DD141616A5 - PROCESS FOR PREPARING NEW ANTIGEN DERIVATIVES - Google Patents

Description

Process for the preparation of new antigenic derivatives

Field of application of the invention

The invention relates to a process for the preparation of novel antigenic derivatives. These novel antigenic derivatives are used for the preparation of pharmaceutical preparations for stimulating immunity. The invention further relates to processes for the preparation of novel intermediates.

More particularly, the invention relates to methods for preparing novel antigen derivatives consisting of an A _n term and min- 'least one order, optionally via a bridge member, covalently linked muramyl peptide "These new antigen derivatives can be, for example, by the Pormel (I)

A -

~ MP

(D

to characterize in more detail «where A is the remainder of an antigen, Z is a bridge member (spacer), IKS is the remainder of a muramyl peptide, and η is an integer greater than 0«, ^ -

1-1 ^; 204, / '- ² "Berlin, d.12.7.1979

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.Ij.Q.sunge_n.

As the antigen, an organic substance is meant, which * the human or animal organism j is recognized as immunologically foreign to the physiological medium, d _o h or recognized as foreign under suitable conditions v can ground / ₀

The antigens include in the first place all, the specific immunization of a living organism against infectious pathogens or undesirable reactions, such as allergic sensitization or rejection of transplanted Premdgewebe, causing substances "in particular antigens are included as ingredients of vaccines"

On the one hand, suitable vaccines are those which are known in the RaIi-. men classical vaccination method for specifically immunologisehen inserted protection against infectious diseases v / earth _e the enthalten.sind as antigens j in such vaccines, the attenuated live or killed, modified or degraded causative agent of infectious diseases Torsoide formed by these pathogens or natural or _e come Synthetically produced subcomponents of pathogens and toxoids in the form of an imprint "Classes of pathogens should be mentioned by name; Viruses, chlamydia ,. Are rickettsia, .Bakterien, protozoa and parasites metazoSische "Preferred antigens such _s as components of vaccines for the treatment of, _e B _& influenza A and B, Parainfluenaa 1-O? respiratory, synovial, rhinovirus or adenovirus-induced respiratory diseases, cytomegalovirus, rubella, measles, mumps, pertussis ^ poliomyelitis ^ herpes simplex 1 and 2 _s varicella and herpes zoster _s rotavirus diseases «hepatitis A, B and others * Rabies _? Foot and mouth disease, trachoma _? Caries caused by meningococci A, B and O, meningitis, pneumococcal disease, influenzae, streptococcus

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cocci (in particular rheumatic fever) _s Pseudomonas and Proteus, typhus, paratyphoid fever, and other diseases caused by enterobacteriaceae, gonorrhea, syphilis, malaria, trypanosomiasis (sleeping sicknesses and Chagas' disease) y leishmaniasis, filarioses, schistosomiases, ankylosstomiases and other worm diseases «, are suitable."

On the other hand, new vaccines must be mentioned that not against pathogens of infectious diseases, but either the body's own constituents, d _{o o} normal and aberrant AutoAns Igene or against sensitizing environmental antigens, d, h "allergens are directed"

In a Pail, the aim is to eliminate by immunization against normal or aberrant autoantigens the function of the body's own molecules (z "B" of hormones, other mediators and humoral and cell receptors) or to cancel the spread or persistence abyp, especially neoplastic cell lines , Preferred antigens as constituents of such vaccines are z, B _e : partial sequences of the human chorionic gonadotropins or constituents of spermatozoa for immunization against mediators of perertility and thus for the immunological elimination of reproductive functions; Mediators of inflammatory processes, in particular in purified form, including the lymphokines secreted by lymphocytes, in particular MIF (macrophage migration inhibitory factor) for immunological suppression _: of inflammatory diseases; Immunologically specific antigen receptors of lymphocytes and antibodies (fractionated antigen-specific lymphocytes, antigen receptors extracted or secreted by these lymphocytes, fractionated antigen-specific antibodies or antibody fragments) for anti-idiotype immunization (immunization against those for the antigen-receptor structures

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characteristic autoantigens) with the aim of eliminating specific immune reactions for the elimination of pathogenic immune processes such as autoimmunity (z «B _o against synovial antigens and immunoglobulins in the primary chronic polyarthritis, against myelin components in degenerative diseases of the central nervous system, against TSH Reζeptoren in autoimmune ThyreoiditiSj against acetylcholine receptors striated muscle at-the. myasthenia _gravis? etc to islet cell components in juvenile diabetes _0). or allergy (eg ₀ B <"to grass pollen, dust or drugs in allergic asthma _s allergic rhinitis or ₀ drug hypersensitivity) or Vei'meidung itself _normal? but unwanted immune responses (eg B ₀ induction of immune tolerance to prevent rejection of transplanted foreign organs and tissues); autologous or cross-reacting with them homologous or heterologous tumor cells _{e s} tumor cell fragments or - "membrane components including Onlcornavirus-coded glycoproteins such as GP 70 _seconds to tumor-specific immunization in the context of prevention and treatment of cancer"

In the other case is attempted or predominantly by immunizing against allergens in place of pathogenetically relevant IgE antibody response inducing ₀ sufficiently IgG and IgA antibody against the sensitizing environmental antigens and thereby diirch trap specific antibodies in the circulation and in the secretions allergens before they react with the bound Mastze11en IgE Aiitikörper and thus the release-allergic mediators can trigger * When diesei "antigen-specific desensitization are the allergens themselves, d _ft h ₀ K ^ B _6, grass pollens, dust or medications antigen components of the vaccines _O

Antigens can, especially if they are low molecular weight.

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quite well and with advantage, to be covalently bonded to a high molecular weight carrier "As carriers are in particular polymers of lactic acid and derivatives thereof, which carry a free carboxyl group at the chain end, such as their esters with glycolic acids, polylactic acid amides or lactic acid polyester amides such as z _e Bo in the GB-PS Ur. Nos. 932,382, alginic acid, polygalacturonic acid, pectic acid, carboxymethylcellulose or agarose. Further suitable carriers are basic, neutral or acidic polyamino acids which are not themselves immunogenic, such as polyaspartic acid, polyglutamic acid, polylysine or polyornithine. Otherwise, any other antigens within the meaning of the definition given here or examples listed are also used as carriers inasmuch as an immune response to them can be accepted or even desired. Thus, for example, a HCG peptide may be covalently bound to tetanus toxoid as a carrier.

It is known that muramyl peptides are good adjuvants capable of enhancing their immunogenicity in a suitable mixture with antigens. However, it has been shown that they exert only a short-term effectiveness, since they are excreted relatively quickly _{in o} the human or animal organism. Above all, they are to induce only under certain, not suitable for clinical use conditions, namely in a mixture with antigens in an emulsion of mineral oil capable of in vivo cell-mediated immunity against soluble _o

Object of the invention

The aim of the invention is to provide a simple process for the preparation of new antigen derivatives for use

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for new vaccination procedures or to simplify common vaccination procedures »

The object of the invention is to find suitable starting compounds and suitable reaction conditions . make ^ to novel derivatives having the desired antigen-run properties, in particular such a _s the L _a ngzeitschutz ensure produce _y '

According to the invention, novel antigen derivatives of the formula I

Ζ _{Λ Λ} «MP ° ™ ^Ί η

(D

where A is the remainder of an antigen ,. Z. is a bridge member / MP of ...., residue of a muramyl peptide and η is an integer greater than 0 '

They may be obtained by condensing together an antigen optionally linked with bridge members with muramyl peptides optionally linked with bridge members, one of the two parts having free amino, hydroxy or mercapto groups and the other carboxylic acid groups, and if desired the compound obtained optionally bonded with bridge members connected carrier *

The condensations take place Z ₆ B ₀ in the way. that a compound in the form of an activated carboxylic acid with the other compound as the free amino, hydroxy or mercapto compound reacting ₀ The activated carboxyl group can, for example, an acid anhydride, preferably an acid azide,

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an acid amide, an imidazolide, isooxazolide or an activated ester. The following may be mentioned as activated esters: cyanine thylester, carboxymethyl ester, p-nitrophenyl thioester, methoxyethyl thioester, acetylaminoethylthioester, p-ITitrophenylester, 2,4j 5-trichlorophenylester , H-hydroxysuccinimide, H-hydroxyphthalimide ester, 8 ~ hydroxyquinoline ester, H-'vliydroxypiperidinester "Active esters may also optionally with a carbodiimide with the addition of U-hydroxysuccinimide, or an unsubstituted or z _e B" is substituted by halogen, methyl or methoxy, 1-Hydroxybenzotriazo .l or 3-L ^T Hydroxy ~ 4 "OXo-3» 4-dihydro-benzo ["d3-1,2,3-triazine are obtained by _e

The leaving groups used in this condensation must be non-toxic or easily removable, in order to avoid su, that the most high-molecular compounds by adsorption toxic portions retained,

It is therefore preferred as active esters such with N-hydroxy-5-succinimide or its C-substitution products, such as H-hydroxymethyl or -dimethylsuccinimid, or the reaction with carbodiimide, such as carbodiimide itself or 1-ethyl-3- (3-dimethylaminopropyl ) -carbodiimide _e

The above reactions are carried out in the usual manner in the presence or absence of diluent, condensing and / or catalytic agents, if necessary at reduced or elevated temperature. Preferably, in order not to destroy the antigens, the reaction is carried out in an aqueous medium and at a pH range of 6-9, primarily 7-8 «

The invention also relates to those embodiments of the method according to which one of one at any stage

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in which the starting materials are prepared under the process conditions or in which a reaction component is employed, if appropriate, in the form of their derivatives, such as their salts and / or in the form of isomer mixtures or pure isomers.

For carrying out the condensations according to the invention it is expedient to use those starting materials which lead to the groups of end-products mentioned above in particular and especially to the end-products specifically described or highlighted.

The starting materials used are known or, if ne \ i _? can be prepared by methods known per se

The muramyl peptides according to the invention linked to the antigen are, in particular, synthetically preparable compounds of the general formula II,

X - R,

(II)

Ro - CH (D)

R _c

COl - CH - COa - CH - CH ₂ CH

- R

wherein X is a carbonyl, carbonyloxy or sulfonyl group,

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Hydrogen, alkyl, optionally substituted benzyl or acyl, Rp optionally substituted alkyl or carbocyclic sehes aryl, R ^ and Rg independently hydrogen, alkyl j optionally substituted benzyl or acyl, R "hydrogen or alkyl, R" and R ^ o hydrogen or liederalkylj , R _{Q is} hydrogen, lower alkyl, free, esterified or etherified hydroxy lower alkyl, free, esterified or etherified mercapto-lower alkyl, free or acylated amino-lower alkyl, cycloalkyl of 5 or 6 carbon atoms, cycloalkyl-lower alkyl whose cycloalkyl contains 5 or 6 carbon atoms, optionally substituted aryl or Aralkylj nitrogen-containing heterocyclyl or heterocyclyl-lower alkyl, R ^ and Rq together also alkylene having 3 or 4 Kohlenstoffa, toms, Rg hydrogen or lower alkyl, the radicals R-JQj Rij and R ^ ₂ independently of a given esterified or amidated carboxy radical and R ^ _{1 is} also hydrogen, or R ^, R. and Rg Triniederalkylsilyl, ir> are "3besondere Trimethylsilyl, or even oligomers thereof, viie they Z" B "in DE-OS 2" 45O _e 355 described and can be isolated by isolation from microorganism cell walls.

According to the invention, the new to be used as starting materials muramylpeptides of the formula II, wherein X is a carbonyl group, R ^ hydrogen, alkyl, optionally substituted benzyl or acyl, Rp optionally substituted alkyl or carbocyclisch.es -aryl, R, and Rg independently hydrogen, alkyl optionally substituted benzyl or acyl, Ro is hydrogen or alkyl, at least one of Rr, Rg and Rj is lower alkyl, Ln is primarily methyl and the others are hydrogen, Rq is hydrogen, alkyl, free esterified or etherified hydroxy lower alkyl, free esterified or etherified mercapto-lower alkyl, free or

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acylated amino-lower alkyl, cycloalkyl, having 5 or 6 carbon atoms, cycloalkyl-lower alkyl, the cycloalkyl radical of which contains 5 or 6 carbon atoms, optionally substituted aryl or aralkyl, nitrogen-containing heterocyclyl or heterocyclyl lower alkyl, R "and Rg together also alkylene of 3 or 4 carbon atoms, and the radicals R-jq? R-i-j and R ..- independently of one another denote an optionally esterified or amidated carbo radical and R 1 also mean Y / acid, if, in a manner known per se, a compound of the formula

CH ₂ ORg

0-R

H-X-R

(IV)

COOH

v / orin X, R ₅ R ^ and R "" have the abovementioned meaning and R ^ ₅ R ° and Rg are the radicals R ^, R and Rg or a readily cleavable protecting group, or a derivative thereof with a compound of the formula.

wherein

Tr i ⁸

- CH - COT r (L)

O -η Ο

CHCH ₀ CH - R

(V)

^R 12 '

Meaning of Rg, ^R - | o * ^R 11 2 have ^ with the proviso that in this. Remains existing

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Carboxy- and, if desired, free hydroxyl groups are protected by readily cleavable protecting groups, condensed and eliminates any protecting groups present.

The condensation is carried out z _e 3, in such a way that reacting the compound IV in the form of the activated carboxylic acid with the amino compound V or that one reacted the acid IV with the compound V, the amino group is in activated form, the activated carboxyl group for example, an acid anhydride, preferably a mixed acid anhydride like a Säureasid, an acid amide, such as an imidazolide, or an activated ester Isoxazolid be _0. When activated esters include in particular: cyanomethyl, carboxymethyl, p-Hitrophenylthioester, p ~ _{Hitrophenylester?} 2,4,5 * trichlorophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, 1-hydroxyphthalimide ester, 8-hydroxyquinoline ester, 2-hydroxy-1,2-dihydro-1-carboethoxy-quinoline ester,. H-hydroxypiperidine ester or enol esters that are with IT-ethyl-5-phenyl-isoxazolium-3-sulfonate ^f GeV / may. Activated esters can also optionally with a carbodiimide with the addition of H-hydroxysuccinimide, or an unsubstituted or z _e B, by halogen, methyl or methoxy substituted 1-hydroxybenzotriazole, 3 ^ hydroxy-4-oxo ~ 3,4-dihydro-benzo | _dJ -1,2,3-triazine be obtained «,

The amino group is activated, for example, by reaction with a phosphite amide "'".

Among the methods of reaction with activated esters are in particular those with N-ethyl-5-phenylisoxazolium ~ 3 ^l sulfonate (Woodward reagent K) or 2 ~ ethoxy-1 _? To mention 2-dihydro-1-carboethoxy-quinoline or carbodiimide «

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Easily removable protection group :! are those known from the peptide or sugar chemistry. Pur carboxy groups are in particular tertiary-butyl, benzyl or benzhydryl and in particular acyl radicals of hydroxy groups, for example lower alkanoyl such as acetyl _e * aroyl radicals such as benzoyl and which derives particularly from carbonic acid radicals such as benzyloxycarbonyl or Niederalko cärbonyl ^ ^ or- Alkyl.- in particular tert-butyl, optionally substituted by siitro, lower alkoxy or halogen substituted benzyl or tetrahydropyranyl or optionally substituted alkylidene radicals which connect the oxygen atoms in the 4- and 6-position may be mentioned. Such alkylidene radicals are, in particular, a lower alkylidene radical, in particular the ethylidene, isopropylidene or propylidene radical, or else an optionally substituted benzylidene radical, preferably substituted in the vicarious position

These protective groups can be cleaved in a conventional manner. Thus, they can be removed by hydrogenolysis z _e B, with hydrogen in the presence of a noble 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 procedure for the preparation of these new starting materials is that in known per se, a compound of formula VI

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CH ₀ - OR?

H ⁰

(VI)

H - COOH

wherein R, R .., R ₂ , H ₇ ,, ^, ^. gamma, with a compound of formula

HN-CH-CH

and Ro is the above meaning

, CH -

12

(VII)

where R? _o , R?., and R? _{2 have} the abovementioned meaning, with the proviso that in the radicals R °, R ° _Q , R ^ and R ° ₂ existing carboxyl and, if desired, free hydroxy groups are protected by readily removable protecting groups, condenses and optionally splits off any protecting groups present »

The condensation is carried out, for example _e in such a way that reacting the compound VI in the form of the activated carboxylic acid with the amino compound VII, or that reacting the acid VI with the compound VII, the amino groups are in activated form. The activated carboxyl group may, for example, be an acid anhydride, preferably a mixed one

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Acid anhydride, an acid amide or an activated ester »/ as such, in particular the above-mentioned acid anhydrides * amides or esters in question * The amino group is activated, for example, by reaction with a phosphite amide.

The easily removable protective groups correspond to those already mentioned above. They can be split off in a manner known per se; eg hydrogenolytically, for example with hydrogen in the presence of a noble metal such as palladium or platinum catalyst or by acid hydrolysis _t

The starting materials can be prepared in manner known per se obtained * Thus one can z _e B "implement appropriate ^ 3-position unsub--substituted sugar with a halogen-Rg-acetamido-R -acetic acid, or a compound of formula III with an amino ~ R ₇ ~ acetic acid whose carboxyl group is protected in the manner shown above, and remove the protective group.

Another method for introducing the seated in the 3-position of the sugar moiety side chain is that one compound

CH ₂ - 0 R

 &.

where X

0 - R

(VIII)

- X - R

₉ R, R ° _s R ^ Rg and R _{13 are} the abovementioned. Meaning, and optionally present in existing hydroxy groups with

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a slightly cleavable protecting group are protected with a compound of the formula

Z-CH - COICH - COlJ - CH - CHgOH - R ° ₂

rq

in which Z represents a reactive esterified hydroxy group and Rg, R? q * ^ I'i ¹¹³² ^ ^- ^ i? ^ ' ^e ° ^ ^s have the meaning given, and any protective groups split off «

A reactive esterified hydroxy group is in particular a hydroxy group esterified with a strong inorganic or organic acid, primarily one which has been esterified with hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid. "

The easily removable protecting groups correspond to those already mentioned above. They can be cleaved off in a manner known per se, Z ₀ B ₀ hydrogenolytically, for example, with hydrogen in the presence of a noble metal such as palladium or platinum catalyst or by acid hydrolysis.

The invention also relates to the new to be used as starting materials muramyl peptides of the formula II wherein · X is a carbonyl group, R _s E, and Rg tri-lower alkylsilyl, primarily trimethylsilyl, Rp is optionally substituted alkyl or carbocyclic aryl, R is hydrogen or alkyl, Ry and Ro is hydrogen or lower alkyl, R _{8 is} hydrogen, lower alkyl, free, esterified or etherified hydroxy lower alkyl,

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free, esterified or etherified mercapto-lower alkyl, free or acylated amino-lower alkyl, cycloalkyl of 5 or 6 carbon atoms, cycloalkyl-lower alkyl, the cycloalkyl of which contains 5 or 6 carbon atoms, _p optionally substituted aryl or aralkyl, nitrogen-containing heterocyclyl or heterocyclyl-lower alkyl _. R ~ and Rg together also alkyls with 3 or 4 carbon atoms * Rn. · Hydrogen or lower alkyl and the radicals R ^ _QS R ^ | and R ₂ independently of one another denote an optionally esterified or amidated carboxy radical and R 1, also denote hydrogen.

These compounds can be obtained v. ^! _r ground when in a known manner a compound of formula

CH ₂ OH

(XI)

CH (D)

10

11

COlT ~ CH ~ COl "CH-CH ₂ CH

(L)

C) J

R

reacted with a reactive ester of a tri-lower alkylsilyl compound,

As reactive esters of a iPriiiiederalkylsilylverbindung be mentioned in particular? Triniederalkyl silyl halides,

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especially "-chlorides or bromides, bis-lower alkyl-silylacetamide or -sulfarnide.

The reaction is preferably carried out in a solvent containing no reactive hydroxy or amino groups, such as dimethylformamide, dioxane, tetrahydrofuran, dimethoxyethane or chloroform

The various parts of the new compounds according to the invention are covalently linked, d _o h _e, the antigen is at least one of its functional groups over a conventional in peptide chemistry linkage with the rest of the muramyl peptide, directly or via a bridge member (spacer) connected.

As bridge members (spacers) are in particular bivalent radicals of aliphatic compounds Z ₀ B, of those having at least two amino groups, at least one amino group and a -Carboxy- or Thiocarboxygruppe, or at least two carboxy or Thiocarboxygruppen, such as aliphatic see diamines, Amino-thiocarboxylic acids, neutral, basic or acidic aliphatic amino acids, di- or oligopeptides,

Are as bridge members called in the first place, cv, ^ - diamino-alkanes, in particular & ₅ ^ - '- Diamino-down alkanes ,. such as ethylenediamine, propylenediamine, Tetraj.nethylendiamin, alkyl dicarboxylic acids such as succinic acid or glutaric acid, ^ s ₁ B or Y -Aminoalkancarbonsäuren, preferably d> -Amino-nied eralkancarbonsäuren, in particular the natural Φ- amino-lower alkanecarboxylic acids ₅ such as glycine, ß Alanine, L-alanine, aminopropylisobutyric acid, valine or leucine

As covalent linking elements, in particular

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acid ester-s Carboxylic acid amide, thiocarboxylic ester or thiocarboxylic acid amide groups called «

The novel compounds prepared according to the invention may have a plurality of covalent linking elements, Depending on the type of bridge members used # Thus, the above formula I ZeBe can obtain the following more detailed Woxm ; · ^: .. ;: *

J.

1? -υ ·

α? 0-1

⁵ J _{0 1} .- X ^iV - ICP

(III)

where A is the remainder of the antigen, T is the remainder of the mimic, MP is the remainder of the muramyl peptides Z- * and Z * ' ^{f are} bi-valent pontics, and X ⁵ _f X ^s! j X ^! ' ^f and X ^{s> / represent} covalent linking elements, and m and η denote integers greater than 0 «

Alkyl is straight-chain or branched alkyl in any position bonded with up to 18 'carbon atoms, but primarily Hiederalkyl «

As substituents of the optionally substituted alkyl group are, above LiniB free or functionally modified '/ hydroxy · - = or mercapto groups, such as etherified or veresterte'Hydroxy- or mercapto, z is ₀ or B _e Hiederalkoxy liiederalkylmercaptogruppen, or halogen atoms, or free or functionally modified carboxyl " , such as carbo-lower alkoxy or carbamoyl groups in question _e Here, the sub-. Substituted alkyl radical, such as liederalkylrest one, two or

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, AP A 61 K / 211 204 -55 084 18

carry several identical or different substituents, in particular free hydroxy groups or halogen atoms »

Carbocyclic aryl radicals are especially monocyclic and bicyclic aryl groups, especially phenyl., But also naphthols can be optionally substituted, for B _{o e} iliederalkylgruppen by free, etherified or esterified hydroxy, _ζ β Β. Uiederalkoxy or Mederalkylendioxy or halogen atoms, and / or irifluoromethyl, mono-, di- or polysubstituiert _e

Aralkyl is especially aryl-lower alkyl, wherein aryl has the meaning given above. Aryl-lower alkyl is primarily benzyl or phenylethyl. wherein the phenyl nucleus may be mono-, di- or polysubstituted.

Optionally substituted benzyl radicals are, in particular, those benzyl radicals which, if appropriate, are in the aromatic nucleus, z _e B _e by IRederalkyl, free, etherified or esterified hydroxy or mercapto groups, _{e e,} haloalkoxy or lower alkylenedioxy, as well as lower alkyl mercapto or C 2 rifluoromethyl groups and / or halogen atoms -, di- or polysubstituiert sindo

Nitrogen-containing heterocyclyl is in particular the radical of a 5- or 6-membered, one or 2 nitrogen atoms contained in the 'ring heterocyclic compound "He may be unsaturated or saturated, and _ζ β Β. contain a fused phenyl radical ,, as such be z "B. called pyrrole, indane, pyridyl or imidazole ring.

An optionally esterified or amidated carboxyl group is primarily the carboxyl group itself, or one with

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a carboxyl group esterified to a lower alkanol or also the carbamoyl group which is unsubstituted on the nitrogen atom or which is substituted by alkyl _s ', in particular haloalkyl, aryl, in the first place phenyl, or aralkyl,: v / ie benzyl, mono- or di-substituted, The carbamoyl group but also an alkyl en-, like the Setra ~. or pentamethylene radical. The carbamoyl group Rg may also be substituted on the nitrogen by -the garbamoyl-methylene group. «

Acyl is especially an acyl radical of an organic acid ,, particularly an organic carboxylic acid "Thus acyl is particularly alkanoyl, especially with 2-18 carbon atoms, in the first place, however, lower alkanoyl _s or .Aroyl as ITaphthoyl 1-naphthoyl _$ ~ 2 and particularly Benzoyl or by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or liederalkanoyloxy substituted benzoyl or naphthyl, or an acyl radical of an organic sulfonic acid, Z ₆ B * an alkanesulfonic acid, in particular an ITiederalkansulfonsäure, or an arylsulfonic acid, in particular an optionally Hiederalkyl- or halogenated substituted phenylsulfonic acid, such as benzenesulfonic acid or p-toluenesulfonic acid, as well as carbamoyl. z © B _e, unsubstituted carbamoyl, HiedereJ-kylcarbamoyl or arylcarbamoyl such as methylene "or phenyl carbsaioyle

Esterified or etherified hydroxy is especially STiederalkoxy or :? ITownaCyloxy, as Uiederalkanoyloxy «

Esterified or etherified mercapto is, in particular, lower alkylmercapto or re-acyl, such as lower alkanoylmercapto.

