Compounds and methods for hematopoietic regeneration

Patent metadata

Field	Value
Publication number	US-10822299-B2
Application number	US-201716304427-A
Country	US
Kind code	B2
Filing date	May 26, 2017
Priority date	May 26, 2016
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

Abstract

The invention relates to compounds that promote hematopoietic regeneration. The invention further relates to methods of promoting hematopoietic regeneration using the novel compounds of the invention.

First claim

We claim:

1. A method of promoting the self-renewal or regeneration of hematopoietic stem cells, comprising administering to a subject a therapeutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
A is selected from alkyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
B is aryl or heteroaryl;
R 4 and R 5 are each independently selected from H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, and halo, or R 4 and R 5 together with the ethylene moiety that separates them may form a ring;
X is selected from O, S, or NR a ;
Q is selected from O, S, or NR a ; and
each instance of R a is selected from H, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, silyloxy, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, amino, sulfonyl, carbonyl, nitro, halo and cyano, or, when X and Q are both NR a , two occurrences of R a together represent a single bond between X and Q.

2. The method of claim 1 , wherein B is not 3,4-dichlorophenyl; and if A is phenyl and B is unsubstituted phenyl, then A is substituted with at least one substituent selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, sulfonyl, carbonyl, halo and cyano.

3. The method of claim 1 , wherein A is selected from alkyl, cycloalkyl, cycloalkenyl, or heterocyclyl.

4. The method of claim 2 , wherein A is selected from methyl, ethyl, propyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, or piperazinyl.

5. The method of claim 2 , wherein A is selected from aryl, aralkyl, heteroaryl, or heteroaralkyl.

6. The method of claim 2 , wherein A is selected from phenyl, benzyl, furanylmethyl, naphthyl, or benzodioxole.

7. The method of claim 1 , wherein A is substituted with at least one substituent selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, sulfonyl, carbonyl, halo and cyano.

8. The method of claim 1 , wherein B is selected from phenyl, furanyl, cyclohexyl, thiophene, or naphthyl.

9. The method of claim 1 , wherein R 4 and R 5 are each independently selected from H, alkyl, or cycloalkyl; or R 4 and R 5 together with the ethylene moiety that separates them form a phenylene ring.

10. The method of claim 1 , wherein the compound has the structure of formula (II) or a pharmaceutically acceptable salt or prodrug thereof:

wherein:
R 1 and R 2 are independently selected from H, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, silyloxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, sulfonyl, carbonyl, nitro, halo and cyano;
n is 0, 1, 2, 3, 4, or 5;
each instance of R 3 is independently selected from alkyl, alkenyl, alkynyl, hydroxy, alkoxy, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, amino, sulfonyl, carbonyl, nitro, halo and cyano; and
R 4 and R 5 are each independently selected from H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, and halo, or R 4 and R 5 together with the ethylene moiety that separates them may form a ring.

11. The method of claim 10 , wherein the compound has the structure of formula (IIb) or (IIc), or a pharmaceutically acceptable salt or prodrug thereof:

12. The method of claim 10 , R 1 is selected from H, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, sulfonyl, carbonyl, nitro, halo and cyano; and R 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, sulfonyl, carbonyl, halo and cyano.

13. The method of claim 1 , wherein the compound has the structure of formula (III), formula (Ma), or a pharmaceutically acceptable salt or prodrug thereof:

wherein:
R 1 and R 2 are independently selected from H, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, silyloxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, sulfonyl, carbonyl, nitro, halo and cyano;
n is 0, 1, 2, 3, 4, or 5;
each instance of R 3 is independently selected from alkyl, alkenyl, alkynyl, hydroxy, alkoxy, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, amino, sulfonyl, carbonyl, nitro, halo and cyano; and
R 4 and R 5 are each independently selected from H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, and halo, or R 4 and R 5 together with the ethylene moiety that separates them may form a ring.

14. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt.

15. The method of claim 1 , wherein the subject is myelosuppressed.

16. The method of claim 1 , wherein the subject has received or is receiving myelosuppressive chemotherapy or radiotherapy, has undergone or is undergoing hematopoietic cell transplantation, or is suffering from with aplastic anemia or a degenerative hematologic disease.

Assignees

• Univ California

Inventors

• Chute John P
• Jung Michael E
• Diers Emelyne

Classifications

• C07C311/44

  having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C205/37

  the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom · CPC title

• C07D295/205

  Radicals derived from carbonic acid · CPC title

• C07D307/46

  Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom · CPC title

• C07C2601/02

  with a three-membered ring · CPC title