Vitamin d receptor antagonists and uses thereof

Abstract

Compound having the following formula (I), wherein the groups R1 and R2 represent independently a functional group selected among a hydrogen and an aliphatic chain; R3 represents a functional group selected among a hydrogen and a methyl; - R5 represents a functional group selected among a hydrogen, a methyl and a methylene; - R6 represents a functional group selected among a hydrogen, methyl, methylene, ethyl and a ethylene; and - wherein the group Q is a carborane substituent having the following molecular formula : C2B10H11R7; wherein R7 represents a functional group selected among a hydrogen and an aliphatic chain; or a pharmaceutical acceptable derivative thereof, for use as a medicament.

Description

[0001] VITAMIN D RECEPTOR ANTAGONISTS AND USES THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to vitamin D receptor antagonists developed to treat all diseases characterized by a pathological excess of vitamin D (hypervitaminosis D) and more specifically to treat hypercalcemia or hypercalciuria, and uses thereof.

[0004] In what follows, the numbers between brackets ([ ]) refer to the list of references provided at the end of the description.

[0005] BACKGROUND OF THE INVENTION

[0006] Calcium homeostasis requires a tight regulation involving parathyroid glands (PTG), intestine, kidney and bones. It is mainly regulated by two natural hormones, the parathyroid hormone (PTH) and the bioactive form of vitamin D3 (1.25D3 ) [1].

[0007] Hypercalcemia together with low / suppressed PTH levels originate from abnormally high 1 ,25D3 levels (hypervitaminosis D) of various etiology, i.e excessive intake, granulomateous diseases and genetic defects. In these patients, hypercalcemia leads to hypercalciuria, nephrocalcinosis and / or renal dysfunctions [2], Hypercalcemia may occur in several rare genetic diseases. Williams Beuren syndrome, for example, is a rare disease with an estimated incidence of 1 / 20,000 births. Hypercalcemia of the newborn is present in 15% of cases and usually disappears during childhood, but abnormalities in calcium and vitamin D metabolism may persist. In adulthood, hypercalcemia can lead to calcium deposits in the kidneys (nephrocalcinosis) which, can affect kidney function.

[0008] Hypercalcemia and / or hypercalciuria can be reduced by diuretics in combination with limiting calcium and vitamin D3 intake. In severe cases, treatments based on bisphosphonates, ketoconazole or glucocorticoids are required to decrease bone resorption and intestinal calcium absorption. However, these treatments do not have sustained effects, and impact dramatically the development of children and the quality of life of patients. Moreover, no selective therapy targeting 1.25D3 signaling is currently available.

[0009] Although high levels of vitamin D are generally not considered dangerous, the hypercalcemia that results can become severe and represents a market of interest. The vitamin D receptor (VDR) is a nuclear hormone receptor activated endogenously by 1 ,25D3, which regulates the transcription of VDR target genes. Although VDR is ubiquitously present, it plays key roles in tissues involved in calcium and phosphate homeostasis (intestine, bone, kidney and parathyroid glands). Hypercalcemia secondary to hypervitaminosis D can be severe and require hospitalization.

[0010] Reference [3] describes a study of the role of VDR in hypercalcemia. VDR ligands have been developed but they suffer of some drawbacks, particularly as they do not demonstrate antagonist effect as required, taking into account they exhibit partial agonistic activities and / or because the VDR binding affinity is far too low. To better illustrate these VDR ligands the following publications can be cited: [3-15] and

[0025] .

[0011] Accordingly, there is a need for new and effective VDR antagonists to treat hypercalcemia or hypercalciuria associated with high vitamin D levels.

[0012] BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 represents the docked structures of 1.1 , I.2, and I.3 into human VDR (hVDR) Ligand Binding Domain (LBD). Distances are shown in A (BO is 1.1 ; BM is 1.2 ; BP is 1.3).

[0014] FIG. 2 represents the competitive binding of 1 ,25D3, 1.1 , I.2, and 1.3 to the full-length human VDR (hVDR). IC50 values are obtained from dose-response curves (10-11 to 10-6 M) and represent the concentration required to displace 50% of the 1.25D3 binding (BO is 1.1 ; BM is I.2 ; BP is I.3).

[0015] FIG. 3 represents the structural accommodation of 1.1 in the zebrafish VDR (zVDR) ligand binding pocket. (A) Hydrogen bond interactions (dashed lines) between 1 ,25D3 (top) or 1.1 (bottom) and VDR. (B) Conformational changes of His423 and His333 side chain upon 1.1 binding (black) compared to VDR-1 ,25D3 (grey) (BO is 1.1 ).

[0016] FIG. 4 represents the carborane-based 1 ,25D3 analog activities in rat intestinal epithelial IEC-18 cells. Cyp24a1 transcript levels in IEC-18 cells treated for 6 h with vehicle, 100 nM 1 ,25D3, 100 nM C1 , or 1 pM 1.1 , I.2, or I.3 . n = 3 independent biological replicates / condition. Data are represented as mean + s.e.m. * p < 0.05 vs. vehicle, one-way ANOVA (BO is 1.1 ; BM is I.2 ; BP is I.3).

[0017] Besides, similar studies for other VDR target genes are reported : for Atp2b1, S100g.

[0018] FIG. 5 represents the carborane-based 1 ,25D3 analog activities in rat intestinal epithelial IEC-18 cells. Cyp24a1 transcript levels in IEC-18 cells treated for 6 h with vehicle, 1 pM 1.1 , 1.2, or 1.3 in the presence of 100 nM 1 ,25D3. n = 3 independent biological replicates / condition. Data are represented as mean + s.e.m. * p < 0.05 vs. vehicle. $ p < 0.05 vs. 1.25D3. one-way ANOVA (BO is 1.1 ; BM is I.2 ; BP is I.3).

[0019] Besides, similar studies for other VDR target genes are reported : for Atp2b1 and S100g. FIG. 6 represents the effects of 1.1, I.2, and 1.3 on mice. Serum calcium levels (A) and body weight (B) of CD-1 mice (n=5 per group) after intraperitoneal (i.p) administration of 1 ,25D3, 1.1 , 1.2, or 1.3 (0.5 pg / kg body weight, dissolved in sesame oil) every other day for three weeks. C. 10 week-old C57BI / 6 mice are daily treated per os for 4 days with 1 pg / kg 1.1, 1.2, or I.3 in the presence of 1 pg / kg 1.25D3 or vehicle, and serum calcium levels are determined 24 h after the last administration. Data are expressed as mean + SEM. ns: p >= 0.05, * p < 0.05 vs. 1.25D3 (BO is 1.1 ; BM is I.2 ; BP is I.3). FIG. 7 represents the effects of 1.1 in a mouse model of idiopathic infantile hypercalcemia (Cyp24a1-null mice). Serum calcium levels in 7-10 weeks old Cyp24a1-null mice treated every other day with vehicle (-), 0.05 or 0.5 pg / kg 1.1. for 1 month. Data are expressed as mean + SEM. * p < 0.05 vs. vehicle. (BO is 1.1). The area between the dotted lines represents the range of serum calcium levels in wild type mice.

[0020] DEFINITIONS

[0021] The term “cholecalciferol” refers herein to vitamin D which is produced from cholesterol in the skin upon sun exposure.

[0022] The term “1 [alpha], 25-dihydroxycholecalciferol” is also named 1,25D3 or calcitriol and refers to the following molecule: and is produced by successive hydroxylation of cholecalciferol at C1 and C25 atoms.

[0023] It is understood that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, carbon and heteroatom substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment and prevention of disorders. Examples of substituents include, but are not limited to aliphatic; heteroaliphatic; alicyclic; heteroalicyclic; aromatic, heteroaromatic; aryl; heteroaryl; alkylaryl; alkyl heteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;

[0024] NRG2SO2NRG3-, or -SO2NRG2-, wherein each occurrence of RG1, RG2and RG3independently includes, but is not limited to, hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, or alkyl heteroaryl moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0025] The term “stable”, as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein. The term "stability" can refer to an ability to resist degradation, to persist in a given environment, and / or to maintain a particular structure.

[0026] The term “aliphatic”, as used herein, includes both saturated and unsaturated, straight chain ( / .e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties. Thus, as used herein, the term “alkyl” includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like. Furthermore, as used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the like encompass both substituted and unsubstituted groups.

[0027] The term “alkyl” includes also “cycloalkyl”. The term “cycloalkyl”, as used herein, refers for example to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of aliphatic, heteroaliphatic or heterocyclic moieties, may optionally be substituted. An analogous convention applies to other generic terms such as “cycloalkenyl”, “cycloal kynyl” and the like.

[0028] Illustrative aliphatic groups for straight and branched alkyl groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-l-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.

[0029] The term “alicyclic”, as used herein, refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to cyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “alicyclic” is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups. Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CEh-cyclopropyl, cyclobutyl, -CHj-cyclobutyl, cyclopentyl, -CH2- cyclopentyl-n, cyclohexyl, -CFh-cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.

[0030] The term “heteroaliphatic” refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom. Thus, a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, / .e., in place of carbon atoms.

[0031] The term “heteroalicyclic”, “heterocycloalkyl” or “heterocyclic”, refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include but are not limited to saturated and unsaturated mono- or polycyclic heterocycles such as morpholino, pyrrolidinyl, furanyl, thiofuranyl, pyrrolyl etc., which are optionally substituted with one or more functional groups, as defined herein. In certain embodiments, the term “heterocyclic” refers to a non-aromatic 5-, 6- or 7- membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds and each 6- membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl , imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl , isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0032] In general, the term “aromatic moiety”, as used herein, refers to stable substituted or unsubstituted unsaturated mono- or polycyclic hydrocarbon moieties having preferably 3- 14 carbon atoms, comprising at least one ring satisfying the Huckel rule for aromaticity. Examples of aromatic moieties include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, phenanthryl and anthracyl. In general, the term “heteroaromatic moiety”, as used herein, refers to stable substituted or unsubstituted unsaturated mono-heterocyclic or polyheterocyclic moieties having preferably 3-14 carbon atoms, comprising at least one ring satisfying the Huckel rule for aromaticity. Examples of heteroaromatic moieties include, but are not limited to, pyridyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, quinazolinyl, dihydroquinazolyl, and tetrahydroquinazolyl.

[0033] It will also be appreciated that aromatic and heteroaromatic moieties, as defined herein, may be attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety and thus also include moieties such as -(aliphatic)aromatic, -(heteroaliphatic)aromatic, - (aliphatic)heteroaromatic, -(heteroaliphatic)heteroaromatic, -(alkyl)aromatic, (heteroalkyl)aromatic, -(alkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the phrases “aromatic or heteroaromatic moieties” and “aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic” are interchangeable. Substituents include, but are not limited to, any of the previously mentioned substituents resulting in the formation of a stable compound.

[0034] In general, the term “aryl” refers to aromatic moieties, as described above, excluding those attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety. In certain embodiments of the present invention, “aryl” refers to a mono- or bicyclic carbocyclic ring system having one or two rings satisfying the Huckel rule for aromaticity, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

[0035] Similarly, the term “heteroaryl” refers to heteroaromatic moieties, as described above, excluding those attached via an aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety. In certain embodiments of the present invention, the term “heteroaryl”, as used herein, refers to a cyclic unsaturated radical having from about five to about ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl , quinolinyl, isoquinolinyl, and the like.

[0036] Substituents for aryl and heteroaryl moieties include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.

[0037] In certain embodiments, the aliphatic group contains about 1-12 aliphatic carbon atoms. In certain other embodiments, the aliphatic group contains about 6-10 aliphatic carbon atoms. In yet other embodiments, the aliphatic group contains about 4-10 aliphatic carbon atoms.

[0038] The terms “alkoxy” (or “alkyloxy”), and “thioalkyl” refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom (“alkoxy”) or through a sulfur atom (“thioalkyl”). Examples of alkoxy groups, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n- hexoxy. Examples of thioalkyl groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0039] The terms “hydroxyl” as used herein refers to a group having the structure -OH, and the term " hydroxyl protecting group", as used herein, unless otherwise indicated, refers to a substituent that is commonly employed to block or protect a hydroxyl on the compound thereby protecting its functionality while allowing for the reaction of other functional groups on the compound. Non-exclusive examples of an hydroxyl protecting group include: acyl groups (e.g., formyl, acetyl, chloroacetyl, trichloroacetyl, O- nitrophenylacetyl, O-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, O-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl, and the like), acyloxy groups (e.g., 1 -tert-butyloxycarbonyl (Boc), methoxycarbonyl, 9- fluorenyl-methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1 ,1 -dimethyl-propynyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, and the like), diphenylmethane, silyl ether (e.g., tert-butyldimethylsilyl ether, abbreviated by “TBS”) and benzylcarbamates. An “hydroxyl group deprotection” as used herein refers to the chemical reaction involving a deprocting agent in order to remove the substituent that had been precedently used to protect the hydroxyl.

[0040] The term “amine” refers to a group having the structure -N(R)2wherein each occurrence of R is independently hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or the R groups, taken together, may form a heterocyclic moiety. The term “alkylamino” refers to a group having the structure -NHR’ wherein R’ is alkyl, as defined herein. The term “aminoalkyl” refers to a group having the structure NH2R’-, wherein R’ is alkyl, as defined herein. In certain embodiments, the alkyl group contains about 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains about 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains about 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, isopropylamino and the like. "Amine protecting group", as used herein, unless otherwise indicated, refers to a substituent that is commonly employed to block or protect an amine on the compound thereby protecting its functionality while allowing for the reaction of other functional groups on the compound. Non-exclusive examples of an amine-protecting group include: acyl groups (e.g., formyl, acetyl, chloroacetyl, trichloroacetyl, O-nitrophenylacetyl,O- nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, O- nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl, and the like), acyloxy groups (e.g., 1 -tert-butyloxycarbonyl (Boc), methoxycarbonyl, 9-fluorenyl- methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1 ,1 -dimethyl-propynyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, and the like), diphenylmethane, and benzylcarbamates.

[0041] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.

[0042] The term “halogenated” denotes a moiety having one, two, or three halogen atoms attached thereto.

[0043] The term “haloalkyl” denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

[0044] The term “acyloxy”, as used herein, does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure -OC(O)Rx, wherein Rxis a substituted or unsubstituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.

[0045] The term “acyl”, as used herein, does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure -C(O)Rx, wherein Rxis a substituted or unsubstituted, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.

[0046] The term “imino”, as used herein, does not substantially differ from the common meaning of this term in the art, and refers to a moiety of structure -C(=NRX)RY, wherein Rxis hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and Ry is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.

[0047] "Sulfonate leaving group", as used herein, unless otherwise indicated, refers to anions with the general formula RSO2O-. Non limiting examples of a sulfonate leaving group include: mesylate (R=CH3), triflate (R=CF3), tosylate (R=CH3C6H4, abbreviated by “Ts”) such as para-tosylate (p-Ts), besylate (R=C6H5), tresylate (R=CH2CF3), and the like. The term “Ci-galkylene”, as used herein, refers to a substituted or unsubstituted, linear or branched saturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms, having a free valence at both ends of the radical. The term “Cp-salkenylene”, as used herein, refers to a substituted or unsubstituted, linear or branched unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to six carbon atoms, having a free valence at both ends of the radical, and wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule.

[0048] As used herein, the terms “aliphatic”, “heteroaliphatic”, “alkyl”, “alkenyl”, “alkynyl”, “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms “alicyclic”, “heterocyclic”, “heterocycloalkyl”, “heterocycle” and the like encompass substituted and unsubstituted, and saturated and unsaturated groups. Additionally, the terms “cycloalkyl”, “cycloalkenyl”, “cycloalkynyl”, “heterocycloalkyl”, “heterocycloalkenyl”, “heterocycloalkynyl”, “aromatic”, “heteroaromatic”, “aryl”, “heteroaryl” and the like, used alone or as part of a larger moiety, encompass both substituted and unsubstituted groups.

[0049] As used herein, the term "carborane", refers to electron-delocalized (non-classically bonded) clusters composed of boron, carbon and hydrogen atoms, as reported in

[0016] . Like many of the related boron hydrides, these clusters are polyhedra or fragments of polyhedra. Carboranes are one class of heteroboranes (see

[0017] ). The electronic structure of these cluster compounds can be described by the Wade-Mingos rules. Like the related boron hydrides, these clusters are polyhedra or fragments of polyhedra, and are similarly classified as c / oso-, nido-, arachno-, hypho-, etc., based on whether they represent a complete (c / oso-) polyhedron or a polyhedron that is missing one (nido-), two (arachno-), three (hypho-), or more vertices. In terms of scope, carboranes can have as few as 5 and as many as 14 atoms in the cage framework. The majority have two cage carbon atoms. Corresponding C-alkyl and B-alkyl analogues are also known in a few cases up to date. The terms “carboranyl” and “carboranic units”, as used herein, refers to a radical corresponding to the carborane structure in which a hydrogen is withdrawn. For a carborane comprising 2 carbone atomes the relative position in between these 2 carbons is identified thanks to the prefix: ortho-, metha- and para- providing the possible name for a radical depending of the relative position in betweens its 2 carbon atoms: ortho-, metha- and para-carboranic units. The term “carborane substituent” refers to a “carboranic units” comprising 2 carbon atoms in which the second remaining hydrogen can be replaced by any organic or inorganic moiety. As used herein, the term "isolated", when applied to a compound or a RNA strand, refers to such compound or RNA strand that are (i) separated from at least some components with which they are associated in nature or when they are made and / or (ii) produced, prepared or manufactured by the hand of man.

[0050] The phrase, “pharmaceutically acceptable derivative”, as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others prodrugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety that is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.

[0051] As used herein, the term "hypercalcemia" refers to a high calcium (Ca2+) level in the serum. The normal range is 2.1-2.6 mmol / L (8.8-10.7 mg / dL, 4.3-5.2 mEq / L), with levels greater than 2.6 mmol / L defined as hypercalcemia. Hypercalcemia together with low / suppressed PTH levels originate from abnormally high 1 [alpha], 25- dihydroxycholecalciferol levels (hypervitaminosis D) of various etiology [e.g. vitamin D 24-hydroxylase (CYP24A1) loss-of-function mutations, also known as “idiopathic infantile hypercalcemia” (IIH)]. In these patients, hypercalcemia leads to hypercalciuria, nephrocalcinosis and / or renal dysfunctions.

[0052] More specifically, a subject with hypercalcemia and / or hypercalciuria together with low or suppressed parathyroid hormone (PTH) levels is a subject with:

[0053] - Vitamin D intoxication

[0054] - Autosomal recessive hypercalcemia

[0055] - Acute disorders associated with dysregulated synthesis of 1 ,25D3 (e.g. subcutaneous fat necrosis), or

[0056] - Genetic diseases associated with dysregulated synthesis or clearance of 25D3, such as:

[0057] - Inborn errors of vitamin D metabolism [e.g. 24-hydroxylase deficiency (CYP24A1 variants)],

[0058] - Phosphate tubular reabsorption defects (e.g. SLC34A1 and / or SLC34A3 variants), - Tubulopathy,

[0059] - Williams syndrome, or

[0060] - Blau syndrome,

[0061] - Idiopathic hypercalcitriolemia,

[0062] - Acquired diseases associated with dysregulated synthesis of 1 ,25D3, such as:

[0063] - Infectious disorders: Tuberculosis, Leprosy, Candidiasis, Cryptococcosis, Histoplasmosis, Coccidiodmycosis, AIDS-related pneumocystis, Cat-scratch fever, or Mycobacterium avium infection,

[0064] - Noninfectious disorders: Sarcoidosis, Silicone-induced granulomatosis, Langerhans cell histiocyosis, Wegener’s granulomatosis, Berylliosis, Lipoid pneumonia, Talc granulomatosis, Infantile fat necrosis, Slack skin disease, Giant cell polymyositis, or Crohn’s disease, or

[0065] - Neoplastic: Hodgkin’s disease, Non-Hodgkin’s lymphoma, Plasma cell granuloma, Dysgerminoma, or Seminoma.

[0066] The most common complication of “subcutaneous fat necrosis” is hypercalcemia. This can be detected on a blood test, so babies with subcutaneous fat necrosis have their blood calcium checked periodically generally for the first months of life. Treatment of subcutaneous fat necrosis focusses on management of hypercalcemia, if it occurs. According to a particular embodiment, the treatment of subcutaneous fat necrosis according to the invention includes the treatment of at least one hypercalcemia period of a subject affected by subcutaneous fat necrosis.

[0067] The term "hypercalciuria" herein refers to a subject with urinary calcium levels higher than 4 mg / kg body weight or 0.1 mmol / kg body weight / 24-hour or a urinary calcium (mg / mL) / creatinine (mg / mL) ratio higher than 0.2. Chronic hypercalciuria is a sign of renal function, nephrocalcinosis, and chronic kidney disease. Patients with hypercalciuria have kidneys that excrete higher levels of calcium than normal, for which there are many possible causes.

[0068] "Therapeutically effective amount" refers to an amount of formulation, composition, or reagent in a pharmaceutically acceptable carrier or a physiologically acceptable salt of an active compound that is of sufficient quantity to ameliorate the undesirable state of the patient, animal, material, or object so treated. "Ameliorate" refers to a lessening of the detrimental effect of the disease state or disorder, in the receiver of the treatment.

[0069] "Pharmaceutical agent or drug" refers to a chemical compound or composition capable of inducing a desired therapeutic or prophylactic effect when properly administered to a subject.

[0070] BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound having the following formula I :

[0071] - wherein the groups Ri and R2represent independently a functional group selected among a hydrogen and an aliphatic chain being at least selected among one of the following: linear, branched, cyclic, substituted and unsubstituted chain; the aliphatic chain being selected among Ci-i2alkyl; C2-i2alkenyl; C2-i2alkynyl; Ci- i2heteroalkyl; C2-i2heteroalkenyl; C2.i2heteroalkynyl; Ce-waryl and C4-wheteroaryl group; each of the foregoing alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroal kynyl, aryl and heteroaryl group, optionally bearing one or more substituents comprising at least one of the atom or function selected from -F; -Cl; - Br; -I; -NO2; -CN; -CF3; -OH ; -O-; -S-; -C(=O)-; -S(=O)-; -SO2-; -SO2; -C(=O)O- and -C(=O)N-; preferably a hydrogen;

[0072] - R3 represents a functional group selected among a hydrogen and a methyl; preferably a hydrogen;

[0073] - R5 represents a functional group selected among a hydrogen, a methyl and a methylene; preferably a methylene;

[0074] - Re represents a functional group selected among a hydrogen, methyl, methylene, ethyl and a ethylene; preferably a hydrogen; and

[0075] - wherein the group Q is a carborane substituent having the following molecular formula : C2B10H11R7; wherein R7 represents a functional group selected among a hydrogen and an aliphatic chain being at least selected among one of the following: linear, branched, cyclic, substituted and unsubstituted chain; the aliphatic chain being selected among Ci.^alkyl; C2-i2alkenyl; C2-i2alkynyl; Ci-i2heteroalkyl; C2- i2heteroalkenyl; C2-i2heteroalkynyl; Ce-waryl and C4-wheteroaryl group; each of the foregoing alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl and heteroaryl group, optionally bearing one or more substituents comprising at least one of the atom or function selected from -F; -Cl; -Br; -I; -NO2; -CN; -CF3; -OH ; -O-;

[0076] -S-; -C(=O)-; -S(=O)-; -SO2-; -SO2; -C(=O)O- and -C(=O)N-;. and preferably a hydrogen; or a pharmaceutical acceptable derivative thereof, for use as a medicament.

[0077] The dotted double bond of the compounds according to formula I means that I is composed of the following compounds of formula la and lb :

[0078] Advantageously, in the compound according to formula I, the group Q is selected among one of the following groups numbered from II to IV, for use as a medicament: , and preferably the group Q is the substituent II.

[0079] Advantageously, the compound according to the present invention is selected among one of the following compounds of formula 1.1 ; I.2 and I.3 , for use as a medicament: The compounds described precedingly in the context of the present invention or a pharmaceutical acceptable derivative thereof, are advantageously for use in the treatment of a disease involving hypercalcemia, hypercalciuria and / or cancer; and preferably for their use in the treatment of a disease involving hypercalcemia and / or hypercalciuria. The preparation of the carborane compound of formula (I) as precedently described in the context of the invention can be prepared according to the following process

[0026] , wherein the carborane compound is prepared according to a two-step procedure starting from the following molecule according to formula (V): Advantageously, in said process the first step involves a carboranyl metal selected from one of the followings molecules numbered from (VI) to (VIII) :

[0080] (VI) (VII) (VIII) wherein M is a metal preferably selected from an alkali metal, and preferably M is Li.

[0081] Advantageously, in this process the second step is a hydroxyl group deprotection.

[0082] The compound described in the context of the present invention or a pharmaceutical acceptable derivative thereof, is advantageously for use in the treatment of hypercalcemia disorders of a subject presenting acute or chronic hypercalcemia.

[0083] Said compound of the invention or a pharmaceutical acceptable derivative thereof, is advantageously for use in the treatment of acute or chronic hypercalciuria

[0084] Said compound of the invention or a pharmaceutical acceptable derivative thereof, is advantageously for use in the treatment of hypercalcemia disorders of a subject presenting acute or chronic hypercalcemia and / or chronic hypercalciuria together with low parathyroid hormone (abbreviated by “PTH”) levels.

[0085] Said compound of the invention or a pharmaceutical acceptable derivative thereof, is advantageously for use in the treatment of a subject suffering from at least one of the following among subcutaneous fat necrosis ; idiopathic infantile hypercalcemia ; and Williams syndrome.

[0086] Advantageaously, said compound is for use in the treatment of a subject with hypercalcemia and / or hypercalciuria together with low or suppressed parathyroid hormone (PTH) levels is a subject with:

[0087] - Autosomal recessive hypercalcemia

[0088] - Acute disorders associated with dysregulated synthesis of 1 ,25D3 (e.g. subcutaneous fat necrosis), or Genetic diseases associated with dysregulated synthesis or clearance of 25D3, such as:

[0089] - Inborn errors of vitamin D metabolism [e.g. 24-hydroxylase deficiency (CYP24A1 variants)],

[0090] - Phosphate tubular reabsorption defects (e.g. SLC34A1 and / or SLC34A3 variants),

[0091] - Tubulopathy,

[0092] - Williams syndrome, or

[0093] - Blau syndrome,

[0094] - Idiopathic hypercalcitriolemia,

[0095] - Acquired diseases associated with dysregulated synthesis of 1 ,25D3, such as:

[0096] - Infectious disorders: Tuberculosis, Leprosy, Candidiasis, Cryptococcosis, Histoplasmosis, Coccidiodmycosis, AIDS-related pneumocystis, Cat-scratch fever, or Mycobacterium avium infection,

[0097] - Noninfectious disorders: Sarcoidosis, Silicone-induced granulomatosis, Langerhans cell histiocyosis, Wegener’s granulomatosis, Berylliosis, Lipoid pneumonia, Talc granulomatosis, Infantile fat necrosis, Slack skin disease, Giant cell polymyositis, or Crohn’s disease, or

[0098] - Neoplastic: Hodgkin’s disease, Non-Hodgkin’s lymphoma, Plasma cell granuloma, Dysgerminoma, or Seminoma.

[0099] Said compound of the invention or a pharmaceutical acceptable derivative thereof, is advantageously for performing the function of reducing the transcript levels of vitamin D receptor (abbreviated by “VDR”) target genes induced by 1a, 25-dihydroxycholecalciferol (abbreviated by “1 ,25D3”) ; preferably with the ability to at least halve the transcript levels induced by 1 ,25D3 ; preferably said compound is evaluated within the range from 10“11to 10’6M.

[0100] Said compound of the invention or a pharmaceutical acceptable derivative thereof, is advantageously for use as a vitamin D receptor antagonist, preferably the VDR is a human vitamin D receptor (abbreviated by “hVDR”).

[0101] Said compound of the invention or a pharmaceutical acceptable derivative thereof, has advantageously an IC50 for the VDR, preferably for the hVDR, equal to 2 x 108or lower, said compounds being evaluated within the range from 10“11to 10“6M.

[0102] Said compound of the invention or a pharmaceutical acceptable derivative thereof, does not exhibit VDR agonist effects, preferably the compound engages a sole weak hydrogen bond with His423 of the zebrafish VDR, preferably the binding to hVDR is evaluated using a 1 ,25D3 assay fluorescence polarization kit (FP)-based competition, preferably the polarscreen Vitamin D receptor competitor assay in vitrogen, under manufacturer conditions and said compounds is evaluated within the range from 10“11to 10“6M.

[0103] Said compound of the invention or a pharmaceutical acceptable derivative thereof, is advantageously for use in the treatment of mice.

[0104] The present invention relates also to a non-therapeutic use of compound as precedently described in the context of the invention, or a pharmaceutical acceptable derivative thereof, in a non-human mammal, preferably the mouse, in a healthy subject not suffering from any syndrome or condition, in particular not suffering from hypercalcemia or hypercalciuria.

[0105] Besides, the present invention relates to a therapeutic method involving any of the compounds precedently presented within the scope of the present invention or a pharmaceutical acceptable derivative thereof, preferably for use in the treatment of a subject suffering of any affection as precedently presented within the context of the present invention.

[0106] Besides, the present invention relates to the use of any compound precedently presented within the scope of the present invention or a pharmaceutical acceptable derivative thereof for the manufacture of a medicament, preferably for the treatment of a subject suffering of any affection as precedently presented within the context of the present invention. Said medicament is preferably for use in the treatment of an animal or a human, preferably a human.

[0107] DETAILED DESCRIPTION OF CERTAIN EXEMPLARY EMBODIMENTS OF THE INVENTION

[0108] 1) Compounds and Process for their preparation

[0109] A process for the preparation of the new compounds 1.1 , 1.2, and I.3, represented in scheme 1. :

[0110] Synthesis of the key intermediate - tosylate V (21% overall yield from 7, 7 steps: Scheme 2)_:

[0111] Selective benzoylation of Inhoffen diol 7 with benzoyl chloride in the presence of 2,6- lutidine in dichloromethane provided the known benzoate 8 in 90% yield, which is oxidized with Dess-Martin periodinane in dichoromethane to give ketone 9 in 97% yield. Wittig reaction between 9 and ylide 10 in toluene afforded vinyl bromide 11 in 74% yield. Miyaura’s Pd-catalyzed Br-B interchange using bis(pinacolato)diboron and [1 ,1 - bis(diphenylphosphino) ferrocene]-dichloro-palladium(ll)-dichloromethane complex as catalyst in the presence of tricyclohexylphosphine and potassium acetate in dimethylsulfoxide gave boronate 5 in 68% yield (44% overall yield from 7, 4 steps). The installation of the vitamin D triene system is accomplished by P(0)-catalyzed tandem cyclization-cross coupling by treating equimolar amounts of enol-triflate 6 and boronate 5 in the presence of catalytic bis(triphenylphosphine)palladium(ll) dichloride and potassium phosphate in aqueous-THF to afford benzoate 12 in 68% yield. Exposure of 12 to diisobutylaluminun hydride in dichloromethane and tosylation of the resulting alcohol 13 with p-toluenesulfonyl chloride in pyridine provided the desired tosylate V in 71% yield for the two last steps (see [18-21]).

[0112] Scheme 2. Synthesis of the key intermediate V from Inhoffen diol 7 :

[0113] Synthesis of the target carborane-containinq vitamin D analogs 1.1 , L2, and L3 :

[0114] The side-chains of target compounds 1.1, I.2, and I.3, containing the ortho-, metha- and para-carboranic units are performed from tosylate V by S / v2-nucleophilic displacement of the tosylate group employing the corresponding carboranyl lithium intermediate. The required carboranyl lithium intermediates are individually prepared by metallation of the corresponding ortho-, meta-, and para-c / oso-carboranes with n-butyllithium. To our delight, the nucleophilic displacement of the tosylate group of V by the carboranyl lithium intermediates take place cleanly to lead the protected carboranyl vitamin D3analogs 15a, 15b, and 15c, which are immediately subjected to deprotection by individual treatment with fluoridric acid in acetonitrile / dichlorometane to provide the desired carboranyl vitamin D analogs l.a (54%), l.b (60%), and l.c (48%), as schown in scheme 3.

[0115] Scheme 3. Synthesis of the target side-chain carboranyl containing vitamin D analogs 1.1, 1.2, and 1.3 :

[0116]

[0117] 15c 1.3

[0118] 2) Experimental details concerning the preparation of the compounds Material and methods:

[0119] All reactions involving oxygen- or moisture-sensitive compounds are carried out under a dry Ar atmosphere using oven-dried or flame-dried glassware and standard syringe / septa techniques, unless when indicated. Liquid reagents or solutions of reagents are added by syringe or cannula techniques. Reaction temperatures refer to external bath temperatures. Reactions at low temperatures are performed in methanol baths cooled with a CRYOCOOL immersion cooler CC-90 (EK-90 de Thermo Fisher Scientific®), provided with a temperature regulator. Reactions at high temperatures are carried out using silicon baths, with a temperature regulator. All dry solvents are distilled under argon immediately prior to use. Tetrahydrofuran (THF), EtsO and toluene are distilled from Na / benzophenone. Pyridine and 2,6-Lutidine are distilled from CaH?. CH2CI2 is distilled from P2O5. DMSO is distilled from CaFh at low pressure and kept over 4 A molecular sieves. fert-Butyl methyl ether (TBME) and CH2CI2 for extractions are used as received. Solutions of n-BuLi in hexanes are titrated with / V-benzylbenzamide before use. The organic extracts are dried over anhydrous Na2SO4, filtered and concentrated using a rotary evaporator at aspirator pressure (20-30 mmHg). Reactions are monitored by thin-layer chromatography (TLC) using aluminum-backed MERCK® 60 silica gel plates (0.2 mm thickness). The chromatograms are visualized first with ultraviolet light (254 nm) and then by immersion in solutions of ceric ammonium molybdate or p-anisaldehyde followed by heating with a heater gun. Flash column chromatography is performed with Merck silica gel 60 (230-400 mesh). All NMR spectra are measured with solutions in CDCI3 in a Bruker® DPX-250 (250 MHz), Varian® Inova 400 (400 MHz) or Bruker® DRX-500 (500 MHz) spectrometers. Chemical shifts are reported on the 6 scale (ppm) downfield from tetramethylsilane (8 = 0.0 ppm) using the residual solvent signal at 8 = 7.26 ppm (1 H, s, CDC ) or 8 = 77.0 ppm (13C, t, CDCI3). Coupling constants (J) are reported in Hz. Distortionless Enhancement by Polarization Transfer (DEPT-135) is used to assign carbon types. NMR signals have been assigned using steroidal numbering. High resolution mass spectra (HRMS) are performed in a Micromass™ Instruments Autospec, Thermo Finningan™ MAT95XP and Applied Biosystems® QSTAR Elite spectrometers. IR spectra are recorded on a silicon disc on a Bruker® IFS-66V and VECTOR 22 FT-IR spectrometers. Optical rotations are measured on a Jasco® DIP-370 polarimeter in a 1 dm cell, [a] and c are given in cm3.g-1 .dm-1 and g.cm-3, respectively. The purity of all compounds reported here is assessed by HPLC, and is identified as > 95%. HPLC purifications are performed on a Shimadzu® preparative liquid chromatograph model LC-8A equipped with a TSP UV-1 absorbance detector, using HPLC Phenomenex™ Luna 5u Silica column (SiO2, 5 p, 100A, 0 250 mm x 21.2 mm, normal phase, isocratic mode; / -PrOH / hexanes). Yields refer to chromatographically purified compounds, unless otherwise stated.

[0120] De-A,B-23,24,25,26127-pentanor-22-benzoyloxi-cholestan-8B-ol, 8 : BzCI

[0121] Benzoyl chloride (1.31 mL, 11.30 mmol, 2 equiv) is added dropwise to a 0 °C cooled solution of diol 7 (1.2 g, 5.65 mmol, 1 equiv) and 2,6-lutidine (1.96 mL, 16.95 mmol, 3 equiv) in CH2CI2 (20 mL). The mixture is stirred for 5 h. The reaction is quenched by the addition of aqueous HCI (5%, 10 mL). The mixture is extracted with TBME (3 x 10 mL) and the combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 2.5 x 5 cm, 0-20% EtOAc / hexanes) to afford the known benzoate 8 (see

[0018] ) [1.6 g, 5.06 mmol, 90%, yellowish oil; Rf = 0.69 (30% EtOAc / hexanes), [o]25D= + 30.2 (c 1.12, CHCI3)].

[0122] 1H NMR (250 MHz, CDCI3): 8 8.04 (d, J = 7.4 Hz, 2H, Har), 7.55 (dd, J = 8.2 and 6.4 Hz, 1 H, Har), 7.44 (t, J = 7.6 Hz, 2H, Har), 4.31 (dd, J = 10.7 and 3.4 Hz, 1 H, H-22), 4.06 (dd, J = 10.7 and 7.1 Hz, 2H, H-8 and H-22), 2.04 - 1 .20 (m, 14H), 1 .10 (d, J = 6.6 Hz, 3H, CH3-2I ), 0.99 (s, 3H, CH3-I8).13C NMR (63 MHz, CDCI3): 8 166.9 (C, C=O), 132.9 (CH, CHar), 130.7 (C, Car), 129.6 (CH, 2xCHar), 128.5 (CH, 2xCHar), 70.0 (CH2, C-22), 69.3 (CH, C-8), 53.5 (CH), 52.5 (CH), 42.1 (C, C-13), 40.4 (CH2), 35.7 (CH), 33.7 (CH2), 26.9 (CH2), 22.71 (CH2), 17.54 (CH2), 17.38 (CH3, CH3-21), 13.71 (CH3, CH3- 18). IR (film, cm-1): 3533 (vO-H), 2941 (vC-H), 2871 (vC-H), 1718 (vC=Oester). HRMS ([ESI-TOF]+, m / z) [M+H]+ calcd for C20H29O3, 317.2111 ; found 317.2110.

[0123] De-A,B-23,24,25,26127-Dentanor-24-benzoyloxi-cholestan-8-one, 9 :

[0124] Dess-Martin periodinane (DMP, 2.4 g, 5.57 mmol, 1.1 equiv) is added to a solution of 8 (1.6 mg, 5.06 mmol, 1 equiv) in CH2CI2 (40 mL). The reaction mixture is stirred at 23 °C for 1.5 h and then concentrated in vacuo. The residue is purified by flash chromatography (SiO2, 0 3 x 6 cm, 30% EtOAc / hexanes) to give ketone 9 [1.54 g, 4.90 mmol, 97%, colorless oil; Rf = 0.70 (20% EtOAc / hexanes), [O]25D = + 0.67 (c 0.92, CHCI3)].

[0125] 1H NMR (250 MHz, CDCI3): 5 8.04 - 7.96 (m, 2H, Har), 7.57 - 7.48 (m, 1 H, Har), 7.41 (t, J = 7.4 Hz, 2H, Har), 4.29 (dd, J = 10.8 and 3.4 Hz, 1 H, H-22), 4.05 (dd, J = 10.8 and 6.8 Hz, 1 H, H-22), 2.45 (dd, J = 11.4 and 7.5 Hz, 1 H), 2.24 - 1.39 (m, 12H), 1.12 (d, J = 6.6 Hz, 3H, CH3-21 ), 0.65 (s, 3H, CH3-I8).13C NMR (63 MHz, CDCI3): 5 211.7 (C, C=O, C- 8), 166.6 (C, C=O), 132.9 (CH, CHar), 130.4 (C, Car), 129.5 (CH, 2xCHar), 128.4 (CH, 2xCHar), 69.6 (CH2, C-22), 61.6 (CH), 53.4 (CH), 49.9 (C, C-13), 40.9 (CH2), 38.8 (CH2), 35.8 (CH), 27.0 (CH2), 24.0 (CH2), 19.2 (CH2), 17.4 (CH3, CH3-21), 12.5 (CH3, CH3-I8). IR (film, cm-1): 2962 (vC-H), 2873 (vC-H), 1714 (vC=O), 1601 (vC=O). HRMS ([ESI- TOF]+, m / z) [M+H]+ calcd for C20H27O3, 315.1955; found 315.1956.

[0126] De-A,B-(8E)-23,24,25,26127-pentanor-8-bromomethylene-24-benzoyloxicholestane, 11 :

[0127] A suspension of (bromomethylene)triphenylphosphonium bromide (2.0 g, 4.55 mmol, 5 equiv) in toluene (18 mL) is sonicated for 30 min and then cooled to -15 °C. After 10 min, a solution of KO / Bu in THF (4.5 mL, 4.50 mmol, 1 M, 4.9 equiv) is added dropwise. The yellow mixture is stirred at -15 °C for 1.5 h and at 0 °C for 30 min. The resulting ylide 10 is cooled to -15 °C. A 0 °C cooled solution of ketone 9 (286 mg, 0.91 mmol, 1 equiv) in toluene (9 mL) is added dropwise via canula. The mixture is stirred at -15 °C for 1.5 h. The reaction is quenched by addition of sat NH4CI (5 mL). The mixture is filtered through a short pad of silica gel, rinsed with EtOAc and concentrated. The residue is purified by flash chromatography (SiO2, 0 2x6 cm, 0-3% EtOAc / hexanes) to give bromide 11 [262 mg, 0.67 mmol, 74%, Rf = 0.71 (20% EtOAc / hexanes), colorless oil, [O]Z5D = + 85.0 (c 1.1 , CHCh)].

[0128] 1H NMR (250 MHz, CDCI3): 5 8.10 - 8.00 (m, 2H, Har), 7.57 (t, J = 7.3 Hz, 1 H, Har), 7.45 (t, J = 7.6 Hz, 2H, Har), 5.67 (s, 1 H, H-7), 4.33 (dd, J = 10.8 and 3.3 Hz, 1 H, H-22), 4.08 (dd, J = 10.7 and 7.0 Hz, 1 H, H-22), 2.90 (dd, J = 10.2 and 2.8 Hz, 1H), 2.08 - 1.24 (m, 12H), 1.14 (d, J = 6.6 Hz, 3H, CH3-21), 0.62 (s, 3H, CH3-I8).13C NMR (63 MHz, CDCI3): 8 166.8 (C, C=O), 144.9 (C, C-8), 133.0 (CH, CHar), 130.6 (C, Car), 129.7 (CH, 2xCHar), 128.5 (CH, 2xCHar), 97.8 (CH, C-7), 69.9 (CH2, C-22), 55.7 (CH), 52.7 (CH), 45.8 (C, C- 13), 39.9 (CH2), 36.4 (CH), 31.1 (CH2), 27.3 (CH2), 22.6 (CH2), 22.3 (CH2), 17.6 (CH3, CH3-21 ), 12.1 (CH3, CH3-18). IR (film, cm-1): 2947 (vC-H), 2870 (vC-H), 1718 (vC=O). HRMS ([ESI-TOF]+, m / z) [M+H]+ calcd for C21 H28BrO2, 319.1254; found 319.1264.

[0129] De-A,B-(8E)-8-[4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-methylene]-24- benzoyloxicholestane, 5 :

[0130] PdCI2(dppf).CH2CI2

[0131] Tricyclohexylphosphine (PCy3, 10.7 mg, 0.038 mmol, 0.06 equiv) and PdCI2(dppf)»CH2CI2(15.7 mg, 0.019 mmol, 0.03 equiv) are dissolved in dry DMSO (2 mL). The mixture is stirred at 23 °C for 20 min. A solution of 11 (250 mg, 0.639 mmol, 1 equiv) in DMSO (5 mL) is added via canula. B2pin2(324 mg, 1.28 mmol, 2 equiv) and KOAc (251 mg, 2.55 mmol, 4 equiv) are successively added. The reaction mixture is stirred at 80 °C for 2 h, cooled to 23 °C and then diluted with H2O (10 mL). The mixture is extracted with TBME (3 x 10 mL) and the combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 1.5 x 6 cm, hexanes) to give 5 [191 mg, 0.44 mmol, 68%, Rf = 0.58 (10% EtOAc / hexanes), yellowish wax, [O]25D = + 62.4 (c 1.0, CHCI3)].

