• 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:
    There are provided novel pyridazinone derivatives having the general formula (I): wherein A represents 5- or 6-membered heterocyclic ring having 1 - 3 nitrogen atoms, which may be substituted by at least one member selected from the group consisting of C1-5 alkyl, cyano, hydroxyl, C1-5 alkoxyl, amino, C1-5 alkylamino, C2-6 dialkylamino, C2 5, acylamino, carboxyl, C2-5 alkoxycarbonyl and carbamoyl, R1 and R2 independently represent hydrogen atom or C1-5 alkyl or R1 and R2 may form together C1-5 alkylene, and the dotted line represents either a single bond or a double bond, and salts thereof.
    公开号:SU1342416A3
    申请号:SU843826169
    申请日:1984-12-13
    公开日:1987-09-30
    发明作者:Окусима Хироми；Нариматсу Акихиро；Кобаяси Макио；Симоода Исао；Китада Есими；Фуруя Рикизо
    申请人:Мицубиси Кемикал Индастриз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    13
    This invention relates to a process for the preparation of novel pyridazinone derivatives of the general formula
    RI (I)
    A-; yn- / L-CH about
    TS-N
    ii
    where A is 4-pyridyl or 2-pyrimidyl;
    R, and Rj - independently of each other - a hydrogen atom or C-alkyl;
    dotted line - single or double bond,
    or their salts with a pharmaceutically acceptable acid, which have cardiotonic activity and can be used in medicine.
    The aim of the invention is to obtain compounds having a higher cardiotonic activity as compared with the known 3 (2H) -pyridazinone derivatives.
    Example 1. (4-Pyridyl) aminophenyl-4,5-dihydro-3 (2H) -pyridazinone.
    3.89 g of 4-bromopyridine hydrochloride and 3.78 g of 6- (4-aminophenyl) -4,5-dihydro-3 (2H) -pyridazinone are dissolved in 50 ml of N, N-dimethylformamide and heated h at 105 C in a stream of gaseous nitrogen. The reaction mixture is poured into 800 ml of water containing 2.12 g of sodium carbonate, precipitated crystals are filtered off, washed with water and dried under reduced pressure to give 4.28 g (70.7%) of the desired product. IR absorption spectrum (KBr) at 1642. Molecular mass, determined by mass spectroscopy, M 266.
    The resulting base is dissolved in methyl alcohol with heating, ethanol is added, saturated with HC1 and the hydrochloride salt of the resulting base is precipitated with sulfuric ether.
    EXAMPLE 2: 6- 4- (2 -Pyrimidinyl) aminophenyl-4,5-dihydro-3 (2H) pyridazinone.
    A mixture consisting of 2 g of 6- (4-aminophenyl) -4,5-dihydro-3 (2H) -pyridazinone and 1.22 g of 2-chloropyrimidine is heated under reflux in 4 ml of dimethylformamide for 4 hours and oh - Laid to precipitate a crystalline substance. The precipitated crystalline substance is filtered off, washed with dimethylformamide and tetrahydro0
    five
    41
    s
    0
    25
    30 35 40
    45
    50
    55
    62
    furan, dried and receive 1.2 g (42.5%) of the target product. The absorption spectrum in the IR spectrum (KBG) at 1670 cm-.
    PRI me R 3. (4-Pyridyl) aminophenyl-4-methyl-4,5-dihydro-3 (2H) - pyridazinone hydrochloride.
    1.02 g of 6- (4-aminophenyl) -4-methyl-4,5-dihydro-3 (2H) -pyridazinone is dissolved in 5 ml of N-methylpyrrolidone, 0.35 ml of triethylamine is added to this solution. heated to 90 ° C, 0.75 g of hydrochloric 4-chloropyridine is added and heating is continued for 2 hours at. The reaction mixture is cooled on ice and 50 ml of acetone is added. The precipitated crystal is filtered off and dissolved in 50 ml of water. The aqueous solution is adjusted to about pH 9 with 1 n. NaOH solution. The precipitated crystal is collected by decantation and washed with a mixture of acetone and n-hexane. The resulting crystalline product is dissolved in 10 ml of DMF and chromatographed on silica gel using chloroform and methanol as eluents. The product fraction is concentrated and dried, the solid residue is dissolved in ethanol and mixed with 1N. with a solution of HCl in ethanol and half a dozen hydrochloride salt, which is precipitated by the addition of benzene, hexane and ethyl acetate, filtered off and dried, and 0.98 g (61.8%) hydrochloride is obtained, m.p. 24.1-244 ° C.
    Example 4. 6-4- (4-Pyridyl) aminophene-5-methyl-4,5-dihydro-3 (2H) - pyridazinone hydrochloride.
    0.81 g of 6- (4-aminophenyl) -5-metsh1-4,5-dihydro-3 (2H) pyridazinone is dissolved in 4 ml of N-methylpyrrolidone, mixed with 0.28 ml of triethylamine, and then heated to 90 ° WITH. 0.60 g of hydrochloric 4-chloropyridine is added and heating is continued for 2 hours at 90 ° C. The reaction mixture is cooled in an ice bath and mixed with 50 ml of acetone to precipitate a crystalline substance. The crystalline substance is dissolved in water and alkalinized with 1N. NaOH solution before precipitation, which chromatograph on silica gel using a mixture of chloroform and methanol. The desired fractions are concentrated, dried and converted to the hydrochloride salt, as
    3
    described in example I, get 0.863 g (68.3%) of hydrochloride, so pl. 249-225 ° C.
    PRI me R 5. (4-Pyridyl) aminophenyl-3 (2H) -pyridazinone hydrochloride.
    A mixture consisting of 2.33 g of hydrochloric 4-bromopyridine and I, 87 g of 6- (4-aminophenyl) -3 (2H) -pyridazinone, is reacted in 30 ml of N, N-dimethylformamide for 4 hours at 110 ° C B current of gaseous nitrogen
    After cooling the reaction mixture, 75 ml of water was added to it. The reaction mixture is neutralized with 2N. sodium hydroxide solution followed by filtration of the precipitated crystalline substance. The crude crystalline substance is recrystallized from a mixture of ethanol and water, thoroughly purified by chromatography on silica gel to remove traces of contaminating impurities, the desired fractions are concentrated, dried and converted to the hydrochloride salt, as described in Product 1, to give 0.23 g hydrochloride. Absorption band in the IR spectrum (KBr) at 1650.
    EXAMPLE 6 A mixture of 2.5 g of 4-chlorine pyridine hydrochloride and 3.15 g of 6- (4-aminophenyl) 4,5-dihydro-3 (2H) -pyridazinone is reacted for 7 hours at 60 ° s The mixture is then cooled, 200 ml of acetone is added and stirred in an ice bath until the crystals precipitate. The crystals falling are filtered, dried, and 3.49 g of 6-4- (4-pyridyl) aminophenyl-4,5-dihydro-3 (2H) -pyridazinone hydrochloride (identified as the compound of Example 1) are obtained.
    Pharmacological and toxicological studies of pyridazinan derivatives 1 for their suitability as cardiac agents were evaluated using the following methods
    The effect on the reduction of the drug in the papillary mucosa with cross circulation in the dog.
    The preparation of the papillary muscle with cross circulation in the dog was prepared according to the method of Endo and Hatpinoto (American Journal of Physiology, 1970, 218, 1459-1463). The effect of the compound was measured by intraarterial injection of the compound dissolved in the solvent into the papillary
    5 about 5
    O 0
    g
    Q
    five
    five
    164
    muscle in order to determine its effect on papillary contraction. The extent of the contraction of the papillary muscles is shown in Table 1.
    Effect on the contraction of the isolated left atrium in a guinea pig.
    The left atrium appeared in a male guinea pig with a body weight of 200-300 g shortly after being hit in the back of its head. The opening of the mitral valve of the heart was fixed at the base of the organ bath filled with 30 ml of Krebs-Henseleit solution with a temperature of 35 C. A gas mixture containing 95% 0 and 5% CO was passed through the Krebs-Henseleit solution in the organ bath. The isometric voltage was measured by connecting the left atrium to the sensor with a filament. The atrium was reported to have a resting voltage of 0.5 g, after which it was excited using rectangular pulses with a duration of 1 ms and a voltage 1.5 times higher than the threshold value at a frequency of 2 Hz using bipolar platinum electrodes.
    After stabilization of the atria for 30 minutes from the moment of its preparation, the test compound in a solvent was added to the organ bath in order to measure its effect. The degree of increase in the contraction of the left atrium is shown in Table 1.
    Effect on myocardial contraction in anesthetized dogs.
     Male and female mongrel dogs with a body weight of 8-15 kg were used. The dog was anesthetized by intravenous injection of pentobarbntal sodium at a rate of 30 mg / kg body weight and artificial respiration was created in it. The dog was opened the rib cage between the fourth and fifth rib, which was inserted. Pericardium is incised to expose the heart. The blood flow through the aorta, which was measured using an electromagnetic blood flow meter, the sensor of which was attached to the upstream part of the aortic arch, was used as an approximate cardiac index (CO). The pressure in the left ventricle (LVP) was measured using a Miller's catheter pressure sensor, and the first derivative of LVP (decay / filling) was measured using a differentiator. Reduction
    S1
    The male ventricle of the right ventricle was measured using a strain gauge attached to the wall. Blood pressure throughout the body was measured at the left femoral artery. Heart rate was measured using an electrocardiogram (lead II) and a cardiotachometer; The compound solution was administered intravenously through the left femoral vein. .
    The maximum value of the decline (filling / falling), the maximum filling and the degree of increase in contraction of the right ventricle and heart function are shown in Table 1.
    Acute toxicity.
    Acute toxicity (LDjo) in intravenous and oral administration in male mice was determined by the method of Richfield and Wilcoxon (Journal of Pharmacology and Experimental Terapique, 1949, 96, 99-113). The result is shown in table 1.


    Table 2 shows the cardiotonic activity data for the known compounds of the pyridazinone II series in comparison with the proposed compound. I eat
    From tab. 2 that the proposed compounds I have advantages over the known pyridazinines and can be used in medicine.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    Method for preparing pyridazinone derivatives of general formulas
    A - NH- /
    N-int
    n
    where A is 4-pyridyl or 2-pyrimidyl;
    R, and
    hydrogen or C -P-alkyl are independent of each other; dotted line - single or double bond,
    or their water-soluble salts with a pharmaceutically acceptable acid, characterized in that the compound of the general formula
    RI P
    one
    where R and R have the indicated meanings, are reacted with a compound of the formula
    A is X, where X is halogen;
    A has the indicated values, in a polar solvent at a temperature of from 60 ° C to another boiling point of the reaction medium, and the desired product is obtained in free form or as a water soluble salt with a pharmaceutically acceptable acid. Priority featured:
    14.12.83- with A - 4-pyridyl and 2-pyrimidyl;
    R and .Ri is hydrogen; - single bond.
    16.03.84- with A - 4-pyridsh1;
     and RI is hydrogen; double
    communication
    Table 1
    97
    341
    ANH - 1-imidazolyl; R, and
    0.03
    Continuation of table 1
    32
    "
    single bond
    double bond
    Salt, for example, hydrochloride soluble in water, giving the opportunity for purposes. Compounds do not form water-soluble salts. Cardiotonic activity at the same doses is much lower than that of the proposed compounds.
    J, jj VHot compound is soluble in acidified water, Cardiotonic activity is much lower than that of the proposed compounds
    1342416
    10 Continued table. 2
    57
    87
    3
    15
    40
    78
    "
    l
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    同族专利:
    公开号 | 公开日
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPH0351706B2|1981-12-28|1991-08-07|Mitsui Toatsu Chemicals|AU578805B2|1985-03-12|1988-11-03|Smith Kline & French Laboratories Limited|Chemical compounds|
    CA1251448A|1985-03-27|1989-03-21|William J. Coates|Pyridazinone derivatives|
    US4806535A|1987-07-22|1989-02-21|Rorer Pharmaceutical Corporation|Imidazolylphenyl and 1,2,4-triazolylphenyl benzopyridazinone and pyridopyridazinone compounds and their use for increasing cardiatonic contractility|
    DE3826855A1|1988-08-06|1990-02-15|Cassella Ag|4,5-DIHYDRO-3-PYRIDAZINONE, PROCESS FOR THEIR PREPARATION AND THEIR USE|
    DE3902316A1|1989-01-26|1990-08-02|Lentia Gmbh|Novel piperazinylalkyl-3-pyridazinones, process for their preparation and their use as hypotensive agents|
    US20040063710A1|2000-11-22|2004-04-01|Tomiya Mano|Ophthalmological preparations|
    WO2002072099A1|2001-03-14|2002-09-19|Mitsubishi Pharma Corporation|Therapeutic and/or preventive agent for diabetic ischemic heart disease|
    WO2002088109A1|2001-04-27|2002-11-07|Mitsubishi Pharma Corporation|Crystal of 6-[4-phenyl]-4, 5-dihydro-3-pyridazinone hydrochloride trihydrate|
    EP1864664A4|2005-03-10|2009-02-18|Mitsubishi Tanabe Pharma Corp|Pharmaceutical preparation|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP58235480A|JPS644517B2|1983-12-14|1983-12-14|
    JP59050693A|JPS60197672A|1984-03-16|1984-03-16|Pyridazinone derivative or its salt|
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