Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-28
2002-07-09
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S075000
Reexamination Certificate
active
06417222
ABSTRACT:
Dopamine is a neuromediator which participates in controlling motricity, cognitive functions and mood, and is involved in the compensation circuit. Five types of dopaminergic receptors have been cloned (D
1
-D
5
) and their levels of expression and cerebral distributions have been analyzed. Among these five types of receptor, at least two types have isoforms (Proc. Natl. Acad. Sci. USA 1998, 95, 7731). Although these five types of dopaminergic receptor are pharmacologically distinct, they have been grouped into 2 subfamilies: the D
1
subfamily, which comprises the D
1
and D
5
receptors, and the D
2
subfamily, which comprises the D
2
, D
3
and D
4
receptors. It is possible to differentiate the pharmacological action of the D
1
and D
2
subfamilies, but it is generally difficult to differentiate the function of the various types within each subfamily.
A dysfunction of dopaminergic transmission is involved in the symptomatology of central nervous system disorders such as schizophrenic psychosis (Neuropsychopharmacol. 1988, 1, 179), certain neurodegenerative diseases such as, for example, Parkinson's disease (Neurodegenerative Diseases; Jolles, G.; Stutzmann, J. M.; Eds; Academic Press, 1994, Chap. 8), depression (J. Clin. Psychiatry, 1998, 59 (Suppl. 5), 60), the dependance on certain substances such as, for example, cocaine, tobacco or alcohol (Cell 1997, 90, 991; Nature 1997, 388, 586). Thus, for example, antagonists of central dopaminergic receptors of the D
2
type constitute a conventional and clinically effective approach in the treatment of the positive symptoms of schizophrenic psychosis. However, most of the compounds having such a mechanism of action also induce adverse side effects such as symptoms of Parkinson type (Pharmacotherapy 1996, 16, 160) and/or neuroendocrine disorders (Acta Psychiatr. Scand. 1989, 352, 24).
Mewshaw et al. (Bioorg. Med. Chem. Lett. 1998, 8, 295) have described phenoxyethylamines of formula:
in which X represents a hydrogen atom, a hydroxyl group, an amino group or a methanesulfonamide group, Y represents a hydrogen atom or a halogen atom and Ar is a phenyl or 2-thienyl group, as being partial agonists of the receptor of the D
2
type.
Patents WO 98/08817, U.S. Pat. No. 5,760,070, WO 98/08843 and WO 98/08819 describe, respectively, 4-aminoethoxyindoles and 4-aminoethoxyindolones as being agonists of dopaminergic receptors of the D
2
type or inhibitors of the synthesis and release of dopamine.
Unangst et al. (J. Med. Chem. 1997, 40, 4026) have described aryloxyalkylamines of formula:
in which X represents a n oxygen or sulfur atom or a CH
2
group; R
1
is a hydrogen or chlorine atom, a hydroxyl or hydroxymethyl group, a nitro group or a hydroxy-carbonyl residue; R
2
and R
3
represent a hydrogen atom, a halogen atom or a methyl group. These compounds are active on the dopaminergic system, in particular on the receptors of the D
4
type, and are potentially useful in the treatment of schizophrenia.
Patent WO 97/23482 describes octahydropyrrolo[1,2-a]-pyrazines of formula:
in which X represents, inter alia, an oxygen atom; m and n=0, 1, 2 and R
1
is an unsubstituted, heterocyclic or non-heterocyclic, polycyclic or non-polycyclic aromatic group. These compounds have affinity for the dopaminergic receptors, in particular for the receptors of the D
4
type.
Patents FR 2 702 211, JP 51 048 627, JP 51 052 146, DE 2 450 616 and WO 96/31461 describe 2-[2-(alkoxy)phenoxy]ethylamine derivatives of formula:
in which R is a C
1
-C
4
alkyl group and R
1
represents a 4-benzenebutyl, piperidine-4-methyl or 4-benzamidobutyl chain. These compounds are claimed as being ligands of the receptors of the 5-HT
1A
subtype (FR 2 702 211 and WO 96/31461) or hypotensive agents and tranquilizers (JP 51 048 627, JP 51 052 146 and DE 2 450 616). Patent EP 707 007 describes arylamines with twofold activity: both antagonist of the receptors of the D
2
type, and agonist of the 5-HT
1A
subtype, and which are useful as antipsychotic agents. The compound EMD-12830 (Drug Data Report 1998, 21) of formula:
is claimed as an atypical antipsychotic agent (i.e. an agent with a reduced propensity to cause side effects of Parkinson type than the conventional antipsychotic agents).
Patent DE 2 364 685 describes phenoxyalkylamines, in particular N-[2-(2-methoxyphenoxy)ethyl]-3- or -4-pyridylmethanamine, are [sic] claimed as hypotensive agents.
Angstein et al. (J. Med. Chem. 196 5, 8, 356) have described aryloxyalkylamines that are active on the cardiovascular system. Among the compounds described is N-[2-(2-methoxyphenoxy)ethyl]benzenemethanamine.
Goldenberg et al. (Chim. Ther. 1973, 8, 259) have described, inter alia, N-[2-(2-methoxyphenoxy)ethyl-2-benzofuranmethanamines as agents with peripheral vasodilatory properties.
4-Methoxy-3-[2-[(phenylmethyl)amino]ethoxy]phenol is described in J. Labelled Compd. Radiopharm. 1993, 33, 1091 and N-[2-(2-methoxyphenoxy)ethyl]furfurylamine is described in FR 1 336 684.
Patent WO 98/11068 describes 1-(2-pyrimidyl)-4-[(3-aryl)benzyl]piperazines as selective ligands of the receptors of the D
4
subtype.
SUMMARY OF THE INVENTION
The present invention relates to a novel family of compounds which correspond to the general formula (1)
The compounds of this invention have antidopaminergic activity, in particular on the receptors of the D
2
subfamily. In this respect, the compounds of the invention are useful in the treatment of conditions resulting from dopaminergic hyperactivity, such as schizophrenic symptoms and dependency on certain substances. However, the antagonist activity of the products of the invention on the receptors of the D
2
type is exerted only during a transient dopaminergic hyperstimulation. In the absence of dopaminergic hyperactivity, that is to say when the dopamine concentration ranges within proportions that are acceptable for normal functioning of the neuron, the compounds of the invention do not induce dopaminergic hypoactivity. The compounds of the invention are thus useful in the treatment of schizophrenic symptoms and have the advantage of being potentially free of the adverse side effects caused by an excessive blocking of the receptors of the D
2
type, such as Parkinsonian symptoms and/or endocrine disorders, at doses that are therapeutically effective for treating schizophrenic psychosis.
The compounds of the invention thus differ from the derivatives of the prior art in their chemical formula and their mechanism of action.
REFERENCES:
patent: 2 248 830 (1975-05-01), None
patent: 94/20466 (1994-09-01), None
patent: 2000032557 (2000-06-01), None
Mewshaw, et al, 1997, Bioorg. Med. Chem. Lett., 8(3), 295-300.
Cuisiat Stéphane
Koek Wouter
Vacher Bernard
D'Souza Small Andrea
Higel Floyd D.
Pierre Fabre Medicament
Sage G. Patrick
The Firm of Hueschen and Sage
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