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WO2018172129A1 - Dérivés d'acide sialique à liaison triple c-c et leur production - Google Patents

Dérivés d'acide sialique à liaison triple c-c et leur production Download PDF

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WO2018172129A1
WO2018172129A1 PCT/EP2018/056147 EP2018056147W WO2018172129A1 WO 2018172129 A1 WO2018172129 A1 WO 2018172129A1 EP 2018056147 W EP2018056147 W EP 2018056147W WO 2018172129 A1 WO2018172129 A1 WO 2018172129A1
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diyl
group
sialic acid
formula
diseases
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German (de)
English (en)
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Horst Prescher
Reinhard Brossmer
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Horst Prescher
Reinhard Brossmer
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Publication of WO2018172129A1 publication Critical patent/WO2018172129A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • the invention relates to derivatives of sialic acid, processes for their preparation, their use, in particular as active pharmaceutical ingredients, conjugates of these derivatives and pharmaceutical compositions containing such compounds.
  • Sialic acid is the generic term for a family of 9-carbon sugars that are all derivatives of neuraminic acid (new) and keto-deoxy-nonulosonic acid (KDN). Typically, these are located at the exposed non-reducing ends of oligosaccharide chains. Sialic acids play diverse roles in mammals and in the human organism (Schauer (2004) Zoology, 107, 49-64; Varki (2008) Trends in Mol. Med., 14, 8, 351-360). Furthermore, they are used by many pathogens, e.g. to achieve efficient infection or to escape the host's immune system (Glycoconjugate J. 2006, vol. 23, issue 1-2, all articles). Many such functions are regulated by proteins that recognize sialic acids (Lehmann et al (2006) Cell-Mol. Life Sci. 63, 1331-1354).
  • Siglecs are Ig-type lectins characterized by an N-terminal V-Set domain that allows specific recognition of sialic acids.
  • An overview of the types of siglec proteins known to date and diseases potentially treatable with siglec inhibitors can be found in Trends in "Pharmacological Sciences 2009, 30 (5), 240-248" and “Current Medicinal Chemistry 201 1, 18, 3537-3550 "and the references included.
  • siglecs are also useful as therapeutic targets when sialic acids or their derivatives are linked to other pharmaceutically active substances (Angata et al 2015 Trends Pharmacol Sci. 36, 10, 645-660).
  • CD22 (Siglec-2) is strongly expressed on B cells. It is known that certain monomeric derivatives of sialic acid with a carboxyalkyl as glycosidically bound Substituents at position 2 act as ligands for CD22, show a very high affinity and have potential suitability as drugs (Prescher et al., 2014 ACS Chem Biol.9 (7): 1444-50; WO2015128344; Madge et al., 2016 Scientific Reports 6, Article Number: 36012).
  • sialic acids and their derivatives in particular those with affinity for siglec-2, can be used for the preparation of therapeutically suitable conjugates (Courtney et al (2009) PNAS 106, 8, 2500-505, Collins et al (2006 ) Journal of Immunology 177, 2994-3003; Chen et al., 2010, Blood 1 15 (23): 4778-86; Schweizer et al., Eur J Immunol., 2012, 42 (10): 2792-802; Macauley et al 2013 J Clin Invest., 123 (7): 3074-83; Macauley et al., 2016 J. Allergy Clin Immunol. Pii: S0091-6749 (16) 30799-0).
  • 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.
  • the invention therefore relates to sialic acid derivatives of the formula (I)
  • a 1 is a group D'-fY ⁇ -D 2 -], ⁇ ;
  • D 1 is a mono- or polycyclic aromatic, partially unsaturated or saturated C 3 -C 14 -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to twelve-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted are substituted by a group X;
  • D 2 is a mono- or polycyclic aromatic, partially unsaturated or saturated C 3 -C 14 -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted are substituted by a group X;
  • Y 1 is -C (O) -, ⁇ S (O) 2 -, ⁇ CH 2 C (O) -, ⁇ NHC (O) - or -OC (O) -, wherein ⁇ denotes the bond to the group A 1 ;
  • Y 2 is -O- or a bond
  • a 2 is a group -N (R y ) -W or -N (H) -W;
  • Y 3 is a bond or group selected from -NHC (O) -, OC (0), - S (O) 2-, C (O) -, CH 2 C (O) - or CH 2 S (0) 2 -, wherein ⁇ denotes the bond to the group D 3 ;
  • Ci-C ö alkyl wherein optionally one or more non-terminal CH 2 groups by O, N (R) and / or C (O) are replaced and wherein in said groups optionally one or more H atoms a group X are replaced, b) mono- or polycyclic aromatic, partially unsaturated or saturated C 3 -C hydrocarbon residue or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, wherein said radicals unsubstituted or a - or substituted several times by a group X;
  • A is a C 3 -Ci5 0 -alkanediyl, where optionally one or more CH 2 groups are replaced by S, S (0) 2, O, N (R X) and / or C (O);
  • Z is -O- or -S-;
  • R 1 is -C (O) OM;
  • R 2 is H, OH, OR y or F;
  • R 3 is H or F;
  • R 4 is -N (R x ) C (O) CH 2 OH, -N (R x ) C (O) R x , -NHC (0) CH 2 F or -NHC (O) CH 2 Cl;
  • R 5 , R 6 are the same or different and selected from OH and OR x ;
  • M is a cation; each R x is independently selected from H, R y and R z ; each R y is independently selected from C 1 -C 4 alkyl, phenyl and benzyl and each R z is independently selected from -C (O) -Ci-C 4 alkyl, -C (O) phenyl and
  • the invention also provides a process for the preparation of sialic acid derivatives of the formula (I). They can be prepared, for example, by a process as shown in Scheme 1.
  • Scheme 1 A process for preparing sialic acid derivatives of the formula (I) wherein T is a leaving group useful for glycosylations (preferably alkyl or aryl), Q is an amino-protecting group, preferably a group C (O) OR y and the other symbols are the have meanings given for formula (I):
  • a sialic acid derivative of the formula (II) is reacted with a tert-butyl-protected hydroxycarboxylic acid to obtain a sialic acid derivative of the formula (III) wherein Z is O.
  • a sialic acid derivative of the formula (III) where Z is S can be prepared analogously to known methods (see, for example, WO 98/03573) from methyl 4-azido-5-acetamido-7,8,9-tri-O-acetyl-2-chloro 3, 4,5-trideoxy-D-glycero- ⁇ -D-galacto-2-nonulopyranosonate (Bioorg. Med. Chem. Lett., 1994, 4, 2457-2460).
  • the sialic acid derivative of Forniel (III) is converted with Z equal to O or S by removal of the acetyl radicals, reduction of the azide and introduction of a protective group into a sialic acid derivative of the formula (IV). Removal of the acetyl radicals from the sialic acid derivative of the formula (III) can be carried out before or after reduction of the azide and introduction of a protective group Q at position 4.
  • the sialic acid derivative of formula (IV) is converted to a sialic acid derivative of formula (V) by replacing the hydroxyl group at position 9 with an azide.
  • sialic acid derivative of Forniel (VI) By reduction of the azide at position 9 of the sialic acid derivative of the formula (V) and reaction of the resulting amine with an amine-reactive reagent, a sialic acid derivative of Forniel (VI) is obtained.
  • the sialic acid derivative of formula (VI) is then attached by removing the amino-protecting group Q at position 4 as well as the tert-butyl protecting group Position 2 and converted by reaction with amine-reactive reagents in a sialic acid derivative of the formula (VII).
  • the sialic acid derivative of the formula (VII) is reacted at the free carboxyl group -COOM with an amine containing a group A 4 .
  • a Sialinklarivat of formula (I) is obtained.
  • the sialic acid derivative of formula (VII) can be reacted on the free carboxyl group -COOM with a monoprotected diamine.
  • the step lengthens the group A 3 where the groups -N (H) - and -C (O) - of the newly formed amide replace -CH 2 - groups in A.
  • Subsequent deprotection of the carboxyl group -COOMethyl and of the protected amine gives a sialic acid derivative of the formula (VIII).
  • Subsequent reaction of the amine of the sialic acid derivative of the formula (VIII) with an amine-reactive reagent containing group A 4 gives a sialic acid derivative of the formula (I).
  • Sialic acid derivatives of the formula (I) in which the group R 2 is OH or OR y can be prepared analogously to known methods (Madge et al., 2016, Scientific Reports 6, Article number: 36012) from methyl 5-acetamido-7,8 , 9-tri-O-acetyl-2,6-anhydro-4-azido-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonate (Carbohydr. Res. 1993, 244, 181 -185).
  • the invention likewise provides a pharmaceutical preparation (medicament) comprising at least one sialic acid derivative of the formula (I) or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
  • the invention further provides the use of a sialic acid derivative of the formula (I) or a pharmaceutically acceptable salt or prodrug thereof as a medicament.
  • a sialic acid derivative of the formula (I) or a pharmaceutically acceptable salt or prodrug thereof as a medicament.
  • 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 .
  • cargo is understood to mean a low-molecular or high-molecular substance which has a biological action or a diagnostically useful effect and is transported to its site of action by means of sialic acid derivative (I);
  • examples are, but are not limited to, low molecular weight drugs (low molecular pharmacologically active substances), organometallic complexes, radioactive substances, fluorescers, positron emitters, cytostatics, RNA, DNA, peptides, oligonucleotides, proteins, antigenic proteins, enzymes and antigens, including low molecular weight antigens
  • Preferred as cargo are a low molecular weight, pharmacologically active substance, a cytostatic, a protein, an antigenic protein, an enzyme, an antigen, a low molecular weight antigen, a DNA, an RNA, an oligonucleotide, a radioactive substance, an organometallic complex, a vaccine and vaccine adjuvants or a peptide.
  • polymers are polymers which contain azido groups or in which an azido group can be incorporated by chemical modification.
  • an azide-containing radical can be incorporated into polylysine by chemical coupling via the ⁇ -amino group of the side chain.
