Compounds for the prevention and treatment of diseases and the use thereof

Abstract

Aspects of the invention relate to novel synthetic compounds having binding affinity with galectin proteins.

1 . A compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein A is independently selected from the group consisting of NRa, CRb, PRc, and amino acid, 
         wherein M is independently selected from the group consisting of NRa, CRb, PRc, ORd, SRe amino acid, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms, 
         wherein Ra is selected from the group consisting of H, H2, CH3, COOH, NH2, COMe, halogen and combinations thereof, 
         wherein Rb is selected from the group consisting of H, H2, O, OH, CH3, COOH, NH2, COMe, halogen and combinations thereof, 
         wherein Rc is selected from the group consisting of O2, PO2, OH, halogen and combinations thereof, 
         wherein Rd is selected from the group consisting of H, CH3, and combinations thereof, 
         wherein Re is selected from the group consisting of OH, O2, S, halogen and combinations thereof, 
         wherein B is OH, NH2, NHAc, or NH-alkyl, wherein the alkyl group comprises 1 to 18 Carbons, 
         wherein W is selected from the group consisting of O, S, CH2, NH, and Se, 
         wherein Y is selected from the group consisting of O, S, NH, CH2, Se, S, P, amino acid, and hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof, 
         wherein R 1 , R 2 , and R 3  are independently selected from the group consisting of H, O2, CO, NH2, SO2, SO, PO2, PO, CH3, linear hydrocarbon, and cyclic hydrocarbon, and 
         wherein the hydrocarbon is one of a) an alkyl group of at least 3 carbons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 carbons substituted with a carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted with an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, b) a phenyl group substituted with at least one carboxy group, a phenyl group substituted with at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted With at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group, d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy group, a heteroaryl group substituted with at least one halogen, a heteroaryl group substituted with at least one alkoxy group, a heteroaryl group substituted with at least one nitro group, a heteroaryl group substituted with at least one sulfo group, a heteroaryl group substituted with at least one amino group, a heteroaryl group substituted with at least one alkylamino group, a heteroaryl group substituted with at least one dialkylamino 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) a saccharide, a substituted saccharide, D-galactose, Deoxygalactose, substituted D-Galctose, C3-[1,2,3]-triaZol-1-yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives, an amino group, a substituted amino group, an imino group, or a substituted imino group. 
       
     
     
         2 . The compound of  claim 1 , wherein A-M is a spacer of at least 2 atoms comprising an amide —N(—Ra)—C(═O)—, sulfonamide —N(—H)—S(═O2)-, a methylether —C(—H2)—O— methylester —C(═O)—O—, carbosulfon —C(—H2)-S(═O)(═O)—, phosphate —O—P(═O)(—OH)—, diphosphate —O—P(═O)(—O)—O—P(═O)(—O)—, Hydrazide —N(—H)—N(—H)—, amino acid, or combinations thereof. 
     
     
         3 . The compound of  claim 1 , wherein A-M is a spacer linked to the anomeric carbon and comprises of an amide —N(—Ra)—C(═O)—, sulfonamide —N(—H)—S(═O2)-, a methylether —C(—H2)-O— methylester —C(═O)—O—, carbosulfon —C(—H2)-S(═O)(═O)—, phosphate —O—P(═O)(—OH)—, diphosphate —O—P(═O)(—O)—O—P(═O)(—O)—, carbohydrazide —C(═O)—NH—NH—, sulfonohydrazide —S(═O)2-NH—NH—, and phosphonic dihydrazide —P(═O)(—NH—NH2)(NH—NH—) spacer. 
     
     
         4 . The compound of  claim 1 , wherein A-M is a spacer of 2 or more atoms linked by single or double bond: C—C, C═C, C—P, C—N, C—O, N—C, N—N, N═N, N—S, N—P, S—N, P—O, O—P, or combination thereof. 
     
     
         5 . The compound of  claim 1 , wherein the A-M spacer comprises PO2 or PO2-PO2 bond linked to the anomeric carbon and to one or more atoms such as C or N or O or S. 
     
     
         6 . The compound of  claim 5 , wherein C or N is linked to the anomeric carbon and PO2 or PO2-PO2 is linked to C or N. 
     
     
         7 . The compound of  claim 1 , wherein the A-M linked to R1 and R2 is N′-methylamide-3,4-difluorobenzene and Y—R 1  is triazole-3-fluorobenzene: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein the A-M spacer is linked to a galactose, a hydroxyl cyclohexane, an aromatic moiety, an alkyl group, an aryl group, an amine group, or amide group. 
     
     
         9 . The compound of  claim 1 , wherein the A-M spacer symmetrically links two galactosides or substituted derivatives thereof or wherein the A-M spacer asymmetrically links two galactosides or substituted derivatives thereof. 
     
     
         10 . A compound or a pharmaceutically acceptable salt or solvate thereof having 
       
         
           
           
               
