Phytosterol derivatives, and compositions comprising the same, for use as medicaments

Abstract

Herein disclosed are compounds of formula (I), which are metabolized into, or act as, analogues of oncosterone (6-oxo-cholestan-3β,5α-diol), a metabolite produced by tumor cells overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing 11β-hydroxysteroid dehydrogenase type 2 (HSD2) and the glucocorticoid receptor (GR), neutralizing the signaling pathway and tumorigenicity of oncosterone. The compounds of formula (I) herein disclosed are thus useful in preventing and / or treating cancers, in subjects, preferably humans, overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing 11β-hydroxysteroid dehydrogenase type 2 (HSD2) and the glucocorticoid receptor (GR). In addition, being analogues of oncosterone, some of the compounds of formula (I) are also useful in the prevention and / or treatment of cancers expressing the glucocorticoid receptor (GR).

Description

1 PHYTOSTEROL DERIVATIVES, AND COMPOSITIONS COMPRISING THE SAME, FOR USE AS MEDICAMENTS

[0001] The present invention refers to the field of pharmaceutical agents. The present 5 invention discloses a group of phytosterol derivatives, as well as pharmaceutical and nutraceutical compositions comprising the same, in particular, for use in the prevention and / or treatment of cancer in subjects overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR). 10 BACKGROUND OF THE INVENTION

[0002] Breast cancer (BC) affects more than 2 million women and is the leading cause of cancer death in women worldwide. Great strides have been made in BC treatment using targeted therapies such as hormonotherapy for BC expressing estrogen and progesterone receptors (ER+, 15 PR+) or with agents targeting BC overexpressing Her2 (Her2+). For so-called triple negative BC which express neither ER, PR nor HER2 (TN), chemotherapies are the reference treatments and few targeted therapies, such as immune checkpoint or PARP inhibitors, are offered to a minority of patients (ref.1). Moreover, TNBC are more aggressive and associated with a poor prognosis and they often affect younger subjects. After chemotherapy these cancers are 20 responsible for many early and late relapses. It is therefore essential to better understand the molecular mechanisms involved in the progression of TNBC with a view to developing novel precision therapeutic strategies to improve the prognosis of these patients.

[0003] Previous publications indicate that 5,6-epoxides of cholesterol (5,6-EC) metabolism is deregulated in some cancers), for example in BC, and promotes ER+ and TN BC development25 (ref.2, 9). This abnormal metabolism is in connection with the overexpression of cholesterol- 5,6-epoxide hydrolase (ChEH) and / or ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) in some subjects. I^^^^^^ ^^ ^^^^^^ ^^^^^^^^ ^^^^-EC ^^^ ^^^ ^-EC are transformed by thecholesterol epoxide hydrolase (ChEH) into cholestane-3^,5^,6^-triol (CT) (ref. 2 and 11). In tumor tissues, CT is further transformed into 6-oxo-cholestan-3^,5^-diol (OCDO, named 30 oncosterone) by the 11^-hydroxysteroid dehydrogenase-type 2 enzyme (11^HSD2).11^HSD22 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone (ref.2). It has been established that OCDO promotes cell proliferation and cell cycle progression in ER+ and TN BC cells by binding to the glucocorticoid receptor (GR) (ref. 2). BC patient samples show significant increased OCDO levels and greater ChEH and 11^HSD2 5 protein expression compared with normal adjacent breast tissues. Moreover, ChEH overexpression and 11^HSD2 expression correlate with a higher risk of patient death and GR expression is correlated with poor progression-free and overall survival in patients with TN and ER-negative BC (ref. 4 to 6), highlighting that OCDO biosynthetic pathway is of major importance to BC pathology. 10

[0004] In that regard, there is a clear need for new therapeutic approaches targeting those subjects overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or in subjects where ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR) expression is detected, for the prevention and treatment of cancer and, in particular in BC, ER+ breast cancer, triple negative breast cancer or invasive breast cancer. 15 BRIEF DESCRIPTION OF THE INVENTION

[0005] One aspect disclosed relates to a compound of formula (I):wherein R1 and R2 are defined according to a proviso selected from the group consisting of (a), 20 (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;3b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration;5c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration,and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a10 ^-stereochemical configuration;and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single 15 bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-;4 R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and -CH=CH2, or is not present when R4 is =CH-CH3; R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2. 5

[0006] When D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, the double bond formed features a trans (E) configuration. When A and B are respectively a group -CH- and a group -C- and are linked together by a double bond forming a moiety, the double bond may be cis (Z) or trans (E), preferably cis (Z). In some embodiments, when A and B are respectively -CH- and -C- and are linked together by a double 10 bond forming a moietythen D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-.

[0007] In some embodiments, R1 and R2 are defined according to the proviso (a), (c) or (d); preferably R1and R2are defined according to the proviso (a) or (d), more preferably R1and R2are defined according to the proviso (a). 15

[0008] In some embodiments, when A and B are respectively -CH2- and -CH- and are linked together by a single bond forming a moiety, D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, R3is H, and R4is -CH2-CH3or -CH3; then R1 and R2 are defined according to the proviso (a) or (d), preferably R1 and R2 are defined according to the proviso (a); and when A and B are respectively -CH2- and -CH- and 20 are linked together by a single bond forming a moiety, D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, R3 is H and R4 is - CH2-CH3 or R3 is -CH3 and R4 is H; then R1 and R2 are defined according to the proviso (a) or (d).

[0009] In some embodiments, when A and B are respectively -CH2- and -CH- and are linked 25 together by a single bond forming a moiety, and D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, and R3 is H, and R4 is -5 CH2-CH3; then R1and R2are defined according to the proviso (a), (b) or (c); or to the proviso (a), (b) or (d), preferably R1 and R2 are defined according to the proviso (a), (b) or (c).

[0010] Another aspect of the present invention refers to a pharmaceutical composition comprising a compound of formula (I): 5wherein R1 and R2 are defined according to a proviso selected from the group consisting of (a), (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;10 b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration;c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration, 156 and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration;5 and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety 10 -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-; R3 is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3 and -CH=CH2, or is not present when R4is =CH-CH3; R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; 15 and wherein R3 and R4 are not both H, -OH, -CH3, -CH2-CH3 or -CH=CH2.

[0011] Another aspect of the present invention refers to a compound of formula (I):wherein R1 and R2 are defined according to a proviso selected from the group consisting of (a), (b), (c) and (d):7 ereochemical configuration and R2 is an oxo group =O;(a) b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration; 5and R2 is an OH with a^-stereochemical configuration,and10 R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration;and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a 15 moiety, or are respectively -CH2- and -CH- and are linked together by a single bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-;8 R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and -CH=CH2, or is not present when R4 is =CH-CH3; R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2; 5 or to a pharmaceutical composition comprising the same, for use in a method of prevention and / or treatment of a disease in a subject, preferably a human.

[0012] Another aspect of the present invention refers to a compound of formula (I):wherein R1 and R2 are defined according to a proviso selected from the group consisting of (a), 10 (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration; 15c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration,9and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration; 5and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single bond forming a moiety10 D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-; R3 is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3 and -CH=CH2, or is not present when R4is =CH-CH3; 15 R4 is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3 and -CH=CH2; and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2; or to a pharmaceutical composition comprising the same, for use in a method of prevention and / or treatment of a cancer in a subject, preferably a human, overexpressing cholesterol-5,6- epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 20 (HSD2) and glucocorticoid receptor (GR).

[0013] Another aspect of the invention refers to a compound of formula (Ia):10wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single 5 bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-; R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and 10 -CH=CH2, or is not present when R4is =CH-CH3; R4 is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3 and -CH=CH2; and wherein R3 and R4 are not both H, -OH, -CH3, -CH2-CH3 or -CH=CH2; or to a pharmaceutical composition comprising the same, for use in a method of prevention and / or treatment of a cancer in a subject, preferably a human, expressing glucocorticoid receptor 15 (GR), i.e. for use as a ligand of the glucocorticoid receptor (GR) in a method of prevention and / or treatment of a disease in a subject, preferably a human.

[0014] Yet another aspect relates to a nutraceutical composition comprising a compound of formula (I):11wherein R1 and R2 are defined according to a proviso selected from the group consisting of (a), (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;5b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration;c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a10 ^-stereochemical configuration,and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration;12and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single 5 bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-; R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and 10 -CH=CH2, or is not present when R4is =CH-CH3; R4 is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3 and -CH=CH2; and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2; and at least one nutraceutically acceptable excipient. 15 BRIEF DESCRIPTION OF THE FIGURES

[0015] [Figure 1] BC cells transform 5,6-^^^^^^^ ^^ ^-sitosterol, i.e., a compound of formula(IIb24^), into OSDO, i.e. a compound of formula (IIa24^^^ ^ ^-sitosterol analogue of OCDOwhich binds to GR and antagonizes OCDO-induced tumorigenicity. Synthesized ^^^^-ES (^^^^^^^^ ^^ ^^^^^^^ ^^^^^^^) 5 µM, was incubated for 48 h in absence or presence of ChEH20 inhibitors (Tam or DDA) at 1 µM with (Fig.1a) MDA-MB231 cells or with (Fig 1b) MCF7 cells. Synthesized ^^^^-EC (5 µM) was incubated for 48 h in absence or presence of ChEH inhibitors (Tam or DDA) at 1 µM with (Fig.1c) MDA-MB231 cells or with (Fig.1d) MCF7 cells. Effect of the solvent vehicle (Control), 1 µM OCDO, 1 µM OCDO + 5 µM ^^^^-ES or 5 µM ^^^^-ES on MDA-MB231 (Fig. 1e) or MCF7 (Fig. 1f) cell proliferation, n = 3. 25 Representative immunoblots analysis of JNKs phosphorylation (Thr183 / Tyr185) in MDA- MB231 (Fig.1g) or MDA-MB468 (Fig.1h) tumor cells treated for 8 h with the solvent vehicle13 (Control), 1 µM OCDO, 1 µM OCDO + 1µM OSDO or 1 µM OSDO, n = 3. (Fig.1i) Effect of the solvent vehicle (Control), 1 µM OCDO, 1 µM OCDO + 1 µM OSDO or 1 µM OSDO on cell proliferation of the indicated cell lines (up left MDA-MB231, up right MDA-MB468, down left MCF7, down right 4T1), n = 2. (Fig. 1j) Representative SPR sensorgrams from two 5 experiments showing the binding of a series of concentrations OSDO (^M) to the GR-LBD captured on a Biacore sensor chip: 6.25 (red); 12.5 (green); 25 (dark blue); 50 (pink); 100 (light blue).

[0016] [Figure 2] Monitoring of tumor growth over time vs treatment in vivo. Immunodeficient mice (10 per group) grafted with MDA-MB231 cells (Fig. 2a and 2c) or 10 immunocompetent mice grafted with 4T1 cells (Fig.2b), or with MDA-MB468 cells (Fig.2d) were treated once a day, 5 days / week and monitored for tumor growth over time. Mice of Figs. 2a and 2b were treated with the control (solvent vehicle) or OSDO (16 µg / kg). Mice of Fig.2c were treated with control (solvent vehicle), OCDO (16 µg / kg), OCDO (16 µg / kg) + OSDO (16 µg / kg) or OSDO (16 µg / kg). Mice of Fig.2d were treated with control (solvent vehicle), OCDO 15 (16 µg / kg), OCDO (16 µg / kg) + OSDO (16 µg / kg) or OSDO (16 µg / kg). Mean tumor volumes (±SEM) are shown, two-^^^ ^^^^^^ ^^^^^^^^^^ ^^^^^^^^^ ^^ ^^^^^^ ^^^ ^ ^^^^^ ^^^^ ^ ^^^^^and ****P < 0.0001. DETAILED DESCRIPTION OF THE INVENTION 20

[0017] As previously indicated, 5,6-epoxides of cholesterol (5,6-EC) metabolism is deregulated in some cancers (ref. 9), for example in BC, promoting ER+ and TN BC development (ref. 2). This abnormal metabolism is in connection with the overexpression of cholesterol-5,6-epoxide hydrolase (ChEH) and with the expression of ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and the glucocorticoid receptor (GR) in some subjects. 25

[0018] As discussed, 5,6-epoxides of cholesterol (5,6-EC) are metabolized by cholesterol-5,6- epoxide hydrolase (ChEH) into cholestane-3^,5^,6^-triol (CT), being this triol further transformed, in tumor tissues, by the 11^-hydroxysteroid dehydrogenase-type 2 enzyme (11^HSD2) into 6-oxo-cholestan-3^,5^-diol (OCDO, named oncosterone) which promotes cell proliferation and cell cycle progression by binding to the glucocorticoid receptor (GR) (ref.2).14

[0019] Phytosterols are plant lipids, having a structure similar to cholesterol with a double bond at position 5-6 (ref. 12). Known phytosterols are, among others, ^^^^^^^^^^^ ^-sitosterol, 24(S)saringosterol, campesterol, stigmasterol, ergosterol, brassicasterol and delta-5-avenasterol; ^^^^^ ^-sitosterol, the most abundant dietary phytosterol.5

[0020] In that connection, the inventors have found that a group of phytosterol derivatives, in particular, the compounds of formula (I) of the present invention or for use according to the present invention, are metabolized into (5,6-epoxides and 3,5,6-triols of formulae I), or act as (3,5-diol, 6-oxo derivatives of formula Ia), analogues of OCDO, produced by tumor cells overexpressing ChEH and / or expressing 11^HSD2 and GR, for example BC tumor cells, 10 binding to GR and / or neutralizing the signaling pathway and tumorigenicity of OCDO. In particular, the 5,6-epoxides derivatives of formula (I) and the 3,5,6-triols of formula (I) may inhibit the biogenesis and tumorigenicity of OCDO which is generated in tumor cells overexpressing ChEH and / or expressing HSD2 and GR. Accordingly the compounds of formula (I) are useful in preventing and / or treating diseases, in particular of cancers, in subjects, 15 preferably humans, overexpressing ChEH and / or expressing 11^HSD2 and GR.

[0021] In addition, the 3,5-diol, 6-oxo derivatives of formula (Ia) may block the effects of OCDO via binding to the GR, and therefore may exert anticancer effects via the GR independently of OCDO biogenesis and therefore, independently of the overexpression of ChEH and expression of HSD2, which are the enzymes involved in OCDO biogenesis. 20 Consequently,, the compounds of formula (Ia) are also useful in the prevention and / or treatment of cancers expressing the glucocorticoid receptor (GR). Compounds of formula (I)

[0022] The phytosterol derivatives of the present invention or for use according to the present 25 invention refer to a compound of formula (I):15wherein R1 and R2 are defined according to a proviso selected from the group consisting of (a), (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;5b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration;c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a10 ^-stereochemical configuration,and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration;16and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single 5 bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-; R3 is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3 and 10 -CH=CH2, or is not present when R4 is =CH-CH3; R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; and wherein R3 and R4 are not both H, -OH, -CH3, -CH2-CH3 or -CH=CH2.

