FR2482960A2 - Immunostimulant and vaccine adjuvant tetra- and penta:peptide(s) - contg. fatty acid acyl gps. e.g. N-alpha-N,N-lauroyl-L-alanyl gamma-D-glutamyl N-epsilon-glycyl-L-lysine - Google Patents

Abstract

Tetra- and penta-peptides, based on the parent applicn. 79.16845, having formula (II) and their salts are new R-NH-CH(CH3)-CO-NH-CH(-CO-R1) -CH2-CH2-CO-NH-CHR2-(CH2)3- CHR4-NH-R3 (II) R is H or a fatty acid resdue (pref. 1-45C alkanoyl (opt. substd. by hydroxy, phenyl or cyclohexyl), 3-30C alkenoyl opt. contg. further double bonds or a mycolic acid residue); R1 is hydroxy, amino or 1-4C alkoxy, opt. substd. by phenyl or nitrophenyl; one of R2 and R4 is H, carboxy, carbamoyl, 2-5C alkoxycarbonyl (opt. substd. by phenyl or nitrophenyl), n-carbonyl-glycyl or N-carbonyl-alaryl (opt. esterified by 1-4C alkyl, opt. substd. by phenyl or nitrophenyl) and the other is H, carboxy, carbamoyl or 2-5C alkoxycarbony, (opt. substd. by phenyl or nitrophenyl); R3 is H, a fatty acid residue or glycyl or D-alonyl with the amino gp. substd. by a fatty acid . (II) are immunostimulants and adjuvants (vaccines) which increase hypersensitivity reactions and/or increase prods. of circulating antibodies w.r.t. antigens with which they are admin.. They stimulate, non-specifically, the defince mechanisms against certain infections and tumours, e.g. histeria monocytogenes intracellular bacterial infections in mice. Activity tests are mentioned.

Description

éventuellement leurs sels, leur préparation et les médicaments qui les contiennent.In the main patent, new tetra- or pentapeptides of general formula have been described:

possibly their salts, their preparation and the medicines containing them.

In the general formula (I),
R represents a hydrogen atom or a fatty acid residue
R1 represents a hydroxy or amino radical,
R2 represents a hydroxy radical or an N-glycyl or ND alanyl residue,
R3 represents a hydrogen atom or a fatty acid residue or a residue
glycyl or D alanyl whose amine function is possibly subs
staggers with a fatty acid residue, it being understood that at least one of the
symbols R2 and R3 represent a glycyl residue or D alanyl and that one
at least of the symbols R and R3 represents or contains a residue of acid
bold, and
R4 represents a hydrogen atom or a carbamoyl radical.

 In the general formula (I), the alanine linked to glutamic acid is in L form, the glutamic acid is in D form, lysine, when R4 represents a hydrogen atom, is in L form and the 2,6-diamino pimelamic acid, when R4 represents a carbamoyl radical, is in the form D, D t L, L; DD, LL (racemic) or D, L (meso).

 By fatty acid residue is meant an alkanoyl radical containing 1 to 45 carbon atoms optionally substituted by a hydroxy, phenyl or cyclohexyley radical an alkenoyl radical containing 3 to 30 carbon atoms and which may contain more than one double bond or a residue of mycolic acid as found in the structure of the bacterial wall of mycobacteria, Nocardia or corynebacteria.

 The products of general formula (I) are particularly useful as immunological adjuvants and as immunostimulants.

 According to the main patent, the tetra- or pentapeptides of general formula (I) can be obtained according to the methods generally used in peptide synthesis; the various reactions are brought into play after blocking by suitable protective groups of the amine or acid functions which must not participate in these reactions, and followed by the unblocking of these functions.

dans laquelle les symboles R et R3 sont définis comme dans le brevet principal, R1 représente un radical hydroxy, amino ou alcoyloxy contenant 1 à 4 atomes de carbone, éventuellement substitué par un radical phényle ou nitrophényle, et l'un des symboles R2 ou R4 représente un atome d'hydrogène ou un radical carboxy, carbamoyle, alcoyloxycarbonyle dont la partie alcoyle qui contient 1 à 4 atomes de carbone est éventuellement substituée par un radical phényle ou nitrophényle, ou un radical N-carbonylglycyle (-OO-NH-CH2-OOOH) ou N-carbonyl D alanyle e [-CO-NH-CH(CH3)-COOH] éventuel- lement estérifié par un radical alcoyle contenant 1 à 4 atomes de carbone (éventuellement substitué par un radical phényle ou nitrophényle) et autre représente un atome d'hydrogène ou un radical carboxy, carbamoyle ou alcoyloxycarbonyle dont la partie alcoyle qui contient 1 à 4 atomes de carbone est éventuellement substituée par un radical phényle ou nitrophényle, étant entendu que les symboles R2 et R4 ne peuvent pas représenter simultanément un atome d'hydrogène et que, lorsque R1 représentant un radical hydroxy ou amino et R4 représentant un atome d'hydrogène ou un radical carbamoyle, R2 ne peut pas représenter un radical carboxy,
N-carbonylglycyle ou N-carbonyl D alanyle, et étant entendu que l'un des symboles R2, R3 et R4 représente ou contient un reste glycyle ou D alanyle et que l'un au moins des symboles R et R3 représente ou contient un reste d'acide gras.This addition concerns the new tetra- and pentapeptides of general formula

in which the symbols R and R3 are defined as in the main patent, R1 represents a hydroxy, amino or alkyloxy radical containing 1 to 4 carbon atoms, optionally substituted by a phenyl or nitrophenyl radical, and one of the symbols R2 or R4 represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms is optionally substituted by a phenyl or nitrophenyl radical, or an N-carbonylglycyl radical (-OO-NH-CH2- OOOH) or N-carbonyl D alanyl e [-CO-NH-CH (CH3) -COOH] optionally esterified by an alkyl radical containing 1 to 4 carbon atoms (optionally substituted by a phenyl or nitrophenyl radical) and other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which containing 1 to 4 carbon atoms is optionally substituted by a phenyl or nitrophenyl radical, it being understood that the symbols R2 and R4 can not cannot simultaneously represent a hydrogen atom and when R1 representing a hydroxy or amino radical and R4 representing a hydrogen atom or a carbamoyl radical, R2 cannot represent a carboxy radical,
N-carbonylglycyle or N-carbonyl D alanyl, and it being understood that one of the symbols R2, R3 and R4 represents or contains a glycyl or D alanyl residue and that at least one of the symbols R and R3 represents or contains a residue fatty acid.

 In the general formula (II), the alanine linked to glutamic acid is in L form, the glutamic acid is in D form, lysine or its derivatives, when one of the symbols R2 or R4 represents a d atom. hydrogen is in L form and 2,6-diamino pimelic acid or its derivatives, when R2 and R4 represent a carboxy radical or a derivative of the acid function, is in D, D form; L, L; DD, LL (radical) or D, L (meso).

dans laquelle R5 représente un atome d'hydrogène, un reste d'acide gras ou un groupement protecteur de la fonction amine tel que le radical
benzyloxycarbonyle ou t.butoxycarbonyle, R6 représente un atome d'hydrogène ou un radical méthyle étant entendu dans ce cas que 12alanine est sous forme D, et R' représente un radical hydroxy ou un radical alcoyloxy contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle sur un tri-ou tétrapeptide de formule générale ::

dans laquelle N représente un reste d'acide gras ou un groupement protecteur de la fonction amine tel que le radical benzyloxycarbonyle ou t.butyloxycarbonyle, R8 représente un radical hydroxy ou amino ou un radical alcoyloxy contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle, l'un des symboles R4 ou Rg représente un atome d'hydrogène ou un radical carboxy, carbamoyle ou alcoyloxycarbonyle dont la partie alcoyle contient i à 4 atomes de carbone et est éventuellement substituée par un radical phényle ou nitrophényle ou un reste N-carbonylglycyle ou Nccarbonyl D alanyle éventuellement estérifié par un radical alcoyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle et l'autre représente un atome d'hydrogène ou un radical carboxys carbamoyle ou alcoyloxycarbonyle dont la partie alcoyle contient t à 4 atomes de carbone et est éventuellement substituée par un radical phényle ou nitrophényle, étant entendu que R4 et R9 ne peuvent pas représenter simultanément un atome d'hydrogène, et R10 représente un atome d'hydrogène ou un reste d'acide gras ou un groupement protecteur de la fonction amine tel que le radical benzyloxycarbonyle ou t.butyloxycarbonyle ou un radical glycyle ou D alanyle dont la fonction amine est éventuellement substituée par un reste d'acide gras ou par un groupement protecteur de la fonction amine tel que le radical benzykxycarbonyle ou t.butyloxycarbonyle, étant entendu que l'un au moins des radicaux R7 ou Rlo représente ou contient un reste d'acide gras et que, R4 et R9 étant définis comme précédemment,
R10 représente un atome d'hydrogène, et que l'un des symboles R4 ou Rg représentant un radical carboxy, l'autre représente un atome dthydrogène ou un radical carbamoyle ou alcoyloxycarbonyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle,
R10 représente un reste d'acide gras ou un groupement protecteur de la fonction amine, un reste glycyle ou D alanyle dont la fonction amine est substituée par un reste d'acide gras ou par un groupement protecteur de la fonction amine, suivie éventuellement du remplacement des radicaux
R5, R7 et/ou R10 (lorsqu'ils représentent ou contiennent un groupement protecteur de la fonction amine) par un atome d'hydrogène et du remplacement des radicaux R' et R8 (lorsqu'ils représentent un radical alcoyloxy contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle) par un radical hydroxy et des radicaux R4 et/ou R9 (lorsqu'ils: représentent ou contiennent un radical alcoyloxycarbonyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle) par un radical carboxy de telle manière que dans le produit final, R1 représentant un radical hydroxy ou amine, R4 représentant un atome d'hydrogène ou un radical carbamoyle R2 soit différent d'un radical carboxy, N-carbonylglycyle ou N-carbonyl D alanyle.According to the present addition, the new products of general formula (II) can be obtained by the action of an amino acid of general formula

in which R5 represents a hydrogen atom, a fatty acid residue or a group protecting the amine function such as the radical
benzyloxycarbonyl or t.butoxycarbonyl, R6 represents a hydrogen atom or a methyl radical being understood in this case that the alanine is in D form, and R 'represents a hydroxy radical or an alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical on a tri- or tetrapeptide of general formula:

in which N represents a fatty acid residue or a group protecting the amine function such as the benzyloxycarbonyl or t.butyloxycarbonyl radical, R8 represents a hydroxy or amino radical or an alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, one of the symbols R4 or Rg represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical in which the alkyl part contains i to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical or a N-carbonylglycyl or Nccarbonyl D alanyl residue optionally esterified by an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carbamoyl or alkyloxycarbonyl carboxyl radical of which the alkyl part contains t to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, etan t understood that R4 and R9 cannot simultaneously represent a hydrogen atom, and R10 represents a hydrogen atom or a fatty acid residue or a group protecting the amine function such as the benzyloxycarbonyl or t.butyloxycarbonyl radical or a glycyl or D alanyl radical whose amine function is optionally substituted by a fatty acid residue or by a group protecting the amine function such as the benzykxycarbonyl or t.butyloxycarbonyl radical, it being understood that at least one of the radicals R7 or Rlo represents or contains a fatty acid residue and that, R4 and R9 being defined as above,
R10 represents a hydrogen atom, and that one of the symbols R4 or Rg represents a carboxy radical, the other represents a hydrogen atom or a carbamoyl or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl radical or nitrophenyl,
R10 represents a fatty acid residue or a protecting group for the amine function, a glycyl or D alanyl residue in which the amine function is substituted by a fatty acid residue or by a protecting group for the amine function, optionally followed by replacement radicals
R5, R7 and / or R10 (when they represent or contain a protective group for the amine function) with a hydrogen atom and the replacement of the radicals R 'and R8 (when they represent an alkyloxy radical containing 1 to 4 atoms carbon optionally substituted by a phenyl or nitrophenyl radical) by a hydroxy radical and R4 and / or R9 radicals (when: they represent or contain an alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical) with a carboxy radical such that in the final product, R1 representing a hydroxy or amine radical, R4 representing a hydrogen atom or a carbamoyl radical R2 is different from a carboxy, N-carbonylglycyl or N-carbonyl D alanyl radical .

More particularly, the new peptides of general formula (II) in which R, R1 and R3 are defined as above and one of the symbols R2 or R4 represents an N-carbonyl glycyl radical or
N-carbonyl alanyl can be obtained by the action of an amino acid of general formula (III), in which R6 and R 'are defined as above and R5 represents a hydrogen atom on a tri- or tetrapeptide of general formula (IV) in which R7 is defined as above, R8 represents an amino or alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, one of the symbols R4 or Rg represents a carboxy radical and the other represents an atom of hydrogen or a carbamoyl or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and R10 represents a fatty acid residue or a group protecting the amine function or a glycyl or D alanyl residue, the amine function is substituted by a fatty acid residue or by an amine function protecting group, it being understood that at least one of the symbols R7 or Rlo represents or contains a residue fatty acid, optionally followed by the replacement of the radical R7 or R10, when it represents or contains a protective group for the amine function, with a hydrogen atom, of the radicals R8 and / or R 'when they represent a alkyloxy radical containing 1 to 4 carbon atoms (optionally substituted by a phenyl or nitrophenyl radical) by a hydroxy radical and the radical R4 or Rg when it represents or contains an alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a radical phenyl or nitrophenyl, by a carboxy radical such that in the final product, R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical,
R2 is different from a carboxy, N-carbonyl.-glycyl or N-carbonyl radical
D alanyl.

 Generally, it is necessary to activate the free acid function of the peptide of general formula (iv) prior to the action of the amino acid of general formula (III). Preferably, the activated derivative of the peptide of general formula (TV) is a mixed anhydride prepared in situ by the action of an alkyl haloformate such as isobutyl chloroformate on the peptide of general formula (IV). The activated derivative is condensed in an organic solvent such as dioxane, tetrahydrofuran, chloroform, toluene or dimethylformami-de or in a hydroorganic medium, in the presence of a base (mineral, such as sodium hydroxide, or organic, such as 18 triethylamine), at a temperature between -10 and + 30OC.