Acylated amino is in particular Miederalkanoylami.no or carbamoylaminoc

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The radicals referred to in the context of the present specification "Hieder" and. Compounds preferably contain up to and including 7, and most preferably to and including 4 carbon atoms

Above, as follows, the general terms may have the following meaning:

Mederalkyl is B z _{0 e} n-propyl, η-butyl, isobutyl, sec "butyl or ter ^ butyl, also n-pentyl ,. n-hexyl, isohexyl or n-heptyl and especially methyl or ethyl. In aryl, cycloalkyl or heterocyclyl-lower alkyl, the lower alkyl radical is in particular methyl or ethyl, where the aryl, cycloalkyl or heterocyclyl radical has the abovementioned meaning,

The lower alkoxy is z _o B _e n-propoxy? n-butoxy, isobutoxy, sec-butoxy or _s-butoxy teifco and mainly methoxy or ethoxy ₀

ITiederalkylmercapto z is _o, n-propyl, n-butyl ,. Isobutyl, sec-butyl or tetrobutylmercap ^ to and primarily methylmercapto or ethylmercapto »

Haloalkylenedioxy is in particular methylenedioxy, ethylene or propylenedioxyo

Halogen is fluorine or bromine, but preferably Ghlor _e

In particular, lower alkanoyl is propionyl or butyryl, but primarily acetyl,

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The novel compounds prepared according to the invention may be in the form of mixtures of isomers or pure isomers. «

Bridge members in the above definitions are in particular o (/ _r Qr-dianiino-lower alkanes, IT-lower alkyl-dicarboxylic acids na, door-independent gv -amino-lower alkanecarboxylic acids * ·: ·: · - · '

In particular, the invention relates to the novel antigen derivatives described in the examples *

The novel antigenic derivatives prepared according to the invention are novel or improved known vaccines and are used for novel vaccination processes or for simplifying conventional vaccination processes (in that Z ₀ B _{0 can} reduce the number of inoculations necessary to maintain protection over longer periods of time) "

According to the invention, in particular, new antigen derivatives are prepared which contain antigen as ingredients of vaccines against parasites, bacteria, viruses, tumor cells, physiological endogenous constituents, their modified forms or subunits thereof, optionally covalently bonded to muramyl peptides of the formula II via bridge members R ^ _$ R ₀₉ R is optionally substituted by hydroxy or lower alkoxy Hiederalkyl or optionally substituted by hydroxyl, Hie mean ₁ Rg and R "is hydrogen ₉ X is carbonyl and R ₂ of the alkoxy., lower alkyl or halogen substituted phenyl, and R-Qt K-Q9 ^ io ^s "^ ^11? ^ 12 ^ ¹¹ ^ ^" 13 ^ ^e ° ^ ^s defined besitzeiie.

According to the invention, in particular new antigenic derivatives are produced, the antigens being used as ingredients of vaccines

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Parasites, - Bacteria »Viruses, tumor cells, physiological endogenous components, their modified forms or subunits thereof, optionally covalently bound via bridging moieties to muramyl peptides of the formula II, in which R 1, R 2, R 9 and R" Y hydrogen, X Carbonyl, R ₂ optionally substituted by hydroxy or lower alkoxy-substituted lower alkyl or optionally hydroxy, lower alkoxy, lower alkyl or halogen-substituted phenyl and R ~ methyl and Rgs Rq, R-in »^ 11» ^ 12 ¹ ^ "^ 13 ^ ^e ° ^ ^s given importance have ₉

According to the invention, primarily novel antigen derivatives are prepared which contain covalently bound antigens as ingredients of vaccines against parasites, bacteria, viruses or gymnocells, physiological endogenous components, their modified forms or subunits thereof, optionally via bridge members, to muramyl peptides of formula II, wherein R ^, R., Rg and R ^ - is hydrogen, X is carbonyl, R ₂ is optionally substituted by hydroxy or methoxy-substituted ITiederalkyl or optionally substituted by hydroxyl, methoxy, methyl, ethyl or halogen, R, is hydrogen or methyl, Rr and Rq V / on Hydrogen, R _Q Mederalkyl _s Mederalkylmercapto ~ niedera3.kyl, Hy droxynie the alkyl, benzyl, p-hydroxybenzyl or phenyl, and R ^ q "R * ^ and R ^ ₂ carboxyl, Carboniederalkoxy, or carbamoyl, and R ^. also mean hydrogen "

According to the invention, in particular new antigen derivatives are prepared which contain antigens as ingredients of vaccines against parasites, bacteria, viruses, tumor cells, physiological endogenous components, their modified forms or subunits thereof, optionally covalently bound via bridge members to muramyl peptides of formula II, wherein R ₁ , R ,, Rg and R ^ are hydrogen, X is carbonyl, R _{2 is} optionally lower hydroxy or methoxy substituted lower alkyl

-24- Berlin, d _{o e} 12 7 · 1979

AP A 61 Κ / 211 204. 55 084 18

or phenyl optionally substituted by hydroxy, methoxy, methyl, ethyl or halogen; Ru and Rq are hydrogen or methyl; R _{Q is} methyl, ethyl-n-propyl, -i-prepyl, 2-methylpropyl, methylmercaptomethyl, hydroxymethyl, hydroxyethyl, phenyl, benzyl or p-Hydroxybensyl and R _0, R ^ and R ^ ₂ is carboxy, carboxy or carbamoyl, R-- also mean hydrogen *

The invention also provides novel antigen derivatives, the antigens are produced, 'as ingredients of vaccines ^ against bacteria viruses, ^f Ilumorzellen _§ physiological body's own constituents, their moö.ifizierten molds or subunits thereof _f. where appropriate bridge Glieders of muramyl peptides of 3? Ormel II! covalently bonded _form? wherein R, R, R ^ and R- _{o are} hydrogen, X is carbonyl, R ^ and Rg together are propylene or butylene and R ₀ , R ^ j, Rg, R ^ q, R ^ and R- ₂ ö.ie have the meaning mentioned above »

According to the invention novel antigen derivatives are prepared such _f that antigen the ingredient of a vaccine against malaria, cholera ^ (Dyphus, meningitis, rheumatic Pieber as a consequence of streptococcal infections, influenza, rabies _s foot and Klauensetichej as well as a vaccine for the prophylaxis and therapy von.Tumorkranlcheiten, for inducing immunity against components of the port planting system, for desensitizing or inducing specific immune tolerances against allergies, for restoring tolerance to endogenous tissue constituent parts and circulating molecules

Furthermore, novel antigen derivatives are prepared in which antigens contain components of Malaria merozoites, type-specific meningococcal polysaccharides JAj B or Streptococcus C _s M proteins, Influenaavirushaemagglutinins, auto-immune tumor cells or tumor cell membrane components, partial sequences

'. "25

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55 084 18

of human chorionic gonadotropin, grass pollen extracts, antispecific T-cell lymphoblasts and their receptors for antigens, or antigen-specific immunoglobulins.

The pharmaceutical preparations according to the invention are those for enteral, such as oral or rectal, as well as parenteral administration to warm-blooded animals, the pharmacologically active ingredient alone or together with a pharmaceutically Applicable carrier material contained

The new pharmaceutical preparations contain from about 10% to about 95%? preferably from about 20% to about 90% of the active ingredient. Pharmaceutical preparations according to the invention in dosage unit form, such as dragées, tablets, capsules, suppositories or ampoules,

The pharmaceutical preparations are prepared in a manner known per se, ζ, B. by means of conventional mixing, granulating, confectioning, dissolving or lyophilising "Thus, one can obtain pharmaceutical preparations for oral administration by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and the mixture or granulate _{0 9} if desirable or necessary after addition of suitable excipients, processed into tablets or dragee cores

Suitable carriers are, in particular, fillers, such as sugars, s.B «, lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogan phosphate, also binders, such as

- 26 - Berlin, a.12.7.ϊ979 AP A 61 K / 211 204 55 084 18

Starch pastes using, _e B _e, corn, wheat, rice or potato starch, gelatin, tragacanth, .Methylcellulose j hydroxypropyl methylcellulose, latriumcarboxymethylcellulose, and / or polyvinylpyrrolidone, and / or, if desired, disintegrators, such as the above-mentioned Starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone, "agar, -alginic acid or a salt thereof, such as sodium alginate _" auxiliaries are primarily flow, lubricating, lubricating, zirconic, talc, stearic acid or salts thereof, such as magnesium or Calciuuistearat, and / or polyethylene glycols Dragee cores are provided with suitable, optionally gastric juice-resistant coatings, where u u ₆ a <, concentrated sugar solutions., Which givenJalt Arab gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide , Lacquer solutions in suitable organic solvents or solvent mixtures or _s for the preparation of Mag acid-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethylcellulose phthalate, used * The tablets or dragee coatings may contain dyes or pigments, Z ₀ B ₀ for the identification or for the labeling of various active ingredients »

Further pharmaceutical preparations which can be used orally are capsules made of gelatin _P and soft closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. O The capsules may contain the active ingredient in the form of granules _? Z ₀ B ₀ in admixture with fillers, such as lactose, binders, such as starches and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers, contained in soft capsules.The active ingredient is preferably in suitable liquids, \ fatty oils _? paraffin oil or

- 27 - Berlin, d _e 7.12.1979 AP A 61 K / 211 204 55 18 Ö84

liquid polyethylene glycols, dissolved or suspended, wherein stabilizers may also be added.

For parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, Z ₆ B _{0 of} a water-soluble salt, further suspensions of Y / irkstoffs, such as corresponding oily injection suspensions, wherein suitable liophile solvent or vehicle, such as fatty oils, Z ₀ B ₉ sesame oil, or synthetic fatty acid ester, for example ethyl oleate or triglycerides, _e B _o, used, or aqueous injection suspensions that contain viscosity-increasing substances, z * B _e contain sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally stabilizers "

A preferred route of administration is in a solution or suspension of the antigen new derivatives thereof, preferably up to 10 weight percent _0, carboxymethylcellulose. _f

The invention also includes the use of the new antigenic derivatives, as pharmacologically active substances, in particular as immunizing agents, preferably in the form of pharmaceutical preparations. "The dosage of the active ingredient depends on the warm-blooded species, the body weight and age and the individual condition, as well as on the mode of administration ,

Here, the new vaccines are applied in accordance with the recognized and known in known vaccination methods dosages in weight or international units, for example, one gives lymphoblast-containing antigenic derivatives in one

f> 1 π

Amount per injection 10 "-10 cell organisms, at intervals of 2 - S weeks 1-6 times * It should be preferably per mg protein 5-200'micro-g muramyl peptides contained.

-28-

28 - Berlin, _ά ο 12 _o 7. AP-1979 A 61 K / 211 204 55 084 18

Preferably, for immunization with soluble compounds, the appropriate amount of antigenic derivative in a rebate solution (BSS) consisting of O ₅ 14 g calcium chloride, 8.0 g sodium chloride, O ₉ 2 g magnesium sulfate ».7HgO, O ₉ 2 g magnesium chloride, 6HO _? o _s 6 g of potassium hydrogen phosphate and 0.24 g of disodium hydrogen phosphate * 2HpO per 1 liter of water · Palls a depot effect is sought, (z ₀ B _e in local, - intradermal or intramolekularer application) can the so-dissolved antigen derivative nor carboxymethylcellulose (final concentration preferably 5% ) are added

Light-soluble macromolecular antigen derivatives are preferably applied as a suspension in BSS and carboxymethyl cellulose as stabilizer (final concentration preferably 5%). In this case, the mixture cooled to ice is preferably subjected to ultrasound treatment in order to produce a stable suspension

Antigen derivatives with cells are primarily produced in a cell culture medium which is particularly suitable for the particular cell type (zeB _e for lymphocytes EAGLE'S high amino acid medium) [? G. Click et al., Cell Immunol vol. 3 ₉ P * 264-276 (1972) J applied «

The novel compounds produced according to the invention bring a pronounced increase in the immune response to the antigen _f, in particular cell-mediated immunity, under clinically acceptable conditions of administration, as can be demonstrated by the experimental arrangements described below ₀ .

1o .Potenzation of cell-mediated immunity in vivo 5 Increase of late-type hypersensitivity to bovines

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Serum albumin (BSA) and sheep erythrocytes (SRBG) in guinea pigs

Pirbright guinea pigs are immunized on day 0 with 1 mg BSA or with 1 mg SRBC ghosts (SRBCG) in complete Freund's adjuvant by injection of 0 _ö 1 ml each of an antigen-adjuvant mixture into both hind paws. 3 weeks later, skin reactions are induced by intracutaneous injection of 100 / μg BSA or * 100 / μg SRBCG in 0.1 ml buffered physiological saline and quantified on the basis of the reaction volume calculated 24 hours after the erythema patch and skin thickness increase. delayed-type reaction) observed antigen-specific increase of the reaction volume is considered as a measure of cell-mediated immunity ο BSA and SRBCG are weak immunogens (alone or in a water-oil Eniulsion with incomplete Freund ¹ schem adjuvant 10 parts BSA solution resp _e SRBCG Suspension in 0 <S% HaCl mixed with 8 _e 5 parts Bayol P and 1 * 5 parts ArIacel A) to induce a delayed-type reaction, but must be added to the mycobacteria for complete immunization in complete adjuvant (5 mg killed and lyophilized M ₀ butyricum per 10 ml Bayol F / Arlacel A) can be applied «

In place of mycobacteria, the new compounds containing as antigen BSA (1 mg BSA, 60 pg LiDP per animal) or as antigen SRBCG (1 mg SRBCG, 25 / μg MDP per animal) either as an antigen-oil mixture or in carboxymethyl cellulose ( CMC) suspended. The new compounds induce, in the absence of mycobacteria in the described experimental arrangement, delayed-type reactions _o

Significant potentiation of late - type reactivity against

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BSA and against SRBCG can also be achieved, that the new compounds not ULTRASONIC in inkomplettes''Freund. ¹ Adjuvant but be applied Suspended in CMC «. In this case, an equal amount of free muramyl peptide, which was added to the CMC mixture, was much less active than the _{: "} new" / irksusbstanz ₀ Thus, it is shown that the to induce cell-mediated immunity even to a soluble protein antigen when administered with body-friendly adjuncts. "

2o potentiation of cell-mediated immunity in vivo: increase in late-type hypersensitivity to BSA 3RBCG in the mouse.

Male MAG mice are immunized with graded doses of non-muramyl peptide-conjugated antigens (BSA agarose or SRBGG) or Muramyl peptide-conjugated antigens (BSA agarose or SRBCG) on day 0. The BSA agarose preparations are placed in a Dosage from 0 ₀ 1 to 100 / μg (equivalent in the new compounds with muramyl peptides of an active substance dose of O _c , OO29 ~ 6 / ug per animal) in a volume of 0 ^ 2 ml buffered saline administered subcutaneously "The SRBCG preparations at a dose of 0 _e 01 - 3 mg (corresponds to intravenitoneally in the volume of 0.5'ml buffered physiological saline intraperitoneally or 0 * 05 ml intradermally (equivalent to the new compounds with muramyl peptides of an active substance dose of O _c 25-75 / day per animal) resp _{e distributed} in 3 foot paws ₀

4 to 20 days later, delayed-type reactions are induced by injection of 100 μg of BSA or 10 ⁸ SRBC in 20 μl of buffered physiological

I! 204 ^{"3 / t} ~ · Berlin, d. 12.07.1979

AP A 61 Κ / 21Ϊ 204 55 084 18

gice saline was induced in the left hind footpad and quantified on the basis of 24- and 48 h post-paw swelling response The observed antigen-specific increase in foot paw volume is considered a measure of cell-mediated immunity _β

From day 14 after immunization with BSA-agarose-MDP-compounds pronounced delayed-type reactions occur even at very low dosage (0 _o 1 / μg, corresponds to O ₀ 006 / μg of active substance). In contrast, free BSA agarose is not able to sensitize for late-type reactions. Similarly, SRBCG ~ MDP ~ compounds, especially after intradermal administration, are capable of inducing late-type hypersensitivity that is significantly more pronounced than that obtained after sensitization with SRBGG not associated with muramyl peptide.

This will also shown _s that the new compounds are able to significantly increase cellular immunity.

3 · Potentiation of humoral immunity in vivo: increase in antibody prodriction against BSA in the mouse.

NIiRI mice are immunized by intraperitoneal injection of 0.1 to 100 / μg BSA coupled with muramyl peptides (0.0014 to 6.0 / μg drug) on day 0, 10, 17 and 28 days later serum samples are taken and their content of anti-BSA antibodies is passive examined Haemagglutinationstechnik "In the dose used is free BSA subimmunogen for the recipient animals, that is _0, it can trigger only a very slight production of antibodies or not. The association of BSA with a muramyl peptide

Berlin, d.12 * 7.1979 AP A 61 K / 211 204 55 084 18

allows a 2-3 fold increase in antibody titer in serum (titer sum of logp titer differences on three batches). "It is also noteworthy that the new compounds, which were also coupled to agarose as carriers, after intraperitoneal or subcutaneous Administration are even more immunogenic ₀

On the basis of the described experiments, it is shown that the novel compounds according to the invention are also capable of significantly increasing humoral immunity *

Embodiment;

The following examples illustrate the invention described above; However, they should not limit their scope in any way, temperatures are given in Celsius degrees. »

211 204 - & ~

example 1

To a solution of 1 g bovine serum albumin in 100 ml of a 0.1 M sodium bicarbonate-0.5 M saline solution is added 500 mg with agitation ---

2-Acetamido-3-0 - ^ [LI- (D 1 -carbamoyl-S-succinimidooxycarbonyl-propyl) -carbamoyl-ethyl] -carbamoyl-methyl} -2-deoxy-D-glucose. The solution is stirred for 4 hours at room temperature and then sterile filtered (MF Milipore, 0.45 pm filter). The conjugated bovine serum albumin is separated in the dialfiltration process by an Amikon UM-10 filter of low molecular weight reaction products or salts and freeze-dried.

The quantitative determination of the bound to the bovine serum albumin muramyl peptide is carried out with the Morgan-Elson reaction after the modification of J.M. Ghuysen et al [in "Methods in Enzymology" j8, (1966) 629]. On average, 60 μg of the muramyl peptide is found in 1 mg of bovine serum albumin compound.

  The succinimido ester used as the starting material can be e.g. produce as follows;

1 mmol of 2-acetamido-3-0 - ^ [LI- (DI-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-ceoxy-D-glucose, 1 mmol of dicyclohexylcarbodiimide and 1.1 mmol of N-hydroxysuccinimide are dissolved in 3 ml of absolute dimethylformamide and stirred in a closed vessel with exclusion of water for 20 hours. The precipitated dicyclohexylurea is separated, the solvent evaporated under high vacuum and the residue treated with ether, then filtered off with suction and dried. The succinimidooxyester thus obtained may be used with exclusion of moisture, e.g. in nitrogen ampoule.

Example 2

Condensation of the antigenic derivative obtained in Example 1 to activated agarose; it uses a commercially available agarose derivative of BIO-RAD, the Affi-gel 10. It contains on an agarose gerlist, ether spacer chains of N-alkyl succinamides, which are esterified with N-hydroxysuccin5.mid. · -.

Dissolve 120 mg of the obtained according to Example 1 of bovine serum albumin derivative in 12.5 ml of 0.1 M phosphate buffer, pH 7.3, at 4 ⁰ C. 500 mg Affi-Gel 10 are then suspended in the solution by shaking and 4 hours at 4 ° C onward. The remaining active ester groups are reacted by treatment with a 1 M ethanolamine.HCl-O, 1 M phosphate buffer solution (pH 7.3) for 30 minutes. The gel is then poured into a column and washed first with 200 ml of 0.1 M phosphate buffer-1 M saline (pH 7.3), then with 20 ml of physiological saline.

The determination of bovine serum albumin-muramyl peptide compounds fused to Affi gel 10 is carried out by the quantitative analysis of representative bovine serum albumin amino acids in total hydrolysates of defined gel aliquots. On average, 9-10 mg of the bovine serum albumin-muramyl peptide derivative is bound to 1 ml of swollen affi-gel 10,

Example 3

Sheep erythrocyte membranes are obtained from fresh sheep blood by the method of Dodge, JI et al., (Arch. Biochem., Biophys., 100, (1963) p., 114-180) to a suspension of 500 mg of sheep erythrocyte membranes in 50 ml of 0.1 M sodium bicarbonate-0.1 M saline

21 \ 204

With stirring, 400 mg of 2-acetamido-3-0- [L 1 - (D -carbamoyl-3-succinimidooxycarbonyl-propyl) -carbamoyl-ethyl] -camoyl-methyl-2-deoxy-D-glucose are added, and the mixture Stirred for 4 hours at room temperature. Thereafter, the erythrocyte membrane conjugate is sedimented by centrifugation at 90,000 g and 4 ° G for one hour. The sediment is washed three times, each by resuspension and ultracentrifugation, with phosphate buffered saline and once with distilled water. The washed erythrocyte membrane conjugate is suspended in 100 ml of distilled water and lyophilized. ·

The quantitative determination of bound to the sheep erythrocytes Muramyldipeptid done with the Morgan-Elson reaction and gives 25 pg muramyl dipeptide per 1 mg erythrocyte membrane.

Example 4

100 mg of Group C polysaccharide of Neisseria meningitidis and 110 mg (0.2 mmol) of 2-acetamido-3-0-Ll- (D-1-carbamoyl-3-N-aminoethyl-carbamoyl-propyl) -carbamoyl-ethyl) -carbamoyl -methyl ^ -2-deoxy-D-glucose-HCl are dissolved in 10 ml of distilled water, the pH of the solution is adjusted to 5 with dilute hydrochloric acid.

19.2 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.HCl are added to the solution with stirring. The mixture is stirred for 1 hour at room temperature, the pH is kept at 5 with addition of dilute sodium hydroxide solution, then 5 ml of 2 M sodium acetate buffer solution, pH 5, are added and stirring is continued for 30 minutes. Subsequently, the pH is adjusted to 7 with sodium hydroxide solution. The solution is sterile filtered and dialyzed at 4 ° C against distilled water and then freeze-dried.

The quantitative determination of Desmethylmuramyldipeptid gekipelt to the C polysaccharide is carried out as described in Example 1 with the Morgan-Elson reaction and yields 80 ug Desraethylmuramyldipeptid per 1 mg of polysaccharide.

The 2-acetamino-3-O-f [LI- (D-1-carbamoyl-3-N-aminoethyl-carbamoyl-propyl) -carbamoyl-ethyl] -methyl] -2-deoxy-D-glucose hydrochloride used can be, for example, as follows:

1 mmol of 2-acetamido-3-O-C [LI- (Dl-carbamoyl-3-carboxy-propylcarbamoyl-ethyl-carbamoyl-methyl'f-^ -deoxy-D-glucose and 2 mmol of N-ethyl- N ^f - (3-dimethyl-aminopropyl) carbodiimide.HCl are dissolved in 10 ml of water and the pH is adjusted to pH 5.0 with hydrochloric acid, then a solution of 5 mmol of ethylenediamine dihydrochloride in 10 ml of water is added The mixture is applied to a weakly acid cation exchange column Amberlite CG 50 II, 2j5 χ 45 cm and a linear gradient of 0.05 M pyridine acetate, pH 6 (300 ml) to 0.5 M pyridine acetate pH 3.7 (300 ml) eluted: The resulting 2-acetamino-3-Ο-ί (LI- (Dl-carbamoyl-SN-aminoethyl-carbamoyl-propyl) -carbarnoyl-ethyl) -carbamoyl-methylf-2 fractions containing deoxy-D-glucose acetate - the fractions are assayed and characterized by isinhydrin or high voltage electrophoresis - are lyophilized and converted to the hydrochloride form is carried out as follows: the lyophilizate is dissolved in 6 ml of 0.2 N HCl and chromatography, ert on a Bio-Gel P2 column, 2.5 χ 90 cm, with water as eluent. The 2 ~ -acetamino-3-O-yl-1- (1-carbamoyl-3-N-aminoethyl-carbamoyl-propyl) -carbamoylethyl] -carbamoyl-methyl-2-deoxy-D-glucose hydrochloride-containing fractions are freeze-dried. The preparation is uniform in high voltage electrophoresis. In the

£ m II £ »% # fif.

Determination of constituents in total hydrolyzates, the molecular ratio is 1 Muramic acid: 1 L-alanine: 1 D-glutamic acid: 1 ethylenediamine found.

In an analogous manner, starting from corresponding muramyldipeptides, the corresponding β'-aminoethylamide is obtained. HCl compounds, namely:

2-acetamido-3-o4D-I- [L-I- (D-l-carbamoyl-3-N-aminoäthylcarbamoyl-propyl) carbamoyl-ethyl] carbamoyl-ethyl <-2-deoxy-D-glucose.HCl,

2-enoylamino-3-O-j D-I- [L-I- (D-1-carbamoyl-3-N-aminoethylcarbamoyl-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose.HCl,

2-Benzoylamino-3-O-H LI- (DI-carbaem 1-3-N-amino-ethyl-carbamoyl-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose.HCl, ·

2-Ace tamino-3-0- < [L- 1- (D ₁ -IN-carbamoyl-methyl-carbamoyl-3-N-aminoethyl-carbamoyl-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D -glucose.HCl.

2-Benzoylamino-3-0-} [L-1- (D 1-1-carbamoyl-S-N-aminoethyl-carbamoyl-propyl) -carbamoyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose.HCl,

2-propionylamino-3-O-y [L-1- (C 1- carbamoyl-S-N-aminoethylcarbamoyl-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose.HCl,

2-Acetylamino-3-0-1 [JL-1- (p-1-carbamoyl-3-N-amino-ethyl-carbamoyl-propyl) -carbamoyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose. HCl,

2-Acetylamino-3-0-f [LI- (Dl-carbamoyl-SN-aminoethyl-carbamoyl-propyl) -carbamoyl-2-hydroxyethyl] -carbamoyl-met hy Ij 2-deoxy-D-glucose.HCl,;

2-Propionylamino-3-0 - [[L 1 - (D 1 (or 3) -carboxy-3 (or 1) -N-aminoethyl-carbamoyl-propyl) -carbamoyl-ethyl] -carbamoyl-methyl] -2-deoxy- D-glucose.HCl,

2-Benzoylamino-3-0-4 [LI (DlN-carbamoyl-methyl-carbamoyl-3-N-aminoethyl-carbamoyl-propyl) -carbamoyl-ethyl] -carbainoyl-methyl-Z-deoxy-D-gl ' ucose.HCl,: 2-Benzoylamino-3-0-3L-1- (D-! -carboxy-3-N-amino-ethyl-carbamoyl-propyl) -carbamoyl-ethyl) -carbamoylmethyl-2-deoxy-D-glucose .HCl, "...

2-Acetamino-3-0-i [LI- (DI-carbamoyl-SN-amino-ethyl-carba-r-molyX-propyl) -carbamoyl-2 '-methyl-propyl-1-carbamoyl-methyl] -2-deoxy-D-glucose. HCl,

2-Acetamino-3-0-> Dl- [LI- (jD-1-carbamoyl-3- (1-N-amino-ethylcarbamoyl) -ethyl-carbamoyl-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D .-glucose .HCl, 2-Acetamino-3 ™ 0-1 [LI- (Dl-carboxy-3-N-aminoethyl-carbamoyl-propyl) -carbamoyl-2 '-methyl-propyl-3-carbamoyl-methyl-2-deoxy -D-glucose.HCl _s

2 ~ acetamido-3-0 ~ HL-I- (D-I-carbamoyl-3-N-aminoethyl-carbamoyl-propyl) -carbamoyl-N, N-tetramethylene] carbamoyl-methyl | 2-deoxy-D-glucose .HCl, 2-Aciethano-3-0-4 [L * 1- (_D-1-carbamoyl-3-N-aminoethylcarbamoyl-propyl) -carbamoyl-ethyl] -N-methyl-carbamoyl-methylC-

2-deoxy-D-glucose.HCl or

2-benzoylamino-3- · 0- \ [LI- (Dl-carbamoyl-SN-aininoäthyl-carbamoyl-propyl) ^{carbamoyl-2-methyl-1-carbamoyl-propylJ} methylf-2-deoxy-D-glucose.HCl.

These compounds are condensed as described above with Group C polysaccharide of Neisseria meningitidis. ,

Example 5

Immediately after extraction, merozoites of the malaria pathogen Plasmodium knowlesi - the total yield from the blood of an infected rhesus monkey [method of obtaining Merozöiten: see GH Mitchel et al ... (1975), Immunology, 29, 397] _r in one

2 1 t 2C

Solution of 100 mg (0.17 mmol) of 2-acetamido-3-0- £ [L 1 - (ΟΙ-car bamoy 1-3-sue eimidooxy-car bony 1-propyl) -carbamoylethyl] -carbamoyl-methyl ^ - 2-deoxy-D-glucose in 15 ml of physiological buffer solution, pH 7.2, suspended. The suspension is incubated for one hour at 37 ⁰ C. Thereafter, the conjugates are sedimented by centrifugation. The sediment is washed by resuspending in physiological buffer solution and centrifuging again. The washed merozoite conjugates are suspended according to GH MLtchel (ref. See above) in 107% autologous rhesus monkey serum and lyophilized.

Quantitative determination of coupled to the Meroziten muramyl done with the Morgan-Elson reaction and yields 40-60} ig muramyl · * 'dipeptide per 1 mg merozoites.

Example 6

In a solution of 200 mg (0.34 mmol) of 2-acetone. amino-3-Ο-ί (LI- (Dl-carbamoyl-3-succinimidooxycarbonylpropyl) -carbamoyl-ethyl) -carbamoyl-methyl-3-2-deoxy-D-glucose in 20 ml of phosphate-buffered saline, pH 7, 2, T 10 lymphoblasts are suspended from CBA / J mice. (The T lymphoblasts are transfected into a mixed lymphocyte culture against C57BL / 6 mouse stimulator cells according to LC Anderson et al., (1977), The Journal of Experimental Medicine , 146, 1124.) The suspension is incubated for 90 minutes at room temperature, after which the lymphoblast conjugates are sedimented by centrifugation and washed by resuspending in phosphate buffered saline and centrifuging again.

_ HO-

The quantitative determination of muramyl dipeptide coupled to the T lymphoblasts is accomplished by the Morgan-Elson reaction (see Example 1) yielding 60-70 μg muramyl dipeptide per 10 T lymphoblasts.

Example 7

In a manner analogous to the above examples bovine seria albumin is coupled with

  2-acetamido-3-O-f D-I [L-I- [D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose, '.

2-Benzoylamino-3-O-1,3-L ~ [JL-I (ID-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-V-2-deoxy-α- _f -β- D-glucose _f

2-benzoylamino-3-0-i | L-l- (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-äthyll-carbamoyl-methyls-2-deoxya, ß-D »glucose,

2-Acetam.ido-3-o4rL ~ l ™ (D-1 ~ carbamoyl! Methyl-car-

c - - ^

bamoyl-3-carboxypropyl) -carbamoylethyl] -carbamoylmethylj-2-deoxy-D-glucose _s . ,

2-Benzamido-2-deoxy-3-0 - [[L-1- (D-1-carbamoyl-3-carboxypropyl) -carbamoyl-propyl] -carbamoylmethyl-D-glucopyranose.

3-0 - ^ [L-I- (D ~ l ~ carbamoyl-3-carboxypropyl) -carbamoylethyl] -carbamoylmethyl-2-deoxy-2-ρropionamido-D-glucose and

2-Acetamido-3-0- £ JL-1- (D-1-carbamoyl-3-carboxypropyl) -carbamoylpropyl] -carbamoylmethyl "<- 2-deoxy-D-glucose.

2-Acetamino-3-0 - / (I ₁ -I- (Dl-carbamyd-S-carboxypropyl) -carbamoyl-2-hydroxyethyl) -carbamoyl-methyl-2-deoxy-D-glucose. 2-propionylamino-3-0 -} [LI- (DI, 3-dicarboxy-propyl) -carbamoyläthyl] -carbamoylmethyif-2-deoxy-D-glucose. 2-benzoylamino-3-0- ) [LI- (DlN-carbamoylmethyl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose.

2-Acetamino-3-o4 D-I- (L-1-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '-methyl-propyl] -carbaraoyl-ethyl-2-desoxy-D-glucose. 2-benzoylamino-3-O-l [L-I- (D-I, 3-dicarboxy-propyl) -carbamoyläthyl) -carbamoylmethy1? -2-deoxy-D-glucose.

2-acetamido-3-0-i [L_-l- (£ -l-carbamoyl "3-carboxy-propyl) carbamoyl-2'-methyl-propyl] carbamoylmethyl ^ -2-deoxy-D-glucose.

 2-Acetamino-3-0-Sp_-1- [1, -1- (DI-carbamoyl 1-3- (L-1-carboxy-methyl) -carbamoyl-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy- D-glucose.

2-acetamido-3-0-ί [L-I- (D-I, 3-dicarboxy-propyl) carbamoyl-2'-methyl-propyl1 "carbamoyl-niethylj-2-deoxy-D-glucose.

2-acetamino, -3-0-HL-l- (D-l-carbamoyl-3-carboxy-propyl) -carbamoy1-N, N-tetramethy1en] -carbamoy1-tnethyit-2-deoxy-D-glucose. _. ·. 2-Acetamino-3-0-J [L-1- (D-1-carbarnoyl-3-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-methyl] -2-deoxy-D-glucose

2-Ben2oylamino-3-0-f [L-I- (D-l-carbamoyl-3-carboxy-propyl) -

carbamoyl-2'-methyl-propyl] -carbamoyl-methyl-1-J-2-deoxy-D-glucose.

Example 8

In a manner analogous to Example 3, sheep erythrocyte membranes coupled with 2-acetamino-3-O-jp_-1- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoy1-ethyl] -carbamoyl-ethylC-2-desoxy are obtained D-glucose.

2 = benzoylamino-3-0-jD ~ l- [L-I- (D-l-carbamoyl-3-carboxy-

* Lr 'S

propyl) carbamoyl-ethyl] carbamoyl-äthylC-2-deoxy-D-Glu

2-benzoylamino-3-0 - ^ [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoy1-athy1] -carbamoylmethylC-2-deoxy-D-glucose.

2-Benzoylamiho-3-0-I [L_-l- (D-1,3-dicarboxy-propyl) -carbamoyläthyl) -carbamoylmethylC-2-deoxy-D-glucose.

2-propionyl amino-3-G-Y [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbarnoyl-ethyl-carbamoyl-methyl-2-deoxy-D-glucose.

2-Acetamino-3-0- [L-1- (D-1-N-carbamoylmethylcarbamo3-1, 3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-desoxy-D-glucose.

2-benzoylamino-3-0-4 [L-I- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] carbamoylmethyl | -2-deoxy-D-glucose.

2-Acetylamino-3-0-S [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose.

2 ~ acetamido-3-0) - [L-l- (D-l-carbamoyl ~ 3-carboxypropyl) carbamoyl-2-hydroxyethyl] -carbamoyImethylf-2-deoxy »D-glucose.

f "^

2-propionylamino-l-3-0 [L-I- (D_-l, 3-dicarboxy-propyl) -carbamoyläthyl] -carbamoylmethyif-2-deoxy-D-glucose. 2-Bezuzo-Alumina-S-O- * [L-I- (p-1-N-carbamoylmethyl-carbamoyl-3-carboxy-propyl) -carbamoy1-ethyl] -carbamoy-1-methyl-2-desoxy-D-glucose.

2-acetamido-3-0 ~ l [L-I - (^ - l-carbamoyl-S-carboxy-propyl) carbamoyl-2'-methyl-propyl] -carbamoylmethylC-2-deoxy-D-glucose. c.

2-acetamido-3-0-SD-l "[L-I- (D-l-carbamoyl-3- (L-1-carboxyethyl) carbamoyl-propyl) -carbamoy1äthy1] -carbamoy1äthy1V-2-deoxy-D-glucose.

2-Acetamino-3-0-l [LI- (D-! _S 3-dicarboxy-propyl) -carbamoy1-. 2 ^f -methyl-propyl] -carbamoyl-methyll-2-deoxy-D-glucose. 2-Benzoylamino <-3-0-ML-1- (di-carbamoyl-S-carboxy-propyl) -carbamoyl-2'- methyl-propyl] carbamoyl-methylJ-2-DeSOx ^^ - D-glucose. ,

2 ί 1 204 - · »- '-' '. '

2-Acetamino-3-0-jJ [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-tert-triethyl] -carbamoy1-methyl-2-deoxy-D-glucose.

2-Acetamino-3-0-V [L-1- (D-1-carbamoyl-O-carboxy-propyl) -carbamoyl-ethyl] -N-methyl-carbamoyl-methyl-2-desoxy-D-glucono

2 ~ ~ acetamido 3-0- | D ^ -I- [L-l-carbamoyl-3-carboxy-propyl) carbamoyl-2'-methyl-propyl] -carbamoyläthyl | -2-deoxy-D-glucose.

Example 9.

In a manner analogous to Example 5 merozoites of the malaria pathogen Plasmodium knowlesi coupled with

2-Acetamino-3-0- £ I) -l- [L-I- (iD-1-carbaraoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose. 2-Benzoylamino-3-O-Jl-L- [L-l- (JD-1-carbanioyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose.

2-ßenzoylamino-3-0- ^ [L.-1- (p_-l-carbamoyl-3 .- <: arboxy "propyl) carbamoyl-ethyl] -2 -carbamoylmethy ll-deoxy-D-glucose, 2-BGnZOyIaUiInO -SOJ [LI- (di, 3-dicarboxy-propyl) -carbamoylethyl) -carbamoylmethylC-2-deoxy-D-glucose. 2-propionylamino-3-0- [L-1- (di-carbamoyl) -3-carboxy -propyl) -carbamoylethyl] -carbamoy! methylC-2-deoxy-D-glucose.

f «j

2-acetamido-3-0-i [L-l- (D-l-N-carbamoylmethylcarbamoyl-3-

* L y

carboxy-propyl) -carbamoyläthylj-carbamoylmethyK-2-deoxy-D-glucose.

2-benzoylamino-3-0-5 [L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -carbamoylmethyli-2-deoxy-D-glucose.

2-Acetylamino-3-0-S [L-1- (D-I-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose. ·

2-acetamido-3-0 '/ [L-I- (D-l-carbamoyl-3-carb © xypropyl) carbamoyl-2-hydroxyethyl] -carbamoylmethyIj-2-deoxy-D-glucose.

2-propionylamino-O ~ 3-j [L-I- (D-I, 3-dicarboxy-propyl) -carbamoyläthyl] -carbamoylmethyIf-2-deoxy-D-giucose. 2-benzoylamino-3-0-? £ L-1 ~ (D-l-N-carbamoylmethyl-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] -carbamoyImethyl | -2-deoxy-D "glucose

2-Acetamino-3-O-i [L-1-> (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-2 ^! methyl-propyl] -carbamoyl'methylC-2-deoxy-D-

glucose.

2-Acetamino-3-o4D-1-iL-1-CD-1-carbamoyl-S- (L-1-carboxy-ethyl) -carbamoy1-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-1-yl-2-deoxy-D-glucose.

2-Ac.etamino-3-0-UL-I- (DI, 3-dicarboxy-propyl) -carbamoyl-2 ^{f-methyl-propyl)} -carbamoyl-methyl% -2-deoxy-D-glucose. 2-Benzoylamino-3-O-ML-1- (di-carbamoyl-3-carboxy-propyl) - 'carbamoyl-2'-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose * -

2-Acetamino-3-0- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-tetramethylene] -carbamoyl-methylr-2-deoxy-D-glucose.

C 2-Acetamino-3-0-f [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl-N-methyl-carbamoyl-methyl-2-deoxy-D-glu-.

2-acetamido-3-0- | DI-iL_-l-carbamoyl-3-carboxy-propyl) -carbamoyl-2 ¹ -methyl-propyl] -carbaraoylethyl | -2-desoxy-D-glucos-e.

Example 10

In a solution of 100 mg of 2 ~ acetate nino ~ 3-0- | DI- [L ₁ -I- "(D 1-1-carbamoyl-3-succinimidooxycarbonyl-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-Iv-2-deoxy-D-gl. Glucose in 10 ml of phosphate buffered saline , pH 7.2, "

O.

one suspends 10 mammal carcinoma cells from the dog. [The tumor cells are named after H.H. Sedlacek, H. Messmann and F.F .. · Seiler, Behring Inst.Mitt., No. 55, 349-355 (1974)

won]. The suspension is incubated for 90 minutes at room temperature. Thereafter, the tumor cell muramyl dipeptide conjugates are pelleted by centrifugation and washed by resuspension in phosphate buffered saline and centrifuged again.

Quantitative determination of muramyl dipeptide coupled to the tumor cells is accomplished by the Morgan-Elson reaction (see Example 1) yielding 60-80 μg muramyl dipeptide per 10 mammary carcinoma cells.

Example H.

In an analogous manner to Example 10 obtained Mamrnacarzinomzellen from the dog coupled with 2-acetamino ~ 3-0-jl) -l- [LI- (Dl-carbamoyl-B-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl | -2-deoxy-D-glucose.

2-Benzoylamino ~ 3-0-} D-I- [L-I- (D-1-carbamoyl-3-carboxy-

4- * ~ ~ \ propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-C-2-deoxy-D-glucono

2-Benzoylamino-3-0- ^ [L-I- (D-1-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoylmethyl-C-2-deoxy-D-glucose. 2-benzoylamino-3-0-f [L-I- (D-I, 3-dicarboxy-propyl) -carbamoyläthyl) -carbamoylmethyIC-2-deoxy-D-glucose. 2-Propionylamino-3-0-y [L-1- (D-I-carbamoyl-3-carboxy-propyl) -carbamoylethyl] -carbamoylmethyl-C-2-deoxy-D-glucose. 2-acetamido-3-0-l [L-I- (D-1-N-carbamoylmethylcarbamoyl-3-carboxy-propyl) -carbamoyläthyl] -carbamoylmethyls-2-deoxy-D-glucose.

2-benzoylamino-3-0-5 [L-I- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] -carbamoylmethyH-2-deoxy-D-glucose. a-acetylamino-S-O-SIL L-iD-l-carbamoyl-S-carboxy-propyl) -carbamoylpropyl] carbamoyl-methyM-2-deoxy-D-glucose. 2-acetamido-3-0-J [L-I- (D-l-carbamoyl-3-carboxypropy1) carbamoyl-2-hydroxyethyl] -carbamoylmethylJ-2-4esoxy-D-glucose,

2-propionylamino-3-0 -) [L-I- (D-I, 3-dicarboxy-propyl) -carbamoylethyl-carbamoyl] methyl. -2-deoxy-D-glucose. 2-Benzoylamino-3-O- [L-I- (D-1-N-carbamoylmethyl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl-carbamoylmethyl-2-de

 , <*

soxy-D-glucose.

2-Acetamino-3-0-4 [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-methylC-2-deoxy-D-glucose.

2-Acetamino-3-0-f [1-1- [L-I- (D-1-carbamoyl-3- (L-1-carboxyethyl) carbamoyl-propyl) -carbamoylethyl] -carbamoylethyl-2-deoxy-D-glucose.

^ LI- (DI, 3-dicärboxy-propyl) -carbamoyl-2 ^{r-methyl-propyl]} carbamoyl-methyl] - '2-deoxy-.D-glucose. 2-Benzoylamino-3-0-f [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-2'-methyl-propyl] rcarbaraoyl-methyl-2-deoxy-D-glucose «

2-acetamino-3-0 ~ Y [L-l- (D-l-carbarnoyl-S-carboxy-propyl) -carbamoyl-N, N-tetramethylene] carbamoyl-methyl t-2-deoxy-D-

glucose. '

2-acetamido-3-0 "| [L-I- (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-N-methyl-äthyll-carbamoyl-methylj-2-de9oxy-D-Glu

2-acetamido-3 ~ 04 Dl-IL-l-carbamoyl-B-carboxy-propyl) rcarbamoyl-2 ^{1 7} l ~ -meth3 propylj-carbamoyläthyl | -2-deoxy ~ D-glucose "

Example 12

To 10 ml of a suspension of foot-and-mouth disease culture vaccine rings in phosphate-buffered saline, 100 mg of 2-acetami-. No ~ 3-o4 [L-l- (D-l-carbamoyl-3-succinimido-oxy-carbonyl-p-propyl) -carbamoyl-kthyl-carbamoyl-methyl-2-desoxy-D-glucose was added. The suspension is shaken for 4 hours at 4 ° C. Thereafter, the virus-muramyl dipeptide conjugate are sterile-filtered by dialysis against water of low

21 1 204 - «- '

separated molecular reaction products and freeze-dried. The quantitative determination of muramyl dipeptide coupled to the viruses is carried out by the Morgan-Elson reaction (see Example 1).

Example 13

In a manner analogous to Example 12, foot-and-mouth habits vaccine coupled with 2-acetamino-3-0-Dl- (LI- (D 1 -l-carbamoyl-3-carboxy-propyl) -carbamoyl-fithyll-carbamoyl-ethyl) are obtained 2-benzoylamino-3-O- <p_ -l- [LI- (p_-1-carbamoyl 1-3-carboxypropyl) -carbamoyl-ethyl-carbamoyl-ethyl-2-) -deoxy-D-glucose. deoxy-D-glucose -

2-Benzoylamino-3-0-5 [L-I- (p_-1-carbamoyl-3-coloroxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose. 2-benzoylamino-3-0-5 [L-l- (D-I, 3-dicarboxy-propyl) -carbamoYläthyl) -carbamoylmethylC-2-deoxy-D-glucose.

2-propionylamino-3-0-5 [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyläthyl] -carbamoylmethylj-2-deoxy-D-glucose. 2 »acetamido-3-0-1 [L-I (D-1-N-carbamoyl! Methylcarbamoyl-3-carboxy-propyl ^ -carbainoylathylj-carbamoylmethyl? -2-deoxy-D-glucose.

2 ~ benzoylamino-3-0-4 [L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -carbamoylmethyK-2-deoxy-D-glucose. 2-acetylamino-3-0-S [L-l- (D-l! Carbamoyl-3-carboxy-propyl) -carbamoylpropyl] carbamoyl-methylC-2-deoxy-D-glucose.

2-acetamido-3-0-y [L-I- (D-l-carbamoyl-3-carboxypropyl) carbamoyl ~ 2-hydroxyethyl] carbamoylmethyl | -2-deoxy-D-glucose. 2-propionylamino-3-O-J [L-I- (p-1, 3-dicarboxy-propyl) -carba-

pyyp

moyläthylj-carbamoylmethylf-2-deoxy-D-glucose.

2-Benzoylamino-3-0- [ L 1-1- (D-1-N-carbamoylmethy1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl-carbamoylmethyl-2-deoxy-D-glucose.

2-Acetamino-3-0-l [L_-l- (£ -l-carbamoyl-3-carboxy-propyl) -carbamoyl-2- ^r- meth'yl-propyl] -carbamoylmethyl ^ -2-deoxy-D-

^ v

2-Acetamino-3-0- (p_-l- [L_-l- (Dl-carbamoyl-3- (L-1-carboxyethyl) -carbamoyl-propyl) -carbamoyl-methyl] -carbamoyl-ethyl-2-deoxy-D-glucose ,

2-acetamido-3-0- | [L-1 ~ (DI _f 3-dicarboxy-propyl) carbamoyl

2'-methyl-propyl) -carbamoyl-methyll-2 = -deoxy-D-glucose.

2-Benzoylamino-3-O-> (LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-2 ¹ -methyl-propyl] -carbamoyl-methylC-2-deoxy-D-

• 3 "

glucose. ·

2-Acetamino-3-0-J [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-tetramethylene] -carbamoyl-methyl-2-deoxy-D-glucose.

2-Acetamino-3-0-p [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -N-methyl-carbamoyl-methyl-2-deoxy-D-glucono

 2-Acetamino-3-0- | D-1 '[L-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoylethyl-2'-deoxy-D-glucose.

Example 14

In a manner analogous to Example 6, T-lymphoblasts of CBA / J mice are coupled with 2α-Ae.etamino-3-o4D-1- [L ₁ -I- (Dl-carbamoyl-O-carboxy-propyl) -carbamoyl-ethyl ] -carbamoyl-. ethyl-2-desoxy-D-glucose. 2-Benzoylamino-3-ί-ί D _- -I- [LI- (D 1 -l-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbainoyl-ethyl-2-desoxy-D-glucose,

2 * - 'B enzoylamino-3-0-J [L _- -I- (di-1-carbamoyl-1- (carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose. 2-Benzoylamino-3-0-5 [LI- (D-IjS-dicarboxy-propyl) -carbamoyl-ethyl) -carbamoylmethyl-2-desoxy-D-glucose. 2-propionylamino-3-0-πL-1- (DI-carbamoyl-3-carboxy-propyl) -carbamoyläthyl] -carbamoy! Methyl ^ -2-deoxy-D-glucose.

211 204 - · «-" ·

2-acetamido-3-0-1 [L-I- (D-l-N-carbamoylmethylcarbamoyl-3-carboxy-propyl) -carbamoyläthyl] carbamoylmethyl <-2-deoxy-D-glucose

 2-benzoylamino-3-0-4 [L-I- (D-1-carbamoyl-3-carboxy-propy1) -carbamoyl-propylj-carbamoylmethylc-2-deoxy-D-glucose.

2-acetylamino-3-0 -> [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoylpropyD-carbamoyl-methyll-2-deoxy-D-glucose.

CJ

2-acetamido-3-0 - / [L-I- (D-l-carbamoyl-3-carboxypropyl) -car "

bamoyl-2-hydroxyethyl] -carbamoy! methyls-2-deoxy-D-glucose.

2-propionylamino-3-0-J [L-l- (p_-l, 3-dicarboxy-propyl) -carbamoyläthylJ-carbamoylmethyIf-2-deoxy-D-glucose. 2-benzoylamino-3-0-J [L-I- (D-1-N-carbamoyImethyl-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] -carbamoylmethyIf-2-deoxy-D-glucose.

2-Acetamino-3-0-T [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-methyl-C-2-deoxy-D-glucose.

) _3_O-5l> -l- [1L-1- (p_-1-carbamoyl-3- (L-1-carboxy-)

ethyl) carbamoyl-propyl) -carbamoyläthyD-carbamoyläthylj-2-deoxy-D-glucose.

2-Acetamino-3-O-yl-Ll (Dl _t 3-dicarboxy-propyl) -carbanioyl-2'-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose. 2-Ben2oylamino-3-0 -> [LI- (Dl-carbamoyl-S-carboxy-propyl) carbamoyl-2'-methyl-propyl] carbamoyl-methylJ-2-deoxy-D-glucose.

2-acetamido-3-0 ~ y [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-tetramethy1en] carbamoyl-methyIj-2-deoxy-D-glucose.

2-acetamido-3-0 - <[L-1- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-ethyl] -N-methyl-carbamoyl-methyl4-2-deoxy-D-glu

2-Acetamino-3-o4-D-l-lL-l-carbamoyl-S-carboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-ethyl-2-deoxy-D-glucose.

Example 15

1 mg bovine serum albumin 2-acetamido-3-O-f [L1 - (] 3-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose conjugate is prepared in 0.1 ml of phosphate buffered saline (PBS) dissolved; to the solution x ^ erdenO ,! ml of a 5% suspension of carboxymethylcellulose in PBS. The mixture is administered intramuscularly to guinea pigs in two equal portions.

Example 16

10 T-lymphoblasts ~ 2-acetamino-3-0'f [L1- (p-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl ~ 2-deoxy-D-glucose conjugates (see Example 6 ) are suspended in 0.5 ml of phosphate buffered saline (PBS); To the suspension is added 0.5 ml of a 5% suspension of carboxymethylcellulose in PBS. 0.1 ml of the mixture is administered subcutaneously per mouse «

Example 17

To 10 ml of a suspension of rabies HDC vaccine Behringwerke in phosphate buffered saline are added 100 mg (O ₅ 17 mmol) of 2-acetamino-3-O-i [LI- (Dl-carbamoyl-3-succinimidooxycarbonyl) propyl) -carbamoyl-ethyl-carbamoyl-methyl-F-Z-deoxy-D-glucose. The virus concentration is 2x10 LD ^ q / mouse in 1 ml suspension. The suspension is shaken for 4 hours at 4 ° C. Thereafter, the muramyl dipeptide-rabies HDC-vaccine conjugate is sterile filtered, separated by dialysis against water of low molecular weight reaction products and freeze-dried. ,

• 211 2

Example 18

Rabbit HBC vaccine Behringwerke coupled with 2-acetamino-3-D-1- (L-1- (di-carbamoyl-3-carboxy-propyl) -carbamoyl-n-thyl) -carbamoyl- analogue to Example 17 is obtained. ethyl-2-desoxy-D-glucose. 2-ßenzoylamino-3-0-} D-I- [L-I- (D-1-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucono

2-Benzoylamino-3- (W [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-C-2-deoxy-D-glucose. 2-Benzoylamino-3-O-f [L- (DI, 3-dicarboxy-propyl) -carbamoylathyl) -carbamoylmethyK-2-deoxy-D-glucose. 2-Propionylamino-3-0-HL-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoylethyl] -carbamoyl-methyl-2-deoxy-D-glucose. 2-Acetamino-3-O-i [L-1- (D-1-N-cambamoylmethylcarbamoyl-3-carboxy-propyl) -carbamoylethyl] -carbamoyl-methyl-2-deoxy-D-glucose

 2-benzoylamino-3-0-i [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propylj-carbamoylmethyl? -2-deoxy-D-glucose.

2-Acetylamino-3-O-ML-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-methyl-2-desoxy-D-glucose. 2-acetamido-3-0 - / [L-I- (D-1-carbamoy1-3-carboxypropyl) -

bamoyl-2-hydroxyethyl] -carbamoylmethyl-2-deoxy-D-glucose 2-propionylamino-3-0-V [L1- (Dl, 3-dicarboxy-propyl) -carbamoyl-ethyl] -carbamoyl-1-methyl-2-deoxy-D glucose. 2-Benzoylamino-3-0 - <[L-I - (^ - 1-N-carbamoylmethyl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose

 2-acetamido-3-0-l [L_-l- (D-l-carbamoyl-3-carboxy-propyl) -

Mr. J

carbamoyl-2'-methyl-propyl] -carbamoylmethylC-2-deoxy-D-glucose.

2-acetamido-3-0 ~ ip_-l- [L_-L- (p_-l-carbamoyl-3- (L-l-carboxyethyl) -carßamoyl-propyl) -carbamoyläthy1] -carbamoyläthylV-

2-deoxy-D-glucose. ,

2-acetamido-3-0-i [L-I- (D-I, 3-dicarboxy-propyl) -carbamoy1-

2 ^l -methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose.

2-benzoylamino-3-0-? IL-l- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-2 ^{I-methyl-propyl]} glucose -carbamoyl-methylj-2-deoxy-D. ': .....

2-Acetaminol-3-O - ^ [L 1 - (Dl-carbamoyl-3-carboxy-propyl-carbamoyl-N, N-tetramethylene] -carbamoyl-methyl-2-deoxy-D-glucose. 2-Acetamino-3 -0-yil-l ~ (Dl-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] -N-methyl-carbamoyl-methylj-2-deoxy-D-glucose.

2-acetamino-3-O-j-D-l-iL-1-carbamoyl-S-carboxy-propyl) -carba-

7. Moyles ^"r 2-methyl-propyl] -carbamoyläthyll-2-deoxy-D-glucose.

Example 19

To 10 ml of a suspension of extracted type A / Victoria / 3/75 influenza virus antigens in phosphate buffered saline are added 100 mg (0.17 mmol) of 2-acetamido-3-0-f [LI- (DI -carbamoyl-S-succinimidooxycarbonyl-propyl) -carbamoyl-ethyl] -carbamoyl-methyl | -2-deoxy-D-glucose. (The virus antigens are obtained according to the tween / ether cleavage method of the Behringwerke, Marburg, Germany - analogous to the preparation of ^^ Begrivac S - * the concentration is 4000 IU in 1 ml suspension). The suspension is shaken for 4 hours at 4 ° C. Thereafter, the viral antigen-muramyl · dipeptide conjugates are separated from low molecular weight reaction products by dialysis against phosphate buffered saline; The dialyzed suspension is frozen and stored until use at -20 ⁰ C.

I Om W · Ύ

Example 20

In an analogous manner to Example 20, influenza virus antigens are coupled to 2-ACeCaHtLnO-S-O-ID-1- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -]

carbamoyl-ethyl] - carbamoyl-1-ethyl- 2- desoxy-D-glucose.

2-benzoylamino-3-0-iD-I- [L-I- (D-l-carbamoyl-3-carboxypropyl) carbamoyl-Hthyl] carbamoyl-Sthylj-2-deoxy-D-glucose.

2-benzoylamino-3-0 - ^ [L-I- (13-1-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] -carbamoylmethylt-2-deoxy-D-glucose. 2-Benzoylamino-3-0-f [LI- (di, 3-dicarboxy-propyl) -carbamoylethyl) -carbamoylmethy1 (2-deoxy-D-glucose, 2-propionylamino-3-O-J [LI- (DI -carbamoy1-3-carboxy-propyl) -carbamoylethyl] -carbamoylmethyl'C-2-deoxy-D-glucose. 2-Acetamino-3-0- [LI- (D-1-N-ca-rbamoylmethylcarbamoyl-3- carboxy-propyl) -carbamoyläthyl] -carbamoyImethyIs-2-deoxy

D-glucose.

2-Benzoylamino-3-0 - <[LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoy1-propyl-carbamoyl-2-deoxy-D-glucose. 2-Acetylamino-3-0-S (1- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl-carbamoyl-methyl-2-deoxy-D-glucose.) 2-Acetamino-3-0 - / [LI- (Dl-carbamoyl-3-carboxypropyl) -carbattioyl-2-bydraxy-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose 2-propionyl-amino-3-O-J [LI- (di, 3-dicarboxy-propyl) -carbamoyl-ethyl ] -carbamoylmethyl-2-deoxy-D-glucose. 2-Benzoylamino-3-0- [[ L - (--NH-carbamoyl-methy1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl) -2-desoxy D-glucose.

2-acetamido-3-0-UL-l- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-2'-methyl-propyl] -carbamoylmethylC-2-deoxy-D-glucose.

2-Acetamino-3-O-ip-1- [L-1- (1-carbamoyl-3- (L-1-carboxyethyl) -carbamoy1-propyl) -carbamoylethyl] -carbamoylethyl-2-deoxy-D -glucose.

2H.

2-acetamido-3-0-f (L-I- (D-I, 3-dicarboxy-propyl) carbamoyl

* L «j

2 ^f -methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose.

2-Ben2oylamino-3-0-IIL I- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-2'-methyl-propyl] carbamoyl-methylj-2-deoxy-D-glucose.

. 2-acetamido-3-0- | ? [Ll- (Dl-carbamoyl "3-carboxy-propyl) -car bamoyl _j-N, N-tetramethylene] -cärbamoyl-niethyl ^-2-deoxy-D-; · Glucose.

2-acetamido-3-0- | (L-l-iD-l-carbamoyl-S-carboxy-propyl) carbamoyl-ethyl] -N-methyl-carbamoyl-methylf-2-deoxy-D ~ glu

2-Acetamino-3-o4-DI- [L-carbamoyl-3-carboxy-propyl) -carbamotnoyl-2- ^f -methyl-propyl-carbamoyl-ethyl-2-deoxy-D-glucose.

Example 21

To 2 ml of a solution of tetanus toxoid in phosphate buffered saline is added 10 mg of 2-acetamido-3-0 ~ £ [L_-l- (D_-1-carbamoyl-3-succinimidoxycarbonyl-propyl) -carbamoyl-ethyl] -carbamoyl -methy1ν - 2- deoxy-D-glucose added. The toxoid concentration is 3 mg / ml. The solution is stirred for 4 hours at 4 ⁰ C. Thereafter, the tetanus toxoid-muramyl dipeptide conjugate is separated by ultrafiltration of low molecular weight reaction products; -is frozen the ultrafiltered solution and stored until use at -20 ⁰ C. The quantitative determination (Morgan-Elson reaction) gives about 50 ^ g of muramyl dipeptide per 1 mg tetanus toxoid-murarayldipeptide conjugate.

211 204 - ^5S -

Example 22

In a manner analogous to Example 21, tetanus toxoid is obtained coupled

2-Acetamino-3-0-Jj) -I- [L-1- (D-I-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-giucose.

2-Benzoylamino-3-O-JD-I- [L ₁ -I- (Dl-carbamoyl-3-carboxypropyl) -carbaiiioyl-ethyl] -J-carbanioyl-h'thyl? -2-deoxy-D-Glu

2-Benzoylamino-3-0- j [I ₁ -I- (D-1-carbamoyl 1-3-carboxypropyl) carbainoyl-h'thyl] -carbamoyl-NiethylC-2-de-Oxy-D-glucose. 2-benzoylamino-3-0-5 [L_-l- (DI ,, 3-dicarboxy-propyl) -carbamoyläuhyl) -carbamoylmcthylC-2-deoxy-D-glucose. 2-Propionylamino-3-0-π L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose. 2-Acetamino-3-0-i [L1- (DINCarbamoylmethylcarbamoyl-3-carboxy-propyl) -carbamoyl-ethyl-1-carbamoylmothyl-2-deoxy-D-glucose.

2-Ben ^ oylamino-3-0-j [LI- (Dl-carbamoyl-S-carboxy-propyl) -earbamoyl-propyl] -carbamoylmethy ll -2-deoxy-D-glucose.

2-Acetylamino-3-0-S [L-I- (D-I-carbamoyl-3-carboxy-propyl) -carbamoylpropyl] carbamoyl-methyl? -2-deoxy-D-glucose.

C ·

2-acetamido-3-0 - / [L-I- (D-l-carbamoyl-3-carboxypropyl) -carbonyl

bamoyl-2-hydroxyethyl j-carbamoylmethyl - 2-deoxy-D-glucose.

2-Propionylamino-3-0-V [L-1- (D-1,3-dicarboxypropyl) -carbamoylethyl] -carbamoylmethyl-2-deoxy-D-glucose. 2-Benzoylamino-3-0-j [L-1 -] - 1-N-carbamoylmethyl-carbamoyl-3-carboxy-propyl) -carbamoyl-h'thyl] -carbamoylmethyl-2-deoxy-D-glucose

2-Acetamino-3-0-f (L1- ( _< D1-carbamoyl-3-carboxy-propyl) -

carbamoyl-2'-methyl-propyl] -carbamoylmethyl (-2-deoxy-D-glucose.

2-AcStBmIHO-SO-ID-I- [LI- (Dl-carbamoyl-3- (L-1-carboxyethyl) -carbamoyl-propyl) -carbamoylethyl] -carbamoyläthy Iy- 2-deoxy-D-glucose.

2-Acetamino-3-0-ί [L-I- (D-I, 3-dicarboxy-propyl) -carbamoy1,2'-methyl-propyl-carbamoyl-methyl] -2-desoxy-D-glucose. 2-Benzoylamino-3-0 -? [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose.

2-Acetatnino-3-0- | [L-I- (D-l-carbamoyl-S-carboxy-ptropyl) -carbamoyl-Ν, Ν-tetramethylene] -carbamoy1-methyIt-27desoxy-D-glucose

 2-acetamido-3-0- <IL-1 (D-I-carbamoy1-3-carboxy-propyl) -

te *%

carbamoyl-ethyl] -N-methyl-carbamoyl-methylj-2-deoxy-D-Glu

2-acetamido-3-o4 DI [Ll ~ carbamoyl-3-carboxy-propyl) - carbamoyl-2 ^{{methyl-propyl1-carbamoyläthyl} |! -2-deoxy-D-glucose.

Example 23

To 10 ml of a solution of cholera toxoid from Vibrio cholerae in phosphate buffered saline are added 50 mg of 2-acetamido-3-O-A [L_~1- (D-1-carbamoyl 1-3-succinimidooxycarbonyl-propyl) -carbamoyl- ethyl] -carbamoyl-methylC ~ 2-deoxy-D-glucose. The protein concentration in the solution is 0.6 mg / ml. The solution is stirred for 4 hours at 4 ° C. Thereafter, the cholera toxoid-muramyl dipeptide conjugate is separated by ultrafiltration of low molecular weight reaction products; The ultrafiltered solution is frozen and stored until use at -20 ⁰ C. Quantitative determination (Morgan-Elson reaction) yields 40-50 μg of muramyl dipeptide per 1 mg cholera toxoid-muramyl dipeptide conjugate.

Example 24

In a manner analogous to Example 23 tetanus toxoid is obtained coupled

2 1 1 20 4 - ^5? -

2-Acetamino-3-0-4 D-I- [L-1- (D-1-carbarnoxy-3-carboxy-propyl) -carbamoyl-ethyl-1-carbamoyl-aHy] - 2-deoxy-D-gluco-cyclo. 2-Benzoylamino-3-0-> D-I- [L-I- (ω-1-carbamoyl-3-carboxypropyl) -carbanioyl-ethyl-carbamoyl-athyH-2-deoxy-D-glucose.

, 2-benzoylamino-3-0-J [L-I- (D ^ -l-carbaraoyl-3-carboxy-propyl) carbamoyl-ethyl] -carbamoylmethylj-2-deoxy-glucose-Ü. 2-Benzoylamino-3-0-5 [L-I- (D-I, 3-dicarboxy-propyl) -carbamoylethyl) -carbamoylmethyl-2-deoxy-D-glucose.

, Z-propionylamino-SO- j [ L-1- (DI-carbarnyl-3-carboxy-propyl) -carbamoylethyl] -carbamoyl-methyls-2-deoxy-D-glucose. 2-Acetamino-3-0-j [LI- (DIN-carbamoyl-methylcarbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-dicoxy-D-glucose.

  2-benzoylamino-3-0-j [L-I- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] carbamoylmethyl / -2-deoxy-D-glucose. 2-acetylamino-3-0 -> [L-l- (D-I-carbamoyl-3-carboxy-propyl) -carbamoylpropyl] carbamoyl-methylv-2-deoxy-D-glucose. 2-Acetamino-3-0 -) [L-1- (Dl-carbamoyl-3-carboxypropyl) -carbitioyl-2-bydroxy-hyliyl-1-carbamoyl-methyl-2-deoxy-D-glucose 2-propionylamino-3-O-J [L1- (DI, 3-dicarboxy-propyl) -carbamoylethyl] -carbamoylmethyif-2-deoxy-D-glucose. 2-Benzoylamino-3-0-j [L-I- (£ -1-N-carbamoylmethy1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose.

2-acetamido-3-0-l [L-l- (2-l-carbamoyl-3-carboxy-propyl) carbamoyl-2'-methyl-propyl] carbamoylmethyl (-2-dcsoxy-D-

glucose.

2-Acetamino-3-o4 D-I- [L-I- (D-1-carbamoyl-3- (L-1-carboxy-)

c.- -s

ethyl) carbamoyl-propyl) -carbamoyläthyl] -carbaraoyläthylj-2-deoxy-D-glucose.

- SB-

2-AceCamino-3-0-V (LI- (di, 3-dicarboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-methyl-1-deoxy-D-glucose. 2-Benzoylamino-3-0 -S (Ll-CD-l-carbamoyl-S-carboxy-propyl)

I ?

carbamoyl-2'-methyl-propyl] carbamoyl-methylj-2-deoxy-D-glucose.

2-Acetantino-3-0) - [L-I- (D-l-carbamoyl-S-carboxy-propyl) -

carbamoyl-N, N-tetramethylene-carbamoyl-rne-Lylj-a-desoxy-D-glucose

2-Acetamino-3-O-j [[L-I- (D-1-carbanioyl-3-carboxy-propyl-1) -carbamoyl-a'-thyl] -N-methylcarbamoyl-methyl-1-deoxy-D-glucono

2-Acetamino-3-0-j D-I- [L-1-carbamoyl-S-carboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoylethyl-2-deoxy-D-glucose.

Example ^ 5

20 mg of a synthetic eicosapeptide identical to the C ~ terminal sequence of human chorionic gonadotropins (HCG) [Reference: CH. Schneider, K. Blaser, Ch. Pfeuti and E. Gruden, Febs Letters, J3Ci, 272 (1975)] and 30 mg of 2-acetamido-3-0- [LI (Dl-carbamoyl-3-succinimidooxycarbonyl) propyl) -carbamoyl-ethyl] -carbamoyl-methyl] -2-deoxy-D ~ glucose are dissolved in 2 ml sodium phosphate buffer solution, pH 7.2. The solution is stirred for 6 hours at room temperature. Thereafter, the eicosapeptide-muramyl dipeptide conjugate is isolated by chromatography on a Sephadex G-25 column (1.4 x 40 cm) with water as the eluent and lyophilized. Quantitative amino acid analysis shows that 1-muramyl dipeptide molecule is bound to 1-eicosapeptide molecule. ,

Example 26

In a manner analogous to Example 25, the C-terminal eicosapeptide fragment of the human

211 204

53-

Chorionic gonadotropins coupled to

2 -Ac et amino-3 -Cw p_ -l- [T ₁ -I- (E) -I-carbamoyl 1-3-carbo-carboxy) carbamoyl-ethyl-2-carbamoyl-ethyl-2-deoxy-D-glucose ,

2-Benzoy! Amino-3-0-3D-I- [L-1- (D-I-carbamoy1-3-carboxypropyl) carbamoyl-ethyl] carbamoyl-athylj-2-deoxy-D-glucose. - ·

2-benzoylamino-3-0-i [L ~ l- (2-l-carbamoyl-3-carboxy-propyl) -carbamoyl-äthylj-carbamoylmethylt ^ -deoxy-D-glucose.

2-Benzoylamino-3-0-S [L-1- (D-I, 3-dicarboxy-propyl) -carbamoylethyl) -carbamoylmethyl (-2-desoxy-D-gluco.

2-Prionylamino-3-O-J (L-1- (D-I-carbamoyl 1-3-carboxycarbonyl) -carbamoylethyl) -carbamylmethyl-2-deoxy-D-glucose.

2-Acetamino-3-0-J (L-1- (D-I-N-carbamoylmethylcarbamoyl-3-carboxy-propyl) -carbamoyl-ethyl) -carbamoyl-methyl-2-deoxy-D-glucose.

2-benzoylamino-3-0 - <(L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoy1-propyl] carbamoylmethyl <-2-deoxy-D-glucose.

2-Acetylamino-3-0-S [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoylpropyl] carbamoyl-methyls-2-deoxy-D-glucose.

2-acetamido-3-0 - / [L-I- (D-l-carbamoyl-3-carboxypropyl) -carbonyl

i 's

biiiiioyl-2-hydroxyethyl] carbamoylmethyl I-2-deoxy-D-glucose 2-propionylamino-3-O-j [LI- (D-1,3-dicarboxy-propyl) -carbamoylethyl] -carbamoyl-methyl-2-deoxy- D-glucose. 2-Benzoylamino-3-0 - <[L-I- (D-I-N-carbamoylmethy1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose.

2-acetamido-3-0-UL-1- (D-1-carbamoyl-3-carboxy-propyl) -

L ~ ~~. y carbamoyl-2'-methyl-propyl] -carbamoylmethylC-2-deoxy-D-glucose.

2-acetamido-3-0-TP_-l- [L-I- (D-l-carbamoyl-3- (L-1-carboxyethyl) carbamoyl-propyl) -carbamoylathyl] -carbamoyläthylj-2-deoxy-D-glucose.

1 1 -204 - * <> -

2-Acetoinino-3-O-IIL-1- (di, 3-dicarboxy-propyl) -carbamoy-2- ^l -methyl-propyl-carbamoyl-metbyl-J-2-deoxy-D-glucose. 2-Benzoylamino-3-O-IL-1- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-2 ^L -methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose

 2-Acetarnino-3-0 ~ j {L - - (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-tetraraethylen] carbamoyl-methyli-2-deoxy-D-glucose.

2-Acetamino-3-0- j [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl-N-methyl-carbamoyl-methyl-2-deoxy-D-glu

2-AceCamino-3-CM D-l-fL-I-carbamoyl-3-carboxy-propyl) - carba-moyl-2'-methyl-propyl] -carbamoylethyl-2-deoxy-D-glucose

Example 27

• Analogously to Example 1 bovine serum albumin is coupled with

2 ~ acetamino-3-0 - <[(Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-methyl (2-deoxy-D-glucose, 2-benzoylamino-3 0 \ [(Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-methyl-2-des -xy-D-glucose,

2-acetamido-3 ~ 0-UL-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methylV-2-deoxy-D-glucose,

2-Acetamino "3-0-j [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-V-2-deoxy-D-glucose,.

2-acetamido-3-0-y [L-l- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-methyl] -2-deoxy-D-. glucose,

2-Benzarnido-3-0- \ [~ Ll (Dl-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-metliyK-2-deoxy-D-glucose. .... -

-I- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-ethyl] -N-propyl-carbamoyl-methylv-2-deoxy-D-glucose,

2-acetamido-3-0-S [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-NJN-pentamethylenJ-carbamoyl-methylv ^ -deoxy-D-glucose,

2-benzoylamino-3-0 - \ [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-N ^ -pentamethylen] carbamoyl-methylC-2-deoxy-D-glucose,

2-acetamido-3-o4 [L-l- (D-l-carbamoyl-S-carboxy-propyl) -N-methyl-carbamoyl-ethyl] carbamoyl-methyl ^ -2-deoxy-D-glucose,

2-acetamido-3-0- \ D-l - [(D-l-carbamoyl-pS-carboxy-propyl) -carbamoyl-methyll-N-methyl-carbamoyl-athyls-2-deoxy-D-glucose,

2-benzoylamino-3-0- ^ D-l - [(D-l-carbamoyl-3-carboxy-propyl) carbamoyl-methyl] -N-methyl-carbamoyl-äthylZ-2-deoxy-D-glucose,

2-Acetamino-3-0 ~ \ D-l- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-ethyl-C-2-deoxy-D-glucose,. ,

-S-O- ^ D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-methyl-carbamoyl-ethylS-2-deoxy-D-glucose,

2-Acetamino-3-0-> D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-2-deoxy-D-glucose,

2-Benzamido-3-0-j D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-ethyl-2-deoxy-D-glucose,

2-Acetamino-3-0-> D-1- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -N-propyl-carbamoyl-ethyl-2-deoxy-D-glucose,

2-acetamido-3-0-iD-l · - [Ll- (Dl-carbamoyl · -3-carboxy-propyl ·) -carbamoyl-N, N-pentamethylene] carbamoyl · -äthyIV-2-deoxy-D- glucose,

2-Benzoylamino-3-0-4 Dl- [Ll - (Dl -carbamoyl-3-carboxy-pr-pyl) -carbamoyl-N, N -pentamethyl-] -carbamoyl-ethyl-2-desoxy -dg ^ ce,

2-Acetamino-3-O-di-1-L-1- (Dl-carbamoyl-3-carboxy-propyl) -N-methyl-carbamoyl-ethyl-1-carbamoyl-α-methyl-2-desoxy -D- '- g ^ cose,

2-Acetamino-3-0- [L 1 - (Dl -carbamoyl-3-carboxy-methyl-phenyl) -carbamoyl-methyl-J-2-deoxy-D-glucoside, 2- Benzoylamino-3-0-HL-1- (Dl -carbamoyl-3-carboxy-ethyl-phenyl) -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzamino-3-0- j [L1] - (Dl -carbamoyl-3-carboxy-propyl) -carbamoyl-2-methyl-mercapto-ethyl] -carbamoyl-methyls-2-deoxy-D-glucose,

2-Benzamino-3-0 - ^ [L-l- (D-L-.carbamoyl-S-ca-r-boxy-.propyl-) -carbamoyl-2-chloroethyl] -carbamoyl-methyl-4-desoxy-D-glucose,

2 ° acetamino-3-0 \ Dl · - [Ll · (Dl · -carba-inoyl · 3,3-dicarboxy-propyl) -carbamoylethyl ·] -carbamoy-1-ethyl-V-2-deoxy-D-glucose, ; 2- (ß «carbomethoxy-succinamido) -3-0- \ [LI- (Dl · · carbamoyl - 3-carboxy-propyl ·) carbamoyl · · ethyl] carbamoyl · · methyl / -2-deoxy D-gl · ucose,

2- (β-Carbomethoxy-succinamido) -3-O-Cd-I- [LI- (di-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl-6-carbamoyl-ethyl-2-one deoxy-D-gl · ucose,

2-Benzamino-3-0-i [LI- (Dl-) carbamoyl-3-trimethylsilyl- (carboxy-propyl) -carbamoyl-ethyl-) -carbamoyl-methyl-2-desoxy- 1, 4,6-tris-trimethyl-silyl-D-glucose. (On contact with water, the trimethylsilyl ester group is rapidly saponified),

1 204 -. ⁶³ ~

2-Acetaniino-2-deoxy-3-0-J [L-I- (D-l-carbamoyl-3-trimethylsilylcarboxy-propyl) carbamoyl-ethyl] -carbamoylmethylv-1,4.6-tris-triraethylsilyl-D-glucose,

2-Acetamino-3-O-H) -1- [LI- (Dl-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] -carbamoyl-ethyl-V-2-dQsoxy-D-glucose, 2-aceto-3-amino -O- ^ Dl- [LI- (Dl-carbamoyl-3-caryboxy-propyl) carbamoyl-2'-hydroxy-propyl-carbamoyl-ethyl-2-deoxy-D-glucose,

2-Acetamino-3-O-Dl- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '- (p-hydroxy-phenyl) ethyl] -carbamoyl-ethyl-2-deoxy -D-glucose,

2-acetamido-3-0- ^ D-l- [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-NJN-tetramethylenl-carbamoyl-ethyl? -2-deoxy-D-glucose,

^ -Glycolylamino-SO-iD-I- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose, 2-glycolylamino-3-0- WL-1- (Dl-carbamoyl-3-carboxy-propyl) -carbamyl-ethyl] -carbamoyl-methyl-2-desoxy-D-glucose

 2- (N-methyl-acetamino) -3-0 - ^ [L-I- (D-l-carbamoyl-3-carboxypropyl) carbamoyl-ethyl] carbamoyl-methylc-2-deoxy-D-glucose.

2- (N-methyl-acetamino) 3-0- ~ £ p ~ l- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-äthylj-carbamoyl-ethyl / -2-deoxy-D-glucose .

2-Acetamino-3-0-Π3-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) carbamoyl-2'-phenylethyl] -carbamoyl-ethyl-V-2-desoxy-D-glucose,

2-acetamido-3-0 - \ [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) -Mthyl] carbamoyl-methylR-2-deoxy-D-glucose,

2-acetamido-3-0 - [[L-l- (D-I- [L-1-carboxy-ethyl] carbamoyl-3-benzylcarboxy-propyl) carbamoyl-ethyl] -carbamoylmethylf-2-deoxy-D-glucose,

2-acetamido-3-0-ML-I (DI, 3-di-carboxy-propyl) -N-methyl- carbampyl-ethyl] -carbamoylinethy ll -2-deoxy-D-glucose.

Example 28

In a manner analogous to Example 3, sheep erythrocyte membranes coupled to 2-acetamido-3-O-ε [(Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-methyl (2-desoxy -D-glucose, 2-benzoylamino-3-0) [(Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-methyl-V-2-deoxy-D-glucose,

2-acetamino ~ 3 ~ 0-UL-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methylv-2-deoxy-D-glucose,

2-acetamino "= 3-0 - [L-I- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] -N-methyl-carbamoyl-methylV-2-deoxy-D-glucose,

2-Acetamino-3-O-O- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl-N-ethyl-carbamoyl-methyl-2-desoxy-D-glucose,

2-BeHZaUiXdO-S-O-UL-1- (D-1-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-2-desoxy-D-glucose

 2-acetamido-3-0-ML-I (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] -N-propyl-carbamoyl-methyll-2-deoxy-D-glucose,

2-acetamido-3-0-S [LI = (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-N _s N-pentamethylene] carbamoyl-methylY ~ 2-deoxy-D ~ glucose,

2-Benzoylamino-3-O- [L-1- (D-i-carbamoyl-o-carboxy-propyl) carbamoyl-N, N-pentamethylene] -carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetamino-3-o4 [L ~ l ~ (Dl-carbamoyl-S-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoy1-methyl »2-deoxy-D-glucose _s

211 2

-S-O-JD-I - [(D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-methylj-N-methyl-carbamoyl-athyi -2-deoxy-D-glucose,

2-benzoylamino-3 = 0- | D-l - [(D-l-carbamoyl-S-carboxy-propyl) carbamoyl-methyl] -N-methyl-carbamoyl-äthylZ-2-deoxy-D-glucose,

2-Acetamino-3-0-JD-1- [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-ethyl-C-2-deoxy-D-glucose,

2-Acetamino-3 »O-) D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-methyl-carbamoyl-ethyl-2-deoxy-D-glucose,.

2-Acetamino-3-0-Id-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-ethyl-2-deoxy-D-glucose,

2-Benzamido-3-0-j D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl-N-ethyl-carbamoyl-ethyl-2-deoxy-D-glucono

2-Acetamino-3-0-> D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl] -N-propyl-carbamoyl-ethyl-V-2-deoxy-D-glucono

Z-acetamino-S-O-iD-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-V-2-deoxy-D-glucose,

2-Benzoylamino-3-0-4 DI- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-peni: amechylene] -carbamoyl-ethyl> -2-deoxy-D- gluce,

2-Acetamino-3-0-j D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoyl-ethyl-V-2-deoxy-D-glucose,

2-> acetamino-3-0-X [L-I- (D-1-carbamoyl-3-carboxy-methyl-phenyl) -carbamoyl-methyl] -2-desoxy-D-glucose,

.1 204 - ⁶⁶ ~

2-Benzoylamino-3-O-HL-1- (Dl-carbamoyl-3-carboxy-niethylphenyl) -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzo-inirlo-3-O-V [LI (Dl -carbamoyl-S-carboxy-propyl) -carbamoyl-2-methyl-mercapto-ethyl] -carbamoyl-methyls-2-deoxy-D-glucose,

2-benzamino-3-0-i [L ~ l- (D-l ~ carboxy-3-carbamoyl-propyl) carbamoyl-2-chloroethyl] carbamoyl-methyl? -2-deoxy-D-glucose,

2-acetamido-3 ~ 0- \ D-l- [L-I- (D-l-carbamoyl-3,3-dicarboxypropyl) -carbamoyläthyl] carbamoyl-ethyl? -2-deoxy-D-glucose,

2- (ß-carbomethoxy-succinamido) -3-0-HL-l- (D-l-carbanioyl-3-carboxy-propyl) -carbamoyl-athyll-carbamoyl-methyl / -2-deoxy-D-glucose ^,

2- (β-carbomethoxy-succinamido) -3-O-Xd-I- [LI- (D 1 -carbamoyl-3-carboxy-f-opyl) -carbamoyl-ethyl] -carbaraoyl-ethyl-2-deoxy-D; glucose,.

2-3- Ben2amino ~ »0-r [L" l "(Dl-carbamoyl" 3 "trimethylsilylcarboxy-propyl)" carbamoyl-ethyl] carbamoyl-methyl? -2-deoxy-l ^ so-tris-trimethylsilyl-D -glucose. (On contact with water, the trimethylsilyl ester group is rapidly saponified),

 2-Acetamino-2-deoxy-3-O-HL-1 "- (D ~ 1-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-V-1,4,6-tris-trimethylsilyl-D-glucose, 2-Acetamino-3-o4D-I-IL-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl-carbamoyl-ethyl-2-deoxy-D-glucose, 2-acyl-amino-3 -0- [D1] [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-2'-hydroxypropyl3-carbaraoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-0- | I) -l- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '- (p ^ hydroxy-phenyl) -ethyl] -carbamoyl-ethyl-2- deoxy-D-glucose,.

21-1.2 '

2-acetamido-3-0- £ D-l- [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-NJN-tetramethylenJ-carbamoyl-äthyli-2-deoxy-D-glucose,

2-Glycolylamino-3-0- ^ Dl- [LI- (Dl-carbaraoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose, 2-glycolylamino-3-0 - £ [Ll (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -carbamoyl-methyl-2-deoxy-D-glucose. 2- (N-methyl-acetamino) -3-O- [L-I- (D-1-carbamoyl-S-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-methyl-1'-deoxy-D-glucose.

2- (N-methyl-acetamino) -3-0- ^ D-l- [L-I- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-ethyl] carbamoyl-äthylf-2-deoxy-D-glucose,

2-acetamido-3-0-n) -! - [L-I- (D-l-.carbamoyl-S-carboxy-propyl) carbamoyl-2'-phenylathylj-carbamoyl-äthyli-2-deoxy-D-glucose,

2-acetamido-3-0 - \ [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) ethyl] carbamoyl-methylf-2-deoxy-D-glucose,

2-acetamino-3-O-J_ [L-1- (D-1- [L-1-carboxy-ethyl] -carbaraoyl-3-benzyl-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose,

2-ACeCaTnInO-S-O-HL-1- (D-1,3-di-carboxy-propyl) -N-methylcarbamoyl-ethyl] -carbamoylmethyl (-2-deoxy-D-glucose.

Example 29 _:

In an analogous manner to Example 4 to obtain group C polysaccharide of Neisseria meningitidis coupled with

2-Acetamino-3-0 - ^ [(Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl-1-methyl-carbamoyl-methyl-2-desoxy-D-glucose, 2-benzoylamino-3-0 ^ [. (Dl-carbamoyl-3-carboxy-propyl) -carbam-d-mecyl] -N-methyl-carbaraoyl-methyl-1-yl-2-deoxy-D-glucose,

2-Acetamino-3-0-j [L-L- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methyl-2-desoxy-D-

glucose,

2-acetamino-3-0 ~ i [L-L- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] -N-methyl-carbamoyl-methyl> -2-deoxy-D-

glucose,

2-acetamino-3-0-} JL-1- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-1-methyl-2-desoxy-D-glucose;

2-Benzamido = 3 "O-S [L-1-CD-1-carbaraoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl) - = 2-deoxy-D-glucose.

2-Acetaraino-3-O-ML-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl-N-propyl-carbamoyl-methyl-4-desoxy-D-glucose,

2-acetamido-3 "O-i [L-1- (D-1-carbaraoyl-S-carboxy-propyl) -carbamoyl-N, N-pentaraethylene] -carbaraoyl-methyl-2-desoxy-D-glucose,

2 "Benzoylamino-3-0 - \ [L-1- (Dl-carbamoyl-S-carboxy-propyl) -car bamoy 1 -N, N-pename thy 1 en] - car bainoy 1 -me thy I ^ - 2 - dexy-D-glucose _s

2-Acetamino ~ 3 ~ o4 [L-l ~ (D-l-carbamoyl-S-carboxy-propyl) -N, -methyl-carbamoyl-ethyl] -carbamoyl-methyl-2-desoxy-D-glucono

• J

2-acetamido-3 »0- \ D-l - [(D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-methylj-N-methyl-carbamoyl-ethyl '? -2-deoxy-D-glucose,

2-Benzoylamino-3-0-> D-1 - [(D-1-carbamoyl-S-carboxy-propyl) -; carbamoyl-methyl] -N-methyl-carbamoyl-äthylZ-2-deoxy-D-glucose,

2-acetamino-3-0 ~ u) -l- [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoy1-ethyl) -N-äthy1-carbamoy1-äthyIC-2-deoxy-D-Glu

cose _s .

21 i 21

2-acetamino-3-0-) D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-methyl-carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-0- (D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-2-deoxy-D-glucose,

2-BeHZaTnIdO-S-O-ID-I- [L-I- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-äthyli-2-deoxy-D-Glu

2-acetamido-3-0- ^ D-l- [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-äthylj-N-propyl-carbamoyl-the ethyl-2-deoxy-D-Glu

2-Acetamino-3-O--ί-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-V-2-deoxy-D-glucose,

2-Benzoylamino-3-0-4 D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-pentamet: ethylene] -carbamoyl-ethyl-V-2-deoxy-D-gluce,

2-ace.tamino-3-0-] D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoyl-ethyl} -2-deoxy-D-glucose,

2-Acetamino-3-0-s [LI- (Dl-carbamoyl-3-carboxy-methyl-phenyl) -carbamoyl-methyl-V-2-deoxy-D-glucose, 2-benzoylamino-3-O-HL-I (Dl-carbamoyl-S-carboxymethylphenyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzamino-3-O-UL-1- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl) 2-methyl-mercapto-ethyl] carbamoyl-methyl? -2-deoxy-D-glucose,

2-benzamino ~ 3-0-HL-l- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-2-chloroethyl] -carbamoyl-methylj-2-deoxy-D-glu

2-acetamido-3-0-JD ~ l- [L-I- (D-l-carbämoyl-3,3-dicärboxy-

propyl) -carbamoyläthy11-carbamoyl-ethyl-j * -2-desoxy-D-glucose,

2- (ß-carbomethoxy-succinamido) -3-0-J? [LI - (D-1-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-methyl -2-deoxy-D-glucose .

2- (β-Carbomethoxy-succinamido) -3-0- (DI-IL-1- (D 1 -alkylcarbamoyl-3-carboxyloxy) -propyl) -carbamoyl-ethyl ] -carbamoyl-ethyl-2-desoxy-D -glucose,

2-Benzamino-3-0-i [L "1- (D-1-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbamoyl-ethyl] -carbatoylo-methyl-2-deoxy-l _s 4,6-tris-trimethylsilyl -D = glucose. (On contact with water, the trimethylsilyl ester group is rapidly saponified),

2-Acetarnino-2-deoxy-3-O-HL-1- (Dl-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbamoyl-ethyl) -1-carbamoylmethyl-4,6,6-tris-trimethylsilyl-D ~ glucose, 2-acetamino-3'4D ~ 1- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-ethyl> -2-deoxy-D-glucose, 2-acetaminophen 3-0 ~) DI- [LI- (Dl-carbamoyl-S-carboxy-propyl) carbamoyl-2'-hydroxy-propyl] -carbamoyl-ethyl-C-2-deoxy-D-glucose,

2-Acefcamino-3-0 »^ D ~ l ~ [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '- (p-h3- ^r -phenyl-phenyl) -ethyl] -carbamoyl-ethyl-2-yl deoxy-D-glucoses

2 »acetamino-3-0-VD-1- [LI- (di-carbamoyl-3-carboxy-propyl) -carnamoyl-Ν, Ν-tetramethylene] -carbamoyl-ethyl-2-deoxy-D-glucose, 2- Glycoly! Amino-3-0- ^ D = 1- [LI- (DI-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose, 2-glycolylamino-3 -0 - \ [LI- (DI-carbamoy1 = 3-carboxy-propyl) carbamoyl-ethyl] -carbamoyl "methyl-2-deoxy-D-glucose".

211 2

2- (N-methyl-acetamino) -3-0-J [L-I- (D-l-carbamoyl-3-carboxypropyl) carbamoyl-ethyl] carbamoyl-methylc-2-deoxy-D-glucose.

2- (N-methyl-acetamino) -3-0- [D-I- [L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-äthyli-2-deoxy-D-glucose,

2-Acetamino-3-0- / D-1- [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-2'-phenylethyl] -carbamoyl-ethyl-4-2-desoxy-D-glucose,

2-acetamido-3-0- \ [LI- (DI-carbamoy1-3-carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) ethyl ·] -carbamoyl-methylj · -2-deoxy-D- glucose,

2-Acetamino-3-0- [L-1- (D-I- [L-I-carboxy-ethyl] -carbamoy1-3-benzylcarboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose,.

2-Acetamino-3-0 - ^ [L-I- (D-I, 3-di-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose.

Example 30

In a manner analogous to Example 5, merozoites of the malaria pathogen Plasmodium knowlesi are obtained

2-Acetamino-3-0- [(Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-methyl-V-2-deoxy-D-glucose, 2-benzoylamino-3-Oy (Dl-carbamoyl-S-carboxy-propyl) -carbonyl.

bamoyl-methyl] -N-methyl-carbamoyl-methyl? -2-deoxy-D-glucose,

2-acetamido-3-0 -? ^ [L-I- (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methyl -2-deoxy-D-glucose,

2-acetamido-3-0- | [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl3-N-methy1-carbamoy1-methy1> -2-deoxy-D-glucose,

2-acetamino '3 ~ 0-yl-l- (D-l ~ carbamoyl "3-carboxy-propyl) - carbamoyl-propyl] -N-ethyl-carbamoyl = methyl] -2-deoxy-D-. glucose,

2-benzamido-3-0-JJL-l- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -13-ethyl-carbamoyl-methyl ^ -2-deoxy-D-glucose.

, 2-Ace: taraino-3-0-A [L1] (Dl- »carbamoyl-3 ~ (carboxy-propyl) -carbamoyl-ethyl] -N-propyl-carbamoyl-methyl-V-2-deoxy-D» glucose .

2-aceto-amino-3-0-S [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N-N-pentamethylene] -carbamoyl-methyl-V-Z-deoxy-D-glucose,

2-Benzoylamino-3-O-UL-1- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N 1 -pentamethylene] -carbamoyl-2-hydroxyethoxy-D-glucose

2-Aca tamino-3-0-J [L-I- (D-1-carbaraoyl-3-carboxy-propyl) -N = methyl-carbamoyl-ethyl] -carbamoyl-methyls-2-deoxy-D-glucono

2-Acetarno-3-0- \ D ~ l - [(D-1-carbaraoyl-3-carboxy-propyl) -carbamoyl-methyll-N-methyl-carbamoyl-ethyl-2-deoxy-D ~ glucose,

2-BeDZOyIaInIno-S-O- ^ D-I- [(D ~ 1-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-ethylZ-2-desoxy-D-glucose,

2-Acetamino ~ 3-0 "p-l- [L-I- (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl) ~ N -ethyl-carbamoyl-ethyl <-2-deoxy-D ~ -glu-

2-Acetamino-3-0-> D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-methyl-carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-0- [D-l- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-2-deoxy-D-'-glucose,

21 1 204 .73-

2-benzamido-3-0- £ D-l- [L-I- (D-l-carbamoyl-S-carboxy-propyl) -

carbamoyl-propyl] -N-ethyl-carbamoyl-ethyl? -2-deoxy-D-glu

2-acetamido-3-0- £ D-l- [L-I- (D-l-carbamoyl-S-carboxy-propyl) -

carbamoyl-ethyl] -N-propyl-carbamoyl-äthyij-2-deoxy-D-Glu

cose, ·

2-Acetamino-3-0-pl- [L1- (D-.l-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-V-2-deoxy-D "- glucose,

2-Benzoylamino-3-0-4 D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-2-desoxy-D-gluce,

2-Acetamino-3-O-J D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-O-UL-1- (D-1-carbamoyl-3-carboxy-methyl-phenyl) -carbamoyl-methyl-2-deoxy-γ-glucose, 2-benzoyl-amino-3-0-HL -I- (Dl-carbamoyl-S-carboxy-methyl-phenyl) -carbamoyl-methyl-V-2-deoxy-D-glucose, 2-benzo-amino-3-O-HL-I- (Dl-carbamoyl-S-carboxy-propyl) carbamoyl-2-methyl-mercapto-äthylJ carbaΓαoyl--methyls-2-deoxy-D-glucose,

2-Benzamino-3-0-j [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2-chloroethyl] -carbamoyl-methyl-2-desoxy-D-glucose,

2-acetamido-3-0- \ D-l- [L-I- (D-l-carbamoyl-3,3-dicarböxypropyl) -carbamoyläthyl3-carbamoyl-äthylj-2-deoxy-D-glucose,

2- (ß-carbomethoxy-succinamido) -3-0 - ^ [L-I- (D-1-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-methyl / -2-deoxy-D-glucose,

2- (ß-carbomethoxy-succinamido) -3-0-Xd-I - [LI- (D-1-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-äthylj-2 'deoxy ~ D -glucöse,.

2-benzamino-3-0 - ([LI- (Dl-carbamoyl-3-trimethylsilylcarboxy-propyl) carbamoyl-ethyl] carbamoyl-methyly-2-deoxy-l, 4,6-tris-trimetiiylsilyl-D-glucose (On contact with water, the trimethylsilyl ester group is saponified rapidly),

2-acetamino ~ 2-deoxy-3-0-ML-I (D-l-carbamoyl-3-trimethylsilylcarboxy-propyl) carbamoyl-ethyl] -carbamoylmethylV-1,4.6-tris-trimethylsilyl-D-glucose,

2-acetamino ~ 3-0- $ di- [LI- (DI-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] carbamoyl _r the ethyl-2-deoxy »D-glucose, 2-acetamido-3-0- ^ Dl- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-hydroxy-propyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-Aceto-amino-3-O-Dl- [LI- (Dl-carbainoyl-3-carboxy-propyl) -carbamoyl-2 '- (p -hydroxy-phenyl) -ethyl-carbamoyl-ethyl-2-deoxy-D- glucose, · - · · .-

2-Acetamino-3-O-yD-1 - [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-tetramethylene] -carbamoyl-ethyl-2-deoxy-D-glucose,

2-Glycolylamino-3-O-fD-1- [L-1- (DI-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose, 2-glycolylamino 3-O-HL-1- (di-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose

 2- (N-methyl-acetamino) -3-O- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-desoxy-D-glucono

W *

2- (N-methyl-acetamino) -3-0-Jp-I- [L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-äthylv-2-deoxy-D-glucose,

2-Acetamino-3-O-Dl-C'l "-! - (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-phenylethyl] -carbamoyl-ethyl-2'-deoxy-D-glucose ,.

21 1

-S-O-O'L-l- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) ethyl] carbamoyl-methyll-2-deoxy-D-glucose,

2-Acetamino-3-0 - [[L-I- (D-I- [L-1-carboxy-ethyl] -carbamoyl-3-benzyl-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetarnino-3-0- £ [L-I- (D-I, 3-di-carboxy-propyl) -N-methyl-

carbaraoyl-äthyll-carbamoylmethyl] -2-deoxy-D-glucose.

Example 31

Analogously to Example 6, T-lymphoblasts of CBA / J mice are obtained coupled to 2-acetamido-3-0 - [[(D-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -N- methyl-carbamoyl-methyl? 2-deoxy-D-glucose, 2-benzoylamino-3-0 ^ [(Dl-carbamoyl-3-carboxy-propyl) -carbaraoyl-methyl] -N-methyl-carbamoyl-methyl-2-desoxy-D ~ glucose, "

2-Acetaraino-3-0-J [L-I- (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methyl? -2-deoxy-D-glucose,

2-acetamido-3-0-V [L-l- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-methyl-carbamoyl-methylV-2-deoxy-D-glucose,

2-acetamido-3-0-> ^ [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-2-desoxy-D-glucose,

2-Eenzamido-3-0-jjL-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl] -2-deoxy-D-glucose.

2 ~ acetamino-3-O-S [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl] -N'-propyl-carbamoyl-methyl-V-2-deoxy-D-glucose,

2-acetamino-3-O-j [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-methyl-2-deoxy-D-glucose,

2-Benzoylamino-3-O-U-L-I-- (D-1-carbamoyl-3-carboxypropyl) carbamoyl-N, N-pentamethyl-3-carbamoyl-methyl-2-deoxy-D-glucose,

2-aceto-amino-3-0-i [L-1- (D-1-carbamoyl-3-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoyl-methyl-2-desoxy-D-glucose,

2-Acetamino-3-O-D-1 - [(D-1-carbaraoyl-S-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-ethyl-V-2-deoxy-D-glucose,

2-Benzoyl-amino-3-O-5D-1- [(D-I-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-ethylZ-2-deoxy-D-

glucose, '

2-AcetaraIno-3 ~ 0- | D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-1-ethyl-C-2-deoxy-D-glucono

2-acetamino-3? 0-) D? L- [LI- (Dl-carbamoyl-S-carboxy-propyl) carbamoyl-propyl-N-methyl-carbamoyl-ethyl-2-desoxy-D-glucose _s

2-acetamino-3-0- |, D-l- [L-I- (D-1-carbamoyl-3-carboxy-propyl) carbamoyl-piropyl-N-ethyl-carbamoyl-methyl-2-deoxy-D-glucose,

2-benzamido-3-0- £ D-l- [L-I- (D-l-carbamoyl-S-carboxy-piopyl) -

carbamoyl-propyl] -N-ethyl-carbamoyl-diethyl? -2-deoxy-D-glu

2-Acetamino-3-0 >> D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbba-moyl-athyll-N-propyl-carbamoyl-ethyl-2-deoxy-D-gluc

1 1 204

-3-0-5D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-V-2-deoxy-D-glucose, "

2-Benzoylamino-3-0-4 D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-V-2-deoxy-D-gluce, '

2-Acetamino-3-O-J D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose,

2-Acetamino-3-0 - \ [L-1- (D-1-carbamoyl-3-carboxy-methyl-phenyl) -carbamoyl-methyl-2-desoxy-D-glucose, 2-benzoylamino-3-0- HL-1- (Dl-carbamoyl-3-carboxy-methylphenyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzo-amino-3-O- j [LI- (Dl-carbamoyl-S-carboxy-propyl ) carbamoyl-2-methyl-mercapto-ethyl] carbamoyl-methyls-2-deoxy-D-glucose,

2-benzamino-3-0-HL-l- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-2-chloroethyl] carbamoyl-methy1? -2-deoxy-D-glucose,

2-acetamido-3-0- ^ D-l- [L-I- (D-l-carbamoyl-3,3-dicarboxypropyl) -carbamoylathy1] carbamoyl-äthylj-2-deoxy-D-glucose,

2- (β-carbomethoxy-succinamido) -3-0- ^ [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoy1-ethyl] -carbamoy1-methyl-2-desoxy-D-glucose,

2- (β-carbomethoxy-succinamido) -3-0- ^ D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose,

2-Benzamino-3-0-T [LI- (D-1-carbamoyl) -3-trimethylsily1-carboxy-propyl) -carbamoy1-ethyl] -carbamoyl-methyl-1-yl-deoxy-1,4,6-tris trimethylsilyl-D-glucose. (On contact with water, the trimethylsilyl ester group is rapidly saponified),

2-Acetamino-2-deoxy-3-O-HL-I- (D-1-carbamoyl-3-trimethyl-silylcarboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-1,4,6-tris-trimethylsilyl-D-glucose ,.

2-Acetamino-3-04D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl-carbamoyl-ethyl-V-2-deoxy-D-glucose,

r - _r J

2-Acetamino-3-0- [D-l- [L-I- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-2'-hydroxy-propyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-0-] J) -l- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '- (p -hydroxy-phenyl) -ethyl] -carbamoyl-ethyl ^ - 2 -deoxy-D-glucose, '

S-O-) D-I- [L-I- (D-1-carbamoyl-3 = carboxy-propyl) -

carbamoyl-N, N-tetramethylene] -carbaraoyl-methyl (2-deoxy-D-glucose,

2-GlyisocyanatoHi-O-SO- ^ DI- [LI- (Dl-carbamoyl-β-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose, 2-glycolylamino ~ 3-0 -UL-l- (Dl-carbaraoyl-S-carboxy-propyl) -carbamoyl-athylj-carbaraoyl-methylj-2-deoxy-D-glucose

 2 - '(N-methyl-acetaraino) ~ 3 ~ 0- [Li ~ (Dl · -carbaraoyl-3-carboxyphenylcarbamoyl-ethyl] -carbamoyl-methylc-2-deoxy-D-glu-cose ,

2- (N-methy1-aceCamino) -3-0- ^ D-l- [L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-äthylf-2-deoxy-D-glucose,

2-Acetamido-3-O-Dl-1-LI- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-phenylethyl] -carbaraoyl-ethyl-2-deoxy-D-glucose , ^v

2-ACeUaInIno-SO- \ [LI- (Dl-carbarnoyl-S-carboxy-propyl) -carbamoyl- ^2f - (p-hydroxyphenyl) -ethyl] -carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetamino-3-0 - [[L-1- (D-I- [L-I-carboxy-ethyl-3-carbamoyl-3-benzylcarboxy-praptopyl) -carbarnoyl-ethyl] -carbamoyl-methyl) -1-deoxy-D-glucose,

2-acetamido ~ 3-0 - ^ [L ~ l (D-I, 3-di-carboxy-propyl) -N-methylcarbaiBoyl-ethyl] carbamoylmethyl | -2-deoxy-D-glucose.

Example 32

In a manner analogous to Example 12, foot-and-mouth disease culture is obtained. Vesicles coupled to 2-acetamido-3-0- [[(D-carbamoyl-3-carboxy-3-propyl) -carbamoylmethyl] -N-ethylcarbamoyl -methylv-2-deoxy-D-glucose, 2-benzoylamino-3-Cm (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-methyl-V-2-deoxy-D-glucose .

2-acetamido-3-0-UL-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methylv-2-deoxy-D-glucose,

2-Acetamino-3-0-i [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl-N-methyl-carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetamino-3-O-IJL-1- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-2-desoxy-D-glucose,

2-benzamido-3-0 ~ UL-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-raethyK-2-deoxy-D-glucose.

2-acetamido-3-0-A [L-I- (D-l-carbaraoyl-S-carboxy-propyl) carbamoyl-ethyl] -N-propyl-carbaraoyl-methyll-2-deoxy-D-glucose,

2-acetamido-3-0-i [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-NJN-pentamethylenl-carbamoyl-methyIv-2-deoxy-D-glucose,

2-B.enzoylamino-3-0-UL-I- (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylen3-carbamoyl-methyIC-2-deoxy-D-glucose,

2-Acetamino-3-0-i [L-i- (D-1-carbamoyl-β-carboxy-propyl) -N-methyl-carbaraoyl-ethyl-carbamoyl-methyl] -2-desoxy-D-glu

2-acetamido-3-0 ~ u) -l ~ [(D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-methylj-N-methyl-carbamoyl-ethyl? -2-deoxy-D-glucose,

2-benzoylamino-3-0- $ D-l - [(D-l-carbamoyl-S-carboxy-propyl) carbamoyl-methyl] -N-methyl-carbamoyl-äthylZ-2-deoxy-D-glucose,

2-acetamino-3-0-} DI- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl) -N-> ethyl-carbamoyl - = '"ethyl-2-desoxy-D- glamorous,

2-Acetamino-3-0-) D-l- [L-I- (D-1-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] -N-methyl-carbamoyl-ethyl? ^ -2-deoxy-D-glucbse,

2-Acetamino-3-0-> D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-methyl-carbamoyl-methyl-T-2-deoxy-D ~ glucose,

2-benzamido-3-0-) D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-ethyl-2-deoxy-D ~ glucose,

2-Ace-tamino-3-0--D-1- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -N-propyl-carbamoyl-a'-ethyl-2-desoxy-D-glucose · 2-Acetam5.no-3-0- [DI- [LI- (Dl-carbaraoyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl (2-deoxy-D) · Glucose,

2-Benzoylaraino ™ 3-0-4 D * 4- [L-I- (D-1-carboxamyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylene-carbamoyl-a'-thyl-Y-2-de

3g,

2-Acetamino-3-0-j D-I- (L-I- (D-1-carbamoyl-S-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose,

2-Acetamino-3-0 - \ [LI- (DI-carbamoyl) -3-carboxy-methyl-phenyl] -carbatoylo-methyl-V-2-desoxy-D-glucose, 2-benzoylamino-3-O-HL-I (bl-carbamoyl-3-carboxy-tnethylphenyll-carbamoyl-2-deoxy-methylv "D ~ glucosev

2-Benzamino-3-0-i [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-2-methyl-mercapto-ethyl] -carbamoyl-methyl-2-desoxy-D-glucose,

2-benzamino-3-0 ~ | jL-l- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-2-chloroethyl] carbamoyl-methyl -2-deoxy-D-glucose,?

2-acetamido-3 ~ 0-u) -l- [L-I- (D-l-carbamoyl-3,3-dicarboxypropyl) -carbamoyläthyl] -carhamoyl-äthylf-2-deoxy-D-glucose,

2- (ß-carbomethoxy-succinamido) -3-0-hL-1 (D-1-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-methyl? -2-deoxy-D-glucose,

2- (β-Carbomethoxy-succinamido) -3-0- (DI- [LI- (D-1-carbaraoyl-3-carboxy-propyl) -carbamoyl-ethyl] -car bamoyi-ethyl-2-deoxy-D-glucose .

2-benzamino-3-0-ΠL-1- (DI-carbamoyl-3-trimethylsilylcarboxy-propyl) carbamoyl-ethyl] -carbampyl-methyly-2-deoxy-l, 4,6-tris-trimethylsilyl-D-glucose , (On contact with water, the trimethylsilyl ester group is rapidly saponified),

2-Acetamino-2-deoxy-3-0-i [L1- (Dl-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbamoyl-ethyl] -carbamoylmethylV- "1,4,6-tris-trimethylsilyl-D-glucose, 2- Acetamino-3-0- ^ Dl- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-ethyl-V-2-deoxy-D-glucose, 2-acetamido-3-0- [ Dl- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-hydroxy-propyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-acetamido-3-0-h) -l- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '- (p-hydroxy-phenyl) ethyl] carbamoyl-2- äthylj deoxy-D-glucose,

2-Acetamino-3-O-s D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl] Ν, N-tetramethylene] -carbamoyi-ethyl-2-deoxy-D-glucose,

Ό- (ί Α - 8Α -

-SO- ^ DI- [LI- (DI-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoy1-ethyl-2-deoxy-D-glucose, 2-glycolylamino-3-0-HL-1- (DI-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose. 2- (N-methyl-acetamino) -3-0 - \ [L-1- (D-l-carbamoyl-3-carboxypropyl) carbamoyl-ethyl] carbamoyl-methylc-2-deoxy-D-glucose.

2- (N -methyl-acetanrinq) -3-0-Jp-I- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-a'-thyl] -carbamoyl-ethyl-2-desoxy glucose,

2-acetamido-3-0- ^ D-1- [L-1- (D-I-carbamoy1-3-carboxy-propyl) carbamoyl-2'-phenylethyl] -carbamoy1-äthyl4-2-deoxy-D-glucose,

2-acetamido-3-0 - \ [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) ethyl] -carbamoy1-methyIj-2-deoxy-D-glucose,

2-Acetamino-3-O-J [LI- (di- [L-1-carboxy-ethyl] -carbamoyl-3-benzyl-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl) 2-deoxy-D-glucose, 2 -Acetamino-3-0- [L 1 - (D 1, 3-di-carboxy-propyl) -N-methylcarbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose.

Example 33

Analogously to Example 17, ToIl-VTUt-HDC vaccine ringlets are coupled to

2-Acetamino-3-0- [[(Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-methyl-2-desoxy-D-glucose, 2-benzoylamino 3-0 ^ [(Dl-carbamoyl-S-carboxy-propyl) -car- "-bamoyl-methyll-N-methyl-carbamoyl-methylS-2-deoxy-D-glucose,

2-Acetamino-3-0-J [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methyl-V-2-deoxy-D-glucose _s . *

f 1 20: 4

-3-0 -} [L-I- (D-l-carbamoyl-3-carboxy-propyl) -

carbamoyl-propyl] -N-ethyl-carbamoyl-methyl> -2-desoxy-D-glucose,

2-acetamido-3-0 - [[L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-methyl] -2-deoxy-D-glucose,

2-benzamido-3-P - [[L-l- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-raethyl'l-2-deoxy-D-glucose. ·

2-acetamino-3-O-AjL-1-XD-1-carbaraoyl-S-carboxy-propyl) -carbamoyl-ethyl] -N-propyl-carbamoyl-methyl> -2-deoxy-D-glucose,

2-Acetarnine-3-0-S [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-methyl-Y-2-deoxy-D-glucose,

2-Benzoylamino-3-0 - [[L-I- (D-1-carbaraoyl-S-carboxy-propyl) -carbaraoyl-N, N-pentamethylene] -carbamoyl-methylC-2-deoxy-D-glucose,

2-acetamido-3-0-i [L-l- (D-l-carbamoyl-3-carboxy-propyl) -N-methyl-carbamoyl-ethyl] carbamoyl-methyl? -2-deoxy-D-Glu

2-Acetamino-3-O-1 - [(D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-methyl-N-methyl-carbamoyl-ethyl-2-desoxy-D-glucose,

2-Benzoylamino-3-O-iD-1 - [(D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-acylZ-2-deoxy-D-glucose,

) -3-0-) D-l [L-I- (D-l-carbamoyl-3-carboxy-propyl) -

carbamoyl-ethyl) -N-ethyl-carbamoyl-ethyl ^ -2-deoxy-D-Glu

2-Acetamino-S-O-iD-1- [L-I- (D-1-carbaraoyl-S-carboxy-propyl) carbaraoyl-propyl] -N-methyl-carbamoyl-ethyl-2-deoxy-D-glucose,

- gtf

2-Acetamino-3-O-jD-1-iL-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl-1-N-ethyl-carbamoyl-2-ethyl-2-o-deoxy-D; glucose y

2-Benzamido-3-0-fD-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-2-desoxy-D-glucono

_; 2, -Aceta.mino-3-0- ^ DI- [LI- (D-1-carbamoyl-S''-carboxy-propyl) -carbamoyl-ethyl] -N-propyl-carbamoyl-ätti'yl ^ -2 -d.esoxy-D-glucose,

2-Acetamino-3-0-pl- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-V-2-deoxy-D-glucose, '.

2-Benzoylamino-3-04 D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-V-2-deoxy-D-gluce,

2-Acetamino ~ 3-0 "2 D-I- [L-I- (D-1-carbambyl-S-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-0-WL-1- (di-carbamoyl-3-carboxy-methyl-phenyl) -carbamoyl-methyl-V-2 "desoxy-D-glucose, 2-benzpylamino-3-O-HL-I (Dl-carbamoyl-3-carboxy-methylphenyl] -carbamoyl-methylj-2-deoxy-D-giucose, 2-benzamino-3-O-J [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl- 2-methyl-mercapto-ethyl] -carbamoyl-methyl-2-desoxy-D-glucose,

2-benzamino-3-0) - [L-I- (D-l-carbamoyl-S-oarboxy-propyl) carbamoyl-2-chloroethyl] carbamoyl-methyl -2-deoxy-D-Glu-?

2-acetamido-3-0- \ Dl- [LI (Dl-carbamoyl-3,3-dicarboxypröpyl) -carbamoyläthyl] carbamoyl-ethyl> -2-deoxy-D-glu

2- (β-Carbomethoxy-succinamido) -3-0-s [LI- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose .

2- (β-carbomethoxy-succinamido) -3-0- ^ D-1- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose,

2-benzamino-3-0-f [L-I- (D-l-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbamoyl-äthyll-carbamoyl-methylj - ^ - deoxy-l, 4,6-tris "trimethylsilyl-D-glucose. (When in contact with water, the trimethylsilyl ester group is rapidly saponified). ' ........

2-Acetamino-2-deoxy-3-O-f [L1- (Dl-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbamoyl-ethyl] -carbamoylmethylv-1,4,6-tris-trimethylsilyl-D-glucose, 2-acetamino -3-0- ^ Dl- [LI- (Dl-carbaraoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-a'thyl'y-2-deoxy-D-glucose, 2-acetamino-3-0 [Dl- [LI- (Dl-carbamoyl-3-carboxy-propyl) carbamoyl-2'-hydroxy-propyl] -carbamoyl-ethyl-2-deoxy-D-glucose,

2-Acetamino-3-O-Dl- [LI- (Dl-carbamoyl-S-carboxy-propyl) carbamoyl-2 '- (p -hydroxy-phenyl) -ethyl] -carbamoyl-ethyl-2-deoxy- D-glucose,

2-acetamino-3-0-) D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-tetramethylene-carbamoyl-ethyl-2-deoxy-D-glucose,

2-Glycolylamino-3-O-iD-1- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose, 2-glycolylamino-3-ol 0 - \ [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose. 2 ~ (N-methyl-acetamino) -3-0-2 [L-I- (D-l-carbamoyl-3-carboxypropyl) carbamoyl-ethyl] carbamoyl-methylc-2-deoxy-D-glucose.

2- (N-methyl-acetamino) -3-0-J_d-l- [LI- (Dl-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-ethyl / -2-deoxy-D-glucose .

2-Acetamino-3-O-D-1- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-phenylethyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-acetamido-3-0-H-L-I- (D-l-carbaraoyl-3-carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) ethyl] carbamoyl-methylR-2-deoxy-D-glucose,

2-Acetamino-3-0- £ [L-1- (DI- [LI-carboxy-ethyl] -carbamoyl-3-benzylcarboxv-propyl) -carbamoyl-ethyl] -carbamoy! Methyl? -? 2-deoxy- D-glucose,

2-Acetamino ~ 3-0 - [[L-I- (D-I, 3-di-carboxy-propyl) -N-methylcarbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose.

Example 34

In an analogous manner to Example 19 to obtain influenza virus antigens type A / Victoria / 3/75 coupled to

2-Acetamino-3-0- [[(Dl-carbamoyl-3-carboxy-propyl) -carbaraoyl-methyl] -N-methyl-carbamoyl-methyl-V-2-deoxy-D-glucose, 2-Benzoylamino-3-0 ^ [(D-1-cärbamoyl-3-carboxy-propyl) carbamoyl-methyl] -N-methyl-carbamoyl-methyli-2-deoxy-D-glucose,

2-acetamino ~ 3-0 - ^ [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methyl -2-deoxy-D-glucose,?

2-acetamido-3-0 -> [L-I- (D-l-carbarnoyl ~ 3 ~ carboxy-propyl) carbamoyl-propyl] -N-methyl-carbamoyl-methylV-2-deoxy-D-glucose,

2-acetamino-3-0- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-2-deoxy-D-glucose,

2-Benzamido-3-0-l [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl] -2-desoxy-D-glucose.

2 1 1 204 - ^8? -

2-acetamido-3-0-

carbanioyl-äthyll-N-propyl-carbamoyl-methylv ^ deoxy-D-glucose, "

2-Acetamino-3-O-i [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-pentamethylene-1-carbamoyl-methyl-V-deoxy-D-glucose,

2-Benzoylamino-3-0-UL-1- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetamino-3-0-5 [L-1- (D-1-carbamoyl-3-carboxy-propyl) -N-methyl-carbamoyl-ethyl] -carbamoyl-methyl-2-desoxy-D-glucono

cose, '

2-Acetamino-3-0-> D-l - [(D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-methyl} -N-methyl-carbamoyl-MthyIv-2-deoxy-D-glucose,

2-Benzoylamino-3-0-> D-l - [(D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-ethyl-Z-2-desoxy-D-

glucose,.

2-Acetamino-3-O-VD-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-ethyl-2-deoxy-D-glucono

cose,.

2-acetamino-3-0-) D-1- [L-I- (D-1-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-methyl-carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-O-1-1- [L-1- (D-I-carbamoyl-3-carboxypropyl) carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-V-2-deoxy-D-

glucose, *

2-Benzamido-3-0-fD-1- [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl-N-ethyl-carbamoyl-ethyl-2-deoxy-D-glucono

2-Acetamino-3-O-iD-1- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -N-propyl-carbamoyl-a'-ethyl-2-desoxy-D-glucono

11 2® J ~ ⁹ * ~

2-acetamino-3-0- VD-I- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-V-2-deoxy-D-glucose,

2-Benzoylamino-3-0-4D-1- (L-1- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -carbamoyl-ethyl-2-deoxy-D-gluce,.

2-Ace tamino »3-0-4 DI- [LI- (Dl-carbamoyl-S-carboxy-propyl) -N-methyl-carbamoyl-ethyl]" carbamoyl-a {: hyly-2-deoxy-D- ^: glucose, ·

2-Acetamino-3-0 - \ [LI- (Dl-Cyanothioyl-3-carboxy-methyl-phenyl) -carbamoyl-methyl-V-2-deoxy-D-glucose, 2-benzoylamino-3-O-HL-I (Dl-carbamoyl-3-carboxy-methyl · -phenyl] -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzo-3-amino-3- [L- (Dl-carbamoyl-S-carboxy-propyl) Carbamoyl-Z-methyl-mercapto-ethyl] -carbamoyl-methyls -2 -desoxy-D-glucose,

2-benzamino-3-0-HL-l- (D-l-carbamoyl-S-carboxy-propyl) carbamoyl-2-chloroethyl] carbamoyl-niethylv-2-deoxy-D-Glu

2-Acetamino-3-O-D-1- [L-I- (D-1-carbamoyl-3,3-dicarboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2- (β-carbomethoxy-succinamido) -3-0-ι [LI- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl / -2 -desoxy-D-glucose,

2- ( ^: β-carbomethoxy-succinamido) -3-30-iD-1 "[LI- (D-1-carbamoyl-3-carboxy-p-opyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy ~ D-glucose,

2-benzamino-3-0-UL-l- (Dl-carbamoyl-3-trimethylsilylcarboxy-propyl) carbamoyl-ethyl] carbamoyl-methylv-2-deoxy-l, 4,6-tris-trimethylsilyl-D-glucose , (When in contact with water, the trimethylsilyl ester group is rapidly saponified),.

211 2Ö4 - ⁸⁹ - ·

2-acetamino-2-deoxy-3-O- [[L-I- (D-1-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbaraoyl-ethyl] -carbamoyl-methyl-1,4,6-tris-trimethylsilyl-D-glucose,

2-Acetamino-3-o4D-1- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl-carbamoyl-ethyl-2-deoxy-D-glucose, 2-aceto-3-0- [Dl - [LI- (Dl-carbamoyl-carboxy-propyl) carbamoyl-2'-hydroxy-propyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-0-> Dl- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '- (p -hydroxyphenyl) -ethyl] -carbamoyl-ethyl-2-deoxy-D -glucose,

-l- [L-I- (D-l-carbamoyl-S-carboxy-propyl) ·

carbamoyl-N, N-tetramethylene-carbamoyl-ethyl-2-desoxy-D-glucose,. ...

2-Glycolylamino-3-0-JD-1- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-dsoxy-D-glucose, 2-glycolylamino 3-0 - \ [LI- (Dl-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] -carbamoyl-methylj-2-deoxy-D-glucose

 2- (N-methyl-acetamino) -3-0-I [L-I- (D-l-carbamoyl-3-carboxypropyl) carbamoyl-ethyl] carbamoyl-methylc-2-deoxy-D-glucöse.

2- (N-methyl-acetamino) -3-0- ^ D-I- [L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-äthyli-2-deoxy-D-glucose,

2-acetamino-3-0-) D-1- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-phenyl-thyl] -carbamoyl-ethoxy-2-desoxy-D-glucose,

2-acetamido-3-0 - \ [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) ethyl] carbamoyl-methylj-2-deoxy-D-glucose,

2-Acetamino-3-0-j_ [L-I- (D-I- [L -! - carboxy-ethyl-1-carbamoyl-3-benzylcarboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose,

2-acetamino-3-0 ~) [L-1- (D-1,3-di-carboxy-propyl) -N-methylcarbamovl-ethyl ether].

Example 35

In an analogous manner to Example 21 is obtained

Tetanus toxoid coupled to

2-Acetamino »3-0-f [(Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-methyl] ~ N -methyl-carbamoyl-methyl (-2-deoxy-D-glucose, 2-benzoylamino) ~ 3 Oi [(Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl] -3-N-methylcarbamoyl-methyl-2-deoxy-D-glu- "' ^:

2-Acetamino-3-0 - \ [L-1- (D-1-carbamoyl-O-carboxy-propyl) -carbamoyl-ethyl) N-ethyl-carbamoyl-methyl-V-2-des-dxy-D-glucose,

2-Acetamino-3-O-j [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbaraoyl-propyl] -N-methyl-carbamoyl-methyl-V-2-deoxy-D-glucose,

2-Acetamino-3-O-hL-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl-N-ethyl-carbamoyl-methyl-2-deoxy-D-glucose. «

2-Benzamido-3-0-UL-1- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyls-2-deoxy-D-glucose.

2-Acetamino-3-0-AJL-1- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl-N-propyl-carbamoyl-methyl-1-deoxy-D-glucose,

2-Acetamino-3-O-L-> [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-N, J-pentamethylene-carbamoyl-ethyl-Y-P-deoxy-D-glucose,

2-Benzoylamino-3-0 - ^ [LI- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-N ₅ N-pentamethyl] -carbamayl-methyl-2-deoxy-D-glucose, 2-acetamido-3-0 ~ J [~ Ll (Dl-carbamoyl-S-carboxy-propyl) -N-methyl-carbamoyl-äthyll-carbaiuoyl-raethyl "- 2-deoxy-D-glucose,

LA I £ Wty

2-acetamido-3-0- \ D-l - [(D-l-carbamoyl-S-carboxy-propyl) -

carbamoyl!

glucose,

carbamoyl-methylJ-N-methyl-carbamoyl-the ethyl-2-deoxy-D-

-S-O-jD-l - [(D-l-carbamoyl-3-carboxy-propyl) carbamoyl-methyl] -N-methyl-carbamoyl-ätfryl2-2-deoxy-D-glucose,

2-acetamido-3-O-u) -l- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetarnine-3-0-> D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl-N-methyl-carbamoyl-ethyl-V-2-deoxy-D-glucose,

2-Acetaraino-3-0-Jd-I- [L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-methylV-2-deoxy-D-glucose,

2-Benzamido-3-0-ίD-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbaraoyl-ethyl-2-deoxy-D-glucono

cose "

2-Acetamino-3-O-D-1- [L-I- (D-1-carbamyl-3-carboxy-propyl) -carbamoyl-ethyl-N-propyl-carbamoyl-ethyl] -2-desoxy-D-glucose,

2-acetamido-3-0-p-1- [L-I- (D-l-carbamoyl-3-carboxy-propyl) ·

carbamoyl-N, N-peni: amethylen] carbamoyl-ethyl 2-deoxy-D-glucose?

2-BeHZoiIiIlNO-S-OjD-I- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-N ₎ -n-pentaraethylene] -carbamoyl-ethyl: hyl-2-desoxy-D-gluce.

2-Acetamino-3-O-> D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -N-me.-butyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetarnine-3-0 - ^ [L- (D ~ 1-carbamoyl-3-carboxy-methylphenyl] -carbamoyl-methyl-V-2-deoxy-D-glucose, 2-benzoylamino-3-0 -? [ L-1- (Dl-carbamoyl-S-carboxy-methylphenyl] carbamoyl-methyIv-2-deoxy-D-glucose,

2-benzamino ~ 3 Q ~ j [LI- (Dl-carbamoyl-S-carboxy-propyl) carbamoyl-2-methyl-mercapto-ethyl] ~ carbamoyl-methyls-2-

deoxy-D-glucose,

2-BeHZaOTIno-S-O-HL-1- (D-1-carbamoyl-S-carboxy-propyl) - 'carbamoyl-2-chloro-ethyl] -carbamoyl-methyl-2-desoxy-D-gluco

cose,

2-acetamido-3-0-U) -l- [L-I- (D-l-carbamoyl-3,3-dicarboxy

propyl) -carbamoyläthyI] carbamoyl-athylv-2-deoxy-D-Glu

2- (ß-carbomethoxy-succinamido) -3-0 - ^ [L-I- (D-1-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-methyl / -2-deoxy-D-glucose,

2- (β-carbomethoxy-succinamido) -3-0- ^ DI- [LI- (D-1-carbamoyl-3-carboxy-p:; -opyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy- D-glucose,

2-benzamino-3-0-f {L-1- (DI-carbamoy1-3-trimethylsilylcarboxy-propyl) -carbamoyl-methylj-äthyl3-carbamoyl-2-deoxy-l, 4,6-tris-trimethylsilyl-D- glucose. (On contact with water, the trimethylsilyl ester group is rapidly saponified),

2-acetamino-2-deoxy-3-0- ^ [LI- (Dl-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbamoyl-ethyl] -carbamoylmethyl-1,6,6-tris-trimethylsilyl-D ~ glucose, 2 -Acetamino-3-0- ^ D »l ~ [LI- (di-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-ethyl-2-deoxy-D-glucose, 2-aceto-amino-3- 0- [Dl- [LI- (Dl-carbamoyl-S-carboxy-propyl) carbamoyl-2'-hydroxy-propyl] carbamoyl-äthylj-2-deoxy-D-glucose,

2-Acetamino ~ 3-0- | p ~ [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-2 '- (p -hydroxy-phenyl) -ethyl] -carbamoyl-ethyl] -2- deoxy-D-glucose.

2-Acetamino 3-O-D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-tetramethylene] -carbamoyl-ethoxy-2-desoxy-D-glucose,

2-Glycolylamino-3-0-fD-I- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carba-arayl-ethyl-2-desoxy-D-glucose, 2-glycolylamino-3-ol 0- | [L 1 - (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl-carbamoyl-methyl-2-desoxy-D-gluco-ano. 2- (N ~ methyl-acetamino) -3-0-2iL-l- (D-l-carbamoyl-3-carboxypropyl) carbamoyl-äthylj-carbamoyl-methylc-2-deoxy-D-glucose.

2- (N-methyl-acetamino) -3-O-J ₁ -DI- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl / 2-deoxy-D-glucose .

2-acetamino-3-O-) D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-2'-phenylethy-carbamoyl-ethyly-2-desoxy-D-glucose,

2-acetamido-3-0-UL-l- (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) -äthyU-carbamoyl-methylR-2-deoxy-D-glucose,

2-Acetamino-3-0 - [[L-1- (DI- [LI-carboxy-ethyl] -carbamoyl-3 "-benzylcarboxy-propyl) -carbamoyl-ethyl] -carbamyl-methyl-2-deoxy-D-glucose, 2 -Acetamino-3-0 - ^ [LI- (dI, 3-di-carboxy-propyl) -N-methy1-carbamoyl-ethyl] -carbamoylmethylf-2-deoxy-D-glucose.

Example 36 '

In a manner analogous to Example 23, cholera toxoid from Vibriocholerae coupled to 2-acetamido-3-0-j [(Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -iT-methyl-carbamoyl-methyl (-2 -deoxy-D-glucose, 2-benzoylamino-3-0j [(Dl-carbaraoyl-3-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-methylV ~ 2-deoxy-D-glucose,

2-Acetamino-3-O-L-1- (D-1-carbainoyl-3-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methyl-V-2-deoxy-D-glucose,

2-Acetamino-3-0- $ [L-I- (D-1-carbamoyl-O-carboxy-propyl) -carbamoyl-propyl] -N-methyl-carbamoyl-methyl> -2-desoxy-D-glucose,. , '· -

.2- = ace-ta.mino-3-0-UL-l -. (Dl-carbamoyl -'-3-c-ar-boxy'-propyl) .carbamoyl-propyl] -N- ethyl-carbamoyl-methylv-2-deoxy-D-glucose,

2-Benzaraido-3-0- \ [LI- (Dl-earbaraoyl-3-carboxy.-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-methyK-2-deoxy-D-glucose.

2-acetamido-3-0-ML-I (D-l-carbamoyl-S-carboxy-propyl) -. Carbamoyl-ethyl] -N-propyl-carbamoyl-methylV-2-deoxy-D-glucose,

2-aceto-amino-3-0-HL-1- (D-1-carbamoyl 1 = 3-carboxy-propyl-1) carbamoyl-N, N-pentamethylene] -carbarnoyl-methyl-V-2-deoxy-D-glucose,

2-benzoylamino-3-0 - \ [L-I- (D-l-carbamo} ^ l-3-carboxy-propyl) -carbaraoyl-N, N-pentarnethylen] carbamoyl-methylv-2-deoxy-D-glucose,

2 «acetamino ~ 3-0-J [L ~ l- (P-l-carbamoyl-3-carboxy-propyl) -N-methyl-carbamoyl-äthyl3-carbamoyl-methyl ^ -2-deoxy-D-glucose,

2-acetamino ~ 3-0 ~ \ D-l ™ [(D-l-carbamoyl-S-carboxy-propyl) -earbamoyl-methyl] -N-methyl-carbamoyl-äthyIs-2-deoxy-D-glucose,

2-benzoylamino-3-0- ^ D-l - [(D-l-carbamoyl-3-carboxy-propyl) -earbamoyl-methyl] -N-methyl-carbamoyl-ethyl ^ -2-deoxy-D-glucose,

2-acetamido-3 ~ 0-jD-1- [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-ethyl ^ -2-deoxy-D-glucose,

211 204

2-acetamino-3-0-) D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -N-methyl-carbamoyl-ethyl-2-desoxy-D-glucose,

2-aceto-amino-3-0- ^ D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-V-2-deoxy-D-glucose,

2-benzamido-3-0-> _D-1- [L-I- (D-1-carbamoyl-S-qarboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-ethyl-2-deoxy-D-glucono

2-acetamido-3-0- ^ D-l- [L-I- (D-l-carbamoyl-a-carboxy-propyl) -

carbamoyl-ethyl] -N-propyl-carbamoyl-the ethyl-2-deoxy ~ D-glucose,

2-ACEI: amino-3-0-iD-l- [L-I- (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-pentamethylene] -cafbamoyl-äthylv-2-deoxy-D-glucose,

2-Benzoylamino-3-0-4 D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-N-pentamethylene-1-carbamoyl-ethyl-V-2-desoxy-D-gluce,.

2-Acetamino-3-0-2 D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -. N-methyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-acetamido-3-0-UL-1- (DI-carbamoyl-3-carboxy-methyl-phenyl] carbamoyl-methyIj -2-deoxy ~ D-glucose, 2-benzoylamino-3-0- \ [LI- (Dl-carbamoyl-S-carboxy-methylphenyl) -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzamino-3-O-HL-1- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl- 2-methyl-mercapto-ethyl] carbamoyl-methyl? -2-deoxy-D-glucose,

2-Alkyl-2-O-HL-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2-chloroethyl] -carbamoyl-methyl-2-deoxy-D-glucose,

2-acetamido-3-0-ld-l- [L-I- (D-l-carbamoyl-S ^ -dicarboxypropyl) -carbamoyläthyl] carbamoyl-äthylj-2-deoxy-D-Glu

2- (β-carbomethoxy-succinamido) -3-0- ^ [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl / -2-desoxy-D-glucose,

2- (ß-carbomethoxy-succinamido) -3-0-iD-l- [Ll- (Dl-carbamoyl-3-carboxy-p :: opyl) carbamoyl-ethyl] carbamoyl-äthylf-2-deoxy-D glucose _t

2-benzamino-3-0-f [LI- (D-1-carbamoy1-3-trimethy1silylcarboxy-propyl) carbamoyl-ethyl] carbamoyl-methylv-2-en-l-soxy, 4,6-tris-trimethylsüyl D-glucose. (On contact with water, the trimethylsilyl ester group is rapidly saponified),

2-Acetamino-2-deoxy-3-O-ML-1- (di-carbamoyl-3-triryl-1-ylylcarboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-1,4,6-tris-trimethylsilyl-D -glucose-, 2-Acetamino-3-o4D-I- [L-1- (Dl-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -carbamoyl-ethyl-V-2-deoxy-D-glucose, 2- Acetamino ~ 3-0- ^ Dl- [LI- (Dl-carbamoyl-S-carboxy-propyl) carbamoyl-2'-hydroxy-propyl] -carbamoyl-ethylv-2-deoxy-D-glucose,

2-Acetamino-3-O-D-1- [L-1- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-2'- (p -hydroxy-phenyl) -ethyl] -carbamoyl-ethyl "2-deoxy-D-glucose,

2 ™ acetamino-3-0 ~ \ D-I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) carbamoyl-N, N-tetramethylene-carbamoyl-ethoxy-2-desoxy-D-glucose,

2 ~ glycolylamino-3-O-iD ~ l- [LI- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D-glucose, 2-glycolo-amino 3-0 - \ [LI- (D-1-carbamoyl-3-carboxy-propyl) carbarnoyl-ethyl) -carbamoyl-methyl-2-deoxy-D-glucose. 2- (N-methyl-acetamino) -3-0- [L-1- (D-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-2-deoxy-D-glucose «

2- (N-methyl-acetamino) -3-.0 ^ di- [LI- (Dl-carbamoyl-3-carboxy-propyl) -cärbamoyl-ethyl] carbamoyl-äthylv-2-deoxy-D-glucose, -

2-Acetamino-3-0- [D-l- [L-I- (D-1-carbamoyl-i-carboxy-propyl) -carbamoyl-2'-phenylethyl] -carbamoyl-ethyl) -2-desoxy-D-glucose,

2-Acetamino-3-O-j [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-2 '- (p-hydroxyphenyl) -ethyl] -carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetamino-3-0 - [[L-1- (D-I- [L-1-carboxy-ethyl-carbamoyl-3-benzyl-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetamino-3-0 - ^ [L-1- (D-I, 3-di-carboxy-propyl) -N-methylcarbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose. ,

Example 37

In a similar way to example. 25, a synthetic eicosapeptide is obtained which is identical to the C-terminal sequence of the human chorionic gonadotropin coupled to 2-acetamino-3-0 - ^ [(Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -N -methyl-carbamoyl-methylV-2-deoxy-D-glucose, 2-benzoylamino-3-Cm (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-methyl] -N-methyl-carbamoyl-methyl> -2- deoxy-D-glucose,

2-acetamido-3-0-UL-I- (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl) -N-ethyl-carbamoyl-methyls-2-deoxy-D-glucose,

2-acetamido-3-0 -> [L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-methyl-carbamoyl-methyls-2-deoxy-D-glucose,

2-Acetamino-3-O-UL-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] τΝ-ethyl-carbamoyl-methyl-2-desoxy-D-glucose,

2-Benzamido-3-0-UL-1- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -N-ethyl-carbamoyl-methyl-2-deoxy-D-glucose.

2-Acetamino-3-0-5 [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -N-propyl-carbamoyl-methyl-2-deoxy-D-glucose,.

2-Acetamino-3-0 - $ [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoy1-N, N-pentamethylene] -carbamoy1-myyiv -2-dexy-D-glucose,

2-benzoylamino-3-0 ^ \ [L-I- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-N, N-pentamethylene] carbamoyl-methylC-2-deoxy-D-glucose,

2-Acetamino-3-O-J [L-I- (D-1-carbamoyl-3-carboxy-propyl) -N-methyl-carbamoyl-ethyl-carbamoyl-methyl-H-deoxy-D-glucose:

2-Acetaro-3-O-D-1 - [(D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-ethyl] -N-metb.yl-carbamoyl-ethyl-2-desoxy-D-glucose,

2-Benzoylamino-3-O-iD-I - [(D-1-carbamoyl-S-carboxy-propyl) -carbarnoyl-methyl-N-methyl-carbamoyl-ethyl-Z-2-desoxy-D-glucose ,.

2-acetamido-3-0- ^ D-l- [L-I- (D-l-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl) -N-äthy1-carbamoy1-Mthy1 <-2-deoxy-D-glucose,

2-acetamino-3-0 ») D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoy-1-propyl-N-methyl-carbamyl-ethyl] -t-2-deoxy-D-glucose,

2-acetamino-3-0-U) -I- [L-I- (D-1-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl-N-ethyl-carbamoyl-methyl-2-desoxy-D-glucose,.

2-benzamido-3-0-jD-I- [L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-propyl] -N-ethyl-carbamoyl-äthyli-2-deoxy-D-glucose,

2-acetamino "3-0- ^ D-l- [L ~ l- (D-l-carbamoyl-S-carboxy-propyl) -carbamoyl-äthyll-N-propyl-carbamoyl-the ethyl-2-deoxy-D-Glu

S-J-

2-acetamido-3 »0-Id-I- [L-I- (D-l-carbamoyl-3-carboxy-propyl) -carbamoy1-N, N-pentamethylene] carbamoyl ~ athyIv-2-deoxy-D-glucose,

2-Benzoylamino-3-0-4 D-I- [L-I- (D-1. ™ car bamoy 1-3 -car boxy ™ pro-

pyl) carbamoyl-N, N-pentamethylene] -carbaraoyl-äthylv-2-deoxy-D-gluce,

2-acetamido-3-O-J-DI- [LI- (Dl-carbamoyl-S-carboxy-propyl) N-me-thi 1-car bamoyl-ethyl] -car bamoyl-ethyl-IJ-2-deoxy-D -glucose,. , 2-Acetamino-3-0 - \ [LI- (Dl-carbamoyl-S-carboxy-methyl-phenyl) -carbamoyl-methyl-2-deoxy-D-glucose, 2-benzoyl-amino-3-0-HL-I - (Dl-carbamoyl-S-carboxy-methyl-phenyll-carbamoyl-methyl-2-deoxy-D-glucose, 2-benzamino-3-O- j [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl] 2-methyl-mercapto-ethyl] carbamoyl-methyls-2-deoxy-D-glucose,

[L-I- (D-1-carbamoyl-S-carboxy-propyl) -

carbamoyl-2-chlorathyl] carbamoyl-methyl? -2-deoxy-D-glucose,

-l- [L-I- (D-l-carbamoyl-SjS-dicarboxypropyl) -carbamoylethyl] -carbamoyl-ethyl-IJ-2-desoxy-D-glucose,

2- (ß-carbomethoxy-succinamido) -3-0-HL-l- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-methyl / -2-deoxy-D-glucose,

2- (β-carbomethoxy-succinamido) -3-0- ^ D-I- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl-3-carbamoyl-ethyl] 2-deoxy-D-glucose,

2-benzamino-3-O-i [L-l- (D-l-carbamoyl-3-trimethylsilylcarboxy-propyl) carbamoyl-ethyl] -carbamoyl-methylj-2-deoxy-l, 4,6-tris-trimethylsilyl-D-glucose. (On contact with water, the trimethylsilyl ester group is rapidly saponified),

2-Acetamino-2-deoxy-3-O- [[LI- (Dl-carbamoyl-3-trimethylsilylcarboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl, V-1,4,6-tris-trimethylsilyl-D-glucose, 2-Acetamino-3-O-Dl- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl-carbamoyl-ethyl-2-deoxy-D-glucose,

- -ΪΟΟ

-SO- ^ Dl- [LI- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-2 ^l -hydroxy-propyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-0- | Dl- [L1- (Dl-carbamoyl-3-carboxy-propyl) carbamoyl-2 '- (p -hydroxy-phenyl) -ethyl] -carbamoyl-ethyl-2-deoxy-D -glucose*

2-Acetamino-3-Q-VD-1- [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-N, N-tetramethylene-carbamoyl-ethyl-C-2-desoxy-D "glucose,

2 "Glycolylamino-3-O-Dl" [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl-carbamoyl-ethyl-2-desoxy-D-glucose, 2-glycolylamino-3-O- ^ [LI (DI carbamoy1-3-carboxy-propyl) -carbaraoyl-diethyl] carbamoyl-methyl? -2-deoxy-D-glucose. 2- (N-methyl-acetamino) -3-0 - ^ [L-l- (D-l-carbamoyl-3-carboxypropyl) carbamoyl-ethyl] carbamoyl-inethylc-2-deoxy-D-glucose.

2- (N-methyl-acetamino) -3-0-Jp-I- [L-I- (D-l-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-äthylv-2-deoxy-D-glucose,

2-Acetamino-3-O-D-1- [L-I- (D-1-carbamoyl-S-carboxy-propyl) carbamoyl-2'-phenylethyl] -carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-0 - \ [L-I- (D-1-carbamoyl-3-carboxy-propyl) -carbaraoyl-2 '- (p-hydroxyphenyl) -ethyl] -carbamoyl-methyl-2-desoxy-D-glucose,

2-Acetamino-3-0-J [L-I- (D-I- [L-I-carboxy-ethyl] -carbarnoyl-3-benzylcarboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetamino-3-0-J [L-I- (D-1,3-di-carboxy-propyl) -N-methylcarbamoyl-ethyl] -carbamoylmethyl-2-deoxy-D-glucose.

Several of the above-mentioned muramyl peptides or their spacer-coupled forms are new. They can be e.g. obtained as described in the following examples:

1 1 '204 - ^ΛΟΛ "

Example 38

A solution of 3.4 g of benzyl 2-acetamino-3-O-p-1-fL-1- [pi-1-carbamoyl-3- (L-1-carboxy-ethyl-carbamoyl) -propyl] - carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-aD-glucopyranoside-benzyl ester in 100 ml of methanol / distilled water 2/1 in the presence of 0.3 g of 10% palladium on carbon at atmospheric pressure and 45 ⁰ C during. Hydrogenated 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 washed 3 times with 40 ml of saturated water each time. Butanol extracted. The organic phases are still 3 times with 40 ml with see. Butanol washed saturated water. The aqueous solutions are combined, evaporated, the residue dissolved in a little distilled water and freeze-dried. This gives the 2-acetandno-3-0- | D ~ l-fL-1- [D-1-carbamoyl-3- (L-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-ethyl-3-carbamoyl-ethyl -2-desoxy-D-glucose as a white powder of fa] p ° = + 9 ° ± 1 ° (distilled water, c = 1.090).

The starting material used is prepared in the following way:

A solution of .6.1 g of benzyl 2-acetamino-3-O-iD-1- [LI- (JD-1-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy- aD-glucopyranoside monohydrate and 3.5 g of L-Alaninbenzylester p-tolulsulfonate in 30 ml of Ν, Ν-dimethylformamide is mixed with 1.4 ml of triethylamine, 1.1 g of N-hydroxy-succinimide and 2.3 g of dicyclohexylcarbodiimide and Stirred for 48 hours at room temperature. The crystallized dicyclohexylurea is filtered off with suction and washed with 10 ml of Ν, Ν-dimethylformamide and the filtrate is evaporated to dryness. The residue is suspended in 100 ml of water, stirred at ⁰ ° C. for 1 hour, the insoluble matter is filtered off with suction, washed with a little ice-water and dried. The product is still dissolved in methanol, with the two

- -ΊΟ2 -

fold amount of ethyl acetate like, sucked off, with little

20 +

Essigester washed and dried: [al _D = + 72 ° -1 ° (methanol, c = 0.998).

In an analogous manner starting from benzyl ~ 2-acetamino ~ 3-0-C [LI- (Dl-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-methyl ^ -2-deoxy-aD-glucopyranoside the 2 "Acetamino-3-O" || L 1 - (»1 -carbamoyl-3 · - (L 1 -. -..- carboxyethyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl methyl 2-desoxy-D-glucose.

Starting from benzyl-3-0- $ Dl- [L _- -I- (D-1-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-2-propiono-amino-α-D-glucopyranoside and glycine benzyl ester p-toluenesulfonate; the 3-0 ~ Ed_-1 ^ LI- [D _- -I-. Carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl-ethyl-2-desoxy-2-propionamino-D-glucose.

Analog are produced:

2-acetamino ~ 3 ~ 0- £ | L »l- [p_-l-carbamoyl-3- (carboxy-methylcarbamoyl) propyl] carbamoyl-äthylj carbamoyl ~ methyIj ₁ -2-deoxy-D-glucose,

2-butyroylamino-3-0- ^ p_-l- ^ I _i -l- [D _- -I-carbamoyl-3- (ll-carboxy-ethyl-carbamoyl) -propyl] - "car-banoyl-äthyIj -carbamoyläthyl3 -2-deoxy-D-glucose,

2-Butyroylamino-3-0-> 1-1- [di-carbamoyl-3- (L-1-carboxyethyl-carbamoyl) -propyl] -carbamoyl-1-yl-carbamoyl-methyl-2-deoxy-D-glucose .

3-0-E ^ L • -! - [p_~ l -carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-ethyl- 1 -carbamoyl-methyl-3-deoxy-2-propiono-amino-D -glucose,

he

2-iso-butyroylamino-3-O-tl L _- -I- [D _- -I-carbamoyl] -3- (L_-1-carboxyi-carbamoyl) -propyl-carbamoyl-propyl-carbamoyl-methyl3-2- deoxy-D ~ glucose,

2 1 1 204 - 403 ~ -

2-iso-butyroylamino-3-O-p-1- (L ₁ -I- [1-carbamoyl-3- (L-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-propyl-carbamoyl-a "thylj-2-deoxy ~ D-glucose,

2-iso-Butyroylamino-3-0-i [! -Ι- [-1 -1-carbamoyl-3- (L-1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-2-methylpropyl-carbamoyl-methyl | -2-desoxy-D-glucose,

2-iso-butyroylamino-3-0-fl) -l- (I ₁ -I- [D_-1-carbamoyl-3- (L-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-2-methylpropyl-1-carbamoyl) ethyl | -2-desoxy-D-glucose 5

2-iso-butyroylamino-3-O-yl-1- [D ^ -I-carbamoyl-3- (carboxymethyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl-1-methyl-2-desoxy-D-glucose .

2-iso-butyroylamino-3-0-> L_-l "" [D_-1-carbamoyl-3- (carboxymethyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl-methyl-2-desoxy-D -glucose,

2-iso-Butyl-o-amino-3-O-fD-1- [1-1-dl-carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoy1-ethyl-1-carbamoyl-ethyl-2-desoxy -D-glucose,

2-iso-butyroylamino-3-0-> L_-l- [D 1-1-carbamoyl-S- (L-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-ethyl-1-ylcarbamoyl-methyl! 3-2- deoxy-D-glucose,

2-iso-Butyroylamino-3-0- | D_-1-Ll - [] Dl-carbamoyl-3- (L-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-ethyl-3-carbamoyl-ethyl-2- deoxy-D-glucose,

2-iso-butyroylamino-3-0-f $ L-l- [D-l-carbamoyl-3- (L-l-car-

ci- - · ^ ~

boxy-propyl-carbamoyl) -propyl] -carbamoyl-ethyl-1-carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetamido-3-O-WL-1- (p-1-carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-2-methyl-propyl-carbamoyl-methyl-1-yl-2-desoxy-D- glucose,

2-acetamino-3-0-) Dl-) 1- (1-carbamoyl-3- (carboxy-methyl-1-carbamoyl) -propyl) -carbamoyl-2-methylpropyl-carbamoyl-ethyl) -1-deoxy-D-glucose .

2 1 1

^ -l- [D-l-carbamoyl-3- (L-I-carboxy-ethylcarbamoyl) -propyl] -carbamoyl-2-ethylpropyl-carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetamino-3-O- £ D-1-fL-1- [D-1-carbamoyl-3- (L-I-carboxy-

c- «- - _

ethyl-carbamoyl) -propyl] -carbamoyl-2-methylpropyl-carbarooyl-ethyl-2-deoxy-D-glucose,

2-Acetamino-3-O-Π LI- [D-1-carbamoyl-3-L-carboxy-propylcarbamoyl) -propyl] -carbamoyl-2-methyl-) -propylj-carbamoylmethyl! -2-deoxy- D-glucose,

2-Butyroylamino-3-0-5ί L-I- [D_-1-carbamoyl-3- (L-1-carboxybutyl-carbamoyl) -propyl) -carbamoyl-ethyl] -carbamoyl-methyl-2-yl-deoxy-D-glucose,

2-acetamido-3-0- D ^ _i ^ -l- L, -L [p ^ -l-carbamoyl-3- (L-1-carboxyethyl-carbamoyl) propyl] carbamoyl-propylj-carbamoyl-ethyl? 2-deoxy-D-glucose,

2-Acetamino-3-0 ~ £ ·} L ₁ -I- [D_-1-carbamoyl-3- (L-1-carboxy-ethylcarbamoyl) -propyl] -carbamoyl-propyl-carbamoyl-methyl-2-deoxy- D-glucosej

2-Acetamino-3-O-p-1-L-1- (D_-1-carbamoyl 1-3- (carboxymethylcarbamoyl) -propyl) -carbamoyl-propyl -carbamoyl-ethyl-2-yl deoxy-D-glucose,

^ -Acetamino-S-O-1-yl-il-tD_-1-carbamoyl-3- (carboxy-methylcarbamoyl) -propyl] -carbamoyl-propyl -carbamoyl-methyl-2-deoxy-glucose,

2-Acetamino-3-O-1-L-1- [D-1-carbamoyl-3- (L-I-carboxy-propylcarbamoyl) -propyl] carbamoyl-ethyl-carbamoyl-methyl-2-desoxy-D-glucose

2-acetamido-3-0- ^ l- ^ D-L-l- [D-l-carbamoyl-3- (L-L "carboxypropyl-carbamoyl) propyl] carbamoyl-ethyl> carbamoyl-äthyli-2-deoxy-D-glucose,

2-Acetamino-3-0-f { LI- [Dl-carbamoyl-3- (L-1-carboxy-2-methylpropyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl-methyl-2-desoxy-D -glucose

21 1 204 -ίο * -.-

2-Ac "etamino-3-O-p-1-1-Ll- [D _- -I-carbamoyl 1-3- (L-1-carboxy-2-methyl-propyl-carbamoyl) -propyl] -carbamoyl- äthylj-carbamoyl-äthyl§-2-deoxy-D-glucose,

2-Acetamono-3-0- £ $ Ll- [Dl-carbamoyl-3- (L-1-carboxy-butylcarbamoyl) -propyl] -carbamoyl-ethylyr- car bamoye-1-yne-1, 5-2-deoxy- D-glucose,

2-butyroylamino-3-O-fc | Ij-I- [D_-1-carbamoyl-3- (carboxy-methyl-carbamoyl) -propyl] -carbamoyl-ethyl-1-carbamoyl-methyl-2-deoxy-D-glucose;

2-Butyroylamino-3-0- | di-1- [L, -l- [^ -l-carbamoyl-S- (Ll-carboxy-propyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl-ethyl-2-desoxy -D-glucose,

2-Butyroylamino-3-0-IIL-1- [D-1-carbamoyl-3- (L-1-carboxypropyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoylmethyl-2-deoxy-D-glucose,

2-Butyroylamino-3-0-cD-IA LI- [Dl-carbamoyl-3- (ll-carboxy-2-methyl-propyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl-ethyl-2-deoxy-D -glucose, 2-butyroylamino-3-0- | iL_-l- [-1 car bamoy 1-3- (LI-carboxy-2-methyl-propyl-carbamoyl) -propyl] -carbamoyl-ethyl-f-carbamoyl -methyli-2-deoxy-D-glucose,

2-Benzoylamino-3-O-IIL_-1- [D-1-carbamoyl-3- (L-1-carboxyethyl-carbamoyl) -propyl] -carbamoyl-ethyl-r-carbamoyl-methyl-2-desoxy-D-glucose,

2-Benzoylamino-3-O-tD-1-L-I- [D-1-carbamoyl-3- (carboxymethyl-carbamoyl) -propyl-carbamoyl-ethyl] -carbamoyl-ethyl-2-deoxy-D-glucose,

2-Benzoylamino-3-O-Fί'L-1- [D-1-carbamoyl-3- (L-1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-propyl-F-carbamoyl-methy I-2-deoxy-D-glucose,

^ -Benzoylamino-S-O- ^ D-l} L-I- [D-l-carbamoyl-3- (carboxymethyl-carbamoyl) -propyl] -carbaxoyl-propylί-carbamoyläthyl ^ -2-deoxy-D-glucose,

2-acetamido-3-0-HL-I- [D-l-carbamoyl-3- (L-1-carboxy-ethyl-

CL j

carbamoyl) -propyl] -carbamoyl-N, N-tetramethylene-carbamoyl-methyl-2-desoxy-D-glucose,. 2-Acetamino-3-0- | D ₁ -I-> LI- [Dl-carbamoyl-3- (L-1-carboxyethyl-carbamoyl) -propyl] -carbamoyl-N, N-tetramethylene-1-carbo-bamoyl-ethyl-halo -2-deoxy-D-glucose,

he

2-ACeUaHiInO-S-O-?) L-I- [D-l-carbamoyl-3- (carboxy-methyl-)

et. - y

carbamoyl) -propyl] -carbamoyl-N, -N-tert-triene. thy learning --car.bamoyl--; methylJ-2-deoxy-D-glucose,

2-acetamido-3-Of D _- -I - ^ - I-tD-l-carbamoyl-3- (carboxy-methylcarbamoyl) propyl] carbamoyl-N, N-tetramethylene -carbamoyläthyli-2-deoxy-D-glucose .

2-Acetamino-3-0-f? L_-l- [D_-1-carbamoyl-3- (L-1-carboxy-1-carbamoyl) -propyl] -carbamoyl-2-hydroxy-ethyl? - carbamoylmethyl II-2- deoxy-D-glucose,

2-Acetamino-3-0-dl-iL-1- [p-1-carbamoyl-3- (L-1-carboxy-ethyl-carbamoyl) -propyl] -carbamoyl-2-hydroxy-ethyl-carbamoyl-ethy! -2-deoxy-D-glucose,

2-Benzoylami.no-3-.0-ii LI- [p-1-carbamoyl-3- (L-1-carboxyethyl-carbamoyl) -propyl] -carbamoyl-2-hydroxy-ethyl-carbamoyl-me-thyl, -2-desoxy-D-glucose,

2-benzoylamino-3-0-FD-I-SL-I- [D-l-carbamoyl-3- (L-1-carboxy

ethyl-carbamoyl) -propyl-1-carbamoyl-2-hydroxy-ethyl-carbamoyl-ethyl-2-desoxy-D-glucose,

2-Acetamino-3-O-CIl-1- [p-1-carbamoyl-3- (L-1-carboxy-methyl) carbamoyl-propyl] -carbamoyl-methyl-carbamoyl-2-ethyl-2-deoxy-D; glucose,

2 "Acetamino-3-0-tp_-1-Ll- [p-i" carbamoyl-3- (L-carboxy-methyl-carbamoyl) -propyl-1-carbamoyl-methyl-carbamoyl-ethyl-2-deoxy- D-glucose,

2-Acetamino-3-O-1-L-I- [D-1-carbamoyl-3- (L, 1-carboxy-methylcarbamoyl) -propyl] -carbamoyl-methyl-1-carbamoyl-methylene -

2-Desoxy-D-glucose,. ,

211

- 401 -

) -3-0- £ d-1) L-I- [D-l-carbamoyl-3- (L-l-carboxy-methyl ·

c- * - ~) -

carbamoyl) -propyl] -carbamoyl-methyl-carbamoyl-ethyl-2-deoxy-D-glucose,

2-Acetamino-3-0-R L · -! - [D-1-carbamoyl-3-QL-1-carboxymethylcarbamoyl) -propyl-carbamoyl-methyl-carbamoyl-methyl-2-deoxy-D-glucose.

Example 39 ·

A solution of 4.2 g of benzyl 2-acetamino-3-O-FIP_ 1- [p-1-carbamoyl-3- (L-5-benzyloxycarbonylamino-5-> carbamoyl-pentylcarbamoyl) -propyl] -carbamoyl- Ethyl-carbamoyl-methyl-2-deoxy-aD-glucopyranoside in 100 ml of methanol / water 2/1 is hydrogenated in the presence of 0.5 10% palladium / carbon at atmospheric pressure and room temperature. The pH of the reaction mixture is kept at pH 6 by addition of 1N-hydrochloric acid. After completion of the hydrogen absorption is filtered off from the catalyst and the filtrate is evaporated to dryness. The residue is dissolved in a little distilled water and freeze-dried. This gives the 2-acetamino-3-O-LJ- [Dl-carbamoyl-3- (LS-amino-S-carbamoyl-pentylcarbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl-methyl -2- deoxy-D-glucose hydrochloride as a white powder.

The starting material used can be prepared as follows:

A solution of 15 g of α-carbobenzoxy - ^ - t-butoxycarbonyl-L-lysine methyl ester in 100 ml of a saturated methanolic ammonia solution is allowed to stand for 48 hours at room temperature and evaporated to dryness. The product, a-carbobenzoyl- ^ - t-butoxycarbonyl-L-lysine amide is

20

recrystallized from methanol / ether, mp. 142 ⁰ C, [al _D -3 ° -1 ° (methanol, c = 1.018).

- ιοί? -

A cooled to 0 ⁰ C solution of 3 g of a-carbobenzoxy-η-butyloxycarbonyl-L-lysinamide in 25 ml of trifluoroacetic acid is stirred for 1 hour and then evaporated to dryness. The residue is mixed with 20 ml of saturated sodium chloride solution and ice, made alkaline with concentrated ammonia solution and extracted with ethyl acetate. The organic phase is washed with saturated brine, dried over sodium sulfate and evaporated to dryness. This gives the a-carbobenzoxy-L-lysinamide as a white foam.

A solution of 5.6 g of benzyl-2-acetamido-3-0- [L ₁ -I- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -. carbamoyl-methyl-2-deoxy-α-D-glucopyranoside and 2.8 g of α-carbobenzoxy-L-lysine amide in 30 ml of N, N-dimethylformamide is treated with 1.1 g of N-hydroxysuccinimide and 2.2 g of dicyclohexylcarbodiimide and stirred at room temperature for 40 hours. The crystallized dicyclohexylurea is filtered off and washed with 10 ml of Ν, Ν-dimethylformamide. The filtrate is evaporated to dryness and the residue is extracted with 100 ml of distilled water for 30 minutes. The insoluble matter is filtered off with suction, washed with water, dried and the benzyl-2-acetamino- 3-0 <ή L_-l- [p_ ~ l- carbarnoyl-3- (L-5-benzyl oxy car bony lamino) 5. carbamoyl-pentyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl-methyl3-2 "desoxy-α-D-glucopyranoside. The product V7 'is recrystallised from methanol / ethyl acetate'.

Analog, is produced:

2-Acetamino-3-0-i-1-ol-{p-1-carbamoyl-3- (5-amino-1-carbamoyl-pentyl-carbamoyl) -propyl] -carbamoyl-ethyl-carbamoyl-methyl-2-desoxy D-glucose hydrochloride.

21 1 204 - ^Λα * ~

Example 40

A solution of 2.8 g of Benzy1-3-0- ([LI- (DI-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoylmethyl {^ -deoxy) -isobutyroylamino-a-glucopyranoside in 80 ml of methanol / distilled water 1/1 is hydrogenated in the presence of 0.3 g of 10% palladium / carbon at normal pressure and 45 ^° C. After work-up and freeze-drying of the residue, the 3-O-j-1-l (D) 1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-methyl | -2-desoxy-2-isobutyroylamino-D-glucose as a white powder.

The starting material used is prepared as follows:

A mixture of the solutions of 21.0 g of benzyl 2- "amino-2-deoxy-4,6-0-isopropylidene-aD-glucopyranoside in 150 ml of chloroform and 9.0 g of potassium bicarbonate in 150 ml of distilled water is added to O with stirring cooled ⁰ C and treated dropwise with 8.5 ml of isobutyric acid chloride. After stirring for 1 hour at room temperature, the organic phase is separated, washed with ice-cold 0.5 η hydrochloric acid, water, a saturated sodium bicarbonate solution and again water, dried and evaporated. the product benzyl-2-deoxy-2-isobutylamino-4.6-0-isopropylidene-.alpha.-D-glucopyranoside is crystallized from 150 ml of ether, mp. 82 ⁰ C, [a] ^ ° = + 109 ° -1 ° (Chloroform, c = l, 017).

A solution of 15.1 g of benzyl 2-deoxy-2-isobutyroylamino-4,6-0-isopropylidene-aD-glucopyranoside in 150 ml of absolute acetonitrile is added in a nitrogen atmosphere with exclusion of moisture and stirring with 1.9 g of sodium hydride (Fluka , Prect.) And stirred at 40 ⁰ C for 1.5 hours. Subsequently, the reaction mixture is cooled to -10 ⁰ C and treated with 5.6 ml of methyl bromoacetate. It is stirred for 15 minutes in an ice bath and 2 hours

- ΛΛΟ -

Room temperature .after. After workup, the benzyl-2-deoxy-2-isobutylamino-4,6-0-isopropylidene-3-O-methoxycarbonyl-methyl-aD-glucopyranoside, which is recrystallized from ether / petroleum ether, mp. 119-120 ⁰ C, [ _a ] 20 _{= +152} o + 1 ° (chloroform, c = 0.963).

A solution of 3.16 g of benzyl 2-deoxy-2-isobutyroylamino-jo-O-isopropylidene-SO-methoxycarbonylmethyl-D-glucopyranosidine, 30 ml of methanol and 10 ml of ins. Sodium hydroxide solution is allowed to stand at room temperature for 1 hour. Add 3 ml of hydrochloric acid and evaporate the solution to dryness. The residue is dissolved in 50 ml of N ₅ N-dimethylformamide and treated with 2.26 g of tert-butyl La-aminobutyroyl-D-isoglutamine hydrochloride and 1.75 EEDQ and allowed to stand at room temperature for 24 hours. Add another 2 g of EEDQ, and allow the mixture to stand for a further 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 in hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness. There is thus obtained the benzyl-3-0-2. [L _- -I- (D ~ 1-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl-carbamoyl-2-diethyl-2-deoxy-2-isobutyl-4-amino-4, 6-0- "isopropylidene-aD-glucopyranoside tert-butyl ester as a white foam.

This product is dissolved in 60 ml of glacial acetic acid, mixed with 60 ml of water while stirring and allowed to stand at room temperature for 24 hours. This solution is evaporated to dryness in a water-jet vacuum and the residue is dissolved in ethanol. It is filtered with activated charcoal and evaporated again to dryness. This gives the benzyl-3-0 - ^ [L-! - [Dl-carbamoyl-S-carboxy-propyl) -carbamoyl-propyl] -carbamoylmethylv-2-deoxy-2-isobutyroylamino-a-glucopyra- noside tert-butyl ester as a white amorphous material from

- ΑΛΛ -

90 A- Ια] ρ = + 74 ° -1 ° (methanol, c = 0.950).

A cooled to 0 ⁰ C solution of 3.9 g of this tert-butyl ester in 40 ml of 98% trifluoroacetic acid is stirred for 1 hour at ^{0 0} C and poured onto 500 ml of absolute ether. The crystallized product is filtered off, washed with ether and dried in vacuo. The resulting powder is dissolved in 40 ml of water / tetrahydrofuran 1/1 and stirred for 30 minutes with 50 ml of ion exchange heart Dowex 3 (acetate form). The ion exchanger is filtered off and washed with 500 ml of tetrahydrofuran / 1-acetic acid. The filtrate is evaporated to dryness and the product crystallized from methanol / ether, mp. 205-206 ⁰ C.

Example 41

A solution of 3.1 g of benzyl-3-0-i [L1- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-1-carbamoyl-methyl-2-deoxy-2-isobutyroylamino-aD Glucopyranoside in 40 ml of methanol / water 1/1 is hydrogenated in the presence of 10% palladium / carbon at atmospheric pressure and 45 ° C. After working up, the 3-0-j [LI- (DI-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl? -2-deoxy-2-isobutyroylamino-D-glucose is obtained as a white powder by freeze-drying.

The starting material used is prepared analogously as described in Example 40:

In the condensation of benzyl 3-O-carboxymethyl ^ -deoxy ^ -isobutyroylamino ^ jo-O-isopropylidene-D-glucopyranoside sodium salt with L-alanyl-D-isoglutamine int. Butyl ester hydrochloride, the benzyl-3-OA [L -1- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-methyl-desoxy-isobutyroylamino-jo-O-isopropylidene-aD-glucopyranoside-tert-butyl ester as a white foam.

0 (ί Ä -ΛΛ *

The hydrolysis of 4.6 ~ 0 Isoprop5 ^'> lidengruppe are benzyl-3-0-HL-I - (DI-carbamoyl-3-carboxypropyl.) - 1-carb amoy a'thy I] carbamoyl-methyl -2 deoxy-2-isobutyroylamino-D-gluco-

20

pyranoside tert-butyl ester of [<xJ _D = + 71 ° + 1 ° (methanol, c = 0.956). , ,

The tert-butyl ester is cleaved with trifluoroacetic acid. This gives the benzyl-3-Ο-ί [L1- (Dl-earba-moylo.l-3-c arboxy -pr ω py1) -carb amo y1-ay1] -carb-amoy 1 -one thy "- 2-deoxy-2-isobutyroylamino-aD-glucopyranoside as a white amorphous product."

Example 42

A solution of 4.2 g of benzyl 2-acetyl-N-methylamino-3-Oj [LI- (Dl-carbamoyl-S-carboxy-propyl-O-carbamoyl-ethyl) -carbamoy-1-methyl] -2- deoxy-D-glucopyranoside in 75 ml Me than oil / water 1/1 was hydrogenated in the presence of 0.5 g of 10% palladium / charcoal at atmospheric pressure and 45 ⁰ C. the catalyst is filtered off and the filtrate evaporated to dryness. the residue is dissolved in a little distilled water and freeze-dried to give the 2-acetyl-N-methyl-amino-3-0- ^ [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoylethyl] -carbamoylmethyIj-2-desoxy -D-glucose as a white powder.

The starting material used is prepared as follows:

A solution of 8.5 g of benzyl 2-aceto-amino-2-deoxy-4,6-O-isopropylidene-3-0-methoxycarbonylmethyl-CC-D-glucopyranoside in 80 ml of absolute acetonitrile is stirred in a nitrogen atmosphere with exclusion of moisture with 0.75 g of sodium hydride (Fluka, pract.) and stirred at 40 ⁰ C for 1 hour. The reaction mixture is then cooled to room temperature and dropped.

21 1

during 4 hours with a solution of 6.0 g of methyl iodide in 50 ml of absolute acetonitrile. After a further 3 hours, the reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate, this solution washed with water, dried over sodium sulfate and evaporated to dryness. This gives the benzyl 2-acetyl-N-methylamino-2-deoxy-4,6-0-isopropylidene-3-O-methoxycarbonylmethyl-cc-D-glucopyranoside as yellow OeI of Rf value 0.45 Kieselgeldlinnschichtplatten in the system methylene chloride / ethyl acetate 85/15.

A solution of 4.4 g of benzyl 2-acetyl-N-methylamino-2-deoxy-4,6-0-isopropylidene-3-O-methoxycarbonylmethyl-α-D-glucopyranoside in 60 ml of methanol and 15 ml of 1N sodium hydroxide solution is added 1 hour left at room temperature, treated with 5 ml of 1N hydrochloric acid and evaporated to dryness. The resulting benzyl 2-acetyl-N-methylamino-3-O-carboxymethyl-2-deoxy-4,6-0-isopropylidene-cc-D-glucopyranoside sodium salt is dissolved in 50 ml of N, N-dimethylformamide and extracted with 3 , 2 g of L-alanyl-D-isoglutamate tert.butyl ester hydrochloride condensed in the presence of 2.5 g of EEDQ. The solution is evaporated to dryness in vacuo and the residue is dissolved in ethyl acetate. This solution is washed with water, ice-cold IN hydrochloric acid, water of a saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness. One obtains the benzyl-2-acetyl-N-methylamino-3-0- \ [L_-l- (Dl-carbamoyl-S-carboxy-propyl) -carbamoyläthyl] -carbamoyl-methylj ^ -deoxy ^ jo-O- isopropylidene-D-glucopyranoside tert-butyl ester as a yellowish foam. This product is dissolved in 45 ml of 0 ⁰ C precooled 95% trifluoroacetic acid and stirred at 0 ⁰ C for 1 hour.

The reaction mixture is poured into 400 ml of absolute ether, the precipitated product is filtered off with suction, washed with ether and dried. By treating this substance with the Dowex 3-acetate ion exchange heart, the trifluoroacetic acid-free benzyl 2-acetyl-N-methylamino-3-0-i [L 1 - (-l-carbamoyl-3-carboxy-propyl) - carbamoylethyl] -carbamoyl-methyl-2-deoxy-aD-glucopyranoside as a white powder. ^{; ;} '-'"

In a similar way are prepared:

2-Acetyl-N-methyl-amino-3-O-iD-1- [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-ethyl] -carbamoyl-ethyl-2-desoxy-D- glucose,

2-Acetyl-N-methyl-amino ~ 3-0- $ "D-I- [L-I- (D-I-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-ethyl-f-2-deoxy-D-glucose,

/ · 2-Acetyl-N-methyl-amino-3-0- ^ · [L-1- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-propyl] -carbamoyl-methyl-2-deoxy-D -glucose,

2-acetyl-N-methyl-amino-3-0 -} [L-1- (D-1-carbanyl-3-carboxypropyl) -carbamoyl-2-methyl-propyl] -carbamoyl-methyl-2-deoxy-D-glucose,

2-Acetyl-N-methyl-amino-3-O-ip _-- L · - [LI- (Dl-carbamoyl-3-carboxy-propyl) -carbamoyl-2'-methyl-propyl] -carbamoyl-kylthyl-2 deoxy-D-glucosej

3-0-S [L-1- (D-1-carbamoyl-3-carboxy-propyl) -carbainoyl-ethyl] -carbamoyl-methyl-2-deoxy-2-propionyl-N-methyl-amino-D-glucose,

2-butyryl-N-methyl-amino-3-0- | _ [L ~ l- (Dl-carbamoyl-3-carboxy-propyl) carbamoyl-ethyl] carbamoyl-methyl ^ -2-deoxy-D-glucose ,

Example 43

The trimethylsilyl ethers can be e.g. create as follows: ". '

2.1 1 2 <

0.3 g of 2-benzamido-2-deoxy-3-0-f [Ll- (Dl-carbamoyl-3-carboxypropyl) -carbamoyl-ethyl] -carbamoyl-raethylj D-glucose is dissolved in 3 ml of dimethylformamide and mixed with 0.4 ml of bis-trimethylsilylacetamide. After 5 hours at 35 ° is concentrated by evaporation in a vacuum to the syrup, from which one can deposit acetamide formed by dissolving in absolute ether or absolute ethyl acetate. After renewed intervention

20

vaporizing a colorless syrup with [a J _n = + 15 ° (c = 0.8, dioxane).

Similarly, syrupy 2-acetamino-2-deoxy-3-0-j [LI- (Dl-carbamoyl-3-trimethylsilyl-carboxy-propyl) -carbamoylethyl] -carbamoylmethyl-1,4,6-tri-trimethylsily is obtained. l-D-glucose with [α] «. = -10 ° (c = 0.91, dioxane). - υ

Upon contact with water, the trimethylsilyl ester group is rapidly saponified so that these derivatives are also suitable for coupling.

Example 44 ·

A 5% solution of benzyl 2-acetamido-3-O-f L-1- (p-1- (L-1-carboxy-ethyl) -carbamoyl-3-carboxypropyl) -carbamoyl-ethyl-carbamoyl methyl 2-2-deoxy-aD-glucopyranoside in tetrahydrofuran / water 2/1 is hydrogenated in the presence of 10% palladium on carbon at normal pressure and room temperature After the theoretical amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is freeze-dried. There is thus obtained the 2-acetamido-3-O-1 L- [JD-I- (L-1-carboxy-ethyl) -carbamoyl-3-carboxypropyl] -carbamoyl-ethyl-carbamoyl-methyl-2-desoxy-D glucose as white powder Rf value in thin-layer chromatogram = 0.21 (ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10). ".

Analogously, the derivative with the true muramic acid is obtained.

The starting material can be prepared as follows:

5.68 g of N-tert-butoxycarbonyl-L-alanyl-D ^ -7-benzyl-glutamyl-L-alaninebenzylester are dissolved in a mixture of 5 ml of trifluoroacetic acid and 5 ml of 1,2-dichloroethane and 16 hours under the exclusion of moisture left at R.Aümtemperatur left. This solution is diluted with 50 ml of tetrahydrofuran, cooled in an ice bath and neutralized with triethylamine. After the addition of the solution of 3.7 g of benzyl-2-acetamido-3-carboxymethyl-2-deoxy-aD-glucopyranoside and 1.38 ml of triethylamine in 100 ml of tetrahydrofuran, the whole is treated with 2.6 g of 2-ethoxy-N -äthoxycarbonyll, 2-.dihydroquinoline and 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 2N hydrochloric acid, water, a saturated sodium bicarbonate solution and water, filtered and freed from solvent. There is thus obtained the benzyl-2-acetamido-3-0-IIL-1- [di- (1-carboxyethyl) carbamoyl-3-carboxy-propyl] -carbamoyl-ethylcarbamoyl-methyl-2-deoxy-dD-glucopyranoside colorless powder, Rf »value = 0.48 (in identical system).

The starting material used can be prepared as follows:

7.15 g of N-tert-butoxycarbonyl-L-alanyl-D-glutamic acid 7-benzyl ester and 6.15 g of L-alanine benzyl ester p-tolulsulfonate are dissolved in 100 ml of anhydrous dimethylformamide. It is cooled in an ice bath and added with stirring successively 4.03 g of N-Hydroxysuecinimid, 3.61 g of dicyclohexylcarbodiimide and finally 1.95 ml of N-methylmorpholine. After 6 hours of stirring at 0 ° and 15 hours at

211

- 44? -

Room temperature, the suspension is cooled, the precipitate (dicyclohexylurea and morpholine hydrochloride) filtered off and the Fil'trat evaporated. The residue is taken up in ethyl acetate, washed several times with water, in citric acid and in sodium bicarbonate solution and again water. The ethyl acetate solution is dried, evaporated and the crystalline residue is recrystallised from ethyl acetate / petroleum ether 1/1, mp 135-136 °, [ α] .gamma. = -9.degree. ± 1.degree. (C = 1, methanol), Rf value = 0.82 (in the above system) and 0.86 (acetonitrile / water 3: 1). ,

Instead of alanine, the protected dipeptide can be extended analogously with other natural L-amino acids.

Example 45 7.5 χ 10 killed Tripanosoma cruzi parasites [pathogens of Chagas disease] are dissolved in a solution of 50 mg 2-cetamino-3-0- [LI- (D-carbamoyl-3-carboxypropyl) -carbamoylethyl] - carbamoyl-methyl-2-desoxy-D-glucose-N-hydroxysuccinimide ester suspended in 6 ml of physiological buffer solution. The suspension is incubated for two hours at 37 ⁰ C. Thereafter, the muramyl dipeptide-conjugated parasites are sedimented by centrifugation. The sediment is washed by resuspension in physiological buffer solution and centrifuging again. The washed parasite-muramyl dipeptide conjugates are suspended in physiological buffer solution and used for immunization.

The quantitative determination of muramyl dipeptide coupled to the trypanosomes is carried out as described in Example 1 using the Morgan-Elson reaction and yields 50-70 mg muramyl dipeptide per mg trypanosomes.

Claims (1)

Berlin, d.12.7.1979 AP A 61 "K / 21T 204 55 084 18 Invention sanction. > o.Process for the preparation of novel antigenic derivatives consisting of an antigen and at least one, optionally, via a bridge member, covalently linked muramyl peptide of the formula I. (D wherein A is the residue of an antigen, Z is a bridge member, MP is the residue of a muramyl peptides and η is an integer greater than 0, characterized in that an optionally linked with bridge members antigen with optionally linked with bridge members-muramylpeptiden, one of the two Parts of free amino, hydroxy or mercapto group and the other carboxylic acid group condensed together « 2 "process according to item 1, characterized in that one reacts the one compound in the form of an activated carboxylic acid with the other as a free amino, hydroxy or mercapto compound, Process for the preparation of muramyl peptides of the general formula CH ₂ OR ₆ (II) Ro - CH (D) I ¹⁰ I ¹¹ CH - CH ₀ CH - R CON - CH - COH - CH - vu _o , Rr ₇ (L) Rq (D) «12Ö ~~ Berlin, d "12.7 · 1979 AP A 61 K / 211 204 55 084 18 where X is a carbonyl group, R is hydrogen, alkyl is unsubstituted or substituted benzyl or acyl, R _{2 is} optionally substituted alkyl or carbocyclic aryl _s / R 'and Rg are each independently hydrogen, alkyl, optionally substituted benzyl or acyl, R 1 is hydrogen or alkyl, at least one of R ", Rq and R, - lower alkyl in the first place-methyl _s and the other hydrogen, R _{8 is} hydrogen, Uiederalkyl, free _f leached or etherified Hydroxiliederalkyl, free, esterified or etherified mercapto-lower alkyl, free or acylated amino-lower alkyl, cycloalkyl having 5 or 6 carbon atoms, cycloalkyl-loweralkyl whose cycloalkyl radical contains 5 or 6 carbon atoms, optionally substituted aryl or aralkyl ,. nitrogen-containing heterocyclyl or heterocyclyl-lower alkyl, R ^ and Rg together also alkylene having 3 or 4 carbon atoms, and the rest and independently one optionally esterified or amidated carboxy radical and R-- also denote hydrogen, characterized in that in a conventional manner a compound of the formula CH ^ OR? (IV) COOH X _$ . and R ₅ R ₂ and RR ° and I ~ have the abovementioned meaning for the radicals R 1 * ^ 4 or" or for Berlin, d _# 12.7.1979 AP A 61 Κ / 211'204 55 084 18 a readily cleavable protecting group, or a DeriTat thereof with a compound of formula HlT-CH-COlT - CHCH ₂ GH - (L) (V) Wherein Rg, ILq, R ^ and R ^ _{2 have} the meaning of R _Q , R-jq »RJ ₁ ; round R ^ ₂ , with the proviso that present in these residues carboxy and, if desired, free hydroxyl groups easily cleavable protecting groups are protected, condensed and optionally splits off existing protecting groups, or that in a known per se, a compound of formula IV
CH ₀ - OR? 0 - (VI) wherein R, R ?, R ₂ , R °, RgjRr-r and Rg have the abovementioned meaning, with a compound of formula -120- Berlin, d. 12.7.1979 AP A 61 K / 211 204 55 084 18 R ' 10 HN-CH-CH ₂ CH , ο
¹ 12 (VII) wherein "and R? _{2 have} the abovementioned meaning with the proviso that present in the radicals Rg _S , R ° qj R ° .j and R ° ₂ existing carboxyl and, if desired, free hydroxy groups are protected by readily cleavable protecting groups, condensed and any protecting groups present, or that you have a connection ,O <4 ° 0 - , Ο (VIII) Έ - X - R wherein X ₅ Rj R ?, R? Rr and R ₁ ^ have the abovementioned meaning, and optionally present therein hydroxy groups are protected with a readily cleavable protecting group, with a compound of the? ormel r: CH - CONCH 11 CON - CH · CH ₂ CH - where Z is a reactive esterified hydroxy represents lgruppe and R? -J υ.ηα.-Έ? ₂ the above-mentioned - 133 - Berlin, d.12.7.1979 AP A 61 K / 211'204 55 084 18 have any given meaning and, if applicable, splits off existing protective groups » 4e Process for the preparation of muramyl peptides of the general formula R ₃ CH (D) 13 rr R (II) , 8 j 10 CON - CH - CON - CH - CH ^ CH - R wherein X is a carbonyl group, R ^, R and Rg 'tri-lower alkylsilyl, primarily trimethylsilyl, Rp optionally substituted alkyl or carbocyclic aryl, R ^ hydrogen, or alkyl, R ^ and R ..-. Hydrogen or IiT ie the alkyl, Ro V / asserstoff, Hiederalkyl, free, supersaturated or etherified hydroxy lower alkyl, free, esterified or etherified mercapto-lower alkyl, free or acylated amino lower alkyl, cycloalkyl having 5 or 6 carbon atoms, cycloalkyl lower alkyl, its cycloalkyl radical 5 or Contains 6 carbon atoms, optionally substituted aryl or aralkyl, nitrogen-containing Heterocyclyl ~ or AJZl- Berlin, d-, 12o7.19.79 AP A 61 K / 211 204 55 084 18 Heterocyclyl-lower alkyl, R "and Rg also alkylene having 3 or 4 carbon atoms, Rq is hydrogen or alkyl and the radicals P ^ ₀ , R ^ Vind R ^ ₂ independently an optionally esterified oä.er amidier th carboxy vmd. R "^ Yfesserstoff also bedeutenj ₉ characterized in that known per se, a compound of formula .Weise - · ·· ;; - -: CH ₂ OH (XI) CH (D) COl - CH - COI - CH CH ₂ CH - ¹ I "R, with a reactive ester of a Ti'i-lower alkylsilyl compound g