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Novel aminoalkyl-oxazole and aminoalkyl-thiazole carboxylic acid amides as regeneration-promoting substances for sensory organs and post-mitotic tissue

A technology of aminoalkylthiazolecarboxamide and aminoalkyloxazolecarboxamide, which is applied in the fields of novel aminoalkyloxazolecarboxamide and aminoalkylthiazolecarboxamide, can solve the problems such as failure to achieve targeted transplantation of stem cells.

Inactive Publication Date: 2013-02-27
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 aminoalkyl-oxazole and aminoalkyl-thiazole carboxylic acid amides as regeneration-promoting substances for sensory organs and post-mitotic tissue
  • Novel aminoalkyl-oxazole and aminoalkyl-thiazole carboxylic acid amides as regeneration-promoting substances for sensory organs and post-mitotic tissue
  • Novel aminoalkyl-oxazole and aminoalkyl-thiazole carboxylic acid amides as regeneration-promoting substances for sensory organs and post-mitotic tissue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

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

[0075] The compounds according to the invention were synthesized starting from amino acid amides 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] A synthetic route starting from amino acid amides on a solid polymer phase is described below. Since most of the synthetic procedures are the same, separate synthetic processes are not used for oxazoles and thiazoles. At the beginning, tryptophanamide ( 11 ), the tryptophan amide ( 11 ) as a particularly preferred compound ( 3 )and( 4 ) raw materi...

Embodiment B

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

[0124] First, typical cell cluster "spheres" were grown in suspension culture starting from stem cells with ear developmental potential isolated from the organ of Corti of postnatal mice. Under culture conditions optimized compared to known methods (Oshima et al., 2007; Senn et al., 2007), supplemented with B27 and N2 of DMEM / F12 Medium (Dulbecco's modified Eagle medium), adding FGF (fibroblast growth factor) and IGF (insulin-like growth factor), approximately 1600 solid spheres / organ of Corti ( 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), Demonstration that the otosphere formed under these conditions is in a dedifferentiated state corresponding to the early state of the Organ of Corti in ontogeny. In addition, cell division in the ear bulb may be demonstrated.

...

Embodiment C

[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 (i.e. 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 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 apex. In this way, it is possible to minimize the effect of gravity while at the same time 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 static cultures.

[0139] In order to demonstrate that, by administering the compounds according to the invention, the supporting cells rem...

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Abstract

The present invention relates to novel aminoalkyl-oxazole and aminoalkyl-thiazole carboxylic acid amides that stimulate the endogenous regeneration of terminally differentiated cells in highly specialized organs, tissues and sensory epithelia in mammals in situ. The claimed low-molecular-weight compounds are able to induce corresponding cell biological changes such as dedifferentiation, proliferation and the subsequent terminal redifferentiation of cells of the normally post-mitotic tissue. The invention in particular relates to compounds with which a de novo formation of hair sensory cells in the organ of Corti can be obtained by inducing cell separation of supporting cells of the inner ear and hearing can be restored after hair cell loss. The compounds according to the invention for the first time enable a causal treatment of inner ear hardness of hearing caused, for example, by noise, ototoxic substances, symptoms of old age or genetic causes on the basis of regenerative biology. The invention further relates to methods for producing the compounds according to the invention, to the formulation (1) (2) thereof as pharmaceutical preparations and to the use thereof for producing pharmaceuticals for regenerative medicine.

Description

[0001] The present invention relates to novel aminoalkyloxazole carboxamides and aminoalkylthiazole carboxamides which stimulate in situ the endogenous regeneration of terminally differentiated cells in highly specialized organs, tissues and sensory epithelium of mammals. [0002] The claimed low molecular weight compounds are capable of inducing corresponding changes in cell biology, such as dedifferentiation, proliferation and subsequent terminal redifferentiation of cells of normally post-mitotic tissues. [0003] The present invention relates in particular to compounds with which the remodeling of the sensory hair cells in the Corti's Organ can be achieved by inducing detachment of the supporting cells of the inner ear, and in the hair cell Hearing is restored after loss. [0004] The invention furthermore relates to processes for the preparation of the compounds according to the invention, their formulation as pharmaceutical preparations and their use for the production of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/34C07D413/06C07D413/12C07D417/04C07D417/12A61K31/421A61K31/422A61K31/427A61P27/16
CPCC07D417/12C07D413/06C07D417/04C07D413/12C07D263/34A61P9/00A61P21/00A61P25/00A61P27/00A61P27/16A61P43/00
Inventor H.艾克霍夫H.勒文海姆
Owner EMC MICROCOLLECTIONS
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