NZ258591A - Use of idazoxan and derivatives thereof in a medicament for treating parkinsons disease - Google Patents

Abstract

A compound of general formula (I), wherein R is a hydrogen atom, a straight or branched C1-4 alkyl radical or a straight or branched C1-4 alkoxy radical; and therapeutically acceptable salts, a racemic mixture or optically active isomers thereof; is used to prepare a drug for treating Parkinson's disease and its development.

Description

New Zealand Paient Spedficaiion for Paient Number £58591 New Zealand No. 258591 International No. PCT/FR93/01196 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 07.12.1992; International filing date: 06 DEC 1993 Classification:^) A61K31/415 Publication date:24 June 1997 Journal No.: 1417 Title of Invention: Use of idazoxan and derivatives thereof in preparing a drug for treating Parkinson's disease and its development Name, address and nationality of applicant(s) as in international application form: PIERRE FABRE MEDICAMENT, 45, Place Abel-Gance, F-92100 Boulogne, France NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION New Zealand No. 258591 International No. PCT/FR93/01196 NO DRAWINGS NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Use of idazoxan and derivatives thereof in preparing a drug for treating Parkinson's disease and its development Name, address and nationality of applicant(s) as in international application form: PIERRE FABRE MEDICAMENT, of 45, Place Abel-Gance, F-92100 Boulogne, France ^ . _ ^ K.2, ':£TCt™ ■:&>,:h- • The present invention relates to the UBe"~of idazoxan and its derivatives, for the preparation of a medicinal product intended for the treatment of Parkinson's disease, its progression in its idiopathic 5 form and its development.

Parkinson's disease is a degenerative disease affecting particularly the neurones of the black substance - pars compacta - and its negrostriated projections. The symptomatic manifestations are motor 10 disorders such as tremors, muscle rigidity, hypokinesia. The diagnosis of the disease is delicate, only a postmortem histological analysis through the detection of cellular degeneration in the black Bubstance makes it possible to assert the diagnosis without ambiguity. This 15 degeneration gives rise to a dopaminergic deficiency which is expressed by these three major disorders. In the absence of this histopathological evidence, the clinical characteristics determine the classification under this disease.

Currently, the treatment of Parkinson's disease is carried out, inter alia, using dopaminergic substances, in particular 1-DOPA, optionally combined with an 1-DOPA decarboxylase inhibitor such as carbidopa, in order to avoid the peripheral side effects of 1-DOPA 25 on the cardiovascular system and to optimize its central effects.

This therapy compensates the too low endogenous cerebral levels of dopamine and improves the symptomatology of the disease, without however treating 3 0 its cause. It has major disadvantages such as tardive dyskinesia, undesirable effects of gastro-intestinal and cardiovascular nature. The effect can be exhausted. In particular, 1-DOPA does not stop the progression of the disease, which is observed after stopping the treatment; 3 5 the symptoms reappear immediately. There is a therapeutic need attached to the recovery of neuronal degeneration.

It is known that idazoxan, 2 -(2 -(1,4-benzo-dioxanyl) ) -2-imidazoline, has antagonistic properties with respect to the alphaa-adrenergic receptors. This n.: compound ij described in Patent EP 3 3 655 by its chemical structure, the process for its synthesis, its pharmaceutical formulations and its therapeutic application as an antidepressant medicinal product.

Other idazoxan derivatives have also been described in Patent EP 92328.

Idazoxan has been clinically studied in humans in the treatment of depression at doses ranging from 5 to 40 mg, 3 times per day over 4 weeks and has shown a 10 significant improvement on the Hamilton scale against a placebo (Drug of the Future .10, No. 9, 782, (1985)).

Various studies have also been carried out on monkeys or rats in order to evaluate the action of various compounds on symptoms similar to those of 15 Parkinson's disease, such as the "symptoms" induced by reserpine in rats (F.C, COLPAERT, Neuropharmacology, 26, 1431, 19 87) or by the neurotoxin MPTP (F.C. COLPAERT et al. , Brain Res. Bull, 26, 627, 1991), or alternatively the symptoms associated, in man, with another 20 extrapyramidal disease : progressive supranuclear paralysis (J. GHIKA et al., Neurology, 41, 986, 1991).

The compounds studied were chosen from various agonists of dopamine, anticholinergics, agonists of 5-HT, histamine and some agonists or antagonists of the alpha- 2 5 adrenergic receptors, including idazoxan.

However, these general studies related to induced diseases which, although possessing a certain number of similarities for few symptoms, are different and differ from it, especially supranuclear paralysis, due to the 3 0 fact that it affects only the intrinsic neurones of the neostriatum and that the dopaminergic treatments (1-DOPA) do not induce improvements.

Now, it has been found, unexpectedly, that the use of idazoxan. or one of its derivatives made it 35 possible not only to treat Parkinson's disease, but also to observe persistence of the improvements obtained even after stopping the treatment.

The present invention therefore relates to the use of idazoxan and its derivatives for the preparation of a medicinal product intended for the treatment of Parkinson's disease, and its development.

