Inhibitors of the renal outer medullary potassim channel
The present invention provides compounds of Formula (I) (Formula (I)) including pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
1. A compound having structural Formula I
or a pharmaceutically acceptable salt thereof wherein:
X is CHR 4 or a bond;
R 1 and R 2 are each independently of one another H, —OH, halogen, —C 1-4 alkyl optionally substituted with 1-9 halogens, —C 3-4 cycloalkyl, or —OC 1-4 alkyl optionally substituted with 1-9 halogens;
R 3 is H or —C 1-4 alkyl;
R 4 is H, —C 1-4 alkyl, or —OC 1-4 alkyl;
R is —H, —OH, oxo, fluoro or —C 1-4 alkyl which is optionally substituted with 1-9 halogens;
Y is —CH 2 — or a bond;
the dashed line between rings A and B represents an optional double bond where rings A and B are fused;
A is a 6 or 7-membered heterocyclic ring having 1 or 2 —N-atoms and optionally 1 double bond;
Z is a nitrogen atom or a carbon atom, where the carbon atom is unsubstituted when the A and B rings are fused by a double bond, or the carbon atom is substituted with —H when the A and B rings are fused by a single bond;
R 6 represents optional substituent groups on ring A which are each independently selected from the group consisting of —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens;
R 7 represents optional substituent groups on ring B which are each independently selected from the group consisting of -halogen, —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens
a and b are each independently 0 or an integer from 1-3;
B is selected from phenyl, pyrimidine, pyrazole, imidazole, imidazoline, 1,2,4-triazole, 1,2,4-triazolone, 1,3-oxazole, oxazolidinone, pyrrolidine, pyridine, pyrazine, pyridazine, piperidine, isoxazole, and pyrrolidinone optionally having a double bond;
C is a cyclic or bicyclic group selected from
(a) phenyl substituted with one group —CN or -tetrazole and optionally with 1-3 groups independently selected from halogen, —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens;
(b) pyridyl, pyrimidyl, pyrazinyl, pyridazolyl or thiazolyl substituted with one group —CN or -tetrazole, and optionally substituted with 1-3 groups independently selected from halogen, —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens;
which is optionally substituted with 1-3 groups independently selected from halogen, —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens;
which is optionally substituted with 1-3 groups independently selected from halogen, —C 1 - 3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens; and
optionally substituted with 1-2 groups selected from —CH 3 , —OCH 3 , and halogen.
2. The compound of claim 1 having Formula II
or a pharmaceutically acceptable salt thereof wherein:
X is CHR 4 or a bond;
R 1 and R 2 are each independently H, F, —C 1-2 alkyl optionally substituted with 1-5 F, or —OC 1-2 alkyl optionally substituted with 1-5 F;
R 3 is H or —C 1-2 alkyl;
R 4 is H or —CH 3 ;
R 5 is —H, —OH, F or —CH 3 ;
Y is —CH 2 — or a bond;
the dashed line between rings A and B represents an optional double bond where rings A and B are fused;
A is a 6 or 7-membered heterocyclic ring having 1 or 2 —N-atoms and optionally one double bond;
Z is a nitrogen atom or a carbon atom, wherein the carbon atom is unsubstituted when the A and B rings are fused by a double bond, or the carbon atom is substituted with —H, when the A and B rings are fused by a single bond;
B is selected from phenyl, pyrimidine, pyrazole, imidazole, imidazoline, 1,2,4-triazole, 1,2,4-triazolone, 1,3-oxazole, oxazolidinone, pyrrolidine, pyridine, pyrazine, pyridazine, piperidine, isoxazole, and pyrrolidinone optionally having a double bond;
C is a cyclic or bicyclic group selected from
(a) phenyl substituted with one group —CN or -tetrazole, and optionally with 1-2 groups independently selected from —CH 3 , —OCH 3 , and halogen;
(b) pyridyl substituted with one group —CN or -tetrazole and optionally with 1-2 groups independently selected from —CH 3 , —OCH 3 , and halogen;
optionally substituted on the phenyl ring with 1-2 groups selected from —CH 3 , —OCH 3 , and halogen;
optionally substituted on the lactone ring with 1-2 groups selected from —CH 3 , —OCH 3 , and halogen; and
optionally substituted with 1-2 groups selected from —CH 3 , —OCH 3 , and halogen.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 3 are each H or —CH 3 ;
R 2 is H;
R 4 is H or —CH 3 ;
R 5 is —H or —OH;
A is a 6 or 7-membered heterocyclic ring having 1 or 2 —N-atoms and optionally one double bond; and
C is a cyclic or bicyclic group selected from
(a) phenyl substituted with one group —CN or -tetrazole, and optionally with 1-2 groups independently selected from —CH 3 , —OCH 3 , and halogen;
(b) pyridyl substituted with one group —CN, and optionally with 1-2 groups independently selected from —CH 3 , —OCH 3 , and halogen;
optionally substituted on the phenyl ring with one group selected from —CH 3 , —OCH 3 , and halogen;
optionally substituted on the lactone ring with one group —CH 3 ; and
optionally substituted with one group —CH 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl, pyrimidine, pyrazole, imidazole, 1,2,4-triazole, 1,2,4-triazolone, 1,3-oxazole, oxazolidinone, pyrrolidine, and pyrrolidinone optionally having a double bond.
5. A compound having a structure selected from the structures below, or a pharmaceutically acceptable salt thereof:
6. A pharmaceutical composition comprised of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6 further comprising an additional active agent selected from losartan, valsartan, candesartan, olmesartan, telmesartan, eprosartan, irbesartan, amlodipine, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril, amiloride, spironolactone, epleranone or triamterene, or a pharmaceutically acceptable salt of any of the foregoing.
8. A method for causing diueresis, natriuresis or both, comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.
9. A method for the treatment of hypertension comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.