The method of obtaining derivatives of n-(3-hydroxy-4-piperidinyl)- (dihydrobenzofuran, dihydro-2h-benzopyran or dihydrobenzoic)-carboxamide, or their salts, or their stereochemical isomeric form

 

(57) Abstract:

Usage: in medicine, as a stimulator of gastrointestinal motility. The invention produktoprovody N-(3-hydroxy-4-piperidinyl)-(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzoic) carboxamid f-ly I, where R1, R2, R3L and A are the corresponding values. Reagent 1: compound f-crystals II, where R1, R2, R3L and A are the corresponding values. Reagent 2: L - W, L are the corresponding values. W is a halogen atom or sulfonyloxy; or aldehyde L=0, where L=0 are combinations of f-crystals of L - H, which has two neighboring atoms of hydrogen, C1-C6alcantera or C3-C6cycloalkenyl replaced = 0, or alkene f-ly NC-CH=CH2. The process is conducted in the medium of reaction inert solvent, optionally in the presence of a base, iodide salt or reducing agent and subsequent transformations of one of the target product to another, as desired, and the selection of the target product in free form or in the form of a therapeutically active non-toxic salt or in the form of stereochemical isomeric form. Structure f-l I and II (see drawing). 1 Il., 5 table.

The invention relates to svodnik N-(3-hydroxy-4-piperidinyl)-(dihydrobenzo - furan, dihydro-2H-benzopyran or dihydrobenzoic)carboxamide, having the activity to stimulate gastrointestinal motility.

Known derivatives (3-hydroxy-4-piperidinyl)benzamide with stimulating activity of gastrointestinal motility.

Derivatives of N-(3-hydroxy-4-piperidinyl)-(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzoic)Carbo - xamiga according to the invention is superior to these known compounds for the pharmaceutical activity of the specified type.

Compounds according to the invention have the formula I

L-N R2(I) where a is a radical of the formula-CH2-CH2- (a-1) -CH2-CH2-CH2- (a-2) or-CH2-CH2-O- (a-3) and one or two hydrogen atoms in the specified radical (a-1) can be replaced WITH1-4is an alkyl radical

R1is halogen,

R2amino group,

R3hydrogen or C1-4-alkyl,

L3-6-cycloalkyl,3-6-alkenyl or L is a radical of the formula-AIk-R5(b-1) -AIk-X-R6(b-2) -AIk-Y-C/=O/-R8(b-3) or-AIk-Y-C/=O/ -NR10R11(b-4) where each AIk is1-6-Alcantara, and

R5is hydrogen, codom, WITH1-6-alkyl, C3-6-cycloalkyl, aloevera, optionally substituted C1-4-alkylcarboxylic, 3-cyano-2-pyridinyl, 2-methyl-5-pyridium, 4-hydroxy-2-pyrimidinyl, 2-methyl-3-pyrazinium or 3,4-dihydro-4-oxo-2-hinazolinam;

X is O or NH,

R8is hydrogen, C1-6-alkyl, 2,4,6-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,6-dichlorophenyl or1-6-alkoxy;

Y is NR9or a simple bond; specified R9is hydrogen, C1-4-alkyl or phenyl;

R10and R11each independently is a C1-6-alkyl, or R10and R11taken together with the nitrogen atom to which they are attached, may form pyrrolidinyl ring;

Het is a system of simple cyclic ether selected from the group consisting of

; R12< / BR>
; or where R12is hydrogen or C1-4-alkyl; or

Het is a heterocyclic system selected from the group consisting of pyridinyl or benzimidazolyl, substituted C1-6-alkyl, or

Het is a monocyclic amide system selected from the group consisting of

where R14is hydrogen or C1-6-alkyl,

R15=O)-CH2or

Het is a bicyclic amide system selected from the group consisting of

;

< / BR>
N ; or R16is1-6the alkyl or vinylmation,

R17is1-6the alkyl and

R18is hydrogen or halogen,

G3is-S-(CH2)2- or-S-CH=CH-,

G4is-CH=CH-CH=CH-, -CH=CCI-CH=CH-, -CH=N-CH=CH - or-N=CH-N=CH-.

In the scope of the invention also includes salts and stereoisomers of these compounds.

The object of the invention is also a method of obtaining these compounds, according to which the exercise of the N-alkylation of the piperidine of formula II

H-N R2(II) where R1, R2, R3and a have the meanings indicated in the formula (I), an intermediate product of the formula L-W (III), where L is the value specified in the formula (I), and W is halogen or sulfonyloxy; or aldehyde of formula L' 0 (IV)

L' 0 is a compound of formula L-H in which two adjacent hydrogen atom in C1-6-alcantera or3-6-cycloalkenyl semeneya; or an alkene of the formula NC-CH= CH2(V) in a reaction inert solvent, optionally in the presence of a base, iodide salt or reducing agent; and NeoMaster the/SUP> A and AIk defined in formula (I), in a reaction inert solvent in the presence of a catalyst and in an atmosphere of hydrogen, the result is a compound of the formula

H2N Alk N R2(I-d) and then enter the specified compound of the formula (I-d) reaction with a reagent of the formula R-W, where R is the R6WITH/=O/-R8or-C/=O/R10R11and

W is halogen or methylthiourea, optionally in a reaction inert solvent, optionally in the presence of base, you get a compound of the formula

R - Alk N R2(I-e) where R1, R2, R3, R9AIk and As defined in formula (I), or, if desired, are deacetylate the compounds of formula

R Alk N R2(I-f) where R1, R2, R3, R8AIk and As defined in formula (I), in a reaction inert solvent in the presence of acid, thus obtain the connection formula

RAlk N R2(I-g) or, if desired, make the connection formulas

C1-6alkyl O __ - Alk N R2(I-h) where R1, R2, R3, R6, AIk, and As defined in formula (I), in a reaction inert solvent in the presence of acid, thus obtain the connection formula

R NH Alk N R2(I-i) and, if desired, make the connection formulas to participate acid salt to the free base by treatment with alkali, and/or get a stereochemical isomeric form.

Used here, the terms "halogen" is shared by fluorine, chlorine, bromine and iodine; alkyl WITH1-C6" defines saturated hydrocarbon radicals with a straight or branched chain, having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 2-methylpropyl and similar; "cycloalkyl3-C6" is the generic definition for cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; "cycloalkane5-C6" is generic for Cyclopentanone and cyclohexanone; "alkenyl3-C6" defines hydrocarbon radicals with a straight or branched chain, containing one double bond and having from 3 to 6 carbon atoms, such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and similar; and when alkenyl3-C6substituted at a heteroatom, then the carbon atom indicated alkenyl3-C6associated with the specified heteroatom is preferably saturated; "alcander1-C6" defines the divalent hydrocarbon radicals with a straight or branched chain, containing from 1 to 6 atoma is undertaken isomers.

Have in mind that the above salts include therapeutically active non-toxic salt additive form, which is able to form compounds of formula (I). The latter can conveniently be obtained by processing forms the Foundation of such appropriate acids as inorganic acids, for example helodermatidae acid, for example hydrochloric, Hydrobromic and similar, sulfuric acid, nitric acid, phosphoric acid and similar; or organic acids such as acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, tanginoa, proportionaly, batandjieva, (Z)-2-batandjieva, (E)-2-batandjieva, 2-hydroxybutanone, 2,3-dihydroxybutyl - new, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, ethanesulfonate, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. On the contrary, the salt form can be processed by alkali developing in the form of a free base.

The compounds of formula (I) containing acidic protons may also be converted to their therapeutically active non-toxic forms salts with meth is ptx2">

The term "additive salt" also includes hydrates and additive form with the solvent that the compounds of formula (I) can form. Examples of such forms are, for example, hydrates, alcoholate and similar.

The compounds of formula (I) have at least two asymmetric carbon atom in its structure, namely the atoms located at the 3 - and 4-position piperidino kernel. Stereochemical isomeric forms of the compounds of formula (I) fall under the scope of the invention. In addition, the compounds of the invention can form CIS/TRANS isomers, more specifically, the substituents in these 3 - and 4-positions piperidino kernel may have either TRANS - or CIS-configuration; such CIS/TRANS isomers also fall under the scope of the invention.

The reaction of N-alkylation of compound (II) compound (III) is conveniently carried out in a reaction inert solvent such as, for example, water, an aromatic hydrocarbon, for example benzene, methylbenzol, xylene, chlorobenzene, methoxybenzo and similar, alkanol, for example methanol, ethanol, 1-butanol, and similar halogenated hydrocarbons such as dichloromethane, trichloromethane and similar, ester, such as ethyl acetate, butyrolactone,1'-oxybisethane, tetrahydrofuran and similar, in a polar aprotic solvent, for example N, N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoramide, 1,3-dimethyl - 3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 1,3-dimethyl-2-imidazolidinone, 1,1,3,3-tetramethylrhodamine, nitrobenzene, 1-methyl-2-Pirro - lidiane and similar, or in mixtures of such solvents.

For trapping of acid that is released during the course of the reaction can be used, the addition of an appropriate base, such as, for example, carbonate, bicarbonate, carboxylate, amide, oxide, hydroxide or alcoholate of an alkaline or alkaline-earth metal, for example sodium carbonate, sodium bicarbonate, potassium carbonate, calcium oxide, sodium acetate, sodium amide, sodium hydroxide, sodium methylate and the same, or organic bases, such as, for example, amine, e.g. N,N-dimethyl-4-pyridylamine, N, N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 1,4-diazabicyclo-(2,2,2)-octane, 4-ethylmorpholine and similar. In some cases it may be appropriate to add iodide salt, preferably the alkali metal iodide, or a crown ether, such as 1,4,7,10,13,16-hexaoxacyclooctadecane and similar. Mixing and slightly rising on N-alkylation in an inert atmosphere, such as, for example, free oxygen, argon or nitrogen gas. Alternative specified N-alkylation may be carried out while applying known in the art conditions of the reactions catalyzed phase transfer. Such conditions include mixing of reagents with a suitable base and optionally in an inert atmosphere, as described above, in the presence of a suitable catalyst phase transfer, such as, for example, a halide, hydroxide, acid sulphate dialkyldimethylammonium, tetraalkylammonium, tetraallylsilane, tetrakisphosphate, and similar catalysts. To enhance the reaction rate can be several suitable elevated temperature.

On this and the following stages of the reaction products can stand out from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art, such as, for example, extraction, distillation, crystallization, trituradora or chromatography.

The compounds of formula (I) can also be transformed into each other using known in the art methods of transformation of functional groups. Some examples of such procedures will be given below.

The compounds of formula (I) containing protective dioxolane ring, can decemlineata, giving relevant exocoetidae. This deacetylase can be carried out in accordance with procedures well-known in the art, for example, by the reaction of starting compounds in aqueous-acid medium.

The compounds of formula (I) containing a cyano-Deputy, can be transformed into the corresponding amines by stirring and, if necessary, heat source cyano-compounds in the environment containing hydrogen, in the presence of an appropriate catalyst, such as, for example, platinum on charcoal, Raney Nickel and the like, catalysts, and optionally in the presence of a base, such as, for example, amine, e.g. N,N-diethylethanamine and similar, or hydroxide, for example sodium hydroxide, and similar. Suitable solvents are, for example, alkanols, such as methanol, ethanol and similar; ethers such as tetrahydrofuran and similar, or a mixture of such solvents.

Pure stereochemical isomeric forms engineering techniques. Diastereoisomer can be separated by physical separation methods such as selective crystallization and chromatography techniques, such as distribution in a counter, and enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids and optically active derivatives.

CIS - and TRANS-diastereomeric the racemates can be further split into their optical isomers, CIS (+), CIS (-), TRANS (+) and TRANS (-) using known techniques.

Pure stereochemical isomeric forms may also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction is stereospecific manner.

The compounds of formula (I) containing Allenby fragment may be present in the "E" or "Z" shape, and the specified E - and Z-symbols have the meanings described in J. Org. Chem. 35, 2849-2868 (1970).

The compounds of formula (I), their pharmaceutically acceptable salts and the possible stereoisomeric forms possess favorable properties promote gastrointestinal peristalsis. In particular, these compounds find detelstvuet results obtained in the following test on "reductions caused by the ascent of the colon".

Stimulating effect of the proposed compounds of formula (I) motility (motor activity) gastrointestinal system may additionally be confirmed, for example, various tests described in The Journal Pharmacology and Experimental Therapeutics, 234, 775-783 (1985) and in Drug Development Research, 8. 243-250 (1986). The test of "emptying from the stomach liquid food in rats", described in the last article, and the test of "emptying from the stomach calorie food in dogs after the appointment of lidamycin" additionally found that typical representatives of a number of compounds also significantly speed up the emptying of the stomach.

In addition, the compounds of formula (I), their pharmaceutically acceptable acid additive salts and the possible stereoisomeric forms have special receptor-binding profile. Some groups of compounds of the invention, particularly compounds in which the radical not substituted by alkyl WITH1-C6have bad T3antagonistic activity induced by high doses of serotonin in the ileum of the Guinea pig. Most of the compounds of the invention do not show the Kim T2receptors and have little or no dopaminergic antagonistic activity.

Due to its useful properties enhance gastrointestinal peristalsis on the basis of these compounds can be prepared in various forms for the purposes of admission.

To prepare the pharmaceutical compositions of the invention an effective amount of a particular compound, in the form of base to acid additive salt, as the active ingredient is thoroughly mixed with a pharmaceutically acceptable carrier, which may take a variety of forms depending on the form of the drug proposed for appointment. These pharmaceutical compositions are presented in the form of a unit dose, preferably for the purpose orally, rectally or via parenteral injection. For example, upon receipt of the compositions in the form of oral dosages may apply any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols, and similar, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, or solid carriers such as starches, sugars, kaolin, lubricants, agents, dezintegriruetsja agents and similar, with the more favorable form of oral dosage units, and in this case obviously apply solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes sterile water, at least a large part, although can include other ingredients, for example, in order to facilitate solubility. Injectable solutions, for example, can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Can also be prepared injectable suspension, in this case, you can apply the appropriate liquid carriers, suspendresume agents and similar. In the compositions suitable for appointment through the skin, the carrier optionally comprises an agent that enhances the penetration and/or a suitable wetting agent, optionally in combination with small amounts of suitable additives of any nature, which does not have a significant adverse impact on the skin. These supplements can facilitate the application to the skin and/or may be useful to obtain the desired compositions. These compositions can be administered in various ways, such as by transdermal, locally, in the form of ointment. Acid additive salts of compounds (I) vsledstvii suitable for the preparation of aqueous compositions.

Particularly beneficial to produce the aforementioned pharmaceutical compositions in the form of dosage units for ease of their purpose and uniformity of dosage. The form of dosage units refers to physically discrete units suitable as unit doses, each unit contains a defined quantity of active ingredient calculated to obtain the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including tablets in the form of a nucleus or coated), capsules, pills, powders, wafers, injectable solutions or suspensions, the number of constituting a full teaspoon, tablespoon, and the like, and segregated multiple combinations of them.

Because of their ability to stimulate peristalsis of the gastrointestinal system, in particular their ability to enhance motor activity of the colon, the described compounds are useful to bring in norm or to improve emptying of the stomach and intestines in subjects suffering from upset peristalsis, for example, decreased motility of the stomach and/or thin and/or thick guts.

Because of the usefulness of p is Inoi activity of the gastrointestinal system, such as, for example, gastroparesis, dyspepsia, accompanied by flatulence, bezyatiny dyspepsia, pseudoprobability, and especially violated the passage of contents through the colon. This will include General purpose effective to stimulate motor activity of the gastrointestinal tract number of the compounds of formula (I), N-oxide, pharmaceutically acceptable acid additive salt or a possible stereoisomeric form of warm-blooded animals. Some specific compounds of the invention also have therapeutic value in the treatment of motor activity of the upper digestive tract and disorders gastroesophageal reflux.

Compounds according to the invention are low toxic. Experts in the art could easily determine the effective amount for stimulating locomotor activity, according to test results, are presented below.

In General it is considered that the effective dose is from about 0.001 to 10 mg/kg of body weight, and more preferably from 0.01 to 1 mg/kg of body weight. The examples are intended to illustrate but not to limit the invention in all its aspects.

Experimental frequent the 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl - oil acid 218 wt.h. trichlormethane and 3,43 wt.h. N, N-diethylethanamine dropwise added 3,63 wt.h. ethylchloride, maintaining the temperature below 10aboutC. After stirring for 1/2 h at 10aboutWith all added to a solution of 6.26 wt.h. ethyl-4-amino-3-methoxy-1-piperidinyloxy - LVL 145 wt. hours of trichloromethane at 10aboutC. Stirring is continued for 1/2 h at room temperature. The reaction mixture was washed with water, 5% sodium hydroxide and water, then dried, filtered and evaporated. The residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain 12.3 wt.h. (93,2%) ethyl-CIS-4-[(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-Ben - zafarani)carbylamine]-3-methoxy-1 - piperidinecarboxylate (intermediate 1).

b). A mixture of 12.3 wt.h. the intermediate product 1, 15.9 wt.h. potassium hydroxide and 156 wt.h. 2-propanol was mixed for 12 hours at a temperature of the return stream. The reaction mixture was evaporated and to the residue was added water. All was evaporated again and the residue was diluted with water. The product was extracted with dichloromethane (2 times) and the combined extracts were dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH<-oxybisethane. The product was filtered and dried to obtain 7,24 wt.h. (71,0%) of CIS-4-amino-5-chloro-2,3-dihydro-N-(3-methods - XI-4-piperidinyl)-2,2-dimethyl-7-benzo - furancarboxylic, so pl. 179,3about(Intermediate 5).

In a similar manner were also obtained intermediate products listed in the table. 1.

P R I m m e R 2.

a). A solution of 9.1 wt.h. 5-chloro-2,3-dihydro-4-benzoguanamine [described in J. Het. Chem. 17(6) 1333 (1980)] 9,6 wt.h. N-bromosuccinimide and 130,5 wt.h. benzene was mixed for 1 h at the temperature of the return stream. The solvent was evaporated and the residue was dissolved in 387,4 wt.h. trichlormethane. The solution was washed with water (2 x 200 wt.h.). The organic layer was dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; C6H14/CH2Cl250 50). Eluent of the desired fraction was evaporated to obtain to 11.8 wt.h. (87,9%) of 7-bromo-5-chloro-2,3-dihydro-4-benzoguanamine (intermediate 8).

b). To a cooled (-70aboutC) and stir the mixture of 15.6 wt.h. solution N. utility in hexane 2.5 polyarnosti and 44.5 wt.h. of tetrahydrofuran was added dropwise a solution of 4 wt.h. the intermediate product 8 26.7 wt.h. of tetrahydrofuran in a stream of nitrogen. The reaction mixture p is Yes (ice) to 44.5 wt.h. tetrahydrofuran (THF). The mass was given the opportunity to warm to room temperature while stirring, and added 80 wt. including water. The aqueous layer was kind of balanced out with hydrochloric acid, and the precipitate was filtered off and dried in vacuum at 60aboutWith receipt of 1.1 wt.h. (32,2%) 4-amino-5-chloro - 2,3-dihydro-7-benzofuranol acid;

So pl. 258,4about(Intermediate 9).

Similarly, there was obtained 8-amino-7-chloro-2,3-dihydro-1,4-benzodi - SYN-5-carboxylic acid (intermediate 10).

P R I m e R 3.

a). A mixture of 40 wt. 'clock methyl-4-(acetylamino)-5-chloro-2-(2-propyloxy)benzoate and 172 wt.h. phenoxybenzoyl stirred for 45 min at 230aboutC. After cooling, the reaction mixture was poured into petroleum ether. The organic layer was separated, dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH 97 3). Eluent of the desired fractions was evaporated and the residue crystallized from acetonitrile to obtain to 11.9 wt.h. methyl 5-(acetylamino)-6-chloro-2H-1-benzopyran-8-carboxy - LVL (intermediate 11).

b). A mixture of 31.3 wt.h. the intermediate product 11,31 wt.h. N,N-diacylates atora palladium on coal. After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was suspenderbelt in the water, and the product was extracted with dichloromethane (2 times). The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified twice by chromatography on a column (silica gel; CH2Cl2/CH3OH 97,5 2,5). Eluent of the desired fraction was evaporated, and the residue crystallized from acetonitrile. The product was filtered and dried to obtain 19.1 wt.h. (69,7%) methyl-5-(acetylamino)-3,4-dihydro-2H-1-benzopyran-8-carboxylate.

So pl. 175,1about(Intermediate 12).

C). A mixture of 19.1 wt.h. the intermediate product 12, 10,22 wt.h. N-chlorosuccinimide and 237 wt.h. acetonitrile was mixed for 1 h at the temperature of the return stream. After cooling, the reaction mixture is poured into 300 wt.h. water. The product was extracted with dichloromethane (2 times) and the combined extracts were washed with water, dried, filtered and evaporated. The residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain to 17.8 wt.h. (81,5%) methyl-5-(acetylamino)-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylate. So pl. 184,2potassium and 20 wt.h. water was mixed for 3 h at the temperature of the return stream. After cooling, the reaction mixture was padillas to pH 4 with concentrated hydrochloric acid. The precipitate was filtered and dried to obtain to 0.65 wt. h (60,7%) of 5-amino-6-chloro-3,4-dihydro-2H-1-banter - EN-8-carboxylic acid. So pl. 225,9about(Intermediate 14).

P R I m e R 4.

a). To a solution of 104,6 wt.h. methyl-2-hydroaxe-4-(acetylamino)benzoate 470 wt. including N, N-dimethylformamide portions were added 24 wt.h. dispersion of sodium hydride in mineral oil (50%) in nitrogen atmosphere. After stirring for 1 h at room temperature, to the mixture was added a solution of 55.2 wt.h. 3-chloro-2-methyl-1-propene in 47 wt.h. N,N-dimethylformamide. Stirring is continued for 3 days at 50aboutC. the Reaction mixture was evaporated, and the residue was dissolved in dichloromethane. This solution was washed with water, 10% sodium hydroxide and water and then dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybisethane. The product was filtered and dried to obtain 65,8 wt.h. (50%) of methyl-4-(acetylamino)-2-[(2-methyl-2-propenyl)oxy]benzoate (intermediate 15).

b). A mixture of 72 wt.h. intermediate 15 and 226 wt.h. 1-METI is I the mixture is poured into ice water. The product was extracted with dichloromethane (2 times) and the combined extracts were washed with water, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybisethane. The product was filtered and dried to obtain 35,4 wt.h. (49,8%) of methyl-4-(acetylamino-2-hydroxy-3-2-methyl-2-propenyl)benzoate. The mother liquid was evaporated, and the residue was consistently suspendible in water and precrystallization of 2,2'-oxybisethane obtaining additional 17.6 wt.h. (24,8%) of methyl-4-(acetylamino-2-hydroxy-3-2-methyl-2-Pro-penyl)benzoate. Total yield: 53,0 wt.h. 74,6% (intermediate 16).

C). A mixture of 126 wt.h. the intermediate product 16 and 1220 wt.h. formic acid is stirred for 20 hours at a temperature of the return stream. After cooling, the reaction mixture was poured into a mixture of ice-water and was extracted with dichloromethane (2 times). The combined extracts were washed with 10% sodium hydroxide and water and then dried, filtered and evaporated. The residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain 105,5 wt.h. (83.8 per cent) methyl-4-(acetylamino)-2,3-dihydro-2,2-dimethyl-7-benzofuranyl - barcelata (intermediate 17).

d). A mixture of 10.5 wt.h. promezhutochnoyee flow. After cooling, the reaction mixture is poured into ice water. The product was extracted with dichloromethane (2 times) and the combined extracts were dried, filtered and evaporated. The residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain to 11.9 wt. h (99,9%) of methyl-4-(acetylamino)-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzophenoneoxymate and (intermediate 18).

e). A mixture of 11.9 wt.h. intermediate 18, 22,4 wt.h. of potassium hydroxide and 200 wt. hours of water were mixed for 3 h at the temperature of the return stream. After cooling, the reaction mixture was padillas to pH 4-5. The precipitate was filtered and dried to obtain to 8.1 wt.h. (83,8%) 4-amine-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranol acid (intermediate 19).

C. obtain the final compounds.

P R I m e R 5. A mixture of 3.9 wt.h. the intermediate product 2, 2.54 wt.h. sodium carbonate, 1 crystal of potassium iodide and 144 wt.h. 4-methyl-2-pentanone stirred for 1 h at a temperature of return flow using water separator. After the addition of 3.2 wt.h. 1-(2-chloroethyl)-3-ethyl-2,3-dihydro-1H-gasoline - imidazol-2-it, stirring was continued over night at a temperature reverse pothouse using chromatography on a column (silica gel; CH2Cl2/CH3OH 96 4). Eluent of the desired fraction was evaporated and the residue is crystallized from 2,2'-oxybisethane. The product was dried in vacuum at 70aboutWith the receipt of 2.30 wt.h. (37.3% ) of CIS-4-amino-5-chloro-N-[1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-yl)e Tyl)C-4-piperidinyl] -2,3-dihydro-7-benzofur - rockboxed. So pl. 173,7about(Connection 1).

P R I m e R 6. A mixture of 4.2 wt.h. monobromide 3-(2-bromacil)-2-methyl-4H-hinzelin-4-it, and 3.3 wt. including intermediate product 2, 4,24 wt.h. sodium carbonate, 160 wt.h. 4-methyl-2-pentanone and a few crystals of potassium iodide were mixed for 20 hours at a temperature of the return stream. The solvent was evaporated and the residue was distributed between trichloroethanol and water. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified twice by chromatography on a column (silica gel; CHCl3/CH3OH 97 3; HPLC; silica gel; C6H5-CH3) ISO-C3H7OH 80 20). Eluent of the desired fraction was evaporated and the residue crystallized from acetonitrile. The product was filtered off and dried in vacuum at 60aboutWith obtaining 3,10 wt.h. (60,5%) of CIS-4-amino-5-chloro-2,3-dihydro-N-[3-methods - XI-1-(2-(2-methyl-4-oxo-3(4H)-hinzelin) ethyl)-4-PI is camping 4,07 wt.h. the intermediate product 7, 3,82 wt.h. sodium carbonate and 200 wt.h. 4-methyl-2-pentanone stirred at reflux (with water separator) for 1 h and Then was added to 2.7 wt. including 6-chloro-2-(3-chlorpropyl)-2H-pyridazin-3-she and stirring at a temperature of return flow continued throughout the night. The reaction mixture was evaporated and the residue was taken in dichloromethane. This solution was washed with water, dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH/NH3/ 95 5). Eluent of the desired fraction was evaporated and the residue was utverjdala 2,2'-oxybisethane. The product was filtered and dried to obtain 3.9 wt.h. (63,7%) of CIS-5-amino-6-chloro-N-[1-(3-(3-chloro-1,6-dihydro-6-oxo-1-pyridazinyl)propyl)- 3-medini]-3,4-dihydro-2H-benzopyran-8-CT - oxamide.

So pl. of 149.5about(Compound 136).

P R I m e R 8. A mixture of 3.4 wt.h. the intermediate product 7, 3.16 wt.h. tetrahydro-2-furnitureleather (ester), 80 wt.h. 4-methyl-2-pentanone and 1.58 wt.h. sodium carbonate were mixed under heating with reflux condenser (with water separator) within 30 hours the Reaction mixture was evaporated and the residue was diluted with water. the were was evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH 95 5). Eluent of the desired fraction was evaporated and the residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain 2,44 wt.h. (57.6%) of CIS-5-amino-6-chloro-3,4-dihydro-N-(3-methoxy-1-)(tet - rehydro-2-furanyl)methyl(-4-piperidinyl)-2H-1-benzopyran-8-carboxamide. So pl. 158,1about(Compound 76).

P R I m e R 9. A mixture of 3.53 wt.h. intermediate 5, 2.1 wt.h. 1-(3-chlorpropyl)-3-ethyl-2-imidazolidinone, 94 wt.h. N,N-dimethylformamide and 1.58 wt. including sodium carbonate were mixed for 20 h at 70aboutC. the Reaction mixture was evaporated and the residue was diluted with water. The product was extracted with dichloromethane (2 times) and the combined extracts were washed with water, dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH/NH3/ 96 4). Eluent of the desired fraction was evaporated and the residue was turned into salt candiate in 2-propanol. The product was filtered and dried to obtain 4,18 wt.h. (70,0%) of candiota CIS-4-amino-5-chloro-N-[1(3-(3-ethyl-2-oxo-1-they - diazolidinyl)propyl)-3-methoxy-4-Piperi - dinyl] -2,3-dihydro-2,2-dimethyl-7-benzofur - rockboxed (1, ,3 wt.h. the intermediate product 2, 2,12 wt.h. sodium carbonate and 47 wt.h. N,N-dimethylformamide stirred for 3 days at 70aboutC. After cooling, the reaction mixture was evaporated. The residue was distributed between dichloromethane and water. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH 95 5). Eluent of the desired fraction was evaporated and the residue crystallized from acetonitrile to which was added a few drops of water). The product was filtered off at 0aboutWith and were dried in vacuum at 40aboutWith the receipt of 2.3 wt.h. (55,8%) of CIS-4-amino-5-chloro-N-[1(1,3-dioxolane-2-yl-methyl)-3-methoxy-4-piperidinyl]-23-carboxamide.

So pl. 149,1about(Compound 83).

P R I m e R 11. A mixture of 2.78 wt.h. 1-(3-chlorpropyl)-2-methyl-1H-benzimidazole, 3.3 wt.h. the intermediate product 2, 2,04 wt.h. N,N-diethylethanamine and 94 wt. including N,N-dimethylformamide stirred for 20 h at 70aboutC. the Reaction mixture was evaporated and to the residue was added water. The product was extracted with dichloromethane (2 times) and the combined extracts were washed with water, dried, filtered and evaporated. The remnant of Christ who rata CIS-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-1-(3-(2-meth - yl-1H-benzimidazole-1-yl)propyl)-4-Pipa - riginal]-7-benzoperoxide. So pl. 151,5about(Compound 27).

P R I m e R 12. A mixture of 3.3 wt.h. the intermediate product 2, and 4.4 wt.h. ethyl N-(2-oxoethyl)-N-phenylcarbamate, 2 wt.h. solution of thiophene (4% methanol was gerasoulis at normal pressure and at 50aboutWith 2 wt.h. 5% of platinum catalyst on coal. After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was diluted with water and the product was extracted with dichloromethane (2 times). The combined extracts were dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH 95 5). Eluent of the desired fraction was evaporated and the residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain is 3.08 wt.h. (58,6%) hemihydrate ethyl CIS-N-[2-[4-[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl) carbon - yl] amino] -3-methoxy-1-piperidinyl] ethyl] N-phenylcarbamate. So pl. 116,4about(Compound 57).

P R I m e p 13. To a stirred mixture of 3.4 wt.h. the intermediate product 7, 2 wt.h. tetrahydrofuran (THF), 2 wt.h. solution of thiophene (4% methanol and 119 wt.h. methanol was added dropwise a mixture of 11 ml of a solution of acetaldehyde in 10% tetrahydrofuran and 8.9 wt.h. tetrahedrals. The residue was dissolved in dichloromethane and this solution was washed with water (2 times), dried, filtered and evaporated. The residue was precrystallization from acetonitrile. The product was filtered and dried to obtain 2,66 wt.h. (72,3%) of CIS-5-amino-6-chloro-N-(1-ethyl-3-methoxy-4-piperidinyl)-3,4-dihydro-2H-1-benzo PI - RAS-8-carboxamide. So pl. 153,8about(Compound 81).

P R I m e R 14. A mixture of 3 wt.h. 1 hexanes, 3.7 wt.h. the intermediate product 3, 1 wt.h. solution of thiophene (4% methanol and 242,5 wt.h. 2-methoxyethanol was gerasoulis at normal pressure and at 50aboutWith 2 wt.h. 5% of platinum catalyst on coal. After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH/NH3/ 98 2). Eluent of the desired fraction was evaporated and the residue is crystallized from 2,2'-oxybisethane. The product was dried in vacuum at 70aboutWith obtaining 3,20 wt. h (68,5% ) of CIS-4-amino-5-chloro-N-(1-hexyl-3-hydroxy-4-piperidinyl)-2,3-dihydro-7-benzo furan - carboxamide.

So pl. 13,4about(Compound 8).

P R I m e R 15. A mixture of 4.5 wt.h. (1,1-dimethylethyl)(2-oxoethyl)methylcarbamate, 5.5 wt.h. promise at normal pressure and at room temperature with 2 wt.h. 10% palladium catalyst on coal. After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was distributed between trichloromethane and water. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was utverjdala 2,2'-oxybisethane (to which was added a few drops of water). The product was filtered off at 0aboutWith and were dried in vacuum at 40aboutWith the receipt of 6.3 wt. h (76,6%) of (1,1-dimethylethyl)-CIS-[2-[4-[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbylamine] 3-methoxy-1-piperidinyl]ethyl]methylcarbamic - one (compound 41).

P R I m e R 16. To heated under reflux to a solution of 17.4 wt. including intermediate product 2 195 wt.h. 2-propanol was added 4.03 wt. h 2-propenenitrile. Stirring at the temperature of reflux distilled continued for 18 hours the Reaction mixture was evaporated and the residue crystallized from 2-propanol. The product was filtered off and dried in vacuum at 60aboutWith the receipt of 14.8 wt.h. (73,7%) of CIS-4-amino-5-chloro-N-[1-(2-cyanoethyl)-3-methoxy-4-piperidinyl]-2, 3-dihydro-7-benzoperoxide.

So pl. 190,7about(Compound 97).

P R I m e R 17. A solution of 15.7 wt.h. CIS-4-avarana and 158 wt.h. methanol was gidrirovaniya at normal pressure and at room temperature with 6 wt.h. Nickel of Rania. After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH(NH3) 93 7). Eluent of the desired fraction was evaporated and the residue crystallized from acetonitrile to which was added a few drops of water). The product was filtered off at 0aboutWith and were dried in vacuum at 40aboutWith the receipt of 8.5 wt.h. (53,6%) of CIS-4-amino-N-[1-(2-amino-ethyl)-3-methoxy-4-piperidinyl]-5-chloro-2,3 - dihydro-7-benzoperoxide (compound 35).

P R I m e R 18. To a cooled (ice bath) mixture of 3.8 wt.h. monohydrate CIS-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-1-[2- (methylamino)ethyl)-4-piperidinyl] -7-benzo - furancarboxylic in 104,3 wt.h. trichloromethane was added to 1.3 wt.h. 1-pyrrolidinecarbonyl chloride. After stirring for 15 min at 0aboutWith dropwise added 1.31 wt.h. N,N-diethylethanamine with temperature up to 10aboutC. Stirring was continued for 20 h at room temperature. The reaction mixture was washed with water, dried, filtered and evaporated is at 0aboutWith and were dried in vacuum at 40aboutWith the receipt of 3.3 wt.h. (73,6%) monohydrate CIS-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-1-[2-[methyl(1-PIR religionisevil)amino]ethyl]-4-Piperi - dinyl]-7-benzoperoxide.

So pl. 112,0about(Compound 43).

P R I m e R 19. A mixture of 1.4 wt.h. 2-chloro-3-pyridylcarbonyl, 3.2 wt. including CIS-4-amino-N-[1-(4-aminobutyl)-3-methoxy-4-PI - pyridinyl]-5-chloro-2,3-dihydro-7-benzofur - rockboxed, 65,8 wt. including N,N-dimethylformamide and 1.3 wt.h. sodium carbonate was mixed for 20 h at 70aboutC. the Solvent was evaporated and the residue was dissolved in trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CHCl3/CH3OH(NH3) 98 2). Eluent of the desired fraction was evaporated and the residue is crystallized from 2,2'-oxybisethane. The product was dried in vacuum at 60aboutWith the receipt of 1.44 wt.h. (35.4%) of hemihydrate CIS-4-amino-5-chloro-N-[1-[4-[(3-cyano-2-PI - riginal)amino]butyl] -3-methoxy-4-Piperi - dinyl]-2,3-dihydro-7-benzofuranes - Mead.

So pl. 129,7about(Connection 6).

P R I m e R 20. A mixture of 1.18 wt.h. 2-chloro-4(3H)-hintline, 2,40 wt.h. compounds 35 and the minimum amount of N,N-dis between dichloromethane and methanol. The organic layer was separated, dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH 90 10). Eluent of the desired fraction was evaporated and the residue crystallized from acetonitrile to which was added a little water). The product was filtered off at 0aboutWith and were dried with receipt of 0.95 wt. hours (37.5% ) of the half hydrate of CIS-4-amino-5-chloro-2,3-dihydro-N-[1-[2-[(3,4-dihydro-4-oxo-2-hintline)am - but]ethyl]-3-methoxy-4-piperidinyl] -7-benzo - furancarboxylic. So pl. 191,8about(Compound 88).

P R I m e R 21. The mixture 4,69 wt.h. dihydrochloride CIS-4-amino-N-[1-(2-amino-ethyl)-3-methoxy-4-piperidinyl] -5-chloro-2,3-dihyd - ro-2,2-dimethyl-7-benzoperoxide, 1.54 wt.h. 2-chloro-3-methylpyridazine and 1.68 wt.h. of calcium oxide were mixed for 20 h at 120aboutC. After cooling, the reaction mixture was diluted with water and the product was extracted with dichloromethane (3 times). The combined extracts were dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH(NH3) 95 5). Eluent of the desired fraction was evaporated and the residue was converted into the salt of candiate in 2-propanol. Product otfiltrovat-2-pyrazinyl)amino etiprednol] -2,2-dimethyl-7-benzofuranyl - oxamide. So pl. 117,1about(Compound 170).

P R I m e R 22. A mixture of 5 wt.h. CIS-5-amino-N-[1-(3-aminopropyl)-3-methoxy-4-Piperi - dinyl] -6-chloro-3,4-dihydro - 2H-1-benzopyran-8-carboxamide, 3.2 wt.h. 2-methylthio-4-pyrimidinone and 79 wt.h. acetonitrile was mixed for 2 days (the weekend) at the temperature of reflux distilled. The reaction mixture was evaporated and the residue was distributed between dichloromethane and ammonia (water). The aqueous layer was separated and was extragonadal dichloromethane (2 times). The combined dichloromethane layers were dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH(NH3) 95 5). Eluent two desired fractions was evaporated and the residues separately crystallized from acetonitrile. The product was filtered off and dried in vacuum at 70aboutWith the first fraction from 2,22 wt.h. (35,2%) hemihydrate CIS-5-amino-6-chloro-3,4-dihydro-N-[1-[3-[(4-hydroxy-2 - pyrimidinyl) amino] propyl]-3-methoxy-4-piperidinyl] 2H-1 - benzopyran-8-carboxamide, so pl. 142,6aboutAnd the second fraction 1.00 wt.h. (15,9%) hemihydrate CIS-5-amino-6-chloro-3,4-dihydro-N-[1-[3-[(4-hydroxy-2 - pyrimidinyl)amino]propyl] -3-methoxy-4-Pipa - riginal]-2H-1 - benzopyran-8-carboxamide.

So pl. 143,5about2Cl2/CH3OH 95 5). Eluent of the desired fraction was evaporated and the residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain 2.4 wt.h. (51,6%) hemihydrate CIS-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-1-(4-oxota - ntil)-4-piperidinyl]-2,2-dimethyl-7-benzo - furancarboxylic. So pl. 137,7about(Compound 112).

P R I m e R 24. A mixture of 6.3 wt.h. compounds 41 and 23.4 wt.h. 2-propanol, saturated with hydrochloric acid and 198 wt.h. methanol was mixed for 15 minutes at the temperature of the return stream. After cooling, the reaction mixture was evaporated. The residue was absorbed by the water and all was podslushivaet ammonia. The product was extracted with trichloromethane and the extract was dried, filtered and evaporated. The residue is crystallized from acetonitrile to which was added a few drops of water). The product was filtered off at 0aboutWith and were dried in vacuum at 40aboutWith the receipt of 3.8 wt.h. (72,9%) monohydrate CIS-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-1-[2-(methyl who adanai bath solution of 2.4 wt.h. CIS-4-amino-N-[1-[2-amino-ethyl] -3-methoxy-4-PI - pyridinyl] -5-chloro-2,3-dihydro-7-benzo - furancarboxylic in to 74.5 wt.h. trichlormethane add 0,86 wt.h. N,N-diethylethanamine, and then added dropwise a solution of 0.77 wt.h. ethylchloride in 29.8 wt.h. trichlormethane. After 0.5 h stirring at room temperature, add water. Separate the organic layer, dried, filtered and evaporated. The residue is purified through column chromatography (silica gel, CH2Cl2/CH3OH(NH3) 98 2). Eluent target fraction is evaporated and the residue is crystallized from acetonitrile (to which are added a few drops of water). The product is filtered at 0aboutWith and dried in vacuum at 40aboutTo get to 0.95 wt. h (32,5%) semi-hydrate ethyl-CIS-[2-[4[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)CARBONYLS - but]-3-methoxy-1-piperidinyl]ethyl]carb - Mat (compound 36).

So pl. 145, 2mmaboutC.

The compounds listed in the table. 2, were prepared according to analogous methods described in any of the previous examples 5-25.

P R I m e R 26. The compounds listed in the table. 3, were prepared according to analogous methods described in any of the examples presented.

C. Pharmacological examples.

P R I m e R 27. Reduction caused by ascending colon (colon) cancer.

The experiment was conducted according to the following method. Segments of the colon length 4.5 cm vertically was suspendibility with preload of 2 g in 100 ml De Jalon (KCl 5.6 mmol; CaCl2x x 2H2O 0.54 mmol; NaHCO35.9 mmol; NaCl 154,1 mmol; glucose 2.8 mmol) at a temperature of 37.5aboutAnd the feeding of the gas mixture of 95% O2and 5% CO2. Reduction was measured as a result of isotopically using a control installation of the displacement sensor 7 HP DSDT-1000, JSID.

After a stabilization period of about 20 minutes was given to 3.4 x 10-6mol of methacholine with the time interval in 15 minutes if he was reproducible reduction in wash solution was administered the test compound. The effect of the compounds were investigated for 10 min and was expressed relative to the maximum concentration, caused by methacholine in the amount of 3.4 x 10-6mol. The effect of typical representatives of compounds of formula (I) shown in table. 4 and 5.

Compounds A, B, C, E and F described in [1] the compound D in [2]

D. Examples of compositions.

P R I m e R 28. Drops for oral administration.

500 wt. including the active ingredient was dissolved the With added 35 l of polyethylene glycol and the mixture is mixed well. Then was added a solution of 1750 wt.h. saharanafrica 2.5 l of purified water and while stirring was added 2.5 liters of flavouring substances cocoa and how much glycol up to a volume of 50 l, giving a solution of oral drops containing 10 mg/ml of active ingredient. The resulting solution was filled into suitable containers.

P R I m e R 29. Solution for oral administration.

9 wt. 'clock methyl-4-hydroxybenzoate and 1 wt.h. propyl-4-hydroxybenzoate was dissolved in 4 l of boiling purified water. In 3 l of this solution were dissolved first 10 wt.h. 2,3-dihydroxybutanedioate acid, after 20 wt.h. the active ingredient. This solution was combined with the remaining part of the first solution and was added to 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 wt.h. saharanafrica was dissolved in 0.5 l of water and added 2 ml of raspberry and 2 ml of gooseberry family essences. The latter solution was combined with the first, water was added in a necessary amount to a volume of 20 liters, giving oral solution containing 5 mg of active ingredient on a full teaspoon (5 ml). The resulting solution was filled into suitable containers.

P R I m e R 30. The capsule.

20 wt.h. the active ingredient, 6 wt.h. lauryl sodium, 56 wt. was sialis together. The resulting mixture was subsequently filled into 1000 suitable hardened gelatin capsules containing 20 mg of active ingredient each.

P R I m e R 31. Tablets, film-coated.

Obtain core tablets. A mixture of 100 wt.h. the active ingredient, 570 wt. including lactose and 200 wt.h. starch is mixed well, after that was moistened with a solution of 5 wt.h. sodium dodecyl sulfate and 10 wt.h. polyvinylpyrrolidone (Kollidon 90in about 200 ml of water. A mixture of wet powder sifted, dried and sifted again. Then thereto was added 100 wt. including microcrystalline cellulose (Avicel) and 15 wt.h. hydrogenated vegetable oil (Sterotex). All well mingled and merged into tablets, giving 10.000 tablets containing 10 mg of active ingredient each.

The coating. To a solution of 10 wt.h. methylcellulose (Methocel 60 HG) in 75 ml of denatured ethanol was added a solution of 5 wt.h. ethyl cellulose (Ethocel 22 cps) in 150 ml of dichloromethane. Then thereto was added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 wt.h. the polyethylene glycol was melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the first, then added 2.5 wt.h. octadecanoate magnesium, 5 wt.h. polyvinyle mixture in covering the device.

P R I m e R 32. Injectable solution.

1.8 wt. 'clock methyl-4-hydroxybenzoate and 0.2 wt.h. propyl-4-hydroxybenzoate was dissolved in about 0.5 l of boiling water for injection. After cooling to about 50aboutWith under stirring was added 4 wt.h. lactic acid, 0.05 to wt. including propylene glycol and 4 wt.h. the active ingredient. The solution was cooled to room temperature and to it was added water for injection in the required amount to 1 l, giving a solution containing 4 mg/ml of active ingredient. The solution was sterilized by filtration (U. S. P. XVII p. 811) and filled in sterile containers.

P R I m e R 33. Medical candles or suppositories.

3 wt. including the active ingredient was dissolved in a solution of 3 wt.h. 2,3-dihydroxybutanedioate acid in 25 ml of polyethylene glycol 400. 12 wt.h. surfactants (SPAN) and triglycerides (Witepsol 555) required up to 300 wt.h. the amount of melted together. The latter mixture is mixed well with the previous solution. Thus obtained mixture was poured into moulds at a temperature of 37-38aboutFor the formation of 100 suppositories containing 30 mg/ml of active ingredient each.

P R I m e R 34. Injectable solution.

60 lo in the amount necessary to bring the mixture up to 1 l, giving a solution containing 60 mg/ml of active ingredient. The solution was sterilized and filled in sterile containers.

The method of obtaining derivatives of N-(3-hydroxy-4-piperidinyl)-(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzoic)-carboxamide of General formula I

< / BR>
salt or a stereochemical isomeric form, And where the radical of the formula

-CH2CH2- (1);

-CH2CH2CH2- (2);

or

-CH2CH2O (3)

one or two hydrogen atoms in the specified radical (1) can be replaced WITH1WITH4-alkyl radical;

R1halogen;

R2amino group;

R3hydrogen or C1WITH4-alkyl;

L3WITH6-cycloalkyl,3WITH6alkenyl or L is a radical of the formula

-Alk R5(1);

-Alk-X-R6(2);

-Alk Y C/=O/ R8(3)

or

-Alk Y C/=O/ NR10R11(4)

where each Alk1WITH6-alcander;

R5hydrogen, cyano WITH3WITH6-cycloalkyl, phenyl, optionally substituted by a halogen atom or Het;

R6hydrogen, C1WITH6-alkyl, C3- C6-cycloalkyl, haloethanol, need not sinila, 2-methyl-3-pyrazinium or 3,4-dihydro-4-oxo-2-hinazolinam;

H O or NH;

R8hydrogen, C1WITH6-alkyl, 2,4,6-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,6-dichlorophenyl or1WITH6-alkoxy,

Y NR9or a simple bond;

R9hydrogen, C1WITH4-alkyl or phenyl;

R10and R11each independently1- C6-alkyl

or R10and R11taken together with the nitrogen atom to which they are attached, may form pyrrolidinyl ring;

Het system is simple cyclic ether selected from the group consisting of

< / BR>
< / BR>
< / BR>
where R12hydrogen or C1WITH4-alkyl,

or Het heterocyclic system is selected from the group consisting of pyridinyl or benzimidazolyl, substituted C1C6-alkyl,

or monocyclic Het amide system selected from the group consisting of

< / BR>
where R14hydrogen or C1WITH6-alkyl;

R15halogen, C1WITH6-alkyl or phenyl;

G1-CH2CH2- CH CH-, or-C(=O)-CH2-;

or Het bicyclic amide system selected from the group consisting of

< / BR>1WITH6-alkyl;

R18hydrogen or halogen;

G3-S (CH2)2- or-S-CH CH-;

G4-CH CH CH CH-, -CH CCl CH CH-, -CH N CH CH - or-N CH N CH-;

or their salts, or their stereochemical isomeric forms, wherein implementing the N-alkylation of the piperidine of formula II

< / BR>
where R1, R2, R3and have the specified values,

the intermediate product of the formula III

L W,

where L is the specified value;

W is halogen or sulfonyloxy,

or aldehyde of the formula IV

L' 0,

where L' 0 is a compound of formula L H, at which two adjacent hydrogen atom in C1WITH6-alcantera or3- C6-cycloalkenyl semeneya,

or alkene of formula V NC CH CH2in a reaction-inert solvent, optionally in the presence of a base, iodide salt or reducing agent

and optionally, if desired, restore the connection formulas I-

< / BR>
where R1, R2, R3And Alk have the above values,

in a reaction-inert solvent in the presence of a catalyst and in an atmosphere of hydrogen, the result is a compound of formula I-d

< / BR>
which is subjected to interaction with the connect is, 8, R10and R11have the specified values;

W is halogen or methylthiourea,

optionally in a reaction-inert solvent, optionally in the presence of base, you get a compound of formula I-e

< / BR>
where R, R1, R2, R3, R9, Alk and have the specified values,

or, if desired, are deacetylate the compounds of formula 1-f

< / BR>
where R1, R2, R3, R8, Alk and have the specified values,

in a reaction-inert solvent in the presence of acid, you get a compound of formula 1-g

< / BR>
or, if desired, convert the compound of formula 1-h

< / BR>
where R1, R2, R3, R6, Alk and have the specified values,

in a reaction-inert solvent in the presence of acid, you get a compound of formula 1-i

< / BR>
and, if desired, convert the compound of formula I in its therapeutically active non-toxic salt by acidification or, conversely, turn acidic salt into the free base by treatment with alkali and/or receive a stereochemical isomeric form.

 

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The invention relates to medicine, namely to Pediatrics, and can be used for the treatment of musculoskeletal disorders in children

FIELD: medicine, neurology.

SUBSTANCE: the present innovation describes arylalkylamines that specifically affect certain types of receptor-operated Ca2+-canals, their application and pharmaceutical compositions for treating neurological disorders or diseases.

EFFECT: higher efficiency.

55 cl, 29 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: method involves rectally introducing mixture produced on base of 5% Novocain solution containing isoniazid, rifamycin, ethambutol in therapeutic doses daily during 21 days. The mixture is pretreated in ultrasonic field during 5 min at 2 MHz frequency.

EFFECT: improved bacteriostatic blood and prostate secret activity.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves applying cannabinoid receptor agonists for treating for transitory relaxation of lower esophageal sphincter and states like gastroesophageal reflux disease, regurgitation, preventing reflux or insufficient mass increase caused by the relaxation.

EFFECT: enhanced effectiveness of treatment.

18 cl, 3 tbl

FIELD: medicine, phthisiology.

SUBSTANCE: method involves firstly the achievement of lymphotropicity of three chemopreparations by addition of 5% glucose and aloe to solutions of these chemopreparations. Then the conduction paravertebral anesthesia is carried out at the level and at side of administration of preparations. Then three chemopreparations are administrated separately in different intercostals sites, 1-3 times per a week, course of 4-12 injections by subcutaneous paravertebral route, parasternal route in I-X intercostals - in projection of regional lymphatic collectors. Method allows reducing the duration of intensive phase in tuberculosis treatment up to 1-3-6 months, to prevent the development of drug-resistant tuberculosis and adverse effects of chemopreparations and to relieve the residual changes of tuberculosis. Invention can be used in treatment of infiltrative, destructive and drug-resistant pulmonary tuberculosis.

EFFECT: improved and enhanced method of treatment.

2 ex

FIELD: medicine; physiotherapy.

SUBSTANCE: two to here days after surgical operation, vibration massage is made by means of vibration apparatus on thorax area of root of lung being opposite to that one which was subject to operation. Vibration massage is made daily at frequency of 90-100 Hz and amplitude of 0,4-0,5 mm during 3-5 minutes for 13-14 days. Starting from the fourth f the fifth day after operation, when both drainages are removed from post-resection pleural cavity, electric-vibration acupressure is made in parallel on skin covers all around total area of thorax by means of massaging device. Vibration-acupressure is made daily at the second part of day after I-II row chemical preparations are given to patient. Frequency of procedure is 35-40 Hz and amplitude 0,5-0,6 mm. Duration of influence is increased gradually from 3 to 13-14 minutes during 11-12 days.

EFFECT: reduced number of pleural-pulmonary complications; uniform ventilation of all parts of segments of lung subjected to operation.

2 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.

EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

FIELD: medicine, phthisiology.

SUBSTANCE: method involves the combined oral and rectal administration of chemopreparations. Ethambutol and pyrazinamide are administrated by oral route in the doses 1.2 g and 1.5 g, respectively. Mixture of chemopreparations as an ultraemulsion is used for rectal administration that is prepared 1 h before administration. The mixture comprises isoniazid (10 mg/kg), rifampicin (600 mg), kanamycin (1 g) and lecithin (20 ml). Therapy is carried out in intensive treatment phase 5 times per a week up to three months and in supporting phase 2 times per a week up to closing destruction cavities. Method provides rapid regression of pulmonary tuberculosis process, to improve tolerance of chemopreparations based on their selective accumulation in lymphatic system of lungs and specific schedule of administration of these chemopreparations. Invention can be used in treatment of destructive form of pulmonary tuberculosis.

EFFECT: improved method of treatment.

1 tbl, 1 ex

Biocidal gel // 2305544

FIELD: pharmaceutical industry, in particular biocide agent.

SUBSTANCE: claimed gel includes hydroxyethyl cellulose, polyguanidine compound (e.g. polyhexamethylene guanidine succinate or poly-(4,9-dioxadodecan guanidine) succinate), glycerol, trilon B, polyethylene glycol, citric acid, perfume composition, and water. Additionally it contains neonol, calcium pantothenate and chamomile extract in specific component ratio.

EFFECT: gel with increased biocidal action.

3 tbl, 3 ex

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to using compound of the formula Z-linker-Z' (1) representing antagonist of chemokinine receptor CXCR4 for preparing a medicinal agent used in mobilization and collection of cell-precursors and/or stem cells in subject. The claimed invention describes also methods for increasing amount of cell-precursors and stem cells in animals using compounds that bind chemokinine receptor CXCR4. Using compound of the formula (1) allows enhancing effectiveness in treatment of HIV and to alleviate unfavorable effects on bone marrow in the process of chemotherapy carrying out.

EFFECT: improved methods for activation.

19 cl, 12 tbl, 1 dwg, 4 ex

FIELD: pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to development of method for preparing rifabutin-containing antibacterial composition. Method involves separate mixing one part of rifabutin with special additives and filling agent and another part of rifabutin with lacking amount of filling agent and their following combining, powdering the mixture with magnesium stearate at stirring and making capsules. Method allows simplifying technology in preparing the preparation in capsulated form owing to optimal technological indices of the prepared composition mixture. The composition shows high stability in storing and therapeutic effectiveness.

EFFECT: valuable pharmaceutical and medicinal properties of composition.

2 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

wherein R represents the group:

m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

EFFECT: improved preparing method, improved methods for treatment, valuable medicinal properties of compounds and composition.

20 cl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein Ar represents phenyl substituted with a group taken among isobutyl, benzoyl, isopropyl, styryl, pentyl, (2,6-dichlorophenyl)-amino-group, α-hydroxyethyl, α-hydroxybenzyl, α-methylbenzyl and α-hydroxy-α-methylbenzyl; R represents hydrogen atom; X means linear (C1-C6)-alkylene, (C4-C6)-alkenylene, (C4-C6)-alkynylene optionally substituted with group -CO2R3 wherein R3 means hydrogen atom, group (CH2)m-B-(CH2)n wherein B means oxygen atom; m = 0; n means a whole number 2; or B means group -CONH; m means a whole number 1; n means a whole number 2 and so on; R1 and R2 are taken independently among group comprising hydrogen atom, linear (C1-C4)-alkyl, hydroxy-(C2-C3)-alkyl and so on. Invention proposes a method for preparing compounds of the formula (I). Invention proposes inhibitors of C5-induced hemotaxis of polymorphonuclear leukocytes and monocytes representing (R)-2-arylpropionic acid omega-aminoalkylamides of the formula (I). Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to hemotaxis of polymorphonuclear leukocytes and monocytes and comprising compounds of the formula (I) in mixture with suitable carrier. Proposes (R)-2-arylpropionic acid omega-alkylamides are useful for inhibition of hemotaxic activation induced C5a and other hemotaxic proteins.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

18 cl, 3 tbl, 23 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of (R)-2-arylpropionamide of the formula (I): , wherein Ar means aryl of the formula (IIIb): F-Arb wherein Arb means phenyl mono- or poly-substituted with the following groups: chlorine, fluorine atom; F means hydrogen atom, linear or branched (C1-C5)-alkyl residue, benzoyl, 2,6-dichlorophenylamino-, 2,6-dichloro-3-methylphenylamino-group; R means hydrogen atom, (C1-C4)-alkyl; X means linear or branched (C1-C6)-alkylene optionally substituted with the group -CO2R4 wherein R4 means hydrogen atom or linear or branched (C1-C6)-alkyl group, phenyl or phenylmethylene group; R1, R2 and R3 mean independently linear or branched (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C3-C6)-alkenyl, aryl, aryl-(C1-C3)-alkyl, or R1 and R2 in common with nitrogen atom (N) to which they are attached form nitrogen-containing 6-membered heterocyclic ring of the formula (II) , and R3 has values indicated above independently wherein in the formula (II) Y means a simple bond, methylene group, oxygen atom, nitrogen atom or sulfur atom; p means a whole number 2; Z- means a pharmaceutically acceptable counterion of quaternary ammonium salts. Also, invention relates to using compound of the formula (I) in treatment of psoriasis, pemphigus and pemphigoid, rheumatic arthritis, intestine chronic inflammatory pathology including ulcerous colitis, acute respiratory distress-syndrome, idiopathic fibrosis, mucoviscidosis, pulmonary chronic obstructive disease and glomerulonephritis, and also for prophylaxis and treatment of injure caused by ischemia and reprefusion. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to chemotaxis of polymorphonuclear leukocytes and monocytes induced by complement C5a fractions and comprising compound of the formula (I) in mixture with a suitable carrier. Also, invention relates to a method for synthesis of compounds of (R)-2-arylpropionamide of the formula (I) that involves interaction of amides of the formula (IV) given in the invention description with compounds of the formula R3Zwherein Z means a leaving group, such as chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, sulfate. Invention provides synthesis of (R)-2-arylpropionic acid omega-aminoalkylamide quaternary ammonium salts used for inhibition of chemotaxis activation induced by the C5a complement component.

EFFECT: valuable properties of compounds and pharmaceutical compositions.

17 cl, 1 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

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