Pyrimidinone derivatives as antimalarial agents

Patent metadata

Field	Value
Publication number	US-9321790-B2
Application number	US-201314409869-A
Country	US
Kind code	B2
Filing date	Jun 21, 2013
Priority date	Jun 22, 2012
Publication date	Apr 26, 2016
Grant date	Apr 26, 2016

Abstract

The invention relates to novel pyrimidinone-based heterocyclic compounds which are parasite growth inhibitors, having the general formula (I) in which Y is a morpholine chosen from three bridged morpholines, L is a bond or a linker, n=0 or 1 and R 2 is a methyl group when n=0 and a hydrogen atom when n=1. Process for the preparation thereof and therapeutic use thereof.

First claim

The invention claimed is:

1. A compound corresponding to formula (I):

wherein
n is 0 or 1;
Y is a bridged morpholine chosen from

L is a linker —CH 2 —CO— such that the carbonyl function is attached to the substituent R 1 , or a (C 1 -C 2 )alkyl, said alkyl being optionally substituted with one or more substituents chosen from (C 1 -C 3 )alkyl and hydroxyl;
R 1 is
linear, branched, cyclic or partially cyclic (C 1 -C 5 )alkyl, optionally substituted with one or more substituents chosen from hydroxyl, aryl and trifluoromethyl,
(C 3 -C 6 )cycloalkyl, optionally substituted with hydroxyl,
aryl, optionally substituted with one or more substituents chosen from halogen, hydroxyl, cyano, —NH 2 , —NH—CO—NH—(C 1 -C 4 )alkyl, morpholine, —SO 2 —(C 1 -C 5 )alkyl and (C 1 -C 5 )alkoxy, said alkoxy being optionally substituted with one or more substituents chosen from:
halogen,
hydroxyl or (C 1 -C 5 )alkoxy,
—COR 3 , in which R 3 is heterocycloalkyl or hydroxyl,
—CONR 4 R 4′ ,
—NR 4 R 4′ , heterocycloalkyl comprising one or two heteroelements chosen from nitrogen and oxygen, and
heteroaryl optionally substituted with one or more substituents chosen from halogen, (C 1 -C 3 )alkyl, hydroxyl and —NH 2 ;

heteroaryl, comprising one or more heteroatoms chosen from nitrogen, sulfur and oxygen, optionally substituted with one or more substituents chosen from:
halogen,
(C 1 -C 3 )alkyl, optionally substituted with one or more halogen atoms,
(C 1 -C 5 )alkoxy, optionally substituted with one or more substituents chosen from halogen, (C 3 -C 5 )cycloalkyl, and heteroaryl optionally substituted with one or more substituents chosen from halogen, (C 1 -C 3 )alkyl, hydroxyl and —NH 2 , and
—NR 5 R 5′ , wherein R 5 and R 5′ are independently chosen from hydrogen, —CO 2 —(C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl and linear or branched (C 1 -C 3 )alkyl, said alkyl group being optionally substituted with one or more hydroxyl,

pyridine bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a nitrogen atom and an oxygen atom,
heterocycloalkyl comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from formyl, acetyl and a —CO 2 —(C 1 -C 4 )alkyl, or —NR 6 R 6′ , wherein R 6 is (C 1 -C 5 )alkyl and R 6′ is (C 1 -C 5 )alkoxy,

R 2 is hydrogen when n is 1, and methyl when n is 0; and
R 4 and R 4′ are independently hydrogen or (C 1 -C 3 )alkyl;

in the form of the base or of an addition salt with an acid or with a base.

2. The compound of formula (I) as claimed in claim 1 , wherein
n is 0 or 1;
Y is bridged morpholine chosen from

L is a linker —CH 2 —CO— such that the carbonyl function is attached to the substituent R 1 , or a (C 1 -C 2 )alkyl, optionally substituted with one or more substituents chosen from (C 1 -C 3 )alkyl and hydroxyl;
R 1 is:
linear or branched (C 1 -C 5 )alkyl, optionally substituted with one or more substituents chosen from hydroxyl and aryl,
(C 3 -C 6 )cycloalkyl,
aryl, optionally substituted with one or more substituents chosen from halogen, hydroxyl, cyano, —NH 2 , —NH—CO—NH—(C 1 -C 4 )alkyl, morpholine, —SO 2 —(C 1 -C 5 )alkyl and (C 1 -C 5 )alkoxy, said alkoxy being optionally substituted with one or more substituents chosen from:
halogen,
hydroxyl or (C 1 -C 5 )alkoxy,
—COR 3 , wherein R 3 is heterocycloalkyl or hydroxyl,
—CONR 4 R 4′ ,
—NR 4 R 4′ , heterocycloalkyl comprising one or two heteroelements chosen from nitrogen and oxygen, and
heteroaryl optionally substituted with one or more substituents chosen from halogen, (C 1 -C 3 )alkyl, hydroxyl and —NH 2 ;

heteroaryl, comprising one or more heteroatoms chosen from nitrogen, sulfur and oxygen, optionally substituted with one or more substituents chosen from:
halogen,
(C 1 -C 3 )alkyl, optionally substituted with one or more halogen,
(C 1 -C 5 )alkoxy, optionally substituted with one or more substituents chosen from halogen, (C 3 -C 5 )cycloalkyl, and heteroaryl optionally substituted with one or more substituents chosen from halogen, (C 1 -C 3 )alkyl, hydroxyl and —NH 2 , and
—NR 5 R 5′ , wherein R 5 and R 5′ are independently chosen from hydrogen, —CO 2 —(C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl and linear or branched (C 1 -C 3 )alkyl, said alkyl group being optionally substituted with one or more hydroxyl,

pyridine bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a nitrogen atom and an oxygen atom,
heterocycloalkyl comprising one or more heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen atom being optionally substituted with a substituent chosen from formyl and acetyl, or
—NR 6 R 6′ , wherein R 6 is (C 1 -C 5 )alkyl and R 6′ is (C 1 -C 5 )alkoxy,

R 2 is hydrogen when n is 1, and methyl when n is 0; and
R 4 and R 4′ are independently hydrogen or (C 1 -C 3 )alkyl;

in the form of the base or of an addition salt with an acid or with a base.

3. The compound of formula (I) as claimed in claim 1 , wherein
Y is bridged morpholine (a)

in the form of the base or of an addition salt with an acid or with a base.

4. The compound of formula (I) as claimed in claim 1 , wherein
n is 0 or 1;
Y is bridged morpholine (a)

L is a linker —CH 2 —CO— such that the carbonyl function is attached to the substituent R 1 , or (C 1 -C 2 )alkyl,
wherein the alkyl is optionally substituted with one or more (C 1 -C 3 )alkyl;

R 1 is
linear, branched, cyclic or partially cyclic (C 1 -C 5 )alkyl, optionally substituted with one or more substituents chosen from hydroxyl, aryl, trifluoromethyl and (C 3 -C 6 )cycloalkyl,
(C 3 -C 6 )cycloalkyl, optionally substituted with hydroxyl,
aryl, optionally substituted with one or more substituents chosen from halogen, hydroxyl, —NH 2 , —NH—CO—NH—(C 1 -C 4 )alkyl, morpholine, —SO 2 —(C 1 -C 5 )alkyl and (C 1 -C 5 )alkoxy, said alkoxy being optionally substituted with one or more substituents chosen from:
halogen,
hydroxyl or (C 1 -C 5 )alkoxy,
—COR 3 , wherein R 3 is heterocycloalkyl or hydroxyl,
heterocycloalkyl comprising one or two heteroelements chosen from nitrogen and oxygen, and
heteroaryl optionally substituted with one or more substituents chosen from halogen, (C 1 -C 3 )alkyl, hydroxyl and —NH 2 ;

heteroaryl, comprising one or more heteroatoms chosen from nitrogen, sulfur and oxygen, optionally substituted with one or more substituents chosen from:
halogen,
(C 1 -C 3 )alkyl optionally substituted with one or more halogen,
(C 1 -C 5 )alkoxy group, optionally substituted with one or more substituents chosen from halogen, (C 3 -C 5 )cycloalkyl, heteroaryl optionally substituted with one or more substituents chosen from halogen, (C 1 -C 3 )alkyl, hydroxyl and —NH 2 , and
—NR 5 R 5′ , wherein R 5 and R 5′ are independently chosen from hydrogen, —CO 2 —(C 1 -C 3 )alkyl, (C 3 -C 5 )cycloalkyl and linear or branched (C 1 -C 3 )alkyl, said alkyl group being optionally substituted with one or more hydroxyl,

pyridine bearing two linked adjacent groups forming, together with the two carbons that bear them, a heterocycle comprising a

Assignees

• Sanofi Sa

Inventors

• El-Ahmad Youssef
• Filoche-Romme Bruno
• Ganzhorm Axel
• Marciniak Gilbert
• Muzet Nicolas
• Ronan Baptiste
• Vivet Bertrand
• Zerr Véronique

Classifications

• A61P33/02

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

• A61P33/00

  Antiparasitic agents · CPC title

• A61P33/12

  Schistosomicides · CPC title

• A61P33/06

  Antimalarials · CPC title

• C09D11/30 Primary

  Inkjet printing inks · CPC title