Heterocyclic arylsulfonamidobenzylic compounds
View Patent ↗Heterocyclic arylsulfonamidobenzylic compounds are provided which are useful in treating lipid disorders, metabolic disorders and cell-proliferative diseases.
1. A compound of the formula:
wherein
R 1 is
wherein
R 11 is pyrrolyl, optionally substituted with from one to four substituents independently selected from the group consisting of halogen, cyano, nitro, R 14 , OR 13 , SR 13 , N(R 13 ) 2 , NHSO 2 R 14 , NHC(O)R 13 , phenyl, phenyl(C 1 –C 8 )alkyl, and phenyl(C 2 –C 8 )heteroalkyl; wherein each R 13 is independently selected from H, (C 1 –C 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl and halo(C 1 –C 8 )alkyl and each R 14 is independently selected from (C 1 –C 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl and halo(C 1 –C 8 )alkyl;
X is a member selected from the group consisting of OH and OR 15 , wherein R 15 is (C 1 –C 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl or halo(C 1 –C 8 )alkyl;
Y is H, (C 1 –C 8 )alkyl, (C 3 –C 8 )cycloalkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl or (C 2 –C 8 )heteroalkyl; with the proviso that when Y is a substituted (C 1 –C 8 )alkyl, the substituents are other than fluorine atoms;
R 2 is a member selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 3 –C 8 )cycloalkyl and (C 4 –C 8 )cycloalkyl-alkyl, wherein any alkyl portions of R 2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino;
R 3 is aryl optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R 16 , OR 16 , SR 16 , COR 16 , CO 2 R 16 , NHR 16 , N(R 16 ) 2 , CONHR 16 , CON(R 16 ) 2 , NHSO 2 R 16 , NHC(O)R 16 , phenyl, phenyl(C 1 –C 8 )alkyl, and phenyl(C 2 –C 8 )heteroalkyl; wherein each R 16 is independently selected from (C 1 –C 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl and halo(C 1 –C 8 )alkyl;
the subscript n is an integer of from 0 to 3; and
each R 4 is independently selected from the group consisting of halogen, cyano, nitro, R 17 , OR 17 , SR 17 , COR 17 , CO 2 R 17 , N(R 17 ) 2 and CON(R 17 ) 2 , wherein each R 17 is independently selected from H, (C 1 –C 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl and halo(C 1 –C 8 )alkyl;
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 , wherein X is OH.
3. A compound of claim 1 , wherein X is OH, and R 1 is
wherein R 11 is pyrrolyl optionally substituted with from one to three substituents independently selected from the group consisting of halogen, cyano, nitro, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, (C 1 –C 8 )haloalkyl, phenyl(C 1 –C 6 )alkyl and phenyl(C 2 –C 6 )heteroalkyl.
4. A compound of claim 3 , wherein R 11 is pyrrolyl, optionally substituted with from one to two substituents independently selected from the group consisting of halogen, cyano, nitro, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, C 1 –C 8 )haloalkyl, phenyl(C 1 –C 6 )alkyl and phenyl(C 2 –C 6 )heteroalkyl.
5. A compound of claim 4 , wherein R 3 is phenyl, optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R 16 , OR 16 , SR 16 , COR 16 , CO 2 R 16 , NHR 16 , N(R 16 ) 2 , CONHR 16 , CON(R 16 ) 2 , NHSO 2 R 16 , NHC(O)R 16 , phenyl, phenyl(C 1 –C 8 )alkyl, and phenyl(C 2 –C 8 )heteroalkyl; wherein each R 16 is independently selected from (C 1 –C 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl and halo(C 1 –C 8 )alkyl.
6. A compound of claim 5 , wherein the subscript n is an integer of from 0 to 2, and each R 4 is independently selected from the group consisting of halogen, (C 1 –C 8 )alkyl and halo(C 1 –C 8 )alkyl.
7. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula:
wherein
R 1 is a member selected from the group consisting of
wherein
R 11 is pyrrolyl optionally substituted with from one to four substituents independently selected from the group consisting of halogen, cyano, nitro, R 14 , OR 13 , SR 13 , N(R 13 ) 2 , NHSO 2 R 14 , NHC(O)R 13 , phenyl, phenyl(C 1 –C 8 )alkyl, and phenyl(C 2 –C 8 )heteroalkyl; wherein each R 13 is independently selected from H, (C 1 –C 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl and halo(C 1 –C 8 )alkyl and each R 14 is independently selected from (C 1 – 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl and halo(C 1 –C 8 )alkyl;
X is a member selected from the group consisting of OH and OR 15 , wherein R 15 is (C 1 –C 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl or halo(C 1 –C 8 )alkyl;
Y is H, (C 1 –C 8 )alkyl, (C 3 –C 8 )cycloalkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl or (C 2 –C 8 )heteroalkyl; with the proviso that when Y is a substituted (C 1 –C 8 )alkyl, the substituents are other than fluorine atoms;
R 2 is a member selected from the group consisting of H, (C 1 –C 8 )alkyl, (C 2 –C 8 )heteroalkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 3 –C 8 )cycloalkyl and (C 4 –C 8 )cycloalkyl-alkyl, wherein any alkyl portions of R 2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino;
R 3 is aryl optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R 16 , OR 16 , SR 16 , COR 16 , CO 2 R 16 , NHR 16 , N(R 16 ) 2 , CONHR 16 , CON(R 16 ) 2 , NHSO 2 R 16 , NHC(O)R 16 , phenyl, phenyl(C 1 –C 8 )alkyl, and phenyl(C 2 –C 8 )heteroalkyl; wherein each R 16 is independently selected from (C 1 –C 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl and halo(C 1 –C 8 )alkyl;
the subscript n is an integer of from 0 to 3; and
each R 4 is independently selected from the group consisting of halogen, cyano, nitro, R 17 , OR 17 , SR 17 , COR 17 , CO 2 R 17 , N(R 17 ) 2 and CON(R 17 ) 2 , wherein each R 17 is independently selected from H, (C 1 –C 8 )alkyl, (C 3 –C 8 )alkenyl, (C 3 –C 8 )alkynyl, (C 2 –C 8 )heteroalkyl and halo(C 1 –C 8 )alkyl;
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 2 , 3 , 4 , 5 or 6 , or a pharmaceutical acceptable salt thereof.