Sulfur analogues of 21-hydroxy-6,19-oxidoprogesterone (21OH-6OP) for treating excess of glucocorticoids
View Patent ↗The present invention is related to novel 21-hydroxy-6,19-oxidoprogesterone (21OH-6OP) analogues, their use as antiglucocorticoids for the treatment and/or prophylaxis of disease associated to an excess of glucocorticoids. In particular, the invention relates to the use of novel 21-hydroxy-6,19-oxidoprogesterone (21OH-6OP) analogues for treating Cushing's syndrome, iatrogenic hypercortisolism or depression. Also the present invention is related to methods of preparing the novel 21-hydroxy-6,19-oxidoprogesterone (21OH-6OP) analogues.
1. A compound of formula (II)
wherein X is S, SO or SO 2 , and R is either H or OH.
2. A compound of formula (IIa)
wherein X is SO or SO 2 .
3. A compound according to claim 1 having the formula.
4. A compound according to claim 2 having the formula.
5. A compound according to claim 2 having the formula.
6. Compound according to claim 1 having the formula.
7. A compound according to claim 1 having the formula.
8. A compound according to claim 1 having the formula.
9. A pharmaceutical composition comprising at least one 21-hydroxy-6, 19-oxido-progesterone analog of formula II:
wherein X is S, SO or SO 2, and R is either H or OH
and one or more suitable carriers thereof.
10. A method for the preparation of the compound according to claim 3 , comprising
a) protecting the 3-keto group of the 19-acetylsulfanysteroid of formula 16 :
b) transforming the 19-acetyl group into a thiol (thioether) group, and
c) performing a hydrolysis of the compound obtained in b.
11. A method for the preparation of the compound according to claim 4 , comprising
subjecting a compound having the formula
to an oxidation.
12. A method for the preparation of the compound according to claim 6 , comprising
a) providing 17-Acetyl-10-hydroxymethyl-13-methyl-1,2,6,7,8,9,10,11,12,13, 14,15,16,17-tetradecahydro-cyclopenta[a]phenanthren-3-one;
b) transforming the 19 hydroxy group into a thioacetoxy group;
c) protecting the 3-keto group thereof;
d) transforming the 19-thioacetoxy group into a thiol group, and
f) performing a hydrolysis of the step d) compound.
13. A method for the preparation of the compound according to claim 7 , comprising
subjecting a compound having the formula
to an oxidation.
14. A method for the preparation of the compound according to claim 5 , comprising
subjecting a compound having the formula
to an oxidation.
15. A method for the preparation of the compound according to claim 8 , comprising
subjecting a compound having the formula
to an oxidation.
16. The method of claim 11 wherein the compound is subjected to an oxidation with potassium monopersulfate.
17. The method of claim 14 , wherein the compound is subjected to an oxidation with potassium monopersulfate.
18. The method of claim 12 , wherein the 3-keto group is protected by an ethylene glycol group.
19. The method of claim 13 , wherein the compound is subjected to an oxidation with potassium monopersulfate.
20. The method of claim 15 , wherein the compound is subjected to an oxidation with potassium monopersulfate.
21. The method of claim 10 , wherein the 3-keto group of the 19-acetylsulfanysteroid of formula 16 is protected by a ethylene glycol group.