CN111527097A - Seleno galactoside compounds for treating systemic insulin resistance disorder and uses thereof - Google Patents

Abstract

Various aspects of the present invention are directed to novel synthetic compounds having binding affinity to galectin proteins for the treatment of systemic insulin resistance disorders.

Description

Selenogalactoside compound for treating systemic insulin resistance disorder and use thereof

inventor

P. G. Traber, E. Zomer, D. Slater, J. M. Johnson, R. George, S. Schechter, and R. Neal.

Related applications

This application claims the benefit of and priority to US Provisional Application Serial No. 62/579,343, filed October 31, 2017, the entire disclosure of which is incorporated herein by reference in its entirety.

technical field

Various aspects of the present invention relate to compounds, pharmaceutical compositions, methods for making compounds, and for treating metabolism mediated, at least in part, by one or more galactose-binding proteins (also known as galectins) obstacle method.

Background technique

Galectins are a family of S-type lectins that bind glycoproteins containing beta-galactosan. So far, 15 mammalian galectins have been isolated. Galectins regulate diverse biological processes such as diabetes, inflammation, fibrogenesis, metabolic disorders, cancer progression, metastasis, apoptosis and immune evasion.

SUMMARY OF THE INVENTION

Various aspects of the present invention pertain to compounds and compositions for use in therapeutic formulations comprising the compound in an acceptable pharmaceutical carrier, for parenteral or enteral administration. In some embodiments, the compositions may be administered orally or topically or parenterally via intravenous or subcutaneous routes.

Various aspects of the present invention relate to compounds, compositions and methods for the treatment of various disorders, including but not limited to the treatment of systemic insulin resistance, in which lectin proteins play a role in the pathogenesis of various disorders. In some embodiments, compounds can reverse Galectin-3 binding to insulin receptors and/or enhance sensitivity to insulin activity in various tissues.

Various aspects of the present invention relate to compounds, compositions and methods for the treatment of, but not limited to, systemic insulin resistance. In some embodiments, systemic insulin resistance is associated with obesity, where elevated Galectin-3 interacts with insulin receptors. In some embodiments, treatment with the compounds of the present invention can restore sensitivity to insulin activity in various tissues.

Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with type 1 diabetes. Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with type 2 diabetes mellitus (T2DM). Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with obesity, gestational diabetes and prediabetes. In some embodiments, the compound restores the sensitivity of cells to insulin activity. In some embodiments, the compounds inhibit the interaction of Galectin-3 with the insulin receptor, which interferes with insulin binding and cellular glucose uptake mechanisms. Various aspects of the invention relate to compounds, compositions and methods for treating low grade inflammation caused by elevated levels of free fatty acids and triglycerides that cause skeletal Insulin resistance in muscle and liver, leading to the development of atherosclerotic vascular disease and NAFLD. Various aspects of the present invention relate to compounds, compositions and methods for treating polycystic ovary syndrome (PCOS) associated with obesity, insulin resistance and compensated hyperinsulinemia. Various aspects of the present invention relate to compounds, compositions and methods for treating diabetic nephropathy and glomerulosclerosis by attenuating integrin and TGF[beta] receptor pathways in chronic kidney disease. In some embodiments, the compounds can inhibit overexpression of the TGFβ receptor signaling system and cause a decrease in renal function triggered by insulin resistance in diabetics and can reverse established diabetic glomerulopathy established lesions.

In some embodiments, the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof. In some embodiments, the compound is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or a combination thereof. In some embodiments, the compounds are administered with one or more antidiabetic drugs. In some embodiments, the administration of the compound of the present invention and the active agent results in a synergistic effect.

Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with obesity, where elevated Galectin-3 interacts with the insulin receptor. In some embodiments, treatment with the compounds of the present invention can restore sensitivity to insulin activity in various tissues.

In some embodiments, the compounds or compositions of the invention bind to the insulin receptor (also known as IR, INSR, CD220, HHF5).

Various aspects of the present invention relate to compounds, compositions and methods of treating diseases caused by disruption of the activity of TGFb1 (transforming growth factor beta 1).

Various aspects of the present invention relate to compounds, compositions and methods for treating diseases associated with the transforming growth factor beta signaling pathway.

Various aspects of the present invention relate to compounds or compositions for the treatment of various chronic inflammatory diseases, fibrotic diseases and cancer. In some embodiments, compounds are capable of mimicking the interaction of glycoproteins with lectins or galectin proteins, which are known to modulate immune recognition, inflammation, fibrogenesis, angiogenesis, cancer progression and Pathophysiological pathways of metastasis.

In some embodiments, the compound includes a pyranosyl and/or furanosyl structure bound to a selenium atom on the anomeric carbon of the pyranosyl and/or furanosyl group .

In some embodiments, specific aromatic substitutions can be added to the galactose or heteroglycoside core to further enhance the affinity of selenium bound pyranosyl and/or furanosyl structures. Such aromatic substitutions can enhance the interaction of the compound with the amino acid residues (eg, arginine, tryptophan, histidine, glutamic acid, etc.) that make up the carbohydrate recognition domain (CRD) of the lectin, and thus Enhances association and binding specificity.

In some embodiments, the compound may comprise a monosaccharide, disaccharide, oligosaccharide of galactose, or a heteroglycoside core bound to a selenium atom (Se) on the anomeric carbon of the galactose or heteroglycoside.

In some embodiments, the compound is a symmetrical digalactoside, wherein two galactosides are joined by one or more selenium bonds. In some embodiments, the compound is a symmetric digalactoside, wherein the two galactosides are bound by one or more selenium bonds, and wherein the selenium is bound to the anomeric carbon of galactose. In some embodiments, the compound is a symmetrical digalactoside, wherein the two galactosides are bound by one or more selenium bonds and one or more sulfur bonds, and wherein the selenium is anomeric with galactose carbon bond. In other embodiments, the compound may be an asymmetric digalactoside. For example, compounds can have various aromatic or aliphatic substitutions on the galactose core.

In some embodiments, the compounds are symmetrical galactosides with one or more seleniums on the anomeric carbon of galactose. In some embodiments, the galactosides have one or more selenium bound to the anomeric carbon of galactose and one or more sulfur bound to the selenium. In some embodiments, the compounds may have various aromatic or aliphatic substitutions on the galactose core.

Without being bound by theory, it is believed that compounds containing selenium-containing molecules make the compounds metabolically stable while maintaining the chemical, physical and allosteric properties of specific interactions with lectins or galectins known to recognize carbohydrates.

In some embodiments, the monogalactosides, digalactosides, or oligosaccharides of galactose of the invention are metabolically more stable than compounds with O-glycosidic or S-glycosidic linkages.

In some embodiments, the compound is a compound of formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof:

where X is selenium,

wherein W is selected from the group consisting of O, N, S, CH, NH and Se,

wherein Y is selected from O, S, C, NH, CH2, Se, S, SO3, PO2, amino acids, including heterocyclic substituted hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives having a molecular weight of about 50-200 D, and combinations thereof Group,

wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,

wherein R1, R2 and _R3 are independently selected from CO, _O2 , SO2, PO2, PO, CH, hydrogen or _a combination of these, and a) alkyl of at least 3 carbons, alkenyl of at least 3 carbons, Alkyl of at least 3 carbons substituted by carboxyl, alkenyl of at least 3 carbons substituted by carboxyl, alkyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino alkyl of at least 3 carbons substituted with both carboxy, alkenyl of at least 3 carbons substituted with both amino and carboxy, and alkyl substituted with one or more halogens, b) benzene substituted with at least one carboxy phenyl, phenyl substituted with at least one halogen, phenyl substituted with at least one alkoxy, phenyl substituted with at least one nitro, phenyl substituted with at least one sulfo, phenyl substituted with at least one amino , phenyl substituted with at least one alkylamino group, phenyl substituted with at least one dialkylamino group, phenyl substituted with at least one hydroxy group, phenyl substituted with at least one carbonyl group, and phenyl substituted with at least one substituted carbonyl group phenyl, c) naphthyl, naphthyl substituted by at least one carboxy, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, naphthyl substituted by at least one nitro, naphthyl substituted by at least one Sulfo-substituted naphthyl, at least one amino-substituted naphthyl, at least one alkylamino-substituted naphthyl, at least one dialkylamino-substituted naphthyl, at least one hydroxy-substituted naphthyl, at least one hydroxy-substituted naphthyl One carbonyl substituted naphthyl and at least one substituted carbonyl substituted naphthyl, d) heteroaryl, at least one carboxy substituted heteroaryl, at least one halogen substituted heteroaryl, at least one alkoxy substituted heteroaryl, heteroaryl substituted with at least one nitro, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, Heteroaryl substituted with at least one dialkylamino, heteroaryl substituted with at least one hydroxy, heteroaryl substituted with at least one carbonyl, and heteroaryl substituted with at least one substituted carbonyl, and e) sugars, Substituted sugar, D-galactose, substituted D-galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl , heteroaryl, heterocycle and derivatives, amino, substituted amino, imino and substituted imino group.

In some embodiments, the compound is of general formula (3) or formula (4) or a pharmaceutically acceptable salt or solvate thereof:

where X is selenium,

wherein W is selected from the group consisting of O, N, S, CH, NH and Se,

wherein Y is selected from the group consisting of O, S, C, NH, CH, Se, S, P, amino acids, including heterocyclic substituted hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives having a molecular weight of about 50-200 D, and combinations thereof,

wherein Z is selected from the group consisting of O, S, N, CH, Se, SO2, PO2 and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,

Among them, n≤24,

wherein R1 and R2 are independently selected from CO, _O2 , SO2, SO, PO2, PO, CH, hydrogen or _a combination of these, and a) alkyl of at least 3 carbons, alkenyl of at least 3 carbons, Carboxyl-substituted alkyl of at least 3 carbons, alkenyl of at least 3 carbons substituted by carboxyl, alkyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino, and Alkyl of at least 3 carbons substituted with both carboxy, alkenyl of at least 3 carbons substituted with both amino and carboxy, and alkyl substituted with one or more halogens, b) phenyl substituted with at least one carboxy , phenyl substituted by at least one halogen, phenyl substituted by at least one alkoxy, phenyl substituted by at least one nitro, phenyl substituted by at least one sulfo, phenyl substituted by at least one amino, Phenyl substituted with at least one alkylamino, phenyl substituted with at least one dialkylamino, phenyl substituted with at least one hydroxy, phenyl substituted with at least one carbonyl, and benzene substituted with at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxy, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, naphthyl substituted by at least one nitro, naphthyl substituted by at least one sulfo naphthyl substituted with at least one amino group, naphthyl group substituted with at least one amino group, naphthyl group substituted with at least one alkylamino group, naphthyl group substituted with at least one dialkylamino group, naphthyl group substituted with at least one hydroxy group, naphthyl group substituted with at least one hydroxy group Naphthyl substituted by carbonyl and naphthyl substituted by at least one substituted carbonyl, d) Heteroaryl, heteroaryl substituted by at least one carboxy, heteroaryl substituted by at least one halogen, substituted by at least one alkoxy Heteroaryl substituted with at least one nitro, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, at least one dialkylamino substituted heteroaryl, at least one hydroxy substituted heteroaryl, at least one carbonyl substituted heteroaryl, and at least one substituted carbonyl substituted heteroaryl, and e) sugars, substituted sugar, D-galactose, substituted D-galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, The group consisting of heteroaryl, heterocycle and derivatives, amino, substituted amino, imino and substituted imino. In some embodiments, n=1. In other embodiments, n=3.

In some embodiments, the compound is a compound of formula (5) or formula (6), or a pharmaceutically acceptable salt or solvate thereof:

where X is Se, Se-Se, Se-S, S-Se, Se-SO2 or SO2-Se,

wherein W is selected from the group consisting of O, N, S, CH, NH and Se,

wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, amino acids and combinations thereof,

wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,

wherein R1, R2, _R3 and R4 are independently selected from CO, _O2 , SO2, SO, PO2, PO, CH, hydrogen or _a combination of these, and a) alkyl of at least ₃ carbons, at least 3 carbon alkenyl, at least 3 carbon alkyl substituted by carboxyl, at least 3 carbon alkenyl substituted by carboxyl, at least 3 carbon alkyl substituted by amino, at least 3 carbon substituted by amino alkenyl, alkyl of at least 3 carbons substituted by both amino and carboxy, alkenyl of at least 3 carbons substituted by both amino and carboxy, and alkyl substituted by one or more halogens, b) by at least one carboxy-substituted phenyl, at least one halogen-substituted phenyl, at least one alkoxy-substituted phenyl, at least one nitro-substituted phenyl, at least one sulfo-substituted phenyl, at least one sulfo-substituted phenyl Amino-substituted phenyl, phenyl substituted with at least one alkylamino, phenyl substituted with at least one dialkylamino, phenyl substituted with at least one hydroxy, phenyl substituted with at least one carbonyl, and phenyl substituted with at least one Substituted carbonyl substituted phenyl, c) naphthyl, naphthyl substituted with at least one carboxyl group, naphthyl substituted with at least one halogen, naphthyl substituted with at least one alkoxy group, naphthyl substituted with at least one nitro group group, naphthyl substituted with at least one sulfo, naphthyl substituted with at least one amino, naphthyl substituted with at least one alkylamino, naphthyl substituted with at least one dialkylamino, naphthyl substituted with at least one hydroxy naphthyl, naphthyl substituted by at least one carbonyl and naphthyl substituted by at least one carbonyl, d) heteroaryl, heteroaryl substituted by at least one carboxy, heteroaryl substituted by at least one halogen, Heteroaryl substituted with at least one alkoxy, heteroaryl substituted with at least one nitro, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, substituted with at least one alkylamino heteroaryl, heteroaryl substituted with at least one dialkylamino, heteroaryl substituted with at least one hydroxy, heteroaryl substituted with at least one carbonyl, and heteroaryl substituted with at least one substituted carbonyl, and e) sugars, substituted sugars, D-galactose, substituted D-galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, The group consisting of alkenyl, aryl, heteroaryl, heterocycle and derivatives, amino, substituted amino, imino and substituted imino.

In some embodiments, the halogen is a fluoro, chloro, bromo or iodo group.

In some embodiments, the compound is a 3-derivatized diselenogalactoside with a fluorophenyltriazole.

Various aspects of the present invention pertain to compounds of formula (5), or a pharmaceutically acceptable salt or solvate thereof:

In some embodiments, the compound is in free form. In some embodiments, the free form is an anhydride. In some embodiments, the free form is a solvate, such as a hydrate.

In some embodiments, the compound is in crystalline form.

Some aspects of the present invention pertain to pharmaceutical compositions comprising a compound of the present invention and, optionally, pharmaceutically acceptable additives such as adjuvants, carriers, excipients, or combinations thereof. In some embodiments, the pharmaceutical composition includes a compound of formula (1), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvent thereof compound and optionally pharmaceutically acceptable additives such as adjuvants, carriers, excipients or combinations thereof.

In some embodiments, the compounds of the present invention bind to one or more galectins. In some embodiments, the compound binds to Galectin-3, Galectin-1, Galectin 8, and/or Galectin 9.

In some embodiments, the compounds of the present invention have high selectivity and affinity for Galectin-3. In some embodiments, the compounds of the invention have an affinity for Galectin-3 from about 1 nM to about 50 μM.

Various aspects of the present invention relate to compositions or compounds that can be used to treat diseases. Various aspects of the present invention relate to compositions or compounds that can be used to treat diseases in which galectins are involved, at least in part, in pathogenesis. Other aspects of the invention relate to methods of treating a disease in a subject in need thereof.

Some aspects of the present invention pertain to methods of treating insulin resistance comprising administering to a subject in need thereof a therapeutically effective amount of formulas (1), (2), (3), (4), (5), (6 ) or a compound of (7) or a pharmaceutically acceptable salt or solvate thereof.

Some aspects of the invention pertain to methods of treating insulin resistance comprising administering to a subject in need thereof a therapeutically effective amount of formula (1), (2), (3), (4), (5), ( A composition of the compound of 6) or (7) or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compounds can be used in conjunction with an active agent. In some embodiments, the active agent is an immunomodulator, an anti-inflammatory drug, a vitamin, a nutraceutical, a supplement, or a combination thereof. In some embodiments, the administration of the compound of the present invention and the active agent results in a synergistic effect.

Some aspects of the invention relate to methods of treating diseases caused by disrupted activity of TGFβ1 (transforming growth factor β1) by reversing the interaction of galectin-3 with its receptor (TGFβ1-receptor) to restore normal levels of regeneration activity.

Some aspects of the invention relate to methods of treating diseases associated with the transforming growth factor beta signaling pathway, which is involved in many cellular and pathological processes in both adult and embryonic development, including cell growth, cell differentiation, apoptosis, cellular Homeostasis and other cellular functions.

Some aspects of the invention relate to methods for treating disorders associated with galectin binding, such as galectin-3 binding to the insulin receptor or the TGFβ1-receptor in humans, wherein the method comprises administering to A subject in need thereof is administered a therapeutically effective amount of at least one compound of formula (1), (2), (3), (4), (5), (6) or (7).

Some aspects of the present invention pertain to compounds of formula (1), (2), (3), (4), (5), (6) or (7), or pharmaceutically acceptable salts or solvates thereof, using Methods of treating disorders associated with galectin binding in a subject in need thereof. Some aspects of the present invention pertain to compounds of formula (1), (2), (3), (4), (5), (6) or (7), or pharmaceutically acceptable salts or solvates thereof, using Methods of treating disorders associated with binding of Galectin-3 to a ligand in a subject in need thereof.

In some embodiments, the subject in need is a mammal. In some embodiments, the subject in need is a human.

Some aspects of the invention relate to methods for treating disorders associated with binding of galectins (such as Galectin-3) to ligands in humans, wherein the methods comprise administering to a human in need thereof a therapeutically effective amount At least one compound of formula (1), (2), (3), (4), (5), (6) or (7) of , or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method of treatment is for systemic insulin resistance.

Description of drawings

The patent or application file includes at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

The present invention will be further described with reference to the accompanying drawings, wherein like numerals are used to refer to like structures throughout the several views. The drawings shown are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

Figure 1 depicts a high resolution 3D structure of the Galectin-3 carbohydrate recognition domain (CRD) binding pocket with three potential interaction sites.

Figure 2 depicts the location of the CRD pocket in the C-terminus of Galectin-3 with bound lactose units.

Figure 3 depicts a map of Galectin-3 CRD sites for enhanced binding - potential synergistic amino acids.

Figure 4 depicts the synthesis of selenogalactoside compounds according to some embodiments.

5A depicts a Fluorescent Polarization Assay Format for the detection of compounds that specifically bind to a CRD, according to some embodiments.

5B depicts a fluorescence resonance energy transfer assay (FRET method) (eg, TGFb1-receptor FRET method) for screening compounds that inhibit the interaction of Galectin-3 with its glycoprotein-ligand, according to some embodiments.

Figure 6A depicts inhibition of galectin-binding moieties using a specific anti-galectin-3 monoclonal antibody binding assay (ELISA method) according to some embodiments.

Figure 6B depicts a functional assay (eg, insulin-receptor ELISA method) to screen for compounds that inhibit the interaction of Galectin-3 with its glycoprotein-ligand, according to some embodiments.

Figure 7 provides examples of compound IC50s by fluorescence polarization-CRD specific determination of compounds according to some embodiments.

Figure 8 provides examples of compound IC50s as determined by the insulin-receptor-galectin-3 ELISA method according to some embodiments.

Figure 9 provides examples of compound IC50s as determined by the TGFb1-receptor-galectin-3 ELISA method according to some embodiments.

Detailed ways

Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various forms. Furthermore, each example given in connection with various embodiments of the present invention is intended to be illustrative and not restrictive. The drawings are not necessarily to scale; some features may be exaggerated to show details of particular components. Furthermore, any measurements, specifications and the like shown in the figures are illustrative and not restrictive. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.

Citation of documents herein is not intended to be an admission that any document cited herein is pertinent prior art, or that the cited document is believed to be essential to the patentability of the claims of this application.

Throughout the specification and claims, unless the context clearly dictates otherwise, the following terms take the meanings explicitly associated herein. The phrases "in one embodiment" and "in some embodiments" as used herein do not necessarily refer to the same embodiment, although they may. Furthermore, the phrases "in another embodiment" and "in some other embodiments" as used herein do not necessarily refer to different embodiments, although they may. Accordingly, as described below, various embodiments of the present invention may be readily combined without departing from the scope or spirit of the present invention.

Also, as used herein, the term "or" is the inclusive "or" operator and is equivalent to the term "and/or" unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for additional factors not described unless the context clearly dictates otherwise. Also, throughout the specification, the meanings of "a," "an," and "the" include plural references.

All percentages expressed herein are weight/weight unless otherwise indicated.

Various aspects of the invention relate to compositions of monosaccharides, disaccharides and oligosaccharides of a galactose (or heteroglycoside) core bound to a selenium atom (Se) at the anomeric carbon of the galactose (or heteroglycoside). In some embodiments, Se-containing molecules render them metabolically stable, while maintaining chemical, physical, and allosteric properties that specifically interact with lectins known to recognize carbohydrates. In some embodiments, specific aromatic substitutions added to the galactose core further enhance the affinity of the selenium-bound pyranosyl and/or furanosyl structures by enhancing their affinity with the carbohydrate recognition domains that make up the lectin (CRD) amino acid residues (eg, arginine, tryptophan, histidine, glutamic acid, etc.) and thus enhance association and binding specificity.

In some embodiments, the compositions or compounds may be used to treat nonalcoholic steatohepatitis with or without liver fibrosis, inflammatory and autoimmune disorders, neoplastic disorders, or cancer.

In some embodiments, the compositions can be used to treat liver fibrosis, renal fibrosis, pulmonary fibrosis, or cardiac fibrosis.

In some embodiments, the composition or compound is capable of enhancing anti-fibrotic activity in organs including, but not limited to, liver, kidney, lung, and heart.

In some embodiments, the compositions or compounds can be used to treat inflammatory disorders of the vasculature, including atherosclerosis and pulmonary hypertension.

In some embodiments, the compositions or compounds can be used to treat cardiac disorders, including heart failure, arrhythmias, and uremic cardiomyopathy.

In some embodiments, the composition or compound can be used to treat renal disease, including glomerulopathy and interstitial nephritis.

In some embodiments, the compositions or compounds can be used to treat inflammatory, proliferative and fibrotic skin disorders, including but not limited to psoriasis and scleroderma.

Various aspects of the invention relate to methods of treating allergic or atopic conditions, including but not limited to eczema, atopic dermatitis, or asthma.

Various aspects of the invention relate to methods of treating inflammatory and fibrotic disorders in which galectins are involved, at least in part, in their pathogenesis by enhancing anti-fibrotic activity in organs including, but not limited to, liver, kidney, lung, and heart.

Various aspects of the present invention relate to methods, compositions or compounds having therapeutic activity for the treatment of nonalcoholic steatohepatitis (NASH). In other aspects, the invention relates to methods of reducing the pathology and disease activity associated with nonalcoholic steatohepatitis (NASH).

Various aspects of the present invention relate to compositions or compounds for use in the treatment of inflammatory and autoimmune disorders, or methods of treating inflammatory and autoimmune disorders, wherein galectins are involved, at least in part, in the pathogenesis of the disorder, the disorder Including but not limited to arthritis, systemic lupus erythematosus, rheumatoid arthritis, asthma and inflammatory bowel disease.

Various aspects of the invention relate to compositions or compounds for the treatment of neoplastic disorders (eg, benign or malignant diseases) in which galectins are at least partially involved in pathogenesis by inhibiting processes promoted by an increase in galectins. In some embodiments, the present invention relates to methods of treating neoplastic disorders (eg, benign or malignant diseases) in which galectins are at least partially involved in pathogenesis by inhibiting processes promoted by an increase in galectins. In some embodiments, the compositions or compounds can be used to treat or prevent tumor cell growth, invasion, metastasis, and neovascularization. In some embodiments, the compositions or compounds can be used to treat primary and secondary cancers.

Aspects of the invention relate to interaction with other antineoplastic agents (including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1, anti-PDL1)), other immunomodulatory agents (including but not limited to anti-OX40) and various mechanisms A composition or compound for the treatment of a neoplastic disorder in combination with one or more other antineoplastic agents.

In some embodiments, a therapeutically effective amount of a compound or composition may be compatible and effectively combined with a therapeutically effective amount of various anti-inflammatory drugs, vitamins, other drugs, and nutritional drugs or supplements, or combinations thereof, or the like.

Galectin

Galectins (also known as galaptins or S-lectins) are a family of lectins that bind beta-galactoside. Galectins: a family of animal beta-galactoside-binding lectins (Galectins: a family of animal beta-galactoside- binding lectins). Cell 76, 597-598, 1994). This family is defined by having at least one characteristic carbohydrate recognition domain (CRD) with affinity for β-galactoside and sharing certain sequence elements. Further structural characterization divided galectins into three subgroups, including: (1) galectins with a single CRD, (2) galectins with two CRDs linked by a linking peptide, and (3) ) group with one member (galectin-3) with one CRD linked to a different type of N-terminal domain. The galectin carbohydrate recognition domain is a beta-sandwish of approximately 135 amino acids. The two sheets are slightly curved, with 6 chains forming concave sides, also called S-faces, and 5 chains forming convex sides, F-faces). Concave sides form grooves in which carbohydrates are bound (Leffler H, Carlsson S, Hedlund M, Qian Y, Poirier F (2004). "Introduction to galectins". Journal of Glycoconjugates (Glycoconj. J.) 19(7-9):433-40).

Various biological phenomena have been shown to be associated with galectins, including development, differentiation, morphogenesis, tumor metastasis, apoptosis, RNA splicing, and the like.

Typically, carbohydrate domains bind to galactose residues associated with glycoproteins. Galectins show affinity for galactose residues attached to other organic compounds, such as in lactose [(β-D-galactoside)-D-glucose], N-acetyl-lactosamine, poly-N - in fragments of acetyllactosamine, galactomannan or pectin. However, it should be noted that galactose itself does not bind to galectins.

Inference based on the presence of galactose-containing residues in a macromolecular background suggests that plant polysaccharides pectin and modified pectins bind to galectin proteins, in this case complex carbohydrates, rather than in animal cells down glycoproteins.

At least 15 mammalian galectin proteins have been identified with one or two carbohydrate domains in tandem.

Galectin proteins are present in the intercellular space where they are assigned many functions, and they are also secreted into the extracellular space with different functions. In the extracellular space, galectin proteins can have multiple functions mediated by their interactions with galactose-containing glycoproteins, including facilitating interactions between glycoproteins that can modulate function, or in Regulation of cell signaling in the context of integral membrane glycoprotein receptors (Sato et al., Galectins as danger signals in host-pathogen and host-tumor interactions: a growing new member of 'alarm proteins' (Galectins as danger signals in host-pathogen and host-tumorinteractions: new members of the growing group of "Alarmins."), "Galectins" (edited by Klyosov et al.), John Wiley and Sons ), 115-145, 2008; Liu et al., Galectins in acute and chronic inflammation, Ann.N.Y.Acad.Sci., 1253:80-91 , 2012). Galectin proteins in the extracellular space can also facilitate cell-cell and cell-matrix interactions Wang et al. Nuclear and cytoplasmic localization of galectin-1 and galectin-3 and their presence in pre-mRNA Roles in splicing (Nuclear and cytoplasmic localization of galectin-1 and galectin-3 and their roles in pre-mRNA splicing), "Galectin" (eds. Klyosov et al.), John Wiley and Sons, 87-95, 2008). Regarding the intracellular space, galectin function appears to be more related to protein-protein interactions, but intracellular vesicle trafficking appears to be related to interactions with glycoproteins.

Galectins have been shown to have domains that promote homodimerization. Therefore, galectins can act as "molecular glue" between glycoproteins. Galectins are present in multiple cellular compartments, including the cell core and cytoplasm, and are secreted into the extracellular space, where they interact with cell surface and extracellular matrix glycoproteins. The mechanism of molecular interaction depends on localization. While galectins can interact with glycoproteins in the extracellular space, interactions of galectins with other proteins in the intracellular space typically occur via protein domains. In the extracellular space, association of cell surface receptors can increase or decrease the ability of receptors to signal or interact with ligands.

Galectin proteins are significantly increased in many animal and human disease states, including but not limited to disorders associated with inflammation, fibrosis, autoimmunity, and neoplasia. Galectins have been directly involved in disease pathogenesis, as described below. For example, disease states that may be galectin-dependent include, but are not limited to: systemic insulin resistance, acute and chronic inflammation, allergic disorders, asthma, dermatitis, autoimmune diseases, inflammatory and degenerative arthritis, immune mediators induced neurological disease, fibrosis of multiple organs (including but not limited to liver, lung, kidney, pancreas and heart), inflammatory bowel disease, atherosclerosis, heart failure, ocular inflammatory diseases, various cancers.

In addition to disease states, galectins are important regulatory molecules in regulating immune cell responses to vaccination, foreign pathogens, and cancer cells.

Those skilled in the art will appreciate that galectins can be bound and/or altered in their affinity for glycoproteins, reduced heterotypic or homotypic interactions between galectins, or otherwise altered Compounds of protein function, synthesis or metabolism can have important therapeutic effects in galectin-dependent diseases.

Galectin proteins, such as Galectin-1 and Galectin-3 have been shown to be significantly increased in inflammation, fibrotic disorders and neoplasia (Ito et al., Galectin-1 as Effective for Cancer Therapy Target: a role in the tumor microenvironment ("Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment"), Cancer Metastasis Rev. PMID: 22706847 (2012), Nangia-Makker et al., Galectin- Galectin-3 binding and metastasis, Methods Mol. Biol. 878:251-266, 2012, Canesin et al., Galectin-3 expression and bladder cancer progression Galectin-3expression is associated with bladdercancer progression and clinical outcome, Tumour Biol., 31: 277-285, 2010, Wanninger et al, Systemic and hepatic in patients with alcoholic cirrhosis Systemic and hepatic vein galectin-3 are increased inpatients with alcoholic liver cirrhosis and negatively correlate with liver function, Cytokine, 55:435- 40, 2011). Furthermore, experiments have shown that galectins, especially galectin-1 (gal-1) and galectin-3 (gal-3), are directly involved in the pathogenesis of these diseases (Toussaint et al., Gal-2 The lectin-1 gene is preferentially expressed at the tumor margin and promotes the infiltration of glioblastoma cells (“Galectin-1, a gene preferentially expressed at the tumor margin, promotesglioblastoma cell invasion”), Mol. Cancer. 11: 32, 2012; Liu et al., 2012, Newlaczyl et al., "Galectin-3-a jack-of-all-trades in cancer", Cancer Lett. 313:123-128, 2011 Banh et al., "Tumor galectin-1 mediates tumor growth and metastasis through regulation of T-cell apoptosis", Cancer Res .), 71:4423-31, 2011; Lefranc et al., “Galectin-1mediated biochemical controls of melanoma and gliomaaggressive behavior”, World J. Biol. Chem., 2: 193-201, 2011, Forsman et al. Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis (“Galectin 3 aggravates joint inflammation and destruction” in antigen-induced arthritis”), Arthritis Rheum., 63:445-454, 2011; de Boer et al., Galectin-3 and cardiac remodeling and heart failure (“Galectin- 3in cardiac remodeling and heartfailure”), Curr. Heart Fail.Rep. 7, 1-8, 2010; Ueland et al. Galectin-3 in heart failure: high levels are associated with all-cause mortality (“Gale ctin-3 in heart failure: high levels are associated with all-cause mortality”), Int J. Cardiol., 150: 361-364, 2011; Ohshima et al., Galectin 3 and its The role of binding proteins in rheumatoid arthritis ("Galectin 3 and its binding protein in rheumatoid arthritis"), Arthritis Rheum., 48: 2788-2795, 2003).

检测是一种体外诊断设备，可以定量测量血清或血浆中的半乳糖凝集素-3，并且可以与临床评估结合使用，以帮助评估被诊断为慢性心力衰竭的患者的预后。内源性蛋白半乳糖凝集素-3浓度的测量可以用来预测或监测接受心脏再同步治疗的患者的疾病进展或治疗效力(参见US 8,672,857)。High levels of serum Galectin-3 have been shown to be associated with several human diseases, such as a more aggressive form of heart failure, making the use of Galectin-3 testing to identify high-risk patients an important part of patient care part. Galectin-3 testing can be used to help physicians determine which patients are at higher risk for hospitalization or death. For example, BGM

The test is an in vitro diagnostic device that quantitatively measures Galectin-3 in serum or plasma and can be used in conjunction with clinical assessments to help assess the prognosis of patients diagnosed with chronic heart failure. Measurement of endogenous protein Galectin-3 concentrations can be used to predict or monitor disease progression or treatment efficacy in patients receiving cardiac resynchronization therapy (see US 8,672,857).

Galectin-3 has been shown to be elevated in patients with metabolic disorders and in obese people with diabetes mellitus associated with systemic insulin resistance. High levels of serum Galectin-3 have been shown to be associated with obesity and diabetes. Diabetes is a long-lasting disease that can be resolved or prevented with care. It is one of the most common metabolic syndromes in the world. Diabetes is mainly associated with the central and peripheral nervous systems and is a chronic complication. Diabetes is a common type of diabetic metabolic syndrome in which the body cannot use glucose and stores it in the blood, which can damage the kidneys, nerves, heart, eyes and cause other complications.

Insulin resistance

Insulin resistance is a characteristic feature of patients with complications of diabetes mellitus (T2DM) and is one of the defining clinical features of metabolic syndrome (MetS). MetS is a group of biochemical and metabolic diseases estimated to affect more than 20% of adults (>20 years of age) or approximately 500 million Americans in the United States. With the obesity epidemic showing no signs of reversing, that number could rise sharply in the future.

The main feature of type 2 diabetes -- insulin resistance -- may develop in people with type 1 diabetes, clinically designated as double diabetes. People with double diabetes always have type 1 diabetes, but with the complication of insulin resistance. The most common cause of developing insulin resistance is obesity, and type 1 diabetes itself is not caused by obesity.

