WO2016079522A1

WO2016079522A1 - Androgen receptor modulators and their use as anti-cancer agents

Info

Publication number: WO2016079522A1
Application number: PCT/GB2015/053528
Authority: WO
Inventors: Andrew D WESTWELL; Fabrizio PERTUSATI; Christopher Mcguigan; Andrea Brancale; Marcella BASSETTO; Salvatore FERLA; Sahar KANDIL
Original assignee: University College Cardiff Consultants Limited
Priority date: 2014-11-20
Filing date: 2015-11-19
Publication date: 2016-05-26

Abstract

Compounds having therapeutic potential as androgen receptor modulators and anti- cancer agents, and methods of making such compounds, are provided. The compounds are structurally related to bicalutamide, enobosarm and enzalutamide, but bear at least one SF₅ group as a substituent.

Description

Androgen receptor modulators and their use as anti-cancer agents

BACKGROUND OF THE INVENTION

[0001] Selective androgen receptor modulators are compounds that bind to androgen receptors to modulate the level of activation of the androgen receptor whilst displacing the binding of endogenous androgens. Selective androgen receptor modulators, when acting as antagonists, have therapeutic potential for treating diseases aggravated by androgens, such as benign prostatic hypertrophy, prostate cancer, and over masculinity in women. When acting as agonists for the androgen receptor, they have therapeutic potential for treating conditions associated with deficiency of androgens in men, such as hypogonadism, frailty and muscle wasting as androgen levels decline with advancing age.

[0002] Typical androgen receptor modulators are bicalutamide, enobosarm and enzalutamide; their structures are shown below:

Bicalutamide

[0003] These compounds are androgen receptor antagonists or partial agonists and are primarily useful for the treatment of prostate cancer. Bicalutamide was launched by AstraZeneca in 1995 under the brand names Casodex and Cosudex. Enobosarm, also known as Ostarine, GTx-024 and MK-2866, is an investigational selective androgen receptor modulator for treatment of conditions such as muscle wasting and osteoporosis. formerly under development by Merck & Company. Enzalutamide , marketed as Xtandi and formerly known as MDV3100, is an androgen receptor antagonist drug developed by the pharmaceutical company Medivation, approved in August 2012 for the treatment of metastatic castration-resistant prostate cancer.

[0004] These compounds and various analogues in development are characterized by an acylated aniline bearing either a nitro or a nitrile substituent, and a trifluoromethyl substituent.

[0005] The trifluoromethyl substituent is sometimes found in therapeutic compounds, typically as a substituent on a phenyl ring, but synthetic methodologies that access such structures are limited. Compounds bearing other perfluoro groups are rare.

[0006] However, these prior disclosures of the use of trifluoromethyl or perfluoro groups in medicinal chemistry have not been enabled or exemplified in the field of selective androgen receptor modulators; and the specifically enabling disclosures only refer to compounds bearing one trifluoromethyl group in the acylated aniline ring.

[0007] In the case of selective androgen receptor modulator MDV3100, described in US2007/254933, all the compounds contain the same cyanotrifluoromethylphenyl moiety, so the use of perfluorosulfanyl groups was not considered. In the case of the selective androgen receptor modulator Ostarine (GTx-024) described in US6569896, the phenyl group substituent is claimed to be either -iodo, - trifluoromethyl, -bromo, - chloro, or trialkylstannyl-, so perfluorosulfanyl groups have not been considered. Patent application, WO2008/127717, regarding the use of selective androgen receptor modulators for the treatment of diabetes, claims one trifluoromethyl as the only trifluoroalkyl substituent considered.

[0008] Bicalutamide is described in US4636505. Claims in this patent include fluoro substitutions in addition to trifluoromethyl, such as perfluoroalkyl up to four carbon atoms, the reference does not include any disclosure for perfluorosulfanyl groups and this patent does not describe any advantages that might be introduced by perfluorosulfanyl groups.

[0009] Bicalutamide, Enobosarm and Enzalutamide are described in WO2013152170 Al . Claims in this patent include different perfluoroalkyl groups replacing the trifluoromethyl group in the acylated aniline ring, with these perfluoroalkyl groups being linear or branched. The reference does not include any disclosure for perfluorosulfanyl groups and this patent does not describe any advantages that might be introduced by perfluorosulfanyl groups. SUMMARY OF THE INVENTION

[0010] The present invention provides novel compounds bearing at least one pentafluorosulfanyl group, that have utility for pharmaceutical research and development and potential therapeutic use as anti-prostate cancer agents, processes for their preparation, intermediates used in these processes and biological activities as modulators of the androgen receptor and anti-prostate cancer agents.

In one aspect of the invention, a compound having the formula (1) is provided:

wherein:

X is CN, N0₂ or H

Y is oxygen or sulfur;

Z is selected from the group consisting of

(i) Ci to C₆ alkoxy,

(ii) C₃ to C₆ cycloalkoxy,

(iii) aryloxy wherein the aryl group is five- or six-membered,

(iv) Ci to C₆ alkyl thioether,

(v) C₃ to C₆ cycloalkyl thioether,

(vi) aryl thioether wherein the aryl group is five- or six-membered,

(vii) Ci to C₆ sulfonylalkyl group,

(viii) C₃ to C₆ sulfonylcycloalkyl group,

(ix) sulfonylaryl group wherein the aryl group is five- or six-membered,

and wherein in each case (i) to (x) said alkoxy, thioether or sulfonylalkyl group optionally bears one or more groups selected from hydroxy, alkoxy (-ORi), -O- alkylene, aryloxy (-OAr), alkylthio (-SRi), -S-alkylene, arylthio (- SAr), alkylsulfoxide (-SORi), -SO-alkylene, arylsulfoxide (-SOAr), alkylsulfone (-S0₂Ri), -S0₂-alkylene, and arylsulfone (-S0₂Ar), wherein each Ri group is independently selected from CI to C4 alkyl, each Ar group is independently a five- or six- membered ring, each Ri and each Ar group optionally bears one or more substituents selected from halogen, carboxamide (where the nitrogen atom optionally bears one or more C1-C4 alkyl groups), acylamino (where the acyl group contains 1 to 4 carbon atoms), and nitrile, and each alkylene group can be straight or branched and optionally substituted with OH. A is either hydrogen, Ci to C₄ alkyl, or acyl, or A together with Z forms a five- or six- member heterocyclic group;

R and R' are, independently, either H, CN, CF₃, OCF₃, SCF₃, halogen, alkyl groups or CO HMe;

q and r are, independently, either 0, 1 or 2;

n and p are, independently, 0 or 1, provided that when n+p > 1.

[0011] For example, compounds analogous to bicalutamide, but having pentafluorosulfanyl groups (SF₅), have the formula (1), wherein X is CN or N0₂; Y is oxygen, Z is 1 -hydroxy- 1- methyl-2-(sulfonyl)ethyl, and A is hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

[0012] This invention provides compounds useful for therapeutic use as anti-prostate cancer agents. The compounds bear at least one SF₅ group in one aromatic ring. Improved therapeutic properties may result from any of (i) higher activity towards the androgen receptor, (ii) better selectivity for androgen receptors compared to binding to other proteins, or better selectivity for androgen receptors in certain tissues, (iii) improved anti-cancer activity against prostate cancer, (iv) improved metabolism or disposition profile, and (v) improved physical properties that may assist with the formulation of a therapeutic product.

[0013] Compounds of the present invention have the formula (1)

wherein:

X is CN, N0₂ or H;

Y is oxygen or sulfur;

Z is selected from the group consisting of

(i) Ci to C₆ alkoxy,

(ii) C₃ to C₆ cycloalkoxy,

(iii) aryloxy wherein the aryl group is five- or six-membered, (iv) Ci to C₆ alkyl thioether,

(v) C₃ to C₆ cycloalkyl thioether,

(vi) aryl thioether wherein the aryl group is five- or six-membered,

(vii) Ci to C₆ sulfonylalkyl group,

(viii) C3 to C₆ sulfonylcycloalkyl group,

(ix) sulfonylaryl group wherein the aryl group is five- or six-membered,

q and r are, independently, either 0, 1 or 2;

n and p are, independently, 0 or 1, provided that when n+p > 1.

Also included are physiologically acceptable salts of compounds of formula (1).

[0014] In one embodiment, the five-member heterocyclic group is 2- thioxoimidazolidin-4-one. Such group may optionally bear one or more groups selected from hydroxy, alkoxy (-ORi), -O-alkylene, aryloxy (-OAr), alkylthio (-SRi), -S- alkylene, arylthio (- SAr), alkylsulfoxide (-SORi), -SO-alkylene, arylsulfoxide (-

SOAr), alkylsulfone (-S0₂Ri), -S0₂-alkylene, and arylsulfone (-S0₂Ar), wherein each

Ri , Ar and alkylidene group is as defined above.

[0015] Nonlimiting examples of such compounds include the following:



[0016] Such compounds are readily prepared using optimised synthetic procedures adapted from the following references: (1) Bang-Chi Chen, Rulin Zhao,Stacey Gove,Bei Wang,Joseph E. Sundeen,Mark E. Salvati, and Joel C. Barrish, "Nucleophilic Aromatic Substitution of Methacryl amide Anion and Its Application to the Synthesis of the Anticancer Drug Bicalutamide", The Journal of Organic Chemistry 2003 68 (26), 10181-10182; and (2) Michael E. Jung, Samedy Ouk, Dongwon Yoo, Charles L. Sawyers, Charlie Chen, Chris Tran, and John Wongvipat, "Structure- Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration- Resistant Prostate Cancer (CRPC)" Journal of Medicinal Chemistry 2010 53 (7), 2779- 2796; the disclosures of which are incorporated by reference herein in their entirety.

