DE102017002810A1 - Sialic acid derivatives with C-C triple bond and their preparation - Google Patents

Abstract

Sialic acid derivatives containing a C-C triple bond are described, processes for their preparation, conjugates prepared therefrom and drugs containing them.

Description

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 (p chauer (2004) Zoology, 107, 49-64 ; Varki (2008) Trends in Mol. Med., 14, 8, 351- 360 ). Furthermore, they are used by many pathogens, for example, to achieve an efficient infection or to escape the immune system of the host ( 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 potentially treatable diseases with Siglec inhibitors can be found in Trends in "Pharmacological Sciences 2009, 30 (5), 240-248" and "Current Medicinal Chemistry 2011, 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 radical act as a glycosidically linked substituent at position 2 as ligands for CD22, show a very high affinity and have a potential suitability as a pharmaceutical ( Prescher et al. 2014 ACS Chem Biol. 9 (7): 1444-50 ; WO2015128344 ; Madge et al. 2016 Scientific Reports 6, Article Number: 36012 ).

Furthermore, it is known that sialic acids and their derivatives, in particular those with affinity for siglec-2, can be used for the preparation of conjugates with therapeutic suitability ( Courtney et al (2009) PNAS 106, 8, 2500-505 ; Collins et al (2006) Journal of Immunology 177, 2994-3003 ; Chen et al. 2010 Blood 115 (23): 4778-86 ; Swiss 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.

wobei die Symbole folgende Bedeutungen haben:

A¹

ist eine Gruppe D¹-[Y²-D^2-]_m-;

D¹

ist ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter C₃-C₁₄-Kohlenwasserstoffrest oder ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter drei- bis zwölfgliedriger heterocyclischer Rest, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind;

D²

ist ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter C₃-C₁₄-Kohlenwasserstoffrest oder ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter drei- bis achtgliedriger heterocyclischer Rest, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind;

Y¹

ist ∼C(O)-, ∼S(O)₂-, ∼CH₂C(O)-, ∼NHC(O)- oder ∼OC(O)-, wobei ∼ die Bindung zur Gruppe A¹ bezeichnet;

Y²

ist -O- oder eine Bindung;

A²

ist eine Gruppe -N(R^y)-W oder -N(H)-W;

W

ist

a)

eine Gruppe -SO₃M oder -SO₂NR^x ₂ oder

b)

eine Gruppe D³-Y³-;

Y³

ist eine Bindung oder eine Gruppe ausgewählt aus ∼NHC(O)-, ∼OC(O)-, ∼S(O)₂-, ∼C(O)-, ∼CH₂C(O)- oder ∼CH₂S(O)₂-, wobei ∼ die Bindung zur Gruppe D³ bezeichnet;

D³

ist

a)

C₁-C₆-Alkyl, wobei gegebenenfalls eine oder mehrere nicht terminale CH₂-Gruppen durch O, N(R^x) und/oder C(O) ersetzt sind und wobei in den genannten Gruppen gegebenenfalls ein oder mehrere H-Atome durch eine Gruppe X ersetzt sind,

b)

mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter C₃-C₁₄-Kohlenwasserstoffrest oder ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter drei- bis achtgliedriger heterocyclischer Rest, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind;

A³

ist ein C₃-C₁₅₀-Alkandiyl, wobei gegebenenfalls eine oder mehrere CH₂-Gruppen durch S, S(O)₂, O, N(R^x) und/oder C(O) ersetzt sind;

A⁴

ist eine Gruppe -C=CH, Bicyclo[6,1,0]non-4-in-9-yl, Dibenzocyclooctinyl, Biarylazacyclooctinonyl, Cyclooctinyloxy, Cyclooctinyl oder Dimethoxyazacyclooctinyl, wobei in den genannten Gruppen gegebenenfalls ein oder mehrere H-Atome durch eine Gruppe X ersetzt sind;

jedes X

ist unabhängig ausgewählt aus Halogen, Cyano, Nitro, Hydroxy, Carboxyl, Carboxymethyl, Hydroxylamino, SO₃M, OSO₃M, SO₂NH₂, SO₂CF₃, PO₃M, OPO₃M, Cyanomethyl, Alkyl, Halogenalkyl, Alkyloxy, Halogenalkoxy, Amino, Alkylamino, Dialkylamino, Trialkylamino, Alkylcarbonyl, Alkylsulfonyl, Alkylsulfoxyl, Alkylaminosulfonyl, Dialkylaminosulfonyl, Alkoxycarbonyl, Alkylcarbonyloxy, Aminocarbonyl, Alkylaminocarbonyl, Alkylcarbonylamino, Dialkylaminocarbonyl oder Oxo (=O), wobei die Alkylgruppen und Alkoxygruppen in diesen Resten 1 bis 4 Kohlenstoffatome enthalten;

m

ist 0 oder 1

Z

ist -O- oder -S-;

R¹

ist -C(O)OM;

R²

ist H, OH, OR^y oder F;

R³

ist H oder F;

R⁴

ist -N(R^x)C(O)CH₂OH, -N(R^x)C(O)R^x, -NHC(O)CH₂F oder -NHC(O)CH₂Cl;

R⁵, R⁶

sind gleich oder verschieden und ausgewählt aus OH und OR^x;

M

ist ein Kation;

jedes R^x

ist unabhängig ausgewählt aus H, R^y und R^z;

jedes R^y

ist unabhängig ausgewählt aus C₁-C₄-Alkyl, Phenyl und Benzyl und

jedes R^z

ist unabhängig ausgewählt aus -C(O)-C₁-C₄-Alkyl, -C(O)-Phenyl und C(O)-CH₂-Phenyl.

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 ¹ - [Y ² -D ^2- ] _m -;

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 by a Group X are substituted;

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 by a Group X are substituted;

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 (O) -, ~S (O) ₂ -, ~C (O) -, ~CH ₂ C (O) - or ~CH ₂ S (O) ₂ -, wherein ~ denotes the bond to the group D ³ ;

D ³

is

a)

C ₁ -C ₆ -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 said groups optionally one or more H atoms a group X have been replaced,

b)

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 by a group X substituted;

A ³

is a C ₃ -C ₁₅₀ alkanediyl, wherein optionally one or more CH ₂ groups are replaced by S, S (O) ₂ , O, N (R ^x ) and / or C (O);

A ⁴

is a group -C = CH, bicyclo [6,1,0] non-4-yn-9-yl, dibenzocyclooctinyl, biarylazacyclooctinonyl, cyclooctinyloxy, cyclooctynyl or dimethoxyazacyclooctynyl, where in the groups mentioned optionally one or more H atoms by a Group X are replaced;

every 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, Alkyloxy, haloalkoxy, amino, alkylamino, dialkylamino, trialkylamino, alkylcarbonyl, alkylsulfonyl, alkylsulfoxyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, Dialkylaminocarbonyl or oxo (= O), wherein 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 (O) 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;

every R ^x

is independently selected from H, R ^y and R ^z ;

every 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 and C (O) -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 the preparation of 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 processes (see, for example, US Pat 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 the formula (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 the formula (VI) is obtained. The sialic acid derivative of the formula (VI) is then converted into a sialic acid derivative of the formula (VII) by removal of the amino-protecting group Q at position 4 and the tert-butyl protective group at position 2 and by reaction with amine-reactive reagents. 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 ³ . 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, wherein the above reactions to A ³ , 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 processes ( 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-enonates (Carbohydr. Res. 1993, 244, 181-185) getting produced.

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.

For 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, pharmacologically active substance, a cytostatic agent, a protein, an antigenic protein, an enzyme, an antigen, a low molecular weight antigen, a DNA, an RNA, an oligonucleotide, a radioactive material, 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. Further, polymers also include non-linear polymers, e.g. Dendrimers understood. 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 made, for example, of atoms, e.g. Gold or iron, from lipids and fat soluble substances such as e.g. Fatty acids, phosphatidylethanolamines or cholesterol, from proteins such as e.g. Viral capsid proteins, from polymers such as e.g. Acrylamide, chitosan, poly (lactide-co-glycolide) (PLGA). 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 may be treated with surface stabilizers, e.g. Polyethylene glycols be equipped.

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 e.g. Succinyl chitosan or carboxymethyl cellulose, homopolymeric amino acids, e.g. 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 the formula (I) can also be linked to a cargo for diagnostic purposes to a conjugate, ie with a cargo with diagnostically useful 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 inhibitors, in particular allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple sclerosis, cancer, viral diseases, such as AIDS , Bacterial diseases, such as streptococci, parasitic diseases such as Chagas disease, diseases in which the immune response in the context of B-cell activation is disturbed, such as Common Variable Immunodeficiency (CVID) and IgA deficiency, in diseases of the blood-forming organs and the blood and used in cancer, for example, lymphomas and myelomas.

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 pharmacologically active conjugate can be carried out particularly easily to form a 1,2,3-triazole ring. In particular, the production of conjugates of azido group-carrying cargoes, such as low molecular weight molecules, DNA, RNA, peptides, nanoparticles, antigens, cells, proteins, viruses, polymers or dendrimers can be carried out 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 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. 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, hydrogen sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, 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.

