Mitochondrial uncouplers for treatment of metabolic diseases and cancer
2-hydroxy-benzoic anilide compounds and derivatives, compositions thereof, and methods for treating metabolic diseases and cancer through uncoupling mitochondria.
1. A compound of formula (I) having the structure:
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 1 is selected from the group consisting of H, M, PO(OH) 2 , PO 2 (OH)M, PO 3 M 2 , PO(OH)R a , PO(OM)R a , PO(R a ) 2 , and C(O)R a , wherein M is a metal cation or an organic amine;
R 2 , R 4 , and R 5 are H;
R 3 is chloro;
X is a 9-membered ring having the structure:
wherein T is O or S; W 3 , X 3 , X 3 ′, Y 3 , and Z 3 are each independently CR b or N;
each R a is independently selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkoxyalkyl, amino, alkylamino, and alkyl-carbonyloxy-alkyl;
each R b is independently selected from the group consisting of H, CN, NO 2 , CO 2 H, CO 2 R a , CF 3 , OCF 3 , SF 3 , C 6-10 aryl, haloalkyl, CONHR a , and C═NR c (N(R d ) 2 );
each R c is independently selected from the group consisting of H, CN, O-alkyl, NH 2 , mono-alkyl substituted amino, and di-alkyl substituted amino; and
each R d is independently selected from the group consisting of H and alkyl, wherein said alkyl is optionally substituted with halogen, CN, NO 2 , CO 2 H, CO 2 R a , CF 3 , OCF 3 , SF 3 , C 6-10 aryl, or CONHR a ; and provided that said 9-membered ring contains at least one nitrogen and is not indole; and provided the compound is not N-(benzo[d]thiazol-2-yl)-5-chloro-2-hydroxybenzamide.
2. The compound of claim 1 , wherein said 9-membered ring is benzothiazole optionally substituted with R b .
3. A compound selected from the group consisting of
5-Chloro-N-(4-fluorobenzo[d]thiazol-2-yl)-2-hydroxybenzamide,
5-chloro-N-(6-fluorobenzo[d]thiazol-2-yl)-2-hydroxybenzamide,
4-Chloro-2-((6-fluorobenzo[d]thiazol-2-yl)carbamoyl)phenyl dimethylcarbamate,
5-Chloro-2-hydroxy-N-(4-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide,
4-chloro-2((4-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamoyl)phenyl, dimethylcarbamate,
5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide,
4-chloro-2((6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamoyl)phenyl, dimethylcarbamate,
4-chloro-2-((4-fluorobenzo[d]thiazol-2-yl)carbamoyl)phenyl dimethylcarbamate,
5-chloro-N-(6-cyanobenzo[d]thiazol-2-yl)-2-hydroxybenzamide, and
a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a therapeutically effective amount of compound according to any of claim 1 , 2 , or 3 , or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
5. A compound of formula (I) having the structure:
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 1 is selected from the group consisting of H, M, PO(OH) 2 , PO 2 (OH)M, PO 3 M 2 , PO(OH)R a , PO(OM)R a , PO(R a ) 2 , and C(O)R a , wherein M is a metal cation or an organic amine;
R 2 , R 4 , and R 5 are H;
R 3 is chloro;
X is a 9-membered ring having the structure:
wherein T is O or S; W 3 , X 3 , X 3 ′, Y 3 , and Z 3 are each independently CR b or N;
each R a is independently selected from the group consisting of H, alkyl, aryl, alkoxy, aryloxy, alkoxyalkyl, amino, alkylamino, and alkyl-carbonyloxy-alkyl;
each R b is independently selected from the group consisting of H, F, CN, NO 2 , CO 2 H, CO 2 R a , CF 3 , OCF 3 , SF 3 , C 6-10 aryl, haloalkyl, CONHR a , and C═NR c (N(R d ) 2 );
each R c is independently selected from the group consisting of H, CN, O-alkyl, NH 2 , mono-alkyl substituted amino, and di-alkyl substituted amino; and
each R d is independently selected from the group consisting of H and alkyl, wherein said alkyl is optionally substituted with halogen, CN, NO 2 , CO 2 H, CO 2 R a , CF 3 , OCF 3 , SF 3 , C 6-10 aryl, or CONHR a ; and provided that said 9-membered ring contains at least one nitrogen and is not indole; and provided the compound is not N-(benzo[d]thiazol-2-yl)-5-chloro-2-hydroxybenzamide.
6. The compound of claim 5 , wherein said 9-membered ring is benzothiazole optionally substituted with R b .
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 5 , or a pharmaceutically acceptable salt thereof, or a prodrug thereof.