WO2014111666A1

WO2014111666A1 - Thieno[3,2-d]pyrimidin-4(3h)-one derivatives and the preparation and pharmaceutical uses thereof

Info

Publication number: WO2014111666A1
Application number: PCT/FR2014/050094
Authority: WO
Inventors: Pierre VERHAEGHE; Anita COHEN; Sylvain Rault; Aurélien LESNARD; Jean-Charles Lancelot; Peggy Suzanne; Nadine AZAS
Original assignee: Universite D'aix-Marseille; Centre National De La Recherche Scientifique; Universite De Caen Basse-Normandie
Priority date: 2013-01-18
Filing date: 2014-01-17
Publication date: 2014-07-24
Also published as: FR3001220B1; FR3001220A1

Abstract

The present invention relates to thieno[3,2-d]pyrimidin-4(3H)-one derivatives, to the preparation method thereof, to the pharmaceutical compositions containing said derivatives, as well as to the therapeutic use of same, particularly as compounds having antiplasmodial activity, with a view to using same as drugs for treating malaria.

Description

Derivatives of thieno [3,2-c /] pyrinidin-4 (3 / - /) - one, their preparation

and Therapeutic Uses FIELD OF THE INVENTION

The present invention relates to thieno [3,2-c /] pyrimidin-4 (3H) -one derivatives, process for their preparation, pharmaceutical compositions containing them and their therapeutic use, in particular as antiplasmodial activity for application as medicaments for the treatment of malaria.

DESCRIPTION OF THE CONTEXT OF THE INVENTION

Malaria, also called malaria, is a parasitosis caused by a protozoan of the genus Plasmodium and transmitted by a female mosquito mosquito of the genus Anopheles during its blood meal. Anopheles female, previously contaminated by sting of a subject malarious, injects to the host (animal or man), during his blood meal, the infesting forms of the parasite contained in his salivary glands. After a few minutes at the injection site, the parasitic parasitic forms pass through the blood capillaries and then rapidly gain the hepatocytes for the first phase of the cycle. Subsequently, the parasites are released into the bloodstream, colonize the red blood cells and destroy them. Many warm-blooded animal species are parasitized by Plasmodiidae, which are subservient to them; Man can not be parasitized by Plasmodium animals, with the exception of P. knowlesi. Of the one hundred and twenty-three species of the genus Plasmodium listed, only four are specifically human: P. falciparum responsible for a large majority of deaths, and three others that cause so-called benign forms of malaria that are not usually fatal: P. vivax, P. ovale, and P. malariae. P. knowlesi that was thought until recently specific to simian species is now to be included among Plasmodium also affecting humans.

The discovery of antimalarial products dates back to ancient times, since Chinese Artemisiaannua was already used in Chinese medicine as an antipyretic. Subsequently, around 1640, cinchona bark was used in Europe for the treatment of intermittent fevers. The active alkaloid, quinine, was isolated only in 1820 by two French chemists, Caventou and Pelletier. The history of synthetic antimalarials begins during the First World War. Among them, chloroquine, whose synthesis was carried out in 1934, facilitated the control of malaria for many years, thanks to its exceptional properties. From the 1960s, the World Health Organization (WHO) initiated the global malaria eradication program with, inter alia, vector control focused on the use of insecticides, as well as the establishment of a prophylaxis and inexpensive and low-toxicity chloroquine chemotherapy. This massive use led to an adaptation of the vector and the parasite: anopheles resistant to insecticides multiplied, while the plasmodial populations became more and more resistant to chloroquine. Since then, chloroquine resistance has spread to all malaria endemic areas, and chemoresistance to other antimalarials has gradually developed (reference 1). Currently, the treatment of malaria alone constitutes a real public health problem, because of the small number of available molecules and the ever increasing multidrug resistance of parasites. For example, most of the countries where P. falciparum is endemic have gradually updated their treatment policies, from chloroquine and sulfadoxine-pyrimethamine, which are unsuccessful, to currently available artemisinin-based combination therapies (ACTs). recommended by WHO. Nevertheless, possible cases of failure of ACT treatment have been identified in four countries in the Greater Mekong Subregion (Cambodia, Myanmar, Thailand, and Vietnam). Despite the high clinical and parasitological efficacy of ACTs to more than 90% worldwide, high rates of failure have been noted in the case of several ACTs, in particular one of the most recent, the dihydroartemisinin-piperaquine combination. , in the Pailin region (Cambodia) (references 2 to 4). In early 201 1, an action plan was launched by WHO to prevent artemisinin resistance (Global plan for artemisininresistancecontainment). However, this type of action must necessarily be accompanied by intensive research in biology and chemistry, particularly to better understand the potential therapeutic targets on the one hand, and to design new drug candidates on the other hand. To limit the risk of developing too fast chemoresistance, these compounds should ideally exert their antiplasmodial action by original mechanisms and complementary to those borrowed by the molecules already used in therapy (references 5 and 6). It should be noted that no new class of antimalarial compounds has been marketed since atovaquone in 1996.

There is therefore a constant need to develop new compounds with increased antiplasmodial properties. For this, these compounds of original chemical structure must have minimal toxicity on human cells and maximum activity on parasites of the genus Plasmodium, which corresponds to a high selectivity index.

The object of the present invention is thus to provide synthetic compounds with in vitro antiplasmodial activity demonstrated on a multi-resistant strain of P. falciparum, as compared to chloroquine and doxycycline used as antimalarial reference substances. In addition, these compounds do not show cytotoxic activity in vitro, compared to doxorubicin used as a reference cytotoxic substance. In vivo antimalarial activity was also evaluated.

In this regard, the present invention provides novel 2-aminothieno [3,2-c /] pyrimidin-4 (3 / - /) - one derivatives and their therapeutic use.

The present invention therefore relates to compounds of general formula

(I):

(I)

in which :

R 1, R 1 and R 2 represent, independently of each other, a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, an OR 'type alkyloxy, where R' represents a C 1 -C 6 alkyl group; C6, R3 and R4 independently of one another represent a hydrogen atom, a C1-C6 alkyl group, a C3-C8 cycloalkyl group,

alternatively, R3 and R4 together with the nitrogen atom to which they are attached may form a heterocycle, optionally substituted by at least one halogen atom, a C1-C6 alkyl group, an aryl, arylalkyl, alkylaryl group, or an alkyloxy group of the type OR ", in which R" represents a C1-C6 alkyl group, their stereoisomers (diastereoisomers, enantiomers), pure or as a mixture, racemic mixtures, geometric isomers, salts, or their mixtures.

The compounds of general formula (I) may comprise one or more asymmetric carbon atoms for example. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, are therefore part of the invention. The enantiomers and diastereoisomers may be prepared by adaptation or application of purification and / or synthesis methods described in the literature and within the scope of the skilled person.

The salts of the compounds of formula (I) can be prepared with pharmaceutically acceptable acids. There may be mentioned, for example, addition salts with mineral acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, or organic such as propionate, acetate, oxalate, succinate, benzoate, fumarate, maleate or methanesulphonate.

The present invention also relates to a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, at least one compound of general formula (I).

The present invention also relates to processes for the preparation of compounds of formula (I). In particular, an object of the invention relates to a method for preparing the compounds according to the invention, which comprises the following steps:

at. condensation and cyclization of a methyl 3-amino-5-arylthiophene-2-carboxylate derivative with ethoxycarbonyl isothiocyanate, preferably this reaction is carried out at reflux; b. the reaction of the compound thus formed with an alkylamine derivative, preferably in the presence of a catalyst, such as in particular mercuric chloride, preferably a refluxing is then carried out.

Advantageously, the process according to the invention comprises, after step b., The following stages consisting of purification c. for example by filtration, of the derivative of general formula (I) obtained in step b; and D. optionally salifying the compound of general formula (I) obtained in step c. by an appropriate mineral or organic acid. The methyl 3-amino-5-arylthiophene-2-carboxylate or derivatives thereof used in step a) are commercially available, in particular by Sigma-Aldrich, Interchim, VWR, Aurora Fine Chemicals, Fluorochem or Ryan. Scientific, commercially unavailable derivatives can be prepared from those commercially available by modifying them according to methods well known to those skilled in the art.

In the context of the present invention, the term "alkyl" denotes a saturated hydrocarbon radical, linear or branched, having 1 to 8 or 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, n-hexyl, n-heptyl and n-octyl may be mentioned. -heylpropyl, 1-methylhexyl or 1-methylheptyl.

The term "cycloalkyl" refers to a cyclic saturated hydrocarbon radical having 3 to 8 carbon atoms. Mention may in particular be made of cyclohexyl, cyclopentyl, cyclopropyl, cyclobutyl, cycloheptyl, norbornyl or adamantyl.

By the term "halogen" is meant the chlorine, bromine, fluorine and iodine atoms.

By the term "heterocycle" denotes a non-aromatic hydrocarbon radical containing one or more heteroatoms such as nitrogen, sulfur and oxygen, substituted or unsubstituted, preferably having 4 to 14 carbon atoms. As examples of heterocycle, there may be mentioned in particular pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-1-yl. The term "aryl" refers to an aromatic hydrocarbon radical preferably having 6 to 14 carbon atoms. Preferably, the aryl radicals according to the present invention are chosen from phenyl, naphthyl (for example 1-naphthyl or 2-naphthyl), anthryl or fluorenyl. Phenyl or naphthyl groups are particularly preferred.

The term "arylalkyl" denotes an aryl group as defined above attached to the remainder of the molecule by an alkyl group as defined above, such as the benzyl group. An arylalkyl group may itself be substituted by at least one halogen atom or an optionally halogenated alkyl radical, such as a perhaloalkyl radical, in particular perfluoroalkyl, such as -CF3.

