Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-09-14
2000-03-28
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514315, 514317, 514319, 514365, 514367, 514 12, A61K 3144, A61K 3830, A61K 3818, A61K 31425
Patent
active
060432519
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of 1-(2-naphth-2-ylethyl)4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridi ne or its addition salts with pharmaceutically acceptable acids for the preparation of drugs intended for the treatment of amyotrophic lateral sclerosis (ALS).
ALS is a serious progressive motor neuron disease which causes muscular atrophy and most often develops in a few years into a fatal respiratory insufficiency.
Very few products are being studied for ALS, particular examples being peptide compounds such as IGF-1 (Insulin-like Growth Factor 1) and BDNF (Brain Derived Neurotrophic Factor), which are described in Annals of Neurology, 1995, 38, 971, and Nature, 1992, 360, 753-759.
The only non-peptide compound to have been tested for this disease is riluzole, whose chemical name is 2-amino-6-trifluoromethoxybenzothiazole, which is apparently capable of slowing down the progression of the disease in a particular group of subjects suffering from ALS (G. Bensimon et al., N. Engl. J. Med., 1994, 330, 585-591; Scrip, 1995, No. 2035:21), but no product effective in the treatment of this disease is currently available on the pharmaceutical market. According to the article by G. Bensimon et al. cited above, riluzole prolongs the survival of patients suffering from ALS, but the side effects, such as asthenia, spasticity and an increase in the transaminase levels, impair the quality of life of said patients.
EP-A-458696 describes the use of 1-(2-naphth-2-ylethyl)4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridi ne, called SR 57746 in the literature, for the preparation of drugs intended for combating neurodegenerative states. In said document the neurotrophic activity of SR 57746 is indicated as being useful in memory disorders, vascular dementia, postencephalitic disorders, postapoplectic disorders, post-traumatic syndromes due to a cranial traumatism, disorders derived from cerebral anoxia, Alzheimer's disease, senile dementia, subcortical dementia such as Huntington's chorea and Parkinson's disease, dementia caused by AIDS, neuropathy derived from morbidity or from damage to the sympathetic or sensory nerves, brain diseases such as cerebral edema, and spinocerebellar degenerations.
The neurotrophic action of SR 57746 on the nervous system is similar to that of NGF, Nerve Growth Factor (EP-A-458696), and, in particular, is said to provide neuroprotection by inducing the effects of the NGF system (J. Fournier, Neuroscience, 1993, 55(3), 629-641).
It has now been found that the administration of SR 57746 or one of its addition salts with pharmaceutically acceptable acids significantly slows down the progression of ALS while at the same time improving the patients' quality of life. This therapeutic action of SR 57746 is not associated with the release of NGF since the latter is not said to be a trophic factor for the motor neurons, as indicated for example in Neuron, 1988, 1(4), 335-43; J. Comp. Neurol., 1982, 210/2, 174-189; and Eur. J. Neurosci., 1993, 5(5), 466-474.
The activity of SR 57746 in the treatment of ALS is therefore unexpected.
Thus, according to one of its aspects, the present invention relates to the use of 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid ine or one of its addition salts with pharmaceutically acceptable acids for the preparation of drugs intended for the treatment of amyotrophic lateral sclerosis.
The clinical activity of SR 57746 in this disease was demonstrated by means of a study performed to evaluate the activity indices on the clinical and functional signs of ALS and to evaluate tolerance after the prolonged administration of 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)- 1,2,3,6-tetrahydropyridine hydrochloride (SR 57746 A).
In this randomized double-blind clinical study, 54 patients received SR 57746 A orally at a dose corresponding to 2 mg/day of the free base, for a period of 8 months. The doses indicated in the present description always refer to the amount of free base administered or contained in the dosage unit.
Several
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"A Phase I/II Study of Recombinant Human Brain-Derived Neurotrophic Factor in Patients with Amyotrophic Lateral Sclerosis", W. G. Bradley et al., Annals of Neurology, vol. 38, No. 6, 1996, p. 971.
"Brain-Derived Neurotrophic Factor Rescues Spinal Motor Neurons from Axotomy-Induced Cell Death", Q. Yan et al., Nature, vol. 360, 1992, pp. 753-759.
"Protective Effects of SR 57746A in Central and Peripheral models of Neurodegenerative Disorders in Rodents and Primates", J. Fournier et al., Neuroscience, vol. 55, No. 3, 1993, pp. 629-641.
"SR 57746A: Inductio of NGF Gene Expression and Synthesis in astrocytoma and Fibroblast Cell Lines and Beneficial Effects in a Peripheral Degenerative Model in Rats", T. Gauthier et al., Fundamental & Clinical Pharmacology, vol. 7, No. 7, 1993. p. 359.
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Douillet Patrice
Fournier Jacqueline
Alexander Michael D.
DuPont Paul E.
MacMillan Keith D.
Sanofi
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