Oestrogen derivatives as inhibitors of steroid sulphatase
The present invention provides a compound comprising a steroidal ring system and an optional group R 1 selected from any one of —OH, a sulphamate group, a phosphonate group, a thiophosphonate group, a sulphonate group or a sulphonamide group; wherein the D ring of the steroidal ring system is substituted by a group R 2 of the formula -L-R 3 , wherein L is an optional linker group and R 3 is selected from groups which are or which comprise one of a nitrite group, an alcohol, an ester, an ether, an amine and an alkene, provided that when R 3 is or comprises an alcohol, L is present; and wherein the A ring of the steroidal ring system is substituted at position 2 or 4 with a group R 4 , wherein R 4 is a hydrocarbyl group.
1. A compound of the formula
wherein R 1 is group selected from any one of —OH, or a sulphamate group of the formula
wherein R 5 and R 6 are independently selected from H, alkyl, cycloalkyl, alkenyl and aryl, or combinations thereof, or together represent alkylene, wherein the or each alkyl or cycloalkyl or alkenyl or aryl optionally contains one or more hetero atoms or groups;
R 2 is a group of the formula -L-R 3 , wherein L is an optional C 1-10 alkylene group and R 3 is a nitrile group, or R 3 is:
(a) a group of the formula
—(R 7 ) n (CR 14 R 15 ) p R 8
wherein n is 0 or 1, p is from 0 to 5;
R 7 is selected from ═CH—, —O— and NR 13 ;
R 8 is —C≡N;
R 13 is selected from H and C 1-10 alkyl;
R 14 and R 15 are each independently selected from H and C 1-10 alkyl; or
(b) a group of the formula —(CR 14 R 15 ) p R 8 ,
wherein p is from 0 to 5,
R 8 is —C≡N,
R 14 and R 15 are each independently selected from H and C 1-10 alkyl; or
(c) a group of the formula —(CH2) p R 8 ,
wherein p is from 0 to 5,
R 8 is —C≡N; or
(d) a group of the formula —(R 7 ) n R 8
wherein n is 0 or 1,
R 7 is selected from ═CH—, —O— and NR 13 ,
R 8 is —C≡N, and
R 13 is selected from H and C 1-10 alkyl;
wherein R 4 is an alkyl or alkoxy group.
2. A compound according to claim 1 wherein R 4 is methoxy.
3. A compound according to claim 1 wherein R 4 is ethyl.
4. A compound according to claim 1 wherein R 1 is —OH.
5. A compound according to claim 1 wherein R 1 is a sulphamate group.
6. A compound according to claim 5 wherein at least one of R 5 and R 6 is H.
7. A compound according to claim 6 wherein each of R 5 and R 6 is H.
8. A compound according to claim 1 wherein p is 0, 1 or 2.
9. A compound according to claim 1 wherein R 13 is —H.
10. A compound according to claim 1 wherein R 3 is a group selected from —CH 2 C≡N and ═CHC≡N.
11. A compound according to claim 1 wherein L is a C 1-5 alkylene, preferably C 1 or C 2 alkylene.
12. A compound according to claim 1 wherein R 2 is of the formula —R 3 .
13. A compound according to claim 1 wherein group R 2 is in an α conformation.
14. A compound according to claim 1 wherein R 1 is a sulphamate group and the compound is suitable for use as an inhibitor of oestrone sulphatase (E.C. 3.1.6.2).
15. A compound according to claim 14 wherein if the sulphamate group on the sulphamate compound were to be replaced with a sulphate group to form a sulphate compound then the sulphate compound would be hydrolysable by a steroid sulphatase enzyme (E.C.3.1.6.2).
16. A compound according to claim 14 wherein if the sulphamate group on the sulphamate compound were to be replaced with a sulphate group to form a sulphate compound and incubated with a steroid sulphatase enzyme (E.C.3.1.6.2) at a pH 7.4 and 37° C. it would provide a K m value of less than 50 mM.
17. A compound according to claim 14 wherein if the sulphamate group on the sulphamate compound were to be replaced with a sulphate group to form a sulphate compound and incubated with a steroid sulphatase enzyme (E.C.3.1.6.2) at a pH 7.4 and 37° C. it would provide a K m value of less than 50 μM.
18. A compound according to claim 1 of the following formula:
wherein R 4 , R 14 , R 15 and p are as defined in claim 1 .
19. A compound according to claim 1 wherein the compound is
20. A compound according to claim 1 wherein the compound is
21. A compound according to claim 1 wherein the compound is