Neurotrophic substituted pyrimidines

1. A compound of the formula

wherein

W is O, CH 2 , CH 2 CH 2 , OCH 2 or CH 2 CH 2 CH 2 ; R 1 is NR 4 R 5 wherein R 4 and R 5 are independently H, OH, C6-10aryl, C2-6alkoxy, C6-10aryloxy, or (C1-6alkyl)j(C6-10aryl)(CH 2 )q (wherein J is 0 or 1 and q is 0-6), provided that when R 4 is H or OH, then R 5 is not H or OH, and wherein the C atoms of R 4 and R 5 may optionally be substituted with one or more substituents selected from the group consisting of:

OH;

halogen;

thio;

thio-oxo;

oxo;

C1-6alkyl;

C2-7alkenyl;

C2-7alkynyl;

C6-10aryl;

C6-10heteroaryl;

hydroxyC1-6alkyl;

dihydroxyC1-6alkyl;

C1-6alkoxy;

C1-6aryloxy;

C6-10heteroaryloxy;

hydroxyC1-6alkoxy;

C1-6alkoxyC1-6alkyl;

C6-10aryloxyC1-6alkyl;

C6-10heteroaryloxyC1-6alkyl;

C3-8cycloalkyl;

C6-10arylC1-6alkyl;

C6-10arylC1-6alkoxy;

C6-10heteroarylC1-6alkoxy;

C1-6alkylcarbonylC1-6alkyl;

C6-10arylcarbonylC1-6alkyl;

carboxyC1-6alkyl;

C1-6alkoxycarbonylC1-6alkyl;

C6-10aryloxycarbonylC1-6alkyl;

C6-10arylC1-6alkyloxycarbonylC1-6alkyl;

cyanoC1-6alkyl;

C1-6alkylthioC1-6alkyl;

C1-6alkylsulfinylC1-6alkyl;

C1-6alkylsulfonylC1-6alkyl;

C6-10arylthioC1-6alkyl;

C6-10arylsulfinylC1-6alkyl;

C6-10arylsulfonylC1-6alkyl;

C6-10arylC1-6alkylthioC1-6alkyl;

C6-10arylC1-6alkylsulfinylC1-6alkyl;

C6-10arylC1-6alkylfulfonylC1-6alkyl;

C6-10heteroarylthioC1-6alkyl;

C6-10heteroarylsulfinylC1-6alkyl;

C6-10heteroarylsulfonylC1-6alkyl;

aziridino;

azetidino;

pyrrolidino;

piperidino;

heptamethyleneimino;

homopiperazino;

N-substituted homopiperazino (wherein the substituent may be C1-6alkyl, C6-10aryl, C6-10arylC1-6alkyl or C6-10heteroaryl);

piperazino;

N-substituted piperazino (wherein the substituent may be C1-6alkyl, C6-10aryl, C6-10arylC1-6alkyl or C6-10heteroaryl);

morpholino;

homomprpholino;

thiomorpholino;

aminoC1-6alkyl;

C1-6alkylaminoC1-6alkyl;

di(C1-6alkyl)aminoC1-6alkyl (wherein the alkyl groups may be the same or different);

C6-10arylaminoC1-6alkyl;

C6-10arylC1-6alkylaminoC1-6alkyl;

di(C6-10aryl)aminoC1-6alkyl (wherein the aryl groups may be the same or different);

di(C6-10arylC1-6alkyl)aminoC1-6alkyl (wherein the arylalkyl groups may be the same or different);

R 12 C(O)C1-6alkyl (wherein R 12 is aziridino, azetidino, pyrrolidino, piperidino, heptamethyleneimino, piperazino, homopiperazino, morpholino, homomorpholine, or thiomorpholino);

C(O)R 6 ; C(O)C(O)R 6 ; C(S)R 6 ; S(O) 2 R 6 ; and C(NR 11 )R 6 (wherein R 11 is H, C1-6alkyl or C6-10aryl and R 6 is H, C1-6alkyl, C1-6alkyl, C6-10aryl, C6-10arylC1-6alkyl or C6-10heteroaryl);

