• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Muramyldipeptide derivatives of the formula wherein X represents an amino acid residue such as of L-alanine, L-serine, L-valine, glycine, etc., and Y represents a group -NH-A or -NHCH(CH2)n-NHCO-A wherein R1 represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a carboxamide group or a carboxyl group, n represents an integer of 1 to 6, A represents a straight or branched chain, saturated or unsaturated aliphatic hydrocarbon residue of 7 to 30 carbon atoms, and "Acyl" means an acyl group of an aliphatic carboxylic acid having 2 to 6 carbon atoms. These compounds have excellent adjuvant activity and/or prophylactic and therapeutic effects against microbial infections.
    公开号:SU1190990A3
    申请号:SU802936451
    申请日:1980-06-20
    公开日:1985-11-07
    发明作者:Сиба Тецуо；Котани Созо；Ямамура Юити；Нагасе Осаму；Огава Хидемаса
    申请人:Дайити Сейяку Ко.,Лтд (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new derivatives of muramyl dipeptide, of the general formula, OHfa,. SSNH2 1SHOSShz I CHNSSNO Xy-MHHSSNH CH CO-T III) where X is the residue of L-alanine, L-serine or L-valine; Y is NHCHCCOOHXCHjXj-NH-CO-A, where A is branched or unbranched Su-C-alkyl, which possesses valuable pharmacological properties. The purpose of the invention is to obtain new derivatives of muramyl dipeptides that have pharmacological advantages over known structural analogues. Example 1. 11.4 g of N-L1- (l (.- 0-benzyl-4,6-0-benzylidene-N-acetylmuramyl-b-alany-B-isrglutaminyl 1-N-benzyloxycarb nyl-L-lysine benzyl ester) suspended in 115 ml of 60% acetic acid and heated to a boiling water bath for approximately 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and water was added to the residue. The precipitated crystals were collected by filtration and recrystallized from dimethylformamide (DMF) -ethyl acetate thus gives 7.6 g of N-1- benzyl ester (L-0-benzyl-K-acetylmura -L-alanyl-E-isoglutaminyl-2-N - benzyloxycarbonyl-L-lysine, mp 207-2. (With decomposition), v; 3 | +56.6 (C 0.3; DMF, after 17 h) .; Calculated,%: C 59.80; H 6.73; N 8.90. 1/2 H, 0 Found,%: C 59.65; H 6.67; N 8.96. The resulting compound solution in an approximately 20-fold excess of acetic acid and hydrogenated in the presence of a palladium-carbon catalyst in a stream of hydrogen at room temperature.After completion, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a mixture of butanol and acetic acid-water (4: 1: 2 by volume) as eluent. The fractions containing the desired substance are concentrated under reduced pressure and passed through a basic ion exchange resin (acetate form). The eluate is freeze-dried, and N - (H-acetylmuramyl-b-alanyl-O-isoglutaminyl) -L-lysine is obtained. 300mg (N-acetylmyl-L-alanyl-P-isoglutaminyl) -L-lysine are suspended in 7 ml of DMF and added at. cooling with ice, 148 mg of active octanoic acid ester and hydrbc Si-5-norbornene-2,3-dicarboxylide and 0.05 ml of N-methylmorpholine. After 30 minutes, the mixture is gradually warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. - The precipitated crystals were separated by filtration and washed successively with dithyl ether and water. Upon recrystallization from a mixture of DMF - DIETSH10YVY ether, obtain 310 mg of N - (K-acetylmuramyl-b-alanyl-B-isoglutaminyl) -Y-octanoyl-b-lysine, so pl. 126-130 ° C (with decomposition.), .8.8 ° (C 0.2, DMF, after 17 h). Calculated,%: C 50.63; H 7.98; N 10.74. ,, gO, 3N ,. 2H, 0. Found,%: C 50,32; H 7.54; N11.00. The following compounds are also synthesized. N - (K-Atstsh1muramil-1-alanyl-B isoglutaminyl) -K -lauroyl-b-lysine, so pl. 174.5-176.5 ° C (s. Decomposition.), 2 (C 0.6, DMF, after 17 h). Calculated.%: C 54.13; H 8.35; N 10.24 .. SztNbbO | "B- Found,%: C 53.90; H 8.40; N 10.17. fj (1d-Atstsh1muramil-b-al anil-D-of .glutaminyl) -Y-stearoyl-b-lysine, so pl. 175.0-177.0 С (with decomposition), oi.p + 25.9 (С 0.6 DMF, after 17 h). Calculated,%; C 57.06; H 8.91; N 9.29. СчзНтвО.