2,4-diaminopyrimidine derivates as dopamine D4 receptor antagoni

Details 2,4-diaminopyrimidine derivates as dopamine D4 receptor antagoni 2,4-diaminopyrimidine derivates as dopamine D4 receptor antagoni

1998-11-09

2000-12-12

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544324, C07D40112, C07D40514, C07D40114, A61K 31505

Patent

active

061599824

DESCRIPTION:

BRIEF SUMMARY
The present invention concerns 2,4-diaminopyrimidine derivatives; it further relates to processes for their preparation, compositions comprising them, as well as their use as a medicine. The compounds of the present invention exhibit specific dopamine D.sub.4 receptor antagonism and may particularly be useful as antipsychotics, especially in the treatment and/or prevention of psychotic disorders such as schizophrenia. In addition, the present invention concerns compounds of formula (I) containing a radioactive isotope; a process of marking dopamine D.sub.4 receptor sites; and a process for imaging an organ.
It is generally accepted knowledge that dopamine receptors are important for many biochemical functions in the animal body. For example, altered functions of these receptors not only participate in the genesis of psychosis, but also of anxiety, emesis, motoric functions, addiction, sleep, feeding, learning, memory, sexual behaviour, regulation of immunological responses and blood pressure. Since dopamine receptors control a great number of pharmacological events, some of which are thus far unknown, there is a possibility that compounds which exhibit a specific binding affinity for the D.sub.4 receptor may exert a wide range of therapeutic effects in humans.
EP-A-0,379,806, published on Aug. 1, 1990, discloses N-[2-[(4-piperidinyl)amino]-4-pyrimidinyl]benzamides and generically describes 2-[(4-piperidinyl)amino]-4-(mono- or di(alkyl)amino)-pyrimidine derivatives, all having therapeutic potential in neurological diseases of the peripheral and central nervous systems of animals. Further, WO 93/17017published on Sep. 2, 1993, generically discloses N-[1-(2,3-dihydro-(1,4-benzodioxin or benzofuranyl)-2-ylalkyl)-4-piperidinyl]-2,4-diaminopyrimidine derivatives showing 5-HT.sub.1-like antagonistic activity.
The 2,4-diaminopyrimidine derivatives of the present invention surprisingly show a high degree of dopamine D.sub.4 receptor binding affinity. Moreover, the present compounds have a selective affinity for the dopamine D.sub.4 receptor over other dopamine receptors in the human body. The subject compounds also show variable affinity for other receptors such as, for example, the .sigma.-binding site.
The present invention concerns compounds having the formula ##STR2## the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein C.sub.3-7 cycloalkyl; or which they are attached, thus forming a pyrrolidine, a piperidine or a perhydro azepine ring; substituted with one, two or three substituents selected from halo, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, C.sub.1-4 alkylcarbonyl, haloC.sub.1-4 alkyl, nitro, amino, cyano and phenyl; and 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-benzofuranyl or benzodioxolanyl; said heteroaryls may optionally be substituted with one, two or three substituents selected from halo, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, C.sub.1-4 alkylcarbonyl, haloC.sub.1-4 alkyl and phenyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo: C.sub.1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C.sub.1-6 alkyl is meant to include C.sub.1-4 alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C.sub.1-6 alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, 1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4 butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,2-propanediyl, 2,3-butanediyl and the like; C.sub.3-6 alkenediyl defines bivalent straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propen-1,3-diyl, 3-buten-1,4-diyl, 2-buten-1,4-diyl, 2-pe

REFERENCES:
Ross, Chapeter 2 in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, P. 33-35, 1990.
Schotte et al. Psychopharmacology 124:57-73, 1996.

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