Glycyrrhetinic acid derivatives for use in treating hyperkalemia

Patent metadata

Field	Value
Publication number	US-11858959-B2
Application number	US-202017429599-A
Country	US
Kind code	B2
Filing date	Feb 6, 2020
Priority date	Feb 7, 2019
Publication date	Jan 2, 2024
Grant date	Jan 2, 2024

Abstract

The present invention provides a compound of formula (I) or a salt thereof: (Formula (I)) wherein X, L, V, R 1 ; R 2 , R 3 and R 4 , are as defined herein. The claimed compounds inhibit the enzyme 11-hydroxysteroid dehydrogenase type 2 (11-HSD2) and as a result are useful in the treatment of hyperkalemia by preventing cortisol from being oxidised to cortisone and thus allowing it to occupy the mineralocorticoid receptor, thus stimulating potassium excretion.

First claim

The invention claimed is:

1. A compound of formula I or a salt thereof:

wherein,
X is a bond, —O—, —C(O)—, —N(R x )—, —C(O)N(R x )—, —N(R x )—C(O)—, —S(O) n —N(R x )— or —N(R x )—S(O) n —;
L is a bond, alkylene wherein one or more non-adjacent methylene groups of said alkylene are replaced with —O—; divalent aryl or divalent heteroaryl; or L is alkylene-Y-alkylene wherein Y is O, NR x , S, SO, SO 2 or a divalent heterocycle; wherein said alkylene groups are optionally substituted with OH, —C(O)O—R 1 , alkyl or alkyl substituted with OH or —C(O)O—R 1 ; and wherein a carbon of said alkylene groups and R x optionally together form a heterocycle; provided that when X is other than a bond, then L is other than a bond;
W is O or S;
Q is a bond or alkylene;
R 1 is H, alkyl, a carbocycle or a heterocycle wherein said alkyl, carbocycle and heterocycle are each optionally substituted with halogen, OH, amino, oxo, carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, a carbocycle optionally substituted with alkyl, haloalkyl, oxo, amino and halogen and a heterocycle optionally substituted with alkyl, oxo, amino and halogen; and a carbocycle or heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino and halogen;
V is —C(O)O—, —C(O)O—(CHR 5 )—O—C(O)—, —C(O)O—(CHR 5 )—O—C(O)—O—, —C(O)O—(CH 2 ) n —Y—C(O)N(R 5 )—, —C(O)N(R 5 )—O—, —NH—C(O)—N(R 5 )— or NH—S(O) n —; wherein Y is a divalent heterocycle optionally substituted with alkyl, halogen, OH, amino, carboxyl and oxo;
R 2 is H or R 5 ;
R 3 is absent or alkyl;
R 4 is absent, H, OH, ═O, —R 6 , —O—R 6 , —C(O)O—R 6 , —O—C(O)—R 6 , —O—C(O)—O—R 6 , —O—C(O)—NR 5 R 6 , —NR 5 R 6 , —NR 5 —C(O)—R 6 , —NR 5 —C(O)—O—R 6 , —NR 5 —SO 2 —R 6 , ═N—O—R 5 ;
R 5 is H or alkyl optionally substituted with a carbocycle or heterocycle wherein said carbocycle and heterocycle are optionally substituted with halogen, OH, oxo and alkyl;
R 6 is H, alkyl, a carbocycle, a heterocycle wherein said alkyl, carbocycle and heterocycle are optionally substituted with halogen, OH, SH, alkylthio, —S(O)-alkyl, —SO 2 -alkyl, amino, —NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxy, alkoxycarbonyl, a carbocycle optionally substituted with halogen, OH, amino or alkyl, or a heterocycle optionally substituted with halogen, OH, amino or alkyl; and wherein one or more non-adjacent methylene groups in each of said alkyl groups of R 6 are optionally replaced with —O— or —S—;
R x is H, —C(O)O—R 1 , or alkyl optionally substituted with —C(O)O—R 1 ; and
n is 1 or 2.

2. The compound of claim 1 , having the structure of any one of Ia-Io:

or Formula Ia′-If′:

3. The compound of claim 1 , wherein V is —C(O)—O— and R 2 is H.

4. The compound of claim 1 , wherein R 1 is methyl, ethyl or isopropyl.

5. The compound of claim 1 , wherein X and L are both bonds.

6. The compound as claimed claim 1 , wherein Q is O.

7. The compound as claimed in claim 1 , wherein R 3 is methyl.

8. The compound as claimed in claim 1 , wherein R 4 is —O—C(O)—R 6 and R 6 is alkyl, carbocycle or heterocycle; wherein said alkyl is optionally substituted with hydroxyl, halogen carboxy, alkoxy, alkylthio, amino, NHC(O)-alkyl, a heterocycle optionally substituted with alkyl; and said carbocycle and heterocycle are optionally substituted with halogen, hydroxyl and alkyl, wherein said alkyl is optionally substituted with hydroxyl, halogen carboxy; and wherein one or more non-adjacent methylene groups is replaced with —O—.

9. The compound as claimed in claim 1 , wherein R 4 is NH 2 , alkoxy, OH, ═N—O-alkyl, ═N—OH.

10. The compound as claimed in claim 1 , wherein R 4 is R 6 and R 6 is phenyl optionally substituted with alkoxy.

11. The compound as claimed in claim 1 , wherein R 4 is R 6 and R 6 is a heterocycle optionally substituted with halogen, alkyl, oxo and alkoxycarbonyl.

12. The compound as claimed in claim 1 , wherein R 4 is —NHC(O)—R 6 .

13. The compound as claimed in claim 1 , claim 1 , wherein R 4 is —NHC(O)—O—R 6 .

14. The compound as claimed in claim 1 , wherein R 4 is —O—C(O)—O—R 6 .

15. The compound as claimed in claim 1 , wherein R 4 is O—R 6 .

16. The compound as claimed in claim 1 , wherein R 4 is —NR 5 R 6 .

17. The compound as claimed in claim 1 , wherein R 4 is —O—C(O)—R 6 and R 6 is methyl, ethyl or cyclopropyl.

18. A method of inhibiting conversion of cortisol to cortisone by 11β-HSD2 comprising contacting 11β-HSD2 with a compound of claim 1 .

19. A method for treating a disease or condition mediated by the conversion of cortisol to cortisone by 11β-HSD2 in a mammal, comprising administering to said mammal an effective amount of a compound as claimed in claim 1 .

20. A method for promoting potassium ion secretion into the colonic lumen of a mammal, comprising administering to said mammal an effective amount of a compound as claimed in claim 1 .

21. A method for treating hyperkalemia in a mammal, comprising administering to said mammal an effective amount of a compound as claimed in claim 1 .

22. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

Assignees

• Ardelyx Inc

Inventors

• Dragoli Dean
• Luehr Gary
• Chen Tao
• Lewis Jason
• Leadbetter Michael

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/12

  for electrolyte homeostasis · CPC title

• A61K31/56

  Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids · CPC title