Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-07
2004-03-09
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S331000, C546S192000, C546S229000
Reexamination Certificate
active
06703406
ABSTRACT:
FIELD OF INVENTION
The present invention relates to the use of the 2,6-disubstituted piperidines, cis-2,6-di-trans-styrylpiperidine and trans-2,6-di-trans-styrylpiperidine, as modulators of nicotinic acetyl-choline receptor mediated neurotransmitter release, uptake and storage. The 2,6-disubstituted piperidines of the present invention can be used for the treatment of drug abuse and withdrawal therefrom, as well as for the treatment of eating disorders such as obesity, and other neuropathologies.
BACKGROUND OF THE INVENTION
Currently, drug discovery is focusing on neuronal nicotinic receptors (nAChRs) as novel targets for the development of therapeutic agents for a wide variety of central nervous system (CNS) diseases including, drug addiction, neuroendocrine, neuropsychiatric and neurological diseases, memory and learning disabilities, eating disorders, and the control of pain, as well as cardiovascular and gastrointestinal disorders. Nicotinic receptor antagonists have good potential as therapeutic agents, since they offer another means of modulating nicotinic receptor function. Nicotinic agonists rapidly desensitize these receptors, essentially inhibiting their function. Thus, inhibition of nicotinic receptor function may be the action, which confers clinical utility, indicating that nicotinic receptor antagonists could also be beneficial in the treatment of diseases for which nicotinic agonists are currently being developed. For example, schizophrenia and drug abuse have both been associated with hyperactivity of CNS dopaminergic systems, and inhibition of nicotinic receptors may be advantageous in reducing such hyperactivity. Furthermore, the availability of subtype-selective nicotinic receptor antagonists will be invaluable agents in both basic and clinical research, with regard to both the treatment and diagnosis of disease. Finally, subtype-selective antagonists will define the role of specific nicotinic receptor subtypes in both physiological function and disease states.
The action of many neuropharmacologically therapeutic agents involve the modulation of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) release, uptake and storage within its respective terminals in the central nervous system (CNS). Most neurotransmitters are stored in synaptic vesicles, which are prominent features of nerve terminals. Concentration into vesicles appears to be responsible for maintaining a ready supply of neurotransmitter available for neuronal exocytotic release into the synaptic cleft. Vesicles also serve the role of protecting the neurotransmitter from metabolic breakdown. One transport site on the vesicle membrane is the vesicular monoamine transporter-2 (VMAT2), whose role is to transport transmitter from the cytosol into the synaptic vesicle. Methoxytetrabenazine (MTBZ) has been used as a radiolabel to probe the interaction of drugs with VMAT2. Once the neurotransmitter is released from the terminal into the synaptic space, it interacts with postsynaptic receptors and subsequently is taken back up into the terminal via the plasma membrane transporter (e.g., the dopamine transporter, DAT and/or the serotonin transporter, SERT). Thus, transporter proteins modify the concentration of neurotransmitter in the cytosolic and vesicular storage pools, thereby having the ability to alter subsequent neurotransmission.
SUMMARY OF THE INVENTION
The present invention is directed to a method of treating an individual who suffers from drug dependence or withdrawal from drug dependence or who suffers from a disease or pathology of the CNS. The method comprises of administering to the individual an effective amount of either cis-2,6-di-trans-styrylpiperidine or trans-2,6-di-trans-styrylpiperidine or an analog thereof, including pharmaceutically acceptable salts of such compounds thereof. As used wherein, the term “effective amount” means an amount of a drug effective to reduce an individual's desire for a drug of abuse or for food, or for alleviating at least one of the symptoms of the disease or pathological symptom of CNS pathology.
The compound can be administered alone, combined with an excipient, or co-administered with a second drug having a similar or synergistic effect. The compound is administered subcutaneously, intramuscularly, intravenously, transdermally, orally, intranasally, intrapulmonary or rectally. The use of cis-2,6-di-trans-styrylpiperidine or trans-2,6-di-trans-styrylpiperidine and derivatives thereof in treating diseases or pathologies of the CNS is implicated. In particular, the treatment of dependencies on such drugs as cocaine, amphetamine, caffeine, nicotine, phencyclidine, opiates, barbiturates, benzodiazepines, cannabinoids, hallucinogens, and alcohol is implicated. Also, the treatment of eating disorders such as obesity is implicated.
In a preferred aspect of the invention, the method of treatment reduces an individual's desire for the drug of abuse or for food by at least one day, but it is also preferred that the treatment method further comprises administering behavior modification counseling to the individual. Although the compound of the present invention is contemplated primarily for the treatment of drug abuse and withdrawal and for eating disorders, other uses are also suggested by the studies discussed herein. Thus, cognitive disorders, brain trauma, memory loss, psychosis, sleep disorders, obsessive compulsive disorders, panic disorders, myasthenia gravis, Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Huntington's disease, attention deficit disorder, hyperkinetic syndrome, chronic nervous exhaustion, narcolepsy, pain, motion sickness and depression, and related conditions are considered to be susceptible to treatment with a compound of the present invention.
As shown by the results of the studies described herein, cis-2,6-di-trans-styrylpiperidine and trans-2,6-di-trans-styrylpiperidine are found to be effective in inhibiting uptake of extracellular 5-HT by serotonergic nerve terminals in the CNS, as well as in inhibiting the binding of [
3
H]MTBZ to vesicle membranes indicating an interaction with VMAT2. These analogs are also nicotinic receptor antagonists, inhibiting nicotine-evoked [
3
H]DA and [
3
H]NE release from rat brain slices. Either or both mechanisms can thereby alter the distribution of the intracellular neurotransmitter pools, and as a result, alter extracellular neurotransmitter concentrations.
DETAILED DESCRIPTION OF THE INVENTION
The 2,6-disubstituted piperidine analogs of the present invention include those contemplated by the following formula (I), without regard to chirality:
wherein:
R
1
represents a hydrogen, methyl, deuteromethyl (CD
3
), tritiomethyl (CT
3
), ethyl, or C
3
-C
7
straight chain or branched alkyl (preferably methyl or ethyl), C
3
-C
6
cycloalkyl, vinyl, allyl, C
4
-C
7
alkenyl (including cis and trans geometrical forms), benzyl, and phenylethyl.
R
2
and R
3
are each independently ortho-, meta-, orpara-substituted moieties, where the substituent is described as hydrogen, methyl, ethyl, or C
3
-C
7
straight chain or branched alkyl, C
3
-C
6
cycloalkyl, vinyl, allyl, C
4
-C
7
alkenyl (including cis and trans geometrical forms), benzyl, and phenylethyl. Further, the substitute moieties can be N-methylamino, N,N-dimethylamino, carboxylate, methylcarboxylate, ethylcarboxylate, propylcarboxylate, isopropylcarboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyloxy, cyano, aminomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfate, methylsulfate, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothiol, fluoro, chloro, bromo, iodo, trifluoromethyl, propargyl, nitro, carbamoyl, ureido, azido, isocyanate, thioisocyanate, hydroxylamino, and nitroso.
The above 2,6-substituted piperidino analogs are preferred in their 2,6-cis geometrical isomeric forms, or in their 2,6-trans geometr
Crooks Peter A.
Dwoskin Linda
Grinevich Vladimir P.
Miller Dennis Keith
Norrholm Seth Davin
Desai Rita
McDermott & Will & Emery
University of Kentucky Research Foundation
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