WO2017216761A1 - Formes solides d'entinostat - Google Patents
Formes solides d'entinostat Download PDFInfo
- Publication number
- WO2017216761A1 WO2017216761A1 PCT/IB2017/053582 IB2017053582W WO2017216761A1 WO 2017216761 A1 WO2017216761 A1 WO 2017216761A1 IB 2017053582 W IB2017053582 W IB 2017053582W WO 2017216761 A1 WO2017216761 A1 WO 2017216761A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- entinostat
- pharmaceutically acceptable
- acceptable excipient
- amorphous
- atleast
- Prior art date
Links
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 title claims abstract description 185
- 229950005837 entinostat Drugs 0.000 title claims abstract description 184
- 239000007787 solid Substances 0.000 title description 26
- 238000000034 method Methods 0.000 claims abstract description 76
- 239000007962 solid dispersion Substances 0.000 claims abstract description 68
- 238000002360 preparation method Methods 0.000 claims abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims description 73
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 65
- 239000000203 mixture Substances 0.000 claims description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 30
- -1 polyethylene Polymers 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- 239000000377 silicon dioxide Substances 0.000 claims description 14
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
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- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
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- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims 1
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- HZUDHRTWQOKGOX-UHFFFAOYSA-N 4-[(pyridin-3-ylmethoxycarbonylamino)methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CNC(=O)OCC1=CC=CN=C1 HZUDHRTWQOKGOX-UHFFFAOYSA-N 0.000 description 8
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- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
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- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 6
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
Definitions
- aspects of the present application relate to stable amorphous Entinostat, its amorphous solid dispersion, processes for their preparation and pharmaceutical compositions thereof. Further, aspects relate to crystalline form of Entinostat, process for its preparation and pharmaceutical compositions thereof.
- the drug compound having the adopted name "Entinostat” has chemical name:Pyridin-3-ylmethyl-N-[[4-[(2-aminophenyl)carbamoyl]phenyl] methyl] carbamate as below.
- Entinostat is an oral synthetic benzamide derivative and the lead in a series of HDAC inhibitors, for the potential treatment of cancer, particularly breast cancer.
- the US FDA has granted breakthrough therapy designation to Entinostat for the treatment of locally recurrent or metastatic ER-positive breast cancer, when added to exemestane in postmenopausal women whose disease had progressed following nonsteroidal aromatase inhibitor therapy.
- US 6174905 B l discloses Entinostat and a salt thereof, its pharmaceutical composition and its use in the treatment of a malignant tumor including colorectal cancer, ovarian cancer, oral cancer, lung carcinoma, breast carcinoma, prostate carcinoma and melanoma. Further, US 6174905 B l exemplified the preparation of Entinostat by reacting 4-aminomethyl-N-[2-(N-tertbutoxycarbonyl)aminophenyl]benzamide with 3- pyridinemethanol in the presence of ⁇ , ⁇ '-carbonyldiimidazole. The compound obtained by this process was extracted into chloroform and concentrated to give crystals of Entinostat, which were then recrystallized from ethanol to give crystalline Entinostat with meltin at 159- 160°C.
- US 6320078 B l describes the synthesis and isolation of Entinostat by reacting 4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzoic acid with 1,2- phenylenediamine to obtain the Entinostat followed by its purification through silica gel column chromatography Entinostat with same melting range of 159- 160°C as described in US 6174905 B l .
- a similar methodology for the synthesis of Entinostat is described in J Med Chem. 1999, 42(15), 3001-3 via a three- step procedure in 50.96% overall yield.
- US RE45499 describes amorphous and crystalline forms of Entinostat, wherein the crystalline forms are designated as polymorph A, B and C.
- US RE45499 states that the prior art processes produces crystalline polymorph A of Entinostat (with melting at 159- 160°C), which is not the thermodynamic ally stable form. Further, it indicates that it was not possible to establish a reliable manufacturing process for polymorph A as pure polymorphic phase and with high chemical purity at larger scale. US RE45499 does not describe the process for the preparation of polymorph C and amorphous form of Entinostat.
- the present application provides a stable amorphous form of Entinostat.
