Inhibitors of abnormal phosphorylation and aggregation of tau protein

Abstract

The present invention relates to anionic lipid oligosaccharides and their use in medicine, in particular in the treatment of pathologies associated with abnormal hyperphosphorylation of the tau protein (eg Alzheimer's disease).

Description

[Technical field]

[0001] The present invention relates to anionic lipid oligosaccharides and their use in medicine, in particular in the treatment of pathologies associated with abnormal hyperphosphorylation of the tau protein (eg Alzheimer's disease). [Background technology]

[0002] Alzheimer's disease (AD) is the most common age-related dementia worldwide. It is responsible for 60-70% of dementia cases according to the World Health Organization (WHO). Over 50 million people worldwide suffer from AD, with 10 million new cases recorded each year. According to WHO projections, the total number of dementia patients is expected to reach 82 million in 2030 and 152 million in 2050.

[0003] The disease not only affects the health and morale of patients and their families, but also represents a significant economic burden to society.

[0004] AD is characterized by the progressive loss of cognitive abilities associated with severe neurodegeneration. Histopathologically, AD is characterized by two types of brain lesions: senile plaques (or amyloid), which are extracellular aggregates of beta-amyloid peptide (Aβ), and neurofibrillary tangles (NFTs), which correspond to intracellular accumulations of abnormally phosphorylated tau protein (MAPT, microtubule-associated protein tau) (p-tau).

[0005] Despite extensive academic and industrial research efforts over the past two decades, no treatment has been developed that can efficiently and sustainably block the progression of neurodegeneration.

[0006] Since the involvement of amyloid plaques and NFTs generated by p-tau is well recognized in the functional changes of neurons, most of the developed treatments have been specifically targeted at the progressive accumulation of beta-amyloid protein, and more recently, tau. However, the failure of therapeutic strategies targeting different episodes of the amyloid J3 (AJ3) cascade indicates that the accumulation of AJ3 is not the central pathological process of the disease, and it may be the abnormal phosphorylation and aggregation of tau that should be targeted to combat the disease.

[0007] Tau protein is a member of the microtubule-associated protein (MAP protein) family. In humans, one of the main roles of tau protein is to stabilize the neuronal cytoskeleton through its interaction with tubulin, which allows axonal stability. In AD, abnormal phosphorylation of tau induces the detachment of the protein from the cytoskeleton, and soluble tau protein aggregates and eventually forms the NFTs characteristic of AD. A positive correlation has been shown between the clinical progression of the disease and the accumulation of abnormally phosphorylated and aggregated tau protein in the brain as neurofibrillary tangles (NFTs) form.

[0008] Some kinases can phosphorylate tau (cdK5, NCLK, GSK-3β and MARK), but this phosphorylation of tau occurs non-specifically, since some other proteins are also their substrates. Therefore, inhibiting one of the kinases does not prevent the action of the others. In line with this, much research has been carried out on kinase inhibitors and phosphatases (also non-specific) as possible therapeutic targets, but to date there have been no positive results that can stop or delay the disease by individually inhibiting the activity of such enzymes, whether kinase inhibitors, phosphatase activators or NFT dissociators. Summary of the Invention [Problem to be solved by the invention]

[0009] At present, the treatments under development targeting tau protein are mainly based on immunotherapy at the extracellular level. The antibodies used are generated against tau fragments and aim at the reduction of the more or less aggregated extracellular form of tau protein. However, such extracellular forms are produced intracellularly by phosphorylation of tau protein, and after extracellular secretion, such aggregated forms of tau appear to act to propagate pathology in brain tissue. Currently, immunotherapy targeting tau protein remains the main hope in the field, with all the difficulties inherent to immunotherapy, in particular with regard to the inaccessibility of intracellular antibodies that stop the process of tau abnormal phosphorylation and aggregation, the stability of such preparations, the production of anti-antibodies, and the need for treatment in a hospital environment (Schroeder SK et al., Neuroimmune Pharmacol. 2016, 11(1):9-25). It is therefore generally agreed that the best strategy involves small, stable molecules capable of blocking tau hyperphosphorylation and aggregation, which can be administered to patients in a non-hospital environment by conventional dosing schedules.

[0010] Thus, there remains a need to provide compounds capable of halting or slowing the progression of pathologies associated with hyperphosphorylation of the tau protein, in particular Alzheimer's disease. [Means for solving the problem]

[0011] The present invention relates to a compound of formula (I) below for use in medicine, in particular in the treatment of tauopathies: [ka] [In the formula, L is a -C(=O)NH-, -C(=O)O- or -C(=O)S- group; R1 is a linear or branched, saturated or unsaturated hydrocarbon chain containing 15, 16, 17 or 18 carbon atoms, optionally substituted at the terminal position by a group selected from -OH, -OR, -NH2, -NHR, -NRR', -COOH, -COOR, -CONHR, -CONRR' and -SR, where R and R' independently represent an alkyl group containing 1 to 6 carbon atoms; R4 is represented by formula (IIa) or (IIb): [ka] [In the formula, R9 and R 10 are each independently a hydrogen atom or a sulfonic acid group in ionized form, R 12 is an alkyl group containing 1 to 6 carbon atoms, R 11 -CH2-OR5 or -CONHR 13 It is based on R5 is a hydrogen atom or an ionized sulfonic acid group; R 13 is an alkyl group containing 1 to 6 carbon atoms. Based on R2, R3, R6, R7 and R8 are each independently a hydrogen atom or an ionized sulfonic acid group; R2, R3, R5, R6, R7, R8, R9 and R 10 At least one of the groups R2, R3, R5, R6, R7, R8, R9 and R 10 At least two of the groups are sulfonic acid groups in ionized form. The present invention relates to a compound of the formula:

[0012] The present invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) as described herein and one or more pharma- ceutically acceptable excipients, and their use in the treatment of tauopathies.

[0013] Other aspects of the invention are described below and in the claims. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows the role of heparan sulfate (HS). [Diagram 2] Western blot showing that GSK3β-mediated phosphorylation of tau at sites specific to Alzheimer's disease is dependent on the presence of heparin in the reaction mixture (Sepulveda-Diaz JE et al., Brain. 2015 May;138(Pt 5):1339-54). [Diagram 3] Western blot showing that abnormal phosphorylation of tau (pTau), revealed by Alzheimer's disease specific antibodies (AT270 and Ser199 / 202), is inhibited by the presence of disulfated C16 maltobionamide (Mal16diS) after a 3 hour in vitro reaction. [Figure 4] Western blot showing that abnormal phosphorylation of tau (pTau), revealed by Alzheimer's disease specific antibodies (AT270 and Ser199 / 202), is inhibited by the presence of disulfated C18 maltobionamide (Mal18diS) after a 3 hour reaction. [Diagram 5] Western blot comparing the p-tau induction ability (as revealed by the AT270 antibody) of disulfated maltobionamide-derived compounds according to the length of the hydrocarbon chain (R1) (Mal14diS to Mal20diS correspond to chains with 14 to 20 carbons) and heparin ("Hep") after a 3-hour reaction. [Figure 6] Western blot assay evaluating abnormal tau phosphorylation (p-tau), revealed by Alzheimer's disease-specific antibodies (AT270 and Ser199 / 202), in different derivatives according to their disaccharide (mono- or disulfated) and carbohydrate chain length (14-20 carbons) after a 3-h reaction. [Figure 7]Western blot comparing the ability of disulfated maltobionamide (Mal16diS, Mal18diS) to protect tau protein from heparin-induced abnormal phosphorylation as revealed by the AT270 antibody, compared to its oxidized form with 16 carbons (Mal16diOx) and 18 carbons (Mal18diOx). [Figure 8] Western blot comparing the effect of disaccharide sulfation (monoS and triS) on the ability of 16- or 18-carbon maltobionamides to efficiently protect tau from heparin-induced aberrant phosphorylation as revealed by the AT270 antibody with two batches of compound (Mal16monoS and Mal16triS for Mal16, and Mal18monoS and Mal18triS for Mal18). [Figure 9] Western blot comparing a persulfated 16-carbon maltobionamide molecule (Mal16perS) with its potent disulfated homologues (Mal16diS, Mal18diS) in their ability to efficiently protect tau from aberrant heparin-induced phosphorylation as revealed by the AT270 antibody. [Figure 10] FIG. 1 shows monitoring of tau protein aggregation by incorporation of Thioflavin T, a fluorescent compound that incorporates into aggregates in the presence of heparin (tau:hep mass ratio 2:1 or 4:1) or the 16-carbon disulfated maltobionamide compound (Mal16diS) (tau:oligo mass ratio 4:1). The number of repeats is represented by n. [Figure 11] FIG. 1 shows the cytotoxicity of carbon number 16 disulfated maltobionamide (Mal16diS) at concentrations of 0.1, 1, 10 or 100 μg / mL. [Figure 12] FIG. 1 shows the cytotoxicity of carbon number 18 disulfated maltobionamide (Mal18diS) at concentrations of 0.1, 1, 10 or 100 μg / mL. [Figure 13]Protection of tau from phosphorylation in cellulo by the 16-carbon disulfated maltobionamide compound (Mal16diS) at concentrations of 1, 10 or 100 μg / mL. t-test: *p<0.05, ***p<0.001; number of replicates≧5. [Figure 14] Protection of tau from phosphorylation in cellulo by the 18-carbon disulfated maltobionamide compound (Mal18diS) at concentrations of 1, 10 or 100 μg / mL. t-test: *p<0.05, ***p<0.001; number of replicates≧5. [Figure 15] Figure 14. Effect of Cell16diS on p-tau upon induction of tauopathy in the SHSY5Y model in cellulo. t-test non-significant; number of replicates > 3. [Figure 16] Figure 1 shows the effect of Lac16diS on p-tau upon induction of tauopathy in the SHSY5Y model in cellulo. t-test: *p<0.05; number of replicates >= 3. [Figure 17] Figure 1 shows the reduction in phosphorylation of moderately present (14 days after culture) tau in cortical cells of rTg4510 mouse model by the 16 carbon disulfated maltobionamide compound (Mal16diS) at a concentration of 0.1 or 1 μg / mL. t-test: **p<0.01, ***p<0.001; number of replicates=4. [Figure 18] Figure 1 shows the reduction in phosphorylation of tau, which is highly present (18 days in culture) in cortical cells of the rTg4510 mouse model, by the 16-carbon disulfated maltobionamide compound (Mal16diS) at a concentration of 0.1 or 1 μg / mL. t-test: non-significant; number of replicates=4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] It has been found that the anionic lipid oligosaccharides described below (compounds of formula (I)) are capable of protecting tau protein from abnormal hyperphosphorylation, do not themselves induce abnormal hyperphosphorylation of tau, and are capable of reducing the aggregation of tau protein induced by heparin, a prototype of hypersulfated heparan sulfate present in Alzheimer's disease (Sepulveda-Diaz JE et al., Brain. 2015 May; 138 (Pt 5): 1339-54).

[0016] The anionic lipid oligosaccharides of the present invention have been found to be useful in the treatment of pathologies associated with abnormal tau protein hyperphosphorylation, in particular in the treatment of Alzheimer's disease, and have been found to be capable of halting or slowing the progression of the disease.

[0017] These anionic lipid oligosaccharides mimic certain properties of heparan sulfate. A team of biologists from Gly-CRRET (Holmes BB et al., Proc Natl Acad Sci USA. 2013 Aug 13; 110(33); Sepulveda-Diaz JE et al., Brain. 2015 May; 138(Pt 5): 1339-54; Maiza A et al, FEBS Lett. 2018 Dec; 592(23): 3806-3818) and other teams around the world (Goedert M et al., Nature. 1996 Oct 10; 383(6600): 550-3; Zhao J et al., Biophys J. 2017 Mar 14; 112(5): 921-932) have shown that heparan sulfate is important for the development and progression of diseases.

[0018] [ka]

[0019] Heparan sulfate is a copolymer of uronic acid (D-glucuronic acid or L-iduronic acid) and D-glucosamine, which is N-acetylated and may contain sulfation sites.

[0020] The Gly-CRRET laboratory has notably shown that the conformational changes in tau that allow for its abnormal hyperphosphorylation and aggregation in neurons result from the protein's interaction with heparan sulfate (HS) chains internalized in neurons of diseased subjects. By acting as a molecular chaperone, HS allows the tau protein to obtain a conformation that favors kinase attack, which leads to the abnormal hyperphosphorylation and aggregation of the protein (Figure 1).

[0021] In addition, studies performed by Gly-CRRET and other teams have shown that HS is a receptor for tau aggregates (proteopathic seeds) on the cell surface and is centrally involved in the transfer of tau fibrils from diseased to healthy cells, a process known as propagation (Holmes BB et al.,Proc Natl Acad Sci USA.2013 Aug 13;110(33)), which is now thought to be responsible for disease spread between cells and different brain regions. The presence of HS in tau inclusions in vivo and their ability to cause phosphorylation, aggregation and propagation of abnormal tau suggests a central role for such polysaccharides in the establishment and progression of neurodegenerative processes.

[0022] Anionic lipid oligosaccharides The compounds of the present invention, or useful in the context of the present invention, have the following formula (I): [ka] [In the formula, L is a -C(=O)NH-, -C(=O)O- or -C(=O)S- group; R1 is a linear or branched, saturated or unsaturated hydrocarbon chain containing 15, 16, 17 or 18 carbon atoms, optionally substituted at the terminal position by a group selected from -OH, -OR, -NH2, -NHR, -NRR', -COOH, -COOR, -CONHR, -CONRR' and -SR, where R and R' independently represent an alkyl group containing 1 to 6 carbon atoms; R4 is represented by formula (IIa) or (IIb): [ka] [In the formula, R9 and R 10 are each independently a hydrogen atom or a sulfonic acid group in ionized form, R 12 is an alkyl group containing 1 to 6 carbon atoms, R 11 -CH2-OR5 or -CONHR 13 It is based on R5 is a hydrogen atom or an ionized sulfonic acid group; R 13 is an alkyl group containing 1 to 6 carbon atoms. Based on R2, R3, R6, R7 and R8 are each independently a hydrogen atom or an ionized sulfonic acid group; R2, R3, R5, R6, R7, R8, R9 and R 10 At least one of the groups R2, R3, R5, R6, R7, R8, R9 and R 10 At least two of the groups are sulfonic acid groups in ionized form. It is a compound of the formula:

[0023] More specifically, the compounds of the present invention, or useful in the context of the present invention, have the following formula (I): [ka] [In the formula, L is a -C(=O)NH-, -C(=O)O- or -C(=O)S- group; R1 is a linear or branched, saturated or unsaturated hydrocarbon chain containing 15, 16, 17 or 18 carbon atoms, optionally substituted at the terminal position by a group selected from -OH, -OR, -NH2, -NHR, -NRR', -COOH, -COOR, -CONHR, -CONRR' and -SR, where R and R' independently represent an alkyl group containing 1 to 6 carbon atoms; R2 is a hydrogen atom or an ionized sulfonic acid group; R3 is a hydrogen atom or an ionized sulfonic acid group; R4 is represented by formula (IIa): [ka] [Wherein, R9 and R 10 are each independently a hydrogen atom or a sulfonic acid group in ionized form. Based on R5, R7 and R8 are each independently a hydrogen atom or an ionized sulfonic acid group; R6 is a hydrogen atom or an ionized sulfonic acid group; R2, R3, R5, R6, R7, R8, R9 and R 10 At least one of the groups R2, R3, R6, R7, R8, R9 and R 10 At least two of the groups are sulfonic acid groups in ionized form. It is a compound of the formula:

[0024] The expression "sulfonic acid group in ionized form" refers to a -SO3- group.

[0025] The compounds of formula (I) are preferably in the form of a salt, in particular in the form of a sodium salt, and therefore the ionized form of the sulfonic acid group is preferably the sodium sulfonate group (-SO3Na).

[0026] In some embodiments, the compound of formula (I) has 2, 3, 4, 5, 6, 7, or 8 sulfonic acid groups in ionized form. Thus, R2, R3, R5, R6, R7, R8, R9, and R 10 groups are sulfonic acid groups in ionizable form. However, because highly charged compounds can induce toxicity, compounds containing two or three ionizable sulfonic acid groups may be preferred.

[0027] In some embodiments, L is a -C(=O)NH- group.

[0028] In some embodiments, compounds of the present invention, or useful in the context of the present invention, have the following formula (Ia): [ka] [In the formula, R1 to R8 are as defined above, and R2, R3, R5, R6, R7, R8, R9 and R 10 At least one of the groups R2, R3, R5, R6, R7, R8, R9 and R 10 At least two of the groups are sulfonic acid groups in ionized form. has.

[0029] In some embodiments, compounds of the present invention, or useful in the context of the present invention, have the following formula (Ib): [ka] [Wherein, R1 to R3 and R5 to R 10 are as described above or as follows, and R2, R3, R5, R6, R7, R8, R9 and R 10 At least one of the groups R2, R3, R5, R6, R7, R8, R9 and R 10 At least two of the groups are sulfonic acid groups in ionized form. has.

[0030] In formula (I), formula (Ia) and formula (Ib), R1 is preferably a linear saturated hydrocarbon chain containing 15, 16, 17 or 18 carbon atoms, preferably 16 or 18 carbon atoms.

[0031] In formula (I), formula (Ia) and formula (Ib), R2, R3 and R 10 is preferably a hydrogen atom.

[0032] In formulae (I), (Ia) and (Ib), R5 is preferably an ionized sulfonic acid group, and R6, R7 and R8 are hydrogen atoms.

[0033] In formula (I), formula (Ia) and formula (Ib), R9 is preferably a sulfonic acid group in ionized form.

[0034] In some embodiments, compounds of the present invention, or useful in the context of the present invention, have the following formula (Ib): [ka] [In the formula, R1 is a linear saturated hydrocarbon chain containing 15, 16, 17 or 18 carbon atoms, preferably 16 or 18 carbon atoms; R2, R3, R6, R7, R8 and R 10 is a hydrogen atom, or R2, R3, R6, R7, R8 and R 10 is a sulfonic acid group in ionized form, and the other groups are hydrogen atoms; R5 and R9 are sulfonic acid groups in ionized form. has.

[0035] In some embodiments, compounds of the present invention, or useful in the context of the present invention, have the following formula (Ib): [ka] [In the formula, R1 is a linear saturated hydrocarbon chain containing 15, 16, 17 or 18 carbon atoms, preferably 16 or 18 carbon atoms; R2, R3, R6, R7, R8 and R 10 is a hydrogen atom, R5 and R9 are sulfonic acid groups in ionized form. has.

[0036] In some embodiments, compounds of the present invention, or useful in the context of the present invention, have the following structure (Ic): [ka] [Wherein, R1 to R3 and R5 to R 10 is as above.] has.

[0037] In some embodiments, compounds of the present invention, or useful in the context of the present invention, have the following structure (Id): [ka] [In the formula, R1, R2, R3, R6~R8 and R 10 is as above.] has.

[0038] In some embodiments, compounds of the present invention, or useful in the context of the present invention, have the following structure (Ie): [ka] [Wherein, R1 to R3 and R5 to R 10 is as above.] has.

[0039] In some embodiments, compounds of the present invention, or useful in the context of the present invention, have the following structure (If): [ka] [In the formula, R1, R2, R3, R6~R8 and R10 is as above.] has.

[0040] In some embodiments, compounds of the present invention, or useful in the context of the present invention, have the following structure (Ig): [ka] [Wherein, R1 to R3 and R5 to R 10 is as above.] has.

[0041] In some embodiments, compounds of the present invention, or useful in the context of the present invention, have the following structure (Ih): [ka] [In the formula, R1, R2, R3, R6~R8 and R 10 is as above.] has.

[0042] In some embodiments, the compound of the invention is a compound of formula (I), with the proviso that the compound is not sodium hexadecyl D-lactobionamide (2,5) sulfate, i.e., sodium hexadecyl D-lactobionamide disulfate, sodium hexadecyl D-lactobionamide trisulfate, and mixtures thereof.

[0043] Non-limiting examples of compounds of formula (I) include compounds of formula (I) shown in Table 1 in the Examples section.

[0044] Process for preparing compounds of formula (I) The following diagrams and procedures illustrate synthetic routes to compounds of formula (I) and should not be construed as limiting.

[0045] The compounds of formula (I) can be prepared in three steps from a disaccharide (e.g., maltose, cellobiose or lactose). The process comprises the following steps: (Step 1) Oxidation of the anomeric position of the disaccharide (Step 2) Synthesis and aminolysis of methyl esters to graft hydrocarbon chains (R1) under solvent-free conditions by mechanosynthesis (Step 3) Selective sulfation or oversulfation of primary hydroxyl groups

[0046] Such a process is illustrated in the following reaction diagram (Diagram 1), where the disaccharide is maltose, it being understood that maltose can be replaced by any suitable disaccharide.

[0047] [ka]

[0048] Diagram 1: Route to synthesis of compound of formula (I) from maltose

[0049] Step 1 : The anomeric position of the disaccharide can be oxidized according to well-known methods, such as method A described in ACS Sustainable Chemistry & Engineering 2016, 4(4), 2432-2438.

[0050] Alternatively, sodium maltobionate can be prepared by photocatalysis (Omri M. et al., ACS Catalysis 2018) with the same conversion: >99% and selectivity: >95% (estimated by NMR).

[0051] Step 2: One-pot synthesis of N-alkyl D-maltobionamide derivatives It is produced by a solvent-free mechanosynthesis process: potassium glycobionate is ground in a ball mill in the presence of a supported acid catalyst (H2SO4 / SiO2) and methanol (the exact amount required for methylation of the carboxylic acid formed), then in a second step an alkylamine is added after total conversion of glycobionic acid to an ester. Quantitative conversions in step 2 are typically greater than 85%, which can be obtained for both steps.

[0052] Step 3 : The sulfation step is carried out in pyridine medium in the presence of the sulfating agent, SO3-pyridine, according to literature protocols (Tetrahedron. 2010 Apr 17;66(16):2907-2918).

[0053] Hereinafter, the expression "a compound of formula (I)" means a compound of formula (I) above, including the compounds described in the "Examples" section. The expression "a compound of formula (I)" means one compound of formula (I) or a mixture of two or more compounds of formula (I).

[0054] therapeutic use It has been found that the compound of formula (I) effectively protects tau protein from abnormal heparin-induced hyperphosphorylation, weakly induces tau protein phosphorylation, and reduces heparin-induced aggregation of tau protein.Therefore, the compound of formula (I) has been proven to be useful in medicine, in particular in the treatment of pathologies associated with abnormal hyperphosphorylation or phosphorylation of tau protein (tauopathy), in particular in the treatment of Alzheimer's disease.The compound of formula (I) acts by inhibiting the abnormal phosphorylation of tau, not by inhibiting kinases, but by protecting tau from these attacks before the process of aggregation and propagation of aggregates.

[0055] The present invention therefore relates to compounds of formula (I) for use in medicine or formulated separately as a medicament.

[0056] More particularly, the present invention relates to compounds of formula (I) for use in the treatment of pathologies associated with abnormal hyperphosphorylation or phosphorylation of tau protein, commonly referred to as "tauopathies." Non-limiting examples of tauopathies include Alzheimer's disease, frontotemporal dementia with parkinsonism on chromosome 17 (FTDP-17), Pick's disease, corticobasal degeneration, and progressive supranuclear palsy (PSP).

[0057] Thus, in certain embodiments, the present invention relates to a compound of formula (I) for use in the treatment of Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease, corticobasal degeneration or progressive supranuclear palsy. In certain embodiments, the present invention relates to a compound of formula (I) for use in the treatment of Alzheimer's disease.

[0058] The present invention also relates to the use of a compound of formula (I) for the preparation of a medicament useful in the treatment of pathologies associated with abnormal hyperphosphorylation or phosphorylation of tau protein (tauopathies), in particular in the treatment of Alzheimer's disease.

[0059] Pharmaceutical Compositions The present invention also relates to pharmaceutical compositions (particularly medicaments) comprising a compound of formula (I) and one or more excipients (particularly one or more pharma- ceutically acceptable excipients), and to the use thereof in the abovementioned therapeutic applications.

[0060] The term "pharmaceutically acceptable" refers to something that is known to be non-toxic and can be used in pharmaceuticals. Pharmaceutically acceptable excipients are well known in the medical literature.

[0061] Excipients are selected according to the desired pharmaceutical form and mode of administration, and such excipients are well known to those skilled in the art.

[0062] Pharmaceutical compositions according to the invention may be administered parenterally, for example intravenously or intradermally, or topically, orally or nasally.

[0063] Parenterally administrable forms include aqueous suspensions, isotonic saline or sterile injection solutions, which may contain pharmacologically compatible dispersants and / or wetting agents. Orally administrable forms include dispersible, orodispersible, effervescent or soluble tablets, soft or hard capsules, powders, granules, as well as oral solutions and oral suspensions. Nasally administrable forms include aerosols. Topically administrable forms include patches, gels, creams, ointments, lotions, sprays, and eye drops. Preferably, the compounds or compositions of the present invention are administered orally or parenterally, particularly intravenously.

[0064] The present invention also relates to a method of treating the above-mentioned conditions, comprising administering to a subject in need thereof an effective dose of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharma- ceutically acceptable excipients.

[0065] The effective dosage of a compound of formula (I) will vary depending on a number of parameters, such as the selected route of administration, the body weight, age, sex, the severity of the condition being treated, and the susceptibility of the individual being treated.

[0066] The following examples are offered for illustrative purposes and should in no way be construed as limiting the invention. EXAMPLES

[0067] I. Test Compounds The test compounds are presented in Table 1 below.

[0068] [Table 1] JPEG2024543187000020.jpg251162

[0069] II. Synthesis of Test Compounds II-1. Chemical Materials and Methods a) Reagents and solvents Reagents used were manufactured by Merck, Acros or Alfa Aesar and were used without purification. Solvents were purchased in anhydrous form or diluted under an inert atmosphere and prepared over 3 or 4 Angstrom molecular sieves.

[0070] b) Ball mill The reaction is carried out in a Fritsch Pulverisette Premium 7 (P7PL) planetary mill equipped with two 20 mL bowls each containing 80 zirconia (ZrO2) balls with a diameter of 5 mm.

[0071] c) Chromatography Thin Layer Chromatography (TLC) Thin-layer chromatography was performed using normal phase ALUGRAM® XtraSIL G / UV 254 Aluminum support or reversed phase: ALUGRAM® RP-18 / UV 254 The technique used to reveal the products after elution was 4% H2SO4 / EtOH or cerium(IV) molybdate: (NH4)4Ce(SO4).2H2O, (NH4)6Mo7O 24 .4H2O, H2SO4, H2O (2.1 g / 5.3 g / 12 mL / 188 mL) and then heated.

[0072] Automated Flash Chromatography Automated flash purification was carried out with a Grace flash instrument (Reveleris® iES FlashSystem). Separation is carried out using commercially available prepacked normal or C18 silica columns (4 g, 12 g, 24 g, 40 g, 80 g). It is possible to carry out purification in normal or reversed phase. The mass of the crude product corresponds to a maximum of 10% of the silica of the prepacked column. The instrument is equipped with a light diffusion detector (LDD) with two wavelength settings and a UV detector.

[0073] d) Compound characterization specific rotation The specific rotation was measured using a Perkin-Elmer 343 polarimeter emitting polarized light at λ=549 nm (sodium D line) at a temperature of 20° C. The concentrations c are expressed in grams per 100 mL of solvent.

[0074] Low resolution mass spectrometry Low-resolution mass spectrometry analysis was carried out on a single quadrupole instrument (Micromass-Waters ZQ) with an electrospray ionization source (Z-spray). This instrument allows analysis in positive or negative ionization mode. The capillary voltage was 3.5 kV and the cone voltage varied from 20 to 120 V. The source temperature was 80 °C and the desolvation temperature was 150 °C. The desolvation and nebulization gas was nitrogen.

[0075] High resolution mass spectrometry High resolution mass spectrometry (HRMS) analysis was carried out on a hybrid quadrupole time-of-flight mass spectrometer (Micromass-Waters Q-TOF Ultima Global) equipped with an electrospray ionization source. The source temperature is 80 °C and the desolvation temperature is 120 °C. The gas used for nebulization and desolvation is nitrogen with flow rates of 20 L / h and 500 L / h, respectively. The capillary voltage is 3.5 kV and the cone voltage varies from 100 to 250 V. Calibration is always performed with orthophosphoric acid before the exact mass measurement. As the accuracy of the exact mass measurement by Q-TOF is less than 5 ppm, it is possible to arrive at the elemental composition of the molecules.

[0076] NMR spectroscopy 1 H and 13 C NMR spectra were generated on a Bruker Advance 400 or 600 MHz spectrometer. 1 H NMR spectra were measured at 400 MHz or 600 MHz. 13C NMR spectra are recorded at 101 MHz or 150 MHz. All experiments are carried out at temperatures close to 25° C. and with deuterated solvents, which also act as references. Chemical shifts are given in ppm and coupling constants in Hertz. NMR spectra are processed using MestReNova.

[0077] Carbon Numbering [ka]

[0078] II-2 Synthesis of Maltobionamide Sulfate Maltobionamide sulfate containing compounds of formula (I) were prepared according to diagram (1) presented herein, except where otherwise specified.

[0079] II.2 a). Procedure for the synthesis of potassium glycobionate A 5% aqueous solution of the disaccharide (250 mg in 5 mL MilliQ water) is placed in a 10 mL microwave tube from CEM, then 2 equivalents of K2CO3 and 2.5 mg of Au / Al2O3 catalyst, prepared according to the protocol described in ACS Sustainable Chem. Eng., 2016, 4, 2432-2438, are added, and the mixture is subjected to ultrasonication to homogenize. Then 1.8 equivalents of 30% H2O2 in water are added, and the mixture is then placed in a CEM Discover microwave device and irradiated at 60°C for 20 minutes using the Dynamic program. The catalyst is then filtered through 0.25 μm PVDF or removed by centrifugation. The filtrate is then freeze-dried and the crude reaction product is 1 The total conversion of aldoses to aldonic acids is monitored by H NMR. The reaction can be carried out in a 35 mL tube for 1 g of disaccharide with a reaction time of 50-70 min depending on the disaccharide.

[0080] Potassium D-Maltobionate (Mal)

[0081] [ka]

[0082] Quantitative yield Appearance: pure white Molecular formula: C 12 H 21 KO 12 MM: 396.39 g.mol -1 ESI-MS: [M-K] - m / z 357 Da 1 H NMR(400 MHz, D2O): δ 5.20 (d, J = 3.9 Hz, 1H, H-1’), 4.17 (dd, J = 6.2, 2.6 Hz, 1H, H-3), 4.13 (d, J = 2.7 Hz, 1H, H-2), 4.03 (dt, J = 7.7, 3.7 Hz, 1H, H-5), 3.98 - 3.89 (m, 2H, H-5’, H-4), 3.89 - 3.80 (m, 3H, 1H-6’a, H-6’b, H-6a), 3.77 (dd, J = 9.2, 9.9 Hz, 1H, H-3’), 3.71 (dd, 1H, J = 11.9, 7.8 Hz, H-6b), 3.59 (dd, J = 9.9, 3.8 Hz, 1H, H-2’), 3.47 (dd, J = 9.1, 10.1 Hz, 1H, H-4’). 13 C NMR(101 MHz, D2O): δ 178.2 (C-1), 100.4 (C-1’), 82.4 (C-4), 73.0 (C-3’), 72.6 (C-2), 72.5 (C-3), 72.4 (C-5), 72.3 (C-5’), 71.8 (C-2’), 69.3 (C-4’), 62.1 (C-6), 60.4 (C-6’).