People with type 1 diabetes are just as prone to obesity and suffer from insulin resistance as everyone else.

Insulin is a hormone with multiple functions, including facilitating the transport of nutrients into cells, regulating various enzymatic activities, and regulating energy homeostasis. These functions involve glucose metabolism in liver, adipose tissue and muscle via intracellular signaling pathways. In the liver, insulin resistance leads to increased hepatic glucose production. In adipose tissue, insulin resistance affects lipase activity, leading to antilipid effects, affecting free fatty acid efflux from adipocytes and increasing circulating free fatty acids.

Recent studies have shown that galectin-3 plasma levels are significantly elevated in human and animal models of obesity.

In obesity, macrophages and other immune cells have been reported to be recruited to insulin target tissues and promote chronic inflammatory states and insulin resistance. Galectin-3, known to be mainly secreted by macrophages, may play a key role in this inflammatory process, thus linking inflammation to decreased insulin sensitivity.

The insulin receptor is a transmembrane protein activated by bound insulin, IGF-I, and IGF-II, and belongs to a class of tyrosine kinase receptors. Insulin receptors play a key role in regulating glucose homeostasis, when dysfunctional or metabolic disorders may lead to a range of clinical manifestations, including but not limited to diabetes. The insulin receptor is encoded by the single gene INSR, which may lead to either IR-A or IR-B subtypes during transcription. Post-translationally these isoforms lead to the formation of proteolytic alpha and beta subunits, which combine to form a transmembrane insulin receptor with a final activity of ≈320 kDa.

The interaction of the insulin receptor and insulin is a checkpoint for a second pathway, Ras-mitogen-active protein kinase (MAPK), which mediates gene expression, and also affects cells that control cell growth and differentiation. PI3K-AKT pathway. Insulin receptor substrates (IRS) are common intermediates that include four distinct family members, IRS1-4. Defects in insulin signaling typically involve insulin receptor substrate-1 (IRS1). Activation of the insulin receptor increases tyrosine phosphorylation of IRS1, which initiates signal transduction. However, when serine 307 was phosphorylated, signaling was attenuated. Other IR or IRS1 inflammation-associated negative regulators including suppressors of cytokine signaling (Socs) may promote ubiquitination, in which ubiquitin (a small protein) binds to another target protein, altering its function and subsequent degradation, For example IRS inactivation.

Some aspects of the invention relate to compounds and uses of compounds that inhibit Galectin-3 for the treatment of insulin resistance.

Galectin inhibitor

Natural oligosaccharide ligands capable of binding Galectin-1 and/or Galectin-3 have been described, such as modified forms of pectin and galactomannan derived from guar gum (see WO 2013040316, US20110294755, WO 2015138438). Synthetic digalactosides such as lactose, N-acetyllactosamine (LacNAc) and thiolactose are effective against pulmonary fibrosis and other fibrotic diseases (WO 2014067986 A1, which is incorporated herein by reference in its entirety).

Advances in protein crystallography and the availability of high-resolution 3D structures of the carbohydrate-recognition domains (CRDs) of many galectins have yielded many with enhanced affinity for carbohydrate-recognition domains with greater affinity than galactose or lactose (WO 2014067986, which is incorporated herein by reference in its entirety). The compounds were shown to be effective in treating an animal model of pulmonary fibrosis, which is thought to mimic human idiopathic pulmonary fibrosis (IPF). For example, thio-digalactopyranosyl (TD-139) substituted with 3-fluorophenyl-2,3-triazolyl has been reported to bind to galectin 3 and to play an important role in pulmonary fibrosis. effective in the mouse model. The compound requires pulmonary administration using an intratracheal instillation or nebulizer (see US 8703720, US 7700763, US 7638623 and US 7230096, the entire contents of which are incorporated herein by reference).

Various aspects of the present invention relate to novel compounds that mimic natural ligands of galectin proteins. In some embodiments, the compound mimics the natural ligand of Galectin-3. In some embodiments, the compound mimics the natural ligand of Galectin-1. In some embodiments, the compound mimics the natural ligand of Galectin-8. In some embodiments, the compound mimics the natural ligand of Galectin-9.

In some embodiments, the compound has a mono-, di-, or oligomeric structure consisting of a galactose-selenium core bound to an isomeric carbon on galactose, and which acts as a linking group for the remainder of the molecule. In some embodiments, the galactose-selenium core can bind to other sugars/amino acids/acids/groups bound to the galectin CRD (as shown in Figure 1 in the high definition 3D structure of Galectin-3) , and together can enhance the compound's affinity for CRD. In some embodiments, the galactose-selenium core can bind to other sugars/amino acids/acids/groups that bind to "site B" of the galectin CRD (as shown in Figure 1 in the HD of Galectin-3 shown in the 3D structure), and together can enhance the affinity of the compound for the CRD.

According to some aspects, the compounds may have substitutions that interact with site A and/or site C to further improve binding to the CRD and enhance its potential as a therapeutic targeting galectin-dependent pathology. In some embodiments, substituents can be selected by in silico analysis (computer-aided molecular modeling) as described herein. In some embodiments, binding assays to the galectin protein of interest can be used to further screen for substituents. For example, compounds can be screened using a galectin-3 binding assay and/or an in vitro model of inflammation and fibrosis in activated cultured macrophages (see Chavez-Galan, L et al., Immunol, 2015;6:263).

According to some aspects, the compound includes one or more specific substitutions of the core galactose-Se. For example, the core galactose-Se can be substituted with specific substituents that interact with residues located within the CRD. Such substituents can significantly increase the associative and potential potency and 'drugability' properties of the compound.

selenium

Selenium has five possible oxidation states (-2, 0, +2, +4, and +6), so it performs well in a variety of compounds with different chemistries. In addition, almost all sulfur-containing compounds, whether inorganic or organic, can be replaced by selenium for sulfur.

Most organic and inorganic selenium compounds are readily absorbed from the diet and transported to the liver - the major organ of selenium metabolism. The general metabolism of selenium compounds follows three main pathways, which depend on chemical properties, namely redox-active selenium compounds, precursors of methylselenol, and selenoamino acids.

Selenium is often considered an antioxidant because it is present in selenoproteins in the form of selenocysteine, but it can also be toxic. However, the toxic effects of selenium are strictly concentration and chemical species dependent. A class of selenium compounds are potent cytostatics with remarkable tumor specificity (Misra, 2015). Sodium selenite has been investigated as a cytotoxic drug in advanced cancer (SECAR, see Brodin, Ola et al., 2015).

Galactoside-selenium compound

Various aspects of the present invention relate to compounds comprising a pyranosyl and/or furanosyl structure bound to a selenium atom on the anomeric carbon of the pyranosyl and/or furanosyl group.

In some embodiments, specific aromatic substitutions can be added to the galactose or heteroglycoside core to further enhance the affinity of the selenium-bound pyranosyl and/or furanosyl structures. Such aromatic substitutions can enhance the interaction of the compound with the amino acid residues (eg, arginine, tryptophan, histidine, glutamic acid, etc.) that make up the carbohydrate recognition domain (CRD) of the lectin, and thus Enhanced association and binding specificity.

In some embodiments, compounds include monosaccharides, disaccharides, and oligosaccharides of galactose or a heteroglycoside core bound to a selenium atom on the anomeric carbon of a galactose or heteroglycoside.

In some embodiments, the compound is a symmetrical digalactoside, wherein the two galactosides are joined by one or more selenium bonds. In some embodiments, the compound is a symmetrical digalactoside, wherein the two galactosides are bound by one or more selenium bonds, and wherein the selenium is bound to the anomeric carbon of galactose. In some embodiments, the compound is a symmetrical digalactoside, wherein the two galactosides are bound by one or more selenium bonds and one or more sulfur bonds, and wherein the selenium is bound to the anomeric carbon of galactose. In other embodiments, the compound may be an asymmetric digalactoside. For example, compounds can have various aromatic or aliphatic substitutions on the galactose core.

In some embodiments, the compounds are symmetrical galactosides, which are monogalactosides with one or more seleniums on the anomeric carbon of galactose. In some embodiments, the galactosides have one or more selenium bound to the anomeric carbon of galactose and one or more selenium bound sulfur. In some embodiments, the compounds may have various aromatic or aliphatic substitutions on the galactose core.

Without being bound by theory, it is believed that compounds comprising Se-containing molecules metabolically stabilize the compounds while maintaining chemical, physical and allosteric properties that specifically interact with lectins or galectins known to recognize carbohydrates. In some embodiments, the digalactosides or oligosaccharides of galactose of the invention are metabolically more stable than compounds with O-glycosidic linkages.

In some embodiments, the digalactosides or oligosaccharides of galactose of the invention are metabolically more stable than compounds with S-glycosidic linkages.

Various aspects of the present invention relate to compounds based on galactosidic structures having a selenium bridge [X] with another galactose, hydroxycyclohexane, aromatic moiety, alkyl, aryl, amine or amide.

As used herein, the term "alkyl" is meant to include 1 to 12 carbon atoms, such as 1 to 7 or 1 to 4 carbon atoms or 3 to 7 carbon atoms. In some embodiments, an alkyl group can be straight or branched. In some embodiments, the alkyl group can also form a ring comprising 3 to 7 carbon atoms, preferably 3, 4, 5, 6 or 7 carbon atoms. Thus, alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, 3-methylbutyl, 2,2-dibutyl Methylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2,2-di Methylpentyl, 2,3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 1-methylcyclopropyl.

As used herein, the term "alkenyl" is meant to include 2 to 12, eg, 2 to 7 carbon atoms or 3 to 7 carbon atoms. Alkenyl includes at least one double bond. In some embodiments, alkenyl includes vinyl, allyl, but-1-enyl, but-2-enyl, 2,2-dimethylvinyl, 2,2-dimethylprop-1 -Alkenyl, pent-1-enyl, pent-2-enyl, 2,3-dimethylbut-1-enyl, hex-1-enyl, hex-2-enyl, hex-3- Alkenyl, prop-1,2-dienyl, 4-methylhex-1-enyl, cycloprop-1-enyl and the like.

As used herein, the term "alkoxy" refers to alkoxy groups containing 1 to 12 carbon atoms, which may include one or more unsaturated carbon atoms. In some embodiments, the alkoxy group contains 1 to 7 or 1 to 4 carbon atoms, which may include one or more unsaturated carbon atoms. Thus, the term "alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, n-hexyloxy, 2-methylpentoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy Oxy, n-heptyloxy, 2-methylhexyloxy, 2,2-dimethylpentyloxy, 2,3-dimethylpentyloxy, cyclopropoxy, cyclobutoxy, cyclopentyl oxy, cyclohexyloxy, cycloheptyloxy and 1-methylcyclopropoxy.

As used herein, the term "aryl" is meant to include 3 to 12 carbon atoms. Aryl can be phenyl or naphthyl. The above groups may be naturally substituted with any other known substituents in the field of organic chemistry. This group may also be substituted with two or more substituents. Examples of substituents are halogen, alkyl, alkenyl, alkoxy, nitro, sulfo, amino, hydroxy and carbonyl. Halogen substituents can be bromine, fluorine, iodine and chlorine. Alkyl is as defined above, containing from 1 to 7 carbon atoms. Alkenyl is as defined above, containing 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms. Alkoxy is as defined below, containing 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, which may contain unsaturated carbon atoms. Combinations of substituents such as trifluoromethyl may be present.

As used herein, the term "heteroaryl" is meant to include any aryl group including 4 to 18 carbon atoms, wherein at least one atom of the ring is a heteroatom, ie, not carbon. In some embodiments, a heteroaryl group can be a pyridine or indole group.

The above groups may be substituted with any other known substituents in the field of organic chemistry. This group may also be substituted with two or more substituents. Examples of substituents are halogen, alkoxy, nitro, sulfo, amino, hydroxy and carbonyl. Halogen substituents can be bromine, fluorine, iodine and chlorine. Alkyl is as defined above, containing from 1 to 7 carbon atoms. Alkenyl is as defined above, containing 2 to 7 carbon atoms, eg 2 to 4 carbon atoms. Alkoxy is as defined below, containing 1 to 7 carbon atoms, eg 1 to 4 carbon atoms, which may contain unsaturated carbon atoms.

Monomer - Selenium - Polyhydroxylation - Cycloalkane

In some embodiments, the compound is a monomeric selenium polyhydroxylated cycloalkane compound having formula (1) or formula (2), or a pharmaceutically acceptable salt or solvate thereof:

where X is selenium,

wherein W is selected from the group consisting of O, N, S, CH, NH and Se,

wherein Y is selected from the group consisting of O, S, NH, CH, Se, S, SO, PO, amino acids, including heterocyclic substituted hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives having a molecular weight of about 50-200 D, and combinations thereof,

wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,

wherein R1, R2 and _R3 are independently selected from CO, _O2 , SO2, PO2, PO, CH, hydrogen or _a combination of these, and a) alkyl of at least 3 carbons, alkenyl of at least 3 carbons, Alkyl of at least 3 carbons substituted by carboxyl, alkenyl of at least 3 carbons substituted by carboxyl, alkyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino alkyl of at least 3 carbons substituted with both carboxy, alkenyl of at least 3 carbons substituted with both amino and carboxy, and alkyl substituted with one or more halogens, b) benzene substituted with at least one carboxy phenyl, phenyl substituted with at least one halogen, phenyl substituted with at least one alkoxy, phenyl substituted with at least one nitro, phenyl substituted with at least one sulfo, phenyl substituted with at least one amino , phenyl substituted with at least one alkylamino group, phenyl substituted with at least one dialkylamino group, phenyl substituted with at least one hydroxy group, phenyl substituted with at least one carbonyl group, and phenyl substituted with at least one substituted carbonyl group phenyl, c) naphthyl, naphthyl substituted by at least one carboxy, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, naphthyl substituted by at least one nitro, naphthyl substituted by at least one Sulfo-substituted naphthyl, at least one amino-substituted naphthyl, at least one alkylamino-substituted naphthyl, at least one dialkylamino-substituted naphthyl, at least one hydroxy-substituted naphthyl, at least one hydroxy-substituted naphthyl One carbonyl substituted naphthyl and at least one substituted carbonyl substituted naphthyl, d) heteroaryl, at least one carboxy substituted heteroaryl, at least one halogen substituted heteroaryl, at least one alkoxy substituted heteroaryl, heteroaryl substituted with at least one nitro, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, Heteroaryl substituted with at least one dialkylamino, heteroaryl substituted with at least one hydroxy, heteroaryl substituted with at least one carbonyl, and heteroaryl substituted with at least one substituted carbonyl, and e) sugars, Substituted sugar, D-galactose, substituted D-galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl , heteroaryl, heterocycle and derivatives, amino, substituted amino, imino and substituted imino groups.

Oligoselenium Polyhydroxylation-Cycloalkane Compounds and Dimeric Selenide Polyhydroxylation-Cycloalkane Compounds

In some embodiments, the compound is a dimer-polyhydroxylated-cycloalkane compound. In some embodiments, the compound is an oligoselenium polyhydroxylated-cycloalkane compound having 3 or more units.

In some embodiments, the compound has the following general formulae (3) and (4) or a pharmaceutically acceptable salt or solvate thereof:

where X is selenium,

wherein W is selected from the group consisting of O, N, S, CH, NH and Se,

wherein Y is selected from the group consisting of O, S, C, NH, CH, Se, S, P, amino acids, including heterocyclic substituted hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives having a molecular weight of about 50-200 D, and combinations thereof,

wherein Z is selected from the group consisting of O, S, N, CH, Se, SO2, PO2 and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,

Among them, n≤24,

wherein R1 and R2 are independently selected from CO, _O2 , SO2, SO, PO2, PO, CH, hydrogen or _a combination of these, and a) alkyl of at least 3 carbons, alkenyl of at least 3 carbons, Carboxyl-substituted alkyl of at least 3 carbons, alkenyl of at least 3 carbons substituted by carboxyl, alkyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino, and Alkyl of at least 3 carbons substituted with both carboxy, alkenyl of at least 3 carbons substituted with both amino and carboxy, and alkyl substituted with one or more halogens, b) phenyl substituted with at least one carboxy , phenyl substituted by at least one halogen, phenyl substituted by at least one alkoxy, phenyl substituted by at least one nitro, phenyl substituted by at least one sulfo, phenyl substituted by at least one amino, Phenyl substituted with at least one alkylamino, phenyl substituted with at least one dialkylamino, phenyl substituted with at least one hydroxy, phenyl substituted with at least one carbonyl, and benzene substituted with at least one substituted carbonyl group, c) naphthyl, naphthyl substituted by at least one carboxy, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, naphthyl substituted by at least one nitro, naphthyl substituted by at least one sulfo naphthyl substituted with at least one amino group, naphthyl group substituted with at least one amino group, naphthyl group substituted with at least one alkylamino group, naphthyl group substituted with at least one dialkylamino group, naphthyl group substituted with at least one hydroxy group, naphthyl group substituted with at least one hydroxy group Naphthyl substituted by carbonyl and naphthyl substituted by at least one substituted carbonyl, d) Heteroaryl, heteroaryl substituted by at least one carboxy, heteroaryl substituted by at least one halogen, substituted by at least one alkoxy Heteroaryl substituted with at least one nitro, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, at least one dialkylamino substituted heteroaryl, at least one hydroxy substituted heteroaryl, at least one carbonyl substituted heteroaryl, and at least one substituted carbonyl substituted heteroaryl, and e) sugars, substituted sugar, D-galactose, substituted D-galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, The group consisting of heteroaryl, heterocycle and derivatives, amino, substituted amino, imino and substituted imino.

In some embodiments, n=1. In some embodiments, n=2. In some embodiments, n=3.

As used herein, the term "alkyl" refers to alkyl groups containing from 1 to 7 carbon atoms, which may include one or more unsaturated carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, which may include one or more unsaturated carbon atoms. The carbon atoms in the alkyl group can form straight or branched chains. The carbon atoms in the alkyl group can also form rings containing 3, 4, 5, 6 or 7 carbon atoms. Thus, the term "alkyl" as used herein includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, 3-methylbutyl , 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl , 2,2-dimethylpentyl, 2,3-dimethylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 1-methylcyclopropyl.

In some embodiments, the compound is a 3-derivatized diselenogalactoside with a fluorophenyltriazole.

Various aspects of the present invention pertain to compounds of formula (7), or a pharmaceutically acceptable salt or solvate thereof:

In some embodiments, the compound has the following general formulae (5) and (6) or a pharmaceutically acceptable salt or solvate thereof:

where X is Se, Se-Se, Se-S, S-Se, Se-SO2 or SO2-Se,

wherein W is selected from the group consisting of O, N, S, CH, NH and Se,

wherein Y is selected from the group consisting of O, S, C, NH, CH, Se, P, amino acids, including heterocyclic substituted hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives having a molecular weight of about 50-200 D, and combinations thereof,

wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and heterocyclic substituted hydrophobic hydrocarbon derivatives comprising 3 or more atoms,

wherein R1, R2, _R3 , and R4 are independently selected from CO, _O2 , SO2, SO, PO2, PO, CH, hydrogen, or _a combination of these, and a) alkyl of at least ₃ carbons, at least 3 carbon alkenyl, at least 3 carbon alkyl substituted by carboxyl, at least 3 carbon alkenyl substituted by carboxyl, at least 3 carbon alkyl substituted by amino, at least 3 carbon substituted by amino alkenyl, alkyl of at least 3 carbons substituted by both amino and carboxy, alkenyl of at least 3 carbons substituted by both amino and carboxy, and alkyl substituted by one or more halogens, b) by at least one carboxy-substituted phenyl, at least one halogen-substituted phenyl, at least one alkoxy-substituted phenyl, at least one nitro-substituted phenyl, at least one sulfo-substituted phenyl, at least one sulfo-substituted phenyl Amino-substituted phenyl, phenyl substituted with at least one alkylamino, phenyl substituted with at least one dialkylamino, phenyl substituted with at least one hydroxy, phenyl substituted with at least one carbonyl, and phenyl substituted with at least one Substituted carbonyl substituted phenyl, c) naphthyl, naphthyl substituted with at least one carboxyl group, naphthyl substituted with at least one halogen, naphthyl substituted with at least one alkoxy group, naphthyl substituted with at least one nitro group group, naphthyl substituted with at least one sulfo, naphthyl substituted with at least one amino, naphthyl substituted with at least one alkylamino, naphthyl substituted with at least one dialkylamino, naphthyl substituted with at least one hydroxy naphthyl, naphthyl substituted by at least one carbonyl and naphthyl substituted by at least one carbonyl, d) heteroaryl, heteroaryl substituted by at least one carboxy, heteroaryl substituted by at least one halogen, Heteroaryl substituted with at least one alkoxy, heteroaryl substituted with at least one nitro, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, substituted with at least one alkylamino heteroaryl, heteroaryl substituted with at least one dialkylamino, heteroaryl substituted with at least one hydroxy, heteroaryl substituted with at least one carbonyl, and heteroaryl substituted with at least one substituted carbonyl, and e) sugars, substituted sugars, D-galactose, substituted D-galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, The group consisting of alkenyl, aryl, heteroaryl, heterocycle and derivatives, amino, substituted amino, imino and substituted imino.

In some embodiments, the halogen is a fluoro, chloro, bromo or iodo group.

In some embodiments, the compound has the formula shown in Table 1 and is an inhibitor of Galectin-3.

Table 1 shows non-limiting examples of monomeric Se galactosides.

Table 1

In some embodiments, the compound has the formula shown in Table 2 and is an inhibitor of Galectin-3.

Table 2 shows non-limiting examples of disaccharides.

Table 2

In some embodiments, the compound has the formula shown in Table 3 and is an inhibitor of Galectin-3.

Table 3 shows non-limiting examples of oligosaccharides.

table 3

The tetrameric Se-galactoside is expected to have a higher affinity for the CRD than the trimeric structure due to the additional potential interaction of hydroxyl groups with amino acids near the CRD (see Example 14).

Without being bound by theory, the galactose-selenium compounds described herein have enhanced stability because their structures are less prone to hydrolysis (metabolism) and oxidation, e.g., unsubstituted aromatic rings, carbon-oxygen systems, carbon - Nitrogen systems, etc.

Computational scoring of ligand-protein affinity

Standard assays to assess the binding capacity of a ligand to a target molecule are known in the art and include, for example, ELISA, Western blot, and RIA. Suitable assays are described in detail herein. In some embodiments, binding kinetics (eg, binding affinity) can be assessed by standard assays known in the art, such as by Biacore analysis. Assays to evaluate the effect of compounds on the functional properties of galectins are described in more detail herein.

One way to determine protein-ligand binding affinity uses structure-based models that predict the interactions of protein-ligand complexes that result when a ligand binds to a protein. Such structures can be studied by x-ray crystallography. In some embodiments, compounds of interest can be screened by "in silico" to predict the affinity of a ligand for a lectin or galectin protein using any scoring system known in the art.

In some embodiments, computational modeling can be used to facilitate structure-based drug design. In silico models are also capable of visualizing protein-compound interactions, conformational strains and possible steric conflicts and avoiding them. In some embodiments, protein-ligand affinity can be scored using Glide (Schrodinger, Portland OR). The combination of the position and orientation of the ligand relative to the protein together with the flexible docking is called the ligand pose and Glide scoring of the ligand pose is done by GlideScore. GlideScore is a quantitative measure that provides an estimate of ligand binding free energy. It has many terms, including force field (electrostatic, van der Waals, etc.) contributions and terms that reward or penalize interactions known to affect ligand binding. It contains two energy elements; the enthalpy and entropy contributions of biological reactions. The thermodynamic principle of enthalpy-entropy compensation is based on the fact that as the binding becomes stronger, the enthalpy becomes more negative, and the entropy tends to decrease accordingly due to the formation of tight complexes. Therefore, the ligand with the lowest GlideScore can be selected.

Methods and compounds are provided for inhibiting Galectin-3 and/or Galectin-1, however the in silico models, assays and compounds described herein can be applied to other galectin proteins and lectins .

Using a computer simulation model of Galectin-3CRD based on the 1KJR crystal structure of human Galectin-3CRD (Sorme, P. et al., (2005), J.Am.Chem. Soc.) 127: 1737-1743) and refined using known "active" and "inactive" compounds of Galectin-3 as training and test sets. The 1KJR crystal structure was chosen because of its unique extended cavity allowing larger substituents (eg indole or naphtalen) at the C3 position of galactose (Vargas-Berebgurl 2013, Barondes 1998, Sorme 2003). Table 4 shows the GlideScore of different digalactosides: (1) thiogalactoside, galactoside, selenogalactoside, diselenogalactoside with the same substituent.

Table 4

The GlideScore data showed that the anomeric carbon (G-625) that introduced selenium onto galactose scored the same as the thiogalactoside (TD-139, also known as G-240). The results also show that the thiogalactoside (TD-139) and selenogalactoside compounds (G-625) have comparable overall estimated free energy predictors. Therefore, thiogalactoside (TD-139) and selenogalactoside compound (G-625) are expected to have comparable affinity and inhibitory effect to galectin-3.

These compounds were tested for their affinity to integrin and galectin-3. Surprisingly, the selenogalactoside compound (G-625) showed about at least 2-fold to about at least 3-fold better affinity for galectin-3 and integrin.

The Se atom allows the rest of the molecule (e.g. G-625) to achieve the observed interaction with TD-139, but as shown in Elisa-based assays and fluorescence polarization assays, compared to galectin-3, TD -139 has better affinity. In some embodiments, the selenogalactoside of formula (1) has an affinity for galectin-3 that is at least two-fold or at least three-fold stronger than TD-139. In some embodiments, the selenogalactoside of the invention has an affinity for galectin-3 that is at least two-fold or at least three-fold stronger than the corresponding thiogalactoside.

The 'drugability' property defined by computational structural analysis takes into account the compound: (1) stereoisomerization, (2) the position of the hydroxyl group on the sugar (eg axial or equator) and (3) the position and nature of the substituents.

1) Stereoisomerization: It should be noted that compounds with the same 2D nomenclature can have different 3D structures, which may lead to very different binding poses as well as different predicted binding free energy predictors, GlideScore.

2) Hydroxyl: The position of the hydroxyl group on the sugar (eg, axial or equatorial) plays an important role in compound binding. In particular, the present invention relates to galactose-based compounds bound to a selenium atom bound to an anomeric carbon, which serves as a linking group for the rest of the molecule.

3) Substituents: According to some aspects, compounds can have substituents that can or are designed to access amino acids that are part of the binding sites, known and unknown, that play a role in ligand binding. Those skilled in the art will understand that galectins bind the monosaccharide galactose with dissociation constants in the millimolar range. It has been shown that the addition of N-acetylglucosamine to galactose can provide additional interactions with adjacent sites that enhance the compound's affinity for galectin-3 by more than 10-fold (Bachhawat-sikder et al., FEBS Lett. 2001 Jun 29, 500(1-2):75-9).

Further addition of non-natural derivatives, such as naphthols, at the 3-position of the saccharide can improve affinity for the low micromolar range, eg, 0.003 mM. This substitution takes advantage of a cation-pi interaction with the surface residue Arg 144.

Human Galectin-3 has a shallow cavity and high solvent accessibility. It is very hydrophilic, but is capable of forming cation-pi interactions with Arg 144 and possibly Trp1 81 (Magnani 2009, Logan 2011). It has been shown that upon ligand binding, Arg 144 moves up 3.5A from the protein surface to form a pocket for Arene-Arginine interactions. It should be noted that Arg 144 is not present in other galectins (eg Gal-1, Gal-9) and this is being exploited in our computer simulation model. Similarly, potency can be improved by exploiting cation-pi interactions with surface residues of Arg 186. For example, triazole substitution on C3 of galactose has been reported to increase the affinity of galectin 3 (Salameh BA et al., Bioorg. Med. Chem. Lett., 2005 Jul 15;15(14):3344-6).

Tryptophan 181 at subsite C is conserved throughout the galectin family. In all reported galectin-sugar complexes, there is π-π stacking between the Trp181 (W181) side chain and the carbohydrate residue accommodated within subsite C (galactose is the natural sugar occupant) interaction.

In order to develop an efficient approach for structure-based design of highly potent galectin inhibitors, such as galectin-3 inhibitors, based on the three-dimensional structure and physicochemical properties of conserved binding sequences, understanding the detailed molecular basis of carbohydrate recognition is very important. High-resolution structural information is of great help in this regard (see Ultra-High-Resolution Structures and Water Dynamics, Saraboji, K et al., Biochemistry, 2012 1 Jan 10;51(1):296-306). While it is clear that the galectin-3CRD site is pre-organized to recognize the sugar-like structure of oxygen (see Figure 2), it is not expected to recognize selenium-containing compounds with two- to three-fold increased activity.

In galectin-3 (see CRD amino acids near the binding pocket in Figure 3), the side chain of Arg144 is capable of adopting different conformations due to its inherent flexibility, which may be facilitated by arginine binding to the aromatic moiety Acid-arene interactions (cation-pi or pi-pi stacking) result in greater affinity.

In some embodiments, computational alanine scanning mutagenesis (ASM) or "in silico alanine scanning" is used to identify key galectin residues that affect ligand affinity. ASM can be performed by sequentially replacing individual residues with alanines to identify residues involved in protein function, stability and shape. Each alanine substitution examines the contribution of a single amino acid to protein function.

To better understand the importance of residues in the CRD binding pocket (Fig. 3), by docking the compound of formula 1 and the galectin-3 inhibitor, 3,3'-dideoxy-3,3' in Glide -Bis-[4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl]-I,I'-sulfanediyl-bis-D-galactopyranoside ( TD139, see WO 2016005311A1, incorporated by reference in its entirety) performed an "in silico alanine scan". Residues predicted to be involved in binding are mutated, and mutation of alanine is expected to have an impact on GlideScore results. Alanine scanning was used to predict the importance of residues for ligand binding.

For example, galectin-3R186S was reported to abolish carbohydrate interactions. R186S has been shown to have selectively lost affinity for LacNAc, the disaccharide moiety normally found on glycoproteins, and has lost the ability to activate neutrophils and intracellular targeting into vesicles. (See Salomonsson E. et al., J Biol Chem. 2010 Nov 5;285(45):35079-91).

Table 5 shows comparative results of in silico alanine scans using the TD-139 compound

table 5

compound replace GlideScore dG TD-139 Galectin-3WT -6.289 100.00 TD-139 Galectin-3-R186A -5.345 84.99 TD-139 Galectin-3-R162A -5.56 88.41 TD-139 Galectin-3-R144A -6.502 103.39 TD-139 Galectin-3-W181A -5.256 83.57 TD-139 Galectin-3-H158A -5.315 84.51 TD-139 Galectin-3-N174A -5.069 80.60

Table 6 shows comparative results of in silico alanine scans using the G-625 compound of formula 1

Table 6

compound replace GlideScore dG G-625 Galectin-3WT -6.254 100 G-625 Galectin-3-R186A -5.989 95.76 G-625 Galectin-3-R162A -5.637 90.13 G-625 Galectin-3-R144A -6.564 104.96 G-625 Galectin-3-W181A -5.37 85.87 G-625 Galectin-3-H158A -5.178 82.80 G-625 Galectin-3-N174A -5.074 81.13

**dG>100 indicates that ligand binding is increased upon alanine mutation, while dG<100 indicates that ligand binding is decreased upon mutation.

These results suggest that the "molecular interaction spectrum" of TD-139 is different from that of G-625. Tables 5 and 6 show the interaction spectra predicted by the computer simulation model. TD 139 was greatly affected by the introduction of the R186A mutation (there was an "about 15% reduction" in GlideScore as a predictor of free binding energy). On the other hand, R186A had less effect on G-625, which was more sensitive to the H158A mutation.

Surprisingly, alanine scans revealed that residue N174 plays an important role in the binding of TD-139 and G-625 compounds. Without being bound by theory, residue N174 may help position the galactose core in an "optimal orientation" that would allow the CRD site to recognize the oxygen-like sugar-like structure.

In silico alanine scans revealed that G-625 has unique binding properties while maintaining interactions with known CRD residues such as Arg162, Arg186 and Arg144. Based on these results, the interaction of site A: S237, site B: D148, sites C-D: A146, K176, G182 and E165 and N166 in the site C loop (Figure 2 and Figure 3) with CRD were explored.

synthetic route

The compounds of the present invention can be prepared by the following general methods and procedures. It should be understood that where typical or preferred process conditions (eg, reaction temperatures, times, molar ratios of reactants, solvents, pressures, pH, etc.) are given, other process conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with factors such as the specific reactants, solvent employed and pH, but such conditions can be determined by one skilled in the art through routine optimization procedures.

In some embodiments, compounds are synthesized using the synthetic route shown in FIG. 4 .

For example, compound G-625 was prepared as detailed in Example 10.

pharmaceutical composition

Various aspects of the present invention pertain to the use of the compounds described herein for the manufacture of a medicament. Some embodiments relate to a compound having formula (1), (2), (3), (4), (5), (6) or (7) or use of a compound or a pharmaceutically acceptable salt or solvate thereof . Some embodiments relate to compounds or uses of compounds of Tables 1-4.

Various aspects of the present invention pertain to pharmaceutical compositions comprising one or more of the compounds described herein. In some embodiments, the pharmaceutical composition includes one or more of the following: pharmaceutically acceptable adjuvants, diluents, excipients and carriers.

The term "pharmaceutically acceptable carrier" refers to a carrier or adjuvant that can be administered to a subject (eg, a patient) with the compositions of the present invention, without destroying its pharmacological activity, and at an administered dose sufficient to provide a therapeutic amount or The compounds are nontoxic in effective amounts.

"Pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media. The use of such media and compounds for pharmaceutically active substances is well known in the art. Preferably, the carrier is suitable for oral, intravenous, intramuscular, subcutaneous, parenteral, spinal or epidural administration (eg, by injection or infusion). Depending on the route of administration, the active compound can be encapsulated in materials to protect the compound from acids and other natural conditions that can inactivate the compound.

Some aspects of the present invention pertain to pharmaceutical compositions comprising a compound of the present invention and optional pharmaceutically acceptable additives such as carriers or excipients. In some embodiments, the pharmaceutical composition includes a compound of formula (1), (2), (3), (4), (5), (6) or (7) or a pharmaceutically acceptable salt or solvent thereof compound and optional pharmaceutically acceptable additives such as carriers or excipients. In some embodiments, a pharmaceutical composition includes a compound of Tables 1-4, or a pharmaceutically acceptable salt or solvate thereof, and optional pharmaceutically acceptable additives, such as carriers or excipients.

In some embodiments, a pharmaceutical composition includes as an active ingredient a compound described herein together with a pharmaceutically acceptable adjuvant, diluent, excipient or carrier. Pharmaceutical compositions may include 1-99 wt% of a pharmaceutically acceptable adjuvant, diluent, excipient or carrier and 1-99 wt% of a compound described herein.

The adjuvants, diluents, excipients and/or carriers that may be used in the compositions of the present invention are pharmaceutically acceptable, ie, compatible with the compounds and other ingredients of the pharmaceutical composition, and not free from their recipients. Harmful. Adjuvants, diluents, excipients and carriers that can be used in the pharmaceutical compositions of the present invention are well known to those skilled in the art.

Effective oral doses of the compounds of this invention in experimental animals or humans can be formulated with various excipients and additives which enhance the absorption of the compounds through the stomach and small intestine.

The pharmaceutical compositions of the present invention may include two or more compounds of the present invention. The compositions can also be used with other drugs known in the art for the treatment of associated disorders.

In some embodiments, pharmaceutical compositions comprising one or more compounds described herein may be suitable for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual or subcutaneous administration, or via the respiratory tract such as Administration is in the form of an aerosol or air suspension fine powder, or is suitable for administration via the eye, intraocular, intravitreal or cornea.

In some embodiments, pharmaceutical compositions comprising one or more compounds described herein may be in the form of, for example, tablets, capsules, powders, injection solutions, spray solutions, ointments, transdermal patches, or suppositories.

Some aspects of the present invention pertain to pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and optional pharmaceutically acceptable additives, such as carriers or excipients.

Effective oral doses can be 10 times and up to 100 times the effective parental dose.

Effective oral doses may be administered in once-daily or divided doses, or twice, three times per week, or monthly.

In some embodiments, the compounds described herein can be co-administered with one or more other therapeutic agents. In certain embodiments, additional agents may be administered separately from the compounds of the present invention (eg, sequentially, eg, on different overlapping schedules, with administration of the compounds of the present invention) as part of a multiple dose regimen. In other embodiments, these agents may be part of a single dosage form, mixed with the compounds of the present invention in a single composition. In another embodiment, these agents may be administered as separate doses administered at about the same time as the compounds of the present invention. When a composition includes a combination of a compound of the present invention and one or more additional therapeutic or prophylactic agents, the dosage levels of both the compound and the additional agent may be within about 1% to 100% of the dose typically administered in monotherapy between, and more preferably, between about 5% and 95%.

In some embodiments, a therapeutically effective amount of a compound or composition may be compatible and effectively combined with a therapeutically effective amount of various anti-inflammatory drugs, vitamins, other drugs, and nutritional drugs or supplements, or combinations thereof, but is not limited to this.

In some embodiments, a compound of Formula (1), (2), (3), (4), (5), (6), or (7) or a compound of Tables 1-4, or a pharmaceutically acceptable The salt or solvate is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combination thereof. In some embodiments, a compound of Formula (1), (2), (3), (4), (5), (6), or (7) or a compound of Tables 1-4, or a pharmaceutically acceptable The salt or solvate is administered with the active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combination thereof. In some embodiments, a compound of Formula (1), (2), (3), (4), (5), (6), or (7) or a compound of Tables 1-4, or a pharmaceutically acceptable The salt or solvate is administered with one or more antidiabetic drugs. In some embodiments, the administration of the compound of the present invention and the active agent results in a synergistic effect. In some embodiments, the active agent is an antidiabetic drug.

As used herein, the term "synergistic effect" refers to the associated effect of two or more agents of the invention such that the combined effect is greater than the sum of the individual effects. In some embodiments, the compound of the present invention and the active agent may be administered simultaneously or sequentially.

Various aspects of the invention relate to combinations with other antineoplastic agents, including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1, anti-PDL1 antibodies), other immunomodulatory agents, including but not limited to anti-OX40 and a variety of mechanisms Compositions or compounds for the treatment of neoplastic disorders in combination with other antineoplastic agents.

Various aspects of the invention relate to combinations with other antineoplastic agents, including but not limited to checkpoint inhibitors (anti-CTLA2, anti-PD1, anti-PDL1 antibodies), other immunomodulatory agents, including but not limited to anti-OX40 and a variety of mechanisms Compositions or compounds for the treatment of neoplastic disorders in combination with other antineoplastic agents.

treatment method

Some aspects of the invention pertain to the use of a compound described herein or a composition described herein for the treatment of disorders associated with galectin binding to ligands. In some embodiments, the galectin is Galectin-3.

Some aspects of the invention relate to methods of treating various disorders associated with galectin binding to ligands. In some embodiments, the methods comprise administering to a subject in need thereof a therapeutically effective amount of at least one compound described herein. In some embodiments, the subject in need is a human with high levels of Galectin-3. Levels of galectins, such as Galectin-3, can be quantified using any method known in the art.

Some aspects of the invention relate to the treatment of diseases caused by disrupted activity of TGFb1 (transforming growth factor beta 1 ) by reversing the interaction of galectin-3 with its receptor (TGFb1-receptor), thereby restoring normal regenerative activity in tissues Methods.

Some aspects of the invention relate to methods of treating diseases associated with the transforming growth factor beta signaling pathway, which are involved in many cellular and pathological processes in adult and embryonic development, including cell growth, cell differentiation, apoptosis, intracellular Homeostasis and other cellular functions.

Some aspects of the invention relate to a method for treating a disorder associated with galectin binding, eg, galectin-3 binding to the human insulin receptor or TGFb1-receptor, wherein the method comprises directing administering to a human in need thereof a therapeutically effective amount of at least one compound of formula (1), (2), (3), (4), (5), (6) or (7) or Tables 1-4 or a pharmacy thereof an acceptable salt or solvate of the above.

Various aspects of the present invention relate to compounds, compositions and methods for treating various disorders in which lectin proteins play a role in pathogenesis, including but not limited to treating systemic insulin resistance. In some embodiments, the compounds bind reversibly to Galectin-3 of the insulin receptor and/or enhance sensitivity to insulin activity in various tissues.

Various aspects of the present invention relate to compounds, compositions and methods for the treatment of, but not limited to, systemic insulin resistance. In some embodiments, systemic insulin resistance is associated with obesity, wherein elevated Galectin-3 interacts with the insulin receptor. In some embodiments, treatment with a compound of the present invention restores sensitivity to insulin activity in various tissues.

Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with type 1 diabetes. Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with type 2 diabetes mellitus (T2DM). Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with obesity, gestational diabetes and prediabetes. In some embodiments, the compound restores the sensitivity of cells to insulin activity. In some embodiments, the compounds inhibit the interaction of Galectin-3 with the insulin receptor, which interferes with insulin binding and cellular glucose uptake mechanisms. Various aspects of the present invention relate to compounds, compositions, and low-grade inflammations for the treatment of atherosclerotic vascular disease and NAFLD due to increased levels of free fatty acids and triglycerides leading to insulin resistance in skeletal muscle and liver, leading to insulin resistance in the liver. method. Various aspects of the invention relate to compounds, compositions and methods for treating polycystic ovary syndrome (PCOS) associated with obesity, insulin resistance, and compensated hyperinsulinemia affecting approximately 65-70% of women with PCOS . Various aspects of the present invention relate to compounds, compositions and methods for treating diabetic nephropathy and glomerulosclerosis by attenuating integrin and TGF[beta] receptor pathways in chronic kidney disorders. In some embodiments, the compounds inhibit overexpression of the TGF[beta] receptor signaling system triggered by insulin resistance in diabetic patients and cause a decrease in renal function, and can reverse the established lesions of diabetic glomerulopathy.

In some embodiments, the compound is administered with a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof. In some embodiments, the compound is administered with an active agent and a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or a combination thereof. In some embodiments, the compounds are administered with one or more antidiabetic drugs. In some embodiments, the administration of the compound of the present invention and the active agent results in a synergistic effect.

Various aspects of the present invention relate to compounds, compositions and methods for treating systemic insulin resistance associated with obesity wherein elevated Galectin-3 interacts with the insulin receptor. In some embodiments, treatment with a compound of the present invention restores sensitivity to insulin activity in various tissues.

In some embodiments, the compounds or compositions of the invention bind the insulin receptor (also known as IR, INSR, CD220, HHF5).

Various aspects of the present invention relate to compounds, compositions and methods for treating disorders caused by disruption of TGFb1 (transforming growth factor beta 1 ) activity.

In some embodiments, the disorder is an inflammatory disease, such as inflammatory bowel disease, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, or ulcerative colitis.

In some embodiments, the disorder is fibrosis, such as liver fibrosis, pulmonary fibrosis, renal fibrosis, cardiac fibrosis, or fibrosis of any organ that impairs the normal function of the organ.

In some embodiments, the disorder is cancer.

In some embodiments, the disorder is an autoimmune disease, such as rheumatoid arthritis and multiple sclerosis.

In some embodiments, the disorder is heart disease or heart failure.

In some embodiments, the disorder is a metabolic disorder, such as diabetes.

In some embodiments, the associated disorder is pathological angiogenesis, such as ocular angiogenesis, diseases or disorders associated with ocular angiogenesis, and cancer.

In some embodiments, the compositions or compounds may be used to treat nonalcoholic steatohepatitis with or without liver fibrosis, inflammatory and autoimmune diseases, neoplastic disorders, or cancer.

In some embodiments, the compositions can be used to treat liver fibrosis, renal fibrosis, pulmonary fibrosis, or cardiac fibrosis.

In some embodiments, the composition or compound is capable of enhancing anti-fibrotic activity in organs including, but not limited to, liver, kidney, lung, and heart.

In some embodiments, the compositions or compounds can be used to treat inflammatory diseases of the vasculature, including atherosclerosis and pulmonary hypertension.

In some embodiments, the compositions or compounds can be used to treat heart disease, including heart failure, arrhythmias, and uremic cardiomyopathy.

In some embodiments, the composition or compound can be used to treat renal disease, including glomerulopathy and interstitial nephritis.

In some embodiments, the compositions or compounds may be used to treat inflammatory, proliferative and fibrotic skin diseases, including but not limited to psoriasis and scleroderma.

Various aspects of the invention relate to methods of treating allergic or atopic disorders, including but not limited to eczema, atopic dermatitis, or asthma.

Various aspects of the invention relate to methods of treating inflammatory and fibrotic disorders in which galectins are involved at least in part in pathogenesis by enhancing anti-fibrotic activity in organs including, but not limited to, liver, kidney, lung, and heart.

Various aspects of the present invention relate to compositions or compounds having therapeutic activity in the treatment of nonalcoholic steatohepatitis (NASH). In other aspects, the invention relates to methods of reducing the pathology and disease activity associated with nonalcoholic steatohepatitis (NASH).

Various aspects of the present invention relate to compositions or compounds for treating inflammatory and autoimmune diseases or methods of treating inflammatory and autoimmune disorders, wherein galectins are involved, at least in part, in pathogenesis, including but not limited to arthritis , systemic lupus erythematosus, rheumatoid arthritis, asthma and inflammatory bowel disease.

Various aspects of the present invention relate to compositions or compounds for the treatment of neoplastic disorders (eg, benign or malignant diseases) wherein galectins are involved at least in part in pathogenesis by inhibiting processes promoted by galectin increases. In some embodiments, the invention relates to a method of treating a neoplastic disease (eg, a benign or malignant disease) in which a process promoted by galectin by inhibiting the increase of galectin is at least partially involved in pathogenesis. In some embodiments, the compositions or compounds can be used to treat or prevent tumor cell growth, invasion, metastasis, and neovascularization. In some embodiments, the compositions or compounds can be used to treat primary and secondary cancers.

In some embodiments, the compound is a monomeric selenium polyhydroxylated naphthenic compound or a pharmaceutically acceptable salt or solvate thereof:

where X is selenium;

wherein Z is a carbohydrate or linker consisting of amino acids of O, S, C, NH, _CH2 , Se, R2 and _R3 ;

wherein W is selected from the group consisting of O, N, S, CH2, NH and Se;

wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, amino acids, and combinations thereof.

wherein _R1 , R2 and _R3 are independently selected from _CO , SO2, SO, PO2, PO, CH, hydrogen, hydrophobic linear and cyclic hydrocarbons including heterocyclic substituents having molecular weights of about 50-200D.

In some embodiments, the hydrophobic linear and cyclic hydrocarbons can include one of: a) an alkyl group of at least 4 carbons, an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, Alkenyl of at least 4 carbons substituted with carboxy, alkyl of at least 4 carbons substituted with amino, alkenyl of at least 4 carbons substituted with amino, alkane of at least 4 carbons substituted with both amino and carboxy group, alkenyl of at least 4 carbons substituted by both amino and carboxy, and alkyl substituted by one or more halogens, b) phenyl substituted by at least one carboxy, phenyl substituted by at least one halogen, phenyl substituted by at least one halogen, at least one alkoxy substituted phenyl, at least one nitro substituted phenyl, at least one sulfo substituted phenyl, at least one amino substituted phenyl, at least one alkylamino substituted phenyl, phenyl substituted by at least one dialkylamino, phenyl substituted by at least one hydroxy, phenyl substituted by at least one carbonyl and phenyl substituted by at least one carbonyl, c) naphthyl, substituted by at least one carboxyl substituted naphthyl, naphthyl substituted with at least one halogen, naphthyl substituted with at least one alkoxy, naphthyl substituted with at least one nitro, naphthyl substituted with at least one sulfo, naphthyl substituted with at least one amino naphthyl substituted with at least one alkylamino group, naphthyl group substituted with at least one dialkylamino group, naphthyl group substituted with at least one hydroxy group, naphthyl group substituted with at least one carbonyl group, and naphthyl group substituted with at least one Carbonyl-substituted naphthyl, d) heteroaryl, heteroaryl substituted with at least one carboxy, heteroaryl substituted with at least one halogen, heteroaryl substituted with at least one alkoxy, substituted with at least one nitro heteroaryl, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, heteroaryl substituted with at least one dialkylamino , heteroaryl substituted by at least one hydroxy, heteroaryl substituted by at least one carbonyl, and heteroaryl substituted by at least one substituted carbonyl, and e) sugars, substituted sugars, D-galactose, substituted D -Galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycle and derivatives; amino , substituted amino, imino or substituted imino group.

In some embodiments, the compound is a dimer-polyhydroxylated-cycloalkane compound.

In some embodiments, the compound has the general formula or a pharmaceutically acceptable salt or solvate thereof:

where X is Se, Se-Se or Se-S;

wherein Z is independently selected from carbohydrates (including, for example, oligomeric Se-galactosides) or linkers consisting of O, S, C, NH, CH, Se and amino acids of _R and R _;

wherein W is selected from the group consisting of O, N, S, CH2, NH and Se;

wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se and amino acids;

wherein R ₁ , R ₂ , R ₃ and R ₄ are independently selected from CO, SO2, SO, PO2, PO, CH, hydrogen, and hydrophobic linear and cyclic hydrocarbons, including heterocyclic substitutions with molecular weights of about 50-200D base.

In some embodiments, the hydrophobic linear and cyclic hydrocarbons can include one of: a) an alkyl group of at least 4 carbons, an alkenyl group of at least 4 carbons, an alkyl group of at least 4 carbons substituted with a carboxy group, Alkenyl of at least 4 carbons substituted with carboxy, alkyl of at least 4 carbons substituted with amino, alkenyl of at least 4 carbons substituted with amino, alkane of at least 4 carbons substituted with both amino and carboxy group, alkenyl of at least 4 carbons substituted by both amino and carboxy, and alkyl substituted by one or more halogens, b) phenyl substituted by at least one carboxy, phenyl substituted by at least one halogen, phenyl substituted by at least one halogen, at least one alkoxy substituted phenyl, at least one nitro substituted phenyl, at least one sulfo substituted phenyl, at least one amino substituted phenyl, at least one alkylamino substituted phenyl, phenyl substituted by at least one dialkylamino, phenyl substituted by at least one hydroxy, phenyl substituted by at least one carbonyl and phenyl substituted by at least one carbonyl, c) naphthyl, substituted by at least one carboxyl substituted naphthyl, naphthyl substituted with at least one halogen, naphthyl substituted with at least one alkoxy, naphthyl substituted with at least one nitro, naphthyl substituted with at least one sulfo, naphthyl substituted with at least one amino naphthyl substituted with at least one alkylamino group, naphthyl group substituted with at least one dialkylamino group, naphthyl group substituted with at least one hydroxy group, naphthyl group substituted with at least one carbonyl group, and naphthyl group substituted with at least one Carbonyl-substituted naphthyl, d) heteroaryl, heteroaryl substituted with at least one carboxy, heteroaryl substituted with at least one halogen, heteroaryl substituted with at least one alkoxy, substituted with at least one nitro heteroaryl, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, heteroaryl substituted with at least one dialkylamino , heteroaryl substituted by at least one hydroxy, heteroaryl substituted by at least one carbonyl, and heteroaryl substituted by at least one substituted carbonyl, and e) sugars, substituted sugars, D-galactose, substituted D -Galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocycle and derivatives; amino , substituted amino, imino or substituted imino group.

The present invention relates to a compound or a pharmaceutically acceptable salt or solvate thereof:

where n≤24;

where X is Se, Se-Se or Se-S;

wherein W is selected from the group consisting of O, N, S, CH2, NH and Se;

wherein Y and Z are independently selected from the group consisting of O, S, C, NH, CH2, Se and amino acids;

wherein R1 and R2 are independently selected from the group consisting _{of CO} , SO2, SO, PO2, PO, CH, hydrogen, hydrophobic linear and cyclic hydrocarbons, including heterocyclic substituents with molecular weights of 50-200D, including but not limited to:

a) alkyl of at least 4 carbons, alkenyl of at least 4 carbons, alkyl of at least 4 carbons substituted with carboxy, alkenyl of at least 4 carbons substituted with carboxy, alkenyl of at least 4 carbons substituted with amino alkyl of at least 4 carbons substituted by amino, alkenyl of at least 4 carbons substituted by both amino and carboxy, alkenyl of at least 4 carbons substituted by both amino and carboxy, and alkenyl of at least 4 carbons substituted by both amino and carboxy or multiple halogen-substituted alkyl groups;

b) phenyl substituted with at least one carboxy, phenyl substituted with at least one halogen, phenyl substituted with at least one alkoxy, phenyl substituted with at least one nitro, phenyl substituted with at least one sulfo , phenyl substituted by at least one amino, phenyl substituted by at least one alkylamino, phenyl substituted by at least one dialkylamino, phenyl substituted by at least one hydroxy, phenyl substituted by at least one carbonyl and phenyl substituted with at least one substituted carbonyl group,

c) naphthyl, naphthyl substituted with at least one carboxy, naphthyl substituted with at least one halogen, naphthyl substituted with at least one alkoxy, naphthyl substituted with at least one nitro, naphthyl substituted with at least one sulfo Naphthyl substituted with at least one amino, naphthyl substituted with at least one alkylamino, naphthyl substituted with at least one dialkylamino, naphthyl substituted with at least one hydroxy, substituted with at least one carbonyl and naphthyl substituted with at least one substituted carbonyl; and

d) heteroaryl, heteroaryl substituted with at least one carboxy, heteroaryl substituted with at least one halogen, heteroaryl substituted with at least one alkoxy, heteroaryl substituted with at least one nitro, Heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, heteroaryl substituted with at least one dialkylamino, substituted with at least one hydroxy Heteroaryl, heteroaryl substituted with at least one carbonyl, and heteroaryl substituted with at least one substituted carbonyl,

e) sugars; substituted sugars; D-galactose; substituted D-galactose; C3-[1,2,3]-triazol-1-yl-substituted D-galactose; hydrogen, alkyl, alkene aryl, aryl, heteroaryl, heterocycle and derivatives; amino, substituted amino, imino or substituted imino.

Example

Example 1: Compounds inhibit the binding of galectins to labeled probes

等人，分析生物化学(Anal Biochem.)，2004年11月1日；334(1)：36-47)测量配体对半乳凝素蛋白的结合亲和力。Fluorescein-labeled probes that bind Galectin 3 and other galectin proteins have been developed and these probes have been used to establish assays (Figures 5A and 5B) using fluorescence polarization (

et al., Anal Biochem., 2004 Nov 1;334(1):36-47) measured the binding affinity of ligands to galectin proteins.

The compounds described herein bind tightly to Galectin-3 as well as other galectin proteins and displace fluorescein-labeled probes with high affinity using the assay (Figure 5A), _IC50 (concentration at 50% inhibition) is about 5 nM to about 40 μM. In some embodiments, the _IC50 is about 5 nM to about 20 nM. In some embodiments, the _IC50 is about 5 nM to about 100 nM. In some embodiments, the _IC50 is about 10 nM to about 100 nM. In some embodiments, the _IC50 is about 50 nM to about 5 μM. In some embodiments, the _IC50 is about 0.5 μM to about 10 μM. In some embodiments, the _IC50 is about 5 μM to about 40 μM.

The claimed compounds were synthesized (see Tables 1, 2, 3 and Figure 4) and tested for binding to CRD in a fluorescence polarization assay (Figure 5A) and showed inhibitory activity (Figure 7).

G-625 - a β-D-galactopyranoside, 3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl-) -β-D-galactopyranosyl-3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-1-selenyl-. G-625 has a monoselenide bridge between two aryl-triazole-galactosides, (see Table 2), has been shown to inhibit Gal-3 binding in fluorescence polarization assays (Figure 7).

G-626 - a β-D-galactopyranoside, 3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl-) -β-D-galactopyranosyl-3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-1-selenyl-. G-625 has a diselenide bridge between two aryl-triazole-galactosides, (see Table 2), has been shown to inhibit Gal-3 binding in a fluorescence polarization assay (Figure 7).

G-662, a seleno-monosaccharide, was synthesized (see Table 1) and shown to inhibit Gal-3 binding in a fluorescence polarization assay (Figure 7).

Example 2: Inhibition of Galectin Binding by Compounds Using FRET Assays

A FRET (Fluorescence Resonance Energy Transfer) assay was developed to evaluate the interaction of galectin proteins, including but not limited to Galectin-3, with model fluorescently labeled probes (see Figure 5B). The compounds described herein bind tightly to Galectin-3 as well as other galectin proteins using the assay and displace the probe with high affinity with an _IC50 of about 5 nM to about 40 μM (at 50% inhibition) concentration). In some embodiments, the IC50 is about 5 nM to about 20 nM. In some embodiments, the IC50 is about 5 nM to about 100 nM. In some embodiments, the IC50 is about 10 nM to about 100 nM. In some embodiments, the IC50 is about 50 nM to about 5 μM. In some embodiments, the IC50 is about 0.5 μM to about 10 μM. In some embodiments, the IC50 is about 5 μM to about 40 μM.

Example 3: Compounds inhibit the binding of galectins to physiological ligands

High levels of serum Galectin-3 have been shown to be associated with obesity and diabetes. Diabetes is a long-lasting disease that can be resolved or prevented with care. It is one of the most common metabolic syndromes worldwide. Diabetes is mainly associated with the central and peripheral nervous systems and is a chronic complication. Diabetes is a common type of diabetic metabolic syndrome in which the body cannot use glucose and stores it in the blood, which can damage the kidneys, nerves, heart, eyes and cause other complications.

Insulin resistance, a characteristic feature of patients with complications of diabetes mellitus (T2DM), is one of the clinical features of metabolic syndrome (MetS), a group of biochemical and metabolic disorders estimated to affect more than 20% of adults in the United States (>20 years old) or about 500 million Americans. With the obesity epidemic showing no signs of reversing, that number could rise sharply in the future.

Insulin is a hormone with multiple functions, including facilitating the transport of nutrients into cells, regulating various enzymatic activities, and regulating energy homeostasis. These functions involve glucose metabolism in liver, adipose tissue and muscle via intracellular signaling pathways. In the liver, insulin resistance leads to increased hepatic glucose production. In adipose tissue, insulin resistance affects lipase activity, leading to antilipid effects, affecting free fatty acid efflux from adipocytes and increasing circulating free fatty acids.

Recent studies have also shown that galectin-3 plasma levels are significantly elevated in human and animal models of obesity.

In obesity, macrophages and other immune cells have been reported to be recruited to insulin target tissues and promote chronic inflammatory states and insulin resistance. Galectin-3, known to be mainly secreted by macrophages, may play a key role in this inflammatory process, thus linking inflammation to decreased insulin sensitivity. Inhibition of galectin-3 may become a new drug target for the treatment of insulin resistance.

The interaction of the insulin receptor and insulin is a checkpoint for a second pathway, the Ras-mitogen-active protein kinase (MAPK), which mediates gene expression, and also affects cells that control cell growth and differentiation. PI3K-AKT pathway. Insulin receptor substrates (IRS) are common intermediates that include four distinct family members, IRS1-4. Defects in insulin signaling typically involve insulin receptor substrate-1 (IRS1). Activation of the insulin receptor increases tyrosine phosphorylation of IRS1, which initiates signal transduction. However, when serine 307 was phosphorylated, signaling was attenuated. Other IR or IRS1 inflammation-associated negative regulators include inhibitors of cytokine signaling (Socs) that may promote ubiquitination, in which ubiquitin (a small protein) binds to another target protein, altering its function and subsequent degradation, For example IRS inactivation.

The claimed compounds (see Tables 1, 2, 3 and 4) were synthesized and tested for their inhibitory activity in the insulin receptor-galectin-3 interaction (Figure 6B).

For example, G-625 - a β-D-galactopyranoside, 3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl -)-β-D-galactopyranosyl-3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-1-selenyl -. G-625 has a monoselenide bridge between two aryl-triazole-galactosides (see Table 2), which showed inhibitory activity in the insulin receptor-galectin-3 interaction (Figure 8 ).

G-662, a seleno-monosaccharide, was synthesized (see Table 1) and showed inhibitory activity in the insulin receptor-galectin-3 interaction (Figure 8).

The compounds claimed in this invention (see Tables 1, 2, 3 and 4) were synthesized and tested for their inhibitory activity on the TGF-beta-1 receptor-galectin-3 interaction. This interaction of TGF-beta receptors with galectin-3 is an important pathological step in many inflammatory and fibrotic pathways. The compounds described herein have been shown to be inhibitors of this interaction (Figure 9).

For example, G-625 - a β-D-galactopyranoside, 3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl -)-β-D-galactopyranosyl-3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-1-selenyl -. G-625 has a monoselenide bridge between two aryl-triazole-galactosides (see Table 2), which showed inhibitory activity in TGF-β receptor-galectin-3 (Figure 9 ).

G-662, a seleno-monosaccharide, was synthesized (see Table 1) and showed inhibitory activity in the TGF-beta receptor-galectin-3 interaction (Figure 9).

Example 4: Compounds that bind to amino acid residues in galectin proteins

Heteronuclear NMR spectroscopy was used to evaluate the interaction of compounds described herein with galectin molecules, including but not limited to galectin-3, to evaluate interacting residues on galectin-3 molecules .

Homogeneous15N-labeled Gal- ³ was expressed in BL21(DE3) competent cells (Novagen), grown in minimal medium, purified on a lactose affinity column, and fractionated on a gel filtration column as previously For Gal-1 (Nesmelova IV, Pang M, Baum LG, Mayo KH, 1H, 13C, and 15N main-chain and side-chain chemical shift assignments (1H, 13C, and 15N) of the 29kDa human galectin-1 protein dimer backbone and side-chain chemical shift assignments for the 29kDa human galectin-1 protein dimer), Biomol NMR Assign, 2008 Dec;2(2):203-205).

Homogeneous15N-labeled Gal-3 was dissolved ^at a concentration of 2 mg/ml in 20 mM potassium phosphate buffer, pH 7.0, using a 95% _H2O /5% _D2O mixture. Binding of ^a series of compounds described herein was investigated using1H- ^15N HSQC NMR experiments. ^{The1H and15N} resonance assignments of recombinant human Gal-3 were previously reported (Ippel H et al., (1)H, (1)H, ( 13)C and (15)N backbone and side-chain chemical shift assignments ((1)H, (13)C, and (15)N backbone and side-chain chemical shift assignments for the 36proline-containing, full length 29kDa human chimera -type galectin-3), Biomol NMR Assign, 2015 Apr;9(1):59-63).

NMR experiments were performed at 30°C on Bruker 600MHz, 700MHz or 850MHz spectrometers equipped with an H/C/N triple resonance probe and an x/y/z triaxial pulsed field gradient unit. A two-dimensional ¹ H- ¹⁵ N HSQC gradient sensitivity-enhanced version was used to apply 256(t1) × 2048(t2) complex data points in nitrogen and proton dimensions, respectively, and the raw data were transformed and processed with NMRPipe and analyzed with NMRview.

These experiments show that the compounds described herein differ in the binding residues of the carbohydrate binding domain of Galectin-3.

Example 5: Cellular Activity of Cytokine Activity Associated with Galectin Binding Inhibition

Example 1 describes the ability of the compounds of the present application to inhibit the binding of physiological ligands to galectin molecules. In the experiments of this example, the functional significance of those binding interactions was evaluated.

One of the interactions with Galectin-3 that is inhibited by the compounds described herein is the TGF-beta receptor. Therefore, experiments were performed to evaluate the effect of compounds on TGR-beta receptor activity in cell lines. Various TGF-beta responsive cell lines, including but not limited to LX-2 and THP-1 cells, were treated with TGF-beta and observed for activation of second messenger systems (including but not limited to phosphorylation of various intracellular SMAD proteins) ) to measure the cellular response. After determining that TGF-beta activates second messenger systems in various cell lines, cells are treated with the compounds described herein. These experiments show that these compounds inhibit the TGF-beta signaling pathway, demonstrating that the inhibition of binding interactions described in Example 1 has a physiological effect in a cellular model.

Cellular assays were also performed to evaluate the physiological significance of inhibiting the interaction of Galectin-3 with various integrin molecules. Cell-cell interaction studies using monocytes in combination with vascular endothelial cells as well as other cell lines. Treatment of cells with the compounds described herein was found to inhibit these integrin-dependent interactions, demonstrating that the inhibition of binding interactions described in Example 1 has a physiological effect in a cellular model. Bioassay Process:

The process of MCF-7 cells (colon cancer) is as follows:

1. Suspend MCF-7 cells in medium (Gibco Lot 1202161) containing Penicillin/Streptomycin 4X Concentrate (4X Pen/Strep) and 0.25% Fetal Bovine Serum.

2. Add 100ul of medium, about 4,000-10,000 cells/well, passages 5 to 30) and incubate the cells at 37°C for at least 24 hours.

3. Serial dilutions of test compounds in assay medium as described above, typically in the range of 100 μg/ml to 20 ng/ml

4. Add 100 ml of serially diluted compounds to the cells in the assay plate in duplicate to a final volume of 200 ml in each well (containing 2x Pen/Strep, 0.25% FBS and indicated compound of)

5. Incubate cells at 37°C for 60-80 hours.

6. Add 20 ml of Promega Substrate [CellTiter 96 Aqueous One Solution] reagent to each well.

7. Incubate cells at 37°C for 4-8 hours and read OD at 490nm.

The process of HTB-38 cells (breast cancer) is as follows:

1. HTB-38 cells were resuspended in medium containing 8 ng/ml h-IFN-γ, penicillin/streptomycin 4x concentrate (4XPen/Strep) and 10% fetal bovine serum (Gibco Lot 1260930).

2. Transfer cells into assay plates at 100 μl/well (4,000-10,000 cells/well, passages 4 to 30).

3. Serial dilutions of test compounds in assay medium as described above, typically in the range of 100 μg/ml to 20 ng/ml

4. Add 100 μl/well of serially diluted compound to cells in duplicate. The final volume of each well is 200μl, containing 4ng/ml h-IFN-γ, penicillin/streptomycin 2x concentrate (2x Pen/Strep),

5. Incubate cells at 37°C for 60-90 hours.

6. Add 20 μl of Promega Substrate [CellTiter 96 Aqueous One Solution] reagent to each well.

7. Incubate cells at 37°C for 4-8 hours and read OD at 490nm.

Cell motility assays were performed to evaluate the physiological significance of inhibiting the interaction of Galectin-3 with various integrins and other cell surface molecules as defined in Example 1. Cell studies were performed using a variety of cell lines in semipermeable membrane separation pore devices. Treatment of cells with the compounds described herein was found to inhibit cell motility, demonstrating that the inhibition of binding interactions described in Example 1 has a physiological effect in a cellular model.

Example 6: In vitro model of inflammation (monocyte-based assay)

AQueous单溶液细胞增殖测定，其含有一种新的四唑化合物[3-(4,5-二甲基-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺苯基)-2H-四唑，内盐；MTS]和一种电子偶联剂(吩嗪乙基硫酸盐；PES))并且通过趋化因子单核细胞趋化蛋白-1(MCP-1/CCL2)的定量测量评价炎性阶段，MCP-1/CCL2是调节炎症细胞过程中单核细胞/巨噬细胞的迁移和浸润的关键蛋白。对主要活性化合物进行其它细胞因子和趋化因子的表达和分泌的跟踪测试。To establish a model of macrophage polarization starting from THP-1 monocyte cultures, THP-1 monocyte cultures were treated with PMA (Phorbol 12-myristate 13-acetate). Differentiate into inflammatory macrophages for 2-4 days. Once differentiated (MO macrophages), macrophages were induced with LPS or LPS and IFN-[gamma] to activate macrophages (M1) into the inflammatory phase for 1-3 days. Cytokine and chemokine profiles were analyzed to confirm the polarization of THP-1-derived macrophages to the inflammatory phase. The effect of anti-galectin 3 compounds on macrophage polarization was first assessed by monitoring cell viability using a colorimetric assay (using tetrazolium reagent) to determine the number of viable cells in proliferation or cytotoxicity assays (Promega, CeilTiter

AQueous single-solution cell proliferation assay containing a novel tetrazole compound [3-(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 -sulfophenyl)-2H-tetrazole, inner salt; MTS] and an electron coupling agent (phenazine ethyl sulfate; PES)) and passed through the chemokine monocyte chemoattractant protein-1 (MCP- Quantitative measurement of 1/CCL2) to assess the inflammatory stage, MCP-1/CCL2 is a key protein regulating monocyte/macrophage migration and infiltration during inflammatory cell processes. The main active compounds were tested for expression and secretion of other cytokines and chemokines.

THP-1 cells are stimulated by microbial endotoxin and transformed into inflammatory macrophages (M1), which secrete inflammatory cytokines such as monocyte chemotactic protein-1 (MCP-1).

In this embodiment, the method steps are as follows:

1) Culture THP-1 cells in medium containing gentamicin

2) Transfer THP-1 cells at 2,000 cells/well into wells of a 96-well plate and incubate for 2 days in assay medium containing 10 ng/ml PMA

3) Serial dilution of test compounds in medium containing LPS (10ng/ml)

4) Add 100ml of compound/LPS solution to each well until the final assay volume of each well is 200ml, and each well also contains gentamicin and 5ng/ml PMA

5) Incubate cells for up to 8 days.

6) Take 60ul samples every other day for bioassay

7) At termination, add 15ml of Promega substrate CeIlTiter 96Aqueous single solution to each well to monitor cytotoxicity (at 490nm)

8) For cellular biomarker evaluation, cells were washed with 1×PBS and extracted with 200 μl of lysis buffer for 1 hour. The extract was run down for 10 minutes and a 120ul sample was taken from the top. All samples were kept at -70°C until testing.

Example 7: Evaluation of Compound Absorption, Distribution, Metabolism and Elimination

The physicochemical properties of the compounds described herein, including but not limited to solubility (thermodynamic and kinetic methods), various pH changes, in biologically relevant media (FaSSIF, FaSSGF, FeSSIF), Log D (octanol/water and Solubility in cyclohexane/water), chemical stability in plasma, and blood partitioning.

Compounds described herein were evaluated for their in vitro permeation properties, including but not limited to PAMPA (parallel artificial membrane permeation assay), Caco-2, and MDCK (wild type).

The animal pharmacokinetic properties of the compounds described herein were evaluated, including but not limited to, by various routes, namely oral, intravenous, intraperitoneal, subcutaneous administration in mice (Swiss Albino, C57, Balb/C), rats ( Wistar, Sprague Dawley), rabbit (New Zealand white rabbit), dog (Beagle), cynomolgus monkey, etc. in vivo pharmacokinetics, tissue distribution, brain-to-plasma ratio, bile excretion and mass balance.

The compounds described herein are evaluated for protein binding, including but not limited to plasma protein binding (ultrafiltration and equilibrium dialysis) and microsomal protein binding.

Evaluation of in vitro metabolism of compounds described herein, including but not limited to cytochrome P450 inhibition, time-dependent inhibition of cytochrome P450, metabolic stability, liver microsomal metabolism, S-9 component metabolism, effect on cryopreserved hepatocytes, Plasma stability and GSH capture.

The compounds described herein are evaluated for metabolite identification, including but not limited to in vitro identification (microsomes, S9 and hepatocytes) and in vivo samples.

Example 8: Affinity of oligomeric Se-galactosides

The affinity of tetrameric Se-galactoside and trimeric Se-galactoside of Table 3 was determined using fluorescence polarization assay. The tetrameric Se-galactoside is expected to have a higher affinity for the CRD than the trimeric structure due to the additional potential interaction of the hydroxyl group with amino acids near the CRD.

Example 9: Cell Culture Adipocyte Model

Cell culture and insulin resistance model using 3T3-L1 fibroblasts, 3T3-L1 fibroblasts were cultured in DMEM containing 10% FCS and GlutaMAX and differentiated into adipocytes as previously reported (Shewan, A.M., van Dam, E.M., Martin, S., Luen, T.B., Hong, W., Bryant, N.J., and James, D.E. (2003), "GLUT4 passes through a trans-Golgi network (TGN) subgroup enriched in Syntaxins 6 and 16 but not TGN38 Domain recycles: involvement of an acidic targeting motif” (“GLUT4 recycles via a trans-Golgi network (TGN) subdomain enriched in Syntaxins 6 and 16 but not TGN38: involvement of an acidic targeting motif”), Molecular and Cell Biology . Biol. Cell) 14, 973-986). Various models of insulin resistance were used. 3T3-L1 adipocytes were cultured in full DMEM medium with varying doses of insulin (10-100 nM) to induce chronic insulin exposure, or with 0.1-1 M dexamethasone (DEX) for 8-24 hours at 37°C or with 1-20ng/ml of TNF was incubated at 37°C for 48h. Medium was replaced twice daily with fresh medium containing TNF. Following insulin resistance treatment, cells were washed and serum starved for 1-2 hours prior to insulin stimulation and assessment of insulin-regulated kinases and processes. This protocol has been previously shown to be sufficient to restore cells to their baseline levels of GLUT4 translocation (Hoehn, K.L., Hohnen-Behrens, C., Cederberg, A., Wu, L.E., Turner, N., Yuasa, T., Ebina, Y. and James, D.E. (2008) IRS1-independent defects define major nodes in insulin resistance. Cell Metab., 7, 421-433)

Experiments were performed with 3T3-L1 fibroblasts differentiated into adipocyte cultures according to the Promega protocol:

1. On day 1, 1 ml of low passage number 3T3L1 cells were thawed and mixed with 9 ml of maintenance medium (MM). Cells were centrifuged at 200xg for 10 minutes and liquid medium was aspirated.

2. Resuspend the cell pellet in 11 ml MM. Cells were plated in 96-well plates at 20,000 cells/100 μl.

3. Cells were grown to confluency at 37°C in 5% _CO2 with medium changes every 2 days. Since these cells adhere poorly during differentiation, cells were plated on collagen-coated plates (Corning, cat. no. 356650). Media removal and addition were performed at the slowest possible pipetting speed.

4. On day 5, replace the medium with 100 μl of Differentiation Medium I (DM-I) and continue to replace every 2 days.

5. On day 12, replace the medium with 100 μl of Differentiation Medium II (DM-II).

6. On day 14, replace the medium with 100 μl of MM, and continue to change the medium every 2 days.

7. Measure insulin response between days 8-11.

3T3L1 adipocytes were assayed as follows:

1. Replace the medium with 100 μl of serum-free MM the day before the assay.

2. On the day of the assay, use 100 μl of DMEM (Life Technologies, cat. no. f11966) without serum or glucose to contain a range of insulin concentrations. Cells were incubated for ₁ h at 37 °C in 5% CO.

3. The medium was removed, 50 μl of 2DG (1 mM) in PBS was added, and the cells were incubated at 25° C. for 10 minutes.

4. Add 25 μl of stop buffer and shake the sample briefly.

5. Add 25 μl of neutralization buffer and shake the sample briefly.

6. Add 100 μl of 2DG6P detection reagent, shake the sample briefly and incubate at 25°C for 1 hour.

Luminescence was recorded on a luminometer with 0.3-1 second integration to assess the cellular effect of Galectin-3 on glucose uptake.

Adipocyte differentiation is monitored by various well-defined insulin-associated activation markers, including insulin receptor (IR) expression and its activation by insulin, but not limited to IR kinase within minutes of insulin exposure active. This insulin activation was inhibited by treatment with Galectin-3. The effect of galectin-3 on IR was also monitored by glucose uptake rate.

The compounds described herein were found to inhibit Galectin-3 action and reversal of insulin resistance and restoration of glucose uptake, demonstrating a physiological and potential therapeutic role in systemic insulin resistance in obesity-related diabetes.

Example 10: Synthesis of G-625

Compound G-625 was synthesized using the following scheme (see Figure 4)

step 1:

(2R,3R,4S,5R,6S)-2-(acetoxymethyl)-4-azido-6-((4-methylbenzoyl)selenyl)tetrahydro-2H-pyridine Pyran-3,5-diyldiacetate (3): To (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-4-azido-6-bromotetrahydro -2H-pyran-3,5-diyldiacetate (1, 1.6 g, 4.06 mmol) and potassium 4-methylbenzeneselenoate (2, 2.41 g, 10.14 mmol) in EtOAc (30 mL) To the solution, tetra-n-butylammonium hydrogen sulfate (2.75 g, 8.12 mmol) and aqueous _Na2CO3 ( ₁₆ mL, 16 mmol) were added sequentially at room temperature (rt) and the reaction mixture was stirred at room temperature for 3 h. Upon completion, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried ( _{Na2SO4 )} , filtered and concentrated in vacuo, and the residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh, gradient 0-30% EtOAc in hexanes]), The title compound (3) was obtained as a white solid (1.38 g, 66%).

¹ H-NMR (400MHz; CDCI3): δ 2.04(s, 3H), 2.06(s, 3H), 2.18(s, 3H), 2.45(s, 3H), 2.76-2.80(m, 1H), 4.03 -4.17 (m, 3H), 5.44-5.53 (m, 3H), 7.27 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H).

Step-2:

(2S,2'S,3R,3'R,4S,4'S,5R,5'R,6R,6'R)-selenobis(6-(acetoxymethyl)-4-azidotetrahydro- 2H-pyran-2,3,5-triyl)tetraacetate (5): (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-4-azido -6-((4-methylbenzoyl)selenyl)tetrahydro-2H-pyran-3,5-diyldiacetate (3, 100 mg, 0.19 mmol) in DMF (4 mL) The solution was degassed with argon for 20 min. The mixture was cooled to -15°C and _{Cs2CO3 (} 127 mg, 0.79 mmol), dimethylamine (2M in THF) (0.39 mL, 0.78 mmol) and (2R,3R,4S,5R)-2-( A solution of acetoxymethyl)-4-azido-6-bromotetrahydro-2H-pyran-3,5-diyldiacetate (307 mg, 0.78 mmol) in DMF (2 mL), and Degas with argon again for 20 min. The reaction mixture was stirred at the same temperature for 5 min. After checking TLC, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried ( _{Na2SO4 )} , filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh, gradient 0-50% EtOAc in hexanes]) to give the title compound (5) as a colorless sticky solid (66 mg, 48% ).

MS: m/z 707(M+AcOH) ⁺ (ES ⁺ )

¹ H-NMR (crude) (400 MHz; CDCl ₃ ): δ 2.04-2.19 (m, 18H), 2.87-2.98 (m, 2H), 4.09-4.17 (m, 6H), 4.60-4.82 (m, 6H) ).

Step-3:

(2S,2'S,3R,3'R,4S,4'S,5R,5'R,6R,6'R)-selenobis(6-(acetoxymethyl)-4-(4-(3- Fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2,3,5-triyl)tetraacetate (7): To (2S,2'S ,3R,3'R,4S,4'S,5R,5'R,6R,6'R)-selenobis(6-(acetoxymethyl)-4-azidotetrahydro-2H-pyran - A solution of 2,3,5-triyl)tetraacetate (5, 130 mg, 0.183 mmol) and 1-ethynyl-3-fluorobenzene (6, 115 mg, 0.918 mmol) in toluene (4 mL) at DIPEA (0.07 mL, 0.366 mmol) and Cul (34 mg, 0.183 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were filtered through a pad of celite, washed with EtOAc, dried ( _{Na2SO4 )} and concentrated in vacuo, and the residue was washed with Et2O (10 mL) to give the title compound (7) as a white solid (164 mg) , 94%).

MS: m/z 949 (M+H) ⁺ (ES ⁺ )

¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 1.83 (s, 3H), 1.85 (s, 3H), 1.90-2.07 (m, 12H), 4.07-4.13 (m, 4H), 4.32-4.40 (m, 2H), 5.36 (d, J=9.5Hz, 1H), 5.48-5.49 (m, 3H), 5.64-5.73 (m, 4H), 7.18 (t, J=8.4Hz, 2H), 7.47- 7.51 (m, 2H), 7.68-7.74 (m, 4H), 8.76 (d, J=10.3 Hz, 2H).

Step-4:

(2R,2'R,3R,3'R,4S,4'S,5R,5'R,6S,6'S)-6,6'-selenobis(4-(4-(3-fluorophenyl)-)- 1H-1,2,3-Triazol-1-yl)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol) (GTJC-010-01): To (2S, 2'S,3R,3'R,4S,4'S,5R,5'R,6R,6'R)-selenobis(6-(acetoxymethyl)-4-(4-(3-fluorophenyl) )-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2,3,5triyl)tetraacetate (7,200 mg, 0.21 mmol) in MeOH (10 mL) To the solution, NaOMe (0.4 mL, 0.42 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. Upon completion, the reaction mixture was acidified with Amberlyst 15H (pH about 6), filtered, washed with MeOH and concentrated in vacuo. The crude residue was subjected to preparative HPLC (reverse phase, X BRIDGE Shield RP, C-18, 19 x 250 mm, 5 μ, gradient 50%-82% ACN in water with 5 Mm ammonium bicarbonate, 214 nm, RT: 7.8 min to give The title compound as a white solid (GTJC-010-01, 18 mg).

LCMS (Method A): m/z 697 (M+H) ⁺ (ES ⁺ ) at 4.51 min, 96% purity.

¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 3.49-3.61 (m, 4H), 3.72 (t, J=6.2Hz, 2H), 3.99 (dd, 2.9&6.6Hz, 2H), 4.36- 4.43 (m, 2H), 4.70 (t, J=5.5Hz, 1H), 4.82 (dd, 2.8&10.5Hz, 2H), 5.19 (d, J=9.7Hz, 2H), 5.31 (d, J=7.2 Hz, 2H), 5.40 (d, J=6.6Hz, 2H), 7.12-7.17 (m, 2H), 7.46-7.51 (m, 2H), 7.66 (dd, J=2.3&10.2Hz, 2H), 7.72 (d, J=7.8 Hz, 2H), 8.67 (s, 2H).

CMS (Method A): Instrument: Waters Acquity UPLC, Waters 3100PDA Detector, SQD; Column: Acquity BEH C-18, 1.7 microns, 2.1 x 100 mm; Gradient [time (min)/solvent B (%) in A] : 0.00/2, 2.00/2, 7.00/50, 8.50/80, 9.50/2, 10.0/2; solvent: solvent A=5mM ammonium acetate aqueous solution; solvent B=acetonitrile; injection volume 1LL; detection wavelength 214nm; The temperature is 30°C; the flow rate is 0.3mL/min.

All publications and patents mentioned herein are incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. See International Application No. PCT/US17/20658, filed March 3, 2017, which is incorporated by reference in its entirety.

