Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-02
2002-06-18
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S431000, C549S011000, C549S021000
Reexamination Certificate
active
06407136
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a series of 1,4-dithiin- and 1,4-dithiepin-1,1,4,4-tetroxide derivatives and their use for the treatment of central nervous system disorders and affective conditions. More particularly, the compounds of the invention are ligands for the human galanin receptor.
BACKGROUND OF THE INVENTION
The galanin neuropeptide is a 29-30 amino acid peptide that is found in mammalian central (CNS) and peripheral (PVS) nervous systems (Bartfai, T.; Hokfelt, T.; Langel, U., Galanin-A Neuroendocrine Peptide.
Crit. Rev. Neurobiol.,
1993, 7, 229-274; Crawley, J. N., Biological Actions of Galanin,
Regulatory Neuropeptides,
1995, 59, 1-16; Kask, K.; Berthold, M.; Bartfai, T., Galanin Receptors: Involvement in Feeding, Pain, Depression, and Alzheimer's Disease.
Life Sci.,
1997, 60,1523-1533). In the CNS, galanin is distributed in axons and neurons located in the thalamus, hypothalamus, cortex, amygdala, hippocampus and spinal cord (Melander, T.; Hokfelt, T.; Rokaeus, A., Distribution of Galanin-like Immunoreactivity in the Rat Central Nervous System.
J. Comp. Neurol,
1986, 248, 475-517; Skofitsch, G.; Jacobowitz, D. M., Immunohistochemical Mapping of Galanin-like Neurons in the Rat Central Nervous System.
Peptides,
1985, 6, 509-516), while in the PVS, it is found in pancreas, gastrointestinal, bladder, and genital tissue (Rokaeus, A., Galanin: A Newly Isolated Biologically Active Peptide.
Trends Neurosci.,
1987, 10, 158-164).
The effects of galanin in mammalian CNS are due to its interaction with at least three galanin receptors, GalR1, GalR2, and GalR3 which have been isolated, characterized, and cloned (Wang, S., Parker, E. M., Galanin Receptor Subtypes as Potential Therapeutic Targets.
Exp. Opin. Ther. Patents,
1998, 8, 1225-1335 and references therein). While GalR1 is predominately found in the CNS, GalR2 and GalR3 are also present in small amounts.
The galanin-1 (GALR-1), galanin-2 (GALR-2) and galanin-3 (GALR-3) receptors are G protein-coupled 7-transmembrane domain receptors which are negatively coupled to cyclic AMP. GALR-1, GALR-2 and GALR-3 are receptors found in rats, monkeys and humans.
The various effects exerted by the galanin neuropeptide include stimulated feeding in rats (Crawley, J. N., Galanin Antagonists Block Galanin-Induced Feeding in the Hypothalamus and Amygdala of the Rat.
Eur. J. Neurosci.,
1993, 5, 1528-1533), enhanced firing of noradrenergic neurons and suppression of serotonin metabolism in rat brain raphe nucleus and locus coeruleus resulting in depressive behavior (Bartfai, T., Langel, U., Galanin Receptor Ligands as Potential Therapeutic Agents in Depression and Neurodegeneration
Eur. J. Med. Che.
1995, 30, 163-174), impairment of cognitive performance in rats (Crawley, J. N., Wenk, G. L., Co-existence of Galanin and Acetylcholine: Is Galanin Involved in Memory Processes and Dementia?
Trends Neurosci.
1989, 12, 278-282), inhibition of dopaminergic cell bodies in the ventral tegmentum resulting in depressive behavior (Weiss, J. M.; Bonsall, R. W.; Demetrikopoulos, M. K.; Emery, M. S.; West, C. H. K., Galanin: A Significant Role in Depression?
Ann. N. Y. Acad. Sci.,
1998, 863, 364-382.), inhibition of acetylcholine release in rat hippocampus resulting in loss of cognition and learning (Chan-Palay, V. L., Galanin Hyperinnervates Surviving Neurons of the Human Basal Nucleus of Meynert in Dementias of Alzheimer's and Parkinson's Disease: A Hypothesis for the Role of Galanin in Accentuating Cholinergic Function in Dementia. 1988
J. Comp. Neurol.
273, 543-557; Crawley, J. N., Wenk, G. L., Co-existence of Galanin and Acetylcholine: Is Galanin Involved in Memory Processes and Dementia?
Trends Neurosci.
1989, 12, 278-282; Crawley, J. N., Functional Interactions of Galanin and Acetylcholine: Relevance to Memory and Alzheimer's Disease
Behav. Brain Res.,
1993, 57,133-141), and potentiation of the spinal analgesic effect of morphine or cholecysokinnin-B antagonists (Wiesenfeld-Hallin, Z., Xu, X. J., Langel, U., Bedecs, K., Hokfelt, T., Bartfai, T., Galanin-Mediated Control of Pain: Enhanced Role After Nerve Injury.
Pro. Natl. Acad. Sci. USA,
1992, 89, 3334-3337.)
Thus a selective antagonist for the galanin receptor, specifically the human GALR (hGALR), may be useful in ameliorating diseases and conditions resulting from the binding of GAL to the hGALR, for example feeding disorders and diseases and conditions arising therein, depression and its attending disorders, or cognitive disorders such as Alzheimer's disease or senile dementia.
Compounds of the general structure of 1,4-dithiin-1,1,4,4-tetroxide derivatives are known in the literature as antimicrobial agents [U.S. Pat. No. 4,097,580, issued Jun. 27, 1978 (A. D. Brewer and R. A. Davis), U.S. Pat. No. 4,094,988, issued Jun. 13, 1978 (R. C. Johnson) and U.S. Pat. No. 4,004,018, issued Jan. 18, 1977 (A. D. Brewer and R. A. Davis) ] and plant growth regulants and herbicides [U.S. Pat. No. 4,026,906, issued May 31, 1977 (A. D. Brewer, R. W. Niedermyer, W. S. McIntire), U.S. Pat. No. 3,920,438, issued Nov. 18, 1975 (A. D. Brewer, R. W. Niedermyer, W. S. McIntire) and U.S. Pat. No. 3,997,323, issued Dec. 14, 1976 (A. D. Brewer, R. W. Niedermyer, W. S. McIntire)].
It is an object of the invention to identify compounds that bind to hGALR. It is another object of the invention to identify compounds which act as antagonist of the hGALR. Still another object of the invention is to identify compounds which are useful for treating conditions and/or disorders mediated by the hGALR. Another object of the invention is to identify compounds which are useful for treating conditions and/or disorders such as eating disorder, obesity, bulimia nervosa, anorexia nervosa, binge eating, diabetes, dyslipidimia, hypertension, memory loss, sleep disturbances, pain, depression, anxiety, Alzheimer's disease, senile dementia, cerebral hemorrhage, or diarrhea.
It has now been found that the 1,4-dithiin- and 1,4-dithiepin-1,1,4,4-tetroxide compounds of the present invention are antagonists for the hGAL receptor. As antagonists of the hGAL receptor, the compounds of the present invention inhibit the GAL-induced inhibition of acetylcholine release in rat hippocampal brain slices. Thus, the compounds of the present invention are useful for treating conditions and/or disorders mediated by the hGALR such as eating disorder, obesity, bulimia nervosa, anorexia nervosa, binge eating, diabetes, dyslipidimia, hypertension, memory loss, sleep disturbances, pain, depression, anxiety, Alzheimer's disease, senile dementia, cerebral hemorrhage, or diarrhea.
SUMMARY OF THE INVENTION
The present invention is direct to compounds of the formulas (I) and (II):
preferably of the formulas:
wherein
R
1
is selected from the group consisting of arC
1
-C
8
alkyl, substituted arC
1
-C
8
alkyl where the substituent is NR
3
R
4
, C
1
-C
8
alkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, where the substituents on the aryl or heteroaryl are independently selected from one or more of halogen, C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, C
1
-C
8
, alkoxy, fluorinated C
1
-C
8
alkyl, fluorinated C
1
-C
8
alkoxy, aryloxy, C
1
-C
8
alkylamido, aryl, carboxy, C
1
-C
8
alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or arC
1
-C
8
alkylamido;
R
2
is selected from the group consisting of C
1
-C
8
alkyl, unsubstituted or substituted arC
1
-C
8
alkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl, where the substituents on the aryl or heteroaryl are independently selected from one or more of halogen, C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, C
1
-C
8
alkoxy, fluorinated C
1
-C
8
alkyl, fluorinated C
1
-C
8
alkoxy, aryloxy, C
1
-C
8
alkylamido, aryl, carboxy, C
1
-C
8
alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or arC
1
-C
8
alkylamido;
R
3
and R
4
are independently selected from hydrogen, C
1
-C
8
alkyl, benzoyl or substituted benzoyl where the substituent is C
1
-C
Lee Daniel H. S.
Reitz Allen B.
Ross Tina Morgan
Scott Malcolm K.
Wang Haou-Yan
Appollina Mary
Lambkin Deborah C.
Ortho-McNeil Pharmaceutical , Inc.
LandOfFree
1,4-dithiin and 1,4-dithiepin-1,1,4,4, tetroxide derivatives... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 1,4-dithiin and 1,4-dithiepin-1,1,4,4, tetroxide derivatives..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 1,4-dithiin and 1,4-dithiepin-1,1,4,4, tetroxide derivatives... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2914737