Claims for Patent: 4,933,456

Summary for Patent: 4,933,456

Title:	Dipyridoxyl phosphate NMRI contrast agents
Abstract:	N,N'-bis-(pyridoxal-5-phosphate)-alkylenediamine-N,N'-diacetic acids, N,N'-bis-(pyridoxal-5-phosphate)-1,2-cycloalkylenediamine-N,N'-diacetic acids, and N,N'-bis-(pyridoxal-5-phosphate)-1,2-arylenediamine-N,N'-diacetic acids, the corresponding monophosphate compounds and monoacetic acid compounds, and their salts and esters form stable, highly soluble chelates with paramagnetic metal ions, and are highly effective NMRI contrast agents. Preferred contrast agents are paramagnetic ion chelates of N,N'-bis-(pyridoxal-5-phosphate)ethylene-diamine-N,N'-diacetic acid, N,N'-bis-(pyridoxal-5-phosphate)trans-1,2-cyclohexylenediamine-N,N'-diacet ic acid, N,N'-bis-(pyridoxal-5-phosphate)trans-1,2-arylenediamine-N,N'-diacetic acid, and the soluble calcium salts thereof. Novel intermediates for forming these compounds are N,N'-bis(pyridoxal-5-phosphate)alkylenediimines, N,N'-bis(pyridoxal-5-phosphate)alkylenediamines, N,N'-bis(pyridoxal-5-phosphate)-1,2-cycloalkylenediimines, N,N'-bis(pyridoxal-5-phosphate)-1,2-cycloalkylenediamines, N,N'-bis(pyridoxal-5-phosphate(-1,2-arylenediamines, and the corresponding monophosphate compounds.
Inventor(s):	Rocklage; Scott M. (Saratoga, CA), Quay; Steven C. (Los Altos Hills, CA)
Assignee:	Salutar, Inc. (Sunnyvale, CA)
Application Number:	07/047,614
Patent Claims:	1. A metal ion chelate of a chelating compound of the formula: ##STR9## wherein: R is hydrogen or ##STR10## R.sub.1 is hydrogen or ##STR11## with the proviso that at least one of R and R.sub.1 is other than hydrogen; R.sub.5 and R.sub.6 are each, independently, hydroxy, alkoxy having from 1 to 18 carbons, hydroxy-substituted alkoxy having from 1 to 18 carbons, amino, or alkylamido having from 1 to 10 carbons; R.sub.3 is alkylene having from 1 to 8 carbons, 1,2-cycloalkylene having from 5 to 8 carbons, or 1,2-arylene having from 6 to 10 carbons; R.sub.4 is hydrogen, hydroxymethyl, alkyl having from 1 to 6 carbons, or ##STR12## each R.sub.7 is, independently, hydrogen, hydroxy-substituted alkyl having from 1 to 18 carbons, or aminoalkyl having from 1 to 18 carbons; and the chelated metal ion is a paramagnetic ion of a metal having an atomic number of from 21 to 29, inclusive, 42, 44, or from 58 to 70, inclusive, or a physiologically biocompatible inorganic or organic salt of said metal ion chelate. 2. A metal ion chelate according to claim 1 wherein R and R.sub.1 are each other than hydrogen, or a salt of said metal ion chelate. 3. A metal ion chelate according to claim 1 wherein each R.sub.7 is hydrogen, or a salt of said metal ion chelate. 4. A metal ion chelate according to claim 1 wherein R and R.sub.1 are each other than hydrogen, R.sub.5 and R.sub.6 are each, independently, hydroxy, alkoxy having from 1 to 8 carbons, hydroxyethyl, dihydroxypropyl, amino, or alkylamido having from 1 to 8 carbons, or a salt of said metal ion chelate. 5. A metal ion chelate according to claim 4 wherein R.sub.3 is alkylene having from 2 to 6 carbons, or a salt of said metal ion chelate. 6. A metal ion chelate of N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid or a salt thereof, wherein the metal ion is as recited in claim 1, or a salt of said metal ion chelate. 7. A metal ion chelate according to claim 4 wherein R.sub.3 is cyclohexyl, or a salt of said metal ion chelate. 8. A metal ion chelate of N,N'-bis(pyridoxal-5-phosphate)-trans-1,2-cyclohexyldiamine-N,N'-diacetic acid or a salt thereof, wherein the metal ion is as recited in claim 1, or a salt of said metal ion chelate. 9. A metal ion chelate according to claim 1 wherein the metal ion is divalent or trivalent, or a salt of said metal ion chelate. 10. A metal ion chelate according to claim 1 wherein the metal ion is chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III), or erbium (III), or a salt of said metal ion chelate. 11. A metal ion chelate according to claim 1 wherein the metal ion is manganese (II), or a salt of said metal ion chelate. 12. A manganese (II) chelate of N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid or a salt thereof, or a salt of said manganese (II) chelate. 13. A manganese (II) chelate of N,N'-bis(pyridoxal-5-phosphate)-trans-1,2-cyclohexyldiamine-N,N'-diacetic acid or a salt thereof, or a salt of said manganese (II) chelate. 14. A metal ion chelate according to claim 1 in the form of a calcium salt of an anionic chelate complex of a paramagnetic metal ion and a chelating compound of formula I, or a salt of said metal ion chelate. 15. A metal ion chelate or salt according to claim 14 wherein the molar ratio of calcium to chelating compound is from 0.05 to 1.0. 16. A metal ion chelate in the form of a calcium salt of the manganese (II) chelate of claim 12 or a salt thereof. 17. A metal ion chelate or salt according to claim 16 wherein the molar ratio of calcium to chelating compound is from 0.05 to 1.0. 18. A sodium-calcium salt of a manganese (II) chelate of N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid or a salt thereof.