• 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 oxyamine esters, in particular to the preparation of 2-acyloxypropylamine derivatives for the formula H2C-0-R HC-C-Kj where R, is alkyl or C is alkyl, octadecenyl or eicosanyl; Rj-C, -C alkyl, R ,, V.J. the same or different means H, C, -C alkyl or benzyl, or together form piperidine or 2-methylpiperazine, or their pharmacologically tolerable salts. The goal is to develop a method for obtaining new compounds. The clustering is carried out from A / compounds of formulas -CH., Where JY is halogen, and formulas HO-R, where E., as indicated above, in an aqueous-organic medium. The resulting compound is reacted with the compound of the form HN (R,) (R4), where R, and R are indicated with the exception of AND, followed by acylation of the resulting compound. The process is carried out with subsequent, if necessary, catalytic hydrogenation to obtain compounds in which Rj and / or, and isolation of the target product in free form or in the form of a salt. 1 table, §
    公开号:SU1470177A3
    申请号:SU874202997
    申请日:1987-07-24
    公开日:1989-03-30
    发明作者:Тростманн Уве；Шехтеле Кристоф；Маннхардт Карл；Рудольф Клаус；Марме Дитер
    申请人:Гедеке Аг (Фирма)；
    IPC主号:
    专利说明:

    one
    This invention relates to a process for the preparation of new amine-containing aliphatic compounds having valuable pharmacological properties, in particular, to a process for the preparation of 2-acyloxypropylamine derivatives of general formula
    Hjc-o-ri
     HC-C-RZ
    I
    I Lz NgS-
    where R, -Cj.4-alkyl or C, d, 8-octadecenyl, or Eicosanil, R -C, j alkyl,
    R and R are the same or different and mean hydrogen,
    C, 4 L benzyl or together form piperidine or 2-methylpiperazine
    or their pharmacologically tolerable salts, which can be used to treat diseases of the heart and blood vessels.
    J

    CM
    The purpose of the invention is to develop a method for producing new amine-containing
     aliphatic compounds with higher activity.
    The invention is illustrated by the following examples.
    Example 1. Stage a. A mixture of 70 ml of 50% sodium hydroxide, b, 2 g (0.5 mol) of epichlorohydrin, 27.0 g (0.1 mol) of octadeccol and 1.7 g of tetrabutylammonium hydrogensulfate in 400 ml of dichloromethane.
     16 hours vigorously stirred at 40 ° C. A further 1.0 g of catalyst is added and stirred for another 4 hours at;) that temperature. From the cooled solution
    The reactions are separated by organic phase), washed with water, dried over magnesium sulfate and magnesium, and the solvent is removed in vacuo. Stage b „
    5.1 g (16 mmol) of a (+) - 1-octadecyloxy 2,3-epoxypropane prepared in accordance with a and 28 g of a 40% solution of dimethylamine in water, which have been melted down for 3 hours, are heated to 80 ° WITH. The solid residue is separated from the cooled solution, washed with water and dissolved in 400 ml of dichloromethane.
     While barely adding 100 ml of 2N hydrochloric acid, the mixture is vigorously stirred for 30 minutes, the organic phase is separated, dried over magnesium sulfate and the solvent is removed in vacuo. After the residue has been absorbed in 200 ml
    : n-pentane while refluxing, the hot suspension is filtered and the residue, after dissolving in dichloromethane, is treated with 2N sodium hydroxide solution. After separation of the organic phase, evaporation over magnesium sulfate and distillation of the solvent in vacuo, the product with m.p. 72-82 0,
    Stage in. A mixture of 2., 7g (7mmol) of Pkht-irradiated according to b (H ;;) 3-dimesh1amino-1-octadecyloxy2-propanol and 2.2 g (21 mmol) of acetic anhydride in 20m pyridine for 24 h at room temperature tcheremeyvayut. In a vacuum. the solvent and excess acetic anhydride are distilled off and the residue is absorbed; a 150 ml of diethyl ether is added after the ether has been added to the syringe;
    The residue is washed with ether and then suspended in 100 ml of hydrostatic ether and then mixed for 60 min. (foc.rie suction on
    | Q
    15
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    25 30
    . ,, AQ
    ,,
    50
    five
    774
    () -3-dimethylamino-1-octadecyloxy-2-propyl acetate hydrochloride is obtained as a colorless product with m.p. 74-75 ° С “Yield 70%. The residual epichlorohydrin is distilled off and the residue is purified by chromatography on a column of silica gel using dichloromethane / cyclohexane in a 2: 1 ratio. A colorless product is obtained with mp. 75-75 ° C.
