Derivatives substituted imidazolidin-2-it, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

Usage: in medicine as antagonists of NT-receptor. The inventive products-derivatives imidazolidin-2-it f-ly I, given in the text description, where R, R1and R2- same or different, hydrogen, halogen, hydroxy, cyano, C1- C4-alkyl, CF3WITH1- C4-alkoxy, C1- C4-alkylthio, nitro or NH2-group. R3radical f-l 2 and 3 contained in the description text, where n is 1 or 2, R8is hydrogen, C1- C4-alkyl or their pharmaceutically acceptable salts. Reagent 1: compound f-ly 4, given in the text description. Reagent 2: carbonyl-containing agent cyclization. Reaction conditions: in a medium of an organic solvent under heating. 3 S. and 2 C. p. F.-ly. 3 table.

The invention relates to new derivatives of 1-phenyl-3-azabicycloalkanes-2-ones, to a method for producing them, to pharmaceutical compositions containing them and to their use as therapeutic agents.

The invention provides new compounds of General formula I

< / BR>
(I) in which each of R, R1and R2that may be the same or different, are hydrogen is-alkylthio-, formyl, C2-C6-alkanoyl, carboxy-, C1-C6-alkoxy-carbonyl, nitro, -N(R4R5)-group, in which each of R4and R5independently is hydrogen, C1-C6-alkyl, formyl or2-C6-alkanoyl; or (R6R7N-SO2group, in which each of R6and R7independently is hydrogen or C1-C6-alkyl;

R3is a group (a) or (b)

(a) (b) in which n is the integer 1 or 2, and R8is hydrogen, C1-C6-alkyl which is not substituted or substituted by phenyl,2-C4-alkenyl,2-C4-quinil, formyl or2-C6-alkanoyl; and pharmaceutically acceptable salts of them.

The formula presented for the compounds of the invention includes all the possible isomers, in particular stereoisomers, and mixtures thereof.

In the compounds of the invention in which the substituent R3is a group (a), such a group may be in the R - or S-configuratie, or a mixture of them.

Similarly, when the substituent R3is a group (b), such a group can be in the endo - or ectocervical or with the metabolites and metabolicheskie predecessors or bioresistance (commonly known as prodrugs predecessors medicines turning the body into an active drug) compounds of formula (I). Namely, the invention includes compounds that have the formula other than the formula (I), but which are nevertheless with the introduction of man become directly or indirectly in vivo (in a living organism) in the compound of formula (I).

The halogen atom may be a fluorine atom, chlorine, bromine or iodine, preferably it is chlorine or bromine. Alkyl, alkenylphenol, alkoxy, alkylthio group can be branched or linear-chain group.

WITH1-C6Is an alkyl group preferably is a C1-C4is an alkyl group such as methyl, ethyl, sawn, ISO-propyl, bucilina, second-bucilina or tert-bucilina, in particular methyl or ethyl.

WITH1-C6The alkoxy group preferably is a C1-C4-alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, preferably methoxy, ethoxy group.

WITH1-C6-Alkylthio group preferably is C1-C4-alkylthio group, such as methylthio, ethylthio, propylthio, butylthio, especially methylthio.

WITH2-C4-Elcapotele is propargyl.

WITH2-C6-Alkanoyloxy group is, for example, WITH2-C4-alcoolica group, in particular acetyl and propylaniline.

Pharmaceutically acceptable salts of compounds of formula (I) include salts of accession of inorganic acids such as nitric, hydrochloric, Hydrobromic, sulphuric, perchloric and phosphoric acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, almond and salicylic acids.

Preferred compounds of the invention are the compounds of formula (I), in which each of R, R1and R2that may be the same or different, is hydrogen, halogen, cyano, CF3WITH1-C4-alkylthio-FROM1-C4-alkoxy -, or-N(R4R5)-group, in which each of R4and R5independently is hydrogen, C1-C4-alkyl, formyl or2-C4-alkanoyl;

R3is a group (a) or (b) in which n is 1 or 2,

(a) (b) and R8is1-C4-alkyl; and pharmaceutically acceptable salts of them.