Claims (29)

1. A method for treating systemic insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof

where X is selenium, wherein W is selected from the group consisting of O, N, S, CH, NH and Se, wherein Y is selected from the group consisting of O, S, NH, CH2, Se, S, SO2, PO2, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substituents having a molecular weight of about 50-200 D, and combinations thereof , wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and hydrophobic hydrocarbon derivatives comprising heterocyclic substituents of 3 or more atoms, wherein R1, R2 and _R3 are independently selected from CO, _O2 , SO2, PO2, PO, CH, hydrogen or _a combination of these, and a) alkyl of at least 3 carbons, alkenyl of at least 3 carbons, Alkyl of at least 3 carbons substituted by carboxyl, alkenyl of at least 3 carbons substituted by carboxyl, alkyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino alkyl of at least 3 carbons substituted with both carboxy, alkenyl of at least 3 carbons substituted with both amino and carboxy, and alkyl substituted with one or more halogens, b) benzene substituted with at least one carboxy phenyl, phenyl substituted with at least one halogen, phenyl substituted with at least one alkoxy, phenyl substituted with at least one nitro, phenyl substituted with at least one sulfo, phenyl substituted with at least one amino , phenyl substituted with at least one alkylamino group, phenyl substituted with at least one dialkylamino group, phenyl substituted with at least one hydroxy group, phenyl substituted with at least one carbonyl group, and phenyl substituted with at least one substituted carbonyl group phenyl, c) naphthyl, naphthyl substituted by at least one carboxy, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, naphthyl substituted by at least one nitro, naphthyl substituted by at least one Sulfo-substituted naphthyl, at least one amino-substituted naphthyl, at least one alkylamino-substituted naphthyl, at least one dialkylamino-substituted naphthyl, at least one hydroxy-substituted naphthyl, at least one hydroxy-substituted naphthyl One carbonyl substituted naphthyl and at least one substituted carbonyl substituted naphthyl, d) heteroaryl, at least one carboxy substituted heteroaryl, at least one halogen substituted heteroaryl, at least one alkoxy substituted heteroaryl, heteroaryl substituted with at least one nitro, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, Heteroaryl substituted with at least one dialkylamino, heteroaryl substituted with at least one hydroxy, heteroaryl substituted with at least one carbonyl, and heteroaryl substituted with at least one substituted carbonyl, and e) sugars, Substituted sugar, D-galactose, substituted D-galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl The group consisting of , heteroaryl, heterocycle and derivatives, amino, substituted amino, imino and substituted imino. 2. A method for treating systemic insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (2) or a pharmaceutically acceptable salt or solvate thereof

where X is selenium, wherein W is selected from the group consisting of O, N, S, CH, NH and Se, wherein Y is selected from O, S, C, NH, CH2, Se, S, SO3, PO2, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substituents having a molecular weight of about 50-200 D, and combinations thereof the group, wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and hydrophobic hydrocarbon derivatives comprising heterocyclic substituents of 3 or more atoms, wherein R1, R2 and _R3 are independently selected from CO, _O2 , SO2, PO2, PO, CH, hydrogen or _a combination of these, and a) alkyl of at least 3 carbons, alkenyl of at least 3 carbons, Alkyl of at least 3 carbons substituted by carboxyl, alkenyl of at least 3 carbons substituted by carboxyl, alkyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino, alkenyl of at least 3 carbons substituted by amino alkyl of at least 3 carbons substituted with both carboxy, alkenyl of at least 3 carbons substituted with both amino and carboxy, and alkyl substituted with one or more halogens, b) benzene substituted with at least one carboxy phenyl, phenyl substituted with at least one halogen, phenyl substituted with at least one alkoxy, phenyl substituted with at least one nitro, phenyl substituted with at least one sulfo, phenyl substituted with at least one amino , phenyl substituted with at least one alkylamino group, phenyl substituted with at least one dialkylamino group, phenyl substituted with at least one hydroxy group, phenyl substituted with at least one carbonyl group, and phenyl substituted with at least one substituted carbonyl group phenyl, c) naphthyl, naphthyl substituted by at least one carboxy, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, naphthyl substituted by at least one nitro, naphthyl substituted by at least one Sulfo-substituted naphthyl, at least one amino-substituted naphthyl, at least one alkylamino-substituted naphthyl, at least one dialkylamino-substituted naphthyl, at least one hydroxy-substituted naphthyl, at least one hydroxy-substituted naphthyl One carbonyl substituted naphthyl and at least one substituted carbonyl substituted naphthyl, d) heteroaryl, at least one carboxy substituted heteroaryl, at least one halogen substituted heteroaryl, at least one alkoxy substituted heteroaryl, heteroaryl substituted with at least one nitro, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, Heteroaryl substituted with at least one dialkylamino, heteroaryl substituted with at least one hydroxy, heteroaryl substituted with at least one carbonyl, and heteroaryl substituted with at least one substituted carbonyl, and e) sugars; Substituted sugar; D-galactose; Substituted D-galactose; C3-[1,2,3]triazol-1-yl-substituted D-galactose; hydrogen, alkyl, alkenyl, aryl, Heteroaryl and heterocycle and derivatives; the group consisting of amino, substituted amino, imino and substituted imino. 3. A method for treating systemic insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of general formula (3) or a pharmaceutically acceptable salt or solvate thereof

where X is selenium, wherein W is selected from the group consisting of O, N, S, CH, NH and Se, wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, P, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substituents having a molecular weight of about 50-200 D, and combinations thereof , wherein Z is selected from the group consisting of O, S, N, CH, Se, S, SO2, PO2 and hydrophobic hydrocarbon derivatives comprising heterocyclic substituents of 3 or more atoms, Among them, n≤24, wherein R1 and R2 are independently selected from CO, _O2 , SO2, SO, PO2, PO, CH, hydrogen or _a combination of these and a) alkyl of at least 3 carbons, alkenyl of at least 3 carbons, carboxylated substituted alkyl of at least 3 carbons, alkenyl of at least 3 carbons substituted with carboxyl, alkyl of at least 3 carbons substituted with amino, alkenyl of at least 3 carbons substituted with amino, amino and carboxyl Alkyl of at least 3 carbons substituted by both, alkenyl of at least 3 carbons substituted by both amino and carboxy, and alkyl substituted by one or more halogens, b) phenyl substituted by at least one carboxy, phenyl substituted with at least one halogen, phenyl substituted with at least one alkoxy, phenyl substituted with at least one nitro, phenyl substituted with at least one sulfo, phenyl substituted with at least one amino, phenyl substituted with at least one amino phenyl substituted with at least one alkylamino group, phenyl substituted with at least one dialkylamino group, phenyl substituted with at least one hydroxy group, phenyl substituted with at least one carbonyl group, and phenyl substituted with at least one substituted carbonyl group , c) naphthyl, naphthyl substituted by at least one carboxy, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, naphthyl substituted by at least one nitro, naphthyl substituted by at least one sulfo substituted naphthyl, naphthyl substituted with at least one amino, naphthyl substituted with at least one alkylamino, naphthyl substituted with at least one dialkylamino, naphthyl substituted with at least one hydroxy, naphthyl substituted with at least one carbonyl Substituted naphthyl and naphthyl substituted by at least one substituted carbonyl, d) heteroaryl, heteroaryl substituted by at least one carboxy, heteroaryl substituted by at least one halogen, substituted by at least one alkoxy Heteroaryl, heteroaryl substituted with at least one nitro, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, heteroaryl substituted with at least one a dialkylamino substituted heteroaryl group, a heteroaryl group substituted with at least one hydroxy group, a heteroaryl group substituted with at least one carbonyl group, and a heteroaryl group substituted with at least one substituted carbonyl group, and e) sugars, substituted Sugar, D-galactose, substituted D-galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, hetero The group consisting of aryl, heterocycle and derivatives, amino, substituted amino, imino or substituted imino. 4. A method for treating systemic insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of general formula (4) or a pharmaceutically acceptable salt or solvate thereof

where X is selenium, wherein W is selected from the group consisting of O, N, S, CH, NH and Se, wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, S, P, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substituents having a molecular weight of about 50-200 D, and combinations thereof , wherein Z is selected from the group consisting of O, S, N, CH, Se, S, SO2, PO2 and hydrophobic hydrocarbon derivatives comprising heterocyclic substituents of 3 or more atoms, Among them, n≤24, wherein R1 and R2 are independently selected from CO, _O2 , SO2, SO, PO2, PO, CH, hydrogen or _a combination of these and a) alkyl of at least 3 carbons, alkenyl of at least 3 carbons, carboxylated substituted alkyl of at least 3 carbons, alkenyl of at least 3 carbons substituted with carboxyl, alkyl of at least 3 carbons substituted with amino, alkenyl of at least 3 carbons substituted with amino, amino and carboxyl Alkyl of at least 3 carbons substituted by both, alkenyl of at least 3 carbons substituted by both amino and carboxy, and alkyl substituted by one or more halogens, b) phenyl substituted by at least one carboxy, phenyl substituted with at least one halogen, phenyl substituted with at least one alkoxy, phenyl substituted with at least one nitro, phenyl substituted with at least one sulfo, phenyl substituted with at least one amino, phenyl substituted with at least one amino phenyl substituted with at least one alkylamino group, phenyl substituted with at least one dialkylamino group, phenyl substituted with at least one hydroxy group, phenyl substituted with at least one carbonyl group, and phenyl substituted with at least one substituted carbonyl group , c) naphthyl, naphthyl substituted by at least one carboxy, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, naphthyl substituted by at least one nitro, naphthyl substituted by at least one sulfo substituted naphthyl, naphthyl substituted with at least one amino, naphthyl substituted with at least one alkylamino, naphthyl substituted with at least one dialkylamino, naphthyl substituted with at least one hydroxy, naphthyl substituted with at least one carbonyl Substituted naphthyl and naphthyl substituted by at least one substituted carbonyl, d) heteroaryl, heteroaryl substituted by at least one carboxy, heteroaryl substituted by at least one halogen, substituted by at least one alkoxy Heteroaryl, heteroaryl substituted with at least one nitro, heteroaryl substituted with at least one sulfo, heteroaryl substituted with at least one amino, heteroaryl substituted with at least one alkylamino, heteroaryl substituted with at least one a dialkylamino substituted heteroaryl group, a heteroaryl group substituted with at least one hydroxy group, a heteroaryl group substituted with at least one carbonyl group, and a heteroaryl group substituted with at least one substituted carbonyl group, and e) sugars, substituted Sugar, D-galactose, substituted D-galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkenyl, aryl, hetero The group consisting of aryl, heterocycle and derivatives, amino, substituted amino, imino and substituted imino. 5. The method of claim 3, wherein n=1. 6. The method of claim 3, wherein n=3. 7. The method of claim 4, wherein n=1. 8. The method of claim 4, wherein n=3. 9. A method for treating systemic insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of general formula (5) or a pharmaceutically acceptable salt or solvate thereof

where X is Se, Se-Se, Se-S, S-Se, Se-SO2 or SO2-Se, wherein W is selected from the group consisting of O, N, S, CH, NH and Se, wherein Y is selected from the group consisting of O, S, C, NH, CH, Se, P, amino acids, hydrophobic linear and cyclic hydrophobic hydrocarbon derivatives including heterocyclic substituents having a molecular weight of about 50-200 D, and combinations thereof, wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and hydrophobic hydrocarbon derivatives comprising heterocyclic substituents of 3 or more atoms, wherein R1, R2, _R3 and R4 are independently selected from CO, _O2 , SO2, SO, PO2, PO, CH, hydrogen or _a combination of these and a) alkyl of at least ₃ carbons, at least 3 carbons alkenyl, alkyl of at least 3 carbons substituted by carboxyl, alkenyl of at least 3 carbons substituted by carboxyl, alkyl of at least 3 carbons substituted by amino, alkene of at least 3 carbons substituted by amino group, alkyl of at least 3 carbons substituted by both amino and carboxy, alkenyl of at least 3 carbons substituted by both amino and carboxy, and alkyl substituted by one or more halogens, b) by at least one Carboxyl substituted phenyl, phenyl substituted with at least one halogen, phenyl substituted with at least one alkoxy, phenyl substituted with at least one nitro, phenyl substituted with at least one sulfo, phenyl substituted with at least one amino Substituted phenyl, phenyl substituted with at least one alkylamino, phenyl substituted with at least one dialkylamino, phenyl substituted with at least one hydroxy, phenyl substituted with at least one carbonyl, and substituted with at least one carbonyl substituted phenyl, c) naphthyl, naphthyl substituted by at least one carboxy, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, naphthyl substituted by at least one nitro , naphthyl substituted by at least one sulfo, naphthyl substituted by at least one amino, naphthyl substituted by at least one alkylamino, naphthyl substituted by at least one dialkylamino, naphthalene substituted by at least one hydroxy group, naphthyl substituted with at least one carbonyl group and naphthyl substituted with at least one carbonyl group, d) heteroaryl, heteroaryl substituted with at least one carboxy, heteroaryl substituted with at least one halogen, heteroaryl substituted with at least one halogen one alkoxy-substituted heteroaryl, at least one nitro-substituted heteroaryl, at least one sulfo-substituted heteroaryl, at least one amino-substituted heteroaryl, at least one alkylamino-substituted Heteroaryl, heteroaryl substituted with at least one dialkylamino, heteroaryl substituted with at least one hydroxy, heteroaryl substituted with at least one carbonyl, and heteroaryl substituted with at least one substituted carbonyl, and e) sugar, substituted sugar, D-galactose, substituted D-galactose, C3-[1,2,3]-triazol-1-yl-substituted D-galactose, hydrogen, alkyl, alkene The group consisting of aryl, aryl, heteroaryl, heterocycle and derivatives, amino, substituted amino, imino and substituted imino. 10. A method for treating systemic insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of general formula (6) or a pharmaceutically acceptable salt or solvate thereof

where X is Se, Se-Se, Se-S, S-Se, Se-SO2 or SO2-Se, wherein W is selected from the group consisting of O, N, S, CH2, NH and Se, wherein Y is selected from the group consisting of O, S, C, NH, CH2, Se, amino acids and combinations thereof, wherein Z is selected from the group consisting of O, S, N, CH, Se, S, P and hydrophobic hydrocarbon derivatives comprising heterocyclic substituents of 3 or more atoms, wherein R1, R2, _R3 and R4 are independently selected from CO, _O2 , SO2, SO, PO2, PO, CH, hydrogen or _a combination of these and a) alkyl of at least ₃ carbons, at least 3 carbons alkenyl, alkyl of at least 3 carbons substituted by carboxyl, alkenyl of at least 3 carbons substituted by carboxyl, alkyl of at least 3 carbons substituted by amino, alkene of at least 3 carbons substituted by amino group, alkyl of at least 3 carbons substituted by both amino and carboxy, alkenyl of at least 3 carbons substituted by both amino and carboxy, and alkyl substituted by one or more halogens, b) by at least one Carboxyl substituted phenyl, phenyl substituted with at least one halogen, phenyl substituted with at least one alkoxy, phenyl substituted with at least one nitro, phenyl substituted with at least one sulfo, phenyl substituted with at least one amino Substituted phenyl, phenyl substituted with at least one alkylamino, phenyl substituted with at least one dialkylamino, phenyl substituted with at least one hydroxy, phenyl substituted with at least one carbonyl, and substituted with at least one carbonyl substituted phenyl, c) naphthyl, naphthyl substituted by at least one carboxy, naphthyl substituted by at least one halogen, naphthyl substituted by at least one alkoxy, naphthyl substituted by at least one nitro , naphthyl substituted by at least one sulfo, naphthyl substituted by at least one amino, naphthyl substituted by at least one alkylamino, naphthyl substituted by at least one dialkylamino, naphthalene substituted by at least one hydroxy group, naphthyl substituted with at least one carbonyl group and naphthyl substituted with at least one carbonyl group, d) heteroaryl, heteroaryl substituted with at least one carboxy, heteroaryl substituted with at least one halogen, heteroaryl substituted with at least one halogen one alkoxy-substituted heteroaryl, at least one nitro-substituted heteroaryl, at least one sulfo-substituted heteroaryl, at least one amino-substituted heteroaryl, at least one alkylamino-substituted Heteroaryl, heteroaryl substituted with at least one dialkylamino, heteroaryl substituted with at least one hydroxy, heteroaryl substituted with at least one carbonyl, and heteroaryl substituted with at least one substituted carbonyl, and e) sugars; substituted sugars; D-galactose; substituted D-galactose; C3-[1,2,3]-triazol-1-yl-substituted D-galactose; hydrogen, alkyl, alkene group consisting of amino, substituted amino, imino and substituted imino groups. 11. The method of any one of claims 1-10, wherein the halogen is a fluorine, chlorine, bromine or iodine group. 12. A method for treating systemic insulin resistance, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (7) or a pharmaceutically acceptable salt or solvate thereof

13. The method of any one of claims 1-10 or 12, wherein the compound has binding affinity for a galectin. 14. The method of any one of claims 1-10 or 12, wherein the compound has binding affinity for Galectin-3. 15. The method of any one of claims 1-10 or 12, wherein the administering step comprises administering the compound and a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or combination thereof. 16. The method of any one of claims 1-10 or 12, wherein in the administering step, the compound is administered in combination with an active agent. 17. The method of any one of claims 1-10 or 12, wherein the administering step comprises administering the compound, a synergistic agent, and a pharmaceutically acceptable adjuvant, excipient, formulation carrier, or thereof combination. 18. The method of claim 15 or 16, wherein in the administering step, the active agent is an immunomodulator, an anti-inflammatory drug, a vitamin, a nutraceutical, a supplement, or a combination thereof. 19. The method of any one of claims 1-10 or 12 for the treatment of systemic insulin resistance associated with type 1 diabetes. 20. The method of any one of claims 1-10 or 12 for the treatment of systemic insulin resistance associated with type 2 diabetes mellitus (T2DM). 21. The method of any one of claims 1-10 or 12 for the treatment of systemic insulin resistance associated with obesity, gestational diabetes or prediabetes. 22. The method of any one of claims 1-10 or 12, wherein treatment with the compound restores cell sensitivity to insulin activity. 23. The method of any one of claims 1-10 or 12, wherein the compound inhibits the interaction of Galectin-3 with the insulin receptor, thereby interfering with insulin binding and cellular glucose uptake mechanisms. 24. The method of any one of claims 1-10 or 12 for the treatment of insulin resistance in skeletal muscle and liver due to elevated levels of free fatty acids and triglycerides, leading to atherosclerotic vascular disease Disease and low-grade inflammation in NAFLD. 25. The method of any one of claims 1-10 or 12 for the treatment of polycystic ovary syndrome (PCOS) associated with obesity, insulin resistance. 26. The method of any one of claims 1-10 or 12 for the treatment of diabetic nephropathy and glomerulosclerosis by attenuating integrin and TGFb receptor pathways in chronic kidney disease. 27. The method of any one of claims 1-10 or 12, wherein the compound inhibits overexpression of the TGF-beta receptor signaling system triggered by insulin resistance in diabetic patients and causes a decrease in renal function, and /or wherein the compound reverses established lesions of diabetic glomerulopathy. 28. The method of any one of claims 1-10 or 12 for the treatment of obstructive sleep apnea (OSA) associated with insulin resistant obesity and diabetes. 29. The method of any one of claims 1-10 or 12, wherein the administering step comprises administering the compound and a synergistically active antidiabetic drug.

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