Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
1998-08-04
2001-03-06
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
C514S731000, C514S732000, C514S764000, C514S765000, C514S903000
Reexamination Certificate
active
06197833
ABSTRACT:
TECHNICAL FIELD
The present invention relates to compositions and methods for protecting cells in the central nervous system of subjects from cell death and for stimulating neuronal survival in subjects with neurodegenerative conditions.
BACKGROUND
Pathological conditions resulting from the accelerated or ongoing death of neurons are prevalent in today's society and include chronic diseases such as Alzheimer's disease and Parkinson's disease, acute diseases such as stroke, brain cell loss that follows myocardial infarction, and acute neuronal injury associated with spinal cord trauma and head trauma. Chronic and acute neurodegenerative diseases and acute neuronal injury as well as associated mortality and morbidity are largely untreatable. The consequences of patient disability resulting from these conditions is a high cost to society of patient care as well as a significant reduction in quality of life. Effective therapeutic approaches directed to the prevention or reduction of neuron death or damage associated with the above conditions are needed. At present, the greatest challenge in the development of therapeutic agents for treating conditions in the brain resulting from neuron loss include obtaining an efficacious drug that is relatively non-toxic, suitable for use in both females and males, and which can readily access the brain across the blood-brain barrier.
Estrogen compounds have been found to protect neurons from cell death and have utility in retarding the progression of neurodegenerative diseases such as Alzheimer's disease. (Simpkins et al. WO 95/12402, Behl et al. (1995) Biochem. Biophys. Res. Commun. 216: 473-482;: Bishop et al. (1994) Molecular and Cellular Neuroscience 5: 303-308; Simpkins et al. (1994) Neurobiology of Aging 15: s195-s197). Furthermore, Simpkins et al. WO 95/12402 has shown that alpha isomers of estrogen compounds, previously thought to be biologically inert, are effective in retarding neurodegeneration. This demonstration provided for the first time an opportunity to administer estrogen therapeutically to men without associated sex-related side effects.
The mechanisms by which estrogen compounds bring about a neuroprotective effect are unknown although these compounds have been shown to have a number of different physiological and biochemical effects on neurons. For example, estrogen has been shown to stimulate the production of neurotrophic agents that in turn stimulate neuronal growth. (REF) Estrogen compounds have also been found to inhibit NMDA-induced cell death in primary neuronal cultures (Bahl et al. Biochem. Biophys Res. Commun. (1995) 216: 973; Goodman et al. J. Neurochem (1996) 66: 1836), and further to be capable of removing oxygen free radicals and inhibiting lipid peroxidation. (Droescher et al. WO 95/13076). However, the potential effect of free radicals on neurons per se is unproven. Droeschler et al. describes a cell free ‘in vitro’ assay systems using lipid peroxidation as an endpoint in which several estrogens as well as vitamin E were shown to have activity. Estradiol has also been reported to reduce lipid peroxidation of membranes (Niki (1987) Chem. Phys. Lipids 44: 227; Nakano et al. Biochem. Biophys. Res. Comm. (1987) 142: 919; Hall et al. J. Cer. Blood Flow Metab. (1991)11: 292. Other compounds including certain 21-amino steroids and a glucocorticosteroid have been found to act as anti-oxidants and have been examined for their use in spinal cord injury as well as head trauma, ischemia, and stroke. (Wilson et al. (1995) J. Trauma 39: 473; Levitt et al. (1994) J. Cardiovasc. Pharmacol 23: 136; Akhter et al. (1994) Stroke 25; 418).
As described above, a number of factors may be involved in neuroprotection. Therapeutic agents that are selected on the basis of a single biochemical mechanism may have limited generalized utility in treating disease or trauma in patients. For example, in order to achieve an anti-oxidant effect in vitro using estrogen, Droescher et al. used very high doses of estrogens. Such doses, even if effective on neurons in vivo, would have limited utility in treating chronic neurological conditions because of associated problems of toxicity that result from prolonged use of high dosages.
It would be beneficial to identify a class of compounds that are non-sex related and have demonstrated biological efficacy in protecting neurons from cell death, where such compounds could be used in the treatment of the chronic as well as the acute conditions caused by neurodegenerative diseases, trauma, and aging at non-toxic dosages. An understanding of the structural requirements for compositions capable of inducing neuroprotection would provide the basis for designing novel drugs that have enhanced neuroprotective properties while at the same time having reduced adverse side effects .
SUMMARY
The present invention satisfies the above stated need for a class of compounds that is effective in protecting neurons from deterioration and cell death arising from disease, trauma or aging and may be used to achieve a similar effect in male and female subjects with minimal adverse side effects.
In a preferred embodiment of the invention, a method is provided for conferring neuroprotection on a population of cells in a subject, having the steps of providing a non-estrogen compound, having a terminal phenol group in a structure containing at least a second ring having a molecular weight that is less than 1000 Daltons; and administering the compound in an effective dose to the population of cells to confer neuroprotection.
In another embodiment of the invention, a method of treating a neurodegenerative condition in a subject is provided, which includes the steps of selecting an effective dose of a compound having a terminal phenol ring having a molecular weight less than 1000 D and at least one additional ring structure covalently linked to the phenol ring; and administering the compound to the subject.
In another embodiment of the invention, the compound used in the method may have a four-ring structure, a three-ring structure or a two-ring structure where the four-ring structure may be administered at an effective dose that achieves a plasma concentration of less than 500 nM. The molecular weight of the compound may be greater than 170 D.
In another embodiment of the invention, the three ring structure is a phenanthrene compound which may further be selected from the group consisting of tetrahydro-phenanthrene and a octahydrophenanthrene more particularly a phenanthrenemethanol or a phenanthrencarboxyaldehyde.
In another embodiment of the invention, the two- ring structure may be fused and include a naphthol and naphthalene or may be a non-fused two ring structure having a linkage group.
In an embodiment of the invention, the terminal phenol ring includes non-steroidal compounds. Embodiments of the invention utilize a compound having a phenolic A ring.
In a further embodiment of the invention, the dosage of the neuroprotective compound results in a plasma concentration of less than 500 nM, more particularly in the range of 0.02 nM-500 nM and more particularly in the range of 0.1 nM-1 nM.
REFERENCES:
patent: 5385947 (1995-01-01), Godel et al.
patent: 0 339 579 (1989-11-01), None
patent: 0 606 661 (1994-07-01), None
patent: 0 659 418 (1995-06-01), None
patent: 0 679 642 A1 (1995-11-01), None
patent: WO87/02666 (1987-05-01), None
patent: WO92/03049 (1992-03-01), None
patent: WO92/07855 (1992-05-01), None
Chemical Abstracts, vol. 96, No. 7, Feb. 15, 1982; abstract No. 46388, Waefelaer, “Structural Analogs of Apomorhine”.
Hall et al.,J. Cer. Blood Flow Metab., (1991), vol. 11, p. 292.
Levitt et al.,J. Cardiovasc. Pharmacol, (1994), vol. 23, p. 136.
Nakano et al.,Biochem, Biophys. Res. Comm., (1987), vol. 142, p. 919.
Niki,Chem. Phys. Lipids, (1987), vol. 44, p. 227.
Stipas,Study Stroke, (1994), vol. 25, p. 418-423.
Wilson et al.,J. Trauma, (1995), vol. 39, p. 473.
J. American Chemical Society, (1960), vol. 82, pp. 5525-5581.
Pure and Applied Chemistry, (1972), vol. 31, pp. 285-322.
Gordon Katherine
Green Pattie S.
Simpkins James W
Apollo Biopharmaceutics, Inc.
Bromberg & Sunstein LLP
Delacroix-Muirheid C.
Jones Dwayne C.
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