Androsterone Derivatives and Method of Use thereof
The disclosure provides androsterone derivatives. The derivatives of the disclosure are useful in the treatment of androgen- and estrogen-associated diseases and disorders, including breast cancer.
1 . A compound comprising the general formula II:
wherein R is selected from the group consisting of an aromatic, an aromatic nitrogen-containing heterocycle, and a non-aromatic nitrogen-containing heterocycle.
2 . The compound of claim 1 , wherein the R group has an aromatic system with electron withdrawing groups.
3 . The compound of claim 1 , wherein the aromatic nitrogen-containing heterocycle is a 5- or 6-membered monocyclic substituent or a bicyclic fused or linked 5- or 6-membered ring.
4 . The compound of claim 3 , wherein the aromatic nitrogen-containing heterocycle is an imidazolyl, an indolyl, a pyridinyl, a pyrimidinyl, a pyrrolyl, a quinolinyl, a tetrazolyl, and a 1,2,4-triazolyl.
5 . The compound of claim 3 , wherein the aromatic nitrogen-containing heterocycle is selected from the group consisting of 2-amino-pyridine, benzimidazole, 2,5-diaminopyridine, 2,4-dimethylimidazole, 2,3-dimethylpyridine, 2,4-dimethylpyridine, 3,5-dimethylpyridine, imidazole, methoxypyridine, γ-picoline, and 2,4,6-trimethylpyridine.
6 . The compound of claim 1 , wherein the non-aromatic nitrogen-containing heterocyle comprises a 4- to 6-membered rings selected from the group consisting of an acetimido, a morpholinyl, a lactam, an imide, a phthalimido, a piperidyl, a piperidino, a piperazinyl, a pyrrolidinyl, and a succinimido.
7 . The compound of claim 6 , wherein the imide is selected from the group consisting of γ-butyrolactam, ε-caprolactam, N-phenyl-β-propiolactam.
8 . The compound of claim 1 , wherein the non-aromatic nitrogen-containing heterocycle is selected from the group consisting of a 1,2-dimethylpiperidine, a 2,5-dimethylpiperazine, a 1,2-dimethylpyrrolidine, a 1-ethylpiperidine, a n-methylpyrrolidine, a morpholine, a piperazine, a piperidine, a pyrrolidine, a 2,2,6,6-tetramethylpiperidine, and a 2,2,4-trimethylpiperidine.
9 . The compound of claim 1 , wherein the R group is an atropine or a scopolamine.
10 . The compound of claim 1 , wherein the R group is a camptothecin analog.
11 . The compound of claim 1 , wherein the R group is selected from the group consisting of:
wherein * indicates the (+) chiral center in the original molecule.
12 . A compound comprising the general formula III:
wherein R is selected from the group consisting of an aromatic, an aromatic nitrogen-containing heterocycle, and a non-aromatic nitrogen-containing heterocycle.
13 . The compound of claim 12 , wherein the R group has an aromatic system with electron withdrawing groups.
14 . The compound of claim 12 , wherein the aromatic nitrogen-containing heterocycle is a 5- or 6-membered monocyclic substituent or a bicyclic fused or linked 5- or 6-membered ring.
15 . The compound of claim 14 , wherein the aromatic nitrogen-containing heterocycle is an imidazolyl, an indolyl, a pyridinyl, a pyrimidinyl, a pyrrolyl, a quinolinyl, a tetrazolyl, and a 1,2,4-triazolyl.
16 . The compound of claim 14 , wherein the aromatic nitrogen-containing heterocycle is selected from the group consisting 2-amino-pyridine, benzimidazole, 2,5-diaminopyridine, 2,4-dimethylimidazole, 2,3-dimethylpyridine, 2,4-dimethylpyridine, 3,5-dimethylpyridine, imidazole, methoxypyridine, γ-picoline, and 2,4,6-trimethylpyridine.
17 . The compound of claim 12 , wherein the non-aromatic nitrogen-containing heterocyle comprises a 4- to 6-membered rings selected from the group consisting of an acetimido, a morpholinyl, a lactam, an imide, a phthalimido, a piperidyl, a piperidino, a piperazinyl, a pyrrolidinyl, and a succinimido.
18 . The compound of claim 17 , wherein the imide is selected from the group consisting of γ-butyrolactam, ε-caprolactam, N-phenyl-β-propiolactam.
19 . The compound of claim 12 , wherein the non-aromatic nitrogen-containing heterocycle is selected from the group consisting of a 1,2-dimethylpiperidine, a 2,5-dimethylpiperazine, a 1,2-dimethylpyrrolidine, a 1-ethylpiperidine, a n-methylpyrrolidine, a morpholine, a piperazine, a piperidine, a pyrrolidine, a 2,2,6,6-tetramethylpiperidine, and a 2,2,4-trimethylpiperidine.
20 . The compound of claim 12 , wherein the R group is an atropine or a scopolamine.
21 . The compound of claim 12 , wherein the R group is a camptothecin analog.
22 . The compound of claim 12 , wherein R is selected from the group consisting of:
23 . A pharmaceutical composition comprising the compound of claim 1 or 12 in a pharmaceutically acceptable carrier.
24 . A method of treating an androgen-associated disease or disorder or an estrogen-associated disease or disorder comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 or 12 .
25 . The method of claim 24 , further comprising administering to the subject a therapeutically effective amount of an agent selected from the group consisting of an antiestrogen or an antiandrogen.
26 . A method of treating or reducing the risk of developing breast cancer comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 or 12 or a pharmaceutical composition thereof.
27 . The method of claim 26 , further comprising administering to the subject a therapeutically effective amount of an antiestrogen agent.
28 . The method of claim 26 , further comprising administering a therapeutically effective amount of an LHRH agonist or antagonist.
29 . The method of claim 26 , further comprising administering a therapeutically effective amount of a second androgenic compound.