Methods for using carboxamide, sulfonamide and amine compounds
Disclosed are uses of carboxamide, sulfonamide and amine compounds for the treatment and amelioration of disorders and conditions related to oxidative stress, mitochondrial dysfunction, free radical damage and metabolic inefficiency, among others. Also described are methods for increasing exercise endurance, exercise efficiency and aerobic workload using the compounds described herein.
1. A method for treating or ameliorating a disorder or condition selected from exercise intolerance resulting from mitochondrial dysfunction, chronic fatigue syndrome resulting from mitochondrial dysfunction, muscle weakness resulting from mitochondrial dysfunction, myoclonus resulting from mitochondrial dysfunction, myoclonus epilepsy, Kearns-Sayre syndrome, Leigh's syndrome, mitochondrial myopathy encephalopathy lactacidosis stroke (MELAS) syndrome, and intermittent claudication in a subject, the method comprising administering to the subject an effective amount of a compound having the structural formula
or a pharmaceutically acceptable salt or N-oxide thereof, wherein
each R 3 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;
w is 0, 1, 2 or 3;
R 14 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;
each R 4 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN and two R 4 on the same carbon optionally combine to form oxo;
x is 0, 1, 2, 3 or 4;
each Q is —CH 2 —, a single bond, —C(O)—, —S(O) 2 — or —CH(CH 3 )—;
the ring system denoted by “A” is monocyclic heteroaryl or phenyl;
each R 5 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN; and
y is 0, 1, 2, 3 or 4;
each R 15 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN, and two R 15 on the same carbon optionally combine to form oxo; and
v is 0, 1, 2, 3 or 4;
G is —CH 2 —, —C(O)—, —S(O) 2 — or —CH(CH 3 )—; and
R 17 is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;
in which
each L is independently selected from —NR 9 C(O)O—, —OC(O)NR 9 —, —NR 9 C(O)—NR 9 —, —NR 9 C(O)S—, —SC(O)NR 9 —, —NR 9 C(O)—, —C(O)—NR 9 —, —NR 9 C(S)O—, —OC(S)NR 9 —, —NR 9 C(S)—NR 9 —, —NR 9 C(S)S—, —SC(S)NR 9 —, —NR 9 C(S)—, —C(S)NR 9 —, —SC(O)NR 9 —, —NR 9 C(S)—, —S(O) 0-2 —, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR 9 C(NR 2 )NR 9 —, —NR 9 SO 2 —, —SO 2 NR 9 — and —NR 9 SO 2 NR 9 —,
each R 7 , R 8 and R 10 is independently selected from H, —(C 1 -C 2 alkyl), —(C 1 -C 2 haloalkyl), —(C 0 -C 2 alkyl)-L-(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-NR 9 (C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-O—(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-C(O)—(C 0 -C 2 alkyl) and —(C 0 -C 2 alkyl)-S(O) 0-2 —(C 0 -C 2 alkyl), and
each R 9 is independently selected from —H, —(C 1 -C 4 alkyl) and —C(O)O—(C 1 -C 4 alkyl) and wherein the subject does not have type 2 diabetes.
2. The method of claim 1 , wherein the administration increases metabolic efficiency in the subject.
3. The method of claim 2 , wherein the method is for treating intermittent claudication.
4. A method according to claim 1 , wherein the ring system denoted by “A” is phenyl, pyridyl, thienyl or furanyl; and
R 17 is phenyl or pyridnyl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN.
5. A method according to claim 1 , wherein the ring system denoted by “A” is phenyl; and
R 17 is phenyl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN.
6. A method according to claim 1 , wherein no R 14 is substituted on the furano carbon.
7. A method according to claim 1 , wherein R 14 is halo, cyano, unsubstituted —(C 1 -C 4 alkyl) or unsubstituted —(C 1 -C 4 haloalkyl).
8. A method according to claim 1 , wherein G is —CH 2 —.
9. A method according to claim 1 , wherein G is —C(O)— or —S(O) 2 —.
10. A method according to claim 1 , wherein
x is 0;
v is 0;
w is 0; and
no R 14 is substituted on the furano carbon, or R 14 is halo, cyano, unsubstituted —(C 1 -C 4 alkyl) or unsubstituted —(C 1 -C 4 haloalkyl).
11. A method according to claim 1 , wherein
x is 0 or 1;
v is 0, 1 or 2; and
w is 0, 1 or 2.
12. A method according to claim 1 , wherein the compound has the structural formula
13. A method according to claim 1 , wherein the compound has the structural formula
in which R 25 is selected from halo, cyano, —(C 1 -C 3 haloalkyl), —O—(C 1 -C 2 haloalkyl), —(C 1 -C 3 alkyl), —O—(C 1 -C 2 alkyl), —C(O)—(C 0 -C 2 alkyl), —C(O)O—(C 0 -C 2 alkyl), —C(O)N(C 0 -C 4 alkyl)(C 0 -C 2 alkyl) and NO 2 .
14. A method according to claim 1 , wherein the compound has the structural formula
15. A method according to claim 14 , wherein
x is 0;
v is 0;
w is 0; and
no R 14 is substituted on the furano carbon, or R 14 is halo, cyano, unsubstituted —(C 1 -C 4 alkyl) or unsubstituted —(C 1 -C 4 haloalkyl).
16. A method according to claim 1 , wherein the compound has the structural formula
17. A method according to claim 16 , wherein
x is 0;
v is 0;
w is 0; and
no R 14 is substituted on the furano carbon, or R 14 is halo, cyano, unsubstituted —(C 1 -C 4 alkyl) or unsubstituted —(C 1 -C 4 haloalkyl).
18. A method according to claim 1 , wherein v is 0 and w is 0.
19. A method according to claim 1 , wherein
x is 0;
v is 0;
w is 0;
Q is a single bond or —CH 2 —;
G is —CH 2 — or —C(O)—; and
no R 14 is substituted on the furano carbon, or R 14 is halo, cyano, unsubstituted —(C 1 -C 4 alkyl) or unsubstituted —(C 1 -C 4 haloalkyl).
20. A method according to claim 1 , wherein
x is 0;
v is 0;
w is 0;
Q is a single bond;
G is —CH 2 —; and
no R 14 is substituted on the furano carbon, or R 14 is halo, cyano, unsubstituted —(C 1 -C 4 alkyl) or unsubstituted —(C 1 -C 4 haloalkyl).
21. A method according to claim 1 , wherein
Q is a single bond or —CH 2 —; and
G is —CH 2 — or —C(O)—.
22. A method according to claim 1 , wherein
Q is a single bond; and
G is —CH 2 —.
23. A method according to claim 1 , wherein the compound is
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethoxy)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-chlorophenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(3-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
N-(1-(2-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
3-chloro-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
3-chloro-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
3-chloro-N-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide;
3-chloro-N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide; or
3-chloro-N-(1-isonicotinoylpiperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[b]thiophene-2-carboxamide.
24. The method of claim 1 , wherein the disorder is exercise intolerance resulting from mitochondrial dysfunction.
25. The method of claim 1 , wherein the method is for treating or ameliorating intermittent claudication in the subject.