Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the invention relates to pyrrolo [2,3-a] carbazole derivatives, process for their preparation and their use.
• Inhibitors of PIM kinases are particularly sought after because of their action in the cardiovascular field, type 2 diabetes, their antiproliferative activity and their potential to inhibit resistance to certain chemotherapy drugs.
• PIM kinases i.e., PIM-1, PIM-2 and PIM-3 kinases, are proto-oncogenes involved, particularly in the cancer process.
• chemotherapeutic agents such as rapamycin and tyrosine kinase-like growth factor receptor inhibitors.
• specific inhibitors of PIM kinases There are very few specific inhibitors of PIM kinases.
• specific inhibitor of PIM kinases is meant a compound that strongly inhibits PIM kinases alone, and little or no most other kinases.
• kinases encoded by the human genome, so the problem of selectivity is critical.
• a compound is said to be specific for the inhibition of a particular type of kinase when it inhibits this type of kinase while it has been tested on at least 30 other kinases.
• kinase inhibiting compounds including PIM kinases are not selective.
• the only families of compounds described as being selective for PIM kinases are: the imidazo [1, 2-6] pyridazines described by Pogacic et al., in Cancer Research 2007, 67, 6916-6924, quercetagetin described by Holder et al., in Molecular Cancer Therapeutics 2007, 6, 163-172, and the ruthenium complexes described by Debreczeni et al., in Angewandte Chemie, Int. Ed., 2006, 45, 1580-1585.
• the invention is based on the discovery that certain pyrrolo [2,3-a] carbazole compounds are selective inhibitors of at least one of the PIM kinases, and that this selectivity is practiced among a panel of 67 kinases tested.
• the invention proposes the use of at least one compound of formula I below:
• R 2 , R 3 and R 4 are identical or different and represent, independently of one another, a hydrogen atom, a halogen atom, a nitro, nitrile, hydroxy or linear C 1 -C 6 alkoxy group; branched, substituted or unsubstituted by one or more R 5 groups, C 5 -C 6 cycloalkoxy optionally substituted with one or more R 5 groups, 5 or 6 membered heterocycloalkoxy optionally substituted by one or more R 5 , -SH groups C 1 -C 6 linear or branched alkylthio, unsubstituted or substituted by one or more R 5 groups, C 6 aryl substituted or unsubstituted by one or more R 5 groups, C 6 aryloxy substituted or unsubstituted by one or more R groups 5 , -NR 3 Rb, -NR 3 C (O) -Ti, -C (N-OH) -T 3 , -C (O)
• R 5 represents a halogen atom, or an alkyl group
• R a and R b are identical or different and each represents independently of the other a hydrogen atom or an alkyl group -C 6 linear or branched haloalkyl, C 1 -C 6 linear or branched, C 6 aryl, where R 3 + R b together with the nitrogen atom to which they are bonded form a saturated or unsaturated monocyclic or bicyclic 5 to 10 membered heterocycle, optionally containing a second heteroatom selected from oxygen and nitrogen, and being optionally substituted with one or more R 5 groups,
• Ti represents a hydrogen atom, a halogen atom, or a linear or branched C 1 to C 6 alkyl group, optionally substituted with a group chosen from -OR 3 , -NR a R b , -CO 2 R 3 , -C (O) R 3 and -C (O) NR a R b ,
• T 2 represents a linear or branched (C 1 -C 6 ) alkylidene chain
• T 3 represents a group chosen from -halogen, -OR 3 , -NR 3 Rb, -CO 2 R 3 , -C (O) R 3 and -C (O) NR a R b in which R 3 and R b are as defined above, t represents an integer between 0 and 3 inclusive, - A, B, C, D denote the rings constituting the compounds of formula I and have only identification purposes for each of these cycles, or one of the salts, optical isomers, racemic mixtures of these compounds, as an inhibitor of the activity of at least one of the PIM-1, PIM-2 and PIM-3 kinases.
• the at least one compound used in formula I in which:
• R 1 is H or a sulfophenyl group
• the at least one compound used has formula I wherein:
• Ri is H or a sulfophenyl group
• the at least one compound of formula I is selected from 1, 10-dihydropyrrolo [2,3-a] carbazole, 1,10-dihydropyrrolo [2,3-a] carbazol-3-carbaldehyde, 1,10-dihydropyrrolo [2,3-a] carbazol-3-carboxamide, 1- (1,10-dihydropyrrolo [2,3-a] carbazol-3-yl-2,2,2-trifluoroethanone, 7 1-bromo-1,10-dihydropyrrolo [2,3-a] carbazole, 7-bromo-1,10-dihydropyrrolo [2,3-a] carbazol-3-carbaldehyde, 7- (2,4-difluorophenyl) 1,1-dihydropyrrolo [2,3-a] carbazol-3-carbaldehyde, 6-bromo-1,10-dihydropyrrolo [2,3-a] carbazol-3-carbaldehy
• the at least one compound of formula I used in the invention is selected from 1, 10-dihydropyrrolo [2,3-a] carbazole, 1,10-dihydropyrrolo [2,3-a] carbazol 3-carbaldehyde, 1,10-dihydropyrrolo [2,3-a] carbazol-3-carboxamide, 1- (1,10-dihydropyrrolo [2,3-a] carbazol-3-yl-2,2, 2-trifluoroethanone, 7-bromo-1,10-dihydropyrrolo [2,3- a] carbazole, 7-bromo-1,10-dihydro-pyrrolo [2,3-a] carbazol-3-carbaldehyde,
• the invention also provides a process for synthesizing the following compounds of formula I:
• Ri is H or a sulfophenyl group
• R 2 , R 3 and R 4 are identical or different and represent, independently of one another, a hydrogen atom, a halogen atom, or a nitro, nitrile, hydroxy or linear C 1 -C 6 alkoxy group; or branched, substituted or unsubstituted by one or more R 5 groups, C 5 -C 6 cycloalkoxy optionally substituted with one or more R 5 groups, 5 or 6 membered heterocycloalkoxy substituted or unsubstituted by one or more R 5 groups, SH, alkylthio C 6 linear or branched, unsubstituted or substituted with one or more R 5 groups, C 6 unsubstituted or substituted by one or more R 5 groups, aryloxy C 6 unsubstituted or substituted by one or more groups R 5 , -NR 3 Rb, -NR 3 C (O) -Ti, -C (N-OH) -T 3 , -C (O) -T
• - R 5 represents a halogen atom or an alkyl group -C 6 linear or branched, aryl, Ce, haloalkyl -C 6 linear or branched, -OR a, -NR a R b, -CO 2 R 3 , -C (O) R 3 and -C (O) NR a R b , nitrile, nitro, -NR 3 C (O) -T 1 , C 1 -C 6 alkoxy, oxo, -S (O) ) 1 -R 3, -S (O) 1 -OR 3, -S (O) t -NR a R b, -P (O) 1 -R 3, - P (O) t -OR a,
• R a and R b are identical or different and are each independently of one another a group selected from a hydrogen atom, an alkyl group in C 1 to C 6 linear or branched haloalkyl, C 1 -C 6 linear or branched, C 6 aryl, wherein R 3 + R b together with the nitrogen atom to which they are bonded together form a saturated or unsaturated monocyclic or bicyclic 5 to 10 membered heterocycle, optionally containing cyclic systems a second heteroatom selected from oxygen and nitrogen, and being optionally substituted with one or more groups R 5 ,
• T 1 represents a hydrogen atom, a halogen atom, or a linear or branched C 1 to C 6 alkyl group, optionally substituted with a group chosen from -OR 3 , -NR a R b , -CO 2 R 3 , -C (O) R 3 and -C (O) NR 3 Rb,
• T 2 represents a linear or branched (Ci-C 6 ) alkylidene chain
• T 3 represents a group chosen from -halogen, -OR 3 , -NR 3 Rb, -CO 2 R 3 , -C (O) Ra and -C (O) NR a R b in which R 3 and R b are such as defined above, t represents an integer between 0 and 3 inclusive, - A, B, C, D denote the rings constituting the compounds of formula I and have only identification purposes for each of these cycles, characterized in that it comprises a Fischer indolization reaction of the 1-benzenesulfonyl-1, 4,5,6-tetrahydro-7H-indol-7-one compound of the following formula II:
• R 1 is H or a sulfophenyl group
• R 2 , R 3 and R 4 are identical or different and represent, independently of one another, a hydrogen atom, a halogen atom, or a nitro, nitrile, hydroxy or linear C 1 -C 6 alkoxy group or branched, substituted or not by one or more R 5 groups, cycloalkoxy, C 5 to C 6 substituted or not by one or more R 5 groups, heterocycloalkoxy 5- or 6-membered unsubstituted or substituted by one or more R 5 groups, -SH C 1 -C 6 linear or branched alkylthio, unsubstituted or substituted by one or more R 5 groups, C 6 aryl substituted or unsubstituted by one or more R 5 groups, C 6 aryloxy substituted or unsubstituted by one or more R groups 5 , -NR 3 Rb, -NR 3 C (O) -Ti, -C (N-OH) -T 3 , -C (O)
• R a and R b are identical or different and each represents independently of the other a hydrogen atom or an alkyl group -C 6 linear or branched haloalkyl, Ci -C 6 linear or branched, aryl at C 6 , where R a + R b together with the nitrogen atom to which they are bonded form a saturated or unsaturated monocyclic or bicyclic heterocyclic ring of 5 to 10 atoms, optionally containing, within the cyclic systems, a second heteroatom selected from oxygen and nitrogen, and being optionally substituted with one or more R 5 groups,
• Ti represents a hydrogen atom, a halogen atom, or a linear or branched C 1 to C 6 alkyl group, optionally substituted with a group chosen from -OR 3 , -NR 3 Rb, -CO 2 Ra, - C (O) R 3 and -C (O) NR 3 R b ,
• T 2 represents a linear or branched (C 1 -C 6 ) alkylidene chain
• T 3 represents a group chosen from -halogen, -OR 3 , -NR a R b , -CO 2 R 3 , -C (O) R 3 and -C (O) NR a R b in which R a and R b are as defined above, t represents an integer between 0 and 3 inclusive, - A, B, C, D denote the rings constituting the compounds of formula I and have only identification purposes of each of these cycles , on the condition of :
• R 1 , R 2 , R 3 and R 4 are not all H at the same time, when R 1 is a sulphophenyl group, then R 2 , R 3 and R 4 are not all H at the same time, and when R 2 is a carboxamide or formyl group, so R 1 , R 3 and R 4 are not all H at the same time.
• these compounds have the formula I in which:
• R 1 is H or a sulfophenyl group
• R 1 is H or a sulfophenyl group
• Ri is H or a sulfophenyl group
• R 2 , R 3 and R 4 are identical or different and represent, independently of one another, a hydrogen atom, a halogen atom, or a nitro, nitrile, hydroxy or C 1 -C 6 alkoxy group; linear or branched, substituted or not by one or more R 5 groups, C 5 -C 6 cycloalkoxy optionally substituted with one or more R 5 groups, 5 or 6-membered heterocycloalkoxy optionally substituted with one or more R 5 groups, -SH, alkylthio C 6 linear or branched, unsubstituted or substituted with one or more R 5 groups, C 6 unsubstituted or substituted by one or more R 5 groups, aryloxy C 6 unsubstituted or substituted by one or more groups R 5 , -NR 3 Rb, -NR 3 C (O) -T 1 , -C (N-OH) -T 3 , -C (O) -T 1 , -C (
• R 5 represents a halogen atom or an alkyl group -C 6 linear or branched C 6 haloalkyl, Ci -C 6 linear or branched, -OR 3, -NR a R b, -CO 2 R 31 -C (O) R 3 and -C (O) NR 3 Rb, nitrile, nitro, -NR 3 C (O) -T 1 , C 1 -C 6 alkoxy, oxo, -S (O) 4 -R 8 , -S (O) 1 -OR 3 , -S (O) t -NR a R b , -P (O) 1 -R 3 , -P (O) 1 -OR 3 ,
• R 3 and R b are the same or different and each independently represents a group chosen from a hydrogen atom, a linear or branched C 1 to C 6 alkyl group or a C 1 to C 6 haloalkyl group; linear or branched C 6 aryl, wherein R 3 + R b together with the nitrogen atom to which they are bonded form a 5 to 10 membered monocyclic or bicyclic, saturated or unsaturated heterocycle, optionally containing cyclic systems a second heteroatom selected from oxygen and nitrogen, and being optionally substituted with one or more groups R 5 ,
• T 1 represents a hydrogen atom, a halogen atom, or a linear or branched C 1 to C 6 alkyl group, optionally substituted with a group chosen from -OR 3 , -NR 3 Rb, -CO 2 R 3 , -C (O) R 3 and -C (O) NR a R b ,
• T 2 represents a linear or branched (C 1 -C 6 ) alkylidene chain
• T 3 represents a group chosen from -halogen, - OR a , -NR 3 Rb, -CO 2 R 3 , -C (O) R 3 and -C (O) NR a R b in which R 3 and R b are as defined previously,
• - 1 represents an integer between 0 and 3 inclusive
• - A, B, C, D denote the rings constituting the compounds of formula I and have only identification purposes for each of these cycles, are selective inhibitors of at least one PIM-1, PIM-2 and PIM-3 kinase when tested on 67 kinases.
• PIM-1, PIM-2 or PIM-3 kinase Because of their selective inhibition properties of at least one PIM-1, PIM-2 or PIM-3 kinase, they exhibit particularly advantageous properties in the anticancer field.
• These compounds can be used either alone or in combination, particularly with other anticancer agents such as, for example, paclitaxel, tamoxifen and its derivatives, cisplatin and its analogues, irinotecan and its metabolites, various alkylants, etoposide, Vinca alkaloids, anthracyclines , nitrosoureas, hormone therapy and radiotherapy.
• anticancer agents such as, for example, paclitaxel, tamoxifen and its derivatives, cisplatin and its analogues, irinotecan and its metabolites, various alkylants, etoposide, Vinca alkaloids, anthracyclines , nitrosoureas, hormone therapy and radiotherapy
• These compounds of formula I can be used as such or in the form of their optical isomers or in the form of a racemic mixture of these optical isomers or an addition salt of these compounds of formula I with an acid or a pharmaceutically acceptable base.
• the preferred, more preferred, and most preferred and even more preferred compounds of formula I used as selective inhibitors of at least one PIM-1, PIM-2 and PIM-3 kinase have been defined above.
• R 2 , R 3 and / or R 4 is a group which is itself substituted with one or more R 5 groups, preferably it is substituted with one or two R 5 groups.
• the two groups R 5 are preferably identical.
• the invention also proposes a process for the manufacture of the compounds of formula I which may be used as an alternative to the conventional process for producing these pyrrolo [2,3-a] carbazole compounds.
• This process comprises a Fischer-indolization reaction, 1-benzenesulfonyl-1, 4,5,6-tetrahydro-7H-indol-7-one with phenylhydrazine or a phenyl-substituted phenylhydrazine with one or more R groups. 5 , in the presence of an ionic liquid, zinc chloride-choline chloride 2: 1.
• 1-Benzenesulfonylpyrrole is used to prepare 1-benzenesulfonyl-1, 4,5,6-tetrahydro-7H-indol-7-one which will be used for the synthesis of the compounds according to the invention.
• the ionic liquid very hygroscopic, can be used directly, or kept under argon in anhydrous ether.
• Step A A solution of the compound of Preparation B (9.65 g, 35.0 mmol) and phenylhydrazine (6.92 mL, 70.3 mmol) in nitromethane (360 mL) is stirred for 3 hours under reflux. .
• Stage B P 2 O 5 (9.91 g, 69.8 mmol) is added to a solution of hexamethyldisiloxane (23.9 mL, 112 mmol) in dichloromethane (350 mL) and the mixture is stirred under reflux for 40 minutes. . The solvent is distilled off and the residual liquid is heated at 180 ° C. for 5 minutes. The oil obtained (PPSE) is diluted in nitromethane (180 mL) and the solution is transferred into the preparation from the previous stage. The mixture is heated with stirring under reflux for 6 hours and then DDQ (3.50 g, 15.4 mmol) is added. The mixture is stirred at room temperature for 12 hours before being filtered through Celite and then concentrated in vacuo.
• a 5M aqueous solution of NaOH (125 ml) is added to a suspension of the compound of Example 1 (3.12 g, 9.0 mmol) in methanol.
• Chlorosulfonyl isocyanate (26.7 ⁇ L, 0.307 mmol) is added at 0 ° C. to a solution of the compound of Example 2 (57.4 mg, 0.278 mmol) in anhydrous acetonitrile (10 mL). The mixture is stirred at 0 ° C. for 1.5 hours and then an aqueous solution of 1N HCl (5 ml) and THF (2 ml) are added. The mixture is stirred at room temperature for 36 hours and then water is added.
• Stage A oxalyl chloride (660 ⁇ l, 7.7 mmol) is added at 0 ° C. and to a suspension of the compound of Example 2 (825 mg, 4.00 mmol) in anhydrous I 1 and 2 O (40 mL). The mixture is stirred at ambient temperature for 4 hours. After filtration, the solid is washed with 1 I and 2 O (2 x 40 mL) which makes it possible to obtain the intermediate acid chloride (972 mg) in the form of a red-brown solid which is used without further purification.
• the combined organic phases are washed with a saturated aqueous solution of NaCl, dried over MgSO 4 , filtered and evaporated.
• the residue obtained is a mixture containing the indolization product, the majority, and the expected product, a minority.
• a solution of the resulting residue and DDQ (0.7 g, 3.1 mmol, the amount required DDQ is determined from the 1 H NMR spectrum of the resulting residue) in dioxane (20 mL) is stirred at room temperature for 15 minutes. hours. After evaporation of the solvent, ethyl acetate is added and the mixture is washed with water and a saturated aqueous solution of NaCl.
• the reaction mixture is concentrated under vacuum and then neutralized with concentrated aqueous HCl solution.
• Ethyl acetate is added, the organic phase is collected, and the aqueous phase is extracted with ethyl acetate (3 * 30 mL).
• the combined organic phases are washed with a saturated aqueous solution of NaCl, dried over MgSO 4 , filtered and evaporated.
• the residue is purified by flash silica gel chromatography (pentane / ethyl acetate 9: 1, 8: 2 and then 7: 3) to obtain the expected compound.
• Step A A suspension of substituted phenylhydrazine hydrochloride and anhydrous sodium acetate in DME (20 mL) is stirred at room temperature for 1 hour.
• the compound of Preparation B (1.10 g, 4.0 mmol) and the ionic liquid of Preparation C (11.54 g, 28 mmol) are added.
• the solvent was evaporated and the mixture is heated at 120 0 C for 12 hours.
• an aqueous solution of 0.5 M hydrochloric acid is added before extraction with ethyl acetate.
• the organic fractions are washed with a saturated aqueous solution of NaCl, dried over MgSO 4 and filtered.
• stage B DDQ is added to this solution and the reaction mixture is stirred at room temperature overnight. The mixture was washed with saturated aqueous NaCl solution 1 dried over MgSO 4 and concentrated in vacuo.
• Stage C the crude reaction product is dissolved in methanol (100 ml), an aqueous solution of 5 M KOH (25 ml) is added and the mixture is refluxed for 12 hours. After cooling, the solvent is removed in vacuo. The residue is neutralized with concentrated hydrochloric acid.
• Step A a mixture of 3-methylphenylhydrazine (1.00 g, 8.2 mmol), the compound of Preparation B (1.65 g, 6.0 mmol) and the ionic liquid of Preparation C (11, 54 28 mmol) and stirred at 120 ° C. for 12 hours. After cooling, a 0.5 M aqueous solution of HCl is added before extraction with ethyl acetate. The combined organic fractions are washed with a saturated aqueous solution of NaCl, dried over MgSO 4 and filtered. The solution contains the expected product and is used directly for the next oxidation step.
• Stages B and C are carried out in the same way as for Examples 25-34.
• Stage B DDQ (953 mg, 4.20 mmol);
• Example 2 i.e. 1,10-dihydropyrrolo [2,3-a] carbazole, of Example 3, i.e. 1,10-dihydropyrrolo [ 2,3-a] carbazol-3-carbaldehyde as well as the compound of Example 5, i.e. 1,1-dihydropyrrolo [2,3-a] carbazol-3-carboxamide were tested on the following 67 kinases:
• MNK2 MAPKAP-K2, MAPKAP-K3, PRAK, CAMKK 1 CAMKKb, CAMK1,
• N. D not determined
• N1 No inhibitor.
• the preferred compounds of the invention are those which have a residual activity percentage of less than or equal to 10%, that is to say the compounds of Examples 2, 3, 5, 6, 15, 16, 40, 44. , 45, 46, 47, 48, 51 and 52.
• IC 50 Mean inhibitory concentrations (IC 50) of some preferred compounds of the invention were determined as follows: CI 5 0 were measured after performing the kinase inhibition assays
• PIM-1, PIM-2 or PIM-3 at 10 different concentrations for each test compound and Cl 50 was determined from the dose-inhibition curves obtained.

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