DK161026B - ANALOGY PROCEDURE FOR THE PREPARATION OF ANTIGEN DERIVATIVES - Google Patents

Description

in

DK 161026 B

The present invention relates to an analogous method for preparing antigenic derivatives.

In particular, the invention relates to a process for preparing novel antigenic derivatives of an antigen and at least one muramyl peptide to be covalently bound thereto, optionally over a bridge link. These novel antigenic derivatives may e.g. is further characterized by the formula A - [Z0_1 - KP] n (I) 10 wherein A is a residue of an antigen, Z a residue (spacer), MP a residue of a muramyl peptide and n an integer greater than 0.

By this means antigen is an organic substance which, by the physiological medium, i.e. the human or animal organism, is perceived as immunologically foreign, or under suitable conditions can be perceived as foreign.

First of all, the antigens include all the substances that cause specific immunization of a living organism against infectious pathogens or unwanted reactions, such as allergic sensitization or rejection of transplanted foreign tissue. This is particularly understood by antigens as constituents of vaccines. In view of the fact that vaccines come, on the one hand, which can be used in the context of classical vaccination methods for immunological protection against infectious diseases. Speaking as antigens contained as active substances in such vaccines, attenuated living or dead, modified or decomposed infectious agents, the toxoids formed by these pathogens, or naturally or synthetically produced subcomponents.

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2 ter of pathogens and toxoids. Specifically, disease-causing classes include viruses, chlamydia, rickets, bacteria, protozoa and metazoic parasites. Preferred antigens are those suitable as components 5 of vaccines for the treatment of e.g. influenza A and B, parainfluenza 1-3? of respiratory syncytial viruses, rhinoviruses or adenoviruses, respiratory diseases, cytomegaly, rubella, measles, mumps, pertussis, poliomyelitis, herpes simplex 1 and 2, variant and herpes zoster, rotavirus diseases, hepatitis A, B and others , rabies, foot-and-mouth disease, trachoma, caries, of meningococci A, B and 0 caused the meningitis, pneumococcal diseases, Ξ. influenza, streptococci (especially rheumatic fever), Pseodomonas and Proteus, typhoid, parativus and other enterobacteria-induced diarrheal diseases, gonorrhea, syphillis, malaria, trypano-somiasis (sleeping sickness and Chagas's disease), leishmaniasis, filariosis, filariosis worm diseases.

20 On the other hand, mention should be made of new vaccines, which are not aimed at provoking infectious disease, but rather either at autologous constituents, i.e. normal and aberrant autoantigens or against sensitizing antigens from the outside world, i.e. allergens.

In one case, by immunization against normal or aberrant autoantigens, it is sought to disrupt the function of autologous molecules (e.g., by hormones, by other mediators, and by humoral and cellular receptors) or to abolish the prevalence or persistence of aberrant, particularly neoplastic cell lines. Preferred antigens as constituents of such vaccines are e.g. partial sequences of human chorionic gonadotropin or components of spermatozoa for immunization against mediators of fertility and thus for immunologically disrupting reproductive functions, mediators of erythema processes, especially in

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5 purified form, including the lymphocytes secreted by lymphocytes, in particular mac (macrophage migration inhibitory factor) for immunological suppression of erythema diseases, immunologically specific antigen receptors on lymphocytes and 5 antibodies (fractionated antigen-specific lymphocytes, from these lymphocytes, or from these lymphocytes, from these lymphocytes antigen-specific antibodies or antibody fragments) for anti-idiotype immunization (immunization against the auto-antigens characteristic of antigen receptor structures) for the purpose of interrupting specific immune responses to elimination of disease-causing immune processes, such as autoimmunity (for example, against synovial antigens and immunogiobulins) polyarthritis, against myelin components in 15 central nervous system degenerative diseases, against TSH receptors in autoimmune thyroiditis, against acetylcholine receptors in the myasthenia gravis cross-striated muscle, against islet cell components in juvenile diabetes, etc.) or allergies (e.g. against grass pollen, dust or drugs in allergic asthma, allergic rhinitis or drug hypersensitivity) or to avoid inherent but undesirable immune responses (eg, induction of immune tolerance to prevent rejection of transplanted foreign organs and tissues), autologous or with them cross-reacting homologous or heterologous tumor cells, tumor cell fragments or membrane components, including oncornavirus-encoded glycoproteins, such as GP 70, for tumor-specific immunization in the context of prophylaxis and therapy of cancer diseases, 50 in another case, instead of the pathogenetically relevant IgE antibody reaction predominantly or sufficiently to induce IgG and IgA antibodies against the sensitizing antigens from the outside, thereby capturing allergenic genes in the circulation and secretions by specific antibodies before these allergens react with the

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4 to mast cells bound IgE antibodies and thus can trigger the release of allergic mediators. In this antigen-specific desensitization, the allergens themselves are, i.e., p. for example, grass pollen, dust or drugs, antigenic components in vaccines.

As antigens, the active substances are preferably used in a vaccine used against parasites, bacteria, viruses, tumor cells, attenuated or killed forms or subcomponents thereof, a vaccine against autologous constituents, immunologic recognition structures, or a vaccine suitable for specific desensitization by allergies.

As antigens, in particular, such active substances are also used in a vaccine used for malaria, cholera, typhoid, meningitis, rheumatic fever due to streptococcal infection, influenza, canine madness, foot-and-mouth disease, as well as those in a vaccine for the prevention of tumor diseases, to induce the reproductive system, to desensitize or induce specific immune tolerances to allergies, to restore tolerance to 20 autologous tissue components and circulating molecules.

As antigens, it is also particularly preferred to use malaria merozoites, type-specific meningococcal polysaccharides A, B or C, st proteins of steptococci, influenza hemagglutinins, autologous tumor cells or tumor cell membrane constituents, partial sequences of human chorionic gonadotropin gene, lymphoblasts and their receptors for antigens or antigen-specific immunogiobulins.

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5

Antigens, especially when low molecular weight, may advantageously be completely covalently bound to a high molecular weight carrier. In particular, carriers should be mentioned polymers of lactic acid and its derivatives which carry on the chain end a free carboxylic group such as its esters of glycolic acids, polylactic acid -amides or lactic acid polyesteramides, such as are described in British Patent Specification No. 932.J82, in addition, alginic acid, polygalacturonic acid, pectic acid, carboxymethyl cellulose or agarose. Speaking as carriers, there are also basic, neutral or acidic polyamino acids which are not themselves immunogenic, such as polyaspartic acid, polyglutamic acid, polylysine or polyornithine. In addition, considering that carriers also come any other antigens of the kind mentioned above or in the examples listed, insofar as an immune response against these can be accepted or even desired. Thus, e.g. an HCG peptide being covalently bound to tetanus toxoid as a carrier.

In particular, muramyl peptides useful in the process are synthetically prepared compounds of the general formula CH2O6.-0 ζ VvOE1 R4O \ Å / V «20/1 - Σ - E2 * / pi 3 R '* - CH (D) * \ E8 E10 E11 CON - CH - CON - CH - CH0CH - E12 l7 lq 2 E '(L) Ey (D) 6

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wherein X represents a carbonyl, carbonyloxy or sulfonyl group, E ^ hydrogen, alkyl, optionally substituted p benzyl or acyl, E optionally substituted alkyl or Na carbocyclic aryl, E and E independently of hydrogen: alkyl, alkyl , optionally substituted benzyl or acyl, E 7 hydrogen or alkyl, E 1 and E 3 hydrogen or lower alkyl,

Q

E hydrogen, low alkyl, free, esterified or etherated hydroxylavalkyl, free, esterified or etherified mercapto-lower alkyl, free or acylated aminolavalkyl, cycloalkyl of 5 or 6 carbon atoms, cycloalkyl-low alkyl of which the cycloalkyl group contains 5 or 6 carbon atoms, optionally substituted aryl or aralkyl, nitrogen-containing heterocyclyl or heterocyclyl-lower alkyl, E 'and E together also the alkylene of 3 or 4 carbon atoms, E ^ hydrogen or lower alkyl, groups E E, E E and E ^^ independently of each other an optionally esterified or amidated carboxyl group and også ^ also hydrogen, or e \ E ^ and E ^ are trilavalkylsilyl, especially trimethylsilyl, or also oligomers thereof, such as e.g. is described in Dt-OS no.

20 2.45Ο.355, which can be obtained by isolation from microorganism cell walls.

The various parts of the new compounds are covalently bonded to each other, i.e. that the antigen is associated with at least one of its functional groups via a peptide chemistry common bond with the muramyl peptide residue, directly or via a spacer.

Especially broled (spacer) serve divalent residues of aliphatic compounds, e.g. of those having at least two amino groups, at least one amino group and one carboxyl or thioearboxyl group, or at least two carboxyl or thiocarboxyl groups such as aliphatic diamines, amino-thiocarboxylic acids, neutral, basic or acidic aliphatic amino acids, di or oligopeptides.

As a bridge, first of all, a, -diaminoalkanes,

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7 especially α, ω-diaminolavalkanes such as ethylenediamine, propylene diamine, tetramethylenediamine, alkyldicarboxylic acids such as succinic or glutaric acid, α, β or γ-aminoalkanearboxylic acids, preferably α-amino-loweralkanecarboxylic acids, especially lower alkane carboxylic acids such as glycine, β-alanine, L-alanine, α-amino-isobutyric acid, valine or leuine.

As the covalent bonding element, mention should be made in particular of carboxylic acid ester, carboxylic acid amide, thiocarboxylic acid ester or thiocarboxylic acid amide groups.

Said new compounds may have several covalent bonding elements depending on the nature of the bridges used.

Thus, the above formula I may e.g. obtain the following more elaborate form 15 Γγ in 'A Ί [χ'Ί - X' "- Ζ, Μ -X1V - ΜΡ (III) .it ^“ 0.1 η

LL Μm J

Γς "1

τ J

0-1 wherein Α is the antigen residue, T carrier residue, MP muramyl peptide-

1V

the remainder, Z1 and Z '"divalent broled and X1, X", X' "and Xx covalent bonding elements, and m and n mean integers greater than 0.

20 Alkyl is straight or branched, in any position bonded alkyl of up to 18 carbon atoms, but primarily low alkyl.

Speaking as substituents in the optionally substituted alkyl group, free or functionally converted hydroxyl or mercapto groups, such as

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8 or esterified hydroxyl or mercapto groups, for example, lower alkoxy or lower alkyl mercapto groups, or halogen atoms, or free or functionally converted carboxyl groups such as carbo-lower alkoxy or carbamoyl groups.

Thereby, the substituted alkyl group, such as the lower alkyl group, may carry one, two or more identical or different substituents, especially free hydroxyl groups or halogen atoms.

Carbocyclic aryl groups are especially monocyclic as well as bicyclic aryl groups, primarily phenyl, but also naphthyl. They may optionally be mono-, di- or polysubstituted, for example, with lower alkyl groups, free, etherified or esterified hydroxyl, e.g. lower alkoxy or low alkylenedioxy, or halogen atoms and / or trifluoromethyl groups.

In particular, aralkyl is aryl-lower alkyl in which aryl has the meaning given above. In the first place, aryl arylalkyl stands for benzyl or phenylethyl, wherein the phenyl nucleus can be mono-, di- or polysubstituted.

Particularly substituted benzyl groups are especially those benzyl groups which in the aromatic core are optionally mono-, di- or polysubstituted, e.g. with low alkyl, free, etherified or esterified hydroxyl or mercapto groups, e.g. lower alkoxy or lower alkylene dioxy, and lower alkyl mercapto or trifluoromethyl groups and / or halogen atoms.

In particular, nitrogen-containing heterocyclyl is a residue of a 5- or 6-membered heterocyclic compound having 1 or 2 nitrogen atoms in the ring. It may be saturated or unsaturated and may e.g. contain an annealed phenyl group.

As such, for example, a pyrrole, indane, pyridyl or imidazole ring should be mentioned.

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9

An optionally esterified or amidated carboxyl group is primarily the carboxyl group itself or a carboxyl group esterified with a low-alkanol, or also a carbamoyl group unsubstituted on the nitrogen atom or mono- or disubstituted with alkyl, especially lower alkyl, aryl, a variety of phenyl or aralkyl such as benzyl. However, the carbamoyl group may also carry an alkylene, such as a tetra or pentamethylene group, the carbamoyl group may also be substituted on the nitrogen atom by a carbamoylmethyl group.

In particular, acyl is an acyl residue of an organic acid, especially of an organic carboxylic acid. Thus, acyl is especially alkanoyl, especially with 2 to 18 carbon atoms, primarily, however, lower alkanoyl, or also aroyl such as naphthoyl-1, naphthoyl-2 and especially benzoyl or with halogen, lower alkyl, low alkoxy, trifluoromethyl, hydroxy or lower alkanoyloxy substituted benzoyl or naphthoyl, or also an acyl residue of an organic sulfonic acid, for example, of an alkanesulfonic acid, especially of a lower alkanesulfonic acid, or of an aryl sulfonic acid, especially of an optionally low alkyl or halogen substituted phenyl sulfonic acid , such as benzenesulfonic acid or p-toluenesulfonic acid, and carbamoyl, e.g. unsubstituted carbamoyl, lower alkylcarbamoyl or arylcarbamoyl such as methyl or phenylcarbamoyl.

In particular, the esterified or etherified hydroxyl is low alkoxy or lavacyloxy such as low alkanoyloxy.

In particular, the esterified or etherified mercapto is low alkyl capo or lavacyl, such as low alkanoyl mercapto,

Acylated amino is especially lower alkanoylamino or carbamoylamino.

They are included in the context of the present description and the requirements of "low" designated groups and compounds

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10 preferably up to 7 and, in the first instance, up to 4 carbon atoms, in the above and the following, the general concepts may have the following meaning: 5 Low alkyl is e.g. n-propyl, n-butyl, isobutyl, sec, butyl or tert-butyl, moreover n-pentyl, n-hexyl, isohexyl or n-heptyl and primarily methyl or ethyl, the aryl, cycloalkyl or heterocyclyllavalkyl is the lower alkyl group especially methyl or ethyl, the aryl, cycloalkyl or heterocyclyl group having the meaning given above,

Low alkoxy is e.g. n-propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy and primarily methoxy or ethoxy.

Low alkyl mercapto is, for example, n-propyl, n-butyl, isobutyl, 15 sec.butyl or tert.butyl mercapto and, first of all, methyl mercapto or etbyl mercapto.

In particular, lower alkylenedioxy is methylenedioxy, ethylene or propylenedioxy.

Halogen stands for fluorine or bromine, preferably 20 chlorine.

Low alkanoyl is especially propionyl or butyryl, but primarily acetyl.

The novel compounds of the present invention may be in the form of mixtures of isomers or of pure isomers.

It is known that muramyl peptides are good adjuvants which, in suitable admixture with antigens, manage to increase their immunogenicity. Admittedly, it turned out that they only

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11 exerts a short-lasting effect as they are relatively rapidly excreted from the human or animal organism.

Above all, they are only unsuitable under certain, for clinical purposes, namely in admixture with antigens 5 in a mineral oil emulsion capable of in vivo inducing a cell-mediated immunity to soluble antigens.

However, the novel compounds prepared according to the present invention produce a marked increase in the immune response to the antigen, in particular also a cell mediated immune under clinically acceptable administration conditions, which can be demonstrated by the test devices described below.

1, Potentiation of cell-mediated immunity in vivo: Increase in slow-reacting hypersensitivity to bovine serum albumin (BSA) and to sheep erythrocytes (SEBC) in guinea pigs,

Pirbright guinea pigs are immunized on day 0 with 1 mg of BSA or with 1 mg of SEBC "Ghosts" (SEBCG) in complete Freundian adjuvant by injection of 0.1 ml of an antigen-adjuvant mixture in each of the hind paws. Three weeks later, skin reactions are triggered by intracutaneous injection of 100 µg BSA or 100 µg SEBCG in 0.1 ml buffered physiological saline, and these reactions are quantitatively determined 24 hours later on the basis of the reaction volume calculated by the erythema surface and the skin thickness increase. The antigen-specific increase in reaction volume observed after 24 hours (slow reaction type) is a measure of cell-mediated immunity. BSA and SEBCG are too weakly immunogenic for alone or in a water-oil emulsion with incomplete Freund's adjuvant (10 parts BSA solution and SEBCG suspension, respectively, in 0.9% Bath mixed with 8.5 parts "Bayol F" and 1.5 parts of "Arlacel A") to induce a slow-type reaction, but, on the other hand, must be applied to complete immunization in complete adjuvant to which mycobacteria (5 mg killed and lyophilized M, butyricum) have been added. per.

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12 10 ml of "Bayol i" / ,, uArlacel A) · Instead of mycobacteria, the new compounds containing antigen containing BSA (1 mg BSA, 60 µg MDP per animal) or SEBCG Cl m.1 SEBOG are applied. 25 µg of MDP per animal) either as 5 antigen-oil mixture or suspended in carboxymethyl cellulose (CMC) .The new compounds induce slow type reactions in the absence of mycobacteria in the described test device.

Significant potentiation of the slow reactivity 10 against BSA and against SEBCG can also be achieved by application of the novel compounds not incorporated in incomplete Freundlian adjuvant, but suspended in CMC. In this case, intramuscular application is found to be particularly effective. Under these circumstances, the same amount of free muramyl peptide blended into the CMC mixture is significantly less active than the new active substance. This shows that the new compounds under clinically acceptable conditions of administration, i.e. by application with drug-friendly companions, able to induce cell-mediated immunity, even against a soluble protein antigen, 2, Potentiation of cell-mediated immunity in vivo: Increase in slow-reacting hypersensitivity to BSA and to SEBCG in mice, MAG-Han Mouse Immunized on Day 0 with stepwise doses of 25 with muramyl peptide non-conjugated antigens (BSA agarose or SEBCG) or with muramyl peptide conjugated antigens (BSA agarose or SEBCG). The BSA-Agarose preparations are applied subcutaneously at a dosage of 0.1 to 100 µg (corresponding to the new compounds with muranyl peptides to a dose of active substance of 0.0029-6 µg per animal) in a volume of 0.2 ml buffered physiological sodium chloride solution. The SEBCG preparations are applied at a dosage of 0.01 to 3 mg (corresponding to the new compounds with muramyl

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13 peptides for a dose of active ingredient of 0.25 - 75 µg per animals) in a volume of 0.5 ml in buffered physiological saline solution intraperitoneally or 0.05 ml intradermally and respectively divided into 3 paws.

4 to 20 days later, slow-type reactions are triggered by injection of 100 µg BSA and 10 µg SEBO respectively into 20 µl of buffered physiological saline solution in the left hind paw, and these reactions are determined quantitatively on the basis of 24 and 48 hours later. potency swelling reaction volume was found. The observed antigen-specific increase in paw volume is a measure of cell-mediated immunity.

On the 14th day after immunization with BSA-agarose MDP compounds, at very low dosage 15 (0.1 µg, equivalent to 0.006 µg of active substance), pronounced slow-type reactions occur. In contrast, free BAS agarose is unable to sensitize to slow-type reactions. likewise: SBBCG-MDP compounds, above all after intradermal, are capable of inducing a slow reactivity that is significantly more pronounced than that obtained after sensitization with SEBOG which is not associated with muramyl peptide.

This also shows that the new compounds manage to significantly increase cellular immunity, 25 3 · Potential humoral immunity in vivo:

Increase in antibody production against BSA in mice.

MEI mice are immunized by 8 intraperitoneal injection of 0.1 to 100 µg of BSA associated with muramyl peptides (0.0014 to 6.0 µg of active substance) on day 0. 10, 17 and 28 days 30 later, serum samples are examined and examined for their content of anti-BSA antibodies with a passive hemagglutination technique. In the dose used, free BSA is subimmuno-

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14 gent for the recipient animals, i.e. that it can trigger no or only a very low production of antibodies. Compounds of BSA with a muramyl peptide enable a double to triple increase of the antibody titer in serum 5 (the titre sum of log, - the titer differences of three bleeding days). It is also noteworthy that, after intraperitoneal or subcutaneous administration, the novel compounds that are additionally coupled to agarose as a carrier are even more potent.

10 By means of the illustrated experiments, it is shown that the compounds of the present invention also succeed in substantially increasing humoral immunity.

The novel antigen derivatives prepared according to the invention are known or improved known vaccines and serve for new vaccination methods or for simplifying common vaccination methods, e.g. the number of vaccinations needed to maintain protection over a longer period of time can be lowered.

In particular, the invention relates to the preparation of novel antigenic derivatives containing antigen, optionally covalently linked over bromine to muramyl peptides of formula II, wherein R 1, R 3, R 4, R 5 and R 7 are hydrogen, X carbonyl and R 2 optionally with hydroxy or lower alkoxy substituted lower alkyl or optionally hydroxy, lower alkoxy, lower alkyl or halogen substituted phenyl and R®, R4, R10, RH, R3-2 and R13 have the meaning given above.

In particular, the invention relates to the preparation of novel antigenic derivatives containing antigen, optionally covalently bonded over bridged to mutamyl peptides of formula II, wherein R 1, R 2, R 6 Dg b 7 are hydrogen, X carbonyl, R 2 optionally hydroxy or lower alkoxy substituted lower alkyl or optionally with hydroxy, lower alkoxy, lower alkyl or halogen substituted phenyl and R 3 methyl, and R

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R R, R10, R r, R20 and R13 have the meaning given above.

The invention relates primarily to the preparation of novel antigenic derivatives containing antigens, optionally covalently bonded over bromine to muramyl peptides of formula II, wherein R 1, R 2, R 6 Qg R 2 -2 are hydrogen, X carbonyl, R 2 optionally with hydroxy or methoxy. substituted lower alkyl or optionally with hydroxy, methoxy, methyl, ethyl or halogen substituted phenyl, R 2 hydrogen or methyl, b 7 and R 2 hydrogen, R 2 lower alkyl, lower alkyl mercapto-lower alkyl, hydroxylavalkyl, benzyl, p-hydroxybenzyl or phenyl and R 12, R , R 2 · 2 carboxyl, lower alkoxycarbonyl or carbamoyl and also hydrogen.

The invention relates primarily to the preparation of novel antigenic derivatives containing antigens, optionally covalently linked over bromine to muramyl peptides of formula II, wherein R 1, R 2, R 6, R 7 and R 2 · 2 are hydrogen, X carbonyl, R 2 optionally with hydroxy or methoxy substituted lower alkyl or optionally with hydroxy, methoxy, methyl, ethyl or halogen substituted phenyl, R 2 and R 3 hydrogen or methyl, R 2 methyl, ethyl, n-propyl, isopropyl, 2-methylpropyl, methylmercaptomethyl, hydroxymethyl, hydroxyethyl, phenyl, benzyl or p-hydroxybenzyl and R 1, R 11 and R 12 carboxy, lower alkoxycarbonyl or carbamoyl and R 11 also hydrogen.

The invention also relates to the preparation of novel antigenic derivatives containing antigens, optionally covalently bonded over bridged, to muramyl peptides of formula II, wherein R 1, R 2, R 2 and R 2 · 2 represent hydrogen, X carbonyl, r 7 and R 2 together. propylene or butylene, and R2, R2, R2, R12, R1 · 1 · and R · * · 2 have the meaning given above.

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16

In particular, bridged in the above definitions are α, ω-di-aminoalkanes, low alkyl dicarboxylic acids, and naturally occurring α-amino-lower alkanoic carboxylic acids.

In particular, the invention relates to the novel antigenic derivatives described in the invention.

The new compounds can be prepared by methods known per se.

Thus, they can be obtained by condensing an optional 10 bridged-linked antigen with optionally broled s mammal-linked muramyl peptides, one of the two moieties containing free amino, hydroxy or mercapto groups, and the other carboxylic acid groups, and if desired, obtained with an optionally bridged bonded carrier.

The condensation thus occurs e.g. by reacting one compound in the form of an activated carboxylic acid with the other compound as free amino, hydroxyl or mercapto compound. The activated carboxyl group 20 can e.g. be an acid anhydride, preferably an acid azide, an acid amide such as an imidazolid, or isooxazolid, or an activated ester. In particular, as activated esters are cyan methyl esters, carboxymethyl esters, p-nitrophenylthio esters, methoxyethylthio esters, acetylaminoethylthio esters, p-nitrophenyl esters, 2,4-, 5-trichlorophenyl esters, N-hydroxysuccinimide ester, N-hydroxy ester, N-hydroxy and N-hydroxypiperidine esters. Optionally, active esters can also be obtained with a carbodiimide with the addition of K-hydr oxysue c inimide or an unsubstituted

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17 substituted or, for example, with halogen, methyl or methoxy substituted 1-hydroxybenzotriazole or 3-hydroxy-zl-oxo-3,4-dihydro-benzo [d] 1,2,3-triazine;

The decomposition groups 5 used in this condensation must be non-toxic or easily removable to prevent the mostly high-molecular-weight compounds from adsorbing toxic components.

Therefore, as active esters, they are preferred with ΪΓ-hydroxysuccinimide or their C-substitution products, such as H-hydroxymethyl or dimethylsuccinimide, or reaction with carbodiimide such as carbodiimide itself or 1-ethyl-3- (3-dimethylaminopropyl) - c arb odiimide ♦

The above reactions are carried out in the usual manner in the presence or absence of diluents or condensing agents and / or catalytic agents, if necessary at reduced or elevated temperature. Preferably, in order not to destroy the antigens, one operates in an aqueous environment and in a pH range. The invention also relates to the embodiments of the process, starting from a compound obtained at some stage of the process as an intermediate and carrying out the missing process steps or producing starting substances under the process conditions, or optionally using a reaction component in the form of its derivatives, such as its salts and / or in the form of isomer mixtures or pure isomers.

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18

In order to carry out the condensations in question, such starting materials are conveniently used which lead to the above-mentioned groups of end products and, above all, to the specially described or highlighted 5 end products.

The starting materials used are known or, if new, can be prepared by known methods.

The antigenic derivatives of the invention can be used in the form of pharmaceutical compositions such as e.g. is for enteral, such as 10 oral or rectal, as well as parenteral administration to warm-blooded animals or humans. The compositions contain the pharmacologically active substance alone or together with a pharmaceutically useful carrier.

The pharmaceutical compositions contain from ca. From about 10 to about 15, about 95%, preferably from about ? 0 to approx. 90% of the active substance. The pharmaceutical compositions may be in unit dosage form, e.g. such as dragees, tablets, capsules, suppositories or ampoules.

The pharmaceutical compositions are prepared in a manner known per se, e.g. by conventional mixing granulation, coating, dissolution or lyophilization methods. Thus, pharmaceutical compositions for oral use can be obtained by combining the active substance with solid carriers, optionally granulating an obtained mixture, and preparing the mixture or granulate, if desired or necessary after the addition of suitable excipients, to tablets or dragee cores.