 The possible replacement of the protective radicals R7 or Rlo by a hydrogen atom and of the protective radicals R8 and R 'by hydroxy radicals and of R4 or R9 by a carboxy radical can be carried out according to known methods, depending on the nature of these groupings. It is particularly advantageous to choose the radicals R7 or Rlo, R8, R 'and R4 or R9 in such a way that their replacement by a hydrogen atom or by a hydroxy or carboxy radical can be carried out in a single step. , R7 or R10 may represent a benzyloxycarbonyl radical and the symbols R8, R 'and R4 or R9 represent a benzyloxy or benzyloxycarbonyl radical, and, under these conditions, the replacement of these radicals by hydrogen atoms or by a hydroxy or carboxy radical depending on the case, is carried out by hydrogenolysis, operating in a suitable organic solvent such as acetic acid (optionally in admixture with another organic solvent such as methanol) or in a hydroorganic solvent, in the presence of a catalyst such as palladium, for example palladium on black, at a temperature in the region of 200C and under a pressure in the region of 760 min of mercury. However, it may be necessary to remove one or more of these protective groups without affecting the others. In this case, the protective groups for the amine functions may be, for example, one a t.butyloxycarbonyl radical (eliminable by acid hydrolysis) and the other a benzyloxycarbonyl radical (eliminable by hydrogenolysis) and the protective groups of the acid functions can be, for example, one a methyl or t.butyl radical (eliminable by acid or basic hydrolysis) and the other a radical benzyl (eliminable by hydrogenolysis).

More particularly, the new peptides of general formula (II) in which R, R1, R2 and R4 are defined as above, and R3 represents a glycyl residue or D alanyl whose amine function is optionally substituted by a fatty acid residue, can be obtained by the action of an amino acid of general formula (III) in which R6 is defined as above, R5 represents a fatty acid residue or a group protecting the amine function and
R 'represents a hydroxy radical, on a tri- or tetrapeptide of general formula (fiv) in which R4, R7, R8 and Rg are defined as above and R10 represents a hydrogen atom, it being understood that at least one of the symbols R5 and R7 represent a fatty acid residue, optionally followed by the replacement of the radical R or R7, when it represents a group protecting the amine function, with a hydrogen atom and of the radical R8, when it represents a alkoxy radical containing i to 4 carbon atoms (optionally substituted by a phenyl or nitrophenyl radical) by a hydroxy radical and radicals R4 and / or R9 (when they represent or contain an alkyloxycarbonyl radical containing 1 to 4 carbon atoms (optionally substituted by a phenyl or nitrophenyl radical) by a carboxy radical in such a way that in the final product, R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical, R2 is different nt of a carboxy, N-carbonylglycyl or N-carbonyl D alanyl radical.

 Generally, it is necessary to activate the acid function of the amino acid of general formula (III) prior to its action on the peptide of general formula (IV). Generally, the activated derivative of the amino acid of general formula (here) is a mixed anhydride prepared in situ by the action of an alkyl haloformate (such as isobutyl chloroformate) on the amino acid of general formula (III) .

The condensation of the activated derivative takes place in an organic solvent such as dioxane, tetrahydrofuran, chloroform, toluene or dimethylformamide or in a hydroorganic medium, in the presence of a base (mineral, such as sodium hydroxide, or organic , such as triethylamine), at a temperature between -10 and + 300C.

 The replacement of the protective radicals R5 or R7 with a hydrogen atom and of the protective radicals R8 and / or R4 and / or R9 with a hydroxy or carboxy radical as the case may be can be carried out according to the known methods depending on the nature of these groupings. It is particularly advantageous to carry out this replacement under the conditions given above.

dans laquelle R7 représente un reste d'acide gras ou un groupement protecteur de la fonction amine et R8 représente un radical amino ou alcoyloxy contenant i à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle, sur un di- ou tripeptide de formule générale

dans laquelle l'un des symboles R4 ou R9 représente un atome d'hydrogènè ou un radical carboxy, carbamoyle, alcoyloxycarbonyle dont la partie alcoyle contient 1 à 4 atomes de carbone et est éventuellement substituée par un radical phényle ou nitrophényle ou un reste N-carbonyl glycyle ou N-carbonyl D alanyle éventuellement estérifié par un radical alcoyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle et l'autre représente un atome d'hydrogène ou un radical carboxy, carbamoyle ou alcoyloxycarbonyle dont la partie alcoyle contient 1 à 4 atomes de carbone et est éventuellement substituée par un radical phényle ou nitrophényle, étant entendu que R4 et R9 ne peuvent pas représenter simultanément un atome d'hydrogène et R10 représente un reste d'acide gras ou un groupement protecteur de la fonction amine ou un reste glycyle ou D alanyle (dont la fonction amine est substituée par un reste d'acide gras ou par un groupement protecteur de fonction amine), l'un au moins des symboles R4 ou R9 et R10 représentant ou contenant un radical glycyle ou D alanyle tel que défini ci -avant et l'un au moins des symboles R7 et R10 représentant ou contenant un reste d'acide gras, suivie éventuellement du remplacement du radical R7 ou Rto (lorsqu'il représente ou contient un groupement protecteur de la fonction amine) par un atome d'hydrogène et des radicaux R8 etjou R4 et/ou Rg (lorsqu'ils représentent selon le cas
un radical alcoyloxy ou alcoyloxycarbonyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle) par un radical hydroxy ou carboxy
Généralement il est nécessaire d'activer la fonction acide libre du dipeptide de formule générale (V) préalablement à son action sur le peptide de formule générale (VI). De préférence, le dérivé activé du dipeptide de formule générale (V) est un anhydride mixte, préparé in situ par action dtun halogénoformiate d'alcoyle tel que le chloroformiate d'isobutyle. Dans ces conditions la condensation effectue comme indiqué ci-dessus pour l'action d'un aminoacide de formule générale (ICI) sur un tripeptide de formule générale (IV). According to the present addition, the new peptides of general formula (II) can be obtained by the action of a dipeptide of general formula

in which R7 represents a fatty acid residue or a protective group for the amine function and R8 represents an amino or alkyloxy radical containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, on a di- or tripeptide of formula general

in which one of the symbols R4 or R9 represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical or an N- residue carbonyl glycyl or N-carbonyl D alanyl optionally esterified by an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the part of which alkyl contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, it being understood that R4 and R9 cannot simultaneously represent a hydrogen atom and R10 represents a fatty acid residue or a protecting group for the amine function or a glycyl or D alanyl residue (the amine function of which is substituted by a fatty acid residue or by a protective group of function amine ion), at least one of the symbols R4 or R9 and R10 representing or containing a glycyl or D alanyl radical as defined above and at least one of the symbols R7 and R10 representing or containing an acid residue fatty, optionally followed by the replacement of the radical R7 or Rto (when it represents or contains a protective group for the amine function) by a hydrogen atom and of the radicals R8 etjou R4 and / or Rg (when they represent as appropriate
an alkyloxy or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical) by a hydroxy or carboxy radical
Generally it is necessary to activate the free acid function of the dipeptide of general formula (V) before its action on the peptide of general formula (VI). Preferably, the activated derivative of the dipeptide of general formula (V) is a mixed anhydride, prepared in situ by the action of an alkyl haloformate such as isobutyl chloroformate. Under these conditions the condensation performs as indicated above for the action of an amino acid of general formula (HERE) on a tripeptide of general formula (IV).

 The possible replacement of the protective radicals R7 or R10 by a hydrogen atom and of the protective radicals R8 and / or R4 and / or Rg by a hydroxy or carboxy radical according to 16 cases is carried out according to the known methods indicated above such that in the final product, R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical, R2 is different from a carboxy, N-carbonyl glycyl or N-carbonyl D alanyl radical.

dans laquelle R7 représente un reste d'acide gras ou un groupement protecteur de la fonction amine, sur un tri- ou tétrapeptide de formule générale

dans laquelle l'un des symboles R4 ou R9 représente un atome d'hydrogène ou un radical carboxy, carbamoyle, alcoyloxycarbonyle dont la partie alcoyle contient 1 à 4 atomes de carbone et est éventuellement substituée par un radical phényle ou nitrophényle ou un reste N-carbonyl glycyle ou N-carbonyl D alanyle éventuellement estérifié par un radical alcoyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle et l'autre représente un atome d'hydrogène ou un radicalicarboxy, carbamoyle ou alcoyloxycarbonyle dont la partie alcoyle contient 1 à 4 atomes de carbone et est éventuellement substituée par un radical phényle ou nitrophényle, étant entendu que
R4 et Rg ne peuvent pas représenter simultanément un atome d'hydrogène,
R8 représente un radical hydroxy, amino ou alcoyloxy contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou -nitrophényle, et R10 représente un reste d'acide gras, un groupement protecteur de la fonction amine ou un radical glycyle ou D alanyle dont la fonction amine est substituée par un reste d'acide gras ou par un groupement protecteur de fonction amine, l'un au moins des symboles R4 ou
R9 et Rlo représentant ou contenant un radical glycyle ou D alanyle tel que défini ci-avant et l'un au moins des symboles R, et R10 représentant ou contenant un reste d'acide gras, suivie éventuellement du remplacement du radical R, ou R10 (lorsqu'il représente ou contient un groupement protecteur de la fonction amine) par un atome d'hydrogène et des radicaux R8 et/ou R4 et/ou Rg (lorsqu'ils représentent ou contiennent un radical'alcoyloxy ou alcoyloxycarbonyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle) par un radical hydroxy ou carboxy selon les cas, dans les conditions décrites ci-dessus pour l'action d'un aminoacide de formule générale (TIR) sur un tri- ou tétrapeptide de formule générale (IV) de telle manière que dans le produit final, R1 représentant un radical hydroxy ou amino, R4 représentant un atome d'hydrogène ou un radical carbamoyle,
R2 soit différent d'un radical carboxy, N-carbonyl glycyle ou N-carbonyl
D alanyle.According to the present addition, the new peptides of general formula (II) can be obtained by the action of a L alanine derivative of general formula

in which R7 represents a fatty acid residue or a protective group for the amine function, on a tri- or tetrapeptide of general formula

in which one of the symbols R4 or R9 represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical or an N- residue carbonyl glycyl or N-carbonyl D alanyl optionally esterified by an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a radicalicarboxy, carbamoyl or alkyloxycarbonyl of which the alkyl part contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, it being understood that
R4 and Rg cannot simultaneously represent a hydrogen atom,
R8 represents a hydroxy, amino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or -nitrophenyl radical, and R10 represents a fatty acid residue, a group protecting the amine function or a glycyl or D alanyl radical whose amine function is substituted by a fatty acid residue or by an amine protecting group, at least one of the symbols R4 or
R9 and Rlo representing or containing a glycyl or D alanyl radical as defined above and at least one of the symbols R, and R10 representing or containing a fatty acid residue, optionally followed by the replacement of the radical R, or R10 (when it represents or contains a group protecting the amine function) with a hydrogen atom and radicals R8 and / or R4 and / or Rg (when they represent or contain an alkyloxy or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical) by a hydroxy or carboxy radical as the case may be, under the conditions described above for the action of an amino acid of general formula (TIR) on a tri- or tetrapeptide of general formula (IV) such that in the final product, R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical,
R2 is different from a carboxy, N-carbonyl glycyl or N-carbonyl radical
D alanyl.

dans laquelle l'un des symboles R4 ou Rg représente un atome dthydrogène ou un radical carboxy, carbamoyle, alcoyloxycarbonyle dont la partie alcoyle contient i à 4 atomes de carbone et est éventuellement substituée par un radical phényle ou nitrophényle ou un reste N-carbonyl glycyle ou N-carbonyl D alanyle éventuellement estérifié par un radical alcoyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle et l'autre représente un atome d'hydrogène ou un radical carboxy, carbamoyle ou alcoyloxycarbonyle dont la partie alcoyle contient 1 à 4 atomes de carbone et est éventuellement substituée par un radical phényle ou nitrophényle, étant entendu que R4 et R9 ne peuvent pas représenter simultanément un atome dthydrogène,
R8 représente un radical hydroxy, amino ou a-lcoyloxy contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle, R10 représente un atome d'hydrogène, un reste d'acide gras, un groupement protecteur de la fonction amine ou un reste glycyle ou
D alanyle dont la fonction amine libre est éventuellement substituée par un reste d'acide gras ou par un groupement protecteur de fonction amine et
R11 représente un atome d'hydrogène, un reste d'acide gras ou un groupement protecteur de la fonction amine, étant entendu que l'un au moins des symboles R4 ou R9 et R10 représente ou contient un reste glycyle ou D alanyle tel que défini ci-avant et que l'un au moins des symboles
R10 et R11 représente un atome d'hydrogène ou, pour Rlo, un radical glycyle ou D alanyle dont la fonction amine est libre, et que lorsque l'un des radicaux R10 ou R11 représente ou contient un reste d'acide gras celui-ci et le reste R"-CO- sont Identiques ou différents, suivis du remplacement du radical R10 ou R11 (lorsqu'il représente ou contient un groupement protecteur de la fonction amine) par un atome d'hydrogène et des radicaux R8 et/ou R4 et/ou R9 (lorsqu'ils représentent ou contiennent un radical alcoyloxy ou alcoyloxycarbonyle contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle) par un radical hydroxy ou carboxy selon les cas de telle manière que dans le produit final, R1 représentant un radical hydroxy ou amino, R4 représentant un atome d'hydrogène ou un radical carbamoyle,
R2 soit différent d'un radical carboy, N-carbonyl-glycyle ou N-carbonyl
D alanyle.According to the present addition, the new peptides of general formula (îî) can be obtained by the action of an acid of general formula
R "-CO-OH (îx) (in which R" -CO- represents a fatty acid residue as defined above) on a tetra- or pentapeptide of general formula

in which one of the symbols R4 or Rg represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains i to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical or an N-carbonyl glycyl residue or N-carbonyl D alanyl optionally esterified by an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical of which the alkyl part contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, it being understood that R4 and R9 cannot simultaneously represent a hydrogen atom,
R8 represents a hydroxy, amino or α-alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, R10 represents a hydrogen atom, a fatty acid residue, a group protecting the amine function or a glycyl residue or
D alanyl whose free amine function is optionally substituted by a fatty acid residue or by a protective group of amine function and
R11 represents a hydrogen atom, a fatty acid residue or a group protecting the amine function, it being understood that at least one of the symbols R4 or R9 and R10 represents or contains a glycyl or D alanyl residue as defined above and that at least one of the symbols
R10 and R11 represents a hydrogen atom or, for Rlo, a glycyl or D alanyl radical whose amine function is free, and that when one of the radicals R10 or R11 represents or contains a fatty acid residue, the latter and the rest R "-CO- are the same or different, followed by the replacement of the radical R10 or R11 (when it represents or contains a group protecting the amine function) with a hydrogen atom and of the radicals R8 and / or R4 and / or R9 (when they represent or contain an alkyloxy or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical) by a hydroxy or carboxy radical depending on the case in such a way that in the final product, R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical,
R2 is different from a carboy, N-carbonyl-glycyl or N-carbonyl radical
D alanyl.

When, in the general formula (X), the symbol R8 represents an amino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and one of the symbols R4 or Rg represents an N-carbonyl glycyl residue or N-carbonyl
D alanyl esterified by an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical or an alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents an atom hydrogen or a carbamoyl or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, the condensation of the acid of general formula (ix) is generally carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide operating in an organic solvent such as methylene chloride or dimethylformamide, at a temperature between -10 and + 300C.

 When, in the general formula (X), one of the symbols R8 represents or contains a hydroxy radical and R4 and / or Rg represents or contains a carboxy radical, it is necessary to activate the acid of general formula (IX) prior to its action on the tetra- or pentapeptide of general formula (X). As activated derivative of the acid of general formula (IX), it is particularly advantageous to use an acid halide or a mixed anhydride prepared in situ by the action of an alkyl haloformate, such as disobutyl chloroformate, in the presence of a base.

 When the acid of general formula (IX) is used in the form of an acid halide, preferably chloride, the reaction is carried out in an organic solvent such as diethyl ether or methylene chloride, in the presence of 'a base (mineral, such as sodium hydroxide, or organic, such as triethylamine), at a temperature between 0 and 300C.

 When the acid of general formula (six) in the form of a mixed anhydride is used, the reaction is carried out in an organic solvent such as dioxane, tetrahydroforan, chloroform, toluene or dimethylformamide or in a hydroorganic medium, in the presence of a base (mineral, such as sodium hydroxide, or organic, such as triethylamine), at a temperature between -10 and +300 (.

 The possible replacement of the Rlo etjou R11 radicals with a hydrogen atom and of the R8 and / or R4 etlou Rg radicals with a hydroxy or carboxy radical is carried out according to the known methods indicated above.

 To obtain a product of general formula (I) in which R represents a fatty acid residue and R3 represents the remainder of the same fatty acid or a glycyl or D alanyl residue in which the amine function is substituted by the rest of the rrEme fatty acid, the condensation of the acid of general formula (IX) is carried out on a product of general formula (X) in which R10 represents a hydrogen atom or a glycyl residue or D alanyl and R11 represents a hydrogen atom or on a product of general formula (X) in which R10 represents or contains a fatty acid residue identical to that of the acid of general formula (IX) used and R represents a hydrogen atom or else on a product of general formula (X) in which R10 represents a hydrogen atom or a glycyl residue or D alanyl and R11 represents a fatty acid residue identical to that of the acid of general formula (IX) used, operating in the usual conditions.

 To obtain a product of general formula (I) in which the symbols R and R3 represent or contain residues of different fatty acids, it is necessary to carry out the condensation of an acid of general formula (IX on a product of general formula (X) in which R10 represents or contains a fatty acid residue different from that of the acid of general formula (IX) used or a protective group for the amine function and R11 represents a hydrogen atom or else on a product of general formula (X) in which R10 represents a hydrogen atom or a glycyl residue or D alanyl and R11 represents a fatty acid residue different from that of the acid of general formula (TX) used or a group protector of the amine function, then, if appropriate, after elimination of this protective group, effecting the condensation of another fatty acid of general formula (IX), operating under the usual conditions.

 The amino acid of general formula (TITI) in which R represents a hydrogen atom or a methyl radical, R 'represents a hydroxy or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and R3 represents a fatty acid residue, can be obtained by the action of an acid of general formula (IX) or an activated derivative of this acid on glycine or D alanine, the acid function of which is optionally protected in the form of an ester followed , where appropriate, the elimination of the protective group for the acid function.

Whether the acid function of glycine or D alanine is protected or not, the condensation takes place under the conditions indicated above for the condensation of the acid of general formula (IX) on the tetra- or pentapeptide of general formula CX ),
The tri- or tetrapeptide of general formula (I) in which one of the symbols R4 and Rg represents a carboxy radical and the other represents a hydrogen atom or a carbamoyl or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted with a phenyl or nitrophenyl radical, R7 represents a fatty acid residue or a protecting group for the amine function, R8 represents an amino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and R10 represents a fatty acid residue or a protecting group for the amine function or a glycyl or D alanyl residue substituted by a fatty acid residue or by a protecting group for the amine function can be obtained by the action, under the usual conditions, of a dipeptide of general formula (V), in which R7 and R8 are defined as above, on an amino acid or a dipeptide of general formula Cri), in which R10 is defined as below ssus and one of the symbols R4 or Rg represents a carboxy radical or an alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carbamoyl or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, followed where appropriate by the replacement of one of the radicals R4 or Rg, when it represents an alkyloxycarbonyl radical containing 1 to 4 carbon atoms (optionally substituted by a radical phenyl or nitrophenyl) by a carboxy radical without affecting the rest of the molecule.

 In particular, when Ra forms with the carbonyl group to which it is linked an ester function, and R4 and N represent an ester function, it may be necessary for the radicals R8, R4 and Rg to be different and chosen so that the replacement of d 'one of the radicals R4 or R9 by a carboxy radical is carried out without touching the radical R8 and the other radical R4 or Rg. In a rare example, one of the radicals R4 or R9 can represent a benzyloxycarbonyl radical which can be eliminated for hydrogenolysis and the radical R8 and the other radical R4 or R9 a methoxy radical which is not sensitive to hydrogenolysis.

 The tri- or tetrapeptide of general formula (IV) in which R7 represents a fatty acid residue or a protecting group for the amine function, R8 represents an amino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl radical or nitrophenyl, one of the symbols R4 or Rg represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl or N-carbonyl glycyl or N-carbonyl D radical alanyl optionally esterified by an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carbamoyl or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a radical phenyl or nitrophenyl, R4 and N cannot simultaneously represent a hydrogen atom and R10 represents a hydrogen atom can be e obtained by the action, under the usual conditions, of a dipeptide of general formula (V) in which R7 and R8 are defined as above on an amino acid or a dipeptide of general formula (VI) in which R4 and R9 are defined as above and R10 represents a protective group for the amine function, followed by the replacement of this protective group with a hydrogen atom, without affecting the rest of the molecule. In particular the protective groups for the amine function defined for R, and R10 must be different and chosen in such a way that the replacement of the radical R10 by a hydrogen atom is carried out without touching the radical R7.

dans laquelle Ra représente un radical amino ou alcoyloxy contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle, dans les conditions décrites ci-dessus pour l'action de l'aminoacide de formule générale (vit) sur le peptide de formule générale CvTiî). The dipeptide of general formula (V) can be obtained by the action of an activated derivative of L alanine of general formula (VIT) in which R7 represents a fatty acid residue or a group protecting the amine function on a derivative of D glutamic acid of general formula

in which Ra represents an amino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, under the conditions described above for the action of the amino acid of general formula (vit) on the peptide of general formula CvTiî).

dans laquelle R8 représente un radical amino ou alcoxy contenant 1 à 4 atomes de carbone éventuellement substitué par un radical phényle ou nitrophényle, dans les conditions décrites précédemment pour l'action d'un acide de formule générale (IX) sur un tétra- ou pentapeptide de formule générale (X). The dipeptide of general formula (V) in which R, represents a fatty acid residue can also be obtained by the action of an acid of general formula (IX) on a dipeptide of general formula

in which R8 represents an amino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, under the conditions described above for the action of an acid of general formula (IX) on a tetra- or pentapeptide of general formula (X).

(dans laquelle Z représente le radical benzyloxycarbonyle) qui, après hydrogénolyse en présence de palladium sur noir, fournit l'acide diamino-2,6 pimélamique.The amino acid or the dipeptide of general formula (VI) in which R4 represents a carboxy radical, R9 represents a carbamoyl radical and R10 represents a fatty acid residue, a group protecting the amine function or a glycyl or D alanyl residue of which the amine function is substituted by a fatty acid residue or by a group protecting the amine function, in racemic form, D, D or L, L can be prepared from the corresponding 2,6-diamino pimelic acid. To this end, the dibenzyl ester of 2,6-dibenzyloxycarbonylamino-2,6 pimelic acid is prepared according to known methods, which is monosaponified according to the method described by A. Arendt and paste Roezniki Ghemii Ann. Soc. shits. Polonoruni, 48, 1305 (1974), Cchem. Abstr. 82, 31497 g (1975)] then transformed by the action of ammoniacal methanol into monoamide of general formula

(in which Z represents the benzyloxycarbonyl radical) which, after hydrogenolysis in the presence of palladium on black, provides 2,6-diamino pimelamic acid.

dans laquel le reste amino en a du groupement carbamoyle peut être protégé par action d'un halogénoformiate d'alcoyle ou de benzyle. Le complexe ainsi formé est déplacé par l'action de l'hydrogène sulfuré pour donner l'aminoacide de formule générale (VI) dans laquelle R4 représente un radical carbamoyle, R9 représente un radical carboxy et R10 représente un groupement protecteur de la fonction amine.Le reste amino en a du groupement carboxy peut être acylé par action d'un dérivé activé d'un acide de formule générale (IX) ou d'un aminoacide de formule générale (ici) dans laquelle R5 représente un reste d'acide gras ou un groupement protecteur de la fonction amine et Rl représente un radical hydroxy. Après rempladement du radical R10 par un atome d'hydrogène par des méthodes qui ne touchent pas au reste de la molécule, on obtient le produit de formule générale (vil) dans laquelle R4 représente un radical carboxy, Rg représente un radical carbamoyle et R10 est défini comme précédemment. By the action of a copper salt such as cupric bromide or basic copper carbonate, on 2,6-diamino pimelamic acid, a complex is formed which can be represented by the formula:

in which the amino residue has a carbamoyl group can be protected by the action of an alkyl or benzyl haloformate. The complex thus formed is displaced by the action of hydrogen sulfide to give the amino acid of general formula (VI) in which R4 represents a carbamoyl radical, R9 represents a carboxy radical and R10 represents a group protecting the amine function. The amino residue at a of the carboxy group can be acylated by the action of an activated derivative of an acid of general formula (IX) or of an amino acid of general formula (here) in which R5 represents a fatty acid residue or a protective group for the amine function and R1 represents a hydroxy radical. After filling of the radical R10 with a hydrogen atom by methods which do not affect the rest of the molecule, the product of general formula (vil) is obtained in which R4 represents a carboxy radical, Rg represents a carbamoyl radical and R10 is defined as above.

 The amino acid or the dipeptide of general formula (VI) in which R4 represents a carboxy radical, Rg represents a carbamoyl radical and R10 represents a fatty acid residue or a glycyl or D alanyl residue in which the amine function is substituted by a residue fatty acid or by a group protecting the amine function, in meso form, in which the carbon atom carrying the radicals R4 and R10 is in n form, can be prepared by the action of an activated derivative of an acid of formula general (IX) or of an amino acid of general formula (III) in which R5 represents a fatty acid residue or a group protecting the amine function on the (D) -monoamide of benzyloxycarbonyl- (D) meso acid -dimino-2,6 pimelic, obtained according to the method described in Belgian patent 821,385, followed by the replacement of the benzyloxycarbonyl radical by a hydrogen atom without affecting the rest of the molecule.

dans laquelle R10 est défini comme ci-dessus et Y représente un groupement protecteur de la fonction amine, en opérant dans les conditions habituelles suivie du remplacement du groupement protecteur Y par un atome dthydro- gène et éventuellement du groupement ester (porté par le reste glycyle ou D alanyle) par un radical hydroxy, sans toucher au reste de la molé- cule.En particulier lorsque R10 représente ou contient un groupement protecteur de la fonction amine, il importe de choisir Y de telle manière que son remplacement par un atome d'hydrogène s'effectue sans toucher au radical Rto. The amino acid, di- or tripeptide of general formula (VI) in which Rg represents a carbamoyl radical, R4 represents an alkyloxycarbonyl radical containing 1 to 4 carbon atoms or an N-carbonyl glycyl or N-carbonyl D alanyl residue optionally esterified by an alkyl radical containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and R10 represents a fatty acid residue or a protecting group for the amine function or a glycyl or D alanyl residue in which the amine function is substituted by a residue fatty diacid or by a protective group for the amine function can be obtained by action under the usual conditions of an amino acid of general formula (ICI) in which R5 represents a hydrogen atom and Rl represents a hydroxy radical, or a corresponding amino ester, or an aliphatic alcohol containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical or its derivatives, on a anino acid or a dipeptide of general formula:

in which R10 is defined as above and Y represents a protective group for the amine function, operating under the usual conditions followed by the replacement of the protective group Y with a hydrogen atom and optionally the ester group (carried by the glycyl residue or D alanyl) with a hydroxy radical, without affecting the rest of the molecule. In particular when R10 represents or contains a group protecting the amine function, it is important to choose Y in such a way that its replacement by an atom of hydrogen takes place without touching the Rto radical.

 When the amino acid of general formula (ICI) optionally esterified reacts with the amino acid of general formula (XV), the procedure is carried out under known conditions which allow the creation of a peptide bond without affecting the rest of the molecule. When an aliphatic alcohol containing 1 to 4 carbon atoms which is optionally substituted by a phenyl or nitrophenyl radical is reacted, the operation is carried out under mild esterification conditions so as not to touch the protective groups Y and R10 and more particularly according to the method of V. Bocchi, Synthesis; p.961 (1979).

dans laquelle R4 est défini comme ci-dessus et y représente un groupement protecteur de la fonction amine, en opérant dans les conditions habituelles, suivie du remplacement du groupement Y par un atome d'hydrogène. The tripeptide of general formula (VI) in which
R9 represents a carbamoyl radical, R4 represents an alkyloxycarbonyl radical or an N-carbonyl glycyl or N-carbonyl D alanyl radical optionally esterified and R10 represents a fatty acid residue or a glycyl or D alanyl residue whose amine function is substituted by a fatty acid residue or a protective group of the amine function can be obtained by the action under the usual conditions of an activated derivative of an acid of general formula (IX) or of an amino acid of general formula (III) , in which R5 represents a fatty acid residue or a protective group for the amine function and 2 'represents a hydroxy radical on an amino acid or a dipeptide of general formula

in which R4 is defined as above and y represents a group protecting the amine function, operating under the usual conditions, followed by the replacement of the group Y by a hydrogen atom.

 The amino acid or the dipeptide of general formula (XVI) can be obtained according to the usual methods used in peptide chemistry for the introduction of a group protecting the amine function from an amino acid or a dipeptide of general formula (VI) in which Rg represents a carbamoyl radical, R4 represents an alkyloxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical or an N-carbonyl glycyl or N-carbonyl D residue optionally esterified alanyl and R10 represents a protective group for the amine function, followed by the replacement of the protective group R10 with a hydrogen atom without affecting the rest of the molecule.-In particular the groups protecting the amino functions of the diamino acid 2,6 pimélamique will be different and chosen so that the replacement of R10 does not entail the replacement of Y.

The di- or tripeptide of general formula (Vl) in which
R9 represents a hydrogen atom and R4 represents a glycyl residue or
D alanyl and R10 represents a fatty acid residue or a glycyl residue or
D alanyl, the amine function of which is substituted by a fatty acid residue or by a protective group for the amine function, can be obtained from L lysine by applying the methods used for the preparation of the di- or tripeptide of general formula ( Vl) in which R9 represents a carbamoyl radical and R4 and R10 have the corresponding definitions.

