Treatment of metabolic disorders in feline 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 in a feline animal, preferably where the metabolic disorder is one or more selected from the group consisting of ketoacidosis, pre-diabetes, diabetes mellitus type 1 or type 2, insulin resistance, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, atherosclerosis, inflammation of the pancreas, neuropathy and/or Syndrome X (metabolic syndrome) and/or loss of pancreatic beta cell function and/or where the remission of the metabolic disorder, preferably diabetic remission, is achieved and/or maintained.

What is claimed: 
     
         1 . A method of treatment or prevention of a metabolic disorder in a feline animal comprising administering to the feline animal one or more SGLT2 inhibitors or pharmaceutically acceptable crystalline forms thereof, wherein:
 the metabolic disorder is one or more selected from the group consisting of ketoacidosis, pre-diabetes, diabetes mellitus type 1 or type 2, insulin resistance, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, atherosclerosis, inflammation of the pancreas, neuropathy and/or Syndrome X (metabolic syndrome) and/or loss of pancreatic beta cell function and/or the remission of the metabolic disorder is achieved and/or maintained; and   the one or more SGLT-2 inhibitors is administered at a dose of 0.01 to 5.0 mg/kg body mass per day.   
     
     
         2 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors 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 R 1  denotes cyano, Cl or methyl; 
         R 2  denotes H, methyl, methoxy or hydroxyl; and 
         R 3  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 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, methyl sulfinyl, methlysulfonyl, ethyl sulfinyl, ethyl sulfonyl, trim ethyl silyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, 
         or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -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 
         R 1  denotes C 1-3 -alkoxy, 
         L 1 , L 2  independently of each other denote H or F, 
         R 6  denotes H, (C 1-3 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; 
         a compound of the formula (16): 
       
       
         
           
           
               
               
           
         
         Sergliflozin, represented by formula (17): 
       
       
         
           
           
               
               
           
         
         a compound represented by formula (18): 
       
       
         
           
           
               
               
           
         
         wherein 
         R 3  is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 
       
     
     
         3 . The method of  claim 2 , wherein the one or more SGLT-2 inhibitors is the glucopyranosyl-substituted benzene derivative of the formula (1), and R 3  is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 
     
     
         4 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors 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 R 1  denotes cyano, Cl or methyl; 
         R 2  denotes H, methyl, methoxy or hydroxy; and 
         R 3  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, methyl sulfanyl, methyl sulfinyl, methlysulfonyl, ethylsulfinyl, ethyl sulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, 
         or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -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: 
       R 3  is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 
     
     
         5 . The method of  claim 1 , wherein:
 the metabolic disorder is diabetes, pre-diabetes, diabetes mellitus type 1, diabetes mellitus type 2 and/or one or more clinical conditions associated with diabetes; and   the one or more clinical conditions is one or more conditions selected from the group consisting of ketoacidosis, insulin resistance, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, atherosclerosis, inflammation of the pancreas, neuropathy, Syndrome X (metabolic syndrome), loss of pancreatic beta cell function and/or diabetic remission.   
     
     
         6 . The method of  claim 1 , wherein the metabolic disorder is pre-diabetes, diabetes mellitus type 1 or diabetes mellitus type 2. 
     
     
         7 . The method of  claim 1 , wherein the metabolic disorder is pre-diabetes or diabetes, and the method effects an elimination of one or more owner-observed signs. 
     
     
         8 . The method of  claim 7 , wherein the owner-observed signs are selected from the group consisting of lethargy, polyuria, polydipsia, weight loss, and polyphagia, that occur secondary to hyperglycemia of untreated animals. 
     
     
         9 . The method of  claim 1 , wherein the feline animal is obese. 
     
     
         10 . The method of  claim 1 , wherein the feline animal is suffering from diabetes. 
     
     
         11 . The method of  claim 1 , wherein the feline animal is suffering from pre-diabetes or diabetes mellitus type 2. 
     
     
         12 . The method of  claim 1 , wherein the feline animal is a cat. 
     
     
         13 . The method of  claim 1 , wherein the pharmaceutically acceptable crystalline form thereof is a crystalline complex between the one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof and one or more amino acids. 
     
     
         14 . The method of  claim 13 , wherein the pharmaceutically acceptable crystalline form thereof is proline or L-proline. 
     
     
         15 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors is administered orally or parenterally. 
     
     
         16 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors is administered as a liquid. 
     
     
         17 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors is administered as a tablet. 
     
     
         18 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors is administered only once per day. 
     
     
         19 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors is administered in combination with insulin. 
     
     
         20 . The method of  claim 1 , wherein the metabolic disorder is diabetes, and the method effects an improvement of glycemic control in otherwise healthy cats with diabetes mellitus not previously treated with insulin.