WO2017216025A1 - Mps-1 inhibitors - Google Patents

Mps-1 inhibitors Download PDF

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Publication number
WO2017216025A1
WO2017216025A1 PCT/EP2017/063927 EP2017063927W WO2017216025A1 WO 2017216025 A1 WO2017216025 A1 WO 2017216025A1 EP 2017063927 W EP2017063927 W EP 2017063927W WO 2017216025 A1 WO2017216025 A1 WO 2017216025A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
fluorophenyl
methoxy
methylsulfonyl
triazolo
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PCT/EP2017/063927
Other languages
French (fr)
Inventor
Holger Paulsen
Lars BOEHMER
Guido Becker
Thomas Zöller
Donald Bierer
Britta Olenik
Sylvia Dworacek
Uwe Muenster
Sven Stein
Wiebke HOLKENJANS
Frank HUCKE
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Bayer Pharma Aktiengesellschaft
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Publication of WO2017216025A1 publication Critical patent/WO2017216025A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention covers crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2- methoxy ⁇ -imethylsulfonyljphenyllaminojll ⁇ ltriazololl ⁇ -olpyridin-e-yljphenyllpropan- amide 4-toluenesulfonate, and crystalline (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulfonate monohydrate, as compounds per se, a method of preparing said crystalline, anhydrous compound, pharmaceutical compsitions and pharmaceutical combinations comprising said crystalline, anhydrous compound, and uses of said crystalline, anhydrous compound in the treatment or prophyl
  • (2R)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]- amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide is known to be a very potent inhibitor of Mps-1 kinase.
  • WO 2013/087579 Al discloses the compound, data showing its pharmaceutical activity, and a method for the preparation of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide.
  • WO 2014/009219 Al discloses an improved method for the preparation of (2/?)-2-(4- fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5- a]pyridin-6-yl)phenyl]propan-amide.
  • WO 2014/195408 Al discloses pharmaceutical compositions comprising (2 ?)-2-(4- fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5- a]pyridin-6-yl)phenyl]propan-amide mainly in amorphous form.
  • One important property of a pharmaceutical compound is its relative bioavailability. Different salts and crystalline forms of the same pharmaceutical compound can and reportedly do have different relative bioavailabilities.
  • the discovery of new pharmaceutically acceptable salts and crystalline forms of a pharmaceutical useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
  • the stability of the pharmaceutical compound as well as of the pharmaceutical formulation containing said compound is an important property, too.
  • the drug load capacity is an important property as well.
  • the maximum size of a tablet or capsule, in particular gel capsule is limited by the ability of a patient swallowing the tablet or capsule. If the drug load capacity is low, more than one tablet has to be taken by the patient. The aim is to keep the quantity of tablets to be taken by a patient low.
  • the present invention thus covers crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]- amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate, of formula (I) :
  • the present invention covers said crystalline, anhydrous (2R)-2-(4-fluorophenyl)-A/-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)- phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate, characterized in that it has XRPD peaks [°2 ⁇ ] (Copper (Cu)) of about 5.4, 15.6, 16.5, 20.0, 24.4, 24.5 and 25.0.
  • the present invention covers said crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)- phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate, characterized in that it has XRPD peaks [°2 ⁇ ] (Copper (Cu)) as given in the Experimental Section, Example 2, herein.
  • This crystalline form of the anhydrous tosylate salt of the present invention shows a high relative oral bioavailability. This is surprising because the solubility of the anhydrous tosylate salt of the present invention in water and acidic aqueous solutions was similar to the water-solubility of the free base (2/?)-2-(4-fluorophenyl)-/V-[4-(2 [2-methoxy-4-(methylsulfonyl)phenyl]- amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide and of the monohydrate of the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-A/-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)- phenyl]amino ⁇ [l,2,4]triazolo[l,5-a] pyridin-6-yl)phenyl
  • the present invention covers a method of preparing crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)- phenyl]amino ⁇ [l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide 4-toluenesulphonate as defined in the claims, said method comprising the steps of : a) providing a suspension of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]prop- anamide in a suspension agent, said suspension agent containing less than 2 vol.-% water; b) optionally heating the suspension to a temperature
  • step a) a suspension of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)- phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide, and p-toluenesulfonic acid in a suspension agent is provided.
  • (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]- amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide can be prepared as described in WO 2013/087579 Al or WO 2014/009219 Al.
  • p-Toluenesulfonic acid is commercially available.
  • p-Toluenesulfonic acid can be used in its anhydrous form (CAS registry number 104-15-4).
  • p- toluenesulfonic acid can also be used in form of its monohydrate (CAS registry number 6192- 52-5). Mixtures containing the anhydrous form and the monohydrate of p-toluenesulfonic acid can be used as well.
  • p-toluenesulfonic acid will be used in form of its monohydrate (CAS registry number 6192-52-5).
  • said p-toluenesulfonic acid is p- toluenesulfonic acid monohydrate.
  • An overstoichiometric amount of p-toluenesulfonic acid may be used: for each mole of (2/?)- 2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5- o]pyridin-6-yl)phenyl]propanamide, 1.05 to 1.5 moles of p-toluenesulfonic acid or p- toluenesulfonic acid hydrate (1:1) are used; more preferably, 1.1 to 1.3 moles are used.
  • Suitable suspension agents are for example acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (M I BK), tetrahydrofuran (TH F), mixtures of said agents or the like.
  • said p-toluenesulfonic acid is added in solution in a solvent, said solvent being said suspension agent.
  • said suspension agent is acetone, methyl ethyl ketone (M EK), methyl isobutyl ketone ( MI BK), tetrahydrofuran (TH F), or a mixture thereof.
  • said suspension agent is a ketone such as acetone, M EK or M I BK, or mixtures thereof; more prefera bly, the suspension agent is M EK.
  • the suspension agent might contain water. The content of water should be below 2% by weight.
  • the amount of the suspension agent is usually in the range from 10 moles to 200 moles for each mole of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]- amino ⁇ [l,2,4]-triazolo[l,5-a] pyridin-6-yl)phenyl] propanamide, prefera bly in the range of 30 to 150 moles for each mole of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyl]amino ⁇ [l,2,4]-triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide, more prefera bly in the range of 50 to 100 moles for each mole of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-
  • the boiling point under normal conditions of M E K is 79.64 °C. So, when M EK is used as the suspension agent, the suspension preferably is heated to a temperature between 64.64 °C and 79.64 °C.
  • the boiling point under normal conditions of acetone is 56 °C. So, when acetone is used as the suspension agent, the suspension preferably is heated to a temperature between 41°C and 56 °C.
  • step c p-toluenesulfonic acid is added.
  • p-toluenesulfonic acid can be used in its anhydrous form, as the monohydrate or as a mixture of the anhydrous form and the monohydrate.
  • all said forms shall be included when referring to p-toluenesulfonic acid hereinafter.
  • p-toluenesulfonic acid is added in form of a solution.
  • the solvent used for solving p-toluenesulfonic acid is the same as the suspension agent.
  • p-toluenesulfonic acid is added in portions.
  • the total amount of p-toluenesulfonic acid is added to the suspension in form of two to five portions; more preferably in form of two or three portions.
  • p-toluenesulfonic acid is added to the heated suspension obtained after step b).
  • the crystallization seed is a crystal of the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4- (2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide having the crystal form as shown in Fig. 2.
  • step c) is divided into the following sub-steps cl), c2), and c3): cl) adding a portion of p-toluenesulfonic acid to the suspension obtained from step b); c2) adding one or more crystallization seeds to the suspension obtained from step c2); c3) repeating step cl) and/or step c2) one or more times until the total amount of p- toluenesulfonic acid is added.
  • the total amount of p-toluenesulfonic acid is the stoichiometric or overstoichiometric amount of p-toluenesulfonic acid which is used for the transformation of 2-(4-fluorophenyl)- /V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-o]pyridin-6- yl)phenyl]propanamide into the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide.
  • the total amount of p-toluenesulfonic acid is in the range of 1 to 1.5 moles per mole of 2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]- amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide.
  • the total amount of p-toluenesulfonic acid is added in two to five portions, more preferably in two or three portions, separated by the addition of one or more crystallization seeds.
  • steps cl), c2) and c3) are replaced by steps cl), c2), c3), c4), and c5):
  • the suspension is stirred after each sub-step.
  • the suspension is stirred the whole time during the sub-steps.
  • step d) the suspension obtained from step c) is stirred, preferably at a temperature between (TB - 15 K) and TB; wherein TB is the boiling point of the suspension agent under normal conditions.
  • TB is the boiling point of the suspension agent under normal conditions.
  • step d) the transformation of 2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide into the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide takes place (salt formation).
  • the solubility of the 4-toluenesulfonate salt in the suspension agent is different from the solubility of the free base in the suspension agent.
  • the solubility of the 4-toluenesulfonate salt is lower than the solubility of the free base.
  • the turbidity of the suspension can be used for monitoring the salt formation: when there is no temporal change of the turbidity of the suspension anymore, the salt formation is completed.
  • the salt formation is finished after 10 to 180 minutes, particularly 90 to 120 min.
  • the supension is cooled down to a temperature at which the desired product (the 4-toluenesulfonate salt) can be separated from the liquid phase (step e)).
