• 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:
    A quinone derivative of the formula (I): in which A is a group of the formula: (IV): or a group of the formula (V): in which X and Y are either the same as or different from each other and each are hydroxy, methoxy or hydrogen; and n is an integer of 1 to 5, and methods of preparing such derivative are disclosed. The compounds exhibit useful pharmacological properties which make them useful in pharmaceutical compositions.
    公开号:SU1447276A3
    申请号:SU864027118
    申请日:1986-03-18
    公开日:1988-12-23
    发明作者:Озава Такаики；Нисикими Моримицу；Сузуки Хироси；Симомура Иосихару；Ямацу Исао；Абе Синиа；Ямада Хироси；Фидзимори Тору；Такаиира Таданобу
    申请人:Эйсай Ко.,Лтд (Фирма)；Нагоя Юниверсити (Фирма)；
    IPC主号:
    专利说明:

    h
    H
    Od
     S
    This invention relates to a process for the preparation of quinone derivatives of the general formula:
    CHjO xD.SNz
    cHjOvAx
    CHjO LL
    CHjCHj
    ICHj-CHsC-CHj-hn CHjj-SNiC-COOH
    where n is an integer equal to 1-5; - which can be used as a therapeutic agent in heart diseases, and also have an inhibitory effect on the activity of ili. phospholipases and antiplatelet action.
    The purpose of the invention is a method of obtaining new hyion derivatives with improved activity.
    The following examples illustrate the invention.
    PRI me R 1.
    A. Preparation of the starting material 6- {7-carboxy-3-methyl-2,6-octadienyl) 2,3,4-trimethoxy-5-methylphenyl.
    5 g of 2,3,4-trimethoxy-5-methylphenol is dissolved in 10 ml of benzene and 10 g of aluminosilicate is added to the resulting solution. 1.8 g of 8-hydroxy-2,6-dimethyl-2,6-octadienoic acid is dissolved in 4 ml of benzene and added to the solution. The resulting solution was incubated for 2 hours at 40-50 ° C, after which the reaction mixture was filtered, the precipitate was washed with diethyl ether, and the filtrate was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate is purified by chromatography on silica gel using a mixture of ether and n-hexene as eluent. 1.3 g of the title compound are obtained as a colorless oily liquid.
    B. Preparation of the starting material 6- (11-carboxy-3,7-dimesh1-2,6,10-dodecatrienyl) -2,3,4-trimethoxy-5-methylphenol. 5 g of 2,3,4-trimethoxy-5-methylphenol is dissolved in 10 ml of benzene and 6 g of silica gel (Wakogel C-200) and 3 g of zinc chloride are added to the resulting solution. 2.4 g of ethyl 2-hydroxy-2,6,10-trimethyl-2,6,10 dodecryanoate are dissolved in 5 ml of benzene and this solution is added to the previously obtained solution. After reacting for 30 minutes at room temperature, the reaction mixture is filtered and the precipitate is washed with diethyl ether, and the filtrate is washed with water.
    five
    0
    5 Q Q

    0
    five
    dried over anhydrous magnesium sulphate and concentrated. The concentrate is dissolved in 50 ml of ethanol and 3 g of caustic soda is added to the solution. After boiling for 30 minutes under reflux, the reaction mixture is poured into dilute hydrochloric acid and extraction is carried out with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, concentrated and purified by chromatography on silica gel using a mixture of ethyl acetate and benzene as eluent. The result is 1.7 g of the title compound as a colorless oily liquid.
    Example. 6- (7-Carboxy-3-methyl-2,6-octadienyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone.
    2 g of 6- (7-carboxy-3-methyl-2,6-oxadienyl) -2,3,4-trimethoxy-5-methylphenol, prepared as described in Example 1A, is added in 20 ml of ethyl acetate and added 5 g of iron chloride hexahydrate are added to the solution obtained. The reaction mixture is stirred for 30 minutes at room temperature, after which 100 ml of ether are added to it, washed with water, dried
    over anhydrous magnesium sulfate and concentrated. The concentrate is purified by chromatography on silica gel using a mixture of ethyl acetate and benzene as eluent. 1.8 g of the title compound are obtained as an orange oily liquid.
    Example 2. 6- (11-Carboxy-3,7-dimethyl-2,6,10-dodecatrienyl) -2,3-dimethoxy-5-methyl-1,4-benzoquinone.
    The process is carried out analogously to example 1 C; the difference is that 1.5 g of 6- (11-carboxy-3,7-dimethyl-2,6,10-dodecatatrienyl) -2,3,4-trimethoxy -5- methylphenol obtained in example 1B. 1.4 g of the title compound are obtained as an orange oily liquid.
    PRI me R 3. 6- (15-Carboxy-3,7,11-trimethyl-2,6,10,14-hexadecaetrafenyl) -2,3-dimethoxy-5-methyl-1,4- benzoquinone.
    The process is carried out analogously to example 1 with the same difference as using 2 g of 6- (15-carboxy-3,7,11-trimethyl2, 6,10,14 hexadecatetraenyl) -2,3,4-trimethoxy- 5-methylphenol. The result is 1.7 g of the title compound as an orange oily liquid.
    PRI me R 4. 6- (19-Carboxy-3,7, 11,15-tetramethyl-2,6,10,14,18-eikopentarenyl) -2,3-dimethoxy-5-methyl- 1.4-6 she zohin he.
    The process is carried out analogously to Example 1 with the difference that 2.5 g of 6- (19-carboxy-3,7,11,15-tetramethyl-2,6,10,14 18-eicosapentarenyl) are used as the starting compound. - 2,3,4-trimethoxy-5-methylphenol. 2.2 g of the title compound are obtained as an orange substance.
    EXAMPLE 5 6- (23-Carboxy-3,7,11,15,19-pentametsh1-2,6,10,14,18, 22-tetracosahexenyl) -2,3-dimethoxy- 5- methyl 1,4-benzoquinone,
    The process is carried out analogously to Example 1 with the difference that 1.3 g of 6- (23-carboxy-3, 7,11,15,19-penta-metsh-2,6,10, 4,18, 22-tetracosahexenenyl) -2,3,4-trimethoxy-5-methylphenol. The result is 1.1 g of the title compound as an orange substance.
    In tab. 1 shows the physico-chemical characteristics of the proposed compounds in accordance with examples 1-5.
    The proposed compounds exert a potent inhibitory effect on the activity of phospholipase, as well as an anthrombicitic effect, which makes it possible to use them as anti-platelet, blood-compatible agents and drugs for the treatment of various heart diseases. In particular, they can be used to treat and / or prevent vascular diseases of the brain, such as TIA (translentischenu-cattack), cerebroinfarct (thrombi and emboli) and cerebral arteriosclerosis; postoperative thrombosis, gastrulation, and disturbances of blood flow occurring during operations, as well as blood circulation outside the body; impaired peripheral blood flow caused by gastrulation or narrowing of the arteries of the extremities, such as Buerger's disease, atherosclerosis obliterans, SLE, and Raynaud's disease; congestive failure, accompanied by edema, pulmonary hyperemia or hepatomegaly; heart disease (angina and myocardial infarction). In addition, they are effective in preventing relapses of postponed diseases and treatment and recovery after these diseases, they are also highly effective in treating and / or preventing inflammatory diseases, such as various rheumatic diseases.
    Example 6: The inhibitory effect on the activity of phospholipase A.
    In order to determine the effectiveness of the tested compounds, they were introduced into the system under study in the amounts indicated in Table. 2, after which the activity of phospholipase A was measured by measuring, using high-speed liquid chromatography, the concentration of myristic acid released by the action of phospholipase from: -cTpafa (myristyl lecithin).
    For comparison, CoQ ,, was used.
    The compound A was tested:
    ABOUT
    CHjOvJl SNS
    soon
    CHjO
    about
    35
    compound C:
    Cun
    Each of the values given in Table 2 means an assessment of the effectiveness of the corresponding compound, i.e. the degree of inhibition of phospholipase A activity by it J.
    From tab. 2 it follows that the proposed compounds are more inhibited by the phospholipase A activity than
    PRI me R 7. Antiplatelet effect on human platelets.
    Suppression of human platelet agglutination with the proposed compounds was studied in vitro experiments. A platelet agglutination test was performed using PAF (thrombocyto-activating factor.
    1-alkyl-2-acegyl-8n-glycero-3-phospholipin), collagen and adenosine diphosphate as initiators.
    Obtaining PRP (plasma enriched with platelets), 9 ob.h. Blood from the brachial vein of a healthy man was mixed with 5 parts by volume. 3.8% sodium citrate solution. The blood was centrifuged at a factor of 100 x for 8 min. The supernatant was collected and the PRP was separated.
    Determination of platelet agglutination. 25 µl of the test solution of various concentrations was added to 0.2 ml of the PRP prepared in the described manner and kept for 3 minutes at which time 25 µl of the specified initiator solution, PAF, collagen and adenosine diphosphate were added to it to initiate agglutination. In such an amount that their final concentration was 10Q ng / ml, 1 µg / ml and 5 µmol, respectively. Platelet aggregation was determined using an aggregometer.
    The effectiveness of the tested compounds was evaluated in comparison with the use. called indference medium containing PRP.
    Compounds A and C were tested (Example 6).
    Compound H:
    about
    CHsOxJlyCHs
    CHjO- Sr V
    compound I:
    About CHJO JL, SNS
    SNZO
    Compound J:
    CHjO
    soon
    CHjO
    The results are shown in Table. 3. Each of the numbers in Table 3 indicates the degree of suppression (%) of agglutination with the corresponding compound.
    From Table 3, it follows that the proposed compounds have a stronger anti-platelet effect than CoQ, ".
    Tests for toxicity. Dp op. To determine the acute toxicity of compound A-J in accordance with the proposed method, orally was administered orally to ddY of a smaller species weighing approximately 525-30 g. A certain average lethal dose (LD 5 °) was no less than 5 500 mg / kg. Compounds A-J were injected in the tail vein with 10 doses of 10.30 and 100 mg / kg. At the same time, all mice survived, which means that the LDyo of each of the compounds is not lower than 0 100 mg / kg.
    The proposed compounds exert an inhibitory effect on the activity of phospholipase, as well as an antiplatelet effect. Therefore, based on these 5 drugs can be prepared, such as anti-platelet, blood-compatible drugs, as well as drugs for the treatment and / or prevention of cardiac or inflammatory diseases, including rheumatic diseases. These may be oral or parenteral preparations, for example, intramuscular, subcutaneous or intravenous administration. They can also be cooked as a candle. The daily dose of the proposed compounds for adults may be 10-1000, preferably 50-500 mg, depending on the disease, condition and age of the patient.
    Based on the proposed compounds, various forms of medicinal preparations can be prepared, for example, tablets, granules, powders, capsules, solutions for injections or suppositories. All these preparations are made by known methods.
    0 Thus, for example, solid preparations for oral administration can be obtained by mixing the active compound or compounds with indifferent constituents of the drug and, if necessary, contacting, bleaching agents, lubricants, dyes and corrective additives and subsequent molding cooked
    five
     1447276
    mixtures into tablets, coated tablets, granules, powders or capsules.
    Examples of indifferent drug ingredients are lactose, corn starch, sucrose, sorbitol and crystalline cellulose. Examples of binders are polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragant, gelatin, shellac wax, hydroxypropyl cellulose, hydroxypropyl starch and polyvinyl pyrrolidone. Examples of disintegrating agents include starch, agar, 5 powdered gelatin, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, and pectin. Examples of lubricating additives are magnesium stearate, 20 NIN, talc, polyethylene glycol, two; silica and hydrogenated vegetable oils. Upon receipt of the proposed drugs can
    Compound A is dissolved in acetone, adsorbed on microcrystalline cellulose and dried, after which corn starch and carboxymethylcellulose calcium salt and refined sugar and then aqueous solution of polyvinylpyrrolidone as a binder are added to it. Pellets are prepared from the resulting mixture in the usual way. Then the tal from the resulting mixture is added to the granules. Form tablets weighing 100 mg each.
    PRI me R 9. Powders, g: Connection C50
    Microcrystalline
    cellulose400
    Corn Starch550
    Compound C is dissolved in acetone, used pharmaceutically, 25 is adsorbed on microcrystalline
    the cellulose and the drying agent, starch is added thereto, and powders are prepared from the resulting mixture in the usual manner.
    Thus, these compounds have activity exceeding the talable dyes. Examples of corrective additives are cocoa powder, peppermint extract, aromatic acids, peppermint oil, Borneo camphor, and cinnamon powder. Tablets or granules prepared as described may be coated with a suitable material, for example with achara or gelatin.
    Preparations for subcutaneous, intramuscular or intravenous injections can be prepared by adding to the active component or components of a substance to set the desired pH of the solvent or solvents, dispersants, buffering additives, stabilizers and preservative dot cans and then processing the mixture in the usual way.
    Typical preparations based on the proposed compounds
    PRI me R 8. Tablets, g:
    Compound A 5
    Corn Starch 10
    Refined Sugar 20
    Calcium salt
    carboxymethylcellulose 10
    thirty
    forged from CoQ

    fo
    35
    F o rmula of the invention
    The method of obtaining quinone derivatives of the general formula
    CHjO
    40
    CHjO
     Y ICH2-CH CCHjCHj
    CHj-hn CHj-CH-if-COOH
    45
    where n is an integer equal to 1-5, characterized in that the compound of the general formula
    one
    CHjOsJY CHsCHj
    CHjO nr CHl M 2-) n CHi-CH-C-COOH
    50
    where X is OXI-,
    Y is a matoxy group, is oxidized.
    eight
    Microcrystalline cellulose 40
    Polyvinylpyrrolidone 5
    Talc10
    Compound A is dissolved in acetone and adsorbed on microcrystalline cellulose and dried, after which corn starch and carboxymethylcellulose calcium salt and refined sugar and then aqueous solution of polyvinylpyrrolidone as a binder are added to it. Pellets are prepared from the resulting mixture in the usual way. Then the tal from the resulting mixture is added to the granules. Form tablets weighing 100 mg each.
    PRI me R 9. Powders, g: Connection C50
    Microcrystalline
    cellulose400
    Corn Starch550
    thirty
    Thus, the data connected have activity greater than
    forged from CoQ

    fo
    35
    F o rmula of the invention
    The method of obtaining quinone derivatives of the general formula
    CHjO
    CHjO
     Y ICH2-CH CCHjCHj
    CHj-hn CHj-CH-if-COOH
    45
    where n is an integer equal to 1-5, characterized in that the unity of the general formula
    one
    CHjOsJY CHsCHj
    CHjO nr CHl M 2-) n CHi-CH-C-COOH
    50
    where X is OXI-,
    Y is a matoxy group, is oxidized.
     144727612
    Table
    Compound End Activity kentsent-phospholipase radiopathy. A,% µmol
    Connecting
    A 4 66
    Connection With 4 25
    ,
     43 56
    Physiological solution of salt-100
     Table3
    compound PAF concentration, (%) Colpagen Adenozing µmol% diphosphate,
    123 4 5
    20
    50
    100
    200
    20
    50
    100
    200
    20
    50
    100
    200
    20
    62.4
    86.6
    3.2
    17.2
    38.1
    84.3
    12.4
    2.1
    22.1
    23.1
    18.3
    8.8 18.2
    13
    1447276
    14 Continuation of table 3
    权利要求:
    Claims (1)
    [1]
    Claim
    35 The method of obtaining quinone derivatives of the General formula about.
    CHj CHj sn 5 о> \ sn 2 -s'n4-sn a % CH g -CH = 5-С00Н where η is an integer equal to 1-5, characterized in that with 45 the unity of the general formula i CHjOxJUcHj CH S Chj
    CHjoArXCHrCH-C-CHi-fo CHj-CH-C-COOH Y.
    where X is hydroxy,
    Υ - methoxy group, subjected to oxidation.
    1447276
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    OMOO O | O l | * 1 σισ>
    > cp O • λ ♦ -
    W>
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    I'm about EP
    I ΟΚΝ I Yu | eP
    I • Ή *
    I SAW | CHO (CHO
    G ^ | O4 CO I CO * 4 n
    NTs o X
    X f h f ί sv X Ф X sv X «« о X φ ч о X g
    Al X φ
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    Table 2
    Compound Final concentration, mcmol The activity of phospholipase A,% Compound A 4 66 Compound C 4 25 COQ fg 43 56
    Saline saline
    100
    Table 3
    Compound Μmol concentration PAF, (%) Kolpagen% Adenosing 'diphosphate,% 1 2 3 4 5 A 20 (27.8) 62,4 12,4 fifty (36.0) - 2.1 100 (42.6) 86.6 22.1 200 (52.9) - '23.1 FROM 20 (3,5) 3.2 - fifty (3.4) - - 100 (12.2) 17,2 - 200 (47.3) - 18.3 n 20 (8.8) 38.1 - fifty (28.2) - - 100 (37.8) 84.3 8.8 200 (47.3) - 18.2 I 20 (2.8) -
    thirteen
    Continuation of table.Z
    1 Q 5 4 5 fifty (3.9) - - 100 (10.8) 24.1 3.9 200 (53.3) - 22.0 J 20 (6.0) - - fifty 2.7 - 16.5 100 24.9 (22.0) 27.1 200 65.3 - 30.1 CoQ 1020 8.0 (6.5) - fifty - - - 100 16,2 (18.7) 8.7 200 19 „0 - 11.3
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    法律状态:
    2007-09-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20040531 |
    优先权:
    申请号 | 申请日 | 专利标题
    JP59111555A|JPH056533B2|1984-05-31|1984-05-31|
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