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    • 专利摘要:
    Novel N-(3-hydroxy-4-piperidinyl)substituted benzamides of formula wherein:R¹ is hydrogen, C₁₋₆alkyl, arylC₁₋₆alkyl, C₁₋₆alkylcarbonyl, aminoC₁₋₆alkyl or mono- and di(C₁₋₆alkyl)aminoC₁₋₆alkyl;R² is hydrogen or C₁₋₆alkyl;R³, R⁴ and R⁵ each independently are hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, halo, hydroxy, cyano, nitro, amino, mono- and di(C₁₋₆alkyl)­amino, aminocarbonyl, arylcarbonylamino, C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, aminosulfonyl, C₁₋₆alkylamino­sulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆alkylthio, mercapto, trifluoromethyl, arylC₁₋₆alkyloxy or aryloxy;Alk is a C₁₋₆alkanediy;X is O, S, NR⁶ C(=O) or C(=S);Het is a five- or six membered heterocyclic ring being optionally fused with a six membered carbocyclic ring, and being optionally substituted;the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are gastrointestinal motility stimulating agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
    公开号:SU1738088A3
    申请号:SU884356073
    申请日:1988-07-11
    公开日:1992-05-30
    发明作者:Анри Поль Ван Дэйл Жорж；Франсуа Влэйминк Фредди；Яннес Ван Лон Карел
    申请人:Жансен Фармасетика Н.В. (Фирма)；
    IPC主号:
    专利说明:

    3
    X 0-, -S-, NH- or -N (C4-C4-alkyl), RI is IR -C-alkyl,
    Hct - 2-pyridyl, MOHO- or disubstituted with C -C-alkyl, three fluoromethyl, chlorine, cyan or pyrrolidinylcarbonyl, -pyridyl, unsubstituted or substituted with C-C ralkil, 2-pyrimidinyl, unsubstituted or substituted with hydroxyl or di (C-C4 alkyl) amine, 2-pyrazinyl, substituted with C-C4 alkyl, chlorine, cyan or C-C4 alkyloxycarbonyl, 2-imidazolyl, substituted with C -C galkyl, 1,2,4-triazolyl, 2-quinolinyl, unsubstituted or 3 -cyano-6- - (C-C4 alkyloxy) substituted, 5,6,7, B-tetrahydroquino linyl-2, substituted by cyano or C, -Sf-alkyl or its N-oxide, 2-thiazolyl, 2- benzimida zolyl, 2-benzthiazolyl or quinoxalinyl,
    motility-stimulating gastrointestinal system activity that can be used for the treatment of warm-blooded animals suffering from reduced motility of the gastrointestinal system.
    The purpose of the invention is the creation of new compounds of general formula (I), based on the known methods, with an increased ability to stimulate the motility of the gastrointestinal system.
    A „Preparation of intermediate compounds. i
    Example 1
    To a stirred and heated under reflux solution for 103 h, cis-4-amino 5-chloro-2-labels- (3-methoxy-4-piperidinyl) benzamide in h, 2-propanol, 19.7 h, 2 -propenonitrile. The mixture is left overnight with stirring and heating under reflux and then over the weekend at room temperature. A second portion of 3 h is added to the mixture, of protenitrile at reflux temperature. After stirring for 3 hours at reflux, the reaction mixture is evaporated and 121 hours are obtained, (100% yield) cis-4-amino-5 chloro-1 D monohydrate (2-cyano 10
    25
    3Р088ч
    ethyl) -3-methoxy-4-piperidinyl -2-methoxybenzamide (intermediate 1).
    Example 2. To a stirred solution of 12.55 part of cis-4 amino-5-chloro-2-methoxy-I- (3-methoxy-4-piperidinyl) benzamide, in 180 h0 NN-dimethylformamide, 5 , 05 parts of N, N- -diethylethanamine and 3.4 parts of 2-chloroacetonitrile. The mixture is stirred for 18 hours at 50 ° C. The solvent is evaporated. The residue is purified by chromatography on a silica gel column using a mixture of tri15 chloromethane and methanol (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is triturated with 1,1-hydroxyethane, the Product is filtered and dried,
    20 get 12.21 parts (86.6 / yield) cis - - -amino-5-chloro-M-1 - (cyanomethyl) 3-methoxy-A-piperidinyl -2-methoxy-benzamide, mp, 130 , And ° C (intermediate compound 2),
    Example 3, A mixture of 3 parts of cis-A-α-amino-5 chloro-M -) - (2-cyanoethyl) -3-methoxypiperidinyl | -2-methoxybenzamide and 200 hours of methanol, saturated with ammonia, is hydrogenated at normal pressure and 2 parts of the catalyst Rane Nickel. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in trichloromethane. The solution is washed with water, dried, filtered and evaporated. The residue is crystallized from acetonitrile. The product is filtered off, dried under vacuum at 60 ° C, and 0 is obtained, part (yield 13%) of cis-α-amino-N- (1 - (3-alinopropyl) -3 methoxy-piperidinyl) -5 chloro 2-methoxy-benzamide, t, mp, 17.8 ° C (intermediate 3).
    In a similar way receive
    45 also: cis-4-amino-H- (1- (2-amino-ethyl) 3-methoxy - -piperidyl) -5-chloro-2-methoxybenzamide, mp, (intermediate) and cis-A -amino-N- (1 - Cl-aminobutyl) 3
    5 (-methoxy- | -piperidyl) -5-chloro- - - -methoxybenzamide, t, mp, (intermediate compound 5).
    Example i.a.K stirring solution, 3 hours, h- (methylamino) -butanol in 750 hours, trichloromethane was added dropwise a solution of 109 parts of bis (1,1-dimethylethyl) bicarbonate at 375 hours, trichloromethane. To complete30
    40
    55
    The reaction mixture is evaporated. The residue was distilled at 26.60 Pa and 50 parts (57.2% yield) of 1,1-dimethyl ethyl ester (α-oxybutyl) methylcarbamic acid were obtained, b.p. 120-128 ° C (intermediate 6) ,
    b. To a stirred and cooled (below 10 C) solution of 150 parts of pyridinium bichromate in 1300 parts of dichloromethane, a solution is added dropwise.
    50 h, (1, 1-dimethylethyl) - (4-hydroxybutyl) - methylcarbamate in 91 parts of dichloromethane. At the end of the addition, stirring is continued for 3 h, in the presence of 112 h. molecular sieves A at room temperature, the reaction mixture was filtered over magnesium sulfate, washed with 1,1-oxybisethane and the filtrate was evaporated. The filtrate is purified by chromatography on a silica gel column using dichloromethane as eluent. Pure fractions are collected and the eluent is evaporated. The residue is dissolved in methylbenzene and the reaction system is again evaporated. 3.5 parts (6.9%) of (1,1-dimethylethyl) methyl (oxybutyl) carbamate are obtained as a residue (intermediate compound 7).
    c.Mix 33 parts of cis-amino 5-chloro-2-methoxy M- (3 methoxy-1-piperidinyl) beamide, 30 parts of (1,1-dimethylethyl) methyl C-oxobutyl) carbamate ,
    3 h,% solution of thiophene in methanol and 00 hours of methanol are hydrogenated at normal pressure and room temperature with 5 parts of a 5% platinum-on-carbon catalyst. After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated and 5.1 parts (100%) of (1, 1-dimethylethyl) -cis-L - (- - / -amino-5 chloro-2-methoxybenzoyl amino / -3 methoxy) are obtained. -1-piperidinyl) butyl / methyl carbamate as a residue (intermediate 8).
    d.Mixture (1, 1-dimethylethyl) -cis10
    15
    20
    filtered and evaporated. The residue is purified on a silica gel column by chromatography eluting with a mixture of trichloromethane and methanol saturated with ammonia in a ratio of 95: 5 by volume. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered off, dried, and 33 parts (78.7%) of cis-α-amino-5-chloro-2-methoxy M-1z-methoxy-1 - (- methylaminobutyl) D-pi-peridinyl benzamide are obtained, t, mp, 129.3 ° C (intermediate 9).
    Similarly, also receive:
    cis-α-amino 5-chloro-2-methoxy-N- - {3 methoxy-1 (3 methylaminopropyl) - - -piperidinyl benzamide as a residue (intermediate compound 10)
    Example 5. To a stirred suspension of 3 hours, cis-A amino-N-1- (2-α-amino-ethyl) 3-methoxy-piperidinyl 5-chloro-2-methoxybenzamide in 78 hours, dichloromethane was added parts of N, N- - diethylatanoamine. Add solution
    5 parts of tetrafluoroborate 2, A, 6-triphenylpyryl at 52 h, dichloromethane. The reaction mixture is stirred for 3 hours and then 1.1 hours, acetic acid, is added. The reaction mixture is left under stirring overnight and then poured into h, 1,1-oxybisethane. Mas lo cured by stirring. The product is filtered off, washed with water and triturated with 1,1-oxybisethano. After filtration for 81 hours, (96.6% yield) cis-1- (2-L- (4-amino-5 chloro-2-methoxybenzoylamino) -3 -methoxy-1-piperidinyl / ethyl) -2, 6- -triphenylpyridinium tetrafluoroborate (intermediate compound 11).
    Similarly, get the same:
    with cis-1 ((- amino-5 chloro-2-methoxybenzoylamino) -3 methoxy-1-piperidinyl / propyl) -2, 4,6-triphenyl pyridinium tetrafluoroborate (intermediate compound 12) and tetrafluoro
    25
    thirty
    35
    40
    -A - (- A-amino-5-chloro-2-methoxybenzo-50 borate 1 (k- / k - (- amino-5-chloro-2-meylamino / 3 methoxy-1-piperidinyl) butyl / methylcarbamate and 250 h, 2-propanol, saturated with hydrochloric acid, stirred and heated under reflux for 15 min. The reaction mixture is evaporated and the residue is taken up in trichloromethane. The organic layer is washed with water, saturated with ammonium hydroxide, dried,
    55
    toxibenzoylamino) -3-methoxy-1-pyperidinyl / butyl) -2, k, 6-triphenylpyridinium (intermediate 1
    Example 6, a, For k hours, oxirane gas is bubbled through a stirred solution of 12.55 hours, cis-α-amino-5 chloro-2-methoxy-H- (3-methoxy-D-piperidinyl) beamide for 60 hours, ethanol and 75 h, water at com
    b
     ,
    -

    ten
    15
    20
    filtered and evaporated. The residue is purified on a silica gel column by chromatography, eluting with a mixture of trichloromethane and methanol, saturated with ammonia, in the ratio 95: 5 by volume. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered off and dried, and 33 parts (78.7%) of cis-α-amino-5-chloro-2-methoxy M-1z-methoxy-1 - (- methylaminobutyl) D-pyperidinyl benzamide are obtained, t, mp, 129.3 ° C (intermediate 9).
    Similarly, also receive:
    cis-amino 5-chloro-2-methoxy-L - - {3 methoxy-1 (3 methylaminopropyl) - - -piperidinyl benzamide as a residue (intermediate compound 10).
    Example 5. To a stirred suspension of 3 hours, cis-A amino-L-1- (2-α-amino-ethyl) 3-methoxy-β-piperidinyl) -5-chloro-2-methoxybenzamide in 78 hours, dichloromethane was added part N, N- -diethylatanamine. Add solution
    5 parts of tetrafluoroborate 2, A, 6-triphenylpyryl at 52 h, dichloromethane. The reaction mixture was stirred for 3 hours and then 1.1 hours, acetic acid was added. The reaction mixture is left under stirring overnight and then poured into h, 1,1-oxybisethane. The oil is cured by stirring. The product is filtered off, washed with water and triturated with 1,1-oxybisethane. After filtration 81 hours, (96.6% yield) of cis-1- (2-L- (4-amino-5 chloro-2-methoxybenzoylamino) -3-methoxy-1-piperidinyl / ethyl) -2, is obtained 6- -triphenylpyridinium tetrafluoroborate (intermediate 11).
    Similarly receive also:
    .c cis-1 ((- amino-5 chloro-2- -methoxybenzoylamino) -3 methoxy-1- -piperidinyl / propyl) -2, 4,6-triphenylpyridinium tetrafluoroborate (intermediate compound 12) and tetrafluoro25
    thirty
    35
    40
    borate 1 (k- / k - (- amino-5-chloro-2-me
    toxibenzoylamino) -3-methoxy-1-pyperidinyl / butyl) -2, k, 6-triphenylpyridinium (intermediate 13).
    Example 6, a, For k hours, oxirane gas is bubbled through a stirred solution of 12.55 hours, cis-α-amino-5 chloro-2-methoxy-H- (3-methoxy-D-piperidinyl) beamide for 60 hours, ethanol and 75 h, water at com
    temperature until the starting material is no longer detected by thin layer chromatography. The reaction mixture is concentrated. The concentrate is dissolved in trichloromethane. The solution is washed with water, dried, filtered and evaporated. The residue is crystallized from acetonitrile. The product is filtered off, dried, and 9.81 parts of product are obtained (yield 68.55%) -amino-5-chloro-M- Ј | - (2-hydroxyethyl) b-methoxy-β-piperilinyl / -2-methoxy-benzamide, m.p. 152.8 ° C (intermediate 1).
    B. To a stirred solution of 5.01 parts of cis-4-amino-5 chloro-M-1- (2- -oxyethyl) 3-methoxy-A-piperidinyl -2-methoxybenzamide 112.5 parts of trichloromethane is added 1, 33 parts of pyridine and 2 parts of thionyl chloride. The mixture is stirred and heated for 7 hours at 50 ° C and then left overnight with stirring at room temperature. The reaction mixture is washed with sodium hydroxide solution and water. The product is extracted with trichloromethane. The extract is dried, filtered, evaporated and 9 h are obtained, cis-α-amino-5 chloro-K-1 - (2-chloroethyl) -3-methoxy-piperidinyl) -2-methoxy-benzamide monohydrate as a residue (intermediate 15) i
    EXAMPLE 7 To a stirred and heated (70 ° C) solution of trans- (phenylmethylamino) peridinol in 180 hours. N, H-dimethylformamide was added 5, S1 parts of chloroacetonitrile. After adding 9.7 parts of M, M-diethylethanamine, the mixture is left overnight with stirring at 70 ° C. After evaporation, the residue is dissolved in dichloromethane. The organic layer is washed with a solution of sodium carbonate in water, dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluted with a mixture of trichloromethane and methanol in a ratio of 90:10 by volume. Pure fractions are collected and the eluent is evaporated. The residue is suspended in 2,2-β-oxibispropane. The product is filtered off and dried, 13.1 hours are obtained, (yield 76.2%) of trans-3-hydroxy-4- (phenylmethylamino) -1 -piperidineacetonitrile, so pl. 113.2 ° C. (intermediate 16),
    B A mixture of 12 parts of trans-3-hydroxy-1 (phenylmethylamino) -1-piperidineacetone 380888
    and 320 parts of methanol, saturated with ammonia, are hydrogenated at normal pressure at room temperature with 3 hours. Rene nickel. After absorption of the calculated amount of hydrogen, the catalyst is filtered off, the filtrate is evaporated to dryness and 11.2 hours are obtained, (yield 91.6%) trans-1-10 - (2-aminoethyl) -l- (phenylmethylamino) -3-piperidinol as a residue (intermediate 17).
    c, To a stirred solution of 11.2 parts of trans-1- (2-aminoethyl) (fe15 nylmethylamino) -3-piperidinol, in 135 parts of ethanol, 5.7 parts of 2-chloropyrimidine was added. After addition of B, including sodium bicarbonate, the reaction mixture was left overnight with stirring and refluxing. After evaporation, the residue is placed in a mixture of dichloromethane and water. The separated organic layer is washed with water, dried, filtered and evaporated. The residue is crystallized from acetonitrile. The product is filtered off, dried and obtained 11.84 h, (yield Ј0.3%) trans- (phenylmethylamino) (2-pyrimidinyl 30 amino) ethyl1-3-piperidinol, mp, 126.9 ° C (intermediate compound 18),
    d. A mixture of 10.6 parts of trans- (phenylmethylamino) -1 2- (2-pyrimidinylamino) -ethyl-3 piperidinol and 200 parts of methanol is hydrogenated under normal pressure at room temperature
    from 2 h, catalyst 10% palladium on carbon. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue is purified by chromatography on a silica gel column, eluting with a mixture of trichloromethane and methanol, saturated with ammonia in the ratio 90:10 to
    d. The second fraction is collected and the eluent is evaporated. 6.6 parts (86.9% yield) of trans-α-amino-1-Ј2- (2-pyrimidinylamino) ethyl-3-piperidinol are obtained as a residue (intermediate
    50 connection 19).
    B. Obtaining basic compounds. Example 8. A mixture of t, 8 parts of cis-A-amino 5-chloro-2-methoxy-M- (3-methoxy-1 - / 4- (methylamine) butyl / - piperidinyl) benzamide and 1.7 hours, 3 chloro-2-pyrazinecarbonitrile melted for 30 minutes at 100 ° C. After cooling, the reaction mixture is placed in a mixture of dichloromethane, water, and amide hydroxide.
    40
    55
    moni The separated organic layer is washed with water, dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a mixture of trichloromethane-methanol in the ratio of 97: 3 by volume. The pure fractions are collected and the eluent is evaporated. The residue is suspended in 2.2; -oxybis propane. The product is filtered off, dried, and 4.66 parts (75.9% yield) of cis-4-emino-5 chloro-N- (1 - / 4- - (3-cyano-2-pyrainylmethylamino) butyl) is obtained. methoxy-4-piperidinyl) -2- -methoxybenzamide hemihydrate, t „pl. 120 ° C (compound 1).
    In a similar way also receive the compound of the formula (see table 1)
    OKG about the axis,
    Hei ("g) q i-0-NH2
    C1
    Example 9. A mixture of 8.56 parts of 2- - bromo-3-methylpyrazine and 0.1 hours of potassium iodide is ground into powder and 2 parts of cis-4-amino-M-1Ј (2-amoethyl) are added -3 methoxy-4-piperidinyl 1-5 chloro-2-methoxybenzamide. The mixture is stirred for 3 hours at 120 ° C. The reaction mixture is placed in dichloromethane and water and alkalinized with ammonium hydroxide. The organic layer is separated, washed with water, dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a mixture of trichloromethane-methanol in a ratio of 95: 5 by volume. The first fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered off, dried and obtained 1.95 h, (yield 36%) cis-4-amino 5-chloro-2-methoxy-M- (3 methoxy-1- / 2- (3-methyl-2-pyrazinylamino) ) ethyl / 4-piperidinyl) benzamide, so pl. 169.5 ° C (compound 25).
    Example 10. A dry mixture of 1.8 parts of 2-chloro-1H-benzimidazole, 4.28 parts of cis-4-amino-M-1- (2-aminoethyl) -3 methoxy-4-piperidinyl3-5- -chloro-2-methoxybenzamide and 0.1 parts of potassium iodide are ground into powder. A few drops of H, M-dimethylacetamide are added to the mixture and stirred for 4 hours at 120 ° C. The reaction mixture is dissolved in a mixture of water and dichloromethane and treated with ammonium hydroxide. The organic layer is separated.
    0
    0
    five
    washed with water, dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a mixture of trichloromethanemethanol in a ratio of 90:10 by volume. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile-2,2-oxy-propane “The product is filtered off, dried and 1.06 parts (18% yield) of cis-4-amino--N- (1- / 2- (1H-benzimidazol-2- ilamino) ethyl / 3-methoxy-4-piperidinyl) 5-chloro-2-methoxybenzamide, mp,
    5,205.8 ° C. (Compound 26).
    Example 11. A mixture of 4.6 parts of cis-4-amino-M- / 1- (4-aminobutyl) -3-methox-ci-4-piperidinyl / -5 chloro-2-methoxy-benzamide, 1, 4 hours of 2-chloropyrimidine and a few drops of M, K-dimethyl tamide are left overnight with stirring at 80 ° C. The reaction mixture is dissolved in a mixture of dichloromethane, water and hydrochloric acid. The separated aqueous layer is treated with sodium carbonate and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a mixture of trichloromethane, methanol, saturated with ammonia (in the ratio 96: 3: 1 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered off and dried, and 1.34 parts (2.1% yield) of cis-4-amino-5 chloro-2-methoxy-—N- (3-methoxy-1-.A- (2-pyrimidinyl-amino ) butyl / -4-piperidinyl) benzamide, m.p. 114.8 ° C (compound 19).
    Similarly receive also:
    Cis-4-amino-5-chloro-I- / 1- (A- / 5-chloro-3 (trifluoromethyl) -2-pyridinylamino / butyl) -3 methoxy-4-piperidinyl / -2-Me5 toxibenzamide monohydrate m.p. 115.9 ° C (compound 27) and cis-4-amino-5-chloro-y- / 1- (4- / 3 chloro-5- (trifluoromethyl) -2-pyridinyl amino) monohydrate. butyl ) -3 methoxy-4-piperidinyl / -2-methoxybenpamide, so pl. 99.7 - 125.2 ° C (compound 28).
    Example 12. A mixture of 1.66 parts of 2-chloro-3-pyridinecarbonitrile, 4.28 parts of cis-amino-N- / 1 - (2-aminoethyl) -3-methoxy-4-piperidinyl / 5 chloro-2 α-methoxybenzamide, 1.3 parts sodium carbonate and 22.5 hours, M, H-dimethylacetamide is stirred at 70 ° C for
    0
    five
    0
    0
    five
    eleven
    1738088
    20 h. The reaction mixture is dissolved in dichloromethane. The organic layer is washed with water, dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a mixture of trichloromethane and methanol (95: 5 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered off and dried, yielding 1.19 parts (yield 21.6%) of cis-4-amino-5-chloro-H- (1- / 2- (3 cyano-2-pyridinylamino) ethyl / -3 methoxy -4- -piperidinyl) -2-methoxybenzamide, so pl. 134.0 ° C (compound 29).
    Similarly, also receive:
    cis-4-amino-5-chloro-M- (1- / 2- (3-chloro -2-pyridinylamino) ethyl / -3 methoxy-4-piperidinyl) -2-methoxybeneamide, m.p. 155.8 ° C (compound 30)}
    Cis-4-amino-5 chloro-H- (1- / 2- (6-chloro-3 pyridazinylamino) ethyl / -3-methoxy-4-piperidinyl) -2-methoxy-benzamide, mp. 228.8 ° C (compound 31) and cis-4-amino-M- (1- / 3 (1H- -benzimidazol-2-ylamino) propyl / -3-methoxy-4-piperidinyl) 5 chloro-2- - methoxybenzamide 2-propanol (2: 1), so pl. 164.8 ° C (compound 32).
    Example 13. A mixture of 1.17 parts of 2-chloropyrimidine, 5.56 parts of cis-4-amino-M- / 1- (3-aminopropyl) 3 methoxy-4-piperidinyl / -5 chloro-2- methoxy-benzamide and 2.7 hours, the mixture is stirred for 6.5 hours. After cooling, sodium carbonate solution is added. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a mixture of trichloromethane-methanol, saturated with ammonia (95: 5 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-pro panol and 2,2-oxybispropane. The product is filtered off, dried and obtained 2.4 hours (yield 35%) of cis-4-amino-5 chloro-2-methoxy-N- (3-methoxy-1 - - / 3 (2-pyrimidinylamino) propyl / - 4- piperidinyl) benzamide, m.p. 15.5 ° C (compound 33).
    In a similar way receive
    , M, K -dimethyl-aceta- at 90 ° C for
    is the same:
    Cis-4-amino-5-chloro-M- (1- / 3- (6-j-chloro-3 pyridazinylamino) propyl / -3- methoxy-4-piperidinyl 2-methoxy
    12 square 176.8 ° С (compound 14 (comparative). K
    five
    five
    2,22 parts of 2,3-dichloropyridine and 5.56 parts of cis-4-amino-N- / 1- (3-aminopropyl) 3-methoxy-4-piperidinyl / -5 chloro-2-methoxybenzamide, are T, B h. M, M-di-methylacetamide. The resulting mixture was stirred for 10 hours at 90 ° C. Sodium carbonate solution. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by silica gel column chromatography using a mixture of trichloromethane and methanol saturated with ammonia (97: 3 by volume) as an element. Pure fractions are collected and the eluent is evaporated. The residue is converted to the ethanedisate salt in 2- -propanol medium. The salt is filtered off and dried to give 0.5 part (yield 6%) of cis-4 amino-5 chloro-M- (1- / 3- (3-chloro-2-pyridinyl) propyl / -3 methoxy
    five
    0
    five
    0
    m.p.
    70 ° C.
    -4-piperidinyl / -2-methoxybenzamide ethanedioate (1: 1) hemihydrate, 216.6 ° C (compound 35).
    Example 15. A mixture of 3.78 parts of CIS-4-amino-M- / 1- (4-aminobutyl) -3- methoxy-4-piperidinyl / -5 chloro-2-methoxybenzamide, 1.66 part 2 -chloro-3-pyridinecarbonitrile, 1.58 parts of sodium carbonate and 90 hours, K, I-dimethylformamide was stirred for 24 hours while the reaction mixture was evaporated. The residue is dissolved in water and the product is extracted twice with dichloromethane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume). The first fraction was removed and the eluent was evaporated. The residue is dissolved in acetonitrile. The product is filtered off and dried, yielding 1.12 parts (23% yield) of cis-4-amino-5 chloro-M- (1- / 4- (3-cyano--2-pyridinylamino) butyl) -3 methoxy- - 4-piperidinyl} -2-methoxybenzamide,
    monohydrate, nenie 36).
    t pl, 103.4 C (connect
    Similarly, also receive:
    cis-4-amino-5 chloro- (1 - / 3- (but-2-pyridinylmethylamino) propyl / -3-methoxy-4-piperidinyl) -2-methoxy, 13
    Benzamide, monohydrate, t, pl. 118.2 ° C (compound 37).
    Example 16. A mixture of 1.56 hours of 2- (methylthio) -pyrimidinol, 3.7 parts of cis-amino-M-j- (3-aminopropyl) -3 methoxy-piperidinyl 1-5 CHLOR-2- -methoxybenzamide and 6 h. of acetonitrile are stirred for 40 h at reflux. Another portion of 0.7 part 2 (methylthio) -4-pyrimidinol is added and the mixture is left over the weekend with stirring and refluxing. The reaction mixture is evaporated. The residue is taken up in trichloromethane. The mixture is washed with water, saturated with ammonium hydroxide, dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column using a mixture of chloroform and methanol saturated with ammonia (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered off and dried, yielding 1.82 h, (yield 39.5%) of cis-4-amino-5 chloro-S (1- / 3- - (4-hydroxy-2-pyrimidinylamino) propyl). methoxy-4-piperidinyl) -2-methoxy-benzamide, monohydrate, mp, 134.2 ° C (compound 38).
    In a similar manner, cis-4-amino 5 chloro-M- (1 / 3- (4-dimethylamino-2-pyrimidinylamino) -propyl / 3-methoxy-4-piperidinyl) -2-methoxybenzamide, m.p. 212.7 ° C (compound 39).
    Example 17. A mixture of 2 parts of 2- -bromothiazole and 4.28 parts of cis-4-amino- -N- / 1- (2-aminoethyl) -3 methoxy-4-pyrididinyl / -5 chloro-2- methoxybenzamide is stirred for 1 h at 60 C. The mixture thickens. It is suspended in 10 parts of pyridine and stirring is continued, with refluxing, until the next morning. The reaction mixture is evaporated. The residue is placed in a saturated solution of sodium carbonate. The product is extracted with chloroform. The extract is dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column using chloroform-methanol (93: 7; v / v) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is taken up in hydrochloride salt in 2-propanol. Salt
    380881
    The mixture is filtered and the free base is isolated in the usual manner and extracted with chloroform. Extract
    dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column using a mixture of chloroform and methanol saturated with ammonia 10 (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of acetonitrile and 2,2-oxybispropane. The product is filtered off, dried and get t5 parts (yield 11%) of cis-4.-amino-5-chloro-2-methoxy-M- (3 methoxy-1- / 2- - (2-thiazolylamino) ethyl / - 4-piperidinyl) benzamide, m.p. 140.9 ° C. (compound 40). 20 |
    Example 18. A mixture of 1.9 parts of 2- chlorobenzothiazole, 3.7 parts of cis-4-ami-HO-N- / 1- (3-aminopropyl) -3 methoxy-4- -piperidinyl / -5-chloro -2-methoxybenzene25 mida and 22.5 hours, methylbenzene is stirred and heated under reflux until morning. 1.6 parts of sodium carbonate was added and the mixture was stirred for 4 hours while heating with reverse flow. The methylbenzene layer is washed with water and left. The precipitated product, which is formed during the reaction, is filtered off and dissolved in chloroorum. The solution is washed with water. The combined organic layers (trichloromethane and methylbenzene) are dried, filtered and evaporated. The residue is purified by silica gel column chromatography using
    as a eluent mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile.
    .. The product is filtered and dried, get 2.06 hours (yield M, 2%) cis-1 - -amino-N- (1- / 3- (2-benzothiazolylamino) propyl / -3-methoxy- - piperidinyl) - 5-chloro-2-methoxybenzamide, so pl.
    50 1b1,5 ° C (compound 1).
    Example 19. To stir the mixture, 28 C. cis-4-amino-M- / 1- (2- -aminoethyl) 3 methoxy-4-piperidyl / -5-, -chloro-2-methoxybenzamide, 1.21 parts M, N-diethylethanamine and 150 hours, chloroform was added a solution of 1.5 parts of dichloropyrimidine in 75 parts of trichloromethane. The mixture is stirred and heated with about 35
    After cooling, the reaction mixture was poured into saturated sodium carbonate solution. The product is extracted with trichloromethane, the extract is washed with water, dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a mixture of trichloromethane and methanol in a ratio of 95: 5 by volume. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered off, dried, and 1.52 parts (yield 29.2%) of cis-amino 5-chloro-2-methoxy-—N- (3-methoxy-1 - [2- (2-pyrimidinyl) butyl] ethyl] monohydrate are obtained. piperidinyl) bezamide, t, pl. I23.5 ° C (compound 2).
    Example 20. To stir and cool a mixture of 5.3 hours. -Amino-M- / 1- (2-hydroxyethyl) 3-labels si-g4-piperidinyl / 5 chloro-2-methoxy-benzamide and 135 parts. M, M dimethylformamide was added 0.75 parts, 50% sodium hydroxide dispersion. After stirring for 30 minutes at room temperature, 2.2 parts of 3, chloropyridine are added, and the mixture is stirred overnight at room temperature. The reaction mixture was poured into water 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 methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred at 1,1-oxybisethane. The product is filtered off and dried, yielding 3.2 parts of cis -amino-5 chloro M- - (1- / 2- (5-chloro-3 pyridinyloxy) ethyl-3-methoxy-β-piperidinyl) -2-methoxy monohydrate - benzamide, t, pl, 179 ° C (compound 3). I
    Similarly, also receive:
    cis-4 amino-5 chloro-N- (1- / 3 - (, 6-dimethyl-2-pyrimidinyl-thio) propyl / -3 methoxy-piperidinyl) hemihydrate so pl.
    98 ° C
    -2-methoxybenzamide, (compound d) |
    cis-4-amino-5-chloro-2- methoxy-M- (3-methoxy-1- / 3- (1H-1,2, - -triazole 5 ylthio) propyl / - -piperidium monohydrate
    five
    five
    0
    0
    five
    Nile) benzamide, t. PL. 130 ° C (compound 5),
    cis-α-amino-5-chloro-2-methoxy- -N- (3-methoxy-1- / 2- (2-pyrimidinto) -ethyl / - -piperidinyl) benzamide, m.p. 177 C (compound 6) J
    Cis-4-amino-5 chloro-2-methoxy- -N- (3-methoxy-1- / 2- (1-methyl-1I-imidazol-2-ylthio) ethyl / -piperidinyl) benzamide, m.p. 118 ° C (compound 7)
    cis-amino-5-chloro-2-methoxy-N- (3-methoxy-1- / 2- (6-methyl-3-pyridyloxy) ethyl / - piperidinyl) benzamide, t, pl, 131 ° C (compound 8) (
    cis-amino-N- (1- / 2- (1H-benzimidazol-2-yl) thioethyl / -3-methoxy-4-pyrididinyl) -5 chloro-2-methoxybenzamide, mp, 221 ° C (compound 9).
    cis-4-amino-5-chloro--2-methoxy-Kt- (3-methoxy- - / - (3-pyridinyloxy) butyl / - piperidinyl) monohydrate-benzamide, mp, 101 ° C (compound 50 ),
    Example 21 Rat gastric emptying is measured by a modified method originally developed by ReynellbiSpray. Rats are deprived of food for 2k hours and isolated into separate cages. Water is removed from the beginning of the experiments.
    Experimental food, which contains a warm suspension of 200 mg of phenol red in kO ml of distilled water, is administered to rats by oral intubation (0, ml / rat) 1/2 hour after subcutaneous administration of 0.63 mg / kg of the compound of formula (I) or saline. Through . half an hour the animals were killed by the displacement of the cervical vertebrae. The keludok is supplied with a naparotomy, quickly ligated in the pylorus and proximal part of the stomach and removed. The stomach is opened and its contents are extracted with 100 ml of 0.1N. sodium hydroxide. The content of phenol red in this extract is evaluated colorimetrically at 558 nm on a spectrophotometer. In tab. 2 shows the individual results after injection of the test compounds and control injections, expressed in units of extinction
    Example 22 (comparative). Table 3 shows the individual test results of example 21 in units of extinction resulting from the subcutaneous administration of the present invention.
    Compounds at a dosage of 0.63 mg / kg of live weight and structurally related compounds (l).
