Deuterated benzylbenzene 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 that are affected by SGLT inhibition.
1. A composition comprising a compound having the structure:
or any stereoisomer or tautomer thereof, or any pharmaceutically acceptable salt thereof, wherein
each R 1 , R 2 , R 3 , R 4 and R 5 is, independently, —H, -D, halo, cyano, nitro, a substituent that is optionally deuterated, or group Q:
each R 6 , R 7 , R 8 , R 9 , and R 10 is, independently, —H, -D, halo, cyano, nitro, or a substituent that is optionally deuterated;
each R 14 , R 15 , and R 16 is, independently, —H or a substituent that is optionally deuterated; and
each R 11 , R 12 , R 13 , R 17 and R 18 is, independently, —H, -D, or halogen; and
R 19 is —H, -D, halo, cyano, or a substituent that is optionally deuterated;
wherein
one of R 1 , R 2 , R 3 , R 4 and R 5 is group Q; and
at least one of R 1 -R 19 is -D or comprises -D, wherein said composition has an isotopic enrichment factor for deuterium of at least 5 for said compound.
2. The composition of claim 1 , wherein one of R 1 , R 2 , R 3 , R 4 and R 5 is group Q;
one of the remaining groups R 1 , R 2 , R 3 , R 4 and R 5 represents hydrogen, deuterium, 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 6 -C 10 cycloalkenyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, C 5 -C 7 cycloalkenyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C 2 -C 4 alkenyl)C 1 -C 3 alkoxy, (C 2 -C 4 alkynyl)C 1 -C 3 alkoxy, (aryl)C 1 -C 3 alkoxy, (heteroaryl)C 1 -C 3 alkoxy, (C 3 -C 10 cycloalkyl)C 1 -C 3 alkyl, (C 3 -C 10 cycloalkyl)C 1 -C 3 alkoxy, (C 5 -C 10 cycloalkenyl)C 1 -C 3 alkyl, (C 5 -C 10 cycloalkenyl)C 1 -C 3 alkoxy, (C 1 -C 4 alkoxy)C 1 -C 3 alkyl, (C 3 -C 7 cycloalkoxy)C 1 -C 3 alkyl, (C 3 -C 7 cycloalkoxy)C 2 -C 4 alkenyl, (C 3 -C 7 cycloalkoxy)C 2 -C 4 alkynyl, (C 3 -C 7 cycloalkoxy)C 1 -C 3 alkoxy, (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 alkoxy, (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 -C 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 alkoxy)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 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 3 -C 10 cycloalkylthio, C 3 -C 10 cycloalkylsulfinyl, C 3 -C 10 cycloalkylsulfonyl, C 5 -C 10 cycloalkenylthio, C 5 -C 10 cycloalkenylsulfinyl, C 5 -C 10 cycloalkenylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl;
two of the remaining groups R 1 , R 2 , R 3 , R 4 and R 5 each independently represent hydrogen, deuterium, 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 alkoxy or C 3 -C 10 cycloalkoxy; and
one of the remaining groups R 1 , R 2 , R 3 , R 4 and R 5 represents hydrogen or deuterium;
one of the groups R 6 , R 7 , R 8 , R 9 and R 10 represents hydrogen, deuterium, 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 alkoxy, C 3 -C 10 cycloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, (C 1 -C 3 alkoxy)C 3 -C 7 cycloalkoxy, C 5 -C 7 cycloalkenyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C 2 -C 4 alkenyl)C 1 -C 3 alkoxy, (C 2 -C 4 alkynyl)C 1 -C 3 alkoxy, (aryl)C 1 -C 3 alkoxy, (heteroaryl)C 1 -C 3 alkoxy, (C 3 -C 10 cycloalkyl)C 1 -C 3 alkyl, (C 3 -C 10 cycloalkyl)C 1 -C 3 alkoxy, (C 5 -C 10 cycloalkenyl)C 1 -C 3 alkyl, (C 5 -C 10 cycloalkenyl)C 1 -C 3 alkoxy, (C 1 -C 4 alkoxy)C 1 -C 3 alkyl, (C 3 -C 7 cycloalkoxy)C 1 -C 3 alkyl, (C 3 -C 7 cycloalkoxy)C 2 -C 4 alkenyl, (C 3 -C 7 cycloalkoxy)C 2 -C 4 alkynyl, (C 3 -C 7 cycloalkoxy)C 1 -C 3 alkoxy, (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 alkoxy, (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 -C 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 alkoxy)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 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 3 -C 10 cycloalkylthio, C 3 -C 10 cycloalkylsulfinyl, C 3 -C 10 cycloalkylsulfonyl, C 5 -C 10 cycloalkenylthio, C 5 -C 10 cycloalkenylsulfinyl, C 5 -C 10 cycloalkenylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl;
two of the remaining groups R 6 , R 7 , R 8 , R 9 and R 10 each independently represent hydrogen, deuterium, 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 alkoxy or C 3 -C 10 cycloalkoxy; and
two of the remaining groups R 6 , R 7 , R 8 , R 9 and R 10 each independently represent hydrogen or deuterium;
R 14 , R 15 and R 16 each independently represent hydrogen, (C 1 -C 18 alkyl)carbonyl, (C 1 -C 18 alkyl)oxycarbonyl, arylcarbonyl, aryl-(C 1 -C 3 alkyl)carbonyl, (C 3 -C 10 cycloalkyl)carbonyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 5 -C 7 cycloalkenyl)C 1 -C 3 alkyl, (aryl)C 1 -C 3 alkyl, (heteroaryl)C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl, heteroaryl, (C 3 -C 7 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 4 alkylsulfonyl, arylsulfonyl, (aryl)C 1 -C 3 alkylsulfonyl, trimethylsilyl or t-butyldimethylsilyl;
R 19 represents 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, deuterium, 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 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 3 -C 7 cycloalkoxy, C 5 -C 7 cycloalkenyloxy, aryloxy, heteroaryloxy, (C 3 -C 7 cycloalkyl)C 1 -C 3 alkoxy, (C 5 -C 7 cycloalkenyl)C 1 -C 3 alkoxy, (aryl)C 1 -C 3 alkoxy, (heteroaryl)C 1 -C 3 alkoxy, aminocarbonyl, hydroxycarbonyl, (C 1 -C 4 alkyl)aminocarbonyl, di-(C 1 -C 3 alkyl)aminocarbonyl, (C 1 -C 4 alkoxy)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 alkoxy)carbonyl-(C 1 -C 3 )alkyl, (C 3 -C 7 cycloalkoxy)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, or cyano,
wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups or portions optionally may be partly or completely substituted with fluorine or deuterium 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 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 ; R a independently represents hydrogen, C 1 -C 4 alkyl or (C 1 -C 4 alkyl)carbonyl, wherein alkyl groups or portions optionally may be partly or completely substituted with fluorine or deuterium.
3. The composition of claim 1 , wherein said composition further comprises an amino acid.
4. The composition of claim 1 , wherein R 11 and R 12 are both -D.
5. The composition of claim 1 , wherein R 13 is -D.
6. The composition of claim 1 , wherein one of R 1 , R 2 , R 3 , or R 5 is halogen.
7. The composition of claim 6 , wherein R 3 is —Cl.
8. The composition of claim 1 , wherein R 4 is Q.
9. The composition of claim 1 , wherein
each R 1 , R 2 , R 3 , R 4 and R 5 is, independently, —H, -D, group Q, halogen, or an optionally deuterated substituent selected from hydroxyl, optionally substituted alkyl, haloalkyl, optionally substituted alkoxyalkyl, optionally substituted alkoxy, haloalkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted alkcycloalkyl;
each R 6 , R 7 , R 8 , R 9 , R 10 is, independently, —H, -D, halogen, or an optionally deuterated substituent selected from hydroxyl, optionally substituted carbamoyl, optionally substituted alkyl, haloalkyl, optionally substituted alkoxyalkyl, optionally substituted alkoxy, haloalkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted alkcycloalkyl; and
each R 14 , R 15 , and R 16 is, independently, —H, optionally substituted alkyl, haloalkyl, optionally substituted alkoxyalkyl, optionally substituted alkoxy, haloalkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkcycloalkyl, —C(O)R A , —C(O)OR A , or —C(O)NR A R B , wherein each R A and R B is, independently, hydrogen, deuterium, or an optionally deuterated substituent selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, and optionally substituted aryl.
10. The composition of claim 9 , wherein R 4 is Q and R 8 is -D, halogen, or an optionally deuterated substituent selected from hydroxyl, optionally substituted alkyl, haloalkyl, optionally substituted alkoxyalkyl, optionally substituted alkoxy, haloalkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted alkcycloalkyl.
11. The composition of claim 10 , wherein R 2 is H; R 3 is halogen; R 5 , R 6 , R 7 , R 9 , and R 10 are H; and R 14 , R 15 , and R 16 are, independently, selected from H, —C(O)R A , —C(O)OR A , or —C(O)NR A R B .
12. The composition of claim 11 , wherein R 3 is —Cl.
13. The composition of claim 11 , wherein R 11 and R 12 are both -D.
14. The composition of claim 11 , wherein R 13 is -D.
15. The composition of claim 11 , wherein R 8 is a deuterated substituent.
16. A composition comprising a compound selected from the group consisting of:
or any stereoisomer or tautomer thereof, or any pharmaceutically acceptable salt thereof;
wherein said composition has an isotopic enrichment factor for deuterium of at least 5 for said compound.
17. The composition of claim 16 , wherein said compound is selected from:
or any stereoisomer or tautomer thereof, or any pharmaceutically acceptable salt thereof.
18. The composition of claim 16 , wherein said compound is selected from:
or any stereoisomer or tautomer thereof, or any pharmaceutically acceptable salt thereof.
19. The composition of claim 16 , wherein said compound is selected from:
or any stereoisomer or tautomer thereof, or any pharmaceutically acceptable salt thereof.
20. The composition of claim 16 , wherein said compound is selected from:
or any stereoisomer or tautomer thereof, or any pharmaceutically acceptable salt thereof.
21. The composition of claim 16 , wherein said compound is
or any stereoisomer or tautomer thereof, or any pharmaceutically acceptable salt thereof.
22. The composition of claim 1 , wherein said isotopic enrichment factor for deuterium is at least 500, 1000, or 3000 for said compound.
23. The composition of claim 1 , wherein said composition further comprises a pharmaceutically acceptable carrier, and wherein said compound of Formula (I) is present in an effective amount.
24. The composition of claim 8 , wherein R 14 , R 15 , and R 16 are H; and wherein R 19 is hydroxy.
25. The composition of claim 24 , wherein R 11 and R 12 are both -D.
26. The composition of claim 24 , wherein R 13 is -D.
27. The composition of claim 24 , wherein R 1 is a deuterated substituent.
28. The composition of claim 24 , wherein R 8 is a deuterated substituent.
29. A method of treating a disease affected by inhibition of the sodium-dependent glucose transporter (SGLT), comprising administering the composition of claim 1 .
30. The method of claim 29 , wherein said disease affected by inhibition of the SGLT is: type 1 diabetes mellitus, type 2 diabetes mellitus, hyperglycemia, diabetic complications, insulin resistance, metabolic syndrome (Syndrome X), hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, or atherosclerosis.
31. The method of claim 29 , wherein said method further comprises administering a second therapeutic agent.
32. The method of claim 31 , wherein said therapeutic agent is: an antidiabetic agent, a lipid-lowering/lipid-modulating agent, an agent for treating diabetic complications, an anti-obesity agent, an antihypertensive agent, an antihyperuricemic agent, an agent for treating chronic heart failure, or an agent for treating atherosclerosis.
33. The method of claim 29 , wherein said disease is type 1 diabetes mellitus or type 2 diabetes mellitus.