An alternate synthesis of the Tat-antagonist 7-chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine

An alternative synthesis of 7-chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine, the compound that inhibits gene expression by HIV-1 at the level of transcriptional transactivation by Tat, has been developed. The process is based on ring expansion of 6-chloro-2-chloromethyl-4-(1H-pyrro...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 1995-04, Vol.3 (4), p.391-395
Main Authors: Maehr, H, Zenchoff, G, Coffen, D L
Format: Article
Language:English
Subjects:
AIDS/HIV
Benzodiazepines - chemical synthesis
Benzodiazepines - pharmacology
Gene Products, tat - antagonists & inhibitors
HIV-1 - drug effects
Humans
Magnetic Resonance Spectroscopy
Methylamines - chemistry
Models, Molecular
Molecular Structure
Pyrroles
tat Gene Products, Human Immunodeficiency Virus
Virus Replication - drug effects
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Summary:An alternative synthesis of 7-chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine, the compound that inhibits gene expression by HIV-1 at the level of transcriptional transactivation by Tat, has been developed. The process is based on ring expansion of 6-chloro-2-chloromethyl-4-(1H-pyrrol-2-yl)quinazoline 3-oxide which leads to the corresponding benzodiazepine Ro24-7429. Quinazoline 3-oxide formation in the presence of boron trifluoride gives a tetracyclic system containing a 2,2-difluoro-1,3,6,2-oxadiazaborine ring that survives ring expansion to 13-chloro-5,5-difluoro-9-(methylamino)-5H-pyrrolo[1',2':3,4]- 1,3,6,2-oxadiazabora[6,5-d]-8H-1,4-benzodiazepin-7-ium hydroxide inner salt. This unusual benzodiazepine does not significantly inhibit Tat-mediated gene expression by HIV-1.
ISSN:0968-0896
DOI:10.1016/0968-0896(95)00026-D