Suitable carriers are in particular fillers such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cell

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19 Lulose preparations and / or calcium phosphates, e.g. tri-calcium phosphate or calcium hydrogen phosphate; further, binders such as starch adhesives, using e.g. of corn, wheat, rice or potato starch, 5 gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and / or, if desired, explosives such as the above starches, , alginic acid or a salt thereof, such as sodium alginate; aids are primarily fluidity control and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and / or polyethylene glycol. Drage cores are provided with suitable, possibly stomach-resistant coatings. uses concentrated sugar solutions optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures, or for the preparation of gastric-resistant coatings, solutions of suitable cellulose acetate or cellulose acetate, phthalate. Dyes or pigments may be added to the tablets or dragee coatings, e.g. for identification or characterization of various active substances.

Other orally useful pharmaceutical compositions are gelatin socket capsules as well as soft closed capsules of gelatin and a plasticizer such as glycerol or sorbitol.

The sachets may contain the active substance in the form of a granule, e.g. in admixture with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycol.

in; DK 161026B

20 cols, stabilizers may also be added.

For parenteral administration, primarily aqueous solutions of an active substance in water-soluble form, e.g. of a water-soluble salt, further, suspensions of the active substance, such as similar oily injection suspensions, using suitable lipophilic solvents or vehicles such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity enhancers, e.g. sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally stabilizers.

A preferred mode of application consists of a solution or suspension of the novel antigenic derivatives containing preferably up to 10% by weight of carboxymethyl cellulose.

The dosage of the active substance depends on the nature, body weight and age of the warm-blooded animal and on the individual condition and the mode of application.

Thereby, the new vaccines are applied in analogy to the known and known dosages in weight units or international units adopted by known vaccination methods; one submits e.g. lymphoblast-containing antigen derivatives in an amount that per injection contains 10-10x cell organisms one to six times at intervals of 2 to 8 25 weeks. Pr. The protein content of murine amylp ep times should preferably be 5 to 200 µg,

For immunization with soluble compounds, the corresponding amount of antigen derivatives is preferably used in one

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21 saline solution (BSS), which consists of 0.14 g of calcium chloride, 8.0 g of sodium etoride, 0.2 g of magnesium sulfate.72 ^ 5 0.2 g of magnesium chloride.GH 2 O, 0.6 g of potassium dihydrogen phosphate and 0, 24 g disodium hydrogen phosphate. 211 ^ 0 pr. 1 liter of water, 5 If a depot effect is sought (for example, by local, intradermal or intramolecular application), additional carboxymethylcellulose (final concentration preferably 5 ° / °) may be added to the antigen derivative thus dissolved -

Non-soluble macromolecular antigen derivatives are preferably applied as a suspension in BSS and carboxymethyl cellulose as a stabilizer (final concentration preferably 5%) * To prepare a stable suspension, the ice-cooled mixture is preferably treated with ultrasonic concentrate with 15 antigen derivatives. is applied primarily in a tissue culture medium which is particularly suitable for the cell type (eg, for lymphocytes "EAGLE1's high, amino acid medium") [cf. Click et al. Cell. Immunol, Vol, 3, 264-276 (1972)].

The novel muramyl peptides of formula II used as starting materials wherein X represents a carbonyl group, R 1 hydrogen, alkyl, optionally substituted 2 benzyl or acyl, R optionally substituted 4 6 alkyl or carbocyclic aryl, R and E independently of 25 is hydrogen, alkyl, optionally substituted benzyl or acyl, B / hydrogen or alkyl, at least one of the groups R 1, R 2 and R 1

ISLAND

other hydrogen, R hydrogen, lower alkyl, free, esterified or etherated hydroxylavalkyl, free, esterified or etherified mercaptolavalkyl, free or acylated amino-lower alkyl, cycloalkyl of 5 or 6 carbon atoms, cycloalkyl-loweralkyl whose cycloalkyl group contains 5 or 6 carbon atoms , optionally substituted aryl or aralkyl, nitrogen-containing heterocyclyl or heterocyclyllavalkyl,

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22 R7 and R8 together also the alkylene having 3 or 4 carbon atoms and the groups R 1, R 1 and R 12 independently of an optionally esterified or amidated carboxyl group and R 11 also hydrogen can be prepared by condensing in a manner known per se 5 a compound of formula oh2or ° 6/0 "Εθ1 (IV)

EO4 (y | _Y

, / Έ - X - R2 RJ - OH (D) I -i?

COOH

wherein X, R2, R3 and R4 have the meaning given above and R4 \ R04 and R8 represent the groups r \ R4 or R8, or a readily cleavable protecting group, or a derivative thereof with a compound of the formula R ° 8 -gOlO -gOll ΉΕ - OH - COH - CHCH 2 CH - R ° 12 (V) R7 (L) R9 wherein R ° 8, R ° "and R0 ^^ and R0 ^" 2 have that of R8 , R ^ "8, 11 1? R and R are defined, with the proviso that the carboxyl and, if desired, free hydroxyl groups present in these groups are protected with readily decomposable protecting groups and optionally leaving protecting groups present.

The condensation thus occurs e.g. by reacting the compound IV in the form of the activated carboxylic acid with the amino compound V, or reacting the acid IV with the compound V, the amino group of which is present

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23 in activated form. The activated carboxyl group may e.g. be an acid anhydride, preferably a mixed acid anhydride such as an acid azide, an acid amide such as an imidazolid or isoxazolid, or an activated ester. In particular, as activated esters are cyan methyl ester, carboxymethyl ester, p-nitrophenylthioester, p-nitroplienyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, IT hydroxy sue c in imide ester, N-hydroxyphthalimide ester, 8-hydroxyquinoline ester ester, 2-hydroxy-1,2-dihydro-1-carboethoxy-quinoline ester, 10 N-hydroxypiperidine ester or enol ester obtained with N-ethyl-5-phenyl-isoxazolium-3'-sulfonate. Activated esters may optionally also be obtained with a carbodiimide with the addition of N-hydroxysuccinimide or an unsubstituted or e.g. with halogen, methyl or methoxy substituted 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydrobenzo [d] 1,2,3-triazine,

The amino group is e.g. activated by reaction with a phosphitamide.

In particular, among the methods of reacting with activated esters, 20 are mentioned with N-ethyl-5-phenylisoxazolium-3 'sulfonate (Woodward Beagens E) or 2-ethoxy-1,2-dihydro-1-carboethoxy-quinoline or carbodiimide.

Easily cleavable protecting groups are those known from the peptide or sugar chemistry. As carboxyl groups especially mention is made of tert, butyl, benzyl or benzhydryl, and as hydroxyl groups especially acyl groups, e.g. lower alkanoyl groups such as acetyl, aroyl groups such as benzoyl and, above all, carbon-derived groups such as benzyl oxycarbonyl or lower alkoxycarbonyl, or alkyl, especially tert.butyl optionally with nitro, lower alkoxy or halogen substituted benzyl or tetrahydropyranyl, or optionally substituted alkylidene groups connecting the oxygen atoms at the 4 and 6 positions. Such alkylidene groups are especially a low alkylidene, primarily a

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24 is an ethylidene, isopropylidene or propylidene group or also an optionally substituted, preferably p-substituted benzylidene group.

These protecting groups can be cleaved in a manner known per se. Thus, one can remove them hydrogenolytically, e.g. with the urban drug in the presence of a precious metal such as palladium or platinum catalyst, or by acid hydrolysis.

The starting materials used are known or can be prepared in a manner known per se.

Another method of preparing these novel starting materials is to condense in a manner known per se, a compound of the formula CH2 - 0R ° 6 -0, / q \ rv ^ O-R01 (VI) R ° 4 - o \ | / o / Η - X - R2 R -CH fel3 \ f8

COE - CH - COOH

U

R '15 wherein R2fR ° \ R3, R ° 4, R0 ^, R * 7 and R0 ^ carried the above meaning, with a compound of the formula

βο10 r ° H

BH - ice - CH2 OH - R012 (VII) r9 wherein R0 ^, R0 ^ '3 · and R0 ^ 2 bear the above meaning, with the proviso that in the groups R0 ^, R0 * ^,

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25 R0 · 1 and R0 · 2 present carboxyl and, if desired, free hydroxyl groups are protected by 1-leaving-protecting groups, and optionally leaving-protecting groups present.

The condensation is thereby effected, for example, by reacting the compound VI in the form of the activated carboxylic acid with the amino compound VII, or by reacting the acid VI with the compound VII, whose amino groups are in activated form. The activated carboxyl group may e.g. be an acid anhydride, preferably a mixed acid anhydride, an acid amide or an activated ester. Speaking as such come especially the aforementioned acid anhydrides, amides or esters. The amino group is e.g. activated by reaction with a phosphitamide.

15 Also, the easily cleavable protecting groups are similar to those already mentioned above. They may be decomposed in a manner known per se, for example, hydrogenolytic, for example, with hydrogen in the presence of a noble metal such as palladium or platinum catalyst or by acid hydrolysis.

The starting materials can be obtained in a manner known per se.

Thus, e.g. correspondingly, in the J position, react unsubstituted sugars with a halogen-R 3 -acetamido-R 4 -acetic acid, or a compound of formula iv with an amino-R 2 -acetic acid whose carboxyl group is protected in the manner shown above and cleaved off protection group.

Another method for carrying out the 3-sided sugar chain side chain consists of reacting a compound of the formula

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26 CH2 - O - E ° 6 / - ° (oh / ^ ° - r01 (VHI) E ° 4 _ o \ _ / Ή - X - E2 R1? Wherein X, E3 E ° \ E0 ^, E0 ^ and E1 has the meaning given above and wherein any hydroxyl groups present are protected by a readily cleavable protecting group, having a compound of the formula E ° 8 ^ olO E0 · * 1 Z - OH - OOHCH - COH - OH - OH20H - E ° 12 (IX) É3 · E7 É9 wherein Z is a reactively esterified hydroxyl group and R3, R7, R9, R ° 3, R ° 10 / R011 and R ° 12 have the meaning given above, and optionally leaving 10 protecting groups present .

In particular, a reactively esterified hydroxyl group is one with a strong inorganic or organic acid esterified hydroxyl group, primarily one that is esterified with hydrogen halides such as hydrogen chloride, bromide or iodide.

The easily cleavable protecting groups are similar to those already mentioned above. They can be split off in a manner known per se, e.g. hydrogenolytic, e.g. with hydrogen in the presence of a precious metal such as palladium-20 or platinum catalyst or by acid hydrolysis.

The novel muramyl peptides of formula 14 6 II used as starting materials, wherein X represents a carbonyl group, R, R and R trilav-2-alkylsilyl, primarily trimethylsilyl, R optionally 27

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substituted alkyl or carbocyclic aryl, R hydrogen or alkyl, 7 13 8 R 'and RJ hydrogen or lower alkyl, R hydrogen, low alkyl, free, esterified or etherified hydroxylavalkyl, free, esterified or etherified mercapto-lower alkyl, free or acylated aminolavalkyl , cycloalkyl of 5 or 6 carbon atoms, cycloalkyl-lower alkyl, the cycloalkyl group of which contains 5 or 6 carbon atoms, optionally substituted aryl or aralkyl, nitrogen-containing heterocyclyl or heterocyclylone lower alkyl, E 'and E together also the alkylene of 3 or 40 carbon atoms. , E 'hydrogen or lower alkyl, and the groups E, 1110 E and E independently of an optionally esterified 11 or amidated carboxyl group and E also hydrogen can be prepared by reacting in a manner known per se a compound of the formula

GH20H

J_o

/ yvoH

15 l \ p / / 'Ή - X - E2 (X), / k1? - CH (D) \ E8 E10 E11 \ I il ip COH - CH - COH - CH - CHOCH - 1 η Iq 2 E7 (L) E9 with a reactive ester of a trilavalkylsilyl compound.

In particular, as reactive esters of a trilavalkylsilyl compound, mention is made of trilavalkylsilyl halides, especially 20-chlorides or bromides, bis-loweralkylsilyl acetamide or sulfamide.

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28

The reaction is preferably carried out in a solvent which does not contain reactive hydroxyl or amino groups such as dimethylformamide, dioxane, tetrahydrofuran, dimethoxyethane or chloroform.

The following examples further illustrate the invention.

Example 1.

To a solution of 1 g of bovine serum albumin in 100 ml of a 0.1 H sodium bicarbonate-0.5 M sodium chloride solution is added with stirring 500 mg of 2-acetamido-3-O- [Ll-10 (D1-carb amoyl-3 -suecinimidoxyc arbonyl-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose. The solution is stirred for 4 hours at room temperature and then sterile filtered ("Mk-Milipore", 0.4-5 µτΒ. filter). The conjugated bovine serum albumin is separated in the dial filtration process by an "Amikon UM-10" filter from low molecular weight reaction products or salts and lyophilized.

The quantitative determination of the muramyl peptide bound to the bovine albumin is done by the Morgan-Elson reaction by the modification of J. M. Ghuysen et al, [in "Methods in 20 Enzymology", 8, (1966), 629]. On average, 60 µg of muramyl peptide is found in 1 mg of bovine serum albumin.

For example, the succinic modoester used as a starting material can be prepared as follows: 1 mmol of 2-acetamido-3-O-> L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethylJ-c arbamoylmethyl 2 -2-De oxy-D-glucose, 1 mmol of dicyclohexylcarbodiimide and 1.1 mmol of M-hydroxysuccinimide are dissolved in 3 ml of absolute dimethylformamide and stirred in a closed container under water exclusion for 20 hours. The precipitated dicyclohexylurea is separated, the solvent is evaporated in high vacuum and the residue is treated with ether, then suctioned and dried. The

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The sucein imidooxyester thus obtained can be stored under moisture exclusion, e.g. in nitrogen vials.

Example 2,

To condense the antigenderivate obtained in Example 1 on activated agarose, a commercially available agarose derivative from BIO-EAD, "Affi-Gel 10", which contains on an agarose skeleton the spacer arms chain of H-alkyl, is used. succinamides esterified with H-hydroxysuec inimide,

120 mg of the bovine serum albumin derivative obtained in Example 1 are dissolved in 12.5 ml of 0.1 M phosphate buffer, pH

7.5 at 4 ° C. 500 mg of "Affi-Gel 10" is then suspended in the solution by shaking and shaken for a further 4 hours at 4 ° C. The remaining residual active ester groups 15 are reacted by 30 minutes treatment with a 1 M ethanol-amine.HCl-0.1 M phosphate buffer solution (pH 7.3) · Then the gel is filled into a column and washed first with 200 ml of 0.1 M phosphate buffer-1 M sodium chloride solution (pH 7.3) 5 then with 20 ml of physiological sodium chloride solution, -Gel 10 "condensed bovine serum albumin muramyl peptide compounds occur by quantitative analysis of representative bovine serum albumin amino acids in total hydrolysates of defined portions of the gel. On average, 9-10 mg of the bovine serum albumin muramyl peptide derivative is bound to 1 ml of swollen "Affi-Gel 10".

Example 5

Vein erythrocyte membranes are recovered from fresh sheep blood by the method of Dodge, J, I, et al ,, [Arch. Biochem.

Biophys. 100, (1963), pages 114-180], To a suspension of 30,000 mg of sheep erythrocyte membranes in 50 µl of 0.1 M sodium hydrogencarbonate-0.1 M sodium chloride solution is added under stirring.

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Stirring 400 mg of 2-acetamido-3-O - [[1- (D1-carbamoyl-3-sucinimidooxycarbonyl-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose, and the mixture is stirred for 4 hours at room temperature. Then the erythrocyte meme-3 brane congugate is sedimented by 1 hour ultracentrifugation at 90,000 g and 4 ° 0. The sediment is washed three times, each time by resuspending and ultracentrifugation, with phosphate buffered sodium chloride solution and once with distilled water.

The washed erythrocyte butane conjugate is suspended in 100 ml of distilled water and lyophilized.

The quantitative determination of the muramyl peptide bound to the sheep erythrocytes is done by the Morgan-Elson reaction and shows a content of 23 muramyl dipeptide per 1 mg ery-thr o cytmembr an.

Example 4.

100 mg of Group C polysaccharide from Heisseria meningitidis and 110 mg (0.2 mmol) of 2-acetamido-3-O- [[1-1-CD-I-carbamoyl-3-N-aminoethyl-carbamoyl] -propyl Dissolve in 10 ml of distilled water and adjust the solution with dilute hydrochloric acid to a pH of 5 · 19. 2 mg of N-ethyl 2 - (3-dimethylaminopropyl) carbodiimide. HCl is added to the solution with stirring. The mixture is stirred for 1 hour at room temperature, the pH is kept at 5 for 25 min of dilute sodium hydroxide solution, and then 5 µl of 2 M sodium acetate buffer solution, pH 5, is added and stirred for an additional 30 minutes. Then adjust the pH to 7 down sodium hydroxide solution. The solution is sterile filtered and dialyzed at 4 ° C with distilled water 30 and then lyophilized.

The quantitative determination of the desmethyl muramyl dipeptide coupled to the C polysaccharide is as described in

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31 Example 1 of the Morgan-Elson reaction and shows a content of 80 µg desmethylmuramyl dipeptide per ml. 1 mg of polysaccharide.

The 2-acetamino-3-O- [L1- (D1-carbamoyl-3-H-5-aminoethyl-carbamoyl-propyl) -carbamoyl-ethyl] -methyl-2-deoxy-D-glucose hydrochloride can e.g. are prepared as follows: 1 mmol of 2-acetamino-3-O -> [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl <-2-deoxy-D- Dissolve 10 glucose and 9 mlnol N-ethyl-N '- (3-dimethyl-aminopropyl) carbodiimide. Dissolve in 10 ml of water and adjust the pH to 5.0 with hydrochloric acid. Then a solution of 5 mmol of ethylenediamine dihydrochloride in 10 ml of water is added. The batch is stirred at pH 3, 0 and room temperature for 6 hours. The mixture is added to a slightly acidic cation exchange column "Amberlite CG 50 II", 2.5 x 45 cm and eluted with a linear gradient from 0.05 M pyridine acetate, pH 6 (300 ml) to 0.5 M pyridine acetate, pH 3.7 (300 ml). The fractions containing the obtained 2-acetamino-3-O- [1- (1) - 1-c arb amoyl-3-H-amino-ethyl-c arb amoyl-propyl) -c arb amoyl -ethyl] -c arb amoyl-methyl ^ -2-deoxy-D-glucose aeetate, which is tested and characterized with ninhydrin and high voltage electrophoresis is lyophilized. The conversion to the hydrochloride form occurs as follows: The lyophilisate is dissolved in 6 µl 0.2 L HCl and chromatographed on a 2.5 x 90 cm Bio-Gel P2 column with water as the eluent. The 2-acetamino-3-O- [L1- (D1-carbamoyl-3-H-aminoethyl-carbamoyl-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-de The oxy-D-glucos e-hydrochloride-containing fractions are freeze-dried. The composition is uniform according to high voltage electrophoresis. In determining the components of the total hydrolysates, the molar ratio is 1 muramic acid: 1 L-alanine: 1 D-glutamic acid: 1 ethylenediamine.

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32 Analogously, from the corresponding muramyl dipeptides, the corresponding β1-aminoethylamide is obtained. HCl compounds, namely: 2-acetamino-3-O- [D1- [L1- (D-1-carbamoyl-3-E-amino) ethyl 3-carbamoyl-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-de s-oxy-D-glucose.HCl, 2-benzyl-amino-3- O- ^ D1- [ L-1- (D-1- c arb amoyl- ^ -E-amino ethyl-c arb amoyl-propyl) -c arb amoyl-ethyl] -c arb amoyl-ethyl ^ -2-deoxy-D-glucose.HCl , 10 '. 2-benzoyl amino-3- [0-] [1- (D1-carb amoyl-3-E-aminoethyl-carbamoyl-propyl) -carbamoyl-ethyl] -carbamoyl-methyl descxy-Dr-glucose .HCl, 2-ac e tamino-3-O - [L-1- (D1E-carbamoyl-methyl-carbamoyl-3-E-aminoethyl-carbamoyl-propyl) - carbamoyl -ethyl] -carbamoyl-methyl-2-2-deoxy-D-glucose. HCl, 2-b enzoylamino-3-O- [[1- (D1-carbamoyl-3-E-aminoethyl] amino acid amoylpropyl} - carb amoylpropyl] - carbamoylmethyl yl-2-deoxy-D-glucose.HCl, 2-propionylamino-3-O - [[1- (D1-carbamoyl-3-E-aminoethyl-20 c arb amoyl-pr opyl) - c arb amoyl-ethyl] - c arb amoy 1-methyl t-2-deoxy-D-glucose.HCl, 2-acetylamino-3-O - [[1- (D1- carbamoyl-3-H-aminoethyl-carb-amoyl-pr opyl) -c-arb-amoyl-pr-opyl] -c-arb-amoyl-methyl-2-deoxy-D-glucose HCl, 2-acetylamino-3-O - [[1- (D1-carbamoyl-3-E-aminoethyl-carbamoyl-propyl) -carbamoyl-2-hydroxyethyl] -carbamoyl-methyl-2-deoxy-D-glucose, HCl, 2-propionylamino 3-O - [[1- (D1- (or 3) -carboxy-3- (or 1) -E-amino ethyl carb amoyl-propyl) -carbamoyl-ethyl] -carb amoyl-methyl-2-deoxy-D-glucose, HCl,

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33 2-Benzoylamino-3-O- [Ll- (D1N-carbamoyl-methyl-carbamoyl-3-N-aminoethyl-carbamoylpropyl) -carbamoyl-ethyl] -carbamoylmethylsubstance 2-deoxy-D-glucose.HG1,2-benzoylamino-3-O- ^ L-1- (Dlc arb oxy-3-N-amino ethyl-carbamino-propyl) -carbamoyl-ethyl ) -carbamoylmethyl-2-deoxy-D-glucose.HCl, 2-ac etamino-3-O - [[1- (D-1-carbamoyl-3-N-amino ethyl-carbamoyl-propyl) -carbamoyl 2'-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose, HCl, 2-ac et amino-3- O- ^ D-1- [L1- (D-1-carbamoyl) - 3- (1-β-amino-ethyl-carbamoyl) -ethyl-carbamoyl-propyl) -carbamoyl-ethyl] -carbamoyl-ethyls-2-deoxy-D-gluc ose.HCl , 2-Acetamino-3-O - [[1- (D1-carboxy-β-h-aminoethyl-carbamoyl-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-methyl -desoxy-D-glucose. HCl, 2-acetamino-3-O-1-carbamoyl-3-N-aminoethyl-carbamoylpropyl) - carbamoyl-N, N-1 ethernethyl and] - c arb amoyl-methyl-2-deoxy-D-glucose. HCl, 2-acetamino-3- O- [L-1- (D ~ 1- c ar b amoyl-3-N-am ino thyl-20-carb amoyl-pr opyl) -c-arb amoyl-e-thyl] -N-me thyl-c-arb amoyl-methyl-2-deoxy-D-glucose.H01 or 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-N-aminoethyl-carbamoyl-propyl) -carbamoyl-21-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glue ose.HCl, 25 These compounds are condensed as described above with group O polysaccharide from Neisseria meningitidis.

Example 5

Immediately after the extraction, merozoites from the malaria parasite Plasmodium knowlesi, the total yield 30 from the blood, are suspended by an infected rhesus monkey [method of extraction].

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34 thing of merozoites: see G ·. H. Mitchel et al., (1975),

Immunology, 29, 397] in a solution of 100 mg (0.17 mmol) of 2-acetamino-3-O-L- (D1-carbamoyl-3-suecinimidooxy-carbonyl-propyl) -carbamoyl-ethyl] -carbamoyl-methyl 2-Dec-5-oxy-D-glucose in 15 ml of physiological buffer solution, pH · 7.2. The suspension is incubated for 1 hour at 37 ° 0. The conjugates are then sedimented by centrifugation. The sediment is washed by resuspending in physiological buffer solution and re-centrifuging. The washed merozoite conjugates 10 are suspended according to G, H. Mitchel (see above) in 10% autologous rhesus monkey serum and lyophilized.

The quantitative determination of the muramyl dipeptide coupled to the merozoites is done by the Morgan-Elson reaction and yields 40-60 µg muramyl dipeptide per 1 mg merozoites.

Example 6.

In a solution of 200 mg (0.34 mmol) of 2-acetamino-3-O- [L-1- (D-1-carbamoyl-3-sue cinimidooxy-c arbonyl-propyl) -carbamoyl-ethyl ] -carbamoyl-methyl 2 -2-deoxy-D-glucose in 20 ml of phosphate buffer-containing physiological sodium chloride solution

Q

In solution, pH 7.2, 10 µl of T-lyrin oblast is suspended from CBA / J mice. (The T-lymphoblasts are recovered in a "mixed lymphocyte culture" against G57BL / 6 mouse stimulator cells according to L. 0. Anderson et al. (1977), The Journal of Experimental Medicine, 146, 1124). The suspension is incubated for 30 minutes at room temperature. Then, the lymphoblast conjugates are sedimented by centrifugation and washed by resuspending in phosphate buffered physiological sodium chloride solution and centrifuged again.

The quantitative determination of the muramyl dipeptide coupled to the T lymphoblasts 30 is done by the Morgan-Elson reaction (see Example 1) and shows a content of 60-70 µg muramyl-7 dipeptide per ml. 101 T lymphoblasts.

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35

Example 7 ♦ By analogy as in the above examples, bovine serum albumin coupled with 2-acetamido-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -5-carbamoyl-ethyl] -carbamoyl ethyl 2- (2-deoxy-D-glucose, 2-benzoylamino-3-O-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-α, β-carbamoyl D-glucose, 2-benzylamino-3-O- [[1- (D-1-carbamoyl-3-carb oxy-propyl) -10-carbamoyl-ethyl] -carbamoyl-methyl α:, β-D-glucose, 2-acetamido-3-O-β [L1- (Dlc arb amoylme thylcarbamoyl-3-c arb oxypr opyl) - c arb amoyle thyl] - c arb amoylme thyl 2-deoxy-D-glucose, 2-benzamido-2-deoxy-3-O - [[1- (D1-carbamoyl-3-carboxy-13-propyl) -carbamoyl-propyl] -carbamoylmethyl glucopyranose, 3- O - [[1- (D1-carbamoyl-3-c arboxypropyl) -c arbamoylethyl] -c arb amoylmethyl] -2-deoxy-2-propionamido-D-glucose, 2-acetamido-3 O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoylpropyl] -carbamoylmethyl] -2-deoxy-D-glucose, 2-acetamino-3-O- [[1- (D1-carbamoyl) 3-carb oxypropyl) -c arb amoyl-2-hydroxyethyl] -c arb amoylmethyl-2- deoxy-D-glucose, 2- propionylamino-3-O- [Ll - (L, 3-dicarboxy-propyl) -c arb amoylethyl] -c arb amoylmethylj-2-deoxy-D-gluc ose, 23 2-benzoylamino-3-O- [[1- (D1N-carbamoylmethyl-carbamoyl-3-c arboxy-propyl) -c arb amoyl-ethyl] -c arb amoylmethyl-2- de s-oxy-D-glucose, 2-acetamino-3- O-D-1- [L-1-carb amoyl-3-c arboxy-propyl) carbamoyl-21-methyl-propyl] pcarbamoylethyl ^ -2-deoxy-D-

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36 glucose, 2-benzoylamino-3-O- [1-1- (1-1,3-dicarboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-desoxy-1-glucose, 2-acetamino -3-O- [[1- (11 -1-carbambyl-3-carboxy-propyl) -3-carbamoyl-2'-methyl-propyl] -carbamoylmethyl-2-deoxy-1-glucose, 2 -acetamino-3-O-ll- [ll- (ll-carbominoyl-3- (Ll-carboxy-ethyl) -carbamoyl-propyl) -c-arbamoyl-ethyl] -c-arbamoyl-ethyl-2-deoxy-1 -gluco se, 2-acetamino-3-O- [1- (1-1,3-dicarboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-methyl-2-deoxy-1 glucose, 2-acetamino-3-O- [[1-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-etr amethylene] -carbamoyl-methyl <-2-deoxy - 1-glucose, 2-acetamino-3-O- [[L-1- (B-1-c arb amoyl-3-c arb oxy-pr opyl) -c arb amoyl-methyl] -N-methyl- carbamoyl-methyl-2-deoxy-1-glucose or 2-benzoylamino-3-O - [[1- (11-carbamoyl-3-carboxy-propyl) -carbamoyl-21-methyl-propyl] -c arb amoyl-methyl ^ -2-de s oxy-1- 20 glucose »

Example 8.

By analogy as in Example 3, sheep erythrocyte membranes coupled with 2-acetamino-3-O-1-1-1- [L1- (1-1-carbamoyl-3-carboxy-propyl) -25-carbamoyl-ethyl] are obtained. -carbamoyl-ethyl ^ -2-des oxy-1-glucose, 2-benzoylamino-3-O-1-1-1- [1-1- (11-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl ] -carbamoyl-ethyl ^ -2-des oxy-1-glucose, 2-benzoylamino-3-O-β [1-1- (1-1-c arbamoyl-3-c arboxy-propyl) - c arb amoyl-ethyl] -carb amoylmethyl-2-deoxy-D-gluc ose, 37

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2-b enzoylamino ~ 3-O-β [L1- (D1, 3-dic arb oxy-pr opyl) -carbam-oyl thyl] -c arb amoylme thyl ^ -2-de soxy-D-gluco se, 2 -propionylamino-3-O-β [L1- (D1-carbamoyl-3-carboxy-propyl) -5c-arbo-ethyl] -c-arb-amoylmethyl-2-deoxy-D-glucose, 2-acetamino-3 0 - [[1- (D1E-carbamoylmethylcarbamoyl-3-c arb oxy-propyl) -c arb amoyl thyl] -c arb amoylmethyl 2 -2-deoxy-D-glucose, 2-benzoylamino-3-O [1- (D1-carbamoyl-3-carboxy-propyl) -10-carbanoyl-propyl] -carbamoylmethyl-2-desoxy-D-glucose, 2-acetylamino-3-O- [[1- (D1) -carbamoyl-3-carb oxy-propyl) -c arb amoylpropyl] -c arbamoyl-methyl ^ -2-deoxy-D-gluc ose, 2-acetamino-3-O - [[1- (D1-carbamoyl) -3-carb oxypropyl) -carbamoyl-2-hydroxyethyl] -carbamoylmethyl-2-deoxy-D-13 glucose, 2-propionylamino-3-O- [[1- (D1,3-dicarboxy-propyl) -carbam -oylethyl] -carbamoylmethyl-2-deoxy-D-glucose, 2-benzylamino-3-O- [[L-1- (D-1-Nc arb amoylmethyl-c arb amoyl-3- c arb oxy -propyl) -c arb amoyl-ethyl] -c arb amoylmethyl 2 - 2-20 deoxy-D-gluco see, 2-ac et amino-3- 0- [[1- (D1-c arb amoyl-3-c arb oxy-propyl) -c arb amoyl-2'-methyl-propyl] -c arb amoylmethyl -soxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3- (L1-carboxy-ethyl) -carbamoyl-propyl) -carbamoylethyl] -carbamoylethyl 2-deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1,3-dicarboxy-propyl) -carbamoyl-2 '-methyl-propyl] -carbamoyl-methyl-3 2- de soxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-21-methyl-propyl] -carbamoyl-methyl -desoxy-I> - glucose, 38

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2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-E, 1,1-tetramethylene] -carbamoyl-methyl <-2-deoxy-D-5-glucose, 2-ac an amino - 3-O- [[1,1- (1) -1-carb amoyl-3-carb oxy-propyl) -c arb amoyl-ethyl] -H-methyl-carb amoyl-methyl -2-deoxy-D-glucose or 2-acetamino-3-O-D1- [L1-carbamoyl-3-carboxy-propyl) -10-carbamoyl-21-methyl-propyl] -carbamoylethyl-2-deoxy -D-glucose.

Example 9

By analogy, as in Example 5, merozoites are obtained from the malaria parasite Plasmodium knowlesi coupled with 2-acetamino ~ 3-O- ^ D1- [L1- (D1-carbamoyl-3-earboxy-propyl) -c arb amoyl-ethyl] - carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzoylamino-3-O- ^ D-1- [L-1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -c 2-benzoylamino-3-O- [L-1- (D-1-carbamoyl-3-carb oxy-propyl) -carbamoyl-2-benzoylamino ethyl] -c arb amoylmethylj-2-deoxy-D-glucose, 2-benzoylamino-3-O- [[1- (D1,3-dicarboxy-propyl) -carbamoylethyl) -carbamylmethyl 2 - 2-Deoxy-D-glucose, 2-propionylamino-3-O- [[1- (D1-carbamoyL-3-carboxy-propyl) -carbamoylethyl] -carbamoylmethyls-2-deoxy-D-glucose , 2-Acetamino-3-O- [[1- (Dlh-carbamoylmethylcarbamoyl-3-carb oxy-propyl) -carbamoylethyl] -carbamoylmethyl-2-des-oxy-D-glucose, 2-benzoylamino-3 -0- [[1- (D1-carbamoyl-3-carboxy-propyl) -carb amoyl-propyl] - carb amoylmethyl-β-the soxy-D-gluc ose,

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39 2-Acetylamino-3-O- [[L-1- (D-1-carb amoyl-3-carb oxy-propyl) -c arb amoylpropyl] -c arb amoylmethyl ^ -2-de s oxy-D-gluc ose, 2-ac et amino-3-O - [[1- (Dlc arb amoyl-3-c arb oxypropyl) -3 c arb amoyl-2-hydroxyethyl)] - c arb amoylme thyl 2 -2-deoxy-D-glucose, 2-propionylamino-3-O- [1- (D1,3-dicarboxy-propyl) -carbamino-ethyl] -carbamoylmethyl deoxy-D-glucose, 2-benzylamino-3-O-β [L- (D-1-ϋ-c arb amoylmethyl-c arbamino-3-carboxy-propyl) -c arb amoyl-ethyl] -carb amoylmethyl-2-deoxy-D-glucose, 2-ac et amino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-21-methyl -propyl] -c-arbamoylmethyl-2-deoxy-D-glucose, 2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3- (L1-carboxy-ethyl) -carbamoyl-1 propyl) -carbamoylethyl] -carbamoylethyl-2-deoxy-D-glucose, 2-acetamino-3- O- [L-1- (D-1,3-di-carb oxy-pyru-1) - carbamoyl-2'-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzylamino-3-O-β [L-1- (D-1-carbamoyl-3 -c arb oxy-pr opy l) -c arb amoyl-21-methyl-propyl] -c arb amoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl) 3-carboxy-propyl) -carb amoyl-li, li-1 ether arne thyl en] - carb amoyl-methyltyl <- 2- de soxy-D-glucose, 2-acetamino-3- o [[1-1- (1) -1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -ϋ-methyl-carbamoyl-methyl-2-deoxy-D-glucose or 2- ac et amino-3-O- ^ D1- [Llc arb amoyl-3-c arb oxy-propyl) -c arb amoyl-21-methyl-propyl] -c arbamoylethyl ^ -2-deoxy-D-

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40 glucose.

Example 10.

In a solution of 100 mg of 2-acetamino-3-O-D1- [L1- (Dlc arb amoyl-3-sue c inimido oxyc arbonyl-propyl) -c arb amoyl-5-ethyl] -carbamoyl-ethyl ^ -2 -desoxy-D-glucose in 10 ml of phospbbate-buffered physiological sodium chloride solution, pH 7? 2,

Q

10 ° mammary carcinoma cells from dogs are suspended. [lumor cells are recovered according to Η. H, Sedlacek, Ξ, Messmann, and E. R. Seiler, Behring Inst, Mitt., No. 35 »34-9-355 (1974 -)] · 10 The suspension is incubated for 90 minutes at room temperature.

Then, the tumor cell-muramyl dipeptide conjugates are sedimented by centrifugation and washed by resuspending in phosphate-buffered physiological sodium chloride solution and centrifuged again.

The quantitative determination of the muramyl dipeptide coupled to the tumor cells is by the Morgan-Elson reaction (see Example 1) and shows a content of 60-80 µg muramyl dipeptide per hour. 10 'mammary carcinoma cells.

Example 11.

Analogously, as in Example 10, mammary carcinoma cells from dogs coupled with 2-acetamino-3-O-D-1- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -c arb are obtained. amoyl-ethyl] -carbamyl-ethyl-2-deoxy-D-glucos, 2-benzoylamino-3-O-, D1- [L1- (D1-carbamoyl-3-carboxy-propyl) - carb amoyl-ethyl] -carb amoyl-ethyl ^ -2-desoxy-D-glucose, 2-benzoylamino-3-O- [[1- (D-1-carbamoyl-3-c arboxy-propyl) - carb amoylethyl] - carb amoylme thy 1,2 - 2-deoxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1,3-dicarboxy-propyl) -carbam-30 2-propionylamino-3-O- [Ll- (D1-carbamoyl-3-carboxy-propyl) -carbamoylethyl] - c aramyl ylme tyl j-2-des oxy-D-glu cose,

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41 2- ac et amino-3- O- [L-1- (DlU-c arb amoylme thylc arb amoyl-3-3 c arb oxy-propyl) - c arb amoyl ethyl] - c arb amoylme thyl j-2 -des oxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl]] -carbamoylmethyl-2- s-oxy-D-glucose, 2-acetylamino-3- [1- (1-carbamoyl-3-carboxy-propyl) -10-carb amoylpropyl] -c-arb amoyl-methyl-2-de-s-oxy-D-gluc us e, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxypropyl) -c arb amoyl-2-hydroxyethyl] -c arb amoylmethyl ^ -2-s oxy-D-glucose, 2 -propionylamino ~ 3-O - [[1- (D1,3-dicarboxy-propyl) -15-carbamoylethyl] -carbamoylmethyl-2-deoxy-D-glucose, 2-benzylamino-3-O- [1- 1- (11-1 -H-c arb amoylmethyl-c arb amoyl-3- c arb oxy-propyl) -c arb amoyl-ethyl] -c arb amoylmethyl-2-deoxy-D-glucose, 2-ac etamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -20-carbamoyl-2'-methyl-propyl] -carbamoylmethyl-2-deoxy-D-glucose, 2 -acetamino-3-O - [[11-1] [11- (D1-carbamoyl-3- (1-1-carboxy-thyl)) -carbamino yl-propyl) -carb amoylethyl] -carb amoylethyl-2-deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1,3-dicarboxy-propyl) -carbamoyl-2'-methyl -propyl] -c arb amoyl-methyl-2-deoxy-D-glucose, 2-benzylamino-3- [O] [L-1- (D-1-carb amoyl-3- carb oxy-propyl) -carbamoyl-21-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy) -propyl) -carbamoyl-N, H-tetramethylene] -carbamoyl-methyl-2-deoxy-D-glucose, 42

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2-acetamino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -5-carbamoyl-ethyl] -N-methyl-carbamoyl-methyl-2-deoxy-D-glucose or 2-acetamirLO -3-0- ^ D1- [L1-carbamoyl-3-carboxy-propyl) -c arb amoyl-2'-methyl-propyl] -c arb amoylethyl ^ -2-deoxy-D-glucose.

Example 12.

To 10 ml of a suspension of foot-and-mouth disease vaccine from Beringwerke in phosphate buffered physiological sodium chloride solution is added 100 mg of 2-acetamino-3-O- [1- (D1 - c arb amoyl-3-sue) c (imido-oxy-carbonyl-propyl) -13-carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose. The suspension is shaken for 4 hours at 4 DEG C., then the viral muramyl dipeptide conjugate is sterilized, separated by dialysis with water from low molecular reaction products and lyophilized. The quantitative determination of the virus-coupled muramyl dipeptide is done by the Morgan-Elson reaction (see Example 1).

Example 13

By analogy, as in Example 12, foot-and-mouth disease vaccine coupled with 23 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-c arb oxy-propyl) -c arb amoyl-ethyl is obtained. ] -carb amoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzylamino-3-O- ^ D1- [L1- (Dlc arb amoyl-3-c arb oxy-propyl) -c arb amoyl- ethyl] -c arb amoyl-ethyl 2 -2-deoxy-D-30 glucose,

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2-benzylamino-3-O- [[11-CB-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose, 43 2-Benzoylamino-3-O- [[1- (D1,3-dicarboxy-propyl) -carbamoylethyl) -carbamoylmethyl] -2-deoxy-D-glucose, 2-propionylamino-3 -0- - c arb amoyl-3- c arb oxy-pr opyl) - c arb amoyl et hyl] - c arb amoylmethyl-2- de s oxy-D-glucose, 2-ac et amino-3- 0- [L-1- (DlNc arb amoylmethylc arb amoyl-3-c arb oxy-propyl) -c arb amoylethyl] -c arb amoylmethyl ^ -2-deoxy-10-D-glucose, 2-benz oylamino -3-O - [[1- (Dlc arbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoylmethyl-2-deoxy-D-glucose, 2-ac ethylamino-3-O-β [L- 1- (D-1-carbamoyl-3-carb oxy-propyl) -carbamoylpropyl] -carbamoyl-methyl-2-deoxy-D-glucose, 13 2-acetamino-3-O - [[1- -carbamoyl-3-carboxypropyl) -carbamoyl-2-hydroxyethyl] -carbamoylmethyl-2-deoxy-D-glucose, 2-propionylamino-3-O-, 3-dic (oxy-propyl) -c arb amoyl e thyl] -c arb amoylmethyl j-2-de s oxy-D-gluc ose., 2-ben zoylamino-3-O- [Ll- (D-1-1T-c arb amoylmethyl-carbamoyl-3- c arb oxy-propyl) -c arb amoyl-ethyl] -c arbamoylmethyl-2-deoxy-D- glucose, 2-acetamino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 * -methyl-propyl] -carbamoylmethyl-2-deoxy-D-23 glucose, 2- acetamino-3-O- [D1- [L1- (D1-carbamoyl-3- (1-1-carboxyethyl) -carbamoyl-propyl) -carb amoylethyl] -carb amoylethyl-2-deoxy-D -glucose, 2-acetamino-3-O-, 3-dicarboxy-propyl) -carbamoyl-21-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose, 44

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2-benzyl-amino-3-O-β [L1- (D1-c arb amoyl-3-c arb oxy-propyl) -c arb amoyl-21-methylpropyl] -c arb amoyl-methyl 2 - 2-deoxy-D-glucose, 2-acetamino-3-O- [1- (1) -1-carbamoyl-3-carboxy-propyl) -5-carbamoyl-K, N-tetr arne thyl en] -carbamoylmethyl-2-deoxy-D-glucose, 2-acetamino-3-O - [L-Ι- (D1-carbamoyl-3-carboxy-propyl) -c arb amoyl-ethyl] -E-methyl-carbamoyl-methyl ^ -2-deoxy-D-glucose or 2-acetamino-3-O- ^ D1- [L1-carbamoyl-3-carboxy-propyl) -carbamoyl-21 -me thyl-pr opyl] - c arb amoyl e thyl ^ - 2-de s oxy-D-glucose.

Example 14.

By analogy as in Example 6, T lymphoblasts 15 are obtained from OBA / J mice coupled with 2-acetamino-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl]:) - c arb amoyl-ethyl] -c arb amoyl-ethyl 2- 2- deoxy-D-gluose, 2-benzylamino-3-O- ^ D1- [1-1- (1-1-c arb amoyl -3-carb oxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-deoxy-1-glucose, 2-benzoylamino-3-O - [[1- (11-carbamoyl-3- carboxy-propyl) -c arb amoyl-ethyl] -c-arb amoylmethyl-2-deoxy-D-glucose, 2-benzoylamino-3-O- [L-1- (D-1,3-dicarboxy) -propyl) -carbamoyl-ethyl) -carbamoylmethyl-2-deoxy-D-glucose, 2-propionylamino-3-O-β [1-1- (1) -1-carbamoyl-3- c arb oxy-pr opyl) -c arb amoylethbyl] -c arb amoylmethyl-2-deoxy-D-glucose, 2-ac etamino-3-O- [[1- (DlKc arb amoylmethylc arb amoyl-3-c arb oxy -propyl) - c arb amoyl e thyl] - c arb amoylme thyl 2 -2-deoxy-30 D-glucose, 45

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2-Benzylamino-3-O- [[1-1- (D-1-c arbamoyl-3-carb oxy-propyl) -c-arb amoyl-propyl] -o-arb-amoylmethyl-2-de s oxy-D-gluc ose, 2-acetylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -c arbamoylpropyl] -carbamoyl-methyl2-deoxy-D-gluc ose, 2-Acetamino-3-O- [[1- (D1-carbamoyl-3-carboxypropyl) -carbamoyl-2-hydroxyethyl] -carbamoylmethyl-2-deoxy-D-glucose, 2- propionylamino-3-O - [[1- (D1,3-dicarboxy-propyl) -c arb amoylethyl] -c arb amoylmethyl <-2-deoxy-D-glucose, 2-benzoylamino-3-O- [L1- (D1Nc arb amoylmethyl-carbamoyl-3-carboxy-propyl) -c arb amoyl-ethyl] -c arb amoylmethyl-2-deoxy-D-glucose, 2-acetamino-3-O- [[D- 1- (D-1-Carbamoyl-3-carboxy-propyl) -carbamoyl-21-methyl-propyl] -carbamoylmethyl-2-deoxy-D-15-glucose, 2-acetamino-3-O-D - [L1- (D1-carbamoyl-3- (L1-carboxyethyl) -c arb amoyl-propyl) -c arb amoylethyl] -c arb amoylethyl 2 -2-deoxy-D-glucose, 2-ac et amino 3-O-H L1- (D-1,3-diarboxy-propyl) -carbamoyl-21-methyl-propyl-1-carbamoyl-methyl 2-Deoxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-methyl -desoxy-D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -25 carbamoyl-N, N-tetramethylene] -carbamoyl-methyl D-Glucose, 2-ac et amino-3- O- [[1- (D1-c arb amoyl-3-c arb oxy-pr opyl) -c arb amoyl-ethyl] N-methyl-carbamoyl · -methyl 2-deoxy-D-glucose, 2-acetamino-3-O- [D1- [L1-carbamoyl-3-carboxy-propyl) -

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46 carbamoyl-21-methyl-propyl] -carbamoylethyl-2-deoxy-D-glucose.

Example 15

1 mg oxal serum albumin-2-acetamino-3-O - [L-1- (D-1-c arb amino-3- c arb oxy-propyl) -c arb amoyl-ethyl] - c arb amoyl-methyl-2-deoxy-D-glucose conjugate is dissolved in 0.1 ml of phosphate buffer containing physiological sodium chloride solution (PBS). In solutions 0.1 ml of a 5% suspension of carboxymethyl cellulose is mixed in PBS. -1Q; muscular to guinea pigs in two equal portions.

Example 16, 10β T-lymph oblaster-2-acetamino-3-O - [L-1- (Dc arb amoyl-3-c arb oxy-propyl) - c arb amoyl-ethyl] - ear amoyl-methyl The β-2-des oxy-D-glucos e-conjugate is (see Example 6) suspended in 0.5 ml of phosphate buffered physiological sodium chloride solution (PBS). In the suspension, 0.5 ml of a 5% solution is mixed. suspension of carboxymethyl cellulose in PBS, Pr, mice is applied 0.1 ml of the mixture subcutaneously.

Example 17, 20 To 10 ml of a suspension of Rabring HDO vaccine from Behringwerke in phosphate buffered physiological sodium chloride solution is added 100 mg (0.17 mmol) of 2-ac et amino-3- 0- [1-1- ( D1-carb amoyl-3-sue c inimido oxy-c arb onyl-propyl) -c arb amoyl-ethyl] -c arb amoyl-methyl-2-de s oxy-D-gluc ose, The virus concentration is 2 x 10 µl LD / mouse in 1 ml suspension, The suspension is shaken for 4 hours at 4 ° G, then the muramyl dipeptide-rabies HDO vaccine conjugate is sterile filtered, separated by dialysis with water from low molecular weight reaction products and lyophilized.

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47

Example 18.

By analogy, as in Example 17, rabies HDC vaccine from Behringwerke coupled with 2-acetamino-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -5-carbamoyl-ethyl] - is obtained. carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzylamino-3- O- ^ D-1- [L-1- (D-1- c arb amoyl-3- c arb oxy-pr opyl) - carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzoylamino-3-O- [L ~ 1- (D1-carbamoyl-3-carboxy) -propyl) -10-carb amoyl-ethyl] -carb amoylmethyl-2-deoxy-D-glucose, 2-benzoylamino-3-O- [Ll- (D1,3-dicarboxy-propyl) - 2-propionylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoylethyl] - c arb amoylmethylj-2-deoxy-D-glu-13 cose, 2-acetamino-3-O-¢ [1-1- (1) -1-Nc arb amoylmethylc arb amoyl-3-c arb oxy-pr opyl) - carb amoyl ethyl] - carb amoylmethyl 3 - 2-deoxy-D-glucose, 2-benzylamino-3-O- [Ll- (Dlc arbamoyl-3-c arb oxy-propyl) - Carbamoyl-propyl] -carbamoylmethyl-2-deoxy-D-glucose, 2-ac ethylamide no-3-O- [[1- (Dlc arbamoyl-3-carb oxy-propyl) -c arb amoylpropyl] -c arb amoyl-methyl] -2-de soxy-D-gluc ose, 2-acetamino-3 0 - [[1- (D1-carbamoyl-3-carboxypropyl) -carbamoyl-2-hydroxyethyl] -carbamoylmethyl ^ -2-deoxy-D-23 glucose, 2-propionylamino ~ 3-0- [L1- (L1,3-dicarboxy-propyl) -c arb amoylethyl] -c arb amoylmethyl <-2-deoxy-D-gluc ose, 2-benzoylamino-3-O - [[1- (D1E-carbamoylmethyl) -carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl

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48 deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-21-methyl-propyl] -carbamoylmethyl-2-deoxy-D-glucose , 2-Acetamino-3-O- £ D1- [II- (D1-carbamoyl-3- (II-1-carboxy-ethyl) -c arb amoylpropyl) - c arb amoyle thyl] - c arb amoylethyl 2 -2-deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1,3-dicarboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-methyl deoxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-methyl D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-E, E-tetramethylene] -carbamoyl-methyl ^ -2-deoxy-D-glucose , 2-Acetamino-3-O - [[1- (L-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -E-methyl-carbamoyl-methyl-2-deoxy-D -glucose or 2-ac etamino-3-O- [D1- [L1-carbamoyl-3-carboxy-propyl) -20-carbamoyl-21-methyl-propyl] -carbamoylethyl-2-deoxy-D-glucose.

Example 19 »

To 10 ml of a suspension of extracted influenza virus antigens of type A / Victoria / 3/75 in phosphate buffered physiological sodium chloride solution is added 100 mg (0.17 mmol) of 2-acetamino-3-O - [[1- (D1-carbamoyl) -3-sue cinimido-oxy- (carb amylpropyl) - carb amoylethyl] - carb amoylmethyl-2,2-deoxy-D-glucose. (The virus antigens are recovered by the tween / ether cleavage method of Behringwerke, Mar-burg, BED - analogous to the preparation of Begrivac S; the concentration is 4000 I.E. in 1 ml suspension). Suspension- 49

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The mixture is shaken for 4 hours at 4 ° C. Thereafter, the virus-antigen-muramyl dipeptide conjugates are separated by dialysis with phosphate buffered physiological sodium chloride solution from low molecular weight reaction products. The dialyzed suspension is frozen and stored at -20 ° C until needed.

Example 20

By analogy, as in Example 19, influenza virus antigen coupled to 2-acetamino-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] is obtained. carb amoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzoylamino-3-O- ^ D1- [L-Ι- (D1-carbamoyl-J-carboxy-propyl) -carbamoy 1 - thyl] -carbamoyl-ethyl-2- deoxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carb amoyl-ethyl] -carb amoylmethyl-2-deoxy-D-gluc ose, 2-benzoylamino-3-O - [[1- (D-1,3-dicarb oxy-propyl 1) -carbamoyl ethyl) -c arbamoylmethyl-2-des oxy-D-gluco se, 2-propionylamino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -c arb amoylethyl] -c arb amoylmethyl -2-deoxy-D-glucose, 2-ac et amino-3- 0- [Ll- (D-1-N-c arb amoylmethyl c arb amoyl-3-c arb oxy-propyl) -c 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoylmethyl 2-Deoxy-D-glucose, 2-acetylamino-3-O - [[1- (Dl -carbamoyl-3-carboxy-propyl) -c arb amoylpropyl] -c arb amoyl-methyl-2-deoxy-D-gluc ose, 2-acetamino-3-O- [L-1- (D- 1-carbamoyl-3-carboxypropyl) - 50

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In carb amoyl-2-hydroxyethyl] - carb amoylmethyl-2-des oxy-D-glucose, 2-propionylamino-3-O - [[1- (D1,3-dic arb oxy-propyl) -c arb amoyl ethyl] -c arb amoylmethyl-2- de soxy-D-glueo, 2-benzoylamino-3-O- [[1- (D1-] ir-carbamoylmethyl-carbamoyl-3-c arb oxy-propyl) -c arb amoyl-ethyl] -c arb amoylmethyl-2-deoxy-D-glue ose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxylic acid) propyl) -carbamoyl-21-methyl-propyl] -carb amoylmethyl-2-deoxy-D-10-glucose, 2-acetamino-3-O- ^ D1- [Ll- (D1-carbamoyl-3- (L1-carboxyethyl) -c arb amoyl-propyl) -c arb amoylethyl] -c arb amoylethyl 2 -2-deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1, 3- dicarboxy-propyl) -carbamoyl-21-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-earboxy-propyl) ) -c arb amoyl-21-methyl-propyl] -c arb amoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O- [1-1- (D1-carbamoyl-3 carboxy-propyl) -20-carb amoyl-E, ΕΓ-tetrame thylen] -carbamoyl-methyl-2-des oxy-D-glucose e, 2-acetamino-3-O-β [L1- (D1-carbamoyl-3-carb oxy-propyl) -c arb amoyl-ethyl] -E-methyl-c arb amoyl-methyl des oxy-D-glucose or 2-acetamino-3-O- ^ D1- [L1-carbamoyl-3-carboxy-propyl) -carbamoyl-21-methyl-propyl] -carbamoylethyl-2-deoxy-D-glucose .

Example 21.

To 2 ml of a solution of tetanus toxoid in phosphate buffer.

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51 of physiological sodium chloride solution containing 10 mg of 2-acetamido-3-O- [Ll- (D1-carbamoyl-3-succinimide-oxycarbonyl-pr opyl) -c arb amoyl-ethyl] -c arb amoylmethyl -2-deoxy-d-glucose. The toxoid concentration is 3 mg / ml. The solution is stirred for 4 hours at 4 ° C. Then, the tetanus toxoid-muramyl dipeptide conjugate is separated by ultrafiltration from low molecular weight reaction products; the ultra-filtered solution is frozen and stored at -20 ° 0 until needed. The quantitative assay (Morgan-10 Elson reaction) shows a content of about 50 µg muramyl dipeptide per ml. 1 mg tetanus toxoid-muramyl dipeptide conjugate.

Example 22, Analogously as in Example 21, tetanus toxoid coupled to 2-acetamino-3-O-β-D1- [L1- (D1-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-ethyl is obtained. 2-Deoxy-D-glucose, 2-benzoylamino-3- O- ^ D1- [L1- (Dlc arb amino-3- c arb oxy-propyl) -c arbamoyl-ethyl] -c arbamoyl-ethyl 2 -2-deoxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -c 2-benzoylamino-3-O - [[1- (D1,3-dicarboxy-propyl) -carbamoyl-ethyl] -carb amoylmethyl-2-de oxy-D-gluc ose, 2-propionylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -c arb amoylethyl] -c arb amoylmethyl <-2-de s oxy-D- glucose, 2-acetamino-3-O - [[1- (D1N-carbamoylmethylcarbamoylmethyl-3-carb oxy-propyl) -c arb amoylethyl] -c arb amoylmethyl] -2-deoxy-D-glucose, i! 52

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2-Benzoylamino-3-O- [L-1- (D-1-c arbamoyl-3-carboxy-propyl) -c-arbo-methyl-propyl] -carb-amoylmethyl-2-des-oxy-D-glucose , 2-Acetylamino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -c arb amoylpropyl] -c arb amoyl-methyl ^ -2-deoxy-D-gluc ose, 5 2-Acetamino-3-O - [[1- (D1-carbaraoyl-3-carboxypropyl) -carbamoyl-2-hydroxyethyl] -carbamoylmethyl] -2-des oxy-D-glucose, 2-propionylamino-3 O - [[1- (D1,3-dicarboxy-propyl) -carbamoylethyl] -carbamoylmethyl] -2-deoxy-D-glucose, 2-benzylamino-3-O- [[1- (D1N-carbamoylmethyl) -carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-desoxy-D-glucose, 2-ac et amino-3-O - [[1- (L1-carbamoyl-3-carboxy) -propyl) -carbamoyl-2 '-methyl-propyl] -carbamyl-methyl-2- deoxy-D-15-glucose, 2-acetamino-3-O- ^ Ll- [L1- (D1- carbamoyl-3- (L1-carboxy-ethyl) -c-arb amoyl-propyl) -c-arbamoyl-ethyl] -c-arb-amoylethyl-2-deoxy-D-glucose, 2-acetamino-3-O -> [L1- (L1 (3-dicarboxy-propyl) -carbamoyl-2β-methyl-propyl] -carbamoyl-meth hyl 2 -2-deoxy-L-glucose, 2-benzoylamino-3-O- [[1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 * -methyl-propyl] -carbamoyl methyl 2 -2-deoxy-L-glucose, 2-acetamino-3-O- [[1- (D-1-carbamoyl-3-carb oxy-propyl) -25c arb amoyl-H, ΪΤ- t a ramethylene] - carb amoylmethyl 2 -2-deoxy-D-glucose, 2-acetamino-3-O- [[1- (L1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -ΪΓ-methylethyl-carb amoyl-methyl-2-deoxy-L-glucose or 2-acetamino-3-O-β> D1- [L1-carbamoyl-3-carb oxy-propyl) - 53

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carbamoyl-21-methyl-propyl] -carbamoylethyl] -2-deoxy-D-glucose.

Example 23

To 10 ml of a solution of cholera toxoid from Vibrio 5 cholerae in phosphate buffered physiological sodium chloride solution is added 50 mg of 2-acetanido-3-O - [[1- (D1-carbamoyl-3-succinimidoxycarbonyl-propyl) -carbamoyl-ethyl] ] -carbamoyl-methylj-2-deoxy-D-glucose. The protein concentration in the solution is 0.6 mg / ml. The solution is stirred for 4 hours at 4 ° 0. Then, the cholera toxoid muramyl dipeptide conjugate is separated by ultrafiltration from low molecular weight reaction products. The ultrafiltered solution is frozen and stored at -20 ° C until needed.

The quantitative assay (Morgan-Elson reaction) shows a content of 4-0-50 µg muramyl dipeptide per ml. 1 mg cholera toxoid-muramyl dipeptide conjugate.

Example 24.

By analogy, as in Example 23, cholera toxoid coupled to 2-acetamino-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl -desoxy-D-glucose, 2-benzoylamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-deoxy-D-25 glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose, 2-benzoylamino [1- (D1,3-dicarboxy-propyl) -carbamoyl-ethyl) -carbamoylmethyl-2-deoxy-D-glucose 2-propionylamino-3-O-1-carbamoyl - 3-c arb oxy; propyl) - c art) amoyl e thyl] - c art) amoylme thyl 2- 2- de s oxy-D-glucose ,; 2-ac et amino-3-O- [[1- (D-1-ΪΓ-c art> amoylmethyl) artoyl-3-c art> oxy-propyl] - c art) amoyl e tyl] - c arb amoylmethyl-2- de s- in oxy-D-glucose, 2-benz oyl amino-3- O- [L-1- (D1-c arb amoyl-3-c arb oxy-pr opyl ) -c arb amoyl-propyl] -c arb amoylmethylbyl 2- 2- deoxy-D-glucose, 2-acetylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -c-arb amoylpropyl] - c arb amoylmethyl 3,2-des oxy-D-gluc ose, 2-ac et amino-3-O- [[1- (Dlc arb amoyl-3-carboxypropyl) -c arb amoyl - 2-hydroxyethyl] -c arb amoylmethyl ^ -2-deoxy-D-glucose, 2-propionylamino-3-O - [[1- (D1, 3-dicarboxy-propyl) -carbamoylethyl] -c arb amoylmethyl -2-deoxy-D-glucose, 2-benzoylamino-3-O- [11 - (D1N-carbamoylmethyl-carbamoyl-3-carb oxy-pr opyl) - c ethyl] - carb amoylmethyl 3,2-deoxy-D-glucose, 2-acetamino-3-O- [L-1- (D-1-carb amoyl-3-carb oxy-propyl) -carbamoyl -2 '-methyl-pr opyl] -carbamoylmethyl-2-deoxy-D-20-glucose, 2-acetamino-3-O- D1- [L1- (D1-carbamoyl-3- (11-carbpxy-ethyl) -carbamoyl-propyl) -carb amoylethyl] -carb amoylethyl ^ -2-deoxy-D-glucose, 2-acetamino-3- 0 -> [11- (D1,3-dicarboxy-propyl) -carbamoyl-21-methyl-propyl] -carbamoyl-methyl ^ -2-deoxy-D-glucose, 2-benzylamino-3-O- [[ L-CD-1-carbamoyl-3-carboxy-propyl) -carbamoyl-21-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-β [L-1- (D-1-carb amoyl-3-carb oxy-propyl) -carbamoyl-N, IT-tetramethylene] -carbamoyl-methyl

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2-acetamino-3-O- [L-1- (D-1-carb amoyl-3-carb oxy-propyl) - carbamoyl-ethyl] -H-me thyl-carbamoyl-me thyl j - 2 - de s oxy-D-glucose or 55 D-glucose, 3 2-acetamino-3-O- ^ D1 - [L1-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-methyl -propyl] -c arb amoylethyl ^ -2-de s oxy-D-glucose.

Example 23

20 mg of a synthetic eicosapeptide which in the C-terminal sequence is identical to human chorionic gonadotropin (HCG) [cf. 0. H, Schneider, E. Blaser, Oh. Pfeuti and E.Gruden,

Bebs Letters, J.O., 272 (1975)] ° S 30 mg of 2-acetamido-3-O- [L-1- (Dlc arb amoyl-3-sue cinimidoxy-carbonyl-propyl) -carbamoyl-ethylJ-carbamoyl Dissolve -methyl 2 -2-deoxy-D-glucose in 2 ml of sodium phosphate buffer solution, pH 7.2. The solution is stirred for 6 hours at room temperature. The eicosa-peptide-muramyl dipeptide conjugate is then isolated by chromatography on a "Sephadex G-p5" column (1.4 x 40 cm) with water as eluate and lyophilized. The quantitative amino acid analysis shows that the 1-muramyl dipeptide molecule is bound to the 1-eicosapeptide molecule.

Example 26

By analogy, as in Example 23, the O-terminal eicosapeptide fragment from human chorionic gonadotropin cob-23 is readily obtained to 2- ac an amino-3- 0- D-1- [L-1- (D1-c arb amoyl - 3- c ar oxy-propyl) -c arb amoyl-ethyl] -c arbamoyl-ethyl ^ -2-des oxy-D-glucose, 2-benz oyl amino-3- O- ^ D-1- [L -1- (D-1-carb amoyl-3-carb oxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose,

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56 2-Benzylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -I-carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glncose, 2-benzoylamino 3-O - [L-1- (D-1,3 ~ the arb oxy-propyl) -carb amoyl-ethyl) -carb amoylmethyl ^ - 2- the s oxy-D-gine ose, 2-propionylamino 3 - [[1- (D1-carbamoyl-3-propoxy-propyl) -carbamoylethyl] -carbamoylmethyl-2-deoxy-D-glucose, 2-ac et amino-3-O- [[1- D-1-N-carb amoylmethyl carb amoyl-3-carb oxy-propyl) -carb amoylethyl] -carb amoylmethyl-2-s-10-oxy-D-glucose, 2-benzoylamino-3- 0- [[1- (D-1-Carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoylmethyl ^ -2-deoxy-D-glucose, 2-acetylamino-3-O - [ L- (D1-carbamoyl-3-carboxy-propyl) -carbamoylpropyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-ac etamino-3-O- [Ll- (D -carbamoyl-3-carboxypropyl) -carbamoyl-2-hydroxy and hy 1] - carbamoylmethyl-2-deoxy-D-glnose, 2-propionylamino-3-O - [L- 1- (1) -1,3-dicarboxy-propyl) -carb amoyl-ethyl] -carb-amoylmethyl <- 2- de soxy-D- 2-benzoylamino-3-O - [[1- (D1N-carbamoylmethyl-carbamino-3-carb oxy-propyl) -carb amoyl-ethyl] -carb amoylmethyl-2-deoxy -D-Glucose, 2-ac etamino-3-O- [[1- (Dlc arbamoyl-3-carboxy-propyl) -carbamoyl-21-methyl-propyl] -carbamoylmethyl-2-deoxy-D-25 glucose, 2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3- (L1-carboxy-ethyl) -carbamoyl-propyl) -carbamoylethyl] -carbamoylethyl-2-deoxy-D-glucose , 2-Acetamino-3-O - [[1- (D1,3-dicarboxy-propyl) -carbamoyl-3 ° 2, -methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glncose, 2-b enzyme 3-O- [L-1- (D-1-carbamoyl-3-carb oxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-methyl D-glucose, 57

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2-ac et amino-3-O - [Ll- (Dlc arb amoyl-3-c arb oxy-propyl) -5 c arb amoyl-ΒΓ, ΪΓ-1 e trame thylene] - c arb amoylmethyl - 2-deoxy-D-glucose, 2-acetamino-3-O- [L-1- (D-1-carb amoyl-3-c arb oxy-propyl) -c arb amoyl-ethyl] - Η-methyl-carbamoyl-methyl-2-de-soxy-D-glncose or 2-ac et amino-3-O-3-D-1- [L-1-c arb amoyl-3-c arb oxy- propyl) -carbamoyl-21-methyl-propyl] -carbamoylethyl-2-deoxy-D-glucose *

Example 27

By analogy as in Example 1, bovine serum albumin 13 coupled with 2-ac is obtained an amino-3-O - [[(D1-carbamoyl-3-carb oxy-propyl) -carb amoylmethyl J-IT 2-benz oylamino-3-O-β [(D1-carbamoyl-3-c arb oxy-propyl) -c arb amoyl-methyl thyl] -N-methylthio-carb amoyl-methyl tyl 2 -2-deoxy-D-20 glucose, 2-ac et amino-3-O - [[1- (Dlc 3-carb oxy-propyl) -c arb amoyl-ethyl) -H-ethyl-carb amoyl-methyl-2-deoxy-D-glucose, 2-ac et amino-3- O-> [L- 1- (D1-carbamoyl-3-carb oxy-propyl) -25 carbamoyl-propylJ-F-methyl-carbamoyl-methyl ^ -2-deoxy-D-glucose, 2-acetamino-3--0-? [1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -1-ethyl-carbamoyl-methyl-2-deoxy-D-glucose, 2-benzamido-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -E-thyl-carbamoyl-methyl-2-deoxy-D-glucose, 58

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2-acetamino-3-O - [[1- [1- (D1-carbamoyl ~ 3-carboxy-propyl) -5-carbamoyl-ethyl] -E-propyl-carbamoyl-methyl] -2-deoxy-D-glucose, 2 -acetamino-3-O - [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-E, E-pent arne thyl en] - carbamoyl-methylthyl-2- de s oxy -D-glucose, 2-benzoylamino-3-O- [[1-1- (1) -1-carbamoyl-3-c arboxy-propyl) -carbamoyl-E, Ep enteamethyl]] - c 2-Acetamino-3-O- [[1-1- (1-1-carbamoyl-3-carb oxy-propyl) -E- methyl-carb amoyl-ethyl] - carb amoyl-methyl-2-deoxy-D-15-glucose, 2-acetamino-3-O- ^ D1 - [(D1-carbamoyl-3-c arb oxy-propyl) -c arb amoylmethyl] -E-methyl-carb amoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzoylamino-3-O- ^ D1 - [(D1- carbamoyl-3-carboxy-propyl) -20-carbamoyl-methylethyl-E-methyl-carbamyl-ethyl-2-deoxy-D-glucose, 2-ac et amino-3- D-1- [L-1- (D1-c arb amoyl-3- c arb oxy-propyl) -c arb amoyl-ethyl) -E-ethyl-c arb amoyl-ethyl -D-glucose, 2-acetamino-3-O- L- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -E-methyl-carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-ac et amino-3- 0- D1- [L-1- (D1- c arb amoyl-3- c arb oxy-propyl) - c arb amoyl-propyl] -E-ethyl-c arb amoyl-methyl-2-de s-30 oxy -D-Glueose, 59

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2-benzamido-3- O- ^ D-1- [L-1- (Dlc arb amoyl-3-carb oxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-ethyl-2-de s oxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -3carbamoyl-ethyl] -N-propyl-carbamoyl-ethyl < -2-deoxy-D-glucose, 2-ac et amino-3-O- [L1- (Nlc arb amoyl-3-c arb oxy-pr opyl) - c arb amoyl-N, Np ent amyl thyl en ] - carb amoyl-ethyl-2,2-deoxy-D-glucose, 2-benzoylamino-3-O-, D1- [11- (D1-carbamoyl-3-carboxy-propyl) -carbamyl N, Np ent amethyl and] -c arb amoyl-ethyl j-2-deoxy-D-gluc ose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) ) -N-methyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-13-deoxy-D-glucose, 2-ac etamino-3-O- [1-1- (D1-carbamoyl-3 -c arb oxy-methyl-phenyl] -carbamoyl-methyl ^ -2-deoxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-methyl-phenyl] -c arb amino-methyl-2-deoxy-D-glucose, 2-benzamino-3-O - [[1- (D1-carbamoyl-3-c arboxy-propyl) -c arb amoyl-2 -methyl-mercapto-ethyl] -c arb amoyl-methylj-2-deoxy-D-glucose, 2-benzamino-3-O-β [L1- (D1-carbamoyl-3-c arb oxy-propyl) -c arb amoyl-2 -chloroethyl] -carbamoyl-methyl-2-de-soxy-D-23 glucose, 2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3,3-dicarboxy-propyl) -carbamoylethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2- (p-carbomethoxy-succinamido) -3-0 - [[1- (D1-carbamoyl-3-carboxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-methyl ^ -2-deoxy-D-glucose, 60

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in 2- (p-carbomethoxy-succinamido) -3-0- £ D1- [L1- (D1-carbamoyl-3- c 3Tb oxy-propyl) - c arb amoyl-ethyl} -c arb amoyl ethyl 2-deoxy-D-glucose, 2-benzamino-3-O-β [1- (d-1-carbamoyl-3-trimethylsilyl-5-carb oxy-propyl) -c-arb-amoyl-ethyl ] - Carb amoyl-methyl-2-deoxy-1,4,6-tris-trimethylsilyl-D-glucose. (Upon contact with water, the trimethylsilyl ester group is hydrolyzed rapidly), 2-acetamino-2-deoxy-3-O - [L-Ι- (D1-carbamoyl-3-trimethylsilyl c arb oxy-pr opyl) - c arb amoyl -e thyl] - carb amoylme thi 1 -10 1,4,6-tris-trimethylsilyl-D-glucose, 2-ac et amino-3-O- ^ D1- [L1- (Dlc arb amoyl-3- c arb oxy-pr opyl) -c arb amoyl-pr opyl] -c arb amoyl-e thyl ^ -2-de s oxy-D-gluc ose, 2-acetamino-3-O- ^ Dl- [Ll- ( D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '-hydroxy-propyl] -carbamoyl-ethyl <2 -2-deoxy-D-glucose, 2-acetamino-3-O-D1 - [1- (D1-oarbamoyl-3-carboxy-propyl) -carbamoyl-2 '- (p-hydroxy-phenyl) -ethyl] -carbamoyl-ethyl 2 -2-deoxy-D-glucose, 2-acetamino 3-0- ^ D1- [L1- (Dlo arb amoyl-3-c arb oxy-propyl) - c arb amoyl-h, ΪΓ-1 e trene thylene] - c arb amoyl-ethyl s oxy-D-glucose, in 2-glycolyl amino-3-O- ^ D1- [L1- (L1-carbamoyl-3-carb oxy-propyl) -carbamoyl-ethyl] -carbamoyl ethyl 2- 2- de soxy-D-glucose, 2-glyc olyl amino-3-O - [[1- (Dlc 3-carb oxy-propyl) -carb-amoyl-ethyl] -carb-amoyl-methyl-2-desoxy-D-glucose, 2- (H-methyl-ac etamino) -3-0- [[1- (D1- c arb amoyl-3-c arb oxy-pr opyl) -c arb amoyl-ethyl] - c arb amoyl-methyl-2-deoxy-D-glucose, 2- (ΪΓ- methyl thio-ac et amino) -3-O- [D1- [L1- (Dlc amboyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-des-2-acetamino-3 0- D1- [L-1- (D1-carbamoyl-3-carb oxy-propyl) -carbamoyl-2'-phenylethyl 1] -carbamoyl-ethyl-2-deoxy-D-glucose, 61

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oxy-D-glucose, 2-acetamino-3-O-β [L-1- (D-1-carbamoyl-3-carb oxy-propyl) -carbamoyl-21- (p-hydroxyphenyl) ethyl ] -c arb amoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O- [[1- (D1- [11-carboxy-ethyl] -carbamoyl-3-benzylcarboxy-propyl) - 2-deoxy-D-glucose or 2-acetamino-3-O- [L-1- (D-1,3-di-carboxy-propyl) -carbamoyl-ethyl] -c E-methyl-c arb amoyl-ethyl] -c arb amoylmethyl-2-de s oxy-D-gluc ose.

Example 28.

By analogy as in Example 3, sheep erythrocyte-13 membranes coupled to 2-acetamino-3-O - [[(D1-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -E-methyl are obtained - c arb amoylmethyl methyl 2 -2-des oxy-D-glucos e, 2-benz oylamino-3-O - [[(Dlc arb amoyl-3-c arb oxy-propyl) -c arb amoyl-methyl] -N-methyl-carb amoyl-methyl ^ -2-des oxy-D-20 glucose, 2-acetamino-3-O-2 [L1- (D1-carbamoyl-3-carboxy-propyl) - 2-Acidamino-D-glucose, 2-ac et amino-3-O - [[1- (D1-carbamoyl-3- c arboxy-propyl) -25 carbamoyl-propyl-E-methyl-carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O -> [1-1- (D ~ 1-c arb amoyl-3-carb oxy-propyl) -c arb amoyl-propyl] -E-ethyl-carb amoyl-methyl-2-deoxy-D-glucose, 2-benzamido-3-O-> [1-1- (D-1-carb amoyl-3-carb oxy-pr opyl) - c arb amoyl-pr opyl] -K-e thyl-c arb amoyl-methyl thyl 2 -2-de s oxy -D- glucose, 62

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2-Acetamino-3-O- [[1- (r -1-carbamoyl-3-carboxy-propyl) -5-carbamoyl-ethyl] -K-propyl-carbamoyl-methyl-2-deoxy -D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-K, N-pentene-thylene] -c-arbamoyl-methyl-2-deoxy -D-glucose, 2-benzoylamino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -c arb amoyl-K, K-pentanethyl]] - c arb amoylmethyl 2 -2-Deoxy-D-glucose, 2-ac etamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -5-methyl-carbamoyl-ethyl] - carb amoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O- / D1- [D1-carbamoyl-3-carb oxy-propyl) -c arb amoyl-methyl] -K- methyl-carb amoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzoylamino-3-O- ^ D1 - [(D1-carbamoyl-3-carboxy-propyl) -carbamoylmethyl] -K-methyl-carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -c arb amoyl-ethyl) -K-ethyl-c arb amoyl-ethyl 2 -2-25 deoxy-D-glucose, 2-ac et amino-3-O-3-D1- [L-1- (Dlc-arb amoyl-3 - c arb oxy-pr o pyl) -c arbamoylpropyl] -N-methyl-carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2- ac et amino-3-O- ^ D1- [Ll- (Dlc arb amoyl - 3-carb oxy-propyl) -c-arb-amoyl-propyl] -K-ethyl-c-arb-amoyl-methyl-2-deoxy-D-glucose,

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63 2-Benzamido-3-O- [D1- [11- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -H-ethyl-carbamoyl-ethyl] -2-deoxy-D-glucose, 2-ac et amino-3-O-D1- [L-1- (Dlc arb amoyl-3-c arb oxy-propyl) - c arb amoyl-ethyl] -K-pr opyl-c arb amoyl thyl j - 2-deoxy-D-glucose, 2-acetamino-3-O-D-1- [L-1- (Dlc arbamoyl-3-c arb oxy-pr opyl) - c arb amoy 1-N , Abentamethylene] - carbamoyl-ethyl-2,2-deoxy-D-glucose, 2-benzoylamino-3-O-, D1- [L1- (D1-carbamoyl-3-carboxy-propyl) - carb amoyl-N, N-pentarnethylene] -c arb amoyl-ethyl <-2-deoxy-D-glucose, 2-ac et amino-3-O- ^ D1- [L-1- (D1-c arb amoyl-3-carb oxy-propyl) -K-methyl-c-arboyl-ethyl] -c-arb-amoyl-ethyl <2-15-deoxy-D-glucose, 2-ac et amino-3-O- [ L-1- (D-1-carb amoyl-3-carb oxy-methyl-phenyl) -c-arb-amoyl-methyl-2-deoxy-D-glucose, 2-benzoylamino-3-o - [[1- (D1-carbamoyl-3-carboxy-methyl-phenyl] -carbamoyl-methyl-2-de-soxy-D-glucos e, 2-b enzamino-3-O-β [L -1- (Dlc arb amoyl-3-c arb oxy-pr opyl) -c arb amoyl-2-methyl-merc apto-ethyl] -c arb amoyl-methyl-2-deoxy-D-glucose, 2-benzamino-3-O- [L-1- (D -1-carbamoyl-3-carboxy-propyl) -carbamoyl-2-chloroethyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3,3- (licarboxy-propyl) -carbamoylethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2- (p-carbomethoxy-succinamido) -3-0 - ^ [L1- ( D1-carbamoyl-3- (carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose, 1- 2- (p-carbomethoxy-STiccinamido) -3-0- 1- [1- (I) -1-carbamoyl-3-carb oxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose, 64

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2-benzamino-3-O- [[1- (1) -1-carbamoyl-3-trimethylsilyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-1,4,6- tris-trimethylsilyl-D-glucose. (Upon contact with water hydro lysis, the trimethylbylsilyl ester group is fast), 2-ac etamino-2-des oxy-3-O- [Ll- (L-carbamoyl-3-trimethyl-silylcarboxy-propyl) -carbamoyl -ethyl] -carbamoylmethyl-1,4-tris-trimethylsilyl-b-glucose, 2-acetamino-3-O- / D1- [11- (D1-carbamoyl-3-carboxy-propyl) - carbamoyl-propyl J-carbamoyl-ethyl 2 -2-deoxy-D-glnose, 2-acetamino-3-O-b-1- [1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-21-hydroxy -propyl] -carbamoyl-ethyl ^ - 2 -15-deoxy-D-glucose, 2-acetamino-3-O-bbl- [L1- (b-carbamoyl-3-carboxy-propyl) -carbamoyl-2 ' - (p-hydroxy-phenyl) -ethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (L1-carbamoyl-3-carboxy-propyl) ) - c arb amoyl-N, h-1 ethernethyl and] - c arb amoyl-ethyl 2 -2-iodooxy-L-glucose, 2-glycolylamino-3-O-βb- [L1- (D1-carbamoyl 3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-glyc olylamino-3-O - [[1- (D1-carbamoyl-3 c (oxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy -D-glucose, 2- (N-methyl-ac etamino) -3-0 -> [L1- (Llc arb amoyl-3-c arb-oxy-pr opyl) - c arb amoyl-ethyl J - c arb amoylmethyl 1- 2-deoxy-D-glucose, 2- (1-methyl-ac et amino) -3-O- [L1- [L1- (L1-carbamoyl-3-carboxy-propyl) -carbamoyl -ethyl] -carbamoyl-ethyl ^ -2-des-2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxypropyl) -carbamoyl-21-phenylethyl] -carbamoyl-ethyl 2-desoxy-D-glucose, 65

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oxy-D-glucose, 2-acetamino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-21- (p-hydroxyphenyl) ethyl] -carbamoyl] methyl 2 -2-deoxy-D-glucose, 2-acetamino-3-O-β [L1- (D1- [L1-carboxyethyl] -c arb amoyl-3-benzylc arb oxy-propyl) -c arb 2-deoxy-D-glucose or 2-acetamino-3-O- [[1- (D-1,3-dicarboxy-propyl) -N-methyl-carbamoyl] amoyl-ethyl] -carb amoylmethyl -ethyl] -c arb amoylmethyl ^ -2-de s oxy-D-gluc ose.

Example 29.

By analogy, as in Example 4, group C-poly-13 saccharide is obtained from Neisseria meningitidis coupled with 2-ac etamino-3-O- [[(D1-carb amoyl-3-c arb oxy-propyl) -c arb amoylmethyl] -N-methyl-c arb amoyl-methyl ^ -2-deoxy-D-glucos e, 2-b enz oylamino-3- O- [[(D-1-carb amoyl- 3-c-arb oxy-propyl) -c-arb-amoyl-methyl] -N-methyl-c-arb-amoyl-methyl-2-des oxy-D-20-glucose, 2-acetamino-3-O-β [1-1 - (1) -1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methyl-2-deoxy-D-glucose, 2-ac et amino-3-O - / [ L- (D-1-carbamoyl-3-carb oxy-propyl) -25 c arb amoyl-propylJ-N-methyl-carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino -3-O-HL-1- (Dlc arb amoyl-3-carboxy-propyl) -c arb amoyl-propyl] -N-ethyl-c-arb amoyl-methyl-2-des oxy-D-glucose, 2- b enz amido-3-O -> [Ll- (Dlc arb amoyl-3-c arb oxy-propyl) - c arb amoyl-pr opyl] -BT-ethyl-c arb amoyl-methyl tbyl oxy-D-glucose, 66

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2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -3c-arbamoyl-ethyl] -Bf-propyl-carbamoylmethyl-2-deoxy-D-glucose, 2-Acetamino-3-O- [[11-CD-1-carbamoyl-3-carb oxy-propyl) -carbamoyl-BT, BT-pentamene thylene] -c arbamoyl-methylj-2 deoxy-D-glncose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -c arb amoyl-BT, BT-p ent amyl en] - c arb amoyl- 2-deoxy-D-glucose, 2-acetamino-3-O- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -Bf-methylthiocarbamoyl - ethyl] - carb amoyl-methyl-2-deoxy-D-15 glucose, 2-ac et amino-3-O-XD-1- [(Dlc -propyl) -carbamoyl methyl j-1-methyl-carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzoylamino-3-O- ^ D1 - [(D1-carbamoyl-3-carboxy-propyl) - 20 carb amoylmethyl] -Bi-methylthiocarbamoyl-ethyl 2 - 2-soxy-D-glucose, 2-acetamino-3--0- ^ D1- [L1- (D1-carbamoyl- 3-carboxy-propyl) -c-arb-amoyl-ethyl)-e-ethyl-c-amo-ethyl-2-deoxy-D-glucose, 2-ac etamino-3-O-D-1 - [L-1- (D1- c arb amoyl-3- c arb oxy-pr opyl) - c arb amoyl-pr opyl] -ΒΓ-methyl] -c arb amoyl-ethyl ^ -2-deoxy-D-glucose, 2-acetamino -3-0- j> D-1- [L-1- (D-1- c arb, amoyl-3- c arb oxy-pr opy 1) - c arb amoyl-pr opyl] -ethyl-c 2-benzamido-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -Ή -ethyl-c arb amoyl-ethyl ^ -2-de s-oxy-D-glucose, 67

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2- ac etamino-3-O-β> D1- [L1- (Dlc amboyl-3-carb oxy-propyl) -carbamoyl-ethyl] -ir-propyl-carbamoyl-ethyl oxy-D-glucose, 2-acetamino-3-O- [D1- [11- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-2-deoxy -D-glucose, 2-benzylamino-3-O- ^ D1- [L1- (Dlc arb amoyl-3-c arboxy-propyl) -c arbamoyl-N, Np ent amylene] - c arb amoyl ethyl 2 -2-deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -U-methyl-carbamoyl-e thyl] - c arb amoyl- e thyl y-, 2-13 deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-methyl-phenyl] -c-arb amoyl) -methyl 2 - 2-deoxy-D-glucose, 2-benzoylamino-3-O - [1- [1- (D1-carbamoyl · arboxy-methyl-phenyl] -carbamoyl-methyl) -2 -desoxy-Dg se, 2-benzamino-3-O- [[1- (Dlc arbamoyl-3-carb oxy-propyl) -carbamoyl-2-methyl-mercapto-ethyl] -carbamoyl-methyl 2-deoxy-D-glucose, 2-benzamino-3-O- [L-1- (D1-carbamoyl-3-carb oxy-propyl) -carbamoyl-2-chloroethyl] -ca rb amoylmethyl 2 -2-deoxy-D-25 glucose, 2-acetamino-3-O-D1- [1'1- (D1-carbamoyl-3,3-cycarboxy-propyl) -carbamoylethyl ] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2- (6-carbornethoxy-sue cinamido) -3-O - [[1- (Dlcarbamoyl-3-c arboxy-propyl) - c arb amoyl-ethyl] -carbamoyl-methyl ^ -2-deoxy-D-glucose, 2- (β-carb orne thoxy-sue cinamido) -3-0- ^ Dl- [Ll- (Dlc arb amyl) - 3-carb oxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-ethyl-2-deoxy-D-glucose, 68

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2-Benzamino-3-O - [L1- (D1-carbamoyl-3-trimethylsilyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-1,4,6-tris-trimethylsilyl -D-glucose. (Upon contact I with water, the trimethylsilyl ester group is hydrolyzed rapidly), in 2-acetamino-2-deoxy-3-O - [[1- (D1-carbamoyl-3-trimethylsilylcarb oxy-propyl) -carbamyl] ethyl ] -c arb amoylmethyl ^ -10 1,4,6-tris-trimethylsilyl-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl- propyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-ac et amino - 3-0-1- [L-1- (D-1-c arbamoy 1-3-c arb oxy-13 propyl) -carbamoyl-2'-hydroxy-propyl] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3 -carboxy-propyl) -carbamoyl-21- (p-hydroxy-phenyl) -ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O- [D1- [L1- (D1) -carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-tetramethylene] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-glycolylamino-3-O- ^ D1- [L1- (D1-carb) amoyl-3-carb oxy-propyl) -g arb amoyl-ethyl] -carb amoyl-ethyl 2 -2-deoxy-D-23 glucose, 2-glycolylamino-3-O-β [L1- (D1- carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyls-2-deoxy D-Glucose, 2- (H-methyl-ac et amino) -3-O - [L1- (Dlc arb amoyl-3- c arb oxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2 -desoxy-D-glucose, 2- (1-methyl-ac et amino) -JO- ^ D1- [L1- (D-1c arbamoyl-J- c arb oxy-propyl) -c arb amoyl-ethyl ] -c arb amoyl-ethyl ^ -2-deoxy-D-glucose, 69 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -5-carbamoyl-2 '- phenylethyl] -carbamoyl-ethyl (-2-deoxy-I) -glucose, 2-ac etamino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '- (p hydroxyphenyl) ethyl] -c-arbamoyl-methyl-2-deoxy-D-glucose, 2-ac etamino-3-O- [[1- (D-1- [Llc arb oxy-ethyl] -c-arb amoyl) - 3- (benzylcarboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose or 2-acetamino-3-O- [[1- (D1,3-dicarboxy-propyl) -1 -Methyl-carbamoyl-etby1] -carbamoylmethyl-2-deoxy-D-glucose, Example 50 «By analogy as in Example 5, merozoites from the malaria parasite Plasmodium knowlesi coupled to 2-acetamino-3- 0- [( d -1-c arb amoyl-3-ca (carboxy-propyl) -carbamoyl-methyl] -1-methyl-carbamoyl-methyl-2-deoxy-D-glucose, 2-benzoylamino-3-O - [(D1-carbamoyl-3 -carboxy-propyl) -c-arb amoyl-methyl] -1-methyl-c-arb-amoyl-methyl-2-de-soxy-D-glucose, 2-acetamino-3-O-β [L1- (D1-carbamoyl- 3-carboxy-propyl) -carbamoyl-ethyl) -IT-ethyl-carb-amoyl-methyl-2-deoxy-D-25-glucose, 2-acetamino-3-O -> [L1- ( D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propylJ-N-methyl-carbamoyl-methyl ^ -2-deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1- carbamoyl-3-carboxy-propyl) -

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70 c arb amoyl-propyl] -ΪΓ-ethyl-c arb amoyl-methyl 2 -2-deoxy-D-glucose, 2-benzamido-3-O-> [L1- (D1-carb amoyl-3 - c arb oxy-propyl) -! V) carb amoyl-pr opyl J -N-ethyl-carb amoyl-methyl-2-desoxy-D-5-glucose, 2-ac et amino-3-O- [1- (Dlc arb amoyl) - 3-Carb oxy-propyl) -carbamoyl-ethyl] -T-propyl-earbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O- [Ll- (Dlc 3-c arboxy-propyl) -10 c arb amoyl-ΪΓ, Np ent ame thyl en-c arb amoyl-methyl 2- 2- de soxy-D-glucose, 2-b enzoylamino-3-O - ^ [ L- (Dlc arb amoyl-3-c arb oxy-propyl) -carb amoyl-F, N-pentamethylene] -carb amoylmethyl <j-2-des oxy-D-glucose, 13 2-ac et amino -3-0- [[1- (Dlc arb amoyl-3-c arb oxy-propyl) -N-methyl-c arb amoyl-ethyl] -c arb amoyl-methyl ^ -2-des oxy-D-glucose, 2-acetamino-3-O-> D1 - [(D1-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -D-methyl-carbamoyl-ethyl <2 -decoxy-D- .20 Glucose, 2-benzylamino-3-O- ^ D1 - [(D1-carbamoyl-3-c arboxy-propyl) -carbamoyl-methylthyl] -ΕΓ-methylthyl-carbamyl-ethyl 2 - 2-s oxy-D-glucose, 2-ac et amino-3- O- ^ D1- [L-1- (D1-c arb amoyl-3-c arb oxy-propyl) -c arb a moyl-ethyl) -D-ethyl-carbamoyl-ethyl ^ -2-desoxy-D-glucose, 2-acetamino-3-O- / D1- [L1- (D1-carbamoyl-3-carboxy-propyl) ) -c arb amoyl-pr opyl] -N-me thyl-c arb amoyl-e thyl y-2- de soxy-D-glucose, 2-acetamino-3-O-D-1- [L- 1- (D1-carbamoyl-3-carboxy-propyl) -c arb amoylpropyl] -N-ethyl-carbamoylmethyl 1 <| - 2- de soxy-D-2--1) enzamido-3-O- ^ D1- [L-1- (D-1- c arb amoyl-3-c arb oxy-propyl) -carbamoyl-propyl ] -N-ethyl-carbamoyl-ethyl-2-desoxy-D-glucose, 71

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glucose, 2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3-carboxy-pr opyl) -carbamoy-1-ethyl] -ΪΓ-pr opyl-c-arboyl-ethyl 2-de s-oxy-D-glucose, 2-ac et amino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, 1T-pentamethylene] -carbamoyl-ethyl ^ -2-10 deoxy-D-glucose, 2-benzoylamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, h- pent arne tyl en] - carb amoyl-e thi 1 j - 2-deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -H-methyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O- [[1- (D1-carbamoyl ~ 3-carboxy-methyl-phenyl) ] -c arb amoyl-methyl ^ -2-de s oxy-D-gluc ose, 2-b enz oylamino-3-O- [[1- (D-1-carb amoyl-3-c arb oxy-methyl- Phenyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzamino-3-O- [L-1- (D-1-carbamoyl-3-carb oxy-propyl) -c arb amoyl-2-methyl-mercapt o-ethyl] -c arb amoyl-methyl-2-deoxy-D-glucose, 2-benzamino-3-O - [[1- (Dlc arb amoyl-3- c (oxy-propyl) -25 carbamoy 1-2-Chloroethyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3,3-aicarboxy-propyl) -carbamoylethyl ] -c arb amoyl-ethyl ^ -2-des oxy-D-glucose, 2- (β-c arb ornethoxy-sue c inamido) -3-O- [L-1- (D-1-c arbamoyl -

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72 3-C arboxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-methyl-2-i-deoxy-D-glucose, 2-C-β-c arborne thoxy-sue c inamido) -3-0 - [D1- [L1- (Dlc arb amino-3-c arb oxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-ethyl 2-deoxy-D-glucose, s 2-benzamino -3-0 - [[1- (D1-carbamoyl-3-trimethylsilyl-; c arb oxy-pr opyl) - c arb amoyl-ethyl] - c arb amoylmethyl-2-deoxy-1,4, 6-tris-trimethylsilyl-D-glucose. (Upon contact with water, the trimethylsilyl ester group is rapidly hydrolyzed) in 10 2-acetamino-2-deoxy-3-O-β [11- (D1-carbanylloyl-3-trimethylsilylcarb oxy-propyl) -carbamoyl -ethyl] -carb amoylmethyl ^ - 1,4,6-tris-trimethylsilyl-D-glucose, 2- ae et amino-3-O- ^ D1- [Ll- (Dlc arb amoyl-3- c arb oxy-pr opyl) -carbamoyl-propyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-acetamino-3-O- ^ 1-1- [L1- (D1-carbamoyl-3-carboxylic acid) propyl) -carbamoyl-21-hydroxy-propyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-ac et amino-3-O- ^ D-1- [L-1- (D1- carbamoyl-3-carboxy-propyl) -carbamoyl-2- (p-hydroxy-phenyl) -ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O- d-1- [L-1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-E, E-tetramethylene] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-glycolylamino-3-O-d-1- [L1- (D-1-c arbamyl-3- c arb oxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-ethyl 2-deoxy-D-glucose, 2-glycolylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -c arb amoyl-methyl-2-deoxy-D-glucose, 2- (E-methyl-ac et amino) -3-O- [Ll- (Dlc arb amoyl-3-carboxy-propyl) -carbamoyl-ethyl] - carb amoyl-methyl-2-deoxy-D-2- (N-methyl-acetamino) -3-O-D1- [L1- (D1-carbamoyl-3-carboxy) -propyl) -carbamoyl-ethyl] -carbamoyl-ethyl 2 -2-deoxy-D-glucose, 73

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glucose, 2- 2- ac etamino-3-O- ^ D1- [L1- (Dlc arb amoyl-3- c arb oxy-pr opyl) -carbamoyl-2'-phenylethyl] -c arb amoyl-ethyl ^ -2 -de s oxy-D-glucose, 2-ac et amino-3-O - [[1- (Dlc arbamyl-3-carb oxy-propyl) -carbamoyl-21- (p-hydroxyphenyl) ethyl] - 2-deoxy-D-glucose, 2-acetamino-3-O- [[1- (D1- [L1-carboxy-ethyl] -carbamoyl-3-benzylcarb oxy-propyl) -c arb amoyl-ethyl] -c arb amoylmethyl-2-deoxy-D-glucose or 2-acetamino-3-O- [[1- (D1,3-dicarboxy-propyl) -N-methyl-carbamoyl-ethyl] carbamoylmethyl ^ -2-deoxy-D-glucose.

Example 31 »Analogously as in Example 6, T-lymphoblasts from CBA / J mice coupled to 2-ac are obtained from amino-3-O- [[(Dlc arb amoyl-3-c arb oxy-propyl) -c arb-amino-methyl] -N-methyl-carbamoyl-methyl-2-deoxy-D-glucose, 2-benzylamino-3-O-β [(D-1-carbamoyl-3-c arb oxy-propyl) -c arb amoylmethyl] -1-methyl-carb amoyl-methyl 2 -2-deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl) -3-carboxy-propyl) -25-carb amoyl-ethyl] -ΪΓ-ethyl-carb-amoyl-methyl-2-deoxy-D-glucose, 2-ac et amino-3-O - [ L- (Dlc arb amoyl-3-c arb oxy-propyl) - c arb amoyl-propyl] -N-methyl-c arb amoyl-methyl ^ -2-deoxy-D-glucose, 2-acetamino-3 -0 -> [L1- (D-1-c arbamoyl-3-c arb oxy-pr opyl) - c arb amoyl-pr opyl J -ΕΓ-ethyl-c arb amoyl-methyl-2-de s oxy -D- glucose, 74

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ii 2-Benzamido-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -5-carbamoyl-propyl] -I-ethyl-carbamoyl-methyl-2-des oxy-Di glucose, 2- ac etamino-3-O-1,1- (Dlc arb amoyl-3- c arb oxy-propyl) -c arb amoyl-ethyl] -ΕΓ-propyl-c arb amoyl-methyl -de s oxy-D- | glucose, 2-ac et amino-3-O - [[1- (Dlc arb amoyl-3-c arb oxy-propyl) -c arb amoyl-U, U-pentame thyl en] -c arb amoylmethyl j-2-deoxy-D-glucose, 2-benzylamino-3-O - [[1- (Dlc arb amoyl-3-c arb oxy-propyl) -c arb amoyl-ΕΓ, ET-p ent ame thyl en] - c arb amoyl-methyl thyl 2 -2-deoxy-15-D-glucose, 2-acetamino-3-O- - c arb amoyl-3-c arb oxy-propyl) -El-methyl -carbamoyl-ethyl] -carbamoyl-methyl-2-desoxy-D-glucose, 2-acetamino-3-O-> D-1 - [(D1-carbamoyl-3-carboxy-propyl) -; 20-carb amoyl-methylthyl] -EF-methylthyl-carbamyl-thylyl-2-deoxy-D-I glucose, 2-benzoylamino-3-O- ^ D1 - [(D1-carbamoyl -3-carboxy-propyl) -carbamoylmethyl] -ET-methyl-carbamoyl-ethyl ^ -2-des oxy-D-glucose, 2- ac et amino-3-O- [L1- (Dlc arb amoyl-3- c arb oxy-pr opyl) - c arb amoyl-ethyl) -ET-ethyl-c arb amoyl-ethyl-2- the s -oxy-D-glucose, 2- ac et amino-3-O- D-1- [L1- (Dlc arb amoyl-3-c arb oxy-pr opyl) - c arb amoyl-pr opyl] -ΕΓ-methyl th c-arb amoyl-ethyl -2-30 deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1 ~ (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -IT-ethyl-carbamoyl -methyl 2 -2-deoxy-D-glucose,

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-7 5 2-Benzamido-3-O-β> D1- [L-1- (D-1-carbamoyl-3-carb oxy-3-propyl) -carbamoyl-propyl] -I-ethyl-carbamoyl -ethyl-2-des-oxy-D-glucose, 2-ac et amino-3-O-D-1- [L-1- (Dlc arb amoyl-3-c arb oxy-propyl) -carbamoyl-ethyl ] -ir-propyl-carbamoyl-ethyl-2-des-oxy-D-glucose, 2-acetamino-3-O- ^ D1- [11- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl -N, D-pentomethylbenzene] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzoylamino-3-O- ^ D1- [L1- (D-1-carbamoyl-3-carboxy-pr opyl) - c arb amoyl-N, IT-p ent arneyl en] - c arb amoyl-e thyl j - 2-15 deoxy-D-glucose, 2-ac et amino-3- 0- £ D-1- [L-1- (D-1-carbamoyl-3-carb oxy-propyl) -N-methyl-1-carb amoyl-ethyl] -c-arbamoyl-ethyl ^ -2-des oxy-D-glucose, 2 -ac et amino-3- O- [L-1- (D-1-carb amoyl-3-carb oxy-methyl-phenyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2 -b enz oylamino-3-O- [Ll- (Dlc arb amoyl-3-c arboxy-methyl-phenyl) -c arb amoyl-methyl ^ - 2- de soxy-D-glucose, 2-b enz amino - 3-0- L-1- (D1- c arb amoyl- 3- c arb oxy-pr opyl) -c arb amoyl-2-methyl-mercapto-ethyl] -carbamoy-1-methyl-2- 25-deoxy-D-glucose, 2-benzamino-3-O-β [ L-1- (D-1-carbamoyl-3-carb oxy-propyl) -c arb amoyl-2-chloroethyl] -c arb amoyl-methyl ^ -2-deoxy-D-glucose, 2-acetamino -3-O-d-1- [L-1- (D1-carbamoyl-3,3-dicarboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

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76 2- (β-Carbomethoxy-succinamido) 3-O- [[1- (Dlc arb amoyl-3 ~ c arb oxy-propyl) -c arb amoyl-ethyl] - c arb amoyl-methyl γ-2-deoxy -D-glucose, 2- (β-carbomethoxy-suecinamido) -3-0- ^ D1- [L1- (D1-carbamino-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl ethyl 2- 2-deoxy-D-glucose, 2-benzene amino-3-O- [[L-1- (D-1-carb amoyl-3-trimethylsilyl-carb oxy-propyl) - carb amoyl-ethyl] - carb amoyl-methyl-2-deoxy-1,4,6-tris-trimethylsilyl-D-glucose. (Upon contact with water, the trimethylsilyl ester group is rapidly hydrolyzed), 2-acetamino-2-deoxy-3-O- [Ll- (Dlc arb amoyl-3-trimethyl-1-silylcarb oxy-propyl) - c arb amoylethyl] - c arb amoylmethyl-1,4,4-tris-trimethylsilyl-D-glucose, 2-acetamino-3-O-> DL- [L1- (D1-carbamoyl-3-carboxylic acid) propyl) - | Carbamoyl-propyl-carbamoyl-ethyl-2-deoxy-D-glucose-2- ae and amino-3-O-D-1- [L-1- (D-1-carbamoyl-3-c (oxy-: propyl) -carbamoyl-2'-hydroxy-propyl] -carbamoyl-ethyl deoxy-D-glucose, 2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '- (p-hydroxy-phenyl) -eth. yl] -carbamoyl-ethyl 2 -2-deoxy-D-glucose, 2-ac et amino-3-O-β> D1- [L-1- (Dlc arb amino-3- c arb oxy-propyl) -c arb amoyl-N, IT-1 ethernethylene] -c arb amoyl-ethyl 2 -2-deoxy-D-glucose, 2-glycollicylamino-3-O- ^ D-1- [L-1- (D -1- c arb amoyl-3- c arb oxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-ethyl ^ -2-des oxy-D-glucose, 2-glyc olylamino-3-O- [ L- (D1-carb amoyl-3-ear oxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-methyl ^ -2-des oxy-D-glucose, 2- (-methyl-ac-et amido) -3- O- [L-1- (D-1- c arb amoyl-3- c arb oxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-methyl ^ -2-deoxy-D - glucose, 77

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2- (U-methyl-ac et amino) - 3-O-D1- [L1- (Dlc arb amoyl-3-5 c arb oxy-pr opyl) - c arb amoyl-ethyl] - c arb amoyl ethyl 2 -2-deoxy-D-glucose, 2-ac etamino-3-O- ^ D1- [1-1- (Dlc arbamoyl-3-carb oxy-propyl) -carbamoyl-21-phenylethyl] -carbamoyl ethyl 2 -2-deoxy-D-glucose, 2-acetamino-3-O- [1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-21- (p-hydroxyphenyl) -ethyl] -c arb amoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O- [[1- (D1- [L1 -c arboxyethyl] -c arb arnoyl-3-benzylc arb oxy) -propyl) -c arb amoyl-ethyl] -c arb amoylmethyl-2-deoxy-D-glucose or 2-acetamino-3-O- [[1- (D1,3-dicarboxy-propyl) -1-methyl] c iso amoyl-ethyl] -c-arb amoylmethyl-2-des oxy-D-glucose,

Example 32, Analogously as in Example 12, foot-and-mouth disease culture vaccine (Behringwerke) coupled to 2-acetamino-3-O-β [(D1-carbamoyl-3-carboxy-propyl) -carbam-1 oyl-methyl] -N-methyl-c arb amoyl-methyl 2 -2-deoxy-D-glucose, 2-benzylamino-3-O - [[(Dlc arb amoyl-3-c arboxy-propyl) -c arb amoylmethyl] -N-methyl-c arb amoylmethyl 3 -2-deoxy-D-glucose, 2-ac et amino-3-O - [[1- (Dlc arb amoyl-3 -c-arb oxy-propyl) -c-arb-amoyl-ethyl) -N-ethyl-c-arb-amoyl-methyl-2-2-des oxy-D-glucose, 2-ac etamino-3-O - [[1- (D1-carbamoyl-3-carb oxy-propyl) - 78

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carb amoyl-pr opyl] -N-methyl-carb amoyl-methyl ^ -2-des oxy-D-! glucose, | ! 2-aeet amino-3-O-β [L1- (Dlc amoyl-3-c arhoxy-propyl) -carbamoyl-propyl] -K-ethyl-carbamoyl-methyl-2-deoxy-DI 5 glucose, 2 -1> enzyme amido-3-O-> [11- (D1-carboxy-3-carboxy-propyl) -c art) amoyl-propyl] -ΪΓ-ethyl-carboxy-methyl - 2-des oxy-D-glucose, 2-ac et amino-3-O - [[1- (Dlc arhamoyl-3-carb oxy-propyl) -10-c arhamoyl-ethyl] -N-propyl -c arh amoyl-methylj-2-de s oxy-D-glucose, 2-ac et amino-3-O- [[1- (Dlc arhamoyl-3-c arhoxy-propyl) -c arh amoyl- if, Kp ent amethylene] -carhamoyl-methyl-2-desoxy-D-glucose, 2-benzylamino-3-O - [[1- (Llc arhamoyl-3-c arboxy-propyl) - carhamoyl-N, ϊΓ-ρ ent arne thyl en] - c arh amoyl-methyl γ-2- des oxy-D-glucose, 2-ac et amino-3-O- [Ll- (D1-carhamoyl -3-carhoxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoyl-methyl-2-des oxy-D-20-glucose, 2-acetamino-3-O-D1 - [(D1- carbamoyl-3-earboxy-propyl) -c arhamoyl-methyl-H-methyl-c arh-amoyl-ethyl-2-deoxy-D-glucose, 2-benzyl-amino-3- 0- [D1 - [(D1-carboxy-3-carb oxy-propyl) -25-carbamoyl-methyl] -H-methyl-carhamoyl-ethyl ^ -2-deoxy-D-glucose, 2-ac et amino-3-O-D-1- [L-1- (D-1-c arhamoyl 1-3-c arhoxy-propyl) - c arh amoyl-ethyl) -IT-ethyl-c arh amoyl ethyl 2- 2-desoxy-D-glucose, 2- ac etamino-3- O- ^ D-1- [L-1- (Dlc arhamoyl-3- c arhoxy-propyl) - c arhamoyl-pr opyl] -N-methyl-c arhamoyl-ethyl j-2-deoxy-D-2-acetamino-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl) - c iso amoyl-propyl] -N-ethyl-c iso amoyl-methyl-2-deoxy-D-glucose, 79

