• 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:
    Angiotensin II analog of the formula I X-Arg-Val-Tyr-Ile-His-Pro-Y(I) wherein X is a radical derived from an aliphatic alpha -aminooxy-carboxylic acid and Y is a radical derived from an aliphatic alpha -amino-carboxylic acid, and acid addition salts and complexes thereof with antagonistic properties useful in the diagnosis and treatment of hypertensions depending on renin.
    公开号:SU845773A3
    申请号:SU782639399
    申请日:1978-07-17
    公开日:1981-07-07
    发明作者:Кишфалуди Лайош；Ньеки Дьердь；Сирмаи Ласло；Карпати Эгон；Гидаи Каталин；Спорни Ласло
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт(Инопредприятие)；
    IPC主号:
    专利说明:

    (54) METHOD OF OBTAINING PEPTIDES
    I
    The invention relates to a method for producing new peptides — biologically active compounds that can be used in medicine.
    The method of increasing the peptide chain B by the method of activated esters, for example pentafluorophenyl ethers, is widely known in the chemistry of peptides.
    The purpose of the invention is to obtain new peptides with valuable pharmaco-logical properties.
    The goal is achieved by the described method of obtaining peptides of general formula I
    X-Arg-Val-Tyr-lleu-His-Pro-Y 15 where X is the residue of an aliphatic carboxylic acid containing an amino-acetyl or szb-aminooxypropyl group in the oC position; 20
    Y - Leu, lieu,
    consisting in the fact that a reactive derivative of the general formula II H-Arg (A) (B) -Ileu-His (E) -Pro-Y-OG25
    where A is tosyl; B is benzyl; E - dinitrophenyl; G is hydrogen or p-nitrobenzyl; , Y has the meanings indicated
    above, is reacted with a reactive derivative of aminoox} and carboxylic acid of general formula 1
    II
    W-X-M where X - has the meanings indicated
    higher
    W benzyloxycarbonyl IL1
    tert-butyloxycarboyl $
    Group;
    pentafluorophenoxy,
    M and from the obtained compound of general formula IV
    W-X-Arg (A) -Val-Tyr (B) -J1eu-His (E) -Pro-Y-OG, where A, 8, E, G, W, and Y are
    above
    protective groups are simultaneously split or stepwise. Production of heptapeptides of general formula 1I used as starting materials is obtained by JT using known methods of peptide chemistry (for example, by the method of activated esters, by the carbodimim method and Tnpfj) the conditions of acidolysis carried out to remove the protective groups after the completion of the peptide bond formation reaction. Preferred for temporary protection of the carboxyl group of the C-terminal amino acid is use of p-nitrobenzyl group (NB), for protection of hydroxyl group of tyrosine - benzyl group (BzE), for protection of imidazole cycle of histidine - dinitrophenyl group (DNPh) and for protection of guanidino group of arginine - tosyl group (Tos). These protective groups resistant to the action of weak acids, as a result of which the tert-b-thyloxycarbonyl group (BOC) is cleaved after the formation of the peptide bond selectively without affecting the above protective groups. The dinitrophenyl on the group can then be removed by thiolysis, and the rest of the indicated fpynes can be removed by the action of liquid hydrogen fluoride. For the purification of the compounds obtained, known methods are used, for example, ion-exchange chromatography on carboxyl methylcellulose. At the same time, most products are obtained in the form of lyophilized powders. Such products can be used directly to form various salts or complexes. The antagonistic effect of the new compounds of the general formula is investigated in animals after the administration of the drug. Blood pressure is measured on the animal's carotid artery. The experiment was conducted in such a way that it caused an increase in pressure by injecting the drug into the vein of the thigh at a dose of 0.5 mg / kg / min. After the stabilization of pressure, a single dose of test substance is administered intravenously or subcutaneously to the animal in an aqueous physiological solution, then the reduction in blood pressure caused by the injected substance is measured. The achieved reduction in blood pressure with intravenous administration of 34 various new compounds is given in Table. 1. These values are the average of six measurements, and the marginal deviations from the average values are also indicated. Dp comparison shows the values achieved using the known Saralazine, i.e. - (N-methyl glycine) -5-1-Vein-8-1-alanine-angiotensin II, under the same conditions. Table D And blood supply The effective start pressure (in mmHg) when administered intravenously at a dose, mg / kg (Aminooxyacetyl, 8-leucine) -an-33 ± 3, 6 -4214.2. Giotensin G1 ( 1-D-o-aminooxypropionyl, 8-leucine) -angiotene-3013, 4 -38t3.8 zine II (1-aminooxyacetyl, 8-isoleucine) -angioten-40i5, 7 -28 ± 2.0 zine II -41i2.5 Saralazin From the data given in Table. 1, it follows that all angiotensin TG analogs, substituted in the first position with an aliphatic carboxylic acid residue containing an o6-aminooxy group, significantly reduce blood pressure. The size of this effect is proportional to the dose. A study was also conducted on subcutaneous administration of new compounds. In this case, carboxymethylcellulose or gelatin is also added to the physiological saline solution containing the test substance. In tab. Table 2 summarizes the research results — average measurements. Conducted in five animals, as well as the magnitude of the limit deviations from the mean values.
    table 2
    (i-Aminooxyacetyl, 200 CMC -21i5.8 8-leucine) -angiotensn II200} Clt -23 ± 2.0 (1 -D-about-aminooxy- 200 propionyl, 8-leucine) -angiotensin 11,200 CMC - carboxymethylcellulo Clt - gelatin. The results given in Table 2 indicate that new compounds, when hypodermically administered, after 60 minutes, significantly reduce the experimentally induced increase in blood pressure. Due to such properties, the proposed compounds, as well as their physiologically compatible salts and complexes, can be used in therapy as a means of lowering blood pressure. The physiologically compatible complexes of these new peptides should be understood as such compounds that are formed by the addition of known, for example, organic substances and give a delayed effect to the active principle. As such complexing agents, for example, gelatin, carboxymethylcellulose, alginic acid esters, polyfloretin phosphates, polyamino acids, as well as other polymers and copolymers can be used. As physiologically compatible salts of new peptides, common salts used in pharmaceutical practice, such as acetates, may be mentioned. New peptides, as well as their fiziolo. The physically compatible salts and complexes are used in therapy in the form of conventional medicines. These devices contain new compounds along with inorganic or organic carriers suitable for enteral and parenteral administration. Drugs can be
    CMC -21 ± 6.7 -24 ± 5.7 -16 ± 5.1 -1
    Jlt -24 ± 5.7 -21 ± 5.6 -9t5.7 -3: 26t7, 2 -13t9.4 -5 21t2.2 -10 ± 2.8 obtained as solid lyophilis; in this case, different carriers can be used as carriers; non-reactive peptides, such as carbohydrates, for example. Concentrated or diluted suspensions or emulsions, which, along with conventional carriers, also contain stabilizing and preserving adjuvants, can be prepared as medicines. Such drugs can be used before all in therapy for the treatment of those syndromes, in the etiology of which the pressure level increased due to renin plays a role; further, they can serve as diagnostic tools for differentiated diagnosis of renal hypertension. Obtaining new peptides of the formula I is illustrated by the examples below. The abbreviations used in the examples correspond to those accepted in the special literature. The groups belonging to α-amino acid are designated by the usual symbols of the corresponding amino acids with O in front of them, for example, Or individuals - amino-oxyacetic acid Oal-o-amio-oxy-propionic acid, etc. Pentafluorophenyl Ost - PFP. In the preparation of various compounds, evaporation of the solvents is always carried out using a rotary evaporator. Melting points are made with the aid of the apparatus Dr. TottoJ
    (BUCHU). Thin-layer chromatography was carried out on Kieselgel G ach Stahl (E.Merck. Darmstadt) plates; Chromatogram manifestations will use the following solvent systems: s
    1. Ethyl acetate: (pyridine-acetic acid-water 20: 6: 11) 95: 5
    2. Ethyl acetate: (pyridine-acetic acid - water 20: 6: 11) 90:10
    3. Ethyl acetate: (pyridine-acetic acid 10 - water 20: 6: 11) - 80:30
    4. Ethyl acetate: (pyridine-acetic acid - water 20: 6: 11) 70:30
    5. n-Butanol: acetic acid: water 4: 1: .515
    6.n-Butanol: acetic acid:: pyridine: water 30: 6: 20: 24
    7. n-Butanol: ethyl acetate: acetic acid J water 1: 1: 1: 1
    The number to a power when R 20 indicates the number of the solvent system used, for example, Rj,.
    Electrophoretic studies on paper are carried out on a LMlM horizontal device of moderate voltage 25 on MN 214 paper in a buffer solution at pH 1.9, containing glutamic acid, a new acid. The voltage is 450 volts, time - 3 hours.
    Thin-layer chromatograms are obtained by ninhydrin after ordinary chlorination with a solution of o-tolidine with yoisy potassium.
    Purification of the target products is carried out as follows.
    From the beginning; ala salts of free peptides with hydrogen fluoride are purified on Sephacryl S-200 Superfine resin (manufactured by Pharmacia Fine chemicals, Uppsala, Schweden) with a gradient elution of 0.01 M (pH 4.5) and 0.4 M (pH 6 , 7) ammonium acetate solutions. The eluate was detected using an LKB Uvicord II instrument (manufactured by LKB, Uppsala, Sweden), and collected using a fraction collector.
    Further purification of the main fraction is carried out on the carboxymethylcellulose as follows.
    0.5 liters of carboxymethylcellulose (CMC-52) is brought to equilibrium in a column with the first buffer solution, then a solution of 0.5 g of peptide in 4 ml of 0.01 M rast 55 ammonium acetate thrown is poured into the column and washed with gradient elution indicated buffer solutions. The rate of elution is 25 mp / h. Collect fractions
    10 ml each and detected with an LKB Uvicord II instrument. The purified target product is obtained by lyophilization of the main fraction.
    Example 1. (1-Aminooxiacetyl, 8-isoleucine) -angiotensin II
    Stage 1: BOC - Arg (Tos) - Val -Tug (Bzl) - lie - His pNPh) - Pro lie - NB.
    To 4.5 g (15 mmol) of isoleucine Initrobenzyl ester hydrochloride in 50 ml of chloroform were added 2I1 ml of triethylamine and 3.81 g (mmol) of BOC-proline pentafluorophenyl ether. The mixture is stirred for 20 minutes at room temperature, the product is extracted with water, then with 10% aqueous citric acid solution. After drying and evaporating the solvent as a residue, the protected dipeptide (Rr 0.8) is dissolved without further purification in 20 ml of an 8 M solution of hydrochloric acid in dioxane. After 10 minutes, the solution was diluted with anhydrous ether and evaporated. Dipettide hydrochloride obtained in the residue (Rr 0.44) is dissolved in 30 ml of chloroform, triethylamine is added to pH 8 and then 8, 8 g (15 mmol) of BOC-histidine pentafluorophenyl ether. After 1.5 hours, 1.65 ml of N, N-dimethylaminoethylamine was added to the solution, and after another 15 minutes the solution was washed with a 10% aqueous solution of citric acid, 1N. hydrochloric acid, water, and a 5% aqueous solution of sodium bicarbonate in the sequence indicated. The organic phases are separated, dried and evaporated. The crude protected tripeptide (R 0.50), without residue, dissolved in 20 ml of an 8 M solution of hydrochloric acid in dioxane. After 15 minutes, the free tripeptide thus obtained (RJ. 0.25) is precipitated by the addition of dry ether, filtered off and washed with ether. The product is immediately dissolved in a mixture of 50 ml of chloroform with 20 ml of dimethylformamide, the pH of the solution is adjusted to 8 with triethylamine and then 6.0 g (15 mmol) of BOC isoleucine pentafluorofenyl ether are added. After 30 minutes, the solvent was evaporated, the residue was dissolved in ethyl acetate. The resulting solution was washed with a 10% citric acid aqueous solution and then with water. After
    drying and evaporating the ethyl acetate solution, the protected hexapeptide (Re 0.56) is isolated with ether and washed with ether.
    The product is then dissolved in 20 ml of an 8 M solution of hydrochloric acid in dioxane, and the free hexapeptide thus obtained (Rf 0.47) is precipitated with dry ether, filtered and washed with ether. The product obtained is immediately dissolved in 50 ml of dimeshgammamide, triethylamine is added to pH 8, after which 7.2 g (12 mmol) of BOC-arginine pentafluorophenyl ester (Tos) are added. The mixture was stirred for 1 h, the solvent was evaporated, the residue was dissolved in chloroform, and the resulting solution was washed with 10% aqueous citric acid solution, 1N. solution of hydrochloric acid and water in the sequence indicated. The organic phase is separated, dried and evaporated, the residue is triturated with ether and filtered. 12.4 g of protected heptapeptide nitrobenzyl ester Arg (Tos) - Val -Tyr (Bzl) - lie - His (DNPh) - Pro-li are obtained (yield 80% of theoretical, calculated on the starting compound - BOC-proline pentafluorophenyl ether ). M.p. 189-l920c. Rjf - 0,55.
    Stage 2: BOC-Oglitz- Arg (Tos) Val - Tug - Jle - His - Pro - lie.
    8.1 g (2 mmol) of BOC-Arg (Tos) -Val-Tyr (Bz1) -JleHis (DNPh) -Pro-1 e nitrobenzyl ester is dissolved in 5 ml of dimethylformamide and 2.9 ml of 2- is added to the solution. mercaptoethanol. After 1 h, the peptide is precipitated with dry ether, filtered off, washed with ether and purified by reprecipitation with ether from methanol. Obtain 2.0 g (74% of theory) nitrobenzyl ester BOCG -Ai (Tos) -Val-Tyr (Bz1) -Ileu-His-Ile (Rj 0.1). The product was dissolved in 30 ml of methanol-acetic acid-water 5: 1: 1 mixture and 1.0 g of palladium on activated carbon was added. Through the solution for 5 hours; hydrogen is passed through, the catalyst is filtered off, the filtrate is evaporated and the residue is triturated with ether. Obtain 1.22 g (75% of theoretical) partially protected heptapeptide (Rf 0,8). The product is dissolved in 5 ml of an 8 M solution of hydrochloric acid in dioxane and after 20 minutes free heptapeptide (-0.1) is precipitated with dry ether.
    The free heptapeptide is filtered off, washed with ether and dissolved in 15 ml of dimethylformamide. The pH of the solution with triethylamine is set to 8 and 0.45 g (1.2 mmol) of BOC-Oglycine pentafluorophenyl ether is added to the solution. After 30 min, the reaction mixture was taken up, the residue was dissolved in 30 ml of cifexi xporoform-dimethylformamide (3: 1) and the solution was washed with 10% citric acid solution and water. After drying and evaporation of the solution, a residue is obtained, which is triturated with ethyl acetate, filtered off and washed with ethyl acetate. 0.46 g of BOC-Oglitz-Agde (Tos) -Val-Tyr-l1e-HIs Pro-IIs are obtained (yield 72% of the theoretical); R 0.23; 0.40.
    Step 3: Removing the protective 0.46 g (0.35 mmol) of BOC-OglitzArg (Tos) -Val-Tyr-ne-Hls-Pro-Ile p | is placed in 2 ml of liquid fluoride of the genus and added to the solution 0.5 ml of thioanisole. The solution is kept at 1 at 0, then the peptide is precipitated with ether, filtered off and taken up in). 0.35 g (yield 100% of theoretical) (1-aminooxyacetyl 8-11e) -angiotensin I I hydrofluoride is obtained. The product is purified as described above (before the examples). Characteristic clean) g product:
      0.26; Rf 0.56; 0.57; 1.00.
    Amino acid analysis results: Pro 1.01 (l); Val 1.0 (l); lie 1.98 (2); Tyr.0.65 (l); His 1.0 (l); iArg 1.03 (1).
    Example 2. (l-L-oi-aminooxy propionyl, 8-isoleucine) -angiotensin
    Step 1: BOC-OAla-Arg (Tos) -Val Tyr-Ile-Hls-Pro-Ile.
    0.6 g (0.5 mmol) of BOC-Arg- (Tos) Val-Tyr-Ile-Hls-Pro-le (example 1, step 2) is dissolved in 5 ml of 8 M hydrochloric acid solution in dioxane . After 20 min, the resulting free peptide (R 0, G) is precipitated with dry ether, filtered and washed. The product isolated in this way was immediately dissolved in 20 ml of dimethylformamide, added; triethylamine to pH 8 then 0.7 g (1.9 mmol) of BOC-Olanine pentafluorophenyl ether. After 30 min the solution is evaporated, the residue
    dissolved in 30 ml of a mixture of chloroform dimethylformamide (3: 1). The resulting solution was washed with 10% aqueous citric acid solution and water. The organic phase is dried, evaporated and the residue triturated with ethyl acetate. Obtain 0.55 g (yield 84% of theoretical) BOC-Ola-Agde (To5) -Ua1-TugJle-His-Pro-lle.
    Rf 0.43; 0,80. Yu
    Stage 2: removal of protecting groups.
    0.53 g (0.42 mmol) of BOC-OA1-; Arg (Tos) Va-Jyg-11e-Hi s-Pro-JIe is dissolved in 2 ml of liquid hydrogen fluoride and added. 0.55 ml of thioanisole. is The solution is kept for 1 h at O-C, then the peptide is precipitated with dry ether, filtered off and progressed with ether.
    0.41-g (1-olanine, 8-isoleucine) -angiotensin li is obtained; the product is cleaned as described above. 0.32; Rf 0.58; Rj 0.59; • Amino acid analysis results: Pro 1.0 (1); Val 1.1 (l); Not 2.02 (2); His 0.9 (l); 0.95 (l) tight; 25 Arg 1.05 ().
    Example 3. (1-Aminooxiacetyl; 8-leucine) -angiotensin II.
    Step 1: BOC-Agde (Tos) -Val-Tyr (Bzl) -ne-His-Pro-Leu 011b. zo
    4.2 g (12 mmol) of leucine nitrobenzyl ester bromide are dissolved in 50 ml of chloroform, and 1.68 ml of triethylamine and 3.81 g (10 mmol) of BOC-35 fluorine-phenyl ester of BOC-proline are added to the solution. The mixture is stirred at room temperature for 20 minutes and then extracted with a 10% aqueous solution of citric acid and water. The organic phase is dried and evaporated. The protected dipeptide obtained as a residue (R. 0.8) was dissolved in 20 ml of an 8 M solution of hydrochloric acid in dioxane without further purification; after 10 minutes, the solution was diluted with dry dioxane and evaporated.
    The free dipeptide obtained in the residue (0.5b) was dissolved in 50 ml of chloro-5 form without further purification, triethylamine was added to the solution to pH 8 and then 8.8 g (15 mmol) of BOC-histidine pentafluorophenyl ether (DNPh). After 30 minutes, 1.65 ml of N, N-dimethylaminoethyl 5 amine was added to the solution, and after another 10 minutes the mixture was washed with a 10% aqueous citric acid solution, 1N. brine solution
    acid, sodium bicarbonate solution and water in the sequence indicated.
    The organic phase is dried and evaporated, the protected tripeptide (Rf 0.65) obtained as a residue is dissolved in 25 ml of 8 M hydrochloric acid solution in dioxane without further purification, and the resulting free tripeptide (Rr i 0.47) is precipitated with dry ether. The tripeptide is filtered off, washed with ether and immediately dissolved in a mixture of 50 ml of chloroform with 20 ml of dimethyl form | Mead. Triethylamine is added to the solution to pH 8 and 6.0 g (15 mmol of BOC-isoleucine pentafluorophenyl ester. After 30 minutes, the solvent is evaporated, the residue is dissolved in ethyl acetate, the solution is washed with 10% aqueous citric acid solution, 1N brine hydrochloric acid and water, the organic phase is dried and evaporated.
    The protected tetrapeptide (Rj. 0.65) obtained in a residue is planted with an n-hexane-ether mixture (7: 3). The product is dissolved in 25 ml of an 8 M solution of hydrochloric acid in dioxane, after 15 minutes the free peptide (Rj. 0.65) is precipitated with dry ether, filtered off, washed with ether and immediately dissolved in 50 ml of chloroform-dimethylformamide (1: one). The pH of the solution is adjusted to 8 with triethylamine and 6.0 g (11.5 mmol) of BOC-titrosine pentafluorophenyl ether are added to the solution. After 15 minutes, the solvent was evaporated, the residue was dissolved in ethyl acetate, 0.66 ml of S, M-dimethylaminoethylamine was added to the solution, and after 15 minutes the mixture was washed with 10% aqueous citric acid solution, 1N. solution of hydrochloric acid and, finally, water. After drying and evaporation of the organic phase with ether, the protected pentapeptide (Rj 0.8) is isolated and dissolved in 20 ml of an 8 M solution of hydrochloric acid in dioxane.
    权利要求:
    Claims (2)
    [1]
    The resulting free Pentapeptide (0., 8) is precipitated with dry ether, filtered, washed with ether and immediately dissolved in 50 ml of dimethylformamide. The pH of the solution with triethylamine is set to 8 and 3.85 g (10 mmol) of BOC-valine pentafluorophenyl ether are added to the solution. After 1 h, the solvent is distilled off, the residue is dissolved in chloroform, the organic phase is extracted in the usual manner with 10% aqueous citric acid solution, I n. hydrochloric acid solution and water. The resulting protected hexapeptide. (R 0.82) was isolated using ether. The product is dissolved in 20 ml of an 8 M solution of hydrochloric acid in dioxane and after 15 minutes free hexapeptide is precipitated with dry ether (Rr 0.55 The free hexapeptide is immediately dissolved in 40 ml of dimethylformamide, triethylamine is added to pH 8 and 6.0 g (B mmol) BOC-arginine pentafluorophenyl ester (Tos), After 30 min, the solvent is distilled off, the residue is dissolved in chloroform, and this solution is washed with 1N hydrochloric acid and water. After drying and evaporation of the solvent with ethanol, the the resulting protected heptapeptide BOC-Arg (ToS) -VaI-Thug (Bz1) -11eHis (DNPh ) -Pro-Leu-ONB (0.62) Yield 7.5 g (50% of the theoretical based on the starting compound pentafluorophenyl ether BOC-Pro). Mp. 186-190 C. Step 2: BOC-Oglitz- Agde (Tos) -Va1 Tyr-rie-His-Pro-Leu 3.45 g (2.26 mmol) BOC-Arg (Tos) -Val-Tyr (Bz -Ile-His (DNPh) -Pro-Leu-ONB dissolved in 10 ml of dimethylformamide, 6.6 ml of 2-mercaptoethanol are added, and partially protected heptapeptide is precipitated with dry ether after 2 hours. 2.9 g of purified BOC-Arg (Tos) -Val-nitrobenzyl ether is obtained by precipitation with ether. Tug (Bzl) -Ile-His-Pro-Leu (93% of theory). 0.12; 0.26. The product is dissolved in methanol-acetic acid-water (5: 1: 1), 1.0 g of 10% palladium on activated carbon is added and hydrogen is passed through the solution for 6 hours. The catalyst is filtered off, the solvent is evaporated and the residue is triturated with ether. Obtain 2.15 g (89% of theoretical) BOC-Arg (Tos) -Val-Tug-Ile-His-Pro-Leu. .. ol-S) g, -7C. oW 0.75; R 0.20. 1.1 g (l mmol) of the obtained product is dissolved in 10 ml of a 8 M solution of hydrochloric acid in dioxane, after 30 minutes the free heptapeptide (Rr 0.08) is precipitated with dry ether, filtered, washed with ether and immediately dissolved in 10 ml of dimesh formamide. Triethylamine was added to the solution to pH 8 and then 0.54 g (1.5 mmol) of pentafluorophenyl ester -VOC-Oglycine. After 30 minutes, the solution was diluted with 30 ml of chloroform and washed with water. After drying and evaporation of the solution, the residue is triturated with ethyl acetate. filtered and washed with ethyl acetate. Obtain 1.05 g (yield 86% of theoretical) BOC-Cglitz-Arg (Tos) -Val-Tyr-I e-His Pro-Leu. 0.23; Stage 3: removal of protective rpyijin .. 0.9 g (0.73 mmol) of BOC-OglitzAgd (Tos) -Val-Thug-Pe-HJs-Pro-Leu p is placed in 5 ml of liquid fluorinated hydrogen and 1 is added, 5 ml-thioanisole A mixture is held for 1.5 h with OC, the peptide is then precipitated with dry ether, filtered off and washed with spfr. Get 0.55 g (yield 80% of theoretical) (1-Oglycine; 8-leucine) -angiotensin II. Product purified 0.33; yut. as described above. Ri is 0.60; Rf 1 and oi; L - 0.55; °° 8 Results of amino acid anal for: Pro 1.0 (1); Va 1.0 (l); lie 1.0 (1); Leu 1.1 (l); His 0.95 (l) Arg 1.0 (1); Tyr 0.7 (l). Example 4 (1-15-o6-Aminoox; propionyl; 8-leucine) -angiotensin I Step 1: BOC-DOAla-Arg (Tos) -Va Tyr-IIe-Hi s-Pro-Leu. 1.1 g (l mmol) of BOC-Arg (Tos) -Va ' Tyr-Ile-His-Pro-Leu is dissolved in 10 ml of an 8 M solution of hydrochloric acid in dioxane and after 30 minutes the free peptide is precipitated with dry ether, precipitated The mixture is filtered and washed with ether. The product is immediately dissolved in 10 ml of dimethylformamide, to the solution is added}: triethylamine to pH 8 and then 0.56 g (1.5 mmol) of pentafluorophenyl. ef1fa BOC-D-Olanin. After 30 minutes, the solution was diluted with chloroform and washed with water. After drying and evaporation of the solvent and the solvent, the residue is triturated with ethyl acetate, filtered and dried with ethyl acetate. 0.95 is obtained (yield 77% of theoretical) BOCOA1a-Arq (Tos) -Val-Tug-1e-H i s-Pro-i-eu; RJ.- 0.29. Step 2: Removing the protective groups of 0.95 g (0.77 mmol) of BOC-D-OAlaArg (Tos) -Va1-Tyr-1I1e-H s-Pro-Leu poured into 4 ml of liquid hydrogen fluoride and 1, 2 ml of thioanisole is added. The solution is kept for 1.5 hours at which time the product is precipitated with dry ether, filtered and washed with ether. Obtain 0.6 g (l-D-Olanin; 8-leucine) -angiotensin II (yield 90% of theoretical), which is purified, as described above. Rj. 0.33; Rf 0.61; Rf 0.56; E (itu MORE amino acid analysis Pro 1.02 (1); Val 1.0 (O; Leu 1.02 (1); Not 1.03 (1); His 1.01 (ij; Arg 0.92 (1 ); Tug 0.8 (l). Formula of the Invention A method for producing peptides of general formula I X-Arg-Val-Tyr-lleu-His-Pro-Y where X is the residue of an aliphatic carboxylic acid containing aminooxyacetyl oro in the L-position amino-oxypropyl group; Y — Leu, lieu, characterized in that p is an effective derivative of general formula II H-Arg {A) -Va1-Tyr (B) -Ileu His (E) -Pro-Y-OG where A is tosyl; B - benzyl; E - dinitrophenyl; G - hydrogen or p-nitrobenzyl; Y - has the meanings indicated above are reacted with an amino-capable amino-carboxylic acid derivative of the general formula III where X is as defined above, W is a benzyloxycarbonyl or tert-butyloxy15arbonyl group; M is pentafluorophenoxy, and from the resulting compound of general formula IV WX-Arg (A) -Val-Tug (B) -11 eu-Si s (E) -Pro-Y-OG where A, B, E, G, W, X and Y are as defined above, split simultaneously or stepwise protecting groups. Sources of information taken into account in the examination f. Lajos Kisfaludy, M.Low, O.Nyeki, T.Szirtes, I.Shon, Die Verven dung von Pentaf1uorphenylestern bei .Peptidsynthesen, Justus Riebigs Annalen der chemie, T973, Heft 9, s ..
    [2]
    2. Schröder E ,, Ljubke K. Peptides, Part I, M, Mir, 1967, p. 116,
    类似技术:
    公开号 | 公开日 | 专利标题
    US4388304A|1983-06-14|Angiotensin-II analogues with antagonizing effects, containing an ester group in position 8, and a process for the preparation thereof
    US4737487A|1988-04-12|VIP type peptides
    US3853837A|1974-12-10|Novel nonapeptide amide analogs of luteinizing hormone releasing factor
    US4619916A|1986-10-28|Tripeptide compounds containing pyroglutamic acid and tryptophan, process for their production and therapeutic applications
    US4420424A|1983-12-13|New peptides and a process for their preparation
    US4866039A|1989-09-12|Peptides containing the 18 to 23 residues of vasoactive intestinal peptide, and analogues
    SU845773A3|1981-07-07|Method of preparing peptides
    FUJINO et al.1968|A new procedure for the pentachlorophenylation of N-protected amino acids
    US3920627A|1975-11-18|Position 1 analogs of {8 phenylglycyl{9 -angiotension II
    US4209442A|1980-06-24|Angiotensin II analogs and process for the preparation thereof
    US3749703A|1973-07-31|Asn15-bovine thyrocalcitonin
    US4018912A|1977-04-19|Tripeptide derivatives with central nervous system activity and preparation thereof
    US4647553A|1987-03-03|Gonadoliberin derivatives and process for the preparation thereof
    Bodanszky et al.1962|8-L-citrulline vasopressin and 8-L-citrulline oxytocin
    JPH09503200A|1997-03-31|Oligopeptide derived from C-reactive protein fragment
    JPH0631314B2|1994-04-27|Novel gonadobereline derivative
    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
    US4330532A|1982-05-18|Angiotensin-II analogues with antagonizing effects, containing an α-hydroxycarboxylic acid residue in position 8, and a process for the preparation thereof
    US4716149A|1987-12-29|Partially modified, retro-inverso neurotensin analogs
    JPH0688968B2|1994-11-09|Tripeptides and pharmaceutical compositions
    US4672054A|1987-06-09|Process for the preparation of angiotensin-II analogues substituted in the 1-, 5- and 8- positions
    US3873510A|1975-03-25|Peptides of ACTH activity containing {60 -aminooxy carboxylic acid on the N-terminal moiety, and a process for the preparation thereof
    US3352844A|1967-11-14|Nleu4-lys17-lys18-alpha1-25-acth-val25-amide
    US4117117A|1978-09-26|Tridecapetide having gastrin effect
    同族专利:
    公开号 | 公开日
    FR2398050A1|1979-02-16|
    YU171378A|1983-01-21|
    YU41431B|1987-06-30|
    HU177133B|1981-07-28|
    DK319478A|1979-01-19|
    FI64140C|1983-10-10|
    SE7807823L|1979-01-19|
    IL55121A|1981-09-13|
    GB2001653B|1982-02-10|
    PL111979B1|1980-09-30|
    AU3800878A|1980-01-17|
    BE869077A|1979-01-18|
    JPS5835504B2|1983-08-03|
    CA1108124A|1981-09-01|
    FR2398050B1|1983-09-09|
    NL7807676A|1979-01-22|
    US4179433A|1979-12-18|
    FI64140B|1983-06-30|
    AU518229B2|1981-09-17|
    SE443790B|1986-03-10|
    IL55121D0|1978-09-29|
    CS201014B2|1980-10-31|
    NO148031C|1983-07-27|
    IN149489B|1981-12-26|
    GB2001653A|1979-02-07|
    FI782250A|1979-01-19|
    AT361143B|1981-02-25|
    DE2831534A1|1979-02-01|
    NO782463L|1979-01-19|
    NO148031B|1983-04-18|
    CH637915A5|1983-08-31|
    ES471793A1|1979-02-01|
    ATA518478A|1980-07-15|
    JPS54119463A|1979-09-17|
    PL208496A1|1979-07-02|
    DE2831534C2|1982-02-18|
    DD137220A5|1979-08-22|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3886134A|1970-03-09|1975-05-27|Morton Norwich Products Inc|Analogues of angiotensin II|
    GB1320104A|1971-05-20|1973-06-13|Norwich Pharma Co|Hepta-and octapeptides|
    US3907762A|1971-12-27|1975-09-23|Univ Sherbrooke|Angiotensin{hd II {B position 8 analogs|
    HU167360B|1972-08-25|1975-09-27|
    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|HU181008B|1980-01-18|1983-05-30|Richter Gedeon Vegyeszet|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|
    HU181009B|1980-01-18|1983-05-30|Richter Gedeon Vegyeszet|Process for preparing angiotensin-ii analogues with antagonictic activity containing in position 1 sarcosyl,hydroxyacetyl or l-alpha-aminoxy-propionyl group and in positiona 8 esteric group|
    HU191961B|1984-08-02|1987-04-28|Richter Gedeon Vegyeszet|Process for producing 1,5 and 8 substituted peptides of angiotenzin-ii antagonistic activity|
    US5036048A|1986-03-07|1991-07-30|Schering Corporation|Angiotensin II receptor blockers as antiglaucoma agents|
    US5182264A|1986-03-07|1993-01-26|Schering Corporation|Angiotensin II receptor blockers as antiglaucoma agents|
    US4772684A|1987-01-20|1988-09-20|Triton Biosciences, Inc.|Peptides affecting blood pressure regulation|
    TWI268138B|2000-05-11|2006-12-11|Kanebo Seiyaku Ltd|Composition containing peptide and electrolyte excretion enhancing substance, and food containing the same|
    AT508569A1|2009-07-23|2011-02-15|Affiris Ag|PHARMACEUTICAL COMPOUND|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU77RI640A|HU177133B|1977-07-18|1977-07-18|Process for preparing angiotensin ii analogues containing alpha- amino-oxy-acid in position 1 with angiotensin ii antagonist activity|
    [返回顶部]