• 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:
    @ The present invention relates to new stable sulpho-adenosyl-L-methionine (SAMe) salts particularly suitable for parenteral use, their production process, and pharmaceutical compositions containing them as active principles. Said salts correspond to the general formula: where n can vary from 1 to 2 and m can vary from 3 to 12. The process for producing said salts consists of the following stages: a) enriching the starting yeast with SAMe; b) lysing the cells and recovering a solution rich in SAMe (cell lysate): c) prepurifying the cell lysate by ultrafiltration; d) passing the prepurified lysate through a column of weak acid ion exchange resin and eluting with the required disulphonic acid; e) passing the eluate of said column through a column of absorption resin and washing with the required disulphonic acid; f) concentrating the eluate of the latter column by reverse osmosis; g) drying the concentrated solution.
    公开号:SU1530100A3
    申请号:SU853898654
    申请日:1985-05-15
    公开日:1989-12-15
    发明作者:Геннари Федерико
    申请人:Биорисерч С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the chemical and pharmaceutical industry and concerns a process for the preparation of a substance of the general formula: sulfoadenyl-L-methionine p (CH, j). (SO, Hj), where up to 2, up to 12.
    The aim of the invention is to increase the solubility of the target product compared with the analog.
    Example 1. Getting 0.2 n. disulfonic acid solutions of the general formula (CH) (SO, H) i.
    75 liters of distilled water, 20 liters of ethanol and 5 liters of n-butanol are added to 21.6 kg (100 mol) of 1, + - dibromobutane. 26, A6 kg (210 mol) of anhydrous sodium sulfite was added and the mixture was heated under reflux for 3 days. At the end of the reaction, 20 liters of distilled water are added and the mixture is distilled until the alcohols are completely removed. The mixture is diluted with water to a final volume of 60 liters and heated until complete dissolution occurs.
    The resulting 1-disodium salt of butanedisulfonic acid is left to crystallize overnight at 4 ° C. The product is filtered and washed with 10 l of water.
    The mother liquors are concentrated in vacuo to a volume of 20 liters and left to crystallize overnight at 4 ° C. The product is filtered and washed with 4 liters of water. The crystalline mass from the two filtrations is resuspended in 50 liters of water and dissolved under hot conditions. The solution was allowed to crystallize at reMeni-ie overnight at. The product is filtered and washed with 5 l of water. Nltrievui spl lu en
    s
    disulfonic acid dried under vacuum.
    The subsequent fraction of the product is obtained by concentrating the mother liquors to 10 liters and keeping them to crystallize overnight at t C, followed by filtration of the product and drying it under vacuum.
    Thus, the 13th form of the 25.2 kg disodium salt is 1, 4-butanedisulfonic acid, monohydrate (90 mol, 90% molar yield).
    Calculated,%: C 17.1, H 3.6, S 22.9.
    C HfeO Cj Naz-HjO
    Found,%: C 17.1, - H 3.7, S 22.9.
    A column is prepared containing 200 liters of Amberlite IR 120 resin preactivated with 6N. HC1 solution until Na ion has disappeared from the eluate, and washed with distilled water until Cl ion has disappeared from the eluate.
    25.2 kg of disodium salt-1, α-tandisulfonic acid, monohydrate are dissolved in 300 l of water and fed to the head of the column. The eluate containing 1, -butanedisulfonic acid is collected, and the column is washed with water until the pH of the eluate reaches 4. The eluate is diluted to a final volume of 900 liters to obtain 0.2N. a solution of 1, -butanedisulfonic acid, which is used to prepare the corresponding salt of sulfoadenosyl-b-methionine.
    I act similarly, but using 20i2 kg of 1,3-dibromopropane as a starting material, 900 l 0.2 n are obtained. 1,3-propanedisulfonic acid solution.
    Using 23 kg of 1,5-dibromopentane, 900 l 0.2 n are obtained. solution of 1,5-pentane disulfonic acid.
    Using kg 1 .5-dibromohexane, 900 l 0.2 n are obtained. solution of 1, 6-hexanedisulfonic.
    Using 27.2 kg of 1,8-dibromoctane, 900 l 0.2 n are obtained. solution of 1,8-octane disulfonic.
    Using 30 kg of 1,10-dibromodecane, 900 l 0.2 n are obtained. solution of 1,10-decanedisulfonic.
    Example 6 Preparation of the sol. Sol-foradenosyl-b-methionine 1.5 (1, (- butane disulphonate).
    220 l of egylacetate and 220 l of water are added at ambient temperature
    g
    five
    d 5
    Q
    0
    five
    0
    1800 kg of yeast enriched in sulfo-adenosyl-L-methionine (6.88 g / kg) according to the Schlenk method.
    After vigorous stirring for jO min, 1000 L 0.35 N was added. sulfuric acid solution and stirring is continued for another 1.5 hours.
    The mixture is filtered through a rotating filter, which is washed with water to obtain 2800 liters of a solution containing k, Q g / l sulfoadenosyl-b-methionine, which is equal to 99 (5% of the amount present in the starting material.
    A solution of sulfoadenosyl-L-methionine, prepared in this way (pH 2.5) is fed to an ultrafiltration unit, where 1000 delayed tubular membranes are used.
    The penetrating stream passing through the membranes is collected in a suitable vessel, while the concentrate is continuously recycled to a final volume of 200 liters. Distilled water is added at this point and recycling is continued until sulfoadenosyl-b-methionine is completely extracted.
    3500 liters of lysate are obtained, the pH of which is adjusted to pH 5 by the addition of 2N. NaOH solution.
    A column is prepared containing kQO L of Amberlite CG 50 resin in the H form, which is thoroughly washed with distilled water.
    The lysate is passed through a resin column at a rate of 800 l / h, which is kept constant throughout the procedure.
    Then 400 l of distilled water, 3200 l of 0.1 mol / l of acetic acid and 00 l of distilled water are successively passed.
    Sulfoadenosyl-b-methionine is eluted with 800 l 0.2 n. solution 1, -butanedisulfonic. 800 l of the thus obtained eluate contains approximately 10 kg of sulfoadenosyl-b-methionine.
    A column is prepared containing 400 liters of Amberlite XA 4 resin, which is pre-activated with 800 liters 0.1 n. NaOH solution and 800 l 0.1 n. solution HjS04, and then thoroughly washed with distilled water.
    The previously obtained sulfo-adenosyl-b-methionine solution is passed through a column at a rate of 200 l / h.
    15
    and the speed is kept constant throughout the process. Then it is passed through it tsol l 0.02 n. solution 1, -butanedisulfonic. An eluate containing sulfoadenosyl-b-methionine (about 1000 liters, containing 10 kg of sulfoadenosyl-L-methionine) is collected. The solution obtained in this way is fed to a flat-type reverse osmosis device, where polyamide desalting membranes are used. In this device, the solution of sulfoadenosyl-b-methionine is concentrated to 80 liters, containing 9, e kg of sulfoadenosyl-b-methionine. Add 5 L 2 n. solution of butanedisulfonic acid. The solution obtained in this way is fed to a spray drying plant, to which it is fed
    air at 1bO Dry product is continuously withdrawing their installation.
    Get 18 kg of powdered product having the following composition in the analysis,%:
    Sulfoadenosyl-Lmethionin5 .9
    1, 4-Butanedisulfonic
    Hjo
    , E 0.2
    the corresponding salt is sulfoadenosyl- L-methionine. 1.5 (1, -butanedisulfonate).
    The product has the appearance of a crystalline white powder, which is soluble in water up to 30% by weight to form a colorless solution and is not soluble in common organic solvents.
    Using thin-layer chromatography, it was found that the product does not contain any impurities.
    Calculated,%: N 11 | 6; C 3.7, 5.1.
    C (, 5C, NADO32
    Found,%: N 11.5; From 5.1.
    The ultraviolet spectrum of the product shows the maximum absorption (in buffer at pH) at 258.5 nm with E ... 193.
    EXAMPLE 3. Preparation of the Salt of sulfoadenosyl-b-methionine "1.5 (1.3 propanedisulfonate).
    The procedure of Example 2 is followed, but using 1,3-propanedisulphonic acid instead of 1, -butanedisulphonic acid.
    Get 17, kg of powder, which in the analysis shows the following composition,%:
    H
    H
    3.8;
    Sulfoadenosyl-L-methionine 1,3-propanedisulfuric acid
    the corresponding salt is sulfoadenosyl-L-methionine 1,5 (1,3-propanedisulfonate).
    The product has the appearance of a crystalline white powder, which is soluble in water up to 30% by weight to form a colorless solution and is not soluble in common organic solvents.
    Thin layer chromatography shows that the product does not contain any impurities.
    Calculated, NA, 8.
    C, 1.5 C HgOeSi
    Found%: N H i, 8.
    The ultraviolet spectrum of the product shows an absorption maximum (in buffer at pH k) at 258.5 nm with E, 199.
    PRI me R. Preparation of sulfoadenosyl-L-methionine 1.5 salt (1,5-pentane disulphonate).
    The procedure of Example 2 is followed, but using 1,5-pentane disulfonic acid instead of 1, -butane disulfonic acid. This gives 18.5 kg of powder, which, when analyzed, shows the following composition.
    N 11.9; C 33.2;
    11.9; C 33.1,
    SulfoadenosylL-methionine53, 3
    1,5-penta disulfonic acid (, 5
    , 2
    the corresponding salt is sulfoadenosyl-L-methionine 1,3 (1.5 pentane disulfonate).
    The product is in the form of a crystalline white powder, which is soluble in water up to 30 wt.% To form a colorless solution and is not soluble in common organic solvents.
    Thin layer chromatography shows that the product does not contain any impurities.
    Calculated,%: N 11.3, C 36.2, H 5 ,.
    C, 5NtsMb05V -1.5
    Found,%: N 11 ,, C 36.2,
    H 5.3.
    The ultraviolet spectrum of the product (in pH buffer) shows an absorption maximum at 258.5 nm with E ((.
    PRI me R 5. Preparation of the salt of sul foadenoyl-b-methionine 0.5 (1,6-hex disulfonate).
    The procedure of Example 2 is followed, but using 1,6-hexane disulfonic acid instead of 1, -6 U disulfonic acid. Get 19 kg of powder, which in the analysis gives the following composition,%:
    Sulfoadenosyl-L-
    methionine51, 8
    1,6-Hexane disulfonic acid Q
    , 2
    the corresponding salt is sulfoadenosyl-L-methionine 1,5 (1,6-hexane disulfonate).
    The product has the appearance of a crystalline white powder, which is soluble in water up to 30 wt.% With the formation of a colorless solution and is not soluble in common organic solvents.
    Thin layer chromatography shows that the product does not contain any impurities.
    Calculated, ° 4: N 0.9; C, 37.6; H 3.6.
    , 5 2iN60sS.1,5 CbN „OBV-g
    Found,%: N 10.8, C 37.5, H 5.6.
    The ultraviolet spectrum of the product (in pH buffer) shows the maximum absorption at 258.5 nm, with ..
    PRI me R 6. Preparation of the salt of sulfoadenosyl-b-methionine 1.5 (octane disulfonate).
    The procedure of Example 2 is followed, but 1,8-octane disulfonic acid is used instead of 1,4-butane disulfonic acid. Get 20 kg of powder, which in the analysis gives the following composition,%:
    Sulfoadenosyl-Lmetioninch9, 3
    1, 8-Octandisulfonic acid50, 5
    but
    0.2
    The product has the appearance of a crystalline white powder, which is soluble in water up to 30% by weight to form a colorless solution and is not soluble in common organic solvents.
    Thin layer chromatography shows that the product is free of any impurities.
    Calculated,%: N 10; C, 0 H 6.0.
    C. 58-1,5 CgHieOfiS
    Found,%: N Yu; C, 39.9; H 5.9.
    The ultraviolet spectrum of the product (in pH 4 buffer) shows an absorption maximum at 258.5 nm with E) at 173.
    PRI me R 7. Preparation of the salt of sulfoadenosyl-b-methionine 1.5 (1.10-decane disulfonate).
    The procedure of Example 2 is followed, but 1,10-decane disulfonic acid is used instead of 1, 4-butane disulfonic acid. Get 21 kg of powder, which in the analysis gives the following composition,%:
    Sulfoadenosyl-L-methionine 46.8
    1,10-Decanedisulphonic acid 53
    , 2
    the corresponding salt is sulfoadenosyl-L-methionine, 5 (1,1 0-decand — gulfone).
    The product has the form of a crystalline white powder, which is soluble in water up to 20 wt.% With the formation of a colorless solution and not soluble in common organic solvents.
    Thin layer chromatography shows that the product is free of any impurities.
    Calculated, 1: N, 9.8; C 2,3; H 6.5.
    . C ,, N ,, 0.8 g
    Found, N 9.9; C 2.4; H 6.5.
    The ultraviolet spectrum of the product (in pH buffer k) shows a maximum at 258.5 nm with E, 16.
    Po1 | Surprising effect is increased solubility compared to analogs, because the compounds obtained are 10 times more soluble
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining sulfoadeno zyl- / .- methionine salt of general formula
    n (CH2) n, - (SO, H) ,,, where P - 1 ... 2;
    ha - 3 ... 12,
    that is, cultures of Saccharomyces Segusialus, Torulopsic utilis, Candida utilis are added to the target product, cells of water solution and ethyl acetate are lysed at a ratio of 1: 1, then 0.35 n. sulfuric acid, the lysate is purified by ultrafiltration through membranes with a pore limit of 100UO dalton, the lysate is passed through a column with a weakly acidic ion exchange resin in the H-form at pH 3.5 to 7 with a flow rate of 1-3 volumes
     1530100
    liquids at 1 hour per one volume of resin, product from the eluag, then the co-mixture is passed through a column and emulsified with ultrafilsty on membrane-berlite at a rate of 0, -1 volumes of polyamide type 100-200 g / l,
    liquids in part to the volume of the resin, and spray dried at 10–200 s,
    washed with a 20 million solution of disulfo; in this case, the temperature of the air at the outgoing acid until the target disappears is 40-100 ° C.
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    同族专利:
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    IN162199B|1988-04-16|
    AT41157T|1989-03-15|
    DE3568581D1|1989-04-13|
    US4990606A|1991-02-05|
    YU81185A|1988-02-29|
    EG17392A|1992-10-30|
    DK215585A|1985-11-17|
    IT1173990B|1987-06-24|
    YU44499B|1990-08-31|
    MX9203625A|1992-07-01|
    ES543199A0|1986-06-16|
    PT80452B|1987-08-19|
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    IE851187L|1985-11-16|
    NO163743C|1990-07-11|
    JPH0630607B2|1994-04-27|
    PT80452A|1985-06-01|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT20938/84A|IT1173990B|1984-05-16|1984-05-16|STABLE SALTS OF SULPHO-ADENOSYL-METHIONINEPARTICULARLY SUITABLE FOR PARENTERAL USE|LV930949A| LV5531A3|1984-05-16|1993-06-30|Sulfoadenosyl-1-methionine frost yield|
    LTRP1267A| LT2597B|1984-05-16|1993-09-29|SULFOADENZZIL-L-METIONIN SALT RECEIPT|
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