Peripherally restricted diphenyl purine derivatives
The invention provides compounds capable of acting as antagonists at cannabanoid receptors according to the following formula: Such compounds may be used to treat conditions for which the cannabinoid receptor system has been implicated, such as obesity, liver disease, diabetes, pain, and inflammation.
1. A compound according to the structure:
wherein:
each R 1 , R 2 , and R 3 is H or a substituent independently selected from the group consisting of halo, OH, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkoxy, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, NR 6 R 7 , NR 6 COR 7 , NR 6 CO 2 R 7 , CR 6 R 7 OR 8 , CONR 6 R 7 , CO 2 R 6 , CN, CF 3 , NO 2 , N 3 , C1-3 alkylthio, R 9 SO, R 9 SO 2 , CF 3 S, and CF 3 SO 2 ;
R 4 is H or C1-10 alkyl;
R 5 is:
or an optionally substituted piperidine ring, connected through a carbon atom;
or R 4 and R 5 taken together form a piperidine ring with the nitrogen atom to which they are attached, wherein the piperidine ring is substituted with a substituent selected from the group consisting of NR 6 SO 2 R 9 , NR 6 CONR 7 R 11 , NR 6 COR 15 , and NR 6 CO 2 R 7 and is optionally further substituted with one or more substituents independently selected from the group consisting of halo, OH, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkoxy, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkaryl, NR 6 R 7 , NR 6 COR 7 , CR 6 R 7 OR 8 , CO 2 R 6 , CN, CF 3 , NO 2 , N 3 , C1-3 alkylthio, R 9 SO, R 9 SO 2 , CF 3 S, and CF 3 SO 2 , NR 6 SO 2 R 9 , NR 6 CONR 7 R 11 , NR 6 CO 2 R 7 , and CONR 6 R 7 ;
or R 4 and R 5 taken together form an optionally substituted thiomorpholine 1,1-dioxide ring;
R 6 , R 7 , and R 8 are independently selected from H and optionally substituted C1-10 alkyl;
R 9 is H, optionally substituted C1-10 alkyl, NR 6 R 7 , or NR 6 COR 7 ;
R 10 is H or optionally substituted C1-10 alkyl;
R 11 is selected from the group consisting of H, optionally substituted C1-10 alkyl, and CR 6 R 7 CO 2 R 8 ;
R 15 is optionally substituted C1-12 alkyl, optionally substituted C1-12 heteroalkyl in the form of an alkyl group having at least one sulfur, oxygen, or nitrogen atom within the chain, optionally substituted C1-6alkyl(amino), or optionally substituted aryl;
L is an optionally substituted C1-15 alkyl group or C1-15 heteroalkyl group in the form of an alkyl group having at least one sulfur, oxygen, or nitrogen atom within the chain; and
m and n are each independently integers from 0 to 5;
wherein optionally substituted hereinabove refers to the optional presence of at least one substituent, selected from the group consisting of halo, C1-10 alkyl, C 1-10 halogenated alkyl, C2-4 alkenyl, C2-4 alkynyl; hydroxyl; amino; alkyl(amino); ureido; acetyl; C1-10 alkoxy; aryl; aralkyl, aryloxy; nitro; azido; cyano; mercapto; alkylthio; CR 6 R 7 OR 8 , CONR 6 R 7 , C(O)OR 6 , C(O)R 6 , SOR 9 , and SO 2 R 9 ;
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. The compound of claim 1 , according to the following structure:
wherein R 12 is selected from the group consisting of halo, OH, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkoxy, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkaryl, NR 6 R 7 , NR 6 COR 7 , CR 6 R 7 OR 8 , CO 2 R 6 , CN, CF 3 , NO 2 , N 3 , C1-3 alkylthio, R 9 SO, R 9 SO 2 , CF 3 S, and CF 3 SO 2 , NR 6 SO 2 R 9 , NR 6 CONR 7 R 11 , NR 6 CO 2 R 7 , and CONR 6 R 7 ;
R 13 is selected from the group consisting of NR 6 SO 2 R 9 , NR 6 CONR 7 R 11 , NR 6 COR 15 , and NR 6 CO 2 R 7 ; and
p is an integer from 0-9;
wherein optionally substituted hereinabove refers to the optional presence of at least one substitute selected from the group consisting of halo, C1-10 alkyl, C1-10 halogenated alkyl, C2-4alkenyl, C2-4 alkynl; hydroxyl; amino; alkyl(amino); ureido; acetyl; C1-10 alkoxy; aryl; aralkyl, aryloxy; nitro; azido; cyano; mercapto ; alkylthio; CR 6 R 7 OR 8 , CONR 6 R 7 , C(O)OR 6 , C(O)R 6, SOR 9 , and SO 2 R 9 ;
or a pharmaceutically acceptable salt or stereoisomer thereof.
3. The compound of claim 1 , according to the following structure:
wherein a and b are integers independently selected from 0 to 9;
or a pharmaceutically acceptable salt or stereoisomer thereof.
4. The compound of claim 1 , according to the following structure:
wherein R 12 is selected from the group consisting of halo, OH, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkoxy, optionally substituted C2-4 alkenyl, optionally substituent C2-4 alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkaryl, NR 6 R 7 , NR 6 COR 7 , CR 6 R 7 OR 8 , CO 2 R 6 , CN, CF 3 , NO 2 , N 3 , C1-3 alkylthio, R 9 SO, R 9 SO 2 , CF 3 S, and CF 3 SO 2 , NR 6 SO 2 R 9 , NR 6 CONR 7 R 11 , NR 6 CO 2 R 7 , and CONR 6 R 7 ; and
q is an integer from 0-9;
wherein optionally substituted hereinabove refers to the optional presence of at least one substituent selected from the group consisting of halo, C1-10 alkyl, C1-10 halogenated alkyl, C2-4alkenyl, C2-4 alkynl; hydroxyl; amino; alkyl(amino); ureido; acetyl; C1-10 alkoxy; aryl; aralkyl, aryloxy; nitro; azido; cyano; mercapto ; alkylthio; CR 6 R 7 OR 8 , CONR 6 R 7 , C(O)OR 6 , C(O)R 6, SOR 9 , and SO 2 R 9 ;
or a pharmaceutically acceptable salt or stereoisomer thereof.
5. The compound of claim 1 , according to the following structure:
wherein R 12 is selected from the group consisting of halo, OH, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkoxy, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkaryl, NR 6 R 7 , NR 6 COR 7 , CR 6 R 7 OR 8 , CO 2 R 6 , CN, CF 3 , NO 2 , N 3 , C1-3 alkylthio, R 9 SO, R 9 SO 2 , CF 3 S, CF 3 SO 2 , NR 6 SO 2 R 9 , NR 6 CONR 7 R 11 , NR 6 CO 2 R 7 , and CONR 6 R 7 ;
R 14 is selected from the group consisting of H, optionally substituted C1-10 alkyl, CR 6 R 7 OR 3 , CONR 6 R 7 , C(O)OR 6 , C(O)R 6 , SOR 9 , and SO 2 R 9 ; and
q is an integer from 0-9;
wherein optionally substituted hereinabove refers to the optional presence of at least one substituent selected from the group consisting of halo, C1-10 alkyl, C1-10 halogenated alkyl, C2-4alkenyl, C2-4 alkynl; hydroxyl; amino; alkyl(amino); ureido; acetyl; C1-10 alkoxy; aryl; aralkyl, aryloxy; nitro; azido; cyano; mercapto ; alkylthio; CR 6 R 7 OR 8 , CONR 6 R 7 , C(O)OR 6 , C(O)R 6, SOR 9 , and SO 2 R 9 ;
or a pharmaceutically acceptable salt or stereoisomer thereof.
6. The compound of claim 1 , according to the following structure:
wherein R 12 is selected from the group consisting of halo, OH, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkoxy, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkaryl, NR 6 R 7 , NR 6 COR 7 , CR 6 R 7 OR 3 , CO 2 R 6 , CN, CF 3 , NO 2 , N 3 , C1-3 alkylthio, R 9 SO, R 9 SO 2 , CF 3 S, CF 3 SO 2 , NR 6 SO 2 R 9 , NR 6 CONR 7 R 11 , NR 6 CO 2 R 7 , and CONR 6 R 7 ;
R 14 is selected from the group consisting of H, optionally substituted C1-10 alkyl, CR 6 R 7 OR 8 , CONR 6 R 7 , C(O)OR 6 , C(O)R 6 , SOR 9 , and SO 2 R 9 ; and
q is an integer from 0-9;
or a pharmaceutically acceptable salt or stereoisomer thereof.
7. The compound of claim 2 , wherein p is 1 and the R 12 substituent is attached to the same carbon as R 13 .
8. The compound of claim 2 , wherein R 15 comprises a cycloalkyl group.
9. The compound of claim 3 , wherein a and b are 1.
10. The compound of claim 1 , selected from the group consisting of:
N-{[4-({[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}methyl)cyclohexyl]methyl}methane sulfonamide;
N-{[4-({[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}methyl)cyclohexyl]methyl}amino sulfonamide;
4-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-1% 6 ,4-thiomorpholine-1,1-dione;
N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}methanesulfonamide;
tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}carbamate;
3-tert-butyl-1-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}urea;
1-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}-3-ethylurea;
tert-butyl 4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate;
8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(piperidin-4-yl)-9H-purin-6-amine;
4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-ethylpiperidine-1-carboxamide;
4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-(propan-2-yl)piperidine-1-carboxamide;
4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-propylpiperidine-1-carboxamide;
N-butyl-4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxamide;
1-(4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidin-1-yl)ethan-1-one;
8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(1-methanesulfonylpiperidin-4-yl)-9H-purin-6-amine;
tert-butyl (3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate;
tert-butyl (3S)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate;
8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-piperidin-3-yl]-9H-purin-6-amine;
8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine;
8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-1-methanesulfonylpiperidin-3-yl]-9H-purin-6-amine;
1-[(3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidin-1-yl]ethan-1-one;
(3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-ethylpiperidine-1-carboxamide;
8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-1-methanesulfonylpiperidin-3-yl]-9H-purin-6-amine;
1-[(3S)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidin-1-yl]ethan-1-one; and
(3S)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-ethylpiperidine-1-carboxamide.
11. The compound of claim 2 , wherein R 13 is NR 6 SO 2 R 9 .
12. The compound of claim 2 , wherein R 13 is NR 6 COR 15 .
13. The compound of claim 2 , wherein R 13 is NR 6 CO 2 R 7 .
14. The compound of claim 11 , wherein R 6 is H.
15. The compound of claim 11 , wherein R 9 is CH 3 .
16. The compound of claim 1 , wherein n is 1 and the R 1 substituent is at the para position and m is 1 and the R 2 substituent is at the ortho position.
17. The compound of claim 16 , wherein R 1 and R 2 are Cl.
18. The compound of claim 1 , wherein R 3 is H.
19. The compound of claim 1 , wherein R 4 is H.
20. The compound of claim 1 , wherein R 10 is H.
21. The compound of claim 1 , wherein R 9 is selected from CH 3 and NH 3 .
22. The compound of claim 2 , wherein R 12 is phenyl or substituted phenyl.
23. The compound of any of claim 1 , wherein the compound comprises one or more chiral centers.
24. A pharmaceutical composition, comprising a compound according to claim 1 and one or more pharmaceutically acceptable carriers.
25. A method for treating obesity, the method comprising administering a compound according to claim 1 to a subject in need of said treating.
26. The compound of claim 1 , wherein:
R 4 is H or C1-10 alkyl;
R 5 is:
or an optionally substituted piperidine ring, connected through a carbon atom;
or R 4 and R 5 taken together form a piperidine ring with the nitrogen atom to which they are attached, wherein the peperidine ring is substituted with a subsituent selected from the group consisting of NR 6 SO 2 R 9 , NR 6 CO 2 R 7 and is optionally further substituted with one or more substituents independently selected from the group consisting of halo, OH, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkoxy, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substitiuted aryl, optionally substituted aralkyl, optionally substituted alkaryl, NR 6 R 7 , NR 6 COR 7 , CR 6 R7OR8,CO 2 R 6 , CN, CF 3 , NO 2 , N 3 , C1-3alkylthio, R 9 SO, R 9 SO 2 , CF 3 SO 2 , NR 6 CONR 7 R 11 , NR 6 CO 2 R 7 , and CONR 6 R 7 ;
or R 4 and R 5 taken together form an optionally subustituted thiomorpholine 1,1-dioxide ring,
wherein optionally substituted hereinabove refers to the optional presence of at least one substituent, selected from the group consisting of halo, C1-10 alkyl, C1-10 halogenated alkyl, C2-4 alkenyl, C2-4 alkynyl; hydroxyl; amino; alkyl(amino); ureido; acetyl; C1-10 alkoxy; aryl; aralkyl, aryloxy; nitro; azido; cyano; mercapto; alkylthio; CR 6 R 7 OR 8 , CONR 6 R 7 , C(O)OR 6 , SOR 9 , and SO 2 R 9 .