WO2018172129A1

WO2018172129A1 - Sialic acid derivatives with c-c triple bond, and preparation thereof

Info

Publication number: WO2018172129A1
Application number: PCT/EP2018/056147
Authority: WO
Inventors: Horst Prescher; Reinhard Brossmer
Original assignee: Horst Prescher; Reinhard Brossmer
Priority date: 2017-03-22
Filing date: 2018-03-13
Publication date: 2018-09-27
Also published as: DE102017002810A1

Abstract

The invention relates to sialic acid derivatives of formula (I) which contain a C-C triple bond, methods for the preparation thereof, conjugates produced therefrom and drugs containing same, wherein the symbols have the meanings defined in the claims.

Description

Sialic acid derivatives with C-C triple bond and their preparation

The invention relates to derivatives of sialic acid, processes for their preparation, their use, in particular as active pharmaceutical ingredients, conjugates of these derivatives and pharmaceutical compositions containing such compounds.

Sialic acid is the generic term for a family of 9-carbon sugars that are all derivatives of neuraminic acid (new) and keto-deoxy-nonulosonic acid (KDN). Typically, these are located at the exposed non-reducing ends of oligosaccharide chains. Sialic acids play diverse roles in mammals and in the human organism (Schauer (2004) Zoology, 107, 49-64; Varki (2008) Trends in Mol. Med., 14, 8, 351-360). Furthermore, they are used by many pathogens, e.g. to achieve efficient infection or to escape the host's immune system (Glycoconjugate J. 2006, vol. 23, issue 1-2, all articles). Many such functions are regulated by proteins that recognize sialic acids (Lehmann et al (2006) Cell-Mol. Life Sci. 63, 1331-1354).

A subset of such proteins are the Siglecs. Siglecs are Ig-type lectins characterized by an N-terminal V-Set domain that allows specific recognition of sialic acids. An overview of the types of siglec proteins known to date and diseases potentially treatable with siglec inhibitors can be found in Trends in "Pharmacological Sciences 2009, 30 (5), 240-248" and "Current Medicinal Chemistry 201 1, 18, 3537-3550 "and the references included. In particular, siglecs are also useful as therapeutic targets when sialic acids or their derivatives are linked to other pharmaceutically active substances (Angata et al 2015 Trends Pharmacol Sci. 36, 10, 645-660).

CD22 (Siglec-2) is strongly expressed on B cells. It is known that certain monomeric derivatives of sialic acid with a carboxyalkyl as glycosidically bound Substituents at position 2 act as ligands for CD22, show a very high affinity and have potential suitability as drugs (Prescher et al., 2014 ACS Chem Biol.9 (7): 1444-50; WO2015128344; Madge et al., 2016 Scientific Reports 6, Article Number: 36012).

It is further known that sialic acids and their derivatives, in particular those with affinity for siglec-2, can be used for the preparation of therapeutically suitable conjugates (Courtney et al (2009) PNAS 106, 8, 2500-505, Collins et al (2006 ) Journal of Immunology 177, 2994-3003; Chen et al., 2010, Blood 1 15 (23): 4778-86; Schweizer et al., Eur J Immunol., 2012, 42 (10): 2792-802; Macauley et al 2013 J Clin Invest., 123 (7): 3074-83; Macauley et al., 2016 J. Allergy Clin Immunol. Pii: S0091-6749 (16) 30799-0).

Although the known derivatives are suitable for attachment to a cargo and the conjugates prepared have the desired properties, there is still a broad scope for improvement, in particular as regards valence, affinity and selectivity, and pharmacological behavior. There is also room for improvement in the production of conjugates. There is also room for improvement regarding the possibility of linking with a cargo. There is also room for improvement in pharmacological compatibility and modes of administration, as well as stability in plasma and liver.

The object of the invention is to provide compounds and methods with which advantages are achieved, at least in one or more of said areas.

It has been found that certain monomeric sialic acid derivatives having a 9-position substituted nitrogen, further substituents at the 4-position, and a triple bond-containing substituent at the 2-position are especially useful as siglec-2 (CD22) ligands and Production of conjugates are suitable. In addition, manufacturing processes have been found that allow flexible and simplified production with improved yields.

The invention therefore relates to sialic acid derivatives of the formula (I)

where the symbols have the following meanings:

A ¹ is a group D'-fY ^ -D ² -], ^;

D ¹ is a mono- or polycyclic aromatic, partially unsaturated or saturated C ₃ -C ₁₄ -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to twelve-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted are substituted by a group X;

D ² is a mono- or polycyclic aromatic, partially unsaturated or saturated C ₃ -C ₁₄ -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted are substituted by a group X;

Y ¹ is -C (O) -, ~S (O) ₂ -, ~CH ₂ C (O) -, ~ NHC (O) - or -OC (O) -, wherein ~ denotes the bond to the group A ¹ ;

Y ² is -O- or a bond;

A ² is a group -N (R ^y ) -W or -N (H) -W;

W is

a) a group -SO 3 M or -SO ₂ NR ^x ₂ or b) a group D ³ -Y ³ -;

Y ³ is a bond or group selected from -NHC (O) -, OC (0), - S (O) 2-, C (O) -, CH ₂ C (O) - or CH ₂ S (0) ₂ -, wherein ~ denotes the bond to the group D ³ ;

D is ³

a) Ci-C _ö alkyl, wherein optionally one or more non-terminal CH ₂ groups by O, N (R) and / or C (O) are replaced and wherein in said groups optionally one or more H atoms a group X are replaced, b) mono- or polycyclic aromatic, partially unsaturated or saturated C ₃ -C hydrocarbon residue or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, wherein said radicals unsubstituted or a - or substituted several times by a group X;

A is a C ₃ -Ci5 ₀ -alkanediyl, where optionally one or more CH ₂ groups are replaced by S, S (0) _2, O, N (R ^X) and / or C (O);

A ⁴ is a group -C = CH, bicyclo [6, l, 0] non-4-yn-9-yl, dibenzocyclooctynyl, biarylazacyclooctinonyl, cyclooctinyloxy, cyclooctynyl or

Dimethoxyazacyclooctinyl, wherein in said groups optionally one or more H atoms are replaced by a group X; each X is independently selected from halogen, cyano, nitro, hydroxy, carboxyl, carboxymethyl, hydroxylamino, S0 ₃ M, OS0 ₃ M, S0 ₂ NH _2, S0 ₂ CF _3, P0 ₃ M, OP0 ₃ M, cyanomethyl, alkyl, Haloalkyl, alkyloxy, haloalkoxy, amino, alkylamino, dialkylamino, trialkylamino, alkylcarbonyl, alkylsulfonyl, alkylsulfoxyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, dialkylaminocarbonyl or oxo (= 0), the alkyl groups and alkoxy groups in these radicals Contain 1 to 4 carbon atoms; m is 0 or 1

Z is -O- or -S-; R ¹ is -C (O) OM; R ² is H, OH, OR ^y or F; R ³ is H or F;

R ⁴ is -N (R ^x ) C (O) CH ₂ OH, -N (R ^x ) C (O) R ^x , -NHC (0) CH ₂ F or -NHC (O) CH ₂ Cl; R ⁵ , R ⁶ are the same or different and selected from OH and OR ^x ;

M is a cation; each R ^x is independently selected from H, R ^y and R ^z ; each R ^y is independently selected from C 1 -C ₄ alkyl, phenyl and benzyl and each R ^z is independently selected from -C (O) -Ci-C ₄ alkyl, -C (O) phenyl and

C (0) -CH ₂ -phenyl.

The invention also provides a process for the preparation of sialic acid derivatives of the formula (I). They can be prepared, for example, by a process as shown in Scheme 1.

Scheme 1: A process for preparing sialic acid derivatives of the formula (I) wherein T is a leaving group useful for glycosylations (preferably alkyl or aryl), Q is an amino-protecting group, preferably a group C (O) OR ^y and the other symbols are the have meanings given for formula (I):

A sialic acid derivative of the formula (II) is reacted with a tert-butyl-protected hydroxycarboxylic acid to obtain a sialic acid derivative of the formula (III) wherein Z is O. A sialic acid derivative of the formula (III) where Z is S can be prepared analogously to known methods (see, for example, WO 98/03573) from methyl 4-azido-5-acetamido-7,8,9-tri-O-acetyl-2-chloro 3, 4,5-trideoxy-D-glycero-β-D-galacto-2-nonulopyranosonate (Bioorg. Med. Chem. Lett., 1994, 4, 2457-2460). Subsequently, the sialic acid derivative of Forniel (III) is converted with Z equal to O or S by removal of the acetyl radicals, reduction of the azide and introduction of a protective group into a sialic acid derivative of the formula (IV). Removal of the acetyl radicals from the sialic acid derivative of the formula (III) can be carried out before or after reduction of the azide and introduction of a protective group Q at position 4. The sialic acid derivative of formula (IV) is converted to a sialic acid derivative of formula (V) by replacing the hydroxyl group at position 9 with an azide. By reduction of the azide at position 9 of the sialic acid derivative of the formula (V) and reaction of the resulting amine with an amine-reactive reagent, a sialic acid derivative of Forniel (VI) is obtained. The sialic acid derivative of formula (VI) is then attached by removing the amino-protecting group Q at position 4 as well as the tert-butyl protecting group Position 2 and converted by reaction with amine-reactive reagents in a sialic acid derivative of the formula (VII). The sialic acid derivative of the formula (VII) is reacted at the free carboxyl group -COOM with an amine containing a group A ⁴ . By subsequent deprotection of the carboxyl group -COOMethyl a Sialinsäurederivat of formula (I) is obtained.

Alternatively, the sialic acid derivative of formula (VII) can be reacted on the free carboxyl group -COOM with a monoprotected diamine. The step lengthens the group A ³ where the groups -N (H) - and -C (O) - of the newly formed amide replace -CH ₂ - groups in A. Subsequent deprotection of the carboxyl group -COOMethyl and of the protected amine gives a sialic acid derivative of the formula (VIII). Subsequent reaction of the amine of the sialic acid derivative of the formula (VIII) with an amine-reactive reagent containing group A ⁴ gives a sialic acid derivative of the formula (I).

Sialic acid derivatives of the formula (I) in which none of the -CH ₂ groups in the group A ^{3 are} replaced by the groups -N (H) - and -C (O) - can be prepared by reacting sialic acid derivatives of the formula (II ) are reacted directly with a hydroxyalkyne (HO-alkanediyl-C = CH). All further reactions can be carried out analogously to the steps from Scheme 1, the said reactions on A, such as the removal of the protective group, are no longer necessary.

Sialic acid derivatives of the formula (I) in which the group R ² is OH or OR ^y , can be prepared analogously to known methods (Madge et al., 2016, Scientific Reports 6, Article number: 36012) from methyl 5-acetamido-7,8 , 9-tri-O-acetyl-2,6-anhydro-4-azido-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonate (Carbohydr. Res. 1993, 244, 181 -185).

The invention likewise provides a pharmaceutical preparation (medicament) comprising at least one sialic acid derivative of the formula (I) or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

The invention further provides the use of a sialic acid derivative of the formula (I) or a pharmaceutically acceptable salt or prodrug thereof as a medicament. By way of example, modifications of individual substituents in pharmacologically active molecules to prodrug forms are described in Nature Drug Discovery Reviews, 2008, 7, 255-270 and in Hydrolysis in Drug and Prodrug Metabolism, Wiley-VCH, 2003, Bernard Testa and Joachim M. Mayer.

The invention also relates to conjugates of a sialic acid derivative of the formula (I) and a component selected from (i) a cargo, (ii) a polymer, (iii) a polymer-linked cargo, (iv) a nanoparticle and (v) a nanoparticle-linked one Cargo, where "linked" preferably means "covalently bound".

The invention relates, for example, to the use of a sialic acid derivative of the formula (I) in a process for linking to a cargo and conjugates resulting therefrom; the covalent attachment of the cargos to the sialic acid derivative takes place by reaction of the CC triple bond of group A ⁴ .

According to the invention, cargo is understood to mean a low-molecular or high-molecular substance which has a biological action or a diagnostically useful effect and is transported to its site of action by means of sialic acid derivative (I); Examples are, but are not limited to, low molecular weight drugs (low molecular pharmacologically active substances), organometallic complexes, radioactive substances, fluorescers, positron emitters, cytostatics, RNA, DNA, peptides, oligonucleotides, proteins, antigenic proteins, enzymes and antigens, including low molecular weight antigens , Preferred as cargo are a low molecular weight, pharmacologically active substance, a cytostatic, a protein, an antigenic protein, an enzyme, an antigen, a low molecular weight antigen, a DNA, an RNA, an oligonucleotide, a radioactive substance, an organometallic complex, a vaccine and vaccine adjuvants or a peptide.

According to the invention, polymers are polymers which contain azido groups or in which an azido group can be incorporated by chemical modification. For example, an azide-containing radical can be incorporated into polylysine by chemical coupling via the ε-amino group of the side chain. Furthermore, polymers also include nonlinear polymers, for example dendrimers. Optionally, the polymers may be linked to one or more covalently bonded cargoes. According to the invention, nanoparticles are understood as meaning particles in the size of 1 to 100 nm. The particles are composed of many copies of the same or several different units which are covalently or non-covalently bound to each other. The particles may be, for example, atoms, such as gold or iron, of lipids and fat-soluble substances such as fatty acids, phosphatidylethanolamines or cholesterol, proteins such as viral capsid proteins, polymers such as acrylamide, chitosan, poly (lactide-co-glycolide) (PLGA ) consist. According to the invention, the nanoparticles contain azido groups or can be modified with azido groups. Optionally, the nanoparticles may be linked to one or more covalently or non-covalently bonded cargoes. Optionally, the nanoparticles can be equipped with surface stabilizers, for example polyethylene glycols.

The compounds of formula (I) and conjugates thereof, for example, for the regulation of the immune system, for example in vaccinations or transplants and for the treatment of diseases, especially allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple sclerosis, viral diseases, such as AIDS, bacterial diseases, parasitic Diseases, genetic diseases, diseases in which the immune response is disturbed in the context of B-cell activation, such as common variable immunodeficiency (CVID) and IgA deficiency, in diseases of the blood-forming organs and the blood and in cancer, for example, lymphomas and myelomas and Gene therapy can be used.

A further aspect of the invention is the use of a sialic acid derivative of the formula (I) for the preparation of a conjugate with a cargo, a polymer, a nanoparticle, a polymer-bound cargo or a nanoparticle-bound cargo, preferably a cargo selected from the group consisting of RNA, DNA, peptides, low molecular weight antigens, antigenic proteins, enzymes and low molecular weight pharmacologically active substances, a polymer selected from the group of linear polysaccharides, eg hyaluronic acid, pectin, cellulose, chitosan and their derivatives, eg succinylchitosan or carboxymethyl cellulose, homopolymeric amino acids, eg polyglutamate or polylysine, a nanoparticle selected from the group of metal nanoparticles (eg a gold or iron nanoparticle), lipid nanoparticles (eg liposomes or micro-micelles), protein nanoparticles (eg virus capsids), lactic acid copolymer nanoparticles (eg poly (lactide-co-glycolide) (PLGA ) Nanoparticles), acrylate-based nanoparticles (eg polyacrylamide nanoparticles) or another pharmaceutically acceptable nanoparticle, wherein the nanoparticles may be covalently or non-covalently loaded with a cargo, for the regulation of metabolic processes, immune reactions, immunizations or desensitizations of the target organism.

A further aspect of the invention is the use of a pharmacologically active conjugate of a sialic acid derivative of the formula (I) according to the invention wherein the cargo is preferably selected from the group consisting of RNA, DNA, peptides, low molecular weight antigens, antigenic proteins, enzymes and low molecular weight pharmacologically active substances, a polymer selected from the group of linear polysaccharides, eg Hyaluronic acid, pectin, cellulose, chitosan and their derivatives e.g. Succinyl chitosan or carboxymethyl cellulose, homopolymeric amino acids, e.g. Polyglutamate or polylysine, a nanoparticle selected from the group of metal nanoparticles, e.g. a gold or iron nanoparticle, lipid nanoparticles, e.g. Liposomes or micro-micelles, protein nanoparticles, e.g. Virus capsids, the lactic acid copolymer nanoparticles, e.g. Poly (lactide-co-glycolide) (PLGA) nanoparticles containing acrylate-based nanoparticles, e.g. Polyacrylamide nanoparticles or another pharmaceutically acceptable nanoparticle, wherein the nanoparticles may be covalently or non-covalently loaded with a cargo, for the treatment of infections, tumor diseases, immune reactions or allergies.

Nanoparticle conjugates are preferably used for the therapy of genetic and immunological diseases as well as neoplasias.

Sialic acid derivatives of formula (I) may also be linked to a cargo for diagnostic purposes to a conjugate, i. with a cargo with diagnostically usable effect; For example, a sialic acid derivative of formula (I) may be linked to a cargo selected from a fluorescent molecule, radiolabelled molecule, or a positron emitter.

Sialic acid derivatives of the formula (I) can also be linked to polyvalent materials. By linking to a polyvalent material, such as a polymer, dendrimer or nanoparticle, effective conjugates having improved properties can be prepared. These conjugates can be used to regulate the immune system, for example, in vaccinations and for the treatment of diseases whose course or activity can be positively influenced by the siglec inliibitoren, in particular allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple sclerosis, cancer, viral diseases, for example AIDS, bacterial diseases, such as streptococci, parasitic Diseases such as Chagas disease, diseases in which the immune response is disturbed in the context of B cell activation, such as Common Variable Immunodeficiency (CVID) and IgA deficiency, used in diseases of the blood-forming organs and the blood and in cancer, for example, lymphomas and myelomas become.

The sialic acid derivatives of the formula (I) according to the invention can be reacted with a cargo-bearing polymer, for example from the group of linear polysaccharides, e.g. Hyaluronic acid, pectin, cellulose, chitosan and their derivatives e.g. Succinyl chitosan or carboxymethyl cellulose, homopolymeric amino acids, e.g. Polyglutamate or polylysine, or a cargo-bearing nanoparticles, for example from the group of metal nanoparticles, e.g. a gold or iron nanoparticle, lipid nanoparticles, e.g. Liposomes or micro-micelles, protein nanoparticles, e.g. Virus capsids, the lactic acid copolymer nanoparticles, e.g. Poly (lactide-co-glycolide) (PLGA) nanoparticles containing acrylate-based nanoparticles, e.g. Polyacrylamide nanoparticles wherein the cargo is preferably selected from the group consisting of RNA, DNA, cytostatics, peptides, low molecular weight antigens, organometallic complexes and low molecular weight pharmaceutically active substances, linked, in which case the polymer or nanoparticles as a spacer between cargo and compound (I. ) acts.

As is apparent from the above, both a derivative of the formula (I) and a conjugate thereof with a cargo, with a polymer, a nanoparticle, a nanoparticle-associated cargo or a polymer-linked cargo are pharmacologically active.

Despite the newly introduced residue A ⁴ of A ^{3, the} sialic acid derivatives of the formula (I) have an increased affinity in comparison to previously known monovalent CD22 ligands which can be used for conjugates. The new residue A ⁴ contains a triple bond, whereby a reaction with a substance containing an azide, to a phamiakologisch effective conjugate can be particularly easily to form a 1,2,3-triazole ring. especially the Production of conjugates of azido-carrying cargoes, such as low molecular weight molecules, DNA, RNA, peptides, nanoparticles, antigens, cells, proteins, viruses, polymers or dendrimers can thereby be effected in a particularly simple manner.

The term "sialic acid derivative of the formula (I)" encompasses all stereoisomeric forms of the compound of the formula (I), in particular E / Z or cis / trans isomers with substituted double bonds or rings and also stereoisomers which extend through the chiral centers of the compounds of the formula (I), in particular enantiomers and diastereoisomers in pure form or in the form of mixtures of any composition, wherein the individual chiral centers are each in the (S) or (R) form.

The preparation of the individual stereoisomers can be carried out, for example, by concentrating the isomer mixtures by customary methods, such as chromatography or crystallization, or by using isomerically pure starting materials. The improvement of the isomers can be carried out at the stage of the starting materials, intermediates or end products of the formula (I). The isomers included according to the invention also include all tautomeric forms of compounds (I) and all mesomorphic forms.

Furthermore, the term "sialic acid derivative of the formula (I)" comprises solvates, for example hydrates or adducts with alcohols, as well as all crystal modifications.

Furthermore, the term "sialic acid derivatives of formula (I)" includes pharmaceutically acceptable salts of compounds (I), including internal (i.e., zwitterionic).

In general, the salts of those cations or the acid addition salts of those acids are suitable, whose cations, or anions, do not adversely affect the pharmacological activity of the compounds (I).

There are as cations in particular ions of the alkali metals, preferably lithium, sodium and potassium, the alkaline earth metals, preferably calcium and magnesium, and the transition metals, preferably manganese, copper, zinc and iron, and ammonium, wherein here, if desired, one to four hydrogen atoms by R ^Y may be replaced, preferably ammonium, dimethylammonium, diisopropylammonium, tetramethylammonium, triethylammonium, tetrabutylammonium, 2- (2-hydroxyeth-1-oxy) eth-1-yl ammonium, di- (2-hydroxyeth-1-yl) -ammonium, trimethylbenzylammonium, furthermore phosphonium ions, sulfonium ions, preferably tri (C 1 -C ₄ -alkyl) sulfonium and sulfoxonium ions, preferably tri (C 1 -C ₄ -alkyl) -sulfoxonium, into consideration. Preference is given to Na, Li, K, Ca, Mg and ammonium (optionally substituted), more preferably Na, Li and K, more preferably Na.

Anions of pharmacologically acceptable acid addition salts are, for example, chloride, bromide, fluoride, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, the anions of C 1 -C ₄ -alkanoic acids, preferably formate, acetate, propionate and butyrate, and other organic acids such as pivalic acid, maleic acid, succinic acid, pimelic acid, fumaric acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, citric acid and adipic acid.

The invention also relates to pharmacologically active metabolites of the compounds (I). In particular, the term metabolites includes enzymes generated by "in vivo" enzymes such as esterases, amidases and other enzymes.

Unless otherwise indicated, symbols which are used multiple times may independently of one another have the same or different meanings.

Unless defined otherwise, the definitions of the symbols given above for formula (I) have the following meanings:

Halogen: fluorine, chlorine, bromine and iodine;

Alkyl: saturated straight-chain, branched or cyclic hydrocarbon radicals preferably having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,

3-methylbutyl, 2,2-dimethylpropyl, 1,1-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3- Dimethylbutyl, 2,3-dimethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,

4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2,2-dimethylcyclopropyl, 2,3-dimethylcyclopropyl, cyclohexyl and cyclooctyl;

Haloalkyl: straight-chain branched or cyclic (as defined above) alkyl groups preferably having 1 to 6 carbon atoms, in which groups the hydrogen atoms are partially or fully replaced by halogen atoms: such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, Dichlorofluoromethyl, chlorodifluoromethyl,

1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,

2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1-fluoro-1-methyl-ethyl, 1 - Fluorocyclopropyl, heptafluoropropyl or nonafluorobutyl;

Alkoxy: -O-alkyl groups having saturated straight-chain, branched or cyclic alkyl radical, which is as defined above and preferably contains 1 to 6 carbon atoms;

Haloalkoxy: straight-chain, branched or cyclic alkoxy radicals as defined above, wherein 1 or more H are replaced by halogen;

Alkylamino: -NH (alkyl) groups having a saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;

Dialkylamino: -N (alkyl) ₂ groups having saturated straight, branched or cyclic alkyl radicals, the same or different, selected from the aforementioned group of alkyls and preferably containing from 1 to 4 carbon atoms;

Trialkylamino: -N (alkyl) ₃ ⁺ groups having saturated straight, branched or cyclic alkyl radicals, the same or different, selected from the aforementioned group of the alkyls and preferably containing from 1 to 4 carbon atoms; Alkylcarbonyl: -C (O) alkyl groups having saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;

Alkylsulfonyl: -S (O) ₂ alkyl groups having a saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;

Alkylsulfoxyl: -S (0) alkyl groups having saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;

Alkylaminosulfonyl: -S (O) ₂ -NH (alkyl) groups having a saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;

Dialkylaminosulfonyl: -S (O) ₂ -N (alkyl) ₂ groups having saturated straight-chain, branched or cyclic alkyl radicals, these being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;

Alkyloxycarbonyl: -C (O) Oalkyl groups having saturated straight, branched or cyclic alkyl radicals selected from the aforementioned group of alkyls and preferably containing from 1 to 4 carbon atoms;

Alkylcarbonyloxy: -O-C (0) alkyl groups having a saturated straight, branched or cyclic alkyl radical selected from the aforementioned group of alkyls and preferably containing from 1 to 4 carbon atoms;

Alkylaminocarbonyl: -C (O) NH (alkyl) groups having a saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms; Dialkylaminocarbonyl: -C (O) N (alkyl) ₂ groups having saturated straight-chain, branched or cyclic alkyl radicals, these being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;

Alkylcarbonylamino: -NH-C (0) alkyl groups having a saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing from 1 to 4 carbon atoms.

It is known to the person skilled in the art that a cyclic or branched alkyl group has at least three carbon atoms. According to the invention, the term "alkyl" is also used for alkylene groups (alkanediyl groups). This is evident from the context.

Mono- or polycyclic, aromatic, partially unsaturated or saturated C 3 -C 14 hydrocarbon radical preferably denotes for D: a) C ₆ -C ₄ -aryldiyl, in particular phenylene-l, 4-diyl, phenylene-l, 3-diyl, phenylene 1, 2-diyl, naphthalene-1, 2-diyl, naphthalene-1, 3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl, naphthalene-1, 6-diyl, naphthalene-1, 7-diyl, naphthalene-1,8-diyl, naphthalene-2,3-diyl, naphthalene-2,6-diyl, naphthalene-2,7-diyl, biphenylene-1,2-diyl, biphenylene-1, 3 - diyl, biphenylene-1,4-diyl, biphenylene-1, 5-diyl, biphenylene-1,6-diyl, biphenylene-1,7-diyl, biphenylene-1,8-diyl, biphenylene-2,3-diyl, Biphenylene-2,6-diyl and biphenylene-2,7-diyl; b) C ₃ -C 8 -cycloalkyldiyl, in particular trans-cyclopropane-1,2-diyl, cyclopropane-1,1-diyl, trans-cyclobutane-1,3-diyl, cis-cyclobutane-1,3-diyl, trans- Cyclopentane-1, 3-diyl, cis-cyclohexane-1,4-diyl, trans-cyclohexane-1,4-diyl, trans-cycloheptane-1,4-diyl, trans-cyclooctane-1,5-diyl and cubane 1,4-diyl.

Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical for D preferably means: a) non-aromatic, saturated or partially unsaturated 5- or 6-membered heterocyclodiyl containing one to three nitrogen atoms and / or one oxygen or sulfur atom or one or two oxygen and / or sulfur atoms, in particular trans -tetrahydrofuran-2,5-diyl, trans -tetrahydrofuran-2,4-diyl, cis -tetrahydrofuran-2,5-diyl, trans -tetrahydrothien-2,5-diyl, trans-tetrahydrothien-2,4-diyl, trans -pyrrolidine-2,5-diyl, trans -pyrrolidine-2,4-diyl, isoxazolidine-2,4-diyl, isoxazolidine-2,5-diyl, isothiazolinedin-2,4-diyl, isothiazolidine-2, 5-diyl, pyrazolidine-l, 3-diyl, trans-oxazolidine-2,4-diyl, trans-thiazolidine-2,5-diyl, imidazolidine-l, 3-diyl, trans-imidazolidine-2,4-diyl, Pyrroline-1, 3-diyl, trans -pyrroline-2,4-diyl, trans -pyrroline-2,5-diyl, trans-piperidine-2,5-diyl, piperidine-1,4-diyl, trans-dioxane 2,5-diyl, trans -tetrahydropyran-2,5-diyl, trans-hexahydropyridazine-3,6-diyl, trans-hexahydropyridazine-1,4-diyl, trans-hexahydropyrimidine-2,5-diyl, hexahydropyrimidine l, 3-diyl, hexahydropyrimidine-l, 4-diyl, piperazine-l, 4-diyl, trans -piperazine-2,5-diyl and piperazine-l, 3-diyl; b) 5-membered heteroaryldiyl containing one to four nitrogen atoms or one to three nitrogen atoms and / or one sulfur or oxygen atom, in particular furan-2,4-diyl, furan-2,5-diyl, thiophene-2,4-diyl , Thiophene-2,5-diyl, pyrrole-2,4-diyl, pyrrole-2,5-diyl, pyrazole-l, 3-diyl, oxazole-2,4-diyl, oxazole-2,5-diyl, l , 3,4-Oxadiazole-2,5-diyl, 1, 2,4-oxadiazole-3,5-diyl, 1, 2,4-thiadiazole-3,5-diyl, 1,4-thiadiazole-2 , 5-diyl, isooxazole-3,5-diyl, thiazole-2,4-diyl, thiazole-2,5-diyl, isothiazole-3,5-diyl, imidazole-2,4-diyl, 2H-tetrazole-2 , 5-diyl, lH (l, 2,4) -triazole-2,5-diyl, lH (l, 2,3) -triazole-l, 4-diyl and lH (l, 2,3) -triazole l, 5-diyl; c) 6-membered heteroaryldiyl containing one to three or one to four nitrogen atoms, in particular pyridine-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridazine-3,6-diyl , Pyrimidine-2,5-diyl, pyrimidine-2,6-diyl, pyrazine-2,5-diyl and tetrazine-3,5-diyl.

