• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Antidepressant agents having the formula <CHEM> wherein R<1> is a polycycloalkyl group; R<2> is methyl or ethyl, X is O or NH; and Y comprises a 5- or 6-membered heterocyclic ring having one or two nitrogens; or fused bicyclic heterocyclic rings having a total of three nitrogen atoms, one in each ring and one angular nitrogen.
    公开号:SU1646488A3
    申请号:SU884613064
    申请日:1988-12-12
    公开日:1991-04-30
    发明作者:Алекс Саккомано Николас；Джеймс Виник Фредерик
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing a new chemical compound of the formula
    which can be used in medicine.
    The purpose of the invention is the search for a method for producing a new compound in the series of hexahydropyrimidin-2-one, which has high antidepressant activity.
    EXAMPLE 1, 5 ~ [3- (Exo ~ Bicyclo [2.2.1] -hept-2-yloxy) -4-methoxyphenyl ^ hexahydro-2-pyrimidinone.
    A. 3 - [(3-Bicyclo [2.2.1] “hept-2yloxy) -4-methoxyphenyl [| glutaronitrile.
    Pianouksusnuyu acid (18.1 g, 0.213 mmol) and exo-norbornilizovanilinovy ester (17.5 g, 71.1 mmol) was dissolved in a mixture of 80 cpx pyridine and 2 ml piperidine and heated at 100 C for 6 to 40 hours. The reaction mixture was cooled to room temperature, poured into 200 ml of water and extracted with 2 to 100. mp ethyl acetate.
    The combined extracts washed with Water, 1 N. HCl solution, saturated NaHC0 3 solution, again with water and dried over magnesium sulfate, then filtered and concentrated under vacuum> cm.
    A brown crystalline precipitate is obtained, which is recrystallized from ether to give 15.1 g
    1646488 (68.5%) of dicyanide as a crystalline solid, mp. 122123 ° C.
    (300 MHz, CDClg): 6.82-6.65 (m, 38); 4.14 (m, 1H); 3.8 (s, 3H);
    3.3 (m, 18); 2.77 (m, 18); 2.45 (m, 1H); 2.3 (m, 18); 1.8-1.0 (m, 88).
    B 3- £ (3-Bicyclo [2 „2.1J-hept-2-yloxy) -4-methoxyphenyl2 glutaramide.
    Glutaronitrile from step A (14.8 g,
    47.7 mmol) was dissolved in 200 ml of acetone and treated at 0 ° C 100 ml of water, 33.8 ml of a 30% solution in r 0 2 and 21.2 ml of 10% Na 2 C0 3 solution, then slowly heated and stirred at room temperature for 14 hours. The reaction mixture was concentrated to 150 ml and the residue was separated in a mixture of 100 ml of water and 200 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude diamine is triturated with ether and G3.8 g (84%) of the diamine is obtained in the form of a crystalline substance, so pl. 175-177 ° C.
    • 1 H-NMR (300 MHz, CDC1.): 6.8-6.6 (m, 3P); 4.15 (m, 18); 3.75 (s, 38); 3.6 (m, 18); 2.6-1.0 (m, 14 8).
    C. 5- £ 3- (exo-Bicyclo [2.2. Lj-hept2-yloxy) -4-methoxyPhenyl ^ -hexahydro2-pyrimidinone.
    Glutaramide from stage B (1g,
    2.89 mmol) is dissolved in pyridine, lead tetraacetate (2.72 g, 6.13 mmol) is added to the solution and stirred for 20 hours at room temperature. The reaction mixture was diluted with water and extracted with 2 X 100 mp ethyl acetate. The organic extracts are washed with HC1 solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is crystallized from ethyl acetate to give 0.60 g (65.7%) of cyclic urea as a crystalline solid, mp. 191-192 ° C, 1 H-NMR (300 MHz, CDCl 3 ) s 6.8-6.6 (m, 3H); 5.35 (br s, 2H); 4.15 (m, 1H); 3.8 (s, 38); 3.4 (m, 48); 3.1 (m, GN); 2.5-1.0 (m, 108).
    The activity of the proposed compound as an antidepressant was determined by the example of despair in behavior. In accordance with this procedure, the state of depression was caused in mice, forcing them to swim in a narrow cylinder containing water, from which there was no way out. This procedure involves the administration of the proposed compound to the mice through the mouth, and then (30 minutes after injection) the mice were placed in a standard 1L glass beaker containing 800 ml of water at 25 ° C. The observer evaluates the ability to move (0 - mobile, 1 - motionless) every 30 s for 5 min, starting after 2 min of the mouse in water. As animals used male mice weighing 20-25 g (Charles River), 10 mice in each experiment. Compared with rolipram. The compounds were used in a solution (carrier) containing Saline (90%), dimethyl sulfoxide (5%) and emulsions. 4 (5%). was administered in a volume of 10 ml / kg. ”Carrier-treated mice typically had a swimming rating of 9, while the use of an antidepressant reduced the immobility, which led to a decrease in swimming rating.
    Comparison of the antidepressant activity of the proposed compound and rolipram on a model of despair in behavior is given below:
    .
    Compound Minimumeffective dose, mg / kg Proposedexo isomer 0.10 endo isomer 3.20 A mixture of endo and exoisomers (7: 3) 0.32 ^ Rolipram 1.78
    From the point of view of biological activity, the exo-isomer of the proposed compound is more effective than the endo-isomer, however, in real practice, a mixture of isomers is preferable due to the relative ease of preparation compared to the pure isomer.
    As can be seen from the data above, the exo-isomer of the proposed compound or its mixture with the endo-isomer is more effective than rolipram, in addition, the proposed compound is less r.voten than rolipram.
    To counter hypothermia caused by reserpine in mice, the proposed compound is at the level of the well-known antidepressant desipramine.
    Thus, the implementation of the proposed method allows to obtain a compound whose exo-isomer is 17.8 times higher in antidepressant activity than rolipram.
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of producing 5- £ 3- (bicyclo 2, 2,1J-hept-2-yloxy) -4-methoxyphenyl hexahydro-2-pyrimidinone of the formula characterized in that the compound of the formula is cyclized in a reaction-inert solvent at room temperature in the presence of tetraacetate lead.
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    同族专利:
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    法律状态:
    优先权:
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