: 230 233oC.

Analysis:

C21H22F3N5O2HCl

Found, C 60,31; H 6,48; N 11,20.

Calculated C 60,42; H Of 6.49; N 11,27.

1H NMR (CDCl3): 12,85 ( d, 1H), 7,4-6,9 (8H), 4,70 ( 1-[6-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)hexyl] -3-ethyl-2,3-dihydro-1H-benzimidazole-2-on (compound 12).

Hydrochloride (from isopropanol).

Melting point: 138 139oC.

Analysis:

C26H33F3N4OHCl

Found, C 61,32; H 6,70; N 10,91.

Calculated C 61,11; H Of 6.71; N 10,96.

1H NMR (CDCl3): 12,91 ( d, 1H), and 7.4 to 6.8 (8H), 4,1-2,8 (14H), of 1.33 (t, 3H), 2,2-1,2 (8H).

1-[4-(4-(methoxyphenyl)piperazine-1-yl)butyl] -3-allyl-2,3-dihydro-1H-benzimidazole-2-on(compound 13).

The dihydrochloride (from isopropanol).

Melting point: 201 204oC.

Analysis:

C25H32N4O22HCl

Found, C 60,93; H 7,01; N 11,24.

Calculated C 60,85; H 6,94; N 11,35.

1H NMR (DMSO-d6/CDCl35:2): 11,07 ( d, 1H), 8,04 (s, 1H + HDO), a 7.2 to 6.8 (8H), 5,90 (m, 1H), 5,2-5,0 (2N), 4,48 (d, 2H), 3,92 (t, 2H), 3,82 (s, 3H), 3,7-3,0 (10H), A 2.0 A 1.7 (4H).

1-[4-(4-(3-chlorophenyl)piperazine-1-yl)butyl] -3-n-hexyl-2,3 - dihydro-1H-benzimidazole-2-on (compound 15).

Hydrochloride (from isopropanol).

Melting point: 108 111oC.

Analysis:

C27H37ClN4OHCl

Found, C 64,31; H 7,56; N 11,12.

Calculated C 64,15; H 7,58; N 11,08.

1H NMR (CDCl3): 12,80 ( d, 1H), 7,2-6,5 (8H), 3,9-2,7 (14N), 2,3-1,2 (N), 0.87 (m, 3H).

1-[4-(4-(3-chlorophenyl)piperazine-1-yl)butyl] -3-methyl-2,3-dihydro-1H-b is oC.

Analysis:

C22H27ClN4OHCl

Found, C 60,51; H 6,53; N 12,81.

Calculated C 60,69; H 6,48; N 12,87.

1H NMR (CDCl3): 12,84 ( d, 1H), AND 7.3 AND 6.7 (8H), 3,93 (t, 2H), 3,42 (s, 3H), OF 4.0 AND 2.9 (10H), 2,1-1,8 (4H).

1. Derivatives benzimidazolone General formula I

< / BR>
where R1and R2the same or different and mean a hydrogen atom, halogen atom, trifluoromethyl, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms, hydroxy, nitro-group or amino group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, atilov with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, cyano, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, or aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms;

R3a hydrogen atom, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms or quinil 2 6 atommy or unsaturated alkyl with 2 to 6 carbon atoms; m and n, independently from each other represent an integer of 1 to 3;

R4phenyl, naphthyl or benzodioxan, unsubstituted or substituted by at least one Deputy from the group comprising halogen atom, trifluoromethyl, cyano, alkoxy with 1 to 3 carbon atoms and alkyl with 1 to 4 carbon atoms, mixtures of their isomers or their acid additive salt.

2. Derivatives of benzimidazole of General formula I under item 1, in which A is absent, B denotes unbranched saturated alkyl with 2 to 4 carbon atoms, m and n mean 2, R4means zameshennoj phenyl ring containing residues from the group comprising methoxy, chlorine and trifluoromethyl, a mixture of their isomers or their acid additive salt.

3. Derivatives of benzimidazole of General formula I on p. 1, representing

1-[2-(4-(3-trifluormethyl-phenyl)piperazine 1-yl)ethyl] -2,3 dihydro-1H-benzimidazole-2-he

1-[4-(4-(3-chloro-phenyl)piperazine-1-yl)butyl] -2,3-dihydro - 1H-benzimidazole-2-he

1-[4-(4-(3-trifluoromethyl-phenyl)piperazine - 1-yl)butyl] -2,3-dihydro-1H-benzimidazole-2-he

1-[4-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)butyl] - 3-methyl-2,3-dihydro-1H-benzimidazole-2-he

1-[4-(4-(3-trifluoromethyl-phenyl)piperazine-1-yl)butyl] - 3-isopropyl-2,3-dihydro-1H-benzimidazole-2-he

1-[3-(4-(3-cryptomate the n-1-yl)butyl]-2,3-dihydro-1H - benzimidazole-2-he

1-[4-(4-(1-naphthyl)piperazine - 1-yl)butyl] -2,3-dihydro-1H-benzimidazole-2-it.

