Compounds useful for treating cancer   

Abstract: The present invention relates to compound (I) wherein: means a pyridazine, a pyrimidine or a pyrazine group, R independently represent a hydrogen atom, a halogen atom or a group chosen among a CN group, a hydroxyl group, a COOR1 group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group, a NO2 group, a NR1R2 group, a (C1-C4)alkoxy group, a phenoxy group and a (C1-C3)alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group, n is 1, 2 or 3, n is 1 or 2, R is a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group, a hydroxyl group, a COOR1 group, a NO2 group, a NR1R2 group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (C1-C3)fluoroalkyl group, a (C1-C4)alkoxy group and a CN group, Z is N or C, Y is N or C, X is N or C, W is N or C, T is N or C, U is N or C, for use as an agent for preventing, inhibiting or treating cancer. Some of said compounds are new and also form part of the invention.

FIELD OF THE INVENTION

The present invention is generally dedicated to the use of compounds for the manufacture of compositions useful to treat cancer.

BACKGROUND OF THE INVENTION

In most of the cancers, mortality is not due to the primary tumor but rather to the derived metastases. This malignant progression which leads to tumor invasion and is clinically defined by the appearance of metastases is the final outcome of the primary loss of cell adhesion and increase of cell motility which together allow invasive cell to leave the initial tumor site and colonize various target tissues.

Metastases are considered as a recurrent feature of uncontrolled malignant progression of cancer. During this process, tumor cells complete their malignant transformation by increasing their migratory capacity. Cancer cells can then disseminate and establish tumor foci in far away sites. Spreading of cancer cells in the organism is the outcome of a series of events called <<metastatic cascade>>: invasion of the tissues around the tumor, venous or lymphatic intravasation, migration and establishment in a distant place of a new colony that escapes from all the defence mechanisms of the organism.

Metastatic invasion, against which there is no efficient therapeutic option available at this time, is by far the major cause of death. Due to the frequency of cancers diagnosed at the metastatic stage and to the therapeutic impasse they represent, the development of molecules that specifically target metastatic invasion is thus a crucial requirement for a major breakthrough in cancer treatments.

The present invention is in keeping with the evidence as published during the last twenty years of a link between changes in RNA alternative splicing and metastatic invasion which has opened to new therapeutic strategies.

SUMMARY

It has now been found that derivatives of formula (I) as defined in formula (I) hereinafter are able to correct defects of alternative splicing, as illustrated in the experimental data hereinafter, a mechanism closely associated with the invasive progression of metastatic cancers, and on the basis of such activity, the compounds are useful in the treatment of cancer.

The present invention therefore relates to compounds of formula (I) as defined below for use as agents for preventing, inhibiting or treating cancer.

The present invention moreover relates to a method of preventing, inhibiting or treating cancer, which comprises at least one step consisting in administering to a patient suffering therefrom an effective amount of a compound as defined in formula (I) below or one of its pharmaceutically acceptable salts.

The present invention further relates to some particular derivatives as such, as defined below.

The present invention also provides pharmaceutical compositions comprising at least one of said particular compounds.

DETAILED DESCRIPTION

According to a first aspect, a subject-matter of the present invention relates to a compound of formula (I)

wherein:

means an aromatic ring wherein V is C or N and when V is N, V is in ortho, meta or para of Z, i.e. forms respectively a pyridazine, a pyrimidine or a pyrazine group,

R independently represent a hydrogen atom, a halogen atom or a group chosen among a —CN group, a hydroxyl group, a —COOR1 group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group, a —NO2 group, a —NR1R2 group, a (C1-C4)alkoxy group, a phenoxy group and a (C1-C3)alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group,

R1 and R2 are independently a hydrogen atom or a (C1-C3)alkyl group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C1-C3)alkyl group, a halogen atom, a hydroxyl group, a —COOR1 group, a —NO2 group, a —NR1R2 group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (C1-C3)fluoroalkyl group, a (C1-C4)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C1-C4)alkyl group,

Z is N or C,

Y is N or C,

X is N or C,

W is N or C,

T is N or C,

U is N or C,

and wherein at most four of the groups V, T, U, Z, Y, X and W are N,

and at least one of the groups T, U, Y, X and W is N,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to one aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is C, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is C, V is C, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is C, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C, T is C, U is C and W is N, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is N and is in para of Z, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is C, V is N and is in para of Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is C, V is N and is in meta of Z and is in para of the bond linked to NR″, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is C, V is N and is in meta of Z and is in para of the bond linked to NR″, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is C, V is C, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is C, V is C, Y is N, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is N and is in meta of Z and in ortho of the bond linked to NR″, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is N and is in para of Z, Y is C, X is C, T is C, U is C and W is N, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is N and is in para of Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is C, Y is N, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is N and is in meta of Z and is in ortho of the bond linked to NR″, Y is N, X is N, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is C, V is C, Y is C, X is C, T is N, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C, T is N, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C, T is C, U is N and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to one preferred aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is C, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another preferred aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is N and is in para of Z, Y is N, X is C, T is C, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another preferred aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is C, V is C, Y is C, X is C, T is N, U is C and W is C, for use as an agent for preventing, inhibiting or treating cancer.

According to another preferred aspect, the present invention relates to a compound of formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C, T is C, U is N and W is C, for use as an agent for preventing, inhibiting or treating cancer.

The compounds of the invention may exist in the form of free bases or of addition salts with pharmaceutically acceptable acids.

Suitable physiologically acceptable acid addition salts of compounds of formula (I) include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate and fumarate.

The compounds of formula (I) and or salts thereof may form solvates (e.g. hydrates) and the invention includes all such solvates.

In the context of the present invention, the term:

“halogen” is understood to mean chlorine, fluorine, bromine, or iodine, and in particular denotes chlorine, fluorine or bromine,

“(C1-C3)alkyl” as used herein respectively refers to C1-C3 normal, secondary or tertiary saturated hydrocarbon. Examples are, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,

“(C1-C3)alkoxy” as used herein respectively refers to O—(C1-C3)alkyl moiety, wherein alkyl is as defined above. Examples are, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy,

“fluoroalkyl group” and “fluoroalkoxy group” refers respectively to alkyl group and alkoxy group as above-defined, said groups being substituted by at least one fluorine atom. Examples are perfluoroalkyl groups, such as trifluoromethyl or perfluoropropyl, and

“patient” may extend to humans or mammals, such as cats or dogs.

According to a particular embodiment, an additional subject-matter of the present invention is a compound of formula (Ia)

wherein:

R independently represent a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group, a —CN group, a hydroxyl group, a —COOR1 group, a (C1-C3)fluoroalkyl group, a —NO2 group, a —NR1R2 group and a (C1-C3)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group, a —NO2 group, a (C1-C3)alkoxy group and a —NR1R2 group,

R1 and R2 are a hydrogen atom or a (C1-C3)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Ib)

wherein:

R independently represent a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group, a —NR1R2 group, a (C1-C3)fluoroalkoxy group, a —NO2 group, a phenoxy group and a (C1-C4)alkoxy group,

R1 and R2 are independently a hydrogen atom or a (C1-C3)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is preferably 1 or 2,

n′ is as defined above and is preferably 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group and a (C1-C4)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Ic)

wherein:

R independently represent a hydrogen atom or a group chosen among a (C1-C3)alkyl group, a (C1-C3)fluoroalkyl group, a —NR1R2 group, a —COOR1 group, a —NO2 group and a (C1-C3)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

R1 and R2 are independently a hydrogen atom or a (C1-C3)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Id)

wherein:

R independently represent a hydrogen atom or a group chosen among a (C1-C3)alkyl group, a (C1-C3)fluoroalkyl group and a (C1-C3)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Ie)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a (C1-C3)alkyl group and a (C1-C3)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (If)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Ig)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a halogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Ii)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Ii)

wherein:

R independently represent a hydrogen atom or a group chosen among a (C1-C3)fluoroalkoxy group and a (C1-C3)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Ij)

wherein:

R independently represent a hydrogen atom or a group chosen among a (C1-C3)fluoroalkoxy group and a (C1-C3)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Ik)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a (C1-C3)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Il)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating cancer.

According to another particular embodiment, an additional subject-matter of the present invention is a compound of formula (Im)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,