Pyrimidine compounds and their use

1. A compound of the formula (I):

wherein

Y and Z represent both nitrogen and X represents CH, forming a pyrimidine derivative, and wherein R 1 and R 2 are each, independently, selected from a group A consisting of

or from a group B, consisting of aryl-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkoxy, heteroaryl-C 1 -C 6 -alkoxy, aryloxy-C 2 -C 6 -alkoxy, heteroaryloxy-C 2 -C 6 -alkoxy, 1-indanyloxy, 2-indanyloxy, aryloxy, heteroaryloxy, arylthio, heteroarylthio, C 5 -C 6 -cycloalkylthio, C 5 -C 8 -alkoxy, C 5 -C 8 -alkylthio, C 3 -C 6 -alkynyloxy, C 3 -C 6 -alkenyloxy, fluoro-C 2 -C 4 -alkoxy, C 4 -C 8 -cycloalkyloxy, C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkoxy, aryl-C 1 -C 4 -alkylthio, heteroaryl-C 1 -C 4 -alkylthio, aryl-C 1 -C 4 -alkylamino, heteroaryl-C 1 -C 4 -alkylamino, heteroaryl and aryl;

with the proviso that:

(i) R 1 and R 2 are different and are not both selected from group A or group B at the same time;

(iii) when X is CH and Z and Y both are nitrogen in formula (I), forming a pyrirnidine derivative, and R 2 is 1-piperazinyl, then R 1 is other than phenoxy, phenyl or phenyl substituted by bromo, and C 5 -C 8 alkoxy; and when R 2 is 4-methylpiperazin-1-yl or 4-(2-hydroxyethyl)piperazin-1-yl, then R 1 is other than 5-nitro-2-furyl;

(iv) when X is CH and Z and Y both are nitrogen in formula (I), forming a pyrimidine derivative, and R 1 is 1-piperazinyl, then R 2 is other than C 5 -C 8 alkoxy;

and where R 3 is H or C 1-4 -alkyl, allyl, 2-hydroxyethyl, 2-cyanoethyl, or a nitrogen protecting group;

R 4 is hydrogen, or C 1-4 alkyl;

and wherein any aryl or heteroaryl residue, alone or as part of another group, in R 1 or R 2 may be independently substituted in one or more positions, by C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -alkylthio, C 2-4 -acyl, C 1-4 -alkylsulphonyl, cyano, nitro, hydroxy, C 2-6 -alkenyl, C 2-6 -alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, —N(R 5 )(R 6 ), aryl, aryloxy, arylthio, aryl-C 1-4 -alkyl, aryl-C 2-4 -alkenyl, aryl-C 2-4 -alkynyl, heteroaryl, heteroaryloxy, heteroarylthio or heteroaryl-C 1-4 -alkyl, aryl-C 1-4 -alkoxy, aryloxy-C 1-4 -alkyl, dimethylamino-C 2-4 -alkoxy; and

wherein any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in R 1 or R 2 in turn may be substituted in one or more postions, independently of each other by C 1-4 -alkyl, C 1-4 -alkoxy, halogen, trifluoromethyl, cyano, hydroxy or dimethylamino; and

R 5 and R 6 independently of each other are hydrogen, methyl or ethyl, or together with the nitrogen atom to which they are bound form a pyrrolidine, piperazine, morpholine, thiomorpholine or a piperidine ring;

or a pharmaceutically acceptable salt, geometrical isomer, tautomer, optical isomer, or N-oxide form thereof.

2. The compound according to claim 1 wherein R 3 is hydrogen and R 1 or R 2 is selected from

3. The compound according to claim 1 wherein R 1 or R 2 is selected from

and where R 3 is hydrogen and R 4 is selected from hydrogen, methyl or ethyl.

4. The compound according to claim 1 wherein R 1 or R 2 is

and where R 3 is hydrogen and R 4 is selected from hydrogen, methyl or ethyl.

5. The compound according to claim 1 , wherein R 1 or R 2 is selected from

6. The compound according to claim 1 , which is selected from the group consisting of:

4-(Benzyloxy)-2-(1-piperazinyl)pyrimidine,

4-[(2-Methoxybenzyl)oxy]-2-(1-piperazinyl)pyrimidine, and

2-{[3-(Benzyloxy)benzyl]oxy}-4-(1-piperazinyl)pyrimidine,

or a pharmacologically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient, together with a pharmaceutically acceptable carrier.

8. A method for the treatment of an eating disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

9. A method for the treatment of obesity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

10. A method for the treatment of Alzheimer's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

11. A method for the treatment of depression, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

12. A method for the treatment of an anxiety disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

13. A method for the treatment of, epilepsy, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

14. A method for the treatment of pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

15. A method for the treatment of schizophrenia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

16. A method of making a compound formula (I):

wherein:

Y and Z represent both nitrogen and X represents CH, forming a pyrimidine derivative, and wherein R 1 and R 2 are each, independently, selected from a group A consistin of

or from a group B, consisting of aryl-C 1 -C 6 -alkoxy, heteroaryl-C 1 -C 6 -alkoxy, aryloxy-C 2 -C 6 -alkoxy, heteroaryloxy-C 2 -C 6 -alkoxy, 1-indanyloxy, 2-indanyloxy, aryloxy, heteroaryloxy, arylthio, heteroarylthio, C 5 -C 6 -cycloalkylthio, C 5 -C 8 -alkoxy, C 5 -C 8 -alkylthio, C 3 -C 6 -alkynyloxy, C 3 -C 6 -alkenyloxy, fluoro-C 2 -C 4 -alkoxy, C 4 -C 8 -cycloalkyloxy, C 3 -C 8 -cycloalkyl-C 1 -C 4 , aryl-C 1 -C 4 -alkylthio, heteroaryl-C 1 -C 4 -alkylthio, aryl-C 1 -C 4 -alkylamino, heteroaryl-C 1 -C 4 -alkylamino, heteroaryl and aryl;

with the proviso that:

(i) R 1 and R 2 are different and are not both selected from group A or group B at the same time; and

(ii) when X is CH and Z and Y both are nitrogen in formula (I), forming a pyrimidine derivative, and R 2 is 1-piperazinyl, then R 1 is other than phenoxy, phenyl or phenyl substituted by bromo, and C 5 -C 8 alkoxy; and when R 2 is 4-methylpiperazin-1-yl or 4-(2-hydroxyethyl) piperazin-1-yl, then R 1 is other than 5-nitro-2-furyl; and

(iii) when X is CH and Z and Y both are nitrogen in formula (I), forming a pyrimidine derivative, and R 1 is 1-piperazinyl, then R 2 is other than C 5 -C 8 alkoxy;

and where R 3 is H or C 1-4 -alkyl, allyl, 2-hydroxyethyl, 2-cyanoethyl, or a nitrogen protecting group;

R 4 is hydrogen, or C 1-4 alkyl;

and wherein any aryl or heteroaryl residue, alone or as part of another group, in R 1 or R 2 may be independently substituted in one or more positions, by C 1-4 -alkyl, C 1-4 -alkoxy, C1-4-alkylthio, C 2-4 -acyl, C 1-4 -alkylsulphonyl, cyano, nitro, hydroxy, C 2-6 -alkenyl, C 2-6 -alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, —N(R 5 )(R 6 ), aryl, aryloxy, arylthio, aryl-C 1-4 -alkyl, aryl-C 2-4 -alkenyl, aryl-C 2-4 -alkynyl, heteroaryl, heteroaryloxy, heteroarylthio or heteroaryl-C 1-4 -alkyl, aryl-C 1-4 -alkoxy, aryloxy-C 1-4 -alkyl, dimethylamino-C 2-4 -alkoxy;

and wherein any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in R 1 or R 2 in turn may be substituted in one or more postions, independently of each other by C 1-4 -alkyl, C 1-4 -alkoxy, halogen, trifluoromethyl, cyano, hydroxy or dimethylamino; and