[0017] Compounds containing additional halogen substitution, such as a fluorine, chlorine, or bromine atom attached to the fluoroalkylaminobenzonitrile moiety may be obtained by analogous routes to the above, either by starting with an appropriate halogenobenzene derivative, such as l-fluoro-4-iodobenzene, instead of the corresponding alkylbenzene compound, or by introducing a different halogen directly by treatment with a halogenating agent such as N-chlorosuccinimide or bromine.

[0018] With regard to the nitrogen-bearing side chain having the substituents A, Y, and Z in the compounds of formula (1), in one embodiment of the invention the side chain is constructed using synthetic methodologies previously used to prepare compounds that possess a trifluoromethyl group, but using pentafluorosulfanyl groups instead. Specific examples are provided below.

[0019] The following schemes are representative of the methodologies for obtaining androgen-receptor modulators of the formula (1):

[0020] For the synthesis of Bicalutamide derivatives:

[0021] For the synthesis of Enobosarm derivatives:

[0022] For the synthesis of Enzalutamide derivatives:

[0023] The following are nonlimiting examples of the invention.

[0024] Example 1. 2-Hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)-3-((3- (pentafluorosulfanyl)phenyl)thio)propanamide

[0025] Methacryloyl chloride (2.63 mL, 27.16 mmol) was added over the course of 10 minutes to a stirring solution of 4-nitro-3-(trifluoromethyl)aniline (0.7 g, 3.4 mmol) in N,N-dimethylacetamide (14 mL) at r.t. After the reaction was complete, the mixture was diluted with ethyl acetate (100 mL), extracted with sat. aq. NaHC0₃ solution (3x25 mL) and with cold brine (4x50 mL). The organic layers were combined, dried over Na₂S0₄ and the solvent vas removed at reduced pressure.

[0026] The crude residue was purified by flash column chromatography («-hexane/ethyl acetate 100:0 v/v increasing to «-hexane/ethyl acetate 80:20 v/v) to give pure N-(4- nitro-3-(trifluoromethyl)phenyl)methacrylamide as a pale yellow solid in the 95% yield. 'H-NMR (CDC1₃), δ: 2.10-2.11 (m, 3H, CH₃), 5.62-5.63 (m, 1H, CE .), 5.89-5.90 (m, 1H, CH₂), 8.00 (bs, 1H, NH), 8.01-8.02 (m, 1H, H-aromatic), 8.05-8.07 (m, 2H, H- aromatic).

¹⁹F-NMR (CDC1₃), δ: -60.07 (s, 3F, CF₃).

¹³C- MR (CDC1₃), δ: 18.55 (CH₃), 25.16 (CH₂), 30.02 (C, C-alifatic), 118.40, 118.45, 118.49, 118.54 (CH, C-aromatic), 120.65, 121.68 (C, C-aromatic), 122.32 (CH, C- aromatic), 122.82, 125.18, 125.45 (C, C-aromatic), 127.14 (CH, C-aromatic), 140.00, 142.14, 143.01 (C, C-aromatic), 166.78 (C, C=0).

[0027] To a stirred solution of N-(4-nitro-3-(trifluoromethyl)phenyl)methacrylamide (0.732 g, 2.67 mmol) in DCM (7 mL) was added 30% hydrogen peroxide (3.6 mL, 32.03 mmol). The reaction mixture was put in a water bath at r.t. and trifluoroacetic anhydride (3.7 mL, 26.7 mmol) was added slowly to the mixture, which was then stirred for 24 h. The reaction mixture was transferred to a separating funnel using DCM (30 mL). The organic layer was washed with distilled water (20 mL), sat. aq. Na₂S₂0₃ (4x20 mL), sat. aq. NaHC0₃ (3x20 mL) and brine (20 mL), dried over Na₂S0₄ and concentrated at reduced pressure to give 2-methyl-N-(3-nitro-4- (trifluoromethyl)phenyl)oxirane-2-carboxamide as a yellow solid in 89% yield.

'H-NMR (CDC1₃), δ: 1.71 (s, 3H, CH₃), 3.03-3.05 (m, 2H, CFb), 7.99 (m, 2H, H- aromatic), 8.03-8.04 (m, 1H, H-aromatic), 8.47 (bs, 1H, NH).

1⁹F-NMR (CDC1₃), δ: -60.11 (s, 3F, CF₃).

¹³C-NMR (CDC1₃), δ: 16.67 (CH₃), 56.71 (C, C-alifatic), 67.48 (CH₂), 118.22, 118.26, 118.31 (CH, C-aromatic), 120.57 (C, C-aromatic), 122.01, 122.08, 122.32 (CH, C- aromatic), 122.75 (C, C-aromatic), 127.09, 127.12 (CH, C-aromatic), 141.22, 143.31 (C, C-aromatic), 169.27 (C, C=0).

[0028] To a mixture of NaH (60% in mineral oil, 0.050 g, 1.23 mmol) in anhydrous THF (2 mL) at 0 °C under Ar atmosphere was added a solution of 3- (pentafluorosulfanyl)benzenethiol (0.26 g, 1.11 mmol) in 1 mL of anhydrous THF. This mixture was stirred at r.t. for 20 minutes. A solution of 2-methyl-N-(3-nitro-4- (trifluoromethyl)phenyl)oxirane-2-carboxamide (0.2 g, 0.74 mmol) in anhydrous THF (3 mL) was added slowly. The reaction mixture was stirred at r.t. o.n. The mixture was then diluted with ethyl acetate (30 mL), washed with brine (15 mL) and water (30 mL), dried over Na₂SC>4 and concentrated under vacuum. The crude residue was purified by flash column chromatography («-hexane/ethyl acetate 100:0 v/v increasing to n- hexane/ethyl acetate 70:30 v/v) to give pure 2-hydroxy-2-methyl-N-(4-nitro-3- (trifluoromethyl)phenyl)-3-((3-(pentafluorosulfanyl)phenyl)thio)propanamide as a pale yellow oil in the 75% yield.

'H-NMR (CDCI₃), δ: 1.52 (s, 3H, CH₃), 3.14 (d, J= 14.2 Hz, 1H, CH₂), 3.73 (s, 1H, OH), 3.76 (d, J= 14.2 Hz, 1H, CH₂), 7.25-7.29 (m, 1H, H-aromatic), 7.44 (dd, Ji= 8.2 Hz, J₂= 0.8 Hz, 1H, H-aromatic), 7.49 (d, J= 7.7 Hz, 1H, H-aromatic), 7.68-7.70 (m, 1H, H-aromatic), 7.72 (dd, Ji= 8.8 Hz, J₂= 2.3 Hz, 1H, H-aromatic), 7.84-7.91 (m, 2H, H-aromatic), 8.98 (bs, 1H, H).

¹⁹F-NMR (CDC1₃), δ: -60.16 (s, 3F, CF₃), 62.70 (d, J= 150.1 Hz, 4F, SF₅), 83.10-84.06 (m, IF, SF₅).

¹³C- MR (CDC1₃), δ: 26.26 (CH₃), 44.49 (CH₂), 75.52 (C, C-alifatic), 118.02, 118.07, 118.11, 118.16 (CH, C-aromatic), 118.42, 120.60 (C, C-aromatic), 121.88 (CH, C- aromatic), 122.77 (C, C-aromatic), 124.69, 124.72, 124.76 (CH, C-aromatic), 124.86, 124.95, 125.13, 125.40, 125.67 (C, C-aromatic, CF₃), 126.93, 127.77, 127.81, 127.84, 129.27, 133.57 (CH, C-aromatic), 153.97, 154.11, 154.24 (C, C-aromatic), 172.75 (C, C=0).

MS (ESI)⁺: 549.0 [M+Na]⁺

[0029] Example 2. 2-Hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)-3-((3- (pentafluorosulfanyl)phenyl)sulfonyl)propanamide

[0030] To a stirring solution of 2-hydroxy-2-methyl-N-(4-nitro-3- (trifluoromethyl)phenyl)-3-((3-(pentafluorosulfanyl)phenyl)thio)propanamide (0.203 g, 0.4 mmol) in DCM (9 mL) was added portionwise MCPBA (0.188 g, 0.84 mmol), maintaining the temperature at 25 °C. The solution was stirred on. The reaction was then quenched with 10% Na₂S₂0₃ (15 mL). The layers were separated and the aqueous phase was extracted with DCM (3x20 mL). The combined organic layers were washed with 1M NaOH and dried over Na₂S0₄, and finally concentrated in vacuo. The crude residue was purified by recrystallization from DCM/«-hexane to give 2-hydroxy-2- methyl-N-(4-nitro-3 -(trifluoromethyl)phenyl)-3 -((3 -

(pentafluorosulfanyl)phenyl)sulfonyl)propanamide as a white solid in the 67% yield. 1H- MR (CDC1₃), δ: 1.67 (s, 3H, CH₃), 3.60(d, J= 14.5 Hz, 1H, CFb), 4.13 (d, J= 14.5 Hz, 1H, CH₂), 4.82 (bs, 1H, OH), 7.71-7.77 (m, 1H, H-aromatic), 7.86 (dd, Ji= 8.8 Hz, J₂= 2.2 Hz, 1H, H-aromatic), 7.97 (d, J= 8.8 Hz, 1H, H-aromatic), 8.00 (d, J= 2.2 Hz, 1H, H-aromatic), 8.04 (dd, Ji= 8.2 Hz, J₂= 1.3 Hz, 1H, H-aromatic), 8.1 1 (d, J= 7.9 Hz, 1H, H-aromatic), 8.28-8.33 (m, 1H, H-aromatic), 9.11 (bs, 1H, H).

1⁹F-NMR (CDC1₃), δ: -62.20 (s, 3F, CF₃), 62.73 (d, J= 150.8 Hz, 4F, SF₅), 80.51-81.48 (m, IF, SF₅).

¹³C- MR (CDC1₃), δ: 27.85 (CH₃), 61.56 (CH₂), 74.51 (C, C-alifatic), 118.20, 118.25 (CH, C-aromatic), 120.57 (C, C-aromatic), 122.08 (CH, C-aromatic), 123.35, 125.13 (C, C-aromatic), 125.92, 127.00, 130.41, 131.06, 131.78 (CH, C-aromatic), 133.73, 133.87, 140.30, 140.86 (C, C-aromatic), 171.18 (C, C=0).

MS (ESI)⁺: 581.0 [M+Na]⁺

[0031] Example 3. 2-Hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)-3-(3- (pentafluorosulfanyl)phenoxy)propanamide

[0032] To a mixture of NaH (60% in mineral oil, 0.080 g, 1.92 mmol) in anhydrous THF (2 mL) at 0 °C under Ar atmosphere was added a solution of 3- (pentafluorosulfanyl)phenol (0.392 g, 1.78 mmol) in 2 mL of anhydrous THF. This mixture was stirred at r.t. for 20 minutes. A solution of 2-methyl-N-(3-nitro-4- (trifluoromethyl)phenyl)oxirane-2-carboxamide (0.200 g, 0.74 mmol) in anhydrous THF (3 mL) was added slowly. The reaction mixture was stirred at r.t. o.n. The mixture was then diluted with ethyl acetate (30 mL), washed with brine (15 mL) and water (30 mL), dried over Na₂S0₄ and concentrated under vacuum. The crude residue was purified by flash column chromatography (whexane- ethyl acetate 100:0 v/v increasing to whexane - ethyl acetate 70:30 v/v) to give pure 2-hydroxy-2-methyl-N-(4-nitro-3- (trifluoromethyl)phenyl)-3-(3-(pentafluorosulfanyl)phenoxy)propanamide as an off- white solid in the 61% yield.

Ή-NMR (CDCI₃), δ: 1.65 (s, 3H, CH₃), 3.32 (bs, 1H, OH), 4.07 (d, J= 9.0 Hz, 1H, CH₂), 4.54 (d, J= 9.0 Hz, 1H, CH₂), 7.08-7.10 (m, 1H, H-aromatic), 7.33 (dd, Ji= 2.7 Hz, h= 1.5 Hz, 1H, H-aromatic), 7.40-7.45 (m, 2H, H-aromatic), 8.01-8.07 (m, 2H, H- aromatic), 8.13 (d, J= 2.1 Hz, 1H, H-aromatic), 9.18 (bs, 1H, H).

1⁹F- MR (CDCI3), δ: -60.13 (s, 3F, CF₃), 62.79 (d, J= 150.1, 4F, SF₅), 83.60-84.24 (m, IF, SF₅).

"C-NMR (CDC1₃), δ: 23.02 (CH₃), 72.79 (CH₂), 75.86 (C, C-alifatic), 113.24, 113.27, 113.31, 117.58, 118.23, 118.28, 118.32 (CH, C-aromatic), 118.37 (C, C-aromatic), 119.51, 119.54, 119.58 (CH, C-aromatic), 120.61 (C, C-aromatic), 122.10 (CH, C- aromatic), 122.79, 124.97, 125.31, 125.58 (C, C-aromatic), 127.14, 129.77 (CH, C- aromatic), 141.35, 143.37, 154.74, 157.35 (C, C-aromatic), 171.28 (C, C=0).

MS (ESI)⁺: 533.0 [M+Na]⁺

[0033] Example 4. 5,5-Dimethyl-3-(4-nitro-3-(trifluoromethyl)phenyl)-2-thioxo-l-(3- (pentafluorosulfanyl)phenyl)imidazolidin-4-one

[0034] 3-(Pentafluorosulfanyl)aniline (0.5 g, 2.28 mmol) was added to a TMSCN solution (1.43 mL, 11.4 mmol) in acetone ( 10 mL). The mixture was heated at 80 °C o.n. The reaction was then concentrated in vacuo and the residue was partitioned between water (15 mL) and ethyl acetate (15 mL). The water phase was re-extracted with ethyl acetate (2x15 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂S0₄ and concentrated to dryness to give 2-methyl-2-((3- (pentafluorosulfanyl)phenyl)amino)propanenitrile as an off-white solid in the 99% yield. 1H- MR (CDCI₃), δ: 1.76 (s, 6H, CH₃), 3.97 (bs, 1H, H), 7.11 (dd, Ji= 8.1 Hz, J₂= 2.1 Hz, 1H, H-aromatic), 7.23-7.26 (m, 1H, H-aromatic), 7.30 (ddd, Ji= 8.2 Hz, J₂= 2.1 Hz, J₃= 0.8 Hz), 7.36-7.41 (m, 1H, H-aromatic).

¹⁹F-NMR (CDC1₃), δ: 62.50 (d, J= 149.8 Hz, 4F, SF₅), 83.90-85.71 (m, IF, SF₅).

1³C- MR (CDC1₃), δ: 28.10 (CH₃), 47.91 (C, C-alifatic), 114.71, 114.75, 117.67, 117.70, 118.79 (CH, C-aromatic), 121.17 (C, C-aromatic), 129.49 (CH, C-aromatic), 141.62, 143.90 (C).

[0035] A solution of NaHC0₃ (0.82 g) in distilled water (4 mL) was stirred for 10 minutes and to it was added DCM (4 mL) followed by 4-nitro-3-(trifluoromethyl)aniline (0.5 g, 2.43 mmol). The reaction mixture was cooled to 0 °C, thiophosgene (0.3 mL, 3.65 mmol) was added dropwise over 10 minutes and the reaction was then stirred at r.t. o.n. The mixture was diluted with DCM (20 mL), washed with brine (20 mL), the organic layer was dried over Na₂S0₄ and concentrated to dryness to give 4- isothiocyanato-l-nitro-2-(trifluoromethyl)benzene as a yellow oil in the 95% yield. 1H- MR (CDC1₃), δ: 7.54 (dd, Ji= 8.6 Hz, J₂= 2.2 Hz, 1H, H-aromatic), 7.64 (d, J= 2.2 Hz, 1H, H-aromatic), 7.97 (d, J= 8.6 Hz, 1H, H-aromatic).

1⁹F- MR (CDC1₃), δ: -60.24 (s, 3F, CF₃).

"C-NMR (CDC1₃), δ: 120.12, 122.30 (C, C-aromatic), 125.03 (CH, C-aromatic), 125.07, 125.12, 125.16, 125.83 (C, CF₃), 127.16, 129.46 (CH, C-aromatic), 136.86, 142.17 (C, C-aromatic, C=heteroatom).

[0036] A mixture of 4-isothiocyanato-l-nitro-2-(trifluoromethyl)benzene (0.250 g, 1.01 mmol) and 2-methyl-2-((3-(pentafluorosulfanyl)phenyl)amino)propanenitrile (0.24 g, 0.84 mmol) in dry DMF (0.5 mL) was stirred at r.t. for 48 h. To this mixture were added MeOH (10 mL) and 2N HC1 (3 mL). The second mixture was refluxed for 6h. After being cooled to r.t., the reaction mixture was poured into cold water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over Na₂S0₄ and concentrated under vacuum. The crude residue was purified by flash column chromatography («-hexane/ethyl acetate 100:0 v/v increasing to «-hexane/ethyl acetate 70:30 v/v) to give 5,5-dimethyl-3-(4-nitro-3-(trifluoromethyl)phenyl)-2-thioxo-l-(3- (pentafluorosulfanyl)phenyl)imidazolidin-4-one as a pale yellow solid in the 23% yield. 1H- MR (CDC1₃), δ: 1.64 (s, 6H, CH₃), 7.54 (d, J= 7.8 Hz, 1H, H-aromatic), 7.64-7.68 (m, 1H, H-aromatic), 7.75-7.79 (m, 1H, H-aromatic), 7.90 (dd, Ji= 8.6 Hz, J₂= 2.1 Hz, 1H, H-aromatic), 7.95 (ddd, Ji= 8.3 Hz, J₂= 2.1 Hz, J₃= 0.8 Hz, 1H, H-aromatic), 8.01 (d, J= 2.1 Hz, 1H, H-aromatic), 8.06 (d, J= 8.6 Hz, 1H, H-aromatic).

¹⁹F-NMR (CDC1₃), δ: -60.15 (s, 6F, CF₃), 62.74 (d, J= 150.4 Hz, 4F, SF₅), 82.29-85.69

(m, IF, SF₅).

¹³C- MR (CDCI3), δ: 23.76 (CH₃), 66.56 (C, C-alifatic), 118.19, 120.37, 122.55, 124.21, 124.49, 124.72, 124.77, 125.05 (C, C-aromatic, CF₃), 125.84, 127.22, 127.25, 127.29, 127.75, 127.79, 127.82, 128.25, 128.30, 128.34, 128.38, 130.16, 132.97, 133.12 (CH, C-aromatic), 135.59, 136.52, 147.43, 154.43, 154.58, 154.73 (C, C-aromatic, CF₃), 174.48, 180.12 (C, C=heteroatom).

MS (ESI)⁺: 536.0 [M+H]⁺

[0037] Compounds of formula (1) have been found to exhibit antagonist effect on the androgen receptor, and are expected to be useful in the treatment of disease states influenced by the modulation of such receptor, such as prostate cancer. Binding and antagonism of the androgen receptor is typically calculated from the IC₅₀ as the concentration of a compound necessary to displace 50% of the fluorescent ligand from the receptor. In the context of the present invention % of receptor modulation at a given concentration is evaluated and the compounds of the present invention typically show mean inhibition > 90% at alO micromolar concentration. Said compounds also show anti-proliferative activities in different prostate cancer cell lines in the low micromolar range, all showing IC₅₀ values lower than the standard compound, R-Bicalutamide. The compounds of the present invention may suitably be used as selective modulators of the androgen receptor and in particular as anti-prostate cancer agents.

[0038] Other conditions which may be treated with the compounds of the invention include different types of cancer.

[0039] The invention provides a method of treating a cancer condition which comprises administering to a mammal (e.g. human) in need thereof an effective amount of a compound of formula (1) as herein defined or a pharmaceutically acceptable salt thereof.

[0040] The invention also provides a compound of formula (1) or a pharmaceutically acceptable salt thereof for use in therapy.

[0041] The invention also provides a compound of formula (1) or a pharmaceutically acceptable salt thereof for use in the treatment of a condition in a mammal for which modulation [especially inhibition/antagonism (which may also translate into inverse or partial agonism in constitutively active receptor systems)] of androgen receptor is beneficial. [0042] The invention also provides the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition in a mammal for which modulation [especially inhibition/antagonism (which may also translate into inverse or partial agonism in constitutively active receptor systems)] of androgen receptor is beneficial.

[0043] In one embodiment, androgen receptor antagonists according to the present invention are used in the treatment of prostate cancer.

[0044] Also provided is the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of prostate cancer in a mammal.

[0045] Also provided is a compound of formula (1) or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer condition in a mammal. Also provided is a compound of formula (1) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance in a mammal, e.g. for use in the treatment of any of the conditions described herein.

[0046] "Treatment" includes prophylaxis, where this is appropriate for the relevant condition(s).

[0047] For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition.

[0048] The pharmaceutical composition can be for use in the treatment of any of the conditions described herein.

[0049] The compounds of formula (1) may be administered by any convenient method, for example by oral, parenteral (e.g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

[0050] Anti-cancer activity: The compounds were tested on a panel of four prostate cancer cell lines. The cell lines LNCaP (androgen-sensitive human prostate adenocarcinoma cells derived from the left supraclavicular lymph node metastasis of a mouse), VCaP (from a metastatic lesion to a lumbar vertebral body of a patient with hormone refractory prostate cancer) and 22Rvl (epithelial cells from a human prostate with a cancer disease) exhibit at least some androgen sensitivity, whereas DU145 (a cell line derived from brain metastasis) are not hormone sensitive. The overall potency of a compound was determined by the geometric mean of the half maximal inhibitory concentration (IC₅₀). The following tables are examples representative of the improvement in biological properties associated with androgen-receptor modulators of the formula (1) in comparison with standard (R)-Bicalutamide.

R-Bicalutamide 46.254 45.412 45.196 51.607 47.047

[0051] Androgen receptor modulation at 10 μΜ:

[0052] From the preceding disclosure, various modifications and alternate embodiments of the invention will be apparent to persons skilled in the art to which the invention pertains. All such modifications and embodiments are within the scope of the invention, which is limited only by the appended claims and equivalents thereof.

