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    • 专利摘要:
    PURPOSE:4,6-Dihydroxy-8-oxo-2,3,6,8-tetrahydrofuro [3,4-g] benzofurane-2-spiro-1'-(6,7-dihydroxy-2', 5', 5', 8a'-tetramethyl-1', 2', 3', 4', 4a', 5', 6', 7', 8', 8a'-decahydronaphthalene) of formula I.
    公开号:SU1056901A3
    申请号:SU802998453
    申请日:1980-10-28
    公开日:1983-11-23
    发明作者:Синохара Масано；Каисе Хироцугу；Накано Есимаса；Изава Такетоси；Осиро Ясуо；Миязаки Васеи
    申请人:Оцука Фармасьютикал Ко,Лтд (Фирма)；
    IPC主号:
    专利说明:

    which is a characteristic signal of lacto; a. The integral ratio of the first peak to the second is approximately 73:27. After 2 after dissolving, the peak at 9.89 ppm. slightly increases, the integral ratio of pico reaches approximately 70:30. Such an integral ratio is achieved 2 hours after dissolution, hardly changing after that. This result shows that the compound (Hb ;,) and the compound (Ib) are in an equilibrium mixture of 7: 3 in the indicated solvent. At. using methanol or pyridine as a solvent, such NMR-spectroscopic analysis does not lead to the conformation of the compound (), which is the tautomer of the compound (1b. |).
    Example 1: Dissolved 2.1. g of silver nitrate in 1 ml of water and add 3.5 ml of 5.8 M aqueous sodium hydroxide solution. The mixture is stirred at room temperature for 20 minutes. Then a solution of 1.0 g of 6.7-dioxy-2.5, 5.8 tetramethyl-1, 2, 3, 4, 4a, 5, 6., 7, 8, 8-decagidronaphalen-1-spiro-2 is added. (6, -7-diformyl-4-hydroxy-2, 3-dihydrobenzofuran) in 2 ml of ethanol. The reaction mixture is stirred at room temperature for 1.5 hours, the pH is adjusted to about 2 with 2N. hydrochloric acid. The reaction mixture is extracted. rut with the same amount of ethyl acetate, distill off the solvent from the extract under reduced pressure. The residue is purified by chromatography on a silica gel column (WaKo C-200 gel), the eluent is a mixture of chloroform-ethyl acetate acetic acid 100: 50: 2 (by volume). A fraction corresponding to Rf 0.37 is collected in thin layer chromatography using a mixture of ethyl acetate-chloroform-acetic acid in a 50: 50: 2 volume ratio as a developing agent, or a fraction corresponding to R 0.71 in thin layer chromatography using a mixture benzene-butanol acetic acid in a volume ratio of 60: 15: 1 as a developing agent. By evaporation of the solvent from the fraction, 700 mg of 4,6-dioxy-8-oxo-2,3, 6, 8-tetragndrofuro- (3,4-o) -benzofyran-2cbIpo-l .- (6, 7-dioxy-2 , 5, 5 | -8-tetramethyl-1, 4, 4a, 5, 6, 7, 8, 8a-decahydronaphthalene in the form of light yellow amorphous crystals.
    b. | w ° -44,8 ° /. C 0.9, methanol) Elemental analysis for C sNZoO. Calculated,% :: C 66.03; H 7.18.
    Found,%: b 65.93; H 7.21.
    () NMR analysis was performed using DM, OD (D55) as a solvent.
    (ii) NMR analysis was performed using pyridine d (Two) as a solvent.
    (iii) NMR analysis was performed 2 hours later and 63 hours after dissolution (NMR spectra after 2 hours and 63 hours after dissolution agreed with each other).
    Dimethyl sulfoxide is used as a solvent.