Polycyclic aromatic, partially unsaturated or saturated heterocyclic radical is preferably for D:

1-benzofuran-4,7-diyl, 1-benzofuran-2,7-diyl, 2-benzofuran-4,7-diyl, 2-benzofuran-3,6-diyl, chromene-5,8-diyl, chromene 3,7-diyl, xanthene-l, 4-diyl, xanthene-2,6-diyl, indazole-4,7-diyl, purine-2,8-diyl, 4H-quinolizine-6,9-diyl, 3 Isoquinoline-1,4-diyl, phthalazine-1,14-diyl, 1,8-naphthyridine-2,6-diyl, quinoxaline-2,6-diyl, quinazoline-5,8-diyl, cinnoline-5,8- diyl, pteridine-2,6-diyl, indolizine-2,6-diyl, indole-4,7-diyl, indole-2,5-diyl, indole-3,6-diyl, isoindole-4,7-diyl, Isoindole-2,5-diyl, carbozol-1, 4-diyl, acridine-1,4-diyl, phenoxazine-1,4-diyl, Benzoxazole-4,7-diyl, benzothiazole-4,7-diyl, benzoimidazole-4,7-diyl, 1H-benzotriazole-4,7-diyl and benzothiophenediyl.

Mono- or polycyclic, aromatic, partially unsaturated or saturated C ₃ -Cj ₄ -

Hydrocarbon radical for D and D is preferably: a) C 6 -C 12 -aryl, in particular phenyl, 1-naphthyl, 2-naphthyl, 1-biphenylene, 2-biphenylene, 1-pyrenyl, 1-anthracenyl, 2-anthracenyl, 9-anthracenyl , 4-indenyl, 2-fluorenyl, 3-fluorenyl, 9-fluorenyl and 3-phenanthrenyl; b) C3-C] ₄ -cycloalkenyl or Cs-Cu-cycloalkadienyl, in particular cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadien-1-yl, cyclohexadien-1-yl and cyclooctadien-1-yl; c) C ₃ -C -cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantan-1-yl, cuban-1-yl and cyclooctyl.

Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical preferably denotes for D ¹ and D ³ : a) non-aromatic, saturated or partially unsaturated 4, 5, 6 or 7-membered heterocyclyl containing one to four nitrogen atoms and / or an oxygen or sulfur atom or one or two oxygen and / or sulfur atoms, in particular

1-aza-2-yclobut-1-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3 Isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 4,5-dihydro-1,3-oxazol-2-yl, 4,5-dihydro-1,3-oxazol-4-yl, 4,5-dihydro-l, 3-oxazol-5-yl, 4,5-dihydro-1,3-thiazol-2-yl, 4 5-dihydro-l, 3-thiazol-4-yl, 4,5-dihydro-l, 3-thiazol-5-yl, 4,5-dihydro-4H-1,3-oxazin-2-yl, 4 5-dihydro-4H-l, 3-thiazin-2-yl, 4,5,6,7-tetrahydro-1,3-oxazepin-2-yl, 4,5,6,7-tetrahydro-l, 3 thiazepin-2-yl,

2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3 Pyrrolin-3-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-monochinyl, 1,3-dioxane-5 yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl,

3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl,

4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 5H-tetrazol-5-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, 1-piperazinyl and 2-piperazinyl; b) 5-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and / or one sulfur or oxygen atom: in particular 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl , 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl , 2-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 1, 2,5-thiadiazol-3-yl, 1, 2,4-thiadiazol-3-yl, 1,2,4 - Thiadiazol-5-yl, l, 2,5-oxadiazol-3-yl, l, 2,4-oxadiazol-3-yl, 1, 2,4-oxadiazol-5-yl, 1,2,3-thiadiazole -4-yl, l, 2,3-thiadiazol-5-yl, l, 2,3,4-thiatriazol-5-yl, l H- (l, 2,3) triazol-1-yl, 1H- ( l, 2,3) triazol-4-yl, lH- (l, 2,3) triazol-5-yl, lH- (l, 3,4) triazol-1-yl and lH- (l, 3,4 ) triazol-2-yl; c) 6-membered heteroaryl containing one to three or one to four nitrogen atoms: in particular 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl.

Polycyclic aromatic, partially unsaturated or saturated heterocyclic radical means for D and D preferably:

1-benzofuran-2-yl, 1-benzofuran-3-yl, 1-benzofuran-5-yl, 1-benzofuran-6-yl, 1-benzofuran-7-yl, 2-benzofuran-1-yl, 2 Benzofuran-3-yl, 2-benzofuran-4-yl, 2-benzofuran-5-yl,

2-Benzofuran-6-yl, 2-benzofuran-7-yl, 2H-chromene-3-yl, 2H-chromene-4-yl, 2H-chromene-5-yl, 2H-chromene-6-yl, 2H- Chromene-7-yl, 2H-chromene-8-yl, xanthen-1-yl, xanthen-4-yl, xanthen-9-yl, indazol-1-yl, indazol-3-yl, indazol-4-yl, Indazol-5-yl, indazol-6-yl, indazol-7-yl, purin-2-yl, purin-6-yl, purin-7-yl, purin-8-yl, quinolin-2-yl, quinoline 3-yl, quinolin-4-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinoline-5 yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, phthalazin-1-yl, phthalazin-3-yl, phthalazin-5-yl, phthalazin-6-yl, 1,8-naphthyridine 2-yl, l, 8-naphthyridin-3-yl, l, 8-naphthyridin-4-yl, l, 8-naphthyridin-6-yl, 1,8-naphthyridin-7-yl, quinoxalin-2-yl, Quinoxalin-5-yl, quinoxalin-6-yl, quinazolin-4-yl, quinazolin-6-yl, cinnolin-3-yl, cinnoline 4-yl, cinnolin-6-yl, pteridin-2-yl, pteridin-4-yl, pteridin-6-yl, pteridin-7-yl, indolizine-1-yl, indol-1-yl, indole-2 yl, indol-3-yl, indol-5-yl, indol-6-yl, indol-7-yl, indol-8-yl, isoindol-1-yl, isoindol-2-yl, isoindol-4-yl, Isoindol-5-yl, carbazol-9-yl, acridin-9-yl, phenoxazin-10-yl, 1-benzothiophene-2-yl, 1-benzothiophene-3-yl, 1-benzothiophene-5-yl, l Benzothiophene-6-yl, 1-benzothiophene-7-yl, 1-benzothiophene-8-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazole-7 yl, benzimidazol-8-yl, 1H-benzotriazole-1-yl, 1H-benzotriazole-5-yl, 1H-benzotriazole-6-yl, 1H-benzotriazole-7-yl, 1H-benzotriazole-8-yl, 4H- 3, 1-benzoxazin-2-yl, 4H-2-benzopyran-2-yl, 2H-isoquinolin-3-yl, benzothiazol-2-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazole-7 yl, benzothiazol-8-yl, benzoxazol-2-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl or benzoxazol-8-yl.

The abovementioned linear or cyclic hydrocarbon radicals and heterocycles may be unsubstituted or monosubstituted or polysubstituted, where the substituents are preferably independently selected from the group X. Depending on the particular chain or ring size, preference is given to 1, 2, 3 or 4 substituents; in the case of halogen substituents substitution up to the maximum possible number (persubstitution) is possible.

Advantageously, the symbols in the formula (I) have the following meanings:

A ¹ is advantageously a group D ¹ - [Y ² -D ² -] _m -

D ¹ is advantageously a mono- or polycyclic aromatic or saturated C ₃ -Cj ₄ - hydrocarbon radical or a monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, where said radicals are unsubstituted or mono- or polysubstituted by a group X. are.

D is advantageously a group of phenylene-l, 4-diyl, phenylene-l, 3-diyl, pyridine-2,5-diyl, pyridazine-3,6-diyl, pyrimidine-2,5-diyl, pyrimidine-2,6 -diyl, pyrazine-2,5-diyl, trans-cyclobutane-l, 3-diyl, trans-cyclopentane-l, 3-diyl, trans -cyclohexane-l, 4-diyl, cuba-1, 4-diyl, thiophene -2,5-diyl, pyrrole-2,4-diyl, pyrrole-2,5-diyl, pyrazole-l, 3-diyl, oxazole-2,4-diyl, oxazole-2,5-diyl, l, 3 , 4-oxadiazole-2,5-diyl, 1, 2,4-oxadiazole-3,5-diyl, isooxazole-3,5-diyl, imidazole-2,4-diyl, 2H-tetrazole-2,5-diyl , 1H (l, 2,4) -triazole-2,5-diyl, lH (l, 2,3) -triazole-l, 4-diyl and lH (l, 2,3) -triazol-l, 5-diyl, wherein said radicals are unsubstituted or mono- or polysubstituted by a group X. ,

Y ¹ is advantageously ~C (0) -, ~CH ₂ C (0) - or ~OC (0) - where ~ denotes the bond to the group A ¹ .

Y is advantageously -O- or a bond.

A ² is advantageously a group -N (R ^y ) -W or -N (H) -W.

W is advantageously a group -SO ₃ M or -SO ₂ NR ^x ₂ or a group D ³ -Y ³ -.

Y is advantageously a bond or a group ~ S (0) ₂ -, ~ C (0) -, ~ CH ₂ -C (0) - or

~ CH ₂ -S (O) ₂ -, where ~ denotes the bond to group D.

D is advantageous a) a Cj-Cs-alkyl, wherein in said groups optionally one or more H atoms are replaced by a group X, b) a monocyclic aromatic or saturated C3-C6 hydrocarbon radical or a monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted by a group X.

A is advantageously a C ₃ -C ₇ 5-alkanediyl, where optionally one or more -CH ₂ - groups are replaced by S, O, N (R ^X ) and / or C (O) and where appropriate a -CH ₂ CH ₂ group is replaced by -C = C-;

A ⁴ is advantageously a group -C = CH, bicyclo [6, l, 0] non-4-yn-9-yl, dibenzocyclooctinyl, biarylazacyclooctinonyl, cyclooctinyloxy, cyclooctynyl or

Dimethoxyazacyclooctinyl, wherein in said groups optionally one or more H atoms are replaced by a group X; X is advantageously identical or different halogen, hydroxy, carboxymethyl, S0 ₃ M, OS0 ₃ M, S0 ₂ CF _3, P0 ₃ M, OP0 ₃ M, cyanomethyl, alkyl, haloalkyl, alkyloxy, haloalkyloxy, amino, alkylamino, dialkylamino, alkylcarbonyl , Alkylsulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino or oxo (= 0), the alkyl groups in these radicals containing from 1 to 3 carbon atoms; m is advantageously 0 or 1

Z is advantageously -O- or -S-;

R ¹ is advantageously -C (O) OM;

R ² is advantageously H, OH or OR ^y ;

R ³ is advantageously H, F;

R ⁴ is advantageously -N (R ^x ) C (O) CH ₂ OH or -N (R ^x ) C (O) R ^x ;

R ⁵ , R ⁶ are preferably the same or different and selected from OH or OR ^X ;

The definitions of the symbols given in formula (I) preferably mean: halogen: fluorine, chlorine and bromine;

Alkyl: saturated, straight-chain, branched or cyclic hydrocarbon radicals having, for example, 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,

3-methylbutyl, 2,2-dimethylpropyl, 1, 1-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3- Dimethylbutyl, 2,3-dimethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,

4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2,2-dimethylcyclopropyl, 2,3-dimethylcyclopropyl and cyclohexyl;

Halogenoalkyl: straight-chain, branched or cyclic alkyl groups having, for example, 1 to 3 carbon atoms (as mentioned above), in which groups hydrogen atoms are partially or completely replaced by halogen atoms: such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, Dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromethyl,

1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,

2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1-fluoro-1-methyl-ethyl, 1-fluorocyclopropyl or heptafluoropropyl;

Alkoxy: -O-alkyl groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned group of the alkyls and containing 1 to 3 carbon atoms;

Alkylamino: -NH (alkyl) groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 2 carbon atoms;

Dialkylamino: -N (alkyl) ₂ groups having saturated, straight-chain, branched or cyclic alkyl radicals, these being identically or differently selected from the abovementioned alkyl group and containing 1 to 2 carbon atoms;

Alkylsulfonyl: -S (O) ₂ alkyl groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 4 carbon atoms;

Alkylaminosulfonyl: -S (O) ₂ -NH (alkyl) groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 3 carbon atoms; Alkoxycarbonyl: -C (O) -O-alkyl Grappen having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 3 carbon atoms;

Alkylcarbonyloxy: -O-C (0) alkyl groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 3 carbon atoms;

Alkylaminocarbonyl: -C (O) NH (alkyl) groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 3 carbon atoms;

Alkylcarbonylamino: -NH-C (0) alkyl groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 3 carbon atoms.

Mono- or polycyclic, aromatic or saturated C ₃ -C ₄ -hydrocarbon radical

1 3

is more preferred for D and D: a) C ₆ -C ₄ -aryl, especially phenyl, naphth-1-yl, naphth-2-yl, biphen-4-yl, biphen-2-yl, anthracene-9-yl, indene 4-yl, fluoren-2-yl, fluoren-3-yl, fluoren-9-yl and phenanthrene-3-yl; b) C -C -cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantan-1-yl, cuban-1-yl and cyclooctyl.

Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical means for D ¹ and D ^{3 more} preferably: a) non-aromatic, saturated or partially unsaturated 4, 5 or 6-membered heterocyclyl containing one to four nitrogen atoms and / or one or two oxygen atoms, especially 1-aza-cyclobut-1-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl , 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 4,5-dihydro-1,3-oxazol-2-yl, 4,5-dihydro-1,3-oxazol-4-yl, 4,5-dihydro-l, 3 oxazol-5-yl, 4,5-dihydro-4H-1,3-oxazin-2-yl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 2-pyrrolin-2-yl, 2-pyrroline-3 yl, 3-pyrrolin-2-yl,

3-pyrrolin-3-yl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-morpholinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 3-hexahydropyridazinyl,

4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 5H-tetrazol-5-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl-1-piperazinyl and 2-piperazinyl; b) 5-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and / or one sulfur or oxygen atom: in particular 2-furyl,

3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 1, 2,5-thiadiazole-3 yl, l, 2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, l, 2,5-oxadiazol-3-yl, l, 2,4-oxadiazol-3-yl, l, 2,4-oxadiazol-5-yl, 1,2,3-thiadiazol-4-yl, l, 2,3-thiadiazol-5-yl, l, 2,3,4-thiatriazol-5-yl, lH- (l, 2,3) triazol-1-yl, lH- (l, 2,3) triazol-4-yl, lH- (l, 2,3) triazol-5-yl, lH- (l, 3,4) triazol-1-yl and 1H- (1, 3,4) triazol-2-yl; c) 6-membered heteroaryl containing one to three nitrogen atoms: in particular 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl,

4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl;

The abovementioned linear or cyclic hydrocarbon radicals and heterocycles may be unsubstituted or monosubstituted or polysubstituted, where the substituents independently are preferably selected from the group X. Depending on the particular chain or ring size, preference is given to 1, 2, 3 or 4 substituents; in the case of halogen substituents substitution up to the maximum possible number (persubstitution) is possible.

The symbols in the formula (I) particularly preferably have the following meanings: D ¹ is preferably a group selected from phenyl, pyrimidin-5-yl, naphth-1-yl, naphthyl and thien-2-yl, where the radicals mentioned are unsubstituted or mono- or polysubstituted by a group X;

D is preferably a group selected from phenylene-l, 4-diyl, pyridine-2,5-diyl, pyrimidine-2,5-diyl and thiophene-2,5-diyl, where the radicals mentioned are unsubstituted or mono- or polysubstituted a group X is substituted;

Y ¹ is preferably ~C (O) - or ~CH ₂ C (O) - where ~ denotes the bond to the group A ¹ ;

Y is preferably a bond;

A is preferably a group -N (H) -W;

W is preferably a group -SO ₃ M;

A is preferably a C ₃ -C ₂ o-alkanediyl, where optionally one or more -CH ₂ - groups are replaced by S, O, N (H) and / or C (O);

A ⁴ is preferably a group -C = CH or bicyclo [6, l, 0] non-4-yn-9-yl; each X is independently preferably selected from fluoro, chloro, hydroxy, carboxyl,

Methyl, trifluoromethyl, methoxy and oxo (= 0); m is preferably 1;

Z is preferably -0-;

R ^x is preferably H, R ^y or R ^z ;

R ^y is preferably methyl, ethyl or benzyl;

R ^z is preferably -C (O) CH ₃ , -C (Q) C (CH ₃ ) ₃ or -C (O) phenyl; R is preferably H; R ³ is preferably H;

R ⁴ is preferably -N (H) C (O) R, more preferably -NHC (O) CH ₃ ;

R ⁵ and R ⁶ are the same or different and are preferably selected from OH, OCH ₃ and

OC (0) CH _3;

M is preferably sodium, potassium, calcium or magnesium.

Further preferred sialic acid derivatives of the formula (I) are those of the formulas (Ia) - (Ic), where the symbols have the meanings and preferences given for formula (I); preferably, R is H:

Even more preferred are sialic acid derivatives of the formulas (Iaa) - (Iac), where the symbols have the meanings and preferences given for formula (I); R ² is preferably H:

Particular preference is given to sialic acid derivatives of the formula (Iba) where the symbols have the meanings and preferences given for formula (I); preferably, R is H:

Furthermore, a process for the preparation of sialic acid derivatives of the formula (I) was sought, which allows the introduction of the substituents at position 9 and position 4 and a subsequent reaction with the carboxylic acid of the glycosidically bound substituent. A particular difficulty here is the carboxyl group of sialic acid (R ¹ in sialic acid derivatives of the formula (I)). In unprotected form, this would lead to by-products in the reaction of the carboxylic acid of the glycosidically bound substituent. The carboxylic acid of the glycosidically bound substituent leads in unprotected Form to problems in the purifications and in the introduction of the substituents at positions 9 and 4 of sialic acid scaffold.

Unexpectedly, already known sialic acid derivatives of the formula (II) can be reacted with tert-butyl-protected hydroxycarboxylic acids in good yield to form sialic acid derivatives of the formula (III) (see Scheme 1 above), without significant cleavage of the protective group, although strongly acidic conditions Use of trifluoromethanesulfonic occur during the reaction. Also, the analysis of the α / β ratio of the glycosidic bond in the reaction product shows an unexpectedly high yield of the biologically active and desired α-anonizing. Of particular advantage are the differently protected carboxyl groups in sialic acid derivatives of the formula (III) which permit selective conversion and simplified purification. All subsequent modifications to positions 9 and 4 can be achieved in good yield. The final cleavage of the tert-butyl protecting group and further modification at position 4 proceeds unexpectedly well and without significant anomerization of the glycosidic bond. The process gives sialic acid derivatives of the formula (VII) in good yield and thereby allows the use of simple purification methods such as extraction, crystallization or normal phase chromatography. In particular, the reactions comprising several reactions of sialic acid derivatives of the formula (III) to sialic acid derivatives of the formula (IV), of sialic acid derivatives of the formula (V) to sialic acid derivatives of the formula (VI) and of sialic acid derivatives of the formula (VI) to sialic acid derivatives of the formula (VII) can be carried out without chromatographic purification of the intermediates. The sialic acid derivatives of the formula (VII) can then be further reacted at the carboxylic acid of the glycosidically linked substituent to sialic acid derivatives of the formula (VIII), which after final elimination of the ester at position 1 and imports of the group A ⁴ in the desired sialic acid derivatives of the formula (I ) can be transferred.

The preparation of sialic acid derivatives of the formula (I) and intermediates can be carried out, for example, according to Scheme 1 above, which is explained in more detail by the following synthesis schemes I to X, where the symbols have the meanings given for formula (I):

Scheme I

T is an aryl or alkyl or forms bonded with the sulfur to the T is another leaving group useful for glycosylations.

Compounds of the formula (III) where Z is O can be prepared, for example, by reacting compounds of the formula (II) with N-iodosuccinimide and a tert-butyl-protected hydroxycarboxylic acid in the presence of trifluoromethanesulfonic acid. As an example, compound 3 was prepared. Useful leaving groups and reaction conditions for glycosylations are described, for example, in Current Organic Synthesis, 2004, 1, 31-46, Current Organic Chemistry, 20 (14): 1465-1476, and "Glycochemical Synthesis: Strategies" and Applications Editor: Shang-Cheng Hung and Medel Manuel L. Zulueta (Editor) ISBN: 978-1-1 18-29984-5 described.

Compounds of the formula (III) where Z is S can be prepared analogously to known processes (see, for example, WO 98/03573) from methyl 4-azido-5-acetamido-7,8,9-tri-O-actyl-2-chloro-3 , 4,5-trideoxy-D-glycero-β-D-galacto-2-nonulopyranosonate (Bioorg. Med. Chem. Lett., 1994, 4, 2457-2460).

Scheme I

Compounds of formula (IX) can be prepared, for example, by cleavage of the O-acetyl groups of compounds of formula (III) wherein Z is O or S. Cleavages of O-acetyl protecting groups are described, for example, in "Protecting Groups" Philip J. Kocienski, 3 ^rd Edition, Thieme 2005, "Carbohydrates: Best Synthetic Methods" HMI Osborn, Academic Press 2003 and "Protective Groups in Organic Chemistry" Peter GM Wuts, Wiley, 2014. As an example, compound 4 was prepared.

Scheme I

The anion of compound X is, for example, an acid radical of an organic acid, e.g. Acetate or formate or an inorganic anion such as e.g. Chloride or sulfate.

Compounds of the formula (X) can be prepared, for example, by reduction of the azide in compounds of the formula (IX) without cleavage of the carboxylic acid protecting groups by means of a suitable reducing agent, for example zinc in dilute acetic acid. The reduction of azido groups is described for example in Angewandte Chemie 2005, 1 17, 5320-5374 and Chem. Rev. 1988, 88 (2), 297-368.

As an example, compound 5 was prepared.

Q in compound (IV) is an amino-protecting group, for example, tert-butyl or benzyloxycarbonyl.

Compounds of formula (IV) can be prepared by introducing an amino-protecting group Q, for example di-tert-butyl dicarbonate, into compounds of formula (X). Amino-protecting groups and reactions for protecting amino groups are described for example in "Protecting Groups", Philip J. Kocienski, 3 ^ld Edition, Thieme 2005, Chem. Rev. 2009, 109, 2455-2504 and "Protective Groups in Organic Chemistry" Peter GM Wuts, Wiley, 2014. For example, compound 6 was prepared.

scheme

Compounds of formula (V) can be prepared, for example, by substitution of the primary hydroxyl group in compounds of formula (IV) with an azide. Such substitution can be carried out, for example, by means of TPP, CBr ₄ and sodium azide in DMF or via two stages, for example via a tosylation of the hydroxyl group and subsequent exchange with the azide. The introduction of azido groups is described, for example, in Angewandte Chemie 2005, 117, 5320-5374 and Chem. Rev. 1988, 88 (2), 297-368.

For example, compound 7 was prepared.

Compounds of the formula (XI) can be prepared, for example, by reduction of the azide to compounds of the formula (V) without removal of further protective groups by means of a suitable reducing agent, for example zinc in dilute acetic acid. The reduction of azido groups is described for example in Angewandte Chemie 2005, 117, 5320-5374 and Chem. Rev. 1988, 88 (2), 297-368.

For example, compound 8 was prepared. Sche

Compounds of formula (VI) may be prepared by reaction of the amine in compounds of formula (XI) to form an amide, a sulfamide, a carbamate or a urea. Corresponding reactions of amines to amides (Y ^{1 =} ~ C (0) or ~CH ₂ C (0)), sulfonamides (Y ¹ = ~ S (0) ₂ ), carbamates (Y ¹ = ~ OC (0)) or Urea (Y ¹ = -NHC (O)) by means of activated reagents or with the aid of coupling reagents are described for example in Tetrahedron 2005, 61, 10827-10852, Chem. Eur. J. 2009, 15, 9040-9416 Mini-Reviews in Organic Chemistry, 2013, 10 (2), 160-170, Journal of Molecular Catalysis A: Chemical 271 (2007) 89-92, Volume 42, Issue 31, 30 July 2001, Pages 5227-5229, Reinhard Brückner: Reaction Mechanisms 3rd Edition Springer Spektrum, Berlin and Heidelberg 2004 and Synthesis, 2007, 3497-3506, Org. Lett, 2012, 14, 2814-2817.

As an example, compound 9 was prepared.

Sche

Compounds of formula (XII) can be prepared by selectively removing the protecting groups Q and tert-butyl in compounds of formula (IV), for example by means of trifluoroacetic acid. Protecting groups and deprotecting reactions are described, for example, in "Protecting Groups" Philip J. Kocienski, 3 Edition, Thieme 2005, Chem. Rev. 2009, 109, 2455-2504 and "Protective Groups in Organic Chemistry" Peter GM Wuts, Wiley, 2014 , As an example, compound 10 was prepared. Shem

Compounds of formula (VII) can be prepared, for example, by reaction of the amine in compounds of formula (XII) with an amine-reactive reagent, for example sulfur trioxide-pyridine complex, an activated carboxylic acid or a sulfonic acid chloride. By the reaction with the amine-reactive reagent, the group A is formed, which is as defined above for formula (I). Optionally, the amine can also be mono-alkylated in a first step and reacted in a second step with another amine-reactive reagent, for example an activated carboxylic acid or sulfonic acid or another haloalkyl. Corresponding reactions of amines by means of activated reagents or with the aid of coupling reagents are described for example in Tetrahedron 57, 2001, 7785-7811, Tetrahedron 2005, 61, 10827-10852, Chem. Eur. J. 2009, 15, 9040-9416 mini-reviews in Organic Chemistry, 2013, 10 (2), 160-170, Journal of Molecular Catalysis A: Chemical 271 (2007) 89-92, Volume 42, Issue 31, 30 July 2001, Pages 5227-5229, Reinhard Brückner: Reaction Mechanisms 3 Edition, Springer Spectrum, Berlin and Heidelberg 2004 and Synthesis, 2007, 3497-3506, Org. Lett., 2012, 14, 2814-2817.

As an example, compound 11 was prepared.

Scheme X

Compounds of formula (VIII) may be prepared, for example, by reaction of the carboxyl group in compounds of formula (VII) with a monoprotected diamine, for example N-Fmoc-1,2-diaminoethane, followed by basic deprotection. Reactions of amines to form an amide by means of activated reagents or with the aid of coupling reagents are described, for example, in Tetrahedron 2005, 61, 10827-10852, Chem. Eur. J. 2009, 15, 9040-9416. Amino-protecting groups and amino-deprotecting reactions are described, for example, in "Protecting Groups" Philip J. Kocienski, 3rd Edition, Thieme 2005, Chem. Rev. 2009, 109, 2455-2504, and "Protective Groups in Organic Chemistry" Peter GM Wuts, Wiley , 2014.

For example, compound 13 was prepared.

