• 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 method of producing 4-cyanopyridazines of the formula IWX: Rl-VNH-AlK-N Y where R is a cycloalkyl group unsubstituted or substituted by one or two chlorine atoms, a fluorine atom, a lower alkyl group, a lower alkyl group, a cyano group, a nitro group, or a trifluoromethyl group, a phenyl group, or a naphthyl group, or a 3-thienyl group ;, R. is hydrogen or a phenyl group; Alk is a -CH group. or group i-CHj-CH-; . , CH X and Y are hydrogen or X. -N is 4-morpholino, 3-oxo-morpholino or group, or their pharmaceutically compatible salts, characterized in that 4-ethoxycarbonyl pyridazone mules II Kg COOSnHy where R and R have the indicated values, process ammonia to produce 4-carboxamide pyridazone of formula III with D2: CC2h N-TS1H where RI and R have the indicated meanings; These compounds are introduced in interaction with phosphorus oxychloride; the resulting compound is introduced into the interaction of O5 X tc with an amine of the formula H „N-Alk-Nxi .., i, 2 I oo where Alk has the indicated value, -X-NH, or 4-morpholino -N vy group, or NHCHj CHjOH; the desired product is isolated in the form of a free base or in the form of salts; if necessary, the resulting product X of formula (I), where the group —N is NHCHjCH OH, is treated with chloroacetyl chloride at room temperature and in the basic solution and obtained
    公开号:SU1274623A3
    申请号:SU843697653
    申请日:1984-01-27
    公开日:1986-11-30
    发明作者:Бизьер Катлен；Кан Жан-Поль；Вермут Камиль-Жорж
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    the compound is cyclized by treating with sodium methoxide to form a product of formula (I), wherein
    at
    the residue N represents a 3-oxo-morpholino radical; said product is isolated as a free base or as a salt.
    Priority featured:
    01.28.83 with RJ - phenyl, Rg - xOx
    Prenat, Alk-CHj-CH ,, - N; -4-morpholino; , c- J 18.11.83 with R - naphthyl or tNENE, R - hydrogen, Alk-CHj-CHj-,
    j N; - 4-morpholino.
    This invention relates to a process for the preparation of 4-cyanopyridazines having psychotropic activity. The purpose of the invention is to search for new compounds with valuable properties. Example 1. 3- (2-morpholinoethylamino) -4-cyano-6-phenyl-pyridazine dihydrochloride, SR 95 191; (I) R CgH5; Alk (CH2) 75.3 g of 3-chloro-4-cyano-6 (4-chlorophenyl) -pyridazine is dissolved in 60 ml of n-butanol and 8 g of H- (2-amino-ethyl) -morpholine is added. The mixture is boiled under reflux for 3 hours, then the mixture is poured into 1000 ml of water. The organic phase is extracted with ether, then extracted with an ethereal solution of 1N sulfuric acid solution. The aqueous phase is separated, alkalized with sodium hydroxide solution and extracted with ether. The ether phase is dried over sulfonated to dryness under vacuum. I get a yellow solid. Vykots 81.3%; m.p. 138 ° C. 6.8 g of the product obtained are dissolved in 100 ml of anhydrous methanol and current-gaseous hydrogen chloride is bubbled. The solvent is evaporated to dryness under vacuum, the residue is treated with anhydrous ether. A precipitate of 3- (2-morpholino-ethylamino) -4-cyano-phenyl-pyridazine dihydrochloride is formed, which is recrystallized twice from isopropanol. Mp 144 ° C (decomposition). The following salts of the same compound can also be obtained from the base. So pl., C 181 (water ethanol) Monocyte Above 260 (water etaglotamat nol) Monochlorohydrate 230 Monofumarate 204 (acetone) Monomelate 168 (acetone) And p and me p 2-17. According to the procedure of Example 1, by reacting the corresponding chlorinated derivative of formula IV with N- (2-amino-ethyl) morpholine, the compounds I described in Table 2 are obtained. 1. Examples 18-22. According to the procedure of Example 1, prepared from the various 3-chloro-pyridazines of compound I, are shown in 2. PRI me R 23. 