• 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:
    Pyrazolo[3,4-d]pyrimidines of the formula I …<IMAGE>… in which… R1 denotes a C1- to C6-alkyl radical, a C2- to C6-alkenyl radical, a C3- to C7-cycloalkyl radical or an aryl radical,… R2 denotes a C2- to C6-alkenyl radical, a C3- to C7-cycloalkyl radical or an aralkyl or hetaralkyl radical having 1 to 6 carbon atoms in the alkyl moiety and which, if desired, is mono- or polysubstituted by halogen, C1- to C6-alkyl, hydroxyl, C1- to C6-alkoxy, C1- to C3-haloalkyl, C3- to C7-alkoxycarbonyl, aminocarbonyl, C2- to C7-alkylaminocarbonyl, C3- to C13-dialkylaminocarbonyl, cyano or C1- to C6-alkylthio and… R3 denotes hydrogen, a C2- to C6-alkyl radical which, if desired, is mono- or polysubstituted by hydroxyl, a tetrahydrofuranyl radical or a tetrahydropyranyl radical,… with the proviso that R2 cannot be unsubstituted benzyl if R1 represents the methyl group,… and their physiologically tolerable salts of inorganic or organic acids are used as medicaments for the treatment of allergic diseases and of bronchospastic and bronchoconstrictive reactions due to inflammation.
    公开号:SU1701111A3
    申请号:SU884355573
    申请日:1988-04-14
    公开日:1991-12-23
    发明作者:Фрибе Вальтер-Гунар；Кампе Вольфганг；Вильхельмс Отто-Хеннинг
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new pyrazolo 3,4-c pyrimidines with pharmacological activity and which can be used in medicine.
    The purpose of the invention is a method for producing new pyrazolo 3,4-c pyrimidines having a higher antiallergic activity.
    Example 1. (3-Chlorobenzyl) cyclopentylamino -1 H-pyrazolo 3,4-pyrimidine.
    A mixture of 12.5 g (80 mmol) 4-chloro-1H-pyra-, 4th pyrimidine, 50.3 g (240 mmol)
    M- (3-chlorobenzyl) cyclopentylamine in 190 ml and -butanol is refluxed for 16 hours. The mixture is concentrated, the residue is treated with dilute sodium hydroxide solution, washed with ether, the pH of the aqueous phase is adjusted to neutral the reaction and the precipitate is filtered off. After recrystallization from ethanol, 19.5 g of the title compound are obtained (74% of theory) with a mp. 18b-187 ° C.
    Example 2. In Example 1, by introducing into the reaction 4-chloro-1H-pyrazo-, 4-b pyrimidine with the corresponding
    s
    secondary amine receive the compounds listed in table. one.
    Example 3. (3-Chlorobenzyl) cyclopentylamino -1- (2,3-dioxypropyl) -1H-pi is resolved 3,4-c pyrimidine,
    To a suspension of 1.5 g (30 mmol) of 50% sodium hydride in 50 ml of NN-dimethylformamide, 9.6 g (30 mmol) of 4-Lb (3-chlorobenzyl) cyclopentylamino-1H-pyrazolo are added dropwise. 3,4-c) pyrimidine (compound of example 1) in 25 mg of 1M, N-dimethylformamide, stirred for 1 hour at 80 ° C, 10.0 g (35 mmol) of 4- (4-toluenesulfononyloxymethyl A) -2,2-dimethyl-1,3-dioxolane in 25 ml of NN-dimethylformsmide, stirred for 3 hours at 80 ° C, concentrated in vacuo, treated with water, extracted with dichloroethane and the extract concentrated. The residue is mixed with 300 ml of 0.1N hydrochloric acid, heated under reflux for 10 hours, allowed to cool, washed with ether and the aqueous phase is alkalinized with sodium hydroxide solution.
    After extraction with dichloromethane and concentration of the extract, 8.2 g of a crude product are obtained, which is purified by chromatography on a violet gel (eluent dmx-chloromethane / methanol 9: 1). This gives 4.1 g (34%) of the desired compound, which after melting with ether melts at 98-100 ° C.
    Example 4. In Example 3, by alkylation with 4-4-toluenesulfonyloxymethyl 2,2-dimethyl-1,3-dioxolane, the compounds shown in Table 2 are obtained. 2
    Example 5. (2,5-Dimethylbenzyl) cyclopentylamino -1- (tetrahydrofurhan-2-yl) -1H-pyrazolo 3,4-b pyrimidn.
    A mixture of 7.8 (35 mmol) 4-chloro-1- (tetrahydrofuran-2-yl) -1H-pyrazolo 3,4-c pyrimidine, 20.3 g (100 mmol) M- (2.5-dimethylben - zil) cyclopentylamine in 100 ml of n-butanol is heated under reflux for 16 hours. The mixture is concentrated, the residue is taken up in water, extracted with dichloromethane, the extract is washed with dilute acetic acid and a dilute sodium hydrocarbonate solution, dried, concentrated and chromatographed. Using a mixture of dichloromegan and methanol (98: 2), 5.0 g of the title compound (37%) was eluted, which, after trituration with ether, melted at 173-174 ° C.
    Example 6. In Example 5, by introducing 4-chloro-1- (tetrahydrofurzn-2-yl) -1H-pyrazolo 3,4-sphyrimidine with the corresponding secondary amine, the compounds shown in Table 2 are obtained. 3,
    Example 7. Compression inhibition of passively sensitized strips
    parenchyma of light guinea pigs in vitro due to antigens.
    For in vitro tests of the compounds proposed by the method, the inhibition of compression of passively sensitized strips of the parenchyma of the light guinea pigs, caused by antigens, is determined. The tests are carried out as follows.
    White guinea pigs of the Pirbright breed
    0 slapped a blow to the head and exsanguinated. The lungs are thoroughly washed in situ with blood Krebs buffer pH 7.4.
    The lungs are then removed, cut into strips (approximately 20x4x4 mm) and for 1 hour.
    5 passively sensitized at room temperature with a homologous anti-ovalbumin antiserum diluted in a ratio of 1:50, and then washed with Krebs buffer.
    0 Antiserum was previously obtained according to the Davies method by repeated injection of guinea pigs of the same ovalbumin breed (twice recrystallized) with the addition of complete Frey5 adjuvant.
    Before use, the antiserum is stored undiluted at -18 ° C. After that, the lung strips are individually suspended in a tensioned state (load of 1.2 g) to the sensors in water banks with a volume of 10 ml.
    The baths are filled with Krebs buffer and continuously passed through them at 37 ° C, the gas being a mixture of 02
    5 (95%) and C02 (5%). The amplified signal resulting from the compression of the strips of the lung is recorded using a chart recorder.
    After the 30-minute assimilation phase, to clarify the ability of parts of organs
    0 react to stimulation caused by histamine, cause control spasms, then the baths are washed, filled with the test compound, the strips are kept in it for 20 minutes at 37 ° C and
    5 using ovalbumin cause compression.
    The inhibitory effect of the proposed compounds is defined as the percentage decrease in the amplitude of compression of the samples in the test compound compared to
    0 compression control untreated samples.
    In tab. 4 shows the inhibition of antigen-induced compression of passively sensitized strips of the parenchyma.
    5 light guinea pigs.
    The compounds of general formula (I) are among the weakly toxic.
    权利要求:
    Claims (1)
    [1]
    The invention The method of producing pyrazolo 3,4-c pyrimidines of the general formula
    R, wg V
    IN
    (i)
    r,
    where Ri is Ci-Sat-alkyl, Ca-Ce-alkenyl, cycloalkyl or phenyl;
    R2 - Cz-C-Cycloalkyl, unsubstituted benzyl or benzyl, substituted by one or more halides, Ci-Ce-alkyl, hydroxy group, Cr-Sat-alkoxy group, Ci-Cz-haloalkyl, C2-C-alkoxycarbonyl, aminocarbonyl, cyano group , Ci-Sb-alktogroup, thienylmethyl or thienylmethyl, substituted with halogen, fluorylmethyl, substituted with Ci-Ce-alkyl, pyridylmethyl; Рз - hydrogen, dioxy-Са-Се-alkyl, tetrahydrofuranyl.
    W
    characterized in that the compound of general formula%
     H
    (Ii)
    where Pz has the indicated meanings, X is a halogen, is reacted with an amine of the general formula
    NNHHg. (
    where Ri and R2 have the indicated meanings, followed by isolation of the target product or alkylation of the compound (I), where RS is hydrogen, to obtain the compound
    (Ogde Rz - DIOXY-C2-Се-alkyl.
    Table 1
    C- (M-Allylcyclohexylamino) -1H-pyrazolo r3, d J pyrimidine
    (3-Methylbenzyl) cyclopentylamino | - -1H-pyrazolo 3 j tljpyrimidine
    (3-Trifluoromethylbenzyl) cyclopentyl amino -1H-pyrazolo 3, bd pyrimidine
     (Z-Methoxybenzyl) cyclopentylamino -1 H-pyrazolo r Zpyrimidine
    (5-Chloro-2-methoxybenzyl) cyclopentyl-amino -1H-pyrazolo 3,4-pyrimidine
    k-ЈN- (3-Bromobenzyl) -cyclopentylamino - -. 1H-pyrazolo 3, -c1 pyrimidine
     (3 Ethoxycarbonylbenzyl) cyclopentylamino -1 H-pyrazolo 3,4-cG} pyrimidine
     (3 Aminocarbonylbenzyl) cyclopentyl but -1H-pyrazolo 3, -cG pyrimidine
    A-) 1- (3-Cyanobenzyl) Cyclopentylamino - -1 I-pyrazolo 3, - pyrimidine
    A-pj- (2,5 Dichlorobenzyl) cyclopentylamino -1 H-pyrazolo 3, A-cG pyrimidine
    (3 Dichlorobenzyl) cyclopentyl-H-pyrazolo}, -L pyrimidine
    (ethanol / water)
    143-145 (ethanol)
    171-172 (ethanol)
    169-170 (ethanol)
    232-235
    (dichloromethane-tanol)
    192-194
    (ethyl acetate)
    135-137
    (ethyl acetate)
    150-160
    (amorphous powder)
    178-180 (ether)
    233-235 (ether)
    168-170
    (naphtha)
    ace
     ° AI (3 tert. Butylbenzyl54iklopentylamino | - 1H-pyrazole 3, -d pyrimidine hydrochloride
    37
    223-225
    (ethyl acetate)
    Example
    Compound
    4- (N-Allylcyclohexylamino) -1 (2,3-dioxypropyl) -1H-pyrazolo) 3, d (pyrimidine)
    (from the compound of example 2 a) C- n- (3-Trifluoromethylbeneyl) cyclotenyl-amino-1- (2,3-dioxypropyl) -1 H-pyrazol GZ i 4-d pyrimidine (from the compound of example 2b)
    i - N- (2,5-Dinetilbeneyl) cyclopentylamine- (2,3-dioxypropyl) -1H pyrazole irimidine (from the compound of example 2l)
    d k-LN- (2-furylmethyl) cyclopentylamins -1- (2,3 dioxypropyl) -H-pyrazolo E, 1-pyrimidine 10 (from the compound of example 2 °)
    e (Thiophen-2-ylmeti) cyclopentylamino-Z-1 - (2,3-dioxypropyl) -1 N-pyrazolo 3, -dj pyrimidine (from the compound of example 2p) M
    f (3-Netoxy6enzyl) cyclopentylamino-I- (2,3-dioxypropyl) -1H-pyrazolo 3 l-dj pyrimidine (from the compound of example 2d) C
    g i-L - (3 Methylbenzyl) cyclopentylamino1-1- (2,3 Dioxypropyl) -1 H-pyrazolo 3,4-i J pyrimidine 65
    h ((3 Bromobenzyl) cyclopentylamino -1- (2,3-dioxypropyl} -1 H-pyrazol.-dj pyrimidine 51
    i (5 Chloro-2-methoxybenzyl) cyclopentyl-amino - 1- (2, 3-dioxypropyl) - 1H-piraeolo-3 - pyrimidine53
    Table 2
    M.p.
    33
    Paslo
    33
    122-123
    (ether)
    60-70 (amorphous dichloromethane-methane l)
    Paslo
    Butter
    175-176 oil, hydrochloride)
    80-82 broadcast
    107-108 (ether)
    132-13 (ether)
    Table 3
    Table 4
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19873712735|DE3712735A1|1987-04-15|1987-04-15|NEW PYRAZOLOPYRIMIDINE, METHOD FOR THE PRODUCTION AND USE THEREOF AS A MEDICINAL PRODUCT|
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