[0083] Potassium D-cellobionate (Cell)

[0084]

Chem.

[0085] Quantitative yield Appearance: pure white Molecular formula: C 12 H 21 KO12 MM:396.39 g.mol -1 ESI-MS:[MK] - m / z 357 Da 1 H NMR(400MHz,D2O):δ 4.63(d,J=7.9Hz,1H,H-1'),4.16(d,J=3.0Hz,1H,H-2),4.09(dd,J=5.4,3.0Hz,1H, H-3),4.05-3.94(m,2H,H-4,H-5),3.91(dd,J=12.4,2.1Hz,1H,H-6'a),3.85(dd,J=1 2.0,3.1Hz,1H,H-6a),3.78-3.71(m,2H,H-6b,H-6'b),3.52(t,J=9.0Hz,1H,H-3'), 3.49-3.44(m,1H,H-5'),3.44-3.38(m,1H,H-4'),3.35(dd,J=9.4,7.9Hz,1H,H-2'). 13 C NMR(101MHz,D2O):δ 178.4(C-1),103.0(C-1'),81.8(C-4),76.0(C-5'),75.6(C-3'),73.4(C-2' ),72.4(C-2),71.8(C-5),71.6(C-3),69.5(C-4'),61.9(C-6),60.6(C-6').

[0086] Potassium D-lactobionate (Lac)

[0087]

change

[0088] Quantitative yield Appearance: pure white Molecular formula: C 12 H 21 KO 12 MM:396.39 g.mol -1 ESI-MS:[MK] - m / z 357 Da 1H NMR(400MHz,D2O):δ 4.59(d,J=7.8Hz,1H,H-1'),4.20(d,J=2.9Hz,1H,H-2),4.13(dd,J=5.3,2 .9Hz,1H,H-3),4.06-3.97(m,2H,H-4,H-5),3.94(d,J=3.4Hz,1H,H-4'),3. 88(dd,J=12.0,3.1Hz,1H,H-6a),3.84-3.72(m,4H,H-6'a,H-6b,H-6'b,H-5 '),3.70(dd,J=10.0,3.4Hz,1H,H-3'),3.59(dd,J=10.0,7.8Hz,1H,H-2'). 13 C NMR(101MHz,D2O):δ 178.5(C-1),103.5(C-1'),81.7(C-4),75.3(C-5'),72.6(C-3'),72.5(C-2) ,71.8(C-5),71.6(C-3),71.1(C-2'),68.7(C-4'),61.9(C-6),61.1(C-6').

[0089] II.2 b). Protocol for the synthesis of N-alkyl-D-glycobionamides via methyl D-glycobionate One gram of crude reacted potassium glycobionate supported on commercial 22% silica (H2S04 / SiO2) and 1.1 eq (approximately 1 g) of sulfuric acid are placed in a 20 mL zirconia bowl with 80 zirconia (ZrO2) balls with a diameter of 5 mm. One milliliter of methanol is added and the mixture is milled in a P7PL for 8 cycles of 5 min at 500 rpm. The reaction is then monitored in normal phase by thin layer chromatography (TLC) (eluent: ethyl acetate / methanol / water 7 / 2 / 1). An amine (1.5 eq.) is then added to the reaction medium in the bowl, followed by 2 mL of methanol. The milling is continued for 12 x 5 min at 500 rpm. The reaction is again monitored by TLC with the same eluent. Once the reaction is complete, the reaction medium is left to dry at room temperature. This re-milled powder is then mixed with unmilled silica and subjected to purification by flash chromatography using the same eluent as for the monitoring of the reaction. The fractions containing glycobionamide are concentrated by rotary evaporation and then lyophilized.

[0090] N-Tetradecyl-D-maltobionamide (Mal14)

[0091]

Chem.

[0092] Yield: 93% Appearance: pure white Molecular formula: C 26 H 51 NO 11 MM: 553.68 g·mol -1 1 1H NMR (400 MHz, pyridine-d5): δ 8.23 (t, 1H, J = 6.0 Hz, NH), 5.76 (d, 1H, J = 3.9 Hz, H-1’), 5.25 (dd, 1H, J = 2.0 Hz, J = 5.3 Hz, H-3), 5.12 (d, 1H, J = 1.8 Hz, H-2), 4.76 (t, 1H, J = 5.0 Hz, H-4), 4.74 - 4.67 (m, 2H, H-5, H-5’), 4.60 (t, 1H, J = 9.2 Hz, H-3’), 4.54 (dd, 1H, J = 1.9 Hz, J = 11.5 Hz, H-6’a), 4.40 (dd, 1H, J = 4.7 Hz, J = 11.3 Hz, H-6a), 4.37 - 4.28 (m, 2H, H-6b, H-6’b), 4.19 (dd, 1H, J = 3.9 Hz, J = 9.5 Hz, H-2’), 4.15 (t, 1H, J = 9.5 Hz, H-4’), 3.55 - 3.40 (m, 2H, C H 2-NH), 1.54 (p, 2H, J = 7.2 Hz, C H 2-CH2-NH), 1.33 - 1.12 (m, 22H, CH2 alkyl chain), 0.88 (t, 3H, J = 6.6 Hz, CH3) 13 13C NMR (101 MHz, pyridine-d5): δ 174.0 (C-1), 103.4 (C-1’), 85.5 (C-4), 75.9 (C-3’), 75.6 (C-5’ ’), 74.8 (C-5), 74.4 (C-2’), 74.3 (C-2), 74.1 (C-3), 72.4 (C-4’), 64.8 (C-6), 63.1 (C-6’), 39.9 ( C H2-NH), 32.6 - 23.4 (CH2 alkyl chain), 14.8 (CH3).

[0093] N-Hexadecyl-D-maltobionamide (Mal16)

[0094] [Chemical formula]

[0095] Yield: 71% Appearance: Pure white Molecular formula: C 28 H 55 NO 11 MM: 581.74 g.mol -1 Yield: 0.72 (EtOAc / MeOH / H2O: 7 / 2 / 1) [α]D 20 : +71.4° (MeOH, c = 0.5) ESI-HRMS: [M+Na] + 604.3663 (calculated value: C 28 H 55 NO 11 for Na 604.3673) 11H NMR (600 MHz, pyridine-d5): δ 8.25 (t, 1H, J = 5.3 Hz, NH), 5.78 (d, 1H, J = 3.9 Hz, H-1’), 5.25 (dd, 1H, J = 2.0 Hz, J = 5.3 Hz, H-3), 5.13 (d, 1H, J = 1.8 Hz, H-2), 4.77 (t, 1H, J = 5.0 Hz, H-4), 4.73 - 4.69 (m, 2H, H-5, H-5’), 4.59 (t, 1H, J = 9.2 Hz, H-3’), 4.53 (dd, 1H, J = 1.9 Hz, J = 11.5 Hz, H-6’a), 4.38 (dd, 1H, J = 4.7 Hz, J = 11.3 Hz, H-6a), 4.34 - 4.29 (m, 2H, H-6b, H-6’b), 4.18 (dd, 1H, J = 3.9 Hz, J = 9.5 Hz, H-2’), 4.14 (t, 1H, J = 9.5 Hz, H-4’), 3.52 - 3.40 (m, 2H, C H 2-NH), 1.53 (p, 2H, J = 7.2 Hz, C H 2-CH2-NH), 1.29 - 1.16 (m, 26H, CH2 alkyl chain), 0.87 (t, 3H, J = 6.6 Hz, CH3) 13 13C NMR (151 MHz, pyridine-d5): δ 173.8 (C-1), 103.3 (C-1’), 85.3 (C-4), 75.8 (C-3’), 75.5 (C-5’ ’ ), 74.7 (C-5), 74.3 (C-2’), 74.2 (C-2), 74.0 (C-3), 72.3 (C-4’), 64.6 (C-6), 63.0 (C-6’), 39.8 ( C H2-NH), 32.5 - 23.3 (CH2 alkyl chain), 14.6 (CH3).

[0096] N-Octadecyl-D-Maltobionamide (Mal18)

[0097]

Chemical Structure

[0098] Yield: 87% Appearance: Pure white Molecular formula: C 30 H 59 NO 11 MM: 609.80 g / mol -1 Yield: 0.71 (EtOAc / MeOH / H2O: 7 / 2 / 1). [α]D 20 : +70.8 (MeOH, c = 0.5) ESI-HRMS: [M+Na] + 632.3980 (calculated for C 30 H 59 NO 11 Na is 632.3986) 1 H NMR (600 MHz, pyridine-d5): δ 8.23 (t, 1H, J = 5.5 Hz, NH), 5.77 (d, 1H, J = 4.0 Hz, H-1’), 5.26 (dd, 1H, J = 2.2 Hz, J = 5.6 Hz, H-3), 5.13 (d, 1H, J = 2.1 Hz, H-2), 4.77 (t, 1H, J = 4.9 Hz, H-4), 4.74 - 4.69 (m, 2H, H-5, H-5’), 4.60 (t, 1H, J = 9.2 Hz, H-3’), 4.53 (dd, 1H, J = 2.2 Hz, J = 11.6 Hz, H-6’a), 4.39 (dd, 1H, J = 4.8 Hz, J = 11.3 Hz, H-6a), 4.35 - 4.30 (m, 2H, H-6b, H-6’b), 4.18 (dd, 1H, J = 4.0 Hz, J = 9.5 Hz, H-2’), 4.15 (t, 1H, J = 9.5 Hz, H-4’), 3.52 - 3.41 (m, 2H, C H 2-NH), 1.56 - 1.51 (m, 2H, C H 2-CH2-NH), 1.29 - 1.17 (m, 30H, CH2 alkyl chain), 0.87 (t, 3H, J = 6.8 Hz, CH3) 13 C NMR (151 MHz, pyridine-d5): δ 173.8 (C-1), 103.3 (C-1’), 85.4 (C-4), 75.8 (C-3’), 75.5 (C-5’), 74.7 (C-5), 74.3 (C-2’), 74.2 (C-2), 74.0 (C-3), 72.3 (C-4’), 64.6 (C-6), 63.0 (C-6’), 39.8( C H2-NH), 32.5 - 23.3 (CH2 alkyl chain), 14.6 (CH3).

[0099] N-Nonadecyl-D-maltobionamide (Mal19)

[0100]

Chem.

[0101] Yield: 69% Appearance: Pure white Molecular formula: C 31 H 61 NO 11 MM: 623.82 g·mol -1 1 1H NMR (400 MHz, pyridine-d5): δ 8.22 (t, 1H, J = 5.5 Hz, NH), 5.78 (d, 1H, J = 4.0 Hz, H-1’), 5.25 (dd, 1H, J = 2.2 Hz, J = 5.6 Hz, H-3), 5.13 (d, 1H, J = 2.1 Hz, H-2), 4.77 (t, 1H, J = 4.9 Hz, H-4), 4.74 - 4.67 (m, 2H, H-5, H-5’), 4.60 (t, 1H, J = 9.2 Hz, H-3’), 4.55 (dd, 1H, J = 2.2 Hz, J = 11.6 Hz, H-6’a), 4.40 (dd, 1H, J = 4.8 Hz, J = 11.3 Hz, H-6a), 4.37 - 4.28 (m, 2H, H-6b, H-6’b), 4.20 (dd, 1H, J = 4.0 Hz, J = 9.5 Hz, H-2’), 4.15 (t, 1H, J = 9.5 Hz, H-4’), 3.55 - 3.40 (m, 2H, C H 2-NH), 1.58 - 1.51 (m, 2H, C H 2-CH2-NH), 1.35 - 1.14 (m, 30H, CH2 alkyl chain), 0.88 (t, 3H, J = 6.8 Hz, CH3) 13 13C NMR (101 MHz, pyridine-d5): δ 173.9 (C-1), 103.4 (C-1’), 85.5 (C-4), 75.9 (C-3’), 75.6 (C-5’), 74.8 (C-5), 74.4 (C-2’), 74.3 (C-2), 74.1 (C-3), 72.4 (C-4’), 64.7 (C-6), 63.1 (C-6’), 39.9( CH2-NH), 32.6 - 23.1 (CH2 alkyl chain), 14.5 (CH3).

[0102] N-Eicosanyl-D-Maltobionamide (Mal20)

[0103]

Chem.

[0104] Yield: 38% Appearance: Pure white Molecular formula: C 32 H 63 NO 11 MM: 637.84 g.mol -1 1 1H NMR (400 MHz, pyridine - d5): δ 8.25 (t, 1H, J = 5.5 Hz, NH), 5.78 (d, 1H, J = 4.0 Hz, H - 1’), 5.25 (dd, 1H, J = 2.2 Hz, J = 5.6 Hz, H - 3), 5.13 (d, 1H, J = 2.1 Hz, H - 2), 4.79 (t, 1H, J = 4.9 Hz, H - 4), 4.76 - 4.68 (m, 2H, H - 5, H - 5’), 4.61 (t, 1H, J = 9.2 Hz, H - 3’), 4.56 (dd, 1H, J = 2.2 Hz, J = 11.6 Hz, H - 6’a), 4.38 (dd, 1H, J = 4.8 Hz, J = 11.3 Hz, H - 6a), 4.44 - 4.27 (m, 2H, H - 6b, H - 6’b), 4.19 (dd, 1H, J = 4.0 Hz, J = 9.5 Hz, H - 2’), 4.15 (t, 1H, J = 9.5 Hz, H - 4’), 3.55 - 3.40 (m, 2H, C H 2 - NH), 1.59 - 1.50 (m, 2H, C H 2 - CH2 - NH), 1.37 - 1.11 (m, 30H, CH2 alkyl chain), 0.88 (t, 3H, J = 6.8 Hz, CH3) 1313C NMR (101 MHz, pyridine-d5): δ 173.9 (C-1), 103.4 (C-1’), 85.4 (C-4), 75.9 (C-3’), 75.6 (C-5’), 74.8 (C-5), 74.4 (C-2’), 74.3 (C-2), 74.1 (C-3), 72.4 (C-4’), 64.7 (C-6), 63.1 (C-6’), 39.9( C H2-NH), 32.4 - 23.4 (CH2 alkyl chain), 14.7 (CH3).

[0105] N-Tetradecyl-D-cellobionamide (Cell14)

[0106]

Chem.

[0107] Yield: 74% Appearance: pure white Molecular formula: C 26 H 51 NO 11 MM: 553.68 g.mol -1 1 1H NMR (400 MHz, pyridine-d5): δ 8.31 (t, 1H, J = 5.9 Hz, NH), 5.35 (t, 1H, J = 3.2 Hz, H-3), 5.29 (d, 1H, J = 2.9 Hz, H-2), 5.27 (d, 1H, J = 7.9 Hz, H-1’), 4.83 - 4.79 (m, 2H, H-4, H-5), 4.53 - 4.47 (m, 3H, H-6a, H-6b, H-6a’), 4.23 (dd, 1H, J = 6.7 Hz, J = 11.8 Hz, H-6b’), 4.19 (t, 1H, J = 8.9 Hz, H-3’), 4.06 (t, J = 8.7 Hz, 2H, H-2’, H-4’), 4.01 - 3.96 (m, 1H, H-5’), 3.53 - 3.37 (m, 2H, C H 2-NH), 1.56 - 1.50 (m, 2H, C H 2-CH2-NH), 1.28 - 1.09 (m, 22H, CH2 alkyl chain), 0.88 (t, 3H, J = 6.8 Hz, CH3) 1313C NMR (101 MHz, pyridine-d5): δ 174.8 (C-1), 106.5 (C-1’), 84.3 (C-4), 79.2 (C-5’), 78.9 (C-3’), 76.0 (C-2’), 73.9 (C-5), 73.4 (C-2), 73.3 (C-3), 72.2 (C-4’), 65.2 (C-6), 63.4 (C-6’), 40.0( C H2-NH), 32.6 - 23.4 (CH2 alkyl chain), 14.6 (CH3).

[0108] N-Hexadecyl-D-cellobionamide (Cell16)

[0109]

Chem.

[0110] Yield: 92% Appearance: pure white Molecular formula: C 28 H 55 NO 11 MM: 581.74 g.mol -1 Yield: 0.72 (EtOAc / MeOH / H2O: 7 / 2 / 1) [α]D 20 : +13.8° (MeOH, c = 0.5) ESI-HRMS: [M + H] + 582.3861 (calculated value: C 28 H 55 NO 11 for 582.3853) 11H NMR (600 MHz, pyridine-d5): δ 8.30 (t, 1H, J = 5.9 Hz, NH), 5.34 (t, 1H, J = 3.2 Hz, H-3), 5.27 (d, 1H, J = 2.9 Hz, H-2), 5.26 (d, 1H, J = 7.9 Hz, H-1’), 4.83 - 4.79 (m, 2H, H-4, H-5), 4.53 - 4.47 (m, 3H, H-6a, H-6b, H-6a’), 4.22 (dd, 1H, J = 6.7 Hz, J = 11.8 Hz, H-6b’), 4.19 (t, 1H, J = 8.9 Hz, H-3’), 4.04 (t, J = 8.7 Hz, 2H, H-2’, H-4’), 3.99 - 3.94 (m, 1H, H-5’), 3.49 - 3.38 (m, 2H, C H 2-NH), 1.55 - 1.48 (m, 2H, C H 2-CH2-NH), 1.27 - 1.15 (m, 26H, CH2 alkyl chain), 0.87 (t, 3H, J = 6.8 Hz, CH3) 13 13C NMR (151 MHz, pyridine-d5): δ 174.7 (C-1), 106.4 (C-1’), 84.2 (C-4), 79.1 (C-5’), 78.8 (C-3’), 75.9 (C-2’), 73.8 (C-5), 73.3 (C-2), 73.2 (C-3), 72.1 (C-4’), 65.1 (C-6), 63.3 (C-6’), 39.9( C H2-NH), 32.5 - 23.3 (CH2 alkyl chain), 14.6 (CH3).

[0111] N-Octadecyl-D-cellobionamide (Cell18)

[0112]

Chemical Structure

[0113] Yield: 97% Appearance: pure white Molecular formula: C 30 H 59 NO 11 MM: 609.41 g.mol -1 Yield: 0.75 (EtOAc / MeOH / H2O: 7 / 2 / 1) [α]D 20 :+14.8° (MeOH, c = 0.5) ESI-HRMS: [M + H] + 610.4175 (calculated value: C 30 H 60 N 11 for 610.4166) 1 1H NMR (400 MHz, pyridine-d5): δ 8.31 (t, J = 5.7 Hz, 1H, NH), 5.34 (br s, 1H, H-3), 5.30 - 5.23 (m, 2H, H-2, H-1’), 4.84 - 4.78 (m, 2H, H-4, H-5), 4.57 - 4.45 (m, 3H, H-6a, H-6b, H-6a’), 4.23 (dd, 1H, J = 6.4 Hz, J = 11.8 Hz, H-6b’), 4.19 (t, 1H, J = 8.8 Hz, H-3’), 4.04 (t, J = 8.3 Hz, 2H, H-2’, H-4’), 3.99 - 3.95 (m, 1H, H-5’), 3.52 - 3.37 (m, 2H, C H 2-NH), 1.53 (p, J = 6.9 Hz, 2H, C H 2-CH2-NH), 1.38 - 1.11 (m, 30H alkyl chain), 0.88 (t, J = 6.8 Hz, 3H, CH3). 13 13C NMR (101 MHz, pyridine-d5): δ 174.6 (C-1), 106.3 (C-1’), 84.1 (C-4), 79.1 (C-5’), 78.8 (C-3’), 75.9 (C-2’), 73.8 (C-5), 73.3 (C-2), 73.2 (C-3), 72.1 (C-4’), 65.0 (C-6), 63.3 (C-6’), 39.8( C H2-NH), 32.5 - 23.3 (CH2 alkyl chain), 14.6 (CH3).

[0114] N-Tetradecyl-D-lactobionamide (Lac14)

[0115]

Chemical Structure

[0116] Yield: 76% Appearance: pure white Molecular formula: C 26 H 51 NO 11 MM:553.68g.mol -1 1 H NMR (600MHz, Pircon-d5): δ 8.18(t,1H,J=5.8Hz,NH),5.34(t,1H,J=3.0Hz,H-3),5.26(d,1H,J=2.4Hz,H-2),5.22(d,1H,J=7.7Hz,H -1'),4.81(dd,1H,J=4.1Hz,J=6.9Hz,H-4),4.78-4.72(m,1H,H-5),4.56-4.45(m,4H,H-2',H-6'a,H-6a , H-6b),4.43(d,1H,J=2.9Hz,H-4'),4.29(dd,1H,J=4.6Hz,J=11.3Hz,H-6'b),4.14(dd, 1H,J=3.2Hz,J=9.4Hz,H-3'),4.08(dd,1H,J=5.4Hz,J=6.4Hz,H-5'),3.52-3.38(m,2H,C H 2-NH), 1.58-1.47(m,2H,C H 2-CH2-NH), 1.32-1.14 (m, 22H, CH2 alkali lock), 0.88 (t, 3H, J = 6.8 Hz, CH3) 13 C NMR (151MHz, Pircon-d5): δ 174.3(C-1),107.0(C-1'),84.8(C-4),77.9(C-5'),75.7(C-3'),74.2(C-2),7 3.8(C-5),73.5(C-2'),73.0(C-3),70.7(C-4'),64.9(C-6),63.0(C-6'),39.9( C H2-NH),32.6-23.4(CH2アルキル Lock),14.7(CH3).

[0117] N-Hexadecyl-D-lactobionamide (Lac16)

[0118]

change

[0119] Yield: 69% Appearance: pure white Molecular formula: C 28 H 55 NO 11 MM: 581.74 g / mol -1 Yield: 0.69 (EtOAc / MeOH / H2O: 7 / 2 / 1) [α]D 20 : +22.0° (MeOH, c = 0.05) ESI-HRMS: [M+H] + 582.3852 (calculated value: C 28 H 55 NO 11 for 582.3853) 1 1H NMR (600 MHz, pyridine-d5): δ 8.19 (t, 1H, J = 5.8 Hz, NH), 5.32 (t, 1H, J = 3.0 Hz, H-3), 5.24 (d, 1H, J = 2.4 Hz, H-2), 5.21 (d, 1H, J = 7.7 Hz, H-1’), 4.80 (dd, 1H, J = 4.1 Hz, J = 6.9 Hz, H-4), 4.74 - 4.71 (m, 1H, H-5), 4.51 - 4.45 (m, 4H, H-2’, H-6’a, H-6a , H-6b), 4.42 (d, 1H, J = 2.9 Hz, H-4’), 4.27 (dd, 1H, J = 4.6 Hz, J = 11.3 Hz, H-6’b), 4.12 (dd, 1H, J = 3.2 Hz, J = 9.4 Hz, H-3’), 4.06 (dd, 1H, J = 5.4 Hz, J = 6.4 Hz, H-5’), 3.48 - 3.38 (m, 2H, C H 2-NH), 1.55 - 1.48 (m, 2H, C H 2-CH2-NH), 1.27 - 1.16 (m, 26H, CH2 alkyl chain), 0.87 (t, 3H, J = 6.8 Hz, CH3) 13 13C NMR (151 MHz, pyridine-d5): δ 174.2 (C-1), 106.9 (C-1’), 84.6 (C-4), 77.8 (C-5’), 75.6 (C-3’), 74.1 (C-2), 73.7 (C-5), 73.4 (C-2’), 72.9 (C-3), 70.6 (C-4’), 64.8 (C-6), 62.9 (C-6’), 39.8( CH2-NH), 32.5 - 23.3 (CH2 alkyl chain), 14.6 (CH3).

[0120] N-Octadecyl-D-lactobionamide (Lac18)

[0121]

Chem.

[0122] Yield: 86% Appearance: Pure white Molecular formula: C 30 H 59 NO 11 MM: 609.80 g.mol -1 Yield: 0.71 (EtOAc / MeOH / H2O: 7 / 2 / 1) [α]D 20 : +136.0° (MeOH, c = 0.025) ESI - HRMS: [M + H] + 610.4166 (calculated value: C 30 H 60 NO 11 for 610.4166) 1 1H NMR (600 MHz, pyridine - d5): δ 8.19 (t, 1H, J = 5.9 Hz, NH), 5.32 (br s, 1H, H - 3), 5.24 (d, 1H, J = 2.5 Hz, H - 2), 5.21 (d, 1H, J = 7.8 Hz, H - 1’), 4.80 (dd, 1H, J = 4.0 Hz, J = 7.0 Hz, H - 4), 4.74 - 4.72 (m, 1H, H - 5), 4.52 - 4.45 (m, 4H, H - 2’, H - 6’a, H - 6a , H - 6b), 4.42 (d, 1H, J = 3.1 Hz, H - 4’), 4.27 (dd, 1H, J = 4.4 Hz, J = 11.2 Hz, H - 6’b), 4.12 (dd, 1H, J = 3.3 Hz, J = 9.5 Hz, H - 3’), 4.06 (dd, 1H, J = 5.0 Hz, J = 7.0 Hz, H - 5’), 3.48 - 3.38 (m, 2H, C H 2 - NH), 1.55 - 1.48 (m, 2H, C H2-CH2-NH), 1.29 - 1.16 (m, 30H, CH2 alkyl chain), 0.87 (t, 3H, J = 6.9 Hz, CH3) 13 C NMR (151 MHz, pyridine-d5): δ 174.2 (C-1), 106.9 (C-1’), 84.7 (C-4), 77.9 (C-5’), 75.6 (C-3’), 74.1 (C-2), 73.7 (C-5), 73.4 (C-2’), 72.9 (C-3), 70.6 (C-4’), 64.8 (C-6), 62.9 (C-6’), 39.8( C H2-NH), 32.5 (CH2 alkyl chain), 30.6 - 23.3 (CH2 alkyl chain), 14.6 (CH3)

[0123] N-Tetradecyl-Melibionamide (Mel14)

[0124]

Chemical formula

[0125] Yield: 60% Appearance: pure white Molecular formula: C 26 H 51 NO 11 MM: 553.35 g.mol -1 11H NMR (400 MHz, pyridine-d5): δ 8.39 (t, J = 5.9 Hz, N-H), 5.46 (d, J = 3.7 Hz, 1H, H-1’), 5.21 (t, J = 3.2 Hz, 1H, H-3), 5.04 (d, J = 3.3 Hz, 1H, H-2), 4.78 - 4.70 (m, 2H, H-4’, H-4), 4.68 (dd, J = 9.9, 3.8 Hz, 1H, H-2’), 4.63 - 4.56 (m, 3H, H-6a,b, H-5’), 4.51 (dd, J = 9.9, 3.1 Hz, 1H, H-3’), 4.42 (d, J = 5.9 Hz, 2H, H-6’a,b), 4.38 - 4.32 (m, 1H, H-5), 3.56 - 3.37 (m, 2H, CH2-N), 1.63 - 1.49 (m, 2H, CH2-CH2-N), 1.33 - 1.12 (m, 22H, CH2 alkyl chain), 0.88 (t, J = 6.7 Hz, 3H, CH3). 13 13C NMR (101 MHz, pyridine-d5): δ 174.5 (C-1), 101.60 (C-1’), 75.3 (C-2), 75.1 (C-4), 73.2 (C-5’), 72.7 (C-3), 72.1 (C-3’), 71.4 (C-5, C-6), 71.4 (C-4’), 71.1 (C-2’), 63.0 (C-6’), 40.0 (CH2-N), 33.0 - 23.4 (CH2 alkyl chain), 14.7 (CH3).

[0126] N-Hexadecyl-Melibionamide (Mel16)

[0127]

Chemical Structure

[0128] Yield: 44% Appearance: Pure white Molecular formula: C 28 H 55 NO 11 MM: 581.38 g.mol -1 11H NMR (400 MHz, pyridine-d5): δ 8.39 (t, J = 5.9 Hz, N-H), 5.45 (d, J = 3.7 Hz, 1H, H-1’), 5.21 (t, J = 3.2 Hz, 1H, H-3), 5.04 (d, J = 3.3 Hz, 1H, H-2), 4.78 - 4.70 (m, 2H, H-4’, H-4), 4.67 (dd, J = 9.9, 3.8 Hz, 1H, H-2’), 4.62 - 4.55 (m, 3H, H-6a,b, H-5’), 4.51 (dd, J = 9.9, 3.1 Hz, 1H, H-3’), 4.41 (d, J = 5.9 Hz, 2H, H-6’a,b), 4.38 - 4.30 (m, 1H, H-5), 3.54 - 3.40 (m, 2H, CH2-N), 1.62 - 1.51 (m, 2H, CH2-CH2-N), 1.34 - 1.12 (m, 26H, CH2 alkyl chain), 0.88 (t, J = 6.7 Hz, 3H, CH3). 13 13C NMR (101 MHz, pyridine-d5): δ 174.5 (C-1), 101.6 (C-1’), 75.3 (C-2), 75.1 (C-4), 73.2 (C-5’), 72.7 (C-3), 72.1 (C-3’), 71.4 (C-5, C-6), 71.4 (C-4’), 71.1 (C-2’), 63.0 (C-6’), 40.0 (CH2-N), 33.0 - 23.4 (CH2 alkyl chain), 14.8 (CH3).

[0129] N-Octadecyl-Melibionamide (Mel18)

[0130]

Chemical Structure

[0131] Yield: 38% Appearance: Pure white Molecular formula: C 30 H 59 NO 11 MM: 609.41 g.mol -1 11H NMR (400 MHz, pyridine-d5): δ 8.39 (t, J = 5.9 Hz, N-H), 5.46 (d, J = 3.7 Hz, 1H, H-1’), 5.21 (t, J = 3.2 Hz, 1H, H-3), 5.04 (d, J = 3.3 Hz, 1H, H-2), 4.78 - 4.70 (m, 2H, H-4’, H-4), 4.68 (dd, J = 9.9, 3.8 Hz, 1H, H-2’), 4.62 - 4.56 (m, 3H, H-6a,b, H-5’), 4.51 (dd, J = 9.9, 3.1 Hz, 1H, H-3’), 4.42 (d, J = 5.9 Hz, 2H, H-6’a,b), 4.38 - 4.31 (m, 1H, H-5), 3.54 - 3.40 (m, 2H, CH2-N), 1.62 - 1.51 (m, 2H, CH2-CH2-N), 1.34 - 1.12 (m, 30H, CH2 alkyl chain), 0.88 (t, J = 6.7 Hz, 3H, CH3). 13 13C NMR (101 MHz, pyridine-d5): δ 174.5 (C-1), 101.6 (C-1’), 75.3 (C-2), 75.1 (C-4), 73.2 (C-5’), 72.7 (C-3), 72.1 (C-3’), 71.4 (C-5, C-6), 71.4 (C-4’), 71.1 (C-2’), 63.0 (C-6’), 40.0 (CH2-N), 33.0 - 23.4 (CH2 alkyl chain), 14.8 (CH3).

