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    • 专利摘要:
    Novel 1-(cyctohexyl)-4-aryl-4-piperidinecarboxylic acid derivatives, bearing in the 4-position of the cyclohexyl ring a cyano group and an aryl moiety, said compounds displaying useful antihistaminic properties.
    公开号:SU1230467A3
    申请号:SU813233002
    申请日:1981-01-23
    公开日:1986-05-07
    发明作者:Стокброекс Раймон；Люйкс Марсель；Уильямс Джоан
    申请人:Жансен Фармасетика Н.В.(Фирма)；
    IPC主号:
    专利说明:

    G is hydrogen or lower alkyl;
    R is hydroxyl, lower alkoxy, lower alkoxy - lower alkoxy, phenoxy - lower alkyl, phenoxy - lower alkoxy in which phenyl can be substituted by lower alkoxy or lower alkyl, amine, di (lower alkyl) amino, di (lower adyl) amino - lower alkoxy, 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl, (1-pyrrolidinyl) - lower alkoxy or (4-morpholinyl j - lower alkoxyl; independently from each other, phenyl or phenyl, new - or disubstituted by different groups selected from halogen atom, lower alkyl, lower alkoxy, alkoxycarbonyl, trif ORMETO or pyridinyl, or thienyl group, their acid addition salts, the stereochemically isomeric, characterized and 1iys the compound of general formula
    and Ag

     0
    where Ag has the indicated values,
    subjected to interaction with the compound of the General formula
    , E
    one
     L A 2
    / Ag
    where R R - and Ar have the above values,
    in the presence of catalytic amounts of a strong acid in an inert organic solvent at a temperature of UJAb
    re KimeFjuH relktsiioipop mlspy, n obtained enam1I oGpney formula
    where R, R, Ar, and Ar have the indicated meanings,
    subjected to reduction in the presence of a complex metal hydride in an inert organic solvent at 30–100 ° C, followed by isolation of the target product in free form as their acid addition salts, or as their stereochemically isomeric forms.
    Priority bye featured:
    24.01.80 with Ar - phenyl or phenyl, mono- or disubstituted with halogen, lower alkyl, lower alkoxyl, or pyridinyl;
    Ar is phenyl or phenyl, mono- or di-substituted by halogen by lower alkyl, 5 lower alkoxy, trifluoromel or pisp1im alkoxycarbonyl, 09/29/80 with Ar-phenyl, mono or disubstituted by lower alko chicarbonyl or trifluoromethyl, or saw;
    Ag - pyridinyl or tiepil.
    . The invention relates to the field of obtaining new pr1) of ivo / (ny piperidine of the general formula
    Ri
    . (}
    - / Mg
    where R is a hydrogen atom or lower alkyl; R is hydroxyl, lower alkoxy, lower alkoxy-lower alkoxy, phenoxy is lower alkyl, phenoxy is lower alkoxy, in which phenyl can be substituted by lower alkyl or lower alkyl, amino, di (lower alkyl) amino , di (lower alkyl) amino - lower alkoxy, 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl, (1-pyrrolidinyl) - lower alkoxy, (4-morpholinyl) - lower alkoxy;
    Ar and Ar are independently of one another phenyl or phenyl monoxy disubstituted with different groups selected from halogen atom, lower alkyl, lower alkoxy, alkoxycarbonyl, trifluoromethyl or pyridinyl, or thienyl,
    or their acid addition salts, or. their stereochemical isomeric forms.
    The purpose of the invention is to develop, on the basis of known methods, a method for the preparation of new piperidine derivatives with a pronounced anti-histamine effect and low toxicity.
    A. Obtaining intermediate products.
    Example. To the Grignard complex, previously stirred from 39.7 wt. H, stirred and heated under reflux. 1-bromo-4-α-fluoro-2-methylbenzene and 5.1 wt.h. magnesium at 225 mph; tetrahydrofuran was added in portions of 8.4 May; h. para formaldehyde. After completion of the reaction, stirring is continued for over heating with a reflux condenser. The reaction mixture is cooled and crushed onto crushed ice and acetic acid. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. Oethink distilled to obtain 14 mach. (47,%) 4-fluoro-2-methylbenzenemethanol; bp (low
    pressure given by a water jet pump).
    In a similar way, 4-chloro-3- (trifluoromethyl) benzomethanol is also obtained; bp 90 ° C at a pressure of 0.4 mm.
    Example2. K 14.3 ma.ch. 14 in m.h. solution is added dropwise with thionyl chloride. 4-fluoro-2-methylbenzenemethanol and 0.9 wt.h, N, N-dimethylformamide B 45 mac.h. methylbenzene when cooled on ice with water. Then 135 may be added, h. methylbeisol and stirring is continued for 1 hour at room temperature. The reaction mixture was evaporated to give 17 mae (100%) 1 - (chloromethyl) -4-fluoro-2-methyl-benzene as a residue.
    In a similar way, 1-chloro-4- (chloromethyl) -2- (trifluoromethyl) benzene is also obtained; bp 100 ° C at a pressure of 10 mm.
    Example 3. May, May 16, h, 1 - (chloromethyl) -4-fluoro-2-methylbenzene, 7.8 parts per hour. of potassium cyanate in a small amount of water, 0.1 May. Potassium iodide and 240 mph. of 2-propanone are stirred and heated under reflux for 22 hours. The reaction mixture is cooled and filtered. The filtrate is evaporated. The carbon dioxide is taken up in water and the product is extracted with methyl benzene. The extract is dried, filtered and evaporated, yielding May 13, h, (87.2%) of 4-fluoro-2-methylbenzene-acetonitrile as residue.
    In a similar way, 4-chloro-2- (trifluoromethyl) benzene-acetonitrile is also prepared; bp 83 ° C at a pressure of 2 mm.
    Example 4. A mixture of 221 May, h, 4-fluorobenzene-acetonitrile, 700 May, h, solution of sodium methoxide (30%) and 900 wt.h., dimethylbenzene is stirred for 5 minutes. Then 309 parts by weight were added dropwise. methyl 2-propenoate (reaction is exothermic: the temperature is reduced to 65 ° C), while the reaction is complete, stirring is continued overnight at reflux temperature. Methanol is distilled off until the internal temperature is reached. After cooling, 1000 May, h 6 n is added dropwise. Hydrochloric acid solution and all this is mixed and heated under reflux for 5 minutes. Poole cooling oil
    are divided. The organic phase is dried, filtered and evaporated. The residue is stirred and heated with a reverse steam bath for 4 hours along with 500 mas. Parts. water and 500 ma.ch. hydrochloric acid solution. After cooling, the product is extracted with trichloromethane. The extract is successively washed with water, a dilute sodium hydroxide solution and again with water until neutralized, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 134.5 parts by weight. 1- (4-fluorophenyl) -4-oxocyclohexane-carbonitrile, m.p. 91.8 C.
    In accordance with the same procedure and using an equivalent amount of a suitable arylacetonitrile as the starting material, the following diclohexanones I of the general formula are also obtained.
    oh oh.
    CN Ag
    one
    Ag
    2-pyridine
    2-OCHs-N
    Temperature, C
    M.p. V0,1
    T, kip. 170 // 0.3 mmHg
    2-och ,, 5-Cf-C, Hj
     (
    W-CPR, 4Cl-CgH
    Z-CHz-CgH
    2,3-Cf, -C.H
    63
    M.p. 147.2
    2-Br-CgH
    2-CH, 4-F-CgH ,,
    2-CH ,, b1
    B o
    2-F-C, H,
    3.4- (CHj),, 2-CH, ZS1-C, H 4-C, H, -C, H.,,
    3-CF, -C N,
    3 S c

    Example 5. To mix and heated under reflux a mixture of 71 wt.h. sodium cyanide, 99 mah. ethanol and 85 math. water, a solution of 134 masses was added dropwise. 2- (chloromethyl) -4-fluoro-1-methylbenzene in 99 parts m. ethanol. After completion of the reaction, stirring is continued at the beginning; 1L for 6 hours at reflux and then overnight at room temperature. The ethanol is distilled off and the residue is taken up in 4-methyl-2-pentanone and water. The layers are separated and the aqueous phase is triply ecethyrutoted using 4-methyl-2-pentanone. The combined organic phases are washed twice with water, dried, filtered and evaporated. The residue is distilled, yielding 98 parts by weight. 5-fluoro--2-methylbenzeneacetonitrile; bp 124-128 With at a pressure of 10 mm.
    Example 6. For a stirred and hot solution of 8.5 mash.h. N, N, N-triethylbenzenemethanammonium chloride, 40 wt.h. sodium hydrokie and 360 ma.ch. A 50% hydrated sodium hydroxide solution adds a 72.7 mash of heat absorber. N, N-Bie (2-chloroethyl) -4-methylbenzene-sulfonamide and 45.5 moles. 254-dichlorobenzeneacetonitrile in 90 parts by weight. Tetrahydrofuran. After completion of the reaction, stirring is continued for 3 hours at 50 ° C. The reaction mixture is cooled, 216 wt.h. methylbenzene and 480 wt.h. water and oil are separated. The organic phase is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 28 parts by weight. (29%) 4- (2,4-di-chlorophenyl) -1- (4-methylphenylsulfonyl) -4-piperidinecarbonitrile, m.p. 45 C. According to the same procedure and using an equivalent amount of a suitable arylacetonitrile, the following is obtained:
    4- (2-fluorophenyl) -1 - (4-methylphenyl-euphonyl) -4-piperidinecarbonitrile as a residue; (
    4- (5-chloro-2-methokeiphenyl (-G- (4-methylphenylsulfonyl) -4-piperidinecarbonitrile;
    1 - (4-methylphenylsulfonyl) - (trifluoromethyl) phenyl-4-piperidinecarbonitrile;
    4- (2-methokephenyl) -1 - (4-methylphenylsulfonyl) -4-piperidinecarbonitrile.
    Example 7. A solution of 29.6 mas.h. N, M-bis (2-chloroethyl) -4-methylbenzene sulfonamide and 14.9 wt.h. 4-fluoro-2-methylbenzeneacetonitrile in 90 wt.h. methylbenzene is added dropwise to a solution of 5.6 wt.h. lithium amide 270 wt.h. methylbenzene at 90 ° C. After completion of the reaction, everything is heated to reflux and stirred at this temperature overnight. The reaction mixture is cooled, poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanol to obtain 27 parts by weight. (72.6%) 4- (4-fluoro-2-methylphenyl) -1 - (4-methylphenylsulfonyl) -4-piperidinecarbonitrile.
    In accordance with the same methodology and using equivalent amounts of suitable starting materials, the following is obtained:
    4- (3-chloro-2-methylphenyl j-1 - (4-methylphenyl-sulfonyl-4-piperidinecarbonitrile;
    4- (5-fluoro-2-methylphenyl) (4-methylphenylsulfonyl) -4-piperidinecarbonitrile, m.p. 168 ° C;
    (B) -4- (2-fluorophenyl-3-methyl-1- (4-methylphenylsulfonitrile) -4-piperidine carbonitrile, mp 154 ° C;
    (A) (±) -4- (2-ftsrphenyl) -3-methyl--1 - (4-methylphenylsulfonesh1) -4-piperidinecarbonitrile, so pl. 135 ° C.
    Example 8. A mixture of 35.8 wt.h. 4- (2-fluorophenyl) -1 - (4-methylphenylsulfonyl) -4-piperidinecarbonitrile and 50 wt.h. 75% aqueous solution of sulfuric acid is stirred for 4 hours at. 192 parts by weight are added dropwise. ethanol. After completion of the reaction, stirring is continued for 5 hours at reflux temperature. The reaction mixture is cooled and poured onto crushed ice. All this is alkalinized with ammonium hydroxide and the product is extracted with dichloromethane. The extract is dried, filtrated and evaporated to obtain 17.2 parts by weight. (68.4%) 4- (2-fluorophenyl) -4-piperidinecarboxylic acid ethyl ester as a residue. Using the same hydrolysis procedure, starting from the corresponding carbonitrile, 4- (3-methylphenyl) -4-piperi-, dicarboxylic acid ethyl ester hydrochloride and 4- (2,4-dichlorophenyl) -4-piperidinecarboxylic acid hydrochloride are obtained. .
    Example 9. 16,32 wt.h. 1- - (4-methylphenylsulfonyl) (trifluoromethyl) -phenyl | -4-piperidinecarbonitrile is added in portions to 35 mash. 75% aqueous solution of sulfuric acid and the mixture is stirred and heated for 15 hours at 155 ° C. Then drop
    add 100 wt.h. ethanol. After completion of the reaction, stirring is continued overnight at reflux temperature. The reaction mixture is cooled.
    and poured onto ice - water. All this is alkalinized with ammonium hydroxide and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is taken up in the hydrochloride salt in 2,2-oxibispropane and 2-propanol. The salt was filtered off and the residue was obtained to give 6% by weight (43.9%) of ethyl ester (ethoxycarbonyl) -phenyl-4-piperidine- hydrochloride,
    carboxylic acid; m.p. 121 ° C.
    "
    Example 10. A mixture of 11.3 wt.h. 1- (4-methylphenylsulfonyl) (trifluoromethyl) -phenyl-4-piperidinecarbonitrile, 5.6 wt.h. potassium hydroxide and 220 wt.h. 1,2-ethanediol is stirred and heated to reflux for 48 hours. The reaction mixture is cooled and decanted.
    on ice - water. All this is acidified.
    hydrochloric acid and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated, the result of 11.8 wt.h. (100%) 1- (4-methylphenylsulfonyl) (trifluoromethyl) -phenyl-4-piperidinecarboxylic acid as a residue.
    I
    In accordance with the same method of hydrolysis and starting from the corresponding carbonitrile receive:
    4- (5-hprp-2-methoxyphenyl) -1- (4-methylphenylsulfonyl) -4-piperidinecarboxylic acid;
    4- (2-methoxyphenyl) -l- (4-methylphenylsulfonyl) -4-piperidinccarboxylic acid L as a residue;
    4- (4-fluoro-2-methylphenyl) -1 - (4-methylphenylsulfonyl) -4-piperidinecarboxylic acid;
    4- (3-chloro-2-methylflnile) -1 - (4-methylphenylsulfonyl) -4-piperidinecarboxylic acid;
    ch- (5- | mountains - 2-methylphenyl) -1 - (4-methyl (|) nnsul15fonn.p) -4 -nnperidinekprobo- acid, so pl. 57 (;;
    (B) -A- (2-fluorofsnnl) -3-methyl-1- - (4-methylphenylsulfonyl) -4-piperidine-carboxylic acid, m.p.
    (A) (+) - A- (2-fluorophenyl) -3-methyl--1 - (A-methylphenylsulfoyl) -4-piperidyl carboxylic acid as a residue.
    Example 11. To a stirred and boiling under reflux mixture of 21 wt.h. 4- (5-chloro-2-methoxy-phenyl) -1 - (4-methylphenylsulfonyl) -4-piperidinecarboxylic acid and 270 May, h. benzene was added dropwise to 36 m.h., thionyl chloride. After completion, all the permega-vapor is heated to reflux for 4 hours. The reaction mixture is evaporated and the residue is washed twice with methyl benzene, giving 22 wt. H. (100%) 4- (5-chloro-2-methoxyphenyl) -1 - (4-methylphenylphenyl) -4-piperidinecarbonylchloride.
    In a similar way receive:
    4- (2-methoxyphenyl) -1- (4-methylphenylsulfonyl) -4 piperidinecarbonyl chloride as a residue;
    1 - (4-methylphenylsulfonyl) - (trifluoromethyl) -phenyl-4-piperidine-carbonyl chloride as a residue;
    4- (4-fluoro-2-methylphenyl) -1- (4-methylphenylsulfonyl) -4-piperidinecarbonyl chloride as a residue;
    4- (3-chloro-2-methylphenyl) -1 - (4-methylphenylsulfonyl) -4-piperidinecarbonyl chloride as a residue;
    4- (5-fluoro-2-methylphenyl) 1-4-.4-methyl-phenylsulfonyl) -4-niperidine carbonyl chloride as a residue;
    (A) -3-methyl- - (4-methylphenylsulfonyl) -4-phenyl-4-niperidinecarbonyl chloride;
    (B) -4- (2-fluorophenyl; -3-methyl-1- (4-methylphenylsulfonyl) -4-piperidinecarbonyl chloride,
    (A) (+) -4- (2-fluorophenyl) -3-methyl-1 - - (4-methylphenylsul1) fonyl) -4-piperidine carbonyl as a residue;
    (B) (-) - 3-Methyl-1- (4-methylphenylsulfonyl) -4-phenyl-4-piperidinecarbonyl chloride;
    (B) (+) - 3-methyl-1- (4-methylphenylsulfonyl) -4-feunyl-4-piperidinecarbonyl chloride in pipa residue.
    Note 12. A mixture of 36.5 sp. Ch 4- (3 x. 1 (1p-, -g.1 (| -yl (b (P1 nl) -1 - (4-me1 nylgh lfg.pch. :) - - 1-pnpern.glinklrbt {il
    io.
    tsporida and 240 ma.ch. ethanol is stirred and heated under reflux overnight fridge. The reaction. The mixture is treated with activated hot charcoal now. The latter is filtered off and the product is allowed to crystallize from the filtrate by spontaneously cooling to room temperature. The product is filtered and dried, yielding 33 mph. (89.1%) 4- (3-chloro-2-methylphenyl) -1 -1 (4-methylphenylsulfonyl) -4-piperidinecarboxylic acid ethyl ester; m.p. 134 ° C. 5 According to the same procedure, esterificin, by reacting the corresponding acid chloride with a suitable alcohol, we obtain:
    4- (5-chloro-2-methoxy-phenyl) -I- (4-methylphenylene sulfonyl) -4-piperidinecarboxylic acid ethyl ester;
    4- (2-methoxyphenyl) -1- (4-methylphenylsulfonyl) -4-piperidinecarboxylic acid ethyl ester;
    1 - (4-methylphenylsulfonyl) -4- 3- (trifluoromethyl) -phenyl} -4- -piperidinecarboxylic acid ethyl ester;
    4- (4-fluoro-2-methylphenyl) -1 - (4-methylphenylsulfonyl) -4-pyr30-peridinicarboxylic acid ethyl ester, mp. 1 5 1 ° C;
    4- (5-fluoro-2-methylphenyl) -I (4-methylphenylsulfonyl) -4-pyperidinecarboxylic acid ethyl ester, m.p. 94 ° C; 35 (A) -phenylmethyl ester, 3-methyl-I- (4-methylphenylsulfonyl) -4-phenyl-4-piperidinecarboxylic acid; .
    (B) Phenylmethyl 4- (2-fluoro-, phenyl) -3-methyl-1- (4-methylphenylsulfo-40-nyl) -4-piperidinecarboxylic acid,. m.p.
    (A) (+) - Phenylmethyl ester 4- (2- -fluorophenyl) -3-methyl-1- (4-methylphenylsulfonyl) -4-piperidinecarboxylic acid45
    lots;
    (B) (+) - P-methyl-1- (4-methylphenylsulfonyl) -4-phenyl-4-piperidinecarboxylic acid phenylmethyl ester;
    (E) () is 3-methyl-1- (4-methylphenylsulfonyl) -4-phenyl-4-piperidinecarboxylic acid phenylmethyl ester;
    (B) Phenylmethyl ester of 3-methyl--1 - (4-methylphenylsulfonyl) -4-phenyl-4-piperidinecarboxylic acid. Example 13. A mixture of 17 ma.ch. 4- (5-chloro-2-methoxy-phenyl) (4-methylphenylsulfonyl) -4-piperidinecarboxylic acid ethyl ester.
    7.5 ma.ch. FenOoah and 135 ma.ch. rotated bromiecho-hydrated kieloty in a ukeueno kielota stirred overnight at room temperature. The reaction mixture is poured over the water and all over with 2.2-hydroxypropane. Upon cooling, the aqueous phase is alkalized with sodium hydrocooxide. The product is ektratragut trichloromethane. Ekektract is washed with water, o- About fraction 22 ma.h., receiving 28 ma.h.
    () c-methylbenzenemethanamine (B) (+) - -3-methyl-1 - (D-methylphenyleulphonyl) - -4-phenyl-4-piperidinecarbonic kielota (1: 1) 15 Laughs 28 ma.ch. s.-methylbenzenemethanamine (B) (+) - 3-methyl-1- (4-methyl-phenylen-L-phonyl) -4-phenyl-4-piperidine-carboxylic bielota (1: 1), 60 wt. concentrated hydrogen chloride 20 kielotes and 1000 mach. water boils for a certain time. The reaction is filtered. The filter cake was rinsed with water and stirred in boiling water. The product is filtered out and grown in trichloromethane. The latter is dried, filtered and evaporated. The precipitates are boiled in 2.2-x bee propane, yielding 19.7 wt.h. (93%) (B) (+) - 3-metshI-l- (4-methylphenyl-30 eulfonyl) -4-phenyl-4-piperidinecarbonyl kieloty.
    shake, filter and evaporate. The hydrochloride is converted to the hydrochloride eol in 2-propanol and 2,2-oxybiepropane, crawling 7 wt.h. (55%) 4- (5-chloro-2-methoxy-eiphenyl) -4-piperidinecarboxylic acid ethyl ester hydrochloride.
    Example 14. A. To a stirred and boiling air solution 73 ma.h. (B) (+) - 3-methyl-1- (4-methylphenyleulphonyl) -4-phenyl-4 piperidinecarbonic kieloty in 3200 wt.h. 2-propanol is added to a 24 math stirrer. (-) .- -methylbenzenemethanamine. Raetvor is given the opportunity to cryalite. The product is filtered and recrystallized three times correspondingly from 4,800, 4,000 and 3,200 wt.h. 2-propanol, getting 27 mph. (27%) o (-methylbenzenemethanamine (B) (-) - 3-methyl-1- (4-methylphenylene sulfonyl) -4-phenyl-4-piperidinecarboxylic bilets - (1: 1).
    Dare 27 ma.ch. o (methylbenzenemethanamine (B) (-) - 3-methyl-1- (4-metsh-1-phenyleulphonyl) -4-phenyl-4-piperidine-carboxone kielota (1: 1), 60 m.h., concentrated hydrochloride-hydrogen kielota and 1000 parts of water are stirred and boiled for a while. The precipitated product is filtered, washed with water and boiled in water. The product is filtered and taken up in trichloromethane. The latter is dried, filtered and evaporated. The residue is stirred at 2, 2-oxibispropane, giving 18.4 ppmw (94%) (B) (-) - 3-methyl-1- (4-methylphenyl-eulphonyl) -4-phenyl-4-piperidinecarboxylic acid.
    B. To a stirred and boiling reflux solution of 100 mash. (B) (+) - 3-methyl-1- (4-methylphenylsulfonyl) 4-fensch-1-4-piperidinecarboxylic acid in 1600 mas. 2-propanol was added a 32.5 mash stopper. (+) -q -methylbenzenemethane-amine in 400 wt.h. 2-propanol. The reaction mixture gives the possibility of cryprimer 15. A suspension of 11 mph. ethyl ether 1- (4-methyl35 phenyleulfonyl) (trifluoromethyl) -phenyl} -4-piperidinecarbonic kielota and 8 ma.ch. tetraethylammonium bromide in 200 ma.h. ethanol is subjected to electrolytic detosylation at
    40 -2.15 V using a mercury cathode and a mixture of Ag and AgCT as a reference electrode. The ethanol solution is decanted and the solvent is distilled off. The residue is taken up in dichlorometa45. The latter is washed three times with water, the mixture is filtered and evaporated. The residue is converted to the hydrochloride salt in 2-propanol and 2,2-hydroxypropane. The salt is filtered off and dried with a yield of 6.9 parts per hour. (85.2%) (trifluoromethyl) -phenyl -4-piperidinecarboxylic acid ethyl ester hydrochloride,
    55 Similarly, receive:
    4- (2- -methoxyphenyl) -4-piperidinecarboxylic acid ethyl ester hydrochloride;
    steel The product is filtered off and the chips are repeatedly recrystallized from 6400, 5600, 4800 and 3200 wt.h. 2-propanol. The product is filtered and recirculated from 2400 wt.h. 2-propanol. It is again filtered, getting 22 may. The filtrate is evaporated and the residue is added to the cryetallized
    Example 15. Suspension 11 ma.h. ethyl 1- (4-methylphenylene sulfonyl) (trifluoromethyl) -phenyl} -4-piperidinecarbonic kielta and 8 ma.ch. tetraethylammonium bromide in 200 ma.h. ethanol is subjected to electrolytic detosylation at
    -2.15 In using a mercury cathode and a mixture of Ag and AgCT as the reference electrode. The ethanol solution is decanted and the solvent is distilled off. The residue is taken up in dichloromethane. The latter is washed three times with water, the mixture is filtered and evaporated. The residue is converted to the hydrochloride salt in 2-propanol and 2,2-hydroxypropane. Salt is filtered off and dried to obtain 6.9 parts per hour. (85.2%) (trifluoromethyl) -phenyl -4-piperidinecarboxylic acid ethyl ester hydrochloride,
    In a similar way receive:
    4- (2- -methoxyphenyl) -4-piperidinecarboxylic acid ethyl ester hydrochloride;
    3
    4- (4- (3) TOP-2-methyl-phenyl) -4-piperidinecarboxylic acid ethyl ester as a residue;
    4- (3-chloro-2-methylphenyl) -4-piperidinecarboxylic acid ethyl ester as a residue;
    (B) -phenylmethyl 3-methyl-4-phenyl-4-piperidinecarboxylic acid (1: 1) ethanedioate;
    (A) Phenylmethyl ester of 3-methyl-4-piperidinecarboxylic acid as a residue;
    4- (5-fluoro-2-methylphenyl) -4-piperidinecarboxylic acid ethyl ester hydrochloride, m.p. 198.8 s;
    4- (2-fluorophenyl) -3-methyl-4-hydrochloride (B) -phenylmethyl ester hydrochloride ester, t.pl., 220 ° C
    ethanedioate (A) (+) - phenylmethyl 4- (2-fluorophenyl) -3-methyl-4-piperidinecarboxylic acid ester (1: 1), m.p. 170 ° C;
    hydrochloride (c) (-) - phenylmetsh: (3-methyl-4-phenyl-4-piperidine carboxylic acid ester;
    3-methyl-4-phenyl-4-piperidinecarboxylic acid hydrochloride (B) (+) - phenylmethyl ester.
    Example 16. To a stirred and boiling under reflux mixture of 14 mash., 4-phenyl-4-piperidinecarbonyl chloride hydrochloride and 130 mash. methyl benzene was added dropwise to 6.9 wt.h. 1-piperidinepropanol. After the addition is complete, stirring is continued overnight at reflux temperature. The methylbenzene phase is decanted and the residual oil is boiled in a mixture of 2,2-oxy-bis-propane and ethanol. The precipitated product is filtered and dried to give 4 May. 3- (1-Piperidinyl) propyl 4-phenyl-4-piperidinecarboxylic ester dihydrochloride monohydrate, m.p. 1 7 6, 1.
    In accordance with and with the use of quantities of suitable als, receive:
    2- (dimethylamino) ethyl 4-phenyl-4-piperidinecarboxylic acid dihydrochloride, mp, 230 ° C;
    3- (dimethylamino) dihydrochloride pro-4-fekyl-4-piperidinecarboxylic ester saw ether (L (m.p. 150 C;
    2 - (- pyrrolidinyl) -ethyl dihydrochloride; f | -tra 4 - feiil-4 using the same piperite method equivalent to the original mother
    25
    five
    - ABOUT
     five
    -;
    - 20
    -
    30 - 35 40 45
    -
    lA acid
    - dincarboxylic acid, so pl.,,
    ethanedioate 2- (4-morpholinyl) ethyl; 4-phenyl-4-piperidinecarboxylic ester (: 1), so pl. 210 ° C.
    Example 17. A mixture of 4.5 May, h 4-OXO-1- (2-pyridinyl) cyclohexane-carbonitrile, 5.2 parts by weight. 4-phenyl-4-piperidinecarboxylic acid ethyl ester, 1 wt. 4-methylbenzene-sulfonic acid and 225 May, part of methyl benzene is stirred and refluxed overnight using a water separator. The reaction mixture is evaporated and the residue is crystallized from 2-propanol, yielding 4.5 m.h. (45%) 1- - 4-cyano-4- (2-pyridinyl) -1-diclohexenyl-4-phenyl-4-piperidine-carboxylic acid ethyl ester, m.p. 160 C.
    In accordance with the same method and using equivalent amounts of respectively substituted cyclohexanes and pyridines, the following is obtained:
    1-C4-cyano-4- (4- -fluorofenyl) -1-cyclohexen-1-yl-4-phenyl-4-piperidinecarboxylic acid ethyl ester as a residue;
    2- (4-cyano-4-phenyl--1-cyclohexen-1-yl) -4-phenyl-4-piperidinecarboxylic acid ethyl ester as a residue J
    1-4-cyano-4- (4-methoxyphenyl) -l-cyclohexen-1-yl3-4-phenyl-4-piperidinecarboxylic acid ethyl ester as a residue;
    (4-chlorophenyl) -4-cyano-1-cyclohexen-1-yl-4-phenyl-4-piperidinecarboxylic acid ethyl ester as a residue;
    - (4-cyano-4-phenyl-1-cyclohexen-1-yl) -4-phenyl-4-piperidinylcarbonyl piperidine as a residue.
    B. Obtaining target compounds.
    Example 18. To a stirred mixture consisting of 4.5 May, h, ethyl ester. 1. 4-cyano-4- (2-pyridinyl) -1-cyclohexyl-4-phenyl-4-piperidinecarboxylic acid and 80 ma.ch. 50 ethanol, added in portions
    0.4 May, h sodium borohydride. After that, stirring is continued first overnight at room temperature and then for 30 minutes at. The reaction mixture is cooled and poured into water. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. Remainder
    55
    Crystallized from 2-nporia-nola to give 2 mth. h, (35%) ethyl ester of I-A-cyano-4- (2-pyridinyl) cyclohexyl-4-phenyl-4-piperidiparboxylic acid, mp, 157.1 ° C, yield 35%.
    According to this method, receive:
    1- (4-cyano-4-phenyl-cyclohexyl) -4-phenyl-4-piperidine-benzoic acid ethyl ester, m.p. 130 ,, output 24%, reaction temperature
    1-4-cyano-4- (4-methoxyphenyl) cyclohexyl | -4-phenyl-4-β-piperidinecarboxylic acid ethyl ester, mp. 122 ,, yield 30%, reaction temperature 100 ° C;
    (4-chlorophepyl) -4-cyanocyclohexyl j-4-phenyl-4-piperidinecarboxylic acid ethyl ester, m.p. 155 ° C yield of 27%, the reaction temperature of 100 ° C
    1-phenyl-4-4-feiyl-4- (1-piperidinyl-carbonyl) -piperidinyl-cyclohec sarcarbopitrile hydrochloride, m.p. 283.2 C, yield 19%, reaction temperature 80 s.
    Example 19. To I ma.ch. solution 2 wt.h. Thiophene at 40 mah. ethanol was added 4.7 wt. 1- (4- -fluoro-2-methylphenyl) -4-oxo-cyclohexancarbonitrile, 5.4 wt.h. 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride, 2 wt.h. sodium acetate and 120 ppm ethanol. The whole mixture is hydrogenated at normal pressure of 30 ° C in the presence of 2 May, h. 10% palladium on charcoal catalyst support. After uptake of the calculated amount of hydrogen, the mixture is filtered with a Khoflo filter and the filtrate is filtered out. From the residue, the free base was taken in the usual manner using ammonium hydroxide and the product was extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel using a mixture of trichloromethane and ethanol (98.5: 1.5 in o6i3eMy) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is subjected to crystallization from ethanol to give 3 parts of (4%) ethyl 4-cyano-4- {4-fluoro-2-methyl-phenyl) cyclohexyl-4-phenyl-4-ethyl - piperidinecarboxylic acid, so pl. 135.2 ° C, yield 33%,
    For the same metric, using equivalent amounts of the corresponding starting materials, get soy
    five
    0
    five
    0
    five
    0
    five
    0
    five
    days presented in the table. in table. 2 and 3 give an elemental analysis for some of them.
    Example 20. In a stirred mixture of 11.7 wt. 1 - 4-cyano-4- (. fluorophenyl) - -cyclohexep-1-yl-1-4-phenyl-4-piperidinecarboxylic acid ethyl ester, 1 wt.h. 30% aqueous solution of sodium methoxide and 320 mash., Methanol in parts is added on 1 May, h. sodium borohydride. After that, stirring is continued overnight at temperature. The reaction mixture is poured into ice water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is subjected to crystallization from ethanol, obtaining 5.9 masses. H. (.B) -ethyl 1-4 cyano-4- (4-fluorophenyl) -1-cyclohexyl -4-phenyl-4-piperidinecarboxylic acid, mp. I45.8 ° C, yield 50%.
    K 2 ma.ch. solution 2 wt.h. Thiophene at 40 mah. ethanol was added 27 mph. 1 - (4-fluorophenyl) -4-oxocyc-lehexanecarbonitrile, 34 wt.h. 4-phenyl-4-piperidinecarboxylic acid ethyl ester, 15 wt. sodium acetate and 400 wt.h. ethanol. The whole mixture is hydrogenated at normal pressure and in the presence of 5 mph. 10% palladium on charcoal catalyst support.
    After absorption of the calculated amount of hydrogen, the catalyst is filtered off. rovyvat on the filter Khuflo and filtrate enter. The free base is isolated from the residue in the usual manner with ammonium hydroxide and extracted with dichloromethane. The extract is dried, filtered and evaporated. The partial precipitate (9.6 ppm) is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (99: 1 by volume) as eluent. The purified fractions were collected and the eluent was evaporated. The residue is converted to the hydrochloride salt in 2-propanol. The crude fraction is filtered and the filtrate is treated with activated charcoal. The latter is filtered off and the filtrate is evaporated, yielding 4.8 parts by weight. (A) I-f4-cyano-4- (4-fluorophenyl) -cyclohexyl with yl-4-phenyl-4-pi-pyridinecarboxylic acid monohydrochloride ester, monohydrate, m.p. 210.7 ° C, yield 8%.
     i o and m 21. By May I h. plant- ..: May. including thiophene at 40 May. h. this .-.- / - (5.3 parts by weight of 1- (5-chloro -.:. H.Hyciphenyl} -4-oceanocyclohexanecar- :./.pril 5.4 May. of ethyl ether ; -phenyl-4-piperidinecarboxylic acid, l-g ohloride, 3 May h, sodium acetate: -.: 00 wt.h. ethanol. The whole mixture of hydro-;):; - h at normal pressure and ji VC in Prevailing 2 lb. platinum-: 1-: from a substrate of wood carbon; 0 / catalyst. After absorbing the calculated amount of hydrogen, the cat .g isator is filtered off and washed with a mixture of acetic acid and .aioi and to the residue;;;; p - sew water. A mixture of nodlachalachi- Psog with sodium hydroxide and so on the product is extracted with trichloromethane.The extract is washed with water, dried, filtered: evaporated. The residue is purified on a chro: -; graphic column on silica gel using a mixture of trichloromethane
    ; ; vV: tnoT (a (99: but volume) in tea-elyu-gg.
    The AND-arve fraction (A-isomer) is collected and the e.gtoent is evaporated. The remainder of the ii.) I of the cryetallisation of the 2.2-ukenobie of the urolan, obtaining 0.8 ma.ch, (8%) (A.)
    - hydrochloric ester - 4- (5 - chlorine te .- :; - and benil) -4-cyanocyclohexyl,; or 4 - pyridheridine of arboxylic acid; i: .r (. 165.5 ° C, yield 8 %, The second fraction (B-isomer) is collected;:; 1- Ug, 1 eluent is passed. The rest of the crystallization from crystallization from 2.2% xybis-p3i (aj: a. Crawl 1.2 mph. ( 12%) (.; O 1 I. instant ether 1-4 (5 chlorine-2 -;,;.: Ok e ifal nyl) -4-cyan o cycle o to e forces J - -4 - () enyl-4 - piperidinecarboxylic acid -. (- m 5 t. l. 3 1 5 8 C; yield 12%.
    Para and measures 22. By 2 May. h of solution of 2 mue.g, thiophene at 40 mae.h, fl: 1.1.5l. 4.4 ma.h., 1- (4- -f ./orophenyl) -4-oxycyclohecananecarbo - -gtsgril May 5th. including (B) -ethyl ester, 1-methyl-4-fe.nyl-4-pineridine-C-; moles, 5 wt.h. acetate; 1 :: three and 160 May. including ethanol. Mixture G is introduced at a normal pressure of 50 ° C in the presence of 2 parts by weight. palladium p.fVi-n on a substrate of wood coal; 0% catalyst. After absorption: as much as hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is purified using column chromatography on elika-: e: ie, ipolgchu gmg. E trichloromethane

    -
    -
    t,
    t
    - Yu
    20
    25
    - and methanol (98: 2 by volume) as eluent. The purified fractions were collected and the eluent was evaporated. The residue is subjected to cryetallization from 2.2-5 oxybielipropane, yielding 3.3 mach. (37%) () ethyl ester -n, iano-4- (4 fluorophenyl) cyclohexyl - J-methyl-4 phenyl 4-piperidine to arb o novano and acid, t. square 1,33, 3 C, yield 0 37%.
    To 1 ma.ch. solution 2 wt.h. thiophene at 40 May, h. ethanol is added May 4j4, part 1 (4-fluorophenyl) 4-oxocyclohexanecarbonitrile, May 5, part (A) - 15-ethyl 3-methyl-4-phenyl-4-piperidinecarboxylic acid and 160 parts of ethanol. / The mixture is hydrogenated at normal pressure and in the presence of 2 May, h. Nalladium on d substrate, reversible coal 10% catalyst,. After the hydrogen content is calculated, the catalyst is filtered off and the filtrate is evaporated. The residue is subject to cryetallization from acetonitrile. receiving 2.6 May, h.
    (28%) (B ,, - A,) ethyl 1-1 4-cyaco 4- (4-fluorophenyl) cyclohekeyl - - 3-me: ts-4 phenyl-4 PIP er idincar side cielotral,. 125; 9 With a yield of 28%.
    P m and m 23, K 1 May, h. May 2 solution, h. thiophene at 40 ppm, 4.4, 1- (4-fluorothienyl) -4-oceanocyclohexanecarbonite-35ril, 4 ppm was added to ethanol. 4 phenyl-4-piperidine-carbokeamide and 120 wt.h. methanol. The mixture is hydrogenated at normal pressure and 50 ° C in the presence of 2 mph. palladium on a substrate of charcoal 10% catalyst. After uptake of the calculated bulk quantity, the catalysts are filtered off and the filtrate is evaporated. The residue is purified by column chromatography n silica gel. Using a mixture of trichloromethane and methanol (99: 1 by volume) as eluent, A-isochoker is obtained, which is subjected to crystallization from 2.2 -oxy-bispropane. The product is filtered off and recrystallized from ethanol 5 to obtain 0.5 parts by weight. (6%) (A) - 1 - 4-g; iano-4- (4-fluorophenyl) - -cycle o g ek eyl J - 4-f e n l - 4-ip ep idin to ar - boxamid, so called 171.4 ° C, yield 6%. 55 After etching with a mixture of trichloromethane and methanol (97: 3 by volume), the B-isomer is obtained, which crystallizes from 2,. 2 -yokieiprona30
     91230467
    on. The product is filtered off and recovered from ethanol to give 1 wt. (12%) (B) -1- 4-cyano-4- (4- -fluorophenyl) cyclehexyl-4-phenyl-4-piperidinecarboxamide, m.p. 243.1 ° C, yield 12%.
    Example 24. A mixture of 4.3 wt.h. 1- (4-fluorophenyl) -4-oceanocyclohexancarbonitrile, 5.3 mo.h. 4- (4-chlorfe20
    The filter is subjected to purification using a column on an silica gel, and using trichloromethane and ethanol (98: 2 by volume) as eluent. The purified fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in ethanol and 2-β-propanol. The salt is filtered off and dried, yielding 0.6 mph. (21.6%)
    nyl) -Y, L-dimethyl-4-piperidinecarboke-O (B.-L) -ethyl ether of 1-4-cyanoamide and 200 wt.h. methanol is subjected to hydrogenation at normal pressure and 50 ° C in the presence of 2 wt.h. platinum on charcoal substrate 5% catalyst. After absorbing 5 NIN of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (99: 1 by volume) as eluent. The purified fractions were collected and the eluent was evaporated. The residue is subjected to crystallization from a mixture of 2-propanol and 2,2-oxybispropane. The product is filtered off (the mother liquor is removed) and dried, yielding 2 parts by weight. (A + B) -4- (4-chlorophenyl) -1- - 4-cyano-4- (4-fluorophenyl) cyclohex25
    -4- (4-fluorophenyl) cyclohexyl-4- (4-methoxyphenyl) -3-methyl-4-piperidinecarboxylic acid monohydrochloride, mp. 240, yield 22%.
    To 1 ma.ch. a raetvora 2 mah.h, thiophene at 40 mah.h. ethanol is added 13 mph. 1- (4-Fluorophenyl) -4-oocyclic-log-neicarbonitrile, 18.4 wt.h. (A) -Phenylmethyl ester of 3-methyl-4-phenyl-4-piperidinecarboxylic acid and 200 wt.h. 2-propanol. The mixture is hydrogenated at normal pressure and 50 ° C in the presence of 2 wt. Parts. platinum on charcoal substrate 5% catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue is purified by column chromatography on
    , N-dimethyl-4-piperidinecarbokeeyl gel, using a mixture of trichloro-
    amide, so pl. 184.4 C. Another fraction crystallized from the mother liquor, yielding 1.5 May, h. (A) -4- - (4-chlorophenyl) -1-4-cyano-4- (4-fluorophenyl) cyclohexyl -K, N-dimethyl-4-β-piperidinecarboxamide, m.p. 21 2, 2 s, yield 18%,
    Example 25. To 1 ma.h. on 2 ma.ch. Thiophene 40 mAh; ethanol was added 1.2 wt.h. 1- (4-α-fluorophenyl) -4-oxocyclog-exancarbo nitrile, 2 wt.h. (A) ethyl ester of 3-methyl-4- (4-methoke-iphenyl) -4-pyridine-carboxylic acid (1: 1) ethanedioate, 2 wt.h. sodium acetate and 120 ppm ethanol. The mixture is hydrogenated at normal pressure and 30 ° C in the presence of 2 wt.h. palladium on charcoal substrate 10% catalyst. After uptake of the calculated amount of hydrogen, the catalyst is filtered on a Huflo filter and washed with acetic acid. The filtrate is evaporated. Free bottling is isolated from the plant in the usual way, using ammonium hydroxide, and extruded with dichloromethane. The extract is dried, filtered and evaporated. 0s20
    The filter is subjected to purification using a column on an silica gel, and using trichloromethane and ethanol (98: 2 by volume) as eluent. The purified fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in ethanol and 2-β-propanol. The salt is filtered off and dried, yielding 0.6 mph. (21.6%)

    -4- (4-fluorophenyl) cyclohexyl-4- (4-methoxyphenyl) -3-methyl-4-piperidinecarboxylic acid monohydrochloride, mp. 240, yield 22%.
    To 1 ma.ch. a raetvora 2 mae. h, a thiophene at 40 mae. h. ethanol is added 13 mph. 1- (4-Fluorophenyl) -4-oocyclic-log-neicarbonitrile, 18.4 wt.h. (A) -Phenylmethyl ester of 3-methyl-4-phenyl-4-piperidinecarboxylic acid and 200 wt.h. 2-propanol. The mixture is hydrogenated at normal pressure and 50 ° C in the presence of 2 wt. Parts. platinum on charcoal substrate 5% catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue is purified by column chromatography on
    methane and methanol (98: 2 by volume) as eluent. The first fraction is collected and the eluent is charged. From the residue, fraction e was obtained by paper chromatography, using heckane, trichloromethane and methanol (100: 100: 0.5 by volume) as eluent. The purified fraction was collected, the eluent was evaporated and 1.5 mph were obtained. (5%) () - (phenylmethyl) - - 4-cyano-4- (4-fluorophenyl) cyclohexyl-3-methyl-4-phenyl-4-piperidinecarboxylate, yield 5%.
    To 1 ma.ch. solution 2 wt.h. Thiophene at 40 mah. ethanol is added 3.5 mas. 1- (4-fluorophenyl) -D-oceano-cyclohecanic carbonitrile, 6 ap. (B) - (Phenylmethyl) 4- (2- -fluorophenyl) -3-methyl-4-piperidinecarboxylic acid ester of hydrochloride,
    4 ma.ch. potassium acetate and 160 wt.h. 2-propanol. Laughs are hydrogenated at normal pressure and 50 ° C in the presence of 2 ma.h. platinum on the substrate -.
    ke of charcoal 5% catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. OS21
    The residue is dissolved in trichloromethane. The solution is washed with water to remove inorganic substances. The organic phase is dried, filtered and vashar. The residue is purified by colo f, night chromatography on silica gel using a mixture of trichloromethane n methanol (98: 2) as eluent. Purified fractions were collected and eluted. B, Bp fraction separated with 10
    2 U) 4
    25
    by paper chromatography using a mixture of trichloromethane, hexane and methanol (100: 100: 0.5 by volume). The purified fraction was collected and the eluent was evaporated. The residue is converted to the hydrochloride salt in 2-propanol. The salt is filtered and dried, yielding 4.4 May. including () -phenylmethyl ester of 1-4-cyano-4- (4-fluorophenyl) cyclohexyl-4- (2-fluorophenyl) -3-methyl-4-piperidinecarboxylic acid mono hydrochloride, t. square 239.4 C, 11% 47%.
    To 1 ma.ch. solution 2 wt.h. thiophene c. 40 ma.ch. ethanol add 3 math. 1 - (4-fluorophenyl) -4-oocycliclohexanecarbonitrile, 18.4 wt.h. (A) -Phenylmethyl ester of 3-methyl-4-phenyl-4-piperidinecarboxylic acid and 160 wt.h. 2-propanol. Laughs are hydrogenated at normal pressure and 50 ° C in the presence of 2 wt.h. platinum on charcoal substrate 5% catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by SILENT chromatography on silica gel using a mixture of trichloro methane and methanol (98: 2 by volume) as eluent. The purified fraction is collected and the eluent is evaporated. The residue is converted to hydrated hydrogen chloride in 2-propanol. The salt is filtered off and dried, yielding 8.4 parts by weight. () -Phenylmethyl 1-4-cyano-4- (4-fluorophenyl) cyclohexyl-3-methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride ester, t, pl. 223 ,, yield 25%.
    To ma.ch. 2 wt.h.tyofe on 40 May, h. ethanol was added 6.6 wt. - (4-fluorophenyl) -4-oxocyclic log-acancarbonitrile, 10.5 wt. Parts (B) 3-methyl-4-phenyl-4-piperidinecarbonate hydrochloride hydrochloride ester phenylmethyl ester, 6 wt.h. potassium acetate and 200 math. 2-lropa yule. Laugh guide
    f, 10
    20
    thirty
    15
    . U) 46722
    It is conducted at normal pressure and 50 ° C in the presence of 4 mph. platinum on charcoal substrate 5% catalyst. After uptake of a very small amount of hydrogen, the catalyst is filtered off and washed with acetic acid. The filtrate is evaporated and the residue is dissolved in water. The mixture is alkalinized with caustic soda and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The purified fractions are collected and the eluent is evaporated. From the residue, the A-Bp fraction is separated by paper chromatography using a mixture of hexane, trichloromethane and methanol (100: 100: 0.5 by volume) as eluent. The purified fraction was collected and the eluent was evaporated, yielding 0.8 parts by weight. (5%) () -phenyl-25-Tyl-1 about 1-4-cyano-4- (4-fluorophenyl) -cyclohexyl-3-methyl-4-phenyl-4-piperidinecarboxylic acid, yield 5%. In the same way, () -phenylmethyl-1-4-cyano-4- - (4-fluorofensch1) cyclohekeyl | -3-methyl-4-phenyl-4-prPeridinecarboxylate, m.p. 131 ° C, 31% yield, reaction temperature
    (A) -phenylmethyl- - 4-cyano-4- - (4-fluorophenyl) cyclohexyl 1-4- (2-fluorophenyl) -3-methyl-4-piperidinecarboxylate “11% yield, reaction temperature
    (B., -Ar,) (-n) -phenylmethyl- -14-cyano-4- (4-fluorophenyl) cyclohexyl-4- (2--fluorophenyl) -3-methyl-4-piperidinecarboxylate monohydrochloride, mp.213, G C; yield 29%, reaction temperature 30 ° C;
    35
    40
    (") (+) -Phenylmethyl- - 4-cyano-4- (4-fluoromethyl) piclohexyl-4- (2- -fluorophenyl) -3-methyl-4-piperidinecarboxyllate, yield 8%, reaction temperature
    (B, Bp) (+) -phenylmethyl-1-4-cyano-4- (4-fluorophenyl) cmclohekeyl-3-methyl-4-ggphenyl-4-pi 11 ridipicarbokeylate, yield 60%, reaction temperature 30 ° C;
    () (-) -Feinylmethyl-1-4-cyano-4- (4-ft (zprfenpl) cylcJIohekeylJ - 3-methyl-4-phenyl-4- | iperpdinecarboxylate, yield 56%, reaction temperature 30 ° WITH.
    For example 26. s. 10.9 May. Part I of the chifira I - i 4-cipo-4- (bSnyl) -1 .yl-D-feinl-4-pi-mg ridiicarb (1nova acid, 11, 2 mas.ch. potassium hydroxide, 50 m.ch.h. water and) 6 ma.ch. 2-flashes per.1shivdtt and boil with reflux for 4 hours. The reaction mixture is filtered in a hot state on a Huflo filter and the filter.at is poured onto .U.O. water. All this is neutralized with acetic acid to pH 6-7. The precipitated product is filtered off, washed three times with water and converted into the hydrochloride salt in ethanol and 2-propanol. The salt is filtered off and suepended in a solution of 1.4 parts by weight. potassium hydroxide in 150 ma.h. water. the free base is extracted four times with 70 m.ch. 1,1-oxybisethane. The aqueous phase is separated and stirred for a sufficient time on a centrifugal evaporator to remove all traces of 1,1-oxybieethane. The clear aqueous phase is acidified with a 10% solution of acetic acid to pH 6. The precipitated product is filtered off, washed with water and dried overnight at 105 ° C to obtain 5.4 parts by weight. (66.6%) 1- (4-cyano-4- (4- -fluorophenyl) cyclohexnl-4-phenyl-4- -piperidinecarboxylic acid, mp 281, 1 ° C.
    In accordance with the same procedure, compounds of the general formula obtained are given in Table 4.
    Example 27. A mixture of 1.2 MAH. (c) 1- (4-cyano-4- (4-fluorophenyl) cyclohexyl-3-methyl-4-phenyl-4-piperidinecarboxylic acid 1- (4-cyano-4- (4-fluorophenyl) cyclohexyl ester) in 80 parts by weight of 2-propanol is hydrogenated at normal pressure and room temperature using 1 wt.h. catalyst; 10% palladium on carbon). After selection of the calculated amount of hydrogen, the catalyst is filtered off and washed with methanol, saturated with ammonia. The filtrate is evaporated and the residue is taken up in a mixture of potassium hydroxide and water. All this is washed with trichloromethane. The aqueous alkaline phase is neutralized with a 10% acetic acid solution. The precipitated product is filtered off, washed with water, dried and converted into methanol to the hydrochloride salt. The salt is filtered off and dried, yielding 2 mph. (66%) monohydrochloride () -l-4-cyano 7
    -A- (A -fluorophenyl) -cyclehexyl i -4- (2- - (tl rophenyl) -3-methyl-4-PIPPeridinecarboxylic acid, mp 300.6 ° C.
    Mixture, May 7th. including (B, -L) -phenyl-5-tyl ester of 1-A-cyano-4- (4-fluoro-fensh) -cyclohekeyl 1-3-methyl-4-phenyl-. -A-Pigteridincarboxylic acid and 270 mas. tetrahydrofuran is hydrogenated at normal pressure and room temperature using
    2 ma.ch. catalyst (10% palladium on coal). After selection of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated.
    5 The residue is converted to the hydrochloride salt in a mixture of methanol and 2,2-oxybis propane. The salt is filtered off and dried, yielding 1 wt. (16%) monohydrate monohydrate (B.-A) -cyano-4- (4-fluorophenyl) cyclohekeyl 1-. -3-methyl-4-phenyl-A-piperidinecarboxylic acid, m.p. 291 ,.
    A mixture of 1.5 mach. () - 1-A-cyano-4- (4-α-fluorophenyl) cyclohekeyl-3-methyl-A-α-Lenyl-A-piperidinecarboxylic acid phenyl methyl ester and 90 wt.h. tetrahydrofuran is hydrogenated at normal pressure and room temperature using
     1 ma.ch. catalyst (10% palladium on coal). After selection of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is treated with water and hydroxide with potassium oxide. Then washed with trichloromethane. The aqueous alkaline phase is neutralized with a 10% acetic acid solution. The precipitated product is filtered off, washed with water, dried and converted to hydrochloride ethanol in methanol and 2, 2-oxybispropane, giving 0.6 m.h. (42%) Monohydrochloride monohydrate (A-A) cyano-4- (A-fluorophenyl) cyclohexylZ-3-.
    5 methyl-A-phenyl-A-piperidinecarboxylic acid, so pl. 261.6 C.
    A mixture of 0.9 mach. 1-A-cyano-4- (4-fluorophenyl) cyclohekeyl-4- (2-fluorophenyl) 0-3-methyl-4-piperidinecarboxylic acid () -phenylmethyl ester 1 and 90 wt.h. tetrahydrofuran is hydrogenated at normal pressure and room temperature using 1 wt. h, a catalyst (10% palladium on coal). After selection of the calculated amount of hydrogen, the catalyst is filtered off and washed with methanol, saturated with ammonia. Filtrate
    evaporated and the residue is taken up in a mixture of water and potassium hydroxide. All this is caused by trichloromethane. The aqueous alkaline phase is neutralized with acetic acid. The precipitated product is filtered off and converted to the hydrochloride salt in methanol and 2,2-oxybispropane. The salt is filtered off and dried, yielding 0.3 pfu (37%) of monohydrate monohydrochloride) -1-4-diano-4- (4-fluorophenyl) diclohexyl | -4- (2-fluorophenyl) -3-me- Tyl-4-pyperidinecarboxylic acid, so pl. 242.2-244.4 ° C. . .
    Example 28. A mixture of 0.7 wt.h. () (+) - Phenylmethyl ester of 1- - 4-cyano-4- (4-fluorophenyl) cyclohex- (2-fluorophenyl) -3-methyl-4-piperidinecarboxylic acid and 90 wt. tetrahydrofuran is hydrogenated at normal pressure and room temperature using 1 May, h. catalyst (10% palladium on carbon). After taking the calculated amount of hydrogen, the catalyst is filtered off. The filter cake is washed with methanol, saturated ammonia and the filtrate is evaporated. The residue is taken up in water and potassium hydroxide. All this is washed with trichloromethane. The aqueous alkaline phase is neutralized with a 10% solution of acetic acid. The precipitated product is filtered off, washed with water, dried and converted to the hydrochloride salt in methanol and 2,2-oxybispropane. The salt was filtered off and dried, yielding 0.3 mas. (49%) monohydrochloride () (±) -1-4-cyano-4- (4-fluorophenyl) cyclohexyl-4- (2-fluorophenyl) -Z-methyl-4-piperidinecarboxylic acid, so pl. 282,
    Similarly, (monogamy) rohichloride () (±) -1- 4-diano-4- (4- -fluorophenyl) diclo g exyl J-4- (2-fluoro-phenyl) -3-methyl-4-piperidinecarboxylic acids, mp 288.8 ° C.
    Example 29. A mixture of 4 ma.ch. (Bp-Bp) (-) - phenylmethyl ester of 1- - 4-diano-4- (4-fluorophenyl) cyclohexyl-3-methyl-4-phenyl-4-piperidinecarboxylic acid and 225 wt. tetrahydrofuran is hydrogenated at normal pressure and room temperature using 2 May. including catalyst (10% palladium on coal). After the selection of the calculated amount of hydrogen, the catalyst is filtered off and washed with methanol, saturated with ammonia.
    The filtrate is evaporated by an. M. The residue is converted to hydrochloride r- (,). In methanol, Salt was filtered off and dried, yielding 3 May. including (82%) monohydrochloride (B-B ,,) - (-) - 1 -1 4-cyano-4- - (4-fluorophenyl) cyclohekeyl 1-3-methyl-4-phenyl-4-piperidinecarboxylic acid - lots, t. pl. 298 ,.
    In a similar way, mono-hydrochloride (B,. -Bp) (+) - -14-cyano-4- - (4-fluorophenyl) -diclohexylJ-3-methyl--4-phenyl-4-piperidinecarboxylic acid, m.p. . 298 ,.
    Example 30. By the method described in PTZimera 18, receive:
    (+) () - Phenylmethyl-1-4-diano-4- (4-fluorophenyl) cyclohekeyl-3-methyl-4-phenyl-4-piperidinecarboxylate, so pl. 130.8 C, yield 27%, reaction temperature 30 C;
    (+) () - 1-4-iano-4- (4-fluorophenyl) cyclohexyl-3-methyl-phenyl-4-piperidic acid monohydrochloride, m.-pl. 300 ° C, yield 58%, reaction temperature 45 ° C;
    3-phenoxypropyl-1-4-cyano-4- (4-fluorophenyl) cyclohekeyl-4-phenyl-4-pyperidinecarboxylate, m.p. 145.0 ° C, yield 47%, reaction temperature 95 ° C;
    3- (4-methokeifenokei) propyl-1-cyano-4- (4-fluorophenyl) cyclohexyl-4-phenyl-4-piperidinecarboxylate, m.p. 189.3 ° C, yield 43%, reaction temperature 100 ° C;
    ethyl 1-4-cyano-4-4- (2,3-dichlorophenyl) cyclohekeyl} -4-phenyl-4-piperidinecarboxylate, m.p. 147.3 ° C, yield 32%, reaction temperature 30 C;
    (B) -ethyl-1- 4- (5-chloro-2-methoxy-phenyl) -4-cyano-cyclohexyl) -4-phenyl-4-piperidinecarboxylate, m.p. 130, G C, yield 21%, temperature of the reaction 66 C;
    ethyl 1-4- (3-chloro-2-methylphenyl) -4-cyanocyclohexyl-4-phenyl-4-piperidinecarboxylate monohydrochloride, so pl. 231.6 C, yield 20%, temperature-. tour reaction 100 ° C;
    3-methoxypropyl-1-4-cyano-4- (4-fluorophenyl) cyclohexyl-4-phenyl-4-pyridinic carboxylate monohydrochloride, T. (., Pl. 256, yield 47%, reaction temperature 30 ° C;
    (A) -1 - D-cyano-4- (4-fluorophenyl) cyclohexyl-4-phenyl-4-piperidinecarbokeamide, m.p. 171.0 ° C, yield 20%, reaction temperature 50 ° C;
    27.
    ethyl-I- {4-cyano-4-Z- (trifluoromethyl) phenyl piclohexyl | -4-phenyl-4-pi peridinecarboxylate monohydrochloride, m.p. 257, yield 22%, reaction temperature 70 C;
    2- (dimethylamino) ethyl 1-g 4-cyano-4- (4-fluorophenyl) diclohexyl-4-phenyl-4-piperidinecarboxylate, m.p. , 8 C, yield 17%, temperature of the reaction is 30 s;
    (A + B) -4- (4-chlorophenyl) -1-4-piano-4- (4-fluorophenyl) diclohexyl-N, N- -dimethyl-4-piperidine rboxylate, m.p. 179.6 ° C, yield 22%, reaction temperature 100 ° C;
    4-l-4-diano-4- (4-fluorophenyl) dic logex-3-phenyl-4-piperidinecarbonylTmorpholine, m.p. 180.6 С, yield 31%, temperature of the reaction 100 ° С; , 2- (1-pyrrolidinyl) ethyl-1-4-dian (4-fluorophenyl) diclohexyl-4-phenyl-4-piperidinecarboxylate, so pl. 116.8 ° C, yield 24%, the reaction temperature,
    2- (4-morpholinyl) ethyl-1-4-diano-4- (4-fluorophenyl) diclohexyl-4-phenyl-4-piperidinecarboxylate, m.p. 125.3 ° C, yield 29%, reaction temperature 70 ° C;
    1- 1- 4-diano-4- (4-fluorophenyl) diclohexyl-4- (3-methylphenyl) -4-pyperidinecarbonyl / pyrrolidine, m.p. 179.9 ° C, yield 24%, reaction temperature 30 ° C;
    ethyl 1-4-diano-4- (4-fluorophenyl) diclohexyl-4-H3- (ethoxycarbonyl) phenyl-4-piperidinecarboxylate, t, pl. 130 ,, output 22%, the temperature of the reaction 30 C.
    Example 31. According to the procedure described in examples 17 and 19, starting from the corresponding diclohexanones and piperidines, the following is obtained:
    ethyl 1-4-cyano-4- (2-pyridinyl) diclohexyl-4-phenyl-4-piperidine carboxyl, so pl. 158.9 ° C, yield 31%, reaction temperature 30 ° C;
    1-phenyl-4-4-phenyl-4- (1-piperidinyl 1) bonyl) -1-piperidinyl-cyclic hexanecarbonitrile hydrochloride, mp 283.2 ° C, 38% yield, reaction temperature 30 C.
    Preparation of monochlorohydrate, (j) -tl- (u-Mc), Threat, 4p-1-C4-diano-4- - (2-thienyl) diclohexyl-3-mtsh I-4-phenyl-4-piperidincarbonic acid.
    728
    Mixture 5 May. including 4-oxo-1- (2-tienyl) -diclohexanecarbopitrile, 6 May .h. bromhydrate (+) - 7P "s-3-methyl-4-phenyl-4-piperidinecarboxylic acid, 1 May. including carbon dioxide, 7 mah. 30% sodium methoxide solution and 225 mash. 2-methoxyethanol is hydrogenated at normal pressure and at room temperature using 2 wt.h. catalyst (10% palladium on charcoal). After the calculated amount of hydrogen has been consumed, the catalyst is filtered off through a Khoflo filter and the filtrate is evaporated. The residual product of the slurry is suspended in 400 wt.h. hot water and subcritical slurry are mixed with acetic acid. The solid product is filtered off, washed three times with water and suspended in methanol. After heating, the suspension is acidified with 2-propanol, saturated with hydrogen chloride. The hydrochloride salt formed is filtered and dried, yielding 3.4 parts by weight. (38.2%) hydrochloride (+) - 1- (and, is), 3oi, 4 (5-1- - 4-diano-4- (2-thienyl) -dikloheksil - -3-methyl-4-phenyl -4-piperidinecarboxylic acid; mp. 260 ° C.
    Found,%: C 63.12; H 6.56; N 6.15.
    Calculated,%: C 64.78; H 6.57; N 6.29.
    A. Producing as described in Example 18 is obtained:
    1-4-diano-4- (fluorophenyl) -1-diclohexen-1-yl-4-phenyl-4-piperidinecarboxamide, m.p. 187.3 С
    Found,%: C 73.79; H 6.25; 9.74.
    Calculated,%: C, 74.42; H 6.49; 10.41.
    1-4-cyano-4- (4-fluorophenyl) -1-cyclo-gce ce H-1-yl -N, N-dyne tyl-4-phenyl-iperidine carboxamide; m.p. 160.5 ° C.
    Found,%: C 74.54; H 6.95; N 9.53.
    Calculated,%: C 75.15; H 7.01; 9.74.
    B. Producing as described in Example 18 is obtained:
    SA) -1-C4-cyano (4-fluorophenyl) dicloxyl-4-phenyl-4-piperidinecarboxyl, so pl. 172.3 C; ,
    (A + B) -4- (4-chlorophenyl) -1-4-cyano-4- (4-fluorophenyl) cyclohex, N-di
    291
    methyl 4-piperidinecarboxamide, m.p. 160.5 ° C.
    The compounds of the formula (O and their pharmaceutically acceptable acid addition salts are potent antihistamines and can be used to prepare medicines for the therapeutic treatment of people and animals. The beneficial antihistamine properties of the compounds of formula (1) are confirmed by the following test method.
    Protection of rats against mortality caused by the compound 48/80.
    Compound 48/80, a mixture of oligome-. The ditch obtained by condensation, p-methoxy-N-methyl-phenylethylamine and formaldehyde, is described as a powerful histamine-releasing agent. Protection against the lethal collapse of the circulatory system, which is produced by the 48/80 compound, can be a simple way of quantifying the anti-histamine activity of the test compounds. Male rats inbredno race Wistar, weighing 240-260 g, were used as experimental animals. After fasting overnight, the rats were transferred to the laboratory (temperature C, relative humidity). Rats were injected subcutaneously or orally with the test compound or solvent (0.9% NaCl solution). After 1 hour, 48/80 compound, freshly diluted in water, was injected intravenously at a dosage of 0.5 mg / kg (0.2 ml / 100 body weight). In control experiments, where 250 animals that were injected with the solvent, were injected with a standard dose of 48/80, no more than 2.8% of the animals survived after 4 hours. Therefore, survival after 4 hours was considered a safe criterion of the protective effect of the administered drug.



    In Tables 5 and 6, for a series of compounds of formula (1), oral doses are given at which rats are protected from lethality by Compound 48/80.
    Toxicological data.
    The LD value (lethal dose for 50% of experimental animals) is in excess of 40 mg / kg body weight for all formulations for which pharmacological data are given.
    thirty
    five
    0
    five
    A preferred compound according to the invention is (Bj, -Bp) (-) - l-4-cyano-4- (4-fluopo-phenyl) cyclohexyl -3-methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride, described in example 29. Test 1.
    The acute oral toxicity of monohydrochloride (B, -Bp) (-) -1 - 4-cyano-4- (4-fluorophenyl) cyclohexyl - 3-methyl-4-phenyl-4-piperidinecarboxylic acid was tested on 30 males and 30 female adult Wistar rats whose initial body weight is 239-277 g for males and 228-269 g for females.
    On the day of the test, the animals were transferred from their cages to a laboratory room with air conditioning (air temperature 22 + 2 ° C; relative humidity 65jfl5%; dark and light alternation cycle 12 hours). They were not fed for the night; tap water should be provided indefinitely. no one's
    HeifapCTBo was administered via a gastric probe, administered through the nose, in amounts expressed in milligrams per kilogram of body weight, in a volume of 1 ml per 100 g of body weight. Animals were placed in separate cages and watched them for 14 days. At regular intervals recorded the number of deaths.
    In addition to the specified solution, test. Two more doses were expelled: 1280 and 2650 mg / kg. Deaths were not observed. Thus, the calculated LDg values 4 days after oral administration of the formulation are as follows: for males - more than 2,560 mg / kg, for females - more than 2,650 mg / kg. Test 2,
    For: this test, 12 adult males and 12 adult mongrel dogs were used. The initial body weight of dogs is 5.0–9.8 kg for males and 4.4–11.8 kg for 0 females.
    () (-) -cyano-4- (4-fluorophenyl) -cyclohexyl-3-methyl-4-phenyl-4-piperidine-carboxylic acid monohydrochloride was orally administered using a probe. A standard concentration of 320 mg per 1 Cpl was used in three different doses: 2.00, 4.00 and 8.00 ml per kg of mass.
    0
    five
    0
    five
    31,
    body, which corresponds to doses of 640, 1280 and 2650 mg / kg. Mortality and significant changes in behavior were recorded immediately after the administration of the formulation, periodically during the first day and at least once a day for 14 days of observation. Body weights were measured before administration of the formulation, after 7 and 14 days. The animals that died during the test after opening were subjected to macroscopic examination. Microscopically tissue was not investigated.
    Mortality. At a dose of 640 mg / kg, one female died on the twelfth day. At a dose of 1280 mg / kg on the sixth day, one male and one female died. At a dose of 2650 mg / kg, two males died on the twelfth and fourteenth day, and two females on the sixth day.
    3046732
    Under the test conditions, oral administration of monohydrochloride (B (.- Bp) (-) - 1-4-cyano-4- (4-fluoroprophenyl) cyclohexyl-3-methyl-4-phenyl-5-4- piperidinecarboxylic acid was fatal for one female out of four at a dose of 640 mg / kg, for one male and one female out of four at a dose of 1280 mg / kg and for two males-10 and two females out of four at a dose of 2560 mg / kg.
    In two dogs, vomiting and pale excrement were observed for 6 hours after administration of the formulation at doses of the highest level. The calculated oral LD, 14 days after administration of the formulation, for both males and females was approximately 2560 mg / kg.
    ts
    20
    Table 1
    NS AR
    ABOUT
    Ii
    C-0-R Ag2
    Ar
    Ag
    .
    C.H,
    ,
    CJ 5


    Ya.N,

    4-F4:, H,


    Ceha
    C.HS C, H,
    4-F-C.H,
    C.HS
    R
    -CHj
    (CH,),
    Based
    c
    -AND-
    - .i
    HC1
    142,23630
    121,64830
    144,16530
    1 "7.74830
    245.7
    15 45
    4-OCH-C H -0- (CH Basis-, 6 53
    35
    Nke
    2-CH,) - (CH4) d- 4-CH, (CH) H
    c, R,
    ""
    CHj-CHj-CH {CHj)
    2-OCHj-C4H -0- (CH) j
    33
    i23046734
    Golodolzhnye table. one
    Continued table. one
    V
    1L
    Och
    WITH
    about
    l
    cho
    f.
    about
    IN
    ABOUT
    SP
    one
    r
    G-
    one
    Cho
    m
    vO

    t
    I f-O) VD
    co
    I

    f
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    e
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    at u
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    and
    about
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    in hG
    c g
    vO CT
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    g
    about
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    Th
    "
    n o
    about
    offi
    m
    M
    and
    D
    I
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    Th

    m
    sh
    U
    P5
     
    lO
    and
    fa
    about
    -
    X
    u
    w u
    CT
    Hz i3i
    V v
    l rt (0
    gP2k
    uu
    about
    to
    and
    evj
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    about

    about
    oh oh

    -PC
    and
    and
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    about i
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    cm
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    - -.G

    r-4
    ABOUT
    1L I l
    m and

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    AND
    about
    (Jx)
    and
    and t
    (L
     I
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    about
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    and I
    fn
    vr
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    and
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    (14
    and
    vi
    and
    v °

    t

    v "
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    I
    (14
    -d and I
    k
    -
    39
    4-F-C K
    Sh.
    Foundation A
    74.0573,446,696,8910,3610.23
    4-F-CgH 4-Cl-C H (h), L 69.2969,, 686,838,988.75
    73.2373,247,217,248,848,73
    76.0875,967,667,788,878,71
    73,2272,237,787,838,548,40
    at L - / / soon
    1 2 K) 4fi7
    40 Table 3
    Table 4
    d o :; ) OO.
    Table 5
    0
    1 to
    d-oK
    2
    l
    Continued table. five
    4-F-C, H. C .hs
    4-F-C, H, 2-CHj, 4-F.-C
    C.HS
    4-F-C, H, a-cFj-c H 4-F-C, 4-F-C H, 4-F-, K, 4-F-CeH, 2-CH ,, 3-Cl-CglI
    2-F-C H,
    2-F-C, HC .HS
    .C, H,
    H H H H
    4-F-C, H, 2-CH .j, 5-Cl-CjHj
    C, KS
    Table 6
    Cv / - / / C-0-T1
    . ,
    Ar Ar R R Isomer-FormDoza active base material, the formation of Il mg / kg IC mass
    CgHgC Hg1-Piperidinyl HHC12.5
    4-F-CgH. Vsnov-0,63
    niya
    4-F-CgH CgH 1-Morpholinyl O, 6
    4-F-CgH 1-Pyrrolidinyl 2.5
    Compiled by B. Gorin Editor V. Petrash Tehred L. Serdyukova Proofreader S, Shekmar
    Order 2463/60. Circulation 379 Subscription
    VNIIGSh of the USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5.
    ".". - - - ---. ----- - -. - - - - - - - - - - - - - - - ---
    Production and printing company, Uzhgorod, st. Design, And
    Continuation of table.5


    HCl
    Base
    HCl
    A, -A / ±) HCl
    B ,, -A (t) HCl
    (-) HCl
    E, -Bp (+) HCl
    Base
    0.0025 0.02
    0.08
    0.63
    0.31
    0,005
    0,0025
    0,0025
    0.08
    权利要求:
    Claims (2)
    [1]
    one . The method of obtaining derivatives of 1-cyclohexyl-4-aryl-4-piperidinecarboxylic acid of the General formula
    A 'where R is hydrogen or lower alkyl;
    R 2 is hydroxyl, lower alkoxyl, lower alkoxy is lower alkoxyl, phenoxy is lower alkyl 9 phenoxy is lower alkoxyl in which phenyl can be substituted with lower alkoxyl or lower alkyl, amino, di (lower alkyl) amino, di (lower-alkyl ) aminon-lower alkoxyl, 4-morpholinylL) 1-pyrrolidinyl, 1-piperidinyl, (1-pyrrolidinyl) lower alkoxyl or (4-mor 1 folinyl) lower alkoxyl;
    Ar and Ar are, independently of one another, phenyl or phenyl mono- or disubstituted by different groups selected from a halogen atom, lower alkyl, lower alkoxy, alkoxycarbonyl, trifluoromethyl, or pyridinyl, or thienyl, or their acid addition salts, or their stereochemical isomeric forms, characterized in that by hydrogenating a mixture of compounds of general formulas where R 1 , R 1 , Ar 1 and Ag 1 have the above meanings, in an inert organic solvent at 30-100 ° C in the presence of a catalyst, such as palladium on charcoal or platinum on charcoal, with osleduyuschim expected product isolation in free form or in the form of their acid addition salts or as stereochemically isomeric forms.
    [2]
    2. A method of obtaining derivatives
    1-cyclohexyl 4-aryl-4-piperidinecarboxylic acid of the general formula
    SU "„ 1230467 AZ
    1 23046 7 where E 5 'is hydrogen or lower alkyl;
    R 2 is hydroxyl, lower alkoxyl, lower alkoxy is lower alkoxyl, phenoxy is lower alkyl, phenoxy is lower al, coxyl, in which phenyl may be substituted with lower alkoxyl or lower alkyl, amino, di (lower alkyl) amino, di ( lower al ~ kil) amino lower alkoxyl, 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl, (1-pyrrolidinyl) lower alkoxyl or (4 ~ morpholy ~ nyl) lower alkoxyl;
    Ar and Ar are, independently of one another, phenyl or phenyl mono- or disubstituted by different groups selected from a halogen atom, lower alkyl, lower alkoxy, alkoxycarbonyl, trifluoromethyl or pyridinyl, or thienyl, or their acid addition salts, or their stereochemical isomeric forms, characterized in that the compound of the general formula where Ag 1 has the above meanings, is reacted with the compound of the general formula ' Ή Οαγ' where R 1 , R 2 and Ag 7 have the above meanings.
    in the presence of catalytic amounts of strong acid in an inert organic solvent at the boiling point of the reaction mixture, and the obtained enamine of the general formula in 1 where R ', R 7 ', Ag 'and Ag 2 have the above meanings, are subjected to reduction in the presence of complex metal hydride in in an inert organic solvent at 30-100 ° C, followed by isolation of the target product in free form or in the form of their acid addition salts, or in the form of their steereochemically isomeric forms.
    Priority on the grounds: January 24, 80, when Ar 1 is phenyl or phenyl mono- or disubstituted with halogen, lower alkyl, lower alkoxyl, or pyridinyl;
    Ar 9 — phenyl or phenyl mono- or disubstituted by halogen ( lower alkyl, lower alkoxy, trifluoromethyl or lower alkoxycarbonyl, 09/29/80; with Ag ”—phenyl, mono or disubstituted by lower alkocarbonyl or trifluoromethyl, or thienyl;
    Ar 9 - pyridinyl or thienyl.
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    同族专利:
    公开号 | 公开日
    PL127483B1|1983-10-31|
    ES498793A0|1982-05-01|
    EP0034415B1|1984-05-30|
    AU6625581A|1981-07-30|
    PL233921A1|1982-06-21|
    PL127679B1|1983-11-30|
    IE50706B1|1986-06-25|
    FI76562B|1988-07-29|
    ES8204421A1|1982-05-01|
    CS221818B2|1983-04-29|
    DK29381A|1981-07-25|
    NO1994012I1|1994-08-30|
    DE3163787D1|1984-07-05|
    AU538130B2|1984-08-02|
    EP0034415A1|1981-08-26|
    DK152670B|1988-04-11|
    FI76562C|1988-11-10|
    BG60472B2|1995-04-28|
    IL61968A|1984-09-30|
    IL61968D0|1981-02-27|
    MY8700593A|1987-12-31|
    ES508441A0|1983-07-01|
    DK152670C|1988-08-22|
    IE810125L|1981-07-24|
    PH16611A|1983-11-24|
    PL229365A1|1982-03-29|
    ES8307219A1|1983-07-01|
    CA1187080A|1985-05-14|
    YU48446B|1998-07-10|
    MA19046A1|1981-10-01|
    US4369184A|1983-01-18|
    NL930017I1|1993-05-03|
    HU183293B|1984-04-28|
    FI810193L|1981-07-25|
    NZ196117A|1984-05-31|
    BG35465A3|1984-04-15|
    YU18381A|1983-10-31|
    GR71898B|1983-08-11|
    NL930017I2|1993-07-16|
    LU88220I2|1994-02-03|
    HK81088A|1988-10-14|
    引用文献:
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    DE1206436B|1957-07-05|1965-12-09|Janssen Pharmaceutica Nv|Process for the preparation of derivatives of 2,2-diaryl-4- -butyronitriles|
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    AU1716995A|1994-03-18|1995-10-09|Ciba-Geigy Ag|Aqueous solution of levocabastine for ophthalmic use|
    US5661163A|1995-06-07|1997-08-26|Merck & Co., Inc.|Alpha-1a adrenergic receptor antagonists|
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    CN1674916A|2002-08-30|2005-09-28|奥坦纳医药公司|The use of the combination of ciclesonide and antihistamines for the treatment of allergic rhinitis|
    CA2636324C|2006-01-06|2012-03-20|Sepracor Inc.|Cycloalkylamines as monoamine reuptake inhibitors|
    NZ573174A|2006-06-01|2012-01-12|Msd Consumer Care Inc|Sustained release pharmaceutical dosage form containing phenylephrine|
    NZ573173A|2006-06-01|2012-03-30|Msd Consumer Care Inc|Phenylephrine pharmaceutical formulation and compositions for colonic absorption|
    MX2010006932A|2007-12-21|2010-10-05|Schering Plough Healthcare|Enhancing photostabilization of oxymetazoline.|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US11492480A| true| 1980-01-24|1980-01-24|
    US06/191,631|US4369184A|1980-01-24|1980-09-29|1--4-aryl-4-piperidinecarboxylic acid derivatives|LV920222A| LV5041A3|1980-01-24|1992-11-27|Method for obtaining 1-cyclohexyl-4-aryl-4-piperidinecarboxylic derivatives or their cleavage-additive islands or their stereochemical isomers |
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