WO2021224186A1 - New pyridine derivatives as radiosensitizers - Google Patents
New pyridine derivatives as radiosensitizers Download PDFInfo
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- WO2021224186A1 WO2021224186A1 PCT/EP2021/061577 EP2021061577W WO2021224186A1 WO 2021224186 A1 WO2021224186 A1 WO 2021224186A1 EP 2021061577 W EP2021061577 W EP 2021061577W WO 2021224186 A1 WO2021224186 A1 WO 2021224186A1
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- 0 CCC(C1=CC=C*(*)C1=O)=O Chemical compound CCC(C1=CC=C*(*)C1=O)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention concerns pyridine derivatives as radiosensitizers, in particular for cancer treatment.
- the present invention also relates to new pyridine derivatives and uses thereof, for example as conjugates for the treatment of cancer.
- Some tumours are treated in first line with radiotherapy or with chemoradiotherapy.
- the challenge is to deliver a cure dose to the tumor while limiting the possibility of serious damages to normal tissues.
- the balance between tumour control and the risk of normal tissue side-effects is given by the therapeutic index of the treatment. Improving the therapeutic index by modulating the tumour/normal tissue response is challenging.
- small molecules could be used as radiosensitizing agents (radiosensitizers) in order to increase the radiosensitivity of the tumours.
- the main characteristics of a radiosensitizer should be a low toxicity without ionizing radiations (healthy tissue) and an enhanced injury to the tumour in presence of ionizing radiations.
- the expectation of getting a supra- additive antitumor effect greater than expected based on the simple addition of each cytotoxic used alone) with minimal secondary effects on healthy tissues if of importance in cancer therapy.
- the aim of the present invention is thus to provide new non-toxic pyridine derivatives.
- the aim of the present invention is also thus to provide non-toxic pyridine derivatives for use as radiosensitizers. Therefore, the present invention relates to a compound having the following formula (I): wherein:
- - Ri is chosen from the group consisting of: H, halogen, hydroxyl (-OH), amino (-NH 2 ), (Ci-C 6 )alkoxy groups, (Ci-C 6 )alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol (-SH), halogen, (Ci- C 6 )alkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl;
- R 2 is chosen from the group consisting of: H, (Ci-C 6 )alkyl, (Ci- C 6 )alkylcarbonyl, (Ci-C 6 )alkoxylcarbonyl, aryl, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted;
- R 3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C 6 )alkoxy groups, (Ci-C 6 )alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl;
- R 4 being chosen from the group consisting of: H, halogen, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci- C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl;
- R 5 is chosen from the group consisting of: H, (Ci-C 6 )alkyl, and aryl, preferably phenyl, said aryl group being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C 6 )alkyl, (Ci- C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl;
- R groups identical or different, are chosen from the group consisting of: H, halogen, and (Ci-C 6 )alkyl; or a pharmaceutically acceptable salt thereof, for use as radiosensitizer.
- the present invention thus concerns new radiosensitizers, preferably used in combination with radiation as explained later.
- C t -C z means a carbon-based chain which can have from t to z carbon atoms, for example C 1 -C 3 means a carbon-based chain which can have from 1 to 3 carbon atoms.
- halogen atom means: a fluorine, a chlorine, a bromine or an iodine.
- alkyl means: a linear or branched, saturated, hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms.
- alkyl means: a linear or branched, saturated, hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms.
- alkoxy means: an -O-alkyl radical where the alkyl group is as previously defined.
- alkyl group is as previously defined.
- alkylamino means: an -NH-alkyl group, the alkyl group being as defined above.
- alkylthio means: an -S-alkyl group, the alkyl group being as defined above.
- haloalkyl means: an alkyl group as defined above, in which one or more of the hydrogen atoms is (are) replaced with a halogen atom.
- fluoroalkyls in particular CF 3 or CHF 2 .
- aryl means: a cyclic aromatic group comprising between 6 and 10 carbon atoms.
- aryl groups mention may be made of phenyl or naphthyl groups.
- heteroaryl means: a 5- to 10-membered aromatic monocyclic or bicyclic group containing from 1 to 4 heteroatoms selected from O, S or N.
- heteroaryl means: a 5- to 10-membered aromatic monocyclic or bicyclic group containing from 1 to 4 heteroatoms selected from O, S or N.
- heteroaryl comprising 5 to 6 atoms, including 1 to 4 nitrogen atoms
- carboxyalkyl means: an HOOC- alkyl- group, the alkyl group being as defined above.
- carboxyalkyl groups mention may in particular be made of carboxymethyl or carboxyethyl.
- the term “carboxyl” means: a COOH group.
- the term “alkylcarbonyl” means a -CO-alkyl group, the alkyl group being as defined above.
- alkoxylcarbonyl means a -CO-O-alkyl group, the alkyl group being as defined above.
- R 2 as defined above is an aryl or heteroaryl group, optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol (-SH), halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylamino, halo(Ci-Ce)alkyl, carboxyl and carboxy(Cr C 6 )alkyl.
- R 5 is an aryl group, substituted or not.
- the compound for the use according to the invention has the following formula (1-1 ):
- Ri, R2, R3, R5, and Z are as defined above in formula (I).
- the compound for the use according to the invention has the following formula (II): wherein:
- - Ri, R 2 , R3, R7, i, and Z are as defined in formula (I), and - R6 is chosen from the group consisting of: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl.
- the compounds of formula (II) correspond to compounds having the formula (I) as defined above, wherein R 5 is a phenyl group, optionally substituted by a R6 group.
- R6 is chosen from the group consisting of: hydroxyl, halogen, in particular F, (Ci-Ce)alkoxy, in particular OMe, and halo(Ci-Ce)alkyl, in particular CF 3 , preferably in para position.
- Preferred groups R6 are OH, F, OMe, and CF 3 , and are preferably in para position.
- the compound for the use according to the invention has the following formula (11-1):
- the compounds of formula (11-1) correspond to compounds having the formula (II) as defined above, wherein R 6 is in para position.
- the compound for the use according to the invention has the following formula (11-2):
- R is F.
- the compound for the use according to the invention has the following formula (II-3): (II-3)
- R 7 is F.
- the compound for the use according to the invention has the following formula (III): wherein Ri, R 2 , R 3 , and Z are as defined in formula (I) above.
- the compound for the use according to the invention has the formula (I), wherein Z is CR 4 , R 4 being as defined above in formula
- a preferred group of compounds for the use according to the invention consists of compounds having the above formula (1-1), wherein Z is CR4, R4 being as defined above in formula (I).
- a preferred group of compounds for the use according to the invention consists of compounds having the above formula (II), wherein Z is CR 4 , R 4 being as defined above in formula (I).
- Another preferred group of compounds for the use according to the invention consists of compounds having the above formula (11-1 ), wherein Z is CR 4 , R 4 being as defined above in formula (I).
- Another preferred group of compounds for the use according to the invention consists of compounds having the above formula (II-2), wherein Z is CR 4 , R 4 being as defined above in formula (I).
- Another preferred group of compounds for the use according to the invention consists of compounds having the above formula (II-3), wherein Z is CR 4 , R 4 being as defined above in formula (I).
- Another preferred group of compounds for the use according to the invention consists of compounds having the above formula (III), wherein Z is CR 4 , R 4 being as defined above in formula (I).
- Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
- a preferred group of compounds used according to the invention consists of compounds of formula (II) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
- Another preferred group of compounds used according to the invention consists of compounds of formula (11-1 ) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
- Another preferred group of compounds used according to the invention consists of compounds of formula (II-2) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
- Another preferred group of compounds used according to the invention consists of compounds of formula (II-3) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
- Another preferred group of compounds used according to the invention consists of compounds of formula (III) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
- R 2 is H.
- a preferred group of compounds used according to the invention consists of compounds of formula (II) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 2 is H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (11-1 ) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 2 is H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (II-2) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 2 is H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (II-3) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 2 is H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (III) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 2 is H.
- R 3 is H.
- a preferred group of compounds used according to the invention consists of compounds of formula (II) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 3 is H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (11-1 ) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 3 is H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (II-2) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 3 is H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (II-3) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 3 is H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (III) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 3 is H.
- a preferred group of compounds used according to the invention consists of compounds of formula (II) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 2 and R 3 are H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (11-1 ) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 2 and R 3 are H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (II-2) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 2 and R 3 are H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (II-3) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 2 and R 3 are H.
- Another preferred group of compounds used according to the invention consists of compounds of formula (III) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R 2 and R 3 are H.
- the compounds used according to the present invention are compounds of formula (I) or (1-1) as defined above, or compounds of formula (II), (11-1 ), (II-2), (II-3) or (III) as defined above, wherein Z is CR 4 , R 4 being chosen from the group consisting of: H, halogen, preferably Br or I, a phenyl group, a p-methoxy-phenyl group, and a pyridinyl group, preferably a pyridin-4-yl group.
- the compounds used according to the invention are different from the following compounds:
- - Ri is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C 6 )alkoxy groups, (Ci-C 6 )alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C 6 )alkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl;
- R 2 is chosen from the group consisting of: H, (Ci-C 6 )alkyl, (Ci- C 6 )alkylcarbonyl, (Ci-C 6 )alkoxylcarbonyl, aryl, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted;
- R 3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C 6 )alkoxy groups, (Ci-C 6 )alkylamino groups, aryl groups, and heteroaryl groups; said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl;
- R 4 being chosen from the group consisting of: H, halogen, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci- C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl;
- R 5 is chosen from the group consisting of: H, (Ci-C 6 )alkyl, and aryl, preferably phenyl, said aryl group being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C 6 )alkyl, (Ci- C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl;
- the compounds according to the invention are compounds of formula (I) as defined above wherein, when Z is N or CH, at least one of Ri, R 2 , and R 3 is not H; and Ri is not Cl.
- the present invention also relates to a compound having the following formula
- Ri, R 2 , R 3 , Z, R , i, and R 5 being as defined above, and wherein, when Z is N or CH, at least one of Ri, R 2 , and R 3 is not H; and Ri is not Cl.
- a group of preferred compounds according to the invention consists of compounds having the above formula (1-1) wherein, when Z is N or CH, at least one of Ri, R 2 , and R 3 is not H; and Ri is not Cl.
- Another group of preferred compounds according to the invention consists of compounds having the above formula (II) wherein, when Z is N or CH, at least one of Ri, R 2 , and R 3 is not H; and Ri is not Cl.