[0023] In some embodiments, R1and R2are defined according to the proviso (a), (b), (c) or (d). In some embodiments, R1and R2are defined according to the proviso (a), (b) or (c). In 15 some embodiments, R1 and R2 are defined according to the proviso (a), (b) or (d). In some embodiments, R1 and R2 are defined according to the proviso (a), (c) or (d). In some embodiments, R1and R2are defined according to the proviso (a) or (d) or according to the proviso (a) or (c). In some embodiments, R1and R2are defined according to the proviso (a).

[0024] In some embodiments, when A and B are respectively a group -CH2- and a group 20 -CH- and are linked together by a single bond forming a moiety, D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, R3 is H, -CH2-CH3or -CH3, and R4is H, -CH2-CH3or -CH3,wherein R3and R4are not both H, -CH3 or -CH2-CH3; then R1 and R2 are defined according to the proviso (a) or (d), preferably R1 and R2 are defined according to the proviso (a); and when A and B are respectively a group 25 -CH2- and a group -CH- and are linked together by a single bond forming a moiety17, D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, R3is H, -CH2-CH3or -CH3, and R4is H, -CH2-CH3or -CH3,wherein R3and R4 are not both H, -CH3 or -CH2-CH3; then R1 and R2 are defined according to the proviso (a) or (d), preferably R1 and R2 are defined according to the proviso (a). 5

[0025] In some embodiments, when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, and D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, R3is H or -CH2-CH3, and R4 is H or -CH2-CH3, wherein R3 and R4 are not both H, or -CH2-CH3, then R1and R2are defined according to the proviso (a), (b) or (d). 10

[0026] In some embodiments, when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, and D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, R3 is H or -CH2-CH3, and R4 is H or -CH2-CH3, wherein R3 and R4 are not both H, or -CH2-CH3, then R1and R2are defined according to the proviso (a), (b) or (c). 15

[0027] The phytosterol derivatives of formula (I) disclosed herein include a hydroxyl group - OH in position C3 and a methyl group in positions C10 and C13 having a ^-stereochemical configuration; as well as a methyl in position C20 with R-stereochemical configuration. The ^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^ ^- ^^ ^-stereochemical configurations are defined as commonlydone for cholesterol and phytosterol derivatives and illustrated herein below:18

[0028] In particular, the present specification refers to Moreau et al. (ref. 12) for the carbon numbering and stereochemical configuration of the different isomers disclosed in the present specification. 5

[0029] Depending on the definition of R1 and R2, the compounds of formula (I) may be selected from the group consisting of a compound of formula (Ia), a compound of formula (Ib), a compound of formula (Ic) and a compound of formula (Id):19or any mixtures thereof, wherein A, B, C, D, E, R3 and R4 are as defined in the claims and 5 embodiments disclosed in the present specification.20

[0030] In some embodiments, when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, R3 is H, -CH2-CH3 or -CH3, and R4 is H, -CH2-CH3 or -CH3, wherein R3 and R4 are not both H, -CH3 or 5 -CH2-CH3; then the compound of formula (I) is a compound of formula (Ia) or a compound of formula (Id), preferably a compound of formula (Ia); and when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, R3is H, -CH2-CH3or -CH3, and R4is H, -CH2-CH3or -CH3,wherein R310 and R4are not both H, -CH3or -CH2-CH3; then the compound of formula (I) is a compound of formula (Ia) or a compound of formula (Id), preferably a compound of formula (Ia).

[0031] In some embodiments, when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, and D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, R3is H 15 or -CH2-CH3, and R4is H or -CH2-CH3,wherein R3and R4are not both H, or -CH2-CH3; then the compounds of formula (I) are selected from the group consisting of a compound of formula (Ia), a compound of formula (Ib) and a compound of formula (Ic), or any mixtures thereof.

[0032] In some embodiments, when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, and D and E are each 20 a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, R3 is H or -CH2-CH3, and R4 is H or -CH2-CH3, wherein R3 and R4 are not both H, or -CH2-CH3; then the compounds of formula (I) are selected from the group consisting of a compound of formula (Ia), a compound of formula (Ib) and a compound of formula (Id), or any mixtures thereof.

[0033] In addition, depending on the definition of A, B, C, D, E, R3 and R4, the compounds 25 of formula (I) may be selected from the group consisting of a compound of formula (II), a compound of formula (III), a compound of formula (IV), a compound of formula (V), a21 compound of formula (VI), a compound of formula (VII), a compound of formula (VIII) and a 523or any mixtures thereof, wherein R1 and R2 are defined according to the claims and embodiments of the present specification. 5

[0034] In some embodiments, the compound of formula (I) is selected from the group consisting of a compound of formula (II), a compound of formula (III), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII) and a compound of formula (IX), or any mixtures thereof; wherein R1 and R2 are defined according to the proviso (a), (b), (c) or (d); preferably wherein 10 R1and R2are defined according to the proviso (a), (c) or (d); preferably, R1and R2are defined according to the proviso (a) or (d); more preferably R1and R2are defined according to the proviso (a); as defined in the claims and embodiments of the present invention.

[0035] In some embodiments the compound of formula (I) is selected from the group consisting of a compound of formula (II), a compound of formula (III), a compound of formula (IV), a 15 compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII) and a compound of formula (IX), wherein the compound of24 formula (II) is selected from the group consisting of formulae (IIa) and (IId); more preferably the compound of formula (II) is a compound of formula (IIa); the compound of formula (V) is selected from the group consisting of formulae (Va) and (Vd), more preferably the compound of formula (V) is a compound of formula (Va); the compound of formula (VI) is selected from 5 the group consisting of formulae (VIa) and (VId), more preferably the compound of formula (VI) is a compound of formula (VIa); and the compound of formula (VIII) is selected from the group consisting of formulae (VIIIa) and (VIIId), more preferably the compound of formula (VIII) is a compound of formula (VIIIa).

[0036] In some embodiments the compound of formula (I) is selected from the group consisting 10 of a compound of formula (II), a compound of formula (III), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII) and a compound of formula (IX), or any mixtures thereof, as defined in the claims and embodiments disclosed in the present specification; wherein the compound of formula (II) is a compound of formula (IIa), a compound of formula (IIb), or a 15 compound of formula (IId); or wherein compound of formula (II) is a compound of formula (IIa), a compound of formula (IIb), or a compound of formula (IIc); preferably wherein the compound of formula (II) is a compound of formula (IIa).

[0037] In some embodiments of the invention, R1 and R2 are defined according to proviso (a), as disclosed in the claims and embodiments of the present specification, and the compound of 20 formula (I) has formula (Ia):wherein A, B, C, D, E, R3 and R4 are as defined in the claims and embodiments disclosed in the present specification.25

[0038] The compound of formula (Ia) may be selected from the group consisting of a compound of formula (IIa), a compound of formula (IIIa), a compound of formula (IVa), a compound of formula (Va), a compound of formula (VIa), a compound of formula (VIIa), a compound of formula (VIIIa) and a compound of formula (IXa), preferably the compound of formula (Ia) 5 may be selected from the group consisting of a compound of formula (IIa), a compound of formula (IIIa), a compound of formula (IVa), a compound of formula (Va), and a compound of formula (IXa): 1027or any mixtures thereof.

[0039] Preferably, the compounds of formulae (IIa), (Va) and (VIa) feature an ^-C24 5 stereochemical configuration and have, respectively, formulae (IIa24^) having C24 (R) stereochemical configuration, (Va24^) having C24 (R) stereochemical configuration, and (VIa24^) having C24 (S) stereochemical configuration; the compound of formula (IVa) features a C24 (S) stereochemical configuration; and the compounds of formulae (VIIa) and (VIIIa) feature a ^-C24 stereochemical configuration and have, respectively, formulae (VIIa24^) 10 having C24 (R) stereochemical configuration, and (VIIIa24^) having C24 (R) stereochemical configuration:29

[0040] Thus, the compounds of formulae (Ia) may be selected from the group consisting of compounds of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), 5 (VIIa), (VIIa24^), (VIIIa), (VIIIa24^) and (IXa), preferably from the group consisting of compounds of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^) and (IXa), or any mixtures thereof.

[0041] In some embodiments, the compounds of formula (Ia) are selected from the group consisting of formulae (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa) and (IXa), preferably from 10 the group consisting of compounds of formulae (IIa), (IIa), (IIIa), (IVa), (Va) and (IXa), as defined in the claims and embodiments of the present invention. Preferably, the compounds of formulae (IIa), (Va) and (VIa) feature a ^-C24 stereochemical configuration and have, respectively, formulae (IIa24^), (Va24^) and (VIa24^); the compound of formula (IVa) features a C24 (S) configuration, and the compounds of formulae (VIIa) and (VIIIa) feature a ^-C24 15 stereochemical configuration and have, respectively, formulae (VIIa24^) and (VIIIa24^), as defined in the claims and embodiments of the present specification.30

[0042] A preferred embodiment of the invention refers to the compound of formula (IIa), even more preferably a compound of formula (IIa24^) featuring a ^-C24 (R) stereochemical configuration.

[0043] R1 and R2 may be defined according to proviso (b) as disclosed in the claims and 5 embodiments of the present specification, and the compound of formula (I) has formula (Ib):wherein A, B, C, D, E, R3 and R4 are as defined in the claims and embodiments disclosed in the present specification.

[0044] In some embodiments of the compound of formula (Ib), when A and B are respectively 10 a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, and D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, then R3is either present and is -OH or -CH=CH2, or is not present when R4 is =CH-CH3; and R4 is =CH-CH3, -OH or -CH=CH2, wherein R3 and R4 are not both -OH or -CH=CH2; when A and B are respectively a group -CH2- and a group -CH-and are linked15 together by a single bond forming a moiety, and D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, then R3is not present and R4 is =CH-CH3; and when A and B are respectively a group -CH- and a group -C- and are linked together by a double bond forming a moiety -CH=CH-, and D and E are each a group - CH- and are linked together by a double bond forming a moiety, then R3 is H or 20 -CH3and R4is H or -CH3, wherein R3and R4are not both H or -CH3.31

[0045] ^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^^ ^^^^^^^ ^ ^^^^-stereochemical configuration, having^ ^^^^^^^ ^^^^^^ ^^ ^ ^^^^-stereochemical configuration^ ^^^^^^ ^ ^^^^^^^ ^^^^^:5 wherein A, B, C, D, E, R3 and R4 are as defined in the claims and embodiments disclosed in the present specification; or may include a mixture ^^ ^^^ ^^^^^^^^^ ^^ ^^^^^^^^ ^^^^^ ^^^ ^^^^^ as a racemic mixture or^^^^^^^^^ ^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^^ ^^ ^^^^^^^^^^^^ ^^^^^^^ ^referably the compound offormula (Ib) comprises a molar ratio of formula (^^^): formula (^^^) of from 50:50, 45:55, 10 30:70, 20:80, 10:90 or 1:99, among others. Preferably the compound of formula (Ib) includes ^^^ ^^^^^^^^^^^^ ^^ ^^^^^^^ ^^^^^ ^^^^ ^^^^ ^^^^ ^^^, more than 55%, more than 65%, morethan 75%, more than 85%, more than 90% enantiomeric excess.

[0046] The compound of formula (Ib) may be selected from the group consisting of a compound of formula (IIb), a compound of formula (IIIb), a compound of formula (IVb), a compound of 15 formula (Vb), a compound of formula (VIb), a compound of formula (VIIb), a compound of formula (VIIIb) and a compound of formula (IXb):335

[0047] One embodiment of the compounds of formula (I) of the invention relates to a compound of formula (Ib) selected from the group consisting of a compound of formula (IIIb), a compound34 of formula (IVb), a compound of formula (Vb), a compound of formula (VIb), a compound of formula (VIIb), a compound of formula (VIIIb) and a compound of formula (IXb), as defined in the claims and embodiments of the present specification. Another embodiment refers to a compound of formula (Ib) selected from the group consisting of a compound of formula (IIIb), 5 a compound of formula (IVb), a compound of formula (VIIb) and a compound of formula (IXb), as defined in the claims and embodiments of the present specification.

[0048] The compounds of formulae (IIb), (IIIb) (IVb), (Vb), (VIb), (VIIb), (VIIIb) and (IXb) ^^^ ^^^^^^^ ^^^ ^^^^^^^ ^^^^ ^^^^-^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^ ^^ ^^^^ ^^^^-stereochemical^^^^^^^^^^^^^^ ^^ ^^^ ^^^^^^^ ^ ^^^^^^^ ^^ ^^^^ ^^^^ ^^^ ^^^^-stereochemical configurations as10 ^ ^^^^^^^ ^^^^^^^ ^^ ^^^^^^^^^ ^^^ ^^^^-stereochemical configuration in enantiomeric excess.

[0049] ^^^^^ ^^^ ^^^^^^^^^ ^^ ^^^^^^^ ^^^^^ ^^^^^^^^^ ^^^ ^^^^^^^ ^^^^ ^^^^-stereochemicalconfiguration may ^^ ^^^^^^^^ ^^^^ ^^^ ^^^^^ ^^^^^^^^^^ ^^ ^^^^^^^^^ ^^ ^^^^^^^^ ^^^^^^^^^^^^^^ ^^^^^^^ ^^^^^^ ^VIb^^^ ^^^^^^^^ ^^^^^^^^ ^^^ ^^^^^^^1536or any mixtures thereof.

[0050] ^^ ^^^^ ^^^^^^^^^^^^ ^^^ ^^^^^^^^^ ^^ ^^^^^^^ ^^^^^ ^^^^^^^^^ ^^^ ^^^^^^^ ^^^^ ^^^^-5 stereochemical configuration may be selected from the group consisting of compounds of ^^^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^ ^VIb^^^ ^^^^^^^^ ^^^^^^^^ ^^^ ^^^^^^, or any mixtures thereof,as defined in the claims and in the embodiments of the present specification. In some ^^^^^^^^^^^^ ^^^ ^^^^^^^^^ ^^ ^^^^^^^ ^^^^^ ^^^^^^^^^ ^^^ ^^^^^^^ ^^^^ ^^^^-stereochemical^^^^^^^^^^^^^ ^^^ ^^ ^^^^^^^^ ^^^^ ^^^ ^^^^^ ^^^^^^^^^^ ^^ ^^^^^^^^^ ^^ ^^^^^^^^ ^^^^^^^10 ^^^^^^^ ^^^^^^^ ^^^ ^^^^^^^ ^^ ^^^ ^^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^ ^he claims and in theembodiments of the present specification.

[0051] ^^ ^^^^^^^^^ ^^^ ^^^^^^^^^ ^^ ^^^^^^^ ^^^^^ ^^^^^^^^^ ^^^ ^^^^^^^ ^^^^ ^^^^-stereochemical configuration may be selected from the group consisting of compounds of ^^^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^ ^VIb^^^ ^^^^^^^^ ^^^^^^^^ ^^^ ^^^^^^^385 or any mixtures thereof.39

[0052] ^^ ^^^^ ^^^^^^^^^^^^ ^^^ ^^^^^^^^^ ^^ ^^^^^^^ ^^^^^ ^^^^^^^^^ ^^^ ^^^^^^^ ^^^^ ^^^^-stereochemical configuration may be selected from the group consisting of compounds of ^^^^^^^^ ^^^^^^^, ^^^^^^^ ^^^^^^ ^VIb^^^ ^^^^^^^^ ^^^^^^^^ ^^^ ^^x^^^^ ^^ ^^^ ^^^^^^^^ ^^^^^^^^as defined in the claims and embodiments of the present specification. In some embodiments, 5^^^ ^^^^^^^^^ ^^ ^^^^^^^ ^^^^^ ^^^^^^^^^ ^^^ ^^^^^^^ ^^^^ ^^^^-stereochemical configuration^^^ ^^ ^^^^^^^^ ^^^^ ^^^ ^^^^^ ^^^^^^^^^^ ^^ ^^^^^^^^^ ^^ ^^^^^^^^ ^^^^^^^, ^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^ ^^^ ^^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^ ^^^ ^^^^^^ ^^^ ^^^^^^^^^^^ ^^ ^^^ presentspecification.

[0053] The 5,6-epoxide of the compounds of formulae (IIb), (IIIb) (IVb), (Vb), (VIb), (VIIb), 10 (VIIIb) and (IXb) features, preferably a ^-stereochemical. Accordingly, the compounds of formulae (IIb), (IIIb), (IVb), (Vb), (VIb), (VIIb), (VIIIb) and (IXb) may include more than 50%, more than 55%, more than 65%, more than 75%, more than 85%, more than 90% enantiomeric excess ^^ ^^^ ^^^^-stereochemical configuration ^^ ^^^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^(VIb^^^ ^^^^^^^^ ^^^^^^^^ ^^^ ^^^^^^.15

[0054] Preferably, the compounds of formulae (IIb), (Vb) and (VIb) feature an ^-C24 stereochemical configuration and have, respectively, formulae (IIb24^) having C24 (R) stereochemical configuration, (Vb24^) having C24 (R) stereochemical configuration and (VIb24^) having C24 (S) stereochemical configuration; the compound of formula (IVb) features a C24 (S) stereochemical configuration; and the compounds of formulae (VIIb) and 20 (VIIIb) feature a ^-C24 stereochemical configuration and have, respectively, formulae41

[0055] The 5,6-epoxide of the compounds of formulae (IIb24^), (IVb24S), (Vb24^), (VIb24^), (VIIb24^) and (VIIIb24^) ^^^ ^^^^^^^ ^ ^-stereochemical configuration and said compoundshave formulae ^^^^^^^^), ^^^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^ ^^^^^^^^^^):542

[0056] In addition, the 5,6-epoxide of the compounds of formulae (IIb24^), (IVb24S), (Vb24^),5 (VIb24^), (VIIb24^) and (VIIIb24^^ ^^^ ^^^^^^^ ^ ^-stereochemical configuration and saidcompounds have formulae ^^^^^^^^), ^^^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^) and^^^^^^^^^^):44

[0057] The 5,6-epoxide of the compounds of formulae (IIb24^), (IVb24S), (Vb24^), (VIb24^), (VIIb24^) and (VIIIb24^) features, preferably a ^-stereochemical configuration. Accordingly, 5 the compounds of formulae (IIb24^), (IVb24S), (Vb24^), (VIb24^), (VIIb24^) and (VIIIb24^) may include more than 50%, more than 55%, more than 65%, more than 75%, more than 85%, ^^^^ ^^^^ ^^^ ^^^^^^^^^^^^ ^^^^^^ ^^ ^^^ ^^^^-stereochemical configuration of formulae^^^^^^^^), ^^^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^ ^^^^^^^^^^).

[0058] Thus, the compounds of formulae (Ib) may be selected from the group consisting of10 ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^(IVb24S^^ ^^^^^24S^^ ^^^^^24S), ^^^^^ ^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^^^), (VIb), (VI^^^^(VI^^^^ ^^I^^^^^), (VI^^^^^), (VIIb), ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^^), (VIIIb),^^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^^^^^), (IXb)^ ^^^^^^ ^^^ ^^^^^^, or any mixturesthereof. In some embodiments, the compounds of formulae (Ib) may be selected from the group15 ^^^^^^^^^^ ^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ (IVb24S^^ ^^^^^24S^^ ^^^^^24S),^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^ ^^^^^^ ^^^^^^ ^^^ ^^^^^^^ ^^ ^^^ ^^^^^^^^thereof.45

[0059] In some embodiments, the compound of formula (Ib) is selected from the group consisting of formulae (IIb), (IIIb), (IVb), (Vb), (VIb), (VIIb), (VIIIb) and (IXb), as defined in the claims and embodiments of the present invention. Preferably, the compounds of formulae (IIb), (IIIb) (IVb), (Vb), (VIb^^ ^^^^^^^ ^^^^^^^ ^^^ ^^^^^ ^^^ ^^^^^^^ ^^^ ^^^^^^^ ^^^^ ^^^^-5 ^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^ ^^ ^^^ ^^^^^^^ ^ ^^^^^^^ ^^ ^^^^ ^^^^ ^^^ ^^^^-stereochemical^^^^^^^^^^^^^^ ^^ ^ ^^^^^^^ ^^^^^^^ ^^ ^^^^^^^^^ ^^^ ^^^^-stereochemical configuration inenantiomeric excess. In some embodiments, the 5,6-epoxide of the compounds of formulae (IIb), (IIIb) (IVb), (Vb), (VIb), (VIIb), (VIIIb) and (IXb) features, preferably a ^-stereochemical configuration. Accordingly, the compounds of formulae (IIb), (IIIb), (IVb), (Vb), (VIb), (VIIb), 10 (VIIIb) and (IXb) may include more than 50%, more than 55%, more than 65%, more than 75%, ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^ ^^^^^^^^^^^^ ^^^^^^ ^^ ^^^ ^^^^-stereochemical configuration.Preferably, the compounds of formulae (IIb), (Vb) and (VIb) feature an ^-C24 stereochemical configuration and have, respectively, formulae (IIb24^) having a C24 R stereochemical configuration, (Vb24^) having a C24 R stereochemical configuration, and (VIb24^) having a 15 C24 S stereochemical configuration; the compound of formula (IVb) features a C24 S stereochemical configuration; and the compounds of formulae (VIIb) and (VIIIb) feature a ^- C24 stereochemical configuration and have, respectively, formulae (VIIb24^) having a C24 R stereochemical configuration, and (VIIIb24^) having a C24 R stereochemical configuration, as defined in the claims and embodiments of the present specification. 20

[0060] R1 and R2 may be defined according to the proviso (c) as disclosed in the claims and embodiments of the present specification, and the compound of formula (I) has formula (Ic):46 wherein A, B, C, D, E, R3 and R4 are as defined in the claims and embodiments disclosed in the present specification.

[0061] In some embodiments of the compound of formula (Ic), when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety 5, and D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, then R3is either present and is -OH or -CH=CH2, or is not present when R4 is =CH-CH3; and R4 is =CH-CH3, -OH or -CH=CH2, wherein R3 and R4 are not both -OH or -CH=CH2when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, and D and E are each a group -CH- 10 and are linked together by a double bond forming a moiety -CH=CH-, then R3is not present and R4 is =CH-CH3; and when A and B are respectively a group -CH- and a group -C- and are linked together by a double bond forming a moiety, and D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, then R3is H or - CH3 and R4 is H or -CH3, wherein R3 and R4 are not both H or -CH3. 15

[0062] In some embodiments of the compound of formula (Ic), when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, and D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, R3is either present and is selected from the group consisting of H, -OH, -CH3 and -CH=CH2, or is not present when R4 is =CH-CH3; R4 is selected from the 20 group consisting of H, -OH, -CH3, =CH-CH3 and -CH=CH2; and wherein R3 and R4 are not both H, -OH, -CH3, or -CH=CH2.

[0063] The compound of formula (Ic) may be selected from the group consisting of a compound of formula (IIc), a compound of formula (IIIc), a compound of formula (IVc), a compound of formula (Vc), a compound of formula (VIc), a compound of formula (VIIc), a compound of 25 formula (VIIIc) and a compound of formula (IXc):485 or any mixtures thereof.49

[0064] One embodiment of the compounds of formula (I) of the invention relates to a compound of formula (Ic) selected from the group consisting of a compound of formula (IIIc), a compound of formula (IVc), a compound of formula (Vc), a compound of formula (VIc), a compound of formula (VIIc), a compound of formula (VIIIc) and a compound of formula (IXc), or any 5 mixture thereof, as defined in the claims and embodiments of the present specification. One embodiment of the compounds of formula (I) of the invention relates to a compound of formula (Ic) selected from the group consisting of a compound of formula (IIIc), a compound of formula (IVc), a compound of formula (VIIc) and a compound of formula (IXc), or any mixture thereof, as defined in the claims and embodiments of the present specification. 10

[0065] Preferably, the compounds of formulae (IIc), (Vc) and (VIc) feature an ^-C24 stereochemical configuration and have, respectively, formulae (IIc24^) having a C24 R stereochemical configuration, (Vc24^) having a C24 R stereochemical configuration, and (VIc24^) having a C24 S stereochemical configuration; the compound of formula (IVc) features a C24 S stereochemical configuration; and the compounds of formulae (VIIc) and (VIIIc) 15 feature a ^-C24 stereochemical configuration and have, respectively, formulae (VIIc24^) having a C24 R stereochemical configuration, and (VIIIc24^) having a C24 R stereochemical51

[0066] Thus, the compounds of formulae (Ic) may be selected from the group consisting of compounds of formulae (IIc), (IIc24^), (IIIc), (IVc), (IV24S), (Vc), (Vc24^), (VIc), (VIc24^), (VIIc), (VIIc24^), (VIIIc), (VIIIc24^) and (IXc), or any mixtures thereof. In some embodiments, the compounds of formulae (Ic) may be selected from the group consisting of 5 compounds of formulae (IIIc), (IVc), (IVc24S), (Vc), (Vc24^), (VIc), (VIc24^), (VIIc), (VIIc24^), (VIIIc), (VIIIc24^) and (IXc), or any mixtures thereof. In some embodiments, the compounds of formulae (Ic) may be selected from the group consisting of compounds of formulae (IIIc), (IVc), (IVc24S), (VIIc), (VIIc24^), and (IXc), or any mixtures thereof.

[0067] R1 and R2 may be defined according to the proviso (d) as disclosed in the claims and 10 embodiments of the present specification, and the compound of formula (I) has formula (Id):wherein A, B, C, D, E, R3 and R4 are as defined in the claims and embodiments disclosed in the present specification.

[0068] In some embodiments of the compound of formula (Id), when A and B are respectively 15 a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, and D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, then R3is either present and is -OH or -CH=CH2, or is not present when R4 is =CH-CH3; and R4 is =CH-CH3, -OH or -CH=CH2, wherein R3 and R4 are not both -OH or -CH=CH2; when A and B are respectively a group -CH2- and a group -CH- and are 20 linked together by a single bond forming a moiety, and D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, then R3is not52 present; and R4is =CH-CH3; and when A and B are respectively a group -CH- and a group -C- and are linked together by a double bond forming a moiety, and D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, then R3 is H or -CH3and R4is H or -CH3, wherein R3and R4are not both H or -CH3. 5

[0069] In some embodiments of the compound of formula (Id), when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, and D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, R3is either present and is selected from the group consisting of H, -OH, -CH3 and -CH=CH2, or is not present when R4 is =CH-CH3; R4 is selected from the 10 group consisting of H, -OH, -CH3, =CH-CH3 and -CH=CH2; and wherein R3 and R4 are not both H, -OH, -CH3, or -CH=CH2.

[0070] In some embodiments the compound of formula (Id) is selected from the group consisting of a compound of formula (IId), a compound of formula (IIId), a compound of formula (IVd), a compound of formula (Vd), a compound of formula (VId), a compound of 15 formula (VIId), a compound of formula (VIIId) and a compound of formula (IXd):54or any mixtures thereof.

[0071] In some embodiments the compound of formula (Id) is selected from the group 5 consisting of a compound of formula (IIId), a compound of formula (IVd), a compound of formula (Vd), a compound of formula (VId), a compound of formula (VIId), a compound of formula (VIIId) and a compound of formula (IXd). In some embodiments the compound of formula (Id) is selected from the group consisting of a compound of formula (IIId), a compound of formula (IVd), a compound of formula (VIId) and a compound of formula (IXd). 10

[0072] Preferably, the compounds of formulae (IId), (Vd) and (VId) feature an ^-C24 stereochemical configuration and have, respectively, formulae (IId24^) having a C24 (R) stereochemical configuration, (Vd24^) having a C24 (R) stereochemical configuration, and (VId24^) having a C24 (S) stereochemical configuration; the compound of formula (IVd) features a C24 (S) stereochemical configuration and has formula (IVd24S); and the compounds 15 of formulae (VIId) and (VIIId) feature a ^-C24 stereochemical configuration and have, respectively, formulae (VIId24^) having a C24 (R) stereochemical configuration, and (VIIId24^) having a C24 (R) stereochemical configuration:56

[0073] Thus, the compounds of formulae (Id) may be selected from the group consisting of compounds of formulae (IId), (IId24^), (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), 5 (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof.

[0074] In some embodiments the compounds of formulae (Id) may be selected from the group consisting of compounds of formulae (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof. In some embodiments the compounds of formulae (Id) may be selected from the group consisting of 10 compounds of formulae (IIId), (IVd), (IVd24S), (VIId), (VIId24^) and (Ixd), or any mixtures thereof.

[0075] Preferably, the compounds of formulae (II), (V) and (VI) feature an ^-C24 stereochemical configuration, and have, respectively, formulae (II24^) having a C24 (R) stereochemical configuration, (V24^) having a C24 (R) stereochemical configuration, and 15 (VI24^) having a C24 (S) stereochemical configuration; the compound of formula (IV) features C24 (S) stereochemical configuration and has formula (IV24S); and the compounds of formulae57 (VII) and (VIII) feature a ^-C24 stereochemical configuration, and have, respectively, formulae (VII24^) and (VIII24^): 558

[0076] The compounds of formula (I) may be selected from the group consisting of formulae 5 (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^), (IXa), ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^^^^ ^^^^^^^ ^^^^^^^ (IVb24S^^ ^^^^^24S^^ ^^^^^24S), ^^^^^ ^^^^^^ ^^^^^^ ^^^^^^^),^^^^^^^), (VIb^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^), (^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^),^^^^^^^^^^^ ^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ (IIc),59 (IIc24^), (IIIc), (IVc), (IVc24S), (Vc), (Vc24^), (VIc), (VIc24^), (VIIc), (VIIc24^), (VIIIc), (VIIIc24^), (IXc), (IId), (IId24^), (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof.

[0077] The compounds of formula (I) may be selected from the group consisting of formulae 5 (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^^^ ^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^^^^ ^^^^^^^ ^^^^^^^ (IVb24S^^ ^^^^^24S^^ ^^^^^24S), ^^^^^ ^^^^^^ ^^^^^^ ^^^^^^^),^^^^^^^), (VIb^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^),^^^^^^^^^^^ ^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^10 (IIIc), (IVc), (IVc24S), (Vc), (Vc24^), (VIc), (VIc24^), (VIIc), (VIIc24^), (VIIIc), (VIIIc24^), (IXc), (IId), (IId24^), (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof.

[0078] The compounds of formula (I) may be selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^),15 (VIIIa), (VIIIa24^^^ ^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^^^^ ^^^^^^^ ^^^^^^^ (IVb24S^^ ^^^^^24S^^ ^^^^^24S), (Vb), (Vb^^^ ^^^^^^ ^^^^^^^),^^^^^^^), (VIb^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^),^^^^^^^^^^^ ^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^(IIc24^), (IIIc), (IVc), (IVc24S), (Vc), (Vc24^), (VIc), (VIc24^), (VIIc), (VIIc24^), (VIIIc), 20 (VIIIc24^), (IXc), (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof.

[0079] The compounds of formula (I) may be selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^^^ ^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ (IVb24S^^ ^^^^^24S),25 ^^^^^24S), ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^(IIc24^), (IIIc), (IVc), (IVc24S), (Vc), (Vc24^), (VIc), (VIc24^), (VIIc), (VIIc24^), (VIIIc), (VIIIc24^), (IXc), (IId), (IId24^), (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof.

[0080] The compounds of formula (I) may be selected from the group consisting of formulae 30 (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^^^ ^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ (IVb24S^^ ^^^^^24S),60 ^^^^^24S), ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^(IVc), (IVc24S), (VIIc), (VIIc24^), (IXc), (IId), (IId24^), (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof. 5

[0081] The compounds of formula (I) may be selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^^^ ^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ (IVb24S^^ ^^^^^24S),^^^^^24S), ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^(IIIc), (IVc), (IVc24S), (VIIc), (VIIc24^), (IXc), (IIId), (IVd), (IVd24S), (VIId), (VIId24^) and 10 (IXd), or any mixtures thereof.

[0082] The compounds of formula (I) may be selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^), (IXa), (IIc), (IIc24^), (IIIc), (IVc), (IVc24S), (Vc), (Vc24^), (VIc), (VIc24^), (VIIc), (VIIc24^), (VIIIc), (VIIIc24^), (IXc), (IId), (IId24^), (IIId), (IVd), (IVd24S), 15 (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof.

[0083] The compounds of formula (I) may be selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^), (IXa), (IIc), (IIc24^), (IIIc), (IVc), (IVc24S), (Vc), (Vc24^), (VIc), 20 (VIc24^), (VIIc), (VIIc24^), (VIIIc), (VIIIc24^), (IXc), or any mixtures thereof.

[0084] The compounds of formula (I) may be selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^), (IXa), (IId), (IId24^), (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof. 25

[0085] Preferably, the compound of formula (I) is a compound of formula (Ia) and may be selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^) and (IXa), more preferably selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^) and (IXa), or any mixtures thereof, even more preferably is a compound of formula 30 (IIa), and yet even more preferably is a compound of formula (IIa24^).61

[0086] The compounds of formula (I) may be prepared by known methods from commercial products, starting for example from the corresponding known phytosterol precursors. The double bond in 5,6-position of the known phytosterol precursors of the compound of formula (I) may be epoxidized by known methods in the art to obtain the epoxide containing compounds 5 of formula (Ib). For example, the epoxidation of the double bond to obtain the 5,6^-epoxides of formula (Ib^) may also be carried out by any suitable method according to the literature, including general methods for epoxidation such as for example treatment with oxone® (potassium peroxymonosulfate) (ref. 20), or with magnesium bis(monoperoxyphthalate) hexahydrate (ref. 21). In one example, said epoxidation is carried out in the presence of a 10 peroxide, preferably a peroxide alcohol or a peroxycarboxylic acid. In some aspects of the invention said epoxidation is carried out in the presence of m-chloroperbenzoic acid.. On the other hand, the epoxidation of the double bond to obtain the 5,6^-epoxides of formula (Ib^) may suitable methods to conduct the epoxidation are those known in the art which are useful to perform stereoselective epoxidation providing preferentially 5,6^-EC, such as: using a 15 ruthenium(II) bioxazoline complex under aerobic conditions (ref. 22), using bis(dipivaloylmethanato)manganese(II) in the presence of molecular oxygen and an aldehyde (Mn(dpm)2 / isobutyraldehyde / O2(ref. 23), using magnesium monoperoxyphthalate in the presence of manganese tetra-o-dichlorophenylporphyrin complexes (ref. 24), using chromyl diacetate (ref.25), or using a catalytic system involving metalloporphyrins (ref.26). 20

[0087] In addition, the 3^,5^,6^-triols of formula (Ic) may be prepared conducting an epoxide ring opening by known methods in the art such as by acidic hydrolysis of epoxide with perchloric acid (ref.14) or bismuth triflate (ref.15). Alternatively, unsaturated 5,6- sterols can give triol with meta-periodic acid (ref.7).

[0088] The 3^,5^^^^-triols of formula (Id) sing a mixture of osmium tetraoxide and 25 hexacyanoferrate(III) starting from the corresponding 5,6-unsaturated sterol precursors (ref. 16).

[0089] Finally, the oxo derivatives of formula (Ia) may be prepared by several methods known in the art, for example, by oxidation of the corresponding 5^,6^-triol sterol precursors with N- bromosuccinimide (ref. 14). Other chemical methods for obtaining the oxo derivatives of 30 formula (Ia) have been well described by Poirot et al, (ref.17).62 Pharmaceutical compositions

[0090] Another aspect of the present invention refers to a pharmaceutical composition comprising a compound of formula (I):5 wherein R1and R2are defined according to a proviso selected from the group consisting of (a), (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a10 ^-stereochemical configuration;c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration,63and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration; 5and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single bond forming a moiety10 D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-; R3 is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3 and -CH=CH2, or is not present when R4is =CH-CH3; 15 R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; and wherein R3 and R4 are not both H, -OH, -CH3, -CH2-CH3 or -CH=CH2; and at least one pharmaceutically acceptable excipient.

[0091] ^^ ^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^ ^^ meant that the ingredients of a pharmaceuticalcomposition are compatible with each other and not deleterious to the subject thereof.20

[0092] ^^^ ^^^^ ^^^^^^^^^^^ ^^ ^^^^ ^^^^^^ ^^^^^ ^ ^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^ ^^^ ^^^^^^agent or active ingredient in a pharmaceutical composition or medicament. Acceptable excipients for therapeutic use are well known in the pharmaceutical art, and are described, for ^^^^^^^^ ^^ ^^^^^^^^^^^ ^^^^^^^^^^^^^^ ^^^^^^^^^ ^^st Edition 2011. The choice of excipient64 can be selected with regard to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense of being not deleterious to the recipient thereof. The at least one pharmaceutically acceptable excipient may be for example, a pharmaceutical vehicle, a binder, a stabilizer, an antioxidant, a diluent, a carrier, a lubricant, a 5 disintegrator, a wetting agent, a dispersing agent, a suspending agent, and the like.

[0093] ^^^ ^^^^ ^^^^^^^^^^^^^^^ ^^^^^^^^ ^^ ^^^^ ^^^^^^ ^^^^^ ^ ^^^^^^^ ^^ ^^^^^ ^^^^^^ ^^^^as solvent or diluent in which the pharmaceutically active agent is formulated and / or administered.

[0094] In some aspects of the invention, said pharmaceutically acceptable excipient may 10 selected among one or more pharmaceutically acceptable solvents, vehicles or stabilizers.

[0095] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^), (IXa), (IIb), ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^24S),15 ^^^^^24S^^ ^^^^^24S^^ ^^^^^ ^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^^^), (VIb^^ ^^^^^^^ ^^^^^^^^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^ ^^^^^^^), (IIIc), (IVc),(IVc24S), (Vc), (Vc24^), (VIc), (VIc24^), (VIIc), (VIIc24^), (VIIIc), (VIIIc24^), (IXc), (IId), (IId24^), (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), 20 (VIIId24^) and (IXd), or any mixtures thereof.

[0096] In some preferred embodiments the pharmaceutical composition comprises a compound of formula (Ia) selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^) and (IXa), or any mixtures thereof, even more preferably comprises a compound of formula (IIa), and yet even more preferably comprises a compound of formula 25 (IIa24^). Therapeutic uses

[0097] The compounds of formula (Ib), formula (Ic) and formula (Id) are metabolized into the compounds of formula (Ia). In particular, the epoxides of formula (Ib) may be metabolized by 30 ChEH into the triol compounds of formula (Ic) and (Id), which may be, in turn metabolized by65 HSD2 into the compounds of formula (Ia) which act as analogues of OCDO, produced by tumor cells overexpressing ChEH and expressing HSD2 and GR, for example BC tumor cells, wherein the compounds of formula (Ia) may bind to GR and neutralize the signaling pathway and tumorigenicity of OCDO, molecule that may promote cell proliferation and cell cycle 5 progression in cancer cells by binding to the glucocorticoid receptor (GR). Indeed, epoxides of formula (Ib) and triol compounds of formula (Ic) and (Id) may inhibit the biogenesis and tumorigenicity of OCDO which occurs in tumor cells overexpressing ChEH and / or expressing HSD2 and GR. For example, it has been established that OCDO levels reach a pharmacologically active concentration in mammary tumors, which is not the case in healthy 10 tissue adjacent to the tumor, being the enzymes involved in OCDO biogenesis in said tumors overexpressed (ChEH-forming protein subunits), or expressed (HSD2) compared with healthy tissue.

[0098] Accordingly, the compounds of formula (I), being selected from the group consisting of formulae (Ia), (Ib), (Ic) and (Id) are useful for the prevention and / or treatment diseases, in 15 particular of cancers overexpressing ChEH and expressing HSD2 and GR.

[0099] In addition, being analogues of OCDO, the compounds of formula (Ia) are thus useful as glucocorticoid receptor ligands and are useful in the prevention and / or treatment of a cancer in a subject, preferably a human expressing GR. These the compounds of formula (Ia) may block the effects of OCDO via binding to the GR, and therefore may exert anticancer effects 20 via the GR independently of OCDO biogenesis and therefore, independently of the overexpression of ChEH and expression of HSD2, which are the enzymes involved in OCDO biogenesis.

[0100] Thus, one aspect of the invention refers to a compound of formula (I):66wherein R1and R2are defined according to a proviso selected from the group consisting of (a), (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;5b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration;c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a10 ^-stereochemical configuration,d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration;67and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single 5 bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-; R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and 10 -CH=CH2, or is not present when R4 is =CH-CH3; R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2; for use in a method of prevention and / or treatment of a disease in a subject, preferably a human.

[0101] Another aspect of the invention refers to a pharmaceutical composition comprising a 15 compound of formula (I):wherein R1 and R2 are defined according to a proviso selected from the group consisting of (a), (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;68b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration;5c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration,and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a10 ^-stereochemical configuration;and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single 15 bond forming a moiety69 D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-; R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and 5 -CH=CH2, or is not present when R4 is =CH-CH3; R4 is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3 and -CH=CH2; and wherein R3 and R4 are not both H, -OH, -CH3, -CH2-CH3 or -CH=CH2; and at least one pharmaceutically acceptable excipients; for use in a method of prevention and / or treatment of a disease in a subject, preferably a human.10

[0102] ^^^ ^^^^ ^^^^^^^^^ ^^^^^^ ^^ ^ ^^^^-blooded animal, more preferably a human,who / which is awaiting or receiving medical care or is or will be the object of a medical procedure.

[0103] The term ^^^^^^^ ^^^^^^ ^^ ^^^^^^^^ ^^ ^^^^ ^^^^^^^ ^^^ ^^ ^^^ ^^^^^ ^^ ^^^^^^^^^^^(i.e. neonate, infant, juvenile, adolescent, adult). In one embodiment, the human is an adolescent 15 or adult, preferably an adult.

[0104] Some embodiments refer to the use of a compound of formula (I), or of a pharmaceutical composition comprising a compound of formula (I), as disclosed in the claims and embodiments of the present invention, in the manufacturing of a medicament for preventing and / or treating a disease in a subject, preferably a human. 20

[0105] Some embodiments refer to a method of preventing and / or treating a disease in a subject, preferably a human, in need thereof, said method comprising administering an effective amount of a compound of formula (I) or of a pharmaceutical composition comprising a compound of formula (I).

[0106] ^^ ^^^^^^^^^^ ^^^^^^^^ ^^ ^^ ^^^^^ ^^^^^^ ^ ^^^^^^^^^^^^^^^ ^^^^^^^^^ ^^25 pharmaceutically effective dose. An effective amount is an amount sufficient to induce a preventive or a therapeutic response against the disease, in particular against a cancer. The therapeutically effective dose depends upon the composition used, the route of administration, the type of mammal (human or animal) being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors, that those skilled in the 30 medical arts will recognize.70

[0107] Another aspect of the invention refers to a compound of formula (I) or to a pharmaceutical composition comprising the same, in particular wherein said compound of formula (I) is selected from the group consisting of a compound of formula (II), a compound of formula (III), a compound of formula (IV), a compound of formula (V), a compound of formula 5 (VI), a compound of formula (VII), a compound of formula (VIII) and a compound of formula (IX), as defined in the claims and embodiments of the present specification, for use in a method of prevention and / or treatment of a disease in a subject, preferably a human.

[0108] Thus, the specification also refers to the use of a compound of formula (I) or of a pharmaceutical composition comprising the same, in particular wherein said compound of 10 formula (I) is selected from the group consisting of a compound of formula (II), a compound of formula (III), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII) and a compound of formula (IX), as defined in the claims and embodiments of the present specification, in the manufacturing of a medicament for preventing and / or treating a disease in a subject, preferably 15 a human.

[0109] In addition, some embodiments refer to a method of preventing and / or treating a disease in a subject, preferably a human, in need thereof, said method comprising administering an effective amount of a formula (I), or of a pharmaceutical composition comprising the same, in particular wherein said compound of formula (I) is selected from the group consisting of a 20 compound of formula (II), a compound of formula (III), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII) and a compound of formula (IX), as defined in the claims and embodiments of the present specification.

[0110] Another aspect of the invention refers to a compound of formula (I) or to a 25 pharmaceutical composition comprising the same, in particular wherein said compound of formula (I) is selected from the group consisting of a compound of formula (Ia), a compound of formula (Ib), a compound of formula (Ic) and a compound of formula (Id), as defined in the claims and embodiments of the present specification, for use in a method of prevention and / or treatment of a disease in a subject, preferably a human. 30

[0111] Thus, the specification also refers to the use of a compound of formula (I) or of a pharmaceutical composition comprising the same, in particular wherein said compound of71 formula (I) is selected from the group consisting of a compound of formula (Ia), a compound of formula (Ib), a compound of formula (Ic) and a compound of formula (Id), as defined in the claims and embodiments of the present specification, in the manufacturing of a medicament for preventing and / or treating a disease in a subject, preferably a human. 5

[0112] In addition, some embodiments refer to a method of preventing and / or treating a disease in a subject, preferably a human, in need thereof, said method comprising administering an effective amount of a formula (I) or of a pharmaceutical composition comprising the same, in particular wherein said compound of formula (I) is selected from the group consisting of a compound of formula (Ia), a compound of formula (Ib), a compound of formula (Ic) and a 10 compound of formula (Id), as defined in the claims and embodiments of the present specification.

