• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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  • 优先权
    • 专利摘要:
    Compounds having antipsychotic activity, characterised bytheformula in which formula R0 and R1 are the same or different and are each selected from hydrogen, halogen, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1, 2 or 3 carbon atoms, and trifluoromethyl, and R2 is selected from hydrogen, halogen, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1, 2, or 3 carbon atoms, and trifluoromethyl, methods for their preparation, pharmaceutical compositions containing them, method for the treatment of psychoses, and the use of the compounds for the preparation of pharmaceutical compositions.
    公开号:SU969164A3
    申请号:SU802969263
    申请日:1980-08-26
    公开日:1982-10-23
    发明作者:Стефан Бенгтссон Карл；Олов Торберг Зет；Ове Егрен Свен
    申请人:Астра Лэкемедель Аб (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for producing new heterocyclic compounds possessing antipsychotic activity, in particular, to a method for producing chlorophthalimidine having the general formula where R, R, Rj have the same or different values and represent hydrogen, halo, alkyl J, alkoxyC-C, trifluoromethyl, or their salts. Pyrrolidium derivatives are known, in particular sulpiride, possessing antipsychotic activity C}. The aim of the invention is to develop a method for synthesizing compounds of the general formula (1), expanding the range of agents with antipsychotic activity. . This goal is achieved by the fact that, according to the method of obtaining the derivatives of phthalimidine of the general formula (1) or their salts, the Compound of the general formula has the indicated values, is set with tin in the presence of hydrochloric acid and the desired product is isolated in free form or as a salt. The method is based on the known reaction of reducing carbonyl oxygen with a metal in an acidic medium. 2. Example 1. Preparation of 2- (4-beisylpiperidyl) -5-fluorophthalimidine. 13.5 g (0.040 mol) of 2- (4-N-benzylpiperidyl) -5-fluorophthalimide is dissolved in 100 ml of acetic acid. 11.2 g (0.094 mol) of tin and a mixture of cooling with ice are added. 22 ml of hydrochloric acid is added dropwise and the mixture is heated to 120 ° C for 16 hours. The clear solution is dissolved to dryness and the residue is dissolved in 100 mp 1N. hydrochloric acid. The product is extracted with 100 units of dichloromethane, the organic layer is dusted with brine and alkalinized with 2N. with other sodium oxide. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo; The residue is a mixture of the desired product with an isomeric 6-ft compound in a ratio of 80-20. The mixture of isomers is separated by liquid chromatography under pressure with the addition of silica gel and a mixture of hexane, ethanol and concentrated ammonia in the ratio 90j9, 8: 0.2. This gives 4.2 g (33%) of 2- (4-N-6 zilpiperidyl) -5-fluorotalimidine with so pl. 128-129 C, - as well as 0.7 g (5% of the isomer, 2-C4-L-benzylpiperidyl) -6 fluorophthalimidine with a mp of 136-138 C. The starting compound is obtained in the following way. 8.0 g (0.050 mol) of 4-fluorophthalic anhydride are dissolved in 500 ml of toluene and the solution is heated to 50 ° C. 9.5 g (0.50 mol) of 4-amino -1-benzylpiperidine are dissolved in 100 ml of toluene and added dropwise over 15 minutes. The mixture is heated under reflux for 16 h, after which the solvent is evaporated in vacuo. The crystalline residue is dewatered by heating to 200 ° C. After cooling, the product is dissolved in chloroform and recrystallized from a mixture of chloroform and isopropanol. The yield of 13.6 g (80%), so pl. 113-114C. Analogously to Example 1, the following compound of formula (1) is obtained: 3.2- (4-L-Benzylpiperidyl) -5-bro phthalimidine with m.p. 173-174 ° C (yield 30%). 4.2- (4-Y-Benzylpiperidyl) -5-chloro phthalimidine with m.p. 151-152 С (yield 20%). 5.2- (4-m-Benzylpiperidil) -6-chlorophthalimidine with so pl. 125-126 ° C (yield 5%). 6f 2-G4-4 | 1-Benzylpiperidyl) -4.7 dimethoxyphthalimidine with m.p.175-177 (22% yield). 7.2- (4-N-Benzylpiperidyl) -5.6dibromophthalimidine with m.p. 17b-180 C (yield 69%). 8.2- (4-N-Benzylpiperidyl) -4.7 dibrmphthalimidine with mp 143-145 C. (yield 51%). 9.5-rX-2-4-N- (4-methoxybenzyl) Piperidyld-phthalimidine with so pl. 135-137 "C (yield 20%). 10.2- (4-Y-Benzylpiperidyl) -4fluorophthalimidine with m.p.290-295 ° C, with decomp. (yield 20%). 11.7-Ftop-2- (4-N-F Ensylpiperidyl) -phthalimidine with m.p., 126-127 ° C (yield 8%). 12. Hydrochloride 5-methyl-2- (4-M-methylbenzyl) -piperidylphthalimide with mp 292-293 “C (31% yield). 13.5-Brom-2-4-N- (4-hlorobenzyl) piperidyl1-phtapimidium with mp 175.5192 C (25% yield). 14.2- (4-N-Benzylpiperidyl) -alimidine with mp 136-138 C, (yield 30%). 15.2- (4-M-Benzylpiperidyl) -6bromophthalimidine with m.p.139-14. (yield 28%). 16.5-Bromo-2- 4-M- (4-methylbenzyl) piperidylZ-phthalimidine with m.p.168.51700s (25% yield). 17. 5-Chloro-2-C4-M- (4-hlLrbenzyl) piperidyl-Phalimidine with m.p.-172174 C (yield 21%). 18.5-chlorop-2-i 4-N- (4-methylbenzyl) piperidyl-phthalimidine with mp 153154 C (yield 33%). 19.5-Chloro-2-; 4-N- (3-trifluoromethylbeisyl) -piperidyl} -phthalimidine with m.p. 115-117 ° С (yield 21%). 20.5-Trifluoromethyl-2- 4-M- (4-methylbenzyl) -piperidyl-phthalimidine c. Mp. 123-125 С (20% yield). 21.5-Trifluoromethyl-2-E4-M- (45sorbenzyl) -piperidyl -pthalimndin with m.p. 130-132 ° C (yield 22%). 22 5-yzoprbpil-2-t4.-N- (4-chlorobenzyl) -piperidyl -phthalimidine c; pl. 162-164 C (yield 20%). 23.. 5-Isopropoxy-2- 4-M- (4-chlorobenzyl) -piperidyl} -phthalimidium with mp 167-168.5 ° C (22% yield). 24. 4,5-Dichloro-2-4-H- (4-chlorobenzyl) -piperidyl-3-phthalimidine with h. 1.177-179 ° C (yield 21%). 25.5-HLOR-2-4-N- (4-ethylbenzyl) piperidyl-phthalimidine with m.p. 1882184 C (yield 20%). 26.5-chlorop-2-4-N- (4-isopropylbenzyl) -piperidyl-phthalimidine with mp 166-1679 (yield 18%). 27.5-Ethyl-2-C4-N- (4-methylbenzyl) pipaE) idyl -faltimndin with m.p. 1.265268s (26% yield). 28.5-Ethoxy-2- 4-K- (4-chlorobenzyl) -piperidyl-phthalimidine with m.p. 186-188 ° C (yield 21%). Example 2. Example 1 is repeated, with the difference that 2- (4-Y-benzylpiperidyl) -6,7-dimethoxyphthalimide is subjected to tin reduction and the resulting base is converted to hydrochloride by addition of hydrochloric acid, followed by crystallization from ethanol. The hydrochloride of 2- (4-K-benzylpiperidyl) 6, 7-dimethoxyphthalimidine with m.p. 26769 C is obtained, the schlod is 25%. The experiments were carried out on rats weighing 225-275 g. Rats are in cages measuring 40–25–30 cm and their waking is observed 5, 20, 40 and 60 minutes after giving apomorphine hydrochloride (1 mg / kg)
    inject subcutaneously into the back of the head. Such a dose and form of application allows a reliable response to be obtained with simultaneous slight changes in the intensity of the response. In addition, the subcutaneous administration of apomorphine allows to achieve significant hyperactivity. Immediately after the injection of these compounds into the cells placed per animal. The stereotype is determined by two methods. One method is to determine the intensity of stereotype according to the following scale:
    0No change in behavior compared to control (saline); no sedative effect
    1 Periodic sniffing
    2Continuous sniffing
    3Continuous sniffing, chewing, licking, biting. ,
    Another method is to determine the number of animals exhibiting hyperactivity caused by apomorphine. Each group consists of 6-8 animals. Control experiments (yes Stereotype AU,
    Connection μmol / kg (intraperitoneally)
    one
    2 3 5 9
    13 15 16 17
    Sulpiride (known)
    cha | salt solution) is carried out simultaneously. According to the first method: EL50 is a dose that: Decreases the intensity of stereotype by 50% after 60, and
    5: according to the second - the dose, which, by, lowers the number of manifestations of animals with hyperactive HocTb by 50% after 60 minutes.
    The results of the experiments are given in
    10 table. The novel compounds are compared with sulpiride. From the data in the table, it is clear that the novel compounds are active inhibitors of dopamine receptors in the brain. Thanks
    For antagonism regarding stereotype and hyperactivity caused by apomorphine, new compounds are likely to block receptors in the striatal and marginal zones.
    20 | in addition, they exhibit better activity than the known agent. There is a close relationship between the blockade of apomorphine and clinical antipsychotic activity.
    2c compounds are likely to exhibit a B1 antipyrematism (; {hototic activity
    when used in medicine.
    I
    Hyperactivity U, µmol / kg (intraperitoneally)
    4.0 2.8 14.0 2.0 2.2 3.4 1.7 3.5 0.9
    45
    权利要求:
    Claims (1)
    [1]
    1.Life; Sciense, 17, 1975, p. 15511556;
    2, Weigand-Hilgetag. Experimental methods in organic chemistry. M., Himi, 1968, p. 79.
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