Antimalarial agents that are inhibitors of dihydroorotate dehydrogenase

Patent metadata

Field	Value
Publication number	US-9238653-B2
Application number	US-201013499031-A
Country	US
Kind code	B2
Filing date	Sep 28, 2010
Priority date	Sep 29, 2009
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

Inhibitors of parasitic dihydroorotate dehydrogenase enzyme (DHOD) are candidate therapeutics for treating malaria. Illustrative of such therapeutic agents include the compound:

and a triazolopyrimidine class of compounds that conform to Formula IX:

and their solvates, stereoisomers, tautomers and pharmaceutically acceptable salts.

First claim

We claim:

1. A compound selected from:

and stereoisomers, tautomers, solvates, prodrugs and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 , wherein said compound has the following formula:

wherein R is selected from Cl, CF 3 or SF 5 ; and stereoisomers, tautomers, solvates, prodrugs and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 wherein said compound is

4. The compound according to claim 1 , wherein the pharmaceutically acceptable salt of said compound is selected from acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, or valerate salts.

5. A pharmaceutical composition comprising a compound selected from the following group:

and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5 , wherein the composition is an oral formulation.

7. A method of inhibiting Plasmodium dihydroorotate dehydrogenase in a subject comprising the administration of a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition thereof to a subject in need thereof.

8. The method according to claim 7 , wherein the compound is administered at a daily dosage of from about 1 mg to about 50 mg per kilo body weight.

9. The method according to claim 7 , wherein the compound is administered at a daily dosage of from about 5 mg to about 25 mg per kilo body weight.

10. The method according to claim 7 , wherein the compound administered is:

11. A method of treating a parasite infection by the inhibition of Plasmodium dihydroorotate dehydrogenase in a subject comprising the administration of a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition thereof to a subject in need thereof.

12. The method according to claim 11 , wherein the parasite infection is malaria.

13. The method according to claim 11 , wherein the parasite infection is a P. falciparum infection.

14. The method according to claim 11 , wherein the compound is administered at a daily dosage of from about 1 mg to about 50 mg per kilo body weight.

15. The method according to claim 11 , wherein the compound is administered at a daily dosage of from about 5 mg to about 25 mg per kilo body weight.

16. The method according to claim 11 , wherein the compound administered is:

17. A pharmaceutical formulation according to claim 5
wherein the compound is of the following formula:

wherein R is selected from Cl, CF 3 and SF 5 ; and stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

18. A pharmaceutical formulation according to claim 5 wherein the compound is

19. A pharmaceutical formulation according to claim 5 wherein the pharmaceutically acceptable salt is selected from acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

Assignees

• Rathod Pradipsinh K
• Floyd David
• Burrows Jeremy
• Marwaha Alka
• Gujjar Ramesh
• Coteron-Lopez Jose
• Phillips Margaret
• Charman Susan A
• Matthews David
• Univ Texas
• Medicines For Malaria Venture Mmv
• Univ Washington

Inventors

• Rathod Pradipsinh K
• Floyd David
• Burrows Jeremy
• Marwaha Alka
• Gujjar Ramesh
• Coteron-Lopez Jose
• Phillips Margaret
• Charman Susan A
• Matthews David

Classifications

• A61P33/00

  Antiparasitic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61P33/06

  Antimalarials · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title