• 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:
    1. Claims for the contracting States : BE, CH, LI, DE, FR, GB, IT, NL, SE, Peptides having the general formula X-Arg-Val-Tyr-Ile-His-Pro-Y-O-A wherein X represents an acyl radical of a N-methyl-aminoacid or of an aliphatic carboxylic acid having in the alpha-position an aminooxy group or a hydroxyl group, each in the L-configuration in case of an asymmetrical carbon atom, Arg represents a radical of L-arginine, Val represents a radical of L-valine, Tyr represents a radical of L-tyrosine, Ile represents a radical of L-isoleucine, His represents a radical of L-histidine, Pro represents a radical of L-proline, Y represents a radical of an aliphatic alpha-hydroxycarboxylic acid having 1 lacking hydrogen atom of its hydroxyl group with respect of this acid beyond the absence of the hydroxyl group of the carboxylic group and A represents hydrogen or an alkyl radical having from 1 to 5 carbon atom(s), as well as their acid addition salts and pharmaceutically useful complexes. 1. Claims for the contracting state AT A process for the preparation of peptides having the general formula X-Arg-Val-Tyr-Ile-His-Pro-Y-O-A wherein X represents an acyl radical of a N-methyl-aminoacid or of an aliphatic carboxylic acid having in the alpha-position an aminooxy group or a hydroxyl group, each in the L-configuration in case of an asymmetrical carbon atom, Arg represents a radical of L-arginine, Val represents a radical of L-valine, Tyr represents a radical of L-tyrosine, Ile represents a radical of L-isoleucine, His represents a radical of L-histidine, Pro represents a radical of L-proline, Y represents a radical of an aliphatic alpha-hydroxycarboxylic acid having 1 lacking hydrogen atom of its hydroxyl group with respect of this acid beyond the absence of the hydroxyl group of the carboxylic group and A represents hydrogen or an alkyl radical having from 1 to 5 carbon atom(s), as well as of their acid addition salts and pharmaceutically useful complexes, characterized in that one condenses in a manner known per se in the peptide chemistry a propper aliphatic alpha-hydroxyl carboxylic acid or a propper alkyl ester of it having from 1 to 5 carbon atoms in the alkyl part or another ester of it only with a protective function of the ester group with the amino acid to be incorporated successively and having on its terminal nitrogen atom a splittable-off protective group and, as far as necessary, on another nitrogen atom being optionally present another splittable-off protective group and/or with the peptide fragment or an ester derivative of it, respectively, successively to be incorporated and having on its terminal nitrogen atom a splittable-off protective group and, as far as necessary, on one or several other nitrogen and/or oxygen atom(s) one or several protective group(s) and, if desired, one carries out with the obtained peptide intermediate protected on the terminal nitrogen atom and with the further peptide intermediate(s) obtained by possible further condensations of this type and protected on the terminal nitrogen atom after having removed the protective group of the terminal nitrogen atom one further condensation or further condensations, respectively, with the amino acid or with the respective amino acid, respectively, successively to be incorporated and having on its terminal nitrogen atom a splittable-off protective group and, as far as necessary, on another nitrogen atom or oxygen atom optionally present another splittable-off protective group and/or with the peptide fragment or an ester derivative of it, respectively, successively to be incorporated and having on its terminal nitrogen atom a splittable-off protective group and, as far as necessary, on one or several other nitrogen and/or oxygen atom(s) optionally present one or several protective group(s) accomplishing as much condensations as are necessary for incorporating all desired amino acid units as well as thereafter in a manner known per se selectively step by step or in one step one removes from the obtained protected peptide derivative the protective group of the terminal nitrogen atom and the possible protective group(s) of other nitrogen atoms or oxygen atoms, respectively, as well as, if desired, the amino group of the aminooxy group optionally present, whereafter, if desired, in a manner known per se one converts the obtained peptide of the general formula I into an acid addition salt or into a complex of it or, if desired, the obtained acid addition salt of the peptide of the general formula I into another acid addition salt or in the peptide of the general formula I, respectively.
    公开号:SU993816A3
    申请号:SU813233003
    申请日:1981-01-16
    公开日:1983-01-30
    发明作者:Ньеки Ольга；Кишфалуди Лайош；Карпати Эгон；Спорни Ласло
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Фирма)；
    IPC主号:
    专利说明:

    (5) METHOD OF CALVING OCTEPEPTIDES
    The invention relates to the production of octapeptides with biological activity, which can be used in medicine for diagnosis and therapy.
    Peptide chemistry widely uses the method of producing peptides by cleaving the protective groups from the corresponding peptide derivatives by thiolysis (in the case of histidime protective group), Cl3 and catalytic hydrogenation (in the case of, for example, the benzyloxycarbonyl group, nitro group, etc.) 2;
    The use of known methods of is allows to obtain new compounds with interesting pharmacological properties.
    The purpose of the invention is to obtain new octapeptides that broaden the arsenal of means of influencing a living organism.
    The goal is achieved by the fact that according to the method of producing octapeptides of the general formula
    X-Arg-Vat-Ty g-1 Wei-H i s-P ro-Y-OA (I),
    Where
    Y-residue of lactic acid, or 1-2-hydroxy-3-methylvaleric
    acids; . A-hydrogen, ethyl,
    protected octapeptide of the general formula Z-X-Arg (N02) -Vat-Tyr (Bzl) -1leu-His (Dnp) -Pro-Y-F, (I) where Z is benzyloxycarbonyl; X and Y are 1. indicated values; Bzt is benzyl; Opr - dinitrophenyl;
    F - ethyl, benzyl,. is treated with 2-mercapto. ethanol to remove the single-trinityl protecting group of histidine, and then the other protecting groups are removed by catalytic hydrogenation.,
    The synthesis of the initial protected octapeptides is carried out by stepwise increasing the peptide chain using the pentafluorophenyl ethers of the corresponding N-tert. butyloxycarbonylamino acids.  The following abbreviations are used in the examples: Lac is L-lactic acid; HMV is L-2-hydroxy-3-methylvaleric acid; PfP - pentafluorophenyl; Voy - t. butylxycarbonyl; BzE is benzyl; Z is benzyloxycarbonyl; Opr - dinitrophenyl.  For thin layer chromatography, silica gel plates (Merck) and the following solvent mixtures are used: 1hexane: ethyl acetate k. , 2 ethyl acetate: pyridine: acetic acid lot: water 20: 6: 11/95: 5, 3 ethyl acetate: pyridine: acetic acid lot: water 20: 6: 11/90: 10, i ethyl acetate: pyridine: acetic acid lot: water 20 : 6: 11/80: 20, 5 ethyl acetate: pyridine: acetic acid: water 20: 6: 11/70: 30 6N-butanol: acetic acid: water: 1: 5 (upper phase) 7N-butanol: acetic acid: pyridine: water 30: 6: 20: 2 8n-butanol: ethyl acetate: acetic acid: water 1: 1: 1: 1.  A ninhydrin solution and a chlorotolidine / potassium iodide mixture are used to detect the spots.  Purification of the final octapeptides was carried out using column chromatography on a column containing O, 5 liters of carboxymethyl cellulose (KMC-52), pre-equilibrated with 0.01 Must of acetic acid ammonium.  The purification was carried out in a gradient elution mode with the use of 1.5 liters of 0.01 M and 1.5 liters of O, C M ammonium acetate solutions, which were fed through a gradient mixer at a speed of 25.  ml / h  The fractions containing the pure final product are lyophilized.  Example 1  The first stage.  A solution of 2.15 g (10 mmol) of Boc-Pro-OH in 10 ml of anhydrous tetrahydrofuran is cooled to 0 ° C and added to it with stirring in portions over 10 minutes 2, g 05 mmol) carbonyldiimidazole.  The mixture is then added in portions over 15 minutes at 0 ° C to a solution of 1.8 g (10 mmol) of lactic acid benzyl ester in 10 ml of anhydrous tetrahydrofuran, stirred for 30 minutes at 0 ° C, 2 hours at and kept overnight in a refrigerator.  The solvent is then distilled off, the residue is dissolved in 30 ml of chloroform, extracted with 1N.  solution of hydrochloric acid (k times 10 ml), water, 10 ml of an aqueous solution of sodium hydrogen carbonate and water.  The organic phase is dried over anhydrous sodium sulphate and evaporated to constant weight.  The residue is dried over P205. 3.0 g of Boc-Pro-Lac-OBzt is obtained (80% of the theoretical yield), 32; 57.  Second Stage, Z-Sar-Arg (N02) -Va -Tyr (Bzf) -lu-flis (Dnp) -Pro-Lac-OBzl.  2.35 g (7.5 mmol) of Boc-Pro-Lac-OBzC is dissolved in 15 ml of 3N.  a solution of NS 1 in dioxane, - incubated for 15 minutes  30 ml of anhydrous ether are added. It is evaporated to dryness.  Residual hydrochloride of the free dipeptide HCf ". H-Pro-Lac-OBzf, 37 was dissolved in 20 ml of dimethylformamide, the solution was adjusted to pH 8 by addition of triethylamine and added. 2.9 g (5 mmol) of Boc-His (Dnp) -OPfp.  The mixture is stirred for 1 hour at room temperature and pH 8.0, the solvent is distilled off.  The residue is dissolved in ethyl acetate, extracted with 10% citric acid solution, 1N.  hydrochloric acid solution, aqueous sodium hydrogen carbonate solution, and water.  The organic phase is dried over anhydrous sodium sulphate, the solvent is distilled off.  The residual protected tripeptide Boc-Hfs (Dnp) -Prd-Lac-OBzE (, 77) is dissolved in 10 ml 8 n.  of a solution of HCt in dioxane, anhydrous ether is added after 20 minutes, the precipitated precipitate is filtered off, washed with ether.  The resulting free tripeptyl hydrochloride HCfH-Hfs (Onp) -Pro-Lac-OBz0 (, 10) was dissolved in 20 ml of dimethylformamide, the pH of the solution was adjusted to 8.0 by addition of triethylamine and 2.78 g (7.5 mmol) was added Boc-lfe-OPfp.  The reaction mixture is stirred for 1 hour at pH 8.0, the solvent is distilled off, the residue is dissolved in ethyl acetate, extracted with 10% citric acid solution, 1N.  hydrochloric acid solution, sodium hydrogen carbonate solution and water.  Then the organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue is triturated with n-hexane and filtered.  The resulting protected tetrapeptide Bocue-I e-His- (Opr) -Rgo-Lac-ORzf (, 67) is dissolved in 10 ml of 9N.  anhydrous ester and the hydrochloride of the free tetrapeptide HC1-H-lEe-His (Dnp) -Pro-Lac-OBzE (, 52} separated, dissolved in 20 ml of dimethyl formamide, The pH of the solution was adjusted to 8.0 by addition of triethylamine and 3.2 g (6 mmol) of Boc-Tyr (Bzt) -OPfp was added.  The mixture is stirred at pH 8.0 for 30 minutes, evaporated, the residue is solution. in ethyl acetate and the solution is mixed with 0.22 mm S, M-dimethylaminoethanol, incubated for 15 minutes.  Then the solution is extracted with a 10% solution of citric acid, 1N.  hydrochloric acid solution, water, sodium carbonate solution and water.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue is triturated with a mixture of n-hexane-ether (8: 2) and filtered.  The Boc-Tyr (Bzt) -lEe-Hs (Dnp) -Pro-Lac-OB2t {RY-0.72) protected pentapeptide obtained was dissolved in 10 ml of 8N.  of an HC solution in dioxane, anhydrous ether and the precipitated hydrochloride of free pentapeptide HCt- are added after 15 minutes. H-Tyr (BzE) -lfe-His (Dnp) -Pgo-Lac-OBzlJ is dissolved in 20 ml of dimethylformamide, the pH of the solution is adjusted to 8.0 by addition of triethylamine and mixed with 2i6 g (6.8 mmol) of Boc- Vat-OPfp.  The mixture is stirred.  1 hour at pH 8.0 and.  evaporated.  The residue is dissolved in ethyl acetate and the solution is extracted as described above.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue is triturated with anhydrous ether and the resulting protected hexapeptide Boc-Vat-Tyr (Bzf) -l e-His (Dnp) -Pro-Lac-OBzB (, 83) is filtered into 10 ml of 8N.  a solution of HC € in dioxane, anhydrous ether is added in 15 minutes and the hydrochloride of free hexapeptide HCtH-VaE-Tvr (Bzt) -l e-His (Dnp) -Pro-Lac-OBz (, 65) is dissolved in 20 ml of dimethylformamide, the pH of the solution was adjusted to 8.0 by the addition of triethylamine, and 2.2 g (5 mmol) of Boc-ArglN -OPfp was added.  The mixture was kept for 1 h. Lree pH 8.0, diluted with ml, chloroform and extracted with 10% citric acid solution, 1N.  a solution of salt 9 66.  .  acid and water.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue is triturated with a mixture of ethanol and ether (1: 1) and the product off-t is distilled.  Received for-.  The protected Boc-Arq (NO ) -Vat-Tyr (BzE) -lte-Hfs (Opp) -Pro-Lac-OBzl (, 65) protected heptapeptide is dissolved in 10 ml of 8N.  of an HCt solution in dioxane, anhydrous ether and hydrochloride of free heptapeptide HCC "H-Ag (N02) -VaE-Ty (Bz e) - I fe-H IS (Dnp) -P go-Lac-OBzl ( R 0,4o) is filtered off, washed with ether and.  The resulting product was then dissolved in 15 ml of dimethylformamide, the pH of the solution was adjusted to 8.0 by addition of triethylamine and 1.8 g (5 mmol) of Z-Sar-OPfp was added.  The mixture was stirred for 30 minutes at 0, diluted with 60 ml of chloroform and extracted with water.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue is triturated with anhydrous ether and the product is filtered off.  The result is 2.12 g (29.6 from the theoretical yield calculated for histidine) Z-Sar-Arg (NO) -VaC-Tyr (Bz8) -lFe-Hf5 (Dnp) -Pro-Lac-OBzf T.  square  204-21 (,).  Third stage.  H-Sar-Arg-Vat-Tyr-IEe-His-Pro-Lac-OH.  N0 1, t5 g (1 mmol) of Z-Sar-Arg-Vaf-Tyr (Bzt) -lfe-His (Dnp) -Pro-Lac-OBzE is dissolved in 5 ml of dimethylformamide and mixed with 2.3 ml (30 mmol ) 2-mercaptoethanol.  The mixture was stirred for 1 h. Anhydrous ether was added, the precipitated precipitate was dissolved in methanol and precipitated again, and ether was added.  In the end, 1.1 g (89% of the theoretical yield) of Z-Sar-Arg (NOo) -Vat-Tyr (Bzf) -lEe-HIs-Pro-Lac-OBzt (, 60) are obtained.  The resulting product is dissolved in AO ml of a mixture of methanol, acetic acid and water (5: 1: 2).  The solution is mixed with 0.6 g of loi-horo palladium catalyst on activated carbon, after which hydrogen gas is passed through the reaction mixture under intensive ne; stirring.  The catalyst is then separated by filtration, washed with methanol-acetic acid-water (5: 1: 1) and the combined filtrate is evaporated.  The residue is triturated with anhydrous ethanol and the product is filtered off.  Get it. 0.7 g (Bk% of theoretical yield) H-Sar-Arg-VaC-Tyr-I Its-His-Pro-Lac-OH, which is purified as described. above the general method.  The result is the target product, having the following characteristics:, 17i. iO; 21  Amino Acid Analysis: Pro 1.0 (l); Va0 1.0 (f); I Its 1.03 (D; Tyr 0.85 (); His 0.85 (I); Arg 0.96 (l); Sar 1.0 (I).   -101, (, 25; 1 H.  acetic acid).  P p and m e p 2.  Sar-Arg-Vat Tyr-l e-His-Pro Lac-0 € t First Stage.  .  k, 3 r (20 mmol) of Boc-Pro-OH is dissolved in 20 ml of anhydrous tetrahydrofuran, the solution is cooled to and for 10 minutes, 4.8 g (30 mmol) of carbonyl imidazole is added in portions to it.  A solution of 2.1 g (20 mmol) of lactic acid ethyl ester in tetrahydrofuran, cooled to 0 ° C, is then added dropwise at 0 ° C.  The reaction mixture is stirred for 30 minutes at 0 ° C for 2 hours at 20 ° C and left overnight.  Then. tetrahydrofuran is removed by distillation.  The residue was dissolved in kO ml of ethyl acetate and the solution was extracted with 1N.  hydrochloric acid solution (2 times 15 ml each), water, sodium hydrogen carbonate solution (2 times 20 ml each time) and water.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue is dried in a desiccator to constant weight.  In the end, get 2,, 22 g (36% of theoretical yield) Boc-Pro-Lac-OEt, 77; 36  Second Stage Z-Sar-Arg (N02) -Va -Tyr (Bz) -lEe-His (Dnp) -Pro-Lac-OEt 1.8 g (6 mmol) of Boc-Pro-Lac-OEt is dissolved in 8 ml 7.5 n.  HCt solution in dioxane, after 15 minutes, 30 ml of ether are added and evaporated.  The residue obtained in the residue of HCH3H-Pro-Lac-OEt (31 is dissolved in 15 ml of dimethylformamide, the pH of the solution is adjusted to 8.0 by addition of triethylamine, and 2.9 g (5 mmol) of Boc-His (Dnp) - OPfp.  The mixture was kept for 1 hour, evaporated and the residue was dissolved in ethyl acetate.  The resulting solution was extracted with 10% citric acid solution, 1N.  hydrochloric acid solution, sodium hydrogen carbonate solution and water.  The organic phase is dried over anhydrous sodium sulfate and the resulting evaporated, the rest protected Boc-His tripeptide (Dinp) -Pro-Lac-OEt (0.69) is dissolved in 20 ml 7.5 n.   bcc HCl in dioxane, anhydrous ether is added after 20 min and the free tripeptide hydrochloride HCtvH-His (Dnp) -Pro-Lac-OEt (0.18) precipitated is dissolved in 15 ml of dimethylformamide, pH. the solution was adjusted to 8.0 by addition of triethylamine and 3.0 g (7.5 mmol) of Boc-1Pe-OPfp was added.  The mixture was kept at 0-30 minutes, evaporated and the residue was dissolved in ethyl acetate.  The resulting solution is extracted as described above.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue was triturated with ether n-hexane (2: 8) and the product was filtered off.  The resulting protected tetrapeptide Boc-lEe His (Dnp). -Pro-Lac-OEt (, 36) was dissolved in 10 ml of 8N.  HCl solution in dioxane, anhydrous ether is added after 15 min and the free tetrapeptide HC1 H lge-His (Dnp) -Pro-Lac-OEt (Rt | Lo, 27) hydrochloride which has precipitated is dissolved in 20 ml of dimethylformamide, pH of the solution is t to 8.0 by addition of triethylamine and 3.24 g (7 mmol) of Boc-Tug (BzE) OPfp are added.  The mixture is kept for 30 min at, 0 and evaporated.  The residue is dissolved in ethyl acetate and the solution is mixed with 0.22 ml of M, M-dimethylaminoethylamine.  After 40 min, the solution is extracted as described above.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue is triturated with n-hexane and the product is filtered off.  The resulting Boc-Tyr (BzE) -lEe-His (Dnp) -Pro-Lac-OEt (, 64) protected pentapeptide is dissolved in 10 ml of 8N.  HCl solution in dioxane, anhydrous ether and hydrochloride of free pentapeptide HC-H-Tyr (Bzg) are added after 15 minutes. -lfe-His (Dnp) -Pro-Lac-OEt (, 33) is dissolved in 15 m of dimethylformamide, the pH of the solution is adjusted to 8.0 by addition of triethylamine and mixed with 2.1 g (5.5 mmol) of Boc-Val -OPfp.  The mixture was kept at 30 MWH at, 0, evaporated and the residue was dissolved in ethyl acetate.  The resulting solution is extracted as described above.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue is triturated with n-hexane and the product is filtered off.  The resulting protected Boc-Vat-Tyr (BzE) -l Her-His (Onp) -Pro-Lac-OEt (, 76) hexapeptide was dissolved in 10 ml of 8N.  HCl solution in dioxane. after 15 minutes, anhydrous ether is added and the hydrochloride of free hexapeptide HClH-Va -Tvr {Bzl2) -lFe-His (Dnp) -Pro-Lac-OEt () is precipitated in 20 ml of dimethylformamide, the pH is adjusted to 8.0 by addition of triethyl amine and mixed with 3. 96 g (6 mmol) Vos-Agde (N02) OPfp.  The mixture was kept at a pH of 8.0. 1 h was diluted with 60 ml of chloroform and extracted as described above.  The organic phase is dried over sodium sulfate and evaporated.  The residue is triturated with anhydrous ethyl alcohol and the product is filtered off.  The resulting protected heptapeptide Boc-Agde (N02) - / at-Tyr (B2t) -1 Ee-Hi S (Dnp) -Pro-Lac-OEt (, 78) is dissolved in 10 ml 8 n.  HCl solution in dioxane, after 15 min. anhydrous ether was added, vol. The precipitated hydrochloride of free heptapeptide rac HCfH-Arg (N02) -VaE-TyciBzt) -lEe-His (Onp) -Pro-Lac-OEt, 56J is dissolved in 20 ml of dimethylformamide, the pH of the solution is adjusted to 8.0 by addition of triethylamine and mixed with 2.12 g (5.5 mmol) of Z-Sar-OPfp.  The mixture was kept at pH 8.0 for 30 minutes and diluted with 60 ml of chloroform.  The resulting solution is extracted as described above.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue is triturated with ether, the product is filtered and recrystallized from ethanol. .  The result is 1.21 g (17.5% of the theoretical yield calculated for histidine) Z-Sar-Arg (N02) -VaE-Tyr (BzE) -lEe-Hi5 (Dnp) -Pro-Lac-OEt.  T.  mp 208-2 12 ° C; ,five.  Third stage.  H-Sar-Arg-VaC Tyr-1te-H1s-Pro-Lac-OEt.  1.21 g (0.88 mmol) of Z-Sar-Arg (N02 -Valf-Tu g-1 te-H is (Dnp) -P go-Lac-OEt is dissolved in 5 ml of dimethylformamide and the resulting solution is mixed with 3 ml of 2-mercaptoethanol.  The mixture is stirred for 1 h, anhydrous ether is added, the precipitated precipitate is filtered off, washed with ether, dissolved in methanol and again precipitated, added ether.  A total of 0.9 g (89%, theoretical yield) of Z-Sar-Arg (M02-Val-Tyr (BzC) -lfe-His-Pro-Lac-OEt (, 59)) is obtained.  The product obtained is dissolved in a mixture containing methanol, acetic acid and water (5: 1: 1).  The solution is mixed with 0.5 g of a 10% palladium catalyst on activated carbon and, with vigorous stirring, hydrogen gas is passed through the solution for 20 h.  Then the catalyst is filtered off, washed with a mixture of methanol-acetic acid-water (3: 1: 1) and the combined filtrate is evaporated.  The residue is triturated with a mixture of ethanol-ether and the product is filtered off.  A total of 0.72 g (9b% of the theoretical yield) of H-Sar-Arg-VaE-Tug-Ite-His-Pro-Lac-OEt is obtained, which is purified by the general procedure described above.  In the end, get a target product with the following characteristics:,, 53; / About D. -f R-O, 36.  Amino Acid Analysis: Pro 1.02 (I); Val 0.97 (i); I Pe 1.08 (i); Tug 0.91 (I); His 1.00 (I); Arg T, 07 (I); Sar 1.0 (I). cij20 -73,5 ° (c.  0 ;; 1 H.  acetic acid).  n p and m e p 3.  Sar-Arg-Va -Tyr-lEe-His-Pro-HMV-OH.  The first stage.  H-HMV-OBzf.  7, 12 g (kQ mmol) of H-HNV-ONa are suspended in 10 ml of ethyl acetate and the suspension is mixed with 20 ml of n.  solution of HC in ethyl acetate. The mixture is stirred for 2 hours, then the pH of the mixture is adjusted to 7 by addition of triethylamine, the precipitated precipitate is filtered, washed with ethyl acetate (2 ml of 20 ml).  The pH of the combined filtrate is adjusted to 6.0 by the addition of triethylamine and 8 ml (60 mmol) of benzyl bromide and 8.4 ml (60 mmol) of triethylamine are added.  The mixture is boiled for 8 hours, the precipitate formed is filtered off and the filtrate is extracted with water, 1N.  hydrochloric acid solution, 5% sodium hydrogen carbonate solution and water.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  8% get 5. 6 g (63% of theoretical yield) H-HMV-OBZ0, which is purified by distillation in vacuum.  T.  kip  l8i} -l86 ° C / 5 mmHg  Art. ; . . .  13.9 ° (acetone). .  The second stage.  Boc-Pro-HMY-OBzl.  2.7 g (12.5 mmol) of Boc-Pro-OH is dissolved in 15 ml of anhydrous tetrahydrofuran, the solution is cooled to and added to it in small portions within 10 minutes 3. 2 g (20 mmol) of carbonyldiimidazole.  The mixture is mixed at 0 ° C with a solution of 2.8 g (12.5 mmol) of H-HMV-OBzl in io ml of tetrahydrofuran, stirred for 30 minutes at 0 ° C, 2 hours at and left overnight in a refrigerator.  After the tetrahydrofuran is distilled off, the residue is dissolved in 40 ml of ethyl acetate.  The resulting solution was extracted with 1N.  solution of hydrochloric acid (2 ra for 15 ml), water, solution of acid sodium carbonate and water.  The organic phase is dried over non-aqueous sodium sulfate and evaporated.  The residue is dried at constant weight.  As a result, 1,19 g (6S% of theoretical yield) was obtained; B6c Pro-HNV-OBzl R 0.90; 33  Third stage.  Z-Sar-Arg {N02) -VaE -Tyr (BzlD-lEe-His (DnD} -Pro-HNV-UBzl 2.52 g (6 mmol) Boc-Pro-HMY-OBzl was dissolved in 8 ml of 8 n.  HCl solution in dioxane, after 15 minutes, 30 ml of anhydrous ether are added and evaporated.  The residual hydrochloride of the free HC1 H-Pro-HMV-OBzl (30) dipeptide is dissolved in 15 ml of dimethylformamide, the pH of the solution is adjusted to 8.0 by the addition of triethylamine and 2.9 g (5 mmol) of Boc-His ( Dnp) -OPfp.  The mixture was kept at pH 8.0 for 1 hour, evaporated and the residue was dissolved in ethyl acetate; The resulting solution was extracted with 1N.  hydrochloric acid solution, water, sodium carbonate solution.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residual protected Boc-His tripeptide (Dnp) -Pro-HHV-OBzl (, 67) was dissolved in 10 ml of 8N.  HCl solution in dioxane, anhydrous ester was added after 20 min. The free tripeptide HCbH-His hydrochloride (Dnp) Pro-HMV (, 18) was precipitated and diluted with 15 ml of dimethylformamide, the pH was adjusted to 8.0 by addition of triethylamine and mixed with 2.4 g (6 mmol) of Boc-1Ce-OPfp.  The mixture is kept for 1 h at, 0 and evaporated.  The residue is dissolved in chloroform and the solution is extracted with water, 1N.  solution of hydrochloric acid and. sodium carbonate solution.  The organic phase is dried over anhydrous sodium sulfate and evaporated.  The residue is triturated with n-hexane, the hexane is separated by decantation, and the residue is triturated with ether and the product is filtered off.  The resulting protected tetrapeptide, Boc-lPe-His (Dnp) -Pro-HMV-OBzC (, 65), is dissolved in 10 ml of 8N.   of an HCt solution in dioxane, anhydrous ester was added after 15 minutes, the hydrochloride of the free tetrapeptide hydrochloride, HCHH-I H-H is (Dnp) -Pro-HMY-OBzl (27), was dissolved in 15 ml of dimethylformamide, adjusted to pH solution to 8.0 by addition of triethylamine and mixed with 2. , 9b g Boc-Tyr (Bzf) -OPfp.  The mixture was incubated for 30 minutes at pH 8.0 and evaporated.  The residue is dissolved in ethyl acetate.  To the resulting solution was added 0.22 ml of M, M-dimethylaminoethylamine, incubated for 10 minutes and extracted.   an aqueous solution of citric acid, 1 n.  solution of hydrochloric acid, 5% ra / g of sodium hydrogen carbonate and water.  The organic phase is dried over anhydrous sodium sulphate and evaporated.  The residue is triturated with n-hexane and the product is filtered off.  The resulting Boc-Tyr BzK) -lEe-His (Dnp) -P protected Pentapeptide. ro-HMV-OBzt (, 75) was dissolved in 10 ml 8 n.  HCl solution in dioxane, anhydrous ester is added after 15 minutes, the hydrochloride of free pentapeptide HCt-H-Tyr Bzn-1Pe-His (Dnp) -Pro-HMV-OBzU (, 60) is dissolved in 20 ml of dimethylformamide, pH the solution was adjusted to 8.0 by addition of triethylamine and mixed with 2.6 g (6 mmol) of Boc-Val-OPfp.  The mixture was incubated for 1 h at pH 8.0 and evaporated.  The residue was dissolved in chloroform and the solution was extracted with 10% citric acid solution, 1N.  hydrochloric acid solution, sodium hydrogen carbonate solution and water.  The organic phase is dried over anhydrous sodium sulphate and boil.  The residue is triturated with n-hexane and the product is filtered off.  The resulting protected hexapeptide Boc-Val -Tyr (B2L) -lEe-His (Dnp) -Pro-HMV-OBzl (. , 71) is dissolved in 10 ml of 8N.  HC1 solution in dioxane, anhydrous ether is added in 15 minutes, the hydrochloride of free hexapeptide HCC-H-VaC-TyrCBzf) -lEe-His (Dnp) -Pro-HMV-OBzf is added to precipitate, dissolved in 20 ml of dimethylformamide, pH the solution is made up to 8.0 by addition of triethylamine and mixed with 2.64 g (6 mmol) of Boc-Arg (NO) -OPFp.  The mixture was incubated for 1 h at pH 8.0 and evaporated.  The residue was dissolved in chloroform, and the solution was extracted with an aqueous solution of citric acid, 1 N, hydrochloric acid, and aqueous
    权利要求:
    Claims (1)
    [1]
    Claim
    25 A method for producing octapeptides of the general formula
    X-Arg-Va ^ -Tyr-Ite-His-Pro-Y-OA, where X is Sar;
    Υ - the remainder of L-lactic acid
    30 or L-2-hydroxy-3-methylvaleric acid;
    A is hydrogen, ethyl, characterized in that the protected octapeptide of the general formula:
    ZX-Arg (N0 2 ) -Vai-Tyr (Bzi) -lte-His (Dnp) -Pro-YF, where Z is benzyloxycarbonyl;
    X and Y have the indicated meanings;
    BzE is benzyl;
    Dnp is dinitrophenyl; F is ethyl, benzyl,.
    treated with 2-mercaptoethanol to remove the histidine dinitrophenyl protecting group, and then the remaining protecting groups are cleaved off by catalytic hydrogenation.
    类似技术:
    公开号 | 公开日 | 专利标题
    Ondetti et al.1968|Side reactions in the synthesis of peptides containing the aspartylglycyl sequence
    US4732890A|1988-03-22|Retro-inverso hexapeptide neurotensin analogs, process for their preparation and pharmaceutical compositions containing them
    EP0301639A2|1989-02-01|Analogues of the bradykinin potentiating peptide BPP 5a and methods for their preparation
    US3931141A|1976-01-06|Novel heptapeptides having gastrin activity
    US4093610A|1978-06-06|Process for producing triglycyl-lysine vasopressin and intermediates therefor
    US3842064A|1974-10-15|Psychopharmacologically active tetra-,penta-,hexa-,and hepta-peptides
    Nissen et al.1975|Polydepsipeptides, 4 Synthesis of the alternating Polydepsipeptides Poly | and Poly |
    SU993816A3|1983-01-30|Process for preparing octapeptides
    Stewart1965|The synthesis and polymerization of peptide p-nitrophenyl esters
    SU772481A3|1980-10-15|Method of preparing pentapeptides or their esters of their salts
    US4209442A|1980-06-24|Angiotensin II analogs and process for the preparation thereof
    US3856770A|1974-12-24|Psychopharmacologically active tetra-, penta-, hexa-, and heptapeptides
    US4623640A|1986-11-18|Peptides
    SU845773A3|1981-07-07|Method of preparing peptides
    US3299035A|1967-01-17|L-aspartyl-l-alanyl-l-phenylalanyl-l-isoleucyl-glycyl-l-leucyl-l-methioninamide and its acid addition salts
    CA1249396A|1989-01-24|Partially retro-inverted decapeptide as a specificrenin inhibitor with high resistance to enzymatichydrolysis
    US3973006A|1976-08-03|Peptide enzyme inhibitors of angiotensin I
    JPH09503200A|1997-03-31|Oligopeptide derived from C-reactive protein fragment
    FR2557114A1|1985-06-28|NOVEL DERIVATIVES OF GONADOLIBERIN, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
    CZ280726B6|1996-04-17|Pentapeptidic precursors of biologically active cyclic dipeptides
    US4204991A|1980-05-27|Sarcosine1 dehydroalanine8 angiotensin II derivatives
    US4301066A|1981-11-17|Preparation of |-LH-RH via the heptapeptide H-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2
    US3272790A|1966-09-13|Polypeptides
    Dagan et al.1986|Tuftsin analogs: synthesis, structure-function relationships, and implications for specificity of tuftsin's bioactivity
    US4102878A|1978-07-25|Process for the preparation of the cholecystokinin-pancreozymin octapeptide amide sulfate ester
    同族专利:
    公开号 | 公开日
    HU181008B|1983-05-30|
    FI73225B|1987-05-29|
    US4330532A|1982-05-18|
    FI810123L|1981-07-19|
    NO151409B|1984-12-27|
    NO151409C|1985-04-10|
    FI73225C|1987-09-10|
    PL229223A1|1982-03-01|
    ES8201129A1|1981-12-01|
    DK149777B|1986-09-29|
    YU42550B|1988-10-31|
    DE3160608D1|1983-08-25|
    AU6627681A|1981-07-23|
    IL61922A|1984-01-31|
    DK149777C|1987-04-21|
    EP0034260B1|1983-07-20|
    AT4197T|1983-08-15|
    ES498583A0|1981-12-01|
    PL130448B1|1984-08-31|
    DK20481A|1981-07-19|
    PH17196A|1984-06-19|
    YU9381A|1983-09-30|
    EP0034260A1|1981-08-26|
    JPS56142251A|1981-11-06|
    CA1149377A|1983-07-05|
    IL61922D0|1981-02-27|
    NO810149L|1981-07-20|
    CS219939B2|1983-03-25|
    AU541000B2|1984-12-13|
    IN153279B|1984-06-23|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3947575A|1969-06-30|1976-03-30|E. R. Squibb & Sons, Inc.|Peptides as argiotensin converting enzyme inhibitors|
    DE2323322A1|1973-05-09|1974-11-28|Hoechst Ag|NEW PEPTIDES WITH BLOOD PRESSURE REDUCING EFFECT AND PROCESS FOR THEIR PRODUCTION|
    US3923770A|1974-05-10|1975-12-02|Francis Merlin Bumpus|{8 Me{hd 2{b Gly{hu 1{b , Ile{hu 8{b {9 -Anziotensin II as an angiotensin antagonist|
    US3923769A|1974-05-10|1975-12-02|Francis Merlin Bumpus|{8 N-Me-Ile{40 ,Ile{hu 8{b {9 -Angiotensin II as an angiotensin antagonist|
    US3915948A|1974-08-05|1975-10-28|Morton Norwich Products Inc|Sarcosyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl-L-histidyl-L-proline|
    DE2457463A1|1974-12-05|1976-06-10|Hoechst Ag|NEW PEPTIDES WITH BLOOD PRESSURE REDUCING EFFECT AND PROCESS FOR THEIR PRODUCTION|
    US3975365A|1975-01-27|1976-08-17|G. D. Searle & Co.|Inhibitory octapeptides angiotensin II|
    US3976770A|1975-02-10|1976-08-24|Francis Merlin Bumpus|Sar'-Thr8 Angiotensin II as an angiotensin II antagonist|
    HU177134B|1977-07-18|1981-07-28|Richter Gedeon Vegyeszet|Process for preparing angiotensin ii analogues containing alpha-hydroxy-acid in position 1 with angiotensin ii antagonist activity|
    HU177133B|1977-07-18|1981-07-28|Richter Gedeon Vegyeszet|Process for preparing angiotensin ii analogues containing alpha- amino-oxy-acid in position 1 with angiotensin ii antagonist activity|US5182264A|1986-03-07|1993-01-26|Schering Corporation|Angiotensin II receptor blockers as antiglaucoma agents|
    DE19529604A1|1995-08-11|1997-02-13|Bayer Ag|Endoparasiticidal agents based on didepsipeptides, new didepsipeptides and a process for their preparation|
    US9572856B2|2009-12-16|2017-02-21|The George Washington University a Congressionally Chartered Not-for-Profit Corporation|Method of treating low blood pressure|
    EP3858437A1|2013-04-26|2021-08-04|La Jolla Pharma, LLC|Compositions and methods for treating renal failure|
    EA037823B1|2013-12-18|2021-05-25|Дзе Джордж Вашингтон Юниверсити, Э Конгрешионэл Чартеред Нон-Фор-Профит Корпорейшн|Method for the treatment of a subject having high output shock and undergoing treatment with catecholamine or vasopressin|
    TW201733610A|2016-01-07|2017-10-01|拉荷亞製藥公司|Methods for administering angiotensin II|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU8080100A|HU181008B|1980-01-18|1980-01-18|Process for producing angiotenzin-ii analogues of antagonistic activity containing sarcosyl-group at the 1-positon,and an alpha-hydroxy-carboxylic acid at the 8-position|
    [返回顶部]