S (+) Desmethylselegiline and its use in therapeutic...

Details S (+) Desmethylselegiline and its use in therapeutic... S (+) Desmethylselegiline and its use in therapeutic...

1999-11-24

2001-04-03

Dage, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S434000, C424S436000, C424S448000, C424S464000, C424S451000, C424S427000, C514S654000

Reexamination Certificate

active

06210706

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides a novel So(+) isomer of desmethylselegiline, i.e., a compound of the formula:
and further provides novel pharmaceutical and other compositions containing this isomer. In addition, the present invention provides novel methods for using this enantiomer in the treatment of selegiline-responsive diseases and conditions in animals, including humans.
BACKGROUND OF THE INVENTION
Two distinct monoamine oxidase enzymes are known in the art: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). The cDNAs encoding these enzymes show different promoter regions and distinct exon portions, indicating they are encoded independently at different gene positions. In addition, analysis of the two proteins has shown differences in their respective amino acid sequences.
The first compound found to selectively inhibit MAO-B was R(−)-N-methyl-N-(prop-2-ynyl)-2-aminophenylpropane, also known as L-(−)deprenyl, R-(−)-deprenyl, or selegiline. Selegiline has the following structural formula:
The selectivity of selegiline in the inhibition of MAO-B is important to its safety profile following oral administration. Inhibition of MAO-A may cause toxic side effects by interfering with the metabolism of tyramine. Tyramine is normally metabolized in the gastrointestinal tract by MAO-A but when MAO-A is inhibited, tyramine absorption is increased following consumption of tyranine-containing foods such as cheese, beer, herring, etc. This results in the release of catecholamines which can precipitate a hypertensive crisis, producing the “cheese effect.” This effect is characterized by Goodman and Gilman as the most serious toxic effect associated with MAO-A inhibitors.
One of the metabolites of selegiline is its Nesmethyl analog. Structurally, desmethylselegiline is the R(−) enantiomeric form of a secondary amine of the formula:
Heretofore, desmethylselegiline was not known to have pharmaceutically usefull MAO-related effects, i.e., potent and selective inhibitory effects on MAO-B. In the course of determining the usefulness of desmethylselegiline for the purposes of the present invention, the MAO-related effects of desmethylselegiline were more completely characterized. This characterization has established that desmethylselegiline has exceedingly weak MAO-B inhibitory effects and no advantages in selectivity with respect to MAO-B compared to selegiline.
For example, the present characterization established that selegiline has an IC
50
value against MAO-B in human platelets of 5×10
−9
M whereas R(−)desmethylselegiline's IC
50
value is 4×10
7
M, indicating the latter is approximately 80 times less potent as an MAO-B inhibitor than the former. Similar characteristics can be seen in the following data measuring inhibition of MAO-B and MAO-A in rat cortex mitochondrial-rich fractions:
TABLE 1
Inhibition of MAO by Selegiline and Desmethylselegiline
Percent Inhibition
selegiline
R(−)desmethylselegiline
Conc.
MAO-B
MAO-A
MAO-B
MAO-A
0.003
&mgr;M
16.70
—
3.40
—
0.010
&mgr;M
40.20
—
7.50
—
0.030
&mgr;M
64.70
—
4.60
—
0.100
&mgr;M
91.80
—
6.70
—
0.300
&mgr;M
94.55
9.75
26.15
0.0
1.000
&mgr;M
95.65
32.55
54.73
0.70
3.000
&mgr;M
98.10
65.50
86.27
4.10
10.000
&mgr;M
—
97.75
95.15
11.75
30.000
&mgr;M
—
—
97.05
—
100.000
&mgr;M
—
—
—
56.10
As is apparent from the above table, selegiline is approximately 128 times more potent as an inhibitor of MAO-B relative to MAO-A, whereas desmethylselegiline is about 97 times more potent as an inhibitor of MAO-B relative to MAO-A. Accordingly, desmethylselegiline appears to have an approximately equal selectivity for MAO-B compared to MAO-A as selegiline, albeit with a substantially reduced potency.
Analogous results are obtained in rat brain tissue. Selegiline exhibits an IC50 for MAO-B of 0.11×10
