The method of obtaining derivatives of 4-oxacilin or chromone or their pharmaceutically acceptable salts

 

(57) Abstract:

Usage: in medicine as specific antagonists of 5-hydroxytryptamine (5-HT) receptors. The inventive product - derived 4-oxacilin or chromane f-ly 1, where R1X, Y and B have the appropriate values. Reagent 1: Amin NR3B f-crystals II, where R3and B are the corresponding values. Reagent 2: compound f-ly III, where R1and X-have the respective meanings or allerease derived. And isolated in free form or in pharmaceutically acceptable salt, or carry out, if necessary, the oxidation of compounds f-ly I, to obtain the N-oxide, or turn the salt of the compound f-crystals of 1 in free base or free base is converted into its pharmaceutically acceptable salt. The structure of the compounds I, II, III; 1 table.

The invention relates to the production of heterocyclic compounds, and in particular, to provide new compounds that may be useful 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 R as well as pharmaceutically acceptable acid salt additive, where R1represents hydrogen or one or more substituents selected from lower alkyl, lower alcosta, groups, halogen atoms, methylenedioxy, halogen (lower) alkyl;

X represents-0 - or NR2where R2represents a lower alkyl lower alkenyl, cyclo (lower) alkyl, cyclo (lower) alkyl-lower alkyl, phenyl (lower) alkyl, phenyl, optionally substituted by halogen atoms, a group of the formula -(CH2)r-Y'-R8(where r is an integer in the range of 1-4, y'represents O or NR5where R5represents hydrogen or lower alkyl, and R8represents hydrogen, lower alkyl or cyclonite alkyl) or a group of formula-Z -, which is associated with regulation 8 of the aromatic ring with the formation of the heterocyclic ring of 5-7 ring elements, in which the ring elements, represented by the index Z, represent one or more methylene groups (optionally substituted by one or more lower alkyl groups),

Y represents NR3where R3represents hydrogen or lower alkyl, and

Represents a saturated azabicyclic ring, or its N-oxide, and rich azabicyclo or (lower) alkyl, or

(III) or

N-R4(IV) in which p is 1, 2 or 3, and R4has the specified values, or

(V) where q is 0,1 or 2.

The term "lower" used in the text, refers to a radical containing up to 6 carbon atoms. Preferably, such radical contains 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. Halogen (lower) alkyl, preferably represents trifluoromethyl. A preferred example, cyclo (lower) alkyl (lower) alkyl is cyclopropylmethyl.

In the radical of the formula II preferably m is 2 and R4represents lower alkyl, preferably methyl. Radical, in which m is 2, R4methyl known as tropan-3-yl, otherwise 8-methyl-8-azabicyclo [3, 2, 1] Octan-3-yl.

The radical of the formula III are known under the name of hioliday doctitle, represents a C1C4-alkyl, especially methyl.

In the radical of the formula (V), q preferably represents a I.

Compounds according to 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 addition, the radicals of the formulae II and IV can have a different configuration corresponding endo-configuration, as in the case of tropine, and Exo-configuration, as in the case of pseudoterpna. Endo-configuration is preferred.

The method according to the invention is carried out using a reaction of acylation of an amine of the formula VI

OTHER3B in which R3and B have the above meanings, acid formula; VII

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 the imide, especially dicyclohexylcarbodiimide. Preferably Amin acelerou acid in the presence of such an agent combinations, as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, ISO-butylchloroformate or diphenylphosphinyl chloride.

Acids of formula VII are known compounds or can be obtained by known methods. For example, the acid, in which X represents-NR2can be obtained according to the following reaction scheme;

< / BR>
Obtained according to the method of the invention compounds can be converted to N-oxides by oxidation.

If according to the method of the invention the compound obtained as an acid additive salt, the free base can be obtained by exposure to the salt solution base. If the reaction product is a free base, an acid additive salt, especially a pharmaceutically acceptable salt, 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 the acid additive salts of the bases.

Examples of salts can serve as salts derived from such inorganic and the new, citric, acetic, mouravyinna, methanesulfonate, n-toluensulfonate, oxalic acid and succinic acid.

Compounds according to the invention 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 according to the invention was tested on 5-HT3antagonistic activity in the vagus nerve of rats in accordance with the following method:

Such a method similar to that described Ireland u Tyers, Br. J. Pharmac, 1987, 90, 229-238 [5] and depends on the ability of 5-HT be depolarized the vagus nerve in vitro.

Segments of the vagus nerve in rats varieties Sprague Dawley was 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 has grown up by the value of the concentration of the reaction to the action of 5-HT before and after the balancing segment of the nerve Krebs solution, containing the test substance. On the basis of these results was carried out by analysis of shilda order to obtain measures of the power of the antagonist, which is expressed by the value of pA2. The results are given in the table.

As noted, the products of the method of the present invention are useful as antagonists of 5-HT3receptors in mammals.

5-HT3antagonists can be used in the treatment of neuro-psychiatric problems such as anxiety, mental health disorders (eg, schizophrenia), drugs or other substances with abuse, disorders of consciousness, in the treatment of such gastrointestinal disorders nausea and vomiting and treating Magrini.

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 similar terms include both prevention and treatment of acute conditions.

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

A suspension of 1,4-dihydro-1-methyl-4-oxoindole-3 was heated for 0.5 h at 80aboutWith obtaining a clear solution. Was added to the system (endo)-3-menotropin the dihydrochloride (1.06 g, 5 mmole), after which was added triethylamine (1.3 g) and the reaction mixture was stirred at 80aboutWith still over 2 hours Then the mixture was cooled, diluted with water (25 ml) 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 (7 ml) and acidified with ethereal hydrochloric acid deposition target compound as hydrochloride (0.55 g), so pl.>300aboutC.

P R I m m e R 2. (Endo)-N-(8-methyl-8-azabicyclo [3, 2, 1] Octan-3-yl)-1,4-dihydro-1-butyl-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 (5 ml) and ethanol (3 ml), then ohla the Denia crystalline product, which sobirali 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 Rashevski ether (3 ml).

In the cooling ice received the product as hydrochloride (0,49 g) so other 267-268aboutC.

P R I m e R 3. (Endo)-N-(8 methyl-8-azabicyclo [3, 2, 1]-Octan-3-yl)-1-benzyl-1,4-dihydro-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 h 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 adding a concentrated aqueous solution of potassium carbonate. The solid is collected, washed with water, dried and recrystallize 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 ethanoate (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-carboxamide.

(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 cooled with ice. The crystalline precipitate was collected by filtration, washed with cyclohexane and dried in vacuum to obtain chroman-3-carbonylchloride (1.2 g).

(C) the Solution chroman-3-carbonylchloride (1.04 g, 5 mmole) in CH2Cl2(20 ml) was bury within 5 minutes to a cooled with ice stir a mixture of (endo)-3-amyotrophy (0.7 g, 5 mmole), anhydrous K2CO3(3G) and CH2Cl2(20 ml). After complete addition, stirring was continued for another 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). This base was dissolved in ethanol (15 ml) and acidified with ethanolic HCl deposition crude hydrochloride (0.9 g). In the three-fold recrystallization from ethanol was obtained 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-til-4-oxoindole-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 cooled to room temperature and was diluted with water (25 ml). The pH value was set equal to 10-11 by adding a small amount 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 as hydrochloride, 1.25 hydrate (0,92 g), so pl. 278-81aboutC (decomp.)

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

A suspension of 1,8-ethano-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. Was added to the system whichC. 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 ethanol: water (2: 1) to obtain the target of 0.7 Foundation. The base was dissolved in hot ethanol (15 ml) and acidified with ethanolic hydrogen chloride to obtain the desired compound as hydrochloride (0.55 g), so pl. >300aboutC.

P R I m e R 7. (Endo)-N-(8-Aza-8-methylbicyclo [3, 2, 1] Octan-3-yl)-1,4-dihydro-1,8-PROPANEDIOL-4-one-3-carboxamide.

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-propylene - Lin-3-carboxylic acid (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 for 6 h and then was added (endo)-3-menotropin (1.0 g, 7,14 mmole) and triethylamine (0.7 g, 7 mmol). Receiving the hydrochloric acid. The precipitate was filtered, washed with water and discarded. 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 substance (3,68 mmole) was dissolved in hot ethanol (15 ml) and added hot oxalic acid dihydrate (0,47 g of 3.73 mmole). The resulting solution was kept overnight in the refrigerator. The precipitate was collected, washed with ethanol and dried to obtain 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. The 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-methoxyethyl)-4-oxoindole-3-the H-benzo (ij) hemolysin-2-carboxylic acid. Product: (endo)-N-(8-methyl-8-azabicyclo (3. 2. 1) Octan-3-yl)-9-fluoro-6,7-dihydro-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, 2, 1) Octan-3-yl)-1-cyclohexyl-1,4-dihydro-4-oxoindole-3-carboxamide, 1: 1 oxalate, 1.5 hydrate, so pl. 217aboutC.

P R I m e p 13. Reagent: 1-(cyclopropylmethyl)-1,4-dihydro-4-oxoindole-3-CT - oil acid. Product:(endo)-N-(8-methyl-8-azabicyclo [3, 2, 1) Octan-3-yl)-1-cyclopropylmethyl-1,4-dihydro-4-oxigeno - Lin-3-carboxamide, hydrochloride, 0.75 hydrate, t, pl. 164-166aboutC (decomp.).

