High affinity ligands for nociceptin receptor ORL-1

Details High affinity ligands for nociceptin receptor ORL-1 High affinity ligands for nociceptin receptor ORL-1

2002-05-23

2004-04-06

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S278000, C544S360000, C546S020000

Reexamination Certificate

active

06716846

ABSTRACT:

BACKGROUND
The nociceptin receptor ORL-1 has been shown to be involved with modulation of pain in animal models. ORL-1 (the nociceptin receptor) was discovered as an “orphan opioid-like receptor” i.e. a receptor whose ligand was unknown. The nociceptin receptor is a G protein coupled receptor. While highly related in structure to the three classical opioid receptors, i.e. the targets for traditional opioid analgesics, it is not activated by endogenous opioids. Similarly, endogenous opioids fail to activate the nociceptin receptor. Like the classical opioid receptors, the nociceptin receptor has a broad distribution in the central nervous system.
In late 1995, nociceptin was discovered and shown to be an endogenous peptide ligand that activates the nociceptin receptor. Data included in the initial publications suggested that nociceptin and its receptor are part of a newly discovered pathway involved in the perception of painful stimuli. Subsequent work from a number of laboratories has shown that nociceptin, when administered intraspinally to rodents, is an analgesic. The efficacy of nociceptin is similar to that of endogenous opioid peptides. Recent data has shown that nociceptin acts as an axiolytic when administered directly into the brain of rodents. When tested in standard animals models of anxiety, the efficacy of nociceptin is similar to that seen with classical benzodiazapine anxiolytics. These data suggest that a small molecule agonist of the nociceptin receptor could have significant analgesic or anxiolytic activity.
Additional recent data (Rizzi, et al,
Life Sci.,
64, (1999), p.157-163) has shown that the activation of nociceptin receptors in isolated guinea pig bronchus inhibits tachykinergic non adrenergic-non cholinergic contraction, indicating that nociceptin receptor agonists could be useful in the treatment of asthma. Also, it has been reported (Ciccocioppo et al,
Physchpharmacology,
141 (1999), p. 220-224) nociceptin reduces the rewarding properties of ethanol in msP alcohol preferring rats, suggesting that intervention of nociceptin could be useful in the treatment of alcohol abuse. In EP 856,514, 8-substituted 1,3,8-trazaspiro[4,5]decan-4-on derivatives were disclosed as agonists and/or antagonists of orphanin FQ (i.e., nociceptin) useful in the treatment of various disorders, including depression; 2-oxoimidazole derivatives disclosed in WO98/54168 were described as having similar utility. Earlier, benzimidazolyl piperidines were disclosed in U.S. Pat. No. 3,318,900 as having analgesic activity.
Potent analgesic agents such as traditional opioids, e.g. morphine, carry with them significant side-effects. Clinically relevant side-effects include tolerance, physical dependence, respiratory depression and a decrease in gastrointestinal motility. For many patients, particularly those subjected to chronic opioid therapy, i.e. cancer patients, these side effects limit the dose of opioid that can be administered. Clinical data suggests that more than one-third of cancer patients have pain which is poorly controlled by present agents. Data obtained with nociceptin suggest the potential for advantages over opioids. When administered chronically to rodents, nociceptin, in contrast to morphine, showed no addiction liability. Additionally, chronic morphine treatment did not lead to a “cross-tolerance” to nociceptin, suggesting that these agents act via distinct pathways.
In view of the current interest in pain relief, a welcome contribution to the art would be additional compounds useful for modifying the effect of nociceptin, a natural ligand to ORL-1 and therefore useful in the management of pain and anxiety. Such a contribution is provided by this invention.
SUMMARY OF THE INVENTION
Compounds of the present invention are represented by formula I
