WO1979000802A1 - Nouveaux composes esters de muramyl-peptide et leurs applications dans les compositions pharmaceutiques et reactifs de laboratoire - Google Patents

Nouveaux composes esters de muramyl-peptide et leurs applications dans les compositions pharmaceutiques et reactifs de laboratoire Download PDF

Info

Publication number
WO1979000802A1
WO1979000802A1 PCT/FR1979/000027 FR7900027W WO7900802A1 WO 1979000802 A1 WO1979000802 A1 WO 1979000802A1 FR 7900027 W FR7900027 W FR 7900027W WO 7900802 A1 WO7900802 A1 WO 7900802A1
Authority
WO
WIPO (PCT)
Prior art keywords
alanyl
group
ester
muramyl
residue
Prior art date
Application number
PCT/FR1979/000027
Other languages
English (en)
French (fr)
Inventor
P Lefrancier
M Parant
J Choay
E Sache
E Lederer
F Audibert
L Chedid
Original Assignee
Anvar
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Anvar filed Critical Anvar
Publication of WO1979000802A1 publication Critical patent/WO1979000802A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
    • C07K9/005—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure containing within the molecule the substructure with m, n > 0 and m+n > 0, A, B, D, E being heteroatoms; X being a bond or a chain, e.g. muramylpeptides

