Substituted 5-alkynyl pyrimidines having neurotrophic activity

1. A compound of Formula I:

wherein

Z is O, NH or S, and m is 0 or 1;

R 1 is (C2–6alkyl) a (C3–10cycloalkyl, C2–9heterocycloalkyl, C5–10aryl, or C4–9heteroaryl) b (C1–6alkyl) c , wherein a, b and c are independently 0 or 1, provided that at least one of a, b and c is 1 and if b is 0, then c is also 0, further providied that, when a is 1, the C2–6alkyl group is the point of attatchment and, when a is 0, the cyclic moity of R 1 is the point of attatchment, and wherein the hetrogroups include from 1 to 4 hetroatoms selected fron the group consisting of N, O and S, and the C and N atoms of the R 1 may optionally be substituted woth one or more substituents selected from the group consisting of:

OH;

halogen:

thio;

oxo;

thioxo;

carboxy;

carboxamide;

C1–7alkylcarbonyl;

C1–7alkylcarbonyloxy

C1–7alkylthiocarbonyl;

C1–8alkyloxy;

hydroxyC2–8alkyloxy;

di-C1–8alkylphosphate ester

C1–8alkylthio;

hydroxyC2–8alkylthio;

C1–8alkylsulfinyl;

C1–8alkylsulfonyl;

C1–5alkyloxyC1–5alkyl;

C1–5alkylthioC1–5alkyl;

C1–5alkylsulfinylC1–5alkyl; and

C1–5alkylsulfonylC1–5alkyl;

R 2 is selected from the group consisting of H, NH 2 and NH—CO—R 3 , where R 3 is H or C1–12 alkyl; and

X is C6–10aryl optionally substituted with one or more substituents (y) selected from the group consisting of:

OH;

NO 2

NH 2

NH—CO—R 4 where R 4 is H, C1–12alkyl, aryl or (C1–6alkyl)aryl

halogen;

C1–6alkyl;

hydroxyC1–6alkyl;

oxoC2–7alkyl;

C2–7alkenyl;

C2–7alkynyl;

C1–6alkoxy;

CF 3 ;

CF 3 C1–6alkyl;

OCF 3 ; and

CF 3 C1–6alkoxy;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein m is 1 and X is phenyl.

3. A compound of claim 1 , wherein m is 1, X is phenyl and R 1 is C2–6alkyl, C3–10cycloalkyl, C6–10aryl, or C6–10arylC2–6alkyl.

4. A compound of claim 1 , wherein m is 1, X is phenyl and R 1 is ethyl, cyclohexyl, phenyl or phenylethyl.

5. A compound of claim 1 , wherein m is 0, X is phenyl and R 1 is piperidino or piperazino.

6. A compound of claim 1 selected from:

2-Amino-5-(4-chlorophenylethynyl)-4-(4-acetylpiperazino)pyrimidine,

4-(trans-4-Hydroxycyclohexylamino)-5-phenylethynylpyrimidine,

4-[2-(2-Hydroxyethoxy)ethylamino]-5-phenylethynylpyrimidine,

5-(4-Chlorophenylethynyl)-4-[2-(2-hydroxyethoxy)ethylamino]pyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-[2-(2-hydroxyethoxy)ethylamino]pyrimidine,

4-(4-(2-Hydroxyethyl)piperazino)-5-phenylethynylpyrimidine,

2-Amino-4-(4-(2-hydroxyethyl)piperazino)-5-phenylethynylpyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(4-(2-hydroxyethyl)piperazino)pyrimidine,

4-(4-Hydroxypiperidino)-5-phenylethynylpyrimidine,

5-(4-Chlorophenylethynyl)-4-(4-hydroxypiperidino)pyrimidine,

2-Amino-4-(4-hydroxypiperidino)-5-phenylethynylpyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(4-hydroxypiperidino)pyrimidine,

4-(2-Hydroxyethylamino)-5-phenylethynylpyrimidine,

2-Amino-4-(2-hydroxyethylamino)-5-phenylethynylpyrimidine,

2-Amino-4-(4-hydroxyanilino)-5-phenylethynylpyrimidine,

2-Amino-4-(4-trans-hydroxycyclohexylamino)-5-(4-n-pentylphenylethynyl) pyrimidine,

2-Acetamido-4-(4-trans-acetoxycyclohexylamino)-5-(4-chlorophenylethynyl) pyrimidine,

2-Amino-5-(4-t-butylphenylethynyl)-4-(4-trans-hydroxycyclohexylamino) pyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(4-hydroxyphenylethylamino)pyrimidine,

2-Amino-4-(4-hydroxyanilino)-5-(4-methoxyphenylethynyl)pyrimidine,

2-Amino-5-(4-propylphenylethynyl)-4-(4-trans-hydroxycyclohexylamino) pyrimidine,

2-Amino-4-(4-hydroxy-2-methylanilino)-5-(4-chlorophenylethynyl)pyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(4-hydroxyanilino)pyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(4-oxocyclohexyloxy)pyrimidine,

2-amino-5-(4-chlorophenylethynyl)-4-[2-(2-hydroxyethoxy)ethoxy] pyrimidine,

2-amino-5-(4-chlorophenylethynyl)-4-(4-hydroxyphenoxy)pyrimidine,

2-amino-5-(4-chlorophenylethynyl)-4-(4-hydroxyphenylthio)pyrimidine,

5-(4-chlorophenylethynyl)-2-formamido-4-(4-hydroxyphenylthio)pyrimidine,

4-(4-Hydroxyanilino)-5-phenylethynylpyrimidine,

5-(4-Chlorophenylethynyl)-4-(4-hydroxyanilino)pyrimidine,

2-Amino-4-[2-(2-hydroxyethoxy)ethylamino]-5-(4-methylphenylethynyl)pyrimidine,

2-Amino-4-(trans-hydroxycyclohexylamino)-5-(4-methylphenylethynyl)pyrimidine,

5-(4-Chlorophenylethynyl)-2-formamido-4-(4-trans-hydroxycyclohexylamino) pyrimidine,

2-Amino-5-(3,4-dichlorophenylethynyl)-4-(4-trans-hydroxycyclohexylamino) pyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(4-oxocyclohexylamino)pyrimidine,

2-Amino-5-(2-chlorophenylethynyl)-4-(4-trans-hydroxycyclohexylamino) pyrimidine,

2-Amino-5-(4-bromophenylethynyl)-4-(4-trans-hydroxycyclohexylamino) pyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(4-trans-hydroxycyclohexylamino) pyrimidine-O-dimethylphosphate ester,

2-Amino-5-(4-chlorophenylethynyl)-4-(3,4-dimethoxyanilino)pyrimidine, and

5-(4-Acetamidophenylethynyl)-2-amino-4-(4-trans-hydroxycyclohexylamino) pyrimidine.

7. A compound of claim 1 selected from:

5-(4-Chlorophenylethynyl)-4-(trans-4-hydroxycyclohexylamino)pyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(4-hydroxyanilino)pyrimidine,

2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-phenylethynylpyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(trans-4-hydroxycyclohexylamino) pyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(cis-4-hydroxycyclohexylamino)pyrimidine,

2-Amino-4-[2-(2-hydroxyethoxy)ethylamino]-5-phenylethynylpyrimidine,

2-Amino-5-(4-chlorophenylethynyl)-4-(2-hydroxyethylamino)pyrimidine, and

2-Amino-5-(4-ethylphenylethynyl)-4-(4-trans-hydroxycyclohexylamino)pyrimidine.

8. A compound of claim 1 according to Formula IA:

wherein p is 0, 1 or 2, and each y (which may be the same or different), R 1 and R 2 are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

9. A compound of claim 8 , wherein R 1 is C2–6alkyl, C3–10cycloalkyl, C6–10aryl, or C6–10arylC2–6alkyl.

10. A compound of claim 8 , wherein R 1 is hydroxycyclohexyl, hydroxyphenyl, hydroxyphenylethyl, hydroxyethyl or hydroxyethoxyethyl.

11. A compound of claim 1 according to Formula IB

wherein p is 0, 1 or 2, and each y (which may be the same or different), R 1 and R 2 are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

12. A compound of claim 11 , wherein R 1 is C2–6alkyl, C3–10cycloalkyl, C6–10aryl, or C6–10arylC2–6alkyl.

13. A compound of claim 11 , wherein R 1 is hydroxycyclohexyl, hydroxyphenyl, hydroxyphenylethyl, hydroxyethyl or hydroxyethoxyethyl.

14. A compound of claim 1 according to Formula IC

wherein p is 0, 1 or 2, and each y (which may be the same or different), R 1 and R 2 are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

15. A compound of claim 14 , wherein R 1 is C2–6alkyl, C3–10cycloalkyl, C6–10aryl, or C6–10arylC2–6alkyl.

16. A compound of claim 14 , wherein R 1 is hydroxycyclohexyl, hydroxyphenyl, or hydroxyethoxyethyl.

17. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier therefor.

18. A method of treating a mammal having a neurodegenerative or neurological disorder of the central or peripheral nervous system selected from the group consisting of Alzheimer's disease, peripheral neuropathy, senile dementia, seizure disorders, Huntington's disease, and Parkinson's disease, which comprises administering to said mammal a therapeutically effective amount of a compound of claim 1 .

19. A pharmaceutical composition, comprising a compound of claim 6 and a pharmaceutically acceptable carrier therefor.

20. A pharmaceutical composition, comprising a compound of claim 7 and a pharmaceutically acceptable carrier therefor.

21. A method of treating a mammal having a neurodegenerative or neurological disorder of the central or peripheral nervous system selected from the group consisting of Alzheimer's disease, peripheral neuropathy, senile dementia, seizure disorders, Huntington's disease, and Parkinson's disease, which comprises administering to said mammal a therapeutically effective amount of a compound of claim 6 .

22. A method of treating a mammal having a neurodegenerative or neurological disorder of the central or peripheral nervous system selected from the group consisting of Alzheimer's disease, peripheral neuropathy, senile dementia, seizure disorders, Huntington's disease, and Parkinson's disease, which comprises administering to said mammal a therapeutically effective amount of a compound of claim 7 .

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

24. A method according to claim 21 , wherein the disorder is Alzheimer's disease.

25. A method according to claim 22 , wherein the disorder is Alzheimer's disease.

26. A method according to claim 18 , wherein the disorder is peripheral neuropathy.

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

28. A method according to claim 22 , wherein the disorder is peripheral neuropathy.

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

30. A method according to claim 21 , wherein the disorder is senile dementia.

31. A method according to claim 22 , wherein the disorder is senile dementia.

32. A method according to claim 18 , wherein the disorder is a seizure disorder.

33. A method according to claim 21 , wherein the disorder is a seizure disorder.

34. A method according to claim 22 , wherein the disorder is a seizure disorder.

35. A method according to claim 18 , wherein the disorder is Huntington's disease.

36. A method according to claim 21 , wherein the disorder is Huntington's disease.

37. A method according to claim 22 , wherein the disorder is Huntington's disease.

38. A method according to claim 18 , wherein the disorder is Parkinson's disease.

39. A method according to claim 21 , wherein the disorder is Parkinson's disease.

40. A method according to claim 22 , wherein the disorder is Parkinson's disease.