Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-28
2002-09-24
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S194000, C546S236000
Reexamination Certificate
active
06455543
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to lobeline analogs, specifically cis-2,6-disubstituted piperidines, and their method of use in the treatment of diseases and pathologies of the central nervous system (CNS), the treatment of drug abuse and withdrawal therefrom as well as to the treatment of eating disorders such as obesity.
BACKGROUND OF THE INVENTION
Alpha-Lobeline (lobeline), a lipophilic nonpyridino, alkaloidal constituent of Indian tobacco, is a major alkaloid in a family of structurally-related compounds found in Lobelia inflata. Lobeline has been reported to have many nicotine like effects, including tachycardia and hypertension (Olin et al., 1995), hyperalgesia (Hamann et al., 1994) and improvement of learning and memory (Decker et al., 1993). Lobeline has high affinity for nicotinic receptors (Lippiello et al., 1986; Broussolle et al., 1989). However, no obvious structural resemblance of lobeline to nicotine is apparent and structure function relationships between S(-)-nicotine and lobeline do not suggest a common pharmacophore (Barlow et al., 1989). Also, differential effects of lobeline and nicotine suggest that these drugs may not be active through a common CNS mechanism, even though lobeline has been considered a mixed nicotinic agonist/antagonist.
Lobeline evokes dopamine (DA) release from rat striatal slices. However, lobeline evoked DA release is neither dependent upon extracellular calcium nor is it sensitive to mecamylamine, a noncompetitive nicotinic receptor antagonist. Thus, lobeline evoked DA release occurs via a different mechanism than does nicotine to evoke DA release (Teng et al., 1997, 1998; Clarke et al., 1996). In this respect, lobeline also inhibits DA uptake into rat striatal synaptic vesicles via an interaction with the dihydrotetrabenazine (DTBZ) site on vesicular monoamine transporter-2 (VMAT2), thus increasing the cytosolic DA available for reverse transport by the plasma membrane transporter (DAT) (Teng et al., 1997, 1998). Thus, lobeline interacts with nicotinic receptors and blocks nicotine-evoked DA release, but also interacts with DA transporter proteins to modify the concentration of DA in the cytosolic and vesicular storage pools, thereby altering subsequent dopaminergic neurotransmission.
SUMMARY OF THE INVENTION
The present invention is directed to a method of treating an individual who suffers from a disease or pathology of the central nervous system (CNS) or for treating an individual for drug dependence or withdrawal for drug dependence. The method comprises of administering to the individual an effective amount of a cis-2,6-substituted piperidino compound, i.e., a lobeline analog, including pharmaceutically acceptable salts of such compounds thereof. As used herein, an “effective amount” refers to 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 a CNS pathology.
The compound can be administered alone, combined with an excipient, 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-disubstituted piperidines and derivatives thereof in treating diseases or pathologies of the CNS is implicated. In particular, the treatment of dependencies of such drugs as cocaine, amphetamine, caffeine, nicotine, phencyclidine, opiates, barbiturates, benzodiazepines, canabinoids, 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 comprise 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, 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, lobeline analogs are found to be effective in inhibiting uptake of extracellular DA by cells of the CNS. Some of these analogs are a also nicotinic receptor antagonists. Either or both mechanisms can thereby work to alter the distribution of the intracellular DA pools and as a result alter extracellular DA concentration.
As used herein the term “lobeline” refers to a compound having the general chemical formula 2-[6-(&bgr;-hydroxyphenethyl)-1-methyl-2-piperidyl]-acetophenone. The term “lobeline analogs” and equivalents thereof as used herein, refers to chemical derivatives of lobeline obtained by oxidation or reduction of lobeline, others obtained by esterification of lobeline and redox derivatives, as well as various substitutions at the N-position of the piperidinyl moiety.
DETAILED DESCRIPTION OF THE INVENTION
The 2,6-disubstituted piperidine lobeline analogs of the present invention include those contemplated by the following formula (I), without regard to chirality:
wherein:
n is zero or an integer in the range from 1 to 3;
X
1
- - - Y
1
and X
2
- - - Y
2
are the same or are independently different from one another and represent a saturated carbon-carbon bond, a cis-carbon-carbon double bond, a trans-carbon-carbon double bond, a carbon-carbon triple bond; a saturated sulfur-carbon bond, a saturated selenium-carbon bond, an oxygen-carbon bond, a saturated nitrogen-carbon bond, a N-alkyl substituted saturated nitrogen-carbon bond where said alkyl is a lower straight chain or branched alkyl, a nitrogen-carbon double bond, or a nitrogen-nitrogen double bond;
R
1
and R
4
are the same or are independently different from one another and represent hydrogen or a lower straight chain or branched alkyl or R
1
and R
4
together form a ring including a —CH
2
—, —CH
2
CH
2
—, —CH
2
CH
2
—CH
2
—, —cis—CH═CH, —cis—CH
2
—CH═CH—or —cis—CH
2
═CH—CH
2
— moiety;
R
2
and R
3
are the same or are independently different from one another and represent a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic moiety; an oxygen containing heterocyclic moiety; a sulfur containing heterocyclic moiety; a selenium containing heterocyclic moiety; a mixed heterocyclic moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and an ortho, meta or para-substituted benzene;
with the proviso that when n=0, R
2
and R
3
are unsubstituted phenyl groups, and X
1
- - - Y
1
and X
2
- - - Y
2
are saturated carbon-carbon bonds, Y
1
cannot be CH
2
, CHOH or C═O, and Y
2
cannot be CH
2
, CHOH, or C═O.
It is preferred that when R
3
and/or R
4
is a saturated hydrocarbon ring, the ring includes, but is not limited to, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.
It is further preferred that when R
3
and/or R
4
is an unsaturated hydrocarbon ring, the ring includes, but is not limited to, benzene, cyclopentene, cyclohexene, cycloheptene, cyclooctene or cyclopentadiene, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.
It is further preferred that when R
3
and/or R
4
is
Crooks Peter A.
Dwoskin Linda P.
Jones Marlon D.
Desai Rita
Rotman Alan L.
University of Kentucky Research Foundation
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