WO2015085888A1 - Monohydrate de 4-(4-(3-(4-chloro-3-(trifluorométhyl)phényl)uréido)-3-fluorophénoxy)-n-d3-méthylpicolinamide - Google Patents

Monohydrate de 4-(4-(3-(4-chloro-3-(trifluorométhyl)phényl)uréido)-3-fluorophénoxy)-n-d3-méthylpicolinamide Download PDF

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WO2015085888A1
WO2015085888A1 PCT/CN2014/093075 CN2014093075W WO2015085888A1 WO 2015085888 A1 WO2015085888 A1 WO 2015085888A1 CN 2014093075 W CN2014093075 W CN 2014093075W WO 2015085888 A1 WO2015085888 A1 WO 2015085888A1
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compound
formula
agents
treatment
limited
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PCT/CN2014/093075
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Dawei Zhang
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Jiangsu Medolution Limited
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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
    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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 relates to 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) -3-fluorophenoxy) -N-d 3 -methylpicolinamide monohydrate, to processes for its preparation, to pharmaceutical compositions comprising it and to its use in the control of disorders.
  • WO 2010/144499 describes the compound of formula (I) as an inhibitor of the VEGF and Raf kinases which may be used for the treatment of disorders in which angiogenesis and hyper-proliferation play an important role, for example in tumor growth and cancer.
  • Tumors stimulate stromal tissue formation through the secretion of soluble growth factor such as PDGF and transforming growth factor-beta (TGF-beta) , which in turn stimulate the secretion of complimentary factors by host cells such as fibroblast growth factor (FGF) , epidermal growth factor (EGF) , and vascular endothelial growth factor (VEGF) (Folkman, J., Semin Oncol, 2002. 29 (6 Suppl 16) , 15-8) .
  • FGF fibroblast growth factor
  • EGF epidermal growth factor
  • VEGF vascular endothelial growth factor
  • Enzyme Raf kinase which may be used for the treatment of disorders in which angiogenesis and hyper-proliferation plays an important role, for example in tumor growth and cancer.
  • the compound of the Formula I is prepared in the manner described in WO 2010/144499 and corresponds to a polymorph which in the following is named as polymorph I.
  • the compound of the Formula II shows a high stability in the pharmaceutical compositions.
  • the present invention provides the compound of the formula I in the monohydrate form which corresponds to the compound of the formula II:
  • the compound of the formula (II) contains water. In comparison to the polymorph I of the compound of the formula (I) , the compound of formula (II) has a clearly differentiable X-ray diffractogram, DSC, and TGA spectrum.
  • Polymorph II of formula (II) is characterized by diffraction peak maximum of 2-theta of 14.9 in its X-ray diffractogram, preferably, by diffraction peaks at 6.0 ⁇ 0.2, 11.9 ⁇ 0.2, 14.9 ⁇ 0.2, 17.8 ⁇ 0.2, 20.8 ⁇ 0.2, 23.8 ⁇ 0.2 and 27.2 ⁇ 0.2 of 2-theta indicated with degree.
  • Polymorph II of formula (II) has the first endothermic peak at about 106-147°C, and the second endothermic peak at about183-204°C in its DSC spectrum, preferably, the first endothermic peak at about 141.72°C, and the second endothermic peak at about 196.00°C.
  • the compound of the formula (II) shows a high stability in the manufacture of pharmaceutical compositions, more soluble than other Polymorphs in water.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula II and a pharmaceutically acceptable carrier.
  • Deuterium (D or 2 H) is a non-radioactive, stable isotope of hydrogen, the natural abundance of deuterium is 0.015%. Compound should be considered to be unnatural, if its level of deuterium has been enriched to be greater than their natural abundance level 0.015%.
  • the abundance of deuterium is substantially greater than the natural abundance of deuterium, which is 0.015%, when a particular position is designated as deuterium.
  • a position designated as deuterium typically has a minimum isotopic enrichment factor of at least 3000 at each atom designated as deuterium in said compound.
  • the concentration of naturally abundant stable hydrogen is small and immaterial compared to the degree of stable isotopic substitution of compounds of this invention.
  • a compound of formula II has abundance for each designated deuterium atom of at least greater than the natural abundance of deuterium, which is 0.015%. In certain embodiments, the deuterium enrichment in compounds of formula II is at least about 1%.
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500, or at least 4000, or at least 4500, or at least 5000, or at least 5500, or at least 6000, or at least 6333.3, or at least 6466.7, or at least 6633.3.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a pharmaceutically acceptable when used with reference to a compound of Formula II is intended to refer to a form of the compound that is safe for administration to a subject.
  • a free base, a salt form, a solvate, a hydrate, a prodrug or derivative form of a compound of Formula II which has been approved for mammalian use, via oral ingestion or any other route of administration, by a governing authority or regulatory agency, such as the Food and Drug Administration (FDA) of the United States, is pharmaceutically acceptable.
  • FDA Food and Drug Administration
  • the compound (s) of Formula II is used to treat a subject by administering the compound (s) as a pharmaceutical composition.
  • the compound (s) in one embodiment, are combined with one or more pharmaceutically acceptable excipients, including carriers, diluents or adjuvants, to form a suitable composition, which is described in more detail herein.
  • excipient denotes any pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API) , which is typically included for formulation and/or administration purposes.
  • API active pharmaceutical ingredient
  • treat refers to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy.
  • Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals.
  • the phrase "effective amount" is intended to quantify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
  • the effective amount in one embodiment, is administered in a single dosage form or in multiple dosage forms.
  • the present invention also relates to a method for using the compound of the formula (II) and compositions thereof, to treat mammalian hyper-proliferative disorders.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of the formula (II) of this invention or composition thereof, which is effective to treat the disorder.
  • Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant) , cholangiocarcinoma (intrahepatic bile duct carcinoma) , and mixed hepatocellular cholangiocarcinoma.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the present invention further provides the use of the compound of the formula (II) for the preparation of a pharmaceutical compositions for the treatment of the aforesaid disorders.
  • the compound of the formula (II) of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compound of the formula (II) of this invention can be combined with known anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • Optional anti-hyper-proliferative agents which can be added to the compositions include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996) , which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine) , epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, pre
  • compositions of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis o/Therapeutics (Ninth 25 Edition) , editor Molinoff et aI., pubi.
  • anti-hyper-proliferative agents suitable for use with the compositions of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
  • cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to:
  • Combination mean for the purposes of the invention not only a dosage form which contains all the components (so-called fixed combinations) , and combination packs containing the components separate from one another, but also components which are administered simultaneously or sequentially, as long as they are employed for the prophylaxis or treatment of the same disease.
  • the active ingredients of the combination according to the invention can be converted in a known manner into the usual formulations, which may be liquid or solid formulations.
  • Examples are tablets, coated tablets, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, solutions. Since the combination according to the invention is well tolerated and in some cases is effective even in low dosages, a wide range of formulation variants is possible. Thus, one possibility is to formulate the individual active ingredients of the combination according to the invention separately. In this case, it is not absolutely necessary for the individual active ingredients to be taken at the same time; on the contrary, sequential intake may be advantageous to achieve optimal effects. It is appropriate with such separate administration to combine the formulations of the individual active ingredients, for example tablets or capsules, simultaneously together in a suitable primary packaging. The active ingredients are present in the primary packaging in each case in separate containers which may be, for example, tubes, bottles or blister packs.
  • Such separate packaging of the components in the joint primary packaging is also referred to as a kit.
  • Further formulations variants which are suitable and preferred for the combination according to the invention are also fixed combinations.
  • "Fixed combination” is intended here to mean pharmaceutical forms in which the components are present together in a fixed ratio of amounts.
  • Such fixed combinations may be, for example, in the form of oral solutions, but they are preferably solid oral pharmaceutical preparations, e.g. capsules or tablets.
  • compositions containing the compound of the formula (II) of the present invention can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the formula (II) of the present invention.
  • a pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compound of the formula (II) of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
  • the compound of the formula (II) can be formulated into solid or liquid preparations such as solid dispersion, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms can be a capsule which can be of the ordinary hard-or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and com starch.
  • the compound of the formula (II) of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin
  • disintegrating agents intended to assist
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (l) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • the compound of the formula (II) of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2, 2-dimethyl-l, l-dioxolane-4-methanol, ethers such as poly (ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly (oxyethylene-oxypropylene) sor ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example di
  • compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • compositions may be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl -cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • compositions of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such material is, for example, cocoa butter and polyethylene glycol.
  • Another formulation employed in the methods of the present invention employs trans dermal delivery devices ( "patches" ) .
  • Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11, 1991, incorporated herein by reference) .
  • Such patches may be constructed for
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations which are known in the art. It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device.
  • the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
  • Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,011,472, issued April 30, 1991.
  • the pharmaceutical compositions of this invention may also be in the form of a solid dispersion.
  • the solid dispersion may be a solid solution, glass solution, glass suspension, amorphous precipitation in a crystalline carrier, eutectic or monotecic, compound or complex formation and combinations thereof.
  • An aspect of the invention of particular interest is a pharmaceutical composition comprising a solid dispersion, wherein the matrix comprises a pharmaceutically acceptable polymer, such as polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate copolymer, polyalkylene glycol (i.e. polyethylene glycol) , hydroxyalkyl cellulose (i.e. hydroxypropyl cellulose) , hydroxyalkyl methyl cellulose (i.e.
  • hydroxypropyl methyl cellulose carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, polymethacrylates, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate copolymer, polyglycolized glycerides, xanthan gum, carrageenan, chitosan, chitin, poyldextrin, dextrin, starch and proteins.
  • compositions comprising a solid dispersion, wherein the matrix comprises a sugar and/or sugar alcohol and/or cyclodextrin, for example sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, inositol, trehalose, isomalt, inulin, maltodextrin, ⁇ -cyclodextrin, hydroxypropyl ⁇ -cyclodextrin or sulfobutyl ether cyclodextrin.
  • a sugar and/or sugar alcohol and/or cyclodextrin for example sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, inositol, treha
  • Additional suitable carriers that are useful in the feomualtions of the matrix of the solid dispersion include, but are not limited to alcohols, organic acids, organic bases, amino acids, phospholipids, waxes, salts, fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and urea.
  • the solid dispersion of the compound of formula (II) in the matrix may contain certain additional pharmaceutical acceptable ingredients, such as surfactants, fillers, disintegrants, recrystallization inhibitors, plasticizers, defoamers, antioxidants, detackifier, pH-modifiers, glidants and lubricants.
  • the solid dispersion of the invention is prepared according to methods known to the art for the manufacture of solid dispersions, such as fusion/melt technology, hot melt extrusion, solvent evaporation (i.e. freeze drying, spray drying or layering of powders of granules) , coprecipitation, supercritical fluid technology and electrostatic spinning method.
  • compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
  • Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations” PDA Journal of Pharmaceutical Science & Technology 1998, 52 (5) , 238-311; Strickley, R.G “Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999) -Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53 (6) , 324-349; and Nema, S. et al, "Excipients and Their Use in Injectable Products” PDA 15 Journal of Pharmaceutical Science & Technology 1997, 51 (4) , 166-171.
  • Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, mono ethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated charcoal) ; aerosol propellants (examples include but are not limited to carbon dioxide, CClF 2 , F 2 ClC-CClF 2 and CClF 3 ; HFA-134a, HFA-227 ) air displacement agents (examples include but are not limited to nitrogen and argon) ; antifungal preservatives (examples include but are not limited to
  • FD&C Red No. 20 FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red
  • clarifying agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
  • encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
  • flavorants examples include but are not limited to amse oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants include but are not limited to glycerol, propylene glycol and sorbitol
  • levigating agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to
  • compositions according to the present invention can be illustrated as follows: Sterile IV Solution: A 5 mg/ml solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1-2 mg/ml with sterile 5% dextrose and is administered as an IV infusion over 60 minutes.
  • Lyophilized powder for IV administration A sterile preparation can be prepared with (i) 100-1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32-327 mg/ml sodium citrate, and (iii) 300-3000 mg Dextran 40.
  • the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/ml, which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/ml, and is administered either IV bolus or by IV infusion over 15-60 minutes.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection: 50 mg/ml of the desired, water-insoluble compound of this invention, 5 mg/ml sodium carboxymethylcellose; 4 mg/ml TWEEN 80; 9 mg/ml sodium chloride; 9 mg/ml benzyl alcohol.
  • Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and. sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • Dosage of the pharmaceutical compositions of the present invention Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day.
  • the daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to . 200 mg/kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the trans dermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the invention further provides a process for preparing the compound of the formula (II) by dissolution of the compound of the formula (I) e.g. in the polymorph I, obtained as described in in WO 2010/144499, in an inert solvent and adding water until the compound of the formula (II) precipitates. The compound of the formula (II) is thus obtained.
  • the invention likewise provides a process for preparing the compound of the formula (II) by suspending the compound of the formula (I) e.g. in the polymorph I, obtained as described in WO 2010/144499, in an aqueous solvent and then stirring or shaking until the desired degree of conversion is attained. The crystals are isolated and dried. The compound of the formula (II) is thus obtained.
  • Suitable inert solvents are lower alcohols, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, l-pentanol or ketones such as acetone, or alkanes such as n-pentane, cyclopentane, n-hexane, cyclohexane, or tetrahydrofuran, or acetonitrile, or toluene, or ethyl acetate, or 1, 4-dioxan or mixtures of the solvents mentioned, or mixtures of the solvents mentioned with water. Preference is given to acetone, methanol, ethanol, mixtures of the solvents mentioned.
  • the processes are generally carried out at atmospheric pressure. However, it is also possible to work at elevated pressure or at reduced pressure (for example in a range of from 0.5 to 5 bar) . It is believed that one skilled in the art, using the preceding information and information available in the art, can utilize the present invention to its fullest extent.
  • Figure 1 DSC-and TGA-thermograms of 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) -3-fluorophenoxy) -N-d3-methylpicolinamide monohydrate (polymorph II) .
  • Figure 2 X-ray diffractograms of 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) -3-fluorophenoxy) -N-d3-methylpicolinamide monohydrate (polymorph II) . Its Data is as following:
  • Example 1 Preparation of 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) -3-fluorophenoxy) -N-d 3 -methylpicolinamide monohydrate (polymorph II) .
  • thermograms are obtained using a DSC or Pyris-l differential scanning calorimeter and TGA thermogravimetric analyzer from Perkin-Elmer.
  • the X-ray diffractograms is achieved by Rigaku Ultima IV ⁇

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Abstract

La présente invention concerne du monohydrate de 4-(4-(3-(4-chloro-3-(trifluorométhyl)phényl)uréido)-3-fluorophénoxy)-N-d 3-méthylpicolinamide, qui est un inhibiteur des kinases du VEGF et des kinases Raf, leurs procédés de préparation, et des compositions pharmaceutiques le comprenant.
PCT/CN2014/093075 2013-12-09 2014-12-05 Monohydrate de 4-(4-(3-(4-chloro-3-(trifluorométhyl)phényl)uréido)-3-fluorophénoxy)-n-d3-méthylpicolinamide WO2015085888A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010144499A2 (fr) * 2009-06-09 2010-12-16 Medolution Limited Dérivés d'urée comme inhibiteurs de kinase
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
WO2011113370A1 (fr) * 2010-03-18 2011-09-22 苏州泽璟生物制药有限公司 Oméga-diphénylurée substituée par un deutérium et ses dérivés, et compositions pharmaceutiques les contenant
CN103301066A (zh) * 2012-03-15 2013-09-18 苏州泽璟生物制药有限公司 一种改善吸收性能的固体分散体及其制备
WO2013166966A1 (fr) * 2012-05-10 2013-11-14 苏州泽璟生物制药有限公司 Polymorphes d'oméga-diphénylurée substituée par du deutérium et contenant du fluor ou de sels de celle-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010144499A2 (fr) * 2009-06-09 2010-12-16 Medolution Limited Dérivés d'urée comme inhibiteurs de kinase
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
WO2011113370A1 (fr) * 2010-03-18 2011-09-22 苏州泽璟生物制药有限公司 Oméga-diphénylurée substituée par un deutérium et ses dérivés, et compositions pharmaceutiques les contenant
CN103301066A (zh) * 2012-03-15 2013-09-18 苏州泽璟生物制药有限公司 一种改善吸收性能的固体分散体及其制备
WO2013166966A1 (fr) * 2012-05-10 2013-11-14 苏州泽璟生物制药有限公司 Polymorphes d'oméga-diphénylurée substituée par du deutérium et contenant du fluor ou de sels de celle-ci

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