[0132] II-2.c). General procedure for sulfation of N-alkyl-glyconamides To 1 g of N-alkyl-glyconamide placed in 50 mL of anhydrous pyridine in a double-neck flask, 2 x 1.1 eq of 50% SO3 / pyridine complex active towards glycobionamide and 3 x 1.1 eq of 50% SO3 / pyridine complex active towards maltotrionamide are added. The progress of the reaction is monitored by reversed-phase thin-layer chromatography (C18 stationary phase, eluent methanol / water 6 / 4). After about 1 hour of reaction, another 1.5 eq of 50% SO3 / active pyridine is added to complete the reaction. The reaction is left under stirring overnight and then treated with a saturated solution of sodium bicarbonate at pH approx. 9 and then evaporated to dryness. The disulfated compound (N-alkyl-glyconamide) or trisulfated N-alkylmaltotrionamide are the majority products obtained in the reaction medium, with a small number of compounds formed that are incompletely sulfated or contain additional sulfate at the first position. The crude reaction is then purified by reversed-phase flash chromatography using a C18 80 g Reveleris column. The mobile phase is a water / methanol mixture at a flow rate of 40 mL / min, with a gradient increasing from 40% methanol to 80% methanol in 10 min. The purified monosulfated, disulfated (highly predominant), and trisulfated N-alkylglycobionamide or trisulfated N-alkylmaltotrionamide fractions are then evaporated to remove the methanol and then lyophilized.

[0133] N-Tetradecyl-6,6'-di-O-sulfo-D-maltobioamide disodium (Mal14diS)

[0134] [ka]

[0135] Yield: 61% Appearance: Pure white Molecular formula:C 26 H 49 NNa2O 17 S2 MM:757.22g.mol -1 Yield: 0.47 (CH3CN / H2O: 3 / 7) TLC-C18 ESI-HRMS: [M+Na] + 780.2133 (calculated value: C 26 H 49 NNa3O 17 Regarding S2, 780.2135) 1 H NMR (600 MHz, D2O): δ 5.22 (d, J = 3.9 Hz, 1H, H-1’), 4.41 - 4.10 (m, 8H, H-6’a, H-6’b, H-2, H-5, H-6a, H-6b, H-3, H-5’), 4.00 (dd, J = 5.7, 3.8 Hz, 1H, H-4), 3.81 (t, J = 9.5 Hz, 1H, H-3’), 3.65 (dd, J = 9.9, 3.8 Hz, 1H, H-2’), 3.57 (t, J = 9.6 Hz, 1H, H-4’), 3.34 - 3.18 (m, 2H, CH2-N), 1.57 (br s, 2H, CH2-CH2-N), 1.33 (br s, 22H, CH2 alkyl chain), 0.92 (t, J = 6.5 Hz, 3H, CH3) 13 C NMR (151 MHz, D2O): δ 173.4 (C-1), 100.5 (C-1’), 82.0 (C-4), 72.7 (C-3’), 71.8 (C-2), 71.7 (C-3), 71.5 (C-2’), 70.5 (C-5’), 69.8 (C-5), 68.9 (C-6), 68.8 (C-4’), 66.7 (C-6’), 39.4 (CH2-N), 32.0 - 22.6 (CH2 alkyl chain), 13.9 (CH3).

[0136] N-Hexadecyl-6,6'-di-O-sulfo-D-maltobioamide disodium (Mal16diS)

[0137]

Chemical Structure

[0138] Yield: 55% Appearance: Pure white Molecular formula: C 28 H 53 NNa2O 17 S2 MM: 785.82 g.mol -1 Yield: 0.52 (CH3CN / H2O: 6 / 4) TLC-C18 [α]D 20 :+53.6°(H2O, c=0.5) ESI-HRMS: [M+Na] + 808.2463 (calculated value: C 28 H 53 NNaO 17 Regarding S2: 808.2448) 1 H NMR(400MHz,D2O):δ 5.21(d,J=3.9Hz,1H,H-1'),4.40-4.09(m,8H,H-6'a,H-6'b,H-2,H-5,H-6a,H-6b,H-3,H-5'),3.99(dd,J=5.7,3.8Hz,1H,H-4) ,3.81(t,J=9.5Hz,1H,H-3'),3.64(dd,J=9.9,3.8Hz,1H,H-2'),3.56(t,J=9.6Hz,1H,H-4'),3.33-3.17(m,2H,CH2-N),1.56(br s,2H,CH2-CH2-N),1.33(br s, 26H, CH2 alkyl chain), 0.92 (t, J = 6.5Hz, 3H, CH3) 13 C NMR(101MHz,D2O):δ 173.4(C-1),100.5(C-1'),82.0(C-4),72.8(C-3'),71.8(C-2),71.7(C-3),71.5(C-2'),70.5(C-5') ,69.8(C-5),68.9(C-6),68.8(C-4'),66.7(C-6'),39.4(CH2-N),32.0-22.6(CH2 alkyl chain),13.9(CH3).

[0139] Sodium N-hexadecyl-6 or 6'-O-sulfo-D-maltobioamide (Mal16monoS) The monosulfated fraction of Mal16 is obtained from crude Mal16diS purified on a flash column and is a mixture of N-hexadecylmaltobionamide sulfated at position 6 and its homolog sulfated at position 6′.

[0140] [ka]

[0141] Yield: 40% Appearance: Pure white Molecular formula:C 28 H 54 NNaO 14 S MM: 683.78 g.mol -1

[0142] N-Hexadecyl-tri-O-sulfo-D-maltobioamide trisodium (Mal16triS) The trisulfated fraction of Mal16 is obtained from crude Mal16diS purified on a flash column and is a mixture of several N-hexadecylmaltobionamide compounds disulfated at the 6 and 6' positions and containing a third sulfate at one of the 2 positions.

[0143] [ka]

[0144] Yield: 6% Appearance: Pure white Molecular formula:C 28 H 52 NNaO 20 S3 MM:887.86g.mol -1

[0145] N-Octadecyl-6,6'-di-O-sulfo-D-maltobionamide disodium (Mal18diS)

[0146] [ka]

[0147] Yield: 49% Appearance: Pure white Molecular formula:C 30 H 57 NNa2O 17 S2 MM:813.88g.mol -1 Yield: 0.44 (CH3CN / H2O: 6 / 4) TLC-C18 [α]D 20:+39.2°(H2O, c=0.125) ESI-HRMS: [M+Na] + 836.2776(Calculated value: C 30 H 57 NNaO 17 Regarding S2 836.2761) 1 H NMR(400MHz,D2O):δ 5.23(d,J=3.8Hz,1H,H-1'),4.45-4.08(m,8H,H-6'a,H-6'b,H-2,H-5,H-6a,H-6b,H-3,H-5'),4.01(t,J=4.8Hz,1H,H-4),3. 83(t,J=9.5Hz,1H,H-3'),3.67(dd,J=9.9,3.5Hz,1H,H-2'),3.58(t,J=9.5Hz,1H,H-4'),3.41-3.10(m,2H,CH2-N),1.58(br s,2H,CH2-CH2-N),1.33(br s, 30H, CH2 alkyl chain), 0.93 (t, J = 6.5 Hz, 3H, CH3). 13 C NMR(D2O,101MHz):δ 173.4(C-1),100.5(C-1'),82.0(C-4),72.8(C-3'),71.8(C-2),71.6(C-3),71.5(C-2'),70.5(C-5') ,69.8(C-5),68.9(C-6),68.9(C-4'),66.7(C-6'),39.5(CH2-N),32.1-22.7(CH2 alkyl chain),13.9(CH3).

[0148] Sodium N-octadecyl-6 or 6'-O-sulfo-D-maltobioamide (Mal18monoS) The monosulfated fraction of Mal18 is obtained from crude Mal18diS purified on a flash column and is a mixture of N-octadecylmaltobionamide sulfated at position 6 and its homolog sulfated at position 6′.

[0149] [ka]

[0150] Yield: 37% Appearance: Pure white Molecular formula:C 30 H 58 NNaO 14 S MM:711.84g.mol -1

[0151] N-Octadecyl-tri-O-sulfo-D-maltobioamide trisodium (Mal18triS) The trisulfated fraction of Mal18 is obtained from crude Mal18diS purified on a flash column and is a mixture of several N-octadecylmaltobionamide compounds disulfated at the 6 and 6' positions and containing a third sulfate at one of the 2 positions.

[0152] [ka]

[0153] Yield: 5% Appearance: Pure white Molecular formula:C 30 H 56 NNaO 20 S3 MM:915.91g.mol -1

[0154] N-Nonadecyl-6,6'-di-O-sulfo-D-maltobionamide disodium (Mal19diS)

[0155] [ka]

[0156] Yield: 47% Appearance: Pure white Molecular formula:C 31 H 59 NNa2O 17 S2 MM:827.90g.mol -1 11H NMR (400 MHz, D2O): δ 5.22 (d, J = 3.8 Hz, 1H, H-1’), 4.42 - 4.09 (m, 8H, H-6’a, H-6’b, H-2, H-5, H-6a, H-6b, H-3, H-5’), 4.00 (t, J = 4.8 Hz, 1H, H-4), 3.82 (t, J = 9.5 Hz, 1H, H-3’), 3.65 (dd, J = 9.9, 3.5 Hz, 1H, H-2’), 3.57 (t, J = 9.5 Hz, 1H, H-4’), 3.35 - 3.15 (m, 2H, CH2-N), 1.57 (br s, 2H, CH2-CH2-N), 1.33 (br s, 32H, CH2 alkyl chain), 0.91 (t, J = 6.5 Hz, 3H, CH3). 13 13C NMR (D2O, 101 MHz): δ 173.4 (C-1), 100.5 (C-1’), 82.0 (C-4), 72.7 (C-3’), 71.9 (C-2), 71.5 (C-3), 71.5 (C-2’), 70.5 (C-5’), 69.8 (C-5), 68.9 (C-6), 68.9 (C-4’), 66.7 (C-6’), 39.5 (CH2-N), 32.1 - 22.7 (CH2 alkyl chain), 13.9 (CH3).

[0157] N-Eicosanyl-6,6'-di-O-sulfo-D-maltobionamide disodium (Mal20diS)

[0158]

Chemical Structure

[0159] Yield: 32% Appearance: Pure white Molecular formula: C 32 H 61 NNa2O 17 S2 MM: 841.32 g.mol -1 11H NMR (400 MHz, D2O): δ 5.23 (d, J = 3.8 Hz, 1H, H-1’), 4.42 - 4.08 (m, 8H, H-6’a, H-6’b, H-2, H-5, H-6a, H-6b, H-3, H-5’), 4.01 (t, J = 4.8 Hz, 1H, H-4), 3.82 (t, J = 9.5 Hz, 1H, H-3’), 3.66 (dd, J = 9.9, 3.5 Hz, 1H, H-2’), 3.57 (t, J = 9.5 Hz, 1H, H-4’), 3.36 - 3.14 (m, 2H, CH2-N), 1.57 (br s, 2H, CH2-CH2-N), 1.33 (br s, 34H, CH2 alkyl chain), 0.91 (t, J = 6.5 Hz, 3H, CH3). 13 13C NMR (D2O, 101 MHz): δ 173.4 (C-1), 100.5 (C-1’), 82.0 (C-4), 72.8 (C-3’), 71.8 (C-2), 71.6 (C-3), 71.5 (C-2’), 70.5 (C-5’), 69.8 (C-5), 68.9 (C-6), 68.9 (C-4’), 66.7 (C-6’), 39.5 (CH2-N), 32.1 - 22.7 (CH2 alkyl chain), 13.9 (CH3).

[0160] N-Hexadecyl-per-O-sulfo-D-maltobioamide sodium salt (Mal16perS)

[0161]

Chem.

[0162] The compound N-hexadecyl-D-maltobionamide (Mal16) (200 mg, 0.34 mmol) and 20 equivalents of 97% SO3 / activated pyridine are introduced into a 20 mL zirconia bowl containing 80 zirconia balls with a diameter of 5 mm, then into a Fritsch P7PL planetary mill. The mixture is ground for 48 cycles of 5 min at 400 rpm. Then, 30 equivalents of NaHCO3 (578 mg, 6.88 mmol) are introduced into the bowl and the mixture is ground again for 6 cycles of 5 min. The crude reaction is then dissolved in milliQ water and dialyzed using a 1000 kD cut-off membrane (3 x 500 mL). After lyophilization, a white solid is obtained and analyzed by high-resolution mass spectrometry. Mal16perS consists of a mixture (524 mg) of trisulfated, tetrasulfated, pentasulfated, hexasulfated, heptasulfated and octasulfated N-hexadecyl-D-maltobionamides.

[0163] N-Tetradecyl-6,6'-di-O-sulfo-D-cellobioamide disodium (Cell14diS)

[0164] [ka]

[0165] Yield: 69% Appearance: Pure white Molecular formula:C 26 H 49 NNa2O 17 S2 MM:757.22g.mol -1 11H NMR (400 MHz, D2O): δ 4.69 (d, J = 7.9 Hz, 1H, H-1’), 4.44 (bs, 1H, H-2), 4.40 - 4.33 (m, 4H, H-6’a, H-6a, H-6b, H-3), 4.33 - 4.10 (m, 2H, H-6’b, H-5), 4.06 (dd, J = 7.7, 3.2 Hz, 1H, H-4’), 3.79 - 3.71 (m, 1H, H-5), 3.60 - 3.48 (m, 2H, H-3’, H-4’), 3.40 (t, J = 8.4 Hz, 1H, H-2’), 3.32 - 3.20 (m, 2H, CH2-N), 1.61 - 1.51 (m, 2H, CH2-CH2-N), 1.33 (s, 22H, CH2 alkyl chain), 0.91 (t, J = 6.4 Hz, 3H, CH3). 13 13C NMR (101 MHz, D2O): δ 173.5 (C-1), 102.6 (C-1’), 80.5 (C-4), 75.3 (C-3’), 73.7 (C-5’), 73.2 (C-2’), 72.9 (C-2), 69.5 (C-3), 69.3 (C-4’), 68.9 (C-5, C-6), 66.8 (C-6’), 39.3 (CH2-N), 31.7 - 22.4 (CH2 alkyl chain), 13.8 (CH3).

[0166] N-Hexadecyl-6,6'-di-O-sulfo-D-cellobioamide disodium (Cell16diS)

[0167]

Chemical Structure

[0168] Yield: 59% Appearance: Pure white Molecular formula: C 28 H 53 NNa2O 17 S2 MM: 785.82 g·mol -1 Yield: 0.6 (H2O / CH3CN: 65 / 35) TLC - C18 ESI - HRMS: [M + Na] + 808.2472 (calculated value for C 28 H 53 NNa3O 17 S2 is 808.2448) 1 1H NMR (400 MHz, D2O): δ 4.69 (d, J = 7.9 Hz, 1H, H-1’), 4.45 (bs, 1H, H-2), 4.40 - 4.27 (m, 4H, H-6’a, H-6a, H-6b, H-3), 4.24 - 4.13 (m, 2H, H-6’b, H-5), 4.07 (dd, J = 7.7, 3.2 Hz, 1H, H-4’), 3.77 - 3.73 (m, 1H, H-5), 3.58 - 3.48 (m, 2H, H-3’, H-4’), 3.44 (t, J = 8.4 Hz, 1H, H-2’), 3.32 - 3.18 (m, 2H, CH2-N), 1.58 - 1.54 (m, 2H, CH2-CH2-N), 1.33 (s, 26H, CH2 alkyl chain), 0.93 (t, J = 6.4 Hz, 3H, CH3). 13 13C NMR (D2O, 101 MHz): δ 173.5 (C-1), 102.6 (C-1’), 80.5 (C-4), 75.3 (C-3’), 73.9 (C-5’), 73.2 (C-2’), 72.9 (C-2), 69.7 (C-3), 69.5 (C-4’), 68.9 (C-5, C-6), 67.0 (C-6’), 39.4 (CH2-N), 32.0 - 22.7 (CH2 alkyl chain), 14.0 (CH3).

[0169] N-Octadecyl-6,6'-di-O-sulfo-D-cellobioamide disodium (Cell18diS)

[0170]

Chemistry

[0171] Yield: 66% Appearance: Pure white Molecular formula: C 30 H 57 NNa2O 17 S2 MM: 813.88 g·mol -1 Yield: 0.22 (CH3CN / H2O: 2 / 8) TLC - C18 ESI - HRMS: [M + Na] + 836.2803 (calculated value: C 30 H 57 NNa3O17 Regarding S2 836.2761) 1 1H NMR (400 MHz, D2O): δ 4.69 (d, J = 7.9 Hz, 1H, H-1’), 4.45 (bs, 1H, H-2’), 4.41 - 4.26 (m, 4H, H-6’a, H-6a, H-6b, H-3), 4.24 - 4.13 (m, 2H, H-6’b, H-5), 4.07 (dd, J = 7.7, 3.2 Hz, 1H, H-4’), 3.78 - 3.72 (m, 1H, H-5), 3.60 - 3.48 (m, 2H, H-3’, H-4’), 3.41 (t, J = 8.4 Hz, 1H, H-2’), 3.32 - 3.18 (m, 2H, CH2-N), 1.63 - 1.52 (m, 2H, CH2-CH2-N), 1.34 (s, 30H, CH2 alkyl chain), 0.93 (t, J = 6.4 Hz, 3H, CH3). 13 13C NMR (101 MHz, D2O): δ 173.4 (C-1), 102.6 (C-1’), 80.5 (C-4), 75.3 (C-3’), 73.9 (C-5’), 73.2 (C-2’), 72.8 (C-2), 69.7 (C-3), 69.5 (C-4’), 68.9 (C-5, C-6), 67.0 (C-6’), 39.4 (CH2-N), 32.0 - 22.7 (CH2 alkyl chain), 13.9 (CH3).

[0172] N-Tetradecyl-6,6'-di-O-sulfo-lactobioamide disodium (Lac14diS)

[0173]

Chemical Structure

[0174] Yield: 72% Appearance: Pure white Molecular formula: C 26 H 49 NNa2O 17 S2 MM: 757.22 g.mol -1 Yield: 0.23 (H2O / CH3CN: 7 / 3) TLC - C18 ESI - HRMS: [M + Na] + 780.2146 (calculated value: C 26 H49 NNa3O 17 Regarding S2, 780.2135) 1 1H NMR (400 MHz, D2O): δ 4.63 (d, J = 7.7 Hz, 1H, H-1’), 4.45 (bs, 1H, H-2), 4.42 - 4.26 (m, 3H, H-6a, H-6b, H-3), 4.24 (d, J = 5.9 Hz, 2H, H-6’a, H-6’b), 4.20 - 4.13 (m, 1H, H-5), 4.08 (dd, J = 8.0, 2.9 Hz, 1H, H-4), 4.09 - 3.94 (m, 2H, H-4’, H-5), 3.72 (dd, J = 10.0, 3.3 Hz, 1H, H-3’), 3.62 (dd, J = 9.9, 7.6 Hz, 1H, H-2’), 3.36 - 3.16 (m, 2H, CH2-N), 1.63 - 1.50 (m, 2H, CH2-CH2-N), 1.32 (s, 22H, CH2 alkyl chain), 0.92 (t, J = 6.4 Hz, 3H, CH3). 13 13C NMR (101 MHz, D2O): δ 173.5 (C-1), 103.1 (C-1’), 80.4 (C-4), 72.9 (C-2), 72.8 (C-4’), 72.4 (C-3’), 70.9 (C-2’), 69.7 (C-3), 69.1 (C-5, C-6), 68.3 (C-5’), 66.7 (C-6’), 39.4 (CH2-N), 32.0 - 22.6 (CH2 alkyl chain), 13.9 (CH3).

[0175] N-Hexadecyl-6,6'-di-O-sulfo-lactobioamide disodium (Lac16diS)

[0176]

Chemical Structure

[0177] Yield: 72% Appearance: Pure white Molecular formula: C 28 H 53 NNa2O 17 S2 MM: 785.82 g.mol -1 Yield: 0.23 (H2O / CH3CN: 7 / 3) TLC - C18 ESI-HRMS: [M+Na] + 808.2473 (Calculated value: C 28 H 53 NNa3O 17 For S2 it is 808.2448) 1 1H NMR (400 MHz, D2O): δ 4.64 (d, J = 7.7 Hz, 1H, H-1’), 4.46 (bs, 1H, H-2), 4.43 - 4.28 (m, 3H, H-6a, H-6b, H-3), 4.24 (d, J = 5.9 Hz, 2H, H-6’a, H-6’b), 4.20 - 4.13 (m, 1H, H-5), 4.08 (dd, J = 8.0, 2.9 Hz, 1H, H-4), 4.05 - 3.99 (m, 2H, H-4’, H-5), 3.72 (dd, J = 10.0, 3.3 Hz, 1H, H-3’), 3.63 (dd, J = 9.9, 7.6 Hz, 1H, H-2’), 3.36 - 3.16 (m, 2H, CH2-N), 1.64 - 1.52 (m, 2H, CH2-CH2-N), 1.33 (s, 26H, CH2 alkyl chain), 0.92 (t, J = 6.4 Hz, 3H, CH3). 13 13C NMR (101 MHz, D2O): δ 173.5 (C-1), 103.1 (C-1’), 80.4 (C-4), 72.9 (C-2), 72.8 (C-4’), 72.4 (C-3’), 70.9 (C-2’), 69.7 (C-3), 69.0 (C-5, C-6), 68.3 (C-5’), 66.7 (C-6’), 39.4 (CH2-N), 32.0 - 22.7 (CH2 alkyl chain), 13.9 (CH3).

[0178] N-Octadecyl-6,6'-di-O-sulfo-lactobioamide disodium (Lac18diS)

[0179]

Chemical Structure

[0180] Yield: 64% Appearance: Pure white Molecular formula: C 30 H 57 NNa2O 17 S2 MM: 813.88 g.mol -1 Yield: 0.36 (H2O / CH3CN: 7 / 3) TLC-C18 ESI-HRMS: [M+Na] + 836.2798 (calculated value: C 30 H 57 NNa3O 17 Regarding S2 836.2761) 1 1H NMR (D2O, 400 MHz): δ 4.65 (d, J = 7.6 Hz, 1H, H-1’), 4.47 (bs, 1H, H-2), 4.43 - 4.28 (m, 3H H-6a, H-6b, H-3), 4.24 (d, J = 5.7 Hz, 2H, H-6’a, H-6’b), 4.18 (d, J = 7.1 Hz, 1H, H-5), 4.15 - 4.06 (m, 1H, H-4), 4.07 - 4.00 (m, 2H, H-4’, H-5), 3.73 (dd, J = 10.1, 3.0 Hz, 1H, H-3’), 3.65 (dd, J = 9.8, 7.6 Hz, 1H, H-2’), 3.36 - 3.16 (m, 2H, CH2-N), 1.65 - 1.49 (m, 2H, CH2-CH2-N), 1.34 (s, 30H, CH2 alkyl chain), 0.93 (t, J = 6.4 Hz, 3H, CH3). 13 13C NMR (D2O, 101 MHz): δ 173.5 (C-1), 103.1 (C-1’), 80.3 (C-4), 72.9 (C-2), 72.8 (C-4’), 72.4 (C-3’), 70.9 (C-2’), 69.7 (C-3), 68.9 (C-5, C-6), 68.3 (C-5’), 66.7 (C-6’), 39.5 (CH2-N), 32.0 - 22.7 (CH2 alkyl chain), 13.9 (CH3).

[0181] N-Tetradecyl-6'-O-sulfo-melibioamide sodium (Mel14monoS)

[0182]

Chemical Structure

[0183] Yield: 48% Appearance: Pure white Molecular formula: C 26 H 50 NNaO 14S MM: 655.28 g / mol -1 Yield: 0.32 (H2O / CH3CN: 7 / 3) TLC-C18 ESI-HRMS: [M+Na] + 678.2750 (calculated for C 26 H 50 NNa3O 14 S is 678.2747) 1 1H NMR (400 MHz, D2O): δ 5.03 (d, J = 3.7 Hz, 1H, H-1’), 4.35 (bs, 1H, H-2), 4.30 - 4.14 (m, 4H, H-6’a, H-6’b, H-5’, H-3), 4.08 (d, J = 3.2 Hz, 1H, H-4’), 4.01 - 3.90 (m, 4H, H-3’, H-5, H-4, H-2’), 3.75 (dd, J = 22, 7.2 Hz, 1H, H-6a, H-6b), 3.38 - 3.12 (m, 2H, CH2-N), 1.66 - 1.50 (m, 2H, CH2-CH2-N), 1.47 - 1.21 (s, 22H, CH2 alkyl chain), 0.92 (t, J = 6.4 Hz, 3H, CH3). 13 13C NMR (101 MHz, D2O): δ 173.7 (C-1), 98.4 (C-1’), 73.6 (C-2), 72.3 (C-4), 70.1 (C-3), 69.6 (C-5), 69.3 (C-3’), 69.2 (C-4’), 68.6 (C-6, C-5’), 68.4 (C-2’), 67.4 (C-6’), 39.4 (CH2-N), 32.1 - 22.7 (CH2 alkyl chain), 13.9 (CH3).

[0184] N-Hexadecyl-6'-O-sulfo-melibioamide sodium (Mel16monoS)

[0185]

Chemical Structure

[0186] Yield: 53% Appearance: Pure white Molecular formula: C 28 H 54 NNaO 14 S MM: 683.32 g / mol -1 Yield: 0.22 (H2O / CH3CN: 7 / 3) TLC-C18 ESI-HRMS: [M+Na] + 706.3082 (calculated value: C 28 H 54 NNa3O 14 for S it is 706.3060) 1 1H NMR (400 MHz, D2O): δ 5.03 (d, J = 3.7 Hz, 1H, H-1’), 4.35 (bs, 1H, H-2), 4.29 - 4.13 (m, 4H, H-6’a, H-6’b, H-5’, H-3), 4.08 (d, J = 3.2 Hz, 1H, H-4’), 4.01 - 3.90 (m, 4H, H-3’, H-5, H-4, H-2’), 3.75 (dd, J = 22, 7.2 Hz, 1H, H-6a, H-6b), 3.37 - 3.14 (m, 2H, CH2-N), 1.63 - 1.52 (m, 2H, CH2-CH2-N), 1.46 - 1.18 (s, 26H, CH2 alkyl chain), 0.91 (t, J = 6.4 Hz, 3H, CH3). 13 13C NMR (101 MHz, D2O): δ 173.7 (C-1), 98.4 (C-1’), 73.6 (C-2), 72.3 (C-4), 70.1 (C-3), 69.6 (C-5), 69.3 (C-3’), 69.1 (C-4’), 68.7 (C-6), 68.6 (C-5’), 68.4 (C-2’), 67.4 (C-6’), 39.4 (CH2-N), 32.1 - 22.7 (CH2 alkyl chain), 13.9 (CH3).

[0187] Sodium N-octadecyl-6'-O-sulfo-melibioamide (Mel18monoS)

[0188]

Chemical Structure

[0189] Yield: 38% Appearance: pure white Molecular formula: C 30 H 58 NNaO 14 S MM: 711.35 g.mol -1 Yield: 0.16 (H2O / CH3CN: 7 / 3) TLC-C18 ESI-HRMS:[M] - 688.3569(Calculated value: C 30 H 58 NO 14 Regarding S 688.3578) 1 H NMR(400MHz,DO):δ 5.03(d,J=3.7Hz,1H,H-1'),4.35(bs,1H,H-2),4.28-4.14(m,4H,H-6'a,H-6'b ,H-5',H-3),4.08(d,J=3.2Hz,1H,H-4'),4.01-3.81(m,4H,H-3',H-5,H-4,H-2 '),3.75(dd,J=22,7.2Hz,1H,H-6a,H-6b),3.37-3.14(m,2H,CH2-N),1.63-1.5 2(m,2H,CH2-CH2-N),1.46-1.18(s,30H,CH2 alkyl chain),0.91(t,J=6.4Hz,3H,CH3). 13 C NMR(101MHz,D2O):δ 173.7(C-1),98.5(C-1'),73.7(C-2),72.3(C-4),70.1(C-3),69.6(C-5),69.3(C-3'),69.1(C-4'), 68.7(C-6),68.6(C-5'),68.4(C-2'),67.4(C-6'),39.4(CH2-N),32.1-22.7(CH2 alkyl chain),13.9(CH3).

[0190] II-3. Synthesis of oxidized glycobionamide The synthesis of oxidized glycobionamide was carried out according to the following reaction diagram (Diagram 2).

[0191] [ka]

[0192] Diagram 2: Synthetic route to oxidized glycobionamides The synthesis of the oxidized glycobionamide involves three steps, the first two of which are identical to the synthesis of the sulfated derivative: oxidation at the anomeric position and a one-pot esterification aminolysis to graft the lipid chain via an amide bond.

[0193] Step 3 : Oxidation of primary hydroxyl groups of disaccharides in CH3CN / H2O mixture by TEMPO / BAIB and NaHCO3 system (48 hours) (Lu, H. et al., Molecules 2016, 21(10), 1301 / 1-1301 / 15) NMR and HRMS analyses indicate that the pyruvate motif has undergone loss of carbon-C6 (by decarboxylation), similar to results reported in the literature (Coggins, AJ et al., Nature Chemistry 2017, 9(4), 310-317; Lee Y et al., Chem Commun 2014, 50).

[0194] In the Mal16diBu-perS compound, two further steps are required: esterification aminolysis (step 4) followed by persulfation (step 5) (in Diagram 2, Bu=Butyl).

[0195] N-Hexadecyl-D-glucuronyl-(α-1,4)-D-xyluronamide (Mal16diOx)

[0196] [ka]

[0197] The N-hexadecyl-maltobionamide derivative (0.60 mmol, 350 mg) is dissolved in a mixture of acetonitrile (4 mL) and mQ H2O (4 mL). The mixture is stirred at 0 °C and TEMPO (1.20 mmol, 187 mg) is added, followed by BAIB (6.02 mmol, 1.94 g) and NaHCO3 (3.01 mmol, 253 mg). The mixture is then stirred at room temperature for 72 h. Ethanol (10 mL) is added and the reaction medium is diluted with EtOAc (100 mL) and mQ H2O (100 mL). The aqueous phase is isolated, extracted with EtOAc (2 × 100 mL) and then lyophilized. The crude reaction is then purified by reversed phase chromatography. The elution gradient is H2O / MeCN: 100 / 0 to 0 / 100 in 20 min. After evaporation and lyophilization, the Mal16diOx compound is obtained in the form of a white powder with a yield of 8% (31 mg).

[0198] M: 623.65 g.mol -1 Formula:C 27 H 47 NNa2O 12 Yield: 0.51 (HO / MeCN: 5 / 5) HRMS: 602.3150 (Actual value C 27 H 49 NO 12 Na 602.3152) 1 H NMR(DO,400MHz):5.14(m,1H,H Glc1’ ), 4.20(m,3H,H Glc2 ,H Glc3 and H Glc5’ ), 4.10(d, 1H, J=6.0Hz, H Glc4 ), 3.93(t,1H,J=9.4Hz,H Glc3’ ), 3.65(d, 1H, J=9, 6Hz, H Glc2’ ), 3.50(t, 1H, J=9.5Hz, H Glc4’ ), 3.22(m,2H,C H 2-NH), 1.55(m,2H,C H2-CH2-NH), 1.32 (m, 26H, CH2 alkyl chain), 0.90 (t, 3H, J=6.2Hz, CH3 alkyl chain) 13 C NMR(DO,100MHz):177.22(C Glc5 ), 176.93(C Glc6’ ), 173.68(C Glc1 ), 100.66(C Glc1’ ),83.33(C Glc4 ),72.84(C Glc2 Or C Glc3 ),72.55(C Glc2 Or C Glc3 ),72.44(C Glc3’ ), 72.07(C Glc4’ ),71.59(C Glc5’ ),71.29(C Glc2’ ),39.38( C H2-NH), 32.09 (CH2 alkyl chain), 30.16-29.11 (CH2 alkyl chain), 27.14 (CH2 alkyl chain), 22.71 (CH2 alkyl chain), 13.86 (CH3 alkyl chain).

