• 专利附录
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  • 权利要求
  • 类似技术
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  • 优先权
    • 专利摘要:
    A process for the preparation of certain 5-substituted dialuric acids, compounds having utility as intermediates for the synthesis of certan hypoglycemic 5-substituted oxazolidine-2,4-diones.
    公开号:SU1080743A3
    申请号:SU813311948
    申请日:1981-07-27
    公开日:1984-03-15
    发明作者:Джозас Раджекас Фаустас；Фаган Холланд Геральд
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    one
    The definition refers to a method for preparing dialuric acid derivatives of the general formula
    ABOUT
    g.
    a radical, tin, a phenyl alkoxy group, or an OO group, and a y atom of sulfur or oxygen. These compounds can be used as intermediates for the preparation of 5-substituted oxazolidium-2-, 4-dioes with hypoglycemic activity. It is known that, under the action of lit; 1 organic compound on ketone, a tertiary alcohol is formed and J. It is also known that alloxan contains four carbonyl groups; groups. The aim of the invention is a new method for the preparation of new compounds of dialuric acid derivatives with a general formula. This goal is achieved by the fact that alloxan is reacted with the organolithium compound of the formula RLi, (II) (glucose in
    Clinically useful hypoglycemic agents show activity in this experiment. .
    Oxazolidin-2,4-dions are prescribed by mammals and hidat clinically for ingestion, either orally or perinterally. It is preferable to administer it orally, as it is more convenient and is prevented.
    1080743Z
    . where R has the indicated values, in an inert solvent at a temperature of from -70 ° to ambient temperature.
    As an inert solvent, a solvent is used in which an organolithium compound is formed, such as, for example, ethyl ether, isopropyl ether, tetrahydrofuran or dioxane.
    X 10.
    possible pain and irritation caused by injection. However, in the case where the patient cannot swallow medigam nt, or if after oral administration the absorption is impaired, as is the case with illness or other abnormalities, it is important that drugs are used for parenteral administration. Regardless of the method of administration, the dose is in precontrolled blood - (glucose in treated blood) (glucose in control blood) 5-substituted oxazolidin-2, -4 diones derived from dialuric acids are used for clinical use as antidiabatic agents. The hypoglycemic activity required for clinical use is determined by the glucose tolerance test procedure. Experimental animals used for these purposes are intact male albino rats. Experimental animals do not feed for about 18-24. The rats are weighed, numbered and divided into groups of five or six animals, as needed. Each group of animals is then administered intraperitoneally (intraperitoneally) a certain dose of glucose (one gram per kilogram) and orally give either water (control animals) or compound I (in an amount usually chosen from the range of 0.1-100 mg / kg) . In both groups, the control and the treated, the amount of glucose in the blood (mg / 100 ml) in the blood samples from the tail was measured over a period of 3 hours. Compared with the glucose content in the control and treated groups, after zero hours, The coefficient of blood glucose reduction after 0.5 h, 1 h, 1 and 3 h is as follows:
    It is approximately .0.10-50 mt / kg of body weight per subject daily, preferably about 0.10 to 10 mg / kg body weight per day, which is administered as a single dose or divided into several. However, the optimal dosage for each individual subject to treatment is determined by the person responsible for the treatment, usually at the beginning of treatment smaller doses are prescribed, and then the dose is gradually increased to determine the most appropriate dosage. It usually varies depending on the specific compound used and on the condition of the subject being treated.
    These compounds may be used in the form of pharmaceutical preparations containing the compound or a pharmaceutically acceptable acid salt thereof in combination with pharmaceutically acceptable carriers or diluents. Suitable pharmaceutically acceptable carriers include inert solid fillers and diluents in sterile aqueous or organic solutions. The active compound is present in such pharmaceutical compositions in amounts sufficient to produce the desired dosage amount in the described range. Thus, for oral administration, the compounds may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, analogous, pharmaceutical compositions may, if necessary, contain additional components, such as flavors, sweeteners : excipients and the like For the parenteral administration, the compounds can be combined with sterile aqueous or organic agents to form an injection. Curable solutions or suspensions. For example, solutions in sesame oil or peanut oil can be used, as well as aqueous solutions of water-soluble pharmaceutically acceptable additive salts of acids and these compounds. Injectable solutions prepared by this method can then be administered.
    intravenously, intraperitoneally, subcutaneously or intramuscularly, and it is preferable to administer humans intramuscularly intramuscularly.
    Example 1. 5-Oxy-5- (5-phenyl-2-furyl) -2,4,6 (1H, 3N, 5H) -pyrimidine trion.
    2-Phenylfuran (5.76 g, 4 mol.%) Is mixed with 100 ml of tetrahydrofuran and cooled until Butyllithium in hexane (2.3 M, 19.1 ml) is added dropwise over time while the temperature is maintained between. -20 and -30 ° C. The reaction mixture is allowed to warm to room temperature and then cooled again to -30 ° C. Freeze-dried alloxan (5.96 g, 42 mmol) in 40 ml of tetrahydrofuran was added over 5 minutes, while the temperature was again maintained at -20 and -30 ° C. The reaction mixture was again allowed to warm to room temperature, then cooled again it to 0 ° C, and 50 ml of 1N hydrochloric acid are added in portions over 2-3 minutes. The sharply cooled reaction mixture is extracted with 10 ml of ethyl acetate. The extract was filtered through anhydrous magnesium sulphate and evaporated to give 5-hydroxy-5- (5-fensh-12-furyl) -2,4,6- (1H, 3N, 5H) -pyrimidine (9.4 g gummy solid, Rf 0.75 (1: 1 mixture of hexane-ethyl acetate) 5% acetic acid) contaminated with starting material (Rf 0.45).
    It p and m e r 2. 5-hydroxy-5- (5-methyl2-furyl) -2,4,6 (1H, 3N, 5H) -pyrimidine trion.
    2-Methylfuran (3.28 g, 3.58 ml, 40 mmol) is mixed with 100 ml of tetrahydrofuran. The reaction mixture, purged with nitrogen, is cooled to -30 ° C and butylity (19.1 ml of a 2.3 M solution in hexane) is added over 10 minutes while maintaining the temperature at (-20) - (- 30) ° C. The reaction mixture is warmed to room temperature and then cooled again to -30 ° C. Sublimated alloxane (5.96 g) in 40 ml of tetrahydrofuranate is maintained dropwise at -20 -30 ° C over 10 minutes. The reaction mixture is warmed to room temperature, cooled.
    to 0 ° C, and 50 ml of 1N hydrochloric acid are added in portions while maintaining the temperature at 0-5 ° C. The reaction mixture is extracted with 100 ml of ethyl acetate. The extract is washed with 25 ml of water, filtered through an anhydrous magnesium sulfate sulphate and evaporated to give a solid 3-hydroxy-5- (5-methyl-2-furyl) 2, 4.6 (1H, 3N, 5H) -pyrimidine trione (6, 3 g, m / e 224). Example 3. 5-Oxy-5- (3-thienyl) -2,4,6 (1H, 3N, 5H) -pyrimidine. Isopropyl ether (40 ml) is cooled to .. For 10 minutes, butyl lithium in hexane (2.4 M, 10 ml, 24 mmol) is added while maintaining the temperature from -70 to -60 C. For 20 minutes 3-bromothiophene (1.9 ml, 20 mmol) was added while maintaining the temperature from -72 to -68 ° C. The mixture was stirred for an additional 30 minutes at (-72) - (- 70) ° C. Sublimated alloxane (3 g, 21 mmol) in 25 ml of tetrahydrofuran was added over 40 minutes while maintaining the temperature from -70 to -65 s. Stirring at this temperature is continued for 15 minutes. The cooling bath is removed and the reaction mixture is stirred for 1 hour at room temperature, then cooled to -5 ° C. Hydrochloric acid (1N.40 ml) is slowly added and the organic phase is separated. The aqueous phase is extracted with 35 ml of ethyl acetate. The combined organic phase / extract mixture is washed with 10 ml of water, dried over aqueous sodium sulfate and concentrated to give a solid 5-hydroxy-5- (3) 1 -2.4.6 (1H, 3N, 5H) pyrimvdin trione (1 , 41 g, 31%; m / e 226). PR and MER 4. 5- (3-Furyl -) - 5 Oxy-2, 4.6 (1H, 3N, 5H) -pyrimidine trion. To obtain 5, - (3-furyl) -5-hydroxy 2,4,6 (1H, 3N, 5H) -pyrimidine trione (1.62 g, oil m / e 210), the procedure of example 3 is used, but replacing 3-bromothiophene 3 bromofuran (2.94 g, 1.8 ml, 20 mmol). Example 5.5-Oxy-5- (5-methoxy-2-thiensh1) -2,4,6 (1B, 3N, 5H) -pyrimidine trion. 2-Methoxythiophene (2.3 g, 20 mmol is dissolved in 35 ml of ether. While cooling, butyl lithium in hexane (2.4 M, 9 ml, 21.6 mmol) is added dropwise over 15 nins, while 1 3 than the temperature while raising this addition to 35 C. The reaction mixture is moved for 1 hour at room temperature. While maintaining the temperature between -20 and -15 C, sublimated alloxan (3 g, 21 mmol) is added over 10 minutes in 20 ml of tetrahydrofuran. The mixture is warmed to room temperature, stirred for 0.5 h, cooled to 5 ° C and cooled sharply with added 35 ml of 1N hydrochloric acid Yorcia.The organic phase is separated and the aqueous phase is extracted with 25 ml of ethyl acetate. The combined organic phase and the extract is backwashed, concentrated to dryness and triturated with hexane to give a solid 5-hydroxy-5 ( 5-methoxy-2-thienyl) 2,4,6 (1H, 3N, 5H) -pyrimidine trione (1.4 g, m / e 256). Example 6. 5-Oxy-5 - / 5- (2phenyl-1 , 3-dioxolan-2-yl) 2-thienyl 7 2, 4.6 (1H, 3N, 5H) -pyrimidine trion. At room temperature, 2-phenyl-2-thienyl-1, 3-dioxolane (3.26 g, 15 mmol) is dissolved in 35 ml of ether. Butyl lithium in hexane (2.4 M, 6.25 ml, 15 mmol) is added dropwise over 15 minutes, while the temperature rises until the mixture is cooled. While keeping the temperature between -15 and for 10 minutes, sublimated alloxan (2.13 g, 15 mmol) in 20 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, cooled to 5 ° C, Reeco cooled 35 ml t n. hydrochloric acid, added in small portions, and extracted with 25 ml of ethyl acetate. The organic layer is subjected to backwash with 15 ml of water, the anhydrous sodium sulfate layer is filtered and evaporated to give 5-hydroxy5-5- (2-fench1-1.3, -dioxolan-2-yl) thienyl | -2, 4.6 (1H , 3N, 5H) -pyrimidine (oil, Rf 0.25) 1: 1 mixture of hexane, Pr and Mp 1. 2-Phenyl-2- (2-thienyl) -, 3-dioxolane. 2-Vienna miltiophene (19 g, 0.1 mmol), ethylene glycol (11 ml, 0.2 mmol), toluene (150 ml) and, p-toluenesulfonic acid (about 0.2 g) are mixed and heated under reflux for 6 h. The resulting by-product, water, is collected in a Dean-Stark trap. TLC (1: 8 ethyl acetate: hexane). This indicates that the reaction is about 40% complete. Ethyl glycol is added. (30 ml) and heating under reflux is continued for 35 hours. The reaction is still incomplete. The reaction mixture is diluted with 200 ml of ether, washed twice with 150 ml portions of water and concentrated to dryness. The residue is chromatographed on approximately 50 ml of silica gel using 1: 8 etipacetate: hexane mixture as an eluent and monitored by TLC. With more rapid advancement of the product through the column, fractions containing the product are collected and evaporated to give 2-phenyl- (2-thienyl) -1,3-dioxolane (8 g, oil, Rf 0.6 (1: 8 mixture of ethyl acetate: hexane) .
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING DERIVATIVES where
    DIALURIC ACID General Form X> ° NOL_ O
    R represents or
    -radical, ί
    where ζ - hydrogen, methyl, phenyl;
    C ^ -C ^ -alkoxy group, or C fc H s '0 Q group, y is sulfur or oxygen, S', available in that alloxane is reacted with a lithium-organic compound of the formula RLi, where R has the above meanings, in an inert solvent at temperatures from -70 ° C to ambient temperature.
    SU < n , 1080743
    1080 743 ϊ
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    同族专利:
    公开号 | 公开日
    GB2080802A|1982-02-10|
    LU83511A1|1982-02-17|
    ZA815130B|1982-07-28|
    US4454320A|1984-06-12|
    PL137143B1|1986-05-31|
    ATA328781A|1986-07-15|
    NZ197855A|1986-09-10|
    PT73438A|1981-08-01|
    SE8104541L|1982-01-29|
    YU185381A|1984-02-29|
    GR75288B|1984-07-13|
    HU184864B|1984-10-29|
    IL63425D0|1981-10-30|
    PT73438B|1983-06-28|
    FI812346L|1982-01-29|
    FR2487347B1|1985-03-29|
    DK334881A|1982-01-29|
    JPS6111950B2|1986-04-05|
    PH16218A|1983-08-09|
    IL63425A|1985-09-29|
    CA1149808A|1983-07-12|
    ES504320A0|1982-12-16|
    JPS5753470A|1982-03-30|
    DE3129294A1|1982-05-06|
    AU7343781A|1982-04-01|
    ES8301942A1|1982-12-16|
    KR850000096B1|1985-02-22|
    BE889760A|1982-01-27|
    FR2487347A1|1982-01-29|
    IT8123174D0|1981-07-27|
    IT1138463B|1986-09-17|
    KR830006234A|1983-09-20|
    CS221844B2|1983-04-29|
    PL232107A1|1982-03-15|
    GB2080802B|1984-02-15|
    AU525565B2|1982-11-11|
    NL8103537A|1982-02-16|
    DD201586A5|1983-07-27|
    NO812560L|1982-01-29|
    CH648024A5|1985-02-28|
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    法律状态:
    优先权:
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