4. Derivatives benzimidazolone General formula I

< / BR>
where R1and R2the same or different and mean a hydrogen atom, halogen atom, trifluoromethyl, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, carboxyl, alexcabanel with 1 to 6 carbon atoms, hydroxy, nitro-group or amino group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, acylamino with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, cyano, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, or aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms;

R3a hydrogen atom, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms or quinil with 2 to 6 carbon atoms;

A group-CO - or-CONH-, or A is absent;

B unbranched or branched, saturated or unsaturated alkyl with 2 to 6 acanthodian, unsubstituted or substituted by at least one Deputy from the group comprising halogen atom, trifluoromethyl, cyano, alkoxy with 1 to 3 carbon atoms and alkyl with 1 to 4 carbon atoms,

mixtures of their isomers or their acid additive salt as a receptor antagonist 5-HT1Aand 5-HT2.

 

Same patents:

The invention relates to organic chemistry, in particular to a method of obtaining an individual stereoisomers of 4-diprosone glutamic acid of General formula

< / BR>
< / BR>
ALK is a lower alkyl

The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

< / BR>
aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

The invention relates to new biologically active chemical compounds, derived diaminodiphenylsulfone General formula;

< / BR>
which is obtained by the interaction equimolecular amounts of diaminodiphenylsulfone and orotovoy acid in water

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to new 3[2H]-pyridazinone derived, as well as to receive them, containing their insecticidal acaricide, nematocide, fungicidal compositions for use in agriculture and horticulture; compositions for removing ticks from animals, where these compositions contain these derivatives as the active ingredient

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to new compounds useful as herbicides, and to their use in weed control in the cultivation of fine-grained cereals

The invention relates to an improved process for the preparation of 1-nitroso-4-methylpiperazine, which finds application in the chemistry of drugs as an intermediate product in the synthesis of 1-amino-4-methylpiperazine and 1-methylpiperazine used for modern drugs: rifampicin, azaleptinum, triftazin, pefloksatsina, tetrazine and other drugs

The invention relates to an improved process for the preparation of 1-nitroso-4-methylpiperazine, which finds application in the chemistry of drugs as an intermediate product in the synthesis of 1-amino-4-methylpiperazine and 1-methylpiperazine used for modern drugs: rifampicin, azaleptinum, triftazin, pefloksatsina, tetrazine and other drugs

The invention relates to the field of chemistry, to a method for the chemical substance that manifests anthelminthic properties, and can be used in agriculture to treat animals

The invention relates to the field of chemistry, to a method for the chemical substance that manifests anthelminthic properties, and can be used in agriculture to treat animals

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to the synthesis of new biologically active compounds, in particular to a method for production of new nitrogen-containing aromatic derivatives having antagonistic activity to the receptor of neurokinin

The invention relates to heterocyclic compounds, specifically to piperazine derivatives, in which the piperazine one nitrogen atom is linked to a fragment of aryloxy or aaltio link oxypropylene or alkanoyloxy, and through another nitrogen atom with the rest of acetanilide

The invention relates to new derivatives of diazepinone having valuable properties, in particular derivatives of diazepinone General formula (I)

< / BR>
where B is one of the divalent residues and) g)

< / BR>
and

X, l, m, n and R1R7have the following meanings:

X Gruppen or, if B denotes the divalent residue (a), a nitrogen atom,

l integer 1, 2 or 3,

m is an integer 1 or 2,

n is an integer of 1 to 4,

R1a hydrogen atom or an unbranched or branched alkyl with 1 to 6 carbon atoms,

R2a hydrogen atom, an unbranched or branched alkyl with 1 to 8 carbon atoms, unbranched or branched alkenyl with 4 to 6 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, unsubstituted or substituted by alkyl with 1 to 3 carbon atoms, substituted, phenyl, unsubstituted or substituted by one or two methyl groups or methoxypropane or one halogen atom, or phenylalkyl with 1 to 3 carbon atoms in the alkyl part, unsubstituted or substituted at the fragrance stands or methoxy group or a halogen atom,

R3and R4the same or the difference is,

R5a hydrogen atom or a chlorine or methyl,

R6and R7the same or different and denote hydrogen atoms or alkali with 1 to 3 carbon atoms, and, in addition, R7may also indicate a halogen atom,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerated acid additive salts, in particular with pharmacological action
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