Benzoquinone derivatives for treating oxidative stress disorders

1. A method of treating a mitochondrial disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I:

wherein:

R 1 and R 2 are independently hydrogen, (C 1 -C 6 )alkyl or —O(C 1 -C 6 )alkyl; or R 1 and R 2 together represent —CH═CH—CH═CH—;

R 3 is (C 1 -C 6 )alkyl;

X is —CH═CH— or —C≡C—;

m is 1-10;

n is 1-5;

k is 1-3, with the proviso that when k is an integer of 2 or 3, n is independently 1-5 in each occurrence of the —X—(CH 2 ) n — group;

Y is —OR 4 , —CN, —C(═O)OR 5 , —C(═O)R 5 , or —C(═O)N(R 6 ) 2 ;

R 4 and R 5 are independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 1 -C 6 )haloalkyl, —C(═O)—NH(C 1 -C 6 )alkyl, —C(═O)—N((C 1 -C 6 )alkyl) 2 , —C(═O)—NH 2 , and phenyl, wherein the phenyl group is optionally substituted with a substituent independently selected from the group consisting of —(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, and halo; and

each R 6 is independently hydrogen or —(C 1 -C 6 )alkyl;

or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, crystalline form, non-crystalline form, hydrate or solvate thereof;

wherein the mitochondrial disorder is selected from the group consisting of Friedrich's Ataxia (FA), Huntington's Disease, Leber's Hereditary Optic Neuropathy (LHON), Parkinson's disease, and Co-Enzyme Q10 Deficiency; and

wherein the compound of Formula I is the sole therapeutically active agent administered to the subject to treat the mitochondrial disorder.

2. The method of claim 1 , wherein X is —CH═CH—.

3. The method of claim 1 , wherein X is —C≡C—.

4. The method of claim 1 , wherein m is 1-5.

5. The method of claim 1 , wherein Y is —OR 4 .

6. The method of claim 5 , wherein R 4 is H.

7. The method of claim 1 , wherein R 1 , R 2 and R 3 are independently —(C 1 -C 4 )alkyl.

8. The method of claim 1 , wherein R 1 and R 2 together represent —CH═CH—CH═CH—.

9. The method of claim 1 , wherein the compound is selected from the group consisting of:

2-(12-hydroxydodeca-5,8-dien-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

2-(10-hydroxydeca-5,8-diyn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

2-(12-hydroxydodeca-5,8-diyn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

2-(10-hydroxydeca-5,8-dien-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

2-(9-hydroxynon-5-yn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

2-(11-hydroxyundeca-5,8-diyn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynenitrile;

13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynoic acid;

13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-dienenitrile;

13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-dienoic acid;

N,N-dimethyl-13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynamide;

13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynamide;

2-(12-hydroxydodeca-5,8-diyn-1-yl)-3-methylnaphthalene-1,4-dione;

2-(11-hydroxyundeca-5,8-diyn-1-yl)-3-methylnaphthalene-1,4-dione;

2-(10-hydroxydeca-5,8-diyn-1-yl)-3-methylnaphthalene-1,4-dione; and

2-(10-hydroxydeca-5,8-dien-1-yl)-3-methylnaphthalene-1,4-dione;

or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, crystalline form, non-crystalline form, hydrate or solvate thereof.

10. The method of claim 1 , wherein the compound is 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone or a crystalline form, non-crystalline form, hydrate or solvate thereof.

11. The method of claim 1 , wherein the compound is administered as a pharmaceutical formulation comprising the compound and a pharmaceutically acceptable excipient.

12. The method of claim 1 consisting of administering a therapeutically effective amount of the compound of Formula I; or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, crystalline form, non-crystalline form, hydrate or solvate thereof.

13. The method of claim 1 , wherein the mitochondrial disorder is Friedrich's Ataxia (FA).

14. The method of claim 1 , wherein the mitochondrial disorder is Huntington's Disease.

15. The method of claim 1 , wherein the mitochondrial disorder is Leber's Hereditary Optic Neuropathy (LHON).

16. The method of claim 1 , wherein the mitochondrial disorder is Parkinson's disease.

17. The method of claim 1 , wherein the mitochondrial disorder is Co-Enzyme Q10 Deficiency.