Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1998-11-23
2000-01-18
Bernhardt, Emily
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
544294, 544360, 544363, 544376, 546144, 546146, 546194, 546203, 546204, 5462841, 546285, 546265, 5462811, C07D21170, C07D29515
Patent
active
060159006
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain N-alkylaminofluorenecarboxamides and pharmaceutical compositions containing them. It also relates to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases. The use of the compounds of this invention to the treatment of these disorders is indicated by the ability of the compounds to bind selectively to dopamine receptor subtypes.
2. Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D.sub.2 receptors in the striatal region of the brain. The dopamine D.sub.3 receptor subtype has recently been identified (Sokoloff, P. et al., Nature 1990, 347, 146). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D.sub.3 receptor may play a major role in the etiology of schizophrenia. Selective D.sub.3 antagonists may be effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics.
U.S. Pat. No. 5,395,835 (May 24, 1994) discloses N-aminoalkyl-2-napthamides which have affinity at dopamine D.sub.3 receptors. The novel compounds of Claim 1 of the present invention differ significantly from this prior art in that they possess a fluorenecarboxamide substructure.
Murray, P. J. et al. (A Novel Series of Arylipiperazines with High Affinity and Selectivity for the Dopamine D.sub.3 Receptor. Bioorg. Med. Chem. Let, 1995, 5, 219) described: carboxamnidobiphenyls which have affinity at dopamine D.sub.3 receptors. The novel compounds of the present invention differ significantly from this prior art in that the two aromatic rings of the aromatic carboxamide are fused at the ortho position to create a tricyclic ring system.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes. Thus, the invention provides compounds of general Formula I useful in the treatment and/or prevention of various neuropsychological disorders. The invention also provides pharmaceutical compositions comprising compounds of Formula I.
The invention further relates to the use of such compounds in the treatment of affective disorders such as schizophrenia, depression, Alzheimer's disease and certain movement disorders such as Parkinsonism and dystonia. Furthermore compounds of this invention are useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. The compounds of the present invention are also useful for the treatment of other disorders which respond to doparninergic blockade such as substance abuse and obsessive compulsive disorder. Since dopamine D3 receptors are concentrated in the limbic system (Taubes, Science 265 (1994) 1034) which controls cognition and emotion, compounds which interact with these receptors have utility in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders involving memory impairment or attention deficit disorders can also be treated with the compounds of this invention that interact specifically with the dopamine D3 receptor subtype.
Accordingly, a broad embodiment of the invention is directed to a compound of Formula I: ##STR2## or the pharmaceutically acceptable salts thereof wherein: G represents a group of the formula ##STR3## where R.sub.a and R.sub.b independently represent hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy, C.sub.1 -C.sub.6 alkoxy or mono- or di-C.sub.1 -C.sub.6 alkylamino; alkyl groups having from one to four carbon atoms; hydrogen, C.sub.1 -C.sub.6 alkyl, halo
REFERENCES:
patent: 5395835 (1995-03-01), Glase et al.
patent: 5659033 (1997-08-01), Yuan et al.
patent: 5932734 (1999-08-01), Yuan et al.
Chen Xi
Yuan Jun
Bernhardt Emily
Neurogen Corporation
Sarussi Steven J.
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