3- (2) 3-0-x-morpholino (-ethylamino) -; 5, cyano-6-phenylpyridazine hydrochloride, SR 95327 A; R, C.H5 .; Alk (CE; to a solution of 3 g of compound 95291 A (example 19) in 54 ml of dichloromethane, a solution of 4, .2 g of sodium hydroxide in 54 ml of water is added, then cooled to -5 to -10 ° C with stirring. Slow 1.17 g of chloroacetyl chloride are added, then the temperature rises to 20 ° C, held for 15 hours at this temperature and with stirring. The organic phase is separated and evaporated to dryness in vacuo to give a yellow color solid, which is used as it is the next step. The resulting product is dissolved in 27 ml of anhydrous methanol and added A solution of sodium methoxide, prepared from 0.24 g of sodium and 27 ml without aqueous methanol, is refluxed for 6 hours and evaporated to dryness. The residue is taken up in water and extracted with ethyl acetate. The organic layer is separated, dried over sodium sulfate and evaporated to dryness. The product is purified by chromatography on a column of non-silica, eluting with a mixture of ethyl acetate / methanol 8/2 by volume. A pale yellow oil (1.5 g) is obtained. It is dissolved in methanol and dry hydrogen chloride gas is bubbled through the solution. The mixture is evaporated to dryness and the residue is treated with a minimum amount of methanol. Anhydrous ether was added, and the hydrochloride precipitate was sucked off. M.p. . PRI me R 24. Galenovo preparation. Gelatin drug capsules are used, containing: Components Amount, mg Active ingredient Aerosil Magnesium stearate Starch STA R X1500 The psychotropic activity of compound SR 95191 (example 3) is measured in three pharmacological tests compared to minaprine and iminaprine used as an antidepressor. The toxicity of the product is compared with the toxicity of standard products. The state of despair. This test is carried out on a female C D 1 (Charleskiver) weighing 18-23 g. The principle of this test is as follows: when a mouse is placed in a narrow vessel filled with water, it flounders, then, after 2-4 minutes, it is immobilized and floats on the abdomen , round: (curved) back, with tucked under the hind legs, makes only a few movements necessary to support the head out of the water. This is the so-called reaction of the father. Some psychotropic drugs, namely antidepressants, prolong the time during which the mouse flounders. The course of the test is as follows. . The test products are administered intraperitoneally 1 hour before the test. Animals are placed in a narrow vessel (JuhYuh x10 cm), filled with water to a height of 6 cm, temperature. The animals are left for 6 minutes in water and the time is measured when the animal remains stationary between the 2nd and 6th minutes. The shorter the time, the more active the substance. Each substance is studied in 10 mice. Results are an average of at least two experiments. Antagonism of ptosis caused by reserpine. This test is performed on a female C D 1 mouse (Charles River) weighing 20+ +1 g. Reserpine causes ptosis 1 hour after it is administered intravenously; some antidepressants counteract this ptosis. The course of the test is as follows. The test substances are administered intraperitoneally. Reserpine is administered simultaneously intravenously at a dose of 2 mg / kg. empty 1 hour after administration of reserpine, the number of animals that have not undergone ptosis is affected. This test is implemented on batches of 10, and the results are more frequent than at least two experiments. State of rotation. Charles River CDI female mice of 20-24 g are first used for unilateral damage to Striaurn by stereotactic injection of α-oxidopamine, 8 µg per animal. the week is empty after this operation, the product is administered intraperitoneally. Ruppam 7 each. I value the number of rotations for 2 min, after and after the introduction of the product. Homo-lateral rotation due to lesion (disease) is considered positive, contralateral rotation is considered negative. Algebraic
    The sum of the rotations of the 7 groups of treated animals is compared with similar indicators in the group of control animals that received only excipient (physiological serum).
    Acute toxicity.
    The test products are administered intraperioneally in increasing doses in batches of 10 min each. The death caused by the test products is noted within 24 hours following
    R2 5
    K1-Mi4NN-lSl
    95331 A
    42632 A C1- / 95324 A /
    8 95274 AH J
    t5
    42329 A NZSO- / O
    C1, 42638 A C1- / O
    ten
    product introduction. Determined for each of the products studied. The results obtained are presented in Table. 3
    5 In the same way, the psychotropic activity of compounds SR 95274 A (Example 8) and SR 95294 A (Example 4) is determined in two pharmacological tests: a state of rotation and antagonism.
    10 to ptosis caused by reserpine. The results are shown in table 4.
    Table 1
    2-SNg () about
    Dihydrochloride, 168 (decomposition)
    Fumarate (2/3), 183-185 (acetone 0.5)
    Dihydrochloride, 228 (isopropanol)
    Dihydrochloride, 170 (methanol)
    Fumarate (1/1), 240-242 (acetone)
    Maleate (1/1), 240-242 (acetone)
    11 42692
    95323 A
    12
    1342639
    14 95330 A
    15 95328
    sixteen
    NC4O
    1795329 (CH,), -N, 1895290 A / N
    95291 A Same H
    nineteen
    20 95332 A (DG
    |
    S O - 21 95292 A CH-42633 RD H (CH) 2 -NH
    22
    The base, 184-186 (isopropanol)
    Dihydrochloride, 260 (decomposition)
    Base 150-151 (isopropanol)
    Dihydrochloride, 278;
    H base, 159
    Foundation, 129
    Monohydrochloride, 210 (decomposition)
    Foundation, 205
    n (methanol)
    table 2
    -Sh-CH, Dichlorohydrate, 100-110
    ijun
    (hygroscopic)
    Dihydrochloride, 124 (decomposition)
    Base, 200-202 (ethanol) Dichlorohydrate, 130-140 N. 0 Dichlorohydrate, 135-140 (decomposition)
    权利要求:
    Claims (1)
    [1]
    The method of obtaining 4-cyanopyridine formula I
    Ρΐ - <$ - ΝΗ-Α1Κ-№
    Ν = Ν Υ
    where K, is a cycloalkyl group, unsubstituted or substituted by one or two chlorine atoms, a fluorine atom, a lower alkoxy group, a lower alkyl group, 'cyano group - ·. sing, nitro or trifluoromethyl group, phenyl group, or E ^ naphthyl group or 3-thienyl group;
    K 2 - hydrogen or phenyl group;
    A1k - group - CH - CH 2 - yly group
    : -CH g -CH-;
    . , · 'N 3
    X and Υ are hydrogen or
    -Ν - 4-morpholino, 3-oxo-morpholino group or group
    Sun 2 -sn 2 he,
    or their pharmaceutically compatible salts, characterized in that 4-ethoxycarbonylpyridazone form — mules II
    to coos 2 n 5
    Ηι4> = 0
    Ν ~ 1ΜΗ
    g D e E ^ and E 2 have the indicated values, treated with ammonia to obtain 4-carboxamide pyridazone formula III
    H 2 CONTAINED
    ^ -0 = 0
    Ν-ΝΗ
    where E x and E 2 have the specified values; these compounds enter into interaction with phosphorus oxychloride; the obtained compound is introduced into interaction with the amine of the formula H „Ν-Α1Ε-Ν <„,
    where A1k has the specified value, "and X 1
    group “Ν ^, - ΝΗ 2 or 4-morpholino5C <”> 1274623
    group or group ΝΗΰΗ 2 ϋΗ 2 ΟΗ; the target product is isolated in the form of a free base, or in the form of salts; if necessary, the resulting product
    xx
    Formula (I)
    where is the group -Ν
    means
    YHCHN 2 CH 2 OH, treated with chloroacetyl chloride at room temperature
    and in the basic solution and the resulting
    1274623
    the compound is cyclized by treatment with sodium methoxide to obtain a product of formula (I), where the residue is 3-oxo-morpholi ·
    but radical; said product is isolated as a free base or as a salt.
    Priority featured:
    01.28.83 at C) - phenyl, - x
    Dorod, A1k-CH, -CH 2 -, Ν '-4-morpholino; . , '# g
    11.18.83 with - naphthyl or fenil, K 2 - hydrogen, Mk-CH 2 -CH 2 -,
    X
    ίΓ γ - 4-morpholino.
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