Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-07
2003-08-26
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S311700
Reexamination Certificate
active
06610725
ABSTRACT:
This is a 371 of PCT/FR00/01835, filed Jun. 29, 2003.
The present invention relates to novel fluorinated benzodioxane imidazoline derivatives corresponding to formula 1.
in which:
R represents a linear, branched or cyclized alkyl or alkenyl group containing 1 to 7 carbon atoms, or a benzyl group,
the fluorine atom on the homocycle can occupy position 5, 6, 7 or 8.
The invention relates to the racemic and enantiomerically pure forms, to the salified forms thereof and also to the process for preparing them.
The invention also relates to the use of these compositions as medicinal products, and also to the preparation of a medicinal product used as an &agr;
2
-adrenergic receptor antagonist and intended in this respect to treat neurodegenerative diseases, and also their progression.
Advantageously, the radical R is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an isobutyl group, a cyclopropylmethyl group, an allyl group or a benzyl group.
Preferably, the fluorine atom occupies position 5.
It has been shown (Mavridis, Neuroscience (1991), 41, 507) that the locus coeruleus plays a predominant role in the recovery of dopaminergic functions altered by administration of MPTP to monkeys. Its destruction brings about a reduction in recovery. Moreover, compounds with &agr;
2
-antagonist action are shown as reducing Parkinson's symptoms in monkeys (Colpaert, Brain Res. Bull., 26, 627, 1991) or in rats (Colpaert, Neuropharmacology, 26, 1431, 1987) by elevating the release of dopamine (Marien, M., Colpaert, F. Effect of (+)-efaroxan on mouse striatal dopamine metabolism in vivo. DOPAMINE 94-Satellite Meeting of the XIIth Int. Congr. Pharmacology, Quebec City, Canada, Jul. 20-24, 1994).
Furthermore, an &agr;
2
-antagonist, idazoxan, is shown as having beneficial action on the deleterious effects of cerebral ischemia (Gustafson, Exp. Brain Res., 86, 555, 1991 et J. Cereb. Blood Flow Metab., 1990, 10, 885) and also in progressive supranuclear paralysis and neurodegenerative disease (Ghika, Neurology, 41, 986, 1991). It has also been shown that compounds with &agr;
2
-antagonist activity induce an increase in the release of acetylcholine in the prefrontal cortex (Tellez, J.Neurochem. (1997), 68, 778).
Thus, a substance activating the noradrenergic system may have the property of opposing the progression of the degeneration of the involved neurons, by reactivating the various cerebral localization systems, whether they are dopaminergic or cholinergic, or whether this involves the release of growth factors (Fawcett et al. J. Neurosci. (1998), 18, 2808-2821). These compounds are thus useful in cases of neurodegenerative diseases of the type such as Parkinson's disease or Alzheimer's disease and their progression, Huntington's chorea, amyotrophic lateral sclerosis, Creutzfeld-Jacob disease, progressive supranuclear paralysis, cognitive and memory disorders, attention deficit and vigilance deficit in the elderly, and also the progression or evolution of these diseases or disorders. Ischemic and post-ischemic cerebral disorders, cerebrovascular accidents and consequences thereof, depression, narcolepsy and male sexual dysfunctions are also concerned, as are disorders associated with acquired immunodeficiency syndrome.
It is known that benzodioxane derivatives such as idazoxan: 2-(1,4-benzodioxan-2-yl)-2-imidazoline, or alkoxy idazoxan: 2-(2-alkoxy-1,4-benzodioxan-2-yl)-2-imidazoline, have &agr;
2
-antagonist properties (J. Med. Chem. (1983), 26, 823; J. Med. Chem. (1985), 28, 1054). These compounds have been patented in GB 2 068 376 for idazoxan and in EP 92328 for alkoxy-idazoxans.
It has been shown in these publications that a large number of idazoxan derivatives have been synthesized and tested for their agonist or antagonist action on the &agr;
1
or &agr;
2
receptors, inter alia, halogenated derivatives, substituted on the aromatic nucleus, have all been found to be less active than or inactive relative to their unsubstituted idazoxan analog (in particular the 6/7-fluoro, chloro or bromo derivative, 5,8-dichloro or 8-chloro derivative). Moreover, the 2-methoxy idazoxan derivative substituted in 6,7 with two methoxy groups showed only extremely marginal activity as an &agr;
2
-presynaptic antagonist.
The compounds of the present invention differ from the known compounds in that they have a fluorine atom in position 5, 6, 7 or 8 of the aromatic nucleus. They have the property of being powerful &agr;
2
-adrenergic receptor antagonists.
It has been found, remarkably, that the presence of this fluorine atom in these positions gives these molecules particularly advantageous properties when compared with their nonfluorinated analog.
The pharmacological properties of the products of the present invention have been studied, inter alia, in comparison with those of 2-methoxy idazoxan (RX 821002) and 2-ethoxy idazoxan (RX 811059), which are structurally related compounds that are derivatives not substituted on the aromatic nucleus.
Specifically, we show, in vivo, the superiority of the pharmacological properties of the products of the present invention in the test of memory deficit induced with scopolamine, of the antagonism of the hypothermia induced with guanabenz, an &agr;
2
-agonist substance, and on the level, in the cortex, of normetanephrine, a metabolite and selective marker for the release of noradrenalin.
Test of the memory deficit induced with scopolamine:
In accordance with the cholinergic hypothesis of the phenomena of learning and memory, scopolamine has amnesiant properties in animals and man. Its administration to a healthy person induces certain amnesia symptoms similar to those observed in Alzheimer's disease. It has been proposed that the scopolamine be used as an experimental pharmacological model of this pathology. The similarities between the memory deficits of Alzheimer's disease and those induced with scopolamine in rats have been published (P. Chopin et M. Briley, The effects of raubasine and dihydroergocristine on an agerelated deficit in passive avoidance learning in rats, J.Pharm.Pharmacol. 42, 375-376, 1990). Scopolamine reduces the capacity for acquisition, memorization and recall in a test of passive avoidance in rats. This involves measuring the reticence, after learning, that the animal has in entering a dark compartment, where it receives a mild electric shock. The administration of scopolamine suppresses this reticence, and the test compounds oppose the effect of scopolamine.
The comparison of the products of the present invention is made with the known compound RX 821002, dextrorotatory enantiomer. The experimental protocol is that published by P. Chopin and M. Briley (Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats: Psychopharmacology, 106, 26-30, 1992).
The results are given in the following table:
MEMORY DEFICIT INDUCED WITH
SCOPOLAMINE
Increase in the time taken to
enter the dark compartment by
Compounds
the treated animals, relative
Active doses over the
to those receiving
range from 0.04 to
scopolamine alone.
2.5 mg/kg.
(% amplitude of the effect)
(+) RX 821002
non-significant
Dextrorotatory compound
201%
of Example 1
Dextrorotatory compound
198%
of Example 2
Tacrine
191%
Donepezil
67%
The compounds of the present invention show appreciable activity over a wide range of doses, in contrast with (+) RX 821002, which is not significantly active. The amplitude of its effect is at least as large as that of tacrine, and more active than that of donepezil, reference compounds used therapeutically for Alzheimer's disease.
The value and the appreciable difference of the products of the invention is thus shown.
Inhibition of the hypothermia induced with Guanabenz:
The assessment of the biological activity of the compounds of the invention is also carried out in vivo by studying the inhibition of the hypothermia induced with a central &agr;
2
-agonist such as guanabenz according to the protocol of S. C. Dilsav
Imbert Thierry
Marien Marc
Mayer Patrice
Pauwels Peters
Anderson Rebecca
Dechert
Pierre Fabre Medicament
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