−7
M whereas desmethylselegiline's IC
50
value is 7.3×10
−7
M, indicating desmethylselegiline is approximately 70 times less potent as an MAO-B inhibitor than selegiline. Both compounds exhibit low potency in inhibiting MAO-A in rat brain tissue, 0.18×10
5
for selegiline, 7.0×10
−5
for desmethylseleine. Thus, in vitro R(−)desmethylselegiline is approximately 39 times less potent than selegiline in inhibiting MAO-A.
Based on its pharmacological profile as set forth above, R(−)desmethylselegiline as an MAO-B inhibitor provides no advantages in either potency or selectivity compared to selegiline. To the contrary, the above in vitro data suggest that use of desmethylselegiline as an MAO-B inhibitor requires on the order of 70 times the amount of selegiline.
The potency of desmethylselegiline as an MAO-B inhibitor in vivo has been reported by Heinonen, E. H., et al. (“Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of MAO-B in human subjects,” referenced in Academic Dissertation “Selegiline in the Treatment of Parkinson's Disease,” from Research Reports from the Department of Neurology, University of Turku, Turku, Finland, No. 33 (1995), pp. 5961). According to Heinonen, desmethylselegiline in vivo has only about one-fifth the MAO-B inhibitory effect as selegiline, i.e., a dose of 10 mg of desmethylselegiline would be required for the same MAO-B effect as 1.8 mg of selegiline. In rats, Barbe reported R(−)desmethylselegiline to be an irreversible inhibitor of MAO-B, with a potency about 60 fold lower than selegiline in vitro and about 3 fold lower ex vivo (Barbe, H. O.,
J. Neural Trans.
(
Suppl.
):32: 131 (1990)).
The various diseases and conditions for which selegiline is disclosed as being to be useful include: depression (U.S. Pat. No. 4,861,800); Alzheimer's disease and Parkinson's disease, particularly through the use of trasdennal dosage forms, including ointments, creams and patches; macular degeneration (U.S. Pat. No. 5,242,950); age-dependent degeneracies, including renal function and cognitive function as evidenced by spatial learning ability (U.S. Pat. No. 5,151,449); pituitary-dependent Cushing's disease in humans and nonhumans (U.S. Pat. No.5,192,808); immune system dysfunction in both humans (U.S. Pat. No. 5,387,615) and animals (U.S. Pat. No. 5,276,057); age-dependent weight loss in mammals (U.S. Pat. No. 5,225,446); and schizophrenia (U.S. Pat. No. 5,151,419). PCT Published Application WO 92/17169 discloses the use of selegiline in the treatment of neuromuscular and neurodegenerative disease and in the treatment of CNS injury due to hypoxia, hypoglycemia, ischemic stroke or trauma. In addition, the biochemical effects of selegiline on neuronal cells have been extensively studied. For example, see Tatton, et al., “Selegiline Can Mediate Neuronal Rescue Rather than Neuronal Protection,”
Movement Disorders
8 (Supp. 1):S20-S30 (1993); Tatton, et al., “Rescue of Dying Neurons,”
J. Neurosci. Res.
30:666-672 (1991); and Tatton, et al., “(−)-Deprenyl Prevents Mitochondrial Depolarization and Reduces Cell Death in Trophically-Deprived Cells,” 11
th Int'l Symp. on Parkinson's Disease,
Rome, Italy, Mar. 26-30, 1994.
Although selegiline is reported as being effective in treating the foregoing conditions, neither the precise number or nature of its mechanism or mechanisms of action are known. However, there is evidence that selegiline provides neuroprotection or neuronal rescue, possibly by reducing oxidative neuronal damage, increasing the amount of the enzyme superoxide dismutase, and/or reducing dopamine catabolism. For example, PCT Published Application WO 92/17169 reports that selegiline acts by directly maintaining, preventing loss of, and/or assisting in, the nerve function of animals.
Selegiline is disclosed as being useful when administered to a subject through a wide variety of routes of administration and dosage forms. For example U.S. Pat. No. 4,812,481 (Degussa AG) discloses the use of concomitant selegiline-amantadine in oral, peroral, enteral, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial

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