Definitions

  • the invention relates to new products endowed with biological and pharmacological properties of great value, which can be used either for the constitution of standardized laboratory reagents for the comparative study of similar biological properties of other compounds, or for the creation of new drugs for human or veterinary use.
  • the invention relates more particularly to new products capable of modifying the immune responses in living warm-blooded beings. More specifically still, it relates to new products capable of stimulating immune responses involving at least one and preferably all of the mechanisms constituting the immune responses with humoral support (opsonins, antibodies) or with cellular support. These mechanisms can be specific (their activation dependent on prior vaccination with a given antigenic mixture, and more especially coming from pathogenic agents) or non-specific (as they are induced by agents such as BCG, corynebacter - laughs or endotoxins).
  • the first line of defense involves, as is well known, leukocytes and macrophages in the circulating blood, capable, when they meet a foreign agent such as an antigen, of phagocytosis and often of destroying it.
  • This phagocytosis can be favored in particular by non-specific constituents of the serum (opsonins), or even by external interventions aimed at activating the macrophages.
  • a second line of defense of the organism brings into play mechanisms triggered by the antigenic constituents of the foreign agent. These immune mechanisms involve cellular differentiations in at least one of the following two main directions.
  • a first type of immune mechanism in fact involves specialized cells (B lymphocytes) which are precursors of cells which secrete immunoglobulins or antibodies. These immunoglobulins or antibodies play an important role in the fight against infections caused by bacteria or other microorganisms which replicate in humoral fluids, or even to neutralize toxins or the like. To this type of action, specific to the antigen considered, is added an indirect action by circulating mediators, and which results in an activation of the cells responsible for phagocytosis, thus reinforcing the non-specific defenses of the organism.
  • the second type of immune mechanism involves specifically sensitized cells belonging to the lymphocyte line (T cells), which interact on the B cells indicated above, or on the macrophages leading to the activation of these or other non-specific cells. .
  • T cells lymphocyte line
  • Klebsiella as infectious strains, with extracellular replication are particularly representative. These bacteria present in effect a large capsule that allows effective phagocytosis only by macrophages. Since this mechanism uses non-specific agents, the results obtained with Klebsiella can be extended to microorganisms which replicate in the same way.
  • Listeria are among the most used microorganisms, and in particular Listeria monocytogenes. These are the basis of biological tests that have become conventional, both for the study of specific and non-specific reactions.
  • cell-mediated immunity constitutes a complex defense system for organisms intervening in many situations, not only vis-à-vis intracellular microorganisms but also vis-à-vis neoplastic growth and the multiplication of many fungal, parasitic agents, etc. ; it is this system which is also involved in the rejection of transplants and many autoimmune processes.
  • compositions or products capable of stimulating the immune defenses of the types indicated above can be of capital importance so much for the study of other substances at the level of "research, as much fundamental as applied, that in the field of human or veterinary therapy.
  • LPS lipopolysaccharides
  • BCG Bacillus Calmette-Guérin
  • BCG itself is not without many drawbacks, which can be demonstrated, for example, in animals, particularly in terms of increasing the host's sensitivity to endotoxins, the production of a hypersensitivity to tuberculin, induction of granulomas, hyperplasia of lymphoid tissue and, in particular in rats, polyarthritis.
  • the aforementioned small molecules are, as is now well known, constituted by N-acyl-muramyl-peptides or certain of their substitution derivatives, characterized by an N-acyl-muramic group to which is attached a peptide chain comprising a first residue aminoacyl directly linked to N-acyl-muramic acid, consisting of a glycyl residue or derived from another levorotatory amino acid, preferably an L-alanyl or L-sefyl residue, and a second aminoacyl group, linked to the first, derived from D-glutamic acid.
  • the most active products as immunological adjuvants consist of N-acetyl-muramyl-peptides, the first aminoacyl residue of which is L-alanyl or L-seryl and the second of which is a D-glutamyl residue whose function carboxyl in ⁇ can be either free, or esterified or amidated (the amide group being able itself to carry substitution groups) and whose carboxyl function in ⁇ can also be either free, or amidated or esterified, or still engaged in a chain longer peptide.
  • the most representative product of the N-acyl-muramyl-peptide series is constituted by N-acyl-muramyl-L-alanyl-D-isoglutamine (MDP).
  • the invention stems from the discovery that the introduction of a lipophilic chain (that is to say, an essentially non-polar hydrocarbon chain) on the ⁇ -carboxylic function of the glutamyl residue led to the production of a new category of muramyl-peptide derivatives characterized in particular by a powerful anti-infectious action. It will be noted that the attachment of the lipophilic chain to the peptide chain, which characterizes the new products according to the invention, goes entirely against what can be observed in the natural water-soluble adjuvant products which can be obtained. from the cell walls of microorganisms, such as mycobacteria, which contain in their structure at least one fragment of peptidoglia. Indeed, some of these natural products may contain lipophilic chains indirectly attached to some of the saccharide units of the peptidoglycan, but have never been found on the chains. peptides of the latter.
  • Products according to the invention also testify to new progress vis-à-vis already known products, in that they prove capable not only of exerting a non-specific stimulating action at the level of the humoral immune defenses, but also cell-mediated immunity.
  • R is preferably either a hydrogen atom or an alkyl group comprising from 1 to 4 carbon atoms
  • R 1 is preferably a hydrogen atom, an alkyl group preferably having at most 4 carbon atoms, a simple or substituted aryl or alkyl-aryl group preferably comprising at most 10 carbon atoms,
  • R 2 is preferably a hydrogen atom or an alkyl, aryl or alkyl-aryl group optionally substituted by groups which do not modify the characteristics of the product and preferably comprising at most 22 carbon atoms,
  • R 4 is a hydrogen atom, an acyl radical preferably comprising at most 4 carbon atoms,
  • R 6 is preferably a hydrogen atom, or a saturated or unsaturated acyl radical, optionally branched, containing from 1 to about 90 carbon atoms, and which can moreover carry functional groups: hydroxyl, carboxyl, carbonyl, amino, cyclopropane, alkoxyl, preferably methoxyl,
  • - X is an aminoacyl residue from the group comprising: L-alanyl, L-arginyl, L-asparagyle, L-aspartyle, L-cystéinyle, L-glutaminyle, L-glutamyle, glycyle, L-histidyle, L-hydroxy-prolyle, L-isoleucyle, L-leucyle, L-lysyle, L-méthionyle, L- ornithyle, L-phenylalanyl, L-prolyle, L-seryle, L-threony- le, L-tryptophanyle, L-t ⁇ rosyle et L-valyle,
  • - Y is either -OH, or an alkoxy radical comprising from 1 to 10 carbon atoms, or -NH 2 , the hydrogens of the amino group possibly being substituted by alkyl radicals of 1 to 10 carbon atoms, or an aminoacyl residue,
  • - A is an aminoacyl residue of the group indicated above for X, or, for the last of the peptide chain, an amino alcohol residue (-NH-CH-CH - O-) corresponding to these aminoacyls (- NH-CH-CO-), it being understood that the groups A present in the same compound may be identical or different, n representing only the total number of groups A in this compound,
  • - n is zero or 1, 2 or 3,
  • - Z is a group -OR ', -NHR', -OCH 2 -CH 2 O-COR 'or -OCH 2 - CHOH-CH 2 O-COR' when the last residue A of the peptide chain is an aminoacyl or a COR 'group when the latter residue A is an amino alcohol, in which R' is a linear or branched alkyl, saturated or not, and may contain hydroxyl, carbonyl, carboxyl, cyclopropane, aryl functional groups, the latter optionally substituted, this group comprising at least 4 carbons and being able to contain up to 90 carbon atoms.
  • the second aminoacyl group in the peptide chain linked to the muramyl group is D-glutamyl residue.
  • the first aminoacyl group (designated by X) can, on the other hand, be chosen from the various aminoacyl groups mentioned above.
  • those in which the first aminoacyl group is L-alanyl are preferred.
  • a second type of preferred compound is that in which this aminoacyl is L-seryl.
  • Another type of preferred compound is that in which this aminoacyl is the glycyl group.
  • first aminoacyl group is L-prolyl, L-threonyl or L-valyl.
  • the number of carbon atoms included in R ' is not limited on the side of large numbers.
  • the increase in the number of carbon atoms, past a certain threshold does not bring any advantages and requires the use of reagents which are difficult to obtain commercially.
  • the group R ′ does not contain more than a hundred carbon atoms, and preferably not more than 90.
  • the lipophilic character reaches an advantageous level as soon as R ′ contains about ten carbons.
  • D-glutamyl residue and the R 'group may be interposed one or more additional aminoacyl residues designated in the general formula by A.
  • these aminoacyles are chosen from the group comprising: alanyl, leucyl, lysyl, glycyl, valyle, glutamyl and isoleucyle.
  • the first aminoacyl fixed in ⁇ of D-glutamyl is L-alanyl.
  • this aminoacyl is L-lysyl or L-glutamyl.
  • the number of aminoacyles between D-glutamyl and the group R ′ can vary from 0 to 3, preferably however it is either 0, 1 or 2.
  • the last aminoacyl can be replaced by the aminoalcohol residue of the same carbon structure as the aminoacyl, the bond with the group R 'then taking the form of an ester of this aminoalcohol with an acyl -CO-R'.
  • the substituent Y can first of all represent the radical -OH, that is to say that the carboxylic function of glutamic acid is found. It can also be the amide form of this acid, that is to say the isoglutaminyl form, Y then being -NH 2 , at least one of the hydrogen atoms of the amino group being able to be substituted by short alkyl radicals comprising from 1 to 10 carbon atoms. It can also be the esterified forms of the acid, Y then being an alkoxy, comprising from 1 to 10 carbon atoms.
  • Y is a hydroxyl
  • Y is -NH 2 .
  • Another preferred form is constituted by the case where Y is either -OCH 3 or -OC 2 H 5 .
  • R is -CH 3 .
  • the R group is hydrogen; we then find the structure of the lower counterpart designated under the name of nor-muramic acid.
  • R is -C 2 H 5 ; to this form corresponds the structure called homo-muramic.
  • the glycosidic linkage of the saccharide part in the products according to the invention can be in ⁇ or ⁇ form.
  • the osidic residue can also receive various substituents, of which the prior literature relating to adjuvants of the muramyl-peptide type has given a certain number of examples.
  • the literature describes products in which the functional groups of the sugar residue are "blocked" by the formation of ester or ether groups on the hydroxyls, or of amide groups on the amino radical in position 2.
  • the substituents of the glucopyranoside cycle have been designated by R 1 , R 2 , R 4 and R 6 . The different positions do not present the same substitution possibilities, position 6 being the one for which the greatest latitude is offered.
  • Preferred compounds are those in which one or more of the substituents R 1 , R 4 and R 6 , independently of each other or simultaneously, are hydrogen.
  • Advantageous compounds are also those for which R 4 is the succinyl group -CO- (CH 2 ) -CO 2 H or the acetyl group.
  • R. is an acyl radical containing from 1 to 4 carbon atoms, and in particular the acetyl (-COCH 3 ), succinyl (-CO (CH 2 ) -CO 2 H) radicals, or alternatively those for which R 6 is the mycoloyl group (approximately C 80 to C 90 ) or corynomycoloyl (C 32 ).
  • R 2 are constituted by the alkyl groups comprising from 1 to 4 carbon atoms and, in a particularly preferred manner, R 2 is -CH 3 .
  • R 1 , R 4 , R 6 are simultaneously a hydrogen atom
  • R and R 2 are -CH 3
  • X is L-alanyl
  • Y is -NH 2
  • (A) n -Z is - an esterified or amidated L-alanyl residue
  • ester or amide residues are preferably those of the butyl, decyl, pentadecyl, eicosyl, benzyl hydrocarbon groups or a residue derived from a mycolic acid such as glyceryl-mycoatate.
  • Particularly preferred groups (A) n -Z are those of formula -NH-CH (CH 3 ) -COO-CH 2 - (CH 2 ) 8 -CH 3 , -NH-CH (CH 3 ) -COO-CH 2 - (CH 2 ) 2 -CH 3 , -NH-CH (CH 3 ) -CONH-CH 2 - (CH 2 ) 8 -CH 3 , -NH-CH (CH 3 ) -COO-CH 2 - (CH 2 ) 18 -CH 3 -NH-CH (CH 3 ) - COO- (CH 2 ) 14 -CH 3 -NH-CH (CH 3 ) -COO-CH 2 -C 6 H 5
  • Preferred compounds according to the invention are in particular the following:
  • R ° being a mycolic acid radical containing from 80 to 90 carbon atoms
  • reaction modes leading to the attachment of a fragment to the contiguous fragment (s) are on the whole little modified by the order in which this integration is carried out, with the exception of course of this order depends, on the one hand, on the choice of the functional groups which react and which, consequently, must be free for the stage considered, and, on the other hand, on the choice of the groups which must be blocked so as not to intervene during of this same step.
  • the products according to the invention can be prepared from the corresponding compounds of the muramyl peptide type. Obtaining these has been described in numerous publications. Optionally, for those whose preparation does not appear expressly in the literature and in particular for the various variants corresponding to the substitutions of the muramyl group or analogous groups, they can be obtained by following the traditional methods of preparation of the corresponding derivatives of the chemistry of oligosaccharide ⁇ .
  • This formation includes for example the preparation of a sodium salt of the hydroxyl in position 3 and the subsequent condensation of the sodium derivative with the salt or the ester of a halogenated ⁇ acid such as chloro-2-propionic acids. or chloroacetic to take up the case of the two patent applications indicated above.
  • a halogenated ⁇ acid such as chloro-2-propionic acids. or chloroacetic to take up the case of the two patent applications indicated above.
  • the halogenated compound used in form L can be prepared according to the method described by SINAY et al (J. Biol. Chem., 1972, 247, 391). Using the appropriate halogen acids, it is possible to prepare all the derivatives corresponding to the different meanings of R. Thus, to introduce a group R with 4 carbons, it is possible to use the salts or esters of chloro-2-butyric acid.
  • the resulting compound in which an amino group is in position 2 of the glucopyranoside ring, can then be again subjected to an acylation treatment, under traditional conditions, with an appropriate acylating agent corresponding to the group R which it is desired to introduce.
  • an appropriate acylating agent corresponding to the group R which it is desired to introduce.
  • acylating agent it is possible in particular to use anhydrides or acid chlorides.
  • substitutions in position 1, 4 and 6 can be carried out by methods which have been described previously and which are traditional in sugar chemistry. When the envisaged substituents are different from each other, as many successive substitution reactions will be carried out as there are distinct substituents. During these reactions, positions which must not be substituted or those which must be the subject of another substitution are temporarily protected by blocking groups according to the usual modes.
  • the blocking groups initially present in the case where one starts, as indicated above, from benzyl-2-acetamido-4, 6-O-benzylidene-2-deoxy-D-glucopyranoside, are eliminated for example by action of acetic acid (60% 1 hour at reflux) and catalytic hydrogenation, as described for example by MERSER et al. (Biochem. Biophys. Res. Commun., 1975, j56, 1316), or by catalytic hydrogenation according to the method of LEFRANCIER et al. (Int. J. Peptide Protein Res .; 1977, 9, 249).
  • glycopeptide syntheses can be carried out either by fixing a first amino acid to the muramyl group, then by fixing the second amino acid to the compound thus obtained, and so on, step by step. It is also possible to separately prepare the entire amino acid peptide chain by amino acid and to attach it to the muramyl group. It is finally possible to choose intermediate processes in which fragments of the chain are prepared, then either to assemble these fragments together to form the complete chain which is then attached to the muramyl group, or to attach a first fragment to the muramyl group, then a second to the product thus obtained, etc. The choice of the sequence is mainly guided by reasons of convenience or efficiency.
  • substitutions Y and Z are advantageously carried out on the glutamyl group before the synthesis of the chain.
  • n is different from O, that is to say when one or more aminoacyl groups complete the peptide chain, the group Z is first attached to the terminal aminoacyl before it is integrated into the peptide chain.
  • Peptide syntheses are carried out according to traditional methods.
  • the activation methods for carboxyls can be used, such as the so-called mixed anhydride method.
  • the peptide synthesis is carried out using a compound of the carbodiimide type such as N, N '-dicyclo-hexylcarbodiimide or equivalent carbodiimides.
  • a review of traditional peptide synthesis modes can be found in J.H. JONES, Chemistry and Industry, 723 (1974).
  • Scheme (I) represents a typical sequence of reactions leading to the obtaining of peptide derivatives corresponding to the AZ part of the general formula (I).
  • An activated ester BOC-A ..- 0R "(succinimide ester, p-nitrophenyl ester, etc.) of an amino acid N- protected (such as for example by the tert-butyloxycarbonyl designated by BOC, or any other suitable group temporary protection of the amino function, used in peptide synthesis) is subjected either to an alcoholysis by a chain alcohol of more than 4 carbons in the presence of imidazole, as catalyst (as indicated by BODANZKY et al., J. Org.
  • an N-protected derivative of an amino acid such as BOC-A'-COOH is selectively reduced to its amino alcohol derivative BOC-A'-CHiffOH according to well known methods.
  • the amino acid can also similarly be reduced to its corresponding amino alcohol, then selectively acylated on its amino function according to methods commonly used in peptide synthesis.
  • the alcohol function thus created can then be esterified by an activated ester (succinimide ester, p-nitrophenyl ester, etc.) of a fatty acid with a chain of more than 4 carbons (R '-COOR "), in the presence of imidazole used as catalyst (as indicated by BODANZKY et al., J. Org. Chem., 1977, 42, 149)
  • This ester can also be made from chloride, anhydride or imidazolide of l fatty acid
  • the sequence of reactions is essentially that described above for the variant of scheme (I).
  • Scheme (II) represents reaction sequences leading to the production of glycopeptide derivatives.
  • a derivative (1) with R .. benzyl radical described by
  • the N-acetyl group can be hydrolysed as always described by GROSS and JEANLOZ, to result in the derivatives of formula (2).
  • the derivatives (2) can then be N-acylated selectively by the action of anhydride of carboxylic acids to result in the derivatives of formula (3).
  • the derivatives of formula (4) can be obtained from the previous ones according to the method described by OZAWA and JEANLOZ (J. Org. Chem-, 1965, 30, 448), using an L- ⁇ -chloroalkanoic acid.
  • the derivatives of formula (4) are coupled with a dipeptide derivative of general formula HXD-Glu (OBzl) -OY, hydrochloride.
  • X corresponds to an amino acid
  • Y for example to an amino-, hydroxy- radical, methylamino-, methoxy- or glycyl-amide.
  • These various peptide derivatives are prepared according to the methods described by LEFRANCIER et al. (Int. J- Peptide Protein Res., 1977, 9, 249, and Int. J. Peptide Protein Res., 1978, in press).
  • the coupling methods used to obtain the glycopeptide derivatives of formula (5) are also described in the articles cited above. However, both in the synthesis of dipeptide derivatives and in that of the derivatives of formula (5), any coupling method used in peptide synthesis can be used.
  • the catalytic hydrogenation of the compounds of formula (5) is carried out in a traditional manner (LEFRANCIER et al., Int. J. Peptide Protein Res., 1977, 9_, 249) to result in the compounds of formula (6).
  • the derivatives of formula (6) are coupled, for example according to * the method described below in detail for the variant (point d), page 71) of preparation of the decyl ester of MDP-L-alanine, using of a carbodiimide and of hydroxybenzotriazole, with one of the derivatives of general formula H- (A) -Z hydrochloride whose scheme (I) gives the synthesis sequence.
  • the compounds of formula (7) are obtained.
  • the derivatives of formula (5) undergo a selective debenzylidenation as described by MERSER et al. (Biochem. Biophys. Res. Commun., 1975, 66, 1316) to give the derivatives of formula (8).
  • the selective acylation of the primary hydroxyl in position 6 of the saccharide residue can then be done directly by the action of a small excess of anhydride of carboxylic acids or acylimidazole.
  • Derivatives of formula (9) are obtained.
  • the derivatives of formula (9) can be synthesized according to a completely different sequence (scheme IV, formula 4) similar to that developed by KUSUMOTO et al. (Tetrahedron Letters, 1976, 47, 4237), from the specific synthesis of the primary alcohol of the saccharide residue.
  • the derivatives of formula (8) are diacylated on the two hydroxyls in positions 4 and 6 of the saccharide residue by the action of an excess of carboxylic acid anhydride, then subjected to a catalytic hydrogenation carried out as usually in the presence of 5% palladium on carbon, to obtain the compounds of formula (13). After coupling with the remainder (A) Z, as before, the compounds (14) according to the invention are obtained.
  • a particular method of preparation of these derivatives consists in making the ⁇ -p-nitrophenyl ester of the blocked peptide fragment BOC-XD-Glu-OY, then in carrying out the alcoholysis with a chain alcohol of more than 4 carbons in pre - Seence of imidazole as catalyst (as indicated by BODAN-ZKY et al., J. Org. Chem., 1977, £ 2, 149).
  • the derivative obtained is coupled with a suitably protected saccharide derivative corresponding to formula (1) (Scheme III) to result in the derivatives of formula (2) according to the method described below in detail in points a), b) and c) for the preparation of the decyl ester of MDP-L-alanine or according to the methods described in MERSER et al. (Biochem. Biophys. Res. Commun., 1974, 466, 1316), LEFRANCIER et al. (Int. J. Peptide Protein Res., 1977, 9, 249, and Int. J. Peptide Protein Res., 1978, J, 289).
  • the compounds of formula (3) are obtained.
  • the derivatives of formula (2) undergo a selective debenzylidenation as described by MERSER et al. (Biochem. Biophys. Res. Commun-, 1975, 66, 1316) to give the derivatives of formula (4).
  • the selective acylation of the primary hydroxyl in position 6 of the saccharide residue can be done directly by action of a small excess of anhydride, or acyl-imidazole of carboxylic acid.
  • the derivatives of formula (5) are thus prepared (if R 1 is a benzyl radical, it can be removed by a catalytic hydrogenation carried out as usual in the presence of 5% palladium on carbon). These derivatives can be synthesized according to a completely different sequence (scheme IV, formula (5)) similar to that developed by KUSUMOTO et al. (Tetrahedron Letters, 1976, 47, 4237).
  • the derivatives of formula (4) are diacylated on the hydroxyls in position 4 and 6 of the saccharide residue by the action of an excess of carboxylic acid anhydride to finally obtain the compounds of formula (7) (subject optionally to a catalytic hydrogenation carried out as usual in the presence of 5% palladium on carbon, if R 1 is initially a benzyl protective radical).
  • the invention also relates to modes of use of the compounds corresponding to the preceding definitions, in particular as a reagent or as an active substance in pharmaceutical compositions.
  • the invention relates to biological reagents, for example standard immunological adjuvants, which can be formed using the compounds according to the invention, in particular with a view to studying the possible adjuvant properties of substances under study, in comparison with such standard adjuvants or, on the contrary, as an agent capable of opposing certain effects linked to the administration of immunosuppressive substances.
  • the invention relates to medicaments containing as active principle at least one of the compounds according to the invention, this medicament being applicable as a regulator of the immune response of the subject to which it is administered.
  • immunogenic agents can be natural or synthetic, and require the use of an agent stimulating the immune system, either that the immunogenic agent is weak by nature, or that it is strong and can be used at very low dose, or that the immunogenic character has been reduced, for example during previous modifications or purifications.
  • the use of the immunoregulatory compounds according to the invention is useful whenever the immunogenic agent does not allow a sufficient response to be induced.
  • the invention relates more particularly still to the application of the compounds in question to the amplification of the immunogenic effect of active principles of vaccines administered to a host, animal or human, in particular in the case where these vaccinating principles belong to the categories of immunogenic agents mentioned above.
  • the invention also also relates to pharmaceutical compositions, the active principle of which consists of at least one of the compounds according to the invention, in combination with the pharmaceutical vehicle suitable for the mode of administration. required or usable, having regard to the nature of the vaccinating principle used.
  • the invention applies in particular to those of vaccinating agents whose immunogenic character is strong but which are difficult to use in normal times due to excessive toxicity or undesirable side effects. It has been confirmed that the adjuvants according to the invention are capable of effectively compensating for the loss of the immunogenic effect which would normally result from a dilution or a reduction in the doses used, in particular with the aim of reducing the toxicity or the aforementioned side effects in a corresponding proportion, and without adversely influencing these latter phenomena.
  • the same effects are observed in the case of strong vaccinating agents whose immunogenic character has been reduced, in particular by thorough purifications, insofar as this proves to be necessary for the corresponding reduction in their harmful toxic or secondary effects.
  • This is in particular the case with the vaccinating principles constituted by bacterial or viral toxoids or, in general, by the vaccinating principles constituted by only part of the constituents initially contained in the bacteria or viruses against which protection is sought.
  • the invention applies to any antigen having undergone chemical or physical transformations aiming to eliminate or modify the parts of the antigen which are responsible for its harmful side effects while preserving the parts which are origin of its immunogenic properties.
  • the invention also relates to the application of the compounds according to the invention for the treatment of infectious diseases.
  • the products according to the invention are clearly distinguished from the antibiotics usually used.
  • the products according to the invention unlike antibiotics, have no bactericidal or bacteriostatic effect in vitro. On the other hand, they can activate the isolated macrophages in vitro and their action in vivo is manifest as will be seen in the examples of pharmacological tests.
  • the action is not limited to certain varieties of microorganisms. This is explained, as we have seen, by the fact that their activity is not direct but develops through the immune defense mechanisms not specific to the host, mechanisms which their administration stimulates and amplifies. This difference in action compared to antibiotics makes these products all the more interesting because they can be used against pathogenic germs that have become resistant to antibiotics.
  • the mode of action of the products according to the invention brings them close to known anti-infectious compounds such as BCG or lipopolysaccharides and as such can be used successfully for the treatment of infections without having the disadvantages , including toxicity, which limit or prohibit the use of LPS or BCG.
  • the application of the products according to the invention includes both the treatment of diseases caused by microorganisms with extracellular growth such as Klebsiella (or even in particular Pseudomonas, staphylococci, streptococci) as that of microorganisms with intracellular growth (Listeria , mycobacteria, corynobacteria ).
  • compositions according to the invention are useful for the treatment or prevention of infectious diseases of bacterial or parasitic origin, or for the inhibition of tumor conditions.
  • the adjuvants according to the invention can be administered to the host - animal or human being - in any way suitable for obtaining the desired effect.
  • the administrations of the immunoregulatory principle, in particular adjuvant, and of the immunogenic agent, in particular of the vaccinating antigen, can be envisaged simultaneously or separately, in the latter case possibly delayed in time, possibly still by similar routes of administration or different (e.g. parenteral and oral routes respectively or vice versa).
  • the invention naturally also relates to the various pharmaceutical compositions into which the compounds according to the invention can be incorporated, where appropriate in combination with other active substances.
  • the compounds I are advantageously combined with immunogenic agents, whether they are, for example, immunogenic agents used at very low doses, or weak immunogenic agents.
  • compositions consist of injectable solutions or suspensions containing an effective dose of at least one product according to the invention.
  • these solutions or suspensions are produced in an isotonic sterilized aqueous phase, preferably saline or glucose.
  • the invention relates more particularly to such suspensions or solutions which are capable of being administered by intradermal, intramuscular or subcutaneous injections. cutaneous, or even by scarification, and in particular pharmaceutical compositions in the form of liposomes, the constitution of which will be explained below.
  • compositions which can be administered by other routes, in particular by oral or rectal route, or also in the form of aerosols intended to come into contact with mucous membranes, in particular the ocular, nasal, pulmonary or vaginal mucous membranes.
  • compositions in which at least one of the compounds according to the invention is associated with pharmaceutically acceptable excipients, solid or liquid, suitable for constituting oral, ocular or nasal forms, or with excipients adapted to the constitution of forms of rectal administration, or also with gelatinous excipients for vaginal administration. It also relates to isotonic liquid compositions containing at least one of the products according to the invention, suitable for administration on the mucous membranes, in particular ocular or nasal. Finally, it relates to compositions formed from pharmaceutically acceptable liquefied gases, of the "propellent" type, in which the products according to the invention are dissolved or kept in suspension, and the expansion of which causes dispersion in an aerosol.
  • the invention also consists of a method for strengthening the immune defenses of the host, comprising administering to it an effective dose of at least one of the products according to the invention, in one of the administration forms which has was mentioned above.
  • doses liable to induce an action mention will be made of doses of 10 to 1000 ⁇ g per kg of body, for example of 50 ⁇ g, when the administration is carried out parenterally, or of a dose from 200 to 20,000 ⁇ g per kg of body, for example from 1000 ⁇ g, for other modes of administration, such as for example the oral route.
  • Liposomes are generally produced from phospholipids or other lipid substances and are formed by hydrated liquid crystals mono or multilamellar. They are usually used in dispersion in an aqueous medium.
  • liposomal forms could lead to an increase in the anti-infectious activity in the tests carried out according to the protocol described below to detect the activity vis-à-vis infection with Klebsiella.
  • compositions according to the invention are presented in the form of liposomes.
  • liposomes we operate in the traditional way. All physiologically acceptable and metabolizable non-toxic lipids capable of forming liposomes can be used.
  • lipids are phospholipids, and in particular natural or synthetic phosphatidyl-cholines (lecithins). Phospholipids can also be used, and among these in particular phosphatidyl-serines, phosphatidyl-inositides or sphingomyelins. Other lipids can also be used, which have been described in particular by WR HARGREAVES and DW DEAMER (Conference on liposomes and their Uses in Biology and Medicine, Sept. 1416, 1977, New York Acad. Sci.) And in the article from Biochem. 1978, 18, p. 3759.
  • the initial dispersion is obtained from a thin film of lipid formed on the wall of a container from a solution of these lipids which had previously been introduced into this container and after evaporation of the solvent.
  • the aqueous phase is then introduced into the container and the dispersion of the lipids within the aqueous solution is formed by agitation of the medium, and usually using ultrasound.
  • a suspension of liposomes having a milky appearance is obtained. It seems that, at this stage, the liposomes are formed of a series of concentric double lipid layers alternating with aqueous compartments.
  • the liposomes thus obtained can be separated from the aqueous medium, for example by centrifugation.
  • the liposomes contained in the centrifugation pellet can then be washed, so as to remove any active substances not incorporated in the liposomes.
  • These can then be resuspended in the buffer solution, in which they can be stored, especially in the cold, preferably at a temperature of the order of + 4 ° C.
  • Such liposomes are stable for extended periods.
  • the initial lipid composition also contains a stabilizing agent, for example cholesterol.
  • a stabilizing agent for example cholesterol.
  • an amphiphilic agent can also be used, which can be added to the initial lipid dispersion in order to allow the final production of iiposomes carrying electrical charges.
  • agents include, for example, diketyl phosphate or phosphatidyl serine, to the extent that one wishes to obtain negatively charged liposomes, or stearylamine, if one wishes to obtain positively charged liposomes.
  • an aqueous buffer solution is added and the mixture is stirred to obtain a dispersion of the lipid film in the aqueous phase leading to the formation of liposomes.
  • the muramyl peptide type compound depending on its solubility characteristics, is introduced either with the lipid phase (lecithin-cholesterol) or into the aqueous buffer solution.
  • the molar proportions of the constituents of the lipid phase are advantageously between 8: 1 and 1: 1 (lecithin: cholesterol).
  • the aqueous phase is buffered so that its pH is close to neutral.
  • a buffer solution for example 0.9% phosphate-NaCl.
  • compositions in the form of liposomes according to the invention may contain other substances compatible with this particular form. They can in particular, to constitute vaccinating compositions, contain immunogenic agents.
  • compositions in the form of liposomes can contain, in addition to the compound of the muramyl peptide type, all the constituents: stabilizers, preservatives, excipients or other active substances capable of being used in the solutions or emulsions injectable presented previously for administration of the muramyl-peptide compounds, provided that they are compatible with this liposome form.
  • Contents of the order of 1 mg of muramyl peptide per 35 mg of lipids are advantageously used.
  • the reaction mixture is diluted with an equal volume of 0.1 N acetic acid and the solution obtained is passed through a column of AG50 WX2, previously equilibrated in the acetic acid mixture 0, 1 N-dimethylformamide (50/50). After concentrating the fractions containing the product, the syrupy residue obtained is taken up in a volume of 5 to
  • N-acetyl ester of N-acetyl-muramyl-L-alanyl-D-isoglutaminyl-L-alanine a) p-toluene sulfonate of the n-butyl ester of L-alanine 891 mg (10 mmol) L-alanine and 2 g (10.5 mmol) of p-toluene sulfonic acid are dissolved in 10 ml of nbutanol and 2 ml of benzene. The reaction mixture is heated at reflux (110-120 ° C) for 3 hours in a soxhlet apparatus, benzene being added regularly.
  • the reaction mixture is concentrated to dryness, taken up in a 0.1 M solution of acetic acid and passed over a column of ion exchange resin sold by the company BIORAD under the name AG-50-W-X2 (8 to 10 ml).
  • the interesting fractions are combined, lyophilized, taken up in a 2.10 -3 M solution of acetic acid and passed through a column of ion exchange resin sold by the company BIORAD under the name AG-1-X2.
  • the interesting fractions are combined and freeze-dried.
  • the product is then chromatographed on a column of silica gel (8 g) in the methanol-chloroform mixture (1: 4). After lyophilization, 158 mg of product is obtained, ie a yield of 36.4%.
  • the product features are: for C 26 H 45 N 5 O 12 , 0.15 CHCl 3 , 0.34 H 2 O
  • reaction mixture is brought to 0 ° C., and 2.5 ml of a 2.5 M KHCO 3 solution are added thereto, then 50 ml of water.
  • the product is extracted with ethyl acetate, and the extract is successively washed with 10% citric acid, with water, with a 3 M NaHCO solution, then with water.
  • reaction mixture After one night at -15 ° C, the reaction mixture is brought to 0 ° C, then added with 3 ml of a 2.5 M KHCO 3 solution . After 1 hour, 100 ml of water are added and the product is extracted with ethyl acetate, the organic phase is washed with 10% citric acid, with water, with a molar solution of KHCO 3 , then with water. It is dried over MgSO 4 , filtered, concentrated to give an uncrystallized residue. 1.22 g of product are obtained, ie a yield of 90.65.
  • D-glutamic acid are hydrogenated in 100 ml of glacial acetic acid, for 41 hours, in the presence of Pd 5% on carbon (1.9 g). After filtration of the catalyst, the acetic acid is evaporated and the residue taken up in 4 ml of chloroform, chromatographed on a column of silica gel (MERCK-type C) in the chloroform-methanol-acetic acid mixture (7: 1: 0 , 2). The fractions containing the product are combined, concentrated, taken up in water and lyophilized.
  • MERCK-type C silica gel
  • N-methylmorpholine and 0.33 ml (2.5 mmol) of isobutyl chloroformate After 3 minutes, a solution of 558 mg (2.2 mmol) of ⁇ -methyl diester hydrochloride, ⁇ -n-butyl acid of D-glutamic acid and 0.24 ml (2.2 mmol) of N-methylmorpholine , in 5 ml of dimethylformamide, cooled to -15 ° C, is added. After one night at -15 ° C, the reaction mixture is brought to 0 ° C, then added with 3 ml of a 2.5 M KHCO 3 solution . After 1 hour, 100 ml of water are added and the product is extracted with ethyl acetate.
  • Beginyloxycarbonylation carried out by the action of a normal solution of hydrochloric acid in glacial acetic acid allows the title compound to be obtained, c) ⁇ -methyl, ⁇ -n-butyl diester of N-acetyl-muramyl- (1- ⁇ -benzyl-4, 6-O-benzylidene) -L-alanyl-D-glutamic 1.037 g (2.2 mmol) of 1- ⁇ -benzyl-4,6-O-benzylidene-N-acetyl-muramic acid are dissolved in 5 ml dimethylformamide.
