Benzylphenyl cyclohexane derivatives and methods of use
Provided are compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by SGLT inhibition.
1. A compound of Formula I:
wherein
A is selected from the group consisting of oxygen and a single bond;
Q is selected from the group consisting of formulae Q 1 to Q 4 ;
Z is methylene optionally substituted with one to two substituents independently selected from halo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkyloxy;
R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, C 1 -C 6 alkyloxy, C 3 -C 10 cycloalkyloxy, cyano, amino and nitro, wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of chlorine, hydroxy, C 1 -C 3 alkoxy and C 1 -C 3 alkyl, and in cycloalkyl and cycloalkenyl groups or portions one or two methylene groups are optionally replaced independently of one another by NR a , O, S, CO, SO or SO 2 , and one or two methyne groups are optionally replaced by N, or in the event that R 1 and R 2 are bound to two adjacent C atoms of the phenyl ring, R 1 and R 2 are optionally joined together to form a C 3 - 5 alkylene, C 3 - 5 alkenylene or butadienylene bridge, which is optionally partly or completely fluorinated and is optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C 1 -C 3 alkoxy and C 1 -C 3 alkyl, and wherein one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO, SO 2 or NR a , and wherein one or two methyne groups optionally may be replaced by N;
R 4 is a member selected from the group consisting of hydrogen, halo, cyano, nitro, amino, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, C 1 -C 6 alkyloxy, C 3 -C 10 cycloalkyloxy, (C 1 -C 6 alkyloxy)C 1 -C 6 alkyloxy, C 5 -C 7 cycloalkenyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C 2 -C 4 alkenyl)C 1 -C 3 alkyloxy, (C 2 -C 4 alkynyl)C 1 -C 3 alkyloxy, (aryl)C 1 -C 3 alkyloxy, (heteroaryl)C 1 -C 3 alkyloxy, (C 3 -C 10 cycloalkyl)C 1 -C 3 alkyl, (C 3 -C 10 cycloalkyl)C 1 -C 3 alkyloxy, (C 5 -C 10 cycloalkenyl)C 1 -C 3 alkyl, (C 5 -C 10 cycloalkenyl)C 1 -C 3 alkyloxy, (C 1 -C 4 alkyloxy)C 1 -C 3 alkyl, (C 3 -C 7 cycloalkyloxy)C 1 -C 3 alkyl, (C 3 -C 7 cycloalkyloxy)C 2 -C 4 alkenyl, (C 3 -C 7 cycloalkyloxy)C 2 -C 4 alkynyl, (C 3 -C 7 cycloalkyloxy)C 1 -C 3 alkyloxy, (C 1 -C 4 alkylamino)C 1 -C 3 alkyl, di-(C 1 -C 3 alkylamino)C 1 -C 3 alkyl, tri-(C 1 -C 4 alkyl)silyl-C 1 -C 6 alkyl, tri-(C 1 -C 4 alkyl)silyl-C 2 -C 6 alkenyl, tri-(C 1 -C 4 alkyl)silyl-C 2 -C 6 alkynyl, tri-(C 1 -C 4 alkyl)silyl-C 1 -C 6 alkyloxy, (C 3 -C 7 cycloalkyl)C 2 -C 5 alkenyl, (C 3 -C 7 cycloalkyl)C 3 -C 5 alkenyloxy, (C 3 -C 7 cycloalkyl)C 3 - 5 alkynyloxy, (C 5 -C 8 cycloalkenyl)C 3 -C 5 alkenyloxy, (C 5 -C 8 cycloalkenyl)C 3 -C 5 alkynyloxy, C 3 -C 6 cycloalkylidenmethyl, (C 1 -C 4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, (C 1 -C 4 alkyl)aminocarbonyl, di-(C 1 -C 3 alkyl)aminocarbonyl, hydroxycarbonyl, (C 1 -C 4 alkyloxy)carbonyl, C 1 -C 4 alkylamino, di-(C 1 -C 3 alkyl)amino, (C 1 -C 4 alkyl)carbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C 1 -C 4 alkylsulfonylamino, arylsulfonylamino, C 1 -C 4 alkylsulfanyl, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 3 -C 10 cycloalkylsulfanyl, C 3 -C 10 cycloalkylsulfinyl, C 3 -C 10 cycloalkylsulfonyl, C 5 -C 10 cycloalkenylsulfanyl, C 5 -C 10 cycloalkenylsulfinyl, C 5 -C 10 cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl and arylsulfonyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and are optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C 1 -C 3 alkoxy and C 1 -C 3 alkyl, and in cycloalkyl and cycloalkenyl groups or portions one or two methylene groups are optionally replaced independently of one another by NR a , O, S, CO, SO or SO 2 , and one or two methyne groups are optionally replaced by N;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 3 alkyloxy and C 3 -C 10 cycloalkyloxy, wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and are optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C 1 -C 3 alkoxy and C 1 -C 3 alkyl, and in cycloalkyl and cycloalkenyl groups or portions one or two methylene groups are optionally replaced independently of one another by NR a , O, S, CO, SO or SO 2 , and one or two methyne groups are optionally replaced by N, or
if R 5 and R 6 are bound to two adjacent C atoms of the phenyl ring, R 5 and R 6 are optionally joined together to form a C 3 -C 5 alkylene, C 3 -C 5 alkenylene or butadienylene bridge, which is optionally partly or completely fluorinated and mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C 1 -C 3 alkoxy and C 1 -C 3 alkyl, and wherein one or two methylene groups are optionally replaced independently of one another by O, S, CO, SO, SO 2 or NR a , and wherein one or two methyne groups are optionally replaced by N;
R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydroxy, (C 1 -C 18 alkyl)carbonyloxy, (C 1 -C 18 alkyl)oxycarbonyloxy, arylcarbonyloxy, aryl-(C 1 -C 3 alkyl)carbonyloxy, (C 3 -C 10 cycloalkyl)carbonyloxy, hydrogen, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 10 cycloalkyl)C 1 -C 3 alkyl, (C 5 -C 7 cycloalkenyl)C 1 -C 3 alkyl, (aryl)C 1 -C 3 alkyl, (heteroaryl)C 1 -C 3 alkyl, C 1 -C 6 alkyloxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 3 -C 7 cycloalkyloxy, C 5 -C 7 cycloalkenyloxy, aryloxy, heteroaryloxy, (C 3 -C 7 cycloalkyl)C 1 -C 3 alkyloxy, (C 5 -C 7 cycloalkenyl)C 1 -C 3 alkyloxy, (aryl)C 1 -C 3 alkyloxy, (heteroaryl)C 1 -C 3 alkyloxy, aminocarbonyl, hydroxycarbonyl, (C 1 -C 4 alkyl)aminocarbonyl, di-(C 1 -C 3 alkyl)aminocarbonyl, (C 1 -C 4 alkyloxy)carbonyl, (aminocarbonyl)C 1 -C 3 alkyl, (C 1 -C 4 alkyl)aminocarbonyl-(C 1 -C 3 )alkyl, di-(C 1 -C 3 alkyl)aminocarbonyl-(C 1 -C 3 )alkyl, (hydroxycarbonyl)C 1 -C 3 alkyl, (C 1 -C 4 alkyloxy)carbonyl-(C 1 -C 3 )alkyl, (C 3 -C 7 cycloalkyloxy)C 1 -C 3 alkyl, (C 5 -C 7 cycloalkenyloxy)C 1 -C 3 alkyl, (aryloxy)C 1 -C 3 alkyl, (heteroaryloxy)C 1 -C 3 alkyl, C 1 -C 4 alkylsulfonyloxy, arylsulfonyloxy, (aryl)C 1 -C 3 alkylsulfonyloxy, trimethylsilyloxy, t-butyldimethylsilyloxy, and cyano; wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions are optionally partly or completely fluorinated and are optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C 1 -C 3 alkoxy and C 1 -C 3 alkyl, and in cycloalkyl and cycloalkenyl groups or portions one or two methylene groups are optionally replaced independently of one another by NR a , O, S, CO, SO or SO 2 ;
and optionally, R 10 and R 11 can be combined with the carbon atoms to which each is attached to form a five- to seven-membered fused cycloalkane or cycloalkene ring that is optionally partly or completely fluorinated and may be mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C 1 -C 3 alkoxy and C 1 -C 3 alkyl, and wherein in the cycloalkyl and cycloalkenyl rings one or two methylene groups are optionally replaced independently of one another by NR a , O, S, CO, SO or SO 2 ;
R 11 is selected from the group consisting of hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkyloxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy or C 3 -C 6 cycloalkyloxy, wherein alkyl, alkenyl, alkynyl and cycloalkyl groups or portions are optionally partly or completely fluorinated, and
R 12 is hydrogen; or
R 11 and R 12 are optionally joined together with the carbon atom to which they are attached to form a C 3 -C 7 spirocycloalkane ring which is optionally partly or completely fluorinated and is optionally mono- or disubstituted by identical or different substituents selected from chlorine, hydroxy, C 1 -C 3 alkoxy and C 1 -C 3 alkyl;
R 13 and R 14 each independently selected from the group consisting of hydrogen, hydroxy, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkyloxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy and C 3 -C 6 cycloalkyloxy, wherein alkyl, alkenyl, alkynyl and cycloalkyl groups or portions are optionally partly or completely fluorinated;
R 15 is selected from the group consisting of oxygen and CR b R c ;
each R a independently is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and (C 1 -C 4 alkyl)carbonyl, wherein alkyl groups or portions are optionally partly or completely fluorinated; and
R b and R c are each independently selected from the group consisting of hydrogen, halo and C 1 -C 4 alkyl, wherein alkyl groups are optionally partly or completely fluorinated;
and pharmaceutically acceptable salts thereof.