The term "alkylaryl" denotes an alkyl group as defined above attached to the remainder of the molecule by an aryl group as defined above.

According to one particular embodiment, the compounds of the invention have the general formula (I) in which at least one of the groups R 3 and R 4 is different from the hydrogen atom.

According to a particular embodiment, R 3 represents a hydrogen atom, an alkyl group or Ci-Ce cycloalkyl, C3-C8, and R ₄ represents an alkyl group Ci-cycloalkyl or C3-Ce.

According to an even more particular embodiment, R3 represents a hydrogen atom and R4 is a C1-C6 alkyl group or a C3-C8 cycloalkyl group, preferably R4 is a C1-C6 alkyl group, and more specifically alkyl. C1-C4, such as in particular methyl, ethyl, n-propyl, isopropyl or tert-butyl, more preferably isopropyl or tert-butyl.

A particular aspect of the invention relates to the compounds of general formula (I) in which R, R 1 and R 2 represent, independently of one another, a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group or Ce, a type OR 'alkyloxy, where R' represents a C1-C6 alkyl group, and wherein one, two or all three groups R, R1 and R2 represents (nt) a hydrogen atom.

According to a more particular embodiment, the invention relates to the compounds of general formula (I) in which R 1 and R 2 represent a hydrogen atom and R represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a type OR 'alkyloxy, where R' represents a C 1 -C 6 alkyl group, more particularly R represents a halogen atom; , a C1-C6 alkyl group, an OR 'type alkyloxy, where R' represents an alkyl group

When R, R 1 or R 2 represents a C 1 -C 6 alkyl group, said alkyl group is preferably C 1 -C 4, in particular methyl or ethyl.

When R, R 1 or R 2 represents a group, an OR 6 type alkyloxy, in which R 'preferably represents a C 1 -C 3 alkyl group, in particular methoxy or ethoxy.

According to a particular variant, the compounds of the invention are of general formula (I) in which:

R 1, R 1 and R 2 represent, independently of each other, a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, an OR 'type alkyloxy, where R' represents a C 1 -C 6 alkyl group; -C6, and

R3 and R4 represent, independently of each other, a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group, with preferably at least one of R3 and R4 groups different from the atom; hydrogen.

According to a more particular variant, the invention relates to compounds of general formula (I) in which:

R, R 1, R 2 represent, independently of each other, a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or an OR 'type alkyloxy, in which R' represents a C 1 -C 6 alkyl group; C6, and

R3 represents a hydrogen atom, a C1-C6 alkyl group, a C3-Ce cycloalkyl group,

R4 represents a C1-C6 alkyl group, a cycloalkyl group

When R 3 and R 4 may form together with the nitrogen atom to which they are attached a heterocycle, optionally substituted according to the definition given above, the heterocycle represents in particular the piperazin-1-yl group, optionally substituted by an arylalkyl group. , such as benzyl. The modes and variants of the invention specified above concerning R, R 1, R 2, R 3 and R 4 correspond to particular modes included in the present invention, including in the pharmaceutical compositions containing the compounds of the invention, their methods of preparation, their therapeutic methods and their uses. These modes and variants of the invention can of course be combined with each other.

According to one particular embodiment of the invention, the compounds are illustrated by the compounds indicated below:

I) 2-Amino-6-phenylthieno [3,2-c] pyrimidin-4 (3 / -) - one

2) 2- (4-Benzylpiperazin-1-yl) -6-phenylthieno [3,2-c] pyhmidin-4 (3H) -one

3) 2-Diethylamino-6-phenylthieno [3,2-c] pyrimidin-4 (3 / -) - one

4) 6-phenyl-2-fe-1-butylaminothieno [3,2-c] pyrimidin-4 (3 H) -one

5) 6-phenyl-2-furyl-4-butylaminothieno [3,2-c] pyrimidin-4 (3H) -alone hydrochloride

6) 2-ethylamino-6- (4-methyl-phenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

7) 6- (4-methylphenyl) -2- (n -propylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

8) 2-Isopropylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

9) 2-Isopropylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one fumarate

10) 2- (1-Ethylpropylamino) -6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3 H) -one

I 1) 2-Isobutylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

12) 6- (4-Methylphenyl) -2- (terbutylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

13) 6- (4-Methylphenyl) -2- (terbutylamino) thieno [3,2-c] pyrimidin-4 (3H) -alone hydrochloride

14) 2-n-butylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

15) 2-n-amylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

16) 2-n-hexylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

17) 2-n-heptylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

18) 2-Diethylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

19) 2-Dipropylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3 H) -one

20) 2-dibutylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

21) 6- (4-methylphenyl) -2- (dipentylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

22) 2- (Butyl-ethyl-amino) -6- (4-methylphenyl) thieno [3,2-c] -pyrimidin-4 (3 H) -one

23) 2- (Butyl-methyl-amino) -6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3 H) -one

24) 6- (4-methylphenyl) -2- (1-phenyl-ethylamino) thieno [3,2-c] pyrimidin-4 (3 H) -one 25) 2- (1-methyl-heptylamino) -6- (4-methylphenyl)

26) 6- (3-methylphenyl) -2- (tert-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -on

27) 6- (3-methylphenyl) -2- (tert-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -one hydrochloride

28) 6- (2-Methylphenyl) -2- (tert-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

29) 6- (2-Methylphenyl) -2- (tert-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -one hydrochloride

30) 6- (4-Chlorophenyl) -2- (ethylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

31) 6- (4-Chlorophenyl) -2- (propylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

32) 2-butylamino-6- (4-chlorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

33) 2-ieri-butylamino-6- (4-chlorophenyl) thieno [3,2-c] pyrimidin-4 (3 / -) - one

34) 2-ieri-butylamino-6- (4-chlorophenyl) thieno [3,2-c] pyrimidin-4 (3 / -) - one fumarate

35) 6- (4-Chlorophenyl) -2- (isopropylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

36) 6- (4-Chlorophenyl) -2- (1-phenyl-ethylamino) thieno [3,2-c] pyrimidin-4 (3H) -on 37) 2- (2-chloro-benzylamino) -6- (4-chlorophenyl) thieno [3,2-c /] pyrimidin-4 (3H) -on

38) 6- (4-chlorophenyl) -2- (1-methyl-heptylamino)

39) 6- (4-Chlorophenyl) -2- (diisopropylamino) thieno [3,2-c] pyrimidin-4 (3H) -on

40) 6- (4-Chlorophenyl) -2- (dipropylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

41) 2-ethylamino-6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

42) 6- (4-fluorophenyl) -2-propylaminothieno [3,2-c] pyrimidin-4 (3H) -one

43) 2-Butylamino-6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

44) 6- (4-fluorophenyl) -2-pentylaminothieno [3,2-c] pyrimidin-4 (3H) -one

45) 6- (4-fluorophenyl) -2-hexylaminothieno [3,2-c] pyrimidin-4 (3 / -) - one

46) 6- (4-fluorophenyl) -2-heptylaminothieno [3,2-c] pyrimidin-4 (3H) -one

47) 2-tert-butylamino-6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

48) 2- (2-Chloro-benzylamino) -6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -on

49) 6- (4-fluorophenyl) -2- (1-phenylethylamino) thieno [3,2-c] pyrimidin-4 (3H) 49

50) 6- (4-fluorophenyl) -2- (1-methylheptylam)

51) 6- (4-fluorophenyl) -2- (isopropylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

52) 2- (Butyl-methylamino) -6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -on

53) 2- (Butyl-ethylamino) -6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

54) 2- (1-Ethylpropylamino) -6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -on

55) 6- (4-fluorophenyl) -2-isobutylaminothieno [3,2-c] pyrimidin-4 (3H) -one 56) 2-Diisopropylamino-6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

57) 2-Dipropylamino-6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

58) 2-dibutylamino-6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

59) 6- (4-fluorophenyl) -2-dipentylaminothieno [3,2-c] pyrimidin-4 (3 / -) - one

60) 6- (4-bromophenyl) -2-ethylaminothieno [3,2-c] pyrimidin-4 (3H) -one

61) 6- (4-bromophenyl) -2-propylaminothieno [3,2-c] pyrimidin-4 (3H) -one

62) 6- (4-bromophenyl) -2-isopropylaminothieno [3,2-c] pyrimidin-4 (3H) -one

63) 6- (4-bromophenyl) -2-butylaminothieno [3,2-c] pyrimidin-4 (3H) -one

64) 6- (4-bromophenyl) -2-pentylaminothieno [3,2-c] pyrimidin-4 (3H) -one

65) 6- (4-bromophenyl) -2-hexylaminothieno [3,2-c] pyrimidin-4 (3H) -one

66) 6- (4-bromophenyl) -2-heptylaminothieno [3,2-c] pyrimidin-4 (3H) -one

67) 6- (4-bromophenyl) -2-tert-butylaminothieno [3,2-c] pyrimidin-4 (3H) -one

68) 6- (4-bromophenyl) -2- (1-ethylpropylamine) thieno [3,2-c] pyrimidin-4 (3H) -one

69) 6- (4-bromophenyl) -2- (1-methyl-heptylamino)

70) 6- (4-bromophenyl) -2- (1-phenylethylamino) thieno [3,2-c] pyrimidin-4 (3 H) -one

71) 6- (4-bromophenyl) -2- (2-chloro-benzylamino) thieno [3,2-c] pyrimidin-4 (3H) -on

72) 6- (4-bromophenyl) -2-dipropylamino-thieno [3,2-c] pyrimidin-4 (3H) -one

73) 6- (4-bromophenyl) -2-diisopropylamino-thieno [3,2-c] pyrimidin-4 (3H) -one

74) 6- (4-bromophenyl) -2-dibutylamino-thieno [3,2-c] pyrimidin-4 (3H) -one

75) 6- (4-bromophenyl) -2-dipentylamino-thieno [3,2-c] pyrimidin-4 (3H) -one

76) 6- (4-bromophenyl) -2- (butyl-methyl-amino)

77) 6- (4-bromophenyl) -2- (butyl-ethyl-amino) -thieno [3,2-c] pyrimidin-4 (3H) -one

78) 2-Ethylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

79) 6- (4-Methoxyphenyl) -2-propylamino-thieno [3,2-c] pyrimidin-4 (3 H) -one 80) -2-isopropylamino-6- (4-methoxyphenyl) -thieno [ 3,2-d] pyrimidin-4 (3 / - /) - one

81) 2-butylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

82) 6- (4-methoxyphenyl) -2-pentylamino-thieno [3,2-c] pyrimidin-4 (3H) -one

83) 2-hexylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

84) 2-heptylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3 H) -on-85) 2- (1-ethylpropylamino) -6- (4-methoxyphenyl) ) thieno [3,2-c /] pyrimidin-4 (3H) -on

86) 2-isobutylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

87) 2-tert-butylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

88) 6- (4-methoxyphenyl) -2- (1-phenyl-ethylamino) H 89) 2- (2-Chloro-benzylamino) -6- (4-methoxyphenyl) thieno [3,2-c] pyrimidine

one

90) 6- (4-methoxyphenyl) -2- (1-methyl-heptylamino) -thi

one

91) 2-Dipropylamino-6- (4-methoxyphenyl) -thieno [3,2-c] pyhmidin-4 (3H) -one

92) 2-diisopropylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyhmidin-4 (3H) -one

93) 2-dibutylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyhmidin-4 (3H) -one

94) 2- (3- (Dimethylamino) propylamino) -6- (4-methoxyphenyl) thieno [3,2-c] pyhm 4 (3H) -one

95) 2- (3- (diethylamino) propylamino) -6- (4-methoxyphenyl)

4 (3H) -one

96) 2- (Butyl-methylamino) -6- (4-methoxyphenyl) -thien

97) 2- (Butyl-ethylamino) -6- (4-methoxyphenyl) -thieno [3,2-c] pyhmidin-4 (3 H) -one 98) 6- (3,4-dimethoxyphenyl) - 2- (heptan-2-ylamino) -thieno [3,2-c] pyhmidin-4 (3 / -) - one

99) 6- (3,4-dimethoxyphenyl) -2- (1-phenyl-ethylamino) -thieno [3,2-c] pyhmidi one

100) 2- (2-Chloro-benzylamino) -6- (3,4-dimethoxyphenyl) -thieno [3,2-c] pyhmidin-4 (3H) -one.

According to one particular embodiment, the compounds of the invention are chosen from compounds (2) - (100).

According to a more particular embodiment of the invention, the preferred compounds are those which are soluble in a polar organic solvent, in particular DMSO, and / or active in vitro with respect to a multidrug K1 strain of P. falciparum. , with a 50% inhibitory concentration (IC 50) in vitro less than or equal to 10.00 μΜ as compared to chloroquine (IC 50 = 0.50 μ) and doxycycline (IC 50 = 5.00 μ) used as reference substances to antiplasmodial activity (see examples).

These are in particular the compounds below:

2) 2- (4-Benzylpiperazin-1-yl) -6-phenylthieno [3,2-c] pyrimidin-4 (3 / -) - one

4) 6-phenyl-2-fe-1-butylaminothieno [3,2-c] pyhmidin-4 (3 / -) - one

5) 6-phenyl-2-furyl-4-butylaminothieno [3,2-c] pyrimidin-4 (3H) -alone hydrochloride 7) 6- (4-methylphenyl) -2- (n-propylamino)

8) 2-isopropylamino-6- (4-methylphenyl) thieno

9) 2-Isopropylamino-6- (4-methylphenyl) thieno fumarate

10) 2- (1-Ethylpropylamino) -6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one 1) 2-isobutylamino-6- (4-methylphenyl) thieno [ 3,2-c /] pyrimidin-4 (3 / - /) - one

12) 6- (4-methylphenyl) -2- (ieri-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

13) 6- (4-Methylphenyl) -2- (ieri-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -one hydrochloride

14) 2-n-butylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

15) 2-n-amylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

16) 2-n-hexylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

17) 2-n-heptylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

24) 6- (4-methylphenyl) -2- (1-phenyl-ethylamino) thieno [3,2-c] pyrimidin-4 (3 H) -one

25) 2- (1-methyl-heptylamino) -6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3 H) -one 26) 6- (3-methylphenyl) -2 - (fe / Î-butylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

27) 6- (3-Methylphenyl) -2- (ieri-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -alone hydrochloride

28) 6- (2-Methylphenyl) -2- (ieri-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

29) 6- (2-Methylphenyl) -2- (ieri-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -alone hydrochloride

30) 6- (4-Chlorophenyl) -2- (ethylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

31) 6- (4-Chlorophenyl) -2- (propylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

32) 2-butylamino-6- (4-chlorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

36) 6- (4-Chlorophenyl) -2- (1-phenyl-ethylamino) thieno [3,2-c] pyrimidin-4 (3 H) -one

37) 2- (2-Chloro-benzylamino) -6- (4-chlorophenyl) thieno [3,2-c] -pyrimidin-4 (3 H) -one 43) 2-butylamino-6- (4- fluorophenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

44) 6- (4-fluorophenyl) -2-pentylaminothieno [3,2-c] pyrimidin-4 (3H) -one

45) 6- (4-fluorophenyl) -2-hexylaminothieno [3,2-c] pyrimidin-4 (3 / -) - one

47) 2-tert-butylamino-6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

49) 6- (4-fluorophenyl) -2- (1-phenylethylamino) thieno [3,2-c] pyrimidin-4 (3 H) -one 51) 6- (4-fluorophenyl) -2- (isopropylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

52) 2- (Butyl-methylamino) -6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

54) 2- (1-Ethylpropylamino) -6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

55) 6- (4-fluorophenyl) -2-isobutylaminothieno [3,2-c] pyrimidin-4 (3H) -one

56) 2-Diisopropylamino-6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

61) 6- (4-bromophenyl) -2-propylaminothieno [3,2-c] pyrimidin-4 (3H) -one

62) 6- (4-bromophenyl) -2-isopropylaminothieno [3,2-c] pyrimidin-4 (3H) -one

63) 6- (4-bromophenyl) -2-butylaminothieno [3,2-c] pyrimidin-4 (3H) -one

65) 6- (4-bromophenyl) -2-hexylaminothieno [3,2-c] pyrimidin-4 (3H) -one

67) 6- (4-bromophenyl) -2-tert-butylaminothieno [3,2-c] pyrimidin-4 (3H) -one

69) 6- (4-bromophenyl) -2- (1-methyl-heptylamino)

71) 6- (4-bromophenyl) -2- (2-chloro-benzylamino) thieno [3,2-c] pyrimidin-4 (3H) -on 73) 6- (4-bromophenyl) -2-diisopropylamino thieno [3,2-c /] pyrimidin-4 (3 / - /) - one 79) 6- (4-methoxyphenyl) -2-propylamino-thieno [3,2-c] pyrimidin-4 (3 / - /) - one

80) 2-Isopropylamino-6- (4-methoxyphenyl) -thieno [3,2-d] pyrimidin-4 (3 / -) - one

81) 2-butylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

82) 6- (4-methoxyphenyl) -2-pentylamino-thieno [3,2-c] pyrimidin-4 (3H) -one

83) 2-hexylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

84) 2-heptylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

85) 2- (1-ethylpropylamino) -6- (4-methoxyphenyl)

86) 2-isobutylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

87) 2-tert-butylamino-6- (4-methoxyphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

89) 2- (2-Chloro-benzylamino) -6- (4-methoxyphenyl) -thieno [3,2-c] pyrimidin-4 (3H) -one

90) 6- (4-methoxyphenyl) -2- (1-methyl-heptylam)

one

94) 2- (3- (Dimethylamino) propylamino) -6- (4-methoxyphenyl) thieno [3,2-c] pyri 4 (3H) -one

95) 2- (3- (Diethylamino) propylamino) -6- (4-methoxyphenyl) thieno [3,2-c] pyrim (3H) -one

96) 2- (Butyl-methylamino) -6- (4-methoxyphosphine)

97) 2- (Butyl-ethylamino) -6- (4-methoxyphenyl) -thieno [3,2-c] pyrimidin-4 (3H) -on 100) 2- (2-Chloro-benzylamino) -6- (3,4-dimethoxyphenyl) -thieno [3,2-c] pyrim (3H) -one.

According to a particular aspect of the invention, the compounds of the invention are chosen from compounds 4, 8, 12, 33, 35, 51, 62, and 80 (cited above), and their salts, such as in particular compounds 5,9,13, or 34.

The subject of the present invention is also the compounds as described above, as medicaments.

The present invention also relates to a pharmaceutical composition comprising at least one compound as described above, in a pharmaceutically acceptable carrier.

It is more specifically a compound according to the invention or a pharmaceutical composition or drug containing it for use in the treatment of malaria.

As stated above, malaria is an infectious disease caused by a parasite of the genus Plasmodium. More specifically, the parasites concerned include P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi. Malaria is characterized in particular by simple and / or pernicious accesses. Simple access is more specifically characterized by the succession of fever over 40 ° C, chills, followed by a drop in temperature accompanied by abundant sweat and a sensation of cold. It can be suspected when returning from an endemic area. These accesses can be repeated every 48 or 72 hours (rhythmic access) for months or even years for certain species. In the case of P. falciparum infection, complications of fatal prognosis (pernicious access) can occur, in the form of acute neurological manifestations grouped under the term of cerebral malaria, often associated with multivisceral failures (cerebral malaria). Without effective treatment, cerebral malaria is fatal in a few days.

According to a particular embodiment of the invention, the subject of the invention is a compound as defined above, a pharmaceutical composition or medicament containing it for use in the treatment of malaria accessions (simple and / or pernicious). The invention also resides in a method of treating malaria in a subject (animal or human) comprising administering to the subject requiring such treatment a therapeutically effective amount of at least one compound of formula (I) .

The term "treatment" (or "treating") means curative, symptomatic or preventative treatment. The compounds of the present invention can thus be used in subjects (such as mammals, in particular animals or humans) suffering from malaria. The compounds of the present invention may also be used prophylactically, in subjects susceptible to malaria, to prevent infection in the event of parasite entry into the body; this may in particular prevent parasitic multiplication in humans (and in particular tourists traveling to countries where malaria is prevalent). Preventive treatment is particularly suitable for children and pregnant women, who have an increased risk of severe malaria. The treatment according to the invention thus makes it possible to prevent malaria, by avoiding parasitic multiplication, to reduce simple or pernicious access, to reduce their intensity or frequency, or to make them disappear, thus improving the condition of the subjects treated.

The pharmaceutical compositions according to the invention advantageously comprise one or more excipients or vehicles, which are pharmaceutically acceptable. For example, saline, physiological, isotonic, buffered, etc., solutions compatible with a pharmaceutical use and known to those skilled in the art may be mentioned. The compositions may contain one or more agents or vehicles selected from dispersants, solubilizers, stabilizers, preservatives, etc. Agents or vehicles that can be used in formulations (liquid and / or injectable and / or solid) include methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, and the like. acacia, liposomes, micelles, etc. The compositions may be formulated as injectable suspensions, gels, oils, tablets, suppositories, powders, capsules, aerosols, etc., possibly by means of galenic forms or devices providing sustained and / or delayed release.

The compounds or compositions according to the invention can be administered in different ways and in different forms. Thus, they can be, for example, administered systemically, orally, parenterally, by inhalation or by injection, for example intravenously, intramuscularly, subcutaneously, transdermally, intraarterially, etc. For injections, the compounds are generally packaged as liquid suspensions, which can be injected by means of syringes or infusions, for example.

It is understood that the rate and / or the dose administered may be adapted by those skilled in the art depending on the subject to be treated and the mode of administration, etc. Administrations may be daily or repeated several times a day. On the other hand, the compositions or treatments according to the invention may furthermore comprise other active agents or active principles, in particular other antimalarial agents. Other aspects of the invention will appear on reading the examples which follow, which should be considered as illustrative and not limiting. The percentages mentioned are expressed by weight, unless otherwise indicated.

EXAMPLES

The in vitro cytotoxic and antiplasmodial properties of the compounds described according to the invention were also evaluated. In order to determine the potential cytotoxicity of the compounds described according to the invention, their antiproliferative activity has been determined on various cell lines, in particular human HepG2 cells (ATCC ref HB-8065) which constitute one of the most widely used cell line for the purpose of pharmaceutical screening because it expresses the liver enzymes responsible for the metabolism of phase I and II. In addition to the revelation If this cytotoxic character is a test molecule, this line can detect the possible formation of toxic metabolites (toxic metabolism). The most active compounds were also tested on CHO cells (ATCC ref CCL-61). Whatever the cell line, the protocol used is that of Mosmann (reference 7) slightly modified. The cells are cultured in microplates and then placed in contact for 24 hours (CHO cells) at 72 hours (HepG2 cells) with different concentrations of the test products, previously dissolved in DMSO. At the exit of the oven, MTT labeling (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) is carried out. Reduced to formazan (purple precipitate) by succinate dehydrogenase mitochondrial present only in living cells, it allows the measurement of absorbance by spectrophotometry at 570 nm. This measurement is carried out 2 h after addition of the MTT, once the cell lysis and the solubilization of the formazan carried out, by addition of DMSO and homogenization of the medium by stirring the plates. The intensity of the violet coloration detected is therefore proportional to the number of living cells present, but also to their metabolic activity. Thus, for each cell line, the cytotoxic concentration 50% (CHO CC50 and HepG2 CC50) is obtained, which corresponds to the concentration of test product which reduces by 50% the viability of the cells relative to a growth control. This concentration is calculated from the dose-response curve modeled mathematically by nonlinear regression. A range of concentrations of doxorubicin, a reference cytotoxic substance, is tested in parallel, as well as a range of DMSO concentrations, in order to demonstrate a possible effect of the solvent on cell growth. The results obtained correspond to the average of three independent experiments carried out each in double test.

To determine the antiplasmodial activity in vitro of the compounds described according to the invention, the compounds were tested against multi-resistant strains of P. falciparum. Two reference plasmodial strains were used, W2 and K1. Strain K1 is a clone of strain W2, they are both resistant to chloroquine, pyrimethamine and proguanil, and are maintained in culture according to the method of Trager and Jensen (reference 8). Parasitaemia is monitored daily by observation of smear cultures thin colored Giemsa. It is maintained between 1 and 6% by dilution with uninfected red blood cells A +. The Sybr Green I method (references 9 and 10) has been used, which makes it possible to selectively mark the parasitic nucleic acids. This method uses fluorimetry to determine parasitaemia after selective labeling of plasmodial DNA. This labeling uses the SYBR Green I reagent, a specific intercalating agent for double-stranded nucleic acids, which makes it fluorophore. The tests are carried out in 96-well microplates and last 48 hours. For each test, four witnesses are prepared:

- A positive control (untreated parasitised red blood cells) provides information on the maximum rate of proliferation of the parasite;

- A negative control (healthy red blood cells) makes it possible to determine the nonspecific fluorescence threshold of healthy red blood cells;

- A solvent control (DMSO) is also included to demonstrate a possible effect of the solvent on parasite growth;

- A linearity control (positive control half diluted with healthy red blood cells) ensures the linearity of the measured fluorescence intensity.

A range of concentrations of chloroquine, a reference substance, is tested in parallel, confirming the level of resistance of the strain. The results are expressed as a 50% inhibitory concentration (IC 50): it is the concentration of test product required to reduce by 50% the parasitaemia of a Plasmodium culture placed in contact with the test product with respect to parasitaemia. of a control culture. The IC50 is calculated from the dose-response curve modeled mathematically by non-linear regression.

Subsequently, for each compound described according to the invention, a selectivity index (IS) is determined, a rapid indicator making it possible to specify the real potential of said compound following a screening operation, relative to its cytotoxic profile. It corresponds to the ratio of its CC50 on its IC50, expressed in the same unit. For example, chloroquine has a 30 μΜ in vitro CC50 on the HepG2 cell line and an in vitro IC50 of 0.50 μΜ against the P. falciparum strain K1, which corresponds to an IS of 60. In the same way, doxycycline has a 20 μΜ in vitro CC50 on the HepG2 cell line and an IC50 in vitro. of 5.00 μΜ against P. falciparum strain K1, which corresponds to an IS of 4.

Furthermore, some compounds have been subjected to an Ames test to evaluate the ability of a substance to induce a reversion in the expression of genes encoding histidine on different strains of Salmonella typhimurium (TA97a and TA100) made auxotrophs for histidine by mutation. A rat liver extract (called S9 Mix) can be added to simulate the effect of metabolism. The strain TA97a makes it possible to detect the mutations by shift of the reading frame (addition of base pairs), while the strain TA100 makes it possible to highlight the mutations by substitution of base pairs. The mutagenic potential of a product is measured by the enumeration of the prototrophic revertants it induces. The protocol we used for this test is a modified version of the Ames test developed by De Méo et al. (reference 1 1). It is a micromethode comprising a pre-incubation in a liquid medium.

Finally, the antimalarial activity in vivo was evaluated in mice infected with Plasmodium berghei according to a technique initially described by Peters (reference 12). According to the protocol used, batches of five mice are infected and then treated, two hours later, intraperitoneally, with a dose of product to be tested. The product is administered once a day, for four consecutive days. A batch of five mice treated with the solvent of the test compound constitutes the control group of the infection. On the fifth day, the parasitaemia of the mice of each batch is evaluated by microscopy. The percentage of decrease in parasitaemia of the product to be tested is then determined relative to the control group. General one-pot synthesis method for 6-aryl-2-aminothieno [3,2-d] pyrimidin-4-one and associated biological properties

0.01 mol of methyl 3-amino-5-arylthiophene-2-carboxylate in the presence of 0.01 mol of ethoxycarbonyl isothiocyanate are stirred for 2 hours at room temperature in 70 ml of dimethylformamide. The solution is then cooled between 0 ° C and + 5 ° C. 3 equivalents of an alkylamine derivative and then 0.01 mol of mercuric chloride are then added. The reaction is stirred at room temperature for 16 hours. The black solution (HgS) formed is refluxed for 1 hour. After cooling, the solution is filtered on celite, then on filter paper. After evaporation, the residue is taken up in acetonitrile, stirred, and filtered on sintered. The powder obtained is recrystallized from acetonitrile. Example 1: 6-Phenyl-2-ironmethylaminothieno [3,2-c (pyrimidin-4 (3H) -one)

Compound 4 of Example 1 is prepared according to the general method of synthesis described above, considering the parameters below.

Methyl 3-Amino-5- (phenyl) -thiophene-2-carboxylate: 2.33 g (0.01 mol) Ethoxycarbonyl isothiocyanate: 1.32 g (1.18 mL)

Diethylamine: 2.19 g (3.10 mL)

Mercuric chloride: 2.715 g (0.01 mol)

The expected compound is obtained with a yield of 62% and is in the form of a beige solid.

It has the following physicochemical characteristics:

Mp> 260 ° C

¹ H NMR (DMSO-d6): 1.25 (s, 9H, (CH ₃ ) ₃ ), 6.66 (s, 1H, NHC (CH ₃ ) ₃ ), 7.38, 7.46, 7. 49 (m, 4H, H-aryl, H-thiophene), 7.77, 7.79 (d, 2H, H-aryl), 8.30 (s, 1H, NH).

The compound thus synthesized has a cytotoxic concentration 50% (CC50) in vitro of 9.80 μΜ on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μΜ) used as a reference substance with cytotoxic activity.

The compound thus synthesized exhibits a 50% inhibitory concentration (IC 50) in vitro of 1.00 μΜ against a multidrug resistant strain K1 of P. falciparum, compared to chloroquine (IC 50 = 0.50 μM) and doxycycline (IC50 = 5.00 μΜ) used as reference substances with antiplasmodial activity.

The compound thus synthesized thus has a selectivity index (IS) of 9.80 compared with chloroquine (IS = 60) and doxycycline (IS = 4). Example 2: 6-Phenyl-2-butylaminothieno [3,2-c] pyrimidin-4 (3H) -one hydrochloride

Compound 5 of Example 2 is prepared according to the synthesis method described below.

0.4 g (0.0013 mol) of 6-phenyl-2-tert-butylaminothieno [3,2-c] pyrimidin-4 (3 / -) - is stirred for 1 hour at 80 ° C. one in 30 mL of ethanol in the presence of one equivalent of concentrated hydrochloric acid. After cooling, the white precipitate obtained is drained and dried.

The expected compound is obtained with a yield of 78% and is in the form of a white powder.

It has the following physicochemical characteristics:

Mp> 260 ° C

CieHisNsOSCI: 335.5 g / mol

The compound thus synthesized has an in vitro CC50 of 1 1, 20 μΜ on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μΜ) used as a reference substance with cytotoxic activity.

The compound thus synthesized exhibits an in vitro IC50 of 1. 58 μΜ against a multiresistant K1 strain of P. falciparum, compared to chloroquine (IC50 = 0.50 μl) and doxycycline (IC50 = 5). , 00 μΜ) used as reference substances with antiplasmodial activity.

The compound thus synthesized thus has an SI of 7.09 compared with chloroquine (IS = 60) and doxycycline (IS = 4).

Example 3 2-Isopropylamino-6- (4-methylphenyl) thieno [3,2-c (pyrimidin-4 (3H) -one)

Compound 8 of Example 3 is prepared according to the general method of synthesis described above, considering the parameters below.

Methyl 3-Amino-5- (4-methylphenyl) -thiophene-2-carboxylate: 2.47 g (0.01 mol)

Ethoxycarbonyl isothiocyanate: 1.32 g (1.18 mL)

Isopropylamine: 1.77 g (2.56 mL)

Mercuric chloride: 2.715 g (0.01 mol) The expected compound is obtained with a yield of 51% and is in the form of a beige solid.

It has the following physicochemical characteristics:

Mp> 260 ° C

¹ H NMR (DMSO-d6): 1. 16 (t, 6H, (CH ₃ ) ₂ ), 2.32 (s, 3H, CH ₃ -C ₆ H ₅ ), 4.00 (m, 1H, CH), 6.37 (m, 1H, NH-CH), 7.25 (d, 2H, H-aryl), 7.47 (s, 1H, H-thiophene), 7.66 (d, 2H, H-aryl), 10.70 (s, 1H, NH).

The compound thus synthesized has an in vitro CC50 of 49.94 μΜ on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μΜ) used as a reference substance with cytotoxic activity. It has an in vitro CC50 greater than 15.6 μl on the CHO cell line compared to doxorubicin (CC50 = 0.6 μΜ) used as reference substance with cytotoxic activity.

The compound thus synthesized exhibits an in vitro IC50 of 0.84 μΜ against a multidrug resistant strain K1 of P. falciparum, compared with chloroquine (IC50 = 0.50 μM) and doxycycline (IC50 = 5). , 00 μΜ) used as reference substances with antiplasmodial activity.

The compound thus synthesized thus has an IS of 59.45 with respect to HepG2 cells, compared to chloroquine (IS = 60) and doxycycline (IS = 4).

No evidence of mutagenicity induced by the synthesized compound tested at 2.5 mM and 25 mM was observed on mutated Salmonella typhimurium strains TA97a and TA100 in the presence and absence of S9 Mix. Example 4 2-Isopropylamino-6- (4-methylphenyl) thieno [3,2-c (4) pyrimidin-4 (3H) -one fumarate

Compound 9 of Example 4 is prepared according to the synthesis method described below.

0.5 g (0.00167 mol) of 2-isopropylamino-6- (4-methylphenyl) -thieno [3,2-c] pyrimidin-4 (3H) -one in solution in 40 ml of isopropanol, in The presence of 0.194 g (0.00167 mol) of fumaric acid is refluxed for 1 h 30. After cooling, the precipitate formed is filtered off, washed with ethyl ether and dried. The expected compound is obtained with a yield of 77% and is in the form of a cream solids.

It has the following physicochemical characteristics:

Pf = decomposition at 245 ° C

The compound thus synthesized has an in vitro CC50 of 26.89 μΜ on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μΜ) used as reference substance with cytotoxic activity.

The compound thus synthesized exhibits an in vitro IC50 of 0.20 μΜ against a multidrug resistant K1 strain of P. falciparum, compared to chloroquine (IC50 = 0.50 μM) and doxycycline (IC50 = 5). , 00 μΜ) used as reference substances with antiplasmodial activity.

The compound thus synthesized thus has an IS of 134.45 compared with chloroquine (IS = 60) and doxycycline (IS = 4).

Example 5 6- (4-Methylphenyl) -2- (4-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

Compound 12 of Example 5 is prepared according to the general method of synthesis described above, considering the parameters below.

Methyl 3-Amino-5- (4-methylphenyl) -thiophene-2-carboxylate: 2.47 g (0.01 mol)

Ethoxycarbonylisothiocyanate: 1.32 g (1.18 mL)

Terf-butylamine: 2.19 g (3.15 mL)

Mercuric chloride: 2.715 g (0.01 mol)

The expected compound is obtained with a yield of 58% and is in the form of a beige solid.

It has the following physicochemical characteristics:

Mp> 260 ° C

¹ H NMR (DMSO-d6): 1.40 (s, 9H, (CH ₃ ) ₃ ), 2.32 (s, 3H, CH ₃ ), 6.07 (s, 1H, NH-C (CH 2) ₃ ) ₃ ), 7.24 (d, 2H, H-Aryl), 7.43 (s, 1H, H-thiophene), 7.67 (d, 2H, H-aryl), 10.50 (s). , 1H, NH). The compound thus synthesized has an in vitro CC50 of 25.58 μl on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μl) used as a reference substance with cytotoxic activity. It shows a 27.5 μΜ in vitro CC50 on the CHO cell line compared to doxorubicin (CC50 = 0.6 μΜ) used as a reference substance to cytotoxic activity.

The compound thus synthesized exhibits an in vitro IC50 of 0.15 μΜ against a multidrug resistant K1 strain of P. falciparum compared to chloroquine (IC50 = 0.50 μΜ) and doxycycline (IC50 = 5). , 00 μΜ) used as reference substances with antiplasmodial activity. It has an in vitro IC50 of 0.10 μΜ against a multidrug-resistant W2 strain of P. falciparum compared to chloroquine (IC50 = 0.70 μM) and doxycycline (IC50 = 6.50 μM). ) used as reference substances withantioplasmodial activity.

The compound thus synthesized thus has an IS of 170.53 vis-a-vis the HepG2 cells and the plasmodial strain K1, compared with chloroquine (IS = 60) and doxycycline (IS = 4). It has a selectivity index (IS) of 255.80 vis-à-vis HepG2 cells and the plasmodial strain W2, compared to chloroquine (IS = 43) and doxycycline (IS = 3).

No signs of mutagenicity induced by the synthesized compound tested at 2.5 mM were observed on mutated Salmonella typhimurium strains TA97a and TA100 in the absence of S9 Mix.

No signs of mutagenicity induced by the synthesized compound tested at 2.5 mM and 10 mM were observed on the mutated strains of Salmonella typhimurium TA97a and TA100 in the presence of S9 Mix. Example 6 6- (4-Methylphenyl) -2- (4-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -one hydrochloride

Compound 13 of Example 6 is prepared according to the same experimental method as that described for the compound of Example 2.

6- (4-Methylphenyl) -2- (tert-butylamino) -thieno [3,2-c] pyrimidin-4 (3H) -one: 0.4 g (0.00128 mol)

Ethanol: 30 mL

Hydrochloric acid: 0.1 mL (0.00128 moles) The expected compound is obtained in a yield of 85% and is in the form of a white solid.

It has the following physicochemical characteristics:

Pf = sublimation at 260 ° C

C17H20N3OSCl: 349.5 g / mol

The compound thus synthesized has an in vitro CC50 of 23.97 μΜ on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μΜ) used as reference substance with cytotoxic activity.

The compound thus synthesized exhibits an in vitro IC 50 of 45 nM against a multiresistant K1 strain of P. falciparum, compared with chloroquine (IC 50 = 0.50 μM) and doxycycline (IC 50 = 5.00 μΜ) used as reference substances with antiplasmodial activity.

