Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-10-08
2002-12-10
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S647000, C514S654000
Reexamination Certificate
active
06492427
ABSTRACT:
BACKGROUND OF THE INVENTION
Deprenyl (also referred to herein as selegiline or R-(−)-N,&agr;-Dimethyl-N-2-propynyl phenethylamine) was first used as an adjunct to conventional drug therapy (L-dihydroxyphenylalanine (L-DOPA) plus a peripheral decarboxylase inhibitor) of Parkinson's disease (PD) in Europe over a decade ago on the basis that as a selective monoamine oxidase-B (MAO-B) inhibitor, it would elevate brain dopamine levels and potentiate the pharmacological action of dopamine formed from L-DOPA, and yet prevent the tyramine-pressor effect observed with non-selective MAO inhibitors. The combined drug therapy was reported to prolong the anti-akinetic effects of L-DOPA, resulting in the disappearance of on-off effects, reduced functional disability, and increased life-expectancy in PD patients (Bernheimer, H., et al., J. Neurolog. Sci., 1973. 20: 415-455, Birkmayer, W., et al., J. Neural Transm., 1975. 36:303-336, Birkmayer, W., et al., Mod. Prob. Pharmacopsychiatr., 1983. 19: 170-177, Birkmayer, W. and P. Riederer, Hassler, R. G. and J. F. Christ (Ed.) Advances In Neurology, 1984. 40(Y): p.0-89004, and Birkmayer, W., et al., J. Neural Transm., 1985. 64(2): p. 113-128).
Studies examining deprenyl as an adjunct to conventional L-DOPA therapy have reported a short term benefit which was usually lost by 1 year or less. Some, but not all, have reported that the levodopa dose can be decreased when taken in conjunction with deprenyl (Elizan, T. S., et al., Arch Neurol, 1989. 46(12): p. 1280-1283, Fischer, P. A. and H. Baas, J. Neural Transm. (suppl.), 1987. 25: p. 137-147, Golbe, L. I., Neurology, 1989. 39: p. 1109-1111, Lieberman, A. N. et al., N.Y. State J. Med., 1987. 87: p. 646-649, Poewe, W., F. Gerstenbrand, and G. Ransomayr, J. Neural Transm. (suppl.), 1987. 25: p. 137-147, Cedarbaum, J. M., M. Hoey, and F. H. McDowell, J. Neurol. Neurosurg. Psychiatry, 1989. 52(2): p. 207-212, and Golbe, L. I., J. W. Langston, and I. Shoulson, Drugs, 1990. 39(5): p. 646-651).
Increasingly, deprenyl is being administered to Parkinson's disease patients following reports (Parkinson, S. G. Arch Neurol 46, 1052-1060 (1989) and U.S.A., Parkinson, S. G. N. Engl. J. Med. 321, 1364-1371 (1989)) that it delays the disease progression; a mechanism has recently been proposed to explain its action (See, e.g., Tatton & Redman 1996).
SUMMARY OF THE INVENTION
It has now been discovered that certain compounds are capable of increasing survival of oligodendrocytes. The invention provides methods for increasing survival of oligodendrocytes both in vivo and in vitro, of preventing or inhibiting death of oligodendrocytes, of preventing or inhibiting the progression of Multiple Sclerosis, and methods for treating Multiple Sclerosis.
In one aspect, the invention provides a method for increasing survival of oligodendrocytes. The method comprises administering to a subject in need thereof an effective amount of a deprenyl compound such that survival of oligodendrocytes is increased. In certain embodiments, the deprenyl compound is represented by the structure:
in which
R
1
is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
R
2
is hydrogen or alkyl;
R
3
is a single bond, alkylene, or —(CH
2
)
n
—X—(CH
2
)
m
; in which X is 0, S, or N-methyl; m is 1 or 2; and n is 0,1, or 2;
R
4
is alkyl, alkenyl, alkynyl, heterocyclyl, aryl or aralkyl; and
R
5
is alkylene, alkenylene, alkynylene and alkoxylene; and
R
6
is C
3
-C
6
cycloalkyl or
or
R
2
and R
4
-R
3
are joined to form, together with the methine to which they are attached, a cyclic or polycyclic group;
and pharmaceutically acceptable salts thereof. In certain embodiments: R
1
is a group that can be removed in vivo; R
1
is hydrogen; R
1
is alkyl; R
1
is methyl; R
2
is methyl; R
3
is methylene; wherein R
4
is aryl; R
4
is phenyl; R
5
is methylene; R
6
is
In certain preferred embodiments, the deprenyl compound is represented by the structure:
in which
R
1
is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
R
2
is hydrogen or alkyl;
R
3
is a bond or methylene; and
R
4
is aryl or aralkyl; or
R
2
and R
4
-R
3
are joined to form, together with the methine to which they are attached, a cyclic or polycyclic group;
and pharmaceutically acceptable salts thereof.
In certain preferred embodiments, the deprenyl compound is represented by the structure:
in which
R
2
is hydrogen or alkyl;
R
3
is a bond or methylene; and
R
4
is aryl or aralkyl; or
R
2
and R
4
-R
3
are joined to form, together with the methine to which they are attached, a cyclic or polycyclic group; and
R
5
is alkylene, alkenylene, alkynylene and alkoxylene;
and pharmaceutically acceptable salts thereof.
In certain preferred embodiments, the deprenyl compound is represented by the structure:
in which
R
1
is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or aryloxycarbonyl;
A is a substituent independently selected for each occurrence from the group consisting of halogen, hydroxyl, alkyl, alkoxyl, cyano, nitro, amino, carboxyl, —CF
3
, or azido;
n is 0 or an integer from 1 to 5;
and pharmaceutically acceptable salts thereof.
In certain preferred embodiments, the patient is a human. In a particularly preferred embodiment, the deprenyl compound is (−)-desmethyldeprenyl.
In another aspect, the invention provides a method for inhibiting Multiple Sclerosis, comprising administering to a patient an effective amount of a deprenyl compound such that Multiple Sclerosis is inhibited. In a preferred embodiment, the deprenyl compound is (−)-desmethyldeprenyl. In certain embodiments, the patient is a human.
In another aspect, the invention provides a method for increasing oligodendrocyte survival in vitro, comprising contacting oligodendrocytes with an effective amount of a deprenyl compound such that oligodendrocyte survival is increased.
In another aspect, the invention provides a method for increasing oligodendrocyte survival in a patient, comprising contacting a oligodendrocyte with a deprenyl compound such that oligodendrocyte survival increases. In preferred embodiments, the patient is a human; the deprenyl compound is (−)-desmethyldeprenyl; and/or the (−)-desmethyldeprenyl is administered transdermally to the patient.
REFERENCES:
patent: 5444095 (1995-08-01), Tatton et al.
patent: 5844003 (1998-12-01), Tatton et al.
patent: WO 96/22068 (1996-07-01), None
patent: WO 96/40095 (1996-12-01), None
patent: WO 97/25421 (1997-07-01), None
patent: WO 97/28791 (1997-08-01), None
Dorland's Illustrated Medical Dictionary, 28thEdition, p. 1174, 1988.*
Bernheimer, H. et al. (1973) “Brain Dopamine and the Syndromes of Parkinson and Huntington. Clinical, Morphological and Neurochemical Correlations”Journal of the Neurological Sciences29:415-455.
Birkmayer, W. et al. (1983) “(−)-Deprenyl Leads to Prologation of L-Dopa Efficacy in Parkinson's Disease”Mod. Probl. Pharmacopsychiat.19:170-176.
Birkmayer, W. and P. Riederer (1984) “Deprenyl Prolongs the Therapeutic Efficacy of Combined L-DOPA in Parkinson's Disease”Advances in Neurology40:475-481.
Birkmayer, W. et al. (1985) “Increased Life Expectancy Resulting from Addition of L-Deprenyl to Madopar® treatment in Parkinson's Disease: A Longterm Study”J. Neural Transm.64:113-127.
Birkmayer, W. et al. (1975) “The Potentiation of the Anti Akinetic Effect after L-Dopa Treatment by an Inhibitor of Mao-B, Deprenil”Journal of Neural Transmission36:303-326.
Cedarbaum, Jesse M. et al. (1989) “A double-blind crossover comparison of Sinement CR4 and standard Sinemet 25/100 in patients with Parkinson's disease and fluctuating motor performance”Journal of Neurology, Neurosurgery, and Psychiatry52:207-212.
Elizan, Teresita S. et al. (Dec. 1989) “Selegiline as an Adjunct to Conventional Levodopa Therapy in Parkinson's Disease”Arch Neurol.46:1280-1283.
Fischer, P.-A. and H. Baas (1987) “Therapeutic efficacy of R-(—)-deprenyl as adjuva
Shankar L. Sai Latha
Tatton Nadine A.
Tatton William G.
Arnold Merideth C.
Criares Theodore J.
Hanley Elizabeth A.
Kim Jennifer
Lahive & Cockfield LLP
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