4-[4-({[4-chloro-3-(trifluoromethyl)phenyl)]carbamoyl}amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide monohydrate

[0001] The invention relates to 4- [4 - ({[4-chloro-3- (trifluoromethyl) phenyl] carbamoyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide monohydrate monohydrate, methods for preparing it, containing it pharmaceutical compositions and its applications in the control of disorders.

[0002] 4- [4 - ({[4-chloro-3- (trifluoromethyl) phenyl] carbamoyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide monohydrate is mentioned in WO 2005/009961 and corresponds to a compound of formula (AND):

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[0003] WO 2005/009961 describes a compound of formula (I) as an Raf kinase enzyme inhibitor that can be used to treat disorders in which angiogenesis and / or hyperproliferation play an important role, for example in the growth of cancer and cancer.

[0004] WO 2006/026500 describes a pharmaceutical composition comprising a solid dispersion of a compound of formula (I) including solvates, hydrates and pharmaceutically available salts in generic form.

[0005] The compound of formula (I) is obtained as described in WO 2005/009961 and corresponds to a polymorph, which is referred to therein as polymorph I with a melting point of 186-206 ° C, a characteristic X-ray diffraction pattern, IR spectrum, Raman spectrum, FIR spectrum. , NIR spectrum and spectrum ¹³Solid-phase C-NMR (Tab. 2-7, Fig. 2-7).

[0006] The invention provides a compound of formula (I) in the form of a monohydrate, which corresponds to a compound of formula (II):

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[0007] The compound of formula (II) contains water in an amount of 3.6% by weight. Compared to polymorph I of the compound of formula (I), the compound of formula (II) has clearly distinguishable X-ray diffraction patterns; NIR spectrum, FIR spectrum, IR spectrum, spectrum¹³Solid-phase C-NMR and Raman spectrum (Figures 2-7).

[0008] Surprisingly, the compound of formula (II) shows great stability in the preparation of pharmaceutical compositions.

[0009] The innovative compound of formula (II) is used in high purity in pharmaceutical formulations. In connection with stability, the pharmaceutical formulation mainly contains the compound of formula (II), without significant fractions of a further form of the compound of formula (I), e.g. a further polymorph of the compound of formula (I). The pharmaceutical composition preferably contains more than 90 weight percent, more preferably more than 95 weight percent, of the compound of formula (II) relative to the total amount of the compound of formula (II) present in the composition.

[0010] The invention also relates to uses of the compound of formula (II) and compositions thereof for the treatment of mammalian hyperproliferative disorders. This includes administering to a mammal in need thereof, including a human, an amount of a compound of formula (II) according to the invention or a composition thereof that is effective in treating a disorder. Hyperproliferative disorders include solid tumors such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive system, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid glands and their distant metastases. These disorders also include lymphomas, sarcomas and leukemia.

[0011] Examples of breast cancer include invasive ductal cancer, invasive lobular carcinoma, in situ ductal carcinoma, and in situ lobular carcinoma.

[0012] Examples of airway cancers include small cell and non-small cell lung cancer, as well as bronchial adenoma and lung and pleural blastoma.

[0013] Examples of brain cancers include brain stem and hypothalamic glioma, cerebellar and cerebral astrocytoma, neural tubercle, ependymoma, as well as neuroectodermal and pineal tumors.

[0014] Tumors of the male reproductive organs include prostate and testicular cancer. Neoplasms of the female reproductive organs include, endometrial, cervical, ovarian, vaginal and vulva cancer as well as sarcoma of the uterus.

[0015] Gastrointestinal neoplasms include cancers of the anus, colon, large intestine, esophagus, gallbladder, stomach, pancreas, rectum, small intestine and salivary glands.

[0016] Neoplasms of the urinary tract include cancers of the bladder, penis, kidneys, renal pelvis, ureter and urethra.

[0017] Eye cancers include intraocular melanoma and retinoblastoma.

[0018] Examples of liver cancers include hepatocellular carcinoma (hepatocellular carcinoma with or without fibro-lamellar variant), bile duct cancer (intrahepatic bile duct cancer), and mixed hepatocellular carcinoma.

[0019] Skin cancers include squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer and non-melanoma skin cancer.

[0020] Head and neck cancers include cancer of the larynx / lower throat / nasopharynx / nasopharynx, and lip and mouth.

[0021] Lymphomas include AIDS-related lymphomas, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease and central nervous system lymphoma.

[0022] Sarcomas include soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0023] Leukemias include acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0024] These disorders are well characterized in humans, but also occur with a similar etiology in other mammals, and can be treated by administering the pharmaceutical compositions of the invention.

[0025] Based on standard laboratory techniques known to evaluate compounds useful for the treatment of hyperproliferative disorders, using standard toxicity tests and standard pharmacological assays to determine the treatment of the conditions identified above in mammals, and by comparing these results with those of known drugs that are used to treat these conditions, an effective dosage of the compounds of the invention can be easily determined for the treatment of any desired indication. The amount of active ingredient to be administered in the treatment of one of these conditions may vary considerably in connection with such considerations as the use of a particular compound and dosage, mode of administration, duration of treatment, age and sex of the patient being treated, and the nature and extent of the condition being treated.

[0026] The invention further provides the use of a compound of formula (II) for the preparation of pharmaceutical compositions for the treatment of said disorders.

Combination with other pharmaceutical agents:

[0027] The compound of formula (II) of the invention may be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutical agents as long as the combination does not cause unacceptable side effects. For example, the compound of formula (II) according to the invention may be combined with those known to be active against hyperproliferation or other indicated agents, and the like, as well as in blends and combinations thereof.

[0028] Optional antiproliferative agents that can be added to the composition include compounds listed in the list of drug regimens for chemotherapy of cancer in

11. edition of the Merck Index, (1996), such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), etirozicin

5-fluorouracil, hexamethylmelamine, hydroxycarbamide, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, tretoxinoxinoximinoxifoxifoxifoxifoxiline and vindesine.

[0029] Other antiproliferative agents suitable for use with the compositions of the invention include those compounds approved for use in the treatment of cancer in Goodman and Gilman's The Pharmacological Basis of Therapeuticss (ninth edition), edited by Molinoff et al., Published on by McGraw-Hill, pages 1225-1287, (1996), such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2 ', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl-ethylenolene fluorodeoxyuridine, monophosphate

5-fluorodeoxyuridine, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl, L-aspartate testosterone, thiotepa, trimethylmelamine, uridine and vinorelbine.

[0030] Other antiproliferative agents suitable for use with the compositions of the invention include other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifene and topotecan.

[0031] In general, the use of cytotoxic and / or cytostatic agents in combination with a compound or composition of the invention will serve to:

(1) obtaining better efficacy in reducing tumor growth or even eliminating the tumor, compared to the administration of any of the agents in monotherapy, (2) providing smaller amounts of chemotherapeutics administered, (3) providing chemotherapy that is well tolerated by the patient, with fewer harmful pharmacological complications than those observed for a single chemotherapeutic agent and some other combination therapies, (4) provide treatment for a broader spectrum of different types of cancer in mammals, especially humans, (5) provide a higher response rate in treated patients, (6) provide longer survival in treated patients compared to standard chemotherapies, (7) provide longer time to tumor progression, and / or (8) obtaining results of efficacy and tolerance at least as good as those for monotherapy compared to known cases, where other combinations of anti-cancer agents have given antagonistic effects.

[0032] "Combination" means, for the purposes of the invention, not only a dosage form that contains all ingredients (so-called fixed combinations), and combination packages containing ingredients separated from each other, but also ingredients that are administered simultaneously or sequentially, provided that are used to prevent or treat the same disease.

[0033] The active ingredients of the combination according to the invention can be converted using a known solution for conventional formulations, which can be liquid or solid formulations. Examples are tablets, coated tablets, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, solutions.

[0034] As the combination according to the invention is well tolerated and in some cases effective even at low dosages, a wide range of formulation variants are possible. Thus, one possibility is to separately formulate the individual active ingredients of the combinations according to the invention. In this case, it is not strictly necessary that the individual active ingredients be taken at the same time; on the contrary, taking them sequentially may be advantageous to achieve optimal results. It is suitable for such separate administration to combine the formulations of the individual active ingredients, for example tablets or capsules, simultaneously 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 packaging. This separate packaging of ingredients in a common primary package is also referred to as a kit.

[0035] Additional formulation variants that are suitable and preferred for the combinations of the invention are also fixed combinations. By definition, "fixed combination" is intended to mean pharmaceutical forms in which the ingredients are present 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.

Pharmaceutical compositions:

[0036] The invention also relates to pharmaceutical compositions comprising a compound of formula (II) according to the invention. These compositions can be used to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purposes of the invention, means a mammal, including a human, in need of treatment for a specific condition or disease. Therefore, the invention includes pharmaceutical compositions which are composed of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula (II) according to the invention. A pharmaceutically acceptable carrier means any carrier that is relatively non-toxic and harmless to the patient in concentrations consistent with the effective activity of the active ingredient, so that no adverse effects attributed to the carrier undermine the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound means that amount which results in or affects a particular condition being treated. The compound of formula (II) of the invention may be administered with pharmaceutically acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and time-coordinated release preparations, orally, parenterally, topically, nasally, ophthalmologically, optically, sublingually, rectally, vaginally and the like.

[0037] For oral administration, the compound of formula (II) may be formulated into solid or liquid preparations such as solid dispersions, capsules, pills, tablets, pastilles, lozenges, meltable flakes, powders, solutions , suspensions or emulsions, and can be prepared according to methods known in the art for the preparation of pharmaceutical compositions. The solid unit dosage form can be a capsule, which can be conventional gelatin, hard or soft types, containing, for example, surfactants, moisturizers and inert fillers such as lactose, sucrose, calcium phosphate and corn starch.

[0038] In a further embodiment, the compound of formula (II) according to the invention can be tableted with conventional tablet supports such as lactose, sucrose and corn starch in combination with binders such as acacia, corn starch or gelatin, disintegrants, which are intended to help the tablet disintegrate and dissolve after administration, such as potato starch, alginic acid, corn starch and guar gum, tragacanth, gum arabic; moisturizing agents designed to improve the flow of the tablet granulate and this prevents the tablet material from adhering to the surface of the stamping dies and tablet punches, for example talc, stearic acid or magnesium, calcium or zinc stearate, dyes, coloring agents and flavorings such as mint, oil stale aroma or cherry, designed to improve the aesthetic quality of tablets and make them more acceptable to the patient. Suitable excipients for use in liquid oral dosage forms include dicalcium phosphate and diluents, such as water and alcohols, for example, ethanol, benzyl alcohol and polyethylene alcohols, with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or for other modification of the physical dosage unit form. For example, tablets, pills or capsules can be coated with shellac, sugar or both.

[0039] 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, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are listed in those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above may also be present.

[0040] The pharmaceutical compositions of the 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 emulsifiers may be (1) naturally occurring gums, such as acacia and tragacanth, (2) naturally occurring phosphatides such as soy and lecithin, (3) partial esters or esters derived from fatty acids and hexitol anhydrides , for example, sorbitan monooleate, (4) condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0041] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, peanut 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. Suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavorings; and one or more sweeteners such as sucrose or saccharin.

[0042] 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 softening agent and a preservative, such as methyl and propyl parabens, and flavoring and coloring agents.

[0043] The compound of formula (II) according to the invention may also be administered parenterally, i.e. subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier, which may be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as polyethylene glycol 400, oil, fatty acid, fatty acid ester or fatty acid glyceride, or acetylation of fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as soap or detergent, suspending agent such as pectin, carbomers, methyl cellulose, hydroxypropyl methylcellulose or carboxymethylcellulose or an emulsifying agent and other pharmaceutical adjuvants.

[0044] Examples of oils that can be used in parenteral formulations of the invention are those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petroleum jelly and mineral oil. 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 alkali metal, ammonium fatty acids, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyldialkylammonium halides, alkylpyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl and olefin sulfonates, alkyl sulfates, olefins, ethers and monoglycerides, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides and copolymers of poly (ethoxyloxypropylene) or ethylene oxide or propylene oxide; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quaternary ammonium salts, as well as mixtures.

[0045] The parenteral compositions of the invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preferably, preservatives and buffers can also be used. To minimize or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant with a hydrophilic lipophilic balance (HLB) from about 12 to about 17. The amount of surfactant in such a formulation ranges from about 5% to about 15% by weight. The surfactant can be a single ingredient having the above HLB or it can be a mixture of two or more ingredients with the desired HLB.

[0046] An illustration of surfactants used in parenteral formulations is a class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and high molecular weight ethylene oxide adducts with a hydrophobic base, formed by condensation of propylene oxide with propylene glycol.

[0047] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents, such as, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; dispersing or wetting agents that can be a naturally occurring phosphatide, such as lecithin, a condensation product of alkylene oxide with fatty acids, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long-chain aliphatic alcohol, for example, heptadeka-ethyleneoxycethanol, condensation of ethylene oxide with a partial ester derived from fatty acids and hexitol, such as polyoxyethylene sorbitan monooleate, or a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

[0048] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. Diluents and solvents that can be used are, for example, water, Ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile solid oils are conventionally used as solvents or suspending agents. Any mild solid oil, including synthetic mono- or diglycerides can be used for this purpose. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

[0049] The 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-irritating excipient which is a solid at ordinary temperatures but liquid at the rectal temperature and will then melt in the rectum to release the drug. Such material means, for example, cocoa butter and polyethylene glycol.

[0050] Another formulation used in the methods of the invention uses transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the invention in controlled amounts. The design and use of transdermal patches for the delivery of pharmaceutical agents are well known in the art (see, e.g., U.S. Patent No. 5,023,252, filed June 11, 1991, incorporated herein by reference.) Such patches may be constructed for continuous, pulsed, or on demand delivery of pharmaceutical agents.

[0051] Controlled release formulations for parenteral administration include liposomal, polymeric microspheres and polymeric gel formulations that are known in the art.

[0052] It may be desirable or necessary to introduce the pharmaceutical composition into the patient's body by means of a mechanical delivery device. The design and use of a mechanical delivery device for the delivery of pharmaceutical agents are well known in the art. Direct techniques for, for example, delivering the drug directly to the brain usually involve placing the drug delivery catheter in the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used to transport agents to specific anatomical regions of the body is described in US Patent No. 5,011,472, filed April 30, 1991.

[0053] The pharmaceutical compositions of the invention may also be in the form of a solid dispersion. The solid dispersion may mean a solid solution, a glass solution, a glass suspension, an amorphous precipitate in a crystalline support, eutectic or monotectic formation of the compound or complex, and combinations thereof.

[0054] A particular aspect of the invention is a pharmaceutical composition comprising a solid dispersion in which the matrix comprises a pharmaceutically acceptable polymer such as polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyalkylene glycol (i.e. polyethylene glycol), hydroxyalkyl cellulose (i.e. hydroxypropyl cellulose) ie. hydroxypropyl methylcellulose), carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, polymethacrylates, polyvinyl alcohol, polyvinyl acetate, copolymer polyvinyl alcohol / polyvinyl acetate, polyglycolyzed glycerin, polyglycerol, carboxylic acid, chagen xanthine,

[0055] Another aspect of the invention is a pharmaceutical composition comprising a solid dispersion in which the matrix contains 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, β-cyclodextrin, hydroxypropyl-e-cyclodextrin or cyclodextrin sulfobutyl ether.

[0056] Additional suitable carriers that are useful in forming the solid dispersion matrix include alcohols, organic acids, organic bases, amino acids, phospholipids, waxes, salts, fatty acid esters, polyoxyethylene fatty acid sorbitan esters, and urea.

[0057] The solid dispersion of the compound of formula (II) in the matrix may contain some additional pharmaceutically acceptable ingredients such as surfactants, bulking agents, disintegrants, recrystallization inhibitors, plasticizers, anti-foaming agents, antioxidants, adhesion-reducing agent, pH modifiers , lubricants and moisturizers.

[0058] The solid dispersion according to the invention is obtained according to methods known in the art for the preparation of solid dispersions, such as melting / melting technology, melt extrusion, solvent evaporation (i.e. freeze drying, spray drying or layering of granule powders), co-precipitation, technology supercritical fluid and electrostatic spinning method.

[0059] The compositions of the invention may also contain other conventional pharmaceutically acceptable mixed ingredients, generally referred to as carriers or diluents, as needed or as desired. Conventional procedures can be used to prepare such compositions in a suitable dosage form. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, MF et al, "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science &amp; Technology 1998, 52 (5), 238-311; Strickley, RG "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999) -part-1" PDA Journal of Pharmaceutical Science &amp; Technology 1999, 53 (6), 324-349; and Nema, S. et al, "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science &amp; Technology 1997, 51 (4), 166-171.

[0060] Commonly used pharmaceutical ingredients that can be used as suitable to formulate the composition for its intended route of administration include:

acidifying agents (examples include acetic acid , citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalizing agents (examples include ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine);

adsorbents (examples include powdered cellulose and activated activated carbon);

aerosol propellants (examples include carbon dioxide, CCl2F2, F2ClC-CClF2 and CClF3) air displacement agents (examples include nitrogen and argon);

antifungal preservatives (examples include benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);

antibacterial preservatives (examples include benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal);

antioxidants (examples include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);

binding materials (examples include block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes and styrenebutadiene copolymers);

buffering agents (examples include potassium metaphosphate, dipotassium phosphate, sodium acetate, anhydrous sodium citrate and sodium citrate dihydrate) transfer agents (examples include acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic injection of sodium chloride and bacteriostatic water for injections) chelating agents (examples include disodium edetate and versenic acid) coloring agents (examples include FD&amp;C Red No. 3, FD&amp;C Red No. 20, FD&amp;C Yellow No. 6, FD&amp;C Blue No. 2, D&amp;C Green No. 5 , D&amp;C Orange No. 5, D&amp;C Red No. 8, caramel and red iron oxide);

clarifying agents (examples include bentonite);

emulsifying agents (examples include acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene monostearate);

encapsulating agents (examples include gelatin and cellulose acetate phthalate) flavors (examples include anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include glycerol, propylene glycol and sorbitol);

powders (examples include mineral oil and glycerin);

oils (examples include peanut oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include lanolin, hydrophilic ointment, polyethylene glycol ointment, petroleum jelly, hydrophilic petroleum jelly, ointment based on white beeswax and petrolatum, ointment based on yellow beeswax and petroleum jelly and ointment with rose water);

Penetration enhancers (transdermal delivery) (examples include monohydroxy or polyhydroxy alcohols, mono- or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, ether oils, phosphatidyl derivatives, phosphatidyl derivatives, , ethers, ketones and ureas) plasticizers (examples include diethyl phthalate and glycerol);

solvents (examples include ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, injectable water, sterile injectable water and sterile irrigation water);

stiffeners (examples include cetyl alcohol, cetyl ester wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax);

suppository bases (examples include cocoa butter and polyethylene glycols (mixtures));

surfactants (examples include benzalkonium chloride, nonoxynol 10, oxoxoxol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (examples include agar, bentonite, carbomers, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose), tragacanth and veegum);

sweeteners (examples include aspartame, dextrose, glycerol, mannitol, propylene glycol, sodium saccharin, sorbitol and sucrose);

tablet release agents (examples include magnesium stearate and talc);

tablet binders (examples include gum arabic, alginic acid, sodium carboxymethyl cellulose, compressible sugar, ethyl cellulose, gelatin, liquid glucose, methyl cellulose, cross-linked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate and shellac);

excipients for direct tabletting (examples include dibasic calcium phosphate);

tablet disintegrants (examples include alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, potassium polacrylin, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate and starch);

tablet lubricants (examples include colloidal silica, corn starch and talc);

tablet moisturizers (examples include calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate);

coating substances for a more vivid color for tablets / capsules (examples include titanium dioxide);

tablet polish agents (examples include carnauba wax and white wax);

thickeners (examples include beeswax, cetyl alcohol and paraffin);

tonicity agents (examples include dextrose and sodium chloride);

viscosity enhancers (examples include alginic acid, bentonite, carbomers, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include heptade-ethoxylated oxycetanol, lecithin, sorbitan monooleate, polyoxyethylene sorbitol monooleate and polyoxyethylene stearate).

[0061] It is believed that one skilled in the art using the above information can make the most of the invention. However, below are examples of pharmaceutical formulations that can be used in the method of the invention.

[0062] The pharmaceutical compositions of the invention can be illustrated as follows:

Sterile intravenous (IV) solution: A 5 mg / ml solution of the desired compound of the invention is prepared using sterile, injectable water, adjusting the pH as 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: The sterile preparation can be prepared with (i) 100-1000 mg of the desired compound of the invention as a lyophilized 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 as either IV bolus intravenous, or as

IV infusion within 15-60 minutes.

Intramuscular suspension: The following solution or suspension may be prepared for intramuscular injection:

mg / ml of the desired water-insoluble compound of the invention 5 mg / ml sodium carboxymethyl cellulose mg / ml TWEEN 80 mg / ml sodium chloride 9 mg / ml benzyl alcohol

Hard-shell capsules: A large number of unit capsules were obtained by filling into a standard two-element hard galantine capsule, each 100 mg powdered active ingredient, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate.

Soft gelatin capsules: A mixture of the active ingredient in an easily absorbed oil, such as soybean oil, cottonseed oil or olive oil, was prepared and injected with a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of active ingredient. The capsules were washed and dried. The active ingredient may be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to obtain a water-miscible drug mix.

Tablets: A large number of tablets were prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg lactose. Appropriate aqueous and non-aqueous coatings can be used to increase palatability, improve elegance and stability, or delay absorption.

Immediate Release Tablets / Capsules: These are solid oral dosage forms prepared by conventional and new methods. These units are taken orally without water, with immediate dissolution and drug delivery. The active ingredient is mixed with a liquid containing an ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are cured into solid tablets or caplets by freeze drying and solid extraction techniques. The drug compounds can be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent ingredients to obtain porous matrices intended for immediate release without the need for [adding] water.

Dosage of pharmaceutical compositions according to the invention:

[0063] Based on standard laboratory techniques known to evaluate compounds useful for treating hyperproliferative disorders, using standard toxicity tests and standard pharmacological assays to determine the treatment of the conditions identified above in mammals, and by comparing these results with those of known drugs that are used to treat these conditions, an effective dosage of the compounds of the invention can be easily determined for the treatment of any desired indication. The amount of active ingredient to be administered in the treatment of one of these conditions may vary considerably in connection with such considerations as the use of a particular compound and dosage, mode of administration, duration of treatment, age and sex of the patient being treated, and the nature and extent of the condition being treated.

[0064] The total amount of 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. The dosage unit may contain from about 0.5 mg to about 1500 mg of active ingredient, and may be administered one or more times a day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and the 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 one to four times a day. Percutaneous concentration will preferably mean this required to maintain a daily dose of from about 0.01 to 200 mg / kg. The daily inhalation dosing regimen will preferably be from 0.01 to 100 mg / kg of total body weight.

[0065] Of course, the specific starting and subsequent dosage regimens for each patient will vary, depending on the nature and severity of the condition, as will be determined by the attending diagnostician, the activity of the particular compound used, the age and general condition of the patient, administration time, route of administration, rate drug secretion, drug combinations, and the like. The desired treatment regimen and the number of doses of a compound of the invention or a pharmaceutically available salt or ester or composition thereof can be determined by those skilled in the art using conventional treatment tests.

Method of obtaining:

[0066] The invention further provides a method for preparing a compound of formula (II) by dissolving a compound of formula (I) e.g. polymorph I, obtained as described in WO 2005/009961, in an inert solvent and adding water until the compound of formula (II) precipitates ). Thereby, a compound of formula (II) is obtained.

[0067] The invention similarly provides a method for preparing a compound of formula (II) by suspending a compound of formula (I) e.g. polymorph I, obtained as described in WO 2005/009961, in an aqueous solvent and then stirring or shaking until the desired degree of conversion is achieved . The crystals were isolated and dried. Thereby, a compound of formula (II) is obtained.

[0068] Suitable inert solvents are lower alcohols, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, 1-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-dioxane or mixtures of said solvents, or mixtures of said solvents with water. Acetone, methanol, ethanol, mixtures of these solvents are preferred.

[0069] It is preferred to obtain the compound of formula (II) by dissolving the compound of formula (I) in the form of polymorph I, obtained as described in WO 2005/009961, in ethanol and adding water until the compound of formula (II) precipitates. Thereby, a compound of formula (II) is obtained.

[0070] Similarly, the preparation of the compound of formula (II) is preferred by suspending the compound of formula (I) in the form of polymorph I, obtained as described in WO 2005/009961, in an aqueous solvent and then stirring or shaking until the desired degree of conversion is achieved at 25 ° C. The crystals were isolated and dried. Thereby, a compound of formula (II) is obtained.

[0071] The methods are generally carried out at atmospheric pressure. However, it is also possible to operate under elevated pressure or reduced pressure (for example in the range of 0.5 to 5 bar).

[0072] It is believed that one of ordinary skill in the art using the above information and information available in the art can make full use of the invention.

[0073] Weight data in the following tests and examples means, unless otherwise stated, weight percent; parts means parts by weight. Solvent ratios, dilution ratios and concentration data for liquid / liquid solutions are based on volume in each case.

Working examples [0074] Thermograms were obtained using a DSC 7 or Pyris-1 differential scanning calorimeter and a TGA 7 thermogravimetric analyzer from Perkin-Elmer. X-ray diffraction patterns were recorded on a Stoe transmission diffractometer. IR, FIR, NIR and Raman spectra were recorded using IFS 66v (IR, FIR), IFS 28 / N (NIR) and RFS 100 (Raman) Fourier spectrometers from Bruker. spectrum¹³Solid phase C-NMR was recorded using a DRX400 NMR spectrometer from Bruker.

Example 1: Preparation of 4- [4 - ({[4-chloro-3- (trifluoromethyl) phenyl] carbamoyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide monohydrate

Example 1.1 [0075] 400 mg 4- [4 - ({[4-chloro-3- (trifluoromethyl) phenyl] carbamoyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide as polymorph I, prepared as described in WO 2005/009961, dissolved in acetone and the solution was filtered. Water was added to a quarter of the filtrate until precipitation. The precipitate was filtered and dried at room temperature and ambient humidity. The sample was tested gravimetrically and corresponded to the title compound.

Example 1.2 [0076] 400 mg of 4- [4 - ({[4-chloro-3- (trifluoromethyl) phenyl] carbamoyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide as polymorph I, prepared as described in WO 2005/009961, dissolved in 50 ml ethanol, and the solution was filtered. A quarter of the solution was allowed to crystallize at about -20 ° C until the solvent was evaporated. The residue was tested by X-ray diffraction and corresponded to the title compound.

Example 1.3 [0077] 100 mg of 4- [4 - ({[4-chloro-3- (trifluoromethyl) phenyl] carbamoyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide as polymorph I, prepared as described in WO 2005/009961, suspended in 2 ml acetonitrile-water (1: 1) and shaken at 25 ° C. After one week, the suspension was filtered and the residue was dried at room temperature and ambient humidity. The residue was tested gravimetrically and corresponded to the title compound.

Example 1.4 [0078] 100 mg of 4- [4 - ({[4-chloro-3- (trifluoromethyl) phenyl] carbamoyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide as polymorph I, prepared as described in WO 2005/009961, suspended in 2 ml tetrahydrofuran-water (1: 1) and shaken at 10 ° C. After two weeks, the suspension was filtered and the residue was dried at room temperature and ambient humidity. The residue was tested by X-ray diffraction and corresponded to the title compound.

Tab. 1: Differential scanning calorimetry and thermogravimetry

<td></td><td>monohydrate</td><td>Polymorph I</td>

<td>Melting point [° C]</td><td>_-</td><td> 186-206</td>

<td>Weight loss [wt%]</td><td> 3,6</td><td> &lt; 0,4</td>

Tab. 2: X-ray diffractometry

<td>Max. Peak monohydrate</td><td>that [2 Theta] Polymorph I</td>

<td> 5,9</td><td> 7,2</td>

<td> 8,1</td><td> 7,3</td>

<td> 9,5</td><td> 8,6</td>

<td> 11,8</td><td> 10,7</td>

<td> 14,9</td><td> 11,5</td>

<td> 16,2</td><td> 12,1</td>

<td> 16,7</td><td> 13,4</td>

<td> 17,2</td><td> 13,6</td>

<td> 17,7</td><td> 14,0</td>

<td> 18,6</td><td> 14,5</td>

<td> 19,0</td><td> 14,8</td>

<td> 20,5</td><td> 15,6</td>

<td> 20,8</td><td> 16,0</td>

<td> 21,2</td><td> 16,5</td>

<td> 22,0</td><td> 17,2</td>

<td> 22,2</td><td> 18,6</td>

<td> 22,4</td><td> 18,8</td>

<td> 22,8</td><td> 19,1</td>

<td> 23,1</td><td> 19,8</td>

<td> 23,7</td><td> 20,1</td>

<td> 24,1</td><td> 20,2</td>

<td> 24,3</td><td> 20,4</td>

<td> 24,7</td><td> 21,8</td>

<td> 24,9</td><td> 22,9</td>

<td> 26,0</td><td> 23,5</td>

<td> 26,2</td><td> 23,8</td>

<td> 26,3</td><td> 24,2</td>

<td> 27,1</td><td> 24,9</td>

<td> 27,2</td><td> 25,2</td>

<td> 27,6</td><td> 25,9</td>

<td> 27,8</td><td> 26,0</td>

<td> 28,7</td><td> 26,4</td>

<td> 29,2</td><td> 26,6</td>

<td> 30,8</td><td> 27,2</td>

<td></td><td> 27,4</td>

<td></td><td> 28,2</td>

<td></td><td> 29,1</td>

<td></td><td> 29,4</td>

<td></td><td> 30,4</td>

<td></td><td> 30,9</td>

<td></td><td> 31,6</td>

<td></td><td> 32,7</td>

<td></td><td> 33,0</td>

<td></td><td> 33,4</td>

<td></td><td> 35,1</td>

<td></td><td> 35,3</td>

<td></td><td> 35,8</td>

<td></td><td> 36,1</td>

<td></td><td> 36,6</td>

<td></td><td> 37,3</td>

Tab. 3: IR spectroscopy

<td colspan="2">Peak maxima [cm^-1]</td>

<td>monohydrate</td><td>Polymorph I</td>

<td> 509</td><td> 512</td>

<td> 536</td><td> 535</td>

<td> 577</td><td> 563</td>

<td> 648</td><td> 572</td>

<td> 662</td><td> 654</td>

<td> 694</td><td> 722</td>

<td> 710</td><td> 744</td>

<td> 723</td><td> 785</td>

<td> 749</td><td> 811</td>

<td> 792</td><td> 836</td>

<td> 807</td><td> 871</td>

<td> 817</td><td> 880</td>

<td> 839</td><td> 906</td>

<td> 852</td><td> 970</td>

<td> 863</td><td> 996</td>

<td> 884</td><td> 1030</td>

<td> 900</td><td> 1044</td>

<td> 914</td><td> 1108</td>

<td> 964</td><td> 1116</td>

<td> 997</td><td> 1131</td>

<td> 1029</td><td> 1143</td>

<td> 1102</td><td> 1151</td>

<td> 1123</td><td> 1176</td>

<td> 1146</td><td> 1207</td>

<td> 1162</td><td> 1233</td>

<td> 1192</td><td> 1246</td>

<td> 1225</td><td> 1261</td>

<td> 1247</td><td> 1300</td>

<td> 1256</td><td> 1317</td>

<td> 1266</td><td> 1336</td>

<td> 1298</td><td> 1416</td>

<td> 1311</td><td> 1431</td>

<td> 1323</td><td> 1471</td>

<td> 1336</td><td> 1487</td>

<td> 1411</td><td> 1506</td>

<td> 1431</td><td> 1546</td>

<td> 1469</td><td> 1572</td>

<td> 1485</td><td> 1596</td>

<td> 1498</td><td> 1657</td>

<td> 1544</td><td> 1720</td>

<td> 1573</td><td> 3077</td>

<td> 1591</td><td> 3255</td>

<td> 1609</td><td> 3306</td>

<td> 1656</td><td> 3350</td>

<td> 1716</td><td> 3389</td>

<td> 3108</td><td></td>

<td> 3252</td><td></td>

<td> 3375</td><td></td>

Tab. 4: Raman spectroscopy

<td>Maksima p monohydrate</td><td>ków [cm^-1] Polymorph I</td>

<td> 85</td><td> 85</td>

<td> 116</td><td> 105</td>

<td> 146</td><td> 151</td>

<td> 176</td><td> 213</td>

<td> 186</td><td> 245</td>

<td> 228</td><td> 317</td>

<td> 241</td><td> 340</td>

<td> 281</td><td> 352</td>

<td> 318</td><td> 375</td>

<td> 356</td><td> 397</td>

<td> 385</td><td> 438</td>

<td> 443</td><td> 457</td>

<td> 541</td><td> 465</td>

<td> 564</td><td> 551</td>

<td> 649</td><td> 659</td>

<td> 661</td><td> 691</td>

<td> 698</td><td> 701</td>

<td> 750</td><td> 746</td>

<td> 793</td><td> 786</td>

<td> 807</td><td> 811</td>

<td> 844</td><td> 849</td>

<td> 861</td><td> 921</td>

<td> 920</td><td> 970</td>

<td> 997</td><td> 997</td>

<td> 1031</td><td> 1030</td>

<td> 1103</td><td> 1099</td>

<td> 1116</td><td> 1111</td>

<td> 1128</td><td> 1116</td>

<td> 1258</td><td> 1209</td>

<td> 1267</td><td> 1261</td>

<td> 1290</td><td> 1284</td>

<td> 1313</td><td> 1300</td>

<td> 1336</td><td> 1314</td>

<td> 1410</td><td> 1336</td>

<td> 1501</td><td> 1405</td>

<td> 1556</td><td> 1427</td>

<td> 1573</td><td> 1504</td>

<td> 1592</td><td> 1541</td>

<td> 1610</td><td> 1597</td>

<td> 1628</td><td> 1613</td>

<td> 1715</td><td> 1657</td>

<td> 2951</td><td> 1717</td>

<td> 3069</td><td> 2951</td>

<td> 3104</td><td> 3071</td>

<td></td><td> 3090</td>

Tab. 5: FIR spectroscopy

<td colspan="2">Peak maxima [cm^-1]</td>

<td>monohydrate</td><td>Polymorph I</td>

<td> 109</td><td> 99</td>

<td> 134</td><td> 117</td>

<td> 153</td><td> 155</td>

<td> 172</td><td> 166</td>

<td> 191</td><td> 187</td>

<td> 239</td><td> 207</td>

<td> 265</td><td> 217</td>

<td> 307</td><td> 231</td>

<td> 318</td><td> 241</td>

<td> 353</td><td> 263</td>

<td> 364</td><td> 297</td>

<td> 384</td><td> 306</td>

<td> 403</td><td> 318</td>

<td> 431</td><td> 329</td>

<td> 441</td><td> 341</td>

<td> 453</td><td> 367</td>

<td> 461</td><td> 375</td>

<td> 485</td><td> 396</td>

<td></td><td> 438</td>

<td></td><td> 454</td>

<td></td><td> 463</td>

Tab. 6: NIR spectroscopy

Peak maxima [cm^-1]

monohydrate

Polymorph I

<td> 4097</td><td> 4041</td>

<td> 4221</td><td> 4098</td>

<td> 4512</td><td> 4190</td>

<td> 4584</td><td> 4230</td>

<td> 4660</td><td> 4296</td>

<td> 4784</td><td> 4414</td>

<td> 4906</td><td> 4542</td>

<td> 5127</td><td> 4604</td>

<td> 6025</td><td> 4681</td>

<td> 6605</td><td> 4808</td>

<td></td><td> 4924</td>

<td></td><td> 6033</td>

<td></td><td> 6632</td>

<td></td><td> 8858</td>

Tab. 7: Spectroscopy ¹³Solid phase C-NMR

<td colspan="2">Peak maxima [ppm]</td><td rowspan="2"></td>

<td>monohydrate</td><td>Polymorph I</td>

<td> 28 110</td><td> 25 105</td><td></td>

(continued)

<td>Maksima p monohydrate</td><td>k [ppm] Polymorph I</td>

<td> 115</td><td> 112</td>

<td> 117</td><td> 116</td>

<td> 121</td><td> 121</td>

<td> 126</td><td> 125</td>

<td> 133</td><td> 127</td>

<td> 139</td><td> 131</td>

<td> 151</td><td> 139</td>

<td> 167</td><td> 149</td>

<td></td><td> 150</td>

<td></td><td> 152</td>

<td></td><td> 166</td>

Prepared and verified

Mirosława Ważyńska Patent attorney