Mineralocorticoid Receptor Antagonists

20100120736

12/593746

March 29, 2007

Compounds of the formula (I) are provided having a steroid skeleton and substitution characteristics in the A and B rings of the steroid skeleton effective for mineralocorticoid receptor antagonism, and rings C and D of the steroid skeleton having substituents thereon according to formula (I), wherein R1 is —OH or ═O; R2 is (C1-3)alkyl or (C2-3)alkenyl; R3 is selected from formulas (IIa), (IIb), (IIc). These compounds are useful in the treatment of inter alia aldosteronism, hypokalemia, hypertension, congestive heart failure, heart fibrosis, renal failure and restenosis. [chemical expression included]

Peeters, Bernardus Wijnand Machijs Marie (Oss, NL); Groen, Marinus Bernard (Oss, NL); Plate, Ralf (Oss, NL)

1. A compound having a steroid skeleton and substitution characteristics in the A and B rings of the steroid skeleton effective for mineralocorticoid receptor antagonism, and rings C and D of the steroid skeleton having substituents thereon according to formula I [chemical expression included] wherein: R1 is —OH or ═O; R2 is (C1-3)alkyl or (C2-3)alkenyl; R3 is selected from: [chemical expression included] Wherein the lowermost carbon is carbon 17 of the D ring. R3a is H, halogen, monocyclic aryl or is (C1-5)alkyl optionally substituted with hydroxy, halogen, (C1-6)alkoxy or (C1-6)acyloxy; R3b is H, (C1-3)alkyl or halogen; and R3c is H, (C1-6)alkyl, (C2-6)alkenyl or (C2-6)alkynyl; R4 is H or (C1-6)alkyl; R5 is H or R4 and R5 taken together are —CH2— as part of a cyclopropa group; is independently in each case either a single bond or a double bond but is a single bond when part of a cyclopropa group; or a pharmaceutically acceptable salt, ester or ether thereof.

2. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 which is a compound of the formula III [chemical expression included] wherein: R1 is —OH or ═O; R2 is (C1-3)alkyl or (C2-3)alkenyl; R3 is selected from: [chemical expression included] Wherein the lowermost carbon is carbon 17 of the D ring and wherein: R3a is H, halogen, monocyclic aryl or is (C1-5)alkyl optionally substituted with hydroxy, halogen, (C1-6)alkoxy or (C1-6)acyloxy; R3b is H, (C1-3)alkyl or halogen; and R3c is H, (C1-6)alkyl, (C2-6)alkenyl or (C1-C6)alkynyl; R4 is H or (C1-6)alkyl; R5 is H or R4 and R5 taken together are —CH2— as part of a 15,16-cyclopropa group; R6 is H, —CN, (C1-6)alkyl, carboxyl(C1-4)alkyl, carboxyl, —C(═O)O(C1-4)alkyl (C1-5)alkylthio, or (C1-5)acylthio. R7 is H or halogen, or R6 and R7 taken together are —CH2— as part of a 6,7 cyclopropa group or, taken together, R6 and R7 form the second bond of a double bond; R8 is H or a halogen atom, or, taken together, R1 and R8 form the second bond of a double bond; R9 is H or (C1-4alkyl; and is in each case, independently, either a single bond or a double bond but is a single bond when part of a cyclopropa group; or a pharmaceutically acceptable ester or ether thereof.

3. A compound or the pharmaceutically acceptable salt, ester or ether thereof, according to claim 1 in which R1 is —OH.

4. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R2 is methyl or ethyl.

5. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R3a is methyl or ethyl optionally substituted with halogen, methoxy or (C1-3)acyloxy.

6. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R3a is methyl or ethyl.

7. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R3b is H or methyl.

8. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R3c is H.

9. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R3 is of the formula IIa.

10. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R4 is methyl or ethyl.

11. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R6 is H, —CN, (C1-4)alkyl, carboxyl, —C(═O)OCH3, (C1-5)acylthio.

12. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R6 is H, methyl, ethyl, propyl, carboxyl, —C(═O)OCH3 or —S(C═O)CH3.

13. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R6 is H, methyl or —S(C═O)CH3.

14. A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R9 is methyl.

15. A compound of the formula I having a steroid skeleton and substitution characteristics in the A and B rings of the steroid skeleton effective for mineralocorticoid receptor antagonism, and rings C and D of the steroid skeleton having substituents thereon according to formula I [chemical expression included] wherein: R1 is —OH or ═O; R2 is (C1-3)alkyl or (C2-3)alkenyl; R3 is selected from: [chemical expression included] Wherein the lowermost carbon is carbon 17 of the D ring R3a is H, halogen, monocyclic aryl or is (C1-5)alkyl optionally substituted with hydroxy, halogen, (C1-6)alkoxy or (C1-6)acyloxy; R3b is H, (C1-3)alkyl or halogen; and R3c is H, (C1-6)alkyl, (C2-6)alkenyl or (C1-C6)alkynyl; R4 is H or (C1-6)alkyl; R5 is H or R4 and R5 taken together are —CH2— as part of a 15,16-cyclopropa group; or a pharmaceutically acceptable salt, ester or ether thereof, with the proviso that (11β)-11-hydroxy-pregn-4-en-3-one, (11β-20S)-11,21-dihydroxy-20-methylpregn-4-en-3-one and (11β-20S)-11,21-dihydroxy-20-methyl-pregn-1,4-dien-3-one are excluded.

16. A compound of the formula I or the pharmaceutically acceptable salt, ester or ether thereof according to claim 15 which is a compound of the formula III [chemical expression included] wherein: R1 is —OH or ═O; R2 is (C1-3)alkyl or (C2-3)alkenyl; R3 is selected from: [chemical expression included] Wherein the lowermost carbon is carbon 17 of the D ring and wherein: R3a is H, halogen, monocyclic aryl or is (C1-5)alkyl optionally substituted with hydroxy, halogen, (C1-6)alkoxy or (C1-6)acyloxy; R3b is H, (C1-3)alkyl or halogen; and R3c is H, (C1-6)alkyl, (C2-6)alkenyl or (C1-6)alkynyl; R4 is H or (C1-6)alkyl; R5 is H or R4 and R5 taken together are —CH2— as part of a 15,16-cyclopropa group; R6 is H, —CN, (C1-6)alkyl, carboxyl(C1-4)alkyl, carboxyl, —C(═O)O(C1-4)alkyl (C1-5)alkylthio, or (C1-5)acylthio; R7 is H or halogen, or R6 and R7 taken together are —CH2— as part of a 6,7-cyclopropa group or, taken together, R6 and R7 form the second bond of a double bond; R8 is H or a halogen atom, or, taken together, R1 and R8 form the second bond of a double bond; R9 is H or (C1-4)alkyl; and is in each case, independently, either a single bond or a double bond but is a single bond when part of a cyclopropa group; or a pharmaceutically acceptable ester or ether thereof, with the proviso that (11β)-11-hydroxy-pregn-4-en-3-one, (11β-20S)-11,21-dihydroxy-20-methylpregn-4-en-3-one and (11β-20S)-11,21-dihydroxy-20-methyl-pregn-1,4-dien-3-one are excluded.

17. (canceled)

18. A pharmaceutical composition comprising a compound of the formula I according to claim 1 or a pharmaceutically acceptable salt, ester or ether thereof.

19. A method of treatment of a condition associated with the mineralocorticoid receptor, comprising administering to a patient in need thereof, a pharmaceutically effective amount of a compound of formula I according to claim 14, or a pharmaceutically acceptable salt, ester or ether thereof.

20. A method of treatment of a condition associated with the mineralocorticoid receptor, comprising administering to a patient in need thereof, a pharmaceutically effective amount of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt, ester or ether thereof.

21. A pharmaceutical composition comprising a compound of the formula I according to claim 14 or a pharmaceutically acceptable salt, ester or ether thereof.

514/177

61; 07; 61

edspap.20100120736