ENZALUTAM IDE DERIVATIVES FOR THE TREATMENT OF PROSTATE AND BREAST

CANCER

Field of the invention The present invention relates to diarylhydantoin compounds for use in the treatment of prostate cancer, in particular castration-resistant prostate cancer, and breast cancer.

Background Prostate cancer represents a major worldwide health problem and is now recognised as the fifth leading cause of death from cancer in men globally. Despite numerous advances in both palliative care and curative treatments, there remains a need for improving methodologies for managing the disease. The difficulties associated with disease management are attributed to a variance in both the stage at which a patient becomes first diagnosed and clinical morbidity across the stages.

As with various malignant cancers, the early disease stage is often characterised by a confined and localised tumour. Diagnosis of prostate cancer within the early disease stage allows practitioners to treat patients by invasive surgery or radiation therapy. In situations where patients are diagnosed at a more advanced stage i.e. when metastasis has occurred, the use of small molecule therapeutics becomes necessary.

Prostate cancer cell growth is a hormone dependent process. In short, testosterone binds to the androgen receptor (AR) which in turn leads to activation of the receptor. AR activation initiates a biochemical cascade that ultimately fuels the growth of prostate cancer cells. Targeting this biochemical pathway through reducing the levels of biological androgens (e.g. testosterone) offers an effective approach to the short-term management of the disease (i.e. stopping or slowing tumour growth).

The established treatment approach for patients suffering from advanced prostate cancer involves testosterone suppression via surgical or medical castration. Owing to the irreversibility of surgical castration several antiantidrogens have also been developed and designed to inhibit the binding of testosterone to the AR and thus prevent downstream growth of prostate cancer cells.

The vast majority of patients (including those receiving antiandrogen therapy) will subsequently progress to a disease state wherein they experience castration-resistant prostate cancer (i.e. hormone-refractory prostate cancer).

Castration-resistant prostate cancer is diagnosed and defined by the ability of cancer cells to continue to grow under circumstances in which hormone levels have been supressed or reduced through surgical or small molecule intervention. Most typically, the disease state is characterised by metastases of the cancer to remote sites away from the prostate. In such cases prostate cancer most commonly metastasises to the bone.

The small molecule therapeutic bicalutamide is one example of an antiandrogen used in the treatment of prostate cancer, and is represented by the following structure:

Bicalutamide

Bicalutamide binds to the androgen receptor disrupting testosterone's ability to do the same. Unfortunately, although bicalutamide is effective in patients presenting with hormone dependent prostate cancer, the drug loses efficacy against AR when the cancer develops into a hormone refractory or hormone independent state.

The shortfall of bicalutamide as a long-term treatment was highlighted by its inability to prevent the progression of prostate cancer to a hormone-refractory stage and to treat hormone-refractory prostate cancer per se. The need for an improved small molecule therapeutic led to the development of the diarylhydantoin enzalutamide, which is represented by the following structure:

Enzalutamide

Enzalutamide displays a higher binding affinity for AR in comparison to bicalutamide. Most importantly, unlike bicalutamide, enzalutamide also prevents the translocation of AR to the cell nucleus and in doing so prevents AR binding to DNA and other cofactors. It is this enhanced activity that led to the approval of enzalutamide as a treatment for castration-resistant prostate cancer.

WO 2006/1241 18 describes enzalutamide amongst a series of structurally related compounds and also provides synthetic approaches to access them.

WO 2010/099238 describes metabolites of enzalutamide, and in particular compounds MI-MV which are represented by the following structures:

It is known that Ml is a biologically inactive metabolite of enzalutamide and conversely that Mil is a biologically active metabolite of enzalutamide (see WO 2010/099238).

There remains a need in the art for compounds with improved pharmacokinetic properties which retain clinical efficacy.

Summary of the invention

Accordingly, in a first aspect, the invention provides a compound of formula (I) or (Γ)

In one embodiment, the invention provides a compound of formula (I)

(I) or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a compound of formula (Γ)

or a pharmaceutically acceptable salt thereof.

The compound of formula (I) is a trityl-protected derivative of enzalutamide. The compound of formula (Γ) is a xanthene-protected derivative of enzalutamide. The trityl and xanthene derivatives provide compounds with certain improved properties compared to their methyl amide equivalent (e.g. enzalutamide). For example, the compounds of formula (I) and (Γ) may have physiochemical properties more suitable for oral exposure, for example improved oral bioavailability and/or a longer half-life, and therefore exhibit reduced dosage requirements. Further, the compounds of formula (I) and (Γ) may have fewer active metabolites and therefore are potentially less toxic. In addition, the compounds of formula (I) and (Γ) have higher organic solubility than enzalutamide and therefore can have a higher drug load in liquid-filled capsules.

Moreover, the applicant has surprisingly found derivatives that can form the required active metabolite MM, but yet are still sufficiently stable to be synthesised and marketed. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) or (Γ) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In one embodiment, the invention provides a compound of formula (I) or (Γ) for use in therapy or for use in medicine.

In particular, the invention provides: - a compound of formula (I) or (Γ) or a salt thereof or a pharmaceutical composition comprising a compound of formula (I) or (Γ) or a pharmaceutically acceptable salt thereof for use in the treatment of prostate cancer, e.g. castration-resistant prostate cancer or hormone-refractory prostate cancer, or breast cancer;

- the use of a compound of formula (I) or (Γ) or a salt thereof for the manufacture of a medicament for the treatment of prostate cancer, e.g. castration-resistant prostate cancer or hormone-refractory prostate cancer, or breast cancer; and

- a method of treating prostate cancer, e.g. castration-resistant prostate cancer or hormone-refractory prostate cancer, or breast cancer comprising administering a compound of formula (I) or (Γ) or a salt thereof or a pharmaceutical composition comprising a compound of formula (I) or (Γ) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In addition, the invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (II) with triphenylmethanol

In one embodiment, the reaction takes place in the presence of an acid, for example a protic acid or a Lewis acid.

In addition, the invention provides a process for preparing a compound of formula (Γ) or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (II) and a compound of formula (III)

(II) (ill)

In one embodiment, the reaction takes place in the presence of an acid, for example a protic acid or a Lewis acid.

General preferences and definitions

Unless the context indicates otherwise, references herein to the compound of formula (I) include the free base as well as ionic, salt, solvate, N-oxide, and protected forms thereof, for example, as discussed below.

In one embodiment, the compound of formula (I) or (Γ) is in the form of a free base.

The compound of formula (I) or (Γ) includes variants with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope H, ² H (D), and ³ H (T). Similarly, references to carbon and oxygen include within their scope respectively ² C, ³ C and ⁴ C and ⁶ 0 and ⁸ 0.

Also encompassed by the compound of formula (I) or (Γ) are any polymorphic forms of the compounds, solvates (e.g. hydrates), and complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds.

Synthetic methods The compound of formula (I) can be prepared by a process comprising reacting a compound of formula (II) with triphenylmethanol.

(II) In particular, the compound of formula (I) is reacted with triphenylmethanol in the presence of an acid e.g. a protic acid or a Lewis acid. In addition, the invention provides a process for preparing a compound of formula (Γ) or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (II) and a compound of formu

(II) (ill) In one embodiment, the reaction takes place in the presence of an acid, for example a protic acid or a Lewis acid.

In accordance with the present invention the term protic acid should be understood as encompassing acids that can be described by both, or either of the Arrhenius acid and Bransted-Lowry acid definitions.

An Arrhenius acid is a substance that, when added to water, increases the concentration of protons (H ⁺ ) ions in the water. For the avoidance of doubt, the increase of protons in water will in fact be represented by an increase in the hydronium ion H ₃ 0 ⁺ as protons per se cannot subsist in water. A Br0nsted-Lowry acid is a species that donates a proton to a Bransted-Lowry base (a proton acceptor). The following equations demonstrate the use and applicability of each of the Arrhenius and Br0nsted-Lowry definitions, the protic acid exemplified being acetic acid:

(a) CH3COOH + H2O ^■ CH3COO + H ₃ 0 ⁺

(b) CH3COOH + NH3 - CH ₃ COCT + NI-l ₄ ⁺

Equation (a) can be described by both definitions of protic acid. First, acetic acid can be said to act as an Arrhenius acid, because following addition to, or reaction with water, the concentration of H ₃ 0 ⁺ increases. Secondly, acetic acid is also acting as a Br0nsted-Lowry acid by donating a proton to water. Equation (b) highlights a similar situation wherein acetic acid donates a proton to ammonia and thus again behaves like a Bransted-Lowry acid, however equation (b) cannot be described by the Arrhenius definition, because the reaction is occurring in the absence of water. Examples of typical protic acids that are considered to fall within the definitions as set out above are acetic acid, formic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, phosphoric acid, benzoic acid, citric acid, tartaric acid, nitric acid, hydrobromic acid, hydrofluoric acid, carbonic acid, potassium bisulfate, anthranilic acid, ethylenediaminetetraacetic acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malonic acid, oxalic acid, peracetic acid, propionic acid, phthalic acid, salicyclic acid, succinic acid and sulfamic acid.

Furthermore, and in accordance with the present invention, it should be understood that the term protic acid is intended to cover protic acids that when added to water in an amount sufficient to form a 1 molar aqueous solution at 25°C, the resulting solution will have pH less than 7 when measured by conventional methods e.g. a pH meter.

In accordance with the present invention the term Lewis acid should be understood as encompassing a species that can accept a pair of electrons (e.g. either in a covalent chemical bonding or chemical co-ordination event) from a Lewis base.

Examples of typical Lewis acids that are considered to fall within the definition as set out above are AICI ₃ , AIBr ₃ , BF ₃ .OEt ₂ , Cu(OTf) ₂ , Yb(OTf) ₂ , Yb(OTf) ₃ , SnCI ₄ , TiCI ₄ and Ti(0/Pr) ₄ . It should however be understood that Lewis acid compounds comprising any of the metals in the following oxidation state are also suitable for use in conjunction with the present invention, Li ⁺ , Na ⁺ , K ⁺ , Be ²⁺ , Mg ²⁺ , Ca ²⁺ , Sr ²⁺ , Al ³⁺ , Ga ³⁺ , ln ³⁺ , Sn ²⁺ , Sc ³⁺ , La ³⁺ , Ti ⁴⁺ , Zr ⁴⁺ , Cr ³⁺ , Fe ³⁺ , Co ³⁺ , lr ³⁺ , Th ⁴⁺ and Yb ³⁺ .

The process for preparing a compound of formula (I) or (Γ) is preferably conducted in a solvent (i.e. an organic solvent) or a mixture of solvents.

It is known in the art which particular solvent is likely to be most appropriate and most effective for each category of chemical transformation. For example, water- or air-sensitive transformations require the use of non-aqueous, non-protic solvents such as acetonitrile, tetrahydrofuran, dioxane, dimethylsulfoxide dichloromethane, chloroform or A/-methylpyrrolidine. Furthermore, water- or air- sensitive reactions may also require an atmosphere of inert gas (to prevent atmospheric water from compromising a transformation) typical inert gases include nitrogen and argon. Alternatively, reactions requiring the use of an aqueous reagent (e.g. aqueous hydrochloric acid or aqueous sodium hydroxide) may require the use of one or more organic co-solvents. In this context, an organic co- solvent is added to aid the dissolution, or partial dissolution of a less polar organic reagent. Typical organic co-solvents for use with such aqueous reagents include, toluene, alcohols (methanol, ethanol, propanol), tetrahydrofuran and dimethylsulfoxide. The only limitation in regard to reaction efficacy when using organic co-solvents with aqueous solvents is the requirement for some degree of miscibility of the organic co-solvent with water. To aid problems with miscibility and or reaction efficacy a phase transfer catalyst is employed (e.g. tetrabutylammonium bromide). Solvents are traditionally categorised into two categories, polar and non-polar. More specifically solvents are allocated into each category according to their dielectric constant. It is generally accepted that solvents displaying a dielectric constant of less than 15 are considered to be non-polar solvents, and solvents displaying a dielectric constant of greater than or equal to 15 are considered to be polar solvents.

Preferred solvents for use in preparing a compound of formula (I) or (Γ) are non-polar solvents. A particularly preferred solvent for use in preparing a compound of formula (I) or (Γ) is benzene or toluene.

It is most preferred where the process of preparing a compound of formula (I), comprising reacting a compound of formula (II) with triphenylmethanol, in the presence of a protic acid or a Lewis acid is conducted in benzene or toluene.

It is most preferred where the process of preparing a compound of formula (Γ), comprising reacting a compound of formula (II) with and a compound of formula (III), in the presence of a protic acid or a Lewis acid is conducted in benzene or toluene. Purification of a compound of formula (I) or (Γ) is simplified by the advantageous crystalline properties the compound per se possesses. Upon completion of the condensation reaction, the resulting precipitate can be collected via filtration and washed with reaction solvent (e.g. benzene). Following washing, the compound of formula (I) or (Γ) can be collected and recrystallised from (i) isopropyl alcohol and (ii) methanol (if deemed necessary).

Purification of the compound of formula (I) or (Γ) by crystallisation offers an improvement in the operational and economical ease of purification and isolation. Recrystallisation of a final compound removes the need for conventional column chromatography and high-performance liquid chromatography techniques, which although well-established and ubiquitous in discovery chemistry, present an unwanted economic and time burden to chemists operating at the process level (i.e. producing multi-kilogram and multi-tonne quantities of drug). Recrystallisation of the final compound also provides an opportunity of reducing upstream purifications through telescoping of individual reaction steps (wherein two or more, previously independent synthetic transformations converge into a "single" process and therefore require only one purification step).

In accordance with the present invention, it is preferred where the process of preparing a compound of formula (I), comprising reacting a compound of formula (II) with triphenylmethanol, in the presence of a protic acid or a Lewis acid is conducted in benzene or toluene and wherein the compound of formula (I) is recrystallised from an alcoholic solvent. It is more preferred where the process of preparing a compound of formula (I), comprising reacting a compound of formula (II) with triphenylmethanol, in the presence of a protic acid or a Lewis acid is conducted in benzene or toluene and wherein the compound of formula (I) is recrystallised from isopropyl alcohol or first from isopropyl alcohol, and secondly from methanol. In accordance with the present invention, it is preferred where the process of preparing a compound of formula (Γ), comprising reacting a compound of formula (II) with a compound of formula (III), in the presence of a protic acid or a Lewis acid is conducted in benzene or toluene and wherein the compound of formula (Γ) is recrystallised from an alcoholic solvent. It is more preferred where the process of preparing a compound of formula (Γ), comprising reacting a compound of formula (II) with a compound of formula (III), in the presence of a protic acid or a Lewis acid is conducted in benzene or toluene and wherein the compound of formula (Γ) is recrystallised from isopropyl alcohol or first from isopropyl alcohol, and secondly from methanol.

Purification of intermediates synthesised en route to the compound of formula (I) and (Γ) can be performed using methods known in the art. Compounds can be purified by, for example, normal phase liquid chromatography, reversed phase high-performance liquid chromatography, recrystallisation or salt formation.

The product of the process can be a compound of formula (I) or (Γ) or a pharmaceutically acceptable salt or solvate thereof.

In particular, the compound of formula (I) can be accessed according to the following synthetic approach:

(I) (II) The compound of formula (I) is provided in a 5-step linear sequence starting from commercially available 2-fluoro-4-nitrobenzoic acid. The synthesis begins with a functional group interconversion of a benzoic acid moiety into a benzamide via an acyl chloride mediated amidation reaction. Following installation of the amide, the p-nitro group is reduced to the corresponding amine via hydrogen transfer over iron metal and acetic acid. The resulting aniline derivative then undergoes a Sn1 alkylation reaction with ethyl bromoisobutyrate and in so forms a coupling partner for the subsequent condensation reaction with 3-trifluromethyl-4-cyanophenyl isothiocyanate. The condensation reaction provides N-desmethyl enzalutamide, which then undergoes a further Sn1 alkylation reaction with trityl alcohol in the presence of paratoluenesulfonic acid (PTSA) to generate the desired trityl derivative.

In particular, the compound of formula (Γ) can be accessed according to the following synthetic approach:

The compound of formula (III) is available in a single step via the reduction of xanthone with a hydride reagent, for example sodium borohydride, according to the following synthetic approach:

The compound of formula (Γ) is provided in a 5-step linear sequence starting from commercially available 2-fluoro-4-nitrobenzoic acid. The synthesis begins with a functional group interconversion of a benzoic acid moiety into a benzamide via an acyl chloride mediated amidation reaction. Following installation of the amide, the p-nitro group is reduced to the corresponding amine via hydrogen transfer over iron metal and acetic acid. The resulting aniline derivative then undergoes a Sn1 alkylation reaction with ethyl bromoisobutyrate and so forms a coupling partner for the subsequent condensation reaction with 3-trifluromethyl-4-cyanophenyl isothiocyanate. The condensation reaction provides N-desmethyl enzalutamide, which then undergoes a further Sn1 alkylation reaction with xanthydrol (III) in the presence of acetic acid to generate the desired xanthene derivative.

In an approach parallel to the synthesis of the trityl derivative, it was envisaged that the ieri-butyl carbonate-containing derivative (formula IV) might also provide a derivative with one or more improved pharmacokinetic properties (e.g. compared to enzalutamide). The compound of formula (IV) was accessed according to the following synthetic approach:

(IV) (ii)

The ieri-butyl carbonate-containing derivative was available from the reaction of N-desmethyl enzalutamide with di-ieri-butyl dicarbonate in the presence of 4-(dimethylamino) pyridine.

However, following purification of compound (IV) analysis indicated that the compound was surprisingly unstable, and thus unsuitable for further development. Pharmaceutical compositions

While it is possible for the compound of formula (I) or (Γ) to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising a compound of formula (I) or (Γ) together with one or more pharmaceutically acceptable excipients, carriers, adjuvants, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.

The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each excipient, carrier, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.

Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.

A preferred composition is one in which the formulation is provided in a capsule. Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.

A particularly preferred capsule formulation comprises a compound of formula (I) or (Γ), and one or more excipient selected from caprylocaproyl macrogol-8 glycerides, butylhydroxyanisole and butylhydroxytoluene. The compound the compound of formula (I) or (Γ) has higher organic solubility than enzalutamide and therefore can have a higher drug load in the preferred liquid-filled capsules.

Pharmaceutical compositions containing a compound of formula (I) or (Γ) can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The compound of formula (I) or (Γ) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation intended for oral administration may contain from 1 ng to 2 mg, for example 0.1 mg to 2 g of active ingredient, more usually from 10 mg to 1 g, e.g. 50 mg to 500 mg, or 0.1 mg to 2 mg.

In accordance with the presence invention, it is preferred where the capsules comprise a compound of formula (I) or (Γ) in an amount of 1 to 250 mg, it is more preferred wherein the capsules comprise a compound of formula (I) or (Γ) in an amount of 50 to 250 mg. The compound of formula (I) or (Γ) will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

Therapeutic uses The present invention provides a compound of formula (I) or (Γ) for use in therapy.

It is anticipated that following administration to a patient in need thereof (for example a human or animal patient) the compound of formula (I) or (Γ) will liberate the biologically active metabolite MM.

(!') MM

Metabolite MM is active against the androgen receptor (AR) and thus by extension, the compounds of formula (I) and (Γ) are therefore also suited towards diseases that are dependent upon and modulated by the activity of the androgen receptor. In particular, the present invention provides a compound of formula (I) or (Γ) for use in the treatment of prostate cancer, and in particular castration-resistant prostate cancer or hormone-refractory prostate cancer. The compound will typically be administered in an amount that is therapeutically or prophylactically useful and which is generally non-toxic. However, in certain situations (for example in the case of life threatening diseases), the benefits of administering a compound of formula (I) or (Γ) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer the compound in an amount that is associated with a degree of toxicity.

The compound may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively, the compound may be administered in a pulsatile manner. A typical daily dose of the compound can be in the range from 100 pg to 100 mg per kilogram of body weight, typically 10 ng to 10 mg per kilogram of bodyweight, more typically 1 μg to 10 mg although higher or lower doses may be administered where required. Ultimately, the quantity of compound administered will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

The compound of the formula (I) or (Γ) can be administered as the sole therapeutic agent or can be administered in combination therapy with one of more other compounds for treatment of a particular disease state. Where the compound of the formula (I) or (Γ) is administered in combination therapy with one or more other therapeutic agents, the compounds can be administered simultaneously or sequentially. When administered sequentially, they can be administered at closely spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).

The compound of formula (I) or (Γ) may also be administered in conjunction with non- chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diets.

For use in combination therapy with another chemotherapeutic agent, the compound of formula (I) or (Γ) and one, two, three, four or more other therapeutic agents can be, for example, formulated together in a dosage form containing two, three, four or more therapeutic agents. In an alternative, the individual therapeutic agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use. A person skilled in the art would know through their common general knowledge the dosing regimens and combination therapies to use. The present invention will now be described with reference to the examples, which are not intended to be limiting.

Examples Example 1

4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-o xo-2-thioxoi

benzamide

Trityl alcohol (8.6 g), N-desmethyl enzalutamide (10 g) and PTSA (2.5 g) were added to benzene (100 mL) at a temperature of 20-30°C. The reaction mixture was heated to 80-85°C and allowed to stir for 3-4 hours. Following which, the reaction mixture was allowed to cool to 10-15°C and stirred for a further 30-60 minutes. The solid precipitate was filtered and the filter cake washed with benzene (15 mL). The product was collected and recrystallised from isopropyl alcohol (450 mL) to obtain the desired product (15 g). The product could be further purified by performing a second recrystallisation from methanol, to obtain the desired product (10 g). H NMR (CDCI ₃ ): δ 1.57-1.60 (d, 6H), 7.16-7.35 (m, 17H), 7.81-7.83 (d, 1 H), 7.94-8.04 (m, 3H), 8.16-8.20 (d, 1 H); ³ C NMR (CDCI ₃ ): δ 23.8, 66.6, 71.2, 1 10.4, 1 14.7, 1 18.0, 123.5, 123.5, 126.2, 126.3, 127.2, 128.1 , 128.6, 132.1 , 135.3, 136.8, 139.0, 139.1 , 144.3, 159.2, 160.8, 174.4, 179.7.

Pure 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1-yl)-2-fluoro- N-trityl benzamide was stored at 2-8°C for 60 days. HPLC analysis of the compound following the storage period indicated no deterioration in purity.

Example 2

Deprotection of 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5, 5-dimethyl-4-oxo-2-thioxoimidazolidin- 1 -yl)- 2-fluoro-N-trityl benzamide to N-desmethyl enzalutamide in trifluoroacetic acid

4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-o xo-2-thioxoimidazolid

benzamide was added to trifluoroacetic acid (9 mL), dichloromethane (0.5 mL) and water (0.5 mL) at a temperature of 20-30°C and stirred for 2 hours. The mixture was allowed to cool to a temperature of 10-20°C and the pH was adjusted to 7-7.5 using a 5% NaOH solution. The mixture was diluted with H ₂ 0 (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated under reduced pressure (at a temperature below 50°C) to obtain a residue. The residue was then analysed by HPLC to identify the proportion of deprotected product. Analysis indicated less than 1 % of unreacted starting material and greater than 90% conversion to N-desmethyl enzalutamide.

Example 3

4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-o xo-2-thioxoi

xanthyl benzamide

Xanthyldrol (1 1 g) and N-desmethyl enzalutamide (10 g) were added to acetic acid at a temperature of 20-30°C. The reaction mixture was heated to 80-85°C and allowed to stir for 3-4 hours. The reaction mixture was then allowed to cool to 20-30°C. Dichloromethane (100 mL) and demineralised water (100 mL) were then added to the mixture and the mixture was heated with stirring at 40-45°C for 30 minutes. The layers were then separated and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were concentrated under reduced pressure (at a temperature below 50°C) to obtain the crude product. The crude material was purified by silica-gel column chromatography (n-hexanes:ethyl acetate). The pure fractions were combined and concentrated to obtain a viscous solid. Trituration of the solid with n-hexanes gave pure 4-(3-(4- Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo imidazolidin-1-yl)-2-fluoro-N-xanthyl benzamide after filtration (4.5 g). H NMR (CDCI ₃ ): δ 1.59 (s, 6H), 6.79-6.81 (d, 1 H), 7.09-7.28 (m, 6H), 7.31-7.35 (t, 3H), 7.54-7.56 (d, 2H), 7.80-7.82 (d, 1 H), 7.94-7.98 (d, 2H), 8.32-8.36 (t, 1 H); ³ C NMR (CDCI ₃ ): δ 23.8, 44.7, 66.6, 1 10.3, 1 14.7, 1 16.8, 1 17.9, 1 18.2, 120.4, 120.5, 122.4, 122.5, 123.7, 126.2, 126.3, 126.9, 127.1 , 129.4, 129.5, 132.1 , 133.4, 133.5, 135.3, 136.8, 139.3, 139.4, 151.1 , 159.0, 161.4, 161.5, 174.4, 179.7.

Pure 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1-yl)-2-fl^ N-xanthyl benzamide was stored at 2-8°C for 21 days. HPLC analysis of the compound following the storage period indicated no deterioration in purity.

Example 4

Deprotection of 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1-yl)- 2-fluoro-N-xanthyl benzamide to N-desmethyl enzalutamide in trifluoroacetic acid

4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-o xo-2-thioxoimidazolidin-1-yl)-2-fluoro-N- xanthyl benzamide was added to trifluoroacetic acid (9 mL), dichloromethane (0.5 mL) and water (0.5 mL) at a temperature of 20-30°C and stirred for 2 hours. The mixture was allowed to cool to a temperature of 10-20°C and the pH was adjusted to 7-7.5 using a 5% NaOH solution. The mixture was diluted with H ₂ 0 (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were concentrated under reduced pressure (at a temperature below 50°C) to obtain a residue. The residue was then analysed by HPLC to identify the proportion of deprotected product. Analysis indicated less than 1 % of unreacted starting material and greater than 90% conversion to N- desmethyl enzalutamide.

Example 5 (comparative) 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoim

butoxycarbonyl benzamide

N-desmethyl enzalutamide (1 g) and DMAP (0.1 g) were added to dichloromethane (20 mL) at a temperature of 20-30°C. To the reaction mixture was added di-ieri-butyl dicarbonate (1 .1 mL) and the mixture was stirred at 20-30°C for 3-4 hours. The reaction mixture was then concentrated under reduced pressure (at a temperature below 30°C) to obtain a residue. The residue was purified using neutral alumina column chromatography (n-hexanes:ethyl acetate) to obtain the desired product as a viscous oil.

Thin layer chromatographic analysis of the purified material on standing and after refrigeration revealed multiple impurities and indicating poor stability of the compound.