Steroids having 1,8-unsaturation and formulations comprising same
View Patent ↗The instant invention provides potent antiandrogen compounds, such as 3β-acetoxyandrost-1,5-diene-17-ethylene ketal and 3β-hydroxyandrost-1,5-diene-17-ethylene ketal, and methods for their use in the prevention and treatment of biological conditions mediated by androgen receptors. Thus, for example, compounds of the invention are useful in the prevention and treatment of prostrate cancer. Furthermore, it has been discovered that compounds of the invention are useful in the prevention and treatment of androgen-independent cancers such as androgen-independent prostrate cancer. Finally, inventive compounds may be used to treat antiandrogen induced withdrawal syndrome.
1. A compound having the structure
or a pharmaceutically acceptable salt of the compound wherein,
A is —CR 9 R 10 —;
E is —C(O)— or —CR 5 R 6 —;
G is —CR 3 R 4 —;
K is —CR 1 R 2 —;
R and R′ independently are —F, —Cl, —Br, —I, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene, substituted or unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH, substituted or unsubstituted lower alkoxy, or —S(O) 0-2 R 14 ;
R 1 is —OR 11 ;
wherein R 11 is —H, substituted or unsubstituted alkyl, substituted or unsubstituted alkene, substituted or unsubstituted alkyne, —C(O)—R 12 , —C(O)—NR 12 R 13 , —C(O)—OR 12 , —C(S)—R 12 , —NR 12 R 13 , —S(O) 2 —R 12 , —S(O) 2 —OR 12 , or —P(O)(OR 12 )(OR 13 ) 0-1 ;
R 2 is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene or substituted or unsubstituted lower alkyne;
R 3 and R 5 independently are —H, —F, —CI, —Br, —I, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene or substituted or unsubstituted lower alkyne;
R 4 and R 6 independently are —H, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH or substituted or unsubstituted lower alkoxy;
R 7 and R 8 independently are —H or substituted or unsubstituted lower alkyl;
R 9 is —OH or substituted or unsubstituted lower alkoxy;
R 10 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene, substituted or unsubstituted lower alkyne, substituted or unsubstituted —S(O) 0-2 (lower alkyl) or R 9 and R 10 , together with the carbon to which they are attached, form a 5-, 6-, or 7- member heterocyclyl or cycloalkyl group;
R 12 and R 13 independently are —H, substituted or unsubstituted alkyl, substituted or unsubstituted alkene, or substituted or unsubstituted alkyne;
R 14 and R 15 independently are —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene, substituted or unsubstituted lower alkyne, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted C 7-12 arylalkyl;
n is 0, 1, or 2; and
n′ is 0, 1, or 2.
2. The compound of claim 1 wherein
R 11 is —H, —C(O)—R 12 or —C(O)—OR 12 ,
R 9 is —OH or —OC(O)CH 3 and n′ is 0.
3. The compound of claim 2 wherein E is —C(O)—.
4. The compound of claim 2 wherein E is —CR 5 R 6 — wherein R 5 is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene or substituted or unsubstituted lower alkyne and R 6 is —OH, or substituted lower alkoxy.
5. The compound of claim 4 wherein R 5 is —H.
6. The compound of claim 4 wherein E is —CR 5 R 6 — wherein R 5 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene, or substituted or unsubstituted lower alkyne.
7. The compound of claim 5 wherein R 4 is —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH or substituted or unsubstituted lower alkoxy.
8. The compound of claim 4 wherein R 4 is —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH or substituted or unsubstituted lower alkoxy.
9. The compound of claim 8 wherein R 4 is —OH.
10. The compound of claim 2 wherein R 4 is —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH or substituted or unsubstituted lower alkoxy.
11. The compound of claim 10 wherein R 4 is —OH and R 3 is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene or substituted or unsubstituted lower alkyne.
12. The compound of claim 11 wherien R 3 is unsubstituted lower alkyl or unsubstituted lower alkyne.
13. The compound of claim 2 wherein R 7 is —H or unsubstituted lower alkyl and R 8 is unsubstituted lower alkyl.
14. The compound of claim 13 wherein R 7 and R 8 are —CH 3 .
15. The compound of claim 4 wherein R 7 and R 8 are —CH 3 .
16. The compound of claim 8 wherein R 7 and R 8 are —CH 3 .
17. A pharmaceutical formulation comprising one or more excipients and a compound having the structure
or a pharmaceutically acceptable salt of the compound wherein,
A is —CR 9 R 10 —;
E is —C(O)—or —CR 5 R 6 —;
G is —CR 3 R 4 —;
K is —CR 1 R 2 —;
R and R′ independently are —F, —Cl, —Br, —I, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene, substituted or unsubstituted lower alkyne, —CN, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR14—C(O)—R 15 , —OH, substituted or unsubstituted lower alkoxy, and —S(O) 0-2 R 14 ;
R 1 is —OR 11 , wherein R 11 is —H, substituted or unsubstituted alkyl, substituted or unsubstituted alkene, substituted or unsubstituted alkyne, —C(O)—R 12 , —C(O)—NR 12 R 13 , —C(O)—OR 12 , —C(S)—R 12 , —NR 12 R 13 , —S(O) 2 —R 12 , —S(O) 2 —OR 12 , and —P(O)(OR 12 )(OR 13 ) 0-1 ;
R 2 is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene or substituted or unsubstituted lower alkyne;
R 3 and R 5 independently are —H, —F, —Cl, —Br, —I, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene or substituted or unsubstituted lower alkyne;
R 4 and R 6 independently are —H, —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH or substituted or unsubstituted lower alkoxy;
R 7 and R 8 independently are —H or substituted or unsubstituted lower alkyl;
R 9 is —OH or substituted or unsubstituted lower alkoxy;
R 10 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene, substituted or unsubstituted lower alkyne, substituted or unsubstituted —S(O) 0-2 (lower alkyl), or R 9 and R 10 , together with the carbon to which they are attached, form a 5-, 6-, or 7- member heterocyclyl or cycloalkyl group;
R 12 and R 13 independently are —H, substituted or unsubstituted alkyl, substituted or unsubstituted alkene, or substituted or unsubstituted alkyne;
R 14 and R 15 independently are —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene, substituted or unsubstituted lower alkyne, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted C 7-12 arylalkyl;
n is 0, 1, or 2; and
n′ is 0, 1 or 2.
18. The pharmaceutical formulation of claim 17 wherein R 11 is —H, —C(O)—R 12 or —C(O)—OR 12 , R 9 is —OH or —OC(O)CH 3 and n′ is 0.
19. The pharmaceutical formulation of claim 18 wherein E is —CR 5 R 6 — wherein R 5 is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene or substituted or unsubstituted lower alkyne and R 6 is —OH, or substituted lower alkoxy.
20. The pharmaceutical formulation of claim 19 wherein R 4 is —COOR 14 , —C(O)NR 14 R 15 , —NO 2 , —NR 14 R 15 , —NR 14 —C(O)—R 15 , —OH or substituted or unsubstituted lower alkoxy.
21. The pharmaceutical formulation of claim 20 wherein R 4 is —OH and R 3 is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkene or substituted and unsubstituted lower alkyne.