Sphingosine kinase inhibitors
View Patent ↗The invention relates to compositions and methods for inhibiting sphingosine kinase and for treating hyperproliferative disease.
1. A pharmaceutical composition comprising a compound or salt of formula (VIII):
and a pharmaceutically acceptable carrier, wherein
X is sulfur;
R 1 is cycloalkyl, or aryl, wherein each ring is optionally substituted with 1, 2, or 3 groups that are independently (C 1 –C 6 ) alkyl, halogen, haloalkyl, —CF 3 , —OCF 3 , —OH, C 1 –C 6 alkoxy, hydroxyalkyl, —CN, —CO 2 H, —SH, —S-alkyl, —NO 2 , or NR′R″, wherein R′ and R″ are independently H or (C 1 –C 6 ) alkyl; and
R 2 is cycloalkyl, or aryl, wherein each ring is optionally substituted with 1, 2, or 3 groups that are independently (C 1 –C 6 ) alkyl, halogen, haloalkyl, —CF 3 , —OCF 3 , —OH, C 1 –C 6 alkoxy, hydroxyalkyl, —CN, —CO 2 H, —SH, —S-alkyl, —NO 2 , or NR′R″, wherein R′ and R″ are independently H or (C 1 –C 6 ) alkyl or R 2 is benzodioxolyl optionally substituted with 1 or 2 groups that are independently halogen, —CF 3 , —OCF 3 , —OH, C 1 –C 6 alkoxy, —CN, —CO 2 H, —SH, —NO 2 , or NR′R″, wherein R′ and R″ are independently H or (C 1 –C 6 ) alkyl.
2. The pharmaceutical composition of claim 1 wherein the compound is 2-(4-Benzo[1,3]dioxol-5-yl-thiazol-2-yl)-3-(3,4-dihydroxy-phenyl)-acrylonitrile, or a pharmaceutically acceptable salt thereof.
3. A method for inhibiting sphingosine kinase in a cell, the method comprising administering a therapeutically effective amount of a sphingosine kinase inhibitor of formula I-1
or a pharmaceutically acceptable salt thereof, wherein
R 1 is cycloalkyl, or aryl, wherein each ring is optionally substituted with 1, 2, or 3 groups that are independently (C 1 –C 6 ) alkyl, halogen, haloalkyl, —CF 3 , —OCF 3 , —OH, C 1 –C 6 alkoxy, hydroxyalkyl, —CN, —CO 2 H, —SH, —S-alkyl, —NO 2 , or NR′R″, wherein R′ and R″ are independently H or (C 1 –C 6 ) alkyl; and
R 2 is cycloalkyl, or aryl, wherein each ring is optionally substituted with 1, 2, or 3 groups that are independently (C 1 –C 6 ) alkyl, halogen, haloalkyl, —CF 3 , —OCF 3 , —OH, C 1 –C 6 alkoxy, hydroxyalkyl, —CN, —CO 2 H, —SH, —S-alkyl, —NO 2 , or NR′R″, wherein R′ and R″ are independently H or (C 1 –C 6 ) alkyl.
4. The method of claim 3 wherein the sphingosine kinase inhibitor is 5-(2,4-Dihydroxy-benzylidene)-3-(4-methoxy-phenyl)-2-thioxo-thiazolidin-4-one.
5. A method for inhibiting sphingosine kinase in a cell, the method comprising administering a therapeutically effective amount of a sphingosine kinase inhibitor of formula (III):
or a pharmaceutically acceptable salt thereof, wherein
R 3 is H, (C 1 –C 6 ) alkyl, halogen, haloalkyl, —CF 3 , —OCF 3 , —OH, C 1 –C 6 alkoxy, hydroxyalkyl, —CN, —CO 2 H, —SH, —S-alkyl, —NO 2 , or NR′R″, wherein R′ and R″ are independently H or (C 1 –C 6 ) alkyl; and
R 4 is H, (C 1 –C 6 ) alkyl, halogen, haloalkyl, —CF 3 , —OCF 3 , —OH, C 1 –C 6 alkoxy, hydroxyalkyl, —CN, —CO 2 H, —SH, —S-alkyl, —NO 2 , or NR′R″, wherein R′ and R″ are independently H or (C 1 –C 6 ) alkyl.
6. The method of claim 5 wherein the sphingosine kinase inhibitor is 4-[4-(4-Chloro-phenyl)-thiazol-2-ylamino]-phenol.
7. A method for inhibiting sphingosine kinase in a cell, the method comprising administering a therapeutically effective amount of a sphingosine kinase inhibitor of formula (VIII):
or a pharmaceutically acceptable salt thereof, wherein
X is sulfur;
R 1 is cycloalkyl, or aryl, wherein each ring is optionally substituted with 1, 2, or 3 groups that are independently (C 1 –C 6 ) alkyl, halogen, haloalkyl, —CF 3 , —OCF 3 , —OH, C 1 –C 6 alkoxy, hydroxyalkyl, —CN, —CO 2 H, —SH, —S-alkyl, —NO 2 , or NR′R″, wherein R′ and R″ are independently H or (C 1 –C 6 ) alkyl; and
R 2 is cycloalkyl, or aryl, wherein each ring is optionally substituted with 1, 2, or 3 groups that are independently (C 1 –C 6 ) alkyl, halogen, haloalkyl, —CF 3 , —OCF 3 , —OH, C 1 –C 6 alkoxy, hydroxyalkyl, —CN, —CO 2 H, —SH, —S-alkyl, —NO 2 , or NR′R″, wherein R′ and R″ are independently H or (C 1 –C 6 ) alkyl, or R 2 is benzodioxolyl optionally substituted with 1 or 2 groups that are independently halogen, —CF 3 , —OCF 3 , —OH, C 1 –C 6 alkoxy, —CN, —CO 2 H, —SH, —NO 2 , or NR′R″, wherein R′ and R″ are independently H or (C 1 –C 6 ) alkyl.
8. The method of claim 7 wherein the sphingosine kinase inhibitor is 2-(4-Benzo[1,3]dioxol-5-yl-thiazol-2-yl)-3-(3, 4-dihydroxy-phenyl) -acrylonitrile.