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Conjugates of haptenes and muramyl-peptides, endowed with immunogenic activity and compositions containing them

  • US 4,639,512 A
  • Filed: 03/11/1983
  • Issued: 01/27/1987
  • Est. Priority Date: 03/15/1982
  • Status: Expired due to Term
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First Claim
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1. An immunogenic and apyrogenic conjugate consisting essentially of a hapten covalently linked to a muramyl peptide, which conjugate comprises a molecular weight which does not exceed 5000,wherein the hapten is selected from the group consisting of peptides, glycopeptides, oligosaccharides, lipopeptides, glycolipids, lipids and steroids which are incapable of inducing an immunological response in vivo except when bound to an immunological carrier;

  • and wherein the muramyl peptide part conjugated to the hapten is derived from the muramyl peptide which has the general formula (I);

    ##STR8## in which the following groups, when not covalently linked to the hapten, have the following meaning;

    R5 is a free carboxyl group or amido group, or a carboxyl group esterified by an aliphatic alcohol possessing from 1 to 10 carbon atoms, or a carboxylgroup substituted by an amino acid possessing itself a free carboxyl group or an amidated group or a carboxyl group esterified by an aliphatic alcohol possessing from 1 to 10 carbon atoms,R is a hydrogen or a methyl group,R2 is an acetamido or a glycoyl-amido group,R1 is either --NH2, or OH, or a radical comprising at the most 10 carbon atoms, corresponding to an alkyl, aryl, arylalkyl or alkylaryl group, optionally bearing hydroxyl-, amido, carboxamido-, sulfonamido-, ether, thioether, ester- or thioester substituentsR4 is a hydroxyl or an oxyacyl group comprising from 1 to 4 carbon atoms,X is an aminoacyl residue of the group comprising;

    alanyl, arginyl, asparagyl, aspartyl, cysteinyl, glutaminyl, glutamyl, glycyl, histidyl, hydroxy-prolyl isoleucyl, leucyl, lysyl, methionyl, phenylalanyl, prolyl, seryl, threonyl, tryptophanyl, tyrosyl, valyl and aminobutyryl,Z is a group substituting the position at C-6 of muramic acid, and which has the following general formula (II);

    

    space="preserve" listing-type="equation">--R.sub.6 --(R.sub.7).sub.xin which x=0 or 1 and in which,if x=0,R6 is hydroxyl or amino and,if x=1,R6 is hydroxyl group or amino, carboxamido, sulfonamide ether or thioether, ester or thioester,R7 then being a chain of --CH2, --CH═

    CH--, --S--, --CO-- or NH groups, --CH2 --;

     --CH═

    CH--, or NH-groups, said groups being optionally replaced or substituted by aryl groups or by carboxlyic, amino, sulfhydryl or hydroxyl groups, or by alkyl groups including up to 5 carbon atoms or by alkylaryl groups, arylalkyl including in all up to 8 carbon atoms or by heterocyclic groups including up to six carbon atoms and one or two oxygen, nitrogen or sulfur atoms, said alkylaryl or arylalkyl groups optionally containing carbonyl groups or being optionally substituted by carboxyl, amino, sulfhydryl or hydroxyl groups, said heterocyclic groups being themselves optionally substituted by alkyl groups which can contain up to 5 carbon atoms, carboxyl, amino, sulfhydryl or hydroxyl, the above said R7 group having none the less a length not exceeding that of an n-decyl hydrocarbon chain,Y is a free or amidated carboxyl group, or an ester group comprising up to 10 carbon atoms, or substituted by an amino acid or is a group of formula (III);

    

    space="preserve" listing-type="equation">--R.sub.8 --(R.sub.9).sub.x                                (III)in which x equals 0 or 1 andin which R8 is an amide or ester linkage when x is equal to zero, or when x is different from zero, R8 is a carboxamido-, ester- or thioester-group, R9 then having the same meaning as R7 ;

    and which conjugate when administered in vivo elicits only antibodies or a cell mediated immunological response involving the hapten.

      

    

  

  
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