The sialic acid derivatives (I) of the present invention are obtainable either from Compound (VII) or Compound (VIII), as set forth below (see Scheme XI and Scheme XII, respectively).

scheme

Compounds of formula (I) can be prepared, for example, by reaction of the carboxyl group in compounds of formula (VII) with a triple bond-containing amine, for example propargylamine, and subsequent deprotection, the group A being "extended" and the groups -N (H) - and -C (O) - of the newly formed amide become part of A. Reactions of amines to form an amide by means of activated reagents or with the aid of coupling reagents are described, for example, in Tetrahedron 2005, 61, 10827-10852, Chem. Eur. J. 2009, 15, 9040-9416. Amino-protecting groups and amino-deprotecting reactions are described, for example, in "Protecting Groups" Philip J. Kocienski, 3rd Edition, Thieme 2005, Chem. Rev. 2009, 109, 2455-2504, and "Protective Groups in Organic Chemistry" Peter GM Wuts, Wiley , 2014.

Compounds of formula (I) may be prepared, for example, by reaction of the amine in compounds of formula (VIII) with a triple bond-containing amine-reactive reagent, for example ((IR, 8S, 9R) -bicyclo [6.1.0] non-4-yn-9 -yl) methyl

(4-nitrophenyl) carbonate are produced. Corresponding reactions of amines by means of activated reagents or with the aid of coupling reagents are described, for example, in Tetrahedron 2005, 61, 10827-10852, Chem. Eur. J. 2009, 15, 9040-9416 Mini-Reviews in Organic Chemistry, 2013, 10 (2 ), 160-170, Journal of Molecular Catalysis A: Chemical 271 (2007) 89-92, Volume 42, Issue 31, 30 July 2001, Pages 5227- 5229, Reinhard Brückner: Reaction Mechanisms 3rd edition, Springer spectrum, Berlin and Heidelberg 2004 and Synthesis, 2007, 3497-3506, Org. Let, 2012, 14, 2814-2817.

As an example, compound 14 was prepared.

Of particular interest are the intermediates of formula (III) as described above, wherein Z = O; A is preferably a C3 _-2 o-alkanediyl, more preferably C _5-2 o-alkanediyl.

The resulting intermediates of the formulas (IX), (X) and (IV) are also of interest.

The sialic acid derivatives of the formula (I) are suitable as such as pharmacologically active compounds, but also for the preparation of pharmacologically active conjugates. Sialic acid derivatives of the formula (I) and their pharmacologically active conjugates are suitable for vaccinations and the treatment of diseases whose occurrence or course are influenced by Siglec-bearing cells, in particular allergies, autoimmune diseases, genetic diseases, chronic inflammation, paraplegia, multiple sclerosis, cancer and viral diseases, such as AIDS and for the regulation of metabolic processes, immune reactions, immunizations or desensitization of the target organism.

Preferred indications are allergies, cancer, autoimmune diseases and use for vaccinations.

Preferred indications are also B-cell-mediated diseases, for example lymphomas or autoimmune diseases.

The sialic acid derivatives of the formula (I) or pharmacologically active conjugates prepared therefrom can be used in combination with other pharmacologically active substances, in particular those which enhance the activity of the sialic acid derivatives of the formula (I) or of the conjugates.

The treatment of a B-cell or siglec-mediated disease, in particular one of the group of allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple sclerosis, cancer, viral diseases (for example AIDS), diseases in which the immune response is disturbed in the context of B-cell activation is (such as Common Variable Immunodeficiency (CVID)) and IgA deficiency comprises administering to a patient affected by the disease a therapeutically effective amount of one of one of the sialic acid derivatives of formula (I) or a pharmacologically active conjugate.

The sialic acid derivatives of the formula (I) can also be used for the preparation of a conjugate for purposes other than those mentioned, for example as diagnostics, in methods for determining the activity of Siglec ligands, as biochemical probes or as intermediates for the preparation of further, in particular pharmacological active, connections.

The sialic acid derivatives of the formula (I) are also suitable as pharmacologically active compounds for pharmaceutical preparations. They act as Siglec ligands, in particular as Siglec-2 (CD22) ligands, for the regulation of the immune system, in particular as an adjuvant in vaccinations and for the treatment of diseases whose course or activity can be influenced by the Siglec ligands, in particular allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple Sclerosis, cancer, viral diseases, such as AIDS, as well as bacterial diseases, such as streptococci, parasitic diseases, such as Chagas disease, diseases in which the immune response is disturbed in the context of B-cell activation, such as common variable immunodeficiency (CVID) and IgA deficiency , in diseases of the blood-forming organs and the blood and in cancer, for example, lymphomas and myelomas. Preferred indications are allergies, autoimmune diseases and CVID.

Treatment in the sense of the invention means a therapeutic treatment, both for the cure of a disease or a condition and for the alleviation of symptoms or slowing down the progression of a disease, as well as a preventive treatment.

The invention also provides a method for treating a siglec mediated disease, in particular from the group of allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple sclerosis, cancer, viral diseases, for example AIDS, diseases in which the immune response in the context of B-cell activation such as common variable immunodeficiency (CVID) and IgA deficiency, wherein a patient of the disease is administered a preferably therapeutically effective amount of a sialic acid derivative of formula (I) or a conjugate thereof.

The invention further provides a sialic acid derivative of the formula (I) or a pharmaceutically acceptable salt thereof as a medicament, in particular for the treatment of siglec-mediated diseases, such as those described above.

The invention furthermore relates to a sialic acid derivative of the formula (I) or a pharmaceutically acceptable salt thereof for use in a method for the treatment of siglec-mediated diseases, in particular those described above.

The invention furthermore relates to a sialic acid derivative of the formula (I) for use in the manufacture of a medicament for the treatment of siglec-mediated diseases, in particular those described above. The invention likewise provides a pharmaceutical preparation (= medicament) containing at least one sialic acid derivative of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The dosage required to achieve a corresponding effect in the treatment or prophylaxis usually depends on the compound to be administered, on the patient, on the nature and severity of the disease or condition and on the nature and frequency of administration, and is at the discretion of the attending physician. Conveniently, the dosage with intravenous administration in the range of 0.1 to 1000 mg, preferably 0.5 to 500 mg, and oral administration in the range of 1 to 1000 mg, preferably 10 to 500 mg, each once or several times a day ,

For the preparation of medicaments, the compounds of the formula I according to the invention or conjugates according to the invention, optionally in combination with other active compounds, together with one or more inert carriers customary in the art and / or diluents, disintegrants, flavoring agents, colorants, etc., e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerine, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures , with processes known in the art in common galenic preparations in solid or liquid form such as Use tablets, dragees, capsules, powders, solutions, suspensions or suppositories.

Administration of the sialic acid derivatives (I) or conjugates of the invention may be by any conventional method, including orally and parenterally, e.g. by intravenous, subcutaneous or intramuscular injections.

The sialic acid derivatives of formula (I) may also be used for other purposes than those mentioned, for example as diagnostics, e.g. in methods for determining the activity of Siglec ligands, as biochemical probes or as intermediates for the preparation of further, in particular pharmacologically active compounds.

Specific embodiments of the invention are as follows: Sialic acid derivatives of the formula (I)

where the symbols have the following meanings:

A ¹ is a group ö '- [Y ² -D ² -] _m -;

D ¹ is a mono- or polycyclic aromatic, partially unsaturated or saturated C ₃ -C ₄ -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to twelve-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted are substituted by a group X;

D is a mono- or polycyclic aromatic, partially unsaturated or saturated C ₃ -C ₄ -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted by a group X is substituted;

Y ¹ is CC (O) -, SS (O) ₂ -, CHCH ₂ C (O) -, NHNHC (O) - or OCOC (O) -, wherein die denotes the bond to the group A ¹ ;

Y ² is -O- or a bond; is a group -N (R ^y ) -W or -N (H) -W;

W is a) a group -S0 ₃ M or -S0 ₂ NR ^x ₂ or

b) a grappe D -Y-;

Y ° is a bond or group selected from -NHC (O) -, OC (0) - S (0) ₂ -, C (0) -, CH ₂ C (O) -, and CH ₂ S (0) ₂ -, wherein ~ denotes the bond to the group D ³ ;

D is ³

a) Ci-C ₆ -alkyl, wherein optionally one or more non-terminal CH ₂ - groups by O, N (R ^X ) and / or C (O) are replaced and wherein in the non-terminal CH ₂ groups optionally one or several H atoms are replaced by a group X, or

b) a mono- or polycyclic aromatic, partially unsaturated or saturated C ₃ -C ₁ 4-hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted are substituted by a group X;

A is a C ₃ -C 15 -alkanediyl where optionally one or more -CH ₂ - groups are represented by -S-, -S (O ₂ ) -, -O-, -N (R ^X ) - and / or -C ( O) - are replaced;

A ⁴ is a group selected from -C = CH, bicyclo [6, l, 0] non-4-yn-9-yl, dibenzocyclooctinyl, biarylazacyclooctinonyl, cyclooctinyloxy, cyclooctynyl or dimethoxyazacyclooctynyl, where in said groups optionally one or more H Atoms are replaced by a group X; each X is independently selected from halogen, cyano, nitro, hydroxy, carboxyl, carboxymethyl, hydroxylamino, -SO ₃ M, -OSO ₃ M, -SO ₂ NH ₂ , -SO ₂ CF ₃ , -PO ₃ M, -OPO ₃ M, cyanomethyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, trialkylamino, alkylcarbonyl, alkylsulfonyl, alkylsulfoxyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, dialkylaminocarbonyl and oxo (= O), wherein alkyl and alkoxy in the above groups contain 1 to 4 carbon atoms; m is 0 or 1

Z is -O- or -S-; R ¹ is -C (O) OM; R ² is H, OH, OR ^y or F; R ³ is H or F;

R ⁴ is -N (R ^x ) C (O) CH ₂ OH, -N (R ^x ) C (O) R ^x , -NHC (O) CH ₂ F or -NHC (O) CH ₂ Cl; R ⁵ and R ⁶ are the same or different and selected from OH and OR ^x ;

M is a cation; each R ^x is independently selected from H, R ^y and R ² ; each R ^y is independently selected from C 1 -C ₄ alkyl, phenyl and benzyl; and each R ^z is independently selected from -C (O) - (C 1 -C ₄ alkyl), -C (O) -phenyl or -C (O) -CH ₂ -phenyl; a pharmaceutically acceptable solvate, salt or prodrug thereof. Sialic acid derivatives according to item 1, wherein D ^{2 is} a mono- or polycyclic, aromatic, partially unsaturated or saturated C ₃ -C ₄ -hydrocarbon radical selected from: i) C ₆ -C ₄ -aryldiyl, in particular phenyl-1,4-diyl , Phenylene-1,3-diyl, phenylene-1,2-diyl, naphthalene-1, 2-diyl, naphthalene-1,3-diyl, naphthalene-1, 4-diyl, naphthalene-1,5-diyl, naphthalene - 1,6-diyl, naphthalene-1, 7-diyl, naphthalene-1,8-diyl, naphthalene-2,3-diyl, naphthalene-2,6-diyl, naphthalene-2,7-diyl, biphenylene-1 , 2-diyl, Biphenylene-1, 3-diyl, biphenylene-1, 4-diyl, biphenylene-1, 5-diyl, biphenylene-1, 6-diyl, biphenylene-1, 7-diyl, biphenyl en-l, 8-diyl, biphenylene 2,3-diyl, biphenylene-2,6-diyl and biphenylene-2,7-diyl;

and

ii) Cs-Cg-Cycloalkyldiyl, in particular trans-cyclopropane-l, 2-diyl, cyclopropane-1,1-diyl, trans-cyclobutane-l, 3-diyl, cis-cyclobutane-1,3-diyl, trans-cyclopentane -1, 3-diyl,

cis-cyclohexane-1, 4-diyl, trans-cyclohexane-1, 4-diyl, trans-cycloheptane-1, 4-diyl, trans-cyclooctane-1,1,5-diyl and cuban-1,4-diyl; a monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical selected from: i) non-aromatic, saturated or partially unsaturated 5- or 6-membered heterocyclodiyl containing one to three nitrogen atoms and / or one oxygen or sulfur atom or a or two oxygen and / or sulfur atoms, in particular trans-tetrahydrofuran-2,5-diyl, trans-tetrahydrofuran-2,4-diyl, cis-tetrahydrofuran-2,5-diyl, trans-tetrahydrothien-2,5-diyl, trans Tetrahydrothien-2,4-diyl, trans -pyrrolidine-2,5-diyl, trans -pyrrolidine-2,4-diyl, isoxazolidine-2,4-diyl, isoxazolidine-2,5-diyl, isothiazolidine-2,4 -diyl, isothiazolidine-2,5-diyl, pyrazolidine

1,3-diyl, trans-oxazolidine-2,4-diyl, trans-thiazolidine-2,5-diyl, imidazolidine-1,3-diyl, trans-imidazolidine-2,4-diyl, pyrroline-1,3-diyl, trans -pyrroline-2,4-diyl, trans -pyrroline-2,5-diyl, trans-piperidine-2,5-diyl, piperidine-l, 4-diyl, trans-dioxane-2,5-diyl, trans- Tetrahydropyran-2,5-diyl, trans-hexahydropyridazine-3,6-diyl, trans-hexahydropyridazine-1, 4-diyl, trans-hexahydropyrimidine-2,5-diyl, hexahydropyrimidine-1,3-diyl, hexahydropyrimidine-1, 4-diyl, piperazine-1, 4-diyl, trans-piperazine-2,5-diyl and piperazine-1,3-diyl; ii) 5-membered heteroaryldiyl containing one to four nitrogen atoms or one to three nitrogen atoms and / or one sulfur or oxygen atom, in particular furan

2,4-diyl, furan-2,5-diyl, thiophene-2,4-diyl, thiophene-2,5-diyl, pyrrole-2,4-diyl, pyrrole-2,5-diyl, pyrazole-1,3 - diyl, oxazole-2,4-diyl, oxazole-2,5-diyl, 1, 3,4-oxadiazole-2,5-diyl, 1,4-oxadiazole-3,5-diyl, l, 2, 4-thiadiazole-3,5-diyl, 1, 3,4-thiadiazole-2,5-diyl, isooxazole-3,5-diyl, thiazole-2,4-diyl, thiazole-2,5-diyl, Isothiazole-3,5-diyl, imidazole-2,4-diyl, 2H-tetrazole-2,5-diyl, 1H (l, 2,4) -triazole-2,5-diyl, 1H (l, 2,3 ) Triazole-l, 4-diyl and lH (l, 2,3) -triazole-l, 5-diyl; and iii) 6-membered heteroaryldiyl containing one to three or one to four nitrogen atoms, in particular pyridine-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridazine-3,6- diyl, pyrimidine-2,5-diyl, pyrimidine-2,6-diyl, pyrazine-2,5-diyl and tetrazine-3,5-diyl.

or c) a polycyclic aromatic, partially unsaturated or saturated heterocyclic radical selected from:

1-benzofuran-4,7-diyl, 1-benzofuran-2,7-diyl, 2-benzofuran-4,7-diyl, 2-benzofuran

3.6-diyl, chromene-5,8-diyl, chromene-3,7-diyl, xanthene-1, 4-diyl, xanthene-2,6-diyl, indazole-4,7-diyl, purine-2,8- diyl, 4H-quinolizine-6,9-diyl, 3-isoquinoline-1,14-diyl, phthalazine-1,4-diyl, 1,8-naphthyridine-2,6-diyl, quinoxaline-2,6-diyl, Quinazoline-5,8-diyl, cinnoline-5,8-diyl, pteridine-2,6-diyl, indolizine-2,6-diyl, indole-4,7-diyl, indole-2,5-diyl, indole 3,6-diyl, isoindole-4,7-diyl, isoindole-2,5-diyl, carbozol-1,4-diyl, acridine-1,4-diyl, phenoxazine-1,4-diyl, benzoxazole-4, 7-diyl, benzothiazole-4,7-diyl, benzoimidazole

4,7-diyl, 1H-benzotriazole-4,7-diyl and benzothiophenediyl;

is.