    The following compounds I-XIII are prepared analogously.
     (|;) - 1-Octadecyloxy-3-piperidino-2-propyl acetate hydrochloride, m.p. 105-106 With simple ether. Yield 69.9%.
    Ii. (b) -3- / 1-benzylamino-1-octa-decyloxy-2 propyl acetate hydrochloride from n-pentane, m.p. 64 ° C. Yield 68%.
    Ill- (;;) - 3-dimethylamino-1-proxy-2-propylpropionate oxalate from ether, m.p. 110-P5 ° C. Yield 62.5%
    IV.1- (2-Methyl) -piperazins-3-octadecyloxy-2 propyl acetate oxalate from ethanol, mp, 75 ° C. Yield 70%.
    V. (+) - 3 Dimethyl amine 0-1-those of tradecyloxy-2-propyl acetate hydrochloride from n-pentane, city of pl. 61-65 ° C. Output
    93.8%.
    VI. (;) - 3-Dimethylamino-1-hexadecyloxy-2-propyl acetate hydrochloride from n-pentane, mp 48-52 S. Zykhod 71%.
    VII o (+) - 3-dimethylamino-eicane-nyloxy-2-propyl acetate hydrochloride from ether, t, mp, -77 ° C. Yield 98%
    VIIIo (;) - 3-Di-n-butylamino-1-octadecyloxy-2-propyl acetatetoxalate KZ n-pentaneJ t, pl. 70-78 ° C. Yield 18.7%.
    IX. (; 0- 3-Dimethylamino-1 octa dscyloxy-2-propyl isobutyrate hydrochloride from n-pentane., Mp 92-94 s, Yield 56., 2%.
    X. (+) -3-Dimethylamino-1 -isobutyl-2-propylacetate-oxalate 5 from ethyl acetate / acetone, m.p. 126-131 ° C. Exit 34 ,, 5%,
    XI. (J -) - 3 (N-benzyl-N-methyl) - amino-1-octadecyloxy-2-propyl hydrochloride from n-pentane, t. 1 l.
    81-86 C. Yield 76.6%.
    XII. (+) 3-Dimethylamino-1- (2-hexadecyl-oxy-) 2-propyl acetate hydroxy-15
    20
    25
    514701
    chloride from H-pentane, mp. 78-89 ° C. The yield is 83.6%.
    Xiii. (4) -3-Dnmethylamino-1- (9-cis-octadecenyloxy) -2-propyl acetate with hydrochloride from n-pentane, mp, 105-108 ° C. Output 90.5%.
    EXAMPLE 2 (j +) - 3-AMHHO-1-OK-tadecyloxy-2-propyl acetate hydrochloride 1.5 g (2.5 mmol), {±), - 3-dibenzyl-O-amino-1 -octadecyloxy-2-propyl acetate hydrochloride., (compound II) is dissolved in 30 ml of ethanol and, under atmospheric pressure and room temperature, in the presence of 0.3 g of palladium on carbon as a catalyst, to saturation is reacted with by hydrogen. It is then filtered, the solvent is distilled off in vacuo and the residue is taken up in 40 ml of ether. When stirring the product is isolated in solid form. square 62 ° C. Yield 95%.
    Analogously prepared from compound XI. (+) - 3-methylamino-1-octadecyloxy-2-propyl acetate hydrochloride (compound XIV) from n-hexane with m.p. 109-PZ C. Yield 61%.
    Biological testing. Protein Kinase C Delay
    To clarify the inhibitory effect of new compounds of the general formula on calcium and phospholipid-dependent protein kinase, this enzyme is enriched using a stomach extract of chicken. In accordance with the well-known technique consisting of two methods of purification, the ability of the enzyme to bind to the cell membrane in the presence of calcium and re-separation from it using calcium-capable compounds with calcium, for example, ethylene bis (hydroxyethylene nitrile), was used. a) tetraacetic acid. At the first enrichment, the protein kinase is bound to the shells of the chicken stomach extract, and at the second dose, to the erythrocyte vesicles. After separation from the membranes of erythrocytes and transfer to another buffer, a preparation of protein kinase C is obtained in a medium of 10 M 4- (2-hydroxyethyl) -1-pig9razine-ethanesulfonyl acid (ICA), 1 mM Ditiotreitol, 0.1% polyethylene glycol with mol. weight. 20,000, having a pH. Under these conditions, the enzyme can be stored at -70 ° C for not
    thirty
    35
    40
    45
    50
    55
    five
    0
    five
    01
    with
    ABOUT
    0
    776
    how many months without loss of activity.
    The enzyme activity was determined by introducing phosphate-labeled 32 phosphate into protein histone-H-1, phosphorylated by protein kinase C. The test contains the following components: 50 mmol PSK (pH 7.5), 1 mmol dithiothreytole, 5 mmol of magnesium chloride, approximately 10 µm of free calcium, 200 µm / ml of histone, 5 µm / ml of phosphatidylserine, 1 µm / ml of 1,2-diolene, 10 µm of adenosine triphosphate, respectively, a suitable amount of the preparation, protein kinase C and the test substance. In the absence of both activators of protein kinase C, phosphatidylserine (PS) and 1,2-diolein (DO), a minor injection of radioactive phosphate can also be measured as an activity independent of protein kinase C.
    In this case, the concentration of the test substances listed in the table in mol / l was determined, providing a 50% delay in the PS-TO protein kinase C activity (value).
    The results of the experiment are shown in the table.
    35
    40
    45
    50
    As can be seen from the table, to achieve a 50% inhibition of the activity of protein kinase, new compounds should be used in a lower concentration: Chii, —than the known compound spingoid, i.e. new compounds have a higher activity.
    HO-R,
    where R has the indicated value, in an aqueous-organic medium and the half formula of the formula
    HO-R,
    The method of obtaining 2-acyloxypropylamine derivatives of general formula
    Н2С- О R J НС-С-К 2
    II o
    / Sat
    NG "- - Lh.
    R, -C.j-C4 - alkyl or .g-octa-2Q decenyl, or eicosanil
    R, j-C is alkyl; and the same or different
    and mean hydrogen
    . or benzyl 25
    or together form
    piperidine or 2 methylpiperzine,
    their pharmacologically tolerable, characterized in that the compound of formula
    thirty
    SH-U
    NA ..
    NgS
    where R, R, and R have the indicated meanings with the exception of hydrogen,
    35 followed by, if necessary, catalytic hydrogenation to obtain compounds, where R3 and / or Where Y is halogen, R4 is hydrogen, and isolation of the target
    Expose to the compound from the compound in free form or in the form of a yium of the formula of the salt.
    NA HjC
    CHj-O-Ri
    "Where R and R have the indicated meanings,
    1 is reacted with a compound of formula
    nk

    R
    where R and R have the indicated meanings with the exception of hydrogen,
    followed by acylation of the resulting compound of the formula
    CH O l 1
    CH-OH
    SNG-::
    R
    and
    权利要求:
    Claims (2)
    [1]
    Claim
    The method of obtaining derivatives
    [2]
    2-acyloxypropylamine of the general formula
    NgS-O-to /
    I
    NS — S-Z 2
    II * 0
    By
    H 2 CX <
    ho-r 4 , where R4 has the indicated meaning, in an aqueous-organic medium and the resulting compound of the formula
    HC where R, and R 4 have the indicated values, are reacted with a compound of the formula
    Where R (-C 3 -C 4 -alkyl or C ^. ^ - octa- 2 q decyl, or eicosanil;
    R 2 -C <-Cj-alkyl;
    R 3 and R ^ are the same or: are different and mean hydrogen,
    With v 4 -alkyl or benzyl 2 $ or together form piperidine or 2-methyl- where R e and R 4 have the indicated meanings. with the exception of hydrogen, followed by acylation of the resulting compound of the formula peiperazine, or their pharmacologically <^ ole, distinguish that the compound of the formula is portable and
    CH 2 -0-K1 he-he
    Where Ϋ is a halogen, is reacted with a compound of the formula where R ^, R and R ^ have the indicated meanings with the exception of hydrogen, followed by, if necessary, catalytic hydrogenation to obtain compounds where R 3 and / or R4 is hydrogen, and the isolation of the target product in free form or in the form of a salt. ·.
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    引用文献:
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    法律状态:
    优先权:
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