DTPA prodrugs, compositions thereof, and methods of using the same

Patent metadata

Field	Value
Publication number	US-9546129-B2
Application number	US-201514721552-A
Country	US
Kind code	B2
Filing date	May 26, 2015
Priority date	Nov 26, 2012
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

Abstract

The present invention relates to trisodium diethylenetriamine pentaacetic acid (DTPA) prodrugs, such as, for example, DTPA di-ethyl esters. The invention further relates to compositions comprising DTPA prodrugs and methods of using the same.

First claim

That which is claimed is:

1. A polymorph of 6,9-bis(carboxymethyl)-3-(2-ethoxy-2-oxoethyl)-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid characterized by a powder x-ray diffraction pattern substantially the same as that shown in FIG. 6D and/or a powder x-ray diffraction pattern having peaks at about 8.1, 12.0, 13.8, 15.4, 16.0, 16.6, 18.3, 19.3, 21.4, 22.1, 24.0, 26.5, and 29.2±0.2 degrees 2 theta,
wherein the polymorph has a melting point in a range from 133° C. to 141° C.

2. The polymorph of claim 1 , wherein the melting point is measured using differential scanning calorimetry over a range of about 25° C. to about 320° C. with a heating rate of about 10.00° C./min.

3. A process of preparing the polymorph of 6,9-bis(carboxymethyl)-3-(2-ethoxy-2-oxoethyl)-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid of claim 1 , comprising
(a) combining DTPA bis-anhydride and absolute ethanol to form a reaction mixture;
(b) heating the reaction mixture to reflux while stirring for about 1.5 hours;
(c) filtering the reaction mixture to form a filtrate;
(d) cooling the filtrate to a temperature below about 20° C. to form a precipitate of a polymorph of 6,9-bis(carboxymethyl)-3-(2-ethoxy-2-oxoethyl)-11-oxo-12-oxa-3,6,9-triazatetradecan-1-oic acid;
(e) filtering the filtrate to obtain the precipitate;
(f) optionally washing the precipitate with cold ethanol;
(g) optionally washing the precipitate with methyl tert-butyl ether to form a filter cake;
(h) optionally mixing the filter cake with ethanol to form a second slurry;
(i) optionally heating the second slurry to a temperature of about 70° C.;
(j) optionally filtering the second slurry to form a second filtrate;
(k) optionally cooling the second filtrate to a temperature below about 20° C. to form a second precipitate;
(l) optionally filtering the second filtrate to obtain the second precipitate; and
(m) optionally drying the precipitate, thereby obtaining the polymorph.

4. A method of treating a subject to remove a radioactive element from the subject comprising:
administering a therapeutically effective amount of the polymorph of claim 1 to a subject, thereby removing the radioactive element from the subject.

5. The method of claim 4 , wherein the administering step delivers to the subject from about 1 mg to about 2,000 mg of the polymorph per kilogram of the subject's total body weight.

6. The method of claim 4 , wherein the administering step is prior to the subject's exposure to a radioactive element.

7. The method of claim 6 , wherein the administering step is carried out to prevent incorporation of a radioactive element into the subject's tissues, organs, bones, or any combination thereof.

8. The method of claim 4 , wherein the administering step is after the subject's exposure to a radioactive element.

9. The method of claim 4 , wherein the radioactive element comprises an isotope of plutonium (Pu), americium (Am), curium (Cm), or any combination thereof.

10. The method of claim 4 , wherein the subject is a mammal.

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Jay Michael
• Mumper Russell
• Huckle James
• Sadgrove Matthew

Classifications

• C07C227/00

  Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton · CPC title

• C07C229/26 Primary

  having more than one amino group bound to the carbon skeleton, e.g. lysine · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D265/33

  Two oxygen atoms, in positions 3 and 5 · CPC title

• A61K31/225

  Polycarboxylic acids · CPC title