Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-08-13
2001-11-06
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S222000, C564S378000
Reexamination Certificate
active
06313175
ABSTRACT:
BACKGROUND OF THE INVENTION
Chemical transmitters are small molecules or peptides that are synthesized in neurons. There are eight classical and generally accepted low-molecular weight transmitter substances: acetylcholine, dopamine, norepinephrine, serotonin, histamine, glycine, glutamate and &ggr;-aminobutyric acid (GABA). The catecholamines, dopamine, norephinephrine and epinephrine (derived from the amino acid tyrosine), the indolamine, serotonin, (derived from the amino acid tryptophan) and histamine (an imidazole) together comprise the “biogenic amines”.
In response to an appropriate stimulus, chemical transmitters are released into a synaptic cleft (gap) where they either bind to a postsynaptic neuron or effector organ; or are removed. There are three mechanisms by which nervous tissue disposes of soluble or unbound transmitter substances: 1) diffusion, 2) enzymatic degradation (e.g. monoamine oxidases degrade biogenic amines); and 3) reuptake by high affinity, chemical transmitter specific uptake mechanisms.
The chemical transmitter serotonin is known to mediate stimulation or inhibition of a variety of smooth muscles and nerves, thereby influencing secretion by exocrine and endocrine glands and functioning of the respiratory, cardiovascular and central nervous systems. Serotonergic neurons are known to be involved in control of sleep, appetite, nutrient selection, blood pressure, mood, endocrine secretion, aggressivity, and numerous other sensitivities to external stimuli.
Certain chemicals or drugs are known to affect serotonin level or activity, thereby producing a therapeutic effect. For example, it has been found that endogenous serotonin levels can be increased by administering its precursor tryptophan. In addition, the drugs fluoxetine (Prozac) and trazodone are thought to increase the availability of serotonin in the presynaptic cleft by blocking its reuptake by presynaptic neurons. These drugs have shown clinical utility for treating depression and stimulating weight loss. Two other “serotonin uptake blockers”, fenfluramine and its principal metabolite norfenfluramine, have also shown clinical utility in treating depression and obesity. In addition to blocking the uptake of serotonin by postsynaptic neurons, norfenfluramine appears to enhance serotonin release from pre-synaptic vesicles.
Although serotonin uptake blockers are considered the most effective class of antidepressants (when compared to monoamine oxidase inhibitors such as phenelzine, and tricyclic compounds, such as imipramine and amitriptyline), currently available compounds have associated side effects. For example fluoxetine (Prozac.®) has been linked to aggressive behavior.
New compounds that increase the availability of serotonin at serotonergic neuronal gap junctions in vivo would be useful for treating a variety of diseases and conditions associated with inadequate serotonin-mediated nerve transmission.
SUMMARY OF THE INVENTION
In one aspect, the instant invention features novel meta substituted arylalkylatnines having a high specificity for serotonergicneurons. Preferred meta substituted arylalkylamines are readily taken up by the central nervous system and peripheral organs innervated by serotonergic neurons. Other preferred meta substituted arylalkylamines bind with high affinity to serotonergic neurons.
In another aspect, the invention features small molecule drugs comprised of the novel meta substituted arylalkylamine compounds. The invention further features therapeutic uses for the novel small molecules for treating or preventing a condition or disorder associated with inadequate serotonin mediated nerve transmission. In preferred embodiments, the disease or condition is depression or obesity. In a preferred method for treating obesity, the pharmaceutical composition is administered in conjunction with a thermogenic drug.
In a further aspect, the instant invention features labeled meta substituted arylalkylamines and uses for the labeled compositions. In one embodiment, labeled meta substituted arylalkylamines can be administered in vivo or in vitro and monitored by a means appropriate for the label to measure the binding of serotonin or a serotonin ligand to serotonergic neurons. Preferred methods for monitoring labeled meta substituted arylalkylamines in vivo include Positron Emission Tomography (PET), Single Photon Emission Computer Tomography (SPECT) or Magnetic Resonance Imaging (MRI).
The instant disclosed small molecules are readily taken up in vivo by serotonergic neurons of the central nervous system (i.e the brain and spinal cord) and peripherally in heart, lung, liver, spleen, kidney and adrenal glands. These small compounds should therefore be safe and effective therapeutic agents. In addition, certain of the compounds have a high affinity for serotonergic neurons. These compounds should be especially potent therapeutics and if labeled, useful imaging agents. Further, some of the compounds are more resistant to in vivo catabolism (e.g. by monoamine oxidase) requiring a low dose to yield a therapeutic effect. The instant disclosed small molecule drugs therefore should result in few, if any, side effects. In addition, the structure of the compounds indicate that meta substituted arylalkylamines (unlike amphetamines, which are not meta substituted) should be nonaddictive drugs.
Additional features and advantages of the invention will become more apparent from the following detailed description and claims.
REFERENCES:
patent: 3573304 (1971-03-01), Eberle et al.
patent: 3663595 (1972-05-01), Beregi et al.
patent: 3733339 (1973-05-01), Horrom
patent: 3769319 (1973-10-01), Boitze et al.
patent: 3843647 (1974-10-01), Buzas et al.
patent: 3856857 (1974-12-01), Beregi et al.
patent: 3886195 (1975-05-01), Beregi et al.
patent: 3956501 (1976-05-01), Beregi et al.
patent: 4025624 (1977-05-01), Alphin et al.
patent: 4115587 (1978-09-01), Lunsford et al.
patent: 4237165 (1980-12-01), Duhault
patent: 4493931 (1985-01-01), Chekroun et al.
patent: 4857553 (1989-08-01), Ward et al.
patent: 4999382 (1991-03-01), Wurtman et al.
patent: 1 802 297 (1969-07-01), None
patent: WO 85/05617 (1985-12-01), None
patent: WO 88/04552 (1988-06-01), None
patent: WO 89/03692 (1989-05-01), None
patent: WO 89/09051 (1989-10-01), None
patent: WO 90/04387 (1990-05-01), None
patent: WO 91/18592 (1991-12-01), None
Gray, N.M. et al., “The effects of stereoisomers of 2-Amino-6(7)- and 9-Amino-9-Trifluoromethylbenzonorbornenes on food intake, . . . ”Pharmacological Research Communications, vol. 16, No. 3, pp. 281-294, 1984.
Zwarenstein, H. and N. Sapeika, “Effect of a Norfenfluramine Deriviative (S780) on NADH Dehydrogenase . . . ”Research Communications in Chemical Pathology and Pharmacology, vol. 5., pp. 1, pp. 233-236, Jan. 1973.
Offermeir, J. and B. Potgieter, “Some effects of fenfluramine and its deriviatives on the central catecholaminergiv systems of mice”Postgraduate Medical Journal, vol. 51 (Suppl. 1), pp. 65-71, 1975.
Pritchard, P.H. and D. N. Brindley, “Studies on the ethanol-induced changes in glycerolipid synthesis in rats and their partial reversal by N-(2-benzoyloxyethyl) norfenfluramine (benfluorex)”J. Pharm. Pharmac., vol. 29, pp. 343-349, 1977.
Becket, A.H. and G.R. Jones, “Metabolic oxidation of aralkl osimes to nitro compounds by fortified 9000g liver supernatants from various species”J Pharm. Pharmac., vol. 29, pp. 416-421, 1977.
Dunn, R.I. et al., “A novel activity cate for rats: Charaterization of some phenylethylamine derivatives . . . ”Clinical and Experimental Pharmacology Physiology, vol. 5, pp. 627-633, 1978.
Fuller, R. W., “Effect of nonfenfluramine and two structural analogues on brain 5-hydroxyindoles and serum prolcatin in rats”J Pharm. Pharmacol., vol. 34, pp. 449-450, 1982.
Coquerel, G. et al., Structure of (R)-Nonfenfluramine Dichloroacetate:Acta Cryst., vol. C44, Part 6, pp. 1017-1020, Jun. 15, 1988.
Mennini, T. et al., “Characterization of High Affinity and Stereospecific [5H]d—Fenfluramine Binding to Rat Brain”Neurochem. Int., vol. 13, No. 3, pp. 345-351, 1988.
Coque
Elmaleh David R.
Fischman Alan J.
Biostream Inc.
Foley Hoag & Eliot LLP
McKane Joseph K.
Wright Sonya N.
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