169280-56-2Relevant articles and documents
Preparation method of chiral phenbutamol sulfonamide compound, intermediate for preparing chiral phenbutamol sulfonamide compound and preparation method of chiral phenbutamol sulfonamide compound
-
, (2022/04/08)
The invention discloses a preparation method of a chiral phenbutamol sulfonamide compound, which comprises the following steps: carrying out substitution reaction on a compound A, establishing a chiral center by using ketoreductase, and carrying out amidation and Hofmann degradation to obtain the chiral phenbutamol sulfonamide compound, the structural formula of the compound A is as follows: Q1 and Q2 are independently selected from heteroatom groups containing one or more of nitrogen, oxygen and sulfur, or H, or Q1 and Q2 are connected to form a ring, and R1 is selected from alkyl with the carbon atom number of 1-6. The preparation method provided by the invention has the advantages of simple steps, few reaction steps, mild reaction of each step, high safety coefficient and low production cost.
Design and biological evaluation of cinnamic and phenylpropionic amide derivatives as novel dual inhibitors of HIV-1 protease and reverse transcriptase
Zhu, Mei,Shan, Qi,Ma, Ling,Wen, Jiajia,Dong, Biao,Zhang, Guoning,Wang, Minghua,Wang, Juxian,Zhou, Jinming,Cen, Shan,Wang, Yucheng
, (2021/05/04)
Upon the basis of both possible ligand-binding site interactions and the uniformity of key residues in active sites, a novel class of HIV-1 PR/RT dual inhibitors was designed and evaluated. Cinnamic acids or phenylpropionic acids with more flexible chain and smaller steric hindrance were introduced into the inhibitors, giving rise to significant improvement in HIV-1 RT inhibitory activity by one or two orders of magnitude, with comparable or even improved potency against PR at the same time, compared with coumarin anologues in our previous studies. Among these inhibitors, 38d displayed a 19-fold improvement in anti-PR activity with IC50 value of 0.081 nM compared to the control DRV. In addition, inhibitor 38c exhibited an excellent anti-RT IC50 value of 0.43 μM, only a 4.7-fold less potent activity than the control EFV. More significantly, the disparate ratio between HIV-1 PR and RT inhibition became more reasonable with ratio of 1: 10.4, just as 37b. Furthermore, the assays on HIV-1 late stage and early stage supported the rationality of designing dual inhibitors. The SAR data as well as molecular modeling studies provided new insight for further optimization of more potent HIV-1 PR/RT dual inhibitors.
Design and evaluation of novel piperidine HIV-1 protease inhibitors with potency against DRV-resistant variants
Zhu, Mei,Zhou, Huiyu,Ma, Ling,Dong, Biao,Zhou, Jinming,Zhang, Guoning,Wang, Minghua,Wang, Juxian,Cen, Shan,Wang, Yucheng
, (2021/06/02)
A novel class of HIV-1 protease inhibitors with flexible piperidine as the P2 ligand was designed with the aim of improving extensive interactions with the active subsites. Many inhibitors exhibited good to excellent inhibitory effect on enzymatic activity and viral infectivity. In particular, inhibitor 3a with (R)-piperidine-3-carboxamide as the P2 ligand and 4-methoxybenzenesulfonamide as the P2’ ligand showed an enzyme Ki value of 29 pM and antiviral IC50 value of 0.13 nM, more than six-fold enhancement of activity compared to DRV. Furthermore, there was no significant change in potency against DRV-resistant mutations and HIV-1NL4?3 variant for 3a. Besides, inhibitor 3a exhibited potent antiviral activity against subtype C variants with low nanomole EC50 values. In addition, the molecular modeling revealed important hydrogen bonds and other favorable van der Waals interactions with the backbone atoms of the protease and provided insight for designing and optimizing more potent HIV-1 protease inhibitors.
Nitrogen-containing heterocyclic amino derivative, preparation method thereof and anti-HIV-1 medicine
-
Paragraph 0393-0395; 0404-0406, (2021/08/21)
The invention provides a nitrogen-containing heterocyclic ring amino derivative, a preparation method thereof and an anti-HIV-1 medicine, and belongs to the technical field of medicine application. The nitrogen-containing heterocyclic ring amino derivative provided by the invention can interfere with the process of hydrolyzing Gap and Gap-Pol precursor polyprotein by HIV-1 protease, and has high HIV-1 protease inhibitory activity; meanwhile, the nitrogen-containing heterocyclic ring amino derivative provided by the invention has remarkable inhibitory activity on wild type anti-HIV-1 medicine strains and high anti-DRV-medicine strains, has low cytotoxicity, and has a good application prospect as an anti-AIDS medicine.
An improved and robust scale-up process aided with identification and control of critical process impurities in darunavir ethanolate
Girigani, Sathyanarayana,Singh, Harnam,Kola, Sankar Rao,Dayanand Yelmeli, Vijayalaxmi,Regula, Venu Gopal,Shah, Sakshi,Jain, Neelu,Kumar, Pramod
, p. 267 - 281 (2019/08/26)
A robust and safe industrial process, including five isolations and drying steps for widely prescribed anti-HIV (protease inhibitor) drug darunavir ethanolate 2, has been developed. A salient feature of this process is the development of procedures enabling the efficient synthesis of multi-kilogram quantity of darunavir ethanolate, and process demonstrations through plant scale preparation are offered where darunavir molecule has been prepared with overall > 70% chemical yield and > 99.8% purity without involving any purification procedure(s), with all possible process impurities below than the desired limit (not more than 0.08%) were isolated, synthesized and characterized. The developed process is entirely robust, very efficient and demonstrated up to kilograms scale.
Rational design and Structure?Activity relationship of coumarin derivatives effective on HIV-1 protease and partially on HIV-1 reverse transcriptase
Zhu, Mei,Ma, Ling,Wen, Jiajia,Dong, Biao,Wang, Yujia,Wang, Zhen,Zhou, Jinming,Zhang, Guoning,Wang, Juxian,Guo, Ying,Liang, Chen,Cen, Shan,Wang, Yucheng
, (2019/12/09)
Since dual inhibitors may yield lower toxicity and reduce the likelihood of drug resistance, as well as inhibitors of HIV-1 PR and RT constitute the core of chemotherapy for AIDS treatment, we herein designed and synthesized new coumarin derivatives characterized by various linkers that exhibited excellent potency against PR and a weak inhibition of RT. Among which, compounds 6f and 7c inhibited PR with IC50 values of 15.5 and 62.1 nM, respectively, and weakly affected also RT with IC50 values of 241.8 and 188.7 μM, respectively, showing the possibility in the future of developing dual HIV-1 PR/RT inhibitors. Creative stimulation for further research of more potent dual HIV-1 inhibitors was got according to the molecular docking studies.
Design, synthesis and biological evaluation of novel HIV-1 protease inhibitors with pentacyclic triterpenoids as P2-ligands
Zhu, Mei,Du, Xiao-Nan,Li, Yun-Ge,Zhang, Guo-Ning,Wang, Ju-Xian,Wang, Yu-Cheng
, p. 357 - 361 (2019/01/04)
The design, synthesis and SAR study of a new series of HIV-1 protease inhibitors with pentacyclic triterpenoids as P2 ligands and phenylsulfonamide as P2′ ligands were discussed. These compounds exhibited micromolar inhibitory potency, among which compound T1c displayed HIV-1 protease inhibition with IC50 values of 0.12 μM, which was 67 times the inhibitory activity of its raw material Ursolic acid (8.0 μM).
Synthesis and biological evaluation of new HIV-1 protease inhibitors with purine bases as P2-ligands
Zhu, Mei,Dong, Biao,Zhang, Guo-Ning,Wang, Ju-Xian,Cen, Shan,Wang, Yu-Cheng
, p. 1541 - 1545 (2019/04/25)
Introducing purine bases to P2-ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitory because of the carbonyl and NH groups promoting the formation of extensive H-bonding interactions. In this work, thirty-three compounds are synthesized and evaluated, among which inhibitors 16a, 16f and 16j containing N-2-(6-substituted-9H-purin-9-yl)acetamide as the P2-ligands along with 4-methoxylphenylsulfonamide as the P2′-ligand, display potent inhibitory effect on the activity of HIV-1 protease with IC50 43 nM, 42 nM and 68 nM in vitro, respectively.
PROCESS FOR THE PREPARATION OF DARUNAVIR
-
Page/Page column 18; 19, (2016/12/22)
The present invention provides a cost effective and industrially feasible process for preparation of Darunavir (I). Also described is the novel salt of intermediate 4-Amino-N- ((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide acid salt (VIII) and its use in the preparation of Darunavir. Formula (I) and (VII).
Process for preparation of Darunavir
-
Page/Page column 30; 31; 32, (2016/11/14)
Provided are a process for preparation of darunavir or solvates or a pharmaceutically acceptable salt thereof substantially free of bisfuranyl impurities and a process for preparation of amorphous darunavir using the darunavir propionate solvate.