[0113] Yet another aspect of the invention refers to a compound of formula (I):wherein R1 and R2 are defined according to a proviso selected from the group consisting of (a), 15 (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration;72c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration,5 and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration;and wherein 10 A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety 15 -CH2-CH2-; R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and -CH=CH2, or is not present when R4 is =CH-CH3; R4 is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3 and -CH=CH2; and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2; 20 for use in a method of prevention and / or treatment of a cancer in a subject, preferably a human, overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^-73 hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR); i.e. for use in a method of prevention and / or treatment of a cancer associated to overexpression of cholesterol- 5,6-epoxide hydrolase (ChEH) and / or expression of ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR). 5

[0114] In some embodiments, the compound for use according to this disclosure is selected ^^^^ ^^^ ^^^^^ ^^^^^^^^^^ ^^ ^^^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^ ^^^^^^^^(VIa^^ ^^^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^ ^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^^^^^^ ^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^^^^^ ^VIb^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^10 ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^ ^^^^^^^^(VIc^^ ^^^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^ ^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^^^ ^^^^^^^^^^^^^^^ ^^^^^ ^^^^^^^^ ^VId^^ ^^^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^ ^^^ ^^^^^^or any mixtures thereof. 15

[0115] In some preferred embodiments , the compound for use according to this disclosure is selected from the group consisting of formulae (IIa), ^^^^^^^^^ ^^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^^^^^^^^ ^^^ ^^^^^^ ^^ ^^^ ^^^^^^^^ ^^^^^^^^ ^^^^ ^^^^ ^^^^^^^^^^ ^^ ^ ^^^^^^^^ ^^ ^^^^^^^^^^^^^ ^^^ ^^^ ^^^^ ^^^^ ^^^^^^^^^^ ^^ ^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^^^^^^

[0116] Another aspect of the invention refers to a pharmaceutical composition comprising a 20 compound of formula (I):wherein R1and R2are defined according to a proviso selected from the group consisting of (a), (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;74b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration;5c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration,and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a10 ^-stereochemical configuration;and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single 15 bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-;75 R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and -CH=CH2, or is not present when R4 is =CH-CH3; R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2; 5 as defined in the claims and the embodiments of the present invention, and at least one pharmaceutically acceptable excipients; for use in a method of prevention and / or treatment of a cancer in a subject, preferably a human, overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR). 10

[0117] Some embodiments refer to the use of a compound of formula (I), or of a pharmaceutical composition comprising a compound of formula (I), as disclosed in the claims and embodiments of the present invention, in the manufacturing of a medicament for preventing and / or treating a cancer in a subject, preferably a human, overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and 15 glucocorticoid receptor (GR).

[0118] Accordingly, some embodiments refer to a method of preventing and / or treating a cancer in a subject in need thereof, preferably a human, overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR), said method comprising administering an effective amount of a 20 compound of formula (I), or of a pharmaceutical composition comprising the same, as disclosed in the claims and embodiments of the present invention.

[0119] In some embodiments, the pharmaceutical composition for use according to this disclosure comprises a compound of formula (I) selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^),25 (VIIIa), (VIIIa24^), (IXa), ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^24S^^ ^^^^^24S^^ ^^^^^24S^^ ^^^^^ ^^^^^^ ^^^^^^ ^^^^^^^),^^^^^^^), (VIb^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^),^^^^^^^^^^^ ^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^(IIc24^), (IIIc), (IVc), (IVc24S), (Vc), (Vc24^), (VIc), (VIc24^), (VIIc), (VIIc24^), (VIIIc), 30 (VIIIc24^), (IXc), (IId), (IId24^), (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof.76

[0120] In some preferred embodiments, the pharmaceutical composition for use according to this disclosure comprises a compound of formula (Ia) selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^) and (IXa), or any mixtures thereof, even more preferably the pharmaceutical composition for use according to this 5 disclosure comprises a compound of formula (IIa), and yet even more preferably the pharmaceutical composition for use according to this disclosure comprises a compound of formula (IIa24^).

[0121] Yet another aspect of the invention refers to a compound of formula (Ia):10 wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety 15 -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-; R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and -CH=CH2, or is not present when R4 is =CH-CH3; R4 is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3 and -CH=CH2; 20 and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2; or to a pharmaceutical composition comprising the same, for use in a method of prevention and / or treatment of a cancer in a subject, preferably a human, expressing glucocorticoid receptor77 (GR), i.e. for use as a ligand of the glucocorticoid receptor (GR) in a method of prevention and / or treatment of a disease in a subject, preferably a human.

[0122] Some embodiments refer to the use of a compound of formula (Ia), or of a pharmaceutical composition comprising a compound of formula (Ia), as disclosed in the claims 5 and embodiments of the present invention, in the manufacturing of a medicament for preventing and / or treating a cancer in a subject, preferably a human, expressing glucocorticoid receptor (GR).

[0123] Accordingly, some embodiments refer to a method of preventing and / or treating of a cancer in a subject, in need thereof, preferably a human, expressing glucocorticoid receptor 10 (GR), said method comprising administering an effective amount of a compound of formula (Ia), or of a pharmaceutical composition comprising the same, as disclosed in the claims and embodiments of the present invention.

[0124] In some preferred embodiments, the pharmaceutical composition for use according to this disclosure comprises a compound of formula (Ia) selected from the group consisting of15 ^^^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^ ^^^^^^^ ^^^ ^^^^^^ ^^ ^^^ mixturesthereof, even more preferably the pharmaceutical composition for use according to this disclosure comprises a compound of formula (IIa), and yet even more preferably the pharmaceutical composition for use according to this disclosure comprises a compound of ^^^^^^^ ^^^^^^^^.20 Cancers and tumors associated to ChEH overexpression and / or HSD2 and GR expression and cancers associated to GR expression.

[0125] The terms ^^^^^^^^ ^^^ ^^^^^^ ^^^^^^^^^^ ^^ ^^^^ overexpression and / or HSD2 andGR ^^^^^^^^^^^ ^^ ^^^^^^^^^^^^^^^ cholesterol-5,6-epoxide hydrolase (ChEH) and / or25 expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor ^^^^^^ as included in the present disclosure, refer to cancers and tumors overexpressing ChEHand expressing HSD2 and GR, wherein the overexpression of ChEH and expression of HSD2 results into oncosterone biogenesis (ref.1, 2, 9) which promotes cell proliferation and cell cycle progression by binding to the glucocorticoid receptor (GR).30

[0126] ^^^ ^^^^ ^^^^^^^ ^^ ^^^^^ ^^^^^^^^^^ ^^ ^^^-hydroxysteroid dehydrogenase type 2^^^^^^ ^^^^^^^^^^^ ^^ ^^^^^^^ ^^^^^^^^^^ ^^ ^^^-hydroxysteroid dehydrogenase type 278 (HSD2)^^ refers to a tumor or a cancer tissue featuring expression of HSD2 in tumor compared to normal adjacent normal tissues or to normal samples from non-cancerous subjects (ref.1, 9).

[0127] ^^^ ^^^^ ^^^^^^^ ^^ ^^^^^ ^^^^^^^^^^ ^^ ^^^^^^^^^^^-5,6-epoxide hydrolase (ChEH)overexpression^ ^^ ^^ancer or tumor overexpressing cholesterol-5,6-epoxide hydrolase5 (ChEH)^ refers to a tumor or a cancer tissue featuring an increased expression of ChEH subunits (EBP and / or DHCR7) when compared to normal adjacent normal tissues or to normal samples from non-cancerous subjects (ref.1, 9).

[0128] ^^^ ^^^^ ^^^^^^^ ^^ ^^^^^ ^^^^^^^^^^ ^^ glucocorticoid receptor (GR) expression^ ^^^^ancer or tumor expressing ^^^^^^^^^^^^^^ ^^^^^^^^ ^^^^^ refers to a tumor or a cancer tissue10 featuring expression of GR when compared to normal adjacent normal tissues or to normal samples from non-cancerous subjects.

[0129] In some embodiments, the cancer in a subject, preferably a human, overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR)may be selected from the group 15 consisting of adrenal gland cancer, adrenocortical adenoma, acute myeloid leukemia, acute lymphoblastic leukemia, bladder cancer, bladder urothelial carcinoma, breast invasive carcinoma, esophageal carcinoma, kidney chromophobe, liver cancer, liver hepatocellular carcinoma, lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, myeloid cancers, neural tumors, neuroblastoma, osteosarcoma, ovarian cancer, ovarian serous 20 cystadenocarcinoma, pancreatic cancer, pancreatic adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, testicular germ cell tumors and uterine corpus endometrial carcinoma; being said breast invasive carcinoma, said liver cancer, said lung cancer, said ovarian cancer, and said pancreatic cancer, a primary tumor or a metastatic tumor.

[0130] In some embodiments, the cancer in a subject, preferably a human, overexpressing 25 cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR)may be selected from the group consisting of breast cancer, cervix cancer, colon adenocarcinoma, colon cancer, intestine cancer, endometrium cancer, head and neck cancer, gastric cancer, esophageal cancer, nasopharyngeal cancer, oral cavity cancer, pituitary cancer, prostate cancer, prostate 30 adenocarcinoma, salivary gland cancer, thyroid cancer, thyroid carcinoma, tongue cancer, uterine cancer and uterine carcinosarcoma; being said breast cancer, said colon cancer, said79 esophageal cancer, said oral cavity cancer, said intestine cancer, said prostate cancer, said thyroid cancer and said thyroid carcinoma a primary tumor or a metastatic tumor.

[0131] In some embodiments, the cancer in a subject, preferably a human, overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid 5 dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR)may be selected from the group consisting of adrenal gland cancer, adrenocortical adenoma, acute myeloid leukemia, acute lymphoblastic leukemia, bladder cancer, bladder urothelial carcinoma, breast cancer, breast invasive carcinoma, cervix cancer, colon adenocarcinoma, colon cancer, intestine cancer, endometrium cancer, head and neck cancer, gastric cancer, esophageal cancer, esophageal 10 carcinoma, kidney chromophobe, liver cancer, liver hepatocellular carcinoma, lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, myeloid cancers, nasopharyngeal cancer, neural tumors, neuroblastoma, osteosarcoma, oral cavity cancer, ovarian cancer, ovarian serous cystadenocarcinoma, pituitary cancer, pancreatic cancer, pancreatic adenocarcinoma, prostate cancer, prostate adenocarcinoma, rectum adenocarcinoma, salivary gland cancer, stomach 15 adenocarcinoma, testicular germ cell tumors, thyroid cancer, thyroid carcinoma, tongue cancer, uterine cancer, uterine carcinosarcoma and uterine corpus endometrial carcinoma; being said breast invasive carcinoma, said liver cancer, said lung cancer, said ovarian cancer, and said pancreatic cancer, a primary tumor or a metastatic tumor.

[0132] In some embodiments the cancer associated with the expression of GR or cancer 20 expressing GR may be selected from the group consisting of adrenal gland cancer, acute myeloid leukemia, bladder cancer, breast cancer, colon cancer, esophageal cancer, liver cancer, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, rectum cancer, renal cancer, renal carcinoma, renal chromophobe carcinoma, renal papillary cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine 25 carcinosarcoma and uterine corpus endometrial carcinoma.

[0133] In some embodiments, the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; 30 transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma80 and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; 5 basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; non-encapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous; adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary 10 serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w / squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; and roblastoma, 15 malignant; Sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malig melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; 20 liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; 25 choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic 30 fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma;81 ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; Hodgkin's lymphoma; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant 5 lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and 10 hairy cell leukemia.

[0134] In a preferred embodiment the cancer overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR) is breast cancer, preferably ER+ breast cancer, triple negative breast cancer or invasive breast cancer. In a preferred embodiment the cancer associated with 15 the expression of GR or cancer expressing GR is breast cancer, preferably ER+ breast cancer, triple negative breast cancer or invasive breast cancer. Combined therapeutic treatments

[0135] The compound of formula (I) or the pharmaceutical composition comprising the same, 20 for use according to the claims and the present description, may be administered prior to, together with, or subsequent to at least one further therapeutic agent.

[0136] In some embodiments, the compound of formula (I) or the pharmaceutical composition comprising the same, for use according to the claims and the present description, is administered in combination with at least two further therapeutic agents (e.g. a Liver-X-Receptor (NR1H2, 25 NR1H3) modulator and a chemotherapeutic agent).

[0137] In some embodiments, the at least one further therapeutic agent is one or more therapeutic agents selected from the group consisting of a hormone therapy, a CDK4 / 6 inhibitor, a Src inhibitor, a chemotherapeutic agent, and a therapeutic agent targeting oncosterone biosynthesis or biogenesis.82

[0138] In some embodiments, the at least one further therapeutic agent is a hormone therapy, in particular a ligand of the microsomal anti-estrogen binding site (AEBS). In some embodiments, the hormone therapy is Tamoxifen, Tesmilifene or 1-[2-[4- (phenylmethyl)phenoxy]ethyl]-pyrrolidine (PBPE). 5

[0139] In some embodiments, the at least one further therapeutic agent is a CDK4 / 6 inhibitor (i.e. Cyclin-dependent kinase 4 and 6 inhibitor). In some embodiments, the CDK4 / 6 inhibitor is Palbociclib, Abemaciclib or Ribociclib.

[0140] In some embodiments, the at least one further therapeutic agent is a Src inhibitor. In some embodiments, the Src inhibitor is Dasatinib. 10

[0141] In some embodiments, the at least one further therapeutic agent is a chemotherapeutic agent selected from the group comprising alkylating agents, anthracyclines, antimetabolites, topoisomerase inhibitors, antibiotics, mitotic inhibitors or protein kinase inhibitors. In some embodiments, the chemotherapeutic agent is selected from the group consisting in Carboplatin, Paclitaxel, Doxorubicin, Methotrexate, Pemetrexed, Cytarabine, 5-Fluorouracil, Capecitabine, 15 Gemcitabine, 6-Mercaptopurine, Azathioprine, Fludarabine, Cladribine, Hydroxyurea, Cyclophosphamide, Ifosfamide, Chlorambucil, Melphalan, Temozolomide, Carmustine, Lomustine, Streptozocin, Busulfan, Procarbazine, Cisplatin, Oxaliplatin, Irinotecan, Topotecan, Etoposide, Vincristine, Vinblastine, Vinorelbine, Docetaxel, Eribulin, Ixabepilone, Epothilone, Bleomycin, Actinomycin D, Daunorubicin, Epirubicin, Pirarubicin, Zorubicin, Aclarubicin, 20 Mitoxantrone, Pixantrone, Idarubicin, Mitomycin, Imatinib, Nilotinib, Erlotinib, Gefitinib, Afatinib, Osimertinib, Cabozantinib, Pazopanib, Sunitinib, Sorafenib, Tivozanib, Axitinib, Lenvatinib, Regorafenib, Vandetanib, Alectinib, Crizotinib, Dabrafenib, Encorafenib, Vemurafenib, Trametinib, Ibrutinib, Ruxolitinib, L-Asparaginase, Bortezomib, Carfilzomib, Ixazomib or Olaparib. 25

[0142] In some embodiments, at least one further therapeutic agent is a therapeutic agent targeting oncosterone biosynthesis or biogenesis. ^^^ ^^^^ ^therapeutic agent targeting^^^^^^^^^^^ ^^^^^^^^^^^^^ ^^ ^therapeutic ^^^^^ ^^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^^^^^ ^^^^^^^according to the present invention, to a treatment which, when administered to a subject suffering from a cancer, lowers the amount of oncosterone generated by the subject. 30

[0143] In some embodiments, the at least one further therapeutic agent is a compound targeting the Liver X Receptor (NR1H2, NR1H3) as a biased agonist like dendrogenin A, a downstream83 effector of oncosterone, or is an agent targeting oncosterone biosynthesis or biogenesis, in particular selected from the group consisting of a ligand of the microsomal anti-estrogen binding site (AEBS), a Selective Estrogen Receptor Modulator (SERM), an EBP (Emopamil Binding site Protein) inhibitor, a 7-dehydrocholesterol reductase (DHCR7) inhibitor, a cholesterol 5 epoxide hydrolase (ChEH) inhibitor, a sigma-1 receptor ligand and a sigma-2 receptor ligand. In some embodiments, the agent targeting oncosterone biosynthesis or biogenesis is selected from the group comprising or consisting in tamoxifen, tesmilifene, raloxifene, terbinafine, haloperidol, trifluoroperazine, clomiphene, toremifene DSP-0390, TASIN (Truncated APC- Selective Inhibitors) compounds, dendrogenins in particular dendrogenin A (DDA), 10 perospirone, nefazodone, aripiprazole, trazodone buspirone, fluoxetine, risperidone, AY9944, BM15766, cariprazine, GW3965, TO091317, LXR-623, flavonoids, beta-sitosterol, fucosterol, campesterol, GSK3987, riccardin, saringosterol, RGX-104 or GSK2033 (ref.10, 11).

[0144] Therapeutic administration 15

[0145] In a particular embodiment, the compounds of formula (I), as disclosed in the claims and embodiments of the present invention, and the pharmaceutical compositions comprising the compounds of formula (I), as disclosed in the claims and embodiments of the present invention, are administered to said subject, alone or with other pharmaceutically acceptable compounds and excipients, by intra-venous, subcutaneous or oral route. Preferably the compounds of 20 formula (I), or the pharmaceutical compositions comprising the compounds of formula (I), as disclosed in the claims and embodiments of the present invention, are administered to said subject, alone or with other pharmaceutically acceptable compounds and excipients, by intra- venous route. Such suitable administration forms as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is25 ^^^^ ^^ ^^^ ^^^^^^ ^^^^^^^ ^^ ^^^^^^^^^^^ ^^^^^^^^^^^^^^ ^^^^^^^^^Combined diagnostic and therapeutic methods

[0146] In addition, in some embodiments, the method of prevention and / or treatment of a cancer in a subject, preferably a human, overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) 30 and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR) comprises, selecting the subject with a method of detecting the presence of a84 cancer associated to cholesterol-5,6-epoxide hydrolase (ChEH) overexpression and / or ^^^- hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR) expression in the subject, preferably a human. Accordingly, the compounds for use and pharmaceutical compositions for use according to the present disclosure refer to further therapeutic uses based 5 on a particular group of subjects which overexpress cholesterol-5,6-epoxide hydrolase (ChEH) and / or express ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR), wherein said group of subjects may be selected with a method of detecting the presence of a cancer associated to cholesterol-5,6-epoxide hydrolase (ChEH) overexpression and / or ^^^- hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR) expression in 10 the subject.

[0147] Methods for detecting the presence of a cancer associated to cholesterol-5,6-epoxide hydrolase (ChEH) overexpression and / or ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR) expression in the subject, preferably a human, may be any of those known in the art for cancer detection, such as for example, biopsy, cytology, endoscopy 15 and imaging methods. For example, adequate imaging diagnostic methods include CT (computer thomography) scanner, positron emission tomography (PET) scanner, MRI, X-rays, NMR, ultrasounds, ^^^^^^^^^^^^ or mammograms.

[0148] In some embodiments, the diagnostic method comprises i) determining the expression level of cholesterol-5,6-epoxide hydrolase (ChEH), ^^^-hydroxysteroid dehydrogenase type 2 20 (HSD2) and glucocorticoid receptor (GR) in a test sample obtained from the subject, ii) comparing the expression level of cholesterol-5,6-epoxide hydrolase (ChEH) determined at step i) with its predetermined reference value and ii) concluding that the subject suffers from a cancer when the expression level of cholesterol-5,6-epoxide hydrolase (ChEH) is higher than its predetermined reference value and / or when ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) 25 and glucocorticoid receptor (GR) expression is detected.

[0149] The term "test sample" means any tissue sample derived from the subject for who the cancer diagnosis is provided. Said tissue sample is obtained for the purpose of the in vitro evaluation. The sample can be fresh, frozen, fixed (e.g., formalin fixed), or embedded (e.g., paraffin embedded). In some embodiments the test sample may result from a suspected tumor 30 resected from the subject. In some embodiments, the test sample may result from a biopsy performed in the suspected primary tumor of the subject or performed in suspected metastatic85 sample distant from a primary tumor of the subject. For example an endoscopic biopsy performed in the bowel of the subject affected by a colorectal cancer.

[0150] In some embodiments the method of detecting the presence of a cancer associated to cholesterol-5,6-epoxide hydrolase (ChEH) overexpression and / or ^^^-hydroxysteroid 5 dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR) expression in the subject, comprises subjecting said subject to a positron emission tomography (PET) scanner.

[0151] In some embodiments, the method of detecting the cancer associated to cholesterol-5,6- epoxide hydrolase (ChEH) overexpression and / or ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR) expression in the subject comprises: 10 - administering a18F-radiolabeled compound of formula (X):wherein: R3is H or OH; and R2, R4, R5, R6, R7and R12are independently selected from18F or H; R8and R9are each OH or are linked to an oxygen atom forming together an epoxide; 15 wherein, when R2is18F, then R3is OH and all R4, R5, R6, R7and R12are H; when R4is18F, then R8and R9are each OH and all R2, R3, R5, R6, R7and R12are H; when R5is18F, then R3is OH and all R2, R4, R6, R7and R12are H; when R6is18F, then R3is OH and all R2, R4, R5, R7and R12are H; 20 when R7is18F, then R3is OH and all R2, R4, R5, R6and R12are H; and when R12is18F, then R3is OH and all R2, R4, R5, R6and R7are H; and wherein at least one of R2, R4, R5, R6, R7and R12is a18F; or a composition comprising the same to the subject; - subjecting the subject to a positron emission tomography (PET) scanner; and86 - collecting the positron emission tomography (PET) signal.

[0152] The methods of detecting the cancer associated to cholesterol-5,6-epoxide hydrolase (ChEH) overexpression and / or ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR) expression and compounds of formula (X) are those disclosed in 5 international application PCT / EP2024 / 050016.

[0153] The compounds of formula (X) are18F-radiolabeled precursors of the oncometabolite cholestan-6-oxo-^^^^^-diol (oncosterone). Since the overexpression of enzyme ChEH and / or expression of enzyme HSD2 results in the production of the oncometabolite oncosterone, the uptake of the18F-radiolabeled compounds of formula (X) may be detected in those tumor tissues 10 where oncosterone (OCDO) is produced.

[0154] In some aspects of the invention, the compounds of formula (X) are those wherein: R2is18F, R3is OH, all R4, R5, R6, R7and R12are H, and R8and R9are each OH or are linked to an oxygen atom forming together an epoxide; or wherein R4is18F, R8and R9are each OH and all R2, R3, R5, R6, R7and R12are H. 15

[0155] In other aspects of the invention the compounds of formula (X) are those wherein R8and R9are each OH or are linked to an oxygen atom forming together an epoxide, and wherein: R5is18F, R3is OH and all R2, R4, R6, R7and R12are H; or R6is18F, R3is OH and all R2, R4, R5, R7and R12are H; or R7is18F, R3is OH and all R2, R4, R5, R6and R12are H; or 20 R12is18F, R3is OH and all R2, R4, R5, R6and R7are H.

[0156] More preferred compounds of formula (X) are those wherein R2is18F, R3is OH, all of R4, R5, R6, R7and R12are H, and R8and R9are each OH or are linked to an oxygen atom forming together an epoxide.

[0157] An even more preferred compound of formula (X) is that wherein R2is18F, R3is OH, 25 all of R4, R5, R6, R7and R12are H and R8and R9are each OH.

[0158] Particularly preferred compounds of formula (X) are those listed in Table 1 hereafter:878889

[0159] In a particular embodiment, the compound of formula (X) disclosed herein is administered to said subject, alone or as part of a pharmaceutically acceptable composition, by intra-venous, subcutaneous or oral route. Preferably the compound of formula (X) disclosed herein is administered to said subject, alone or as part of a pharmaceutically acceptable 5 composition, by intra-venous route.

[0160] ^^^ ^^^^ ^^^^^^^^^^^^^^^^^ ^^ ^ ^^^^^^^ ^^^^^^^ ^^^^^ ^^^^^^^^^^^^^^^^^ ^^^^^ ^^^^^^^^^the active agent or active ingredient (compounds of formula I or another the cancer treatment) or a diagnostic agent (compound of formula X), alone or as part of a pharmaceutically acceptable composition, to the subject. 10 Nutraceutical compositions

[0161] The compounds of formula (I) disclosed in the present specification may also be used in nutraceutical compositions which may be used, as a dietary supplement, for example, for preventing the onset of a cancer overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) 15 and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid90 receptor . Thus, yet another aspect relates to a nutraceutical composition comprising a compound of formula (I):wherein R1and R2are defined according to a proviso selected from the group consisting of (a), 5 (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration; 10c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration,91 d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration;and wherein 5 A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single bond forming a moietyD and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety 10 -CH2-CH2-; R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and -CH=CH2, or is not present when R4 is =CH-CH3; R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2; 15 and at least one nutraceutically acceptable excipient.

[0162] As for the pharmaceutically acceptable excipients, the term ^nutraceutically acceptable excipient^ refers to the ingredients of a nutraceutical composition are compatible with each other and not deleterious to the subject thereof.

[0163] In some embodiments, the nutraceutical composition according to this disclosure 20 comprises a compound of formula (I) selected from the group consisting of formulae (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^), (VIa), (VIa24^), (VIIa), (VIIa24^), (VIIIa), (VIIIa24^^^ ^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^^^^ ^^^^^^^^ ^^^^^^^^ ^^^^^^^^^^^^^ ^^^^^^^ ^^^^24S^^ ^^^^^24S^^ ^^^^^24S^^ ^^^^^ ^^^^^^ ^^^^^^ ^^^^^^^^^ ^^^^^^^),(VIb^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^^^ ^^^^^^^^), (VIIb), (VIIb^^^ ^^^^^^^^ ^^^^^^^^^),25 ^^^^^^^^^^^ ^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^(IIc24^), (IIIc), (IVc), (IVc24S), (Vc), (Vc24^), (VIc), (VIc24^), (VIIc), (VIIc24^), (VIIIc),92 (VIIIc24^), (IXc), (IId), (IId24^), (IIId), (IVd), (IVd24S), (Vd), (Vd24^), (VId), (VId24^), (VIId), (VIId24^), (VIIId), (VIIId24^) and (IXd), or any mixtures thereof.

[0164] In some preferred embodiments, the nutraceutical composition according to this disclosure comprises a compound of formula (Ia) selected from the group consisting of formulae 5 (IIa), (IIa24^), (IIIa), (IVa), (IVa24S), (Va), (Va24^) and (IXa), or any mixtures thereof, even more preferably the nutraceutical composition according to this disclosure comprises a compound of formula (IIa), and yet even more preferably the nutraceutical composition according to this disclosure comprises a compound of formula (IIa24^). 10 EXAMPLES Materials and methods Materials

[0165] OCDO (oncosterone or cholestan-^^^ ^^-diol-6-one, C4000-000), was from Steraloids.^-sitosterol was from Extrasynthèse (France). AS602801 (bentamapimod, HY-14761) is from 15 MedChemTronica. MCF-7, MDA-MB-231, MDA-MB-468 and 4T1 cells were from LGC Standards. Penicillin and streptomycin (50 U / ml) was from Sigma-Aldrich (P0781) and L- Glutamine from Invitrogen (25030024). The antibodies anti-phospho-c-Jun (Ser63) II (9261S), anti-c-Jun (60A8) (9165S), anti-phospho-Src Family (Tyr416) (6943S), anti-Src (36D10) (2109S), anti-phospho-SAPK / JNK (Thr183 / Tyr185) (81E11) (4668), anti-SAPK / JNK (9252s), 20 anti-GAPDH (D16H11) XP (5174S), anti-glucocorticoid receptor (D6H2L) (12041S), were from Cell Signaling. The antibody anti-actin clone C4, (mab1501) was from Merck millipore. The antibodies anti-HSP90 alpha / beta (F-8) (5174S), anti-glucocorticoid receptor (G5) (sc- 393232) and anti-JNK1 (37) (sc-136205) were from Santa-Cruz. The antibody FITC-conjugated BrdU clone 3D4 (364104) was from BioLegend. 25 Cell culture

[0166] ^^^^^ ^^^^ ^^^^^ ^^ ^^^^ ^^ ^ ^^^^^^^^^^ ^^^^^^^^^^ ^^^^ ^^ ^^^^ ^^^ ^^^^ ^^^^^ ^^^^tested once a month for mycoplasma contamination using Mycoalert Detection kit (Lonza, France) and cultured until passage 20. MCF-7 cells were grown in RPMI 1640 medium (Invitogen 21875091) supplemented with 5% fetal bovine serum (FBS), MDA-MB-468 cells in 30 RPMI 1640 medium (Invitogen 21875091) with 10% FBS, 4T1 in RPMI 1640 medium93 (Invitogen, 21875091) with 10% FBS and MDA-MB-231 in DMEM (Invitogen, 41966029) with 10% FBS. All the cells lines were cultured in 1% penicillin and streptomycin (50 U / ml) (Sigma / Merck, P0781). Compounds 5

[0167] 5,6^-EC (5,6^-epoxide of cholesterol), 5,6^-EC (5,6^-epoxide of cholesterol) were synthesized from cholesterol as reported (ref. 13, ref. 3). 5,6^-ES, 5,6^-ES (5,6^- and 5,6^-epoxides of formula, respectively, (IIb^24^) ^^^ ^^^^^^^^^ were synthesized from^-sitosterol as reported (ref. 13). CT (cholestane-3^,5^,6^-triol) and OCDO (oncosterone or cholestan-^^^ ^^-diol-6-one) were synthesized as reported (ref.7; ref.2). The synthesis of [14C]-10 and [2H]- 5,6^-EC, 5,6^-EC, -CT and -OCDO were performed as reported before (ref.3; ref.7; ref. 18) from [14C]-cholesterol (Perkin^Elmer) or [2H]-cholesterol (Sigma-Aldrich). All other reagents were purchased from Sigma^Aldrich (St. Louis, MO). All commercially available chemicals were used without further purification. The progress of the reactions was monitored by TLC using silica gel aluminum sheets and detection with 50% methanolic H2SO4. 15 Atmospheric pressure column chromatography was performed on Merck-grade 773470^230 mesh silica and reversed-phase HPLC on a Perkin^Elmer LC200 series with Ultrasep ES 100 RP 18, 6.0 ^m; Bischoff, Leonberg, Germany. Melting points were determined with a Kofler apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a Bruker spectrometer AC300. Solutions were prepared in deuterated methanol (CD3OD), with 20 tetramethylsilane (TMS) as internal standard. EI-MS and CI-MS spectra were obtained with a quadrupolar NERMAG R10-10 spectrometer. Infrared (IR) spectra were recorded on a Perkin^ Elmer IR-881 spectrometer. Optical rotations were measured with a PerkinElmer 241 polarimeter. Elemental analyses were carried out at the Institut des Sciences Analytiques, Villeurbanne (France) with the MA-E2^01 method for carbon and hydrogen composition and 25 the MA-E2-13 for oxygen. ^^^^^^^^^ ^^^ ^^^ ^^^^^^^^ ^^^^^^^^^ ^^ ^^^^-Epoxy-^^-sitostan-^^-^^ ^^^^^-ES) ^ ^^^^-epoxide of formula (IIb^24^) m-Chloroperbenzoic acid (mCPBA) (4.25 mmol) in methylene chloride (10 mL) was added ^^^^^^^^ ^^ ^ ^^^^^^^^ ^^ ^^^ ^-sitosterol (2.5 mmol) in methylene chloride (25 mL) over a30 period of 1 min at room temperature. The reaction mixture was stirred over 2 hours and then washed with aqueous sodium sulfite (10%) and sodium hydrogenocarbonate (5%) and dried94 over anhydrous sodium carbonate. The solvents were evaporated under reduced pressure to give the crude product. Recrystallization of the crude product in acetone / water (9:1) gave the ^-epoxide as white needles (0.54 g, 54%): Rf[EtOAc] = 0.68; 1H NMR (300 MHz, CDCl3) ^ 3.96-3.85- (1H, m, H-3), 2.91 (1H, d, J = 4.3 Hz, H-6), 1.05 (3H, H-19), 0.89 (3H, d, J = 6.6 5 Hz, H-21), 0.86-0.79 (9H, m, H-26, H-27, H-29), 0.6 (3H, s, H-18). MS (DCI / NH3) m / z: 431 (MH+), 448 (M+NH4+) ^^^^^^^^^ ^^^ ^^^ ^^^^^^^^ ^^^^^^^^^ ^^ ^-Sitosterol-3,5,6-triol (ST) - Compound offormula (IIc24^) A solution of aqueous metaperiodic acid (10 mmol, 5.5 mL) was added to a solution of 10 ^-sitosterol (1 mmol) in THF (15 ml). The suspension was stirred for 24 hours at room temperature. The mixture was washed with excess 10% aqueous sodium thiosulfate and a white precipitate appeared in a colorless solution. The resulting mixture was extracted with ethyl acetate (40 mL). The extract was washed with 5% aqueous sodium bicarbonate and brine. The organic layer was then dried over MgSO4, and the solvent removed under reduced pressure. The 15 crude product was purified by flash chromatography (CombiFlash NextGen) on a silica column (12G; column volume (CV) = 16.8 ml) using an ethyl acetate gradient in hexane (50% EtOAc for 2 CV, then to 100% EtOAc in 15 CV and 100% EtOAc for 5 CV; flow rate = 30 ml / min) with elution at 12^14 CV. ST was obtained as an amorphous white solid (49% yield): Rf (ethyl acetate) 0.3. ^H (CDCl3 / MeOD) 3.99-3.88 (1H, m, H-3), 3.39 (broad t, 1H, H-6), 1.08 (3H, H- 20 19), 0.83 (3H, d, J = 6.6 Hz, H-21), 0.79-0.73 (9H, m, H-26, H-27, H-29), 0.6 (3H, s, H-18). MS (DCI / NH3) m / z: 449 (MH+), 431 (M+-H2O). Procedure for the chemical synthesis of OSDO - Compound of formula (IIa24^) ST (0.11 mmol) was dissolved in diethyl ether (22.5 ml), methanol (3.75 ml), and water (3.75 ml). N-bromosuccinimide (2.7 mmol; 25 eq) was added and the reaction mixture was stirred at 25 room temperature for 3 h. Diethyl ether (30 ml) was added and the organic layer was washed with brine. Then, the aqueous layer was washed with CHCl3. Organic layers were pooled, dried under MgSO4, and evaporated. The crude product was purified by flash chromatography on a silica column (12G; column volume (CV) = 16.8 ml) using an ethyl acetate in chloroform (30% EtOAc for 20 CV, then to 100% EtOAc in 5 CV and; flow rate = 30 ml / min) with an elution at 30 12 CV. OSDO was obtained as an amorphous white solid (63% yield). Rf [EtOAc] = 0.67; ^H95 (CDCl3) 3.89-3.78 (1H, m, H-3), 2.71 (t, J = 13.3 Hz, 1H, H-7), 0.84 (3H, d, J = 6.6 Hz, H-21), 0.79-0.72 (9H, m,H-26, H-27, H-29), 0.7 (3H, H-19), 0.57 (3H, s, H-18).; MS (DCI / NH3) m / z: 447.4 (MH+), 464.4 (M+NH4+). GC-MS analysis 5

[0168] Cells were plated in 100mm tissue culture plates at a density of 0.5x106cells per plate. Cells were allowed to adhere for 24 h and were treated by 5 µM 5,6-ES with or without 2.5 µM tamoxifen, or DDA. After a 48 h incubation, the cells were washed with PBS, trypsinized and counted. Cell suspension was centrifuged at 1200 rpm for 5 minutes at 4°C and lipid extraction was performed on cell pellet. 1 ml of methanol containing the internal standard [d7]5,6^-EC; 10 [d7]5,6^-EC, [d6]-CT and [d6]-OCDO (50 ng each) and 2 ml of chloroform were added. The suspensions were vortexed 30 s, 1ml of 8.8% aqueous KCl was added. After centrifugation at 2500 rpm for 5 minutes at 4°C, organic layers were collected and the solvent was evaporated under a stream of nitrogen. The residue was dissolved in 1 ml toluene and oxysterols were separated from cholesterol by solid phase extraction. Silica cartridges (100 mg), previously15 equilibrated with n-hexane, were loaded with toluene-dissolved samples. Cholesterol and non- cholesterol neutral sterols were eluted with 1% propan-2-ol in hexane before eluting cholesterol and phytosterol oxydes with 30% propan-2-ol in n-hexane. Solvent was evaporated under nitrogen and samples stored at -80°C before GC / MS analysis. Silylation of hydroxyl groups was performed at 60 °C after addition of a silylation reagent (pyridine: hexaméthyldisilazane: 20 triméthylchlorosilane (3 / 2 / 1, v / v / v) for 30 minutes. The TMSi-ethers were evaporated under a gentle stream of nitrogen and the residue was dissolved in 100 µl n-hexane. The same procedure was performed for all synthesized purified compounds for structural identification. Quantification of the above-described isolated cells TMSi-ethers was performed by gas chromatography- mass spectrometry in the selected ion monitoring mode using the 25 characteristic ions for the individual compounds. We used the ratios between the areas of corresponding oxysterols and the corresponding cholesterol derivatives internal standards [2H]- ^^^^-^^^ ^^^^-EC, -CT and -OCDO. The silylated oxysterols were separated Analyses wereperformed on an Agilent 7890A GC equipped with a G4513A series automatic liquid sampler and interfaced with an Agilent 5975C mass spectrometer (Agilent Technologies; Palo Alto, 30 CA). Separation was carried out on a 30 m capillary column (HP-5MS 30 m 0.25 mm ID, 0.25 mm thickness). Quantification of OS was carried out using the isotope dilution method (ref.19).96 Surface plasmon resonance (SPR) Assays. All binding studies based on SPR technology were performed on a BIAcore T200 optical biosensor instrument (GE Healthcare) as described in (ref. 2). Immobilization of the GST- tagged LBD of human GR (A15668) (from Thermo Fisher Scientific) was performed by 5 covalent coupling of the protein to the chip surface using amine coupling (CM5) sensor chips in PBS-P+ buffer (20 mM phosphate buffer, pH 7.4, 2.7 mM KCl, 137 mM NaCl, and 0.05% surfactant P20; GE Healthcare). All immobilization steps were performed at a flow rate of 10 ^l / min, with a final concentration of 20 ^g / mL. The total amount of immobilization was 11,000^ 12,000 RU. Channel Fc1 was used as a reference surface for nonspecific binding measurements. 10 A low mass weight-multiple-cycle kinetics analysis to determine affinity constants was carried out by injecting different concentrations of OSDO (6.25 ^M to 100 ^M) in PBS. Each sensorgram (expressed in RUs as a function of time in seconds) represents a differential response where the response on an empty reference channel (Fc1) was subtracted. Binding parameters were obtained by fitting the overlaid sensorgrams with the 1:1 Langmuir binding 15 model of the Biacore T200 Evaluation software v2.0 or the Steady State affinity model of the BIAevaluation software v3.1. Cell Proliferation assays

[0169] MCF7 (0.12 million), MDA-MB231 (0.10 million), MDA-MB468 (0.15 million) and 4T1 cells (0.08 million) were seeded in 6-well plates and in the appropriate complete medium 20 for 24 h. Then, cells were treated for the indicated time and in the appropriate medium supplemented with 5% FBS, with either the solvent vehicle (control), OCDO (1 µM), OCDO (1 µM) + OSDO (1 µM) or OSDO (1 µM). OSDO was added 30 minutes before OCDO. After 24 h, cells were trypsinized, washed and resuspended in PBS containing 0.4% trypan blue. Live cells were counted using a Malassez counting chamber. 25 Western blot

[0170] MCF7 (0.7 millions), MDA-MB231 (0.5 millions) and MDA-MB468 (0.7 millions) cells were seeded in 100 mm diameter dishes and cultured for 48 h in the appropriate complete medium. Then, cells (60% confluence) were treated for 8 h with the solvent vehicle (control), OCDO (1 µM), OCDO (1 µM) + OSDO (1 µM) or 1 µM OSDO (OSDO was added 30 minutes 30 before OCDO) in the appropriate complete medium without serum. At the end of the treatment, a gentle cell scraping on ice were performed twice. After centrifugation at 1200 rpm for 597 minutes at 4°C, the cells were lysed in 100 µl to 500 µl of RIPA buffer (Sigma R0278) supplemented with a cocktail of protease (Sigma P2850) and phosphatase inhibitors (Sigma P5726 and P0044). Cell lysates were centrifuged at 12000 rpm for 10 minutes at 4°C and protein dosage was performed with a Pierce BCA dosage Kit (ThermoFisher Scientific, 23225). 5 Proteins were separated on 10% (life Technologies, NP0315) or 4-12% (Life Technologies, NPO335) Bis-Tris polyacrylamide gel, electrotransferred onto polyvinylidene difluoride membranes (GE Healthcare, 10600023) activated in methanol. Membranes were incubated over-night at 4°C with the indicated primary antibodies as indicated diluted in TBS-Tween 5% BSA or Milk solution, washed and incubated with the secondary antibody for 1 h at 25°c. 10 Visualization was achieved with an Enhanced Chemiluminescence Plus kit (BIO-RAD, 1705061) and chemiluminescence was revealed with Pixi (Genesys) or Chemidoc (BIORAD) imaging systems. Quantification was performed with Image J software. In vivo studies

[0171] Six weeks old NMRI-Foxn1 nu / nu and Balb / c female mice (Janvier, France) were 15 maintained in specific pathogen-free conditions and were included in protocols only following ^^^^^^^ ^^^^^^^^^^^ ^^^ ^^ ^^^ ^^^^^^ ^^^^^^^^^^ ^^^ ^^^ ^^^^ ^^^ ^^^ ^^ ^^^^^^^^^^ ^^^^^^^were conducted according to the ethical guidelines of our institution and followed the general regulations governing animal experimentation. Exponentially growing MDA-MB231, MDA- MB468 or 4T1 cells were collected, washed twice in PBS and resuspended in PBS. MDA- 20 MB231 tumor cells (3 to 5 x 106in 200 µl PBS / matrigel, 1 / 1 volume), MDA-MB468 tumor cells (3 to 5 x 106in 200 µl PBS / matrigel, 1 / 1 volume) and 4T1 tumor cells (90000 cells in 100 µl PBS) were injected subcutaneously into the flank of mice. The mice were treated subcutaneously, one day after tumor cell transplantation, once a day, 5 days a week with the solvent vehicle (control), OSDO (16 µg / kg), OCDO (16 µg / kg) and OCDO (16 µg / kg) + OSDO 25 (16 µg / kg), as indicated. Mice were examined daily and body weights were measured twice per week. In all the experiments, the tumor volume was determined by direct measurement with a caliper and was calculated using the formula (width2× length) / 2. Statistical Analyses

[0172] Tumor growth curves in animals were analyzed for significance by two-way ANOVA30 ^^^^^^^^ ^^ ^ ^^^^^^^ ^^^^-test. Cell proliferation assays and gene reporter assays were98 analysed for significance by one-^^^ ^^^^^ ^^^^^^^^ ^^ ^ ^^^^^^^ ^^^^-test. Prism softwarewas used for all the analyses. Results 5 BC cells transform 5,6-epoxide of ^-sitosterol, i.e., compound of formula (IIb24^) into OSDO, i.e. compound of formula (IIa24^), a ^-sitosterol analogue of OCDO which binds to GR and antagonizes OCDO-induced tumorigenicity.

[0173] Regarding the structural homology between 5,6-ECs and 5,6-epoxides of ^-sitosterol (5,6-epoxy-sitostan-3^-ol, 5,6-ES, compound of formula IIb24^), we studied the possibility of 10 the transformation of 5,6^-ES in BC cells into sitostane-^^^^^^^^-triol (ST, compound of formula IIc24^) and 6-oxo-sitostan-^^^^^-diol +(OSDO, compound of formula IIa24^), by the enzymes ChEH and 11^-HSD2 that produce CT and OCDO respectively (ref. 2). We first chemically synthesized 5,6^-^^^ ^^ ^^^ ^^^^ ^^^^ ^-sitosterol according to previouslypublished procedure developed for the synthesis of OCDO from cholesterol (ref. 2, 7). We 15 incubated synthesized ^^^^-ES with TN and ER+ BC cells for 48 h in absence or presence of ChEH inhibitors. The incubation of ^^^^-ES with MDA-MB231 (Fig.1a) or MCF7 cells (Fig. 1b) generates ST and OSDO, identified by gas chromatography coupled to mass spectrometry (GC / MS) exactly as described previously (ref. 8)^ ^^^ ^^^^^^^^^ ^^^^ ^^^ ^^^^-^^^ ^^^^-ES, STand OSDO, were respectively 12.61, 12.76, 13.58 and 15.00 min. The quantifying ions were for20 ^^^^^ ^^^ ^^^^^ ^^^ ^^^^-^^ ^^^ ^^^^-ES, 546.4 and 456.3 for ST and 472.3 and 318.2 forOSDO. When ^^^^-ES was incubated with a ChEH inhibitor, tamoxifen or dendrogenin A (ref. 2,3), the transformation of 5,6^-ES into ST and OSDO was drastically inhibited in both cell lines (Fig.1a-b), indicating that 5,6^-ES is transformed into ST and then OSDO by the enzymes producing CT and OCDO respectively (ref. 2). As controls, we treated MDA-MB231 and25 ^^^^ ^^^^^ ^^^^ ^^^^-EC in absence or presence of tamoxifen or dendrogenin A and confirmed^^^^ ^^^^-EC transformation into CT and then OCDO was inhibited in both cell lines by ChEHinhibitors (Fig.1c-d). The evaluation of 5,6^-ES on TN and ER+ BC cell proliferation after 48 h of treatment showed that 5,6^-ES significantly inhibited OCDO-induced cell proliferation of both MDA-MB231 (Fig. 1e) and MCF7 cells (Fig. 1f). The study of the biologic activity of 30 OSDO in BC cells indicated that OSDO inhibited JNK phosphorylation stimulated by OCDO (Fig. 1g-h) and blocked the proliferation of different TN or ER+ BC cell lines promoted by99 OCDO as well as basal proliferation (Fig. 1i). Surface plasmon resonance (SPR) assays revealed that OSDO bound to the ligand-binding domain of GR (Fig.1j), indicating that OSDO is a ligand of GR as OCDO (ref.2). Together these data indicate that OSDO binds to GR and antagonizes JNK activation and mitogenicity stimulated by OCDO. 5

[0174] We then determined the impact of OSDO on the growth of human MDA-MB231and mouse 4T1 tumors grafted onto nude or Balb / c mice respectively. As shown in Fig.2a-b, OSDO significantly inhibited the growth of both tumors compared to control. In addition, OSDO significantly inhibited MDA-MB231 tumor proliferation induced by OCDO by 50 % (Fig.2c). We then determined the impact of OSDO on the growth of human MDA-MB468. OSDO10 significantly inhibited the growth of MDA-MB468 tumors compared to control and MDA- MB468 tumor proliferation induced by OCDO by 60 % (Fig.2d). References 1. Leon-Ferre, R. A., and Goetz, M. P. (2023) Advances in systemic therapies for triple 15 negative breast cancer. BMJ 381, e071674; doi: https: / / doi.org / 10.1136 / bmj-2022-071674 2. 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Tetrahedron, 2010 https: / / doi.org / 10.1016 / j.tet.2010.01.089 16. Minato et al J Org Chem, 1990 https: / / doi.org / 10.1021 / jo00289a066) 25 17. Poirot et al., Biochimie 2018 https: / / doi.org / 10.1016 / j.biochi.2018.04.008 (page 141 paragraphe 2.2) 18. Soules R, Noguer E, Iuliano L, Zerbinati C, Leignadier J, Rives A, de Medina P, Silvente- Poirot S, Poirot M. Chem Phys Lipids. 2017 Oct;207(Pt B):92-98. doi: 10.1016 / j.chemphyslip.2017.05.006. Epub 2017 May 26. PMID: 28554594 30 19. Segala et al., Biochem Pharmacol. 5,6-Epoxy-cholesterols contribute to the anticancer pharmacology of tamoxifen in breast cancer cells; 2013 Jul 1;86(1):175-89. doi: 10.1016 / j.bcp.2013.02.031. Epub 2013 Mar 7, PMID: 23500540101 20. ^^^^^^ ^^ ^^^^^^ ^^ ^^^^ ^^^^^^^^^ ^^^^^^^^^ ^^ ^^-^^^^^^^^^^^ ^^-steroids, Lipids volume39, pages805^809, 2004; DOI: 10.1007 / s11745-004-1300-9 21. J. 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Ramasseul R et al, Inversion of stereoselectivity in epoxidation of steroids by magnesium monoperoxyphthalate induced by manganese porphyrins; Journal of Molecular Catalysis Volume 63, Issue 2, 1 December 1990, Pages 167-17115 25. ^^ ^^ ^^^^^^^^^^ ^^ ^^^^ ^^^^^-Epoxidation of 3ß-Cholesteryl Acetate and its Analogues;Naturforsch.44b, 806 -810 (1989) 26. Synthèse de nouvelles métalloporphyrines halogénées : accès à de nouveaux catalyseurs biomimétiques d'oxydation ; PhD Thesis from Pascal Hoffman; https: / / www.theses.fr / 1991TOU30207 20

Claims

102 CLAIMS 1. A compound of formula (I):wherein R1 and R2 are defined according to a proviso selected from the group consisting 5 of (a), (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration; 10c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration,103 d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration;and wherein 5 A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single bond forming a moiety; D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a 10 moiety -CH2-CH2-; R3 is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3 and -CH=CH2, or is not present when R4 is =CH-CH3; R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; and wherein R3 and R4 are not both H, -OH, -CH3, -CH2-CH3 or -CH=CH2; 15 for use in a method of prevention and / or treatment of a cancer in a subject, preferably a human, overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^- hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor (GR); preferably the cancer overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) and glucocorticoid receptor 20 (GR) is selected from the group consisting of adrenal gland cancer, adrenocortical adenoma, acute myeloid leukemia, acute lymphoblastic leukemia, bladder cancer, bladder urothelial carcinoma, breast cancer, breast invasive carcinoma, cervix cancer, colon adenocarcinoma, colon cancer, intestine cancer, endometrium cancer, head and neck cancer, gastric cancer, esophageal cancer, esophageal carcinoma, kidney chromophobe, 25 liver cancer, liver hepatocellular carcinoma, lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, myeloid cancers, nasopharyngeal cancer, neural tumors,104 neuroblastoma, osteosarcoma, oral cavity cancer, ovarian cancer, ovarian serous cystadenocarcinoma, pituitary cancer, pancreatic cancer, pancreatic adenocarcinoma, prostate cancer, prostate adenocarcinoma, rectum adenocarcinoma, salivary gland cancer, stomach adenocarcinoma, testicular germ cell tumors, thyroid cancer, thyroid carcinoma, 5 tongue cancer, uterine cancer, uterine carcinosarcoma and uterine corpus endometrial carcinoma; being said breast invasive carcinoma, said liver cancer, said lung cancer, said ovarian cancer, and said pancreatic cancer, a primary tumor or a metastatic tumor; and more preferably being the cancer breast cancer, even more preferably ER+ breast cancer, triple negative breast cancer or invasive breast cancer a ER+ breast cancer, triple 10 negative breast cancer or invasive breast cancer.

2. A compound for use according to claim 1, wherein the compound of formula (I) is a compound of formulae (Ia):wherein A, B, C, D, E, R3and R4are as defined in claim 1. 15 3. The compound for use according to any of claims 1 or 2, wherein the compound of formula (I) is selected from the group consisting of formulae (IIa), (IIIa), (IVa), (Va),107 4. The compound for use according to any of claims 1 to 3, wherein the subject is selected with a method of detecting the presence of a cancer overexpressing cholesterol-5,6- epoxide hydrolase (ChEH) and / or expressing ^^^-hydroxysteroid dehydrogenase type 2 (HSD2) in said subject; preferably wherein said method of detecting a cancer 5 overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^- hydroxysteroid dehydrogenase type 2 (HSD2) is selected from the group consisting of biopsy, cytology, endoscopy and imaging.

5. The compound for use according to claim 4, wherein the method of detecting the cancer overexpressing cholesterol-5,6-epoxide hydrolase (ChEH) and / or expressing ^^^- 10 hydroxysteroid dehydrogenase type 2 (HSD2) in the subject comprises: - administering a18F-radiolabeled compound of formula (X):wherein: R3is H or OH; and R2, R4, R5, R6, R7and R12are independently selected from18F or 15 H; R8and R9are each OH or are linked to an oxygen atom forming together an epoxide; wherein, when R2is18F, then R3is OH and all R4, R5, R6, R7and R12are H; when R4is18F, then R8and R9are each OH and all R2, R3, R5, R6, R7and R12are H; 20 when R5is18F, then R3is OH and all R2, R4, R6, R7and R12are H; when R6is18F, then R3is OH and all R2, R4, R5, R7and R12are H; when R7is18F, then R3is OH and all R2, R4, R5, R6and R12are H; and when R12is18F, then R3is OH and all R2, R4, R5, R6and R7are H; and wherein at least one of R2, R4, R5, R6, R7and R12is a18F;108 or a composition comprising the same to the subject; - subjecting the subject to a positron emission tomography (PET) scanner; and - collecting the positron emission tomography (PET) signal.

6. A compound of formula (Ia): 5wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single bond forming a moiety; 10 D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-; R3 is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3 and -CH=CH2, or is not present when R4is =CH-CH3; 15 R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; and wherein R3 and R4 are not both H, -OH, -CH3, -CH2-CH3 or -CH=CH2; for use in a method of prevention and / or treatment of a cancer in a subject, preferably a human, expressing glucocorticoid receptor (GR); preferably the cancer expressing glucocorticoid receptor (GR) is selected from the group 20 consisting of adrenal gland cancer, acute myeloid leukemia, bladder cancer, breast cancer, colon cancer, esophageal cancer, liver cancer, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, rectum cancer, renal cancer, renal carcinoma, renal chromophobe carcinoma, renal papillary cancer, skin cancer,109 stomach cancer, testicular cancer, thyroid cancer, uterine carcinosarcoma and uterine corpus endometrial carcinoma; and more preferably being the cancer breast cancer, even more preferably ER+ breast cancer, triple negative breast cancer or invasive breast cancer a ER+ breast cancer, triple 5 negative breast cancer or invasive breast cancer.

7. The compound for use according to any of claims 1 to 6, wherein the compound of formula (I) is administered prior to, together with, or subsequent to at least one further therapeutic agent selected from the group consisting of a hormone therapy, a CDK4 / 6 inhibitor, a Src inhibitor, a chemotherapeutic agent, and a therapeutic agent targeting oncosterone 10 biosynthesis or biogenesis.

8. A compound of formula (I):wherein R1 and R2 are defined according to a proviso selected from the group consisting of (a), (b), (c) and (d):15 -stereochemical configuration and R2 is an oxo group =O;b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration;110c) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration,5 and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a^-stereochemical configuration;and wherein 10 A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a single bond forming a moiety, D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a 15 moiety -CH2-CH2-; R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and -CH=CH2, or is not present when R4 is =CH-CH3; R4 is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3 and -CH=CH2; and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2; 20 with the provisos that111 when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, D and E are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-, R3 is H, -CH2-CH3 or -CH3, and R4 is H, -CH2-CH3 or -CH3, wherein R3 and R4 are not both H, -CH3 or 5 -CH2-CH3; then R1and R2are defined according to the proviso (a) or (d); and when A and B are respectively a group -CH2- and a group -CH- and are linked together by a single bond forming a moiety, D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, R3 is H, -CH2-CH3 or -CH3, and R4is H, -CH2-CH3or -CH3,wherein R3and R4are not both H, -CH3or -CH2-CH3; 10 then R1and R2are defined according to the proviso (a) or (d).

9. The compound according to claim 8, wherein R1 and R2 are defined according to proviso (a), and the compound of formula (I) has formula (Ia):

10. The compound according to any of claims 8 or 9, wherein D and E are each a group -CH2- 15 and are linked together by a single bond forming a moiety -CH2-CH2-.

11. The compound of formula (Ia) according to any of claims 8 to 10, selected from the group consisting of compounds of formulae (IIa), (IIIa), (IVa), (Va), and (IXa):11312. A pharmaceutical composition comprising a compound of formula (I) according to any of claims 8 to 11. 5 13. The pharmaceutical composition according to claim 12, further comprising at least one further therapeutic agent selected from the group consisting of a hormone therapy, a CDK4 / 6 inhibitor, a Src inhibitor, a chemotherapeutic agent and a therapeutic agent targeting oncosterone biosynthesis or biogenesis.

14. A compound of formula (I) according to any of claims 8 to 11, or a pharmaceutical 10 composition according to any of any of claims 12 or 13, for use in a method of prevention and / or treatment of a disease in a subject, preferably a human.

15. A nutraceutical composition comprising a compound of formula (I):wherein R1 and R2 are defined according to a proviso selected from the group consisting 15 of (a), (b), (c) and (d): a) R1 ^^ ^^ ^^^^ ^-stereochemical configuration and R2 is an oxo group =O;114b) R1 and R2 ^^^ ^^^^^^ ^^ ^^ ^^^^^^ ^^^^ ^^^^^^^ ^^^^^^^^ ^^ ^^^^^^^ ^^^^ ^^ ^- or a^-stereochemical configuration; (b) 5^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with aal configuration,(c) and d) R1 is a -^^ ^^^^^ ^^^^ ^-stereochemical configuration and R2 is an OH with a10 ^-stereochemical configuration;and wherein A and B are respectively -CH- and -C- and are linked together by a double bond forming a moiety, or are respectively -CH2- and -CH- and are linked together by a 15 single bond forming a moiety; D and E are each a group -CH- and are linked together by a double bond forming a moiety -CH=CH-, or are each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-;115 R3is either present and is selected from the group consisting of H, -OH, -CH3, -CH2-CH3and -CH=CH2, or is not present when R4 is =CH-CH3; R4is selected from the group consisting of H, -OH, -CH3, -CH2-CH3, =CH-CH3and -CH=CH2; and wherein R3and R4are not both H, -OH, -CH3, -CH2-CH3or -CH=CH2; 5 and at least one nutraceutically acceptable excipient.

16. The nutraceutical composition according to claim 15, wherein R1 and R2 are defined according to proviso (a), and the compound of formula (I) has formula (Ia):

17. The nutraceutical composition according to any of claims 15 or 16, wherein D and E are 10 each a group -CH2- and are linked together by a single bond forming a moiety -CH2-CH2-.

18. The nutraceutical composition according to any of claims 15 to 17, selected from the group consisting of compounds of formulae (IIa), (IIIa), (IVa), (Va), and (IXa):

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