or a pharmaceutically acceptable salt or solvate thereof, wherein:
the dotted line represents an optional double bond;
X
1
is R
5
—(C
1
-C
12
)alkyl, R
6
—(C
3
-C
12
)cycloalkyl, R
7
-aryl, R
8
-heteroaryl or R
10
—(C
3
-C
7
)heterocycloalkyl;
X
2
is —CHO, —CN, —NHC(═NR
26
)NHR
26
, —CH(═NOR
26
), —NHOR
26
, R
7
-aryl, R
7
-aryl(C
1
-C
6
)alkyl, R
7
-aryl(C
1
-C
6
)alkenyl, R
7
-aryl(C
1
-C
6
)-alkynl, —(CH
2
)
v
OR
13
, —(CH
2
)
v
COOR
27
, —(CH
2
)
v
CONR
14
R
15
, —(CH
2
)
v
NR
21
R
22
or —(CH
2
)
v
NHC(O)R
21
, wherein v is zero, 1, 2 or 3 and wherein q is 1 to 3 and a is 1 or 2;
or X
1
is
 and X
2
is hydrogen;
or X
1
and X
2
together form a spiro group of the formula
m is 1 or 2;
n is 1, 2 or 3, provided that when n is 1, one of R
16
and R
17
is —C(O)R
28
;
p is 0 or 1;
Q is —CH
2
—, —O—, —S—, —SO—, —SO
2
— or —NR
17
—;
R
1
, R
2
, R
3
and R
4
are independently selected from the group consisting of hydrogen and (C
1
-C
6
)alkyl, or (R
1
and R
4
) or (R
2
and R
3
) or (R
1
and R
3
) or (R
2
and R
4
) together can form an alkylene bridge of 1 to 3 carbon atoms;
R
5
is 1 to 3 substituents independently selected from the group consisting of H, R
7
-aryl, R
6
—(C
3
-C
12
)cycloalkyl, R
8
-heteroaryl, R
10
—(C
3
-C
7
) heterocycloalkyl, —NR
19
R
20
, —OR
13
and —S(O)
0-2
R
13
;
R
6
is 1 to 3 substituents independently selected from the group consisting of H, (C
1
-C
6
)alkyl, R
7
-aryl, —NR
19
R
20
, —OR
13
and —SR
13
;
R
7
is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C
1
-C
6
)alkyl, R
25
-aryl, (C
3
-C
12
)cycloalkyl, —CN, —CF
3
, —OR
19
, —(C
1
-C
6
)alkyl—OR
19
, —OCF
3
, —NR
19
R
20
, —(C
1
-C
6
)alkyl-NR
19
R
20
, —NHSO
2
R
19
, —SO
2
N(R
26
)
2
, —SO
2
R
19
, —SOR
19
, —SR
19
, —NO
2
, —CONR
19
R
20
, —NR
20
COR
19
, —COR
19
, —COCF
3
, —OCOR
19
, —OCO
2
R
19
, —COOR
19
, —(C
1
-C
6
)alkyl-NHCOOC(CH
3
)
3
, —(C
1
-C
6
)alkyl-NHCOCF
3
, —(C
1
-C
6
)alkyl-NHSO
2
—(C
1
-C
6
)alkyl, —(C
1
-C
6
)alkyl-NHCONH—(C
1
-C
6
)alkyl or
 wherein f is 0 to 6; or R
7
substituents on adjacent ring carbon atoms may together form a methylenedioxy or ethylenedioxy ring;
R
8
is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (C
1
-C
6
)alkyl, R
25
-aryl, (C
3
-C
12
)cycloalkyl, —CN, —CF
3
, —OR
19
, —(C
1
-C
6
)alkyl-OR
19
, —OCF
3
, —NR
19
R
20
, —(C
1
-C
6
)alkyl-NR
19
R
20
, —NHSO
2
R
19
, —SO
2
N(R
26
)
2
, —NO
2
, —CONR
19
R
20
, —NR
20
COR
19
, —COR
19
, —OCOR
19
, —OCO
2
R
19
and —COOR
19
;
R
9
is hydrogen, (C
1
-C
6
)alkyl, halo, —OR
19
, —NR
19
R
20
, —NHCN, —SR
19
or —(C
1
-C
6
)alkyl-NR
19
R
20
;
R
10
is H, (C
1
-C
6
)alkyl, —OR
19
, —(C
1
-C
6
)alkyl-OR
19
, —NR
19
R
20
or —(C
1
-C
6
)alkyl-NR
19
R
20
;
R
11
is independently selected from the group consisting of H, R
5
—(C
1
-C
6
)alkyl, R
6
—(C
3
-C
12
)cycloalkyl, —(C
1
-C
6
)alkyl(C
3
-C
12
)cycloalkyl, —(C
1
-C
6
)alkyl-OR
19
, —(C
1
-C
6
)alkyl-NR
19
R
20
and
 wherein q and a are as defined above;
R
12
is H, (C
1
-C
6
)alkyl, halo, —NO
2
, —CF
3
, —OCF
3
, —OR
19
, —(C
1
-C
6
)alkyl-OR
19
, —NR
19
R
20
or —(C
1
-C
6
)alkyl-NR
19
R
20
;
R
13
is H, (C
1
-C
6
)alkyl, R
7
-aryl, —(C
1
-C
6
)alkyl-OR
19
, —(C
1
-C
6
)alkyl-NR
19
R
20
; —(C
1
-C
6
)alkyl-SR
19
; or aryl (C
1
-C
6
) alkyl;
R
14
and R
15
are independently selected from the group consisting of H, R
5
—(C
1
-C
6
)alkyl, R
7
-aryl and
 wherein q and a are as defined above;
R
16
and R
17
are independently selected from the group consisting of hydrogen, R
5
—(C
1
-C
6
)alkyl, R
7
-aryl, (C
3
-C
12
)cycloalkyl, R
8
-heteroaryl, R
8
-heteroaryl(C
1
-C
6
)alkyl, —C(O)R
28
, —(C
1
-C
6
)alkyl(C
3
-C
7
)-heterocycloalkyl, —(C
1
-C
6
)alkyl-OR
19
and —(C
1
-C
6
)alkyl-SR
19
;
R
19
and R
20
are independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
12
)cycloalkyl, aryl and aryl(C
1
-C
6
)alkyl;
R
21
and R
22
are independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
12
)cycloalkyl, (C
3
-C
12
)cycloalkyl(C
1
-C
6
)alkyl, (C
3
-C
7
)heterocycloalkyl, —(C
1
-C
6
)alkyl(C
3
-C
7
)-heterocycloalkyl, R
7
-aryl, R
7
-aryl(C
1
-C
6
)alkyl, R
8
-heteroaryl(C
1
-C
12
)alkyl, —(C
1
-C
6
)alkyl-OR
1

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