• 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:
    Hydantoin derivatives, of formula: a process for the preparation thereof and pharmaceutical compositions containing the derivatives as active ingredients, particularly remedies for treatment of dieseases caused by stress.
    公开号:SU847916A3
    申请号:SU782650052
    申请日:1978-08-16
    公开日:1981-07-15
    发明作者:Кониси Дзин-Емон
    申请人:Ниппон Зоки Фармасьютикал Ко,Лтд (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new hydantoin derivatives of the formula x-. 0 NH. Where at least one of the radicals R, R and Ro means a group other than hydrogen and may be the same or different and means hydrogen, halogen, alkyl group, oxyalkyl group, haloalkyl group or group of the formula OR ,, where R means hydrogen, saturated or an unsaturated straight or branched chain aliphatic hydrocarbon group, an aralkyl group or an alkali metal atom, and X is an alkyl group, a thienyl group or a group of the general formula
    R-f
    v.L
    where R, Rj, Rrt and X have the indicated meanings, with cyanide and ammonium carbonate, ammonium bicarbonate or their mixture, with the release of the target
    30 where, RS & which may or may not be the same or different, mean hydrogen, halogen, alkyl group, oxyalkyl group, haloalkyl group or group of the formula ORy (and Ry has the same meaning then vrykie) or their salts having biological activity. The known method of hydantoin cycle formation is the interaction of ketones with potassium cyanide and ammonium carbonate at 40–200 ° C. 1. The purpose of the invention is to synthesize new hydantonic derivatives with biological activity. The goal is achieved by the method of obtaining hydantoin derivatives by reacting a compound of the general formula
    product in its free form, if necessary, by dealkylation, or by dearylation, or by incorporation as a salt.
    These cyanides and ammonium compounds are generally used in excess as compared with ketones.
    The solvent can be used, for example, methanol, ethanol, propanol, ethyl acetate, dioxane, morpholine, formamide, acetamide or dimethylformamide. You can also use a mixture of solvents with water or aqueous solvents.
    The heating temperature is usually 40–20 (I and the heating time is 1–100 h. The temperature and time can be adjusted according to the initial materials and solvent.
    The dealkylation reaction can be carried out in a relatively short period of time, for example, by reacting the compound with anhydrous aluminum chloride in a substantially anhydrous solvent, such as benzene or toluene.
    The aralkylating reaction can be carried out by contacting the compound with hydrogen in the presence of a catalyst. For example, the reaction can be carried out by allowing the compound to absorb hydrogen gas in the presence of palladium on carbon in a solvent such as dioxane or the like.
    The compounds of the invention can be isolated or purified by known methods. The desired product can be obtained by repeated precipitation and / or recrystallization using a suitable solvent. In addition, non-bleaching treatments, such as discoloration, can be carried out. Compounds thus obtained can be identified by measuring melting points, IR analysis, elemental analysis, and the like.
    Example 1 2.0 g of 2- (4-hydroxybenzoyl) -thiophene is heated together with 5.3 g of potassium cyanide, 17.1 g of ammonium carbonate, 20 ml of formaldehyde and 10 ml of water in a stainless steel bomb with periodic stirring at 120 ° C within 72 hours. The reaction liquid is acidified to pH 4 with concentrated hydrochloric acid, and mixed with water to obtain precipitates. The precipitates obtained in this way are filtered with water, filtered and extracted with ethanol while they are hot. Extract is heated
    under reflux with a small amount of activated carbon, filtered while hot, and then cooled to obtain 2.0 g of 5- (4-hydroxyphenyl) -5- (2-thienyl) -hydanthion as white crystals.
    Example 2. 55.3 g of 3-chloro-4, 4-dimethoxybenzophenone, 65.1 g of potassium cyanide, 96 g of ammonium carbonate and 94.8 g of ammonium bicarbonate are loaded into an autoclave together with 500 ml of formamide and 100 ml of water and the whole mixture is heated with stirring at 120 ° C for 48 hours. The reaction liquid is acidified with concentrated hydrochloric acid, mixed with water and left to stand in a cold place overnight. The precipitates thus obtained are washed with water and filtered. The filter residue is dissolved in 80% ethanol water with heating, decolorized with activated carbon and recrystallized from ethanol-chloroform to obtain 40.0 g of white crystals of 5- (3-chloro-4-methoxyphenyl) -5- (4-methoxyphenyl ) -hydantoin.
    Example 3. 34.5 g of 4,4-dimethoxy-3-methylbenzophenone, 66.7 g of potassium cyanide and 232.2 g of ammonium bicarbonate are heated with stirring to 120 ° C together with 500 ml of formalin and 100 ml of water in an autoclave. After 72 hours, the reaction liquid was acidified with concentrated hydrochloric acid, mixed with water and left to stand overnight. The precipitate thus obtained is filtered off. The precipitate is dissolved in acetone, decolorized with activated carbon when heated and recrystallized from hexane-acetone to obtain 22.7 g of white crystals of 5- (4-methoxy-3-methylphenyl) -5- (4-methoxyphenyl) -hydantoin
    Example 4. 100 g of 4,4-dioxybenzophenone, 152.1 g of potassium cyanide and 426.3 g of ammonium carbonate are heated with stirring to 750 ml of formamide and 150 ml of water in an autoclave for 48 hours.
    The reaction mixture is acidified with concentrated hydrochloric acid, mixed with water and left to stand overnight. The precipitate thus obtained is filtered off. The precipitate is decolorized with activated carbon and recrystallized from 50% methanol to obtain 111.4 g of white crystals of 5,5-bis (4-hydroxyphenyl) -hydantoin.
    Examples 5-28. The compounds are prepared according to examples 1-4.
    The compounds of Examples 1-28 are listed in Table. one.
    Table
    - {3,4,5-trimethoxyphenyl) -hydantoin 130-133 72.2 For example 29. 11.0 g of 5,5-bis {2-benzylphenyl) -hydantoin (Example L2) is reduced in 150 ml of diox rta in the presence of 2 g of palladium-CARBON catalyst in an autoclave at a hydrogen pressure of E.kg / cm at room temperature. After uptake of hydrogen is complete, the entire mixture is heated at 80 ° C and a hydrogen pressure of 10 kg / cm for 5 hours. The reaction liquid is filtered to remove the catalyst and concentrated under reduced pressure, and the resulting precipitate is filtered off. The product is recrystallized from cmcetic acetone-chloroform to obtain 3.4 g of 5,5-bis (2-hydroxyphenyl) -hydantoin in the form of white crystals. Example 30. 9.8 g of 5- (4-methyroxy-3-methylphenyl) -5- (4-methoxyphenyl) -hydanthion (Example 3) are suspended in 600 ml of toluene. Received
    Continued table. 1, the suspension was mixed with 40.0 g of anhydrous aluminum chloride, heated to and stirred for 3 hours. The reaction liquid was allowed to cool and poured into a mixture of dilute hydrochloric acid and ice, and then diluted with benzene. The resulting residue is washed and dissolved in methanol. The solution is heated with activated carbon and filtered while hot. The filtrate is mixed with water and allowed to stand in a cold place, resulting in the precipitation of 5- (4-hydroxy-3-methylphenyl) -5- (4-hydroxyphenyl) -hydantoin as white granular crystals. The crystals are filtered and dried. Output 7.5 g. Pry 31-36. Compounds were prepared as described in Example 30. The compounds of Examples 29-36 are listed in Table. 2. Table 2
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining hydantoin derivatives of general formula 1
    where at least one of the radicals R, Rj and K „means a group other than hydrogen and may be the same or different. And means hydrogen, halogen, alkyl group, oxyalkyl, haloalkyl. a group or group of the formula ORy, where Ry is hydrogen, a saturated or unsaturated aliphatic hydrocarbon group with a straight or branched chain, an aralkyl group or an alkali metal atom, X is an alkyl group, a thienyl group or a group of the general formula II
    R
    AT,/
    where R, R 5 and R, which may be the same or different and denote hydrogen, halogen, alkyl group, oxyalkyl group, haloalkyl group or a group of the formula
    OR, where R has the indicated meanings, or their salts, characterized in that the Compound of general formula III
    where R, R ,,
    R and X have the indicated
    values, subjected to interaction with cyanide and ammonium carbonate, ammonium bicarbonate or their mixture, with the selection of the target product in a free form, or, if necessary, dealkylation or dearalkylation or isolation as a salt.
    Information sources,
    taken into account during the examination 1. R. Elderfield. Heterocyclic compounds. M., I.L., 1961, Vol. 5, p. 204.
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    同族专利:
    公开号 | 公开日
    AU520592B2|1982-02-11|
    US4281009A|1981-07-28|
    EP0006407B1|1984-05-16|
    DE2862404D1|1984-06-20|
    JPS554305A|1980-01-12|
    JPS6121471B2|1986-05-27|
    CA1122602A|1982-04-27|
    EP0006407A1|1980-01-09|
    AU4020078A|1980-04-03|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2409755A|1946-10-22|Method for obtaining s |
    CH174461A|1934-10-30|1935-01-15|Chem Ind Basel|Process for the preparation of a hydantoin.|
    GB644800A|1940-09-09|1950-10-18|Parke Davis & Co|Method for obtaining hydantoins|
    US2366221A|1942-03-13|1945-01-02|James J Spurlock|5-substituted-5- hydantoins|
    US2711413A|1952-11-19|1955-06-21|Indiana University Foundation|5-phenyl-5-hydantoin and salts thereof|
    DE1017172B|1956-05-19|1957-10-10|Heyden Chem Fab|Process for the preparation of 5- -5-ethylhydantoin or its 3-methyl- and 3-oxymethyl-substituted derivatives|
    DE1135915B|1961-06-29|1962-09-06|Asta Werke Ag Chem Fab|Process for the production of new, anticonvulsant spirohydantoins|
    FR5885M|1966-09-23|1968-03-18|
    US3577520A|1969-12-19|1971-05-04|Emile Constantin Savini|Dentifrice compositions containing 5,5-diaryl - 2,4 -imidazolidinediones and process of treating pyorrhea|
    CH587903A5|1973-05-07|1977-05-13|Ciba Geigy Ag|
    JPS6021151A|1983-07-15|1985-02-02|Nisshin Steel Co Ltd|Continuous casting device for thin plate|US4672101A|1985-09-09|1987-06-09|The Dow Chemical Company|Polyepoxy aromatic hydantoins|
    DE3643403A1|1986-12-19|1988-06-30|Shell Agrar Gmbh & Co Kg|BENZOPHENONE AND METHOD FOR THE PRODUCTION THEREOF|
    JPH05262654A|1992-03-18|1993-10-12|Kaken Pharmaceut Co Ltd|Chronic fatigue syndrome therapeutica agent|
    AU754989B2|1998-11-16|2002-11-28|Nippon Zoki Pharmaceutical Co., Ltd.|A therapeutic agent for intractable vasculitis|
    JP4711523B2|2001-02-13|2011-06-29|日本臓器製薬株式会社|Hypoalbuminemia improving agent|
    TWI353979B|2002-04-10|2011-12-11|Nippon Zoki Pharmaceutical Co|Novel crystal form of 5-hydroxy-1-methylhydantoin|
    CN1659136A|2002-04-18|2005-08-24|弗吉尼亚大学专利基金会|Novel sodium channel blockers|
    US20060241163A1|2005-04-20|2006-10-26|Kaoru Okamoto|Optically active -hydantoin derivative|
    US20060241162A1|2005-04-20|2006-10-26|Kaoru Okamoto|Optically active -hydantoin derivative|
    US7326764B2|2005-05-20|2008-02-05|General Electric Company|Transparent compositions, methods for the preparation thereof, and articles derived therefrom|
    US7323536B2|2005-05-20|2008-01-29|General Electric Company|Transparent compositions, methods for the preparation thereof, and articles derived therefrom|
    US10202355B2|2013-02-12|2019-02-12|Buck Institute For Research On Aging|Hydantoins that modulate bace-mediated app processing|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP53071236A|JPS6121471B2|1978-06-13|1978-06-13|
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