Methods for the treatment of synucleinopathies

• US 20050288298A1
• Filed: 03/18/2005
• Published: 12/29/2005
• Est. Priority Date: 03/18/2004
• Status: Abandoned Application

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Liu, Zhihua, Lansbury, Peter T.
• Application Number:
  US11/084,740
• Publication Number:
  US 20050288298A1
• Time in Patent Office: Days
• US Class Current: 514/253.03
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Methods are provided of treating synucleinopathies, such as Parkinson'"'"'s Disease, Diffuse Lewy Body Disease and Multiple System Atrophy, comprising administering to a synucleinopathic subject one or more farnesyl transferase inhibitor compounds.

Claims

1-42. -42. (canceled)

43. A method of treating a synucleinopathic subject, the method comprising, administering to a synucleinopathic subject a farnesyl transferase inhibitor compound of the formula:

44. The method of claim 43 wherein there is a single bond at carbon atom 11, X is CH, Z is ═

O and R⁵, R⁶, R⁷ and R⁸ are hydrogen.

45. The method of claim 44 wherein X¹ is bromo, X² is chloro, X³ is bromo and X⁴ is hydrogen.

46. The method of claim 45 wherein Z is ═

O;

v is 1, w is 1, and Y¹ and Y² are hydrogen.

47. The method of claim 46 wherein R¹⁹ a nd R²⁰ are independently selected from hydrogen, aryl and heterocycloalkyl wit h the proviso that R¹⁹ and R²⁰ are not both hydrogen.

48. The method of claim 47 wherein;

the aryl group is substituted with alkoxy; and

the heterocycloalkyl group is substituted with —

COOR¹⁰ wherein R¹⁰ is hydrogen or alkyl.

49. The method of claim 43 wherein there is a single bond at carbon atom 11, X is CH, Z is ═

O, R⁵, R⁶, R⁷ and R⁸ are hydrogen, X¹ is bromo, X² is chloro, X³ is bromo and X⁴ is hydrogen, v is 1, w is 1, and Y¹ and Y² are hydrogen, R¹⁹ and R²⁰ are independently selected from hydrogen, aryl and heterocycloalkyl;

wherein the aryl group is substituted with alkoxy; and

the heterocycloalkyl group is substituted with —

COOR¹⁰ wherein R¹⁰ is hydrogen or alkyl, with the proviso that R¹⁹ and R²⁰ are not both hydrogen.

50. The method of claim 43, wherein the compound is a compound shown in FIG. 8.

51. The method of claim 43, wherein the compound is a compound shown in FIG. 9.

52. The method of claim 43 wherein there is a single bond at carbon atom 11, X is CH, Z is ═

O and R⁵, R⁶, R⁷ and R⁸ are hydrogen.

53. The method of claim 52 wherein X¹ is bromo, X² is chloro, X³ is bromo and X⁴ is hydrogen.

54. The method of claim 53 wherein Z is ═

O;

v is 1, w is 1, and Y¹ and Y² are hydrogen.

55. The method of claim 54 wherein R¹⁹ and R²⁰ are independently selected from hydrogen, alkyl, aryl and heterocycloalkyl with the proviso that R¹⁹ and R²⁰ are not both hydrogen.

56. The method of claim 54 wherein the alkyl group is substituted with —

OR¹⁰, alkoxy, —

OCOR¹⁰, —

CONR¹⁰R¹² or —

COOR¹⁰, wherein R¹⁰ and R¹² are independently selected from hydrogen, alkyl or alkoxy;

the aryl group is substituted with alkoxy; and

the heterocycloalkyl group is substituted with —

COOR¹⁰ wherein R¹⁰ is hydrogen or alkyl.

57. The method of claim 43 wherein there is a single bond at carbon atom 11, X is CH, Z is ═

O, R⁵, R⁶, R⁷ and R⁸ are hydrogen, X¹ is bromo, X² is chloro, X³ is bromo and X⁴ is hydrogen, v is 1, w is 1, and Y¹ and Y² are hydrogen, R¹⁹ and R²⁰ are independently selected from hydrogen, alkyl, aryl and heterocycloalkyl, wherein the alkyl group is substituted with —

OR¹⁰, alkoxy, —

OCOR”

, —

CONR¹⁰R¹² or —

COOR¹⁰, wherein R¹⁰ and R¹² are independently selected from hydrogen, alkyl or alkoxy;

the aryl group is substituted with alkoxy;

the heterocycloalkyl group is substituted with —

COOR¹⁰ wherein R¹⁰ is hydrogen or alkyl, with the proviso that R¹⁹ and R²⁰ are not both hydrogen.

58. The method of claim 43 wherein X is CH and Z is ═

O.

59. The method of claim 43 wherein X is CH, Z is ═

O, R⁵, R⁶, R⁷ and R⁸ are hydrogen, and X¹ is bromo.

116. The method of claim 43, wherein the synucleinopathic subject has a synucleinopathy selected from the group consisting of:

Parkinson'"'"'s disease, diffuse Lewy body disease, and multiple system atrophy disorder.

117. The method of claim 116 wherein the subject is a human.

118. The method of claim 117, wherein the effective amount comprises about 10 ng/kg of body weight to about 1000 mg/kg of body weight at a frequency of administration from once a day to once a month.

119. The method of claim 118, further comprising administering to the subject an amount of one or more non-farnesyl transferase inhibitor compounds effective to treat a neurological disorder.

120. The method of claim 119, wherein each non-farnesyl transferase inhibitor compound is selected from the group consisting of:

dopamine agonist, DOPA decarboxylase inhibitor, dopamine precursor, monoamine oxidase blocker, cathechol 0-methyl transferase inhibitor, anticholinergic, and NMDA antagonist.

121. The method of claim 119, wherein each non-farnesyl transferase inhibitor compound is selected from the group consisting of Memantine, Aricept, and other acetylcholinesterase inhibitors.

60-115. -115. (canceled)

122-125. -125. (canceled)