 The amino acid of general formula (VII) in which R7 represents a fatty acid residue can be obtained by the action of an acid of general formula (IX) or of an activated derivative of this acid on L alanine whose function acid is optionally protected in the form of an ester, optionally followed by the replacement of the ester function with the carboxy function, operating under the conditions indicated above for the action of the acid of general formula (IX) on the tetra- or pentapeptide of general formula (X).

The tri- or tetrapeptide of general formula (VIII) can be obtained by the action, under the usual conditions, of an acid derivative
D glutamic of general formula (XI), the amine function of which is protected and in which R8 represents an amino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, on a di- or tripeptide of general formula (Vl) in which one of the symbols R4 or Rg represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical or an N-carbonyl glycyl or N-carbonyl residue n alanyl optionally esterified by an alkyl radical containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical in which the alkyl part contains i to 4 atoms carbon and is optionally substituted by a phenyl or nitrophenyl radical ,. it being understood that R4 and Rg cannot simultaneously represent a hydrogen atom and R10 represents a fatty acid residue or a protective group of amine function or a glycyl or D alanyl residue in which the amine function is substituted by a residue of fatty acid or an amine protecting group (at least one of the symbols R4 or Rg and R10 representing a glycyl or D alanyl radical as defined above), followed by the possible replacement of the radical R8 and / or R4 and / or R9 (when they represent or contain an alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl radical) by a hydroxy or carboxy radical as the case may be, without affecting the rest of the molecule.
R8 forms with the carbonyl group to which it is linked an ester function, and R4 and / or R9 represent an ester function, it may be necessary that the radicals R8 and R4 and / or Rg be different and chosen so that the replacement of d 'one of the radicals R4 or R9 by a carboxy radical is carried out without touching the radical R8 and the other radical R4 or Rg. For example, one of the radicals R4 or Rg can represent a benzyloxycarbonyl radical, which can be eliminated by hydrogenolysis and the radical R8 a methoxy radical and the other radical R4 or Rg a methoxycarbonyl radical which are not sensitive to hydrogenolysis.

The tetra- or pentapeptide of general formula (X) can be obtained, under the usual conditions, by the action of an activated derivative of L alanine of general formula (VII) in which R7 represents a fatty acid residue or a group protector of the amine function on a tri- or tetrapeptide of general formula (VIII) in which
R8 represents a hydroxy, amine or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, one of the symbols R4 or R9 represents a hydrogen atom or a carboxy, carbamoyl, alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical or an N-carbonyl glycyl or N-carbonyl D alanyl radical optionally esterified by an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, it being understood that R4 and Rg cannot simultaneously represent a hydrogen atom , and R10 represents a fatty acid residue or an amine protecting group or a glycyl or D alan residue yl the amine function of which is substituted by a fatty acid residue or by a protective group of amine function, it being understood that at least one of the radicals R4 or R9 and R10 represents a glycyl or D alanyl residue as defined above before and that one of the radicals R7 or R10 represents or contains a protective group of amine function, followed by the replacement of the radical R, and / or R10 (when they represent or contain a protective group of the amine function) by an atom of hydrogen and the possible replacement of the radicals R8 and / or R4 and / or R9 (when they represent or contain an alkyloxy or alkyloxycarbonyl radical containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical) by a hydroxy radical or carboxy as the case may be, without touching the rest of the molecule. When the symbols R7 and R10 represent or contain protective groups of amine function, it is possible to choose different protective groups and chosen in such a way that the replacement of one of these groups is carried out without touching the other.

 When R8, R4 and R9 form an ester function, it is possible that the radicals R8, R4 and R9 are different and chosen so that the replacement of one of the radicals R4 or Rq by a carboxy radical is carried out without affecting the radical R8 and to the other radical R4 or R9. For example, one of the radicals R4 or Rg may represent a benzyloxycarbonyl radical eliminable by hydrogenolysis and the radical R8 a methoxy radical and the other radical R4 or Rg an alkyloxycarbonyl radical which are not sensitive to hydrogenolysis.

 The tetra- or pentapeptide of general formula (X) can be obtained by the action, under the usual conditions, of a dipeptide of general formula (V) on the di- or tripeptide of general formula (VI) under the conditions given above for prepare the tri- or tetrapeptide of general formula (IV), followed by the elimination of the protective groups R7 and / or R10 under the conditions given above.

The present addition also relates to a process for preparing the products of general formula (II) by peptide synthesis of
Merrifield in solid phase.

dans laquelle l'un des symboles R4 et Rg représente un radical carboxy ou N-carbonyl glycyle ou N-carbonyl D alanyle et autre représente un atome d'hydrogène ou un radical carbamoyle ou alcoyloxycarbonyle dont la partie alcoyle contient 1 à 4 atomes de carbone et est éventuellement substituée par un radical phényle ou nitrophényle, R12 représente un reste d'acide gras ou un groupement protecteur de la fonction amine ou un radical glycyle ou D alanyle dont la fonction amine est substituée par un reste d'acide gras ou par un groupement protecteur de la fonction amine et R13 représente un groupement protecteur de la fonction amine, étant entendu que, lorsque R8 qui est défini ci-après représente un radical amino et R4 représente un atome d'hydrogène ou un radical carbamoyle, Rg ne peut pas représenter un radical carboxy,N- carbonyl
glycyle ou N-carbonyl D alanyle, et que lorsque R12 et R13 représentent ou contiennent chacun un groupement protecteur de la fonction amine, ces groupements protecteurs sont différents, puis, après déblocage de la fonction amine protégée par R13, à condenser - soit l'acide D glutamique dont les fonctions amine et a-carboxy sont convenablement protégées, c'est-à-dire le produit de formule générale ::

dans laquelle R13 est défini comme ci-dessus et R8 représente un radical amino ou un radical alcoyloxy contenant 1 à 4 atomes de carbone éventuel-lement substitué par un radical phényle ou nitrophényle, puis, après déblocage de la fonction amine protégée par le radical R13,
- soit un dérivé de la L alanine de formule générale

dans laquelle R13 est défini comme précédemment, puis après déblocage des fonctions amines protégées par R13 et/ou R12, éventuellement l'acide gras de formule générale (IX),
- soit un dérivé de la L alanine de formule générale ::

dans laquelle R représente un reste d'acide gras, - soit le dipeptide de formule générale

dans laquelle R8 est défini comme précédemment et R14 représente un reste d'acide gras ou un groupement protecteur de la fonction amine étant entendu que, lorsque R14 représente un groupement protecteur de la fonction amine, celui-ci peut être différent du groupement protecteur R12 du peptide de formule générale (XVII) et que, on fait ensuite éventuellement réagir l'acide de formule générale (IX) après déblocage des fonctions amines protégées par les radicaux R14 et/ou R12, puis à séparer le produit obtenu de son support et à éliminer si nécessaire les groupements protecteurs des fonctions amines et carboxy. The process essentially consists in fixing on a suitable support a di- or tripeptide of general formula:

in which one of the symbols R4 and Rg represents a carboxy or N-carbonyl glycyl or N-carbonyl D alanyl radical and the other represents a hydrogen atom or a carbamoyl or alkyloxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, R12 represents a fatty acid residue or a protecting group for the amine function or a glycyl or D alanyl radical in which the amine function is substituted by a fatty acid residue or by a protective group for the amine function and R13 represents a protective group for the amine function, it being understood that, when R8 which is defined below represents an amino radical and R4 represents a hydrogen atom or a carbamoyl radical, Rg cannot represent a carboxy radical, N- carbonyl
glycyl or N-carbonyl D alanyl, and when R12 and R13 each represent or contain a protective group for the amine function, these protective groups are different, then, after unblocking the amine function protected by R13, to be condensed - either the D glutamic acid, the amine and a-carboxy functions of which are suitably protected, that is to say the product of general formula:

in which R13 is defined as above and R8 represents an amino radical or an alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, then, after release of the amine function protected by the radical R13 ,
- or a derivative of L alanine of general formula

in which R13 is defined as above, then after unblocking the amine functions protected by R13 and / or R12, optionally the fatty acid of general formula (IX),
- or a derivative of L alanine of general formula:

in which R represents a fatty acid residue, - either the dipeptide of general formula

in which R8 is defined as above and R14 represents a fatty acid residue or a protective group for the amine function, it being understood that, when R14 represents a protective group for the amine function, this may be different from the protective group R12 of the peptide of general formula (XVII) and that the acid of general formula (IX) is then optionally reacted after unblocking the amine functions protected by the radicals R14 and / or R12, then separating the product obtained from its support and if necessary, remove the protective groups from the amine and carboxy functions.

dans laquelle R4, R8, Rg et R12 sont définis comme ci-dessus et R15 représente un groupement protecteur de la fonction amine, étant entendu que lorsque R12 et R15 représentent ou contiennent chacun un groupement protecteur de la fonction amine, ces groupements protecteurs sont différentes, puis, après déblocage de la fonction amine protégée par R15, de condenser :: - soit un dérivé de la L alanine de formule générale (XIX), puis, après déblocage des fonctions amines protégées par R13 et/ou R12, éventuellement l'acide gras de formule générale (IX), - soit un dérivé de la L alanine de formule générale (XX), puis à séparer le produit obtenu de son support et à éliminer, si nécessaire, les groupements protecteurs des fonctions amines et carboxy.According to a variant of the process, it is possible to fix on a suitable support the peptide of general formula

in which R4, R8, Rg and R12 are defined as above and R15 represents a protective group for the amine function, it being understood that when R12 and R15 each represent or contain a protective group for the amine function, these protective groups are different , then, after release of the amine function protected by R15, to condense :: - either a L alanine derivative of general formula (XIX), then, after release of the amine functions protected by R13 and / or R12, optionally the fatty acid of general formula (IX), - or a derivative of L alanine of general formula (XX), then separating the product obtained from its support and eliminating, if necessary, the protecting groups for the amine and carboxy functions.

dans laquelle R4, R8, Rg et R12 sont définis comme ci-dessus et R16 représente un groupement protecteur de la fonction amine, étant entendu que, lorsque R12 et R16 représentent ou contiennent chacun un groupement protecteur de la fonction amine, ces groupements peuvent être différents, puis, après déblocage des fonctions amines protégées par R16 et/ou R12, de condenser I1 acide de formule générale (IX), puis de séparer le.produit obtenu de son support et d'éliminer, si nécessaire, les groupements protecteurs des fonctions amines et carboxy. According to another variant of the process, it is possible to fix the peptide of general formula on an appropriate support:

in which R4, R8, Rg and R12 are defined as above and R16 represents a protective group for the amine function, it being understood that, when R12 and R16 each represent or contain a protective group for the amine function, these groups can be different, then, after unblocking the amino functions protected by R16 and / or R12, to condense the acid of general formula (IX), then to separate the product obtained from its support and to remove, if necessary, the protective groups from amine and carboxy functions.

 Herrifield peptide synthesis can also be carried out by fixing on a suitable support a product of general formula (XVIII) or (XXI) in which R8 represents a radical h; droxy- and the symbols R13 and R14 are respectively defined as above and the y-carboxy radical is protected, then, after unblocking the protective group then activation of the acid function, by reacting the di- or tripeptide of general formula (XVII) whose amine and carboxy functions are suitably protected, then if necessary, an acid of general formula (in).

dans laquelle R12 est défini comme précédemment et l'un des symboles
R4 ou Rg représente un radical carboxy et l'autre représente un atome d'hydrogène ou un radical carbamoyle ou alcoyloxycarbonyle dont la partie alcoyle contient i à 4 atomes de carbone et est éventuellement substituée par un radical phényle ou nitrophényle, et R17 représente un groupement protecteur de la fonction amine ou un reste d'un D aminoacide de formule générale

dans laquelle R8 est défini comme précédemment et R18 représente un groupement protecteur de la fonction amine ou un reste d'un L aminoacide de formule générale ::

dans laquelle R19 représente un groupement protecteur de la fonction aminz ou un reste d'acide gras défini précédemment, étant entendu que lorsque R17, R18 ou R19 représentent un groupement protecteur de la fonction amine, ce groupement est différent de R12 lorsque celui-ci représente ou contient un groupement protecteur de la fonction amine,
R12 pouvant cependant être identique à R19, et: - lorsque R17 représente un groupement protecteur de la fonction amine, d'éliminer ce groupement protecteur, puis de condenser ::
- soit un dérivé de l'acide D glutamique de formule générale (XXV) dans laquelle R18 représente un groupement protecteur de la fonction amine, puis, après élimination de R18, de condenser un dérivé de la L alanine de formule générale (XXVi) dans laquelle R19 est défini comme précédemment et,lorsque R19 et/ou R12 représente un groupement protecteur de la fonction amine, d'éliminer les radicaux R19 et/ou R12, puis de condenser l'acide de formule générale (IX),
- soit un dérivé de l'acide D glutamique de formule générale (XXV) dans laquelle R13 représente un reste d'un L aminoacide de formule générale (XXVI) dans laquelle Rlg est défini comme précédemment, et, lorsque R19 et/ou R12 représentent ou contiennent un groupement protecteur de la fonction amine, d'éliminer les radicaux R19 et/ou R12, puis de condenser l'acide gras de formule générale (in), - lorsque R17 représente un reste dssun aminoacide de formule générale (XXV) dans laquelle R13 représente un groupement protecteur de la fonction amine, d'éliminer ce groupement protecteur, puis de condenser un dérivé de la L alanine de formule générale (XXVI) dans laquelle Rlg est défini comme précédemment et, lorsque R19 et/ou R12 représentent ou contiennent un groupement protecteur de la fonction amine, d'éliminer les radicaux Rqg et/ou R12, puis de condenser acide gras de formule générale (IX), et - lorsque R17 représente un reste d'un aminoacide de formule générale (XXV) dans laquelle R13 représente un reste d'un L aminoacide de formule générale (XXVI) dans laquelle R19 représente un groupement protecteur de la fonction amine, d'éliminer les radicaux R19 et/ou R12, puis de condenser l'acide gras de formule générale (IX).When in the general formula (II), one of the symbols R2 or R4 represents an N-carbonyl glycyl or N-carbonyl D alanyl radical and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical of which the alkyl part contains 1 to 4 carbon atoms and is substituted by a phenyl or nitrophenyl radical, it being understood that when R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical R2 cannot represent a radical N-carbonyl glycyl or N-carbonyl D alanyl, it is possible to fix on a suitable support glycine or D alanine whose amine function is protected, then after unblocking the amine function, to condense an amino acid or a peptide of formula general ::

in which R12 is defined as above and one of the symbols
R4 or Rg represents a carboxy radical and the other represents a hydrogen atom or a carbamoyl or alkyloxycarbonyl radical in which the alkyl part contains i to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, and R17 represents a group protector of the amine function or a residue of a D amino acid of general formula

in which R8 is defined as above and R18 represents a protective group for the amine function or a residue of an L amino acid of general formula:

in which R19 represents a protective group for the aminz function or a fatty acid residue defined above, it being understood that when R17, R18 or R19 represent a protective group for the amine function, this group is different from R12 when the latter represents or contains a protective group for the amine function,
R12 can however be identical to R19, and: - when R17 represents a protective group for the amine function, to eliminate this protective group, then to condense:
- or a derivative of D glutamic acid of general formula (XXV) in which R18 represents a protective group for the amine function, then, after elimination of R18, to condense a derivative of L alanine of general formula (XXVi) in which R19 is defined as above and, when R19 and / or R12 represents a protective group for the amine function, to eliminate the radicals R19 and / or R12, then to condense the acid of general formula (IX),
- or a derivative of D glutamic acid of general formula (XXV) in which R13 represents a residue of an L amino acid of general formula (XXVI) in which Rlg is defined as above, and, when R19 and / or R12 represent or contain a protective group for the amine function, to eliminate the radicals R19 and / or R12, then to condense the fatty acid of general formula (in), - when R17 represents a residue of an amino acid of general formula (XXV) in which R13 represents a protective group of the amine function, to eliminate this protective group, then to condense a derivative of L alanine of general formula (XXVI) in which Rlg is defined as above and, when R19 and / or R12 represent or contain a protective group for the amine function, to eliminate the radicals Rqg and / or R12, then to condense fatty acid of general formula (IX), and - when R17 represents a residue of an amino acid of general formula (XXV) in which R13 rep contains a residue of an L amino acid of general formula (XXVI) in which R19 represents a protective group for the amine function, to eliminate the radicals R19 and / or R12, then to condense the fatty acid of general formula (IX) .

 When in the general formula (II), R3 represents a glycyl or D alanyl radical whose amine function is optionally substituted by a fatty acid residue, the introduction of such a radical can be carried out at any stage of Merrifield synthesis.

For example, it is possible to fix on a suitable support the product of general formula (XVII) in which R12 represents a protective group for the amine function different from R13, then to eliminate R12 without touching R13 and to condense a derivative of glycine or D alanine, the amine function of which is substituted by a protective group for the amine function or a fatty acid residue, then, after elimination of R13, to condense the product of general formula (XVIII) or (XXI) under the conditions indicated above, or it is possible to fix on a suitable support the product of general formula (XVII) in which R12 represents a protective group for the amine function, then to condense a product of general formula (XVIII) or ( XXI) under the conditions indicated above, then, after elimination of R12, to condense the glycine or the D alanine whose amine function is substituted by a group protecting the amine function or a residue of a fatty cide.

 The supports which are particularly suitable are chloromethylated or hydroxymethylated styrene-divinylbenzene copolymers.

Preferably the chloromethylated styrene-divinylbenzene (98-2 or 99-1) copolymer is used.

 The peptides of general formula (XVII), (XVIII), (XXI), (XXII) or (XXIII) are attached to the chloromethylated support according to the usual methods, in particular by reacting the peptide of general formula ( XVII), (XVIII), (XXI), (XXII) or (XXTII) in solution in an organic solvent such as methanol and in the presence of an acid acceptor such as triethylamine. It is particularly advantageous to heat the reaction mixture to a temperature close to the boiling point of the solvent.

 In the processes described above, the condensation of amino acids, peptides or acids on an amino acid or a peptide fixed on an appropriate support is carried out according to the usual methods used in peptide chemistry. It is the same with regard to the blocking and unblocking of the various functions which do not participate in the reactions.

The protecting groups for the amine functions of the peptides of general formula (XVII), (XVIII), (XXI), (XXII) or (XXIII) must be chosen in such a way that their elimination takes place without affecting the peptide support bond. In particular the radicals R1s,
R14, R15 and R16 must be different from the radical R12 when the latter represents or contains a protective group for the amine function and be such that their elimination is effected without touching the protective group R12 and the peptide-support bond.

Generally the ester functions represented by R4, R8 or
R9 are chosen in such a way that, during the cleavage of the peptide-support bond, the radicals R4, R8 or R9 can be either conserved or transformed into carboxy or carbamoyl radicals depending on whether the cleavage will be acid hydrolysis, alcoholysis or ammonolysis.

 More particularly, the peptide-support bond, which is of a benzylic nature, is cut by treatment using a hydrobromic acid-trifluoroacetic acid mixture by regenerating an acid function.

 The new tetra- or pentapeptides of general formula (II) can be optionally purified by physical (such as crystallization or chromatography) or chemical (such as salt formation, crystallization thereof and then decomposition) methods.

 The new products according to the invention can be transformed into addition salts with acids or into metal salts or into addition salts with organic bases depending on the nature of the substituents.

 The addition salts with acids can be obtained by the action of the new products on acids in an appropriate solvent.

Generally, the product is dissolved in water by adding the theoretical amount of acid and then the solution obtained is lyophilized.

 The metal salts or the addition salts with organic bases can be obtained by the action of the new compounds on mineral or organic bases in an appropriate solvent. Generally, the product is dissolved in water by adding the theoretical amount of base and then the solution obtained is lyophilized.

 The new compounds according to the present invention are adjuvants and stimulants of immunity: they increase the hypersensitivity reactions and / or the production of circulating antibodies vis-à-vis the antigens with which they are administered and they stimulate non-specific defense reactions against certain infections (for example infection of the mouse with the intracellular bacterium Listeria monocytogenes).

 In vitro, they are active at molar concentrations generally between 10-3 3 and 10 8, in particular in the following tests - stimulation of DNA synthesis (mitogenic power) according to the technique of G. MARCHAL, Ann. Immunol. (Inst. Pasteur), 125 C, 519 (1974).

- stimulation of the allogenic reaction (histo-incompatibility reaction) according to the technique of RW DUTTON, J. exp. Ned., 122, 759 (1966) and
AB PECK and F.ll. BACH, -J. Immunol. Methods, 3, 147 (1973) - stimulation of antibody production according to the technique of
PH KLESIUS, Proc. Soc. exp. Biol. Med. (NY), 135, 155 (1970) and
H. VAN DIJZ and N. BLOKSMA, J. Immunol. Methods, 14, 325 (1977) - increase in the number of phagocytic macrophages according to the technique of J. MICHL et al., J. exp. Med., 144, 1465 (1976) - stimulation of acid phosphatase activity and N- acetylglucosamidinase (lysosomal enzymes of macrophages) in the absence of an increase in lactic dehydrogenase according to the technique of P. DAVIES and paste
J. exp. Med., 139, 1262 (1974).

In vivo, in mice, at doses between 1 and 30 mg / kg, they increase delayed hypersensitivity and the production of antibodies in particular according to the TE MILLER technique and paste
J. Nath. Cancer Inst., 51, 1669 (1973).

 In the guinea pig, they increase the hypersensitivity reaction and the production of antibodies against bovine gammaglobulin coupled with the hapten dinitrophenol according to the technique of F. FLOCtH and paste Immunol.

 o @@@@ ic., Z. 7 41 (l978).

In mice, they stimulate the defense reactions against infection of the mouse with Listeria monocytogenes at doses between 1 and 100 mg / kg according to the technique of RN FAUVE and B. HEVIN, CR Acad. Sci. (D), 285, 1589 (1977)
In mice, they stimulate the power of elimination of colloidal carbon by the reticuloendothelial system according to the BN HALPERN technique and paste Ann. Institut Pasteur, 80, 582 (1951).

 In rabbits, at doses generally between 0.1 and 3 mg / kg, they stimulate the formation of serum anti-influenza virus antibodies according to the technique of G.H. CERNER et al., Biomedicines 22, 440 (1975).

 The following examples, given without limitation, illustrate the present addition.

 The products according to the present addition can form complexes with alkali or alkaline earth metals; it follows that the results of the elementary analysis of the products can deviate significantly from the theoretical values. However, the structure of the products is confirmed by the C / N ratio which is in agreement with the theory, by the amino acid content, and by their homogeneity in chromatography on minde layer of silica gel.

EXAMPLE 1
0.433 cm3 of isobutyl chloroformate is added to a solution, maintained at -5 ° C., of 698 mg of N-benyloxycarbonylglycine in a mixture of 65 cm3 of tetrahydrofuran and 0.467 cm3 of triethylamine. The mixture is stirred for 20 minutes at -5 ° C., then a solution cooled to 0 ° C. of 1.81 g of Na-LN- (N-lauroyl L alanyl) -yD glutamylj L methyl lysinate is added to a mixture of 3 , 33 cm3 of sodium hydroxide i N and 10 cm3 of water. The reaction mixture is stirred for 40 minutes at SOC then for 36 hours at around 190C, then is acidified to pH 1 by addition of 6 cm3 of hydrochloric acid iN Evaporated tetrahydrofuran under reduced pressure (20 mm of mercury) at 500C. The concentrate is extracted 5 times with 150 cm 3 in total of ethyl acetate. The combined ethyl acetate phases are washed with 30 cm3 of 0.1 N hydrochloric acid, dried over sodium sulfate. After dry concentration under reduced pressure (20 μm of mercury) at 50 ° C., 2.53 g of oil is obtained which is dissolved in 100 cm3 of ethyl acetate containing 6 g of neutral silica gel (0, The mixture is concentrated to dryness and the whole is loaded onto a column 3 cm in diameter containing 50 g of neutral silica gel (0.04-0.063 mm).

 Eluted successively with 80 cm3 of ethyl acetate, 280 cm3 of an ethyl acetate-acetic acid mixture (95-5 by volume), collecting 40 cm3 fractions. Fractions 4 to 8, combined, are concentrated to dryness under reduced pressure (20 mm of mercury) at 50 C.

 2.33 g of oil are obtained, which is again chromatographed.

This oil is dissolved in 60 cm3 of acetic acid containing 5 g of neutral silica gel (0.04-0.063 mm). The mixture is concentrated to dryness and the whole is loaded onto a column 3 cm in diameter containing 100 g of neutral silica gel (0.04-0.063 mm).

 Eluted successively with 680 cm3 of ethyl acetate, 360 cm3 of a mixture of ethyl acetate acetic acid (97.5-2.5 by volume) 360 cm3 of a mixture of ethyl acetate-acetic acid ( 95-5 by volume) 360 cm3 of an ethyl acetate-acetic acid mixture (90-10 by volume) 240 cm3 of an ethyl acetate-acetic acid mixture (80-20 by volume), collecting fractions 40 cm3. Fractions 32 to 41 combined are concentrated to dryness under reduced pressure (? 0 mm of mercury) at 500 C.

 1.35 g of Na-CN- (N-lauroyl L alanyl) -y-D glutamyl] Ns- (benzyloxycarbony1 glycyl) L methyl lysinate are thus obtained in the form of an oil.

Rf = 0.47 Csilicagel, ethyl acetate-acetic acid
(1-1 by volume)].

 1.3 g of Na-LN- (N-lauroyl L alanyl) -y-D glutamylj Ne- (benzyloxycarbonyl glycyl) L methyl lysinate are dissolved in 35 cm3 of acetic acid. 1.3 g of palladium on black (3% palladium) are added and a light stream of hydrogen is passed through for 2.5 hours.

After filtration and concentration of the filtrate to dryness under reduced pressure (20 min of mercury) at 500 ° C., an oily residue is obtained which is triturated until sprayed in 50 cm 3 of ether. The powder is separated by filtration and air dried. 910 mg of crude product are thus obtained which is chromatographed on a column 2 cm in diameter containing 40 g of neutral silica gel (0.04-0.063 mm). Eluted successively with 160 cm 3 of ethyl acetate, 80 cm 3 of a mixture of ethyl acetate and acetic acid (50-50 by volume) and 420 cm 3 of acetic acid, collecting 20 cm 3 fractions. Fractions 14 to 20, combined, are concentrated to dryness under reduced pressure (20 mm of mercury) at 50 C.

The residue obtained is triturated in 40 cm3 of ether. After filtration and air drying, 370 mg of Na-EN- (N-lauroyl L alanyl) -y are obtained.
D glutamyl] Ne-glycyl L methyl lysinate in the form of a cream powder.

Rf = 0.50 (silica gel; n.butanol-pyridine-acetic acid-water
(50-20-6-24 by volume) 3
Rf = 0.27 (silica gel; acetic acid)
Calc% analysis = C 58.07 H 8.91 N 11.68
Tr. 57.0 8.6 11.1
Sulfuric ash: 22%
After total hydrolysis, analysis on a Technicon autoanalyzer reveals the presence of the following amino acids
Ala 1.00 (theory = 1)
Glu 1.01 (theory = i)
Gly 0.98 (theory = 1)
Lys 0.96 (theory = i)
N α - [N- (N-lauroyl L alanyl) -yD glutamyl] L methyl lysinate can be prepared as follows:
1.3 cm3 of isobutyl chloroformate are added to a solution,
maintained at -50C, 4.91 g of N-aluroyl L alanyl- α-D ben glutamate
zyle in a mixture of 250 em3 of tetrahydrofuran and 1.4 cm3 of
triethylamine. The mixture is stirred for 20 minutes at -50C, then
a solution cooled to 0 C of NE-benzyloxy hydrochloride is added
carbonyl L methyl lysinate in a mixture of 10 cm3 of 1N sodium hydroxide and
10 cm3 of water. The reaction mixture is stirred for 10 minutes to
-50C, then for 4 Days at a temperature close to 20 C. Then,
the reaction mixture is acidified to pal l by addition of 20 cm3
1N hydrochloric acid. We evaporate it. tetrahydrofuran by concentra
tion under reduced pressure (20 mm of mercury) at 45 C. The concentrate is
extracted 5 times per 150 cm3 in total of chloroform. The chloro- phases
formics, renies, are washed with 40 cm3 of 0.1N hydrochloric acid and dried over sodium sulfate. After dry concentration under reduced pressure (20 mm of mercury) - at 50 C, a pale yellow oil is obtained which is dissolved in 60 cm5 of chloroform containing 15 g of neutral silica gel (0.04-0.063 mm ). The mixture is concentrated to dryness and the whole is loaded onto a column 5 cm in diameter containing 150 g of neutral silica gel (0.04-0.063 mm). Eluted successively with 2.5 l of acetate. ethyl and 400 cm3 of an ethyl acetate-acetic acid mixture (95/5 by volume), collecting fractions of 100 cm5. Fractions 6 to 27, combined, are concentrated to dryness under reduced pressure (20 mm of mercury) at 500C. 3.47 g of N α [O-benzyl N- (N-lauroyl) are thus obtained.
L alanyl) -yD glutamyl] NE -benzyloxycarbonyl L methyl lysinate in the form of a white powder.

Rf = 0.70 [silica gel; ethyl acetate-acetic acid (95/5 by volume
Rf = 0.40 [silica gel; ethyl acetate
3.43 g of N α [O-benzyl N- (N-lauroyl L alanyl) are dissolved
YD glutamyl] N # -benzyloxycarbonyl L methyl lysinate in 70 cm3 of acetic acid. 3.45 g of palladium on black (3% of palladium) are added then a light stream of hydrogen is passed through for 2 hours.