3. Sialic acid derivatives according to item 1 or 2, wherein one of D ¹ and D ³ or both are independent: a) a mono- or polycyclic, aromatic, partially unsaturated or saturated C ₃ -C hydrocarbon radical selected from: i) C ₆ - Ci ₄ -aryl, in particular phenyl, 1-naphthyl, 2-naphthyl, 1-biphenylene, 2-biphenylene, 1-pyrenyl, 1 -Anthracenyl, 2-anthracenyl, 9-anthracenyl, 4-indenyl, 2-fluorenyl, 3- Fluorenyl, 9-fluorenyl and 3-phenanthrenyl; ii) C ₃ -C | ₄ -cycloalkenyl or C ₅ -C ₁₄ -cycloalkadienyl, in particular cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadien-1-yl, cyclohexadien-1-yl and cyclooctadiene-1-yl; and iii) C ₃ -C 8 cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantan-1-yl, cuban-1-yl and cyclooctyl, a monocyclic aromatic, partially unsaturated or saturated tri-to eight-membered heterocyclic radical from: i) non-aromatic, saturated or partially unsaturated 4, 5, 6 or 7-membered heterocyclyl containing one to four nitrogen atoms and / or one oxygen or sulfur atom or one or two oxygen and / or sulfur atoms, in particular Aza-2-yclobut-1-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,

2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl,

3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl,

4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl,

5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 4,5-dihydro-1,3-oxazol-2-yl, 4,5-dihydro-1,3-oxazol-4-yl, 4 5-Dihydro-1,3-oxazol-5-yl, 4,5-dihydro-1,3-thiazol-2-yl, 4,5-dihydro-1,3-thiazol-4-yl, 4,5- Dihydro-1,3-thiazol-5-yl, 4,5-dihydro-4H-1,3-oxazin-2-yl, 4,5-dihydro-4H-1,3-thiazin-2-yl, 4 5,6,7-tetrahydro-1,3-oxazepin-2-yl, 4,5,6,7-tetrahydro-l, 3-thiazepin-2-yl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 1-piperidinyl, 2- Piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-morpholinyl, 3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl , 5-hexahydropyrimidinyl, 5H-tetrazol-5-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, 1-piperazinyl and

2-piperazinyl; ii) 5-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and / or one sulfur or oxygen atom: in particular 2-furyl,

3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-isothiazolyl, 4-isothiazolyl, 5- Isothiazolyl, 2-imidazolyl, 4-imidazolyl, l, 2,5-thiadiazol-3-yl, 1, 2,4-thiadiazol-3-yl, l, 2,4-thiadiazol-5-yl, l, 2, 5-Oxadiazol-3-yl, 1, 2,4-oxadiazol-3-yl, 1, 2,4-oxadiazol-5-yl, 1, 2,3-thiadiazol-4-yl, 1, 2,3- Thiadiazol-5-yl, l, 2,3,4-thiatriazol-5-yl, lH- (l, 2,3) triazol-1-yl, lH- (l, 2,3) -triazol-4-yl, lH- (l, 2,3) triazol-5-yl, lH- (l, 3,4) triazol-1-yl and lH- (l, 3,4) triazol-2-yl; and iii) 6-membered heteroaryl containing one to three or one to four nitrogen atoms: in particular 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- Pyrimidinyl and 2-pyrazinyl; a polycyclic aromatic, partially unsaturated or saturated heterocyclic radical selected from: 1-benzofuran-2-yl, 1-benzofuran-3-yl, 1-benzofuran-5-yl, 1-benzofuran-6-yl,

1-benzofuran-7-yl, 2-benzofuran-1-yl, 2-benzofuran-3-yl, 2-benzofuran-4-yl,

2-Benzofuran-5-yl, 2-benzofuran-6-yl, 2-benzofuran-7-yl, 2H-chromene-3-yl, 2H-chromene-4-yl, 2H-chromene-5-yl, 2H- Chromene-6-yl, 2H-chromene-7-yl, 2H-chromene-8-yl, xanthen-1-yl, xanthen-4-yl, xanthen-9-yl, indazol-1-yl, indazole-3 yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, purin-2-yl, purin-6-yl, purine

7-yl, purin-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinoline-1 yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, phthalazin-1-yl, phthalazin-3-yl, Phthalazin-5-yl, phthalazin-6-yl, l, 8-naphthyridin-2-yl, l, 8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 1,8-naphthyridine-6 yl, l, 8-naphthyridin-7-yl, quinoxalin-2-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinazolin-4-yl, quinazolin-6-yl, cinnolin-3-yl, cinnoline 4-yl, cinnolin-6-yl, pteridin-2-yl, pteridin-4-yl, pteridin-6-yl, pteridin-7-yl, indolizine-1-yl, indol-1-yl, indole-2 yl, indol-3-yl, indol-5-yl, indol-6-yl, indol-7-yl, indol-8-yl, isoindol-1-yl, isoindol-2-yl, isoindol-4-yl, Isoindol-5-yl, carbazol-9-yl, acridin-9-yl, phenoxazin-10-yl, 1-benzothiophene-2-yl, 1-benzothiophene-3-yl, 1-benzothiophene-5-yl, 1 - Benzothiophene-6-yl, 1-benzothiophene-7-yl, 1-benzothiophene

8-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, benzimidazol-8-yl, 1H-benzotriazole-1-yl, 1H- benzotriazole-5-yl, 1H-benzotriazole-6-yl, 1H-benzotriazole-7-yl, 1H-benzotriazole-8-yl, 4H-3,1-benzoxazin-2-yl, 4H-2-benzopyran-2-yl, 2H-isoquinoline 3-yl, benzothiazol-2-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl, benzothiazol-8-yl, benzoxazol-2-yl, benzoxazol-5-yl, benzoxazole-6 yl, benzoxazol-7-yl or benzoxazol-8-yl. , Sialic acid derivatives according to one of the items 1-3, wherein D ^{1 is} a monocyclic or polycyclic aromatic or saturated C ₃ -C ₄ -hydrocarbon radical or a monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, where the radicals mentioned unsubstituted or mono- or polysubstituted by a group X.

5. sialic acid derivatives according to any one of items 1-4, wherein D ^{2 is} selected from phenylene

1,4-diyl, phenylene-1,3-diyl, pyridine-2,5-diyl, pyridazine-3,6-diyl, pyrimidine-2,5-diyl, pyrimidine-2,6-diyl, pyrazine-2,5- diyl, trans-cyclobutane-l, 3-diyl, trans-cyclopentane-1,3-diyl, trans-cyclohexane-l, 4-diyl, cuban-l, 4-diyl, thiophene-2,5-diyl, pyrrole 2,4-diyl, pyrrole-2,5-diyl, pyrazole-l, 3-diyl, oxazole-2,4-diyl, oxazole-2,5-diyl, 1,3,4-oxadiazole

2,5-diyl, 1, 2,4-oxadiazol-3,5-diyl, isoxazole-3,5-diyl, imidazole-2,4-diyl, 2H-tetrazole-2,5-diyl, 1H, (1, 2, 4) -triazole-2,5-diyl, 1H (l, 2,3) -triazole-1, 4-diyl and 1H (l, 2,3) -triazole-1, 5-diyl, wherein said radicals are unsubstituted or substituted one or more times by a group X.

6. sialic acid derivatives according to any one of items 1-5, wherein Y ¹ is ~C (O) -, ~CH ₂ C (O) - or ~OC (O) -, wherein ~ denotes the bond to the group A ¹ .

7. sialic acid derivatives according to any one of items 1-6, wherein Y ^{3 is} a bond or a group ~ S (0) ₂ --C (O) -, ~CH ₂ -C (O) - or ~CH ₂ -S (C -) ₂ -, where ~ denotes the bond to the group D ³ .

8. sialic acid derivatives according to any one of items 1-7, wherein D ^{3 is} selected from:

a) C 1 -C ₅ -alkyl, where appropriate one or more H atoms being replaced by a group X,

and

b) monocyclic aromatic or saturated _C3-C6 hydrocarbon radical or monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted by a group X. , Sialic acid derivatives according to any one of items 1-8, wherein A ^{3 is} a C ₃ -C 75 alkanediyl, wherein optionally one or more -CH ₂ groups are replaced by S, O, N (R ^X ) and / or C (O) ,

10. sialic acid derivatives according to any one of items 1-9, wherein each X is independently selected from halogen, hydroxy, carboxymethyl, S0 ₃ M, OS0 ₃ M, S0 ₂ CF _3, P0 ₃ M, OP0 ₃ M, cyanomethyl, alkyl, haloalkyl , Alkyloxy, haloalkyloxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkylsulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino and oxo (= 0), the alkyl groups in these radicals containing from 1 to 3 carbon atoms.

1 1. Sialic acid derivatives according to any of items 1-9, wherein R ⁴ is -N (R ^x ) C (O) CH ₂ OH or -N (R ^x ) C (O) R ^x .

12. sialic acid derivatives according to any one of items 1-11, wherein one of D ¹ and D ³ or both are independent:

a) mono- or polycyclic, aromatic or saturated C ₃ -C ₄ -hydrocarbon radical selected from: i) C ₆ -C ₄ -aryl, in particular phenyl, naphth-1-yl, naphth-2-yl, biphen-4-yl, Biphen-2-yl, anthracene-9-yl, inden-4-yl, fluoren-2-yl, fluoren-3-yl, fluoren-9-yl and phenanthren-3-yl; and ii) C ₃ -C ₈ cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantane-1-yl, cuban-1-yl and cyclooctyl; b) monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical selected from: i) non-aromatic, saturated or partially unsaturated 4, 5 or 6-membered heterocyclyl containing one to four nitrogen atoms and / or one or two oxygen atoms, in particular 1-aza-cyclobut-1-yl, 2-tetrahydrofuranyl,

3-tetrahydrofuranyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl,

4-isoxazolidinyl, 5-isoxazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl,

5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 4,5-dihydro-1,3-oxazol-2-yl, 4,5-dihydro-1,3-oxazol-4-yl, 4 5-dihydro-1,3-oxazol-5-yl, 4,5-dihydro-4H-1,3-oxazin-2-yl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 2-pyrroline-2 yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl,

1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-monochinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl,

3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl,

4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 5H-tetrazol-5-yl, 1H-tetrazole

5-yl, 2H-tetrazol-5-yl-1-piperazinyl and 2-piperazinyl; ii) 5-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and / or one sulfur or oxygen atom: in particular 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl , 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2 Isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 1, 2,5-thiadiazol-3-yl, 1, 2,4-thiadiazole

3-yl, l, 2,4-thiadiazol-5-yl, l, 2,5-oxadiazol-3-yl, l, 2,4-oxadiazol-3-yl, l, 2,4-oxadiazole-5 yl, l, 2,3-thiadiazol-4-yl, l, 2,3-thiadiazol-5-yl, 1,2,3,4-thiazolidazol-5-yl, l H- (l, 2, 3) Triazol-1-yl, 1H- (1,2,3) triazol-4-yl, 1H- (1,2,3) triazol-5-yl, 1H- (1, 3,4) triazole-1 -yl and 1H- (1, 3,4) triazol-2-yl; iii) 6-membered heteroaryl containing one to three nitrogen atoms: in particular

2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl,

4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl. Sialic acid derivatives according to any one of items 1-12, wherein D ^{1 is} a group selected from phenyl, pyrimidin-5-yl, naphth-1-yl, naphth-2-yl and thien-2-yl, wherein said radicals are unsubstituted or - or are repeatedly substituted by a group X. Sialic acid derivatives according to any one of items 1-13, wherein D ^{2 is} a group selected from phenylene-l, 4-diyl, pyridine-2,5-diyl, pyrimidine-2,5-diyl and thiophene-2,5-diyl wherein the radicals mentioned are unsubstituted or mono- or polysubstituted by a group X. Sialic acid derivatives according to any one of items 1-14, wherein Y ¹ is ~C (O) - or ~CH 2 C (O) -, wherein ~ denotes the bond to the group A ¹ . Sialic acid derivatives according to any one of items 1-15, wherein Y ^{2 is} a bond. Sialic acid derivatives according to any one of items 1-16, wherein A ^{2 is} a group -N (H) -W, and W is preferably a -S0 ₃ M group. Sialic acid derivatives according to any one of items 1-17, wherein A ³ is C ₃ -C ₂ o-alkanediyl, wherein optionally one or more -CH ₂ - groups are represented by S, O, N (R ^X ) and / or C (O) are replaced. Sialic acid derivatives according to any one of items 1-18, wherein A ⁴ is -C-CH or bicyclo [6, l, 0] non-4-yn-9-yl. Sialic acid derivatives according to any one of items 1-19, wherein each X is independently selected from fluoro, chloro, hydroxy, carboxyl, methyl, trifluoromethyl, methoxy and oxo (= 0). Sialic acid derivatives according to any one of items 1-20, wherein R ⁴ is -N (R ^x ) C (O) CH ₂ OH or -N (R ^x ) C (O) R ^x , more preferably -NHC (0) CH _3. Sialic acid derivatives according to any one of items 1-21, represented by the formulas (Ia) - (Ic), wherein the symbols have the meanings given in items 1-21:

2

preferably in the formulas (Ia) - (Ic) R is H.

Sialic acid derivatives according to any one of items 1 to 22, represented by the formulas (L (lac), wherein the symbols have the meanings given in items 1 to 22:

Preferably in the formulas (Iaa) - (Iac) R ² is H. Sialic acid derivatives according to any one of items 1 to 23, wherein Z is -O-. Sialic acid derivatives according to any one of items 1 to 24, wherein R ⁵ or R ⁶ or both are OH. Sialic acid derivatives according to any one of items 1-25, wherein R ² or R ³ or both are H, preferably R and R are both H. Sialic acid derivatives according to any one of items 1-26, wherein A ³ is a C3-C ₅₀ alkanediyl (preferably C ₃ -C ₂₀ -alkanediyl), where one or more -CH ₂ - groups by -O-, -N (R ^X ) - and / or -C (O) - are replaced; Preferably, A ³ contains one or more amido groups -C (O) -NH-. Sialic acid derivatives according to any one of items 1-27, represented by formula (Iba), wherein the symbols have the meanings given in items 1-27:

A conjugate of at least one sialic acid derivative, a pharmaceutically acceptable solvate, salt or prodrug thereof as defined in any one of items 1 to 28 and a Component selected from a cargo, a nanoparticle, a polymer and a polymer or nanoparticle-associated cargo. A conjugate according to item 29, wherein the nanoparticles (eg selected from gold nanoparticles and liposomes) carry the sialic acid derivative, the pharmaceutically acceptable solvate, salt or prodrug thereof covalently bound on the surface of the nanoparticles or non-covalently or covalently bound inside. A conjugate according to item 29, wherein the cargo is selected from RNA, DNA, peptides, enzymes, low molecular weight antigens, antigenic proteins and low molecular weight pharmacologically active substances. A conjugate according to item 29, wherein the cargo is a diagnostically useful cargo selected from a fluorescent molecule, a radiolabelled molecule and a positron emitter. Sialic acid derivatives according to any one of items 1 to 28 or a conjugate according to any one of items 29-31 for use in vaccination, regulation of the immune system, as well as for the treatment or prevention of allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple sclerosis, cancer, viral diseases, bacterial diseases, parasitic diseases, genetic diseases, diseases in which the immune response is disturbed in the context of B cell activation and diseases of the blood-forming organs and the blood. Conjugate according to item 32 for use in the diagnosis of B-cell based diseases, eg lymphomas. A pharmaceutical composition comprising at least one sialic acid derivative, a pharmaceutically acceptable solvate, salt or prodrug thereof as defined in any one of items 1 to 28, or a conjugate as defined in any one of items 29-32 and at least one member selected from a pharmaceutically acceptable carrier, pharmaceutically acceptable excipients and pharmaceutically acceptable excipient and optionally one or more other drugs. A process for preparing a sialic acid derivative as defined in any one of items 1 to 28, comprising

the reaction of a compound of formula VIII

in which all symbols have the meanings given in point 1,

with an amine reactive reagent containing the group A ⁴ as defined in item 1;

or

the reaction of a compound of formula VII

with an amine containing the group A ⁴ and subsequent removal of the protective groups.

Process according to item 36, wherein the compound of formulas VII and VIII are each prepared by multi-step synthesis from the compound of formula (III)

where all symbols have the meanings given in point 1.

A method according to item 37, wherein the compound of formula (III) with Z

Reaction of a compound of the formula (II)

wherein T = aryl or alkyl is prepared with a tert-butyl protected hydroxycarboxylic acid. Intermediates for the preparation of sialic acid derivatives of formula (I) as defined in any one of items 1 to 28 selected from the group consisting of

anion

preferably Z-O in the formulas (III), (IV), (IX) and (X).

Use of a sialic acid derivative of the formula (I), a prodrug, solvate or salt thereof as defined in any one of items 1 to 28 for the preparation of a conjugate in which the sialic acid derivative, prodrug, solvate or salt thereof is covalently or non-covalently linked to a optionally polymer- or nanoparticle-linked - cargo selected from RNA, DNA, peptides, enzymes, low molecular weight antigens, antigenic proteins and low molecular weight pharmacologically active substances. 7

41. Use of a sialic acid derivative of the formula (I), a prodrug, solvate or salt thereof as defined in any one of items 1 to 28 for the preparation of a conjugate in which the sialic acid derivative, prodrug, solvate or salt thereof is covalently or non-covalently a - optionally polymer- or nanoparticle-linked - cargo selected from fluorescent molecule, radiolabeled molecule and positron emitter is linked.

The invention is further illustrated by the following example without thereby limiting it.

A. Synthesis of Compound 14.

The synthesis was carried out stepwise as shown in Scheme 2.

All but not described compounds were purchased or prepared according to known literature procedures.

Silica gel Si60 43-60mm or RP-18 silica gel (YMC CO LTD., YMC ODS-AQ) was used for chromatographic purifications.

Solvents were removed by means of a vacuum rotary evaporator at reduced pressure and a bath temperature of 40 ° C. In the following syntheses, this step is referred to as "concentration".

The reactions and substances were monitored by thin layer chromatography. For this purpose silica-coated aluminum plates with fluorescence indicator were used (Merck TLC silica gel 60 F ₂ 5 ₄ ). The substance was detected under UV light at 366 and 254 nm. The chromatograms were then sprayed with dilute sulfuric acid and heated to detect the substances. Amines were sprayed with ninhydrin solution and heated for detection. Details and other detection methods are illustrated in "Thin Layer and Paper Chromatography Reagent Reagents" by Merck (1970).

Abbreviations

ACN acetonitrile

DMF N, N-dimethylformamide

DCM dichloromethane

DIPEA N, N-diisopropylethylamine

EtOH ethanol

EtOAc ethyl acetate

HAc acetic acid

HATU 0- (7-azabenzotriazole-1-yl) -N, N, ', Ν'-tetramethyluronium

HRMS High resolution mass spectrometry

MeOH methanol

TEA triethylamine

TLC Dünnschichtchromatografi e Connection 1

Produced by: Bioorg. Med. Chem. Lett. 1994, 4, 2457-2460 Compound 2

17 g of Compound 1 was dissolved in 50 ml of ACN and 5.48 g of sodium thiophenolate was added. The suspension was stirred for 4 h and concentrated. The residue was dissolved in dichloromethane and poured into ice-cold, dilute hydrochloric acid. The organic phase was washed with dilute hydrochloric acid and cold NaHCO ₃ solution, dried with Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in DCM and purified on silica gel (DCM to MeOH gradient) of thiophenol residues. TLC Rf: 0.76 (EtOAc), UV positive

Connection 3

2.40 g of compound 2 and 1.11 g of tert-butyl 6-hydroxyhexanoic acid were dissolved in 30 ml of ACN. At -40 ° C, 0.184 ml of trifluoromethanesulfonic acid and 318 mg of N-iodo-succinimide were added. The reaction was stirred for another hour at -40 ° C and heated to 0 ° C over 3 h. The solution was diluted with DCM, washed with saturated NaHC0 ₃ and Na ₂ S0 _3, dried, filtered and concentrated with MgS0. ₄ The residue was purified over silica gel (DCM to MeOH gradient). Yield: 2.56 g TLC Rf: 0.76 (EtOAc), black after heating with H ₂ S0 ₄ , UV negative even after heating with H ₂ S0 ₄ ; Ή NMR (300 MHz, CDCl ₃ ) δ ppm 5.46 (d, J = 8.18 Hz, 1H), 5.39 (ddd, J = 8.17, 4.62, 2.38 Hz, 1H), 5.31 (dd, J = 8.65, 1.53 Hz, 1H), 4.36-4.26 (m, 2H), 4.18 (dd, J = 12.51, 4.80 Hz, 1H), 3.93-3.70 (m, 5H), 3.38 (td, J = 11.23, 9.01 Hz, 1H), 3.22 (td, J = 9.39, 6.48 Hz, 1H), 2.63 (dd, J = 13.05, 4.39 Hz, 1H), 2.21 (dd, J = 7.87, 7.04 Hz, 2H), 2.16 (s, 3H), 2.15 ( s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.71 (t, J = 12.94 Hz, 1H), 1.66-1.28 (m, 15H); MS (ESI-pos) Calcd for C ₂₈ H ₄₄ N ₄ 0 ₁₃ [M + Na] ^+: 667.28 g / mol, found 667.3

Connection 4

2.50 g of compound 3 was dissolved in 20 ml of dry MeOH. The solution was admixed with 0.15 ml of NaOMe solution (30%) and stirred for 60 minutes. The solution was neutralized with Dowex Monosphere 650C in H ⁺ form and filtered. The solution was processed directly. TLC Rf: 0.55 (1: 6: 1 EtOAc: MeOH: HAc20%) Connection 5

A solution obtained as described above and containing 2.0 g of Compound 4 in 60 ml of dry MeOH was added 15 ml of water. After addition of 1.74 g of zinc and 2.08 g of NH ₄ Cl, the suspension was stirred for 5 h, treated with 60 ml of MeOH, filtered and concentrated. The residue was processed directly. TLC Rf: 0.21 (1: 6: 1 EtOAc: MeOH: HAc20%)

Connection 6

The residue obtained as described above, containing 2.0 g of compound 5, was suspended with 20 ml of MeOH and 4.2 ml of TEA, admixed with 4.15 g of Boc anhydride, stirred for 5 hours and filtered. The solution was concentrated and the residue was dissolved in a mixture of EtOAc and 2% acetic acid. The organic phase was washed with sat. NaHCO ₃ and sat. NaCl, dried with MgS0 ₄ , filtered and concentrated. The residue was purified over silica gel (contaminant was eluted with EtOAc, the product was eluted with EtOAc: MeOH 10: 1). TLC Rf: 0.59 (1: 6: 1 EtOAc: MeOH: HAc20%); Ή NMR (500 MHz, CD ₃ OD) δ ppm 6.82 (d, J = 6.52 Hz, 1H), 5:04 (br s, 1H), 4.70 (d, J = 8:08 Hz, 1H), 4.00-3.61 (m, 10H), 3.53 (dd, J = 8.71, 1.08 Hz, 1H), 3.43 (dd, J = 9.73, 1.52 Hz, 1H), 3.24 (td, J = 9.05, 6.72 Hz, 1H), 2.64 (dd, J = 12.96, 4.04 Hz, 1H), 2.19 (t, J = 7.50 Hz, 2H), 1.97 (s, 3H), 1.73 (t, J = 12.79 Hz, 1H), 1.60-1.49 (m, 4H), 1.44 (s, 9H), 1.43 (s, 9H), 1.35-1.27 (m, 2H); HRMS (ESI-pos) Calcd for C ₂₇ H ₄₈ N ₂ Oi ₂ [M + H] ^+: 593.3280 g / mol, found 593.3267

Connection 7

1.2 g of compound 6 and 3.08 g of NaN ₃ were dissolved twice in 20 ml of dry DMF and concentrated. The anhydrous residue was redissolved in 20 ml of DMF and 1.5 g of CBr ₄ and 0.755 g of triphenylphosphine were added at 0 ° C. The suspension was stirred at 0 ° C. for 1 h and at RT for 24 h. 10 ml of MeOH was added and the solution was stirred for a further 24 h and concentrated. The residue was dissolved in EtOAc and washed twice with water. The organic phase was dried with MgSO ₄ , filtered and concentrated. The residue was purified over silica gel (EtOAc). Yield 0.840 g; TLC-RF: 0.81 (9: 1 DCM: MeOH) or 0.85 (EtOAc); 1H NMR (300 MHz, CDC1 ₃ ): δ ppm 6.76 (d, J = 5.90 Hz, 1H), 4.63 (d, J - 7.52 Hz, 1H), 4.06 (ddd, J - 8.92, 6.26, 2.02 Hz, 1H ), 3.96-3.82 (m, 4H), 3.78 (td, J = 9.06, 6.33 Hz, 1H), 3.72-3.57 (m, 1H), 3.63 (dd, J = 12.48, 2.40 Hz, 1H), 3.52 3.39 (m, 3H), 3.24 (td, J = 8.80, 6.63 Hz, 1H), 2.65 (dd, J = 12.88, 3.47 Hz, 1H), 2.20 (t, J = 7.43 Hz, 2H), 1.99 (s, 3H), 1.73 (t, J = 12.70 Hz, 1H), 1.64-1.19 (m, 24H); MS (ESI-pos) calculates for C27H47N5O1 1 [M + Na] ⁺ : 640.32 g / mol, found 640.3

Connection 8

0.82 g of compound 7 was dissolved in 20 ml of MeOH and 5 ml of water. After addition of 0.24 g of zinc and 0.29 g of NH ₄ Cl, the suspension was stirred for 1 h, filtered and concentrated. The residue was processed directly. TLC Rf: 0.16 (9: 1 DCM: MeOH)

Connection 9

376 mg of 4- (4-fluorophenyl) benzoic acid were dissolved in 5 ml DMF and 0.94 ml TEA and 636 mg HATU were added to the solution. After 20 sec, the solution was added to a solution containing 830 mg of Compound 8 in 5 ml of DMF and 0.93 ml of TEA. After 20 minutes, filtered and concentrated. The residue was dissolved in EtOAc and the solution was washed with dilute HCl and sat. NaHCO ₃ , dried with MgSO ₄ and concentrated. The residue was purified over RP18 silica gel (H ₂ O to ACN). Yield: 640 mg; TLC Rf: 0.27 (1:19 DCM: MeOH); Ή NMR (500 MHz, CD ₃ OD) δ ppm 7.91 (d, J = 8.58 Hz, 2H), 7.71-7.65 (m, 4H), 7.19 (t, J = 8.81 Hz, 2H), 4.02 (ddd, J = 8.56, 7.28, 3.36Hz, 1H), 3.91-3.75 (m, 6H), 3.66-3.58 (m, 1H), 3.57 (dd, J = 13.83, 7.22Hz, 1H), 3.47 (dd, J = 8.64 , 1.42 Hz, 1H), 3.34 (td, J = 9.15, 6.50 Hz, 1H), 2.53 (dd, J = 12.94, 4.03 Hz, 1H), 2.17 (t, J = 7.36 Hz, 2H), 1.91 (s , 3H), 1.74 (t, J = 12.87 Hz, 1H), 1.62-1.46 (m, 4H), 1.42 (s, 9H), 1.41 (s, 9H), 1.36-1.27 (m, 2H); MS (ESI-pos) calcd for C ₄₀ H ₅₆ FN ₃ Oi ₂ [M + Na] ⁺ : 812.37 g / mol, found 812.4

Connection 10

640 mg of compound 9 were dissolved in 10 ml of DCM and admixed with 5 ml of trifluoroacetic acid. After 4 h, it was concentrated and the residue was redissolved three times with 20 mL DCM and reconcentrated. The residue was further processed directly.

