University of California

Cook Imaging Corporation

E. R. Squibb Sons, Inc.

Biophysica Foundation

Ramachandran Ranganathan

Milos Sovak

Thangavel Arunachalam

Novel nonionic contrast agents of the formula ##STR1## or dimers of the formula ##STR2## are disclosed where X, Z and R.sub.1 -R.sub.5 are as defined herein.

Nonionic radiographic contrast agents

Methods are provided for substituting aromatic carboxylic acids and derivatives thereof and amino substituted aromatic carboxylic acids and derivatives thereof, by forming imides and imide-amides, respectively, by acylation with aliphatic carboxylic acids, substituting at least one nitrogen atom under mild basic conditions with an aliphatic compound having as alkylating agent a displaceable functionality and removing undesired acyl groups, as appropriate.

Process for producing non-ionic radiographic contrast media utilizing

Novel non-ionic contrast media are efficiently prepared from generally available ionic contrast media. Particularly, polyhydroxyhalohydrocarbons are employed with a triiodo-substituted acylamido benzoic acids in aqueous weakly basic media to selectively substitute the amido nitrogen, followed by activation of the carboxyl group for amide formation.

Non-ionic contrast media from ionic contrast media

Novel non-ionic contrast media of a hitherto unknown combination of low osmolality and low viscosity are efficiently prepared from generally available ionic contrast media or non-iodinated precursors. Particularly, polyhydroxyhalo-hydrocarbons are employed with a triiodo-substituted acylamido benzoic acids in aqueous weakly basic media to selectively substitute the amido nitrogen, followed by activation of the carboxyl group for amide formation.

Non-ionic polyol contrast media from ionic contrast media

Methods and compositions are provided for preparing polyhydroxylated polyiodo non-ionic contrast media. Particularly, substituted polyiodobenzamides are prepared, wherein the benzamide nitrogen is polyhydroxylated by allylic substitution on the nitrogen and oxidation of the olefinic group to provide for polyhydroxyl substitution. Amino substituents on the benzamide may be polyhydroxylated by allyl substitution or acryl substitution. All of the olefins may be oxidized simultaneously to glycols to provide for water soluble relatively non-toxic contrast media in efficient economical processes. Alternatively, the same compounds can be synthesized by alkylating N-acylbenzamide with polyacetoxyalkyl or dioxolanylalkyl halides, followed by removal of the protective groups.

Methods and compositions involving polyhydroxylated polyiodo non-ionic

Novel intermediates for non-ionic polyiodo amino-substituted benzenepolyamides having polyol substituents on the amide nitrogens are provided which are 5-amino-6-hydroxy-1,3-dioxepanes. The compounds provide an economic and efficient route to novel contrast media having excellent chemical and physiological properties. Also provided are methods for preparing the subject compounds.

Novel amino-dioxepane intermediates for the synthesis of new non-ionic

Novel methods are provided for synthesizing 2-amino-2-tetritol, by positive halogen addition to protected 1,4-dioxybutene-2 in the presence of a nitrile, resulting in addition of a halo functionality and the nitrile functionality across the double bond. Upon hydrolysis, the desired erythro-product can be obtained in stereochemically good yield.

Growing community of inventors

Princeton, NJ, United States of America

Ramachandran Ranganathan