Diaryl purine derivatives with improved bioavailability
This disclosure is directed to various compounds and methods of preparation of improved compounds that are capable of functioning as cannabinoid receptor 1 (CB1) antagonists with reduced central nervous system (CNS) side effects. The application is also directed to pharmaceutical compositions containing one or more of these compounds, which may also contain one or more additional therapeutic agents. It is also directed to methods of treatment of various conditions that may be responsive to antagonism of the CB1 receptors, including, but not limited to, metabolic syndromes (including liver disease, obesity, and diabetes).
1. A compound represented by the Formula III:
or a pharmaceutically acceptable salt thereof, wherein each R 1 and R 2 is independently C 1-8 alkoxy, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-6 heterocycle, —CONR 5 R 6 , —COR 7 , cyano, H, halo, —NR 5 R 6 , —NR 8 COR 7 , —NR 8 CONR 5 R 6 , —NR 8 SO 2 R 7 , —NR 8 SO 2 NR 5 R 6 , —SO 2 NR 5 R 6 or —SO 2 R 7 ;
R 4 is C 1-8 alkoxy, C 1-8 alkyl, C 3-8 cycloalkyl, or H;
R 13 is —C(═NR 9 )R 12 , —C(═NR 9 )NR 10 R 11 , heteroaryl, NHR 15 or NR 15 R 19 ;
R 14 is aryl, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-6 heterocycle, heteroaryl or H; or R 13 and R 14 together make a 3-8 member ring;
R 15 is C 1-8 alkyl(heteroaryl), C 1-8 alkyl(heterocycle), —C(═NR 9 )NR 10 R 11 , —C(═NR 9 )R 12 , CONR 16 R 11 , —CON(R 11 )SO 2 R 12 , heteroaryl, heterocycle, or —SO 2 NR 16 R 11 ;
each R 5 , R 6 , R 8 R 10 , R 11 , and R 19 is independently aryl, C 1-8 alkyl, C 1-8 alkyl(aryl), C 1-8 alkyl(heteroaryl), C 1-8 alkyl(heterocycle), C 1-8 alkyl(C 3-8 cycloalkyl), C 3-8 cycloalkyl, H, heteroaryl or heterocycle; or R 5 and R 6 together make a 3-8 member ring which may be substituted with one or more heteroatoms; or R 5 and R 8 together make a 4-8 member ring which may be substituted with one or more heteroatoms; or R 10 and R 11 together make a 3-8 member ring which may be substituted with one or more heteroatoms; or R 11 and R 16 together make a 3-8 member ring which may be substituted with one or more heteroatoms;
each R 7 and R 12 is independently aryl, C 1-8 alkyl, C 1-8 alkyl(aryl), C 1-8 alkyl(heteroaryl), C 1-8 alkyl(heterocycle), C 1-8 alkyl(C 3-8 cycloalkyl), C 3-8 cycloalkyl, heteroaryl or heterocycle; or R 7 and R 8 together make a 4-8 member ring which may be substituted with one or more heteroatoms; or R 11 and R 12 together make a 4-8 member ring which may be substituted with one or more heteroatoms;
R 9 is C 1-8 alkoxy, C 1-8 alkyl, C 3-8 cycloalkyl, cyano, H, or hydroxyl;
R 16 and R 18 is independently aryl, C 1-8 alkyl(aryl), C 1-8 alkyl(heteroaryl), C 1-8 alkyl(heterocycle), heteroaryl or heterocycle;
R 17 is C 1-8 alkyl(heteroaryl), C 1-8 alkyl(heterocycle), heteroaryl or heterocycle; and
wherein n and m are independently integers from 0 to 5.
2. The compound of claim 1 , wherein R 4 is H.
3. The compound of claim 1 , wherein R 1 is at the meta and/or para positions.
4. The compound of claim 1 , wherein at least one R 2 is in the ortho position.
5. The compound of claim 1 , wherein R 1 is F, Cl, CF 3 , CN, OCF 3 or OCHF 2 .
6. The compound of claim 1 , wherein R 2 is F, Cl, CF 3 or Me.
7. The compound of claim 1 , wherein R 13 is NHR 15 or NR 15 R 19 .
8. The compound of claim 1 , wherein R 15 is —CONR 16 R 11 .
9. The compound of claim 1 , wherein R 15 is —C(═NR 9 )NR 10 R 11 or —C(═NR 9 )R 12 .
10. The compound of claim 1 , wherein R 10 is aryl, heteroaryl, C 1-8 alkyl, C 3-8 cycloalkyl, or C 1-6 alkyl(C 3-8 cycloalkyl).
11. The compound of claim 1 , wherein R 11 is H.
12. The compound of claim 1 , wherein R 14 is H.
13. The compound of claim 1 , wherein R 16 is aryl, C 1-8 alkyl(aryl), C 1-8 alkyl(heteroaryl) or heteroaryl.
14. The compound of claim 1 , wherein n and m are independently 1 or 2.
15. A pharmaceutical composition, comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers.
16. A method for treating or delaying the progression of disorders associated with fatty livers a subject in need thereof that are alleviated by antagonizing the CB1 receptor, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 so as to treat or delay the progression of the disorder involving fatty livers in the subject.
17. The method of claim 16 , wherein the disorder is diabetes, dyslipidemia, or obesity.
18. The method of claim 17 , wherein the disorder is fatty liver disease.
19. The method of claim 18 , wherein the fatty liver disease is alcoholic steatosis or nonalcoholic steatohepatitis (NASH).
20. The method of claim 16 , wherein the compound is formulated or co-administered with a second agent wherein the second agent is an anti-depressant, a blood pressure lowering agent, or a lipid lowering agent.