One-step synthesis of phosphate-based inhibitors and applications thereof

Patent metadata

Field	Value
Publication number	US-11555047-B2
Application number	US-202017005917-A
Country	US
Kind code	B2
Filing date	Aug 28, 2020
Priority date	Oct 31, 2019
Publication date	Jan 17, 2023
Grant date	Jan 17, 2023

Abstract

One-step methods for forming phosphate-based enzyme inhibitors are disclosed. Methods include reacting o-phosphorylethanolamine with an acyl chloride at acidic conditions. Acyl chlorides can be derivatized. The phosphate-based enzyme inhibitors can inhibit enzymes of the pentose phosphate pathway including D-ribose-5-phosphate aldose-ketose isomerase enzymes such as T. cruzi ribose 5-phosphate isomerase type B and D-ribulose-5-phosphate 3-epimerase enzymes. Methods can be used in forming pharmaceutical compositions for use in treatment of disease caused by kinetoplastid parasites including T. cruzi, T. brucei , and Leishmania spp.

First claim

What is claimed is:

1. A method for forming a phosphate-based enzyme inhibitor, the method comprising:
combining o-phosphorylethanolamine with phenylacetyl chloride having the following structure:

to form a reaction mixture; and
maintaining the reaction mixture at a pH of from about 4 to about 6, wherein the phosphate-based enzyme inhibitor is a D-ribose-5-phosphate aldose-ketose isomerase inhibitor and/or a D-ribulose-5-phosphate 3-epimerase inhibitor.

2. The method of claim 1 , wherein the step of maintaining the reaction mixture at a pH of from about 4 to about 6 comprises adding a base to the reaction mixture.

3. A method for forming a pharmaceutical composition comprising
combining the phosphate-based enzyme inhibitor of claim 1 with a pharmaceutically acceptable carrier.

4. The method of claim 3 , wherein the method comprises forming the pharmaceutical composition as discrete units.

5. The method of claim 3 , further comprising combining the phosphate-based enzyme inhibitor with a sweetening agent, a flavoring agent, a coloring agent, or a preserving agent.

6. The method of claim 3 , further comprising combining the phosphate-based enzyme inhibitor with an inert solid diluent.

7. The method of claim 3 , wherein the pharmaceutical composition is in the form of a suspension, an aerosol, a cream, an ointment, a lotion, or a powder.

8. A pharmaceutical composition comprising:
a phosphate-based enzyme inhibitor having the following structure:

in which R 2 is hydrogen, halogen, C1-C4 alkyl halogen, C1-C4 alkyl, or C1-C4 alkoxy; and
a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8 , wherein the enzyme inhibitor comprises 2-(2-phenylacetamido)ethyl dihydrogen phosphate.

10. A method of inhibiting a D-ribose-5-phosphate aldose-ketose isomerase and/or a D-ribulose-5-phosphate 3-epimerase comprising locating the pharmaceutical composition of claim 8 in an area comprising a D-ribose-5-phosphate aldose-ketose isomerase and/or a D-ribulose-5-phosphate 3-epimerase.

11. The method of claim 10 , wherein the method inhibits type B T. cruzi ribose 5-phosphate isomerase type B and/or ribulose 5-phosphate 3-epimerase.

12. The method of claim 10 , wherein the area comprises a parasitic organism, the parasitic organism carrying the D-ribose-5-phosphate aldose-ketose isomerase and/or a D-ribulose-5-phosphate 3-epimerase.

Assignees

• Univ South Carolina
• Univ North Carolina State

Inventors

• D'Antonio Edward
• Pierce Joshua

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61K31/661

  Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion {or mevinphos} · CPC title

• C07F9/4087 Primary

  Esters with arylalkanols · CPC title

• C07F13/00 Primary

  Compounds containing elements of Groups 7 or 17 of the Periodic Table · CPC title