Glycyrrhetinic acid derivatives for treating hyperkalemia

Patent metadata

Field	Value
Publication number	US-11768319-B2
Application number	US-201816636596-A
Country	US
Kind code	B2
Filing date	Aug 6, 2018
Priority date	Aug 4, 2017
Publication date	Sep 26, 2023
Grant date	Sep 26, 2023

Abstract

The present invention provides a compound of formula (I) or a salt thereof: (I) wherein X, L, V, R1, R2, R3 and R4, are as defined herein. These compounds are inhibitors of 11-hydroxysteroid dehydrogenase type 2 (11-HSD-2) and are used to treat hyperkalemia.

First claim

What is 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 —;
V is —C(O)O—, —C(O)N(R 5 )—, —C(O)N(R 5 )O—, —NH—C(O)—N(R 5 )— or NH—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;
R 1 is alkyl 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; wherein one or more non-adjacent methylene groups in any of the foregoing alkyl groups is replaced with O;
R 2 is H or R 1 ;
R 3 is absent, Me; provided that when —X-L-C(O)O—R 1 depends from the carbon to which R 3 depends then R 3 is absent; or R 3 is —Z-L-C(O)O—R 1 wherein Z is a bond, —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 —; and
R 4 is absent, H or OH; provided that when —X-L-C(O)O—R 1 depends from the carbon to which R 4 depends then R 4 is H or absent;
R 5 is H or alkyl;
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 or salt of claim 1 , having the structure of any one of Formula Ia-Ir:

or a salt thereof.

3. The compound or salt of claim 1 , wherein X is a bond.

4. The compound or salt of claim 1 , wherein L is a bond.

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

6. The compound or salt as claimed in claim 1 , wherein R 2 is H.

7. The compound or salt as claimed in claim 1 , wherein R 3 is H.

8. The compound or salt as claimed in claim 1 , wherein R 4 is H.

9. The compound salt as claimed in claim 1 , wherein X is absent and L is aryl or heteroaryl.

10. The compound or salt of claim 9 , wherein L is phenyl, triazole or isoxazole.

11. The compound or salt of claim 10 wherein R 3 is hydrogen.

12. The compound or salt as claimed in claim 11 wherein R 2 and R 4 are each H.

13. The compound or salt as claimed in claim 1 , wherein X is O.

14. The compound or salt as claimed in claim 1 , wherein X is —C(O)—.

15. The compound or salt as claimed in claim 1 , wherein R 1 is alkyl 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 heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino and halogen; wherein one or more non-adjacent methylene groups in said alkyl is replaced with O.

16. The compound or salt of claim 15 , wherein R 1 is methyl, propyl, hydroxyethyl, 2,2,2-trifluoroethyl, 1,1-trifluoromethylethyl, 2-morpholinoethyl, 2-(1H-imidazol-1-yl)ethyl, 2-(pyridin-2-yl)ethyl, —CH 2 —C(O)OH, —CH 2 —C(O)O-Me, —CH 2 —C(O)NH 2 , —CH 2 —C(O)NMe 2 , —CH 2 —C(O)O-t-butyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, (pivaloyloxy)methyl, ((isopropoxycarbonyl)oxy)methyl, (S)-1-((isopropoxycarbonyl)oxy)ethyl, (R)-1-((isopropoxycarbonyl)oxy)ethyl, 2-morpholino-2-oxoethyl, 2-(4-methylpiperazin-1-yl)-2-oxoethyl or (R)-quinuclidin-3-yl.

17. The compound or salt of claim 15 , wherein R 1 is methyl.

18. A method of inhibiting conversion of cortisol to cortisone by HSD2 comprising contacting HSD2 with a compound of claim 1 or a pharmaceutically acceptable salt thereof.

Assignees

• Ardelyx Inc

Inventors

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

Classifications

• A61P7/08

  Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04) · CPC title

• A61P3/12

  for electrolyte homeostasis · CPC title

• G02B3/0056 Primary

  arranged along two different directions in a plane, e.g. honeycomb arrangement of lenses (G02B3/0043 takes precedence; miniaturised objectives for electronic devices employing wafer level optics G02B13/0085) · CPC title

• A61K31/58

  containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048}) · CPC title

• C07J63/008 Primary

  Expansion of ring D by one atom, e.g. D homo steroids · CPC title