Substitute pyrimidine compounds and the use thereof

Details Substitute pyrimidine compounds and the use thereof Substitute pyrimidine compounds and the use thereof

1997-01-14

2002-01-29

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S310000, C544S316000, C544S319000, C544S324000, C544S332000, C544S182000, C514S241000, C514S242000, C514S245000, C514S269000, C514S272000, C514S274000

Reexamination Certificate

active

06342604

ABSTRACT:

The invention relates to substituted pyrimidine compounds and to the use of such compounds. Said compounds have valuable therapeutic properties and can be used in particular to treat disorders which respond to dopamine D
3
ligands.
Compounds which are of the type under discussion here and have physiological activity have in some cases been disclosed. Thus, DE 21 39 082 and DE 22 58 561 describe pyrimidine derivatives and pyrimidone derivatives with basic substituents as drugs for lowering blood pressure. These pyrimidine and pyrimidone derivatives have the formulae:
where in (A) X is, inter alia, sulfur, A is C
1
-C
6
-alkylene, and R
1
, R
2
, R
3
and Z are various substituents. In (B), X and Y are each oxygen or sulfur, A is C
2
-C
6
-alkylene and R and Z are various substituents.
Neurons receive their information inter alia via G protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of them is dopamine.
Confirmed findings on the presence of dopamine and its physiological function as neurotransmitter have been published. Cells which respond to dopamine are connected with the etiology and schizophrenia and Parkinson's disease. These and other disorders are treated with drugs which interact with dopamine receptors.
By 1990, two subtypes of dopamine receptors had been clearly defined pharmacologically, namely D
1
and D
2
receptors.
Sokoloff et al., Nature 1990, 347: 146-151, found a third subtype, namely D
3
receptors. They are expressed mainly in the limbic system. The D
3
receptors differ structurally from the D
1
and D
2
receptors in about half the amino-acid residues.
The effect of neuroleptics has generally been ascribed to their affinity for D
2
receptors. Recent receptor-binding studies have confirmed this. According to these, most dopamine antagonists, like neuroleptics, have high affinity for D
2
receptors but only low affinity for D
3
receptors.
DE-A 19 46 172 describes heterocyclic ethers of the formula
where R
1
is a mononuclear, unsaturated, nitrogen-containing, heterocyclic ring system which may be substituted by lower alkyl, lower alkoxy, phenylalkyl or phenyl groups, R
2
is phenyl which is unsubstituted or substituted by lower alkyl or lower alkoxy groups or chlorine or bromine atoms and which may contain 1 or 2 nitrogen atoms in the ring, and A is a straight-chain or branched alkylene radical with 2 to 6 carbon atoms. These compounds have &agr;-sympathicolytic activity and accordingly have a sedative, hypotensive and vasodilating effect.
We have now found, surprisingly, that certain pyrimidine compounds have a high affinity for the dopamine D
3
receptor and a low affinity for the D
2
receptor. They are thus selective D
3
ligands.
The present invention therefore relates to the use of pyrimidine compounds of the general formula I:
where
A is C
1
-C
18
-alkylene which may comprise at least one group selected from O, S, NR
4
, CONR
4
, NR
4
CO, COO, OCO and a double or triple bond,
B is
R
1
, R
2
, R
3
are selected, independently of one another, from among H, halogen, OR
4
, NR
4
R
5
, SR
4
, CF
3
, CN, CO
2
R
4
and C
1
-C
8
-alkyl which is unsubstituted or substituted by OH, OC
1
-C
8
-alkyl or halogen,
R
4
is H, C
1
-C
8
-alkyl which is unsubstituted or substituted by OH, OC
1
-C
8
-alkyl or halogen,
R
5
has the meanings indicated for R
4
or is COR
4
or CO
2
R
4
;
Ar is phenyl, pyridyl, pyrimidyl or triazinyl, where Ar may have from one to four substituents which are selected, independently of one another, from OR
5
, C
1
-C
8
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, halogen, CN, CO
2
R
4
, NO
2
, SO
2
R
4
, SO
3
R
4
, NR
4
R
5
, SO
2
NR
4
R
5
, SR
4
, CF
3
, CHF
2
, a 5- or 6-membered carbocyclic aromatic or non-aromatic ring and a 5- or 6-membered heterocyclic aromatic or non-aromatic ring having 1 to 3 hetero atoms which are selected from O, S and N, where the ring may be unsubstituted or substituted by C
1
-C
8
-alkyl, Hal, OC
1
-C
8
-alkyl, OH, NO
2
, CF
3
, and where Ar may also be fused to a carbocyclic or heterocyclic ring of the type defined above,
 and the salts thereof with physiologically tolerated acids for producing a pharmaceutical composition for treating disorders which respond to dopamine D
3
receptor antagonists or agonists.
The invention also relates to the pyrimidine compounds of the formula I′
where
A, B, Ar, R
1
, R
2
and R
3
have the meanings stated in claims
1
to
8
, and the salts thereof with physiologically tolerated acids, excepting the compounds of the formula
wherein R
1
is OH or SH, R
2
and R
3
are, independently one of another, H, C
1
-C
6
-alkyl, OC
1
-C
6
-alkyl, SC
1
-C
6
-alkyl, CO
2
H, OH, SH, NR
4
R
5
or halogen, where R
4
and R
5
are H or C
1
-C
6
-alkyl, A is SC
1
-C
6
-alkylene, NHC
1
-C
6
-alkylene or N(C
1
-C
6
-alkyl)-C
1
-C
6
-alkylene, B is
and Ar is phenyl which may have one or more substituents selected from C
1
-C
4
-alkyl, OC
1
-C
4
-alkyl, SC
1
-C
4
-alkyl, NO
2
, CF
3
, F, Cl or Br.
The compounds used according to the invention are selective dopamine D
3
receptor ligands which intervene regioselectively in the limbic system and, because of their low affinity for the D
2
receptor, have fewer side effects than classical neuroleptics, which are D
2
receptor antagonists. The compounds can therefore be used to treat disorders which respond to dopamine D
3
receptor antagonists or agonists, eg. for treating disorders of the central nervous system, in particularly schizophrenia, depression, neuroses and psychoses. They can additionally be used to treat sleep disorders and nausea and as antihistamines.
Within the scope of the present invention, the following terms have the meanings indicated below: alkyl (also in radicals such as alkoxy, alkylamino, etc.) means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and, in particular, 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of one another, from OH and OC
1
-C
8
-alkyl.
Examples of an alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl, etc.
Alkylene stands for straight-chain or branched radicals having, preferably, 2 to 15 carbon atoms, particularly preferably3 to 10 carbon atoms.
The alkylene groups may comprise at least one of the abovementioned groups. This can—just like the double or triple bond mentioned—be arranged in the alkylene chain at any point or at the end of the chain so that it connects the chain to the pyrimidine residue. The latter is preferred. When the alkylene group comprises a double or triple bond, it has at least three carbon atoms in the chain.
Halogen is F, Cl, Br, I and, in particular, Cl, Br, I.
R
1
, R
2
and R
3
are preferably, independently of one another, H, C
1
-C
8
-alkyl, NR
4
R
5
, SR
4
or OR
4
, where R
4
and R
5
are, independently of one another, H or C
1
-C
8
-alkyl.
Ar preferably has one or two substitutents which are selected, independently of one another, from OR
5
, C
1
-C
8
-alkyl, Hal, CN, CO
2
R
4
, NO
2
, SO
2
R
4
, SO
3
R
4
, NR
4
R
5
, SO
2
NR
4
R
5
, SR
4
, CF
3
, CHF
2
, a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- to 6-membered heterocyclic, aromatic or non-aromatic ring having 1 to 3 hetero atoms which are selected from O, S and N, where the ring may be unsubstituted or substituted by C
1
-C
8
-alkyl, Hal, OC
1
-C
8
-alkyl, OH, NO
2
, CF
3
and where Ar may also be fused to a carbocyclic or heterocyclic ring of the type defined above.
If Ar has one or two substituents, these are preferably in the m position.
They are preferably selected independently from halogen, CF
3
, CHF
2
, CN, NO
2
, OR
4
, NR
4
R
5
, C
1
-C
8
-alkyl, OC
1
-C
8
-alkyl, phenyl and SR
4
, where R
4
and R
5
are H or C
1
-C
8
-alkyl. If one of the substituents is C
1
-C
8
-alkyl, a branched group and, in particular, isopropyl or t-butyl is preferred.
Ar preferably has at least one substituent and is, in particular,
where D
1
, D
2
and D
3
are, independently of one an

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