R 2 is H or NH 2 , provided that when W is CH 2 , then R 2 is NH 2 ;

X is a C6-10 aryl ring or a C6-10 heteroaryl ring optionally substituted with one or more substituents Y selected from the group consisting of:

halogen;

C1-6 alkyl;

C2-7alkenyl;

C2-7alkynyl;

C6-10aryl;

C6-10heteroaryl;

OR (wherein R is H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl or C6-10arylC1-6alkyl);

NR 9 R 10 (wherein R 9 and R 10 may be the same or different and are H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl, or C6-10arylC1-6alkyl);

NROR;

C(O)NR 9 R 10 ;

C(O)OR;

C(O)R;

NRC(O)NR 9 R 10 ;

NRC(O)R;

NRC(O)OR;

CR(OH)R;

OC(O)R;

S(O)nR′ (wherein R′ is C1-6alkyl, C3-8cycloalkyl, C6-10aryl or C6-10arylC1-6alkyl and n is 0, 1 or 2);

NRS(O)mR′ (wherein m is 1 or 2);

S(O) 2 NR 9 R 10 ;

NO 2 ;

CN;

CF 3 ; and

OCF 3 ;

wherein each C6-10heteroaryl group is an aryl ring having 1 to 4 carbon atoms replaced by heteroatoms selected from the group consisting of N, O and S; or a pharmaceutically acceptable ester, amide or salt thereof.

2. A compound according to claim 1 , wherein W is O or CH 2 and X is substituted phenyl.

3. A compound according to claim 1 , wherein R 1 is 4-hydroxyanilino or 4-hydroxybenzylamino; W is O; X is phenyl optionally substituted with 4-chloro, 2,4-dichloro, 4-bromo, 2-fluoro-4-chloro, 2-chloro-4-fluoro, 2-methyl-4-chloro, 4-methyl, or 4-ethyl; and R 2 is NH 2 .

4. A compound of the formula

wherein a and b are 0 or 1 and a+b=1; m is 0−2; R 2 is H or NH 2 , provided that when a is 1, then R 2 is NH 2 ; R 13 is phenyl or benzyl optionally substituted with up to three substituents selected from the group consisting of:

OH;

halogen;

C1-6alkyl;

hydroxyC1-6alkyl;

dihydroxyC1-6alkyl;

C1-6alkoxy;

hydroxyC1-6alkoxy;

C1-6alkoxyC1-6alkyl, and

carboxyC1-6alkyl;

and each Y is selected from the group consisting of:

halogen;

C1-6 alkyl;

C2-7alkenyl;

C2-7alkynyl;

C6-10aryl;

C6-10heteroaryl;

OR (wherein R is H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl or C6-10arylC1-6alkyl);

NR 9 R 10 (wherein R 9 and R 10 may be the same or different and are H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl, or C6-10arylC1-6alkyl);

NROR;

C(O)NR 9 R 10 ;

C(O)OR;

C(O)R;

NRC(O)NR 9 R 10

NRC(O)R;

NRC(O)OR;

CR(OH)R;

OC(O)R;

S(O)nR′ (wherein R′ is C1-6alkyl, C3-8cycloalkyl, C6-10aryl or C6-10arylC1-6alkyl and n is 0, 1 or 2);

NRS(O)mR′ (wherein m is 1 or 2);

S(O) 2 NR 9 R 10 ;

NO 2 ;

CN;

CF 3 ; and

OCF 3 ;

wherein each C6-10heteroaryl group is an aryl ring having 1 to 4 carbon atoms replaced by heteroatoms selected from the group consisting of N, O and S; or a pharmaceutically acceptable ester, amide or salt thereof.

5. A compound according to claim 4 , wherein R 13 is phenyl substituted with 1 or 2 hydroxyl groups.

6. A compound according to claim 4 , wherein R 13 is benzyl substituted with 1 or 2 hydroxyl groups.

7. A compound selected from the group consisting of:

2-Amino-4-(4-hydroxyanilino)-5-(4-chlorophenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(2,4-dichlorophenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(4-bromophenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(2-fluoro-4-(chlorophenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(2-chloro-4-(fluorophenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(2-methyl-4-(chlorophenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(4-methylphenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(4-ethylphenoxy)pyrimidine;

2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxy-2-methylanilino)pyrimidine;

2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxy-4-methylanilino)pyrimidine;

4-(4-Acetoxyanilino)-2-amino-5-(4-chlorophenoxy)pyrimidine;

2-Amino-5-(4-chlorophenoxy)-4-(2-(2-proprionyloxyethoxy)ethylamino) pyrimidine hydrochloride;

2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxy-2-chloroanilino)pyrimidine;

2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxy-3-chloroanilino)pyrimidine;

2-Amino-4-(methoxyamino)-5-(4-chlorophenyloxy)pyrimidine;

2-Amino-4-(2-hydroxyethoxyamino)-5-(4-chlorophenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-phenoxypyrimidine;

2-Amino-4-(4-hydroxy-2-methylanilino)-5-phenoxypyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(2-chlorophenoxy)pyrimidine;

2-Amino-4-(4-hydorxy-2-methylanilino)-5-(2-chlorophenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(4-chloro-2-methylphenoxy)pyrimidine;

2-Amino-4-(4-hydroxy-2-methylanilino)-5-(4-chloro-2-methylphenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(4-chloro-2-methylphenoxy)pyrimidine;

2-Amino-4-(4-hydroxyanilino)-5-(4-butylphenoxy)pyrimidine;

2-Amino-4-(4-hydroxy-2-methylanilino)-5-(4-butylphenoxy)piperidine;

2-Amino-4-(4-hydroxyanilino)-5-(4-methoxyphenoxy)pyrimidine;

2-Amino-4-(4-hydroxy-2-methylanilino)-5-(4-methoxyphenoxy)pyrimidine; and

2-Amino-4-(4-hydroxy-2-methylanilino)-5-(2-methoxyphenoxy)pyrimidine.

8. A pharmaceutical composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier therefor.

9. A pharmaceutical composition, comprising a compound according to claim 4 and a pharmaceutically acceptable carrier therefor.

10. A pharmaceutical composition, comprising a compound according to claim 7 and a pharmaceutically acceptable carrier therefor.

11. A method of treating a mammal having a neurodegerative or neurological disorder of the central or peripheral nervous system, which comprises administering to said mammal a therapeutically effective amount of a compound according to claim 1 .

12. A method according to claim 11 , wherein the disorder is a dementing disorder.

13. A method according to claim 12 , wherein the disorder is Alzheimer's disease.

14. A method according to claim 12 , wherein the disorder is senile dementia.

15. A method according to claim 11 , wherein the disorder is peripheral neuropathy.

16. A method according to claim 11 , wherein the disorder is a nerve injury.

17. A method of treating a mammal having a neurodegenerative or neurological disorder of the central or peripheral nervous system, which comprises administering to said mammal a therapeutically effective amount of a compound according to claim 4 .

18. A method according to claim 17 , wherein the disorder is a dementing disorder.

19. A method according to claim 18 , wherein the disorder is Alzheimer's disease.

20. A method according to claim 18 , wherein the disorder is senile dementia.

21. A method according to claim 17 , wherein the disorder is peripheral neuropathy.

22. A method according to claim 17 , wherein the disorder is a nerve injury.

23. A method of treating a mammal having a neurodegenerative or neurological disorder of the central or peripheral nervous system, which comprises administering to said mammal a therapeutically effective amount of a compound according to claim 7 .

24. A method according to claim 23 , wherein the disorder is a dementing disorder.

25. A method according to claim 24 , wherein the disorder is Alzheimer's disease.

26. A method according to claim 24 , wherein the disorder is senile dementia.

27. A method according to claim 23 , wherein the disorder is peripheral neuropathy.

28. A method according to claim 23 , wherein the disorder is a nerve injury.