- Synthesis and characterization of novel analogues of lopinavir
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The present work describes the identification, origin, synthesis, characterization and control of four novel analogues of lopinavir viz. leucine analogue of lopinavir, isoleucine analogue of lopinavir, methyl analogue of lopinavir and dihydroxy analogue of lopinavir.
- Reddy, Peketi Rajesh,Musunuri, Sivanadh,Ramasekhara Reddy,Subrahmanyam Chittala,Murthy,Krishnamohan
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p. 151 - 158
(2021/01/06)
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- Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere
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The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C2-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2′ position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2′ position without significantly affecting potency. However, the group on the opposite P2/P2′ position had a dramatic effect on potency depending on the size and shape of the side chain. Cocrystal structures of inhibitors with wild-type HIV-1 protease revealed that the bis-THF moiety retained similar interactions as observed in the darunavir-protease complex regardless of the position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights into optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.
- Rusere, Linah N.,Lockbaum, Gordon J.,Henes, Mina,Lee, Sook-Kyung,Spielvogel, Ean,Rao, Desaboini Nageswara,Kosovrasti, Klajdi,Nalivaika, Ellen A.,Swanstrom, Ronald,Kurt Yilmaz, Nese,Schiffer, Celia A.,Ali, Akbar
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supporting information
p. 8296 - 8313
(2020/09/22)
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- Preparation method of ritonavir and lopinavir intermediates
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The invention discloses a preparation method of ritonavir and lopinavir intermediates. The method comprises the steps: using L-phenylalanine as a raw material to react with benzyl chloride in potassium carbonate and an alkaline aqueous solution to obtain N, N-dimethylformamide; condensing with acetonitrile under the action of sodium amide; carrying out addition reaction with benzyl magnesium chloride; sequentially reducing enamine and carbonyl by using sodium borohydride/methanesulfonic acid and sodium borohydride/trifluoroacetic acid reagents; obtaining a stereoselective product, namely, dibenzylamino-3-hydroxy-5-amino-1, 2, 4-triazole under the induction effect of a chiral inducer; the stereoselective product reacts with di-tert-butyl methyl dicarbonate in a potassium carbonate/tetrahydrofuran solution, ammonium formate and palladium/carbon are used for reduction debenzylation, and the intermediate BDH is obtained. The preparation method is high in stereoselectivity, the diastereomeric excess (de%) value of the chiral product is high, the reaction steps are short, the product yield is high and generated three wastes are few.
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- Sulfonamide compound and preparation method and application thereof (by machine translation)
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The invention discloses a novel sulfamide compound, and a preparation method and application thereof. The preparation method of the novel sulfamide compound comprises the following steps: performing reaction on a compound 6 to generate a compound 9, obtaining a compound 12 by the compound 9, obtaining a compound 15 by the compound 12, obtaining a compound 21 by the compound 15, and obtaining a compound 4 by the compound 21; performing reaction on a compound 8 to generate a compound 11, obtaining a compound 14 by the compound 11, obtaining a compound 17 by the compound 14, obtaining a compound22 by the compound 17, and obtaining a compound 5 by the compound 22. Optionally, the compound 22 is subjected to reaction to generate a compound 3. The novel sulfamide compound can serve as an HIV-1protease inhibitor.
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Paragraph 0071-0078
(2020/12/29)
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- Molecular tools that block maturation of the nuclear lamin A and decelerate cancer cell migration
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Lamin A contributes to the structure of nuclei in all mammalian cells and plays an important role in cell division and migration. Mature lamin A is derived from a farnesylated precursor protein, known as prelamin A, which undergoes post-translational cleavage catalyzed by the zinc metalloprotease STE24 (ZPMSTE24). Accumulation of farnesylated prelamin A in the nuclear envelope compromises cell division, impairs mitosis and induces an increased expression of inflammatory gene products. ZMPSTE24 has been proposed as a potential therapeutic target in oncology. A library of peptidomimetic compounds were synthesized and screened for their ability to induce accumulation of prelamin A in cancer cells and block cell migration in pancreatic ductal adenocarcinoma cells. The results of this study suggest that inhibitors of lamin A maturation may interfere with cell migration, the biological process required for cancer metastasis.
- Matralis, Alexios N.,Xanthopoulos, Dimitrios,Huot, Geneviève,Lopes-Paciencia, Stéphane,Cole, Charles,de Vries, Hugo,Ferbeyre, Gerardo,Tsantrizos, Youla S.
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p. 5547 - 5554
(2018/10/15)
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- Synthesis of novel heterocyclic sulfonamides as protease inhibitors of HIV-1
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Background: HIV-1 protease is a prime target for drug therapy due to its integral role in HIV viral replication. Several protease inhibitors such as lopinavir and tipranavir were shown to possess potent inhibitory activities against the HIV virus. Due to the high mutation rate of HIV, resistance remains a major problem in the treatment of this virus and design and synthesis of new protease inhibitors is an area of continued interest in new drug discovery research. Methods: Utilizing the key fragments of structures of both peptide-based and non-peptide-based protease inhibitors lopinavir and tipranavir, we explored designing some new compounds. Results: Six new protease inhibitors were designed and synthesized based on the key structural fragments in lopinavir and tipranavir. The designed new compounds contain heterocyclic groups such as thiophene, isoxazole, and imidazole groups, and the best compound exhibited 0.6 nm of the protease inhibitory activity. Conclusion: We have prepared some novel heterocyclic sulfonamides utilizing a key fragment based approach by recombining structural fragments of the potent protease inhibitors lopinavir and tipranavir. Some of these newly designed compounds showed good to excellent HIV-1 protease inhibitory activity, which indicated that this method would be useful for the discovery of new drug lead compounds that target HIV.
- Ding, Yili,Smith, Kenneth L.,Vara Prasad, Chamakura V.N.S.,Wang, Bingyun
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- PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE (2S,3S,5S)-5-AMINO-2-N,N-DIBENZYLAMINO-3-HYDROXY-1,6-DIPHENYLHEXANE
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The present invention relates to the purification of (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) by making its crystalline acid addition salt, which can be used as such to produce Lopinavir/Ritonavir with high purity and yield. Formula III
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Page/Page column 2; 4
(2010/12/29)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE (2S,3S,5S)-5-AMINO-2-N,N-DIBENZYLAMINO-3-HYDROXY-1,6-DIPHENYLHEXANE
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The present invention relates to the purification of (2S,3S,5S)-5-amino-2-N,N-dibenzylamino-3-hydroxy-1,6-diphenylhexane (III) by making its crystalline acid addition salt, which can be used as such to produce Lopinavir /Ritonavir with high purity and yield. Formula III
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Page/Page column 9-10; 13
(2009/01/24)
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- Anti-coronavirus compounds
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A method of treating coronavirus infection. The method includes administering to a subject suffering from or being at risk of suffering from such infection an effective amount of a compound of formula (I). Each variable in this formula is defined in the specification.
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Page/Page column 11
(2008/06/13)
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- A PROCESS FOR THE SYNTHESIS OF 2-AMINO-5-PROTECTED AMINO-3-HYDROXY-1, 6-DIPHENYLHEXANE OR A SALT THEREOF - AN INTERMEDIATE FOR ANTIVIRAL DRUGS
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The present invention relates to an improved process for preparing 2-amino-5-protected-amino-3-hydroxy-1,6-diphenylhexane compounds or acid addition salts thereof, which can be useful intermediates for preparing compounds with antiviral activity. The present invention further provides a process for preparing HIV protease inhibitors, lopinavir and ritonavir.
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Page/Page column 19
(2008/06/13)
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- Processes and intermediates for preparing retroviral protease inhibitors
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The instant invention provides processes and intermediates employed in the synthesis of ((2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane and analogs thereof.
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- Retroviral protease inhibiting compounds
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A compound comprising a substituent of the formula (II) is disclosed as an HIV protease inhibitor. Intermediates for making such compounds and processes for making such intermediates are also disclosed.
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- Reduction of an enaminone: Synthesis of the diamino alcohol core of ritonavir
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The reduction of (5S)-2-amino-5-dibenzylamino-4-oxo-l,6-diphenylhex-2-ene was optimized for diastereoselectivity and overall conversion to (2S,3S,5S)-5-amino-2-dibenzylamino-3-hydroxy-l,6-diphenylhexane (2a). A two-step reduction sequence is described wherein the enamine is reduced with a borane-sulfonate derivative followed by reduction of the resulting ketone with sodium borohydride. The desired 2a was obtained with 84% diastereoselectivity and an acyclic 1,4 stereoinduction ratio of 14:1. This methodology has been used to produce multikilogram quantities of the diamino alcohol core, of Ritonavir and should be general to the synthesis of related diamino hydroxyethylene isosteres.
- Haight, Anthony R.,Stuk, Timothy L.,Allen, Michael S.,Bhagavatula, Lakshmi,Fitzgerald, Michael,Hannick, Steven M.,Kerdesky, Francis A.J.,Menzia, Jerome A.,Parekh, Shyamal I.,Robbins, Timothy A.,Scarpetti, David,Tien, Jien-Heh J.
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- 2-isoxazoline derivative and process for producing the same, and process for producing related derivatives from the same
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The present invention provides useful intermediates for the synthesis of 2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivatives which serve as intermediates in the synthesis of medicines such as retrovirus protease inhibitors including human immunodeficiency virus (HIV) protease inhibitors, and a method for preparing these intermediates using the former intermediates. More particularly, the invention provides methods for preparing a 2-isoxazoline derivative represented by formula ?1! and a 2,5-diamino-1,6-diphenyl-3-hydroxyhexane derivative obtainable by reducing the 2-isoxazoline derivative and represented by formula ?6!: STR1 (wherein Ph is phenyl; and each of R1 and R2 independently represents hydrogen, acyl, alkyloxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, arylaminocarbonyl, alkyl, arylalkyl, aryl, alkylsulfonyl, arylalkylsulfonyl, or arylsulfonyl, or R1 and R2 are linked to each other to represent divalent acyl).
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- Process for the preparation of a substituted 2,5-diamino-3-hydroxyhexane
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A process is disclosed for the preparation of the substantially pure compound of the formula: STR1 comprising catalytic hydrogenation of a compound of the formula: STR2 wherein R6 and R7 are independently selected from STR3 wherein Ra and Rb are independently selected from hydrogen, loweralkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and STR4 wherein the naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo; or R6 and R7 taken together with the nitrogen atom to which they are bonded are STR5 wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl; or an acid addition salt thereof.
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- Process for the preparation of a substituted 2,5-diamino-3-hydroxyhexane
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Intermediates and processes are disclosed which are useful for the preparation of a substantially pure compound of the formula: STR1 wherein R6 and R7 are each hydrogen or R6 and R7 are independently selected from STR2 wherein Ra and Rb are independently selected from hydrogen, loweralkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and STR3 wherein the naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo; or R6 is as defined above and R7 is R7a OC(O)--wherein R7a is loweralkyl or benzyl; or R6 and R7 taken together with the nitrogen atom to which they are bonded are STR4 wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl and R8 is hydrogen or --C(O)R" wherein R" is loweralkyl, alkoxy, benzyloxy or phenyl wherein the phenyl ring is unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo; or an acid addition salt thereof.
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