Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-27
2003-09-30
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S261100, C514S303000, C514S320000, C514S321000, C514S323000, C514S324000, C544S264000, C546S113000, C546S197000, C546S199000, C546S201000, C546S202000
Reexamination Certificate
active
06627645
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds that affect cholinergic receptors, especially muscarinic receptors. The present invention provides compounds that are agonists of cholinergic receptors including muscarinic receptors, especially the m1 and m4 subtype of muscarinic receptors. The invention also provides methods of using the provided compounds for modulating conditions associated with cholinergic receptors, especially for treating or alleviating disease conditions associated with muscarinic receptors, e.g., m1 or m4 subtypes of receptors.
BACKGROUND OF THE INVENTION
Muscarinic cholinergic receptors mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems, gastrointestinal system, heart, endocrine glands, lungs, and other tissues. Muscarinic receptors play a central role in the central nervous system for higher cognitive functions, as well as in the peripheral parasympathetic nervous system. Five distinct muscarinic receptor subtypes have been identified, m1-m5. The m1 subtype is the predominant subtype found in the cerebral cortex and is believed to be involved in the control of cognitive functions; m2 is the predominant subtype found in heart and is believed to be involved in the control of heart rate; m3 is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation; m4 is present in brain and may be involved in locomotion; and m5, present in brain, may be involved in certain functions of the central nervous system associated with the dopaminergic system.
Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by loss of acetylcholine in the brain. This is believed to be the result of degeneration of cholinergic neurons in the basal forebrain, which innervate areas of the association cortex, and hippocampus, which is involved in higher processes.
Efforts to increase acetylcholine levels have focused on increasing levels of choline, the precursor for acetylcholine synthesis, and on blocking acetylcholine esterase (AChE), the enzyme that metabolizes acetylcholine. Administration of choline or phosphatidylcholine has not been very successful. AChE inhibitors have shown some therapeutic efficacy, but may cause cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, diarrhea, anorexia, weight loss, myopathy and depression. Gastrointestinal side effects have been observed in about a third of the patients treated. In addition, some AChE inhibitors, such as tacrine, have also been found to cause significant hepatotoxicity, with elevated liver transaminases observed in about 30% of patients. The adverse effects of AChE inhibitors have limited their clinical utility.
Known m1 muscarinic agonists such as arecoline have also been found to be weak agonists of m2 as well as m3 subtype and are not very effective in treating cognitive impairment, most likely because of dose-limiting side effects.
There is a need for compounds that increase acetylcholine signaling or effect in the brain. Specifically there is a need for muscarinic agonists that are active at various muscarinic receptor subtypes in the central and peripheral nervous system. Furthermore, there is a need for more highly selective muscarinic agonists, such as m1- or m4-selective agents, both as pharmacological tools and as therapeutic agents.
SUMMARY OF THE INVENTION
The present invention provides compounds that affect cholinergic, especially muscarinic, receptors that have agonist activity at the m1 or m4 subtype of muscarinic receptors, or both. The compounds of the invention are of the general formula (I):
wherein:
Z
1
is CR
1
or N, Z
2
is CR
2
or N, Z
3
is CR
3
or N, and Z
4
is CR
4
or N, where no more than two of Z
1
, Z
2
, Z
3
and Z
4
are N;
W
1
is O, S, or NR
5
, one of W
2
and W
3
is N or CR
6
, and the other of W
2
and W
3
is CG; W
1
is NG, W
2
is CR
5
or N, and W
3
is CR
6
or N; or W
1
and W
3
are N, and W
2
is NG;
G is of formula (II):
Y is O, S, CHOH, —NHC(O)—, —C(O)NH—, —C(O)—, —OC(O)—, —(O)CO—, —NR
7
—, —CH═N—, or absent;
p is 1, 2, 3, 4 or 5;
Z is CR
8
R
9
or absent;
each t is 1, 2, or 3;
each R
1
, R
2
, R
3
, and R
4
, independently, is H, amino, hydroxyl, halo, or straight- or branched-chain C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
heteroalkyl, C
1-6
haloalkyl, —CN, —CF
3
, —OR
11
, —COR
11
, —NO
2
, —SR
11
, —NHC(O)R
11
, —C(O)NR
12
R
13
, —NR
12
R
13
, —NR
11
C(O)NR
12
R
13
, —SO
2
NR
12
R
13
, —OC(O)R
11
, —O(CH
2
)
q
NR
12
R
13
, or —(CH
2
)
q
NR
12
R
13
, where q is an integer from 2 to 6, or R
1
and R
2
together form —NH—N═N— or R
3
and R
4
together form —NH—N═N—;
each R
5
, R
6
, and R
7
, independently, is H, C
1-6
alkyl; formyl; C
3-6
cycloalkyl; C
5-6
aryl, optionally substituted with halo or C
1-6
alkyl; or C
5-6
heteroaryl, optionally substituted with halo or C
1-6
alkyl;
each R
8
and R
9
, independently, is H or straight- or branched-chain C
1-8
alkyl;
R
10
is straight- or branched-chain C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkynyl, C
1-8
alkylidene, C
1-8
alkoxy, C
1-8
heteroalkyl, C
1-8
aminoalkyl, C
1-8
haloalkyl, C
1-8
alkoxycarbonyl, C
1-8
hydroxyalkoxy, C
1-8
hydroxyalkyl, —SH, C
1-8
alkylthio, —O—CH
2
—C
5-6
aryl, —C(O)—C
5-6
aryl substituted with C
1-3
alkyl or halo, C
5-6
aryl, C
5-6
cycloalkyl, C
5-6
heteroaryl, C
5-6
heterocycloalkyl, —NR
12
R
13
, —C(O)NR
12
R
13
, —NR
11
C(O)NR
12
R
13
, —CR
11
R
12
R
13
,—OC(O)R
11
, —(O)(CH
2
)
S
NR
12
R
13
or —(CH
2
)
S
NR
12
R
13
, s being an integer from 2 to 8;
R
10
′ is H, straight- or branched-chain C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkynyl, C
1-8
alkylidene, C
1-8
alkoxy, C
1-8
heteroalkyl, C
1-8
aminoalkyl, C
1-8
haloalkyl, C
1-8
alkoxycarbonyl, C
1-8
hydroxyalkoxy, C
1-8
hydroxyalkyl, or C
1-8
alkylthio;
each R
11
, independently, is H, straight- or branched-chain C
1-8
alkyl, C
2-8
alkenyl, C
2-8
alkynyl, C
2-8
heteroalkyl, C
2-8
aminoalkyl, C
2-8
haloalkyl, C
1-8
alkoxycarbonyl, C
2-8
hydroxyalkyl, —C(O)—C
5-6
aryl substituted with C
1-3
alkyl or halo, C
5-6
aryl, C
5-6
heteroaryl, C
5-6
cycloalkyl, C
5-6
heterocycloalkyl, —C(O)NR
12
R
13
, —CR
5
R
12
R
13
, —(CH
2
)
t
NR
12
R
13
, t is an integer from 2 to 8; and
each R
12
and R
13
, independently, is H, C
1-6
alkyl; C
3-6
cycloalkyl; C
5-6
aryl, optionally substituted with halo or C
1-6
alkyl; or C
5-6
heteroaryl, optionally substituted with halo or C
1-6
alkyl; or R
12
and R
13
together form a cyclic structure;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
The present invention further provides pharmaceutical compositions including an effective amount of a compound of formula (I) or pharmaceutically acceptable salts, esters, or prodrugs thereof.
Also provided are methods of increasing an activity of a cholinergic receptor comprising contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of a compound of formula (I), as well as kits for performing the same. Preferably, the receptor is a muscarinic receptor of the m1 or m4 subtype. The receptor may be located in the central nervous system, peripheral nervous system, gastrointestinal system, heart, endocrine glands, or lungs; and the receptor may be a truncated, mutated, or modified cholinergic receptor.
Furthermore, the present invention relates to a method of activating a cholinergic receptor comprising contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of at least one compound of formula (I), as well as kits for performing the method. In a preferred embodiment, the compound is selective for the m1 or m4 muscarinic receptor subtype, or both. In another preferred embodiment, the compound has little or substantially no effect on m2 or m3 activity.
Another aspect of the present invention relates to a method of treating a disease condition associated with a cholin
Andersson Carl-Magnus A.
Friberg Bo Lennart M.
Skjaerbaek Niels
Spalding Tracy A.
Uldam Allan K.
Acadia Pharmaceuticals Inc.
Chang Ceila
Knobbe Martens Olson & Bear LLP
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