Novel carbazole derivatives that sensitize cells to anticancer drugs

Abstract

The present invention relates to a compound of formula (I) Regarding TIFF2022551457000029.tif54154, where R, R 1 and R 2 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms, - an acyl group containing 1 to 10 carbon atoms, -carboxyl group, - an amide group containing 1 to 10 carbon atoms, and linear, cyclic or branched, saturated or unsaturated imino groups, optionally substituted by alkyl groups, and where R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, -hydroxyl group, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, - an acyl group containing 1 to 10 carbon atoms, - a carbonate group containing 1 to 10 carbon atoms, -carboxyl groups, and -cyano group.

Description

[Technical Field]

[0001] The present invention relates to novel carbazole derivatives of formula (I).

[0002] The present invention also relates to a process for preparing the compounds of formula (I).

[0003] The present invention also relates to pharmaceutical compositions comprising such compounds of formula (I).

[0004] Finally, the present invention also relates to compounds of formula (I) for use in a method for the treatment of cancer. [Background technology]

[0005] Cutting-edge technology Currently, various cancers, including lung, breast, and ovarian cancers, are treated with paclitaxel. Paclitaxel is a drug that targets cellular microtubules, binding to the taxane site of β-tubulin and stabilizing the microtubule lattice by strengthening lateral and / or longitudinal tubulin contacts. At high concentrations, paclitaxel promotes microtubule assembly. At low, clinically relevant concentrations, paclitaxel primarily inhibits microtubule dynamics without significantly affecting microtubule-polymer mass.

[0006] However, paclitaxel's poor solubility, its toxicity, and susceptibility to multidrug resistance mechanisms still severely limit its use.

[0007] Furthermore, germline mutations in the LKB1 gene, a known tumor suppressor gene, are frequently observed in cases of lung adenocarcinoma or uterine tumors. Such mutations also account for the majority of cases of Peutz-Jeghers syndrome, which induces polyp formation and an increased incidence of malignant tumors, particularly gastrointestinal and breast tumors.

[0008] This high prevalence of LKB1-deficient cells in these cancers indicates the urgency to focus on developing therapies that target such cells. Summary of the Invention

[0009] Object of the invention One object of the present invention is to provide improved treatments for cancer that can alleviate the above limitations.

[0010] In particular, the present invention aims to provide a solution to the technical problem of reducing the toxicity of compounds that stabilize cell microtubules, in particular paclitaxel.

[0011] The present invention aims to provide a solution to the technical problem of reducing resistance to compounds that stabilize microtubules, in particular resistance to paclitaxel.

[0012] The present invention aims to provide a solution to the technical problem of providing a novel treatment that targets LKB1-deficient cells.

[0013] One object of the present invention is to provide compounds for use in pharmaceutical treatment, especially against cancer, which are able to alleviate the above technical limitations.

[0014] Another object of the present invention is to reduce resistance to compounds that stabilize microtubules, particularly resistance to paclitaxel.

[0015] Another object of the present invention is to provide compounds that are selectively cytotoxic to LKB1-deficient cells. [Brief explanation of the drawings]

[0016] [Figure 1]FIG. 1 shows the change in HeLa cell viability as a function of paclitaxel (PTX) concentration, alone or in combination with various concentrations of compound (Ia) (0.5, 1, 6, 12, and 25 μM). [Figure 2] Shown are images of cellular microtubules (top) and DNA (bottom) from cells treated with DMSO (control) or 12 μM or 25 μM of compound (Ia). [Figure 3] Shown are images of chromosome consolidation in cells treated with DMSO (control) or 12 μM or 25 μM of compound (Ia). [Figure 4] The cell cycle distribution of HeLa cells treated with 12 or 25 μM of compound (Ia) or DMSO (control) was analyzed by flow cytometry. After 24 h, the curves corresponding to DMSO and 12 μM compound (Ia) are essentially superimposable at steps subG1, G1, and S. [Figure 5] Figure 1 shows the cell cycle distribution of HeLa cells treated with paclitaxel at concentrations of 1 nM or 5 nM, or DMSO (control). Cell cycle analysis was performed by flow cytometry. [Figure 6] 1 shows the cell cycle distribution of HeLa cells treated with a mixture of compound (Ia) (12 μM) and paclitaxel (1 nM) or DMSO (control). Cell cycle analysis was performed by flow cytometry. [Figure 7] 1 is a graph showing the in vivo change in tumor size over time depending on the treatment the mice received (paclitaxel alone, compound (Ia) alone, or a combination of paclitaxel and compound (Ia)). [Figure 8] 1 is a graph showing cell viability of LKB1-deficient cells or cells into which LKB1 was reintroduced as a function of the concentration of compound (Ia). [Figure 9] 1 is a graph showing cell viability of RPE-1 cells incubated with compound (Ia) alone or a combination of paclitaxel and compound (Ia). DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description of the Invention The present invention relates to compounds of formula (I):

[0018] [ka]

[0019] where R, R 1 and R 2 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms, - an acyl group containing 1 to 10 carbon atoms, -carboxyl group, - an amide group containing 1 to 10 carbon atoms, and linear, cyclic or branched, saturated or unsaturated imino groups, optionally substituted by alkyl groups, and where R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, -hydroxyl group, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, - an acyl group containing 1 to 10 carbon atoms, - a carbonate group containing 1 to 10 carbon atoms, -carboxyl groups, and -cyano group.

[0020] The compounds of formula (I) of the present invention may also be in their tautomeric, racemic, enantiomeric or polymorphic form, or in the form of a pharmaceutically acceptable salt.

[0021] Surprisingly, the present inventors have found that the compound of formula (I) of the present invention enhances the effect of compounds that stabilize cellular microtubules, particularly the effect of paclitaxel, without significantly increasing its toxicity.Such compounds of formula (I) can enable the use of low doses of compounds that stabilize microtubules, particularly paclitaxel, in cancer treatment, and can limit the occurrence of resistance.

[0022] Compounds of formula (I) are capable of sensitizing cells to low, non-toxic doses of compounds that stabilize microtubules, particularly paclitaxel.

[0023] The compound of formula (I) alone does not significantly affect interphase microtubule dynamics and exhibits moderate cytotoxicity, but it exerts synergistic cytotoxic effects with microtubule-stabilizing compounds, particularly paclitaxel.

[0024] Without being bound by theory, the inventors believe that compounds of formula (I) induce modulation of microtubule dynamics and increase the accumulation of microtubule-stabilizing compounds within microtubules.

[0025] Furthermore, it has surprisingly been discovered by the present inventors that the compounds of formula (I) of the present invention are selectively cytotoxic to LKB1-deficient cells.

[0026] It is understood that the present invention refers to groups or moieties that are "substituted," which means that at least one hydrogen radical of the group or moiety is replaced with an atom or group of atoms, called a substituent.