  • Lipophilic adjuvants at a rate of 1.0 mg, are introduced with the chloroform phase.
  • the solution is evaporated on a rotary evaporator under vacuum at a temperature below 30 ° C so as to obtain a thin film of lecithin + cholesterol on the inside wall of the flask.
  • the buffer solution is poured slowly into the flask while maintaining the temperature at 55 ° C.
  • the content is then subjected to gentle stirring at 55 ° C. so as to obtain a liposome suspension containing the envisaged adjuvant. Leave to stand for about 1 hour.
  • the preparation is then subjected to sonication at 0 ° C under nitrogen or argon atmosphere for 30 seconds (0.3 kW).
  • the suspension is further centrifuged at 100,000 g, the pellet is taken up in the phosphate-NaCl buffer. The operation is repeated six times. The pellet finally obtained is taken up in phosphate-NaCl buffer, at the chosen volume.
  • the toxicity of the products according to the invention was studied by parenteral administration on mice. It has been found that the toxic doses are of an order of magnitude much higher than that of the doses at which these products manifest their activity. Thus, the lethal dose 50 of the products according to the invention tested is greater than 5 mg / kg of animal in the adrenalectomized mouse, whose sensitivity to endotoxins is well known.
  • mice Groups of 8 two-month-old Swiss mice receive, by subcutaneous injection (SC), 0.5 mg of antigen constituted by bovine serum albumin (BSA) with 0.1 mg or without the substance tested in isotonic saline.
  • This high dose of antigen because it is at the limit of the paralyzing dose vis-à-vis the immune response, therefore results in a weak or no response to the antigen alone in the controls; it therefore constitutes a severe criterion for demonstrating the activity of an adjuvant substance.
  • the mice receive, by the same route of administration, a booster containing 0.1 mg of the same antigen.
  • the antibody level is determined, six days after the booster, by passive hemagglutination using sheep red cells treated with formalin and covered with the antigen studied according to the method described by AA HIRATA and MW BRANDISS (J. Immunol., 100, 641-648, 1968).
  • the antibody titre represented by the maximum serial dilution agglutinating a given quantity of sheep red cells, reaches a maximum on the 36th day and is established as follows:
  • the ovalbumin (constituting the antigen) at a rate of 1 mg is prepared in 0.1 ml of an emulsion of saline isotonic solution, in an oily phase constituted either by the incomplete Freund's adjuvant (FIA), or by l complete adjuvant (FCA) formed by the FIA to which is added 0.1 mg of whole Mycobacterium smegmatis cells.
  • the compound according to the invention is administered in an amount of 0.05 mg added to the emulsion containing the FIA.
  • the animals are bled.
  • the specific antibody content of ovalbumin is measured by precipitation of the antibody-antigen complex in the equivalence zone.
  • the quantity of protein nitrogen contained in this precipitate is evaluated according to the Folin method.
  • the average values of the antibody contents are indicated in the results table. These values express the quantity, in micrograms of nitrogen precipitable by the antigen, per milliliter of serum.
  • the administration of the product also generates a delayed type hypersensitization in the subject treated with respect to the antigen, hypersensitization which is revealed by the skin test.
  • hybrid mice C57B1 / 6 x AKR F1 used at the INSTITUT PASTEUR were used, from strains from the breeding of C.N.R.S. at ORLEANS.
  • Infection with Klebsiella pneumoniae strain of capsular type 2, biotype d, is made from a culture of 16 hours in the medium for pneumococci (n ° 53515, INSTITUT PASTEUR).
  • the infecting dose is 2.10 4 Klebsiella; it is administered intramuscularly.
  • test product is carried out intravenously in 0.2 ml of pyrogen-free physiological solution, the controls receiving the solution alone. It is carried out 24 hours before inoculation. The results of these tests are reported in the following table. The percentage of protection indicated is the difference in the percentages of survivors in the treated group compared to the control group.
  • results show a significantly increased protection by applying the Student's t test, for the animals having received the products according to the invention compared to the control animals.
  • the action of the product according to the invention was compared with that of BCG, the antiinfectious properties of which are well known in this field.
  • the action of LPS, Corynebacterium granulosum, and of Mur-NAc-L-Ala-D-isoGln (MDP) was also determined, again by way of comparison.
  • the treatment of mice and inoculation are carried out intravenously.
  • the products injected are in solution or suspension in 0.2 ml of pyrogen-free physiological solution. Witnesses only receive the solute.
  • the dose of Listeria administered in all trials is 1.10 3 units.
  • the tests were carried out by varying the doses of products tested and the time interval separating the treatment from the inoculation of Listeria monocytogens (either 1 or 7 days). The number of mice surviving on the 5th and 10th day following the inoculation is monitored, and the percentage of protection is determined as for the previous tests.
  • the liposomes were prepared as described above. a) Toxicity on the adrenalectomized mouse
  • mice The products, doses administered and effects on mortality of groups of six mice are shown below. Number of dead mice
  • MDP-L-Ala-glyceryl-mycolate liposomes (10 ⁇ g of MDP derivative) 2.07 ⁇ 1.13
  • a second series of tests is carried out on Wistar rats, under the following conditions.
  • the antigen is ovalbumin injected subcutaneously into male Wistar rats in a volume of 0.5 ml at a dose of 0.5 mg.
  • the adjuvant preparations are injected simultaneously at the indicated dose.
  • the animals receive a booster of 0.5 mg of antigen alone per the same way.
  • the sera are taken and tested under the same conditions as in mice with the appropriate antigen.
  • CDM 200 ⁇ g 4.97 ⁇ 0.82
  • the antigen is ovalbumin injected in aqueous solution via the plantar route into male Hartley guinea pigs in a volume of 0.1 ml in each hind leg, at a dose of 1 mg per guinea pig.
  • the adjuvant preparations are injected simultaneously with the indicated doses.
  • the animals receive 0.025 mg of antigen dermally, in a volume of 0.1 ml.
  • the diameter of skin reactions is measured after 48 hours. The animals are bled and the titer measured.
  • results grouped in the following table show, for an equal content of test compound, a significant improvement in the effectiveness for the liposome form compared to the solution.
  • the tests are carried out under the conditions of 5 °). a dose of Listeria monocytogen, known to typically cause cell-type infection.
  • the treatment of mice and inoculation are carried out intravenously.
  • the products are injected in the form of liposomes at the doses indicated.
  • witnesseses receive only isotonic solute.
  • the dose of Listeria administered in all trials is 1.10 3 cells.
  • the tests were carried out by varying the time interval separating the treatment from the inoculation of Listeria monocytogens (either 1, or 4, or 8 days). The number of mice surviving on the 5th and 10th day following the inoculation is monitored, and the percentage of protection is determined as for the previous tests.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Genetics & Genomics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
  • Saccharide Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
PCT/FR1979/000027 1978-03-20 1979-03-20 Nouveaux composes esters de muramyl-peptide et leurs applications dans les compositions pharmaceutiques et reactifs de laboratoire WO1979000802A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7808049 1978-03-20
FR7808049A FR2420545A1 (fr) 1978-03-20 1978-03-20 Nouveaux esters de l'acide n-acetyl-muramyl-aminoacyl-glutamique ou des derives de substitution de celui-ci a proprietes anti-infectieuses et/ou d'adjuvants immunologiques

