Pharmaceutical composition comprising an omega-carboxyaryl substituted diphenyl urea for the treatment of cancer

2937881 wo 2006/094626 [61/112006/001574

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Pharmaceutical composition comprising an omega-carboxyaryl substituted diphenylurea for the treatment of cancer

٠ 01 3

This invention relates to novel pharmaceutical compositions and their use for treating hyperproliferative disorders such as cancer, either as a single agent or in combination with other cancer therapies, and to the process for their preparation.

Background of the invention

Diarylureas are a class of serine/threonine kinase inhibitors as well as tyrosine kinase inhibitors known in the art (Smith et al., Bioorg. Med. Chem. Lett. 010.. أع 2118,509-2115, ,ا Cancer Res. 2000, 6 (suppl.), 335, Lyons et al., Endocr.-Relat. Cancer 2001, 8, 219225, Lowinger et al., Curr. Pharm. Design 2002, 8, 99-110 ). Omega-carboxyaryl diphenylureas are disclosed in 000/42012 and WOOO/41698. In particular, it has been discovered that the diphenylurea of ​​formula (1),

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also referred to as BAY 43-9006 or 4-{4-[({f4-chloro-320 (trifluoromethyl)phenyl]amino}carbonyl)-amino]phenoxy}-A-methylpyridine

-2-carboxamide, and its pharmaceutically acceptable salts are effective inhibitors of raf, VEGFR-2, p38 and PDGFR kinases. These enzymes all represent molecular targets of interest for the treatment of hyperproliferative diseases, including cancer. Therefore, the compound of the formula (I) will be used as a medicine for the treatment of the above-mentioned diseases.

Despite the progress described in the art regarding kinase inhibitors, there is still a need for drugs for the treatment of cancer. In particular, there is still a need for improved oral pharmaceutical compositions which can be easily absorbed and which would thereby increase patient compliance. The oral pharmaceutical composition should provide a plasma concentration of the active agent which is sufficient to effect effective therapy. This depends on the solubility and release behavior of

MA 2937831 (/1012006/001574 wo 2006/094626! active agent. In the case of a solid pharmaceutical composition, the dissolution properties and the chemical and mechanical stability are important. In order to reinforce patient compliance, the oral pharmaceutical composition should not be taken more than three times a day, a lower number of doses being much better: and in the case of a tablet, the dimensions of the tablet should not be very large to allow good swallowing. The dimensions of a tablet depend on the amount of active agent needed for effective therapy and the amounts of excipients. The type and amount of excipients in combination with the method of preparation are essential for the release properties, the bioavailability of the compound in mammals, the stability and the industrial applicability of the method of manufacture of the pharmaceutical composition.

The object of the present invention is to provide a pharmaceutical composition containing the compound of formula (1) which should not be applied more than three times a day in order to achieve an effective plasma concentration of the compound of formula (I). In the case of a tablet or capsule as an oral pharmaceutical composition, they should not be very large in order to allow good swallowing and a maximum of two should be taken at the same time.

Description of the invention

The present invention relates to a pharmaceutical composition containing the compound of formula (I) in high concentration and at least one pharmaceutically acceptable excipient, to the use of the composition for the treatment of hyperproliferative diseases, such as cancer, either alone or in combination with other anti-cancer therapies, and the process for preparing said composition.

The pharmaceutical composition according to the invention surprisingly displays good bioavailability of the compound of formula (I), and effective plasma concentration is achieved. In addition, the pharmaceutical composition according to the invention ensures good stability of the compound of formula (I).

Although the tablets according to the invention have a high concentration of the compound of formula (I), they display surprisingly good release properties, good bioavailability, high stability and sufficient hardness. Since the pharmaceutical composition according to the invention contains a high concentration of the compound of formula (I), the dimensions of the composition can be made in such a way as to allow good swallowing of the composition. Therefore, the

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ملا pharmaceutical composition can be easily absorbed and supports high patient compliance.

The expression compound of formula (I), active agent or compound of this invention does not refer solely to the methylamide of the acid 4(4-[3-(45 chloro-3-fluoromethylphenyl)-ureido]-phenoxy}- pyridine-2-carboxylic acid, as illustrated in formula I, but also refers to its polymorphs, its solvates, its hydrates, its pharmaceutically acceptable salts, or a combination thereof.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid (tosylate salt), Lnaphthalenesulfonic acid, 215 naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts include salts of inorganic bases, such as salts containing alkaline cations (e.g., 11

Naou[), alkaline earth cations (e.g., Mg⁺², 021 or Ba⁺²), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those resulting from the protonation or peralkylation of triethylamine, Λ/ ,Ν-diethylamine, /,/7-1071011814111118, lysine, pyridine, TVjTV-dimethylaminopyridine (DIP), 1,4diazabïcydo[2.2.2]octane (DABCO), 1,5-013280171014.3.01-11011-5-819 (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

For purposes of the invention, solvates are those forms of compounds where the solvent molecules form a complex in the solid state and include, but are not limited to, for example, ethanol and methanol. Hydrates are a specific form of solvates, where the solvent molecule is water.

The β-toluenesulfonic acid salt of 4(4-(3-(4chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide (tosylate salt of compound (I) ) is preferably used in the pharmaceutical composition according to the invention Most preferably the β-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3trifluoromethylphenyl)-ureido] acid methylamide -phenoxy}-pyridine-2-carboxylic exists in at least 80% in the stable polymorph 1. Ideally the p40 toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoro acid methylamide)

MA 2937831

PCTEP2OO6/OO1574 wo 2006/094626 methylphenyl)-ureidoj-phenoxy}-pyridine-2-carboxylic exists in at least 80% in the stable polymorph 1 and in a micronized form.

The micronization can be carried out by usual grinding methods known to competent persons, preferably hot air grinding.

The micronized form can have an average particle size of 0.5 10 ة 11 preferably from 1 to 6 30, most preferably from 1 to 3 01. The particle size indicated is the average of the particle size distribution measured by laser diffraction known to competent persons ( measuring device: HELOS, Sympatec).

The process for the preparation of 4{4-[3-(4-Chloro-3-trifluoromethylphenyl)-ureido]phenoxy}-pyridine-2-carboxylic acid methylamide /-011510041149 salt and its polymorph 1 stable is described in patent applications EP 04023131.8 etEP 04023130.0.

The pharmaceutical composition of!^,invention contains the compound of formula (I) in a portion of at least 40%, preferably at least 45%, most preferably at least 50%, most preferably at least 55% by weight of the composition.

Preference is given to a pharmaceutical composition containing the o-toluenesulfonic acid salt of 4(4-[3-(420 chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2- carboxylic acid in a portion of at least 55%, preferably at least 62%, most preferably at least 69%, ideally at least 75% by weight of the composition.

The total amount of active ingredient (of compound of formula I) to be administered preferably orally using the pharmaceutical composition of the present invention will generally range from about 0.1 mg/kg to about 50 mg/kg of body weight. per day. Based on known standard laboratory techniques for evaluating compounds useful for the treatment of hyperproliferative disorders, passing standard toxicity tests and standard pharmacological assays for determining treatment of the above-identified conditions in mammals , and comparing these results to the results of known drugs that are used to treat these conditions, the effective dosage of the pharmaceutical compositions of this invention can be readily determined by those skilled in the art. The amount of active ingredient administered may vary widely depending on such considerations as the particular compound and dosage unit employed, mode and time of administration, duration of treatment, age, sex and medical condition. genera! of the patient being treated, the nature and severity of the condition being treated, drug metabolism and rate of excretion,

$293.78

WO 2006/094626 PCT/EP2006/001574 potential drug combinations and drug-drug interactions, and the like.

Preference is given to an amount of the compound of formula (I) in the pharmaceutical composition of 20 to 2000 mg, preferably 40,800 ة mg, most preferably 50 to 600 mg.

Particular preference is given to an amount of the ptoluenesulfonic acid salt of 4{4-[3-(4-chloro-3trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide in the composition pharmaceutical from 27 to 2740 mg, preferably from 54 to 1096, most preferably from 68 to 822 mg.

The pharmaceutical composition according to the invention is administered once or more, preferably up to three times, most preferably up to twice a day. Preference is given to oral administration. With each administration, the number of tablets or capsules taken at one time should not exceed two.

Nevertheless, it would sometimes be advantageous to deviate from the specified amounts, depending on the body weight, the individual behavior towards the active ingredient, the type of preparation and the time or interval during which the administration takes place. For example, sometimes quantities lower than the aforementioned minimum quantities are sufficient while at other times the specified upper limit must be exceeded. When administering relatively large amounts, it would be desirable to divide them into several individual doses spread over the day.

This pharmaceutical composition will be used to achieve the desired pharmacological effect, preferably by oral administration to a patient in need thereof, and will have advantageous properties with respect to drug release, bioavailability, and/or compliance. in mammals. For purposes of this invention, a patient is a mammal, including a human, who requires treatment for the particular condition or disease from which he suffers.

The pharmaceutical composition comprises suitable administration forms which deliver the compound of the invention in a rapid manner, for example tablets (uncoated or coated tablets), tablets which disintegrate rapidly in the oral cavity or capsules. optionally filled with granules (e.g. soft or hard gelatinous capsules), coated tablets, powders, sachets, granules, pellets, dragees, chewable tablets, dispersible tablets, troches and lozenges.

Preference is given to tablets, granules, capsules possibly filled with granules, pellets, dragees, tablets

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2937831

702006/094626 PCT / EP2OO6 / OO1574 chewable, dispersible tablets, trochisques and lozenges. Most preferably, the forms of application are tablets, granules and capsules optionally filled with granules. Ideally, the form of application is a tablet.

The tablet in accordance with the invention displays, for example, a hardness greater than 80 N, preferably greater than or equal to 100 N.

The pharmaceutical composition according to the invention, preferably a tablet or a capsule, has dimensions which allow good swallowing. Good swallowing also depends on the format used. For example, the longest dimension of an oval tablet or capsule is less than or equal to 25 mm. For example, a round tablet should have a diameter less than or equal to 8 13 mm.

The pharmaceutical composition according to the invention exhibits good release properties. Additionally, preference is given to dosage forms where the compound of the invention is delivered in a rapid manner, also known as immediate release dosage form. In accordance with the present invention, the immediate release dosage forms have a Q value (30 minutes) of 75% according to the USP release method with device 2 (paddle, 75 20 rpm, in HCl OIM + dodecylsulfate sodium 1%).

The pharmaceutical composition according to the invention is stable for more than 18 months.

A pharmaceutically acceptable excipient is any excipient that is relatively non-toxic and harmless to a patient at concentrations compatible with effective activity of the active ingredient such that any side effects attributable to the excipient do not interfere with the beneficial effects of active ingredient.

Examples of pharmaceutically acceptable excipients in accordance with the invention are disintegrants, binders, lubricants, fillers, plasticizers, surfactants and wetting agents, film formers and coating materials, and colorants e.g. pigments.

Disintegrants include, but are not limited to, croscarmellose sodium, crospovidone, alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, polacrilin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate, partially hydrolyzed starch, sodium carboxymethyl starch and starch. Preference is given to croscarmellose sodium and/or cross-linked polyvinylpyrrolidone, particular preference is given to croscarmellose sodium.

MA 2937881 ا — PCT/EP2OO6/OO1574

The amount of disintegrant contained in the pharmaceutical composition ؛ can be 0 to 15%, preferably 5 to 12%, of the total weight of the composition.

ا Binders include but are not limited to hydroxypropyl cellulose, ؛ hypromellose (hydroxypropyl methylcellulose, HPMC), microcrystalline cellulose, acacia, alginic acid, carboxymethylcellulose, ا methylcellulose, hydroxyethylcellulose,: ethylhydroxyethylcellulose, polyvinyl alcohol, polyacrylates, calcium carboxymethylcellulose, sodium carboxymethylcellulose, compressible sugar, 111101111050, gelatin, liquid glucose, methylcellulose, polyvinylpyrrolidone and pregelatinized starch. Preference is given to a hydrophilic binder which is soluble in the granulation liquid, particular preference is given to hypromellose (hydroxypropyl methylcellulose, HPMC) and/or polyvinylpyrrolidone, preference is ideally given to hypromellose .

The quantity of binder contained in the pharmaceutical composition can be from 0 to 15%, preferably from 0.5 to 8%, of the total weight of the composition.

Lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate, and polyethylene glycol. Preference is given to magnesium stearate.

The quantity of lubricant contained in the pharmaceutical composition can be from 0 to 2%, preferably from 0.2 to 0.8%, of the total weight of the composition.

Fillers include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, silicated microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose, for example the anhydrous form or the hydrated form such as the monohydrated form, dextrose, maltose, sucrose, glucose, fructose or maltodextrin, cellulose powder, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. Preference is given to microcrystalline cellulose, mannitol, lactose and/or dicalcium phosphate, particular preference is given to microcrystalline cellulose.

The amount of filler contained in the pharmaceutical composition can be from 0 to 60%, preferably from 3 to 20%, of the total weight of the composition.

Surfactants and wetting agents include, but are not limited to, 11031330041171808 oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, 0017011171118 stearate,

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ما 100170111118 sorbitan monolaurate, benzalkonium chloride, nonoxynol 10, Foxtoxynol 9, polysorbates e.g. 20, 40, 60 or 80, sorbitan monopalmitate, sodium salts of fatty alcohol sulfates such as sodium lauryl sulfate, sodium dodecyl sulfate, sodium salts of sulfosuccinates such as sodium dioctylsulfosuccinate, partial esters of fatty acids with alcohols such as glycerol monostearate, partial esters of fatty acids with sorbitans such as sorbitan monolaurate, partial esters of fatty acids with polyhydroxyethylene sorbitans such as polyethyleneglycol sorbitan monolaurate, polyethyleneglycol sorbitan monostearate or polyethyleneglycol sorbitan monooleate, alcohol ethers fatty acids with polyhydroxyethylene, esters of fatty acids with polyhydroxyethylene, 41111000 and propylene oxide (Pluronic®) copolymers and ethoxylated triglycerides. Preference is given to sodium lauryl sulfate.

The amount of surfactant contained in the pharmaceutical composition can be from 0 to 5%, preferably from 0.1 to 2%, of the total weight of the composition.

Film formers and coating materials include, but are not limited to, liquid glucose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (Phypromellose, HPMC), methylcellulose,

Ethylcellulose, cellulose acetate phthalate, shellac, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate such as Kollidon® VA64 BASF, copolymers of esters of acrylic and/or methacrylic acid with trimethylammonium methylacrylate, copolymers of dimethylaminomethacrylic acid and esters methacrylic acid neutrals, polymers of methacrylic acid or methacrylic acid esters, copolymers of ethyl ester of acrylic acid and methyl ester of acrylic acid, and copolymers of acrylic acid and methyl ester of acrylic acid. Preference is given to hydroxypropyl methylcellulose (Phypromellose, HPMC) as film forming agent.

Plasticizers include, but are not limited to, polyethylene glycol, diethyl phthalate, and glycerol. Preference is given to polyethylene glycol.

Dyes include but are not limited to pigments, inorganic pigments, 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, Iron Oxide Red, Iron Oxide Yellow, and Titanium Dioxide. Preference is given to red iron oxide, yellow iron oxide and titanium dioxide.

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Other commonly employed pharmaceutical excipients which may be: used as appropriate to formulate the composition for its intended route of administration include, but are not limited to: acidifying agents e.g. acetic acid, citric acid , fumaric acid, hydrochloric acid and nitric acid: alkalizing agents, for example: ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine and trolamine: adsorbents, for example powdered cellulose and activated carbon: stabilizers and antioxidants eg ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulphite, formaldehyde sodium sulfoxylate and sodium metabisulphite: other binders for example block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrenebutadiene copolymers; buffering agents for example potassium metaphosphate, dipotassium phosphate, sodium acetate, anhydrous sodium citrate and hydrated sodium citrate ؟ encapsulants eg gelatin, starch and cellulose derivatives, flavoring agents, odor maskers eg anise oil, cinnamon oil, cocoa, menthol, orange essential oil, peppermint essence and vanillin: humectants, for example glycerol, propylene glycol and sorbitol: sweeteners for example aspartame, dextrose, glycerol, mannitol, propylene glycol, sodium saccharin, sorbitol and sucrose: anti-adherents by example magnesium stearate and talc: direct compression excipients eg dicalcium phosphate, lactose and microcrystalline cellulose • tablet polishing substances eg carnauba wax and white wax.

Preference is given to a pharmaceutical composition containing the compound of formula (1) in a portion of at least 40%, a filler in a portion of 0 to 60%, a disintegrant in a portion of 0 to 15%, a binder in one portion of 0 to 15%, a lubricant in a portion of 0 to 2% and a surfactant in a portion of 0 to 5% by weight of the composition.

Preference is also given to a pharmaceutical composition containing the j-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2carboxylic acid methylamide in a portion of at least 55%, microcrystalline cellulose as filler in a portion of 0-60%, croscarmellose sodium as 40 disintegrant in a portion of 0-15%, Phypromellose as a binder in a portion of 0-15%, magnesium stearate as a lubricant in one serving

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IA from 0 to 2% and sodium lauryl sulfate as a surfactant in a portion of 0 to 5% by weight of the composition.

Particular preference is given to a pharmaceutical composition containing the compound of formula (I) in a portion of at least 55%, a filler in a portion of 3 to 20%, a disintegrant in a portion of 5 to 12%, a binder in one portion from 0.5 to 8%, a lubricant in one portion from 0.2 to 0.8% and a surfactant in one portion from 0.1 to 2% by weight of the composition.

Particular preference is also given to a pharmaceutical composition containing the β-toluenesulfonic acid salt of 4(4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]0110)-0 methylamide. /1111108-2-010011911 in one portion at least 75%, microcrystalline cellulose as filler in one portion 3-20%, croscarmellose sodium as disintegrant in one portion 5-12%, Phypromellose as binder in one portion from 0.5 to 8%, magnesium stearate as lubricant in one portion of 0.2 to 8% and sodium lauryl sulfate as surfactant in one portion of 0.1 to 2% by weight of the composition.

The pharmaceutical composition in accordance with the invention comprises water in an amount less than or equal to 6%, preferably less than or equal to 3%, most preferably less than or equal to 1.5% by weight of the composition. The water content of the composition is determined by the Karl-Fischer method which is known to competent persons.

Manufacturing process

The present invention also relates to a process for the manufacture of a solid and oral pharmaceutical composition in accordance with the invention, wherein the compound of formula (I) is mixed with at least one pharmaceutically acceptable excipient.

Preference is given to a method of making a solid, oral pharmaceutical composition in accordance with the invention, wherein

a) the compound of formula (I) and at least one pharmaceutically acceptable excipient are wet granulated,

b) the granule is mixed with the lubricant and optionally with one or more other pharmaceutically acceptable excipients,

c) the post-mix granule is subdivided into unit doses,

d) and the product of step c) is optionally coated with one or more other pharmaceutically acceptable excipients.