[0199] N-Octadecyl-D-glucuronyl-(α-1,4)-D-xyluronamide (Mal18diOx)

[0200] [ka]

[0201] The N-hexadecyl-maltobionamide derivative (0.82 mmol, 500 mg) is dissolved in a mixture of acetonitrile (5 mL) and mQ H2O (5 mL). The mixture is stirred at 0 °C and TEMPO (1.64 mmol, 256 mg) is added, followed by BAIB (8.20 mmol, 2.64 g) and NaHCO3 (4.10 mmol, 344 mg). The mixture is then stirred at room temperature for 48 h. Ethanol (5 mL) is added and the reaction medium is diluted with EtOAc (200 mL) and mQ H2O (200 mL). The aqueous phase is isolated, extracted with EtOAc (2 x 200 mL) and then lyophilized. The crude reaction is then purified by reversed phase chromatography. The elution gradient is H2O / MeCN: 100 / 0 to 0 / 100 in 20 min. After evaporation and lyophilization, the Mal18diOx compound is obtained in the form of a white powder, with a yield of 17% (90 mg).

[0202] M: 651.70 g.mol -1 Formula:C 29 H 51 NNa2O 12 Yield: 0.48 (HO / MeCN: 5 / 5) HRMS: 630.3466 (Actual value C 29 H 53 NO 12 (630.3465 for Na) 1 H NMR(DO,400MHz):5.14(m,1H,H Glc1’ ), 4.20(m,3H,H Glc2 ,H Glc3 and H Glc5’ ), 4.10(d, 1H, J=6.0Hz, H Glc4 ), 3.94(t,1H,J=8.7Hz,H Glc3’ ), 3.66(d,1H,J=9,6Hz,H Glc2’ ), 3.50(t, 1H, J=9.5Hz, H Glc4’ ), 3.21(m,2H,C H 2-NH), 1.54(m,2H,C H2-CH2-NH), 1.32 (m, 30H, CH2 alkyl chain), 0.88 (t, 3H, J=6.2Hz, CH3 alkyl chain) 13 C NMR(DO,100MHz):177.31(C Glc5 ), 176.94(C Glc6’ ), 173.68(C Glc1 ), 100.71(C Glc1’ ),82.38(C Glc4 ), 72.80(C Glc2 Or C Glc3 ),72.55(C Glc2 Or C Glc3 Or C Glc3’ ), 72.04(C Glc4’ ),71.74(C Glc5’ ),71.23(C Glc2’ ),39.43( C H2-NH), 32.24 (CH2 alkyl chain), 30.68-29.19 (CH2 alkyl chain), 27.35 (CH2 alkyl chain), 22.82 (CH2 alkyl chain), 13.84 (CH3 alkyl chain).

[0203] N-Hexadecyl-(D-glucuronyl-(α-1,4)-D-xyluronamide)dibutylamide (Mal16diBu)

[0204] [ka]

[0205] N-Hexadecyl-D-glucuronyl-(α-1,4)-D-xyluronamide (0.127 mmol, 79 mg) and H2SO4 / SiO2 22 wt% (0.305 mmol, 136 mg) are added to a zirconia bowl containing 80 zirconia balls with a diameter of 5 mm. MeOH (0.15 mL) is added. The media is milled in a planetary ball mill (P7PL) in reverse mode at 500 rpm for 8 cycles of 5 min with a 2 min break. The resulting methyl ester is directly involved in the subsequent reaction under the same milling conditions. 99.5% butylamine (0.381 mmol, 38 μL) is followed by MeOH (0.15 mL) and then added to the bowl. The media is milled in a planetary ball mill (P7PL) in reverse mode at 500 rpm for 8 cycles of 5 min with a 2 min break. The crude reaction mixture is dissolved in MeOH, filtered to remove H2SO4 / SiO2 and evaporated. The residue is purified by automated flash chromatography on a 15 g SiO2 cartridge. The elution gradient is EtOAc / MeOH: 100 / 0 to 80 / 20 in 30 min. After evaporation and lyophilization, the Mal16diBu compound is obtained in the form of a white powder with a yield of 40% (35 mg).

[0206] M: 689.93 g.mol -1 Formula:C 35 H 67 N3O 10 Yield: 0.57 (EtOAc / MeOH: 9 / 1) 1 H NMR (600MHz, pyridine-d5,): 8.34 (m, 3H, NH), 5.70 (d, 1H, J = 3.2Hz, H Glc1’ ), 5.22(d, 1H, J=5.1Hz, H Glc2 ), 5.03(m,8H,H Glc3 ,H Glc4 ,H Glc5’ and OH), 4.59 (t, 1H, J = 9.1 Hz, H Glc3’ ), 4.27(t,1H,J=9.4Hz,H Glc4’ ),4.13(dd,1H,J=9,5Hz,J=3.4Hz,H Glc2’), 3.45(m,5H,C H 2-NH), 3.27(s x ,1H,J=6.5Hz,C H 2-NH), 1.53(m,6H,C H 2-CH2-NH), 1.24 (m, 30H, CH2 hexadecylamine and butylamine chains), 0.86 (t, 3H, J=6.1Hz, CH3 hexadecylamine and butylamine chains), 0.79 (m, 6H, CH3 hexadecylamine and butylamine chains). 13 C NMR (150 MHz, pyridine-d5,): 173.53 (C Glc1 ), 171.75(C Glc5 Or C Glc6’ ), 171.71(C Glc5 Or C Glc6’ ), 103.19(C Glc1’ ),84.74(C Glc4 ), 74.61(C Glc3’ ),74.16(C Glc4’ ),74.10(C Glc2 ), 73.91(C Glc3 Or C Glc5’ ), 73.22(C Glc2’ ),39.85( C H2-NH butyl chain), 39.68 ( C H2-NH butyl chain), 39.47 ( C H2-NH hexadecyl chain), 32.09 (CH2 hexadecyl chain), 32.38 (CH2 butyl chain), 32.36 (CH2 butyl chain), 30.58-29.98 (CH2 hexadecyl chain), 27.66 (CH2 hexadecyl chain), 23.31 (CH2 hexadecyl chain), 20.79 (CH2 butyl chain), 20.69 (CH2 butyl chain), 14.65 (CH3 hexadecyl chain), 14.26 (CH3 butyl chain), 14.24 (CH3 butyl chain)

[0207] N-Hexadecyl-(D-glucuronyl-(α-1,4)-D-xyluronamide)dibutylamide persulfate (Mal16diBu-perS)

[0208] [ka]

[0209] The Mal16diBu-perS derivative is obtained according to the same procedure described for obtaining Mal16perS. The Mal16diBu compound (35 mg, 0.051 mmol) and 16 equivalents of 97% SO3 / activated pyridine are introduced into a 20 mL zirconia bowl containing 80 zirconia balls with a diameter of 5 mm, then into a Fritsch P7PL planetary mill. The mixture is ground at 400 rpm for 48 cycles of 5 min. Then, 16 equivalents of NaHCO3 (69 mg, 0.81 mmol) are introduced into the bowl, and the mixture is ground again for 6 cycles of 5 min. The crude reaction is then dissolved in milliQ water and dialyzed using a 1000 kD cutoff membrane (3 x 500 mL). Mal16diBu-perS (52 mg) is obtained in the form of a mixture of the trisulfates, tetrasulfates and pentasulfates of N-hexadecyl-(D-glucuronyl-(α-1,4)-D-xyluronamide) dibutylamide.

[0210] III. Biological Data 1) In vitro study of abnormal tau phosphorylation Phosphorylation of tau protein is the most common post-translational modification that regulates tau activity and function. The longest tau isoform (4R2N, 441 amino acids) containing 85 potential phosphorylation sites was used. On the one hand, phosphorylation of tau protein in vitro is induced (Figure 5), on the other hand, it is induced by a competitive process between LG2A molecule and heparin, which is conventionally used to induce abnormal phosphorylation of tau in vitro (Figures 3, 4, 6, 7, 8, 9, and 10).

[0211] In the study of abnormal phosphorylation of tau, GSK3β, a kinase centrally involved in this process in the brains of subjects with Alzheimer's disease (AD), was used. Analysis of phosphorylation of tau by GSK3b at sites specific to AD is possible by Western blot techniques using specific antibodies that recognize abnormally phosphorylated sites in the brain or cerebrospinal fluid of AD subjects, such as the AT270 antibody that recognizes threonine 181 (Thr181), the PHF1 antibody that recognizes serine 396 and serine 404 (Ser396 / Ser404), and the AT8 antibody that recognizes the Ser199 / Ser202 / Thr205 sites.

[0212] Testing Protocol The composition of the reaction medium is as follows:

[0213] Induction : Tau protein (40 μg / mL) (Millipore) is phosphorylated in a buffer (40 mM Tris [pH 7.5], 20 mM MgCl2, 0.1 mg / mL BSA and 0.1 mM DTT) with 4 ng / mL GSK3β enzyme (Promega) in the presence of 48 μM ATP (Sigma-Aldrich) and protease inhibitors (Sigma-Aldrich, 1 / 100). LG2A molecules are added at 12 μg / mL and these effects are compared to those observed with the addition of heparin at the same concentration.

[0214] Competition : Tau protein (40 μg / mL) is phosphorylated by 4 ng / mL GSK3β enzyme (Promega) in the presence of 48 μM ATP (Sigma-Aldrich) and protease inhibitors (Sigma-Aldrich, 1 / 100) in the above buffer. The ability of LG2A molecules (60 μg / mL) to compete with heparin (12 μg / mL; Sigma-Aldrich) is evaluated. Thus, a molecule is defined as a "protector" from abnormal phosphorylation of tau if the signal in the presence of the molecule is less than the signal obtained with heparin alone.

[0215] In both systems (induction or competition), tau protein is incubated with stirring at 37° C. in the presence of the various factors presented above. The reaction kinetics is monitored by taking 8 μL samples at 1.5, 3 and 6 hours of incubation. Loading buffer (Euromedex) and β-mercaptoethanol (Sigma-Aldrich) are added to each sample. The samples are then stored at −20° C. until analysis by Western blot.

[0216] After denaturation of the samples by heating at 95°C for 5 min, the samples were deposited onto a 10% acrylamide gel placed in an electrophoresis tank containing migration buffer (0.25 M Tris; 1.6 M glycine; 20% SDS; pH 8.6) along with molecular weight markers (PrecisionPlusProtein™ Dual Color Standards; BIO-RAD).

[0217] The controls used in this phosphorylation assay and subsequent Western blots were as follows: - "native tau" protein, i.e. non-phosphorylated tau protein. - Tau protein phosphorylated by GSK3b alone in the absence of heparin. - Tau protein phosphorylated in the presence of heparin, designated "tau + heparin." - An "external standard" corresponding to tau protein phosphorylated for 3 hours in the presence of heparin. This standard is run in an independent test from the phosphorylation test in the presence of LG2A compound. This ensures that the Western Blot is performed accurately.

[0218] Migration occurs at a constant voltage of 80 V until the proteins reach the separating gel, visualized by a migration front of bromphenol blue contained in the loading buffer, and then at a constant voltage of 120 V until the migration front reaches the other end of the gel.

[0219] At the end of migration, semi-dry transfer is performed on a polyvinylidene fluoride (PVDF) membrane using the "Trans-blot Turbo RTA Transfer Kit, PVDF" (Bio-Rad). The PVDF membrane is previously activated in methanol (VWR) and then placed in the transfer buffer provided by the kit.

[0220] The transfer is carried out at 25V for 10 minutes.

[0221] Once the transfer of proteins onto the PVDF membrane is complete, a saturation step is carried out in PBS supplemented with 3% skim milk powder (Merck Millipore) and 0.1% Tween 20 (VWR) for 1 h at room temperature under agitation.

[0222] The membrane is then incubated overnight under agitation at 4° C. in a solution of PBS, 0.1% Tween and 1% milk containing a primary antibody specific for tau phosphorylation sites (AT270, ThermoScientific or S199-202, Millipore).

[0223] After incubation of the PVDF membrane with the selected primary antibody, a series of three 5-minute membrane washes are performed with PBS and 0.1% Tween under agitation, and the membrane is incubated for 1 hour at room temperature under agitation in a solution of 1x PBS, 0.1% Tween and 1% milk containing diluted secondary antibody (Jackson Immuno-Research).

[0224] After three washes of 5 min each with PBS and 0.1% Tween, followed by one wash with PBS, the membrane is exposed using the "Immobilon Forte Western HRP Substrate" kit (Merck Millipore) and the signal is recorded with a LI-COR instrument (Odyssey).

[0225] result In the absence of heparin (highly sulfated HS), phosphorylation of tau on sites specific to AD is not observable (Sepulveda-Diaz et al., 2015) (Figure 2). However, in the presence of heparin (highly sulfated HS), phosphorylation occurs at all tau sites (pTau), recapitulating the process of abnormal hyperphosphorylation that occurs in cells prior to the establishment of tauopathy.

[0226] Using in vitro tests, it was demonstrated that the synthesized disulfated C16 maltobionamide (Mal16diS) participates in total competition with heparin (hep) and prevents heparin from inducing tau phosphorylation on two tau abnormal phosphorylation sites specific to Alzheimer's disease, analyzed by reactions starting from 1.5 hours and up to 6 hours (AT270 and Ser199 / 202). Thus, the abnormal phosphorylation of tau (pTau) revealed by antibodies specific to Alzheimer's disease (AT270 and Ser199 / 202) is inhibited by the presence of disulfated C16 maltobionamide (Mal16diS) after 3 hours of in vitro reaction. The results are shown in Figure 3.

[0227] Similarly, synthetic disulfated C18 maltobionamide (Mal18diS) participates in total competition with heparin (Hep) on tau AD sites after 1.5, 3 and 6 hours of reaction (AT270). Thus, the abnormal phosphorylation of tau (pTau) revealed by Alzheimer's disease specific antibodies (AT270 and Ser199 / 202) is inhibited by the presence of disulfated C18 maltobionamide (Mal18diS) after 3 hours of reaction (Figure 4).

[0228] However, when the ability of maltobionamide compounds with hydrocarbon chains (R1) containing 14 to 20 carbon atoms (Mal14diS-Mal20diS) to induce abnormal phosphorylation of tau by themselves was tested, i.e., in the absence of heparin, it was demonstrated that the longer the hydrocarbon chain of the compound, the more it induced p-tau (Figure 5).

[0229] Therefore, for the same ability to protect tau from abnormal phosphorylation, it is preferable to select compounds with the shortest lipid chain length.

[0230] Effect of disaccharides Analogous disulfated cellobionamide and lactobionamide derivatives with hydrocarbon chains containing 14-18 carbon atoms were synthesized to test the influence of the disaccharide properties.

[0231] Regarding the ability to participate in full competition with heparin, only the cellobionamide compounds containing a hydrocarbon chain with 16 carbon atoms and the lactobionamide compounds containing a hydrocarbon chain with 18 carbon atoms, "Cell16diS", "Cell18diS", "Lac16diS" and "Lac18diS", showed similar results to disulfated maltobionamides containing a hydrocarbon chain with 16 carbon atoms ("Mal16diS") and a hydrocarbon chain with 18 carbon atoms ("Mal18diS") in a 3-hour reaction, as shown in Figure 6, after 1.5 to 6 hours of tau phosphorylation by GSK3b.

[0232] The melibionamide derivatives, "Mel14monoS", "Mel16monoS" and "Mel18monoS", which contain a hydrocarbon chain of 14, 16 or 18 carbons, respectively, do not compete with heparin for the abnormal phosphorylation of tau (Figure 6). Thus, it appears that the single anionic charge or the disaccharide conformation of these latter derivatives competes with heparin and is unfavorable for preventing the abnormal phosphorylation of tau.

[0233] Effects of sulfation Oxidized compounds similar to maltobionamide containing 16 or 18 carbon hydrocarbon chains were synthesized to estimate the requirement of sulfation of the sugar moiety of the compound for anti-p-tau activity. It was observed that the oxidized compound containing a 16 carbon hydrocarbon chain ("Mal16diOx") was less effective in preventing tau phosphorylation than the disulfated maltobionamide compound (Mal16diS) with the same chain length (Figure 7). The oxidized compound with an 18 carbon hydrocarbon chain ("Mal18diOx") does not compete with heparin, unlike the disulfated analog containing an 18 carbon hydrocarbon chain ("Mal18diS").

