US2012178781A1PendingUtilityA1
Kappa opioid receptor ligands
Est. expiryFeb 17, 2025(expired)· nominal 20-yr term from priority
A61P 37/02A61P 43/00A61P 9/12A61P 37/06A61P 37/08A61P 9/10A61P 25/16A61P 31/12A61P 25/18A61P 3/04A61P 25/30A61P 25/32A61P 25/06A61P 25/24A61P 25/36A61P 25/08A61P 25/04A61P 25/00C07D 211/22A61K 31/53A61K 31/4545A61K 31/445C07D 405/12A61P 1/12A61K 31/506A61P 11/14C07D 409/12A61P 13/00A61P 19/02
51
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Kappa opioid receptor antagonists are provided that yield significant improvements in functional binding assays to kappa opioid receptors, and the use of these antagonists in treatment of disease states that are ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions.
Claims
exact text as granted — not AI-modified1 - 21 . (canceled)
22 . A kappa opioid receptor antagonist represented by formula (I):
wherein
G is H, OH, OCOC 1-8 alkyl, CONH 2 , NHCHO, NH 2 , NHSO 2 C 1-8 alkyl, or NHCO 2 C 1-8 alkyl;
R 1 is C 1-8 alkyl or one of the following structures:
Y 1 is H, 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 ;
Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;
Y 3 is H, 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 ;
R 2 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;
R 3 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;
wherein R 2 and R 3 may be bonded together to form a C 2-8 alkyl group;
R 4 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;
Z is O or S;
n is 0, 1, 2 or 3;
R 6 is a group selected from the group consisting of structures (a)-(p):
Q is O, S, SO or SO 2 ;
X 1 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl;
X 2 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl,
or X 1 and X 2 together form ═O, ═S, or ═NH;
R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , CH 2 (CH 2 ) n Y 2 , or C(═NH)NR 16 R 17 ,
R 8 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 9 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 10 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 11 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 12 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 13 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 14 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 15 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 16 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl; and
R 17 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl,
or a pharmaceutically acceptable salt thereof.
23 . The kappa opioid receptor antagonist of claim 22 , wherein
Y 3 is H; and R 2 and R 3 are each, independently, H, C 1-8 alkyl, C 3-8 alkynyl, C 3-8 alkynyl, or CH 2 -aryl substituted by one or more substituents Y 1 .
24 . The kappa opioid receptor antagonist of claim 22 , wherein
R 1 is C 1-8 alkyl, or one of the following structures:
Y 3 is H;
R 2 and R 3 are each, independently, H or C 1-8 alkyl, wherein R 2 and R 3 cannot both be H at the same time; and
R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .
25 . The kappa opioid receptor antagonist of claim 22 , wherein
R 1 is C 1-8 alkyl; Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ; Y 3 is H; R 2 and R 3 are each, independently, H or methyl, wherein R 2 and R 3 cannot both be H at the same time; R 4 is H, C 1-8 alkyl, CO 2 C 1-8 alkyl, or CH 2 -aryl substituted by one or more substituents Y 1 and the stereocenter adjacent to R 4 is in an (S) configuration; R 6 is a group having a formula selected from the group consisting of structures (d)-(p); and R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .
26 . The kappa opioid receptor antagonist of claim 22 , wherein
R 1 is methyl, Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCO 2 R 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ; Y 3 is H; R 2 and R 3 are each H or methyl, such that when R 2 is H, R 3 is methyl and vice versa; R 4 is C 1-8 alkyl, or CO 2 C 1-8 alkyl, and the stereocenter adjacent to R 4 has a configuration of (S); and R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , or CH 2 (CH 2 ) n Y 2 .
27 . The kappa opioid receptor antagonist of claim 22 , which is in the form of a pharmaceutically acceptable salt.
28 . The kappa opioid receptor antagonist of claim 22 , wherein R 6 is structure (a), (b) or (c).
29 . The kappa opioid receptor antagonist of claim 22 , wherein R 6 is one of (d)-(p).
30 . The kappa opioid receptor antagonist of claim 22 , which is represented by the formula:
wherein Q is defined in claim 22 .
31 . A pharmaceutical composition comprising an effective amount of a kappa opioid receptor antagonist of claim 22 and a physiologically acceptable carrier.
32 . A kappa opioid receptor antagonist represented by formula (I):
wherein
G is H, OH, OCOC 1-8 alkyl, CONH 2 , NHCHO, NH 2 , NHSO 2 C 1-8 alkyl, or NHCO 2 C 1-8 alkyl;
R 1 is C 1-8 alkyl or one of the following structures:
Y 1 , is H, 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 ;
Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;
Y 3 is H, 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 ;
R 2 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;
R 3 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;
wherein R 2 and R 3 may be bonded together to form a C 2-8 alkyl group;
R 4 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;
Z is O or S;
n is 0, 1, 2 or 3;
R 6 is a group selected from the group consisting of structures (d)-(p):
Q is CH 2 ;
X 1 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl;
X 2 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl;
or X 1 and X 2 together form ═O, ═S, or ═NH;
R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , CH 2 (CH 2 ) n Y 2 , or C(═NH)NR 16 R 17 ,
R 8 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 9 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 10 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 11 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 12 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 13 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 14 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 15 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 16 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl; and
R 17 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl,
or a pharmaceutically acceptable salt thereof.
33 . The kappa opioid receptor antagonist of claim 32 , wherein
Y 3 is H; and R 2 and R 3 are each, independently, H, C 1-8 alkyl, C 3-8 alkynyl, C 3-8 alkynyl, or CH 2 -aryl substituted by one or more substituents Y 1 .
34 . The kappa opioid receptor antagonist of claim 32 , wherein
R 1 is C 1-8 alkyl, or one of the following structures:
Y 3 is H;
R 2 and R 3 are each, independently, H or C 1-8 alkyl, wherein R 2 and R 3 cannot both be H at the same time; and
R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .
35 . The kappa opioid receptor antagonist of claim 32 , wherein
R 1 is C 1-8 alkyl; Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ; Y 3 is H; R 2 and R 3 are each, independently, H or methyl, wherein R 2 and R 3 cannot both be H at the same time; R 4 is H, C 1-8 alkyl, CO 2 C 1-8 alkyl, or CH 2 -aryl substituted by one or more substituents Y 1 and the stereocenter adjacent to R 4 is in an (S) configuration; R 6 is a group having a formula selected from the group consisting of structures (d)-(p); and R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .
36 . The kappa opioid receptor antagonist of claim 32 , wherein
R 1 is methyl, Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCO 2 R 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ; Y 3 is H; R 2 and R 3 are each H or methyl, such that when R 2 is H, R 3 is methyl and vice versa; R 4 is C 1-5 alkyl, or CO 2 C 1-8 alkyl, and the stereocenter adjacent to R 4 has a configuration of (S); and R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , or CH 2 (CH 2 ) n Y 2 .
37 . The kappa opioid receptor antagonist of claim 32 , wherein R 6 is structure (d), (e), (f) or (g).
38 . The kappa opioid receptor antagonist of claim 32 , wherein R 6 is one of (h)-(p).
39 . A pharmaceutical composition comprising an effective amount of a kappa opioid receptor antagonist of claim 32 and a physiologically acceptable carrier.
40 . A method of binding a kappa opioid receptor in a subject in need thereof, comprising administering to the subject an effective amount of the kappa opioid receptor antagonist represented by the formula (I):
wherein
G is H, OH, OCOC 1-8 alkyl, CONH 2 , NHCHO, NH 2 , NHSO 2 C 1-8 alkyl, or NHCO 2 C 1-8 alkyl;
R 1 is C 1-8 alkyl or one of the following structures:
Y 1 is H, 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 ;
Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;
Y 3 is H, 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 ;
R 2 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;
R 3 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;
wherein R 2 and R 3 may be bonded together to form a C 2-8 alkyl group;
R 4 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;
Z is N, O or S, wherein when Z is S or O there is no R 5 ;
R 5 is H, C 1-8 alkyl, C 3-8 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 ;
n is 0, 1, 2 or 3;
R 6 is a group selected from the group consisting of structures (a)-(p):
Q is O, S, SO or SO 2 ;
X 1 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl;
X 2 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl,
or X 1 and X 2 together form ═O, ═S, or ═NH;
R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , CH 2 (CH 2 ) n Y 2 , or C(═NH)NR 16 R 17 ,
R 8 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 9 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 10 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 11 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 3-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 12 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 13 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 14 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 15 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl;
R 16 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl; and
R 17 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′, wherein Y 2 ′ is H, CF 3 , or C 1-6 alkyl,
or a pharmaceutically acceptable salt thereof.
41 . The method of claim 40 , wherein administration of the compound provides an effect in the subject selected from the group consisting of cytostatic, antimigraine, immunomodulator, immunosuppressive, antiarthritic, antiallergic, virucidal, anti-diarrheal, antipsychotic, antischizophrenic, antidepressant, uropathic, antitussive, antiaddictive, anti-smoking, hypotensive agents, treating and/or preventing paralysis resulting from traumatic ischemia, general neuroprotection against ischemic trauma, anti-diuretic, stimulant, anti-convulsants, and anti-obesity.
42 . The method of claim 40 , wherein the subject has a disease state selected from the group consisting of opiate addiction, cocaine addiction, nicotine addiction and ethanol addiction.
43 . The method of claim 40 , wherein
Y 3 is H; and R 2 and R 3 are each, independently, H, C 1-8 alkyl, C 3-8 alkynyl, C 3-8 alkynyl, or CH 2 -aryl substituted by one or more substituents Y 1 .
44 . The method of claim 40 , wherein
R 1 is C 1-8 alkyl, or one of the following structures:
Y 3 is H;
R 2 and R 3 are each, independently, H or C 1-8 alkyl, wherein R 2 and R 3 cannot both be H at the same time; and
R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .
45 . The method of claim 40 , wherein
R 1 is C 1-8 alkyl; Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ; Y 3 is H; R 2 and R 3 are each, independently, H or methyl, wherein R 2 and R 3 cannot both be H at the same time; R 4 is H, C 1-8 alkyl, CO 2 C 1-8 alkyl, or CH 2 -aryl substituted by one or more substituents Y 1 and the stereocenter adjacent to R 4 is in an (S) configuration; R 5 is H, C 1-8 alkyl, or CH 2 CO 2 C 1-8 alkyl; R 6 is a group having a formula selected from the group consisting of structures (d)-(p); and R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .
46 . The method of claim 40 , wherein
R 1 is methyl, Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCO 2 R 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ; Y 3 is H; R 2 and R 3 are each H or methyl, such that when R 2 is H, R 3 is methyl and vice versa; R 4 is C 1-8 alkyl, or CO 2 C 1-8 alkyl, and the stereocenter adjacent to R 4 has a configuration of (S); R 5 is H; and R 7 is H, C 1-8 alkyl, CH 2 aryl substituted by one or more substituents Y 1 , or CH 2 (CH 2 ) n Y 2 .
47 . The method of claim 40 , which is in the form of a pharmaceutically acceptable salt.
48 . The method of claim 40 , wherein R 6 is structure (a), (b), (c) or (d).
49 . The method of claim 40 , wherein R 6 is one of (e)-(p).
50 . The method of claim 40 , which is represented by the formula:
wherein Q is defined in claim 40 .Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.