阅读说明：本技术 一种基于氮杂双环[x，y，0]烷酮骨架的二肽模拟物及其制备方法 (Dipeptide mimetic based on azabicyclo [ X, Y, 0] alkanone framework and preparation method thereof ) 是由 孙海鹰 席婉琳 杜蕾 于 2020-05-25 设计创作，主要内容包括：本发明公开了一种基于氮杂双环[X,Y,0]烷酮骨架的二肽模拟物及其制备方法,该二肽模拟物具有如下结构：<Image he="260" wi="400" file="DDA0002506260580000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,n＝1-4；R<Sup>1</Sup>为氨基、烷胺基、取代的烷胺基、氮原子取代或非取代的烷基酰胺基、氮原子取代或非取代的芳基酰胺基、氮原子取代或非取代的杂芳基酰胺基、氮原子取代或非取代的烷氧基酰胺基、羟基、取代的烷氧基、取代的烷基、取代的芳基或取代的杂环芳基；X为O或NR<Sup>3</Sup>；R<Sup>2</Sup>和R<Sup>3</Sup>为氢原子、取代或非取代的烷基、取代或非取代的环烷基、取代或非取代的芳基、取代或非取代的杂芳基；所述取代基均指烷基、环烷基、芳基或杂环芳基,并提供该二肽模拟物的制备方法,本发明的二肽模拟物代谢稳定性好、生物利用度高、透膜能力强,制备方法路线较短、效率较高且具有通用性。(The invention discloses a nitrogen heterocyclic ring [ X, Y, 0]]Dipeptide mimetics of an alkanone backbone and methods of making the same, the dipeptide mimetic having the structure: wherein n is 1-4; r 1 Is amino, alkylamino, substituted alkylamino, nitrogen substituted or unsubstituted alkylamido, nitrogen substituted or unsubstituted arylamido, nitrogen substituted or unsubstituted heteroarylamido, nitrogen substituted or unsubstituted alkoxyamido, hydroxyl, substituted alkoxy, substituted alkyl, substituted aryl or substituted heterocyclic aryl; x is O or NR 3 ；R 2 And R 3 Is hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroAn aryl group; the substituent group refers to alkyl, cycloalkyl, aryl or heterocyclic aryl, and the preparation method of the dipeptide mimic is provided.)

1. A dipeptide mimetic based on an azabicyclo [ X, Y, 0] alkanone scaffold having the structure:

wherein n is 1-4; r¹Is amino, alkylamino, substituted alkylamino, nitrogen substituted or unsubstituted alkylamido, nitrogen substituted or unsubstituted arylamido, nitrogen substituted or unsubstituted heteroArylamido, nitrogen substituted or unsubstituted alkoxyamido, hydroxyl, substituted alkoxy, substituted alkyl, substituted aryl or substituted heterocycloaryl; x is O or NR³；R²And R³Is hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituents all refer to alkyl, cycloalkyl, aryl or heterocyclic aryl.

2. The diazabicyclo [ X, Y, 0] alkanone-based peptidomimetic of claim 1, wherein the dipeptide mimetic is one of the following structures:

5a (3S, 6S, 8aS) -6- (((tert-butoxycarbonyl) amino) methyl-5-oxooctahydroindole-3-carboxylic acid methyl ester;

5b (3S, 6R, 8aS) -5-oxo-6-phenyloctahydroindolizine-3-carboxylic acid methyl ester;

5c (3S, 6R, 8aS) -5-oxo-6- (o-tolyl) octahydroindolizine-3-carboxylic acid methyl ester;

5d (3S, 6R, 8aS) -5-oxo-6- (m-tolyl) octahydroindolizine-3-carboxylic acid methyl ester;

5e (3S, 6R, 8aS) -5-oxo-6- (p-tolyl) octahydroindolizine-3-carboxylic acid methyl ester;

5f (3S, 6R, 8aS) -5-oxo-6- (4-cyanophenyl) octahydroindolizine-3-carboxylic acid methyl ester;

5g of (3S, 6R, 8aS) -5-oxo-6-isobutyloctahydroindolizine-3-carboxylic acid methyl ester;

5h (3S, 6R, 8aS) -5-oxo-6-propyloctahydroindolizine-3-carboxylic acid methyl ester;

5i (3S, 6R, 8aS) -5-oxo-6-cyclobutyl octahydroindolizine-3-carboxylic acid methyl ester;

5j (3S, 6R, 8aS) -5-oxo-6-cyclopentyl octahydroindolizine-3-carboxylic acid methyl ester;

5k (3S, 6R, 8aS) -5-oxo-6-cyclohexyl octahydroindolizine-3-carboxylic acid methyl ester;

5l methyl (3S, 6S, 9aS) -6-amino-5-oxooctahydro-1H-pyrrolo [1,2-a ] aza-3-carboxylate;

