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    • 专利摘要:
    Novel (1-piperidinylalkyl)pyrimidinone derivatives of the formula …<CHEM>… the pharmaceutically acceptable acid-addition salts and the stereochemically isomeric forms thereof, which compounds are useful in the treatment of psychosomatic disorders; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
    公开号:SU1313349A3
    申请号:SU833656351
    申请日:1983-10-27
    公开日:1987-05-23
    发明作者:Эдмонд Жозефине Кеннис Лудо；Ванденберк Ян；Каролус Мертенс Йозеф
    申请人:Жансен Фармасетика Н.В. (Фирма)；
    IPC主号:
    专利说明:

    eleven
    The invention relates to a method for producing novel (1-pyperi; 5-alkylalkyl) pyrimidino derivatives having biological activity that can be used in medicine.
    The purpose of the invention is a method for producing new derivatives (l-piperidinyl alkyl) pyrimidinone 5 is a specific antagonist to serotonin.
    Obtaining intermediate compounds.
    Example 1. A mixture of 30 parts of 4-ox-2-mercapto-6-methyl-5-pyrimidine-ethanol, 25 hours, potassium carbonate, 270 hours, K, K-dimethyl 11, ethamide and 75 parts of water are stirred at room temperature and at the same time add in one portion 36 h, 1, 3-d1: -1 bromopropasO
    on: temperature rises to bO and. The mixture is stirred overnight at room temperature. Then it is evaporated and water is added to the residue. The solid product is washed with water and dried in vacuo at 00 ° C, 21 h (58%) of 3,4-dihydro-7- (2-hydroxyethyl) -8-methyl-2H, 6H - pyri-dado 2, are obtained. -in LI, 3 -thiazin-6-one, mp, 155 ° C (intermediate 1).
    A mixture of 20 parts of 3,4-dihyd, po-7- (2-oxy ethyl) -8-methyl-2H56H-pyrimide 2, I-BJ LI, 3 thiazin-6-one, 50 parts of acetic acid and 180 h A 67% aqueous solution of hydrobromic acid in acetic acid is heated to reflux temperature with stirring. Stirring is continued overnight at the temperature of reflux. The reaction mixture is evaporated and the solid residue is triturated in 2-propanol. . The product is filtered and dried, get 24 hours (100%) 7- (2-bromoethyl) - 3,4-dihydro-8-methyl-2H, 6H-pyrimido 2,1-V3 LI, 3 thiazin-6-it monobromide, so pl. C (intermediate compound 2),
    Example 2. To a solution of 40 parts of sodium hydroxide in 500 parts of water, 400 hours of 2-propanol is added with stirring. 186.23 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidine ethanol are dissolved in this mixture. The resulting solution is dropwise introduced over a period of 2.66 hours into a stirred and refluxed mixture 210 hours of sodium hydrogencarbonate, 1635 hours of 1,2-dibromoethane and 1600 hours of 2-propanol. Mixed: no
    0
    33492
    continue for 2 hours at reflux temperature. The reaction mixture is cooled to room temperature and the solvent is evaporated. The remaining current is mixed three times with 750 parts of trichloromethane at room temperature. The trichloromethane phases are evaporated and the residue is crystallized from 300 parts of a mixture of trichloromethane and methanol (85:15
    0 volume) and 100 hours of hexane. The product is filtered off, washed with 2,2-oxy-bipropane and dried in vacuum for 3 hours at 60 ° C., 51 parts are obtained. 2, 3-dihydro-6- (2-hydroxyethyl) -7-methyl 5H-thiazolo 3,2 -and pyrimidine-5-she. Ma-. the exact solution is purified by column chromatography on silica gel using a mixture of trichloromethane-methanol (90:10 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is boiled in 50 parts of a mixture of trichloromethane and methanol (85:15 by volume). After addition of 50 parts of hexane, the mixture is stirred at room temperature. The product is filtered off, washed with 2,2-hydroxy-bipropane, dried, yielded 17 parts 2, 3-dihydro-6- (2-hydroxyethyl) -7-methyl 5H-thiazolo 3, 2-a-pyrimidine-5-one. Total yield: 68 parts of 2,3-dihydro-6- (2-hydroxyethyl) -7-methyl-5H-thiazolo 3,2-a pyrimidine-5-one, m.p. 148.7 С
    (intermediate 3).
    J
    In 79.6 hours, 25z-dihydro-6- (2-hydroxyethyl) -7-methyl-5H-thiazolo 3, 2-a pyrimidin-5-one is added dropwise successively 95 parts of acetic acid and 303 parts of a 30% aqueous solution of hydrobromic acid in acetic acid at a temperature below 45 ° C. The mixture is then heated to reflux temperature and stirred for 17.25 hours at reflux temperature. The reaction mixture is cooled to room temperature. The product is filtered off, mixed with 52 parts of 2-propanol. The product is filtered off, washed with 40 parts of 2-propanol, dried under vacuum at 50 ° C. and recrystallized from methanol., 102.3 hours are obtained, 6- (2-bromoethyl) -2,3-di-hydro-7-methyl- 5H-thiazolo W, 2-a pyri-MIDIN-5-OH monobromohydrate, m.p.
    g 237.2 C. (intermediate compound 4). Example 3. A mixture of 50 h, 2-thiazolamine, 76 parts of 3-acetyl-4,5-dihydro-2 (3N) -furan, 1.2 parts of hydrochloric acid concentrate and 270 hours.
    Methylbenzene is stirred and refluxed for 2 hours using a water separator. The reaction mixture is cooled and 340 parts of phosphoryl chloride are added to it at 20–30 ° C. The mixture is slowly heated to 100-1 ° C and stirred for 2 hours at this temperature. The reaction mixture is evaporated and the residue is poured onto a mixture of crushed ice and ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanol and 1,1-hydroxybisethane, 36 parts of 6- (2-chloroethyl) -7-methyl-5H-thiazolo 3,2-aj pyrimidin-5-one (intermediate compound 5) are obtained. I
    Example 4 A mixture of 30 parts of 4-ox-2-mercapto-6-methyl-5-pyrimidine ethanol, 6.8 parts of sodium hydroxide 15 parts of acid sodium carbonate and 100 parts of 2-propanol are stirred at room temperature. 180 hours of tetrahydrofuran and 170 hours of water are added to the temperature. Then, 25 parts of H-chloro-2-butanone and 0.2 parts of N, N, N-triethylbenzenemethanamine chloride are added in one portion and the entire mixture is stirred and heated to 60 ° C, which is maintained for 1 hour. overnight at room temperature. The reaction mixture is filtered, the filtrate is salted out. The organic phase is separated, dried, filtered and evaporated to give 36 parts of 5- (2-hydroxyethyl 6-methyl-2- (1-methyl-2-oxopropyl) (ZN) -pyrimidinone) as an oily residue (intermediate with - unity 6).
    . A mixture of 36 parts of 5- (2-hydroxyethyl) -6-methyl-2 (1-methyl-2-oxopropyl) (3N) pyrimidinone and 240 parts of a 60% aqueous solution of hydrobromic acid is stirred and heated for 4 hours. to 90 ° C. The reaction mixture is evaporated and the residue is suspended in 400 parts with 2-propanol and dried, 44 parts are obtained. 6- (2-bromoethyl) -2,3,7-trimethyl-5H-thiazolo h, 2 -and pyrimidine-5-one monobromide, so pl. 172 C (intermediate compound 7).
    Example 5. A mixture of 90 h, po-2-pyridinamine, 90 parts of 3-acetyl-4,5-dihydro-2 (3N) -furanone and 810 parts of methylbenzene is stirred at room temperature. 510 hours of phosphoryl chloride is added dropwise over 1 hour, the temperature rises to 40 ° C. The reaction mixture is slowly heated to the temperature of refluxing and the mixture is stirred and refluxed for 5 hours. The solvent is evaporated. The hot residue is drunk on a mixture of crushed ice and ammonium hydroxide. After stirring for 30 minutes, the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by purification and chromatography on silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2-oxibispropane, 54.8 parts of 3- (2-chloroethyl) -2-methyl-7-nitro-4P-pyrido, 2-a pyrimidine-4-it is obtained, m.p. 170 ° C (intermediate compound 8). I
    A mixture of 40 parts of 3- (2-chloroethyl) -2-methyl-7-nitro-4P-pyrido l, 2-a pyrimidine-4-one and 240 parts of methanol is hydrogenated under normal pressure and at room temperature. use 0.5 part of platinum oxide. After the calculated amount of hydrogen is consumed, the catalyst is separated by filtration, the filtrate is evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in acetonitrile and 2-propanol. The salt is separated by filtration and dissolved in water when heated. The solution is treated with activated charcoal. The latter is separated by filtration on Hifpo, the filter cake is washed with water. The filtrate is stirred in a dilute solution of ammonium hydroxide. The precipitated product is separated by filtration, washed with water and petroleum ether, and then dried, yielding 19.4 parts of 7-amino-3- (2-chloroethyl -2-methyl-4H-pyrido D, 2-a pyrimidin-4-one ; mp 185 C (intermediate 9).
    51
    Example 6 To the stirred and refluxing Grignard complex, previously obtained from 112.2 parts of bromo-4-methoxybenzene, 15 hours, magnesium and 540 parts of tetrahydrofuran, a solution of 84 parts of ethyl is added dropwise. 4- (4-fluorobenzoyl. P) -1-piperidinecarboxylate in 360 parts of tetrahydrofuran. After that, it is stirred for 2 hours while refluxing. After cooling to 10 ° C, the reaction mixture is poured into a mixture of 300 parts of ice and 40 parts of acetic acid. The mixture is stirred for 5 minutes. 360 parts of methylbenzene are added. The organic layer is separated, dried, filtered and evaporated to give 100 parts of ethyl 4-c4 fluorophenyl) -oxy-4-methoxyphenyl) methyl -1-piperidinecarboxylate as an oily residue (intermediate 10).
    A mixture of 100 parts of ethyl 4- (4-fluorophenyl) -oxy- (4-methoxyphenyl) methyl -1-piperidinecarboxylate, 1200 parts of hydrochloric acid concentrate and 160 parts of ethanol is stirred and refluxed for 24 hours. Hydrogen chloride gas is fed to saturation and the whole mixture is then stirred and refluxed for 3 hours. The reaction mixture is evaporated and the oily residue is dissolved in 1000 hours of water by heating. After cooling, the solution is washed twice with 210 parts of 1,1-oxybisethane and alkalinized with ammonium hydrate. The precipitated product is separated by filtration and suspended in 160 h, acetonitrile. The product is separated by filtration and suspended twice in 80 hours of methanol, obtained after drying 44.4 parts (52%) of 4- (4-fluorophenyl) - (4-piperidinylidene) -methyl phenol, m.p. 260 ° C (intermediate 11).
    Example 7. In a stirred and Grignard defpegming complex, previously obtained from 70 parts of 1-bromo-4-fluorobenzene and 10 parts of magnesium in 270 parts of tetrahydrofuran, a solution of 25 parts of ethyl 1- (phenylmethyl) was added dropwise -4-piperidinecarboxylate in 90 parts of tetraide, rofuran. After that, it is stirred for 2 hours at the temperature of reflux. The reaction mixture is cooled and poured onto a saturated solution of ammonium chloride. The organic phase is separated., Dried, filtered and evaporated, semi 9 .6
    40 4. (5i, 1) (4-fluorophenyl) -1- (phenylmethyl) -4-piperidinemethanol as a residue (intermediate 12).
    A mixture of 40 parts of nos, o6-bis (4-fluorofensch1) -1- (phenylmethyl) -4-piperidinemethanol, 120 parts of hydrochloric acid solution and 50 parts of acetic acid is stirred and refluxed for
    2h The reaction mixture is cooled and water and methylbenzene are added to it, three layers are obtained. The two upper phases are separated and treated with ammonium hydroxide. The organic phase is separated, dried, filtered and evaporated. The residue is crystallized on 2,2-oxybispropane; 26 parts of 4-bis (4-fluorophenyl) methylene -1- (phenylmethyl) piperidine are obtained (intermediate compound 13).
    I
    A mixture of 1.6 parts (4-fluorophenyl) methylene -1- (phenylmethyl) piperidine and 80 parts methanol is hydrogenated at normal pressure and room temperature with 1 part 5% rhodium-supported charcoal catalyst. After the calculated amount of hydrogen has been consumed, the catalyst is separated off by filtration and the filtrate is evaporated to give 1.2 parts of 4-bis (4-fluorophenyl) methylene piperidine as a residue (intermediate 14).
    Example 8. To a mixture of 600 parts of bromobenzene and 223 parts of aluminum chloride, stirred and heated to 40 ° C, are added in portions to 168.8 parts of 1-acetyl- 4-11 hyperinocarbonyl chloride. After
    this is stirred for 1 hour at 50 ° C. overnight at room temperature. The reaction mixture is poured into a mixture of 1500 hours of crushed ice and hydrogen chloride. Blend thoroughly
    stirred. The precipitated product is separated by filtration, washed with 2,2 - oxybispropane and dissolved in a mixture of 2250 parts of trichloromethane and 200 parts of water. Layers are separated. Organic layer
    dried, filtered and evaporated. The solid residue is suspended in 280 parts of 2,2-hydroxy-propane. The product is separated by filtration, dried, and 94 parts (34%) of 1-acet-1-4- (4-bromobenzoyl) piperidine are obtained,
    m.p. 120 C (intermediate compound1 g-h
    15).
    In the stirred and defective IV complex of the Grignard, obtained a preliminary outcome of 52.5 parts of 1-bromine713
    4-fluorobenzene, 7.5 parts of magnesium and 216 hours of tetrahydrofuran are added dropwise a solution of 94 parts of 1-acetyl-4- (4-bromobenzoyl) piperidine in 450 parts of tetrahydrofuran. After that, they are stirred for 5 hours at the temperature of reflux vegetables. The reaction mixture is cooled, poured into a mixture of 300 hours, crushed ice and 40 parts of acetic acid and stirred for 15 minutes. 450 parts of methylbenzene are added. The organic layer is separated, dried, filtered and evaporated. The residue is taken up in methyl benzene and the mixture is evaporated. The residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated to give 75 parts of 1-acetyl-y6- (4-bromophenyl) -ab- (4-fluorophenyl) -4-piperidine-methanol as a residue (intermediate 16).
    A mixture of 75 parts of 1-acetyl-about- (4-bromophenyl) - ab- (4-fluorophenyl) -4-piperidine-methanol, 600 parts of hydrochloric acid concentrate and 80 parts of ethanol are stirred and refluxed for 18 hours. . The reaction mixture is evaporated. 500 parts of water are added to the residue. The solution is treated with ammonium hydroxide. The product is extracted twice with 375 parts of trichpormethane. The combined organic layers are washed with 100 parts of water, dried, filtered and evaporated. The oily residue is purified by chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume), saturated with ammonia, as eluent. Pure fractions are collected, the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanol. The mixture is evaporated. The residue is cured in 80 hours, acetonitrile. The product is separated by filtration (the filtrate I is preserved) and crystallized from 160 parts of acetonitrile at 0 ° C. The product is filtered off (the filtrate II is preserved) and dried, yielded 36 hours ,. 4- (bromophenyl) - (4- ;.-. Fluorophenyl) methylene —IPP yrididinhydrochloride.
    Filtrate I and filtrate II are concentrated to a volume of 40 hours. The concentrate is crystallized. The product is separated by filtration and dried, resulting in 4 hours. 4- (4-bromophenyl- (4-fluorophenyl) methylene-3-pipervdinlorgtsrata.
    98
    Total yield: 40 parts (75%) of 4- (4-bromophenyl) - (4-fluorophenyl) methylene piperidine hydrochloride (intermediate 17).
    Example 19. In a stirred and cooled Grignard complex, prepared in advance from a mixture of 134 parts of 4-chloro-1-methylpiperidine, 25 parts of magnesium and 652.5 parts of tetrahydrofuran, a solution of 170 parts was added dropwise (4 -fluorophenyl) - (3-pyridinyl) methanol in 405 parts of tetrahydrofuran at 10-20 ° C. After that, it is stirred for 1 hour at room temperature and for 30 minutes at reflux temperature. After cooling, the mixture is decomposed into its constituent parts, for which it is poured into a mixture of crushed ice and ammonium chloride. 270 parts of methylbenzene are added. The organic layer is separated, dried, filtered and evaporated. The residue is boiled in acetonitrile with activated carbon. The latter is separated by filtration on Khiflo, and the filtrate is evaporated, 240 parts (95%) of the o- (4-fluorophenyl) -ob- (1-methyl-4-piperidinyl) -3-pyridine methanol are obtained as a residue (intermediate compound 18).
    A mixture of 240 parts of oi- (4-fluorofensch1) (1-methyl-4-piperidinsh1) -3-pyridine-methanol and 900 parts of a 48% aqueous solution of hydrobromic acid in water is stirred and refluxed for 1 hour. The mixture is concentrated to one third of its volume. The concentrate is treated with a solution of sodium hydroxide. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified using a chromatography column on silica gel and a mixture of trichloromethane and methanol (90:10 by volume), saturated with ammonia, as eluent. Pure fractions are collected and the elute is evaporated. The residue is crystallized from a mixture of petroleum ether and a small amount of 2,2-oxybis-propane (10: 1 by volume). The product is separated by filtration and dried to give 112.5 parts (48%) of 3- (4-syrup) - (1-methyl-4-piperidinylidene) methyl pyridine, m.p. 93.1 ° C (intermediate 19).
    In a stirred solution of 180 parts of ethyl carbonate in 600 parts of trichloromethane, 110 parts of 3- (4-fluorophenyl) - (1-methyl-4 9 1) are added dropwise to the solution.
    piperidinylidene) methyl pyridine in 600 parts of trichloromethane. After that, the mixture is heated to reflux and stirring at reflux is continued for 16 hours. The reaction mixture is evaporated. The residue is stirred in water and the mixture is alkalinized with sodium hydroxide solution. The product is extracted from 4-methyl-2 penta non. The extract is dried, filtered and evaporated to give 100 parts (75%) of ethyl 4- (4-fluorophenyl) - (3-pyridinyl) methylene -1-piperidinecarboxylate as a residue (intermediate 20).
    A mixture of 100 parts of ethyl 4- (4-fluorophenyl) - (3-pyridinyl) methylene -1-piperidinecarboxylate and 375 hours, the 48% aqueous hydrobromic acid solution is stirred and refluxed for 3 hours. The reaction mixture is evaporated. The residue is washed with 2,2-oxibispropane. The latter is decanted, the residue is stirred in water and the whole mixture is alkalinized with sodium hydroxide solution. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is subjected to purification using chromatographic columns (2x) on silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (80:20 by volume), as eluent. The main fraction was collected and the eluent was evaporated. 30 parts (37%) of 3- (4-fluorophenyl) - (4-piperidinylidene) methyl pyridine were obtained as a residue (intermediate 21).
    Similarly, 4- (4-fluorophenyl) - (2-thienyl) methylene piperidine (intermediate compound 22) was also obtained from the corresponding 1x starting materials (intermediate compound 22) Example 10. A stirred solution was 50.9 parts (L, o (; - bis ( 4-fluorophenyl) 1,2,3,6-tetra-agidro-1- (phenylmethyl) -4-pyridinemethanol in 270 parts of tetrahydrofuran is added 750 parts of IN solution of hydrochloric acid. The mixture is stirred first for 7 hours at a temperature refluxing, and then for 8 hours at room temperature. The precipitated product is separated by filtration. The filtrate is evaporated until all traces of tetragon are removed. Po- furan. After cooling the solid. the precipitated product was separated by filtration and suspended together with the precipitated product which retain
    334910
    in 80 hours of acetonitrile. The product is separated by filtration and stirred in 40 parts of acetonitrile by heating. After cooling to 10 ° C, the product is separated.
    5 by filtration and dried; 32.6 parts (58.7%) of (4-fluorophenyl) methylene — 1- (phenylmethyl) -3-piperidinol hydrochloride, so-called pl. 266 C (intermediate compound 23).
    0 A mixture of 27.8 parts of (4-fluorophenyl) methylene -1- (phenylmethyl) -3-piperidinol hydrochloride and 200 parts of methanol is subjected to hydrogenation at normal pressure and at room temperature with 3 parts of 10% palladium catalyst on charcoal. When the calculated amount of hydrogen has been consumed, the catalyst is filtered off and the filtrate is evaporated. The residue is suspended in 80 parts of acetonitrile. The product is separated by filtration and dried; 21-, 9 parts (100%) of 4-bis (4-fluorofensch1) methylene -3-piperidinol hydrochloride, so-called pl. 260 С (about interstitial compound 24).
    Example 11. In a stirred and cooled (ice bath) solution of 141.5 hours, 4-pyridinecarbonyl chloride hydrate of chloride in 400 parts of fluorobenzene
    0 add portions of 399 h, chloride. aluminum. After that, the mixture is slowly heated to the temperature of refluxing and stirred at refluxing for 6 hours.
    5, the mixture is cooled, crushed ice is poured off and acidified with 240 parts of a 10 N hydrochloric acid solution. The layers are separated. The acidic aqueous phase is washed twice with 180 parts of methylbenzene, basified with 60% sodium hydroxide solution. The product is extracted three times with dichloromethane. The combined extracts are dried, filtered and evaporated. The residue was dissolved in 900 parts of methyl benzene and the treatment solution was rubbed with activated charcoal. The latter is separated by filtration and the filtrate is evaporated. The residue is crystallized from 2,2-oxybispropane, 152 hours are obtained.
    50 (75.5%) (4-fluorophenyl) - (4-pyridinyl) methanol, m.p. 85.5 ° C (intermediate connecting 25).
    Pre-receive the fc Grignard complex from 22.75 parts of 1-bromo-4-fluorobenzene, 3.2 parts of magnesium and 45 parts of anhydrous tetrahydrofuran. The whole mixture is cooled in 2-propanol WITH at a temperature of from -20 to-25 C. Rast1113
    a thief of 20.1 parts of (4-fluorophenyl) - (4-pyridinyl) methanol in 45 parts of anhydrous methyl benzene is added dropwise over 30 minutes at a temperature of -20 ° C. After that, the whole mixture is stirred for overnight at room temperature. After cooling to 0 ° C, the reaction mixture is decomposed into its constituent parts by adding dropwise 50 hours of acetic acid. After stirring for 1 hour at room temperature, the precipitated product is separated by filtration and stored. From the filtrate, the organic layer is separated, washed with 50 parts of water, dried, filtered and evaporated. The solid residue and the precipitated product, which was stored, was washed with water and distilled under azeotropic conditions with 180 h of methylbenzene. The solid distillate is suspended in 80 parts of acetonitrile. The product is separated by filtration and dried, whereby 28 parts (94%) of isi are obtained, ob-bis (4-fluorophenyl) -4-pyridinemethanol (intermediate 26).
    I
    Into a stirred mixture, 89.2 parts of ot, o | / -bis (4-fluorophenyl) -4-pyridinomethanol and 720 parts of acetonitrile, 55.6 parts of (bromomethyl) benzene are added dropwise at reflux temperature. After that, stirred for 22 h at refluxing. The reaction mixture was incubated for 2 days at room temperature. The product is separated by filtration and the filtrate is concentrated to a volume of 50 hours. The product is crystallized, filtered, washed together with the product that has been preserved, using 2.2 - oxybispropane and dried, it is obtained 139.5 parts (C99.2%) (4-fluorofensh1) oxymethyl -1 - (phenylmethyl) -pyridinium- bromide (intermediate compound 27)
    140.5 parts of a 4-bis (4-fluorophenyl) oxymethyl -1- (phenylmethyl) pyridinium bromide in 640 parts of methanol are added dropwise to the solution that is reabsorbed by the solution of sodium borohydride at room temperature (this requires cooling with an ice-water mixture). After that, the mixture is stirred and refluxed for 30 minutes. After cooling to room temperature, 800 parts of water are added. The mixture is aged overnight. The reaction mixture is evaporated until the methanol is completely removed. 1040 parts of dichloromethane are added. The layers are separated. Organizational912
    The cis layer was washed with 200 parts of water, dried, filtered and evaporated. The residue is taken up in dry methylbenzene and the mixture is evaporated to give 111 parts (94.5%)
    (, (4-fluorophenyl) -1,2,3,6-tetrahydro-1- (phenylmethyl) -4-pyridinemethanol as an oily residue (intermediate 28). Mixture 50.9 parts oi. , (4-fluorophenyl) 1, 2,3,6-tetrahydro-1- (phenylmethyl) -4-pyridinemethanol, 320 parts of methanol and 800 parts of 1 N hydrochloric acid solution, are first stirred for 3 hours at reflux temperature, and then for 56 hours at room temperature. The whole mixture is evaporated until the methanol is completely removed. The free base is liberated with ammonium hydroxide.
    The product is extracted using
    1040 parts of dichloromethane. The extract is washed with 100 parts of water, dried, filtered and evaporated. The residue is dissolved in 270 parts of dimethylformamide. The mixture is heated to 60 ° C. At 80 ° C, add
    2.5 hours. 50% sodium hydride dispersion. After stirring for 1 hour at 80 ° C, the mixture is cooled to room temperature. 9 parts of iodomethane are added dropwise. After this stage is completed, the mixture is stirred and heated to 40 ° C in 30 minutes. After cooling, the reaction mixture is poured onto 2000 parts of ice-water mixture. The product is extracted twice with 450 parts of methyl benzene. The combined extracts are dried, filtered and evaporated. The oily residue is purified by chromatography on silica gel.
    using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, resulting in 29.6 parts (57%) of (4fluorophenyl) methylene3-3-methoxy-1- (phenylmethyl) piperidine as a residue (intermediate 29).
    A mixture of 29.6 parts of (4-fluorophenyl) methylene-3-methoxy-1- (phenylmethyl) piperidine and 200 parts of methanol was hydrogenated under normal pressure and at room temperature with 2 parts of palladium on charcoal catalyst at 2%. After the calculated amount of hydrogen is consumed, the catalyst is filtered off and the filtrate is evaporated. The residue is purified using chromium1313
    photographic column on silica gel using first a mixture of trichloromethane and methanol (90:10 by volume), and then a mixture of trichloromethane and methanol (80:20 by volume) saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanol. The mixture was evaporated, the oily residue was solidified at 70 hours. 1, l-oxybisethane. The products are separated by filtration and dried to give 16.3 h, (63.4%) (4-fluorophenyl) methylene-3-methoxypiperidine chloro hydrate (intermediate 30).
    Example 12. A stirred and refluxed Grignard complex, obtained in advance from 15 parts of magnesium, 112.2 parts -bromo-4-methoxybenzene and 540 parts of tetrahydrofuran, is added dropwise a solution of 80 parts ethyl. 4-benzosh1-1-piperidinecarboxyl and 360 parts of tetrahydrofuran at reflux temperature. After that, stirred for 2 h at refluxing. After cooling overnight, the reaction mixture was poured into a mixture of 300 hours, crushed ice and 40 parts of acetic acid at 10 ° C. After stirring for 15 minutes, the layers were separated, the organic layer was dried, filtered and evaporated. The residue is taken up in methylbenzene and the latter is evaporated. The residue is suspended three times at 70 hours. 2,2-oxybispropane and the latter is decanted each time. The residue was evaporated to dryness, and 106 parts of ethyl 4-hydroxy (4-methoxyphensh1) phenylmethyl -1-piperidinecarboxylate were obtained as a residue (intermediate 31).
    A mixture of 106 parts of ethyl 4-hydroxy (4-methoxyphenyl) phenylmethyl -1-piperidinecarboxylate, 1200 parts of hydrochloric acid concentrate and 200 parts of ethanol is stirred and refluxed for 18 hours. Hydrogen chloride gas is bubbled through the mixture and stirred for 18 hours at reflux temperature. The mixture is evaporated. The residue is dissolved in a mixture of 200 h, ethanol and 1950 parts of a 48% aqueous solution of hydrobromic acid in water. The mixture is stirred and refluxed overnight. After evaporation, the residue is suspended in 1000 hours, water and treated with ammonium hydroxide. The oil is dissolved in 2100 hours.
    914
    trichloromethane. The solution is washed with 500 parts of water, dried, filtered and evaporated. The residue is suspended three times in 70 hours. 2,2-Oxybispropane
    and the latter is evaporated each time. The residue is precipitated from acetonitrile (40 parts), the product is separated by filtration and dried, and 20 parts (25%) of 4-phenyl (4-pyridinylidene) methyl phenol are obtained, m.p.
    260 C (intermediate 32)
    EXAMPLE 13 To the stirred and refluxing Grignard complex, previously obtained from 80.2 parts of 4-chloro-1-methylpiperidine, 14.6 hours.
    magnesium and 270 parts of tetrahydrofuran, a solution of 101 parts of (2-fluorophenyl) phenylmethanone in 450 parts of tetrahydrofuran is added dropwise. Then stirred for 18 hours at a temperature of
    refluxing. The reaction mixture is cooled in an ice bath and decomposed into components using a solution of 32 parts of ammonium chloride in 160 parts of water. After stirring for 30 minutes, the product is filtered off and taken up with tetrahydrofuran. The filtrate is evaporated, the residue is taken up in methylbenzene, and the latter is again evaporated in a boiling water bath. Remainder
    dissolved in 700 parts of 2,2-oxybispropane. The turbid solution is filtered and hydrogen-chloride is bubbled through the filtrate. The solid is separated by filtration and suspended in 1000 parts of water. The suspension is treated with ammonium hydroxide and extracted twice with 280 parts of 1,1-oxybisethane. The combined extracts are dried, filtered and evaporated. The oily residue is crystallized from
    240 h. Acetonitrile. After cooling, the product is separated by filtration and dried, resulting in 66 parts (44%) of cyl / - (2-fluorophenyl) - I-methyl-o {, -phenyl-4-piperidinemethanol
    (intermediate 33).
    I
    To the stirred mixture 66.0 parts of o6- (2-fluorophenyl) -I-methyl-Qi-phenyl-4piperylzdinmethanol and 450 parts of methylbenzol were added dropwise 28.2 parts. ethylcarbonyl chlorohydrate. After that, they are stirred overnight at a temperature of d4 | ligation. Reactionary
    the mixture was diluted with 630 parts of dimethylbenzene and the whole mixture was stirred and refluxed overnight. The precipitate is separated by filtration and the filtrate is evaporated. The residue is cured with stirring.
    151
    at 210 hours. 2,2-oxybispropane. The products were filtered and dried to give 27 h, (34.5%) ethyl 4- (2-fluorophenyl) oxyphenylmethyl -1-piperidinecarboxylate (intermediate 34),
    A mixture of 26.0 parts of ethyl-4- (2-fluorophenyl) oxyphenylmethyl -1-piperidinecarboxylate and 375 hours, a 48% aqueous solution of hydrobromic acid in water, is stirred and refluxed for 60 hours. The reaction mixture is evaporated and the residue is suspended in 250 hours of water. The mixture is treated with ammonium hydroxide and stirred for 1 hour at room temperature. The product is extracted three times with 300 parts of trichloromethane. The combined extracts are dried, filtered and evaporated. The residue was purified by noMomji chromatography on silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (90:10 by volume), as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted into the chlorhydrate salt in 2-propanol. The mixture is evaporated and the solid residue is suspended in 80 parts of acetonitrile. The product is separated by filtration and dried; 14.3 parts (65%) of 4- (2-fluorophenyl) -phenyl methyl 3-piperidine hydrochloride are obtained, m.p. 260 C (intermediate 35). . Getting the target products.
    Example 14. A mixture of 3.8 parts of 6- (2-chloroethyl) -7-methyl-5H-thiazolo 3,2-a2 pyrimidin-5-one, 3.5 parts of 4-bis (4-fluorophenyl) methylene) piperidine , 10 parts sodium carbonate, 0.1 parts potassium iodide, and 240 parts 4-methyl-2-pentanone are mixed and refluxed for 20 hours using a water separator. The reaction mixture was filtered hot and the filtrate was evaporated. The residue is subjected to chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile, 2.8 parts of (4-fluorophenyl) ethyl are obtained; methyls -1 is piperidinyl 3 ethyl - 7-methyl-5H-thiazolo 3,2-a pyrimidin-5-one, mp 145.5 ° C (compound 1).
    Under the conditions of Example 14, 6- (2-thienyl) -methyl349 b is prepared.
     -piperidinyl e-3-2,3-dihydro-7-methyl-5H-thiazolr 3,2-a pyrimidine-5-one (E) -2-butanedioate (1: 1), so pl. 204.2 ° C.
    Similarly, using equivalent amounts of the corresponding; their starting materials, the compounds listed in Table 2 are obtained. 2
    Example 15. A mixture of 7.4 hours
    7- (2-bromoethyl) -3,4-dihydro-8-methyl-2H, bH-pyrimido 2,1 -v l, ZZ thiazin-6-one monobromohydrate, 6.6 parts 4- (diphenylmethylene) piperidine hydrochloride, 12 parts sodium carbonate and 120 parts 4-methyl-2 pentanone are stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by chromatography.
    silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2-oxy-bis-propanone. The product is separated by filtration and recrystallized from 2-propanol to give 5.5 parts (60%) (diphenylmethylene) 1-piperidinyl ethyl-3,4-dihydro-8-methyl-2H, bH-pyrimido 2, -in 1, zin-6-she, so pl. 176.0 ° C (compound 104).
    Similarly, using the equivalent amount of coolness x of starting materials, the following is obtained:
    6- (diphenylmethylene) -1-piperidinyl ethyl-3,7-dimethyl-5H-thiazolo Q 3,2-a pyrimidin-5-one, yield 35%, mp. 150.6 ° C (compound 105);
     (4-methylphenyl) methylene -1-piperidinyl-ethyl-3, 7-dimethyl-5H-thiazsho 3, pyrimidine-5-one, .j yield 41%, so pl. 167.8 ° C (compound 106);
    (diphenylmethylene) -1-piperidinyl ethyl -2,3-dihydro-7-methyl-5H-thiazolo 3,2-a pyrimidin-5-one di0
    hydrochloride, yield 17%, so pl. 271.1 С
    (compound 107) ;.
    7- (4-methylphenyl) methyl J-1-piperidinyl 3 ethyl-3, 4 dihydro-8-methyl-2H, 6H-pyrimido 2, l-BJQ,) g thiazin-6-one, 31% yield m.p. 124.0 ° C (compound 108);
    (4-methylphenyl) methi-piperidinyl, 3-dihydro-7-methyl-5H-thiazolo 3,2-adipyrimIDIN-5-OH dihydrochloride monohydrate, yield 23%, m.p. 117 ° C (compound 109);
    6- 2- 4-bis (4-chlorophenyl) methyl ev 1-piperidinyl | ethyl -2,3-dihydro-7-methyl-5H-thiazolo 3,2-a pyrimidine-Zon, yield 56%, mp. 177.5 ° C (compound 10);
    6- 2- 4- (4-fluorophenyl) phenylmethylene -1-piperidinyl ethyl-7-methyl-5I-thiazolo 3,2-a pyrimidine-5-one, 66% yield, m.p. 126.2 ° C. (compound 111).
    Example 16. A mixture of 5.6 parts of 6- (2-bromoethyl 1) -3,7-dimethyl-5H-thiazol-3, 2-a pyrimidin-5-one monobromohydrate, 3.5 parts (4- fluorophenyl) methylene piperidine, 2 parts of 30% methylate solution, 3 parts, 8 parts of sodium carbonate and 240 parts. 4-methyl-2-pentaine foam is stirred and refluxed for 20 hours using a water separator. The reaction mixture was filtered hot and the filtrate was evaporated. The residue is chromatographed on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile and 4.3 parts (72.8%) are obtained. (4-Fluorophenyl) -methylene -1 -piperidinyl ethyl - 3,7-dimethyl-5H-thiazolo 3,2-a-pyri- midin-5-it, yield 72.8%, so pl. 183.8 ° C (compound 112).
    Similarly, using equivalent amounts of the corresponding starting materials, the compounds listed in Table 2 are obtained. 2
    Example 17. A mixture of 4.5 hours of 3- (2-chloroethyl) -5,7,8,9-tetrahydro-2-metsh1-4H-pyrido l, 2-a pyrimidin-4-one monohydrochloride, 4.6 h 4- (4-fluorophenyl) phenylmethyl en piperidine chlorohydrate, 2 parts of a 30% sodium methoxide solution, 8 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of 4-methyl 2-pentanone stirred and refluxed for 22 hours. The reaction mixture was filtered while hot, and the filtrate was evaporated. The residue is subjected to chromatography on silica gel using a mixture of tricl. Ormethane and methanol (92: 8 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in acetonitrile and 2-propanol. Salt is separated.
    five
    0
    five
    0
    five
    0
    five
    0
    five
    4.8 parts (60%) of (4-fluorophenyl) phenylmethylene -1-piperidinyl} ethylJ-6,7,8,9-tetrahydro-2-methyl-4H-pyrido l, 2- AZ pyrimidine-4-one dihydrochloride, so pl. 264, (compound).
    Similarly, using equivalent amounts of the corresponding starting materials, one obtains:
    3- (4-fluorophenyl) (3-methylphenyl) methylene - - - piperidinyl ethyl - 6,7,8,9-tetrahydro-2-methyl-4H-pyrido l, 2-a pyrimidin-4-one, m.p. 166, (compound 138);
     4-. (4-fluorophenyl) phenylmethylene -1-piperidinyl ethyl-7-methyl-5H-thiazolo 3, 2-a pyrimidin-5-one monohydrochloride, mp. 239.3 ° C (compound 139);
    3- 2- 4-. (4-fluorophenyl) 3- (trifluoromethyl) phenyl methylene -1-piperidinyl, 7,8,9-tetrahydro-2-methyl-4H-pyrido, 2-a pyrimidin-4-one dichloro-hydrate, so pl. 254.0 ° C (compound 140);
    7-amino-3-L2-1 - bis (4-fluorophenyl) methylene -1-piperidinyl ethyl -2-methyl-4H-pyrido 1, 2-a pyrimidin-4-one,
    m.p. 209.9 ° C (compound 141). i
    Example 18. About 75 parts of a 50% dispersion of sodium hydride was suspended twice in 14 parts of petroleum ether, the latter decanted each time. The residue is suspended in 9 hours. K, K-dimethylformamide and added in one portion to the stirring solution 7., 35 parts of (4-fluorophenyl) - (4-hydroxyphenyl) methylene-piperidinyl ethyl 3 J, 7-dimethyl- 5H-thiazolo 3, 2-a pyrimidin-5-one at 45 o'clock N, N-dimethylformide. The mixture is heated to 45 C and stirred for 30 minutes at 45 ° C. After cooling to 25 ° C, 2.13 parts of iodomethane are added in one portion (exothermic reaction: the temperature rises to 30 ° C). Stirring is continued for 1 hour at room temperature. The reaction mixture is poured into 300 parts of ice-water mixture. The precipitated product is separated by filtration and dissolved in 240 parts of 4-meth; 1l-2-pentanone. The organic phase is washed with 100 parts of water, dried, filtered and evaporated. The solid residue is suspended in 40 parts of acetonitrile. The product is separated by filtration and crystallized from 40 parts of acetonitrile. After cooling19
    The product is filtered off and dried, and 3 parts (40%) of (4-fluorophenyl) (4-methoxyphenyl) methylene -1-piperidinyl 3, 7-dimethyl-5H-thiazolo 3,2-a pyrimidine-5 are obtained. - it 140.2 ° C. (compound 142).
    Similarly, receive:
    3- 2- 4- (4-fluoropensch1) (4-methoxy-phenyl) methylene -1-piperidinyl3 2-methyl-4H-pyrido II, 2-a pyrimidin-4- he dihydrochloride monohydrate, so pl. 257.7 ° C (compound 143);
    (4-fluorophenyl) (4-methoxy phenyl) methylene -1-piperidinyl 7-methyl-5H-thiazolo 3,2-aZpyrimidine-5-one monohydrochloride, m.p. 165.7 ° C (compound 144);
    7- 2- 4- (4-fluorophenyl) (4-methoxy-phenyl) methylene -1-pilyridinyl 3,4-dihydro-8-methyl-2H, bN-pyrimido 2,1-in 1 jSlthiazin-6-one dichlorohydrate m.p. 271.1 ° C (compound 145);
     (4-fluorophenyl) (4-methoxy-phenyl) methylene -1-piperidinyl ethyl - 6,7,8,9-tetrahydro-2-methyl-4H pyrido 1,2-aZ-pyrimidin-4-one dihydrochloride, t. square 268.5 ° C (compound 146);
     (4-fluorophenyl) (2-thienyl) methylene -1-piperidinyl-ethyl-7-methyl-5H-thiazolo 3,2-a pyrimidine-5-odi dihydrochloride monohydrate, yield. 43%, mp. 235.2 ° C (compound 157);
    6- f2- 4- (4-fluorophenyl) (2-thienyl) methylene -1-piperidinyl ethyl-3,7-dimethyl-5H-thiazolo 3,2-a pyrimidine-5- one, yield 28%, t .pl. 149.6 ° C (compound 158);
    6- (4-fluorophenyl) (2-thienyl) -methylene-1-piperidinyl-ethyl} -2, 3-dihydro-7-methyl-5H-thiazolo (3,2-a) pyrimidine-5-one dihydrochloride monohydrate, yield 58%, so pl. 222.7 ° C (compound 159);
    3- (4-fluorophenyl) (2-thienyl) methylene -1-piperidinyl} -ethyl-6,7,8, 9-tetrahydro-4H-pyrido (1,2-a) pyrimidin-4-ODIN dihydrochloride, yield 80%, so pl. 271.7 ° C (compound 160).
    Example 19, Mixture of 4 parts (4-fluorophenyl) methylene -1-piperidinyl ethyl-7-methyl-5H-thiazolo 3, 2-a1-pyrimidin-5-one, 1.3 parts (+) R- / R, 3-dioxybutanedioic acid and 96 parts of 2-propanol are stirred and heated until the products are completely dissolved. The solution is cooled with stirring. The product is filtered and dried, get 5,1 hours
    920,
    (98%) (+) -6- (4-fluorophenyl) M-methyl-α-piperidinyl-ethyl-7-methyl-5H-thiazolo 3,2-a pyrimidin-5-one, 3-dioxybutanedione (1: 1 )
    yield 98%, so pl. 98.7 ° C (compound 1 47).
    Using similar reactions, accompanied by the formation of salt, also get:
    3- 2- 4-bis (4-fluorophenyl) methylene - 1-piperidinyl ethyl -2-methyl-4H-pyrido, pyrimidin-4-one sulfate (1: 2) dihydrate, yield 35%, so pl. 188.7 C (compound 148);
    3- (4-fluorophenyl) methylene-1-piperidinyl ethyl -2-methyl-4H-pyrido l, 2-a pyrimidin-4-one (Z) -2-6yTeH- dioat, 47% yield, m.p. . 201.8 ° C (compound 149);
    3- 2- 4-bis (4-fluorophenyl) methyl-HJ-1-piperidinyl ethyl -2-methyl-4H-pyrido l, 2-a pyrimidin-4-one 2-hydroxy-1,2,3-propane tricarboxylate ( 1: 1), yield 33%, so pl. 172.0 ° C (compound 150);
    6- 2- 4-Sbis (4-fluorophenyl) methylene2-1-piperidinyl. -Ethyl1-7-methyl-5H-thiaG 1
    3,2-aJ pyrimidin-5-one (Z) -2-6y-tenioate (1: 1), 71% yield, m.p. 180.3 ° C (compound 151);
    6- 2- C4-bis (4-fluorophenyl) methylene-1-piperidinyl ethyl-7-methyl-5H-thiazolo 3, 2-a pyrimidine-5-one sulfate (1: 2) monohydrate, yield 78%, m.p. 178.6 C (compound 152);
    (4-fluorophenyl) methylene - 1-piperidinyl ethyl-7-methyl-5H-thiazolo 3,2-a pyrimidine-5-ch 2-hydroxy-1,2,3-propane tricarboxylate (1: 1) monohydrate , yield 41%, so pl. 149.1 C (compound 153);
    (4-Fluorophenyl) methylene - 1-piperidinyl ethyl-7-methyl-5H-thiazolo 3,2-a pyrimidine-5-one phosphate (5: 2) monohydrate, yield 52%, mp. 150.6 ° C (compound 154);
    6- 2-.4-bis (4-fluorophenyl) methylene} - 1-PIP e ridinyl ethyl-7-methyl-5H-thiazolo 3,2-a pyrimidine-5-one dichlorohydride, 32% yield m.p. 188, (compound 1 55).
    Example 20 5 parts of bis (4-fluorophenyl) methylene -1-piperidiyl ethyl -2-methyl-4H-pyrido l, 2-a irimidin-4-one dihydrochloride are dissolved in water and the base is liberated with ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is stirred in a dilute solution of ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue 5 is crystallized from a mixture of 4-methyl-2-pentanone and 2,2-oxybispropane. The product is separated by filtration and dried, 2.2 h, (4-fluorophenyl) methylene -1-piperidinyl-ethyl 3-2-O methyl-4H-pyrido 1, 2-aZpyrimidin-4-one are obtained, m.p. 108.7 ° C (compound 156).
    In tab. 1 shows the constants obtained by the proposed method of compounds.
    Biological tests of the compounds obtained under the conditions of the proposed method were carried out.
    In the combined test on rats of apomorphine (APO), 5-hydroxytryptamine (serotonin, TR5) and nor-epinephrine (NOR), adult samdov Wistar rats (weight 240 ± 10 g) are taken as experimental animals. After an overnight fast, these animals are injected subcutaneously (1 ml / 100 g) with an aqueous solution of the test compound, then the animals are placed under observation in isolated cells. After 30 minutes, the rats were injected intravenously with 1.25 mg / kg of apomorphine hydrochloride (APO), after which, observed for 1 hour, the presence of such apomorphine-induced effects as excitability and characteristic chewing was determined. Then, 40 mg / kg of 5-hydroxytryptamine (TRY) was administered intravenously to the same animals, after which typical consequences for tryptamine were noted as bilateral increasing spasmodic effects. Two hours after the start of the test, 1.25 mg / kg of norepinephrine (NOR) was intravenously injected into the same animals and possible deaths were observed for 1 hour.
    In tab. 3 shows the values of the ED of a number of compounds tested. The value of Efljo is the dose (mg / kg body weight) that protects 50% of the animals from the effects of the administration of apomorphine, 5-hydroxytryptamine or norepinephrine.
    The test compounds obtained according to the proposed method are opposed to compounds having a similar structure (the first are in the left half of Table 4, the others in its right half).
    ABOUT
    five
    0
    The court according to the results given in the table. 4, the contrasted compounds are antagonists with respect to 5-hydroxytryptamine (serotonin) and aporomorphine and norepinephrine. The compounds of the proposed method are antagonists solely with respect to serotonin.
    Derivatives (-piperidinylalkyl) pyrimidinone are slightly toxic at a dose of 40 mg / kg body weight, lethal. Not observed in any case, in one animal, which indicates that the LDj-Q for the tested compounds should be significantly higher than 40 mg / kg live weight.
    However, they are specific antagonists with respect to serotonin.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derivatives (1-25 piperidinylalkyl) pyrimidinone General formula
    /
    X
    where R H, OH, X - S, CH
    five
    R,
     2
     I
    R, R,
    Rj - Н А -
    WITH -;
    2
    OR
    RZ H, R, - CH
    -C, -, -CHjCH CH -,
    3
    0
    R, R R. - RC R, - R - hydrogen.
    NH
    z
    H, R.
    CH,
    hydrogen; R 5
    0
    five
    3
    - H;
    halogen, g - R - methyl; Ar is phenyl, phenyl substituted by halogen or methyl, pyridyl;
    Ar - pheny.p, phenyl substituted by halogen, hydroxy, methoxymethyl or trifluoromethyl group, or their addition salts with pharmaceutically acceptable acidic acids, characterized in that the compound of the general formula
    H. N. A u g
    where X, A have the indicated meanings; V / - halogen.
     SS
    introduced into interaction with piperidine of the general formula
    R
    HN
    AH
    where R, AG, Ar have the indicated values,
    in A-methyl-2-pentanone in the presence of an alkaline agent.
    Priority featured:
    11.11.82 with R - N; X - S, CH, CH-CH; A -, - or
    R
     -
    (sh.,
    -C-C-, where R Kg is H, CH,,
    Rarf
    Rj is CHj, Ar, is phenyl, phenyl substituted by halogen or methyl; Ar - phenyl, phenyl, substituted with halogen, oxy-, methoxy-, trifluoromethyl.
    07.27.83 at. R-OH, AXIS ,,, X - -TCH / -CHRR.
    A - -C-6-, where halogen; R4-H; K is methyl; Ar is phenyl substituted with pyridyl; Ar ,, - phenyl, phenyl, substituted with halogen, oxy-, methoxy-, trifluoromethyl.
    Table 1
    R
    -
    Base 0,00071
    - -0.0025
    0,0013 0,0013
    -, 0025
    -, 0025 2HC1
    2HCI 2HC1
    2HC1
    0,00032 .СО, 0025 0,0025 0,00071
    T..SSC 1: CCCH,) 2iCjH, A-OH-CjH,
    75SClIi-CHj, 2HCj, IIf4-OH-SbH4
    78С1 СНСН-СН2НC il, -OH-СN
    80SCH SI 2HC llj4-OH-C il
    81S С1ЬС (СН,) 2НCjHy2-СН, -С4Н4
    85SCH С СН,) 2НC HjЗ-СР-СЬН
    86CHjCHj-CH.i-CH 2HCj Hj. 3-CF, -CeH
    87CH-CHCHN CH2HS H, 3-CF-CtH
    89. SСН СН2НCJ1,3-CF, -CbH
    90SCH.i-CHi2НсНН, З-СР -С Н
    92CHjCHj-CH-CHi 2 H, 2-CH-C H4 Butandi-0.00032
    nova-acid
    A4 table
    D. / Shp, k l
    A UTG.
    - y-Shg-Shg- (, o
    one
    ,
    Ag Ag ARO TRY NOR .. yi, TBV p
    Performance XAI AGRO TRY KOR
    LILL: 1iIL1SCH CH 4G-SbH5 40 0.16 40 ASCHrCH, 0.02 0.01 0.63
    113S CHj -CHjiF-C HjAF-C Hj 400.08 40BS. CH, -CH 4F-C, Hj 0,220,110,78 3CHj-CHj CHj-CH, AF-CjH, 4F-CjH5 400.04 40CCH, -CH, CHj-CHj4F-C (Hs 1,250,162,5
    114S CHj-CHj4F-C4H5AF-CjHj 400.04 40DS CH, -CH, 4F-C, HjO, 310,631.25
     CH CH4F-C6H54F-CjH5 400, OU 40ECH: CH CH CH4F-CjH5O, l6O, 1O1.25
    Compiled by V. Volkov Editor I. Nikolaichuk Tehred I. Popovich Corrector L. Patay
    Order 1983/58 Circulation 372Subscription
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab. 4/5
    Production and printing company, Uzhgorod, st. Project, 4
    e 0,00071
    0,0025
    0,0013 0,0013
    0,0025
    0,0025
    0,00032 .СО, 0025 0,0025 0,00071
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    IN159576B|1987-05-30|
    GR81277B|1984-12-11|
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    法律状态:
    优先权:
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    US06/517,612|US4485107A|1982-11-01|1983-07-27|[[Bismethylene]-1-piperidinyl]alkyl-pyrimidinones|LV920230A| LV5045A3|1982-11-01|1992-11-27|Method for obtainingpyrimidinone derivatives|
    LTRP368A| LT2083B|1982-11-01|1993-02-26| PIRIMIDINON'S BONUS RECEIVING BUDGET|
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