GlyT-1 inhibitors

• US 6,667,336 B2
• Filed: 02/15/2002
• Issued: 12/23/2003
• Est. Priority Date: 02/16/2001
• Status: Expired due to Fees

• Current Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Original Assignee: NPS Allelix Corp., Allelix Neuroscience, Inc. (Shire plc)
• Inventors: Schumacher, Richard, Hopper, Allen T., Delaney, William, Wang, Zhaoqing, Egle, Ian, Tehim, Ashok, Maddaford, Shawn
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US10/077,579
• Publication Number:
  US 20030176489A1
• Time in Patent Office: 676 Days
• Field of Search: 514/444, 514/438, 549/59, 549/77
• US Class Current: 514/444
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 409/10 linked by a carbon chain containing aromatic rings

Abstract

The invention provides a pharmaceutical for treatment of neurological and neuropsychiatric disorders comprising a compound of the formula:

or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of formula 1

wherein:

Ar₁ is a thiophene group which may be 2 or 3 thiophene and is optionally substituted with up to one substituent selected from methyl or ethyl;

Ar₂ is selected from thiophene, furan and substituted phenyl, wherein the substituent on the phenyl group is selected from C_1-6 alkyl, halo, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, cyano

and a salt, solvate and hydrate thereof.

2. A compound according to claim 1 wherein Ar₁ is 2-thiophene.

3. A compound according to claim 1 wherein Ar₁ is 2-(3-methylthiophene).

4. A compound according to claim 1 wherein Ar₁ is 3-thiophene.

5. A compound according to claim 1 wherein Ar₁ is 3-(4-methylthiophene).

6. A compound according to claim 1 wherein Ar₂ is substituted phenyl where the substituent is selected from CF₃, Me, iPr, MeO, CN, and CF₃O.

7. A compound according to claim 1 wherein Ar₂ is furan.

8. A compound according to claim 1 wherein Ar₂ is thiophene.

9. A compound according to claim 1 selected from the group consisting of:

(Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(2-Thienyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(2-Furyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methoxyphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-(Trifluoromethoxy)phenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Cyanophenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(2-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-(Trifluoromethyl)phenyl)phenyl)-1-(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methoxyphenyl)phenyl)-1-(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine; and

(Z)-N-(1-(4-(3-Methylphenyl)phenyl)-1-(2-(3-methylthienyl))prop-1-en-3-yl)sarcosine.

11. The compound of claim 9, (Z)-N-(1-(4-(2-Furyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine.

12. The compound of claim 9, (Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine.

13. A composition comprising a compound of claim 1 and a carrier.

15. A composition comprising a compound of claim 11 and a carrier.

16. A composition comprising a compound of claim 12 and a carrier.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 11 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 12 and a pharmaceutically acceptable carrier.

30. A method for treating a patient having a medical condition for which a glycine transport inhibitor is indicated, comprising the step of administering to the patient a pharmaceutical composition as defined in claim 17.

31. A method according to claim 30 in which the medical condition is schizophrenia.

32. A method according to claim 31 wherein wherein Ar₁ of the compound is 2-thiophene.

33. A method according to claim 32 wherein the compound according to formula 1 Ar₁ is 2-(3-methylthiophene).

34. A method according to claim 31, wherein in the compound according to formula 1 Ar₁ is 3-thiophene.

35. A method according to claim 31, wherein in the compound according to formula 1 Ar₁ is 3-(4-methylthiophene).

36. A method according to claim 31, wherein in the compound according to formula 1 Ar₂ is substituted phenyl where the substituent is selected from CF_3, Me, iPr, MeO, CN, and CF₃O.

37. A method according to claim 31, wherein in the compound according to formula 1 Ar₂ is furan.

38. A method according to claim 31, wherein in the compound according to formula 1 Ar₂ is thiophene.

39. A method according to claim 31, wherein the compound according to formula 1 is selected from the group consisting of:

(Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)-1(3-thienyl)prop-1 -en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(2-Thienyl)phenyl)1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(2-Furyl)phenyl)1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methoxyphenyl)phenyl)1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-(Trifluoromethoxy)phenyl)phenyl)1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Cyanophenyl)phenyl)1-(3-thienyl)prop-1-en-3yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl-1(2thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-(Trifluoromethyl)phenyl)phenyl)-1(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methoxyphenyl)phenyl)1-(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine; and

(Z)-N-(1-(4-(3-Methylphenyl)phenyl)1-(2-(3-methylthienyl))propyl-1-en-3-yl)sarcosine.

40. A method according to claim 31, wherein the compound according to formula 1 is (Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(2-methylphenyl)prop-1-en-3-yl)sarcosine.

41. A method according to claim 31, wherein the compound according to formula 1 is (Z)-N-(1-(4-(2-Furyl)Phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine.

42. A method according to claim 31, wherein the compound according to formula 1 is (Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine.

43. A method according to claim 30 in which the medical condition is cognitive dysfunction.

44. A method according to claim 43, wherein wherein Ar₁ of the compound is 2-thiophene.

45. A method according to claim 43, wherein in the compound according to formula 1 Ar₁ is 2-(3-methylthiophene).

46. A method according to claim 43, wherein in the compound according to formula 1 Ar₁ is 3-thiophene.

47. A method according to claim 43, wherein in the compound according to formula 1 Ar₁ is 3-(4-methylthiophene).

48. A method according to claim 43, wherein in the compound according to formula 1 Ar₂ is substituted phenyl where the substituent is selected from CE_3, Me, iPr, MeO, CN, and CF₃O.

