Anti-malarial agents

Patent metadata

Field	Value
Publication number	US-12509439-B2
Application number	US-202117917593-A
Country	US
Kind code	B2
Filing date	Apr 8, 2021
Priority date	Apr 9, 2020
Publication date	Dec 30, 2025
Grant date	Dec 30, 2025

Abstract

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

First claim

The invention claimed is:

1 . A compound according to Formula (I):

wherein X is selected from N and CH; when X is CH: R is selected from —CF 3 , —CHF 2 , —O-cyclopropyl, —O-isopropyl, —OCHF 2 , —CN, —OCH 2 CF 3 and —NH(C═O)CH 3 ; and when X is N: R is —CF 3 ; or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active form, or pharmaceutically active derivative thereof.

2 . The compound according to claim 1 , wherein X is CH.

3 . The compound according to claim 1 , wherein X is N.

4 . The compound according to claim 1 , wherein R is —CF 3 .

5 . The compound according to claim 1 , wherein R is O-cyclopropyl.

6 . The compound according to claim 1 , wherein R is —O-isopropyl.

7 . The compound according to claim 1 , wherein R is —OCHF 2 .

8 . The compound according to claim 1 , wherein R is —CN.

9 . The compound according to claim 1 , wherein R is —OCH 2 CF 3 .

10 . The compound according to claim 1 , wherein R is —NH(C═O)CH 3 .

11 . The compound according to claim 1 , said compound being selected from the group consisting of:
N-(3-cyano-4-fluorophenyl)-1-oxo-2-(2,2,2-trifluoroethyl)-3-(6-(trifluoromethyl) pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; N-(3-cyano-4-fluorophenyl)-3-(6-(difluoromethyl) pyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; N-(3-cyano-4-fluorophenyl)-3-(6-cyclo propoxypyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; N-(3-cyano-4-fluorophenyl)-3-(6-isopropoxypyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; (3-cyano-4-fluorophenyl)-3-(6-(difluoromethoxy) pyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; N-(3-cyano-4-fluorophenyl)-3-(6-cyanopyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; N-(3-cyano-4-fluorophenyl)-1-oxo-3-(6-(2,2,2-trifluoroethoxy) pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; 3-(6-acetamidopyridin-3-yl)-N-(3-cyano-4-fluorophenyl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; and N-(3-cyano-4-fluorophenyl)-1-oxo-2-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl) pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and a pharmaceutically acceptable salt, hydrate, solvate, tautomer, polymorph, racemic mixture, optically active form, or pharmaceutically active derivative thereof.

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

13 . The pharmaceutical composition according to claim 12 , said composition further comprising an antimalarial co-agent.

14 . The pharmaceutical composition according to claim 13 , wherein the co-agent is selected from artemisinin, arthemether, artesunate, dihydroartemisinin, chloroquine, hydroxychloroquine, quinine, quinidine, mefloquine, amodiaquine, a combination of atovaquone and proguanil, clindamycin, doxycycline, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, primaquine, quinacrine, 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)-] (Cipargamin, KAE609, CAS Registry Number: 1193314-23-6), 2-(1,1-difluoroethyl)-5-methyl-N-[4-(pentafluoro-λ 6 -sulfanyl) phenyl]-[1,2,4]triazolo [1,5-a]pyrimidin-7-amine (DSM265, CAS Registry Number: 1282041-94-4), Morpholine, 4-[2-(4-cis-dispiro [cyclohexane-1,3′-[1,2,4]trioxolane-5′,2″-tricyclo [3.3.1.13,7]decan]-4-ylphenoxy) ethyl]-] (Artefenomel, OZ439, CAS Registry Number: 1029939-86-3), 4-Quinolinecarboxamide, 6-fluoro-2-[4-(4-morpholinylmethyl) phenyl]-N-[2-(1-pyrrolidinyl) ethyl]-(DDD107498, CAS Registry Number: 1469439-69-7), Ethanone, 2-amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl) amino]-5,6-dihydro-8,8-dimethylimidazo [1,2-a]pyrazin-7 (8H)-yl]-(Ganaplacide, KAF-156, CAS Registry Number 1261113-96-5), 5-[4-(Methylsulfonyl) phenyl]-6′-(trifluoromethyl) [3,3′-bipyridin]-2-amine (MMV390048, CAS Registry Number: 1314883-11-8), 4(1H)-Quinolinone, and 6-chloro-7-methoxy-2-methyl-3-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-(ELQ-300, CAS Registry Number: 1354745-52-0).

15 . A method for the stereoselective preparation of the enantiomers of a compound of Formula (I) as set forth in claim 1 , said method comprising a step of separation of the enantiomers of Formula (III) by stereoselective salt recrystallization with 1-2 equivalents of a chirally pure amine and transforming the specific enantiomers of Formula (III) into the corresponding enantiomer of Formula (I), in presence of an optionally substituted phenylamine

16 . A method for treating malaria in a subject, wherein said method comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically active derivative thereof in a subject in need thereof.

17 . An intermediate of Formula (III)

wherein X is selected from N and CH; when X is CH: R is selected from —CF 3 , —CHF 2 , —O-cyclopropyl, —O-isopropyl, —OCHF 2 , —CN, —OCH 2 CF 3 , and —NH(C═O)CH 3 ; and when X is N: R is —CF 3 .

18 . The intermediate according to claim 17 , said intermediate being selected from the group consisting of:
3-(6-cyclopropoxypyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (III-1); 3-(6-methoxypyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (III-2); 1-oxo-2-(2,2,2-trifluoroethyl)-3-(6-(trifluoromethyl) pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (III-3); 1-oxo-3-(6-(2,2,2-trifluoroethoxy) pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (III-4); 3-(6-acetamidopyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (III-5); 3-(6-cyanopyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (III-6); 3-(6-(difluoromethoxy) pyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (III-7); 3-(6-(difluoromethyl) pyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (III-8); and 1-oxo-2-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl) pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (III-9).

19 . An intermediate of Formula (IV-2)

(IV-2), N-(3-cyano-4-fluorophenyl)-3-(6-methoxypyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide or an intermediate of Formula (V-2)

(V-2), N-(3-cyano-4-fluorophenyl)-3-(6-hydroxypyridin-3-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.

20 . A method of preparation of the stereoselective preparation of an intermediate of Formula (III), said metho

Assignees

• Univ Kentucky Res Found
• Medicines For Malaria Venture Mmv

Inventors

• Guy Rodney Kiplin
• Hammill Jared T
• Floyd David
• Burrows Jeremy
• Brand Stephen

Classifications

• A61K45/06

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

• A61P33/06

  Antimalarials · CPC title

• 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

• C07D403/04

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

• C07D401/04 Primary

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