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    • 专利摘要:
    NEW MATERIAL:A compound of formula I [R<1> is (substituted) aryl or heteroaryl; R<2> is lower alkyl; R<3> and R<4> are H or lower alkyl; R<5> is H, lower alkyl or acyl; X is lower alkylene which may contain a heteroatom; the broken line represents 2 double bonds on a pyrazole ring; R<5> is bonded to either one of the 1- or 2-position] or a salt thereof. EXAMPLE:5-Ethyl-3-methylamino-7-( 4-methylbenzyl )pyrazolo[3,4-d]pyrimid ine-4,6(5H,7H)-dione. USE:A treating and preventive agent for mental symptoms including dementia symptoms caused by cerebral apoplexy, head external injury and brain atrophic disease, neurosis, etc. For example, useful for preventing and treating amnesia, hyermnesia, disorientation, affect incontinence and behavior anomaly. PREPARATION:For example, a compound of formula II is reacted with a compound of the formula R<3>-NCS to give a compound of formula III.
    公开号:SU1591811A3
    申请号:SU874202196
    申请日:1987-03-13
    公开日:1990-09-07
    发明作者:Takekhiko Naka；Jesiyasu Furukava；Akinobu Nagaoka
    申请人:Takeda Chemical Industries Ltd；
    IPC主号:
    专利说明:

    The invention relates to a method. . for the preparation of new pyrazolo 13,4-a] pyrimidine derivatives capable of activating brain functions and metabolism.
    The aim of the invention is a method for producing new derivatives of pyrazolo (3,4-0-3pyrimidine, exhibiting a different biological activity than the known structural analogues.
    To obtain 3-butyl hydrazino 1- (4-methoxybenzyl) uracil in a mixture
    3-butyl-6-chlororacil (5.0 g, 24.6 mmol) of potassium carbonate (4.4 g, 32 mm) and potassium iodide (0.17 g, 1 mmol) in 50 ml of dimethylformamide (DMF) are added
    4-methoxybenzyl chloride (4.65 * ml, 32mM). The mixture was stirred at room temperature for 5 hours, then conc. 15 are centered under reduced pressure, and the resulting y residue is diluted with water (50 ml) and extracted with chloroform (100 ml). .
    The organic layer was washed with water, 20 dried over magnesium sulfate and concentrated to dryness, resulting in a brown syrup.
    The syrup is purified by preparative chromatography on silyl 25 gel (elution with chloroform) to give 3-butyl-6-chloro-1- (4-methoxybenzyl) uracil as an oil. Then, hydrazizone hydrate (20 ml) was added to a solution of oil in ethanol (50 ml), and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to obtain crude crystals. - After recrystallization from a 70% ethanol solution, the desired product was obtained in the form of light yellow crystals (4.23 g, 54%), mp. 167170 ^ 0 .. ’.
    Calculated,%: C 60.36; H 6.97; to N, 17.60.
    C ί6 Η 22 Ν4.0 3 .
    Found,%: C 60.48; H 6.88;
    N, 17.51.
    Similarly receive compounds 45 are given in table. one. ,
    νηνη 2
    Χ-Βι
    PRI me R 1. 7-Benzyl-3-methylaminb-5-propylpyrazolo (3,4-D] pyrimidine-4,6 (5H, 7H) -dione.
    A solution of 1-benzyl-6-hydrazino-3propyluracil (2.0 g, 7.3 mmol) and methyl isocyanate (1.5 ml, 22 mmol) L in DMF (20 ml) was stirred at 120 ° C for 20 hours. ethanol (20 ml) was added, the solution was then cooled, whereby colorless needles (1.6 g, 70%) were obtained, mp. 307-310 ° C.
    Calculated ',%: C 61.33; H, 6.11;
    N, 22.35.
    Found,%: C 61.40; H, 6.02:
    N 22 25.
    Example 2 3-Methylamino-5-propyl-7- (2-chlorobenzyl) pyrazolo (3,4-C] pyrimidin-4,6 (5H, 7H); - dione.