  • step g) the desired product (the 4-toluenesulfonate salt) is separated from the liquid phase.
  • the separation of the anhydrous 4-toluenesulfonate salt in step g) may be done for example, by filtering, washing and drying. Washing is preferably performed using the suspension agent, prefera bly acetone, M EK or M I BK.
  • the drying is done at a temperature of about 20°C to a bout 70°C.
  • drying is done over a period of a bout 30 minutes to about 5 hours, longer if need be.
  • drying is done by reduced pressure.
  • the pressure is about 0.1 m Bar to a bout 100 m Bar, more prefera bly about 1 mBar to about 10 m Bar.
  • when drying is done by reduced pressure it is done over a period of a bout 30 minutes to a bout 5 hours.
  • the monohydrate 4- toluenesulfonate salt is formed to a certain extent, it can be converted to the anhydrous 4- toluenesulfonate salt by stirring in the (waterless) suspension agent, particularly at elevated temperatures.
  • the present invention relates to a method of preparing crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]- amino ⁇ [l,2,4]triazolo-[l,5-o]pyridin-6-yl)phenyl]propanamide 4-toluenesulphonate as defined in the claims, said method comprising the steps of:
  • step B) preferably heating the suspension of step a) to a temperature between (TB -
  • a small amount of the generated crystalline form of the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4- (2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide can be effectively used as crystallization seed for the preparation of the next batch.
  • a method of preparing crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a] pyridin-6-yl)phenyl] propanamide 4-tolu- enesulphonate comprising the steps of: a) providing a suspension of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide in a suspension agent; b) preferably heating the suspension to a temperature between (TB - 15 K) and TB; wherein TB is the boiling point of the suspension agent under normal conditions; c)
  • the described crystalline form of the anhydrous 4-toluenesulfonate salt can be used to prepare pharmaceutical compositions for the treatment of cancer, in particular of pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer and/or gastric cancer.
  • the present invention covers a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form of the anhydrous 4-toluenesulfonate salt as defined in the claims, and at least one pharmaceutically acceptable excipient.
  • the present invention covers a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form of the anhydrous 4-toluenesulfonate salt as defined in the claims prepared according to the processes of the present invention, and at least one pharmaceutically acceptable excipient.
  • anhydrous 4-toluenesulfonate salt according to the present invention can be administered in a suitable manner, such as, for example, via the oral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • anhydrous 4-toluenesulfonate salt according to the present invention is administered in suitable administration forms.
  • anhydrous 4-toluenesulfonate salt according to the present invention for oral administration, it is possible to formulate the anhydrous 4-toluenesulfonate salt according to the present invention to dosage forms known in the art that deliver the anhydrous 4-toluenesulfonate salt according to the present invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble
  • orally- disintegrating tablets films/wafers, films/lyophylisates
  • capsules for
  • anhydrous 4-toluenesulfonate salt according to the present invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear- rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • anhydrous 4-toluenesulfonate salt according to the present invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia,
  • fillers and carriers for example cellulose, microcrystalline cellulose (such as, for example, AviceT), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos 3 ⁇ 4 )),
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • bases for suppositories for example polyethylene glycols, cacao butter, hard fat
  • solvents for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins
  • surfactants, emulsifiers, dispersants or wetters for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette 3 ⁇ 4 ), sorbitan fatty acid esters (such as, for example, Span " ), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween * ), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor * ), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic 3 ⁇ 4 ), buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), isotonicity agents (for example glucose, sodium chloride), adsorbi
  • stabilisers for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • antioxidants for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • preservatives for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate
  • colourants for example inorganic pigments such as, for example, iron oxides, titanium dioxide
  • flavourings • flavourings, sweeteners, flavour- and/or odour-masking agents.
  • the present invention furthermore relates to pharmaceutical compositions which comprise the anhydrous 4-toluenesulfonate salt according to the present invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to its use according to the present invention.
  • compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease.
  • a pharmaceutically acceptable excipipient is preferably an excipient that is relatively nontoxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the excipoent do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount is preferably that amount which produces a result or exerts an influence on the particular condition being treated.
  • the active ingredient can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the pharmaceutical composition is an immediate release formulation.
  • Immediate release refers to a composition that releases the active ingredient (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide substantially completely into the gastrointestinal tract of the patient within a period of less than an hour, usually between about 0.1 and about 1 hour and less than about 0.75 hours from ingestion. Such a delivery rate allows the drug to be absorbed by the gastrointestinal tract in a manner that is bioequivalent to an oral solution.
  • the pharmaceutical composition is an IR-tablet made by wet granulation or direct compression, preferably by direct compression.
  • wet granulation was applied, some degree of dissociation of the anhydrous tosylate salt, to the respective acid and base, was observed.
  • H PMC hydroxypropyl methylcellulose
  • the pharmaceutical composition preferably comprises a disintegrant.
  • the disintegrant is selected from the group consisting of croscarmellose sodium and sodium starch glycolate.
  • the disintegrant is croscarmellose sodium which comprises from 1 % to 10 % w/w, or from 2 % to 8 % w/w, or from 3 % to 7 % w/w of the composition.
  • the pharmaceutical composition preferably comprises a surface stabilizer, preferably a cellulosic stabilizer.
  • cellulosic stabilizer include, but are not limited to, hydroxypropyl cellulose (H PC), and hydroxypropyl methyl cellulose (H PMC).
  • the surface stabilizer is hydroxypropyl methyl cellulose which comprises from 1 % to 10 % w/w, or from 2 % to 7 % w/w, or from 3 % to 5 % w/w of the composition.
  • the composition further comprises one or more lubricants, wherein the one or more lubricants comprise up to about 5 weight % of the composition.
  • the one or more lubricants are each individually selected from the group consisting of sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, glyceryl behenate, and polyethylene glycol.
  • one lubricant is magnesium stearate, wherein the compositon comprises from 0.1 % to 1.5 % w/w magnesium stearate.
  • one lubricant is sodium lauryl sulfate, wherein the composition comprises from 0.1 % to 1.5 % w/w sodium lauryl sulfate.
  • the IR-tablet contains mannitol, croscarmellose sodium, and magnesium stearate.
  • the pharmaceutical composition might comprise residual amounts of solvents, in particular water. Usually, the residual moisture content between 0 and 5 % by weight, preferably between 0 and 2 weight %.
  • the pharmaceutical composition of the present invention is administered to a patient in form of one or more pharmaceutical dosage units, a pharmaceutical dosage unit usually being a tablet or a capsule.
  • a pharmaceutical dosage unit usually being a tablet or a capsule.
  • the total weight of the pharmaceutical dosage unit can be varied as desired, for reasons of practicality it is preferable for the total weight of a single oral dosage unit to be in the range from 50 mg to 1000 mg, particularly from 50 mg to 400 mg, and more particularly 50, 60, 70, 80, 90 mg.
  • the pharmaceutical dosage unit containing the 4- toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)- phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide is a tablet.
  • the present invention covers pharmaceutical combinations, in particular medicaments, comprising :
  • a cancer in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.
  • a "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)- phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate of the present invention as defined in the claims, and a further active ingredient are present together in one unit dosage or in one single entity.
  • a first active ingredient such as crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)- phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyri
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit.
  • a non- fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • agents for the treatment and/or prophylaxis of cancer include:
  • the present invention covers use of crystalline, anhydrous (2 ?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ - [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate as defined in the claims, for the treatment or prophylaxis of a cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.
  • a cancer in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.
  • the present invention covers use of crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ - [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate as defined in the claims, for the preparation of a medicament for the prophylaxis or treatment of a cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.
  • the present invention covers a method of treating cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer and/or gastric cancer, said method comprising administering crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)- phenyl]amino ⁇ [l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate as defined in the claims, or a pharmaceutical composition comprising said crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]- amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)pheny
  • stationary phase YMC Triart C18 (150 mm length, 3.0 mm ID, 3 ⁇ /12 nm particle size); mobile phase A: 0.58 g diammonium hydrogen phosphate + 0.66 g ammonium dihydrogen phosphate / 1 L water; mobile phase B: acetonitrile; UV detection at 210 nm; oven temperature: 40 °C, injection volume: 5.0 ⁇ , flow rate: 15.0 min at 0.8 mL/min, 0.8 mL/min -> 1.2 mL/min (2.3 min), 7.7 min holding time at 1.2 mL/min; linear gradient in 2 steps: 40 % B -> 66 % B (13.0 min), 66 % B -> 85 % B (2.0 min), 10 min holding time at 85 % B; HPLC method 2:
  • stationary phase Chiracel OD-RH (150 mm length, 4.6 mm ID, 5 ⁇ particle size); mobile phase A: 1.0 mL trifluoroacetic acid / 1 L water; mobile phase B: acetonitrile; UV detection at 210 nm; oven temperature: 20 °C, injection volume: 10.0 ⁇ , flow rate: 1.0 mL/min; gradient: isocratic at 60 % B (25 min); enantiomeric purity of (2R)-2-(4-fluorophenyl)-N-[4-(2- ⁇ [2- methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide.
  • XRPD X-ray powder diffraction
  • the X-ray tube with copper anode was operated by 40 kV and 40 mA.
  • the 2 ⁇ scans were performed between 2 ° ⁇ 2 ⁇ ⁇ 40° 2 ⁇ ⁇ 35 ° (stepwidth 0.5 ° ).
  • Data acquisition and evaluation were performed using the STOE WinX pow software package.
  • an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed.
  • intensities in an X-ray diffraction pattern may fluctuate depending upon crystal ha bitus of the material and measurement conditions employed. It is further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle theta for a conventional X-ray diffraction pattern at a given temperature is typically a bout ⁇ 0.1, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles.
  • the term "about" when used herein in reference to X-ray powder diffraction patterns means that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figure disclosed herein. Any crystal form that provides X-ray diffraction patterns that is substantially identical to those disclosed in the accompanying Figure falls within the scope of the present invention.
  • the a bility to ascertain whether the polymorphic forms of a compound are the same albeit the X- ray diffraction patterns are not completely identical is within the purview of one of ordinary skill in the art.
  • thernnoanalytical data may be obtained with a measurement error that is dependent upon the measurement conditions employed.
  • the melting point is influenced by parameters like particle size, chemical purity, physical purity, measurement conditions (e.g. heating rate, and instrumental set-up).
  • Example 1 Preparation of crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2- methoxy-4-(methylsulfonyl)phenvnamino ⁇ fl,2,41triazolofl,5-a1pyridin-6- vDphenyllpropanamide 4-toluene-sulfonate : method 1 (without seeding)
  • Figure 1 shows the x-ray diffractogram of the crystalline , anhydrous (2/?)-2-(4-fluorophenyl)- /V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2 4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide 4-toluenesulphonate.
  • Table 1 X-ray powder diffraction data - strongest reflectionsstandard substance for system suitability test: silicon, Si (NIST 640b);
  • Example 2 Preparation of crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2- methoxy-4-(methylsulfonyl)phenyllamino ⁇ [l,2,41triazolo[l,5-alpyridin-6- vDphenyllpropanamide 4-toluenesulphonate : method 2 : with seeding
  • reaction mixture a suspension
  • tosylate anhydrate salt seeded with the tosylate anhydrate salt. Seeding was repeated after 15 min, i.e. after dosing of 9 ml in total.
  • the suspension was heated to 70°C for 10 min and then cooled to 20°C within 2h. After stirring overnight the product was isolated by filtration. 11.9 g (91% of theory) were isolated.
  • Thermogravimetry showed a wheight loss of 0.2 weight-% while heating from 32.2°C to 150°C.
  • Figure 2 shows the x-ray diffractogram of the crystalline , anhydrous (2/?)-2-(4-fluorophenyl)- /V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide 4-toluenesulfonate.
  • Table 2 X-ray powder diffraction data - strongest reflections standard substance for system suitability test: silicon, Si (NIST 640b);
  • Figure 3 shows the x-ray diffractogram of the crystalline (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-o]pyridin-6- yl)phenyl]propanamide 4-toluenesulfonate monohydrate (compound of formula (II), herein also referred to as "the monohydrate tosylate salt”):
  • Example 4 Preparation of crystalline (2/?)-2-(4-fluorophenyl)-/ ⁇ /-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyllamino ⁇ [l,2,41triazolo[l,5-alpyridin-6-yl)phenyllpropanamide 4- toluene-sulfonate monohydrate : method 2 : with seeding
  • the precipitate was isolated by suction filtration and washed two times with 60 ml 2-butanone (each). The product was dried in vacuum (approximately 60 mbar) at 50°C for 5h. 6.5 g (81 % of theory) were isolated.
  • Thermogravimetry showed a wheight loss of 2.4 weight-% while heating from 31.6°C to 125°C.
  • Figure 4 shows the x-ray diffractogram of the crystalline (2R)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-o]pyridin-6- yl)phenyl]propanamide 4-toluenesulfonate monohydrate obtained with seeding.
  • Example 5 Stability assessment of the crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4- (2- ⁇ [2-methoxy-4-(methylsulfonyl)phenyllamino ⁇ [l,2,41triazolo[l,5-alpyridin-6- vDphenyllpropanamide 4-toluene-sulphonate ("anhydrous tosylate salt") 6.55 g of the crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2- ⁇ [2-methoxy-4- (methylsulfonyl)phenyl]amino ⁇ [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulphonate, 3.2 g of hydroxypropyl methylcellulose (HPMC), and 0.5 g of sodium dodecyl sulfate (SDS)
  • the suspension was stirred at room temperature (20 °C to 25 °C) for 48 h.
  • Example 6 Preparation of a pharmaceutical composition containing the crystalline, anhydrous (2R)-2-(4-fluorophenyl)-/ /-[4-(2- ⁇ [2-methoxy-4-(methylsulfonyl)phenvn- amino ⁇ [l,2,4ltriazolo[l,5-alpyridin-6-yl)phenyllpropanamide 4-toluenesulphonate
  • Example 5 The suspension of Example 5 (85.42 g) was sprayed on a mixture consisting of 36 g lactose monohydrate, 38.5 g Avicel PH 101, and 4.5 g Ac-Di-Sol by means of a fluid bed granulator. 0.68 g of magnesium stearate was added to 81,16 g of the obtained mixture.
  • Approximately 0.4 mL of whole blood was collected via an indwelling jugular catheter.
  • the blood samples were centrifuged (approx. 5 min.) in order to obtain plasma which was then transferred to the appropriately labelled vials and stored frozen (-20°C) until analysis for parent drug.
  • Plasma samples were analysed via LC/MS/MS for parent drug concentration and pharmacokinetic parameters using ToxKin.
  • Plasma concentration-time courses run almost parallel after administration of these formulations ( Figures 5 and 6).
  • the peak plasma concentration was observed 4 h after administration for the Tylose suspension of the free base, free base reference solution, the tosylate monohydrate suspension and for the anhydrous tosylate suspension, respectively.
  • Cmax,norm [0.237 (reference solution), 0.0191 (free base tylose suspension), 0.173 (tosylate monohydrate tylose suspension) kg/L] and AUCnorm [3.63 (reference solution), 0.316 (free base tylose suspension) and 2.43 (tosylate monohydrate suspension) kg-h/L] differed across these formulations with corresponding relative bioavailabilities amounting to 100%, 8.7% and 66.9%, respectively.
  • Cmax,norm [0.289 (reference solution), 0.129 (anhydrous tosylate tylose suspension) kg/L] and AUCnorm [3.74 (reference solution) and 2.62 (anhydrous tosylate suspension) kg-h/L] differed across the two formulations with corresponding relative bioavailabilities amounting to 100%, and 70.0%, respectively.
  • Example 8 Apparent dissolution rates Apparent dissolution rates (ADR) were determined using the USPIV Flow-Through-Cell as described previously (Muenster U et al. European Journal of Pharmaceutics and Biopharmaceutics 102 (2016) 191-201.):
  • ADRs were determined using the mini-flow-through-cell (USP apparatus IV, Sotax, Basel, Switzerland), equipped with 400 ⁇ cells. Before filling the cells with glass beads and API, a Whatman glass microfiber filter membrane (Whatman, Kent, United Kingdom) was placed on the bottom of the cell. Then, 30% of the cell volume was filled with 0.1 mm glass beads (Fisher Scientific, Germany).
  • API referring to free base.
  • the API was then covered by a thin layer of 0.1 mm glass beads, followed by filling of another 30% of the cell volume with 1 mm glass beads (Sartorius, Germany). Then, the mixture of API, 0.1 mm glass beads, and 1 mm glass beads was mixed with a spatula until homogeneity was achieved, according to visual inspection. Then the remaining free cell space was filled with 0.1 mm glass beads, and the cell covered on top with the same Whatman glass microfiber filter membrane as was used to cover the bottom of the cell. Flow-through-cells were then equilibrated to 37°C in a water bath.
  • a flow rate of 2 ml/min using aqueous media (phosphate citrate buffer, pH 6.8, 50 mOsm/kg; acetate buffer, pH 4.5, osmolarity, 75 mOsm/kg; 0.1 M HCI, pH 1, fasted state simulated intestinal fluid (FaSSIF; www.biorelevant.com) and fed state simulated intestinal fluid (FeSSIF; www.biorelevant.com) was applied to the Flow-Through- Cells, and 2 min fractions of 4 ml each were collected up to 14 min after the start of the experiment. The amount of dissolved compound in each fraction was determined by H PLC (HP1100,Waldbronn, Boblingen, Germany). Cumulative API amounts after 14 minutes of respective fractions are reported in the following table.

Abstract

The present invention covers crystalline, anhydrous (2R)-2-(4-fluorophenyl)-N-[4-(2-{[2- methoxy-4-(methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]propan- amide 4-toluenesulfonate, and crystalline (2R)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulfonate monohydrate, as compounds per se, a method of preparing said crystalline, anhydrous compound, pharmaceutical compositions and pharmaceutical combinations comprising said crystalline, anhydrous compound, and uses of said crystalline, anhydrous compound in the treatment or prophylaxis of a cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.

Description

MPS-1 INHIBITORS
The present invention covers crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2- methoxy^-imethylsulfonyljphenyllaminojll^^ltriazololl^-olpyridin-e-yljphenyllpropan- amide 4-toluenesulfonate, and crystalline (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulfonate monohydrate, as compounds per se, a method of preparing said crystalline, anhydrous compound, pharmaceutical compsitions and pharmaceutical combinations comprising said crystalline, anhydrous compound, and uses of said crystalline, anhydrous compound in the treatment or prophylaxis of cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.
BACKGROUND OF THE INVENTION
(2R)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide is known to be a very potent inhibitor of Mps-1 kinase. WO 2013/087579 Al discloses the compound, data showing its pharmaceutical activity, and a method for the preparation of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide.
WO 2014/009219 Al discloses an improved method for the preparation of (2/?)-2-(4- fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5- a]pyridin-6-yl)phenyl]propan-amide.
WO 2014/195408 Al discloses pharmaceutical compositions comprising (2 ?)-2-(4- fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5- a]pyridin-6-yl)phenyl]propan-amide mainly in amorphous form. One important property of a pharmaceutical compound is its relative bioavailability. Different salts and crystalline forms of the same pharmaceutical compound can and reportedly do have different relative bioavailabilities. The discovery of new pharmaceutically acceptable salts and crystalline forms of a pharmaceutical useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
In addition to the relative bioavailability, the stability of the pharmaceutical compound as well as of the pharmaceutical formulation containing said compound is an important property, too. Furthermore, the drug load capacity is an important property as well. The maximum size of a tablet or capsule, in particular gel capsule, is limited by the ability of a patient swallowing the tablet or capsule. If the drug load capacity is low, more than one tablet has to be taken by the patient. The aim is to keep the quantity of tablets to be taken by a patient low. DESCRIPTION of the INVENTION
Surprisingly and unexpectedly, it was observed that a crystalline form of the anhydrous 4- toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide shows superior properties in terms of its pharmacological usability compared to the free base (2/?)-2-(4- fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5- a]pyridin-6-yl)phenyl]propanamide or other salts thereof.
In accordance with a first aspect, the present invention thus covers crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate, of formula (I) :
Figure imgf000004_0001
(I), hereinafter also referred to as the "anhydrous tosylate salt" or "anhydrous 4- toluenesulfonate salt",
characterized in that it has XRPD peaks [°2Θ] (Copper (Cu)) of about 5.4, 15.6, 16.5, 20.0, and 24.4. In accordance with an embodiment of the first aspect, the present invention covers said crystalline, anhydrous (2R)-2-(4-fluorophenyl)-A/-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate, characterized in that it has XRPD peaks [°2Θ] (Copper (Cu)) of about 5.4, 15.6, 16.5, 20.0, 24.4, 24.5 and 25.0.
In accordance with another embodiment of the first aspect, the present invention covers said crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate, characterized in that it has XRPD peaks [°2Θ] (Copper (Cu)) as given in the Experimental Section, Example 2, herein.
This crystalline form of the anhydrous tosylate salt of the present invention shows a high relative oral bioavailability. This is surprising because the solubility of the anhydrous tosylate salt of the present invention in water and acidic aqueous solutions was similar to the water-solubility of the free base (2/?)-2-(4-fluorophenyl)-/V-[4-(2 [2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide and of the monohydrate of the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-A/-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a] pyridin-6-yl)phenyl] propanamide.
But the relative oral bioavailibility of the anhyd rous tosylate salt of the present invention was significantly higher than that of said free base (see Experimental Section, Example 7, herein).
In accordance with a second aspect, the present invention covers a method of preparing crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide 4-toluenesulphonate as defined in the claims, said method comprising the steps of : a) providing a suspension of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]prop- anamide in a suspension agent, said suspension agent containing less than 2 vol.-% water; b) optionally heating the suspension to a temperature of between ( TB - 15 K) and ΓΒ; wherein TB is the boiling point of the suspension agent under normal conditions; cl) adding a portion of p-toluenesulfonic acid to the suspension obtained from step b); c2) adding one or more crystallization seeds to the suspension obtained from step cl); c3) repeating step cl) and, optionally, repeating step c2) one or more times until the total amount of said p-toluenesulfonic acid is added ; d) stirring the suspension, particularly at a temperature of between ( TB - 15 K) and TB; e) optionally cooling down the suspension to a temperature of below 50°C; g) separating the thus-formed (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]prop- anamide 4-toluenebenzenesulfonate salt from the liquid phase, thereby providing said crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulphonate as defined in the claims.
In step a) a suspension of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide, and p-toluenesulfonic acid in a suspension agent is provided.
(2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide can be prepared as described in WO 2013/087579 Al or WO 2014/009219 Al. p-Toluenesulfonic acid is commercially available. p-Toluenesulfonic acid can be used in its anhydrous form (CAS registry number 104-15-4). Surprisingly, it was obeserved that p- toluenesulfonic acid can also be used in form of its monohydrate (CAS registry number 6192- 52-5). Mixtures containing the anhydrous form and the monohydrate of p-toluenesulfonic acid can be used as well.
In a particular embodiment, p-toluenesulfonic acid will be used in form of its monohydrate (CAS registry number 6192-52-5).
In accordance with an embodiment of the second aspect, said p-toluenesulfonic acid is p- toluenesulfonic acid monohydrate.
An overstoichiometric amount of p-toluenesulfonic acid may be used: for each mole of (2/?)- 2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5- o]pyridin-6-yl)phenyl]propanamide, 1.05 to 1.5 moles of p-toluenesulfonic acid or p- toluenesulfonic acid hydrate (1:1) are used; more preferably, 1.1 to 1.3 moles are used. Suitable suspension agents are for example acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (M I BK), tetrahydrofuran (TH F), mixtures of said agents or the like.
In accordance with another embodiment of the second aspect, said p-toluenesulfonic acid is added in solution in a solvent, said solvent being said suspension agent.
In accordance with another em bodiment of the second aspect, said suspension agent is acetone, methyl ethyl ketone (M EK), methyl isobutyl ketone ( MI BK), tetrahydrofuran (TH F), or a mixture thereof.
In a particular em bodiment of the second aspect, said suspension agent is a ketone such as acetone, M EK or M I BK, or mixtures thereof; more prefera bly, the suspension agent is M EK. The suspension agent might contain water. The content of water should be below 2% by weight. If the water content is higher, the monohydrate of the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide (compound of formula ( II) as defined supra) as well as other hydrates might be formed in a certain amount.
The amount of the suspension agent is usually in the range from 10 moles to 200 moles for each mole of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]-triazolo[l,5-a] pyridin-6-yl)phenyl] propanamide, prefera bly in the range of 30 to 150 moles for each mole of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]-triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide, more prefera bly in the range of 50 to 100 moles for each mole of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- {[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide, most prefera bly in the range of 60 to 80 moles for each mole of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide. In step b), the suspension is optionally heated to a temperature between ( TB - 15 K) and TB. TB is the boiling point of the suspension agent under normal conditions.
The boiling point under normal conditions of M E K is 79.64 °C. So, when M EK is used as the suspension agent, the suspension preferably is heated to a temperature between 64.64 °C and 79.64 °C.
The boiling point under normal conditions of acetone is 56 °C. So, when acetone is used as the suspension agent, the suspension preferably is heated to a temperature between 41°C and 56 °C.
In principle, it is also possible to perform the method according to the present invention not under normal conditions but under i ncreased or decreased pressure conditions. In case of increased or decreased pressure the preferred temperature range should be adjusted accordingly.
In step c), p-toluenesulfonic acid is added.
As mentioned a bove, p-toluenesulfonic acid can be used in its anhydrous form, as the monohydrate or as a mixture of the anhydrous form and the monohydrate. For simplification purposes, all said forms shall be included when referring to p-toluenesulfonic acid hereinafter.
Particularly, p-toluenesulfonic acid is added in form of a solution. Preferably, the solvent used for solving p-toluenesulfonic acid is the same as the suspension agent.
In a particular em bodiment of the second aspect, p-toluenesulfonic acid is added in portions. Prefera bly, the total amount of p-toluenesulfonic acid is added to the suspension in form of two to five portions; more preferably in form of two or three portions. Usually, p-toluenesulfonic acid is added to the heated suspension obtained after step b). However, in principle it is also possible to add all or part of the p-toluenesulfonic acid already to the suspension of step a) or a respective suspension during the heating process.
As mentioned above, one or more crystallization seeds are added to the suspension. The crystallization seed is a crystal of the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4- (2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide having the crystal form as shown in Fig. 2.
It is not necessary to add one or more crystallization seeds in order to get the crystal form as shown in Fig. 1. But the process can be run much more reliably when crystallization seeds are added. Furthermore, the crystal-size distribution is better and can be controlled more effectively, when crystallization seeds are added. Without crystallization seeds it is possible that a supersaturated solution is generated from which the salt is precipated suddenly. In that case, finer particles are generated which are more difficult to separate from the liquid phase and which enclose more suspension agent. So, the addition of crystallization seeds is neccessary to obtain a much-improved crystalline form. As mentioned above in relation to the second aspect, step c) is divided into the following sub-steps cl), c2), and c3): cl) adding a portion of p-toluenesulfonic acid to the suspension obtained from step b); c2) adding one or more crystallization seeds to the suspension obtained from step c2); c3) repeating step cl) and/or step c2) one or more times until the total amount of p- toluenesulfonic acid is added.
