Inhibitors of the renal outer medullary potassium channel

Patent metadata

Field	Value
Publication number	US-9765074-B2
Application number	US-201414774390-A
Country	US
Kind code	B2
Filing date	Mar 10, 2014
Priority date	Mar 15, 2013
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

The present invention provides compounds of Formula I

and the 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.

First claim

What is claimed is:

1. A compound having structural Formula I

or a pharmaceutically acceptable salt thereof wherein:
Z is

X 1 , X 2 and X 3 are each independently selected from C(R 4 ) or N;
one of X 4 and X 5 is * —C and the other is C(R 4 ) or N;
provided that at least one and at most two of X 1 , X 2 , X 3 , X 4 and X 5 is N;
Each R 4 is independently —H, halo (particularly —F or —Cl), —CN, —C 3-6 cycloalkyl, —C(O)OC 1-4 alkyl, —OC 1-4 alkyl, or —C 1-4 alkyl optionally substituted with —OH or 1-3 of —F;
wherein * indicates the point of attachment to the N-tetrazolyl ring and ** indicates the point Of attachment to —CH(R 9 )—;
R 1 is —H, halo particularly —F, —OH, or —OC 1-3 alkyl particularly —OCH 3 ;
m is an integer selected from zero (R 3b is absent) and 1 (R 3b is present);
R 2 is —H, ═O (oxo), —OH, —C 1-3 alkyl or —OC 1-3 alkyl;
R 3a is —H, —C 3-4 cycloalkyl or —C 1-3 alkyl optionally substituted with —OCH 3 or 1 to 3 of —F;
R 3b is —H or —C 1-3 alkyl, or R 3b is absent when the dashed bond is a double bond;
or R 3a and R 3b are joined together with the carbon to which they are both attached to form cyclopropyl or cyclobutyl;
R 5 is —H, halo, —C 3-6 cycloalkyl or —C 1-3 alkyl optionally substituted with —O—C 1-3 alkyl;
R 6 is —H or —C 1-3 alkyl;
R 7 is —H or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F;
R 8 is —H or —C 1-3 alkyl;
or R 7 and R 8 are joined together with the carbon to which they are both attached to form —C 3-4 cycloalkyl;
R 9 is —H, —F, —OH, —C 1-3 alkyl, —OC 1-3 alkyl or —CH 2 OH;
R 10 is —H, —C 1-3 alkyl optionally substituted with —OH, —OCH 3 , or 1 to 3 of —F;
R 11 is —H, —C 1-3 alkyl optionally substituted with —OH, —OCH 3 , or 1 to 3 of —F;
or R 10 and R 11 are joined together to represent —CH 2 —CH 2 —, —CH 2 —N(CH 3 )—CH 2 — or —CH 2 OCH 2 —;
R 12 and R 13 are each independently —H, halo (particularly —F or —Cl), —CN, —C 3-6 cycloalkyl, —C(O)OC 1-4 alkyl, —OC 1-4 alkyl, or —C 1-4 alkyl optionally substituted with or —OH or 1-3 of —F; and
the dashed bond (“ - - - ”) represents a single or double bond provided that:
(i) when m is 1, then the dashed bond is a single bond; and
(ii) when m is zero and R 2 is not ═O, then the dashed bond is a double bond.

2. The compound of claim 1 having structural Formula II or a pharmaceutically acceptable salt thereof:

3. The compound of claim 1 having structural Formula III or a pharmaceutically acceptable salt thereof:

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Z is:

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Z is

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Z is

7. The compound of claim 1 having structural Formula IV or a pharmaceutically acceptable salt thereof:

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein:
X 1 , X 2 , X 3 and X 4 are each independently selected from C(R 4 ) or N; provided that at least one and at most two of X 1 , X 2 , X 3 and X 4 is N;
each R 4 is independently —H or —C 1-4 alkyl optionally substituted with 1-3 of —F;
R 2 is —H, ═O, —OH, —C 1-3 alkyl or —OC 1-3 alkyl;
R 3a is —H, —C 3-4 cycloalkyl or —C 1-3 alkyl optionally substituted with —OCH 3 or 1 to 3 of —F;
R 3b is —H or —C 1-3 alkyl, or R 3b is absent when the dashed bond is a double bond;
R 5 is —H or —CH 3 ;
R 6 is —H or —CH 3 ;
R 7 is —H, —CH 3 or —CH 2 OH;
R 8 is —H or —CH 3 ;
R 9 is —H, —F, —OH, —C 1-3 alkyl, —OC 1-3 alkyl; and
the dashed bond (“- - - ”) represents a single or double bond provided that:
(i) when m is 1, then the dashed bond is a single bond; and
(ii) when m is zero and R 2 is not ═O, then the dashed bond is a double bond.

9. The compound of claim 1 selected from:
8-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane, single isomer,
8-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2S)-2-hydroxy-2-[6-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2R)-2-hydroxy-2-[4-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2S)-2-hydroxy-2-[4-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2R)-2-hydroxy-2-[6-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2R)-2-hydroxy-2-[2-(1H-tetrazol-1-yl)pyrimidin-5-yl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2S)-2-hydroxy-2-[2-(1H-tetrazol-1-yl)pyrimidin-5-yl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2R)-2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2S)-2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2R)-2-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-hydroxyethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2S)-2-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-hydroxyethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2R)-2-hydroxy-2-[2-methoxy-4-(1H-tetrazol-1-yl)phenyl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2S)-2-hydroxy-2-[2-methoxy-4-(1H-tetrazol-1-yl)phenyl]ethyl}-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-8-azoniaspiro[4.5]decane,
8-{(2R)-2-hydroxy-2-[2-(1H-tetrazol-1-yl)pyrimidin-5-yl]ethyl}-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-8-azoniaspiro[4.5]decane,
8-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-8-azoniaspiro[4.5]decane,
8-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-8-azoniaspiro[4.5]decane,
8-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-8-azoniaspiro[4.5]decane,
8-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-2-(

Assignees

• Merck Sharp & Dohme

Inventors

• Pasternak Alexander
• Ding Fa-Xiang
• Dong Shuzhi
• Biswas Dipshikha
• Tang Haifeng
• Jiang Jinlong
• Yang Cangming
• Gu Xin

Classifications

• A61K31/401

  Proline; Derivatives thereof, e.g. captopril · CPC title

• A61K31/417

  Imidazole-alkylamines, e.g. histamine, phentolamine · CPC title

• A61K31/554

  having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem · CPC title

• C07D471/20

  Spiro-condensed systems · CPC title

• A61K31/5386

  spiro-condensed or forming part of bridged ring systems · CPC title