    . A solution of 6-hydrazino-3-propyl-1- (2chlorobenzyl) uracil (1 ^ 33 g, 4.3 mmol) and methyl isocyanate (0.9 ml, 12.9 mmol) in DMF (20 ml) is heated to 120 ° C. within 20 hours, methanol (10 ml) was added to the solution. After cooling, crystals are obtained. After recrystallization from a mixture of DMF and methanol, a colorless crystal '(0.64 g 42%) is obtained, mp. > 300 ° C.
    Calculated,%: C 55.25; H 5.22;
    N, 20.14. ·
    C H N "O S1Y £ g.
    Found,%: C 55.53; H 5.42;
    N, 20.03.
    Example 3. 3-Methylamino-5-pro. pil-7- (3-chlorobenzyl) pyrazolo (3,4-D] pyrimidin-4,6 (5H, 7H) -dione.
    A solution of 6-hydrazino-3-propyl-1 (3-chlorobenzyl) uracil (3.0 g, 9.6 mmol) and methyl isothiocyanate (2.2 ml, 32 mmol) in DMF (30 ml) is heated to 120 ° C. for 27 hours. 50% methanol (10 ml) was added to this solution. After cooling. mixtures get crystals. After recrystallization from a mixture of DMF and methanol, colorless crystals (1.22 g, 36%) are obtained, mp. 263-265 ° C.
    Calculated,%:, C 55.25; H 5.22;
    N, 20.14.
    C: & H, ^ ΟΙΝ ^ Ο ^.
    Found,%: 0 55.34; H, 5.31 ;.
    N, 20.12.
    PRI me R 4. 3-Methylamino-5-propyl-7- (3-chlorobenzyl) pyrazolo (3,4-D] pyrimidin-4,6 (5H, 7H) -dione.
    6- (4-Methylthiopolucarbazide) -3-propyl- 1- (3-chloro benzyl) ur acyl.
    A solution of 6-hydrazino-3-propyl-1- (3chlorobenzyl) uracil (4.0 g, 13 mmol) and methyl isothiocyanate (1.16 ml, 17 mmol) in DMF (15 ml) was stirred at 50 ° C for 5 hours Then evaporated and 5%: C 58.00; H 5.48;
    . 159181 irradiate a crystalline product. After recrystallization from a mixture of DMF, methanol and water, colorless crystals (4.15 g, 84%) are obtained, mp. 221-223 σ Ο.
    Calculated,%: C 50.32; H 5.28;
    N, 18.34.
    Ο, ί n 2o С1П ^ 0 2 .
    Found,%: C 50.61; H 5.80;
    N, 18.19.
    A solution of 6- (4-methylthiopolucarbazide) 3-propyl-1- (3-chlorobenzyl) uracil (3.81 g, 10 mmol) in DMF (40 ml) was stirred at 100 ° C for 20 hours. Then, in the · reaction solution 50% methanol solution (20 ml) is added and> the mixture is cooled. The resulting crystals were recrystallized from a mixture of DMF and methanol and colorless crystals (2.49 g, 72%) were isolated, mp. 263-265 ° C.
    Calculated,%: C 55.25; H 5.22;
    N, 20.14.
    C 16 H < N C1H 5 O 2 .
    Found,%: C 55.29; H 5.18;
    N, 20.13.
    EXAMPLE 5. 3-Methylamino-5-propyl-7- (4-chlorobenzyl) pyrazolo £ 3,4-D} pyrimidin-4,6 (5H, 7H) -dione.
    A solution of 6- (4-methylthiopolucarbazide) 3-propyl-1- (4-chlorobenzyl) uracil (4.8 g, 12.6 mmol), prepared as described in Example 4, in DMF (50 ml) was stirred at 100 ° C in for 40 hours
    A 50% methanol solution (20 ml) was added to the solution, and the mixture was cooled. The obtained crystals were recrystallized from a mixture of DMF and methanol and colorless crystals (2.8 g, 50%) were isolated, mp. 305-307 ° C.