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glucose, 2-benzamido-3-O-D-1- [L-1- (D-1-c arb amoy 1- 3- c arb oxy-propyl) - c arb amoyl-propyl] -N -ethyl-carbamoyl-ethyl j-2-desoxy-D-glucose, 2-ac etamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carb oxy-propyl) -c arb amoyl-ethyl] -Π-propyl-c arb amoyl-ethyl-2-des-10-oxy-D-glucose, 2-ac et amino-3-O-3-D1- [L-1- (D1-c arb amoyl-3-carb oxy-propyl) -c arb amoyl-N, Π-pentarnethylene] -c arb amoyl-ethyl ^ -2-deoxy-D-glucose, 2-b enzoylamino-3-O- ^ D1- [ L- (D1-carbamoyl-3-carboxy-13-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-ac et amino-3-O- 1- (Dlc arb amoyl-3- c arb oxy-propyl) -N-methyl-c arb amoyl-ethyl] -c arb amoyl-ethyl-2-deoxy-D-glucose, 2-ac et amino-3 -0- ^ [L1- (D1- c arb amoyl-3- c arb oxy-methyl-phenyl] -c arb amoyl-methyl ^ - 2- de s oxy-D-gluc ose, 2-b enz oylamino-3 -0- £ [L-1- (D-1-c arb amoyl-3-c arb oxy-methyl-phenyl) -carbamoyl-methyl ^ -2-deoxy-D-gluc ose, 2-b enazmino -3-0- £ [Ll- (Dlc arb amoyl-3-c arb oxy-propyl) -25 c arb amoyl-2-methyl-mercapt o-ethyl] -c arbamoyl-methyl-2-deoxy-D-glucose, 2-benzamino-3-O - [[1- (Dlc arb amoyl-3-carb oxy-propyl) -c arb amoyl-2-chloroethyl] -c arb amoyl-methyl-2-deoxy-D-glucose, 2-ac etamino-3-O- [L1- (Dlc arb amoyl-3,3-dicarboxy- (80)

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propyl) - carb amoyl ethyl] - carb amoylethyl ^ -2-des oxy-D-glucose, 2- (β-carb ornethoxy-suecinamido) -3-0- [Ll- (Dlc arb amoyl-3 - c arb oxy-pr opyl) - c arb amoyl-e thyl] -c arb amoyl-methyl-2 - 2-5 deoxy-D-glucose, 2- (β-carbomethoxy-succinamido) -3-O-D -1- [L-1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzamino-3- 0 - [[1- (D-1-Carbamoyl-3-trimethylsilyl-10-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-des-oxy-1,4,6-triso trimethylsilyl-D-glucose * (Upon contact with water, the trimethylsilyl ester group is rapidly hydrolyzed), 2-acetamino-2-deoxy-3-O - [[1- (D1-carbamoyl-3-trimethyl-silylcarb oxy-propyl) -c arb amoyl-ethyl] -c arb amoylmethyl-1,4 1,4-tris-trimethylsilyl-D-glucose, 2-acetamino-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl) ) - carbamoyl-propyl] -carhamoyl-ethyl ^ -2-deoxy-D-glucose, 2-ac et amino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carb oxy-propyl) - carbamoyl-2'-hydroxy-propyl] -carbamoyl-ethyl ^ -2-deoxy-D-20 glucose, 2-acetamino-3-O-D-1- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-21 - (p-hydroxy-phenyl) - ethyl] -c arb amoyl-ethyl 2 -2-deoxy-D-glucose, 2-ac etamino-3-O-βD1- [Ll- (Dlc arb amoyl-3-c arb oxy-propyl) -25 carb amoyl -N, Nt etr amethylene] -carbamoylethyl ^ -2-deoxy-D-glucose, 2-glycolylamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carb amoyl-ethyl ^ -2-desoxy-D-glucose, 2-glycolylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) - carb amoyl-ethyl] -c arb amoyl-methyl-2-deoxy-D-gluc ose, 81

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2- (ϊΓ-me thy-1-ac et amino) - 3-O- / [L-1- (D1-c arb amino-3- c arb-oxy-propyl) -c arbamoyl-ethyl] - c arb amoyl-methylj-2-de-soxy-D-glucose, 2- (N-methyl-acetamino) -3-O-D1- [L1- (D1-carbamoyl-3-5 c arb oxy-propyl) -c arb amoyl-ethyl] -carbamoyl-ethyl-2-des-oxy-D-glucose, 2-ac et amino-3-O-D-1- [L-1- (D-1-carb amoyl-3 - carb oxy-propyl) -carbamoyl-2'-phenylethyl] -carbamoyl-ethyl ^ 2-deoxy-D-glucose, 2-ac etamino-3-O - [[1- (Dlc arbamoyl-3- carb oxy-propyl) -c arb amoyl-2 '- (p-hydroxyphenyl) ethyl] -c arb amoyl-methyl-2-deoxy-D-glucose, 2-ac et amino-3-O- [L -1- (D-1- [L-1-carb oxy-ethyl) -c arb amoyl-3-benzylcarb oxy-propyl) -c arb amoyl-ethyl] -c arb amoylmethyl deoxy-D-glucose or 2-acetamino-3-O - [[1- (D1,3-dicarboxy-propyl) -N-methyl-arb amoyl-ethyl] -c-arb-amoylmethyl] -2-deoxy-D- gluc ose,

Example 35 »Analogously as in Example 17, rabies HDC-20 vaccine (Beringwerke) coupled to 2-acetamino-3-O - [[(D-1-carbamoyl-3-carboxy-propyl) -carbamoyl] is obtained. -methyl] -N-methyl-carb amoyl-methyl ^ -2-deoxy-D-gluc ose, 2-benzoylamino-3-O- [[(D-1-carbamoyl-3-c propyl) -c arb amoyl-methyl] -N-methyl-c arb amoyl-methyl 2 -2-deoxy-D-25 glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3 -carboxy-propyl) -c-arb amoyl-ethyl) -N-ethyl-c-arb-amoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O- [Ll- (Dlc-arb amoyl) -3-carb oxy-propyl) -

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82 o arb amoyl-pr opyl] -It-methyl-c arb amoyl-methyl) -2-deoxy-D-glucose, 2-ac etamino-3- (0) -L-1- (Dlc arb amoyl- 3-c arb oxy-propyl) -c arb amoyl-propyl J-E-ethyl-c arb amoyl-methyl 2 -2-deoxy-D-5 glucose, 2-benzamido-3-O-H Ll- ( D1- c arb amoyl-3- c arb oxy-propyl) -c arb amoyl-propyl] -E-ethyl-c arb amoyl-methyl ^ -2-deoxy-D-glucose, 2-acetamino-3- 0- [[1- (D1 - carb amoyl-3-carb oxy-propyl) -10 c-arb amoyl-ethyl] -E-propyl-carbamoyl-methyl-2- 2 -soxy-D -glucose, 2-ac etamino-3-O - [[1- (Dlc arb amoyl-3-carboxy-propyl) -c arb amoyl-E, Ep ent ame thyl en] - c arb amoylmethyl thyl j - 2 -des oxy-D-glucose, 2-benzoylamino-3 "O - [[1- (D1-carbamoyl-3-carboxy-propyl) - carbamoyl-E, E-pentamethylene] -carbamoyl-methyl) -2- deoxy-1-D-glucose, 2-ac etamino-3-O- [L1- (D1-carbamoyl-3-carb oxy-propyl) -E-methyl-carbamoyl-ethyl] - carbamoyl-ethyl methyl 2- 2-des oxy-D-20 glucose, 2-ac etamino-3-O-> D-1- (Dlc arb amoyl-3-c arb oxy-propyl) -carbamoyl-meth yl] -E-methyl-carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzylamino-3-O- ^ D1- [(Dlc arb amoyl-3-c arb oxy-propyl) -carb amoyl-methyl] -E-methyl-carb-amoyl-ethyl) -2-deoxy-D-glucose, 2-ac et amino-3-O-D-1- [L-1- (Dlc - 3- c ar oxy-pr opyl) -c arb amoyl-ethyl) -E-ethyl-c arb amoyl-ethyl 2 - 2-deoxy-D-glucose, 2-acetamino-3-O-> D1- [ L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl JE-methyl-carbamoyl-ethyl ^ -2-deoxy-D-2-ac et amino-3-O- ^ D1- [ L- (D1-carbamoyl-3-carb oxy-propyl) -c-arb amoyl-propyl] -H-ethyl-c-arbamoyl-methyl-2-deoxy-D-glucose, 83

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glucose, 3 2-benzamido-3-O-D-1- [L1- (D1-carbamoyl-3-c arb oxy-pr opyl) - c arb amoyl-pr opyl] -ΪΓ-ethyl-c arb amoyl-ethyl ^ -2-de s-oxy-D-glucose, 2-ac et amino-3-O- ^ D1- (Dlc arb amoyl-3-c arb oxy-propyl) -c arb amoyl-ethyl] -N-propyl-carb amoyl-ethyl ^ -2-deoxy-D-10 glucose, 2-ac et amino-3- O-> D-1- [L-1- (D1-c arb amoyl - 3-carb oxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl 2 -2-deoxy-D-glucose, 2-benzylamino-3-O- ^ D1- [L1- (Dlc arbamoyl-3-carb oxy-propyl) -c arb amoyl-N, N-pentamethylene] -c arb amoyl-ethyl-2-deoxy-D-glucose, 2-ac etamino-3-O- 1- [L1- (Dlc arb amoyl-3-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -c arb amoyl-ethyl ^ -2-des-oxy-D-glucose, 2-acetamino -3-O - [[1- (D1-carbamoyl-3-carboxy-methyl-phenyl] -carbamoyl-methyl] -2-deoxy-D-gluc ose, 2-benzylamino-3- £ [li- (d -1-c arbamoyl-3-c arboxy-methyl-phenyl] -c-arb amoyl-methyl ^ -2-des oxy-D-gluc ose, 2-b enzamino-3-O-j * [Ll- (Dlc arb amoyl- 3- c arb oxy-pr op vi) -25 carbamoyl-2-methyl-mercapto-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzamino-3-O- [[1- (D1-carbamoyl-3-carboxylic acid) propyl) -c arb amoyl-2-chloroethyl] -c arb amoyl-methyl ^ -2-deoxy-D-glucose, 2-ac et amino-3-O- ^ D1- [L1- (Dlc arbamoyl-3 , 3-hic arb oxy- 84

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propyl) -carbamoylethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose | cose, 1- 2- (O-carbomethoxy-succinamido) -3-O- [[1- (D-1-carbamoyl- | 3-carb oxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-methyl ^ -2- | 5 deoxy-D-glucose, 2- (β-carbomethoxy-sue cinamido) - 3-O-D-1- [1-1- (D-1-carb amo; oyl-3-c-arb) oxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-ethyl-1-2-deoxy-D-glucose, 1-2-benzamino-3-O-1-1- (D1-carbamoyl-1 3-trimethylsilyl-1-carb oxy-propyl) -c-arb amoyl-ethyl] -c-arb-amoyl-methyl-2- S-deoxy-1,4-6,6-tris-trimethylsilyl-D-glucose. (Upon contact with water, the trimethylsilyl ester group is hydrolyzed rapidly), in 2-acetamino-2-deoxy-3-O - [[1- (D1-carbamoyl-3-trimethylsilyl] carb oxy-pr opyl) - carb amoyl-ethyl] -carb amoylmethyl-1,4-, 6-tris-trimethylsilyl-D-glucose, in 2-ac et amino-3-O-D-1- [L-1- (D -1-carb amoyl-3-carb oxy-propyl) -c arb amoyl-propyl] -c arb amoyl-etbyl <-2-deoxy-D-glucose, i.

2- ae an amino-3-O- [D-1- [L-1- (D-1-carbamoyl-3-carb oxy-propyl) -carbamoyl-21-hydroxy-propyl] - c arb amoyl-e thyl-2-de s oxy-D-gluc ose, 2-ae et amino-3-O-D-1- [1-1- (D1-c arb amoyl-3-c arb oxy-pr opyl) -carbamoyl-2 '- (p-hydroxy-phenyl) -ethyl] -carbamoyl-e-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-D - [L1 ~ (D1-carbamoyl-3-carboxypropyl) -carbamoyl-B ',] -tetramethylene] -carbamoyl-ethyl 2 -2-deoxy-D-glucose, 2-glycolylamino-3-O-D -1- [L-1- (D-1- c arb amoyl-3- c arb oxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-ethyl ^ -2-des oxy-D-glucose .

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2-glycolylamino-3-O - [L-1- (D-1-carb amoyl-3-carb oxy-propyl) -carb amoyl-ethyl] -carb amoyl-methylj-2 2- (N-methyl-acetamino) -3-O - [[1- (D1-carbamoyl-3-carboxy-3-propyl) -carbamoyl-ethyl] -carbamoyl-methyl deoxy-D-glucose, 2- (N-methyl-ac etamino) -3-O-D1- [L-1- (D-1-carbamoyl-3-carb oxy-propyl) -carbamoyl -ethyl] -c arb amoyl-ethyl ^ -2-des-oxy-D-glucose, 2-ac et amino-3-O- ^ D1- [L-1- (D-1-carb amoyl-3 - c arb οχτ-pr opyl) -c arb amoyl-2 '-phenylethyl] -c arb amoyl-ethyl ^ - 2-deoxy-D-glucose, 2-ac etamino-3-O - [[1- (Dlc arb amoyl-3-carboxy-propyl) -carbamoyl-21- (p-hydroxyphenyl) -ethyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-ac et amino-3-O- [[1- (D-1-Carboxy-ethyl] -carbamoyl-3-benzylcarboxy-propyl) -carb amoyl-ethyl] -carb amoylmethyl-2-deoxy-D-glucose or 2-ac an amino-3-O- [[1- (D1,3-dicarboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose.

Example 34.

By analogy, as in Example 19, infTuenza virus antigens of type A / Victoria / 3/75 coupled to 2-acetamino-3-O-1-c arb amoyl-3-c arb oxy-propyl) are obtained. c arb amoyl-methyl] -N-methyl-c arb amoyl-methyl-2-deoxy-D-glucose, 2-benzylamino-3-O - [[Dlc arb amoyl-3-c propyl) - carbamoyl-methyl] -h-methyl-carbamoyl-methyl-2-deoxy-D-glucose, 2-ac etamino-3-O- [[1- (D1-carbamoyl-3-carb oxy) (propyl) - (carb amoyl-ethyl) -IT-ethyl-carb amoyl-methyl-2-deoxy-D-glucose, 86

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2-ac etamino-3-O - [[L-1- (D-1-carbamoyl-3-carboxy-propyl) -j-carbamoyl-propyl] -N-methyl-carbamoyl-methyl-2-deoxy-D- glucose, 2-acetamino-3-O-HL-1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl JK-ethyl-carbamoyl-methyl-2-deoxy -D-glucose, 2-benzamido-3-O - [[1- (Dlc arb amoyl-3-c arb oxy-propyl) -c arb amoyl-propyl] -Ή-ethyl-c arb amoyl-methyl -2-deoxy-D-glucose, 2-ac et amino-3-O -> [L1- (D1-carbamoyl-3-carb oxy-propyl) - jc-arboyl-ethylJ-D-propyl -c arb amoyl-methyl 2-des oxy-D- | Glucose, 2-acetamino-3- 0- [L-1- (Dlc arb amoyl-3-c arb oxo-pr opyl) -c arb amoyl-U, IT-pent arnethyl and] -c arb amoyl- methyl 2 -2-deoxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-D, ΪΓ-pentamethylene] - U isoamoyl-methyl-2-des-oxy-D-glucose, 2-acetamino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -N-methyl-carbamoyl-ethyl] - carb amoyl-methyl-2-des oxy-D-glucose, 2-acetamino-3-O -> [(D1-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl J-JT-methyl-c 2-benzoylamino-3-O-D1 - [(D1-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -ΪΓ-methyl hy 1- carb amoyl-ethyl ^ -2-des oxy-D-glucose, 2-ac et amino-3-O-β-D-1- [L-1- (D-1- c arb amoyl-3- carb oxy-pr opyl) - carb amoyl-ethyl) -N-ethyl-carb amoyl-ethyl] -2-des oxy-D-glucose, 87

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2-Acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -N-methyl-carbamoyl-ethyl ^ -2-deoxy-D -glucose, 2-acetamino-3-O- D1- [li-1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -ethyl-carbamoylmethyl - 2-deoxy-D-glucose, 2-benzamido-3-O-D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl j-Sf-ethyl-c arb amoyl-ethyl j-2-deoxy-D-glucose, 2-ac et amino-3- 0- D-1- [L-1- (D-1-carb amoyl-3-carb oxy-propyl) -carbamoyl-ethyl] -N-propyl-carbamoyl-ethyl <-2-15-deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) - carb amoyl-N, Np ent arnethylene] -c arb amoyl-euhyl ^ -2-deoxy-D-glucose, 2-benzoylamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-20 propyl) -c arb amoyl-U, N-pent arnethylene] -c arb amoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [li-1- (D1-carbamoyl 3-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O-β [1-1- (1- -c arb amoyl-3-c arb oxy-me thyl-phenyl] -c arb amoyl-methyl-2-des oxy-D-glucose, 2-benzoylamino-3-O- [[1- (D1-carbamoyl-3-carboxy-methyl-phenyl] -c-arb amoyl -methylj-2-des oxy-D-glucose, 2-benzamino-3-O - [1- '- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2-methylethyl more c apt o-ethyl] - carb amoylmethyl j-2-deoxy-D-glucose, 2-benzamino-3-O-j [[1- (D1-carbamoyl ~ 3-carboxy-propyl) - c arb amoyl-2-chloroethyl] - c arb amoyl-methyl 2 -2-s oxy-D-glucose, 88

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2-acetamino-3-O-D-1- [L-1- (D-1-carbamoyl-3,3-dicarboxy-propyl) -carbamoylethyl] -carbamoyl-ethyl-2-deoxy-D- Glucose, 2- (β - c arb omethioxy sue c inamido) - 3-0- [1-1- (Dlc arb amoyl-3- c arb oxy-propyl) -c arb amoyl-ethyl] -c arb amoy 1-methyl-2- (2-deoxy-D-glucose, 1-2- (β-carbomethoxy-succinamido) -3-O-) -DI- [L1- (D1-carbamoyl-3-carb oxy) -propyl) -c-amoyl-ethyl] -c-amoyl-ethyl (2-deoxy-1) -glucose ,; 2-Benzamino-3-O- [[L-1- (D-1-carbamoyl-3-trimethylsilyl-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-15-deoxy-1,4 tris-trimethylsilyl-D-glucose. (Upon contact with water, the trimethylsilyl ester group is rapidly hydrolyzed), 2-Acetamino-2-deoxy-3-O - -c-arbamoylmethyl-1,4-tris-trimethylsilyl-1) -glucose, 2-acetamino-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamyl] -propyl] -carbamoyl-ethyl-2-decoxy-D-glucose, 2-ac et amino-3-O- [D1- [L1- (Dlc-arboyl-3-c-arb oxy-propyl) -carbamoyl -21-hydroxy-propyl] -carbamoyl-ethyl-β-2-deoxy-D-25-glucose, 2-ac et amino-3-O- [D1- [L1- (Dlc arb amoyl-3-c arb oxy- propyl) -carbamoyl-2 '- (p-hydroxy-pbenyl) -ethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1- carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-tetramethylene] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-glycolylamino-3-O-D1- [L1- (D1-carbamoyl) -3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose, 89

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2-glyc olylamino-3- O- [L-1- (D-1- c arb amoyl-3-carboxy-propyl) -c arb amoyl-ethyl] -c arb amoyl-methyl \ -2-de s oxy-D-glucose, 2- (E-methyl-acetamino) -3-O- [L-1- (Dlc-arboyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl 2-Deoxy-D-glucose, 2- (E-me thy-1-ac et amino) - 3-O-β-D1- [L-1- (D-1-carb amoyl-3-c-arb oxy) per opyl) - carb amoylethyl] - carb amoylethyl ^ -2-deoxy-D-glucose, 2-ac etamino-3-O- ^ D-1- [L-1- (D1-carbamoyl -3-carb oxx-propyl) -carbamoyl-2'-phenylethyl] -carbamoyl-ethyl] -2-deoxy-D-glucose, 2-acetamino-3-O-β [L1- (D1-carbamoyl-3 -carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) -ethyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-ac et amino-3-O - [[1- (D1- [Llc arb oxyethyl] -c arb amoyl-3-benzylcarboxy-propyl) -carbamoyl-ethyl] -c arb amoylmethyl 2 -2-deoxy-D-glucose or 2-acetamino-3-O - [[1 (D1,3-dicarboxy-propyl) -N-methyl-carb amoyl-ethyl] -c arb amoylmethyl-2-de s oxy-D-gluco s e.

Example 35.

Analogously as in Example 21, tetanus toxoid coupled to 2-acetamino-3-O - [[(D1-carbamoyl-3-carboxy-propyl) -carbamoylmethyl] -E-methyl-carbamoyl is obtained. -methyl-2-deoxy-D-glucose, 2-benzylamino-3-O- [[(D1-carbamoyl-3-carb oxy-propyl) - 30c arbamylmethyl]] - E-methyl-carb amoyl-methyl ^ -2-des oxy-D- 90

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glucose, 2-acetamino-3-O- [[1- (1> -1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl) -H-ethyl-carbamoyl-methyl-2-des oxy-D-! glucose, | | 2-acetamino-3-O- [L-1- (D-1-carbamoyl-3-carboxy-propyl) - carbamoyl-propyl] -H-methyl-carbamoyl-methyl (-2-deoxy-1) -g glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl propyl] -H-ethyl-carbamoyl-methyl-2-deoxy-I) -10 glucose, in 2-benzamido-3-O - [[1- (Dlc arb amoyl-3-c arb oxy-propyl) -! carb amoyl-propyl j -ethyl-carb amoyl-methyl 2-deoxy-D-! glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -H-propyl-carbamoyl-methyl-2-desoxy D-glucose, 2-acetamino-3-O-β [L1- (D1-carbamoyl-3-carboxy-propyl) -c arb amoyl-H, Hp ent arne thyl en] - c arb amoyl-methyl thyl <-2 -soxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-H, Π-pentamethylene] -carbamyl methyl th 2 -2-deoxy-D-glucose, 2-ac et amino-3-O - [[1- (Dlc arb amoyl-3-c arb oxy-propyl) -Π-methyl-c arb amoyl) ethyl] -c arb amoyl-methyl ^ -2-deoxy-D-25 glucose, 2-acetamino-3-O-> D-1 - [(Dlc arbamoyl-3-c arb oxy-propyl) -c arb amoylmethyl] -Π-methyl-carb amoylethyl ^ -2-des oxy-D-glucose, 2-benzylamino-3-O- ^ D1 - [(D1-carbamoyl-3-c arb oxy-propyl) - 30 carb amoyl-methyl] -Π-methyl-carb amoyl-ethyl 2 -2-deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1 -carbamoyl-3-carboxypropyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-ethyl-2-deoxy-D-glucose, 91

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2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-3-propyl) -carbamoyl-propyl] -N-methyl-carbamoyl-ethyl ^ -2-deoxy-D -glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -D-ethyl-carbamoyl-methyl-2-deoxy -D-glucose, 2-benzamido-3-O- ^ D1- [L1- (Dlc arb amoyl-3-c arb oxy-propyl) -c arb amoyl-propyl] -N-ethyl-c arb amoyl -ethyl 2 -2-de s-oxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -N-propyl carbamoyl-ethyl 2 -2-15-deoxy-D-glucose, 2-ac et amino-3-O- [D1- [L1- (Dlc arbamyl-3-carb oxy-propyl) -carbamoyl-N, N- pentarnethylene] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-benzylamino-3-O- ^ E1- [L1- (D1-carbamoyl-3-carb oxy-propyl) -carb amoyl-if, D-pentamethylene] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -N -methyl-carb amoyl-ethyl] -c arb amoyl-ethyl-2-deoxy-D-glucose, 2-ac et amino-3-O- [[1- (D1-carbamoyl-3-c arb oxy) -methyl-phenyl] -c arb amoyl -methyl-2-deoxy-D-glucose, 2-benzylamino-3-O - [[1- (D1-carbamoyl-3-carb oxy-methyl-phenyl] -c-arb amoyl-methyl 2 -2-des oxy-D-glucose, 2-benzamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) - carbamoyl-2-methyl-mercapto-ethyl] -carbamoyl methylj-2-deoxy-D-glucose, | 2-Benzamino-3-O- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2-chloroethyl] -carbamoyl-methyl-2-deoxy-D-glucose, 92

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2-acetamino-3-O-D-1- [L-1- (D1-carbamoyl-3,3-dicarboxy-propyl) -carbamoylethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2 - (β-carbethoxy-succinamido) -3-0- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2- (p-carbomethoxy-succinamido) -3-0- £ D1- [L1- (D1-carbamoyl-3-carb oxy-propyl) -carbamoyl-ethyl] -c-arbamyl-e thyl 2 -2-deoxy-L-glucose, 2-b ehz amino-3-D- [L1- (L1-g arb amoyl-3-trimethylsilyl] -carb oxy-propyl) - c arb amoyl ethyl] -carbamoylmethyl \ -2- [15] deoxy-1,4-, 6-tris-trimethylsilyl-D-glucose. [Upon contact with water, the trimethylsilyl ester group is hydrolyzed rapidly), 2-acetamino-2- deoxy-3- [2- [1-Cd-1-carbamoyl-3-trimethylsilylcarb oxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-1,4-, 6-tris-trimethylsilyl -D-glucose, 2-acetamino-3-O-1H) -1- [L1- (b1-carbamoyl-3-carboxy-propyl) -c arb amoylpropyl] -c arb amoyl-ethyl 2-deoxy-D-glucose, 2-acetamino-3-O-D-1- [L-1- (L-carbamoy 1- (3-carboxy-propyl) -carbamoyl-21-hydroxy-propyl] -carbamoyl-ethyl ^ -2-deoxy-25-D-glucose, 2-acetamino-3-O- ^ Ll- [Ll - (L1-carbamoyl-3-carboxy-propyl) -carbamoyl-21 - (p-hydroxy-phenyl) -ethyl] -carbamoyl-ethyl-2-deoxy-L-glucose, 2-acetamino-3- 0-> D1- [L1- (L1-carbamoyl-3-carboxy-propyl) -carbamoyl-F, 11-tetramethylene] -carbamoyl-ethyl ^ -2-deoxy-1-glucose, 2-glycolylamino -3-0- ^ D1- [L1- (D1-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 93

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2-glycolylamino-3-O- [[1- (D1-carDamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl] -2-deoxy-D-glucose, 2- (iT-methylethyl ac etamino) -3-0- [L-1- (D-1-carb amoyl-3-carb oxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2- deoxy-D-glucose, 2- (ϊΓ-methyl-ac etamino) -3-O-D D- [L- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] - carbamoyl-ethyl ^ -2-deoxy-P.-glucose, 2-acetamino-3-O- ^ D1-LL-1- (hI-carbamoyl-3-carboxy-propyl) -carbamoyl-2t-phenylethyl] -carbamoyl ethyl j-2-15 deoxy-D-glucose, 2-acetamino-3-O-j * [L1- (Dlc arb amino-3- c arb oxy-pr opyl) -carbamoyl-2 '- (p-hydroxyphenyl) -ethyl] -c-arb-amoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-1-c-arb oxy-ethyl] -c-arb-amoyl-3-b-enzyloxy-propyl) - cis-amoyl-ethyl] -c-arb-amoylmethyl-2-deoxy-D-glucose or 2-acetamino-3-O--1,3-dicarboxy-propyl) -N-methyl-c-ar-amoyl-ethyl] -c arb amoylmethyl-2-de-soxy-D-glucose.

Example 36.

Analogously to Example 23, cholera toxoid from Vibrio cholerae coupled to 2-acetamino-3-O - [[(D1-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl is obtained. -methyl-2-deoxy-D-glucose, 2-benzylamino-3-O-β [p-1-carbamoyl-3-carb oxy-propyl) - carb amoylmethyl] -methyl - c arhamoyl-methyl-2,2-des oxy-D-glucose,

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94 2-ac et amino-3-O- [L-1- (Dlc amoyl-3-c arhoxy-propyl) -carbamoyl-ethyl) -ethyl-c-arbamoyl-methyl D | 5 lncose, ii I 2-acetamino-3-O -> [L1- (D1-carbamoyl-3-carhoxy-propyl) - I c arhamoyl-pr opyl J -ΪΓ-methyl-c arh amoyl-methyl 2-de s oxy- i D-glucose, | 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) - in 10c of arbo-amo-propyl J-ΪΓ-ethyl-c-arboyl-methyl-2-deoxy-D - in glucose, 2-benzamido-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -c arhamoyl-propyl] -U-ethyl-c arhamoyl-methyl 2-Acetoxy-D-glucose, 2-acetamino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -c aramoyl-ethyl] -ΪΓ-propyl-c arh amoyl-methyl-2-desoxy-D-glucose, 2-ac et amino-3-O- [L-1- (D-1-carb amoyl-3-carb oxy-propyl) - : c arh amoyl-ΪΓ, Np ent arne thyl en] - c arh amoyl-methyl <- 2- de s-20-Oxy-D-glucose, 2-b enz oylamino-3-0- £ [L-1- ( D -1-c arh amoyl-3-c arhoxy-propyl) -c arh amoyl-isr, ΪΓ-pent arne thyl en] - c arh amoyl-methyl ^ -2-des oxy-D-glucose, 2-acetamino - 3-O- [[1- (Dc arb amoyl-3-c arhoxy-propyl) -N-25-methyl-c arh-amoyl-ethyl] - c-arh-amoyl-methyl glucose, 2-acetamino-3-O- / Dl - [(Dlc amoyl-3-c arboxy-propyl) -c arhamoyl-methyl JE-methyl-carb amoyl-ethyl ^ -2-de soxy-D-glucose . 2-Benzoylamino-3-O- ^ D1 - [(D1-carbamoyl-3-carboxy-propyl) -carbamoylmethyl] -U-mehyl-carbamoylethyl ^ -2-deoxy -D-2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -ET-ethyl-carbamoyl-ethyl ^ -2-desoxy-D -glucose, 95

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glucose, 5 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -ET-me t he 1 - c ar b amo y 1 - e thy 1β-2-deoxy-D-glucose, 2-acetamino-3-O- [D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -ΕΓ-ethyl-carbamoyl-methyl 2-Deoxy-D-10-glucose, 2-benzamido-3-O-D1- {L1- (D1-carbamoyl-3-carboxy-propyl) -c arbamoyl-propyl] -ET-e-thyl-c arbamoyl-thylyl-2-s oxy-D-glucose, 2-3οεΐ8Μχηο-3-0- (Β-1- [Ι.1- (Β-1-οβΛΜο71-3-ο8Λο ^ -ρΓορ71)) -15-carbamoyl-ethyl] -ΕΓ-propyl-carbamoyl-ethyl 2 -2-deoxy-D-glucose, 2-acetamino-3-O- in Dlr Ll- (D1-carbamoyl-3-carboxy-propyl) -c-arbamoyl -ΕΓ, Εί-pent arne thyl en] -carbamoyl-ethyl ^ -2-des oxy-D-glucose, 2-benzoylamino-3-O- ^ D1- [Ll- (D1-carbamoyl-3-carboxy-propyl) ) -carbamoyl-N, ΕΓ-pentamethyl and] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O- ^ Ll- [Ll- (D1-carbamoyl - propyl) -N-me thy 1 -carbamoyl-e thy 1] -carbamoyl-ethyl 2 -2-deoxy-D-25 glucose, 2 -acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-methyl-phenyl] -carbamoyl-methyl] -2-deoxy-D-glucose, 2-benzoylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-methyl-phenyl] -carbamoyl-methyl ^ -2-deoxy-D-glucose, 2-benzamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) 96 - carbamoyl-2-methyl-mercapto-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose,

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in 2-benzamino-3-O- [1- (D-1-carbamoyl-3-carboxy-propyl) - | carbamoyl-2-chloroethyl] -carbamoyl-methyl ^ -2-deso: xy-D- | ! 5 glucose, [(2-acetamino-3-O-) D1- [11- (D1-carbamoyl-3,5- [1-carbo: xylopropyl) -carbamoylethyl] -carbamoyl-ethyl 2-Deoxy-D-glucose, 2- (β-carbomethoxy-succinamido) -3-0- [1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl -2-deoxy-D-glucose, 1- 2- (p-carbomethoin-succinamido) -3-O- [D1- [1-1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl] ethyl] -carbamoyl-ethyl-1-2-desosy-D-glucose, in 1 (1,2-benzamino-3-O -> [Ir-1- (D1-carbamoyl-3-trimethylsilyl) - ) carboxy-propyl) -carbamoyl-ethyl] -c-arbamoyl-methyl-2-deoxy-1,4,6-tris-trimethylsilyl-D-glucose (Upon contact with water, the trimethylsilyl ester group is rapidly hydrolyzed), 2- acetamino-2-deoxy-3-O - [[1- (D1-carbamoyl-3-trimethyl-silylcarboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-1,4,6-tris-trimethylsilyl-D glucose, 2-acetamino-3-O-D1- [11- (11-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-ethyl 2 -2-deoxy-D-glucose, 2-acetamino 3-0- ^ Dl- [1-1- (Dl-carba moyl-3-carboxy-propyl) -carbamoyl-21-hydroxy-propyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [11- (D1-carbamoyl) -3-carboxy-propyl) -carbamoyl-2 '- (p-hydroxy-phenyl) -ethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-acetamino-3-O- 1-1- (D1-carbamoyl-3-carboxy-propyl) - 97

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carbamoyl] tf, 1T-tetramethylene] -carbamoyl-ethyl 2 -2-deso: xy-1> -glucose, 2-glycolamino-5-O-D1- [L1- (D1-carbamoyl-3-carboxy-propyl) ) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-5-glucose, 2-glycolamino-3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] - carbamoyl-methyl-2-deoxy-D-glucose, 2- (N-methyl-ac et amino) -3-O-L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] - carbamoyl-methyl-2-deoxy-D-10-glucose, 2- (U-methyl-acetamino) -3-O-D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-des-oxy-D-glucose, 2-ac etamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -15 carbamoyl-2 '- phenylethyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-acetamino-3-O - [[1- [1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '- (p hydroxyphenyl) -ethyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1- [L1-carboxy-ethyl] -carbamoyl-3-benzylcarboxy-1 opyl) -carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose or 2-ac ethamino-3-O- [L-1- (D-1,3-dicarboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose.

Example 37.

By analogy as in Example 25, a synthetic eicosapeptide identical to the C-terminal sequence of the human chorionic gonadotropin coupled to 2-ac etamino-3-O - [[D1-carbamoyl-3-carboxy-propyl] is obtained. ) - carbamoyl-methyl] -H-methyl-carbamoyl-methyl-2-des oxy-D- glucose,

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98 | 2-Benzoylamino-3-O - [[(D-1-carbamoyl-3-carboxy-propyl) -carlamino-methyl] -1-methyl-1-carbamoyl-methyl at 1β-2-desoxy D-5 Glucose: 2-acetamino-3-O- [1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-earbamoyl-methyl I) -glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -] - 10 carbamoyl-propyl] -N-methyl-carbamoyl-methyl deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl ^ -2-deoxy-D- glucose, 2-benzamido-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -c arbamoyl-propyl] -1-ethyl-carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -N-propyl-carbamoyl-methyl ^ -2-deoxy-D-20-glucose, 2-acetamino -3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -β-carbamoyl-N, F-pentamethyleri] -carbamoyl-methyl-2-deoxy-D-glucose, 2-b enzoylamino 3-0-1-1- (D1-carbamoyl-3-carboxy-propyl) -25 carbamoyl-ϊί, N-pentamethylene] -carbamoyl-meth yl -2-deoxy-D-glucose, 2-acetamino-3-O - [1- (D1-carbamoyl-3-carboxy-propyl) -h-methyl-carbamoyl-ethyl] -carbamoyl-methyl 2-Deoxy-D-glucose, 2-acetamino-3-O- ^ D1 - [(D1-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -ΪΓ-methyl-carbamoyl-ethyl-2 deoxy-D-

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2-Benzoylamino-3-O-l) -1- [(D1-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -h-methyl-carbamoyl-ethyl-2-deoxy-D glucose, 9¾ glucose, 5 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -II-ethyl-carbamoyl-ethyl ^ -2-deso: xy-D-glucose, 2-acetamino-3-O-1L) -1- [11- (D1-carbamoyl-3-carbo: xy-propyl) ~ carbamoyl-propyl] -H-methyl-carbamoyl-ethyl ~ 2-deso: xy-I) -10 glucose, 2-ac etamino-3-O-βD1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -h-ethyl-carbamoyl -methyl-2-deoxy-I) -glucose, 2-benzamido-3-O- ^ D1- [L1- (D-1-carbamoyl 1-3-carb oxy-propyl) -15-carbamoyl-propyl ] -N-ethyl-carbamoyl-ethyl ^ -2-deso: xy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carbo: Ky-propyl) -carbamoyl -ethyl] -IT-propyl-carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O-β> D1- [L1- (D1-carbamoyl-3-carboxy-propyl) - v. Λ carbamoyl-N, K-pentamethylene] -carbamoyl-ethyl-2-deoxy-1) -glucose, 2-benzoylamino-3-O-D1- [L1- (D1-carbamoyl-3-carboxylic acid) per opyl) carb amoyl-N, 1T-pentamylethyl] -carbamoyl-ethyl 2 -2-deoxy-D-glucose, 2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -ΪΤ-methyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O-L1- (D1-carbamoyl-3-carboxy-methyl-phenyl) -carbamoyl methyl 2 -2-deoxy-D-gluco se, 100

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i (i 2-Benzoylamino-3-O -> [Ll- (D1-carbamoyl-3-carboxy-methyl-Λ-phenyl) -carbamoyl-methyl-2-deoxy-D-glucose e, 2-benzamino -3-0 - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2-methyl-mercapto-ethyl] -carbamoyl-methyl] -2-deoxy-D-glucose, 2-benzamino -3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -I-carbamoyl-2-chloroethyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O- ^ D1- [L1- (I) -1-carbamoyl-3,3-dicarboxy-propyl) -carbamoylethyl] -carbamoyl-ethyl ^ -2-deso: xy-I) -glucose, 2- (β carbomethosy-succinamido) -3-O-L- (D1-carbamoyl-3-carb oxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-des-oxy-D-glucose, 2- (p -carbomethoxy-succinamido) -3-O- [D1- [D1- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl D-glucose, 2-benzamino-3-O - [[1- (D1-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-1.4.6 tris-trimethylsilyl-D-glucose. (Upon contact with water, the trimethylsilyl ester group is rapidly hydrolyzed), 2-ac etamino-2-deoxy-3-O- [[1- (D1-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbamoyl-ethyl ] -carbamoylmethyl-1,4,6-tris-trimethylsilyl-D-glucose e, 2-ac etamino-3-O- ^ Ll- [Ll- (D1-carbamoyl-3-carboxy-propyl) -25 carbamoyl-propyl] - c arbamoyl-ethyl 2 -2-deoxy-L-gluco 2,2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '-hydroxy -propyl] -carbamoyl-ethyl-2-deoxy-1) -glucose, 2-ac etamino-3-O-D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 ' - (p-hydroxyphenyl) ethyl] carbamoyl-ethyl ^ -2-

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101 deoxy-D-glucose, 2-acetamino-3-O-D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-H, E-tetramethyl and] -carbamoyl-ethyl -desoxy-D-glucose, 2-glycolamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy -D-glucose, 2-glycolamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl ^ -2-deoxy-D -glucose, 2- (N-methyl-ace tamino) -3-O- [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl] -2-deoxy-D -glucose, 2- (N-methyl-ac et amino) -3-0- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-deoxy -D-glucose, 2-acetamino-3-O- ^ D1- [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '-phenyl ethyl] -carbamoyl-ethyl D-glucose, 2-acetamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) -ethyl] -carbamoyl-methyl deoxy-D-glucose, 2-acetamino-3-O - [[1- (D1- [L1-carboxy-ethyl] -carbamoyl-3-benzyl) rboxy-propyl] -carbamoyl-ethyl] -carbamoylmethyl 2-deoxy-D-glucose or 2-acetamino-3-O - [[1- (D1,3-dicarboxy-propyl) -h-methyl-carbamoyl-ethyl] carbamoylmethyl ^ -2-deoxy-D-glucose.

Various of the above muramyl peptides or their spacer-linked forms are novel. For example, they can obtained as described in the following examples.

Example 38

102

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I C

A solution of 3 µg of benzyl-2-acetamino-3-O-D-1- ^ L-1- [D-1- carbamoyl-3- (L1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-ethyl-2-deso: new aD-glucopyranoside-benzyl: ester in 100 ml of methanol / distilled water (2 : 1) hydrogenated under the presence of 0.3 g of 10% palladium on coal at normal pressure and 45 ° C for 24 hours. The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in 40 ml of water and this solution is extracted three times, each time with 10 40 ml of water-saturated sec-butanol. The organic phases are washed three more times, each time with 40 ml sec, butanol-saturated water.

The aqueous solutions are collected and evaporated and the residue is dissolved in slightly distilled water and lyophilized. There is thus obtained 2-acetamino-3-O-D-1- [L-1- [D-1-carbamoyl-3- (L-1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl] -l ethyl -2-deoxy-D-gluc os e as a white powder with [a] + = + 9 ° ± i ° (distilled water, c = 1.090).

The starting material used is prepared as follows:

To a solution of 6.1 g of benzyl-2-acetamino-3-O- [D1- [1-1-20 (D1-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-ethyl ^ -2-deoxy -aD-glucopyranoside monohydrate and 3.5 g of D-alanine benzyl ester p-toluenesulfonate in 30 nil of E, E-dimethylformamide are added 1.4 ml of triethylamine, 1.1 g of hydro-hydroxy-succinic imide and 2.3 g of dicyclohexy 1 carbodiimide and the mixture is stirred for 48 hours at room temperature. The crystallized dicyclohexylurea is extracted and washed with 10 ml of E, E-dimethylformamide and the filtrate is evaporated to dryness. The residue is suspended in 100 ml of water and stirred for one hour at 0 ° C, and the insoluble components are suctioned off, washed with a little ice water and dried. The product is now dissolved in methanol, precipitated with twice the amount of ethyl acetate, suctioned off, washed with a little ethyl acetate and dried: [oc] + = + 72 ° -1 ° (methanol, c = 0.998).

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103 Analogously, benzyl-2-acetamino-3-O- [[1- (D1-carbamoyl-3-carbo: xypropyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-α Glucopyranoside 2-acetamino-3-O-1H-1- (D1-carbamoyl-3- (L1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoylmethyl-2-deoxy-D -glucose.

From benzyl-3-O-d-1- [L1- (D1-carbamoyl-3-carboxy-5β-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-2-propionamino-aD -glucopyranoside and glycine benzyl ester p-10 toluene sulfonate are prepared 3-O- D1- ^ L1- [D1-carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-ethyl-2-s oxy-2-propionamino-D-gluco s e.

Analogously prepared: 2-acetamino-3-O- [L1- [D1-carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-methyl-2-deoxy-D-glucose, 2-butyroylamino-3-O-D1- [L1- [11-carbamoyl-3- (L1-carb-oxy-ethyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-ethyl-2-desoxy D-glucose, 2-butyroylamino-3-O- ^ L1- [D1-carbamoyl-3- (L1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl-methyl-2-deoxy-D glucose, 3- O- [11- [D1-carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-methyl-2-deoxy-2- propionamino-D-glucose, 2 -isobutyroylamino-3-O- ^ Ll- [D1-carbamoyl-3- (1H-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-propyl-4-carbamoyl-methyl-2-deoxy-D -glucose, 2-isobutyroylamino-3-O-D1- [L1-CD-1-carbamoyl-3- (L1-carboxy-ethyl-carbamoyl) -propyl] -carbamoy-1-propyl-1-carbam oyl-ethyl -2-deoxy-D-glucose,

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104 I (2-Isobutyroylamino-3-O-βL1- [D1-carbamoyl-3- (D1-carboxyethyl-carbamoyl) -propyl] -earbamoyl-2-methylpropyl-4-carbamoyl-methyl - 2-deoxy-D-glucose, 2-isobutyroylamino: no-3-O-D1- []] 1- [D1-carbamoyl-3- (11-1V) -Carboxy-ethyl-carbamoyl) -propyl ] -carbamoyl-2-methylpropyl β-carbamoyl-ethyl-2-deoxy-D-glucose, 1- (2-isobutyroylamino-3-O-11) - [D1-carbamoyl-3- (carboxy-1-methyl-carbamoyl) ) -propyl] -carbamoyl-ethyl-carbamoyl-methyl-2-deoxy-D-glucose, 2-isobutyroylamino-3-O- [11] - [D1-carbamoyl-3- (carboxymethyl-carbamoyl) ) -propyl] -carbamoyl-ethyl-carbamoyl-methyl-2-deoxy-D-glucose, in 2-isobutyroylamirLO-3-O-D1-6L1- [D1-carbamoyl-3- (carboxy-methyl-carbamoyl) ) -propyl] -carbamoyl-ethyl ^ -carbamoylethyl-2-deoxy-D-glucose, (2-isobutyroylamino-3-O-11-[D1-carbamoyl-3- (L1-carboxy-1'-ethyl) -carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-methyl-2-deoxy-D-glucose, 2-isobutyroylamino-3-O-D1- [1- [D1-carbamoyl-3- (Ll -20-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-ethyl-2-deoxy-D-glueose, 2-isobutyroylamino-3-O- ^ Ll- [D1-carbamoyl-3- ( 1-carboxy-propyl-carbamoyl) -propyl] -carbamoyl-ethyl j-carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-1-Ll- [D1-carbamoyl-3- (carboxy) -methyl-carbamoyl) -propyl] -carbamoyl-2-methylpropyl ^ -carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-D1- ^ L1- [D1-carbamoyl-3 - (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-2-methyl-ethylene-arbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O- -carbamoyl-3- (D1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-2-methylpropyl ^ -carbamoyl-methyl-2-deoxy-D-glucose, 105

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2-acetamino-3-O-D-1- [L-1 ~ [D1-carbainoyl-3- (Ir-1-carboxy-3-ethyl-carbamoyl) -propyl] -carbamoyl-2-methylpropyl-4-carbamoyl -ethyl-2-deoxy-D-glucose, 2-acetamino-3-O- [L1- [D1-carbamoyl-3- (L1-carbo: xy-propyl-carbamoyl) -propyl] -carbamoyl-2-methyl propyl β-carbamoyl-methyl-2-deoxy-D-glucose, 2-butyroylamino-3-O-β-L1- [D1-carbamoyl-3- (L1-carboxy-butyl-carbamoyl) -propyl] -carbamoyl-ethyl 2-Carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-D1- [11] - [D1-carbamoyl-3- (L-1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl -propyl 3-carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O- [11] - [D1-carbamoyl-3- (D1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl propyl 1-carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-D1- [11] - [D1-carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-propyl 2-Carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O- ^ Ll- [D1-carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-propyly-carbamoyl-methyl 2-deoxy-glucose, 2-acetamino-3- O- [L1- [D1-carbamoyl-3- (D1-carboxy-propyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O D1- [L1- [D1-carbamoyl-3- (D1-carboxypropyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-ethyl-2-deoxy-D-glucose, in 106-2-acetamino -3-O-lr-1- [D1-carbamoyl-3- (1'-1-carboxy-2'-methylmethylpropyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoylmethyl-2-deoxy -D-glucose, 2-acetamino-3-O- D1- ^ L1- [D1-carbamoyl-3- (II-1-carboxy-2-methyl-propyl-carbamoyl) -propyl] -carbamoyl-ethyl -carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3- * 0- ^ Ll- [D1-carbamoyl-3- (L1-carboxy-butyl-: carbamoyl) -propyl] -carbamoyl- ethyl 2 -carbamoyl-methyl-2-deoxy-D-glucose ,; 2-Butyroylamino-3-O-L-1- [D-1-carbamoyl-3- (carboxy-methyl-1-carbamoyl) -propyl] -carbamoyl-ethyl-1-carbamoyl-methyl-2-I deoxy-D-glucose, 2-butyroylamino-3-O-D1- [L1- [D1-carbamoyl-3- (D1-carb-oxo-propyl-1-carbamoyl 1) -propyl] -carbamoyl -ethyl ^ -carbamoyl-ethyl-2-deoxy-D-glucose, 2-butyroylamino-3-O- ^ Ll- [D1-carbamoyl-3- (D1-carboxy-propyl-carbamoyl) -propyl] -carbamoyl ethyl 2-carbamoyl-methyl-2-deoxy-D-glucose, 2-butyroylamino-3-O-D1-111- [D1-carbamoyl-3- (b1-carboxy-2-methyl-propyl) -carbamoyl) -propyl] -carbamoyl-ethyl <- carbamoyl-ethyl-2-deoxy-D-glucose, 2-butyroylamino-3-O- ^ Ll- [D1-carbamoyl-3- (11-carboxy-2-methyl) -propyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzoylamino-3-O- ^ Ll- [D1-carbamoyl-3- (11-carboxy) -ethyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzoylamino-3-O-D1-1-CD-1-carbamoyl-3- (carboxylic acid) with thylcarbamoyl) propyl] -carbamoyl-ethyl-j-carbamoyl-ethyl-2-deoxy-D-glucose, 2-benzoylamino-3-O- ^ Ll- [D1-carbamoyl-3KL-1 “Carboxy-ethyl-carbamoyl) -propyl-carbamoyl -propyl 3-carbamoyl-methyl-2-deoxy-D-glucose, 107

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2-Benzoylamino-3-O-D1- [L1- [D1-carbamoyl-3- (carboxy-3-methyl-carbamoyl) -propyl] -carbamoyl-propyl-4-carbamoyl-ethyl-2-deoxy-D-glucose, 2 -acetamino-3-O- ^ L1- [D1-carbamoyl-3- (L1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-Ν, Ν-tetramethylene-carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-D1- [11-CD-1-carbamoyl-3- (D1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-H, H-tetramethylene-1-carbamoyl-ethyl-2 deoxy-D-glucose, 2-acetamino-3-O- ^ Ll- [D1-carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-ΪΓ, Nt etr amethylene j -carbamoyl-methyl - 2-deoxy-D-glucose, 2-acetamino-3-O-D1- [L1- [D1-carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-N, N-tetramethylene ethyl 2-deoxy-D-glucose, 2-acetamino-3-O- ^ Ll- [D1-carbamoyl-3- (1H-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-2-hydroxy -ethyl ^ -carbamoyl-methyl-2-deoxy-D-glucose, 2-acetamino-3-O-D1- ^ Ll- [D1-carbamoyl-3- (1 <- 1 - carboxyethyl-carbamoyl) - propyl] -carbamoyl-2-hydroxyethyl ^ -carbamoyl-ethyl-2-deoxy-D-glucose, 2-benzoylamino-3-O- ^ Ll- [D1-carbamoyl-3- (L1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-2-hydroxy -ethyl ^ -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzoylamino-3-O-D1- ^ Ll- [D1-carbamoyl-3- (L1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl 2-Hydroxy-ethyl 3-carbamoyl-ethyl-2-deoxy-D-glucose, 2-acetamino-3-O-2 Ll- [D1-carbamoyl-3- (L1-carboxyloxymethyl) - carbamoyl-propyl] -carbamoyl-methyl-carbamoyl-methyl-2-deoxy-D-glucose, 108

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; 2-Acetamino-3-O-D1- [L1- [, D1-carbamoyl-3- (1-carboxy-methyl-carbamoyl) -propyl] -carbamoyl-methyl-1-carbamoyl-ethyl-2-desoxy D-Glucose, I 2-Acetamino-3-O- ^ Ll- [D1-carbamoyl-3- (L1-carbo: xy-methyl-1-carbamoyl) -propyl] -carbamoyl-methyl ^ -carbamoyl-methyl-2 ! deoxy-D-glucose, in 2-acetamino-3-O-D1- [L1- [D1-carbamoyl-3- (Ir-1-carboxy-methyl-carbamoyl) -propyl] -carbamoylmethyl-3-carbamoyl -ethyl-2-deso: xy-D - glucose and 2-acetamino-3-O- ^ Ll- [D1-carbamoyl-3- (L1-carboxy-methyl-carbamoyl) -propyl] -carbamoyl-methyl -carbamoyl-methyl-2-s oxy-D-gluc ose.

Example 39 »

A solution of 4.2 g of benzyl-2-acetamino-3-O- [L1- [D1-carbamoyl-3- (h-5-benzylozycarbonylamino-5-carbamoyl-pentyl-carbamoyl) -propyl] -carbamoyl-ethyl -carbamoylmethyl -2-20 des oxy-α-D-glucopyranoside in 100 ml of methanol / water (2: 1) is hydrogenated in the presence of 0.5 g of 10% palladium on coal at normal pressure and room temperature. Thereby the pH of the reaction mixture is maintained at 6 by the addition of 1 N hydrochloric acid.

After hydrogen uptake is completed, the catalyst 25 is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in slightly distilled water and lyophilized. There is thus obtained 2-acetamino-3-O- [11] - [D1-carbamoyl-3- (1-5-amino-5-earbamoyl-pentyl-carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-methyl -2-deoxy-D-glucose hydrochloride as a white powder.

The starting material used can be prepared as follows:

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109

A solution of 15 g of oc-carbobenzoxy - tert-butoxycarbonyl-L-lysine methyl ester in 100 ml of a saturated methanolic ammonia solution is left at room temperature for 48 hours and evaporated to dryness. The product, α-carbobenzoyl-tert-butoxy-carbonyl-L-lysinamide is recrystallized from methanol / ether, m.p. 142 ° C, [α] D = -3 ° ± 1 ° (methanol, c = 1.018).

A solution cooled to 0 ° 0 of 3 S a-carbobenzoic acid. butoxycarbonyl-Ir-lysinamide in 25 µl of trifluoroacetic acid is stirred for one hour and then evaporated to dryness. To the residue is added 20 ml of saturated sodium chloride solution and ice, and the mixture is made alkaline with concentrated ammonia solution and extracted with ethyl acetate. The organic phase is washed again with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. Thus, α-carbobenzoxy-L-lysinamide is obtained as a white foam.

To a solution of 5-6 g of benzyl-2-acetamino-3-O- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl ^ -carbamoyl-methyl-2-deoxy] α-D-glucopyranoside and 2.8 g of α-carbobenzoxy-L-lysinamide in 30 ml of Ν, ϊΤ-dimethylformamide are added 1.1 g of 20 E-hydroxysuccinimide and 2.2 g of dicyclohexylcarbodiimide and the mixture is stirred for 40 hours at room temperature. The crystallized dicyclohexylurea is extracted and washed with 10 ml of IT, E-dimethylformamide. The filtrate is evaporated to dryness and the residue is extracted for 30 minutes with 100 ml of distilled water. The undissolved constituents are sucked off, washed with water and dried and are benzyl-2-acetamino-3-O-L-1- [D-1-c arbamoyl-3 ~ (L-5 ~ benzyloxycarbonylamino-5-carbamoyl-pentyl -carbamoyl) -propyl] -carbamoyl-ethyl ^ -carbamoyl-methyl-2-deoxy-ct-D-glucopyranoside. The product is recrystallized from methanol / ethyl acetate.

Analogously prepared: 2-acetamino ~ 3-O-1- [1- [D1-carbamoyl-3- (5-amino-L1-carbamoyl) -pentyl-carbamoyl) -propyl] -carbamoyl-ethyl carbamoyl-110

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methyl -2-deso: xy-D-glucose hydrochloride.

Example 40.

in

Ecl solution of 2.8 g of benzyl-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-methyl] -2-des-5-oxy-2 isobutyroylamino-α-D-glucopyranoside in 80 ml of methanol / distilled water (1: 1) is hydrogenated in the presence of 0.3 g of 10 6 palladium on coal at normal pressure and 45 ° C. After processing and freeze drying of the residue, 3-0- [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-10-propyl] -carbamoyl-methyl ^ -2-deoxy-2 are obtained. -isobutyroylamino-D-; glucose as a white powder.

in

The starting material used is prepared as follows: In a mixture of the solutions of 21.0 g of benzyl-2-amino-2-] desoxy [4,6-O-isopropylidene-α-glucopyranoside in 150 ml of chloroform and 9.0 g of potassium hydrogen carbonate in 150 ml of distilled water is cooled with stirring to 0 ° C and 8.5 ml of isobutyric acid chloride is added dropwise. After stirring for 1 hour at room temperature, the organic phase is separated, washed with ice-cold 0.5 L hydrochloric acid, water, a saturated sodium hydrogen carbonate solution and again with water, dried and evaporated.

The product, benzy 1 -2 - the s oxy-2-i s obuty lamino -4, 6-O-isopropylidene-α-D-glucopyranoside is crystallized from 150 ml of ether, m.p. 82 ° 0, [α] D = + 109 ° -1 ° (chloroform, c = 1.017).

file a solution of 15.1 g of benzyl-2-deoxy-2-isobutyroyl-amino-4,6-O-isopropylidene α-D-glucopyranoside in 150 ml of absolute acetonitrile in a nitrogen atmosphere under moisture exclusion and stirring 1.9 g of sodium hydride (Pluka, pract.) and stir for 1 1/2 hours at 40 ° C. Then, the reaction mixture is cooled to -10 ° C and 5.6 ml of bromoacetic acid methyl ester are added. He stirs for another 15 minutes in an ice bath and for 2 hours at room temperature. After working up, benzyl-2-deoxy-2-isobutylaminozi-, 6-

JLL

DK 161026B

O-isopropylidene-3-O-methoxycarbonylmethyl-α-D-glucopyranoside, which is recrystallized from ether / petroleum ether, m.p. 119-120 ° C, [α] D = + 152 ° ± 1 ° (chloroform, c = 0.963).

A solution of 3.16 g of benzyl-2-deso2- -2-isobutyroylamino-4,5,6-isopropylidene-3-O-methoxycarbonylmethyl-α-D-glucopyranoside in 30 ml of methanol and 10 ml of 1 N sodium hydroxide solution is recommended. room temperature for 1 hour. 3 ml of 1N hydrochloric acid are added and the solution is evaporated to dryness. The residue is dissolved in 50 ml of N, dim-dimethyl 1 formamide to which is added 2.26 g of La-aminobutyroyl-D-isoglutamine-tert-butyl ester hydrochloride and 1.75 g of EEDQ, and the mixture is allowed to stand for 24 hours. at room temperature. 0.2 g of EEDQ is added and the mixture is left for another 24 hours. The solvent is distilled off and the residue dissolved in ethyl acetate / water. The organic phase is separated and washed with ice-cold 1 35Γ hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness. There is thus obtained benzyl-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoylmethyl-2-deoxy-2-isobutylamino-4, 6-O-isopropylidene-α-D-gluco-pyranoside tert-butyl ester as a white foam.

This product is dissolved in 60 ml of glacial acetic acid, 60 ml of water is added with stirring and the mixture is allowed to stand for 24 hours at room temperature. This solution is evaporated in water jet vacuum to dryness and the residue is dissolved in ethanol. Filter with activated charcoal and evaporate again to dryness. There is thus obtained benzyl-3-O - [[1- [D1-carbamoyl-3-carboxy-propyl] -carbamoyl-propyl] -carbamoyl-methyl-2-deoxy-2-isobutyroylamino-α-D-glucopyranoside tert butyl ester as a white amorphous white material with [a] + = + 74 ° + 1 ° (methanol, c = 0.950).

A solution cooled to 0 ° 0 of 3.9 g of this tert.butyl ester in 40 ml of 98% trifluoroacetic acid is stirred for 1 hour at 0 ° C and poured onto 500 ml of absolute ether. The crystalline

DK 161026E

112 serrated product is aspirated, washed with ether and dried in vacuo. The obtained powder is dissolved in 4-0 ml of water / tetrahydrofuran (1: 1) and stirred for 30 minutes with 50 ml of ion-exchange resin "Dowex 3" (acetate form). The ion exchanger is filtered off and washed with 500 ml of tetrahydrofuran / 1 E acetic acid. The filtrate is evaporated to dryness and the product is crystallized from methanol / ether, m.p. 205-206 ° C.

Example 41, In En. solution of 3 »1 g benzyl-3-O-L1- (Dlc arbamoyl-3- 10 carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-des-1-oxy-2-isobutyroylamino-α-D-glucopyranoside in 40 ml of methanol / water (1: 1) is hydrogenated in the presence of 10% palladium on coal at normal pressure and 4-5 ° C. After reprocessing! 3-O- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamide

| V. 'N

[15-ethyl] -carbamoylmethyl <-2-deso: xy-2-isobutyroylamino] D-glucose as a white powder by freeze-drying.

The starting material used is prepared analogously to Example 40.

in

Condensation of benzyl-3-O-carboxy-methyl-2-deoxy-2- isobutyroylamino-4,6-O-isopropylidene-α-D-glucopyranoside sodium salt with L-alanyl-D-isoglutamine-tert-butyl ester hydrochloride occurs benzyl-3-O-β [L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-decoxy-2-isobutyryl-amino-4,6-O -is up opylidene-α-D-glucopyranosert tert.butyl ester as a white foam. Hydrolysis of the 4.6-O-ice opropylidene group gives benzyl-3-O-β [L-1- (D-1-carbamoyl

v. S

3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-des-oxy-2-isobutyroylamino-α-D-glucopyranoside tert-butyl ester with [α] + = + 71 ° -1 ° (methanol, c = 0.956 ).

The tert.butyl ester is cleaved with trifluoroacetic acid. He thus obtains benzyl-3-O-1- (D-1-carbamoyl-3-carbo-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-2-isobutyroyl

DK 161026 B

113 amino-α-D-glucopyranoside as a white amorphous product.

Example 42

A solution of 4.2 g of benzyl-2-acetyl-E-methylamino-3-O- [1-1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -5-carbamoyl-methyl -2-deso: xy-D-glucopyranoside in 75 ml of methanol / water (1: 1) is hydrogenated in the presence of 0.5 s of 10% palladium on coal at normal pressure and 45 ° C. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in slightly distilled water and lyophilized. There is thus obtained 2-acetyl-N-methyl-amino-3-O - [[1-CD-1-carbamoyl] -carboxy-propyl) -carbamoylethyl] -carbamoylmethyl-2-des oxy-D-glucose as a white powder.

The starting material used is prepared as follows:

To a solution of 8.5 g of benzyl-2-acetamino-2-deoxy-4.6-15-O-isopropylidene-3-O-methoxycarbonylmethyl-α-D-glucopyranoside in 80 ml of absolute acetonitrile is added to a nitrogen atmosphere with stirring. moisture exclusion 0.75 S sodium hydride (Eluka, pract.) and stirring for 1 hour at 40 ° C. The reaction mixture is now cooled to room temperature and a solution of 6.0 g of methyl iodide in 50 ml of absolute acetonitrile is added dropwise over 4 hours. After a further 3 hours, the reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate and this solution is washed with water, dried over sodium sulfate 25 and evaporated to dryness. There is thus obtained benzyl-2-acetyl-N-methylamino-2-deoxy-4,6-O-isopropylidene-3-O-methoxy-carbonyl-methyl-α-D-glucopyranoside as a yellow oil having the Rf value of 0, 45 on silica gel thin sheets in the methylene chloride / ethyl acetate system (85:15).

A solution of 4.4 g of benzyl-2-acetyl-1T-methylamino-2-des-oxy-4,6-O-isopropylidene-3-O-methoxycarbonylmethyl-α-D-glucopyranoside in 60 ml of methanol and 15 ml 1 ΪΓ sodium 114

DK 161026 E

hydroxide solution is left at room temperature for 1 hour, and 5 ml of 1N hydrochloric acid is added and evaporated to dryness.

The benzyl-2-acetyl-N-methylamino-3-O-carboxylic acid xymethyl-2-deoxy-4,6-isopropylidene-α-D-glucopyranoside sodium salt ΐ 5 dissolved in 50 ml of ΪΓ, 1-dime thylformamide and condensed with 3.2 g of 1-alanyl-D-isoglutamine tert.butyl ester hydrochloride I in the presence of 2.5 g of EEDQ. The solution is evaporated! in vacuo to dryness and the residue is dissolved in ethyl acetate.

In Han, this solution was washed with water, ice-cold 1 N hydrochloric acid, in 10 water, a saturated sodium hydrogen carbonate solution and water, in a drying over magnesium sulfate and evaporated to dryness. There is thus obtained henzyl-2-acetyl-1-methylamino-3-O - [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoylethyl] -carbamoyl-1-methyl 4,6-O-isopropylidene-α-D-glucopyranoside tert.hutyl ester as a yellow foam. This product is dissolved in 45 ml of 95% trifluoroacetic acid, which has been previously cooled to 0 ° 0 and stirred for 1 hour at 0 ° 0. The reaction mixture I is poured onto 400 ml of absolute ether and the precipitated product is suctioned off, washed with ether and dried. By treating this substance with the ion-exchange resin "Dowex 3" in acetate form, the trifluoroacetic acid-free benzyl-2-acetyl-ethyl-amino-3-O-β> [L- (D1-carbamoyl-3-carboxy-pr opyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-α-D-glucopyranoside as a white powder.

Analogously prepared: 2- ac ethyl-H-methyl-amino-3-O- [D1- [1-1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl 2-decoxy-D-glucose, 2-ac ethyl-H-methyl-amino-3-O-D1- [1-1- (D1-carbamoyl-3-30-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 2-acetyl-E-methyl-amino-3-O-11- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoyl methyl 2 -2-deoxy-D-glucose, v

DK 161026 B

115 2-Acetyl-N-methyl-amino-3-O- [[1- (I) -1-carbamoyl-3-carboxy-propyl) -carbamoyl-2-methyl-propyl] -carbamoyl-methyl the s-oxy-D-glucose, 2-acetyl-N-methyl-amino-3-O- ^ D1- [L1- (D1-carbamoyl-3-5 carboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-ethyl ^ -2-deoxy-D-glucose, 3- O -L1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-2-propionyl H-methylamino-D-glucose and 2-butyryl-N-methylamino-3-O - [[1- (D1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl ^ -2-deoxy-D-glucose.

Example 43

The trimethylsilyl ether can. eg. are prepared as follows: 0.3 g of 2-benzamido-2-deoxy-3-O - [[1- (D1-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-methyl] -D-glucose is dissolved in 3 ml of dimethylformamide and 0.4 ml of bis-trimethylsilylacetamide are added. After 5 hours at 35 ° C, evaporate in vacuo to a syrup from which, by dissolving in 20 absolute ether or absolute ethyl acetate, the acetamide formed can be separated. After re-evaporation, a colorless syrup is obtained with [a] + = + 15 ° (dioxane, c = 0.8).

Analogously, syrupy 2-acetamino-2-deoxy-3-O- [[1- (D1-carbamoyl-3-trimethylsilyl-carboxy-propyl) -25-carbamoylethyl] -carbamoylmethyl] -1,4-, 6-trisol is obtained. trimethylsilyl-D-glucose with [α] D = -10 ° (dioxane, c = 0.91).

Upon contact with water, the trimethylsilylester group is rapidly hydrolyzed so that these derivatives are also suitable for coupling.

116 DK 1610261

Example 44

A 5% solution of benzyl-2-acetamido-3-O- [L1- [D-1- (L-1-carboxy-ethyl) -carbamoyl-3-carboxypropyl] -carbamoyl-ethyl ^ -carbamoyl-methyl 2-Deoxy-ox-D-glucopyranoside in tetrahydrofuran / water (2; 1) is hydrogenated in the presence of 10% palladium on coal Ted normal pressure and room temperature. After taking up the theoretical amount of hydrogen, the catalyst is filtered off and the filtrate is freeze-dried. There is thus obtained 2-acetamido-3-O-L-l- [. D-1- (L-1-carboxy-ethyl) -carbamoyl-3-carboxypropyl-carbamoyl-ethyl-2-carbamoyl-methyl-2-deoxy-D-glucose as a white powder. Bf value in thin layer chromatogram = 0.21 (ethyl acetate / n-hutanol / pyridine / acetic acid / water I 42: 21: 21: 6: 10).

In the analogous manner, the derivative is obtained with real muramic acid.

The starting material can be prepared as follows: 5.68 g of E-tert.butoxycarbonyl-L-alanyl-DY-benzyl-glutamyl-L-alanine benzyl ester are dissolved in a mixture of 5 ml of trifluoroacetic acid and 5 ml of 1,2-dichloroethane and be left under moisture exclusion for 16 hours at room temperature. This solution is diluted with 50 ml of tetrahydrofuran, cooled in an ice bath and neutralized with triethylamine. After adding a solution of 3.7 g of benzyl-2-acetamido-3-carboxymethyl-2-deoxy-α-D-glucopyranoside and 1.38 ml of triethylamine in 100 ml of tetrahydrofuran, 2.6 g of 2-ethoxy-B-ethoxycarbonyl 25 1,2-dihy dr o quino 1 in and the mixture is allowed to stand for 24 hours at room temperature. After evaporation of the solvent, the residue is dissolved in chloroform / methanol (9: 1), washed with water, ice-cold 2 Ή hydrochloric acid, water, a saturated sodium hydrogen carbonate solution and water, filtered and solvent-free. There is thus obtained benzyl-2-acetamido-3-O- [L1- [D1- (L1-carboxy-ethyl) -carbamoyl-3-carboxy-propyl] -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-aD -glucopyranoside as a colorless powder, Bf value = 0.48 (in an identical system).

DK 161026 B

117

The starting material used can be prepared as follows: 7.15 S of H-tert.butoxycarbonyl-L-alanyl-D-glutamic acid γ-benzyl ester and 6.15 g of L-alanine benzyl ester p-toluenesulfonate are dissolved in 100 ml of anhydrous dime thylformamide. One is cooled in an ice bath and successively, with stirring, 4.03 g of R-hydr oxysuc c inimi d, 3? 61 g di cy c 1 o hexyl c ar b o di imi d and finally 1.95 md N-methylmorpholine. After stirring for 6 hours at 0 ° C and 15 hours at room temperature, the suspension is cooled, the precipitate (di cy c 1 ohexy lur ins t o f and morpholine hydrochloride) is filtered off and the filtrate is evaporated. The residue is taken up in ethyl acetate, washed several times with water, 1 H citric acid and 1 ΪΤ sodium hydrogen carbonate solution and again with water.

The ethyl acetate solution is dried and evaporated and the crystalline residue is recrystallized from ethyl acetate / petroleum ether (1: 1), m.p. 135-136 ° C, [α] D = -9 ° ± 1 ° (methanol, c = 1), Rf = 0.82 (in the above system) and 0.86 (acetonitrile / water 3 · *) 1) · Instead of alanine, the protected dipeptide can be extended by other natural L-amino acids by analogy.

Example 45

ISLAND

7.5 x 10 killed Trypanosoma cruzi parasites (causing Chagas disease) are suspended in a solution of 50 mg of 2-acetamino-3-O - [[1- (D-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoylmethyl 2 -2-deoxy-D-glucose-R-hydroxysuccin imide ester in 6 ml of physiological buffer solution. The suspension is incubated for 2 hours at 37 ° 6. Subsequently, the parasites conjugated to the muramyl dipeptide are sedimented by centrifugation. The sediment is washed by resuspension in physiological buffer solution and re-centrifuged. The washed parasite-30 muramyl dipeptide conjugates are suspended in physiological buffer solution and used for immunization.

The quantitative determination of the coupling to the trypanosorns

DK 161026 E

118 lead muramyl dipeptide occurs as in Example 1 with the Morgan-Elson reaction and shows a content of 50-70 mg in muramyl dipeptide per ml. mg of trypanosomes.

i i i

Claims (16)

An analogous method for producing antigenic derivatives of an antigen and at least thus, optionally over a bridged, covalently linked muramyl peptide, and optionally an optionally crosslinked condensed bazaar, characterized in that an optional bridged-associated antigen is condensed with optionally bromine-linked muramyl peptides, one of the two parts containing at least one free amino, hydroxy or mercapto group and the other at least one carboxylic acid group, preferably by reacting one compound in the form of an activated carboxylic acid with the other compound as free amino, hydroxy, or mercapto compound and, if desired, condenses the resulting compounds to an optionally bridged carrier. Process according to claim 1, characterized in that one reactant is reacted in the form of an activated carboxylic acid with the other reactant as free amino, hydroxy or mercapto compound. Process according to one of Claims 1 or 2, characterized in that the starting materials are selected so as to obtain an antigenic derivative of the formula X A "Μ Γ Γ Ί I - X '" - Z "' - X1V - MP L Z ' J LJ 0.1 n | _ I 0-1 Jm L "* Γ ς" ί m L oi DK 161026 E wherein A is an antigen residue, T a carrier residue, MP a muramyl peptide residue, Z 'and Z "' divalent bridged and X ', X ", X" and I Xiv are covalent connecting elements, and m and n mean 5 integers greater than 0. Process according to claim 1, 2 or 3, characterized in that the starting materials are selected so as to prepare an antigen derivative of the formula A-20-1-101 (I) n 10 wherein A is a residue of an antigen, Z broled, MP a residue of a muramyl peptide and n an integer greater than 0. Method according to one of claims 1 to 4, characterized in that as an antigen an active substance is used in a vaccine against parasites, bacteria, viruses, tumor cells, attenuated or killed forms or subcomponents thereof, in a vaccine against autologous constituents or immunological identification structures, or in a vaccine suitable for specific allergy desensitization. Method according to one of claims 1 to 4, characterized in that as an antigen an active substance is used in a vaccine against malaria, cholera, typhoid, meningitis, rheumatic fever due to streptococcal infections, influenza, rabies, foot and mouth disease , as well as in a vaccine 25 for prophylaxis and therapy of tumor diseases, for the induction of immunity to components of the reproductive system, for desensitization or induction of specific immunotoxic agents. 121 DK 161026 B allergens to restore tolerance to autologous tissue constituents and circulating molecules. Process according to one of Claims 1 to 4, characterized in that as antigen, malarial monocytes are used, type-specific meningococcal polysaccharides A, B or C, streptococcal influenza viruses, influenza virus hemagglutinins, autologous tumor cells or tumor cell membrane components. , partial sequences of human chorionic gon-adotropin, grass pollen extracts, antigen-specific T-cell lymphoblasts and their antigen receptors, or antigen-specific immunogiobulins. Process according to one of claims 1 to 7, characterized in that one of the formula CH20R6 K4ON- ^ / N - X - R R3 - CH (D) R13 (II) \ R8 R10 R11 \ 1 II is used as muramyl peptide R 2 (D) wherein X is a carbonyl, carbonyloxy or sulfonyl group, R 1 hydrogen, alkyl, optionally substituted benzyl or acyl, R 2 optionally substituted alkyl or carb-20-cyclic aryl, and R 2 is independently hydrogen, alkyl, optionally substituted benzyl or acyl, R 3 hydrogen or alkyl, R 3 and R 3 is hydrogen or lower alkyl, R 2 hydrogen, lower alkyl, free, esterified or etherified mercapto-lower alkyl, free or acylated aminolavalkyl, cycloalkyl of 5 or 6 carbon atoms, cycloalkyl lower alkyl, whose cycloalkyl group contains 5 or 6 carbon-5 atoms, optionally substituted aryl or aralkyl, nitrogen-containing heterocyclyl or heterocyclyllavalkyl, R? i and r8 also together represent the alkylene having 3 or 4 carbon atoms, r9 hydrogen or lower alkyl and the groups R 2 O, R 2 and R 2 independently of each other an optionally esterified or 10-amidated carboxyl group and R 2 also hydrogen, wherein R 4, in R 4 and R 2 may also mean trilavalkylsilyl, especially trimethylsilyl, or oligomers thereof, such as e.g. is described in German Publication No. 2,450,355 and can! is recovered by isolation from microorganism cell walls. Method according to one of claims 1-3 and 5-8, characterized in that the antigen is fixed to a high molecular weight carrier, preferably using a carrier. lactic acid polymer and its derivatives which carry on the chain end a free carboxyl group, alginic acid, polygalacturonic acid | Acid, pectins, carboxymethyl cellulose, agarose or a basic, neutral or acidic polyamino acid. Process according to one of claims 1 to 9, characterized in that the starting materials are selected so that the antigen derivatives as covalent compound elements 25 contain carboxylic ester, carboxylic acid amide, thiocarboxylic acid ester or thiocarboxylic acid amide groups. Method according to one of Claims 1 to 10, characterized in that the starting materials are selected such that the antigen is separated from the muramyl peptide by a spacer. Process according to one of claims 1 to 11, characterized in that one of the formula II shown in claim 8 is used as the muramyl peptide, wherein R 4, R 2, R 4, R 6 and b 7 are hydrogen, X carbonyl and R or DK 161026 B lower alkoxy substituted lower alkyl or optionally with hydroxy, lower alkoxy, lower alkyl or halogen substituted phenyl. Process according to one of Claims 1 to 11, characterized in that one of the formula II shown in claim 8 is used as a muramyl peptide, wherein R 1, R 4, R 6 and R 2 are hydrogen, X carbonyl, R 2 optionally hydroxy or lower alkoxy. substituted lower alkyl or optionally with hydroxy, lower alkoxy, lower alkyl or halogen substituted phenyl and R 3 methyl. Process according to one of claims 1 to 11, characterized in that one of the formula II shown in claim 8 is used as a muramyl peptide, wherein R 1, R 4, R 3 and R 3 are hydrogen, X carbonyl, R 2 optionally with hydroxy or methoxy substituted lower alkyl or optionally with hydroxy, methoxy, methyl, ethyl or halogen substituted phenyl, R3 hydrogen or methyl, R? and R 2 hydrogen, R 8 lower alkyl, lower alkyl mercapto-lower alkyl, hydroxylavalkyl, benzyl, p-hydroxybenzyl or phenyl, R 10, R 2 and R 2 carboxy, lower alkoxycarbonyl or carbamoyl and R 11 also hydrogen and R 13 hydrogen. Process according to one of Claims 1 to 11, characterized in that one of the formula II shown in claim 8 is used as muramyl peptide, wherein R 1, R 4 and R 2 are hydrogen, X carbonyl, R 2 optionally with hydroxy or methoxy. substituted lower alkyl or optionally with hydroxy, methoxy, methyl, ethyl or halogen substituted phenyl, R3 and R9 hydrogen or methyl, b7 hydrogen or lower alkyl, R3 methyl, ethyl, n-propyl, isopropyl, 2-methylpropyl, methylmercaptomethyl, hydroxymethyl , hydroxyethyl, phenyl, benzyl or p-hydroxybenzyl, R43, r11 and R12 carboxyl, lower alkoxycarbonyl or carbamoyl and R 1 also hydrogen and R 3 hydrogen. DK 16102 Process according to one of claims 1 to 11, characterized in that one of the formula II is used as a muramyl peptide, wherein R 2, R 2 and R 2 are hydrogen, X carbonyl and R 2. and R 2 together propylene or butylene. in