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

Patent metadata

Field	Value
Publication number	US-9969681-B2
Application number	US-201615374390-A
Country	US
Kind code	B2
Filing date	Dec 9, 2016
Priority date	Nov 26, 2012
Publication date	May 15, 2018
Grant date	May 15, 2018

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. 6A and/or a powder x-ray diffraction pattern having peaks at about 7.6, 12.4, 13.5, 14.0, 15.3, 18.1, 18.7, 18.8, 21.0, 22.5, 23.4, 24.5, 28.7, and 35.7±0.2 degrees 2 theta,
wherein the polymorph has a melting point in a range from about 110° C. to about 121° 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, ethanol, and pyridine to form a reaction mixture;
(b) stirring the reaction mixture under nitrogen for about 24 hours;
(c) adding the reaction mixture to dichloromethane to form a dichloromethane solution;
(d) cooling the dichloromethane solution to a temperature of 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 dichloromethane solution to obtain the precipitate;
(f) optionally washing the precipitate with dichloromethane during the filtering step; and
(g) 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

• C07C229/16 Primary

  to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids · CPC title

• C07D265/33

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

• C07C227/20

  by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates · CPC title

• C07C229/26 Primary

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

• A61K31/225

  Polycarboxylic acids · CPC title