Treatment of metabolic disorders in canine 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 canine animal, preferably where the metabolic disorder is one or more selected from ketoacidosis, pre-diabetes, insulin dependent diabetes mellitus, insulin resistance diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia induced cataract formation, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, inflammation of the pancreas, metabolic disorder consequences, such as hypertension, renal dysfunction and/or musculoskeletal disorders, and/or Syndrome X (metabolic syndrome), wherein preferably the development of hyperglycemia induced cataract formation is prevented or remission is achieved and/or wherein preferably the development of metabolic disorder consequences, such as hypertension, renal dysfunction and/or musculoskeletal disorders, is prevented or progression is slowed or remission is achieved.

1 . A method of treatment and/or prevention of a metabolic disorder in a canine animal comprising administering to the canine animal a composition comprising one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof;
 wherein:
 the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof is administered to the canine animal at a dose of 0.01 to 5.0 mg/kg bodyweight; and 
 the metabolic disorder is one or more selected from the group consisting of ketoacidosis, pre-diabetes, insulin dependent diabetes mellitus, insulin resistance diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia induced cataract formation, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, inflammation of the pancreas, metabolic disorder consequences comprising hypertension, renal dysfunction and/or musculoskeletal disorders, and Syndrome X (metabolic syndrome). 
   
     
     
         2 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof is administered at a dose of 0.01 to 4.0 mg/kg bodyweight. 
     
     
         3 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof is administered at a dose of 0.01 to 2.0 mg/kg bodyweight. 
     
     
         4 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof is administered at a dose of 0.01 to 1.0 mg/kg bodyweight. 
     
     
         5 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors are selected from the group consisting of the following compounds or pharmaceutically acceptable forms thereof:
 a glucopyranosyl-substituted benzene derivative, represented by the following formula (1):   
       
         
           
           
               
               
           
         
         wherein R 1  denotes cyano, Cl or methyl (most preferably cyano); 
         R 2  denotes H, methyl, methoxy or hydroxy (most preferably H) 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, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, 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; and most preferably R3 is cyclopropyl, 
         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; 
         1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, represented by the following formula (2): 
       
       
         
           
           
               
               
           
         
         Dapagliflozin, represented by the following formula (3): 
       
       
         
           
           
               
               
           
         
         Canagliflozin, represented by the following formula (4): 
       
       
         
           
           
               
               
           
         
         Empagliflozin, represented by the following formula (5): 
       
       
         
           
           
               
               
           
         
         Luseogliflozin, represented by the following formula (6): 
       
       
         
           
           
               
               
           
         
         Tofogliflozin, represented by the following formula (7): 
       
       
         
           
           
               
               
           
         
         Ipragliflozin, represented by the following formula (8): 
       
       
         
           
           
               
               
           
         
         Ertugliflozin, represented by the following formula (9): 
       
       
         
           
           
               
               
           
         
         Atigliflozin, represented by the following formula (10): 
       
       
         
           
           
               
               
           
         
         Remogliflozin, represented by the following formula (11): 
       
       
         
           
           
               
               
           
         
         a thiophene derivative represented by the following formula (12): 
       
       
         
           
           
               
               
           
         
         wherein R denotes methoxy or trifluoromethoxy; 
         1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by the following formula (13): 
       
       
         
           
           
               
               
           
         
         a spiroketal derivative represented by the following formula (14): 
       
       
         
           
           
               
               
           
         
         wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl; 
         a pyrazole-O-glucoside derivative represented by the following 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 represented by the following formula (16): 
       
       
         
           
           
               
               
           
         
         Sergliflozin, represented by the following formula (17): 
       
       
         
           
           
               
               
           
         
          and
 a compound represented by the following formula (18): 
 
       
       
         
           
           
               
               
           
         
         
           wherein:
 R3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 
 
         
       
     
     
         6 . The method of  claim 5 , wherein R3 for formula (1) is selected from the group consisting of cyclopropyl, ethyl, ethinyl, (R)-tetrahydrofuran-3-yloxy and (S)-tetrahydrofuran-3-yloxy. 
     
     
         7 . The method of  claim 1 , wherein the development of hyperglycemia induced cataract formation is prevented or remission is achieved and/or the development of metabolic disorder consequences prevented or progression is slowed or remission is achieved. 
     
     
         8 . The method of  claim 1 , wherein the canine animal is suffering from diabetes. 
     
     
         9 . The method of  claim 1 , wherein the canine animal is suffering from pre-diabetes or insulin dependent diabetes. 
     
     
         10 . The method of  claim 1 , wherein the canine animal is a dog. 
     
     
         11 . The method of  claim 1 , wherein the pharmaceutically acceptable form thereof is a crystalline complex between the one or more SGLT-2 inhibitors and one or more amino acids. 
     
     
         12 . The method of  claim 11 , wherein the one or more amino acids comprise proline. 
     
     
         13 . The method of  claim 11 , wherein the one or more amino acids comprise L-proline. 
     
     
         14 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof is administered orally or parenterally. 
     
     
         15 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof is administered once per day. 
     
     
         16 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof is administered in combination with insulin in a simultaneous, a sequential and/or a chronologically staggered co-administration. 
     
     
         17 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof is administered in a chronologically staggered combination with a long acting insulin. 
     
     
         18 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors is selected from the group consisting of:
 a glucopyranosyl-substituted benzene derivative represented by the following formula (1):   
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes cyano, Cl or methyl (most preferably cyano); 
       R 2  denotes H, methyl, methoxy or hydroxy (most preferably H) 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, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, 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; and most preferably R3 is cyclopropyl,
 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 the following formula (3): 
 
 
       
         
           
           
               
               
           
         
         
           Canagliflozin, represented by the following formula (4): 
         
       
       
         
           
           
               
               
           
         
         Empagliflozin, represented by the following formula (5): 
       
       
         
           
           
               
               
           
         
         Ertugliflozin, represented by the following formula (9): 
       
       
         
           
           
               
               
           
         
       
       and
 a compound represented by the following formula (18): 
 
       
         
           
           
               
               
           
         
         wherein:
 R3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 
 
       
     
     
         19 . The method of  claim 1 , wherein the one or more SGLT-2 inhibitors is selected from the group consisting of:
 a glucopyranosyl-substituted benzene derivative represented by the following formula (1):   
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes cyano, Cl or methyl (most preferably cyano); 
       R 2  denotes H, methyl, methoxy or hydroxy (most preferably H) 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, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, 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; and most preferably R3 is cyclopropyl,
 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;
 Canagliflozin, represented by the following formula (4): 
 
 
       
         
           
           
               
               
           
         
         Empagliflozin, represented by the following formula (5): 
       
       
         
           
           
               
               
           
         
         Ertugliflozin, represented by the following formula (9): 
       
       
         
           
           
               
               
           
         
       
       and
 a compound represented by the following formula (18): 
 
       
         
           
           
               
               
           
         
         wherein: 
       
       R3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. 
     
     
         20 . A method of treatment and/or prevention of a metabolic disorder in a canine animal comprising administering to the canine animal a composition comprising one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof,
 wherein:
 the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof is administered to the canine animal at a dose of 0.01 to 5.0 mg/kg bodyweight; and 
 the metabolic disorder is selected from the group consisting of clinical conditions associated with pre-diabetes, insulin dependent diabetes mellitus and insulin resistance. 
   
     
     
         21 . The method of  claim 20 , wherein the clinical conditions are one or more conditions selected from the group consisting of ketoacidosis, insulin resistance, obesity, hyperglycemia, hyperglycemia induced cataract formation, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, inflammation of the pancreas, metabolic disorder consequences comprising hypertension, renal dysfunction and/or musculoskeletal disorders, and Syndrome X (metabolic syndrome).