- the present application provides a process for the preparation of an amorphous form of Entinostat, comprising the steps of:
- step a) a) providing a solution of Entinostat in a suitable solvent or a mixture thereof; b) removing the solvent from the solution obtained in step a);
- step c) optionally combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
- the present application provides amorphous solid dispersion of Entinostat together with atleast one pharmaceutically acceptable excipient.
- the present application provides a process for the preparation of an amorphous solid dispersion of Entinostat, comprising the steps of: a) providing a solution of Entinostat and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
- step d) optionally combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
- the present application provides a pharmaceutical composition
- a pharmaceutical composition comprising amorphous form of Entinostat or the amorphous solid dispersion of Entinostat together with atleast one pharmaceutically acceptable excipient.
- the present application provides a crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 +0.2° 2 ⁇ .
- the present application provides a process for the preparation of crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ⁇ 0.2° 2 ⁇ comprising the steps of:
- the present application provides a pharmaceutical composition
- a pharmaceutical composition comprising crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ⁇ 0.2° 2 ⁇ together with atleast one pharmaceutically acceptable excipient.
- Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous form of Entinostat prepared by the method of Example No 4.
- Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous Solid dispersion of Entinostat and Povidone K-30 prepared by the method of Example No 5.
- Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Entinostat and HPMC-AS prepared by the method of Example No 6.
- Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous form of Entinostat prepared by the method of Example No 7.
- Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Entinostat with Syloid prepared by the method of Example No 8.
- Figure 6 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Entinostat with Copovidone prepared by the method of Example No 9.
- Figure 7 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Entinostat with Soluplus prepared by the method of Example No 10.
- Figure 8 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Entinostat with Eudragit-LlOO prepared by the method of Example No 11.
- Figure 9 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Entinostat with HPC-L prepared by the method of Example No 12.
- Figure 10 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Entinostat with HPMC prepared by the method of Example No 13.
- Figure 11 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Entinostat with HPMC and Syloid prepared by the method of Example No 14.
- Figure 12 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Entinostat with Eudragit-LlOO and Neusilin prepared by the method of Example No 15.
- Figure 13 is an illustrative X-ray powder diffraction pattern of crystalline form of Entinostat prepared by the method of Example No 2
- Figure 14 is an illustrative X-ray powder diffraction pattern of crystalline form of Entinostat prepared by the method of Example No 3
- the present application provides a stable amorphous form of Entinostat.
- the present application provides a stable amorphous form of Entinostat which is suitable for powder handling and downstream processes.
- Amorphous form of Entinostat of the present application was surprisingly found to be highly stable under mechanical stress such as grinding or milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.
- the present application provides a stable amorphous form of Entinostat with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity as per X-ray diffraction analysis.
- the present application provides an amorphous form of Entinostat characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 1 or 4.
- PXRD powder X-ray diffraction
- the present application provides a process for the preparation of an amorphous form of Entinostat, comprising the steps of:
- step a) a) providing a solution of Entinostat in a suitable solvent or a mixture thereof; b) removing the solvent from the solution obtained in step a);
- step c) optionally combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
- suitable solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3- C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
- the suitable solvent may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2- butanol, 1-pentanol, 2-pentanol, 3-pentanol; dichloro methane; tetrahydrofuran; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
- alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2- butanol, 1-pentanol, 2-pentanol, 3-pentanol
- dichloro methane such as acetone, methyl ethyl ketone, methyl isobutyl ketone
- esters solvents such as methyl acetate, ethyl
- providing a solution at step a) may be carried out by dissolving Entinostat in a suitable solvent or by taking the reaction mixture containing Entinostat directly.
- a solution of Entinostat can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
- a solution of Entinostat may be filtered to make it clear, free of unwanted particles.
- the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydro se, to remove colored components, etc., before filtration.
- removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application.
- removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.
- the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
- the isolation of an amorphous form of Entinostat at step c) involves recovering the solid obtained in step b).
- the solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
- the amorphous form of Entinostat obtained from step b) may be optionally dried before or after isolating it at step c).
- Amorphous form of Entinostat obtained at step c) may be optionally combined with atleast one pharmaceutically acceptable excipient at step d).
- amorphous form of Entinostat may be combined with excipient using a technique known in art or by the procedures disclosed in the present application.
- amorphous form of Entinostat may be combined with excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as grinding in a mortar-pestle, blending in rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of Entinostat and atleast one pharmaceutically acceptable excipient.
