IP Library › Granted Patent US 8,716,527

Granted Patent B2

US 8,716,527 · App. 12/919,007 · Granted May 6, 2014

2-substituted-

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Quick Facts

Patent No.: US 8,716,527
App. No.: 12/919,007
Granted: May 6, 2014
Kind: B2

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Abstract

Methods of treating or suppressing oxidative stress diseases including mitochondrial diseases, impaired energy processing disorders, neurodegenerative diseases and diseases of aging are disclosed, as well as compounds useful in the methods of the invention, such as 2- substituted-p-quinone derivatives as disclosed herein.

Claims (167)

1. A compound of Formula III:

where R is selected from the group consisting of:

where the * indicates the point of attachment of R to the remainder of the molecule;

A is (C 1 -C 4 )-alkylene, (C 2 -C 4 )-alkenylene, or (C 2 -C 4 )-alkynylene;

B 3 is C(O) or S(O) 2 ;

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

R 2 is (C 1 -C 6 )-alkyl;

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

R 35 and R 36 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, (C 1 -C 40 )-alkyl, (C 2 -C 40 )-alkenyl, (C 2 -C 40 )-alkynyl, aryl and heterocyclyl;

where the alkyl, alkenyl and alkynyl groups may independently optionally be substituted with one or more substituents selected from the group consisting of:

—OR 10 , —SR 10 , —CN, —F, —Cl, —Br, —I,—NR 10a R 10b , oxo, C 3 -C 6 -cycloalkyl, aryl, -aryl-(C 1 -C 6 )-alkyl, heteroaryl, heterocyclyl, —C(O)—R 11 , —C(O)—C 0 -C 6 -alkyl-aryl, —C(O)—O—R 11 , —C(O)—O—C 0 -C 6 -alkyl-aryl, —C(O)—N—R 11a R 11b , —C(O)—NH—C 0 —C 6 -alkyl-aryl, —NH—C(O)—R 11 , and —NH—C(O)—C 0 -C 6 -alkyl-aryl; and

where the aryl, heteroaryl and heterocyclyl rings may independently be further substituted with one or more substituents selected from the group consisting of: (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, —CN, —F, —Cl, —Br, —I, —NR 10a R 10b , oxo, hydroxy, (C 1 -C 6 )-alkoxy, —C(O)—(C 1 -C 6 )-alkyl and —C(O)—O—(C 1 -C 6 )-alkyl; and

where one of the carbons of the alkyl, alkenyl, or alkynyl groups may be replaced by a heteroatom selected from the group consisting of O, N and S; or

R 35 and R 36 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with one or more substituents selected from the group consisting of: oxo, —OR 10 , —SR 10 , —CN, —F, —Cl, —Br, —I, —NR 10a R 10b , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl; —(C 1 -C 6 )-alkyl-hydroxy, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl , —C(O)—OH, and —C(O)—O—(C 1 -C 6 )-alkyl;

R 10 , R 10a , and R 10b are independently selected from the group consisting of H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, aryl, -aryl-(C 1 -C 6 )-alkyl, heteroaryl, heterocyclyl, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)—aryl and —C(O)—(C 1 -C 6 )-alkyl-aryl;

R 11 , R 11a , and R 11b are independently selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl; or R 11a and R 11b together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with oxo, —OR 10 , —SR 10 , —CN, —F, —Cl, —Br, —I, —NR 10a R 10b , (C 1 -C 6 ) alkyl, (C 1 -C 6 )-haloalkyl; —(C 1 -C 6 )-alkyl- hydroxy, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl , —C(O)—OH, or —C(O)—O—(C 1 -C 6 )-alkyl; and

M and M′ are independently selected from the group consisting of hydrogen, —C(O)—R 12 , —C(O)—(C 2 -C 6 )-alkenyl, —C(O)—(C 2 -C 6 )-alkynyl, —C(O)—aryl; —C(O)—heteroaryl, —C(O)O—R 12 , —C(O)NR 12a R 12b , —SO 2 OR 12 , —SO 2 -(C 1 -C 6 )-alkyl, —SO 2 —(C 1 -C 6 )- haloalkyl; —SO 2 -aryl, —SO 2 —NR 12a R 12b , —P(O)(OR 12a )(OR 12b ), and C-linked mono or di-peptide, where R 12 , R 12a , and R 12b are independently hydrogen or (C 1 -C 6 )-alkyl optionally substituted with —OH, —NH 2 , —NH((C 1 -C 6 )-alkyl), —N ((C 1 -C 4 )-alkyl) 2 , —C(O)—OH, —C(O)—O—(C 1 -C 4 )-alkyl or halogen;

with the proviso that the compound is not:

N-(4-hydroxy-3,5-dimethylphenyl)-5-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)pentanamide or 5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-N-(4-hydroxy-3,5-dimethylphenyl)pentanamide;

or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

2. A compound of Formula IIIa:

where:

A is (C 1 -C 4 )-alkylene, (C 2 -C 4 )-alkenylene, or (C 2 -C 4 )-alkynylene;

B is —C(O)NR 4 — or —S(O) 2 NR 4 —;

R 1 , R 2 , and R 3 are independently (C 1 -C 6 )-alkyl;

R 4 is hydrogen or (C 1 -C 6 )-alkyl;