    Calculated,%: C 55.25; H 5.22;
    N, 20.14 ..
    with „n and sn 5 about 2 .
    Found,%: C N 20.23.
    55.21; H 5.25;
    Example 6. 3-Methylamino-5-propyl — 7- (4-fluorobenzyl) pyrazolo [3,4-D} pyrimidin-4,6 (5H, 7H) -dione.
    A solution of 6-hydrazino-3-propyl-1- (4-fluorobenzyl) uracil (1.5 g, 5.1 mmol) and methyl isothiocyanate (1.2 ml, 17 mmol) in DMF (20 ml) is heated to 120 ° C and maintained at this temperature for 24 hours. A 50% methanol solution (10 ml) was then added and the mixture was cooled. After recrystallization from a mixture of DMF, methanol and water, light yellow crystals (0.62 g, 36%) are obtained, mp. 262-265 ° C.
    Calculated, N 21.14.
    Found,%: C 57.73; H 5.37;
    7 N, 21.39.
    Example 7. 7- (4-Bromobenzyl) -3methylamino-5-propylpyrazolo £ 3,4-D] pyrimidin-4,6 (5H, 7H) -dione.
    A solution of 1- (4-bromobeksyl) -6-hydrazino-3-propyluracil (4.15 g, 11.8 mmol) and methyl isothiocyanate (2.7 ml, 40 mmol) in DMF (50 ml) is heated to 120 ° C and maintained at this temperature; 5 for 24 hours. A 50% methanol solution (15 ml) was added to the reaction solution, and the mixture was cooled. After re '; crystallization from a mixture of DMF. and methanol give colorless needles (2.19 g, 20 47%), so pl. 308-310 ° C. ,.
    Calculated,%: C 48.99; H 4.63;
    N, 17.85.
    C 16 H 18 VgM 5 ° 2 .
    Found,%: C 48.59; H 4.52;
    17.98. ·
    EXAMPLE 8. 3-Methylamino-5tpropyl-7-phenethylpyrazolo C3,4-D] pyrimidin-4,6 (5H, 7H) -dione.
    A solution of 6-hydrazino-3-propyl-1-phenethylluracil (1.5 g, 5.2 mmol) and methyl isothiocyanate (1.1 ml, 16 mmol) in DMF (15 ml) was stirred at 60 ° C for 2 hours, and then at 120 ° C. for 15 hours. A 50% methanol solution (10 ml) was added and the mixture was cooled. After recrystallization from a mixture of DMF and methanol, colorless crystals (0.7 g, 41%) are obtained, mp. 23b-258 in S.
    Calculated,%: C 62.37; H, 6.47; N21.39. ' 8 17 to 2 ί ^ 5θ 1
    Found,%: C 62.40; H 6.03;
    • N 21.64.
    ^ 5 Π PRI me R 9. 3-Methylamino-5-propyl-7- (3-phenylpropyl) pyrazolo £ 3,4-D 3 pyrimidin-4,6 (5Н <7Н) -dione.
    A solution of 6-hydrazino-3-propyl-1- (3phenylpropyl) uracil (1.7 g, 6.3 mmol) 3 0 and methyl isothiocyanate (0.8 ml, 12 mmol) in DMF (20 ml) was stirred at 60 ° C. for 2 hours, and then at 100 ° C for 12 hours. Methanol (10 ml) was added to the solution, and the mixture was cooled. After recrystallization from a mixture of DMF and methanol, colorless needles (0.9 g, '47%) are obtained, mp. 267-269 ° C.
    Calculated,%: - C 63.32; H 6.79;
    N, 20.51. ' C 1 $ Η 2 3 Ν 5θ
    Found 7 ": C 63.18; H 6.59;
    N20.38.
    Example 10. 7-Benzyl-2-butyryl- $
    3-methylamino-5-propyl-2H-pyrazolo.
    '£ 3.4- <3] pyrimidin-4.6 (5H, 7H) -dione.
    A mixture of 7-benzyl-3-methylamiuo-5-propylpyrazolo [3,4-P] pyrimidin-4,6 (5H, 7H) -dione (0.7 g, 2.2 mmol) and butyric anhydride (0.71 g , 4.5 mM) in pyridine (10 ml). The mixture was stirred at 60 ° C for 24 hours. The reaction solution was evaporated to dryness, the residue was purified by silica gel chromatography (20 g, chloroform). $ 1 After recrystallization from a mixture of acetone and isopropyl ether, colorless needles are obtained (0.61 g,.
    7.1%), mp 138-139 ° C.
    Calculated,%; C, 62.65; H 6.57; twenty
    N, 18.26.
    S r „N 25 LuO e .
    Found,%: C 62.82; H, 6.64;
    N, 18.41. '25
    Example 11. 2-Acetyl-7- (3-chlorobenzyl) -3-methylamino-5-propyl-7- (3chlorobenzyl) -2H-pyrazolo (3,4-P] pyrimidin-4,6 (5H, 7H) - dion.
    Solution of 7- (3-chlorobenzyl) -3-methylamino-5-propyl ~ 7- (3-chlorobenzyl) pyrazo · '* lo £ 3,4-c1] pyrimidin-4,6 (5Н, 7Н) -dione ( 1.0 g, 2.9 mmol) and acetic anhydride (1.0 ml, 9.8 mmol) in pyridine (15 ml) were stirred at 80 ° C for 5 hours. The solution was evaporated to dryness and the residue 35 was triturated with water (10 ml). After recrystallization from a mixture of chloroform and ether, colorless are obtained. · Needles (0.95 g, 85%), mp. 169-171 ^ 0.
    Calculated,%: C 55.46; H 5.17;
    N, 17.96. ·
    STR 0 *
    Found,%: C 55.13; H 5.19;
    N, 18.51.
    Example 12. 2-Isobutyryl-3-methylamino-5-propyl-7- (3-chlorobenzyl) 2H-pyrazolo [3,4-ά] pyrimidine-4,6 (5H, 7H) -dione.
    Solution of 3-methylamino-5 ~ proyl-7- (3-chlorobenzyl) pyrazolo [3,4-ά] pyrimidin-4,6 (5H, 7H) -dione (0.7 g, 2.0 mmol) and isobutyric anhydride (1.0 ml, mmol) in pyridine (10 ml) was stirred at 80 ° C for 5 hours. Dos. Solution. xa is evaporated, and the residue is triturated with water (10 ml). After recrystallization from a mixture of chloroform and ether, colorless needles (0.5 g, 59%) are obtained, mp. 154-155 ° C.
    Calculated,%: C 57.48; H 5.79;
    N, 16.76.
    Ρι 0 η 24 οιν £ ο 3 .
    Found,%: C 57.20; H 5.70;
    N, 16.97.
    Example 13. 2-Methoxycarbonyl3-methylamino-5 ~ propyl-7- (3-chloroben-, zyl) -2H-pyrazolo [3,4-8] pyrimidine-4,6 (5H, -7H) -dione.
    To a mixture of 3 - methylamino-5-propyl-7 (3-chlorobenzyl) pyrazolo £ 3,4-c1] pyrimidin-4,6 (5H, 7H) -dione (1.0 g, 2.9 mmol) and triethylamine (1 , 2 ml of 8.6 mmol) in dioxane (50 ml) was added dropwise methyl chloroformate (0.66 ml, 8.5 mmol) at room temperature and the mixture was stirred at the same temperature for 20 hours. The mixture was evaporated to dryness and the residue was triturated with water (10 ml). After recrystallization from a mixture of chloroform and methanol, colorless crystals (1.0 g 86%) are obtained, mp. 164-166 ° C.
    Calculated,%: C 53.27; H '4.97; N17.26.
    C, g H 1o C1P 5 O 4 .
    Found,%: C 53.44; H 4.91;
    N, 17.43.
    EXAMPLE 14. 2-Butyryl-3-methylMino-5-propyl-7- (3-chlorobenzyl) -2 Npyrazolo [3,4-H] pyrimidine-4,6 (5H, 7H) * ion.
    A mixture of 7- (3-chlorobenzyl) -3-methylamino-5-propyl-7- (3-chlorobenzyl) pyrazolo [3,4-s!] Pyrimidin-4,6 (5H, 7 N, Hudione (0.7 g, 2 mmol) and butyric anhydride (0.64 g, 4 mmol) in pyridine (10 mp) was stirred at 60 ° C for 27 hours, the Reaction solution was evaporated to dryness, and the residue was purified by silica gel chromatography (18 g, chloroform). After Recrystallization from a mixture of acetone and isopropyl ether gives colorless needles (0.63 g, 75%), mp 152-153 ° C.
    Calculated,%: C 57.48; H 5.79;
    N, 16.76.
    С 20 Н ^ С1П 5 О 3 .
    Found ^%: C 57.45; H 5.78;
    N, 16.64.
    Example 15. 7-Benzyl-5-butyl3-methylaminopyrazolo [3,4-P] pyrimidine 4.6 (5H, 7H) -dione.
    A solution of 1-benzyl-3-butyl-6-hydrazinouracil (4.0 g 13.9 mmol) and methyl isothiocyanate (2.85 mh, 41.7 mmol) in
    DMF (50 ml) is stirred at 120 C |
    159181-1 over a period of 20 hours. Methanol (20 ml) was added to the solution and the mixture was cooled, whereby crystals were obtained. After recrystallization from a mixture of DMF and methanol, colorless crystals (3.0 g, 66%) are obtained, mp. 282-284 ° C.
    Calculated,%: C 62.37; H, 6.47;
    N, 21.39.
    S 1ALA
    Found,%
    C, 62.60; H 6.55;
    N, 21.32.
    Example 16. 7-Benzyl-5-butyl-_
    3-dimethylaminopyrazolo [3,4th] pyrimidin-4-, 6 (5H, 7H) -dione.
    Using the methodology of example 1, light yellow crystals are obtained, after recrystallization from an 80% ethanol solution giving colorless needles, so pl. 177-179 ° C. Calculated,%: C 63.32; H 6.79;
    N, 20.51.
    Found,%: C 63.39; H 6.86;
    N, 20.43. 25
    Example 17. 7-Benzyl-5-butyl2-methyl-3-methylamino-2H-pyrazolo [3,4-H) pyrimidin-4,6 (5H, 7H) -dione.
    A mixture of 7-benzyl-5-butyl-3-methylaminopyrazolo [3,4-H] pyrimidin-4,6 (5Н, 3 θ 7Н) -dione (1.5 g, 4.58 mmol), methyl iodide (0.48 ml, 6 mmol) and potassium carbonate (0.82 g, 6 mmol) were stirred at room temperature for 12 hours.
    The mixture was evaporated to dryness and the residue was extruded with chloroform and water. The organic layer was washed with water, dried over magnesium sulfate and evaporated to dryness, resulting in a solid. After recrystallization from a 80% ethanol solution of ethanol, colorless needles (0.88 g, 50%) are obtained, mp ’· 146-148 C.
    Calculated, -%: C 63.32; H 6.79;
    N, 20.51.
    , C | N 2 dp d 0 2 "
    Found,%: C 63.55; H 6.86;
    N, 20.29.
    Example 18. 5-Butyl-7- (4-methoxybenzyl) -3-methylaminopyrazolo [3,4-H] pyrimidin-4,6 (5H, 7H) -dione.
    A solution of 3-butyl-6-hydrazino-1- (4 methoxybenzyl) uracil (2.0 g, 6.3 mmol) and methyl isothiocyanate (1.36 ml, 20 mmol) in DMF (20 ml) was stirred at 120 ° C for 20 h. Ethanol (20 ml) was added to the solution and the mixture was cooled, resulting in crude crystals. After recrystallization from a mixture of DMF and ethanol,
    yellow crystals (one 91 g 57%), mp 292-2-94 ° C. ' Calculated,%: FROM 56.43; H 5.57; N, 19.36. С 17 Н 2 ( С1М ^. Found,%: С 56 , 51; n 5.49;
    N19.22.
    Example 19. 5-Butyl-7- (4-chlorobenzyl) -3-methylaminopyrazolo [3,4-8} pyridin-4,6 (5H, 7H) -dione.
    A solution of 3-butyl-1 ~ (4-hlorbeneil) gidrazinouratsila-6 (3.0 g, 9.3 mmol) and methyl isothiocyanate (2.0 ml, 29 mmol) in DMF (30 ml) was stirred at 120 ° C for 2θ hours. Ethanol (20 ml) was added to the solution, and the mixture was cooled, resulting in crude crystals. After recrystallization from a mixture of DMF and ethanol, lightlog is obtained.
    same molten crystals (one 91 g .57%), so pl. 29th 2-294 ° C. Calculated,%: FROM 56.43; And 5.57; N 19.36. with n and r0 C1 ^ o 2 . Found,%: C 56 , 51; N 5.49; N 19.22.
    Example 20. 5-Butyl-3-methylamino-7- (2-nitrobenzyl) pyrazolo [3,4-D]. Pyrimidine-4,6 (5H, 7I) -dione ·.
    A solution of 3-butyl-6-hydrazino-1- (2 nitrobenzyl) uracil (4.0 g 12 mmol) and methyl isothiocyanate (2.4, 36 mmol) in DMF (40 ml) was stirred at 120 ° C for 20 hours. ethanol (20 ml) is added to the solution and the mixture is cooled, as a result, crystals are obtained which, after recrystallization from a mixture of DMF and · ethanol, turn into colorless needles (2.0 g, 45%), so pl.
    300 ° C.
    Calculated,%: C 54.83; H 5.41;
    N, 22.57.
    C A
    Found,%
    With 54.89; H 5.31;
    N, 22.43.
    Π RI me R 21. 5-Butyl-Z-methyl-. amino-7- (4-nitrobenzyl) pyrazolo £ 3,4-ά] pyrimidin-4,6 (5H, 7H) -dione.
    A solution of 3-butyl-6-hydrazino-1- (4 nitrobenzyl) uracil (1.7 g, 5 mmol) and 'methylisothiocyanate ^ (0.7 ml, 10 mmol) in DMF (20 ml) was stirred at 120 ° C. within 20 hours, ethanol (20 ml) was added to the solution and the mixture was cooled.
    As a result of recrystallization of the obtained crystalline product, light yellow crystals are isolated.
    m 159181
    -, (0.61 g, 32%), mp 2-77-279 ^ 0 (from '
    mixtures of DMF and ethanol),
    Calculated,%: C 54.83; H 5.41;
    N22.57. . , - 5
    Found,%: C 54.80; H, 5.11; (
    N 22,511 ‘
    PRI me R 22. 5-Butyl-3-methylamino-7- (2-benzylaminoethyl) pyrazolo-3 SZ, 4-83 pyrimidine-4,6 (5H, 7H) -dione.
    Using the method of example 1, get colorless needles (0.32 g, 43%), so pl. 198-200 ° C (from a mixture of DMF, methanol and water). ,fifteen
    Calculated,%: C 61.60; H 7.08;
    N, 22.69.
    Found,%: C 61.51; H 6.87;
    N, 22.58. ' twenty
    PRI me R 23. 5-Butyl-7 (4-methoxybenzyl-3-ethylamino) pyrazolo (3,4-ά] pyrimidine-4,6 (5H, 7H) -dione.
    A solution of 3-butyl-6-hydrazino-1- (4 methoxybenzyl) uracil (0.64 g, 2 mmol) and 25 ethyl isocyanate (0.53 ml, 6 mmol) in DMF (6 ml) was stirred at 90 ° C for 14 hours and then at 110 ° C. for 14 hours. Water (2 mmol) was added to the solution and the mixture was cooled, whereby 30 crystals were obtained. After recrystallization from a mixture of DMF; ethanol and. water gets colorless needles (0.52 g,
    70%), mp 234-236 ° C.
    Calculated,%: C 61.44; H 6.78; 35
    N, 18.86.
    ο 19 η μ ν 6 ο 3 .
    Found,%: C 61.35; H 6.93;
    N, 18.77.
    PRI me R 24. Chlorohydrate 7- (4— to aminobenzyl) -5-butyl-3-methylaminopyrazolo [3,4-ά] pyrimidine-4,6 (5H, 7H) -dione.
    To a suspension of 5-butyl-3-methylamino 7- (4-nitrobenzyl) pyrazolo £ 3.4- (1 ^ pyrimidin-4,6 (5H, 7H) -dione (1 g, 2.6 mmol) 45 in concentrated hydrochloric acid (5 ml) and ethanol (2.5 ml) are added dropwise a solution of stannous chloride (3.75 g) in ethanol (5 ml) at room temperature with stirring. The mixture is stirred at room temperature for 24 hours, and then evaporated to dryness. · The residue is crystallized from hot water, resulting in 55 yellow crystals (0.42 g, 46%), mp 73 ° C.
    Calculated,%: C 52.64; H 6.24;
    N, 21.67.
    s p n 1g m 6 o g ns1 · 1 / 2H 2 0.
    Found,%: C 52.48; H 5.73;
    N21.35.
    Experiment 1. The regenerative effect of the proposed compounds is studied using a passive avoidance test. The installation consists of light and dark cameras. 5 week old male mice. first placed in a bright chamber. When animals enter a dark chamber, they receive an electric discharge through the mesh floor (0.5 MA, 5 s). Then these animals remain conscious for several weeks that they received an electric shock. The reflex deposited in the memory of the mouse is destroyed, and then the effect of the proposed compound is examined. The mice, after being subjected to an electric discharge, are placed in a 4-liter glass vessel filled with carbon dioxide gas. When they stop breathing, the animals are removed and breathing is restored using artificial respiration techniques. After this, the mice lose the reflex associated with the tested electric shock.
    I -. - ΐ
    The next day, conduct a test for recovery in mice of the specified reflex. Mice are again placed in the light chamber of the apparatus for passive avoidance and the time until the animals are sent to the dark chamber is measured. Those animals that have been treated with carbon dioxide, in the General case, again sent to the dark chamber after 10-20 seconds. In mice injected with the proposed compound, the reflex is restored in memory and they do not enter the dark chamber or end up there after a long time. The effect of the test compound is checked by comparing the average value (8 animals in the group) of the period of time during which the mice remain in the light chamber with the same indicator for the control group (which is administered only a suspension of 5% gum arabic that does not contain the test compound). The results are expressed as a percentage change in the indicator relative to the average value (100) in the control group. The test compounds are used intraperitoneally 30 minutes before the test or by the dental method 60 min before the test in the form of a sus) 3 pensions in a 5% solution of gum arabic (dose 5 or 20 mg / kg).
    The results are shown in table-2. Experiment 2. In the experiment, 5 male Wistar rats were used in a maze with 8 radial rays. The symmetrical 8-beam labyrinth consists of 80 cm long strokes extending from the center of the platform, each stroke having 10 cups with a feed briquette. Rat-free rats are placed in the center of the platform and are given the opportunity to choose freely 4 moves. The rat is removed from the installation immediately after the fourth choice and 15 return it to its cage. At various time intervals, the rat is placed in the center of the platform and allowed to continue the search. At the same time, the number of correct reactions is fixed during the implementation of the fifth or eighth choice (these are the choices of moves that the rat has not visited before) and the total number of errors (the number of moves that the rat has already passed). If the delay between two consecutive experiments is less than 4 hours, then an increase in the number of correct reactions and a decrease in the total number of errors are observed in the rat.
    During the experiment, the rat is removed from the installation immediately after the fourth choice and scopolamine (0.5 mg / kg, intraperitoneal method) and the test compound (10 μ / kg, intraperitoneal method) are administered simultaneously. After 1 h, the rat was again placed in the installation and allowed to continue the search. In the experiment, 7-12 rats are used in the group.
    The results are shown in table. 3 (each value is the mean value ί standard error).
    As the data in table. 3, the spatial memory in the rat was noticeably destroyed under the influence of scopolamine, which is proved by a decrease in the correct reactions and an increase in the total number of errors. The compound of example 3 improved spatial memory after the formation of its deficiency as a result of exposure to scopolamine, while there was a significant increase in the correct reactions and a decrease in the total number of errors.
    Experiment 3. Male Uistar rats are used, in which bilateral olfactory coryphae are removed by suction. Each rat is placed on a plate (30x7x4.5 cm) located on one side of a large cage (30x30x30 cm) equipped with a mesh floor. When the rat leaves the platform, it receives an electrical discharge (0.6 mM, for 1 s). Then the rat is returned to its cage for 1 min, after which they arrange a second test. This procedure is repeated until the animal spends 180 s on the platform without leaving it, or until 10 trials. In each test, time is recorded when the rat leaves the platform. 8-10 rats were used in each group, and the test compound was administered intraperitoneally 1 hour before the start of the test.
    The test results for generating an avoidance reflex for 180 s on the platform are given in table. four.
    Control rats with the removed olfactory bulb, which were injected with saline, showed a significant increase in the number of tests to develop a reflex compared to rats for which this operation was only simulated. The compound of example 3 leads to a noticeable and significant improvement in learning to passively avoid rats with a bulb removed.
    The proposed compound has low toxicity (with dental use): ΠΠ ί0 10,000 mg / kg ve. body sa (rats).
    Derivatives of pyrazolo £ 3.4 -. ^ Pyrimidine and their salts can be used due to their ability to activate brain function and metabolism for tera-. FDI and prevention in mammals, including humans, neurosis and mental illnesses, including dementia caused by cerebral apoplexy, head injuries or encephalotropic diseases (Arzimer’s disease, etc.), as well as for the prevention and treatment, for example, memory loss, delayed reactions, loss of orientation, emotional restraint and dystrophy.
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives of pyrazolo DH, 4-8 ^ pyrimidine General formula
    X "1" ·> O
    15 159181 / · where Κ ϊ is phenyl unsubstituted or substituted by one halogen atom, -Ν0 2 or a lower alkoxy group;
    1 .16 ; at 50-120 ° C for 2-24 hours, the resulting and optionally isolated intermediate of the formula
    K, and K 3 — lower alkyl; K 4 'is hydrogen;
    K ^ - is hydrogen, lower alkyl or lower acyl, with the group K $ · attached at the 1- or 2-position of the pyrazole 'ring;
    X is lower alkylene;
    the dashed line indicates the presence of two double bonds in the piraeol ring, or their pharmaceutically acceptable salts, characterized in that the compound of the formula νΛ Π
    Ο ^ ΝΗΝΗ- 0-ΝΗΗ 3 δ
    II
    Χ-Βι *
    ν τ values, additionally heated at 9014-20 h with the release of the compound mules where
    K e and X have the indicated
    120 ° C for—
    Un
    but.
    0¼ 'ΝΗΝΗπ 25
    1 1 Χ-Ηι where K ,, K 2 and X have the indicated meanings, are reacted with an isothio-30 cyanate of the formula
    To 3 - N = C = 5,.
    where cd has the indicated value,
    I 4 ^ ΝΗ N.
    Гдеι where K l , K 2 , values, or, if necessary, it is subjected to interaction with an alkylating or acylating agent with isolation of the target product in free form or in the form of a pharmaceutically acceptable salt.
    K 3 and X have the indicated
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    同族专利:
    公开号 | 公开日
    KR870008882A|1987-10-21|
    JPS6310788A|1988-01-18|
    KR880009021A|1988-09-13|
    引用文献:
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    US8697710B2|2008-12-06|2014-04-15|Intra-Cellular Therapies, Inc.|Optionally substituted 3-amino-4--4,5-dihydro-2H-pyrazolo [3,4-d]pyrimidin-6-ones|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP5792086|1986-03-14|
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