WO2013166966A1 - Polymorphes d'oméga-diphénylurée substituée par du deutérium et contenant du fluor ou de sels de celle-ci - Google Patents

Polymorphes d'oméga-diphénylurée substituée par du deutérium et contenant du fluor ou de sels de celle-ci Download PDF

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WO2013166966A1
WO2013166966A1 PCT/CN2013/075343 CN2013075343W WO2013166966A1 WO 2013166966 A1 WO2013166966 A1 WO 2013166966A1 CN 2013075343 W CN2013075343 W CN 2013075343W WO 2013166966 A1 WO2013166966 A1 WO 2013166966A1
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polymorph
compound
formula
ray powder
powder diffraction
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PCT/CN2013/075343
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Chinese (zh)
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冯卫东
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苏州泽璟生物制药有限公司
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    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention belongs to the field of medicine, and in particular to a polymorph of a fluorine-containing deuterated ⁇ -diphenylurea or a salt thereof, and more particularly, to 4-(4-(3-(4-chloro-)- Polymorphic form of 3-(trifluoromethyl)phenyl]acylurea)-3-fluoro-phenoxy)-2-(indenylfluorene, fluorene, fluorene-tris-methyl)pyridineamide or a salt thereof Background technology
  • the compound of formula I has the formula C 21 H 12 D 3 ClF 4 N 4 O 3 and has a molecular weight of 485.83, which is a white to off-white crystalline powder; odorless; tasteless. Very soluble in dimethyl sulfoxide or dimethylformamide, slightly soluble in methanol, slightly soluble in acetone, absolute ethanol or glacial acetic acid, almost insoluble in water, melting point 224 ⁇ 230 °C.
  • the compound of formula I is a compound which inhibits raft ⁇ enzyme and is suitable for the preparation of a medicament for the treatment of cancer and related diseases.
  • all of the compounds currently used for the preparation of the corresponding drugs are amorphous compounds, and polymorphs of the compounds of the formula I have not yet been developed.
  • a compound of formula I or a pharmaceutically acceptable salt thereof there is provided a compound of formula I or a pharmaceutically acceptable salt thereof Polymorph
  • the pharmaceutically acceptable salt is p-toluenesulfonate.
  • the polymorph is a polymorph I of the compound of formula I, wherein the polymorph I has one or two X-ray powders selected from the group consisting of Diffraction characteristic peaks: 7.224 ⁇ 0.2 °, and 14.507 ⁇ 0.2
  • the polymorph I further has one or two X-ray powder diffraction characteristic peaks selected from the group consisting of: 13 ⁇ 363 ⁇ 0 ⁇ 2 ⁇ , 17.192 ⁇ 0.2°, ⁇ 19 ⁇ 779 ⁇ 0 ⁇ 2 ⁇ .
  • the polymorph I has an X-ray powder diffraction pattern (X PD) substantially as shown in Figure 2a.
  • the differential scanning calorimetry pattern of the polymorph I has a maximum peak at 211.8-214.1 °C.
  • the polymorph I has a differential scanning calorimetry (DSC) substantially as shown in Figure 2b.
  • the polymorph is a polymorph II of a compound of formula I, wherein the polymorph II has one or more X-ray powders selected from the group consisting of Diffraction characteristic peaks: 22.323 ⁇ 0.2°, 24.199 ⁇ 0.2°, and ⁇ 24 ⁇ 830 ⁇ 0 ⁇ 2 ⁇ .
  • the polymorph II further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 18 ⁇ 573 ⁇ 0 ⁇ 2 ⁇ , 21.671 ⁇ 0.2°, 23.507 ⁇ 0.2°, and 25 ⁇ 166 ⁇ 0 ⁇ 2 ⁇ .
  • the polymorph II has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the differential scanning calorimetry pattern of the polymorph II has a maximum peak at 196.2-198.6 °C.
  • the polymorph II has a differential scanning calorimetry (DSC) substantially as shown in Figure lb.
  • DSC differential scanning calorimetry
  • the polymorph is a polymorph III of p-toluenesulfonate of the compound of formula I, wherein the polymorph III has one or two selected from the group consisting of The X-ray powder diffraction characteristic peak of the group: 4.476 ⁇ 0.2°, and the ⁇ 13 ⁇ 357 ⁇ 0 ⁇ 2 ⁇ .
  • the polymorph III further has one or more X-ray powder derivatives selected from the group consisting of The characteristic peaks are: 16 ⁇ 517 ⁇ 0 ⁇ 2 ⁇ , 18.037 ⁇ 0.2°, 21 ⁇ 786 ⁇ 0 ⁇ 2. ⁇ 22 ⁇ 990 ⁇ 0 ⁇ 2 ⁇ .
  • the polymorph III has an X-ray powder diffraction pattern substantially as shown in Figure 3a.
  • the differential scanning calorimetry pattern of the polymorph III has a maximum peak at 239.5-241.7 °C.
  • the polymorph III has a differential scanning calorimetry pattern substantially as shown in Figure 3b.
  • the p-toluenesulfonate of the compound of formula I is 1/1 p-toluenesulfonate, wherein the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1.
  • a polymorph according to the first aspect of the invention for the preparation of a pharmaceutical composition for inhibiting a phosphokinase such as raf kinase.
  • the pharmaceutical composition is for the treatment and prevention of cancer.
  • composition comprising:
  • a process for the preparation of a polymorph according to the first aspect of the invention which comprises the steps of: pharmaceutically acceptable a compound of formula I or a compound of formula I
  • the accepted salt is recrystallized in an inert solvent to obtain the polymorph described in the first aspect of the invention.
  • the process for preparing the polymorph I comprises the steps of: recrystallizing the polymorph II obtained above in methanol to obtain the polymorph I.
  • the method for preparing the polymorph III comprises the steps of: recrystallizing the polymorph I obtained above and p-toluenesulfonic acid in an inert solvent to obtain the polymorph. Item III. It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here. DRAWINGS
  • Panel la shows the X-ray powder diffraction pattern of the polymorph II of Example 1.
  • Figure lb shows a differential scanning calorimetry diagram of Polymorph II of Example 1.
  • Figure lc shows an NMR chart of the polymorph II of Example 1.
  • Figure 2a shows an X-ray powder diffraction pattern of the polymorph I of Example 2.
  • Figure 2b shows a differential scanning calorimetry diagram of the polymorph I of Example 2.
  • Figure 2c shows an NMR chart of the polymorph I of Example 2.
  • Figure 3a shows an X-ray powder diffraction pattern of Polymorph III of Example 3.
  • Figure 3b shows a differential scanning calorimetry diagram of the polymorph III of Example 3.
  • Figure 3c shows an NMR chart of the polymorph III of Example 3.
  • the inventors have unexpectedly discovered 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureide)-3-fluoro-phenoxy) by long-term and intensive research.
  • a pharmaceutical composition of a kinase (such as raft chymase) is more advantageous for treating diseases such as cancer.
  • the polymorph of the present invention is difficult to lift, easy to collect, and wasteful in the process of manufacturing a drug such as dispensing.
  • compound of formula I refers to 4-(4-(3-(4)) having the structural formula I. -Chloro-3-(trifluoromethyl)phenyl]urea)-3-fluoro-phenoxy)-2-(indenofluorene, anthracene, fluorene-tris-methyl)pyridineamide.
  • the solid does not exist in an amorphous form or in a crystalline form.
  • the molecules are positioned within the three-dimensional lattice lattice.
  • polymorphism this property is called "polymorphism"
  • Different polymorphs of a given material may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystalline form, bulk mode, fluidity, and/or solid state stability. Crystallization
  • the solubility limit of the compound of interest can be exceeded by operating the solution to complete crystallization on a production scale. This can be done in a number of ways, for example by dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Alternatively, the volume of the liquid can be reduced by boiling, atmospheric evaporation, vacuum drying or by some other means.
  • the solubility of the compound of interest can be lowered by adding an antisolvent or a solvent having a low solubility in the compound or a mixture of such a solvent. Another alternative It is to adjust the pH to reduce the solubility.
  • crystallization See Crystallization, Third Edition, JW Mullens, Butterworth-Heineman Ltd., 1993, ISBN 075061 1294.
  • salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble than the starting material in the reaction medium, the addition of a suitable acid or base can result in direct crystallization of the desired salt. Also, in the medium in which the final desired form is less soluble than the reactant, the completion of the synthesis reaction allows the final product to crystallize directly.
  • optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed.
  • many crystallization methods use a combination of the above strategies.
  • One embodiment is to dissolve the compound of interest in a solvent at elevated temperatures, followed by controlled addition of an appropriate volume of anti-solvent to bring the system just below the level of saturation. At this point, seed crystals of the desired form can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.
  • room temperature generally refers to 4-30 °C, preferably 20 ⁇ 5 °C.
  • polymorph of the invention includes a polymorph of a compound of formula I or a salt thereof (e.g., p-toluenesulfonate), and also includes different polymorphs of a compound of formula I.
  • polymorph I or polymorph II of a compound of formula I or a polymorph III of a 1/1 p-toluenesulfonate of a compound of formula I, wherein the compound of formula I and p-toluenesulfonic acid The molar ratio is 1:1.
  • the polymorph of the compound of formula I of the present invention has a specific crystal form and has a specific characteristic peak in an X-ray powder diffraction (XPD) pattern.
  • the polymorph I has one or two X-ray powder diffraction characteristic peaks selected from the group consisting of: 7.224 ⁇ 0.2°, and 14.507 ⁇ 0.2 In another preferred embodiment, the polymorph I further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 13 ⁇ 363 ⁇ 0 ⁇ 2 ⁇ , 17.192 ⁇ 0.2°, Wo 19 ⁇ 779 ⁇ 0 ⁇ 2 ⁇ .
  • polymorph I has an X-ray powder diffraction pattern substantially as shown in Figure 2a.
  • the polymorph II has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of 22 ⁇ 323 ⁇ 0 ⁇ 2 ⁇ , 24 ⁇ 199 ⁇ 0 ⁇ 2 ⁇ , and ⁇ 24 ⁇ 830 ⁇ 0 ⁇ 2 ⁇ .
  • the polymorph II further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 18 ⁇ 573 ⁇ 0 ⁇ 2 ⁇ , 21.671 ⁇ 0.2°, 23.507 ⁇ 0.2°, and 25 ⁇ 166 ⁇ 0 ⁇ 2 ⁇ .
  • the polymorph II has an X-ray powder diffraction pattern substantially as shown in Figure la.
  • the polymorph III has one or two X-ray powder diffraction characteristic peaks selected from the group consisting of: 4.476 ⁇ 0.2 °, and 13.357 ⁇ 0.2
  • the polymorph III further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 16 ⁇ 517 ⁇ 0 ⁇ 2 ⁇ , 18.037 ⁇ 0.2°, 21 ⁇ 786 ⁇ 0 ⁇ 2. ⁇ 22 ⁇ 990 ⁇ 0 ⁇ 2 ⁇ .
  • the polymorph III has an X-ray powder diffraction pattern substantially as shown in Figure 3a. Differential scanning calorimetry
  • DSC differentiated calorimetric scanning analysis
  • DSC assay methods are known in the art.
