Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-12-22
2001-02-27
Rotman, Alan L (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S336000, C514S339000, C514S341000, C514S357000, C546S283400, C546S275100, C546S272100, C546S277100, C546S334000
Reexamination Certificate
active
06194581
ABSTRACT:
The present invention relates to novel compounds which are capable of modulating acetylcholine receptors. Invention compounds are useful, for example, for treatment of dysfunction of the central or autonomic nervous systems including dementia, cognitive disorders, neurodegenerative disorders, extrapyramidal disorders, convulsive disorders, cardiovascular disorders, endocrine disorders, pain, gastrointestinal disorders, eating disorders, affective disorders, and drug abuse. In addition, the present invention relates to pharmaceutical compositions containing these compounds, as well as various uses therefor.
BACKGROUND OF THE INVENTION
By modulation of 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 and gastrointestinal motility and function. 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 can selectively 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 that the class of pyridine compounds defined herein are modulators of 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 cerebral membrane binding sites. 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 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; 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 cardia arrhythmias, as well as co-medication uses in surgical applications.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided compounds having the structure (Formula I):
wherein:
A is a 1, 2, 3, 4, 5 or 6 atom bridging species linking C
3
of the pyridine ring with N
&agr;
,
wherein A is selected from a straight chain or branched chain alkylene moiety having up to six atoms in the backbone thereof, or a substituted alkylene moiety, a straight chain or branched chain alkenylene moiety having up to six atoms in the backbone thereof, or a substituted alkenylene moiety, an alkynylene moiety having up to six atoms in the backbone thereof, or a substituted alkynylene moiety, —O—, —C(O)—, —C(S)—, —S—, —S(O)— and/or —S(O)
2
-containing alkylene moiety; provided, however, that any heteroatom contained in A is separated from N
&agr;
by at least three carbon atoms; and further provided that when A is a —C(O)— or —C(S)— containing alkylene moiety, at least one methylene unit intervenes between the —C(O)— or —C(S)— moiety of A and N
&agr;
; and further provided that N
&agr;
is not conjugated with an alkenyl or alkynyl moiety,
wherein A and B can optionally combine to form a monocyclic ring containing A, N
&agr;
and B, wherein at least one methylene unit intervenes between such ring and C
3
of the pyridine ring;
B is a 1, 2, 3 or 4 atom bridging species linking N
&agr;
with Z,
wherein B is selected from a straight chain or branched chain alkylene moiety having up to four atoms in the backbone thereof, or a substituted alkylene moiety, a straight chain or branched chain alkenylene moiety having up to four atoms in the backbone thereof, or a substituted alkenylene moiety, an alkynylene moiety having up to four atoms in the backbone thereof, or a substituted alkynylene moiety, —O—, —C(O)—, —C(S)—, —N
&bgr;
(R
&bgr;
)—, —S—, —S(O)— and/or —S(O)
2
-containing alkylene moiety, wherein R
&bgr;
is hydrogen or a lower alkyl moiety; provided, however, that any heteroatom contained in B is separated from N
&agr;
by at least 2 carbon atoms, and further provided that when B is a —C(O)— or —C(S)— containing alkylene moiety, at least one methylene unit intervenes between the —C(O)— or —C(S)— moiety and N
&agr;
; and further provided that N
&agr;
is not conjugated with an alkenyl or alkynyl moiety, and
wherein B and R
&agr;
can optionally combine to form a monocyclic ring containing B, R
&agr;
and N
&agr;
;
Z is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, cyano, cyanomethyl, carboxyl, carbamate, sulfonyl, sulfonamide, aryloxyalkyl, or —OR
Z
, wherein R
Z
is hydrogen, lower alkyl or aryl, or
Z is not present when A and B cooperate to form a ring containing A, N
&agr;
and B, or when R
&agr;
and B cooperate to form a ring containing B, R
&agr;
and N
&agr;
;
R
&agr;
is selected from hydrogen or lower alkyl; and
R
2
, R
4
, R
5
and R
6
are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, halogen, cyano, nitro;
—S(O)R′, —S(O)
2
R′, —S(O)
2
OR′ or —S(O)
2
NHR′, wherein each R′ is independently hydrogen, lower alkyl, alkenyl, alkynyl or aryl; provided, however, that when R
2
, R
4
, R
5
or R
6
is —S(O)R′, R′ is not hydrogen; and further provided that when R′ is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom;
—C(O)R″, wherein R″ is selected from hydrogen, alkyl, substituted alkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl
Cosford Nicholas D.
Vernier Jean-Michel
Desai Rita
Lee Shu M.
Merck & Co. , Inc.
Rose David L.
Rotman Alan L
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