Method for producing n-aryl-alpha-aminocarboxamides or their salts with pharmaceutically acceptable

专利摘要:
Novel N-aryl- alpha -amino-carboxamides of the formula <CHEM> the pharmaceutically acceptable acid-addition salts and possible stereochemically isomeric forms thereof, which compounds are useful as antiarrhythmic agents in patients suffering from irregular cardiac rhythms; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
公开号:SU1313344A3
申请号:SU843722251
申请日:1984-04-10
公开日:1987-05-23
发明作者:Анри Поль Ван Даль Жорж；Франс Леопольд Де Бруйн Марсель；Густаф Селин Вердонк Марк
申请人:Жансен Фармасетика Н.В. (Фирма)；
IPC主号:

专利说明:

h) 2-pyrimidinyl, 1,3-dihydro-2H- -inden-2-yl; tetrahydro-4H-pyran-4-yl; 3-oxo-1-cyclohexenyl; 1,4,5,6-tetrahydro-2-pyrimidinyl, or their pharmaceutically acceptable salts or a possible stereochemical isomeric form, which have an anti-arrhythmic effect and can be used in medicine. The goal is to create substances of the specified class with better activity. The preparation of new compounds I is carried out from the ethyl ester of the corresponding acid and amine.
one
This invention relates to the chemistry of heterocyclic coeffKueuHH, in particular to a process for the preparation of novel CG-aryl-pb-aminocarboxamides of general formula I:
Have
Cn ar


R
de type is an integer equal to 1,
2 or 3, moreover, the sum of the type is equal to 4, and one hydrogen atom in the radical can be substituted by a lower alkyl or lower alkoxy group;
R, is hydrogen or lower alkyl.
R is hydrogen, lower alkyl, acetyl or benzyl;
Cs is hydrogen or lower alkyl,
or R and 1 together with the nitrogen atom form a morpholine ring;
Ar is unsubstituted phenyl, phenyl with one substituent, such as 2-NI3111II alkoxy or 3-trifluoromethyl; phenyl with two substituents, such as lower alkoxy or halogen; phenyl with three substituents, such as lower alkyl, hydroxyl, lower alkoxy, halogen, di (lower alkyl)
B, NHAr, where P, and Ar - are indicated above, in two ways: a) in 1,1-oxybisethane or tetrahydrofuran medium in the presence of lithium-butane under a nitrogen atmosphere with cooling; b) in tetrahydrofuran medium in the presence of NaOH or LiNH. The selection of the target product is carried out either in free form or in the form of a pharmaceutically acceptable salt or a stereochemically isomeric form. , Compounds I .. provide normalization of heart rhythm and a decrease in the number of extrasystoles. 7 tab.
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five
five
an amino group, with one of the substituents necessarily lower alkyl;
L is hydrogen, (oxy) (phenyl) alkyl; lower alkyl, which may be substituted by phenyl, cyclopropyl, cyclopentyl, hydroxyl, lower alkoxy, phenoxy, phenylcarbonyl, piperidinecarbonyl, lower alkoxycarbonyl, aminocarbonyl, cyano, amino, amino, dihydroxycarboxylic diphenylamino group, (2,6-dimethylphenyl) a shnabarbonili, (2 oxycyclohexyl) aminocarbonyl, (2-oxycyclohexyl 1) amino group, 1-piperidinyl; 2-propenyl, 3-phenyl-2-propenyl; cyclopentyl, which may be substituted in position by 2-hydroxyl, amino, acetylamino, benzylamino, (hydroxy-lower alkyl) amino, (benzyl) (hydroxy-lower alkyl) amino, (lower alkyloxycarbonyl) lower alkyl; cyclohexyl, which may be substituted by two radicals selected from the groups including the lower one; zlkyl, (di-lower alkyl amino) lower alkyl, a radical of the formula OR, where R4 is water;
genus, lower halyl or benzyl radical of the formula -OCFj, where
Rj is lower alkyl, phenyl or (methoxy) (phenyl) (trifluoromethyl) methyl, a radical of the formula NR, where R is lower alkyl, a radical of the formula Nlffl, where RY is hydrogen, lower alkyl, lower alkylsulfonyl or benzyl, the radical Formulas - NHCRg, where Rg O
lower alkyl, phenyl, amino, or lower alkyloxy, for the L is a radical of the formula —CRq.
ABOUT
R 3 is lower alkyl, lower apyloxy, benzyloxy, 3,4,5-trimethoxyphenyl or cyclohexyl, because L is a radical of the formula
Othu

N 1
Hio
hydrogen, lower alkyl or lower alkyloxycarbonyl; hydrogen, hydroxy or lower alkyloxy, a radical of formula
oi
-СН -С-СНг-Вй й
where B is hydroxymethyl, benzyloxymethyl, hydroxy, 4-halophenoxy, amino, di-lower alkyl amino, benzylamino or dibenzylamino; Ria is hydrogen or lower alkyl; or L 2-pyr Uldine 1, 1,3-dihydro-2H-inden-2-yl, tetrahydro-4H-pyran-4-yl, 3-oxo-1-cyclohexenyl, 1,4,5,6- -tetrahydro-2-pyrimidinyl, or their salts with a pharmaceutically acceptable acid or a possible stereochemical isomeric form, possessing 1X antiarrhythmic effect, which can be used in medicine.
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The aim of the invention is to create, on the basis of known methods, a method of obtaining new compounds with valuable pharmacological properties.
Obtaining intermediate compounds. one
Example 1. A mixture of 73.5 hours of 2,6-dimethyl-4-nitrobenzene amine and 180 parts of formic acid is stirred and heated under reflux for 5 hours. After cooling, the mixture is stirred until it reaches room temperature. The mixture is poured into crushed ice. The precipitated product is filtered and crystallized from 2-propanol. Again filtered and suchatat in vacuum at 80 C. Get 62.3 hours (73%) K- (2,6-dimethyl-4-nit (intermediate
0
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0
five
0
rofenyl) formamide compound 1).
A mixture of 30 parts of N- (2,6-dimethyl-4-nitrophenyl) formamide and 400 hours of methanol is hydrogenated at normal pressure and room temperature using 2 parts of catalyst — 10% palladium on carbon. After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the product is allowed to crystallize. The precipitated product is stirred in warm 2-methoxy.ethanol. The whole mixture is filtered and the filtrate is evaporated. The residue is crystallized from 400 h, methanol. The product is filtered (the filtrate is preserved) and dried. A first fraction of 16.4 g (66%) of N- (4-aMHHo-2,6-dimethylphenyl) formamide is obtained.
The stored filtrate is evaporated. The concentrate is allowed to crystallize - c. The product is filtered and dried. Get the second fraction - 7.2 hours (29%) of K- (4-amino-2,6-dimethylphenyl) formamide. M.p. 233.4 C (intermediate compound 2).
A mixture of 23 parts of poly (oxymethylene) a, 23 parts of K- (4-amino-2,6-dimethylphenyl) formamide, 2 parts of a 4% solution of thiophene in methanol and 540 parts of 2-labeled
five
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five
Seethanol is hydrogenated at normal pressure and 70 ° C using 3 parts of catalyst — 10% palladium on carbon. After consuming the calculated amount of hydrogen, 10 parts of acetic acid are added and the catalyst is filtered off. The filtrate is evaporated, the residue is dissolved in water and treated with a 50% hydroxide solution.
51
on three . The precipitated product is filtered and crystallized from methanol. The product is filtered and dried. Get the first fraction of 16.61, hours (dimethylamino) -2,6-dimethylphenyl forms Yes
The mother liquor (methanol-filtrate) is evaporated and the residue is stirred in 2,2-oxybnpropane. The product is filtered and dried. A second fraction is obtained — 4.06 parts (di-methylamino) -2,6-diketylphenyl formamide; m.p. 216.3 C intermediate compound 3).
A mixture of 3 hours (dimethylamino) -2 -2,6-dimethylphenyl formamide and 50 hours, 1N of the hydrochloric acid solution is stirred and heated with reflux for 1 hour. After cooling, the mixture is treated with 50% sodium hydroxide solution. The product is extracted twice with dichloromethane. The organic layer is washed once with water, dried, filtered and evaporated. The residue is dissolved in netil benzene and the whole mixture is again evaporated. Get 2.4 hours (93%) to, m 3,5-tetramethyl-1,4-benzenediamine residue (intermediate compound 4)
Example 2. To a stirred suspension of 100 parts of (4-hydroxy-2,6-dimethylphenyl) -formamide in 1200 parts of a 2-propanone were added in portions of 124.3 hours of potassium carbonate, then 75 , 7 parts of dimethyl sulfate. After the addition is complete, stirring is continued overnight under reflux. The whole mixture is filtered while hot and the filtrate is evaporated. The residue is crystallized from acetonitrile. After cooling, the product is filtered and dried. 62.4 g (58%) are obtained. 11- (4-methoxy-2,6-dimethylphenyl) formamide (intermediate compound 5).
A mixture of 18.5 parts of N- (4-ketoxy-2, b-dimethylphenyl) formamide. 55.16 parts of H, I-diethyl ethanamine and 337 hours of dichloromethane are stirred and heated under reflux. A solution of 21.61 parts of trichloromethyl carbonyl chloride in 104 parts of dichloromethane is added dropwise over two hours. The mixture is stirred at reflux for 30 minutes. After cooling, the mixture is washed three times with 10% sodium carbonate solution, dried, filtered and evaporated. The residue is purified by the method of column chromatography.
graphs on silica gel using methylbenzene as eluent. Collect the first fraction and eluent is evaporated. The residue is crystallized from petroleum ether. The product is filtered and dried. 8.2 parts (49%) of 2-isocyano-5-methoxy-1,3-dimethylbenzene are obtained (intermediate 6). Example Z.K stirred
and cooled (OH) mixture of 5 parts of 2-aminocyclohexanol, 5.3 parts of sodium carbonate, 180 hours, sodium carbonate and 180 parts of sodium carbonate are added dropwise 9.7 hours, 2-chloroacetyl chloride
at 0-5 ° C. The reaction mixture is slowly cooled to room temperature and 50 parts of water are added. Separate the layers. The organic phase is dried, filtered and evaporated. The residue is purified by filtration and on silica gel using trichloromethyl: methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, and the residue is crystallized from 2,2-hydroxybis-propane. The product is filtered off and dried. 5 h, (61%) trans-2- -: slor-H- (2-hydroxycyclohexyl) acetamide, m.p. 212.3 C (intermediate compound 7). ,
Example 4. To a stirred solution of 9.2 h, trans-2- (diethyl-amino) methyl-cyclohexanol at 45 h.
tetrahydro (1 urana is added in parts 2.4 hours. 50% sodium hydride dispersion. After the addition is complete, continue:; stir for 1.3 hours under reflux. After cooling, add to dropwise 5) , 85 parts of methanesulfonyl chloride at a temperature below 10 ° C (exothermic reaction). After the addition is complete, stirring is continued for 2 hours. After cooling to 0 ° C, the reactive mixture is decomposed by adding water dropwise. The product is extracted with 1, 1-oxybisethane. The organic layer is washed with water, dried, filtered and evaporated The remaining oil is purified by silica gel column chromatography with an eluent — a mixture of trichloromethane and methanol (90:10 by volume). Pure fractions are collected, the eluent is evaporated. 6.9 parts (90.4%) of trans-2-diethylamino methyl are obtained. piclohexanomethane sulfonate (ester) as
oily residue (intermediate 8).
Example 5 To a stirred mixture of 197.3 parts of N- (phenylmethyl) benzenemethamine and 3 parts of water are added dropwise 92.5 parts of (chloromethyl) oxyrane at -5 ° C (exothermic reaction: the temperature rises up to 3 s). After stirring for 4 hours at 0 ° C, the mixture is allowed to warm to room temperature and stirring is continued for 2 days. at room temperature. Then 1440 parts of tetrahydrofuran are added, together with a 30% sodium methoxide solution, and the whole is stirred overnight at room temperature. 400 parts of water are added and the layers are separated. The organic phase is washed with water, dried, filtered and evaporated. 153.6 parts (100%) of N, K-bis (phenylmethyl) oxiranmethamine are obtained in the form of an oily residue (intermediate 9).
