Benzimidazole compounds differentiate a mammalian stem cell into mesodermal or cardiomyocyte cells

摘要

Methods and small molecule compounds for stem cell differentiation are provided. One example of a class of compounds that may be used is represented by the compound having the structure IA or IB in the form of free base or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof:;
R1 is independently hydrogen or (C1-C6)alkyl; R2 is independently hydrogen, (C1-C6)alkyl, aryl, or heteroaryl; R2′ is independently hydrogen, (C1-C6)alkyl, CF3 or C2F5; R3 is independently (C1-C6)alkyl, aryl, 2-tetrahydrofurylmethyl, an aliphatic tertiary amine, or 4-methoxybenzyl; or R2 and R3 may be joined together to form a 5 or 6 member ring lactone; R4 is independently hydrogen, (C1-C6)alkyl, a 2- or 4-R5-substituted aromatic ring selected from a 4-R5-phenyl or a 2-R5-5-pyridyl, aryl, heteroaryl, aliphatic tertiary amine or halogen; and R5, R5′, R6, R6′, R7, R7′, are each independently hydrogen, (C1-C6)alkyl, aryl, optionally substituted phenyl, heteroaryl, a heterocyclic ring, an aliphatic tertiary amine, or halogen.

主权项

1. A method for producing mammalian mesodermal or cardiomyocyte cells from mammalian stem cells, comprising contacting within the same suitable medium Activin A and the stem cells with a compound of structure II in the form of a free base or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof: wherein: A is NH; and B is an aromatic ring, wherein the aromatic ring is optionally substituted phenyl, optionally substituted benzyl, or has the structure ofor is an unsaturated 5 or 6 member ring, optionally substituted, containing a heteroatom wherein the heteroatom is N or O,
or A is absent and B is optionally substituted phenyl, D is N or CH, E is N, CH, C—R, or C—OH; F is N or CH, G is aryl, heteroaryl or cyclohexyl optionally substituted by 1 to 5 R1; I is N or C; R is hydrogen or (C1-C6)alkyl; R1, when present, independently are (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)thioalkoxy, hydroxy, halogen, CF3, or C2F5; and R2 independently are hydrogen, (C1-C6)alkyl, optionally substituted phenyl, optionally substituted benzyl, or (C1-C6)alkoxy.