Novel aminoalkyloxazole carboxamides and aminoalkylthiazole carboxamides as regeneration-promoting substances of sensory organs and postmitotic tissues

An aminoalkyl oxazole carboxamide, mitotic technology, which is applied to medical preparations containing active ingredients, sensory diseases, organic active ingredients, etc., can solve the problem of not realizing the targeted transplantation of stem cells and the like

Inactive Publication Date: 2015-11-25
EMC MICROCOLLECTIONS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no targeted or functionally relevant transplantation of stem cells into the inner ear has been achieved so far

Method used

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  • Novel aminoalkyloxazole carboxamides and aminoalkylthiazole carboxamides as regeneration-promoting substances of sensory organs and postmitotic tissues
  • Novel aminoalkyloxazole carboxamides and aminoalkylthiazole carboxamides as regeneration-promoting substances of sensory organs and postmitotic tissues
  • Novel aminoalkyloxazole carboxamides and aminoalkylthiazole carboxamides as regeneration-promoting substances of sensory organs and postmitotic tissues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A-2-

[0074] Example A-Synthesis of 2-[1-aminoalkyl]oxazole-4-carboxamide and the corresponding 2-[1-aminoalkyl]thiazole-4-carboxamide

[0075] Starting from amino acid amides, compounds according to the invention were synthesized using publications on the preparation of similar compounds (Videnov et al., 1996; Stanchev et al., 1999; Stankova et al., 1999; Kaiser et al.; 2000).

[0076] The purity and identity of intermediates and final products were checked by HPLC and mass spectrometry. Additionally, the final product was characterized by NMR spectroscopy. All starting materials and reagents are commercially available.

[0077] Synthetic routes starting from amino acid amides on solid polymer phases are described below. Since most of the synthetic procedures are the same, no separate synthetic procedures are used for oxazoles and thiazoles. At the beginning, tryptophan amide ( 11 ) synthesis, the tryptophan amide ( 11 ) is used as a particularly preferred compound ( 3 )and( ...

Embodiment B

[0123] Example B - Demonstration of regenerative properties in in vitro cell culture assays

[0124] First, typical cell cluster "spheres" are grown in suspension culture starting from stem cells with ear development potential isolated from the organ of Corti of postnatal mice. Under optimized culture conditions compared to known methods (Oshima et al., 2007; Senn et al., 2007), supplemented B27 and N2 of DMEM / F12 medium (Dulbecco's modified Eagle medium), after adding FGF (fibroblast growth factor) and IGF (insulin-like growth factor), about 1600 solid spheres / organ of Corti can be generated from stem cell cultures ( figure 1 C).

[0125] by labeling at the protein level ( figure 1 A) and confirmation of multiple stem cell markers at the mRNA level ( figure 1 B), confirming that the otosphere formed under these conditions is in a dedifferentiated state that corresponds to the early state of the organ of Corti in ontogeny. Additionally, cell division in the ea...

Embodiment

[0137] Example C - Demonstration of regenerative properties in an in vitro organ culture model

[0138] To confirm the effects observed in cell culture experiments in native organs (ie in situ in the complex cellular structure of the organ of Corti), a form of organ culture was used in which the tissue to be cultured (in the present invention case, the entire inner ear of a mouse) was placed in a rotating cylinder (Zylinder) filled with culture medium (Hahn et al., 2008). Before the start of the experiment, the cochlea was opened in the scala tympani region from the base and from the tip. In this way, it is possible to minimize the effects of gravity while achieving optimal gas and nutrient exchange between the tissue of the organ of Corti and the culture medium. Under these conditions, the explants can be cultured longer than stationary cultures.

[0139] To demonstrate that, by administering the compounds according to the invention, Sertoli cells remaining in the organ of ...

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Abstract

A method of treating inner ear hardness of hearing and restoring hearing of humans and animals after damage and loss of sensory hair cells in an organ of Corti based on regeneration biology includes administering a therapeutically effective amount of a compound including aminoalkyloxazole and aminoalkylthiazole carboxylic acid amides, or a pharmaceutically acceptable salt, a stereoisomer, a stereoisomer mixture, a tautomer or a prodrug compound thereof, directly or indirectly to damaged tissue structures in a cochlea, optionally, by transtympanal injection into a middle ear, by application to a round or oval window of an inner ear or by injection into the inner ear.

Description

[0001] The present invention relates to novel aminoalkyloxazolecarboxamides and aminoalkylthiazolecarboxamides that stimulate in situ the endogenous regeneration of terminally differentiated cells in highly specialized organs, tissues and sensory epithelia of mammals. [0002] The claimed low molecular weight compounds are capable of inducing corresponding cellular biological changes, such as de-differentiation, proliferation and subsequent terminal redifferentiation of cells of normal post-mitotic tissues. [0003] The present invention specifically relates to compounds with which the re-formation of sensory hair cells in the organ of Corti'schen Organ can be achieved by inducing cell detachment of the supporting cells of the inner ear, and can be used in the event of loss of hair cells. Hearing will be restored later. [0004] The present invention further relates to a process for the preparation of the compounds according to the invention, their formulation as pharmaceutical ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/34C07D413/06C07D413/12C07D417/04C07D417/12A61K31/421A61K31/422A61K31/427A61P27/16
CPCC07D413/06C07D263/34C07D413/12C07D417/04C07D417/12A61P9/00A61P21/00A61P25/00A61P27/00A61P27/16A61P43/00
Inventor H.艾克霍夫H.勒文海姆
Owner EMC MICROCOLLECTIONS
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