Publications (1)

Publication Number Publication Date
WO1979000802A1 true WO1979000802A1 (fr) 1979-10-18

Family

ID=9206038

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR1979/000027 WO1979000802A1 (fr) 1978-03-20 1979-03-20 Nouveaux composes esters de muramyl-peptide et leurs applications dans les compositions pharmaceutiques et reactifs de laboratoire

Country Status (3)

Country Link
JP (1) JPS55500167A (enrdf_load_stackoverflow)
FR (1) FR2420545A1 (enrdf_load_stackoverflow)
WO (1) WO1979000802A1 (enrdf_load_stackoverflow)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0221821A3 (en) * 1985-11-01 1988-01-27 Centre National De La Recherche Scientifique (Cnrs) New aerosol composition for in vivo imaging and therapy
US8987263B2 (en) 2002-10-10 2015-03-24 Meir Shinitzky Basic esters of fatty alcohols and their use as anti-inflammatory or immunomodulatory agents
US9969283B2 (en) 2013-09-10 2018-05-15 General Electric Company Battery changing system and method

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6042398A (ja) * 1983-08-18 1985-03-06 Toshiyuki Hamaoka ムラミルジペプチド活性エステル誘導体

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2325387A1 (fr) * 1975-09-29 1977-04-22 Wellcome Found Preparations antigeniques et medicament comprenant ces preparations
DE2710454A1 (de) * 1976-03-10 1977-09-22 Anvar Antiinfektioese methylester, verfahren zu ihrer herstellung und sie enthaltende arzneimittel
FR2349600A1 (fr) * 1976-04-26 1977-11-25 Syntex Inc Nouveaux adjuvants immunologiques
FR2361902A1 (fr) * 1975-12-10 1978-03-17 Ciba Geigy Ag Derives de la glucosamine et leur procede de fabrication

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS52139018A (en) * 1976-03-10 1977-11-19 Anvar Immuno adjuvant and antiinfection adjuvant composed of mainly nnacetyll muramiccllalanyllddglutamic ester or nnacetyllmuramiccllalanylldd isoglutamic ester

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2325387A1 (fr) * 1975-09-29 1977-04-22 Wellcome Found Preparations antigeniques et medicament comprenant ces preparations
FR2361902A1 (fr) * 1975-12-10 1978-03-17 Ciba Geigy Ag Derives de la glucosamine et leur procede de fabrication
DE2710454A1 (de) * 1976-03-10 1977-09-22 Anvar Antiinfektioese methylester, verfahren zu ihrer herstellung und sie enthaltende arzneimittel
FR2349600A1 (fr) * 1976-04-26 1977-11-25 Syntex Inc Nouveaux adjuvants immunologiques

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0221821A3 (en) * 1985-11-01 1988-01-27 Centre National De La Recherche Scientifique (Cnrs) New aerosol composition for in vivo imaging and therapy
US8987263B2 (en) 2002-10-10 2015-03-24 Meir Shinitzky Basic esters of fatty alcohols and their use as anti-inflammatory or immunomodulatory agents
US9969283B2 (en) 2013-09-10 2018-05-15 General Electric Company Battery changing system and method

Also Published As

Publication number Publication date
FR2420545B1 (enrdf_load_stackoverflow) 1981-03-27
JPS55500167A (enrdf_load_stackoverflow) 1980-03-27
FR2420545A1 (fr) 1979-10-19

Similar Documents

Publication Publication Date Title
EP0004512B1 (fr) Composés esters de muramyl-peptide et leurs applications dans les compositions pharmaceutiques et réactifs de laboratoire
EP0035429A1 (fr) Complexe vaccinal contenant un antigène spécifique et vaccin le contenant
EP0089290B1 (fr) Conjugués d'haptènes et de muramyl-peptides, doués d'activité immunogène et compositions les contenant
EP0003833B2 (de) Antigenderivate, Verfahren zu deren Herstellung, diese enthaltende pharmazeutische Präparate
CH640866A5 (fr) Oligomeres de composes du type muramyl-peptide et medicaments les contenant.
EP0015810A1 (fr) N-acétyl-L-(N-méthyl-alanyl)-D-isoglutamine et compositions la contenat, pour l'utilisation en tant que régulateurs des mécanismes immunitaires
EP0013651B1 (fr) Muramyl-peptides fixés sur polymères peptidiques et médicaments les contenant
EP0165123B1 (fr) Dérivés lipophiles de muramylpeptides ayant des propriétés d'activation des macrophages, compositions les contenant et procédé pour les obtenir
EP0006068B1 (fr) Composés du type muramyl-peptide et médicaments les contenant
WO1979000802A1 (fr) Nouveaux composes esters de muramyl-peptide et leurs applications dans les compositions pharmaceutiques et reactifs de laboratoire
FR2862306A1 (fr) Composition vaccinale
CA2063721C (fr) Medicament immunostimulant a base de glycopeptidolipides polaires de mycobacterium chelonae
EP0139554B1 (fr) Dérivés de Muramyl-peptides et de stéroides ayant des propriétés d'activation des macrophages
CA2761917C (fr) Procede de detoxification du lipopolysaccharide (lps) ou du lipide a des bacteries a gram-negatif
WO1992001475A1 (fr) Compositions a base de principes actifs de medicaments hydrophobes solubilisables dans un solvant aqueux
WO2010130899A1 (fr) Vaccin meningocoque a base de lipooligosaccharide (los) et de proteine de neisseria meningitidis
JPS6225679B2 (enrdf_load_stackoverflow)
CH619470A5 (en) Process for the preparation of 2-(2-acetamido-2-deoxy-3-O-D-glucopyranosyl)-D-propionyl-L-seryl-D-iso glutamine and 2-(2-acetamido-2-deoxy-3-O-D-glucopyranosyl)-D-propionyl-L-seryl-D-glu tamic acid
JPH0278623A (ja) インターフェロン誘起剤
JPS632922A (ja) ドラツグキヤリア
JP2002179577A (ja) 抗腫瘍物質及び抗腫瘍剤
CH619469A5 (en) Process for the preparation of the esters of N-acetyl-muramyl-L-alanyl-D-glutamic acid and of N-acetyl-muramyl-L-alanyl-D-isoglutamine
IE48735B1 (en) Muramyl-peptide ester compounds and their application in pharmaceutical compositions and laboratory reagents
CA2216599A1 (fr) Derives et conjugues du mdp presentant une activite stimulatrice de la fonction hematopoietique et composition les contenant
WO2016047509A1 (ja) ペプチド結合リポソーム、細胞傷害性ｔリンパ球活性化剤、及び抗腫瘍ワクチン

Legal Events

Date Code Title Description
AK Designated states

Designated state(s): DK JP