    The conditions for measuring the NMR spectrum are as follows:
    Spectral ...
    amplitude9-100 5G100 8 “DOO
    Filter, C0.10 / 1 0.4
    Pp power, Q0.05 0.05 0.05 Sweep time,
    min555
    1 irina sweep,
    million dollars 101010
    End sweep, ppm, .000
    I
    Example 2. Suspended 0.64 g of silver oxide in 1 n. aqueous solution of sodium hydroxide and 1.0 g of 6,7-dioxy2, 5, 5, 8a-tetramethyl-1, 2, 3, 4, 4a, 5, 6, 7, 8a are added with stirring at room temperature -decahydronaphLIN-1-SPIRO-2- (6, 7-diformyl-4oxy-2, 3-dihydrobenzofuran.a). The mixture is stirred at the same temperature for 1 hour and the precipitate is washed 5 times in 10 ml of water. The washings were combined with the filtrate and concentrated hydrochloric acid (36%) was added, adjusted to pH 2–3, followed by cooling to 0–10 ° C. The precipitated crystals are collected by filtration, washed 5 times with 10 ml of ice water and dried. : Dissolve the dry poroppo crystals in 50 ml of ethyl acetate ,. from; Separate the insoluble material by filtration. The fi ltrate is concentrated to a volume of 5 ml under reduced pressure. To a concentrated solution of surplus 50 Pg ligronin, the mixture is well stirred and allowed to cool to 0-10 ° C. The precipitated crystals were filtered off, washed twice with 20 m of hydronine and dried, yielding 0.01 g of 4,6-dioxy-8-sco-2, 3, 6, 8-tetrahydrofuro- (3, 4-0) -benzo- furan-2-, spiro-1- (6, 7-dioxy-2, 5, 5, 8a-tetramethyl-1, -2, 3, 4, 4-56, 7, 8, 8a-dakagidronaphthalene). The physicochemical properties of the complete compound are similar to those given in Example 1. Example 3. Dissolve 1.0 g of 6.7 dioxy-2, 5, 5, 8a-tetramethyl, 1, 2, 3, 4, 4a, 5, b, 7, 8, 8a-deca hydronaphthalen-1-spiro-2- (b, 7-diformyl-4-hydroxy-2, 3-dihydrobenzophen wound) in 50 ml of 10% aqueous sodium hydroxide solution and at that time skip After the solution was raised at 50 ° C, the solution was stirred for 30 minutes, acidified with hydrochloric acid to pH 2–3, and the precipitated crystals were filtered. The crystals are washed with io ml of cold water 5 times and dried. The crystals are dissolved in 50 ml of ethyl acetate and the insoluble material is separated by filtration. I process the filtrate with activated charcoal and concentrate to a volume of 5 ml under reduced –100M pressure. The concentrated rasp of the thief is added to 50 ml of ligronin with vigorous stirring. The precipitated crystals are collected by filtration, washed with ligroin and dried. Obtain 0.72 g of 4, b-dioxy-8-oxo2, 3, b, 8-tetrahydrofuro- (3, 4 -) - benzofuran-2-spiro-1- ( 6, 7-dioxy 2, 5, 5, 8a-tetramethyl-1, 2, 3, 4a, 5, b, 7, 8, 8a-decahydronaphthalene). The physicochemical properties of the obtained compound are similar to those given in Example 1. EXAMPLE 4 Dissolve 1.0 g of b, 7-dioxy-2, 5, 5, 8a-tetramethyl, 1, 3, -4-43 -5, b, 7, 8, 8a-decagide ronaphthalen-1-spiro, 2, - (b, 7-diformyl-4-hydroxy-2, 3-dihydrobenzofuran) in 25 ml of 1 N. aqueous solution of potassium hydroxide and 50 ml of an aqueous solution of 0.578 g of potassium permanganate is added in portions with stirring. After the potassium permanganate color has disappeared, stirring is stopped. The precipitate is filtered off using sellaite as filter aid. The filtrate is acidified with hydrochloric acid to pH 2. The precipitated crystals are filtered off, washed with 10 ml of water 3 times and then sumat. The dried crystals are dissolved in 30 ml of ethyl acetate. The insoluble material is filtered off, the filtrate is decolorized and concentrated under reduced pressure. 50 ml of ligroin is added to the concentrated solution and the mixture is stirred. The precipitated crystals are filtered off, washed with ligroin and dried under reduced pressure. 0.9 g of 4, b-dioxy-8-oxo-2, 3b is obtained. 8-tetrahydrofuro- (3, 4-g) -benzofuran-2-spiro-1- (6, 7-DIOXI-2, 5-, 5, 8a-tetramethyl-1, 2, 3, 4, 4a, 5 , b, 7, 8, 8a-decahydronaphthalene (11, the physicochemical properties of the obtained compound are similar to those shown in example 1. Example 5. To 5 ml of 0.4N aqueous solution of sodium hydroxide and 5 ml of ethanol was added 418 mg 4 , 6-DIOXI-8-OXO-2, 3, b, 8-tetrahydrofuro- (3, 4 -) - benzofuran-2, spiro-1- (b, 7-dioxy-2, 5, 5, 8a-decahydronaphthalene The mixture was stirred at 30-40 ° C for 30 minutes in a stream of nitrogen. After the reaction, the solvent was distilled off under reduced pressure. The residue was dried, and then added there is 10 ml of acetone. The part soluble in acetone is filtered off. The remaining crude crystals are recrystallized from water-acetone. 342 mg of disodium salt are obtained B., 7-DIOXI-2, 5, 8, tetramethyl-1, 2, 3, 4, 4a, 5, b, 7, 8, 8a-decahydronaphalin-1-spiro-2- (7-carboxylate-b-formyl-4-oxide-2, 3-dihydrobenzofuran as light yellow amorphous crystals: 44.2 ° (C -1.25, HgO.) Elemental analysis for Calculated,%: C 59.74; H 6.10. Found,%: C 59.48; H 5.91. Ultra-violet spectral analysis: H, O 252. nm (20500), 51 ° fiss 330 nm {e 45900). NMR analysis was performed using (flSS) as a solvent. The conditions for NMR measurements are as follows: spectral amplitude 9-100; sweep time 5 min; filter 0.1 s, sweep width 10 mn, USD; PF power 0.05 ms; end of sweep O ppm Example b. 418 mg of 4,6-dioxy-8-OXO-2, 3-b, 8-tetrahydrofuro- (3, 4 -) - benzofuran-2-spiro-1- (b, 7-dioxy-2, 5, 5, 8 a-tetramethyl-1, 2, 2, 4, 4 a, 5, b, 7, 8, 8a-e ehagronaphthalene) and with stirring add 0.33 mol bn. an aqueous solution of sodium hydroxide. The mixture is stirred for 10 minutes in a stream of nitrogen. The precipitated crystals are filtered off, washed three times with 10 ml of ethyl acetate and dried. 390 mg of disodium salt of b, 7dioxy-2, 5, 5, 8a-tetramethyl-1, 2, 3, 4, 4a, 5, b, 7, 8, 8a, decahydronaf alin-1-spiro-2- { 7-carboxylate-b-formyl-4-oxide-2, 3-dihydrobenzofuran (1b) in the form of light yellow amorphous crystals. The physicochemical properties of the obtained compound are similar to those given in Example 5. The term complement refers to a complex group of proteins in body fluids, which, working together with antisense and other factors, plays an important role as a carrier of immune, allergic, immunochemical and / or immunopathological reactions. Reactions in which the complement is involved, occur in the blood suturing or in other body fluids and, therefore, are considered as humoral reactions.
    Compounds possessing anti-complementary activity are known, such as ethylenediaminetetraacetic acid (EDTA), Suldox, phlorizin hydroxybenzene derivatives, guanidines and phenoxyacetals, phosphonate esters, chlorophyllin, glycyrrhizin, etc.
    However, these compounds are unsatisfactory for practical purposes, as they are highly toxic or have low anti-complementary activity. There are currently no commercially available anticomplementary compounds or agents.
    Therapeutic agents. The resulting sesquiterpene derivatives of the general formula (I) and their salts are useful as preparations for the treatment of nephritis. In this case, they are incorporated into pharmaceutical formulations along with the usual pharmaceutical acceptable carriers, which are, for example, diluents or excipients, such as excipients, extenders, bonding agents, wetting agents, disintegrating agents, surfactants and lubricants, which usually used for the preparation of drugs, depending on the method of administration of individual forms of deza.
    For treatment, various forms of dosage and methods of administering a medicine as a treatment for nephritis can be selected according to the purpose of treatment. Typical dosage forms | are tablets, pills, powders, such as: liquid preparations, suspensions, emulsions, granules, capsules, suppositories and preparations for injection of liquids, suspensions, emulsions, and the like.
    When forming a pharmaceutical composition in the form of a tablet containing a sesquiterpene derivative of general formula (I) or its salt as an active ingredient, a wide range of known carriers can be used. Examples of suitable carriers are ekcipionty f lactose, sucrose, sodium eloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders (water, ethanol, progant, simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and poly
    vinylpyrrolidone, disintegrating agents (dry starch, sodium aldehyde, agar powder, kelp powder, sodium hydrogencarbonate, Tween, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose), disintegrate inhibitors (sucrose, cheese, ceryer serine glycerin, glycerihyridin, starch and lactose, starch and lactose); , cocoa and hydrogenated oils; absorption promoters (quaternary ammonium bases and sodium lauryl sulfate; wetting agents (glycerin and starch); absorbents. (starch, lactose, kaolin, bentonite and colloid cream niev acid) and lubricants (purified. talc, salts of stearic acid, boric acid powder).
    A wide range of known carriers can be used to form a pharmaceutical formulation1 in the form of pills. Examples of suitable carriers are excipients (glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc), binders (gum arabic powder, tragacanth powder, gelatin and ethanol) and dysentegrasive agents (laminaria and agar) . Pills and tablets can be coated with sugar, gelatin, and the film can be coated with two or more layers.
    When forming the pharmaceutical composition in the form of candles, a wide range of known carriers can be used, for example, butter, cocoa, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.
    When an injection preparation is prepared from the pharmaceutical formulation, the resulting liquid solution or suspension is preferably sterilized and they are isotonic with respect to the blood. When formulating a pharmaceutical formulation in the form of a suspension or emulsion solution, any known diluents can be used, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters in sufficient quantity to provide a therapeutic jade agent, chlorine, sodium glucose or glycerol. to prepare isotonic solutions. In addition, the therapeutic agent may contain common soluble adjuvants, / buffers, analgesic agents and preservatives, in some cases, coloring agents, perfumes, flavoring agents, sweeteners, and other medications may be added. The amount of the compound of the general form () or its pharmaceutically acceptable salts, which as an active ingredient may be incorporated into a pharmaceutical composition useful in the treatment of nephritis, is not limited and may vary within very wide limits. An appropriately therapeutically effective amount is usually 1-70% by weight, preferably 5-50% by weight of the total formulation. There is no particular limitation on the method of using the therapeutic agent as an agent for treating neuritis. The therapeutic agent may be administered by any method suitable for a particular form of therapeutic agent. For example, tablets, pilkshy liquid preparations, suspensions, emulsions, granules and capsules are taken orally. Injections are injected intravenously, alone or with conventional auxiliary agents (glucose and amino acids). In addition, if required, the therapeutic agent can be administered simply by intramuscularly, intracutaneously, subcutaneously, or into the nutrient-peritoneal system. The dosage of the medication for treating nephritis is usually chosen according to the purpose of use, systomies and the like. The dosage of the compound of formula (1) is 0.5-20 mg / kg body weight per day, in one or several doses. The compounds of Formula (I) possess anti-complementary activities and are also useful as therapeutic agents for the treatment of auto-immune diseases, collagen diseases and rheumatism. The test results of the pharmacological action of the compounds of general formula (I) and their salts. The test compound (1b) (di-sodium salt) has various substituents: R, - ((-COONol. Lymphoclicular activity. Measured and confirmed using a test procedure. In particular, 0.5 ml of the aqueous dispersion of each test subject was loaded into the test tube. compounds, 0.5 ml of immune particles (EA),., containing 1-10 cells / ml, 1 ml of a 5-fold diluted solution of Veronal Buffer Solution (GvB) containing isotonic gelatin and 0.5 ml of complementary serum (cj.p. p.), diluted in 150 pa3QVP- + diluted liquid. The mixture is kept heated, until 60 minutes, then 5 ml of ice-cold physiological saline solution is added. The mixture is centrifuged. The adsorption of the supernatant layer separated at the optics determines the duration of inhibition of hemolysis of the immune particles by the test compound. activity. 50% inhibition of hemolysis Y (ml), measured by the indicated method. Acute toxicity. Values for the test compounds when administered orally for rats are given in. tab. 1. Therapeutic effect on nephritis of the nephrotoxin type. The bark of the kidney of the rat is homogenized in an equal amount of saline. The homogenized mixture is mixed with the complex Freund's auxiliary additive (the product of the Difco koIvu adia) in a 1: 1 volume ratio. 2 ml of the resulting mixture is injected intramuscularly to a rabbit (body weight of 3100 g) for immunization. After 1.5 months, blood is taken from the rabbit medulla and serum is prepared. The resulting serum is inactivated at 5b ° C for 30.. ((then salted with a 40% saturated ammonium sulfate aqueous solution and fractionated. An immunoglobulin-globulin (IgG) fraction was collected to produce NT. It was estimated using male Wistar rats weighing 150 to 160 g. For each compound is replicated three times. Test compound is administered intraperitoneally, once every 24 hours for 7 days. After 1 hour after administering test compound, NT is used on the third day. NT is injected intravenously in the amount of 1 ml into the tail vein of each rat. As a comparative compound and Chlorophyllin (CP) is used, and the total level of protein urea in the total amount of urine excreted over 24 hours is measured by a turbidimetric method, using bovine serum albumin as a control in combination with sulfosalicylic acid. 2. Each of the tested compounds listed in Table 3 was injected intraperitoneally to rats with nephritis of the Geimann type (all bodies from 300 to 350 g) once a day for 7 days. and then the amount of protein urea, mg / day, as described above, was measured. CP was used for comparison, and physiological saline was used for control. For each test, the compounds made three replications. The results are shown in the table. The level of protein urea in a healthy rat is from 0 to 5 to 5 kg / day. When the level of protein urea exceeds this interval becomes greater than 10 mg / day, it is safe to say that nephritis has arisen. As can be seen from the results of Table 2, nephritis is found in the control group. 3 other groups the amount of protein uchevin after 10 days. after administration, is essentially such J.e as in a healthy rat. Therefore, the administration of the proposed compounds inhibits the primary and secondary reactions. When the same test was carried out with the proposed compounds, it was found that all of them inhibit the primary reaction of nephrotoxin-type nephritis. Therapeutic effect on jade type Geimann. In the test, male Wister rats weighing from 180 to 200 g were used. The bark of the rat kidney was extracted and homogenized with an equal amount by volume of saline. The homogenate is centrifuged at 1500G for 1 hour. The supernatant that has emerged is cleaned and mixed with Freund's 37R complete auxiliary additive in a volume ratio of 0.4: 1. The resulting mixture was injected intraperitoneally in rats in an amount of 0.5 ml per rat. After this, the same amount of an additive was injected every 2 weeks. until the level of protein-urea did not exceed 100 mg / day (for 6-8 weeks). After 2-3 weeks. after the onset of the test, the body weight of the rat rises to 400-500 g and the normal level of protein urea is 5-15 mg / day. As seen from the results of Table 3, the proposed compounds can treat nephritis of the Heimann type. This test was performed with other compounds of the formula, and a substantial activity was also found in the treatment of nephritis such as Heiman. Example 7. A 500 ml culture medium (the composition is given below) is loaded into a 500 ml Sakagug-sh flask and Stack vj b ot rijssp K-76 is cultured at 28 ° C and pH 6 for 4 days with shaking. Formulation of the culture medium,%: Glycerol. 0.5 Starch1.0 Lactose0.2 Powdered soybeans0.5 Drainage extract0.1 Malt extract 0.2, 0.3 yjg5O40.05. A 30-liter vessel for fermentation is charged with 20 liters of culture of the indicated composition. One cola of the resulting dried crop is cultivated at a temperature of 28 ° C culture medium for 5 days. Mixed at 400 rpm and aerated at 1 L per 1 L culture medium per minute. The resulting culture broth is centrifuged at 8,000 rpm to remove microbial cells. 5 L of methanol is added to the supernatant, the mixture is stirred and settled for 3 hours. The mixture is centrifuged and solid particles are removed. The supernatant is extracted with an equal volume of ethyl acetate. The solvent of the ethyl acetate layer is distilled off under reduced pressure. The residue is dissolved in methanol and passed through a column of activated carbon. The eluate is concentrated to dryness under reduced pressure. The dry mass was dissolved in chloroform-ethyl acetate 1: 1 (by volume) and gel filtered through a Sephadex LH-20 column. The filtrate is subjected to thin layer chromatography (using ethyl acetate-chloroform-acetic acid as a solvent carrier in a volume ratio of 50: 50: 2) and the fraction with Rf 0.34, which has anti-complementary activity, is collected. In another embodiment, the filtrate is subjected to thin layer chromatography (using benzene-butanol-acetic acid mixture as a carrier solvent in a volume ratio of 60: 15: 5) and the fraction c is collected. Rf 0.58, which has anticomplementary activity. Evaporation of the solvent from f) shares receive. 2.0 g b, 7-dioxy-2, 5, 5, 8-meter methyl-1, 2, 3, 4, -4a, 5, 6, 7, B, 8a-decahydronaphthalen-1-spiro-2- (6, 7-diformyl-4-hydroxy-2, 3-dihydrobenzofuran), was a pale yellow weakly acidic compound with anti-complementary activity. The preparation of this compound is confirmed by the following physicochemical properties. 1 - L8 ° (C 2.5, methanol). Elemental analysis for S.2z H joOg. Calculated,%: C 68.64; H 7.51. Found,%: C 68.58; H 7.55. Analysis of the ultraviolet absorption spectrum (UV): ethanol. P 246 im (e 16474), g max 307 nm (e 6659). NMR analysis was performed using pyridine-ds (2,2-dimethyl-2-silapentane-5-sodium sulfonate) (DCC) as a solvent as an external standard. Measurement conditions NMR trace: Spectrum amplitude Filter, s, 0.1 RF output, MHz 0.5 Sweep time, min, 5 Sweep width, million, dol10. End of the sweep, ppm. About Example 8. A 100 ml Sakagush flask with a capacity of 500 ml is charged. a culture medium having the formula presented below, and the known strain 5BacLeBol1 5 cbartarum IfO 5389 is cultivated in medium at a temperature of 28 C for 4 days. at pH 6 with shaking. Recipe for culture medium,%: Glycerin 0.5 Starch, 1.0 Lactose 0.2 Soybean Powder 0.5 Yeast Extract 0.1 Malt Extract 0.2 CaCOe 0.3 MgS040.05 A 30-liter inlet vessel is loaded with 20 l the culture medium of the indicated composition and two flasks with the cultures of the inoculated crop were isolated, at 2 ° C for 5 days. with mixing with speed. 30 rpm and during aeration, the wire is MO, with a speed of 1 l Md 1 l Medium per minute. The resulting culture broth is centrifuged at BOOP rpm to remove microbial cells. 5 liters of methanol was added to the supernatant, the mixture was stirred and settled for 3 hours. The mixture was centrifuged and the solids removed. The supernatant is extracted with an equal volume of ethyl acetate. The solvent of the ethyl acetate layer is removed under reduced pressure, the wire is concentrated to a dry residue. The residue was dissolved in methanol and passed through a column of activated charcoal. The eluate is concentrated to dryness under reduced pressure, dissolved in a mixture of chloroform and ethyl acetate 1: 1 (by volume) and subjected to gel filtration. Through a column of Cephalex LH-20. Collect the fraction of active peak thin layer chromatography. By evaporation of the solvent, 2.2 g {b, 7-dioxy-2,5,5,8a-tetramethyl 1, 2 / 3,4,43,5,6,7,8, Ba-dakagi D roiaftalin-1-spiro 2 are obtained. - / C6., 7-difet-mil-4-hydroxy-2,; 3-dihydrobenzofur, which is a pale yellow weakly acidic compound with anti-complementary activity. This compound has physicochemical properties similar to the compound in Example 1. Example 9. Stachijbot ys5p.T.789 is cultured and purified in Example 7, except that the culture medium given below is 7.5 and the culture temperature is maintained equal to 32 ° C. The composition of the cultural environment,%:. Glycerin 0, 5 Glucose 1,2. Wheat tincture0.5 Dry yeast0.1 Malt extract 0.2 MtfSO 0.05 Nace0.3 So get 6,7-dioxy-2,5,5,8a-tetramethyl-1, 2,3,4,4a, 5, b , 7,8,8a-dequahydro-naphtha. Alin-l-thio-2 / (6, 7-diformyl-4-hydroxy-2, 3-dihydrobenzofuran), which is a light yellow weakly acidic compound with anti-complementary activity. The physicochemical properties of this compound correspond to the properties of the compound obtained in Example 7, Pr and measures lO.Stachijbotrys 3p-T-791 are cultivated and purified in Example 7, except that the culture medium has the following composition and its pH is adjusted to 5.5, the temperature of the medium is maintained with equal. The composition of the cultural,%: Glycerin 0.5. Starch1.0 Sucrose0.2 Soybean Powder 0.5. Zepton 0.1 Malt extract 0.2 jyigSO 0.3 ne0.05 So, b, 7-dioxy-2, 5,5,8a-tetramethyl-1,2-3,4,4a, 5, b, 7,8 are obtained, 8a-decahydronaphthalen-1-spiro-2 - (6, 7-diformyl-4 goxy-23-dihydrobenzofuran), which is a pale yellow weakly acidic compound, has anti-complementary activity. The physicochemical properties of this compound correspond to the properties of the dinene compound obtained in Example 1. Example 11. Disodium salt of the compound (GH). and 250 ml of glucose is dissolved in distilled water for injection to a total amount of 5 ml. The solution is poured into a 5 ml vial. The vial was flushed with nitrogen and heated for 15 minutes at 121 ° C to sterilize the solution to form an injection. . Example 12. SOU mg of compound (lb) 5 mg of sodium sulfite and distilled water for injection are used up to a total of 5 ml. The preparation for injection was prepared according to the procedure of Example 7. Example 13. Use 500 mg of compound (ib), 5 mg of sodium sulfite and distilled water for injection to a total amount of 5 ml. The preparation is prepared for injection according to the method of Example 1. Example 14. 75Q of compound (1b) and a semi-synthetic glyceride base are used up to a total amount of 2000 mg. Compound (1b) is added to the floor of a synthetic glyceride base, mixed and suspended. The mixture is placed in a mold and yes: it is allowed to cool by itself. The product is removed and thus a candle is obtained. Example 15. Use 750 mg of the compound obtained in Example 1, 90 mg of vitamin E and a semi-synthetic glyceride base to a total amount of 2000 mg. A candle is prepared according to the procedure of Example 10. Example 16. 150 mg of compound (1b) 40 g of Aviul, (trade name is Asahi Ka Kabushihi Kayya product),. 30 g of corn starch and 2 g of magnesium stearate are mixed and crushed, and then pelletized with pound E and izokryvayut sugar (R 10 mm), the resulting tablets are coated with a film of a covering agent consisting of 10 g of TC-5 (trade name 1 x 1 shlimelcelllglozi 3 g of polyethylene glycol 6000 is a product of Shinetsu Chem I nd), 40 g of castor oil and 40 g of methanol for the production of film-coated tablets. Example 17. 100 g connected (1,), 40 g of Aviuel, 30 g of corn
    Anti-complementary
    Test compound activity y, ml
    Ta bl litsa
    Beverage ID 50 mg / kg of starch and 2 g of magnesium stearate are mixed, ground, tableted with polyurethane and coated with sugar C "{10 I" M}. The resulting tablets are coated with a film of film-forming agent consisting of 5.7 g methacrylic acid methyl acrylate copolymer, 0.6 g of triacetin and 50.4 g of ethanol, to form enteric coated tablets. Example 18.150 g of compound (1b) 1 g of citric acid, 33.5 g of lactose, 70 g of dicalcium phosphate,; 30 g of Pluronic Pluronic G-68 and 15 g of sodium lauryl sulfate are mixed. The mixture is sifted through a sieve 60 and subjected to wet granulation with an alcohol solution consisting of 15 g of polyvinylpyrrolidone, 4.5 g of Carbovax 1500 (polyethylene glycol) and 45 g of Carbovax 6000 (polyethylene glycol). In some cases, ethanol (the appropriate amount) is added to convert the powder to a paste-different mass. 30 grams of corn starch are added and mixing is continued until homogeneous particles are formed. The particles are passed through a No. 10 sieve, placed in a trough, dried in an oven at 100 ° C for 12-14 hours. The dried particles are sieved through a sieve 16 and mixed with 3 g of dry sodium lauryl sulfate and 3 g of dry magnesium stearate. The mixture is pressed into the desired shape on a tablet machine. The heartbells obtained in this way are varnished and sprinkled with talcum powder to prevent moisture absorption. The cores are coated with the first layer, and then lacquer the required number of times, for oral administration. In order to completely round and smooth the tablets, the first and smoothing layer is again applied, and the coloring coating is applied until the desired color is obtained. After sugchi, the coating of the tablets is polished to give the tablets a uniform gloss.
    60 40
    1c CVi orphi) 2in
    500 Note. The days represent the compound being administered, which was over 1
    Chlorophyllin
    (with Lavne Kie)
    T a and c a 2 a count, the time from the use of h before the application of NT. Ta bl and c and 3
    Continued table. 3
    权利要求:
    Claims (1)
    [1]
    How to get sesquiterpen output compounds of the general formula
    Where is the formyl group;
    Rj is a carboxyl group, or together with the carbon atoms of the benzene ring to which they are bonded form a Lactone] ring W.
    'or their salts, which is distinguished by the fact that the compound of the formula group (is subjected to oxidation by an oxidizing agent, such as silver oxide or alkali metal permanganate, at ambient temperature in the presence of alkali metal hydroxide or oxygen, or in the presence of air alkali metal hydroxides at 50 ° C.
    类似技术:
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    同族专利:
    公开号 | 公开日
    JPS589114B2|1983-02-18|
    BE867095A|1978-11-16|
    JPS5436255A|1979-03-16|
    AU3608678A|1979-11-15|
    SU980620A3|1982-12-07|
    AU514815B2|1981-02-26|
    ZA782683B|1979-05-30|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    EA000025B1|1995-06-27|1998-02-26|Эгиш Дьодьсердьяр Рт.|Oxaindene derivatives, process for production thereof , pharmaceutical composition on their base, administering and medical treatment|
    JPS6129009U|1984-07-27|1986-02-21|
    US5173499A|1988-04-15|1992-12-22|T Cell Sciences, Inc.|Compounds which inhibit complement and/or suppress immune activity|
    US5366986A|1988-04-15|1994-11-22|T Cell Sciences, Inc.|Compounds which inhibit complement and/or suppress immune activity|
    KR100651650B1|2000-10-12|2006-11-30|한국화학연구원|Anti-cancer composition comprising sesquiterpene compounds isolated from ferulae resina|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP52078641A|JPS589114B2|1977-06-30|1977-06-30|
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