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    • 专利摘要:
    Peptide derivatives, which act on the central nervous system, correspond to the general formula (I), X-Y-W-NH2 (I> wherein X is L-pyroglutamyl, D-pyroglutamyl, L-2-keto-imidazolidine-4-carbonyl, L-6- keto-pipecolyl, L-thiazolidine-4- carbonyl, L-prolyl or orotyl group, Y is L-leucyl, L-norvalyl or L-histidyl group, and W is L-prolyl, D-prolyl, L-thiazolidine- 4-carbonyl, L-pipecolyl, L-homoprolyl, L-leucyl, L-isoleucyl, L-methionyl or D- pipecolyl group, or the W-NH2 group stands for pyrrolidyl or piperidyl group, with the proviso that if X is L-pyroglutamyl and Y is L-histidyl group, W is other than L-prolyl, L- homoprolyl or D-pipecolyl group, and if X is L-pyroglutamyl and Y is L-leucyl or L-norvalyl, W is other than L-prolyl, and pharmaceutically acceptable complexes thereof.
    公开号:SU1085505A3
    申请号:SU802940703
    申请日:1980-06-26
    公开日:1984-04-07
    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 new tripeptides — biologically active compounds that can be used in medicine. PL. 1C
    In peptide chemistry, the method of producing peptides by stepwise building up a peptide chain, starting from the C-terminal amino acid with the help of activated esters of M-protected amino acids, for example, pentafluorine esters of l, is widely used.
    The purpose of the invention is to obtain new tripeptides with valuable pharmacological properties. The goal is achieved by a method for producing tripeptides of the general formula
    X-y-W-NHj, (I) where X is L-pyroglutamyl, D is pyroglutamyl, L-b-ketopipekolil, 1 ketoimidazolidin-4-carbonyl L-thiazolidine-4-carbonyl} Y is L-norvalyl, L is lecyl; W — U-prolyl, T-prolyl, L-isoleucyl, L-homoprolyl, L-pipecolyl, L-thiazolidin-4-carbonyl,
    that amide amino acids of the general formula
    H-VJ-NH, (C)
    where W - has the indicated values is acylated with W-tert butyloxycarbonylamino acid pentafluorophenyl ester of the general formula
    Boc-Y-OR {p, (111 where Baugh is tert-butyloxycarbonyl} Pfp is pentafluorophenyl; Y - has the indicated values, from the resulting protected dipeptide of the general formula:
    Boc-y-W- NH,, W where Baugh, W and W - have the specified values,
    by lecylolysis, a free dipeptide of general formulas is obtained
    H-y-w-NHj,. (V) where Y and W are the indicated values,
    which is acylated with N-benzyloxycarbonylamino acid pentafluorophenyl ester of the general formula
    Z -X-OPfp, (VI) where Z is benzyloxycarbonylf X and Pfp have the indicated values, to obtain a protected tripeptide of the general formula
    g; -yyy / -Sh2 Cvu)
    where Z, X, Y and A / have the indicated meanings,
    from which the N-terminal quenched group is removed by catalytic hydrogenation ...
    In the examples explaining the practical implementation of the proposed method for producing tripeptides, the following abbreviations are used:
    - L-homoprolin;
    , Nrgo kic
    -L-2-ketoimidapackine-4carboxylic acid;
    -L-b-ketopiperidine-2-carcr
    boom acid;
    Pi p - ui-pipecolic acid; Tea -L-thiazolidine-4-carboxylic acid;
    DCSG
    -dicyclohexylcarbodiimide DCN
    -dicyclohexylurea;
    Pf p-OH - pentafluorophenol; DMF - dimethylformamide. Optical rotation is measured using a Perkin-Elmer 141 field meter.
    Thin-layer chromatography was carried out on Kieselgel Gnach Stahl plates from Merck FGG in the following solvent systems:
    1. Chloroform: methanol - 9: 1.
    2. Ethyldetate: (pyridine: acetic acid: water - 20: 6: 11) - 95: 5.
    3. Ethyl acetate: (pyridine: acetic acid: water - 20: 6: 11 - 9: 1.
    4. Ethyl acetate: pyridine: acetic acid: water - 20: 6: 11) - 8: 2.
    5. Ethyl acetate: (pyridine: acetic acid: water - 20: 6: 11) -3: 2.
    6. Ethyl acetate: (pyridine: acetic acid: water - 20: 6: 11) - 2: 3.
    The spots on the chromatogram / 1mAh are detected using ninhydrin solution, followed by incubation for 5 minutes at 105 ° C with a solution of potassium tidydine iodide after preliminary treatment with chlorine gas.
    Purification of the final compounds was carried out using column chromatography using Merck Silica 6 sorbent (Germany) with a particle size of 0.062-0.2 them.
    Example 1. Amide L-pyroglutamyl-L-l it.cyl-b-pipecol and nova acid.
    Stage 1 Amide hydrochloride, L-leucyl-b, pipecolic acid. 1.54 g (12 mmol) of H-P, -i P-WH2 are suspended in 20 ml of DMF, 5.16 g (13 mmol) of Boc-LeuOPfp, 1.68 ml (12 mmol) are added. triethylamine with stirring. The resulting solution was evaporated in vacuo and the oil obtained in the residue was dissolved in 60 ml of chloroform. The solution is mixed with 0.2 gl of 2- (dimethylamino) ethylamine, washed after 5 minutes with 1 and. a solution of hydrochloric acid (3 times 20 ml each), 1 and. solution of sodium bicarbonate (3 times. 20 ml) and water (3 times 20 ml), dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 3 ml of ethyl acetate and the solution is mixed with 10 ml of 5N. hydrochloric acid solution in etilacetate. After 1 h, the reaction mixture was diluted with ether, the precipitated precipitate was filtered and dried in vacuo over anhydrous sodium sulfate. 3.12 g (94%) of H-Leu-Pip-NHjHCl are obtained. 46 (5). Amino acid analysis. С С 0.95 (1,011; Leu 1,0 СЬЬЬ 0.95 (1 elemental analysis. Calculated,%: С 15.90; H 8.01; N15.90. CJ HjgOa N (mol. Weight 352.44 U Found ,%: C 57.77; H 8.20; N 15.83. Stage 2. Benzyloxycarbonyl-1-pyroglutamyl-CH-leucyl-1, -pipecolinic acid amide. 3.13 g (11.2 mmol H-Leu -Pi p-MHg and 4.94 g ((11.5 mmop) Z-Ce, p-OR {p is created in 35 MP of DNFA and the solution is mixed with 1.57 ml (11.2 mg-mol) of triethylamine The reaction mixture was stirred with 5 MHHj, 1.57 ml (11.2 mmol) of triethylamine was added, stirred for 20 minutes and evaporated in vacuo. The residue was dissolved in 50 ml of chloroform and the solution was washed with 1N hydrochloric acid ( 2 times 30 ml each), 1N sodium bicarbonate solution (30 m times and 30 ml of water. The organic phase is dried over anhydrous sodium sulfate and dried. The amorphous residue nepeT-ie is sewed with cold ether, the ether is decanted and the remaining oil is -hexane before hardening. The amorphous product thus obtained (4.7 g) is crystallized from ethyl acetate-ether mixture. 3.32 g are obtained (b1 Z-CEp-LeO-.Pip- (4H2. T.gsh. 143-144 ° C, 51 (4), Lot p -97.2 °, AcOH) Elemental analysis Calculated,%: C, 61.71} H, 7.04; N11.51. , N4 (mol, weight 486, .57) Found,%: C 61.67; H 7.05; N 11.40. Stage 3. Amide of L-pyroglutamyl-b leucyl-1-pipecolic acid. 2.1 g (4.32 mmol) of Z-CEp-Leu-p pNH is dissolved in 40 ml of methanol, 0.2 g of 10% palladium on activated carbon is added as a catalyst and hydrogen gas is passed into the reaction mixture. within 1 h. Then the catalyst is filtered off, the filtrate is evaporated to a residue triturated with ether. The crude product thus obtained (1.48 g) was dissolved in 2 ml of water, clarified with activated charcoal and filtered. 4 g of sodium chloride are dissolved in the filtrate, and the solution is washed with chloroform (3 ml times). The organic phase is dried over anhydrous sodium sulphate, evaporated and the amorphous precipitate is triturated with a mixture of ethyl acetate and ether. In the end, get 1.33 g (87,5% KB P-Leu-P (, - p-NH7., 60 (5),, 4 (C 1. ASOH). Elemental analysis. Calculated,%: C 57 , 94, H 8.01, W 15.90. CijH- NO (.. yl. Weight 352.44) Found,%: C 57.77, H, 8.20 H, 15.83. Amino acid analysis. Sbi 0 , 95 1.01-, Leli 1.0 (1.0), 0.95 (1.0). Example 2. Amide of L-pyroglutamyl-1-leucyl-1.-thiazolidine-4-carboxylic acid. 1. Leucyl-1-thiazolidine-4-carboxylic acid amide hydrochloride 1. 1.81 g (11 mmol) of H-Tca-NHgHCP are suspended in 30 ml of DMF and mixed with 3.97 g (10 mmol) of Boc-Leu-OP4p , 1.49 g (11 mmol) of 1-hydroxy-benztriazole and 1.22 Nui (11 mmol) of W-methylmorpholine. The resulting solution is left to stand overnight at room temperature. The solution was then evaporated in vacuo and the residue was dissolved in 80 ml of chloroform.The solution was washed with 1N hydrochloric acid solution (3 times 20 ml), 1N sodium carbonate solution (3 times 20 mp) and 10 mp. water, dried over anhydrous sodium sulphate and evaporated in vacuo.The flocculent amorphous residue is dissolved in 5 ml of ethyl acetate, mixed with 10 ml of 7 n. hydrochloric acid solution and ethyl acetate. After 1 hour, the reaction mixture was diluted with ether. The resulting precipitate was filtered and dried in vacuo over anhydrous sodium hydroxide. In the end, get 1.84 g (b5%) H-Leu-Tca-NH.jx Kise. , 25 (5), m.p. 170-174 ° C (decomp.) Step 2. Benzyloxycarbonyl L-pyroglutamyl-b-leucyl-b-thiazolidine-4-carboxylic acid amide. 1.69 g (6 1M) N-1ets-Tsa-KH2-NCE are suspended in 20 ml of DMF and mixed with 2.7 g (6.3 mmol) of Z-CP-OPfp and 0.84 ml (b mmol) of triethylamine . The mixture is stirred for 20 minutes at room temperature, then evaporated in vacuo. The residue is dissolved in 50 ml of chloroform and the solution is washed with 1N. a solution of hydrochloric acid (3 times in 10 ml), 1 n. sodium bicarbonate solution (3 times 10 ml); and 10 ml of water. The organic phase is evaporated, the residue is triturated with ether and the resulting crude product is purified by repeated precipitation from ethyl acetate-ether. 1.64 g (56% -) Z -CEp-Leu-HH is obtained. M.p. 108-110 ° C,, 46 (.4), ailD -130.30 (, AcOH
    Stldi 3. Lmid L-monoglutamyl .g :: 1 yl-1-thia 1 Olidine-4-carboxylic acid,
    1.62 g (g, 3 mmol) T: -Cfp-Leu-TcaHtlj is dissolved in 6 ml of ice-cold 3.5 g. solution of methyl bismuth in glacial acetic acid. The solution is left to stand for 1.5 hours at O - 5 ° C. The reaction mixture is then diluted with ether, the upper phase is decanted and the remaining oil is dissolved in 20 N water. The aqueous solution is neutralized with solid sodium bicarbonate and extracted with ether (3 times 10 ml each time). The aqueous phase is evaporated in vacuo, the residue is dissolved in 20 ml of chloroform, the solution is dried with anhydrous sodium sulfate and evaporated. The amorphous residue is triturated with ether and dried. The resulting crude product (1.13 g) is dissolved in the elution liquid (4), injected into a column filled with 20 g of silica gel. The column was eluted with the same mixture of solvents. From the fraction containing the crude product, 0.78 g of amorphous product is recovered. This product is dissolved in 20 MP of water, the solution is clarified with activated charcoal and lyophilized. Obtain 0.62 g CepLeu-Tca-NH (53% of theory). U 0.53 (.5) ,, 0 (, AcOH)
    Amino acid analysis. SvI 0.94 (1.0); Leu 1.0 (1.01.
    Example 3. Amide L-pyroglutamyl-1-leucyl-T) -proline.
    Step 1. Amide hydrochloride: -L leucyl-T} -prol.
    0.91 g (8 mmol) of H-D-Pro-NH and 3.2 (8 mmol) of Boc-Leu-Opfp are dissolved in 30 MP of DMF, mixed with 1.12 ml (in mmol) of triethylamine. The reaction mixture was incubated overnight and evaporated. The residue is dissolved in 60 ml of chloroform, the solution is washed with 1N. hydrochloric acid (2 times in 20 ml), 1 n. sodium hydroxide solution (3 times 20 ml each and 20 MP of water, dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 5 ml of ethyl acetate, mixed with 7 ml of 4N solution of hydrogen chloride in ethyl acetate. The reaction mixture is diluted after 1 h ether, the precipitate formed is filtered off and dried in vacuo over anhydrous sodium hydroxide, to give 1.54 g (73%) of H-Ley-Pr o-NH2HCe.
    Step 2. Benzyloxycarbonyl-L-pyroglutamyl-L-leucyl-D-poline amide.
    1.54 g (5.8 mmol) of H-L, eu- -Pro-CN. HCt is dissolved in 20 ml of DMF, mixed with 0.81 ml (5.8 mmol) of triethylamine and 2.58 g (b mmol)
    Z-C p-OR1r. The reaction mixture was stirred for 5 minutes, 0.81 ml (5.8 mmol) of triethylamine was added, stirred for 10 minutes and evaporated in vacuo. The residue is dissolved in 60 ml of chloroform, the solution is washed with 1N. a solution of hydrochloric acid (about 15 hp times with 1N sodium hydroxide solution (3 times with 15 ml) and 15 ml of water, dried over anhydrous sulfate
     rub and evaporated. The amorphous residue is triturated with ether. The resulting crude product (2.1 g) is recrystallized from 5 ml of ethyl acetate. In the end, get 1.8 g (66%) Z - CEp-Leu-D5 Pro-MHj. M.p. 153-157 ° С,, 38 U) ,, 5 ° С (С 1, АСОН).
    Step 3. Amide L-pyroglutamyl, L-lecyl-B-proline. 1.5 t (3.25 mmol) of 2 -Cf, P-beu-B-Pf-o0 1 is dissolved in 70 ml of methanol, the solution is mixed with 0.3 g of 10% palladium on activated carbon as a catalyst and hydrogen is passed through the solution for 1 h, the catalyst is filtered off, the filtrate is evaporated and the amorphous residue is mixed with ether. The resulting crude product of 0.94 g is dissolved in water, the solution is clarified with Q activated carbon and filtered, and the filtrate is lyophilized. Obtain 0.87 g (79% lce p-Leu-D-Pt-o -. NHg., 47 (5), 40 (, AcOn),
    Amino acid analysis. CEul, 02 (1.0); L her 1.0. (1.0) V Pro 0.96 (1.0).
    five .
    Example 4. Amide of L-pyroglutamyl-b-norvalyl-b-isoleucine.
    Step 1. Amide of t-butyloxycarbonyl-L-norvalyl-1-isoleucine.
    3.7 g (19 mmol) H-IEe-NHjHCe
    was dissolved in 30 ml of DMF, 2.7 ml (18 mmol) of triethylamine and 6.63 g (17.3 mmol) of Boc-Nva-OPlp were added with stirring, and after 5 min, 2.4 ml- (17, 3 mmol) three ethyl amine a. After iO min, the reaction mixture is evaporated in vacuo. The residue is dissolved in 100 ml of chloroform, the solution is washed with 1N. hydrochloric acid solution (2 times
    0 to 20 ml), 1 n. a solution of carbonate Hc1tri (2 x 20 ml) and 20 ml of water, dried over anhydrous sodium sulfate and evaporated. The crystalline residue is dissolved with ether
    5 and dried. In the end, get 4.7 g
    (83%) Boc-Nva-3 e-NH. M.p. 192 1940s, 60 (2) ,, 7 (, methanol).
    Stage 2. Amide hydrochlorideL -Nor0 vapil-b-isoleudine.
    4.5 g (13.7 mmol) of Boc-Mva-jee-WHg are suspended in 20 ml of ethyl acetate and mixed with 12 ml of 6N. solution of hydrochloric acid in ethyl acetate, through
    5 1 h. Was diluted with ether, the precipitate was separated by filtration and the crude product (3.6 g) was recrystallized from a mixture of methanol and ether. 3.5 g (96%) of H-Nve-JEe-NH- are obtained. her M.p. 254-255 С,, 45 (5),, 8 (, methanol). Step 3. Benzyloxycarbonyl-b-pyroglutamyl-1-norvapyl-b isoleiine amide. 3.3 g (l2.4 mmol) of H-Nva-TCe-NH-HCE is dissolved in 40 MP of DMF. While stirring, 1.74 ml (12.4 mmol) of triethylamide and 5.85 g (l3.6 mmol 2-C6p-OR {p) were added to the solution. After 5 m, 1.74 ml (12.4 mmol three ethylamine. The reaction mixture is diluted with ether, stirred, left to stand for 2 hours in a refrigerator and then filtered. B, 5.11 g (86%) are obtained 7. Mua-Zee-IN.pl.252 -253 ° С, R, 0.6 (. 4Г; 1ЫЗ -57 ,, АСОН). Stage 4, AmideL-Pyroglutamyl-L Norvalyl-1-isleucine. 4.75 g (10 mmol) Z-Gtp-Nva- eEVJH2 is dissolved in 200 ml of acetic acid and after adding 1 g of 10% palladium on activated charcoal as a catalyst for 1 hour. hydrogen gas is triturated through the solution. At the end of the hydrogenation, the catalyst is filtered off, the filtrate is evaporated, and the residue is triturated with ether to obtain 3.34 g (98%) of Cep-Nva-1 e-NHtJl98% of theory). mp. 267-270 ° (decomp.),, 61 (5), Mi-50.2 (, AcOH) Amino acid analysis. CSu 0.94 (1.0); Nv а 1.0 (1.0, CheE 1.05 (l , Elemental analysis. Calculated,%: C, 56.45 H 8.29; "16.46. | L H-gwO N,} (mol. Weight 340.43) Found,%: C 56.56; H 8.37; “16.28. Example 5. Amide L-thiazolidin-4-carbonyl-b-leucyl-and-proline. Step 1. 5-L-cycl-L-proline amide hydrochloride. , 28 g (20 mmol) of H-Pho-NH and 3.97 (10 mmol) of Boc-L ell-OR {p are dissolved in 40 ml of DMF and after 5 minutes the solution is evaporated in vacuo. The residue is dissolved in 80 ml of chloroform, the solution is washed with 1 and. hydrochloric acid (3 times 20 ml each), 1 n. sodium bicarbonate solution (3 times 20 ml each and 20 ml of water, dried over anhydrous sodium sulphate and evaporated. The residue is dissolved in 5 ml of ethyl acetate, the solution is mixed with 10 ml of 5N solution of hydrogen chloride in ethyl acetate. After 50 minutes, the reaction mixture is diluted with ether, the precipitate formed is filtered by BcUOT and dried under vacuum with anhydrous sodium hydroxide. In the end, 2.42 g (, 91 g) of HL o -14-o-Nil ,, X r R 20, are obtained (P. Step 2. Amide, tn 1: 1Olidium-4-ka} b, NIL - L-l her cycl - L-prol and A. 5.13 g (22 mmol) of Vos-Tsa-OM and 4.0S g (22 mmol) P .ipOH is dissolved in 60 mp ethyl acetate while cooling with ice and stirring, it is mixed with 4.12 g (20 mmol) of DCCA. The reaction mixture is stirred for 2 hours at 0-5 ° C, then the DMC is filtered off, the filtrate and the residue is dissolved in 50 ml of H-hexane. washed with 1N sodium bicarbonate solution (B. 25 ml) and 25 ml of water, dried over anhydrous sodium sulfate and evaporated. The thus obtained 7.32 g of Boc-Tca-OPip is dissolved in 20 ml of DMF and the solution is added 5.23 g (20 mmol) of H-Leu-Pro-MNO-HCC in 30 ml of DMF are added to the suspension. The mixture is then cooled with ice and 2.8 g (20 mmol) of triethyl mine are added with stirring. After 5 minutes, 2.8 (20 mmol) of triethylamine are added, stirred for 20 minutes and evaporated in vacuo. The residual oil was dissolved in 100 ml of chloroform, and the solution was washed with 1N. hydrochloric acid (3 times 30 ml) 1 n. sodium bicarbonate solution (3 times 30 ml) and 30 ml of water, dried over anhydrous sodium sulfate and evaporated. The remaining 8.84 g of Boc-Tca-Leu-P o-NH2 is dissolved in 15 ml of ethyl acetate, and the solution is mixed with 15 ml of 6N. a solution of hydrochloric acid in ethyl acetate and after 1 h, diluted with ethyl acetate. The resulting precipitate is triturated, filtered and dried in vacuum over anhydrous caustic soda. In this way, 8.05 g of crude product is obtained, which is dissolved in 80 ml of water, the solution is extracted with ether (3 times 20 ml), then the pH of the aqueous solution is set to 8 and the solution is extracted with chloroform (3 times 20 ml). The combined chloroform extracts are dried over anhydrous sodium sulfate and evaporated. The residue is triturated with ether and dried. In the end, get 5,20 g (76%) N-Tsag Lets-P o-NH,. M.p. 159-ieo C, R {0.63 (5), LDi,;) j, -162.9 ° (, AcOH). Amino acid analysis. Ueul, 0 1.0); Pro 0.95 (1.0). Elemental analysis. Calculated,%: C 52.61, H 7.65; 16.36; N 9.36. (say .. weight 342.46). Found,%: C 52.45; H 8.03; 16.51; H 9.59. Example 6. Amide 1-2-ketoimidazolidin-4-carbonyl-b-leucyl-b proline.
    Step 1. Benzyloxycarbonyl-L-2-keto-imidazalidine-4-carboxylic acid pentafluorophenyl ester. 10.56 g (40 mmol) of Z-Ktc-OH and 9.09 (44 mmop) of P-OH are dissolved in a mixture of 100 ml (.1: 2) of a mixture of DMF and dioxane (1: 2). Restavor is cooled with ice and perembiivanija mixed with 9.06 g (44 mmol) DCGK. The reaction mixture is stirred at 0 ° C for 1.5 hours, then the DCM is filtered off, the filtrate is evaporated and the oil obtained in the residue is mixed in C-hexane for crystallization. The resulting crude product (16.46 g) is recrystallized from 50 ml of ethyl acetate. This gives 12.75 g (. - Cls-OPip. Mp. 146-148 s, 53 (1) -, ot 2, - -42.1 (, ethyl acetate).
    Elemental analysis.
    Calculated: C 50.25, H 2.58, VI 6.51, F 22.08.
    C;, gH, F NjO (mol. Weight 430.29)
    Found,%: C. 49.88, H 2.35, W 6.66; F 21.81.
    Step 2. Benzyloxycarbonyl-1-2-ketoimidazolidin-4-carbonyl-1-leucyl-b-proline amide. 2.38 g (9 mmol) of H-Leu-PtO-WHJHCE are suspended in 30 ml of DMF and mixed with 3.87 g (9 mmol) of —KA with OPfi and 1.26 ml (9 mmol) of triethylamine, stirred for 5 minutes and 1.26 ml (9 mmol) of triethylamine are added, stirred for 20 minutes and evaporated in vacuo. The residue was dissolved in 50 ml of chloroform, the solution was washed with 1N. a solution of hydrochloric acid (2 times 10 ml), 1 n. a solution of sodium carbonate (2 times in 10 ml), 10 ml of water, dried over anhydrous sodium sulfate and evaporated. The residue obtained in the residue is added to the ether to crystallize and is filtered off. The resulting crude product (3.31 is boiled in 30 ml of ethyl acetate. After cooling, the suspension is left to stand for a few hours in the refrigerator and filtered. It is obtained 3.0 g (70%) -K-jc-Leu-ProHH,. Mp 172-174 s;, 18 (4), -102.6 ° (, AcOH).
    Elemental analysis.
    Calculated,%: C 58.34; H, 6.60; N, 14.79.
    Cg (mol. Weight 473.50)
    Found,%: C 57.52, H 6.62, W 14.62.
    Stage 3. Amide U -2-ketoimidazo, lidin-4-carbonyl-b-leucyl-b-proline 1.2 g (2.4 mmole Z-K c-Leu-ProKHg is dissolved in 30 ml of water, the solution is mixed with 0.25 g of 10% palladium on activated carbon as a catalyst and hydrogen gas is passed through the mixture for 4 hours.The catalyst is then filtered, the filtrate and the amorphous residue are dried in vacuo over.The resulting product (0.75 g) is dissolved in water, the solution is clarified with activated carbon and lyophilized. As a result, 0.61 g (71%) of Ki c-Lem-Pro-NH, Rj 0.35 (, 5), s, 32, -98.4 ( C 1, AcOH).
    Lmino acid analysis. Leu 1.0 (1.0) -, Pro 0.96 (1, 0).
    Example 7. Amide L-6-ketopipekalil-b-leutil-1, -proline.
    Art. 1. Pentafluorophenyl ether L, -6-ketopipecolyl carboxylic acid.
    4.3 g (30 mmol) of 1N-6-ketopipekolinic acid and 6.07 g (33 mmol of P | p-OH are dissolved in 100 ml of chloroform, and the solution is mixed with 6.8 g (33 mmol)) with ice cooling and stirring. The mixture was stirred for 1 h at OC, then left to stand overnight in a refrigerator.The next day the precipitated DMC was filtered off, the filter was evaporated and the crystalline residue was triturated with H-hexane. The resulting crude product (9.87 g) was dissolved in 20 ml of ethyl acetate, the solution is left to stand for 1 hour in the refrigerator, then clarified with activated charcoal. and evaporated. The resulting oil was dissolved in the residue dissolved in a mixture of 5 ml of ethyl acetate and 20 ml of hexane and the solution allowed to stand overnight in the refrigerator and on day slduyuschy precipitated crystals were separated by filtration. A 6.34
    (68.5%) Krs-OR {p. M.p. 96-98c, t (, 0 (ethyl acetate).
    - Elemental analysis. Calculated,%: C 46.62, H 2.61,
    N 4.53, F 30.72.
     (mol. weight 309.20) Found: C, 46.37; H, 2.88;
    N 4.26, 30.51.
    Stage 2. Amig L-b-ketopipekolyl L-leucyl-C-proline. 1.32 g (5 mmol) of H-Leu-Pco-NH. it is suspended in 20 ml and mixed with 1.61 g (5.2 mmol Krs-ORGR and 0.7 (5 mmol) triztilamine) while cooling with ice and stirring. The reaction mixture is stirred for 5 min, added 0.7 ml (5 mmol ) triethylamine, stirred for another 20 minutes and evaporated in vacuo.The crystalline residue is triturated with ether, the crystals are filtered, washed on the filter with ether and chloroform and extruded. In the end, 1.27 g of t72%) Kpc-Leu-Pbo-NH2 are obtained. M.p. 214216 ° C,, 41 (5) -, ui -83 ° 4c-l, AcO
    Amino acid analysis. , L-Amino-adipic acid 0.99 (1.0), ie, 1.00 (1.0); Pro 0.98 (1.0).
    Example 8. Amide L.-6-ketopipekshil-1, -norvalyl-1-Proline,
    Stage 1. AmideL-norvalyl-b-proline hydrochloride.
    2.2 g (20 mmol) of H-Pt o-NH2 and 3.83 g (10 mmol) of Boc-P | a-OPf p is dissolved in 40 ml of DMF, kept for 5 minutes and evaporated in vacuo. The residue is dissolved in 50 ml of chloroform, the solution is washed with 1N. hydrochloric acid (3 times in 10 ml), 1 n. sodium bicarbonate solution (3 times 10 ml of 10 ml of water, dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 10 ml of ethyl acetate, mixed with 10 ml of 5N solution of hydrogen chloride in ethyl acetate. After 30 minutes, the reaction mixture is diluted with ether , the precipitated precipitate is filtered off and dried in vacuum over caustic soda. In the end, 1.83 g (73%) of H-Hva-Pro-NHvHCe., 10 (4),
    Stage 2. Amide L-b-ketopipekolil C-norvalyl-b-proline. 2.38 g (9.5 mmol H-Nva-Pno-NH -HCp are suspended in 30 ml and mixed with 30.09 g (10 mmol) and 1.33 ml (9.5 mmol) of triethylamine while cooling with ice and stirring The reaction mixture is stirred for 5 minutes, 1.33 (9.5 mmol) of triethylamine is added, stirred for another 20 minutes and evaporated in vacuo. The crystalline residue is triturated with ether, filtered, washed on the filter with ethanol and dried. The resulting crude product 3.66 g is dissolved in water, the solution is clarified with activated carbon and evaporated, the crystalline residue is triturated with 10 ml of ethanol. The mixture is left in the refrigerator Nike and then filtered. Get 2.10 g (b5%) Kpc-Leu-Pfo-NH / g., So .. 192-193 ° C,, 31 (5), i; oi.l -83, 2 ° (. C 1, AcOH) ..
    Amino acid analysis, L-Amino-adipic acid 1.02 (1, fNua 1.0 (1.01, PKO 0.97 (1.0).
    Elemental analysis
    Calculated,%: C 56.78, H 7.74, N 16.56.
    С | (, МЦО (small, Weight 338.40)
    Found%: C 56, 55, H 8.00, M16.37,
    Example 9, Dmid-pyroglutamyl-b-leucyl-1 -proline,
    Step 1. Benzyloxycarbonyl-B-pyroglutamic acid pentafluorophenyl ester,
    4.55 g (18 mmol) of Z-D-CCp-OH and 3.68 (20 mmol) of PipOH are dissolved in 50 ml of ethyl acetate and the solution is mixed with 4.12 g (20 mmol) of DCGH with stirring and ice-cooling. the reaction mixture is stirred. 1 h at 0®C, then the LCM is filtered,
    the filtrate y11a1: 1, residue in oct in n -hexane for the redistribution. The resulting crude product (7.3 g) was dissolved in 20 MJ of ethyl acetate, the solution was left in a tacin for 1 hour in 5 refrigerators, then clarified with activated charcoal and evaporated. The residual oil was dissolved in 5 ml of ethyl acetate and the product was added by adding 20 MP H-hexane osanodagate. 0 6.60 g are obtained (85% | ZD-CGp-OPip. Mp. 81-82 s, 84. (1) -40.1 (, ethyl acetate. Elemental analysis. Calculated,%: C 53.16 N 2,82,5 C 3,26, F 22,13.
       5 (mol. Weight 429.30) Found,%: C 53.28, H 3.04, M 3.02, F 21.86.
    Stage 2. Amide of benzyloxycarbo-0nyl-D-pyroglutamyl-L-leucyl-L-proline.
    3.24 g (12.3 mmol) of H-Leu-Pt-o-NH HC are suspended in 50 ml of DMF and mixed with 5.6 under ice-cooling and stirring 5. g (13 mmol) of Z-DCCp-OPfp and 1.72 ml (12.3 mmol) of triethylamine. The reaction mixture was stirred for 5 minutes, 1.72 ml (12.3 mmol) of triethylamine was added, stirred for 20 minutes and evaporated in vacuo. The residue is dissolved in 120 ml of chloroform, the solution is washed with 1N. with a solution of hydrochloric acid (2 times 30 ml each), a 1N solution of carbonate, three times (3 times 30 ml) and 30 ml of water, dried over anhydrous sodium sulfate and evaporated. The residue is taken up in ether for crystallization. The resulting thus, the crude product (5.31 g) is boiled with 50 ml of ethyl acetate, the resulting suspension is left to stand for 3 hours in the refrigerator, and the precipitated product is separated by filtration to give 4.61 g (80%) of Z-O -C8p-Leu-Pro-VH2 T, pl. 189-194 C. 5, 44 (.4) -31 / 2 ° (, AcOH).
    Stage 3. Amide L-pyroglutamyl-leucyl-b-proline.
    4.48 g (9.5 mmol) -p-C € pL, eu-ProNHj is dissolved in 200 methanol and the pAst0 thief is mixed with the catalyst — 0.9 g of 10% palladium on activated carbon and passed through the mixture for 1 h gaseous hydrogen. Then the catalyst is filtered off, the filtrate is evaporated, the residue is triturated with ether. The product obtained (3.07 g) was dissolved in water, the solution was clarified with activated charcoal and lyophilized. As a result, 2.90 g (90.5%) of D-CEp-Leu-pboHH; , 40 С5) ,,, AsOH Y,
    Amino acid analysis. Glu 0.93 45 (1.0); Leu 1.0 (1.0); Pro 0.98 (1.0),
    Example 10. I, -6-k (topiperidin-2-carboiyl-b-norvoril-1, homoprolin.
    Step 1. Amide of trut-butyloxycarbonyl-b-homoproline.
    2.29 g (10 mmol) of Boc-HPfO-OH are dissolved in 30 ml of ethyl acetate, the solution is mixed with 1.4 ml (10 mmol of triethylamine, cooled to -10 ° C) and 1.3 ml (10 ml) are added dropwise. mmol) of chlorobolic acid ester. After stirring for 15 minutes at -10 ° C, ammonia gas is passed through the reaction mixture for 0.5 hours and left for 2 hours at 0-5 seconds. The precipitate is then filtered, the filtrate is evaporated and the residue is obtained the oil is dissolved in 30 ml of chloroform. The solution is washed with 1N hydrochloric acid (2 x 10 ml), 1 n sodium bicarbonate solution (2 x 10 ml) and 10 ml of water are dried over anhydrous sodium sulphate, evaporated and the residue oil is taken up in n-hexane for crystallization. The crude product (l, 95 g) obtained in this way is recrystallized from a mixture of ethyl acetate and ether. 78 g (78%) BocHPt-o-NH, mp 138-140 ° C, R. 0.43 (2), 85 ° (c 1, AcOH).
    Stage 2. AmideL homoproline hydrochloride.
    1.6 g (7 mmol) of Boc-HPi-o-NHg is dissolved in 10 ml of ethyl acetate and mixed with 10 ml of bn. solution of hydrogen chloride in ethyl acetate. After 1 h, the reaction mixture is diluted with ether, the residue is triturated with ether and filtered.
    In total, 1.05 g (91%) of HHPf-o-IH is obtained. M.p. 178-180 ° C. C {0.32 (6),, 2 (C l, methanol).
    Step 3. Amidor hydrochloride of norvalyl-L-homoprolin. 0.99 g (b lmol) of H-HPho-NH HCE is suspended in 20 ml of DMF and 0.84 ml (b mmol of triethylamine and 2.3 g (b mmol) of BaughNva-OPfp) are added with peat. After 15 min 0.84 MP (b mmol) of triethylamine is added, the mixture is stirred for 1 hour and evaporated in vacuo. The residue is dissolved in 50 ml of chloroform, the solution is washed with 1N pcicTBOpOM hydrochloric acid, 1N sodium hydroxide solution ( ml, dried over anhydrous sodium sulfate and evaporated. The residual oil is dissolved in 6 ml of ethyl acetate and mixed with 10 ml of a bn solution of hydrochloric acid in ethyl acetate, after 1 h of reaction The mixture is diluted with ether, the amorphous precipitate is triturated and dried in vacuo over anhydrous caustic n. 1 (a total of 1 is obtained, 22 g (89.5%) of 11-Nva-HProNll, HC. H 0.12 (5.
    - Stage 4. Amide L-b-ketopiperidin-2-carbonyl-m-ior-al-L-homopl l and n-.
    1.22 g (5.37 mmol) of H-Nva-HProKI2SPD are dissolved in 20 g of DMF, 1 cm³iJIIDId with 0.75 ml (5.37 mmol) of triethylamine and 1.7 g (5.5 ml of Crs-ORGR. Reaction the mixture was stirred for 5 minutes, O, 75 ml (5.37 mmol) of triethylamine was added, stirred for 20 minutes and evaporated in vacuo. The residue was triturated with ether and the resulting amorphous crude product 1.8 g applied to a column prepared from 40 g of shikagel , and elution with a mixture of solvents (4). The fractions containing the pure product are combined and evaporated to give 1.11 g of the pure product, which is dissolved in water, clarified with activated carbon and lyophilized. As a result, Crc-Hva-HPro-N fi7 (53% of theory) is obtained. D {35 (5), -44, b (, AcOH).
    The pharmacological activity of the tripeptides obtained by the proposed method was studied using the above biological tests 1 - b.
    1. Inhibition of haloperidol catalepsy in rats. . ANIMAL 40 mg / kg of haloperidol 4-chlorophenyl) -1-3- (p-fluorobenzoyl) propyl-piperidin-4-ol was administered subcutaneously and the onset of catalepsy was monitored after 120 min. Then the rats are divided into groups of 10 animals and administered intravenously with doses of TRG-Cep-H 5PfO-NH2 and the described tripeptides. Animals of the control group received physiological saline solution. After 15, 10, 90, 120 minutes after treatment, the effect of increasing the catalepsy of individual compounds was tested, the animals were considered cataleptic, if their front paws mounted on a 7-cm-high column could not coordinate their position for 30 seconds.
    Of the animals that did not show catalepsy, an appropriate value for individual effective substances was determined by probbitanization.
    Experiments were performed with male rats weighing 160-180 g.
    2. Potentiation of locomotor activity caused by L-DOP,
    Animals were intraperitoneally injected at a dose of 40 mg / kg N-methyl-M-propargnylbenzylamine (pargyline), and then 20 mg / kg TRH or the described tripeptide to be studied, and finally 100 mg / kg L -dopa. 30, 60, and 90 min after this treatment, the locomotor activity of the animals was measured. The established values are given in the table in percent, calculated on the values obtained with animals treated with hgs. For these experiments, 15 male mice weighing 18-22 g are used. 3. Reperto-hypothermic recurrent effect on mice. Male mice weighing 18-22 g, are divided into groups of 10 animals, and intraceptively administered with reserpine at doses of 5 mg / kg. After 16 h, animals are dosed in doses of 20 mg / kg of TRG or Tripeptide to be studied. The rectal temperature of animals was measured before treatment with reserpine (in the table: normal), 16 hours after treatment with reserpine in the table: cut,) and 1 or 2 hours after administration of the tripeptide under study (in the table after treatment. Table shows the average rectal temperature measured in groups of 10 mice 4. Effect on the duration of sleep caused by hexobarbital Male mice, divided into groups of 10 animals, are intravenously administered 60 mg / kg of hexobarbital sodium, 10 minutes later the animals are intraperitoneally administered t dose 20 mg / kg TGW weight or tripeptide to be studied. Sleep times are given in the table as a percentage, based on the values measured in animals of the control group (average values for groups of 10 animals). 5. Ethnic anesthesia. the sexes weighing 1822 g divided into groups of 20 animals each, 4.5 ethanol are administered intraperitoneally, and 10 minutes later the animals are administered intraperitoneally at a dose of 20 mg / kg of the tested tripeptide. The sleep time in the table is indicated in percents (the average value of the pn of the group of 20 animals), based on the values measured in animals of the control group. 6. Hormonal activity (TRH action) in rats. Male rats (Wistar) weighing about 200 g, divided into groups of 7-8 animals, are administered intravenously in doses of 20 mg / kg TEG or the tripeptide studied. The TRG-reaction of animals is determined 15 minutes after the administration of TRG or the tripeptide under study from the animal plasma, as a result of a radioimmune study. Relative efficacy calculated by the method of four points, while the effectiveness of TRG was taken as 100. The average values of the biological effectiveness of the compounds of general formula (1) f determined as a result of the described pharmacological methods are presented in the table.
    When marking. Time of gvksobarbitalnogo sleep:; (X ± E) 38,411.36 min; ethanol sleep: (XtE). 46,9 ± 2.17 min. From the data in the table it is clear that the described analogs of TRGs have an “reading effect on the central nervous system. From this point of view, such derivatives are particularly advantageous, for KOTOIXJX in position 2 of the TRH molecule there is an aliphatic amino acid with a straight or branched carbon chain. From the standpoint of this action, preferred are also those TRH analogs, in which in position 1 there is a 6-ketotype colic acid. In these produced hormonal effects, TRH is either completely absent or reproduced to a minimum, and at the same time the effect exerted on the central nervous system increases significantly, in some cases even 8 times.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING TRIPEPTIDES of general formula
    X-y-W-NHg, where X is L-pyroglutamyl, D-pyroglutamyl, L-6-ketopipecolyl, L-ketoimidazolidine-4-carbonyl; b-thiazolidine-4-carbonyl
    Y is L-norvalyl, L, -leucyl;
    p is L-prolyl, I) -prolyl, L -isoleucyl, L-homoprolyl, B-pipecolyl, L-thiazolidine-4-carbonyl, wherein the amino acid amide has the general formula hw-nh 2 , where W has the indicated meanings , acylated with N-tert-butyloxycarbonylamino acid pentafluorophenyl ether of the general formula
    Vos-U-OR ί p } where Vos - tert-butyloxycarbonyl;
    Pfp pentafluorophenyl;
    y has the indicated meanings from the obtained protected dipeptide of the general formula
    Boc-U-Vi-MH 2 , where Boc, Y and W have the indicated meanings, a free dipeptide of the general formula is obtained by acidolysis
    Н-У - «- МН 2 , where У and W have the indicated meanings, which are acylated with p-fluorophenyl ether of N-carbobenzoxy amino acids of the general formula
    Z is X-OPfp, where Z is benzyloxycarbonyl; X and P have the indicated meanings until a protected tripeptide of general formula is obtained
    Z-X-Y-W- HX 2 , where 2, X, Y and W have the indicated meanings, from which the N-terminal protecting group is removed by catalytic hydrogenation.
    SU, m 1085505>
    1083505
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