[0234] Thus, disaccharide sulfation is essential to compete with heparin (the prototype of oversulfated HS present in Alzheimer's disease) and prevent abnormal phosphorylation of tau.

[0235] To refine the importance of disaccharide sulfation, maltobionamide derivatives “mal16monoS” and “mal18monoS”, containing hydrocarbon chains with 16 or 18 monosulfated carbons, respectively, or “mal16triS” and “mal18triS”, containing hydrocarbon chains with 16 or 18 trisulfated carbons, respectively, were synthesized.

[0236] The compounds "Mal16monoS", "Mal16triS", "mal18monoS" and "mal18triS" showed (i) a slight decrease in the ability to protect tau against heparin-induced phosphorylation when maltobionamide lost sulfate ("Mal16monoS" and "Mal18monoS"), and (ii) maintenance of this ability to protect tau when the compounds gained sulfate ("Mal16triS" and "Mal18triS") (Figure 8).

[0237] Moreover, when the 16-carbon maltobionamide compound was persulfated (Mal16perS), it retained the ability to protect tau from heparin-induced abnormal phosphorylation, similar to its disulfated homologue of the same lipid chain length (Figure 9).

[0238] 2) Induction of tau protein aggregation The ability of the 16-carbon disulfated maltobionamide compound "Mal16diS" to induce tau protein aggregation, another step in the development of neurofibrillary tangles, was evaluated.

[0239] Therefore, the ability of this molecule to induce or inhibit tau aggregation in vitro (Figure 10) was evaluated by the test described in the paper by Sui et al., 2015, in which tau aggregation was monitored by incorporation of Thioflavin T (ThT).

[0240] Testing Protocol The aggregation tests are carried out using tau protein (4R2N isoform, 441 amino acids) specially synthesized by the supplier Tebu-bio (manufactured 17 / 04 / 19; initial concentration: 2.47 mg / mL) in a final volume of 100 μL in black 96-well plates under various conditions: Tau protein alone (0.71 mg / mL) in buffer (40 mM Tris [pH 7.45], 200 mM NaCl, 2 mM EDTA, and 1 mM DTT) Tau protein (0.71 mg / mL) was diluted in the above buffer in the presence of heparin at 0.35 mg / mL (mass ratio 2 / 1) or 0.175 mg / mL (mass ratio 4 / 1). Tau protein (0.71 mg / mL) in the presence of Mal16diS at 0.175 mg / mL (mass ratio 4 / 1) in the above buffer.

[0241] 100 μL of 50 μM ThT (Sigma-Aldrich) is immediately added to each well and the plate is then incubated under agitation at 37° C. Monitoring of the formation of tau protein aggregates is possible by monitoring the incorporation of thioflavin, which causes fluorescence emission, and is performed by reading at 0, 24, 40, 48 and 71 hours with an Infinite M1000 spectrofluorometer (Tecan) at Exc wavelength 450 nm / Em wavelength 510 nm.

[0242] result The test compound Mal16diS induces tau protein aggregation less strongly compared to heparin up to 72 hours of reaction (FIG. 10).

[0243] 3) In cellulo study of abnormal tau phosphorylation Prior to the in cellulo tau phosphorylation study, a cytotoxicity assay was performed on the neuroblastoma cell line, SH-SY5Y.

[0244] a) Cytotoxicity test Cytotoxicity tests were performed for the molecules that showed the best potential in the in vitro tau phosphorylation assay: maltobionamide disulfate with carbon number 16 and maltobionamide disulfate with carbon number 18. To assess the toxicity level of such molecules by their concentration in the cellular environment, the MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was performed upstream of the in cellulo phosphorylation assay (Figures 11 and 12).

[0245] Testing Protocol SH-SY5Y (ATCC-CRL-2266) cells were developed in a 37°C, 5% CO2 incubator in Dulbecco's Modified Eagle's Complete Medium (DMEM-GlutaMAX™, LifeTechnologies) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin.

[0246] For this, SH-SY5Y cells are cultured in 6-well plates at a cell density of 200,000 cells / well and differentiated for 5 days using retinoic acid (10 μM, Sigma-Aldrich). On day 6, cells are contacted with LG2A molecules at various concentrations (0.1, 1, 10 or 100 μg / mL) in a final volume of 2 mL. After 24 hours, MTT (5 μg / mL; Sigma-Aldrich) is added to the cell culture medium for 2 hours at 37° C. Then, the medium is removed and 200 μL of pure dimethyl sulfoxide (DMSO, Sigma-Aldrich) is added to each well. The entire content of each well is transferred to a 96-well plate and the absorbance is measured at 562 nm using an InfiniteM1000 spectrofluorometer (Tecan).

[0247] result The 16-carbon disulfated maltobionamide (Mal16diS) was not toxic to SH-SY5Y at a minimum dose of 0.1 μg / mL to a maximum dose of 100 μg / mL (FIG. 11).

[0248] Similarly, 18-carbon disulfated maltobionamide (Mal18diS) was shown to be non-toxic to SH-SY5Y from a low dose of 0.1 μg / mL to a high dose of 100 μg / mL (FIG. 12).

[0249] Furthermore, test compounds did not appear to induce a more inflammatory state in HMC3 cells when added at doses of 0.1, 1 or 10 μg / mL after stimulation with lipopolysaccharide (LPS) (50 ng / mL) compared to the same cells receiving only LPS via interleukin 6 assay (data not shown).

[0250] b) In cellulo test using SH-SY5Y strain The model of induced tau phosphorylation in the SH-SY5Y cell line described in the paper from the Gly-CRRET laboratory was used here ( Sepulveda-Diaz et al., 2015 ).

[0251] Testing Protocol Briefly, SH-SY5Y cells are seeded in 6-well plates and differentiated using retinoic acid (10 μM, SigmaAldrich) for 5 days. On day 6, cells are placed in the presence of Mal16diS and Mal18diS molecules at various concentrations (1, 10 or 100 μg / mL) in a final volume of 2 mL, in parallel with wells to which no molecules were added. After 24 hours, the molecules are removed and a stress inducer (H2O2, SigmaAldrich) is added to the cell culture medium for 30 minutes. Cells are then washed with 1×PBS, then lysed and collected in RIPA buffer (ThermoFisher). Protein extracts (10 μg) from the cells are then analyzed by Western blot following the same procedure described above.

[0252] The phosphorylation site of tau tested here is the S262 site (ThermoFisher) and is normalized to the expression of GAPDH protein (SigmaAldrich). The bands are quantified using the Odyssey software of the LI-COR instrument, which allows the ratio of pTau / GAPDH to be calculated for each condition. The ratio obtained for each concentration of the molecule is then expressed as a percentage of the ratio obtained for the control, i.e., cells not treated with the molecule. Thus, values ​​less than 100% correspond to the protection provided by the molecule in this cell model of tau phosphorylation induction.

[0253] The test was repeated for each molecule dose at least four times for the "Mal16diS" and "Mal18diS" molecules and at least two times for the "Cell16diS" and "Lac16diS" molecules. The mean values ​​and standard deviations of the repetitions are shown in Figures 13 to 16, and each of the values ​​obtained for each dose is compared by t-test with the value of the control without the addition of any molecule. Statistical differences with p-values ​​<0.05 are represented by "*" and <0.001 by "***".

[0254] result The two lowest doses tested (1 μg / mL and 10 μg / mL) of 16-carbon disulfated maltobionamide ("mal16diS") significantly reduced tau phosphorylation in SH-SY5Y cells by 30% and 40% (p<0.01) compared to untreated cells (Figure 13).

[0255] For 18-carbon disulfated maltobionamide ("mal18diS"), a significant decrease in tau phosphorylation is observed with increasing concentrations of the compound. At the highest dose of 100 μg / mL, a decrease in tau phosphorylation of up to 60% (p<0.001) is observed compared to untreated cells, while the lowest dose provides nearly 30% protection from oxidative stress-induced tau phosphorylation (Figure 14).

[0256] At the lowest dose of 1 μg / mL, 16-carbon disulfated cellobionamide ("cell16diS") caused an approximately 34% decrease in tau phosphorylation in SH-SY5Y cells compared to untreated cells, but this difference was not statistically significant. This was also the case for doses of 10 μg / mL and 100 μg / mL of this compound, which resulted in 17% and 20% protection of tau, respectively (FIG. 15).

[0257] Finally, the 16-carbon disulfated lactobionamide ("lac16diS"), at the lowest dose of 1 μg / mL, produces a nearly significant (p=0.069) 25% reduction in tau phosphorylation in SH-SY5Y cells. A dose of 10 μg / mL of this compound was not tested. The highest dose of 100 μg / mL of this molecule produces a 54% (p<0.01) protection from tau protein phosphorylation compared to untreated control cells (FIG. 16).

[0258] c) In cellulo study in cortical cells of rTg4510 mice Cortical cells from rTg4510 mice mutated for the human tau protein (P301L) were used as a primary cell model that, unlike previous cell models (Santa Cruz et al., Science, 2005), expresses tauopathy without induction by effectors.

[0259] Testing Protocol Cortical cells were extracted at E16 from mouse embryos expressing the P301L mutation and cultured in 6-well plates. On day 14 (moderate tau phosphorylation) or day 18 (severe tau phosphorylation), cells extracted from the same embryo were placed in the presence of Mal16diS molecules at various concentrations (0.1 or 1 μg / mL) in a final volume of 2 mL for 24 h, in parallel with wells of cells from the same embryo to which no molecule had been added.

[0260] 24 hours after treatment with the molecules, the cells are washed with 1x PBS, then lysed and collected in RIPA buffer (ThermoFisher). Protein extracts (10 μg) from the cells are then analyzed by Western blot following the same procedure as above.

[0261] The phosphorylation site of tau tested here is the S262 site (ThermoFisher) and is normalized to the expression of total tau protein (K9JA, Dako). The bands are quantified using the Odyssey software of the LI-COR instrument, which allows the ratio of pTau / Tau to be calculated for each condition. The ratio obtained for each concentration of the molecule is then expressed as a percentage of the ratio obtained for cells not treated with the molecule. Thus, values ​​less than 100% correspond to the protection provided by the molecule in this cell model of phosphorylation expression of tau.

[0262] The test was repeated at least three times for each dose of the "Mal16diS" molecule. The mean values ​​and standard deviations of the repetitions are shown in Figures 17 and 18, and each of the values ​​obtained for each dose is compared by t-test with the value of cells without the addition of the molecule. Statistical differences according to p-values ​​are represented by "**" for <0.01 and "***" for <0.001.

[0263] result Both tested doses (0.1 μg / mL and 1 μg / mL) of 16-carbon disulfated maltobionamide ("mal16diS") allowed a significant reduction in tau phosphorylation of 48% (p<0.01) and 64% (p<0.001) at moderate levels (D14) in cortical cells of rTg4510 mice compared to untreated cells (Figure 17, n=4).

[0264] This reduction in phosphorylation in primary cultures of cortical cells is maintained when cells exhibit a more severe phosphorylation (D18) prior to treatment, notably a 39% reduction at a dose of 0.1 μg / mL and a 53% reduction at 1 μg / mL of “mal16diS” ( FIG. 18 , n=4).

Claims

1. The following formula (I): 【Chemistry 1】 [In the formula, L is a —C(═O)NH—, —C(═O)O— or —C(═O)S— group; R １ is a linear or branched, saturated or unsaturated hydrocarbon chain containing 15, 16, 17 or 18 carbon atoms, with terminal groups of -OH, -OR, -NH ２ -NHR, -NRR', -COOH, -COOR, -CONHR, -CONRR' and -SR, where R and R' independently represent an alkyl group containing 1 to 6 carbon atoms, and R ４ is represented by formula (IIa) or (IIb): 【Chemistry 2】 [In the formula, R ９ and R １０ are, independently of one another, a hydrogen atom or a sulfonic acid group in ionized form, R １２ is an alkyl group containing 1 to 6 carbon atoms. is the basis of R １１ is -CH ２ -OR ５ or -CONHR １３ It is the basis, R ５ is a hydrogen atom or an ionized sulfonic acid group, R １３ is an alkyl group containing 1 to 6 carbon atoms, R ２ , R ３ , R ６ , R ７ and R ８ are, independently of one another, a hydrogen atom or a sulfonic acid group in ionized form, R ２ , R ３ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ At least one of the groups is a sulfonic acid group in ionized form. A pharmaceutical comprising the compound of formula (I).

2. The pharmaceutical according to claim 1, wherein at least two of the groups R2, R3, R5, R6, R7, R8, R9 and R10 are ionized sulfonic acid groups.

3. R １１ But CH ２ -OR ５ group (in the formula, R ５ is as defined in claim 1. The pharmaceutical composition according to claim 1, 4. The compound of claim 1, wherein the compound has the following formula (Ib): 【Transformation 3】 [In the formula, R １ ~R ３ and R ５ ~R １０ is as defined in claim 1. The pharmaceutical composition of claim 1, wherein 5. The compound of claim 1, wherein the compound has the following formula (Ic): 【Chemistry 4】 [In the formula, R １ ~R ３ and R ５ ~R １０ is as defined in claim 1. The pharmaceutical composition of claim 1, wherein 6. The compound of claim 1, wherein the compound has the following structure (Ie): 【Transformation 5】 [In the formula, R １ ~R ３ and R ５ ~R １０ is as defined in claim 1. The pharmaceutical composition of claim 1, wherein 7. The compound of claim 1, wherein the compound has the following structure (Ig): 【Transformation 6】 [In the formula, R １ ~R ３ and R ５ ~R １０ is as defined in claim 1. The pharmaceutical composition of claim 1, wherein

8. R １ 2. The method of claim 1, wherein is a linear saturated hydrocarbon chain containing 15, 16, 17 or 18 carbon atoms.

9. The pharmaceutical composition of claim 8, wherein R 1 is a linear saturated hydrocarbon chain containing 16 or 18 carbon atoms.

10. R ２ , R ３ , R ６ , R ７ , R ８ and R １０ is a hydrogen atom, and R ５ and R ９ The pharmaceutical composition according to claim 1, wherein is an ionized sulfonic acid group.

11. The compound of claim 1, wherein: 【Transformation 7】 The pharmaceutical composition according to claim 1, which is selected from the group consisting of:

12. The medicament according to any one of claims 1 to 11 for use in the treatment of a tauopathy.

13. A medicament according to any one of claims 1 to 11 for use in the treatment of Alzheimer's disease.

14. The pharmaceutical composition according to any one of claims 1 to 11, wherein the pharmaceutical composition comprises the compound of formula (I) and one or more pharmaceutically acceptable excipients.

15. 15. The medicament according to claim 14 for use in the treatment of a tauopathy.

16. The following structure (Ic): 【Transformation 8】 [In the formula, R １ is a linear or branched, saturated or unsaturated hydrocarbon chain containing 15, 16, 17 or 18 carbon atoms, with terminal groups of -OH, -OR, -NH ２ -NHR, -NRR', -COOH, -COOR, -CONHR, -CONRR' and -SR, where R and R' independently represent an alkyl group containing 1 to 6 carbon atoms, and R ５ is a hydrogen atom or an ionized sulfonic acid group, R ９ and R １０ are, independently of one another, a hydrogen atom or a sulfonic acid group in ionized form, R ２ , R ３ , R ６ , R ７ and R ８ are, independently of one another, a hydrogen atom or a sulfonic acid group in ionized form, R ２ , R ３ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ At least one of the groups is a sulfonic acid group in ionized form. A compound having the formula:

17. The compound of claim 16, wherein at least two of the groups R2, R3, R5, R6, R7, R8, R9 and R10 are ionized sulfonic acid groups.

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