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Step a: Wet granulation

The compound of formula (I), the filler, preferably microcrystalline cellulose, the binder, preferably Phypromellose, the wetting agent, preferably sodium lauryl sulphate and optionally the disintegrant, preferably croscarmellose sodium, are granulated in the liquid. granulation by a wet granulation process. The granulation process ends when the granulate achieves a “snowball consistency”. The mass of the wet granulation is optionally sized and then dried in a suitable device for example in a fluidized bed dryer at an admitted air temperature within the range of 50 to 12000, preferably 80 to 100°C, until to obtain a residual humidity of less than or equal to 3%, preferably less than or equal to 1.5% (loss on drying). The dry granules are optionally sieved, for example using a 1 to 2 mm sieve.

The wet granulation process can be carried out in a high shear mixer or in a fluidized bed granulator, preferably in a high shear mixer for wet granulation. The compound of formula (1) may be initially charged as a solid to the vessel or it is dissolved and/or suspended in the granulation liquid.

Preference is given to a wet granulation process where the wetting agent is first dissolved in the granulation liquid, then the mixture containing the compound of formula (I), the filler, the binder and a portion of the disintegrant is added . The mixture is mixed before granulation for 1 to 10 minutes, preferably for 1 to 5 minutes.

Alternatively, the wetting agent can be added to the dry mix and/or the binder can be dissolved and/or suspended in the granulation liquid.

In the wet granulation process, the amount of granulation liquid is preferably 40 to 70%, most preferably 50 to 60%, by weight of the dry powder mixture.

Preferably, the compound of formula (I) is used in a crystalline form, very preferably in a micronized form. The micronized form can have an average particle size of 0.5 10 ة pm, preferably 1 to 6 pm, most preferably beyond 3 pm.

The mass of the wet granulation is preferably sized by means of a grater from 2 to 8 mm, preferably from 4 to 6 mm.

Solvents such as granulating liquids and film-coating liquids include, but are not limited to, ethanol, acetone, glycerol, isopropanol, purified water, and mixtures thereof. Preferably, the liquids of

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2937831 wo 2006/094626 PCT/EP2006/001574 granulation are purified water, ethanol, acetone or mixtures thereof, most preferably purified water.

Preference is given to a process for the manufacture of a solid, oral pharmaceutical composition according to the invention, in which the disintegrant 5 is partly used in the granulation process described under a) and in the mixing process described under b) . Most preferably, an amount of the disintegrant representing 3 to 6% of the total weight of the composition is used in step a) and the remainder is used in step b).

Step b: Mixing

The granulate is mixed with the lubricant, preferably magnesium stearate, and with the rest of the disintegrant, preferably croscarmellose sodium, by means of a suitable device, for example a drum mixer, for 5 to 10 minutes.

Step c: Subdivision/Compression of the tablet

The mixture is subdivided into unit doses and further processed into the desired form of administration known to those skilled in the art, for example by filling into sachets or capsules. One or more additional pharmaceutically acceptable excipients are optionally added. Preferably, the mixture is subdivided into unit doses and compressed into tablets using, for example, a standard rotary tablet press at typical compression speeds of 25,000-250,000 tablets/hour.

Step d: Lamination

The product of step c) is coated with one or more additional pharmaceutically acceptable excipients.

Preference is given to a process for the manufacture of a solid and oral pharmaceutical composition according to the invention, where the additional pharmaceutically acceptable excipient or excipients are selected from the group of plasticizers, film formers and colorants. The plasticizer, preferably polyethylene glycol, the film-forming agent, preferably hypromellose and the colorants, preferably red and/or yellow iron oxide, are combined with film-coating liquids, preferably water. purified, to produce a homogeneous coating suspension which is carried, preferably atomized, on the product of step c), preferably on the tablets in a suitable coating device for example a drum coating device perforated. Other water-soluble pigments or dyes or combinations thereof can be used to modify the color of the coating.

MA 2937831 wo 2006/094626 PCT/EP2OO6/OO1574

Alternative methods of manufacturing a solid and oral pharmaceutical composition in accordance with the invention are:

. The compound of formula (I) and at least one pharmaceutically acceptable excipient are mixed without granulation and compressed directly into tablets or filled into capsules or sachets. Other excipients can be used to produce the formulation. The product may optionally be coated with one or more other pharmaceutically acceptable excipients.

The compound of formula (I) alone or the compound of formula (I) and at least one pharmaceutically acceptable excipient are processed by a dry granulation method and then formed into tablets or filled into capsules or sachets. Other excipients can be used in the formulation.

Optionally, the product can be coated with one or more other pharmaceutically acceptable excipients.

Method of treating hyperproliferative disorders

The present invention also relates to a method of using the pharmaceutical composition according to the invention to treat hyperproliferative disorders in mammals, including cancer. This method involves administering the pharmaceutical composition, preferably orally, to a mammal in need thereof, including a human, in an amount effective to treat the disorder. The term hyperproliferative disorders and/or cancer does not only refer to solid tumors, such as cancers of the breast, respiratory tract, brain, genitals, digestive tract, urinary tract, eyes, liver, skin , head and neck, thyroid, parathyroid and their distant metastases, but also includes lymphomas, sarcomas and leukaemias.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of airway cancer include, but are not limited to, small cell lung carcinoma and non-small cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to, brainstem and hypothalamic glioma, cerebellar and cerebral fastrocytoma, medulloblastoma, pependymoma, as well as neuroectodermal tumors and tumors of the pineal region.

MA 2937831 wo 2006/094626 PCT/EP2OO6/OO1574

Male genital tumors include, but are not limited to, prostate and testicular cancer. Female genital tumors include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as uterine sarcoma.

Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small intestine, and salivary gland cancer.

Urinary tract tumors include, but are not limited to, cancers of the bladder, penis, kidney, renal pelvis, ureter, and urethra.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer include, but are not limited to, primary liver cancer (hepatocellular carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell carcinoma, and non-melanoma skin cancer.

Head and neck cancers include, but are not limited to, laryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and cancer of the lip and oral cavity.

Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and central nervous system lymphoma.

Sarcomas include, but are not limited to, soft tissue sarcoma, fibrosarcoma, osteosarcoma, malignant histiocytofibroma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoid leukemia, chronic myelogenous leukemia, hairy cell leukemia.

These disorders are well characterized in humans, but they also exist with a similar etiology in other mammals, and can be treated by administering the pharmaceutical compositions of the present invention. For purposes of this invention, a patient is a mammal, including a human being, in need of treatment for the particular condition or disease from which he suffers.

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Combination therapy

The pharmaceutical compositions of this invention can be administered as a single agent or in combination with one or more other therapies where the combination produces no unacceptable side effects. For example, they may be combined with cytotoxic agents, signal transduction inhibitors, or with other anticancer agents or anticancer therapies, as well as mixtures and combinations thereof.

In one embodiment, the pharmaceutical compositions of the present invention can be combined with cytotoxic anticancer agents. Examples of such agents can be found in the 111 edition of the Merck Index (1996). These agents include, but are not limited to, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, aetoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin c, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine and vindesine.

Other cytotoxic drugs suitable for use with the pharmaceutical compositions of the invention include, but are not limited to, compounds whose use in the treatment of neoplastic diseases is recognized in Goodman and Gilman's The Pharmacological Basis of Therapeutics (ninth edition, 1996, McGraw Hill). These agents include, but are not limited to, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel,

Ethinylestradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, pidarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan , mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, Puridine and vinorelbine.

Other cytotoxic anticancer agents suitable for use in combination with the compositions of the invention also include newly discovered cytotoxic active ingredients such as oxaliplatin, gemcitabine, capecitabine, 10011110118 and its natural or synthetic derivatives, temozolomide ( Quinn et al., J. Clin. Oncology 2003, 21(4),

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646-651), tositumomab (Bexxar), trabedectin (Vidal and Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3181), and Eg5 spindle kinesin protein inhibitors (Wood et al., Curr. Opin. Pharmacol. 2001, 1, 370-377).

In another embodiment, the pharmaceutical compositions of the present invention may be combined with other signal transduction inhibitors. Signal transduction inhibitors that target the EGFR family, such as EGFR, HER-2 and HER4 (Raymond et al., Drugs 2000, 60 (Suppl.1), 15-23: Harari et al., Oncogene 2000, 19 (53), 610210 6114), and their respective ligands are of particular importance. Examples of such agents include, but are not limited to, antibody therapies such as Herceptin (trastuzumab), Erbitux (cetuximab), and pertuzumab. Examples of such therapies also include, but are not limited to, small molecule kinase inhibitors such as ZD15 1839/Iressa (Baselga et al., Drugs 2000, 60 (Suppl.1), 33-40), OSI -774 /

Tarceva (Pollack et al. L Pharm. Exp. Ther. 1999, 291(2), 739-748), 01-1033 (Bridges, Curr. Med. Chem. 1999, 6, 825-843), GW-2O16 ( Lackey et al., 922 AACR Meeting, New Orleans, March 24-28, 2001, abstract 4582), CP724,714 (Jani et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3122), ΗΚΙ- 272 (Rabindran et al. Cancer Res.

2004, 64, 3958-3965) and ΕΚΒ-569 (Greenberger et al., 111 NCLEORTCAACR Symposium on New Drugs in Cancer Therapy, Amsterdam, November 7-10, 2000, abstract 388).

In another embodiment, the pharmaceutical compositions of the present invention may be combined with other signal transduction inhibitors targeting receptor kinases of split-domain families (VEGFR, FGFR, PDGFR, flt-3, c- kit, c-fms and the like), and their respective ligands. These agents include, but are not limited to, antibodies like Avastine (bevacizumab). These agents also include, but are not limited to, small molecule inhibitors such as STI-571/Gleevec (Zvelebil, Curr. Opin. Oncol., Endocr. Metab. Invest. Drugs 2000, 2(1), 74- 82), ΡΤΚ-787 (Wood et al.. Cancer Res. 2000, 60(8), 2178-2189), SU-H248 (Demetri et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3001 ), ZD-6474 (Hennequin et al., 922 AACR Meeting, New Orleans, March 24-28, 2001, abstract 3152), AG13736 (Herbst et al. Clin. Cancer Res. 2003, 9, 16 (suppl 1), abstract 0253), KRN-951 (Taguchi et al., 955 AACR Meeting, Orlando, FL, 2004, abstract 2575), CP-547,632 (Beebe et al., Cancer Res. 2003 , 63, 7301-7309), CP673,451 (Roberts et al., Proceedings of the American Association of Cancer Research 2004, 45, abstract 3989), CHIR-258 (Lee et al., Proceedings of the

American Association of Cancer Research 2004, 45, abstract 2130), MLN-518

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)940:) امرلاها) abbreviated 4539).

In another embodiment, the pharmaceutical compositions of the present invention may be combined with inhibitors of the ÜSH pathway Leopoid et al., Proceedings of the American Association of Cancer Research

2004, 45, abstract 4003), and ARRY-142886 (Wallace et al., Proceedings of the

American Association of Cancer Research 2004, 45, abstract 3891).

In another embodiment, the pharmaceutical compositions of the present invention can be combined with rhistone deacetylase inhibitors. Examples of such agents include, but are not limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology 2004.23: abstract 3024)7 LBH-589 ( Beck et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3025), MS-275 (Ryanet al. Proceedings of the American Association of Cancer Research 2004, 45, abstract 2452), and

FR-9O1228 (Piekarz et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3028).

In another embodiment, the pharmaceutical compositions of the present invention can be combined with other anticancer agents such as proteasome inhibitors, and m-TOR inhibitors. These include, but are not limited to, bortezomib (Mackay et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3109), and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research 2004, 45, abstract 3849).

In general, the use of cytotoxic and/or cytostatic anticancer agents in combination with the pharmaceutical compositions of the present invention will serve to:

(1) provide greater efficacy in reducing the growth of a tumor or even eliminating the tumor compared to the administration of one of the agents alone, (2) allowing the administration of lower quantities of the agents administered, (3) result in a chemotherapeutic treatment protocol that is well tolerated by the patient with fewer deleterious pharmacological complications than seen with single-agent chemotherapies and some other combination therapies,

MA 2937831 wo 2006/094026 101/112006/001574 (4) to provide treatment for a wider spectrum of different types of cancer in mammals, especially humans, (5) to provide a higher rate of response in patients treated, (6) provide longer survival time among treated patients compared to standard chemotherapy treatments, (7) provide longer time for tumor progression, and/or (8) produce efficacy and tolerability results at least as good as those of agents used alone, compared to known cases where other combinations of anticancer agents produce antagonistic effects. It is believed that a person skilled in Part can, by using the foregoing information and the information available in Part, take full advantage of the present invention.

It should be apparent to persons of ordinary skill in the art that changes and modifications may be made to this invention without departing from the spirit or scope of the invention as set forth herein.

All publications, applications and patents cited above and below are incorporated herein by reference.

Data relating to weight are, unless otherwise indicated, percentages by weight and parts are parts by weight.

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Examples:

Example 1: Immediate release tablet containing the tosylate salt of the compound of formula (I) and optionally a subsequent coating

1.1.1 Composition of tablets containing the 0-toluenesulfonic acid salt of 4(4-13-(4-0100-3trifluoromethylphenyl)-ureido٦-phenoxy}-pyridine-2-carboxylic acid methylamide (tosylate salt of the compound ( I))

<td>Composition [mgZtablet]</td><td>tablet A 50 mg</td><td>tablet B 200mg</td><td>tablet c 200mg</td><td>tablet D 400mg</td>

<td>Drowned in tablet:</td><td>step a), b)</td><td>step a), b), c) ii</td><td>step a), b), c) i</td><td>step a), b), c) i</td>

<td>Tosylate salt of compound (1) micronised</td><td>68.5mg</td><td>274.0mg</td><td>274.0mg</td><td>548.0mg</td>

<td>microcrystalline cellulose</td><td>4.0mg</td><td>16.0mg</td><td>16.0mg</td><td>32.0mg</td>

<td>Croscarmellose sodium</td><td>9.1mg</td><td>36.4mg</td><td>36.4mg</td><td>72.8mg</td>

<td>Hypromellose (5 cP)</td><td>2.55mg</td><td>10.2mg</td><td>10.2mg</td><td>20.4mg</td>