Examples of predpochtitel the-2-he; 1-(1-azabicyclo-[2.2.2. -Oct-3-yl)-3-(3,5-dichlorophenyl)-imidazolidin-2-he; 1-(1-azabicyclo-[2.2.2. -Oct-3-yl)-3-(4-amino-3-chloro-phenyl)-imidazolidin - 2-he; 1-(1-azabicyclo-[2.2.2.-Oct-3-yl)-3-(3-amino-4-chlorophenyl)-imidazolidin - 2-he;

1-(1-azabicyclo-[2.2.2.-Oct-3-yl)-2-(3 - bromophenyl)-imidazolidin-2-he;

1-(1-azabicyclo-[2.2.2.-Oct-3-yl)-3-(3 - triptoreline)-imidazolidin - 2-he;

1-(1-azabicyclo-[2.2.2. -Oct-3-yl)-3-Fe-Nile-imidazolidin-2-he; 1-(1-azabicyclo-[2.2.2.-Oct-3-yl)-3-(3-methoxyphenyl(-imidazolidin-2-it, and pharmaceutically acceptable salts of them, especially chlorhydrate.

Compounds of the invention and their salts can be obtained by the method involving the reaction of interaction of the compounds of formula II

in which R, R1, R2and R3have some higher values, with a carbonyl-containing agent cyclization and, if necessary, conversion of the compounds of formula (I) and another compound of formula (I) and/or, if necessary, conversion of the compounds of formula (I) into a pharmaceutically acceptable salt thereof, and/or, if necessary, converting a salt into a free compound, and/or, if necessary, separation of the mixture of isomers of compounds formulae (I) at the individual isomers.

Carbonyl-containing agent cyclization, according to the invention, averaging acid, in particular the methyl ether of Harborview acid, urea or N, N-carbonyldiimidazole, the latter is preferred.

The cyclization reaction can be carried out in an aprotic organic solvent selected, for example, tetrahydrofuran, benzene, toluene and xylene, at temperatures of reaction varied from approximately the 50aboutC to the boiling temperature under reflux, and if necessary in an inert atmosphere, for example nitrogen.

The compound of formula (I) may be converted, if necessary, into another compound of formula (I). For example, the compound of formula (I) in which one or more of R, R1and R2is amino group can be converted into another compound of formula (I) in which one or more of R, R1and R2is2-C6-alkanolamine or formylamino group.

The compound of formula (I) in which one or more of R, R1and R2is a carboxy group may be converted into another compound of formula (I) in which one or more of R, R1and R2is1-C6-alkoxycarbonyl, and Vice versa. These optional transformations can be carried out by known methods.

divide mixture of isomers into the individual isomers can be carried out by known methods.

For example, separation of a mixture of geometrical isomers, for example endo - and actisorb, can be carried out by fractional crystallization from a suitable solvent or by chromatographic or by using column chromatography, or liquid chromatography high pressure.

The compounds of formula (II), which are new, can be obtained by reaction of compounds of formula (III)

R in which R, R1and R2have the above specified values, or with the compound of the formula (IV) or formula (V) or a salt, in particular the hydrochloride.

0(IV) 0 (V) in which R8and n are as defined above values, thus obtaining the compound of formula (II) in which R3is as defined above, the values in paragraphs (a) or (b), respectively.

The reaction of the compound of formula (III) with the compound of the formula (IV) or (V) may be carried out under known in the field methods. According to a preferred embodiment of the invention, if the reaction gives a mixture of isomers of compounds of formula (II), before subjecting them to the specified cyclization reaction, this mixture of isomers can be separated into the individual isomers, for example endo - and actinometry, on the E.

The compounds of formula (III), (IV) and (V) are known compounds or can be obtained from known compounds and by known methods.

When in the above-described compounds are groups that require protection during the above reactions, such groups can be protected in a conventional manner to the reaction, and then subjected to removal of protection (to release). Examples of protective groups javlautsa groups commonly used in the chemistry of peptides.

Compounds of the invention are active against serotoninergicheskoi system, in particular as antagonists NT3receptor, as evidenced, for example, the fact that they have been found, are active when antagonization of chemoreflex von Bezold-Jarisha caused by 5-HT in shot rats according to the method described by Tsardom (G. R. Fozard Naunyn-Schmiedeborgis arch. Pharmacol, 326, 36-44 (1984).

In table.1 shows in vivo T3-antagonistic activity obtained in this test for exemplary compounds of the invention -1(1-azabicyclo-[2.2.2.-Oct-3-yl)3-(3-chloro-phenyl)imidazolidin-2-it (internal code FCE 26778).

T a b l I C a 1. The reflex inhibition of Bezel astesiano rat.

Values are averaged S. E. M. of 6 animals

Compounds of the invention are potent and selective inhibitors bind3N-GR65630 (selectany antagonist of 5-HT3receptor) according to the method described by Kilpatrick and others (I. G. Kilpatrick et al. Nature, 330, 746-748 (1987)).

In table.2 Pivdenny data obtained by in vivo tests for exemplary compounds of the invention FCE 26778 compared with known reference compounds MDL 72222 and Metoclopramide.

MDL 72222 is a compound of formula

< / BR>
GR 65630 is a compound of formula

< / BR>
(In the case of MDL 72222, see the journal Nature, 330, 746-748 (1987), and in the case of Metoclopramide, see the directory Merck Indey 10th edition 6019, page 880).

Compound were able to interact with the 5-HT3-serotonin receptors labeled with3N-GR 65630 in antoinella cortical layer (entorhinal cortex) of rat brain. Of these compounds FCE 26778 interacted according to the model of two-site nonlinear selection while MDL 72222 and Metoclopramide displace3N-GR 65630 for nonlinear single-site selection: this is the reason why only one (not two) Ki-value reported in the table.2 for the last DW of the invention compared to the standard.

Due to these activities, the compounds of the invention can be useful, for example, in the treatment of disorders of the Central nervous system, such as, for example, fear and psychosis, and/or treatment of disorders of intestinal motility, and/or vomiting. Due to these activities, the compounds of the invention can be useful as, for example, anti-migraine or anti addiction to the excessive use of drugs, or as activators cognitive abilities. Compounds of the invention javlautsa useful as analgesics. Analgesic activity of the compounds is confirmed by, for example, the fact that they are active when the test formalin-induced inflammatory pain described by Dubuisson and Dennis in the article: "The formalin test: a quantitative study of analgetic of morphine, meperidine and brain stem stimulation in rats and cats" Pain 4, 161, 1977)). Due to its analgesic properties, the compounds of formula (I) can be useful, for example, in the treatment of pain in mammals, for example in the treatment of some forms of inflammatory pain in humans. The level of dosages suitable for the purpose of adults compounds of the invention or for the prevention or therapeutic treatment may vary within the of soedineniya, from patient to patient, subjected to curing, as well as on the nature and severity of the disorder. For example, in the case of the compounds of this invention are 1-(1-azabicyclo-[2.2.2.-Oct-3-yl)-3-(3-harfe - Nile-imidazolidin-2-it is appropriate oral administration in the dosage in this limit. Preferably, the compounds can be assigned, for example in the form of single or separated total doses, so that the total daily dosage was in the range of from about 0.020 to about 10 mg/kg per day. These dosing regimens can be adjusted to provide the optimum therapeutic response. Compounds of the invention can be administered in the form of various dosage forms, for example orally in the form of tablets, capsules, pills, coated with sugar or film of liquid solutions or suspensions.

