Cannabinoid receptor ligands
View Patent ↗There are disclosed compounds of the formula a prodrug thereof, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound or of said prodrug; which exhibit anti-inflammatory and immunodulatory activity. Also disclosed are pharmaceutical compositions containing said compounds and methods of using the compounds for the treatment of various diseases and conditions.
1. A compound of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein:
R 1 is H, alkyl, haloC 1 -C 6 alkyl, cycloalkyl, cycloalkylNH—, arylalkyl, heterocycloalkyl, heteroaryl, N(R 2 ) 2 , or NR 2 aryl, unsubstituted aryl or aryl substituted with one to three X;
R 2 is the same or different in each occurrence and is independently selected from H or C 1 -C 6 alkyl;
R 3 is H, C 1 -C 6 alkyl, Cl, F, CF 3 , OCF 2 H, OCF 3 , OH or C 1 -C 6 alkoxy;
R 4 is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cycloalkyl, alkenyl, aryl, benzyl, arylNH—, cycloalkylNH—, N(R 2 ) 2 , or NR 2 aryl, said alkyl, alkoxy, cycloalkyl, alkenyl, or aryl optionally substituted with one to three X;
R 5 is H or C 1 -C 6 alkyl;
R 6 is H or C 1 -C 6 alkyl; or
R 5 and R 6 taken together with the carbon atom to form a carbonyl group;
L 1 is —S(O 2 )—, —S(O)—, or —S—;
L 2 is —S(O 2 )—, —S(O)—, or —S—;
X is the same or different, and is independently selected from H, halogen, CF 3 , CN, OCF 2 H, OCF 2 CF 3 , OCF 3 , OR 2 , C 1 -C 6 alkyl, cycloalkyl, cycloalkoxy, C 1 -C 6 alkoxy, alkoxyC 1 -C 6 alkoxy, O-cycloalkyl, cycloalkylamino, cycloalkylalkoxy, heteroalkyl, —OSO 2 R 2 , —COOR 2 , —CON(R 2 ) 2 , NHR 2 , arylNH—, N(R 2 ) 2 , or NR 2 aryl;
Y is a covalent bond, —CH 2 —, —S(O 2 )—, or
Z is a covalent bond, —CH 2 —, —S(O 2 )— or
or
Y, R 1 , Z and R 2 can be taken together with the nitrogen atom to form a heterocycloalkyl; with the proviso that if Y is a covalent bond, R 1 cannot form a N—N bond with the nitrogen atom; and
n is an integer of 0 to 4,
with the proviso that, when R 1 ═R 2 ═H or lower alkyl, Y=Z=covalent bond, n=0 or R 3 at each occurrence is H, L 1 =L 2 =S or —S(O 2 )—, X=H, and R 4 is unsubstituted C 1 -C 6 alkyl or phenyl substituted once with —CON(H) 2 or —CON(Me) 2 , then R 5 and R 6 are each independently H or C 1 -C 6 alkyl.
2. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug;
wherein X and R 4 as shown in the table below:
X
R 4
A
—OCH 3
B
—OCH 3
C
—OCF 2 H
F
—OCH 3
G
—CH 3
I
—OCH 3
J
—OCF 3
L
Cl
O
Cl
Q
CH 3
Z
—OCH 3
AA
—OCH 3
C 3 H 7
AB
—CF 3
AC
—CF 3
AF
—CF 3
AI
—CF 3
AK
Cl
AQ
Cl
AU
Cl
AX
Cl
C 3 H 7
BA
—OCF 3
BB
—OCF 3
BC
—OCF 3
BG
—OCH 3
CB
—CH 3
CE
Cl
CW
OH
CX
OH
DA
—OCF 2 H
FR
H
FS
H
FT
H
FW
H
3. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug;
wherein X and R 4 are as shown in the table below:
X
R 4
R
—CF 3
S
Cl
W
Cl
AE
—CF 3
AG
—CF 3
AH
—CF 3
AR
Cl
AS
Cl
BD
—OCF 3
BJ
—OCH 3
BZ
—CH 3
CA
—CH 3
FY
H
FZ
H
GI
Cl
GJ
—OCH 3
GL
OH
GM
OCH(CH 3 ) 2
GN
.
4. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug;
wherein X, R 1 and R 4 as shown in the table below:
X
R 1
R 4
A
—OCH 3
—CH 3
C
—OCF 2 H
—CH 3
G
—CH 3
—CH 3
L
Cl
—CH 3
R
—CF 3
—CF 3
S
Cl
—CF 3
AB
—CF 3
—CH 3
AT
Cl
—N(CH 3 ) 2
BA
—OCF 3
—CH 3
BD
—OCF 3
—CF 3
BZ
—CH 3
—CF 3
FS
H
—CH 3
FY
H
—CF 3
XXX
—CF 3
XXXII
—CN
—CF 3
XXXIII
—NH 2
—CF 3
XXXIV
—CF 3
XXXIX
—CONH 2
—CF 3
XXXX
—OCH 3
—CF 3
XXXXI
—OH
—CF 3
XXXII
—CF 3
XXXIII
—CF 3
XXXIV
—CF 3
XXXXV
—CF 3
.
5. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —OCH 3 and R 1 is —CH 3 .
6. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —OCF 2 H and R 1 is —CH 3 .
7. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —CH 3 and R 1 is —CH 3 .
8. The compound according to claim 1 of the formula
a prodrug thereof or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is Cl and R 1 is —CH 3 .
9. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —CF 3 and R 1 is —CF 3 .
10. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is Cl and R 1 is —CF 3 .
11. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —CF 3 and R 1 is —CH 3 .
12. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is Cl and R 1 is —N(CH 3 ) 2 .
13. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —OCF 3 and R 1 is —CH 3 .
14. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —OCF 3 and R 1 is —CF 3 .
15. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —CH 3 and R 1 is —CF 3 .
16. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is H and R 1 is —CH 3 .
17. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is H and R 1 is —CF 3 .
18. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is cyclopropyl and R 1 is —CF 3 .
19. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is cyclopropyl and R 1 is CH 3 .
20. A pharmaceutical composition comprising an effective amount of a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, according to claim 1 and a pharmaceutically acceptable carrier.
21. A pharmaceutical composition comprising an effective amount of a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug, according to claim 3 and a pharmaceutically acceptable carrier.
22. A pharmaceutical composition made by combining a compound, a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of a compound or of said prodrug, of claim 1 and a pharmaceutically acceptable carrier therefor.
23. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, stereoisomer of the compound or of said prodrug; wherein X is —OCF 3 and R 1 is —CH 3 .
24. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —OCF 2 H and R 1 is —CH 3 .
25. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —CH 3 and R 1 is —CH 3 .
26. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is Cl and R 1 is —CH 3 .
27. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prod rug; wherein X is —CF 3 and R 1 is —CF 3 .
28. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is Cl and R 1 is —CF 3 .
29. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —CF 3 and R 1 is —CH 3 .
30. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is Cl and R 1 is —N(CH 3 ) 2 .
31. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —OCF 3 and R 1 is —CH 3 .
32. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —OCF 3 and R 1 is —CF 3 .
33. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is —CH 3 and R 1 is —CF 3 .
34. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is H and R 1 is —CH 3 .
35. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is H and R 1 is —CF 3 .
36. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is cyclopropyl and R 1 is —CF 3 .
37. The compound according to claim 1 of the formula
a prodrug thereof, or a pharmaceutically acceptable salt, or stereoisomer of the compound or of said prodrug; wherein X is cyclopropyl and R 1 is CH 3 .