Pyruvate kinase activators for use in therapy

Patent metadata

Field	Value
Publication number	US-9404081-B2
Application number	US-201214115292-A
Country	US
Kind code	B2
Filing date	May 3, 2012
Priority date	May 3, 2011
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

Described herein are methods for using compounds that activate pyruvate kinase.

First claim

What is claimed is:

1. A method for increasing the lifetime of red blood cells (RBCs) in need thereof comprising contacting blood with an effective amount of (1) a compound of formula I or a pharmaceutically acceptable salt thereof; (2) a composition comprising a compound of formula I or a salt thereof, and a carrier or (3) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein:

W, X, Y and Z are each independently selected from CH or N;
Q and Q 1 are independently selected from a bond or NR b ;
A is optionally substituted bicyclic aryl or optionally substituted bicyclic heteroaryl;
L is a bond, —C(O)—, —(CR c R c ) m —, —OC(O)—, —(CR c R c ) m —OC(O)—, —(CR c R c ) m —C(O)—, —NR b C(S)—, or —NR b C(O)— (wherein the point of the attachment to R 1 is on the left-hand side);
R 1 is selected from alkyl, carbocycle, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of R d ;
each R 3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —OR a , or two adjacent R 3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
each R 4 is independently selected from halo, haloalkyl, alkyl, hydroxyl, ═O, —OR a and phenyl, or two R 4 taken together with the carbon atoms to which they are attached form a bridged, fused or spyro-fused carbocycle, an aryl or a heteroaryl;
each R a is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl;
each R b is independently selected from hydrogen and alkyl;
each R c is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two R c taken together with the carbon atoms to which they are attached form an optionally substituted carbocycle;
each R d is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R a , —OC(O)R a , —C(O)OR a , —SR a , —NR a R b and —OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
n is 0, 1, or 2;
m is 1, 2 or 3;
h is 0, 1, 2;
g is 0, 1 or 2;
the sum of g+h is equal to or greater than 2; and
p is 1 or 2.

2. The method of claim 1 , wherein the compound is added directly to whole blood or packed cells extracorporeally.

3. The method of claim 1 , wherein the pharmaceutical composition is administered to a subject in need thereof.

4. A method for regulating 2,3-diphosphoglycerate levels in blood in need thereof comprising contacting blood with an effective amount of (1) a compound of formula I or a pharmaceutically acceptable salt thereof; (2) a composition comprising a compound of formula I or a salt thereof, and a carrier or (3) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
wherein:

W, X, Y and Z are each independently selected from CH or N;
Q and Q 1 are independently selected from a bond or NR b ;
A is optionally substituted bicyclic aryl or optionally substituted bicyclic heteroaryl;
L is a bond, —C(O)—, —(CR c R c ) m —, —OC(O)—, —(CR c R c ) m —OC(O)—, —(CR c R c ) m —C(O)—, —NR b C(S)—, or —NR b C(O)— (wherein the point of the attachment to R 1 is on the left-hand side);
R 1 is selected from alkyl, carbocycle, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of R d ;
each R 3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —OR a , or two adjacent R 3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
each R 4 is independently selected from halo, haloalkyl, alkyl, hydroxyl, ═O, —OR a and phenyl, or two R 4 taken together with the carbon atoms to which they are attached form a bridged, fused or spyro-fused carbocycle, an aryl or a heteroaryl;
each R a is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl;
each R b is independently selected from hydrogen and alkyl;
each R c is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two R c taken together with the carbon atoms to which they are attached form an optionally substituted carbocycle;
each R d is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R a , —OC(O)R a , —C(O)OR a , —SR a , —NR a R b and —OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
n is 0, 1, or 2;
m is 1, 2 or 3;
h is 0, 1, 2;
g is 0, 1 or 2;
the sum of g+h is equal to or greater than 2; and
p is 1 or 2.

5. A method for treating hemolytic anemia comprising administering to a subject in need thereof a therapeutically effective amount of (1) a compound of formula I or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
wherein:

W, X, Y and Z are each independently selected from CH or N;
Q and Q 1 are independently selected from a bond or NR b ;
A is optionally substituted bicyclic aryl or optionally substituted bicyclic heteroaryl;
L is a bond, —C(O)—, —(CR c R c ) m —, —OC(O)—, —(CR c R c ) m —OC(O)—, —(CR c R c ) m —C(O)—, —NR b C(S)—, or —NR b C(O)— (wherein the point of the attachment to R 1 is on the left-hand side);
R 1 is selected from alkyl, carbocycle, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of R d ;
each R 3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —OR a , or two adjacent R 3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
each R 4 is independently selected from halo, haloalkyl, alkyl, hydroxyl, ═O, —OR a and phenyl, or two R 4 taken together with the carbon atoms to which they are attached form a bridged, fused or spyro-fused carbocycle, an aryl or a heteroaryl;
each R a is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl;
each R b is independently selected from hydrogen and alkyl;
each R c is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two R c taken together with the carbon atoms to which they are attached form an optionally substituted carbocycle;
each R d is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R a , —OC(O)R a , —C(O)OR a , —SR a , —NR a R b and —OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
n is 0, 1, or 2;
m is 1, 2 or 3;
h is 0, 1, 2;
g is 0, 1 or 2;
the sum of g+h is equal to or greater than 2; and
p is 1 or 2.

6. A method for treating sickle cell anemia comprising administering to a subject in need thereof a therapeutically

Assignees

• Su Shin-San Michael
• Agios Pharmaceuticals Inc

Inventors

• Su Shin-San Michael

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title