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    • 专利摘要:
    Arylpiperazinyl-ethyl(or butyl)-heterocyclic compounds and their pharmaceutically acceptable acid addition salts are neuroleptic agents. They are useful in the treatment of psychotic disorders.
    公开号:SU1644716A3
    申请号:SU884355508
    申请日:1988-03-01
    公开日:1991-04-23
    发明作者:Эдамс Лоу Джон (Ш)；Эдам Нейгл Артур
    申请人:Пфайзер Инк. (Фирма)；
    IPC主号:
    专利说明:

    saturate with added HC1 gas, and the mixture is concentrated to a dry residue to obtain 0.70 g (40%) of a yellow salt, mp. above 200 ° C.
    NMR spectrum (Ј, CDC13): 1.9 (m, 4H); 2.95 (m, 16H); 6.8-7.2 (m, 6H).
    Example. 6- (2- (4- (6-Hydr-i hydroxy-8-quinolyl) piperazinyl) ethyl) -benzoxazoloH
    In a 35 ml round-bottom flask, equipped with a condenser and nitrogen inlet, 0.84 g (3.5 mmol) of 6-bromoethylbenzoxazolone, 0.80 g (3.5 mmol) of 6-hydroxy-8-piperazinyl0 are added.
    five
    ri, and evaporated to a solid. It is triturated with isopropyl ether to obtain 5.0 g (6.1%) of white solid 6-fluoro-1-naphthoic acid
    NMR spectrum (Ј, DMSO-dg): 7.8 - 8.0 (m, 5H); 8.6 (m, 1H).
    B. In a 125 ml round-bottomed flask equipped with a condenser, a separating funnel and a nitrogen inlet, 5.0 g (26.3 mol) of 6-fluoro-1-naphthoic acid and 50 ml of acetone are added. To a stirred suspension, 6.25 ml (28.9 mmol) of diphenylphosphoryl azide and 4 ml (28.9 mmol) are added dropwise.
    triethylamine. The reaction mixture is heated under reflux for 1 hour, drunk into water / ethyl acetate and filtered. The filtrate is washed with water and brine, dried over sodium sulfate and evaporated. The residue is further treated with HC1 to form the hydrochloride salt, and then released with sodium hydroxide to obtain the free base of 6-fluoro-1-amino-naphthalene as an oil, 1.0 g (24%).
    C. To a 125 ml round-bottom flask equipped with a condenser and nitrogen inlet, 1.0 g (6.21 mmol) of b-fluoro-1-aminonaphthalene, 1.8 g
    (7.76 mmol} S-benzyl-bis (2-chloroethyl) amine hydrochloride, 3.3 ml (19.2 mmol) of diisopropylethylamine
    and isopropanol. The reaction mixture is heated for 24 hours under reflux, cooled and evaporated to an oil. The oil is taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated to an oil. The oil is chromatographed on silica gel using methylene chloride as eluant to give 1.5 g (75.5%) oil, 1-benzyl 4- (6-fluoron-naphthyl) piperazine.
    D. In a 125 ml round-bottom flask, equipped with a nitrogen inlet, 1.5 g (4.69 mmol) of 1-benzyl-4- (b-fluoronaphthyl) piperazine, 1.2 ml are added.
    (31.3 mmol) of formic acid, 3.0 g (5%) of palladium on carbon and 50 MJJ of ethanol. The reaction mixture is stirred at room temperature for 16 hours, the catalyst is filtered off under nitrogen and the solvent is evaporated. Oil, L- (1- () naphthyl) piperazine (0.420 g, 39%), is used directly in the next step.
    E. To a 100 ml round-bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen inlet, 0.420 g (1.83 mmol) of N- (1-naphthyl) piperazine, 0.440 g (1.83 mmol) of 6- ( 2-bromoethyl) -benzoxazolone, 194 mg
    (1.83 mmol) of sodium carbonate, 50 ml of methyl isobutyl ketone and a catalytic amount of sodium iodide. The reaction mixture is heated at reflux for 3 days, cooled and evaporated to a brown resin. The resin is divided between 50 ml of water and 75 ml of ethyl acetate, the pH is adjusted to aqueous 1N. NaOH solution,
    Q

    „
    50
    about 5
    five
    the layers were separated, and the ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over sodium sulfate and evaporated, then chromatographed on silica gel. The fractions containing the product are combined and evaporated, the residue is taken up in ether / methylene chloride, treated with gaseous HC1, and the resulting chlorinated water is extracted from the salt salt to give a white solid, mp. 295-300 0, 214 mg (yield 22%),
    Example 10. 6- (4- (4- (1-Naphthyl) piperazinyl) butyl) -benzoxazolone.
    A. In a half-liter round-bottom flask equipped with a mechanical stirrer and a nitrogen inlet, 200 g of polyphosphoric acid, 16.7 g (0.1 mol) of 4-bromobutyric acid and 13.51 g (0.1 mol) of benzoxazolone are added. The reaction mixture is heated at 115 ° C for 1 hour and at 60 ° C for 1.5 hours. It is then poured onto ice, stirred for 45 minutes, the solid is filtered off and washed with water. The solid is suspended in acetone, stirred for 20 minutes, filtered, washed with summer ether and dried to give 12.3 g (43%) of a white solid 6- (4-bromobutyryl) -benzoxazolone.
    NMR spectrum (8, DMSO-dg): 1.77 (quin., 2H); 3.00 (t, 2H); 3.45 (t, 2H); 7.0-7.8 (m, ЗН).
    B. To a 100 ml three-neck round-bottomed flask, equipped with an addition funnel, thermometer and nitrogen inlet, add tO g (0.035 mol) b- (4-bromobutyryl) benzoxazolone and
    26.08 ml (0.35 mmol). trifluoroacetic acid. 12.93 ml (0.080 mol) of triethylsilane is added dropwise to the stirred suspension, and the reaction mixture is stirred for 16 hours at room temperature. Then the reaction mixture is drunk into water, and the resulting white solid is filtered off and washed with water. Then it is suspended in isopropyl ether, stirred and filtered to obtain a white solid - 6- (4-trifluoroacetoxybutyl) -benzoxazolone, mp. 100-103 ° C, 10.47 g (98.7%).
    C. In a 250 ml round-bottom flask equipped with a nitrogen inlet, 5.0 g (0.0164 mol) of 6- (trifluoroacetoxybutyl) benzoxazolone, 100 ml of metaol and 1 g of sodium carbonate were added. The reaction mixture is stirred at room temperature for 1 h, evaporated and the residue is taken up in methylene chloride / methanol, washed with aqueous HCl, dried over sodium sulfate, and evaporated to a white solid — 6 (4-hydroxybutyl) -benzoxazolone, .JQ
    130-133 ° C, 2.57 g (75.7%).
    D. In a 100 ml round-bottom flask, equipped with a condenser and nitrogen inlet, 2.2 g (0.0106 mol) of 6- (4-hydroxybutyl) -benzoxazolone, 2.12 g (0.09808 mol) of triphenylphosphine are added,
    and 200 ml of carbon tetrachloride. The reaction mixture was heated for 3 days under reflux, evaporated and chromatographed on silica gel using methylene chloride / ethyl acetate as eluent to give 1.8 g (75.3%) of white solid 6- (4-chlorobutyl) benzoxazolone m.p. 125 - 127 ° С.25
    E. In a 125 ml round-bottom flask, equipped with a condenser and a nitrogen inlet, 0.658 g (3.10 mmol) of 6- (4-h-butyl) benzoxazolone, 0.7 g (3.10 mmol) of p- (1- naphthyl) piperazine, JQ 0.328 g sodium carbonate, 2 mg sodium iodide and 50 ml isopropanol. The reaction mixture is heated for 3 days with a cold condenser, evaporated, taken up in sodium sulfate and evaporated. The residue is chromatographed on silica gel using ethyl acetate as eluant, and the product is dissolved in acetone, precipitated with ethereal HCl, and the white solid is filtered off, washed with acetone and dried to give 0.676 g (46.0%) of a white solid, m.p. 231-233 C.
    Example 11. 6- (2- (4- (3- (N- (3-trifluoromethyl) phenyl) indazolyl) pipera-45 zinyl) ethyl) benzoxazolone
    In a 125 ml round-bottom flask, fitted with a refrigerator, 1.0 g (2.89 mmol) of P- (3-trifluoromethylphenyl) indazolyl) piperazine, 0.70 g of e (2.89 mol) 6- (2 -bromoethyl) benzoxazolone, 0.31 g (2.89 mol) of sodium carbonate and 50 ml of methyl isobutyl ketone, and the mixture is heated for 18 hours under reflux. The reaction mixture is cooled55
    yield and share between ethyl acetate and water. The ethyl acetate layer is separated, washed with water and with a saturated aqueous solution of sodium chloride, and dried.

    -
    five
    g
    five
    over sodium sulfate and evaporate to an oil. The oil is chromatographed on silica gel using ethyl acetate / methylene chloride as eluant, and the product fractions are collected and dissolved in ether, precipitated with gaseous hydrogen chloride, and the solid is collected to obtain the hydrochloride salt of the target compound, m.p. 280-282 ° C, 0.75 g (47%).
    Example 12. 5- (2- (4- (1-Naphthyl) piperazinyl) ethyl) oxindole.
    A. In a 250 ml round-bottom flask, equipped with a condenser and nitrogen inlet, 30.7 g (230 mmol) of aluminum chloride, 150 ml of carbon disulfide and 3.8 ml (48 mmol) of chloroacetylchloride are added. To the stirred mixture was added 5.0 g (37 mmol) of oxindole in portions over 15 minutes. The reaction mixture is stirred for another 10 minutes. Then heated for 2 hours under reflux. The reaction mixture is cooled, added to ice, stirred well, the beige precipitate is filtered off, washed with water and dried to give 7.67 g (97%) of 5-chloro-acetyloxycin-dol.
    NMR spectrum (Ј, flMCO-d6): 3.40 (s, 2H); 5.05 (s, 2H); 6.8-7.9 (m, 3N).
    B. In a 100 ml round-bottom flask, equipped with a condenser and a nitrogen inlet, 5.0 g (23.9 mmol) of 5-chloroacetyloxyindole and 18.5 ml of trifluoroacetic acid are added. To the stirred solution was added 8.77 ml (54.9 mmol) of triethylsilane while cooling to prevent exothermic heating, and the reaction mixture was stirred for 16 hours at room temperature. Then the reaction mixture was poured into ice water, stirred
    and the beige solid is filtered off, washed with water and hexane and dried to give 5- (2-chloroethyl) oxindole, m. m. 168-170 ° C, 3.0 g (64%).
    C. In a 50 ml round-bottom flask, equipped with a condenser and nitrogen inlet, 370 mg (1.69 mmol) of 5- (2-chloroethyl) oxindole, 400 mg (1.69 mmol) of N- (1-naphthyl) piperazine are added. hydrochloride salt, 200 mg (1.69 mmol) of sodium carbonate, 2 mg of sodium iodide, and 50 ml of methyl isobutyl ketone. The reaction mixture is heated under reflux for 24 hours, cooled and evaporated. The residue is taken up in ethyl acetate, washed with water and brine, dried
    over sodium sulfate and evaporated. The residue is chromatographed on silica gel with ethyl acetate, and the product fractions are collected and evaporated to give a foam. The foam is dissolved in ether, treated with gaseous HC1, and the precipitate is collected, washed with ether and dried to give a white solid, mp. 303-305 ° C, 603 mg (84%). ten
    Example 13. 6- (2- (4- (4- (2,1,3-Benzothiadiazolyl) piperazinyl) ethyl) benoxazolone.
    A.In a 125 ml round-bottom flask, equipped with a condenser and a nitrogen inlet 15, add 2.0 g (13.2 mmol) of 4-amino-2,1,3-benzothiadiazole, 2.54 g (13.2 mmol) mechlorethamine hydrochloride, 4.19 g (39.6 mmol) of sodium carbonate, 2 mg of sodium iodide and 50 ml of 20 ethanol. The reaction mixture is heated
    2 days under reflux, cooled. And evaporated. The residue is taken up in methylene chloride, washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel using ethyl acetate / methanol as eluant, and the product fractions are collected and evaporated to an oil - 4- (2,1,3, -benzothiadiazolyl) -M-30 methylpiperazine, 628 mg (20%).
    NMR spectrum (Ј, CDC13): 2.5 (s, 3N); 2.8 (m, 4H); 3.6 (m, 4H); 6.8 (m, 1H); 7.5 (m, 2H).
    B. In a 25 ml round-bottom flask, equipped with a condenser and nitrogen inlet, 620 mg- (2.64 mmol) of 4- (2,1,3-benzothiadiazolyl) -M-methyl-piperazine, 0.224 ml (2 , 64 mmol) of chloroformate and 15 ml of dichloro-Q ethane. The reaction mixture is heated
    16 h at reflux, cooled and evaporated. The residue is chromatographed on silica gel using methylene chloride / ethyl acetate as the eluant, and product fractions are collected to give a yellow solid, 4- (2,1,3-benzothiadiazilyl) -H-vinyloxycarbonylpiperazine, 530 mg (69%). 50
    NMR (S, CDC13): 3.6 (m, 4H); 3.8 (m, 4H); 4.4-5.0 (m, 2H); 6.6-7.6 (m, 4H).
    C. In a 50 ml round-bottom flask, equipped with a condenser and a nitrogen inlet, 530 mg (1.83 mmol) of 4- (2,1,3-benzothiadiazolyl) -Y-vinyl-hydroxycarbonylpiperazine and 25 ml of ethylamine are added.
    nola, and the suspension is saturated with gaseous HC1. The reaction mixture is heated for 2.75 hours under reflux, cooled and evaporated. The residue was triturated with acetone to give a yellow solid N- (2,1,3-benzothiadiazolyl) piperazine, m.p. 240-244 ° C, 365 mg (62%).
    D. To a 125 ml round-bottom flask, equipped with a condenser and nitrogen inlet, add 365 mg (1.13 mmol) of N- (2,1,3-benzothiacyazolylJ-piperazine, 275 mg (1.13 mmol) 6- (2 -bromoethyl) benzoxazolone, 359 mg (3.39 mmol) of sodium carbonate, 2 mg of sodium iodide and 40 ml of ethanol. The reaction mixture is heated for 2 days under reflux, cooled and evaporated. The residue is taken up in methylene chloride, washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel using ethyl acetate (methanol as eluant), and product fractions are collected; It is created in methylene chloride / methanol, precipitated by the addition of an ethereal HCl solution, and the solid is filtered off, washed with ether and dried to give 228 mg (45%), mp 166-170 ° C.
    Example 14. 6- (2- (4- (1-Naphthyl) - gshperazinyl) ethyl) benzothiazolone.
    Into a 100 ml round-bottom flask, equipped with a condenser and nitrogen inlet, 1.0 g (3.88 mmol) of 6- (2-bromoethyl) benzothiazolone, 822 mg (3.88 mmol) of L- (1-naphthyl) piperazine are added. , 410 mg (3.88 mmol) of sodium carbonate and 50 ml of methyl isobutyl ketone. The reaction mixture is heated under reflux for 24 hours, cooled and evaporated. The residue is taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated. The resulting solid is treated with hot ethyl acetate to give a white solid, mp 198-220 ° C, 540 mg (36%).
    Example 15. 6- (2- (4-3-Benzoisothiazolyl) piperazinyl) ethylbenzoxazolone.
    In a 125 ml round-bottom flask, equipped with a refrigerator, 4.82 g (0.022 mol) of M- (3-benzoczothiazolyl) piperazine (prepared according to the methods of US Pat. No. 4,411,901), 5.32 g (0.022 mol) of 6- (2-Bromo) ethylbenzoxazone; 2.33 g (0.022 mol) of sodium carbonate and 50 ml of methylisobutyl ketone. The mixture is heated for 18 hours with a reflux hood. The reaction was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to an oil. The oil is chromatographed on silica gel using ethyl acetate as eluent, and the product fractions are collected and triturated with methylene chloride / isopropyl ether to give a white solid, t. 185-187 C.
    NMR spectrum (CDC13): 1.7 (broad s, 1H) | 2.8 (m, 8H); 3.6 (m, 4H); 6.9-8.0 (m, 7H).
    Example 16. 5- (2- (4-1,2-benz-isothiazol-3-yl) piperazinyl) ethyl) oxyindol.
    In a 125 ml round-bottom flask equipped with a nitrogen inlet and a condenser, 0.62 g (3.20 mmol) of 5- (2-chloroethyl) -oxindole, 0.70 g (3.20 mmol) of N- (1, 2 benzisothiazol-3-yl) goserazine, 0.68 g (6.40 mmol) of sodium carbonate, 2 mg of sodium iodide and 30 ml of methyl isobutyl ketone. The reaction mixture is heated under reflux for 40 hours, cooled, filtered and evaporated. The residue is chromatographed on silica gel, elshira by-products with ethyl acetate (1 L) and the product with 4% methanol in ethyl acetate (1.5 L). Product fractions (, 2 in

    „., -.-, -. . . .. 5% methanol in ethyl acetate) evaporated, taken in methylene chloride and precipitated by adding ether saturated with HC1; the solid is filtered and washed with ether, dried and washed with acetone. The latter is done by suspending the solid in acetone and filtering. The title compound is obtained as a high-melting, non-hygroscopic solid, mp, 288-288.5 ° C, 0.78 g (59%).
    50
    By the method similar to the method for preparing 5- (2-4- (1,2-benzisothiazol-3-yl) piperazinyl) ethyl) oxindole, the following compounds are prepared.
    5- (2- (4- (1,2-Benzisothiazol-3-yl) piperazinyl) ethyl) -1-ethyloxindole hydrochloride, 25%, so pl. 278-278 ° C;
    5- (2- (4- (1,2-Benzisothiazol-3-yl) piperaeinyl) ethyl) -1-methyloxindole hydrochloride hemihydrate, 42%, so pl. 283-285 ° C; mass spectrum,%: 392 (1), 232 (100), 177 (31).
    50
    five
    " five
    0

    Found,%: C 60.37; H 5.84; N 12.77.
    CMH44N4OSHCl 1 / 2HtO.
    Calculated,%: C 60.33; H 5.98; N 12.79.
    5- (2- (4- (1,2-Benzisothiazol-3-yl) piperazinyl) ethyl) -1- (3-chlorophenyl) oxindole hydrochloride hydrate, 8%, so pl. 221-223 ° C; mass spectrum,%: 488 (1), 256 (4), 232 (100), 177 (15).
    I
    Found,%: C 59.95; H 5.01; N 10.14.
    CrTng; GS1Y405-.
    Calculated,%: C 59.67; H 5.19; N 10.31.
    5- (2- (4-1,2-Benzisothiazol-3-yl) piperazinyl) ethyl) -3,3-dimethyloxindol hydrochloride hemihydrate, 40%, mp, 289-291 ° C; mass spectrum,%: 406 (1), 232 (100), 177 (42).
    Found,%: C 61.44; H 6.22; N 12.01.
    C2 HZ6N4OS HC1.
    Calculated,%: C 61.11; H 6.24; N 12.39.
    5- (2 (4- (1,2-Benzisothiazol-3-yl) piperazinyl) ethyl) -1,3-dimethyl-oxindole, 76%, Topl. 256 ° C.
    5- (2- (4-1,2-Benzisothiazol-3-yl) piperazinyl) ethyl) -spiro) cyclopentane-1,3) -indolin-27-one hydrochloride hemihydrate, 50%, so pl. 291-293 ° C (decomp.); mass spectrum,%: 432 (1); 232 (100); 200 (11), 177 (36).
    Found,%: C 63.01; H 6.32; N 11.34.
    C HggN OS HCl 1 / 2H20.
    Calculated,%: C, 62.81; H 6.33; N 11.72.,
    5- (2- (4- (1,2-Benzisothiaool-3-yl) pperperaxyl) ethyl-1,3,3 trimethyloxyn-dol hydrochloride hemihydrate, 63%, mp 225-257 ° C; mass spectrum ,%: 420 (1), 232 (100), 177 (37).
    Found,%: C 61.97; H 6.34; N 11.93.
    C24H eN4OS.HCl 1 / 2H20.
    Calculated,%: C, 61.85; H 6.49; N 12.02.
    5- (2- (4- (1,2-Benzisothiazol-3-yl) piperazinyl) ether) -6-fluorooxindole hydrochloride hydrate, 18%, so pl. 291-293 ° C; mass spectrum,%: 396 (1), 132 (10 °) 177 (53) /
    Found,%: C 56.39; H 5.30; N 12.19.
    SauNa, .HCl- 1 / 2HgO.
    Calculated,%: C 55.93; H 5.36; N 12.42.
    5- (2- (4- (1,2-Benzisothiazol-3-yl) piperazinyl) ethyl) -7-fluoroxyindole hydrochloride, 9%, so pl. 253 ° C;
    5- (2- (4- (1,2-Benzisothiazol-3-yl) piperazinyl) ethyl) -6-chlorooxindole hydrochlorporide, 20%, so pl. more than 300 ° C; mass spectrum,%: 488 (1), 256 (4), 232 (100), 177 (15).
    Found,%: C 52.83; H 4.93; N 11.42.
    C2, HZ (CN4OS - HC1 1 / 2HgO.
    Calculated,%: C 52.50; H 4.71; N 11.39.
    5- (2- (4- (1,2-Benzisothiazol-3-yl) piperazinyl) ethyl) -6-fluoro-3,3-dimethyloxindole hydrochloride, 35%, so pl. 284-286 ° C.
    Found,%: C 58.03; H 5.79; N 11977.
    CZ3H2S-FN4OS HC1 Hz ° Calculated.,%: C 57.67; H 5.89;
    N 11.70.
    5- (4- (4- (1,2-Benzisothiazol-3 yl) piperazinyl) butyl) oxindole hemihydrate, 26%, t „pl. 131-135 ° C; mass spectrum,%: 406 (2); 280 (8); 243 (65); 232 (23); 177 (45); 163 (100).
    Found,%: C, 66.83; H 6.30; N 13.08.
    C2} H26N4OS-1 / 2H10.
    Calculated,%: C, 66.48; H 6.55; N 13.48.
    5- (4- (4- (1,2-Benzisothiazol-3-yl) piperazinyl) butyl) -7-fluoroxyindole hydrate, 7%, Topl. 126-129 ° C; mass spectrum,%: 424 (3).
    Found,%: C 57.96; H 5.62; N 11.47.
    сгзнг5.гы4оЗ Нго „
    Calculated,%: C 57.67; H 5.89; N 11.70.
    5- (4- (4- (1,2-Benzisothiazol-3-yl) piperazinyl) butyl) -1-ethyloxindole hemihydrate, 25%, mp, 126-128 ° C; mass spectrum,%: 434 (2); 298 (10); 271 (55); 232 (34); 177 (53); 163 (100),
    Found,%: C 67.94; H 6.73; N 12.21.
    Cf5H30N4OS 1 / 2HaO.
    Calculated,%: C 67.69; H 7.04; N 12.63.
    0
    five
    0
    five
    0
    five
    0
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    five
    5- (2- (4-Naphthalen-1-yl) piperazinyl) ethyl) -1-ethyloxindole hydrochloride hydrate, 21%, mp, bol. 300 HP; mass spectrum,%: 399 (1); 225 (96); 182 (30); 70 (100).
    Found,%: C 69} 09; H 6.72; N 9.20.
    С26Нм About НС1-НгО.
    Calculated,%: C 68.78; H 7.10; N 9.26.
    5- (2- (4- (Naphthalen-1-yl) piperazinyl) ethyl) -6-fluorooxindole hydrochloride, 23%, Topl. 289-291 ° C; mass spectrum,%: 399 (1), 232 (3); 225 (100); 182 (32);
    70 (84).
    Found,%: C 62.42; H 5.82;
    N 8.77.
    C24H24FN3HC1 1/2 CHzCla.
    Calculated,%: C, 62.82; H 5.60; N 8.97.
    5- (2- (4- (Naphthalen-1-yl) piperazinyl) ethyl) -7-fluorooxindole hydrochloride, 22%, so pl. 308 ° C (decomp.); mass spectrum,%: 389 (1); 225 (100),
    Found,%: C 58.82; H 5.80; N 8.27.
    Cr4H24RK30 -HCl1 SNgS12.
    Calculated,%: C 58.78; H 5.93; N 8.23.
    Example 17. 6- (4- (2- (3-benzisothiazolyl) piperazinyl) ethyl) phenyl) benzothiazolone.
    In a 100 ml round-bottom flask, equipped with a condenser and nitrogen inlet, 1.03 g (4 mmol) of 6- (2-bromoethyl) -benzothiazolone, 0.88 g (4 mmol) of M-benzisothiazolyl piperazine, 0.84 g (8 mmol) of sodium carbonate, 2 mg of sodium iodide and 40 ml of methyl isobutyl ketone. The reaction mixture is heated for 36 hours under reflux, cooled, filtered and the filtrate is evaporated. The residue is chromatographed on silica gel using ethyl acetate as eluent to give an oil, which is taken up in methylene chloride and precipitated by the addition of ether saturated with HCl. The solid is filtered off, washed with ether, dried for a short time, washed with a minimum amount of acetone and dried to give a white solid, mp. 288-290 ° C, 1.44 g (76.7%).
    Example 18 A. In accordance with the general procedure for preparing 5- (chloroacetyl) oxindole in Example 12A, approach g; the following intermediates are prepared from their oxindoles:
    5- (chloroacetyl) -1-ethyl-oxindol (81%, mp. 157-159 ° C); NMR (CDC1.); 1.30 (t, 3N); 3.60 (s, 2H); 3.85 (sq. 2H); 4.70 (s, 2H); 6.85-8.15 (m, 2H);
    5- (chloroacetyl) 1-methyloxindole (See E, 0C1N02, 92%, t.an. 201-202 ° C); 1- (3-chlorophenyl) 5- (chloroacetyl) oxyindol (98%, mp. 143-145 ° C);
    NMR (DMSO-a6): 3.85 (bs, 2H); 5.10 (s, 2H); 6.8 (d, 1H); 7.4-7.6 (m, 4H); 7.9 (s- + d, 2H); mass spectrum,%: 319 (17); 270 (100); 179 (46) 178 (38);
    1, 3-dimethyl-5- (chloroacetyl) oxindole (97%, mp. 20b-207 ° C);
    . 5- (chloroacetyl) -spirocyclopentane f 1, 3 -indol-2-one (99%, mp. 203-204 ° C (decomp.)); NMR (DMSO-dg): 2.0 (bs, 8H); 4.95 (s, 2H); 6.9 (d, 1H); 7.8 (d + C, 2H); 10.6 (broad s, 1H) 5- (chloroacetyl) -1,3,3-trimethyloxine fraction (82%, mp 182-185DG);
    NMR (CDC15): 1.45 (s, 6H); 3.25 (s, 3N); 4.65 (s, 2H); 6.9 (d, 1H); 7.9 (s, 1H); 8.0 (d, 1n);
    6-fluoro-5- (chloroacetyl) oxindole (96%, mp. 178-180 ° C); NMR (DMSO-dg) 3.5 (s, 2H); 4.8 (d, 2H); 6.7-7.2 (m, 2H); 7.8 (d, 1H);
