Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C317/00—Sulfones; Sulfoxides
  • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
  • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• 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.
• Androgens are produced by testes and adrenal glands and they play a critical role in the development and physiology of normal prostate.
• BPH benign prostate hyperplasia
• PCa prostatic neoplasia which can progress to adenocarcinoma
• BPH and PCa BPH and prostate cancer
• 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.
• ADT hormone or androgen deprivation therapy
• AR ligand-binding pocket of the androgen receptor
• 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.
• 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.
• 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.
• CRPC castration-resistant prostate cancer
• HRPC hormone-refractory prostate cancer
• 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.
• drugs targeting AR signaling could still be effective in the prevention and treatment of CRPC.
• 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.
• 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.)
• the present invention provides new arylamide derivatives having formula (I)
• R2 is halo or trifluoromethyl
• 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;
• R1 1 is branched C 3- 5-alkyl or cyclo-C 3- 6-alkyl
• R1 1 isopentyl
• R2 is trifluoromethyl
• R9 is hydrogen
• 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.
• 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.
• 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.
• 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.
• cyclo-C3-6-alkyl is meant cyclopropyl, cyclobutyl, cy- clopentyl or cyclohexyl.
• halo is meant fluoro, chloro, bromo or iodo.
• Preferred compounds of formula (I) are those where R2 is chloro or trifluoromethyl.
• R8 is chloro, fluoro or trifluoromethyl.
• R9 is trifluoromethyl, hydrogen or fluoro, preferably hydrogen or fluoro.
• 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-hydroxy-3- [(3-methylbutane)sulfonyl]propanamide; N-(3-chloro-4-cyanophenyl)-2-hydroxy-3-[(3-methylbutane)sulfonyl]-
• the arylamides of the invention may be prepared by methods de- scribed below.
• 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),
• the compounds of the present invention were synthesized using commercially available anilines, phenylacetic acids, thiols, phenols and amines as starting materials.
• Cyclopropylthiol was prepared according to the method described in JACS 1992, 114(9), 3492-3499.
• 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.
• DHT dihy- drotestosterone
• 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).
• 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.
• 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.
• 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.
• DMEM Dulbecco's Modified Eagle Medium
• FBS fetal bovine serum
• penicillin 6.25 U/ml
• streptomycin 6.25 pg/ml
• luciferase (LUC) reporter gene plasmid pPB-286/+32-LUC; PB, probasin promoter
• 5 ng of AR expression plasmid pSG5-hAR
• 5 ng of pCMN/ ⁇ an internal, beta-galactosidase control for transfection efficiency and cell growth
• 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 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.
• 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).
• 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 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).
• 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).
• 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
• LNCaP human prostate adenocarcinoma cell line
• 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 ⁇ of the Cell Titer reagent was added into 100 ⁇ 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.
• 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.

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