Example 6 To a stirred mixture of 25 hours (8-butenyl) oxymethyl benzene and 390 parts of dichloromethane, 18.49 parts of sodium bicarbonate are added in portions. All this is cooled to 5 ° C and added quickly over parts of 48.9 parts of 3-chlorobenzenecarboperic acid. After the addition is complete, stirring is continued, first for 30 microns in an ice bath, then overnight at room temperature. The precipitate is filtered off and the mixture is washed thoroughly with dichloromethane. The filtrate is washed successively five times with 100 parts of a saturated solution of sodium sulfite, and five times with 100 parts of a sodium carbonate solution, twice 200 parts of 2.5% sodium hydroxide solution, and twice 200 hours . water. The organic layer is dried, filtered and evaporated. The residue is purified by silica gel column chromatography using eluant, trichloromethane. Pure fractions are collected and the eluent is charged. The residue is distilled with methylbenzene. 24 hours (80%) of 2- (phenylmethoxy) ethyl oxirane are obtained as a residue (intermediate 10).
In a similar manner, methyl 2- (phenylmethoxy) etch1 oxirane is obtained as a residue (intermediate compound I)
Example 7. 39 hours 39 parts of trans-2- (phenylmethyl) amino cyclopentanol are suspended in 100 parts of cyanomethane at
cooling in an ice bath. Then, 60.3 parts of triphenylphosphine, 60 parts of cyanomethane, 31.2 parts of carbon tetrachloride and 20.6 parts of N, N-diethylethamine (endothermic reaction) are added successively. All this is stirred for 8 hours at C. After standing overnight in ice and the reaction mixture is filtered and the filter cake is washed with cold cyanomethane. The filtrate is evaporated. Add 175 hours of petroleum ether and evaporate again. The residue is stirred for 5 minutes, filtered and the filtrate is evaporated. The residue is distilled. 29.8 parts (84%) of 6- (phenylmethyl) -6-aza-biaiclo 3.1.0 hexane are obtained, b.p. 71-86 ° C at a pressure of 0.5 mm (intermediate 12).
Example 8. A mixture of 100 parts of 4- - (methylamino) -1- (phenylmethyl) -4-pyridinecarboximide and 1000 parts of a concentrated hydrochloric acid solution is stirred at reflux for 24 hours. The reaction mixture is evaporated. The residual oil crystallized from 250 parts of 6N hydrochloric acid. The solid product is recrystallized from 200 parts. 6N hydrochloric acid. 58 parts of 4- (methylamino) -1- (phenylmethyl) -4-piperidinecarboxylate are obtained, m.p. 146-255 ° C (decomp.) (Intermediate 13).
A solution of 101.7 parts of dichloride 4- (methylamino) -1- (phenylmethyl -4-piperidinecarboxylic acid in 300 parts of water is made alkaline with ammonium hydroxide until the resulting precipitate dissolves. The solution is neutralized with acetic acid. After cooling, the precipitate is filtered and dried at 49.8 parts of 4- - (methylamino) -1- (phenylmethyl) -4-piperidinecarboxylic acid are obtained, mp 272 ° C (intermediate 14).
A solution of 4- (metshtamino) -1- (phenylmethyl) -4-piperidinecarboxylic acid and 22 parts of sodium hydroxide in 700 parts of water is hydrogenated at normal pressure and 30 ° C with five parts of catalyst - 10% palladium on carbon . After uptake of the calculated amount of hydrogen, the catalyst is filtered off and washed with water. In the filtrate, the layers are separated; the aqueous phase is pack9131
ryvaet. 89.7 parts of 4-methylamino-4-piperidinecarboxylate sodium are obtained in the form of a residue (intermediate 15).
Dissolve 90 hours, 4- (methylamine) -4-piperidine-carboxyl sodium in a mixture of 1200 parts of water and 2 hours, sodium hydroxide. Then add another 20 hours.
additionally alkaline with sodium hydroxyde. The precipitated product is filtered and crystallized from a mixture of water and 50% sodium hydroxide solution. The product is filtered and recrystallized from water. 101.7 parts (54.6%) of 4- (4-morpholinyl) -1- (phenylmethyl) -4-piperidinecarboxylate sodium (sodium hydroxide) are obtained. The resulting solution
108 parts of tetrahydrofuran are diluted and tO the exact compound 18
cooled to 5.degree. C. With stirring. A mixture of 4.9 hours. 4- (4-morpholinyl) -1 is added dropwise a solution of 89.7 hours (phenylmethyl) carbonacetate in 162 hours for 1.5 hours. tetrahydrofuran at a temperature below 10 ° C. At the end of the addition, stirring is continued for 3.5 hours on ice
- (Phenylmethyl) -4-piperidinecarboxylate sodium and 100 parts of hexamethylphosphoric triamide are heated to 160 ° C with stirring. After cooling to room temperature, 1.84 parts of bromoethane are slowly added. Continue stirring at room temperature for 24 hours. Reactant 1, G-oxybisethane. The aqueous phase of the ney-20 mixture is drunk at 400 parts of water. Wane at temperatures below 10 ° C. The reaction mixture is washed three times.
Trace with acetic acid. The precipitated product is filtered off, washed with water and dried. 108 parts (74%) of 4 (methyl fflno) -l- (phenylmethoxycarbonyl) -4 piperidinecarboxylic acid are obtained. -T. square 250 С (intermediate connection 16).
Carbon dioxide gas is passed through a stirred suspension of 107 hours, 4- (methylamino) -1- (phenylmethoxycarbonyl) -4-piperid, incarboxylic acid in 1500 hours 1,5-dioxane; first for 30 minutes at room temperature, then after
 heating with reflux for 1.75 h. 35-piperidinone in 1200 h of dichloromethane at a temperature of reflux cooling add 360 hours of ethyl carbonic to the drop. Dry nitrogen gas is then introduced while simultaneously giving the mixture
bonochloridate. At the end of the addition, all this is agitated when heated with reflux (3 hours for 3 hours).
cool to room temperature.
bonochloridate. At the end of the addition, neither of these is stirred when heated with reflux (3m for 3 hours).
The solvent was distilled off, and the plant residue was added dropwise, 353.5 parts. N-divorced in dimethylbenzene. Successive
distilled off again under vacuum in a boiling water bath. 116.5 h, (phenylmethyl) -1-methyl-2,4-dioxo 3-oxa -, 8-diazaspiro 4,5 dekan-8 carboxylate c are obtained. as residue (intermediate 17).
Example 9. A solution of 184 parts of 4- (4-morpholinyl) -1- (phenylmethyl) -4- -piperidinecarboxylate in 2880 parts of 12 n. Hydrochloric acid solution is mixed with reflux for 5 days. The reaction mixture is evaporated. The residue is dissolved in 1000 parts of water. The solution is first alkalized with sodium hydroxide to pH 7-8, washed successively three times with trichpormethane and once with 1.1-oxybisethane, then
ABOUT
additionally alkaline with sodium hydroxyde. The precipitated product is filtered and crystallized from a mixture of water and 50% sodium hydroxide solution. The product is filtered and recrystallized from water. 101.7 parts (54.6%) of 4- (4-morpholinyl) -1- (phenylmethyl) -4-piperidinecarboxylate sodium are obtained (i.e., a mixture of 4.9 parts of 4- (4-morpholinyl) -1- (phenylmethyl) -4-piperidinecarboxylate sodium and 100 parts of hexamethylphosphoric triamide are heated to 160 ° C. with stirring.After cooling to a precipitate, the product is filtered off, washed thoroughly with water and dissolved in trichloromethane.The solution is washed three times with water, dried, filtered and evaporated. The residue solidified — while stirring in 2.2-hydroxy-propane. The product was filtered and dried. 2.08 parts (41.7%) of ethyl 4- (4th) were obtained. rfolinil) -1- (phenylmethyl) -5-piperidinecarboxylate; mp 76.4 C. Intermediate 19).
I'll try it on. To a stirred mixture of 580 parts of 1- (phenylmethyl) -3-piperidinone, in 1200 hours of dichloromethane, 360 hours is added dropwise.
bonochloridate. At the end of the addition, all this is agitated when heated with reflux (dm for 3 h. Then
ethylethanamine and continue moving at reflux overnight. The reaction mixture is cooled and washed with water. The organic layer is separated, dried, filtered and evaporated. The residue is distilled. A fraction is obtained - 27-1 parts of ethyl-3-oxo-1 piperidinecarboxylate, b.p. i31-140 c at a pressure of 1 - 1.5 mm (promez; daily compound 20).
Example P. To a stirred mixture of 17.1 parts of ethyl-4-oxo-1-piperidinecarboxylate and 225 parts of trichloromethane was added dropwise a solution of 16 parts of bromine in 75 parts of trichloromethane l. at (-5) -0C. The trichloromethane phase is washed with ice water, dried, filtered and evaporated. Get 25 hours
ethyl 3-bromo-4-oxo-1-piperidinecarboxylate silat in the oily residue (intermediate 21).
To the stirred mixture of 200 parts of a 30% solution of sodium methanolate and 640 parts of methanol was added 250 parts of ethyl 3-bromo-4-oxo-1-piperidinecarboxylate silate at 20 ° C. The whole was stirred for 3 hours at room temperature. The solvent is distilled off and the oily residue is dissolved in 2,2-oxybispropane. The solution is washed with water, dried, filtered and vasharivat. 190 parts of ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate are obtained in the form of an oily residue (intermediate compound 22).
To a stirred mixture of 35 parts of ethyl-3-hydroxy-1,4-dimethoxy-1-piperidinecarboxylate and 144 parts of W, K-dimethyl formamide are added in portions of 8.2 parts of a 50% hydride dispersion sodium: exothermic reaction (temperature rises to 30 ° C; must be cooled in a water bath to maintain the temperature below 30 ° C). The mixture is stirred for 1.50 hours at 30 ° C. and then cooled to room temperature. 24.1 parts of iodomethane are added dropwise (strongly exothermic reaction), maintaining the temperature below 30 ° C. After the addition is completed, the measurement is continued for 2 days. at room temperature. The reaction mixture was poured into water, and the product was extracted with 4-methyl-2-β-pentanone. The extract is washed with water, dried, filtered and vasharivat. 35.9 parts (95.7%) of ethyl 3,4,4-trimethoxy-1-piperidinecarboxylate are obtained in the form of an oily residue. (intermediate 23),
A mixture of 56.2 parts of ethyl 3,4,4-trimethoxy-1-piperidinecarboxylate and 1850 parts of a 1% aqueous solution of sulfuric acid was stirred at reflux for 2.50 parts. The reaction mixture was cooled to room temperature and alkalized. sodium carbonate. The product is extracted with dichloromethane. The extract is washed with saturated sodium chloride solution, dried, filtered and evaporated. 41.2 parts (90.4%) of ethy-1-3-methoxy-4-oxo-1-piperidinecarbsyl is obtained as an oily residue (interm. Compound 24).
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Example 12. A mixture of 321.5 parts of 4- (ethylamino) -1- (phenylmethyl) 4-piperidinecarboximide and 3600 parts of 12 N hydrochloric acid solution was stirred under reflux for 48 hours. The reaction mixture was concentrated to a volume of 1000 hours. The precipitated product is filtered off (the filtrate is retained), washed with 100 parts of water and 240 parts of ethanol, dried, and the first fraction is obtained - 283 parts (65.2%) of 4- (ethylamino) - hydrochloride 1- (phenylmethyl) -4-piperidinecarboxylic acid, m.p. 260-262 ,.
The preserved filtrate is concentrated to a volume of 300 hours. The precipitated product is filtered off and crystallized from 300 parts of water. After cooling to 0 ° C and seeding, the product is filtered, washed with ethanol and dried. A second fraction is obtained — 51 parts (11.75%) of monohydrate of hydrochloric 4- (ethylamino) -1- (phenylmethyl) -4-piperidinecarboxylic acid (intermediate compound 25).
A mixture of 330 parts of dichlorohydrate 4- (ethylamino) -1- (phenylmethyl) -4-piperidinecarboxylic acid monohydrate and 1800 parts of water is gradient at. normal pressure and room temperature 5 hours of catalyst - 10% palladium on carbon. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. 245.8 parts of dichloride 4- (ethylamino) -4-piperidinecarboxylic acid monohydrate were obtained as a residue (intermediate 26).
To a stirred mixture of 245.8 parts of monohydrate dichloride 4- (ethylamino) -4-piperidinecarboxylic acid in 1800 parts of water are added 149.5 parts of sodium hydroxide followed by the addition of 1080 parts of tetrahydrofuran. After cooling to 5 ° C, 187.5 hours of (phenylmethyl) -carbonochloride are added dropwise over 2 hours. At the end of the addition, stirring is continued for 4 hours at 5 ° C. The reaction mixture is washed twice with 350 hours. 1,1-Oxybispropane. The aqueous phase is neutralized with acetic acid. The precipitated product is filtered off and boiled in 2000 hours of water. After cooling to temperature C, the product is filtered 13
There are washed with ethanol and dried. 223 parts (78%) of 4- (ethylamino) -1 -1 (phenylmethoxy) carbonyl 4-piperidinecarboxylic acid (interm. Compound 27) are obtained.
A stirred suspension of 153.2 hours „4- (ethylamino) (phenylmethoxy) carbonyl-P-A-piperidinecarboxylic acid in 1900 hours. 1,4-dioxane is heated with reflux, carefully introducing gaseous carbon dioxide. For 2 hours, carbon dioxide gaseous gas is weakly bubbling through the suspension heated with reflux. The reaction mixture is allowed to cool with stirring and passing dry nitrogen for 2 hours. The solvent is evaporated and the residue is again distilled with benzene. The solid residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, and 112 parts (67.5%) of (fenkpmethyl) 1-ethyl-2,4-dioxo-3-oxa-1,8-diazaspi- Ro 4.5 decan-8-carboxylate, t.il, 127.5 ° C (intermediate 28
Example 13 To stirring the 1st mixture under reflux of a mixture of 403 parts of ethyl-3- (phenylmethyl) -amino butanoate and 160 parts of ethanol, is added dropwise in 100 hours of ethyl-2-propenoate. After stirring overnight at reflux temperature, a second portion of 100 parts of ethyl propenoate is added dropwise. At the end of the addition, stirring is continued at reflux temperature for 48 hours. The reaction mixture is evaporated and a mixture of ethyl-N-2- (ethoxycarbonyl) -1 ethyl -I- (phenylethyl) -p-alanine and ethyl -N-2- (ethoxycarbonyl) ethyl -N, (fe; -nylmethyl) -B-alanine as an oily residue. The latter is stirred at room temperature from 17 hours sodium carbonate in 900 parts of trichloromethane. Then, 217 hours are added dropwise. ethylcarbonate. At the end of the addition, stirring is continued overnight. The mixture is washed with water, dried, filtered and evaporated. The residue is extracted with a dilute hydrochloric acid solution. The acidic aqueous phase is washed with 2.2-oxibispropane; The free base is partitioned with hydroxide and extracted with 2,2-oxy-isopropane. The extract is washed with water, dried, filtered and embedded in, -264.5 parts is obtained ethyl-N- 2- (ethoxycarbonyl)
13344 14
-1-methylethyl-N- (phenylmethyl) -alanine as a residue (intermediate 29).
A mixture of 192.8 parts of ethyl-M- 2- (ethoxy-5 carbonyl) -1-methylethyl-W- (phenylmethyl-p-alanine, and 280 parts of absolute ethanol is stirred in a hydrogenation apparatus. Then 45 h Hydrochloric acid solution. After cooling, 10 hours of a catalyst — 5% palladium on carbon — are added, and the mixture is shaken at room temperature until 1 equivalent of hydrogen is taken up. The catalyst is filtered off and
t5 the filtrate is evaporated. 150 parts of ethyl hydrochloride-K 2- (ethoxycarbonyl) -1-methylethyl-3-alanine are obtained in the form of an oily residue (intermediate 30).
20 K stirred mixture 105 h.
ethyl K-2- (ethoxycarbonyl) -1-methyl-zt1-sh) -p-alanine, 63.8 parts of I, I-diethyl-ethanamine and 1200 parts of trichloromethane are added dropwise at room temperature 61, 4 parts ethyl carbonate. Stirring at room temperature is continued overnight. The reaction mixture is evaporated. Water was added to the residue, and the product was extracted with 2.2-oxibispropane. The extract is dried, filtered and evaporated. 114 parts of ethyl 3- (ethoxycarbonyl) .2- (ethoxycarbonyl) amino butanoate are obtained. as a residue (about 35 interconnection compound 31).
To a stirred solution of sodium toxoid prepared in advance from 9.5 parts of sodium and 80 parts of ethanol, add 225 hours: dimethylbenzene. This 40 NOL is distilled off. A mixture of 97 parts of ethyl-3 - ((ethoxycarbonyl) 2- (ethoxycarbonyl) ethyl-amino (butanoate and 45 parts of dimethylbenzene when heated to 110-120 ° C) is added dropwise to the residue.
 continuous distillation of ethanol. After the addition is complete, stirring is continued at 110-120 ° C for 1 hour. The reaction mixture is cooled and 50 parts of acetic acid and 50 hours of water are added to it. After a short mixing, the layers are separated. The organic phase is dried, filtered and evaporated. 54 parts of diethyl-2-methyl-4-oxo-1, 3-piperidinecarbok .55 silat are obtained in the form of the residue (intermediate 32).
Stirring 54 parts dieth1-2-metil-4-oxy-1,3-piperidinecarboxylate
1513
and a solution of 42 parts of ethanedicarboxylic acid in 300 parts of water and heated with reflux for 40 hours. The reaction mixture is cooled. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. 28 parts of ethyl 2-methyl-4-oxo-1-piperidinecarboxylate are obtained as a residue (intermediate 33).
EXAMPLE 14 A mixture of 111.5 parts of ethyl 4-amino-1- (phenylmethyl) -4-piperidinecarboxylate, 50 parts of poly (oxymethylene) a, 3 hours 4% - A solution of thiophene in methanol and 480 parts of ethanol is hydrogenated at normal pressure and a temperature of 50 ° C. 5 parts of a catalyst — 10% palladium on carbon. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue is dissolved in dichloromethane. The solution is washed with a dilute sodium hydroxide solution and once with water, dried, filtered and evaporated. I get 117, 9 parts (96%) ethyl-4- (dimethylamino) -1- (phenylmethyl) -4-piperidinecarboxylat as a residue (intermediate 34).
A mixture of 40 parts of ethyl 4- (dimethylamino) -1- (phenylmethyl) -4-piperidinecarboxylate and 400 parts of ethanol is hydrogenated at normal pressure and at a temperature of 50 ° C. 4 parts of catalyst - 10% palladium on carbon. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in methylbenzene and evaporation is continued. 21.2 h, (76.8%) ethyl 4- (dimethylamino) -4-piperidinecarboxylate are obtained as a residue (intermediate 35).
Example 15. A mixture of 19 parts of 7-oxobicyclo 4.1 .0 heptane, 21.2 parts of ethyl 4- (dimethylamino) -4-piperidinecarboxylate, 500 parts of water and 400 parts of ethanol is stirred under heating reflux for 10 hours. The reaction mixture is concentrated to a part volume and the product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted to the hydrochloride salt in 525 h, 1, l-oxybisethane and 2-propanol. The solvent is decanted and the residue is stirred in 1,1 - -oxybisethane. The latter is decanted again, and the residue is crystallized from
34416
240 h. Acetonitrile. The product is filtered off and dried, and 40.0 parts of ethyl trans-4- - (dimethylamino) -1- (2-hydroxycyclohexyl) are obtained.
-4-piperidinecarboxylate, so pl.
173.4 ° C (intermediate 36),
To a stirred mixture of 25.06 parts of ethyl trans-4- (dimethylamino) -1 - (2-hydroxycyclohexyl) -4-piperidinecarboxylate and 270 parts of tetrahydrofuran are added in portions of 4.32 parts of 50% sodium hydride dispersions (mildly exothermic). The mixture is heated to 50 ° C. and cooled again to room temperature.
 temperature 11.92 parts of iodomethane are then added dropwise. At the end of the addition, all this is heated with reflux and stirring is continued for 2 hours at reflux temperature. Another 0.8 part of the 50% sodium hydride dispersion is added in portions and the whole is heated to 50 ° C. After cooling to room temperature, add
 2.28 parts of iodomethane and continue stirring for 2 hours at temperature. round of phlegm. The reaction mixture is cooled and 200 parts of sodium chloride solution are added. The layers are separated, and the aqueous phase is extracted with methyl benzene. The combined organic layers are dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent.
The first fraction is collected and the eluent is evaporated. The residue was again purified by silica gel column chromatography using a mixture of trichloromethane and methanol (saturated with ammonia (95: 5 by volume)) as eluent. Pure fractions are collected and the eluent is distilled off. The first fraction is obtained - 6.26 parts of ethyl trans-4- (dimethylamino) -1- (2-methoxycyclohexyl) -4-piperidinecarboxylate.
Collect the second fraction and evaporate the eluent. A second fraction is obtained — 8.7 parts of ethyl trans-4- (dimethylamino) -1- (2-methoxycyclohexyl) -4-piperidinecarboxylate (intermediate 37).
Example 16. 45,5h. 1,1-Oxybisethane is cooled in a 2-prop-HoH / COj bath at a temperature of -50 ° C in a nitrogen atmosphere. Then, 25 h of 1-lithium butane is added thereto at a temperature of
0
five
0
five
1713
minus (40-50) ° С. A solution of 6.57 h, 4-butoxy-2,6-dimethylbenzene amine at 14 h, is added dropwise, 1, 1 -o.-hydroxybisane within 30 minutes at a temperature of approximately -45 ° C. At the end The addition is continued by stirring for 15 minutes at - 40 ° C. A solution of 8.95 h, ethyl 4- (dimethylamino) -1- (phenylmethyl) -4-piperidinecarboxylate is added dropwise at 14 h. 1, l-Oxybisethane over 45 ppm. The mixture is allowed to slowly warm to room temperature and stirred overnight at this temperature, 1,1-Oxybisethane is distilled off while adding 90 hours of tetrahydrofuran. The mixture was stirred at reflux for 20 hours. After cooling, 8 parts of 2-propanol and water were added. The layers are separated. The aqueous phase is extracted with dichloromethane. The combined organic layers are dried, filtered and evaporated. The residue is purified by silica gel column chromatography using as eluent a mixture of trichloromethane and a mixture of methanol (95: 5 by volume). The first fraction is collected and the extract is distilled off. The residue is crystallized from 2,2-oxy-bispropane. The product is filtered and dried. 4.03 h, (30%) of N- - (4-butoxy-2,6-dimethylphenyl) -4- (dimethyl amino) -1- (phenylmethyl) -4-piperidinecarboxamide, m.p. 195 C (compound 13). Yield 30%.
In a similar way, the following compounds are also prepared:
4- (dimethylamino) (dimethyl-amino) -2,6-dimethylphenyl -1 - (phenylmethyl) -4-piperidinecarboxam: id, mp, 196.8 ° C (compound 15), yield 33%;
TRANS-4- (dimethylamino) -N- (2,6-dimethylphenyl) -1- (2-methoxycyclohexyl) -4-piperidinecarboxamide 5 mp 131.5 ° C (compound 18), yield 26.4%
(Phenylmethyl) -4- (2,5-dimesh1phenyl) aminocarbonyl-4- (methyl amn-no) -piperidinecarboxylate, m.p. 157.5 C (compound 19), yield 22%;
(Phenylmethyl) -4- | (5-chlorine 2-methyl-NILE) amino-carbonyl -4- (e-tilamino) -1 - -piperidinecarboxonlate, mp, 124.1 ° C (compound 21), o: o 39.2 %;
4- (adylethylamino) -N- (2,6-dimethylphenyl) -1 - (1 -methylethylethyl) -4-piperidinecarboxamide, mpx. 196.4 C (combine some 2), yield 18%.
334418
Example 17. To a stirred solution of 1.4 parts. K- (2,6-dimethylphenyl) -4- (methylamino) -1- (1-methylethyl) -4-piperidinecarboxamide in 60 parts. 2 to 5 propanol add a few drops. 2-propanone, saturated with hydrogen chloride. The precipitated product is filtered and stirred for 2 hours in 2-propanone and a small amount of 10 water. Then again suigate is filtered off in air. 1.40 parts of dihydrate of two-hydrochloride (2,6-dimethylphenyl) -4- (methylamino) (1-methylethyl) -4-piperi-5 dincarboxamide are obtained, m.p. 219, (compound 232).
Example 18. A mixture of 6 parts of trans- 4- (dimethylamino) N- (2,6-dimethylphenyl) - - (. -Oxycyclohexyl) -4-piperidinecarboxamide, 1.2 parts of (-) (R, R ) j-2,3-dioxybutandiicyrboxylic acid, 120 parts of acetonitrile and 120 parts of 2-propanol are stirred at refgaox min. The clear solution is allowed to crystallize. The product was filtered and recrystallized from 200 parts of a mixture of acetonitrile and 2-propanol (50:50 by volume). The product is filtered off and recrystallized again from 144 parts of a mixture of acetonitrile and 2-propanol. 2.58 h, (69%) of (-) - trans-4- (dimethyl-aivMHo) -TJ- (2,6-dimethylphenyl) -1 - (2-hydroxycyclohexyl) -4-piperidinecarbox-35 amide are obtained and (-) - S- (R, P.) -2,3-dioxy-. butandioatz (2: 1), -7.1251 (with 1% in methanol) (compound 233),
A solution of 2.58 parts of (.-) trans-4- (dimethyl amino) -N- (2,6-dimethylphenyl) (2- -oxycyclohexyl) -4-piperidinecarboxamide and (-) (R ", R) -2,3-Dioxy-butanedioate (2: 1) in 100 parts of water is treated with sodium carbonate. The product is extracted twice with dichloromethane. The combined organic layers were washed with 50 parts of water, dried, filtered and evaporated. The residue is crystallized from 2-propanol. To obtain (dimethylamino) -N (2, b-dimethylphenyl) -1 - (2-oxide-5P-hexyl) -4-piperidinecarboxamnd, m.p. 167, Mgg +2.37 (with 1% in methanolO (compound 234).
Example 19. A mixture of 10 parts of trans-4- (dinethylamino) -N- (2,6-dimeth: ylphenyl) -1 - (2-oxidelohexyl) -4- -piperidinecarboxamide, 2.05 parts (+) - - R- (R, R) -2,3-dioxybutane dicarboxylic acid and 240 parts of a mixture of 2-propanol and acetonitrile (50:50 by volume) are stirred at reflux for 15 minutes. The clear solution is allowed to crystallize. The product is filtered and recrystallized five times, respectively, from 360, 360, 304, 288 and 240 parts of a mixture of acetonitrile and 2-propanol (50:50 by volume). 3.49 parts of (+) - trans-4- - (dimethylamino) -N- (2,6-dimethylphenyl) -1- (2-hydroxycyclohexyl) -4-piperidinecarboxamide.and (+) (E, R) -2,3-dioxybutanedioate (2: 1); v g +7.8156 (with 1% in methanol) (compound 235).
A solution of 3.49 parts of (+) - trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) -1- (2-. -Oxycyclohexyl) -4-piperidinecarboxamide and (+) - Gk- (E, D) -2,3-Dioxy-butandioate 2: 1} in 150 parts of water is treated with sodium carbonate. The product is extracted twice with dichloromethane. The combined extracts are washed with 80 parts of water, dried, filtered and evaporated. The residue is crystallized from 2-propanol. The product is filtered and dried. 2-, 09 parts (71%) of (-) - -trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) -1 - (2-hydroxycyclohexyl) -4- -piperidinecarboxamide, m.p. . 167.2 C (compound 236).
Example 20. To a stirred mixture of 12.5 parts of (phenylmethyl) ethyl-4-ethylamino-1,4-piperidinecarboxylate, 6.1 parts of (2,6-dimethyl) benzene-amine and 90 parts of tetrahydrofuran 2.4 hours of sodium hydride dispersion 50% (foaming) was added. After completion of this operation, stirring is continued for 1 hour at room temperature and another 4 hours with reflux. The reaction mixture is cooled, 16 hours of 2-propanol are added dropwise, then 50 parts of water are added. The layers are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by silica gel column chromatography using a mixture of trichloromethane and methanol (95: 3 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is taken up in methylbenzene and the latter is evaporated again to form 7.4 parts of (phenylmethyl) -4- (2,6-dimethylphenyl) amino-carbonyl-4- (ethylamino) -piperidinecarboxylate, m.p.
149, (compound 39). Yield 46%.
In some compounds, the stereo-chemical structure is not determined experimentally. In these cases, it is usually customary to define the stereochemical isomeric forms in the following way: the release of the first is Form A, the selection of the second is the Form B. In this case, no reference is made to the actual stereochemical configuration.
Following a similar procedure and using equivalent amounts of the corresponding starting materials, the following substances are obtained:
N- (4-butoxy-2,6-dimethylphenyl) -4- (dimethylamino) -4-piperidinecarboxamide m.p. 190 C (compound 22), yield 3%
-4 (dimethylamino) (dimethylamino) -2, 6-dimethylphenyl-4-piperidinecarboxamide hemihydrate, so pl. 167.9 C (compound 24), yield 2%;
N- (2,6-dimethylphenyl) -4- (phenylmethyl) amino -4-piperidinecarboxamide, m.p. 133 ° C (compound 27), yield 5%
N- (2,6-dimethylphenyl) -4- (ethylamino) -4-piperidinecarboxamide m.p. 140 C (compound 28), yield 7%;
K- (4-methoxy-2-methylphenyl) -4- (methyl amino) -4-piperidinecarboxamide. m.p. .86 ° C (compound 32), yield 2%;
(A) - (Phenylmethyl) -4- (2,6-dimethylphenyl) aminocarbonyl-3-methyl-4- (methylamino) -1-piperidinecarboxylate, m.p. 149 C (compound 40), yield 53.7%;
(Phenylmethyl) -4- (2,6-dimesh1-phenyl) aminocarbonyl-3-methoxy-4- (methylamino) -1-piperidinecarboxylate, m.p. 149.5 ° C (compound 41), yield 72%;
(Phenylmethyl) -4- (2-chloro-6-methylphenyl) amino Arbonyl-4- (methylamino) -1 -1-piperidinecarboxylate, m.p. 141, (compound 42), yield 62%;
(phenylmethyl) -4- (4-methoxy-2-methylphenyl) aminocarbonyl -4- (methylamino) -1-piperidinecarboxylate, m.p. 110 ° C (compound 44), yield 66%;
(phenylmethyl) -4- (2-methoxyphenyl) aminocarbonyl -4- (methylamino) - -piperidinecarboxylate, m.p. 81 C (compound 45), yield 71%;
(Phenylmethyl) -4-L (5-chloro-2-metsh1-phenyl) aminocarbonyl -4- (methylamino) -1 -1-piperid 11H-carboxylate, m.p. 98 C (compound 46);
211
(Phenylmethyl) -4- (4-methoxn-2,6-dimethylphenyl) aminocarbonyl-4- (methylamino) -piperidinecarboxylate, m.p. 135 ° C (compound 48), yield 65%;
4- (dimethylamino) -C- (2,6-dimethylphenyl) -3-methoxy 4-pippridinecarboxamide, m.p. 166.2 ° C (compound 68), yield 2.5%;
4- (dime tilamino) -N-4-piperidinecar boksamid, t. Gsh. 121 ° C (compound 70), yield 3%;
 4- (dimethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarbokeamide, mp, 194.5 ° C (compound 71), yield 4%;
B- (2.6 dimethylphenyl) -4- (methylash5-but) -4-piperidinecarboxamide, t, mp, 150 ° C (compound 72), yield 3%;
N- (2,6-dimethylphenyl) -4 ™ (ethylmethyl amino) -4-piperidinecarboxamide, mp, 176.0 ° C (compound 73), yield 5%;
4- (diethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 195.5 ° C (compound 74), yield 2%;
(A) -4- (dimethylamine o) -W- (2,6-dimethyl-phenyl) -3-methyl-4-piperidinecarboxamide (compound 76), yield 8%;
4- (dimethylamino) N- (2,6-dimethylphenyl) -2-methyl-4-piperidinecarboxamide, m.p. 121 ° C (compound 77), yield 4.5%;
4 (dimethylamino) -I- (2,4,6-trimethylphenyl) -4-piperidinecarboxamide, m.p. 154, (compound 80), yield 4%.
Example 21. To 108 parts of tetrahydrofuran was added 31.9 parts of 1-lithium butaHa at 0 ° C and under nitrogen atmosphere. At 0-5 ° C, a solution of 11.3 parts of N, N, 3,5-tetramethyl-1,4-benzenediami in 36 parts of tetrahydrofuran (THF) is added dropwise over 30 minutes. After the addition is complete, stirring is continued for 15 minutes at room temperature. At room temperature, a solution of 18.02 parts of ethyl 4- (dimethylamino) -1 - (phenylmethyl) -4-piperidinecarboxylate in 36 hours is added dropwise over 15 minutes. After the addition is complete, stirring is continued. overnight with in a system fitted with a reflux condenser. The reaction mixture is cooled, water is added and the layers are separated. The water phase is extracted with dichloromethane. The combined organic layers are dried, filtered and evaporated. The residue is stirred at 2.2 422
The product is filtered off and recrystallized from acetonitrile. The reaction product is filtered off (the filtrate is discarded) and dried to form the first fraction — 7.10 h, 4- (dimethylamino) (dimethyl amino) -2 5b-dimethylphenyl -1- (phenylmethyl) -4 -piperidinecarboxamide. The filtrate that was discarded was evaporated. The residue was purified by chromatography on a column of silica gel, using a mixture of trichloromethane and methanol saturated with ammonia (96: 4 by volume) as eluent. Take away
the first fraction and eluent is evaporated. The residue is recrystallized from acetonitrile. The product is filtered off and the sutaat is formed to form the second fraction — 1 part 4- (dimethyl amino) -W- (4-dimethylamino-2, 6-dimethylphenyl) -1- (phenylmethyl) -4-piperidinecarboxamide. Total yield: 8.10 parts (33%) 4- (dimethylamino W- (4-dimethylamino-2,6-dimethylphenyl) -1- (phenylmethyl) -4-piperidinecarboxyl Shda, so pl. 196.8 C (compound 15), yield 33%.
Following a similar procedure and using equivalent amounts of the corresponding starting materials, the following compounds are obtained:
(phenylmethyl) -4- (2,6-dimetylphenyl) aminocarbonyl 4- (ethylmethylamino) -1- piperidinecarboxylate, m.p. 211.7 C (compound 51), yield 69%;
4- (diethylamino.) -N- (2,6-dimethylphenyl) (- methylethyl) -47piperidinecarboxamide, mp, 177.5 C (compound 53), yield 18.7%;
1-cyclopentyl-4- (diethylamino) -N (: ;; J 6-dimethylphenyl) -4-piperidinecarboxboxamide, m.p. 177, (compound-, 53), yield 18.7%;
(Phenylmethyl) -4- (diethylamino) -4- (2,6-dimetylphenyl) aminocarbonyl ./ - 1-piperidinecarboxylate, m.p. 219 C (compound 55), yield 35%;
(Phenylmethyl) -4- (5-chloro-2-methylphenyl) aminocarbonyl1 -4- (diethylamino) -1-piperidinecarboxylate, m.p.
137.2 ° C (compound 56), yield 8%;
(Phenylmetre: yl) -4- (dimethylamino) -4- - (2,6-dimethylphenyl) aminocarbonylZ-3-methoxy-1-piperidinecarboxylate, mp 182 C (compound 57), yield 44%:
(Phenylmethyl) -4- (2-chloro-6-methyl-Fensh1) aminocarbonyl-4- (dimethylamino)
ten
15
-1-11 Hyperidic acid, so pl. 228.5 ° C (compound 58), yield 49%;
(phenylmethyl) -4- (dimethylamino) -4-. - (2,6-dime tylphenyl) aminocarbonyl -1 - -piperidinecarboxylate, so pl. 232.5 C 5 (compound 61) yield 37.2%;
(Phenylmethyl) -4- (dimethylamino) -4- (4-methoxy-2-methylphenyl) aminocarbonyl-piperidinecarboxylate, m.p. 141 ° C (compound 63), yield 52%;
(Phenylmethyl) -4- (dimethylamino) -4- - (2-methoxyphenyl) aminocarbonyl -1 - piperidinecarboxylate, m.p. 146 C (compound 64), yield 50.4%;
(Phenylmethyl) -4- (dimethylamino) -4- (4-methoxy-2,6-dimethylphenyl) amino-carbonyl -1-piperidinecarboxylate, m.p. 208 C (compound 67), yield 48%;
N- (2-chloro-6-methylphenyl) -4- (dimethylamino) -4-piperidinecarboxamide, m.p. 173, (compound 83) yield 5.5%;
N- (5-chloro-2-methylphenyl) -4- (diethyl-amino) -4-piperidinecarboxamide, m.p. 101 s (compound 84), yield 4%;
cis-4- (dimethylamino) -N- (2,6-dimethylphenyl) -3-methoxy- (1,4-bipiperidine) -4-carboxamide. m.p. 111.5 C (compound 85), yield 3%;
4- (dimethylamino) -N- (2,6-dimethylphenyl) - (1,4-biperidine) -4-carboxamide. mp, 180.5 ° C (compound 86), yield 2.5%;
trans-4-amino-I- (2,6-dimethylphenyl) 35. / o / 200J, 5% yield;
-1- (2-hydroxycyclohexyl) -4-piperi-
dincarboxamide. m.p. 174.8 C (compound 187), yield 19%; one
4-aMHHo-N- (2,6-dimethylphenyl) -1- - (1-methylethyl) 4-piperidinecarboxamide. m.p. 103 ° C (compound 188), yield 32%;
W- (2,6-dimethylphenyl) -4- (ethylamino) -} - (1-methylethyl) -4-piperidinecarbox-45 amide, m.p. (compound 189), yield 18%;
4-amino-1-cyclopentyl-N- (2,6-dith. Mp. 130, (compound 192), yield 15%;
1 - 3- (diethylamino) -2-hydroxypro- (dimethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide. m.p. 113, (compound 193), yield 12%;
4- (dimethylamino) -N- (2,6-dimetylphenyl) -1- (1,4,5,6-tetrahydro-2-pyrimidinyl) -4-piperidinecarboxamide, m.p. 238, (compound 194), yield 4.5%
4- (dimethylamino) -N- (2,6-dimethylphenyl) -1 - (2-hydroxy-1-methyl-2-phenyl ethyl) -4-piperidinecarboxampd, mp. 185, (compound 195), yield 18%;
trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) -1- (4-hydroxycyclohexyl) -4-piperidinecarboxamide, m.p. 84.2 ° C (compound 196), yield 17%;
cis-4- (dimethylamino) -N- (2,6-dime-20 tylphenyl) -1- (4-hydroxycyclohexyl) -4-piperidinecarboxamide. m.p. 215 C (compound 197), yield 14%;
4- (dimethylamino) (2,4-dihydr-25 hydroxybutyl) -N- (2,6-dimethylphenyl) -4-pi peridinecarboxamide. m.p. 157 C (compound 198), yield 6%;
1- (2,4-dihydroxy-2-methylbutyl) -4- (dimethylamino) -N- (2,6-dimethylphe-30-nyl) -4-piperidinecarboxamide, m.p. 163 C (compound 199), yield 2%;
() -l- (lQ, 2/3, 5) -1- (2,5-dihydroxycyclohexyl) -4- (dimethylamino) -N - (2,6-dimethylphenyl) -4-piperidinecarboxamide. m.p. 188.5 C (compound
40
(i) (lq, 2,5a) J 1- (2,5-dihydroxycyclohexyl) -4-dimethylaminr- -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 187 C (compound 201), yield 11%;
(jt) (a, 2p, 4a) -1 - (2,4-dihyd roxycyclohexyl) -4-dimethylamino-N- - (2,6-dimethylphenyl) -4-piperidinecarboxamide. m.p. 21. C (compound 202), yield 14%;
TRANS-2-C4- (dimethylamino) -4-, (2,6-dimethylphenyl) aminocarbonyl -1
methylphenyl) -4-piperidinecarboxamide, - -
m.p. 124 ° C (compound 190), yield 50-piperidinyl cyclohexyl propanoate 22%;
1- (3-amino-2-hydroxypropyl) -4- - (dimethylamino) -N- (2,6-dimethylphenyl-4-piperidinecarboxamide. Mp 156.2 ° C (compound 19C yield 1.5% ; 55
4- (dimethylamino) -N- (2,6-dimethyl-phenyl) -1- (2-hydroxy-3- (phenylmethyl)
m.p. 174.3 ° C (compound 203), 2%;
trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) -1- (2-hydroxy-1-cyclohexyl-4-piperidinecarboxamide acetate ester) so pl. 168.5 ° C (compound 204), yield 2.5%;
trans- 2-4- (dimethylamino) -4- (2,
  t
h saw cut / 1 f. 1 and / l - l-n - 1 LycnnjiMciiuiy grai - i-L amini; -Ch-l
aminoZPropyl-4-piperidinecarboxamide, -dimethylLenyl) aminocarbonylZ-pipe10
15
. - five
-
-
31334424
m.p. 130, (compound 192), yield 15%;
1 - 3- (diethylamino) -2-hydroxypro- (dimethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide. m.p. 113, (compound 193), yield 12%;
4- (dimethylamino) -N- (2,6-dimetylphenyl) -1- (1,4,5,6-tetrahydro-2-pyrimidinyl) -4-piperidinecarboxamide, m.p. 238, (compound 194), yield 4.5%;
4- (dimethylamino) -N- (2,6-dimethylphenyl) -1 - (2-hydroxy-1-methyl-2-phenylethyl) -4-piperidinecarboxampd, mp. 185, (compound 195), yield 18%;
trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) -1- (4-hydroxycyclohexyl) -4-piperidinecarboxamide, m.p. 84.2 ° C (compound 196), yield 17%;
cis-4- (dimethylamino) -N- (2,6-dime-20 tylphenyl) -1- (4-hydroxycyclohexyl) -4-piperidinecarboxamide. m.p. 215 C (compound 197), yield 14%;
. 200J, yield 5%;
4- (dimethylamino) (2,4-dihydr-hydroxybutyl) -N- (2,6-dimethylphenyl) -4-pyperidinecarboxamide. m.p. 157 C (compound 198), yield 6%;
1- (2,4-dihydroxy-2-methylbutyl) -4- (dimethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 163 C (compound 199), yield 2%;
() -l- (lQ, 2/3, 5) -1- (2,5-dihydroxycyclohexyl) -4- (dimethylamino) -N- - (2,6-dimethylphenyl) -4-piperidinecarboxamide. m.p. 188.5 C (compound
(i) (lq, 2,5a) J 1- (2,5-dihydroxycyclohexyl) -4-dimethylaminr- -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 187 C (compound 201), yield 11%;
(jt) (a, 2p, 4a) -1 - (2,4-dihydroxycyclohexyl) -4-dimethylamino-N- - (2,6-dimethylphenyl) -4-piperidinecarboxamide. m.p. 21. C (compound 202), yield 14%;
TRANS-2-C4- (dimethylamino) -4-, (2,6-dimethylphenyl) aminocarbonyl -1- -
-piperidinyl cyclohexyl propanoate
-piperidinyl cyclohexyl propanoate
m.p. 174.3 ° C (compound 203), yield 2%;
trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) -1- (2-hydroxy-ester-cyclohexyl) -4-piperidinecarboxamide acetate ester) so pl. 168.5 ° C (compound 204), yield 2.5%;
trans- 2-4- (dimethylamino) -4- (2.6 t
  i-L amini; -Ch-l
-dimethylLenyl) aminocarbonylZ-pipe2513
Ridinyl cyclohexyl} bezozoate, m.pg (compound 205), 4% yield;
() - 2- 4-dimethylamino) -4- (2,6-dimethylphenyl) aminocarbonyl -1-piperidinyl3 cyclohexyl -o6 methoxy- - (trifluoromethyl) benzyl acetate, mp, 190 ° С (compound 206), yield 2%;
(B) dimethylamino) -dimethylphenyl) aminocarbonyl -1-piperidinyl cyclohexyl-th-methoxy-l i- -Frifluoromethyl) benzyl acetate, so pl. 176.7 ° C (compound 207), yield 2%;
(A +) (dimethylamino) -4-G (256-dimethylphenyl) aminocarbonyl -1-piperidinyl cyclohexyl-C-methoxy -, - - (trifluoromethyl) benzyl acetate, m.p. 200 C. (compound 208), yield 2%;
(B -) - 2-C4 (dimethylamino) -4- (2, -dimethylLenyl) aminocarbonyl -1 - piperidinyl cyclohexyl-D-c-methoxy-O- - (trifluoromethyl) benzyl acetate, t, mp, 176 C (compound 209), yield 2%;
TRANS-4 (dimethylamine) -G1- (2, b-dimethylphenyl) -3-hydroxy- (., 4-bipiperidine) -4 carboxamide. t, pl. 166.6 ° C (compound 210), yield 4.5%;
trans-4- (dimethylamino) -1 (2b-dimethyl) enyl) -4 -hydroxy- (1, 3 -bigshperidine) -4-carboxamide, t, mp, 180.6 C (compound 211) , yield 1.5%
Example 22 To an intermixed solution of 14.16 parts of 4-chloro-2-methylbenzylamine in 135 parts of tetrahydrofusion, 3,, 65 hours, in portions, are added in portions, 65 liters, and aykdas under reflux. After the addition is complete - stirring is continued :: for 2 hours at reflux temperature. After cooling at room temperature, a solution of 14.92 h, ethyl trans-4- (dimethyl-amino) - (2-hydroxycyclohexyl) -4- -piperidine carboxylate in 45 h THF is added dropwise, after THF. Stirring is continued for 3 hours at reflux temperature and overnight at room temperature. Carefully add 50 h, water n then 200 h, water. The product dvg / kdy is extracted with dichloromethane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography on a column of silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The second fraction is collected and
426
the eluent is evaporated. The residue is recrystallized from 2,2-oxybispropane. The product is filtered off and dried to form 5.8 parts (29%) of trans-K- (4 chloro-2-methylphenyl) -4- (dimethyl-amino) -1-g (2-hydroxycyclohexyl) -4- -piperidinecarboxamide m.p. 127.7 ° C (compound 257), yield 29%. Following the same procedure and using equivalent amounts of the corresponding starting materials, the following substances are obtained:
trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) -1- (2-hydroxycyclohexn-1 -4-piperidinecarboxamide, mp, 165.5 ° C (compound 89), yield 9%;
tras-4- (dimethylamino) -1- (2-hydroxycyclohexyl) -N- (4-methoxy-2-metophenyl) -B-methyl-4-piperidinecarboxamide, mp 133.5 ° С (compound 126), yield 11%;
trans-H1- (2 of 6-dimethylphenyl) -1- (2- -hydroxycyclohexyl) -4- (4-morpholyl) -4 piperidinecarboxamide, m.p.
242 C (compound 127);
tr an with-4- (dimethylamino) -ZH- (2,6-dimethylphenyl) (phenylmethyl) -amino cyclohex-3-4-piperidinecarboxamide, t „pl„ 157, (compound 128), yield 23%;
trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) (phenylmethyl) amino piclodenyl-4-piperidinecarboxamide, m.p. 101 C (compound 129), output
thirty%;
1-cyclopentyl-4 (, in the case of thyl amino) -N- (2 5 6-dimethylphenyl) -4-piperidinecarb-oxamide, m.p. 175.2 C (compound 130), yield 31%;
4 (acetylmethylamino) (2,6-dimethylphenyl) -1- (1-methylethyl) -4-piperidinecarboxamide, m.p. 187.5 ° C (compound 157), yield 39.5%; 4- (dimethylamino) -C- (2, b-dimethylphenyl) (3 methylcyclohexyl) -4-piperidinecarboxamide, mp, 173.8 ° C (compound 158), yield 44%;
4- (dimethylamino) -N- (2,6-dimethylphenyl) (3-oxo-1 cyclohexenyl) -4-piperidinecarboxamide, m.p. 270 ° C (compound 159) yield 12%;
(dimethylamino) -H- (2,6-dimethylphenyl) (3-hydroxycyclohexyl). -4-piperidinecarboxamide, m.p.
147.9 C (compound 60), yield 8.5% j trans-4- (dimethylamino) -N- (2,6-dietilfeni.p) -1 - (3-hydroxycyclohexyl),
2713
-A-pilyridinic carboxamide, mp, 219.4 ° C (compound 161), 9% code;
4- (dimethylamino) -I- (2,6-dimethylphenyl) -1 - (2-propenyl) -A-piperidine-carboxamide, mp, 144.5 C (compound 162), yield 43.8% ;
1- (2-diethylamino) -ethyl-4- (di-methyl amine) -N- (2,6-dimethylphenyl) -4- -piperidinecarboxamide, mp. 97, (compound 163), yield 25%;
N- (2,6-dimethylphenyl) -1 - (1-methyl-ethyl) -4- (phenylmethyl) amino-4-niperi din carboxamide, m.p. 152.5 C (compound 164), yield 60%;
(-cyclopentyl -N- (2,6-dimethylphenyl-4- (phenylmethyl} amino-4-piperidine-carboxamide, m.p. 171.5 C (compound 165), yield 65%;
N- (5-chloro-2-methylphenyl) -1-cyclopentyl-4- (diethylamino) -4-piperidine-carboxamide dihydrochloride hemihydrate so pl. 201.2 C (compound 166), yield 30%;
4- (dimetylamino) -N- (2,6-dimethylphenyl) -1- (2-hydroxyethyl) -4-piperidinecarboxamide, m.p. 167 C (compound. 167), yield 12%;
trans-1- (2-diethylamino) methyl (cyclohexyl) -4- (dimethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide, e.g. 144.5-147.2 ° C (compound 168), yield 17%;
4- (dimethylamino) -N- (2,6-dimetylphenyl) -1- (2-pyrimindinyl) -4-piperidine carboxamide, m.p. 160.5 C (compound 169), yield 61%;
4- (dimethylamino) -H- (2,6-dimethylphenyl) 2- (1-piperidinyl) -piperidinecarboxamide. mp, 144.5 ° C (compound 170), yield 38%;
(diethylamino) -2-methylethyl- -4- (dimethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 121.4 ° C (compound 171), yield 24%;
4- (dimethylamino) -N- (2,6-dimethylphenyl) -1-2-oxo-2- (1-piperidinyl) -ethyl3-4-piperidinecarboxamide, m.p. 160 ° C (compound 172), yield 50%;
N- (2,6-dimethylphenyl) -4- (ethylmethylamino) (-phenylethyl) -4-piperidinecarboxamide, m.p. 183 C (compound 173), yield 39.5%;
4- (2,6-dimethylphenyl) aminocarbonyl-4- (ethylmethyl amino) -CC-methyl-1 - -piperidine acetamide, m.p. 214.5 C (compound 174), yield 23.4%;
4- (diethylamino) -N- (2,6-dimethylphenyl) (- oxopropyl) -4-piperidine428
carboxamide. m.p. 154.1 ° C (compound 175), yield 69.5%;
4- (dimethylamino) -N- (2,6-dimethylphenyl) -1- (1-phenylethyl) -4-piperidinecarboxamide. m.p. 183.3 C (compound 176), yield 26%;
4- (diethylamino) -N- (2,6-dimethylphenyl) (3,4,5-trimethoxybenzoyl) -4- -piperidinecarboxamide, m.p. 197.5 C
(compound 177), yield 51%;
4- (dimethylamino) -N- (2,6-dimethylphenyl) -1 (phenylamino) ethyl -4-pyridine carboxamide. m.p. 157 C (compound 178), yield 25%;
- (1-benzoylethyl) -4- (dimethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide. m.p. 163 C (compound 179), yield 66%;
4- (dimethylamino) -N- (2,6-dimethylphenyl) -4- (2,6-dimethylphenyl) amino-carbonyl -1-piperidine ietamide, m.p. 202.7 C (compound 180), yield 26%;
4- (dimethylamino) -N- (2,6-dimethylphenyl) -1- (3-phenyl-2-propenyl) -4-pi-. peridinocarboxamide, m.p. 155.5 ° C (compound 181), yield 35.7%;
4- (dimethylamino) -N- (2,6-dimethylphenyl) aminocarbonylZ-1-piperidinetamide, m.p. 241.7 s (compound 182) yield 39%;
trans-4- (dimethylamino) -4- (2,6-dimethylphenyl) aminocarboyl -N- (2- -hydroxycyclohexyl) -1-piperidine acetamide monohydrate, mp. 171, (compound 183) yield 11%;
4- (dime tilamino) -N- (2,6-dime typhenyl) -1- (3-phenylpropyl) -4-piperidinecarboxamide, m.p. 107.5 ° C (compound 184), yield 15%;
1- (cyclohexylcarbonyl) -4- (dimethylamino) -N- (2,6-dimethylphenyl) -4- -piperidinecarboxamide, m.p. 175.5 ° C (compound 185), yield 61%;
ethyl 4- (dimethylamino) -4- (2,6-dimethylphenyl) aminocarbonyl -1-piperidine acetate, m.p. 127.5 ° C (compound 186), yield 50.6%;
TRANS-4- (dimethylamino) -N- (2,6-dimethylphenyl) -ethyl-4-hydroxy- - (1,3-bipiperidine) -4-carboxamide, T.Sh1. 173.3 ° C (compound 212), yield 14%;
4- (dimethylamino) -N- (2,6-dimethylphenyl) -1 -3sht1- (1,4-bipiperidine) -4-carboxamide, m.p. 147, Z C (compound 213), yield 41%;
29
13
trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) -ethyl-3-hydroxy- - (1,4-bipiperidine) -4-carboxamide, m.p. (compound 214), yield 16%;
Cis-4- (dimethylamino) -N- (2 ,, 6-dimethylphenyl) -ethyl-3-methoxy- (1,4 - -gigperidine) -4-carboxamide, mp, 156.5 C ( compound 215), yield 19.7%;
trans-1- (2-aminocyclohexyl) -4- - (dimethyl amino) -N- (2,6-dimetylphenyl-4-piperidinecarboxamide, mp 168.3 ° C (compound 216), yield 2 %;
trans-1- (2-aminocyclopentyl) -4- - (dimethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 131, C (compound 2 17), yield 1%;
trans-1- 2- (acetylamino) cyclohex- (dimethylamino) -ZH- (2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 275.3 ° C (compound 218), yield 30%;
TRANS-1- 2- (acetylamino) cyclopent-A- (dimethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide, mp. 199, (compound 219), yield 33%;
trans-4- (dimethyl n is shno) -N- (2,6-dimethylfeil) -1-2-C (methylsulfonyl) aMHHoJ cyclohexyl -4-piperidinecarboxamide, m.p. 234, (compound 220), yield 41%;
ethyl trans- (2- 4- (dimethylamino) -4- (2,6-dimethylphenyl) aminocarbonyl-1-piperidinyl-Zcyclohexyl carbamate, mp 243.7 ° C (compound 221), output- 39% ;
trans-4- (dimethylamino) (2,6-dimethylphenyl) (1-oceanopropyl) amino cyclohexyl -4-piperidinecarboxamide; m.p. 268.7 C (compound 222), yield 31%;
trans-1-12- (benzoylamino) cyclohex (dimethylamino) -N- (2,6-dimethylphenyl) 4-piperidinecar 3 oxy amide, m.p. 250 C (compound 223), yield 34%;
trans-1- 2- (aminocarbonyl) amino cyclohexyl -4- (dimethylamino) -N- (2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 243 C (compound 224), yield 18%;
trans-4- (dimethylamino) -N- (2,6-dimetylfenyl) -1 - {2- t (2-hydroxyethyl) phenylmethyl-amino-cyclopentyl) -4-piperidinecarboxamide, m.p. 161.4 C (compound 225), yield 4.5%;
trans-4- (dimethylamino) (dimethylamino) -cyclohexyl-H- (2,6-dimethylphenyl) -4-1 Shperidine carboxamide,













four
thirty
m.p. 170, (compound 226), yield 40%;
trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) -1 (methylamino) -cyclohexyl -4-piperidinecarboxamide, m.p. 188.4 C (compound 229), yield 7%;
trans-4- (dimethylamino) -N- (2,6-dimethylphenyl) -1-2- (ethylamino) -cyclohexyl3-4-pip.ridin carboxamide, mp, 176.1 C (compound 230), yield 8%;
trans-4- (dimethyl amino) -N- (2,6-dimethylphenyl) (2-hydroxyethyl) amino cyclohexyl -4-piperidinecarboxamide, so pl. 168.9 ° C (compound 231), vpsod 16%;
(phenylmethyl) -3- (2,6-dimethylphenyl amine 11ocarbonyl | -3- (methyl amino) -1-pyridinecarboxylate, mp 107.6 ° C (compound 239), yield 82%;
trans-3- (dimethylamino) -N- (2,6-di methylphenyl) -1- (2-hydroxycyclohexyl -3-piperidinecarboxamide, mp. 170, 4 ° C (compound 242), yield 11%;
-cyanomethyl-4- (dimethylamino) -N- - (2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 193.3 ° C (compound 250), yield 69.2%;
1- (2-aminoethyl) -4- (dimethylamino) -N-2 (2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 162.6 ° C (compound 251), yield 1%;
trans-4- (dimethylamino) -N- (2,6-di-methyl-phenyl) -1-1.2-c 2-hydroxycyclohexyl) a; mino-ethyl-4-piperidinecarboxamide, m.p. 141.8 C (compound 252), yield 14%;
trans-4- (dimethylamino) -1- (2-hydroxycyclohexyl) -N- (4-hydroxy-2,6-dimethylphenyl) -4-piperidinecarboxamide, m.p. 207, (compound 254), yield 9.5%;
N- (4-bromo-2,6-dimethylphenyl) -4- - (dimethylamino) -1 - (phenylmethyl) -4-piperidinecarboxamide, m.p. 189, (compound 255), yield 48%;
ethyl 4- (4-bromo-2,6-dimethylphenyl) aminocarbonyl-4- (dimethylamino) -1- piperidinecarboxylate, m.p. 135, (compound 256), yield 41%;
N- (4-6poM-2,6-dimethylphenyl) -4- (dimetylamino) -4-piperidinecarboxamide, m.p. 144.9 ° C (compound 258), yield 2%;
trans-N- (2,4-dichlorofensh1) -4-dimethylamino) -1- (2-hydroxycyclohexyl) 31131334432
salts and their possible stereochemical isomeric forms exhibit excellent antiarrhythmic properties and as such are valuable means for normalizing disturbed heart rhythms. Antiarrhythmic effect of the proposed compounds is studied in an experiment conducted on dogs. The experiment was carried out with neuroleptanalgesia (1 ml per 10 kg of live weight) fentanyl (0.4 mg / ml) and droperidol (20 mg / ml). Sixteen hours after the ligature was applied to the anterior 262), the yield was 20.4% of the descending branch of the left co4- (dimethylamino) -I- (4-fluoro-2,6-di- -5 ronary artery in dogs, revealing methylphenyl) -4 piperidinecarboxamide, multifocal gastric arrhythm. m. 187 ° C (compound 263), yields.
3%; Test compounds are administered intra-4- (dimethylamino) -M- (4-fluorotinated after the control period
-2,6-dimethylphenyl) -1- (2-hydroxycyc- 30 minutes. Minimal effective up to-4-piperidinecarboxamide, so pl.
112, (compound 259), yield 12%;
trans-N- (2,5-dichlorophenyl) -4- (dimethylamino) -1- (2-hydroxycyclohexyl) -4-piperidinecarboxamide, m.p. 129 C 5 (compound 260), yield 9%;
trans-N- (4-bromo-2,6-dimethylphenyl) -4- (dimethylamino) -1- (2-hydroxycyclohexyl) -4-piperidinecarboxamide, m.p. 197.5 ° C (compound 261), yield 14%; 0
4- (dimethylamino) -W- (4-fluoro-2,6-dimethylphenyl) -1- (Lenylmethyl) -4-piperidinecarboxamide, m.p. 114 ° C (comp. 25
logexyl) -4-piperidinecarboxamide, mp, .150.0 C (compound 264), yield 11%;
trans-N- (2-chloro-5-methylphenyl) -4- - (dimethylamino) -1- (2-hydroxycyclohexyl) -4-piperidinecarboxamide, m.p. 100.2 ° C (compound 265), yield 14%;
trans-4- (dimethylamino -N- (4-fluoro--2,6-dimethylphenyl) -1- (2-hydroxycyclohexyl) -4-piperidinecarboxamide, mp 156.8 ° C (compound 266), yield 19 %;
trans-4- (dimethylamino) -N- (4-fluoro-2-metsh1phenyl) -1- (2-hydroxycyclohexyl) -4-piperidinecarboxamide., so pl. 35 123.6 ° C (compound 267), yield 10%;
TpaHC-N -. (5-chloro-4-fluoro-2-methylphenyl) -4- (dimethylamino) -1- (2-hydroxy-cyclohexyl) -4-piperidinecarboxamide,
thirty
for, it is capable of causing a normal heart rhythm, a significant decrease in the number of extrasystoles and an increase in the number of normal beats, as well as the duration of the effect of the compound at the specified minimum effective dose (ODP in mg / kg of live weight) are given in Table. 4-6.
Due to their active ability to normalize heart rhythm disturbances, the compounds proposed are advantageously used as antiarrhythmic agents.
The proposed compounds can be prepared in various pharmaceutical forms, for which an effective amount of a specific compound as a base or acid addition salt as active
mp, 167.9 ° C (compound 268), yield O and the redients are thoroughly mixed with ° 5 pharmaceutically acceptable carrier,
trans-N- (2-chloro-4-fluoro-5-methylfe- that can be in a wide variety of nyls) -. 4- (dimethylamino) -1- (2-hydroxy-forms, depending on the
the form of the preparation to be administered, with the indicated amount being an amount effective to normalize the disturbance of the heart rhythms.
Such pharmaceutical compositions are preferably formulated in a single dosage form, preferably for oral, rectal or parenteral administration. When preparing the compositions in the form of oral dosages, the substances mentioned in use any of the usual Tablets 1-3, pharmaceutical media, such as water,
The compounds of formula I are their pharmacids, glycols, oils, alcohols, and the like. for acceptable acid-additive preparations of liquid preparations, precyclohexyl) -4-piperidinecarboxamide, m.p. 120, (compound 269), yield 20%;
trans-4- (dimethylamino) -1- (2-hydroxycyclohexyl) -N- (3-hydroxy-2,6-dimethylphenyl) -4-piperidinecarboxamide
monohydrate, so pl. 174.2 ° C (compounds,), yield 18%.
Example 23. Following the procedure described in Example 22 and using the appropriate starting mothers.
for, it is capable of causing a normal heart rhythm, a significant decrease in the number of extrasystoles and an increase in the number of normal beats, as well as the duration of the effect of the compound at the specified minimum effective dose (ODP in mg / kg of live weight) are given in Table. 4-6.
Due to their active ability to normalize heart rhythm disturbances, the compounds proposed are advantageously used as antiarrhythmic agents.
The proposed compounds can be prepared in various pharmaceutical forms, for which an effective amount of a specific compound as a base or acid addition salt as active
Yes redients are thoroughly mixed with a pharmaceutically acceptable carrier,
appointed for oral administration, for example, suspensions, syrups, elixirs and solutions; or solid carriers, for example, starches, sugars, lubricants, binding agents, dispersing agents and the like. for preparing powders, pills, capsules and tablets,
In connection with the ease of administration, tablets and capsules are the most preferred oral single dose forms. Of course, solid pharmaceutical carriers are used in these cases. Dp of the parenteral composition, the carrier usually contains sterilized water, although other ingredients may be prepared, for example, in which the carrier includes saline solution, glucose solution or a solution of a mixture of salt and glucose. Injection solutions can also be prepared. In this case, suitable liquid carriers, suspending agents and the like can be identified. The salts of formula I are more suitable for the preparation of aqueous compositions due to their greater water solubility than the corresponding bases.
It is especially preferable to formulate these pharmaceutical compositions in a single dosage form in order to facilitate the administration and achieve uniform dosage. The single dosage form refers to physically discrete units, suitable, for use as a unit dose, each unit containing a predetermined amount of active ingredient calculated on the required therapeutic dose.
action in combination with the required pharmaceutical carrier.
Examples of such single dosage forms are tablets (including tablets with incisions and coatings), capsules, pills, powders, wafers, solutions or suspensions for injection and t, p., As well as individual quantities of them.
The amount of active ingredient per single dose is 0.25-100 mg, preferably 0.5-20 mg.
The following typical compositions can be prepared for the normalization of cardiac abnormalities: rhythms in the form of a single dosage, suitable
systematic administration to animals and humans.
Drops for oral administration. The composition is designed for 50 liters of solution for oral administration dropwise, containing 10 mg of the active ingredient - 4- (dimethylamino) (2,6-dimethylphenyl) -1- (2-hydroxycyclohexyl) -4-piperidinecarboxamide per I ml:
Active ingredient, g 500 2-hydroxypropanoic acid, l0.5 Saccharin sodium, g 1750 cocoa flavor, l2.5 Purified water, l 2.5 Polyethylene glycol, l Up to 50 The active ingredient is dissolved in 2-hydroxypropanoic acid and 1.5 l of polyethylene glycol at 60-80 ° C. After cooling to 30-40 seconds, 35 l of polyethylene glycol is added to the solution and the mixture is thoroughly mixed. A solution of sodium saccharin in 2.5 liters of purified water is then added and, with stirring, cocoa flavoring and polyethylene are added to the desired volume. The resulting solution is poured into containers.
Injection solution. The composition is designed for a 20 l parenteral solution containing 2 mg of the active ingredient - 4- (dimethyl-amino) -N- (2,6-dimethylphenyl) -1- (2-hydroxycyclohexyl) -4-cyperidinecarboxamide per 1 ml :
Active ingredient, g 40 2,3-dioxybutane dicarboxylic acid, g 20 Methyl 4-hydroxybenzoate, g 36 Propyl 4-hydroxybenzoate, g 4 Water for injection, l Up to 20 4 oxybenzoate methyl and propyl dissolved in approximately 10 liters boiling water W1. injection. After cooling to 50 ° C, 2,3-dioxybutane dicarboxylic acid is added with stirring and then the active ingredient. The solution is cooled to room temperature and water is added for injection to the desired volume. The solution is sterilized by filtration (USP) XVII, p. 811) and poured into sterile containers. Solution for oral administration. The composition is designed for 20 liters of oral solution containing 5 mg of the active ingredient - 4- (dime35131
ylamino) -N- (2, .6-dimethylphenyl) -l- (2- oxycyclohexyl) -4-piperidinecarboxyme 1 tbsp (5 ml): Active ingredient, g 20 2,3-Dioxybutanecarboxylic acid, r10
Saccharin sodium, g40
1,2,3-Propantriol, l 12 70% solution of sorbitol, l3 Methyl-4 oxybenzoate, g 9 Propsh1-4-hydroxybenzoate, g 1 Malinova Essenzi, ml 2 Essenti gooseberry, ml 2 Purified water, l Up to 20 4 The methyl and nitro oxibozoates are dissolved in 4 liters of boiling purified water. 2.3 l of dioxybutane dicarboxylic acid is then dissolved in 3 l of this solution, then the active ingredient. The resulting solution is combined with the remaining part of the first solution, and a solution of 1,2,3-propantriol and sorbitol is added to it. Sodium saccharin is dissolved in 0.5 l of water and raspberry essence and gooseberry essence are added. The latter solution is combined with the first, water is added to the desired volume and the resulting solution is poured into containers.
Tablets with a film coating. 10,000 compressed tablets containing 10 mg of 4- (dimethylamino) -K- - (2,6-dimethylphenyl) -1- (2-hydroxycyclohexyl) -4-piperidinecarboxamide each as an active ingredient are prepared as follows: :
Tablet contents Active ingredient, 100 g Lactose, g570
Starch, g200
Polyvinylpyrrolidone
(Kollidon K 90), hr
Microcrystalline cellulose (Avicell), g 100 Sodium dodecyl sulfate, g 5 Hydrated vegetable oil (Sterotex), g 15
Methylcellulose coating
(Methocell 60 HG), g 10 ethyl cellulose
(Ethocfel 22 spP), g 5 1,2,3-Propantriol, ml 2.5 Polyethylene glycol 6000, g 10 Concentrated dye suspension (Opaspray K-1-2109) MP30
five
five
34436
Polyvinylpyrrolidone (povidone), g5
Magnesium Octadecanoate, g 2.3 Preparation of the contents of the tablet.
The mixture of the active ingredient, lactose and starch is thoroughly mixed and then moistened with a solution of sodium dodecyl sulfate and polyvinylpyrro-lidone with approximately 200 mp of water. The wet powder is sieved, dried and sieved again. The microcrystalline cellulose is then added and the tablets are pressed.
Coating preparation. A solution of methylcellulose in 150 ml of dichloromethane is added to a solution of methylcellulose in 75 ml of denatured ethanol. Then 75 ml of 0 dichloromethane and 1,2,3-propantriol are added. The polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the first one, magnesium octadecanoate, Polyvinylpyrrolidone and the concentrated coloring suspension are added thereto and the mixture is homogenized.
The contents of the tablets are coated with the mixture in a coating device.
Cooking candles. One hundred candles, each containing 3 mg of the active ingredient 4- (di-methylamino) -N- (2,6-dimethylphenyl) -1-5 - (hydroxycyclohexyl) -4 piperidine carbox amide, prepared from the following composition :
Active ingredient, g 0,3 2,3-Dioxybutane carboxylic acid, g 3 Polyethylene glycol 400, ml 25
Surfactant (Spau) g 12 Triglycerides (Witersol 555), up to 300
The active ingredient is dissolved in a solution of 2,3-dioxybutane dicarboxylic acid in polyethylene glycol 400. At the same time, the surfactant and the black glycerides are melted. This mixture is thoroughly mixed with the first solution. The mixture thus obtained is poured into molds at 37-38 ° C to form candles.
Normalization of heart rhythms in patients suffering from disorders of the mark
0
five
3713
Transitional regimes are facilitated by the systematic introduction of an effective amount of at least one compound of formula I, its acid-additive salt, or its stereochemically isomeric form1.1 in admixture with a pharmaceutical carrier.
Although the amount of active ingredient to be taken may vary over a wide range depending on the specific circumstances, daily doses of from 0.005 to about 1 mg / kg of live weight when administered once or repeatedly taken are usually sufficient.
 The data table. 7 reflect the structural features of the known and proposed compounds. The procedures for preparing these compounds are similar to those described.
Toxicity data Trans-4- (Dimethylamino) -N- (2,6-dimethylphenyl) -1 - (2-hydroxycyclohexyl) -4- -piperidinecarboxamide is administered in various doses orally or intravenously to dogs or rats. The LDzo value is defined as the dose at which 50% of animals die, mg / kg. Rat body weight (intravenously) 0.61 Rats (oral) 5.35
Dogs (intravenously) 0.58 Dogs (orally) 4.15 Thus, a method has been proposed for the preparation of compounds of formula I possessing valuable pharmacological properties.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining N-aryl-about-amino-carboxamides of the general formula
About R ./Cn,H,
L --- N
Y CnHan- N-R2
--nii n
R:
50
de type - an integer equal to 1 2 or 3, and the type is equal to 4 and one hydrogen atom in the radical C Hj can be replaced by a lower alkyl or lower alkoxy group; R is hydrogen or lower al; - kil;
O
(five
344
five
0
five
thirty
35
40
45
50
,,
38
R is hydrogen, lower alkyl, acetyl or benzyl;
K „- hydrogen or lower alkyl, or P. 2 and RJ together with the nitrogen atom form a morpholino ring;
Ar - unsubstituted phenyl, phenyl with one substituent, such as 2-lower
alkoxy or 3-trifluoromethyl, phenyl with two substituents, such as lower alkyl, lower alkoxy or halogen; phenyl with three substituents, such as lower alkyl, hydroxyl, lower alkoxy, halogen, di (lower; alkyl) amino group, and one of the substituents is necessarily lower alkyl;
L is hydrogen, (oxy) (phenyl) lower alkyl, lower alkyl, which may be substituted by phenyl, cyclopropyl, diclopentyl, hydroxyl, lower alkoxy, phenoxy, phenylcarbonyl, piperidinylcarbonyl. lower alkoxycarbonyl, aminocarbonyl, cyano,. amino group, di-lower alkyl) -amino group, phenylamino group, dibenoylamino group, (2,6-dimethylphenyl) aminocarbonyl, (2-hydroxycyclohexyl) aminocarbonyl, (2-hydroxycyclohexane 1) amine-nogroup, 1 - scrap, 2-propenyl, 3-phenyl-2-propenyl, cyclopentyl, which may be substituted in position 2 with hydroxyl, amino, acetylamino, benzylamino, (hydroxy-lower alkyl) amino (benzyl) (hydroxy-lower alkyl) amino group, (lower alkyloxycarbonyl) lower alkyl,. cyclohexyl, which can be mixed with two
radicals selected from the groups including lower alkyl, (di-lower acylamino lower alkyl, a radical of the formula - OR, where R is hydrogen, lower alkyl or benzyl,
radical formula - OCR ..
II Oh
where Ry is lower alkyl, phenyl, or (methoxy) (phenyl) (trifluoromethyl) methyl, a radical of the formula —NCRJ, where Pg is lower alkyl, a radical of the formula —INB where 1 is hydrogen, lower alkyl, lower alkylsulfonyl or benzyl, a radical of the formula - NHCRg, where Rg is the lowest
ABOUT;
alkyl, phenyl, amino. a group, or a lower alkyloxy group,
whether L is a radical of the formula CRo,
11 o
where RO is lower alkyl, lower alkyloxy, benzyloxy, 3,4,5-trimethoxyphenyl or cyclohexyl, or L is a radical of the formula
6
R.
L
hydrogen, lower alkyl or. lower alkyloxycarbonyl; 40 hydrogen, hydroxy or lower alkyloxy, radical of formula
he
 GH2 C - CH2Ri2
Ri3
R
g
R l
1b
oxymethyl, benzyloxymethyl, hydroxy, 4-halo-phenoxy, amino, di-lower alkylamino, benzyl-amino, or dibenzylamino; hydrogen or lower alkyl, 2-pyrimidinyl, 1,3-dihydro-2H-inden-2-yl, tetra
hydro-4H-pyran, 4-yl, 3-oxo-1-cyclohexenyl, 1,4,5,6-tetrahydro-2-pyrimidinyl,
or their salts with a pharmaceutically acceptable acid or a possible stereochemical isomeric form, characterized by the fact that the corresponding acid of the general formula
About 1 / 2t / C - OS2K5
SpNgp / -H-i Nz
where R, R, Lmin have the indicated values
subjected to interaction with the amine of the General formula
Hn-ar
four
0
five
0,
five
0
five
where R, and Ar have the indicated meanings, in a medium of 1,1-oxybis-tan or tetrahydrofuran in the presence of 1-lithium butane in a nitrogen atmosphere with cooling, or in a medium of tetrahydrofuran in the presence of sodium hydride or lithium amide with the release of the desired product in free form, in the form of a salt with a pharmaceutically acceptable acid or in stereochemically isomeric form.
The priority is as follows: 11.04.83 - m and p is an integer equal to 1, 2 or 3, with th and m and n being equal to 4, and one hydrogen atom in radical С Н may be substituted by lower alkyl or lower alkoxy group, n is hydrogen or lower alkyl; B is hydrogen, lower alkyl, acetyl or
benzyl, R, is hydrogen or lower al- - -.
kil; or R D together with the nitrogen atom form a morpholino ring; Ar is unsubstituted phenyl, phenyl with two or three substituents, such as lower alkyl or halogen, with one of the substituents lower alkyl; L.- hydrogen, lower alkyl, which can be substituted by phenyl, cyclopropyl, hydroxyl, lower alkoxyl, phenyl, phenylcarbonyl,. piperidinecarbonyl, lower alkoxycarbonyl, aminocarbonyl, cyano group, amine, di- (lower alkyl)
Al13
dibenoylamine (2,6-dimethylphenyl) aminocarbonyl, (2-hydroxycyclohexyl) amino group, 2-propenyl; 3-yenyl-2-propenyl; cyclopentyl, which may be substituted in position 2 — by hydroxyl, amino, acetylamino, cyclohexyl, which may be replaced by two radicals selected from. groups including lower alkyl (di-lower alkylamines lower alkyl, a radical of the formula Oli ,, e Pd is hydrogen, lower alkyl or benzyl, a radical of the formula OCRj, where Rj O
lower alkyl, NHK, where R is hydrogen, lower alkyl, or pa, is a cyclic formula of formula, where Rg is lower alkyl, lower
ABOUT
Aluchoxy, benzyloxy, 3,4,5-trimethoxyphenyl or cyclohexyl, or L is a radical of the formula:
T.
N hio
where B iQ is hydrogen, lower papkyl or lower alkyloxycarbonyl, R is hydrogen, hydroxyl or apkyl oxyl;
21 „02.84 - with a type - an integer equal to 1, 2 or 3, moreover, the sum of the type is 4 and one hydrogen atom in the radical can be mixed with a lower alkyl or lower alkoxy group; RI is hydrogen or lower alkyl; R, j - hydrogen, lower alkyl, acetyl
4 42
or benzyl; R, is hydrogen or lower alkyl, or R and ER together with the nitrogen atom form a morpholine ring; Ar is phenyl substituted by one or several groups selected from the following 11 groups: lower alkoxy, trifluoromethyl, hydroxyl, di (lower alkyl) amino group, L - lower alkyl substituted by 1-piperidinyl, cyclopentyl, in position 2 substituted by benzylamino, oxy-lower alkyl-amino, benzyl (oxy-lower alkyl) amino, t lower alkoxycarbonyl) lower alkyl, cyclohexyl,
mixed with two radicals - OCR, P
where Well is phenyl or (methoxy) (phenyl) (trifluoromethyl) methyl, the radical NHR 5 where R- is lower alkylsulfonyl or benzyl, the radical is NHCRg, where
ABOUT
Rg - lower alkyl, phenyl, amino group or lower alkoxygroup, L - radical Aormuly
OH - CH2-C-CH2B12
Neither
where R, j is 4-halo-phenyl, hydroxyl, dibenzylamino, amino, benzylamino (di-lower alkyl) amino, oxymethyl, benzyloxymethyl, R, g. - hydrogen or lower alkyl.
P)
I'm X
t; you rt H
with
Yu
CS1YUO
00
00
00
1L
1L
Gshug 3M # t "I
about ONO Cvl- T
CHO - G ONO About
- --Cvl Сч1
00
CNI
oo
CS1 SG1
"S GO
""
sch
I. t
there about
t
by
and
(P
w and
a: o
"
w and
Wi
S
(P
and
g. and
with
there about
tr,
there about
J l
but:
I j | |
X s
Well
i
Sc |
Och
GP
CTi
CI
ABOUT
but
about
00
(Ti
oh
oh oh
 1313344
and
-and.
50
table 2
-and.
m
About II
C-NH
Ij-ch
I OSH SNY
0-C-C-f 7
II I / o cr
about
Tablipa four
continuation of table 4
1L
cho o
- go
LO 1L CN1 CN
-d
- in
- T5
I MS
U
to
S
Xrt
+ R.
ttc
x i
4D
F
and
w and
a: and
Well
and
s with;
h:
F
about ;
0)
(W o
: O u
C-J
About x
and
(h
about t:
about
Well
cm
oh oh
CN
CTi o - CSJ
- in I I
 + and 13. "
- I CN
f F
and
w and
w and
and
there about
and
P
and
Well
CJ
about
and
Well
U
l
there about
U
 pn
1-1- (
U
Well
Well
Well
Well
about b:
0)
I-, o
i
Before
Well
CN
CN) CM
f
CN
about,
GL
go
with
- g I I
TlLll with.
- I rg
O) to g
U
tJ
U
h: and
I
vO
I with
CN
Zi
and
X
and
n: s
X
with;
about "
ABOUT)
and about R "
S
: j I
about
CVI
oo
m or w sh -
--Y - About go
Ltd
with about
about
fl a
Eo Well m ft
and f
nj ft
about rt ft t
O) x

go
: and
I
emergency
about;
xc
CJ
I
emergency
and
5 o
X
WITH
DC
and
U
h; about
but:
U
CJ
about
uh c
t
-do: and
X
and
sn e;
wasps
X
and
Zy u
h:
d: n:
X
-d- og oj
CN-
00
OL r-sl
to
CNi
G - C -
--TH
OJCNICsJ
65
1313344
ABOUT
L 1 () - 1-С СН2 - Ar Ar
known compound
(sn,) sn
s, n.
sn,
2,6-Dimethylphenyl A-Cl-CgH- 5 (CH,) CH CH, 2.6-Di- 0.16
methylphenyl Same CgHj 5 CH, CH, Same 0.63
CgHj.
Cyclohex
Phenyl
3-Cl-CgH
Compiled by N. Naryshkova. Editor N. Egorov. Tehred I. Popovich Corrector. Shekmar
1983/58
Circulation 372 Subscription VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, F-35, Raushsk nab. 4/5
Production and printing company, Uzhgorod, st. Project, 4
66
Table 7
Have
-Rl
Ro
compound of formula
H-CjH CHj CH,
0.16
Cyclo-CH, CH, - hexyl
0.16

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法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US48402183A| true| 1983-04-11|1983-04-11|

---

US58194884A| true| 1984-02-21|1984-02-21|

---