    Comparison of the data contained in the table. 3 (proposed compounds), and data from Table. L (known compounds) demonstrates that the proposed compounds substantially stimulate gastric emptying at low dosage, such as O, bsmg / k, live weight, while known compounds are much less effective at this dosage. Based on the above data, it can be concluded that the use of the proposed compounds increases gastric emptying, on average by approximately 65%, while the use of closely related known compounds only leads to an increase of approximately 20% with such a low dosage.
    The compounds of formula (I) are of low toxicity.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining cis-derivatives of N- (3 hydroxy-4-piperidinyl) benzamide of the general formula (T)
    OR
    Het
     °°
    T8
    Het - 2-pyridyl, mono- or disubstituted with C -C-alkyl, trifluoromethyl, chlorine, cyan, or pyrrolidinylcarbo- | Nil, -pyridyl, unsubstituted or substituted by C -C-Arfil, 2-pyrimidinyl, unsubstituted or substituted by hydroxyl or di (Kil) amine, 2-pyrazinyl, substituted With With Sgrakl, chlorine, cyan or C-C-Elkyl - hydroxycarbonyl, 2-imidazolyl, substituted C-C-alkyl, 1,2,4-triazolyl, 2-quinolinyl, unsubstituted or 3 cyano-6- - (C-Cf-alkyloxy) substituted, 5,6, 7,8-tetrahydroquinolinyl-2-substituted cyano or C-C-alkyl or its N-oxide, 2-thiazolyl, 2-benzimidazolyl, 2-benzthiazolyl, or quinoxalinyl, in that
    piperidine of the general formula
    OR2 About ORi
    H-X- (CH2) I Q-NH2
    Cl
    alkylate compound of the General formula
    llet - w,
    where W is chlorine, bromine or methylthio, in an inert solvent and, if necessary, in the presence of potassium iodide or the corresponding
    nineteen
    1738088
    20 Continuation tlbl. one
    Continue tlbl. 2
    OSCH about OCH3
    L-lT} -NH- (g
    Table 3
    Table OCH3 ABOUT,
    L-iT -ira- - -MHz ci
    Content in
    red phenol stomach, units of extinction
     1.05
     (dH2h- 101 (CH2) 2-1,1,5
    0- (SNg) 3 t 12 kOCH3
    F-Q-s- (loo
    (CHz) 3- 1J2 SG3 Control1.1
    Compiled by N.Naryshkov Editor M.Nedoluzhenko Tehrer A.Kravchuk Proofreader M.Samborska
    Order 1909 Circulation: Subscription
    VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab., A / 5
    Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101
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    同族专利:
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CA1183847A|1981-10-01|1985-03-12|Georges Van Daele|N-benzamide derivatives|
    US4634704A|1983-10-06|1987-01-06|Janssen Pharmaceutica, N.V.|Anti-allergic five membered heterocyclic ring containing N--4-piperidinamines|
    ZW12187A1|1986-07-03|1989-02-01|Janssen Pharmaceutica Nv|4-piperidinebutanamide derivatives|
    CA1317940C|1987-09-25|1993-05-18|Georges H. P. Van Daele|Substituted n-benzamides|CA1317940C|1987-09-25|1993-05-18|Georges H. P. Van Daele|Substituted n-benzamides|
    US5374637A|1989-03-22|1994-12-20|Janssen Pharmaceutica N.V.|N-carboxamide derivatives|
    GB9005014D0|1990-03-06|1990-05-02|Janssen Pharmaceutica Nv|N.carboxamide derivatives|
    JP2524420B2|1990-05-16|1996-08-14|明治製菓株式会社|Piperidine derivatives and antiulcer agents containing them as active ingredients|
    US5082847A|1990-07-18|1992-01-21|SyntexInc.|Carbostyril compounds connected via an oxyalkyl group with a piperidine ring and having pharmaceutical utility|
    US6096761A|1996-02-15|2000-08-01|Janssen Pharmaceutica N.V.|Esters of 3-hydroxy-piperidinemethanol derivatives|
    NZ330263A|1996-02-15|1999-06-29|Janssen Pharmaceutica Nv|Esters of 3-hydroxy-piperidinemethanol derivatives to improve gastric emptying|
    AT251139T|1997-07-11|2003-10-15|Janssen Pharmaceutica Nv| - NORCISAPRIDE APPLICABLE FOR 5-HT3 AND 5-HT4 CONDITIONAL DISEASES|
    TW548103B|1997-07-11|2003-08-21|Janssen Pharmaceutica Nv|Bicyclic benzamides of 3- or 4-substituted 4--piperidine derivatives|
    TW570920B|1998-12-22|2004-01-11|Janssen Pharmaceutica Nv|4--piperidine benzamides for treating gastrointestinal disorders|
    DK2194053T3|2004-01-07|2013-07-01|Armetheon Inc|Methoxypiperidine derivatives for use in the treatment of gastrointestinal and central nervous system disorders.|
    KR100976063B1|2007-03-16|2010-08-17|동아제약주식회사|Novel benzamide derivatives and process for the preparation thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US7484587A| true| 1987-07-17|1987-07-17|
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