• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 优先权
    • 专利摘要:
    Imidazoline derivatives of the formula wherein R1 is alkyl C1-7, alkenyl C2-4, cycloalkenyl C4-7, cycloalkyl C4-7 or phenyl; and their non-toxic salts. Processes for the preparation and pharmaceutical compositions thereof. The compounds exhibit presynaptic az- adrenoreceptor antagonism.
    公开号:SU1197566A3
    申请号:SU823385605
    申请日:1982-01-28
    公开日:1985-12-07
    发明作者:Борне Чаплео Кристофир；Лесли Маерс Питер
    申请人:Рекитт Энд Колман Продактс Лимитед (Фирма)；
    IPC主号:
    专利说明:

     eleven
    The invention relates to a process for the preparation of new imidioline derivatives of the general formula
    (one)
    where R, is methyl, ethyl, N-propyl, N-projenyl, cycloalkenyl C4-Cg or phenyl, which have physiological activity.
    The purpose of the invention is the synthesis of new imidazoline derivatives with valuable properties.
    Example 1. Hydrochloride (2-methyl-1,4-benzodioxanyl) 2-imidazoline ..
    ; a) 2-Methyl-1,4-benzodioxan-2-carboxylic acid.
    A mixture (, 23.7 g) of 2-hydroxymethyl-2-methyl-1, 4-benzodioxane and 3-hydroxy-3-methyl-2H-1, 5-benzodioxepine (ratio of approximately 3: 1) is transferred with 1N aqueous sodium hydroxide solution (135 ml) and cooled to. A solution of potassium permanganate (42 g) in water (165 ml) is slowly added, so that the temperature is kept below 10 ° C. After 48 hours at room temperature, the mixture is filtered, the filtrate is acidified with 1M aqueous sulfuric acid and extracted with methylene chloride. The extracts are washed with an aqueous solution of sodium bicarbonate, the aqueous layer is acidified with sulfuric acid. Extraction with methylene chloride followed by washing, drying, and evaporation of the extracts gives carboxylic acid (11.5 g); m.p. 125-129.5 ° C.
    S) 2-Methyl-1,4-benzodioxan-2-.
    -carboxamide.
      .
    A mixture of 2-methyl-1,4-benzodioxane-2-carboxylic acid (10.28 g) and thionyl chloride (7.8 ml) was heated in anhydrous toluene (40 ml) for 1 hour at 90-100 s. Removal of solids and excess thionyl chloride in vacuo gives a crude carbonyl chloride, which slowly solidifies. A solution of this intermediate in anhydrous dioxane (25 ml) is added slowly to stirred aqueous ammonia (d 0.88 26 ml) while cooling (0-10 ° C). After 1 h, water (300 ml) is added, the solid is collected by the filter with a boil, washed with a vdb, and then
    62
    dried, get carboxamide (8.3 g) so pl. 127-128 ,.
     2-Cyano-2-methyl-1,4-benzo; dioxane.
    A stirred mixture of 2-methyl-1, 4-benzodioxan-2-carboxamide (8.17 g), phosphorus pentoxide (17 g) and anhydrous toluene (175 ml) is heated under reflux for 4 hours. the bed layer is decanted from the residue, the latter is washed by decantation with additional toluene. Filtration and evaporation of the solvent gives a solid residue (5.18 g). Crystallization from ethanol gives the cyano compound (4.4 g); m.p. 88-89 p.
    J Hydrochloride (2-methyl-1, 4-benzodioxanyl) 3 -2-imidazoline.
    A mixture of 2-cyano-2-methyl-1,4-benzodio pissane (0.61 g), methylate. sodium (16 mg) and methanol (2.3 ml) was stirred for 18 hours to obtain an almost pure solution. When cooling
    to 0-10 C, a solution of ethylene diamide (0.235 g) in methanol (1 ml) is added dropwise with stirring. After a few minutes, a solution of hydrogen chloride in methanol (0.65 ml of a 5.6 M solution) is added dropwise, and the mixture is then allowed to warm to room temperature. After 16 h, the mixture was slightly acidified with methanolic hydrogen chloride and
    filtered to remove solids. Adding diztile ether to the filtrate gives a solid, which is collected by filtration (o, 84 g; 2 collections). Recrystallization from a mixture of ethanol and diethyl ether containing hydrogen chloride gives, after drying, hydrochloride.
    imidazoline; m.p. 258-261 ° C (excreted as 1/4 hydrate).
    PRI mme R 2. 2 - |; 2-C2-Ethyl-1, 4-benzodioxanyl) -2-imidazolin.
    and 2-Oxymethyl-2-etsh1-1,4-benzodioxane.