• Halogen: Fluor, Chlor, Brom und Iod;
• Alkyl: gesättigte geradkettige, verzweigte oder cyclische Kohlenwasserstoffreste mit vorzugsweise 1 bis 8 Kohlenstoffatomen, wie 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-Dimethylcylopropyl, 2,3-Dimethylcylopropyl, Cyclohexyl und Cyclooctyl;
• Halogenalkyl: geradkettige verzweigte oder cyclische (wie vorstehend definierte) Alkylgruppen mit vorzugsweise 1 bis 6 Kohlenstoffatomen, wobei in diesen Gruppen die Wasserstoffatome teilweise oder vollständig durch Halogenatome ersetzt sind: wie Chlormethyl, Brommethyl, Dichlormethyl, Trichlormethyl, Fluormethyl, Difluormethyl, Trifluormethyl, Chlorfluormethyl, Dichlorfluormethyl, Chlordifluormethyl, 1-Chlorethyl, 1-Bromethyl, 1-Fluorethyl, 2-Fluorethyl, 2,2-Difluorethyl, 2,2,2-Trifluorethyl, 2-Chlor-2-fluorethyl, 2-Chlor-2,2-difluorethyl, 2,2-Dichlor-2-fluorethyl, 2,2,2-Trichlorethyl, Pentafluorethyl, 1-Fluor-1-methyl-ethyl, 1-Fluorcyclopropyl, Heptafluorpropyl oder Nonafluorbutyl;
• Alkoxy: -O-Alkyl Gruppen mit gesättigtem geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser wie vorstehend definiert ist und vorzugsweise 1 bis 6 Kohlenstoffatome enthält;
• Halogenalkoxy: geradkettige, verzweigte oder cyclische Alkoxyreste wie vorstehend definiert, wobei 1 oder mehr H durch Halogen ersetzt sind;
• Alkylamino: -NH(Alkyl) Gruppen mit gesättigtem geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und vorzugsweise 1 bis 4 Kohlenstoffatome enthält;
• Dialkylamino: -N(Alkyl)₂ Gruppen mit gesättigten geradkettigen, verzweigten oder cyclischen Alkylresten, wobei diese gleich oder verschieden sind, aus der vorstehend genannten Gruppe der Alkyle ausgewählt sind und vorzugsweise 1 bis 4 Kohlenstoffatome enthalten;
• Trialkylamino: -N(Alkyl)₃ ⁺ Gruppen mit gesättigten geradkettigen, verzweigten oder cyclischen Alkylresten, wobei diese gleich oder verschieden sind, aus der vorstehend genannten Gruppe der Alkyle ausgewählt sind und vorzugsweise 1 bis 4 Kohlenstoffatome enthalten;
• Alkylcarbonyl: -C(O)Alkyl Gruppen mit gesättigtem geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und vorzugsweise 1 bis 4 Kohlenstoffatome enthält;
• Alkylsulfonyl: -S(O)₂Alkyl Gruppen mit gesättigtem geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und vorzugsweise 1 bis 4 Kohlenstoffatome enthält;
• Alkylsulfoxyl: -S(O)Alkyl Gruppen mit gesättigtem geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und vorzugsweise 1 bis 4 Kohlenstoffatome enthält;
• Alkylaminosulfonyl: -S(O)₂-NH(Alkyl) Gruppen mit gesättigtem geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und vorzugsweise 1 bis 4 Kohlenstoffatome enthält;
• Dialkylaminosulfonyl: -S(O)₂-N(Alkyl)₂ Gruppen mit gesättigten geradkettigen, verzweigten oder cyclischen Alkylresten, wobei diese aus der vorstehend genannten Gruppe der Alkyle ausgewählt sind und vorzugsweise 1 bis 4 Kohlenstoffatome enthalten;
• Alkyloxycarbonyl: -C(O)OAlkyl Gruppen mit gesättigtem geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und vorzugsweise 1 bis 4 Kohlenstoffatome enthält;
• Alkylcarbonyloxy: -O-C(O)Alkyl Gruppen mit gesättigtem geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und vorzugsweise 1 bis 4 Kohlenstoffatome enthält;
• Alkylaminocarbonyl: -C(O)NH(Alkyl) Gruppen mit gesättigtem geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und vorzugsweise 1 bis 4 Kohlenstoffatome enthält;
• Dialkylaminocarbonyl: -C(O)N(Alkyl)₂ Gruppen mit gesättigten geradkettigen, verzweigten oder cyclischen Alkylresten, wobei diese aus der vorstehend genannten Gruppe der Alkyle ausgewählt sind und vorzugsweise 1 bis 4 Kohlenstoffatome enthalten;
• Alkylcarbonylamino: -NH-C(O)Alkyl Gruppen mit gesättigtem geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und vorzugsweise 1 bis 4 Kohlenstoffatome enthält.
• Dem Fachmann ist bekannt, dass eine cyclische oder verzweigte Alkylgruppe mindestens drei Kohlenstoffatome aufweist. Erfindungsgemäß wird der Begriff „Alkyl“ auch für Alkylengruppen (Alkandiylgruppen) gebraucht. Dies ist jeweils aus dem Zusammenhang ersichtlich.

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 (O) alkyl groups having saturated straight-chain, branched or cyclic alkyl radicals, 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 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;
• Alkylcarbonyloxy: -OC (O) 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 (O) 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.

1. a) C₆-C₁₄-Aryldiyl, insbesondere Phenylen-1,4-diyl, Phenylen-1,3-diyl, Phenylen-1,2-diyl, Naphthalin-1,2-diyl, Naphthalin-1,3-diyl, Naphthalin-1,4-diyl, Naphthalin-1,5-diyl, Naphthalin-1,6-diyl, Naphthalin-1,7-diyl, Naphthalin-1,8-diyl, Naphthalin-2,3-diyl, Naphthalin-2,6-diyl, Naphthalin-2,7-diyl, Biphenylen-1,2-diyl, Biphenylen-1,3-diyl, Biphenylen-1,4-diyl, Biphenylen-1,5-diyl, Biphenylen-1,6-diyl, Biphenylen-1,7-diyl, Biphenylen-1,8-diyl, Biphenylen-2,3-diyl, Biphenylen-2,6-diyl und Biphenylen-2,7-diyl;
2. b) C₃-C₈-Cycloalkyldiyl, insbesondere trans-Cyclopropan-1,2-diyl, Cyclopropan-1,1-diyl, trans-Cyclobutan-1,3-diyl, cis-Cyclobutan-1,3-diyl, trans-Cyclopentan-1,3-diyl, cis-Cyclohexan-1,4-diyl, trans-Cyclohexan-1,4-diyl, trans-Cycloheptan-1,4-diyl, trans-Cyclooctan-1,5-diyl und Cuban-1,4-diyl.

Mono- or polycyclic, aromatic, partially unsaturated or saturated C ₃ -C ₁₄ -hydrocarbon radical preferably means for D ² :

1. a) C ₆ -C ₁₄ aryldiyl, in particular phenylene-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, biphenylene-1,8-diyl, biphenylene-2,3-diyl, biphenylene-2,6-diyl and biphenylene-2,7-diyl;
2. 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.

1. a) nicht-aromatisches, gesättigtes oder teilweise ungesättigtes 5- oder 6-gliedriges Heterocyclodiyl, enthaltend ein bis drei Stickstoffatome und/oder ein Sauerstoff- oder Schwefelatom oder ein oder zwei Sauerstoff- und/oder Schwefelatome, insbesondere 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-Pyrrolidin-2,5-diyl, trans-Pyrrolidin-2,4-diyl, Isoxazolidin-2,4-diyl, Isoxazolidin-2,5-diyl, Isothiazoli-din-2,4-diyl, Isothiazolidin-2,5-diyl, Pyrazolidin-1,3-diyl, trans-Oxazolidin-2,4-diyl, trans-Thiazolidin-2,5-diyl, Imidazolidin-1,3-diyl, trans-Imidazolidin-2,4-diyl, Pyrrolin-1,3-diyl, trans-Pyrrolin-2,4-diyl, trans-Pyrrolin-2,5-diyl, trans-Piperidin-2,5-diyl, Piperidin-1,4-diyl, trans-Dioxan-2,5-diyl, trans-Tetrahydropyran-2,5-diyl, trans-Hexa-hydropyridazin-3,6-diyl, trans-Hexahydropyridazin-1,4-diyl, trans-Hexahydropyrimidin-2,5-diyl, Hexahydropyrimidin-1,3-diyl, Hexahydropyrimidin-1,4-diyl, Piperazin-1,4-diyl, trans-Piperazin-2,5-diyl und Piperazin-1,3-diyl;
2. b) 5-gliedriges Heteroaryldiyl, enthaltend ein bis vier Stickstoffatome oder ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom, insbesondere Furan-2,4-diyl, Furan-2,5-diyl, Thiophen-2,4-diyl, Thiophen-2,5-diyl, Pyrrol-2,4-diyl, Pyrrol-2,5-diyl, Pyrazol-1,3-diyl, Oxazol-2,4-diyl, Oxazol-2,5-diyl, 1,3,4-Oxadiazol-2,5-diyl, 1,2,4-Oxadiazol-3,5-diyl, 1,2,4-Thiadiazol-3,5-diyl, 1,3,4-Thiadiazol-2,5-diyl, Isooxazol-3,5-diyl, Thiazol-2,4-diyl, Thiazol-2,5-diyl, Isothiazol-3,5-diyl, Imidazol-2,4-diyl, 2H-Tetrazol-2,5-diyl, 1H(1,2,4)-Triazol-2,5-diyl, 1H(1,2,3)-Triazol-1,4-diyl und 1H(1,2,3)-Trazol-1,5-diyl;
3. c) 6-gliedriges Heteroaryldiyl, enthaltend ein bis drei bzw. ein bis vier Stickstoffatome, insbesondere Pyridin-2,5-diyl, Pyridin-2,4-diyl, Pyridin-2,3-diyl, Pyridazin-3,6-diyl, Pyrimidin-2,5-diyl, Pyrimidin-2,6-diyl, Pyrazin-2,5-diyl und Tetrazin-3,5-diyl.

Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical is preferably for D ² :

1. 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-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-1,4-diyl, trans-dioxane-2,5-diyl, trans -tetrahydropyran-2,5-diyl, trans-hexa hydropyridazine-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;
2. 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-1,3-diyl, oxazole-2,4-diyl, oxazole-2,5-diyl, 1 , 3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, 1,2,4-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 (1,2,4) -triazole-2,5-diyl, 1H (1,2,3) -triazole-1,4-diyl and 1H (1,2,3) -triazole 1,5-diyl;
3. 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.

• 1-Benzofuran-4,7-diyl, 1-Benzofuran-2,7-diyl, 2-Benzofuran-4,7-diyl, 2-Benzofuran-3,6-diyl, Chromen-5,8-diyl, Chromen-3,7-diyl, Xanthen-1,4-diyl, Xanthen-2,6-diyl, Indazol-4,7-diyl, Purin-2,8-diyl, 4H-Chinolizin-6,9-diyl, 3-Isochinolin-1,4-diyl, Phthalazin-1,4-diyl, 1,8-Naphthyridin-2,6-diyl, Chinoxalin-2,6-diyl, Chinazolin-5,8-diyl, Cinnolin-5,8-diyl, Pteridin-2,6-diyl, Indolizin-2,6-diyl, Indol-4,7-diyl, Indol-2,5-diyl, Indol-3,6-diyl, Isoindol-4,7-diyl, Isoindol-2,5-diyl, Carbozol-1,4-diyl, Acridin-l,4-diyl, Phenoxazin-1,4-diyl, Benzoxazol-4,7-diyl, Benzothiazol-4,7-diyl, Benzoimidazol-4,7-diyl, 1H-Benzotriazol-4,7-diyl und Benzothiophendiyl.

Polycyclic aromatic, partially unsaturated or saturated heterocyclic radical is preferably D ² :

• 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-1,4-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.

1. a) C₆-C₁₄-Aryl, insbesondere Phenyl, 1-Naphthyl, 2-Naphtyl, 1-Biphenylen, 2-Biphenylen, 1-Pyrenyl, 1-Anthracenyl, 2-Anthracenyl, 9-Anthracenyl, 4-Indenyl, 2-Fluorenyl, 3-Fluorenyl, 9-Fluorenyl und 3-Phenanthrenyl;
2. b) C₃-C₁₄-Cycloalkenyl oder C₅-C₁₄-Cycloalkadienyl, insbesondere Cyclopropenyl, Cyclobutenyl, Cyclopentenyl, Cyclohexenyl, Cycloheptenyl, Cyclooctenyl, Cyclopentadien-1-yl, Cyclohexadien-1-yl und Cyclooctadien-1-yl;
3. c) C₃-C₈-Cycloalkyl, insbesondere Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Adamantan-1-yl, Cuban-1-yl und Cyclooctyl.

Mono- or polycyclic, aromatic, partially unsaturated or saturated C ₃ -C ₁₄ -hydrocarbon radical means for D ¹ and D ³ preferably:

1. a) C ₆ -C ₁₄ aryl, especially 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;
2. b) C ₃ -C ₁₄ cycloalkenyl or C ₅ -C ₁₄ cycloalkadienyl, in particular cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadien-1-yl, cyclohexadien-1-yl and cyclooctadien-1-yl;
3. c) C ₃ -C ₈ -cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantan-1-yl, cuban-1-yl and cyclooctyl.

1. a) nicht-aromatisches, gesättigtes oder teilweise ungesättigtes 4, 5, 6 oder 7-gliedriges Heterocyclyl, enthaltend ein bis vier Stickstoffatome und/oder ein Sauerstoff- oder Schwefelatom oder ein oder zwei Sauerstoff- und/oder Schwefelatome, insbesondere 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-lsothiazolidinyl, 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-1,3-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, 1,3-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 und 2-Piperazinyl;
2. b) 5-gliedriges Heteroaryl, enthaltend ein bis vier Stickstoffatome oder ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom: insbesondere 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, 1,2,5-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, 1,2,3,4-Thiatriazol-5-yl, 1H-(1,2,3)Triazol-1-yl, 1H-(1,2,3)Triazol-4-yl, 1H-(1,2,3)Triazol-5-yl, 1H-(1,3,4)Triazol-1-yl und 1H-(1,3,4)Triazol-2-yl;
3. c) 6-gliedriges Heteroaryl, enthaltend ein bis drei bzw. ein bis vier Stickstoffatome: insbesondere 2-Pyridinyl, 3-Pyridinyl, 4-Pyridinyl, 3-Pyridazinyl, 4-Pyridazinyl, 2-Pyrimidinyl, 4-Pyrimidinyl, 5-Pyrimidinyl und 2-Pyrazinyl.

Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical means for D ¹ and D ³ preferably:

1. a) 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 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-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-1,3-thiazepine-2 yl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-im idazolidinyl, 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, 1,3-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;
2. 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-thiadiazole -5-yl, 1,2,5-oxadiazole 3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazole-5 yl, 1,2,3,4-thiatriazol-5-yl, 1H- (1,2,3) triazol-1-yl, 1H- (1,2,3) triazol-4-yl, 1H- (1 2,3) triazol-5-yl, 1H- (1,3,4) triazol-1-yl and 1H- (1,3,4) triazol-2-yl;
3. 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 ¹ and D ³ 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, xanthene 9-yl, indazol-1-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, purin-2-yl, purine-6 yl, purin-7-yl, purin-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, Isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, phthalazin-1-yl, phthalazine 3-yl, phthalazin-5-yl, phthalazin-6-yl, 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 1,8- 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, cinnolin-4-yl, C innolin-6-yl, pteridin-2-yl, pteridin-4-yl, pteridin-6-yl, pteridin-7-yl, indolizin-1-yl, indol-1-yl, indol-2-yl, indole 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, benzimidazole 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, benzothiazol-7-yl, benzothiazole 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.

A¹

ist vorteilhaft eine Gruppe D¹-[Y²-D²-]_m-.

D¹

ist vorteilhaft ein mono- oder polycyclischer aromatischer oder gesättigter C₃-C₁₄-Kohlenwasserstoffrest oder ein monocyclischer aromatischer, partiell ungesättigter oder gesättigter vier- bis sechsgliedriger heterocyclischer Rest, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind.

D²

ist vorteilhaft eine Gruppe Phenylen-1,4-diyl, Phenylen-1,3-diyl, Pyridin-2,5-diyl, Pyridazin-3,6-diyl, Pyrimidin-2,5-diyl, Pyrimidin-2,6-diyl, Pyrazin-2,5-diyl, trans-Cyclobutan-1,3-diyl, trans-Cyclopentan-1,3-diyl, trans-Cyclohexan-1,4-diyl, Cuban-1,4-diyl, Thiophen-2,5-diyl, Pyrrol-2,4-diyl, Pyrrol-2,5-diyl, Pyrazol-1,3-diyl, Oxazol-2,4-diyl, Oxazol-2,5-diyl, 1,3,4-Oxadiazol-2,5-diyl, 1,2,4-Oxadiazol-3,5-diyl, Isooxazol-3,5-diyl, Imidazol-2,4-diyl, 2H-Tetrazol-2,5-diyl, 1H(1,2,4)-Triazol-2,5-diyl,

Y¹

1H(1,2,3)-Triazol-1,4-diyl und 1H(1,2,3)-Triazol-1,5-diyl, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind. ist vorteilhaft ∼C(O)-, ∼CH₂C(O)- oder ∼OC(O)- wobei ∼ die Bindung zur Gruppe A¹ bezeichnet.

Y²

ist vorteilhaft -O- oder eine Bindung.

A²

ist vorteilhaft eine Gruppe -N(R^y)-W oder -N(H)-W.

W

ist vorteilhaft eine Gruppe -SO₃M oder -SO₂NR^x ₂ oder eine Gruppe D³-Y³-.

Y³

ist vorteilhaft eine Bindung oder eine Gruppe ∼S(O)₂-, ∼C(O)-, ∼CH₂-C(O)- oder ∼CH₂-S(O)₂-, wobei ∼ die Bindung zur Gruppe D³ bezeichnet.

D³

ist vorteilhaft

a)

ein C₁-C₅-Alkyl, wobei in den genannten Gruppen gegebenenfalls ein oder mehrere H-Atome durch eine Gruppe X ersetzt sind,

b)

ein monocyclischer aromatischer oder gesättigter C₃-C₆-Kohlenwasserstoffrest oder ein monocyclischer aromatischer, partiell ungesättigter oder gesättigter vier- bis sechsgliedriger heterocyclischer Rest, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind.

A³

ist vorteilhaft ein C₃-C₇₅-Alkandiyl, wobei gegebenenfalls eine oder mehrere -CH₂-Gruppen durch S, O, N(R^x) und/oder C(O) ersetzt sind und wobei gegebenenfalls eine -CH₂CH₂-Gruppe durch -C=C- ersetzt ist;

A⁴

ist vorteilhaft eine Gruppe -C=CH, Bicyclo[6,1,0]non-4-in-9-yl, Dibenzocyclooctinyl, Biarylazacyclooctinonyl, Cyclooctinyloxy, Cyclooctinyl oder Dimethoxyazacyclooctinyl, wobei in den genannten Gruppen gegebenenfalls ein oder mehrere H-Atome durch eine Gruppe X ersetzt sind;

X

ist vorteilhaft gleich oder verschieden Halogen, Hydroxy, Carboxymethyl, SO₃M, OSO₃M, SO₂CF₃, PO₃M, OPO₃M, Cyanomethyl, Alkyl, Halogenalkyl, Alkyloxy, Halogenalkyloxy, Amino, Alkylamino, Dialkylamino, Alkylcarbonyl, Alkylsulfonyl, Alkylaminosulfonyl, Dialkylaminosulfonyl, Alkyloxycarbonyl, Alkylcarbonyloxy, Aminocarbonyl, Alkylaminocarbonyl, Alkylcarbonylamino oder Oxo (=O), wobei die Alkylgruppen in diesen Resten 1 bis 3 Kohlenstoffatome enthalten;

m

ist vorteilhaft 0 oder 1

Z

ist vorteilhaft -0- oder -S-;

R¹

ist vorteilhaft -C(O)OM;

R²

ist vorteilhaft H, OH oder OR^y;

R³

ist vorteilhaft H, F;

R⁴

ist vorteilhaft -N(R^x)C(O)CH₂OH oder -N(R^x)C(O)R^x;

R⁵, R⁶

sind vorteilhaft gleich oder verschieden und ausgewählt aus OH oder OR⁵;

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 advantageous a mono- or polycyclic aromatic or saturated C ₃ -C ₁₄ hydrocarbon radical or a monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, wherein said radicals are unsubstituted or mono- or polysubstituted by a group X.

D ²

is advantageously a group of 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-1,3-diyl, trans-cyclopentane-1,3-diyl, trans-cyclohexane-1,4-diyl, cubane-1,4-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, 1,2,4-oxadiazole-3,5-diyl, isooxazole-3,5-diyl, imidazole-2,4-diyl, 2H-tetrazole-2,5-diyl, 1H (1,2,4) -triazole-2,5-diyl,

Y ¹

1H (1,2,3) -triazole-1,4-diyl and 1H (1,2,3) -triazole-1,5-diyl, wherein said radicals are unsubstituted or mono- or polysubstituted by a group X. , is advantageously ~C (O) -, ~CH ₂ C (O) - or ~OC (O) - where ~ denotes the bond to the group A ¹ .

Y ²

is advantageous -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 ³

is advantageously a bond or a group ~S (O) ₂ -, ~C (O) -, ~CH ₂ -C (O) - or ~CH ₂ -S (O) ₂ -, where the bond to the group D ³ denotes.

D ³

is advantageous

a)

a C ₁ -C ₅ -alkyl, where in the groups mentioned optionally one or more H atoms are replaced by a group X,

b)

a monocyclic aromatic or saturated C ₃ -C ₆ -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 ³

is advantageously a C ₃ -C ₇₅ -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 [6,1,0] non-4-yn-9-yl, dibenzocyclooctinyl, Biarylazacyclooctinonyl, cyclooctinyloxy, cyclooctynyl or dimethoxyazacyclooctynyl, wherein in said groups optionally one or more H atoms a group X is replaced;

X

is advantageously identical or different halogen, hydroxyl, carboxymethyl, SO ₃ M, OSO ₃ M, SO ₂ CF ₃ , PO ₃ M, OPO ₃ M, cyanomethyl, alkyl, haloalkyl, alkyloxy, haloalkyloxy, amino, alkylamino, dialkylamino, alkylcarbonyl, Alkylsulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino or oxo (= O), the alkyl groups in these radicals containing from 1 to 3 carbon atoms;

m

is advantageous 0 or 1

Z

is advantageous -0- or -S-;

R ¹

is advantageous -C (O) OM;

R ²

is advantageously H, OH or OR ^y ;

R ³

is advantageous 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 advantageously the same or different and selected from OH or OR ⁵ ;

• Halogen: Fluor, Chlor und Brom;
• Alkyl: gesättigte, geradkettige, verzweigte oder cyclische Kohlenwasserstoffreste mit beispielsweise 1 bis 6 Kohlenstoffatomen, wie Methyl, Ethyl, Propyl, 1-Methylethyl, Butyl, 1-Methyl-propyl, 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-Dimethylcylopropyl, 2,3- Dimethylcylopropyl und Cyclohexyl;
• Halogenalkyl: geradkettige, verzweigte oder cyclische Alkylgruppen mit beispielsweise 1 bis 3 Kohlenstoffatomen (wie vorstehend genannt), wobei in diesen Gruppen Wasserstoffatome teilweise oder vollständig durch Halogenatome ersetzt sind: wie Chlormethyl, Brommethyl, Dichlormethyl, Trichlormethyl, Fluormethyl, Difluormethyl, Trifluormethyl, Chlorfluormethyl, Dichlorfluormethyl, Chlordifluormethyl, 1-Chlorethyl, I-Bromethyl, 1-Fluorethyl, 2-Fluorethyl, 2,2-Difluorethyl, 2,2,2-Trifluorethyl, 2-Chlor-2-fluorethyl, 2-Chlor-2,2-difluorethyl, 2,2-Dichlor-2-fluorethyl, 2,2,2-Trichlorethyl, Pentafluorethyl, 1-Fluor-1-methyl-ethyl, 1-Fluorcyclopropyl oder Heptafluorpropyl;
• Alkoxy: -O-Alkyl Gruppen mit gesättigtem, geradkettigem, verzweigtem oder cyclischen Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und 1 bis 3 Kohlenstoffatome enthält;
• Alkylamino: -NH(Alkyl) Gruppen mit gesättigtem, geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und 1 bis 2 Kohlenstoffatome enthält;
• Dialkylamino: -N(Alkyl)₂ Gruppen mit gesättigten, geradkettigen, verzweigten oder cyclischen Alkylresten, wobei diese gleich oder verschieden aus der vorstehend genannten Gruppe der Alkyle ausgewählt sind und 1 bis 2 Kohlenstoffatome enthalten;
• Alkylsulfonyl: -S(O)₂Alkyl Gruppen mit gesättigtem, geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und 1 bis 4 Kohlenstoffatome enthält;
• Alkylaminosulfonyl: -S(O)₂-NH(Alkyl) Gruppen mit gesättigtem, geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und 1 bis 3 Kohlenstoffatome enthält;
• Alkoxycarbonyl: -C(O)-OAlkyl Gruppen mit gesättigtem, geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und 1 bis 3 Kohlenstoffatome enthält;
• Alkylcarbonyloxy: -O-C(O)Alkyl Gruppen mit gesättigtem, geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und 1 bis 3 Kohlenstoffatome enthält;
• Alkylaminocarbonyl: -C(O)NH(Alkyl) Gruppen mit gesättigtem, geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und 1 bis 3 Kohlenstoffatome enthält;
• Alkylcarbonylamino: -NH-C(O)Alkyl Gruppen mit gesättigtem, geradkettigem, verzweigtem oder cyclischem Alkylrest, wobei dieser aus der vorstehend genannten Gruppe der Alkyle ausgewählt ist und 1 bis 3 Kohlenstoffatome enthält.

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-methyl-propyl, 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;
• Haloalkyl: 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-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 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) -Oalkyl 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;
• Alkylcarbonyloxy: -OC (O) 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 (O) 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.

1. a) C₆-C₁₄-Aryl, insbesondere Phenyl, Naphth-1-yl, Napht-2-yl, Biphen-4-yl, Biphen-2-yl, Anthracen-9-yl, Inden-4-yl, Fluoren-2-yl, Fluoren-3-yl, Fluoren-9-yl und Phenanthren-3-yl;
2. b) C₃-C₈-Cycloalkyl, insbesondere Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Adamantan-1-yl, Cuban-1-yl und Cyclooctyl.

Mono- or polycyclic, aromatic or saturated C ₃ -C ₁₄ -hydrocarbon radical means for D ¹ and D ^{3 more} preferably:

1. a) C ₆ -C ₁₄ aryl, in particular phenyl, naphth-1-yl, naphth-2-yl, biphen-4-yl, biphen-2-yl, anthracen-9-yl, inden-4-yl, fluorene -2-yl, fluoren-3-yl, fluoren-9-yl and phenanthren-3-yl;
2. b) C ₃ -C ₈ -cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantan-1-yl, cuban-1-yl and cyclooctyl.

1. a) nicht-aromatisches, gesättigtes oder teilweise ungesättigtes 4, 5 oder 6-gliedriges Heterocyclyl, enthaltend ein bis vier Stickstoffatome und/oder ein oder zwei Sauerstoffatome, insbesondere 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-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, 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 und 2-Piperazinyl;
2. b) 5-gliedriges Heteroaryl, enthaltend ein bis vier Stickstoffatome oder ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom: insbesondere 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, 1,2,5-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, 1,2,3,4-Thiatriazol-5-yl, 1H-(1,2,3)Triazol-1-yl, 1H-(1,2,3)Triazol-4-yl, 1H-(1,2,3)Triazol-5-yl, 1H-(1,3,4)Triazol-1-yl und 1H-(1,3,4)Triazol-2-yl;
3. c) 6-gliedriges Heteroaryl, enthaltend ein bis drei Stickstoffatome: insbesondere 2-Pyridinyl, 3-Pyridinyl, 4-Pyridinyl, 3-Pyridazinyl, 4-Pyridazinyl, 2-Pyrimidinyl, 4-Pyrimidinyl, 5-Pyrimidinyl und 2-Pyrazinyl;

Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical means for D ¹ and D ^{3 more} preferably:

1. 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, 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-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrroline 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-piperad cinyl and 2-piperazinyl;
2. 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-thiadiazole -5-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,3-thiadiazole-4 -yl, 1,2,3-thiadiazol-5-yl, 1,2,3,4-thiatriazol-5-yl, 1H- (1,2,3) triazol-1-yl, 1H- (1,2 , 3) triazol-4-yl, 1H- (1,2,3) triazol-5-yl, 1H- (1,3,4) triazol-1-yl and 1H- (1,3,4) triazole 2-yl;
3. 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 respective chain or ring size, 1, 2, 3 or 4 are preferred substituent; in the case of halogen substituents substitution up to the maximum possible number (persubstitution) is possible.

D¹

ist bevorzugt eine Gruppe ausgewählt aus Phenyl, Pyrimidin-5-yl, Napth-1 -yl, Napth-2-yl und Thien-2-yl, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind;

D²

ist bevorzugt eine Gruppe ausgewählt aus Phenylen-1,4-diyl, Pyridin-2,5-diyl, Pyrimidin-2,5-diyl und Thiophen-2,5-diyl, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind;

Y¹

ist bevorzugt ∼C(O)- oder ∼CH₂C(O)- wobei ∼ die Bindung zur Gruppe A¹ bezeichnet;

Y²

ist bevorzugt eine Bindung;

A²

ist bevorzugt eine Gruppe -N(H)-W;

W

ist bevorzugt eine Gruppe -SO₃M;

A³

ist bevorzugt ein C₃-C₂₀-Alkandiyl, wobei gegebenenfalls eine oder mehrere -CH₂-Gruppen durch S, O, N(H) und/oder C(O) ersetzt sind;

A⁴

ist bevorzugt eine Gruppe -C=CH oder Bicyclo[6,1,0]non-4-in-9-yl;

jedes X

ist unabhängig bevorzugt ausgewählt aus Fluor, Chlor, Hydroxy, Carboxyl, Methyl, Trifluormethyl, Methoxy und Oxo (=O);

m

ist bevorzugt 1;

Z

ist bevorzugt -0-;

R^x

ist bevorzugt H, R^y oder R^z;

R^y

ist bevorzugt Methyl, Ethyl oder Benzyl;

R^z

ist bevorzugt -C(O)CH₃, -C(O)C(CH₃)₃ oder -C(O)Phenyl;

R²

ist bevorzugt H;

R³

ist bevorzugt H;

R⁴

ist bevorzugt -N(H)C(O)R^x, noch bevorzugter NHC(O)CH₃;

R⁵ und R⁶

sind gleich oder verschieden und bevorzugt ausgewählt aus OH, OCH₃ und OC(O)CH₃;

M

ist bevorzugt Natrium, Kalium, Calcium oder Magnesium.

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, naphth-2-yl and thien-2-yl, wherein said radicals are unsubstituted or mono- or polysubstituted by a group X;

D ²

is preferably a group selected from phenylene-1,4-diyl, pyridine-2,5-diyl, pyrimidine-2,5-diyl and thiophene-2,5-diyl, where the radicals mentioned are unsubstituted or mono- or polysubstituted by a Group X are substituted;

Y ¹

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

Y ²

is preferably a bond;

A ²

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

W

is preferably a group -SO ₃ M;

A ³

R ₃ is preferably a C ₃ -C ₂₀ -alkanediyl, where appropriate 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 [6,1,0] non-4-yn-9-yl;

every X

is independently preferably selected from fluoro, chloro, hydroxy, carboxyl, methyl, trifluoromethyl, methoxy and oxo (= O);

m

is preferably 1;

Z

is preferably -0-;

^Rx

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 (O) C (CH _{3) 3} or -C (O) phenyl;

R ²

is preferably H;

R ³

is preferably H;

R ⁴

is preferably -N (H) C (O) R ^x , 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 (O) 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); R ² is preferably 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); R ² is preferably 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 the 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 any significant cleavage of the protective group, although strongly acidic conditions occur by using trifluoromethanesulfonic acid 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-anomer. 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 converted further to sialic acid derivatives of the formula (VIII) on the carboxylic acid of the glycosidically bound substituent, which after final cleavage of the ester at position 1 and introduction of the group A ⁴ into 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):

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, 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: 978-1-118-29984-5 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-acteyl-2-chloro-3 , 4,5-trideoxy-D-glycero-β-D-galacto-2-nonulopyranosonate ( Bioorg. Med. Chem. Lett. 1994, 4, 2457-2460 ) getting produced.

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.

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, 117, 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 US Pat "Protecting Groups", Philip J. Kocienski, 3 ^rd 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.

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.

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 (O) or ~CH ₂ C (O)), sulfonamides (Y ¹ = ~S (O) ₂ ), carbamates (Y ¹ = ~OC (O)) 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 Spectrum, Berlin and Heidelberg 2004 and Synthesis, 2007, 3497-3506, Org. Lett., 2012, 14, 2814-2817.

As an example, compound 9 was prepared.

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 US Pat "Protecting Groups" Philip J. Kocienski, 3 ^rd 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.

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 ^{2 is} formed, which is as defined above for formula (I). Optional can 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 US Pat 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 3rd 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.

Compounds of formula (VIII) can 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, and subsequent 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 US Pat Tetrahedron 2005, 61, 10827-10852, Chem. Eur. J. 2009, 15, 9040-9416 , Amino-protective groups and reactions for deprotecting amino groups are described, for example, in US Pat "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).

Compounds of the formula (I) can be prepared, for example, by reaction of the carboxyl group in compounds of the formula (VII) with a triple bond-containing amine, for example propargylamine, and subsequent removal of the protective groups, whereby the group A ^{3 is} "extended" and the groups N (H) - and -C (O) - of the newly formed amide each become part of A ³ . Reactions of amines to form an amide by means of activated reagents or with the aid of coupling reagents are described, for example, in US Pat Tetrahedron 2005, 61, 10827-10852, Chem. Eur. J. 2009, 15, 9040-9416 , Amino-protective groups and reactions for deprotecting amino groups are described, for example, in US Pat "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 ((1R, 8S, 9R) -bicyclo [6.1.0] non-4-yn-9 -yl) methyl (4-nitrophenyl) carbonate. Corresponding reactions of amines by means of activated reagents or with the aid of coupling reagents are described, for example, in US Pat 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. Lett., 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 ³ is preferably a C _3-20 alkanediyl, more preferably C _5-20 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, as well as 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 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 inflammations, paraplegia, multiple sclerosis, cancer, viral diseases, for example AIDS, as well as bacterial Diseases such as streptococci, parasitic diseases, such as Chagas disease, diseases in which the immune response is disrupted 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 the formula (I) can also be used for purposes other than those mentioned, for example as diagnostic agents, for example 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.

• 1. Sialinsäurederivate der Formel (I)
  
  wobei die Symbole folgende Bedeutungen haben:

  A¹

  ist eine Gruppe D¹-[Y²-D²-]_m-;

  D¹

  ist ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter C₃-C₁₄-Kohlenwasserstoffrest oder ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter drei- bis zwölfgliedriger heterocyclischer Rest, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind;

  D²

  ist ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter C₃-C₁₄-Kohlenwasserstoffrest oder ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter drei- bis achtgliedriger heterocyclischer Rest, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind;

  Y¹

  ist ∼C(O)-, ∼S(O)₂-, ∼CH₂C(O)-, ∼NHC(O)- oder ∼OC(O)-, wobei ∼ die Bindung zur Gruppe A¹ bezeichnet;

  Y²

  ist -O- oder eine Bindung;

  A²

  ist eine Gruppe -N(R^y)-W oder -N(H)-W;

  W

  ist

  a)

  eine Gruppe -SO₃M oder -SO₂NR^x ₂ oder

  b)

  eine Gruppe D³-Y³-;

  Y³

  ist eine Bindung oder eine Gruppe ausgewählt aus ∼NHC(O)-, ∼OC(O)-, ~S(O)₂-, ∼C(O)-, ∼CH₂C(O)- und ∼CH₂S(O)₂-, wobei ∼ die Bindung zur Gruppe D³ bezeichnet;

  D³

  ist

  a)

  C₁-C₆-Alkyl, wobei gegebenenfalls eine oder mehrere nicht terminale CH₂-Gruppen durch O, N(R^x) und/oder C(O) ersetzt sind und wobei in den nicht terminalen CH₂-Gruppen gegebenenfalls ein oder mehrere H-Atome durch eine Gruppe X ersetzt sind, oder

  b)

  ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter C₃-C₁₄-Kohlenwasserstoffrest oder ein mono- oder polycyclischer aromatischer, partiell ungesättigter oder gesättigter drei- bis achtgliedriger heterocyclischer Rest, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind;

  A³

  ist ein C₃-C₁₅₀-Alkandiyl, wobei gegebenenfalls eine oder mehrere -CH₂-Gruppen durch -S-, -S(O₂)-, -O-, -N(R^x)- und/oder -C(O)- ersetzt sind;

  A⁴

  ist eine Gruppe ausgewählt aus -C≡CH, Bicyclo[6,1,0]non-4-in-9-yl, Dibenzocyclooctinyl, Biarylazacyclooctinonyl, Cyclooctinyloxy, Cyclooctinyl oder Dimethoxyazacyclooctinyl, wobei in den genannten Gruppen gegebenenfalls ein oder mehrere H-Atome durch eine Gruppe X ersetzt sind;

  jedes X ist unabhängig ausgewählt aus Halogen, Cyano, Nitro, Hydroxy, Carboxyl, Carboxymethyl, Hydroxylamino, -SO₃M, -OSO₃M, -SO₂NH₂, -SO₂CF₃, -PO₃M, -OPO₃M, Cyanomethyl, Alkyl, Halogenalkyl, Alkoxy, Halogenalkoxy, Amino, Alkylamino, Dialkylamino, Trialkylamino, Alkylcarbonyl, Alkylsulfonyl, Alkylsulfoxyl, Alkylaminosulfonyl, Dialkylaminosulfonyl, Alkoxycarbonyl, Alkylcarbonyloxy, Aminocarbonyl, Alkylaminocarbonyl, Alkylcarbonylamino, Dialkylaminocarbonyl und Oxo (=0), wobei Alkyl und Alkoxy in den vorstehenden Gruppen 1 bis 4 Kohlenstoffatome enthalten;

  m

  ist 0 oder 1

  Z

  ist -O- oder -S-;

  R¹

  ist -C(O)OM;

  R²

  ist H, OH, OR^y oder F;

  R³

  ist H oder F;

  R⁴

  ist -N(R^x)C(O)CH₂OH, -N(R^x)C(O)R^x, -NHC(O)CH_ZF oder -NHC(O)CH₂Cl;;

  R⁵ und R⁶

  sind gleich oder verschieden und ausgewählt aus OH und OR^x;

  M

  ist ein Kation;

  jedes R^x

  ist unabhängig ausgewählt aus H, R^y und R^z;

  jedes R^y

  ist unabhängig ausgewählt aus C₁-C₄-Alkyl, Phenyl und Benzyl; und

  jedes R^z

  ist unabhängig ausgewählt aus -C(O)-(C₁-C₄-Alkyl), -C(O)-Phenyl oder -C(O)-CH₂-Phenyl;

  ein pharmazeutisch verträgliches Solvat, Salz oder Prodrug davon.
• 2. Sialinsäurederivate gemäß Punkt 1, wobei D²
  1. a) ein mono- oder polycyclischer, aromatischer, partiell ungesättiger oder gesättiger C₃-C₁₄-Kohlenwasserstoffrest ausgewählt aus:
     1. i) C₆-C₁₄-Aryldiyl, insbesondere Phenylen-1,4-diyl, Phenylen-1,3-diyl, Phenylen-1,2-diyl, Naphthalin-1,2-diyl, Naphthalin-1,3-diyl, Naphthalin-1,4-diyl, Naphthalin-1,5-diyl, Naphthalin-1,6-diyl, Naphthalin-1,7-diyl, Naphthalin-1,8-diyl, Naphthalin-2,3-diyl, Naphthalin-2,6-diyl, Naphthalin-2,7-diyl, Biphenylen-1,2-diyl, Biphenylen-1,3-diyl, Biphenylen-1,4-diyl, Biphenylen-1,5-diyl, Biphenylen-1,6-diyl, Biphenylen-1,7-diyl, Biphenylen-1,8-diyl, Biphenylen-2,3-diyl, Biphenylen-2,6-diyl und Biphenylen-2,7-diyl; und
     2. ii) C₃-C₈-Cycloalkyldiyl, insbesondere trans-Cyclopropan-1,2-diyl, Cyclopropan-1,1-diyl, trans-Cyclobutan-1,3-diyl, cis-Cyclobutan-1,3-diyl, trans-Cyclopentan-1,3-diyl, cis-Cyclohexan-1,4-diyl, trans-Cyclohexan-1,4-diyl, trans-Cycloheptan-1,4-diyl, trans-Cyclooctan-1,5-diyl und Cuban-1,4-diyl;
  2. b) ein monocyclischer aromatischer, partiell ungesättigter oder gesättigter drei- bis achtgliedriger heterocyclischer Rest ausgewählt aus:
     1. i) nicht-aromatisches, gesättigtes oder teilweise ungesättigtes 5- oder 6-gliedriges Heterocyclodiyl, enthaltend ein bis drei Stickstoffatome und/oder ein Sauerstoff- oder Schwefelatom oder ein oder zwei Sauerstoff- und/oder Schwefelatome, insbesondere 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-Pyrrolidin-2,5-diyl, trans-Pyrrolidin-2,4-diyl, Isoxazolidin-2,4-diyl, Isoxazolidin-2,5-diyl, Isothiazolidin-2,4-diyl, Isothiazolidin-2,5-diyl, Pyrazolidin-1,3-diyl, trans-Oxazolidin-2,4-diyl, trans-Thiazolidin-2,5-diyl, Imidazolidin-1,3-diyl, trans-Imidazolidin-2,4-diyl, Pyrrolin-1,3-diyl, trans-Pyrrolin-2,4-diyl, trans-Pyrrolin-2,5-diyl, trans-Piperidin-2,5-diyl, Piperidin-1,4-diyl, trans-Dioxan-2,5-diyl, trans-Tetrahydropyran-2,5-diyl, trans-Hexahydropyridazin-3,6-diyl, trans-Hexahydropyridazin-1,4-diyl, trans-Hexahydropyrimidin-2,5-diyl, Hexahydropyrimidin-1,3-diyl, Hexahydropyrimidin-1,4-diyl, Piperazin-1,4-diyl, trans-Piperazin-2,5-diyl und Piperazin-1,3-diyl;
     2. ii) 5-gliedriges Heteroaryldiyl, enthaltend ein bis vier Stickstoffatome oder ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom, insbesondere Furan-2,4-diyl, Furan-2,5-diyl, Thiophen-2,4-diyl, Thiophen-2,5-diyl, Pyrrol-2,4-diyl, Pyrrol-2,5-diyl, Pyrazol-1,3-diyl, Oxazol-2,4-diyl, Oxazol-2,5-diyl, 1,3,4-Oxadiazol-2,5-diyl, 1,2,4-Oxadiazol-3,5-diyl, 1,2,4-Thiadiazol-3,5-diyl, 1,3,4-Thiadiazol-2,5-diyl, Isooxazol-3,5-diyl, Thiazol-2,4-diyl, Thiazol-2,5-diyl, Isothiazol-3,5-diyl, Imidazol-2,4-diyl, 2H-Tetrazol-2,5-diyl, 1H(1,2,4)-Triazol-2,5-diyl, 1H(1,2,3)-Triazol-1,4-diyl und 1H(1,2,3)-Triazol-1,5-diyl; und
     3. iii) 6-gliedriges Heteroaryldiyl, enthaltend ein bis drei bzw. ein bis vier Stickstoffatome, insbesondere Pyridin-2,5-diyl, Pyridin-2,4-diyl, Pyridin-2,3-diyl, Pyridazin-3,6-diyl, Pyrimidin-2,5-diyl, Pyrimidin-2,6-diyl, Pyrazin-2,5-diyl und Tetrazin-3,5-diyl.
     oder
  3. c) ein polycyclischer aromatischer, partiell ungesättigter oder gesättigter heterocyclischer Rest ausgewählt aus:
     • 1-Benzofuran-4,7-diyl, 1-Benzofuran-2,7-diyl, 2-Benzofuran-4,7-diyl, 2-Benzofuran-3,6-diyl, Chromen-5,8-diyl, Chromen-3,7-diyl, Xanthen-1,4-diyl, Xanthen-2,6-diyl, Indazol-4,7-diyl, Purin-2,8-diyl, 4H-Chinolizin-6,9-diyl, 3-Isochinolin-1,4-diyl, Phthalazin-1,4-diyl, 1,8-Naphthyridin-2,6-diyl, Chinoxalin-2,6-diyl, Chinazolin-5,8-diyl, Cinnolin-5,8-diyl, Pteridin-2,6-diyl, Indolizin-2,6-diyl, Indol-4,7-diyl, Indol-2,5-diyl, Indol-3,6-diyl, Isoindol-4,7-diyl, Isoindol-2,5-diyl, Carbozol-1,4-diyl, Acridin-1,4-diyl, Phenoxazin-1,4-diyl, Benzoxazol-4,7-diyl, Benzothiazol-4,7-diyl, Benzoimidazol-4,7-diyl, 1H-Benzotriazol-4,7-diyl und Benzothiophendiyl; ist.
• 3. Sialinsäurederivate gemäß Punkt 1 oder 2, wobei einer von D¹ und D³ oder beide unabhängig sind:
  • a) ein mono- oder polycyclischer, aromatischer, partiell ungesättigter oder gesättigter C₃-C₁₄-Kohlenwasserstoffrest ausgewählt aus:
    1. i) C₆-C)₄-Aryl, insbesondere Phenyl, 1-Naphthyl, 2-Naphtyl, 1-Biphenylen, 2-Biphenylen, 1-Pyrenyl, 1-Anthracenyl, 2-Anthracenyl, 9-Anthracenyl, 4-Indenyl, 2-Fluorenyl, 3-Fluorenyl, 9-Fluorenyl und 3-Phenanthrenyl;
    2. ii) C₃-C₁₄-Cycloalkenyl oder C₃-C₁₄-Cycloalkadienyl, insbesondere Cyclopropenyl, Cyclobutenyl, Cyclopentenyl, Cyclohexenyl, Cycloheptenyl, Cyclooctenyl, Cyclopentadien-1-yl, Cyclohexadien-1-yl und Cyclooctadien-1-yl; und
    3. iii) C₃-C₈-Cycloalkyl, insbesondere Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Adamantan-1-yl, Cuban-1-yl und Cyclooctyl,
• b) ein monocyclischer aromatischer, partiell ungesättigter oder gesättigter drei- bis achtgliedriger heterocyclischer Rest ausgewählt aus:
  1. i) nicht-aromatisches, gesättigtes oder teilweise ungesättigtes 4, 5, 6 oder 7-gliedriges Heterocyclyl, enthaltend ein bis vier Stickstoffatome und/oder ein Sauerstoff- oder Schwefelatom oder ein oder zwei Sauerstoff- und/oder Schwefelatome, insbesondere 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-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-1,3-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, 1,3-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 und 2-Piperazinyl;
  2. ii) 5-gliedriges Heteroaryl, enthaltend ein bis vier Stickstoffatome oder ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom: insbesondere 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, 1,2,5-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, 1,2,3,4-Thiatriazol-5-yl, 1H-(1,2,3)Triazol-1-yl, 1H-(1,2,3)Triazol-4-yl, 1H-(1,2,3)Triazol-5-yl, 1H-(1,3,4)Triazol-1-yl und 1H-(1,3,4)Triazol-2-yl; und
  3. iii) 6-gliedriges Heteroaryl, enthaltend ein bis drei bzw. ein bis vier Stickstoffatome: insbesondere 2-Pyridinyl, 3-Pyridinyl, 4-Pyridinyl, 3-Pyridazinyl, 4-Pyridazinyl, 2-Pyrimidinyl, 4-Pyrimidinyl, 5-Pyrimidinyl und 2-Pyrazinyl;
• c) ein polycyclischer aromatischer, partiell ungesättigter oder gesättigter heterocyclischer Rest ausgewählt aus:
  • 1-Benzofuran-2-yl, 1-Benzofuran-3-yl, 1-Benzofuran-5-yl, 1-Benzofuran-6-vl, 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-Chromen-3-yl, 2H-Chromen-4-yl, 2H-Chromen-5-yl, 2H-Chromen-6-yl, 2H-Chromen-7-yl, 2H-Chromen-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, Chinolin-2-yl, Chinolin-3-yl, Chinolin-4-yl, Chinolin-6-yl, Chinolin-7-yl, Chinolin-8-yl, Isochinolin-1-yl, Isochinolin-3-yl, Isochinolin-4-yl, Isochinolin-5-yl, Isochinolin-6-yl, Isochinolin-7-yl, Isochinolin-8-yl, Phthalazin-1-yl, Phthalazin-3-yl, Phthalazin-5-yl, Phthalazin-6-yl, 1,8-Naphthyridin-2-yl, 1,8-Naphthyridin-3-yl, 1,8-Naphthyridin-4-yl, 1,8-Naphthyridin-6-yl, 1,8-Naphthyridin-7-yl, Chinoxalin-2-yl, Chinoxalin-5-yl, Chinoxalin-6-yl, Chinazolin-4-yl, Chinazolin-6-yl, Cinnolin-3-yl, Cinnolin-4-yl, Cinnolin-6-yl, Pteridin-2-yl, Pteridin-4-yl, Pteridin-6-yl, Pteridin-7-yl, Indolizin-1-yl, Indol-1-yl, Indol-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-Benzothiophen-2-yl, 1-Benzothiophen-3-yl, 1-Benzothiophen-5-yl, 1-Benzothiophen-6-yl, 1-Benzothiophen-7-yl, 1-Benzothiophen-8-yl, Benzimidazol-1-yl, Benzimidazol-2-yl, Benzimidazol-5-yl, Benzimidazol-6-yl, Benzimidazol-7-yl, Benzimidazol-8-yl, 1H-Benzotrialzol-1-yl, 1H-Benzotrialzol-5-yl, 1H-Benzotrialzol-6-yl, 1H-Benzotrialzol-7-yl, 1H-Benzotrialzol-8-yl, 4H-3,1-Benzoxazin-2-yl, 4H-2-Benzopyran-2-yl, 2H-Isochinolin-3-yl, Benzothiazol-2-yl, Benzothiazol-5-yl, Benzothiazol-6-yl, Benzothiazol-7-yl, Benzothiazol-8-yl, Benzoxazol-2-yl, Benzoxazol-5-yl, Benzoxazol-6-yl, Benzoxazol-7-yl oder Benzoxazol-8-yl.
• 4. Sialinsäurederivate gemäß einem der Punkte 1-3, wobei D¹ ein mono- oder polycyclischer aromatischer oder gesättigter C₃-C₁₄-Kohlenwasserstoffrest oder ein monocyclischer aromatischer, partiell ungesättigter oder gesättigter vier- bis sechsgliedriger heterocyclischer Rest ist, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind.
• 5. Sialinsäurederivate gemäß einem der Punkte 1-4, wobei D² ausgewählt ist aus Phenylen-1,4-diyl, Phenylen-1,3-diyl, Pyridin-2,5-diyl, Pyridazin-3,6-diyl, Pyrimidin-2,5-diyl, Pyrimidin-2,6-diyl, Pyrazin-2,5-diyl, trans-Cyclobutan-1,3-diyl, trans-Cyclopentan-1,3-diyl, trans-Cyclohexan-1,4-diyl, Cuban-1,4-diyl, Thiophen-2,5-diyl, Pyrrol-2,4-diyl, Pyrrol-2,5-diyl, Pyrazol-1,3-diyl, Oxazol-2,4-diyl, Oxazol-2,5-diyl, 1,3,4-Oxadiazol-2,5-diyl, 1,2,4-Oxadiazol-3,5-diyl, Isooxazol-3,5-diyl, Imidazol-2,4-diyl, 2H-Tetrazol-2,5-diyl, IH(1,2,4)-Triazol-2,5-diyl, 1H(1,2,3)-Triazol-1,4-diyl und 1H(1,2,3)-Triazol-1,5-diyl, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind.
• 6. Sialinsäurederivate gemäß einem der Punkte 1-5, wobei Y¹ gleich ~C(O)-, ~CH₂C(O)- oder ~OC(O)- ist, wobei ~ die Bindung zur Gruppe A¹ bezeichnet.
• 7. Sialinsäurederivate gemäß einem der Punkte 1-6, wobei Y³ eine Bindung oder eine Gruppe ~S(O)₂-, ~C(O)-, ~CH₂-C(O)- oder ~CH₂-S(O)₂- ist, wobei ~ die Bindung zur Gruppe D³ bezeichnet.
• 8. Sialinsäurederivate gemäß einem der Punkte 1-7, wobei D³ ausgewählt ist aus:
  • a) C₁-C₅-Alkyl, wobei gegebenenfalls ein oder mehrere H-Atome durch eine Gruppe X ersetzt sind, und
  • b) monocyclischer aromatischer oder gesättigter C₃-C₆-Kohlenwasserstoffrest oder monocyclischer aromatischer, partiell ungesättigter oder gesättigter vier- bis sechsgliedriger heterocyclischer Rest, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind.
• 9. Sialinsäurederivate gemäß einem der Punkte 1-8, wobei A³ ein C₃-C₇₅-Alkandiyl ist, wobei gegebenenfalls eine oder mehrere -CH₂-Gruppen durch S, O, N(R^x) und/oder C(O) ersetzt sind.
• 10. Sialinsäurederivate gemäß einem der Punkte 1-9, wobei jedes X unabhängig ausgewählt ist aus Halogen, Hydroxy, Carboxymethyl, SO₃M, OSO₃M, SO₂CF₃, PO₃M, OPO₃M, Cyanomethyl, Alkyl, Halogenalkyl, Alkyloxy, Halogenalkyloxy, Amino, Alkylamino, Dialkylamino, Alkylcarbonyl, Alkylsulfonyl, Alkylaminosulfonyl, Dialkylaminosulfonyl, Alkyloxycarbonyl, Alkylcarbonyloxy, Aminocarbonyl, Alkylaminocarbonyl, Alkylcarbonylamino und Oxo (=O), wobei die Alkylgruppen in diesen Resten 1 bis 3 Kohlenstoffatome enthalten.
• 11. Sialinsäurederivate gemäß einem der Punkte 1-9, wobei R⁴ gleich -N(R^x)C(O)CH₂OH oder -N(R^x)C(O)R^x ist.
• 12. Sialinsäurederivate gemäß einem der Punkte 1-11, wobei einer von D¹ und D³ oder beide unabhängig sind:
  • a) mono- oder polycyclischer, aromatischer oder gesättigter C₃-C₁₄-Kohlenwasserstoffrest ausgewählt aus:
    • i) C₆-C₁₄-Aryl, insbesondere Phenyl, Naphth-1-yl, Napht-2-yl, Biphen-4-yl, Biphen-2-yl, Anthracen-9-yl, Inden-4-yl, Fluoren-2-yl, Fluoren-3-yl, Fluoren-9-yl und Phenanthren-3-yl; und
    • ii) C₃-C₈-Cycloalkyl, insbesondere Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Adamantan-1-yl, Cuban-1-yl und Cyclooctyl;
  • b) monocyclischer aromatischer, partiell ungesättigter oder gesättigter drei- bis achtgliedriger heterocyclischer Rest ausgewählt aus:
    • i) nicht-aromatisches, gesättigtes oder teilweise ungesättigtes 4, 5 oder 6-gliedriges Heterocyclyl, enthaltend ein bis vier Stickstoffatome und/oder ein oder zwei Sauerstoffatome, insbesondere 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-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, 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 und 2-Piperazinyl;
    • ii) 5-gliedriges Heteroaryl, enthaltend ein bis vier Stickstoffatome oder ein bis drei Stickstoffatome und/oder ein Schwefel- oder Sauerstoffatom: insbesondere 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, 1,2,5-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, 1,2,3,4-Thiatriazol-5-yl, 1H-(1,2,3)Triazol-1-yl, 1H-(1,2,3)Triazol-4-yl, 1H-(1,2,3)Triazol-5-yl, 1H-(1,3,4)Triazol-1-yl und 1H-(1,3,4)Triazol-2-yl;
    • iii) 6-gliedriges Heteroaryl, enthaltend ein bis drei Stickstoffatome: insbesondere 2-Pyridinyl, 3-Pyridinyl, 4-Pyridinyl, 3-Pyridazinyl, 4-Pyridazinyl, 2-Pyrimidinyl, 4-Pyrimidinyl, 5-Pyrimidinyl und 2-Pyrazinyl.
• 13. Sialinsäurederivate gemäß einem der Punkte 1-12, wobei D¹ eine Gruppe ausgewählt aus Phenyl, Pyrimidin-5-yl, Napth-1-yl, Napth-2-yl und Thien-2-yl ist, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind.
• 14. Sialinsäurederivate gemäß einem der Punkte 1-13, wobei D² eine Gruppe ausgewählt aus Phenylen-1,4-diyl, Pyridin-2,5-diyl, Pyrimidin-2,5-diyl und Thiophen-2,5-diyl ist, wobei die genannten Reste unsubstituiert oder ein- oder mehrfach durch eine Gruppe X substituiert sind.
• 15. Sialinsäurederivate gemäß einem der Punkte 1-14, wobei Y¹ gleich ~C(O)- oder ~CH₂C(O)- ist, wobei ~ die Bindung zur Gruppe A¹ bezeichnet.
• 16. Sialinsäurederivate gemäß einem der Punkte 1-15, wobei Y² eine Bindung ist.
• 17. Sialinsäurederivate gemäß einem der Punkte 1-16, wobei A² eine Gruppe -N(H)-W ist, und W bevorzugt eine Gruppe -SO₃M ist.
• 18. Sialinsäurederivate gemäß einem der Punkte 1-17, wobei A³ gleich C₃-C₂₀-Alkandiyl ist, wobei gegebenenfalls eine oder mehrere -CH₂- Gruppen durch S, O, N(R^x) und/oder C(O) ersetzt sind.
• 19. Sialinsäurederivate gemäß einem der Punkte 1-18, wobei A⁴ gleich -C=CH oder Bicyclo[6,1,0]non-4-in-9-yl ist.
• 20. Sialinsäurederivate gemäß einem der Punkte 1-19, wobei jedes X unabhängig ausgewählt ist aus Fluor, Chlor, Hydroxy, Carboxyl, Methyl, Trifluormethyl, Methoxy und Oxo (=O).
• 21. Sialinsäurederivate gemäß einem der Punkte 1-20, wobei R⁴ gleich N(R^x)C(O)CH₂OH oder -N(R^x)C(O)R^x ist, bevorzugter -NHC(O)CH₃.
• 22. Sialinsäurederivate gemäß einem der Punkte 1-21, dargestellt durch die Formeln (Ia)-(Ic), wobei die Symbole die in Punkt 1-21 angegebenen Bedeutungen haben:
  
  
  
  vorzugsweise ist in den Formeln (Ia) - (Ic) R² gleich H.
• 23. Sialinsäurederivate gemäß einem der Punkte 1-22, dargestellt durch die Formeln (Iaa) - (Iac), wobei die Symbole die in Punkten 1-22 angegebenen Bedeutungen haben:
  
  
  
  vorzugsweise ist in den Formeln (Iaa) - (Iac) R² gleich H.
• 24. Sialinsäurederivate gemäß einem der Punkte 1-23, wobei Z gleich -O- ist.
• 25. Sialinsäurederivate gemäß einem der Punkte 1-24, wobei R⁵ oder R⁶ oder beide OH sind.
• 26. Sialinsäurederivate gemäß einem der Punkte 1-25, wobei Roder R³ oder beide H sind, vorzugsweise R² und R³ beide H sind.
• 27. Sialinsäurederivate gemäß einem der Punkte 1-26, wobei A³ ein C₃-C₁₅₀-Alkandiyl (vorzugsweise C₃-C₂₀-Alkandiyl) ist, bei dem ein oder mehrere -CH₂- Gruppen durch -O-, -N(R^x)- und/oder -C(O)- ersetzt sind; vorzugsweise enthält A³ ein oder mehrere Amidogruppen -C(O)-NH-.
• 28. Sialinsäurederivate gemäß einem der Punkte 1-27, dargestellt durch Formel (Iba), wobei die Symbole die in Punkten 1-27 angegebenen Bedeutungen haben:
  
  vorzugsweise ist in Formel (Iba) R² gleich H.
• 29. Konjugat aus mindestens einem Sialinsäurederivat, einem pharmazeutisch verträglichen Solvat, Salz oder Prodrug davon wie in einem der Punkte 1 bis 28 definiert und einem Bestandteil ausgewählt aus einem Cargo, einem Nanopartikel, einem Polymer und einem Polymer- oder Nanopartikel-verknüpften Cargo.
• 30. Konjugat gemäß Punkt 29, wobei die Nanopartikel (z.B. ausgewählt aus Goldnanopartikeln und Liposomen) das Sialinsäurederivat, das pharmazeutisch verträgliche Solvat, Salz oder Prodrug davon kovalent gebunden auf der Oberfläche der Nanopartikel tragen oder nicht kovalent oder kovalent gebunden im Inneren tragen.
• 31. Konjugat gemäß Punkt 29, wobei das Cargo ausgewählt ist aus RNA, DNA, Peptiden, Enzymen, niedermolekularen Antigenen, antigenen Proteinen und niedermolekularen pharmakologisch wirksamen Substanzen.
• 32. Konjugat gemäß Punkt 29, wobei das Cargo ein diagnostisch nutzbares Cargo ist, ausgewählt aus einem fluoreszierenden Molekül, einem radioaktiv markierten Molekül und einem Positronenemitter.
• 33. Sialinsäurederivate gemäß einem der Punkte 1 bis 28 oder ein Konjugat gemäß einem der Punkte 29-31 zur Verwendung bei Impfungen, der Regulation des Immunsystems, sowie zur Behandlung oder Vorbeugung von Allergien, Autoimmunerkrankungen, chronischen Entzündungen, Querschnittslähmung, multipler Sklerose, Krebs, Viruserkrankungen, bakteriellen Erkrankungen, parasitären Erkrankungen, genetischen Krankheiten, Krankheiten, bei denen die Immunantwort im Rahmen der B-Zellenaktivierung gestört ist und Krankheiten der blutbildenden Organe und des Blutes.
• 34. Konjugat gemäß Punkt 32 zur Verwendung bei der Diagnose von B-Zell basierten Krankheiten, z.B. Lymphome.
• 35. Ein Arzneimittel, umfassend mindestens ein Sialinsäurederivat, ein pharmazeutisch verträgliches Solvat, Salz oder Prodrug davon wie in einem der Punkte 1 bis 28 definiert, oder ein wie in einem der Punkte 29-32 definiertes Konjugat und mindestens einen Bestandteil ausgewählt aus einem pharmazeutisch verträglichen Träger, pharmazeutisch verträglichen Exzipienten und pharmazeutisch verträglichen Hilfsstoff und optional ein oder mehrere andere Arzneistoffe.
• 36. Verfahren zur Herstellung eines Sialinsäurederivats wie in einem der Punkte 1 bis 28 definiert, umfassend
  • a) die Umsetzung einer Verbindung der Formel VIII
    
    bei der alle Symbole die in Punkt 1 angegebenen Bedeutungen haben, mit einem aminreaktiven Reagens enthaltend die Gruppe A⁴, die wie in Punkt 1 definiert ist; oder
  • b) die Umsetzung einer Verbindung der Formel VII
    
    mit einem die Gruppe A⁴ enthaltenden Amin und anschließende Entfernung der Schutzgruppen.
• 37. Verfahren gemäß Punkt 36, wobei die Verbindung der Formeln VII und VIII jeweils durch mehrstufige Synthese aus der Verbindung der Formel (III) hergestellt werden
  
  wobei alle Symbole die in Punkt 1 angegebenen Bedeutungen haben.
• 38. Verfahren gemäß Punkt 37, wobei die Verbindung der Formel (III) mit Z = O durch Umsetzung einer Verbindung der Formel (II)
  
  wobei T = Aryl oder Alkyl ist, mit einer tert.-Butyl geschützten Hydroxycarbonsäure hergestellt wird.
• 39. Zwischenprodukte zur Herstellung von Sialinsäurederivaten der Formel (I) wie in einem der Punkte 1 bis 28 definiert, ausgewählt aus der Gruppe bestehend aus
  
  
  
  
  
  vorzugsweise gilt Z=O in den Formeln (III), (IV), (IX) und (X).
• 40. Verwendung eines Sialinsäurederivates der Formel (I), eines Prodrugs, Solvates oder Salzes davon, wie in einem der Punkte 1 bis 28 definiert zur Herstellung eines Konjugates, bei dem das Sialinsäurederivat, Prodrug, Solvat oder Salz davon kovalent oder nicht-kovalent mit einem - optional Polymer- oder Nanopartikel-verknüpftem - Cargo ausgewählt aus RNA, DNA, Peptiden, Enzymen, niedermolekularen Antigenen, antigenen Proteinen und niedermolekularen pharmakologisch wirksamen Substanzen verknüpft ist.
• 41. Verwendung eines Sialinsäurederivates der Formel (I), eines Prodrugs, Solvates oder Salzes davon, wie in einem der Punkte 1 bis 28 definiert zur Herstellung eines Konjugates, bei dem das Sialinsäurederivat, Prodrug, Solvat oder Salz davon kovalent oder nicht-kovalent mit einem - optional Polymer- oder Nanopartikel-verknüpftem - Cargo ausgewählt aus fluoreszierendem Molekül, radioaktiv markiertem Molekül und Positronenemitter verknüpft ist.

Specific embodiments of the invention are as follows:

• 1. sialic acid derivatives of the formula (I)
  
  where the symbols have the following meanings:

  A ¹

  is a group D ¹ - [Y ² -D ² -] _m -;

  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 by a Group X are substituted;

  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 by a Group X are substituted;

  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 (O) -, ~S (O) ₂ -, ~C (O) -, ~CH ₂ C (O) - and ~CH ₂ S (O) ₂ -, wherein ~ denotes the bond to the group D ³ ;

  D ³

  is

  a)

  C ₁ -C ₆ -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 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 by a group X are substituted;

  A ³

  is a C ₃ -C ₁₅₀ alkanediyl, where appropriate one or more -CH ₂ groups 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 [6,1,0] 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 _Z 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;

  every R ^x

  is independently selected from H, R ^y and R ^z ;

  every 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 according to item 1, wherein D ²
  1. a) a mono- or polycyclic, aromatic, partially unsaturated or saturated C ₃ -C ₁₄ -hydrocarbon radical selected from:
     1. i) C ₆ -C ₁₄ aryldiyl, in particular phenylene-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, biphenylene-1,8-diyl, biphenylene-2,3-diyl, biphenylene-2,6-diyl and biphenylene-2,7-diyl; and
     2. ii) 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;
  2. b) a monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical selected from:
     1. 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 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, 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-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-1,3-diyl, hexa hydropyrimidine-1,4-diyl, piperazine-1,4-diyl, trans-piperazine-2,5-diyl and piperazine-1,3-diyl;
     2. 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, 1,2,4-oxadiazole-3,5-diyl, 1,2,4-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 (1,2,4) -triazole-2,5-diyl, 1H (1,2,3) -triazole-1,4-diyl and 1H (1,2,3) -triazole 1,5-diyl; and
     3. 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
  3. 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-1,4-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, carbozole-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 ₁₄ -hydrocarbon radical selected from:
    1. i) C ₆ -C 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;
    2. ii) C ₃ -C ₁₄ cycloalkenyl or C ₃ -C ₁₄ cycloalkadienyl, in particular cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadien-1-yl, cyclohexadien-1-yl and cyclooctadien-1-yl; and
    3. iii) C ₃ -C ₈ -cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantan-1-yl, cuban-1-yl and cyclooctyl,
• b) a monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical selected from:
  1. 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 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-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-1,3-thiazepine-2 yl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-im idazolidinyl, 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, 1,3-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;
  2. 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-thiadiazol-3-yl, 1,2,4-thiadiazole -5-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,3-thiadiazole-4 -yl, 1,2,3-thiadiazol-5-yl, 1,2,3,4- Thiatriazol-5-yl, 1H- (1,2,3) triazol-1-yl, 1H- (1,2,3) triazol-4-yl, 1H- (1,2,3) triazol-5-yl , 1H- (1,3,4) triazol-1-yl and 1H- (1,3,4) triazol-2-yl; and
  3. 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;
• c) 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-vl, 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, xanthene 9-yl, indazol-1-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, purin-2-yl, purine-6 yl, purin-7-yl, purin-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, Isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, phthalazin-1-yl, phthalazine 3-yl, phthalazin-5-yl, phthalazin-6-yl, 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl, 1,8-naphthyridin-4-yl, 1,8- 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, cinnolin-4-yl, C innolin-6-yl, pteridin-2-yl, pteridin-4-yl, pteridin-6-yl, pteridin-7-yl, indolizin-1-yl, indol-1-yl, indol-2-yl, indole 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, benzimidazole 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, benzothiazol-7-yl, benzothiazole 8-yl, benzoxazol-2-yl, benzoxazol-5-yl, benzoxazol-6-yl, benzoxazol-7-yl or benzoxazol-8-yl.
• 4. sialic acid derivatives according to any one of items 1-3, wherein D ^{1 is} a mono- or polycyclic aromatic or saturated C ₃ -C ₁₄ hydrocarbon radical or a monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, wherein said radicals 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-1,3-diyl, trans-cyclopentane-1,3-diyl, trans -cyclohexane-1,4 -diyl, cuban-1,4-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, 1,2,4-oxadiazole-3,5-diyl, isooxazole-3,5-diyl, imidazole-2,4 -diyl, 2H-tetrazole-2,5-diyl, IH (1,2,4) -triazole-2,5-diyl, 1H (1,2,3) -triazole-1,4-diyl and 1H (1 , 2,3) -triazole-1,5-diyl, wherein said radicals are unsubstituted or mono- or polysubstituted 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 (O) ₂ -, ~C (O) -, ~CH ₂ -C (O) - or ~CH ₂ -S ( O) 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, wherein optionally one or more H atoms are replaced by a group X, and
  • b) monocyclic aromatic or saturated C ₃ -C ₆ -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.
• 9. 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 by S, O, N (R ^x ) and / or C (O ) are replaced.
• 10. Sialic acid derivatives according to any one of items 1-9, wherein each X is independently selected from halogen, hydroxy, carboxymethyl, SO ₃ M, OSO ₃ M, SO ₂ CF ₃ , PO ₃ M, OPO ₃ M, cyanomethyl, alkyl, haloalkyl , Alkyloxy, haloalkyloxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkylsulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino and oxo (= O), the alkyl groups in these radicals containing from 1 to 3 carbon atoms.
• 11. sialic acid derivatives according to any one 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 ₁₄ -hydrocarbon radical selected from:
    • i) C ₆ -C ₁₄ aryl, in particular phenyl, naphth-1-yl, naphth-2-yl, biphen-4-yl, biphen-2-yl, anthracen-9-yl, inden-4-yl, fluorene -2-yl, fluoren-3-yl, fluoren-9-yl and phenanthren-3-yl; and
    • ii) C ₃ -C ₈ cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantan-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-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrroline 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-piperad cinyl 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-thiadiazol-3-yl, 1,2,4-thiadiazole -5-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,3-thiadiazole-4 -yl, 1,2,3-thiadiazol-5-yl, 1,2,3,4-thiatriazol-5-yl, 1H- (1,2,3) triazol-1-yl, 1H- (1,2 , 3) triazol-4-yl, 1H- (1,2,3) triazol-5-yl, 1H- (1,3,4) triazol-1-yl and 1H- (1,3,4) triazole 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.
• 13. 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 unsubstituted or substituted one or more times by a group X.
• 14. Sialic acid derivatives according to any one of items 1-13, wherein D ^{2 is} a group selected from phenylene-1,4-diyl, pyridine-2,5-diyl, pyrimidine-2,5-diyl and thiophene-2,5-diyl , Wherein said radicals are unsubstituted or monosubstituted or polysubstituted by a group X.
• 15. 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 .
• 16. sialic acid derivatives according to any one of items 1-15, wherein Y ^{2 is} a bond.
• 17. 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 group -SO ₃ M.
• 18. sialic acid derivatives according to any one of items 1-17, wherein A ³ is C ₃ -C ₂₀ alkanediyl, wherein optionally one or more -CH ₂ - groups by S, O, N (R ^x ) and / or C (O ) are replaced.
• 19. sialic acid derivatives according to any one of items 1-18, wherein A ⁴ is -C = CH or bicyclo [6,1,0] non-4-yn-9-yl.
• 20. 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 (= O).
• 21. 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 (O) CH ₃ ,
• 22. 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 item 1-21:
  
  
  
  preferably in the formulas (Ia) - (Ic) R ² is H.
• 23. Sialic acid derivatives according to any one of items 1-22, represented by the formulas (Iaa) - (Iac), where the symbols have the meanings given in items 1-22:
  
  
  
  preferably in the formulas (Iaa) - (Iac) R ² is H.
• 24. sialic acid derivatives according to any one of items 1-23, wherein Z is -O-.
• 25. sialic acid derivatives according to any one of items 1-24, wherein R ⁵ or R ⁶ or both are OH.
• 26. sialic acid derivatives according to any one of items 1-25, wherein Roder R ³ or both are H, preferably R ² and R ^{3 are} both H.
• 27. sialic acid derivatives according to any one of items 1-26, wherein A ^{3 is} a C ₃ -C ₁₅₀ alkanediyl (preferably C ₃ -C ₂₀ alkanediyl) in which 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-.
• 28. 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:
  
  preferably in formula (Iba) R ² is H.
• 29. 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.
• 30. 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 internally.
• 31. 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.
• 32. The conjugate of item 29, wherein the cargo is a diagnostically useful cargo selected from a fluorescent molecule, a radiolabelled molecule, and a positron emitter.
• 33. 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.
• 34. Conjugate according to item 32 for use in the diagnosis of B-cell based diseases, eg lymphomas.
• 35. 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 of items 29-32 and at least one member selected from a pharmaceutically acceptable Carrier, pharmaceutically acceptable excipient and pharmaceutically acceptable excipient, and optionally one or more other drugs.
• 36. A process for the preparation of a sialic acid derivative as defined in any one of items 1 to 28, comprising
  • a) the reaction of a compound of formula VIII
    
    in which all symbols have the meanings given in item 1, with an amine-reactive reagent containing the group A ⁴ , which is defined as in item 1; or
  • b) the reaction of a compound of formula VII
    
    with an amine containing the group A ⁴ and subsequent removal of the protective groups.
• 37. The method 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.
• 38. The method according to item 37, 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.
• 39. 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
  
  
  
  
  
  preferably Z = O in the formulas (III), (IV), (IX) and (X).
• 40. 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 covalent or non-covalent with 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 is linked.
• 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.

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 ₂₅₄ ). 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

O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium

HRMS

High resolution mass spectrometry

MeOH

methanol

TEA

triethylamine

TLC

TLC

Connection 1

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

Connection 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 NaHCO ₃ and Na ₂ SO ₃ , dried with MgSO ₄ , filtered and concentrated. 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 SO ₄ , also UV negative after heating with H ₂ SO ₄ ; ¹ H NMR (300 MHz, CDCl ₃₎ δ ppm 5:46 (d, J = 18.8 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 O 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 MgSO 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%); ¹ H 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 O ₁₂ [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-R _F : 0.81 (9: 1 DCM: MeOH) or 0.85 (EtOAc); ¹ H NMR (300 MHz, CDCl 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, 6.33Hz, 1H), 3.72-3.57 (m, 1H), 3.63 (dd, J = 12.48, 2.40Hz, 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) Calcd for C ₂₇ H ₄₇ N ₅ O ₁₁ [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 via RP18 silica gel (H ₂ O to ACN). Yield: 640 mg; TLC Rf: 0.27 (1:19 DCM: MeOH); ¹ H 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 = 12.87Hz, 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 O ₁₂ [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-SO ₃ complex were added in portions within 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%); ¹ H 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) calculated Na ₂ O ₁₃ S [MH] for C ₃₁ H ₃₈ FN ₃ ^-: 712.19 g / mol, found 712.2

Connection 12

A solution of 100 mg of compound 11 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 treated with 2 ml NaHCO ₃ and 10 ml water and purified over RP18 silica gel (H ₂ O to ACN). The product fractions were concentrated to 6 ml and processed directly. TLC R f: 0.77 in 1: 3: 1 (EtOH: EtOAc: HAc 20%); ¹ H 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, 3.36 Hz, 1H), 3.88-3.70 (m, 6H), 3.55 (dd, J = 13.66, 7.61 Hz, 1H), 3.48 (dd, J = 8.70, 0.89 Hz, 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 = 7.51Hz, 2H), 1.99 (s, 3H), 1.77 (t, J = 12.77Hz, 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 ₁₄ S [M-H] ^-: 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 0.116 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 rinsed with dilute 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%); ¹ H 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 (i.e. , 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 = 11.95, 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

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 for CD22. The soluble CD22 protein was expressed in the cell line CHO-Lec1 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 ) tested as a reference. The relative affinity is indicated as rIP (relative inhibitory affinity).

15.1 ±4.4 1 14

0.016 ±0.005 963 15*

2.2 (16) ^{Ref 1} 16*

- (182)^{Ref 2} Ref 1: Collins et al (2006) Journal of Immunology 177, 2994-3003 Ref 2: XXVIII International Carbohydrate Symposium, July 17-21, 2016, New Orleans Poster / Abstract 294 * nicht innerhalb der Patentansprüche 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 No. structure IC ₅₀ micro M rIP BPC New5 Ac *

15.1 ± 4.4 1 14

0.016 ± 0.005 963 15 *

2.2 (16) ^{Ref 1} 16. *

- (182) ^{Ref 2} Ref 1: Collins et al (2006) Journal of Immunology 177, 2994-3003 Ref 2: XXVIII International Carbohydrate Symposium, July 17-21, 2016, New Orleans Poster / Abstract 294 * not within the claims

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2015128344 [0004, 0129]
• WO 9803573 [0012]

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Claims (16)

Sialic acid derivatives of the formula (I)

where the symbols have the following meanings: A ¹ is a group D ¹ - [Y ² -D ² -] _m -; 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 CC (O) -, SS (O) ₂ -, CHCH ₂ C (O) -, NHNHC (O) - or -OC (O) - where die is the Y ² bond to group A. ¹ denotes; is -0- 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 (O) -, ~S (O) ₂ -, ~C (O) -, ~CH ₂ C (O) -, and ~CH ₂ S (O) ₂ -, wherein ~ denotes the bond to the group D ³ ; D ³ is a) C ₁ -C ₆ -alkyl, where one or more non-terminal CH ₂ groups are optionally replaced by O, N (R ^x ) and / or C (O) and where in the non-terminal CH ₂ - Optionally substituted one or more H atoms by a group X, or b) 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 trifunctional to eight-membered heterocyclic radical, wherein said radicals are unsubstituted or mono- or polysubstituted by a group X; A ³ is a C ₃ -C ₁₅₀ -alkanediyl, where optionally one or more -CH ₂ - groups 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 [6,1,0] non-4-yn-9-yl, dibenzocyclooctinyl, biarylazacyclooctinonyl, cyclooctinyloxy, cyclooctynyl or dimethoxyazacyclooctinyl, 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 ^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. Sialic acid derivatives according to Claim 1 represented by the formulas (Ia) - (Ic), the symbols corresponding to those in Claim 1 have given meanings:

Sialic acid derivatives according to Claim 1 or 2 represented by the formulas (Iaa) - (Iac), the symbols corresponding to those in Claim 1 have given meanings:

Sialic acid derivatives according to one of the Claims 1 to 3 where Z is -O-. Sialic acid derivatives according to one of the Claims 1 to 4 where R ^{4 is} selected from -N (H) C (O) R ^x . Sialic acid derivatives according to one of the Claims 1 to 5 represented by formula (Iba), wherein the symbols in Claim 1 have given meanings:

Sialic acid derivatives according to one of the Claims 1 to 6 where R ⁵ or R ⁶ or both are OH. Sialic acid derivatives according to one of the Claims 1 to 7 where R ² and R ^{3 are} both H. A conjugate of at least one sialic acid derivative, a pharmaceutically acceptable solvate, salt or prodrug thereof as in any of Claims 1 to 8th and a component selected from a cargo, a polymer, a nanoparticle, a polymer-associated cargo, and a cargo associated with a nanoparticle. Sialic acid derivatives according to one of the Claims 1 to 8th or a conjugate according to Claim 9 for use in vaccination and the regulation of the immune system, and 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. Use of a sialic acid derivative according to any one of Claims 1 to 8th or a conjugate according to Claim 9 for the manufacture of a medicament for use in vaccination and in the regulation of the immune system, and 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. Use of a sialic acid derivative according to any one of Claims 1 to 8th 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 in any of Claims 1 to 8th defined, or a like in Claim 9 defined conjugate and at least one component selected from a pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and pharmaceutically acceptable excipient. Process for the preparation of a sialic acid derivative as in one of Claims 1 to 8th comprising the reaction of a compound of formula VIII

in which all the symbols in Claim 1 have been given with an amine-reactive reagent containing the group A ⁴ , as described in Claim 1 is defined; or b) the reaction of a compound of formula VII

with an amine containing the group A ⁴ and subsequent removal of the protective groups. Method according to Claim 14 wherein the compound of formulas VII and VIII are each prepared by multi-step synthesis from the compound of formula (III)

where all symbols are in Claim 1 have given meanings. Method according to Claim 15 in which the compound of the formula (III) where Z is O by reacting a compound of the formula (II)

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