• 专利附录
  • 专利说明
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    • 专利摘要:
    The invention provides compounds of the formula: wherein each of R1, R2 and R3, which can be the same or different is hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxv, amino, hydroxy or nitro; R4 is hydrogen or alkyl of 1 to 7 carbon atoms; X is (R5 is hydrogen or hydroxy) and n is 1-4; and their non-toxic pharmaceutically acceptable acid addition salts. These compounds exhibitvaluable pharmacological activity and are useful in the treatment of mammals, especially as anti- hypertensive agents. Furthermore, some of the compounds have proved to possess diuretic, ß-blocking activity and/or antithrombotic activity. The compounds may be made by a variety of methods and may be incorporated in pharmaceutical compositions also comprising a compatible pharmaceutically acceptable carrier.
    公开号:SU1074404A3
    申请号:SU813243254
    申请日:1981-02-12
    公开日:1984-02-15
    发明作者:Йоханнес Карьялайнен Арто；Ойва Антеро Куркела Кауко
    申请人:Фармос Ихтюмя Ой (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to imidazole derivatives of the general formula (CH21p 1 Cl I where R .R and Rn can be the same or different and are hydrogen chlorine, methyl methyl,.-CO or CH-OH group 1-4, or their salts which has anti-pertonic properties, as well as such pharmacological properties, such as blocking, anti-thrombotic and anti-microbial activity. A method is known for the synthesis of organic compounds based on the addition of Grignard reagents to polarized multiples in an organic solvent l . Purpose izob reteni is the synthesis of new compounds with valuable phacological properties. The goal is achieved by the method of obtaining compounds of formula (1) based on the Grignard reaction, an imidazolald guide of the general formula O where R / (has the indicated value, interacts with the aryl magnesium halide formulas (CHzlj ngl al | P where n, R2 and Ra have the indicated value. NIN and. are halogen, with isolation of the target product in free form or as salt, Example 1. 4- 3- (2, 6-Dimethylphenyl) -1 - o.ksy propyl J - them and evil. 4.8 g of dry magnesium shavings pour 100 ml of dry tetrahydrof wound (THF). The mixture is heated to boiling, and a solution of 42.6 g of 2- (2, b-dimigylphenyl) -1-bromoethane in 100 ml of dry tetrahydrofuran is added dropwise at such a rate as to keep the mixture boiling slightly. After the addition is complete, the reaction mixture is refluxed for an additional 30 minutes. The reaction mixture is cooled before and slowly in small portions, 7.0 g of 4-imidazole ldehyde is added. After the addition is complete, the reaction mixture is refluxed for 5 hours. Then the reaction mixture is cooled and poured into 200 ml of cold water containing 20 ml of concentrated hydrochloric acid. A portion of the tetrahydrofuran was distilled off to obtain a smaller volume of the mixture, and the tetrahydrofuran was replaced with water. This mixture is washed twice with 50 ml portions of chloroform. The aqueous layer is made alkaline with sodium hydroxide solution (pH about 8). The precipitate formed is washed with water, added to 100 ml of 4N. NaOH solution and the mixture is thoroughly stirred for 1 h. The precipitate is filtered off, washed several times with water and dried .. The crude product is recrystallized from a mixture of water and ethyl alcohol to give „10 D g of product, melting at 157-158 s. H-NMR spectrum: 2.3 (m. 2H); 2.6 (s.bN); 3.0 (M.2H); 5.15 (t.H), 5.45 (p.2H); 7.25 (s.ZN); 7.35 (C81H); 8.0 (p. IK). . Mass spectrum: 230 (21%); 212 (20), 197 (13); 133 (11); 124 (7%); 119 (18%) 118 (23); 117 (18); 115 (11); ill (98); 98 (100); 97 (69); 95 (8); 93 (7); 91 (21); 82 (27) / 81 (10%). Example 2. (2,6-Dimethylphenyl) -1-oxopropyl-imidazole. It follows the procedure described in Example 1, with the exception of Using 9.6 g of 4-imidazolaldehyde: A precipitate at a pH of about 8 is added to 4 n. the sodium hydroxide solution and the mixture is thoroughly stirred for 1 h and filtered. The filtrate is neutralized with hydrochloric acid and the precipitate is filtered off. The cake on the filter is mixed with water and dried. The yield of the crude product is 9.5 g, its melting point is 132-148 ° C. The product in ethyl acetate solution is converted to the hydrochloride, melting point 172-178 ° C. Spectrum- H-NMR (HC 1-salt): 2.35 (s.bH); 3.1 (p. 4H); 4.55 (p.2H); 7.0 (s. ZN); 8.15 (s. 1H); 8.55 (s. 1H). In Examples 3-26, the procedure of Example 1 is repeated, except that the corresponding (substituted phenyl) 1-bromoalkane is used instead of 2- (2, 6-dimethylphenyl) -1-bromoethane, and in Examples 12, 13, 15, 17 , 18 and 19. Instead of 4-imidazolaldehyde, 5-methyl-4-imidazolaldehyde is used.
    Example 3. 4 C-tsz, 4-Dimethylphenyl) -1-hydroxypropyl | -imidazole. m.p. 70-74 C (from a mixture of water and ethanol):
    H-NMR spectrum: 2.0 (m.2H); 2.2 (s, bN); 2.6 (m. 2H); 4.5 (t. 1H) / 5.2 s. 2H); 6.9 (m. 4H); 7,6
    (p. 1H);
    PRI me R 4. 4- (1-Oxy-3-phenylpropyl) -imidazole, so pl. 144,146 ° C (out of water), so pl. hydrochloride 153-155 ° C (from isopropyl alcohol
    NMR NMR: 2.25 (m. 2H) /:
    2.7 (m. 2H); 4., 75 (m. 1P); 4.75 (t. 1H); 5.15 (p. 2H), 7.0 (p. 1H); 7.25 (s. 5H); 7.65 (s. 1H). Mass spectrum: 202 (8%), 181 (6),. 169 (3); 156 (3); 115 (4) .; 111 (10), 98 (100); 97 (76); 91 (16), - 82 (7%).
    Example 5. 4-C-A 2, 3-Dimethylphenyl) -1-hydroxypropyl-imidazole, So pl. 130-134 0.
    H-NMR (HC1) spectrum: 2.1 (m. 2H) 2.15 (s. 3H) .V 2.25 (s. ZN), 2.7 (m. 2H)., 4.85 (t. 1H ), 5.1 (p. 2H), 6.95 (p. GH), 7.4 (p. 1H), 8.7 (p. 1H). ,
    C p and measures 6. (3-Methylphenyl) -1-rxypropyl 1-imidazole, mp 104-10.6 ° C ..
    H-NMR spectrum: 2.15 (m. 2H); 2, (p. 2.6 (m. 2H); 4.7. (T. 1H), 5.1 (s. 2H); 7.0 (m. 5I); 7.6 (c.lH
    Example 7. (4-ethylphenyl) -1-6xypropylT-imilazole, t; mp 120-124 ° C .;
    Spectrum H-NMR: (m. 2H), 2.3 (p. 3N); 2.65 (m. 2H); 4.75 (t.H); 5.15 (s. 2H); 7.05 (m. 5H) 17.65
    (.e. 1n) ..-:,
    EXAMPLE 8 (2-Methylphenyl) -X-hydroxypropyl-11-imidazole, mp 164-166 ° C hydrochloride (from a mixture of iso-propanol and ethyl acetate).
    H-NMR spectrum: 1.9 (m. 2H) / 2.1 (p. 3N); 2.55 (m. 2H); 4.6 (s.ZN);
    4.8 (t. 1H); 7.0 (s. 4H); 7.2. (p. 1H); 8.5 (p. 1H).
    Example 9. (2, b7Dimethylphenyl) -l-oxypentyl-imidazole, so pl. 129-134 ° C.
    H-NMR spectrum (trifluoroacetic acid added): 1.2-2-1.9
    (m. bn); 2.5 (s. Bn); 4.3 (t. 1n);
    5.5 (s. 2H); 6.8 (s. ZN); 7.35
    (p. 1H), 8.65 (p. 1H) ,,
    Example 10, 4-t2- (2-chlorophenyl) -l-hydroxyethyl3-imidazole, mp. hydrochloride 1b4-167 ° C.
    H-NMR spectrum (trifluoroacetic acid added): 3.85 (d. 2H
    5.1 (t. 1n); 5.5 (2n); 7.0 (sd);
    7.25 (M. 4H); 7.65 (s. 1H).
    ; P p and meRe 11. 2, 6-Dichlorophenyl) -1-hydroxyethyl-imidazole, so pl. 138-141 C, m.p. . Hydrochloride 201-203 C (out of water).
