Method of producing n-acetylmuramil peptides

专利摘要:
L'invention est relative à de nouveaux agents adjuvants immunologiques solubles dans l'eau. Ces agents répondent à une formule de type dans laquelle R est notamment un groupe alcoyle de 1 à 10 carbones. Ces composés sont utiles comme adjuvants immunologiques, notamment pour favoriser les réponses immunitai- res vis-à-vis d'antigènes dont l'immunogénicité est faible.
公开号:SU1326197A3
申请号:SU792777850
申请日:1979-06-05
公开日:1987-07-23
发明作者:Пъер Лефрансье；Моник Паран；Франсуаз Одибер；Луи Шедид；Жан Шоай；Эдгар Ледере
申请人:Ажанс Насьональ Де Валоризасъон Де Ля Решерш (Анвар) (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing new biologically active H-acetylmuramyl peptides of the general formula
H, OH (ciu.nu p)
KSOSNz
CO-X-l: H-CH-COQRi
Ш2СН2С01 Нг
where X is L-alanyl, L-seril, L-valyl; R - linear or branched
, -alkyl,
which can be used in medicine.
The purpose of the invention is to obtain new biologically active N-acetylmuramyl peptides with immunoregulatory properties in combination with low pyrogenicity.
Example 1, N-acetylmuramyl-b-alanyl-B-glutamine f I methyl ester
a) N-tert-butyloxyxycarbonyl-B-glutamine (II) methyl ester.
To a solution of 1.5 g (6.2 mmol) of N-tert-butyloxycarbonyl-B-glutamine in 60 ml of absolute methanol at O ° C is added dropwise a solution of diazomethane in ether until a yellow color appears in the reaction solution, stirred the reaction mixture is 10 min at and 10 min at room temperature. The progress of the reaction is controlled by thin layer chromatography (those) on silica gel plates using solvent systems: n-butanol - acetic acid - water (4: 1: 5), n-butanol - pyridine - acetic acid - water (30:20: 6:24) and chloroform - methanol (5: 1). After completion of the reaction, excess diazomethane is decomposed by the addition of acetic acid. The reaction mixture is then evaporated to dryness, the residue is dissolved in a minimum amount of ethyl acetate and the product is precipitated from the solution by removing petroleum ether.
A total of 1.42 g (89.7%) of compound (II) is obtained at mp 86-90 ° C; e + 24.7 ° (C 1; methanol).
Found,%: C 50.62; H 7.75; N 10.82.
Calculated,%: C 50.76; H 7.75; N 10.76.
0
15
20
25
30 25 40 45 gg
five
b) N-tert-butyloxy methyl ester in sicarbonyl-b-alanyl-B-glutamine (III).
1.4 g (5.4 mmol) of compound (II) is treated with 1N hydrochloric acid solution in glacial acetic acid. The reaction mixture is kept for 30 minutes, evaporated to dryness, the residue is dried in vacuum over KOH and dissolved in 25 ml of DMF. To the resulting solution, 0.6 ml (5.4 mmol) of N-methylmorpholine and 1.86 g (6.5 mmol) of N-tert-butyloxycarbonyl-b-alanine N-hydroxy succinimide ester are added. The reaction mixture is left overnight and then evaporated to dryness. The residue is dissolved in a mixture of chloroform - isopr opanol - acetic acid (100: 0.5: 0.62) and chromatographed on a column (27x3 cm) filled with silica with is. using chloroform-isopropanol-acetic acid as an eluent (100: 5: 2). The fractions containing the product are combined and evaporated to dryness. The residue is crystallized from isopropanol-isopropyl ether.
A total of 1.035 g of compound (III) with a m.p. 115-116 ° C; GS / d -9 ° (methanol).
Found,%: C 50.79; H 7.40; N 12.42.
C.
Calculated,%: C 50.74; H 7.60; N 12.68.
c) L-alanyl-B-glutamine (IV) methyl ester hydrochloride.
332 mg (1 mmol) of compound (III) are treated with 3 ml of 1N hydrochloric acid in glacial acetic acid. The reaction mixture is kept for 30 minutes and evaporated to dryness. The residual oil is dried in a vacuum over KOH,
d) l-cf-0-benzyl-4,6 j O-benzylidene-H-adylmuramyl-b-alanyl-B-glutamine (V) methyl ester.
471.5 g (1 mmol) of 1 o-0-benzyl-4,6 O-benzylidene-M-acetylmyl amyl acid are dissolved in 5 ml of DMF containing 0.11 ml (1 mmol) of N-methylmorpholine. To the resulting solution was added at Oj13 ml (1 mmol) of isobutyl chloroformate. The reaction mixture was incubated for 3-5 minutes, a solution of 268 mg (1 mmol) of compound (VI) and 0.11 ml (1 mmol) of N-methylmorpholine in 5 ml of DMF was added to it cooled to -15 ° C. The reaction mixture overnight at -15 With, when 31
Add 1 ml of a 2.5 M potassium bicarbonate solution, incubate for 30 minutes at 0 ° C and add water. The precipitate is filtered, npof-ibiBaroT 1 M potassium bicarbonate solution and dried in a vacuum over P,
In total, 620 mg (90.5%) of compound (V) are obtained with a mp. 215-220 ° C; tci +92, (DMF).
e) N-acetylmuramyl B-alanyl-B-glutamine methyl ester (I).
587.6 mg (0.86 mmol) of compound (V) dissolved in 35 ml of glacial acetic acid are hydrogenated for 60 hours in the presence of 450 mg of 5% palladium on activated carbon as a catalyst. Then the catalyst is filtered off, the filtrate is evaporated in vacuo. The residue is dissolved in a 0.1 M solution of acetic acid and chromatographed on a column (10x1 cm) filled with Amberlite AG 50W-X2 ion exchange resin, using a 0.1 M solution of acetic acid as eluent. The fractions containing the product are lyophilized and the resulting product is again chromatographed on a column filled with Amberlite AG1 X-2 ion exchange resin. The fractions containing the product are lyophilized. A total of 290 mg of product is obtained, which is dissolved in n-butanol – acetic acid – water (65:10:25) and chromatographed on a column filled with silica gel, using the n-butanol – acetic acid –– system as eluent. water (65:10:25). The fractions containing the product are combined and extracted with water. The aqueous phase is separated and lyophilized.
In total, 234.4 mg of Compound (I) are obtained with a mp. 108-112 ° C; foi j +34.3 (ice on acetic acid).
Found,%: C 45.46; H 6.76; N 10.56.
С2оНз4 N401, -1.25 HiO
Calculated,%: C: 45.50; H 6.95;
N 10.59.
Example 2. K-acetylmuramyl-b-alanyl-B-glutamine (VI) n-Butyl ester
a) L-benzyloxycarbonyl-b-alanyl D-glutamine (VII)
2.4 g (16.4 mmol). D-glutamine is dissolved by heating in 35 ml of water. To the solution was added 2.3 ml (16.4 mmol) of triethylamine and 4.62 g
974
(14.4 mmol) of N-oxysuccinimide ester of L-benzyloxycarbonyl-b-alanine in 70 ml of anhydrous tetrahydrofuran. The reaction mixture is kept at 4 ° C for 48 hours, 0.5 ml (3.85 mmol) of dimethylaminopropylamine is added, the reaction mixture is kept at room temperature for 1 hour, diluted with 65 ml of water, acidified with 4N HC1 at 0 ° C to pH 2.2-3.0. Then tetrahydrofuran is distilled off in vacuum, and the residue is kept overnight at. The precipitate is filtered off, washed with a minimum amount of cooled water and crystallized from ethanol.
A total of 2.87 g (62%) of compound (VII) are obtained, with a mp. 179-182 ° C; -13.3 (methanol).
Found,%: C 54.18; H 5.80; N 11.77,
Cfb itNiO.
Calculated,%: C 54.69; H 6.02; N 11, 96,
b) N-benzyloxycarbonyl-b-alanyl-P-glutamine n-butyl ester (VIII).
350 mg (1 mmol) of compound (VII) are dissolved in a mixture of 15 ml of tetrahydrofuran and 5 ml of water. To the solution was added an aqueous 20% CSjCO solution (1 mmol). The solution is evaporated to dryness, the residue is dissolved in DMF and again evaporated, the residue is dried over P205. This procedure is repeated several times. The resulting dry residue is dissolved in 30 ml of DMF. To the resulting solution was added 0.12 ml (1.1 mml) of 1-bromo-n-butane, dispensed for 20 hours, and monitored completion of the reaction using TLC on silica gel in an ethyl acetate-pyridine-acetic acid-water system (6: 2: 0.6: 1), add 0.06 ml (0.55 mmol) of 1-bromo-n-butane, hold for 20 h, evaporate to a minimum volume and precipitate the product with water.
In the end, get 332 mg (81,5%) of the compound (V11I) with so pl, 148-150 C,
Found,%: C 58.91; H 7.12; N 10.26.
CeoHjjNjO
Calculated,%: C 58.95; H 7.17; N 10.31.
c) n-Butyl ether of L-alanyl-B-glutamine (IX),
330 mg (0.8 mmol) of the compound (VIII) dissolved in 30 ml of the fret. acetic acid, hydrogenated for 4 hours in the presence of 330 mg as a catalyst
513
5% palladium on activated carbon and 1 ml of 1N. HC1. The end of the reaction is controlled with those on silica gel in the system ethyl acetate - pyridine - acetic acid - water (6: 2: 0.6: 1). After completion of the reaction, the catalyst is filtered off, the filtrate is evaporated, the residue is dried in vacuum over PJ O. A total of 254 mg (100%) of compound (IX) are obtained as an oil.
d) n-Butyl ether 1 O / -0-benzyl-4,6-0-benylidene-Y-acetylmuramyl-L-alanyl-B-glutamine (X),
Prepared analogously to example 1 (step d), starting from 0.9 mmol of 1-o / - O-benzyl-4,6-0-benzylidene-K-acetylm ramilic acid and 0.8 mmol of compound (IX). The result is a compound (X) with the release of 81.2%, so pl. 220-235 s; Gy d + 82.6 ° (DMF).
Found,%: C 61.77; H 7.03;
N 7.03.
N
,, Calculated,%: 7.71.
C 61.14; H 6.93;
e) N-acetylmuramyl-b-alanyl-B-glutamine (VI) n-Butyl ester.
472 mg (0.6 mmol) of the compound (X) dissolved in 30 ml of glacial acetic acid are hydrogenated for 40 hours in the presence of 470 mg of 5% palladium on activated carbon as a catalyst. After completion of the reaction, which is controlled by chloroform-methanol on silica gel (50:15 the catalyst is filtered off, the filtrate is evaporated. The residue is dissolved in chloroform-methanol (50:15) and chromatographed on a column filled with silica gel-60 (33 d) using the chloroform-methanol system as the eluent (50:15). The fractions containing the product are combined and evaporated to dryness. The residue is dissolved in water, the solution is subjected to ultrasound and then lyophilized.
A total of 157 mg (48%) of compound (VI) + 34.8 ° (acetic acid) are obtained.
Found,%: C 48.26; H 7.08; N 9.74.
C2 H4oN40;, - 1/3
Calculated,%: C, 48.24; H 7.50; N 9.78.
PRI me R 3. n-Decyl ether K-ace tmuramyl-b-alanyl-B-glutamine (XI).



It is carried out analogously to example 2. As a result, compound (XI) is obtained from + 30 ° C, ice on acetic acid), mp. .
Found,%: C 53.97; H 8.06; N 8.47.
29 I52N4071 0.15 СНС1з.
Calculated,%: C, 53.97; H 8.08; N 8.61.
I Example 4. K-acetylmuramyl-b-alanyl-B-glutamine n-propyl ester (XII).
Synthesized as in Example 2. As a result, compound (XII) is obtained with 0 +32.3 (ice on acetic acid).,
Found,% C 44.5; H 6.30; N 8.40.
CjiHjgN o., 0,6 cHcij-atssoon
Calculated,%: C 44.4; H 6.40; N 8.40.
Example 5. H-acetylmuramyl-b-alanyl-B-glutamine n-hexyl ester (XIII).
Synthesized as in Example 2. As a result, compound (XIII) + 29.5 ° (ice on acetic acid) is obtained.
Found,%: C 49.4; -N 7.40; Q9,10.
C25N44M40 "-0, ZSNS1z
Calculated,%: C 49.6; H.7.30; . N 9,10 ..
Example 6. N-acetylmuramyl-b-alanyl-B-glutamine (XIV) ethyl ester.
Synthesized as in Example 2. As a result, compound (XIV) is obtained with G (+34 (ice on acetic acid)).
Found,%: C 46.4; H 7.1; N 10.3.
Cj, Hj, N, 0 ,,
Calculated,%: C, 46.4; H 7.3; N 10.2.
Example 7. M-taacetylmuramyl-b-alanyl-B-glutamine n-Pentyl ester (XV).
Synthesized as in Example 2. As a result, compound (XV) is obtained with (+ 36.5 ° (ice on acetic acid).
Found,%: C 49.3; H 7.7; N 9.6.
C2H 2N40ii 1,
Calculated,%: C 49.4; H 7.6; N 9.3.
Example 8. N-acetylmyramyl-L-valyl-B-glutamine n-butyl ester (XVI).
713
Synthesized as in Example 2. As a result, compound (XVI) is obtained with, (ice on acetic acid),
Found,%: C 50.5; H 7.5; N 8.6.
Cj N4 0,25 CHj COOH. N. About
Calculated,%: C 50.52; H 7.86; N 8.57.
Example 9. n Butyl ester of M-acetylmuramyl-b-seryl-B-glutamine (XVII).
Synthesized as in Example 2. As a result, compound (XVII) is obtained with +39.4 (C-1; ice on acetic acid).
Found,%: C 48.8; H 7.0; N 9.8.
C ,, N ,, N, 0,2
Calculated,%: C 48.9; H 7.14; N 9.9.
The resulting N-acetylmuramyl peptides have been studied as immunological additives.
The toxicity of N-acetylmuramyl peptides prepared according to the proposed method has been studied in rabbits when administered parenterally. It was found that the toxic doses of the studied compounds are significantly higher than the doses at which their activity is detected. Toxic effects occur at doses equal to or greater than 5 mg / kg.
When determining the pyrogenic activity, the change in body temperature in rabbits within 3 hours after the administration of N-acetylmuramyl peptides was studied. The results obtained are presented in Table. one.
Table 1
five
 WITH
 five
0
thirty

°
five
five
978
From the table. 1 of the data we can conclude that in doses -, at which the activity of the proposed compounds appears, they do not have the ability to cause febrile effects.
In determining the activity as immunological additives in the aqueous phase, the effect of the N-acetylmuramyl peptides, obtained according to the proposed method, on the amount of anti- was studied. albumin antibodies. Groups of 8 mice of the Swiss breed aged 2 months injected subcutaneously with 0.5 mg of antigen, consisting of bovine serum albumin, with or without the addition of the studied compounds in isotonic saline in an amount of 0.1 mg. Antigen without the addition of the studied compounds serves as a control. After 30 days, the same antigen at a dose of 0.1 mg was administered subcutaneously to mice. At the same time, for comparison, the effect of 2- (2-acetamido-2-deoxy-3-0-B-glucopyrazonyl) -B-propionyl-b-alanyl-B-isoglutamine (MDP ) "
The amount of antibodies is determined by passive hemagglutination using sheep erythrocytes treated with formalin and covered with the antigens under study. Studies were performed after the first injection of antigen and after repeated injection to determine primary and secondary immune recall.
Indicators of the amount of antibodies are expressed in logarithm with a base 2 of the maximum serum dilution agglutinating a certain amount of the red blood bodies of the rams.
The results are presented in Table. 2
table 2
3.57 + 1.78 8, FOR ± 1.34 8.43 + 1.52 8.72 + 1.23
The results show that the proposed compounds administered in isotonic saline cause a marked increase in the amount of antibodies produced.
When determining activity as immunological additives in the oil phase. The increase in the number of specific antibodies produced by the antigen was studied after its introduction in the presence of additives of the studied compounds, administered in the form of a water-in-oil emulsion. The experiments were carried out on guinea pigs weighing 350 g (groups of 6 individuals). The preparations are injected subcutaneously into the pads of both hind pads, Ovalbumin at the rate of 1 mg in the emulsion 0.1 ml of isotonic saline solution in oil form, consisting of incomplete adjuvant Freyda (NAF), the test compounds are injected into the amount of 0.1 mg in the form of additives to the emulsion, containing NAF. For comparison, experiments were performed using MDP as an additive. After 18 days after immunization, possible manifestations of inhibited hypersensitivity to the antigen are examined, for which 0.01 mg ovalbine min is administered subcutaneously to the animal's side, and after 48 hours a reaction is observed at the site of ovalbumin injection, the size of the induced lesions. The irritations are measured in -.5 Ill. meters. 21 days after injection, animals are bled and the content of antibodies specific to ovalbumin is measured in the resulting serum, as a result of precipitation, the antibody-antigen complex in the equilibrium zone. The amount of protein azo
that contained in the sediment is determined by the method of Folin.
Mean values of antibodies are given in Table. 3, These values indicate the amount of nitrogen in the protein precipitated by the antigen in micrograms in 1 ml of serum.
Table 3
five
P
5 QL Q g
five
0
From the obtained results it follows that the studied compounds, administered as an oily emulsion, significantly increase the amount of antibodies produced in response to the introduction of the antigen, and also cause the appearance of inhibited hypersensitivity to the same antigen, and both of these effects The least measure is equal, in contrast to the effects observed when using MDP as an additive.
The study of anti-infective activity against Klebsiella was carried out according to a known method. Klebsiella pneumouiae, administered at a dose of 1-2 .10 intramuscularly to mice, causes the death of most, if not all, animals within a week after administration. After 8 days, the survival rate of the animals is significantly increased. Survival rates were observed in groups of mice infected under the conditions described and treated with the N-acetylmuramyl peptides described. For conducting experiments, we use the hybrid hybrid rock (C57B1) 6xAKR / F1. supplied by the Pasteur Institute, where they are obtained from the sample supplied by C.N.R.S. in Orleans. The Klebsiella pneumoniae infectious culture, a strain of capsular type 2, biotype d, is obtained from a 16-hour culture in the medium for obtaining pneumococci (No. 53515, Pasteur Institute), an infection dose of 2 10 Klebsiella, which is administered intramuscularly. Test compounds
II13
are administered intravenously in 0.2 ml of pyrogenic saline. Control animals are given only saline. The test compounds are administered to animals 24 hours after infection. As a result of the conducted research, it was established that compounds VI and XI show anti-infectious activity, which follows from a higher percentage of surviving animals as compared with the control group.
Data on the anti-infective activity of compound VI are presented in Table. four.
Table
12
Research on the effects of coaguli
blood is carried out by a known method
The whole amount of blood taken for the experiment is divided into two parts, one of which is centrifuged to obtain a plasma without platelets (PBT). 1 ml of blood is incubated in a plastic capsule in the presence of 100 µg of the test compound. In addition, capsules containing 0.1 ml of PBT are prepared, to which 0.1 ml of the incubation mixture is added every hour for 5 hours, followed by 0.1 ml of a 0.025 M solution of calcium chloride. The coagulation time is measured and the activity of the studied compounds with respect to coagulation is determined as a dependence of the reduction of the coagulation time with respect to a control sample in which saline is used. The results obtained are compared with those obtained with a lipopolyaccharide (LPS), a substance that significantly promotes coagulation, taken as a reference.
The results are presented in Table. five.
As a result of the research, it was found that the proposed compounds, unlike LPS, do not accelerate the coagulation of blood.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining N-acetylmuramyl peptides of the general formula
CH20N
-about
(10 H, OH (oL or | 5)
0
0
five
 -NRCOCHj
TDX- NH-GH-COORi
CH CH CONHi,
f
where X is L-alanyl, L-seril, L-valyl; R - linear or branched
C-C-alkyl,
characterized in that it is protected. a derivative of muramyl acid of the general formula
/ OCH2 Ph-CH -0 Q UAup)
0 / J- / СНзСН Т НССНз
COOY
where Ph is phenyl; R2 is benzyl;
Y is hydrogen.
° V
H
0 s40
55
condense with a common mule dipeptide
H-X-NH-CH-COORi
CH2, CH2CO2 H2.
13132619714
where X and R have the indicated meanings of the groups by catalytic hydrogenation, followed by removal of the protective vanes in the presence of acetic acid.

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申请号 | 申请日 | 专利标题

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FR7816793A|FR2428051B1|1978-06-05|1978-06-05|

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