Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-30
2003-01-07
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S084000, C546S085000, C546S088000
Reexamination Certificate
active
06503922
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to bridged nicotine analogs of N-octylnicotinium iodide (NONI) that have selective antagonist properties at &agr;3&bgr;2-containing nicotinic receptor subtypes and to a method of using such compounds to treat central nervous system pathologies. The present invention also relates to pharmaceutical compositions containing these compounds, as well as various uses thereof.
BACKGROUND OF THE INVENTION
Formula (I) below shows the structure of S-(−)-nicotine (NIC), which activates neuronal nicotinic receptors evoking release of dopamine (DA) from presynaptic terminals in the central nervous system (CNS). NIC is a legal substance of dependence that produces many of its effects on the CNS, some of which may be considered to be beneficial, e.g., mood elevation, arousal and learning and memory enhancement. NIC produces its effect by binding to a family of ligand-gated ion channels, stimulation by acetylcholine (ACh) or NIC causes the ion channel to open, and cations to flux with a resulting rapid (in msec) depolarization of the target cell.
Over the last 12 years, there has been a substantial increase in studies on brain nicotinic receptors. These nicotinic receptors are composed of four subunit domains: 2&agr;, &bgr;, &ggr; and &dgr; or &egr;. Neuronal nicotinic receptors are composed of only two subunits, &agr; and &bgr; and are believed to assemble with the general stoichiometry of 2&agr; and 3&bgr;. Eight subtypes of the &agr; subunit (&agr;2 to &agr;9) and three subtypes of the &bgr; unit (&bgr;2 to &bgr;4) are found in CNS. The most common nicotinic receptor species in the brain is composed of two &agr;4 and three &bgr;2 subunits, i.e., &agr;4&bgr;2. These subunits display different, but overlapping, patterns of expression in the brain.
For the most part, the actual subunit compositions and stoichiometries of nicotinic receptors in the brain remain to be elucidated. Thus, neuronal nicotinic receptor subtype diversity originates from differences in the amino acid sequence at the subunit level and from the multiple combinations of assemblies of subunits into functional receptor proteins afford wide diversity of pharmacological specificity.
In spite of the extensive diversity in neuronal nicotinic receptor messenger RNA expression, only a limited number of tools are available to study the pharmacology of native receptors. Radioligands are used in many such studies. [
3
H]NIC appears to label the same sites in the brain as [
3
H]ACh. It has been estimated that over 90% of [
3
H]NIC binding in the brain is due to association with a receptor that is composed of &agr;4 and &bgr;2 subunits. Also, nicotinic receptor subtypes can be studied using an assay such as NIC-evoked [
3
H]DA release from rat straital slices. Nicotinic receptors are located in the cell body and terminal areas of the nigrostriatal system. NIC facilitates DA release from striatal nerve terminals. Studies strongly suggest that the [
3
H]DA release assay is useful to probe the &agr;3&bgr;2-containing subtype of the nicotinic receptor.
The structural and functional diversity of CNS nicotinic receptors has stimulated a great deal of interest in developing novel, subtype-selective agonists. Some of these agonists are currently being evaluated in clinical trials for cognitive enhancement and neuroprotective effects potentially beneficial for diseases such as Alzheimer's and Parkinson's Disease. Surprisingly, little attention a has been focused on developing subtype-selective antagonists for neuronal nicotinic receptors.
A class pyridino N-substituted nicotine analogs having formula (II) below are known antagonists that inhibit nicotine evoked [
3
H]DA release from dopaminergic nerve terminals in the brain. The abbreviated nomenclature is given in parentheses.
These compounds are useful in the treatment of nicotine abuse, smoking cessation therapy, as an antidote for nicotine intoxication, treatment of cognitive disorders such as Alzheimer's disease and for the treatment of Parkinson's disease. The compounds and their method of use were the subject of U.S. Pat. No. 5,691,365, issued Nov. 25, 1997. The content of this patent is incorporated herein by reference.
The invention disclosed herein is directed to another new class of efficacious and subtype-selective nicotinic antagonists at nicotinic receptors in the CNS. These compounds comprise bridged nicotine analogs of NONI.
SUMMARY OF THE INVENTION
The present invention provides; for bridged nicotine analogs of N-octylnicotinium iodide (NONI) compounds having potent and selective antagonistic activity at neuronal nicotinic receptor subtypes. The compounds competitively inhibit CNS acting nicotinic receptor agonists that are acting as putative &agr;3&bgr;2 neuronal nicotinic receptor in the CNS.
A preferred embodiment of the invention provides for a method of antagonizing the nicotinic receptor comprising administering of a pharmaceutically effective amount of a compound of the invention.
Still another embodiment the invention provides a method for the treatment of psychostimulant abuse (including nicotine abuse, amphetamine abuse, methamphetamine abuse, alcohol abuse and cocaine abuse), as smoking cessation therapy, as an antidote for nicotine intoxication comprising administering of a pharmaceutically effective amount of a compound according to the invention, as a therapeutic agent for the treatment of pathologies of the GI tract, including irritable bowel syndrome, colitis and related disorders.
This invention further provides a method of treatment of CNS disorders associated with the alteration of normal neurotransmitter release in the brain, including conditions such as Alzheimer's disease as well as other types of dementia, Parkinson's disease, cognitive dysfunction (including disorders of attention, focus and concentration), attention deficit syndrome, affective disorders, mood and emotional disorders such as depression, panic anxiety and psychosis, Tourette's syndrome, schizophrenia, eating disorders and the control of pain comprising administering of a pharmaceutically effective amount of a compound according to the invention.
The above and other objects of the invention will become readily apparent to those of skill in the relevant art from the following detailed description and figures, wherein only the preferred embodiments of the invention are shown and described, simply by way of illustration of the best mode of carrying out the invention. As is readily recognized the invention is capable of modifications within the skill of the relevant art without departing from the spirit and scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides, novel bridged-ring compounds corresponding to the schematic structure formulas III and IV below:
wherein
A is a 1, 2 or 3 atom bridging species selected from straight chain or branched chain alkylene moiety having up to 3 atoms in the backbone thereof, or a substituted alkenylene moiety having up to 3 atoms in the backbone thereof, or a C(O), O, C(S), S, S(O) or S(O)
2
containing alkylene moiety, provided however, that any heteroatom contained in A is separated from N by at least one carbon atom;
B is a 1, 2 or 3 atom bridging species selected from straight chain or branched chain alkylene moiety having up to 3 atoms in the backbone thereof, or a substituted alkenylene moiety having up to 3 atoms in the backbone thereof, or a C(O), O, N(Y
1
), C(S), S, S(O) or S(O)
2
containing alkene moiety, wherein Y
1
is hydrogen or lower alkyl or aryl;
R
1
is selected from hydrogen, lower alkyl (e.g., C
1
-C
10
alkyl, preferably C
1
-C
6
alkyl, and more preferably methyl, ethyl, isopropyl or isobutyl) or an aromatic group-containing species;
R
2
is selected from hydrogen or lower alkyl;
R
3
, R
4
and R
5
are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl; alkenyl; substituted alkenyl; alkynyl; subst
Crooks Peter A.
Dwoskin Linda P.
Grinevich Vladimir P.
Xu Rui
Aulakh C. S.
McDermott & Will & Emery
University of Kentucky Research Foundation
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