Heterocyclic compounds and expansion agents for hematopoietic stem cells
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 disorders is provided. An expansion agent for hematopoietic stem cells and/or hematopoietic progenitor cells is provided, containing a compound represented by the formula (I): (wherein X, Y, Z, Ar 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in the description), a tautomer, amide, ester, or pharmaceutically acceptable salt of the compound or a solvate thereof, which can expand hematopoietic stem cells and/or hematopoietic progenitor cells.
1. A compound of formula (I):
wherein:
R 1 is a methyl group;
R 2 , R 3 , and R 4 are a hydrogen atom;
R 5 is a phenyl group, substituted with —V 1 , —V 2 , V 3 , or V 4 wherein
—V 1 is —(CH 2 )m 1 M 1 NR 8 R 9 ,
wherein M 1 is —(C═O)—or —(SO 2 )—, m 1 is an integer of 0, 1, or 2,
R 8 is a hydrogen atom or a C 1-3 alkyl group, and
when m 1 =0, R 9 is
—(CH 2 )m 2 OR 10 , wherein m 2 , is an integer of 1 or 2, and R 10 is a hydrogen atom, a C 1-3 alkyl group or —(CH 2 )m 3 T, wherein m 3 is an integer of 1 or 2, and T is a hydroxyl group, a C 1-6 alkoxy group or a C 1-6 alkyl group,
—(CH 2 )m 4 NR 11 R 12 , wherein m 4 is an integer of 1 or 2, and each of
R 11 and R 12 is independently a hydrogen atom or —(CH 2 )m 5 Q, wherein m 5 is an integer of 1 or 2, and Q is a hydroxy group, a C 1-3 alkoxy group, —
NR 13 R 14 , wherein each of R 13 and R 14 is independently a hydrogen atom or a C 1-3 alkyl group, or R 11 and R 12 mean, together with each other as —NR 11 R 12 , a substituent of formula (II) or (III):
wherein R 15 is a hydrogen atom, a C 1-3 alkyl group or an amino-protecting group, and
when m 1 =1 or 2,
R 9 is a hydrogen atom or —(CH 2 )m 2 OR 10 , wherein m 2 is an integer of 1 or 2, and R 10 is a hydrogen atom, a C 1-3 alkyl group or —(CH 2 )m 3 T, wherein m 3 is an integer of 1 or 2, and T is a hydroxyl group, a C 1 - 6 alkoxy group or a C 1-6 alkyl group, —(CH 2 )m 4 NR 11 R 12 , wherein m 4 is an integer of 1 or 2, and each of R 11 and R 12 is independently a hydrogen atom or —(CH 2 )m 5 Q, wherein m 5 is an integer of 1 or 2, and Q is a hydroxy group, a C 1-3 alkoxy group, —NR 13 R 14 , wherein each of R 13 and R 14 is independently a hydrogen atom or a C 1-3 alkyl group, or R 11 and R 12 mean, together with each other as —NR 11 R 12 , a substituent of formula (II) or (III):
wherein R 15 is a hydrogen atom, a C 1-3 alkyl group or an amino-protecting group,
—V 2 is —(CH 2 )m 6 NR 16 R 17 ,
wherein m 6 is an integer of 1 or 2, and each of R 16 and R 17 is independently a hydrogen atom, a C 1-3 alkylcarbonyl group or a C 1-3 alkylsulfonyl group,
—V 3 is M 2 NR 18 (CH 2 )m 7 R 19 ,
wherein M 2 is —(C═O)—or —(SO 2 )-, m 7 is an integer of 1 or 2, R 18 is a hydrogen atom or a C 1 - 3 alkyl group, and R 19 is a C 2-9 heterocyclyl group or a C 2-14 aryl group, and
—V 4 is —(C═O)—(piperazine-1,4-diyl)—U;
wherein U is —(CH 2 )m 2 OR 10 , wherein m 2 is an integer of 1 or 2, and R 10 is a hydrogen atom, a C 1-3 alkyl group or —(CH 2 )m 3 T, wherein m 3 is an integer of 1 or 2, and T is a hydroxyl group, a C 1-6 alkoxy group or a C 1-6 alkyl group, —(CH 2 )m 4 NR 11 R 12 , wherein m 4 is an integer of 1 or 2, and each of R 11 and R 12 is independently a hydrogen atom or —(CH 2 )m 5 Q, wherein m 5 is an integer of 1 or 2, and Q is a hydroxy group, a C 1-3 alkoxy group, —NR 13 R 14 , wherein each of R 13 and R 14 is independently a hydrogen atom or a C 1-3 alkyl group, or R 11 and R 12 mean, together with each other as —NR 11 R 12 , a substituent of formula (II) or (III):
wherein R 15 is a hydrogen atom, a C 1-3 alkyl group or an amino-protecting group;
R 6 is a hydrogen atom;
R 7 is a phenyl group optionally substituted with one or more of a C 1-6 alkyl group, a C 1-3 alkyl group substituted with one or more halogen atoms, a halogen atom, a C 1-3 alkoxy group, or a C 1-3 alkoxy group substituted with one or more halogen atoms,
Ar 1 is a C 4-6 arylene substituted with one or more substituents independently represented by —V 6 ,
wherein V 6 is a hydrogen atom, a halogen, a C 1-3 alkoxy group, or a C 1-3 alkoxy group substituted with a halogen,
X is a hydroxyl group, and
Y and Z are oxygen,
a tautomer, amide, ester, or pharmaceutically acceptable salt of the compound or a solvate thereof.
2. The compound of claim 1 , wherein,
Ar 1 is formula (IV):
a tautomer, and amide, an ester, or a pharmaceutically acceptable salt of the compound or a Solvate thereof.
3. The compound of claim 2 , wherein R 5 is a phenyl group substituted with one or more substituents of any of formula (V) to (XXII):
a tautomer, an amide, an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
4. The compound of claim 3 , wherein R 7 is a phenyl group, substituted with one or more methyl groups, one or more t-butyl groups, one or more halogen atoms, one or more methoxy groups, one or more trifluoromethyl groups or one or more trifluoromethoxy groups, a tautomer, an amide, an ester , or a pharmaceutically acceptable salt of the compound or a solvate thereof.
5. The compound of claim 4 , wherein R 1 is a methyl group,
a tautomer, an amide, an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
6. The compound of claim 5 ,
wherein R 5 is a phenyl group substituted with one or more substituents having formula (V);
a tautomer, an amide, an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
7. The compound of claim 5 , wherein R 5 is a phenyl group substituted with one or more substituents having formula (VI);
a tautomer, an amide an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
8. The compound of claim 5 , wherein R 5 is a phenyl group substituted with one or more substituents having foil iula (VII):
a tautomer, an amide an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
9. The compound of claim 5 , wherein R 5 is a phenyl group substituted with one or more substituents having formula (VIII);
a tautomer, an amide an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
10. The compound of claim 5 , wherein R 5 is a phenyl group substituted with one or more substituents having formula (IX);
a tautomer, an amide an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
11. The compound of claim 5 , wherein R 5 is a phenyl group substituted with one or more substituents having formula (X);
a tautomer, an amide an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
12. The compound of claim 5 , wherein R 5 is a phenyl group substituted with one or more substituents having formula (XI);
a tautomer, an amide an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
13. The compound of claim 5 , wherein R 5 is a phenyl group substituted with one or more substituents having formula (XII);
a tautomer, an amide an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
14. The compound of claim 5 , wherein R 5 is a phenyl group substituted with one or more substituents having formula (XIII);
a tautomer, an amide an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
15. The compound of claim 5 , wherein R 5 is a phenyl group substituted with one or more substituents having formula (XVIII);
a tautomer, an amide an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
16. A method for expanding CD34+cells, the method comprising: contacting CD34+cells, in an ex vivo culture, with stem cell factor (SCF) and the compound of claim 1 or, a tautomer, an amide, an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof.
17. The method of claim 16 , further comprising contacting the CD34+cells with at least one factor selected from the group consisting of interleukin-3 (IL-3), interleukin-6 (IL-6), interleukin-11 (IL- 1), flk2/flt3 ligand (FL), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), thrombopoietin (TPO), and erythropoietin (EPO).
18. The method of claim 16 , further comprising contacting the CD34+cells with flk/flt3 ligand (FL).
19. The method of claim 16 , wherein the CD34+cells are obtained from bone marrow, liver, spleen, peripheral blood, or cord blood.
20. The method of claim 19 , wherein the CD34+cells are obtained from cord blood.
21. The method of claim 20 , further comprising contacting the CD34+cells with flk/flt3 ligand (FL).
22. A composition comprising, the compound of claim 1 , a tautomer, an amide an ester, or a pharmaceutically acceptable salt of the compound or a solvate thereof; and a pharmaceutically acceptable additive.
23. The compound of claim 1 , wherein R 7 is a phenyl group optionally substituted with one or more of a methyl, t-butyl, halogen, methoxy, trifluoromethyl, or trifluoromethoxy.
24. The compound of claim 1 , wherein Ar 1 is thiophenediyl, phenylene, or pyridinediyl.
25. The compound of claim 1 , wherein Ar 1 is one of the following formulas