[0132] 1H NMR (250 MHz, CDCI3): 6 8.04 (d, J = 7.0 Hz, 2H, Har), 7.61 - 7.50 (m, 1 H, Har), 7.44 (t, J = 7.2 Hz, 2H, Har), 4.93 (s, 1 H, H-7), 4.32 (dd, J = 9.9 and 2.0 Hz, 1 H, H-22), 4.06 (dd, J = 10.4 and 7.0 Hz, 1 H, H-22), 3.19 (d, J = 12.8 Hz, 1 H, H-14), 2.12 - 1.37 (m, 12H), 1.26 (s, 12H, 4XCH3COB), 1.12 (d, J = 6.4 Hz, 3H, CH3-21 ), 0.60 (s, 3H, CH3-18).13C NMR (63 MHz, CDCI3): 8 166.9 (C, C-8), 165.8 (C=O, Car), 132.9 (CH, CHar), 130.6 (C, Car), 129.6 (CH, 2xCHar), 128.5 (CH, 2xCHar), 82.7 (C, 2xCH3COB), 70.0 (CH2, C- 22), 57.8 (CH, C-7), 53.6 (CH), 46.4 (C, C-13), 40.4 (CH2), 36.4 (CH, C-20), 33.3 (CHZ), 27.1 (CH2), 25.0 (CH3, 2XCH3COB), 24.9 (CH3, 2xCH3COB), 24.4 (CH2), 22.5 (CH2), 17.6(CH3, CH3-21), 12.3 (CH3, CH3-18). IR (film, cm-1): 2980 (vC-H), 2870 (vC-H), 1780 (vC=O), 1639 (vC=C). HRMS ([ESI-TOF1+, m / z) [M+H]+ calcd for C27H4oB04, 439.3014; found, 439.302. 23,24,25l26l27-Pentanor-22-benzoyloxy-1a-tert-butyldimethylsilyloxy-vitamin D3 tert-

[0133] Butyldimethylsilyl Ether, 12 :

[0134] An aqueous solution of K3PO4 (5 mL, 2M, 15 equiv) is added to a solution of boronate 5 (300 mg, 0.684 mmol, 1 equiv) and enol-triflate 6 (424 mg, 0.821 mmol, 1.2 equiv) in THF (5 mL). Then, PdCI2(PPh3)2.CH2Cl2 (24 mg, 0.034 mmol, 0.05 equiv) is added. The reaction mixture is vigorously stirred in the dark for 1.5 h. The reaction is quenched by addition of H2O (10 mL). The mixture is extracted with TBME (3x10 mL) and the combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 2,5x6 cm, hexanes) to give 12 [300 mg, 0.44 mmol, 68%, Rf = 0.77 (5% EtOAc / hexanes), white foam, [O]25D = + 2.2 (c 0.48, CHCI3)].

[0135] 1H NMR (250 MHz, CDCI3): 8 8.06 (d, J = 8.0 Hz, 2H, Har), 7.57 (t, J = 6.9 Hz, 1 H, Har), 7.45 (t, J = 7.7 Hz, 2H, Har), 6.25 (d, J = 11.4 Hz, 1 H, H-6), 6.04 (d, J = 11.1 Hz, 1 H, H- 7), 5.22 - 5.14 (s, 1 H, H-19), 4.87 (s, J = 2.2 Hz, 1 H, H-19), 4.41 - 4.29 (m, 2H, H-22), 4.25 - 4.14 (m, 1 H, H-1), 4.10 - 4.02 (m, 1 H, H-3), 2.90 - 2.78 (m, 1 H, H-9), 2.46 (dd, J = 13.1 and 3.3 Hz, 1 H, H-4), 2.22 (dd, J = 13.1 and 7.2 Hz, 1 H, H-4), 1.92 - 1.45 (m, 14H), 1.14 (d, J = 6.4 Hz, 3H, CH3-21 ), 0.90 - 0.81 (m, 18H, 2xCH3CSi), 0.59 (s, 3H, CH3-I8), 0.11 - 0.00 (m, 12H, 4xCH3Si).13C NMR (63 MHz, CDCh): 6 166.9 (C=O, Car), 148.4 (C, C-10), 140.7 (C, C-8), 135.4 (C, C-5), 133.0 (CH, CHar), 130.7 (C, Car), 129.7 (CH, 2xCHar), 128.5 (CH, 2xCHar), 123.2 (=CH, C-6), 118.2 (=CH, C-7), 111.4 (CH2, C- 19), 72.2 (CH, C-1), 70.1 (CH2, C-22), 67.7 (CH, C-3), 56.2 (CH), 53.4 (CH), 46.2 (CHZ), 46.0 (C, C-13), 44.9 (CH2), 40.6 (CH2), 36.5 (CH), 29.0 (CH2), 27.4 (CHZ), 26.0 (CH3, 3xCH3CSi), 25.96 (CH3, 3xCH3CSi), 23.6 (CH2), 22.4 (CH2), 18.4 (C, CH3CSi), 18.3 (C, CH3CSi), 17.7 (CH3, CH3-2I ), 12.2 (CH3, CH3-I8), -4.5 (CH3, 2xCH3Si), -4.6 (CH3, CH3Si), -4.9 (CH3, CH3Si). IR (film, cm1): 2918 (vC-H), 2849 (vC-H), 1724 (vC=O). HRMS ([APCI-TOF]+, m / z) [M+H]+ calcd for C4iH67O4Si2, 679.4572; found 679.4574.

[0136] 23,24,25l26l27-Pentanor-1a-tert-Butyldimethylsilyloxy-22-hydroxy-vitamin D3 tert-

[0137] Butyldimethylsilyl Ether, 13 :

[0138] A solution of DIBAL-H (1.5 mL, 1 M, 3 equiv) is added dropwise to a -78 °C cooled solution of 12 (300 mg, 0.442 mmol, 1 equiv) in CH2CI2(10 mL). The reaction mixture is stirred in the dark for 1 h and then allowed to reach 23 °C. The reaction is quenched by addition of H2O (20 mL) and aqueous HCI (5%, 10 mL). The mixture is stirred for 15 min and then extracted with CH2CI2 (3 x 10 mL). The combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 2 x 6 cm, hexanes) to give 13 [247 mg, 0.430 mmol, 97%, yellow foam, Rf = 0.14 (5% EtOAc / hexanes), [o]25D= + 42.8 (c 0.60, CHCI3)].

[0139] 1H NMR (250 MHz, CDCI3): 8 6.24 (d, J = 11.3 Hz, 1 H, H-6), 6.02 (d, J = 11 .2 Hz, 1 H, H- 7), 5.18 (s, 1 H, H-19), 4.86 (s, 1 H, H-19), 4.37 (dd, J = 6.3 and 3.8 Hz, 1 H, H-1), 4.19 (ddd, J = 10.8, 7.2 and 3.8 Hz, 1 H, H-3), 3.65 (dd, J = 10.5 and 3.0 Hz, 1 H, H-22), 3.38 (dd, J = 10.5 and 6.7 Hz, 1 H, H-22), 2.87 - 2.77 (m, 1 H, H-9), 2.44 (dd, J = 13.0 and 3.3 Hz, 1 H), 2.21 (dd, J = 13.0 and 7.1 Hz, 1 H, H-4), 2.03 - 1.24 (m, 15H), 1.05 (d, J = 6.5 Hz, 3H, CH3-2I), 0.88 (s, 18H, 2x CH3CSi), 0.55 (s, 3H, CH3-I8), 0.06 (s, 12H, 4x CH3Si).13C NMR (63 MHz, CDCI3): 8 148.5 (C, C-10), 140.9 (C, C-8), 135.3 (C, C-5), 123.2 (=CH, C- 6), 118.1 (=CH, C-7), 111.3 (=CH2, C-19), 72.2 (CH, C-1), 68.1 (CH2, C-22), 67. 7 (CH, C-3), 56.2 (CH), 52.9 (CH), 46.2 (CH2), 46.0 (C, C-13), 44.9 (CH2), 40.6 (CHZ), 39.24 (CH), 29.0 (CH2), 27.4 (CH2), 26.00 (CH3, 3xCH3CSi), 25.96 (CH3, 3xCH3CSi), 23.6 (CH2), 22.4 (CH2), 18.4 (C, CH3CSi), 18.3 (C,CH3CSi),17.0 (CH3, CH3-21), 12.2 (CH3, CH3-I8), -4.5 (CH3, 2xCH3Si), -4.6 (CH3, CH3Si), -4.9 (CH3, CH3Si). HRMS ([ESI-TOF]+, m / z) [M+H]+ calcd for C34H63O3Si2, 575.4310; found 575.4309.

[0140] 23,24,25l26l27-Pentanor-1a-tert-butyldimethylsilyloxy-22-p-toluenesulfonyloxy-vitamin

[0141] D3 tert-Butyldimethylsilyl Ether, 4 : p-Toluenesulfonyl chloride (120 mg, 0.629 mmol, 2.4 equiv) is added to a 0 °C cooled solution of 13 (154 mg, 0.268 mmol, 1 equiv) in pyridine. The bright yellow reaction mixture is stirred in the dark at -4 °C for 12 h. The reaction is quenched by addition of sat CUSO (20 mL). The mixture is extracted with TBME (3 x 10 mL). The combined organic phases are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 2 x 6 cm, hexanes) to give 4 [143 mg, 0.196 mmol, 73%, colorless foam, Rf = 0.72 (20% EtOAc / hexanes), [a]25D= + 3.2 (c 0.20, CHCI3)].

[0142] 1H NMR (250 MHz, CDCI3): 8 7.79 (d, J = 8.3 Hz, 2H, Har), 7.34 (d, J = 8.4 Hz, 2H, Har), 6.22 (d, J = 11.3 Hz, 1 H, H-6), 5.99 (d, J = 11.6 Hz, 1 H, H-7), 5.17 (s, 1 H, H-19), 4.84 (s, 1 H, H-19), 4.36 (dd, J = 6.5 and 4.1 Hz, 1 H, H-1 ), 4.24 - 4.12 (m, 1 H, H-3), 3.97 (dd, J = 9.2 and 2.9 Hz, 1 H, H-22), 3.79 (dd, J = 9.2 and 6.3 Hz, 1 H, H-22), 2.85 - 2.75 (m, 1 H), 2.51 - 2.39 (m, 3H), 2.20 (dd, J = 13.2 and 6.9 Hz, 2H), 2.03 - 1.06 (m, 17H), 1.01 - 0.79 (m, 18H, 2xCH3CSi), 0.49 (s, 3H, CH3-I8), 0.05 (s, 12H, 4xCH3Si).13C NMR (63 MHz, CDCI3): 8 148.5 (C, C-10), 144.7 (C, Car), 140.4 (C, C-8), 135.5 (C, C-5), 133.2 (C, Car), 129.9 (2xCH, Car), 128.1 (2xCH, Car), 123.1 (=CH, C-6), 118.3 (=CH, C-7), 111.3 (=CHZ, C-19), 75.7 (CH2, C-22), 72.2 (CH, C-1 ), 67.6 (CH, C-3), 56.0 (CH), 52.3 (CH), 46.1 (C, C-13), 45.9 (CH2), 44.9 (CH2, C-2), 40.4 (CHZ, C-12), 36.7 (CH), 28.9 (CHZ), 27.1 (CHZ), 25.99 (CH3, 3xCH3CSi), 25.96 (CH3, 3xCH3CSi), 23.5 (CH2), 22.2 (CH2), 21.8 (CH3, CH3- Ts), 18.37 (C, CH3CSi), 18.30 (C, CH3CSi), 17.1 (CH3, CH3-21), 12.1 (CH3, CH3-I8), -4.5 (CH3, 2xCH3Si), -4.6 (CH3, CH3Si), -4.9 (CH3, CH3Si). HRMS ([APCI-TOF]+, m / z) [M+H]+ calcd for C4iH6gO5SSi2, 729.4399; found 729.4399.

[0143] 23,24,25l26l27-Pentanor-1a-hvdroxy-22-o-c / oso-carboranyloxy-vitamin D3, 1.1

[0144] A solution of n-BuLi in hexanes (78 pL, 2.5 M, 2 equiv) is added dropwise to a 0 °C cooled solution of o-c / oso-carborane (28 mg, 0.195 mmol, 2 equiv) in Et2O (2.5 mL). The bath is removed and the cloudy mixture is stirred for 1 h. The reaction mixture is cooled to 0 °C and stirred for 5 min. A solution of 4 (71 mg, 0.097 mmol, 1 equiv) in Et2O (1.5 mL) is added via cannula to the resulting carboranyl lithium 14a. The yellow mixture is stirred in dark at 0 °C for 2 h. The cooling bath is removed and the reaction mixture is stirred at 23 °C for 12 h. The reaction is quenched by addition of H2O (10 mL). The mixture is and extracted with TBME (3 x 10 mL). The combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 1 ,5 x 8 cm, 1-5% EtOAc / hexanes) to give 23,24,25,26,27-pentanor-1 a-tert- butyldimethylsilyloxy-22-o-c / oso-carboranyloxy-vitamin D3tert-butyldimethylsilyl ether (15a) [45 mg, 0.064 mmol, 66%, Rf = 0.55 (10% EtOAc / hexanes)]. A solution of 15a (64 mg, 0.091 mmol, 1 equiv) in CH2CI2 / CH3CN (4 mL, 1 :3) is treated with aqueous HF (48%, 15 drops). The mixture is stirred at 23 °C for 2 h and then poured into sat NaHCO3(50 mL). The mixture is stirred for 30 min and then extracted with CH2CI2 (3 x 20 mL). The combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 1.5 x 6 cm, 60% EtOAc / hexanes) and then repurified by HPLC (Phenomenex SiO2, Luna Silica(2) 5 pm, 20% / -PrOH / hexanes) to afford 1.1 [31 mg, 0.066 mmol, 72%, white solid Rf = 0.50 (60% EtOAc / hexanes), [O]Z5D = + 26.7 (c 0.24, CHCI3)].

[0145] 1H NMR (400 MHz, CDCI3): 5 6.35 and 5.99 (d, J = 11.2 Hz, 2H, H-6 and H-7), 5.32 (s, 1 H, H-19), 4.98 (s, 1 H, H-19), 4.46 - 4.39 (m, 1 H, H-1 ), 4.26 - 4.19 (m, 1 H, H-3), 2.79 (dd, J = 12.2 and 3.6 Hz, 1 H), 2.63 (s, 1 H, H-24), 2.59 (dd, J = 14.0 and 2.7 Hz, 1 H), 2.30 (dd, J = 13.4 and 6.4 Hz, 2H), 2.01 (dd, J = 13.6 and 7.3 Hz, 2H), 1.96 - 1.86 (m, 4H), 1.84 - 1.70 (m, 3H), 1.63 (d, J = 9.2 Hz, 6H), 1.56 - 1.39 (m, 4H), 1.23 (ddd, J = 16.4, 12.7 and 6.8 Hz, 4H), 1.08 (d, J = 6.4 Hz, 2H), 0.85 (d, J = 5.4 Hz, 3H, CH3-21 ), 0.52 (s, 3H, CH3-18).13C NMR (101 MHz, CDCI3): 6 147.8 (C, C-10), 142.8 (C, C-8), 133.2 (C, C- 5), 125.0 (=CH, C-6), 117.4 (=CH, C-7), 111.9 (=CH2, C-19), 85.2 (C, C-23), 70.9 (CH, C- 1 ), 67.0 (CH, C-3), 58.6 (CH, C-24), 56.5 (CH), 56.3 (CH), 45.9 (C, C-13), 45.4 (CH2), 45.2 (CH2), 43.0 (CH2), 40.4 (CH2), 37.2 (CH), 29.1 (CH2), 27.7 (CH2), 23.6 (CH2), 22.3 (CH2), 20.5 (CH3, CH3-21 ), 12.0 (CH3, CH3-18). IR (film, cm-1): 3375 (vO-H), 2916, 2851 (vC-H), 2607 (vB-H). HRMS ([APCI-TOF]+, m / z) [M+H]+ calcd for C24H45BI0O2, 475.4345; found 475.4383.

[0146] 23,24,25,26,27-Pentanor-1a-hvdroxy-22-m-c / oso-carboranyloxy-vitamin D3, L2. :

[0147] A solution n-BuLi in hexanes (104 pL, 2.5 M, 2 equiv) is added dropwise to a 0 °C cooled solution of m-c / oso-carborane (50 mg, 0.347 mmol, 2.6 equiv) in Et2O (3 mL). The cooling bath is removed and the cloudy mixture is stirred at 23 °C for 1 h. The resulting solution of carboranyllithium 14b is cooled to 0 °C and stirred for 5 min. A solution of 4 (95 mg, 0.130 mmol, 1 equiv) in Et2O (2.5 mL) is added via cannula. The yellow mixture is stirred in darkness at 0 °C for 30 min. The cooling bath is removed and the reaction mixture is stirred at 23 °C for 12 h. The reaction is quenched by addition of H2O (10 mL). The mixture is extracted with TBME (3 x 10 mL). The combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 1 ,5 x 5 cm, 0-2% EtOAc / hexanes) to give 23,24,25,26,27-pentanor-1 a-tert- butyldimethylsilyloxy-22-m-c / oso-carboranyloxy-vitamin D3terf-butyldimethylsilyl ether (15b) [82 mg, 0.117 mmol, 90%, Rf = 0.88 (10% EtOAc / hexanes)]. A solution of 15b (82 mg, 0.117 mmol, 1 equiv) in CH2CI2 / CH3CN (4 mL, 1 :3) is treated with aqueous HF (48%, 15 drops). The reaction mixture is stirred at 23 °C for 2 h and then poured into sat NaHCO3(50 mL). The mixture is stirred for 30 min and then extracted with CH2CI2(3 x 20 mL). The combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 1.5 x 4 cm, 60% EtOAc / hexanes) and then repurified by HPLC (Phenomenex SiO2, Luna Silica(2) 5 pm, 20% / -PrOH / hexanes) to afford I.2 [37 mg, 0.053 mmol, 67%, white solid, Rf = 0.38 (60% EtOAc / hexanes), [O]25D = + 8.5 (c 0.92, CHCI3)].

[0148] 1H NMR (400 MHz, CDCI3): 5 6.4 and 6.0 (d, J = 11 .2 Hz, 2H, H-6 and H-7), 5.32 (s, 1 H, H-19), 4.99 (s, 1 H, H-19), 4.42 (dd, J = 7.5 and 4.2 Hz, 1 H, H-1), 4.22 (dq, J = 9.5 and

[0149] 3.3 Hz, 1 H, H-3), 2.90 (s, 1 H, H-24), 2.81 (dd, J = 12.2 and 3.6 Hz, 1 H), 2.58 (dd, J =

[0150] 13.3 and 2.7 Hz, 2H), 2.31 (dd, J = 13.4 and 6.4 Hz, 2H), 2.13 (d, J = 14.8 Hz, 2H), 2.05 - 1.41 (m, 18H), 1.32 - 1.12 (m, 4H), 0.98 (d, J = 6.2 Hz, 3H, CH3-21), 0.56 (s, 3H, CH3- 18).13C NMR (101 MHz, CDCI3): S 147.8 (C, C-10), 142.7 (C, C-8), 133.4 (C, C-5), 124.9 (=CH, C-6), 117.5 (=CH, C-7), 111.9 (=CH2, C-19), 77.4 (C, C-23), 70.9 (CH, C-1), 67.0 (CH, C-3), 56.5 (CH), 56.4 (CH), 55.0 (CH, C-24), 45.9 (C, C-13), 45.3 (CH2), 43.2 (CH2), 43.0 (CH2), 40.4 (CH2), 37.9 (CH), 29.1 (CH2), 27.8 (CH2), 23.6 (CH2), 22.4 (CH2), 20.5 (CH3, CH3-21 ), 12.1 (CH3, CH3-18). IR (film, cm-1): 3373 (vO-H), 2931 , 2851 (vC-H), 2600 (vB-H). HRMS ([APCI-TOF]+, m / z) [M+H]+ calcd for C24H45BIO02, 475.4345; found 475.4379.

[0151] 23,24,25,26,27-Pentanor-1a-hvdroxy-22-p-c / oso-carboranyloxy-vitamin D3, L3 :

[0152] A solution of n-BuLi in hexanes (109 pL, 2.5 M, 2 equiv) is added dropwise to a 0 °C cooled solution of p-c / oso-carborane (39 mg, 0.271 mmol, 2 equiv) in Et2O (3 ml_). The bath is removed and the cloudy mixture is stirred at 23 °C for 1 h. The resulting solution of carboranyllithium 14c is cooled to 0 °C and stirred for 5 min. A solution of 4 (99 mg, 0.136 mmol, 1 equiv) in Et20 (2.5 ml_) is added via cannula. The yellow mixture is stirred in dark at 0 °C for 2 h. The cooling bath is removed and the mixture is stirred at 23 °C for 12 h. The reaction is quenched by addition of H2O (10 mL). The mixture is extracted with TBME (3 x 10 mL). The combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 1.5x6 cm, 0-2% EtOAc / hexanes) to give 23,24,25,26,27-pentanor-1a-tert-butyldimethylsilyloxy-22-p- c / oso-carboranyloxy-vitamin D3 tert-butyldimethylsilyl ether (15c) 17 [64 mg, 0.091 mmol, 67%, Rf = 0.85 (10% EtOAc / hexanes)]. A solution of compound 15c (64 mg, 0.091 mmol, 1 equiv) in CH2CI2 / CH3CN (4 mL, 1 :3) is treated with aqueous HF (48%, 15 drops). The mixture is stirred at 23 °C for 2 h and then poured into sat NaHCOa (50 mL). The mixture is stirred for 30 min and then extracted with CH2CI2 (3 x 20 mL). The combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (SiO2, 0 1.5 x 6 cm, 60% EtOAc / hexanes) and then repurified by HPLC (Phenomenex SiO2, Luna Silica(2) 5 pm, 20% / -PrOH / hexanes) to afford 1.3 [31 mg, 0.066 mmol, 72%, white solid Rf = 0.50 (60% EtOAc / hexanes), [O]25D = + 26.7 (c 0.24, CHCI3)].

[0153] 1H NMR (400 MHz, CDCI3): 8 6.35 and 5.99 (d, J = 11.2 Hz, 2H, H-6 and H-7), 5.32 (s, 1 H, H-19), 4.98 (s, 1 H, H-19), 4.46 - 4.39 (m, 1 H, H-1), 4.26 - 4.19 (m, 1 H, H-3), 2.79 (dd, J = 12.2 and 3.6 Hz, 1 H), 2.63 (s, 1 H, H-24), 2.59 (dd, J = 14.0 and 2.7 Hz, 1 H), 2.30 (dd, J = 13.4 and 6.4 Hz, 2H), 2.01 (dd, J = 13.6 and 7.3 Hz, 2H), 1.96 - 1.86 (m, 4H), 1.84 - 1.70 (m, 3H), 1.63 (d, J = 9.2 Hz, 6H), 1.56 - 1.39 (m, 4H), 1.23 (ddd, J = 16.4, 12.7 and 6.8 Hz, 4H), 1.08 (d, J = 6.4 Hz, 2H), 0.85 (d, J = 5.4 Hz, 3H, CH3-21 ), 0.52 (s, 3H, CH3-I8).13C NMR (101 MHz, CDCI3): 8 147.8 (C, C-10), 142.8 (C, C-8), 133.2 (C, C- 5), 125.0 (=CH, C-6), 117.4 (=CH, C-7), 111.9 (=CHZ, C-19), 85.2 (C, C-23), 70.9 (CH, C- 1), 67.0 (CH, C-3), 58.6 (CH, C-24), 56.5 (CH), 56.3 (CH), 45.9 (C, C-13), 45.4 (CHZ), 45.2 (CH2), 43.0 (CH2), 40.4 (CH2), 37.2 (CH), 29.1 (CH2), 27.7 (CH2), 23.6 (CHZ), 22.3 (CH2), 20.5 (CH3, CH3-2I ), 12.0 (CH3, CH3-I8). IR (film, cm-1): 3375 (vO-H), 2916, 2851 (vC-H), 2607 (vB-H). HRMS ([APCI-TOF]+, m / z) [M+H]+ calcd for C24H45Bi0O2, 475.4345; found 475.4383.

[0154] 3) Experimental details concerning the Biological activities of the compounds

[0155] Material and methods:

[0156] Docking

[0157] Docking studies to predict the binding of compound 1.1, I.2 and I.3 for VDR are carried out using the GOLD program (version Suite 5.2). A modified crystal structure (addition of hydrogens, reconstitution of gaps and correction of His tautomers) of the complex between 1 ,25D3-human (h) VDR ligand binding domain (LBD) is chosen as protein (PBD code: 1 DB1 ). The Ligand Binding Pocket (LBP) of the mutant LBD is defined as Binding Site with the automatic active-site detection on, and the radius is set to 10 A. The conformations for each ligand in the active site of the protein are sampled using a genetic algorithm (GA). The ligands are docked in 25 independent genetic algorithm (GA) runs, for each of which a maximum of 125000 GA operations are performed on a single population of 100 individuals. Operator weights for crossover, mutation, and migration in the entry box are used as default parameters (95, 95, and 10, respectively), as well as the hydrogen bonding (4.0 A) and van der Waals (2.5 A) parameters. The different poses are ranked according to the force-field-based CHEMPLP scoring function and GoldScore is used as a re-scoring function. The 3 best solutions are obtained with an associated score, and these results are compared with the solutions for 1 ,2503.

[0158] Chemical

[0159] 1 ,25D3 and carborane compounds (1.1 , 1.2, 1.3 and C1 ) are dissolved in absolute ethanol at 10'2M and stored at -20 °C.

[0160] Human VDR Binding Assay

[0161] Binding affinity to VDR is evaluated using a 1 ,2503 assay fluorescence polarization kit (FP)-based competition (Polarscreen Vitamin D receptor competitor assay, Invitrogen) under manufacturer conditions. Compounds are evaluated within the range from 10“11to 10“6M. The polarized fluorescence is measured in a 384-well black plate using a Mithras LB 940 (Berthold Technologies™).

[0162] Biochemistry

[0163] DNA segment encoding His-tagged LBD of zebrafish VDR (amino acid 156-453) are inserted into pET15b. Recombinant proteins are produced in Escherichia coli BL21 DE3 after induction with 1 mM IPTG (OD600 ~ 0.7) at 23 °C for 4 hours. Soluble proteins are purified using affinity chromatography columns (HisTrap™ FF crude, 17-5286-01 , GE) followed by size exclusion chromatography (HiLoad Superdex™ 200, 28-9893-35 GE) equilibrated in Tris HCI 10 mM pH7, NaCI 200 mM, TCEP 1 mM. Expression of zVDR LBD (residues 156-453) and the following purification are done as previously described (Rovito et al. 2020). The protein is concentrated using Amicon ultra-30 (Millipore) to 3-7 mg / ml and incubated with a two-fold excess of ligands and a three-fold excess of the coactivator SRC-1 NR2 peptide (686-RHKILHRLLQEGSPS-700). Crystals of BO-bound zVDR LBD are obtained in NaAcetate 2.5M. Protein crystals are mounted in a fiber loop and flash-cooled under a nitrogen flux. Data collection from a single frozen crystal are performed at 100 K on the PX2 beamline at ESRF (France). The raw data are processed with XDS (see

[0022] ). The structures are solved and refined using Phenix® (see

[0023] ) and iterative model building using COOT™ (see

[0024] ).

[0164] Cell lines

[0165] IEC-18 rat intestinal epithelial cells (ATCC) are grown in Dulbecco's modified Eagle's medium (DMEM) 4.5 g / l glucose supplemented with 5 % fetal calf serum (FCS), 1 mM Sodium Pyruvate, 0.1 UI / mL insulin and 40 pg / mL gentamicin. Cells at 80 % confluency are grown in medium supplemented with 5% charcoal-treated FCS for 48 h.

[0166] RNA isolation and analysis

[0167] Total RNA is isolated from cells using TRI Reagent (Molecular Research Center, Inc), according to the manufacturer’s protocol. RNA is quantified by spectrophotometry (Nanodrop®, Thermo Fisher®), and cDNA prepared using 2 pg of total RNA, random hexamers and SuperScriptll reverse transcriptase (Thermo Fisher®) following the manufacturer's instructions. Quantitative PCR reactions are performed using the Light Cycler 480 SYBR Green I Master X2 Kit (Roche®) according to the supplier’s protocol. Oligonucleotides are listed in Extended Data Table 1. RpIpO is used as the housekeeping gene.

[0168] Extended Data Table 1.:

[0169] Cyp24a1 , 5’-TCCATGAGGCTTACCCCAAG-3’ (sense) and 5’- GCGTATTCACCCAGAACCGT-3’ (antisense); Atp2b1 , 5’-

[0170] GTGGAGGTTCCATTCAGGGG-3’ (sense) and 5’-CTCGGATACCCCACAGGAGT-3’ (antisense); S100g, 5’-GACAGCAAGCAGCACAGAAAA-3’ (sense) and 5’- TGGACAGCTGGTTTGGATCG-3’ (antisense); RpIpO, 5’-

[0171] ACTCGCTTCCTAGAGGGTGT-3’ (sense) and 5 - AGTCGAAAAGACCGAATCCCA-3’ (antisense) (use as a housekeeping gene).

[0172] Determination of serum calcium levels after VDR ligand treatments

[0173] Long term treatments

[0174] Male Swiss CD-1 mice are housed in the Santiago de Compostela University temperature- and light-controlled animal facility. Mice (5 per group) are injected intraperitoneally every other day for three weeks with 1.25D3, 1.1 , I.2, or 1.3 (0.5 pg / kg body weight) dissolved in sesame oil. The control group (n=5) is injected with sesame oil. Mice are weighed the last day of the treatment. Serum calcium levels are determined using the QuantiChom Calcium Assay Kit (BioAssay Systems™, Hayward, USA). Data are expressed as mean + SEM. Animal studies are approved by the University of Santiago de Compostela Ethics Committee for Animal Experiments.

[0175] Hypercalcemic mice

[0176] C57BL / 6J and Cyp24a1-null mice are housed in the IGBMC temperature- and light- controlled animal facility and fed ad libitum (Safe diets, D04, France). Ten week-old C57BL / 6J male mice are administered per os with 1 ,25D3, alone or in combination with 1.1 , I.2, or I.3, dissolved in oil (sunflower oil, Auchan) (0.5 pg / kg body weight in 100 pL). Six to nine weeks old Cyp24a1-null mice are administered every other day per os with 1.1 , dissolved in oil (0.05 ou 0.5 pg / kg body weight in 100 pL) for one month. Blood is collected in lithium heparin tubes (microvette, Sarstedt), and centrifuged at 400 g for 10 min at 4°C. Serum calcium levels are determined using colorimetric assays (MAK022, Sigma Aldrich®) according to the supplier’s protocol and an AU-480 automated laboratory work station (Beckman Coulter France SAS, Villepinte, France) for wild-type and Cyp24a1-null mice, respectively. All animal experimental protocols are conducted in compliance with French and EU regulations on the use of laboratory animals for research, and approved by the IGBMC Ethical Committee and the French Ministry (#10047-2017052615101492 and #21776-2019082318288737).

[0177] Results:

[0178] The transcript levels of Cyp24a1, the highly responsive VDR target gene, are similarly induced in the presence of 1 ,25D3 and of C1 , an analog bearing an o-carboran at the C25 atom of the lateral side chain of 1 ,25D3, in human MCF-7 breast cancer cells (see [5])- To predict the binding of 1 ,25D3 analogs with a shorter lateral side chain and bearing a o-, m- or p-carboran, the docking to hVDR of 1.1 , 1.2, or I.3, bearing the carboran in ortho, meta and para position, respectively, is determined. All of these compounds have a docking to hVDR ligand binding domain (LBD) up to 98 % similar to 1.25D3 (see Fig. 1).

[0179] To compare experimentally the binding of these carborane-based analogs to hVDR, competitive VDR binding assays are performed. The affinity of 1.1 , 1.2, or 1.3 for VDR is 3- , 3.5- and 3-fold lower than that of 1 ,25D3, respectively (IC50 M: 1.25D3: 2.88 x 10’9; BO: 8.51 x 109; BM: 1.02 x 108, and BP: 8.4 x 109) (see Fig. 2).

[0180] X ray analysis of the zVDR LBD- 1.1 complex is also performed. The crystals belong to the space group P6s22, with one LBD complex per asymmetric unit. Superposition of the VDR LBP in the presence of 1.1 or 1.25D3 shows that positioning of the A-ring and C / D- rings are similar positioned (see Fig. 3A). The 1-OH and 3-OH groups in the A-ring of 1.1 form hydrogen bonds similar to those of 1 ,25D3: with Ser265 and Arg302 and with Tyr175 and Ser306, respectively (see Fig. 3A). In contrast to the 25-OH group of 1 ,25D3 that forms specific hydrogen bonds with His333 and His423, a sole weak hydrogen bond with His423 is formed with a boron atom of 1.1 (3.3 A). The side chain of His333 (loop 6- 7) is reoriented and shifted outwards and does not interact with 1.1 (see Fig. 3B), thus 1.1 fails to stabilize this key residue for VDR agonistic activities. In addition, a shift of the Ca for the last turn of helix H11 is observed (0.7 A). Taken together, these results indicate that the VDR does not adopt an agonistic conformation when 1.1 is bound, in constrast to C1.

