Heterocyclic compounds, or their pharmaceutically acceptable additive salt of the acid, or n-oxide heterocyclic compounds, or its additive salt of the acid

 

(57) Abstract:

Usage: in medicine as specific antagonists of 5-hydroxytryptamine (5-HT)receptors for the treatment of neuropsychiatric devices. The inventive product-heterocyclic compounds f-crystals I. R1X, Y and B have the respective meanings or their pharmaceutical acceptable additive salt of the acid, or n-oxide heterocyclic compounds, or additive salt of the acid. These compounds are used in pharmaceutical compositions in amounts of from 0.5 to 750 mg per dose. Connection structure of f-crystals I:

The invention relates to heterocyclic compounds. Mainly present invention relates to new Amida and esters, processes for their preparation, their use and pharmaceutical compositions containing such substances. The new compounds of the invention are used as antagonists of specific 5-hydroxytryptamine (5-HT) receptors.

In some descriptions of the known patents disclosed the 5-HT3antagonists of various structures, for example, in EP-A-0200444, [1] SW-A-2153821 [2] SAINT-AND-2125398 [3] and EP-A-323077 [4]

The new compounds of the present invention correspond to General formula

R to nimbley a hydrogen atom or one or more substituents selected from lower alkyl, lower alkoxy, halogen atom, methylendioxy or halo(lower)alkyl, X represents-O - or-NR2where R2represents lower alkyl, lower alkenyl, cyclo(lower)alkyl, cyclo(lower)alkyl lower alkyl, phenyl, optionally substituted by a halogen atom, a phenyl (lower)alkyl, a group of the formula -(CH2)r-Y-R8where r is an integer having a value in the range of 1-4, Y' represents 0 or NR5where R5represents a hydrogen atom or lower alkyl, and R8represents a hydrogen atom, lower alkyl or cyclo(lower)alkyl, or a group of the formula Z -, which is associated with regulation 8 of the aromatic ring resulting in the formation of a heterocyclic ring of 5-7 elements in which the elements of the ring represented by Z index represent one or more methylene groups optionally substituted by one or more lower alkyl groups, Y is 0 or NR3where R3represents a hydrogen atom or lower alkyl, and is a rich azabicyclic ring or N-oxide, and rich azabicyclic ring has the formula

N-R4in which m is 2, 3 or 4, a R4represents vtorichnogo connection or additive salt of the acid.

The term "lower" used in the text refers to a radical containing up to 6 carbon atoms. Preferably such a radical containing up to 4 carbon atoms. For example, the lower alkyl group may have a normal or branched structure and may represent a methyl, ethyl, propyl or butyl. A preferred example of the lowest alkenyl is allyl. The lower alkoxy group may represent, for example, methoxy, ethoxy, propoxy or butoxy. Cyclo(lower) alkyl group may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Aryl group, preferably represents a phenyl group which may be optionally substituted by one or more substituents having the meanings indicated above for R1. In the case where R1represents one or more halogen substituents, such substituents preferably represents chlorine or fluorine. Halo(lower)alkyl substituent preferably represents trifluoromethyl. A preferred example, cyclo(lower)alkyl lower alkyl is cyclopropylmethyl. Aryl(lower) alkyl group, preferably represents a benzyl or sameda X represents NR2where R2represents-Z-, the compounds correspond to the formula

R

In this formula, preferred examples of Z include -(CH2)nwhere n is 2 or 3, alkyl substituted di - or tri-methylene chain, for example, -CH2CH (lower Alky)-, -CH2With(lower Alky)2 or a chain containing alkylenes group (optionally substituted lower alkyl).

M is preferably equal to 2, and R4represents lower alkyl, preferably methyl. Radical, in which m is 2 and R4methyl known as tropan-3-yl, otherwise-8-methyl-8-azabicyclo(3,2,1)octane-3-yl.

The radical of the formula III is known as hinokitiol, or 1-azabicyclo[2,2,2]Octan-3-yl.

Compounds of the invention can contain one or more asymmetric carbon atoms and therefore they can exist in different stereoisomeric forms. For example, such compounds may exist in the form of racemates or optically active forms. Optically active forms can be obtained by splitting of the racemate or by using optically active form of the original substance in the following ways. In addition, the radicals of the formulae II and IV can have different configurations correspond to the I is preferred.

Compounds of the invention can be obtained by known methods from known starting substances or raw materials that can be obtained by conventional methods. According to one of the ways to obtain the amide of formula 1 in which Y represents NR3amines of the formula VI

OTHER3B in which R3and have the specified values, acelerou acid formula

R (where R1and X have the values specified) or its allermuir derived. Examples alleluya derivatives can be galodamadruga (e.g. acid chlorides), azides, anhydrides, imidazolides (e.g., obtained from carbonyldiimidazole), activated esters or 0-acyl urea obtained from a carbodiimide such as dialkylammonium, especially dicyclohexylcarbodiimide. Preferably Amin acelerou acid in the presence of such an agent combinations, as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, ISO-butylchloroformate or diphenylphosphinyl chloride.

Ester according to the invention in which Y represents-O - can be obtained by esterification of the acid of formula VII with an alcohol of the formula VIII

B-OH (which has the specified values). The etherification can be carried out by ordinary Matteotti acid acceptor.

Acids of formula VII are known compounds or they can be obtained by known methods. For example, the acid, in which X represents-NR2- can be obtained according to the following reaction scheme:

R R

< / BR>
Another way of obtaining the amides of the present invention (Y= -NR3-) is the cyclization of compounds of formula IX

in which R1, R2, R3and have these values, R6represents (lower) alkyl, e.g. ethyl. The cyclization can be carried out in the presence of such cyclodehydration agent, as polyphosphoric acid. Starting material of formula IX can be obtained by the reaction of an amine of the formula

R where R1and R2have the specified values, with an unsaturated compound of the formula

in which R3, R6and B have the above significance, and R7represents (lower)alkyl, preferably ethyl. The reaction can be carried out by heating the reagents as such, or in the presence of a suitable solvent.

Another method of preparing compounds of the invention in which X represents-NR2-, where R2represents lower alkyl, cyclo(lower)alkyl, cyclo(lower)alkyl-lower al the BR> R where R1, R2, Y and B have the above meanings; R9represents a leaving group such as halogen (e.g. fluorine or chlorine), or alkyl - or aryl-sulfonyloxy group. This cyclization can be performed by processing such a strong base like sodium hydride. The educt of the formula (XII) can be obtained by methods known for analogous compounds.

Compounds of the invention in which X represents-NR2-, where R2represents lower alkyl, lower alkenyl, lower quinil, cyclo(lower)alkyl, cyclo(lower)alkyl-lower alkyl, aryl, aryl(lower)alkyl or -(CH2)r-Y-R8can be obtained by alkylation of the corresponding compounds in which X represents-NH-. This alkylation can, if necessary, to carry out for example by reaction with (lower) alkyl, lower alkenyl, lower quinil, cyclo(lower) alkyl, cyclo(lower)alkyl lower alkyl, aryl, aryl (lower) alkyl or -(CH2)r-Y-R8the halide in the presence of a base. The original compound in which X represents-NH - can be obtained by a method similar to that described above from an appropriately substituted compound (VII). Connection in which a represents the radical (II)-(V), for example, hydrogen peroxide or percolate.

If any of these methods, the reagent contains group confirmed different effects under the conditions used for carrying out this reaction, then such group may be protected, and then the protective group can be removed.

If in the above methods, the compound of the invention obtained as salt accession acid, free base can be obtained by exposure to the salt solution accession acid base. On the contrary, if the reaction product is a free base, salt accession acid, especially pharmaceutically applicable Sol accession acid, can be obtained by dissolving the free base in a suitable organic solvent and treatment of the acid solution in accordance with the traditional methods of obtaining salt accession acids from bases.

Examples of salts of touch acids can serve as substances derived from such organic and inorganic acids as sulfuric, hydrochloric, Hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, muraven possess pharmacological activity. As a rule, they are antagonists of specific 5-hydroxytryptamine receptors in warm-blooded animals. These compounds have 5-HT3antagonistic activity and, therefore, are a valuable substances in cases when the desired antagonism of 5-HT3the receptors. 5-HT3antagonists are referred to as "antagonists" "neuronal" 5-hydroxytryptamine receptors and serotonin (5-hydroxy-tryptamine) M-receptor antagonists.

Compounds of the invention were tested on 5-HT3antagonistic activity in the vagus nerve of rats in accordance with the following procedure.

Such a method similar to that described by Irelandor and Tierce in Br.J.Pharmac, 1987, 90, 229-238, and depends on the ability of 5-HT be depolarized the vagus nerve in vitro.

Segments of the vagus nerve in rats species Sprague-Dawley, were placed in perspektivy the camera and was filled with Krebs solution. Electrodes placed at each end of the segment of the nerve was used to record the potential difference which arose in the course of adding various concentrations of 5-HT to one of the ends of the segment of the nerve. This method was obtained according to the concentration of the reaction to the action of 5-HT before and after uravnovesena the analysis shilda order to obtain measures of the power of the antagonist, pronounced RA value2. The results are given in the table.

Further, the invention provides the use of compounds of formula I, or its pharmaceutically applicable salt accession acid as an antagonist of 5-HT3receptors in mammals.

5-HT3antagonists can be used in the treatment of neuropsychiatric disorders such as anxiety, mental disorders (e.g. schizophrenia), dependence on drugs or other substances with abuse, disorders of consciousness; for such gastrointestinal disorders nausea and vomiting in the treatment of migraine. The invention provides the use of compounds of the invention in one or more of these treatments. The invention also provides a method of one or more of these treatments, which consists in applying to a warm-blooded animal an effective amount of compounds of the invention.

In the case of some of these States clearly that the compounds of the invention can be used prophylactically as well as for relief of acute symptoms. It should be borne in mind that used in the text, the term "treatment" or a similar term VLAN useful in the treatment of nausea and vomiting associated with cancer themoderatevoice.com agents and radiation therapy. In this regard, the compounds of the invention are used in the treatment of cancer chemotherapeutic agents (such cytotoxic or cytostatic agents as cisplatin, doxorubicin and cyclophosphamide) and under irradiation. Accordingly, the present invention also provides a product containing an anti-cancer chemotherapeutic agent and a compound of the invention in the form of a combined preparation for simultaneous, separate or sequential use in cancer therapy.

According to another aspect of the invention provides a pharmaceutical composition comprising a compound of the invention together with pharmaceutically applicable carrier. To obtain such a pharmaceutical composition can be any suitable carrier known in this field. In such compositions, the carrier is typically a solid or liquid substance or mixture of solids and liquids.

Solid forms of such compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatin capsules), suppositories and uterine rings. A solid carrier can be one or more substances acting as amduscia, compression means, a binder or destructive tablets agents; it can also be a capsule material. In powders, the carrier is a finely ground solid substance in a mixture with finely ground active ingredient. In tablets, the active ingredient is mixed with carrier having the necessary compression properties and the proper proportions, and form the product of the desired shape and size. Such powders and tablets preferably contain up to 99% for example, 0.03 to 99% preferably 1-80% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose polyvinylpyrrolidone, low-melting waxes and ion exchange resins.

The term "composition" means a formulation of the active ingredient in the capsule in which the active ingredient (in the presence or absence of carriers) is surrounded by carrier, which is thus associated with him. Similarly prepare Sasha.

Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and composition under pressure the IOM liquid medium, as water, an organic solvent, a mixture thereof or pharmaceutically applicable oils or fats. The liquid carrier can contain other pharmaceutical additives, such as solubilization, emulsifiers, buffer, preservative agents, sweetening agents, flavors, suspendresume agents, thickeners, coloring agents, viscosity regulators, stabilizers or osmoregulatory. Suitable examples of liquid carriers for oral and parenteral use can serve as water (particularly containing these additives, for example, cellulose derivatives, preferably a solution of sodium carboxymethylcellulose) alcohols (including monohydroxy alcohols and polyhydric alcohols, such as glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut and peanut butter). In the case of parenteral administration, the carrier can also be an oily ester, for example, etiloleat and isopropyl myristate. Sterile liquid carriers are used in a sterile liquid compositions for parenteral use.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be used, for example, intramuscularly, venue orally active it can be used orally in liquid or solid composition form.

Compounds according to the invention can also be applied by instillation into the nose. When forming for nasal application of such compositions can include a compound of the invention in a liquid medium; such compositions can be used, for example, in the form of a spray or drops. As the liquid carrier may be used water (which may contain additional components which provide the desired isotonicity and the viscosity of the composition). The composition may also contain such additional eccipienti as protecting agents, surface-active agents, etc., Such compositions may contain a device for nasal application, which allows the use of such a composition in the form of drops or spray. In the application of the aerosol reservoir composition should also contain propellant.

Pharmaceutical compositions for the treatment and/or prevention of nausea or vomiting may contain in addition to the compounds of the invention cyclo-oxygenase inhibitor. Examples of cyclo-oxygenase inhibitors can serve as systemic NSAIDs, such as indomethacin and piroxicam.

Preferably, the pharmaceutical composition was in the form of a unit dosage, for example in the form of tabung ingredient. The unit dosage form can be a packaged composition, for example powders in bags, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can represent, for example, a capsule or a tablet as such, or it can represent the appropriate number of any such compositions in Packed form.

The amount of active ingredient in a unit dose of the composition can vary from 0.5 mg to less than 750 mg or more, in accordance with the particular need and the activity of the active ingredient.

