Medi-physics, Inc.

Concat, Ltd.

Chelator LLC

General Electric Company

Harry S Winchell

Rosa L Cyjon

Joseph Y Klein

Haim Zaklad

Elliot D Simhon

Ofer Klein

Tz-Hong Lin

Morton Barak

Ronald M Baldwin

Parmer Van Fleet, Iii

Dale K Wells

Samuel B Beaudry

James F Lamb

Thomas C Hall

Eliot D Simhon

Charles A Panneciere

Compounds that demonstrate chelation affinity and selectivity for first transition series elements are administered to patients suffering from such conditions as ischemia, prolonged seizures and trauma to provide neuroprotection, cardioprotection, or both. These compounds when administered form complexes with chelatable iron and copper cations and thereby mitigate the ability of these cations to catalyze Haber-Weiss reactions that form toxic hydroxy free radicals that cause tissue injury. These compounds also form complexes with chelatable zinc cations thereby inhibiting the cytotoxicity associated with excess chelatable zinc.

Neuroprotection and cardioprotection afforded by chelators with high affinity and specificity for cations of first transition series elements

This invention involves synthesis and use of a class of compounds with chelation affinity and selectivity for first transition series elements. Administration of the free or conjugated compound, or physiological salts of the free or conjugated compound, results in decrease in the in vivo bioavailability of first transition series elements and/or removal from the body of first transition series elements and elements with similar chemical properties. These characteristics make such compounds useful in the management of diseases associated with a bodily excess of first transition series elements and elements with similar chemical properties. This invention demonstrates that such compounds inhibit mammalian, bacterial, and fungal cell replication and are therefore useful in the treatment of neoplasia, infection, inflammation, immune reponse, and in termination of pregnancy. Since these compounds are capable of descreasing the in vivo availability of tissue iron they are useful in management of free radical mediated tissue damage, and oxidation mediated tissue damage. When combined with radioisotopic or paramagnetic cations of first transition series elements, or elements with chemical properties similar to those of first transition series elements, prior to their administration, the resulting complexes are useful as diagnostic agents in nuclear medicine and magnetic resonance imaging (MRI).

Compounds with chelation affinity and selectivity for first transition series elements: use in medical therapy and diagnosis

Polyamines containing at least two nitrogen atoms monosubstituted with pendant arms capable of coordinating metal cations, or with precursors of such pendant arms, all nitrogen atoms of the polyamines except two being fully substituted and the remaining two bearing one H atom each, are cyclized by reaction with a bridging agent that contains two sites that each bear a reactive group capable of undergoing a nucleophilic attack by one of the two N-H groups on the polyamine. Unlike the prior art, cyclization occurs in preference over polymerization of the polyamine, even in reaction mixtures in which the polyamine is at high concentration. A process is also disclosed whereby linear polyamines in which the terminal amine groups are primary amines are substituted with methylenephosphonate ester groups, with one such substituent on each nitrogen atom of the polyamine. The process involves the use of a trialkyl or triaryl phosphite, and unlike the prior art, monosubstitutions at all nitrogen atoms are achieved in preference over disubstitutions at the terminal primary amines. Finally, a novel class of N,N&prime;,N&Prime;-tris(methylenephosphonate or methylephosphonic acid-substituted)-1,4,7-triazaheptanes are disclosed as new compositions of matter.

Processes for synthesis of cyclic and linear polyamine chelators containing N-monosubstituted coordinating arms

This invention involves the use of a class of compounds with chelation affinity and selectivity for first transition series elements. Application or administration of the free or conjugated compound, or physiological salts of the free or conjugated compound, results in decrease of the bioavailability and/or chemical action of first transition series elements. These characteristics make such compounds useful in cosmetics and personal care products to decrease odor arising from microbial growth on body surfaces and in body cavities, decrease microbial growth on teeth, plaque, and gums that cause tooth decay and gum disease, inhibition of oxidative damage to the skin, inhibition of enzymatic action of metalloenzymes dependent on first transition series elements, and inhibition of reperfusion injury.

