Cephalotaxanes, their method of preparation and their use in treatment of cancers, leukemias, parasites including those resistant to usual chemotherapeutic agents and as reversal agents

1. A compound selected from the group consisting of

and a compound having formula (I)

wherein

W is O or NH;

Q is COZ-R 8 ;

Z is O, S, or NH, and

or Z-R 8 is NR 12 R 13 , R 12 and R 13 representing respectively R 9 and R 10 ; R 9 , R 10 are independently H, deuterium, unbranched or branched unsubstituted C 1 -C 30 alkyl, C 1 -C 30 alkyl being substituted at the end of the hydrocarbonated chain by a hydroxy or alkoxy group, unsubstituted C 3 -C 30 cycloalkyl, unsubstituted aryl, unsubstituted aryl-(C 1 -C 30 )-alkyl, aryl or aryl-(C 1 -C 30 ) alkyl being substituted by a halogen atom, a methoxy group or a nitro group, where aryl or the aryl fragment is a mono- or poly-cyclic group, optionally containing one heteroatom selected from O, S or N, unsubstituted C 2 -C 30 alkenyl, unsubstituted C 2 -C 30 alkynyl, unsubstituted C 1 -C 30 trihalogenoalkyl, unsubstituted C 1 -C 30 alkylamino-(C 1 -C 30 ) alkyl, unsubstituted C 1 -C 30 dialkylamino (C 1 -C 30 )-alkyl, or unsubstituted amino-(C 1 -C 30 )-alkyl, or

where R 14 , R 15 , R 16 are independently H, halogen, unsubstituted C 1 -C 30 alkyl, unsubstituted C 3 -C 30 cycloalkyl, unsubstituted aryl, unsubstituted aryl-(C 1 -C 30 )-alkyl, unsubstituted C 2 -C 30 alkenyl or unsubstituted C 2 -C 30 alkynyl, unsubstituted C 1 -C 30 trihalogenoalkyl, m is 0 to 4,

and R 11 is deuterium, unbranched or branched unsubstituted C 2 -C 30 alkyl, C 1 -C 30 alkyl being substituted at the end of the hydrocarbonated chain by a hydroxy or alkoxy group,

unsubstituted C 3 -C 30 cycloalkyl, unsubstituted aryl, unsubstituted aryl-(C 1 -C 30 )-alkyl, aryl or aryl-(C 1 -C 30 ) alkyl being substituted by a halogen atom, a methoxy group or a nitro group, where aryl or the aryl fragment is a mono- or poly-cyclic group, optionally containing one heteroatorn selected from O, S or N, unsubstituted C 2 -C 30 alkenyl, unsubstituted C 2 -C 30 alkynyl, unsubstituted C 1 -C 30 trihalogenoalkyl, unsubstituted C 1 -C 30 alkylamino-(C 1 -C 30 ) alkyl, unsubstituted C 1 -C 30 dialkylamino (C 1 -C 30 )-alkyl, or unsubstituted amino-(C 1 -C 30 )-alkyl, or

where R 14 , R 15 , R 16 are independently H, halogen, unsubstituted C 1 -C 30 alkyl, unsubstituted C 3 -C 30 cycloalkyl, unsubstituted aryl, unsubstituted aryl-(C 1 -C 30 )-alkyl, unsubstituted C 2 -C 30 alkenyl or unsubstituted C 2 -C 30 alkynyl, unsubstituted C 1 -C 30 trihalogenoalkyl, m is 0 to 4,

and wherein R 1 may be CH 3 when Z represents S or NH;

R 1 is H, OH, OMe, unsubstituted O—(C 1 -C 30 )-alkyl, unsubstituted O-aryl-(C 1 -C 30 )-alkyl, unsubstituted O—(C 2 -C 30 )-alkenyl, unsubstituted O—(C 3 -C 30 )-cycloalkyl or null, and R 2 is H or OH, or R 1 , R 2 together form —O—; R 3 and R 4 are OMe, or R 3 and R 4 together form —OCH 2 O—; R is H, unsubstituted C 1 -C 30 alkyl or O-protecting group, and R 6 is —(C—Y)Me 2 , —CH═CMe 2 , or an unsubstituted aryl group or R and R 6 together form —CMe 2 -,

Y is H, OH or halogen;

n=0 to 8;

R 5 is H, OH, OMe, unsubstituted O—(C 1 -C 30 )-alkyl, unsubstituted O-aryl-(C 1 -C 30 )-alkyl, unsubstituted O—(C 2 -C 30 )-alkenyl, unsubstituted O—(C 3 -C 30 )-cycloalkyl or unsubstituted O-aryl; and

the dotted line is null or forms a double bond depending on the meaning of R 1 .

2. A compound of formula (I) according to claim 1 , wherein the dotted line forms a double bond,

R 1 is null,

R 2 is H,

R 3 and R 4 together form —O—CH 2 —O—, and

R 5 is OMe.

3. A compound of formula (I) according to claim 1 , wherein the dotted line is null,

R 1 and R 2 represent —O—,

R 3 and R 4 together form —O—CH 2 —O—, and

R 5 is OMe.

4. A compound of formula (I) according to claim 2 , wherein n=1 to 3.

5. A compound of formula (I) according to claim 1 , wherein W is O.

6. A compound according to claim 1 selected from the group consisting of the following compounds 66 to 90:

7. A process for preparing a compound of formula (I) according to claim 1 , wherein W represents O,

said process comprising the following steps i) and ii):

i) hydrolyzing selectively the compound of formula (II)

 wherein

R 1 is H, OH, OMe, unsubstituted O—(C 1 -C 30 )-alkyl, unsubstituted O-aryl-(C 1 -C 30 )-alkyl, unsubstituted O—(C 2 -C 30 )-alkenyl, unsubstituted O—(C 3 -C 30 )-cycloalkyl or null and, R 2 is H or OH, or R 1 and R 2 together form —O—;

R 3 and R 4 are OMe, or R 3 and R 4 together form —OCH 2 O—;

R is H, unsubstituted C 1 -C 30 -alkyl or O-protecting group, and

R 6 is —(C—Y)Me 2 , —CH═CMe 2 , or an unsubstituted aryl group;

or R and R 6 together form —CMe 2 —;

Y is H, OH or halogen;

n=0 to 8;

R 5 is H, OH, OMe, unsubstituted O—(C 1 -C 30 )-alkyl, unsubstituted O-aryl-(C 1 -C 30 )-alkyl, unsubstituted O—(C 2 -C 30 )-alkenyl, unsubstituted O—(C 3 -C 30 )-cycloalkyl or unsubstituted O-aryl;

the dotted line is null or forms a double bond depending on the meaning of R 1 ;

Z is O or S; and

R 17 is unsubstituted C 1 -C 30 -alkyl, unsubstituted C 2 -C 30 -alkenyl, unsubstituted C 3 -C 30 -cycloalkyl, unsubstituted C 2 -C 30 -alkynyl, unsubstituted aryl-(C 1 -C 30 )-alkyl or unsubstituted aryl, with an agent in hydro-organic solvent mixture to give as reaction product, amphoteric acid of formula (III)

wherein R 1 to R 5 , R and R 6 are defined as above,

ii) performing the esterification of the above obtained amphoteric acid of formula (III) with an esterification agent and a compound of formula R 8 -ZH,

and wherein the steps (i) and ii) are carried out successively or simultaneously.

8. The process according to claim 7 , wherein the esterification agent is a lewis acid or protonic acid.

9. The process according to claim 7 , wherein the amphoteric acid of formula (III) is activated with an imide or by formation of a mixed anhydride or an acid chloride.

10. The process according to claim 9 , wherein the imide is dicyclohexylcarbodiimide of diisopropylcarbodiimide.

11. The process according to claim 9 , wherein the mixed anhydride is formed with 2,3,6-trichlorobenzoic acid by contact with 2,4,6-trichlorobenzoyl chloride in the presence of a base.

12. The process according to claim 7 , wherein the steps i) and ii) are carried out simultaneously, without isolation of the amphoteric acid of formula (III), via a reaction of transesterification performed in the presence of an acidic or basic catalyst.

13. The process according to claim 12 , wherein the catalyst is a base.

14. The process according to claim 12 , wherein the catalyst is a lewis acid or a protonic acid.

15. The process according to claim 7 , wherein Z is O and R 17 is methyl.

16. The process according to claim 13 , wherein the catalyst is an alkaline hydride.

17. A pharmaceutical composition which comprises a therapeutically effective amount of at least one compound according to claim 1 associated with one or more pharmaceutically acceptable carriers.

18. A method for inhibiting mammalian parasites, which comprises administering to a mammal in need of such a treatment a therapeutically effective amount of at least one compound of claim 1 .

19. A method for treating leukemia which comprises administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound of claim 1 .