DEUTERATED BENZYLBENZENE DERIVATIVES AND METHODS OF USE
First Claim
Patent Images
1. A composition comprising a compound having the structure:
6 Assignments
0 Petitions
Accused Products
Abstract
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.
70 Citations
47 Claims
-
1. A composition comprising a compound having the structure:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 35, 36, 37, 38)
-
2. The composition of claim 1, wherein one of R1, R2, R3, R4 and R5 is group Q;
-
one of the remaining groups R1, R2, R3, R4 and R5 represents hydrogen, deuterium, halo, cyano, nitro, amino, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C1-C6 alkoxy, C3-C10 cycloalkoxy, (C1-C6 alkoxy)C1-C6 alkoxy, C5-C7 cycloalkenyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C2-C4 alkenyl)C1-C3 alkoxy, (C2-C4 alkynyl)C1-C3 alkoxy, (aryl)C1-C3 alkoxy, (heteroaryl)C1-C3 alkoxy, (C3-C10 cycloalkyl)C1-C3 alkyl, (C3-C10 cycloalkyl)C1-C3 alkoxy, (C5-C10 cycloalkenyl)C1-C3 alkyl, (C5-C10 cycloalkenyl)C1-C3 alkoxy, (C1-C4 alkoxy)C1-C3 alkyl, (C3-C7 cycloalkoxy)C1-C3 alkyl, (C3-C7 cycloalkoxy)C2-C4 alkenyl, (C3-C7 cycloalkoxy)C2-C4 alkynyl, (C3-C7 cycloalkoxy)C1-C3 alkoxy, (C1-C4 alkylamino)C1-C3 alkyl, di-(C1-C3 alkylamino)C1-C3 alkyl, tri-(C1-C4 alkyl)silyl-C1-C6 alkyl, tri-(C1-C4 alkyl)silyl-C2-C6 alkenyl, tri-(C1-C4 alkyl)silyl-C2-C6 alkynyl, tri-(C1-C4 alkyl)silyl-C1-C6 alkoxy, (C3-C7 cycloalkyl)C2-C5 alkenyl, (C3-C7 cycloalkyl)C3-C5 alkenyloxy, (C3-C7 cycloalkyl)C3-C5 alkynyloxy, (C5-C8 cycloalkenyl)C3-C5 alkenyloxy, (C5-C8 cycloalkenyl)C3-C5 alkynyloxy, C3-C6 cycloalkylidenmethyl, (C1-C4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl, di-(C1-C3 alkyl)aminocarbonyl, hydroxycarbonyl, (C1-C4 alkoxy)carbonyl, C1-C4 alkylamino, di-(C1-C3 alkyl)amino, (C1-C4 alkyl)carbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C1-C4 alkylsulfonylamino, arylsulfonylamino, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C3-C10 cycloalkylthio, C3-C10 cycloalkylsulfinyl, C3-C10 cycloalkylsulfonyl, C5-C10 cycloalkenylthio, C5-C10 cycloalkenylsulfinyl, C5-C10 cycloalkenylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl; two of the remaining groups R1, R2, R3, R4 and R5 each independently represent hydrogen, deuterium, halo, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C3 alkoxy or C3-C10 cycloalkoxy; and one of the remaining groups R1, R2, R3, R4 and R5 represents hydrogen or deuterium; one of the groups R6, R7, R8, R9 and R10 represents hydrogen, deuterium, halo, cyano, nitro, amino, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C1-C6 alkoxy, C3-C10 cycloalkoxy, (C1-C6 alkoxy)C1-C6 alkoxy, (C1-C3 alkoxy)C3-C7 cycloalkoxy, C5-C7 cycloalkenyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C2-C4 alkenyl)C1-C3 alkoxy, (C2-C4 alkynyl)C1-C3 alkoxy, (aryl)C1-C3 alkoxy, (heteroaryl)C1-C3 alkoxy, (C3-C10 cycloalkyl)C1-C3 alkyl, (C3-C10 cycloalkyl)C1-C3 alkoxy, (C5-C10 cycloalkenyl)C1-C3 alkyl, (C5-C10 cycloalkenyl)C1-C3 alkoxy, (C1-C4 alkoxy)C1-C3 alkyl, (C3-C7 cycloalkoxy)C1-C3 alkyl, (C3-C7 cycloalkoxy)C2-C4 alkenyl, (C3-C7 cycloalkoxy)C2-C4 alkynyl, (C3-C7 cycloalkoxy)C1-C3 alkoxy, (C1-C4 alkylamino)C1-C3 alkyl, di-(C1-C3 alkylamino)C1-C3 alkyl, tri-(C1-C4 alkyl)silyl-C1-C6 alkyl, tri-(C1-C4 alkyl)silyl-C2-C6 alkenyl, tri-(C1-C4 alkyl)silyl-C2-C6 alkynyl, tri-(C1-C4 alkyl)silyl-C1-C6 alkoxy, (C3-C7 cycloalkyl)C2-C5 alkenyl, (C3-C7 cycloalkyl)C3-C5 alkenyloxy, (C3-C7 cycloalkyl)C3-C5 alkynyloxy, (C5-C8 cycloalkenyl)C3-C5 alkenyloxy, (C5-C8 cycloalkenyl)C3-C5 alkynyloxy, C3-C6 cycloalkylidenmethyl, (C1-C4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl, di-(C1-C3 alkyl)aminocarbonyl, hydroxycarbonyl, (C1-C4 alkoxy)carbonyl, C1-C4 alkylamino, di-(C1-C3 alkyl)amino, (C1-C4 alkyl)carbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C1-C4 alkylsulfonylamino, arylsulfonylamino, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C3-C10 cycloalkylthio, C3-C10 cycloalkylsulfinyl, C3-C10 cycloalkylsulfonyl, C5-C10 cycloalkenylthio, C5-C10 cycloalkenylsulfinyl, C5-C10 cycloalkenylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl; two of the remaining groups R6, R7, R8, R9 and R10 each independently represent hydrogen, deuterium, halo, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C3 alkoxy or C3-C10 cycloalkoxy; and two of the remaining groups R6, R7, R8, R9 and R10 each independently represent hydrogen or deuterium; R14, R15 and R16 each independently represent hydrogen, (C1-C18 alkyl)carbonyl, (C1-C18 alkyl)oxycarbonyl, arylcarbonyl, aryl-(C1-C3 alkyl)carbonyl, (C3-C10 cycloalkyl)carbonyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C5-C7 cycloalkenyl)C1-C3 alkyl, (aryl)C1-C3 alkyl, (heteroaryl)C1-C3 alkyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, (C3-C7 cycloalkyl)C1-C3 alkyl, (C5-C7 cycloalkenyl)C1-C3 alkyl, (aryl)C1-C3 alkyl, (heteroaryl)C1-C3 alkyl, C1-C4 alkylsulfonyl, arylsulfonyl, (aryl)C1-C3 alkylsulfonyl, trimethylsilyl or t-butyldimethylsilyl; R19 represents hydroxy, (C1-C18 alkyl)carbonyloxy, (C1-C18 alkyl)oxycarbonyloxy, arylcarbonyloxy, aryl-(C1-C3 alkyl)carbonyloxy, (C3-C10 cycloalkyl)carbonyloxy, hydrogen, deuterium, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C10 cycloalkyl)C1-C3 alkyl, (C5-C7 cycloalkenyl)C1-C3 alkyl, (aryl)C1-C3 alkyl, (heteroaryl)C1-C3 alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C7 cycloalkoxy, C5-C7 cycloalkenyloxy, aryloxy, heteroaryloxy, (C3-C7 cycloalkyl)C1-C3 alkoxy, (C5-C7 cycloalkenyl)C1-C3 alkoxy, (aryl)C1-C3 alkoxy, (heteroaryl)C1-C3 alkoxy, aminocarbonyl, hydroxycarbonyl, (C1-C4 alkyl)aminocarbonyl, di-(C1-C3 alkyl)aminocarbonyl, (C1-C4 alkoxy)carbonyl, (aminocarbonyl)C1-C3 alkyl, (C1-C4 alkyl)aminocarbonyl-(C1-C3)alkyl, di-(C1-C3 alkyl)aminocarbonyl-(C1-C3)alkyl, (hydroxycarbonyl)C1-C3 alkyl, (C1-C4 alkoxy)carbonyl-(C1-C3)alkyl, (C3-C7 cycloalkoxy)C1-C3 alkyl, (C5-C7 cycloalkenyloxy)C1-C3 alkyl, (aryloxy)C1-C3 alkyl, (heteroaryloxy)C1-C3 alkyl, C1-C4 alkylsulfonyloxy, arylsulfonyloxy, (aryl)C1-C3 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, C1-C3 alkoxy and C1-C3 alkyl, and in cycloalkyl and cycloalkenyl groups or portions one or two methylene groups are optionally replaced independently of one another by NRa, O, S, CO, SO or SO2;
Ra independently represents hydrogen, C1-C4 alkyl or (C1-C4 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 R11 and R12 are both -D.
-
5. The composition of claim 1, wherein R13 is -D.
-
6. The composition of claim 1, wherein one of R1, R2, R3, or R5 is halogen.
-
7. The composition of claim 6, wherein R3 is —
- Cl.
-
8. The composition of claim 1, wherein R4 is Q.
-
9. The composition of claim 1, wherein
each R1, R2, R3, R4 and R5 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 R6, R7, R8, R9, R10, and R19 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; andeach R14, R15, and R16 is, independently, —
H, -D, 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)RA, —
C(O)ORA, or C(O)NRARB, wherein each RA and RB is, independently, hydrogen, deuterium, or an optionally deuterated substituent selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, and optionally substituted aryl.
- 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;
-
10. The composition of claim 9, wherein R4 is Q and R8 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 R2 is H;
- R3 is halogen;
R5, R6, R7, R9, and R10 are H; and
R14, R15, and R16 are, independently, selected from H, D, —
C(O)RA, —
C(O)ORA, or —
C(O)NRARB.
- R3 is halogen;
-
12. The composition of claim 11, wherein R3 is —
- Cl.
-
13. The composition of claim 11, wherein R11 and R12 are both -D.
-
14. The composition of claim 11, wherein R13 is -D.
-
15. The composition of claim 11, wherein R8 is a deuterated substituent.
-
16. The composition of claim 1, wherein said compound is selected from the group consisting of:
-
17. The composition of claim 16, wherein said compound is selected from:
-
18. The composition of claim 16, wherein said compound is selected from:
-
19. The composition of claim 16, wherein said compound is selected from:
-
20. The composition of claim 16, wherein said compound is selected from:
-
21. The composition of claim 16, wherein said compound is
-
22. The composition of claim 1, wherein said isotopic enrichment factor for deuterium is at least 500, 1000, or 3000.
-
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.
-
35. A method of treating or preventing a disease affected by inhibition of the sodium-dependent glucose transporter (SGLT), comprising administering the composition of claim 1.
-
36. The method of claim 35, 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.
-
37. The method of claim 35, wherein said method further comprises administering a second therapeutic agent.
-
38. The method of claim 37, 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.
-
2. The composition of claim 1, wherein one of R1, R2, R3, R4 and R5 is group Q;
-
24. A composition comprising a compound having the structure:
- View Dependent Claims (25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 39, 40)
-
25. The composition of claim 24, wherein one of R1, R2, R3, R4 and R5 is group Q;
-
one of the remaining groups R1, R2, R3, R4 and R5 represents hydrogen, deuterium, halo, cyano, nitro, amino, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C1-C6 alkoxy, C3-C10 cycloalkoxy, (C1-C6 alkoxy)C1-C6 alkoxy, C5-C7 cycloalkenyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C2-C4 alkenyl)C1-C3 alkoxy, (C2-C4 alkynyl)C1-C3 alkoxy, (aryl)C1-C3 alkoxy, (heteroaryl)C1-C3 alkoxy, (C3-C10 cycloalkyl)C1-C3 alkyl, (C3-C10 cycloalkyl)C1-C3 alkoxy, (C5-C10 cycloalkenyl)C1-C3 alkyl, (C5-C10 cycloalkenyl)C1-C3 alkoxy, (C1-C4 alkoxy)C1-C3 alkyl, (C3-C7 cycloalkoxy)C1-C3 alkyl, (C3-C7 cycloalkoxy)C2-C4 alkenyl, (C3-C7 cycloalkoxy)C2-C4 alkynyl, (C3-C7 cycloalkoxy)C1-C3 alkoxy, (C1-C4 alkylamino)C1-C3 alkyl, di-(C1-C3 alkylamino)C1-C3 alkyl, tri-(C1-C4 alkyl)silyl-C1-C6 alkyl, tri-(C1-C4 alkyl)silyl-C2-C6 alkenyl, tri-(C1-C4 alkyl)silyl-C2-C6 alkynyl, tri-(C1-C4 alkyl)silyl-C1-C6 alkoxy, (C3-C7 cycloalkyl)C2-C5 alkenyl, (C3-C7 cycloalkyl)C3-C5 alkenyloxy, (C3-C7 cycloalkyl)C3-C5 alkynyloxy, (C5-C8 cycloalkenyl)C3-C5 alkenyloxy, (C5-C8 cycloalkenyl)C3-C5 alkynyloxy, C3-C6 cycloalkylidenmethyl, (C1-C4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl, di-(C1-C3 alkyl)aminocarbonyl, hydroxycarbonyl, (C1-C4 alkoxy)carbonyl, C1-C4 alkylamino, di-(C1-C3 alkyl)amino, (C1-C4 alkyl)carbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C1-C4 alkylsulfonylamino, arylsulfonylamino, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C3-C10 cycloalkylthio, C3-C10 cycloalkylsulfinyl, C3-C10 cycloalkylsulfonyl, C5-C10 cycloalkenylthio, C5-C10 cycloalkenylsulfinyl, C5-C10 cycloalkenylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl; two of the remaining groups R1, R2, R3, R4 and R5 each independently represent hydrogen, deuterium, halo, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C3 alkoxy or C3-C10 cycloalkoxy, one of the remaining groups R1, R2, R3, R4 and R5 represents hydrogen or deuterium; one of the groups R6, R7, R8, R9 and R10 represents hydrogen, deuterium, halo, cyano, nitro, amino, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C1-C6 alkoxy, C3-C10 cycloalkoxy, (C1-C6 alkoxy)C1-C6 alkoxy, C5-C7 cycloalkenyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, (C2-C4 alkenyl)C1-C3 alkoxy, (C2-C4 alkynyl)C1-C3 alkoxy, (aryl)C1-C3 alkoxy, (heteroaryl)C1-C3 alkoxy, (C3-C10 cycloalkyl)C1-C3 alkyl, (C3-C10 cycloalkyl)C1-C3 alkoxy, (C5-C10 cycloalkenyl)C1-C3 alkyl, (C5-C10 cycloalkenyl)C1-C3 alkoxy, (C1-C4 alkoxy)C1-C3 alkyl, (C3-C7 cycloalkoxy)C1-C3 alkyl, (C3-C7 cycloalkoxy)C2-C4 alkenyl, (C3-C7 cycloalkoxy)C2-C4 alkynyl, (C3-C7 cycloalkoxy)C1-C3 alkoxy, (C1-C4 alkylamino)C1-C3 alkyl, di-(C1-C3 alkylamino)C1-C3 alkyl, tri-(C1-C4 alkyl)silyl-C1-C6 alkyl, tri-(C1-C4 alkyl)silyl-C2-C6 alkenyl, tri-(C1-C4 alkyl)silyl-C2-C6 alkynyl, tri-(C1-C4 alkyl)silyl-C1-C6 alkoxy, (C3-C7 cycloalkyl)C2-C8 alkenyl, (C3-C7 cycloalkyl)C3-C5 alkenyloxy, (C3-C7 cycloalkyl)C3-C5 alkynyloxy, (C5-C8 cycloalkenyl)C3-C5 alkenyloxy, (C5-C8 cycloalkenyl)C3-C5 alkynyloxy, C3-C6 cycloalkylidenmethyl, (C1-C4 alkyl)carbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, (C1-C4 alkyl)aminocarbonyl, di-(C1-C3 alkyl)aminocarbonyl, hydroxycarbonyl, (C1-C4 alkoxy)carbonyl, C1-C4 alkylamino, di-(C1-C3 alkyl)amino, (C1-C4 alkyl)carbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C1-C4 alkylsulfonylamino, arylsulfonylamino, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C3-C10 cycloalkylthio, C3-C10 cycloalkylsulfinyl, C3-C10 cycloalkylsulfonyl, C5-C10 cycloalkenylthio, C5-C10 cycloalkenylsulfinyl, C5-C10 cycloalkenylsulfonyl, arylthio, arylsulfinyl or arylsulfonyl, two of the remaining groups R6, R1, R8, R9 and R10 each independently represent hydrogen, deuterium, halo, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C3 alkoxy or C3-C10 cycloalkoxy, two of the remaining groups R6, R7, R8, R9 and R10 each independently represent hydrogen or deuterium; R14, R15 and R16 each independently represent hydrogen, (C1-C18 alkyl)carbonyl, (C1-C18 alkyl)oxycarbonyl, arylcarbonyl, aryl-(C1-C3 alkyl)carbonyl, (C3-C10 cycloalkyl)carbonyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C5-C7 cycloalkenyl)C1-C3 alkyl, (aryl)C1-C3 alkyl, (heteroaryl)C1-C3 alkyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, (C3-C7 cycloalkyl)C1-C3 alkyl, (C5-C7 cycloalkenyl)C1-C3 alkyl, (aryl)C1-C3 alkyl, (heteroaryl)C1-C3 alkyl, C1-C4 alkylsulfonyl, arylsulfonyl, (aryl)C1-C3 alkylsulfonyl, trimethylsilyl or t-butyldimethylsilyl, R19 independently represents hydroxy, (C1-C18 alkyl)carbonyloxy, (C1-C18 alkyl)oxycarbonyloxy, arylcarbonyloxy, aryl-(C1-C3 alkyl)carbonyloxy, (C3-C10 cycloalkyl)carbonyloxy, hydrogen, deuterium, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C10 cycloalkyl)C1-C3 alkyl, (C5-C7 cycloalkenyl)C1-C3 alkyl, (aryl)C1-C3 alkyl, (heteroaryl)C1-C3 alkyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C7 cycloalkoxy, C5-C7 cycloalkenyloxy, aryloxy, heteroaryloxy, (C3-C7 cycloalkyl)C1-C3 alkoxy, (C5-C7 cycloalkenyl)C1-C3 alkoxy, (aryl)C1-C3 alkoxy, (heteroaryl)C1-C3 alkoxy, aminocarbonyl, hydroxycarbonyl, (C1-C4 alkyl)aminocarbonyl, di-(C1-C3 alkyl)aminocarbonyl, (C1-C4 alkoxy)carbonyl, (aminocarbonyl)C1-C3 alkyl, (C1-C4 alkyl)aminocarbonyl-(C1-C3)alkyl, di-(C1-C3 alkyl)aminocarbonyl-(C1-C3)alkyl, (hydroxycarbonyl)C1-C3 alkyl, (C1-C4 alkoxy)carbonyl-(C1-C3)alkyl, (C3-C7 cycloalkoxy)C1-C3 alkyl, (C5-C7 cycloalkenyloxy)C1-C3 alkyl, (aryloxy)C1-C3 alkyl, (heteroaryloxy)C1-C3 alkyl, C1-C4 alkylsulfonyloxy, arylsulfonyloxy, (aryl)C1-C3 alkylsulfonyloxy, trimethylsilyloxy, t-butyldimethylsilyloxy, or cyano, and R21 is H, D, or hydroxy, 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, C1-C3 alkoxy and C1-C3 alkyl, and in cycloalkyl and cycloalkenyl groups or portions one or two methylene groups are optionally replaced independently of one another by NRa, O, S, CO, SO or SO2;
Ra independently represents hydrogen, C1-C4 alkyl or (C1-C4 alkyl)carbonyl, wherein alkyl groups or portions optionally may be partly or completely substituted with fluorine or deuterium.
-
-
26. The composition of claim 24, wherein G is G1.
-
27. The composition of claim 26, wherein G1 has the following structure:
-
28. The composition of claim 27, wherein R22 is -D.
-
29. The composition of claim 27, wherein R11 and R12 are both -D.
-
30. The composition of claim 27, wherein
each R1, R2, R3, R4 and R5 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 R6, R7, R8, R9, R10, and R19 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; andeach R14, R15, and R16 is, independently, hydrogen, deuterium, 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)RA, —
C(O)ORA, or —
C(O)NRARB, wherein each RA and RB is, independently, hydrogen, deuterium, or an optionally deuterated substituent selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, and optionally substituted aryl.
- 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;
-
31. The composition of claim 30, wherein R4 is Q and R8 is an optionally deuterated substituent selected from optionally substituted alkyl and optionally substituted alkoxy.
-
32. The composition of claim 24, wherein said compound is selected from the group consisting of:
-
33. The composition of claim 24, wherein said isotopic enrichment factor for deuterium is at least 500, 1000, or 3000.
-
34. The composition of claim 24, wherein said composition further comprises a pharmaceutically acceptable carrier, and wherein said compound of Formula (II) is present in an effective amount.
-
39. A method of treating or preventing a disease affected by inhibition of the sodium-dependent glucose transporter (SGLT), comprising administering the composition of claim 24.
-
40. The method of claim 39, 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.
-
25. The composition of claim 24, wherein one of R1, R2, R3, R4 and R5 is group Q;
-
41. A method of enriching the deuterium content of a diarylmethylene compound, wherein said method comprises
(a) combining: i. a diarylmethylene compound having a structure according to - View Dependent Claims (42, 43, 44, 45, 46, 47)
-
42. The method of claim 41, wherein the mixture of (ii) further comprises mineral oil.
-
43. The method of claim 41, wherein said phase-transfer catalyst is a tetraalkylammonium salt.
-
44. The method of claim 43, wherein said phase transfer catalyst is tetrabutylammonium bisulfate.
-
45. The method of claim 41, wherein 1-20 mol % of said phase transfer catalyst relative to said diarylmethylene compound is used in the mixture of (a).
-
46. The method of claim 41, wherein each R′
- and R″
is optionally substituted phenyl.
- and R″
-
47. The method of claim 46, wherein each R′
- and R″
has the following structure;
- and R″
-
42. The method of claim 41, wherein the mixture of (ii) further comprises mineral oil.
Specification
- Resources
Thank you for your request. You will receive a custom alert email when the Litigation Campaign Assessment is available.
×
-
Current AssigneeTheracos Inc
-
Original AssigneeTheracos Inc
-
InventorsFeng, Yan, Peng, Kun, Dong, Jiajia, LV, Binhua, Tang, Xinxing, Seed, Brian, Chen, Yuanwei, Xu, Min, Du, Jiyan, Roberge, Jacques Y., Xu, Baihua, Xu, Ge, Zhang, Lili
-
Granted Patent
-
Time in Patent OfficeDays
-
Field of Search
-
US Class Current514/460
-
CPC Class CodesA61K 2300/00 Mixtures or combinations of...A61K 31/35 having six-membered rings w...A61K 45/06 Mixtures of active ingredie...A61P 19/06 Antigout agents, e.g. antih...A61P 3/00 Drugs for disorders of the ...A61P 3/04 Anorexiants; Antiobesity ag...A61P 3/06 AntihyperlipidemicsA61P 3/10 for hyperglycaemia, e.g. an...A61P 43/00 Drugs for specific purposes...A61P 7/10 Antioedematous agents; Diur...A61P 9/04 Inotropic agents, i.e. stim...A61P 9/10 for treating ischaemic or a...A61P 9/12 AntihypertensivesC07D 309/10 Oxygen atoms