49. A method according to claim 43, wherein in the compound according to formula 1 Ar₂ is turan.

50. A method according to claim 43, wherein in the compound according to formula 1 Ar₂ is thiophene.

51. A method according to claim 43, wherein the compound according to formula 1 is selected from the group consisting of:

(Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(2-Thienyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(2-Furyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methoxyphenyl)phenyl)1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-(Trifluoromethoxy)phenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Cyanophenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1 -(2-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-(Trifluoromethyl)phenyl)phenyl)-1-(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methoxyphenyl)phenyl)1-(3-(4-methylthienyl))prop-1en-3-yl)sarcosine; and

(Z)-N-(1-(4-(3-Methylphenyl)phenyl)-1-(2-(3-methylthienyl))prop-1-en-3-yl)sarcosine.

52. A method according to claim 43, wherein the compound according to formula 1 is (Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(2-methylphenyl)prop-1-en-3-yl)sarcosine.

53. A method according to claim 43, wherein the compound according to formula 1 is (Z)-N-(1-(4-(2-Furyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine.

54. A method according to claim 43, wherein the compound according to formula 1 is (Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)- 1(3-thienyl)prop-1-en-3-yl)sarcosine.

10. The compound (Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(2-methylphenyl)prop-1-en-3-yl)sarcosine.

14. A composition comprising a compound of claim 10 and a carrier.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 10 and a pharmaceutically acceptable carrier.

21. A method of preparing an iodide C;

comprising;

a) reducing intermediate B

 

with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al); and

b) treating the resulting intermediate with iodine to give the iodide C.

22. A method of preparing an intermediate D;

comprising;

a) reducing intermediate B

 

with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) and treating the resulting intermediate with iodine to give iodide C

b) converting the alcohol moiety of iodide C to a bromide; and

c) displacing the bromide with sarcosine t-butyl ester to the provide intermediate D.

23. The method of claim 22, wherein the conversion of step (b) comprises treatment with N-bromosuccinimide and triphenylphosphine.

24. A method of preparing an intermediate E

Ar₁ is thienyl optionally substituted by up to one methyl or ethyl,

the method comprising:

a) reducing intermediate B

 

with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) and treating the resulting intermediate with iodine to give iodide C

b) converting the alcohol moiety of iodide C to a bromide;

c) displacing the bromide with sarcosine t-butyl ester to provide an intermediate D

d) coupling the intermediate D with a boronic acid of the formula Ar₁B(OH)₂, wherein Ar₁ is as described above, in the presence of a palladium (0) catalyst to give the intermediate of the formula E.

25. The method of claim 24, wherein the conversion of step (b) comprises treatment with N-bromosuccinimide and triphenylphosphine.

26. A method of preparing a compound of the formula G

Ar₁ is thienyl optionally substituted by up to one methyl or ethyl, and

Ar₂ is selected from the group consisting of thienyl, furyl and substituted phenyl, wherein phenyl substituents are selected from C_1-6 alkyl, halo, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, and cyano;

the method comprising;

a) reducing intermediate B

 

with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) and treating the resulting intermediate with iodine to give iodide C

b) converting the alcohol moiety of iodide C to a bromide;

c) displacing the bromide with sarcosine t-butyl ester to provide intermediate D

d) coupling intermediate D with a boronic acid of the formula Ar₁B(OH)₂, wherein Ar₁ is as described above, in the presence of a palladium (0) catalyst to give an intermediate of the formula E

e) coupling intermediate E with an aryl boronic acid of the formula Ar₂B(OH)₂, wherein Ar₂ is as described above, in the presence of a palladium (0) catalyst to give intermediate F

f) hydrolyzing the ester group of the intermediate F to give the compound of the formula G.

27. The method of claim 26, wherein the conversion of step (b) comprises treatment with N-bromosuccinimide and triphenylphosphine.

28. The method of claim 27, wherein the hydrolysis of step (f) comprises treatment with formic acid.

29. A compound of the formula C, D or E

Ar₁ is thienyl optionally substituted by up to one methyl or ethyl.

55. A method according to claim which the medical condition is Alzheimer'"'"'s disease.

56. A method according to claim 55, wherein wherein Ar₁ of the compound is 2-thiophene.

57. A method according to claim 55, wherein in the compound according to formula 1 Ar₁ is 2-(3-methylthiophene).

58. A method according to claim 55, wherein in the compound according to formula 1 Ar₁ is 3-thiophene.

59. A method according to claim 55, wherein in the compound according to formula 1 Ar₁ is 3-(4-methylthiophene).

60. A method according to claim 55, wherein in the compound according to formula 1 Ar₂ is substituted phenyl where the substituent is selected from CF_3, Me, iPr, MeO, CN, and CF₃O.

61. A method according to claim 55, wherein in the compound according to formula 1 Ar₂ is furan.

62. A method according to claim 55, wherein in the compound according to formula 1 Ar₂ is thiophene.

63. A method according to claim 55, wherein the compound according to formula 1 is selected from the group consisting of:

(Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)-1-(3-thienyl)prop-1 -en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(2-Thienyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(2-Furyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methoxyphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-(Trifluoromethoxy)phenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Cyanophenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(2-thienyl)prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-(Trifluoromethyl)phenyl)phenyl)-1-(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine;

(Z)-N-(1-(4-(3-Methoxyphenyl)phenyl)-1-(3-(4-methylthienyl))prop-1-en-3-yl)sarcosine; and

(Z)-N-(1-(4-(3-Methylphenyl)phenyl)-1-(2-(3-methylthienyl))prop-1-en-3-yl)sarcosine.

64. A method according to claim 55, wherein the compound according to formula 1 is (Z)-N-(1-(4-(3-Thienyl)phenyl)-1-(2-methylphenyl)prop-1-en-3-yl)sarcosine.

65. A method according to claim 55, wherein the compound according to formula 1 is (Z)-N-(1-(4-(2-Furyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine.

66. A method according to claim 55, wherein the compound according to formula 1 is (Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine.