Heavy Drug Discovery II - Engele Net

This is a chronic comprehensive disease caused by absolute or relative insulin deficiency, or decreased sensitivity of target cells to insulin, in which type 2 diabetes occurs as a result of a joint effect of insulin resistance and β cellular dysfunction.
in the last decade, there are two main types of small molecule oral antisaccharides studied, namely DPP-IV inhibitors (Gretin drugs) and SGLT2 inhibitors (Grete drugs).
this paper, the author will make a simple introduction to the discovery and optimization process of Engele Net.
, originally developed by Grigg Ingham, later developed jointly with Lilly, was first approved for listing by the European Medicines Agency (EMA) on 22 May 2014 and by the US F The DA was approved for listing on December 26, 2014 by the Japan Medicines and Medical Devices Administration (PMDA) and on September 21, 2017 by the CFDA for listing in China under the ®.
sales, Engel's net global sales reached $3,354 million, according to the 2019 annual report, and it is a compound with Ingre's net composition.
2015 Grigg Ingelheim approved the listing of "Ingley Net/Hydrochloride", "Ingre Net/Ligligletin", also has a good market performance;
its structural and 3D models are as follows: Engele net development process, comparative advantage, because it has six similar drugs on the market before, of course, but also faced with a narrow development space, breaking through the patent difficult adverse factors.
Grigg Ingham first used the structure of the Figure 1 pass as the pilot structure, and carried out a large number of official group derivatives of R1-R7.
1 pilot structure R1, R2 mainly H, F, Br, I, 1-4 carbon alkyl, 2-4 carbon ene- based, 3-7 carbon cyclane, cyanide, methyl, replace methyl and so on; R3, R4, R5 are mainly H, F, Br, I, cyanide, nitro, 1-3 carbon alkyl, 1-3 carbon alkyl, halogen-replaced 1-3 carbon alkyl and so on; R6, R7a, R7b, R7c are mainly H, 1-8 carbon alkyl niobium, 1-8 carbon alkyl alkyl, alkyl, aromatic 1-3 carbon alkyl, etc.
by synthesizing a large number of molecular and molecular activity tests, it is finally found that the Figure 2 pass has good activity, and continues to have a large number of derivatives of R8.
2 after the initial optimization of the general part of the optimization molecules shown in Figure 3, and synthesis of a relatively small number of molecules for activity testing, and finally found compound 5, that is, the discovery of Ngre net.
the molecule in Part 3, and the researchers then studied the compound's synthetic path.
synthesis route 1 (Figure 4), starting with 5-bromine-2-chlorobenzene as the starting material, after the steps of acrylamide, fuchsylization, reduction, de-protection, upper protection, etc.
Figure 4 Synthesis Route 1 Synthesis Route II (Figure 5), starting with 2-chlorine-5 iodized benzoic acid as the starting material, after acrylamide, fuchsylization, replacement, reduction and other steps to synthesize Ingle net.
Figure 5 Synthesis Route II Of course, route one used butyl lithium reagents and low temperature conditions, harsh conditions, route 2 with mild format reagents instead of butyl lithium, temperature does not need to be controlled to -78 degrees so low, to lll.1 directly after the use of triethyl chlorosilane reduction recrystaining can obtain high purity Ofgel net, the method can already be 100 kg level of production.
, of course, better routes are always on the way.
references: 1. SGLT2 inhibitor diabetes drug synthesis route summary, drug crossing; 2. Chinese Journal of New Drugs, 2016, Volume 25, Issue 6; 3. US7579449B2; 4. WO2006120208A1; 5. WO2011039107A1。
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