Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases
Described herein, inter alia, are compounds useful for the prevention or treatment of hyperproliferative diseases or disorders.
1. A method for treating a disease or disorder related to nuclear receptor activity in a subject, comprising administering a compound, or a pharmaceutically acceptable salt thereof, to the subject in need of such treatment, the compound having the formula:
wherein Het is a heterocyclic unit of 6 atoms comprising
(i) 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;
(ii) 0 or 1 double-bonded substituent on the heterocyclic unit selected from the group consisting of oxygen and sulfur; and
(iii) 3 to 4 single-bonded substituents on the heterocyclic unit independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, CN, NO 2 , OR 11 , SR 11 , NR 11 R 12 , NH(CO)OR 11 , NH(CO)NR 11 R 12 , NR 12 (CO)R 11 , O(CO)R 11 , O(CO)OR 11 , O(CS)R 11 , NR 12 (CS)R 11 , NH(CS)NR 11 R 12 , NR 12 (CS)OR 11 , wherein two of said single-bonded substituents may be connected together with the atoms to which they are bonded to form a cycle, which is aromatic, substituted aromatic, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl;
A is sulfur and B is oxygen;
R 11 and R 12 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, or substituted heterocyclic aromatic or non-aromatic, wherein R 11 and R 12 , both on the same single bonded substituent, can be connected together with the atoms to which they are bonded to form a cycle, which can be heterocyclic aromatic or non-aromatic, or substituted heterocyclic aromatic;
R 1 is selected from aryl and substituted aryl;
R 2 and R 3 are independently selected from hydrogen, aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl, or, together with the carbon to which they are linked, form a cycle which can be cycloalkyl or substituted cycloalkyl.
2. A method for treating prostate cancer in a subject comprising administering a compound, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, the compound having the formula:
wherein Het is a heterocyclic unit of 6 atoms comprising
(i) 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;
(ii) 0 or 1 double-bonded substituent on the heterocyclic unit selected from the group consisting of oxygen and sulfur; and
(iii) 3 to 4 single-bonded substituents on the heterocyclic unit independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, CN, NO 2 , OR 11 , SR 11 , NR 11 R 12 , NH(CO)OR 11 , NH(CO)NR 11 R 12 , NR 12 (CO)R 11 , O(CO)R 11 , O(CO)OR 11 , O(CS)R 11 , NR 12 (CS)R 11 , NH(CS)NR 11 R 12 , NR 12 (CS)OR 11 , wherein two of said single-bonded substituents may be connected together with the atoms to which they are bonded to form a cycle, which is aromatic, substituted aromatic, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl;
A is sulfur and B is oxygen;
R 11 and R 12 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, or substituted heterocyclic aromatic or non-aromatic, wherein R 11 and R 12 , both on the same single bonded substituent, can be connected together with the atoms to which they are bonded to form a cycle, which can be heterocyclic aromatic or non-aromatic, or substituted heterocyclic aromatic;
R 1 is selected from aryl and substituted aryl;
R 2 and R 3 are independently selected from hydrogen, aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl, or, together with the carbon to which they are linked, form a cycle which can be cycloalkyl or substituted cycloalkyl.
3. The method of claim 2 , wherein the compound, or a pharmaceutically acceptable salt thereof is administered at a dosage in the range of from about 0.01 mg per kg body weight per day to about 500 mg per kg body weight per day.
4. The method of claim 2 , wherein the compound, or a pharmaceutically acceptable salt thereof, is administered at a dosage in the range of from about 0.1 mg per kg body weight per day to about 200 mg per kg body weight per day.
5. The method of claim 2 , wherein the compound, or a pharmaceutically acceptable salt thereof, is administered at a dosage in the range of from about 1 mg per kg body weight per day to about 50 mg per kg body weight per day.
6. The method of claim 2 , wherein the compound, or a pharmaceutically acceptable salt thereof is administered at a dosage of about 10 mg per kg body weight per day.
7. The method of claim 2 , wherein the prostate cancer is hormone sensitive prostate cancer or hormone refractory prostate cancer.
8. The method of claim 2 , wherein the compound has a form selected from the group consisting of a solution, dispersion, suspension, powder, capsule, tablet, pill, time release capsule, time release tablet, and time release pill.
9. The method of claim 2 , wherein R 1 is selected from the group consisting of phenyl and substituted phenyl.
10. The method of claim 9 , wherein the substituted phenyl is substituted by at least one fluorine atom.
11. The method of claim 2 , wherein R 2 and R 3 are independently selected from the group consisting of methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, and bromomethyl.
12. The method of claim 2 , wherein R 2 and R 3 , together with the carbon to which they are linked, form a cycle which can be cycloalkyl or substituted cycloalkyl.
13. The method of claim 2 , wherein Het is selected from the group consisting of 6-membered rings of the compounds
R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, CN, NO 2 , OR 11 , SR 11 , NR 11 R 12 , NH(CO)OR 11 , NH(CO)NR 11 R 12 , NR 12 (CO)R 11 , O(CO)R 11 , O(CO)OR 11 , O(CS)R 11 , NR 12 (CS)R 11 , NH(CS)NR 11 R 12 , NR 12 (CS)OR 11 ;
any of R 4 , R 5 , R 6 , and R 7 can be connected to any of R 4 , R 5 , R 6 , and R 7 to form a cycle which can be aromatic, substituted aromatic, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl.
14. The method of claim 13 , wherein R 4 is selected from the group consisting of CN and NO 2 ;
R 5 is selected from the group consisting of trifluoromethyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, and halogen; and
R 6 , and R 7 are independently selected from the group consisting of hydrogen, alkyl, and halogen.
15. The method of claim 14 , wherein R 5 is selected from the group consisting of trifluoromethyl and iodide; and
R 6 and R 7 are independently selected from the group consisting of hydrogen and halogen.
16. The method of claim 13 , wherein Het is selected from the group consisting of
17. The method of claim 7 , wherein the prostate cancer is hormone sensitive prostate cancer.
18. The method of claim 7 , wherein the prostate cancer is hormone refractory prostate cancer.
19. The method of claim 2 , wherein said compound is formulated as a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or adjuvant.