By idazoxan and its derivatives, there is understood the compound of general formula X: in which R represents a hydrogen atom, a linear or branched C^-C^ alkyl radical, or a linear or branched Ci-C., alkoxy radical, and its therapeutically acceptable salts, its racemate or its optically active isomers. 10 Preferably, R represents a hydrogen atom, a methoxy radical or an n-propyl radical.

PHARMACOLOGICAL STUDY A pharmacological study was carried put in which 6 groups of mice were formed: Group A : Group B : Group C : Group D : Group E : represents- the control group of untreated mice, represents the group of mice having a deficiency in the activity of the locus caeruleus, after administration of DSP4 (neurotoxin selectively affecting the noradrenergic system) represents the group of , mice- having a degeneration of the dopaminergic negrostriated route as is indicated by the reduced level of striatal dopamine one week after treatment, without affecting the locus caeruleus, after administration of MPTP (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine) a neurotoxin which produces parkinsonian signs. represents the model group of pathological mice, after administration of both DSP4 and MPTP.

The mice of Group D compounds according LU O * { tL. 0 CO CD CD 1 i £ CO Lu are then treated with th«[M, l£l C=> o& to the invention :l Q UJ > LU O LU ££ 2-(2-(1,4-benzodioxanyl))-2-imidazoline (El), 2-methoxy-2- (2 - (1,4-benz odioxanyl) ) - 2 -imidazoline (E2) and 2-n-propyl-2-(2-(1,4-benzodioxanyl))-2-imidazoline (E3).

The mice of Group D are then treated with 1-DOPA + carbidopa (reference antiparkinsonian product).

The mice of Group D are then treated with apomorphine (dopaminergic agonist).

The results are given in Table 1 below: TABLE 1 Experimental Cortical NA Striatale DA * to *** level of degeneration estimated by decrease of cortical NA. and striatale DA levels.

The cortical levels of noradrenaline and the striatal dopamine levels are measured after stopping the treatment. It is thus observed that the treatment with .idazoxan or its derivatives (Group E) brings about a slowing down of the degeneration of dopaminergic neurones caused by DSP4 and MPTP and objectivized by the slowing 3 0 down of the decrease in striatal dopamine compared with 1-DOPA (Group F) or with apomorphine (Group G) .

A particularly unexpected improvement is therefore observed for the striatal DA level using idazoxan and its derivatives according to the invention 3 5 compared with 1-DOPA and apomorphine.

The use of idazoxan was also studied in squirrel monkeys according to a procedure similar to that of M. MAVRIDIS et al. , Neuroscience 4JL, 507 (1991).

Group F : Group G : group level level A - - B. * C - * + p * * * * El * * E2 * * E3 * * p + * * * G * : ' The behavioral, biochemical and histological results show that a lesion of the noradrenergic system induces degeneration of the negrostriated route after administration of MPTP. The administration of idazoxan 5 reduces the effect of the lesion of the negrostriated route and improves the development.

GALKNUCAIi STUDY The pharmaceutical compositions are administered orally in the form of hard gelatin capsules or tablets 10 containing doses of 1 to 20 0 mg of active ingredient, more particularly 5, 10, 20 and 40 mg per tablet, or intravenously in the form of injectable solutions containing ->ses of 0.1 to 10 mg of idazoxan.

CLINICAL STUDY 20 patients satisfying the idiopathic criteria of Parkinson's disease were selected and a double blind study was carried out against 1-DOPA.

The administrations were carried out orally, for 1-DOPA, in a dose range increasing from 500ng to 4g per day, and for idazoxan from the initial dose of 3 times 5mg per day, increasing to a maximum of 3 times 40g per day, the practitioner defining the exact posology for each patient.

The efficacy of the treatments were measured on motor symptoms, of the action, intention or passive tremor type, on hypokinesia (late symptoms) and 25 flickering of the eyelids (early symptom of the disease) . The observations were made during the treatment and after stopping the treatment in order to demonstrate recovery and persistence of the improvement of the symptoms.

Claims (4)

IDAZOXAN 1-DOPA during treatment persistence of improvement after treatment during treatment: persistence of improvement after treatment Late symptoms + + +++ O Baxly symptoms ++ ++ +++ O O : no changes compared with the former treatment + to +++ improvement. These results show, compared with the prior art treatments, a clear improvement which persists after treatment, both for the early symptoms and the late symptoms. - 7 - 258 59 1 CLAIMS

1. Uee of a compound of general formula I in which. R represents a hydrogen atom/ a linear or branched Ct-C4 alkyl radical or a linear or branched C1-C4 5 alkoxy radical, and its therapeutically acceptable salts, its racemate or its optically active isomers for the preparation, of a medicinal product intended for the treatment of Parkinson's disease, and its development. 10

2. Use according to Claim 1, characterized in that R represents a hydrogen atom.

3 . Use according to Claim 1, characterized in that R represents a stethoxy radical.

4. Use according to Claim 1, characterized in 15 that R represents an n-propyl radical. END OF CLAIMS MR