зКбНаО. Found,%: C 57.21; H 8.87; N 9.19. N - (N-Acetylmuramyl-B alanyl-P-isrglutaminyl) -N -triacontanoyl-L-lysine, m.p. 165.0-168 ° C (decomposed). 3 Calculated,%: C 61.03; H 9.78; N 7.76. C55Hit O ,, (1-1 / 2) -N.O. Found,%: C 6Q, 89; -H 9.58; N 7.63. . . N - (N-Acetylmyl-L-l-alanyl-D-isoglutamine) isopentadecano and -L-lysine, so pl. 144.5-147.5 С (from the distribution. + 20.2 ° (C 0.3; DMF, after 17 h). Calculated,%: C 56.85; H 8.59; N 9.95. C4OH "0" Hb. Found,%: C 57.26; H 8.63; N 9.81. N - (L-Acetylmuramsh-b-seryl-O-isoglutaminyl) -Y -stearoyl-b-lizi, mp 175.0-177 ° С (with decomp.), (Y: + 27.8 ° (С 0.5, DMF, calculated in 17 hours,%: С 55.52; H 8.78; N 9, 04. C ,, H, gO ,, Ng (1-1 / 2) H, 0. Found,.%: C 55.46; H 8.62; N 9, .06. N - (H-Acesh1muramil- B-valyl-B-isoglutamine) -N-stearol-L-lysine m.p., 182.0-185.0 ° С (with decomposition), 22.8 (C 0.5,. DMF, after 17 h Calculated,%: C 58.48; H 9.05; N 9.01; C 5H8gO, eMb-1/2 H, 0. Found,%: C 58.48; H 8.89; N 9. , 12. Example 2. 300 mg of N-acetyl muramsh1-b-alanyl-B-isoglutamine, dissolved in 2 mp DMF, in Alternatively, 72 ml of octylamira, 64 mg (0.56 mmol) of N-hydroxysuccinimide and 7 ml of tetrahydrofuran are added. 115 ml (0.56 mmol) of dicyclohexylcarbodiimide are added to this mixture while cooling with ice and nepe-stirring. The mixture is heated to room temperature and allowed to stand overnight. The cyclone cyclohexylurea which precipitates is filtered off and the filtrate is concentrated under reduced pressure and water is added to reduce the precipitate. Recrystallization of the precipitate from a mixture of DM and diethyl ether gives 165 mg of N-acetic muramyl-b-alanyl-B-isoglutamino-amide, mp. 1 /, 0-175,5 ° С (with decomposition. 30.5 (C 0.4, acetic acid, in t hours). Calculated,%: C 52.15; H 8.26; N 11.26 90, oN, .H, 0. Found,%: C, 51.88; H, 8.00; N, 11.35 ... Also, the following compounds are obtained: L-Acetylmuramyl-b-alanyl-B-isoglutamine lauryl amide, mp 186-187 ° C (with decomposition), 30.0 (0.5, acetic acid, after 21 h). Calculated,%: C 54.20; H 8.82; N 10.20. C ,,, oN, - (1-1 / 2). Found,%: C 54.43; H, 8.60; N, 9.88. L-Acetylmuramyl-L-alanyl-B-isoglutamine stearylamide, mp 189 -190 ° C (with decomposition.), 28.0 ° (C 0.5, acetic acid, after 21 hours). Calculated,%: C 59.00; H 9.39; N 9.30. C3, H ,, 0, oN5-1 / 2 H, 0. Found,%: C 58.80, H 9.37; N 9.33. L-Acetylmuramyl-1-valyl-B-isoglutes stearylamine m.p., 217-219 ° C- (with decomposition.) Calculated,%: C 59.96; H 9.57; N 8.97, C, H730, oN, -1 / 2 HjO; %: C 59.73; H 9.58; N 9.16, Method for preparing the active fatty acid ester. 1.0 Mmol of fatty acid is dissolved in 10 ml of tetrahydrofuran and 206 mg of dicyclohexylcarbodiimide and 179 are added with stirring and ice-cooling. mg of N-hydroxy-5-norbornene-2, 3-dicarboximide. After 30 minutes, the mixture is slowly warmed to room temperature and left to stand for 5 hours. The dicyclohexylurea precipitated is precipitated, the filtrate is concentrated, the diethyl ether is added to the residue, and the insoluble part is filtered off. The filtrate is concentrated to dryness under reduced pressure, to give the active fatty acid ester and N-hydroxy-5-norbornene-2, 3-zhikarboksimida as white crystals. In the case of the preparation of the active triacontanoate, use a mixed solvent - tetrahydrofuran - with chloroform (1 : 1 by volume), in groups of twenty Sld-ddy mice / 26 + lg, 5 weeks old
    0.1 mg each of the compounds and control compounds were administered subcutaneously, respectively. After 24 h, the mice were infected by subcutaneous administration of E. coli inoculum strain E 77156, material 6x10 x 9x10 and 1.2x10 cells / baby, respectively. The effect was judged by the percentage of survivors 7 days after infection. As can be seen from the results given in table. 1, the proposed compounds demonstrated an excellent prophylactic effect against this infection.
    Adjuvant activity.
    A corneal test was carried out on guinea pigs, which is considered to be one of 5 indicators of adjuvant activity. As shown in the table. 2, the results indicate that the proposed compounds have an adjuvant activity of the same, and even 10, higher than the muramyl dipeptide.
    G,.
    Control compounds 1-4 and compounds 1-11 are listed in Tables 1 15 and 2.
    0.9
    152
    Control compound 1: (N-acetylmuramyl-L-alanyl-O-isoglutaminyl) -L-lysine.
    Control compound 2: N-acetylmuramyl-b-alanyl-B-isoglutam.
    Control Compound 3: N-acetylmuramyl-b-seryl-B-isoglutamine.
    Control compound 4: N-acetylmuramyl-b-valyl-B-isoglutamine.
    . , The proposed connection 1: N-CN-acetylmuramyl-b-alanyl-B-isoglutamine) -K-octanoyl-b-lysine.
    Suggested compound 2: N —CN-acetylmuramyl-b-alanyl-B-isoglutaminyl) -Y-lauroyl-b-lysine.
    The proposed connection 3: N - (N-adetilmuramyl-b-alanyl-B-isoglutamine) -Y-.stearoyl-b-lysine. .
    The proposed -compound 4: (N-acetylmuramkl-b-seryl-B-isoglutamine) -H-stearoyl-b-lysine .;
    The proposed connection 5: N - (N-acetylmuranyl-b-vapil-B-isoglutamine 1) -Y-stearoyl-L-lysine.
    Proposed compound 6: N - (N-acetylmuramyl-b-alanl-B-isoglutamine 1) -Y-triacontanoyl-lysine.
    The proposed compound 7: N - (N-acetylmuramyl-b-alyl-B-isoglutamine) -H-isopentadecanol-b-lysine.
    Suggested compound 8: N-acetylmuramyl-L-alanyl-B-isoglutamine octylamide.
    Suggested compound 9: N-acetylmuramyl-b-alanyl-B-isoglutamine lauryl amide.
    Suggested compound 10: N-acetylmuramyl-b-alanyl-B-isoglutamine stearylamide.
    Proposed compound 11: N-acetylmuramyl-b-valyl-B-nzoglutamine stearylamide.
     (L-acetylmuramyl-L-alanyl-B-isoglutaminyl) -K-stearoyl-L-lysine is a typical example of the proposed compound and has toxicity (LBj.) Determined on the basis of table. 3
    Table 3
    As can be seen from the table. 3, said compound is effective at; A dose of 10.0 g / mouse (26 g). This fact shows that the detailed dose of this compound is more than 100 times the effective dose and, therefore, the proposed compounds are safe and useful pharmaceutical agents.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING MURAMYL DIPEPTIDE DERIVATIVES of the general formula
    SNGON
    ΜψΌΗ N CHYsosn 3 5 0№g
    CH3CH3CO-X ~ MNSHN g CH g CO-Y where X is the residue of L-alanine, L-serine or L-valine;
    Υ - nhch (cooh) (ch 2 ) 4 -nh-co-a, where A is a branched or unbranched C -C % -alkyl., Which consists in the fact that the compound of the general formula : a-coon, where A - has the indicated meaning, is reacted with N-hydroxy-5-norbornene-2,3-dicarboximide or N-oxysuccinimide in the presence of dicyclohexylcarbodiimide in tetrahydrofura’s medium, in some cases, in a mixture with chloroform at room temperature for 1-24 hours, and the resulting compound is reacted with a compound of the general formula
    CH 2 0H
    J-OH-OH Nof
    TMNOSOSNs sn 3 snso-X — conh 2 soon.
    - ^ HCHCH 2 CH 2 CONH CH (CH 2 VNH 2
    09, SU Щ, 1190990 where X - has the indicated value, in the medium N ( N-dimethylformamide at room temperature for 1-24 hours
    >
    1 . 1190990
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