  • polymers also include nonlinear polymers, for example dendrimers.
  • the polymers may be linked to one or more covalently bonded cargoes.
  • nanoparticles are understood as meaning particles in the size of 1 to 100 nm. The particles are composed of many copies of the same or several different units which are covalently or non-covalently bound to each other.
  • the particles may be, for example, atoms, such as gold or iron, of lipids and fat-soluble substances such as fatty acids, phosphatidylethanolamines or cholesterol, proteins such as viral capsid proteins, polymers such as acrylamide, chitosan, poly (lactide-co-glycolide) (PLGA ) consist.
  • the nanoparticles contain azido groups or can be modified with azido groups.
  • the nanoparticles may be linked to one or more covalently or non-covalently bonded cargoes.
  • the nanoparticles can be equipped with surface stabilizers, for example polyethylene glycols.
  • the compounds of formula (I) and conjugates thereof for example, for the regulation of the immune system, for example in vaccinations or transplants and for the treatment of diseases, especially allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple sclerosis, viral diseases, such as AIDS, bacterial diseases, parasitic Diseases, genetic diseases, diseases in which the immune response is disturbed in the context of B-cell activation, such as common variable immunodeficiency (CVID) and IgA deficiency, in diseases of the blood-forming organs and the blood and in cancer, for example, lymphomas and myelomas and Gene therapy can be used.
  • 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,
  • a further aspect of the invention is the use of a sialic acid derivative of the formula (I) for the preparation of a conjugate with a cargo, a polymer, a nanoparticle, a polymer-bound cargo or a nanoparticle-bound cargo, preferably a cargo selected from the group consisting of RNA, DNA, peptides, low molecular weight antigens, antigenic proteins, enzymes and low molecular weight pharmacologically active substances, a polymer selected from the group of linear polysaccharides, eg hyaluronic acid, pectin, cellulose, chitosan and their derivatives, eg succinylchitosan or carboxymethyl cellulose, homopolymeric amino acids, eg polyglutamate or polylysine, a nanoparticle selected from the group of metal nanoparticles (eg a gold or iron nanoparticle), lipid nanoparticles (eg liposomes or micro-micelles), protein nanoparticles (eg virus caps
  • 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.
  • 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.
  • 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
  • Nanoparticle conjugates are preferably used for the therapy of genetic and immunological diseases as well as neoplasias.
  • Sialic acid derivatives of formula (I) may also be linked to a cargo for diagnostic purposes to a conjugate, i. with a cargo with diagnostically usable effect;
  • 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.
  • a polyvalent material such as a polymer, dendrimer or nanoparticle
  • effective conjugates having improved properties can be prepared.
  • These conjugates can be used to regulate the immune system, for example, in vaccinations and for the treatment of diseases whose course or activity can be positively influenced by the siglec inliibitoren, in particular allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple sclerosis, cancer, viral diseases, for example AIDS, bacterial diseases, such as streptococci, parasitic Diseases such as Chagas disease, diseases in which the immune response is disturbed in the context of B cell activation, such as Common Variable Immunodeficiency (CVID) and IgA deficiency, used in diseases of the blood-forming organs and the blood and in cancer, for example, lymphomas and myelomas become.
  • CVID Common Variable Immunodeficiency
  • IgA deficiency used in diseases
  • 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.
  • 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 chi
  • 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.
  • PLGA Poly (lactide-co-glycolide)
  • 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
  • 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.
  • 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 phamiakobericht effective conjugate can be particularly easily to form a 1,2,3-triazole ring.
  • conjugates of azido-carrying cargoes such as low molecular weight molecules, DNA, RNA, peptides, nanoparticles, antigens, cells, proteins, viruses, polymers or dendrimers can thereby be effected in a particularly simple manner.
  • 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.
  • sialic acid derivative of the formula (I) comprises solvates, for example hydrates or adducts with alcohols, as well as all crystal modifications.
  • sialic acid derivatives of formula (I) includes pharmaceutically acceptable salts of compounds (I), including internal (i.e., zwitterionic).
  • 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).
  • R Y may be replaced, preferably ammonium, dimethylammonium, diisopropylammonium, tetramethylammonium, triethylammonium, tetrabutylammonium, 2- (2-hydroxyeth-1-oxy) eth-1-yl ammonium, di- (2-hydroxyeth-1-yl) -ammonium, trimethylbenzylammonium, furthermore phosphonium ions, sulfonium ions, preferably tri (C 1 -C 4 -alkyl) sulfonium and sulfoxonium ions, preferably tri (C 1 -C 4 -alkyl) -sul
  • Anions of pharmacologically acceptable acid addition salts are, for example, chloride, bromide, fluoride, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, the anions of C 1 -C 4 -alkanoic acids, preferably formate, acetate, propionate and butyrate, and other organic acids such as pivalic acid, maleic acid, succinic acid, pimelic acid, fumaric acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, citric acid and adipic acid.
  • the invention also relates to pharmacologically active metabolites of the compounds (I).
  • metabolites includes enzymes generated by "in vivo" enzymes such as esterases, amidases and other enzymes.
