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Title:
ARYLAMIDE DERIVATIVES HAVING ANTIANDROGENIC PROPERTIES
Document Type and Number:
WIPO Patent Application WO/2013/104831
Kind Code:
A1
Abstract:
The invention relates to novel arylamide derivatives having formula (I) and stereoisomers and pharmaceutically acceptable salts thereof, where R2, R8, R9 and R11 are as defined in the claims. The arylamide derivatives of formula (I) have antiandrogenic properties. The invention also relates to compounds of formula (I) for use as a medicament and to pharmaceutical compositions comprising them and to their preparation.

Inventors:
RATILAINEN JARI (FI)
KOISTINAHO MILLA (FI)
MUONA ANU (FI)
Application Number:
FI2013/050028
Publication Date:
July 18, 2013
Filing Date:
January 11, 2013
Export Citation:
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Assignee:
MEDEIA THERAPEUTICS LTD (Microkatu 1, Kuopio, FI-70210, FI)
International Classes:
C07C317/46; A61K31/277; A61P35/00
Domestic Patent References:
WO2010116342A22010-10-14
WO2012007644A12012-01-19
WO2008011072A22008-01-24
WO2010116342A22010-10-14
WO2010092546A12010-08-19
Foreign References:
EP0100172A11984-02-08
EP0100172A11984-02-08
Other References:
PERLMUTTER M; LEPOR H.: "Androgen deprivation therapy in the treatment of advanced prostate cancer", REV UROL., vol. 9, no. 1, 2007, pages S3 - S8, XP055277500
CHEN CD; WELSBIE DS; TRAN C; BAEK SH; CHEN R; VESSELLA R; ROSENFELD MG; SAWYERS CL.: "Molecular determinants of resistance to antiandrogen therapy", NAT MED, vol. 10, no. 1, January 2004 (2004-01-01), pages 33 - 39
TAPLIN ME: "Drug insight: role of the androgen receptor in the development and progression of prostate cancer", NAT CLIN PRACT ONCOL., vol. 4, no. 4, April 2007 (2007-04-01), pages 236 - 244, XP055114300, DOI: doi:10.1038/ncponc0765
HARA T; MIYAZAKI J; ARAKI H; YAMAOKA M; KANZAKI N; KUSAKA M; MIYAMOTO M.: "Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome", CANCER RES., vol. 63, no. 1, 1 January 2003 (2003-01-01), pages 149 - 153, XP002382326
JACS, vol. 114, no. 9, 1992, pages 3492 - 3499
Attorney, Agent or Firm:
KOLSTER OY AB (Iso Roobertinkatu 23, P.O. Box 148, Helsinki, FI-00121, FI)
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Claims:
Claims

1 . An arylamide derivative having formula (I)

(I)

and stereoisomers and pharmaceutically acceptable salts thereof; where

R2 is halo or trifluoromethyl; and

R8 and R9 are selected from the group consisting of hydrogen, halo and trifluoromethyl, provided that at least one of R8 and R9 is other than hy- drogen; and

R1 1 is branched C3-5-alkyl or cyclo-C3-6-alkyl;

provided that when R1 1 is isopentyl, R2 is trifluoromethyl and R9 is hydrogen, then R8 is not fluoro.

2. Arylamide derivative according to claim 1 , where R2 is chloro or trifluoromethyl.

3. Arylamide derivative according to claim 1 or 2, where R8 is chloro, fluoro or trifluoromethyl.

4. Arylamide derivative according to any one of claims 1 - 3, where R9 is trifluoromethyl, hydrogen or fluoro.

5. Arylamide derivative according to claim 1 , where R1 1 is tert-butyl, isopropyl, isopentyl, cyclopropyl, cyclopentyl or cyclohexyl.

6. Arylamide derivative according to claim 1 , where the arylamide derivative is selected from the group consisting of:

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3- [(3-methylbutane)sulfonyl]propanamide;

N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-[(3-methylbutane)sulfonyl]-

2- [4-(trifluoromethyl)phenyl]propanamide;

N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-(propane-2-sulfonyl)-2-[4- (trifluoromethyl)phenyl]propanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-2-hydroxy-

3- (propane-2-sulfonyl)propanamide; N-(3-chloro-4-cyanophenyl)-3-(cyclohexanesulfonyl)-2-hydroxy-2-[4 (trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-3-(cyclopentanesulfonyl)-2-hydroxy-2- [4-(trifluoronnethyl)phenyl]propanannide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-3-(cyclo- hexanesulfonyl)-2-hydroxypropanamide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-3-(cyclo- pentanesulfonyl)-2-hydroxypropanamide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-2-hydroxy- 3-(propane-2-sulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-2-(3,4-difluorophenyl)-2-hydroxy-3-[(3- methylbutane)sulfonyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-(3,4-difluorophenyl)-2-hydroxy-3-(pro pane-2-sulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-2-hydroxy-3-[(3-met hylbutane)sulfonyl]propanamide;

N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-2-hydroxy-3-(propa- ne-2-sulfonyl)propanamide;

N-[4-cyano-3-(trifluoronnethyl)phenyl]-2-hydroxy-3-[(3-nnethylbutane)- sulfonyl]-2-[4-(trifluoronnethyl)phenyl]propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-(propane-2-sulfo- nyl)-2-[4-(trifluoronnethyl)phenyl]propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(3,4-difluorophenyl)-2-hyd- roxy-3-[(3-methylbutane)sulfonyl]propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(3,4-difluorophenyl)-2-hyd- roxy-3-(propane-2-sulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-2-(3,4-difluorophenyl)-2-hydroxy-3-(2- methylpropane-2-sulfonyl)propanannide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-2-hydroxy- 3-(2-methylpropane-2-sulfonyl)propanannide;

N-(3-chloro-4-cyanophenyl)-3-(cyclopropanesulfonyl)-2-(3,4- difluorophenyl)-2-hydroxypropanamide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-3- (cyclopropanesulfonyl)-2-hydroxypropanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-(2- methylpropane-2-sulfonyl)-2-[4-(trifluoromethyl)phenyl]propanamide; N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(cyclopropanesulfonyl)-2- hydroxy-2-[4-(trifluoromethyl)phenyl]propanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-2-hydroxy- 3-(2-methylpropane-2-sulfonyl)propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(cyclopropanesulfonyl)-2-(4- fluorophenyl)-2-hydroxypropanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(3,4-difluorophenyl)-2- hydroxy-3-(2-methylpropane-2-sulfonyl)propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(cyclopropanesulfonyl)-2- (3,4-difluorophenyl)-2-hydroxypropanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-(2- methylpropane-2-sulfonyl)-2-[3-(trifluoromethyl)phenyl]propanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(cyclopropanesulfonyl)-2- hydroxy-2-[3-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-(2-methylpropane-2- sulfonyl)-2-[3-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-3-(cyclopropanesulfonyl)-2-hydroxy-2- [3-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-2-hydroxy-3-(2- methylpropane-2-sulfonyl)propanannide;

N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-3- (cyclopropanesulfonyl)-2-hydroxypropanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-(propane-2- sulfonyl)-2-[3-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-(propane-2-sulfonyl)-2-[3- (trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-(2-methylpropane-2- sulfonyl)-2-[4-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-3-(cyclopropanesulfonyl)-2-hydroxy-2- [4-(trifluoronnethyl)phenyl]propanannide;

and pharnnaceutically acceptable salts thereof.

7. A pharmaceutical composition comprising an effective amount of one or more arylamide derivatives or pharmaceutically acceptable salts thereof according to any one of claims 1 to 6 together with a suitable carrier and conventional excipients.

8. Arylamide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for use as medicament.

9. Arylamide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for use in the treatment of androgen re- ceptor related disorders.

10. Arylamide derivative or a pharmaceutically acceptable salt thereof for use according to claim 9, where the disorder is benign prostate hyperplasia.

1 1 . Arylamide derivative or a pharmaceutically acceptable salt thereof for use according to claim 9, where the disorder is cancer.

12. Arylamide derivative or a pharmaceutically acceptable salt thereof for use according to claim 1 1 , where the cancer is selected from the group consisting of prostate cancer and castration-resistant prostate cancer.

13. Arylamide derivative or a pharmaceutically acceptable salt thereof for use according to any of claims 9 to 12, wherein the said compound is administered simultaneously, separately or sequentially with another active agent.

14. A process for preparing an arylamide derivative of formula (I) as defined in claim 1 , comprising reacting an epoxy compound of formula (5), where R2, R8 and R9 are as defined in claim 1 , with a a compound of formula (II),

R1 1 -SH (II) where R1 1 is as defined in claim 1 and oxidizing the obtained thio compound to obtain a compound of formula (I).

15. The process according to claim 14, where the process is carried out via the following reaction steps

6 7

Description:
ARYLAMIDE DERIVATIVES HAVING AN IANDROGENIC PROPERTIES

THE FIELD OF THE INVENTION

The present invention relates to new arylamide derivatives, their preparation, pharmaceutical compositions containing them and their use in the treatment of androgen receptor related disorders, such as benign prostate hyperplasia and cancer, particularly prostate cancer and/or castration-resistant prostate cancer.

BACKGROUND OF THE INVENTION

Androgens are produced by testes and adrenal glands and they play a critical role in the development and physiology of normal prostate. The etiology of benign prostate hyperplasia (BPH) and prostatic neoplasia which can progress to adenocarcinoma is androgen-dependent. Treatment of choice for BPH and prostate cancer (PCa) is reduction of androgen action in the prostate. In fact, almost 90% of men between ages 40 - 90 years develop either BPH or PCa. PCa is the second leading cause of cancer-related death and the most frequently diagnosed malignancy in men. PCa remains incurable in metastatic setting. As the incidence of PCa increases with age, the number of newly diagnosed cases rises continuously due to increased life expectancy of the population.

The conventional initial treatment for PCa is hormone or androgen deprivation therapy (ADT). Experimental ADT was first described already in 1941 . ADT via surgical castration or by chemical castration using luteinizing hormone releasing hormone agonists is universally accepted first-line therapy in advanced PCa. See Perlmutter M, Lepor H. Androgen deprivation therapy in the treatment of advanced prostate cancer Rev Urol. 2007; 9(Suppl 1 ): S3-S8 and references therein.

Maximal androgen blockade is achieved by combining ADT with an anti-androgen treatment. Anti-androgens compete with endogenous androgens, testosterone and dihydrotestosterone, for binding in the ligand-binding pocket of the androgen receptor (AR). AR belongs to the superfamily of nuclear hormone receptors and is mainly expressed in reproductive tissues and muscles. Ligand binding to AR promotes its dissociation from heat shock proteins and other chaperones, leading to dimerization of the receptor, phosphorylation and subsequent translocation into the nucleus where AR binds to andro- gen responsive elements present in the regulatory regions of multiple genes involved in the growth, survival and differentiation of prostate cells.

The first non-steroidal anti-androgen, flutamide was approved for PCa in 1989 and the structurally related compounds, bicalutamide and nilutam- ide, were launched in 1995 and 1996, respectively. Non-steroidal compounds are more favorable than steroidal anti-androgens in clinical applications because of the lack of cross-reactivity with other steroid receptors and improved oral bioavailability. Of this structural class of propanamide anti-androgens, bicalutamide is the most potent, best tolerated and the leading anti-androgen on the market. Bicalutamide is described in patent literature for example in European patent EP 0100172. Certain arylamide derivatives have also been described in documents WO 2008/01 1072 A2, WO 2010/1 16342 and WO 2010/092546 as selective androgen receptor modulators.

flutamide bicalutamide nilutamide

Unfortunately, although ADT and anti-androgen treatment typically result in early beneficial responses, PCa then progresses to a state where androgen deprivation fails to control the malignancy despite minimal testosterone levels. This state is termed castration-resistant prostate cancer (CRPC) (or hormone-refractory prostate cancer, HRPC) and is the lethal form of the disease. CRPC is believed to emerge after genetic and/or epigenetic changes in the prostate cancer cells and it is characterized by re-activation of the growth of cancer cells that have adapted to the hormone-deprived environment in the prostate.

The growth of cancer cells in CRPC remains dependent on the function of AR and studies over the past decade demonstrate that CRPC cells employ multiple mechanisms to re-activate AR. See Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular de- terminants of resistance to antiandrogen therapy. Nat Med 2004 Jan; 10(1 ): 33-39 and references therein. The major mechanisms include amplification of AR gene or up-regulation of AR mRNA or protein, point mutations in AR that allow activation of the AR by non-androgenic ligands or even anti-androgens, changes in the expression levels of co-activators and co-repressors of AR transcription, and expression of alternatively spliced and constitutively active variants of the AR. Thus, drugs targeting AR signaling could still be effective in the prevention and treatment of CRPC.

The limited utility of currently available anti-androgens is most likely related to an incomplete AR inhibition under certain circumstances (Taplin ME. Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol. 2007 Apr; 4(4): 236-244). Multiple molecular mechanisms may contribute to the failure of standard anti-androgen treatments. The use of anti-androgens that target ligand-binding domain of the AR, such as bicalutamide, can lead to selection of prostate cancer cells that harbor point mutations in the ligand-binding domain. In some cases these mutations can cause prostate cancer cells to convert antagonists to agonists. AR mutations are found in 10 - 40% of metastatic tumors. More than 70 mutations in the AR have been discovered, which result in increased basal activity of the receptor or widened ligand specificity.

For example, threonine to alanine mutation in amino acid 877 is the most frequently found mutation in PCa patients and converts flutamide, cypro- tenone (steroidal anti-androgen), progesterone and oestrogens agonistic in AR. Mutation in amino acid 741 from tryptophan to either leucine or cysteine accounts for the switch of bicalutamide from anti-androgen to an agonist (Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M, Miyamoto M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003 Jan 1 ; 63(1 ): 149-153.)

In addition to point mutations in AR, increased receptor levels can cause anti-androgens to function as agonists (Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004 Jan; 10(1 ): 33- 39). The antagonist-agonist conversion has significant clinical relevance. Ap- proximately 30% of men with progressing PCa experience a paradoxical drop in serum prostate specific antigen levels after discontinuation of the anti- androgen treatment.

To date, treatment for CRPC has been disappointing with expected survival estimated at 7 to 16 months. Despite recent addition of two novel treatment options for CRPC, the therapeutic prostate cancer vaccine sip- uleucel-T and novel testosterone synthesis inhibitor abiraterone acetate, efficient novel agents that specifically target AR are still needed.

More specifically, there is a need for new anti-androgen compounds that are more potent than bicalutamide in antagonizing the activities of endog- enous androgens on AR. There is also a need for new anti-androgen compounds that exhibit minimal agonism in AR. Importantly, there is a need for novel anti-androgens that do not gain agonistic activity in CRPC related mutant ARs or in CRPC related settings in which AR is present at high amounts. In addition, there is a need for non-steroidal, non-toxic molecules with drug-like properties that can be used in the treatment and prevention of BPH, PCa and CRPC.

Now it has been surprisingly found that the arylamide derivatives according to the present invention overcome the disadvantages related to bicalutamide and other arylamide derivatives known in the art. SUMMARY OF THE INVENTION

The present invention provides new arylamide derivatives having formula (I)

(I) and stereoisomers and pharmaceutically acceptable salts thereof; where

R2 is halo or trifluoromethyl; and

R8 and R9 are selected from the group consisting of hydrogen, halo and trifluoromethyl, provided that at least one of R8 and R9 is other than hydrogen; and

R1 1 is branched C 3- 5-alkyl or cyclo-C 3- 6-alkyl;

provided that when R1 1 is isopentyl, R2 is trifluoromethyl, and R9 is hydrogen, then R8 is not fluoro.

The invention also relates to pharmaceutical compositions comprising an effective amount of one or more arylamide derivatives of formula (I) or pharmaceutically acceptable salts thereof together with a suitable carrier and conventional excipients.

Further the invention relates to arylamide derivatives of formula (I) or pharmaceutically acceptable salts thereof for use as a medicament.

The invention also relates to arylamide derivatives of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of androgen receptor related diseases.

Finally the invention provides a process for preparing arylamide derivatives of formula (I). DETAILED DESCRIPTION OF THE INVENTION

The arylamides of formula (I) according to the present invention possess at least one asymmetric carbon atom, i.e. the carbon atom, to which the hydroxyl is attached. Thus, the compounds exist in racemic form and optically active forms. All these forms are encompassed by the present invention.

Examples of branched C3-5-alkyl groups are isopropyl, iso- and tert- butyl and iso- and tert-pentyl.

By the term "cyclo-C3-6-alkyl" is meant cyclopropyl, cyclobutyl, cy- clopentyl or cyclohexyl.

By the term "halo" is meant fluoro, chloro, bromo or iodo. Preferred compounds of formula (I) are those where R2 is chloro or trifluoromethyl.

Further preferred compounds of formula (I) are those wherein R8 is chloro, fluoro or trifluoromethyl. Preferred are also those wherein R9 is trifluoromethyl, hydrogen or fluoro, preferably hydrogen or fluoro.

Further preferred compounds of formula (I) are those wherein one or both of R8 and R9 are independently selected from the group consisting of chloro, fluoro and trifluoromethyl.

Preferred compounds of formula (I) are also those where R1 1 is tert-butyl, isopropyl, isopentyl, cyclopropyl, cyclopentyl or cyclohexyl, prefera- bly isopropyl, isopentyl, cyclopentyl or cyclohexyl.

Especially preferred compounds of formula (I) are those wherein R2 is chloro, R8 is trifluoromethyl, R9 is hydrogen and R1 1 is cyclopentyl.

Examples of particularly preferred specific compounds are: 2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-h ydroxy-3- [(3-methylbutane)sulfonyl]propanamide; N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-[(3-methylbutane)sulf onyl]-

2- [4-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-(propane-2-sulfonyl)- 2-[4- (trifluoronnethyl)phenyl]propanannide;

N-[4-cyano-3-(trifluoronnethyl)phenyl]-2-(4-fluorophenyl)-2- hydroxy-3- (propane-2-sulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-3-(cyclohexanesulfonyl)-2-hydroxy -2-[4 (trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-3-(cyclopentanesulfonyl)-2-hydrox y-2-[4- (trifluoronnethyl)phenyl]propanannide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-3- (cyclohexa nesulfonyl)-2-hydroxypropanamide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-3- (cyclo- pentanesulfonyl)-2-hydroxypropanamide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-2- hydroxy-

3- (propane-2-sulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-2-(3,4-difluorophenyl)-2-hydroxy- 3-[(3- methylbutane)sulfonyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-(3,4-difluorophenyl)-2-hydroxy- 3-(pro pane-2-sulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-2-hydroxy-3-[( 3-met hylbutane)sulfonyl]propanamide;

N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-2-hydroxy-3-(p ropa- ne-2-sulfonyl)propanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-[(3-nnethy lbuta- ne)sulfonyl]-2-[4-(trifluoronnethyl)phenyl]propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-(propane-2 -sulfo- nyl)-2-[4-(trifluoronnethyl)phenyl]propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(3,4-difluorophenyl) -2-hyd- roxy-3-[(3-methylbutane)sulfonyl]propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(3,4-difluorophenyl) -2-hyd- roxy-3-(propane-2-sulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-2-(3,4-difluorophenyl)-2-hydroxy- 3-(2- methylpropane-2-sulfonyl)propanannide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-2- hydroxy- 3-(2-methylpropane-2-sulfonyl)propanannide; N-(3-chloro-4-cyanophenyl)-3-(cyclopropanesulfonyl)-2-(3,4- difluorophenyl)-2-hydroxypropanamide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-3- (cyclopropanesulfonyl)-2-hydroxypropanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-(2- methylpropane-2-sulfonyl)-2-[4-(trifluoromethyl)phenyl]propa namide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(cyclopropanesulfony l)-2- hydroxy-2-[4-(trifluoronnethyl)phenyl]propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-2-h ydroxy- 3-(2-methylpropane-2-sulfonyl)propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(cyclopropanesulfony l)-2-(4- fluorophenyl)-2-hydroxypropanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(3,4-difluorophenyl) -2- hydroxy-3-(2-methylpropane-2-sulfonyl)propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(cyclopropanesulfony l)-2- (3,4-difluorophenyl)-2-hydroxypropanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-(2- methylpropane-2-sulfonyl)-2-[3-(trifluoromethyl)phenyl]propa namide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(cyclopropanesulfony l)-2- hydroxy-2-[3-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-(2-methylpropane-2- sulfonyl)-2-[3-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-3-(cyclopropanesulfonyl)-2-hydrox y-2- [3-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-2-hydroxy-3-(2 - methylpropane-2-sulfonyl)propanannide;

N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-3- (cyclopropanesulfonyl)-2-hydroxypropanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-(propane-2 - sulfonyl)-2-[3-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-(propane-2-sulfonyl)- 2-[3- (trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-(2-methylpropane-2- sulfonyl)-2-[4-(trifluoronnethyl)phenyl]propanannide;

N-(3-chloro-4-cyanophenyl)-3-(cyclopropanesulfonyl)-2-hydrox y-2- [4-(trifluoronnethyl)phenyl]propanannide; and pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts and their preparation are well- known in the art.

The arylamides of the invention may be prepared by methods de- scribed below. For example the compounds of formula may be prepared by reacting an epoxy compound of formula (5), where R2, R8 and R9 are as defined above, with a compound of formula (II),

R1 1 -SH (II) where R1 1 is as defined above, and oxidizing the obtained thio compound to obtain a compound of formula (I). The process is preferably carried out via the following reaction steps:

GENERAL SYNTHESIS PROCEDURE

The compounds of the present invention were synthesized using commercially available anilines, phenylacetic acids, thiols, phenols and amines as starting materials.

General method for the synthesis of the intermediate (3)

A corresponding phenyl acetic acid (2) (3.89 mmol) was dissolved in dichloromethane and cooled in an ice bath to +5 - 0°C. 0.66 ml (2 equivalents) of oxalyl chloride was dropped in dichloromethane while keeping the tempera- ture at +5 - 0°C. After addition was complete the ice bath was removed and the mixture was allowed to warm to room temperature (RT). After stirring for 4 hours, the mixture was cooled to 0°C and the aniline (1 ) (3.89 mmol) was added in dimethylacetamide (10 ml). The resulting mixture was stirred at RT and monitored by TLC. After completion of the reaction, the mixture was poured in ice water and extracted with dichloromethane. The Organic phase was washed with water and dried over Na 2 SO and evaporated to give (3).

General method for the synthesis of the intermediate (4)

1 .7 mmol of (3), 0.075 g (1 .8 equivalents) of paraformaldehyde and 0.412 g of K2CO3 was mixed in NMP (N-methyl pyrrolidone, 2 ml). The mixture was heated to 90°C and stirred for 3 hours. After cooling to RT 10 ml of water was added and the mixture was extracted with di-isopropyl ether (2 x 10 ml). The organic phase was washed with water (1 x 10 ml) and evaporated to give (4). The product was used for the synthesis of (5) without further purification. General method for the synthesis of the intermediate (5)

1 .0 mmol of the intermediate (4) and 10 mg of 2,6-ditertbutyl-4- methylphenol was dissolved in CH 2 CI 2 (20 ml). 0.5 g (2 equivalents) of MCPBA was added. The mixture was stirred at RT overnight. The mixture was extracted with Na 2 CO 2 and water. The organic phase was evaporated in vacuo to give the epoxide (5). Product was used without further purification for the synthesis of (6).

General method for the synthesis of (6)

To 3.0 (2 equivalents) mmol of K 2 CO 3 in THF (5 ml), 2.2 mmol (1 .5 equivalents) of a corresponding thiophenol or phenol was added in THF (7.5 ml) at 0°C. Mixture was stirred at 0°C for 30 min. 1 .5 mmol of the epoxide (5) in THF (7.5 ml) was added at 0°C. The resulting mixture was stirred at RT for 2h, heated up to 50°C and stirred for 12 h. After cooling the reaction was quenched with water. The resulting mixture was extracted with AcOEt. The organic phase was concentrated to get the crude material which was used for the synthesis of (7) without further purification. In case of phenols used in the reactions, the products were purified using flash chromatography.

General method for the synthesis of (7)

0.45 mmol of (6) was dissolved in CH 2 CI 2 (20 ml). MCPBA (0.90 mmol, 2 equivalents) was added and the mixture was stirred at RT. After com- pletion of the reaction monitored by TLC reaction was quenched by saturated sodium sulphite solution in water and extracted with dichloromethane. The organic layer was washed with saturated sodium sulphite solution, dried over Na 2 SO and evaporated. Products were purified using flash chromatography. Preparation of cyclopropylthiol

Cyclopropylthiol was prepared according to the method described in JACS 1992, 114(9), 3492-3499.

EXAMPLES

The compounds listed in Table 1 below were prepared using the synthesis procedure described above and illustrate the present invention.

Table 1

GENERAL DESCRIPTION OF THE PHARMACOLOGICAL PROPERTIES OF THE COMPOUNDS OF THE PRESENT INVENTION

The arylamide derivatives of the present invention show high antag- onistic activity in AR. Antagonistic activity in AR refers to potency of the compound to compete and/or inhibit the activity of natural AR ligands such as dihy- drotestosterone (DHT) and testosterone. The present invention provides compounds having antagonistic activity in AR to compete and/or inhibit the activity of non-natural AR ligands, such as synthetic androgens or anti-androgens used as medicaments (but which may exert deleterious side-effects).

Further, the present invention provides compounds that demonstrate potent anti-androgen activity in a dose-dependent manner. A major disadvantage of bicalutamide is incomplete AR antagonism. In the case of bicalu- tamide, increasing concentrations do not provide significant extra benefit. More potent anti-androgens than bicalutamide may be needed to treat advanced stage of PCa characterized by elevation of AR levels, thus there is a need for potent anti-androgens that can compensate for the elevated AR levels in a dose-dependent manner. The present invention provides compounds that exert minimal agonistic effects in AR.

The compounds of the present invention can be used to treat AR- related diseases, such as BPH and PCa. The compounds can also be used to treat CRPC. Further, the compounds can be used in combination with other anti-androgen treatments.

The compounds of the present invention do not gain agonistic activity in CRPC related mutations. By CRPC related mutations, all mutations that affect the development, progression or severity of the disease are referred. The CRPC related mutation may have resulted from androgen deprivation - induced enrichment of prostate cancer cells harboring the said mutation. For instance tryptophan 741 to leucine or to cysteine mutation and also threonine 877 to alanine mutation are referred.

The compounds of the present invention retain their antagonistic activities when AR levels are elevated.

The following tests and results are provided as to demonstrate the present invention in an illustrative way and should not be considered as limiting in the scope of invention. Further, the concentrations of the compounds in the assays are exemplary and should not be taken as limiting. A person skilled in the art may define pharmaceutically relevant concentrations with methods known in the art.

EXPERIMENTS

To elucidate the potency of the compounds of the present invention to function as anti-androgens and to demonstrate that the compounds of the present invention retain their antagonistic activity in conditions known to confer agonistic activities in the first-line anti-androgen medications in clinical use (such as flutamide or bicalutamide, BIC) a series of in vitro studies was designed. These studies were based on measuring AR transactivation using a reporter gene assay, which is a well-established, golden standard assay in AR research. Depending on the presence or absence of natural AR ligand such as testosterone, this reporter gene assay can be used to determine both antagonistic and agonistic activity of the compounds. BIC was used as a reference compound in all studies representing currently available standard anti- androgen treatment. AR transactivation assay

COS-1 cells (American Type Culture Collection, ATCC) were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), penicillin (6.25 U/ml) and streptomycin (6.25 pg/ml) and seeded onto 48-well plates (50 000 cells/well) one day before transfection. Transfection media containing 2.5% charcoal-stripped FBS in DMEM was changed on cells 4 h prior to transfection. Cells were transfected with 50 ng of luciferase (LUC) reporter gene plasmid (pPB-286/+32-LUC; PB, probasin promoter), 5 ng of AR expression plasmid (pSG5-hAR), and 5 ng of pCMN/β (an internal, beta-galactosidase control for transfection efficiency and cell growth) using TranslT-LT1 reagent (Mirus Bio Corporation) according to the manufacturer's instructions. One day after transfection, triplicate wells received either (i) vehicle (EtOH-DMSO), (ii) 50 nM testosterone (reference agonist, from Ma- kor or Steraloids Inc.), (iii) increasing concentrations of BIC (reference antagonist) or (iv) compound of the present invention alone (to test for agonism) or (v) increasing concentrations of BIC (reference antagonist) or (vi) compound of the present invention together with the reference agonist in a competitive setting (50 nM; to test for antagonism of testosterone induced AR transcription). After 18 h, reporter gene activities (LUC and beta-galactosidase) were determined according to standard methods. The data are expressed as relative LUC activity (luciferase light units divided by beta-galactosidase A420 n m to control for transfection efficiency) of a given compound in relation to the activity of a reference test item (=100%).

Alternatively, commercial Human AR Reporter Assay System (INDIGO Biosciences was used. In this assay, non-human mammalian cells are engineered to express human WT AR together with LUC reporter gene linked to AR-responsive promoter. 400 pM 6-alpha-FI testosterone, FIT, was used as a reference agonist in a competitive setting. The two reporter gene systems resulted in comparable data.

Agonism in WT AR

Agonism in WT AR of compounds of the present invention was measured in AR transactivation assay in COS-1 cells by exposing the trans- fected cells to test compounds alone as described above. Testosterone was used as a reference agonist. Relative LUC activity representing the level of AR activation was measured. The response obtained by the reference agonist was set as 100%. The compounds of the present invention did not show agonism in WT AR.

Antagonism in wild type (WT) AR

Antagonism in WT AR of compounds of the present invention was measured in AR transactivation assay in COS-1 cells in competitive setting using testosterone as a reference agonist as described above. Alternatively IN- DIGO Bioscience's Human AR Reporter Assay System was utilized. Known anti-androgen BIC was used as a reference antagonist. Relative LUC activity representing AR-dependent transcription obtained by exposure to reference agonist alone was set to 100%. The compounds of the present invention were efficient antagonists in WT AR (Table 2).

Table 2. Antagonism in WT AR

Ex Relative LUC activity (%) indicating residual androgen activity in relation to reference agonist (100%)

10 microM

1 2

2 5

3 8

4 8

5 6

6 5

7 3

8 5

9 8

10 5

1 1 16

12 5

13 10

14 1

15 4

16 1

18 19

19 16

20 13

21 6

22 2

23 7

25 9

27 5

28 4

29 3

30 2

31 4

BIC 13 One of the major limitations in the use of currently available anti- androgens, such as flutamide and BIC, is the antagonist-agonist conversion observed in mutated AR.

Agonism in W741 L mutant AR

Agonism in W741 L AR of compounds of the present invention was measured in AR transactivation assay in COS-1 cells as described above except that AR expression vector harboring the W741 L mutation was used instead of the WT AR. The transfected cells were exposed to test compounds alone. BIC was used as a reference compound. As reported in literature, BIC functions as an agonist in this mutant AR variant and the relative LUC activity representing AR-dependent transcription induced by BIC was set to 100%. The compounds of the present invention did not show agonism in W741 L AR (Table 3).

Agonism in T877A mutant AR

Agonism in T877A AR of compounds of the present invention was measured in AR transactivation assay in COS-1 cells as described above except that AR expression vector harboring the T877A mutation was used. The transfected cells were exposed to test compounds alone. Testosterone was used as reference agonist, and its' relative LUC activity representing AR- dependent transcription was set to 100%. The compounds of the present in- vention did not show agonism in T877A AR (Table 3).

Table 3. Agonism in W741 L and T877A mutant AR

Gene expression in VCaP cells

Quantitative RT-PCR was used to study the ability of the compounds of the present invention to inhibit AR target gene expression. VCaP cells (ATCC) were seeded onto 12-well plates (3 x 10 5 cells/well) and triplicate wells were treated with either (i) vehicle (EtOH-DMSO), or (ii) 1 nM R1881 (reference agonist, Perkin-Elmer), or (iii) increasing concentrations of BIC (reference antagonist), or (iv) the test compound together with the reference agonist (1 nM) (all final concentrations). After 18 h, total RNA was extracted using TRIzol® Reagent (Invitrogen Life Technologies) and converted to cDNA using Transcriptor First Strand cDNA synthesis Kit (Roche Diagnostics GmbH) following manufacturer's instructions. cDNA was used as a template in RT-qPCR, which was carried out using Mx3000P Real-Time PCR System (Stratagene), FastStart SYBR Green Master Mix (Roche) and specific primers for AR target genes, PSA, TMPRSS2 and FKBP51. Analyzed GAPDH mRNA levels were used to normalize the amounts of total RNA between the samples. Fold changes (ligand inductions) were calculated using the formula 2 "(ΔΔα) , where

AACt is ACt ( i igand)- ACt(EtOH-DMSO), ACt W3S Ct( gen e X)- Ct(GAPDH) 3nd Ct W3S the cycle at which the threshold was crossed. Gene expression data were expressed as relative mRNA level (mRNA level of the gene of interest divided by mRNA level of GAPDH) of each gene for a given compound. The compounds of the present invention efficiently silenced AR target gene expression in VCaP cells. LNCaP proliferation assay

The ability of the compounds of the present invention to inhibit prostate cancer cell growth was studied in androgen sensitive human prostate adenocarcinoma cell line, LNCaP (ATCC). The LNCaP cells may be also genetically modified to over-express AR, thus mimicking CRPC. The cells were seeded onto 96-well plates (5000 cells/well) and cultured for 24h. The six replicate wells were treated either with (i) vehicle (DMSO) or (ii) 0.1 nM R1881 (reference agonist, Perkin-Elmer), or (iii) increasing concentrations of BIC (the reference antagonist), or (iv) the test compound together with the reference agonist (0.1 nM) (all final concentrations) for 5 days. LNCaP cell proliferation was measured on day 0, day 1 , day 3 and day 5 using Promega's Cell Titer 96 ® AQ U eous One Solution Cell Proliferation Assay kit according to manufacturer's instructions. 20 μΙ of the Cell Titer reagent was added into 100 μΙ of cell culture medium in each well and the cells were allowed to grow for one hour in the incubator. The culture medium was transferred into the wells of the meas- uring plate and the absorbance at 492 nm was recorded. The compounds of the present invention inhibited LNCaP proliferation.

The compounds of the present invention exhibit little or no agonistic activity to androgen receptor. Because these compounds are potent AR antagonists they can be used not only to treat prostate cancer but to treat other androgen receptor related conditions and diseases such as benign prostate hyperplasia, hair loss, acne, hirsutism, male hypersexuality or polycystic ovarian syndrome.

The compound of the present invention may be used alone or in combination i.e. administered simultaneously, separately, or sequentially, with other active agents. As it pertains to the treatment of cancer, the compounds of this invention are most preferably used alone or in combination with anti-androgenic cancer treatments. Such compounds may also be combined with agents which suppress the production of circulating testosterone such as LHRH agonists or antagonists or with surgical castration.

The present invention also contemplates use of an antiestrogen and/or aromatase inhibitor in combination with a compound of the present invention, for example, to assist in mitigating side effects associated with anti- androgen therapy such as gynecomastia.

AR belongs to the superfamily of nuclear receptors and the compounds of the present invention can also be used as scaffolds for drug design for other nuclear hormone receptors such as estrogen receptor or peroxisome proliferator-activated receptor. Therefore, the compounds of the present invention can also be further optimized to be used in treating other conditions and diseases such as ovarian cancer, breast cancer, diabetes, cardiac diseases, metabolism related diseases of the periphery and central nervous system in which nuclear receptors play a role.

The compounds of the invention may be administered by intravenous injection, by injection into tissue, intraperitoneally, orally, or nasally. The composition may have a form selected from the group consisting of a solution, dispersion, suspension, powder, capsule, tablet, pill, controlled release capsule, controlled release tablet, and controlled release pill.