P R I m e R 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-carbox-Samid, 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] octane-3-amine (3-aminophenylamino) was obtained N-(1-azabicyclo [2, 2, 2] octane-3-yl)-1,4-dihydro-1-methyl-4-oxoindole-3-carboxamide, hydrochloride, hydrate, so pl. 179-181aboutC.

P R I m e R 16. (Endo)-N-(9-methyl-9-azabicyclo [3, 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 isobutylparaben (0.96 g, 7.03 mmole) and the mixture was stirred for 1H. Was added triethylamine (1.4 g, 14 mmol) and (endo)-3-amino-9-methyl-9-azabicyclo [3, 3, 1] nonan the dihydrochloride (1,58 g of 6.96 mmole). After 3 days the reaction mixture was cooled with methanol and 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 the ratio of 1;1 in the IPA system:methanol (2:1,15 ml) to obtain the target compound in a 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-dihydro-4-oxo-quinoline-3-carboxamide. 1,4-Dihydro-1-butyl-4-oxoindole-3-CT-oil acid was subjected to reaction 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)-4-(8-methyl-8-azabicyclo [3, 2, 1] Octan-3-yl-1-ethyl-6-fluoro-1,4-dihydro-4-oxoindole-3-carboxamide.

P R I m e R 19. Using the following methods, using the appropriate reagents were obtained; (endo)-N-(8-methyl-8-azabicyclo [3, 2, 1] octane 3-yl)-1,4-dihydro-1-cyclopropyl-4-oxoindole-3-carboxamide and the corresponding 1-cyclobutyl, 1-cyclopentyl, 1-tert-butyl 1-(but-3-enyl) analogues, (endo)-N-(8-methyl-8-azabicyclo [3, 2, 1] Octan-3-yl)-1,4-dihydro-1-ethyl-6,7-methylenedioxy-4-oxoindole-3-carboxamide (endo)-N-(8-methyl-8-azabicyclo) [3, 2, 1] Octan-3-yl)-1,4-dihydro-1-ethyl-7-fluoro-4-oxoindole-3-carboxamide and analogues, in which 7-fluoro Deputy substituted 7-trifluoromethyl, 8-fluorine, 6,7-Diptera and 6-chloro-8-stands.

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, etc., 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, fumarate, 0.75 hydrate, so pl. 213-216aboutC.

(c) (R)-(-)-N-(azabicyclo [2, 2, 2] octane-3-yl)-1-cyclohexyl-1,4-dihydro-4-oxigeno-Lin-3-carboxamide, 1:1 oxalate, 0.75 hydrate, etc., 173-177aboutC.

(d) (S)-(+)-N-(1-azabicyclo [2, 2, 2] octane-3-yl)-1-cyclohexyl-azabicyclo [3, 2, 1] Octan-3-yl)-cyclopropyl-1,4-dihydro-4-oxoindole-3-carboxamide, 1: 1 fumarate, 0.75 hydrate, etc., 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, etc., 232aboutC (decomp.)

(g) (endo)-N-(8-methyl-8-azabicyclo [3, 2, 1] Octan-3-yl)-1,4-dihydro-1-ethyl-4-oxo-7-trifloromethyl-3-carboxamide, fumarate, 0.25 hydrate, T. R. 225-227aboutWITH

(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, etc., 226-229aboutC (decomp.)

(i) (endo)-N-(8-azabicyclo [3, 2, 1] Octan-3-yl-1,4-dihydro-1-ethyl-6,7-methylindol-C-4-oxoindole-3-carboxamide 1: 1 maleate, etc., 240aboutC (decomp.)

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

P R I m e R 21. Endo-N-(8-ethyl-8-azabicyclo [3, 2 - 1] octane-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-oxoindole-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 charformat of isobutyl (0 [3, 2, 1] Octan-3-yl) amine (0,61 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 ml, 7.2 mmol) in chloroform (10 ml) and the mixture stirred at room temperature for 25 hours

To the reaction mixture were added chloroform and dilute NaOH solution. The organic layer was removed and the aqueous layer 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 and the precipitate fell out of the target compound as hydrochloride, 1 1/4 hydrate, etc., <250C (decomp. over 202aboutC).

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

(Endo)-N-(8-methyl-8-azabicyclo [3, 2, 1] Octan-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 in ice. Was added 1-chloroethyl-chlorine is ipatio under reflux for 1 h, and the solvent evaporated. The residue was dissolved in methanol and boiled under reflux in a day (24 hours). The reaction mixture is evaporated, and the residue was chromatographically on basic alumina (activity 11-111), was suirable a mixture of chloroform:methanol (10: 0.1 to>>0,4). All of the selected product (1.54 g, 4,06 mmol) was dissolved in hot ethanol (10 ml) was added fumaric acid (0.45 g, 3.88 mmol). The solution was filtered, cooled and recrystallized from ethanol (20 ml) and a small amount of water, receiving (endo)-N-(8-azabicyclo [3, 2, 1] Octan-3-yl)-1-cyclohexyl-1,4-dihydro-4-oxoindole-3-carboxamide, 1: 1 fumarate, hemihydrate as a white solid (0,77 g), etc. 137-239aboutC.