  • 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,
  • 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,
  • 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;
  • Alkylsulfonyl -S (O) 2 alkyl groups having a saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;
  • Alkylsulfoxyl -S (0) alkyl groups having saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;
  • Alkylaminosulfonyl -S (O) 2 -NH (alkyl) groups having a saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;
  • Dialkylaminosulfonyl -S (O) 2 -N (alkyl) 2 groups having saturated straight-chain, branched or cyclic alkyl radicals, these being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;
  • Alkyloxycarbonyl -C (O) Oalkyl groups having saturated straight, branched or cyclic alkyl radicals selected from the aforementioned group of alkyls and preferably containing from 1 to 4 carbon atoms;
  • Alkylcarbonyloxy -O-C (0) alkyl groups having a saturated straight, branched or cyclic alkyl radical selected from the aforementioned group of alkyls and preferably containing from 1 to 4 carbon atoms;
  • Alkylaminocarbonyl -C (O) NH (alkyl) groups having a saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms; Dialkylaminocarbonyl: -C (O) N (alkyl) 2 groups having saturated straight-chain, branched or cyclic alkyl radicals, these being selected from the abovementioned alkyl group and preferably containing 1 to 4 carbon atoms;
  • Alkylcarbonylamino -NH-C (0) alkyl groups having a saturated straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and preferably containing from 1 to 4 carbon atoms.
  • alkyl is also used for alkylene groups (alkanediyl groups). This is evident from the context.
  • Mono- or polycyclic, aromatic, partially unsaturated or saturated C 3 -C 14 hydrocarbon radical preferably denotes for D: a) C 6 -C 4 -aryldiyl, in particular phenylene-l, 4-diyl, phenylene-l, 3-diyl, phenylene 1, 2-diyl, naphthalene-1, 2-diyl, naphthalene-1, 3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl, naphthalene-1, 6-diyl, naphthalene-1, 7-diyl, naphthalene-1,8-diyl, naphthalene-2,3-diyl, naphthalene-2,6-diyl, naphthalene-2,7-diyl, biphenylene-1,2-diyl, biphenylene-1,
  • Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical for D preferably means: a) non-aromatic, saturated or partially unsaturated 5- or 6-membered heterocyclodiyl containing one to three nitrogen atoms and / or one oxygen or sulfur atom or one or two oxygen and / or sulfur atoms, in particular trans -tetrahydrofuran-2,5-diyl, trans -tetrahydrofuran-2,4-diyl, cis -tetrahydrofuran-2,5-diyl, trans -tetrahydrothien-2,5-diyl, trans-tetrahydrothien-2,4-diyl, trans -pyrrolidine-2,5-diyl, trans -pyrrolidine-2,4-diyl, isoxazolidine-2,4-diyl, isoxazolidine-2,5-diyl, isothiazolinedin
  • Polycyclic aromatic, partially unsaturated or saturated heterocyclic radical is preferably for D:
  • Hydrocarbon radical for D and D is preferably: a) C 6 -C 12 -aryl, in particular phenyl, 1-naphthyl, 2-naphthyl, 1-biphenylene, 2-biphenylene, 1-pyrenyl, 1-anthracenyl, 2-anthracenyl, 9-anthracenyl , 4-indenyl, 2-fluorenyl, 3-fluorenyl, 9-fluorenyl and 3-phenanthrenyl; b) C3-C] 4 -cycloalkenyl or Cs-Cu-cycloalkadienyl, in particular cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadien-1-yl, cyclohexadien-1-yl and cyclooctadien-1-yl;
  • Monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical preferably denotes for D 1 and D 3 : a) non-aromatic, saturated or partially unsaturated 4, 5, 6 or 7-membered heterocyclyl containing one to four nitrogen atoms and / or an oxygen or sulfur atom or one or two oxygen and / or sulfur atoms, in particular
  • Polycyclic aromatic, partially unsaturated or saturated heterocyclic radical means for D and D preferably:
  • 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.
  • substituents are preferably independently selected from the group X.
  • 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.
  • a 1 is advantageously a group D 1 - [Y 2 -D 2 -] m -
  • D 1 is advantageously a mono- or polycyclic aromatic or saturated C 3 -Cj 4 - hydrocarbon radical or a monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, where said radicals are unsubstituted or mono- or polysubstituted by a group X. are.
  • D is advantageously a group of phenylene-l, 4-diyl, phenylene-l, 3-diyl, pyridine-2,5-diyl, pyridazine-3,6-diyl, pyrimidine-2,5-diyl, pyrimidine-2,6 -diyl, pyrazine-2,5-diyl, trans-cyclobutane-l, 3-diyl, trans-cyclopentane-l, 3-diyl, trans -cyclohexane-l, 4-diyl, cuba-1, 4-diyl, thiophene -2,5-diyl, pyrrole-2,4-diyl, pyrrole-2,5-diyl, pyrazole-l, 3-diyl, oxazole-2,4-diyl, oxazole-2,5-diyl, l, 3 , 4-ox
  • Y 1 is advantageously ⁇ C (0) -, ⁇ CH 2 C (0) - or ⁇ OC (0) - where ⁇ denotes the bond to the group A 1 .
  • Y is advantageously -O- or a bond.
  • a 2 is advantageously a group -N (R y ) -W or -N (H) -W.
  • W is advantageously a group -SO 3 M or -SO 2 NR x 2 or a group D 3 -Y 3 -.
  • Y is advantageously a bond or a group ⁇ S (0) 2 -, ⁇ C (0) -, ⁇ CH 2 -C (0) - or
  • D is advantageous a) a Cj-Cs-alkyl, wherein in said groups optionally one or more H atoms are replaced by a group X, b) a monocyclic aromatic or saturated C3-C6 hydrocarbon radical or a monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted by a group X.
  • Z is advantageously -O- or -S-;
  • R 1 is advantageously -C (O) OM
  • R 2 is advantageously H, OH or OR y ;
  • R 3 is advantageously H, F
  • R 4 is advantageously -N (R x ) C (O) CH 2 OH or -N (R x ) C (O) R x ;
  • R 5 , R 6 are preferably the same or different and selected from OH or OR X ;
  • halogen fluorine, chlorine and bromine
  • Alkyl saturated, straight-chain, branched or cyclic hydrocarbon radicals having, for example, 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,
  • Halogenoalkyl straight-chain, branched or cyclic alkyl groups having, for example, 1 to 3 carbon atoms (as mentioned above), in which groups hydrogen atoms are partially or completely replaced by halogen atoms: such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, Dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromethyl,
  • Alkoxy -O-alkyl groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned group of the alkyls and containing 1 to 3 carbon atoms;
  • Alkylamino -NH (alkyl) groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 2 carbon atoms;
  • Dialkylamino -N (alkyl) 2 groups having saturated, straight-chain, branched or cyclic alkyl radicals, these being identically or differently selected from the abovementioned alkyl group and containing 1 to 2 carbon atoms;
  • Alkylsulfonyl -S (O) 2 alkyl groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 4 carbon atoms;
  • Alkylaminosulfonyl -S (O) 2 -NH (alkyl) groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 3 carbon atoms;
  • Alkoxycarbonyl -C (O) -O-alkyl Grappen having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 3 carbon atoms;
  • Alkylcarbonyloxy -O-C (0) alkyl groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 3 carbon atoms;
  • Alkylaminocarbonyl -C (O) NH (alkyl) groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 3 carbon atoms;
  • Alkylcarbonylamino -NH-C (0) alkyl groups having a saturated, straight-chain, branched or cyclic alkyl radical, this being selected from the abovementioned alkyl group and containing 1 to 3 carbon atoms.
  • D and D is more preferred for D and D: a) C 6 -C 4 -aryl, especially phenyl, naphth-1-yl, naphth-2-yl, biphen-4-yl, biphen-2-yl, anthracene-9-yl, indene 4-yl, fluoren-2-yl, fluoren-3-yl, fluoren-9-yl and phenanthrene-3-yl; b) C -C -cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantan-1-yl, cuban-1-yl and cyclooctyl.
  • C 6 -C 4 -aryl especially phenyl, naphth-1-yl, naphth-2-yl, biphen-4-yl, biphen-2-yl, anthracene-9-yl, indene 4-
  • 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.
  • substituents independently are preferably selected from the group X.
  • 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.
  • D 1 is preferably a group selected from phenyl, pyrimidin-5-yl, naphth-1-yl, naphthyl and thien-2-yl, where the radicals mentioned are unsubstituted or mono- or polysubstituted by a group X;
  • D is preferably a group selected from phenylene-l, 4-diyl, pyridine-2,5-diyl, pyrimidine-2,5-diyl and thiophene-2,5-diyl, where the radicals mentioned are unsubstituted or mono- or polysubstituted a group X is substituted;
  • Y 1 is preferably ⁇ C (O) - or ⁇ CH 2 C (O) - where ⁇ denotes the bond to the group A 1 ;
  • Y is preferably a bond
  • A is preferably a group -N (H) -W;
  • W is preferably a group -SO 3 M
  • A is preferably a C 3 -C 2 o-alkanediyl, where optionally one or more -CH 2 - groups are replaced by S, O, N (H) and / or C (O);
  • Methyl, trifluoromethyl, methoxy and oxo ( 0); m is preferably 1;
  • Z is preferably -0-
  • R x is preferably H, R y or R z ;
  • R y is preferably methyl, ethyl or benzyl
  • R z is preferably -C (O) CH 3 , -C (Q) C (CH 3 ) 3 or -C (O) phenyl; R is preferably H; R 3 is preferably H;
  • R 4 is preferably -N (H) C (O) R, more preferably -NHC (O) CH 3 ;
  • R 5 and R 6 are the same or different and are preferably selected from OH, OCH 3 and
  • M is preferably sodium, potassium, calcium or magnesium.
