- Process research and development for an efficient synthesis of the HIV protease inhibitor BMS-232632
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Development of an efficient and scalable process for the human immunodeficiency virus (HIV) protease inhibitor BMS-232632 1-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl)L-tert- leucinyl]-amino}-4(S)-hydroxy-6-phenyl-2-azahexane, is described. The key step in the synthesis of the intermediate N-1-(tert-butyloxycarbonyl)-N-2-[4-(pyridin-2-yl)benzylidene]hydrazone (11) was the Pd-mediated coupling of boronic acid 9 with 2-bromopyridine. An efficient procedure was developed for the chemoselective reduction of hydrazone 11 to hydrazine carbamate 4. The key intermediate N-(tert-butyloxycarbonyl)-2(S)-amino-1-phenyl-3(R)-3,4-epoxy-butane (6) was prepared stereoselectively from chiral diol 10. The subsequent union of 4 and 6 followed by coupling with N-methoxycarbonyl-L-tert-leucine provided the free base BMS-232632 in high yield. Evaluation of a variety of salts and identification of bisulfate salt 19 with enhanced bioavallability are also described.
- Xu, Zhongmin,Singh, Janak,Schwinden, Mark D.,Zheng, Bin,Kissick, Thomas P.,Patel, Bharat,Humora, Michael J.,Quiroz, Fernando,Dong, Lin,Hsieh, Dau-Ming,Heikes, James E.,Pudipeddi, Madhusudhan,Lindrud, Mark D.,Srivastava, Sushil K.,Kronenthal, David R.,Mueller, Richard H.
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- TABLETED COMPOSITIONS CONTAINING ATAZANAVIR
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Disclosed are compressed tablets containing atazanavir sulfate, optionally with another active agents, e.g., anti-HIV agents, granules that contain atazanavir sulfate and an intragranular lubricant that can be used to make the tablets, compositions comprising a plurality of the granules, processes for making the granules and tablets, and methods of treating HIV.
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Paragraph 0077; 0078; 0079; 0080
(2018/06/01)
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- PROCESS FOR THE PREPARATION OF ATAZANAVIR BISULFATE
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The present invention relates to an improved process for the preparation of Atazanavir bisulfate Form A. The present invention also relates to a pharmaceutical composition using the Atazanavir bisulfate Form A of the invention.
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Paragraph 0085
(2015/07/15)
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- NOVEL AZA-PEPTIDES CONTAINING 2,2-DISUBSTITUTED CYCLOBUTYL AND/OR SUBSTITUTED ALKOXY BENZYL DERIVATIVES AS ANTIVIRALS
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The present invention relates to novel aza-peptides containing 2,2-disubstituted 5 cyclobutyl and/or substituted alkoxy benzyl derivatives of formula (I) and compositions for inhibiting Human Immunodeficiency Virus (HIV) and process for making the compounds.
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Page/Page column 34
(2011/07/30)
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- PROCESS FOR THE PREPARATION OF ATAZANAVIR SULFATE SUBSTANTIALLY FREE OF DIASTEREOMERS
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The present invention provides atazanavir sulfate substantially free of diastereomeric impurities. The present invention also provides atazanavir sulfate having D-tertiary leucine analogues less than 0.1%. The present invention further relates to an improved process for preparing atazanavir sulfate, substantially free of its diastereoisomeric impurities, which comprises of reacting diamino compound (IV) with N-methoxycarbonyl-(L)-tertiary-leucine (V) having D-isomer less than 0.1 % to obtain atazanavir base; conversion of atazanavir base to atazanavir sulfate by reacting with sulfuric acid and crystallization of atazanavir sulfate from suitable organic solvent(s).
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Page/Page column 16
(2011/10/03)
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- Azapeptide derivatives as HIV protease inhibitors
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This invention relates to novel compounds of the Formula Ib: that are azapeptides, and pharmaceutically acceptable salts thereof. More specifically, the invention relates to novel azapeptide compounds that are derivatives of the HIV protease inhibitor atazanavir sulfate. This invention also provides pyrogen-free compositions comprising one or more compounds of the invention and a carrier, and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are treated by administering HIV protease inhibitors. The invention also relates to the use of one or more of the disclosed compounds as reagents in analytical studies involving atazanavir.
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Page/Page column 33-34
(2009/01/24)
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- HIV PROTEASE INHIBITING COMPOUNDS
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A compound of the formula (I) 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 118
(2010/02/12)
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- New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: Candidates for clinical development
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On the basis of previously described X-ray studies of an enzyme/aza- dipeptide complex, aza-dipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) or orthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis (L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.
- Bold, Guido,F?ssler, Alexander,Capraro, Hans-Georg,Cozens, Robert,Klimkait, Thomas,Lazdins, Janis,Mestan, Jürgen,Poncioni, Bernard,R?sel, Johannes,Stover, David,Tintelnot-Blomley, Marina,Acemoglu, Figan,Beck, Werner,Boss, Eugen,Eschbach, Martin,Hürlimann, Thomas,Masso, Elvira,Roussel, Serge,Ucci-Stoll, Katharina,Wyss, Dominique,Lang, Marc
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p. 3387 - 3401
(2007/10/03)
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- ANTIVIRALLY ACTIVE HETEROCYCLIC AZAHEXANE DERIVATIVES
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There are described compounds of formula I*, STR1 wherein R. sub.1 is lower alkoxycarbonyl,R 2 is secondary or tertiary lower alkyl or lower alkylthio-lower alkyl, R. sub.3 is phenyl that is unsubstituted or substituted by one or more lower alkoxy radicals, or C 4-C 8 cycloalkyl,R. sub.4 is phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl that is bonded by way of a ring carbon atom, has from 5 to 8 ring atoms, contains from 1 to 4 hetero atoms selected from nitrogen, oxygen, sulfur, sulfinyl (--SO--) and sulfonyl (--SO 2--) and is unsubstituted or substituted by lower alkyl or by phenyl-lower alkyl,R 5, independently of R 2, has one of the meanings mentioned for R 2, andR 6, independently of R. sub.1, is lower alkoxycarbonyl,or salts thereof, provided that at least one salt-forming group is present. The compounds are inhibitors of retroviral aspartate protease and can be used, for example, in the treatment of AIDS. They exhibit outstanding pharmacodynamic properties.
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