1h-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells

a technology of pyrrole and pyrrole, which is applied in the field of 1hpyrrole2, 5dione compounds, can solve the problems of increasing hair cell numbers, affecting the survival of stem/progenitor supporting cells, and affecting the survival of stem cells, so as to reduce the activity of tgf beta

Inactive Publication Date: 2021-09-30
FREQUENCY THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes methods for inducing stem cell properties in supporting cells in the cochlear tissue, which can lead to the production of stem cells and the differentiation of stem cells into tissue cells. The methods involve activating pathways and mechanisms involved in stem cell properties using small molecules. The resulting stem cells have the ability to divide for many generations and maintain the ability to differentiate into tissue cells. The stem cells produced also express stem cell markers. The methods can be used to improve auditory functioning in subjects with cochlear implants. The patent also describes a method for generating Myo7a+ cochlear cells. Overall, the patent provides methods for inducing stem cell properties in supporting cells and promoting their differentiation into tissue cells for regenerative medicine applications.

Problems solved by technology

Uncontrolled self-renewal may lead to overgrowth of stem cells and possibly tumor formation, while uncontrolled differentiation may exhaust the stem cell pool, leading to an impaired ability to sustain tissue homeostasis.
Permanent damage to the hair cells of the inner ear results in sensorineural hearing loss, leading to communication difficulties in a large percentage of the population.
In addition, these methods increase hair cell numbers but decrease supporting cell numbers.
Since supporting cells are known to have specialized roles (Ramirez-Camancho 2006, Dale and Jagger 2010), loss of these cells could create problems in proper cochlear function.

Method used

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  • 1h-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells
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  • 1h-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells

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Experimental program
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General Experimental Methods

[0396]1H NMR spectra were recorded on Bruker Avance III 400 MHz and Bruker Fourier 300 MHz and TMS was used as an internal standard.

[0397]LCMS was taken on a quadrupole Mass Spectrometer on Agilent LC / MSD 1200 Series (Column: C18 (50×4.6 mm, 5 μm) operating in ES (+) or (−) ionization mode; T=30° C.

Synthetic Schemes

[0398]

Experimental Procedures:

Synthesis of Intermediate 2.

[0399]

[0400]To a solution of intermediate 1 (20 g, 213 mmol) in MeCN (540 ml) was ethyl (E)-4-oxo-butenoate (28.6 g, 223 mmol). The reaction mixture was heated to 80° C. and stirred for 6 hrs. The reaction mixture was concentrated under reduced pressure, the residue was purified by flash column chromatography (eluted with Dichloromethane / MeOH from 1:0 to 200:1) to give the crude intermediate 2 (25 g) as brown solid.

Synthesis of Intermediate 3.

[0401]

[0402]To a solution of crude intermediate 2 (25 g) in MeOH (100 ml) was added NH3 / MeOH (6 M, 100 ml). The reaction mixture was stirred at roo...

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Abstract

The present invention relates to 1H-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem / progenitor supporting cells, including inducing the stem / progenitor cells to proliferate while maintaining, in the daughter cells, the capacity to differentiate into tissue cells.

Description

RELATED APPLICATIONS[0001]This application is a division of U.S. application Ser. No. 16 / 474,220, filed Jun. 27, 2019, now allowed, which is a U.S. National Phase application, filed under U.S.C. § 371, of International Application No. PCT / US2017 / 067885, filed on Dec. 21, 2017, which claims priority to, and the benefit of, U.S. Application Nos. 62 / 484,282, filed Apr. 11, 2017, and 62 / 441,060, filed Dec. 30, 2016, the entire contents of each of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to 1H-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem / progenitor supporting cells, including inducing the stem / progenitor cells to proliferate while maintaining, in the daughter cells, the capacity to differentiate into tissue cells.BACKGROUND OF THE INVENTION[0003]Stem cells exhibit an extraordinary ability to generate multiple cell types in the body. Besides embryonic stem cells, tissue specific stem cells ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D519/00A61K9/00C07D487/04
CPCC07D519/00A61K45/06C07D487/04A61K9/0046A61K31/5517A61P1/04A61P43/00
Inventor LOOSE, CHRISTOPHERTAIT, BRADLEYMANCHANDA, RAJESHMCLEAN, WILL
Owner FREQUENCY THERAPEUTICS INC
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