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Preparation and Medical Uses of Novel Nitric Oxide Releasing Imidates, Amidines Derived Therefrom, and Enamines

Posted Nov 30 2011 7:00pm

Description of Invention:
Nucleophile/nitric oxide adducts (N2O2- diazeniumdiolates) spontaneously dissociate at physiological pH to release nitric oxide (NO) by stable first order kinetics. The bulk of the known and patented NIH compositions and methods using diazeniumdiolates are derived from amine nucleophiles. The formation of these amine-derived diazeniumdiolates requires exposure of the nucleophile to NO gas with the attendant occurrence of possible unwanted side reactions, or preparation of O2 alkylated diazeniumdiolates that may release toxic by-products. Also, amine-derived diazeniumdiolates may dissociate into carcinogenic N-nitroso compounds and the primary amines may decompose into unstable diazotates. These inventors thus developed diazeniumdiolates in which the N2O2- functional groups are bonded to carbon atoms. This work has resulted in imidoester-, amidine- and enamine-derived diazeniumdiolates that spontaneously release NO under physiological conditions.

Previous amidine-linked NO releasing compounds were prepared using NO gas after acetamidation of amine groups. This invention provides a simple, robust method of preparing diazeniumdiolated imidates from cyano compounds. As with other imidoesters, these diazeniumdiolated imidoesters react with nucleophiles allowing formation of a wide range of NO releasing derivatives. For example, imidoesters are extensively used as protein crosslinking reagents because they react with primary amines to form amidine bonds. These already diazeniumdiolated and purified imidoesters can thus be used to directly attach amidine NO-releasing groups onto molecules such as peptides and medicinals without exposing them to NO gas or its potentially toxic by-products. Some of these compounds may also release nitroxyl (HNO, NO-) in solution under physiological conditions.

Ernst V Arnold (NCI)
Joseph A Hrabie (NCI)
Larry K Keefer (NCI)

Patent Status:
HHS, Reference No. E-276-2002/0
US, , Patent No. 6,949,530, Issued 27 Sep 2005
US, , Patent No. 7,348,319, Issued 25 Mar 2008
US, , Patent No. 6,673,338, Issued 06 Jan 2004
US, , Patent No. 7,105,502, Issued 12 Sep 2006

Relevant Publication:
  1. Arnold EV, et al. Reaction of nitric oxide with benzyl cyanide to yield a bis-diazeniumdiolated imidate. Tetrahedron Lett. 2000 Oct 28;41(44):8421-8424. [ doi:10.1016/S0040-4039(00)01535-5 ]

For Licensing Information Please Contact:
Betty Tong Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-594-6565
Fax: 301-402-0220

Ref No: 735

Updated: 12/2011

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