R 30 is hydrogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, aryl, or heterocyclyl,

where the alkyl, alkenyl or alkynyl groups may optionally be substituted with —OR 10 , —SR 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10 ', oxo, (C 3 -C 6 )-cycloalkyl, aryl, -aryl-(C 1 -C 6 )-alkyl, heteroaryl, heterocyclyl, —C(O)—R 11 , —C(O)—(C 0 -C 6 )-alkyl-aryl, —C(O)—O—R 11 , —C(O)—O—(C 0 -C 6 )-alkyl-aryl, —C(O)—N—R 11 R 11 ', —C(O)—NH—(C 0 -C 6 )-alkyl-aryl, —NH—C(O)—R 11 , or —NH—C(O)—(C 0 -C 6 )-alkyl-aryl; or where one of the carbons of the alkyl, alkenyl, or alkynyl groups may be replaced by a heteroatom selected from the group consisting of O, N and S; and

where the aryl, heteroaryl and heterocyclyl rings may independently be further substituted with one or more substituents selected from the group consisting of: (C 1 -C 6 )-alkyl, (C 1 - C 6 )-haloalkyl, —CN, —F, —Cl, —Br, —I, —NR 10 R 10 ', oxo, hydroxy, (C 1 -C 6 )-alkoxy, —C(O)—(C 1 -C 6 )-alkyl and —C(O)—O—(C 1 -C 6 )-alkyl; or

R 30 and R 4 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with oxo, —OR 10 , —SR, —CN, —F, —Cl, —Br, —I, —NR 10 R 10 ′, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, —(C 1 -C 6 )-alkyl- hydroxy, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl , —C(O)—OH, or —C(O)—O—(C 1 -C 6 )-alkyl;

R 10 and R 10 ′ are independently selected from the group consisting of H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, aryl, -aryl-(C 1 -C 6 )-alkyl, heteroaryl, heterocyclyl, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)-aryl, and —C(O)—(C 1 -C 6 )-alkyl-aryl; or

R 10 and R 10 ′ together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with one or more substituents independently selected from the group consisting of oxo, —OH, —F, —Cl, —Br, —I, —NR 11 R 11 ′, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy; (C 1 -C 6 )—haloalkyl, —(C 1 -C 6 )-alkyl- hydroxy, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl , —C(O)OH, and —C(O)O—(C 1 -C 6 )-alkyl;

R 11 and R 11 ′ are independently selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl; or

R 11 and R 11 ′ together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with oxo, —OR 10 , —SR 10 , —CN, —F, —Cl, —Br, —I, NH 2 , —NH(C 1 -C 4 )-alkyl, —N((C 1 -C 4 )-alkyl) 2 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, —(C 1 -C 6 )-alkyl-hydroxy, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)—OH, or —C(O)—O—(C 1 -C 6 )-alkyl; and

with the proviso that the compound is not:

N (4 hydroxy-3,5-dimethylphenyl)-5-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)pentanamide;

or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

3. The compound of claim 2 , where R 4 is hydrogen and R 30 is (C 1 -C 6 )-alkyl substituted with hydroxy, —O—(C 1 -C 6 )-alkyl, or —C(O)O—(C 1 -C 6 )-alkyl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

4. The compound of claim 2 , where R 4 is hydrogen and R 30 is (C 1 -C 6 )-alkyl substituted with —NR 10 R 10 ′, where R 10 and R 10 ′ are independently selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, aryl, -aryl-(C 1 -C 6 )-alkyl, heteroaryl, heterocyclyl, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)-aryl and —C(O)—(C 1 -C 6 )-alkyl-aryl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

5. The compound of claim 2 , where R 4 is hydrogen and R 30 is (C 1 -C 6 )-alkyl substituted with a heterocyclyl or heteroaryl group; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

6. The compound of claim 2 , where R 4 and R 30 together with the nitrogen atom to which they are attached form an optionally substituted 3 to 8-membered nitrogen containing heterocyclyl ring;

or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

7. The compound of claim 2 , where R 4 is hydrogen and R 30 is (C 1 -C 6 )-alkyl optionally substituted with aryl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

8. The compound of claim 1 , where the compound is selected from the group consisting of:

N-(2-hydroxyethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-p-tolyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(3,4-dimethoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-(trifluoromethyl)phenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(benzo[d][1,3]dioxol-5-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(3-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(3-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(3-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2,3-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(3,4-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(3,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(pyridin-3-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(pyridin-4-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

2-methyl-N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-fluorophenyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2,6-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2,6-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(3,4-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(3,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-methyl-N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-chlorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-fluorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(pyridin-3-ylmethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-(pyridin-4-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-aminophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-amino-4-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-benzyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

2-methyl-N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(3-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(2-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(4-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-(3-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-benzyl-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-benzyl-N-ethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-benzyl-N-isopropyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

N-((1-hydroxycyclopropyl)methyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;

2,3,5-trimethyl-6-(4-oxo-4-(pyrrolidin-1-yl)butyl)cyclohexa-2,5-diene-1,4-dione;

N-(1-hydroxy-2-methylpropan-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide; and

2-(4-(4-hydroxypiperidin-l-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;

or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

9. The compound of claim 2 , additionally comprising a pharmaceutically acceptable excipient.

10. The compound of claim 1 , additionally comprising a pharmaceutically acceptable excipient.

11. The compound of claim 8 , additionally comprising a pharmaceutically acceptable excipient.

12. A method of treating an oxidative stress disorder wherein the disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON), Friedreich's Ataxia (FA), Co-Enzyme Q10 Deficiency, Parkinson's disease, and Huntington's Disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .

13. The compound of claim 1 , where the compound is selected from the group consisting of: