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WO2017108781A1 - Abemaciclib de forme iv - Google Patents

Abemaciclib de forme iv Download PDF

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Publication number
WO2017108781A1
WO2017108781A1 PCT/EP2016/081908 EP2016081908W WO2017108781A1 WO 2017108781 A1 WO2017108781 A1 WO 2017108781A1 EP 2016081908 W EP2016081908 W EP 2016081908W WO 2017108781 A1 WO2017108781 A1 WO 2017108781A1
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WIPO (PCT)
Prior art keywords
abemaciclib
degrees
cancer
crystalline form
acetonitrile
Prior art date
Application number
PCT/EP2016/081908
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English (en)
Inventor
Wolfgang Albrecht
Sebastian RABE
Original Assignee
Ratiopharm Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ratiopharm Gmbh filed Critical Ratiopharm Gmbh
Publication of WO2017108781A1 publication Critical patent/WO2017108781A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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 present invention relates to a crystalline form of abemaciclib, a method of preparing the same, as well as a pharmaceutical composition comprising the same.
  • abemaciclib N- ⁇ 5-[(4-ethyl- l-piperazinyl)methyl]-2- pyridinyl ⁇ -5-fluoro-4-(4-fluoro- 1 -isopropyl-2-methyl- 1 H-benzimidazol-6-yl)-2- pyrimidinamine.
  • abemaciclib can be referred to as [5-(4-ethyl-piperazin- l- ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H- benzoimidazol-5-yl)-pyrimidin-2-yl] -amine.
  • Abemaciclib is represented by the following chemical structure according to Formula (I):
  • Abemaciclib also known as bemaciclib, LY-2835219 is an orally available selective inhibitor of the cycline dependent kinases 4 and 6 (CDK4/6).
  • CDKs are a family of protein kinases which aroused curiosity due their role in regulating the cell cycle. It was found that they play a crucial role in many human cancers, where they are overactive or CDK-inhibiting proteins are not functional. Hence, it is rational to inhibit CDK function in order to prevent unregulated proliferation of cancer cells.
  • the active pharmaceutical ingredient is developed for the treatment of breast cancer and the non-small-cell lung carcinoma (NSCLC).
  • NSCLC non-small-cell lung carcinoma
  • WO 2010/075074 Al The active pharmaceutical ingredient abemaciclib in form of the free base is known from WO 2010/075074 Al . Further, said document discloses that the described compounds may be in form of an addition salt, wherein the hydrochloride and the mesylate are reported to be preferred.
  • Example 1 of WO 2010/075074 A 1 describes the final coupling of 5-[(4- ethylpiperazin- l-yl)methyl]pyridin-2-amine and 6-(2-chloro-5-fluoro-4- pyrimidinyl)-4-fluoro-2-methyl- l-( l -methylethyl)- lH-benzimidazole (CAS-no. 1231930-42-9) in a twenty- gram scale.
  • the product abemaciclib in form of the free base was purified by silica gel chromatography using dichloromethane/methanol (98/2) followed by dichloromethane/2M N3 ⁇ 4 in methanol (98/2) as eluents.
  • the resulting product appears to be obtained in an amorphous state.
  • Example 31 crystalline Form I was obtained by mixing amorphous abemaciclib with acetone and isolating the precipitate by vacuum filtration and subsequent drying.
  • Example 32 crystalline Form III was obtained by mixing amorphous abemaciclib with acetone and heating the slurry. The product was isolated by vacuum filtration and subsequent drying.
  • Abemaciclib Form I is described to be a yellow solid. However, abemaciclib Form I is reported to have an disadvantageous high hygroscopicity, especially at higher humidity and/or temperatures, which is undesirable in the production of a pharmaceutical formulation. Further, said Form I is also reported to have unfavourable electrostatic properties which significantly hamper the processability to a dosage form.
  • Abemaciclib Form III is decribed to be a yellow solid. However, the solubility of abemaciclib Form III seems to be improvable. In addtion, abemaciclib Form III is reported to show a disadvantageous hygroscopicity, in particular at higher humiditiy and/or temperatures. As mentioned above, the properties of form III result in difficulties during the production of oral dosage forms.
  • abemaciclib having superior properties.
  • abemaciclib should be provided in a form being little electrostatic.
  • abemaciclib should be provided in stable from, wherein the form should show a stability being not inferior compared to the stability of forms I and III. According to the present invention, the above objectives are unexpectedly achieved by a specific crystalline form of abemaciclib.
  • a subject of the invention is a crystalline form of abemaciclib having an X- ray powder diffraction peak at 6.8 degrees 2 ⁇ (+ 0.2 degrees 2 ⁇ ).
  • This form of abemaciclib is hereinafter referred to as polymorphic Form IV of abemaciclib.
  • Abemaciclib Form IV is present in the form of the free base and can preferably also refer to solvates and hydrates thereof.
  • a crystal form may be referred to herein as being characterized by data selected from two or more different data groupings, for example by a powder XRD pattern, having a group of specific peaks or by a powder XRD pattern as shown in a figure depicting a diffractogram, or by "a combination thereof (or “combinations thereof or “any combination thereof).
  • a combination thereof or “combinations thereof or “any combination thereof”.
  • the skilled person may characterize a crystal form using a group of three, four or five characteristic powder XRD peaks and supplement this characterization with one or more additional feature(s) observed in the powder X-ray diffractogram, e.g., an additional peak, a characteristic peak shape, a peak intensity or even the absence of a peak at some position in the powder XRD pattern.
  • the skilled person may in some instances characterize a crystal form using a group of three, four or five characteristic powder XRD peaks and supplement that characterization with one or more additional feature(s) observed by using another analytical method, for example using one or more characteristic peaks in a solid state IR spectrum, solid state NMR or characteristics of the DSC thermogram of the crystal form that is being characterized.
  • XRPD peaks are recorded using copper Kc ⁇ /Kc ⁇ radiation with a wavelength of 1.5406 A (weighted mean of Cu Kcii and Cu Ka 2 ). Further, unless indicated otherwise, XRPD peaks are reported as degrees 2 ⁇ values with a standard error of + 0.2 degrees 2 ⁇ .
  • a crystal form may be referred to herein as being characterized by graphical data "as depicted in" a particular figure.
  • Such data include for example powder X-ray diffractograms.
  • the skilled person will understand that such graphical representation of data may be subject to small variations, e.g. in peak relative intensities and peak positions, due to factors such as variations in instrument response and variations in sample concentration and purity, which are well-known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the figures herein with graphical data generated for an unknown crystal form and confirm as to whether the two sets of graphical data characterize the same crystal form or two different crystal forms.
  • abemaciclib Form IV can preferably have one or more further X-ray powder diffraction peaks at 15.3, 27.1 and/or 28.2 degrees 2 ⁇ (+ 0.2 degrees 2 ⁇ ).
  • abemaciclib Form IV can preferably have one or more further XRPD diffraction peak(s) at 6.0, 12.0, 18.5, 21.0 and/or 26.1 degrees 2 ⁇ (+ 0.2 degrees 2 ⁇ ).
  • abemaciclib Form IV can be characterized by XRPD diffraction peak(s) at degrees 2 ⁇ + 0.2 degrees 2 ⁇ (intensity %): 6.0 (52), 6.8 (32), 7.5 (3), 10.4 (5), 12.0 (19), 13.4 (5), 13.9 (6), 15.3 (29), 15.6 (10), 16.3 (5), 18.2 (7), 18.5 (16), 19.2 (8), 19.9 (7), 21.0 (100), 22.2 (5), 22.7 (8), 25.0 (7), 26.1 (32), 27.1 (14), 28.2 (14) and 31.7 (6).
  • An XRPD diffraction pattern of the crystalline form of abemaciclib according to the present invention, abemaciclib Form IV is shown in Figure 1.
  • the abemaciclib Form IV can preferably have an endotherm with an onset temperature of 123°C ( ⁇ 5°) and a peak temperature of 133°C ( ⁇ 1°).
  • the temperatures are measured by differential scanning calorimetry, wherein the measurement is carried out at Mettler Toledo DSC 822 E at a temperature range of 30°C to 350°C, a heating rate of 10°C/min and using software: STARe Version.8.10.