Claims

What is claimed is:

1. A compound represented by the formula (1)

wherein:

X is CN, N0₂ or H;

Y is oxygen or sulfur;

Z is selected from the group consisting of

(i) Ci to C₆ alkoxy,

(ii) C₃ to cycloalkoxy,

(iii) aryloxy wherein the aryl group is five- or six-membered,

(iv) Ci to C₆ alkyl thioether,

(v) C₃ to C₆ cycloalkyl thioether,

(vi) aryl thioether wherein the aryl group is five- or six-membered,

(vii) Ci to C₆ sulfonylalkyl group,

(viii) C₃ to C₆ sulfonylcycloalkyl group,

(ix) sulfonylaryl group wherein the aryl group is five- or six-membered,

and wherein in each case (i) to (x) said alkoxy, thioether or sulfonylalkyl group is of 1 to 6 carbon atoms and may be cycloalkyl, and wherein in each case (i) to (xii) said alkyl, cycloalkyl, alkoxy or aryl group optionally bears one or more groups selected from hydroxy, alkoxy (-ORi), -O-alkylene, aryloxy (-OAr), alkylthio (-SRi), -S- alkylene, arylthio (- SAr), alkylsulfoxide (-SORi), -SO-alkylene, arylsulfoxide (- SOAr), alkylsulfone (-S0₂Ri), -S0₂-alkylene, and arylsulfone (-S0₂Ar), wherein each Ri group is independently selected from CI to C4 alkyl, each Ar group is independently a five- or six- membered ring, each Ri and each Ar group optionally bears one or more substituents selected from halogen, carboxamide, where the nitrogen atom optionally bears one or more C1-C4 alkyl groups, acylamino, where the acyl group contains 1 to 4 carbon atoms, and nitrile, and each alkylene group can be straight or branched and optionally substituted with OH;

A is hydrogen, Ci to C₄ alkyl, or acyl, or A together with Z forms a five- or six- member heterocyclic group that optionally bears one or more groups selected from hydroxy, alkoxy (-ORi), -O-alkylene, aryloxy (-OAr), alkylthio (-SRi), -S-alkylene, arylthio (- SAr), alkylsulfoxide (-SORi), -SO-alkylene, arylsulfoxide (-SOAr), alkylsulfone (-SO₂R₁), -S0₂-alkylene, wherein each Ri group is independently selected from CI to C4 alkyl, each Ar group is independently a five- or six-membered ring, each Ri and each Ar group optionally bears one or more substituents selected from halogen, carboxamide (where the nitrogen atom optionally bears one or more C1-C4 alkyl groups), acylamino (where the acyl group contains 1 to 4 carbon atoms), and nitrile, and each alkylene group can be straight or branched and optionally substituted with OH. R and R' are, independently, either H, CN, CF₃, OCF₃, SCF₃, halogen, alkyl groups or CO HMe;

q and r are, independently, either 0, 1 or 2;

n and p are, independently, 0 or 1, provided that when n+p > 1.

2. A compound according to claim 1, wherein A together with Z forms a five - member heterocyclic group corresponding to 2- thioxoimidazolidin-4-one.

3. A compound according to claim 2, wherein the five-member heterocyclic group formed by A together with Z bears one or more groups selected from hydroxy, alkoxy (- ORi), -O-alkylene, aryloxy (-OAr), alkylthio (-SRi), -S-alkylene, arylthio (- SAr), alkylsulfoxide (-SORi), -SO-alkylene, arylsulfoxide (-SOAr), alkylsulfone (-S0₂Ri), - S0₂-alkylene, wherein each Ri group is independently selected from CI to C4 alkyl, each Ar group is independently a five- or six-membered ring, each Ri and each Ar group optionally bears one or more substituents selected from halogen, carboxamide (where the nitrogen atom optionally bears one or more C1-C4 alkyl groups), acylamino (where the acyl group contains 1 to 4 carbon atoms), and nitrile, and each alkylene group can be straight or branched and optionally substituted with OH.

4. A compound according to Claim 1, having any one of the following formulas:

5. A compound according to Claim 1, having the formula:

6. A compound according to Claim 1, having the formula:

7. A compound according to Claim 1, synthesized by any one of the following routes a- c:

MCPBA, DCM rt, on

8. A compound comprising a physiologically acceptable salt of a compound recited in any one of claims 1-7.

9. A method of treating a condition for which modulation of androgen receptor is beneficial, which comprises administering to a mammal (e.g. human) in need thereof an effective amount of a compound recited in any one of claims 1-7, or a physiologically acceptable salt thereof.

10. A method as claimed in claim 9, wherein the condition is prostate cancer or hormone-resistant prostate cancer.

11. A method as claimed in claim 9, wherein the condition is any type of cancer.

12. Use of a compound as recited in any one of claims 1-7, or a physiologically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition in a mammal for which modulation of an androgen receptor is beneficial.

13. Use as recited in claim 12, wherein the condition is prostate cancer.

14. A compound as recited in any one of claims 1-7, or a physiologically acceptable salt thereof, for use in therapy.

15. A compound as recited in any one of claims 1-7, or a physiologically acceptable salt thereof, for use in the treatment of a condition in a mammal for which modulation of the androgen receptor is beneficial.

16. A compound as recited in any one of claims 1-7, or a physiologically acceptable salt thereof, for use in the treatment of prostate cancer.

17. A pharmaceutical composition comprising a compound as recited in any one of claims 1-7, or a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier.