• 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 tetradecapeptide <IMAGE> +tr <IMAGE> is described along with corresponding non-toxic pharmaceutically-acceptable acid addition salts as well as intermediates useful in the synthesis of the tetradecapeptide. This tetradecapeptide as well as its pharmaceutically-acceptable acid addition salts exhibit various activities including inhibition of the release of gastric acid and reduction of gut motility.
    公开号:SU730295A3
    申请号:SU782607708
    申请日:1978-04-20
    公开日:1980-04-25
    发明作者:Эдвин Шилдс Джеймс
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing a new cyclic tetodeadepeptide of the formula N-E-Val-Gly-1 | -Cis-11-Lys-1. - Asp-U-Phen-b-Phen-b-Trp-L-Lys-L-Tpe-b-Phen-b-Tre-b-Cep-V-5
    -Cis-OH (D-Val'-somatostatin) or its salts - biologically active compounds that may find application. In medicine ..
    A known method for locking a disulfide bridge between two sulfhydryl groups present in a cysteine polypeptide molecule by oxidation with atmospheric oxygen is widely used in peptide chemistry (1).
    The purpose of the invention is the preparation of a new cyclic tetradecapapeptide or its salts having interesting pharmacological properties.
    This is achieved by the well-known method ** of producing a cyclic tetradecapapeptide of the formula 1: HD-Ban-L-Gly-L-Cis-L-Lys-L-DSP-L-Phen-L-Phen-L-TRp-and-Lys- L-Tre-L-Phen-O-Tre-b-Ser-L-Cis-OH or its salts, consisting in the fact that the corresponding straight-chain tetradeapeptide of the formula II: H-O-Val-Gly-b-Cis- L-Lys-L-Acn-L-Phen-L-Phen-L-Trp-L-Lys- „and ~ Thp-L-Phen-L-Thp-1 | -Cep-L-Cis-OH is reacted with an oxidizing agent.
    In addition to that, air oxygen is used as an oxidizing agent.
    To obtain a product of formula I, a linear chain tetradecapapeptide is processed under conditions that cause its oxidation by converting two sulfhydryl groups present in the molecule, one in each cysteinyl half, into a disulfide bridge. This can be done by treating the diluted linear heterodecapeptide solution with any of a variety of oxidizing agents, including, for example, iodine and potassium ferrocyanide. Air can also be used as an oxidizing agent, the pH of the mixture being usually from 2.5 to 9.0, and more preferably from 7.0 to 7.6. When air is used as an oxidizing agent, the concentration of the peptide solution is usually not more than 0.4 mg of the peptide per milliliter of solution and usually about 50 mg / ml.
    Pharmaceutically acceptable non-toxic acid addition salts include salts of organic and inorganic acids, for example, hydrochloric, sulfuric, sulfonic, tartaric, fumaric, hydrobromic, glycolic, citric, maleic, phosphoric succinic, acetic acid, nitric benzoic acid, ascorbicene, tolbenzoic, , sulfonaphthalene and propionic, more additive salts, from acetic acid. Any numerical salts can be the usual method.
    PRI me R. Oxidation is somatostatin.
    A solution of reconstituted D-Val * somatostatin (374 ml, theoretically 175 mg) was diluted with 147 ml of 0.2 M acetic acid and concentrated ammonium hydroxide was added to 6.77 ml of distilled * 50 μg / ml to 6.7. The solution was stirred at room temperature in the dark for 64 hours. Ellman titration indicated the end of the oxidation.
    The mixture was concentrated in vacuo to 10 ml. The concentrate is diluted with 10 ml of glacial acetic acid and desalted by passing through a column of Sephades C-25 F (column size 5.0x90 cm); the product is eluted at a temperature of 26 ° C with degassed 50% acetic acid, elution rate: 246 ml / h, the volume of collected fractions is 16.4 ml, after purification. monitored by the absorption of fractions at 280 μm. Fractions O 49-64 (787-1050 ml) were collected, lyophilized in the dark, The dry product was dissolved in 15 ml of degassed 0.2 M acetic acid, and the solution was placed in a Sephadex C-25 column. Chromatography was carried out under the following conditions: solvent - degassing 0.2 M acetic acid, temperature 26 C, flow rate 475 ml / h, volume of collected fractions 16.6 ml, column size 5.0x150 · cm. Chromatography progress was monitored spectrophotometrically at 280 mmk. Fractions No. 157-172 (2590-2855 ml) were collected, a peak of 2667 and 280 mkm, the combined fractions were lyophilized to dryness in the dark. Using ultraviolet spectroscopy, the presence of 95 mg of product in a dry mass was shown (54.3% yield from the reduced form).
    The resulting product was dissolved in 5 mJ .50% acetic acid and
    Preferred from reconstituted in D-Valvody for concentration. To adjust the pH, the mixture is rechromatographed in a Sephadex C-25 F column. Under the following conditions: degassed 50% acetic acid, temperature 26 ° C, flow rate 53.2 ml / h , fractions volume 8.87 ml, column sizes 2.5x180 cm.
    The measure of light absorption at 280 mmk of each fraction, plotted depending on the fraction number, shows one large peak on the curve. Fractions No. 58-60 (488-532 ml), peak 505 at 280 mmk are combined, lyophilized in the dark · to dryness. 2b
    A product is obtained with (</ D - -42.1 ° (c = 1%, in acetic acid), amino acid analysis: 0.98 Val, 1.1 2 Cis, 1.81 2 Lys, 0.95 Asp, 2 f 94 3 Fen, 0.80 Trp, 1.91 2 Thr, .0.85 Ser. Ratio (Gly + Lie): 3 = 1.
    The following three 21 hour hydrolysis were carried out:
    1) in the presence of dimethyl sulfoxide to oxidize cysteine to cysteic acid;
    2) removal of thioglycolic acid
    3) without removal or oxidation
    All values obtained are the average values of three hydrolysis, with the exception of the following: Cis and Ser only 1 / and 2 /; Trp only 2 /, Fen’s only 2 / and 3 /.
    权利要求:
    Claims (2)
    [1]
    Claim
    1. A method of obtaining a cyclic tetradecapeptide of the formula 1: H-D-Val-Gli-i-Cis-Ts-Liz-L-Asp-b-Phen-Ts-Phen-
    -U-Tpn-C-Lys-Tre-C-Phen-t-Tre-L-Cep-U-Cis — OH or its salts, characterized by the fact that the corresponding straight-chain tetradeapeptide of the formula I: H — O — Val -Gly-b-Cis-b-Lys-L-Acn-L-Phen-Ts-Phen-b-TRp-t-Liz-L-Tpe-L-Phen-b-Tre-.C-Ser-b- Cis-OH is reacted with an oxidizing agent.
    [2]
    2. The method of Pop. 1, characterized in that oxygen of the air is used as the oxidizing agent.
    类似技术:
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    同族专利:
    公开号 | 公开日
    PL206280A1|1980-01-02|
    JPS53132588A|1978-11-18|
    PT67913A|1978-05-01|
    US4100117A|1978-07-11|
    YU91578A|1983-01-21|
    BE866117A|1978-10-19|
    RO81079B|1983-05-30|
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    GB1596328A|1981-08-26|
    IT7822552D0|1978-04-20|
    PL114533B1|1981-02-28|
    IE780765L|1978-10-21|
    GR68945B|1982-03-29|
    BG28703A3|1980-06-16|
    DE2816854A1|1978-11-02|
    IE46868B1|1983-10-19|
    AU519275B2|1981-11-19|
    ATA282878A|1980-07-15|
    IL54533A|1982-11-30|
    ZA782247B|1979-12-27|
    DK174278A|1978-10-22|
    DD135900A5|1979-06-06|
    CS202096B2|1980-12-31|
    AR221699A1|1981-03-13|
    FR2387941B1|1983-06-10|
    AT361142B|1981-02-25|
    ES476901A1|1979-10-16|
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    NZ187009A|1981-04-24|
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    RO76054A|1981-08-17|
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    CA1113928A|1981-12-08|
    CA1102315A|1981-06-02|
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    PL115827B1|1981-05-30|
    SE7804397L|1978-10-22|
    IL54533D0|1978-07-31|
    FI64576B|1983-08-31|
    FR2387941A1|1978-11-17|
    AU3525378A|1979-10-25|
    HU177435B|1981-10-28|
    引用文献:
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    US4372884A|1975-08-06|1983-02-08|The Salk Institute For Biological Studies|Pharmaceutically active peptides|US4202802A|1978-10-02|1980-05-13|Eli Lilly And Company|Peptides related to somatostatin|
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    GB8423431D0|1984-09-17|1984-10-24|Sandoz Ltd|Organic compounds|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/789,472|US4100117A|1977-04-21|1977-04-21|Somatostatin analogs and intermediates thereto|
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