Method for expanding hematopoietic stem cells using heterocyclic compound

Patent metadata

Field	Value
Publication number	US-9527828-B2
Application number	US-74666608-A
Country	US
Kind code	B2
Filing date	Dec 6, 2008
Priority date	Dec 6, 2007
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

An expansion agent for hematopoietic stem cells and/or hematopoietic progenitor cells useful for improvement in the efficiency of gene transfer into hematopoietic stem cells for gene therapy useful for treatment of various hematopoietic disorders is provided.
A method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells, which comprises culturing hematopoietic stem cells and/or hematopoietic progenitor cells ex vivo in the presence of a compound represented by the formula (I) (wherein X, Y, X, Ar 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are defined in the description), a tautomer or pharmaceutically acceptable salt of the compound or a solvate thereof.

First claim

The invention claimed is:

1. A method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells, which comprises culturing hematopoietic stem cells and/or hematopoietic progenitor cells ex vivo in a medium containing at least one compound represented by the following formula (I), a tautomer or pharmaceutically acceptable salt or a solvate thereof:

wherein
R 1 is a hydrogen atom or a C 1-3 alkyl group,
R 2 , R 3 and R 6 are hydrogen atoms,
R 4 is a hydrogen atom or a C 1-6 alkyl group,
Ar 1 is represented by the formula (III):

R 5 is a C 2-14 aryl group

substituted with:
(1) one or more hydrogen atoms,
(2) one or more halogen atoms,
(3) one or more carbamoyl groups,
(4) one or more sulfamoyl groups,
(5) one or more C 1-3 alkylsulfonyl groups,
(6) one or more C 1-3 alkyl groups
or
(7) one or more C 1-3 alkoxy groups,
and, when the C 2-14 aryl group is a nitrogen-containing C 2-14 aryl group, the C 2-14 aryl group may be an N-oxide thereof,
R 7 is a phenyl group which may optionally be substituted with:
(1) one or more C 1-10 alkyl groups which may be substituted with one or more halogen atoms,
(2) one or more halogen atoms,
(3) one or more C 1-10 alkoxy groups, or
(4) one or more C 1-3 alkoxy groups which may be optionally substituted with one or more halogen atoms,

X is OH, and
each of Y and Z is an oxygen atom.

2. The method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells according to claim 1 , wherein the hematopoietic stem cells and/or hematopoietic progenitor cells to be expanded are CD34 + CD38 − cells.

3. The method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells according to claim 1 , further comprising:
combining at least one blood cell stimulating factor with the cells and the compound represented by the formula (I) in the culturing.

4. The method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells according to claim 3 , wherein the at least one blood cell stimulating factor is selected from the group consisting of stem cell factor (SCF), interleukin 3 (IL-3), interleukin 6 (IL-6), interleukin 11 (IL-11), flk2/flt3 ligand (FL), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), thrombopoietin (TPO), and erythropoietin (EPO).

5. The method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells according to claim 3 , wherein the blood cell stimulating factor is a stem cell factor (SCF) and/or a flk/flt3 ligand (FL).

6. The method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells according to claim 1 , wherein the hematopoietic stem cells and/or hematopoietic progenitor cells are obtained from bone marrow, liver, spleen, peripheral blood, or cord blood.

7. The method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells according to claim 6 , wherein the hematopoietic stem cells and/or hematopoietic progenitor cells are obtained from cord blood.

8. The method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells according to claim 7 , wherein hematopoietic stem cells and/or hematopoietic progenitor cells obtained from cord blood are cultured in the presence of a stem cell factor (SCF) and/or a flk2/flt3 ligand (FL).

9. The method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells according to claim 1 , wherein
each of R 1 and R 4 is independently a hydrogen atom or a C 1-3 alkyl group,
and
Y and Z are oxygen atoms.

10. The method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells according to claim 1 ,
wherein R 5 is a phenyl group substituted with a carbamoyl group.

11. A method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells, which comprises culturing hematopoietic stem cells and/or hematopoietic progenitor cells ex vivo in a medium containing at least one compound selected from the group consisting of:

a tautomer or pharmaceutically acceptable salt or a solvate thereof.

12. A method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells, which comprises culturing hematopoietic stem cells and/or hematopoietic progenitor cells ex vivo in a medium containing the following compound

a tautomer or pharmaceutically acceptable salt or a solvate thereof.

13. A method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells, which comprises culturing hematopoietic stem cells and/or hematopoietic progenitor cells ex vivo in a medium containing the following compound

a tautomer or pharmaceutically acceptable salt or a solvate thereof.

14. A method for expanding hematopoietic stem cells and/or hematopoietic progenitor cells, which comprises culturing hematopoietic stem cells and/or hematopoietic progenitor cells ex vivo in a medium containing the following compound

a tautomer or pharmaceutically acceptable salt or a solvate thereo

Assignees

• Nishino Taito
• Ishiwata Norihisa
• Miyaji Katsuaki
• Iwamoto Shunsuke
• Asai Yasuyuki
• Yui Makiko
• Nissan Chemical Ind Ltd
• Reprocell Incorporated

Inventors

• Nishino Taito
• Ishiwata Norihisa
• Miyaji Katsuaki
• Iwamoto Shunsuke
• Asai Yasuyuki
• Yui Makiko

Classifications

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C12N5/0647

  Haematopoietic stem cells; Uncommitted or multipotent progenitors · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P7/06

  Antianaemics · CPC title