    (chloroacetyl) oxindole (91% mp. 194-196 ° C), NMR (DMSO-d); 3.68 (s, 2H); 5.13 (s, 2H); 7.65-7.9 (d, 2H);
    6-chloro-5- (chloroacetyl) oxindole
    (99%, mp. 206–207 ° C);
    5- (chloroacetyl) -3, 3-dimethyl-6-fluoro-oxindole (89%, mp. 185–188 ° C); 5 (jf-chlorobutyryl) oxindole (84%, oil ;, mass spectrum,%: 239; 237 (55);
    1-ethyl-5- (lf-chlorobutygyl) oxindole (99%, oil); NMR (CBC1E): 1.2 (t, 3N); 1.5-2.7 (m, 5H); 3.0-3.2 (m, 2H) 3.5-4.0 (m, 3N); 6.8-7.0 (d, 1H); 7.9 (s, 1H); 7.95 (d, 1H);
    5-0 chlorobutyryl) 7-fluorooxindole (53%, mp. 156-160 ° C);
    I
    B. By the method used for
    obtaining 5- (2-chloroethyl) -oxindole in example 12B, receive the following:
    5- (2-chloro ethyl) -1-ethyloxindol (93%, mp. 120-122 ° C); NMR (CDCl1): 1.30 (t, 3N); 3.1 (t, 2H); 3.55 (s, 2H); 3.65-4.0 (m, 4H); 6.8-7.3 (m, ЗН):
    5- (2-chloroethyl) -1-methyloxindol (99%, mp. 127-130 ° C); NMR (CDC13): 3.1 (t, 2H); 3.2 (s, 2H); 3.5 (s,
    five
    0
    five
    0
    five
    2H); 3.75 (t, 2H); 6.8 (d, 1H); 7.15 (s, 1H); 7.2 (d, 1H);
    5- (2-chloroethyl) -1- (3-chlorophenyl) oxindole (83%, mp 75 - 76 ° C);
    5- (2-chloroethyl) -1,3-dimethyloxindole (58%, mp. 73-75 ° C); NMR (CDCl1): 1.45-1.55 (d, 3N); 3.0-3.2 (t, 2H); 3 25 (s, ZN); 3.30-3.60 (KB, 1H); 3.65-3.90 (t, 2H); 6.85-6.90 (d, 1H); 7.15% (s, 1H); 7.15-7.30 (d, 1H);
    5 - (2-chloroethyl) -spiro cyclopentane-1.1,3 j-indoline-27-one, (92%, mp. 140-142 ° C); NMR (DMSO-s): 2.8 (bs, 8H); 2.90 (t, 2H); 3.7 (t, 2H); 6.6-7.1 (m, 3N); 10.2 (broad s, 1H);
    5- (2-chloroethyl) -1- (3,3-trimethyl) oxindole (83%, oil);
    5- (2-chloroethyl) -6-fluorooxindole (62%, mp. 188-190 ° C); NMR (DMSO-sY: 3.05 (t, 2H); 3.5 (2, 2H); 3.85 (t, 2H); 6.6-6.7 (m, 2H);
    5- (2-chloroethyl) -7 fluorooxindole (79%, t „pl. 176-179 ° С; mass spectrum,%: 213 (50); 180 (20); 164 (100), 136 (76);
    5- (2-chloroethyl) -6-chlorooxindole (94%, mp. 210-211 ° C);
    5- (2-chloroethyl) -3,3-dimethyl-6-fluoro-oxindole (C42 H1E C1FNO, 84%, mp. 195-); NMR (DMSO-dg): 1.3 (s, 6H);
    3.05 (t, 2H); 3.7 (t, 2H); 6.65 (d, 1H); 7.1 (d, 1H); 10.1 (imp. S, 1H);
    5- (4-chlorobutyl) oksivdol (40%, oil); NMR (CDC1): 1.6-2.0 (m, 4H);
    2.6 (m, 2H); 3.6 (m, 4H); 6.8-7.15 (m, 3N); 9.05 (broad s, 1H);
    5- (4-chlorobutyl) -1-ethyloxindol (48%, oil); NMR (CDCl1): 1.25 (t,
    ZN); 1.5-1.95 (m, 4H); 2.6 (m, 2H); 3.5 (s, 2H); 3.55 (t, 2H); 3.75 (q „2H); 6.7-7.2 (m, 3N);
    5- (4-chlorbutyl) -7-fluorooxindol
    (71%, mp. 168-173 C). I
    The neuroleptic activity of the proposed compounds can be demonstrated by methods based on standard techniques. In accordance with one method, adult rats of the race of the Spague-Dawley (males) are pretreated with appropriate doses of the test compound by subcutaneous injection. After half an hour, all rats are injected intraperitoneally with 1 mg / kg of apomorphine hydrochloride dissolved in a 0.1% ascorbate solution. The behavior of the rats is assessed according to the following scale 5, 15, 25, 35 and 45 minutes later, counting from the injection.
    apomorphine: 0 alertness, but without unnecessary movements; 1 movement in the cage; 2 periodic sniffing and snorting; 3 continuous sniffing and sniffing with periodic mouth movements; and 4 continuous licking and chewing.
    The neuroleptic activity of the proposed compounds makes them useful for the treatment of human mental illness. For example, these compounds are useful for treating mental disorders of the schizophrenic type and, in particular, the compounds are useful for alleviating or alleviating symptoms such as anger, anxiety, excessive aggressiveness, intensity and social or emotional detachment of the mental. the sick.
    A neuroleptic compound of the general formula or a pharmaceutically acceptable salt thereof may be administered to a human as such or predominantly in combination with pharmaceutically acceptable carriers or diluents as a pharmaceutical composition, according to standard pharmaceutical practice. The compound may be administered orally or parenterally. Parteral administration includes especially intravenous and intramuscular administration. In addition, in a pharmaceutical composition comprising a compound of the general formula or a pharmaceutically acceptable salt thereof, the active ingredient has a mass ratio. the carrier is usually from 1: 6 to 2: 1, preferably 1: 4-1: 1. However, in any case
    In addition, the chosen ratio depends on such factors as the solubility of the active component, the dosage given and the exact route of administration.
    The proposed compounds are categorized as non-toxic.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining piperazine heterocyclic compounds of the general formula. 15
    Ar-l N-C2H
    where Ar is naphthyl or benzoisothiazolyl; X and Y, together with the phenyl to which they are attached, form oxindolyl, optionally substituted by one chlorine atom, benzoxazolone or “; - benzothiazolonyl,
    or their pharmaceutically acceptable acid addition salts, such that piperazine of the general formula, where Ar has the indicated meanings, is reacted with a compound of the formula
    Na1C2H4
    where X and Y have the indicated meanings; Hal - halogen atom „
    Dopamine Test
    Ar-lsQvJC
    Benzoisothiazolyl
    Benzoisothiazolyl
    Naphthyl
    Table continuation
    Benzothiazolonyl25
    6-Chloro-oxin-22 refilled
    Benzoxazolonyl16
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    同族专利:
    公开号 | 公开日
    CN1015057B|1991-12-11|
    PH24119A|1990-03-05|
    NO880901L|1988-09-05|
    HUT50330A|1990-01-29|
    NO170977B|1992-09-28|
    IL85495A|1993-05-13|
    CZ281257B6|1996-07-17|
    FI880941A0|1988-03-01|
    DK173065B1|1999-12-13|
    EG18398A|1993-02-28|
    LU90944I2|2002-10-07|
    DE10299021I1|2002-09-26|
    ZA881447B|1989-10-25|
    BA98296A|2001-09-14|
    JPS63301861A|1988-12-08|
    FI91868B|1994-05-13|
    DE10299021I2|2007-05-10|
    DK108388A|1988-09-03|
    PL270925A1|1988-12-08|
    FI880941A|1988-09-03|
    MX173362B|1994-02-23|
    IL85495D0|1988-07-31|
    HU207860B|1993-06-28|
    CN88101642A|1988-09-14|
    CA1300139C|1992-05-05|
    MX10621A|1993-09-01|
    EP0281309B1|1991-12-27|
    PL157897B1|1992-07-31|
    NO2002004I2|2007-02-12|
    CZ131788A3|1996-05-15|
    ES2040838T3|1993-11-01|
    EP0281309A1|1988-09-07|
    IE60849B1|1994-08-24|
    DE3867089D1|1992-02-06|
    YU40688A|1989-12-31|
    AU583762B2|1989-05-04|
    IE880574L|1988-09-02|
    YU46639B|1994-01-20|
    GR3003459T3|1993-02-17|
    PT86866B|1992-05-29|
    AR244673A1|1993-11-30|
    NO880901D0|1988-03-01|
    KR900003492B1|1990-05-21|
    DK108388D0|1988-03-01|
    FI91868C|1994-08-25|
    PT86866A|1988-03-01|
    JPH0710837B2|1995-02-08|
    NO170977C|1993-01-06|
    MY103352A|1993-06-30|
    AT70833T|1992-01-15|
    DD272077A5|1989-09-27|
    NZ223694A|1990-02-26|
    KR880011142A|1988-10-26|
    AU1253788A|1988-09-01|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US8700423|1987-03-02|
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