Small-molecule inhibitors of the androgen receptor
View Patent ↗The present invention provides a method of inhibiting an androgen receptor by administering a compound of Formula I: or a compound of Formula II: wherein R 1 , R 2 , R 3 and R 8 are each independently hydrogen or C 1-6 alkyl. R 4 is absent or is hydrogen, C 1-6 alkyl or C 1-6 alkyl-OH. R 5 is hydrogen, C 1-6 alkyl or —NR 6 R 7 . R 6 and R 7 are each independently hydrogen or C 1-6 alkyl, or are combined with the nitrogen to which they are attached to form a heterocycloalkyl having from 5 to 7 ring members. L is a linker of C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene or C 3-6 cycloalkylene. The compounds of Formula I include the salts, hydrates and prodrugs thereof. Each R 9 is H, C 1-6 alkyl, —OH or —O—C 1-6 alkyl. The compounds of Formulas I and II include the salts, hydrates and prodrugs thereof. By administering the compound of Formula I or II, the method inhibits the androgen receptor.
1. A method of inhibiting the androgen receptor, the method comprising:
administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula Ic:
wherein
the dashed line is absent;
R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
R 4 is a member selected from the group consisting of hydrogen, C 1-6 alkyl and C 1-6 alkyl-OH;
R 5 is a member selected from the group consisting of hydrogen, C 1-6 alkyl and —NR 6 R 7 ;
R 6 and R 7 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl, or are combined with the nitrogen to which they are attached to form a heterocycloalkyl having from 5 to 7 ring members;
and salts thereof, thereby inhibiting the androgen receptor.
2. The method of claim 1 , wherein
R 1 is H; and
R 2 , R 3 , R 4 and R 5 are each C 1-6 alkyl.
3. The method of claim 1 , wherein the compound is:
4. The method of claim 1 , wherein the salt forms comprise a counterion selected from the group consisting of pamoate, chloride, bromide, succinate, maleate and acetate.
5. The method of claim 1 , wherein the patient suffers from a disease selected from the group consisting of prostate cancer, ovarian cancer, acne vulgaris, breast cancer, polycystic ovary syndrome, benign prostatic hyperplasia, alopecia, and hirsutism.
6. The method of claim 5 , wherein the disease is prostate cancer.
7. The method of claim 6 , wherein the disease is primary prostate cancer.
8. The method of claim 6 , wherein the disease is hormone refractory prostate cancer.
9. The method of claim 1 , wherein the administration is via topical, oral, intravenous, intradermal, intramuscular or parenteral administration.
10. The method of claim 5 , wherein the disease is alopecia and the administration is topical.
11. The method of claim 1 , wherein the compound of Formula Ic is administered with a course of hormonal therapy, wherein the compound for hormonal therapy is selected from the group consisting of an anti-androgen and a LnRH agonist.
12. The method of claim 11 , wherein the compounds are administered separately.
13. The method of claim 11 , wherein the compounds are admixed.
14. The method of claim 11 , wherein the compounds are administered at the same time.
15. The method of claim 11 , wherein the compounds are administered at different times.
16. The method of claim 11 , wherein the compound of Formula Ic is administered in combination with a therapeutically effective amount of a compound selected from the group consisting of bicalutamide, flutamide, hydroxyflutamide, nilutamide, spionolactone, cyproterone acetate, ketoconazole, finasteride and dutasteride.
17. The method of claim 11 , wherein the compound of Formula Ic is administered in combination with a therapeutically effective amount of a coumarin.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula Ic:
wherein
the dashed line is absent;
R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
R 4 is a member selected from the group consisting of hydrogen, C 1-6 alkyl and C 1-6 alkyl-OH;
R 5 is a member selected from the group consisting of hydrogen, C 1-6 alkyl and —NR 6 R 7 ;
R 6 and R 7 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl, or are combined with the nitrogen to which they are attached to form a heterocycloalkyl having from 5 to 7 ring members;
in combination with a therapeutically effective amount of a compound selected from the group consisting of an anti-androgen and a LnRH agonist.