- amorphous form of Entinostat may be combined with the excipient by evaporating the suspension or solution of amorphous form of Entinostat and atleast one pharmaceutically acceptable excipient.
- pharmaceutically acceptable excipient may include, but not limited to an inorganic oxide such as Si0 2 , Ti0 2 , Zn0 2 , ZnO, A1 2 0 3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross- linked styrene divinyl benzene or any other excipient at any aspect of present application.
- an inorganic oxide such as Si0 2 , Ti0 2 , Zn0 2 , ZnO, A1 2 0 3 and zeolite
- a water insoluble polymer is selected from the group consisting of cross-
- pharmaceutically acceptable excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica or Syloid; Magnesium aluminometasilicates such as Neusilin; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose or Neusilin or hydroxypropyl methyl cellulose acetate succinate.
- silicon dioxide e.g. colloidal or fumed silicon dioxide or porous silica or Syloid
- Magnesium aluminometasilicates such as Neusilin
- copolymers such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer
- cellulose preferably microcrystalline cellulose or Neusilin or hydroxypropyl methyl cellulose acetate succinate.
- Amorphous form of Entinostat isolated at step c) or d) may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- the drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
- the drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
- the present application provides pharmaceutical composition comprising amorphous form of Entinostat and atleast one pharmaceutically acceptable excipient.
- the present application provides amorphous solid dispersion of Entinostat together with atleast one pharmaceutically acceptable excipient.
- the present application provides amorphous solid dispersion of Entinostat together with atleast one pharmaceutically acceptable excipient characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 2, 3, 5 to 12.
- PXRD powder X-ray diffraction
- the present application provides a process for the preparation of an amorphous solid dispersion of Entinostat, comprising the steps of: a) providing a solution of Entinostat and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
- step d) optionally combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
- suitable solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
- the suitable solvent may be selected from the group consisting of alcohol solvents such as methanol, ethanol, 2-propanol, 1 -butanol, 2- butanol, 1-pentanol, 2-pentanol, 3-pentanol; dichloromethane, tetrahydrofuran; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
- alcohol solvents such as methanol, ethanol, 2-propanol, 1 -butanol, 2- butanol, 1-pentanol, 2-pentanol, 3-pentanol
- dichloromethane tetrahydrofuran
- ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone
- Atleast one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co- povidone NF, polyvinylacetal diethylamino acetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO or Eudragit-LlOO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose phthal
- Solid dispersions of the present application also include the solid dispersions obtained by combining Entinostat with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
- providing a solution at step a) may be carried out by dissolving Entinostat and atleast one pharmaceutically acceptable excipient in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.
- a solution of Entinostat and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
- a solution of Entinostat and the excipient may be filtered to make it clear, free of unwanted particles.
- the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
- removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application.
- removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, agitated thin film drying and the like.
- the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
- the isolation of an amorphous solid dispersion of Entinostat and excipient at step c) involves recovering the solid obtained in step b).
- the solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
- the amorphous solid dispersion of Entinostat and excipient obtained from step b) may be optionally dried before or after isolating at step c).
- Amorphous solid dispersion of Entinostat obtained at step c) may be optionally combined with atleast one additional pharmaceutically acceptable excipient at step d).
- amorphous solid dispersion of Entinostat may be combined with additional excipient using a technique known in art or by the procedures disclosed in the present application.
- amorphous solid dispersion of the present application may be combined with additional excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as grinding in a mortar-pestle, blending in a rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous solid dispersion of Entinostat with pharmaceutically acceptable excipient and atleast one additional pharmaceutically acceptable excipient.
- amorphous solid dispersion of the present application may be combined with additional excipient by evaporating the suspension or solution of amorphous solid dispersion of Entinostat and additional excipient.
- pharmaceutically acceptable additional excipient may be same or different from the excipient used in the preparation of amorphous solid dispersion of Entinostat.
- Additional excipient may include, but not limited to an inorganic oxide such as Si0 2 , Ti0 2 , Zn0 2 , ZnO, A1 2 0 3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
- pharmaceutically acceptable additional excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica or Syloid; Magnesium aluminometasilicates such as Neusilin; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose or Neusilin or hydroxypropyl methyl cellulose acetate succinate.
