Compounds and compositions used to epigenetically transform cells and methods related thereto

Patent metadata

Field	Value
Publication number	US-9458131-B2
Application number	US-201214356024-A
Country	US
Kind code	B2
Filing date	Nov 8, 2012
Priority date	Nov 8, 2011
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

This disclosure relates to compounds, compositions and methods of epigenetically transforming cells. In certain embodiments, the disclosure relates to methods of generating epigenetically altered cells comprising mixing isolated cells with compositions disclosed herein under conditions such that epigenetically altered cells are formed. In certain embodiments, the disclosure contemplates inducing cells, such as adult somatic cells or cells that are not naturally pluripotent, into cells with chemically induce pluripotency. In certain embodiments, the disclosure contemplates certain compounds disclosed herein, compounds disclosed herein optionally substituted with one or more substituents, derivatives, or salts thereof, for these purposes.

First claim

What is claimed:

1. A composition comprising a compound having Formula II:

or salts thereof wherein,
R 2 is alkylamino or (alkyl) 2 amino optionally substituted with one or more, the same or different, R 7 ;
R 4 is alkoxy optionally substituted with one or more, the same or different, R 7 ;
R 3 , R 5 , and R 6 are each the same or different hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 3 , R 5 , and R 6 are optionally substituted with one or more, the same or different, R 7 ;
R 7 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkyl sulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 7 is optionally substituted with one or more, the same or different, R 8 ;
R 8 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R 13 and R 14 are alkyl wherein each R 13 and R 14 are optionally substituted with one or more, the same or different, R 15 ;
R 15 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15 is optionally substituted with one or more, the same or different, R 16 ; and
R 16 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

2. The composition of claim 1 , wherein the compound is selected from:
7-((5-aminopentyl)oxy)-N 2 -(3-(dimethylamino)propyl)-6-methoxy-N 4 ,N 4 -dimethylquinazoline-2,4-diamine and
7-((5-aminopentyl)oxy)-6-methoxy-N 2 ,N 2 ,N 4 ,N 4 -tetramethylquinazoline-2,4-diamine or salts thereof.

3. The composition of claim 1 further comprising a DNA methylation inhibitor, a histone deacetylase (HDAC) inhibitor, a Rho-associated kinase (ROCK) inhibitor, Wnt inhibitor, GSK-3beta inhibitor, or a dihydropyridine.

4. The composition of claim 3 , wherein the DNA methylation inhibitor is 5-azacitidine or decitabine.

5. The composition of claim 3 , wherein the HDAC inhibitor is vorinostat-suberoylanilide hydroxamic acid (SAHA), trichostatin A (TSA), or valproic acid (VPA).

6. The composition of claim 3 , wherein the ROCK inhibitor is 4-(1-aminoethyl)-N-(pyridin-4-yl)cyclohexanecarboxamide (Y-27632) or salt thereof.

7. The composition of claim 3 , wherein the dihydropyridine is 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid, methyl ester (BayK8644), ester, derivative, or salt thereof.

8. The composition of claim 3 , wherein the GSK-3beta inhibitor is 6-[[2-[[4-(2,4-dichlorophenyl)-5-(5-methyl-1H-imidazol-2-yl)-2 pyrimidinyl]amino]ethyl]amino]-3-pyridinecarbonitrile (CHIR99201) or salt thereof.

9. The composition of claim 1 , further comprising leukemia inhibitory factor (LIF), fibroblast growth factors (FGFs), MEK, or TGF-β.

10. A composition comprising a compound having Formula IA:

or salts thereof wherein,
R 1 , R 3 , R 4 , R 5 , and R 6 are each the same or different hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are optionally substituted with one or more, the same or different, R 7 ;
R 7 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 7 is optionally substituted with one or more, the same or different, R 8 ;
R 8 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R 9 and R 10 are each the same or different hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 9 and R 10 are optionally substituted with one or more, the same or different, R 11 ;
or R 9 and R 10 come together to form a heterocyclyl optionally substituted with one or more, the same or different, R 11 ;
R 11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein is optionally substituted with one or more, the same or different, R 12 ; and
R 12 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

11. The composition of claim 10 , wherein the compounds are selected from:
N 4 -(1-benzylpiperidin-4-yl)-N 2 -(piperidin-1-yl)quinazoline-2,4-diamine,
N 4 -(1-benzylpiperidin-4-yl)-N 2 -(4-methylpiperazin-1-yl)quinazoline-2,4-diamine, and
N 4 -(1-benzylpiperidin-4-yl)-N 2 -morpholinoquinazoline-2,4-diamine, or salts thereof.

Assignees

• Yoon Young-Sup
• Cheng Xiaodong
• Han Ji Woong
• Mai Antonello
• Univ Emory

Inventors

• Yoon Young-Sup
• Cheng Xiaodong
• Han Ji Woong
• Mai Antonello

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title