  • abemaciclib Form IV can preferably have two further endotherm with an onset temperature of 174°C (+ 2°) and 181°C (+ 2°) as well as peak temperatures of 176°C ( ⁇ 1°) and 182°C ( ⁇ 1 °), respectively. The measurements are carried out as described above.
  • the abemaciclib Form IV can preferably have an exotherm with an onset temperature of 137°C ( ⁇ 5°) and a peak temperature of 140°C ( ⁇ 2°). The measurements are carried out as described above.
  • a DSC thermogram of the crystalline form of abemaciclib according to the present invention, abemaciclib Form IV, is shown in Figure 2.
  • the abemaciclib of the present invention shows an advantageous solubility in water, for example compared to abemaciclib Form III.
  • the present abemaciclib shows an advantageous hygroscopicity, for example compared to abemaciclib Form I.
  • a further subject of the present invention is a process for preparing the crystalline form of the abemaciclib according to the present invention, comprising the steps of
  • abemaciclib preferably abemaciclib in form of its free base, for example amorphous abemaciclib, abemaciclib Form I and/or abemaciclib Form III as described in WO 2010/075074 Al , is provided.
  • Abemaciclib in form of its free base can preferably also refer to solvates and hydrates thereof.
  • step (b) the abemaciclib from step (a) is suspended in an organic solvent.
  • solvents having similar properties as acetonitrile are used.
  • acetonitrile is used.
  • step (b) is carried out at a temperature of from 20°C to the boiling point of acetonitrile.
  • the boiling point of acetonitrile is 82°C at a pressure of 1013 mbar.
  • the boiling point of the acetonitrile in the suspension might be slightly higher than 82°C.
  • step (b) is carried out at a temperature of from 60°C to the boiling point of acetonitrile.
  • Particularly preferred step (b) can be carried out at the boiling point of acetonitrile in the suspension, i.e. under reflux conditions.
  • step (b) is carried out under mechanical movement, such as stirring.
  • step (b) includes keeping the suspension at a temperature between 20°C and the boiling point of acetonitrile, preferably at the boiling point of acetonitrile, and stirring for 0.5 to 6 hours, preferably 0.75 to 4 hours, more preferably 1 to 2.5 hours.
  • the suspension In case the suspension is raised to a temperature above 20°C the suspension can preferably be cooled again to 20°C, preferably under stirring.
  • Step (c) of isolating the crystalline form of the abemaciclib of the present invention can preferably comprise filtering the solution of step (b), for example through a folded filter to obtain the resulting solid.
  • the resulting solid can preferably be triturated and subsequently preferably dried. Drying can preferably be carried out under reduced pressure of from 5 to 200 mbar, in particular 10 to 150 mbar. Drying can be preferably carried out at a temperature of 20°C to 80°C, more preferably 30°C to 70°C. Drying can for example be carried out in a compartment dryer. Drying can preferably last 2 to 8 hours.
  • the resulting product is crystalline abemaciclib Form IV. As can be seen from the above, abemaciclib Form IV is easily available by a process without the use of complex, time and cost-intensive process steps.
  • the present invention furthermore relates to pharmaceutical compositions comprising the crystalline form of abemaciclib according to the present invention, wherein the pharmaceutical compositons additionally contain at least one pharmaceutically acceptable excipient.
  • compositions can for example be fillers, binders, glidants, disintegrants, lubricants, flow regulating agents and release agents. Suitable excipients are for example disclosed in "Lexikon der Hilfsstoffe fiir Pharmazie, Kosmetik und angrenzende füre", published by H.P. Fielder, 4 th
  • filler generally means substances which serve to form the body of the tablet in the case of tablets with small amounts of active agent (e.g. less than 60% by weight). This means that fillers "dilute" the active agent(s) in order to produce an adequate tablet compression mixture. The normal purpose of fillers therefore is to obtain a suitable tablet size.
  • preferred fillers are lactose, lactose derivatives, starch, starch derivatives, treated starch, chitin, cellulose and derivatives thereof, calcium phosphate, calcium hydrogen phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulphate, dextrates, dextrin and/or dextrose and hydrogenated vegetable oil. Fillers can be present in an amount of 0 to 80% by weight, preferably in an amount of 10 to 60% by weight based on the total weight of the composition.
