• 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:
    The invention relates to heterocyclic compounds, in particular to the preparation of 3-amino-4-methyl-6-phenyl-pyridazine (AMPP), which has a psi-stimulating effect. The goal is to obtain more effective compounds in the specified class. The synthesis of AMPP is carried out from 3-chloro-4-methyl-6-phenylpyridazine and a five-fold excess of hydrazine hydrate at boiling for 1.5 hours. The obtained 3-hydrazino-4-methyl-6-phenylpyridazine is hydrogenated at 5 atm for 48 hours in the presence of nickel Rene in the environment of methanol or ethanol. AMPP has mp. 130-132 ° C, gross f-la C. N N ,,. AMPP can be used in the treatment of psychomotor abnormalities. By its antidepressant and dopamine-modicating effect, AMPP is close to the known minacan, but is less toxic (AMPP 226 mg / kg, minaprine bsmg / cP) and does not show a convulsive effect. 3 tab. § CO with 00 ate O5 QO O5 CM
    公开号:SU1356961A3
    申请号:SU833632064
    申请日:1983-08-15
    公开日:1987-11-30
    发明作者:Вермут Камиль-Жорж；Бизьер Катлин；Дави Орас
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of pyridazine 3-amino-4-methyl-6-phenylpyridazine novel derivatives of formula (1)
    , SNZ // / V; NH
    possessing psychotropic (psychostimulating) action.
    The purpose of the invention is to develop a method for a pyridazine derivative that exhibits the same psychotropic effect as a structural analog of 3.- (2-morpholinoethyl) amy: but-4-methyl-6-phenylpyridazine (mininalin), but less toxic and not having a convulsive effect.
    Example 1 3-amine o-4-methyl-6-phenylpyridazine (1) (hydrochloride).
    A. 3-hydrazino-A-methyl-6-phenylpyridazine.
    Laughter: 5 g of 3-chloro-4-methyl-6-phenylpyridazine and 12 ml of cydrate tidrate with reverse refrigerators for 1.5 hours. After cooling, a precipitate is formed from the reaction mixture, which is dried and washed in a small amount of water. Isopropanol-isopropyl ether is crystallized from the mixture; 4.5 g are obtained, m.p. .
    B. Dissolve 6.5 g of the resulting product in a minimum amount of methanol and add 2.5 g of Rene nickel. Hydrogenated at a pressure of 5 atm for 48 h. The catalyst was filtered off and the solvent was evaporated. The residue is recrystallized from isopropanol-isopropyl ether.
    Weight 5.25 g, m.p. 130-132 ° C.
    Calculated,%: C 71.35; H 5.94j 22.70.
    Found,%: C 71.30; P 5.90; 22.65.
    Hydrochloride: 1.2 equivalents of hydrochloric acid gas are added to 2 g of base dissolved in a minimum amount of zopropanol, then the product is precipitated by the addition of ether. A white powder of 1.7 g is obtained. M.p. 172-174 ° C.
    Compound (1) was pharmacologically tested to determine its effect on the central nervous system, as well as toxicity,
    Acute toxicity.
    Compound (1) and minaprin administered intragastrically increasing
    569612
    doses to groups of .10 mice. The effect of animal exposure to the test product was observed within 24 hours after its administration.
    Based on the results obtained, LDjo was determined for each product tested, i.e. dose, causing the death of 50% of the animals studied.
    Q In the same experiments, the maximum convulsive dose of the product was determined, i.e. the minimum dose at which its convulsive effect manifests itself.
    15 The results obtained are summarized in table. one .
    Compound (1) is significantly less toxic and has a convulsive effect than the drug
    2Q minaprin.
    Antidepressant action. Depression Reactions The test was conducted on females. DCi (Charles River), weighing 18-23 g.
    25 The principle of the test is complete as follows. A mouse placed in a limited vessel filled with water starts to beat first, then stops for 2-4 minutes and swims on the life of the animal, the back is rounded, the hind legs are tucked in, the animal makes only a few movements necessary to maintain its head above the water . This is the so-called depression reaction.
    Anti-depressant drugs prolong the time of resistance of the animal.
    The test products (compound 1 and .minaprine) were administered intragastrically 1 hour before the test.
    Q Animals were placed in a restricted vessel (10x10x10) filled with water to a height of 6 cm, water temperature was 24t2 C. Animals were placed in water for 6 minutes, the time of immobilization of animals was from 2 to 6 minutes. The shorter this period, the more active the substance.
    Each substance was examined in a group of 10 mice. Took the average
    gQ results from two experiments. Antagonism of ptosis caused by reserpine.
    This text was carried out on female DCi (Charles Iver) weighing 20 + 1 g. Rezerpin causes ptosis, 1 hour after intragastric administration, some ptose counteract the appearance of ptosis: motivodepressive means.
    55
    The following procedure was carried out. The test substance was administered intragastrically. Reserpine was administered once intravenously at a dose of 2 mg / kg. One hour after the administration of reserpine, the number of animals showing no signs of ptosis is noted.
    This test was conducted on groups of 10 smaller ones, the results are expressed as a percentage (i.e., animals that did not detect signs of ptosis) and are average values for two experiments.
    The results are summarized in Table 2. Dopaminomimetic action. The dopaminomimetic effect of the products of the present invention has been studied on the striped dopaminergic receptors of mice.
    Unilateral damage to dopaminergic black-striped neurons causes increased sensitivity of dopamine receptors at the level of striped bodies. The resulting asymmetry is manifested in the fact that the animal rotates in the opposite direction to the location of the most stimulated receptors.
    After intragastric administration of the test products, the number of turns performed by the animals is counted for 2 minutes.
    The results are expressed as percent variations with respect to control individuals who did not receive the test product.
    The results obtained in compound (1) are listed in Table 3, where the results for min-prin are also given.
    From Tables 1, 2, and 3, it follows that compound (1) as a whole has antidepressant and dopaminomimetic effects of the same order as minaprin.
    Compared with minaprine, compound (1) is very low toxic and practically does not have a convulsive effect.
    five
    0
    five
    0
    five
    Thus, compound (I) can be used in therapy in all cases of abnormalities in psychomotor behavior. It may be prescribed in cases of hyperkinesia in children, latent depression in adults, in case of severe depression, senile depression, as well as in violation of memory and senile abnormalities.
    Compound (1) may be administered orally or by injection. The therapeutic compositions can be in solid or liquid form and can be prepared, for example, in the form of tablets, granules, paste, suppositories or injection preparations.
    The dosage may vary within wide limits depending on the type and severity of the disease, as well as the method of administration of the drug. For adults, when administered orally, the dosage is most often 0.010-0.0500 g and is distributed, depending on the case, into several doses.
    For example, the following preparations are given:
    Tablets mg:
    Compound (1)
    (hydrochloride) 200
    Microcrystalline
    cellulose
    Lactose
    Magnesium stearate
    100 197 3
     zoo
    权利要求:
    Claims (1)
    [1]
    1. Method for preparing 3-amino-4-methyl-6-phenylpyridazine of formula
    , Chv
    BUT ./
    characterized in that 3-chloro-4-methyl-6-phenylpyridazine in water reacts with a fivefold excess of hydrazine, the resulting 3-hydrazino-4-methyl-6-phenylpyridazine is hydrogenated in the presence of Rene nickel in ethanol or methanol.
    513569616
    Table 1
    ConnectionL p Limit
    (mg / kg; i, P) convulsive dose (mg / kg; i, p)
    3- (2-morpholinoethyl) amino-4-methyl-b-phenylpyridazine (minaprin) 63 (52-77) 35
    Connection 1
    (hydrochloride) 226200
    c .J-L- -T-ShLG -.-. M1 - I-G.-G-GSH -GP-- - - - -...- .- I-- - -
    table 2
    Connection of ptosis, Behavioralist lymphatic repressions (Behavioral zappin (, Despair),% skra- mg / kg, i, p) of the duration of immobilization
    3- (2-Morpholinoethyl) - amino-4-metsh1-6-phenylpyridazine (minaprin) 5 / 4-7 / 10 mg / kg 35%
    Compound (1)
    (hydrochloride) 8.6 / 8.3-9 / 10 mg / kg 24%
    i. p - intragastrically.
    Table 3
    Compound Dose, mol / kg; Average number
     i.p lateral rotations for 2 min in% with respect to control individuals
    Minaprin5,391
    Compound (1)
    (hydrochloride) 5,389
    i.p - intragastrically.
    VNIIPI
    Order 5817/58 Circulation 372
    Random polygons pr-tie, Uzhgorod, st. Project, 4
    Subscription
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