The compound thus synthesized thus has an IS of 532.67, compared to chloroquine (IS = 60) and doxycycline (IS = 4)

The compound thus synthesized induces a decrease in parasitaemia by half compared to a control group of the infection, after in vivo administration to a batch of five mice infected with Plasmodium berghei, intraperitoneally, at a dose of 10 mg / kg. daily for four consecutive days.

Example 7 2-7e-Butylamino-6- (4-chlorophenyl) thieno [3,2-c (pyrimidin-4 (3H) -one)

Compound 33 of Example 7 is prepared according to the general method of synthesis described above, considering the following parameters.

Methyl 3-amino-5- (4-chlorophenyl) thiophene-2-carboxylate: 2.67 g (0.01 mol)

Ethoxycarbonyl isothiocyanate: 1.32 g (1.18 mL)

Butylamine: 2.194 g (2.96 mL)

Mercuric chloride: 2.715 g (0.01 mol)

The expected compound is obtained with a yield of 55% and is in the form of a white solid.

It has the following physicochemical characteristics:

Mp> 260 ° C Ci ₆ H ₆ N ₃ OSCI: 333.5 g / mol

¹ H NMR (DMSO-d6): 1.22 (s, 9H, (CH ₃ ) ₃ ), 3.87 (m, 1H, NH- (CH ₃ ) ₃ ), 6.09 (s, 1H). , NH), 7.33 (s, 1H, H-thiophene), 7.55 (d, 2H, H-Aryl), 7,82 (d, 2H, H-Aryl). The compound thus synthesized has an in vitro CC50 of 15.02 μΜ on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μΜ) used as a reference substance with cytotoxic activity. It has an in vitro CC50 of 29.3 μΜ on the CHO cell line compared to doxorubicin (CC50 = 0.6 μΜ) used as reference substance with cytotoxic activity.

The compound thus synthesized exhibits an in vitro IC50 of 0.83 μl against a multidrug resistant K1 strain of P. falciparum, compared to chloroquine (IC50 = 0.50 μl) and doxycycline (IC50 = 5). , 00 μΜ) used as reference substances with antiplasmodial activity.

The compound thus synthesized thus has an IS of 18.10 vis-à-vis the HepG2 cells, compared to chloroquine (IS = 60) and doxycycline (IS = 4).

No signs of mutagenicity induced by the synthesized compound tested at 2.5 mM were observed on the mutated Salmonella typhimurium strains TA97a and TA100 in the presence and absence of S9 Mix.

Example 8 2-7e-Butylamino-6- (4-chlorophenyl) thieno [3,2-c (4) pyrimidin-4 (3H) -one fumarate

Compound 34 of Example 8 is prepared according to the same experimental method as that described for the compound of Example 4.

2-7e-1-butylamino-6- (4-chlorophenyl) -3H-thieno [3,2-c] pyrimidin-4-one 0.4 g (0.0012 moles)

Isopropanol: 30 mL

Fumaric acid: 0.14 g (0.0012 moles)

The expected compound is obtained with a yield of 74% and is in the form of a white powder.

It has the following physicochemical characteristics:

Pf = decomposition at 260 ° C

C2oH ₂ ON ₃ O ₅ SCI: 449.5 g / mol The compound thus synthesized has an in vitro CC50 of 15.63 μΜ on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μΜ) used as a reference substance with cytotoxic activity.

The compound thus synthesized thus has an IS of 78.15 compared with chloroquine (IS = 60) and doxycycline (IS = 4).

Example 9 6- (4-Chlorophenyl) -2- (isopropylamino) thieno [3,2-c (pyrimidin-4 (3H) -one)

The compound of Example 9 is prepared according to the general method of synthesis described above, considering the following parameters.

Methyl 3-amino-5- (4-chlorophenyl) thiophene-2-carboxylate: 2.67 g (0.01 mol)

Ethoxycarbonyl isothiocyanate: 1.32 g (1.18 mL)

Isopropylamine: 1.77 g (2.56 mL)

Mercuric chloride: 2.715 g (0.01 mol)

The expected compound is obtained in a yield of 69% and is in the form of a white solid.

It has the following physicochemical characteristics:

Mp> 260 ° C

Ci ₅ H ₄ N ₃ OSCI: 319.5 g / mol

¹ H NMR (DMSO-d6): 0.99 (d, 6H, (CH ₃ ) ₂ ), 4.02 (m, 1H, CH (CH ₃ ) ₂ ), 6.79 (m, 1H, NH-CH), 7.51 (d, 2H, H-Aryl), 7.53 (s, 1H, H-thiophene), 7.79 (d, 2H, H-Aryl), 8.10 (s). , 1H, NH).

The compound thus synthesized has an in vitro CC50 greater than 15.63 μΜ on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μΜ) used as reference substance with cytotoxic activity.

The compound thus synthesized exhibits an in vitro IC50 of 0.65 μl against a multidrug resistant K1 strain of P. falciparum, as compared to chloroquine. (IC50 = 0.50 μΜ) and doxycycline (IC50 = 5.00 μΜ) used as reference substances with antiplasmodial activity.

The compound thus synthesized thus has an IS greater than 24.05 compared to chloroquine (IS = 60) and doxycycline (IS = 4).

Example 10 6- (4-Fluorophenyl) -2- (isopropylamino) thieno [3,2-c (pyrimidin-4 (3H) -one)

Compound 51 of Example 10 is prepared according to the general method of synthesis described above, considering the parameters below.

Methyl 3-amino-5- (4-fluorophenyl) thiophene-2-carboxylate: 2.51 g (0.01 mol)

Ethoxycarbonyl isothiocyanate: 1.32 g (1.18 mL)

Isopropylamine: 1.77 g (2.56 mL)

Mercuric chloride: 2.715 g (0.01 mol)

The expected compound is obtained with a yield of 65% and is in the form of a whitish powder.

It has the following physicochemical characteristics:

Mp> 260 ° C

Ci ₅ Hi ₄ N ₃ OSF: 303 g / mol

¹ H NMR (DMSO-d6): 1.02 (t, 6H, (CH ₃ ) ₂ ), 3.71 (m, 1H, NH-CH), 4.01 (m, 1H, CH), 6.49 (s, 1H, NH), 7.29 (m, 2H, H-aryl), 7.51 (s, 1H, H-thiophene), 7.82 (m, 2H, H-aryl) ).

The compound thus synthesized has an in vitro CC50 of 33.07 μΜ on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μΜ) used as reference substance with cytotoxic activity.

The compound thus synthesized exhibits an in vitro IC50 of 0.51 μΜ against a multidrug resistant K1 strain of P. falciparum, compared with chloroquine (IC50 = 0.50 μM) and doxycycline (IC50 = 5). , 00 μΜ) used as reference substances with antiplasmodial activity.

The compound thus synthesized thus has a SI of 64.84 compared with chloroquine (IS = 60) and doxycycline (IS = 4). Example 11: 6- (4-Bromophenyl) -2- (isopropylamino) thieno [3,2-c (pyrimidin-4 (3H) -one)

Compound 62 of Example 11 is prepared according to the general method of synthesis described above, considering the parameters below.

Methyl 3-amino-5- (4-bromophenyl) thiophene-2-carboxylate: 3.12 g (0.01 mol)

Ethoxycarbonyl isothiocyanate: 1.32 g (1.18 mL)

Propylamine: 1.77 g (2.46 mL)

Mercuric chloride: 2.715 g (0.01 mol)

The expected compound is obtained with a yield of 51% and is in the form of a gray powder.

It has the following physicochemical characteristics:

Pf = decomposition at 168 ° C

Ci ₅ Hi ₄ N ₃ OSBr: 364 g / mol

¹ H NMR (DMSO-d6): 1.16 (t, 6H, (CH ₃ ) ₂ ), 3.99 (m, 1H, CH), 3.41 (m, 1H, NH-CH), 6.28 (m, 1H, NH), 7.56 (s, 1H, H-thiophene), 7.64 (d, 2H, H-aryl), 7.72 (d, 2H, H-aryl) )

The compound thus synthesized has an in vitro CC50 of 15.85 μl on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μl) used as a reference substance with cytotoxic activity.

The compound thus synthesized exhibits an in vitro IC50 of 1.74 μΜ against a multiresistant K1 strain of P. falciparum, compared to chloroquine (IC 50 = 0.50 μM) and doxycycline (IC 50 = 5). , 00 μΜ) used as reference substances with antiplasmodial activity.

The compound thus synthesized thus has an IS of 9.1 l compared to chloroquine (IS = 60) and doxycycline (IS = 4).

Example 12 2- (lsopropylamino) -6- (4-methoxyphenyl) thieno [3,2-d] pyrimidin-4 (3H) -one

Compound 80 of Example 12 is prepared according to the general method of synthesis described above, considering the parameters below.

Methyl 3-amino-5- (4-methoxyphenyl) thiophene-2-carboxylate: 2.63 g (0.01 mol) Ethoxycarbonyl isothiocyanate: 1.32 g (1.18 ml)

Isopropylamine: 1.77 g (2.56 ml)

Mercuric chloride: 2.715 g (0.01 mol)

The expected compound is obtained with a yield of 59% and is in the form of a white powder.

It has the following physicochemical characteristics:

Mp = 180 ° C

¹ H NMR (DMSO-d6): 1.17 (d, 6H, (CH ₃ ) ₂ ), 3.82 (s, 3H, OCH ₃ ), 3.99 (m, 1H, C ₃ H (CH ₃ )). ₂ ), 6.23 (m, 1 H, NHCH), 7.01 (d, 2H, H-aryl), 7.41 (s, 1H, H-thiophene), 7.72 (d, 2H, H-aryl), 10.62 (s, 1H, NH).

The compound thus synthesized has an in vitro CC50 of 68.17 μΜ on the HepG2 cell line compared to doxorubicin (CC50 = 0.2 μΜ) used as a reference substance with cytotoxic activity.

The compound thus synthesized exhibits an in vitro IC50 of 0.50 μl against a multidrug resistant K1 strain of P. falciparum, compared to chloroquine (IC50 = 0.50 μl) and doxycycline (IC50 = 5). , 00 μΜ) used as reference substances with antiplasmodial activity.

The compound thus synthesized thus has a SI of 136.34 compared with chloroquine (IS = 60) and doxycycline (IS = 4).

REFERENCES

1) Pradines, B .; Dormoi, J .; Briolant, S .; Bogreau, H .; Rogier, C. Rev. Francoph. Lab., 2010,422, 51.

2) Uhlemann, A. C .; Fidock, D. A. Lancet, 2012, 379, 1928.

3) Yeung, S .; Socheat, D .; Moorthy, V. S .; Mills, A. J. Lancet, 2009, 374, 1418.

4) Miiller, O .; Sié, A .; Meissner, P .; Schirmer, R.H .; Kouyaté, B. Lancet, 2009, 374, 1419.

5) Gamo, F. J .; Sanz, L. M .; Vidal, J .; From Cozar, C; Alvarez, E .; Lavandera, J. L .; Vanderwall, D.E .; Green, D. V. S .; Kumar, V .; Hasan, S .; Brown, J. R .; Peishoff,

C. E .; Cardon, L. R .; Garcia-Bustos, J. F. Nature, 2010, 465, 305.

6) Guiguemde, W. A .; Shelat, A. A .; Bouck, D .; Duffy, S .; Crowther, G. J .; Davis, P.H .; Smithson, D.C .; Connelly, M .; Clark, J .; Zhu, F .; Jiménez-Diaz, M. B .; Martinez, M. S .; Wilson, E. B .; Tripathi, A. K .; Gut, J .; Sharlow, E. R .; Bathurst, I .; El Mazouni, F .; Fowble, J.W .; Forcing, I .; McGinley, P.L .; Castro, S .; Angulo- Barturen, I .; Ferrer, S .; Rosenthal, P. J .; Derisi, J. L .; Sullivan, D. J .; Lazo, J. S .; Roos, D. S .; Riscoe, M. K .; Phillips, M. A .; Rathod, P. K .; Van Voorhis, W. C .; Avery, V. M .; Guy, R. K. Nature, 2010, 465, 31 1.

7) Mosmann, T. J. Immunol. Methods, 1983, 65, 55.

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10) Bennett, T. N .; Paguio, M .; Gligorijevic, B .; Seudieu, C; Kosar, A. D .; Davidson, E .; Roepe, P. D. Antimicrob. Agents Chemother., 2004, 48, 1807.

1) De Méo, M .; Laget, M .; Di Giorgio, C; Guiraud, H .; Botta, A .; Castegnaro, M .; Dumenil, G. Mutat. Res., 1996, 340, 51.

12) Peters, W .; Portus, J.H .; Robinson, B.L. Ann. Too much. Med. Parasitoi, 1975, 69, 155.

Claims

1 - Compounds of general formula (I):

(I)

in which :

R 1, R 1 and R 2 represent, independently of each other, a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, an OR 'type alkyloxy, where R' represents a C 1 -C 6 alkyl group; C6,

R3 and R4 represent, independently of each other, a hydrogen atom, a C1-C6 alkyl group or a C3-C8 cycloalkyl group, with at least one of R3 and R4 groups different from the atom hydrogen,

alternatively R3 and R4 together with the nitrogen atom to which they are attached may form a heterocycle, optionally substituted by at least one halogen atom, a C1-C6 alkyl group, an aryl, arylalkyl, alkylaryl group, or a alkyloxy group of the type OR ", in which R" represents a C1-C6 alkyl group, with at least one of the groups R3 and R4 different from the hydrogen atom, their stereoisomers (diastereoisomers, enantiomers), pure or as a mixture, racemic mixtures, geometric isomers, salts, or mixtures thereof.

2- compounds according to claim 1, characterized in that R3 represents a hydrogen atom and R4 is a C1-C6 alkyl group or a C3-C8 cycloalkyl group, preferably R4 is a C1-C6 alkyl group, and more specifically C1-C4 alkyl, such as especially methyl, ethyl, n-propyl, isopropyl, or tert-butyl.

3. Compounds according to claim 1 or 2, characterized in that R, R 1 and R 2 represent, independently of each other, a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group or an alkyloxy group. of type OR ', where R' represents a C1-C6 alkyl group, and wherein one, two or all three groups R, R1 and R2 represents (nt) a hydrogen atom.

4. Compounds according to one of claims 1 to 3, characterized in thatR1 and R2 represent a hydrogen atom and R represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, an alkyloxy of the OR 'type, where R' represents a C1-C6 alkyl group, more particularly R represents a halogen atom, a C1-C6 alkyl group, an OR 'type alkyloxy, where R' represents an alkyl group; C1-C6.

5. Compounds according to one of claims 1 to 4, characterized in that they are chosen from:

2- (4-Benzylpiperazin-1-yl) -6-phenylthieno [3,2-c] pyrimidin-4 (3 H) -one

2-Diethylamino-6-phenylthieno [3,2-c] pyrimidin-4 (3 / -) - one

6-phenyl-2-butyl-butylaminothieno [3,2-c] pyrimidin-4 (3 / -) - one

6-phenyl-2-di-n-butylaminothieno [3,2-c] pyrimidin-4 (3H) -alone hydrochloride

2-ethylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-methylphenyl) -2- (n-propylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-isopropylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-Isopropylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one, fumarate 2- (1-ethylpropylamino) -6- (4-methylphenyl) thieno [ 3,2-c /] pyrimidin-4 (3 / - /) - one

2-isobutylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-methylphenyl) -2- (ie / Î-butylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-methylphenyl) -2- (ie / Î-butylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one,

hydrochloride

2-n-butylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-n-amylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-n-hexylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-n-heptylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-Diethylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H) -one

2-dipropylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-dibutylamino-6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3 / -) - one

6- (4-methylphenyl) -2- (dipentylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one 2- (butyl-ethyl-amino) -6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3H) -on ^

2- (butyl-methyl-amino) -6- (4-methylphenyl ^

6- (4-methylphenyl) -2- (1-phenyl-ethyl) amine

2- (1-methyl-heptylamino) -6- (4-methylphenyl) thieno [3,2-c] pyrimidin-4 (3H-6- (3-methylphenyl) -2- (tert-butylamino) thieno [3 , 2-c /] pyrimidin-4 (3 / - /) - one

6- (3-methylphenyl) -2- (tert-butylamino) thieno [3,2-c] pynmidin-4 (3H) -alone hydrochloride

6- (2-methylphenyl) -2- (ieri-butylamino) thieno [3,2-c /] pyrimidin-4 (3H) -one

6- (2-Methylphenyl) -2- (ieri-butylamino) thieno [3,2-c] pyrimidin-4 (3H) -one hydrochloride

6- (4-chlorophenyl) -2- (ethylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-chlorophenyl) -2- (propylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-butylamino-6- (4-chlorophenyl) thieno [3,2-c] pyrimidin-4 (3 / -) - one

2-ieri-butylamino-6- (4-chlorophenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-ieri-butylamino-6- (4-chlorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one, fumarate 6- (4-chlorophenyl) -2- (isopropylamino) thieno [ 3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-Chlorophenyl) -2- (1-phenyl-ethylam)

2- (2-Chloro-benzylamino) -6- (4-chlorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -on 6- (4-chlorophenyl) -2- (1-methyl-heptylamino) thieno [3,2-c] pyrimidin-4 (3H) -on 6- (4-chlorophenyl) -2- (diisopropylamino) thieno [3,2-c] pyrimidin-4 (3H) -one 6- (4-chlorophenyl) -2- (dipropylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-ethylamino-6- (4-fluorophenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-fluorophenyl) -2-propylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-butylamino-6- (4-fluorophenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-fluorophenyl) -2-pentylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-fluorophenyl) -2-hexylaminothieno [3,2-c] pyrimidin-4 (3 / -) - one

6- (4-fluorophenyl) -2-heptylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-tert-butylamino-6- (4-fluorophenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2- (2-Chloro-benzylamino) -6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -on 6- (4-fluorophenyl) -2- (1-phenyl-ethylamino) thieno [3,2-c] pyrimidin-4 (3H) -on 6- (4-fluorophenyl) -2- (1-methyl-heptylamino) thieno [3,2-c] pyrimidin-4 (3H) 6- (4-fluorophenyl) -2- (isopropylamino) thieno [3,2-c] pyrimidin-4 (3H) -one

2- (butyl-methylamino) -6- (4-fluorophenyl) thieno [3,2-c /] pyrimidin-4 (3H) -on 2- (Butyl-ethylamino) -6- (4-fluorophenyl) thieno [3,2-c] -pyrimidin-4 (3 H) -one-2- (1-ethylpropylamino) -6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -one 6- (4-fluorophenyl) -2-isobutylaminothieno [3,2-c] pyrimidin-4 (3H) -one

2-diisopropylamino-6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -on-2-dipropylamino-6- (4-fluorophenyl) thieno [3,2-c] ] pyrimidin-4 (3 / - /) - one

2-dibutylamino-6- (4-fluorophenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-fluorophenyl) -2-dipentylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-bromophenyl) -2-éthylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-bromophenyl) -2-propylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-Bromophenyl) -2-isopropylaminothieno [3,2-c] pyrimidin-4 (3H) -one 6- (4-bromophenyl) -2-butylaminothieno [3,2-c] pyrimidine -4 (3 / - /) - one

6- (4-bromophenyl) -2-pentylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-bromophenyl) -2-hexylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-bromophenyl) -2-heptylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-bromophenyl) -2-ieri-butylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-bromophenyl) -2- (1-ethylpropylamine) thieno [3,2-c] pyrimidin-4 (3 H) -ol-6- (4-bromophenyl) -2- (1-methyl) -2- heptylamino) ^

6- (4-bromophenyl) -2- (1-phenylethylamino) thieno [3,2-c] pyrimidin-4 (3H) -on 6- (4-bromophenyl) -2- (2-chloro-benzylamino) thieno [3,2-c] pyrimidin-4 (3H) -on 6- (4-bromophenyl) -2-dipropylamino-thieno [3,2-c] pyrimidin-4 (3 / -) - one 6- (4-bromophenyl) -2-diisopropylamino-thieno [3,2-c] pyrimidin-4 (3H) -one 6- (4-bromophenyl) -2-dibutylamino-thieno [3,2- c /] pyrimidin-4 (3 / - /) - one

6- (4-bromophenyl) -2-dipentylamino-thieno [3,2-c] pyrimidin-4 (3H) -one 6- (4-bromophenyl) -2- (butyl-methyl-amino) - thieno [3,2-c] pyrimidin-4 (3H) -o [6- (4-bromophenyl) -2- (butyl-ethyl-amino) -thieno [3,2-c]] pyrimidin-4 (3H) ) -one 2-ethylamino-6- (4-methoxyphenyl) -thieno [3,2-c] -pyrimidin-4 (3 H) - -one 6- (4-methoxyphenyl) -2-propylamino-thieno [3] 2- (2-cyl) pyrimidin-4 (3H) -2-isopropylamino-6- (4-methoxyphenyl) -thieno [3,2-d] pyrimidin-4 (3H) -one 2- butylamino-6- (4-methoxyphenyl) -thieno [3,2-c] pyrimidin-4 (3 / -) - one 6- (4-methoxyphenyl) -2-pentylamino-thieno [3,2-c] ] pyrimidin-4 (3 / - /) - one 2-hexylamino-6- (4-methoxyphenyl) -thieno [3,2-c] pyrimidin-4 (3 / -) - one 2-heptylamino-6- (4-Methoxyphenyl) -thieno [3,2-c] pyrimidin-4 (3 / -) - one 2- (1-ethylpropylamino) -6- (4-methoxyphenyl) thieno [3,2-c] ] pyrimidin-4 (3H) -o 2-isobutylamino-6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-iert-butylamino-6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-methoxyphenyl) -2- (1-phenyl-ethylamino)

2- (2-chloro-benzylamino) -6- (4-methoxyphenyl) -tn

6- (4-methoxyphenyl) -2- (1-methyl-heptylamino)

2-dipropylamino-6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-diisopropylamino-6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-dibutylamino-6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2- (3- (dimethylamino) propylamino) -6- (4-methoxyphenyl) thieno [3,2-c /] pyrim

4 (3H) - one

2- (3- (diethylamino) propylamino) -6- (4-methoxy ^

4 (3H) -one

2- (butyl-methylamino) -6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3H) - ^

2- (butyl-ethylamino) -6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3H) -on

6- (3,4-dimethoxyphenyl) -2- (heptan-2-yl-amino) ^ -thté

6- (3,4-Dimethoxyphenyl) -2- (1-phenyl-ethylamino) -thieno [3,2-c] pyrimidine

2- (2-chloro-benzylamino) -6- (3,4-dimethoxyphenyl) ^

one.

6. Compounds according to one of claims 1 to 5, characterized in that they are chosen from:

2- (4-Benzylpiperazin-1-yl) -6-phenylthieno [3,2-c] pyrimidin-4 (3 H) -one

6-phenyl-2-butyl-butylaminothieno [3,2-c] pyrimidin-4 (3 / -) - one

6-phenyl-2-di-n-butylaminothieno [3,2-c] pyrimidin-4 (3H) -alone hydrochloride

6- (4-methylphenyl) -2- (fe / Î-butylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

hydrochloride 2-n-butylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-n-amylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-n-hexylamino-6- (4-methylphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-methylphenyl) -2- (1-phenyl-ethylamino) thieno [3,2-c] pyrimidin-4 (3H) -2- (1-methyl-heptylamino) -6- (4-methylphenyl)

6- (3-methylphenyl) -2- (feri-butylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-butylamino-6- (4-chlorophenyl) thieno [3,2-c] pyrimidin-4 (3 / -) - one

6- (4-Chlorophenyl) -2- (1-phenyl-ethylamino) thieno [3,2-c] pyrimidin-4 (3H) -on 2- (2-chloro-benzylamino) -6- (4-chlorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -on-2-butylamino-6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3 / -) - one

6- (4-fluorophenyl) -2-pentylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-fluorophenyl) -2-hexylaminothieno [3,2-c] pyrimidin-4 (3 / -) - one

2-ieri-butylamino-6- (4-fluorophenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-fluorophenyl) -2- (1-phenylethylamino) thieno [3,2-c] pyrimidin-4 (3H) -on 6- (4-fluorophenyl) -2- (isopropylamino) thieno [3 , 2-c /] pyrimidin-4 (3 / - /) - one

2- (Butyl-methylamino) -6- (4-fluorophenyl) thieno [3,2-c] pyrimidin-4 (3H) -on 2- (1-ethylpropylamino) -6- (4-fluorophenyl) thieno [3 2-c /] pyrimidin-4 (3H) -on 6- (4-fluorophenyl) -2-isobutylaminothieno [3,2-c] pyrimidin-4 (3 / -) - one

2-diisopropylamino-6- (4-fluorophenyl) thieno [3,2-c /] pyrimidin-4 (3H) -one

6- (4-bromophenyl) -2-propylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-bromophenyl) -2-isopropylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-bromophenyl) -2-butylaminothiéno [3,2-c /] pyrimidin-4 (3 / - /) - one 6- (4-bromophenyl) -2-hexylaminothieno [3,2-c] pyrimidin-4 (3H) -one 6- (4-bromophenyl) -2-feri-butylaminothieno [3,2-c] ] pyrimidin-4 (3 / - /) - one

6- (4-bromophenyl) -2- (1-ethylpropylamine) thieno [3,2-c] pyrimidin-4 (3H) -on

6- (4-bromophenyl) -2- (1-methyl-heptylamino) tht

6- (4-bromophenyl) -2- (2-chloro-benzylamino) thieno [3,2-c /] pyrimidin-4 (3H) - ^

6- (4-bromophenyl) -2-diisopropylamino-thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-methoxyphenyl) -2-propylamino-thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-isopropylamino-6- (4-methoxyphenyl) thieno [3,2-d] pyrimidin-4 (3 / - /) - one

2-butylamino-6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-methoxyphenyl) -2-pentylamino-thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-hexylamino-6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-Heptylamino-6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2- (1-ethylpropylamino) -6- (4-methoxyphenyl) -tN

2-isobutylamino-6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

2-iert-butylamino-6- (4-methoxyphenyl) thieno [3,2-c /] pyrimidin-4 (3H) -one

2- (2-chloro-benzylamino) -6- (4-methoxyphenyl) ^ -tn

6- (4-Methoxyphenyl) -2- (1-methyl-heptylamino) -thieno [3,2-c] pyrimidine

2- (3- (dimethylamino) propylamino) -6- (4-methoxyphenyl) thieno [3,2-c /] pyri

4 (3H) -one

2- (3- (diethylamino) propylamino) -6- (4-methoxyphenyl) thieno [3,2-c /] pyrim

4 (3H) -one

2- (butyl-methylamino) -6- (4-methoxyphenyl) - ^

2- (butyl-ethylamino) -6- (4-méthoxyphé

2- (2-Chloro-benzylamino) -6- (3,4-dimethoxyphenyl) -thieno [3,2-c] pyrimidin-one.

7- Compounds according to one of claims 1 to 6, characterized in that they are chosen from:

6-phenyl-2-butyl-butylaminothieno [3,2-c] pyrimidin-4 (3 / -) - one

2-fe / i-butylamino-6- (4-chlorophenyl) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one

6- (4-chlorophenyl) -2- (isopropylamino) thieno [3,2-c /] pyrimidin-4 (3 / - /) - one 6- (4-fluorophenyl) -2- (isopropylamino) thieno [3,2-c /] pyrimidin-4 (3H) -on

6- (4-bromophenyl) -2-isopropylaminothiéno [3,2-c /] pyrimidin-4 (3H) -on

2-isopropylamino-6- (4-methoxyphenyl) thieno [3,2-d] pyrimidin-4 (3H) -on

and their salts.

8- Compounds according to any one of claims 1 to 7 for use as medicaments.

9. A pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, at least one compound of general formula (I):

(I)

in which :

R3 and R4 independently of one another represent a hydrogen atom, a C1-C6 alkyl group, a C3-C8 cycloalkyl group,

10- Pharmaceutical composition according to the preceding claim, characterized in that the compound of formula (I) is as defined in one of claims 1 to 8. 1 1 - Compounds or pharmaceutical composition according to one of the preceding claims, for use in the treatment of malaria.

12- Compounds or pharmaceutical composition according to one of claims 1 -10, for use in the treatment of malaria access.