• 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:
    Imidazoline derivatives of the formula having the RS or S configuration wherein R1 is alkyl C1-4, allyl, benzyl, phenethyl or hydroxyalkyl C2-4, and their non-toxic salts. Processes for their preparation and pharmaceutical compositions thereof. The compounds exhibit presynaptic a2-adrenoreceptor antagonist activity.
    公开号:SU1217257A3
    申请号:SU833576788
    申请日:1983-04-12
    公开日:1986-03-07
    发明作者:Робин Стиллингз Майкл
    申请人:Рекитт Энд Колман Продактс Лимитед (Фирма)；
    IPC主号:
    专利说明:

    one
    The invention relates to the preparation of imide derivatives of the general formula
    FROM
    - J) -1
    G1.
    - g - g -
     - I a.
    n
    skyl, allyl, benzyl, phenethyl or oxyalkyl
    LI -j j
     4 posses2
    OR THEIR non-toxic salts, the most biological activity
    The purpose of the invention is the synthesis of new compounds with valuable properties
    PRI me R 1.
    a) (2-Methoxy-1,4-benzodioxanil) | -2-imidazolin-2-bromo-2-cyano-1,4-benzodioxane.
    A mixture of 15 g of 2-cyano-1,4-benzodioxane, 16.5 g of N-bromosuccinimide and 0.2 g of 2,2-azobis- (2-methylpropionitrile) in 400 ml of carbon tetrachloride is heated with stirring under reflux for 14 h. The mixture is cooled and precipitated succinimide is removed. Upon evaporation, an oil is obtained which is purified by column chromatography (silica gel 60.70–230 mesh / petroleum ether b.p. 40–60) to give 19 g of bromonitrile.
    NMR (CDClg) S: 7.0 (4H, S, Ar-H); 4.5 (/ H, ABq, LUN Z Z, -),
    b) Ethyl- 2- (2-bromo-1, 4.-benzodio-oxacyl) J -2-imidoate hydrochloride,
    A stream of gaseous hydrogen chloride at low speed passes through a solution of 5.0 g of bromonitrile, the preparation of which is described in 1.16 ml of ethanol in 150 ml of dry diethyl ether at 0-5 ° for 0.5 h. The reaction mixture is kept at 0 in for 14 h, after which the crystalline imidoate is filtered off, washed with dry distilled ether, and dried. 53g yield
    IR max 2750; 1670 cm
    c) (2-methoxy-1,4-benzodioxane) | -2-imidazolin.
    Suspension of the described imidoate hydrochloride (1.3 g) in dry methano7257.
    Le (7.5 ml) is stirred and cooled at 0-5. At the same time, 0.325 ml of ethylene diamine is added dropwise to the solution. The resulting solution was stirred at room temperature for 2 hours and then vortexed into saturated sodium bicarbonate solution. The aqueous layer is extracted with methylene chloride which is dried and
    o evaporated to give a solid. When purified using column chromatography (kiesel gel 60.70–230 mesh / methylene chloride-2% methanol by volume), 0.25 g of pure (2-methoxy-t, 4-benzodioxanyl) -2 is obtained. -imidazoline m.p. 90-91.
    NMR (CDC1,) 8 .; 7.0 (4H S, Ar-H) 5.0 (IH, wide S, - N-H-);
    0 4.3 (2H, AB q, I 11H Z,)
    3.8 (4H, S, N —CH — CH — N); 3.4 (MN,
    S - based
    Example 2
    2- 2- (2-methoxy-1,4-benzodiox-5 nyl) -2-imidazoline.
    A solution of 3.0 g of 2-bromo-2-cyano-1,4-benzodioxane in 60 ml of dry methanol is cooled to 0 ° C and 100 ml of sodium methoxide are added. After over-stirring the solution at 0-10 ° C, 0.825 g of ethylenediamine is added over 15-30 minutes, and then 3 ml is added dropwise over the course of 2 minutes
    5 M solution of NSD in methanol. The solution is stirred for 30 minutes at 0-10 ° C. then cooled to room temperature and stirred for 3 hours. Then the reaction mixture is treated in the manner described in Example It to produce a pure substance. Its purity is determined by thin layer chromatography. Output 2.7 g. The substance is identical to the product obtained in example 1.
    40
    In examples 3-11, are given in table. 1, substances are prepared analogously to example 1 using the appropriate alcohol R —OH instead of methanol in step 1.
    The compounds of Examples 1-11 are prepared as described in the racemic or RS configuration.
    The formological activity of the proposed compounds is determined
    using the following procedures.
    1. Antagonism to pre- and postsynaptic fii-adrenoreceptor in experiments with isolated tissues.
    3
    Antagonism of the presynaptic oi-adrenoreceptor is assessed by determining the magnitude of the RA compared to the inhibitory effects of clonidine, a well-known antagonist of the presynaptic cig adrenoreceptor on the seven rat canal stimulated at a frequency of 0.1 Hz.
    This in vito model is especially useful as a baseline for studying the presynaptic activity in an isolated state, since the physiological nature of the family tissue of the duct is such that the postsynaptic receptors located in it are least accessible to exogenous agents. Another tissue of the rat anoccigial muscle is used to establish the magnitude of the activity of the postsynaptic ' -adrenoreceptor. Antagonism of noradrenoidal contractions is used to determine the pA value on postsynaptic oi, adrenoreceptors. The ratio between presynaptic-adrenoceptor antagonism (compared to the action of clonidine on the rat seminal duct and the antagonism of the post-synaptic syndrome. rat anoccygial mice) are used to evaluate adrenoreceptor selectivity.
    In tab. 2 shows the results obtained with (2-methoxy-1,4-benzodioxanyl) 3 -2-imidazoline (Example 1), (1,4-benzodioxanyl) -2-imidazoline (A) and (2- -methyl- 1,4-benzodioxanil) -2-imidazolin (c), as well as the results obtained in tests of standard drugs: non-selective, antagonist ui -adrenoreceptor pentol-mnn, selective presynaptic antagonist yohimbin, highly selective postsynaptic antagonist pras.osin and. antidepressant, mianzerin, which shows the properties of a non-selective pre- and postsynaptic adrenoreceptor anatagonist as part of its pharmacological profile.
    The results presented in table. 2 are an average of at least 5 experiments.
    The data given in table. 2 show that of all those studied
    7257
    compounds, the compound obtained in example 1 is the most potent antagonist of the presynaptic β-adrenoreceptor and has about 10 times higher activity than the analogous unsubstituted compound (A), and 10 times higher activity than the analogous 2-methyl-substituted
    0 connection (B). In addition, it has high selectivity for presynaptic sites.
    In tab. 3 presents the results of biological activity for
    5 other compounds, except that in the test of the presynaptic -adrenoreceptor antagonist, another IC14304 antagonist (5-bromQ-6- (2-imidazolin-2-ylamino) -quinoxalin-tartrate) is used in place of clonidine, as well as for comparison: results for compound A.
    In decapitated rats, in which 5 Compound A was administered intravenously at doses of 3–1000 ~ 4 g / kg to fix the pressor response to the administered dose, the maximum increase in diastolic pressure 0 of blood was 33–4 mm Hg. at a dose of 100 | g / kg, no significant effect on the diastolic blood pressure was observed when using the other three compounds 5 in the same dose range.
    Antagonism to presynaptic u.kryes adrenoreceptor, put to sleep with a puncture of the spinal cord.
    Activity on Semester - Q - rat's superior duct when administered intravenously.
    This test model provides an opportunity to assess the antagonism to the presynaptic oig-adrenoreceptor compared with the action of clonidine on the rat seed carcinoma. Blood pressure and contractions of the vas deferens caused by stimulation in rats put to sleep by puncturing the spinal cord are altered using a known method. Clonidine (100 µg / kg for intravenous administration) results in a prolonged pressor I response and an extended 5 inhibition of contractions of the vas deferens. Test drugs are injected intravenously in a cumulative dosage regimen, and their methods are
    0
    The ability to reverse inhibition of the stimulation of the hypogastric nerve reflects their presynaptic antago-anism.
    In tab. Figure 4 shows the relative activity of antagonists to presynaptic α-adrenergic receptors in rats put to sleep with a puncture of the spinal cord, and doses of antagonists given that cause a 50% reversal of the inhibition of the stimulation of the hypogastric nerve, and represent at least 4 experiments.
    Under these experimental conditions, all studied compounds, with the exception of mianserin, lead to the complete reversal of the inhibitory effects of clonidine on the stimulation of the hypogastric nerve.
    In tab. 3 shows the pharmacological data for the compounds of Examples 10 and 11 in comparison with Compound A.
    The maximum treatment for mianserin is 36% when administered intravenously with a cumulative dose of 4.4 mg / g. From tab. 3, it can be seen that the compound obtained according to Example 1 is the most active antagonist of the presynaptic receptor-receptor among all studied.
    The pharmaceutical composition may be in a form suitable for oral, perctal or parenteral administration. Compositions for oral administration can be in the form of capsules, tablets, granules or liquid preparations, such as elixirs, syrups or suspensions.
    Tablets contain a compound of formula 1 or a non-toxic salt thereof as an impurity in a sensory agent suitable for the preparation of tablets. Such sensing agents may be inert diluents, such as calcium phosphate, microcrystalline cellulose, lactose, sucrose, or dextrose; granulating agents and disintegrating agents. such.
    as starch, binding agents such as starch, gelatin, polyvinylpyrrolidone or acacia; and 5 lubricating agents, such as magnesium stearate, stearic acid or talc.
    Capsule compositions may contain the present compounds 0 or nontoxic salts thereof mixed with an inert solid diluent, such as calcium phosphate, lactose, or kaolin in a hard gelatin capsule.
    Compositions for parenteral administration may be in the form of sterile preparations for injection, such as solutions or suspensions, for example, in water, saline or 1,3-batanediol. 0 For ease of administration and dosage compliance accuracy. The compositions described are preferably used in unit dosage form. For oral administration of 5, the unit dosage form contains 1-200 mg, preferably 5-50 mg, of a compound of formula 1 or a non-toxic salt thereof. Unit dosage forms for parenteral-Q leg administration contain 0.1-10 mg of a compound of formula 1 or its non-toxic salt per ml of the preparation.
    Using the proposed compound, the following compositions are prepared.
    Example. A mixture of 1 wt.h. 2- (2-methoxy-1,4-benzodioxanil) | -2 -2-imidazoline and 4 parts by weight microcrystalline cellulose together with 1% magnesium stearate is compressed into tablets. Preferably, the size of the tablets correspond to the content of 1,5,10 or 25 mg of the active ingredient,
    II p and m e p 2. A mixture of 1 wt.h. (2-methoxy-1,4-benzodioxanil) | - -2-imidazoline and 4 parts by weight spray dried lactose together with 1% magnesium stearate is placed in hard gelatin capsules. Preferably, the capsules contain 1, 5jlO or 25 mg of the active ingredient.
    -Et
    206-210 43 53,98 6.10 9,66 С N N.O, HCl - f НО 53,70 FROM TGbT
    p-Prg95-97
    22 64.10 6.92 10.68 63.89 7.13 10.40
    100-102
    92-93
    19 63.02. 63.31
    24 x20 65.13
    Allyl 73-76
    - 139-141
    9 - (CH j) Rob 165-166
    10 - (142-145
    11 - (CHj,) OH X
    55 64,606, .76 С,
    64,206,2010,60
    16 68,345,958,86 S .., 0. 1/3 Н „0
    68.18TTeG8G772 8 18 g e. g
    57 63,2.45,877,76 С „Н, N„ 0, - НС1
    V - 4-7 -, -., JJf V
    63,175,94 / 764
    41 59,086,1010,60 C AND N O.
    59,206,4610,41
    29
    ji
    The product, obtained as a free base, is an oil RF - 0.56 (the volume ratio of chloroform to methanol is 4: 1)
    :Table 2
    A B Example 1
    Pentamina

    Table 1
    Cn ieNaOj

    1050 10,41
    10.14 10.06
    SiN, i °
    C ,, H ,,,

    225 871 776.
    4.8
    Table 4
    121725710
    Continuation of table 2
    TabaZa
    Table3
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives ‘imidazoline of the General formula
    0-B t or their non-toxic salts, ·.
    where R | - C ( - C 4 - alkyl, allyl, benzyl, phenethyl or hydroxyalkyl C 1 C 4 "
    featuring AND th with i that compound common formulas Vg ^ oVr-nh cd
    where R z is methyl or ethyl; THEM - hydrogen chloride, is reacted with at least a molar equivalent of ethylene. diamine and alcohol of the general formula
    R ( - OH, where R (has the indicated values ^ with the isolation of the target product in free form or in the form of a salt.
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