  • sialic acid derivatives of the formula (I) are those of the formulas (Ia) - (Ic), where the symbols have the meanings and preferences given for formula (I); preferably, R is H:
  • sialic acid derivatives of the formula (II) can be reacted with tert-butyl-protected hydroxycarboxylic acids in good yield to form sialic acid derivatives of the formula (III) (see Scheme 1 above), without significant cleavage of the protective group, although strongly acidic conditions Use of trifluoromethanesulfonic occur during the reaction.
  • the analysis of the ⁇ / ⁇ ratio of the glycosidic bond in the reaction product shows an unexpectedly high yield of the biologically active and desired ⁇ -anonizing.
  • 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 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.
  • 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.
  • sialic acid derivatives of the formula (VII) can then be further reacted at the carboxylic acid of the glycosidically linked substituent to sialic acid derivatives of the formula (VIII), which after final elimination of the ester at position 1 and imports of the group A 4 in the desired sialic acid derivatives of the formula (I ) can be transferred.
  • 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.
  • compound 3 was prepared.
  • Useful leaving groups and reaction conditions for glycosylations are described, for example, in Current Organic Synthesis, 2004, 1, 31-46, Current Organic Chemistry, 20 (14): 1465-1476, and "Glycochemical Synthesis: Strategies” and Applications Editor: Shang-Cheng Hung and Medel Manuel L. Zulueta (Editor) ISBN: 978-1-1 18-29984-5 described.
  • Compounds of 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.
  • a suitable reducing agent for example zinc in dilute acetic acid.
  • the reduction of azido groups is described for example in Angewandte Chemie 2005, 1 17, 5320-5374 and Chem. Rev. 1988, 88 (2), 297-368.
  • compound 5 was prepared.
  • Q in compound (IV) is an amino-protecting group, for example, tert-butyl or benzyloxycarbonyl.
  • Compounds of formula (IV) can be prepared by introducing an amino-protecting group Q, for example di-tert-butyl dicarbonate, into compounds of formula (X).
  • Amino-protecting groups and reactions for protecting amino groups are described for example in "Protecting Groups", Philip J. Kocienski, 3 ld Edition, Thieme 2005, Chem. Rev. 2009, 109, 2455-2504 and "Protective Groups in Organic Chemistry” Peter GM Wuts, Wiley, 2014.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 "Protecting Groups” Philip J. Kocienski, 3 Edition, Thieme 2005, Chem. Rev. 2009, 109, 2455-2504 and "Protective Groups in Organic Chemistry” Peter GM Wuts, Wiley, 2014 , As an example, compound 10 was prepared. Shem
  • Compounds of formula (VII) can be prepared, for example, by reaction of the amine in compounds of formula (XII) with an amine-reactive reagent, for example sulfur trioxide-pyridine complex, an activated carboxylic acid or a sulfonic acid chloride. By the reaction with the amine-reactive reagent, the group A is formed, which is as defined above for formula (I).
  • 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.
  • compound 11 was prepared.
  • Compounds of formula (VIII) may be prepared, for example, by reaction of the carboxyl group in compounds of formula (VII) with a monoprotected diamine, for example N-Fmoc-1,2-diaminoethane, followed by basic deprotection. Reactions of amines to form an amide by means of activated reagents or with the aid of coupling reagents are described, for example, in Tetrahedron 2005, 61, 10827-10852, Chem. Eur. J. 2009, 15, 9040-9416. Amino-protecting groups and amino-deprotecting reactions are described, for example, in "Protecting Groups” Philip J. Kocienski, 3rd Edition, Thieme 2005, Chem. Rev. 2009, 109, 2455-2504, and "Protective Groups in Organic Chemistry” Peter GM Wuts, Wiley , 2014.
  • a monoprotected diamine for example N-Fmoc-1,2-diaminoethan
  • 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 formula (I) can be prepared, for example, by reaction of the carboxyl group in compounds of formula (VII) with a triple bond-containing amine, for example propargylamine, and subsequent deprotection, the group A being "extended” and the groups -N (H) - and -C (O) - of the newly formed amide become part of A.
  • Reactions of amines to form an amide by means of activated reagents or with the aid of coupling reagents are described, for example, in Tetrahedron 2005, 61, 10827-10852, Chem. Eur. J. 2009, 15, 9040-9416.
  • Compounds of formula (I) may be prepared, for example, by reaction of the amine in compounds of formula (VIII) with a triple bond-containing amine-reactive reagent, for example ((IR, 8S, 9R) -bicyclo [6.1.0] non-4-yn-9 -yl) methyl
  • compound 14 was prepared.
  • sialic acid derivatives of the formula (I) are suitable as such as pharmacologically active compounds, but also for the preparation of pharmacologically active conjugates.
  • Sialic acid derivatives of the formula (I) and their pharmacologically active conjugates are suitable for vaccinations and the treatment of diseases whose occurrence or course are influenced by Siglec-bearing cells, in particular allergies, autoimmune diseases, genetic diseases, chronic inflammation, paraplegia, multiple sclerosis, cancer and viral diseases, such as AIDS and for the regulation of metabolic processes, immune reactions, immunizations or desensitization of the target organism.
  • Preferred indications are allergies, cancer, autoimmune diseases and use for vaccinations.
