Pan-antagonists for the androgen receptor and androgen associated with anti-androgen withdrawal
Disclosed herein are novel antagonists of the androgen receptor and androgen receptor mutations associated with clinical failure of currently prescribed anti-androgens and use of said antagonists in the treatment of conditions associated with inappropriate activation of the androgen receptor.
1. A method for the treatment of a mammal suffering from an androgen-dependent disorder comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I)
wherein R 1 is hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, methyl acrylate, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 2 is hydrogen, hydroxy, fluoro, chloro, cyano, C 1 -C 5 alkanoate, C 1 -C 5 alkylamino, or C 1 -C 6 alkyl optionally substituted with hydroxy or acrylate; and
R 3 is hydrogen, C 1 -C 6 alkyl, fluoro, chloro, bromo, or cyano;
a compound of formula (II)
wherein R 4 is plenyl optionally substituted with hydroxy; C 1 -C 6 phenylalkyl; or benzyl optionally substituted with hydroxy, C 1 -C 6 alkoxy optionally substituted with methoxy or cyano, C 1 -C 6 alkyl, C 1 -C 5 alkanoate, or C 1 -C 5 alkylamine;
or a combination thereof wherein the androgen-dependent disorder I selected from the group consisting of prostate cancer, acne, seborrhea, hirsutism, alopecia and hidradenitis suppurativa.
2. The method of claim 1 , wherein the mammal is suffering from prostate cancer.
3. The method of claim 1 , wherein the mammal is suffering from acne, seborrhea, hirsutism, alopecia, or hidradenitis suppurativa.
4. The method of claim 1 , wherein the mammal is a human.
5. The method of claim 1 , wherein the compound is co-administered with an anti-androgen.
6. The method of claim 5 , wherein the anti-androgen is flutamide, bicalutamide, or a combination thereof.
7. The method of claim 1 , wherein the compound is selected from the group consisting of
or a combination thereof.
8. A method for monitoring the effectiveness of treatment of a subject with a compound of formula (I)
wherein R 1 is hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, methyl acrylate, or C 1 -C 6 alkyl optionally substituted with hydroxy;
R 2 is hydrogen, hydroxy, fluoro, chloro, cyano, C 1 -C 5 alkanoate C 1 -C 5 alkylamino, or C 1 C 6 alkyl optionally substituted with hydroxy or acrylate; and
R 3 is hydrogen, C 1 -C 6 alkyl, fluoro, chloro, bromo, or cyano;
or a compound of formula (II)
wherein R 4 is phenyl optionally substituted with hydroxy; C 1 -C 6 phenylalkyl; or benzyl optionally substituted with hydroxy, C 1 -C 6 alkoxy optionally substituted with methoxy or cyano, C 1 -C 5 alkanoate, or C 1 -C 5 alkylamine;
the method comprising the steps of
obtaining a pre-administration sample from a subject prior to administration of the compound;
(ii) detecting the level of androgen receptor activity in the pre-administration sample;
(iii) obtaining one or more post-administration samples from the subject;
(iv) detecting the level of androgen receptor activity in the post-administration samples;
(v) comparing the level of androgen receptor activity in the pre-administration sample with the post administration sample or samples; and
(vi) altering the administration of the compound to the subject accordingly.
9. The method of claim 8 , wherein the compound is selected from the group consisting of