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    • 专利摘要:
    Muramyldipeptide derivatives of the formula: <IMAGE> wherein Y represents a mycoloyl group or a synthetic higher acyl group having total carbon number of C30-C90 and having at least a branched chain of long alkyl group on the alpha -position thereof, Q represents an -L-alanyl-D-isoglutamine group, a -glycyl-D-isoglutamine group or an -L-seryl-D-isoglutamine group; SALTS OF SUCH DERIVATIVES; THE METHOD OF PREPARING SUCH DERIVATIVES AND THEIR SALTS; THE DERIVATIVES AND THEIR SALTS HAVING POTENT IMMUNOADJUVANT ACTIVITIES AND ANTITUMOR ACTIVITY AND BEING APPLICABLE AS THE AGENT FOR THE IMMUNOTHERAPY OF CANCER FOR HUMANS AND ANIMALS.
    公开号:SU793384A3
    申请号:SU772497271
    申请日:1977-06-22
    公开日:1980-12-30
    发明作者:Ямамура Юичи；Шиба Тецуо；Азума Ичиро；Кусумото Соичи；Хираяма Тадамаса；Кусама Цунео
    申请人:Дайити Сейяку Ко, Лтд (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a method for producing muramylpeptide derivatives having biological activity that can be used in me. In peptide chemistry, a carbodiimide method of condensing amino acids and peptide fragments among themselves with compounds that have free carboxyl group l is known. Organic chemistry also widely uses transesterification reactions 2. The purpose of the invention is to obtain synthetic compounds with interesting pharmacological properties using known chemical methods. The goal is achieved by obtaining the derivatives of muramyl peptide of the general formula I OH IfflCOCH NSSSCNOC where Y is a micomikoolyl, core "inomico-LOIL-, nocardomikoloil- or synthetic acyl group with the number of carbon atoms from Cj to, in the C-position, it has a branch in the C-position, it has a branch in the C-position. chain; Q is i-alanyl7 O-isoglutamyl glycyl-O-isoglutamyl-, L-seryl-0-isoglutamyl, consisting in the fact that benzyl-N-acetyl-α-muramide of the formula II-JO NO KNCOH 2 H, C (HCOOH where Z - benzyl, subject to interaction with mycomycolic, cordinomicoic, nocardicoleic or synthetic fatty acid containing from to a carbon chain, having an extensive alkyl chain in the oC-position, and with a dipeptide selected from the group 1-alanyl-0-isoglutamine, glycine-O -isoglutamine or 1-seryl-0-isoglutamine, in any sequence.
    The carboxyl group of the starting material, i.e., benzyl M-acetyl-C-muramide (11), is protected by a suitable protecting group, for example, diphenylmethyl. This protection of the carboxyl group may prevent undesirable side reactions in the subsequent steps. The hydroxyl group of the Cb-b compound is then activated by treatment with tosyl chloride or methanesulfonyl chloride in a basic solvent, for example, pyridine.
    The resulting tosylate is reacted with an alkali metal mycolate in a suitable polar solvent, for example dimethylformamide or dimethyl sulfoxide at a temperature of 100-140 ° C. The reaction proceeds smoothly if it is carried out in a non-polar solvent, e.g. benzene, in the presence of a catalytic amount of a cyclic polyester, e.g. 18-crown-6.
    The protecting group of the carboxyl group of the compound (II) thus obtained is removed, for example, with trifluoroacetic acid. The product obtained is reacted with a dipeptide, for example, L-alanyl-O-isoglutamine benzyl ester in the presence of the W / ego approach of a condensing agent, for example, dicyclohexylcarbodilmide and N-hydroxysuccinimide. This reaction is carried out with stirring in a suitable non-polar solvent, for example ethyl acetate, benzene, dioxane or tetrahydrofuran, at room temperature.
    Finally, the remaining protecting groups are removed by a conventional method, for example, by hydrogenation in the presence of palladium black or platinum or by treatment with hydrobromic acid in acetic acid.
    The desired compound can also be obtained by reacting benzyl-N-acethyl-c6-myramide at the beginning with a dipeptide, and then with mycolic acid or a synthetic fatty acid.
    One of the starting materials, mycoleic acid, can be obtained by hydrolyzing the bacteria Mycobacterium tuberculosis M .., M. Smegmatis. Mycolic acid can be an individual acid or a mixture of higher fatty kilos; having a total number of carbon atoms of 28-90 and an od-notation in which is replaced by a long side chain from the gshyl group and the fi-position is replaced by a hydroxyl group.
    The preparation thus obtained is a mixture of several types of mycolic acid and, if necessary, individual acid can be isolated by further purification. However, in terms of the biological activity in this invention, gender
    cleaning to a separate acid is not so important and a mixture of several types of acid can be used.
    All mycolic acids obtained in a mixture are higher fatty kilos with a total number of carbon atoms of 70-90 and having a long side chain of the alkyl group (,) in the oL-position.
    On the other hand, nocardicolic acid, cynicomicolic acid, or arthrobacterial micolic acid having a total carbon number of 28-70 and a long side chain from the alkyl group (Cg-C) in the ct position and hydroxyl group in the p- can be listed as the middle class of mycolic acids. position
    Nocardia acteroides, N. rubra, N. Brasiliensu or N. can be used as bacteria of the species Nocardia for the production of nocardomicole acid. PoIychromogenes, etc.
    As bacteria of the species Co ginobacterium and Arthrobacter for the preparation of corinomicular acid, Srynodiphtheriye can be used, p. pseudotubercu 1 OSis, c xerosis, c. renale, Arthrobacter simplex, A. flavescens.
    Obtaining several types of mycolic acid.
    1. Wax D. Whole bacilli, cell walls and cell membranes of the Musobacterium tuberculosis strain of Loma B, are hydrolyzed with alkali and chromatographed on an activated clay column. Get mycolic acid.
    To a solution of 0.50 g of mycolic acid in 5 ml of chloroform was added one drop of a 1% phenolphthalein solution and the mixture was titrated with 2.405 ml of 0.2N methanolic KOH.
    It follows that the average molecular weight of the mycolic acid as a monobasic acid is 1186
    The solution is concentrated under reduced pressure, methanol is added to the residue, the insoluble materials are filtered off and 0.51 g of mycolate of potassium are obtained. Yield 98%; m.p. 7183 ° C.
    Elemental analysis of mycolic acid:
    Found,%: С81.57; H13.48.
    Calculated,%: C 81.33; H 13.62.
    From the average molecular weight obtained by titration and elemental analysis, it is determined that the average molecular formula of a mycolic acid should be Cgo Oj 5 1176.
    2. The whole bacilli Nocardia asteroides 131 are hydrolyzed with alkali, esterified (methyl esterification), purified in a chromatography column with silica gel, and then hydrolyzed to obtain medium mycolic acid. A mixture of 1.24 g of medium mycolic acid (nocardicoleic acid) and 2 ml of 3N methanol solution of KO is heated for 2.5 hours under reflux, then concentrated under reduced pressure, the residue is dissolved in 100 ml of diethyl ether and washed with 1N hydrochloric acid and then water. The solution is dried over MgSO4, concentrated in vacuo. The residue is washed with ice-cold eol and dried over phosphorus pentoxide under reduced pressure to obtain 0.82 g of a waxy product. Yield 73%. Elementary analysis,%: C 79.69} K 12.76. A drop of 1% phenolphthalein solution is added to a solution of 870 mg of nocardicolic acid in 10 ml of chloroform and the mixture is titrated with 2.465 ml of 0.5N methanol KOH (f 0.92). From this, the average molecular weight of nocardomicoic acid as monobasic acid 767 is calculated. The solution is concentrated in vacuo, the residue is dissolved in diethyl ether and filtered. The filtrate is concentrated under reduced pressure to obtain 0.88 g of a wax-like product, yield: 98%. From the elementary analysis and the average molecular weight obtained, the molecular form of nocardicolic acid is determined with, 768. : 3. Whole Boryllus Corynobacteri diphteria PW8 is treated as described for Nocardia asteroides 131 to obtain a medium mycolic acid. A mixture of 0.53 g of methyl ester of medium mycoleic acid (cordinomicole acid) and 2 ml of 3 N methanol solution of KOH are heated under reflux condenser 2 , 5 hours. After concentration under reduced pressure, the residue is dissolved in 15 ml of diethyl ether, washed with a 1N aqueous solution of HC, and then with water. The solution is dried over anhydrous MgSO4, concentrated under reduced pressure. The resulting residue is dissolved in a small amount of methanol. The solution is cooled, the precipitated wax-like product is separated by decantation, washed with cold methanol, dried under reduced pressure, and 0.41 g of a wax-like product is obtained. Yield 80%. Elementary analysis,%: C 76.48; H 12.69. A drop of phenolphthalein is added to a solution of 385 mg of corinomicular acid in 5 ml of chloroform and the mixture is titrated with 1.47 ml of 0.5N methanol solution of KOH (f 1.00). From this, the average molecular weight of corinomic acid, as a monobasic acid, is calculated to be 524. The solution is concentrated under reduced pressure. the residue is dissolved in ether, filtered. The filtrate is concentrated under reduced pressure to give 412 mg of a wax-like product. Exit 99%. From the elementary analysis and the average molecular weight, the molecular formula for nocardomicoic acid Cj, 519 is determined. Example l. 0.8 g of diphenyldiazomethane is added to a solution of 1.0 g of benzyl-M-acetyl-cJl-muramide in 10 ml of tetrahydrofuran. The mixture is stirred for 30 minutes at room temperature. After removal of the solvent, the residue is crystallized from hexane. After recrystallization from a mixture of ethyl acetate and hexane, 1.3 g of diphenylmethyl 1-d -O-benzyl-M-acetylmuraminic acid are obtained. After recrystallization from the same solvent, the product is obtained; m.p. 155-156 ° C; 122 ° (c 1.0; chloroform). Elementary analysis for C ,,. Calculated,%: C 67.74; H 6.42 N 2.55. Found,%: C 67.62; H 6.50; N 2.52. 1.2 g of tosyl chloride is added to a solution of 0.3 g of diphenylmethyl ester of 1-o.-benzyl-M-acetylmuraminic acid in 3 ml of pyridine, the mixture is stirred for one hour, then poured into water and the product is extracted with ethyl peptide. The ethyl acetate solution was successively washed with 0.3N sodium hydroxide solution, 1N hydrochloric acid and water, and then dried over anhydrous magnesium sulphate. After distilling off the solvent in vacuo, the residue was purified by silica gel column chromatography (10 g). The product was eluted with a mixture of benzene: ethyl acetate (5: 1) to obtain 0.34 g of pure 1-ci-0-benzyl-6-tosyl-N-acetyl-2-amino-acid diphenylmethyl ester; m.p. 68-73 ° C; 84.4 ° (with 0.5; chloroform). Elementary analysis for Calculated,%: C 64.85; H 5.87; N 1.99; S 4.56. Found,%: C 64.68; H 5.92; N 1.93; S 4.31. To a solution of 0/33 g of 1-o-0-benzyl-6-0-tosyl-N-acetylmuraminic acid diphenylmethyl ester in 10 ml of benzene was added 0.38 g of potassium mycicolyte and the mixture was heated under reflux for 3 hours. The solvent is distilled off in vacuo; the residue is distilled with acetone. The insoluble material is chromatographed on a silica gel column. The eluate (with a mixture of benzene and ethyl acetate 10: 1 v / v) is treated with ether solution of diazomethane at room temperature. The solvent is distilled off in vacuo, the residue is again chromatographed on a column of silica gel.
    Methylmicol is eluted with benzene, benzene-ethyl acetate (10: 1), and the eluate is collected. The solvent is distilled off, the residue is crystallized from acetone, to obtain 0.32 g of 1-o-0-benelyl-6 0-micromicoloyl-H-acetylmuramic acid diphenylmethyl ester; m.p. 54-57 ° Cj 32.6 ° (with 0.5} chloroform),
    Elementary analysis for
    --zh - (9- (10.5
    Calculated,%: C 78.07f H 11.27}
    N 0.82.
    Found,%: C 78.34} H, 11.48; N 0.85.
    A mixture of 0.3 g of 1-o-0-benzyl-b-0-micomicoloyl-N-acetylmuraminic acid diphenylmethyl ester and 1 ml of anisole was dissolved in 20 ml of chloroform.
    To the ice-cooled solution was added 3.0 ml of trifluoroacetic acid, and the mixture was stirred for 30 minutes, then to it. acetone is added and the solvent is removed in vacuo. The residue is washed with ethanol, dissolved in 10 ml of tetrahydrofuran.
    To the solution, cooled in an ice bath, 75 mg of N-hydroxysuccinimide, 65 mg of 1-alanine-0-isoglutamine benzyl ester hydrochloride, 24 mg of triethylamine dissolved in O, 2 ml of tetrahydrofuran and 37 mg of dicyclohexycarbodiimide are added with stirring. Stirring is continued overnight, while the temperature rises to room temperature.
    The resulting triethylamine hydrochloride and N, N-cyclohexyl urea are filtered off. The solvent is distilled off in vacuo, the residue is dissolved in ethanol, filtered and chromatographed on silica gel. The product was eluted with benzene-acetone (3: 1) and the solvent was distilled off.
    The residue is crystallized from a mixture of benzene and methanol, to obtain 0.124 g of 1-c benzyl ester (-0-benzyl-6-0-micromicoloyl-M-acetylamuramide-1-alanyl-O-isoglutamine, mp 171172C; 1, 30, 2 ° (with 0.5; chloroform).
    Elementary analysis for
    B, 5 4Calculated,%: C 74.13; H 11.01;
    N 3.06.
    Found,%: C 63.63; H 11.05; N 3.18.
    76 mg of benzyl ester 1-o1-0-ben3 yl-6-0-micromikoloyl-N-acetylmuramyl-1-alanyl-0-isoglutamine is dissolved in 20 MP tetrahydrofuran and subjected to hydrogenolysis in the presence of palladium black. The solvent is then distilled off in vacuo. The residue is crystallized from a mixture of ether and ethanol to give 64 mg of 6-0-micomikoloyl-M-acetyl mures 1 Mil-1-alanyl-0-isoglugamin; m.p. 137-160®C; d.J +
    + 24.3 ° (after 9 min, with 0.4; tetrahydrofuran - water 50: 1) 25.8 ° (after 24 h, with 0.4 tetrahydrofuranvod 50: 1).
    Elementary analysis for
    five . .
    Calculated,%: C 71.25; H 11.48;
    N 3.36. Found,%: C 71.08; H 11.40;
    N 3.26.
    .. Example 2. In 15 ml of benzene, 0.48 g of diphenylmethyl ester 1-of-0-benzyl-N-acetylmuramyl acid and 0.03 g of 18-Crohn-6 are dissolved.
    To the solution, 0.31 g of potassium cinnamon is added and the solution is boiled for 5 hours under reflux for 3 hours.
    After cooling, the reaction mixture is washed with 0.1N hydrochloric acid and water, and dried. The solvent is distilled off in vacuo, the residue is chromatographed on a silica gel column. The eluate from benzene-ethyl acetate (5: 1) is concentrated and 0.30 g of 1-c-0-benzyl-6-0-corinomicoloyl-M-acetylmuraminoic acid diphenyl methyl ester is obtained; 58.4 ° (c 1.0; chloroform).
    Elementary analysis for
    ) about Calculated,%: C 73,17; H 9.5;
    N 1.33.
    Found,%: C, 72.85; H 9.27;
    N 1.40.
    0.22 g of 1-o-diphenylmethyl ester (-0-benzyl-6-0-corinomicolo-H-acetylmuraminic acid and O, 1 ml of anisole is dissolved in 10 ml of dichloromethane.
    1.6 ml of trifluoroacetic acid was added to the ice-cooled solution. After stirring for 30 minutes, the solvent is distilled off in vacuo. The residue is chromatographed on silica gel. After elution with a mixture of benzene and ethyl acetate 5: 1, anisole and diphenylmethanol, the product was eluted with a mixture of chloroform and methanol (5: 1), the eluate was collected, the solvent was distilled off in vacuo to give 1-6 -0-0-benzyl-6-0-corinomycoloyl M-acetylmuraminic acid. To this product, 89 mg of hydrochloric benzyl ether are added. 1-alanyl-0-isoglutamine and 0.036 ml of triethylamine in 5 ml of tetrahydrofuran.
    42 mg of N-hydroxysuccinimide and 46 mg of dicyclohexylcarbodiimide are added to the cooled mixture (-15 ° C) and the mixture is stirred for one hour at the same temperature. The temperature is raised to room temperature and stirring.
    Q continue overnight.
    The resulting triethylamine hydrochloride and N, N-dicyclohexyl moiety are filtered. The solvent is distilled off, the residue is washed with a mixture
    5 methanol and water (1: 1) and ether. After recrystallization from the mixture with methanol, 0.13 g of 1-c6-0-benzyl-6-0-measly m-coloyl-M-acetylmuramyl-1-alanyl-isoglutamine benzyl ester is obtained; m.p. 172-174C; ioLl- + 53.7 (c 1.0; chloroform). Elementary analysis for -66, 4 Calculated,%: C 67.54; H 9.28; N 4.77. Found,%: C 67.50; H 9.10; N 5.01. 105 mg of 1-c-0-benzyl-6-0-korinomikoloyl-N-ace benzyl ester muramyl-1-alanyl-0-isoglutamine are dissolved in 8 ml of tetrahydrofuran. The product is subjected to hydrogenolysis in the presence of palladium black at 28 ° C. The solvent is distilled off in vacuo. The residue is crystallized from a mixture of methanol, eLir and acetone, to obtain 59 mg of b-O-korinomicolo-M-acetylmuramyl-L-alanyl-O-isoglutamine; m.p. 1,155C; oi J + 31.9 (with 0.88; tetra hydrofuran - water 50: 1). Elementary analysis for Pw Hq60i 5 l4 25 On: 0. Calculated,%: C 60.14; H 9.80; N 5.40. Found,%: C 59.81; H 9.60; N 5.29. Example 3. Under the conditions described in example 2, from 0.35 g of 1-c / -0-benzyl-M-acetic acid diphenyl tiyl ester and muraminic acid 0.31 g of potassium dicalcate potassium, 0.34 g of di l-ct0-benzyl-O-nocardomicoloyl-M-acetylmuraminic acid phenylmethyl ester; otJ. + 46.7 ° (with 1, chloroform). Elementary analysis for 82 ili o io, 6 Calculated,%: C 75.79; H 10.08; N 1.08. Found,%: C 75.38; H 10.15; N 1.03. After treating 0.24 g of diphenylmethyl ester of l-ot-0-benzyl-b-O-nocardomy and coloyl-M-acetylmuraminic acid with trifluoacetic acid, a free carboxylic acid is obtained, which is condensed with 75 mg of L-alany-O-chloroyl-benzyl ester isogluamine, under conditions similar to those described in Example 2, 0.14 g of 1-in-1-benzyl ester is obtained (0-benz-6-0-nocardomicoloyl-N-acetylmura-L-alanyl-O-isoglutamine; mp 16 i67 ° C; oL2 + 44.7 (s 1.0; chloroform). Elementary analysis for X4- Calculated,%: C 70.91; H 9.85} N 3.94. Found,%: C 70 , 99; H 9.92; N 3.92. 84 mg of this compound hydrogenation under the conditions described in Example 2 is obtained; 51 mg of 6-0-nocardomicoloyl-M-acetylmuramyl-1-alanyl-O-isoglutamine are obtained; mp 154157 ° C (with decomposition); rtL ° + 30.0 ° (c 1.0; tetrahydrofuran - water 50: 1, after 24 hours). Elementary analysis for, -5 2.0Calculated,%: C 66.22; H 10.32; N 4.41. Found,%: C 66.07; H 10.58; N 4.26. Example 4. To a solution of a mixture of 1-oC-O-benzyl-6-0-micomikoloyl-M-acetylmuraminic acid diphenylmethyl ester and 0.2 ml of anisole in 20 ml of dichloromethane 3 ml of trifluoroacetic acid are added. After stirring the solution for 30 minutes, the solvent was distilled off in vacuo. The residue is chromatographed on a silica gel column. After elution with anisole and dienylmethane, a mixture of benzene and ethyl acetate (5: 1), the solvent was replaced with a mixture of chloroform and methanol (5: 1), the eluate was collected and the solvent was distilled off in vacuo to give 1-O6-0-benzyl-6- 0-mikomikoloil-M-acetylmuraminic acid. To the product, 0.15 g of benzyl hydrochloride eLira 0-.benzyl-1-seryl-0-isoglutamine and 0.05 ml of triethnlamine in 10 ml of tetrahydrofuran are added, the solution is cooled to. Then, with stirring, gradually, over one hour, 50 mg of N-hydroxysuccinimide and 69 mg of dicyclohexylcarbolium imide are introduced into the solution and stirring is continued overnight at room temperature. The hydrochloric triethylamine and N, N-dicyclohexyl urea formed as a by-product is filtered off and the solvent is distilled off. The residue is subjected to silica gel column chromatography. The product is eluted with a mixture of chloroform and methanol (30: 1), the eluate is collected and the solvent is distilled off. The residue is crystallized from a mixture of benzene and methanol to obtain 0.35 g of 1-o benzyl ester (-0-benzyl-6-0-micomikoloyl-N-acetylmuramide-O-benzyl-L-seryl-0-isoglutamine; mp. 164-166C; Ea.l25 + 32.1 ° (with 0.5; chloroform). Elementary analysis for 14.5 4Calculated,%: C 74.39; H 10.74; N 2.89. Found:%: C 74.41; H 10.59; N 2.87. A solution of 0.2 g of benzyl ester of l-zi-0-benzyl-6-0-mikomikoloil-N-acetylmuramyl-0-benzyl-L-serial-D-isogluamine in 20 ml of tetrahydrofuran, they are hydrogenated in the presence of palladium black at room temperature. The solvent is distilled off in a vacuum. The residue is crystallized from a mixture of tetrahydrofuran and methanol, I obtain 0.14 g of b-O-mycomicol-K-acetylmur mil-1-seryl-0-isoglutamine; mp 114-120 ° C (with decomposition); fci J 25 + + 35.2 ° (with l, 9j tetrahydrofuranvod 50: 1, after 48 hours). Elementary analysis for 9 188, 5 4 С 71.33; H 11.39; Calculated,%; N 3.36. 11.33; С 71 , 03; H Found,% N 3.42. Example 5. Starting from 0.5 g of 1-o-O-benzyl-6-0 diphenylmethyl ester, nocardomicoloyl-M-acetylmuramyl-L-seryl-O-isoglutamine, using the procedure of Example 4, 6-0-nocardomicoloyl-N-acetylmuramyl-L-seryl-O-isoglutamine; m.p. 125130 ° С (with decomposition) jCoiLJ If + 32.2 (s 1.0; tetrahydrofuran - water 50: 1, after 48 h). Elementary analysis for 4.6 4 Calculated,%: C 65.85; H 10.21; N 4.39. Found,%: C 65.62; H 10.33; N 4.48. Example 6. To a solution of 0.5 g of sodium in 5 ml of anhydrous methanol was added 3.6 g of diethyl malonate. After stirring at 50 ° C for 20 minutes, 6.0 g of tetra-decyl bromide was added to the reaction mixture at the same temperature, then the mixture was boiled under reflux for 5 hours. After cooling, ether was added to the solution. The sodium bromide precipitated is filtered off and the solvent is distilled off. The resulting oil is added to 15 ml of anhydrous methanol containing 0.5 g of sodium. Then 6.0 g of tetradecyl bromide was introduced into the solution and the solution was boiled under reflux for 5 hours. After cooling, the mixture is diluted with water and the product is extracted with ether. The ether extract is washed with water and dried. Solvent from nit. The residue is recrystallized from ethanol to obtain 6.7 g of diethyl-2, 2-bistetradecylmalonate; m.p. 30-32C. To a solution of 2.7 g of potassium hydroxide in a mixture of 100 ml of water and 20 ml of ethanol was added 6.5 g of diethyl 2,2-bistetra decylmalonate. The solution is boiled under reflux for 10 hours, then cooled and acidified with 3 M sulfuric acid, and the product is extracted with ether. The ether extract is washed with water and dried. The solvent is distilled off, the residue is heated for 1 hour at 190-200s and then recrystallized from methane; 4.9 g of 2-tetradecylhexadecanoic acid are obtained; m.p. 73.5-75 Elementary analysis for Calculated,%: C 79.57; H 13.36. Found,%: C 79.57; H 13.35. A solution of 1.0 g of 2-tetradecylhexadecanoic acid and 0.79 g of thionyl chloride in 5 ml of benzene was heated under reflux for 7 hours. After removing benzene and thionyl chloride, anhydrous benzene was added to the residue, then benzene was distilled off. This operation is repeated 3 times to completely remove the thionyl chloride. The residue is crystallized from anhydrous hexane; 0.75 g of 2-tetradecylhexadecanoyl chloride is obtained; m.p. 51-53 ° C. To a solution of 0.85 g of lo (.-0-benzyl-N-acetylmyl-L-alanyl-O-isoglutamine benzyl ester in 35 ml of anhydrous pyridine) is added at 1718 ° C with 4.9 g of 2- chloride tetradecylhexadecanoyl dissolved in 35 ml of anhydrous tetrahydrofuran. After 45 minutes the mixture is diluted with 20 ml of water and the solution is stirred for 35 minutes at room temperature. Then the reaction mixture is acidified with 1 m hydrochloric acid to pH 3, the product is extracted with chloroform. The chloroform extract is washed with an expensive solution salt, dried. After removing the solvent, the residue is chromatographed Comfort in a column of silica gel. The product is eluted with a mixture of chloroform and methanol - {20: 1), the eluate is collected and concentrated, the residue is crystallized from methanol to obtain 0.75 g of benzyl ester 6-0- (2-tetradecylhexadecanoyl) -l-tX, - 0-benzyl-M-acetylmuramyl-1-alanyl-D-isoglutamine; m.p. 173-174 ° C. Elementary analysis for 68 101 L1 4 Calculated,%: C 68.39; H 9.20; N 5.06. Found,%: C 68.04; H 9.29; N 5.03. 0.70 g of the benzyl ether thus obtained in 15 ml of tetrahydrofuran is stirred in the presence of palladium black in an atmosphere of hydrogen at 30 ° C for 15 days. The resulting product is subjected to chromatography on a silica gel column, eluting with a mixture of chloroform, methanol, and acetic acid (95: 5: 3). The eluate is collected, concentrated, and the residue is dissolved in a mixture of dioxohydride (1: 1). The solution is lyophilized to give 0.50 g of 6-0- (2-tetradecylhexadecanoyl) -N-acetylmuramyl-L-anyl-O-isogluthamine a; m.p. 152-155C. Elemental analysis for Hg, 4-2H20. . Calculated,%: C, 61.16; H 9.74; N 5.82. Found,%: C 61.10; H 9.60; N 5.83. Example 7. To a solution of 0.65 g of 1-β-benzyl-6-0-mikomikolyl-I-acetylmuramic acid diphenylmethyl ester and 1 ml of anisole in 20 ml of chloroform were added 3.0 ml of trifluoroacetic acid, cooled to a temperature of ice tours. After stirring for 30 minutes, acetone was added to the reaction mixture. The solvent is distilled off in vacuo. The residue is washed with ethanol and then dissolved in 10 ml of tetrahydrofuran. With stirring, 75 mg of N-hydroxysuccinimide, is added to the ice-cooled solution. 72 mg of dicyclohexylcarbodiimide and 1.2 mmol of triethylamine in O, 2 ml of tetrahydrofuran and 237 mg of benzylglycyl-D-isoglutamite hydrochloride. The reaction mixture is then stirred overnight at room temperature. Precipitated triethylamine hydrochloride and N, N-dicyclohexyl urea are filtered off. The solvent is distilled off in vacuo, the residue is chromatographed on silica gel. The eluate in a benzene-acetone mixture (3: 1) is collected, in addition to the initial fraction of the effluent solution, and the solvent is distilled off. The residue is recrystallized from a mixture of benzene and ethanol to give 0.284 g of 1-c (-0-benzyl-0-micomikoloyl-M-acetylmuramylglycyl-D-isoglutamine benzyl ether; mp. 148-150 ° C; LJ% 5 + 36.7 ° (with 0.5f chloroform). Elementary analysis for, 5 СНзОН. Calculated,%: C 73.39; H 11.03; N 3.03. Found,%: C 73.27; H 10, 83; N 2.87. A solution of 0.23 g of 1-c-0-benzyl-6-0-m comicoloyl-M-acetylmuramylglycyl-D-isoglutamine benzyl ester in 40 ivn tetrahydrofuran is hydrogenated in the presence of palladium on carbon at room temperature The solvent is distilled off in vacuo, the residue is dissolved in ethanol, The solution is chromatographed on silica gel. The products are eluted with chloroform: ethanol (10: 1), the eluate is collected, except for the very first fraction. The solvent is distilled off and the residue is recrystallized from ether-ethanol, to give 0.135 g of 6-0 micromoyl N-acetylmuramylglycyl-O-isoglutag shea; mp, 206–207 ° C; Go1 |) + 37.1 ° (after 9 min + 39.1 °, after 20 h, with 0.4, tetrahydrofuran-water 50 :one). Elementary analysis Calculated,%: C 71.90; H 11.48; N 3.42. Found,%: C 71.81; H 11.23; N 3.40. Example 8. B-0-triacontanoyl-H-acetylmuramyl-1-alanyl-0-isoglutamine is prepared by the method described in Example 2. Melting point 192 s (decomposition). Elementary analysis,%: Calculated for C4 () .4 С 63.47; H 9.79; K 6.04; Found,%: C 63.26; H 9.81; N 5.91. Example 9. C-0- (2-Tetradecylhexadecanoyl) -N-acetylmyl-L-alanyl-0-isoglutamine is prepared by the method described in Example 6; m.p. 152-155 ° C. Calculated for HjO,%: C 61.16; H 9.74; N 5.82. Found,%: C 61.10; H 9.60; | J 5.83. Example 10. 6-0- (2-Dococyltetracosanoyl) -M-acetylmuramyl-1-alanyl-0-isoglutamine is prepared by the method described in Example 2; m.p. 150 ° C (decomposition). Calculated for O-js C 67.79; H 10.68; N 4.86. 1%, C: 67.40; H 10.57; N 4.67. Example 11. 6-0- (2-Dococyl-3-hydroxyhexacosoyl) -N-acetylmuramyl-α-alanyl-0-isoglutamine is obtained by the method described in Example 2; m.p. 169-170s (decomposition) + + 22.0 (with 0.5; chloroform: methanol 1: 1). Calculated for H 2 O-gz 4%: C, 66.80; H 10.63; N 4.65. Found,%: C 66.49; H 10.42; N..4.56. Example 12. 6-0- (2-Tetradecyl-3-hydroxyoctadecanoyl) -N-acetylmuramyl-1-alanyl-0-isoglutamine is prepared by the method described in Example 2; m.p. 170-172 ° C (decomposition) + h - 30.8 ° (with 0.5, chloroform: meta NOL 1: 1). Calculated for Cj-, H94f., -, N, p 63.06; H 9.75; N 5.77. Found,%: C 62.66; H 9.67; N 5.65. Example 13. 6-0- (2-Dococylgetracosanoyl) -Y-acetylmuramyl-b-. β-seryl-0-isoglutamine is prepared by the method described in Example 2; m.p 170-180s (decomposition). Calculated dl. 1 = 2%: C, 66.35; H 10.54; N 4.76. Found,%: C 66.16; H 10.56; N 4.67. Example 14. 6-0- (2-Docodyl-3-hydroxyhexacosanoyl) -N-acetylmuramyl-1-seryl-0-isoglutamine is prepared by the method described in Example 2; m.p. 165-180 C (decomposition). Calculated for C, H 0 N: C 65.44; H 10.41; N 4.56. Found,%: C 65.22; H 10.44; N 4.41. eobotnny. -, and. The method of obtaining npontfeo4t ix moore amyl dipipeptides of the general formula - SNHOU O J) (LF) H, BUT 1 BHdoCH, HjddHCoq where Y is mikomikrloil-, kordinomomiko-lOIL-, nocardicololo-or synthetic acyl group with the number of groups of atoms, in addition to the number of in-spaced groups, in the body of population of the body of gene oi is a branched alkyl chain; Q - 1-alanyl-0-isoglutamyl, glcyl-O-isoglutamyl and L-seryl-0-isoglutamyl-, characterized in that benzyl-N-acetyl-c -mramcd of the general formula II CH2 OL, but Chg " . NHCOdH. HsdCHciooH where Z is benzyl, podshishot interaction with mikomikolevaya, kardinomykolevoy, nocardomikolevuyu or synthetic fatty acid containing from C to CJ-Q carbon chain, having in.-Position branched alkyl chain, and a dipeptide selected from the group 1-alanyl- 0-isoglutamine, glycyl-O-isoglutamine or 1-seryl-0-isoglutamine in any sequence. Priority on the basis of signs: June 28, 76, with Y — a micoloyl group, the total number of carbon atoms is 7090; Q - 1-alanyl-0-isoglutamine. 16.12.76 when U is a micolo group, the total number of carbon atoms is 7090; Q - glycyl-O-isoglutamine. 03.02.77 when Y is a micolo group, the total number of carbon atoms is 2866; Q - 1-alanyl-0-isoglutamine. Sources of information taken into account in the examination 1.E. Schroeder, K. Lubke. Peptides, Part I, M., Mir, 1967, p. 116. 2. Weigand-Hilgetag. Experimental methods in organic chemistry. M. Himi, 1968, p. 352.
    权利要求:
    Claims (1)
    [1]
    The method of obtaining the derivative of amyldipeptides of the general formula ι murΎ where Υ -
    H * 0H, shcoch,
    H3WHC0Q * mycomicoloyl-, cordinomicoloyl-, nocardomicoloyl- or synthetic acyl group with the number of carbon atoms from St, o to C $ o , having a branched alkyl chain in the οί-position;
    1-alanyl-0-isoglutamyl-, glycyl-D-isoglutamyl and L-seryl-D-isoglutamyl-, wherein t
    I
    Hhcochj
    NZbCCHSOOH where Ζ is benzyl, is reacted with myco-mycolic, cordin-mycolic, nocardomicoleic or synthetic fatty acid containing from C ^ o to C O carbon chain having a branched alkyl chain in the C-position and with a dipeptide selected from groups 1.-alanyl-0-isoglutamine, glycyl-D-isoglutamine or L-seryl-O-isoglutamine in any sequence.
    Priority by signs:
    06/28/76 at Υ - mycoloyl group, the total number of carbon atoms is 7090; Q is L-alanyl-D-isoglutamine.
    12/16/76 at Υ - mycoloyl group, the total number of carbon atoms 7090; Q is glycyl-O-isoglutamine.
    02.03.77 at Υ - mycoloyl group, the total number of carbon atoms is 2866; Q is L-alanyl-O-isoglutamine.
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    同族专利:
    公开号 | 公开日
    FR2375249B1|1980-04-11|
    DE2728324C2|1988-07-07|
    US4101536A|1978-07-18|
    NL171063C|1983-02-01|
    NL171063B|1982-09-01|
    SE7707276L|1978-02-10|
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    CA1105005A|1981-07-14|
    DE2728324A1|1978-01-12|
    CH624124A5|1981-07-15|
    FR2375249A1|1978-07-21|
    GB1563561A|1980-03-26|
    SE446740B|1986-10-06|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP7407276A|JPS5914038B2|1976-06-23|1976-06-23|
    JP51150328A|JPS6033119B2|1976-12-16|1976-12-16|
    JP1112277A|JPS5398922A|1977-02-03|1977-02-03|Novel melamyldipeptide derivative|
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