- Another group of preferred compounds according to the invention consists of compounds having the above formula (11-1 ) wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
- Another group of preferred compounds according to the invention consists of compounds having the above formula (II-2) wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
- Another group of preferred compounds according to the invention consists of compounds having the above formula (II-3) wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
- Another group of preferred compounds according to the invention consists of compounds having the above formula (III) wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
- the present invention also relates to compounds having the following formula
- R 2 , R 3 , R7, i, and R 5 are as defined above in formula (I), and
- - R’ is chosen from the group consisting of: halogen, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-Ce)alkylthio, (Ci-C 6 )alkylamino, halo(Cr C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl.
- the present invention also relates to compounds having the following formula (V): wherein:
- R 2 , R 3 , R7, i, and R 5 are as defined above in formula (I), and
- - R’i is chosen from the group consisting of: halogen other than Cl, hydroxyl, amino, (Ci-C 6 )alkoxy groups, (Ci-C 6 )alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl; or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a compound having the following formula
- R 2 , R 3 , R7, i, and R 5 are as defined above in formula (I), and
- - R’I is chosen from the group consisting of: hydroxyl, amino, (Ci-C 6 )alkoxy groups, (Ci-C 6 )alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C 6 )alkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl; or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a compound having the following formula
- R 2 , R 3 , R7, i, and R 5 are as defined above in formula (I), and
- R”i is chosen from the group consisting of: halogen, hydroxyl, amino, (Ci- C 6 )alkoxy groups, (Ci-C 6 )alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C 6 )alkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, (Ci-C 6 )alkylamino, halo(Ci-C 6 )alkyl, carboxyl and carboxy(Ci-C 6 )alkyl; or a pharmaceutically acceptable salt thereof.
- the compounds of the invention have one of the following formulae numbered from 1 to 9:
- the present invention also relates to a conjugate molecule comprising one or more compound(s) according to the invention, having the formula (I) as defined above, said compound(s) being covalently bound to at least one cell binding agent.
- the present invention also relates to a conjugate molecule comprising one or more compound(s) according to the invention, having the formula (1-1), (II), (11-1), (II- 2), (II-3), (III), (IV), (V), (VI) or (VII) as defined above, said compound(s) being covalently bound to at least one cell binding agent.
- the present invention also relates to a conjugate molecule being a compound according to the invention to which is bound to at least one payload, optionally through a linker or covalently conjugated, thereby forming a single molecule.
- Suitable payloads include, but are not limited to, peptides, polypeptides, proteins, antibodies, or antigen-binding fragments thereof, antigens, nucleic acid molecules, polymers, small molecules, mimetic agents, drugs, inorganic molecules, organic molecules, and radioisotopes.
- Suitable payloads include, but are not limited to, cell binding agents, chemotherapeutic agents, targeted therapy agents, cytotoxic agents, ligands for cellular receptor(s), immunomodulatory agents, pro-apoptotic agents, anti- angiogenic agents, photodetectable labels, contrast agents, radiolabels, and the like.
- a cell binding agent is a molecule with affinity for a biological target.
- the cell binding agent may be, for example, a ligand, a protein, an antibody, more particularly a monoclonal antibody, a protein or antibody fragment, a peptide, an oligonucleotide or an oligosaccharide.
- the function of the binding agent is to direct the biologically active compound towards the biological target.
- the conjugate of the invention is an antibody drug conjugate (ADC).
- ADC antibody drug conjugate
- the payload is an antibody, particularly monoclonal antibody, sdAb, VHH, intrabody, or single-chain antibodies (scFv).
- the conjugate of the invention comprises a linker unit between the compound of the invention and the payload.
- the linker is cleavable under intracellular conditions, such that cleavage of the linker releases the compound of the invention from the payload in the intracellular environment.
- the linker unit is not cleavable and the compound of the invention is released, for example, by payload degradation.
- the linker is cleavable by a cleaving agent that is present in the intracellular environment (e.g., within a lysosome or endosome or caveolea).
- the linker can be, e.g., a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease.
- the cleavable linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values.
- the pH-sensitive linker hydrolyzable under acidic conditions.
- an acid-labile linker that is hydrolyzable in the lysosome e.g., a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like
- an acid-labile linker that is hydrolyzable in the lysosome e.g., a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like
- Such linkers are relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome.
- the linker is cleavable under reducing conditions (e.g., a disulfide linker).
- a disulfide linker e.g., a disulfide linker.
- disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2- pyridyldithio)butyrate) and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha- (2-pyridyl-dithio)toluene), SPDB and SMPT.
- SATA N-succinimidyl-S-acetylthioacetate
- SPDP N-succinimidyl
- the present invention also relates to the compound according to the invention, having the formula (I) as defined above or the conjugate as mentioned above, for use as drug.
- the present invention also relates to the compound according to the invention, having the formula (1-1 ), (II), (11-1), (II-2), (II-3), (III) , (IV), (V), (VI) or (VII) as defined above for use as drug.
- the present invention also relates to a medicament comprising a compound of formula (I) as defined above or the conjugate as defined above, or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a medicament comprising a compound of formula (1-1), (II), (11-1), (II-2), (II-3), (III), (IV), (V), (VI) or (VII) as defined above, or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a pharmaceutical composition, comprising a compound of formula (I) as defined above or the conjugate as defined above, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
- the present invention also relates to a pharmaceutical composition, comprising a compound of formula (1-1), (II), (11-1), (II-2), (II-3), (III), (IV), (V), (VI) or (VII) as defined above, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
- compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, and also at least one pharmaceutically acceptable excipient.
- Said excipients are selected, according to the pharmaceutical form and the mode of administration desired, from the usual excipients which are known to those skilled in the art.
- compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or the salt thereof, can be administered in unit administration form, as a mixture with conventional pharmaceutical excipients, to animals and to human beings for the treatment of the disorders and diseases below.
- the suitable unit administration forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants.
- oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions
- sublingual, buccal, intratracheal intraocular and intranasal administration forms, forms for administration by inhalation
- topical, transdermal, subcutaneous, intramuscular or intravenous administration forms rectal administration forms, and implants.
- the compounds according to the invention can be used in creams, gels, ointments or lotions.
- the present invention also relates to a compound of formula (I) as defined above or the conjugate as defined above, for use in treating cancer.
- the present invention also relates to a compound of formula (1-1 ), (II), (11-1), (II- 2), (II-3), (III), (IV), (V), (VI) or (VII) as defined above for use in treating cancer.
- the present invention also relates to a compound of formula (I) as defined above or the conjugate as defined above, for use in treating cancer in combination with radiotherapy and/or with any anticancer drug.
- the present invention thus concerns the field of cancer treatment and the use of new synthetized pyridine derivatives as radiosensitizers in combined therapy with radiation and methods to improve the therapeutic index of tumours treated in first-line with radiotherapy or chemo-radiotherapy (soft tissue sarcoma, glioblastoma, head and neck carcinoma, lung carcinoma, cervix carcinoma, bladder carcinoma, rectum carcinoma and anal carcinoma) using these new radiosensitizers.
- chemo-radiotherapy soft tissue sarcoma, glioblastoma, head and neck carcinoma, lung carcinoma, cervix carcinoma, bladder carcinoma, rectum carcinoma and anal carcinoma
- the present invention also relates to a compound of formula (1-1 ), (II), (11-1), (II- 2), (II-3), (III), (IV), (V), (VI) or (VII) as defined above, for use in treating cancer in combination with radiotherapy and/or or with any anticancer drug.
- the compound, the conjugate and/or the pharmaceutical composition according to the invention is administered in combination with additional cancer therapies.
- the compound, the conjugate and/or the pharmaceutical composition of the invention may be administered in combination without or with targeted therapy, immunotherapy such as immune checkpoint therapy and immune checkpoint inhibitor, co-stimulatory antibodies, or chemotherapy.
- Immune checkpoint therapy such as checkpoint inhibitors include, but are not limited to programmed death-1 (PD-1) inhibitors, programmed death ligand-1 (PD-L1) inhibitors, programmed death ligand-2 (PD-L2) inhibitors, lymphocyte-activation gene 3 (LAG3) inhibitors, T-cell immunoglobulin and mucin-domain containing protein 3 (TIM-3) inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, B- and T-lymphocyte attenuator (BTLA) inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors, Indoleamine 2,3-dioxygenase (IDO) inhibitors, killer immunoglobulin-like receptors (KIR) inhibitors, KIR2L3 inhibitors, KIR3DL2 inhibitors and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1 ) inhibitor
- checkpoint inhibitors include antibodies anti-PD1 , anti-PD-L1 , anti- CTLA-4, anti-TIM-3, anti-LAG3.
- Co-stimulatory antibodies deliver positive signals through immune-regulatory receptors including but not limited to ICOS, CD137, CD27, OX-40 and GITR.
- anti-PD1 antibodies include, but are not limited to, nivolumab, cemiplimab (REGN2810 or REGN-2810), tislelizumab (BGB-A317), tislelizumab, spartalizumab (PDR001 or PDR-001), ABBV-181 , JNJ-63723283, Bl 754091 , MAG012, TSR-042, AGEN2034, pidilizumab, nivolumab (ONO-4538, BMS-936558, MDX1106, GTPL7335 or Opdivo), pembrolizumab (MK-3475, MK03475, lambrolizumab, SCH-900475 or Keytruda) and antibodies described in international applications W02004004771 , W02004056875, W02006121168, WO2008156712, W02009014708, W02009114335, WO2013043569 and WO2014047350
- anti-PD-L1 antibodies examples include, but are not limited to, LY3300054, atezolizumab, durvalumab and avelumab.
- anti-CTLA-4 antibodies include, but are not limited to, ipilimumab (see, e.g., US patents US6,984,720 and US8,017,114), tremelimumab (see, e.g., US patents US7, 109,003 and US8, 143,379), single chain anti-CTLA4 antibodies (see, e.g., international applications W01997020574 and W02007123737) and antibodies described in US patent US8,491 ,895.
- ipilimumab see, e.g., US patents US6,984,720 and US8,017,114
- tremelimumab see, e.g., US patents US7, 109,003 and US8, 143,379
- single chain anti-CTLA4 antibodies see, e.g., international applications W01997020574 and W02007123737
- Example of KIR inhibitor is IPH4102 targeting KIR3DL2.
- the compound, the conjugate and/or the pharmaceutical composition of the invention is administered to the patient in combination with targeted therapy.
- Targeted therapy agents are drugs designed to interfere with specific molecules necessary for tumor growth and progression.
- targeted therapy agents such as therapeutic monoclonal antibodies target specific antigens found on the cell surface, such as transmembrane receptors or extracellular growth factors.
- Small molecules can penetrate the cell membrane to interact with targets inside a cell. Small molecules are usually designed to interfere with the enzymatic activity of the target protein such as for example proteasome inhibitor, tyrosine kinase or cyclin-dependent kinase inhibitor, histone deacetylase inhibitor.
- Targeted therapy may also use cytokines.
- Examples of such targeted therapy include with no limitations: Ado-trastuzumab emtansine (HER2), Afatinib (EGFR (HER1/ERBB1), HER2), Aldesleukin (Proleukin), alectinib (ALK), Alemtuzumab (CD52), axitinib (kit, PDGFRbeta, VEGFR1/2/3), Belimumab (BAFF), Belinostat (HDAC), Bevacizumab (VEGF ligand), Blinatumomab (CD19/CD3), bortezomib (proteasome), Brentuximab vedotin (CD30), bosutinib (ABL), brigatinib (ALK), cabozantinib (FLT3, KIT, MET, RET, VEGFR2), Canakinumab (IL-1 beta), carfilzomib (proteasome), ceritinib (ALK
- the compound, the conjugate and/or the pharmaceutical composition of the invention is administered to the patient in combination with chemotherapy.
- chemotherapy has its general meaning in the art and refers to the treatment that consists in administering to the patient a chemotherapeutic agent.
- Chemotherapeutic agents include, but are not limited to alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; du
- the compound, the conjugate and/or the pharmaceutical composition of the invention is administered to the patient in combination with radiotherapy.
- radiation therapies include, but are not limited to external beam radiotherapy (such as superficial X-rays therapy, orthovoltage X-rays therapy, megavoltage X-rays therapy, radiosurgery, stereotactic radiation therapy, fractionated stereotactic radiation therapy, hypofractionated radiotherapy, cobalt therapy, electron therapy, fast neutron therapy, neutron-capture therapy, proton therapy, intensity modulated radiation therapy (IMRT), 3-dimensional conformal radiation therapy (3D-CRT) and the like; brachytherapy; unsealed source radiotherapy; tomotherapy and the like; or minibeam radiation therapy.
- external beam radiotherapy such as superficial X-rays therapy, orthovoltage X-rays therapy, megavoltage X-rays therapy, radiosurgery, stereotactic radiation therapy, fractionated stereotactic radiation therapy, hypofractionated radiotherapy, cobalt therapy, electron therapy, fast neutron therapy, neutron
- Gamma rays are another form of photons used in radiotherapy. Gamma rays are produced spontaneously as certain elements (such as radium, uranium, cesium and cobalt 60) release radiation as they decompose, or decay.
- radiotherapy may be hadrontherapy (using beams from charged particles like protons or other ions such as carbon), proton radiotherapy or proton minibeam radiation therapy.
- Proton radiotherapy is an ultra-precise form of radiotherapy that uses proton beams (Prezado Y, Jouvion G, Guardiola C, Gonzalez W, Juchaux M, Bergs J, Nauraye C, Labiod D, De Marzi L, Pouzoulet F, Patriarca A, Dendale R.
- Radiotherapy may also be FLASH radiotherapy (FLASH-RT) or FLASH proton irradiation.
- FLASH radiotherapy involves the ultra-fast delivery of radiation treatment at dose rates several orders of magnitude greater than those currently in routine clinical practice (ultra-high dose rate) (Favaudon V, Fouillade C, Vozenin MC. The radiotherapy FLASH to save healthy tissues. Med Sci (Paris) 2015 ; 31 : 121-123. DOI: 10.1051/medsci/20153102002); Patriarca A., Fouillade C. M., Martin F., Pouzoulet F., Nauraye C., et al.
- Radiotherapy may also be hypofractionated radiotherapy (Shah JL, Li G, Shaffer JL, Azoulay Ml, Gibbs IC, Nagpal S, Soltys SG. Stereotactic Radiosurgery and Hypofractionated Radiotherapy for Glioblastoma. Neurosurgery.
- the cancer is selected from the group consisting of: soft tissue carcinoma, glioblastoma, head and neck carcinoma, lung carcinoma, cervix carcinoma, bladder carcinoma, rectum carcinoma, and anal carcinoma.
- cancers that may be treated by the compounds or conjugates of the invention include, but are not limited to: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leio
- the cancer is selected from the group consisting of: benign, metastatic and malignant neoplasias, and also including acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, Bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid,
- the present invention also relates to a method for treating the pathological conditions indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.
- Figure 1 Survival fraction of CCD-19Lu (triangles), SF-763 (open squares), ME- 180 (closed circles) and U-373 MG (closed squares) cell lines treated with increasing doses of X-rays (Philips/YXYLON generator) performed in the high throughput screening in 384-wells. Data represent mean ⁇ standard errors.
- Figure 2 Dose-response curves of compound 2 on CCD-19Lu (A), SF-763 (B), ME-180 (C) and U-373 MG (D) cell lines without (upper curve) or following 4 (medium curve) or 6 (lower curve) Gy irradiation. Each dot represents an independent experiment (three replicates).
- Figure 3 Dose-response curves of compound 6 on CCD-19Lu (A), SF-763 (B), ME-180 (C) and U-373 MG (D) cell lines without (upper curve) or following 4 (medium curve) or 6 (lower curve) Gy irradiation. Each dot represents an independent experiment (three replicates).
- Figure 4 Dose-response curves of Olaparib® on CCD-19Lu (A), SF-763 (B), ME-180 (C) and U-373 MG (D) cell lines without (upper curve) or following 4 (medium curve) or 6 (lower curve) Gy irradiation. Each dot represents an independent experiment (three replicates).
- Figure 5 Isobolographic graph analysis of the association of compound 2 with radiation on ME-180 (A) and U-373 MG (B) cell lines for a survival isoeffect of 50% (SI50). The different replicates are all plotted under the envelope of additivity showing the supra-additive effect.
- Figure 6 Survival fraction of ME-180 (circles) and U-373 MG (squares) cell lines treated with increasing doses of X-rays (XRAD-320/PXI generator) performed for the validation of the hits on 96-well plates. Data represent mean ⁇ standard errors.
- Figure 7 Dose-response curves of compound 2 on ME-180 (A) and U-373 MG (B) cell lines without (circles) or following 2 (closed squares), 4 (triangles) or 6 (open squares) Gy irradiation. Each dot represents the mean ⁇ standard errors of duplicates.
- Figure 8 Isobolographic graph analysis of the association of compound 2 TT310p with radiation on ME-180 (A) and U-373 MG (B) cell lines. The survival at 20% of the different replicates are all plotted under the envelope of additivity showing the supra-additive effect.
- Figure 9 Survival fraction of A549 cell line treated with increasing doses of X- rays (XRAD-320/PXI generator) performed on 96-well plates. Data represent mean ⁇ standard errors.
- Figure 10 Dose-response curves compound 2 (A) and compound 6 (B) on A549 cell line ME-180 (A) and U-373-MG (B) without (circles) or following 2 (closed squares), 4 (triangles) or 6 (open squares) Gy irradiation. Each dot represents the mean ⁇ standard errors of duplicates.
- Figure 11 Isobolographic graph analysis of the association of compound 2 (A) and compound 6 (B) with radiation on A549 cell line for a survival isoeffect of 20% (SI20). The different replicates are all plotted under the envelope of additivity showing the supra-additive effect.
- Example 1 High-throughput pyridine-derivative and irradiation screening
- High-throughput chemo-irradiation screening Cells were seeded on barcoded 384-well plates and allowed to attach overnight. Cells were then exposed to 11 -point concentration range of the 160 compounds (from 0.17nM to 10 mM) and incubated at 37°C for 24 h. Cells were further irradiated at 0, 4 or 6 Gy and incubated for additional 3 days at 37°C prior cell fixation and DAPI nuclei labelling.
- Cell survival was determined using an automated high-throughput wide-field microscopy system (INCell 2200 - GE Healthcare). Six individual images were acquired for each well of the experimental plates and each labelled nucleus was detected using an automated nuclei segmentation custom-developed method. All survival curves represent at least three independent experiments.
- Isobolograms The combination of radiotherapy and chemotherapy is not easy to assess, as the dose-response curve of each treatment is nonlinear (according to the Hill equation for drug alone and to linear-quadratic model for radiation alone). In that case, to determine if the effect of the combined treatment is greater or less that would be expected on the basis of the response of each agent alone, Steel and Peckham developped the isobolographic concept based on the built of an envelope of additivity in an isoeffect plot (Steel G.G. and Peckham M.J., Int. J. Radiat. Oncol. Biol. Phys. (1979) 5:85-91).
- This envelope of additivity is based on the calculation of isoeffect curves according to Mode I (independent mechanisms of action of the two agents) and Mode II (dependent mechanisms of action of the two agents).
- This graph delimited three regions: the region of additivity inside the envelope, the region of supra-additivity (or synergy) under the envelope and the region of sub-additivity or antagonism above the envelope.
- the cytotoxic interactions of the selected compounds and radiation at 50% survival isoeffect (SI50) were evaluated on the three cancer cell lines using this method.
- the median and mean of the three SI50 replicates of combined treatments were calculated according to Hill equation after fitting the experimental curves obtained with 4 and/or 6 Gy and these points were plotted on the graph.
- the effect of a given drug in combination with radiation was categorized as supra-additive, additive or antagonist. Results.
- the normal lung fibroblasts displayed a typical radiation dose-response profile due to a higher radiosensitivity and activation of senescent death pathways (Schreiber V. etal. (2006) PARP-2: Structure- Function Relationship. In: Poly(ADP-Ribosyl)ation. Molecular Biology Intelligence Unit. Springer, Boston, MA).
- Hit validation For hit validation, ME-180 and U-373 MG cells were manually seeded in 96-well plates and treated after 24h with drug concentrations ranging from 13.7 nM to 10 mM. After 24h, plates were irradiated at 0, 2, 4 or 6 Gy at a dose rate of 0.8 Gy / min using a XRAD-320 X-rays generator (PXI) of 12.5 mA intensity, 320 kVp voltage, filtered by 0.75 mm Sn, 0.25 mm Cu and 1 .5 mm Al. The source-sample distance was 60 cm and a 5-cm PMMA block was placed under the sample to provide backscatter.
- PXI XRAD-320 X-rays generator
- Figure 7 showed the typical dose-response curves of compound 2 on ME-180 (A) and U-373 MG (B) cell lines following 0 Gy (closed circles), 2 (closed squares), 4 (triangles) and 6 Gy (open squares) irradiation.
- the isobolographic analysis showed that compound 2 presents also a supra-additive effect on both cell lines when combined with this new source of X-rays even with an isoeffect considered as low as 20% survival (Figure 8).
- Example 3 Extending the radiosensitizing effect of Pyridine-derivatives to other cell lines
- A549 cells were manually seeded in 96-well plates and treated after 24h with drug concentrations ranging from 123.4 nM to 10 mM. After 24h, plates were irradiated at 0, 2, 4 or 6 Gy at a dose rate of 0.8 Gy / min using a XRAD-320 X-rays generator (PXI) as for example n°2. Three days after irradiation, cells were fixed (4% formaldehyde, 15 minutes), washed and the nuclei were labeled. An automatic nuclei cell counting was achieved using the Incucyte® imaging system. All the nuclei inside each whole well of the the 96-well plates were considered.
- PXI XRAD-320 X-rays generator
- the cytotoxic interactions of the two selected compounds and radiation at 20% survival isoeffect (SI20) were evaluated on A549 cells as for example n°2 using the isobolographic method. Depending on the position inside the isobologramm, the hits evaluated in combination with radiation were categorized for their supra-additivity.
- A549 cells exposed to increased doses of X-ray radiation was obtained 72h post-irradiation ( Figure 9).
- Figure 10 showed the typical dose-response curves of compound 2 (Figure 10A) and compound 6 (Figure 10B) on A549 cells following 0 Gy (closed circles), 2 (closed squares), 4 (triangles) and 6 Gy (open squares) irradiation.
- the isobolographic analysis also confirmed that the two hits presented a supra-additive effect (SI20) when combined with X-rays ( Figure 11 ), thereby demonstrating their potential application as radiosensitizing agents on different cell models where chemoradiation is the gold standard treatment.
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Abstract
The present invention relates to a compound having the following formula (I) wherein: - R1 is chosen from the group consisting of: H, halogen, hydroxyl, amino, alkoxy groups, alkylamino groups, aryl groups, and heteroaryl groups; - R2 is chosen from the group consisting of: H, alkyl, alkylcarbonyl, alkoxylcarbonyl, aryl, and heteroaryl groups; - R3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, alkoxy groups, alkylamino groups, aryl groups, and heteroaryl groups, - Z is N or CR4; R5 is chosen from the group consisting of: H, alkyl, and aryl; - i is 1 or 2, and the R7 groups are chosen from the group consisting of: H, halogen, and alkyl; for use as radiosensitizer.
Description
NEW PYRIDINE DERIVATIVES AS RADIOSENSITIZERS
The present invention concerns pyridine derivatives as radiosensitizers, in particular for cancer treatment. The present invention also relates to new pyridine derivatives and uses thereof, for example as conjugates for the treatment of cancer.
Some tumours (most of them are carcinomas) are treated in first line with radiotherapy or with chemoradiotherapy. The challenge is to deliver a cure dose to the tumor while limiting the possibility of serious damages to normal tissues. The balance between tumour control and the risk of normal tissue side-effects is given by the therapeutic index of the treatment. Improving the therapeutic index by modulating the tumour/normal tissue response is challenging. To this aim, small molecules could be used as radiosensitizing agents (radiosensitizers) in order to increase the radiosensitivity of the tumours. The main characteristics of a radiosensitizer should be a low toxicity without ionizing radiations (healthy tissue) and an enhanced injury to the tumour in presence of ionizing radiations. The expectation of getting a supra- additive antitumor effect (greater than expected based on the simple addition of each cytotoxic used alone) with minimal secondary effects on healthy tissues if of importance in cancer therapy.
Until now, many anticancer agents are known to be toxic perse but are still used as radiosensitizers as they induce more cell death when combined with radiation than radiation alone. The development of new non-toxic (on healthy tissues) radiosensitizing agents is of importance in oncology.
The aim of the present invention is thus to provide new non-toxic pyridine derivatives.
The aim of the present invention is also thus to provide non-toxic pyridine derivatives for use as radiosensitizers.
Therefore, the present invention relates to a compound having the following formula (I):
wherein:
- Ri is chosen from the group consisting of: H, halogen, hydroxyl (-OH), amino (-NH2), (Ci-C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol (-SH), halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R2 is chosen from the group consisting of: H, (Ci-C6)alkyl, (Ci- C6)alkylcarbonyl, (Ci-C6)alkoxylcarbonyl, aryl, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted;
- R3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- Z is N or CR4, R4 being chosen from the group consisting of: H, halogen, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino,
hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci- C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R5 is chosen from the group consisting of: H, (Ci-C6)alkyl, and aryl, preferably phenyl, said aryl group being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci- C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- i is 1 or 2;
- the R groups, identical or different, are chosen from the group consisting of: H, halogen, and (Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof, for use as radiosensitizer.
The present invention thus concerns new radiosensitizers, preferably used in combination with radiation as explained later.
According to the invention, the expression "Ct-Cz" means a carbon-based chain which can have from t to z carbon atoms, for example C1-C3 means a carbon-based chain which can have from 1 to 3 carbon atoms.
According to the invention, the term "halogen atom" means: a fluorine, a chlorine, a bromine or an iodine.
Within the present application, the term "alkyl" means: a linear or branched, saturated, hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms. By way of examples, mention may be made of methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl groups.
According to the invention, the term "alkoxy" means: an -O-alkyl radical where the alkyl group is as previously defined. By way of examples, mention may be made of -0-(Ci-C4)alkyl groups, and in particular the -O-methyl group, the -O-ethyl group, as -0-C3alkyl group, the -O-propyl group, the -O-isopropyl group, and as -0-C4alkyl group, the -O-butyl, -O-isobutyl or -O-tert-butyl group.
According to the invention, the term "alkylamino" means: an -NH-alkyl group, the alkyl group being as defined above.
According to the invention, the term "alkylthio" means: an -S-alkyl group, the alkyl group being as defined above.
According to the invention, the term "haloalkyl" means: an alkyl group as defined above, in which one or more of the hydrogen atoms is (are) replaced with a halogen atom. By way of example, mention may be made of fluoroalkyls, in particular CF3 or CHF2.
According to the invention, the term "aryl" means: a cyclic aromatic group comprising between 6 and 10 carbon atoms. By way of examples of aryl groups, mention may be made of phenyl or naphthyl groups.
According to the invention, the term "heteroaryl" means: a 5- to 10-membered aromatic monocyclic or bicyclic group containing from 1 to 4 heteroatoms selected from O, S or N. By way of examples, mention may be made of imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, benzotriazolyl, quinolinyl and isoquinolinyl groups.
By way of a heteroaryl comprising 5 to 6 atoms, including 1 to 4 nitrogen atoms, mention may in particular be made of the following representative groups: pyrrolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl and 1 ,2,3-triazinyl.
Mention may also be made, by way of heteroaryl, of thiophenyl, oxazolyl, furazanyl, 1 ,2,4-thiadiazolyl, naphthyridinyl, quinoxalinyl, phthalazinyl, imidazo[1 ,2- a]pyridine, imidazo[2,1-b]thiazolyl, cinnolinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothiophenyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1 ,2,4-triazinyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolyl, 1 ,3,4-thiadiazolyl, thiazolyl, isothiazolyl, carbazolyl, and also the corresponding groups resulting from their fusion or from fusion with the phenyl nucleus.
According to the present invention, the term "carboxyalkyl" means: an HOOC- alkyl- group, the alkyl group being as defined above. As examples of carboxyalkyl groups, mention may in particular be made of carboxymethyl or carboxyethyl.
According to the present invention, the term "carboxyl" means: a COOH group.
According to the invention, the term “alkylcarbonyl” means a -CO-alkyl group, the alkyl group being as defined above.
According to the invention, the term “alkoxylcarbonyl” means a -CO-O-alkyl group, the alkyl group being as defined above. According to an embodiment, when R2 as defined above is an aryl or heteroaryl group, optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol (-SH), halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-Ce)alkyl, carboxyl and carboxy(Cr C6)alkyl. Preferably, in formula (I) as defined above, R5 is an aryl group, substituted or not.
Preferably, in formula (I) as defined above, i=1 and R? is F.
According to an embodiment, the compound for the use according to the invention has the following formula (1-1 ):
Ri, R2, R3, R5, and Z are as defined above in formula (I).
According to an embodiment, the compound for the use according to the invention has the following formula (II):
wherein:
- Ri, R2, R3, R7, i, and Z are as defined in formula (I), and
- R6 is chosen from the group consisting of: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl.
The compounds of formula (II) correspond to compounds having the formula (I) as defined above, wherein R5 is a phenyl group, optionally substituted by a R6 group.
Preferably, in formula (II), R6 is chosen from the group consisting of: hydroxyl, halogen, in particular F, (Ci-Ce)alkoxy, in particular OMe, and halo(Ci-Ce)alkyl, in particular CF3, preferably in para position.
Preferred groups R6 are OH, F, OMe, and CF3, and are preferably in para position.
According to an embodiment, the compound for the use according to the invention has the following formula (11-1):
Ri, R2, R3, R7, i, and Z being as defined in formula (I), and R6 being as defined in formula (II).
The compounds of formula (11-1) correspond to compounds having the formula (II) as defined above, wherein R6 is in para position.
According to an embodiment, the compound for the use according to the invention has the following formula (11-2):
Ri, R2, R3, R6, R7, and Z being as defined above. Preferably, in formula (II-2), R is F.
According to an embodiment, the compound for the use according to the invention has the following formula (II-3):
(II-3)
Ri, R2, R3, R6, R7, and Z being as defined above. Preferably, in formula (II-3), R7 is F.
According to an embodiment, the compound for the use according to the invention has the following formula (III):
wherein Ri, R2, R3, and Z are as defined in formula (I) above.
According to an embodiment, the compound for the use according to the invention has the formula (I), wherein Z is CR4, R4 being as defined above in formula
(I)·
A preferred group of compounds for the use according to the invention consists of compounds having the above formula (1-1), wherein Z is CR4, R4 being as defined above in formula (I).
A preferred group of compounds for the use according to the invention consists of compounds having the above formula (II), wherein Z is CR4, R4 being as defined above in formula (I).
Another preferred group of compounds for the use according to the invention consists of compounds having the above formula (11-1 ), wherein Z is CR4, R4 being as defined above in formula (I).
Another preferred group of compounds for the use according to the invention consists of compounds having the above formula (II-2), wherein Z is CR4, R4 being as defined above in formula (I).
Another preferred group of compounds for the use according to the invention consists of compounds having the above formula (II-3), wherein Z is CR4, R4 being as defined above in formula (I).
Another preferred group of compounds for the use according to the invention consists of compounds having the above formula (III), wherein Z is CR4, R4 being as defined above in formula (I).
Preferably, in formula (I) or (1-1) above, Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
A preferred group of compounds used according to the invention consists of compounds of formula (II) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
Another preferred group of compounds used according to the invention consists of compounds of formula (11-1 ) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
Another preferred group of compounds used according to the invention consists of compounds of formula (II-2) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
Another preferred group of compounds used according to the invention consists of compounds of formula (II-3) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
Another preferred group of compounds used according to the invention consists of compounds of formula (III) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group.
Preferably, in formula (I) or (1-1 ) above, or in formula (II), (11-1), (II-2), (II-3) or (III), R2 is H.
A preferred group of compounds used according to the invention consists of compounds of formula (II) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R2 is H.
Another preferred group of compounds used according to the invention consists of compounds of formula (11-1 ) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R2 is H.
Another preferred group of compounds used according to the invention consists of compounds of formula (II-2) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R2 is H.
Another preferred group of compounds used according to the invention consists of compounds of formula (II-3) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R2 is H.
Another preferred group of compounds used according to the invention consists of compounds of formula (III) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R2 is H.
Preferably, in formula (I) above, or in formula (II) or (III), R3 is H.
A preferred group of compounds used according to the invention consists of compounds of formula (II) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R3 is H.
Another preferred group of compounds used according to the invention consists of compounds of formula (11-1 ) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R3 is H.
Another preferred group of compounds used according to the invention consists of compounds of formula (II-2) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R3 is H.
Another preferred group of compounds used according to the invention consists of compounds of formula (II-3) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R3 is H.
Another preferred group of compounds used according to the invention consists of compounds of formula (III) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R3 is H.
A preferred group of compounds used according to the invention consists of compounds of formula (II) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R2 and R3 are H.
Another preferred group of compounds used according to the invention consists of compounds of formula (11-1 ) as defined above, wherein Ri is chosen from the group
consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R2 and R3 are H.
Another preferred group of compounds used according to the invention consists of compounds of formula (II-2) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R2 and R3 are H.
Another preferred group of compounds used according to the invention consists of compounds of formula (II-3) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R2 and R3 are H.
Another preferred group of compounds used according to the invention consists of compounds of formula (III) as defined above, wherein Ri is chosen from the group consisting of: H, a phenyl group, a pyridinyl group, preferably a pyridin-4-yl group, and a furanyl group, preferably a furan-2-yl group, and R2 and R3 are H.
According to an embodiment, the compounds used according to the present invention are compounds of formula (I) or (1-1) as defined above, or compounds of formula (II), (11-1 ), (II-2), (II-3) or (III) as defined above, wherein Z is CR4, R4 being chosen from the group consisting of: H, halogen, preferably Br or I, a phenyl group, a p-methoxy-phenyl group, and a pyridinyl group, preferably a pyridin-4-yl group.
According to a preferred embodiment, the compounds used according to the invention are different from the following compounds:
wherein:
- Ri is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R2 is chosen from the group consisting of: H, (Ci-C6)alkyl, (Ci- C6)alkylcarbonyl, (Ci-C6)alkoxylcarbonyl, aryl, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted;
- R3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups; said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- Z is N or CR4, R4 being chosen from the group consisting of: H, halogen, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci- C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R5 is chosen from the group consisting of: H, (Ci-C6)alkyl, and aryl, preferably phenyl, said aryl group being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci- C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- i is 1 or 2;
- the R groups, identical or different, are chosen from the group consisting of: H, halogen, and (Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof, provided that the compound of formula (I) is different from the following compounds:
According to an embodiment, the compounds according to the invention are compounds of formula (I) as defined above wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
The present invention also relates to a compound having the following formula
Ri, R2, R3, Z, R , i, and R5 being as defined above, and wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl. A group of preferred compounds according to the invention consists of compounds having the above formula (1-1) wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
Another group of preferred compounds according to the invention consists of compounds having the above formula (II) wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
Another group of preferred compounds according to the invention consists of compounds having the above formula (11-1 ) wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
Another group of preferred compounds according to the invention consists of compounds having the above formula (II-2) wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
Another group of preferred compounds according to the invention consists of compounds having the above formula (II-3) wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
Another group of preferred compounds according to the invention consists of compounds having the above formula (III) wherein, when Z is N or CH, at least one of Ri, R2, and R3 is not H; and Ri is not Cl.
The present invention also relates to compounds having the following formula
- Ri, R2, R3, R7, i, and R5 are as defined above in formula (I), and
- R’ is chosen from the group consisting of: halogen, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-Ce)alkylthio, (Ci-C6)alkylamino, halo(Cr C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl.
The present invention also relates to compounds having the following formula (V):
wherein:
- R2, R3, R7, i, and R5 are as defined above in formula (I), and
- R’i is chosen from the group consisting of: halogen other than Cl, hydroxyl, amino, (Ci-C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof.
The present invention also relates to a compound having the following formula
- R2, R3, R7, i, and R5 are as defined above in formula (I), and
- R’I is chosen from the group consisting of: hydroxyl, amino, (Ci-C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups,
said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof.
The present invention also relates to a compound having the following formula
- R2, R3, R7, i, and R5 are as defined above in formula (I), and
- R”i is chosen from the group consisting of: halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof.
Preferably, the compounds of the invention have one of the following formulae numbered from 1 to 9:
The present invention also relates to a conjugate molecule comprising one or more compound(s) according to the invention, having the formula (I) as defined above, said compound(s) being covalently bound to at least one cell binding agent.
The present invention also relates to a conjugate molecule comprising one or more compound(s) according to the invention, having the formula (1-1), (II), (11-1), (II- 2), (II-3), (III), (IV), (V), (VI) or (VII) as defined above, said compound(s) being covalently bound to at least one cell binding agent.
The present invention also relates to a conjugate molecule being a compound according to the invention to which is bound to at least one payload, optionally through a linker or covalently conjugated, thereby forming a single molecule.
Examples of suitable payloads include, but are not limited to, peptides, polypeptides, proteins, antibodies, or antigen-binding fragments thereof, antigens, nucleic acid molecules, polymers, small molecules, mimetic agents, drugs, inorganic molecules, organic molecules, and radioisotopes.
Examples of suitable payloads include, but are not limited to, cell binding agents, chemotherapeutic agents, targeted therapy agents, cytotoxic agents, ligands for cellular receptor(s), immunomodulatory agents, pro-apoptotic agents, anti- angiogenic agents, photodetectable labels, contrast agents, radiolabels, and the like.
According to the invention, a cell binding agent is a molecule with affinity for a biological target. The cell binding agent may be, for example, a ligand, a protein, an antibody, more particularly a monoclonal antibody, a protein or antibody fragment, a
peptide, an oligonucleotide or an oligosaccharide. The function of the binding agent is to direct the biologically active compound towards the biological target.
In some embodiments, the conjugate of the invention is an antibody drug conjugate (ADC). Accordingly, the payload is an antibody, particularly monoclonal antibody, sdAb, VHH, intrabody, or single-chain antibodies (scFv).
In some embodiments, the conjugate of the invention comprises a linker unit between the compound of the invention and the payload. In some embodiments, the linker is cleavable under intracellular conditions, such that cleavage of the linker releases the compound of the invention from the payload in the intracellular environment. In yet other embodiments, the linker unit is not cleavable and the compound of the invention is released, for example, by payload degradation.
In some embodiments, the linker is cleavable by a cleaving agent that is present in the intracellular environment (e.g., within a lysosome or endosome or caveolea). The linker can be, e.g., a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease.
In some embodiments, the cleavable linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values. Typically, the pH-sensitive linker hydrolyzable under acidic conditions. For example, an acid-labile linker that is hydrolyzable in the lysosome (e.g., a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like) can be used. (See, e.g., U.S. Pat. Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661). Such linkers are relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome.
In some embodiments, the linker is cleavable under reducing conditions (e.g., a disulfide linker). A variety of disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2- pyridyldithio)butyrate) and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha- (2-pyridyl-dithio)toluene), SPDB and SMPT. (See, e.g., Thorpe et al., 1987, Cancer Res. 47:5924-5931 ; Wawrzynczak et al., In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C. W. Vogel ed., Oxford U. Press, 1987. See also U.S. Pat. No. 4,880,935).
The present invention also relates to the compound according to the invention, having the formula (I) as defined above or the conjugate as mentioned above, for use as drug.
The present invention also relates to the compound according to the invention, having the formula (1-1 ), (II), (11-1), (II-2), (II-3), (III) , (IV), (V), (VI) or (VII) as defined above for use as drug.
The present invention also relates to a medicament comprising a compound of formula (I) as defined above or the conjugate as defined above, or a pharmaceutically acceptable salt thereof.
The present invention also relates to a medicament comprising a compound of formula (1-1), (II), (11-1), (II-2), (II-3), (III), (IV), (V), (VI) or (VII) as defined above, or a pharmaceutically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition, comprising a compound of formula (I) as defined above or the conjugate as defined above, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
The present invention also relates to a pharmaceutical composition, comprising a compound of formula (1-1), (II), (11-1), (II-2), (II-3), (III), (IV), (V), (VI) or (VII) as defined above, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, and also at least one pharmaceutically acceptable excipient.
Said excipients are selected, according to the pharmaceutical form and the mode of administration desired, from the usual excipients which are known to those skilled in the art.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or the salt thereof, can be administered in unit administration form, as a mixture with conventional pharmaceutical excipients, to animals and to human beings for the treatment of the disorders and diseases below.
The suitable unit administration forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.
The present invention also relates to a compound of formula (I) as defined above or the conjugate as defined above, for use in treating cancer.
The present invention also relates to a compound of formula (1-1 ), (II), (11-1), (II- 2), (II-3), (III), (IV), (V), (VI) or (VII) as defined above for use in treating cancer.
The present invention also relates to a compound of formula (I) as defined above or the conjugate as defined above, for use in treating cancer in combination with radiotherapy and/or with any anticancer drug.
The present invention thus concerns the field of cancer treatment and the use of new synthetized pyridine derivatives as radiosensitizers in combined therapy with radiation and methods to improve the therapeutic index of tumours treated in first-line with radiotherapy or chemo-radiotherapy (soft tissue sarcoma, glioblastoma, head and neck carcinoma, lung carcinoma, cervix carcinoma, bladder carcinoma, rectum carcinoma and anal carcinoma) using these new radiosensitizers.
The present invention also relates to a compound of formula (1-1 ), (II), (11-1), (II- 2), (II-3), (III), (IV), (V), (VI) or (VII) as defined above, for use in treating cancer in combination with radiotherapy and/or or with any anticancer drug.
In some embodiments, the compound, the conjugate and/or the pharmaceutical composition according to the invention is administered in combination with additional cancer therapies. In particular, the compound, the conjugate and/or the pharmaceutical composition of the invention may be administered in combination without or with targeted therapy, immunotherapy such as immune checkpoint therapy and immune checkpoint inhibitor, co-stimulatory antibodies, or chemotherapy.
Immune checkpoint therapy such as checkpoint inhibitors include, but are not limited to programmed death-1 (PD-1) inhibitors, programmed death ligand-1 (PD-L1) inhibitors, programmed death ligand-2 (PD-L2) inhibitors, lymphocyte-activation gene
3 (LAG3) inhibitors, T-cell immunoglobulin and mucin-domain containing protein 3 (TIM-3) inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, B- and T-lymphocyte attenuator (BTLA) inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors, Indoleamine 2,3-dioxygenase (IDO) inhibitors, killer immunoglobulin-like receptors (KIR) inhibitors, KIR2L3 inhibitors, KIR3DL2 inhibitors and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1 ) inhibitors. In particular, checkpoint inhibitors include antibodies anti-PD1 , anti-PD-L1 , anti- CTLA-4, anti-TIM-3, anti-LAG3. Co-stimulatory antibodies deliver positive signals through immune-regulatory receptors including but not limited to ICOS, CD137, CD27, OX-40 and GITR.
Examples of anti-PD1 antibodies include, but are not limited to, nivolumab, cemiplimab (REGN2810 or REGN-2810), tislelizumab (BGB-A317), tislelizumab, spartalizumab (PDR001 or PDR-001), ABBV-181 , JNJ-63723283, Bl 754091 , MAG012, TSR-042, AGEN2034, pidilizumab, nivolumab (ONO-4538, BMS-936558, MDX1106, GTPL7335 or Opdivo), pembrolizumab (MK-3475, MK03475, lambrolizumab, SCH-900475 or Keytruda) and antibodies described in international applications W02004004771 , W02004056875, W02006121168, WO2008156712, W02009014708, W02009114335, WO2013043569 and WO2014047350.
Examples of anti-PD-L1 antibodies include, but are not limited to, LY3300054, atezolizumab, durvalumab and avelumab.
Examples of anti-CTLA-4 antibodies include, but are not limited to, ipilimumab (see, e.g., US patents US6,984,720 and US8,017,114), tremelimumab (see, e.g., US patents US7, 109,003 and US8, 143,379), single chain anti-CTLA4 antibodies (see, e.g., international applications W01997020574 and W02007123737) and antibodies described in US patent US8,491 ,895.
Examples of anti- VISTA antibodies are described in US patent application US20130177557.
Examples of inhibitors of the LAG3 receptor are described in US patent US5,773,578.
Example of KIR inhibitor is IPH4102 targeting KIR3DL2.
In some embodiments, the compound, the conjugate and/or the pharmaceutical composition of the invention is administered to the patient in combination with targeted therapy. Targeted therapy agents, are drugs designed to interfere with specific molecules necessary for tumor growth and progression. For example, targeted
therapy agents such as therapeutic monoclonal antibodies target specific antigens found on the cell surface, such as transmembrane receptors or extracellular growth factors. Small molecules can penetrate the cell membrane to interact with targets inside a cell. Small molecules are usually designed to interfere with the enzymatic activity of the target protein such as for example proteasome inhibitor, tyrosine kinase or cyclin-dependent kinase inhibitor, histone deacetylase inhibitor. Targeted therapy may also use cytokines. Examples of such targeted therapy include with no limitations: Ado-trastuzumab emtansine (HER2), Afatinib (EGFR (HER1/ERBB1), HER2), Aldesleukin (Proleukin), alectinib (ALK), Alemtuzumab (CD52), axitinib (kit, PDGFRbeta, VEGFR1/2/3), Belimumab (BAFF), Belinostat (HDAC), Bevacizumab (VEGF ligand), Blinatumomab (CD19/CD3), bortezomib (proteasome), Brentuximab vedotin (CD30), bosutinib (ABL), brigatinib (ALK), cabozantinib (FLT3, KIT, MET, RET, VEGFR2), Canakinumab (IL-1 beta), carfilzomib (proteasome), ceritinib (ALK), Cetuximab (EGFR), cofimetinib (MEK), Crizotinib (ALK, MET, ROS1), Dabrafenib (BRAF), Daratumumab (CD38), Dasatinib (ABL), Denosumab (RANKL), Dinutuximab (B4GALNT1 (GD2)), Elotuzumab (SLAMF7), Enasidenib (IDH2), Erlotinib (EGFR), Everolimus (mTOR), Gefitinib (EGFR), Ibritumomab tiuxetan (CD20), Sonidegib (Smoothened), Sipuleucel-T, Siltuximab (IL-6), Sorafenib (VEGFR, PDGFR, KIT, RAF),(Tocilizumab (IL-6R), Temsirolimus (mTOR), Tofacitinib (JAK3), Trametinib (MEK), Tositumomab (CD20), Trastuzumab (HER2), Vandetanib (EGFR), Vemurafenib (BRAF), Venetoclax (BCL2), Vismodegib (PTCH, Smoothened), Vorinostat (HDAC), Ziv-aflibercept (PIGF, VEGFA/B).
In some embodiments, the compound, the conjugate and/or the pharmaceutical composition of the invention is administered to the patient in combination with chemotherapy. As used herein, the term “chemotherapy” has its general meaning in the art and refers to the treatment that consists in administering to the patient a chemotherapeutic agent. Chemotherapeutic agents include, but are not limited to alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and
cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; methylhydrazine derivatives including N- methylhydrazine (MIH) and procarbazine; PSK polysaccharide complex); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2, 2', 2"- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids,
e.g., paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-1 1); topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; capecitabine; anthracyclines, nitrosoureas, antimetabolites, epipodophylotoxins, enzymes such as L-asparaginase; anthracenediones; hormones and antagonists including adrenocorticosteroid antagonists such as prednisone and equivalents, dexamethasone and aminoglutethimide; progestin such as hydroxyprogesterone caproate, medroxyprogesterone acetate and megestrol acetate; estrogen such as diethylstilbestrol and ethinyl estradiol equivalents; antiestrogen such as tamoxifen; androgens including testosterone propionate and fluoxymesterone/equivalents; antiandrogens such as flutamide, gonadotropin releasing hormone analogs and leuprolide; and non-steroidal antiandrogens such as flutamide; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
According to an embodiment, the compound, the conjugate and/or the pharmaceutical composition of the invention is administered to the patient in combination with radiotherapy. Suitable examples of radiation therapies include, but are not limited to external beam radiotherapy (such as superficial X-rays therapy, orthovoltage X-rays therapy, megavoltage X-rays therapy, radiosurgery, stereotactic radiation therapy, fractionated stereotactic radiation therapy, hypofractionated radiotherapy, cobalt therapy, electron therapy, fast neutron therapy, neutron-capture therapy, proton therapy, intensity modulated radiation therapy (IMRT), 3-dimensional conformal radiation therapy (3D-CRT) and the like; brachytherapy; unsealed source radiotherapy; tomotherapy and the like; or minibeam radiation therapy. Gamma rays are another form of photons used in radiotherapy. Gamma rays are produced spontaneously as certain elements (such as radium, uranium, cesium and cobalt 60) release radiation as they decompose, or decay. In some embodiments, radiotherapy may be hadrontherapy (using beams from charged particles like protons or other ions such as carbon), proton radiotherapy or proton minibeam radiation therapy. Proton radiotherapy is an ultra-precise form of radiotherapy that uses proton beams (Prezado Y, Jouvion G, Guardiola C, Gonzalez W, Juchaux M, Bergs J, Nauraye C, Labiod D, De Marzi L, Pouzoulet F, Patriarca A, Dendale R. Tumor Control in RG2 Glioma-
Bearing Rats: A Comparison Between Proton Minibeam Therapy and Standard Proton Therapy. Int J Radiat Oncol Biol Phys. 2019 Jun 1 ;104(2):266-271. doi: 10.1016/j.ijrobp.2019.01 .080; Prezado Y, Jouvion G, Patriarca A, Nauraye C, Guardiola C, Juchaux M, Lamirault C, Labiod D, Jourdain L, Sebrie C, Dendale R, Gonzalez W, Pouzoulet F. Proton minibeam radiation therapy widens the therapeutic index for high-grade gliomas. Sci Rep. 2018 Nov 7;8(1):16479. doi: 10.1038/s41598- 018-34796-8). Radiotherapy may also be FLASH radiotherapy (FLASH-RT) or FLASH proton irradiation. FLASH radiotherapy involves the ultra-fast delivery of radiation treatment at dose rates several orders of magnitude greater than those currently in routine clinical practice (ultra-high dose rate) (Favaudon V, Fouillade C, Vozenin MC. The radiotherapy FLASH to save healthy tissues. Med Sci (Paris) 2015 ; 31 : 121-123. DOI: 10.1051/medsci/20153102002); Patriarca A., Fouillade C. M., Martin F., Pouzoulet F., Nauraye C., et al. Experimental set-up for FLASH proton irradiation of small animals using a clinical system. Int J Radiat Oncol Biol Phys, 102 (2018), pp. 619-626. doi: 10.1016/j.ijrobp.2018.06.403. Epub 2018 Jul 11). Radiotherapy may also be hypofractionated radiotherapy (Shah JL, Li G, Shaffer JL, Azoulay Ml, Gibbs IC, Nagpal S, Soltys SG. Stereotactic Radiosurgery and Hypofractionated Radiotherapy for Glioblastoma. Neurosurgery. 2018 Jan 1 ;82(1):24- 34, doi: 10.1093/neuros/nyx115; Botti M, Kirova YM, Dendale R, Savignoni A, Fromantin I, Gautier C, Bollet MA, Campana F, Fourquet A. Hypofractionated breast radiotherapy in 13 fractions, perfect tolerance or delayed early reaction? Prospective study of Curie Institute. Cancer Radiother. 2009 Apr;13(2):92-6, doi:
10.1016/j.canrad.2008.11 .009).
According to an embodiment, the cancer is selected from the group consisting of: soft tissue carcinoma, glioblastoma, head and neck carcinoma, lung carcinoma, cervix carcinoma, bladder carcinoma, rectum carcinoma, and anal carcinoma.
The compounds or conjugates according to the invention are particularly deemed useful for the treatment of cancer including solid tumors such as skin, breast, brain, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds or conjugates of the invention include, but are not limited to: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, gastrointestinal:
esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, Villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor nephroblastoma, lymphoma, leukemia), bladder and urethra (Squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, Sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, Sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastom, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell Sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors, Nervous System: skull (osteoma, hemangioma, granuloma, Xanthoma, Osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinomapinealoma, glioblastoma multiform, oligodendroglioma, Schwannoma, retinoblastoma, congenital tumors), Spinal cord (neurofibroma, meningioma, glioma, Sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma, Serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), Vulva (Squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, Squamous cell carcinoma, botryoid Sarcoma embryonal rhabdomyosarcoma, fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia acute and chronic, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic Syndrome), Hodgkin’s disease, non- Hodgkin’s lymphoma malignant lymphoma; Skin: malignant melanoma, basal cell carcinoma, Squamous cell carcinoma, Karposi's Sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, and Adrenal glands: neuroblastoma.
According to an embodiment, the cancer is selected from the group consisting of: benign, metastatic and malignant neoplasias, and also including acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, Bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing’s sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatin-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma and Wilm's tumor.
The present invention, also relates to a method for treating the pathological conditions indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.
FIGURES
Figure 1 : Survival fraction of CCD-19Lu (triangles), SF-763 (open squares), ME- 180 (closed circles) and U-373 MG (closed squares) cell lines treated with increasing doses of X-rays (Philips/YXYLON generator) performed in the high throughput screening in 384-wells. Data represent mean ± standard errors.
Figure 2: Dose-response curves of compound 2 on CCD-19Lu (A), SF-763 (B), ME-180 (C) and U-373 MG (D) cell lines without (upper curve) or following 4 (medium curve) or 6 (lower curve) Gy irradiation. Each dot represents an independent experiment (three replicates).
Figure 3: Dose-response curves of compound 6 on CCD-19Lu (A), SF-763 (B), ME-180 (C) and U-373 MG (D) cell lines without (upper curve) or following 4 (medium curve) or 6 (lower curve) Gy irradiation. Each dot represents an independent experiment (three replicates).
Figure 4: Dose-response curves of Olaparib® on CCD-19Lu (A), SF-763 (B), ME-180 (C) and U-373 MG (D) cell lines without (upper curve) or following 4 (medium curve) or 6 (lower curve) Gy irradiation. Each dot represents an independent experiment (three replicates).
Figure 5: Isobolographic graph analysis of the association of compound 2 with radiation on ME-180 (A) and U-373 MG (B) cell lines for a survival isoeffect of 50% (SI50). The different replicates are all plotted under the envelope of additivity showing the supra-additive effect.
Figure 6: Survival fraction of ME-180 (circles) and U-373 MG (squares) cell lines treated with increasing doses of X-rays (XRAD-320/PXI generator) performed for the validation of the hits on 96-well plates. Data represent mean ± standard errors.
Figure 7: Dose-response curves of compound 2 on ME-180 (A) and U-373 MG (B) cell lines without (circles) or following 2 (closed squares), 4 (triangles) or 6 (open squares) Gy irradiation. Each dot represents the mean ± standard errors of duplicates.
Figure 8: Isobolographic graph analysis of the association of compound 2 TT310p with radiation on ME-180 (A) and U-373 MG (B) cell lines. The survival at 20% of the different replicates are all plotted under the envelope of additivity showing the supra-additive effect.
Figure 9: Survival fraction of A549 cell line treated with increasing doses of X- rays (XRAD-320/PXI generator) performed on 96-well plates. Data represent mean ± standard errors. Figure 10: Dose-response curves compound 2 (A) and compound 6 (B) on A549 cell line ME-180 (A) and U-373-MG (B) without (circles) or following 2 (closed squares), 4 (triangles) or 6 (open squares) Gy irradiation. Each dot represents the mean ± standard errors of duplicates.
Figure 11 : Isobolographic graph analysis of the association of compound 2 (A) and compound 6 (B) with radiation on A549 cell line for a survival isoeffect of 20% (SI20). The different replicates are all plotted under the envelope of additivity showing the supra-additive effect.
EXAMPLES
Example 1 : High-throughput pyridine-derivative and irradiation screening
Small molecule library. For this screen 160 different molecules were used. All compounds were synthetized in-house (Institut Curie, UMR9187 / U1196 unit), dissolved in 100% dimethyl sulfoxide (DMSO) or water.
Cell lines and cell culture. Two human glioblastoma cancer cell lines, U-373 MG (ECACC, 08061901 , radioresistant), SF-763 (BTRC Tissue Core, UCSF, radiosensitive) and the cervical cancer cells ME-180 (ATCC, FITB-33, radiosensitive) were used in this study. Fluman pulmonary normal fibroblasts CCD-19Lu (ATCC, CCL-210) were used as normal tissue control. All cell lines were negative for mycoplasma contamination and were authentified by short tandem repeat (STR) profiling (Institut Curie, Genomic Platform). The appropriate cell plating density was adapted to a well of 384-well plate in the presence of their recommended cell media.
Irradiation in 384-well plates. Cells were seeded in wells of 384-well plate and allowed to attach overnight in complete growth media. Cell plates were then exposed to an orthovoltage X-ray generator Philips/YXYLON (13.1 mA intensity, 320 kVp voltage, filtered by 0.4 mm Sn, 0.25 mm Cu, 1 mm Al). The source-sample distance was 60 cm and a 5-cm PMMA block was placed under the sample to provide backscatter. The average dose-rate, over all wells of the plate, was 1.15 Gy.min-1. Plates were exposed to variable doses of X-ray radiation alone or to two doses (4 or 6 Gy) for the screen. Survival fractions were calculated and the data was adjusted to best fit to the classical linear-quadratic equation. From this model, the radiobiological alpha and beta parameters were calculated in order to establish isobolographic analysis. Survival curves represent at least three independent experiments.
High-throughput chemo-irradiation screening. Cells were seeded on barcoded 384-well plates and allowed to attach overnight. Cells were then exposed to 11 -point concentration range of the 160 compounds (from 0.17nM to 10 mM) and incubated at 37°C for 24 h. Cells were further irradiated at 0, 4 or 6 Gy and incubated for additional 3 days at 37°C prior cell fixation and DAPI nuclei labelling.
Cell survival was determined using an automated high-throughput wide-field microscopy system (INCell 2200 - GE Healthcare). Six individual images were
acquired for each well of the experimental plates and each labelled nucleus was detected using an automated nuclei segmentation custom-developed method. All survival curves represent at least three independent experiments.
Data processing. To normalize the survival data, the signals from the compound-treated wells were processed and expressed as a ratio of the 0 Gy DMSO/H2O control wells from each plate. For each cell line, cell count by well was multiplied by a normalization factor (n). Cell count was then converted as survival fraction. A 4-parameter log-logistic model (Hill equation) was used to fit the data. From this model, the area under the curve, the minimum, the maximum doses and the IC50 (dose leading to 50% effect on cell survival) were also computed. A first criterion based on IC50 (IC50 OGy > 3 x IC50 4/6Gy) was applied to select the compounds that increased toxicity when associated to irradiation, on any cancer cell lines. The second criterion filtered out the compounds that also affected cell survival of the fibroblast cell line without irradiation.
Isobolograms. The combination of radiotherapy and chemotherapy is not easy to assess, as the dose-response curve of each treatment is nonlinear (according to the Hill equation for drug alone and to linear-quadratic model for radiation alone). In that case, to determine if the effect of the combined treatment is greater or less that would be expected on the basis of the response of each agent alone, Steel and Peckham developped the isobolographic concept based on the built of an envelope of additivity in an isoeffect plot (Steel G.G. and Peckham M.J., Int. J. Radiat. Oncol. Biol. Phys. (1979) 5:85-91). This envelope of additivity is based on the calculation of isoeffect curves according to Mode I (independent mechanisms of action of the two agents) and Mode II (dependent mechanisms of action of the two agents). This graph delimited three regions: the region of additivity inside the envelope, the region of supra-additivity (or synergy) under the envelope and the region of sub-additivity or antagonism above the envelope. The cytotoxic interactions of the selected compounds and radiation at 50% survival isoeffect (SI50) were evaluated on the three cancer cell lines using this method. The median and mean of the three SI50 replicates of combined treatments were calculated according to Hill equation after fitting the experimental curves obtained with 4 and/or 6 Gy and these points were plotted on the graph. Depending on the position inside the isobologramm, the effect of a given drug in combination with radiation was categorized as supra-additive, additive or antagonist.
Results.
The survival curves of CCD-19Lu, ME-180, SF-763 and U-373 MG cells exposed to increased doses of X-rays were obtained 72h post-irradiation (Figure 1). Based on the survival fraction at 4 (SF ) and 6 (SF6) Gy, the results showed that the most radioresistant is the cell line U-373 MG (SF4=0.75 ± 0.058; SF6=0.63 ± 0.059), following by the other cancer cell line ME-180 (SF4=0.74 ± 0.12; SF6=0.53 ± 0.07) and the cell line SF-763 (SF4=0.62 ± 0.09; SF6=0.49 ± 0.11 ). The normal lung fibroblasts displayed a typical radiation dose-response profile due to a higher radiosensitivity and activation of senescent death pathways (Schreiber V. etal. (2006) PARP-2: Structure- Function Relationship. In: Poly(ADP-Ribosyl)ation. Molecular Biology Intelligence Unit. Springer, Boston, MA).
Over 160 compounds tested in this high-throughput screening (FITS) in combination with radiation, generating 1 ,920 dose-response curves, a group of new non-toxic pyridine derivatives from the present invention were found to radiosensitize cancer cells with supra-additive effects without any corresponding toxic effect on normal fibroblasts. Figure 2 and 3 showed the typical drug dose-response curves of increasing doses of compound 2 (Figure 2) and compound 6 (Figure 3) on CCD-19Lu- (A), SF-763 (B), ME-180 (C) and U-373 MG (D) cell lines without (upper curve) or following 4 (medium curve) or 6 (lower curve) Gy irradiation. Our process was validated by the use in a blind position of Olaparib®, a radiosensitizer now in clinical trials, as positive control in our FITS (Figure 4). As expected, this molecule was part of the selected supra-additive hits and was more toxic on fibroblasts than the previous compounds.
All the compounds selected after the application of the criteria 1 and 2 of our FITS were analysed using the isobolographic method. All the pyridine derivatives compounds of the present invention showed supra-additive effects when combined with radiation. The cytotoxic interaction of the compound 2 and radiation at 50% survival isoeffect (SI5o) was evaluated on the cancer cell lines and is showed on Figure 5. The SI5o of each replicate, their mean and median were plotted on the graph under the envelope of additivity and were categorized as supra-additive.
Example 2: Pyridine-derivative hit validation after HTS in combination with radiation
Hit validation. For hit validation, ME-180 and U-373 MG cells were manually seeded in 96-well plates and treated after 24h with drug concentrations ranging from 13.7 nM to 10 mM. After 24h, plates were irradiated at 0, 2, 4 or 6 Gy at a dose rate of 0.8 Gy / min using a XRAD-320 X-rays generator (PXI) of 12.5 mA intensity, 320 kVp voltage, filtered by 0.75 mm Sn, 0.25 mm Cu and 1 .5 mm Al. The source-sample distance was 60 cm and a 5-cm PMMA block was placed under the sample to provide backscatter. Three days after irradiation, cells were washed with PBS, fixed with 4% formaldehyde for 15 minutes, washed again with PBS then kept in 1% paraformaldehyde at 4°C until analysis as previously described for the HTS. The cytotoxic interactions of the selected compounds and radiation at 20% survival isoeffect (SI20) were evaluated on the two cancer cell lines. The median and mean of three SI20 replicates of combined treatments were calculated according to Hill equation after fitting the experimental curves obtained after 2, 4 and 6 Gy and these points were plotted on the graph. Depending on the position inside the isobologramm, the hit evaluated in combination with radiation was categorized for its supra-additivity.
Results.
In order to provide definite evidence of supra-additivity against the cancer cells obtained previously from the HTS, one of the hit of the present invention was selected in order to confirm the initial results. For this, a non-automated compound testing using another X-ray source and isobolographic analysis independent of the previous HTS chemoradiation screening was performed on two cancer cell lines: ME-180 and U-373 MG.
The survival curves of ME-180 (circles) and U-373 MG (squares) cells exposed to increased doses of radiation using a new X-ray source were obtained 72h post irradiation (Figure 6). Using this new irradiation device, while the U-373 MG cell line showed the same radiobiological parameters as those found for the HTS (SF =0.70 ± 0.11 ; SF6=0.61 ± 0.07), the ME-180 cell line was found to be more radiosensitive with this different X-ray source (SF4=0.53 ± 0.06; SF6=0.33 ± 0.09).
Figure 7 showed the typical dose-response curves of compound 2 on ME-180 (A) and U-373 MG (B) cell lines following 0 Gy (closed circles), 2 (closed squares), 4 (triangles) and 6 Gy (open squares) irradiation. The isobolographic analysis showed
that compound 2 presents also a supra-additive effect on both cell lines when combined with this new source of X-rays even with an isoeffect considered as low as 20% survival (Figure 8).
Example 3: Extending the radiosensitizing effect of Pyridine-derivatives to other cell lines
To extend the use as radiosensitizers of the pyridine derivatives compounds described, the combination of two hits (compounds 2 and 6) from the present invention was evaluated with radiation on A549 cell line (non-small cell lung cancer cell line, ATCC CC-185).
For this, A549 cells were manually seeded in 96-well plates and treated after 24h with drug concentrations ranging from 123.4 nM to 10 mM. After 24h, plates were irradiated at 0, 2, 4 or 6 Gy at a dose rate of 0.8 Gy / min using a XRAD-320 X-rays generator (PXI) as for example n°2. Three days after irradiation, cells were fixed (4% formaldehyde, 15 minutes), washed and the nuclei were labeled. An automatic nuclei cell counting was achieved using the Incucyte® imaging system. All the nuclei inside each whole well of the the 96-well plates were considered.
The cytotoxic interactions of the two selected compounds and radiation at 20% survival isoeffect (SI20) were evaluated on A549 cells as for example n°2 using the isobolographic method. Depending on the position inside the isobologramm, the hits evaluated in combination with radiation were categorized for their supra-additivity.
Results.
The survival curve of A549 cells exposed to increased doses of X-ray radiation (XRAD-320 generator) was obtained 72h post-irradiation (Figure 9). As expected A549 cells was found to be more radiosensitive than ME-180, SF-763 and U-373-MG cells used previously (SF =0.30 ± 0.046; SF6=0.22 ± 0.043).
Figure 10 showed the typical dose-response curves of compound 2 (Figure 10A) and compound 6 (Figure 10B) on A549 cells following 0 Gy (closed circles), 2 (closed squares), 4 (triangles) and 6 Gy (open squares) irradiation. The isobolographic analysis also confirmed that the two hits presented a supra-additive effect (SI20) when combined with X-rays (Figure 11 ), thereby demonstrating their potential application as radiosensitizing agents on different cell models where chemoradiation is the gold standard treatment.
Claims
- Ri is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R2 is chosen from the group consisting of: H, (Ci-C6)alkyl, (Ci- C6)alkylcarbonyl, (Ci-C6)alkoxylcarbonyl, aryl, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted;
- R3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- Z is N or CR4, R4 being chosen from the group consisting of: H, halogen, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino,
hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci- C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R5 is chosen from the group consisting of: H, (Ci-C6)alkyl, and aryl, preferably phenyl, said aryl group being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci- C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- i is 1 or 2;
- the R7 groups, identical or different, are chosen from the group consisting of: H, halogen, and (Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof, for use as radiosensitizer.
2. The compound for the use of claim 1 , wherein said compound has the following formula (II):
wherein:
- Ri, R2, R3, R7, i, and Z are as defined in claim 1 , and
- R6 is chosen from the group consisting of: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl.
3. The compound for the use of claim 2, wherein R6 is chosen from the group consisting of: hydroxyl, halogen, in particular F, (Ci-C6)alkoxy, in particular OMe, and halo(Ci-C6)alkyl, in particular CF3, preferably in para position.
5. The compound for the use of any one of claims 1 to 4, wherein Z is CR4, R4 being as defined in claim 1 , R being preferably chosen from the group consisting of: FI, halogen, a phenyl group, a p-methoxy-phenyl group, and a pyridinyl group.
6. The compound for the use of any one of claims 1 to 5, wherein Ri is chosen from the group consisting of: FI, a phenyl group, a pyridinyl group, and a furanyl group.
7. The compound for the use of any one of claims 1 to 6, wherein R2 is FI and/or R3 is FI.
- Ri is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R2 is chosen from the group consisting of: H, (Ci-C6)alkyl, (Ci- C6)alkylcarbonyl, (Ci-C6)alkoxylcarbonyl, aryl, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted;
- R3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- Z is N or CR4, R4 being chosen from the group consisting of: H, halogen, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci- C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R5 is chosen from the group consisting of: H, (Ci-C6)alkyl, and aryl, preferably phenyl, said aryl group being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci- C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- i is 1 or 2;
- the R groups, identical or different, are chosen from the group consisting of: H, halogen, and (Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof, provided that the compound of formula (I) is different from the following compounds:
or a pharmaceutically acceptable salt thereof.
- Ri is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R2 is chosen from the group consisting of: H, (Ci-C6)alkyl, (Ci- C6)alkylcarbonyl, (Ci-C6)alkoxylcarbonyl, aryl, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted;
- R3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R5 is chosen from the group consisting of: H, (Ci-C6)alkyl, and aryl, preferably phenyl, said aryl group being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci- C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- i is 1 or 2;
- the R7 groups, identical or different, are chosen from the group consisting of: H, halogen, and (Ci-C6)alkyl; and
- R’ is chosen from the group consisting of: halogen, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol,
halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci- C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl, or a pharmaceutically acceptable salt thereof.
- Ri is chosen from the group consisting of: halogen other than Cl, hydroxyl, amino, (Ci-C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R2 is chosen from the group consisting of: H, (Ci-C6)alkyl, (Ci- C6)alkylcarbonyl, (Ci-C6)alkoxylcarbonyl, aryl, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted;
- R3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R5 is chosen from the group consisting of: H, (Ci-C6)alkyl, and aryl, preferably phenyl, said aryl group being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci- C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- i is 1 or 2;
- the R groups, identical or different, are chosen from the group consisting of: H, halogen, and (Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof.
- R’i is chosen from the group consisting of: hydroxyl, amino, (Ci-C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R2 is chosen from the group consisting of: H, (Ci-C6)alkyl, (Ci- C6)alkylcarbonyl, (Ci-C6)alkoxylcarbonyl, aryl, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted;
- R3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R5 is chosen from the group consisting of: H, (Ci-C6)alkyl, and aryl, preferably phenyl, said aryl group being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-C6)alkyl, (Ci- C6)alkoxy, (Ci-C6)alkylthio, (Ci-C6)alkylamino, halo(Ci-C6)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- i is 1 or 2;
- the R groups, identical or different, are chosen from the group consisting of: H, halogen, and (Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof.
- R”i is chosen from the group consisting of: halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- C6)alkyl, (Ci-Ce)alkoxy, (Ci-Ce)alkylthio, (Ci-C6)alkylamino, halo(Ci-Ce)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R2 is chosen from the group consisting of: H, (Ci-Ce)alkyl, (Ci- C6)alkylcarbonyl, (Ci-C6)alkoxylcarbonyl, aryl, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted;
- R3 is chosen from the group consisting of: H, halogen, hydroxyl, amino, (Ci- C6)alkoxy groups, (Ci-C6)alkylamino groups, aryl groups, and heteroaryl groups, said aryl and heteroaryl groups being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci- Ce)alkyl, (Ci-Ce)alkoxy, (Ci-Ce)alkylthio, (Ci-C6)alkylamino, halo(Ci-Ce)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- R5 is chosen from the group consisting of: H, (Ci-Ce)alkyl, and aryl, preferably phenyl, said aryl group being optionally substituted with one or several substituents independently selected from: amino, hydroxyl, thiol, halogen, (Ci-Ce)alkyl, (Ci- C6)alkoxy, (Ci-Ce)alkylthio, (Ci-C6)alkylamino, halo(Ci-Ce)alkyl, carboxyl and carboxy(Ci-C6)alkyl;
- i is 1 or 2;
- the R groups, identical or different, are chosen from the group consisting of: H, halogen, and (Ci-C6)alkyl; or a pharmaceutically acceptable salt thereof.
14. A conjugate molecule comprising one or more compound(s) according to any one of claims 8 to 13, covalently bound to at least one cell binding agent.
15. The compound of any one of claims 8 to 13 or the conjugate of claim 14, for use as drug.
16. A medicament comprising a compound according to any one of claims 8 to 13 or the conjugate of claim 14, or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition, comprising a compound according to any one of claims 8 to 13, or the conjugate of claim 14, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
18. A compound according to any one of claims 8 to 13 or the conjugate of claim 14, for use in treating cancer, optionally in combination with radiotherapy and/or or with any anticancer drug.
19. The compound or conjugate for the use of claim 18, wherein the cancer is selected from the group consisting of: soft tissue carcinoma, glioblastoma, head and neck carcinoma, lung carcinoma, cervix carcinoma, bladder carcinoma, rectum carcinoma, and anal carcinoma.
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