阅读说明：本技术 具有激动sirt6乙酰化活性的化合物、sirt6激动剂及其应用 (Compound with activation SIRT6 acetylation activity, SIRT6 agonist and application thereof ) 是由 张健 赵明珠 魏嘉呈 于 2019-10-18 设计创作，主要内容包括：本发明提供一种具有激动SIRT6乙酰化活性的化合物,或其药学上可接受的盐,具有式(I)所示的结构。本发明还提供应用该化合物获得的SIRT6激动剂及该SIRT6激动剂在尤其是制备治疗SIRT6介导的相关疾病的药物中的应用。(The invention provides a compound with agonistic SIRT6 acetylation activity, or pharmaceutically acceptable salt thereof, which has a structure shown in a formula (I). The invention also provides a SIRT6 agonist obtained by applying the compound and application of the SIRT6 agonist in preparing a medicament for treating related diseases mediated by SIRT 6.)

1. A compound having agonistic SIRT6 acetylation activity, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (I):

wherein, X₁、X₂、X₃、X₄Each independently represents a hydrogen atom or a halogen; y represents a hydrogen atom, a methyl group or a halogen; r represents a carboxamide group, a cyano group or a nitrogen-containing heterocycle.

2. The compound of claim 1, wherein the halogen is fluorine, chlorine, bromine, or iodine.

3. The compound of claim 1, wherein said carboxamide group is formamide, a formylaliphatic amine, or a formylaromatic amine.

4. The compound of claim 1, wherein the nitrogen-containing heterocycle is triazole, tetrazole, imidazole, pyrrole, pyrazole, oxazole, isoxazole, thiazole, or thiadiazole.

5. A compound according to claim 1, wherein R represents

6. The compound of claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (I) has a structure of formula (II) or (III):

7. the compound of claim 1, wherein the compound has a structure represented by formula (compound 1) to (compound 29):

8. a SIRT6 agonist comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. Use of the compound of claim 1 or the SIRT6 agonist of claim 7 in the manufacture of a medicament for the treatment of a SIRT6 mediated related disease.

Technical Field

The invention relates to the technical field of medicinal chemistry, in particular to a compound with activation SIRT6 acetylation activity, a SIRT6 agonist obtained by applying the compound and application of the SIRT6 agonist in preparing a medicament for treating related diseases mediated by SIRT 6.

Background

SIRT6 belongs to Histone Deacetylase (HDACs) family III, and contains 7 members (SIRT 1-7). SIRT6 is widely expressed in various tissues of mammals, and SIRT6 is involved in genome stability maintenance, DNA repair, inflammation, and glucose and lipid metabolism mainly by catalyzing deacetylation and monoadenosine diphosphate ribosylation of related proteins in cells in vivo, and is closely related to heart diseases, diabetes, obesity, cancer, aging, and the like. The SIRT6 activity up-regulation is considered to be one of new strategies for treating various diseases, so the research on the SIRT6 small molecule agonist has important significance for the development of SIRT6 mediated related disease drugs.

The patent CN109384694A discloses a SIRT6 small molecule agonist with triphenylring disulfonamide as a mother nucleus, but the acetylation activity of the SIRT6 small molecule agonist still needs to be improved.

Therefore, there is a need for a new SIRT6 agonist to overcome the above-mentioned deficiencies of existing SIRT6 agonists.

Disclosure of Invention

The invention aims to provide a compound with activation SIRT6 acetylation activity or pharmaceutically acceptable salt thereof, which can obviously improve SIRT6 deacetylation activity, can be further used as a SIRT6 agonist and applied to preparation of drugs for related diseases.

In order to achieve the above object, the present invention provides a compound having agonistic SIRT6 acetylation activity, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (I):

wherein, X₁、X₂、X₃、X₄Each independently represents a hydrogen atom or a halogen; y represents a hydrogen atom, a methyl group or a halogen; r represents a carboxamide group, a cyano group or a nitrogen-containing heterocycle.

In one embodiment of the present invention, the halogen is fluorine, chlorine, bromine or iodine.

In one embodiment of the present invention, the carboxamide group is formamide, formyl aliphatic amine or formyl aromatic amine.

In an embodiment of the invention, the nitrogen-containing heterocycle is triazole, tetrazole, imidazole, pyrrole, pyrazole, oxazole, isoxazole, thiazole or thiadiazole.

In one embodiment of the invention, R represents

In one embodiment of the invention, the pharmaceutically acceptable salt of the compound of formula (I) has a structure of formula (II) or (III):

in a preferred embodiment of the present invention, the compound having agonistic SIRT6 acetylation activity has a structure represented by formula (compound 1) to (compound 29):

the invention also provides a SIRT6 agonist comprising a compound of any of the above or a pharmaceutically acceptable salt thereof.

The invention also provides application of the compound and the pharmaceutically acceptable salt thereof or the SIRT6 agonist in preparing medicines for treating related diseases mediated by SIRT 6.

The compound with the SIRT6 agonizing acetylation activity or the pharmaceutically acceptable salt thereof can obviously agonize the deacetylation activity of SIRT6 in vitro experiments, and has important significance for development of SIRT 6-mediated related disease drugs.

Drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.

FIG. 1: the fluorescence quantification method measures the fold of SIRT6 deacetylation activity activated by the preferred compound at 100 μ M.

FIG. 2: the fluorescent quantitative method detection shows that the concentration of the compound 1 dependently activates the SIRT6 deacetylation activity, and the half maximal Effect Concentration (EC) of the SIRT6 deacetylation activity₅₀) 1.5 +/-0.2 mu M; compound 2 concentration-dependently activated SIRT6 deacetylation activity with half maximal Effect Concentration (EC)₅₀) 2.3 +/-0.3 mu M; compound 8 concentration-dependently activated SIRT6 deacetylation activity with half maximal Effect Concentration (EC)₅₀) 3.3 +/-0.3 mu M; compound 23 concentration-dependently activated SIRT6 deacetylation activity with half maximal Effect Concentration (EC)₅₀) 60.1. + -. 4.5. mu.M, approximately 40-fold more active SIRT6 deacetylation at 400. mu.M.

Detailed Description

Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the accompanying drawings are illustrative only for the purpose of explaining the present invention, and are not to be construed as limiting the present invention.

The following disclosure provides many different embodiments or examples for implementing different features of the invention. To simplify the disclosure of the present invention, the components and arrangements of specific examples are described below. Of course, they are merely examples and are not intended to limit the present invention. Furthermore, the present invention may repeat reference numerals and/or letters in the various examples, such repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and/or configurations discussed. In addition, the present invention provides examples of various specific processes and materials, but one of ordinary skill in the art may recognize applications of other processes and/or uses of other materials.

The invention provides a compound shown as a structural formula (I) or a pharmaceutically acceptable salt thereof.

Wherein, X₁、X₂、X₃、X₄The same or different, represents a hydrogen atom or a halogen, and Y represents a hydrogen atom, a methyl group or a halogen. The halogen refers to fluorine, chlorine, bromine or iodine. R represents a carboxamide group, a cyano group, or a nitrogen-containing heterocycle.

In this example, the compound represented by the formula (I) has a specific structure represented by the formulae (compound 1) to (compound 29).