    Mixed mixture of pyrocatechol
    (l4.0 g) ,. 2-ethylene epichlorohydrin
    (15.3 g), sodium hydroxide (5.1 g) and water (50 ml) are heated at 90 ° C under nitrogen for 4 hours. While cooling, water is added, the product
    extracted with methylene chloride. The combined extracts are washed with 2N sodium hydroxide aqueous solution, water, and brine, dried
    3
    and evaporated to give an oil (10.8 g) IKD (ax 3650-3200, 3000-2850.
    c) (2-Ethyl-1,4. -benzodioxanyl) -2-imidazoline.
    The resulting 2-ethylbenzodioxane methanol is converted to the corresponding imidazoline compound of example 1. After adding a methanolic solution of hydrogen chloride as in example 1 g, most of the solvent is removed in vacuo, the residue is partitioned between aqueous sodium bicarbonate solution and ethyl acetate. subsequent evaporation of the solvent gives a solid, which is dissolved with light gasoline (6080 s) to obtain a free imidazoline base; t, pl. 98-100 C.
    Froze (2-Phenyl-1,4-benzodioxanyl)} - 2-imidazolin.
    Pyrocatechin and 2-phenylephichlorohydrin are reacted to form an intermediate 2-oximesh1-2-phenyl-1,4-beisodioxane (according to example 2a, which is converted to the imidazoline compound according to example 26. The free base is recrystallized from light gasoline (60-80s) mp 114.5-116 ° C.
    EXAMPLE 4 (2- Isopropenyl-1, 4-benzodioxanyl) -2-imidazoline .a) 2-Cyano-2- (l-hydroxy-1-methyl ethyl) -1,4-benzodioxane.
    A suspension of 2-cyano-1,4-benzodioch {san (40 g) and anhydrous carbonate (potassium (176 g) v. Acetone (500 ml) | pereusheyat and heated under reflux for 5 days. The mixture is cooled and inorganic the salts are removed by filtration. After evaporation of the acetone under vacuum, the residue is distributed between methylene chloride RIDOM and 2N aqueous sodium hydroxide solution. The organic layer is washed with 2N aqueous sodium hydroxide solution (2 times), 5% hydrochloric acid, brine, and then dried by passing it through an absorbent made of cotton and wool. Evaporation in a vacuum and The orange oil (37) Required product was passed by passing it through a column of silica, MA (ZOO g) using methylene chloride as eluent. Those fractions that, according to test data, have an Rf value of 0.2 (CNHS), and evaporated 7
    75664
    in vacuo to give the desired hydroxy compound (14.5 g); m.p. 63-69 C (18 g of unreacted 2-cyano-1, 4-benzodioxane is regenerated with 5 columns).
    b 2-Cyano-2-isopropenyl-1,4-benzodioxane.
    A solution of the indicated hydroxy compound (0.80 g) in dry pyridine (8. ml at
    Room temperature is treated by adding dropwise phosphorus oxychloride (1 ml) over 5 minutes. The solution is then heated at 60-70 ° C for 18 h, cooled and poured
    5 gently on a mixture of ice and water. The mixture is extracted with methylene chloride (3 times 50 ml), the extracts are washed with brine, dried and evaporated to obtain the desired isopropyl compound (0.62 g); Rf 0.75 (CHCF).
    c) (2-Isopropenyl-1, 4-benzodioxanyl) -2-imidazoline.
    The indicated isopropenyl compound is reacted with ethylene diamine in Example 1d-. After adding a methanolic solution of hydrogen chloride, most of the solvents are removed in vacuo, the remainder is dissolved between the aqueous solution
    sodium bicarbonate. and methylene chloride. Drying the organic phase, followed by evaporation of the solvent, gives a solid, which is recrystallized from light gasoline (60-80 ° C) to obtain an imidazoline free base; m.p. 108-110 C.
    PRI me R 5. (2-Isopropyl-1, 4-benzodioxanyl) -2-imidazoline.
    0 A solution of (2-isopropenyl-1,4-benzodioxanyl)} -2-imidazoline (0.80 g) in ethanol (O ml) with 10% palladium on carbon (80 g) is hydrogenated at atmospheric pressure and room temperature in for 6.5 hours
    The mixture is filtered, the palladium residues are washed with ethanol (2 x 10 ml) and the combined filtrates are evaporated to dryness under reduced. pressure. The resulting solid (0.8 g) is recrystallized from light gasoline 6080 ° C) to give isopropyl benzodioxane (0.3 g); m.p. 124-125 ° C.
    5 EXAMPLE 6. (2-Cyclohex-1-yl-1, 4-benzodioxanyl) -2-imidazoline. Prepared according to example 4 using cyclohexanone instead of acetone by reaction at about. The product has a mp. 122-124 0. Example. (2-Cyclopen-1-anil-1, 4-benzo-dioxy-I) 3-2-imidazoline. Prepared according to example 4 using cyclopentanone instead of acetone when carrying out the reaction at about 90 C. The product has so pl. 83-85 ° C. . Example (2-Propyl-1, 4-6-benzodioxanyl) -2-imidazolin. Prepared according to Example 2 using 2-n-propylene epichlorohydrin prepared by treatment with 1-chloro-2-hydroxy-2-chloromethylpentane, prepared by the reaction of n-propyl magnesium bromide with 1, 3-dichloroacetoma in anhydrous toluene, the product has m.p. 113-115 C. EXAMPLE 9. (2-cyclobut-1-phenyl-1,4-benzodioxanyl) -2-imidazoline hydrochloride. Prepared in Example 4c using cyclobutanone with tetrahydrofuran as a cosolvent instead of acetone and conducting the reaction at approximately 65 C. The product had an Rf value of 0.38 (CHCfj) methanol 4: 1 (v / v). P and m 8 p 10. 2 - {; 2- (2-Cyclopeneyl-1, 4-benzodiox. Anil) 1 -2-imidazoline. A solution of (2-cyclopent-1-ensh -1,4-benzodioxanyl) -2-imidazoline (0.50 g) in ethanol (10 ml) with 10% palladium on carbon (80 mg) is hydrogenated at atmospheric pressure and room temperature. temperature for 3.5 hours. The mixture is filtered, the filtrate is evaporated to dryness under reduced pressure, to give a brown oil (0.5 g). The oil is partitioned between 2N aqueous hydrochloric acid and diethyl ether. The aqueous layer was basified with sodium bicarbonate and then extracted with diethyl ether. The organic phase is evaporated with HjTo and evaporated under reduced pressure to give a solid (0.15 g), which is recrystallized from hexane to give a solid (0.10 g), mp. .} 35-136 ° C. Elemental analysis data are presented in Table. I. The pharmacological activity of the compounds obtained by the proposed method is determined as follows. one . Antagonism of pre- and postsynaptic tsf -adrenoreceptors in ex-, Perimentov with a dedicated tissue. Antagonism of presynaptic 2 adrenoreceptors evaluated with; by determining pA values with respect to the inhibitory effects of clonidine, well known. a presinoptic agonist, a renoreceptor on the blood vessels of rats stimulated at a frequency of 0 Hz. This in vitro model is particularly useful as a starting screen for studying the presynaptic activity in isolation, since the physiological nature of the tissues of the excretory vessels is such that the postsynaptic receptors located in them are especially unavailable for exogenous agents. As a consequence, an alternative tissue, rat killer anococcugeus, is used to establish the postsynaptic oi -adrenoreceptor activity. Antagonism of norepinephrine counteraction is used to determine pAg values in postsynaptic o, α-adrenoreceptors. The correlation of presynaptic LJ-adrenoceptor antagonism (compared to clonidine on rat excretory vessels) and postsynaptic oi) adrenoreceptor antagonism (compared to noradrenaline antacocgeus counteraction in rats) is used to assess adrenoreceptor selectivity. I In tab. Table 2 presents the test data for the compound of Example 1 and standard drugs: a non-selective antagonist of oi-adrenoreceptor phentolamine), a selective presynaptic antagonist (yohimbin), a highly selective postsynaptic antagonist (prazosin) and an antideprosant (mianserin), which shows the properties of the antagonist (prazosin) and the antideprhosant (myanserin), an antagonist, an antagonist, an antagonist; postsynaptic adrenoreceptor as part of its pharmacological profile. The table is supplemented with results for the known compound B of the formula
    9 with t with activity of the compound of formula A.
    Postsynaptic studies (e,
    Both for agonist and antagonist studies, an apococcygeus rat is used. The ability of compounds to induce antacne anococcygeus muscle reflects the postsynaptic activity of the oti-adrenoreceptor agonist. The activities of compounds with contractile properties are determined by comparison with phenylylin, which is a selective postsynaptic O6f-adrenoreceptor agonist.
    Antagonistic activity is tested by determining the inhibitory effects of the compounds on norepinephrine counteracting anococcygeus. muscle
    The results of the definitions are presented in table. 5, (the first column indicates the position of the methyl substituent in formula A).
    From tab. 5, it can be seen that the compound of Example 1 is more selective (more than 2 times) than the compound of formula A. None of the other seven compounds are as selective as the compound of formula A, they are 0-2 antagonists, have significantly reduced activity. In some cases, Ob2-agonism becomes a sign of their profile.
    . The compounds of formula (1) or their non-toxic salts are used in the treatment of depression. A method for treating depression involves administering to people an anti-depressant effective amount of a compound of formula (D) or a non-toxic salt thereof.
    The pharmaceutical compositions may be in a form suitable for oral, rectal or parenteral administration. Oral compositions can be in the form of capsules, tablets, granules or liquid preparations (elixirs, syrups or suspensions).
    Tablets contain a compound of formula 1G) or its non-toxic salt in a mixture with excipients, which is 9756610
    ry are suitable for the manufacture of tablets. These excipients may be inert diluents calcium phosphate, microcrystalline
    5 cellulose, lactose, sucrose or dextrose), granulating and de-integrating agents (starch), binding agents (starch, gelatin, polyvinylpyrrolidone or acacia)
    10 and lubricating agents (magnesium stearate, stearic acid or talc).
    Capsule compositions may contain the compound or its non-toxic salt mixed with an inert solid diluent, such as calcium phosphate, lactose or kaolin, in a hard gelatin capsule.
    Compositions for parenteral. prescriptions can be in the form of sterile injectable preparations, such as solutions or suspensions, for example, in water, saline or 1,3-butanediol.
    For convenience and dosage accuracy
    the compositions are preferably used in the form of dosage units. For oral administration, the dosage unit form contains 1-200 mg, preferably 10-50 mg) of the compound of formula (1) or its non-toxic salt. Parenteral dosage forms. Bath units contain 0.1-10 mg of the compound of formula (1) or its non-toxic salt per ml of the preparation.
    35 The following are examples of compositions in which all parts are given by weight.
    Example 1. A mixture of 1 part of hydrochloride (2-methyl-, A-benzodiox40-sanyl) -2-imidazoline and 4 parts of microcrystalline cellulose together with 1% CTeaipaTa magnesium is pressed into tablets which contain 10, 25 or 50 mg of the active ingredient.
    45 Example 11. A mixture of 1 part of (2-methyl-1, 4-benzodioxanyl) -2-imidazoline hydrochloride and A part of spray-dried acotose together with 1% magnesium stearate is filled in
    50 hard gelatin capsules that contain 10.25 or 50 mg of the active ingredient.
    table 2
    AjA result means that the compound is inactive at a concentration that could give this result.
    Activity relative to clonidine 1.
    l
    Activity relative to the compound of formula A Activity relative to phenylephrine 1.
    # -IHt
    Selectivity for the compound of formula
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING PRODUCTION-
    IMIDAZOLINE of the general formula 1 where R ^ is methyl, ethyl, n-propyl, and -propenyl, cycloalkenyl C 4 -C 6 or phenyl, a different compound of the general formula 11
    Ng ° - H bh o Gzd, ™ 'where R ( - has the indicated meanings;
    R 2 is methyl or ethyl;
    HX — hydrogen chloride, is reacted in an alcohol of the general formula R ^ OH with at least 1 molar equivalent of ethylene diamine to give the desired product or a compound of formula (1), where B (-C-propenyl) is hydrogenated in the presence of a palladium-carbon catalyst to obtain the compounds of formula (1), in which R. / H-propyl.
    Priority by signs: 01/30/81, for R (-methyl, ethyl, H-propyl or H-propenyl. 07/28/81, for R> 4 -cycloalkenyl C 4 -C $ or phenyl.
    <0>
    * 1197566
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    PL235152A1|1983-07-18|
    DE3262919D1|1985-05-15|
    NO156865C|1987-12-09|
    IE820209L|1982-07-30|
    CS245766B2|1986-10-16|
    FI67544C|1985-04-10|
    ES8302694A1|1983-01-16|
    IL64880A|1985-04-30|
    PT74354A|1982-02-01|
    PT74354B|1983-07-04|
    GR75168B|1984-07-13|
    GB2092139A|1982-08-11|
    ES509131A0|1983-01-16|
    HU190983B|1986-12-28|
    NO156865B|1987-08-31|
    EP0058006B1|1985-04-10|
    NZ199469A|1984-03-16|
    FI820262L|1982-07-31|
    EP0058006A1|1982-08-18|
    PL137716B1|1986-07-31|
    AU545344B2|1985-07-11|
    PH17747A|1984-11-27|
    NO820258L|1982-08-02|
    CA1176638A|1984-10-23|
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    法律状态:
    优先权:
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