• 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 heterocyclic compounds and, in particular, to the preparation of 4,5-dihydrooxazole derivatives of the formula @ where A-CH = CH- R 1 and R 3 - methyl R 2 - lower alkoxy, which can be used in medicine. The purpose of the invention is the detection of compounds that more actively influence the secretion of gastric juice. The preparation is carried out by the reaction of a substituted oxazolyl-1,3-dihydrobenzimidazole-2-thione with a substituted pyrimidine hydrochloride in the presence of at least two equivalents of a strong base in a lower alcohol medium, followed by oxidation of the resulting compound with an equivalent amount of peracid or hydrogen peroxide in acetic acid. The oxidation is preferably carried out with 3-chloroperbenzoic acid in chloroform at -25 ...- 10 ° C. 1 hp ff, 3 tab.
    公开号:SU1574177A3
    申请号:SU874203301
    申请日:1987-09-09
    公开日:1990-06-23
    发明作者:Биндер Дитер；Ровенски Франц；Петер Фербер Хуберт
    申请人:Хеми Линц Аг (Фирма)；
    IPC主号:
    专利说明:

    sd 1
    Ј
    sj
    The invention relates to oxazole derivatives, in particular, to a process for the preparation of new derivatives of 4,5-di-hydroxazoles of the general formula
    R,
    RlvVR
    f-CHa y
    at
    3d)
     where A is Fj, R3 is methyl;
     lower alkoxy, compounds of general Formula (I) cause blockade (H ++ K -adenosine triphosphoric acid and therefore can be used, for example, to treat or prevent stomach ulcers and duodenal ulcers and other diseases in medicine caused by (increased) gastric acid secretion.
    The purpose of the invention is to develop a method for producing new compounds having a higher activity affecting the secretion of gastric juice.
    The compounds can be used in a mixture with a suitable pharmaceutical, organic or inorganic carrier substance for intestinal or parenteral administration. For example, water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly and .P. Pharmaceutical preparations May exist in solid form, such as tablets, dragees, suppositories, capsules, or in liquid form, such as solutions, suspensions, or emulsions. If necessary, they are sterilized and / or contain auxiliary substances, such as preservatives, stabilizers or emulsifying agents, salts for changing the osmotic pressure or buffer solutions. They can also be prescribed in combination with other therapeutically valuable substances.
    I
    Example 1. 5- (4,5-Dihydro-2-oxazolyl}.-2-ChZ, 5-dimethyl-4-methoxy-2-pyridyl) methylthio - H-benzimidazole (formula (I), where A -, R, and R, CH3, P OCH3; 1C H; n 0).
    6.00 g (27.4 mmol) of 5- (4,5-dihydro-2-oxazolyl) -J, 3-dihydrobenzimidazol-2-thione (A -) and 6.08 g (27.4 mmol) of 2-chloromethyl-4-methoxy- -3.5 dimethylpyridine hydrochloride is suspended in 120 ml of methanol and 27.8 ml (55.6 mmol) of a 2N aqueous solution of NaOH are instilled within 12 min. The temperature rises to 30 ° C. The mixture is stirred at room temperature for another 3 hours, evaporated to dryness and the residue is taken up in 140 ml of water. The addition of glacial acetic acid is acidified to pH 4.5 and extracted three times with 200 ml of chloroform. The combined organic phases are dried over sodium sulfate with activated charcoal, filtered and evaporated. The residue is adjusted with acetonitrile, the crystals are sucked off and dried at 50 C / / 20 mbar. For further purification, the feathers are crystallized from acetone.
    The output of 5.6 g of yellowish crystals (55.5% of theory), so pl. 188-190 ° C (acetone). With HMSN40Z. The original substance is obtained as follows.
    4-Chloro-1J (2-Oxyethyl) -3-nitrobenzoic acid amide.
    64.4 g (0.319 mol) of 4-chloro-3-nitrobenzoic acid are kneaded in 400 ml of thionyl chloride and heated for 3 hours under reflux. It is then evaporated and the residue is dissolved in 300 ml of absolute methylene chloride. At 5 -10 ° C, this solution is instilled into a solution of 40.9 g (0.670 mol) of ethanolamine in 400 ml of absolute methylene chloride for 2 hours. Another 30 minutes is stirred, the precipitate is filtered off with suction, washed twice with 0. 10 ml of 0.25 n.NS and once with 100 ml of water and dried at 50 ° C / 20 mbar. The output of 83.1 g of light yellow crude product contains 1 mol of water of crystallization (99% of theory), so pl. 130-5 133 ° C (dioxane).
    Amide 4-chloro-K- (2-chloroethyl) -3-nitrobenzoic acid.
    101.0 g (0.385 mol) of 4-chloro-M- (2-hydroxyethyl) -3-nitrobenzoic acid amide are mixed in 450 ml of thionyl chloride in portions. The remaining 30 minutes is stirred at room temperature and then evaporated in vacuo.
    The output of 99.1 g of yellowish crystals 5 (98% of theory), so pl. 94-96 ° C (dioxane).

    five
    2- (4-Chloro-3-nitro-phenyl) -4,5-dihydrooxazole.
    99.0 g (0.376 mol) of 4-chloro-M- (2-chloroethyl) -3-nitrobenzoic acid amide are heated in 800 ml of ethanol with stirring to 70 ° C and 217 ml (0.434 mol) of 2N aqueous is added NaOH solution. Stir for another 30 minutes at 70 C. After that, evaporate and absorb the residue in water. Suction is washed with water and dried at 50 ° C / / 20 mbar.
    Output 74.2 g (87% of theory), so pl. 89-90 ° C (diisopropyl ether).
    2- (4-Amino-3-nitro-phenyl) -4,5-di-hydroxazole,
    10.0 g (44.1 mmol) of 2- (4-chloro-3- -nitrophenyl) -4,5-dihydrooxazole is heated in a steel autoclave in 60 ml of tert-butylamine 9 h to 1 25 C. Then evaporated in vacuo and note
    Sew dry, crushed into fine powder, residue in 20 ml of 85% o-Phosphoric acid at 80 ° C. Stir for 30 minutes at 80 ° C. Then it is cooled, diluted to 125 ml with ice water, covered with 15 ml of ethyl acetate, adjusted to a pH of 8 with ammonia and cooled under ice cooling. The mixture is vigorously stirred for 10 minutes and the precipitate is filtered off with suction. It is washed with water and a small amount of ethyl acetate and dried at 50 ° C / 20 mbar.
    The yield of 5.7 g of yellow crystals (62.3% of theory), so pl. 215-217 C
    (methanol).
    5- (4,5-Dihydro-2-cazolyl) -benzimidazol-2-thione.
    10.0 g (48.3 mmol) of 2- (4-amino-3- -nitrophenyl) -4,5-dihydrooxazole
    dissolved in 80 ml of dioxane and 400 ml of methanol, and in a medium-pressure apparatus for hydrogenation, hydrogenated using Rhen ' s 2 nickel to the calculated absorption of hydrogen at room temperature. The catalyst is sucked off through a filter aid and the filtrate is evaporated to dryness. The residue was dissolved in 500 ml of ethanol, 9.4 g (72.2 mmol) of sodium methylxanthate was added and heated at reflux for 3 hours. It is then evaporated in vacuo, the residue is taken up in 200 ml of water and dissolved by the addition of 13 ml of 2N. NaOH. Mix with 2 tablespoons of active carbon, mix for a short time and suck through the filter aid. The filtrate is acidified with glacial acetic acid to pH 4.5, the precipitated precipitate is sucked off and washed three times with water. Dry at 60 ° C / 20 mbar.
    The output of 7.4 g of brownish crystals (69.9% of theory), so pl. 265-268 ° С (partial decomposition from 200 ° С).
    Example 2. 5- (4,5-Dihydro-2-oxazolyl) 2- (3,5-dimethyl-4-methoxy-2-pyridyl) -methylsulfinyl -1H- -benzimidazole (Formula (I), where A -, R, and Rz - CHy, R2 - OCH3J B4 H, n - 1) (compound A).
    To a solution of 6.5 g (17.6 mmol) of 5- - (4,5-dihydro-2-oxazolyl) -2- Ј (3,5-dimethyl-4-methoxy-2-pyridyl) methyl-tis -1H-benzimidazole in 200 ml of chloroform. Instilled with stirring at -12 ...- 10 ° С a solution of 3.65 g (18.0 mmol) of 85% 3-chlorobenzoic acid in 65 ml of chloroform in
    0
    5 0 0
    five
    0
    five
    five
    776
    for 30 minutes The mixture was stirred for 1 v at -3 ° C and then extracted twice with a total of 40 ml of sodium bicarbonate solution. The aqueous phases are washed once with 50 ml of chloroform and the combined organic phases are dried over sodium sulfate with the addition of active carbon, filtered and evaporated. The residue is crystallized from ethanol and recrystallized from ethanol with the addition of active carbon.
    Yield 3.05 g of yellowish crystals (45.0% of theory), so pl. 112- 114 ° C with decomposition (ethanol).
    Biological activity is determined as follows.
    The effect of the dose on the secretion of gastric juice in rats with superimposed ligature on the pylorus (Pylorus ligatur).
    The substance is suspended in increasing doses in 0.5% aqueous solution of Tween 80 and orally administered to rats one hour before the ligature is applied to the pylorus. As a control, a 0.5% aqueous solution of Tween 80 serves. 4 hours after applying the ligature, the concentration and volume of gastric acid is determined, and the total amount of acid and EDSO are calculated from them (EDg-o is the concentration causing 50% inhibition of gastric juice secretion).
    The duration of inhibition of the secretion of gastric juice in rats with superimposed ligature on the pylorus.
    Comparison is carried out with 5 acetyl-1- (4- -methoxy-3,5-dimethyl-2-pyridyl) -methylsulfinylJ-3H-thieno (2,3, -q) -imidazole (compound B) . The ED50 for Compound A 340 mg / kg, and for Compound B 556 mg / kg, was administered orally to the rats 14 hours before the ligature was applied to the pylorus. Four hours after applying the ligature to the pylorus, the concentration and volume of gastric acid is determined, and the total amount of acid and the inhibition of the secretion of gastric juice are calculated.
    The effect of protecting cells.
    To determine the effect of the cells, test compounds to rats one hour after the administration of Compound A or B are administered orally 1 ml of 100% ethanol. After another hour, the animals were sacrificed and the area of the damaged gastric mucosa was measured.
    Determination of strong toxicity.
    To determine the latter, Compound A or B was orally administered to mice in separate doses of O (control) 1000, 2500 ml and 5000 mg / kg. Each dose is tested on 10 animals (in five males and 5 females). Twice a day, all animals are examined for death or signs of poisoning and after two weeks they are subjected to an autopsy.
    The results of the effect of the dose of Compound A and B on the secretion of gastric juice in rats are shown in Table 1. Table 2 shows the effect of compounds A and B on the secretion of gastric juice in rats with a ligature superimposed on the pylorus after 18 hours.
    The results of the study of the protective effect of Compounds A and B cells are presented in Table 3.
    The results of toxicological studies.
    For compound A:
    It was impossible to establish the LD50, because: during the test, not a single experimental animal died. The observation did not establish any difference in the behavior of the control group of animals and the Group of animals to which compound A. was given. No difference in food intake from the control group of animals. At the autopsy, it was not possible to detect signs of any pathological changes in the organs of dead animals.
    For compound B:
    The LD50 could not be established, because none of the experimental animals died during the tests. The observation did not reveal any difference in the behavior of the control group of animals and groups of animals that were given compound B. No difference in the reception of the letter from the control group of animals. At the autopsy, it was not possible to detect signs of any pathological changes in the organs of the killed animals.
    The inhibitory effect of omeprazole and substance A is determined on - ATPase and 1C50 is calculated
    Omeprazole 28.0
    Substance A 5.3
    Thus, the proposed method allows to obtain 4 55-dihydrooxazole derivatives with biological
    0
    activity affecting the secretion of gastric juice at an EDyo dose of 61 mg / kg (ED50 155 mg / kg for a known). In this case, the substances obtained by the proposed method delay the secretion of gastric acid after 18 hours, even up to 78% versus 13% for the known.
    I
    What concerns toxicological
    studies prior to their results did not indicate differences between compounds A and B. Both studied compounds are non-toxic. No deaths, no signs of poisoning were found.
    权利要求:
    Claims (2)
    [1]
    1. A method for preparing the 4,5-dihydrooxazoles of the general Formula.
    where A is ETCE - methyl j
    R2 is lower alkoxy,
    by reacting a compound of the general formula
    n i
    to
    No
    H
    where a has the specified value, with a compound of the general formula
    2 K.H.CHTS.HIch
    TY nx
    X-SNZ
    where X is chlorine,
     have the indicated value in the presence of at least two equivalents of a strong base in the environment of a lower alcohol, followed by oxidation of the obtained compound of the general Formula
    where A, have the indicated meanings,
    Note.
    Edg. for compound A it is 61 mg / kg; for compound B it is 155 mg / kg. Vol, - volume5 ml} KonZ - concentration, mlkE / l;
    GS - total acid, ml / 4 h,
    S - deviation from the standard
    N is the number of experimental animals.
    equivalent amount of hydrochloride or hydrogen peroxide in acetic acid.
    [2]
    2. The method according to claim 1, about aphid tea and with the fact that oxidation is carried out with 3-chloroperbenzoic acid in chloroform medium at -25 ...- 10 C.
    Table 1
    table 2
    Note. N
    LI
    the number of experimental animals;
    lesion index (indicates affected area).
    Editor O. Golovach
    Compiled by B. Odintsov
    Tehred M. Khodanich M. Samborska Proofreader
    Order 1649
    Circulation 318
    VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab. 4/5
    Production and Publishing Combine Patent, g, Uzhgorod, st. Gagarin, 101
    Subscription
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    法律状态:
    优先权:
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