Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-12-22
2003-10-14
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S288000, C546S289000, C546S290000, C546S293000, C546S296000, C546S297000, C546S298000, C546S300000, C546S301000, C546S302000, C546S303000, C546S306000, C546S307000, C546S308000, C546S309000, C546S310000, C546S312000, C546S314000, C546S323000, C546S326000, C546S328000, C546S329000, C546S333000, C546S334000, C546S335000, C546S336000, C546S337000
Reexamination Certificate
active
06632823
ABSTRACT:
The present invention relates to compounds which potentiate neurotransmission by promoting the release of neurotransmitters such as acetylcholine, dopamine and norepinephrine. More particularly, the present invention relates to compounds that are capable of modulating acetylcholine receptors. Invention compounds are useful, for example, for treatment of dysfunction of the central and autonomic nervous systems (e.g. dementia, cognitive disorders, neurodegenerative disorders, extrapyramidal disorders, convulsive disorders, cardiovascular disorders, endocrine disorders, pain, eating disorders, affective disorders, drug abuse, and the like). Invention compounds are also expected to exhibit neuroprotective effects. In addition, the present invention relates to pharmaceutical compositions containing these compounds, as well as various uses therefor.
BACKGROUND OF THE INVENTION
By modulating neurotransmitter release (including dopamine, norepinephrine, acetylcholine and serotonin) from different brain regions, acetylcholine receptors are involved in the modulation of neuroendocrine function, respiration, mood, motor control and function, focus and attention, concentration, memory and cognition, and the mechanisms of substance abuse. Ligands for acetylcholine receptors have been demonstrated to have effects on attention, cognition, appetite, substance abuse, memory, extrapyramidal function, cardiovascular function, pain, gastrointestinal motility and function, as well as exhibiting neuroprotective effects. The distribution of acetylcholine receptors that bind nicotine, i.e., nicotinic acetylcholine receptors, is widespread in the brain, including the basal ganglia, limbic system, cerebral cortex and mid- and hind-brain nuclei. In the periphery, the distribution includes muscle, autonomic ganglia, the gastrointestinal tract and the cardiovascular system.
Acetylcholine receptors have been shown to be decreased, inter alia, in the brains of patients suffering from Alzheimer's disease or Parkinson's disease, diseases associated with dementia, motor dysfunction and cognitive impairment. Such correlations between acetylcholine receptors and nervous system disorders suggest that compounds that modulate acetylcholine receptors will have beneficial therapeutic effects for many human nervous system disorders. Thus, there is a continuing need for compounds which have the ability to modulate the activity of acetylcholine receptors. In response to such need, the present invention provides a new family of compounds which modulate acetylcholine receptors.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, we have discovered a novel class of substituted pyridine compounds (containing an ether, ester, amide, ketone or thioether functionality) that promote the release of ligands involved in neurotransmission. More particularly, compounds of the present invention are capable of modulating acetylcholine receptors.
The compounds of the present invention are capable of displacing one or more acetylcholine receptor ligands, e.g.,
3
H-nicotine, from mammalian neuronal membrane binding sites. In addition, invention compounds display activity in cell lines which express recombinant acetylcholine receptors. It can readily be seen, therefore, that invention compounds may act as agonists, partial agonists, antagonists or allosteric modulators of acetylcholine receptors. Therapeutic indications for compounds with activity at acetylcholine receptors include diseases of the central nervous system such as Alzheimer's disease and other diseases involving memory loss and/or dementia (including AIDS dementia); cognitive dysfunction (including disorders of attention, focus and concentration), disorders of extrapyramidal motor function such as Parkinson's disease, progressive supramuscular palsy, Huntington's disease, Gilles de la Tourette syndrome and tardive dyskinesia; mood and emotional disorders such as depression, anxiety and psychosis; substance abuse including withdrawal symptoms and substitution therapy; neurocrine disorders and dysregulation of food intake, including bulimia and anorexia; disorders or nociception and control of pain; autonomic disorders including dysfunction of gastrointestinal motility and function such as inflammatory bowel disease, irritable bowel syndrome, diarrhea, constipation, gastric acid secretion and ulcers; phaeochromocytoma, cardiovascular dysfunction including hypertension and cardiac arrhythmias, as well as co-medication uses in surgical applications. Compounds with activity at acetylcholine receptors have also been shown to have neuroprotective effects.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided methods of modulating the activity of acetylcholine receptors. As employed herein, the phrase “modulating the activity of acetylcholine receptors” refers to a variety of therapeutic applications, such as the treatment of Alzheimer's disease and other disorders involving memory loss and/or dementia (including AIDS dementia); cognitive dysfunction (including disorders of attention, focus and concentration), disorders of extrapyramidal motor function such as Parkinson's disease, progressive supramuscular palsy, Huntington's disease, Gilles de la Tourette syndrome and tardive dyskinesia; mood and emotional disorders such as depression, panic, anxiety and psychosis; substance abuse including withdrawal syndromes and substitution therapy; neuroendocrine disorders and dysregulation of food intake, including bulemia and anorexia; disorders of nociception and control of pain; neuroprotection; autonomic disorders including dysfunction of gastrointestinal motility and function such as inflammatory bowel disease, irritable bowel syndrome, diarrhea, constipation, gastric acid secretion and ulcers; pheochromocytoma; cardiovascular dysfunction including hypertension and cardiac arrhythmias, comedication in surgical procedures, and the like.
The compounds of the present invention are especially useful for the treatment of Alzheimer's disease as well as other types of dementia (including dementia associated with AIDS), Parkinson's disease, cognitive dysfunction (including disorders of attention, focus and concentration), attention deficit syndrome, affective disorders, and for the control of pain. Thus modulation of the activity of acetylcholine receptors present on or within the cells of a patient suffering from any of the above-described indications will impart a therapeutic effect.
Invention methods comprise contacting cell-associated acetylcholine receptors with a concentration of a compound of Formula Z sufficient to modulate the activity of said acetylcholine receptors, compounds having Formula Z being defined as follows:
or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof,
wherein:
A and B are independently selected from —N— or —C—, with the proviso that one of A and B is —N—;
each of R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from hydrogen, halogen, cyano, cyanomethyl, nitro, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, heterocyclic, substituted heterocyclic, trifluoromethyl, pentafluoroethyl, —OR
A
, —O—C(O)—R
A
, —O—C(O)—N(R
A
)
2
, —SR
A
, —NHC(O)R
A
or —NHSO
2
R
A
, wherein R
A
is selected from H, lower alkyl, substituted lower alkyl, aryl or substituted aryl, or —NR
B
R
B
, wherein each R
B
is independently selected from hydrogen or lower alkyl, such that when A is —N—, R
1
is absent and when B is —N—, R
3
is absent;
D is optionally present; and when D is present, D is selected from lower alkylene, substituted lower alkylene, cycloalkylene, substituted cycloalkylene, lower alkenylene, substituted lower alkenylene, or lower alkynylene;
E is optionally present; and when E is present, E is selected from —O—
Cosford Nicholas D. P.
McDonald Ian A.
Vernier Jean-Michel
Coleman Brenda
Merck & Co. , Inc.
Rose David L.
Rubin David
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