[0027] Examples of preferred substituents are halogen (chloro-, iodo-, bromo-, or fluoro-); alkyl; alkenyl; alkynyl; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyano; amide; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (—O); haloalkyl (e.g., trifluoromethyl); cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which may be monocyclic or fused or non-fused polycyclic, or monocyclic or fused or non-fused polycyclic. heterocycloalkyl, which may be fused or polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); CO2CH3; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and such moieties may also be optionally substituted with fused ring structures or bridges, e.g., —OCHO—. These substituents may optionally be further substituted with a substituent selected from such groups.

[0028] This invention refers to "acyl" groups, which are known as moieties derived by removal of a hydroxyl group from a carboxylic acid. Examples of acyl groups are aldehydes, ketones, esters, amides, or acyl chlorides.

[0029] Preferably, in the compounds of formula (I) according to the invention, R, R 1 and R 2 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, -X is selected from the group consisting of a hydrogen atom, a halogen atom, and a hydroxyl group, n is an integer between 1 and 10, x is the number of X present in the alkyl group, preferably x is 1, and X is at the terminal position of the alkyl group, formula -C n H 2n+1-x X x an alkyl group of -R a is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, formula -C(O)OR a an acyl group of an acyl group of the formula —C(O)H, -carboxyl group (-COOH), -R b is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula —C(O)NR b an amide group of, and -R c is selected from the group consisting of a hydrogen atom or an alkyl group that is linear, saturated, and contains 1 to 10 carbon atoms, or a phenyl group, of the formula -C=NR c an imino group of R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, -hydroxyl group, - linear, saturated, and n is an integer between 1 and 10, Formula -C n H 2n+1 an alkyl group of -R d is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, the formula -OR d an alkoxy group of -R a is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, formula -C(O)OR a an acyl group of -R eis a hydrogen atom or a linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl group of the formula -C(O)R containing 1 to 10 carbon atoms. e an acyl group of -R f is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula -OC(O)OR f Carbonate groups of -carboxyl group (-COOH), and -cyano group (-CN).

[0030] More preferably, in the compounds of formula (I) according to the present invention, R and R 1 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, - linear, saturated, and alkyl groups containing 1 to 10 carbon atoms; R 2 is selected from the group consisting of: - hydrogen atom, - a halogen atom, -X is selected from the group consisting of a hydrogen atom, a halogen atom, and a hydroxyl group, n is an integer between 1 and 10, x is the number of X present in the alkyl group, preferably x is 1, and X is at the terminal position of the alkyl group, formula -C n H 2n+1-x X x an alkyl group of -R a is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, formula -C(O)OR a an acyl group of an acyl group of the formula —C(O)H, -carboxyl group (-COOH), -R b is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula —C(O)NR b an amide group of, and -R c is selected from the group consisting of a hydrogen atom or an alkyl group that is linear, saturated, and contains 1 to 10 carbon atoms, or a phenyl group, of the formula -C=NR c the imino group of R 3 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, - linear, saturated, and n is an integer between 1 and 10, Formula -C n H 2n+1 and an alkyl group of R 4 is selected from the group consisting of: - hydrogen atom, - a halogen atom, -hydroxyl group, - linear, saturated, and n is an integer between 1 and 10, Formula -C n H 2n+1 an alkyl group of -R d is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, the formula -OR d an alkoxy group of -R a is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, formula -C(O)OR a an acyl group of -R e is a hydrogen atom or a linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl group of the formula -C(O)R containing 1 to 10 carbon atoms. e an acyl group of -R f is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula -OC(O)OR f Carbonate groups of -carboxyl group (-COOH), and -cyano group (-CN).

[0031] Even more preferably, in the compounds of formula (I) according to the present invention, R and R 1 teeth, Hydrogen atom, salt Basic atoms, and methyl groups; R 2 represents a hydrogen atom, a methyl group, or a -COH group, and X represents a salt. Basic atoms, odor Basic atom, iodine atom, and an alkyl group of formula -CHX, selected from the group consisting of alkyl groups, alkyl hydroxyl groups, and hydroxyl groups; a is a methyl or ethyl group, formula -C(O)OR a acyl groups of the formula -C(O)H, carboxyl groups (-COOH), R b is a methyl or ethyl group, formula -C(O)NR b the amide group, and R c is a phenyl group, formula -C=NR c an imino group consisting of selected from the group R 3 , R 5 and R 6 is a hydrogen atom, salt Basic from the group consisting of atoms, methyl groups and ethyl groups are independently selected, and R 4 is a hydrogen atom, a methyl group, a hydroxyl group aryl group ,salt Basic atoms, odor Basic Atom, Fluorine Basic Atom, Yo Ion atom, R d is a methyl or ethyl group, the formula -OR d an alkoxy group, R a is a methyl or ethyl group, formula -C(O)OR a acyl group, R e The methyl group, ethyl group, and -C(O)R, which are straight-chain propyl, straight-chain pentyl, -CHCH-cyclopentyl, and (para-methyl)phenyl groups; e acyl group, R f is a methyl or ethyl group, formula -OC(O)OR f The carbonate group, carboxyl group (-COOH), and cyano group ( -CN).

[0032] Advantageously, in the compounds of formula (I) according to the invention, R and R1 is a hydrogen atom, and and methyl groups; R 2 is selected from the group consisting of a hydrogen atom, a —COH group, and a —CHOH group; R 3 , R 5 and R 6 is a hydrogen atom, salt Basic atoms, and ethyl groups. Selected, and R 4 is a hydrogen atom, hydroxy aryl group ,salt Basic atoms, odor Basic Atom, Fluorine Basic atom, R f is an ethyl group, formula -OC(O)OR f Carbonate group, and R a is a methyl group, formula -C(O)OR a and an acyl group selected from the group consisting of:

[0033] According to one embodiment, the compounds of formula (I) according to the invention are 3 , R 4 , R 5 , and R 6 wherein at least three of the substituents selected from the group consisting of: are hydrogen atoms.

[0034] According to one embodiment, in the compounds of formula (I) according to the invention, R 4 is not a hydrogen atom.

[0035] According to one embodiment, in the compounds of formula (I) according to the invention, R 4 is a halogen atom.

[0036] According to one embodiment, the compounds of formula (I) according to the invention comprise R, R 1 , and R 2 At least one of the substituents selected from the group consisting of is a hydrogen atom.

[0037] According to one embodiment, the compounds of formula (I) according to the invention comprise R, R 1 , and R 2 At least two of the substituents selected from the group consisting of are hydrogen atoms.

[0038] According to one embodiment, R=R 1 =R 2 =H.

[0039] In a preferred embodiment, the compound of formula (I) is selected from the group consisting of:

[0040] [ka] [ka] [ka]

[0041] In a preferred embodiment, the compound of formula (I) is selected from the group consisting of:

[0042] [ka] [ka]

[0043] Preferably, the compound of formula (I) is selected from the group consisting of a compound of formula (Ia), a compound of formula (If), a compound of formula (Ih), a compound of formula (Ie), a compound of formula (Im), a compound of formula (In), a compound of formula (Ic), a compound of formula (Is), and any combination thereof.

[0044] Preferably, the compound of formula (I) is selected from the group consisting of a compound of formula (Ia), a compound of formula (If), a compound of formula (Ih), a compound of formula (Ie), and any combination thereof.

[0045] Preferably, the compound of formula (I) is selected from the group consisting of a compound of formula (Ia), a compound of formula (If), a compound of formula (Ih), and any combination thereof.

[0046] Preferably, the compound of formula (I) is selected from the group consisting of a compound of formula (Ia), a compound of formula (If), a compound of formula (Ih), a compound of formula (Ic), a compound of formula (Is), and any combination thereof.

[0047] More preferably, the compound of formula (I) is selected from the group consisting of a compound of formula (Ia), a compound of formula (Ic), a compound of formula (Is), and any combination thereof.

[0048] Advantageously, the compound of formula (I) is a compound of formula (Ia).

[0049] Advantageously, the compound of formula (I) is a compound of formula (Ic), a compound of formula (Is), and any combination thereof.

[0050] The present invention also relates to a process for preparing the compounds of formula (I) according to the invention, which comprises the steps of: Compounds of formula (II):

[0051] [ka]

[0052] with a compound of formula (III)

[0053] [ka]

[0054] Or a compound of formula (IV)

[0055] [ka]

[0056] a) contacting the Here, R, R 1 and R 2 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms, - an acyl group containing 1 to 10 carbon atoms, -carboxyl group, - an amide group containing 1 to 10 carbon atoms, and linear, cyclic or branched, saturated or unsaturated imino groups, optionally substituted by alkyl groups, and where R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, -hydroxyl group, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, - an acyl group containing 1 to 10 carbon atoms, - a carbonate group containing 1 to 10 carbon atoms, -carboxyl groups, and -cyano group.

[0057] Preferably, the process for preparing the compound of formula (I) according to the present invention comprises the steps of: Compounds of formula (II):

[0058] [ka]

[0059] with a compound of formula (III)

[0060] [ka]

[0061] a) contacting the Here, R, R 1 and R 2 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms, - an acyl group containing 1 to 10 carbon atoms, -carboxyl group, - an amide group containing 1 to 10 carbon atoms, and linear, cyclic or branched, saturated or unsaturated imino groups, optionally substituted by alkyl groups, and where R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, -hydroxyl group, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, - an acyl group containing 1 to 10 carbon atoms, - a carbonate group containing 1 to 10 carbon atoms, -carboxyl groups, and -cyano group.

[0062] In one embodiment, the process for preparing a compound of formula (I) comprises step a') contacting a compound of formula (III) with an acid as described above prior to contacting said compound of formula (III) with a compound of formula (II) or (IV), preferably a compound of formula (II).

[0063] Preferably, the acid in step a) or a') is acetic acid.

[0064] Preferably, step a) is carried out at a temperature of from 25°C to 120°C, more preferably from 60°C to 100°C, for a period of typically from 15 to 180 minutes, more preferably from 60 to 150 minutes.

[0065] Preferably, step a') is carried out at a temperature of from 15°C to 40°C, more preferably from 20°C to 30°C, for a period of typically from 1 minute to 60 minutes, more preferably from 10 minutes to 20 minutes.

[0066] According to a particular embodiment, step a) is carried out in an organic solvent, preferably in an alcohol containing from 1 to 8 carbon atoms, more preferably in ethanol.

[0067] Preferably, in the method of the present invention: R, R 1 and R 2 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, -X is selected from the group consisting of a hydrogen atom, a halogen atom, and a hydroxyl group, n is an integer between 1 and 10, x is the number of X present in the alkyl group, preferably x is 1, and X is at the terminal position of the alkyl group, formula -C n H 2n+1-x X x an alkyl group of -R a is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, formula -C(O)OR a an acyl group of an acyl group of the formula —C(O)H, -carboxyl group (-COOH), -Rb is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula —C(O)NR b an amide group of, and -R c is selected from the group consisting of a hydrogen atom or an alkyl group that is linear, saturated, and contains 1 to 10 carbon atoms, or a phenyl group, of the formula -C=NR c an imino group of R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, -hydroxyl group, - linear, saturated, and n is an integer between 1 and 10, Formula -C n H 2n+1 an alkyl group of -R d is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, the formula -OR d an alkoxy group of -R a is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, formula -C(O)OR a an acyl group of -R e is a hydrogen atom or a linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl group of the formula -C(O)R containing 1 to 10 carbon atoms. e an acyl group of -R f is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula -OC(O)OR f Carbonate groups of -carboxyl group (-COOH), and -cyano group (-CN).

[0068] More preferably, in the method of the present invention: R, and R 1 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, - linear, saturated, and alkyl groups containing 1 to 10 carbon atoms; R 2 is selected from the group consisting of: - hydrogen atom, - a halogen atom, -X is selected from the group consisting of a hydrogen atom, a halogen atom, and a hydroxyl group, and n is an integer between 1 and 10; n The alkyl group of X -R a is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, formula -C(O)OR a an acyl group of an acyl group of the formula —C(O)H, -carboxyl group (-COOH), -R b is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula —C(O)NR b an amide group of, and -R c is selected from the group consisting of a hydrogen atom or an alkyl group that is linear, saturated, and contains 1 to 10 carbon atoms, or a phenyl group, of the formula -C=NR c the imino group of R 3 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - a halogen atom, - alkyl groups that are linear, saturated, and contain 1 to 10 carbon atoms, and R 4 is selected from the group consisting of: - hydrogen atom, - a halogen atom, -hydroxyl group, - linear, saturated, and alkyl groups containing 1 to 10 carbon atoms; -R d is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, the formula -OR d an alkoxy group of -R ais a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, formula -C(O)OR a an acyl group of -R e is a hydrogen atom or a linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl group of the formula -C(O)R containing 1 to 10 carbon atoms. e an acyl group of -R f is a straight-chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula -OC(O)OR f Carbonate groups of -carboxyl group (-COOH), and -cyano group (-CN).

[0069] Even more preferably, in the method of the present invention: R, and R 1 is a hydrogen atom, salt Basic atoms, and methyl groups And, R 2 represents a hydrogen atom, a methyl group, or a -COH group, and X represents a salt. Basic atoms, odor Basic atom, iodine atom, and an alkyl group of formula -CHX, selected from the group consisting of alkyl groups, alkyl hydroxyl groups, and hydroxyl groups; a is a methyl or ethyl group, formula -C(O)OR a acyl groups of the formula -C(O)H, carboxyl groups (-COOH), R b is a methyl or ethyl group, formula -C(O)NR b the amide group, and R c is a phenyl group, formula -C=NR c an imino group selected from the group consisting of R 3 , R 5 and R 6 is a hydrogen atom, salt Basic from the group consisting of atoms, methyl groups and ethyl groups are independently selected, and R 4 is a hydrogen atom, a methyl group, a hydroxyl group aryl group,salt Basic atoms, odor Basic Atom, Fluorine Basic Atom, Yo Ion atom, R d is a methyl or ethyl group, the formula -OR d an alkoxy group, R a is a methyl or ethyl group, formula -C(O)OR a acyl group, R e The methyl group, ethyl group, and -C(O)R, which are straight-chain propyl, straight-chain pentyl, -CHCH-cyclopentyl, and (para-methyl)phenyl groups; e acyl group, R f is a methyl or ethyl group, formula -OC(O)OR f The carbonate group, carboxyl group (-COOH), and cyano group ( -CN).