The invention includes farmatsevticheskii compositions containing the compound of the invention in combination with pharmaceutically acceptable excipient (which can be a carrier or a diluent). The type of pharmaceutical compositions containing compounds in combination with pharmaceutically acceptable carriers or diluents, depends on the appropriate method of application. The composition can be costamante in the form of aqueous or oil solutions, or suspensions, tablets, pills, gelatin capsules, syrups, drops or suppositories.

For oral administration the pharmaceutical composition containing the proposed connection is made preferably in the form of tablets, pills or gelatin capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannit, sorbitol, cellulose; lubricants, for example silica, talc, stearic acid, magnesium stearate or calcium, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatin, methylcellulose, carboxymethylcellulose, gum Arabic, tragakant, polyvinylpyrrolidone; disaggregated substances such as starch, alginic acid, alginates, sodium starch glycolate, and mixtures causing rapid liberation of gas bubbles; dyestuffs; sweeteners; wetting, such as lecithin, Polysorbate, laurylsulfate; and non-toxic and pharmacologically inactive substances used in the preparation of medicines. These pharmaceutical preparations can be produced in a known manner, for example by mixing, granulating, tabletting,ü, for example, syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol. Suspensions and emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the current connection pharmaceutically acceptable carrier, e.g. sterile water, olive oil, etiloleat, glycols, e.g. propylene glycol, and, if necessary, an appropriate amount of hydrochloride lidocaine. The solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of a sterile aqueous isotonic salt solutions. Suppositories can contain wide with the current connection pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol, a surfactant based on a complex ester of polyoxyethylene and sorbinovoj fatty acids or lecithin.

P R I m e R 1. N-(1-Azabicyclo-[2.2.2]-Oct-3-yl)-N'-(3-chlorophenyl)-1,2-diamantane, under nitrogen atmosphere, add hydrochloride 3-binucleation (1.01 g, 0,00627 mol). the pH is brought to pH 6 by adding Les - Danai acetic acid. The two portions add cyanoborohydride sodium (0.74 g, to 0.0117 mol). The reaction mixture was refluxed for 10 h, cooled, and then filtered. After evaporation to dryness the residue is dissolved in water, alkalinized 20% aqueous solution of sodium hydroxide and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness. The residue is purified instant chromatography on silica gel (methylene chloride methanol 30% ammonium hydroxide, 150: 50:5 as eluent) to obtain the target product of the reaction in the form of a transparent SLA (0.66 g).

C15H22ClN3requires, With 64,38; N. Of 7.93; N 15,02; Cl 12,67

Found, 64,64; N 8,02; N 14,81; Cl 12,27.

P R I m m e R 2. N-(endo-8-methyl-8-azabicyclo-[3.2.1]-Oct-3-yl)-N'-(3-chlorophenyl)-1,2 - diaminoethane;

N-(Exo-8-methyl-8-azabicyclo-[3.2.1] Oct-3-yl)-N'-(3-chlorophenyl)-1,2 - diaminoethane.

To a stirred solution of N-(3-chlorophenyl)-1,2-diaminoethane from 2.06 g, 0.01 mol) in 50 ml of anhydrous methanol under nitrogen atmosphere, on Aut cyanoborohydride sodium (1.25 g, 0.02 mol). The reaction mixture was refluxed for 8 h, cooled, and then filtered. After evaporation the residue is dissolved in water, alkalinized 20% sodium hydroxide solution and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness. The residue is purified using instant chromatography on silica gel (methylene chloride-methanol-30% ammonium hydroxide, 150:50:5 as eluent) to obtain 1.2 g of endproduct reaction in the form of a white solid (so pl. of 82.5-85,5aboutC).

C16H24ClN3requires, With 65,40; N 8,23; Cl 12,07; N 14,30

Found, C 65,06; H 8,04; Cl 12,07; N 14,19,

followed by 0.52 g of Ecoproduct reaction in the form of a white solid (so pl. 62-64aboutC).

Found, 64,87; N 7,94; N 13,85; Cl 11,81.

