- 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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- 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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- 2-pyridyl P1'-substituted symmetry-based human immunodeficiency virus protease inhibitors (A-792611 and A-790742) with potential for convenient dosing and reduced side effects
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A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies. Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum, low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs, and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds against protease inhibitor resistant strains of HIV was also determined.
- DeGoey, David A.,Grampovnik, David J.,Flentge, Charles A.,Flosi, William J.,Chen,Yeung, Clinton M.,Randolph, John T.,Klein, Larry L.,Dekhtyar, Tatyana,Colletti, Lynn,Marsh, Kennan C.,Stoll, Vincent,Mamo, Mulugeta,Morfitt, David C.,Nguyen, Bach,Schmidt, James M.,Swanson, Sue J.,Mo, Hongmei,Kati, Warren M.,Molla, Akhteruzzaman,Kempf, Dale J.
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supporting information; experimental part
p. 2571 - 2586
(2010/02/28)
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- HIV protease inhibiting compounds
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A compound of the formula is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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Page/Page column 98; 99
(2010/02/12)
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- HIV protease inhibiting compounds
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A compound of the formula is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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Page/Page column 131-132
(2010/02/12)
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- Novel Lopinavir analogues incorporating non-Aromatic P-1 side chains - Synthesis and structure-activity relationships
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The HIV protease inhibitor Lopinavir has a pseudosymmetric core unit incorporating benzyl groups at both P-1, P-1′ positions. A series of analogues incorporating non-aromatic side chains at the P-1 position were synthesized and the structure-activity relationships explored.
- Sham, Hing L.,Zhao, Chen,Li, Leping,Betebenner, David A.,Saldivar, Ayda,Vasavanonda, Sudthida,Kempf, Dale J.,Plattner, Jacob J.,Norbeck, Daniel W.
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p. 3101 - 3103
(2007/10/03)
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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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- RETROVIRAL PROTEASE INHIBITING COMPOUNDS
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A compound of the formula: STR1 is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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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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- Pharmaceutical composition
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A solid pharmaceutical composition is disclosed which comprises a pharmaceutically acceptable adsorbent or a mixture of pharmaceutically acceptable adsorbents to which is adsorbed a mixture of (1) a pharmaceutically acceptable organic solvent or a mixture of pharmaceutically acceptable organic solvents, (2) an HIV protease inhibiting compound and (3) one or more pharmaceutically acceptable acids. The solid composition can optionally be encapsulated in a hard gelatin capsule.
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