[0181] Besides, the transcript levels of Cyp24a1 are determined in rat intestinal epithelial (IEC- 18) cells. Cyp24a1 transcript levels are induced by 50-fold in cells treated for 6 h with 1 ,25D3 or with C1 compared to vehicle. In contrast, they are similar in vehicle- and in 1.1- , I.2-, or 1.3- treated cells (see Fig. 4). In addition, Cyp24a1 transcript levels induced by 1 ,25D3 are 2-fold lower in the presence of 1.1 (see Fig. 5), showing that 1.1 reduces 1 ,25D3-induced VDR transcriptional activities in vitro. Additional results are also obtained with other responsive VDR target genes, as shown in Fig. 4 and 5.

[0182] The in vivo effects of 1.1, 1.2, and 1.3 are also investigated. Wild-type mice are injected intraperitoneally every other day for three weeks with 0.5 pg / kg 1.25D3, 1.1 , 1.2, and 1.3. Whereas administration of 1 ,25D3 induced hypercalcemia, serum calcium levels of mice treated with 1.1, I.2, and 1.3 are similar to those of vehicle-treated mice (see Fig. 6A). In agreement with these results, bodyweight is reduced only in hypercalcemic mice (see Fig. 6B). Importantly, whereas mice treated with 1 pg / kg 1 ,25D3 for 4 days are hypercalcemic, a co-treatment with 1.1, I.2, and I.3 reduce the serum calcium levels by at least 30 % (see Fig. 6C). Note that the serum calcium levels in mice co-treated with 1 ,25D3 and 1.1 or I.2 are normocalcemic (see Fig. 6C). Cyp24a1-null mice have high circulating levels of 1.25D3 together with suppressed PTH and hypercalcemia, and are a model of idiopathic infantile hypercalcemia

[0027] , Cyp24a1 mice were treated with 1.1 every other day for one month. The results show that 1.1 at 0.5 pg / kg normalises serum calcium levels. These results show that treatment with 1.1 and I.2 does not induce hypercalcemia and that they normalise 1 ,25D3-induced hypercalcemia. REFERENCES

[0183] [1] Bacchetta, J., Edouard, T., Laverny, G., Bernardor, J., Bertholet-Thomas, A., Castanet, M., Garnier, C., Gennero, L, Harambat, J., Lapillonne, A., Molin, A., Naud, C., Salles, J.P., Laborie, S., Tounian, P., and Linglart, A. 2022, Vitamin D and calcium intakes in general pediatric populations: A French expert consensus paper. Arch Pediatr. 29, 312-325.

[0184] [2] Lenherr-Taube, N., Young, E.J., Furman, M., Elia, Y., Assor, E., Chitayat, D., Uster, T., Kirwin, S., Robbins, K., Vinette, K.M.B., Daneman, A., Marshall, C.R., Collins, C., Thummel, K., Sochett, E., and Levine, M.A. 2021 ,. Mild Idiopathic Infantile Hypercalcemia-Part 1 : Biochemical and Genetic Findings. J Clin Endocrinol Metab. 106, 2915-2937.

[0185] [3] Rovito, D., Belorusova, A.Y., Chalhoub, S., Rerra, A.L, Guiot, E., Molin, A., Linglart, A., Rochel, N., Laverny, G., and Metzger, D. 2020, Cytosolic sequestration of the vitamin D receptor as a therapeutic option for vitamin D-induced hypercalcemia. Nat Commun. 11 , 6249.

[0186] [4] Fujii, S., Masuno, H., Taoda, Y., Kano, A., Wongmayura, A., Nakabayashi, M., Ito, N., Shimizu, M., Kawachi, E., Hirano, T., Endo, Y., Tanatani, A., and Kagechika, H., 2011, Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands: direct observation of hydrophobic interaction between protein surface and carborane. J Am Chem Soc. 133, 20933-20941.

[0187] [5] Otero, R., Seoane, S., Sigueiro, R., Belorusova, A.Y., Maestro, M.A., Perez- Fernandez, R., Rochel, N., and Mourino, A. 2016, Carborane-based design of a potent vitamin D receptor agonist. Chem Sci. 7, 1033-1037.

[0188] [6] Maestro, M.A., Molnar, F., and Carlberg, C. 2019, Vitamin D and Its Synthetic Analogs. J Med Chem. 62, 6854-6875.

[0189] [7] EP1683786

[0190] [8] US6329357

[0191] [9] JP2005247768

[0192]

[0010] EP160136

[0193]

[0011] W0200370716

[0194]

[0012] CN 108853503

[0195]

[0013] EP1343390

[0196]

[0014] WO2022078877

[0197]

[0015] CA2224440

[0198]

[0016] Grimes, R. N., Carboranes 3rd Ed., Elsevier, Amsterdam and New York, 2016, ISBN 9780128018941

[0017] Greenwood, Norman N.; Earnshaw, Alan, 1997, Chemistry of the Elements (2nd ed.). Butterworth-Heinemann, p. 181-189. ISBN 978-0-08-037941-8

[0199]

[0018] DeBerardinis, A. M.; Lemieux, S.; Hadden, M. K. Analogues of the Inhoffen-Lythgoe diol w anti-proliferative activity. Bioorg. Med. Chem. Lett. 2013, 23, 5367-5370

[0200]

[0019] Gogoi, P.; Sigueiro, R.; Eduardo, S.; Mouriho, A. An expeditious route to 1 ,25- Dihydroxyvitamin D3 and Its analogues by an aqueous tandem palladium-catalyzed A- ring closure and suzuki coupling to the C / D unit Chem.- Eur. J. 2010, 16, 1432-1435

[0201]

[0020] Trost, B. M.; Dumas, J.; Villa, M. New strategies for the synthesisof vitamin D metabolites via palladium-catalyzed reactions. J. Am. Chem. Soc. 1992, 114, 9836-9845

[0202]

[0021] Ishiyama, T.; Ishida, K.; Miyaura, N. Synthesis of Pinacol Arylboronates via crosscoupling reaction of bis(pinacolato)diboron with chloroarenes catalyzed by palladium(O)- tricyclohexylphosphine complexes. Tetrahedron 2001, 57, 9813-9816

[0203]

[0022] Kabsch, W. Software XDS for image rotation, recognition and crystal symmetry assignment. Acta Crystallogr D Biol Crystallogr. 2010, 66, 125-132

[0204]

[0023] Afonine PV, Grosse-Kunstleve RW, Adams PD. CCP4 Newsl 2005; 42, contribution 8

[0205]

[0024] Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr 2004, D60: 2126-2132

[0206]

[0025] EP20306196.5

[0207]

[0026] B. Brito de Almeida pinto et al. “Carboran-based design of active ligands of nuclear recptors for BNCT’, Msc Thesis, University of Porto, 2018

[0208]

[0027] St-Arnaud R et al., “Vitamin D and Diseases of Mineral Homeostasis: A Cyp24a1 R396W Humanized Preclinical Model of Infantile Hypercalcemia Type 1.”; Nutrients, 2022, (PMID: 35956396)

Claims

CLAIMS1. Compound having the following formula (I) :- wherein the groups Ri and R2represent independently a functional group selected among a hydrogen and an aliphatic chain being at least selected among one of the following: linear, branched, cyclic, substituted and unsubstituted chain; the aliphatic chain being selected among Ci-i2alkyl; C2-i2alkenyl; C2-i2alkynyl; Ci. i2heteroalkyl; C2-i2heteroalkenyl; C2-i2heteroalkynyl; Co- wary I and C4-wheteroaryl group; each of the foregoing alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroal kynyl, aryl and heteroaryl group, optionally bearing one or more substituents comprising at least one of the atom or function selected from -F; -Cl; - Br; -I; -NO2; -CN; -CF3; -OH ; -O-; -S-; -C(=O)-: -S(=O)-; -SO2-; -SO2; -C(=O)O- and -C(=O)N-; preferably a hydrogen;- R3 represents a functional group selected among a hydrogen and a methyl; preferably a hydrogen;- R5 represents a functional group selected among a hydrogen, a methyl and a methylene; preferably a methylene;- Re represents a functional group selected among a hydrogen, methyl, methylene, ethyl and an ethylene; preferably a hydrogen; and- wherein the group Q is a carborane substituent having the following molecular formula : C2B10H11R7; wherein R7 represents a functional group selected among a hydrogen and an aliphatic chain being at least selected among one of the following:linear, branched, cyclic, substituted and unsubstituted chain; the aliphatic chain being selected among Ci-^alkyl; C2-i2alkenyl; C2-i2alkynyl; Ci.^heteroalkyl; C2- i2heteroalkenyl; C2-i2heteroalkynyl; Ce- aryl and C4-ioheteroaryl group; each of the foregoing alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl and heteroaryl group, optionally bearing one or more substituents comprising at least one of the atom or function selected from -F; -Cl; -Br; -I; -NO2; -CN; -CF3; -OH ; -O-; -S-; -C(=O)-; -S(=O)-; -SO2-; -SO2; -C(=O)O- and -C(=O)N-; and preferably a hydrogen; or a pharmaceutical acceptable derivative thereof, for use as a medicament.

2. Compound for its use according to claim 1 , wherein the group Q is selected among one of the following groups numbered from (II) to (IV):, and preferably the group Q is the substituent (II).

3. Compound for its use according to any of claim 1 or 2, wherein is the compound (I) selected among one of the following compounds of formula (1.1 ); (1.2) and (1.3) :

4. Compound according to any of claims 1 to 3, or a pharmaceutical acceptable derivative thereof, for use in the treatment of hypercalcemia disorders of a subject presenting acute or chronic hypercalcemia.

5. Compound according to any of claims 1 to 3, or a pharmaceutical acceptable derivative thereof, for use in the treatment of acute or chronic hypercalciuria.

6. Compound according to any of claims 1 to 5, or a pharmaceutical acceptable derivative thereof, for use in the treatment of hypercalcemia disorders of a subject presenting acute or chronic hypercalcemia and / or chronic hypercalciuria together with low PTH levels.

7. Compound according to claim 6, or a pharmaceutical acceptable derivative thereof, for use in the treatment of a subject suffering from at least one of the following among subcutaneous fat necrosis ; idiopathic infantile hypercalcemia ; and Williams syndrome.

8. Compound according to any of claims 1 to 7, or a pharmaceutical acceptable derivative thereof, performing the function of reducing the transcript levels of VDR target genes induced by 1 ,25D3.

9. Compound according to claim 8, or a pharmaceutical acceptable derivative thereof, for use as a vitamin D receptor antagonist.

10. Compound according to any of claims 1 to 9, or a pharmaceutical acceptable derivative thereof, for use in the treatment of a non-human mammal.

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