2. A compound of claim 1 , wherein A is a single bond.
3. A compound of claim 1 , wherein Z is CH 2 .
4. A compound of claim 1 , wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkyloxy, and cyano.
5. A compound of claim 4 , wherein R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo and C 1 -C 6 alkyl.
6. A compound of claim 4 , wherein R 1 is selected from the group consisting of hydrogen, halo and C 1 -C 6 alkyl, and R 2 and R 3 are each hydrogen.
7. A compound of claim 1 , wherein R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkyloxy, C 3 - C 10 cycloalkyloxy, (C 3 -C 10 cycloalkyl)C 1 -C 3 alkyloxy, (C 3 -C 7 cycloalkyl)C 3 - 5 alkenyloxy, and (C 3 -C 7 cycloalkyl)C 3 - 5 alkynyloxy.
8. A compound of claim 1 , wherein R 5 and R 6 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkyloxy, and cyano.
9. A compound of claim 8 , wherein R 5 and R 6 are each independently selected from the group consisting of hydrogen, halo and C 1 -C 6 alkyl.
10. A compound of claim 9 , wherein R 5 and R 6 are each hydrogen.
11. A compound of claim 1 , wherein R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydroxy, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, (C 3 -C 7 )cycloalkyloxy, aryloxy and (C 3 -C 7 )cycloalkyl-(C 1 -C 3 )alkyloxy, wherein alkyl and cycloalkyl groups or portions are optionally partly or completely fluorinated.
12. A compound of claim 11 , wherein R 7 , R 8 , R 9 and R 10 are each hydroxy.
13. A compound of claim 1 , wherein R 11 is hydroxy.
14. A compound of claim 1 , having Formula IA:
wherein
R 1 is a member selected from the group consisting of hydrogen, halo and C 1 -C 6 alkyl;
R 4 is a member selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkyloxy, C 3 -C 10 cycloalkyloxy, (C 3 -C 10 cycloalkyl)C 1 -C 3 alkyloxy, (C 3 -C 7 cycloalkyl)C 3 - 5 alkenyloxy, and (C 3 -C 7 cycloalkyl)C 3 - 5 alkynyloxy; and
Q is a member selected from formulae Q 1A to Q 4A :
wherein
R 11 is hydroxy; and
R 15 is a member selected from the group consisting of oxygen and CR b R c , wherein R b and R c each independently is a member selected from the group consisting of hydrogen and halo.
15. A compound of claim 14 , wherein Q is a member selected from the group consisting of Q 1A and Q 3A .
16. A compound of claim 1 , selected from the group consisting of
(1R,2R,3S,4R,5R,6S)-4-(4-chloro-3-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol;
(1R,2R,3S,4R,5R,6S)-4-(4-chloro-3-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol;
(1R,2R,3S,4R,5R,6S)-4-(4-chloro-3-(4-cyclopropylbenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol;
(1R,2R,3S,4R,5R,6S)-4-(4-chloro-3-(4-propylbenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol;
(1R,2R,3S,4R,5R,6S)-4-(4-chloro-3-(4-cyclohexylbenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol;
((1S,2R,3R,4S,5R,6R)-3-(4-chloro-3-(4-ethylbenzyl)phenyl)-2,4,5,6-tetrahydroxycyclohexyl)methyl acetate;
(1R,2S,3R,4R,5S,6R)-4-(2-(4-ethylbenzyl)phenoxy)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol;
(1R,2R,3S,4S,6R)-4-(4-chloro-3-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)-5-methylenecyclohexane-1,2,3-triol;
(4S,5S,6R,7R,8R)-4-(4-chloro-3-(4-ethylbenzyl)phenyl)-8-(hydroxymethyl)spiro[2.5]octane-5,6,7-triol;
1-(4-(2-chloro-5-((1R,2S,3R,4R,5S,6R)-2,3,4,6-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)benzyl)phenyl)ethanone; and
(1R,2R,3S,4R,5R,6S)-4-(4-chloro-3-(4-(1-hydroxyethypbenzyl)phenyl)-6-(hydroxymethypcyclohexane-1,2,3,5-tetraol.
17. A compound of claim 1 which is isotopically labeled.
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 .
19. A method of treating a disease or condition mediated by SGLT, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
20. A method of treating diabetes, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
21. A method in accordance with claim 20 , wherein said diabetes is type 1 diabetes.
22. A method in accordance with claim 20 , wherein said diabetes is type 2 diabetes.
23. A method in accordance with claim 20 , wherein said compound is administered in combination with a therapeutic agent selected from the group consisting of antidiabetic agents, lipid-lowering/lipid-modulating agents, agents for treating diabetic complications, anti-obesity agents, antihypertensive agents, antihyperuricemic agents, and agents for treating chronic heart failure or atherosclerosis.
24. A method in accordance with claim 19 , wherein said disease or condition is selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, hyperglycemia, diabetic complications, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, and atherosclerosis.
25. A compound of the formula:
26. A method of treating a disease or condition mediated by SGLT, wherein said disease or condition is selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, hyperglycemia, diabetic complications, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure and atherosclerosis, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 25 .
27. A method of treating diabetes, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 25 .
28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 25 .