COMPOUNDS WITH CHELATION AFFINITY AND SELECTIVITY FOR FIRST TRANSITION SERIES ELEMENTS AND THEIR USE IN COSMETICS AND PERSONAL CARE PRODUCTS, INHIBITION OF METALLOENZYMES, AND INHIBITION OF REPERFUSION INJURY

Compounds with chelation affinity and selectivity for first transition elements and their use in cosmetics and personal care products, inhibition of metalloenzymes, and inhibition of reperfusion injury

Compounds with chelation affinity selectivity for first transition

This invention involves synthesis and use of a class of compounds with chelation affinity and selectivity for first transition series elements. Administration of the free or conjugated compound, or physiological salts of the free or conjugated compound, results in decrease in the in vivo bioavailability of first transition series elements and/or removal from the body of first transition series elements and elements with similar chemical properties. These characteristics make such compounds useful in the management of diseases associated with a bodily excess of first transition series elements and elements with similar chemical properties. This invention demonstrates that such compounds inhibit mammalian, bacterial, and fungal cell replication and are therefore useful in the treatment of neoplasia, infection, inflammation, immune response, and in termination of pregnancy. Since these compounds are capable of descreasing the in vivo availability of tissue iron they are useful in management of free radical mediated tissue damage, and oxidation mediated tissue damage. When combined with radioisotopic or paramagnetic cations of first transition series elements, or elements with chemical properties similar to those of first transition series elements, prior to their administration, the resulting complexes are useful as diagnostic agents in nuclear medicine and magnetic resonance imaging (MRI).

Compounds with chelation affinity and selectivity for first transition

Polyphosphonate ligands containing three or more phosphonate groups, combined with paramagnetic metal cations and administered in the form of pharmacologically acceptable salts, are useful as MRI contrast enhancement agents, which tend to localize in bone tissue without being conjugated to bone-specific biomolecules. Triazacyclononanes and tetraazacyclododecanes, with dihydroxyphosphorylmethyl or dihydroxyphosphorylethyl groups, optionally substituted at the methyl or ethyl bridges with alkyl, aryl, hydroxyl or amino groups, are particularly preferred.

MRI image enchancement of bone and related tissue using complexes of

Ligands with three or more nitrogen atoms incorporated into a linear or cyclic backbone structure, with the nitrogen atoms substituted with a combination of phosphonate groups and nonphosphonate groups, of which at least two are phosphonate groups, are disclosed. These ligands are combined with paramagnetic metal cations and administered in the form of pharmacologically acceptable salts, are useful as MRI contrast enhancement agents, which tend to localize in bone tissue without being conjugated to bone-specific biomolecules. Triazacyclononanes and tetraazacyclododecanes, with dihydroxyphosphorylmethyl or dihydroxyphosphorylethyl groups linked to the backbone nitrogens are preferred.

MRI image enhancement using complexes of paramagnetic cations and amine

MRI image enhancement of bone and related tissue using complexes of

Diagnostic reagents comprising a chelating agent and stannous tin which are suitable for conversion to radiopharmaceuticals by the addition of a radionuclide, such as suitable forms of technetium 99m, are stabilized against oxidation and/or hydrolysis by the addition to said complex of ascorbic acid, erythorbic acid, pharmaceutically acceptable inorganic salts thereof or mixtures thereof.

Stable diagnostic reagents

Certain radioiodine containing amines useful as brain imaging agents are disclosed. The compounds of the invention are represented by the formula ##STR1## wherein I is a radioisotope of iodine with I-123 being preferred, R is lower alkyl or halogen, R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of hydrogen and lower alkyl, R.sub.3 and R.sub.4 are the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl and substituted carbamoyl methyl or R.sub.3 and R.sub.4 taken together with the nitrogen to which they are attached form a 5- or 6-membered ring which may be substituted with one or more lower alkyl groups, x is 0 to 4, y is 0 to 3 and z is 0 or 1 and pharmaceutically acceptable acid addition salts thereof.

Amines useful as brain imaging agents

Certain radioiodine containing amides useful as brain imaging agents are disclosed. The compounds of the subject invention are represented by the formula ##STR1## wherein I is a radioisotope of iodine with I-123 being preferred, R.sub.1 and R.sub.2 are the same or different and are selected from the grooup consisting of hydrogen, hydroxy, alkyl, aryl, substituted aryl, aralkyl, anilino and carbamoylmethyl or R.sub.1 and R.sub.2 taken together with the nitrogen to which they are attached form a 5- or 6-membered ring.

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Lafayette, CA, United States of America

Harry S Winchell