3-alkoxybenzylamine derivatives and their use as medicines...

Details 3-alkoxybenzylamine derivatives and their use as medicines... 3-alkoxybenzylamine derivatives and their use as medicines...

2001-05-29

2002-02-26

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S353000, C564S347000, C514S651000

Reexamination Certificate

active

06350913

ABSTRACT:

Dopamine is a neuromnediator which is involved in controlling motricity, cognitive functions and moods, and is involved in the compensation circuit. Five types of dopaninergic receptor (D
1
-D
5
) have been cloned 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 pharmacologically different, these five types of dopaminergic receptor have been grouped into two subfamilies: the subfamily D
1
, which comprises the D
1
and D
5
receptors, and the subfamily D
2
which comprises the D
2
, D
3
and D
4
receptors. It is possible to differentiate the pharmacological action of the subfamilies D
1
and D
2
, 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 disorders of the central nervous system 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), and dependency on certain substances such as, for example, cocaine, tobacco or alcohol (Cell 1997, 90, 991; Nature 1997, 388, 586).
Thus, for example, antagonists of the D
2
-type central dopaminergic receptors constitute a conventional and clinically effective approach towards treating the positive symptoms of schizophrenic psychosis. However, most of the compounds with such a mechanism of action also induce adverse side effects such as Parkinson-type symptoms (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 disclosed 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 D
2
-type receptors.
Patents WO 98/08817, U.S. Pat. No. 5,760,070, WO 98/08843 and WO 98/08819 respectively disclose 4-aminoethoxyindoles and 4-aminoethoxyindolones as being agonists of D
2
-type dopaminergic receptors or inhibitors of dopamine synthesis and release.
Unangst et al. (J. Med. Chem. 1997, 40, 4026) have disclosed aryloxyalkylamines of formula:
in which X represents an 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 hydroxycarbonyl 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 D
4
-type receptors, and are potentially useful for treating schizophrenia.
Patent WO 97/23482 discloses octahydropyrrolo[1,2-a]pyrazines of formula:
in which X represents, inter alia, a hydrogen atom; m and n=0, 1 or 2 and R
1
is an unsubstituted, heterocyclic or non-heterocyclic, polycyclic or non-polycyclic aromatic group. These compounds have affinity for dopaminergic receptors and in particular for the D
4
-type receptors.
Patents FR 2 702 211, JP 51 048 627, JP 51 052 146, DE 2 450 616 and WO 96/31461 disclose 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, 4-piperidinemethyl or 4-benzamidobutyl chain. These compounds are claimed as being ligands of the 5-HT
1A
sub-type receptors (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 discloses arylamines with twofold activity simultaneously antagonist towards D
2
-type receptors and agonist towards 5-HT
1A
sub-type receptors, 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 less of a propensity to induce Parkinson-type side effects than conventional antipsychotic agents).
Patent DE 2 364 685 discloses phenoxyalkylamines, in particular N-[2-(2-methoxyphenoxy)ethyl]pyrid-3- or 4-ylmethanamine are claimed as hypotensive agents.
Angstein et al. (J. Med. Chem. 1965, 8, 356) have disclosed aryloxyalkylamines which are active on the cardiovascular system. Among the compounds disclosed is N-[2-(2-methoxyphenoxy)ethyl]benzenemethanamine.
Goldenberg et al. (Chim. Ther. 1973, 8, 259) have disclosed, inter alia, N-[2-(2-methoxyphenoxy)ethyl-2-benzofuranmethanamines as agents with peripheral vasodilatatory properties.
4-Methoxy-3-[2-[(phenylmethyl)amino]ethoxy]phenol is disclosed in J. Labelled Compd. Radiopharm. 1993, 33, 1091 and N-[2-(2-methoxyphenoxy)ethyl]furfurylamine is disclosed in FR 1 336 684.
3-(Cyclopentyloxy)benzenemethanamine derivatives of formula:
in which R represents a hydroxyl or methoxy group and R
1
represents an aromatic group or a substituted acyl or thioacyl group, are claimed as phosphodiesterase inhibitors in patents WO 97/46561, WO 95/20578, WO 95/04045, WO 94/02465 and WO 93/15044 or as active agents in the treatment of cardiac insufficiency in U.S. Pat. No. 4,971,959.
Patent WO 92/00968 discloses derivatives of formula:
in which R represents a C
4
-C
6
cycloalkyl group and X is a hydrogen, fluorine or chlorine atom, are claimed for their activity in controlling disorders dependent on TNF production.
Patent WO 98/01417 discloses aromatic and heteroaromatic compounds of formula:
in which Ar
2
is, inter alia, an aromatic group optionally substituted with a non-cyclic lower alkoxy group. These compounds are claimed as influencing calcium receptors.
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 subfamily D
2
. In this respect, the compounds of the invention are useful in the treatment of complaints 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 D
2
-type receptors is exerted only during a transient dopaminergic hyperstimulation. In the absence of dopaminergic hyperactivity, i.e. when the dopamine concentration varies within proportions that are acceptable for normal functioning of neurones, the compounds of the invention do not induce a dopaminergic hyperactivity. 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 brought about by excessive blocking of the D
2
-type receptors, such as Parkinson-type 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.
DETAILS OF THE INVENTION
More specifically, the present invention relates to novel compounds corresponding to the general formula (1):
in which:
X
1
is a hydrogen, chlorine or fluorine atom;
X
2
has the same meaning as X
1
;
R
1
represents:
a hydrogen, chlorine or fluorine atom;
a substituent R
4
, a hydroxyl (OH) group, an alkoxy (OR
4
) group, an alkylcarbonyloxy (OC(O)R
4
) group, an alkylcarbonyl (C(O)R
4
) group, an amino (NH
2
) group, an alkylamino (NHR
4
) group, a dialkylamino (N(R
4
)
2
) group, a [lacuna] (NHC(O)R
4
) group or a cyano (CN) group;
R
2
is a substituent R
4
or an alkoxy (OR
4
) group;
R
3
has the same meaning as R
1
;
R
4
represents:
a linear or branched C
1
-C
5
alkyl radical optionally substituted with 1 or 2 fluorine atoms or a hydroxyl (OH) group and optionally containing a double bond;
a 3-,

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