Claims for Patent: 8,835,502

Summary for Patent: 8,835,502

Title:	Treatment of friedreich\'s ataxia using histone deacetylase inhibitors
Abstract:	The invention provides methods of treating Friedreich\'s ataxia using histone deacetylase inhibitors.
Inventor(s):	Gottesfeld; Joel M. (Del Mar, CA), Jenssen; Kai (San Diego, CA), Herman; David M. (San Diego, CA), Burnett; Ryan (San Diego, CA), Chou; C. James (San Diego, CA)
Assignee:	The Scripps Research Institute (La Jolla, CA)
Application Number:	13/862,727
Patent Claims:	1. A method of treating or delaying the onset of Friedreich's ataxia in a mammal comprising administering to the mammal a histone deacetylase inhibitor in an amount effective to inhibit a histone deacetylase in the mammal, wherein the histone deacetylase inhibitor is a compound of formula I: ##STR00067## wherein: n is 2 to about 10; R.sup.l is aryl or heteroaryl; R.sup.2 is aryl or heteroaryl; R.sup.a and R.sup.b are each independently H, alkyl, aryl, heteroaryl, or a nitrogen protecting group; wherein any alkyl, aryl or heteroaryl is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, nitro, cyano, halo, alkyl, trifluoromethyl, alkoxy, aryl, and NR.sup.cR.sup.d or any combination thereof; wherein R.sup.c and R.sup.d are each independently hydrogen, alkyl, or C(.dbd.O)OR.sup.e wherein R.sup.e is H or alkyl; or a salt thereof. 2. The method of claim 1, wherein the histone deacetylase inhibitor is administered to the mammal in an amount effective to increase the level of histone acetylation in the mammal. 3. The method of claim 1, wherein the histone deacetylase inhibitor is administered to the mammal in an amount effective to increase frataxin mRNA in the mammal. 4. The method of claim 1, wherein the histone deacetylase inhibitor interacts with a class I histone deacetylase. 5. The method of claim 4, wherein the class I histone deacetylase is selected from the group consisting of a histone deacetylase 1, histone deacetylase 2, histone deacetylase 3, histone deacetylase 8, and a histone deacetylase that has a deacetylase domain exhibiting from 45% to 93% identity in amino acid sequence to deacetylase 1, histone deacetylase 2, histone deacetylase 3, and histone deacetylase 8. 6. The method of claim 4, wherein the class 1 histone deacetylase is selected from the group consisting of a histone deacetylase 1, histone deacetylase 2, histone deacetylase 3, and histone deacetylase 8. 7. The method of claim 4, wherein the class I histone deacetylase is a histone deacetylase 1. 8. The method of claim 4, wherein the class I histone deacetylase is a histone deacetylase 2. 9. The method of claim 4, wherein the class I histone deacetylase is a histone deacetylase 3. 10. The method of claim 4, wherein the class I histone deacetylase is a histone deacetylase 8. 11. The method of claim 1, wherein the mammal has a GAA triplet repeat in intron 1 of the frataxin gene. 12. The method of claim 1, wherein R.sup.l or R.sup.2 is phenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2-aminophenyl; 3-aminophenyl; 4-aminophenyl; 2-methoxyphenyl; 3-methoxyphenyl; 4-methoxyphenyl; 2,4-dimethoxyphenyl; 3,5-dimethoxyphenyl; 3,4,5-trimethoxyphenyl; 2,4-diaminophenyl; 3,5-diaminophenyl; 3,4,5-triaminophenyl; 2-pyridinyl; 3-quinolinyl; or 8-quinolinyl. 13. The method of claim 1, wherein R.sup.a is H, R.sup.b is H, or both R.sup.a and R.sup.b are H. 14. The method of claim 1, wherein R.sup.a is a nitrogen protecting group; R.sup.b is a nitrogen protecting group; or both R.sup.a and R.sup.b are nitrogen protecting groups. 15. The method of claim 1, wherein the compound of formula I has a structure selected from the group consisting of: ##STR00068## ##STR00069## a salt of a compound thereof; and any combination thereof. 16. A method for preparing a compound of formula I: ##STR00070## wherein: n is 2 to about 10; R.sup.1 is aryl or heteroaryl; R.sup.2 is aryl or heteroaryl; R.sup.a and R.sup.b are each independently alkyl, aryl, heteroaryl, or a nitrogen protecting group; wherein any alkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of amino, nitro, cyano, halo, alkyl, trifluoromethyl, alkoxy, aryl, and NR.sup.cR.sup.d; wherein R.sup.c and R.sup.d are each independently hydrogen, alkyl, or C(.dbd.O)OR.sup.e wherein R.sup.e is H or alkyl; or a salt thereof; comprising contacting a compound of formula V: ##STR00071## with one or more coupling agents and a compound of formula VI: R.sup.2--NH(R.sup.b) (VI) to provide the compound of formula I. 17. A method for preparing a compound of formula I: ##STR00072## wherein: n is 3 to about 10; R.sup.1 is aryl or heteroaryl; R.sup.2 is aryl or heteroaryl; R.sup.a and R.sup.b are H, alkyl, aryl, heteroaryl, or a nitrogen protecting group; wherein any alkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, nitro, cyano, halo, alkyl, trifluoromethyl, alkoxy, aryl, and NR.sup.cR.sup.d; wherein R.sup.c and R.sup.d are each independently hydrogen, alkyl, or C(.dbd.O)OR.sup.e wherein R.sup.e is H or alkyl; the method comprising: (a) contacting a compound of formula II: ##STR00073## with a dehydrating agent to provide a compound of formula III: ##STR00074## (b) contacting the compound of formula III with a compound of formula IV: R.sup.1--NH(R.sup.a) (IV) to provide a compound of formula V: ##STR00075## (c) contacting the compound of formula V with one or more coupling agents and a compound of formula VI: R.sup.2--NH(R.sup.b) (VI) to provide the compound of formula I. 18. A pharmaceutical composition comprising a compound of formula I: ##STR00076## wherein: n is 2 to about 10; R.sup.1 is aryl or heteroaryl; R.sup.2 is aryl or heteroaryl; R.sup.a and R.sup.b are each independently, alkyl, aryl, heteroaryl, or a nitrogen protecting group; wherein any alkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of amino, nitro, cyano, halo, alkyl, trifluoromethyl, alkoxy, aryl, and NR.sup.cR.sup.d; wherein R.sup.c and R.sup.d are each independently hydrogen, alkyl, or C(.dbd.O)OR.sup.e wherein R.sup.e is H or alkyl; or a salt thereof; in combination with a pharmaceutically acceptable carrier. 19. The composition of claim 18, wherein the composition is in the form of a tablet, capsule, elixir, or a sustained-release formulation. 20. The method of claim 16, wherein the compound of formula I is in an amount effective to inhibit a histone deacetylase or increase frataxin mRNA levels in a mammalian cell.

Details for Patent 8,835,502

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2025-11-11
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2025-11-11
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2025-11-11