• 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:
    3-0-( beta -D-Glucuronopyranosyl)-soyasapogenol B represented by the formula (I): <IMAGE> (I) and salts thereof and process for preparing the same are disclosed. The compound represented by the formula (I) and salts thereof have anticomplementary activity and are useful as therapeutic agents for autoimmune diseases, collagen diseases, and rheumatic diseases.
    公开号:SU1190989A3
    申请号:SU802954186
    申请日:1980-07-31
    公开日:1985-11-07
    发明作者:Синохара Масанао；Накано Есимаса；Каисе Хироцугу；Изава Такетоси；Миязаки Васеи
    申请人:Оцука Фармасьютикал Ко.,Лтд (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a method for preparing a new derivative with sapogen la p; namely 3-D- (D-glucuronopyranosyl) -co sapogenol B of the formula OH CHg, OH with anti-complementary activity. The purpose of the invention is to develop a method for obtaining a new compound 3-0- (I-B-glucuronopyranosyl) -co sapo genol B, which has advantages in pharmacological activity over glycyrrhizin. Example 1. A. Co Saponin B (500 g) is dissolved in 30 ml of methanol. After adding 1.5 ml of 15N of sulfuric acid, the solution is heated under reflux for 3.5 hours. Cold water is added to the reaction mixture to form a precipitate which is collected and washed extensively with water. Pre-precipitates adsorb onto a silica gel pad and develop with a mixture of chloroform and ethanol alternately (20: 1 by volume 200 ml 10: 1 by volume 150 ml 5: 1 by volume 200 ml and 2: 1 by volume 200 ml) to obtain 71 mg 3-0- (6-0-methyl-B-p-glucuronopyranosyl) -co saponin B. The compound obtained is dissolved in 2 ml of methanol and 2 ml of 1N. an aqueous solution of sodium hydroxide is added to the first solution, followed by heating under reflux for 2 hours. Thereafter, the reaction mixture is mixed with cold water, the pH value is set to 1 with T n. aqueous solution of hydrochloric acid and extracted with n-butanol. The n-butanol fraction is concentrated to dryness under reduced pressure. By crystallizing the residue from a mixture of chloroform and acetone (in a ratio of 1: 1 by volume), 50 mg of 3-p- (B-glucuronopyranosyl) -co-sapogen-laV, m.p. 231-232 ° C (with decomp.). Calculated,%: C 68.11, H 9.21. Found:% C, 67.85; H, 9.08. Silica gel thin-layer chromatography using Kiesel GeBE (commercial name for Merck silica gel). 1. Chloroform-methanol-water (with a volume ratio of 65: 35: 8). R.j 0.38. 2. Isopropanol-2 n. ammonia water solution (with a volume ratio of 100: 15) R 0.21. Solubility: well soluble in methanol, ethanol, n-propanol, n-butanol, aqueous solutions of alkali, pyridine, dimethyl sulfoxide and dimethylformamide soluble in acetone, ethyl acetate and methyl ethyl ketone; slightly soluble in benzene, chloroform ,, - diethyl ether, n-hexane and petroleum ether. B. Co saponin B (500 mg) is dissolved in 30 ml of ethanol saturated with hydrogen chloride, and the solution is refluxed for 3 hours. Cold water is added to the reaction mixture to precipitate the precipitate, which is collected and washed with water . The residue is then purified on a silica gel column by the method of chromatography (eluent: mixture of chloroform and ethanol in a volume ratio of 20: 1.10: 1, 5: 1.2: O, and 75 mg of 3-0- (6-0-ethyl- B-glucuronopyranosyl) -co sapogenol B. The compound obtained is mixed with 2 ml of ethanol and 2 ml of 1N aqueous potassium hydroxide solution and the mixture is heated under reflux for 2 hours. The reaction mixture is mixed with cold water, set pH of about 1 with 1N aqueous hydrochloric acid, followed by extraction with n-butanol. n-butanol fraction and evaporated to dryness in vacuo and the residue crystallized from a mixture of chloroform and acetone (1: 1 by volume). 45 mg of 3-0- (0-B-glucuronopyranosyl) -co saponin B is obtained, mp 231-232 ° C (with decomposition). Example 2. Co saponin C (D g) is dissolved in 70 ml of distilled water. And the solution is mixed with 5 ml of a 15N aqueous hydrochloric acid solution, followed by refluxing in te3
    2.5 hours. The reaction mixture is extracted with n-butanol. The n-butanol fraction is evaporated to dryness under vacuum. The residue is adsorbed on a silica gel column and developed with a mixture of chloroform and ethanol (in a volume ratio of 20: 1, .10: 1, 5: 1, 2: 1). 350 mg of C-O-B-glucuronopyranosyl) -co saponin B are obtained, mp 231232C (decomposed). - Example 3. 3-0- (6-0-Methyl-B-glucuronopyranosyl) -co-sapogenol B (70 mg) is added to 2 ml of dioxane and 1, -5 ml of 15N H.N. 80 is added to the mixture. The resulting mixture is heated under reflux for 2.5 hours. The reaction mixture is extracted with ng-butanol and the n-butanol fraction is concentrated to dryness under reduced pressure .. The residue is adsorbed on a column of silica gel and developed with a mixture of chloroform-ethanol in sequence 20: 110: 1-5: 1-2: t (by volume) to obtain 24 mg of 3-0 - ((-B-glucuronopyranolysis) from sapogenol B, so pl. 231232 ° C. (with different).
    EXAMPLE 4 A solution of 1 g of saponin B in 70 ml of distilled water | Noah of water was sewn with 5 ml of aqueous jpacTBOpa, which contained 3.6 g of trifluoroacetic acid, and the mixture was heated under reflux for 2 hours. the mixture is extracted with n-butanol6m „. The n-butanol fraction 1 is concentrated to dryness under reduced pressure. The residue is adsorbed on a silica gel column. And: developed with chloroform-ethanol in the sequence 1-10: 1-5: 1-2: 1. (by volume) with dosage 175 mg 3-0 - (- EH glucuronopyranosyl) -co sapogenol B, so pl. 231-232С (with diff.). .
    Example 5. 3-0- (6-0-Methyl-p-D-glucuronopyranosyl) -co sapogenral B (70 mg) is added to 2 ml of water and 1.5 ml of concentrated 1 ml is added to the mixture. Noah acid. The resulting mixture is heated at 50 ° C. for 6 hours. The reaction mixture is extracted with n-butanol and the n-butanol fraction is concentrated to dryness under reduced pressure. The residue is adsorbed on silica gel in a "column" and is displayed with chloroform-ethanol in series with (20: 1, 10: 1, 5: 1, 2: 1, by volume) to give 22 mg of 3-0- (
    909894
    -O-glucuronidase-tso sapogenol B, so pl. 231-232 0 (decomposition).
    Example 6. 3-0- (6-0-Methyl-fJ-D-glucuronopyranosyl) -co-sapogenol 5 V (70 kg) is added to 2 ml of dimethyl sulfoxide and 2 ml of 1N is added to the mixture. sodium hydroxide solution. The resulting mixture is heated at 110 ° C. for 2 hours. After mixing the reaction
    ) 0 mixture with cold water and adjusting the pH to 1 with 1 n. aqueous hydrochloric acid, the reaction mixture is extracted with n-butanol. and. the n-butanol fraction is concentrated to
    15 is dry under reduced pressure. The residue is adsorbed on a column of silica gel and is developed with a mixture of choroformethanol in series (20: 1, 10: 1.5: 1.2: 1 by volume) with
    2Q to obtain 3-0- (jb -D-glucuronopyran-zil) -co-sapogenol B, mp.231-232 C (decomposition).
    Example 7. 3-0- (6-0-Methyl- / -D-glucuronopyranosyl) -co sapogenol B
    25 (70 mg) was added to 2 ml of dimethylformamide, and 3 ml of 1N was added to the mixture. sodium bicarbonate. The resulting mixture is heated at 90 ° C for 3.5 hours. After mixing the reaction
    Blend the mixture with cold water and adjust the pH to 1 with 1 n. aqueous solution of hydrochloric acid, the reaction mixture is extracted with n-butanol and the n-butanol fraction
    , dry up under reduced pressure. The residue was adsorbed on a silica gel column and developed with chloroform-ethanod in a series of formulations (20: 1, 10: 1, 5: 1, 2: 1 by volume) to give 27 mg of 3-0- (D-B-hl okuronpyranosyl ) -co-sapogenol B, m.p. 231-232С (decomposition.
    Example 3-0- (6-0-Methyl / 1-D-glucuronopyranosyl) -co sapogenol
    5 V (70 mg) was added to 2. ml of tetrahydrofuran, and 45 ml of 1N was added to the mixture. potassium carbonate. The resulting mixture is boiled under reflux for 1 hour. After the mixture has been stirred, the mixture is cold.
    water and bring the pH to 1. . using 1 n. aqueous solution of hydrochloric acid, the reaction mixture is extracted with n-butanol and the 5 n-butanol fraction is concentrated to dryness under reduced pressure. The residue is adsorbed on a column of silica gel and developed with a mixture of chloroform-ethanol in series (20 -: 1, 10-: 1, 5: 1, 2: 1 by volume) to obtain 19 mg 3-0 - (/ -B -glucuronapyranosyl-co-sapogenol B, having a melting point of 231 2-32 ° C (decomposition). . . Offered, I have. anti-blocking activity and are used as therapeutic agents for autoimmune diseases. . . . Pharmacological testing. Test compounds: A. ZgO-f-B-glucuronopyranosyl) -co sapogenol-8. B. Glycyrrhysin (compound for comparison) ... . Anti-complementary activity. The tests are as follows, Into a test tube. load 0.5m of water dispersion of each of the tested compounds, O, 5 ml of sensitized red blood cells (SE), but this culture contained 1x10 cells / ml, 1 ml of five-fold diluted Veronal buffer solution containing isotonic gelatin (This 5 -An times the dilution solution for clarity is named ЖВБ) and 0.5 ml of serum complement (guinea pig complement) diluted with T50 raz-HPD. The mixture is held at 37 ° C for 60 minutes. Then 5 ml of ice-cold saline was added to it and the mixture was centrifuged. The spectral absorption capacity of the separated upper layer was determined at, and the degree of inhibition of hemolysis of sensitized erythrocytes by the test compounds was measured. 50% of the value of inhibitory hemolysis activity (V / ml), from the proposed method proposed, is shown in Table. 1 for each compound tested. Acute toxicity. Acute toxicity (LDS, mg / kg body weight) of the tested compounds was determined in mice with intratubular peritoneum. nominal administration in the case of compound A and intravenous administration of compound B. The results are shown in Table. 1. Table 1 As can be seen from the results presented .x. at. tab. .1, the acute toxicity value (LDur) of the proposed compound of this order is that which allows its use as a therapeutic agent. Therapeutic effect on nephrotoxin, causing nephritis. Nephrotoxin rats (for short, NT) were prepared as follows. Kara adrenal glands of a rat are uniformly mixed with an equal amount of saline. The homogenized mixture was mixed with the full Freund's stimulus (Difco product) in a 1: 1, 2 volume ratio. ml of the resulting mixture was intramuscularly injected into a rabbit (weighing 3100 g) to immunize a rabbit. After a month and a half; they took blood from the rabbit's heart and got it short. The resulting serum was inactivated at -56 ° C for 30 minutes, then salted with 40% saturated ammonium sulphate aqueous solution and fractionated. Fractions of Y-globulin (IU-H) were collected to obtain NF. The evaluation of the therapeutic effect was performed on male Wistar rats with a body weight of 150-160 g with three replications for each test -. compounds. The test compound was administered intraperitoneally once a day for 7 days. One hour after administration of the test compound, NT (nephrotoxin) was administered on day 3. NT was injected intravenously. in the amount of 1 ml. into the tail vein of each rat. Physiological salt solution was used in the control group .-; . The level of proteinuria (the total amount of urine excreted. During the 24-hour period) was measured by protein opacification using bovine serum albumin.
    as a reference, with sulfosalicylic acid.
    The results are presented in Table. 2
    g
    table 2
    Average value
    The proposed connection is.
    (3 mg / body)
    The day number is counted from the time of administration of the test compound, which occurs one hour before the administration of nephrotoxin.
    The proteinuria level of healthy rats ranges from 0.5-5 mg / day. If the level of proteinuria exceeds these limits, especially if the level of proteinuria is above 10 mg / day, then it is safe to say that nephritis occurs. As you can see from the results, Table. 2, nephritis was found in the control group, and in the case of the application of the proposed compounds tested, the level of proteinuria from the time of administration of nephrotoxin up to 10 days after the administration is substantially the same as in healthy rats. Thus, the introduction of the proposed compounds inhibits primary and secondary immune responses.
    Therapeutic action in jade Heiman.
    In the experiment, the Wister rats of males weighing 180–200 g were used. The bark was extracted over 23
    20
    33
    1.2
    0.9
    7
    2.9 1.8
    13 2.7
    9 1.1
    renal rats and homogenized with an equal amount of saline by volume. The homogenate was centrifuged at 1500 for 1 hour. The upper layer of the liquid was purified by a known method and mixed with the Complete Freund stimulator 37. Ra (manufactured by Difco in a ratio of 0.4: 1 by volume.
    The resulting mixture was intraperitoneally injected with isological rats in the amount of 0.5 mg per rat. Then the same amount of the mixture was injected every two weeks up. until the proteinuria reached a level greater than 100 mg per day. The period was 6-8 weeks.
    Each of the test compounds was intraperitoneally administered to rats suffering from Heiman nephritis (weighing 300,350 g) once a day for 7 days and then the level of proteinuria (mg / day) was measured by the method described. Saline was used for control. The results are presented in Table. 3
    The level of proteinuria, mg / day
    Indicators
    one
    132
    127
    121 105
    135,117
    129
    116
    Table 3
    21
    14
    126
    135
    114 103 109 105 109 132 121
    122
    119
    109
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING 3-0 - (/ 3-0-GLUCURONPYRANOSYL) -SOYASAPOGENOL IN FORMULA I characterized in that the compound of the formula
    BUT OH where R is C ^ -Cg alkyl, hydrolyzed at 50-110 ° C for
    1-6 hours and the compound of formula I is isolated from / hydrolyzate.
    09) SLJ (ί »1190989>
    类似技术:
    公开号 | 公开日 | 专利标题
    LINDSTEDT1957|The Turnover of Cholic Acid in Man.* Bile Acids and Steroids 51.
    Peterson et al.1955|The physiological disposition and metabolic fate of hydrocortisone in man
    SU1190989A3|1985-11-07|Method of producing 3-0-| soyasapogenol b
    Ochs et al.1977|Reversal of advanced digitoxin toxicity and modification of pharmacokinetics by specific antibodies and Fab fragments
    Pruitt et al.1973|Disposition of diazoxide in children
    Loeb et al.1971|Incorporation of l-leucine-14 C into immunoglobulins by jejunal biopsies of patients with celiac sprue and other gastrointestinal diseases
    Hellström et al.1962|Turnover of deoxycholic acid in the rabbit
    Bendich et al.1947|Immunochemical Studies on Blood Groups. V. Further Characterization of Blood Group A and O Substances from Individual Hog Stomachs1a
    NORMAN et al.1973|Excretion of bile acids in extrahepatic biliary atresia and intrahepatic cholestasis of infancy
    PT89120B|1993-04-30|PROCESS FOR THE PREPARATION OF NEW SUBSTITUTED 2-PIPERAZINYL-2-OXO-ETHYLENE FLAVONOID DERIVATIVES
    US4530934A|1985-07-23|Pharmaceutically active ursolic acid derivative
    ROSEMBERG et al.1960|The effects of progressive reduction of sodium intake on adrenal steroid excretion and electrolyte balance in a case of congenital adrenal hyperplasia of the saltlosing type
    Bourke et al.1965|Mechanisms of renal excretion of urobilinogen.
    RAY et al.1950|COMPOUNDS FOR CANCER RESEARCH. V. RADIOACTIVE SULFONAMIDES1
    Wu et al.1988|Nicotinamide as a rapid-acting inhibitor of renal brush-border phosphate transport
    WO1989003836A1|1989-05-05|Factors associated with essential hypertension
    JP4178584B2|2008-11-12|Antiallergic agent
    Heatley et al.1960|Some experiments on intrinsic factor
    Sisenwine et al.1975|The presence of dl-, d-and l-norgestrel and their metabolites in the plasma of women
    SE445646B|1986-07-07|SOYASAPOGENOL B-ASSOCIATION FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS WITH ANTI-COMPLEMENTS OR ANTINE-FRITIC ACTIVITIES AND COMPOSITIONS THEREOF
    Dickinson et al.1993|Studies on the renal excretion of the acyl glucuronide, phenolic glucuronide and sulphate conjugates of diflunisal.
    Krönig et al.1972|A case of severe repeated immunological reactions to intermittent rifampicin treatment
    US6130211A|2000-10-10|Phosphocholinate cardenolides
    SJÖQUIST et al.1991|Pharmacokinetics of Salazosulfapyridine |: Pharmacokinetics of SASP after a single intravenous or oral administration in the dog.
    Muggleton et al.1959|Absorption, metabolism and elimination of pempidine in the rat
    同族专利:
    公开号 | 公开日
    AU527201B2|1983-02-24|
    AU4499579A|1979-10-04|
    NO154584C|1986-11-05|
    FI67559C|1985-04-10|
    DK126679A|1979-10-01|
    GB2020290A|1979-11-14|
    NO790994L|1979-10-02|
    ES478874A1|1980-10-01|
    CA1128498A|1982-07-27|
    SU1074408A3|1984-02-15|
    NL7902449A|1979-10-02|
    FR2421179B1|1983-03-18|
    PH16275A|1983-08-26|
    DK162102B|1991-09-16|
    ES8102148A1|1981-01-16|
    MX6305E|1985-03-29|
    IT7948551D0|1979-03-30|
    AR227624A1|1982-11-30|
    DE2911353C2|1987-10-29|
    NO154584B|1986-07-28|
    PT69423A|1979-04-01|
    DK162102C|1992-02-24|
    JPS54130551A|1979-10-09|
    BE875105A|1979-09-26|
    ZA791061B|1980-03-26|
    FI791011A|1979-10-01|
    SE7902866L|1979-10-16|
    JPS5822120B2|1983-05-06|
    SE434269B|1984-07-16|
    GB2020290B|1982-10-27|
    ATA236079A|1982-05-15|
    FI67559B|1984-12-31|
    US4217345A|1980-08-12|
    AT369426B|1982-12-27|
    FR2421179A1|1979-10-26|
    DE2911353A1|1979-10-11|
    ES487982A0|1981-01-16|
    IT1126812B|1986-05-21|
    BE875106A|1979-09-26|
    CH640868A5|1984-01-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPS578115B2|1976-11-16|1982-02-15|
    JPS6236008B2|1977-02-04|1987-08-05|Otsuka Pharma Co Ltd|
    AU528415B2|1978-03-31|1983-04-28|Otsuka Pharmaceutical Co., Ltd.|Anticomplementary agents|AU528415B2|1978-03-31|1983-04-28|Otsuka Pharmaceutical Co., Ltd.|Anticomplementary agents|
    DE3040246C2|1979-10-29|1985-01-10|Osaka Chemical Laboratory Co., Ltd., Osaka|Soy Saponins A &darr; 1 &darr; and A? 2? and their use|
    JPH0621072B2|1986-11-12|1994-03-23|呉羽化学工業株式会社|Immunomodulator consisting of estradiol derivative|
    US6784159B2|2000-09-29|2004-08-31|Her Majesty The Queen In Right Of Canada, As Represented By The Minister Of Agriculture|Triterpene saponins from soybeans for treating kidney disease|
    EP1422509A1|2002-11-01|2004-05-26|Streck Laboratories, Inc.|Lysing Reagent and Method of Lysing Red Blood Cells for Hematology|
    JP4960096B2|2003-09-22|2012-06-27|ペントラコールゲゼルシャフトミットベシュレンクテルハフツング|Use of compounds that reduce the biological effects of IL-6|
    US20070141121A1|2005-12-20|2007-06-21|Calton Gary J|Method of treating kidney disease|
    KR20140037107A|2011-06-28|2014-03-26|제이-오일 밀스, 인코포레이티드|Soyasapogenol composition|
    CN106589043B|2015-10-16|2019-02-26|复旦大学|Aryl substituted acryl triterpene compound is preparing the purposes in anticomplement medicament|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP53038536A|JPS5822120B2|1978-03-31|1978-03-31|
    [返回顶部]