5m methyl (3S, 6S, 9aS) -6- ((di-tert-butoxycarbonyl) amino) -5-oxooctahydro-1H-pyrrolo [1,2-a ] aza-3-carboxylate;

5n methyl (3S, 6S, 9aS) -6- ((tert-butoxycarbonyl) amino) -5-oxooctahydro-1H-pyrrolo [1,2-a ] aza-3-carboxylate;

5o (3S, 6R, 9aS) -5-oxo-6-phenyloctahydro-1H-pyrrolo [1,2-a ] aza-3-carboxylic acid methyl ester;

5p (3S, 6R, 9aS) -5-oxo-6-isobutyloctahydro-1H-pyrrolo [1,2-a ] aza-3-carboxylic acid methyl ester;

5q (3S, 6R, 9aS) -5-oxo-6-cyclobutyloctahydro-1H-pyrrolo [1,2-a ] aza-3-carboxylic acid methyl ester;

5R (3S, 6R, 9aS) -5-oxo-6-cyclopentylactahydro-1H-pyrrolo [1,2-a ] aza-3-carboxylic acid methyl ester;

5S (3S, 6R, 9aS) -5-oxo-6-cyclohexyloctahydro-1H-pyrrolo [1,2-a ] aza-3-carboxylic acid methyl ester.

3. A method of preparing the azabicyclo [ X, Y, 0] alkanone scaffold-based dipeptide mimetic of claim 1 comprising the steps of:

(1) the compound 1 is subjected to RCM reaction to generate a compound 2;

(2) addition of compound 2 to a halogen, pseudohalogen or halogen substitute is further eliminated to produce compound 3;

(3) introduction of compound 3 into R by transition metal catalyzed coupling reaction¹To produce compound 4;

(4) hydrogenating and reducing the double bond in the compound 4 to obtain an all-cis isomer compound 5, wherein the compound 5 is a dipeptide simulant based on an azabicyclo [ X, Y, 0] alkanone framework;

wherein n is 1-4; r¹Is amino, alkylamino, substituted alkylamino,Nitrogen atom substituted or unsubstituted alkylamido, nitrogen atom substituted or unsubstituted arylamido, nitrogen atom substituted or unsubstituted heteroarylamido, nitrogen atom substituted or unsubstituted alkoxyamido, hydroxyl, substituted alkoxy, substituted alkyl, substituted aryl or substituted heterocycloaryl; x is O or NR³；R²And R³Is hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituents all refer to alkyl, cycloalkyl, aryl or heterocyclic aryl.

4. The method for preparing the azabicyclo [ X, Y, 0] alkanone skeleton-based dipeptide mimetic according to claim 3, wherein the step (1) is performed by the following steps: dissolving the compound 1 in a solvent, adding a catalyst under the protection of nitrogen, refluxing until the reaction is complete, concentrating and purifying.

5. The method of claim 4 for the preparation of dipeptide mimetics based on an azabicyclo [ X, Y, 0] alkanone scaffold, wherein: the solvent is anhydrous toluene, and the catalyst is Grubbs catalyst.

6. The method for preparing the azabicyclo [ X, Y, 0] alkanone skeleton-based dipeptide mimetic according to claim 3, wherein the step (2) is performed by the following steps: dissolving the compound 2 in a solvent, dropwise adding one of halogen, pseudohalogen or halogen substitute solution at the temperature of-20-0 ℃, after the reaction is completed, transferring the reaction solution into an ice bath, dropwise adding organic base, after the reaction is completed, concentrating and purifying.

7. The method of claim 6 for the preparation of dipeptide mimetics based on an azabicyclo [ X, Y, 0] alkanone scaffold, wherein: the solvent is DCM.

8. The method for preparing the azabicyclo [ X, Y, 0] alkanone skeleton-based dipeptide mimetic according to claim 3, wherein the step (3) is performed by the following steps: adding a reagent, a catalyst, a ligand and alkali for coupling into the compound 3, exchanging with nitrogen, adding a solvent, reacting under the protection of nitrogen, diluting a reaction solution after the reaction is completed, extracting, drying, concentrating and purifying.

9. The method of claim 8 for the preparation of dipeptide mimetics based on an azabicyclo [ X, Y, 0] alkanone scaffold, wherein: the solvent is one of DMF, DMSO, DME, DMA, 1, 4-dioxane, acetonitrile, ethyl acetate, 1, 2-dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, pyridine, tetrahydrofuran, n-hexane, n-heptane, water, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.

10. The method for preparing the azabicyclo [ X, Y, 0] alkanone skeleton-based dipeptide mimetic according to claim 3, wherein the step (4) is performed by the following steps: dissolving the compound 4 in a solvent, adding a catalyst, introducing hydrogen to react completely, filtering the catalyst, and concentrating and purifying a filtrate.

Technical Field

The invention relates to a dipeptide mimic and a preparation method thereof, in particular to a dipeptide mimic based on an azabicyclo [ X, Y, 0] alkanone framework and a preparation method thereof.

Background

Polypeptides have received increasing attention in the development of new drugs due to their broad pharmacological activity over the last decades. Many of the polypeptides are important signal molecules, can be combined with various receptors on cell membranes and in cells to generate corresponding physiological functions, and can also be used for researching protein-protein interaction, so that the polypeptides can be used as lead compounds in the development of many new drugs. The polypeptide has inherent defects, such as poor metabolic stability, low bioavailability, poor membrane permeability and the like, and the solubility of a plurality of polypeptides is not ideal, so that different methods are adopted to modify the structure of the polypeptide, and the defects are overcome by a common method in the research and development of medicaments taking the polypeptide as a lead. In the optimization and modification of polypeptides, replacing a portion of a fragment in a polypeptide with a conformationally constrained peptidomimetic is a widely proven effective strategy. Azabicyclo [ X.Y.0] alkanone amino acid derivatives are a class of peptidomimetics which are studied to more deeply mimic dipeptides. The compound contains a rigid bicyclic structure, substituents can be introduced at multiple positions of the bicyclic structure, and the configuration of a chiral center can be changed to simulate a specific polypeptide conformation and control the orientation of the substituents. Such compounds were originally designed as peptidomimetics that mimic beta turns, but subsequent applications have not been limited to mimicking beta turns. By changing the size of the ring and the configuration of the chiral center, a variety of derivatives with different structures can be designed. The derivatives of indolizin-2-one amino acids and pyrrolazepin-2-one amino acids, which are peptidomimetics of dipeptides, have found widespread use in a number of new drug development programs, such as the development of ACE and NEP inhibitors, thrombin inhibitors, caspase (caspases) inhibitors, farnesyl transferase inhibitors, Smac mimetics, prostaglandin F2 alpha allosteric modulators, integrin receptor ligands, ORL1 antagonists, hepatitis c virus inhibitors, and the like. Because of the wide application of the peptide mimics in the research and development of new drugs, the development of new effective synthetic methods is of great significance in the research and development of new drugs. The currently reported synthesis method of the azabicyclo [ X.Y.0] alkanone amino acid derivative has the defects of long route and low yield.

Disclosure of Invention

The purpose of the invention is as follows: the first purpose of the invention is to provide a dipeptide simulacrum based on an azabicyclo [ X, Y, 0] alkanone framework with good metabolic stability, high bioavailability and strong membrane permeability, and the second purpose of the invention is to provide a preparation method of the dipeptide simulacrum based on the azabicyclo [ X, Y, 0] alkanone framework with short route, high efficiency and universality.

The technical scheme is as follows: the dipeptide mimetics of the invention based on the azabicyclo [ X, Y, 0] alkanone backbone have the following structure:

wherein n is 1-4; r¹Is amino, alkylamino, substituted alkylamino, nitrogen substituted or unsubstituted alkylamido, nitrogen substituted or unsubstituted arylamido, nitrogen substituted or unsubstituted heteroarylamido, nitrogen substituted or unsubstituted alkoxyamido, hydroxyl, substituted alkoxy, substituted alkyl, substituted aryl or substituted heterocyclic aryl; x is O or NR³；R²And R³Is hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituents all refer to alkyl, cycloalkyl, aryl or heterocycloaryl.

The invention relates to a method for producing dipeptide mimetics based on an azabicyclo [ X, Y, 0] alkanone skeleton, comprising the following steps:

the compound 1 is subjected to RCM reaction to generate a compound 2;

addition of compound 2 to a halogen, pseudohalogen or halogen substitute is further eliminated to produce compound 3;

introduction of compound 3 into R by transition metal catalyzed coupling reaction¹To produce compound 4;

hydrogenating the double bond in compound 4 to obtain an all-cis isomer compound 5, wherein the compound 5 is a dipeptide mimetic based on an azabicyclo [ X, Y, 0] alkanone skeleton;

wherein n is 1-4; r¹Is amino, alkylamino, substituted alkylamino, nitrogen substituted or unsubstituted alkylamido, nitrogen substituted or unsubstituted arylamido, nitrogen substituted or unsubstituted heteroarylamido, nitrogen substituted or unsubstituted alkoxyamido, hydroxyl, substituted alkoxy, substituted alkyl, substituted aryl or substituted heterocyclic aryl; x is O or NR³；R²And R³Is hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituents all refer to alkyl, cycloalkyl, aryl or heterocycloaryl.

Has the advantages that: compared with the prior art, the invention has the following remarkable advantages: the dipeptide mimics have good metabolic stability, high bioavailability, strong membrane permeability and high solubility; the synthesis steps are short, the synthesis operation is simple and convenient, different substituents can be conveniently introduced through coupling, and the substrate development is easy to carry out.

Detailed Description

The technical solution of the present invention is further illustrated by the following examples.