               
           
         
         wherein A-M is representing a spacer of at least 2 atoms comprising an amide —N(—Ra)—C(═O)—, sulfonamide —N(—H)—S(═O2)-, a methylether —C(—H2)-O-methylester —C(═O)—O—, carbosulfon —C(—H2)-S(═O)(═O)—, phosphate —O—P(═O)(—OH)—, diphosphate —O—P(═O)(—O)—O—P(═O)(—O)—, carbohydrazide —C(═O)—NH—NH—, sulfonohydrazide —S(═O)2-NH—NH—, and phosphonic dihydrazide —P(═O)(—NH—NH2)(NH—NH—) or combinations thereof, 
         wherein A is independently selected from the group consisting of NRa, CRb, PRc, and amino acid, 
         wherein M is independently selected from the group consisting of NRa, CRb, PRc, ORd, SRe amino acid, and hydrophobic hydrocarbons derivatives including heterocyclic substitutions of 3 or more atoms. 
         wherein Ra is selected from the group consisting of H, H2, CH3, COOH, NH2, COMe, halogen and combinations thereof, 
         wherein Rb is selected from the group consisting of H, H2, O, OH, CH3, COOH, NH2, COMe, halogen and combinations thereof, 
         wherein Rc is selected from the group consisting of O2, PO2, OH, halogen and combinations thereof, 
         wherein Rd is selected from the group consisting of H, CH3, and combinations thereof, 
         wherein Re is selected from the group consisting of OH, O2, S, halogen and combinations thereof, 
         wherein B is OH, NH2, NHAc, or NH-alkyl wherein the alky comprises 1 to 18 Carbons, 
         wherein W is selected from the group consisting of O, S, CH2, NH, or Se, 
         wherein X is selected from the group consisting of O, N, S, CH2, NH, and PO2, 
         wherein Y and Z are independently selected from the group consisting of O, S, C, NH, CH2, Se, S, P, amino acid, and hydrophobic linear and cyclic hydrophobic hydrocarbons derivatives including heterocyclic substitutions of molecular weight of about 50-200 D and combinations thereof, 
         wherein R1, R2, R3, are independently selected from the group consisting of CO, O2, SO2, SO, PO2, PO, CH, Hydrogen, hydrophobic linear hydrocarbon, and hydrophobic cyclic hydrocarbon, wherein the hydrocarbon is one of: 
       
       a) an alkyl group of at least 3 carbons, an alkenyl group of at least 3 carbons, an alkyl group of at least 3 carbons substituted with a carboxy group, an alkenyl group of at least 3 carbons substituted with a carboxy group, an alkyl group of at least 3 carbons substituted with an amino group, an alkenyl group of at least 3 carbons substituted With an amino group, an alkyl group of at least 3 carbons substituted with both an amino and a carboxy group, an alkenyl group of at least 3 carbons substituted with both an amino and a carboxy group, and an alkyl group substituted with one or more halogens, 
       b) a phenyl group substituted with at least one car boxy group, a phenyl group substituted With at least one halogen, a phenyl group substituted with at least one alkoxy group, a phenyl group substituted with at least one nitro group, a phenyl group substituted with at least one sulfo group, a phenyl group substituted with at least one amino group, a phenyl group substituted with at least one alkylamino group, a phenyl group substituted with at least one dialkylamino group, a phenyl group substituted with at least one hydroxy group, a phenyl group substituted with at least one carbonyl group and a phenyl group substituted with at least one substituted carbonyl group, 
       c) a naphthyl group, a naphthyl group substituted with at least one carboxy group, a naphthyl group substituted with at least one halogen, a naphthyl group substituted with at least one alkoxy group, a naphthyl group substituted with at least one nitro group, a naphthyl group substituted with at least one sulfo group, a naphthyl group substituted With at least one amino group, a naphthyl group substituted with at least one alkylamino group, a naphthyl group substituted with at least one dialkylamino group, a naphthyl group substituted with at least one hydroxy group, a naphthyl group substituted with at least one carbonyl group and a naphthyl group substituted with at least one substituted carbonyl group; and 
       d) a heteroaryl group, a heteroaryl group substituted with at least one carboxy group, a heteroaryl group substituted with at least one halogen, a heteroaryl group substituted with at least one alkoxy group, a heteroaryl group substituted with at least one nitro group, a heteroaryl group substituted with at least one sulfo group, a heteroaryl group substituted with at least one amino group, a heteroaryl group substituted with at least one alkylamino group, a heteroaryl group substituted with at least one dialkylamino 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, 
       e) saccharide, a substituted saccharide, D-galactose, substituted D-galactose, C3-[1,2,3]-triaZol-1-yl-substituted D-galactose, hydrogen, an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, and a heterocycle and derivatives; an amino group, a substituted amino group, an imino group, or a substituted imino group. 
     
     
         11 . A composition comprising a therapeutically effective amount of the compound of  claim 1  and a pharmaceutically acceptable adjuvant, excipient, formulation carrier or combinations thereof. 
     
     
         12 . A composition comprising a therapeutically effective amount of the compound of  claim 1  and a therapeutically effective amount of an anti-inflammatory drug, vitamin, pharmaceutical drug, nutraceutical drug, supplement, or combinations thereof. 
     
     
         13 . A method of treatment of a disease in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound according to  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein the disease is a disorder related to pathological disease due to elevated galectin-3. 
     
     
         15 . The method of  claim 13 , wherein the disease is nonalcoholic steatohepatitis, fibrosis, cirrhosis, inflammatory disorder, autoimmune disorder, neoplastic condition, metabolic disorder or cancer. 
     
     
         16 . The method of  claim 15 , wherein the inflammatory disorder is inflammatory bowel disease, Crohn's disease, multiple sclerosis, Systemic Lupus Erythematosus, arthritis, rheumatoid arthritis, asthma or ulcerative colitis. 
     
     
         17 . The method of  claim 15 , wherein the fibrosis is liver fibrosis, kidney fibrosis, lung fibrosis, or heart fibrosis. 
     
     
         18 . The method of  claim 15 , wherein the autoimmune disorder is rheumatoid arthritis or multiple sclerosis. 
     
     
         19 . The method of  claim 13 , wherein the disease is heart failure, arrhythmias, uremic cardiomyopathy, chronic kidney and lung diseases, skin autoimmune, or proliferative and fibrotic skin disorder. 
     
     
         20 . The method of  claim 15 , wherein the neoplastic condition is a benign or malignant neoplastic disease.