  • Preferred indications are also B-cell-mediated diseases, for example lymphomas or autoimmune diseases.
  • 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.
  • 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
  • sialic acid derivatives of the formula (I) can also be used for the preparation of a conjugate for purposes other than those mentioned, for example as diagnostics, in methods for determining the activity of Siglec ligands, as biochemical probes or as intermediates for the preparation of further, in particular pharmacological active, connections.
  • the sialic acid derivatives of the formula (I) are also suitable as pharmacologically active compounds for pharmaceutical preparations. They act as Siglec ligands, in particular as Siglec-2 (CD22) ligands, for the regulation of the immune system, in particular as an adjuvant in vaccinations and for the treatment of diseases whose course or activity can be influenced by the Siglec ligands, in particular allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple Sclerosis, cancer, viral diseases, such as AIDS, as well as bacterial diseases, such as streptococci, parasitic diseases, such as Chagas disease, diseases in which the immune response is disturbed in the context of B-cell activation, such as common variable immunodeficiency (CVID) and IgA deficiency , in diseases of the blood-forming organs and the blood and in cancer, for example, lymphomas and myelomas.
  • Preferred indications are allergies, autoimmune diseases and CVID.
  • Treatment in the sense of the invention means a therapeutic treatment, both for the cure of a disease or a condition and for the alleviation of symptoms or slowing down the progression of a disease, as well as a preventive treatment.
  • the invention also provides a method for treating a siglec mediated disease, in particular from the group of allergies, autoimmune diseases, chronic inflammation, paraplegia, multiple sclerosis, cancer, viral diseases, for example AIDS, diseases in which the immune response in the context of B-cell activation such as common variable immunodeficiency (CVID) and IgA deficiency, wherein a patient of the disease is administered a preferably therapeutically effective amount of a sialic acid derivative of formula (I) or a conjugate thereof.
  • 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
  • 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 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.
  • 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 ,
  • 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.
  • 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.
  • sialic acid derivatives of formula (I) may also be used for other purposes than those mentioned, for example as diagnostics, e.g. in methods for determining the activity of Siglec ligands, as biochemical probes or as intermediates for the preparation of further, in particular pharmacologically active compounds.
  • a 1 is a group ö '- [Y 2 -D 2 -] m -;
  • D 1 is a mono- or polycyclic aromatic, partially unsaturated or saturated C 3 -C 4 -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to twelve-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted are substituted by a group X;
  • D is a mono- or polycyclic aromatic, partially unsaturated or saturated C 3 -C 4 -hydrocarbon radical or a mono- or polycyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical, where the radicals mentioned are unsubstituted or mono- or polysubstituted by a group X is substituted;
  • Y 1 is CC (O) -, SS (O) 2 -, CHCH 2 C (O) -, NHNHC (O) - or OCOC (O) -, wherein die denotes the bond to the group A 1 ;
  • Y 2 is -O- or a bond; is a group -N (R y ) -W or -N (H) -W;
  • W is a) a group -S0 3 M or -S0 2 NR x 2 or
  • Y ° is a bond or group selected from -NHC (O) -, OC (0) - S (0) 2 -, C (0) -, CH 2 C (O) -, and CH 2 S (0) 2 -, wherein ⁇ denotes the bond to the group D 3 ;
  • Ci-C 6 -alkyl wherein optionally one or more non-terminal CH 2 - groups by O, N (R X ) and / or C (O) are replaced and wherein in the non-terminal CH 2 groups optionally one or several H atoms are replaced by a group X, or
  • A is a C 3 -C 15 -alkanediyl where optionally one or more -CH 2 - groups are represented by -S-, -S (O 2 ) -, -O-, -N (R X ) - and / or -C ( O) - are replaced;
  • Z is -O- or -S-;
  • R 1 is -C (O) OM;
  • R 2 is H, OH, OR y or F;
  • R 3 is H or F;
  • R 4 is -N (R x ) C (O) CH 2 OH, -N (R x ) C (O) R x , -NHC (O) CH 2 F or -NHC (O) CH 2 Cl;
  • R 5 and R 6 are the same or different and selected from OH and OR x ;
  • M is a cation; each R x is independently selected from H, R y and R 2 ; each R y is independently selected from C 1 -C 4 alkyl, phenyl and benzyl; and each R z is independently selected from -C (O) - (C 1 -C 4 alkyl), -C (O) -phenyl or -C (O) -CH 2 -phenyl; a pharmaceutically acceptable solvate, salt or prodrug thereof.
  • Cs-Cg-Cycloalkyldiyl in particular trans-cyclopropane-l, 2-diyl, cyclopropane-1,1-diyl, trans-cyclobutane-l, 3-diyl, cis-cyclobutane-1,3-diyl, trans-cyclopentane -1, 3-diyl,
  • a polycyclic aromatic, partially unsaturated or saturated heterocyclic radical selected from:
  • D 1 is a monocyclic or polycyclic aromatic or saturated C 3 -C 4 -hydrocarbon radical or a monocyclic aromatic, partially unsaturated or saturated four- to six-membered heterocyclic radical, where the radicals mentioned unsubstituted or mono- or polysubstituted by a group X.