The catalyst is separated by filtration, washed twice with 20 cm3 in total of acetic acid, the combined filtrates are concentrated to dryness under reduced pressure (20 mm of mercury) at 50 C. The residue is triturated in 50 cm3 of ether . A powder is thus obtained which is separated by filtration and which is dried in air. 1.89 g of Na-tN- (N-lauroyl L alanyl) -y-D glutamyl] L methyl lysinate are thus obtained.

Rf = 0.50 Csilicagel; not. butanol-pyridine-acetic acid
water (50-20-6-24 by volume)]
Rf = 0.29 Csilicagel; acetic acid].

EXAMPLE 2
1.07 cm3 of isobutyl chloroformate is added to a solution, maintained at -5 ° C., of 4.026 g of N-lauroyl L alanyl-aD benzyl glutamate in a mixture of 135 cm3 of tetrahydrofuran and 1.15 cm3 of triethylamine. The mixture is stirred for 20 minutes at -7 ° C., then a solution cooled to 40 ° C. of N & alpha hydrochloride ;-( benzyloxycarbonylglycyl) L lysinamide is added in a mixture of 8.2 cm3 of 1N sodium hydroxide and 22 cm3 of water. The reaction mixture is stirred for 10 minutes at around -5 ° C., then for 65 hours at around 200 ° C., then is acidified to pH 1 by adding 11 cm3 of 1N hydrochloric acid.

The tetrahydrofuran is evaporated under reduced pressure (20 mm of mercury) at 450C. The concentrate is diluted by adding 50 cm3 of water. The precipitate formed in the concentrate is separated by filtration, washed 3 times with 75 cm 3 in total of water and dried. 5.58 g of white solice are thus obtained which is dissolved in 70 cm3 of acetic acid containing 12 g of neutral silica gel (0.04-0.063 mm). The mixture is concentrated to dryness and the whole is loaded onto a column 3 cm in diameter containing 100 g of neutral silica gel (0.04-0.063 mm).

 Eluted successively with 350 cm3 of ethyl acetate 250 cm3 of an ethyl acetate-acetic acid mixture (95-5 by volume) 850 cm3 of an ethyl acetate-acetic acid mixture (9-1 in volumes) 450 cm3 of an ethyl acetate-acetic acid mixture (75-25 by volume) 350 cm3 of an ethyl acetate-acetic acid mixture (1-1 by volume), collecting 50 cm3 fractions. Fractions 34 to 39, combined, are concentrated to dryness under reduced pressure (20 mm of mercury) at 50 c.

The meringue obtained is taken up in 50 cm3 of ether, triturated until complete spraying, separated by filtration and dried under reduced pressure (0.3 mm of mercury). 1.43 g of a- (benzyloxycarbonyl glycyl) N-LO1-benzyl N- (N-lauroyl L alanyl) -yD glutamyl] are thus obtained.
Lysinamide.

Rf = 0.88 Lsilicagel; n.butanol-pyridine-acetic acid-water
(50-20-6-24 by volume)]
Rf = 0.37 Lsilicagel; ethyl acetate-acetic acid
(3-1 by volume)]
1.43 g of Na- (benzyloxycarbonylglycyl) Ne- [O-benzyl N- (N-lauroyl L alanyl) -yD glutamyl] L lysinamide are dissolved in 85 cm3 of acetic acid. 1.43 g of palladium on black (3% palladium) is added) and a light stream of hydrogen is passed through for 2 hours.

The catalyst is separated by filtration, washed twice with 20 cm 3 in total of acetic acid, the combined filtrates are concentrated to dryness under reduced pressure (20 mm of mercury) at 50 ° C. The oily residue thus obtained is triturated in 75 ml of ether and gives a solid which is separated by filtration. 990 mg of white solid are thus obtained, to which 490 mg of a similar product obtained in the same way is added, and which is chromatographed on a column 2 cm in diameter containing 29 g of neutral silica gel (0.04-0.063 mm). Eluted with acetic acid, collecting 40 cm3 fractions. Fractions 13 to 32, combined, are concentrated to dryness under reduced pressure (20 mm of mercury) at 500 C. This gives 510 mg of Na-glycyl Ne- [N- (N-lauroyl L alanl) - yD glutamyl] Lysinamide.

Rf = 0.42 [silica gel; n.butanol-pyridine-acetic acid-water
(50-20-6-24 by volume)]
Wedge analysis% = C 57.51 H 8.97 N 14.37
Tr. 54.9 8.6 13.3
Sulfuric ash: 1.6%
After total hydrolysis, analysis on a Technicon autoanalyzer reveals the presence of the following amino acids:
Ala 1.04 (theory = 1)
Glu 0.99 (theory = 1)
Gly 1.00 (theory = 1)
Lily 0.95 (theory = 1)
Na- (benzyloxycarbonyl glycyl) L lysinamide hydrochloride can be prepared as follows:
4.18 g of N α-( benzyloxycarbonyl glycyl) Nt.butyl-oxycarbonyl L lysinamide are dissolved in 80 cm 3 of an anhydrous solution of hydrochloric acid 1.7 N in acetic acid. The mixture is stirred for 2 hours at a temperature in the region of 200 c, then the reaction medium is added to 400 cm3 of anhydrous ether. An oily precipitate is separated by decantation, washed with 200 cm3 of ether and dried under reduced pressure (0.3 mm of mercury). 3.16 g of Na- (benzyloxycarbonylglycyl) L lysinamide hydrochloride are thus obtained in the form of a paste.

Rf = 0.48 [silica gel; n.butanol-pyridine-acetic acid-water
(50-20-6-24 by volume)].

N α-( benzyloxycarbonyl glycyl) NE -t.butyloxycarbonyl
Lysinamide can be prepared as follows
1.267 cm3 of isobutyl chloroformate is added to a solution, maintained at −1 ° C., of 2.397 g of N-benzyloxycarbonyl glycine in a mixture of 35 cm3 of tetrahydrofuran and 1.365 cm3 of triethylamine. The mixture is stirred for 20 minutes at -30 ° C., then a solution cooled to 5 ° C. of 3.25 g of Ne-t.butyloxycarbonyl L lysinamide in 50 cm 3 of tetrahydrofuran is added. The reaction mixture is stirred for 15 minutes at around -5 ° C., then for 20 hours at around 20 ° C. The insoluble material is separated by filtration, then the tetrahydrofuran is evaporated under reduced pressure (20 mm of mercury) at 450C.

The concentrate is diluted by adding 150 cm3 of water, extracted 3 times with 225 cm3 in total of ethyl acetate. The ethyl acetate phases, combined, are washed successively with 60 cm3 of 0.1 N ice-cold hydrochloric acid, 60 cm3 of a 10% solution of sodium carbonate and twice with 120 cm3 in total of a solution saturated with sodium chloride and dried over sodium sulfate. After concentration to dryness under reduced pressure (20 mm of mercury) at 450C, 4.18 g of Na- (benzyloxycarbonyl glycyl) Ne-t.butyloxycarbonyl L lysinamide are obtained in the form of an oil.

Rf = 0.77 Lsilicagel; ethyl acetate-acetic acid
(3-1 by volume)]
Ne-t.butyloxycarbonyl L lysinamide can be prepared as follows
1.3 cm3 of isobutyl chloroformate are added to a solution maintained at -50C of 3.8 g of Na-benzyloxycarbonyl Ne-t.butyloxycarbonyl L lysine in a mixture of 38 cm3 of chloroform and 1.4 cm3 of triethylamine . The mixture is stirred for 20 minutes at -5 ° C., then a light stream of ammonia is sent for 3 hours.

Then, the reaction medium is diluted by adding 100 cm of chloroform, washed twice with 100 cm in total of a 10% solution of sodium carbonate, 5 times with 250 cm3 in total of water and dried over sulphate of sodium. After concentrating to dryness under reduced pressure (20 mm of mercury) at 50 C, 3.76 g of Na-benzyioxycarbonyl Ne-t.butyl-oxycarbonyl L lysinamide melting at 142-144 C. are obtained.

Rf = 0.52 Lsilicagel; ethyl acetate
3.7 g of Na-benzyloxycarbonyl Ne-t.butyloxycarbonyl are dissolved
L lysinamide in 130 cm3 of acetic acid. 3.7 g of palladium on black (3% palladium) are added and a light stream of hydrogen is passed through for 2 hours. The catalyst is separated by filtration, washed twice with 20 cm 3 in total of acetic acid; the combined filtrates are concentrated to dryness under reduced pressure (20 mm of mercury) at 50 C.

The oily residue is triturated in 200 cm3 of ether. After decantation and drying, 3.25 g of Ne-t.butyloxycarbonyl L lysinamide are obtained.

Rf = 0.60 Lsilicageî; n.butanol-pyridine-acetic acid-water
(50-20-6-24 by volume)]
EXAMPLE 3
0.31 cm3 of isobutyl chloroformate is added to a solution, maintained at −110 ° C., of 506 mg of N-benzyloxycarbonyl glycine in a mixture of 40 cm3 of tetrahydrofuran and 0.34 cm3 of triethylamine. The mixture is stirred for 20 minutes at -11 ° C., then a solution cooled to 50C of 1.69 g of N6-L01-benzyl N- hydrochloride (N-lauroyl L alanyl) -yD glutamyl] DD is added. , LL diamino-2,6 pimelamic in a mixture of 4.84 cm3 of 1N sodium hydroxide and 40 cm3 of water. The reaction mixture is stirred for a few minutes at around -10 ° C., then for 65 hours at around 200 G. Then it is acidified to pH 1 by adding 10 cm3 of 1N hydrochloric acid. The tetrahydrofuran is evaporated by concentration under pressure reduced (20 tmn of mercury) to 500C. The white precipitate which appears in the concentrate is separated by filtration, washed 4 times with 80 cm 3 in total of water and dried in the open air. 1.74 g of crude product are obtained which is dissolved in 30 cm3 of acetic acid containing 5 g of neutral silica gel (0.040.063 mm) - The mixture is concentrated to dryness under reduced pressure (20 mm of mercury) to sooc and the whole is loaded onto a column 30 mm in diameter containing 60 g of neutral silica gel (0.04-0.063 niai).

 Eluted successively with 160 cm 3 of an ethyl acetate-acetic acid mixture (9-1 by volume) 560 cm 3 of an ethyl acetate-acetic acid mixture (8-2 by volume), collecting fractions of 20 cm3. Fractions 16 to 25 combined, are concentrated to dryness under reduced pressure (20 niai of mercury) at 50 C.

The amorphous solid obtained is taken up in 30 cmd of ether, triturated until total spraying, separated by filtration and dried under reduced pressure (0.3 ml of mercury). 320 mg of acid are thus obtained.
N6-O -benzyl N- (N-lauroyl L alanyl) -yD glutamyl] N2-benzyloxycarbonyl glycyl DD, LL diamino-2,6 pimelamic.

 320 mg of N6- [O-benzyl N- (N-lauroyl L alanyl) -y-D glutamyl3 N2-benzyloxycarbonyl glycyl DD, LL diamino-2,6 pimelamic acid are dissolved in 25 cm3 of acetic acid. 320 mg of palladium on black (<3% palladium) are added) and a slight stream of hydrogen is passed through for 2 1/4 hours. After filtration and dry concentration of the filtrate under reduced pressure (20 mm of mercury) at 50 ° C., 290 mg of solid is obtained which is chromatographed on a column 1 cm in diameter containing 6 g of neutral silica gel (0 , 04-0.063 mm).

Eluted with acetic acid, collecting 5 cm 3 fractions.

Fractions 25 to 32 combined, are concentrated to dryness under reduced pressure (20 mm of mercury) at 50 C. The amorphous solid obtained is taken up in 20 cm3 of ether, separated by filtration and dried under reduced pressure (0.3 mm of mercury) at 20 C. This gives 30 mg of N6- [N- (N-lauroyl L alanyl) - &gamma;-D glutamyl] N-glycyl DD, LL 2,6-diamino pimelamic acid.

Rf = 0.22 [silica gel> n.butanol-pyridine-acetic acid-water
(50-20-6-24 by volume)]
After total hydrolysis, analysis on a Technicon autoanalyzer reveals the presence of the following amino acids:
Ala 0.95 (theory = 1)
Glu 1.04 (theory = 1)
Gly 1.00 (theory = 1)
Dap 0.95 (theory = 1)
N6- [O-Benzyl-N- (N-lauroyl) hydrochloride
L alanyl) -yD glutamyl] LL, DD diamino-2,6 pimelamic can be prepared as follows
0.56 cm3 of isobutyl chloroformate is added to a solution, maintained at -5 ° C., of 2.12 g of N-lauroyl L alanyl- &alpha;-D benzyl glutamate in a mixture of 86 cm3 of tetrahydrofuran and 0, 6 cm3 of triethylamine. The mixture is stirred for 30 minutes at -5 ° C., then a solution cooled to 20 ° C. of 1.25 g of N2-t.butyloxycarbonyl DD, LL diamino-2,6 pimelamic acid in a mixture of 4.32 cm3 is added. 1N soda and 43 cm3 of water. The reaction mixture is stirred for a few minutes at around -5 ° C., then for 18 hours at around 200G.

Then, it is acidified by adding 50 cm3 of a saturated solution of citric acid. The tetrahydrofuran is evaporated by concentration under reduced pressure (20 niai of mercury) at 500 c. The concentrate is extracted 5 times with 200 cm 3 in total of ethyl acetate. The combined ethyl acetate phases are washed with 25 cm3 of water, dried over sodium sulfate After concentration to dryness under reduced pressure (20 ml of mercury) at 50 ° C., an oil is obtained which is dissolved in a mixture of 50 cm3 of ethyl acetate and 10 cm3 of acetic acid containing 10 g of neutral silica gel (0.04-0.063 mm). The mixture is concentrated to dryness under reduced pressure (20 mm of mercury) at 50 C and the whole is loaded on a column 2 cm in diameter containing 50 g of neutral silica gel (0.04-0.063 niai).

 Eluted successively with 200 cm3 of ethyl acetate, 280 cm3 of an ethyl acetate-acetic acid mixture (95-5 by volume) 320 cm3 of an ethyl acetate-acetic acid mixture (9-1 by volume) by collecting 40 cm3 fractions. Fractions 5 to 13 combined, are concentrated to dryness under reduced pressure (20 mm of mercury) at 50 C.

2.23 g of N6- [O-benzyl N- (N-lauroyl L alanyl) - &gamma; - are thus obtained.
D glutamyl] Nt.butyloxycarbonyl LL, DD diamino-2,6 pimelamic as oil.

Rf = 0.39 (silica gel; ethyl acetate-acetic acid
(9-1 by volume
2.19 g of N6-LO1-benzyl N- (N-lauroyl L alanyl) acid are dissolved
2 y-glutamyl] N -t.butyloxycarbonyl DD, LL diamino-2,6 pimelamic in 22 cm3 of an anhydrous saturated solution of hydrochloric acetic acid. It is left in contact for 3 hours at 200C, then concentrated to dryness under reduced pressure (20 mm of mercury) at 500C. 1.74 g of hydrochloride of N6-L01-benzyl N- (N-lauroyl L alanyl) - &gamma;-D glutamyl] DD, LL diamino-2,6 pimelamic acid are thus obtained in the form of partially crystallized oil. .

Rf = 0.47 [silica gel; n.butanol-pyridine-acetic acid-water
(50-20-6-24 by volume)]
Rf = 0.26 [silica gel; acetic acid
Nt.butyloxycarbonyl DD, LL diamino-2,6 pimelamic acid can be prepared as follows
4 g of N2-t.butyloxycarbonyl N6-benzyloxycarbonyl DD, LL diamino-2,6 pimelamic acid are dissolved in 100 cm3 of acetic acid.

4 g of palladium on black (3% palladium) are added and a light stream of hydrogen is passed through for 3 hours. The catalyst is separated by filtration, washed with 10 cm 3 of acetic acid, the combined filtrates are concentrated to dryness under reduced pressure (20 mm of mercury) at 50 ° C. The oily residue thus obtained is triturated in 50 cm3 of ether until complete spraying. After filtration and drying, 3 g of N-t acid are thus obtained. butyloxycarbonyl DD, LL 2,6-diamino pimelamic.

Rf = 0.34 [silica gel; acetic acid]
EXAMPLE 4
To a solution of 7.87 g of Na-t.butyloxycarbonyl Ne- (benzyl-oxycarbonyl glycyl) -lysine in 70 cm3 of ethanol, 15 g of styrene-divinylbenzene (98-2) chloromethylated copolymer containing 1.2 are added. milliequivalent of chlorine per gram. The reaction medium is stirred for 10 minutes at 20 ° C., then 2.25 cm 3 of triethylamine is added and the stirring is continued for 65 hours at 78 ° C. The polymer is filtered, washed successively with 3 times 300 cm3 in total of ethanol and 3 times 300 cm3 in total of methylene chloride, then dried under reduced pressure (0.3 niai of mercury) at 200C. Na-t.butyloxycarbonyl N (benzyloxycarbonyl glycyl) L lysyl-polymer is thus obtained.

After total hydrolysis, analysis on a Technicon autoanalyzer reveals the presence of the following amino acids
Gly 0s35 mmol per gram of polymer
Lys 0.33 mmol per gram of polymer
The glutamic acid D is attached to the blockpolymer dipeptide by carrying out the following series of operations in a reactor fitted with an agitator and, at its base, with a sintered glass filter i) Three successive washes of the blocked dipeptide are carried out -polymer by
100 cmd of methylene chloride each time. each addition of
solvent is followed by stirring for 3 minutes, then wringing.

2) The t.butyloxycarbonyl protective group is then removed
by adding 100 cm3 of a trifluoroacetic acid-chloride mixture
methylene (il-in volumes), stirring for 20 minutes then
spinning.

3) The resin is then washed successively with
a / 3 times 100 cm3 of methylene chloride
b / 3 times 100 cm3 of methanol
ci 3 times 100 cm3 of methylene chloride
stirring for 3 minutes after each addition of solvent and
wringing each time.

4) The dipeptide-polymer is then neutralized by adding 100 cm3 of a
methylene chloride-triethylamine mixture (9-1 by volume) stirring
for 10 minutes then spin.

5) The resin is then washed with
3 times roe cm3 of methylene chloride
stirring for 3 minutes after each addition of solvent and
wringing each time 6) 5.2 g of Nt.butyloxycarbonyl Ol-benzyl 05-succinimido acid are added
D glutamic acid dissolved in 100 cm3 of methylene chloride and
stir for 18 hours and spin.

7) The resin is washed successively with
a / 3 times 100 cm3 of methylene chloride
b / 3 times 100 cm3 of acetic acid
c / 3 times 100 cm3 of methylene chloride
stirring for 3 minutes after each addition of solvent and
wringing each time.

8) 5.2 g of Nt.butyloxycarbonyl Ol-benzyl 05-succinimido acid are added
D glutamic solution in 100 cm3 of methylene chloride and
stir for 18 hours and spin.

9) The resin is washed successively with
a / 3 times 100 cm3 of methylene chloride
b / 3 times 100 cm3-d1 acetic acid
c / 3 times 100 cm3 of methylene chloride
stirring for 3 minutes after each addition of solvent and
wringing every time
Na- (01-benzyl Nt.butyloxycarbonyl is thus obtained
D glutamyl) N # - (benzyloxycarbonyl glycyl) t lysyl-polymer.

 The alanine is hung on the blocked-polymer tripeptide by repeating the previous operations n 1, 2, 3, 4, 5, 6 and 9.

Operation 6 is modified as follows
Was successively added: a / 4.7 g of Nt.butyloxycarbonyl L alanine in solution in 100 cm3 of
methylene chloride and stirred for 10 minutes b / 5.16 g of dicyclohexylcarbodiimide and stirred for 16 hours and
wring.

 Na-E01-benzyl N- (t.butyloxycarbonyl L alanyl) -y-D glutamyl] Ne- (benzyloxycarbonyl glycyl) L lysyl-polymer is thus obtained.

 The octanotic acid is hung on the blockpolymer tetrapeptide by repeating the previous operations n 1, 2, 3, 4, 5, 6 and 9.

Operation 6 is modified as follows:
A / 1.64 g of octanotque acid dissolved in 100 cm3 of chloride is successively added
methylene and stirred for 10 minutes b / 2.35 g of dicyclohexylcarbodiimide and stirred for 16 hours and
wring.

 Na-tOl-benzyl N- (N-octanoyl L alanyl) -y-D glutamyl Ne- (benzyloxycarbonyl glycyl) L lysyl-polymer is thus obtained.

 The polymer is suspended in 100 cm3 of trifluoroacetic acid contained in a reactor fitted with an agitator and, at its base, a sintered glass filter. A suspension of hydrobromic acid is passed through this suspension for 90 minutes. Then, the resin is drained and washed 3 times with 300 cm 3 in total of acetic acid, stirring for 3 minutes after each addition of acetic acid and wringing each time. The filtrates are combined and concentrated to dryness under reduced pressure (20 mm of mercury) at 500C. The oily residue obtained is taken up twice with a total of 50 cm 3 of methanol and concentrated to dryness each time under reduced pressure (20 mm of mercury) at 500 C. This gives approximately 2 g of oil which is chromatographed on a column 1.6 cm in diameter containing 15 g of neutral silica gel (0904-0,063 niai).

 Eluted successively with 300 cm3 of an ethyl acetate-acetic acid mixture (3-1 by volume) 250 cm3 of an ethyl acetate-acetic acid mixture (1-1 by volume) 250 cm3 of a mixture ethyl acetate-acetic acid - (1-3 by volume) and 350 cm3 of acetic acid, collecting fractions of 50 cm3.

 Fractions 8 to 23 combined are concentrated to dryness under reduced pressure (20 ml of mercury) at 500C. This gives 0.94 g of a cream powder which is again chromatographed on a column 1.5 cm in diameter containing 10 g of neutral silica gel (0.04-0.063 mm).

Eluted successively with 100 cm3 of ethyl acetate and 500 cm3 of an ethyl acetate-methanol mixture (9-t by volume), collecting 50 cm3 fractions. Fractions 6 to 10 combined, are concentrated to dryness under reduced pressure (20 niai of mercury) at 50 C. This gives 390 mg of N & alpha hydrobromide; - [O-methyl N- (N-octanoyl L alanyl) -yD glutamyl] Ne-glycyl L methyl lysinate.

Rf = 0.69 Lsilicagel; n.butanol-pyridine-acetic acid-water
(50-20-6-24 by volume)]
Rf = 0.75 [silica gel; isoamyl alcohol-pyridine-water
(35-35-30 by volume)]
Calc% analysis = C 48.90 H 7.58 N 10.97
Tr. 45.3 6.8 10.1
Sulfuric ash: 5.21 7.

After total hydrolysis, analysis on a Technicon autoanalyzer reveals the presence of the following amino acids
Ala 1.00 (theory = 1)
Glu 0.90 (theory = 1)
Gly 1.16 (theory = 1)
Lys 1.10 (theory = 1)
Na-t.butyloxycarbonyl N # - (benzyloxycarbonyl glycyl)
Lysine can be prepared according to the method of M. KHOSLA and paste Indian J. Chem. 5, 237 (1967).

 The present addition also relates to pharmaceutical compositions which contain at least one compound according to the invention in combination with one or more diluents or excipients which are compatible and pharmaceutically acceptable. These compositions can be used either as adjuvants for vaccines or as non-specific stimulants of anti-infectious and anti-tumor immunity.

 Used as adjuvants for vaccines, the products according to the invention are administered at the same time and by the same route as the antigen (viral, bacterial, parasitic or of other nature) against which it is desired to increase in the immunized subject (man or domestic animal) ) cellular immunity reactions (delayed type hypersensitivity) or the production of circulating or local antibodies.

 The products are administered in relatively low doses (of the order of mg), mixed with the antigen and by the same route (intramuscular, subcutaneous, intravenous, intranasal, buccal).

If necessary, the product and the antigen can be emulsified in a suitable oily excipient or incorporated into liposomes.

 As non-specific immunostimulants, they are administered in doses of between 0.1 and 50 mg / kg parenterally (intravenously, subcutaneously, intramuscularly), intranasally, buccally, rectally, or possibly intratumorally.

 As solid compositions for oral administration, tablets, pills, powders or granules can be used.

In these compositions the active product is mixed with one or more diluents such as sucrose, lactose or starch. These compositions can also include substances other than diluents, for example a lubricant, such as magnesium stearate.

 As liquid compositions for oral administration, there may be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing inert diluents, such as water or paraffin oil. These compositions can include substances other than diluents, for example wetting, sweetening or flavoring products.

 The compositions for parenteral administration can be sterile aqueous solutions, suspensions or emulsions. As a vehicle in these latter cases, one can. use polyethylene glycol, propylene glycol, vegetable oils, in particular olive oil, and injectable organic esters, for example ethyl oleate.

These compositions can also contain adjuvants, in particular wetting agents, emulsifiers or dispersants.

 Sterilization can be done in several ways, for example using a bacteriological filter, incorporating sterilizing agents into the composition or by heating. They can also be prepared in the form of solid compositions, rendered sterile for example by irradiation, which can be dissolved in sterile water or dispersed in any other sterile injectable medium, optionally at the time of use.

 The compositions for intra-nasal administration can be aqueous sterile solutions, suspensions or emulsions which can optionally be combined with a compatible propellant.

 The compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients, such as cocoa butter or suppo-wax.

The following example, given without implied limitation, illustrates a composition according to the invention: EXAMPLE
An intravenous solution having the following composition - NaSN- (N-lauroyl L alanyl) -yD glutamylj is prepared according to the usual technique
Ne-glycyl L methyl lysinate ... 0.5 g - solution for injection ... 5 cm3

Claims (11)

REvENn I CATION S 1 - A new tetra- or pentapeptide characterized in that it corresponds to the general formula in which R represents a hydrogen atom or a fatty acid residue, R1 represents a hydroxy, amino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, one of the symbols R2 or R4 represents a hydrogen atom or a carboxy, carbamoyl, alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms is optionally substituted by a phenyl or nitrophenyl radical, or an N-carbonyl glycyl or N-carbonyl D alanyl radical optionally esterified by an alkyl radical containing i to 4 carbon atoms (optionally substituted by a phenyl or nitrophenyl radical) and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms is optionally substituted by a phenyl radical or ni trophenyl, R3 represents a hydrogen atom or a fatty acid residue or a glycyl or D alanyl residue, the amine function of which is optionally substituted by a fatty acid residue, it being understood that the symbols R2 and R4 cannot represent simultaneously a hydrogen atom, and that, when R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical, R2 cannot represent a carboxy, N-carbonyl glycyl or N-carbonyl D alanyl radical , and it being understood that one of the symbols R2, R3 and R4 represents or contains a glycyl or D alanyl residue and that at least one of the symbols R and R3 represents or contains a fatty acid residue, and it being understood that alanine linked to glutamic acid is in L form, glutamqieu acid or its derivatives is in D form, lysine or its derivatives, when one of the symbols R2 or R4 represents a hydrogen atom is in form L and 2,6-diamino pimelic acid or its derivatives, when R2 and R4 r epresent a carboxy radical or a derivative of the acid function is in D, D form; L, L; DD, LL (racemic) or D, L meso, and its salts. 2 - A new tetra- or pentapeptide according to claim i, characterized in that the fatty acid residue is an alkanoyl radical containing 1 to 45 carbon atoms, optionally substituted by a hydroxy, phenyl or cyclohexyl radical, an alkenoyl radical containing 3 to 30 carbon atoms and may contain more than one double bond, or a residue of mycolic acid. 3 - Process for preparing a product according to claims i or 2 characterized in that an amino acid of general formula is made to act:

 in which R5 represents a hydrogen atom or a fatty acid residue or a group protecting the amine function, R6 represents a hydrogen atom or the methyl radical, it being understood that in this case the alanine is in D form and R1 represents a hydroxy radical or an alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical on a tri- or tetrapeptide of general formula:

 in which R7 represents a fatty acid residue or a protecting group for the amine function, R8 represents a hydroxy, amino or alkoxy radical containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, one of the symbols R4 or R9 represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical or an N-carbonyl glycyl or N-carbonyl D alanyl radical optionally esterified by an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains i to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyl radical loxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, it being understood that R4 and Rg cannot simultaneously represent a hydrogen atom, and R10 represents a hydrogen atom or a fatty acid residue or a protective group for the amine function or a glycyl or D alanyl radical whose amine function is optionally substituted by a fatty acid residue or by a protective group for the amine function, it being understood that one at least radicals R7 or R10 represents or contains a fatty acid residue and that, R4 and Rg being defined above, R10 represents a hydrogen atom and that, when one of the symbols R4 or Rg represents a carboxy radical, the other represents a hydrogen atom or a carbamoyl or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, Rlo represents a fatty acid residue or a protective group for the amine function or a glycyl or iD alanyl residue in which the amine function is substituted by a fatty acid residue or a protective group for the amine function, then optionally replaces the radicals R5, R7 and / or R10 (when they represent or contain a protective group for the amine function) with a hydrogen atom and the radicals R 'and R8 (when they represent an alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical) by a hydroxy radical and by radicals R4 and / or Rg (when they represent or contain an alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical) by a carboxy radical, it being understood that in the final product, R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a radical carbamoyl, R2 is different from a carboxy, N-carbonyl glycyk or N-carbonyl D alanyk radical and isolates the product obtained optionally in the form of a salt. 4 - A process according to claim 3 for the preparation of a product according to claim 1 or 2 in the formula of which R2 or R4 represents an N-carbonyl glycyl or N-carbonyl-D alanyl radical characterized in that one makes react an amino acid of general formula

 in which R 'represents a hydroxy or alkoxy radical containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and R6 represents a hydrogen atom or the methyl radical, on a tri- or tetrapeptide of general formula

 in which R7 represents a fatty acid residue or a protecting group for the amine function, R8 represents an amino or alkoxy radical containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, one of the symbols R4 or Rg represents a carboxy radical and the other represents a hydrogen atom or a carbamoyl or alkyloxycarbonyl radical containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and Rlo represents a fatty acid residue or a protecting group for the amine function or a glycyl or D alanyl residue whose amine function is substituted by a fatty acid residue or by a group protecting the amine function, it being understood that at least one of the symbols R7 or R10 represents a residue of fatty acid, then optionally replaces the radical-R7 or R10, when it represents or contains a protective group for the amine function, with a hydrogen atom, the radicals R 'and / or R8, when they represent an alkyloxy radical containing i to 4 carbon atoms, optionally substituted by a phenyl or nitrophenyl radical, by a hydroxy radical and the radical R4 and Rg, when it represents or contains an alkyloxycarbonyl radical containing 1 to 4 carbon atoms and optionally substituted by a phenyl or nitrophenyl radical, by a carboxy radical, it being understood that in the final product, RI represents a hydroxy or amino radical , R4 representing a hydrogen atom or a carbamoyl radical, R2 is different from a carboxy, N-carbonyl glycyie or N-carbonyl D alamyl radical, and isolates the product obtained optionally in the form of a salt. 5 - A process according to claim 3 for the preparation of a product according to claim I or 2 in the formula of which R3 represents a glycyl or D alanyl residue whose amine function is optionally substituted by a fatty acid residue, characterized in what we do react an amino acid of general formula

 in which R5 represents a fatty acid residue or a protective group for the amine function and R6 represents a hydrogen atom or the methyl radical, on a tri- or tetrapeptide of general formula

 in which R7 represents a fatty acid residue or a protecting group for the amine function, R8 represents a radical / amino or alkyloxy containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, one of the symbols R4 or R9 represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl, N-carbonyl glycyl or N-carbonyl-D alanyl radical, the acid function is optionally protected and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, it being understood that R4 and R9 cannot simultaneously represent a hydrogen atom, it being understood that at least one of the symbols R5 and R7 represents a residue of fatty acid, then optional ment replaces the radical R5 or R7, when it represents a group protecting the amine function, with a hydrogen atom, the radical R8 when it represents an alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl radical or nitrophenyl, by a hydroxy radical and of radicals R4 and / or Rg, when they represent or contain an alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, by a carboxy radical, it being understood that in the final product R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical, R2 is different from a carboxy radical, N-carbonyl glycyl or N-carbonyl-D alanyl, and isolates the product obtained optionally in the form of a salt. 6 - A process for the preparation of a product according to claim 1 or 2 characterized in that a dipeptide of general formula is reacted:

 in which R7 represents a fatty acid residue or a protecting group for the amine function and R8 represents an amino or alkoxy radical containing I to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, on a di- or tripeptide of formula general

 in which one of the symbols R4 or R9 represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical or an N- residue carbonyl glycyl or N-carbonyl D alanyl optionally esterified by an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the part of which alkyl contains 1 to 4 carbon atoms and is optionally substituted a phenyl or nitrophenyl radical, it being understood that R4 and Rg cannot simultaneously represent a hydrogen atom ,. and R10 represents a fatty acid residue or a protective group for the amine function or a glycyl or Alanyl residue in which the amine function is substituted by a fatty acid residue or a protective group for the amine function, one at less of the symbols R4 or Rg and R10 representing or containing a glycyl or D alanyl radical and at least one of the symbols R7 and Rlo representing or containing a fatty acid residue, then optionally replaces the radical R7 or Rlo when it represents or contains a protective group for the amine function, by a hydrogen atom and radicals R8 and / or R4 and / or Rg, when they represent, as the case may be, an alkyloxy radical or an alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, by a hydroxy or carboxy radical, it being understood that in the final product, R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical, R2 is different from a carboxy, N-carbonyl glytyl or N-carbonyl D alanyl radical, and isolates the product obtained optionally in the form of a salt. 7 - A process for preparing a product according to claim 1 or 2 characterized in that a L alanine derivative of general formula is reacted:

 in which R7 represents a fatty acid residue or a protective group for the amine function, on a tri- or tetrapeptide of general formula

 in which R8 represents a hydroxy, amino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, one of the symbols R4 or Rg represents a hydrogen atom or a carboxy, carbamoyl, alkyloxycarbonyl radical of which the alkyl part contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical or an N-carbonyl glycyl residue or N-carbonyl D alanyl optionally esterified by an alkyl radical containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical of which the alkyl part contains 1 with 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, it being understood that R4 and R9 cannot simultaneously represent a hydrogen atom and R10 represents a fatty acid residue or a protecting group for the amine function or a glycyl or D alanyl radical in which the amine function is substituted by a fatty acid residue or a protective group for the amine function, at least one of the symbols R4 or R9 and R10 representing or containing a glycyl or D alanyl residue and at least one of the symbols and and Rlo representing or containing a fatty acid residue, then optionally replaces the radical R or Rlo, when it represents or contains a gro highly protective of the amine function by a hydrogen atom, and the radicals R8 and / or R4 and / or R9, when they represent or contain an alkyloxy or alkyloxycarbonyl radical containing i to 4 carbon atoms optionally substituted by a radical phenyl or nitrophenyl, with a hydroxy or carboxy radical, it being understood that in the final product R1 representing a hydroxy or amine radical, R4 representing a hydrogen atom or a carbamoyl radical, R2 is different from a carboxy, N-carbonyl glycyl or N-carbonyl D ala born radical and isolates the product obtained optionally in the form of a salt. 8 - A process for the preparation of a product according to claim i or 2 characterized in that an acid of general formula R "-CO -OH in which R" -CO- represents a fatty acid residue is reacted , or an activated derivative of this acid, on a tetra- or pentapeptide of general formula

 in which one of the symbols R4 or Rg represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical or an N- residue carbonyl glycyl or N-carbonyl D alanyl optionally esterified by an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and the other represents a hydrogen atom or a carboxy, carbamoyl or alkyloxycarbonyl radical of which the alkyl part contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, it being understood that R4 and Rg cannot simultaneously represent a hydrogen atom, R8 represents a hydroxy, amino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and R10 represents a hydrogen atom, a fatty acid residue, a group protecting the amine function or a residue glycyl or D alanyl, the amine function of which is optionally substituted by a fatty acid residue or a group protecting the amine function, R11 represents a hydrogen atom, a fatty acid residue or a group protecting the amine function, it being understood that at least one of the symbols R4 or Rg and R10 represents or contains a glycyl or D alanyl residue and that l 'at least one of the symbols R10 and R11 represents a hydrogen atom or, for Rlo, a glycyl or D alanyl radical whose amine function is free and that when one of the radicals Rqg OR R11 represents or contains a residue of fatty acid this and the rest R "-CO- are identical or different, then, optionally replaces the radical R10 or R11, when it represents or contains a group protecting the amine function, with a hydrogen atom and radicals R8 and / or R4 and / or R9 when they represent or contain an alkyloxy or alkyloxycarbonyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical by a hydroxy or carboxy radical, it being understood that in the final product R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical, R2 is different from a carboxy, N-carbonyl glycyl or N-carbonyl D alanyl radical, and isolates the product obtained optionally in the form of a salt. 9 - Process for preparing a product according to claim i or 2 characterized in that a di- or tripeptide of general formula is fixed on an appropriate support

 in which one of the symbols R4 or Rg represents a carboxy radical, N-carbonyl glycyl or N-carbonyl-D alanyl and the other a hydrogen atom or a carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, R12 represents a residue fatty acid or a protective group for the amine function or a glycyl or D alanyl radical whose function. amine is substituted by a fatty acid residue or a protective group for the amine function and R13 represents a protective group for the amine function, it being understood that, when R8 which is defined below represents an amino radical and R4 represents a hydrogen atom or a carbamoyl radical, R9 cannot represent a carboxy or N-carbonyl-glycyl or N-carbonyl-D alanyl radical and that when R12 and .R13 represent or contain a protecting group for the amine function, these protecting groups are different, then, after unblocking the amine function protected by R13, we condense - either D glutamic acid, the amine and a-carboxy functions are suitably protected, i.e. the product of general formula

 in which R3 is defined as above and R8 represents an amino radical or an alkyloxy radical containing i to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, then, after release of the amine function protected by R13, or a derivative L alanine of general formula

 in which R13 is defined as above, then, after unblocking the amino functions protected by R13 and / or R12, optionally The fatty acid of general formula R'-COOH,  or a L alanine derivative of general formula

 in which R represents a fatty acid residue, - either the dipeptide of general formula

 in which R8 is defined as above and R14 represents a fatty acid residue or a protective group for the amine function, it being understood that, when R14 represents a protective group for the amine function, this is different from the protective group R12 defined above then, optionally after unblocking the amine functions protected by the radicals R14 and / or R12, the acid of general formula R'-OOOH, then separates the product obtained from its support and eliminates, if necessary, the groups protectors of the amine and carboxy functions, and isolates the product obtained optionally in the form of salt. 10 - Process for preparing a product according to claims 1 or 2 characterized in that lton fixes on a suitable support the peptide of general formula

in which one of the symbols R4 or Rg represents a carboxy radical, N-carbonyl glycyl or N-carbonyl D alanyl and the other a hydrogen atom or a carbamoyl or alkyloxycarbonyl radical, the alkyl part of which contains 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, R12 represents a residue d fatty acid or a protecting group for the amine function or a glycyl or D alanyl radical in which the amine function is substituted by a fatty acid residue or a protecting group for the amine function, R8 represents an amino or alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, R15 represents a protective group for the amine function, it being understood that when R8 represents an amino radical and R4 represents a hydrogen atom or a carbamoyl radical, R9 cannot represent a carboxy, N-carbonyl glycyl or N-carbonyl D radical alanyl, and that when R12 and R15 represent or contain a protective group for the amine function, these protective groups are different, then, after unblocking the amine function protected by R15, we condense - either an alanine L derivative of general formula

in which R15 is defined as above, then optionally, after release of the amino functions protected by R15 and / or R12, the acid of general formula R'COOH, - either a derivative of -L alanine of general formula

 in which R represents a fatty acid residue, then separates the product obtained from its support, then eliminates, if necessary, the protective groups of the amine and carboxy functions, and isolates the product obtained optionally in the form of a salt.  it - Process for the preparation of a product according to claim i or 2, characterized by the fact that the peptide of general formula is fixed on an appropriate support

in which one of the symbols R4 or R9 represents a carboxy radical, N-carbonyl glycyl or N-carbonyl of alanyl and the other a hydrogen atom or @@ @ adi @ al carbamoyl or alkyloxycarbonyl in which the alkyl part contains @ 4 carbon atoms optionally substituted by a phenyl radical on nitrophenyl, r12 represents a fatty acid residue or a group protecting the amine lunction or a glycyl radical or D @@ anyle, the amino tone of which is substituted by a fatty acid residue or a group protecting the amino linkage, R8 represents an ainino or alkoxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical, R16 represents a pro reader group of the -amine function, it being understood that when R8 represents an amine radical and R4 represents a hydrogen atom or a cartbamoyl radical, Rg cannot represent a carboxy, N-carbonyl glycyl or N radical -carbonyl D alanyl, and when R12 and R16 represent or contain a protective group for the amine function, these protective groups can be different, then after unblocking the amine functions protected by R16 and / or R12> the acid of formula is condensed general R'CO-OH in which -R '-oe- represents a fatty acid residue, then separates the product obtained from its support, eliminates, if necessary the protective groups of the amine and carboxy functions, and isolates the product obtained optionally in the form of salt. 12 - Process for preparing a product according to claim d or 2 in which one of the symbols R2 or R4 represents an N-carbonylglycyl or N-carbonyl D alanyl radical and the other represents a hydrogen atom or a radical carboxy, carbamoyl or alkyloxycarbonyl in which the alkyl part contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical, it being understood that, R1 representing a hydroxy or amino radical, R4 representing a hydrogen atom or a carbamoyl radical, R2 cannot represent an N-carbonyl glycyl or N-carbonyl D alanyl radical, characterized in that the glycine or la-D alanine whose amine function is protected is fixed on a suitable support, eliminates the protective group, then condenses a = amino acid of general formula:

in which one of the symbols R4 or Rg represents a carboxy radical and the other represents a dihydrogen atom or a carbamoyl or alkyloxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms and is optionally substituted by a phenyl or nitrophenyl radical , R12 represents a fatty acid residue or a protecting group for the amine function or a glycyl or D alanyl radical in which the amine function is substituted by a fatty acid residue or a protecting group for the amine function and R17 represents a protective group for the amine function or a residue of a D amino acid of general formula

in which R8 represents an amine radical or an alkyloxy radical containing 1 to 4 carbon atoms optionally substituted by a phenyl or nitrophenyl radical and R18 represents a group protecting the amine function or a residue of an L amino acid of general formula:

 in which R19 represents a protective group for the amine function or a fatty acid residue, it being understood that when R17, R18 or R4 represent a group for protecting the amine function, this group is different from R12 When the latter represents or contains a protective group for the amine-function1 R12 which may however be identical to Rlg, and - when R17 represents a protective group for the amine-function, eliminates this protective group, then condenses - or a derivative of a D amino acid defined above for which R18 represents a protective group for the amine function, then, after elimination of R18, condenses a derivative of L alanine defined above for which R19 is defined as above and, when R19 and / or R12 represents a protective group for the amine function, eliminates the radicals R19 and / or R12, then condenses an acid of general formula R'COOH,  - or a derivative of a D amino acid defined above for which R18 represents a residue of an L amino acid defined above for which R19 is defined as above, and, when R19 and / or R12 represent or contain a protective group of the amine function, eliminates the radicals Rtg and / or R12, then condenses the fatty acid of general formula R'COOH, - when R17 represents a residue of an amino acid defined above for which R18 represents a protective group of the amine function, eliminates this protective group, then condenses a derivative of L alanine defined above for which Rtg is defined as above and, when Rrg and / or R12 represent or contain a protective group of the amine function, eliminates the radicals R19 and / or R12, then condenses the fatty acid of general formula RtCOOH, and - when R17 represents a residue of a D amino acid defined above for which R18 represents a residue of an L amino acid defined above for which R19 represents a protective group for the amine function eliminates the radicals R19 and / or Rt2, then condenses the fatty acid of general formula R'COOH, separates the product obtained from its support, if necessary eliminates the protective groups of the amine and carboxy functions, and isolates the product obtained optionally in the form of a salt. 13 - Medicinal product characterized in that it consists of the product according to claim 1 in the pure state or in the presence of one or more diluents or adjuvants compatible and pharmaceutically acceptable.