Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds
View Patent ↗Processes are provided for the synthesis of diarylthiohydantoin and diarylhydantoin compounds. Medicinal products containing the same find particular use in treating prostate cancer, including castration-resistant prostate cancer and/or hormone-sensitive prostate cancer.
1. A process for preparing a compound of formula (I,2-I):
wherein:
X is S or O;
Y 1 and Y 2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms;
R 1 is L 1 -C(═O)—NR 4 R 5 , or L 1 -CN; where L 1 is a single bond or C 1 -C 8 alkylene;
R 4 is H or C 1 -C 8 alkyl;
R 5 is C 1 -C 8 alkyl; and
R 2 is fluoro;
said process comprising reacting the compound of formula D:
wherein R 6 is C 1 -C 8 alkyl;
with the compound of formula (F,2-F):
where X is S or O,
to yield the diarylthiohydantoin or diarylhydantoin compound of formula (I,2-I):
2. A process for preparing a compound of formula (I,2-I):
wherein:
X is S or O;
Y 1 and Y 2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms;
R 1 is L 1 -C(═O)—NR 4 R 5 , or L 1 -CN; where L 1 is a single bond or C 1 -C 8 alkylene;
R 4 and R 5 are independently selected from H and C 1 -C 8 alkyl; and
R 2 is hydrogen or fluoro;
said process comprising reacting the compound of formula A:
wherein LG is a leaving group, Br, or I;
with the compound of formula B:
to yield a compound of formula C:
reacting the compound of formula C with a compound of formula R 6 -LG under alkylating conditions or with a compound of formula R 6 —OH under esterification conditions to form the compound of formula D:
wherein R 6 is C 1 -C 8 alkyl; and
reacting the compound of formula D with the compound of formula (F,2-F):
where X is S or O,
to yield the diarylthiohydantoin or diarylhydantoin compound of formula (I,2-I):
3. The process of claim 1 , wherein X is S.
4. The process of claim 1 , wherein Y 1 and Y 2 are both methyl.
5. The process of claim 1 , wherein Y 1 and Y 2 together with the carbon to which they are attached combine to form a cyclobutyl ring or a cyclopentyl ring.
6. The process of claim 1 , wherein L 1 is a single bond.
7. The process of claim 1 , wherein R 1 is —C(═O)—NHCH 3 .
8. The process of claim 1 , wherein Y 1 and Y 2 are both methyl and R 1 is —C(═O)—NHCH 3 .
9. A process for preparing a compound of formula (I, 2-Ia):
wherein:
X is S or O;
Y 1 and Y 2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms;
R 7 is C—COOH, where L 1 is a single bond or C 1 -C 8 alkylene and
R 2 is hydrogen or fluoro; said process comprising reacting the compound of formula Aa:
with the compound of formula B:
to yield a compound of formula Ca:
reacting the compound of formula Ca with a compound of formula R 6 -LG under alkylating conditions or with a compound of formula R 6 —OH under esterification conditions to form the compound of formula Da:
wherein R 6 is C 1 -C 8 alkyl;
and reacting the compound of formula Da with the compound of formula (F,2-F):
where X is S or O, to yield the diarylthiohydantoin or diarylhydantoin compound of formula (I,2-Ia):
10. The process of claim 9 , wherein X is S.
11. The process of 9 , wherein Y 1 and Y 2 are both methyl, R 7 is —C(═O)—OH, and R 2 is F.
12. The process of claim 2 , wherein X is S.
13. The process of claim 2 , wherein Y 1 and Y 2 are both methyl.
14. The process of claim 2 , wherein Y 1 and Y 2 together with the carbon to which they are attached combine to form a cyclobutyl ring or a cyclopentyl ring.
15. The process of claim 2 , wherein L 1 is a single bond.
16. The process of claim 2 , wherein R 1 is —C(═O)—NHCH 3 .
17. The process of claim 2 , wherein R 1 is —C(═O)—NH 2 .
18. The process of claim 2 , wherein R 2 is F.
19. The process of claim 2 , wherein Y 1 and Y 2 are both methyl, R 1 is —C(═O)—NHCH 3 , and R 2 is F.
20. The process of claim 2 , wherein Y 1 and Y 2 are both methyl, R 1 is —C(═O)—NH 2 , and R 2 is F.