Connection 11

The residue obtained as described above containing 510 mg of Compound 10 was dissolved in 10 ml of water and adjusted to pH 9 with dilute NaOH. 368 mg of pyridine-S0 ₃ complex were added portionwise over 2 h, keeping the pH to pH 9 with dilute NaOH. After addition of 2 ml of sat. NaHCO ₃ was stirred for 1 h and then purified on RP18 silica gel (H ₂ O to ACN). Yield 390 mg: TLC Rf: 0.74 in 1: 3: 1 (EtOH: EtOAc: HAc20%); Ή NMR (500 MHz, CD ₃ OD) δ ppm 7.93 (d, J = 8.62 Hz, 2H), 7.71-7.67 (m, 4H), 7.19 (t, J = 8.83 Hz, 2H), 4.05 (ddd, J = 8.71, 7.55, 3.31 Hz, 1H), 3.84 (s, 3H), 3.81-3.72 (m, 4H), 3.60 (dd, J = 13.80, 7.49 Hz, 1H), 3.46 (dd, J = 8.81, 0.72 Hz, 1H), 3.35-3.30 (m, 1H), 2.98 (dd, J = 13.23, 4.33 Hz, 1H), 2.14 (dd, J = 7.80, 7.35 Hz, 2H), 1.98 (s, 3H), 1.75 (t, J = 12.84Hz, 1H), 1.61-1.49 (m, 4H), 1.40-1.28 (m, 2H); MS (ESI-neg) calcd for C ₃ iH ₃₈ FN ₃ Na ₂ O ₁₃ S [MH] ^" : 712.19 g / mol, found 712.2

Connection 12

A solution of 100 mg of compound 1 1 and 87 mg of ethylenediamine mono-Fmoc in 5 ml of DMF was admixed with 0.131 ml TEA and 72 mg HATU. After 5 minutes, the solution was acidified with dilute acetic acid. The solution was mixed with 2 ml of NaHC0 ₃ and 10 ml of water and purified over RP18 silica gel (H ₂ 0 to ACN). The product fractions were concentrated to 6 ml and processed directly. TLC Rf: 0.77 in 1: 3: 1 (EtOH: EtOAc: HAc20%); Ή NMR (500 MHz, CD ₃ OD) δ ppm 7.94-7.87 (m, 2H), 7.79-7.75 (m, 2H), 7.73-7.60 (m, 6H), 7.36 (t, J = 7.45 Hz, 1H) , 7.28 (t, J = 7.43 Hz, 2H), 7.21-7.13 (m, 2H), 4.31 (d, J = 6.91 Hz, 2H), 4.16 (t, J = 6.83 Hz, 1H), 4.05 (ddd, J = 8.33, 7.66, 3.36Hz, 1H), 3.88-3.70 (m, 6H), 3.55 (dd, J = 13.66, 7.61Hz, 1H), 3.48 (dd, J = 8.70, 0.89Hz, 1H), 3.37 -3.29 (m, 1H), 3.27-3.16 (m, 4H), 2.98 (dd, J = 13.25, 4.33 Hz, 1H), 2.81 (dd, J = 14.34, 7.07 Hz, 1H), 2.14 (t, J = 7.51 Hz, 2H), 1.99 (s, 3H), 1.77 (t, J = 12.77 Hz, 1H), 1.63-1.44 (m, 4H), 1.39-1.24 (m, 2H), 2.90-2.77 (m, 1H); MS (ESI-neg) calcd for C ₄₈ H ₅₅ FN ₅ O ₄ S [MH] ^': 976.34 g / mol, found 976.3

Connection 13

To a suspension of 158 mg of compound 12 in 6 ml of water, obtained as described above, was added 2 ml of ethanol and 0.79 ml of 1M NaOH. After 3 h, the suspension was neutralized with 20% acetic acid, concentrated and purified via RP18 (0.5% HAc to ACN). The residue was processed directly into. TLC Rf: 0.43 in 1: 2: 1 (EtOH: EtOAc: HAc20%)

Connection 14 A solution of 182 mg of compound 13 in 1 ml of DMF and 0.1 16 ml of TEA was admixed with 77 mg of exo BCN-active NPE (CAS 1380006-72-3) and stirred for 2 h. 2 ml of 20% acetic acid and 20 ml of water were added and the solution was purified on RP18 silica gel. First, it was flushed with dil. NaHCO ₃ until 4-nitrophenyl was removed and then eluted with a water: ACN gradient). Yield: 130 mg; TLC Rf: 0.28 in 1: 2: 1 (EtOH: EtOAc: HAc20%); 1H NMR (500 MHz, CD ₃ OD): δ ppm 7.91 (d, J = 8.56 Hz, 2H), 7.72-7.66 (m, 4H), 7.19 (t, J = 8.82 Hz, 1H), 4.10 (d, J = 8.11 Hz, 2H), 4.06 (ddd, J = 8.71, 8.11, 3.37 Hz, 1H), 3.83 (dd, J-13.61, 3.33 Hz, 1H), 3.76 (td, J = 9.27, 6.48 Hz, 1H ), 3.71 (dd, J = 10.22, 1.88 Hz, 1H), 3.60 (t, J = 10.21 Hz, 1H), 3.50 (dd, J = 13.62, 7.83 Hz, 1H), 3.50-3.43 (m, 1H) , 3.44 (dd, J-8.98, 1.78 Hz, 1H), 3.40 (ddd, J = 1 1.95, 10.62, 4.57 Hz, 1H), 3.28-3.22 (m, 2H), 3.21-3.16 (m, 2H), 3.06 (dd, J = 12.68, 4.56 Hz, 1H), 2.28-2.09 (m, 8H), 2.01 (s, 3H), 1.68-1.48 (m, 7H), 1.40-1.30 (m, 3H), 0.95- 0.85 (m, 2H); HRMS (ESI-neg) calcd for C ₄₃ H ₅₄ FN ₅ Na ₂ O ₁₄ S [MH] ^" : 984.3060 g / mol, found 980.3066

B. Biological tests

The biological activity of the substances was determined in an ELISA-based inhibition assay as described in "ACS Chem. Biol. 2014, 9, 1444-1450." The sialic acid derivatives of formula (I) inhibit the binding of soluble CD22 to immobilized IgM in proportion to their affinity to CD22 The soluble CD22 protein was expressed in the cell line CHO-Lecl and isolated as described "ACS Chem. Biol. 2014, 9, 1444-1450". The known substance "BPCNeu5Ac" (J. Exp. Med., 2002, 195, 1207-1213) was tested as a reference in the tests In addition, the known substance 15 (WO2015128344) was also tested as reference The relative affinity is expressed as rIP (relative Inhibitory affinity).

Table I shows the affinity or relative inhibitory potency (rIP) of the sialic acid derivative 14 according to the invention and other monovalent derivatives of sialic acid and the reference substance BPC Neu5Ac hitherto used for the preparation of conjugates. Table I

Ref 2: XXVIII International Carbohydrate Symposium, July 17-21, 2016, New Orleans Poster / Abstract 294

* not within the claims

Claims

1. sialic acid derivatives of the formula (I)

where the symbols have the following meanings:

A ¹ is a group D ^] - [Y ² -D ² -] _m -;

D ¹ is a mono- or polycyclic aromatic, partially unsaturated or saturated C ₃ -C 4 -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to twelve-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted a group X is substituted;

D ² is a mono- or polycyclic aromatic, partially unsaturated or saturated C 3 -C ₄ -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted a group X is substituted; is -C (O) -, -S (O) ₂ -, CH ₂ C (O) -, NHC (O) - or -OC (O) -, wherein bond to group A denotes ¹ ; Y is -O- or a bond;

A ² is a group -N (R ^y ) -W or -N (H) -W; W is

a) a group -S0 ₃ M or -S0 ₂ NR ^x ₂ or

b) a group D -Y -;

Y ³ is a bond or group selected from -NHC (O) -, OC (0) -, S (0) ₂ -, C (O) -, CH ₂ C (O) -, and CH ₂ S (0) ₂ -, wherein ~ denotes the bond to the group D ³ ;

D is ³

a) Cj-Cö-alkyl, wherein optionally one or more non-terminal CH ₂ - groups are replaced by O, N (R ^X ) and / or C (O) and wherein in the non-terminal CH ₂ groups optionally one or more H atoms are replaced by a group X, or

b) a mono- or polycyclic aromatic, partially unsaturated or saturated C ₃ -C ₄ -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted a group X is substituted;

A ³ is a C ₃ -C ₅ alkanediyl, wherein optionally one or more -CH ₂ - groups by -S-, -S (0 ₂ ) -, -O-, -N (R ^X ) - and / or -C (O) - are replaced;

A ⁴ is a group selected from -C ^ H, bicyclo [6, l, 0] non-4-yn-9-yl, dibenzocyclooctinyl, biarylazacyclooctinonyl, cyclooctinyloxy, cyclooctynyl or dimethoxyazacyclooctynyl, where in said groups optionally one or more H Atoms are replaced by a group X; each X is independently selected from halogen, cyano, nitro, hydroxy, carboxyl, carboxymethyl, hydroxylamino, -SO ₃ M, -OSO ₃ M, -SO ₂ NH ₂ , -SO ₂ CF ₃ , -PO ₃ M, -OPO ₃ M, cyanomethyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, trialkylamino, alkylcarbonyl, alkylsulfonyl, alkylsulfoxyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, dialkylaminocarbonyl and oxo (= 0) wherein alkyl and alkoxy in the above groups contain 1 to 4 carbon atoms; m is 0 or 1

Z is -O- or -S-;

R ¹ is -C (O) OM;

R ² is H, OH, OR ^y or F;

R ³ is H or F;

R ⁴ is -N (R ^x ) C (O) CH ₂ OH, -N (R ^x ) C (O) R ^x , -NHC (0) CH ₂ F or -NHC (O) CH ₂ Cl; R ⁵ and R ⁶ are the same or different and selected from OH and 0R ^X ; M is a cation; each R ^x is independently selected from H, R ^y and R ^z ; each R ^y is independently selected from C 1 -C 4 alkyl, phenyl and benzyl; and each R ^z is independently selected from -C (O) - (C 1 -C ₄ -alkyl), -C (O) -phenyl or -C (O) -CH ₂ -phenyl; a pharmaceutically acceptable solvate, salt or prodrug thereof.

2. sialic acid derivatives according to claim 1, represented by the formulas (Ia) - (Ic), wherein the symbols have the meanings given in claim 1:

3. sialic acid derivatives according to claim 1 or 2, represented by the formulas (Iaa) (Iac), where the symbols have the meanings given in claim 1:

4. sialic acid derivatives according to any one of claims 1 to 3, wherein Z is -O-.

5. sialic acid derivatives according to any one of claims 1 to 4, wherein R ^{4 is} selected from -N (H) C (0) R \

6. sialic acid derivatives according to any one of claims 1 to 5, represented by formula (Iba), wherein the symbols have the meanings given in claim 1:

7. sialic acid derivatives according to any one of claims 1 to 6, wherein R ⁵ or R ⁶ or both are OH.

8. sialic acid derivatives according to any one of claims 1 to 7, wherein R and R are both H.

A conjugate of at least one sialic acid derivative, a pharmaceutically acceptable solvate, salt or prodrug thereof as defined in any one of claims 1 to 8 and a component selected from a cargo, a polymer, a nanoparticle, a polymer linked cargo, and a a cargo linked to a nanoparticle.

10. sialic acid derivatives according to any one of claims 1 to 8 or a conjugate according to claim 9 for use in vaccines and the regulation of the immune system, as well as for the treatment or prevention of allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple sclerosis, cancer, viral diseases, bacterial diseases, parasitic diseases, genetic diseases, diseases in which the immune response in the context of B cell activation is disturbed and diseases of the blood-forming organs and the blood.

1. Use of a sialic acid derivative according to any one of claims 1 to 8 or a conjugate according to claim 9 for the manufacture of a medicament for use in vaccinations and in the regulation of the immune system, as well as for the treatment or prevention of allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple Sclerosis, cancer, viral diseases, bacterial diseases, parasitic diseases, genetic diseases, diseases in which the immune response in the context of B-cell activation is disturbed and diseases of the blood-forming organs and the blood.

12. Use of a sialic acid derivative according to any one of claims 1 to 8 for linking with a cargo, a polymer, nanoparticles, a cargo-carrying polymer or cargo-bearing nanoparticles.

A pharmaceutical composition comprising at least one sialic acid derivative, a pharmaceutically acceptable solvate, salt or prodrug thereof as defined in any of claims 1 to 8, or a conjugate as defined in claim 9 and at least one member selected from a pharmaceutically acceptable carrier, pharmaceutically acceptable Excipient and pharmaceutically acceptable excipient.

14. A process for the preparation of a sialic acid derivative as defined in any one of claims 1 to 8, comprising

the reaction of a compound of formula VIII

in which all symbols have the meanings given in claim 1, with an amine-reactive reagent containing the group A ⁴ as defined in claim 1;

or

b) the reaction of a compound of formula VII

with an amine containing the group A and subsequent deprotection.

15. The method according to claim 14, wherein the compound of the Fomieln VII and VIII are each prepared by multi-step synthesis of the compound of formula (III)

where all symbols have the meanings given in claim 1.

16. The method according to claim 15, wherein the compound of formula (III) with Z = O by reacting a compound of formula (II)

wherein T = aryl or alkyl is prepared with a tert-butyl protected hydroxycarboxylic acid.