Compounds and methods for treatment of hypertension
View Patent ↗Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles and azepino[4,5-b]indoles are described. The compounds may bind to and are adrenergic receptor α 2B antagonists. The compounds may also bind to and antagonize adrenergic receptor α 1B . The compounds may find use in therapy, e.g., to (i) reduce blood pressure and/or (ii) promote renal blood flow and/or (iii) decrease or inhibit sodium reabsorption. The compounds may also be used to treat diseases or conditions that are, or are expected to be, responsive to a decrease in blood pressure. Use of the compounds to treat cardiovascular and renal disorders is particularly described.
1. A compound of the formula (A-III):
or a salt, solvate or N-oxide thereof, wherein:
R 1 is H; C 1 -C 5 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C 3 -C 8 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C 2 -C 5 alkenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; or —C(O)O—C 1 -C 5 alkyl; or is taken together with R 2a or R 3a to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; or is taken together with R 4a or R 5a , where present, to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety;
each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;
R 2a is H; optionally substituted C 1 -C 5 alkyl; optionally substituted C 2 -C 5 alkenyl; or optionally substituted aryl; or is taken together with R 1 or R 5a , where present, to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; or is taken together with R 3a to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety; or is taken together with R 4a , where present, to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety;
R 3a is H; optionally substituted C 1 -C 5 alkyl; optionally substituted C 2 -C 5 alkenyl; or optionally substituted aryl; or is taken together with R 1 or R 4a , where present, to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; or is taken together with R 2a to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety; or is taken together with R 5a , where present, to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety;
R 4a is H; optionally substituted C 1 -C 5 alkyl; optionally substituted C 2 -C 5 alkenyl; or optionally substituted aryl; or is taken together with R 3a to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; or is taken together with R 1 to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety; or is taken together with R 2a to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety; or is taken together with R 5a , where present, to form a methylene (—CH 2 —) moiety;
R 5a is H; optionally substituted C 1 -C 5 alkyl; optionally substituted C 2 -C 5 alkenyl; or optionally substituted aryl; or is taken together with R 2a to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; or is taken together with R 1 to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety; or is taken together with R 3a to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety; or is taken together with R 4a , where present, to form a methylene (—CH 2 —) moiety;
each R 2b , R 3b , R 4b and R 5b is independently H, optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl, or optionally substituted aryl;
X is N;
t is 1, 2 or 3;
each R 6 and R 6a is independently H; hydroxyl; halo; C 1 -C 5 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C 2 -C 5 alkenyl; optionally substituted C 1 -C 5 alkoxy; or optionally substituted —C(O)C 1 -C 5 alkyl;
R 7 is H; halo; optionally substituted C 1 -C 5 alkyl; or optionally substituted aryl;
R 9 is H or optionally substituted C 1 -C 5 alkyl;
R 8 and R 10 are taken together to form a bond; and
Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with 1 to 3 substituents independently selected from the group consisting of halo, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, halo-substituted C 1 -C 5 alkyl, halo-substituted C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy, C 3 -C 8 cycloalkoxy, cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of halo, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, halo-substituted C 1 -C 5 alkyl, halo-substituted C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy, C 3 -C 8 cycloalkoxy, cyano, carboxyl, aminoacyl and acylamino.
2. The compound of claim 1 , or a salt, solvate or N-oxide thereof, wherein the compound is of the formula (A-I):
wherein:
R 1 is H; C 1 -C 5 alkyl optionally substituted with 1 to 3 halogen atoms or hydroxyl; C 3 -C 8 cycloalkyl optionally substituted with 1 to 3 halogen atoms or hydroxyl; C 2 -C 5 alkenyl; or —C(O)O—C 1 -C 5 alkyl;
each R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a and R 5b , where present, is independently H or optionally substituted C 1 -C 5 alkyl;
R 6 is H, halogen, C 1 -C 5 alkyl optionally substituted with 1 to 3 halogen atoms, hydroxyl, optionally substituted C 1 -C 5 or optionally sutstituted —C(O)C 1 -C 5 alkyl;
each R 7 and R 9 is independently H or optionally substituted C 1 -C 5 alkyl; and
Q is aryl or heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, halo-substituted C 1 -C 5 alkyl, halo-substituted C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy C 3 -C 8 cycloalkoxy, cyano and acylamino of the formula —C(O)N(R a )R b where each R a and R b is independently H or C 1 -C 5 alkyl.
3. The compound of claim 1 , or a salt, solvate or N-oxide thereof, wherein the compound is of the formula (A-IIIA):
wherein:
R 1 is H; C 1 -C 5 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C 3 -C 8 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, hydroxyl, carboxyl and perhaloalkyl; C 2 -C 5 alkenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; or —C(O)O—C 1 -C 5 alkyl, or is taken together with R 2a or R 3a to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;
R 2a is H, optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl or optionally substituted aryl, or is taken together with R 1 to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;
R 3a is H, optionally substituted C 1 -C 5 alkyl, optionally substituted C 2 -C 5 alkenyl or optionally substituted aryl, or is taken together with R 1 to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;
X is N;
each R 6 is H; hydroxyl, halo, C 1 -C 5 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl; optionally substituted C 1 -C 5 alkoxy; or optionally substituted —C(O)C 1 -C 5 alkyl;
R 7 is H, halo, optionally substituted C 1 -C 5 alkyl, or optionally substituted aryl;
R 8 and R 10 are taken together to form a bond;
R 9 is H or optionally substituted C 1 -C 5 alkyl; and
Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with 1 to 3 substituents independently selected from the group consisting of halo, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, halo-substituted C 1 -C 5 alkyl, halo-substituted C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy, C 3 -C 8 cycloalkoxy, cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of halo, C 1 -C 5 alkyl, C 3 -C 8 cycloalkyl, halo-substituted C 1 -C 5 alkyl, halo-substituted C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy, C 3 -C 8 cycloalkoxy, cyano, carboxyl, aminoacyl and acylamino.
4. The compound of claim 3 , or a salt, solvate or N-oxide thereof, wherein R 1 is C 1 -C 5 alkyl.
5. The compound of claim 3 , or a salt, solvate or N-oxide thereof, wherein each R 2a and R 3a is H.
6. The compound of claim 3 , or a salt, solvate or N-oxide thereof, wherein R 6 is halo or C 1 -C 5 alkyl.
7. The compound of claim 3 , or a salt, solvate or N-oxide thereof, wherein R 7 is H or C 1 -C 5 alkyl.
8. The compound of claim 3 , or a salt, solvate or N-oxide thereof, wherein R 7 is C 1 -C 5 alkyl.
9. The compound of claim 8 , or a salt, solvate or N-oxide thereof, wherein R 9 is H.
10. The compound of claim 3 , or a salt, solvate or N-oxide thereof, wherein R 9 is H.
11. The compound of claim 3 , or a salt, solvate or N-oxide thereof, wherein Q is unsubstituted pyridyl; unsubstituted pyrimidyl; unsubstituted pyrazinyl; unsubstituted phenyl; pyridyl substituted with halo, CH 3 , CF 3 , CONH 2 , OH, or OCH 3 ; pyrimidyl substituted with halo, CH 3 , CF 3 , CONH 2 , OH, or OCH 3 ; pyrazinyl substituted with halo, CH 3 , CF 3 , CONH 2 , OH, or OCH 3 ; or phenyl substituted with halo, CH 3 , CF 3 , CONH 2 , OH, or OCH 3 .
12. The compound of claim 11 , or a salt, solvate or N-oxide thereof, wherein Q is an unsubstituted pyridyl.
13. The compound of claim 11 , or a salt, solvate or N-oxide thereof, wherein Q is pyridyl substituted with halo, CH 3 , CF 3 , CONH 2 , OH, or OCH 3 .
14. The compound of claim 11 , or a salt, solvate or N-oxide thereof, wherein Q is phenyl substituted with halo, CH 3 , CF 3 , CONH 2 , OH, or OCH 3 .
15. The compound of claim 3 , or a salt, solvate or N-oxide thereof, wherein R 1 is CH 3 ; R 6 is CH 3 ; and Q is unsubstituted pyridyl.
16. A compound selected from the group consisting of Compound Nos. 78, 124 and 335:
or a salt thereof.
17. The compound of claim 16 , wherein the compound is:
or a salt thereof.
18. The compound of claim 16 , wherein the compound is:
or a salt thereof.
19. The compound of claim 16 , wherein the compound is:
or a salt thereof.
20. A pharmaceutical composition comprising a compound of claim 1 , or a salt, solvate or N-oxide thereof, and a pharmaceutically acceptable carrier or excipient.
21. A pharmaceutical composition comprising a compound of claim 17 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
22. A pharmaceutical composition comprising a compound of claim 18 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
23. A pharmaceutical composition comprising a compound of claim 19 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.