- silicon dioxide e.g. colloidal or fumed silicon dioxide or porous silica or Syloid
- Magnesium aluminometasilicates such as Neusilin
- copolymers such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer
- cellulose preferably microcrystalline cellulose or Neusilin or hydroxypropyl methyl cellulose acetate succinate.
- Amorphous solid dispersion of Entinostat isolated at step c) or d) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- the drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
- the drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
- the present application provides pharmaceutical composition comprising amorphous solid dispersion of Entinostat with atleast one pharmaceutically acceptable excipient and atleast one additional pharmaceutically acceptable excipient.
- the present application provides pharmaceutical compositions comprising amorphous Entinostat and atleast one pharmaceutically acceptable excipient, in particular in the form of solid dispersions and adsorbates, and a process for preparing the same.
- the pharmaceutically acceptable excipient is selected from the excipients at any aspect of present application.
- the present application provides adsorbates, wherein Entinostat is associated with a suitable substrate.
- Suitable substrate may be a particulate and/or porous substrate, wherein this substrate has an outer and/or inner surface onto which the API may be adsorbed. This means that if the substrate has pores, these pores are filled by the Entinostat and the substrate remains unaffected, it does not, at least not essentially, change during and / or after the adsorption.
- the suitable substrate is selected from the excipients at any aspect of present application.
- Amorphous form of Entinostat or its solid dispersion may be obtained alternatively either by employing a melt-extrusion technique or by combining a solution of Entinostat as obtained any of the aspects of present application with a suitable anti-solvent.
- amorphous product may be obtained by employing suitable melt-extrusion conditions or any of the procedures known in the art for obtaining amorphous product by melt-extrusion technique.
- solution of Entinostat may be combined with the anti- solvent at suitable temperature and for sufficient time to obtain amorphous product.
- Suitable anti-solvent is a solvent, wherein Entinostat has low solubility and it may include, but not limited to aliphatic or cyclic ethers solvents, aliphatic or aromatic hydrocarbons or the like.
- amorphous Entinostat or its solid dispersion may be obtained by ball milling Entinostat or mixture of Entinostat and a suitable excipient under suitable milling conditions known in the art.
- the present application provides amorphous Entinostat, its solid dispersion or pharmaceutical composition comprising Entinostat having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
- the present application provides a crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ⁇ 0.2° 2 ⁇ .
- the present application provides a crystalline form of Entinostat characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 13 or 14.
- PXRD powder X-ray diffraction
- the present application provides a process for the preparation of crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ⁇ 0.2° 2 ⁇ , comprising the steps of:
- Entinostat that used in step a) of this aspect may be either in crystalline form or amorphous form and it may be purified by methods known in the art such as recrystallization, acid-base treatment or chromatography, before using.
- step a) may be carried out by combining Entinostat with a solvent selected from the group comprising of methyl tert. butyl ether, ethyl acetate or mixture thereof.
- Entinostat may be combined with a solvent at any suitable temperatures, such as at about 0°C to about the reflux temperature of the solvent or mixture thereof.
- the mixture of Entinostat and solvent may be either a heterogeneous or homogeneous phase.
- step b) of this aspect may be carried out by stirring the mixture of step a).
- Mixture of step a) may be stirred for sufficient time to complete formation of crystalline Entinostat.
- the mixture of Entinostat and solvent may be stirred for atleast 0.5 hour or more.
- the mixture of Entinostat and solvent may be stirred at suitable temperature for the formation of crystalline form of Entinostat.
- the mixture may be stirred at temperature between 0°C and 50°C. Preferably between 15°C and 40°C.
- step c) of this aspect may be carried out by the isolation of crystalline form of Entinostat by any methods known in the art or procedures described in the present application.
- crystalline Entinostat may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
- isolated crystalline form of Entinostat may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
- the drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C or any other suitable temperatures. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
- Entinostat that may be used in the previous aspect of the invention as starting material may be in any solid form either in crystalline or amorphous form.
- Entinostat that may be used as starting material in the present application may be prepared according to any methods known in the art or according to the procedures described or exemplified in the present application.
- Entinostat may prepared according to a process comprising the steps of a) reacting a 4-(aminomethyl)benzoic acid of formula (II) or its active derivatives with Pyridin-3-yl methanol of formula (III) to obtain 4-(((pyridin- 3 -ylmethoxy)carbonylamino) methyl) benzoic acid of formula (IV) or derivatives thereof.
- step (b) optionally, purifying Entinostat obtained in step (b) to provide pure Entinostat.
- starting compounds of formula (II) and (III) may be obtained according to methods known in the art or from the commercially available sources.
- Step a) may be carried out by reacting a 4-(aminomethyl)benzoic acid of formula (II) with Pyridin-3-yl methanol of formula (III) in the presence a suitable coupling agent to convert alcohols and amines into carbamates such as 1, 1- carbonyldiimidazole (CDI), or the like.
- a suitable coupling agent to convert alcohols and amines into carbamates such as 1, 1- carbonyldiimidazole (CDI), or the like.
- Step a) may be carried out by reacting a 4-(aminomethyl)benzoic acid of formula (II) with Pyridin-3-yl methanol of formula (III) in the presence a suitable base which include, but not limited to hydroxides such as sodium hydroxide, potassium hydroxide; metal carbonates such sodium carbonate, potassium carbonate; or the like.
- a suitable base include, but not limited to hydroxides such as sodium hydroxide, potassium hydroxide; metal carbonates such sodium carbonate, potassium carbonate; or the like.
- Step a) may be carried out in a suitable inert solvent.
- suitable solvents include, but are not limited to: alcohols such as for examples, methanol, ethanol, isopropyl alcohol, 1-propanol, 1-butanol, 2-butanol, or the like; hydrocarbons such as for examples, toluene, xylene, hexanes, heptanes, cyclohexane or the like; halogenated hydrocarbons such as for example dichloro methane, ethylene dichloride, chloroform, or the like; ethers such as for examples diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane or the like; polar aprotic solvents such as for examples, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone or the like;
- Step a) may be carried out at a temperature ranging from about 10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 20°C to the reflux temperature of the solvent.
- the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
- step (a) i.e., compound of Formula IV or its salts may be isolated as solid or used directly for the next step from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
- the salts of compound of Formula IV obtained compound in step (a) may be optionally further purified by recrystallization or by slurring in a suitable solvent or by column chromatography or any other suitable technique.
- step (a) i.e., the compound of Formula IV or its salts may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.
- the compound of Formula IV or its salts can be used directly in the next step without drying.
- Step b) may be carried out by treating 4-(((pyridin-3- ylmethoxy)carbonylamino)methyl) benzoic acid of formula (IV) or derivatives thereof of step a) with 1,2-phenylene diamine to obtain Entinostat.
- 4-(((pyridin-3-ylmethoxy)carbonylamino)methyl) benzoic acid of formula (IV) may be treated with 1,2-phenylene diamine in the presence of suitable coupling agents.
- the suitable coupling agent includes but are not limited to 1,1- carbonyldiimidazole (CDI), ⁇ , ⁇ '-Dicyclohexylcarbodiimide (DCC), N, N'- diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide (EDC) or a salt thereof, 0-(benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium- tetrafluoroborate (TBTU), 0-(benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium- hexafluorophosphate (HBTU), 0-(7-azabenzotriazol- l-yl)-N,N,N',N'- tetramethyluronium-hexafluorophosphate (HATU), (benzo
- Step b) reaction may be carried out in the presence of a neutralizing agent such as trifluoro acetic acid (TFA).
- a neutralizing agent such as trifluoro acetic acid (TFA).
- Step b) may be carried out in a suitable inert solvent.
- suitable solvents include, but are not limited to: alcohols such as for examples, methanol, ethanol, isopropyl alcohol, 1-propanol, 1-butanol, 2-butanol, or the like; hydrocarbons such as for examples, toluene, xylene, hexanes, heptanes, cyclohexane or the like; halogenated hydrocarbons such as for example dichloro methane, ethylene dichloride, chloroform, or the like; ethers such as for examples diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane or the like; polar aprotic solvents such as for examples, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone or the like;
- Step b) reaction may be carried out at a temperature ranging from about 10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 20°C to the reflux temperature of the solvent.
- the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
- the product of step (b) may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.
- Step c) of this aspect may be carried out by, Optionally purifying the product of step b).
- Purification of Entinostat obtained in step b) may be purified according to method known in the art or procedures described in any aspect or exemplified in the instant application.
- purification of Entinostat obtained in step b) may be carried out by recrystallizing or slurring in a suitable solvent or mixture of solvents or by column chromatography or any other suitable technique or combinations thereof.
- suitable solvent may be selected from the group comprising methyl tert. butyl ether, ethyl acetate or mixtures thereof.
- the present application provides a pharmaceutical composition
- a pharmaceutical composition comprising crystalline form of Entinostat, characterized by a PXRD pattern comprising the peaks at about 4.32, 4.71, 8.63, 15.86, 16.56 and 17.30 ⁇ 0.2° 2 ⁇ together with atleast one pharmaceutically acceptable excipient.
- Atleast one pharmaceutically acceptable excipient of this aspect may be selected from the excipients described in any of the earlier aspects.
- the present application provides Entinostat, its crystalline form or pharmaceutical composition comprising Entinostat having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
- inert solvent when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
- amorphous form of Entinostat and “amorphous Entinostat” indicate that the Entinostat is present in substantially amorphous state in the composition (e.g. solid dispersion, adsorbate or pharmaceutical composition).
- substantially amorphous denotes that 90 %, preferably 95 % or 99 %, more preferably all of the Entinostat being present in the solid dispersion, on the adsorbate or in the pharmaceutical composition is amorphous.
- an "amorphous" Entinostat composition denotes a Entinostat- containing composition, which does not contain substantial amounts, preferably does not contain noticeable amounts, of crystalline portions of Entinostat e.g. measurable upon X- ray powder diffraction analysis.
- solid dispersion when used in the present application, denotes a state where most of the Entinostat, preferably 90%, 95% or all of the Entinostat of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix.
- solid dispersion relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way.
- the two components form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.
- the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer.
- it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
- absorbate when used in the present application, specifies that the Entinostat is, preferably evenly, and preferably homogeneously, distributed on the inner and/or outer surface of the particulate substrate.
- crystalline form of Entinostat and “crystalline Entinostat” indicate that the Entinostat is present in substantially crystalline state in the composition (e.g. solid dispersion, adsorbate or pharmaceutical composition).
- substantially crystalline denotes that 60 %, preferably 85 % or 90 %, more preferably all of the Entinostat being present is crystalline.
- Example-1 Preparation of 4-(((pyridin-3-ylmethoxy)carbonylamino)methyl) benzoic acid.
- Entinostat 1.0 g was dissolved in methanol (70 mL) at 28°C and filtered the solution to make it particle free. The clear solution was spray dried with 85% aspirator, flow rate of 6 mL/ minute and inlet temperature of 28 °C and out let temperature of 22°C to obtain the title compound.
- XRPD Amorphous.
- Example-5 Preparation of Amorphous solid dispersion of Entinostat and povidone K-30.
- Entinostat (0.25 g) and povidone K-30 (0.25 g) were dissolved in methanol (20 mL) at 28°C and filtered the solution to make it particle free. The clear solution was taken into a Buchi flask and evaporated the solvent completely using rotavapour under vacuum at 30°C to obtain residue. The residue was stored at room temperature for 24 hours to obtain title compound.
- XRPD Amorphous.
- Example-6 Preparation of Amorphous solid dispersion of Entinostat and HPMC-AS
- Amorphous Entinostat (0.35 g) of example- 1 and HPMC-AS (0.35 g) were combined and ground in a mortar-pestle for 5 minutes at 28°C to obtain the title compound.
- XRPD Amorphous.
- Example-7 Preparation of Amorphous form of Entinostat.
- Entinostat (1.0 g) was dissolved in a mixture of methanol (30 mL) and dichloromethane (30 mL) at 28°C and filtered the solution to make it particle free. The clear solution was spray dried with 85% aspirator, flow rate of 6 mL/ minute and inlet temperature of 30°C and out let temperature of 25°C to obtain the title compound.
- XRPD Amorphous.
- Amorphous Entinostat (0.15 g) of example- 1 and Syloid (0.15 g) were combined and ground in a mortar-pestle for 5 minutes at 28°C to obtain the title compound.
- XRPD Amorphous.
- Example-9 Preparation of Amorphous solid dispersion of Entinostat and Copovidone.
- Entinostat (0.25 g) and Copovidone (0.25 g) were dissolved in methanol (35 mL) at 30°C and filtered the solution to make it particle free. The above clear solution was taken into a Buchi flask and evaporated the solvent completely form the mixture using rotavapour under vacuum at 60°C to obtain title compound.
- XRPD Amorphous.
- Entinostat (0.25 g) and Eudragit-LlOO (0.25 g) were dissolved in methanol (40 mL) at 30°C and filtered the solution to make it particle free. The above clear solution was taken into a Buchi flask and the solvent was evaporated completely using rotavapour under vacuum at 60°C to obtain title compound.
- XRPD Amorphous.
- Example-12 Preparation of Amorphous solid dispersion of Entinostat and HPC- L
- Entinostat (0.50 g) and HPC-L (0.50 g) were dissolved in methanol (80 mL) at 29°C and filtered the solution to make it particle free. The above clear solution was taken into a Buchi flask and the solvent was evaporated completely using rotavapour under vacuum at 60°C to obtain title compound.
- XRPD Amorphous.
- Example- 13 Preparation of Amorphous solid dispersion of Entinostat and HPMC.
- Entinostat (0.30 g) was dissolved in methanol (36 mL) at 29°C and filtered the solution to make it particle free.
- HPMC (0.30 g) was added and heated to 60°C to obtain clear solution. The above clear solution was taken into a Buchi flask and the solvent was evaporated completely using rotavapour under vacuum at 60°C to obtain title compound.
- XRPD Amorphous.
- Example-14 Preparation of Amorphous solid dispersion of Entinostat, HPMC and Syloid.
- Amorphous solid dispersion obtained in example- 10 (0.18 g) and Syloid (0.09 g) were combined and ground in a mortar-pestle for 5 minutes at 29°C to obtain the title compound.
- XRPD Amorphous.
- Example- 15 Preparation of Amorphous solid dispersion of Entinostat, Eurdragit-LlOO and Neusilin.
- Amorphous solid dispersion obtained in example-8 (0.20 g) and Neusilin (0.10 g) were combined and ground in a mortar-pestle for 5 minutes at 29°C to obtain the title compound.
- XRPD Amorphous.
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Abstract
Des aspects de la présente invention concernent de l'entinostat amorphe, stable, sa dispersion solide amorphe, des procédés pour leur préparation et des compositions pharmaceutiques associées. En outre, des aspects concernent la forme cristalline de l'entinostat, son procédé de préparation et des compositions pharmaceutiques associées.
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WO2022238389A2 (fr) | 2021-05-10 | 2022-11-17 | Johnson Mattheypublic Limited Company | Nouvelles formes d'entinostat |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6174905B1 (en) * | 1996-09-30 | 2001-01-16 | Mitsui Chemicals, Inc. | Cell differentiation inducer |
WO2010022988A1 (fr) * | 2008-08-29 | 2010-03-04 | Bayer Schering Pharma Aktiengesellschaft | Polymorphe b de n-(2-aminophényl)-4-[n-(pyridine-3-yl)-méthoxycarbonyl-aminométhyl]-benzamide (ms-275) |
CN104610133A (zh) * | 2015-01-26 | 2015-05-13 | 亿腾药业(泰州)有限公司 | 一种抗癌新药恩替诺特的合成方法 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6174905B1 (en) * | 1996-09-30 | 2001-01-16 | Mitsui Chemicals, Inc. | Cell differentiation inducer |
WO2010022988A1 (fr) * | 2008-08-29 | 2010-03-04 | Bayer Schering Pharma Aktiengesellschaft | Polymorphe b de n-(2-aminophényl)-4-[n-(pyridine-3-yl)-méthoxycarbonyl-aminométhyl]-benzamide (ms-275) |
CN104610133A (zh) * | 2015-01-26 | 2015-05-13 | 亿腾药业(泰州)有限公司 | 一种抗癌新药恩替诺特的合成方法 |
Non-Patent Citations (1)
Title |
---|
TSUNEJI SUZUKI ET AL.: "Synthesis and Histone Deacetylase Inhibitory Activity of New Benzamide Derivatives", J MED CHEM., vol. 42, no. 15, 1999, pages 3001 - 3003, XP002158227, [retrieved on 19990630] * |
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WO2022238389A2 (fr) | 2021-05-10 | 2022-11-17 | Johnson Mattheypublic Limited Company | Nouvelles formes d'entinostat |
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