HSP90-inhibiting zearalanol compounds and methods of producing and using same
Zearalanol compounds are described and demonstrated or predicted to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents in the treatment and prevention of various disorders. Methods of synthesis and use of such compounds are also described and claimed.
1. A compound of structure IIa or IIb
wherein
R and R 3 are independently selected from OR 10 , optionally substituted lower alkyl and H;
R 2 is —OCH 3 ;
R 5 is selected from H, lower alkyl, aryl and perhaloalkyl;
R 10 is selected from H, lower alkyl, aryl, C(O)NR 11 2 , C(O)OR 11 and C(O)R 11 ;
R 11 is selected from H, optionally substituted alkyl and aryl;
L is O;
“a-b-” is selected from -E-CH 2 —, -E-C(O)—, and —(O)C-E;
“-c-d-” is selected from CH(OH)—CH(OH), CH═CH, O═C—CH 2 , and CH 2 C═O; and
E is O;
wherein the substituents of an optionally substituted group are independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylthio, arylthio, heteroarylthio, oxo, oximes, carboxyesters, carboxamido, acyloxy, F, Cl, Br, I, ON, NO 2 , N 3 , C(O)CH 3 , CO 2 CH 3 , CO 2 H, C(O)NH 2 , OR 17 , SR 17 and NR 18 R 19 , wherein R 17 is selected from hydrogen C1-C8 alkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 haloalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C2-C8 haloalkynyl, aryl, and heteroaryl wherein said alkyl, heteroalkyl, haloalkyl, alkenyl, heteroalkenyl, haloalkenyl, alkynyl, heteroalkynyl, haloalkynyl, aryl and heteroaryl groups are optionally substituted with F, Cl, Br, I, N0 2 , CN, OR 18 , SR 18 , NR 18 R 19 , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C2-C6 alkenyl, or allyl, and wherein R 18 and R 19 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein said compound is represented by the formula:
wherein
R 1 is selected from H and Ac;
“-c-d-” is selected from CH(OH)—CH(OH) and —CH═CH—; and n and n 1 are selected from 1 and 2.
3. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt according to claims 1 or 2 and a pharmaceutically acceptable carrier.
4. A compound according to claim 1 of structure IIa wherein
R is —OH;
R 3 is H;
R 5 is -Me; and
“-c-d-” is —CH 2 —C(O)—.
5. A compound according to claim 1 of structure IIa wherein
R is —OCH 3 ;
R 3 is H;
R 5 is -Me; and
“-c-d-” is —CH 2 —C(O)—.
6. A compound according to claim 1 of structure IIa wherein
R is —OC(O)Me;
R 3 is H;
R 5 is H;
“-a-b-” is —O—CH 2 —; and
“-c-d-” is —CH═CH—.
7. A compound according to claim 1 of structure IIb wherein
R is —OH;
R 3 is H;
R 5 is H;
“-a-b-” is —O—CH 2 —; and
“-c-d-” is —CH 2 —C(O)—.
8. A compound according to claim 1 of structure IIb wherein
R is —OH;
R 3 is H;
R 5 is H;
“-a-b-” is —O—CH 2 —; and
“-c-d-” is —(O)C—CH 2 —.
9. The compound according to claim 2 wherein
R 1 is H; and
“-c-d-” is CH(OH)—CH(OH).
10. The compound according to claim 2 wherein
R 1 is Ac;
“-c-d-” is —CH═CH—; and
n=n 1 =1.
11. A compound according to claim 1 selected from