# US 10,245,328 B2 · Gadolinium complex comprising DO3A-tranexamic acid conjugate

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- Number: US 10,245,328 B2
- Document ID: US10245328B2
- Status: Granted
- Kind: B2
- Application number: 15/110,386
- Filed: 2015-01-08
- Published: 2016-11-17
- Granted: 2019-04-02
- Earliest claimed: 2014-01-10
- Assignees: Kyungpook National University Industry-Academic Cooperation Foundation
- Applicants: Kyungpook National University Industry-Academic Cooperation Foundation
- Inventors: Tae-Jeong Kim; Yong Min Chang
- Web page: https://patentgrep.com/patent/US10245328B2

## CPC

- A61K 49/108: {the metal complex being Gd-DOTA}
- A61K 49/106: {the complex-forming compound being cyclic, e.g. DOTA}
- C07D 257/02: not condensed with other rings
- C07F 5/00: Compounds containing elements of Groups 3 or 13 of the Periodic Table
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present disclosure relates to a magnetic resonance imaging (MRI) contrast agent containing a gadolinium complex, and more specically, to a DO3A-tranexamic acid compound having a structure of a chemical formula 1, or an ester compound thereof, and gadolinium complexes thereof. The DO3A-tranexamic acid compound or the ester compound thereof may be used to prepare gadolinium complexes. The gadolinium complexes exhibit thermodynamic and kinetic stabilities, and show the relaxation rate equal to that of the clinical contrast agent which is currently commercially available. Therefore, the gadolinium complexes can be widely used as an MRI contrast agent.

## Claims

### Claim 1

A DO3A-tranexamic acid compound having a structure of a following chemical formula 1, or an ester compound thereof:
where R is H, NH2 or CONN (CH2)2NH2.

### Claim 2 (depends on 1)

A method for producing the DO3A-tranexamic acid or the ester compound thereof of claim 1, wherein R═CONH(CH2)2NH2 (compound 1c), wherein the method comprises:
a) adding and agitating bromoacetyl bromide into trans-4 (aminomethyl)cyclohexaneethylcarboxylate hydrochloride to form a first mixture;
b) adding and agitating DO3A-(tBuO)3 to the first mixture to produce DO3A (tBuO)3 tranexamic ethyl ester conjugate;
c) adding 1,2-diaminoethane to the DO3A (tBuO)3 tranexamic ethyl ester conjugate to form a second mixture;
d) removing a solvent from the second mixture under a low pressure and then dissolving the resultant product in methanol and then performing silica gel chromatography thereto;
e) adding TFA to the product subjected to the chromatography to deprotect a tert-butyl group; and
f) drying the thus-resulting product in a vacuum state to obtain the DO3A-tranexamic acid or the ester compound thereof.

### Claim 3 (depends on 1)

A method for producing the DO3A-tranexamic acid or the ester compound thereof of claim 1, wherein R═NH2 (compound 1d), wherein the method comprises:
a) adding and agitating di-tert-butyl dicarbonate to trans-1,4-diaminocyclohexane to form a first mixture:
b) adding and agitating bromoacetyl bromide to the first mixture to form a second mixture;
c) adding and agitating DO3A-(tBuO)3 to the second mixture to produce DO3A (tBuO)3 tranexamic amine conjugate;
d) removing a solvent from the resultant product under a low pressure and then dissolving the resultant product in methanol and then performing silica gel chromatography thereto;
e) adding TFA to the product subjected to the chromatography to deprotect a tert-butyl group; and
f) drying the thus-resulting product in a vacuum state to obtain a DO3A-tranexamicamine compound.

### Claim 4 (depends on 1)

A method for producing the DO3A-tranexamic acid or the ester compound thereof of claim 1, wherein R═H (compound 1e), wherein the method comprises:
a) adding and agitating bromoacetyl bromide to (aminomethyl)cyclohexane to prepare a first mixture;
b) adding and agitating DO3A-(tBuO)3 to the first mixture to prepare DO3A-(tBuO)3 tranexamic conjugate;
c) removing a solvent from the resultant product under a low pressure and then dissolving the resultant product in methanol and then performing silica gel chromatography thereto;
d) adding TFA to the product subjected to the chromatography to deprotect a tert-butyl group; and
e) drying the thus-resulting product in a vacuum state to obtain the DO3A-tranexamic acid or the ester compound thereof.

### Claim 5 (depends on 1)

A composition for a complex ligand (L), wherein the composition contains the DO3A-tranexamic acid or the ester compound thereof of claim 1.

### Claim 6 (depends on 1)

A complex containing the DO3A-tranexamic acid or the ester compound thereof of claim 1 as a ligand (L), wherein the complex contains a metal atom coordinated with the ligand.

### Claim 7 (depends on 6)

The complex of claim 6, where the metal atom is gadolinium (Gd).

### Claim 8 (depends on 6)

A MRI contrast agent containing the complex of claim 6 as an effective component.

### Claim 9 (depends on 8)

The MRI contrast agent of claim 8, wherein the contrast agent has ECF (extracelluar fluid) image contrast function.