The invention also encompasses compounds in the absence of the media themselves when such compounds are unit dosage form.

P R I m e R 1. (Endo)-N'-(8-methyl-8-azabicyclo[3.2.1]Octan-3-yl)-1,4-dihydro-1-me - til-4 - oxoindole-3-carboxamide.

A suspension of 1,4-dihydro-1-methyl-4-oxoindole-3-carboxylic acid (1,02 g, 5 mmole) and carbonyldiimidazole of 0.85 g, 5 mmole) in dimethylformamide (15 ml) was stirred and heated for 0.5 h at 80aboutWith obtaining a clear solution. (Endo)-3-menotropin the dihydrochloride (1.06 g, 5 mmole) was added to the system after which was added triethylamine (1.3 g) and the and the precipitated product (1.2 g) was collected and recrystallized from water (150 ml) to obtain 0.7 g of the target base. This base was dissolved in ethanol (ml) and acidified with ethereal hydrochloric acid deposition target compound as hydrochloride (0,55 e g), so pl. 300aboutC.

P R I m m e R 2. (Endo)-11-(8-methyl-azabicyclo[3,2,1]Octan-3-yl)-1,4-dihydro-1-BU - Tyl - 4 - oxoindole-3-carboxamide.

A mixture of 1-butyl-1,4-dihydro-4-oxoindole-3-carboxylic acid (0,98 g, 4 mmole), carbonyldiimidazole (0.7 g, 4.4 mmole) and dimethylformamide (12 ml) was stirred for 1.5 h at 80aboutC. Then was added (Endo)-3-menotropin (0.56 g, 4 mmole) and stirring was continued for another 1.5 h at the same temperature. The solvent was removed and the residue was diluted with water and ice (15 g). The precipitated solid was collected, washed with ice water and dried in the air. The base was dissolved in a hot mixture of water (15 ml) and ethanol (3 ml), then cooled in ice and podslushivaet to pH 11 by addition of concentrated aqueous ammonia with the purpose of deposition of crystalline product, which was collected and washed with cold dilute solution of ammonia. Then the purified base (0,82 g) was dissolved in ethanol (8 ml), acidified with ethanolic HCl and was diluted with ether (3 ml).

In the cooling Paluch.1]-Octan-3-yl)-1-benzyl-1,4-Digi - DRO-4 - oxoindole-3-carboxamide.

1-Benzyl-1,4-dihydro-4-oxoindole-3 - carboxylic acid (1,96 g, 7.03 is mmole) in dry DMF (20 ml) was treated with carbonyl diimidazol (1,14 g? 7.04 baby mortality mmole) at room temperature and the mixture for 3 hours was heated at 80aboutC. was Added (endo)-3-menotropin (0,99 g, 7.0 mmole) and heating was continued overnight (19 h) obtaining a suspension. The resulting mixture was diluted with water (40 ml) and the pH was set equal to 9-10 by addition of concentrated aqueous rastvor potassium carbonate. The solid is collected, washed with water, dried and recrystallized from ethanol (20 ml) and water (20 ml) to give the free base (1,72 g). This substance was dissolved in boiling ethanol (15 ml) and the solution was acidified with ethanolic hydrogen chloride. The resulting precipitate was collected, washed with ethanol and dried at 80aboutWith vacuum to obtain the target compound as hydrochloride, hydrate, 1,3 ethanolate (1,91 g) so pl. 296-297aboutC.

P R I m e R 4. (Endo)-N-(8-Aza-8-methylbicyclo[3.2.1]Octan-3-yl)chroman-3-carboxy - MFA.

a) a Mixture of chroman-3-carboxylic acid (1.25 g) and thionyl chloride (6 ml) was heated under reflux for 5 minutes Then the reaction mixture was diluted with cyclohexane (15 ml) and ohlord is of chroman-3-carbonyl chloride (1.2 g).

(b) the Solution Hronom-3-carbonyl chloride (1.04 g, 5 mmole) in CH2CL2(20 ml) was bury for 5 min with ice stir a mixture of (endo)-3-amyotrophy (0.7 g, 5 mmole), anhydrous K2CO3(3 g) and CH2Cl2(20 ml). After complete addition, stirring was continued for 0.5 h and the mixture was diluted with water (50 ml). The organic phase was separated, dried (Na2SO4) and evaporated with the formation of a solid (1.7 g). The base was dissolved in ethanol (15 ml) and acidified with ethanolic HCl order of deposition of the crude hydrochloride (0.9 g). In the three-fold recrystallization from ethanol got a target compound in the form of pure hydrochloride (0.3 g), so pl. 300aboutC.

P R I m e R 5. (Endo)-N-(9-methyl-azabicyclo[3,3,1]non-3-yl)-1,4-dihydro-1-methyl-4 - oxoindole-3-carboxamide.

A suspension of 1,4-dihydro-1-methyl-exogenesis-3-carboxylic acid (1,02 g, 5 mmole) and carbonyldiimidazole of 0.85 g, 5 mmol) in DMF (15 ml) was stirred and heated for 3 h at 85aboutWith obtaining a clear solution. Added (endo)-3-aminogatan the dihydrochloride (1.13 g, 5 mmol) and diisopropylethylamine (1.29 g, 10 mmol) and heating was continued overnight (19 h). The solution was chilled is the number of an aqueous solution of potassium hydroxide. The precipitated solid was collected, washed with water and dried to obtain the target base (1,25 g), which was three times recrystallized from mixtures of water/ethanol. The base was dissolved in hot ethanol (12 ml) and acidified with ethanolic hydrogen chloride to obtain the desired compound in the form of hydrochloride, 1.25 hydrate (0,92 g), so pl. 278-81oC (decomp.).

P R I m e R 6. (Endo-N-(8-methyl-8-azabicyclo[3.2.1]Octan-3-yl)-1,8-ethanol-1,4-di - hydro-4-oxoindole-3-carboxamide.

A suspension of 1,8-ethano-1,4-1,4-dihydro-4-oxoindole-3-carboxylic acid (1.08 g, 5 mmol) and carbonyldiimidazole (0,89 g, 5.5 mmol) in dimethylformamide (15 ml) was stirred and heated for 1.25 h at 80aboutWith obtaining a clear solution. (Endo)-3-menotropin (0.7 g, 5 mmol) was added in a single portion and the reaction mixture was stirred for 2 h at 80aboutC. the Reaction mixture was cooled with ice and diluted with water (25 ml) and the precipitated product was collected and recrystallized twice from a mixture of: water (2: 1) to give 0.7 g of the target base. The base was dissolved in hot ethanol (15 ml) and acidified with ethanolic hydrogen chloride with the formation of the target compound as hydrochloride (0.55 g), so pl. 300the oksamid.

The target compound was obtained according to the method of example 6, replacing the 1.8-ethano-1,4-dihydro-4-oxoindole-3-carboxylic acid, 1,8-propane-1,4-dihydro-4-oxoindole-3-carboxylic acid. The reaction product was obtained as hydrochloride, T. pl. 300aboutC.

P R I m e R 8. (Endo)-N-(8-methyl-8-azabicyclo[3.2.1]Octan-3-yl)-1,4-dihydro-4-oxo - 1-n - propilinian-3-carboxamide.

1,4-Dihydro-4-oxo-1-n-propilinian-3-carboxylic acid was 1.58 g, PC 6.82 mmole) and triethylamine (0.7 g, 7 mmole) was dissolved in dichloromethane (20 ml) in an argon atmosphere. Immediately, with stirring, was added chloride diphenylphosphine (1.6 g, 6,76 mmole). The resulting solution was left for 6 h and then was added (endo)-3-menotropin (1.0 g, 7,14 mmole) and triethylamine (0.7 g, 7 mmol). The resulting solution was left for 3 days and then evaporated. The residue was dissolved in water and acidified with concentrated hydrochloric acid. The residue was filtered off, washed with water and throw them away. The filtrate was podslushivaet sodium carbonate and evaporated. The residue was twice treated with ethyl acetate, the ethyl acetate is evaporated and the residue was treated with water (6 ml) and concentrated ammonia (1 ml) to give a white solid (1.34 in). This material (3,68 mmole) was dissolved in hot ethanol (15 ml) yecenia night in the refrigerator. The precipitate was collected, washed with ethanol and dried with the formation of the target compound in the form of oxalate hemihydrate (1.24 g), so pl. 227-231aboutC.

P R I m e R s 9-14. Following the procedure of example 1, but replacing 1,4-dihydro-1-methyl-4-oxoindole-3-carboxylic acid, the following reagents were obtained the following products.

P R I m e R 9. Reagent: 1,4-dihydro-1-ethyl-4-oxoindole-3-carboxylic acid.

Product: (endo)-N-(8-methyl-8-azabicyclo[3,2,1]Octan-3-yl)-1,4-dihydro-1-ethyl-4 - oxoindole-3-carboxamide, hydrochloride, hemihydrate, so pl. 298-302aboutC.

P R I m e R 10. Reagent: 1,4-dihydro-1-(2-methoxyethyl)-4-oxoindole-3-carbon - Wai acid.