    H-NMR (HCI-salt) spectrum: 3.4 (d. 2H); 4.8 (s. ZN); 5.2 (T.IH); 7.2 (Q. IH); 7.3 (s. ZN); (p.1n)
    Example 12. (2-Chlorophenyl) -1-oxethyl 3 -5-methyl-imideol.
    NMR spectrum (HGI-sp): 1.65 (p. 3N); 3.05 (d, 2H); 4.6 (p. ZN);
    5.0 (t. 1H); 7.0 (m. 4H); 8.4 (s / 1H). /
    PRI me R 13; (2,6-Dichlorophenyl) -1-hydroxyethyl} -5-methyligshdazol, m.p. hydrochloride 193-195s (out of water).
    Spectrum n-NMR: 1.5 (s. ZN), 3.3 (d. 2H); 4.3 (s. 2H); 5.1 {t.H) .7.0 (s. GZ); 8.4 (s. 1H).
    Example 14. (J-Methylphenyl) -1-hydroxyethylZ-imidazole, m. square hydrochloride 142-145 C.
    Spectrum H-NMR (HC17SOl): 2.2 (C. 3N); 3.05 (d, 2H); 4.65 (s. ZN) 5.05 (t. 1H); 6.9-7.2 (m. 5H); 8.55 (p. 1H)., "
     PRI me R 15. 4-13- 2, 6 -Dimethylphenyl) -1-hydroxypropyl-5-methylimidazole. Mp. hydrochloride 166 1680s.
    Spectrum.n-NMR (HC 1 -sol): 2.1 (- p. 6H); 2.25 (s. ZN) .; 4.8 (s. ZN); 6.8 (p. ZN) | 8.6 (p. 1JI). ,, /
    EXAMPLE 16 4- {2- (2,6-Dimethylphenyl) -1 hydroxyethyl - imidazo.l, m.p. hydrochloride 179-181 ° C.
    H-NMR spectrum: 2.2 (s. 6H), 3.2 (d. 2H); (s, ZN); 5.05 (t. 1H),
    7.1 (s. ZN), 7.2 (s. 1H); 8.6 (C.1H).
    Pr and m er 17. 4- (3-Phenyl-1-hydroxypropyl) -5-methylimidazole, so pl. base 134-136 ° C.
    Example 18I (2,3-Dimethylphenyl) -1-hydroxyethyl.-3-methylimidazole, m.p. bases 167-171s, so pl. hydrochloride 173-175 C.
    Example 19. 4- (2-Phenyl-1-hydroxyethyl) -5-methyl-imidazrl, so pl. base 111-120 C, so pl. hydrochloride 154-15bs. ,,;
    Example 20 4- {3- (2,4,6Trimethylphenyl) -1-hydroxypropyl D-imidazole, m.p. hydrochloride 153-155 C (from isopropyl alcohol);
    PRI me R 21. (4-Methylphenyl) - 1-hydroxyethyl-imidazole. m.p. base 152-154 ° C (from isopropyl on the back: mouth).
    Example 22. (4-Ethylphenyl) -1-oxylpropyl imidazole, mp. Hydrochloride 124-129 ° C (from ethyl acetate).
    PRI me R 2; 3. 4- (2-Phenyl-1-hydroxyethyl) -imidazole, m.p. base 155-157 ° C (id naonpontmoBoro alcohol). . , Example 12, p. 24 (2, b-Dichlorophenyl) -1-hydroxybutyl-imidazole, m.p. bases 53-55 ° C. Example. 25. (2-Methyl phenyl) -1-oxethyl1-imidazole, m.p. base 149-151 ° C (from isopropyl alcohol), so pl. hydrochloride 176-178 C (from ethyl alcohol). PRI me R 26. (2,6-Dimethylphenyl) -1-hydroxyethyl-5-methyl-. imidazole, so pl. hydrochloride 177 179 ° C. Example 27. (2,6-Dimethylphenyl) -ethyl} -imidazole. 2- (2, 6-Dimethylphenyl) ethyl glyoxaldethylacetal. 9 g of magnesium shavings close 400 ml of dry tetrahydrofuran and. the mixture is heated to boiling. 2 to 2 are added to this mixture; .b-Dimethylphenyl) -1-6roethane at such a rate as to keep the mixture boiling slightly. When magnesium chips react, containing. Grignard reagent solution is cooled to room temperature. Then the reaction mixture is added dropwise over 3 hours to a cooled 1y (with) solution of diethoseacetic acid and piperidinyl and (00., 8 g) in 200 ml of dry tetrahydrofuran. After addition is complete, the reaction mixture is stirred for 2 hours at approximately 5 ° C. The mixture is then poured into a cold solution of sulfuric acid (2%) with a volume of 1000 fttn. This solution is extracted with toluene and the combined toluene extracts are washed with water and evaporated to dryness to obtain a residue weighing about 95 g. This residue is distilled under reduced pressure. The cervical fraction is distilled below 120 ° C, 0.6 mm Hg. the effluent is discarded and the balance (about 66 g) is crude 2- (2, b-dimethylphenyl) ethylglyldio-saldis ethyl acetal, which is used in the next step without purification. 1,1-Litoxy-2-hydroxy-4- (2,6-dime-tilfenyl) -butane). Bb g of crude 2- (2,6-dimethylphenyl) ethyl glyoxal diethyl acetal is dissolved in 250 ml of ethyl alcohol and 5.0 g of sodium borohydride is added in small portions at a lower temperature. After the addition is complete, the mixture is stirred overnight at room temperature. About 100 ml of ethyl alcohol are distilled off and 300 ml of water is added. The solution is extracted with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated to dryness. The yield is about 60 g of a light red-brown oil which is directly used in the next step. 4-C2 (2, b-Dimethylphenyl) ethyl | -imidazole. 6.0 g of the oil obtained in the previous step and 150 ml of formamide are combined and stirred at 150 ° C, passing through a solution of ammonia gas for 6 hours. The mixture is cooled to room temperature and 400 ml of water is added. Upon cooling, concentrated hydrochloric acid is added until the pH is 3-4. The solution is blasted with toluene, cooled and the pH is set to | 10-12 with 20% sodium hydroxide solution. The mixture is extracted with chloroform iOM and the combined chloroform extracts are extracted with a 10% acetic acid solution. The combined acetic acid extracts are alkalinized (pH 10 -. 12) with cooling with 20% sodium hydroxide solution. The product is extracted in chloroform and the combined chloroform extracts are washed with water and dried over sodium sulfate. The solution is evaporated dry to obtain 4-2-2,6-dimethylphenyl-ethyl-imidazole-base, approximately 24 g. Hydrochloride is prepared, a solution of the base in ethyl acetate is added and a solution of HCE in isopropyl alcohol is added to a pH of approximately 4. The mixture is cooled and filtered and the cake on the filter is washed with a small amount of ethyl acetate. After recrystallization from a small amount of isopropyl alcohol, the melting point is 201-204 ° C. The base isolated from hydrochloride has a melting point of 117-113 ° C. H-NMR (HCE-salt) spectrum: 1.9 (s. BN); 2.6 (p. 4H), 4.95 (p. 2H), (p. Sign); 6.95 (p. 1H); 8.5 (p. 1H). C-NMR (HC-salt) spectrum: 19.86 (KB): 24.20 (t); 29.12 (t); 116.19 (d) / 127.32 (d); 129.02 (d), 133.48 (d), Ministry of Health, 89 (s), 137.52 (s),. 137.70 (o). . In Examples 28-31, the procedure of Example 35 is repeated with the exception that instead of 2- (2, b-dimethylphenyl) -1-bromoethane, the corresponding is used. the resulting (substituted phenyl) -1-bromoalkane. .. Example 28. (2-Methylphenyl) ethylZ-imidazole, melting point of hydrochloride 179-183 ° C (from isopropyl alcohol).
    LN-NMR spectrum: 2.2 (s. ZN), 2.8 (s. 4H); 4.75 (s. 2H); 6.95. . (p. 1H); 7.0 (s. 4H); 8.45 (oo.) :
    Mass spectrum: 186 (75%); 185 (17), 171 (22); 157. (6); 142 (6), 115 (4); 105 (47) .; 104 (8); 103 (5); 95 (10); 91 (4); 82 (12), - 91 (100%) .:
    Example 29.. (3, -Meti Jfenil) -ethyle - imidazl, so pl. 78 81 ° C ;:
    H-NMR (HC1-salt) spectrum: 2, (s. 3H); 2.65 (s. 4H); 4.65. (P. 2H); 6.8 (m.5H), 8.45- (s. 1H),.
    Example 30. 4- 2- (2., 3D-Dimethyl-Phenyl) .- ethyl 3-imidazole, m.p. 146-148 C С 193-197 ° C in the form of hydrochloride ... .... g
    Spectrum n-NMR (HC1-salt): 2.0 (s. ZN); 2.05 (s. ZN); 2.75 (p. 4H), 4.7 (s. 2H); 6., 75 (p. GH) / 6.91 (p. 1H); 8.5 (s, 111).
    PRI me R 31. 4 (2,6-Di-; methylphenyl) - butyl-3-imidaeol, so pl. 154-162 ° C hydrochloride (from a mixture of ethyl acetate and isopropyl alcohol). ;.
    . Spectrum N-YMR (it is salt): 1.2. (m. 4H) ;. 1.9 (s. 6H); 2.2 (m. 4H), 4.6.5 (s. 2H); 6.55 (s. 4H); 8.4 (s. 1H). , C-NMR spectrum (ne-salt): 20., 33 (KB); 24.67 (f); 28.29 (t) / 29.00 (t); 29.77 (t); 115; 37 (d) / 126.21 (d), 128.73. (e) / 133.59 (d), 134.30 (s); 136.52 (s); 139.80 (s).
    In Examples 32 and 39, the procedure of Example 1 is repeated, except that the corresponding (substituted phenyl) -1-bromoalkane is used instead of 2- (2b-dimethylphenyl) -1-bromoethane and 5-methyl-4- is used instead of 4-imidazolaldehyde. imidazolaldehyde.
    Example 32. 4-t2- (2, -Dimethylphenyl) -l-oxyethyl3 -5-methylimide 3 ol, so pl. gi drohl ori 169-170 C.
    PRI me R 33. (3,4-dimethylphenyl) -1-hydroxyethyl-5-methi imidazole, mp. hydrochloride 161-163 ° C.
    The antihypertensive properties of imidazole derivatives were determined using the following procedure. :. .
    First anesthetized with urethane lynx Spregyu-Dowley normal. weight. After that, the femoral arteia was connected with a polyethylene tube with a KpioBHHoro pressure transducer. The test substance was then injected into the femoral vein and the blood pressure and frequency of the pulse were recorded with the help of a recorder. . .
    In further trials, anti-hypertonic properties were used to self-test spontaneously hypertonic Wistar rats (SGK). the test derivative was administered orally / the stomach with the help of a tube; Blood pressure was measured from needles; one using indirect bloodless
    ..method;.:., /: ... .-; ..;. -.
    In the experiment, three-month spontaneously hypertonic rats were used to test the anti-hypertrophic properties: for 4 weeks. The test derivative was iodine daily for each rat with drinking water and blood pressure from the tail was measured by the standard electrical method. ,;
    In additional trials, the anti-apertonic effect was studied.
    on dogs. In these tests, individual doses were administered intravenously and blood pressure was measured intravenously and intraarterially.
    Activity. When p-blocking
    measured outside the body as follows.
    The atrium of the guinea pig was isolated and the inhibitory activity of the compound against the chronotropic action of the isolated atrium induced by isoprenaline was measured.
    Antimicrobial activity was determined outside the body according to
    with quantitative antimicrobial and antifungal activity using an agar diffusion method for the following standard organisms: StaphyloCOCCUS aureas, Streptoc-occus pyogenes, Escheric chla col i., Proteus mirabilis, Pseudomonas aeruginosus, Candida albicans a Aspergitusis, Pseudomonas aeruginosus, Candida albicans Aperpergitis, Candida albicans and Aspergitusis, irabilisis, Pseudomonas aeruginosus, Candida albicans a Aspergitusis, irabilisis, Pseudomonas aeruginosus, Candida. .
    Antithrombotic activity
    investigated in the body of mice barely. blowing way.
    The compounds to be administered were administered orally, and then the arihidonic acid was administered intravenously. The inhibitory activity of the tested compounds against arachidonic acid-induced pulmonary thromboembolism was investigated. With additional testing, antirrhmbus activity was investigated outside the body. The inhibitory activity of the compounds against ADPy of collagen-induced platelet aggregation was measured. In this test, cow platelets were used. To 1.2 ml of plasma containing 50 thousand platelets, 1 mm; 50 µl of the compound solution to be tested was added. After 10 minutes
    incubations were added ADP or collagen. Platelet aggregation was determined by turbidimetry at h = 605 nm. Acute toxicity was determined using female NMRI mice.
    ; at the age of 7 months weighing 30-40 g. The test compound was administered intravenously. Thus, it was found during the study that the blood pressure of the anesthetized rats described was normal with a weight of 4-2- (2 (b-dimethylphenyl) ethyl-imidazole, having a value of I-D5 60 mg / kg intravenous , causes a recorded decrease in blood pressure at a dose of 30 µg / kg intravenously. At a dose of 1000 µg / kg, the intravenous decrease in blood pressure was quite distinct and at a dose of 300 µg / kg, an intravenous decrease in blood pressure was 20%. , with an average pulse rate decrease of 1 5%. The effect of this effect was at least 60 g-ssn (after this time the test was stopped). Since the LDgo value for intravenous administration for mice was 60 mg / Kg, it can be concluded that the therapeutic range of dosages ve-Sma wide. When the anti-hypertensive effect of the compound was measured on vigorous SGC rats, it was found that the decrease in blood pressure was about 15% at a dosage of 3 kg / kg orally (. p.) and 20%. doses of 5 mg / kg p.o, 1 h after administration. When testing antihypertensive properties for a 4-week period on spontaneously hypertonic rats, it was found that with a daily dose of 250 µg / kg p.o. a significant reduction in blood pressure is achieved. In toxicological experiments conducted at the same time, it was found that a daily dose of a compound of 10 mg / kg does not lead to any toxic symptoms. From these experiments, it can be concluded that the therapeutic limit of the dosages of this compound is very broad. . In addition, it was found that in the tests performed, the decrease in blood pressure was smooth and prolonged. In tests on dogs, an intravenous dosage of 30 µg / kg was found to result in a prolonged 20% decrease in blood pressure. 4- 2- (2-Methylphenyl) -ethyl: -imidazole, having a value of 50 mg / kg intravenously (di mice) / eases blood pressure by 25%, it was measured 1 h after a dose of 10 mg / kg p .about. The duration of this effect was prolonged for at least 6 h (after this time, the trial was stopped). For 1-t, 2- (2,6-dichlrrphenyl-ethyl) -imidazole with an LD5 value of 50 mg / kg intravenously for mice, a decrease in Blood pressure was 30% it was measured 30 minutes after a dose of O, 4 mg / kg intravenously. For 4-C3-2,6-dimethylphenyl) propyl-imidazole with mg / kg intravenously (for the following results were obtained. At a dosage of 100 µg / kg intravenously, a decrease in blood pressure was 13% after 30 minutes , at a dosage of 10 mg / kg, bp - 18%, 1 h after administration. The duration of affect was prolonged: in the latter case, it was more than 6 hours. (2, b-Dimethylphenyl) -butyl-imidazole with a value of 135 mg / kg intravenously (for mice, a decrease in blood pressure of about 10% at a dosage of 10 kg / kg bp (1 hour after administration) is provided. FOR (2-chlorophenyl) -oxyethyl-imidaeol with a mg / kg V value. U: Utterly (for mice), a decrease in pressure was 30%, which was measured 30 minutes after a 0.7 mg / kg dose was administered intravenously. 4-2-2,6-dimethylphenyl-oxyethyl imazole with mg / kg intravenous (for mice) a decrease in Blood pressure was 25%, which was measured 30 minutes after a dose of 0.1 mg / kg intravenously. 4-) 2- (2, 6 dichlorophenyl) -oxyethyl-imilazole with an LDjo value of 110 mg / kg intravenously (for mylium), a decrease in blood pressure was 30%, which was measured 1. h after administration any dose of 0.3 mg / kg intravenously. For a dose of 1 mg / kg intravenously, a decrease in blood pressure was 50%. For (2, 6-dimethylphenyl -1-oxo-ethyl-imidazole with an LDjjj value of 15.0 mg / kg intravenously (for mice), the blood pressure drop was 15%, which was measured 1 hour after the 20 mg / kg oral dose was administered orally 4- 2- (2f 3-Dimethylphenyl) -ethyl-imidazole, which has a value of 45 mg / kg intravenously (for M1), causes a decrease in blood pressure by 20%, which was measured 30 minutes after a dose of 1 mg / kg intravenously. 30 min after administration of 3 mg / kg intravenously. The pulse rate decreased by 20%. (2 6-Diethylphenyl) ethyl with LOfo value of .60 mg / kg of intravenous mice) There is a decrease in blood pressure, starting with doses of 0.03 0, 1 mg / kg intravenously. A 20% pressure drop was noted — blood over the chest, 30 minutes after a dose of 1-3 mg / kg intravenously. So, it was found that the trans-isomer (2, b-dimethylphenyl) -ethenyl -. -imidazole, having an LDog value of 50 kg / kg intravenously (for mice), when examining blood pressure on anesthetized rats, of normal weight, causes a distinct decrease in blood pressure at a dosage of 10 µg / kg intravenously. At a dose of 300 µg / kg, an intravenous decrease, the blood pressure was 20% and a decrease in the pulse rate of 24%. This effect was observed 20 minutes after administration. For 4-.2 (2.6 dichlorophenyl-) ethenyl-5-methylimidazole with a LijQ value of 100 mg / kg intravenously (for mice), a noticeable decrease in blood pressure was observed at a dose of 300 µg / kg intravenously, and a decrease in pulse rate for dose 1 mg / kg intravenously. A dose of 3 mg / kg intravenously leads to a 30% decrease in blood pressure, which is measured 20 minutes after administration. For 4-t3- (2,6-dimethylphenyl) -1-Propenyl 3 Imidazole with an LDjo value of 7.5 mg / kg intravenous (for mice) a dose of 1-3 mg / kg intravenously leads to a 20% decrease in blood pressure, as measured 20 minutes after administration. For 4-W- (2, 3-dimethylphenyl) -l-propenylJ-imidazole with a Yuuo value of 75 mg / kg intravenously (for mice) a dose of 0.3-1 mg / kg intravenously leads to a 20% decrease in pressure blood, which is measured 20 minutes after administration. Ll (2, b-dichlorophenyl) -zen.il2-imidazole with a value of 10 85 mg / kg intravenously (for mice) a decrease in blood pressure was .25% at the dose. 1 mg / kg intravenously. For the same dose, the bullet frequency was reduced by 30%. These measurements were made 20 minutes after administration. In the antimicrobial test, 4-2- (2, b-di-chloro-phenyl) -ethenyl-sol was active at a dose of 1000 mg / against all standard types of bacteria and fungi. 4- 2- (2-Chlorophenyl) -ethenyl-5-dazol with a value of 85 mg / kg intravenously (for mice) was active at a dose of 1000 μg / ml against all types of bacteria, but not against fungi. 4- 2- (2, b-Dichlorophenyl) -ethenyl 3-5-methyl imidazole was active at 1000 mg / ml cosa against all bacterial species and Candida aibi, but not against Aspergillus niger. (2 | 6-Dimethylphenyl) -1-pentenyl-imidazole with an LDjo value of 40 mg / kg intravenously (for mice it was active at a dose of 100 µg / ml against E. Coli U Staph a..urens. At a dose of 1000 µg / ml, it was active against all other types of bacteria and fungi; When tested (3 -blocks {4- {2-2 b-dichlorophenyl) -1-oxystil-5-methylimidazole activity at a concentration of 1 μg / mp, 68% - Inhibition of the chromotropic effect induced by HpM isoprenal and 59% inhibition of the inotropic effect induced by isoprenaline rm. This compound was p-selective. 75 mg / kg for the minor, When testing (3.-blocking activity of 4- 2- (2-chlorophenyl) -ethenyl-5-methylimidazole at a concentration of 1 μg / ml, a 67% inhibition of chronotropic effect occurs induced by isoprenaline. (2, 6-Dimethylphenyl) -1-pentenyl-imidazod causes 57% inhibition of the isroprenalin-induced hrrotropic effect at a concentration of 1 μg / ml When tested in the antithrombotic activity (in the body) (2--. -chlorophenyl) -ethenyl-5-methylimidazole protected 4 out of 5 mice from arachidonic acid-induced pulmonary thrommbrembism at a dosage of 10 mg / kg P.O. . . . In comparison with the test (outside the body), the anti-rrhythmic activity of 4- 3- (2, 3-dimethylphenyl) -1-propenyl-imidazrl. Inhibits completely the aggregation of platelets, induced by a colleague, and clearly inhibits the aggregation induced by ADF. For mice, the value is equal to 75 / kg When testing anti-thrombosis activity, each of the compounds (2 ib-dimethylphenyl} uethyl-5-methylimidazole, -4-2- (2, b-dichlorophenyl) -1-hydroxyethyl-5-methylimidazole and 4- (2- (2, b- diethylphenyl} -ethyl-imidazrel inhibits fully collagen-induced platelet aggregation and clearly inhibits the aggregation induced by ADP In the examples given, which show shifts in the H or C-NMR spectra, these spectra were recorded on a Brucker WB 80 OS instrument using as a standard tetramethylsilane or sodium salt of 3- (trimethylsilyl) -propanesulfonic oy, from these spectra were summarized in the table the chemical shifts presented (bmln. 131074 dg. The letters s, d., t. and m. iypo were used to designate a siglet, doublet, triplet, or multiplet, respectively. In the same link In addition, the number of hydrogen atoms is indicated. In some examples, coupling constants I (HZ) for protons typical for trans-cis isomers are given. Dp compounds indicated as bases were analyzed in deuterated methanol, deuterated acetone or deuterosolane chloroform, while the same elichiny to compounds mentioned as the hydrochlorides 0414, were analyzed in deuterium oxide., MS / determined for instrument-Pepkin ElmepRMl using straight entry system. The temperature used corresponded to the lowest temperature required to evaporate the compound as a base. In these examples, the strongest and most significant fragment ions, from the point of view of the structure, are given as m / e values. In parentheses are given the fragment intensity relative to the main peak.
    权利要求:
    Claims (1)
    [1]
    The method of obtaining imidazole derivatives of the general formula / -— χΛ 'And where · R h , P. 2 and R 5 can be the same or different and are hydrogen, chlorine, methyl /.
    R ^, - methyl /
    X is a group СО · or> СН-ОН, * h is an integer of 1-4 / or their salts, which differs with I in that imidazolaldehyde of the general formula
    N ι: N
    1, where HZ has the indicated meaning, is reacted with an aryl magnesium halide of the general formula
    Ri. · 'Wherein R 2 and Rg are as defined above and are halogen, with isolation of the desired product in the free form or in salt form.
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    同族专利:
    公开号 | 公开日
    NO810478L|1981-08-14|
    FI73415B|1987-06-30|
    US4333947A|1982-06-08|
    CA1167454A|1984-05-15|
    NO154089C|1986-07-16|
    AT2322T|1983-02-15|
    FI73415C|1987-10-09|
    JPH0215538B2|1990-04-12|
    DE3160905D1|1983-10-27|
    DK151627B|1987-12-21|
    DK151627C|1988-06-20|
    NO153455B|1985-12-16|
    US4684659A|1987-08-04|
    ZA81977B|1982-03-31|
    NZ196251A|1983-05-31|
    EP0034473A3|1981-11-18|
    GB2069481B|1983-07-27|
    IE810274L|1981-08-13|
    CA1160238A|1984-01-10|
    IE50772B1|1986-07-09|
    FI73416C|1987-10-09|
    DK57181A|1981-08-14|
    GB2069481A|1981-08-26|
    US4568686A|1986-02-04|
    FI73416B|1987-06-30|
    NO154089B|1986-04-07|
    AU6716381A|1981-08-20|
    IL62111A|1985-03-31|
    DD156260A1|1982-08-11|
    NO810479L|1981-08-14|
    AU537028B2|1984-05-31|
    DK157861C|1990-07-30|
    IE50771B1|1986-07-09|
    FI810389L|1981-08-14|
    EP0034474A1|1981-08-26|
    IL62110A|1986-01-31|
    NZ196250A|1983-06-17|
    NO153455C|1986-05-07|
    IE810275L|1981-08-13|
    DK57281A|1981-08-14|
    DE3160036D1|1983-03-03|
    EP0034473B1|1983-09-21|
    EP0034473A2|1981-08-26|
    JPS56128768A|1981-10-08|
    JPH0249308B2|1990-10-29|
    AT4709T|1983-10-15|
    AU6716481A|1981-08-20|
    DK157861B|1990-02-26|
    ZA81978B|1982-03-31|
    FI810250L|1981-08-14|
    AU528275B2|1983-04-21|
    EP0034474B1|1983-01-26|
    JPS56128767A|1981-10-08|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8004748A|GB2069481B|1980-02-13|1980-02-13|Substituted imidazole derivatives|
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