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    • 专利摘要:
    The invention relates to new peptide derivatives which act on the central nervous system and correspond to the general formula (I), Glp-X-Y-NH-A (I) wherein X is L-norleucyl, L-leucyl, L-norvalyl, D-leucyl, L-prolyl, L-2-aminobutyryl, L-valyl, L-threonyl, L-isoleucyl, L-2-aminodecanoyl, L-cyclohexylalanyl or L-tert.-butyl-seryl group and Y is L-prolyl group, or X is L-histidyl group and Y is L-homoprolyl or D-pipecolyl group, furthermore A is hydrogen, a C1-10 alkyl group or a C1-3 alkyl group having a dimethylamino substituent, with the proviso that if X is L-leucyl group, A is other than hydrogen, and pharmaceutically acceptable complexes thereof. These compounds are prepared by methods commonly applied in the peptide chemistry.
    公开号:SU963463A3
    申请号:SU802938611
    申请日:1980-06-26
    公开日:1982-09-30
    发明作者:Кишфалуди Лайош；Сиртеш Тамаш；Балашпири Лайош；Палоши Ева；Шпорни Ласло；Шаркади Адам
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing tripeptidamides, new biologically active compounds that can be used in medicine.
    In peptide chemistry, a stepwise method of producing peptides is widely used by striking a chain from the C-terminus of the original amino acid with the modification of activated amino acid derivatives, for example, pentaftrphenyl ethers 1.
    The use of known methods allows to obtain new compounds with interesting pharmacological properties.
    The purpose of the invention is to obtain new tripeptidamides, expanding the arsenal of means of influencing a living organism.
    The goal is achieved by a method for producing tripeltidamides of general formula I.
    Glp-X-Y-NH-L U) where X is Lell, D is Leu, nleu.val,
    nval, Thr, Pro, L-o-aminobutyryl, 1, -o-aminodecanoyl, 1, -cyclohexylalanil, 1; cA-t-butyl seril:
    Y - Pro;
    A is hydrogen, Allc (G,),
    (CH3) (C, -C), provided that if X is Leu, then A has a meaning different from hydrogen,
    or X - His, Y - HPPO, D - pipecolyl, which consists in increasing the peptide chain, starting with amidic acid amide of the general formula I
    Y - NH - A. (I) where Y and A have the indicated meanings, with amino acids and their derivatives
    ts or the corresponding dipeptide by the method of pentafluorophenyl ethers or by the azide method and, in the case of using glutamic acid, cyclization of the latter to pyroglutamine with
    20 subsequent removal of the protective groups.
    The following abbreviations are used in the examples:
    Ada is L-2-aminodecanoic acid;
    25
    Abu - L-2-aminobutyric acid;
    Cha is L-cyclohexyl-alanine;
    Dopa - Dioxyphenium Palan;
    Pip - L-pipecolic acid;
    HPO - L-homoproline; DAK - 2-dimethylaminoethyl; DCC - dicyclohexyl-carbodiimide; PFPOM - pentafluorophenol; DCU - dicyclohexyl urea; DMFA - dimethylformamide. Optical rotation values are measured using a Perkin-Elmer polarimeter 141. Silica gel plates (E, Merck) are thinned by thin-layer chromatographic studies. The following solvent mixtures are used in chromatography: (1) chloroform: methanol 9: 1; C2} ethyl acetate: (pyridine: acetic acid water 20: 6: 11) 9: 1; (3) ethyl acetate: (pyridine acetic acid: water 20: 6: 11) 8: 2; (4) ethyl acetate: (pyridine: acetic acid: water 20: 6: 11) 3: 2. Ninhydrin solution is used for detection. After spraying, the plates are dried for about 5 minutes at. Then, the chromatograms are treated with chlorine gas, blown with air and sprayed with a solution of o-tolidine potassium iodide. Silica gel (E. MegsK) with a particle size of 0.062-0.2 mm is used for chromatographic purification on a column. Example 1. L-Pyroglutamyl-b-norleucyl-b-prolinamide. 1-stage. A solution of 2.28 g (20 mmol) of HProNH, and 3.95 g (10 mmol) of BocNleu OPFPI was dissolved in 40 ml of dimethyl form of the amide, and after 5 minutes I evaporated in vacuo. The residue obtained in the residue was dissolved in 50 ml of chloroform, the solution was washed three times in a separating funnel with 10 ml of 1N. hydrochloric acid solution, then three times 10 mp 1 n. sodium bicarbonate solution and finally once 10 MP of water is dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 5 ml of ethyl acetate and the solution is mixed with 10 ml of 5N. solution of hydrochloric acid in ethyl acetate. After 30 minutes, the reaction mixture was diluted with ether, the precipitated product was filtered and dried in vacuo over anhydrous sodium hydroxide. 2.48 g of HNleu-Pro-NH, HCl is obtained (94% of the theoretical yield calculated for BOC-Nleu 70PFP); 0.20. J 2-Stage: Benzyloxycarbonyl-L-Pyroglutamyl-b-norlecyl-b-prolinamide. A solution of 1.05 g (-4 mmol) of HNleu-Pro-NHj-HCl in 10 ml of dimethylforma and cooled with ice and not cooled, mixed with stirring, with 0.56 ml (4 mmol) of triethylamine and 1.89 g (4, 4 mmol) Z-Glp-OPFP. After 5 minutes without stopping stirring, 0.56 ml (4 mmol) of triethylamine is added to the mixture, stirred for another 20 minutes, then evaporated to dryness in vacuo. The residue was dissolved in 40 ml of chloroform, the solution was shaken twice in a separatory funnel with 10 ml of 1N. hydrochloric acid, three times with 10 ml of 1N. sodium bicarbonate solution and finally with 10 ml of water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The residue obtained in the residue is crystallized from ether, the resulting crude product (1.52 g) is recrystallized from 8 ml of ethyl acetate. 1.36 g of Z-Clp-Nleu-Pro-NH j are obtained (72% of the theoretical; t, pl.146-148 ° C); R 0.32fa / - -79.8 (in acetic acid) .- Calculated,%: C 61.00; H - 6.83; N 11.86 Nd C 60.90 H 7.04; Found,% N, 11.87. Mol. Weight.472,55. Stage 3: b-pyroglutamyl-b-norlecyl-b-prolinamide. A solution of 1.16 g (2.46 mmol) of Z-Glp-Nleu-Pro-NH in 25 ml of methanol is mixed with 0.2 g of a 10% palladium / activated carbon catalyst and hydrogen gas is passed through the solution for 30 min. Then the catalyst is filtered off, the filtrate is evaporated, the solid amorphous residue is triturated with ether, filtered. The resulting crude product (0.72 g) was dissolved in water, the solution was clarified with activated carbon, and the clear aqueous solution was lyophilized. Obtain 0.66 g of Glp-Nleu-Pro-NHj (79.5% of theoretical); R 0,43, rfJ -77,1 (, in acetic acid). Amino acid analysis: Glp 0.96 (1.0), Nleu 1.00 (1.0), Pro 1.00 (1.0). Example 2. L-Pyroglutamyl-b-norvalyl-b-prolinamide. Stage 1: L-norvalyl b-prolinamide hydrochloride. A solution of 2.2 g (20 mmol) of HPro-N% and 3.83 g (10 mmol) of BOC-Nval-OPFP in 40 ml of dimethylformamide, was left for 5 minutes, then evaporated in vacuo. The residual oil was dissolved in 50 ml of chloroform, the solution was shaken three times in a separatory funnel with 10 ml of 1N. hydrochloric acid, three times with 10 ml of 1N. sodium bicarbonate solution and, finally, once with 10 ml of water, dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 5 ml of ethyladetate and the solution is mixed with 10 ml of 5N. solution of hydrochloric acid in ethyl acetate. Through. The reaction mixture is diluted with ether for 30 minutes, the precipitated product is filtered off and dried under vacuum.
    anhydrous sodium hydroxide. 1.83 g of li-Nval-Pro-NHj-HCl are obtained (73% of the theoretical yield calculated for Boc-Nval-OPFP); 0.10.
    Stage 2: benzyloxycarbonyl-L-pyroglutamyl-b-norvalyl-b-prolinamide.
    . A suspension of 1.25 g (5 mmol) of H-Nval-Pr-NHj-HCl in 15 ml of dimethylformamide is mixed with 0.7 ml (5 mmol of triethylamine and 2.15 g (5 mmol) of Z- Gl-OPFP. After 5 minutes, 0.7 ml (5 mmol) of triethylamine was added, the mixture was stirred for another 20 minutes and then evaporated in vacuo .. The residue was dissolved in 50 m of chloroform, the solution was shaken three times in a separating funnel with 10 ml of 1 hydrochloric acid, three times with 1U ml of 1N sodium bicarbonate solution and, finally, with 10 ml of water, dried over anhydrous sodium sulfate and evaporated. ether, the precipitated product 1.8 g is filtered off and recrystallized from a mixture of ethanol and ether. Get 1.66 g of Z-Glp-Nval-Pro-NHj. (72% of theoretical), so pl.166-167s, to / 0,29, -87,5 (, in acetic acid)
    Calculated,%: C 60.25; H 6.59N 12.22.
    Found,%: C 60.08; H 6.70;
    N 12.15.
    Mol.ves.458,52.
    Stage 3: b-pyroglutamyl-b-norvalyl-b-prolinamide.
    A solution of 1.42 g (3.1 mmol) of Z-Glp-Nval-Pro-NH2 in 30 ml of methanol is mixed with 0.2 g of a 10% catalyst; palladium / activated carbon and hydrogen gas is passed through the solution for 30 minutes. The catalyst is filtered off, the filtrate is evaporated. The solid amorphous residue is triturated with ether and filtered; The product obtained is dissolved in water, the solution is decolorized by treatment with activated carbon, and the clear aqueous solution is lyophilized. Obtain 0., 95 g of Glp-Nval-Pro-NHj (94% of theoretical), 0.36, fj -87.0 ° (in acetic acid).
    Amino Acid Analysis: Glu 0.97, (1.0), Nval 1.09 (1.0), Pro 1.00 (1.0).
    Example 3. L-Pyroglutamyl-b-prolyl-b-prolinamide ..
    Stage 1: L-prolyl-L-prolinamide hydrochloride.
    2.28 g (mmol) of H-Pro-NHa. and 3.81 g (10 mmol) of BOC-Pro-LVPP are dissolved in 40 ml of dimethylformamide, the solution is shaken three times in a separating funnel with 10 tui 1N. hydrochloric acid, TRICHDA with 10 MP 1 n.
    sodium bicarbonate solution and once with 10 ml of water, dried over anhydrous sodium sulfate and evaporated. The residue pacTBopsnoT in 5 ml of ethyl acetate and mixed with 10 ml of 5N. hydrochloric acid solution. After 30 minutes, the reaction mixture was diluted with ether, the precipitated product was filtered and dried in vacuo over anhydrous sodium hydroxide. Obtain 2.06 g of H-Pro-Pro-NHj-HC1 (83% of theoretical yield, calculated on Boc-Pro-OPFP); 0.05.
    Stage 2: benzyloxycarbonyl-1-pyroglutamyl-1-prolyl-L-prolinamide suspension.
    0.75 g (3 mmol) of H-Pro-Pro-NHa ilCl in 10 ml of dimethylformamide is mixed with O, 42 ml (3 mmol of triethylamine and 1.35 (3.15 mmol) Z- Glp-OPFP. After 5 minutes, 0.42 ml (3 mmol) of triethylamine was added and, after 10 minutes of stirring, the resulting thick suspension was evaporated in vacuo. The crystalline residue was triturated with 8 ml of ethanol and left in the refrigerator for 3 hours. The resulting precipitate was filtered and dried, 1.0 g of Z-Glp-Pro-Pro-NHg. (73% of theory) are obtained, mp 247-248 v (c), R 0.19; GaL) -82, B (, in acetic acid).
    Calculated,%: C 60.52H, 6.18; N 12.27.
     N4
    Found,%: C 60.03; H 6.30 /
    N 12.20.
    Mol. Weight 456.50 ..
    Stage 3: b-pyroglutamyl-b-prolyl-b-prolinamide.
    To a solution of 1.0 g (2.2 mmol) of Z-Glp-Pro-Pro-NH / j in 50 ml of acetic acid, 0.2 g of a 10% palladium / activated angle catalyst is added and hydrogen gas is passed through the mixture in for an hour. The catalyst is filtered off, the filtrate is evaporated and the residue is triturated with ether. The resulting amorphous crude product (0.60 g) was dissolved in water, decolorized with activated charcoal and the clear aqueous solution was lyophilized. 0.50 g of Glp-Pro-Pro-NH (from theoretical) are obtained; R 0.10 -223.1 ° (in acetic acid).
    Example 4. b-Pyroglutamyl-b-valyl-b-prolinamide.
    Stage 1: L-valyl-L-prolinamide hydrochloride.
    A solution of 0.49 g (4.2 mule) H-Pro-NHa.  and 0.82 g (2.14 mmol) of Boc-Val-OPFP in 10 ml of dimethylformamide after 30 minutes, one hundred times evaporated in vacuo.  The residual oil obtained is a solution of 10 ml of chloroform, the solution is washed twice in a separating funnel 3 m 1 n.  hydrochloric acid, three times - 3 ml of 1 n.  sodium bicarbonate solution and finally, with 3 ml of water, dried over without aqueous sodium sulfate and evaporated. The residue is dissolved in 3 ml of ethyl acetate and mixed with 3 ml of 5N.  solution of hydrochloric acid in ethyl acetate.  After 1 hour, the reaction mixture is diluted with ether, the precipitate is filtered and dried in vacuo over anhydrous sodium hydroxide.  0.51 g of H-Val-Pro-NHj is obtained (95% of the theoretical yield, calculated on Boc-Va-1-OPFP); 0.10.  Stage 2: benyloxycarbonyl-b-pyroglutamyl-b-valyl-b-prolinamide.  A suspension of 0.38 g (1.52 mmol) I-Wa-Pro-NH2. 10 ml of dimethylformamide are cooled with ice and stirred with 0.22 ml (1.52 mmol) of triethylamine and 0.69 g (1.6 mmol) of Z-Glp-OPFP.  After 10 minutes, 0.22 ml (1.52 mmol) of triethylamine was added to the mixture and, after stirring additionally for 30 minutes, the reaction mixture was evaporated in vacuo.  The residue is dissolved in 15 ml of chloroform, the solution is washed twice in a separating funnel with 5 ml of 1N.  hydrochloric acid, three times 5 ml of 1N.  a solution of sodium bicarbonate and, finally, 5 ml of water, dry over anhydrous sodium sulphate and evaporate in vacuum.  The oily residue is crystallized, 0.54 g of Z-Glp-Val-Pro-NH, (77% of the theoretical) are obtained from the ether, t. square IbIb C, R 0.30, -100.5 (, in acetic acid).  Stage 3: b-pyroglutamyl-b-valyl-b-prolinamide.  A solution of 9.65 g (21.2 mmol of Z-Glp-Val-Fro-NH2 in 300 ml of water, after adding 2 g of a 10% palladium / activated carbon catalyst, hydrogen gas is passed in a flow of 5 hours.  The catalyst is filtered. The filtrate is evaporated.  The residual oil is dissolved in ethanol.  The solution is evaporated.  This operation is repeated twice.  The resulting amorphous solid residue is triturated with ether to obtain 4.47 g of Glp-Val-Pro-NHi (L5% of theory), 0.34, L –104.9 ° (in acetic acid).  Amino acid analysis. : Glu 1.03 (1.01); Val 1.00 (1.0); Pro 0.94 () - Example 5.  L-Pyroglu tamil-E-isoleucyl-1, -prolinamide.  Stage 1: benzyloxycarbonyl-b Isoleucyl-b-prolinamide.  51.4 g (0.1 mol) of Z-Ile-OPFP and 12.5 g (0.11 mol) of H-Pro-NH-i are dissolved in 250 ml of dimethylformamide. and the solution is mixed with 14.0 ml of 0.1 mol) triethylamine.  The reaction mixture is left overnight at room temperature, then evaporated in vacuo.  Resulting oil. dissolved in 500 MP of chloroform, the solution is successively washed in a separatory funnel twice with 100 ml of 1N.  hydrochloric acid, twice 100. ml 1 n.  sodium bicarbonate solution and once with 100 ml of water, dried over anhydrous sodium sulfate and evaporated.  The oily residue is crystallized from a mixture of 100 ml of ether and 100 ml of n-hexane.  The crude product (31.7 g) is recrystallized from a mixture of 60 ml of ethyl acetate and 60 ml of n-hexane.  Obtain 30.32 g of Z-Ileu-Pro-NH, 2 (84% of theory), t. square  127-128C, Rf | - 0.54.  Stage 2: L-isoleucyl-b-prolinamide hydrochloride.  To a solution of 24.0 g (66.5 mmol) of Z-Ileu-Pro-W in 470 ml of methanol was added 30 ml of 2.4N.  a methanol solution of hydrochloric acid and 4 g of a 10% palladium / activated carbon catalyst and hydrogen gas is passed through the mixture for one hour.  The catalyst is filtered off, the filtrate is evaporated.  The residue is triturated with ether, the crude product (20 g) is recrystallized from a mixture of methanol and ether.  16.05 g of H-Ileu-Pro-Nii HC1 are obtained (81% of the theoretical), t. square  135-140 ° C., R 0,15. .  Stage 3: benzyloxycarbonyl-b-pyrogl. utamyl-1-isoleucyl-b-prolinamide.  A suspension of 0.90 g (3.5 mmol) of H-Ileu-Pro-NHj-HCl in 20 ml of dimethylformamide is mixed with 0.49 ml (3.5 mmol) of triethylamine and 1.57 g (3, 7 mmol) Z-Glp-OPFP.  After 5 minutes, 0.49 ml (3.5 mmol) of triethylamine was added, the mixture was stirred for another 20 minutes and evaporated in vacuo.  The residue is dissolved in 30 ml of chloroform, and the solution is washed successively in a separatory. funnel thrice 7 ml 1 n.  hydrochloric acid, three times 7 ml of 1 n.  sodium bicarbonate solution and finally. once with 7 ml of water, dried over anhydrous sodium sulfate and evaporated.  The residual oil is treated several times with ether, the ether is decanted, the crystallized product is filtered off, dissolved in ethyl acetate and again precipitated by the addition of ether.  1.18 g of Z-Glp-Ileu-Pro are obtained. -Nhj  (71.5% of theoretical), t. square  87-89 C, 0.36, V. J -91.4 ° (in acetic acid}.  Calculated,%: C 61.00: H 6.83 N 11.6.   "four .  Found,%: C 59.19; H 6.88 N 11.15.  Mol weight 427.55.  Stage 4: - pyroglutamyl -, - isoleucyl-1. -prolinamide.  To a solution of 4.72 g (10 mmol) of Z-Glp-1 leu-rro-NH, j in 100 ml of methanol, 1 g of a 10% palladium catalyst / activated angle was added. Hydrogen gas was passed through the mixture for one hour.  The catalyst is filtered off, the filtrate is evaporated and the residue is triturated with ether.  The resulting crude product, 3.22 g), is dissolved in water and the solution is clarified with activated charcoal.  A clear aqueous solution is lyophilized, 3.3 g of Glp-Ileu-Pro-NIia (98% of theory) are obtained, Rf 0, 45, b; J2 -100.7 ° (in acetic acid) Amino acid analysis: Glu 95 (1 , 0), Not 1.00 (1.0), Pro 1.02 (1, Example 6.  L-pyroglutamyl-b-o-aminobutyl-b-prolinamide.  Stage 1: pentafluorophenyl ether tert. -butyloxycarbonyl-L-: -aminobutyric acid.  A suspension of 7.7 g (20 mmol) of BOC-LI-ON-ONL in 60 ml of ether is mixed with 20 ml of 2N.  sulfuric acid and shaken to dissolve the suspended substance.  The ether phase is separated by washing in a separatory funnel 20 2 n.  sulfuric acid and then 20 ml of water, dried over anhydrous sulfate. rub and evaporated.  The residual oil (4.14 g) and 3.7 g (20 mmol) of pentafluorophenol was dissolved in 25 ml of ethyl acetate, the solution was cooled below 5 ° C and 3.92 g (19 mmol) of dicyclohexylcarbodiimide was mixed with stirring.  The reaction mixture is stirred for an hour, cooled in an ice bath, filtered. There is precipitated dicyclohexylurea, the filtrate is evaporated.  The residual oil was dissolved in n-hexane and the solution was left in the refrigerator for an hour.  The precipitated dicyclohexidurea is filtered off and the filtrate is concentrated to a volume of 20 ml, with the onset of crystallization the suspension is left in the refrigerator overnight, then the crystals are filtered off.  5.57 g of Boc-Abu-OPFP are obtained (76% of the theoretical), t. square  83-84 ° C, 0.8b, Gs; l -32.8 (in ethyl acetate).  Calculated,%: C, 48.79: H, 4.37 / N, 3.79; F, 25.7.  C, 5I, b04 NP Found: C 48.55; H 4.28 / N 3.70; I- 25.44.  Mol weight 369.29.  2 stage; hydrochloride-L-c-aminobutyryl-, 1, -prolinamide.  A solution of 3.2 g (28 mmol) of H-Pro-N and -5.16 g (14 mixtures) of Boc-Abu-OPFP in 60 ml of dimethylformaglide is kept for 5 min and then evaporated in vacuo.  The residual oil was dissolved in 100 ml of chloroform, the solution was washed in a separatory funnel twice with 20 gll I of oil.  sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated.  The residual oil is dissolved in 20 ml of ethyl acetate and mixed. with 20 ml 6n.  solution of hydrochloric acid in ethyl acetate.  After one hour, the reaction mixture was diluted with ether, the precipitated product was filtered, dried in vacuo over anhydrous sodium hydroxide.  The resulting crude product (3.86 g) is triturated with 20 ml of cold (dimethylformamide).  2.40 g of H-Abu-Pro-N11 (73% of the theoretical yield, calculated on Boc-Abu-OPFP) are obtained, 0.10.  Stage 3: benzyloxycarbonyl-L-pyroglutamyl-I, -c-a 1Inobutyryl-L-prolinamide.   2.13 g (9 mmol) of H-Abu-Pro-Nll is stirred up in 30 m. p dimethylformagshda and under ice cooling and stirring, mixed with 1.26 ml (9 mmol) of triethylamine and 3.95 g (9.2 mmol) of Z-Glp-OPFP.  After 5 minutes, another 1.26 ml (9 mmol) of triethylamine was added to the mixture, and after 20 minutes of stirring, the reaction mixture was evaporated in vacuo.  The crystalline residue is triturated with 20 ml of ethanol, left in the refrigerator overnight and filtered.  3.30 g of L-Glp-Abu-Pro-NH (82% of theory) are obtained. square 17517600, RJ O, 2 8, raj 25- -99.6 (, in acetic acid).  Stage 4: L-pyroglutamyl-L-1- {-aminobutnryl-L-prolinamide.  A solution of 2.67 g (6 mmol) of Z-Glp-Abu-Pro-Nil-jj in 100 ml of acetic acid is mixed with 0.5 g of a 10% palladium / activated carbon catalyst, and gaseous water flow is passed through the mixture for one hour.  The filter is filtered. la: from, the filtrate is evaporated and the residue is triturated with ether.  The resulting product (1.82 g) is dissolved in water, the solution is decolorized with activated charcoal and the clear aqueous solution is lyophilized. 1.70 g of Glp-Abu-Pro-NH (91% of theory) are obtained, R- | 0.24, (3, -102.5 ° (.  in acetic acid).  Etc.  and measure 7.  B-Pyroglutamyl-b-c6-aminodecanoyl-b-prolinamide.  Stage 1: hydrochloride L-oC-aminodecanoyl-L-prolinamide.  A solution of 1.37 g (12 mmol) of N-Pro-NHi and 2.72 g (6 g-fül) of Boc-Ada-OPFP in 20 MP of dimethylformamide is incubated for 5 minutes, then evaporated in vacuo. The residual oil was dissolved in 50 ml of chloroform, the solution was washed in a separatory funnel three times with 10 ml of 1N.  hydrochloric acid, three times 20: lp 1 n.  sodium bicarbonate solution and, finally, twice 10 ml of water, dried over anhydrous sodium sulphate and evaporated.  The residual oil was dissolved in 3 ml of ethyl acetate and mixed with 5 ml of 6.  solution of hydrochloric acid in ethyl acetate.  After standing for 1 hour, the reaction mixture is diluted with ether, the precipitated product is filtered off and dried in vacuo over anhydrous sodium hydroxide.  1.75 g of H-Ada Pro-NH — HCl is obtained (91% of the theoretical yield, calculated on Boc-Ada-OPFP).  Stage 2: benzyloxycarbonyl-L-pyroglutamyl-L-t “-aminodecanoyl-L-prolinamide.  A solution of 1.75 g of 5.5 mmol) H-AdaPro-NHg and 2.58 g (6 mmol) of Z-Glp-OPFP in 30 ml of dimethylformamide is mixed with O, 77 ml (5.5 mmol) of triethyl on.  After 5 minutes, another 0.77 MP (5.5) triethylamine was added to the mixture, and after 20 minutes of stirring, the reaction mixture was evaporated in vacuo.  The residue is dissolved in 50% chloroform, the solution is washed in a separating funnel three times with 2Q ml of 1N.  hydrochloric acid solution, three times 20 mp 1 n.  the solution of sodium bicarbonate and, finally, twice with 20 ml of water, dried over anhydrous sodium sulfate and evaporated.  The residual foamed oil is triturated with ether, the resulting gelatinous type suspension is left to stand for 2 hours in a refrigerator, then the precipitate is filtered and dried.  The crude product (2.61 g) is recrystallized from 20 ml of ethyl acetate.  2.45 g of Z-Glp-Ada-Pro-NH are obtained.  (84% of theoretical with whom, t. square  103-105 ° С, Яф 0,19, MJ -63,7 (in acetic acid and sulphate,%: C 63.62-, H 7.63 N 10.60.   4 Found,%: C 63.24; H 7.81, N 19.47.  Mol weight 528.65.  .  Stage 3: b-pyroglutamyl-b-oC-aminodecanoyl-b-prolinamide.  A solution of 1.9 g (3.6 mmol) of Z-Glp-Ada-Pro-NHj B 40 ml of acetic acid is mixed with 0.2 g of 10% catalysis (a mountain of palladium / activated carbon and gaseous gas is passed through the mixture for one hour hydrogen.  The catalyst is then filtered off, the filtrate is evaporated and the residue is dissolved in water.  The aqueous solution is decolorized with activated carbon and evaporated.  The residual oil obtained is dissolved in 30 ml of chloroform, the solution is dried over sodium sulfate and evaporated.  The foamed, amorphous, hardened residue is triturated with ether, filtered off and dried.  1.20 g of Glp-Ada-Pro-Nilu (02% of theory), 0, is obtained. 55, -66.2 (, in acetic acid).  Example 8  L-H, iroglutami L-b-cyclohexyl-alanyl-b-prolinamide.  Stage 1: pentafluorophenyl ester of tert-butyloxycarbonyl-b-cyclohexyl-Nin.  The suspension of g (20 mmol) of Boc-Cha-OH DCHA in 80 ml of ether is mixed with 20 ml of 2N.  sulfuric acid.  The mixture is shaken until the solid is completely dissolved, then the ether phase is separated, washed with 20 ml of 2N.  sulfuric acid with 20 ml of water, dried over sodium sulfate and evaporated.  The resulting oil- (5.7 g) was dissolved in 30 ml of ethyl acetate, mixed with 3.7 g (20 mmol) of PFPOH.  the mixture is cooled to and mixed with 4.12 g (20 mmol) of dicyclohexylcarbodiimide.  The reaction mixture is stirred for one hour at this temperature, then the precipitated dicyclohexyl urea, the filtrate is evaporated and the residue obtained is dissolved in 30 ml of n-hexane.  The solution is left in the refrigerator for an hour, while the newly precipitated dicyclohexyl urea is filtered off and the filtrate is diluted with 70 ml of n-hexane.  The diluted solution is washed. in a separatory funnel five times 40 ml of 1N.  sodium bicarbonate solution, twice with 40 ml of water, dried over anhydrous sodium sulfate and evaporated.  The resulting oil crystallizes.  8.48 g of Boc-Cha-OPFP (97% of the theoretical) are obtained, t. square 75-77C, 0.88.  Calculated,% s C 54,92; H 5.53; 3.20 | P 21.72.  Cr.  Found,%: C 54.67-H 5.66N 3.11-, F 21.43: Mol.  you 437.41.  Stage 2: L-cyclohexyl-alanyl-b-prolinamide hydrochloride.  A solution of 2.28 g (20 mmol) of H-Pro-NHj, and 4.37 (10 mmol) of Boc-Cha-OPFP in 40 ml of dimethylformamide after 5 minutes, is one hundred times evaporated in vacuo.  The residual oil was dissolved in 80 ml of chloroform, the solution was washed in a separatory funnel three times with 20 ml of 1N.  hydrochloric acid, three times 20 ml of 1N.  sodium bicarbonate solution and finally. once with 20 ml of water, dried over anhydrous sodium sulphate and evaporated.  The residual oil was dissolved in 8 ml of ethyl acetate, mixed with 10 ml of 5N.  solution of hydrochloric acid in ethyl acetate  - yut ether, ylpav in precipitate. .  st is filtered and dried in vacuum over anhydrous caustic soda.  2.98 g of H-Cha-Pro-Ni are obtained. - NA (97% of theoretical yield, counted on Boc-Cha-OITP).  Stage 3: benzyloxycarbonyl-b-pyroglutamyl-b-cyclohexylalanyl prolinamide.  A solution of 2.43 g (8 mmol) of Il-Cha-Pro-Niri-IS1 and 3.60 g (8.4 mmol) of Z-Glp-OPFP in 25 ml of dimethylformamide is mixed with 1.12 ml (8 mmol) of triethylamine.  After 5 minutes, another 1.12 gl (8 mmol) of triethylamine was added and the reaction mixture was stirred for 20 minutes and evaporated in vacuo.  The residue is dissolved in 80 ml of chloroform, the solution is washed in a separating funnel three times with 20 ml of 1N.  hydrochloric acid, three times 20 ml of 1N.  sodium bicarbonate solution and, finally, 20 times water, dried over anhydrous sodium sulfate and evaporated; The residue obtained in the residue is crystallized from ether, the crude product obtained (3.88 g) is recrystallized from 30 ml of ethyl acetate.  3.32 Z-Glp-Cha-Pro-Nll are obtained (81% of the theoretical), t. square 165-166 ° C, Rf | 0.17, ij -67.3 (, in acetic acid).  Calculated,%: C 63.26; H 7.08; N 10.93.  (Found,%: C 63.15- H 7.04, N 10.91 Mol. weight 512.61.  Stage 4: b-pyroglutamyl-b-cyclohexyl-alanyl-b-prolinamide.  A solution of 3.07 g (6 mmol) of Z-Glp-Cha-Pro-NHi 60 ml of ethanol, mixed with 0.6 g of a 10% catalyst palladium / activated carbon and hydrogen gas flowing through the mixture for 2 h.  The catalyst is filtered off, the filtrate is evaporated and the residue is triturated with ether.  2.15 g of amorphous solid Glp-Cha-Pro-NHT are obtained.  (95% of theoretical 0.50, i: otJ b -70.9 ° (, in acetic acid).  Example 9  B-pyroglutam-trepenil-l-pollin id  Stage 1: hydrochloride O-benzyl-l-threonyl-b-proline1 d.  A solution of 1.43 g (12.5 mmol) of H-Pr-NHI and 2.98 g (6.27 mmol) of Boc-Thr (-OPFP was dissolved in 20 ml of dimethylformer amide, incubated for 5 minutes and evaporated in vacuo.  The residual oil was dissolved in 30 ml of chloroform, and the solution was washed in a separatory funnel twice with 10 ml of 1N.  hydrochloric acid, three times 10 ml 1 n.  sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated.  The oil obtained in the residue was dissolved in 4 ml of ethyl acetate and smeared with 5 ml of 5N.  solution of hydrochloric acid in ethyl acetate.  The reaction mixture was kept at room temperature for 1 hour and diluted with ether, the precipitate was filtered off and dried in vacuo over anhydrous sodium hydroxide.  2.05 g of H-Thr are obtained (B7. 1) -Pro-NIIj-HCl (95% of theoretical), 0.40.  Stage 2: benzyloxycarbonyl-i, -pyroglutamyl-L-O-benzyltreonyl-b-proline 1id.  To a solution of 2.05 g (6 mmol) I-Thr (Bzl) -Pro-NH2-PS1 and 2.69 g.  (6.27 mmol) Z-Glp-OPFP in 21 mp of dimethylformamide is added dropwise 0.84 ml (6) of triethylamine, and after 5 minutes, another 0.84 ml (6 mmol) of triethylamine is added, 20 min. the mixture is stirred and then evaporated in vacuo, the residue is dissolved in 50 ml of chloroform, the solution is washed in a separatory funnel twice with 10 ml of 1N.  hydrochloric acid and three times 10 ml of 1N.  sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated.  The residual oil is treated with ether and cooled, the product solidifies in an amorphous state.  The product obtained (2.76 g) is dissolved in ethyl acetate and the solution is decolorized with activated charcoal.  The carbon is filtered off, the filtrate is evaporated and the solid, amorphous, foamed residue is dispersed with ether.  2.47 g of Z-Glp-Thr (Bzl) -Pro-Kll2 are obtained (75% of the theoretical).  Stage 3: b-pyroglutamyl-b-threonyl-b-prolinamide.  A solution of 2.04 g (3.7 mmol) of Z-Glp-Thr (Bz: l) -Pro-NIl2.  40 ml of acetic acid are mixed with 0.4 g of a 10% catalyst with palladium / activated carbon and hydrogen gas is passed through the mixture for 4 hours.  The catalyst is filtered off, the filtrate is evaporated and the residue is triturated with ether.  The obtained amorphous product (1.31 g) is placed in a column containing 30 g of silica gel (particle size: 0.063-0.2 mm) and the product is eluted with a mixture of solvents (3).  The fractions of the eluates containing the pure product are combined and evaporated, the crude product obtained as a residue is taken up in ether.  0.72 g of Glp-Thr-Pro-Nll is obtained. , (59.5% of theoretical), R | - 0.16, loLJ -90.0 ° (, in acetic acid).  Amino acid analysis: Glu 1.00 (1.0), Thr 0.99 (1.0), Pro 1.03 (1.0).  Example 10  L-Pyroglutamyl-O-tert-butyl-b-seryl-1, -prolinampd.  Stage 1: 0-tert-butyl. - seryl-prolinamide-semi-oxalate.  8.0 g (70 mmol) of H-Pro-NHa, and 16.0 g (34.7 mmol) of Z-Ser () -OPFP are dissolved in 120 ml of dimethylformamide and the solution is evaporated in vacuum after 5 minutes.  The residual oil was dissolved in 300 ml of chloroform, the solution was washed in a separatory funnel three times with 80 ml of 1N hydrochloric acid, three times with 80 ml of 1N.  sodium bicarbonate solution and, finally, once with 80 ml of water, dried over anhydrous sodium sulfate and evaporated.  The residual oil (18 g) and 4.37 g (34.7 mmol) of the dihydrate of oxalic acid are dissolved in 300 ml of methanol, the solution is mixed with 3 g of a 10% palladium catalyst activated carbon and the mixture is passed through the mixture for one hour gaseous hydrogen.  The catalyst is filtered off, the filtrate is evaporated, the residue is triturated with ethyl acetate and dried in vacuo. .  10.8 g of H-Ser (B) -Pgo-NH - (COOH) 2 are obtained.  (90% of theoretical yield, calculated on Z-Ser (We) -OPFP in the form of an amorphous gyroscopic substance), RSf 0.22.  Stage 2: Bvnzyloxycarbonyl-L-pyroglutamyl-o-tert-butyl-b-seryl-L-prolinamide.  A solution of 6.43 g (18.5 mmol) of H-Ser (Bu-t) -Pro-NHi- (COOH) and 3.97 g (18.5 mmol) of Z-Glp-OPFP. in 80 ml di.  -methyl forms and mixed with 5.18 ml (37 mmol) of triethylamine.  After 5 m, the reaction mixture is evaporated in vacuo and the crystalline residue is triturated with ether.  The resulting crude product (9.53 g) is recrystallized from 120 mp of methanol.  By . 7.70 g of Z-Glp-Ser (But) -Pro-NHi (83% of the theoretical), t. mp 226-229c, 0.46, OO 71.6® (, in acetic acid).  I Calculated,%: C 59.75, H 6.82; IN 11.15.  - /: c, Found,%: C 59.55; H 6.95 N 11.09.  Mol  weight 502.57.  Stage 3: L-pyroglutamyl-O-tert-butyl-b-seryl-b-prolinamide.  .  4.02 g (8 mmol) of Z-Glp-Ser (Bu) -Pro-NHj are dissolved in 160 ml of metaiol and the solution is mixed with 0.8 g of TO% palladium / activated carbon catalyst, through the mixture for 30 minutes hydrogen gas is passed.  The catalyst is filtered off, the filtrate is evaporated.  The residual oil crystallized from ether, the J crystallites are filtered and dried.  2.50 g of Glp-Ser are obtained (BU -Pro-NHi (85% of the theoretical), t. square 186-187 "C, R4 0.45, W: -60.8 ° (in acetic acid) Amino acid analysis: Glu 1.03 (1.0), Ser 1.00 (1.0), Pro 1, 00 (1.0).  Calculated,%: C 55.42: H 7.66, N 15.21 C, 7 H2 D% Found,%: C 55.07 ;; H 7.61; N 14.94.  Mol  weight 368.44.  . Example 11  L-Pyroglutamyl-B-leucyl-b-prolinamide.  Stage 1: tert-butyloxycarbonyl-B-leucyl pentafluorophenyl ether.  A solution of 4.62 g (20 mmol) of Boc-D-Leu-OH and 4.23 g (22 mmol) of PFPOH — mixed with 4.12 g (20 mmol) of dicyclohexylcarbodiimide in 50 ml of ethyl acetate under ice-cooling and stirring.  The reaction mixture is stirred, cooled in an ice bath, the precipitated dicyclohexylurea is filtered off and the filtrate is evaporated.  The residual oil was dissolved in 100 ml of n-hexane, the solution was left in the fridge for an hour and the dicyclohexyl urea precipitated was filtered off.  The filtrate is washed in a separating funnel five times with 50 ml of 1N.  sodium bicarbonate solution and twice 50 ml of water, dried over anhydrous sodium sulfate and evaporated.  The residue obtained is crystallized overnight.  7.0 g of Boc-D-Leu-OPFP (88% of theory) are obtained, t. square 53-55 C, L 4-31,7 (, in ethyl acetate).  Calculated,%: C, 51.39; H 5.07 / N 3.53iF 23.91 C HrOi and NFf Found,%: C 51.51; H 4.68; N 3,66; F 23.65.  Mol weight 397.35.   Stage 2: D-leucyl-b-proline mid hydrochloride.  .  A solution of 3.42 g (30 mmol) of H-Pro-NH and 60.0 g (15 mmol) of Boc-D-Leu-OPFP in 60 MP of dimethylformamide after 5 minutes is one hundred times evaporated in vacuo.  The residue is dissolved in 100 ml of chloroform, the solution is swirled in a separatory funnel twice with 20 mp 1N.  hydrochloric acid solution, three times 20 ml of 1 N, sodium bicarbonate solution and, finally, once with 20 ml of water, dried over anhydrous sodium sulfate and evaporated.  The residual oil was dissolved in 10 ml of ethyl acetate, the solution was washed off with 15 ml of 4N.  hydrochloric acid / ethyl acetate solution, after one hour, the reaction mixture is diluted with ether, the precipitate is filtered off and dried in vacuum over anhydrous sodium hydroxide.  3.66 g of H-D-Leu-Pro-NHg-HCl (92.5% of theoretical yield, calculated on Boc-D-Leu-OPFP) are obtained, 0.25. .
    Stage 3: benzyloxycarbonyl-L-pyroglutamyl-O-leucyl-b-prolinamide.
    A solution of 3.66 g (13.9 mmol of HD-Leu-Pro-NHj. HCl and 6.43 g (15 mmol) of Z-Glp-OPFP in 50 ml of dimethylformamide is mixed with ice and stirring with 1.95 ml (13 , 9 mmol) of triethylamine. The mixture is stirred for 5 minutes and then an additional 1.95 ml (13.9 mmol) of triethylamine is added to it, the reaction mixture is stirred for another 20 minutes and evaporated in vacuo. The residue is dissolved in 120 ml of chloroform, the solution washed in a separating funnel three times with 30 ml of 1N hydrochloric acid solution, three times with 30 MP of 1N sodium bicarbonate solution, and finally 30 times with water once, dried over anhydrous sodium sulfate and evaporated. The oil obtained in the residue is crystallized after treatment with ether.The crude product obtained (6 g) is recrystallized from 30 ml of ethanol to give 5.48 g of Z-Glp-D-Leu-Pro-NHi (77% of theory), t. 188919 .4С VRf 0.48; И25 ЗЗ, 2 (, in acetic acid).
    Stage 4: b-pyroglutamyl-b-leucyl-b-prolinamide.
    A solution of 3.78 g (8 mmol) of Z-Glp-D-Leu-Pro-NH in 150 mA methanol, mixed with 0.8 g of 10% catalyst, palladium on activated carbon and passing hydrogen gas through the mixture for an hour . The catalyst is filtered off, the filtrate is evaporated and the residue is triturated with ether. The resulting crude product (2.5 g) is dissolved in water, decolorized with activated charcoal and the clear aqueous solution is lyophilized. 2.35 g of Glp-D-Leu-Pfo-NH are obtained (87% of theoretical, R 0.48,, 3 (, in acetic acid).
    Example 12. L-Pyroglutamyl-b-leucyl-b-proline-ethylamide.
    1- Stage: L-leucyl-L-proline-ethylamide hydrochloride.
    A suspension of 1.67 g (7.2 mmol) of H-Pro-NH-Et- (COOH) i in 20 ml of ethyl acetate is mixed with 2.0 ml (14.4 mmol) of triethylamine and 2.38 g (6 mmol ) Boc-Leu-OPFP. After 5 min, the reaction mixture was washed in a separatory funnel twice with 5 ml of 1N. hydrochloric acid solution, three times 5 ml of 1N. sodium bicarbonate solution and finally, once with 5 MP of water, dried over anhydrous sodium sulfate and evaporated. The resulting oil is treated with 10 MP 5 n. hydrochloric acid in ethyl acetate solution, after 20 minutes, the mixture is diluted with ether, the precipitate is filtered and dried in vacuum over anhydrous sodium hydroxide. 1.46 g of hygroscopic H-Leu-Pro-NH-Et-HC1 are obtained.
    (83% of theoretical yield, calculated on Boc-Leu-OPFP), R 0.43.
    Stage 2: benzyloxycarbonyl-b-pyroglutamyl-b-leucyl-b-proline.
    1.17 g (4 mmol) of H-Leu-Pro-NH-Et-HC1 and 1.72 g (4 mmol) of Z-Glp-OPF are dissolved in 15 MP of dimethylformamide and mixed with 0.56 ml (4 mmol) triethylamine. After 5 min., the remaining 0.56 ml (4 mmol) of triethylamine is added and the mixture is evaporated in vacuo. The resulting oil is dissolved in 40 MP of chloroform, the solution is washed in a separating funnel twice with 10 ml of 1N hydrochloric solution acid, three times 10 ml of 1N sodium bicarbonate solution and, finally, once with 10 ml of water, dried over anhydrous sodium sulfate and evaporated. The residue is triturated with n-hexane and filtered to obtain 1.61 amorphous Z-Glp-Leu-Pro-NH-Et (80,5% of theory), "4 0.50, s /.- 89,0 ° (, in acetic acid).
    Stage 3: b-pyroglutamyl-b-leucyl-b-propyne-ethylamide.
    A solution of 1.07 g (2.14 mmol) of Z-Glp-Leu-Pro-NH-Et in 30 ml of water is mixed with 0.25 g of a 10% palladium / activated carbon catalyst and hydrogen gas is passed through the mixture for half an hour . The catalyst is filtered off, the filtrate is evaporated, the oily residue is dissolved in 20 MP of chloroform, the solution is dried over anhydrous sodium sulfate and evaporated. The cured after foaming residue is triturated with a mixture of ether and n-hexane. Obtain 0.52 g of Glp-Leu-Pro-NH-Et (66% of theoretical). 0,57ЛЫ35 -94,5 (, in acetic acid).
    Example 13. L-Pyroglutamyl-b-leucyl-b-propyl-n-decylamide.
    Stage 1: benzyloxycarbonyl-L-propyne-n-decylamide.
    A solution of 5.0 g (20 mmol) of Z-Pro-OH in 50 W of dimethylformamide is taken up with 2.8 ml (20 mmol) of triethylamine and cooled to -10 ° C. At this temperature, first stirring is added dropwise, 2 8 mp (21.5 mmol) of chlorobolic acid isobutyl ester and after 10 min 4.4 MP (22 mmol) of n-decylamine. After the addition is complete, the mixture is stirred for 30 minutes and then for 2 hours at room temperature. The resulting suspension is filtered, the filtrate is evaporated and the residue is dissolved in 100 MP of ethyl acetate. The solution is washed in a separating funnel four times 50 MP 1 n. hydrochloric acid solution, twice 50 MP of water, dried over anhydrous sodium sulfate HbJM and evaporated. The residue obtained in the residue crystallizes upon treatment with n-hexane. 5.43 g of Z-Pro-NH-f Hj (70% of theory) are obtained, mp. 7880 C, 0.75. .2-Stage: L-proline n-decylamide-puloxalate. A solution of 5.0 g (12.9 IMol) Z-Pro-NH-QpHj and 2.02 g (16 mmol) of oxalic acid dihydrate in 100 ml of methanol is mixed with 0.8 g of a 10% catalyst palladium / activated carbon and gaseous hydrogen is passed through the mixture for 2 hours. Upon completion, the hydrogenation reaction mixture is heated, the catalyst is filtered off and the filtrate is evaporated. The crystalline residue is triturated with ether, the ether is filtered off. 3.9 g of H-Pro-NH-qpH2, -n (COOH) a (88% of theory), m.p. 152-154C, R 0.16. 3-. stages: hydrochloride L-leucyl-L-proline-n-decylamide. A solution of 3.44 g (.100 mol) H-Pro-NH-C, II, - () 2. and 2.0 g (5 mmol) of Boc-Leu-OPFP in 30 ml of dimethylformamide is mixed with 2, .8 ml (20 mmol) of triethylamine. After 5 minutes, the reaction mixture is evaporated and the residue obtained is dissolved in 50 ml of n-hexane. The solution is washed in a separatory funnel five times with 30 ml of 1N. hydrochloric acid solution, three times 30 2SH 1 n. sodium bicarbonate solution and, finally, once with 30 ml of water and evaporated. The residue obtained in the residue is dissolved in 10 MP 5 n. ethyl acetate solution, the solution is left for 30 minutes and evaporated. The amorphous residue foaming under vacuum is triturated with n-hexane and dried in vacuo over anhydrous sodium hydroxide. 1.05 g of H-Leu-Pro-NH-C is obtained H .-, - HCl (60% of theoretical yield, calculated on Boc-Leu-OPFP),. 0.17. Stage 4: Bbnziloxycarbonyl-L-monoglutamyl-L-leucyl-L-proline-decylamide. A solution of 1.03 g (2.55 mmol) of H-Leu-Pro-NH-C H, j in 10 ml of dimethylforma P da is mixed with 0.36 g-sh (2.55 triethylamine and 1.1 g (2, 55 mmol) Z-Glp-OPFP. The mixture is stirred for 5 minutes, then another 0.36 ml (.2.55) of triethylamine is added to it and, after 20 sq. Of stirring, the reaction mixture is evaporated in vacuo. The residue is dissolved in 20 ml of chloroform, the solution is washed in a separating funnel five times with 10 ml of 1N hydrochloric acid solution, three times with 10 ml of 1N sodium bicarbonate solution and, finally, once with 10 M.rt of water, dried over anhydrous sodium sulfate, and evaporated. the oil is crystallized from zfir. Obtain 1.22 g of Z-Glp-Leu-Pro-Nl -C ILj (78% of theoretical), so pl. 10 8-109 C, Sch 0.50, -74.5 (in acetic acid). Calculated,%: C, 66.64; H, 8.55; N, 9.14., Found:%: C, 66.43, H, 8.84, N, 9.13; mol. Weight 612.82. : L-pyroglutamyl-L-leucyl-L-proline-n-decylamide. 1.22 g (2 mmol) of Z-Glp-Leu-Pro-NH-C pHj are dissolved in 30 ml of methano, the solution is mixed with 0.2 g 10% catalyst palladium / activated carbon and hydrogen gas is passed through the mixture for 30 minutes. The catalyst is filtered off, the filtrate is evaporated and the resulting oil is treated with n-hexane. The precipitate is filtered off. The crude product (0.85 g) is recrystallized from 4 ml of ethyl acetate. Obtain 0.74 g of Glp-Leu-Pro-NH-C, oH.2 (77% of theoretical), so pl. 140-141 C, ,, 3 ° (, in acetic acid). Amino acid analysis: Glu 0.97 (1.0), Leu 1.00 (1.0), Pro 1.01 (1.0). Example 14. L-Pyroglutamyl-L-leucyl-L-proline- (2-dimethylaminoethyl) -amide. Stage 1: tert-butyloxycarbonyl-L-pollin (2-dimethylaminoethyl) -amide. A solution of 11.43 g (30 mmol) of Boc-Pro-OPPP in 100 ml of ether is mixed with 6.54 MP (60 mmol) of H, M-dimethylamino-ethanol and left to stand for 10 minutes. The mixture is washed in a separating funnel three times with 30 ml of water, the aqueous phases are combined by adding solid sodium carbonate, the pH is adjusted to 10 and the solution is extracted with ethyl acetate (4 x 20 ml). The organic phases are combined, washed with 20 ml of water, dried over anhydrous sodium sulphate and evaporated. The residual oil crystallized on standing. 6.71 g of Boc-Pro-UH-CH2 CH2 (CH3) / g are obtained. (78.5% of theoretical),, 29. Stage 2: L-leucyl-L-primer (.2-dimethylaminoethyl) amide dihydrOchloride. 6.71 g (23.5 mmol) of Boc-Pro-NH-Cli, (CE) are treated with 30 ml of 5N for 30 minutes. a solution of hydrochloric acid in ethyl acetate, then the mixture is evaporated. The residue obtained is dissolved in 50 ml of chloroform and triethylag is mixed with 2.8 ml (20 mmol) of triethylag. The resulting clear solution was diluted with 6.74 g (17 mmol) of Boc-Leu-OPFP, and after 1 hour of stirring, another 2.8 ml (20) of triethylamine was added dropwise. The mixture was left overnight and evaporated the next day. The residue obtained is dissolved in 50 ml of water, the pH of the solution is adjusted to 10 by adding solid sodium carbonate, the protected dipeptide is extracted from the aqueous phase with ethyl acetate. The ethyl acetate phase is separated, dried over anhydrous sodium sulphate and evaporated. The oil obtained in the residue is treated with 5 n for an hour. with a solution of hydrochloric acid in ethyl acetate, the reaction mixture is evaporated and the residue is triturated with ether. After filtration, the amorphous, highly hygroscopic product is dried in vacuum over anhydrous caustic soda. 4.5 g of H-Leu-Pro-NH-CH, CHi-N () are obtained. 2HCl, R 0.05.
    Stage 3: L-pyroglutamyl-L-leucyl-L-proline- (2-dimethylaminoethyl) -amide.
    A solution of 2.6 g (7 mmol) of H-Leu-Pro-NH-CH CH, (CH3-) i-2HC1 is dissolved in 30 ml of dimethylformaDa, mixed with 1.86 ml (14 mmol) of triethylamine. The precipitated product is filtered off and the mother liquor is added dropwise.
    add, with stirring, to an ice-cooled solution of 3.29 g
    I (7.7 mmol) Z-Glp-OPFP in 10 ml of dimethylformamide. At the end of the addition, the reaction mixture is left on
    Mchi is then evaporated in vacuo. The residual oil is dissolved in 50 ml of water, the solution using concentrated hydrochloric acid; acidified to pH 3 and washed three times in a separatory funnel with 20 ml of ethyl acetate. Then the pH value of the aqueous solution is adjusted to 10 by addition of solid sodium carbonate and the basic solution is extracted with ethyl acetate (5-30 ml). The organic phases are combined, dried over anhydrous sodium sulphate and evaporated. The resulting oily protected dipeptide (3.05 g, 5.6 mmol) is dissolved in 60 ml of water, the solution is mixed with 5.6 ml of 1N. a solution of hydrochloric acid and 0.6 g of a 10% catalyst was palladium / activated carbon and hydrogen gas was passed through the mixture for 30 min. After filtering off the catalyst, the filtrate is evaporated, the resulting oil is dissolved in a mixture of 50 ml of chloro, form and 20 ml of 1N. sodium bicarbonate solution. The phases are separated, the chloroform layer is dried over anhydrous sodium sulfate and filtered. The resulting amorphous product (2.0 g) was dissolved in water, the solution was treated with activated charcoal and the clear aqueous solution was lyophilized. 12 g of Glp-Leu-Pro-NHCH CH2, N (CH, (60% of theoretical), 0.06,, l ° (, in acetic acid) are obtained
    Amino acid analysis: Glu 1.02 (1.0), Leu 1.00 (1.00), Pro 1.03 (1.0).
    Example 15. Amide of L-pyroglutamyl-L-histidyl-P-pipecolinic acid.
    Stage 1: benzyloxycarbonyl-B-pipecolic acid amide.
    A solution of 13.15 g (50 Fül) of Z-D-Pip-OH in 100 ml of ethyl acetate is mixed with 7.0 ml (50 mmol) of triethylamine. The mixture is cooled to -20 ° C and at this temperature, while stirring, 6.5 ml (50 mmol) of chlorobolic acid isobutyl ester are added dropwise. After 15 min stirring at -10 ° C, ammonia gas is passed into the mixture for one and a half hours. The precipitate is filtered, the mother liquor is washed in a separating funnel 1 n. solution of hydrochloric acid, then 1 n. sodium bicarbonate solution and finally water, dried over anhydrous sodium sulphate and evaporated. The residue is crystallized from a mixture of ethyl acetate and ether, and 11.5 g of ZD-Pip-NlIj (88% of the theoretical) are obtained, mp 114-115 ° C, R 0.50,, 0 (1, acetic acid).
    calculated,%: N 10,68.
    Q4lUO N5.
    Found,% :. N 10.63
    Mol weight 262.30.
    Stage 2: P-pipecolinic acid amide.
    A solution of 3.93 g (15 mmol) of Z-Pip-NH in 75 ml of methanol is mixed with 0.5 g of a 10% catalyst palladium / activated carbon and hydrogen gas is passed through the mixture for an hour. The catalyst is filtered off. The mother liquor is evaporated and the residue is triturated with ether. I get 1.70 g of H-D-Pip-NH.2 (90% of the theoretical), so pl.1b1-1bzs ,, IO,
    G (, 0 ° (, in methanol).
    Z-stage: benzyloxycarbonyl-b-glutaminyl-b-histidine hydrazide.
    71.0 g (0.165 mol) of Z-Gln-His-OM pacTBopsnoT in 700 ml of dimethylformamide and the solution is mixed with 33.6 ml (0.495 mol) of hydraenohydrate. The reaction, the mixture is left for 3 days, then diluted with 600 ml of ethyl acetate and kept in a refrigerator overnight. The next day, the precipitate is filtered off. The resulting crude product (71.65 g) is recrystallized from 1800 ml of methanol. 55.1 g of Z-Gln-His-: N2.H3 are obtained (78% of the theoretical), mp.198-200s, R | 0.28.
    Calculated,%: C, 52.90; H.5.84; N 22.72
     H
    Found,%: C 51.21; H 5.73,
    N 22.7.
    Mol weight 431.40.
    Stage 4: benzyloxycarbonyl-b-glutaminyl-b-histidyl-b-pipecolinic acid amide.
    A suspension of 5% 39 g (12.5 mmol) of Z-Gln-His-N2 H in 100 ml of dimethylformamide is mixed with 4.6 ml (37.5 mmol) of 8.1 n. hydrochloric acid solution in dioxane. The resulting solution was cooled to -20 ° C, the temperature was raised to 1.43 MP (13.7 mmol) tert-butylnitrile-a was added dropwise to it with stirring. The reaction mixture was stirred for 20 minutes, then 3.5 ml (25 mmol) of three were added dropwise to the mixture:; tylamine, a solution of 1.57 g (12.5 mmol) of H-D-Pip-NHj. and finally another 1.75 ml (12.5 mmol) of triethylamine. Then the reaction mixture was stirred at -10 ° C for one hour and left overnight in a refrigerator at 2 ° C. The next day, the precipitate is filtered off, the mother liquor is evaporated in a vacuum. The amorphous residue is triturated with ethyl acetate. The resulting crude is placed on a silica gel column and the product is eluted with a mixture of solvents (2). The fractions containing the pure product are combined and evaporated, the residue is triturated with ether and filtered. Get 2, .76 g of amorphous Z-Gln-His-D-Pip-NHi (42% of theoretical)., R 0,101
    5th stage; amide b-gigroglutamyl-histidyl-B-pipecolinic acid.
    . A solution of 2.63 g (5 mmol) of Z-Gln-His D-Pip-NH2 ml of acetic acid, mixed with 0.5 g of a 10% catalyst, palladium / activated carbon and hydrogen gas passed through the solution for an hour. The catalyst is filtered off, the mother liquor is heated to 60-70 ° C, the mixture is kept at this temperature for 30 minutes and then evaporated in vacuo. The residue is dissolved in water, the solution is treated with Dowex-2 resin in OH-form and evaporated. The resulting crude product is introduced into a silica gel column and eluted with a mixture of solvents (1). Fractions containing pure product,. they are combined and evaporated, the residue is dissolved in water, the solution is clarified with activated ylem and the clear vodka solution is evaporated. The amorphous residue is dried in vacuo over phosphoric anhydride. Get 704 mg Glp-His-D-Pip-NHa (51% of theoretical), RW 0,10,, 0 ° (in water).
    Amino acid analysis: Glu 1.03 (1.0), His 1.00 (1.0), Pip 0.96 vl, 07.
    EXAMPLE 16 .L-Pyroglutamyl-b-histidyl-b-homoprolinamide.
    Stage 1: tert-butyloxycarbonyl-b-homoprolinamide.
    2.29 g (10 mmol; BOC-HPgo is dissolved in 30 ml of ethyl acetate, the solution is mixed with 1.4 ml (10 g. 1 mol) of triethylamine and cooled to. Maintaining the temperature of the reaction mixture -10 ° C, is added dropwise 1.3 ml (10 mmol) of isobutyl chlorotic acid ester. After 15 minutes of stirring, gaseous gas is passed through the reaction mixture for half an hour, after which the mixture is left for 2 hours at a temperature from 0 to 5 ° C. The precipitate is filtered off evaporated and the residual oil was dissolved in 30 ml of chloroform 5. The solution was washed in a separator in Onke twice 10 ml of 1N hydrochloric acid solution, then twice 10 ml of 1N sodium bicarbonate solution and finally once 10 ml Q water, dried over anhydrous sodium sulfate and evaporated. The resulting oil crystallizes from n hexane. The resulting crude product (1.96 g) is recrystallized from 5 mixture of ethyl ether and 1.78 g of Boc-HPro-NIi, (78% of theory), mp 138-140 C; R 0.43, , 85 (in acetic acid) ,.
    Calculated,%: C 57.87; H JB, 83; N 12.27.
    OMN ,, „About N5.
    Found,%: C 57.6.0; H 8.89, N 12, .11.
    Mol. Weight 228.29.
    5 2nd stage: L-homoprolinamide hydrochloride.
    1.6 g (7 mmol) of Boc-HPro-NH is dissolved in 10 ml of ethyl acetate with heating. The solution is cooled to room temperature 0 and mixed. with 10 ml 6 n. solution of hydrochloric acid in ethyl acetate. The reaction mixture is left for an hour, then diluted with ether, the resulting precipitate is triturated 5 and filtered. Obtain 1.05 g of N-NRgo-NH / -HC1. (91% of theoretical), so pl. 178-180 ° С, 0.32, ro (j25 +26.2 (, in methanol).
    Stage 3: benzyloxycarbonyl 1-glutaminyl-b-histidyl-b-homoprolinamide.
    A suspension of 5.39 g (12.5 mmol) of Z-Gln-.His-N2.H (see Example 15, Stage 3) in 100 ml of dimethylformamide
    5 is mixed with 4.6 ml (37.5 mmol) of 8.1 n hydrochloric acid solution in dioxane. The resulting solution is cooled to -20 ° C, then the temperature is raised before and with stirring, the research mixture is added dropwise to 1.63 gl (13.7 mmol) of tert-butylnitrile. The reaction mixture is stirred at -10 ° C for 20 minutes, then mixed with 3.5 ml (25 mmol) of three 5 ethylamine. A solution of 2.07 g (12.5 mmol) ll-MPro-Ntl-ll (; i in 10 ml of dimethylformamide is stirred with 1 , 75 ml (12.5 mmol of triethylamine. The precipitate is filtered. The resulting solution is cooled to -10 ° C and added dropwise to the azide solution, and finally 1.75 ml (12.5 mmol) of triethyl are added to the mixture amine. The reaction mass is stirred for one hour and then left overnight at 2 C. The next day, the precipitate is filtered, the filtrate is evaporated in vacuo and the amorphous residue is triturated with ethyl acetate. The resulting crude product is introduced onto a silica gel column and eluted with a mixture of solvents (2). The fractions containing the pure product are combined and evaporated, and the residue is triturated with ether to give 2.35 g of Z-Gln-His- HPro-NH (36% of theoretical 0.30. 4-stage: b-pyroglutamyl-b-histidyl-L-homoproli-namide. A solution of 2.1 g (4 mmol) of Z-Gln-his-HPro-NH. In 40 ml of acetic acid is mixed with 0.4 g of a 10% palladium / activated carbon catalyst and hydrogen gas is passed through the mixture for one hour. The catalyst is filtered off; the mother liquor is heated to a temperature of from 60 to and at, this temperature is kept for 30 minutes and then evaporated in vacuo. The crude product obtained in the residue was treated with an ion exchange resin, as described in Example 15, Step 5, and cleaned on a column of silica gel. 618 mg of Glp-His-HPro-NHi are obtained (56% of theoretical), R 0.08,, 0 (, in methanol). Amino acid analysis: Glu 0.97 (1.0), - His 1.00 (1.0), HPro 0.91 (1.0 The tripeptides obtained according to the invention were tested for their pharmacological effects using the biological methods described below. 1 Suppression of haloperidol-catalepsy in rats. 40 mg / kg of haloperidol-4- (p-chlorophenyl) -1-rt 3- (p-fluorobenzoyl) -propyl-piperidin-4-ol was subcutaneously injected into animals and after 120 min they controlled the onset. catalepsy, then the rats are divided into groups of 10 animals in each and administered intravenously to the TRH positions and the corresponding tripeptides. Animals of the control group 15.30, 90, and 120 minutes after treatment, the catalepsy-eliminating effect of individual compounds is checked. Cataleptic is considered to be those animals that, if placed on the 7-cm column with their front paws. Do not change their position during 30 s. The experiments were carried out with WiStar rats, males weighing from 160 to 180 g. 2. Potentiation of locomotor activity in mice. Animals were first injected intraperitoneally with 40 mg / kg L-methyl-L-propargyl-benzylamine, then 20 mg / kg TRU, respectively, equal doses of the new tripeptides studied, and finally 100 mg / kg L-Dopa. After 30.60 and 90 minutes after treatment, the locomotor activity of the animals is measured, certain values are indicated in the table in percent (compared with the values obtained in animals treated with TRH). For the experiments, 15 male mice weighing from 18 to 22 g were used. . 3. Pezeppin-hypoter w-stimulating action in mice. Male mice weighing from 18 to 22 g were divided into groups of 10 pieces each, 5 mg / kg of reserpine were administered intraperitoneally, after 16 hours, animals were treated with doses of 20 mg / kg of TRH and the corresponding tripeptide. The rectal temperature of the animals is measured before being treated with reserpine. The table shows the mean rectal temperatures measured in every 10 mice. 4. Effect on the duration of sleep caused by hexobarbital. Male mice, divided into groups of 10 pieces each, were injected intravenously with 60 mg / kg hexabarbital-Na, and then after 10 minutes, TRH corresponding to the studied tripeptide was administered intraperitoneally at a dose of 20 mg / kg. The table shows the sleep time in percent relative to the values measured in animals of the control group (average values from 10 animals). 5. Ethanol anesthesia. Mice of mixed sex weighing 18 to 22 g, divided into groups of 20 animals each, were administered intraperitoneally with 4.5 g of ethanol, and after 10 minutes, the studied tripeptides were administered intraperitoneally in doses of 20 mg / kg. The table shows the periods of sleep in percent relative to the values measured in animals of the control group (average values of t, 1e 20 animals). 6. Hormonal activity (TRH action) in rats .. Wistar rats-males weighing about 200 g are divided into groups of 7-8 animals each and administered intravenously in doses of 20 mg / kg TRH and the corresponding tripeptides studied, the TRH response of animals is measured 15 minutes after treatment with TRH and the corresponding plasmid compounds of the animals under study by radioimmunoassay. The relative action level is calculated by the four-point method using TOA 101 Computer, and the action level TRH is considered to be 100.
    The biological effects of certain compounds of general formula I, as determined by the above pharmacological methods, are summarized in the table. . .
    It can be seen from the table. By replacing His with an aliphatic amino acid with a straight or branched carbon chain in a TRH molecule, termination or significant reduction in TSH release is caused, for example, suppression of haloperidol-induced cadalepsy QT is stronger by 2-7 times. Some new TRH analogs also show significant potentiation of locomotor activity, corresponding to
    a decrease in the sleep period caused by hexobarbital or ethanol.
    权利要求:
    Claims (1)
    [1]
    The new tripeptides obtained according to the invention, as well as their Pharmaceutically used salts or Complexes, can be used in the form of conventional drugs in therapy. These drugs contain the active substances accompanied by intestinal or parenteral inorganic or organic carriers. Drugs can be made, for example, in the form of solid lyophilisates, to which compounds that do not react with the peptides are added as carriers, for example, carbohydrates, they can also be made in the form of concentrated or diluted suspensions or emulsions or tablets or preparations dp injection. No. 319634. Formula of the invention. Method for populating tripeptidamides of general formula i. . Glp-X-Y-NH-A (T) 5 where X is Leu, D-Leu, Nleu, lieu, Val, Nvai. Thr, Pro, L-rf-aminobu-. teryl, L-a-aminodecanoyl, b-cyclohexylalanil, 1 - “: - tert-,“ -butyl-seryl - tt - 10 vr D). . , A - hydrochloride / A1K (C; (-0.0), (CHj) NA1K (),. Provided that X is Leu, then A has a meaning different from hydrogen or X is His, Y HPO, D- Pipecolil, characterized in that the peptide chain is expanded, starting from 3-32 amides of an amino acid of the general form of the set (ri-to-iNn-rt III where Y and A have the indicated values, with amino acids, Their derivatives of the corresponding dipeptide method " pentafluorophenyl ethers or by the azide method and, in the case of using glutamic acid, cyclization of the latter to pyroglutamine, followed by removal of the protective groups. ny attention in examination 1. Bodansky M., Klausner Y.S. Activated esters and strategies for peptide synthesis.- Chemistry of polypeptides. Edited by P.Katosonis. M., Mir, .1977, pp. 30-51 .
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    同族专利:
    公开号 | 公开日
    PL225268A1|1981-10-16|
    ATA334680A|1983-06-15|
    FR2460292A1|1981-01-23|
    FI74473C|1988-02-08|
    DK149611B|1986-08-11|
    AU538100B2|1984-07-26|
    AT373578B|1984-02-10|
    FI802057A|1980-12-29|
    AU5971980A|1981-01-08|
    NL8003767A|1980-12-30|
    CS239907B2|1986-01-16|
    CA1151154A|1983-08-02|
    DE3024313C2|1991-05-29|
    SE447261B|1986-11-03|
    BE884014A|1980-12-29|
    US4299821A|1981-11-10|
    FI74473B|1987-10-30|
    SE8004744L|1980-12-29|
    DD151746A5|1981-11-04|
    IL60407A|1984-11-30|
    IL60407D0|1980-09-16|
    HU180925B|1983-05-30|
    IT1150023B|1986-12-10|
    GB2058080A|1981-04-08|
    FR2460292B1|1983-11-18|
    IT8023096D0|1980-06-26|
    DK274680A|1980-12-29|
    GB2058080B|1983-02-23|
    CS458480A2|1985-05-15|
    DE3024313A1|1981-01-29|
    JPS5636442A|1981-04-09|
    DK149611C|1987-01-26|
    CH650518A5|1985-07-31|
    PL127100B1|1983-09-30|
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    HU79RI717A|HU180925B|1979-06-28|1979-06-28|Process for producing tripeptide-amides trh-analogues,effectives on the central nerve systhem|
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