• 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:
    Compounds of the formula I <CHEM> wherein the groups R, R0, R1, R2 and W are as defined in the specification, exhibit valuable pharmacological properties, especially as aromatase inhibitors.
    公开号:SU1549478A3
    申请号:SU884203990
    申请日:1988-01-18
    公开日:1990-03-07
    发明作者:Мэфьюс Баумэн Роберт；Эдуард Стил Ронэлд；Джонстэн Браун Лесли
    申请人:Циба Гейги Ан (Фирма)；
    IPC主号:
    专利说明:

    (21) 4203990 / 23-04 (62) 4202145 / 23-04
    (22) 01/18/88
    (23) 03/06/87
    (31) 837489
    (32) 03/07/86
    (33) US
    (46) 07.03.90. Bul
    Number 9
    (71) Ciba Geigy AH (SN) (72) Robert Mathews Bowman (GB), Ronald Edward Steele (US) and Leslie Johnston Brown (GB)
    (53) 547,781.785.07 (088.8)
    (56) Buhler, K., Pearson, D. Organic syntheses. 4.2. - M .: Mir, 1973, p. 431.
    (54) METHOD FOR OBTAINING HETEROCYCLOSE-BREATED TOLUNITRILES OR THEIR PHARMACEUTICALLY ACCEPTABLE SALTS
    (57) The invention concerns heterocyclic substances, in particular the preparation of tolunitriles of the common f-ly Ґ-CHE, l-CbH4-CnMe where W is 1-imidazolyl, 1- (1,2,4-triazolyl); Rt is cyanophenyl, or their pharmaceutically acceptable salts, which are inhibitors of both aromatics and estrogen biosynthesis in mammals. The goal is to create new, more active substances of the indicated class. Synthesis is carried out by cyanidation of the corresponding halophenyl using metal cyanide, followed by isolation of the target product in free form or in the form of salt New compounds can be used to treat gynostomy, estrogen-dependent breast cancer in animals. 1 table
    and
    This invention relates to a process for the preparation of new heterocyclo-substituted tolunitriles or to their pharmaceutically acceptable salts, which are inhibitors of aromatic activity and inhibitors of estrogen biosynthesis in mammals.
    The purpose of the invention is the synthesis of new compounds with valuable pharmacological properties that are superior in their biological activity to a structural analogue of the same effect.
    Example. 4-alpha- (4-cyanophenyl) -1 -imidazolylmethyl β-benzonitrile.
    A mixture of 0.85 g of 4-alpha- (4-chlorophenyl) -1-imidazolylmethylGH of benzonitrile and 1.0 g of cyanide containing monovalent copper is heated in 10 ml of NjN-dimethylformamide in a nitrogen atmosphere at 120 ° C for 11 hours. Reaction mixture cooled, diluted with 10 ml of water and extracted with ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated. The resulting oil is chromatographed on silica gel with ethyl acetate to give the desired product. It is subjected to further treatment with succinic acid to obtain hemisuccinate salt, so pl. 149-150 ° G,
    PRI mme R 2. In analogy to Example 1, 4-alpha- (2-cyanophenyl) -1-imidazolylmethylG-benzo-nitrile „is obtained.
    ssh &
    SP
    P1
    00
    IR spectrum (ON): 2240 media, M / e: 384. Hydrochloride salt (hygroscopic), so pl. 90 ° C (dec),
    EXAMPLE 3, 4-alfa- (4-cyanophenyl) - -imidazolylmethyl-benzonitrile.
    A solution of 0.88 g of 1-chloro-4 gulf- (4-chlorophenyl) -1 -imidazolylmethyl-benzene and 1.0 g of cyanide containing monovalent copper in 10 ml of WjN-dimethylformamide is heated under nitrogen at 120 ° C for 14 h. The reaction mixture is cooled, diluted with 10 ml of water and extracted with ethyl acetate. The organic extracts are sugate over sodium sulfate and evaporated. The resulting oil is chromatography on silica gel with ethyl acetate to give the desired product. It is subjected to further treatment with succinic acid to obtain the hemucuccinate salt, so pl. 149-150 C.
    Example 4, 4-alpha- (4-cyano- | phenyl) -1 - (1, 2,4-trnazolyl) methyl ben zonitrile.
    A solution of 0988 g of 1-chloro-4-alpha- (4-chlorophenyl) -1- (1,2,4-tri-aaolyl) methyl benzene and 1.0 g of cyanide containing monovalent copper in 10 ml The n, K-dimethylformamide is heated in a nitrogen atmosphere at 120 ° C for 15 hours. The reaction mixture is cooled, diluted with 10 ml of water and extracted with ethyl acetate. The organic extracts are dried over sodium sulfate and evaporated. The resulting oil is chromatographed on silica gel with ethyl acetate to give the desired product, mp. 181-183 ° C.
    The data on the biological activity of the compounds are tabulated (inhibition of the aromatase activity in vivo). Test: Suppression
    uterine hypertrophy caused by andro-, where W and E have the indicated meanings
    standidon, which indicates that metal cyanide is injected with aromatase degassing, in the immature content of the target product in the free
    rats-samkah.vide or in the form of s.oli.
    The minimum oral dose inducing significant suppression of uterine hypertrophy, µg / kg
    10 13 14
    1-chloro-4- | oi- (4-chlorophenyl) -1-imidazolylmethyl benzene (comparative)
    3
    0.3
    100
    Dunnett test (2P 0.01). According to the proposed method, low toxic compounds with valuable pharmacological properties have been obtained, allowing them to be used for the treatment of diseases such as gynecomaster, estrogen dependent breast cancer in females and others.
    权利要求:
    Claims (1)
    [1]
    Formula invention
    The method of obtaining heterocyclo-substituted tolunitriles of the general formula
    CEN
    where W is 1-imidazolyl;
    K „- cyanophenyl,
    or their pharmaceutically acceptable salts, characterized in that the compound of the formula
    Sn Hal
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/837,489|US4749713A|1986-03-07|1986-03-07|Alpha-heterocycle substituted tolunitriles|
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