| Title: |
Derivatives of Azaindoles as Inhibitors of Protein Kinases ABL and SRC |
| Document Number: |
20110312959 |
| Publication Date: |
December 22, 2011 |
| Appl. No: |
13/148988 |
| Application Filed: |
February 12, 2010 |
| Abstract: |
The present invention relates to compounds of general formula I and use thereof as inhibitors of protein kinases AbI and Src and the method of production thereof. The present invention also relates to pharmaceutical compositions and medici-nal products comprising these compounds. [chemical expression included] |
| Inventors: |
Yasri, Abdelaziz (Castelnau Le Lez, FR); Cheve, Gwénaël (Saturargues, FR); Bories, Cédric (Montpellier, FR); Delon, Louis (Montpellier, FR) |
| Claim: |
1. Compounds of general formula I: [chemical expression included] in which R represents: a group NHCOR1, or a group NR3R4 where R1 represents: an aryl, preferably phenyl, group optionally mono- or polysubstituted with: a halogen atom, preferably bromine, fluorine, chlorine, or iodine a nitro group, a cyano group, a methylthiazyl group, an alkoxy, preferably methoxy, group, a trifluoroalkoxy, preferably trifluoromethoxy, group, an aryloxy, preferably phenyloxy, group, a trifluoroalkyl, preferably trifluoromethyl, group, a substituted or unsubstituted sulphonamide group, preferably N-methyl sulphonamide, a heteroaryl, preferably pyridazyl group, or pyridazinyl group optionally mono- or poly-substituted with a halogen atom, preferably chlorine, a linear or branched C1-C6 alkyl group, preferably methyl, or a group selected from the groups A, B, C, D or E as defined below: [chemical expression included] a heteroaryl group, preferably a pyridyl group optionally mono- or poly-substituted with a sulphanyl preferably propylsulphanyl, group, a thiophenyl group, a thiazyl group, an imidazyl group, a pyrazyl group optionally mono- or polysubstituted with an alkyl group, preferably methyl, a quinoxaline group, a dihydrobenzofuranyl group, or an indyl group, a cycloalkyl group, preferably cyclopropyl, a linear or branched C1-C6 alkyl group, preferably ethyl, isopropyl, or a C1-C6 aralkyl group, preferably phenylalkyl, preferably phenylmethyl, optionally mono- or poly-substituted with an alkoxy group, preferably methoxy, and/or a halogen atom, preferably bromine. R2 represents: an ester group COOR14, an alkyl group CH2R9, CH2OCOR10, CH2NR11R12, an amide group CONR7R8, or a group COR13, R7 and R8, which may be identical or different, represent: a hydrogen atom, a C1-C6 aminoalkyl group, preferably N,N-dimethylaminopropyl, or a C1-C6 morpholinoalkyl group, preferably N-morpholinoethyl, R9 represents: a heteroaryl group, preferably imidazyl or pyrryl, a heterocyclic group, preferably N-morpholinyl or tetrahydrofuranyl, an alkoxy group, preferably methoxy, or a hydroxyl group, R10 represents: a heteroaryl group, preferably quinoxaline, R11 and R12, which may be identical or different, represent: a hydrogen atom, a linear or branched C1-C6 alkyl group, preferably tert-butyl, an aralkyl group, preferably phenylalkyl, preferably phenylmethyl, a C1-C6 alkoxyalkyl group, preferably methoxyethyl, a cycloalkyl group, preferably cyclohexyl, optionally mono- or polysubstituted with a C1-C6 alkyl group, preferably methyl, an aryl, preferably phenyl, group, optionally mono- or polysubstituted with: a halogen atom, preferably bromine, a cyano group, a sulphonamide group, a nitro group, a C1-C6 alkyl group, preferably methyl, an alkoxy, preferably methoxy, group, or a hydroxyl group, or a heteroaryl group, preferably a pyridyl group, R13 represents a heterocyclic group, preferably N-morpholyl, R14 represents: a linear or branched C1-C6 alkyl group, preferably methyl, or an aryl group, preferably phenyl, optionally substituted with an alkoxy preferably methoxy, group, R3, R4, which may be identical or different, represent: a hydrogen atom, a group CH2R15, a heteroaryl group, preferably pyridyl, indyl, benzimidazyl, or pyrazyl optionally substituted with a C1-C6 alkyl group, preferably methyl, or an aryl, preferably phenyl, group optionally mono- or polysubstituted with: an alkoxy preferably methoxy, group, a trifluoroalkoxy, preferably trifluoromethoxy, group, a halogen atom, preferably bromine, chlorine or iodine a trifluoroalkyl preferably trifluoromethyl, group, a CONHalkyl group, preferably CONHmethyl, an NHCOalkyl group, preferably NHCOmethyl, a sulphonamide group, a linear or branched C1-C6 alkyl group, preferably methyl, or a methanesulphonamide group, R15 represents: an aryl, preferably phenyl, group optionally mono- or poly-substituted with: a halogen atom preferably bromine, chlorine, an alkoxy preferably methoxy, group, a trifluoroalkoxy preferably trifluoromethoxy, group, a linear or branched C1-C6 alkyl group, preferably methyl, a C1-C6-trifluoroalkyl group, preferably trifluoromethyl, a heteroaryl group, preferably pyridazinyl, optionally mono- or poly-substituted with a halogen atom, preferably chlorine, a sulphonamide group, or a methanesulphonamide group, a group selected from the groups A, B, C, D or E as defined above, or a heteroaryl group. preferably: a thiophenyl group, a thiazyl group, optionally mono- or polysubstituted, preferably with a group selected from the groups A, B, C, D or E as defined above, an imidazyl group, an indyl group, optionally mono- or polysubstituted, preferably with a linear or branched C1-C6 alkyl group, preferably methyl, a pyrazyl group, optionally mono- or polysubstituted, preferably with a linear or branched C1-C6 alkyl group, preferably ethyl, or with a group selected from A, B, C, D or E groups as defined above, a pyridyl group optionally mono- or polysubstituted with an alkoxy, preferably methoxy, group, or a group selected from the groups A, B, C, D or E as defined above, a group selected from the groups A, B, C, D or E as defined above, a pyrimidinyl group optionally mono- or polysubstituted, preferably with a group selected from the groups A, B, C, D or E as defined above, a benzimidazyl group, optionally mono- or polysubstituted, preferably with a linear or branched C1-C6 alkyl group, preferably methyl, or a 1-H pyrrolo[2,3-b]pyridyl group |
| Claim: |
2. Compound according to claim 1 of general formula II [chemical expression included] R1 and R2 as previously defined. |
| Claim: |
3. Compound according to claim 1 of general formula III [chemical expression included] R2, R3 and R4 as previously defined. |
| Claim: |
4. Compound according to claim 1 of general formula XIV [chemical expression included] In which Ro represents: an aryl group, preferably phenyl, optionally mono- or polysubstituted, preferably with: a halogen atom, preferably bromine or chlorine, an alkoxyl group, preferably methoxy, a linear or branched alkyl group, preferably C1-C6 alkyl group, preferably methyl group, a C1-C6 trifluoroalkyl group, preferably trifluoromethyl, a trifluoroalkoxy group, preferably trifluoromethoxy, a sulphonamide group, a methylsulphonamide group, a group chosen from the group A, B, C, D or E as defined above, a heteroaryl group. preferably: a thiazyl group, substituted or not, preferably substituted by a group chosen from A, B, C, D or E groups as defined above, a thiophenyl group, an imidazil group, an indyl group, optionally mono- or polysubstituted, preferably with a linear or branched C1-C6 alkyl group, preferably methyl, a pyrazyl group, optionally mono- or polysubstituted, preferably with a group chosen from A, B, C, D or E groups as defined above, or by a linear or branched C1-C6 alkyl, preferably ethyl, a benzimidazyl group, optionally mono- or polysubstituted, preferably with a C1-C6 alkyl group, preferably methyl, a piridyl group, optionally mono- or polysubstituted, preferably with a a group chosen from A, B, C, D or E groups as defined above, a pirimidinyl group, optionally mono- or polysubstituted, preferably with a group chosen from A, B, C, D or E groups as defined above, a 1-Hpyrrolo[2,3-b]pyridyl group |
| Claim: |
5. Compound according to claim 1 of general formula XV [chemical expression included] In which Rp represents: a heteroaryl group, preferably a pyridyl group, an aryl group, optionally mono- or polysubstituted, preferably with a: an alkoxyl group, preferably a methoxy, a halogen atom, preferably bromine or iodine, a —CONHalkyl group, preferably —CONHmethyl, a C1-C6 alkyl group, preferably methyl. |
| Claim: |
6. Compound according to claim 1 of general formula XVI [chemical expression included] In which Rq represents: an aryl group, preferably phenyl, optionally mono- or poly substituted, preferably with: a linear or branched alkyl group, preferably C1-C6 alkyl group, preferably methyl group, a group chosen from the group A, B, C, D or E as defined above. |
| Claim: |
7. Method for treating a disease selected from the group consisting of chronic or acute myeloproliferative disorders, colorectal cancer, gastrointestinal cancers, breast cancer, ovarian cancer, lung cancer comprising inhibiting a protein kinase by administering to a patient in need a compound according to claim 1. |
| Claim: |
8. Method according to claim 7, characterized in that the protein kinase is kinase AbI. |
| Claim: |
9. Compound according to claim 7, characterized in that the protein kinase is kinase c-Src. |
| Claim: |
10. Compound according to claim 1, characterized in that it is selected from the group constituted of methyl 5-(2-bromobenzamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, methyl 5-(2-fluoro-6-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, N-(2-((4-hydroxyphenylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-bromobenzamide, N-(2-((1H-pyrrol-2-yl)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-bromobenzamide, 2-bromo-N-(2-(methoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide, or 5-(2-bromobenzamido)-N-(3-(dimethylamino) propyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide. |
| Claim: |
11. Medicinal product, characterized in that it contains, as active principle, a compound according to claim 1. |
| Claim: |
12. Medicinal product according to claim 11, characterized in that it is used in the case of deregulation of protein kinases in diseases selected from the group comprising chronic or acute myeloproliferative disorders, colorectal cancer, gastrointestinal cancers, breast cancer, ovarian cancer, lung cancer. |
| Claim: |
13. Pharmaceutical composition, characterized in that it contains, as active principle, a compound according to claim 1 and a pharmaceutically acceptable excipient. |
| Claim: |
14. Composition according to claim 13, characterized in that it is used in the case of deregulation of protein kinases in diseases selected from the group comprising chronic or acute myeloproliferative disorders, colorectal cancer, gastrointestinal cancers, breast cancer, ovarian cancer, lung cancer. |
| Claim: |
15. Method of preparation of the compounds according to claim 1, characterized in that it comprises at least the stages of: a) catalytic hydrogenation of methyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, in the presence of palladium on charcoal and under hydrogen atmosphere b) reaction of the amine formed with various acyl chlorides to give the corresponding amides at yields ranging from 15 to 74% after purification on silica gel and c) production and characterization of the compound. |
| Claim: |
16. Method of preparation of the compounds according to claim 1, characterized in that it comprises at least the stages of: a) selective reduction of the ester function of methyl 5-(2-bromobenzamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate by lithium aluminium hydride at room temperature, b) conversion of the alcohol to alkane bromide by PBr3, at room temperature for 18 h in THF (raw yield of 81%), said reaction being followed by the following stages c) or d) c) dissolution in methanol, to give the methoxyazaindole obtained by reaction of the solvent on the halogenated function, at room temperature d) reaction of the alkane bromide with a primary or secondary amine in anhydrous dimethylformamide, at room temperature for 18 h, to give the corresponding 7-azaindoles at yields ranging from 9 to 96% after purification on silica gel and e) production and characterization of the compound. |
| Claim: |
17. Method of preparation of the compounds according to claim 1, characterized in that it comprises at least the stages of: a) saponification of the ester of methyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate by lithium hydroxide, b) peptide coupling by means of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI) hydrochloride and morpholine, c) hydrogenation of the amide obtained by catalytic palladium, d) reaction of the compound obtained with various acyl chlorides, in the presence of triethylamine in dimethylformamide, to obtain the desired 7-azaindoles, and e) production and characterization of the compound. |
| Claim: |
18. Method of preparation of compounds according to claim 1, characterized in that it comprises at least the stages of: a) reaction of methyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate with aqueous ammonia at room temperature for 24 hours to obtain the primary amide of azaindole, b) hydrogenation of the compound obtained on Pd/C, c) reaction with 3-fluorobenzoyl to give the desired compound, and d) production and characterization of the compound. |
| Claim: |
19. Method of preparation of compounds according to claim 1, characterized in that it comprises at least the stages of: a) reaction of methyl 5-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylate with various acyl chlorides, b) saponification of the compounds obtained by the action of potassium hydroxide under reflux in a water-methanol mixture, c) reaction of the compound obtained on various alcohols or amines, and d) production and characterization of the compound. |
| Current U.S. Class: |
5142/345 |
| Current International Class: |
61; 61; 07; 61; 61; 61; 61; 07; 61 |
| Accession Number: |
edspap.20110312959 |
| Database: |
USPTO Patent Applications |