<td>Magnesium Stearate</td><td>0.425mg</td><td>1.7mg</td><td>2.55 [9 (1.70 - 2.55mg)</td><td>5.10mg</td>

<td>Sodium lauryl sulfate</td><td>0.425mg</td><td>1.7mg</td><td>1.7mg</td><td>3.4mg</td>

<td>Weight</td><td>85.0mg</td><td>340.0mg</td><td>340.85mg (340.0 - 340.85mg)</td><td>681.70mg</td>

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

<td>lamination ؟</td><td></td><td></td><td></td><td> --------2</td>

<td>Opadry Red YS2-15531</td><td> —</td><td>10.0mg</td><td></td><td></td>

<td>Hypromellose (15 cP)</td><td> —</td><td> -----</td><td>6.00mg (4.8-7.2mg)</td><td>9.0mg (7.2-10.8mg)</td>

<td>Macrogol 3350 (polyethylene glycol)</td><td> —</td><td> —</td><td>2.00mg (1.6-2.4mg)</td><td>3.0mg (2.4-3.6mg)</td>

<td>Titanium dioxide</td><td> —</td><td> —</td><td>1.73mg (1384-207618)</td><td>1.6mg (1.28-1.92mg)</td>

<td>Iron oxide (red)</td><td> —</td><td> —</td><td>0.27mg (0.216-0.3241119)</td><td></td>

<td>Iron oxide (yellow)</td><td> .....</td><td> —</td><td> —</td><td>1.4mg (1.12-1.68mg)</td>

<td>Lamination weight</td><td> —</td><td>10.0mg</td><td>10.0mg (8.0-12.0mg)</td><td>15.0mg (12.0-18.0mg)</td>

<td>Total tablet weight</td><td>85.0mg</td><td>350.0mg</td><td>350.85mg (348 - 352.85mg)</td><td>696.7mg (348.0 - 352.85mg)</td>

<td>Tablet size</td><td>round</td><td>round</td><td>round</td><td>oval</td>

<td>Tablet dimensions</td><td>diameter: 6mm</td><td>diameter: 10 mm height: 4.5 (0.3)mm</td><td>diameter: 10 mm height 0.3±) 4.5 ا) mm</td><td>length: 18 mm, width 8 mm</td>

^#1 magnesium stearate margin may apply depending on manufacturing conditions film coating margin may apply depending on manufacturing conditions - fixed rate of film coating components: 60% hypromellose - 20% polyethylene glycol 17.3% titanium dioxide - 2.7% iron oxide “Opadry Red YS-15531 commercial ready-to-use embedding system.

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1.2 Manufacturing process

Step a) Granulation

4{4-[3-(4-Chloro3-trifluoromethylphenyl)ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide (tosylate salt of micronized compound (1), microcrystalline cellulose, croscarmellose sodium, and phypromellose are mixed for 2 minutes in a high shear mixer in order to obtain a powdered mixture. Sodium lauryl sulfate is dissolved in water. The powder mixture is granulated with the solution in a wet granulation process using a high shear mixer. The granulation process is complete when the granulate achieves a snowball consistency. The wet granulation mass is sized using a 4 mm grater and then dried in a fluid bed dryer at an inlet air temperature of 80 - 100 ٥C until a residual moisture of 0.3 up to 0.7% by weight (loss on drying). The dry granules are sieved using a 2 mm sieve.

Step b) Compression into tablets

The granulate is mixed with the magnesium stearate and the croscarmellose sodium using a tumbler mixer for 5-10 minutes. The mixture is subdivided into unit doses and compressed into tablets using a standard rotary tablet press at typical compression speeds of 25,000 to 250,000 tablets/hour.

Step c) Lamination

Alternative i:

Hypromellose, polyethylene glycol (Macrogol), titanium dioxide and red iron oxide are combined with purified water to produce a homogeneous film-coating suspension which is spray-dried onto the tablets in a perforated drum coater.

Alternate ii.

Commercially available Opadry Red YS-15531 is combined with purified water to produce a homogeneous film-coating suspension which is spray-dried onto tablets in a perforated drum coater.

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1.3 Properties of tablets

Table 1: Study of the release of the compound of formula (1) from tablets B and c

Release of the compound of formula (I) in% of the total weight of the composition.

<td></td><td>15 minutes</td><td>30 minutes</td><td>45 minutes</td><td>60 minutes</td>

<td>Tablet B</td><td> 94</td><td> 97</td><td> 97</td><td> 97</td>

<td>Tablet c</td><td> 96</td><td> 99</td><td> 99</td><td> 99</td>

Each value represents the average of 6 individual results. Apparatus USP 2, 900 ml of 0.1 N HCl ا 1% sodium lauryl sulphate, 100 rpm

The tablets have a stability that lasts for more than 18 months (real-time stability data) and a hardness that exceeds 100 N.

The water content of the tablets is less than 1.5% by weight of the composition (determination: Karl-Fischer method)

2]