Treatment of metabolic disorders in equine animals

Abstract

One or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof are provided for use in the treatment and/or prevention of a metabolic disorder of an equine animal. For example, the treatment and/or prevention can be for laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndrome in an equine animal.

1 . A method of treating or preventing a metabolic disorder in an equine comprising administering an SGLT2 inhibitor or pharmaceutically acceptable form thereof, wherein the metabolic disorder is one or more disorders selected from laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndrome. 
     
     
         2 . The method according to  claim 1 , wherein said SGLT2 inhibitor or pharmaceutically acceptable form thereof is selected from the group consisting of the following compounds or pharmaceutically acceptable forms thereof:
 a glucopyranosyl-substituted benzene derivative of the formula (1)   
       
         
           
           
               
               
           
         
         wherein R1 denotes cyano, Cl or methyl; 
         R2 denotes H, methyl, methoxy or hydroxyl; and 
         R3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethyl sulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, 
         wherein R3 is preferably selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; 
         or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C1-3-alkyl)-carbonyl; 
         Dapagliflozin, represented by formula (3): 
       
       
         
           
           
               
               
           
         
         Canagliflozin, represented by formula (4): 
       
       
         
           
           
               
               
           
         
         Empagliflozin, represented by formula (5): 
       
       
         
           
           
               
               
           
         
         Luseogliflozin, represented by formula (6): 
       
       
         
           
           
               
               
           
         
         Tofogliflozin, represented by formula (7): 
       
       
         
           
           
               
               
           
         
         Ipragliflozin, represented by formula (8): 
       
       
         
           
           
               
               
           
         
         Ertugliflozin, represented by formula (9): 
       
       
         
           
           
               
               
           
         
         Atigliflozin, represented by formula (10): 
       
       
         
           
           
               
               
           
         
         Remogliflozin, represented by formula (11): 
       
       
         
           
           
               
               
           
         
         a thiophene derivative of the formula (12) 
       
       
         
           
           
               
               
           
         
         wherein R denotes methoxy or trifluoromethoxy; 
         1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene; 
         represented by formula (13); 
       
       
         
           
           
               
               
           
         
         a spiroketal derivative of the formula (14): 
       
       
         
           
           
               
               
           
         
         wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl; 
         a pyrazole-O-glucoside derivative of the formula (15) 
       
       
         
           
           
               
               
           
         
         wherein 
         R1 denotes C1-3-alkoxy, 
         L1, L2 independently of each other denote H or F, 
         R6 denotes H, (C1-3-alkyl)carbonyl, (C1-6-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; 
         a compound of the formula (16): 
       
       
         
           
           
               
               
           
         
         Sergliflozin, represented by formula (17): 
       
       
         
           
           
               
               
           
         
         a compound represented by formula (18): 
       
       
         
           
           
               
               
           
         
         wherein 
         R3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 
       
     
     
         3 . The method of  claim 2 , wherein said SGLT2 inhibitor or pharmaceutically acceptable form thereof is selected from the group consisting of the following compounds or pharmaceutically acceptable forms thereof:
 a glucopyranosyl-substituted benzene derivative of the formula (1)   
       
         
           
           
               
               
           
         
         wherein R1 denotes cyano, Cl or methyl; 
         R2 denotes H, methyl, methoxy or hydroxy; and 
         R3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethyl sulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano; 
         wherein R3 is preferably selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; 
         or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C1-3-alkyl)-carbonyl. 
         Dapagliflozin, represented by formula (3): 
       
       
         
           
           
               
               
           
         
         Canagliflozin, represented by formula (4): 
       
       
         
           
           
               
               
           
         
         Empagliflozin, represented by formula (5): 
       
       
         
           
           
               
               
           
         
         Ertugliflozin, represented by formula (9): 
       
       
         
           
           
               
               
           
         
         a compound represented by formula (18): 
       
       
         
           
           
               
               
           
         
         wherein: 
         R3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 
       
     
     
         4 . The method according to  claim 1 , wherein the metabolic disorder is a clinical condition or sign associated with insulin resistance or hyperinsulinaemia. 
     
     
         5 . The method according to  claim 1 , wherein the metabolic disorder is hyperinsulinemia and/or insulin resistance, and wherein said hyperinsulinemia and/or insulin resistance is associated with one or more of laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndrome. 
     
     
         6 . The method according to  claim 1 , wherein the equine animal is a horse or a pony. 
     
     
         7 . The method according to  claim 1 , wherein the equine animal is obese and/or exhibits regional adiposity. 
     
     
         8 . The method according to  claim 1 , wherein the composition comprises a crystalline complex of the SGLT2 inhibitor or pharmaceutically acceptable form thereof and an amino acid, and the amino acid is proline. 
     
     
         9 . The method according to  claim 1 , wherein the SGLT2 inhibitor or pharmaceutically acceptable form thereof is administered orally or parenterally. 
     
     
         10 . The method according to  claim 1 , wherein the SGLT2 inhibitor or pharmaceutically acceptable form thereof is administered orally. 
     
     
         11 . The method according to  claim 1 , wherein the SGLT2 inhibitor or pharmaceutically acceptable form thereof is administered in a range of from 0.01 to 5 mg/kg body weight per day. 
     
     
         12 . The method according to  claim 1 , wherein the SGLT2 inhibitor or pharmaceutically acceptable form thereof is administered in a range of from 0.02 to 1.0 mg/kg body weight per day. 
     
     
         13 . The method according to  claim 1 , wherein the SGLT2 inhibitor or pharmaceutically acceptable form thereof is administered in a range of from 0.03 to 0.4 mg/kg body weight per day. 
     
     
         14 . The method according to  claim 1 , wherein the SGLT2 inhibitor or pharmaceutically acceptable form thereof is administered once per day. 
     
     
         15 . The method according to  claim 1 , wherein the equine animal is not obese and/or is present with muscle wasting and/or exhibits hyperglycemia. 
     
     
         16 . The method of  claim 1 , wherein the composition comprises a 1:1:1 crystalline complex of the SGLT2 inhibitor or pharmaceutically acceptable form thereof, L-proline and water in a crystalline form. 
     
     
         17 . The method according to  claim 16 , wherein the 1:1:1 crystalline complex is characterized by an X-ray powder diffraction pattern that comprises peaks at 20.28, 21.14 and 21.64 degrees 2Θ (±0.1 degrees 2θ), wherein said X-ray powder diffraction pattern is made using CuK α1  radiation. 
     
     
         18 . The method of  claim 1 , wherein said laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndrome is associated with insulin resistance and/or hyperinsulinemia.