Product: (endo)-N-(8-methyl-8-azabicyclo[3,2,1]Octan-3-yl)-1,4-dihydro-1-2-labels - Sitel)-4-oxoindole-3-carboxamide, 1: 1 fumarate, so pl. 243-245aboutC.

P R I m e R 11. Reagent: 9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H, 5H-benzo(ij)hemolysin-2-carboxylic acid.

Product: (endo)-N-(8-methyl-8-azabicyclo[3,2,1]Octan-3-yl)-9-fluoro-6,7-dihyd - ro - 5-methyl-1-oxo-1H, 5H-benzo(ij)hemolysin-2-carboxamide, hydrochloride 1/4 hydrate, so pl. 320aboutC.

P R I m e R 12. Reagent: 1-cyclohexyl-1,4-dihydro-4-oxoindole-3-carboxylic acid.

Product: (endo)-N-8-methyl-8-azabicyclo[3,22">

P R I m e p 13. Reagent: 1-(cyclopropylmethyl)-1,4-dihydro-4-oxoindole-3-Carbo - new acid.

Product: (endo)-N-(8-methyl-8-azabicyclo[3,2,1] Octan-3-yl)-1 - cyclopropylmethyl-1,4-dihydro-4-oxoindole-3-carboxamide, hydrochloride, 0.75 hydrate, so pl. 164-166aboutC (decomp.).

14. Reagent: 1-(4-forfinal)-1,4-dihydro-4-examinalion-3-carboxylic acid.

Product: (endo) - N-(8-methyl-8-azabicyclo[3,2,1]Octan-3-yl)-1-(4-forfinal)-1,4 - dihydro-4-oxoindole-3-carboxamide, hydrochloride, T. pl. 240aboutC (decomp. ).

P R I m e R 15. Following the procedure of example 1, but replacing (endo)-3-menotropin 1-azabicyclo[2.2.2] Octan-3-amine (3-aminoquinuclidine) was obtained N-(1-azabicyclo[2,2,2] Octan-3-yl)-1,4-dihydro-1-methyl-4-oxoindole-3-carbox semihydrogenic, hydrate, so pl. 179-181aboutC.

P R I m e R 16. (Endo)-N-(9-methyl-9-azabicyclo[3,3,1]nonan-3-yl)-1,4-dihydro-1 - ethyl-4 - oxoindole-3-carboxamide.

A suspension of 1,4-dihydro-1-ethyl-4-oxoindole-3-carboxylic acid (1.52 g, 7 mmol) and triethylamine (0.7 g, 7 mmol) in dichloromethane (20 ml) was stirred at room temperature in an argon atmosphere for 1 h was Added isobutyl chloroformate (0.96 g, 7.03 is mmole and the mixture was stirred for one hour. Was added triethylamine (1.4 g, 14 mmol) and (endo)-3-amino-9-the solvents evaporated. The residue was treated with water (10 ml) and concentrated ammonia (2 ml), the solid is collected, washed with concentrated ammonia solution and dried. This substance was converted into its salt with fumaric acid in a ratio of 1:1 in the system of the FORMER: methanol (2:1, 15 ml) to give the target compound 1:1 fumarata, hemihydrate (73,1%), so pl. 184-185aboutC.

P R I m e R 17. (Endo)-N-(9-methyl-9-azabicyclo[3,3,1]nonan-3-yl)-1-butyl-1,4-di - hydro - 4-oxo-quinoline-3-carboxamide.

1,4-Dihydro-1-butyl-4-oxoindole-3-carboxylic acid is reacted with (endo)-3-amino-9-methyl-9-azabicyclo[3.3.1] nananom according to the method of example 16 and the target compound was obtained in the form of the maleate of 1:1, so pl. 203-205aboutC.

P R I m e R 18. (Endo)-N-(8-methyl-8-azabicyclo[3,2,1]Octan-3 - yl-1-ethyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxamide.

Carried out the reaction between 1,4-dihydro-1-ethyl-6-fluoro-4-oxoindole-3-carboxylic acid (endo)3-aminotrophum according to the method of example 16 and the target compound was obtained as hydrochloride, 0.75 hydrate, so pl. 315-317aboutC.

P R I m e R 19. Following the techniques above and using the appropriate reaganites received: (endo)-N-(8-methyl-8-azabicyclo[3,2,1] octane 3-yl)-1,4-dihydro-1-cyclopropyl-4-exohi - until-8-azabicyclo[3,2,1]Octan-3-yl)-1,4-dihydro-1 - ethyl-6,7-methylenedioxy-4-oksihinolina-3-carboxamide; (endo)-N-(8 - methyl-8-azabicyclo[3,2,1] Octan-3-yl)-1,4-dihydro-1-ethyl - 7-fluoro-4-oxoindole-3+carboxamid and analogues, in which 7-fluoro Deputy replaced by 7-trifluoromethyl, 8-fluoro; 6,7-debtor and 6-chloro-8-methyl.

P R I m e R 20. Using the method of example 16, receive the following connections:

a) (endo)-N-(8-methyl-8-azabicyclo[3,2,1]Octan-3-yl)-1,4-dihydro-1-ethyl - 8-fluoro-4-oxoindole-3-carboxamide, hydrochloride, cybertiger, so pl. 296-300aboutC (decomp.).

(b) (endo)-N-(8-methyl-8-azabicyclo[3,2,1]Octan-3-yl)-1-(4-butenyl)-1,4 - dihydro-4-oxoindole-3-carboxamide, poumarat, 0,75 e hydrate, so pl. 213-216aboutC.

C) (R)-(-)-N-) 1-azabicyclo[2,2,2]Octan-3-yl)-1-cyclohexyl-1,4-dihydro-4-oxigeno - Lin-3-carboxamide, 1:1 oxalate, 0.75 hydrate, so pl. 173-177aboutC.

(d) (S)-(+)-N-(1-azabicyclo[2,2,2]Octan-3-yl)-1-cyclohexyl-1,4-dihydro 4-oxoindole-3-carboxamide, 1:1 oxalate, 1.25 hydrate, so pl. 179-183aboutC.

(e) (endo)-N-(8-methyl-8-azabicyclo[3,2,1] Octan-3-yl)cyclopropyl - 1,4-dihydro-4-oxoindole-3-carboxamide, 1: 1 fumarate, 0.75 hydrate, so pl. 201-3aboutC.

(f) (endo)-N-(8-methyl-8-azabicyclo[3,2,1] Octan-3-yl)-1-cyclobutyl-1,4 - dihydro-4-oxoindole-3-carboxamide, fumarate, 1.25 hydrate, so pl. 232aboutC (decomp.).

(g) (endo)-N-(8-methyl-8-azabicyclo[3,2,1] Octan-3-and the

(h) (endo)-N-(8-methyl-8-azabicyclo[3,2,1] Octan-3-yl(1-)1,1-dimethylethyl)-1,4 - dihydro-4-oxoindole-3-carboxamide, 1:1 maleate, so pl. 226-229aboutC (decomp.).

(i) (endo)-N-(8-methyl-8-azabicyclo[3,2,1] Octan-3-yl)-1,4-dihydro - 1-ethyl-6,7-methylenedioxy-4-oxoindole-4-carboxy - Ministry of foreign Affairs, 1:1 maleate, so pl. 240aboutC (decomp.).

(j) (endo)-N-(8-methyl-8-azabicyclo[3,2,1]Octan-3-yl-1-cyclopentyl-1,4-di - hydro - 4-oxoindole-3-carboxamide, 1:1 maleate, so pl. 181-184aboutC.

P R I m e R 21. Endo-N-(8-ethyl-8-azabicyclo[3,2,1]Octan-3-yl)-1-cyclohexyl-1,4-dihydro - 4-oxoindole-3-carboxamide.

N-Methylmorpholine (0.4 ml, of 3.64 mmol) was added to a solution of 1-cyclohexyl-1,4-dihydro-4-examinalion-3-carboxylic acid (0,80 g, 2,95 mmol) in anhydrous THF (25 ml) in an argon atmosphere. The solution was cooled to -15aboutC for 0.25 h before it was added colorformat of isobutyl (0,4 mll, is 3.08 mmol). To the resulting solution was added a solution of dihydrochloride of endo-N-(8-ethyl-8-azabicyclo[3,2,1] Octan-3-yl-)amine (0.71 g, 2,69 mmol), N-methyl morpholine (0.4 ml, of 3.64 mmol), anhydrous DMF (5 ml) and anhydrous THF (10 ml) at -10aboutC. After stirring for 20 h the solution was added triethylamine (1.0 in mll, 7.2 mmol) in chloroform (10 ml) and the mixture stirred at room temperature for 25 h Loy was washed with chloroform. The combined organic extracts were washed with brine, dried (anhydrous Na2So4) and evaporated in vacuum to obtain a transparent liquid, which highlighted the connection specified in the header, in the form of the base (0.74 g). The base was dissolved in ethanol solution of hydrogen chloride until precipitation of the target compound as hydrochloride, 11/4 hydrate, etc. > 250aboutC (decomp. over 202aboutC).

P R I m e R 22. (Endo)-N-(8-azabicyclo[3,2,1.Octan-3-yl-1-cyclohexane - 1,4-dihydro-4-oxoindole-3-carboxamide.

(Endo) - N-8-methyl-8-azabicyclo[3,2,1]OK - tan-3-yl)-1-cyclohexyl-1,4-dihydro-4 - oxoindole-3-carboxamide (1.0 g, 2.54 mmol) was dried and suspended in 1,2-dichloroethane (30 ml) in an argon atmosphere, and cooled with ice. Added chloroformate 1-chloroethyl (0,28 ml of 0.37 g, at 2.59 mmol) and left to warm for 1 h to room temperature. Then the solution was boiled under reflux for 1 h and the solvent evaporated. The residue was dissolved in methanol and boiled under reflux day (24 hours). The reaction mixture is evaporated, the residue was chromatographically on the primary okaimono (activity II-III), was suirable a mixture of chloroform: methanol (10:0.1 to>> 0,4). Total product listed, cooled and recrystallization from ethanol (20 ml) and a small amount of water to obtain (endo)-N-(8-azabicyclo[3,2,1]Octan-3-yl)-1-cyclohexyl-1,4-dihydro-4-oxacin Olin:1 fumarate, hemihydrate as a white solid (0,77 g), etc., 237-239aboutC.

P R I m e R 23. (Endo, Antilles)-(endo, SYN)-N-(8-methyl-8-azabicyclo[3.2.1] Octan-3-yl-1-cyclohexyl-1,4 - dihydro-4-oxoindole-3-carboxamide N-oxide.

(Endo)-N-(8-methyl-8-azabicyclo[3,2,1] Octan-3-yl)-1-cyclohexyl-1,4 - dihydro-4-oxoindole-3-carboxamide (of 7.93 g, 10 mmol) in methanol (10 ml) was treated with 27.5 wt/wt. aqueous hydrogen peroxide (3.2 g). The solution was diluted with water (30 ml) and the methanol evaporated. Added a slurry of platinum (carbon catalyst with water and the mixture was filtered. The filtrate is evaporated to dryness, the residue is evaporated with a mixture of toluene: ethanol 4:1, receiving the solid residue (2,48 g) containing a mixture of anti and SYN-N-oxides. The solid residue was dissolved in hot ethyl acetate (25 ml) and methanol (1.5 ml) and boiled to sedimentation, then cooled. The solid is collected, washed with ethyl acetate and dried. Received (endo, anti)-N-(8-methyl-8-azabicyclo[3,2,1] Octan-3-yl)-1-cyclohexyl-1,4-dihydro - 4-oxoindole-3-carboxamide N-oxide, dihydrate in the form of a white solid (0,91 g), the through centrifugual chromatography on silica gel (strata. 2 mm) and were suirable a mixture of chloroform: methanol: 0,888 g of ammonia (10:1: 0,1). Shin-N-oxide was obtained in the form of glass induced crystallization using rasshireniya to powder with cold ether, and then with hot ethyl acetate. The solid is collected and dried in vacuum at 75aboutWith during the day. Received (endo, SYN)-N-(8-methyl-8-azabicyclo[3,2,1]Octan-3-yl)-1-CEC - logical-1,4 - dihydro-4-oxoindole-3-carboxamide N-oxide, 0.9 hydrochloride, as a white solid (50 mg), pl. 223-232aboutWith

Heterocyclic compounds of General formula

< / BR>
where R1hydrogen or one or two substituent selected from lower alkyl, halogen atom, lower alkoxy-, methylenedioxy or halo (lower) alkyl,

X is O or NR2where R2lower alkyl, lower alkenyl, cyclo (lower)alkyl, cyclo(lower)alkyl-lower alkyl, phenyl, optionally substituted by a halogen atom, a phenyl(lower)alkyl, a group of General formula -(CH2)2Y'-R8where r=1-4 integer, Y' is O or R5where R5hydrogen or lower alkyl, R8hydrogen, lower alkyl or cyclo(lower)alkyl, or X is a group of formula-Z - which is associated with regulation 8 of the aromatic ring to form heterocyclic rings Jolee methylene groups, optionally substituted by one or more lower alkyl groups, Y Is O or NR3where R3hydrogen or lower alkyl;

B rich azabicyclic ring of General formula

< / BR>
where m is 2, 3 or 4,

R4hydrogen or lower alkyl,

or their pharmaceutically acceptable additive salt of the acid, or N-oxide heterocyclic compounds, or its additive salt of the acid.

 

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