R 5 and R 6 independently of each other are hydrogen, methyl or ethyl, or together with the nitrogen atom to which they are bound form a pyrrolidine, piperazine, morpholine, thiomorpholine or a piperidine ring;

or a pharmaceutically acceptable salt, geometrical isomer, tautomer, optical isomer, or N-oxide form thereof;

the method comprising:

(a) contacting a compound of the following formula:

wherein

Y and Z represent both nitrogen and X represents CH, forming a pyrirnidine derivative, and wherein each Hal is independently a halogen; with a compound selected from the group consisting of:

(i) R 2 —OH, wherein R is aryl-C 1 -C 6 -alkyl, heteroaryl-C 1 -C 6 -alkyl, aryloxy-C 2 -C 6 -alkyl, heteroaryloxy-C 2 -C 6 -alkyl, 1-indanyl, 2-indanyl, aryl, heteroaryl, C 5 -C 8 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkenyl, fluoro-C 2 -C 4 -alkyl, C 4 -C 8 -cycloalkyl, or C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, each of which is optionally substituted;

(ii) R 2 —SH, wherein R 2 is aryl, heteroaryl, C 5 -C 6 -cycloalkyl, C 5 -C 8 -alkyl, aryl-C 1 -C 4 -alkyl, or heteroaryl-C 1 -C 4 -alkyl, each of which is optionally substituted;

(iii) R 2 —NH 2 , wherein R 2 is aryl-C 1 -C 4 -alkyl or an heteroaryl-C 1 -C 4 -alkyl, each of which is optionally substituted; or

(iv) R 2 —B(OH) 2 ; wherein R 2 is heteroaryl or aryl, each of which is optionally substituted;

to form a compound of formula (IX):

wherein R 2 is selected from Group B as defined above; and

(b) contacting the compound of formula (IX) with a compound selected from the group consisting of:

or

(a′) contacting a compound of the following formula:

wherein Y and Z represent both nitrogen and X represents CH, fonriing a pyrimidine derivative, and wherein each Hal is independently a halogen; with a compound selected from the group consisting of:

to form a compound of formula (XIII):

wherein Am is an amine residue selected from the group consisting of:

(b′) contacting contacting the compound of formula (XIII) with a compound selected from the group consisting of:

(i) R 1 —OH, wherein R 1 is aryl-C 1 -C 6 -alkyl, heteroaryl-C 1 -C 6 -alkyl, aryloxy-C 2 -C 6 -alkyl, heteroaryloxy-C 2 -C 6 -alkyl, 1-indanyl, 2-indanyl, aryl, heteroaryl, C 5 -C 8 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkenyl, fluoro-C 2 -C 4 -alkyl, C 4 -C 8 -cycloalkyl, or C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl, each of which is optionally substituted;

(ii) R 1 —SH, wherein R 1 is aryl, heteroaryl, C 5 -C 6 -cycloallcyl, C 5 -C 8 -alkyl, aryl-C 1 -C 4 -alkyl, or heteroaryl-C 1 -C 4 -alkyl, each of which is optionally substituted;

(iii) R 1 —NH 2 , wherein R 1 is aryl-C 1 -C 4 -alkyl or an heteroaryl-C 1 -C 4 -alkyl, each of which is optionally substituted; or

(iv) R 1 —B(OH) 2 ; wherein R 1 is heteroaryl or aryl, each of which is optionally substituted;

to form a compound of the following formula:

wherein R 1 is selected from Group B as defined above;

thereby producing a compound of claim 1 .

17. The compound according to claim 1 , wherein R 3 is an acyl- or alkoxycarbonyl group forming a cleavable amide or carbamate linkage.

18. A method for the treatment of urinary incontinence, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .