Inhibitors of the renal outer medullary potassium channel
View Patent ↗This invention relates to compounds having structural Formula I: and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir1.1). The compounds of Formula I are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.
1. A compound having structural Formula I:
or a pharmaceutically acceptable salts thereof wherein:
represents a heterocyclic ring selected from the group consisting of:
Z 1 is selected from the group consisting of:
Z 2 is selected from the group consisting of:
X is selected from the group consisting of —H, —OH, —OC 1-3 alkyl, —F, oxo, NH 2 , and —CH 3 ;
Y is selected from the group consisting of —H, —OH, —OC 1-3 alkyl, —F, oxo, NH 2 , and —CH 3 ;
X 1 and Y 1 are each independently selected from the group consisting of —H and —CH 3 ;
X 2 and Y 2 are each —O—;
provided that when X is oxo then X 1 is absent and when Y is oxo then Y 1 is absent; and further provided that when neither X 2 nor Y 2 is present, then at least one of X and Y is selected from the group consisting of —OH, —OC 1-3 alkyl, —F and oxo;
R 1 and R 2 are each independently selected from the group consisting of —H, -halo, —C 3 -C 6 cycloalkyl, —OR 8 , —SR 8 , —SOR 8 , —SO 2 R 8 , —(CH 2 ) n OR 8 and C 1 -C 6 alkyl optionally substituted with 1-3 of —F;
one of R 3a and R 3b is selected from the group consisting of —CN and —NO 2 and the other is R e ;
one of R 4a and R 4b is selected from the group consisting of —CN and —NO 2 and the other is R f ;
R 5 and R 6 are each independently selected from the group consisting of —H, —C 1-6 alkyl, —C 3-6 cycloalkyl, —CF 3 , —CHF 2 , —CH 2 F and —CH 2 OH;
R 7 is selected from the group consisting of —H, —CH 3 , —CF 3 , —CHF 2 , —CH 2 F and —CH 2 OH;
R a and R b are each independently selected from the group consisting of (a) —H, (b) halo, (c) —C 1-6 alkyl optionally substituted with 1-3 of —F, (d) —C 3-6 cycloalkyl, (e) —OC 1-3 alkyl optionally substituted with 1-3 of —F, (f) —OR 8 , (g) —CO 2 C 1-6 alkyl optionally substituted with 1-3 of —F, (h) —(CH 2 ) n OR 8 , (i) —SR 8 , (j) —SOR 8 , (k) —SO 2 R 8 , (l) —NHCOR 8 and (m) —NHSO 2 R 8 ;
R c and R d are each independently selected from the group consisting of (a) —H, (b) halo, (c) —C 1-6 alkyl optionally substituted with 1-3 of —F, (d) —C 3-6 cycloalkyl, (e) —OC 1-3 alkyl optionally substituted with 1-3 of —F, (f) —OR 8 , (g) —CO 2 C 1-6 alkyl optionally substituted with 1-3 of —F, (h) —(CH 2 ) n OR 8 , (i) —SR 8 , (j) —SOR 8 , (k) —SO 2 R 8 , (l) —NHCOR 8 and (m) —NHSO 2 R 8 ;
R e and R f are each independently selected from the group consisting of (a) —H, (b) halo, (c) —C 1-6 alkyl optionally substituted with 1-3 of —F, (d) —C 3-6 cycloalkyl, (e) —OC 1-3 alkyl optionally substituted with 1-3 of —F, (f) —OR 8 , (g) —CO 2 C 1-6 alkyl optionally substituted with 1-3 of —F, (h) —(CH 2 ) n OR 8 , (i) —SR 8 , (j) —SOR 8 , (k) —SO 2 R 8 , (l) —NHCOR 8 and (m) —NHSO 2 R 8 ;
n is an integer selected from 1, 2 and 3;and
R 8 is independently selected at each occurrence from the group consisting of —H, —C 3-6 cycloalkyl and —C 1-6 alkyl optionally substituted with 1-3 of —F.
2. The compound of claim 1 wherein at least one of X, Y, X 2 and Y 2 is present, and when neither X 2 nor Y 2 is present, then at least one of X and Y is selected from the group consisting of —OH, —OC 1-3 alkyl, —F and oxo, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 wherein Z 1 is selected from the group consisting of:
Z 2 is selected from the group consisting of:
X is selected from the group consisting of —H, —OH, —OC 1-3 alkyl, —F, oxo, NH 2 , and —CH 3 ;
Y is selected from the group consisting of —H, —OH, —OC 1-3 alkyl, —F, oxo, NH 2 , and —CH 3 ;
X 1 and Y 1 are each independently selected from the group consisting of —H and —CH 3 ; and
X 2 and Y 2 are each —O—;
provided that when X is oxo then X 1 is absent and when Y is oxo then Y 1 is absent;
and further provided that at least one of X and Y is selected from the group consisting of —OH, —OC 1-3 alkyl, —F and oxo, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 2 wherein Z 1 is selected from the group consisting of:
and
Z 2 is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 3 wherein
is
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 wherein Z 1 is z1-iv or a pharmaceutically acceptable salt thereof.
7. The compound of claim 3 having structural Formula X
or a pharmaceutically acceptable salt thereof wherein:
is
R 1 is selected from —H and —CH 3 ;
R c is selected from —H and —CH 3 ; and
Z 2 is selected from z2-ii, z2-iv, z2-v and z2-vi.
8. The compound of claim 1 selected from the group consisting of:
5,5′-[3,8-diazabicyclo[3.2.1]octane-3,8-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one);
5,5′-[2,5-diazabicyclo[2.2.2]octane-2,5-diylbis(1-hydroxyethane-2,1-diyl)](4-methyl-2-benzofuran-1(3H)-one);
5,5′-[2,5-diazabicyclo[2.2.1]heptane-2,5-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one);
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier.