Glycoside derivatives and uses thereof

Abstract

The present invention provides a compound of formula I; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

1 . A compound represented by structural formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutiacally acceptable salt thereof, wherein:
 A is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         V is hydrogen, halo or —OR 1b ; 
         R 1 , R 1a  and R 1b  are independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 6-10 aryl-C 1-4 alkyl, —C(O)C 6-10 aryl and —C(O)C 1-6 alkyl; 
         R 2  and R 2a , for each occurrence, are independently selected from the group consisting of halo, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy; 
         R 3  is halo, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxy, or haloC 1-3 alkoxy; 
         R 4  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R 5  is an amino acid sidechain; 
         R 6  is a C 1-6  alkyl, C 3-10 carbocyclyl, C 3-10 carbocyclyl-C 1-4 alkyl, 3- to 10-membered heterocyclyl, (3- to 10-membered heterocyclyl)-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl, or (5- to 10-membered heteroaryl)-C 1-4 alkyl; 
         R 7 , for each occurrence, is independently hydrogen, C 1-6 alkyl, C 3-10 carbocyclyl, C 3-10 carbocyclyl-C 1-4 alkyl, 3- to 10-membered heterocyclyl, (3- to 10-membered heterocyclyl)-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5- to 10-membered heteroaryl, or (5- to 10-membered heteroaryl)-C 1-4 alkyl; 
         n is 0, 1, 2, or 3; and 
         q is 0, 1, or 2. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0. 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein q is 0. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is —OR 1b . 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 1a , and R 1b  are hydrogen. 
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is C 1-4 alkyl or C 3-6 cycloalkyl, 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is ethyl or cyclopropyl. 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is ethyl 
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 5  is a naturally occurring amino acid sidechain selected from the group consisting of the sidechain of glycine, alanine, cysteine, asparagine, glutamine, glutamic acid, arginine, aspartic acid, histidine, lysine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophane, tyrosine, and valine. 
     
     
         12 . The compound of  claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 5  is the sidechain of valine. 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
 (R)-2-amino-3-methyl-butyric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester;   carbonic acid (2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester methyl ester;   carbonic acid (2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester ethyl ester;   carbonic acid (2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester isobutyl ester;   carbonic acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester ethyl ester;   carbonic acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester isobutyl ester;   Carbonic acid tert-butyl ester (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester;   carbonic acid bicyclo[2.2.1]hept-2-ylmethyl ester (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester;   carbonic acid (2R, 3S,4R, 5R, 6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester (S)-1-phenyl-ethyl ester;   phosphoric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester diethyl ester; phosphoric acid (2R,3S,4R,5R,6S)-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester diethyl ester;   phosphoric acid mono-{(2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl} ester.   
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier. 
     
     
         17 . A method of treating a disease or condition mediated by the sodium D-glucose co-transporter in a subject, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method according to  claim 17 , wherein the disease or condition is metabolic syndrome, Syndrome X, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, a body weight disorder, obesity, or a leptin related disease. 
     
     
         19 . The method according to  claim 18 , wherein the disease or condition is dyslipidemia, obesity, insulin resistance, hypertension, microalbuminemia, hyperuricaemia, or hypercoagulability. 
     
     
         20 . A pharmaceutical combination comprising:
 i) a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof,   ii) at least one compound selected from
 a) antidiabetic agents, 
 b) hypolipidemic agents, 
 c) anti-obesity agents, 
 d) anti-hypertensive agents, 
 e) agonists of peroxisome proliferator-activator receptors.