Naphthyl benzoxazoles and benzisoxazoles as estrogenic agents
View Patent ↗This invention provides estrogen receptor modulators of formula I, having the structure wherein R 1 , R 2 , R 3 , and R 4 , and X as defined in the specification, or a pharmaceutically acceptable salt thereof.
1. A compound of formula I having the structure,
R 1 , R 3 , and R 4 are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6 or N(R 5 )COR 6 ;
R 2 is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, triflouroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6 carbon atoms, sulfonoalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, furanyl, thienyl, —NO 2 , —NR 5 R 6 , —N(R 5 )COR 6 , —CN, —CHFCN, —CF 2 CN, alkynyl of 2-7 carbon atoms, or alkenyl of 2-7 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6 or N(R 5 )COR 6 ;
R 5 and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, aryl of 6-10 carbon atoms, —CN, —CHFCN, or —CF 2 CN; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, —COR 7 , —CO 2 R 7 , —NO 2 , CONR 7 R 8 , NR 7 R 8 or N(R 7 )COR 8 ;
R 7 and R 8 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6-10 carbon atoms;
X is O, S;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein X is O or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 , wherein
R 1 is hydrogen;
R 4 is hydrogen;
R 2 is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, phenyl, trifluoroalkyl of 1-6 carbon atoms, furyl, thienyl, thioalkyl of 1-6 carbon atoms, —CN, —CH 2 CN, —COR 5 , C 2 R 5 , CONHR 5 R 6 , alkynyl of 2-7 carbon atoms, or alkenyl of 2-7 carbon atoms;
R 3 is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkoxy of 1-6 carbon atoms, or trifluoroalkyl of 1-6 carbon atoms;
R 5 and R 6 are each, independently, hydrogen or alkyl of 1-6 carbon atoms;
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 , wherein
X is O;
R 1 is hydrogen;
R 2 is hydrogen or halogen;
R 3 is hydrogen;
R 4 is hydrogen;
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 , which is
a)2-(6-Hydroxy-1-naphthyl)-1,3-benzoxazol-5-ol;
b)2-(6-Hydroxy-1-naphthyl)-1,3-benzoxazol-6-ol;
c)2-(6-Hydroxy-2-naphthyl)-1,3-benzoxazol-5-ol;
d)2-(6-Hydroxy-2-naphthyl)-1,3-benzoxazol-6-ol;
e)2-(5-Hydroxy-1-naphthyl)-1,3-benzoxazol-6-ol;
f)2-(4-Hydroxy-1-naphthyl)-1,3-benzoxazol-5-ol;
g)2-(4-Hydroxy-1-naphthyl)-1,3-benzoxazol-6-ol;
h)2-(5-Bromo-6-hydroxy-1-naphthyl)-1,3-benzoxazol-6-ol;
or a pharmaceutically acceptable salt thereof.
6. A compound which is 2-(1-naphthyl)-1,3-benzoxazol-6-ol or a pharmaceutically acceptable salt thereof.
7. A compound of formula IV having the structure
wherein
R 1 , R 3 , and R 4 are each independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6 or N(R 5 )COR 6 ;
R 2 is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, triflouroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6 carbon atoms, sulfonoalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, furanyl, thienyl, —NO 2 , —NR 5 R 6 , —N(R 5 )COR 6 , —CN, —CHFCN, —CF 2 CN, alkynyl of 2-7 carbon atoms, or alkenyl of 2-7 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluroalkyl, trifluoroalkoxy, —COR 5 , —CO 2 R 5 , —NO 2 , CONR 5 R 6 , NR 5 R 6 or N(R 5 )COR 6 ;
R 5 and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, aryl of 6-10 carbon atoms, —CN, —CHFCN, or —CF 2 CN; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, —COR 7 , —CO 2 R 7 , —NO 2 , CONR 7 R 8 , NR 7 R 8 or N(R 7 )COR 8 ;
R 7 and R 8 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6-10 carbon atoms;
X is O, S; and
R 10 and R 11 are alkyl of 1-6 carbon atoms.