SGLT-2 inhibitors, methods of making them, and uses thereof
View Patent ↗The present invention relates to compounds which are inhibitors of sodium dependent glucose co-transporter-2 (SGLT-2). These compounds are used in the treatment of various disorders, including diabetes, impaired glucose tolerance, insulin resistance, retinopathy, nephropathy, neuropathy, cataracts, hyperglycemia, hyperinsulinemia, hyperchlolesterolemia, elevated blood level of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis, and hypertension. These compounds and compositions are also useful for treating and preventing kidney stones, hyperuricemia, gout, and hyponatremia. Methods of making these compounds are also described in the present invention.
1. A compound of formula (III):
wherein
Y is
R 5 is Cl, F, or methyl;
R 6 , R 7 , and R 8 are H;
R 9 is CH 2 OH or SMe;
R 10 is H, lower alkyl, lower alkenyl, or lower alkynyl, wherein each lower alkyl, lower alkenyl, or lower alkynyl is optionally substituted 1-3 times by R e ;
R 11 is H, methyl, ethyl, or gem-dimethyl;
R e is halogen, CF 3 , CF 2 H, OCF 3 , OCF 2 H, CN, OR g , NR g R h , COR g , CONR g R h , NR g COR h , SO 2 R g , 3 to 10-membered carbocycle, or 3 to 10-membered heterocycle, wherein the each of the 3 to 10-membered carbocycle or 3-10-membered heterocycle is optionally substituted 1-3 times with halogen, CF 3 , CF 2 H, OCF 3 , OCF 2 H, CN, OR g , NR g R h , COR g , CONR g R h , NR g COR h , or SO 2 R g ; and
R g and R h are each, independently, H, lower alkyl, lower alkenyl, or lower alkynyl;
or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
2. The compound according to claim 1 , wherein:
Y is
R 5 is Cl;
R 6 , R 7 , and R 8 are H;
R 9 is CH 2 OH;
R 10 is methyl, ethyl, or isopropyl; and
R 11 is H, methyl, ethyl, or gem-dimethyl.
3. The compound according to claim 1 , wherein:
Y is
R 5 is Cl;
R 6 , R 7 , and R 8 are H;
R 9 is CH 2 OH;
R 10 is methyl, ethyl, or isopropyl; and
R 11 is H.
4. The compound according to claim 1 , wherein:
Y is
R 5 is Cl;
R 6 , R 7 , and R 8 are H;
R 9 is CH 2 OH;
R 10 is H, H lower alkyl, lower alkenyl, or lower alkynyl, wherein each lower alkyl, lower alkenyl, or lower alkynyl is optionally substituted 1-3 times by R e ; and
R 11 is H, methyl, ethyl, or gem-dimethyl.
5. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
1-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-3,5,5-trimethylimidazolidine-2,4-dione;
1-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-3-isopropylimidazolidine-2,4-dione;
1-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-3-propylimidazolidine-2,4-dione;
1-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-3-methylimidazolidine-2,4-dione;
1-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)imidazolidine-2,4-dione;
1-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-3-ethylimidazolidine-2,4-dione;
1-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-3-tritylimidazolidine-2,4-dione;
3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-1-methylimidazolidine-2,4-dione;
3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)imidazolidine-2,4-dione;
3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-1-ethylimidazolidine-2,4-dione;
3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-1-isopropylimidazolidine-2,4-dione; and
3-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)-1-propylimidazolidine-2,4-dione.
6. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
7. A compound of formula (III):
wherein
Y is
R 5 is Cl or methyl;
R 6 , R 7 , and R 8 are H;
R 9 is CH 2 OH;
R 10 is H, H lower alkyl, lower alkenyl, or lower alkynyl, wherein each lower alkyl, lower alkenyl, or lower alkynyl is optionally substituted 1-3 times by R e ;
R 11 is H, methyl, ethyl or gem-dimethyl;
R e is halogen, CF 3 , CF 2 H, OCF 3 , OCF 2 H, CN, OR g , NR g R h , COR g , CONR g R h , NR g COR h , SO 2 R g , 3 to 10-membered carbocycle, or 3 to 10-membered heterocycle, wherein the each of the 3 to 10-membered carbocycle or 3-10-membered heterocycle is optionally substituted 1-3 times with halogen, CF 3 , CF 2 H, OCF 3 , OCF 2 H, CN, OR g , NR g R h , COR g , CONR g R h , NR g COR h , or SO 2 R g ; and
R g and R h are each, independently, H, lower alkyl, lower alkenyl, or lower alkynyl;
or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.