Non-steroidal progesterone receptor modulators
The present invention provides compounds according to general Formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a prodrug thereof. More particularly, the present invention provides high affinity non-steroidal compounds which are agonists, partial agonists or antagonists of the progesterone receptor.
1. A compound according to Formula I, or a pharmaceutically
acceptable salt thereof
wherein R1, R3, R4, R5 and R10 independently are selected from the group consisting of H, halogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, OH, CN, O(1-4C)alkyl, S(O) m (1-4C)alkyl, optionally substituted with one or more halogen atoms, C(O)(1-4C)alkyl, OC(O)(1-4C)alkyl and NR19R20,
R2 is selected from the group consisting of H, halogen, NO 2 , NR11R12, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, OH, O(1-4C)alkyl, S(1-4C)alkyl and OC(O)(1-4C)alkyl,
R6 is selected from the group consisting of H, C(Y)R15, C(O)OR16, C(S)NR17, (1-6C)alkyl, (1-6C)alkoxy-substituted (1-4C)alkyl and (CH 2 ) n C(O)OR21,
R7 is H or R7 is selected from the group consisting of (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl, all optionally substituted with one or more halogen atoms,
R8 and R9 independently are selected from the group consisting of H and (1-4C)alkyl,
R11 and R12 independently are selected from the group consisting of H, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl, and (6-10C)arylsulfonyl,
R15 is H or R15 is selected from the group consisting of (1-6C)alkyl, (3-6C)cycloalkyl, (2-4C)alkenyl or (2-4C)alkynyl, (6-10C)aryl, 1,4-bisaryl, amino(1-4C)alkyl, hydroxyl(1-4C)alkyl, and carboxy(1-4C)alkyl, all optionally substituted with one or more halogen atoms,
R16 is (1-6C)alkyl, optionally substituted with one or more halogen atoms,
R17 is selected from the group consisting of (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (3-6C) cycloalkyl, all optionally substituted with one or more halogen atoms,
X is O,
Y is selected from the group consisting of O, S, and NH,
R18 is selected from the group consisting of H and (1-4C)alkyl,
R19 is selected from the group consisting of H and (1-4C)alkyl,
R20 is selected from the group consisting of H, (1-4C)alkyl, CH 2 (6-10C)aryl, C(O)(1-6C)alkyl and C(O)NH(1-4C)alkyl,
R21 is selected from the group consisting of H and (1-6C)alkyl,
m is 0, 1 or 2, and
n is 1, 2 or 3,
provided that (i) when R1, R2, R3, R4, and R5 are H, R8, R9 and R10 are H, and R6 is ethyl or C(O)CH 3 then R7 is not H;
(ii) when R1, R2, R3, R4, and R5 are H, R8, R9 and R10 are H, and R6 is methyl then R7 is not methyl; and
(iii) when R1, R2, R3, R4, and R5 are H, R8, R9 and R10 are H, and R6 is H then R7 is not H or ethyl.
2. The compound according to claim 1 , wherein R2 is selected from the group consisting of H, halogen, NO 2 , and NR11R12; and
R11 and R12 independently are selected from the group consisting of H, (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl and (6-10C)arylsulfonyl.
3. The compound according to claim 1 , wherein R1 and R5 are H and R3 and R4 are selected from H or halogen.
4. The compound according to claim 1 , wherein
R6 is selected from H or C(Y)R15 and
R15 is (1-4C)alkyl optionally substituted with one or more halogen atoms or H.
5. The compound according to claim 1 , wherein
R2 is selected from the group consisting of H, halogen and NO 2 ; and
R15 is (1-2C)alkyl optionally substituted with one or more halogen atoms.
6. The compounds according to claim 1 , wherein
R11 is H and R12 is selected from the group consisting of (1-6C)alkoxycarbonyl, (1-4C) alkylsulfonyl and (6-10C)arylsulfonyl.
7. The compound according to claim 1 , wherein
R2 is H,
R3 is halogen,
R15 is methyl, optionally substituted with 1-3 halogen atoms and
Y is O or S.
8. The compound according to claim 1 , wherein R4 is H and X is O.
9. The compound according to claim 1 , wherein R2 is H or halogen,
R3 and/or R4 are independently selected from the group consisting of H, CN, halogen, (2-4C)alkenyl and C(O)(1-4C)alkyl, and
R5 and/or R10 are independently selected from H or halogen.
10. The compound according to claim 1 , wherein R8 and R9 are H.
11. The compound according to claim 9 , wherein R6 is H or C(Y)R15 and
R15 is (1-4C)alkyl, optionally substituted with one or more halogen atoms, or H.
12. The compound according to claim 11 , wherein Y is O or S, and
R15 is methyl, optionally substituted with one or more halogen atoms.
13. A pharmaceutical composition, comprising:
the compound according to claim 1 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliaries.