Mineralocorticoid Receptor Antagonists

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

wherein:

R 1 is —OH or ═O;

R 2 is (C 1-3 )alkyl or (C 2-3 )alkenyl;

R 3 is selected from:

Wherein the lowermost carbon is carbon 17 of the D ring.

R 3a is H, halogen, monocyclic aryl or is (C 1-5 )alkyl optionally substituted with hydroxy, halogen, (C 1-6 )alkoxy or (C 1-6 )acyloxy;

R 3b is H, (C 1-3 )alkyl or halogen; and

R 3c is H, (C 1-6 )alkyl, (C 2-6 )alkenyl or (C 2-6 )alkynyl;

R 4 is H or (C 1-6 )alkyl;

R 5 is H or R 4 and R 5 taken together are —CH 2 — 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

wherein:

R 1 is —OH or ═O;

R 2 is (C 1-3 )alkyl or (C 2-3 )alkenyl;

R 3 is selected from:

Wherein the lowermost carbon is carbon 17 of the D ring

and wherein:

R 3a is H, halogen, monocyclic aryl or is (C 1-5 )alkyl optionally substituted with hydroxy, halogen, (C 1-6 )alkoxy or (C 1-6 )acyloxy;

R 3b is H, (C 1-3 )alkyl or halogen; and

R 3c is H, (C 1-6 )alkyl, (C 2-6 )alkenyl or (C 1 -C 6 )alkynyl;

R 4 is H or (C 1-6 )alkyl;

R 5 is H or R 4 and R 5 taken together are —CH 2 — as part of a 15,16-cyclopropa group;

R 6 is H, —CN, (C 1-6 )alkyl, carboxyl(C 1-4 )alkyl, carboxyl, —C(═O)O(C 1-4 )alkyl (C 1-5 )alkylthio, or (C 1-5 )acylthio.

R 7 is H or halogen, or R 6 and R 7 taken together are —CH 2 — as part of a 6,7 cyclopropa group or, taken together, R 6 and R 7 form the second bond of a double bond;

R 8 is H or a halogen atom, or, taken together, R 1 and R 8 form the second bond of a double bond;

R 9 is H or (C 1-4 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.

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

4 . A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R 2 is methyl or ethyl.

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

6 . A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R 3a is methyl or ethyl.

7 . A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R 3b is H or methyl.

8 . A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R 3c is H.

9 . A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R 3 is of the formula IIa.

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

11 . A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R 6 is H, —CN, (C 1-4 )alkyl, carboxyl, —C(═O)OCH 3 , (C 1-5 )acylthio.

12 . A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R 6 is H, methyl, ethyl, propyl, carboxyl, —C(═O)OCH 3 or —S(C═O)CH 3 .

13 . A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R 6 is H, methyl or —S(C═O)CH 3 .

14 . A compound or the pharmaceutically acceptable salt, ester or ether thereof according to claim 1 in which R 9 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

wherein:

R 1 is —OH or ═O;

R 2 is (C 1-3 )alkyl or (C 2-3 )alkenyl;

R 3 is selected from:

Wherein the lowermost carbon is carbon 17 of the D ring

R 3a is H, halogen, monocyclic aryl or is (C 1-5 )alkyl optionally substituted with hydroxy, halogen, (C 1-6 )alkoxy or (C 1-6 )acyloxy;

R 3b is H, (C 1-3 )alkyl or halogen; and

R 3c is H, (C 1-6 )alkyl, (C 2-6 )alkenyl or (C 1 -C 6 )alkynyl;

R 4 is H or (C 1-6 )alkyl;

R 5 is H or R 4 and R 5 taken together are —CH 2 — 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

wherein:

R 1 is —OH or ═O;

R 2 is (C 1-3 )alkyl or (C 2-3 )alkenyl;

R 3 is selected from:

Wherein the lowermost carbon is carbon 17 of the D ring and wherein:

R 3a is H, halogen, monocyclic aryl or is (C 1-5 )alkyl optionally substituted with hydroxy, halogen, (C 1-6 )alkoxy or (C 1-6 )acyloxy;

R 3b is H, (C 1-3 )alkyl or halogen; and

R 3c is H, (C 1-6 )alkyl, (C 2-6 )alkenyl or (C 1-6 )alkynyl;

R 4 is H or (C 1-6 )alkyl;

R 5 is H or R 4 and R 5 taken together are —CH 2 — as part of a 15,16-cyclopropa group;

R 6 is H, —CN, (C 1-6 )alkyl, carboxyl(C 1-4 )alkyl, carboxyl, —C(═O)O(C 1-4 )alkyl (C 1-5 )alkylthio, or (C 1-5 )acylthio;

R 7 is H or halogen, or R 6 and R 7 taken together are —CH 2 — as part of a 6,7-cyclopropa group or, taken together, R 6 and R 7 form the second bond of a double bond;

R 8 is H or a halogen atom, or, taken together, R 1 and R 8 form the second bond of a double bond;

R 9 is H or (C 1-4 )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.