The total amount of p-toluenesulfonic acid is the stoichiometric or overstoichiometric amount of p-toluenesulfonic acid which is used for the transformation of 2-(4-fluorophenyl)- /V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6- yl)phenyl]propanamide into the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4-(2- {[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide. So, the total amount of p-toluenesulfonic acid is in the range of 1 to 1.5 moles per mole of 2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide.
In a particular embodiment of the second aspect, the total amount of p-toluenesulfonic acid is added in two to five portions, more preferably in two or three portions, separated by the addition of one or more crystallization seeds.
In accordance with another embodiment of the second aspect, said steps cl), c2) and c3) are replaced by steps cl), c2), c3), c4), and c5):
cl) adding a first portion of p-toluenesulfonic acid to the suspension obtained after step b), the first portion having an amount 0} of 10 weight-% to 30 weight-% of the total amount of p-toluenesulfonic acid; c2) adding one or more crystallization seeds to the suspension obtained from step cl); c3) adding a second portion of p-toluenesulfonic acid to the suspension obtained from step c2), the second portion having an amount Q2 of 10 weight-% to 100 weight-% of the total amount of p-toluenesulfonic acid; c4) adding one or more crystallization seeds to the suspension obtained from step c3); c5) if neccessary, adding a third portion of p-toluenesulfonic acid to the suspension obtained from step c4), the third portion having an amount Q3 = (100 weight-% - Q1 - Q2) of the total amount of p-toluenesulfonic acid.
Usually, the suspension is stirred after each sub-step. Alternatively, the suspension is stirred the whole time during the sub-steps.
In step d), the suspension obtained from step c) is stirred, preferably at a temperature between (TB - 15 K) and TB; wherein TB is the boiling point of the suspension agent under normal conditions. By means of adjusting the temperature the crystallization process can be controlled.
During step d), the transformation of 2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide into the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide takes place (salt formation).
Usually, the solubility of the 4-toluenesulfonate salt in the suspension agent is different from the solubility of the free base in the suspension agent. For example, when MEK, MIBK or acetone is used as suspension agent, the solubility of the 4-toluenesulfonate salt is lower than the solubility of the free base.
So, the turbidity of the suspension can be used for monitoring the salt formation: when there is no temporal change of the turbidity of the suspension anymore, the salt formation is completed.
When TH F is used as a suspension agent, it is possible that a clear solution instead of a suspension is obtained. In this case, other process control measures have to be taken (e.g. Raman spectroscopy).
Usually, the salt formation is finished after 10 to 180 minutes, particularly 90 to 120 min.
After completion of the salt formation, the supension is cooled down to a temperature at which the desired product (the 4-toluenesulfonate salt) can be separated from the liquid phase (step e)).
In step g), the desired product (the 4-toluenesulfonate salt) is separated from the liquid phase. The separation of the anhydrous 4-toluenesulfonate salt in step g) may be done for example, by filtering, washing and drying. Washing is preferably performed using the suspension agent, prefera bly acetone, M EK or M I BK.
Prefera bly, the drying is done at a temperature of about 20°C to a bout 70°C. Prefera bly, drying is done over a period of a bout 30 minutes to about 5 hours, longer if need be. Optionally, drying is done by reduced pressure. Prefera bly, the pressure is about 0.1 m Bar to a bout 100 m Bar, more prefera bly about 1 mBar to about 10 m Bar. Preferably, when drying is done by reduced pressure, it is done over a period of a bout 30 minutes to a bout 5 hours.
If (for example due to a high content of water in the suspension agent) the monohydrate 4- toluenesulfonate salt is formed to a certain extent, it can be converted to the anhydrous 4- toluenesulfonate salt by stirring in the (waterless) suspension agent, particularly at elevated temperatures.
In a further aspect, the present invention relates to a method of preparing crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo-[l,5-o]pyridin-6-yl)phenyl]propanamide 4-toluenesulphonate as defined in the claims, said method comprising the steps of:
A) providing a suspension of the monohydrate of the 4-toluenesulfonate
(2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]-triazolo[l,5-a] pyridin-6-yl)phenyl] propanamide in a suspension agent;
B) preferably heating the suspension of step a) to a temperature between (TB -
15 K) and TB;
C) stirring of the suspension, prefera bly at a temperature between (TB - 15 K) and TB;
D) optionally cooling down the suspension to a temperature below 50 °C; E) separating the anhydrous 4-toluenesulfonate salt from the liquid phase.
Everything described in the previous section with respect to steps a), b), d), e), and g) shall apply analogously to steps A), B), C), D), and E).
After having performed any one of the methods of the present invention, a small amount of the generated crystalline form of the 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4- (2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide can be effectively used as crystallization seed for the preparation of the next batch.
A method of preparing crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a] pyridin-6-yl)phenyl] propanamide 4-tolu- enesulphonate is provided, said method comprising the steps of: a) providing a suspension of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide in a suspension agent; b) preferably heating the suspension to a temperature between (TB - 15 K) and TB; wherein TB is the boiling point of the suspension agent under normal conditions; c) adding p-toluenesulfonic acid to the suspension; d) stirring of the suspension, preferably at a temperature between (7B - 15 K) and TB; e) optionally cooling down the suspension to a temperature below 50°C; g) separating the 4-toluenesulfonate salt from the liquid phase.
The described crystalline form of the anhydrous 4-toluenesulfonate salt can be used to prepare pharmaceutical compositions for the treatment of cancer, in particular of pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer and/or gastric cancer.
In accordance with another aspect, the present invention covers a pharmaceutical composition comprising the crystalline form of the anhydrous 4-toluenesulfonate salt as defined in the claims, and at least one pharmaceutically acceptable excipient.
In accordance with another aspect, the present invention covers a pharmaceutical composition comprising the crystalline form of the anhydrous 4-toluenesulfonate salt as defined in the claims prepared according to the processes of the present invention, and at least one pharmaceutically acceptable excipient.
It is possible for the anhydrous 4-toluenesulfonate salt according to the present invention to have systemic and/or local activity. For this purpose, it can be administered in a suitable manner, such as, for example, via the oral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
For these administration routes, it is possible for the anhydrous 4-toluenesulfonate salt according to the present invention to be administered in suitable administration forms.
For oral administration, it is possible to formulate the anhydrous 4-toluenesulfonate salt according to the present invention to dosage forms known in the art that deliver the anhydrous 4-toluenesulfonate salt according to the present invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the anhydrous 4-toluenesulfonate salt according to the present invention in crystalline and/or amorphised and/or dissolved form into said dosage forms. Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear- rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
The anhydrous 4-toluenesulfonate salt according to the present invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,
• fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, AviceT), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos¾)),
• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),
• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),
• solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette¾), sorbitan fatty acid esters (such as, for example, Span"), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween*), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor*), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic¾), buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), isotonicity agents (for example glucose, sodium chloride), adsorbents (for example highly-disperse silicas), viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, CarbopoT); alginates, gelatine), disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab¾), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSof)), flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosif)), coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon"), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragi ), capsule materials (for example gelatine, hydroxypropylmethylcellulose), synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit¾), polyvinylpyrrolidones (such as, for example, Kollidon*), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), • plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),
• penetration enhancers,
• stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),
• preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),
• colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),
• flavourings, sweeteners, flavour- and/or odour-masking agents.
The present invention furthermore relates to pharmaceutical compositions which comprise the anhydrous 4-toluenesulfonate salt according to the present invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to its use according to the present invention.
These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease.
A pharmaceutically acceptable excipipient is preferably an excipient that is relatively nontoxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the excipoent do not vitiate the beneficial effects of the active ingredient.
A pharmaceutically effective amount is preferably that amount which produces a result or exerts an influence on the particular condition being treated. For oral administration, the active ingredient can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
In a preferred embodiment, the pharmaceutical composition is an immediate release formulation.
"Immediate release" (hereinafter also abbreviated to "IR") refers to a composition that releases the active ingredient (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide substantially completely into the gastrointestinal tract of the patient within a period of less than an hour, usually between about 0.1 and about 1 hour and less than about 0.75 hours from ingestion. Such a delivery rate allows the drug to be absorbed by the gastrointestinal tract in a manner that is bioequivalent to an oral solution.
In a preferred embodiment, the pharmaceutical composition is an IR-tablet made by wet granulation or direct compression, preferably by direct compression. When wet granulation was applied, some degree of dissociation of the anhydrous tosylate salt, to the respective acid and base, was observed. By addition of hydroxypropyl methylcellulose (H PMC), the stability of the anhydrous tosylate salt in the formulation could be increased. The pharmaceutical composition preferably comprises a disintegrant. Preferably, the disintegrant is selected from the group consisting of croscarmellose sodium and sodium starch glycolate.
In a preferred embodiment, the disintegrant is croscarmellose sodium which comprises from 1 % to 10 % w/w, or from 2 % to 8 % w/w, or from 3 % to 7 % w/w of the composition. The pharmaceutical composition preferably comprises a surface stabilizer, preferably a cellulosic stabilizer. Examples of cellulosic stabilizer include, but are not limited to, hydroxypropyl cellulose (H PC), and hydroxypropyl methyl cellulose (H PMC).
In a preferred embodiment, the surface stabilizer is hydroxypropyl methyl cellulose which comprises from 1 % to 10 % w/w, or from 2 % to 7 % w/w, or from 3 % to 5 % w/w of the composition.
In another preferred embodiment, the composition further comprises one or more lubricants, wherein the one or more lubricants comprise up to about 5 weight % of the composition. Preferably, the one or more lubricants are each individually selected from the group consisting of sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, glyceryl behenate, and polyethylene glycol.
In a preferred embodiment, one lubricant is magnesium stearate, wherein the compositon comprises from 0.1 % to 1.5 % w/w magnesium stearate.
In another preferred embodiment, one lubricant is sodium lauryl sulfate, wherein the composition comprises from 0.1 % to 1.5 % w/w sodium lauryl sulfate.
In a preferred embodiment, the IR-tablet contains mannitol, croscarmellose sodium, and magnesium stearate.
The pharmaceutical composition might comprise residual amounts of solvents, in particular water. Usually, the residual moisture content between 0 and 5 % by weight, preferably between 0 and 2 weight %.
The pharmaceutical composition of the present invention is administered to a patient in form of one or more pharmaceutical dosage units, a pharmaceutical dosage unit usually being a tablet or a capsule. Although the total weight of the pharmaceutical dosage unit can be varied as desired, for reasons of practicality it is preferable for the total weight of a single oral dosage unit to be in the range from 50 mg to 1000 mg, particularly from 50 mg to 400 mg, and more particularly 50, 60, 70, 80, 90 mg.
In a preferred embodiment, the pharmaceutical dosage unit containing the 4- toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide is a tablet. In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising :
• one or more first active ingredients, in particular crystalline, anhydrous (2R)-2-(4- fluorophenyl)-A/-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate as defined in the claims,
and
• one or more further active ingredients, in particular for the treatment and/or prophylaxis of a cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.
The term "combination" in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.
A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate of the present invention as defined in the claims, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a "fixed combination" is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
A non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non- fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
The crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate of the present invention as defined in the claims can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}- [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate of the present invention as defined in the claims can be combined with known agents for the treatment and/or prophylaxis of cancer.
Examples of agents for the treatment and/or prophylaxis of cancer include:
1311-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin I I, antithrombin II I, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG- epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa- 2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc- HYN IC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin. In accordance with another aspect, the present invention covers use of crystalline, anhydrous (2 ?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}- [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate as defined in the claims, for the treatment or prophylaxis of a cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.
In accordance with another aspect, the present invention covers use of crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}- [l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate as defined in the claims, for the preparation of a medicament for the prophylaxis or treatment of a cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer. In accordance with another aspect, the present invention covers a method of treating cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer and/or gastric cancer, said method comprising administering crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate as defined in the claims, or a pharmaceutical composition comprising said crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate as defined in the claims, or a pharmaceutical combination comprising said crystalline, anhydrous (2/?)-2- (4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5- a]pyridin-6-yl)-phenyl]propanamide 4-toluenesulfonate as defined in the claims, to a patient in need thereof. EXPERIMENTAL SECTION
General The following Table lists the abbreviations used in this paragraph, and in the Examples section.
Figure imgf000025_0001
PEG polyethylene glycol p.o. oral (per os) ppm parts per million
Rt Retention time
SDS sodium dodecyl sulfate
TGA Thermogravimetry
UV ultra violet
XRPD X-ray powder diffraction
HPLC method 1:
stationary phase: YMC Triart C18 (150 mm length, 3.0 mm ID, 3 μηη/12 nm particle size); mobile phase A: 0.58 g diammonium hydrogen phosphate + 0.66 g ammonium dihydrogen phosphate / 1 L water; mobile phase B: acetonitrile; UV detection at 210 nm; oven temperature: 40 °C, injection volume: 5.0 μΐ, flow rate: 15.0 min at 0.8 mL/min, 0.8 mL/min -> 1.2 mL/min (2.3 min), 7.7 min holding time at 1.2 mL/min; linear gradient in 2 steps: 40 % B -> 66 % B (13.0 min), 66 % B -> 85 % B (2.0 min), 10 min holding time at 85 % B; HPLC method 2:
stationary phase: Chiracel OD-RH (150 mm length, 4.6 mm ID, 5 μηη particle size); mobile phase A: 1.0 mL trifluoroacetic acid / 1 L water; mobile phase B: acetonitrile; UV detection at 210 nm; oven temperature: 20 °C, injection volume: 10.0 μί, flow rate: 1.0 mL/min; gradient: isocratic at 60 % B (25 min); enantiomeric purity of (2R)-2-(4-fluorophenyl)-N-[4-(2-{[2- methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide.
HPLC method 3:
stationary phase: Acclaim Trinity PI (50 mm length, 3.0 mm ID, 3 μηη particle size); mobile phase A: 7.70 g ammonium acetate + 1.9 mL glacial acetic acid / 1 L water; mobile phase B: acetonitrile; UV detection at 220 nm; oven tennperature: 40 °C, injection volume: 6.0 μΐ, flow rate: 0.8 mL/min; gradient: isocratic at 35 % B (8 min); assay of 4- methyl benzenesulfonic acid in a range of 21.2-25.9 % (Rt = 3.4 min, determined against a suita ble 4-methyl benzenesulfonic acid reference standard).
X-RAY CRYSTALLOGRAPHY :
Data collection for X-ray powder diffraction (XRPD) was carried out in transmission mode on automated STOE Powder Diffractometers using germanium- monochromatized CuKcci -radiation. The X-ray tube with copper anode was operated by 40 kV and 40 mA. The 2Θ scans were performed between 2 °< 2Θ < 40° 2Θ < 35 ° (stepwidth 0.5 ° ). Data acquisition and evaluation were performed using the STOE WinXpow software package. One of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in an X-ray diffraction pattern may fluctuate depending upon crystal ha bitus of the material and measurement conditions employed. It is further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle theta for a conventional X-ray diffraction pattern at a given temperature is typically a bout ± 0.1, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, the term "about" when used herein in reference to X-ray powder diffraction patterns means that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figure disclosed herein. Any crystal form that provides X-ray diffraction patterns that is substantially identical to those disclosed in the accompanying Figure falls within the scope of the present invention. The a bility to ascertain whether the polymorphic forms of a compound are the same albeit the X- ray diffraction patterns are not completely identical is within the purview of one of ordinary skill in the art. THERMOGRAVIMETRY
One of ordinary skill in the art will appreciate that thernnoanalytical data may be obtained with a measurement error that is dependent upon the measurement conditions employed.
In particular, the melting point is influenced by parameters like particle size, chemical purity, physical purity, measurement conditions (e.g. heating rate, and instrumental set-up).
Example 1 : Preparation of crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2- methoxy-4-(methylsulfonyl)phenvnamino}fl,2,41triazolofl,5-a1pyridin-6- vDphenyllpropanamide 4-toluene-sulfonate : method 1 (without seeding)
Figure imgf000028_0001
Without seeding:
10 g (17.9 mmol) of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide were suspended in 2-butanone (100 ml) and heated to 65°C 4.08 g (21.4 mmol) 4-toluenesulfonic acid monohydrate in 2- butanone (20 ml) were added at 65°C. The suspension dissolved and the product precipitated from solution. The mixture was stirred for 21h at 65°C. The mixture was cooled to 20°C over 2h. After 2h stirring at 20°C the precipitate was isolated by suction filtration and washed two times with 100 ml 2-butanone (each). The product was dried in vacuum (approximately 60 mbar) at 50°C for 7h. 12.4 g (95 % of theory) were isolated.
Thermogravimetry showed a weight loss of 0.2 weight-% while heating from 32.0°C to 150°C. Figure 1 shows the x-ray diffractogram of the crystalline , anhydrous (2/?)-2-(4-fluorophenyl)- /V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2 4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide 4-toluenesulphonate. Table 1: X-ray powder diffraction data - strongest reflectionsstandard substance for system suitability test: silicon, Si (NIST 640b);
ref-nr. 489 SF XRD01
Peak List:
Pos. [°2Θ]
5 4
7,2
9,3
10,7
10,9
11,7
12,4
14,2
14,3
14,5
15,2
15,6
15,8
16,1
16,5
17,2
17,5
17,9
18,2
18,5
18,7 ,0,2,4,6,8,0,7,1,3,8,7,0,4,4,7,0,1,0,3,7,1,4,2,4,7,8,9,3,8,5,2,7 32,3
32,8
33,0
33,3
33,8
34,1
34,6
35,6
36,3
36,6
37,3
37,9
Example 2 : Preparation of crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2- methoxy-4-(methylsulfonyl)phenyllamino}[l,2,41triazolo[l,5-alpyridin-6- vDphenyllpropanamide 4-toluenesulphonate : method 2 : with seeding
10 g (17.9 mmol) of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide were suspended in 2-butanone (110 ml) and heated to 65°C. 4.08 g (21.4 mmol) 4-toluenesulfonic acid monohydrate in 2- butanone (20 ml) were added at 65°C over a period of 90 min. After addition of 5 ml of this solution, i.e. 20 min after start of dosing, the reaction mixture (a suspension) was seeded with the tosylate anhydrate salt. Seeding was repeated after 15 min, i.e. after dosing of 9 ml in total. The suspension was heated to 70°C for 10 min and then cooled to 20°C within 2h. After stirring overnight the product was isolated by filtration. 11.9 g (91% of theory) were isolated.
Thermogravimetry showed a wheight loss of 0.2 weight-% while heating from 32.2°C to 150°C.
Water content was determined by the Karl-Fischer method to be 0.1 %. HPLC Method 1: RT= 10.52 min (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-
(methylsulfonyl)phenyl]amino}[l,2,4]triazolo
[l,5-a]pyridin-6-yl)phenyl]propanamide
HPLC Method 2: RT= 14.5 min; 100% enantiomeric purity; (R)-enantiomer.
HPLC Method 3: RT= 3.01 min; 4-toluenesulfonic acid lH-NMR(DMSO-d6): δ = 1.43 (3H), 2.29 (3H), 3.20 (3H), 3.88 (1H), 4.00 (3H), 7.10-7.21 (4H), 7.41-7.51 (5H), 7.56 (1H), 7.70-7.78 (5H), 7.98 (1H), 8.51 (1H), 8.72 (1H), 9.16 (1H), 10.22 (lH) ppm.
Figure 2 shows the x-ray diffractogram of the crystalline , anhydrous (2/?)-2-(4-fluorophenyl)- /V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide 4-toluenesulfonate.
Table 2: X-ray powder diffraction data - strongest reflections standard substance for system suitability test: silicon, Si (NIST 640b);
ref-nr. 489 SF XRD01
Peak List:
Pos. [°2Θ]
5,4
7,2
9,3
10,7
10,9
11,7 ,4,2,5,2,6,8,1,5,1,5,9,2,5,7,1,2,4,0,7,2,3,9,8,0,4,5,7,0,0,3,7,1 27,5
28,7
29,0
29,4
29,8
30,4
31,3
31,7
32,4
32,8
33,0
33,4
34,1
34,5
35,6
36,6
37,2
Example 3 : Preparation of crystalline (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-
(methylsulfonyl)phenyllannino}[l,2,41triazolo[l,5-alpyriclin-6-yl)phenyllpropanamide 4; toluene-sulfonate monohydrate: method 1 : without seeding
Figure imgf000034_0001
10 g (17.9 mmol) of (2/?)-2-(4-fluorophenyl)-W-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide were suspended in 2-butanone (100 ml) and water (2.4 ml) and heated to 65°C. 4.08 g (21.4 mmol) 4-toluenesulfonic acid monohydrate in 2-butanone (20 ml) were added at 65°C. The suspension dissolved and the product precipitated from solution. The mixture was stirred for 21h at 65°C and then cooled to 20°C within 2h. After 2h stirring at 20°C the precipitate was isolated by suction filtration and washed two times with 100 ml 2-butanone (each). The product was dried in vacuum (approximately 60 mbar) at 50°C for 7h. 11.4 g (85 % of theory) were isolated.
Thermogravimetry showed a wheight loss of 2.2 weight-% while heating from 32.6°C to 100°C. lH-N MR(DMSO-d6): δ = 1.43 (3H), 2.29 (3H), 3.20 (3H), 3.87 (1H), 4.00 (3H), 4.40-4.95 (broad signal, water) 7.09-7.21 (4H), 7.41-7.50 (5H), 7.55 (1H), 7.69-7.78 (5H), 7.97 (1H), 8.51 (1H), 8.67 (1H), 9.15 (1H), 10.21 (1H) ppm. Figure 3 shows the the x-ray diffractogram of the crystalline (2/?)-2-(4-fluorophenyl)-/V-[4-(2- {[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6- yl)phenyl]propanamide 4-toluenesulfonate monohydrate (compound of formula (II), herein also referred to as "the monohydrate tosylate salt"):
Figure imgf000035_0001
(ID standard substance for system suitability test: silicon, Si (N IST 640b);
ref-nr. 489 SF XRD01
Peak List:
Pos. [°2Θ] ,3,7,3,1,6,0,71,42,33,94,7,4,9,5,3,5,8,6,16,77,17,77,88,28,49,49,59,70,10,51,21,51,92,32,52,83,2 3,6
24,2
24,5
24,7
25,1
25,4
26,1
26,9
27,5
27,8
28,4
29,0
30,0
30,3
31,4
31,8
32,2
32,6
33,8
35,2
37,2
Example 4 : Preparation of crystalline (2/?)-2-(4-fluorophenyl)-/\/-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyllamino}[l,2,41triazolo[l,5-alpyridin-6-yl)phenyllpropanamide 4- toluene-sulfonate monohydrate : method 2 : with seeding
Figure imgf000038_0001
6 g (10.7 mmol) of (2/?)-2-(4-fluorophenyl)-/V-[4-(2 [2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide were suspended in 2-butanone (60 ml) and water (1.4 ml) and heated to 70°C. A solution of 2.4 g (12.9 mmol) 4- toluenesulfonic acid monohydrate in 2-butanone (9.7 ml) was prepared and added to the suspension over 90 min. After addition of 10% (1.2 g) of the solution 10 mg of seeds, (2/?)-2- (4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l 5- o]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate monohydrate, were added to the suspension. After complete addition of the toluenesulfonic acid monohydrate solution stirring was continued for lh at 70°C. The mixture was cooled to roomtemperature over 2h and stirred at this temperature for 16h. The precipitate was isolated by suction filtration and washed two times with 60 ml 2-butanone (each). The product was dried in vacuum (approximately 60 mbar) at 50°C for 5h. 6.5 g (81 % of theory) were isolated.
Thermogravimetry showed a wheight loss of 2.4 weight-% while heating from 31.6°C to 125°C.
Figure 4 shows the the x-ray diffractogram of the crystalline (2R)-2-(4-fluorophenyl)-/V-[4-(2- {[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6- yl)phenyl]propanamide 4-toluenesulfonate monohydrate obtained with seeding.
Example 5 : Stability assessment of the crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4- (2-{[2-methoxy-4-(methylsulfonyl)phenyllamino}[l,2,41triazolo[l,5-alpyridin-6- vDphenyllpropanamide 4-toluene-sulphonate ("anhydrous tosylate salt") 6.55 g of the crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulphonate, 3.2 g of hydroxypropyl methylcellulose (HPMC), and 0.5 g of sodium dodecyl sulfate (SDS) were mixed in 75.17 g water.
The suspension was stirred at room temperature (20 °C to 25 °C) for 48 h.
The crystalline, anhydrous (2 ?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulphonate was stable. There was no formation of the monohydrate tosyalte salt, i.e. crystalline (2/?)-2- (4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5- a]pyridin-6-yl)phenyl]propanamide 4-toluenesulphonate monohydrate.
Example 6: Preparation of a pharmaceutical composition containing the crystalline, anhydrous (2R)-2-(4-fluorophenyl)-/ /-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenvn- amino}[l,2,4ltriazolo[l,5-alpyridin-6-yl)phenyllpropanamide 4-toluenesulphonate
The suspension of Example 5 (85.42 g) was sprayed on a mixture consisting of 36 g lactose monohydrate, 38.5 g Avicel PH 101, and 4.5 g Ac-Di-Sol by means of a fluid bed granulator. 0.68 g of magnesium stearate was added to 81,16 g of the obtained mixture.
Tablets of 180 mg weight (arithmetic mean) were pressed.
Example 7 : Oral Bioavailability
In accordance with WO 2014/195408, in order to investigate the relative bioavailability of the anhydrous tosylate salt and the tosylate monohydrate and in comparison of the free base, a studies were conducted in Wistar rats with oral administration of aqueous Tylose suspension. Each of them is referenced to the formulation of the free base in PEG400/EtOH/Solutol HS 15 (70/5/25).
In the studies microcrystalline aqueous suspension of 0.5% Tylose¾ (w/v) and the reference solution (PEG400/EtOH/Solutol = 70/5/25) have been administered to male Wistar rats (n = 4 each) at 1.9 mg/kg. Approximately 0.4 mL of whole blood was collected via an indwelling jugular catheter. The blood samples were centrifuged (approx. 5 min.) in order to obtain plasma which was then transferred to the appropriately labelled vials and stored frozen (-20°C) until analysis for parent drug. Plasma samples were analysed via LC/MS/MS for parent drug concentration and pharmacokinetic parameters using ToxKin.
Plasma concentration-time courses run almost parallel after administration of these formulations (Figures 5 and 6). The peak plasma concentration was observed 4 h after administration for the Tylose suspension of the free base, free base reference solution, the tosylate monohydrate suspension and for the anhydrous tosylate suspension, respectively. Cmax,norm [0.237 (reference solution), 0.0191 (free base tylose suspension), 0.173 (tosylate monohydrate tylose suspension) kg/L] and AUCnorm [3.63 (reference solution), 0.316 (free base tylose suspension) and 2.43 (tosylate monohydrate suspension) kg-h/L] differed across these formulations with corresponding relative bioavailabilities amounting to 100%, 8.7% and 66.9%, respectively.
The comparison of the anhydrous tosylate to the reference solution provided the following data:
Cmax,norm [0.289 (reference solution), 0.129 (anhydrous tosylate tylose suspension) kg/L] and AUCnorm [3.74 (reference solution) and 2.62 (anhydrous tosylate suspension) kg-h/L] differed across the two formulations with corresponding relative bioavailabilities amounting to 100%, and 70.0%, respectively.
Suspensions of (A) the compound of formula (I), (B) the compound of formula (II) and (C) the free base ((2/?)-2-(4-fluorophenyl)-W-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo-[l,5-a]pyridin-6-yl)phenyl]propanamide) in aqueous Tylose solutions (0.5%) were administered to Wistar rats. The results are summarized in the following table:
Figure imgf000040_0001
Example 8 : Apparent dissolution rates Apparent dissolution rates (ADR) were determined using the USPIV Flow-Through-Cell as described previously (Muenster U et al. European Journal of Pharmaceutics and Biopharmaceutics 102 (2016) 191-201.):
ADRs were determined using the mini-flow-through-cell (USP apparatus IV, Sotax, Basel, Switzerland), equipped with 400 μΙ cells. Before filling the cells with glass beads and API, a Whatman glass microfiber filter membrane (Whatman, Kent, United Kingdom) was placed on the bottom of the cell. Then, 30% of the cell volume was filled with 0.1 mm glass beads (Fisher Scientific, Germany).
On top of that was placed 1 mg of API, referring to free base. The API was then covered by a thin layer of 0.1 mm glass beads, followed by filling of another 30% of the cell volume with 1 mm glass beads (Sartorius, Germany). Then, the mixture of API, 0.1 mm glass beads, and 1 mm glass beads was mixed with a spatula until homogeneity was achieved, according to visual inspection. Then the remaining free cell space was filled with 0.1 mm glass beads, and the cell covered on top with the same Whatman glass microfiber filter membrane as was used to cover the bottom of the cell. Flow-through-cells were then equilibrated to 37°C in a water bath. Finally, a flow rate of 2 ml/min using aqueous media (phosphate citrate buffer, pH 6.8, 50 mOsm/kg; acetate buffer, pH 4.5, osmolarity, 75 mOsm/kg; 0.1 M HCI, pH 1, fasted state simulated intestinal fluid (FaSSIF; www.biorelevant.com) and fed state simulated intestinal fluid (FeSSIF; www.biorelevant.com) was applied to the Flow-Through- Cells, and 2 min fractions of 4 ml each were collected up to 14 min after the start of the experiment. The amount of dissolved compound in each fraction was determined by H PLC (HP1100,Waldbronn, Boblingen, Germany). Cumulative API amounts after 14 minutes of respective fractions are reported in the following table.
Measured in vitro dissolution API In vivo ^g/14min.) dissolution API
Compound pH 1 pH PH FaSSIF FeSSIF Frel rat p.o.
4.5 6.8 (pH 6.5) (pH 5.5)
(2R)-2-(4-fluorophenyl)-
N-[4-(2-{[2-methoxy-4- < 10 < 10 < 10 55 225 9% @ 1.9mg/kg
(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5
-a]pyridin-6- yl)phenyl]propanamide
Tosylate monohydrate < 10 < 10 < 10 139 433 67% @
1.9mg/kg
Anhydrous Tosylate < 10 < 10 < 10 164 525 70% @
1.9mg/kg
Data show that apparent dissolution of the free base, (2R)-2-(4-fluorophenyl)-N-[4-(2-{[2- methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide, and both salt fornns in standard aqueous media at pH 1, 4.5, and 6.8 was low (< 10μg / 14 minutes released). When looking at apparent dissolution in FaSSIF and FeSSIF, both salt forms dissolved faster than the free base. This observation most likely explains the increased oral bioavailability of the two salt forms in rat after oral application of crystalline API suspensions, when compared to free base (see table above).

Claims

1. Crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate, characterized in that it has XRPD peaks [°2Θ] (Copper (Cu)) of about 5.4, 15.6, 16.5, 20.0, and 24.4.
2. The crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanannide 4- toluenesulfonate according to claim 1, characterized in that it has XRPD peaks [°2Θ] (Copper (Cu)) of about 5.4, 15.6, 16.5, 20.0, 24.4, 24.5 and 25.0.
3. Crystalline (2/?)-2-(4-fluorophenyl)-/\/-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate monohydrate, characterized in that it has XRPD peaks [°2Θ] (Copper (Cu)) of about 5.7, 13.9, 15.8, 18.2, and 18.4.
4. The crystalline (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate monohydrate according to claim 3, characterized in that it has XRPD peaks [°2Θ] (Copper (Cu)) of about 5.7, 13.9, 15.8, 18.2, 18.4, 22.8 and 25.1.
5. A method of preparing crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2- methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6- yl)phenyl]propanamide 4-toluenesulphonate according to claim 1 or 2, said method comprising the steps of : a) providing a suspension of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-
(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide in a suspension agent, said suspension agent containing less than 2 vol.-% water; b) optionally heating the suspension to a temperature of between (7B - 15 K) and 7B; wherein 7B is the boiling point of the suspension agent under normal conditions; cl) adding a portion of p-toluenesulfonic acid to the suspension obtained from step b); c2) adding one or more crystallization seeds to the suspension obtained from step cl);
c3) repeating step cl) and, optionally, repeating step c2) one or more times until the total amount of said p-toluenesulfonic acid is added; d) stirring the suspension, particularly at a temperature of between (7B - 15 K) and 7B; e) optionally cooling down the suspension to a temperature of below 50°C; g) separating the thus-formed (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide 4-toluenebenzenesulfonate salt from the liquid phase, thereby providing said crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulphonate.
6. The method according to claim 5, wherein said p-toluenesulfonic acid is p-toluenesulfonic acid monohydrate.
7. The method according to claim 5 or 6, wherein said p-toluenesulfonic acid is added in solution in a solvent, said solvent being said suspension agent.
8. The method according to any one of claims 5 to 7, wherein said suspension agent is acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), tetrahydrofuran (THF), or a mixture thereof.
9. The method according to any one of claims 5 to 8, wherein steps cl), c2) and c3) are replaced by steps cl), c2), c3), c4), and c5): adding a first portion of p-toluenesulfonic acid to the suspension obtained from step b), said first portion having an amount Q1 of 10 weight-% to 30 weight-% of the total amount of said p-toluenesulfonic acid; adding one or more crystallization seeds to the suspension obtained from step cl);
adding a second portion of p-toluenesulfonic acid to the suspension obtained from step c2), the second portion having an amount Q2 of 10 weight-% to 100 weight-% of the total amount of p-toluenesulfonic acid; adding one or more crystallization seeds to the suspension obtained from step c3); if neccessary, adding a third portion of p-toluenesulfonic acid to the suspension obtained from step c4), the third portion having an amount Q3 = (100 weight-% - Q1 - Q2) of the total amount of p-toluenesulfonic acid.
10. Crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-A/-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate according to claim 1 or 2, characterized in that it is prepared according to a method according to any one of claims 5 to 9.
11. Crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)- phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate according to claim 1 or 2, or as prepared according to a method according to any one of claims 5 to 9, for use in the treatment or prophylaxis of a cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.
12. A pharmaceutical composition comprising crystalline, anhydrous (2/?)-2-(4-fluorophenyl)- /V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6- yl)phenyl]propanamide 4-toluenesulfonate according to claim 1 or 2, or as prepared according to a method according to any one of claims 5 to 9, and one or more pharmaceutically acceptable excipients.
13. The pharmaceutical composition according to claim 12, which comprises mannitol, croscarmellose sodium, and magnesium stearate.
14. The pharmaceutical composition according to claim 12 or 13, for the prophylaxis or treatment of cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer and/or gastric cancer.
15. A pharmaceutical combination comprising:
• one or more first active ingredients, which is crystalline, anhydrous (2 ?)-2-(4- fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate according to claim 1 or 2, or as prepared according to a method according to any one of claims 5 to 9,
and
• one or more further active ingredients, in particular anticancer agents.
16. Use of crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulfonate according to claim 1 or 2, or as prepared according to a method according to any one of claims 5 to 9, for the treatment or prophylaxis of a cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.
17. Use of crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulfonate according to claim 1 or 2, or as prepared according to a method according to any one of claims 5 to 9, for the preparation of a medicament for the prophylaxis or treatment of a cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non- small cell lung carcinoma, breast cancer, and/or gastric cancer.
18. A method of treating cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer and/or gastric cancer, said method comprising administering crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2- methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a] pyridin-6- yl)phenyl]propanamide 4-toluenesulfonate according to claim 1 or 2, or as prepared according to a method according to any one of claims 5 to 9, or a pharmaceutical composition comprising said crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2- methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a] pyridin-6- yl)phenyl]propanamide 4-toluenesulfonate according to any one of claims 12 to 14, or a pharmaceutical combination comprising said crystalline, anhydrous (2/?)-2-(4-fluorophenyl)- /V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6- yl)phenyl]propanamide 4-toluenesulfonate according to claim 15 or 16, to a patient in need thereof.
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Citations (3)

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WO2013087579A1 (en) 2011-12-12 2013-06-20 Bayer Intellectual Property Gmbh Substituted triazolopyridines and their use as ttk inhibitors
WO2014009219A1 (en) 2012-07-10 2014-01-16 Bayer Pharma Aktiengesellschaft Method for preparing substituted triazolopyridines
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WO2013087579A1 (en) 2011-12-12 2013-06-20 Bayer Intellectual Property Gmbh Substituted triazolopyridines and their use as ttk inhibitors
WO2014009219A1 (en) 2012-07-10 2014-01-16 Bayer Pharma Aktiengesellschaft Method for preparing substituted triazolopyridines
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