  • sialic acid derivatives according to any one of items 1-11, wherein one of D 1 and D 3 or both are independent:
  • C 3 -C 4 -hydrocarbon radical selected from: i) C 6 -C 4 -aryl, in particular phenyl, naphth-1-yl, naphth-2-yl, biphen-4-yl, Biphen-2-yl, anthracene-9-yl, inden-4-yl, fluoren-2-yl, fluoren-3-yl, fluoren-9-yl and phenanthren-3-yl; and ii) C 3 -C 8 cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantane-1-yl, cuban-1-yl and cyclooctyl; b) monocyclic aromatic, partially unsaturated or saturated three- to eight-membered heterocyclic radical selected from: i) non-aromatic, saturated or partially unsaturation
  • Sialic acid derivatives according to any one of items 1-19, wherein each X is independently selected from fluoro, chloro, hydroxy, carboxyl, methyl, trifluoromethyl, methoxy and oxo ( 0).
  • R preferably in the formulas (Ia) - (Ic) R is H.
  • R 2 is H.
  • the cargo is a diagnostically useful cargo selected from a fluorescent molecule, a radiolabelled molecule and a positron emitter.
  • a pharmaceutical composition comprising at least one sialic acid derivative, a pharmaceutically acceptable solvate, salt or prodrug thereof as defined in any one of items 1 to 28, or a conjugate as defined in any one of items 29-32 and at least one member selected from a pharmaceutically acceptable carrier, pharmaceutically acceptable excipients and pharmaceutically acceptable excipient and optionally one or more other drugs.
  • T aryl or alkyl is prepared with a tert-butyl protected hydroxycarboxylic acid.
  • sialic acid derivative of the formula (I), a prodrug, solvate or salt thereof as defined in any one of items 1 to 28 for the preparation of a conjugate in which the sialic acid derivative, prodrug, solvate or salt thereof is covalently or non-covalently linked to a optionally polymer- or nanoparticle-linked - cargo selected from RNA, DNA, peptides, enzymes, low molecular weight antigens, antigenic proteins and low molecular weight pharmacologically active substances. 7
  • 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.
  • Silica gel Si60 43-60mm or RP-18 silica gel (YMC CO LTD., YMC ODS-AQ) was used for chromatographic purifications.
  • a solution of 100 mg of compound 1 1 and 87 mg of ethylenediamine mono-Fmoc in 5 ml of DMF was admixed with 0.131 ml TEA and 72 mg HATU. After 5 minutes, the solution was acidified with dilute acetic acid. The solution was mixed with 2 ml of NaHC0 3 and 10 ml of water and purified over RP18 silica gel (H 2 0 to ACN). The product fractions were concentrated to 6 ml and processed directly.
  • connection 14 A solution of 182 mg of compound 13 in 1 ml of DMF and 0.1 16 ml of TEA was admixed with 77 mg of exo BCN-active NPE (CAS 1380006-72-3) and stirred for 2 h. 2 ml of 20% acetic acid and 20 ml of water were added and the solution was purified on RP18 silica gel. First, it was flushed with dil. NaHCO 3 until 4-nitrophenyl was removed and then eluted with a water: ACN gradient).
  • the biological activity of the substances was determined in an ELISA-based inhibition assay as described in "ACS Chem. Biol. 2014, 9, 1444-1450.”
  • the sialic acid derivatives of formula (I) inhibit the binding of soluble CD22 to immobilized IgM in proportion to their affinity to CD22
  • the soluble CD22 protein was expressed in the cell line CHO-Lecl and isolated as described "ACS Chem. Biol. 2014, 9, 1444-1450".
  • the known substance "BPCNeu5Ac” J. Exp. Med., 2002, 195, 1207-1213
  • the known substance 15 (WO2015128344) was also tested as reference
  • the relative affinity is expressed as rIP (relative Inhibitory affinity).
  • Table I shows the affinity or relative inhibitory potency (rIP) of the sialic acid derivative 14 according to the invention and other monovalent derivatives of sialic acid and the reference substance BPC Neu5Ac hitherto used for the preparation of conjugates.

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Abstract

L'invention concerne des dérivés d'acide sialique de formule (I), lesquels contiennent une liaison triple C-C, des procédés permettant de les produire, des conjugués produits à partir desdits dérivés et des médicaments les contenant. Formule (I) dans laquelle les symboles ont la signification définie dans les revendications.
PCT/EP2018/056147 2017-03-22 2018-03-13 Dérivés d'acide sialique à liaison triple c-c et leur production WO2018172129A1 (fr)

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DE102017002810.9 2017-03-22
DE102017002810.9A DE102017002810A1 (de) 2017-03-22 2017-03-22 Sialinsäurederivate mit C-C Dreifachbindung und deren Herstellung

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024259007A3 (fr) * 2023-06-14 2025-04-17 Osprey Biopharmaceuticals, Inc. Ligands siglec, conjugués et leurs méthodes d'utilisation

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