Arylpiperazine opioid receptor antagonists

1. An opioid receptor antagonist represented by the formula (I):

wherein

R is OH, OC 1-6 alkyl, C 2-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl substituted by one or more groups Y 1 , CH 2 -aryl wherein the aryl group is substituted by one or more groups Y 1 , OCOC 1-8 alkyl, COC 1-8 alkyl, CONH 2 , NHCHO, NH 2 , NHSO 2 C 1-8 alkyl, or NHCO 2 C 1-8 alkyl;

Y 3 is hydrogen, Br, Cl, F, CF 3 , NO 2 , OR 8 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 or CH 2 (CH 2 ) n Y 2 ;

R 1 , R 2 , R 3 and R 4 are each, independently, one of the following structures:

or R 1 and R 2 , R 2 and R 3 and/or R 3 and R 4 are bonded together to form a cyclo alkyl group or a bridged heterocyclic ring,

wherein at least one of R 1 , R 2 , R 3 and R 4 is other than hydrogen;

each Y 1 is, independently, hydrogen, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR 8 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , or CH 2 (CH 2 ) n Y 2 , or two adjacent Y 1 groups form a —O—CH 2 —O— or —O—CH 2 CH 2 —O— group;

each Y 2 is, independently, hydrogen, CF 3 , CO 2 R 9 , C 1-8 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , COCH 2 R 9 ,

each n is, independently, 0, 1, 2 or 3;

each o is, independently, 0, 1, 2 or 3;

each R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is, independently, hydrogen, C 1-8 alkyl, CH 2 -aryl wherein the aryl group is substituted by one or more substituents OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′;

each Y 2 ′ is, independently, hydrogen, CF 3 , or C 1-6 alkyl;

R 5 is

—CH 2 CH 2 —X—R 6 , or

R 6 is C 2-8 alkenyl, C 1-4 alkyl substituted C 4-8 cycloalkyl, C 1-4 alkyl substituted C 4-8 cycloalkenyl, or thiophene;

X is a single bond, —C(O)— or —CH(OR 15 )—;

R 15 hydrogen, C 1-6 alkyl, —(CH 2 ) q -phenyl or —C(O)—R 16 ;

R 16 is C 1-4 alkyl or —(CH 2 ) q -phenyl;

each q is, independently, 1, 2 or 3;

R 17 is hydrogen, C 1-8 alkyl, CO 2 C 1-8 alkylaryl substituted by one or more groups Y 1 , CH 2 -aryl substituted by one or more groups Y 1 , or CO 2 C 1-8 alkyl;

R 18 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 alkynyl, CH 2 CO 2 C 1-8 alkyl, CO 2 C 1-8 alkyl or CH 2 -aryl substituted by one or more groups Y 1 ;

R 19 is a group selected from the group consisting of structures (a)-(p):

Q is NR 21 , CH 2 , O, S, SO, or SO 2 ;

each Y 4 is, independently, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR 22 , CO 2 R 23 , C 1-6 alkyl, NR 24 R 25 , NHCOR 26 , NHCO 2 R 27 , CONR 28 R 29 , or CH 2 (CH 2 ) n Y 2 ,

or two adjacent Y 4 groups form a —O—CH 2 —O— or —O—CH 2 CH 2 —O— group;

p is 0, 1, 2, or 3;

R 20 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkenyl, CH 2 OR 30 , or CH 2 -aryl substituted by one or more substituents Y 1 ;

each R 21 is, independently, hydrogen, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 31 R 32 , NHCOR 33 , NHCO 2 R 34 , CONR 35 R 36 , CH 2 (CH 2 ) n Y 2 , or C(═NH)NR 37 R 38 ;

R 30 is hydrogen C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkenyl, CH 2 O 2 C 1-8 alkyl, CO 2 C 1-8 alkyl, or CH 2 -aryl substituted by one or more substituents Y 1 ;

R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 and R 38 are, independently, hydrogen, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′;

Z is N or S, wherein when Z is S, there is no R 18 ;

X 1 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, or C 2-8 alkynyl;

X 2 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, or C 2-8 alkynyl;

or X 1 and X 2 together form ═O, ═S, or ═NH;

or a pharmaceutically acceptable salt thereof.

2. The opioid receptor antagonist of claim 1 , wherein

R is OH, OC 1-3 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, aryl substituted by one or more groups Y 1 , CH 2 -aryl wherein the aryl group is substituted by one or more groups Y 1 , OCOC 1-4 alkyl, COC 1-4 alkyl, CONH 2 , NHCHO, NH 2 , NHSO 2 C 1-4 alkyl, or NHCO 2 C 1-4 alkyl; and

Y 3 is hydrogen, Br, Cl, F, CF 3 , NO 2 , OR 8 , CO 2 R 9 , C 1-3 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 or CH 2 (CH 2 ) n Y 2 .

3. The opioid receptor antagonist of claim 2 , wherein

R 1 , R 2 , R 3 and R 4 are each, independently, one of the following structures:

or R 1 and R 2 , R 2 and R 3 and/or R 3 and R 4 are bonded together to 5 to 7 membered alkyl group or a bridged heterocyclic ring,

wherein at least one of R 1 , R 2 , R 3 and R 4 is other than hydrogen.

4. The opioid receptor antagonist of claim 1 , wherein R is OH, OC 1-2 alkyl, C 1-2 alkyl, C 1-2 haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl substituted by one or more groups Y 1 , CH 2 -aryl wherein the aryl group is substituted by one or more groups Y 1 , COC 1-2 alkyl, CONH 2 , NHCHO, NH 2 , NHSO 2 C 1-2 alkyl, or NHCO 2 C 1-2 alkyl.

5. The opioid receptor antagonist of claim 1 , wherein R is OH, OCH 3 , OCF 3 , COCH 3 , OCOCH 3 , CONH 2 , NHCHO, NH 2 , NHSO 2 CH 3 , or NHCO 2 CH 3 .

6. The opioid receptor antagonist of claim 1 , wherein R is OH, OCH 3 , or OCF 3 .

7. The opioid receptor antagonist of claim 1 , wherein Y 3 is hydrogen.

8. The opioid receptor antagonist of claim 1 , wherein R 1 , R 2 , R 3 and R 4 are each, independently, one of the following structures:

or R 1 and R 2 , R 2 and R 3 and/or R 3 and R 4 are bonded together to 5 to 7 membered alkyl group or a bridged heterocyclic ring,

wherein at least one of R 1 , R 2 , R 3 and R 4 is other than hydrogen.

9. The opioid receptor antagonist of claim 1 , wherein R 1 , R 2 , R 3 and R 4 are each, independently, hydrogen, methyl or ethyl, wherein at least one of R 1 , R 2 , R 3 and R 4 is other than hydrogen.

10. The opioid receptor antagonist of claim 1 , wherein R 1 , R 2 , R 3 and R 4 are each, independently, hydrogen or methyl, wherein at least one of R 1 , R 2 , R 3 and R 4 is methyl.

11. The opioid receptor antagonist of claim 1 , wherein R 1 , R 2 , R 3 and R 4 are each, independently, hydrogen or methyl, wherein at least one of R 1 , R 2 , R 3 and R 4 is methyl.

12. The opioid receptor antagonist of claim 1 , wherein

R is OH, OCH 3 , or OCF 3 ;

Y 3 is hydrogen; and

R 1 , R 2 , R 3 and R 4 are each, independently, hydrogen, methyl or ethyl, wherein at least one of R 1 , R 7 , R 1 and R 4 is other than hydrogen; and

R 5 is —(CH 2 ) n -phenyl, wherein n is 3.

13. The opioid receptor antagonist of claim 1 , wherein R 2 is other than hydrogen as defined above.

14. The opioid receptor antagonist of claim 13 , wherein R 2 is C 1-8 alkyl.

15. The opioid receptor antagonist of claim 13 , wherein R 2 is methyl or ethyl.

16. The opioid receptor antagonist of claim 13 , wherein R 2 is methyl.

17. The opioid receptor antagonist of claim 1 , wherein R 5 is

wherein n is 0, 1, 2 or 3.

18. The opioid receptor antagonist of claim 1 , wherein R 5 is

wherein n is 2 or 3.

19. The opioid receptor antagonist of claim 1 , wherein R 5 is

wherein n is 1, 2 or 3.

20. The opioid receptor antagonist of claim 13 , wherein R 5 is

wherein n is 0, 1, 2 or 3.

21. The opioid receptor antagonist of claim 1 , wherein R 5 is —CH 2 CH 2 —X—R 6 .

22. The opioid receptor antagonist of claim 1 , wherein R 5 is

23. A pharmaceutical composition, comprising the opioid receptor antagonist of claim 1 and a pharmaceutically acceptable carrier.