WO2013104829A1 - Novel arylamide derivatives having antiandrogenic properties - Google Patents

Abstract

The invention relates to novel arylamide derivatives having formula (I), and stereoisomers and pharmaceutically acceptable salts thereof, where R_A, R_B, R_C, R', R'', z and X 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.

Description

NOVEL ARYLAMIDE DERIVATIVES HAVING ANTIANDROGENIC 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 to 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 WO 2008/01 1072 A2, WO 2010/1 16342 A2, and WO 2010/092546 A1 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 dis- ease. 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 func- tion 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 determinants 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. Approximately 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, effi- cient, 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 endogenous 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 one of more of 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)

and stereoisomers and pharmaceutically acceptable salts thereof; wherein

A is selected from the group consisting of H, halogen, C-i-6-alkyl, C-i- 6-haloalkyl, C-i-2-perhaloalkyl, C-i-6-hydroxyalkyl, Ci-6-aminoalkyl, C-i-6-alkoxy, C-i-6-haloalkoxy, C-i-2-perhaloalkoxy, Ci-2-alkoxy-Ci-6-alkylenyl, C-i-6-alkyl- sulfonyl, arylsulfonyl, and NHR, wherein R is H or C-i-6-alkyl; arylamide, C-i-6- alkylamide, arylsulfonamide, C-i-6-alkylsulfonannide, and aryl;

R' and R" are each independently selected from the group consist- ing of H and C-i-6-alkyl;

z is an integer 0 to 3;

RA is a mono- or bicyclic, aromatic or heteroaromatic, ring system having 6 to 10 ring atoms, whereby the said mono- or bicyclic ring system comprises 0 to 2 or 0 to 4 nitrogen ring atoms, respectively, and the other ring atoms are carbon atoms, said ring system being unsubstituted or substituted one or more times, and where said substituents may be located at any appropriate locations and are represented by R_A';

each R_A' is independently selected from the group consisting of halogen, C-i-6-alkyl, C-i_-6-haloalkyl, C-i_-2-perhaloalkyl, hydroxy, C-i_-6-alkoxy, NO₂, CN, C(O)R, COOR, CONHR, NR₂, NHCOR, NHCOCF₃, NHCONHR, NHCOOR, OCONHR, where each R is independently hydrogen or C-i_-6-alkyl, and (CH₂)_nCHO, where n is an integer 0 - 6; or

when R_A is a monocyclic ring, two adjacent R_A' may be joined together to form a substituted or unsubstituted bridge;

R_B is an aromatic or heteroaromatic ring system having 6 ring atoms comprising 0 to 2 nitrogen ring atoms, while the other ring atoms are carbon atoms, said ring system being substituted one or more times, and where said substituents may be located at any appropriate locations and are represented by R_B';

each R_B' is independently selected from the group consisting of halogen, C-i-6-alkyl, C-i_-6-haloalkyl, C-i_-2-perhaloalkyl, hydroxy, C-i_-6-alkoxy, NO₂, CN, C(O)R, COOR, CONHR, NR₂, NHCOR, NHCOCF3, NHCONHR, NHCOOR, OCONHR, SR, S(O)R, SO₂R, and NHCSCH_3, where R is as defined above; or

two adjacent R_B' may form with the carbon atoms, to which they are attached, a substituted or unsubstituted aliphatic or heteroaliphatic, aromatic or heteroaromatic ring;

X is selected from the group consisting of O, S, S(O), SO₂, and NR'", where R'" is selected from the group consisting of H, Ci_-6-alkyl, and COR, where R is as defined above; or

when z is 0, then X may be N and form together with R_c a heterocyclic ring selected from the group consisting of morpholine, 1 ,2,4-triazole, imidazole and N-substituted imidazole; and

Rc, when not forming a ring with X as defined above, is selected from the group consisting of H, C-i_-6-alkyl, C_2-6-alkenyl, C_3-4-cycloalkyl, C-i_-6- haloalkyl, C-i_-2-perhaloalkyl, C_2-6-haloalkenyl, C-i_-6-CN-alkyl, C-i_-6-alkoxy, and an aryl, heteroaryl, aliphatic or heteroaliphatic, 5 - 7-membered ring, which ring systems are optionally substituted with one or more substituents, and where said substituents may be located at any appropriate locations and represented by Rc', each R_c' being independently selected from the group consisting of halogen, C-i_-6-alkyl, C-i_-6-haloalkyl, C-i_-2-perhaloalkyl, hydroxy, C-i_-6-alkoxy, NO₂, CN, C(O)R, COOR, CONHR, NR₂, NHCOR, NHCOCF₃, NHCONHR, NHCOOR, OCONHR, NHSO₂R, SR, S(O)R, SO₂R, and NHCSCH₃, where R is as defined above.

The invention also relates to pharmaceutical compositions compris- ing an effective amount of one or more arylamide derivatives of formula (I) or/and 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 may possess at least one asymmetric carbon atom, i.e. the carbon atom, to which the group A is attached. Thus, the compounds may exist in racemic form and optically active forms. All these forms are encompassed by the present inven- tion.

The term "Ci-6-alkyl" or "Ci-2-alkyl" as used herein and hereafter as such or as part of a substituent group, e.g. (per)haloalkyl, alkoxy, or hydroxy- alkyl, relates to linear or branched saturated hydrocarbon group containing suitably 1 to 6 or 1 to 2, respectively, carbon atoms and thus C-i-2-alkyl includes methyl and ethyl, and C-i-6-alkyl additionally includes n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, tert-butyl, and branched and straight chain pentyl and hexyl.

The term "halo" as used herein and hereafter by itself or as part of other groups refers to elements from Group 17 lUPAC style of the periodic ta- ble and includes CI, Br, F and I. Preferred halogens are CI and F.

The term "haloalkyi" as used herein and hereafter refers to any of the above alkyl groups where one or more hydrogen atoms are replaced by halogen(s), preferably F or CI. Examples of haloalkyi groups include without limitation chloromethyl and fluoromethyl. The term "perhaloalkyl" is understood to refer to an alkyl group, in which all the hydrogen atoms are replaced by hal- ogen atoms. Preferred examples include trifluoromethyl (-CF₃) and trichloro- methyl (-CCI₃).

The term "C_2-6-alkenyl" as used herein and hereafter relates to unsaturated linear or branched hydrocarbon groups having one or more double bonds and containing suitably 2 to 6 carbon atoms.

The term "Ci_-6-alkoxy" as used herein and hereafter refers to a -O-(Ci_-6-alkyl) group where the "Ci_-6-alkyl" has the above-defined meaning. Examples of preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, and n-propyloxy.

The term "Ci_-6-alkylenyl" as used herein and hereafter refers to a divalent group derived from a straight or branched chain hydrocarbon of having suitably 1 to 6 carbon atoms. Representative examples of alkylenyls include, but are not limited to, -CH₂-, -CH(CH₃)-, -C(CH₃)₂-, -CH₂CH₂-, and -CH₂CH₂CH₂-. As used herein, the term hydroxyalkyl (e.g. hydroxymethyl) is interchangeable with the term hydroxyalkylenyl.

The term "aryl" as used herein and hereafter, refers to group derived from an aromatic six membered hydrocarbon ring i.e. phenyl ring. Such a ring may be unsubstituted or substituted with one or more, preferably one or two, substituents each independently selected from the group consisting of halo- gen, C-i_-6-alkyl, C-i_-6-haloalkyl, C-i_-2-perhaloalkyl, hydroxy, C-i_-6-alkoxy, CN, and NO₂. Typical examples of aryl include phenyl (Ph), fluorophenyl, chlorophenyl, and difluorophenyl.

The term "substituted" refers to a substituent group as defined herein in which one or more bonds to a hydrogen atom contained therein are re- placed by a bond to a non-hydrogen atom unless otherwise denoted. The said group may be substituted independently with one or more, preferably 1 , 2, or 3, substituent(s) attached at any available atom to produce a stable compound, e.g. a phenyl may be substituted one or more times with the denoted substituents) attached to 0-, p- or/and m-position of the phenyl ring.

The term "aliphatic, heteroaliphatic, aromatic or heteroaromatic ring" refers to a saturated 4- to 7-membered ring, where 1 to 3 carbon atoms may be replaced by heteroatoms selected from O, S and N. Such a ring may be substituted with one or more substituents, each independently selected from the group consisting of halogen, C-i_-6-alkyl, C-i_-6-haloalkyl, C-i_-2-perhaloalkyl, hydroxy, C_1-6-alkoxy, CN, NO₂, COR, COOH, CONHR, NR₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, where R is hydrogen or C-i-6-alkyl; NHCSCH_3, Ci_-6-alkylthio, Ci_-6-alkylsulfinyl and Ci_-6-alkylsulfonyl; the substituent(s) being preferably CN, CF₃, F or CI. Typical examples of groups formed by the rings falling under the term "aliphatic, heteroaliphatic, aromatic or heteroaromatic ring" and the R_B ring, to which they are fused, are naphtalene, tetrahydronaphtalene, quinoline and benzofuran.

The term "substituted or unsubstituted bridge" refers to C_3- -alkylene bridge, wherein one or two methylene units may independently be replaced by O, S, C(O), or NR, where R is hydrogen or C-i_-6-alkyl. Such bridge may be unsubstituted or substituted with one or two substituents selected from the group consisting of C-i_-6-alkyl, C-i_-6-haloalkyl, C-i_-2-perhaloalkyl, and aryl (Ar). Typical examples of groups formed by two adjacent R_A' or R_B' groups include -OC(CH₃)₂O-, -OCHC(CH₃)₂CH-O-, -OC(Ph)₂O-, -OCH(Ar)O-, and -N(CH₃)CH₂O-.

The term "an aryl, heteroaryl, aliphatic or heteroaliphatic, 5- to 7- membered ring" in the definition of R_c refers to saturated or unsaturated ring system having suitably 5 to 7 ring members, 0 to 3 of which being a heteroa- tom selected from O, S and N, the other members being carbon atoms. The ring may be substituted with one or more, preferably 1 , 2 or 3, substituents each independently selected from the group consisting of halogen, Ci_-6-alkyl, C _-6- haloalkyl, C _-2-perhaloalkyl, hydroxy, C _-6-alkoxy, CN, NO₂, COR, COOR, CONHR, NR₂, NHCOCHs, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, where R is hydrogen or C _-6-alkyl; NHCSCH_3, C _-6-alkylthio, C _-6- alkylsulfinyl and C-i_-6-alkylsulfonyl; the substituent(s) being preferably CN, CF₃, F or CI.

The term "aromatic" refers to ring systems comprising a delocalized conjugated pi system, e.g. an arrangement of alternating single and double bonds, where all the contributing atoms arranged in one or more rings are essentially in the same plane and the number of the pi delocalized electrons satisfies Huckel's Rule. The term is meant to encompass also prevalent tautomer- ic forms of such ring systems with given substituents even if the resulting tautomeric form is non-aromatic.

In accordance with the present invention preferred compounds of formula (I) are those wherein X is O, S, S(O) or SO₂, more preferably O, S or SO₂, most preferably SO₂. Further preferred compounds of formula (I) are those where z is 0 or 1 . A is advantageously selected from the group consisting of H, methyl, hydroxymethyl and methoxymethylene.

Examples of monocyclic R_A include phenyl and pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl, preferably substituted by one, two, or three sub- stituents as described earlier. R_A is preferably a monocyclic ring.

Examples of bicyclic R_A include indolyl, isoindolyl, azaindolyl, quino- linyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxaline, naphthydrine, pyr- rolo[2,3-b]pyridinyl, indolizinyl, imidazo[1 ,5-a]pyridinyl, imidazo[1 ,2-a]pyridinyl imidazo[1 ,2-a]pyridinyl, imidazo[1 ,2-b]pyridazin-6-yl, indazolyl, triazolo[4,3-a]- pyridinyl, triazole[4,3-b]pyridazinyl, pyrazolo[4,3-b]pyridinyl, pyrazolo[4,3-c]pyr- idinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,4-c]pyridinyl, pyrrolo[1 ,2-a]pyridazinyl, pyrrolo[1 ,2-a]pyrimidinyl, pyrrolo[1 ,2-b]pyridazinyl, tetrazolo[1 ,5-a]pyrimidinyl, benzoimidazolyl,and benzotriazolyl, preferably substituted by one, two, or three substituents as described earlier.

R_A is advantageously selected from radicals of formulae (Aa) or (Ac), more advantageously from (Aa) and (Ab):

wherein R1 to R5 and R1 ' are each independently H or R_A'; preferably R2 and R3 or R1 ' are each independently selected from H, C-i_-2- perhaloalkyl, CN, NO₂, and halogen, and R1 , R4, and R5 are each H. Preferably R_A is (Aa).

R_A' is preferably selected from the group consisting of halogen, C_halky!, C-i-6-haloalkyl, C-i_-2-perhaloalkyl, hydroxy, C-i_-6-alkoxy, NO₂, and CN.

Further preferred compounds of formula (I) are those wherein R_A is substituted with one, two or three substituent(s), each independently R_A', pref- erably each independently selected from the group consisting of halogen, NO₂, CN, and CF₃.

Advantageously one, i.e. first, R_A' is CI, F, or CF₃ and another, i.e. second, R_A' is independently NO₂ or CN, the said two i.e. first and second R_A' being preferably adjacent to each other. Advantageously one or two R_A' substituents) are each independently selected from the group consisting of CI, F, CN, methoxy, and CF₃.

Examples of R_B include phenyl, pyridine, pyrazine, pyrimidine, and pyridazine, preferably substituted by one, two, or three substituents as de- scribed earlier.

R_B is advantageously selected from radicals of formulae (Ba) and

(Bb):

wherein R6 to R10 are each independently H or R_B' provided that at least one of R6 to R10 is R_B'; preferably R6, R7 and R10 are each H, and one or both of R8 and R9 are each independently selected from the group consisting of CI, F, CN, methoxy, OH, and CF₃, while the other may also be H.

Preferably R_B' is selected from the group consisting of halogen, C-|. 6-alkyl. C-i-6-haloalkyl, C-i_-2-perhaloalkyl, hydroxy, C-i_-6-alkoxy, NO₂, and CN.

Further preferred compounds of formula (I) are those wherein R_B is substituted with one or two substituent(s), each independently R_B', preferably each independently selected from the group consisting of halo, CN, methoxy, and CF₃.

Rc is advantageously H, C-i_-6-alkyl, preferably methyl, ethyl, or iso- propyl, or phenyl, which is optionally substituted by one or two substituents each independently selected from R_c', preferably from the group consisting of F, CI, and CF₃. Preferred

wherein each Y is independently C or N, and other symbols are as defined above; preferably R1 is H or R_A\ one of R2 and R3 is RA' and the other is independently H or R_A\ each R_A' being preferably selected from the group consisting of halo, CN and C-i-2-perhaloalkyl; one of R8 and R9 is RB' and the other is independently H or R_B', each R_B' being preferably selected from the group consisting of halo, CN, and C-i-2-perhaloalkyl; X is selected from the group consisting of S, SO, SO2, and O; and Rc is as defined earlier, preferably C-i-3-alkyl, or phenyl or benzyl substituted one or more times, preferably one or two times, with R_c';

and pharmaceutically acceptable salts thereof.

Further preferred compounds are those of formula (l-b)

(l-b) wherein each Y is independently C or N; and other symbols as defined above, or preferably R1 is H or R_A', one of R2 and R3 is R_A' and the other is independently H or R_A', each R_A' being preferably selected from the group consisting of halo, CN, and Ci_-2-perhaloalkyl; one of R8 and R9 is R_B' and the other is independently H or R_B', each R_B' being preferably selected from the group consisting of halo, CN, and Ci_-2-perhaloalkyl; X is selected from the group consisting of S, SO, SO₂, and O; and R_c is as defined earlier, preferably C-i-3-alkyl, or phenyl or benzyl substituted one or more times, preferably one or two times, with R_c';

and pharmaceutically acceptable salts thereof.

Also preferred compounds are those of formula (l-c)

wherein each Y is independently C or N; and other symbols are as defined above; preferably R1 is H or R_A\ one of R2 and R3 is RA' and the other is independently H or R_A\ each R_A' being preferably selected from the group consisting of halo, CN, and C-i-2-perhaloalkyl; one of R8 and R9 is RB' and the other is independently H or R_B\ each R_B' being preferably selected from the group consisting of halo, CN, and C-i-2-perhaloalkyl; and Rc is as defined above, preferably C-i-3-alkyl; and A' is H or C-i-6-alkyl;

and pharmaceutically acceptable salts thereof.

Examples of particularly preferred specific compounds are:

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

N-(3-chloro-4-cyanophenyl)-3-[(4-fluorobenzene)sulfonyl]-2-[4-(tri- fluoromethyl)phenyl]propanamide;

N-(3-chloro-4-cyanophenyl)-3-[(3,4-difluorobenzene)sulfonyl]-2-(3,4- difluorophenyl)propanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)-2-(4-fluoro- phenyl)propanamide;

N-(3-chloro-4-cyanophenyl)-3-[(3,4-difluorophenyl)sulfanyl]-2-[4-(tri- fluoromethyl)phenyl]propanamide;

N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-3-{[(4-chlorophenyl)- methane]sulfonyl}propanamide;

N-(3-chloro-4-cyanophenyl)-3-[(4-chlorobenzene)sulfonyl]-2-(4- chlorophenyl)propanamide;

N-(3-chloro-4-cyano-2-fluorophenyl)-2-(3,4-difluorophenyl)-3-hydr- oxy-2-(methoxymethyl)propanamide;

N-(3-chloro-4-cyano-2-fluorophenyl)-2-(3,4-difluorophenyl)-3-meth- oxy-2-(methoxymethyl)propanamide;

2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3- (ethanesulfonyl)propanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-3-hydroxy- 2-methylpropanamide; N-(3-chloro-4-cyanophenyl)-3-(4-chlorobenzenesulfonyl)-2-(6- chloropyridin-3-yl)propanamide;

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

N-(3-chloro-4-cyanophenyl)-3-[(4-chlorophenyl)methanesulfonyl]-2- (6-chloropyridin-3-yl)propanannide;

3- (ethanesulfonyl)-2-(4-fluorophenyl)-N-[4-nitro-3- (trifluoronnethyl)phenyl]propanannide;

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

2-(6-chloropyridin-3-yl)-N-[4-nitro-3-(trifluoronnethyl)phenyl]-3- (propane-2-sulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-2-(3,4-difluorophenyl)-3- (ethanesulfonyl)propanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-cyanophenyl)-3- (ethanesulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-3-(4-fluorobenzenesulfonyl)-2-[6- (trifluoronnethyl)pyndin-3-yl]propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-cyano-3-fluorophenyl)-3- (ethanesulfonyl)propanamide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-3- (ethanesulfonyl)-2-methylpropanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)-2-(4- fluorophenyl)-2-methylpropanannide;

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

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

2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2- methyl-3-(propane-2-sulfonyl)propanannide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-3- methanesulfonyl-2-methylpropanamide;

2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3- methanesulfonyl-2-nnethylpropanannide;

N-(3-chloro-4-cyanophenyl)-3-(4-chlorobenzenesulfonyl)-2-(4- chlorophenyl)-2-methylpropanannide; N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-3- nnethanesulfonyl-2-nnethylpropanannide;

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 described below. For example the compounds of formula (I), where X is NR'", O, S, S(O) or SO_2, and A is H may be prepared by reacting an amide compound of formula (3),

0

where R_A and R_B are as defined above, with paraformaldehyde in suitable reaction conditions, preferably at 90 °C, to obtain a compound of formula (4)

4

and then reacting the obtained compound of formula (4) with a compound of formula (l l).

Rc-(CR'R")_Z-X'H (II)

where Rc, R', R" and z are as defined earlier and X' is NHR'", O or S, to obtain a compound of formula (I), where X is NR'", O or S, and then, if desired, oxidizing the obtained compound where X is S to obtain a compound of formula (I), where X is S(O) or SO2.

The process is preferably carried out via the following reaction steps: (i)

3

For another example, compounds of formula (I), where X is O and A is hydroxymethylenyl or alkoxymethylenyl, may be prepared by reacting an amide of formula (3),

where R_A and R_B are as defined above, with paraformaldehyde in suitable reaction conditions, preferably at 50 °C, to obtain a product of formula (8)

8

and then reacting compound of formula (8) with 2 equivalents of Ci_-6-alkyliodine to obtain a compound of formula (9)

9

where Rc is corresponding C-i-6-alkyl and then, optionally, reacting compound of formula (9) with 2 equivalents of another C-i-6-alkyliodine to obtain compound of formula (10)

where A is the corresponding another C-i_-6-alkyl;

or alternatively reacting compound of formula (8) with 5 equivalents of C-i-6-alkyliodine to obtain a compound of formula (10), where R_c and A' are both the corresponding C-i_-6-alkyl.

The process is preferably carried out via the following reaction steps: (ii)

10

For yet another example, the compound of formula (I) where A is C-i- 6-alkyl, C-i-6-haloalkyl or Ci-2-perhaloalkyl, may be prepared by esterifying the compound of formula (2)

then reacting the obtained compound with Ci_-6-alkyl-, C-i_-6-halo- alkyl-, or Ci_-2-perhaloalkyliodide, and then reacting the thus obtained compound with paraformaldehyde to obtain a compound of formula (13)

13

where X is S or O and A is the corresponding Ci_-6-alkyl, C-i_-6- haloalkyl, or C-i_-2-perhaloalkyl; and, if desired, reacting the said compound with C-i-6-alkyl- or aryl(CR'R")_z-halide- to obtain corresponding compound of formula (14)

14

where R_C(CR'R")_Z is C _-6-alkyl or aryl(CR'R")_z-; and then transforming the obtained compound of formula (13) or (14) to the corresponding free acid and reacting the said acid with compound of formula (1 )

NH₂

1

to obtain a compound of formula (I) where X is O or S and Rc is H, C-i-6-alkyl or aryl(CR'R")_z-; and then, if desired, oxidizing the obtained compound where X is S to obtain a compound of formula (I), where X is S(O) or SO₂.

The process is preferably carried out via the following reaction steps: (iii)

Alternatively, compounds of the invention wherein A is preferably C-i-6-alkyl, Ci_-6-haloalkyl, or C-i_-2-perhaloalky may be prepared by reacting a compound of formula (18)

where R_B is as defined above, with a halide of formula (III) A-hal (III)

where A is as defined above, preferably C-i_-6-alkyl, C-i_-6-haloalkyl, or C-i-2-perhaloalkyl, and hal is halide, preferably I, to obtain a compound of formula (19)

wherein A is as above, and then reacting the obtained compound with methyldihahde, preferably methyldiodide, to obtain a compound of formula

where hal is halide, preferably I,

reacting the obtained compound of formula (20) with a compound of formula (II)

R_C-(CR'R")_Z-X'H (II)

where R_c, R', R" and z are as defined earlier and X' is NHR'", O or

S, to obtain a compound of formula (21 a)

and, if desired, oxidizing the obtained compound where X is S to obtain a compound of formula (21 b), where X is S(O) or SO₂,

hydrolyzing, preferably with sulphuric acid, the compound of formula (21 a) or (21 b) to obtain an acid of formula (22)

(CR'

(22) reacting the obtained compound of formula (22) with a compound of formula (1 )

1

wherein R_A is as defined above, to obtain a compound of formula (I)

(C

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. 4-cyano-3-fluorothiophenol was synthesized from 4- cyano-3-fluorophenol using method described in WO 2008/008022. 4-cyano-3- chloro-2-fluoroaniline was synthesized from 3-chloro-2-fluoroaniline using method described in US 2005/0197359.

General method for the synthesis of the intermediate (3)

Method-3A: A corresponding 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 temperature 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 add- ed 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 Na₂SO₄ and evaporated to give (3). Intermediate (3) was purified by flash chromatography.

Method-3B: A corresponding phenyl acetic acid (2) (0.58 mmol) and aniline (1 ) (0.58 mmol) was dissolved in DMF (1 ml). 1 .16 mmol of HATU (2- (1 H-7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyl uranium hexafluorophosphate methanaminium) (2 equivalents) was added and the mixture was stirred for 5 minutes. 1 .75 mmol of TEA (3 equivalents) was added at RT and the resulting mixture stirred for 16 hours. After completion of the reaction confirmed by TLC water was added (5 ml). The mixture was extracted with EtOAc Organic layer was washed with diluted HCI (3 x 15ml), dried over sodium sulphate and concentrated to get crude intermediate (3). Intermediate (3) was purified by flash chromatography. General method for the synthesis of the intermediate (4) and (8)

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.

Compound of formula (8) was obtained in the above reaction conditions with the exception that the reaction mixture was heated to 50 °C General method for the synthesis of (5)

To 0.125 (2 equivalents) mmol of NaH in dry THF (2 ml), 0.094 mmol (1 .5 equivalents) of a corresponding thiophenol was added in THF (1 ml). Mixture was stirred at room temperature for 15 min. 0.062 mmol of the in- termediate (4) in THF (2 ml) was added at room temperature. The resulting mixture was stirred at RT for 16h. After completion of the reaction monitored by TLC reaction was quenched by adding 20% aqueous acetic acid (1 ml). The resulting mixture was extracted with EtOAc. The organic phase was separated, washed with water and concentrated to get the crude material which was used for the synthesis of (6) without further purification.

General method for the synthesis of (6)

0.45 mmol of (5) was dissolved in CH₂CI₂ (20 ml). MCPBA (0.90 mmol, 2 equivalents) was added and the mixture was stirred at RT. After completion 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 Na₂SO and evaporated. Products were purified using flash chromatography.

General method for the synthesis of (9) and (10)

To 0.104 mmol of NaH (2 equivalents) in dry THF (2 ml) 0.052 mmol of intermediate (5) was added in dry THF (5 ml) at 0°C. The resulting mixture was stirred for 30 minutes at 0°C. 0.104 mmol of alkyl iodine (2 equivalents) was added dropwise in to the reaction mixture. The resulting mixture was stirred at RT for 1 h. After completion of the reaction confirmed by TLC the reaction was quenched by adding water (10 ml). The resulting mixture was ex- tracted with EtOAc. Organic layer was washed with water (2 x 20ml) and brine (20 ml), dried over sodium sulphate and concentrated to give crude (9). Product was purified using flash chromatography.

Reaction at RT for 16h using 5 equivalents of NaH and 5 equivalents of alkyl iodine gave compound (10) after flash chromatography. Synthesis of 2-(4-fluorophenyl)-3-hydroxy-2-methylpropanoic acid derivatives

4-Fluorophenyl acetic acid (19.5 mmol) was dissolved in MeOH (15 ml). SOCI₂ (39 mmol, 2 equivalents) was dropped in and the mixture was stirred at room temperature (RT) for 1 h. The solvent was removed in vacuo and the oily residue was diluted by CH₂CI₂. Organic layer was washed with water (3 x 50 ml), dried over sodium sulphate and concentrated. Crude material was purified by flash chromatography to yield methyl-2-(4-fluorophenyl)- acetate.

Methyl-2-(4-fluorophenyl)acetate (2.9 mmol) then was dissolved in dry THF. NaH (3.3 mmol, 1 .1 equivalents) was added and the resulting mixture was stirred at RT for 45 minutes. CH₃I (3.3 mmol, 1 .1 equivalents) was added dropwise and the mixture was stirred at RT for 3 hours. Reaction was quenched with aqueous NH₄CI and extracted with EtOAc (2 x 50 ml). Organic layer was washed with water, dried over sodium sulphate and concentrated. Purification by flash chromatography gave methyl-2-(4-fluorophenyl)-propion- ate.

Methyl 2-(4-fluorophenyl)propionate (0.27 mmol) and paraformaldehyde (0.82 mmol, 3 equivalents) was dissolved in DMF (1 ml). NaH (0.04 mmol, 0.16 equivalents) was added and the resulting mixture was stirred at RT for 2.5 hours. Water was added and the mixture was extracted with EtOAc. Organic layer was washed with brine, dried over sodium sulphate and concentrated. Purification by flash chromatography gave methyl 2-(4-fluorophenyl)-3- hydroxy-2-methylpropanoate.

LiOH (0.42 mmol, 3 equivalents) was added to the mixture of methyl

2-(4-fluorophenyl)-3-hydroxy-2-methylpropanoate (0.14 mmol) in THF (0.5 ml) and water (0.5 ml). Resulting mixture was stirred at RT for 3 hours. After completion of the reaction the mixture was concentrated and the residue acidified with diluted HCI solution. Aqueous layer was extracted with CH₂CI₂. Organic layer was dried over sodium sulphate and concentrated to give 2-(4-fluoro- phenyl)-3-hydroxy-2-methylpropanoic acid, which was used for further reactions without purification.

2-(4-fluorophenyl)-3-hydroxy-2-methylpropanoic acid was then converted to final product by the general procedure for the synthesis of intermedi- ate (3).

General method for synthesis of intermediate (19)

NaH (4.9 mmol) was added to a stirred solution of substituted phe- nylacetonitrile (18) (3.2 mmol) in THF (5 ml) at 0 °C and the resulting mixture was stirred for 1 hour. AlkyI iodide (6.5 mmol) was added dropwise, the mixture was allowed to warm to RT and stirring was continued until TLC showed completion of the reaction. The reaction was quenched by adding water (10 ml). The resulting mixture was extracted with EtOAc. Organic layer was washed with water (2 x 20ml) and brine (20 ml), dried over sodium sulphate and concentrated to give crude (19). Product was purified using flash chromatography.

Synthesis of intermediate (20)

A solution of DIPA (di-isopropyl amine, 3.6 mmol) in THF (1 ml) was treated with butyllithium (3.6 mmol) at -78°C and the resulting mixture was stirred for 20 minutes under nitrogen atmosphere. The mixture was allowed to slowly warm up to 0°C within 30 minutes. The formation of yellow transparent solution indicated the formation of LDA. The mixture was cooled to -78°C and (18) (3.0 mmol) was added dropwise in THF (1 ml) and the mixture stirred at - 78°C for 1 hour. Di-iodomethane (6.0 mmol) was added and the mixture was allowed to warm to RT. After stirring for 16 hours at RT, the reaction was quenched with saturated NH CI. The resulting mixture was extracted with EtOAc. The organic phase was dried over Na₂SO₄ and evaporated to give brown semisolid crude (20).

Synthesis of intermediate (21a)

A solution of alkylthiol (0.66 mmol) in THF (0.5 ml) was treated with NaH (0.32 mmol) at 0°C. After stirring for 30 minutes, a solution of (20) (0.16 mmol) in THF (0.5 ml) was added. The mixture was allowed to warm up to RT and the stirring was continued for 18 hours. After completion of the reaction confirmed by 1 H-NMR, reaction was quenched with diluted HCI and the mixture was extracted with EtOAc. Evaporation of the solvent gave (20).

Synthesis of intermediate (21 b)

(21 b) was prepared according to the general oxidation method de- scribed for intermediate (6).

Synthesis of intermediate (22)

H₂SO₄ (0.28 ml) was added to a stirred mixture of (D) (0.26 mmol) in water (0.7 ml) at RT. The resulting mixture was refluxed for 6 hours. After cooling to RT, water was added and the mixture extracted with EtOAc. Evapo- ration of the solvent gave an oily residue, which was mixed with diluted NaOH and stirred for 15 minutes at RT. After extraction with EtOAc (removed), the aqueous phase was acidified with diluted HCI and extracted with EtOAc. Organic phase was evaporated under vacuum to get (22). Synthesis of final product (I), wherein A is alkyl

(I) was prepared from acid (22) and aniline using the method described in Tetrahedron Letters, 2007, 48(6), 979-983.

EXAMPLES

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

Table 1. Names and 1 H-NMR characteristics of Example molecules of the present invention

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

The arylamide derivatives of the present invention show high antagonistic activity in AR. Antagonistic activity in AR refers to potency of the com- pound 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 compounds of the present invention provide one or more benefits over known AR antagonistic compounds. These benefits include but are not limited to lack of agonism in mutant AR, improved chemical or metabolic stability, improved oral bioavailability or improved safety and toxicological properties. 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_nm 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 us- ing testosterone as a reference agonist as described above. Alternatively INDIGO 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

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 PCa cells

Quantitative RT-PCR may be used to study the ability of the compounds of the present invention to inhibit AR target gene expression in PCa cells such as VCaP cells. VCaP cells are good choice of cells as they are derived from hormone-refractory PCa patient with AR amplification thus representing CRPC model. PSA, TMPRSS2 and FKBP51 are examples of AR target genes. The AR target genes are specified by using target gene specific primers in the PCR reaction. The specific AR target gene expression is normal- ized to total RNA in the sample. E.g. GAPDH mRNA levels may be used in normalization.

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 ad- enocarcinoma cell line, LNCaP. 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 24 h. The six replicate wells were treated either with (i) vehicle (DMSO) or (ii) 0.1 nM R1881 (reference ag- onist, 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_ue0us One Solution Cell Proliferation Assay kit according to manufacturer's instruc- tions. 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 measuring plate and the absorbance at 492 nm was recorded. The compounds of the present invention inhibited LNCaP proliferation.

UTILITY OF THE INVENTION

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 may also be further optimized to be used for 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.

Claims

Claims

1. An arylamide derivative having formula (I)

(I)

or a stereoisomer or pharmaceutically salt thereof;

wherein

A is selected from the group consisting of H, halogen, Ci_-6-alkyl , C-|. 6-haloalkyl, C-i_-2-perhaloalkyl, C-i_-6-hydroxyalkyl, Ci_-6-aminoalkyl, C-i_-6-alkoxy, C-i-6-haloalkoxy, C-i_-2-perhaloalkoxy, Ci_-2-alkoxy-Ci_-6-alkylenyl, C-i_-6-alkyl- sulfonyl, arylsulfonyl, and NHR, wherein R is H or C-i_-6-alkyl; arylamide, C-i_-6- alkylamide, arylsulfonamide, Ci_-6-alkylsulfonamide, and aryl;

R' and R" are each independently selected from the group consisting of H and C-i_-6-alkyl;

z is an integer 0 to 3;

R_A is a mono- or bicyclic, aromatic or heteroaromatic, ring system having 6 to 10 ring atoms, whereby the said mono- or bicyclic ring system comprises 0 to 2 or 0 to 4 nitrogen ring atoms, respectively, and the other ring atoms are carbon atoms, said ring system being unsubstituted or substituted one or more times, and where said substituents may be located at any appro- priate locations and are represented by R_A';

each R_A' is independently selected from the group consisting of halogen, C-i-6-alkyl, C-i_-6-haloalkyl, C-i_-2-perhaloalkyl, hydroxy, C-i_-6-alkoxy, NO₂, CN, C(O)R, COOR, CONHR, NR₂, NHCOR, NHCOCF₃, NHCONHR, NHCOOR, OCONHR, where each R is independently hydrogen or C-i_-6-alkyl, and (CH₂)_nCHO, where n is an integer 0 - 6; or

when R_A is a monocyclic ring, two adjacent R_A' may be joined together to form a substituted or unsubstituted bridge;

R_B is an aromatic or heteroaromatic ring system having 6 ring atoms comprising 0 to 2 nitrogen ring atoms, while the other ring atoms are carbon atoms, said ring system being substituted one or more times, and where said substituents may be located at any appropriate locations and are represented by R_B';

each R_B' is independently selected from the group consisting of halogen, C-i-6-alkyl, Ci_-6-haloalkyl, C-i_-2-perhaloalkyl, hydroxy, C-i_-6-alkoxy, NO₂, CN, C(O)R, COOR, CONHR, NR₂, NHCOR, NHCOCF₃, NHCONHR, NHCOOR, OCONHR, SR, S(O)R, SO₂R, and NHCSCH_3, where R is as defined above; or

two adjacent R_B' may form with the carbon atoms, to which they are attached, a substituted or unsubstituted aliphatic or heteroaliphatic, aromatic or heteroaromatic ring;

X is selected from the group consisting of O, S, S(O), SO₂, and NR'", where R'" is selected from the group consisting of H, Ci_-6-alkyl, and COR, where R is as defined above; or

when z is 0, then X may be N and form together with R_c a heterocy- die ring selected from the group consisting of morpholine, 1 ,2,4-triazole, imidazole and N-substituted imidazole; and

Rc, when not forming a ring with X as defined above, is selected from the group consisting of H, C-i_-6-alkyl, C_2-6-alkenyl, C_3-4-cycloalkyl, C-i_-6- haloalkyl, C-i_-2-perhaloalkyl, C_2-6-haloalkenyl, Ci_-6-CN-alkyl, C-i_-6-alkoxy, and an aryl, heteroaryl, aliphatic or heteroaliphatic, 5 - 7-membered ring, which ring systems are optionally substituted with one or more substituents, and where said substituents may be located at any appropriate locations and represented by Rc', each R_c' being independently selected from the group consisting of halogen, C-i_-6-alkyl, C-i_-6-haloalkyl, C-i_-2-perhaloalkyl, hydroxy, C-i_-6-alkoxy, NO₂, CN, C(O)R, COOR, CONHR, NR₂, NHCOR, NHCOCF₃, NHCONHR, NHCOOR, OCONHR, NHSO₂R, SR, S(O)R, SO₂R, and NHCSCH_3, where R is as defined above.

2. Arylamide derivative according to claim 1 , wherein R_c is selected from the group consisting of H, Ci_-6-alkyl, and phenyl, which is optionally sub- stituted by one or two substituents each independently selected from R_c'.

3. Arylamide derivative according to claim 1 or 2, wherein R_A is selected from radicals of formulae (Aa) to (Ac),

wherein R1 to R5 are each independently H or R_A'.

4. Arylamide derivative according to claim 3, where R2 and R3 or R1 ' are each independently selected from H, C-i-2-perhaloalkyl, CN, NO2, and halogen, and R1 , R4, and R5 are each H.

5. Arylamide derivative according to any one of claims 1 to 4, wherein R_B is selected from radicals of formula (Ba) or (Bb),

wherein R6 to R10 are each independently H or R_B'.

6. Arylamide derivative according to claim 4, where R6, R7 and R10 are each H, and one or both of R8 and R9 are each independently selected from the group consisting of CI, F, CN, methoxy, OH, and CF₃, while the other may also be H.

7. Arylamide derivative according any one of claims 1 to 6, wherein z is 0 or 1 .

8. Arylamide derivative according any one of claims 1 to 7, wherein X is selected form the group consisting of O, S, S(O) and SO2.

9. Arylamide derivative according to claim 1 , selected from the group consisting of formulae (l-a), (l-b), and (l-c):

wherein each Y is independently C or N; R1 is H or R_A\ one of R2 and R3 is RA' and the other is independently H or R_A\ one of R8 and R9 is RB' and the other is independently H or R_B\ X is selected from the group consisting of S, SO, SO2, and O; and Rc is as claimed in claim 1 ;

(l-b)

wherein each Y is independently C or N; R1 is H or R_A\ one of R2 and R3 is R_A' and the other is independently H or R_A\ one of R8 and R9 is R_B' and the other is independently H or R_B\ X is selected from the group consisting of S, SO, SO₂, and O; and R_c is as claimed in claim 1 ;

(l-c)

wherein each Y is independently C or N; R1 is H or R_A', one of R2 and R3 is R_A' and the other is independently H or R_A', one of R8 and R9 is R_B' and the other is independently H or R_B', and R_c is as claimed in claim 1 ; and A' is H or C-i-6-alkyl;

and pharmaceutically acceptable salts thereof.

10. Arylamide derivative as claimed in claim 9, wherein arylamide derivate is a compound of formula (l-a), wherein R1 is H, one of R2 and R3 is R_A' and the other is independently H or R_A', each R_A' is selected from the group consisting of halo, CN and Ci_-2-perhaloalkyl; one of R8 and R9 is R_B' and the other is independently H or R_B', each R_B' is selected from the group consisting of halo, CN, and C-i_-2-perhaloalkyl; X is SO2; and R_c is C-i_-3-alkyl, or phenyl or benzyl substituted one or more times with R_c', each R_c' is selected from the group consisting of F, CI, and CF₃.

1 1 . Arylamide derivative as claimed in claim 9, wherein arylamide derivate is a compound of formula (l-b), wherein R1 is H, R2 and R3 is R_A' and the other is independently H or R_A\ each R_A' is selected from the group consisting of halo, CN, and Ci_-2-perhaloalkyl; one of R8 and R9 is R_B' and the other is independently H or R_B\ each R_B' is selected from the group consisting of halo, CN, and C-i_-2-perhaloalkyl; X is SO₂, and R_c is C-i_-3-alkyl, or phenyl or benzyl substituted one or more times with R_c', each R_c' is selected from the group consisting of F, CI, and CF₃.

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

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

N-(3-chloro-4-cyanophenyl)-3-[(4-fluorobenzene)sulfonyl]-2-[4-(tri- fluoromethyl)phenyl]propanamide;

N-(3-chloro-4-cyanophenyl)-3-[(3,4-difluorobenzene)sulfonyl]-2-(3,4- difluorophenyl)propanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)-2-(4-fluoro- phenyl)propanamide;

N-(3-chloro-4-cyanophenyl)-3-[(3,4-difluorophenyl)sulfanyl]-2-[4-(tri- fluoromethyl)phenyl]propanamide;

N-(3-chloro-4-cyanophenyl)-2-(4-chlorophenyl)-3-{[(4-chlorophenyl)- methane]sulfonyl}propanamide;

N-(3-chloro-4-cyanophenyl)-3-[(4-chlorobenzene)sulfonyl]-2-(4- chlorophenyl)propanamide;

N-(3-chloro-4-cyano-2-fluorophenyl)-2-(3,4-difluorophenyl)-3-hydr- oxy-2-(methoxymethyl)propanamide;

N-(3-chloro-4-cyano-2-fluorophenyl)-2-(3,4-difluorophenyl)-3-meth- oxy-2-(methoxymethyl)propanamide;

2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3- (ethanesulfonyl)propanamide;

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

N-(3-chloro-4-cyanophenyl)-3-(4-chlorobenzenesulfonyl)-2-(6- chloropyridin-3-yl)propanamide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3- (propane-2-sulfonyl)propanamide; N-(3-chloro-4-cyanophenyl)-3-[(4-chlorophenyl)methanesulfonyl]-2- (6-chloropyridin-3-yl)propanamide;

3-(ethanesulfonyl)-2-(4-fluorophenyl)-N-[4-nitro-3- (trifluoronnethyl)phenyl]propanannide;

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

2-(6-chloropyridin-3-yl)-N-[4-nitro-3-(trifluoronnethyl)phenyl]-3- (propane-2-sulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-2-(3,4-difluorophenyl)-3- (ethanesulfonyl)propanamide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-cyanophenyl)-3- (ethanesulfonyl)propanamide;

N-(3-chloro-4-cyanophenyl)-3-(4-fluorobenzenesulfonyl)-2-[6- (trifluoronnethyl)pyndin-3-yl]propanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-cyano-3-fluorophenyl)-3- (ethanesulfonyl)propanamide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-3- (ethanesulfonyl)-2-methylpropanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(ethanesulfonyl)-2-(4- fluorophenyl)-2-methylpropanannide;

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

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

2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2- methyl-3-(propane-2-sulfonyl)propanannide;

2-(4-chlorophenyl)-N-[4-cyano-3-(trifluoronnethyl)phenyl]-3- methanesulfonyl-2-nnethylpropanannide;

2-(6-chloropyridin-3-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3- methanesulfonyl-2-nnethylpropanannide;

N-(3-chloro-4-cyanophenyl)-3-(4-chlorobenzenesulfonyl)-2-(4- chlorophenyl)-2-methylpropanannide;

N-[4-cyano-3-(trifluoromethyl)phenyl]-2-(4-fluorophenyl)-3- methanesulfonyl-2-nnethylpropanannide;

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising an effective amount of one or more arylamide derivatives or/and pharmaceutically acceptable salts thereof according to any one of claims 1 to 12 together with a suitable carrier and conventional excipients.

14. Arylamide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for use as a medicament.

15. Arylamide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for use in the treatment of androgen receptor related disorders.

16. Arylamide derivative or a pharmaceutically acceptable salt thereof for use according to claim 15, wherein the disorder is benign prostate hyperplasia.

17. Arylamide derivative or a pharmaceutically acceptable salt thereof according to claim 15, wherein the disorder is cancer.

18. Arylamide derivative or a pharmaceutically acceptable salt thereof according to claim 17, wherein the cancer is selected from the group consisting of prostate cancer and castration-resistant prostate cancer.

19. Arylamide derivative or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 18, wherein the said com- pound is administered simultaneously, separately or sequentially with another active agent.

20. A process for preparing an arylamide derivative of formula (I) as defined in claim 1 , comprising reacting an amide compound of formula (3),

H

O

3

where R_A and R_B are as defined above, with paraformaldehyde in suitable reaction conditions, preferably at 90 °C to obtain a compound of formula (4)

4

and then reacting the obtained compound of formula (4) with a compound of formula (l l).

Rc-(CR'R")z-X'H (II) where R_c, R', R" and z are as defined earlier and X' is NHR'", O or S, to obtain a compound of formula (I), where X is NR'", O or S, and then, if desired, oxidizing the obtained compound to obtain a compound of formula (I), where X is S(O) or SO₂; or

or reacting an amide compound of formula (3),

3

where R_A and R_B are as defined above, with paraformaldehyde in suitable reaction conditions, preferably at 50 °C, to obtain a product of formula (8)

8

and then reacting compound of formula (8) with 2 equivalents of Ci_-6-alkyliodineto obtain a compound of formula (9)

9

where Rc is corresponding C-i-6-alkyl and then, optionally, reacting compound of formula (9) with 2 equivalents of another C-i-6-alkyliodine to ob- tain compound of formula (10)

10

where A is the corresponding another C-i_-6-alkyl

or alternatively reacting compound of formula (8) with 5 equivalents of C-i-6-alkyliodine to obtain a compound of formula (10), where R_c and A' are both the corresponding C-i_-6-alkyl; or esterifying the compound of formula (2)

HO. o then reacting the obtained compound with C-i-6-alkyl-, C-i-6-halo- alkyl-, or C-i-2-perhaloalkyliodide, and then reacting the thus obtained com- pound with paraformaldehyde to obtain a compound of formula (13)

13

where X is S or O and A is the corresponding Ci_-6-alkyl, C-i_-6- haloalkyl, or C-i_-2-perhaloalkyl; and, if desired, reacting the said compound with C-i-6-alkyl- or aryl(CR'R")_z-halide- to obtain corresponding compound of formu- la

14

where R_C(CR'R")_Z is C_1-6-alkyl or aryl(CR'R")_z-;

and then transforming the obtained compound of formula (13) or (14) to the corresponding free acid and reacting the said acid with compound of formula (1 )

NH₂

1

to obtain a compound of formula (I) where X is O or S and Rc is H, C-i-6-alkyl or aryl(CR'R")_z-; and then, if desired, oxidizing the obtained compound where X is S to obtain a compound of formula (I), where X is S(O) or SO₂;

or reacting a compound of formula (18)

N^^Rb 18

where RB is as defined above, with a halide of formula () A-X () where A is as defined above, preferably Ci_-6-alkyl, Ci_-6-haloalkyl, or C-i-₂-perhaloalky, and X is halide, preferably I, to obtain a compound of formula (19)

wherein A is as above, and then reacting the obtained compound with methyldihahde, preferably methyldiodide, to obtain a compound of formula

where hal is halide, preferably I,

reacting the obtained compound of formula (20) with a compound of formula (II)

R_C-(CR'R")_Z-X'H (II)

where R_c, R', R" and z are as defined earlier and X' is NHR'", O or

S, to obtain a compound of formula (21 )

and, if desired, oxidizing the obtained compound where X is S to obtain a compound of formula (21 ), where X is S(O) or SO2,

hydrolyzing, preferably with sulphuric acid, the compound of formula (21 ) to obtain an acid of formula (22)

reacting the obtained compound of formula (22) with a compound of formula (1 )

NH₂

1

wherein R_A is as defined above, to obtain a compound of formula (I) (C

21 . The process according to claim 20, where the process is carried out via the following reaction steps (i), (ii), (iii) or (iv):

6 7

(I)