P R I m e R 23. (Endo, anti) - (endo-SYN)-N-(8-methyl-8-azabicyclo [3, 2, 1] Octan-3-yl)-1-cyclohexyl-1,4-dihydro-4-oxoindole-carboxamide-N-oxide.

(Endo)-N-(8-methyl-8-azabicyclo [3, 2, 1] Octan-3-yl)-1-cyclohexyl-1,4-dihydro-4 - oxacillin-3-carboxamide (3,93 g, 10 mmol) in methanol (10 ml) was treated with 27.5 wt. aqueous hydrogen peroxide (3.2 g). The solution was diluted with water (30 ml) and the methanol evaporated. Added suspensio platinum/carbon catalyst with water, and the mixture was filtered. The filtrate is evaporated to dryness, and the residue evaporated with a mixture truegreen ethyl acetate (25 ml) and methanol (1.5 ml) and boiled until has not yet begun deposition, 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), etc., 174-177aboutC.

A portion (250 mg) again collected substance containing a mixture of SYN-and anti-N-oxides were separated using chromatography on a rotating plate on silica gel (strata. 2 mm) and were suirable a mixture of chloroform:methanol: 0,888 ammonia (10: 1: 0.1). Shin-N-oxide was obtained in the form of glass, which was subjected to crystallization with cold ether, and then hot elicitation. Solid grinding collected and dried in vacuum at 75aboutWith during the night. Received (endo, SYN)-N-(8-methyl-8-azabicyclo [3, 2, 1] Octan-3-yl)-1-cyclohexyl-1,4-dihydro-4-oxoindole-3-ka-rboxylic N-oxide, 0.9 hydrochloride, as a white solid (50 mg), etc., 223-232aboutC.

P R I m e R 24. The conversion of oxalate of example 12 in free base.

Mix a solution of oxalate of example 12 (2.5 g) in warm water (100 ml) was podslushivaet to pH 9 by addition of saturated aqueous solution of kabanata potassium. Then the mixture was cooled with ice, and saiden is UP>aboutC.

The method of obtaining derivatives of 4-oxacilin or chromone General formula I

< / BR>
where R1hydrogen or one or more substituents selected from lower alkyl, lower alkoxygroup, halogen atom, methylenedioxy, halogen(lower)alkyl;

X is oxygen or-NR2-, where R2lower alkyl, lower alkenyl, cyclo(lower)alkyl, cyclo(lower)alkyl lower alkyl, phenyl(lower)alkyl, phenyl, optionally substituted by a halogen atom, a group of the formula (CH2)ry1R8, where r is oxygen or NR5where R5hydrogen or lower alkyl, R8hydrogen, lower alkyl or cyclo(lower)alkyl or a group of formula-Z-, which is associated with regulation 8 of the aromatic ring with the formation of the heterocyclic ring of 5 to 7 ring elements, in which the ring elements identified by the subscript Z represents one or more methylene groups optionally substituted by one or more lower alkyl groups;

Y 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

< / BR>
< / BR>
where p is 1, 2 or 3;

R4has Okasan, characterized in that carry out the acylation of amine of General formula II

OTHER3B,

where R3and B have the above values,

the acid of General formula III

< / BR>
where R1and X have the above values,

or allermuir derived and isolated in free form or in pharmaceutically acceptable salt or carry out, if necessary, the oxidation of compounds of General formula I with obtaining its N-oxide, or make salt compounds of General formula I in free base or free base is converted into its pharmaceutically acceptable salt.

 

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The invention relates to chemical means of protection of plants, particularly to herbicide compositions based on derivatives of sulfonylurea

The invention relates to new biologically active compounds derived pyrimidine-4-or their pharmaceutically acceptable salts with serotoninergicheskoi, dopaminergically, antihistaminic activity, and compositions on their basis

The invention relates to a method for producing 6-fluoro-1,2-benzisothiazole formula

(I) where R is a hydrogen atom, a lower alkyl or a group of the formula

orwhere R1means-Cho or - CN, namely, that on-halogenoalkane derivative of the formula:

where R has the above meanings, is subjected to the interaction with R3SH, where R3- benzyl, environment aprotic organic solvent, with the formation of the compounds of formula

(III)where R and R3have the specified values, which are subjected to interaction with a halogenation agent to obtain the corresponding sulfanilamide formula

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(I)

Polucheniya pharmaceutically active compounds, which can be used, for example, as antipsychotic agents and as inhibitors of reuptake of serotonin

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

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n is an integer 1 or 2, which have a high and strictly selective antiacetylcholinesterase activity and can find application in medicine

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Antibacterial // 2024258
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NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity

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