Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the invention thus relates to the compound ethyl 8-oxo-9-[3-(1 H-benzimidazol-2- yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate, salt, crystalline form, cocrystal, formulation, processes for preparation thereof, application thereof as medicaments, pharmaceutical compositions and new uses thereof particularly as Aurora kinase inhibitors.
• mpound F The compound ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9- hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate in free base form, referred to hereinafter as mpound F, conforms to the formula (F) below:
• the present invention accordingly provides the compound ethyl 8-oxo-9-[3-(1 H- benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3- carboxylate or compound F of formula (F) below:
• the present invention accordingly provides the compound I as defined above or sulphate salt of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9- hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate, which therefore has the formula (I) below:
• the present invention accordingly provides the compound I as defined above or sulphate salt of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9- hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate, characterized in that it is in crystalline form.
• the present invention accordingly provides the compound II as defined above or cocrystal of the product of formula (F), ethyl 8-oxo-9-[3-(1 H-benzimidazol-2- yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate.
• the present invention accordingly provides the compound II as defined above or cocrystal of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro- 2H-pyrrolo[3,4-b]quinoline-3-carboxylate, characterized in that it is the cocrystal with L- malic acid.
• the present invention likewise provides the formulations as defined above, characterized in that they comprise said compound of formula (F), ethyl 8-oxo-9-[3-(1 H- benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3- carboxylate, or said sulphate salt compound I of the product of formula (F) or said cocrystal compound II of the product of formula (F), as defined above.
• the compounds I and II or formulations as defined above that are provided by the invention are selective inhibitors of Aurora kinases.
• the present invention likewise relates to pharmaceutical compositions comprising these compounds.
• These compounds may be used as anti-cancer agents.
• the invention also relates to processes for obtaining these compounds and to some of the intermediates in said processes.
• a number of cancer treatment strategies are aimed at inhibiting the Aurora-type kinases, particularly Aurora A and B, which are involved in the regulation of mitosis; in this regard, see Nature Reviews 2004, 4, 927-936; Cancer Res. 2002, 94, 1320; Oncogene 2002, 21 , 6175; Mol. Cell. Biol. 2009, 29(4), 1059-1071 ; Expert Opin. Ther. Patents 2005, 15(9), 1 169-1 182; Clin. Cancer Res. 2008, 14(6), 1639).
• Aurora inhibitor compounds for example, MLN-8237 from Millennium, AZD-1 152 from Astra-Zeneca or SNS-314 from Sunesis
• MLN-8237 is selective for Aurora A
• AZD-1 152 is selective for Aurora B. Since both kinases, Aurora A and B, are deregulated in cancer, inhibiting both Aurora A and B provides an advantage over selective inhibition of one kinase or the other.
• multi-kinase compounds are in existence, such as the compound AT-9283 from Astex, which inhibit a number of kinases, including Aurora A and B.
• the cyclic nucleotide phosphodiesterase enzyme PDE3 plays a major part in the signalling mediated by the cyclic nucleotides cAMP and cGMP that takes place in the myocytes of the smooth cardiac and vascular muscles.
• the inhibition of PDE3 by small molecules has an inotropic and vasodilatory action, which may prove to be useful on a short-term basis for the treatment of certain cardiomyopathies in which defects in cardiac contraction are a feature. It has been shown, however, that the long-term use of these molecules increases mortality in this type of patient.
• the use of PDE3 inhibitors in patients who do not have this type of pathology, such as patients affected by cancer may give rise to unwanted effects on cardiac rhythm.
• WO 01/36422 describes compounds having a different tricyclic structure.
• the compound does not include a phenyl ring substituted by the group -O-benzimidazolyl at the top of the trycyclic ring system.
• WO 2005/016245 describes anti-cancer compounds having a different tricyclic structure, of formula (b):
• R4 can represent a substituted phenyl group. Substitution by the group -O-benzimidazolyl is neither described nor suggested.
• R2 represents a substituted aryl or heteroaryl group
• X represents N or CR7
• R5 and R6 may both represent H or CH 3 .
• No example in WO 2007/012972 contains the
• R4 and R5 may optionally form a 5- or 6-membered ring.
• the crystalline sulphate salt and the cocrystal that are subject-matter of the present invention have demonstrated a greatly enhanced (solubility, stability) physicochemical profile, which has allowed the development of formulations compatible with administration to human beings.
• the crystalline sulphate salt or cocrystal thus formulated has demonstrated a significant activity on xenografted models of human tumours in mice.
• this sulphate salt or compound I is crystalline whereas the base and many other salts such as, for example, hydrochloride, phosphate, p- toluenesulphonate and naphthalene-1 ,5-disulphonate of this product are amorphous;
• this salt or compound I, the compound II and formulations, that are subject-matter of the present invention are much more soluble in aqueous medium than the amorphous base or compound F, and therefore allow better formulation properties for administration to human beings.
• the advantages of the sulphate salt and of the cocrystal with L-malic acid are therefore, in particular, those of being more stable than the base under storage conditions at high temperature and humidity. Crystalline compounds are therefore easier to weigh and distribute than the amorphous base.
• the advantages of the formulation are in particular those of compatibility with intravenous (iv) administration to human beings: the formulation allows a reduction in the incidence of an oxidation impurity (example 3) and the provision of a solution which is stable at 5°C for several months and is compatible with clinical use.
• the present invention provides in particular the formulations as defined above, characterized in that they are in the form of a micellar solution.
• the present invention particularly provides the formulations as defined above, characterized in that they are in the form of a micellar solution compatible with intravenous administration.
• the products are detected by an Acquity PDA diode-array UV/vis detector (Waters, wavelength range scanned: 192-400 nm), a Sedex 85 light scattering detector (Sedere, nebulizing gas: nitrogen, nebulizing temperature: 32°C, nebulizing pressure 3.8 bar) and an Acquity SQD mass spectrometer (Waters, operating in positive and negative mode, mass range scanned: 80 to 800 amu).
• an Acquity PDA diode-array UV/vis detector Waters, wavelength range scanned: 192-400 nm
• Sedex 85 light scattering detector Sedex 85 light scattering detector
• Sedex 85 light scattering detector Sedex 85 light scattering detector
• an Acquity SQD mass spectrometer Waters, operating in positive and negative mode, mass range scanned: 80 to 800 amu.
• the spectra are recorded on a Bruker spectrometer, the product being dissolved in DMSO-d6.
• the chemical shifts ⁇ are expressed in ppm.
• the infrared spectrum is recorded at between 4000 and 400 cm “1 on a Nicolet Nexus spectrometer as a KBr disk, with a resolution of 2 cm “1 .
• optical rotations were recorded on a Perkin-Elmer 341 polarimeter.
• the analyses were carried out on a Bruker D8-Advance diffractometer in Bragg- Brentano configuration.
• the sample is placed in a gate of the Anton Paar TTK450 temperature chamber, on a silicon slide.
• the sample is flattened by rotating movements on the silicon slide in order to give a planar surface of constant thickness.
• the diffractograms were recorded in the 2 ⁇ angle range of 2°-40° in continuous mode, using 2 ⁇ angular increments of 0.033° and an acquisition time per step of 0.5 s.
• the solubility of the compounds is measured in ultra-purified water, in an HCI-buffered medium of pH 1 , in an acetate-buffered medium of pH 4.7 and in a phosphate-buffered medium of pH 7.4.
• the ultra-purified water is obtained from a Millipore production system.
• the HCI-buffered medium of pH 1 is prepared by diluting to 1/10 a ready-to-use HCI 1 N solution sold by Merck.
• the acetate-buffered medium of pH 4.7 is prepared by adding 0.75 g of sodium acetate trihydrate to 0.35 ml of pure acetic acid, which is made up to 250 ml with ultra-purified water.
• the phosphate-buffered medium of pH 7.4 is prepared by adding 40.5 ml of 0.1 M disodium hydrogenphosphate solution to 9.5 ml of 0.1 M sodium dihydrogen phosphate solution, which is then made up to 100 ml with ultra-purified water.
• Crystallizers Approximately 20 mg of compound in question for the study are placed in four crystallizers. Two crystallizers are closed non-hermetically and placed in two ovens (brand name, model) temperature-controlled at 50°C and 80°C respectively. Two crystallizers are left open and placed in two desiccators containing a pre-saturated KCI solution which generates a relative humidity in the desiccator of -80%. The two desiccators are then placed in two Heraeus UT6060 ovens temperature-controlled at 50°C and 80°C respectively.
• the crystallizers After 14 days of storage, the crystallizers are closed hermetically and their temperature is brought naturally to 21 °C (ambient temperature). The four samples of the compound in question are then analysed by powder X-ray diffraction to verify the physical stability, and by HPLC to verify the chemical stability, of the compound.
• the capacity to inhibit the kinase activity of the enzyme is estimated by measuring the residual kinase activity of the enzyme in the presence of different concentrations of the test compound (generally 0.17 to 10000 nM). A dose-response curve is produced, which allows an IC 5 o (50% inhibitory concentration) to be ascertained.
• the kinase activity is measured by a radioactive assay of the amount of radioactive phosphate (33P) incorporated into a fragment of the protein NuMA (Nuclear Mitotic Apparatus protein) after 30 min of incubation at 37°C.
• the test compound is first dissolved at different concentrations in dimethyl sulphoxide (DMSO).
• the radioactivity is then measured using a TRILUX I450 Microbeta counter (Wallac).
• TRILUX I450 Microbeta counter In each plate, there are eight control wells: four positive controls (maximum kinase activity), for which measurement is made in the presence of enzyme and substrate and in the absence of compound of the invention, and four negative controls (background noise), for which measurement is made in the absence of enzyme, substrate and test compound.
• the measurements are given in Table I.
• the recombinant human enzyme Aurora A used is expressed in entire form with a poly-Histidine tag in N-terminal position and is produced in E.coli.
• Aurora B The entire human enzyme Aurora B is co-expressed with a fragment of the human protein Incenp (aa 821-918) in a baculovirus system and is expressed in insect cells.
• Aurora B has a poly-Histidine tag in N-terminal position, while the Incenp fragment possesses a Glutathione-S-Transferase (GST) tag in N-terminal position.
• GST Glutathione-S-Transferase
• the two proteins form a complex which is called Aurora B/lncenp.
• a fragment (aa1701-21 15) of the human protein NuMA with a poly-Histidine tag in C-terminal position is expressed in recombinant form in E.coli. This fragment is used as substrate.
• the present invention further provides any process for preparing the compounds I, II and formulation as defined above.
• the present invention accordingly provides any process for preparing the compound I as defined above or sulphate salt of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]- 4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate, and particularly the process as defined in scheme 1 above or else the processes as described in the experimental section.
• the present invention accordingly provides any process for preparing the compound II as defined above or cocrystal of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]- 4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate, and particularly the processes as described in the experimental section.
• the present invention accordingly provides any process for preparing a formulation as defined above, and particularly the processes as described in the experimental section.
• Example 1 preparation of the sulphate of ethyl 8-oxo-9-r3-(1 H-benzimidazol-2- yloxy)phenvn-4,5,6,7,8,9-hexahvdro-2H-pyrrolor3,4-b1quinoline-3-carboxylate, laevogyratory enantiomer
• a 10 I reactor is charged under argon and with stirring with 2.5 I of THF, 180 g of 2- chlorobenzimidazole (1.18 mol) and 325 ml of 3,4-dihydro-2H-pyran (6.56 mol, 3 eq.).
• the reactor is heated until dissolution takes place (temperature of the medium: 40°C).
• 6.3 g of para-toluenesulphonic acid (0.033 mol, 0.028 eq.) are introduced.
• the temperature is maintained at between 49 and 52°C for 2.5 hours.
• the system is cooled to 12°C and 7.65 g of sodium methoxide (0.142 mol, 0.12 eq.) are added, with stirring maintained, over a total time of 15 minutes.
• the aqueous phase obtained is subsequently extracted with 4 x 2.5 I of ethyl acetate (AcOEt).
• the organic phases are then combined, washed with 3 I of water and then with 2 I of saturated NaCI solution, and finally dried by addition of MgS0 4 overnight.
• a fraction of 158 g of the crude material obtained above is dissolved hot in 1.5 I of an n-heptane/AcOEt mixture (8/2 by volume), combined with 500 g of silica (70-30 mesh) and the whole is stirred for 45 minutes.
• the suspension obtained is filtered on Celite and washed with 3 I of an n-heptane/AcOEt mixture (8/2 by volume).
• the organic phase obtained is concentrated to dryness under reduced pressure.
• the residue is resuspended in 200 ml of isopropyl ether by mechanical stirring and treatment with ultrasound, and then filtered on a glass frit (porosity 3).
• the solid obtained is washed with 2x40 ml of ispropyl ether and dried under reduced pressure at 40°C for 16 hours, to give 68 g of solid.
• a similar treatment applied to the rest of the crude product produces 87.8 g of solid.
• An aliquot fraction of 0.8 g of the material obtained may be purified by chromatography on a cartridge of 50 g of silica (10-90 ⁇ ) (Biotage SNAP, KP-Sil) eluted with an isocratic stage of dichloromethane for 20 minutes, then a gradient from 0 to 1 % by volume of isopropanol in dichloromethane over one hour, and finally an isocractic stage of dichloromethane/isopropanol (99/1 by volume) for 20 minutes.
• the fractions containing the expected product are combined, to give 0.21 g of a yellow solid.
• the laevogyratory enantiomer is purified from the crude product of example D1 on a Welk-01 RR chiral column, 10 ⁇ , 80x350 mm (Regis, USA) eluted with an n- heptane/dichloro-methane/ethanol/triethylamine mixture (50/47.5/2.5/0.1 by volume). The elution of the products is detected by UV spectroscopy at 265 nm. Quantities of 10 g of the crude product described in example D1 are injected in each operation. Under these conditions, the peak corresponding to the laevogyratory enantiomer is eluted with a tr of between 50 and 80 min.
• the crystals are then combined with 70 ml of ethyl acetate and the mixture is taken to reflux for 30 minutes. After return to ambient temperature, the crystals are collected by filtration, washed with 30 ml of ethyl acetate and dried under reduced pressure at 70°C overnight. This gives 3.04 g of yellow crystals: melting point 242-244°C, acetonitrile: 0.2 mol/mol (NMR), H 2 0 5.9% (1 .9 mol/mol).
• the principal bands are centred at: 3424; 3209; 2939; 2621 ; 1684; 1635; 1578; 1471 ; 1372; 1 188; 1042; 782; 762; 586 cm "1
• the present invention accordingly provides the compound I as defined above, or sulphate salt of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9- hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate, characterized in that its melting point is 242-244°C,
• Example 2 preparation of the cocrystal of the laevogyratory enantiomer of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4- b]quinoline-3-carboxylate with L-malic acid (compound II).
• Example 2.b preparation of the cocrystal of the laevogyratory enantiomer of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4- b]quinoline-3-carboxylate with L-malic acid (compound II).
• Example 2.c preparation of the cocrystal of the laevogyratory enantiomer of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4- b]quinoline-3-carboxylate with L-malic acid (compound II).
• the crystallization is initiated with 2 mg of cocrystal of the laevogyratory enantiomer of ethyl 8-oxo-9-[3-(1 H- benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate with L-malic acid, and then 250 microlitres of ethyl acetate are added. The suspension obtained is left with stirring overnight at ambient temperature.
• reaction mixture is stirred at ambient temperature. The solution blackens and then a precipitate appears. After 30 minutes of reaction, the reaction mixture is 0 concentrated under reduced pressure and the residue is taken up in 100 ml of water. The resulting solution is extracted with 5x100 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated under reduced pressure. The residue is taken up in a minimal volume of a dichloromethane/methanol mixture (1/1 , v/v), combined with 6 g of chromatography-grade silica (40-63 ⁇ ) and concentrated again.
• the resulting power is placed in a chromatography cartridge, which is subsequently installed at the top of a column of 100 g of silica (10-90 ⁇ , Biorad), and the assembly is fitted to a Biotage chromatography instrument.
• the column is eluted with a gradient from 0 to 5% of isopropanol in dichloromethane in 10 column volumes in accordance with the standard conditions given by the Biotage chromatography software.
• the homogeneous fractions are combined and concentrated under reduced pressure, to give 1.77 g of a yellow solid.
• the solid is taken up in 150 ml of saturated aqueous sodium hydrogen carbonate solution and extracted with 3 x 150 ml of ethyl acetate.
• the organic phases are combined, washed with 150 ml of saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated under reduced pressure.
• the previous aqueous phases are combined, extracted with 1x150 ml of toluene, and then 2x150 ml of a toluene/ethyl acetate mixture (1/1 , v/v), and the organic phases are combined, washed with 150 ml of saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated under reduced pressure.
• the concentrated residues of the organic phases are resuspended in 50 ml of ethyl acetate and the suspension is taken to reflux for 15 minutes and then allowed to cool to ambient temperature.
• the diffractogram recorded for the intermediate E1 is characterized by a diffusion halo throughout the angular range studied (2° - 40° to 2 ⁇ ) which is characteristic of an amorphous product.
• the diffractogram recorded for compound I is characteristic of a crystalline product.
• the diffractogram recorded is shown in Figure 4-1 and the details of the principal diffraction peaks are given in Table 4-1 .
• the present invention accordingly provides the compound I as defined above or sulphate salt of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9- hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate having the X-ray diffractogram as defined in Figure 4-1 below.
• the diffractogram recorded for compound II is characteristic of a crystalline product.
• the diffractogram recorded is shown in Figure 4-2 and the details of the principal diffraction peaks are given in Table 4-2.
• the present invention accordingly provides the compound II as defined above or cocrystal with L-malic acid of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]- 4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate having the X-ray diffractogram as defined in Figure 4-2 below:
• Figure 4-1 Powder X-ray diffractogram recorded for compound I as obtained in accordance with the experimental conditions detailed in example 1.
• Table 4-1 2 ⁇ angular position, interplanar spacing and relative intensity of the principal diffraction peaks recorded for compound I as obtained in accordance with the experimental conditions detailed in example 1.
• Figure 4-2 Powder X-ray diffractogram recorded for compound II (cocrystal) as obtained in accordance with the experimental conditions detailed in example 2.
• Table 4-2 2 ⁇ angular position, interplanar spacing and relative intensity of the principal diffraction peaks recorded for the compound II (cocrystal) as obtained in accordance with the experimental conditions detailed in example 2.
• the solubility of compound I and compound II is measured in ultra-purified water, in a pH 1 HCI-buffered medium, in a pH 4.7 acetate-buffered medium and in a pH 7.4 phosphate- buffered medium.
• Table 5-1 Solubility values for compounds I and II, measured after 16 h of stirring an ultra-purified water, in a pH 1 HCI buffer, in a pH 4.7 acetate buffer and in a pH 7.4 phosphate buffer (target 2 mg/ml).
• Example 6 determination of the stability of compounds I and II under different conditions
• Figure 6-1 compares the powder X-ray diffractograms recorded for the four aliquots of compound I taken from the four crystal I izers, stored for 14 days under the four different humidity and temperature conditions.
• the diffractograms recorded for the aliquots kept for 14 days at 50°C/ambient humidity, 50°C/80% relative humidity and 80°C/ambient humidity are comparable with the diffractogram recorded for compound I as received.
• the diffractogram recorded for the aliquot kept for 14 days at 80°C/80% relative humidity is different from that recorded for the compound I as received.
• Table 6-1 reports the percentage degradation, determined by HPLC for the four aliquots of compound I stored under the four stress conditions. These results demonstrate the chemical stability of compound I over 14 days under conditions of 50°C/ambient humidity, 50°C/80% relative humidity and 80°C/ambient humidity, and the chemical instability of compound I over 14 days under conditions of 80°C/80% relative humidity.
• Figure 6-1 Powder X-ray diffractograms recorded for the aliquots of compound I stored for 14 days under conditions of 50°C/ambient humidity (HN), 50°C/80% relative humidity (HR), 80°C/ambient humidity (HN) and 80°C/80% relative humidity (HR), compared with the diffractogram of compound I recorded as received.
• HN 50°C/ambient humidity
• HR 50°C/80% relative humidity
• HR 80°C/ambient humidity
• HR 80°C/80% relative humidity
• Table 6-1 Percentage degradation of compound I stored for 14 days under stress conditions of 50°C/ambient humidity, 50°C/80% relative humidity, 80°C/ambient humidity and 80°C/80% relative humidity
• Figure 6-2 compares the powder X-ray diffractograms recorded for the four aliquots of compound II taken from the four crystal I izers, stored for 14 days under the four different humidity and temperature conditions.
• the diffractograms recorded for the aliquots kept for 14 days at 50°C/ambient humidity, 50°C/80% relative humidity, 80°C/ambient humidity and 80°C/80% relative humidity are comparable with the diffractogram recorded for compound I as received.
• Table 6-2 reports the percentage degradation, determined by HPLC for the four aliquots of compound II stored under the four stress conditions.
• Figure 6-2 Powder X-ray diffractograms recorded for the aliquots of compound II 15 stored for 14 days under conditions of 50°C/ambient humidity (HN), 50°C/80% relative humidity (HR), 80°C/ambient humidity (HN) and 80°C/80% relative humidity (HR), compared with the diffractogram of compound II recorded as received.
• HN 50°C/ambient humidity
• HR 50°C/80% relative humidity
• HR 80°C/ambient humidity
• HR 80°C/80% relative humidity
• Table 6-2 Percentage degradation of compound II stored for 14 days under stress conditions of 50°C/ambient humidity, 50°C/80% relative humidity, 80°C/ambient humidity and 80°C/80% relative humidity
• Example 7 Formulation with 5 mg/ml (active ingredient) in micellar solution for i.v administration
• the suspension is stirred for around 15 minutes until dissolution takes place, and then 4.5 ml of 5% aqueous glucose solution (G5) containing 17.5 mg of ascorbic acid (for the solution with 3.5 mg/ml of ascorbic acid) or 2.5 mg of ascorbic acid (for the solution with 0.5 mg/ml of ascorbic acid) are added.
• G5 5% aqueous glucose solution
• the mixture is acidified to a pH of 2 using H2SO4 and then stirred until complete homogeneity is obtained.
• the pH is raised to 3 by addition of 1 N NaOH.
• the volume lastly, is made up to 5 ml by addition of G5.
• the formulation is kept under nitrogen in antibiotic flasks for storage at 4°C in the absence of light.
• Example 8 Formulation with 5 mg/ml (of active product) formed from the sulphate of the laevogyratory enantiomer of ethyl 8-oxo-9-r3-(1 H-benzimidazol-2- yloxy)phenvn-4,5,6,7,8,9-hexahvdro-2H-pyrrolor3,4-b1guinoline-3-carboxylate (example 1 , compound I) in micellar solution for i.v administration
• a round-bottomed flask is charged with 300 mg of ascorbic acid, then with 8 ml of 5% glucose (G5). The suspension is stirred until a solution is obtained, and then 250 ⁇ of ethanol and 750 mg of polysorbate 80 or Solutol HS15 (BASF) are added.
• the invention likewise provides a process for preparing the crystalline sulphate salt and the cocrystal and the formulation as defined above.
• the present invention accordingly provides a process for preparing compound I as defined in Claims 1 to 6 or sulphate salt of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2- yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate, as defined in scheme 1 below:
• the present invention accordingly provides a process for preparing the compound II as defined above, characterized in that:
• the present invention accordingly provides a process for preparing a formulation as defined above, characterized in that:
• the sulphate salt of the compound and the cocrystal with L-malic acid of formula (F) exhibit both solubility properties and stability properties that are greater than those of the compound of formula (F) in the form of the base or a hydrochloride, phosphate, p-toluenesulphonate or naphthalene-1 ,5- disulphonate salt, and which make it particularly well suited to the manufacture of medicaments.
• the physicochemical properties of the compound of formula (F) in sulphate salt or L- malic acid cocrystal form also allow it to be kept under the usual conditions, without excessively onerous precautions in relation to the presence of light, temperature and humidity.
• micellar solution A formulation in micellar solution has been shown which is suited to the intravenous administration of the compound of formula (F), allowing the compound of formula (F) to be stabilized for a number of weeks to a number of months, and this solution is even more stable when it is produced from the sulphate form of the compound of formula (F).
• the sulphate salt of the compound I according to the present invention is an anti-cancer agent.
• the cocrystal of the compound II according to the present invention is an anticancer agent.
• compound I, II and the formulations according to the present invention can be used for preparing medicaments, especially medicaments intended for treating cancers, especially those mentioned below.
• the invention provides medicaments which comprise the sulphate salt, the cocrystal or the formulations defined above. These medicaments are used therapeutically, particularly in the treatment of cancers, especially those mentioned below.
• a further subject of the invention is therefore the use of the sulphate salt for preparing a medicament intended for treating the cancers referred to below.
• the present invention relates to pharmaceutical compositions comprising the sulphate salt as active principle.
• These pharmaceutical compositions include an effective dose of the sulphate salt, and also at least one pharmaceutically acceptable excipient.
• Said excipients are selected, according to the pharmaceutical form desired and the administration route desired, from the customary excipients which are known to the skilled person.
• the invention therefore extends to pharmaceutical compositions comprising as active principle at least one of the medicaments as defined above.
• compositions of the present invention may further comprise, where appropriate, active principles of other antimitotic medicaments such as, more particularly, those based on taxol, cis-platin, DNA intercalating agents and others.
• compositions may be administered orally, parenterally or locally by topical application to the skin and the mucous membranes, or by intravenous or intramuscular injection.
• compositions may be solid or liquid and may take any of the pharmaceutical forms that are commonly used in human medicine, such as, for example, plain or film- coated tablets, pills, lozenges, gel capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods.
• the active principle may be incorporated in these preparations in excipients which are normally employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fats of animal or plant origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, and preservatives.
• the usual dosage which is variable according to the product used, the individual treated and the condition in question, may be, for example, from 0.05 to 5 g per day in adults, or preferably from 0.1 to 2 g per day.
• the present invention accordingly provides a medicament characterized in that it comprises the compound I as defined above in the form of the sulphate salt of ethyl 8- oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4- b]quinoline-3-carboxylate.
• the present invention accordingly provides a medicament characterized in that it comprises the compound II as defined above in the form of the cocrystal of ethyl 8-oxo- 9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4- b]quinoline-3-carboxylate.
• the present invention accordingly provides a medicament characterized in that it comprises a formulation of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]- 4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate as defined above.
• the present invention further provides a pharmaceutical composition characterized in that it comprises, as active principle, the compound I or sulphate salt of ethyl 8-oxo-9- [3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline- 3-carboxylate as defined above and also at least one pharmaceutically acceptable excipient.
• the present invention further provides a pharmaceutical composition characterized in that it comprises, as active principle, the compound II or cocrystal of ethyl 8-oxo-9-[3- (1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3- carboxylate as defined above and also at least one pharmaceutically acceptable excipient.
• the present invention further provides a pharmaceutical composition characterized in that it comprises, as active principle, a formulation of ethyl 8-oxo-9-[3-(1 H-benzimidazol- 2-yloxy)phenyl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate as defined above and also at least one pharmaceutically acceptable excipient.
• the present invention additionally provides for the use of the compound I as defined above, or sulphate salt of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9- hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate for preparing a medicament intended for treating cancer.
• the present invention additionally provides for the use of the compound II as defined above or cocrystal of ethyl 8-oxo-9-[3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5,6,7,8,9- hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylate for preparing a medicament intended for treating cancer.
• the present invention additionally provides for the use of a formulation of ethyl 8-oxo-9- [3-(1 H-benzimidazol-2-yloxy)phenyl]-4,5 ! 6 ! 7 ! 8 ! 9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3- carboxylate as defined above, for preparing a medicament intended for treating cancer.
• a medicament of this kind may in particular be intended for the treatment or prevention of a disease in a mammal.
• the present invention particularly provides for the use of the compounds I or II or formulation as defined above for preparing a medicament intended for the prevention or treatment of diseases associated with uncontrolled proliferation.
• the present invention more particularly provides for the use of the compounds I or II or formulation as defined above for preparing a medicament intended for the treatment or prevention of a disease selected from the following group: blood vessel proliferation disorders, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthmas, thromboses, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscular degeneration, bacterial infection, especially by Listeria monocytogenes and cancers.
• a disease selected from the following group: blood vessel proliferation disorders, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthmas, thromboses, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscular degeneration, bacterial infection, especially by Listeria monocytogenes and cancers.
• the present invention accordingly provides, very particularly, for the use of the compounds I or II or formulation as defined above for preparing a medicament intended for the treatment or prevention of oncological diseases, and particularly intended for the treatment of cancers.
• the products of the present invention cited may in particular be used for the treatment of primary tumours and/or metastases, more particularly in gastric, hepatic, renal, ovarian, colonic, prostatic and lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in melanomas, in lymphoid or myeloid haematopoietic tumours, in sarcomas, in brain, larynx and lymphatic system cancers, and in bone and pancreatic cancers.
• NSCLC and SCLC prostatic and lung
• the present invention also provides for the use of the compounds I or II or formulation as defined above for preparing medicaments intended for the chemotherapy of cancers.
• Medicaments of this kind intended for the chemotherapy of cancers may be used alone or in combination.
• the products of the present application may in particular be administered alone or in combination with chemotherapy or radiotherapy or else in combination, for example, with other therapeutic agents.
• Such therapeutic agents may be commonly used anti-tumour agents.
• Kinase inhibitors include butyrolactone, flavopiridol and 2(2-hydroxyethylamino)-6- benzylamino-9-methylpurine, which is called olomoucine.
• the present invention further provides, as new industrial products, the synthesis intermediates of formulae A1 , B1 , C1 , D1 and E1 as defined in the preparation of the examples above.
• the sulphate salt may be administered in a unit administration form, as a mixture with conventional pharmaceutical excipients, to animals and to human beings for the prophylaxis or the treatment of the above disorders or diseases.
• the appropriate unit administration forms include forms for oral administration such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, and sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for administration by inhalation, for topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms, and implants.
• the compounds according to the invention may be used in creams, gels, ointments or lotions.
• Said unit forms are dosed to allow daily administration of 0.01 to 20 mg of active principle per kg of body weight, depending on the formulation.
• the dosage appropriate for each patient is determined by the physician according to the administration route and to the weight and response of said patient.
• the present invention in another of its aspects, also relates to a method for treating the pathologies indicated above, which comprises administering to a patient an effective dose of sulphate.

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• 2010
  • 2010-11-17 FR FR1059456A patent/FR2967413A1/fr active Pending
• 2011
  • 2011-11-16 WO PCT/IB2011/055115 patent/WO2012066486A1/en active Application Filing
  • 2011-11-17 TW TW100142135A patent/TW201307339A/zh unknown
  • 2011-11-17 UY UY0001033738A patent/UY33738A/es unknown
  • 2011-11-17 AR ARP110104285A patent/AR083901A1/es not_active Application Discontinuation

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