  • a binder is generally a substance which is capable of increasing the strength of the resulting dosage form, especially the resulting tablets.
  • Suitable binders are for example polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, sugars, dextran or corn starch. Binders can be present in an amount of 0 to 30% by weight, preferably in an amount of 2 to 15% by weight based on the total weight of the composition.
  • Glidants can be used to improve the flowability.
  • Suitable glidants are for example alkaline earth metal salts of fatty acids, like stearic acid.
  • the glidant can be present for example in an amount of 0 to 2% by weight, preferably in an amount of 0.5 to 1.5% by weight based on the total weight of the composition.
  • Disintegrants are compounds which enhance the ability of the dosage form, preferably the ability of the tablet, to break into smaller fragments when in contact with a liquid, preferably water.
  • Suitable disintegrants are for example croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone (crospovidone), sodium carboxymethylglycolate and sodium bicarbonate.
  • the disintegrant can be present in an amount of 0 to 20% by weight, preferably in an amount of 1 to 15% by weight based on the total weight of the composition.
  • a suitable flow regulating agent is for example colloidal silica.
  • the flow regulating agent can be present in an amount of 0 to 8% by weight, preferably in an amount of 0.1 to 3% by weight based on the total weight of the composition.
  • a suitable release agent is for example talcum.
  • the release agent can be present in an amount of 0 to 5% by weight, preferably in an amount of 0.5 to 3% by weight based on the total weight of the
  • the parmaceutical composition can preferably be further processed into an oral doasage form, such as a capsule or tablet.
  • the oral dosage form preferably a tablet or a capsule, more preferably a tablet, can preferably be coated, preferably film coated.
  • film coatings without affecting the release of the active ingredient, gastric juice-resistant film coatings,
  • film coatings can be prepared by using film-forming agents, such as waxes, cellulose derivatives, poly(meth)acrylate, polyvinylpyrrolidone, polyvinyl acetate phthalate, and/or shellac or natural rubbers, such as carrageenan. It is preferred that the present tablet is coated with a gastric juice-resistant film coating. Alternatively, a capsule comprising a gastric juice-resistant film coating can be used.
  • the gastric juice-resistant film coating preferably is a film coating being stable in the pH range of about 0.7 to 3.0, which is supposed to be the pH value of human gastric juice found in the stomach. However, in an environment with a pH value of 5 to 9, which is supposed to be present in the (small) intestine of the human body, the gastric juice-resistant film coating preferably dissolves and the drug can be released.
  • the gastric juice-resistant film coating (often also referred to as enteric coating) can comprise film-forming agents, for example fats, fatty acids, waxes, alginates, shellac, polyvinyl acetate phthalate, cellulose derivatives such as carboxy methyl ethyl cellulose, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate trimellitate, and meth(acrylic)acid copolymers, such as methyl acrylate-methacrylic acid copolymers, methyl methacrylate-methacrylic acid copolymers, and Eudragits (for example Eudragit ® L30D, Eudragit ® L, Eudragit ® S).
  • film-forming agents for example fats, fatty acids, waxes, alginates, shellac, polyvinyl acetate phthalate, cellulose derivatives such
  • the coating is preferably free of active ingredient. It is further preferred that the thickness of the coating is 10 ⁇ to 2 mm, preferably from 50 to 500 ⁇ .
  • the preferred coating may comprise a film-forming agent and one or more of the following: lubricant, surfactant, glidant, pigment and water.
  • the preferred coating according to an embodiment of the present invention can comprise, along with the film-forming agent, e.g. stearic acid as lubricant for plasticizing and dissolving the polymer, sodium lauryl sulfate as a surfactant for wetting and dispersing, talc as glidant, iron oxide yellow and/or titanium oxide as pigment(s) and optionally purified water.
  • the film-forming agent e.g. stearic acid as lubricant for plasticizing and dissolving the polymer
  • sodium lauryl sulfate as a surfactant for wetting and dispersing
  • talc as glidant
  • iron oxide yellow and/or titanium oxide as pigment(s) and optionally purified water.
  • the present pharmaceutical composition and/or the oral dosage form of the present invention can be prepared by the methods well-known to a person skilled in the art, such as dry and wet granulation and direct compression.
  • the pharmaceutical composition and/or the oral dosage form can be administered one to three times a day, preferably once or twice a day, more preferably once a day.
  • the pharmaceutical composition and/or the oral dosage form can be administered every 12 hours, wherein the administration can be carried out continuously, i.e. contrary to other similar active pharmaceutical ingredients, such as palbociclib and ribociclib, there is no need for a discontinuation of the administration after 3 weeks.
  • the present invention further relates to the crystalline form of abemaciclib according to the present invention for use in the treatment of cancer, preferably for use in the treatment of breast cancer.
  • cancer includes both solid tumors and hematological malignancies.
  • Cancers include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer (e.g. adenocarcinoma, NSCLC and SCLC), bone cancer (e.g.
  • osteosarcoma colon cancer
  • rectal cancer thyroid cancer
  • brain and central nervous system cancers glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (e.g. liposarcoma), bladder cancer, liver cancer (e.g. hepatocellular carcinoma), kidney cancer (e.g. renal cell carcinoma), myeloid disorders (e.g. AML, CML, myelodysplasia syndrome and promyelocytic leukemia) and lymphoid disorders (e.g.
  • myeloid disorders e.g. AML, CML, myelodysplasia syndrome and promyelocytic leukemia
  • lymphoid disorders e.g.
  • leukemia multiple myeloma, mantle cell lymphoma, ALL, CLL, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma).
  • the present invention is directed to a method of treating and/or preventing cancer, preferably treating and/or preventing breast cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline from of abemaciclib according to the present invention or the pharmaceutical composition according to the present invention.
  • Solvent B water + 0.1% formic acid + 0.05% heptafluorobutyric Flow: 1.0 ml/min
  • Solvent B water + 0.2% formic acid + 0.1% heptafluorobutyric acid Flow: 1 ml/min
  • Aluminium crucible 40 ⁇ ⁇ Lid: Perforated
  • the sample was analyzed on a D8 Advance X-ray powder diffractometer (Bruker- AXS, Düsseldorf, Germany). The sample holder was rotated in a plane parallel to its surface at 20 rpm during the measurement. Further conditions for the measurements are summarized in the table below. The raw data were analyzed with the program EVA (Bruker-AXS, Germany). The samples were layered onto a silicon specimen holder. standard measurement
  • the hygroscopicity was determined by dynamic vapor sorption (DVS) analysis. Approximately 200 mg of each solid state were weighed on a sample plate and subjected to the apparatus. The humidity inside was varied in a range of 0 to 95% RH and the mass change (dm [%]) of the samples measured continuously.
  • DVD dynamic vapor sorption
  • test substance 280 mg (exactly weighed) test substance was weighed into a glass vial, followed by addition of 2.5 mL solvent (water, 0.01M HC1, 20 mM NaOAc/HOAc pH 4.5, 50 mM KH 2 P0 4 pH 6.8, FASSIf).
  • solvent water, 0.01M HC1, 20 mM NaOAc/HOAc pH 4.5, 50 mM KH 2 P0 4 pH 6.8, FASSIf.
  • a stirring bar was added, the vial was fixed in a block heater at 37 °C and the suspension was stirred with approximately 250 rpm. After 15 min and 1 hour samples were withdrawn, filtered through a 0.2 ⁇ disposable filter, diluted with solvent and quantified by UHPLC/UV.
  • Tris(dibenzylidene- acetone)dipalladium(O) ( 142 mg; 0.2 mmol) was added and the slurry heated to 100°C. The slurry was stirred for 19 h when HPLC indicated complete conversion of pyrimidyl benzimidazol. The mixture was allowed to cool to room temperature and diluted with dichloromethane. The slurry was filtered over a Whatman glass fiber filter and the obtained filtrate extracted with aqueous HC1 (4N; 2 x 25 mL). The collected aqueous extracts were stirred with charcoal (250 mg), filtered (Whatman) and basified with aqueous NaOH (17% ; 30 mL).
  • Abemaciclib Form I (5 g; 9.8 mmol) was suspended in acetonitrile (50 mL) and stirred under reflux conditions for 2 hours and subsequently for one hour at 20°C. The slurry was filtered off and dried under reduced pressure for 2 hours.
  • Table 1 Water adsorption of the different polymorphs of abemaciclib at distinct humidity
  • abemaciclib forms I and III show a considerable hygroscopicity with a mass increase of 6 and 8.5% w/w respectively, representing approximately 2 equivalents of water.
  • Abemaciclib Form IV already contained of 2.3% w/w water under ambient conditions, increasing to a maximum of 3.4% w/w at 95% RH, which represents 1 equivalent of water. Water absorption and desorption is reversible and also the crystalline form remained unchanged for all polymorphs after completion of the experiment.
  • abemaciclib Form IV shows a signifcantly higher solubility than abemaciclib Form III in all investigated solvents. Further, abemaciclib Form IV shows substantially the same solubility as abemaciclib Form I in 50 mM KH 2 P0 4 having a pH corresponding to the one in the small intestine and in FaSSiF simulating the intestine under sober conditions. Stability:
  • abemaciclib Form IV A novel polymorph of abemaciclib, namely abemaciclib Form IV, has been provided.
  • Abemaciclib Form IV exhibits an advantageous stability.
  • abemaciclib Form IV shows a significantly reduced hygroscopicity compared to the known polymorphs I.
  • solubilty of Form IV is superior compared to known polymorphic Form III. Consequently, Form IV is little hygroscopic on the one hand and well soluble on the other hand.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau abemaciclib de forme cristalline, son procédé de préparation ainsi qu'une composition pharmaceutique le contenant.
PCT/EP2016/081908 2015-12-22 2016-12-20 Abemaciclib de forme iv WO2017108781A1 (fr)

Applications Claiming Priority (2)

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EP15202053.3 2015-12-22
EP15202053 2015-12-22

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019102492A1 (fr) 2017-11-23 2019-05-31 Mylan Laboratories Limited Polymorphes cristallins d'abémaciclib
WO2019195569A1 (fr) 2018-04-05 2019-10-10 Johnson Matthey Public Limited Company Formes solides d'abémaciclib, leur utilisation et leur préparation
WO2021030843A1 (fr) 2019-08-13 2021-02-18 Johnson Matthey Public Limited Company Formes solides d'abemaciclib, leur utilisation et leur préparation
WO2022162122A1 (fr) 2021-01-29 2022-08-04 Biotx.Ai Gmbh Inhibiteur de netose génétiquement vérifié destiné à être utilisé dans le traitement d'une infection par sras-cov2
CN116251066A (zh) * 2022-12-28 2023-06-13 北京鑫开元医药科技有限公司 一种阿贝西利片及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010075074A1 (fr) * 2008-12-22 2010-07-01 Eli Lilly And Company Inhibiteurs de protéine kinases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010075074A1 (fr) * 2008-12-22 2010-07-01 Eli Lilly And Company Inhibiteurs de protéine kinases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MICHAEL O. FREDERICK ET AL: "A synthesis of abemaciclib utilizing a Leuckart-Wallach reaction", TETRAHEDRON LETTERS, vol. 56, no. 7, 1 February 2015 (2015-02-01), GB, pages 949 - 951, XP055255707, ISSN: 0040-4039, DOI: 10.1016/j.tetlet.2014.12.082 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019102492A1 (fr) 2017-11-23 2019-05-31 Mylan Laboratories Limited Polymorphes cristallins d'abémaciclib
WO2019195569A1 (fr) 2018-04-05 2019-10-10 Johnson Matthey Public Limited Company Formes solides d'abémaciclib, leur utilisation et leur préparation
US12011442B2 (en) 2018-04-05 2024-06-18 Macfarlan Smith Limited Solid-state forms of Abemaciclib, their use and preparation
WO2021030843A1 (fr) 2019-08-13 2021-02-18 Johnson Matthey Public Limited Company Formes solides d'abemaciclib, leur utilisation et leur préparation
WO2022162122A1 (fr) 2021-01-29 2022-08-04 Biotx.Ai Gmbh Inhibiteur de netose génétiquement vérifié destiné à être utilisé dans le traitement d'une infection par sras-cov2
CN116251066A (zh) * 2022-12-28 2023-06-13 北京鑫开元医药科技有限公司 一种阿贝西利片及其制备方法

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