Abstract: A chromogenic assay is described for the identification and isolation of drug-resistant HIV protease mutants. Coversely, the assay is useful to screen for new inhibitors of HIV protease, e.g., inhibitors not affected by drug-resistance of the HIV protease. This color screening assay contains a vector comprising a regulatable promoter which controls the transcription of two adjacent structural sequences, one sequence coding for HIV protease or mutant thereof, the other sequence coding for beta-galactosidase with an amino acid substrate insert cleavable by HIV protease. A library of HIV proteases is also described and is isolated in the form of a collection of such vectors, which is a color screen vector library.
Type:
Grant
Filed:
April 2, 1993
Date of Patent:
July 25, 1995
Assignee:
Merck & Co., Inc.
Inventors:
Jon H. Condra, Donald J. Graham, Leah Gotlib
Abstract: An asymmetric synthesis of (S)-(-)-6-chloro-4-cyclopropyl-3,4-dihydro-4-[(2-pyridyl)ethynyl]-2(1H)-qu inazolinone comprises the chiral addition of 2-pyridylacetylide to N.sup.1 -protected 6-chloro-4-cyclopropyl-2-quinazolinone followed by removal of the protecting group.
Type:
Grant
Filed:
November 8, 1993
Date of Patent:
July 18, 1995
Assignee:
Merck & Co., Inc.
Inventors:
Mark A. Huffman, Nobuyoshi Yasuda, Ann E. DeCamp, Edward J. J. Grabowski
Abstract: 4-Chloro-2-cyclopropylcarbonylaniline is prepared by condensation of 4-chloroaniline with 4-chlorobutyronitrile to form a 2-(4-chlorobutyryl)-4-chloroaniline, followed by ring closure of the 4-chlorobutyryl group to a cyclopropylcarbonyl moiety.
Type:
Grant
Filed:
June 10, 1994
Date of Patent:
June 20, 1995
Assignee:
Merck & Co., Inc.
Inventors:
Alan Douglas, Ioannis Houpis, Audrey Molina, Ralph P. Volante, Nobuyoshi Yasuda
Abstract: A regioselective process is disclosed for synthesis of 1R-amino-2S-indanol or 1S-amino-2R-indanol, wherein the stereochemical integrity of the carbon-oxygen bond at C-2 in the indene oxide starting material is retained.
Type:
Grant
Filed:
March 11, 1994
Date of Patent:
May 30, 1995
Assignee:
Merck & Co., Inc.
Inventors:
Thomas R. Verhoeven, F. Edward Roberts, Christ H. Senanayake, Kenneth M. Ryan
Abstract: Compounds of formula ##STR1## where R.sup.1 and R.sup.2 are independently hydrogen or optionally-substituted C.sub.1-4 alkyl or aryl, or R.sup.1 and R.sup.2 are joined together to form a monocyclic or bicyclic ring system, are HIV protease inhibitors. These compounds are useful in the treatment of infection by HIV and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of treating infection by HIV are also described.
Type:
Grant
Filed:
May 7, 1993
Date of Patent:
May 9, 1995
Assignee:
Merck & Co., Inc.
Inventors:
Joseph P. Vacca, Bruce D. Dorsey, James P. Guare, M. Katharine Holloway, Randall W. Hungate, Rhonda B. Levin
Abstract: Incubation of ##STR1## with a preparation from mammalian organ yields as biotransformation product the compound 3-[2-(benzoxazol-2-yl)ethyl]-5-(1-hydroxyethyl)-6-methyl-2-(1H)-pyridinone . This product is useful in the prevention or treatment of infection by HIV and the treatment of AIDS.
Type:
Grant
Filed:
February 24, 1992
Date of Patent:
February 7, 1995
Assignee:
Merck & Co. Inc.
Inventors:
Suresh K. Balani, Steven M. Pitzenberger, Harri G. Ramjit
Abstract: Incubation of ##STR1## with a preparation from mammalian organ yields as biotransformation products the 5-(1-hydroxy)ethyl pyridinone analog as well as the 5-(1-hydroxy)ethyl pyridyl and the 5-(2-hydroxy)ethyl pyridyl derivatives.
Type:
Grant
Filed:
February 24, 1992
Date of Patent:
November 15, 1994
Assignee:
Merck & Co., Inc.
Inventors:
Suresh K. Balani, Laura R. Kauffman, Anthony D. Theoharides
Abstract: Zaragozic acids isolated from a culture of MF5465 have been subjected to photoreaction, then derivatized at the 4-keto position. The resulting derivatives are active as squalene synthetase inhibitors and are useful in the treatment of hypercholesterolemia.
Type:
Grant
Filed:
November 24, 1992
Date of Patent:
June 21, 1994
Assignee:
Merck & Co., Inc.
Inventors:
Laszlo R. Treiber, Doss, George A., Byron H. Arison
Abstract: Cholesterol lowering compounds and compositions are formed from the photochemical treatment of the Zaragozic Acids followed by esterification. These compounds and compositions are active squalene synthetase inhibitors useful in the treatment of hypercholesterolemia.
Type:
Grant
Filed:
November 24, 1992
Date of Patent:
May 31, 1994
Assignee:
Merck & Co., Inc.
Inventors:
John G. MacConnell, Byron H. Arison, George A. Doss, Richard L. Monaghan
Abstract: New Zaragozic acids have been isolated from a culture of MF5465. These compounds and their derivatives are active as squalene synthetase inhibitors and are useful in the treatment of hypercholesterolemia.
Type:
Grant
Filed:
September 2, 1992
Date of Patent:
May 10, 1994
Assignee:
Merck & Co., Inc.
Inventors:
Claude Dufresne, Prakash S. Masurekar, Leslie A. Ferrell, Deborah L. Zink, Margaret S. Sosa
Abstract: Novel aminopyridones inhibit HIV reverse transcriptase, and are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.
Type:
Grant
Filed:
November 4, 1992
Date of Patent:
May 3, 1994
Assignee:
Merck & Co., Inc.
Inventors:
Jacob M. Hoffman, Jr., Walfred S. Saari, Clarence S. Rooney, John S. Wai
Abstract: An efficient process for the preparation of styrylbenzoxazoles and derivatives thereof comprises reacting a methylbenzoxazole with an aromatic aldehyde in the presence of strong base at low temperature, followed by warming. The condensation products are inhibitors of H.sup.+ K.sup.+ -ATPase, and are also useful as penultimate compounds in the preparation of inhibitors of HIV reverse transcriptase.
Type:
Grant
Filed:
October 14, 1992
Date of Patent:
March 1, 1994
Assignee:
Merck & Co., Inc.
Inventors:
Ralph P. Volante, Joseph E. Lynch, Ioannis Houpis, Audrey Molina
Abstract: Novel cytochalasins are the biotransformed products after incubation with a substrate in a culture of the microorganism Kibdelosporangium sp. (Merck Culture Collection MA 6559), ATCC No. 53771. The compounds of the present invention inhibit HIV protease and are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as a compound, pharmaceutically acceptable salt, pharmaceutical composition ingredient, whether or not as a prodrug or as a combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines.
Type:
Grant
Filed:
September 25, 1992
Date of Patent:
October 5, 1993
Assignee:
Merck & Co., Inc.
Inventors:
Shieh-Shung T. Chen, George A. Doss, Russell B. Lingham
Abstract: Fermentation of the microorganism Streptomyces sp. (MA6804), ATTC No. 55095, in the presence of the HIV reverse transcriptase inhibitor ##STR1## yields a 5-(1-hydroxy)ethyl analog which is useful in the prevention or treatment of infection by HIV and the treatment of AIDS.
Abstract: Incubation of 3-[2-benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2-(1H)-pyridinone ##STR1## with a preparation from mammalian organ yields as biotransformation product the 6-hydroxymethyl analog. This product is useful in the prevention or treatment of infection by HIV and the treatment of AIDS.
Abstract: Incubation of 3-[(4,7-dichlorobenzoxazol-2-yl)methyl]amino-5-ethyl-6-methyl-2-(1H)-pyrid inone ##STR1## with a preparation from mammalian organ yields as biotransformation products the 5-(1-hydroxy)ethyl and 6-hydroxymethyl analogs. These products are useful in the prevention or treatment of infection by HIV and the treatment of AIDS.
Type:
Grant
Filed:
March 10, 1992
Date of Patent:
April 6, 1993
Assignee:
Merck & Co., Inc.
Inventors:
Suresh K. Balani, Anthony D. Theoharides, Laura R. Kauffman
Abstract: A dipeptide isostere is the biotransformed product after incubation with a culture of Streptomyces. It inhibits HIV protease, and is useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as a compound, pharmaceutically acceptable salt, pharmaceutical composition ingredient, whether or not as a prodrug or as a combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.
Type:
Grant
Filed:
February 27, 1992
Date of Patent:
March 9, 1993
Assignee:
Merck & Co., Inc.
Inventors:
Laszlo R. Treiber, Lawrence F. Colwell, Jr., Byron H. Arison, Georgette Dezeny, Russell B. Lingham, Wayne J. Thompson, Suresh K. Balani
Abstract: Novel dipeptide isosteres are the biotransformed products after incubation with rat liver slices. They inhibit HIV protease, and are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.
Type:
Grant
Filed:
February 27, 1992
Date of Patent:
February 23, 1993
Assignee:
Merck & Co., Inc.
Inventors:
Suresh K. Balani, Harri G. Ramjit, Steven M. Pitzenberger, Michael S. Schwartz, Anthony Y. H. Lu