[0070] Advantageously, in the method of the invention: R, and R 1 are independently selected from the group consisting of a hydrogen atom and a methyl group; R 2 is selected from the group consisting of a hydrogen atom, a —COH group, and a —CHOH group; R 3 , R 5 and R 6 is a hydrogen atom, salt Basic atoms, and ethyl groups. Selected, and R 4 is a hydrogen atom, hydroxy aryl group ,salt Basic atoms, odor Basic Atom, Fluorine Basic atom, and R f is an ethyl group, formula -OC(O)OR f Carbonate group, and R a is a methyl group, formula -C(O ) OR a and an acyl group selected from the group consisting of:

[0071] According to one embodiment, in the compound of formula (II), R 3 , R 4 , R 5 , and R 6 At least three of the substituents selected from the group consisting of are hydrogen atoms.

[0072] According to one embodiment, in the compound of formula (III), R, R 1 , and R 2 At least one of the substituents selected from the group consisting of is a hydrogen atom.

[0073] According to one embodiment, in the compound of formula (III), R, R 1 , and R 2 At least two of the substituents selected from the group consisting of are hydrogen atoms.

[0074] According to one embodiment, in the compound of formula (III), R=R 1 =R 2 =H.

[0075] According to one embodiment, in the compound of formula (IV), R, R 1 , and R 2 At least one of the substituents selected from the group consisting of is a hydrogen atom.

[0076] According to one embodiment, in the compound of formula (IV), R, R 1 , and R 2 At least two of the substituents selected from the group consisting of are hydrogen atoms.

[0077] According to one embodiment, in the compound of formula (IV), R=R 1 =R 2 =H.

[0078] In a preferred embodiment, in the method according to the invention, the compound of formula (II) is selected from the group consisting of:

[0079] [ka]

[0080] Preferably, the compound of formula (II) is selected from the group consisting of a compound of formula (II-a), a compound of formula (II-c), a compound of formula (II-d), and any combination thereof.

[0081] Advantageously, the compound of formula (II) is a compound of formula (II-a).

[0082] In another preferred embodiment, the compound of formula (III) is selected from the group consisting of:

[0083] [ka]

[0084] Preferably, the compound of formula (III) is a compound of formula (III-a) or a compound of formula (III-c). Highly preferably, the compound of formula (III) is a compound of formula (III-a).

[0085] In another preferred embodiment, the compound of formula (IV) is selected from the group consisting of:

[0086] [ka]

[0087] Preferably, the compound of formula (IV) is a compound of formula (IV-b).

[0088] According to one embodiment, the method according to the invention further comprises a step b) of chemical modification of the compound obtained from step a). Preferably, step b) is a reduction of the acyl group. Preferably, step b) comprises contacting the compound obtained from step a) with a compound that reduces aldehydes, such as a borohydride salt, preferably sodium borohydride. More preferably, step b) is a reduction of the aldehyde, preferably by contacting the compound obtained from step a) with a compound that reduces aldehydes, such as a borohydride salt, preferably sodium borohydride.

[0089] Preferably, step b) is carried out at a temperature of from 15° C. to 40° C., more preferably from 20° C. to 30° C., typically for a period of from 60 to 150 minutes.

[0090] The present invention also relates to pharmaceutical compositions, characterized in that they contain at least one compound of formula (I) according to the invention and at least one pharmaceutically acceptable excipient.

[0091] The phrase "pharmaceutically acceptable excipient" refers to any diluent, adjuvant, or vehicle, such as preservatives, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents.

[0092] The pharmaceutical compositions of the present invention can be administered by any suitable route, for example, oral, buccal, inhalation, sublingual, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, and intracoronary) administration. Thus, the pharmaceutical compositions of the present invention may be provided in a variety of forms, such as hard gelatin capsules, capsules, compressed tablets, orally ingested suspensions, lozenges, or injectable solutions, ointments, or any other form suitable for the method of administration.

[0093] The exact formulation, route of administration, and dosage can be selected by an individual physician, taking into account the patient's condition.Dosage and administration interval can be individually adjusted to provide a plasma level of the compound of formula (I) sufficient to maintain preventive or therapeutic effect.Therefore, the amount of pharmaceutical composition administered depends on the subject to be treated, the subject's weight, the severity of the disease, and the method of administration.In one embodiment, the amount of compound of formula (I) administered depends on the response of the treated subject to the co-administered compound that stabilizes cellular microtubules.

[0094] The present invention also relates to a pharmaceutical composition, characterized in that it comprises at least one compound of formula (I) according to the invention, at least one compound that stabilizes cellular microtubules, preferably human cells, and at least one pharmaceutically acceptable excipient.

[0095] According to the present invention, compounds that stabilize cellular microtubules stabilize microtubule polymers and protect them from depolymerization, thus inhibiting the process of cell division as well as other different processes that depend on microtubule dynamics.

[0096] Preferably, the compound that stabilizes cellular microtubules is selected from the group consisting of taxanes, epothilones, TPI-287, carbazitaxel, zampanolide, dactylolide, discodermolide, taccalonolide, davunetide, eleutherobin, dictyostatin, and sarcodictyins A and B.

[0097] More preferably, the compound that stabilizes cellular microtubules is selected from the group consisting of taxanes.

[0098] Advantageously, the compound that stabilizes cellular microtubules is paclitaxel.

[0099] In particular, the cellular microtubule stabilizing compounds according to the invention are active in vitro on HeLa cells. According to one embodiment, the cellular microtubule stabilizing compounds according to the invention are active in vitro on HeLa cells at concentrations of 5 nM or less, preferably strictly less than 5 nM.

[0100] The present invention also relates to compounds of formula (I) according to the invention for use in a method for the treatment of diseases and / or disorders selected from the group consisting of cancer and disorders involving microtubule deregulation.

[0101] The present invention also relates to a method for treating a disease and / or disorder selected from the group consisting of cancer and disorders involving microtubule deregulation, said method comprising therapeutically effective administration of a compound of formula (I) to a subject in need thereof.

[0102] The present invention also relates to the use of compounds of formula (I) according to the invention for the manufacture of a medicament for the treatment of diseases and / or disorders selected from the group consisting of cancer and disorders involving microtubule deregulation.

[0103] According to the present invention, a disorder involving deregulation of microtubules is a disorder involving deregulation of microtubule dynamics.

[0104] Preferably, the disorder involving deregulation of microtubules is selected from the group consisting of neurological diseases such as Alzheimer's disease or schizophrenia, cardiac diseases, and spinal cord injuries.

[0105] The present invention also relates to a compound of formula (I) according to the invention for use in a method for treating a cancer selected from the group consisting of cancers requiring stabilization of cell microtubules, preferably by a taxane, and cancers caused by LKB1-deficient cells.

[0106] Preferably, the cancer treatable by a compound that stabilizes cellular microtubules is selected from the group consisting of breast cancer, ovarian cancer, liver cancer, lung cancer, pancreatic cancer, and prostate cancer.

[0107] Preferably, the cancer induced by LKB1-deficient cells is selected from the group consisting of lung adenocarcinoma and uterine cancer, cervical cancer, breast cancer, intestinal cancer, testicular cancer, pancreatic cancer, and skin cancer.

[0108] Advantageously, the compounds of formula (I) according to the invention are used in a method for the treatment of cancers selected from the group consisting of breast cancer, ovarian cancer, lung cancer, liver cancer, uterine cancer, and AIDS-associated Kaposi's sarcoma.

[0109] The present invention also relates to a compound of formula (I) according to the invention for use in a method for the treatment of the human or animal body, characterized in that it is co-administered with at least one compound that stabilizes cellular microtubules, preferably human cells.

[0110] Preferably, the compound that stabilizes cellular microtubules is selected from the group consisting of taxanes, epothilones, TPI-287, cabazitaxel, zampanolide, dactylolide, discodermolide, taccalonolide, davunetide, eleutherobin, dictyostatin, and sarcodictyins A and B, preferably a taxane.

[0111] Advantageously, the compound that stabilizes cellular microtubules is paclitaxel.

[0112] The present invention also relates to a compound of formula (I) according to the invention for use in a method of treatment of the human or animal body, characterized in that the compound of formula (I) is administered to a patient having LKB1-deficient cells.

[0113] According to the present invention, LKB1-deficient cells are cells that do not express active liver kinase B1 (LKB1) because the STK11 gene encoding LKB1 has undergone a germline mutation or because LKB1 activity has been inactivated by various mechanisms, including mutation.

[0114] The invention will be better understood on reading the following non-limiting examples. [Example]

[0115] Example 1: Synthesis of compounds of formula (I) Compounds of formula (II) were synthesized according to the following published methods: - Tabka et al., European Journal of Medicinal Chemistry (1989), 24(6), 605-610, - Lancelot et al., Heterocyles (1990), 31(2), - Lancelot et al., Gazzetta chimica Italiana, 121, 1991, - Lancelot et al., (1986), 22 eme Rencontres Internationales de chimie therapeutique, Clermont-Ferrand, September 3-5, 124, - Lancelot et al., (1989), 25 eme Rencontres Internationales de chimie therapeutique, Grenoble, July 2-5, - Panno et al., Nuovi 1,4-Dimethil carbazoli: Sintesi, Reattivitae valutazione Biologica. Tesi Di Dottorato d'Universita Calabria: Universita Della Calabria, 2011. Compounds of formula (III-a) (CAS: 696-59-3), (III-c) (CAS: 50634-05-4), and (IV-b) (CAS-110-13-4) are commercially available.

[0116] Synthesis of compounds (Ia), (Id), (Ie), (If), (Ii), (Im), (In), (Ip), and (Iq) Compounds of formula (III-a) (0.0033-0.0044 mol) were stirred in 50 mL of acetic acid at room temperature for 15 minutes. Then, 1 equivalent of compound of formula (II-x) (x = ai) was added. The mixture was heated at 80 °C for 1 hour and 30 minutes. After cooling, the solution was concentrated under reduced pressure. The residue was redissolved in 50 mL of saturated sodium bicarbonate solution and then extracted with 70 mL of ethyl acetate. The organic phase was washed with water, decanted, dried over magnesium sulfate, and concentrated under reduced pressure. Compounds of formula (Ix) (x = a, d, e, f, j, m, n, p, q) were obtained by crystallization in acetonitrile.

[0117] Synthesis of compounds (Ic), (Ih), and (Ik) The compound of formula (III-c) (0.0041 mol) was stirred in 50 mL of acetic acid at room temperature for 15 minutes. Then, 1 equivalent of the compound of formula (II-x) (x = a, d, e) was added. The mixture was heated at 80 °C for 2 hours. After cooling, the solution was concentrated under reduced pressure. The residue was redissolved in 50 mL of a saturated solution of sodium bicarbonate and then extracted with 70 mL of ethyl acetate. The organic phase was washed with water, decanted, dried over magnesium sulfate, and evaporated. The compound of formula (Ix) (x = c, h, k) was obtained by crystallization in acetonitrile.

[0118] Synthesis of compounds (Ib), (Ig), (Ij), and (Io) Compounds of formula (II-x) (x = a, d, e, g) (0.0041-0.0049 mol) were heated in 50 mL of absolute ethanol at 80 °C for 2 hours in the presence of 1.2 equivalents of compound of formula (IV-b) and 0.3 mL of acetic acid. After cooling, the solution was concentrated under reduced pressure. The residue was redissolved in 40 mL of saturated sodium bicarbonate solution and then extracted with 60 mL of ethyl acetate. The organic phase was washed with water, decanted, dried over magnesium sulfate, and concentrated under reduced pressure. Compounds of formula (Ix) (x = b, g, j, o) were obtained by crystallization in acetonitrile.

[0119] Synthesis of compound (Is) The compound of formula (Ic) (0.35 mmol) was stirred in 2 ml of dry methanol and 2 ml of dry tetrahydrofuran at 0° C. Two equivalents of sodium borohydride were added. The mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure. The residue was redissolved in 5 ml of ice water and then extracted twice with 5 ml of ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated. The compound of formula (Is) was obtained by purification by chromatography on silica gel (diethyl ether).

[0120] Compounds (Ia) to (Iq) and (Is) were characterized by IR spectroscopy and / or NMR spectroscopy. The properties of each compound are summarized in the following table.

[0121] [Table 1-1] [Table 1-2] [Table 1-3]

[0122] Example 2: Evaluation of the cytotoxicity of paclitaxel (PTX) in combination with compounds of formula (I) 2.1. Cytotoxicity to HeLa cells Cell viability was analyzed using the colorimetric Prestoblue assay (Invitrogen, #A13262). Cells were seeded at a density of 2,500 cells per well in 96-well microplates (Greiner, #655077) and allowed to adhere for 24 hours before treatment with DMSO (final concentration 0.1%) or the indicated drug concentrations for 72 hours. After 72 hours of treatment, 10 μL of Prestoblue was added to each well, and the cells were incubated for an additional 45 minutes. The absorbance of each well was measured using a FLUOstar Optima microplate reader (excitation, 544 nm; emission, 580 nm).

[0123] First, the cytotoxicity of compounds (Ia), (Ic), (If), (Ih), (Ie), (Im), (In), and (Is) against HeLa cells was evaluated using the "Prestoblue" assay described above.

[0124] Compound (Ia) is slightly cytotoxic and has a GI 50 The values ​​(50% of growth inhibition) were 19.4μM-21.8μM.

[0125] Compounds (If) and (Ie) are also slightly toxic and have a GI 50 The GI values ​​were 16.2 μM and 14.8 μM, respectively. 50 The GI value for both compounds (Ic) and (Is) is 1.06 μM. 50 The value is 2 μM.

[0126] HeLa cells were then treated for 72 hours with various concentrations of paclitaxel (0.05, 0.1, 0.25, 0.5, 1, 2.5, 5 nM) and a mixture of compounds (Ia), (If), (Ih), (Ie), (Im), (In), (Ic), and (Is).

[0127] The following results were obtained:

[0128] [Table 2]

[0129] GI of paclitaxel 50 It can be observed that decreases with increasing compound (Ia) concentration.

[0130] At a concentration of 12 μM of compound (Ia) (a concentration at which compound (Ia) itself does not exhibit cytotoxicity), the GI 50 is the GI Response of paclitaxel alone 50 This is a 2.2-fold decrease compared to (1.5 nM vs. 0.68 nM).

[0131] Similar results are observed when compounds (If), (Ih), (Ic), and (Is) are combined with paclitaxel, and to a lesser extent when compounds (Ie), (Im), or (In) are combined with paclitaxel.

[0132] These results highlight the synergistic effect of administering compounds of formula (I) in combination with paclitaxel.

[0133] 2.2. Effects on apoptosis Apoptosis assays were performed using flow cytometry with the FITC Annexin V Apoptosis Detection Kit I (BD Biosciences, #556547) and analyzed with FCS express software.

[0134] [Table 3]

[0135] Compared to DMSO, no additional apoptosis was detected when compound (Ia) was applied at a concentration of 12 μM for 48 hours, but at 25 μM, cell death was induced by apoptosis. These results indicate that compound (Ia) is moderately toxic.

[0136] When combined with paclitaxel, compound (Ia) also exhibits a synergistic effect on cell apoptosis.

[0137] 2.3. Cytotoxicity against murine cancer cells Cell viability was analyzed using the colorimetric Prestoblue assay (Invitrogen, #A13262). Cells were seeded at a density of 2,500 cells per well in 96-well microplates (Greiner, #655077) and allowed to adhere for 24 hours before treatment with DMSO (final concentration 0.1%) or the indicated drug concentrations for 72 hours. After 72 hours of treatment, 10 μL of Prestoblue was added to each well, and the cells were incubated for an additional 45 minutes. The absorbance of each well was measured using a FLUOstar Optima microplate reader (excitation, 544 nm; emission, 580 nm).

[0138] The synergistic effect of the combination of compound of formula (Ia) and paclitaxel is also observed in a mouse breast cancer cell line (4T1 cells) (Figure 1).

[0139] Example 3: Effect of compounds of formula (I) on cell cycle and mitosis The effect of compounds of formula (I) on the cell cycle and mitosis of HeLa cells was analyzed by flow cytometry and immunofluorescence.

[0140] For flow cytometry analysis, HeLa cells were treated with the indicated concentrations of compound (Ia) for 12, 24, and 48 hours. The cells were then harvested and washed in PBS by centrifugation. 5 The cells were fixed in 1 mL of 70% methanol overnight at 4 °C. After washing twice with PBS, the cells were fixed with 50 μg mL -1 of propidium iodide and 0.2 mg.mL -1The cells were incubated with RNase A / PBS for 30 min at 37°C and then analyzed. The percentage of cells in specific cell cycle phases (G0, G1, S, G2, and M) was determined using an Accuri C6 flow cytometer (Becton Dickinson).

[0141] Results are expressed as the mean ± SD of three separate experiments. Significance was determined by Student's t-test (*p<0.05, **p<0.01, ***p<0.0001 compared to control).

[0142] For immunofluorescence analysis, cells were grown for 48 hours on glass coverslips placed in 24-well microplates. When the cells reached 70% confluence, the medium was replaced with fresh medium supplemented with compound (Ia). After 5 hours of exposure to compound (Ia), the cells were fixed and permeabilized with absolute methanol at -20°C for 6 minutes. After washing and saturating with 3% BSA / PBS, the cells were incubated with anti-α-tubulin antibody (1:4000) at room temperature (RT) for 45 minutes. The cells were washed twice again and subsequently incubated with Alexa 488-conjugated anti-mouse antibody (1:1000) for 30 minutes at room temperature. DNA was added at 20 μg / mL. -1 The sections were stained with Hoechst 33342 and coverslips were mounted on microscope slides with Mowiol 4-88 (Calbiochem, #475904). Images were captured on a Zeiss AxioimagerM2 microscope equipped with AxioVision acquisition software and analyzed using Fiji software.

[0143] The effect of compound (Ia) on cellular microtubules was determined. Compound (Ia) treatment (12-25 μM) did not visibly disrupt the microtubule network of interphase cells (Figure 2).

[0144] As shown in Figure 3, defects in chromosome assembly were observed in some mitotic cells in the cell population treated with 12 μM of compound (Ia). The occurrence of such defects increased with higher doses (25 μM) of compound (Ia).

[0145] The effect of a high dose (25 μM) of compound (Ia) on microtubule dynamic instability parameters was measured using time-lapse fluorescence microscopy of GFP-EB3 transfected cells (Table 1).

[0146] [Table 4]

[0147] Compound Ia decreased the microtubule growth rate and length, as indicated by an increase in distance-based catastrophe frequency and an increase in pause time, indicating that 25 μM compound Ia inhibited microtubule dynamics.

[0148] Flow cytometry analysis showed that compound (Ia) at a concentration of 12 μM caused a significant delay in the completion of metaphase, as cells were blocked in the G2 / M phase (Figure 4). When compound (Ia) was applied at a concentration of 25 μM, the majority of cells were blocked in prometaphase.

[0149] Example 4: Effect of the combination of the compound of formula (I) and paclitaxel (PTX) on cell cycle and mitosis Flow cytometry analysis was performed using HeLa cells. HeLa cells were treated with the indicated concentrations of paclitaxel, with or without compound (Ia), for 12, 24, and 48 hours, then fixed with methanol, stained with propidium iodide, and analyzed by flow cytometry. Results are expressed as the mean ± SD of three separate experiments. Significance was determined by Student's t-test (*p<0.05, **p<0.01, ***p<0.0001 compared to control).

[0150] Flow cytometry analysis showed that after 15 hours of treatment with 5 nM paclitaxel, half of the cell population was blocked in the G2 / M phase, and nearly 20% of the cells had already undergone apoptosis. Subsequently, the proportion of cells in G2 / M gradually decreased, paralleling an increase in the number of apoptotic (subG1) or multinucleated cells (Figure 5).

[0151] As shown in Figure 6, the combination of 1 nM paclitaxel (PTX) with 12 μM compound (Ia) induced a cell cycle block that was nearly superimposable with the block observed when cells were treated with 5 nM paclitaxel. The similarity of the results obtained with the combination to those obtained with 5 nM paclitaxel indicates that the overall effect of the combination is due to an increase in the effect of paclitaxel by compound (Ia).

[0152] Example 5: Compound (Ia) and paclitaxel (PTX) act synergistically against tumor growth in vivo The effects of coadministration of compound (Ia) and paclitaxel and the effects of compound (Ia) and paclitaxel injected separately on tumor growth were compared in a tumor mouse model.

[0153] In the first series of experiments (not shown), HeLa cell tumors were evaluated for their sensitivity to therapeutic doses of paclitaxel. To this end, mice bearing large tumors formed from xenografted HeLa cells received intravenous (iv) injections of paclitaxel (2–8 mg / kg) every two days for 10 days. In the same experiment, the effects of compound (Ia) (15–60 mg / kg, iv), injected on the same schedule, were analyzed. There was no significant difference in the body weight of animals treated with paclitaxel or compound (Ia) compared with those treated with the vehicle. Furthermore, the animals showed no signs of discomfort, indicating good tolerability of the treatment. Paclitaxel induced a significant reduction in tumor size when administered at 4 mg / kg and 8 mg / kg. Compound (Ia) did not induce a significant effect on tumor size, regardless of the injected dose, although tumors tended to shrink with increasing compound (Ia) concentrations. The results confirmed the antitumor effect of high concentrations of paclitaxel in this model. The results also show that compound (Ia) does not have significant antitumor activity when applied alone, even at high concentrations.

[0154] A second experiment was conducted to study the effect of low doses (2-3 mg / Kg) of paclitaxel in combination with different concentrations of compound (Ia) on tumor size.

[0155] The protocol for this combination study was as follows: 72 NMRI nude mice (5-week-old female) were inoculated with 10 x 10 exponentially dividing HeLa cells into the right flank. 6 The tumor volume was approximately 200 mm 3When the mice reached 100 mg / kg / day, i.e., 9 days after cell injection, they were randomly divided into 9 groups of 8 mice each and received intravenous injections of drugs every 2 days. The first group received 2 mg / kg paclitaxel, the second group received 3 mg / kg paclitaxel, the third group received 40 mg / kg compound (Ia), the fourth group received 60 mg / kg compound (Ia), the fifth group received a combination of compound (Ia) (40 mg / kg) and paclitaxel (2 mg / kg), the sixth group received a combination of compound (Ia) (40 mg / kg) and paclitaxel (3 mg / kg), the seventh group received a combination of compound (Ia) (60 mg / kg) and paclitaxel (2 mg / kg), the eighth group received a combination of compound (Ia) (60 mg / kg) and paclitaxel (3 mg / kg), and the ninth group received vehicle (14% DMSO, 14% Tween 80 and 72% PBS). Tumor growth was monitored three times a week using sliding calipers.

[0156] No changes in body weight were observed throughout the study, suggesting that the combination was well tolerated. As shown in Figure 7, the combination of paclitaxel and compound (Ia) significantly affected tumor size, whereas administration of each compound separately had no effect. This antitumor effect varied in a dose-dependent manner with respect to compound (Ia) and paclitaxel concentrations. These results demonstrate that the synergistic effect observed between paclitaxel and compound (Ia) in vitro also occurs in vivo, leading to therapeutic efficacy.

[0157] Example 6: Evaluation of the effect of compounds of formula (I) on LKB1-deficient cells The concept of synthetic lethality was applied to evaluate the selective toxicity of compound (I) against LKB1-deficient cells. This method involves determining whether the combination of a mutation leading to LKB1 deficiency and the action of compound (I) causes lethality, but the mutation itself is not lethal, nor is compound (I) alone. The differential cytotoxicity of compound (I) against LKB1-deficient cells was measured in MEF KO LKB1 cells (LKB1-deficient cells) or cells in which LKB1 was reintroduced. Cell viability analysis using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide): Assays were performed in 96-well microplates. LKB1 KO MEF cells (LKB1- / -) and LKB1-rescued MEF cells (LKB1+ / +) were seeded at 20,000 cells per well and grown for 24 hours. The medium was then replaced with fresh medium containing compound (Ia) (0–25 μM) or DMSO (0.25%). The cells were grown for an additional 48 hours. Next, 20 μL of 5 mg / mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution was added to each well and incubated at 37°C for 4 hours. The medium was discarded, and 100 μL of a 1:1 DMSO:ethanol solution was added to each well and mixed by gentle shaking for 10 minutes. The absorbance at 570 nm was measured using a microplate reader.

[0158] The results obtained are shown in FIG.

[0159] Example 7: Evaluation of the effect of compounds of formula (I) in combination with paclitaxel on the viability of non-cancerous cells RPE-1 cells were incubated with the indicated combinations of Compound (Ia) / paclitaxel for 72 hours. The percentage of viable cells was calculated after Prestoblue assay as described above. Data are shown as the mean ± SEM of three independent experiments.

[0160] The results obtained are shown in FIG.

[0161] It can be seen that the compound of formula (I) does not exhibit toxicity to non-cancerous cells. (Note that the effect of different doses of compound (Ia) alone on cell viability can be seen at the x-coordinate = 0 in the graph of Figure 9, which corresponds to 0 nM paclitaxel.) The GI of PTX 50 The cytotoxicity of compound Ia (7 nM) was higher in this cell line than in HeLa cells. When used in combination with PTX, compound Ia was able to synergistically affect cell viability at high doses (25 μM). These results indicate that compound Ia does not induce additional toxicity.

Claims

1. Compounds of formula (I): 【Chemistry 1】 Here, R, R 1 and R 2 are independently selected from the group consisting of: - hydrogen atom, - halogen atom, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms; - an acyl group containing 1 to 10 carbon atoms, -carboxyl group, an amide group containing 1 to 10 carbon atoms, and linear, cyclic or branched, saturated or unsaturated imino groups, optionally substituted by alkyl groups, and Here, R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - halogen atoms, -hydroxyl group, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms; - an alkoxy group containing 1 to 10 carbon atoms, - an acyl group containing 1 to 10 carbon atoms, - a carbonate group containing 1 to 10 carbon atoms, -carboxyl group, and -cyano group.

2. 10. A compound of formula (I) according to claim 1, Here, R, R 1 and R 2 are independently selected from the group consisting of: - hydrogen atom, - halogen atom, -X is selected from the group consisting of a hydrogen atom, a halogen atom, and a hydroxyl group, n is an integer between 1 and 10, x is the number of X present in the alkyl group, and X is at the terminal position of the alkyl group, n H 2n+1-x X x an alkyl group of -R a is a straight chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula —C(O)OR a an acyl group of an acyl group of the formula —C(O)H, -carboxyl group (-COOH), -R b is a straight chain and saturated alkyl group containing 1 to 9 carbon atoms, represented by the formula —C(O)NR b an amide group of, and -R c is a hydrogen atom or an alkyl group that is straight-chain, saturated, and contains 1 to 10 carbon atoms or a phenyl group, c an imino group of Here, R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - halogen atoms, -hydroxyl group, - linear, saturated, and n is an integer between 1 and 10, formula -C n H 2n+1 an alkyl group of -R d is a straight chain and saturated alkyl group containing 1 to 9 carbon atoms, d NoA Alkoxy group, -R a is a straight chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula —C(O)OR a an acyl group of -R e is a hydrogen atom or a straight-chain, cyclic or branched, saturated or unsaturated, substituted, containing 1 to 10 carbon atoms, of the formula -C(O)R e an acyl group of - a carbonate group containing 1 to 10 carbon atoms, -carboxyl group (-COOH), and -cyano group (-CN), compound.

3. A compound of formula (I) according to claim 1 or 2, where R and R 1 are independently selected from the group consisting of: - hydrogen atom, - halogen atom, - alkyl groups that are linear, saturated and contain from 1 to 10 carbon atoms; Here, R 2 is selected from the group consisting of: - hydrogen atom, - halogen atoms, -X is selected from the group consisting of a hydrogen atom, a halogen atom, and a hydroxyl group, n is an integer between 1 and 10, x is the number of X present in the alkyl group, and X is at the terminal position of the alkyl group, n H 2n+1-x X x an alkyl group of -R a is a straight chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula —C(O)OR a an acyl group of an acyl group of the formula —C(O)H, -carboxyl group (-COOH), -R b is a straight chain and saturated alkyl group containing 1 to 9 carbon atoms, represented by the formula —C(O)NR b an amide group of, and -R c is a hydrogen atom or an alkyl group that is straight-chain, saturated, and contains 1 to 10 carbon atoms or a phenyl group, c the imino group of Here, R 3 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - halogen atom, - linear, saturated, and n is an integer between 1 and 10, formula -C n H 2n+1 and an alkyl group of Here, R 4 is selected from the group consisting of: - hydrogen atom, - halogen atom, -hydroxyl group, - linear, saturated, and n is an integer between 1 and 10, formula -C n H 2n+1 an alkyl group of -R d is a straight chain and saturated alkyl group containing 1 to 9 carbon atoms, d NoA Alkoxy group, -R a is a straight chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula —C(O)OR a an acyl group of -R e is a hydrogen atom or a straight-chain, cyclic or branched, saturated or unsaturated, substituted, containing 1 to 10 carbon atoms, of the formula -C(O)R e an acyl group of -R f is a straight chain and saturated alkyl group containing 1 to 9 carbon atoms, of the formula —OC(O ) OR f Carbonate groups of -carboxyl group (-COOH), and -cyano group (-CN), compound.

4. A compound of formula (I) according to any one of claims 1 to 3, where R and R 1 is independently selected from the group consisting of a hydrogen atom, a chlorine atom, and a methyl group. Selected, Here, R 2 represents a hydrogen atom, a methyl group, or a -COH group, and X represents a chlorine atom, a bromine atom, or an iodine atom. and a hydroxyl group, 2 The alkyl group of X, R a is a methyl group or an ethyl group, the formula -C(O)OR a an acyl group of the formula —C(O)H; a carboxyl group (—COOH); R b is a methyl group or an ethyl group, the formula -C(O)NR b an amide group of, and R c is a phenyl group, the formula -C=N-R c an imino group consisting of selected from the group Here, R 3 , R 5 and R 6 consists of hydrogen atoms, chlorine atoms, methyl groups, and ethyl groups are independently selected from the group Here, R 4 is a hydrogen atom, a methyl group, a hydroxyl group, a chlorine atom, a bromine atom, or a fluorine atom , iodine atom, R d is a methyl group or an ethyl group, d an alkoxy group of R a is a methyl group or an ethyl group, the formula -C(O)OR a an acyl group of R e is a methyl group, an ethyl group , straight chain propyl group, straight chain pentyl group, —CH 2 CH 2 -cyclopentyl group, and (para-methyl)phenyl group, of the formula -C(O)R e an acyl group of R f is a methyl group or an ethyl group, the formula -OC(O)OR f The carbonate group, carboxyl group (-COOH), and cyano groups (—CN), compound.

5. A compound of formula (I) according to any one of claims 1 to 4, where R and R 1 are independently selected from the group consisting of a hydrogen atom and a methyl group; Here, R 2 represents a hydrogen atom, a —COH group, and a —CH 2 OH groups, Here, R 3 , R 5 and R 6 is independently selected from the group consisting of a hydrogen atom, a chlorine atom, and an ethyl group. independently selected, and Here, R 4 represents a hydrogen atom, a hydroxyl group, a chlorine atom, a bromine atom, a fluorine atom, R f is an ethyl group, the formula -OC(O)OR f Carbonate group of, and R a is a methyl group, formula -C(O) OR a and an acyl group selected from the group consisting of compound.

6. R 3 , R 4 , R 5 , and R 6 A compound of formula (I) according to any one of claims 1 to 5, characterized in that at least three of the substituents selected from the group consisting of are hydrogen atoms.

7. Compounds of formula (I) according to any one of claims 1 to 6, characterized in that the compounds are selected from the group consisting of: 【Chemistry 2-1】 【Chemistry 2-2】 [Chemistry 2-3]

8. In the presence of an acid, Compound of formula (II): 【Transformation 3】 with a compound of formula (III) 【Chemistry 4】 Or a compound of formula (IV) 【Transformation 5】 a) contacting the Here, R, R 1 and R 2 are independently selected from the group consisting of: - hydrogen atom, - halogen atom, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms; - an acyl group containing 1 to 10 carbon atoms, -carboxyl group, an amide group containing 1 to 10 carbon atoms, and linear, cyclic or branched, saturated or unsaturated imino groups, optionally substituted by alkyl groups, and Here, R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of: - hydrogen atom, - halogen atom, -hydroxyl group, - linear, cyclic or branched, saturated or unsaturated, optionally substituted alkyl groups containing 1 to 10 carbon atoms; - an alkoxy group containing 1 to 10 carbon atoms, - an acyl group containing 1 to 10 carbon atoms, - a carbonate group containing 1 to 10 carbon atoms, -carboxyl group, and -cyano group, A method for preparing a compound of formula (I) according to any one of claims 1 to 7.

9. A pharmaceutical composition, characterized in that it comprises at least one compound of formula (I) according to any one of claims 1 to 7, and at least one pharmaceutically acceptable excipient.

10. A compound of formula (I) according to any one of claims 1 to 7 for use in a method for the treatment of diseases and / or disorders selected from the group consisting of cancer, and disorders involving microtubule deregulation.

11. A compound of formula (I) according to any one of claims 1 to 7 for use in a method for treating a cancer selected from the group consisting of cancers requiring stabilisation of cell microtubules and cancers induced by LKB1 deficient cells.

12. A compound of formula (I) according to any one of claims 1 to 7 for use in a method of treatment of the human or animal body, characterized in that said compound is co-administered with at least one compound which stabilizes cellular microtubules.

13. The compounds that stabilize cellular microtubules include taxanes, epothilones, TPI-287, cabazitaxel, zampanolide, 13. The compound of formula (I) for use according to claim 12, selected from the group consisting of dactylolide, discodermolide, taccalonolide, davunetide, eleutherobin, dictyostatin, and sarcodictyin A and B.

14. 14. A compound of formula (I) for use according to claim 12 or 13, wherein said compound that stabilizes cellular microtubules is paclitaxel.

15. A compound of formula (I) according to any one of claims 1 to 7 for use in a method of treatment of the human or animal body, characterized in that the compound of formula (I) is administered to a patient having LKB1 deficient cells.

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