P R I m e R 3. Hydrochloride of 1-(1-azabicyclo-[2.2.2]-Oct-3-yl)-3-(3-chlorophenyl)-imida-solidin-2-it.

To a stirred solution of N-(1-azabicyclo-[2.2.2]-Oct-3-yl)-N'- (3-chlorophenyl)-1,2-diaminoethane (2.7 g, 0,0097 mol) in anhydrous tetrahydrofuran (10 ml) is added N,N-carbonyldiimidazole (2,04 g of 0.0125 mol). The reaction mixture is refluxed in the course is on anhydrous sodium sulfate. After filtration and evaporation to dryness, the reaction product is purified using flash chromatography on silica gel (methylene chloride methanol 30% ammonium hydroxide, 180:20:2 as eluent), followed by treatment with excess hydrochloric acid in the sample. The crude salt is collected by filtration and recrystallized from absolute ethanol, obtaining 1.5 g of the target reaction product; melting point 234-239aboutC.

Acting in a similar way can be obtained the following compounds or in the form of a free product of the reaction, either in the form of its hydrochloric salt:

Hydrochloride of 1-(1-azabicyclo-[2.2.2]-Oct-3-yl)-3-(5-chloro-2-methoxy - phenyl)-imidazolidin-2-she's so square 209-215aboutC;

1-(1-Azabicyclo-[2.2.2] -Oct-3-yl)-3-(5 - chloro-2 oksifenil)imidazolidin-2-it, so pl. 164-167aboutC;

Hydrochloride (endo)-1-(8-methyl-8-azabicyclo-[3.2.1] -Oct-3-yl)-3- (3-chlorophenyl)imidazolidin-2-it, so pl. 264-268aboutC;

Hydrate hydrochloride (Exo)-1-(8-methyl-8-azabicyclo-[3.2.1]-Oct-3-yl)-3-(3-chlorophenyl) imidazolidin-2-it, so pl. 239-243aboutC;

Hydrochloride (endo)-1-(9-methyl-9-azabicyclo-[3.3.1] -non-3-yl)-3- (3-chlorophenyl)imidazolidin-2-it, so pl. 243-249aboutWith; (Exo)-1-(9-methyl-9-azabicyclo-[3.3.1] -non-3-yl)-3-(3-chlorophenyl)imidazole is)imidazolidin-2-it, so pl. 224-228aboutC;

Hydrochloride (endo)-1-(9-methyl-9-azabicyclo-[3.3.1] -non-3-yl)-3- (5-chloro-2-methoxyphenyl)imidazolidin-2-it, so pl. 100aboutC;

1-(1-Azabicyclo-[2.2.2] -Oct-3-yl)-3-Fe-delimitation-2-it, so pl. 140-143aboutC;

Hydrochloride of 1-(1-azabicyclo-[2.2.2] -Oct-3-yl)-3-(3,5-dichlorophenyl) imidazolidin-2-it, so pl. 248,5-254aboutC;

1-(1-Azabicyclo-[2.2.2]-Oct-3-yl)-3-(3 - triptoreline)imidazolidin-2-it, so pl. 130,5-134,5aboutC;

Hydrochloride of 1-(1-azabicyclo-[2.2.2] -Oct-3-yl)-3-(3-methylthiophenyl) imidazolidin-2-it, so pl. 205aboutC (decomp.);

1-(1-Azabicyclo-[2.2.2]-Oct-3-yl)-3-(4 - amino-3-chlorophenyl)-imidazo - lidin-2-it, so pl. 176,5-182aboutC;

1-(1-Azabicyclo-[2.2.2] -Oct-3-yl)-3-(4 - chlorophenyl)imidazolidin-2-it, so pl. 175-178aboutC;

1-(1-Azabicyclo-[2.2.2] -Oct-3-yl)-3-(3 - methoxyphenyl)imidazolidin-2-it, so pl. 120-133aboutC;

1-)1-Azabicyclo-[2.2.2] -Oct-3-yl)-3-(3-bromophenyl)imidazolidin-2-it, so pl. 132-136aboutC;

1-(1-Azabicyclo-[2.2.2]-Oct-3-yl)-3-(3 - cyanophenyl)imidazolidin-2-it, so pl. 163-167aboutC;

Hydrochloride of 1-(1-azabicyclo-[2.2.2]-Oct-3-yl)-3-(3-nitrophenyl)imidazolidin-2-it, so pl. 220aboutC (decomp.);

1-(1-Azabicyclo-[2.2.2]-Oct-3-yl)-3-(3 - were)imidazolidin-2-it, so pl. 122-126aboutC;

1-(1-Azabicyclo-[2.2.2]-Oct-3-yl)-3-(3 - amino-4-chlorophenyl)imidazolidin so pl. 235aboutC (decomp.); and 1-(1-Azabicyclo-[2.2.2]-Oct-3-yl)-3-(3-chloro-4-nitrophe - nil)imidazolidin-2-it, so pl. 155,5-160,5aboutC.

P R I m e R 4. Tablets, each weighing 150 mg and containing 60 mg of active ingredient, can be obtained by mixing and pressing the following ingredients, in mg, the Hydrochloride of 1-(1-Aza - bicyclo-[2.2.2]-Oct-3-yl)-3-(3-harfe - nil)imidazole - DIN - 2-it 60 Starch 50 Microcrystal - symbolic cellulose 30 Polyvinylpyrrolidone 5 Sodium carboxy - methyl starch 4.5 magnesium Stearate 0.5 to

P R I m e R 5. Capsules, each dosed at 200 mg and containing 80 mg of the active substance, can be obtained as follows, mg, the Hydrochloride of 1-(1-Aza - bicyclo-[2.2.2] -Oct-3-yl)- -3-(3-chlorophenyl) them - gazolidon-2-it is 80 Corn starch 60 Microcrystal - symbolic cellulose 59 Stearate 1

This dosage form can be encapsulated in a dual hard gelatin capsules and dosed 200 mg for each capsule.

P R I m e R 6. Ampoules for parenteral administration, containing 70 mg of the active substance, is prepared as follows: 70 mg of the hydrochloride of (endo)-1-(8-methyl-8-azabicyclo-[3.2.1] -Oct-3-yl)-3-(3-chlorophenyl)them-gasoline on-2 dissolved in 2 ml of sterile water. Ampoule fill the resulting solution, sealed and wiped the KSA of Bezold-Jerichau

1. Derivatives substituted imidazolidin-2-it General formula I

< / BR>
where each of R, R1and R2that may be the same or different, is hydrogen, halogen, hydroxy, cyano, C1- C4-alkyl, CF3C1- C4-alkoxy, C1- C4-alkylthio-, nitro-, or NH2-group;

R3group

< / BR>
where n is an integer 1 or 2;

R8is hydrogen or C1- C4-alkyl;

or their pharmaceutically acceptable salts.

2. Connection on p. 1, selected from the group consisting of 1-(1-azabicyclo- /2.2.2/-Oct-3 - yl)-3-(3-chlorophenyl)- imidazolidin-2-it, 1-(1-azabicyclo-/2.2.2/-Oct - 3-yl)-3-( 3,5-dichlorophenyl)-imidazolidin-2-it; 1-(1-azabicyclo- /2.2.2/-Oct-3-yl)-3-(4-amino-3-chlorophenyl)-imidazolidin-2-it; 1-(1-azabicyclo-/2.2.2/-Oct-3-yl )-3-(3-amino-4-chlorophenyl)-imidazolidin-2-it; 1-(1-azabicyclo-/2.2.2/-Oct-3-yl)-3- (3-bromophenyl)-imidazolidin-2-it; 1-(1-azabicyclo-/2.2.2/-Oct-3-yl )-3-(3-triptoreline )-imidazolidin-2-it; 1-(1-azabicyclo-/2.2.2/-Oct-3-yl )-3-phenyl-imidazolidin-2-it; 1-(1-azabicyclo-/2.2.2/-Oct-3-yl )-3-(3-methoxyphenyl)-imidazolidin-2-it,

or its pharmaceutically acceptable salt.

3. The method of obtaining compounds of formula I on p. 1 or their pharmaceutically acceptable salts, featuring the

subjected to reaction with carbonyl-containing agent cyclization and, if necessary, turn the compound of the formula I into another compound of formula I, and/or, if necessary, turn the compound of formula i, its pharmaceutically acceptable salt and/or, if necessary, turn the salt into the free compound, and/or, if necessary, separate the mixture of isomers of compounds of the formula I into the individual isomers.

4. The pharmaceutical composition antagonist NT3receptors containing the active agent and pharmaceutically acceptable carrier and/or diluent, wherein the active agent it contains an effective amount of the compounds of formula I on p. 1 or its pharmaceutically acceptable salt.

5. Connection on p. 1 as antagonists NT3-receptor.

 

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The invention relates to new biologically active pyridyl - or pyrimidinediamine derivative of piperazine or 1,4-disallocation, or their pharmacologically active acid additive salts with psychotropic action

The invention relates to medicine and relates to a pharmaceutical composition inhibiting tumor growth

The invention relates to new derivatives of benzimidazole, possessing valuable pharmacological properties, in particular a derivative of benzimidazole of General formula I

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(I) where R1in position 4 means fluorine atom, chlorine or bromine, alkyl with 1-4 carbon atoms, cycloalkyl, vermeil, deformity or trifluoromethyl;

R2alkoxyl with 3-5 carbon atoms, substituted imidazolium in position 3, 4 or 5, alkoxyl with 2-5 carbon atoms, a substituted benzimidazole or tetrahydroimidazo in position 2, 3, 4 or 5, 2-(imidazol-1-yl)-ethoxyl provided that R4means 1H-tetrazolyl, alkylsulfonate with 1-4 carbon atoms, benzosulfimide or generalconclusions, unsubstituted or substituted at the nitrogen atom by alkyl with 1-6 carbon atoms, phenyl, cycloalkyl, phenylalkyl, cycloalkylation, bicyclohexyl or the biphenyl alluminare, in which the acyl radical is alkanoyl with 1-7 carbon atoms, alkoxycarbonyl with a total of 2-4 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, benzoyl, benzazolyl, generalkonsulin, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoic or Central electoral commissions substituents from the group includes fluorine atom, chlorine or bromine, methyl, methoxy, phthalimido, hemophthalmia, 2-carboxymethylamino or 2-carboxymethylamino, and one carbonyl group in phthalimidopropyl replaced by methylene, alkylamino or dialkylamino, one methylene group in hoofdlijnen may be substituted by one or two alkyl groups, and the phenyl nucleus may be optionally mono - or tizamidine the alkyl or alkoxyl, and the substituents may be the same or different and are wholly or partially gidrirovanny, unsubstituted or substituted by one or two alkyl groups or one tetramethylenebis or pentamethylene group 5-, 6 - or 7-membered, alkylamino or alkenylamine in which one methylene group may be replaced by a carbonyl or sulfonyl, imides bicycloalkyl-2,3-dicarboxylic acid and imine bicycloalkyl-2,3-dicarboxylic acid, where bicycloalkanes and bicycloalkanes part can contain 9 or 10 carbon atoms can be substituted by 1, 2 or 3 methyl groups, and endometrioma group may be replaced by oxygen atom, amidinopropane, unsubstituted or substituted by one or two alkyl groups is whether the two alkyl groups or tetramethylene or pentamethylene, maleinimide, unsubstituted or mono - or disubstituted by identical or different substituents from among alkyl and phenyl, linked through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup, oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and mentioned heteroaromatic rings in the carbon skeleton may be substituted by alkyl with 1-6 carbon atoms or phenylalkyl to 5-membered and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methylene group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom of the formed pyridine ring with the sulfur atom, or formed anilinophenol phenyl ring by one or two methyl groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroalkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene bridge, and available if needed in the imidazole ring NH group may be substituted by an alkyl group with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl, imidazolidinedione group, unsubstituted or substituted alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene, pyridazin-3-one and dihydropyridin-3-one, which is in position 2 can be substituted and,

the group R7-NR6CO NR5where R5a hydrogen atom, alkyl with 1-8 carbon atoms, cycloalkyl with 5-7 carbon atoms or phenylalkyl;

R6a hydrogen atom, alkyl with 1-8 carbon atoms, alkenyl with 3-5 carbon atoms, phenyl, phenylalkyl or cycloalkyl with 5-7 carbon atoms,

R7a hydrogen atom or alkyl with 1-6 carbon atoms,

one of the radicals R5, R6or R7may mean bicyclohexyl or diphenylol, R6and R7together with the enclosed nitrogen atoms means the unbranched alkalinising with 4-6 carbon atoms, or R5and R6ashamed mean alkylen with 2-4 carbon atoms, 1H, 3H-hinzelin-2,4-Dion-3-yl, pentamethylene-oxazoline-2-yl, or R1a hydrogen atom or is in position 5, 6 or 7 atoms fluorine, chlorine or bromine, an alkyl group with 1-4 carbon atoms, vermeil, deformity or trifluoromethyl; R2bound through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup and the oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and said heteroaromatics and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom, or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methine group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom formed piperidino ring sulfur atom, or formed anilinophenol phenyl ring, one or two methine groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroaromatic rings in the carbon skeleton may additionally be monogamist fluorine atom, chlorine or bromine, the alkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene my with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl,

R3a hydrogen atom, an alkyl group with 1-5 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, or cycloalkyl with 3-5 carbon atoms,

R4carboxyl, cyano, 1H-tetrazolyl, 1-triphenyl-methyl-tetrazolyl, alkoxycarbonyl with the total number of carbon atoms 2-5, alkanesulfonyl, arylsulfonamides, triftormetilfullerenov, and if nothing else is specified, then the above alcoolica, alkyl and CNS part can contain 1-3 carbon atoms, and cycloalkyl part of 3-7 carbon atoms, and moreover, if (a) R1a hydrogen atom, R3N-propyl and R4carboxyl, R2in position 6 does not mean 3-methylimidazo[4,5-b]pyridine-2-yl or 3-n-hexyl-imidazo[4,5-b]pyridine-2-yl, or if (b) R1a hydrogen atom, R3n-propyl or n-butyl and R41H-tetraza the sawdust and R4carboxyl, R2in position 5 or 6 does not mean 1-methylbenzimidazole-2-yl or 6 position 1H-butylbenzothiazole-2-yl, 1,5-dimethylbenzimidazole-2-yl or 1-methyl-5-trifluoromethyl-benzimidazole-2-yl, or if g) R1a hydrogen atom, R3n-butyl and R4carboxy or 1H-tetrazolyl, R2in position 6 does not mean 1-methylbenzimidazole-2-yl, or if d) R1a hydrogen atom, R3n-butyl and R4carboxyl, R2in position 6 does not mean benzimidazole-2-yl, mixtures of them 1-, 3-isomers or individual isomers and hydrates and salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which are used, for example, as antagonists of angiotensin II, the method of obtaining derivatives of benzimidazole containing the substances, medicinal product and method of its production

The invention relates to medicine, in particular to pharmacology and Oncology

The invention relates to new derivatives of benzimidazole, with a strong pharmacological action, as well as to intermediate compounds for their production

The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/УZ;

Y represents a single bond, 0, NR7or; Z represents hydrogen, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6that may be the same or different, represent hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

R8, R9, R10, R11which may be the same or different, represent hydrogen, lower alkyl or benzyloxycarbonyl, or their N-alkyl
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