Combination of a bis-thiazolium salt or a precursor thereof and artemisinin or a derivative thereof for treating acute malaria

1. A combination comprising, as active ingredients,

a bisthiazolium salt, which is a compound of formula (VI):

in which

Rb represents:

a group R 1 which itself represents a C 1 to C 5 alkyl radical, optionally substituted with an aryl radical, a hydroxyl, an alkoxy, in which the alkyl radical contains from 1 to 5 carbon atoms, or aryloxy,

or else a group T, T representing the group of formula:

in which:

R 2 represents a hydrogen atom, a C 1 to C 5 alkyl group or a —CH 2 —COO—(C 1 to C 5 )alkyl group;

R 3 represents a hydrogen atom, a C 1 to C 5 alkyl or alkenyl radical, optionally substituted with —OH, a phosphate group, an alkoxy radical, in which the alkyl radical is C 1 to C 3 , or aryloxy; or an alkyl (or aryl)carbonyloxy group;

or else R 2 and R 3 together form a ring containing 5 or 6 carbon atoms; R 2 and R 3 may be linked so as to form a ring or a heterocycle containing 5 to 7 members, optionally comprising one or more heteroatoms O and/or S;

Z represents a C 6 to C 21 alkylene radical, optionally with insertion of one or more multiple bonds, and/or one or more heteroatoms O and/or S, and/or of one or more aromatic rings, and the pharmaceutically acceptable salts of these compounds,

with the proviso that Z does not represent a C 6 to C 8 alkylene radical, when Rc, Rd, R 2 and R 3 represent a methyl radical, or when Rc and Rd, on the one hand, and R 2 and R 3 , on the other hand, together form aromatic rings containing 6 carbon atoms;

Rd represents R 2 as defined above or P, P representing the group of formula:

Rc represents R 3 as defined above or U, U representing the group of formula:

wherein Rb=T, if Rc=R 3 and Rd=R 2 ; Rd=P, if Rc=R 3 and Rb=R 1 ; and Rc=U, if Rb=R 1 , and Rd=R 2 , in the form of a free base or of a salt,

or a precursor thereof chosen from the compounds of formulae (I) to (V),

the compound (I) corresponding to the formula:

in which

A and A′ are identical to or different from one another and represent:

either, respectively, a group A 1 and A′ 1 of formula:

where n is an integer from 2 to 4; R′ 1 has the same definition as R 1 above, but can also be a hydrogen atom;

and W represents a halogen atom chosen from chlorine, bromine or iodine, or a nucleofugal group selected from the group consisting of CH 3 —C 6 H 4 —SO 3 , CH 3 —SO 3 , CF 3 —SO 3 and NO 2 —C 6 H 4 —SO 3 ,

or a group A 2 which represents a formyl radical —CHO or an acetyl radical —CO—CH 3 ,

B and B′ are identical to or different from one another and represent:

either, respectively, the groups B 1 and B′ 1 , if A and A′ represent, respectively, A 1 and A′ 1 , B 1 and B′ 1 representing a group R 1 , as defined above,

or, respectively, the groups B 2 and B′ 2 , if A and A′ represent A 2 , B 2 or B′ 2 being the group R 1 as defined above, or a group of formula:

in which —Ra represents an RS— or RCO— group, where R is a linear, branched or cyclic, C 1 to C 6 alkyl radical, optionally substituted with one or more hydroxyl, alkoxy or aryloxy groups, or an amino group and/or a —COOH or COOM group, where M is a C 1 to C 3 alkyl; a phenyl or benzyl radical, in which the phenyl radical is optionally substituted with at least one C 1 to C 5 alkyl or alkoxy radical, said radicals being optionally substituted with an amino group, or with a nitrogenous or oxygenated heterocycle, a —COOH group or a —COOM group; or a group —CH 2 -heterocycle, in which the heterocycle has 5 or 6 elements and is nitrogenous and/or oxygenated;

R 2 represents a hydrogen atom, a C 1 to C 5 alkyl radical or a —CH 2 —COO(C 1 to C 5 )alkyl group;

and R 3 represents a hydrogen atom; a C 1 to C 5 alkyl or alkenyl radical, as appropriate substituted with —OH, a phosphate group, an alkoxy radical, in which the alkyl radical is C 1 to C 3 , or aryloxy; or an alkyl (or aryl)carbonyloxy group;

or else R 2 and R 3 together form a ring containing 5 or 6 carbon atoms; R and R 3 may be linked so as to form a ring containing 5- to 7 atoms (carbon, oxygen, sulphur);

α represents:

either a single bond, when A and A′ represent A 1 and A′ 1 : or when A and A′ represent A 2 , which is a —CHO or —COCH 3 group, and B 2 and B′ 2 represent:

or, when A and A′ represent A 2 and B 2 and B′ 2 represent R 1 , a group of formula:

or a group of formula:

in which (a) represents a bond towards Z and (b) a bond towards the nitrogen atom,

Z represents a C 6 to C 21 alkylene radical, optionally with insertion of one or more multiple bonds, and/or one or more heteroatoms O and/or S, and/or one or more aromatic rings, and the pharmaceutically acceptable salts of these compounds, with the proviso that R′ 1 does not represent H or a C 1 or C 2 alkyl radical, when n=3 or 4, R 1 represents a C 1 to C 4 alkyl radical and Z represents a C 6 to C 10 alkylene radical;

the compound (II) corresponding to the formula:

the compound (III) corresponding to the formula:

the compound (IV) corresponding to the formula:

the compound (V) corresponding to the formula:

in which Ra, R 1 , R′ 1 , R 2 , R 3 , W, n and Z are as defined above,

and

artemisinin or a derivative thereof, chosen from artesunate, artemether, arteether, hydroartemisinin or dihydroartemisinin,

for the treatment and/or prevention of severe malaria.

2. The combination of claim 1 , wherein the bisthiazolium salt of formula (VI), is chosen from the group consisting of:

1,12-dodecamethylenebis[4-methyl-5-(2-hydroxyethyl)thiazolium] dibromide;

1,12-dodecamethylenebis[4-methyl-5-(2-methoxyethyl)thiazolium] diiodide;

1,12-dodecamethylenebis(4-methylthiazolium) diiodide;

1,16-hexadecamethylenebis[4-methyl-5-(2-methoxyethyl)thiazolium] diiodide;

3,10-dioxadodecamethylenebis[5-(1,4-dimethyl)thiazolium] diiodide;

3,10-dioxadodecamethylenebis[5-(1-benzyl-4-methyl)thiazolium] dibromide;

dodecamethylenebis[5-(1-methyl-4-ethoxycarbonylethyl)thiazolium] diiodide;

dodecamethylenebis[5-(1-methyl-4-ethoxycarbonylethyl)thiazolium] dibromide;

dodecamethylenebis[4-(1-methyl)thiazolium] diiodide; and

dodecamethylenebis[4-(1-benzyl)thiazolium] dibromide.

3. The combination of claim 1 , wherein each of the active ingredients is administered simultaneously or sequentially.

4. A pharmaceutical composition comprising therapeutically effective doses of artemisinin or of a derivative thereof, and of at least one bisthiazolium salt of formula (VI), or a precursor thereof, as defined in claim 1 , and also at least one pharmaceutically acceptable excipient, for the treatment of severe malaria.

5. The pharmaceutical composition of claim 4 , wherein the bisthiazolium salt of formula (VI) is 1,12-dodecamethylenebis[4-methyl-5-(2-hydroxyethyl)thiazolium] dibromide.

6. The pharmaceutical composition according of claim 5 wherein the artemisinin derivative is artesunate.

7. The pharmaceutical composition of claim 6 wherein the composition is suitable for oral, rectal or injectable administration.

8. A method of treating severe malaria comprising administering to a patient in need thereof the combination of claim 1 .

9. A kit for the treatment of severe malaria, comprising, on the one hand, at least one bisthiazolium salt, which is a compound of formula (VI) or a precursor thereof, and, on the other hand, at least artemisinin or a derivative thereof, as defined in claim 1 , said compound of formula (VI) or a precursor thereof and the artemisinin or a derivative thereof being in distinct compartments and being intended to be administered simultaneously or sequentially.

10. The kit of claim 9 comprising, on the one hand, at least 1,12-dodecamethylenebis[4-methyl-5-(2-hydroxyethyl)thiazolium] dibromide, and, on the other hand, at least artesunate.

11. The combination of claim 1 wherein said aryl radical in the definition of group R 1 is a phenyl radical.

12. The combination of claim 1 wherein said aryloxy in the definition of group R 1 is a phenyloxy.

13. The combination of claim 1 wherein Z represents a C 13 to C 21 alkylene radical.

14. The pharmaceutical composition of claim 6 wherein the composition is suitable for intravenous injection.

15. The pharmaceutical composition of claim 14 wherein the composition is suitable for intravenous injection in the form of a drip.