• 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 provides novel compounds of the formula: or wherein R, is H, an alkyl of 1 to 4 carbon atoms or -CH2OH; R2 is H or CH3; R3 is -CH3, -CH2CH3, -CH2CH2CH3, R4 is H or OH; or R3 and R4 together represent =CH2, =CH-CH3, =CH-CH2-CH3, or X is or Rs, R6 and R7, which can be the same or different are H, -CH3, -CN2CH3, halogen, OH or -OCH3 or R5 is hydrogen and R6 and R7 together form an -O-CH2-O-bridge between two adjacent carbon atoms in the phenyl group; -CHR8- is -CH2-, -CH(CH3)-, -CH(-CH2CH3)-, -CH(-CH2CH2CH3)-, or or or or -CH2CH2CH2CH3; n is 0 to 4; and their non-toxic pharmaceutically acceptable acid addition salts and mixtures thereof. Processes for the preparation of these compounds are described, as are novel pharmaceutical compositions comprising at least one of the compounds or their salts. The compounds and their non-toxic salts exhibit valuable pharmacological activity and are useful in the treatment of mammals, especially as antihypertensive agents. Furthermore. some of the compounds have proved to possess anthrombotic and diuretic activity. Antimycotic and antifungal properties have also been found.
    公开号:SU1241990A3
    申请号:SU823463047
    申请日:1982-07-09
    公开日:1986-06-30
    发明作者:Карьялайнен Арто-Иоханнес；Ойва Антеро Куркела Кауко；Калерво Похьяла Эско
    申请人:Фармос Ихтюмя Ой (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to new adazole derivatives of the general formula
    th
    e at B
     -iЙ .5
    R, H; R, -H, 2-Cl, 2 - CHj5 .g;
    Rj-H, 3-CH, 4-CHb, 6-CH3;
    KugSNz,
    2СНз
    c, n,
    Cho
    cm.
    Rj-H, OH or B-CRt d
    with B CH-CH-
    K'bs-SN; Rg-H, CHj; i
    , CHj 5,
    f
    with, CHj;
    Rj-Z-CH ,, 2-Cl; Cr-6-CH3, 6-Cl; Rg-H, CH ,;
    ,,
    possessing antihypertensive properties.
    The purpose of the invention is the synthesis of new compounds with valuable properties.
    The compounds of general formula I and their non-toxic salts can be used as antihypertensive agents for the treatment of mammals.
    Example 1. 4-fo, Bis (-2-methylphenyl) oxymethyl-5-methylimidazole
    4.9 g (0.2 mol) of dried magnesium chips are coated with 50 ml of dry tetra hydrofuran. The mixture is heated to boiling and a solution of 34 g (0.2 mol) of 2 bromotoluene in 50 ml of dry tetrahydrofuran is added dropwise at this rate to obtain a smooth reaction. After the addition is complete, the reaction mixture is heated under reflux for about 30 minutes to
    419902
    as long as the magnesium shavings no longer react. Rer
    The active mixture is cooled to C and added in small portions.
    sj 9.3 g of methyl ester of 5-methyl-4-imidazolecarboxylic acid. After the addition is complete, the mixture is heated under reflux for another 2 hours and the solvent is distilled off to obtain () half of the original volume. The mixture is cooled and poured with stirring into 300 ml of cold water containing 15 ml of concentrated sulfuric acid. After 13 hours, stirring continued for another 15 minutes and then the mixture is filtered. The precipitate filtered from: acidic water, short, is the compound sulphate, extracted with chloroform. After
    20 evaporation of the crude product is recrystallized from acetone, m.p. 169-1 7 1 ° C.
    And pm. Mep 2., (2-methyl phenyl) oxymethylZimidazole.
    25 Reagent Grinra rashuchayut of
    63.4 g of p-bromotoluene and 9.6 g of Mg-CTpym-rsi in 20 ml of THF. 2.6 g of methyl 4-- -imidazole-carboxylic acid ester are digested with this solution.
    30 and the reaction mixture is heated. 5 h. The mixture is poured into cold water, which contains 60 ml of concentrated HC, Gu, and the product rochloride is filtered, washed with chloroform and re-crystallized from isopropanol; 23 g (73%), so pl. .78-179 ° C.
    The hydrochloride is obtained in a mixture, water-ethanol with sodium hydroxide, m.p. 138- 40 ° C; Example 3. 4- (c /, - Diphenyl) oxymethyl 1-methylimidazole.
    The compound is prepared by the method described in Example 2, except that bromobenzene is used instead of o-bromotoluene and 5-methIOT 4-imidase Olcarboxylic acid methyl ester instead of 4-imidazole-carboxylic acid methyl ester; yield 18.5 g (70%), so pl. 188-190 0 (as the basis45
    50
    ethanol;
    Example 4. 4-Ll - (2-Methylphenyl) j -2-methypbenzyl-zimidazole.
     4- L ° i., (-2-methylphenyl) oximetes, p and 4idaeol are dissolved in 1-00 ml of acetic acid-55 hydrochloric acid. 100 mg of Pd / C are added and the reaction mixture is stirred vigorously under hydrogen atmosphere at 60 ° C until 3
    There is a reaction. The mixture is then filtered and distilled to a smaller volume. 70 ml of water are added, the mixture is washed twice with 20 ml of chloroform. The aqueous phase is alkalinized with NaOH and extracted with chloroform (ml). The combined extra chloroform acts are washed with water (1x10 ml) and dried over. The solution is evaporated to dryness. Vpsod 93%, so pl. 228-231 C (from ethanol). Hydrochloride in ethyl acetate-isopropanol: so pl. 245-254 ° C.
    Example 5. 4- (o-Phenylbenzene 1) 5-methylimidazole.
    The compound is obtained from 4- (o., OC-phenyl) oximesh1-5 methylimidazole in accordance with the method described in example 4. Yield 69%, mp. 198 - .204 ° C (from ethanol).
    EXAMPLE 6. (2-Methylfensh1-xC- (2-methylbenzyl) 3-5-methylimidazole.
    The compound was prepared according to the method described in Example 4, using 4-Go, o (-bis- (2-methyl-I phenyl) oxymethyl-5-methylimidazole as starting material. Yield 79%, mp. ( from the water-ethanol system).
    Example/. (2,3-Dimethylphenyl) -D (-methylJoxymethyl Iimidazol, 1- (4-imidazolyl) -1- (2,3-dimethylphenyl) ethylene and 4- (- methyl-2,3-dimethylbenzyl) imidazole.
    In order to obtain 2,3-dimethylmagnesium bromide in the first stage, 4.9 g of dry magnesium chips are sprayed with 50 ml of dry THF. The mixture is heated to boiling and a solution of 37 g of 2,3-dimethyl-bromobenzene in 50 ml of dry THF is added dropwise at such a rate to obtain a smooth reaction. The reaction mixture is then heated under reflux for 30 minutes until the magnesium chips stop reacting.
    In the same way, in another flask, methylmagnesium bromide is prepared from 2.4 g of magnesium shavings and 9.5 g of bromide in THF.
    Another flask with 12.6 methyl ester of 4-imidazolecarboxylic acid is added to 100 ml of dry THF and the mixture is stirred at heating to about. A solution of 2,3-dimethyl-magnesium bromide, previously obtained, and immediately a solution of methyl magnesium bromide are added to this mixture. For 4
    the reaction pieces are heated under reflux for several hours. The solvent is then distilled off to obtain approximately half of the original volume. The mixture is cooled and poured with stirring into 350 ml of cold water containing 50 ml of concentrated sulfuric acid. Stirring is continued for another 15 minutes and then the mixture is filtered.
    The pH of the filtrate is adjusted to slightly basic medium and the mixture is extracted with methylene chloride (3 x 50 ml). The combined, methylene chloride extracts are washed with water and evaporated to dryness. The residue, which contains crude (2,3-dimethylfensh1) -o (-methyl-oxymethyl e-Idazol, is further purified on a chromatographic column with silica gel using chloroform-methanol as the solvent.
    1- (4-Imidazole) -1- (2,3-dimethylphenyl) -ethiene is then obtained from this product by heating it with potassium hydrogen sulphate at 36 ° C, b.p. bases 137-.
    4- (o-methyl-2, 3-dimethylbenzyl) - imidazole is obtained by hydrogenation with a Pd / C catalyst in 2 n. HC1 in accordance with the described method. The following compounds were obtained in the same way: 4- (o-methyl--2,6-dimet schbenzyl) imidazole, m.p. (oxapat): 98-99 C; 4- (o (-ett-2,3-dimethylbenzyl) imidazole, m.p.
    (HC1-salt): 175-1 4- (o: -butyl-2-methylbenzyl) imidazole.
    Physical properties of compounds
    General formula I are presented in
    tab. one.
    The antihypertensive properties of the proposed compounds were determined by the following methods.
    Sprague-Dawley rats of normal weight were first anesthetized with urethane. Thereafter, the femoral artery was connected using a polyethylene tube with a blood pressure sensor. The test compound was injected into the femoral vein or intraperitoneally and the blood pressure and pulse rate were recorded using a recording device. In the experiment to determine the antihypertensive properties, Wistar type rats were used. The test derivative was administered through a tube, orally in the same 512419906
    Ludok. Blood pressure was measured. Anti-hypertonic effect
    on the tail, the indirect indirect compound of the general formula I is presented in the following table. 2.- ..
     ,Table
    4- (C-Methyl) - HC1: 208-210
    2,6-dimethylbenzylZimidazole
    4- (o (-methyl) - HC1: 161-165
    -2,3-dimethylbenzyl imidazole
    4- (-methyl-2- HGl: 156-160
    - methylbenhash)
    imidazole


    Oxalate: 214-216
    HC1: 175-177
    HC1-salt: oil
    HC1: 96-100
    HC1: 97-98
    Ground of decision: 137-140
    IH-NMR: 6CDC Ij 11-, 4 (1H, broad); 7.19 (1H, C); 6.83 (ЗН, С); 6.56 (lH, C); 4.52 (2H, KB 6); 2.11 (6H, C); 1.63 {ЗН, д6)
     (a, vi, tse hydrochloride): bsbzo 149.8 (1C, C); 139.1 (1C, C); 137.6 (2C, C); 134.9 (1C, d); 130.8 (2C, d); 128.4 (1C, d) .; 116.6 (1C-d); 32.8 (1C, d) 20.6 (20, KB); 17.0 (1C, q)
    IH-CID (HC1-salt): 1.708 (d, 3N); 2.370 (broad.с, ЗН); 4.688 (square 1H); 4.933 (C, 2H); 7.079-7.263 (m, 3N); 7.361 (C, 1H); 8.780 (C, 1H)
     (HC1-salt): signals at ppm 16,529 | 21,917; 22,462; 34,662; 117,881; 126, 660; 128,385; -131.079; 135,650; 136.952; 140.161; 140,163; 142,855
    1c-NMR (HCl-salt): 1.63 (d, 3N); 2.40
    (
    ZN
    4.52 (sq. „1H);
    5,50 tC, НрО); 6.9-7.2 (m, 3N); 7.36 (C, 1I :); 8.83 (d, 1H)
     (HCl-salt): 2,104 (C, ZN); 2.313 (s, 3N); 5.187 (C, 2H); 5.358 (C, 1H);
    dimethylphenyl) ethylene







    HC1: 260-262
    Oxalate: 161-165
    HC1: 194-198
    Oxalate: 176-179
    HC1: 257-258
    HC1: 210-212
     250-252
    Continued table. one
    6.106 (C, 1H); 7.03-7.22 (m, 4H); 8.98 (C, 1H)
    13c-NMR (HC 1-salt): signals at 18.073 million; 21.857; 118,789; 119,455; 127,961; 129,475; 132,230; 135,802; 136,498; 136,892; 137.921; 139,949; 140,070
    1 NMR: 8.82 (1H, d); 7.36 (1H, d); 7.20 (1H, broad s); 7.08 (SNS); 2.20 (bNs) 1-Г, 82 (ЗН, д, 1.2)
    IH-NMR (oxalate): 8.75 (1H broad, s); 7.05 (GC); 7.00 (SNS); 3.00 (Pnm); 2.20 (6HC); 1.31 (ZNd)
    IH-NMR (HC1-salt): 8.70 (Bc); 6.9 (4Hc); 3.65 (1Nm); 3.21 (2H, d 8); 2.39 (6H broad, s); 1.45 (LAR 7)
    IH-NMR (HC1-salt): 1.1 (t, 3N); 2.35
    (s, 6H) ;, 2.4 (sq. 2H); 4.8 (broad, s,
    Hg.0); 7.1 (2xC, 3 + 1H); 7.65 (C, 1H); 8.95 (C, 1H)
    1c-NMR (HC1-salt): 1.9 (C, 3H); 4.6 (broad s, H2.0); 6.85 (C, 1H); 7.0-7.4 (m, 1 + ЗН); ° 7.6 (С, 1Н)
    1- (4-Imidazolyl) -1- (2 ,, 3-dimethylphenyl) -ethylene
    (2,6-Dimethylphenyl) -1-methylethenyl imidazole
    (2dB-imetilfenil) tetiltilT-imidazole
    4- 2- (2,6-Jaimethylphenip) -propyl 7-imidazole
    (2,6-Dimethylphenyl), - 2- -ethylethyl imidazole
    4 - L2 - {2, 6-Dimethylphenyl l) - -1-ethylethenylimidazole
    4-G2 (2,6-Dichlorophenip) -1 - -methimetenyl-imidazole 50
    40
    40
    0.1-0.3 38 intravenously
    40
    0.1 20 intravenously
    3 30 intravenous
    3 25 intravenously
    3 35 intraperi-, tonal
    0.3 25 intravenously
    eleven
    4-G2- (2,6-Dimethylphenyl) -1- -methylethyl 1-5 methylimidazole
    4-12- (2,6-Dimethylphenyl) -1-ethylethyl-imidazole
    (2,6-Dimethylphenyl) -1- -ethyl-1-hydroxyethyl 1-imidazole
    12 Continued table. 2
    I
    0,003-0,1 41 intravenously
    0.03-3 29 intravenously
    3-30 23 intravenously
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING SUBSTITUTED IMIDAZOLE DERIVATIVES of the general formula where, at B = —C — Rq — H;
    R-5
    R z -H, 2-C1, 2-CH 3 , 4-C2.H5;
    'R3-H, 3-CH-, 4-CH. '6-CH 3 ;
    R4-CH 3 , C 2 Hs,
    CH 3
    Cl4 z
    R5 - H, OH or B = -d - i
    R 6 R 7 1 1 at B = —CH — CH — Rq — H; And g -2-CH 3 ; R 5 -6-CH 3 ; r £ -h, cn 3 , R T -H, CH 3 , CH 2 CH 3 ; sn 2 sn 3 ,
    R "Rg G 4 1 at B = -C - C - Rq-R, CH 3 ; R z -2-CH 3 , 2-C1; R, —6 — CH3, 6-C1;
    Rg-H, CH};
    - R 3 —H, CH d , characterized in that the compound of general formula
    N θ JyC-OR 10
    Y where Rq has the indicated meaning; R-fo is alkyl or aryl;
    ° y = H or benzyl, (S is reacted with a Grignard reagent of the general formula on 1M ^ - (CH g ) p - / L 2
    H3 where R 4 , Rj have the indicated meanings; η = 0, 1, and the resulting compound is hydrogenated or, if necessary, reacted with KHSO4 and, if necessary, the resulting product is hydrogenated.
    SU .. ”1241990 AZ! 241990 and
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB08121333A|GB2101114B|1981-07-10|1981-07-10|Substituted imidazole derivatives and their preparation and use|LV920315A| LV5063A3|1981-07-10|1992-12-17|Method of obtaining substituted imidazole derivatives|
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