Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-22
2002-05-28
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S324000
Reexamination Certificate
active
06395742
ABSTRACT:
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
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
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
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
1-like
antagonistic activity.
The 2,4-diaminopyrimidine derivatives of the present invention surprisingly show a high degree of dopamine D
4
receptor binding affinity. Moreover, the present compounds have a selective affinity for the dopamine D
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 &sgr;-binding site.
The present invention concerns compounds having the formula
the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein
Alk is C
1-6
alkanediyl or C
3-6
alkenediyl;
R
1
is hydrogen or C
1-4
alkyl;
R
2
and R
3
each independently are hydrogen, C
1-6
alkyl or C
3-7
cycloalkyl; or
R
2
and R
3
may also be taken together with the nitrogen atom to which they are attached, thus forming a pyrrolidine, a piperidine or a perhydro azepine ring;
R
4
is hydrogen or halo;
Q is aryl, aryloxy, di(aryl)methyl or heteroaryl;
aryl is naphthyl or phenyl, said naphthyl and phenyl may optionally be substituted with one, two or three substituents selected from halo, hydroxy, C
1-4
alkyl, C
1-4
alkyloxy, C
1-4
alkylcarbonyl, haloC
1-4
alkyl, nitro, amino, cyano and phenyl; and
heteroaryl is quinolinyl, isoquinolinyl, pyridinyl, thienyl, indolyl, 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
1-4
alkyl, C
1-4
alkyloxy, C
1-4
alkylcarbonyl, haloC
1-4
alkyl and phenyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
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
1-6
alkyl is meant to include C
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
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
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-penten-1,5-diyl, 3-penten-1,5-diyl, 3-methyl-2-buten-1,4-diyl, 3-hexen-1,6-diyl and the like; and the carbon of said C
3-6
alkenediyl connected to the nitrogen atom of the piperidine ring preferably is saturated; haloC
1-4
alkyl is defined as polyhalosubstituted C
1-4
alkyl, in particular C
1-4
alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl.
The heteroaryl group represented by Q may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heteroaryl group is benzodioxolanyl, it may be a 2-benzodioxolanyl, 4-benzodioxolanyl, 5-benzodioxolanyl, 6-benzodioxolanyl and 7-benzodioxolanyl; when it is quinolinyl, it may be 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl; when it is 2,3-dihydro-benzofuranyl, it may be 2,3-dihydro-benzofuran-2-yl, 2,3-dihydro-benzofuran-3-yl, 2,3-dihydro-benzofuran-4-yl, 2,3-dihydro-benzofuran-5-yl, 2,3-dihydro-benzofuran-6-yl and 2,3-dihydro-benzofuran-7-yl.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salts can be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, hydroxy-acetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, flumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
The term “stereochemically isomeric forms” as used hereinbefore and hereinafter defines all the possible isomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, and in particular the racemic mixture, of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are obviously intended to be encompassed by formula (I).
Preferably, R
1
is C
1-4
alkyl.
Preferably, R
2
is C
1-6
alkyl or C
3-7
cycloalkyl and R
3
is hydrogen or C
1-6
alkyl, or R
2
and R
3
are taken together with the nitrogen atom to which they are attached, thus forming a pyrrolidine ring. Preferably, Alk is a straight chained C
1-6
alkanediyl or a straight chained C
3-6
alkenediyl, more in particular, Alk is methylene, 1,3-propanediyl or 1,4-butanediyl. Suitably, aryl is 2-naphthyl, 3-naphthyl, phenyl or mono- or disubstituted phenyl. Suitably, heteroaryl is optionally substituted 2-quinolinyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-indolyl, 2,3-dihydro-1,4-benzodioxin-2-yl, 2,3-dihydrobenzofuran-5-yl or 5-benzodioxolanyl.
A first group of particular compounds are those compounds of formula (I) wherein Alk is a straight chained C
1-6
alkanediyl and Q is optionally substituted
Bosmans Jean-Paul Rene Marie Andre
Love Christopher John
Van Lommen Guy Rosalia Eugene
Appollina Mary A.
Janssen Pharmaceutica N.V.
Liu Hong
Shah Mukund J.
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