Heterocyclic compounds and expansion agents for hematopoietic stem cells

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 disorders is provided. An expansion agent for hematopoietic stem cells and/or hematopoietic progenitor cells containing a compound represented by the formula (I) (wherein X, Y, Z, Ar 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R6 and R 7 are as defined in the description), a tautomer, prodrug 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 , R 2 , R 3  and R 4  are independently a hydrogen atom or a C 1-10  alkyl group optionally substituted with one or more halogen atoms; 
         R 5  is a C 2-14  aryl 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 any of those mentioned above or a hydrogen atom, —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 the same as R 9  other than a hydrogen atom 
 
       
       
         
           
           
               
               
           
         
         R 6  is a hydrogen atom or a C 1-10  alkyl group optionally substituted with one or more halogen atoms, 
         R 7  is a C 2-14  aryl group substituted with one or more substituents independently represented by —V 5 ,
 wherein V 5  is a hydrogen atom, a hydroxy group, a protected hydroxy group, an amino group, a protected amino group, a thiol group, a protected thiol group, a nitro group, a cyano group, a halogen atom, a carboxy group, a carbamoyl group, a sulfamoyl group, a sulfo group, a formyl group, a C 1-3  alkoxy group optionally substituted with one or more halogen atoms, a C 1-10  alkyl group (optionally substituted with one or more halogen atoms, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 1-10  alkylcarbonyloxy group, a C 1-10  alkoxycarbonyl group, a C 1-10  alkoxy group, a C 1-10  alkylcarbonyl group, a C 1-10  alkylcarbonylamino group, a mono-C 1-10  alkylamino group, a di-C 1-10  alkylamino group, a C 1-10  alkylsulfonyl group, a C 1-10  alkylaminosulfonyl group, a C 1-10  alkylaminocarbonyl group, a C 1-10  alkylsulfonylamino group, or a C 1-10  thioalkyl group), 
 
         Ar 1  is a C 2-14  arylene group substituted with one or more substituents independently represented by —V 6 ,
 wherein V 6  is the same as V 5  defined above, 
 
         X is OR 20 , wherein R 20  is a hydrogen atom, a C 1-10  alkyl group, or a C 1-10  alkylcarbonyl group, wherein the C 1-10  alkyl group and the C 1-10  alkylcarbonyl group are optionally substituted with one or more substituents independently represented by —V 7 , wherein V 7  is the same as V 5 , and V 5  is the same as defined above, and 
         Y and Z are independently an oxygen atom or a sulfur atom, 
         a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is a hydrogen atom or a C 1-6  alkyl group optionally substituted with one or more halogen atoms,
 R 2 , R 3 , R 4 , and R 6  are a hydrogen atom,   Ar 1  has a formula (IV):   
       
         
           
           
               
               
           
         
         R 7  is a phenyl group optionally substituted with:
 one or more C 1-10  alkyl groups optionally 
 substituted with one or more halogen atoms; 
 one or more halogen atoms; 
 one or more C 1-10  alkoxy groups; or 
 one or more C 1-3  alkoxy groups optionally 
 substituted with one or more halogen atoms, 
 
         X is OH, 
         Y and Z are an oxygen atom, 
         a tautomer, a prodrug 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, prodrug, 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, prodrug, 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, prodrug or 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, prodrug, 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, prodrug, 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 formula (VII),
 a tautomer, prodrug, 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, prodrug, 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, prodrug, 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, prodrug, 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, prodrug, 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, prodrug, 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, prodrug, 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 substituent having formula (XVIII),
 a tautomer, prodrug, or a pharmaceutically acceptable salt of the compound or a solvate thereof.   
     
     
         16 . An expansion agent, comprising the compound of  claim 1 , a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof, as an active ingredient. 
     
     
         17 . A method for expanding at least one type of cells selected from the group consisting of hematopoietic stem cells and hematopoietic progenitor cells, the method comprising culturing at least one type of cells selected from the group consisting of hematopoietic stem cells and hematopoietic progenitor cells ex vivo in the presence of the compound of  claim 1 , a tautomer or a pharmaceutically acceptable salt of the compound or a solvate thereof. 
     
     
         18 . The method of  claim 17 , wherein the at least one type of cells are CD34 +  cells. 
     
     
         19 . The method of  claim 17 , wherein the at least one type of cells are CD34 + CD38 −  cells. 
     
     
         20 . The method of  claim 17 , wherein the at least one type of cells are HPP-CFU colony forming cells. 
     
     
         21 . The method of  claim 17 , wherein the at least one type of cells are SRC. 
     
     
         22 . The method of  claim 17 , further comprising adding a blood cell stimulating factor. 
     
     
         23 . The method of  claim 22 , wherein the blood cell stimulating factor is at least one 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). 
     
     
         24 . The method of  claim 23 , wherein the blood cell stimulating factor is at least one selected from the group consisting of stem cell factor (SCF) and flk/flt3 ligand (FL). 
     
     
         25 . The method of  claim 17 , wherein the at least one type of cells are obtained from a bone marrow, a liver, a spleen, peripheral blood, or cord blood. 
     
     
         26 . The method of  claim 25 , wherein the at least one type of cells are obtained from cord blood. 
     
     
         27 . The method of  claim 26 , further comprising adding at least one selected from the group consisting of stem cell factor (SCF) and flk/flt3 ligand (FL). 
     
     
         28 . A reagent or reagent kit comprising the compound of  claim 1 , a tautomer, or a pharmaceutically acceptable salt of the compound or a solvate thereof, as an active ingredient. 
     
     
         29 . A method for producing transformed hematopoietic stem cells, the method comprising:
 transferring a gene into at least one type of cells selected from the group consisting of hematopoietic stem cells and hematopoietic progenitor cells and simultaneously culturing the at least one type of cells ex vivo in the presence of the compound of  claim 1 , a tautomer, or a pharmaceutically acceptable salt of the compound or a solvate thereof; or   culturing the at least one type of cells ex vivo in the presence of the compound of  claim 1 , a tautomer, or a pharmaceutically acceptable salt of the compound or a solvate thereof, to obtain cells carrying a gene and then expanding the cells carrying a gene.   
     
     
         30 . The method of  claim 29 , further comprising adding at least one blood cell stimulating factor. 
     
     
         31 . The method of  claim 30 , wherein the blood cell stimulating factor is at least one 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). 
     
     
         32 . The method of  claim 29 , wherein the at least one type of cells are obtained from a bone marrow, a liver, a spleen, peripheral blood, or cord blood. 
     
     
         33 . Hematopoietic stem cells obtained by the method of  claim 17 . 
     
     
         34 . Transformed hematopoietic stem cells obtained by the method of  claim 29 . 
     
     
         35 . A cell therapy material obtained by a process comprising transplanting at least one type of cells obtained by the method of  claim 17  into a human to treat a disease. 
     
     
         36 . A cell therapy material obtained by a process comprising transplanting the hematopoietic stem cells obtained by the method of  claim 29  into a human for treatment of a disease. 
     
     
         37 . A pharmaceutical agent comprising, as an active ingredient, the compound of  claim 1 , a tautomer, prodrug, or a pharmaceutically acceptable salt of the compound or a solvate thereof. 
     
     
         38 . The cell therapy material of  claim 35 , wherein the disease is leukemia, aplastic anemia, myelodysplastic syndrome, malignant lymphoma, multiple myeloma, myeloproliferative disease, a genetic blood disease, a solid tumor, an autoimmune disease, immunodeficiency, diabetes mellitus, nerve injury, muscle injury, cerebral infarction, myocardial infarction, or obstructive arteriosclerosis.