  • a DSC scan of the crystal form can be obtained by using a NETZSCH DSC 204 F1 differential scanning calorimeter at a temperature increase rate of 10 ° C per minute from 25 ° C to 250 ° C.
  • the polymorph of the compound of formula I of the present invention has a specific characteristic peak in a differential calorimetric scanning (DSC) chart.
  • the differential scanning calorimetry pattern of the polymorph I has a maximum peak at 211.8-214.rC.
  • the polymorph I has a differential scanning calorimetry (DSC) substantially as shown in Figure 2b.
  • the differential scanning calorimetry spectrum of the polymorph II has a maximum peak at 196.2-198.6 °C.
  • the polymorph II has a differential scanning calorimetry (DSC) substantially as shown in Figure lb.
  • DSC differential scanning calorimetry
  • the differential scanning calorimetry pattern of the polymorph III has a maximum peak at 239.5-241.7 °C.
  • the polymorph III has a differential scanning calorimetry pattern substantially as shown in Figure 3b.
  • Nuclear magnetic resonance can also be employed to aid in the determination of crystal structure, the method of which is known in the art.
  • the invention preferably employs Bruker Avance III plus-400 MHz.
  • active ingredient refers to a polymorph of the invention, ie a polymorph of a compound of formula I, and of course a polymorph of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt is, for example but not limited to, p-toluenesulfonate.
  • the polymorph of the present invention Since the polymorph of the present invention has excellent inhibitory activity against phosphokinase (Kinase M column such as rafi ⁇ enzyme, the polymorph of the present invention and the pharmaceutical composition containing the polymorph of the present invention as a main active ingredient It can be used for the treatment, prevention and alleviation of diseases mediated by phosphokinase (Kinase M column such as raft ⁇ enzyme. According to the prior art, the polymorph of the invention can be used for the treatment of the following diseases: cancer, cardiovascular disease, obesity, Diabetes and so on.
  • compositions of the present invention comprise a polymorph of the invention in a safe and effective amount and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount is meant that the amount of the compound (or polymorph) is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains from 1 to 2000 mg of the polymorph/agent of the invention, more preferably from 10 to 200 mg of the polymorph/agent of the invention.
  • the "one dose" is a capsule or a tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gels Substances, which are suitable for human use and must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are compatible with the active ingredients of the present invention and between them without significantly reducing the efficacy of the active ingredients.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moist Wet agents (such as sodium decyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween®
  • moist Wet agents such as sodium decyl sulfate
  • the mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include, but are not limited to, oral, intratumor, rectal, parenteral (intravenous, intramuscular or subcutaneous), And topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) moisturizing An agent, for example, glycerin; (d) a disintegrant, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; f) absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, troches, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric materials and waxy materials. The active ingredient may also form a microcapsule form with one or more of the above excipients as necessary.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, Sweeteners, flavorings and spices.
  • the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture of these and the like.
  • a suspending agent for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms of the polymorphs of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
  • polymorphs of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the polymorph of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective effective dose for a person weighing 60 kg.
  • the daily dose is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the use of the polymorph is also provided for the preparation of a pharmaceutical composition for inhibiting a phosphokinase (e.g., raft chymase) for use in the treatment of diseases such as cancer.
  • a pharmaceutical composition for inhibiting a phosphokinase e.g., raft chymase
  • the invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
  • the materials used in the present invention are commercially available unless otherwise specified. Example 1
  • the X-ray powder diffraction pattern is shown in la, the parameters of each peak are shown in Table 1, the differential scanning calorimetry (DSC) is shown in Figure lb, and the 1H NMR spectrum is shown in lc.
  • the X-ray powder diffraction pattern is shown in Figure 2a, and the parameters of each peak are shown in Table 2.
  • Differential Scanning Calorimetry (DSC) is shown in Figure 2b, and 1H NMR is shown in Figure 2c.
  • the polymorph I (10 g) obtained in Example 2 was suspended in 150 mL of ethanol, 1.4 g of p-toluenesulfonic acid monohydrate was added, the temperature was raised to 80 ° C until clarification, and the filtrate was heated to reflux to clarify. A solution of 3.4 g of p-toluenesulfonic acid monohydrate in 10 mL of ethanol was added, and the mixture was stirred under constant temperature for 30 min, and then cooled to 25 ° C, and filtered to give 12 g of the title compound.

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Abstract

L'invention porte sur des polymorphes d'oméga-diphénylurée substituée par du deutérium et contenant du fluor ou de sels de celle-ci, plus précisément sur des polymorphes de 4-(4-(3-(4-chloro-3-(triméthyl)phényl)acylurée)-3-fluorophénoxy)-2-(N-1',1',1'-trideutérométhyl)picolinamide, comprenant un polymorphe I de celui-ci, un polymorphe II de celui-ci et un polymorphe III d'un p-toluènesulfonate de celui-ci. Lesdits polymorphes sont appropriés pour être utilisés dans la préparation de compositions pharmaceutiques qui inhibent une phosphokinase (telle que la raf kinase).
PCT/CN2013/075343 2012-05-10 2013-05-08 Polymorphes d'oméga-diphénylurée substituée par du deutérium et contenant du fluor ou de sels de celle-ci WO2013166966A1 (fr)

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CN201210143861.6A CN103387536B (zh) 2012-05-10 2012-05-10 含氟的氘代ω-二苯基脲或其盐的多晶型物
CN201210143861.6 2012-05-10

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US20090069388A1 (en) * 2007-09-11 2009-03-12 Protia, Llc Deuterium-enriched sorafenib
WO2010135579A1 (fr) * 2009-05-22 2010-11-25 Concert Pharmaceuticals, Inc. Dérivés fluorés de diaryl urée
CN102459180A (zh) * 2009-06-09 2012-05-16 江苏迈度药物研发有限公司 作为激酶抑制剂的脲衍生物
WO2011113368A1 (fr) * 2010-03-18 2011-09-22 苏州泽璟生物制药有限公司 Procédé de préparation de diphénylurée deutérée substituée par un fluoro
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WO2015085888A1 (fr) * 2013-12-09 2015-06-18 Jiangsu Medolution Limited Monohydrate de 4-(4-(3-(4-chloro-3-(trifluorométhyl)phényl)uréido)-3-fluorophénoxy)-n-d3-méthylpicolinamide

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