Anti-malarial agents

Patent metadata

Field	Value
Publication number	US-10214495-B2
Application number	US-201615741786-A
Country	US
Kind code	B2
Filing date	Jul 12, 2016
Priority date	Jul 13, 2015
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

The present invention is related to a use of aminopyrazine derivatives in the manufacture of a medicament for preventing or treating malaria. Specifically, the present invention is related to aminopyrazine derivatives useful for the preparation of a pharmaceutical formulation for the inhibition of malaria parasite proliferation.

First claim

The invention claimed is:

1. An aminopyrazine according to Formula (I),

wherein X is CH or N; as well as pharmaceutically acceptable salts, complexes, polymorphs, tautomers, geometrical isomers, and optically active forms thereof.

2. An aminopyrazine according to claim 1 wherein X is N.

3. An aminopyrazine according to claim 1 wherein X is CH.

4. An aminopyrazine according to claim 1 , wherein the aminopyrazine is selected from the following group:
4-(5-amino-6-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)benzoic acid; and 4-(5-amino-6-(6-(trifluoromethyl)pyridin-3yl)pyrazin-2-yl)benzoic acid; as well as pharmaceutically acceptable salts, complexes, polymorphs, tautomers, geometrical isomers, and optically active forms thereof.

5. An aminopyrazine according to claim 1 , wherein the aminopyrazine is 4-(5-amino-6-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)benzoic acid.

6. An aminopyrazine according to claim 1 , wherein the pharmaceutically acceptable salt is selected from Lithium, sodium and ammonium salt.

7. A pharmaceutical formulation containing at least one aminopyrazine according to claim 1 , and a pharmaceutically acceptable carrier, diluent or excipient thereof.

8. A pharmaceutical formulation according to claim 7 further comprising an antimalarial agent.

9. A pharmaceutical formulation according to claim 8 wherein the antimalarial agent is selected from artemisinin or an artemisinin and its derivatives (such as artemether or dihydroartemisinin, chloroquine, quinine, mefloquine, amodiaquine, atovaquone/proguanil, doxycycline, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, primaquine, quinacrine, doxycycline, atovaquone, proguanil hydrochloride, piperaquine, ferroquine, tafenoquine, arterolane, Spiro[3H-indole-3,1′-[1H]pyrido[3,4-b]indol]-2(1H)-one, 5,7′-dichloro-6′-fluoro-2′,3′,4′,9′-tetrahydro-3′-methyl-,(1′R,3′S)- (CAS Registry Number: 1193314-23-6), Sulfur, [4-[[2-(1,1-difluoroethyl)-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]amino]phenyl] pentafluoro-] (CAS Registry Number: 1282041-94-4), Morpholine,4-[2-(4-cis-dispiro [cyclohexane-1,3′-[1,2,4]trioxolane-5′,2″-tricyclo[3.3.1.1 3,7 ]decan]-4-ylphenoxy)ethyl]- (CAS Registry Number: 1029939-86-3), [3,3′-Bipyridin]-2-amine, 5-[4-(methylsulfonyl)phenyl]-6′-(trifluoromethyl)- (CAS Registry Number: 1314883-11-8), Ethanone, 2-amino-142-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5,6-dihydroim idazo [1,2-a]pyrazin-7(8H)-yl]-(CAS Registry Number 1261109-90-3).

10. An aminopyrazine according to claim 1 , or a pharmaceutical formulation thereof for use in the prevention and/or treatment of malaria.

11. An aminopyrazine for use according to claim 10 wherein the aminopyrazine is to be administered in combination with a co-agent useful in the treatment of malaria.

12. An aminopyrazine for use according to claim 11 wherein the antimalarial agent is selected from artemisinin or an artemisinin and its derivatives (such as artemether or dihydroartemisinin, chloroquine, quinine, mefloquine, amodiaquine, atovaquone/proguanil, doxycycline, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, primaquine, quinacrine, doxycycline, atovaquone, proguanil hydrochloride, piperaquine, ferroquine, tafenoquine, arterolane, Spiro[3H-indole-3,1′-[1H]pyrido[3,4-b]indol]-2(1H)-one, 5,7′-dichloro-6′-fluoro-2′,3′,4′,9′-tetrahydro-3′-methyl-,(1′R,3′S)- (CAS Registry Number: 1193314-23-6), Sulfur, [4[[2-(1,1-difluoroethyl)-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]amino]phenyl] pentafluoro-] (CAS Registry Number: 1282041-94-4), Morpholine, 4-[2-(4-cis-dispiro [cyclohexane-1,3′-[1,2,4]trioxolane-5′,2″-tricyclo[3.3.1.1 3,7 ]decan]-4-ylphenoxy)ethyl]- (CAS Registry Number: 1029939-86-3), [3,3′-Bipyridin]-2-amine, 5-[4-(methylsulfonyl)phenyl]-6′-(trifluoromethyl)- (CAS Registry Number: 1314883-11-8), Ethanone, 2-amino-142-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-5,6-dihydroimidazo [1,2-a]pyrazin-7(8H)-yl]-(CAS Registry Number 1261109-90-3).

13. A process for the preparation of an aminopyrazine derivative according to Formula (I) comprising the step of reacting an intermediate of Formula (5) in presence of lithium hydroxide monohydrate as follows:

wherein X is CH or N.

14. An intermediate of Formula (5)

wherein X is CH.

15. An intermediate of Formula (5)

wherein X is N.

16. A method of preventing and/or treating malaria in a patient, wherein the said method comprises administering an aminopyrazine derivative according to claim 1 , or a pharmaceutically active derivative thereof in a patient in need thereof.

17. A method for inactivating parasitic infection in a cell comprising the step of contacting the cell with an effective amount of at least one compound according to claim 1 , or a pharmaceutically active derivative thereof.

Assignees

• Medicines For Malaria Venture Mmv
• Univ Cape Town

Inventors

• Waterson David
• Witty Michael John
• Chibale Kelly
• STREET Leslie
• Gonzalez Cabrera Diego
• Paquet Tanya

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D241/20 Primary

  Nitrogen atoms (nitro radicals C07D241/16) · CPC title

• A61K31/4965

  Non-condensed pyrazines · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title