WO2006042383A1

WO2006042383A1 - Vitamin-d analogue useful in a pharmaceutical composition

Info

Publication number: WO2006042383A1
Application number: PCT/BE2005/000147
Authority: WO
Inventors: Roger Bouillon; Annemieke Verstuyf; Pierre De Clercq; Maurits Vandewalle
Original assignee: K.U. Leuven Research & Development; Universiteit Gent
Priority date: 2004-10-19
Filing date: 2005-10-18
Publication date: 2006-04-27
Also published as: GB0423091D0

Abstract

The present invention relates to 14-epi-1α,25-(OH)2D3 analogues whereby the side chain contains at least two heteroatoms, pharmaceutical compositions and to their use for the treatment or prevention of bone disorders such as osteoporosis.

Description

VITAMIN-D ANALOGUE USEFUL IN A PHARMACEUTICAL COMPOS ITION

FIELD OF THE INVENTION

The present invention relates to a vitamin D₃ analogue, in particular a specific C/D cis-fusion analogue of Vitamin D₃. This invention further relates to a pharmaceutical composition comprising this vitamin D₃ analogue as an active ingredient, said composition being useful as a medicine, particularly for the prevention or treatment of bone diseases, more particularly osteoporosis.

The present invention provides furthermore methods for the preparation of this Vitamin D₃ analogue.

BACKGROUND OF THE INVENTION

Vitamin D of either nutritional (vitamin D₂ or D₃) origin or produced in the skin under the influence of ultraviolet light is metabolized in several tissues to produce numerous vitamin D metabolites. 1 ,25(OH)₂D₃ (calcitriol) plays a central role in calcium and bone homeostasis through binding to the vitamin D receptor (hereinafter referred as VDR) in calcium-related target organs including intestine, bone, kidney and parathyroid glands. 1 ,25(OH)₂D₃ behaves as a classical steroid hormone as its synthesis is feedback controlled by several hormones, ions and humoral factors to maintain a normal body homeostasis of plasma and bone minerals. The binding of 1 ,25(OH)₂D₃ to VDR triggers a sequence of events, eventually leading to changes in the transcription of 1 ,25(OH)₂D₃ target genes. Moreover there is some evidence for vitamin D and some of its metabolites and analogues to act via non- genomic mechanisms, either by activating ion channels or other membrane related or second messenger signals.

Bone turnover is a homeostatic process in nature which is necessary for the renewal of defective bone that occurs as a result of normal aging or trauma. This process is essential to the maintenance of skeletal integrity and is performed by the activity of two cell types, the bone resorbing osteoclasts and the bone forming osteoblasts. Currently, bone loss disorders such as osteoporosis are treated with anti-bone resorption agents such as antiestrogens or biphosphonates. The treatment of osteoporosis with 1 ,25(OH)₂D₃ is still controversial as both an increase in bone mineral density (BMD) in the spine and forearm with reduction of vertebral fractures, as the opposite have been reported. In addition the use of relatively high doses of 1 ,25(OH)₂D₃ in patients with osteoporosis has been hampered by the induction of hypercalcemia and hypercalciuria.

U.S. Patent No. 6,017,907 describes the synthesis and biological activi¬ ties of a group of vitamin D analogues, including C/D cis-fused analogues. The biological activities described in this document refer to inhibition of cell proliferation, induction of cell differentiation, treatment and prevention of immune disorders, inflammatory diseases, skin disorders, hyperproliferative disorders and cancer, and improving the function of cells in which calcium is an essential regulating agent. U.S. Patent No. 6,017,907 teaches, based on figure 6 showing an evaluation in rachitic chicks after treatment for ten consecutive days with three individual compounds referred as 4, 5 and 58, by measuring serum and bone calcium and serum osteocalcin, that these vitamin D₃ analogues have strikingly lower effect on calcium and bone homoeostasis, i.e. do not have the same toxic effect as previously known vitamin D₃ compounds. U.S. Patent No. 6,017,907 does not teach or suggest using these vitamin D₃ analogues for the therapy or prevention of bone disorders such as osteoporosis, renal osteodystrophy or osteomalacia.

There is a need in the art for vitamin D₃ analogues being potent bone protecting agents by selectively targeting bone formation rather than bone resorption or intestinal calcium absorption, thus leading to less calcemic effects (such as hypercalcemia or hypercalciuria) than 1 ,25(OH)₂D₃. There is also a need in the art for vitamin D₃ analogues which are both efficient and safe in the treatment of bone disorders such as osteoporosis, renal osteodystrophy or osteomalacia.

SUMMARY OF THE INVENTION

We have now discovered a novel vitamin D₃ analogue, more particularly a specific C/D cis-fusion analogue of vitamin D₃ with two heteroatoms, preferably two oxygen atoms, in the sidechain of the D ring. We have also discovered that this novel Vitamin D₃ analogue surprisingly has a potent and selective profile on bone formation, rather than on bone resorption or intestinal calcium absorption when compared with Vitamin D₃ and other analogues thereof. This property makes it surprisingly useful for the prevention or treatment of bone disorders such as, but not limited to, Paget's disease, renal osteodystrophy, osteomalacia and osteoporosis.

The novel compound of present invention maintains most of the essential characteristics of vitamin D₃ action but with a more selective biolo¬ gical pattern (bone anabolic effects). Its chemical structure includes modifica- tions both in the central CD-region (14-epimerisation) and in the side chain of the D ring in the form of a 22-oxa substitution.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows changes (expressed in percentage) in the vertrebral bone mineral density (BMD), as measured by dual-energy X-ray absorptio¬ metry on day 78, of 6-month old rats which (from left to right) have been sham-operated (SHAM) or ovariectomized (OVX) or, after being allowed to lose bone for 2 months, treated during 82 days with the vitamin D compound of the invention administered once daily, seven days a week at a dose of 30 μg/kg/day. SHAM and OVX control animals were treated with vehicle (arachis oil).

Figure 2 shows the body weight, as a function of time, of 6-month old rats which have been sham-operated (SHAM) or ovariectomized (OVX) or, after being allowed to lose bone for 2 months, treated during 82 days with the vitamin D compound of the invention administered once daily, seven days a week at a dose of 30 μg/kg/day. SHAM and OVX control animals were treated with vehicle (arachis oil).

Figure 3 shows serum calcium levels, determined at the end of experiment, in 6-month old rats which (from left to right) have been sham- operated (SHAM) or ovariectomized (OVX) or, after being allowed to lose bone for 2 months, treated during 82 days with the vitamin D compound of the invention administered once daily, seven days a week at a dose of 30 μg/kg/day. SHAM and OVX control animals were treated with vehicle (arachis oil).

Figure 4 shows serum osteocalcin levels, determined at the end of experiment, in 6-month old rats which (from left to right) have been sham- operated (SHAM) or ovariectomized (OVX) or, after being allowed to lose bone for 2 months, treated during 82 days with the vitamin D compound of the invention administered once daily, seven days a week at a dose of 30 μg/kg/day. SHAM and OVX control animals were treated with vehicle (arachis oil).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the compound corresponding to the following structure

said compound being also named (1 f?,3R)-5-((E)-2-((1 S,3aS,7aR)-1 -((1 S)-I- (3-hydroxy-3-methylbutoxy)ethyl)-7a-methyloctahydro-4H-inden-4-ylidene)- ethylidene)cyclohexane-1 ,3-diol or, using abbreviations and notations standard in the vitamin-D field, 14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃. The present invention also relates to a pharmaceutical composition including said compound as an active ingredient, optionally together with one or more pharmaceutically acceptable excipients, diluents or carriers as inactive ingredients. In such a pharmaceutical composition, 14-epi-19-nor-22- oxa-1α,25-(OH)₂D₃ is preferably present in a concentration range (drug loading ratio) from about 0.1 to "100% by weight, preferably about 0.5-50% by weight, more preferably 1-30% by weight. Such a pharmaceutical composition may be in the form of a dose comprising from about 1 μg to 1 ,000 mςj, preferably or alternatively from about 200 μg to 500 mg, more preferably or alternatively from about 300 μg to about 100 mg, of the compound of this invention, 14-epi-19-nor-22~oxa~1 α,25-(OH)₂D₃, together with one or more pharmaceutically acceptable excipients, diluents or carriers

The present invention also relates to the use of this compound for the manufacture of a medicament for the treatment or prevention of bone disorders such as, but not limited to, osteoporosis, renal osteodystrophy, osteomalacia or Paget's disease in a mammal, more specifically in a human being, in particular in osteoporotic patients such as, but not limited to, postmenopausal women, postoophorectomy women, men with androge n deficiency, and elderly people at risk of osteoporotic fractures. The present invention also relates to a method of prevention or treatment of the above mentioned bone disorders in a mammal, more specifically in a human being, by administering to said mammal a therapeutically effective amount of th e above compound. In such a treament, the present invention shows th e unexpected advantage, compared to other vitamin D₃ analogues, of minimal or no side effects such as decreased renal function and/or hypercalcemia. The novel compound of this invention can be used alone in the appropriate form and route of administration, or can be used in combination with one or more other drugs known to be of therapeutic value in the same bone disorder, more specifically, in osteoporosis, osteomalacia or Paget's disease. Therefore, the invention further relates to a pharmaceutical composition comprising:

(a) a therapeutically effective amount of 14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃, and

(b) a therapeutically effective amount of at least one drug effective as a biologically active agent with respect to a bone disorder selected from trie group consisting of osteoporosis, osteomalacia and Paget's disease.

Preferably, said compound (a) and said at least one drug (b) are present in the above composition in respective proportions such as to provide a synergistic effect against said bone disorder, i.e. wherein the therapeutical effectiveness of the combination of 14-epi-19-nor-22-oxa-1a,25-(OH)₂D₃ and said drug is greater than the therapeutical effectiveness of each of 14— epi-19- nor-22-oxa-1α,25-(OH)₂D₃ or the drug alone by a statistically significant margin. This composition may be for instance in the form of a CDmbined preparation for simultaneous, separate or sequential use in therapy or prevention of bone disorders, e.g. in the form of a kit comprising a first container containing a therapeutically effective amount of 14-epi-19-nor-22- oxa-1α,25-(OH)₂D₃, and further comprising a second container containing a therapeutically effective amount of said at least one drug. In such a composition, the weight proportion of 14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃ with respect to said at least one drug (b) may be in the range of, but not limited to, about 5 to 95%, preferably 10 to 90%, more preferably 20 to 80%, depending upon the kind of drug (b). Many classes of drugs (b) may be considered for inclusion into the above (optionally synergistic) composition. A first class of drugs (b) consists of bisphosphonates known as being active in the treatment of osteoporosis such as, but not limited to, alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, neridronate, risedronate, zoledronic acid, incadronate, minodronate and olpadronate. A second class of drugs (b) consists of selective estrogen receptor modulators known as being active in the treatment of osteoporosis such as, but not limited to, raloxifene, tamoxifen, and droloxifene. As used herein, a selective estrogen receptor modulator (hereinafter referred as SERM) is a compound that either directly or through its active metabolite functions as an estrogen receptor antagonist (an " anti- estrogen ") in breast tissue, yet provides estrogenic or estrogen-like effect on bone tissue and on serum cholesterol levels (i.e. by reducing serum cholesterol). Non-steroidal compounds that function as estrogen receptor antagonists in vitro or in human or rat breast tissue (especially if the compound acts as an antiestrogen on human breast cancer cells) is likely to function as a SERM. Conversely, steroidal antiestrogens tend not to function as a SERM because they tend not to display any beneficial effect o n serum cholesterol. Non-steroidal antiestrogens found to function as a SERM include, but are not limited to, raloxifene, tamoxifen, droloxifene and a compound identified as EM-1538 in U .S. Patent No. 6,670,346. A SERM suitable for the present invention may be administered in the same dosage as known in the art when this compound is used as an anti-estrogen. Still other classes of drugs (b) include oestrogen supplements, fluorides and the like.

The therapeutically effective amount of the compound (a) of this invention, especially for the treatment of the above described bone disord ers in humans and other mammals, corresponds to an amount which ensu res plasma levels whereby the desired positive biological effect is present. Depending upon the pathologic condition to be treated and the patient's condition, the said effective amount may be divided into several sub-units per day or per week, or may be administered at more than one day intervals. The term " therapeutically effective amount " as used herein may vary according to a range of factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated. Although particular dosage regimes are described herein, the person skilled in the art appreciates that these dosage regimes may be altered, after due consideration of said factors for each class of patients or each individual patient, in order to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the requirements of the therapeutic situation. In addition, the compositions of the present invention can be administered as frequently as necessary to achieve a suitable therapeutic response in the patient being treated. For the purposes of the present invention a first aspect of " therapeutic amount " relates to compositions delivering the compound according to the present invention wherein the plasma level of said compound is from about 0.1 pg^mL to about 100 mg/mL in humans or higher mammals. Another aspect relates to compositions delivering the compound according to the present invention wherein said plasma level of said compound is from about 0.1 pg/mL to about 25 mg/mL in humans or higher mammals. Another aspect relates to composi¬ tions delivering the compound according to the present invention wherein said plasma level of said compound is from about 1 pg/mL to about 1 mg/mL in humans or higher mammals. Yet another aspect relates to compositions which deliver a compound according to the present invention wherein said plasma level of said compound is from about 1 pg/mL to about 10 μg mg/mL in humans or higher mammals. Another aspect relates to compositions which deliver a compound according to the present invention wherein said plasma level of said compound is from about 1 ng/mL to about 25 mg/mL in humans or higher mammals.

Administration of the compositions of the present invention can achieve the desired therapeutic amounts in vivo as measured by the plasma level in various ways. It is not necessary to provide the therapeutic amou nt of compound in a single dose, for example, a single pill. Therefore, the formulator can vary the size of the dosage, and therefore the amount of the active compound in the compositions.

As is conventional in the art, the evaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the median effect principle described by Chou et al. in Adv. Enzyme Reg. (1984) 22:27. Briefly, this principle states that interactions (synergism, additivity, antagonism) between two drugs can be quantified using the combination index (hereinafter referred as Cl) defined by the following equation:

^x ED;¹ ED/² wherein ED_x is the dose of the first or respectively second drug used alone (1a, 2a), or in combination with the second or respectively first drug (1 c, 2c), which is needed to produce a given effect. The said first and second drug have synergistic or additive or antagonistic effects depending upon Cl < 1 , Cl = 1 , or Cl > 1 , res pectively.

This principle may be applied to a combination of the drug (a) of this invention together with other drugs (b) that exhibit therapeutic effects on the above described bone disorders, e.g. calcium metabolism-related disorders.

The present invention further provides veterinary compositions comprising a therapeutically effective amount of 14-epi-19-nor-22-oxa- 1 α,25-

(OH)₂D₃ together with one or more veterinary carriers therefor. Veterinary carriers are materials useful for the purpose of administering the composition to mammals other than human beings and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient of the invention. These veterinary compositions may be administered orally, parenterally or by any other desired route, depending upon the species of mammal to be prevented or treated from a bone disease. The therapeutically effective amount of 14-epi-19~nor~22-oxa- 1α,25-(OH)₂D₃ in such veterinary compositions may be adapted to each species of mammals, starting from the therapeutically effective amount determined in rats from the following experimentation of the invention, and using the guidance formula for converting doses from one animal species to another animal species.

More generally, the invention relates to 14-epi-19-nor-22-oxa-1ot,25- (OH)₂D₃ being useful as an agent having biological activity or as a diagnostic agent. Any of the uses mentioned with respect to the present invention may be restricted to a non-medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.

The compound of this invention is preferably provided as a pure enantiomer, i.e. an individual optically active form having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of the desired enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%. A pure isomeric form of this compound is defined as an isomer substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term " stereoisomerically pure " or " chirally pure " relates to a compound having a stereoisomeric excess of at least about 80% (i.e. at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The compound of this invention, when intended to be included in a pharmaceutical composition, may be formulated with conventional carriers and excipients, which can be selected in accordance with ordinary pharmaceutical practice. For instance, tablets may contain excipients, glidants, fillers, binders and the like. Aqueous formulations are preferably prepared in sterile form and, when intended for delivery by other than oral administration, are usually isotonic. Pharmaceutical formulations optionally contain excipients such as those set forth in the " Handbook of Pharmaceutical Excipients " (1986) and may include ascorbic acid and/or other antioxidants, chelating agents, carbohydrates such as dextrin-containing compounds (e.g. maltodextrins and/or cyclodextrins), hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.

The term " pharmaceutically acceptable carrier " as used herein means any material or substance with which the active ingredient is formu lated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the pharmaceutical compositions of this invention can suitably be in the form of concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.

Suitable pharmaceutical carriers for use in the pharmaceutical compositions and formulations of the invention are well known to those skilled in the art. They also include additives such as, but not limited to, wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredient, in a one-step or multi-steps procedure, with the selected one or more carrier materials and, where appropriate, the other additives such as surface-active agents. They may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 μm, namely for the manufacture of microcapsules for controlled or sustained release of the active ing redient.

Suitable surface-active agents, also known as emulsifiers, that can be used in the pharmaceutical compositions of the present invention include non- ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water- soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher (C10-C₂2) fatty acids, e.g. the sodium or potassium salts of oleic acid, stearic acid or natural fatty acid mixtures obtainable from coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimi- dazole derivatives preferably having 8 to 22 carbon atoms; and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Examples of alkylarylsulphonates are the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl-naphtalenesulphonic acid or a naphtalenesulphonic acid/formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose include natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as, but not limited to, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lyso- lecithin, cardiolipin, dioctanylphosphatidylcholine, dipalmitoylphoshatidyl- choline and mixtures thereof in various proportions.

Suitable non-ionic surfactants include polyethoxylated and polypropoxy- lated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule , alkylarene- sulphonates and dialkylsulphosuccinates such as, but not limited to, polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing from 3 to 10 glycol ether groups and from 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and/or from 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing from 1 to 10 carbon atoms in the alkyl chain, which adducts contain from about 20 to 250 ethyleneglycol ether groups and/or from 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic su rfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolic ethers, polypropy- lene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.

Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon radicals optionally su bstituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C₈-C₂₂ alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated Ci-C₄ alkyl, benzyl and/or hydroxy Ci-C₄ alkyl radicals.

A more detailed description of surface-active agents suitable for this purpose may be found for instance in " McCutcheon's Detergents and Emulsifiers Annual " (MC Publishing Group, Ridgewood, New Jersey, 1981 ), " Tensid-Taschenbuch ", 2^nd ed. (Hanser Verlag, Vienna, 1981 ) and " Encyclopaedia of Surfactants " (Chemical Publishing Co., New York, 1981).

The compound of this invention may be administered by any route appropriate for the bone disorder to be treated. Suitable routes include, but are not limited to, oral, rectal, nasal, topical (including transdermally, ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intra-arterially, intradermal, intrathecal and epidural) routes. The preferred route of administration may vary in accordance with certain clinical parameters, for example with the condition of the patient to be treated.

Pharmaceutical formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. A suitable tablet may be made by compression or molding, optionally with one or more pharmaceutically acceptable inactive ingredients such as described hereinabove. Compressed tablets may be prepared by compressing, in a suitable compressing machine, the active ingredient in a free-flowing form such as a powder, granules, beads or pellets, optionally admixed with one or more pharmaceutically acceptable excipients such as binders, lubricants, inert diluents, preservatives, and surface-active or dispersing agents. Molded tablets may be made by molding , in a suitable molding machine, a mixture of the powdered active compound moistened with suitable amounts of one or more inert liquid diluents. The tablets may optionally be further coated, and may be formulated so as to provide slow or controlled release of the active ingredient therein.

The pharmaceutical formulations of the invention are optionally in the form of a topical ointment or cream. When formulated in an ointment, the active ingredient may be admixed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30 % by weight of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups either in a monorneric form such as, but not limited to, propylene glycol, butane-1 ,3-diol, mannitol, sorbitol and glycerol, or in apolymeric form such as polyethylene glycol (with various numbers of repeating units, including PEG 400) and mixtures thereof. Topical formulations may desirably include at least a compound which enhances absorption or penetration of the active ingredient through the skin or other areas of application. Examples of such dermal penetration enhancers include, but are not limited to, dimethylsulfoxide and related analogues. The solubility of the active compound of this invention in most pharmaceutically acceptable oils is quite high. Thus a cream formulation may suitably include one or more straight or branched chain, mono- or dibasic alkyl esters such as, but not limited to, di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP, the three latter being preferred esters. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns, which may be administered by rapid inhalation through the nasal passage from a container. Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include oily solutions of the active ingredient.

When the pharmaceutical formulation is intended for a female patient, the active compound of the invention may be delivered into the systemic circulation through the vaginal mucosa from a vaginal device incorporated with a transmucosal vaginal composition. Said composition may be formulated and incorporated into the device as a suppository, cream, spray, gel, film, powder, foam, ointment, microcapsules, nanocapsules or a capsule containing microparticles or nanoparticles; and said vaginal device may be a vaginal tampon, vaginal ring, vaginal strip, vaginal capsule, vaginal tablet, vaginal pessary, vaginal cup or vaginal sponge; and said composition is delivered to the vaginal mucosa by inserting said device into the vagina.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the patient; and aqueous and non-aqueous sterile suspensions which may include one or more suspending agents and/or thickening agents. The formulations may be presented in unit-dose or rnulti-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dosage formulations are those containing a daily dose or a weekly dose, as described herein, or an appropriate fraction thereof, of the active ingredient of this invention.

The present invention also provides controlled release pharmaceutical formulations, containing as an active ingredient the novel compound of the invention, in which the release of the active ingredient is controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of said compound. Controlled release formulations adapted for oral administration in which discrete units comprising the compound of the invention can be prepared according to conventional methods in the art.

Additional ingredients may be included in order to control the duration of action of the active ingredient in the composition. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino-acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethylmethacrylate and other similar polymers. Such compositions include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and the like. Depending upon the selected route of administration, the pharmaceutical composition may require protective coatings.

In view of the fact that, when the novel active ingredient (a) according to this invention is used in combination with one or more other drugs (b), they do not necessarily bring out their joint therapeutic effect directly at the same time in the mammal to be treated, the corresponding composition may also be in the form of a medical kit or package containing the two ingredients in separate compartments. In the latter context, each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.

Another aspect of the invention relates to methods and intermediates for the preparation of 14-epi-19-nor-22-oxa-1α,25-(OH )₂D₃. The following example 1 provides a preferred synthetic method for preparing said novel vitamin D compound in good yield and with a minimum number of synthetic steps. However, the skilled person understands that other manufacturing routes may be used while producing the desired vitamin D compound in a reasonably similar yield and with a similar purity, even at the expense of additional synthetic steps and/or starting from different molecules and reactants.

The preferred synthetic method for preparing the novel vitamin D compound of this invention starts from the 22-oxa-25-OH ketone (please provide full IUPAC nomenclature for this compound — has been provided by Prof. De Clercq) designated as compound 1 in the following scheme. The preferred synthetic method for preparing the novel vitamin D compound of this invention includes a first step wherein said 22-oxa-25-OH ketone is epimerized by reaction with an epimerizing agent optionally in the presence of a suitable solvent for the ketone and the epimerizing agent. Preferably this first step is carried out under basic conditions, e.g. the epimerizing agent being an alkaline alcoholate such as sodium or potassium methanolate or ethanolate, and the solvent being an alcohol such as methanol or ethanol. Preferably this first step include separation of the mixture of epimers by any suitable method such as chromatography, more preferably high performance liquid chromatography (hereinafter referred as HPLC). As a result of this first step, the epimer ketone designated as compound 2 in the following scheme is produced as a novel intermediate.

In a second step, the novel intermediate compound 2 is reacted with a molar excess of a suitable phosphine oxide such as, but not limited to, the hydroxyl-protected phosphine oxide designated as compound 3 in the following scheme. Reaction preferably takes place under inert and anhydrous conditions in the presence of an alkyl metal wherein the alkyl group has from 1 to 5 carbon atoms and wherein the metal is an alkaline metal, preferably such as butyl lithium and the like, for instance under a nitrogen or argon atmosphere, and preferably at a temperature below O⁰C, more preferably between about -80⁰C and about -20⁰C. Reaction also preferably takes place in the presence of one or more organic solvents such as tetrahydrofuran, hexane, cyclohexane, or mixtures thereof. The molar excess of the suitable phosphine oxide may be quite significant, i.e. may involve a molar ratio from about 1.5 to about 10 with respect to the novel intermediate compound 2. As a result of this second step, the epimer ketone designated as compound 4 in the following scheme is produced as a novel intermediate still having protecting groups (here tributylsilyl) at carbons 1 and 3 of the vitamin D structure.

In a third and final step, the novel intermediate compound 4 is deprotected, using deprotection methods standard in the art and suitable for the relevant protecting groups. A recommended method for deprotecting a tributylsilyl group involves the use, in a suitable organic solvent, of a molar excess of a reactant such as, but not limited to, tetrabutylammonium fluoride.

In each of the second and third steps of the preparation method, it is preferred to purify the intermediate or final product formed by means of standard purification methods such as, but not limited to, HPLC. The following examples are only illustrative of methods for making the specific vitamin D₃ compound of the invention, methods of evidencing its biological activities and methods of using it as an active ingredient in a medicament for therapeutic treatment. They should by no means be meant to limit the scope of the various aspects of the present invention.

Example 1- synthesis of (1R3ffl-5-((E)-2-((1 S,3aSJaRV1-((1 S)-1-(3-hvdroxy- 3-methylbutoxy)ethyl)-7a-methyloctahvdro-4/-/-inden-4-ylidene)ethylidene)- cvclohexane-1 ,3-diol (14-epi-19-nor-22-oxa-1α,25-(OI-0?D3)

The synthesis of 14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃ was performed according to the following scheme. Synthesis starts from the ketone designated below as compound 1 ((1 S,3aR,7aR)-1-((1 S)-1-(3-hydroxy-3- methylbutoxy)ethyl)-7a-methyloctahydro-4H-inden-4-one), which is readily available by deprotecting the corresponding trimethylsilyl derivative, the latter being obtained for instance as described by Y. Fall in Tetrahedron Lett. (1997) 38:4909-4912.

Epimerization of compound 1 :

To ketone 1 (0.043 g, 0.15 mmol) in MeOH (2 ml_) was added MeONa (30 wt.

% in MeOH; 0.01 ml_) and the solution was stirred at room temperature for 16 hours. The solvent was removed under a nitrogen stream, and the resulting residue was passed through a short column of silica gel (the eluent being a n- hexane/ethyl acetate mixture 1 :1). The crude product was purified by HPLC on silica gel (using a n-hexane/ethyl acetate 2:1 mixture) so as to provide the epimer ketone 2, (1 S,3aS,7aR)-1 -((1 S)-1 -(3-hyd roxy-3-methylbutoxy)ethyl)- 7a-methyloctahydro-4H-inden-4-one, (0.038 g) with a 88% yield. The latter was fully characterized as follows:

- R_f (n-hexane/ethyl acetate 2:1 ) 0.20;

- [α]_D ^rt +67.0 (c = 5.25, CHCI₃);

- IR (KBr film) absorption bands at 3498, 2967, 1704, 1469, 1372, 1162, 1087 and 567 cm^"1; - proton nuclear magnetic resonance (hereinafter referred as ¹H NMR) (360 MHz, CDCI₃): chemical shifts at δ = 3.81 (1 H, td, J = 9.1 , 4.1 Hz), 3.48- 3.37 (2 H, m), 2.45-2.20 (4 H, m), 2.12 (1 H , m), 1.95-1.50 (9 H, m), 1.22 (6 H, s), 1.15 (3 H, d, J = 6.2 Hz) and 1.05 (3 H, s) ppm;

- carbon nuclear magnetic resonance (hereinafter referred as ¹³C NMR) (75 MHz, CDCI₃): chemical shifts at δ = 213.5, 75.5, 70.4, 65.4, 61.0, 51.8,

48.4, 41.8, 39.4, 35.0, 29.7, 28.8, 23.6, 23.2, 21.7 and 18.8 ppm;

- mass spectrum MS m/z (%): 282 (M⁺, 1 ), 267 (2), 237 (1 ), 179 (14), 152 (17), 113 (30), 87 (29), 69 (100) and 43 (42).

Coupling of epimer 2:

To a solution of the 19-nor A-ring phosphine oxide shown in the above scheme with formula 3 (0.285 g, 0.5 mmole, being available e.g. from Perlman et al. in Tetrahedron Lett. (1991 ) 32:7663-7666) in 5.0 ml_ dry tetrahydrofuran (hereinafter referred as THF) at -78 °C under an argon atmosphere was dropwise added n-BuLi (0.44 mmole as a 2.5 M solution in hexane, 0.175 ml_). The formed dark-red solution was then stirred at -78 °C for 1 hour, and a solution of the epimer ketone 2 (0.035 g, 0.1 mmole) in dry THF (1.5 ml_) was dropwise added. The red solution was stirred at -78 °C for 2 hours and was then allowed to warm up to room temperature. The reaction mixture was loaded onto a silica gel column and the reaction product was eluted (n- hexane/ethyl acetate/triethylamine, 9:1 :0.1 mixture) to afford the protected 1 ,25-D₃ analogue shown in the above scheme with formula 4, (1R,3R)-5-((E)- 2-((1 S,3aS,7aR)-1 -((1 S)-1 -(3-hydroxy-3-methylbutoxy)ethyl)-7a-methylocta- hydro-4H-inden-4-ylidene)ethylidene)-1 ,3-bis(te/f-butyIdimethylsilyloxy)cyclo- hexane.

Deprotection of the 1,25-D₃ analogue 4: To a solution of 4 (0.052 g, 0.1 mmole) in THF (2.8 ml_) was added tetrabutylammonium fluoride (1.5 mmole as a 1 M solution in THF, 1.5 ml_). The reaction mixture was stirred at room temperature for 12 hours and then loaded onto a silica gel column. The reaction product was eluted (n- hexane/dimethylketone 4:6 mixture) and further purified by HPLC (π-hexane/ dimethylketone 65:35 mixture) so as to provide the desired 1 ,25-D₃ analogue shown in the above scheme with formula 5 (0.034 g) with a yield of 83% over the combination of coupling and deprotection steps). The latter was fully characterized as follows:

- R_f (n-hexane/dimethylketone 2:3 mixture) 0.40; - [α]_D ^rt +72.0 (c = 1.00, CHCI₃);

- IR (KBr film) absorption bands at 3382, 2931 , 1618, 1377 and 1049 cm^"1;

- ¹H NMR (500 MHz, CDCI₃): δ = 6.25 (1 H, d, J = 11.3 Hz), 6.04 (1 H, d, J = 11.3 Hz), 4.11 (1 H, m), 4.08 (1 H, m), 3.81 (1 H, td, J = 9.2, 3.7 Hz), 3.59- 3.49 (2 H, m), 2.70 (1 H, dd, J = 13.5, 3.6 Hz), 2.49 (2 H, m), 2.28 (2 H, m), 2.18 (1 H, dd, J = 13.5, 6.5 Hz), 2.10-1.40 (14 H, m), 1.27 (3 H, s), 1.25 (3

H, s), 1.12 (3 H, d, J = 6.2 Hz) and 0.94 (3 H, s) ppm;

- ¹³C NMR (75 MHz, CDCI₃): δ = 142.6, 131.4, 123.9, 119.0, 76.3, 70.6, 67.5, 67.2, 65.1 , 57.0, 54.8, 45.4, 44.8, 42.1 , 41.8, 37.3, 36.5, 29.8, 28.7, 24.4, 23.6, 23.1 , 20.5, 18.0 and 14.2 ppm; and - MS m/z (%): 406 (M⁺, 2), 388 (M⁺ - 18, 1 ), 302 (10), 273 (4), 229 (3), 187 (8), 161 (17), 113 (25), 91 (28) and 69 (100).

Example 2 - binding properties of (1R3RV5-((E)-2-((1 S,3aS,7aR)-1 -((1 S)-I- (3-hvdroxy-3-methylbutoxy)ethyl)-7a-methyloctahvdro-4H-inden-4-ylidene)- ethylidene)cvclohexane-1 ,3-diol (14-epi- 19-nor-22-oxa-1α,25-(OH)?D3)

Affinity for vitamin D receptor (VDR)

The following methods used to evaluate the binding properties of the compound 5 produced in example 1 (14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃) are state of the art techniques used for steroid hormone (including vitamin D) binding assays.

The affinity of 14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃ to the vitamin D receptor was evaluated by its abil ity to compete with [³H]1α,25(OH)₂D₃ for binding to high speed supernatant from intestinal mucosa homogenates obtained from normal pigs. Incubation was performed at 4°C for 20 hours and phase separation was obtained by addition of dextran-coated charcoal. The relative affinity of 14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃ was calculated from its concentration needed to displace 50% of [³H]1α,25(OH)₂D₃ from its receptor compared with the activity of 1α, 25(OH)₂D₃ (which was assigned a value of

100 %).

Affinity for human vitamin D binding protein (hDBP)

Binding of (1 R,3R)-5-((E)-2-((1 S,3aS,7af?)-1 -((1 S)- 1 -(3-hydroxy-3- methylbutoxy)ethyl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)- cyclohexane-1 ,3-diol (14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃) to hDBP was perfor-med at 4°C. Briefly, [³H]I α,25(OH)₂D₃ and 1α,25(OH)₂D₃ or 14-epi-19- nor-22-oxa-1α,25-(OH)₂D₃ were added in 5 μl ethanol into glass tubes and incubated with hDBP (0.18 μM) in a final volume of 1 ml (0.01 M Tris-HCI buffer and 0.154 M NaCI, pH 7.4) for 3 hours at 4°C. Phase separation was then obtained by the addition of 0.5 ml of cold dextran-coated charcoal.

Results

Table 1 below shows that (1 R,3R)-5-((E)-2-((1 S,3aS,7aR)-1-((1 S)-1-(3- hydroxy-3-methylbutoxy)ethyl)-7a-methyloctahydro-4H-inden-4-ylidene)- ethylidene)cyclohexane-1 ,3-diol (14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃) displayed 12 times lower affinity for VDR compared with 1 ,25(OH)₂D₃ and no affinity for hDBP.

Table 1

Example 3 - in vivo activity of 14-epi-19-nor-22-oxa-1α,25-(OH)?D3.

Eight weeks old, male NMRI mice were fed with a vitamin D-replete diet

(0.2% calcium, 1% phosphate, 2O00 U vitamin D/kg; commercially available from Hope Farms, Woerden, The Netherlands). Groups of six mice were intraperitoneally injected daily during 7 consecutive days with different doses of 1 ,25(OH)₂D₃ (0.1 , 0.2 and 0.4 μg/kg/day) or 14-epi-19-nor-22-oxa~1α,25-

(OH)₂D₃ (i.e. compound 5 of example 1 ). The control group was injected with vehicle (arachis oil). The average weight of each group of 6 mice was determined at the beginning and at the end of the experiment. The following parameters were evaluated:

- serum calcium was measured by a microcolon metric assay (Sigma, St. Louis, Missouri).

- femurs were removed and femur calcium content was measured in HCI- dissolved bone ash (obtained by heating for 24 hours in an oven at 100⁰C), using the same technique as for serum calcium.

Student's t-tests were carried out to detect significant differences; p < 0.05 was accepted as being significant.

Results

The following biological profile was demonstrated in a first screening assay injecting mice during 7 consecutive days intraperitoneally with several doses of 14-epi-19-nor-22-oxa-1 α, 25-(OH)₂D₃ (i.e. compound 5 of example 1 ) or vehicle as a control. Table 2 demonstrates a highly advantageous selectivity profile of 14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃ with no significant increase in serum calcium levels compared to vehicle treated animals together with significant increase in calcium content in bone (at least 12 % more than vehicle-treated animals). The preferential activity of this compounds on bone without major calcemic side effects allows the in vivo administration of this compound for the treatment of metabolic bone diseases where bone loss is a major concern. Table 2

Example 4 - restoration of bone loss by 14-epi-19-nor-22-oxa-1α,25-(OH)9D₃.

The following ovariectomized rat model is a standard animal model for testing the effects of bone active agents.

Virgin female Sprague-Dawley rats were obtained from Charles Rivers Labs., Portage, Missouri. Animals were ovariectomized (hereinafter abbre¬ viated as OVX) or sham-operated (SHAM) by Charles Rivers Labs, at S months of age and allowed to lose bone for 2 months. The rats were pair- housed in polycarbonate cages throughout the acclimatization and study period. The rats received Harlan Teklad #8604 Rodent Blox (Harlan Industries, Indianapolis, Indiana) food and water ad libitum. Each group consisted of 5 to 6 rats. The pre-treatment groups were sacrificed at the start of treatment (day 0) 60 days post-ovariectomy. All other rats were treated during 82 days with the compound 5 produced in example 1 (14-epi-19-nor- 22-oxa-1α,25-(OH)₂D₃) or with vehicle (control) by oral gavage administred once daily, seven days a week.

Rats were euthanized after 82 days of treatment. Body weights were recorded upon arrival, once weekly prior to the start of treatment, at start of treatment, and once weekly thereafter. These weights were used for health evaluation and randomization.

Anesthetized animals were scanned in vivo using the dual-energy X-ray absorptiometry (DXA, Hologic 4500A (DXA: Hologic^® QDR-2000 Plus bone densitometer; Hologic^®, Inc., Waltham, Massachussetts) prior to the beginning of the treatment period and at day 78. At necropsy, blood was obtained by cardiac puncture. Serum was separated and stored at -80 ⁰C. Measurements included calcium determined by a colorimetric assay and osteocalcin (marker for bone turnover) determined by a a Rat MID™ Osteocalcin ELISA kit obtained from Nordic Bioscience Diagnostics.

In vivo administration of 30 μg/kg/day 14-epi-19-nor-22-oxa-1α,25- (OH)₂D₃ (i.e. compound 5 of example 1) resulted in an increase in trabecular bone mineral density (BIVlD) compared to the OVX rats with vehicle treatment, as shown in Figure 1. No animals lost weight during the 82 days of treatment, as shown in Figure 2, thus providing a good indication of general healthness of all rats used in this experiment. Serum calcium levels were not increased after 82 days of treatment, compared to the vehicle treated OVX and SHAM rats, as shown in Figure 3. The osteocalcin levels (osteocalcin is a specific bone protein considered as a marker of metabolic activity of osteoblasts) in the serum of OVX rats treated with 30 μg/kg/day 14-epi-19-nor-22-oxa-1α,25- (OH)₂D₃ are higher than the osteocalcin levels in vehicle treated OVX rats, as shown in Figure 4.

All these data together show that the administration of 30 μg/kg/day 14- epi-19-nor-22-oxa-1α,25-(OH)₂D₃ (i.e. compound 5 of example 1 ) in rats provides a strong increase in bone mineral content and serum osteocalcin content without elevating serum calcium levels. These observations are fully consistent with the requirements of a prevention or treatment of a bone disorder such as, but not limited to, osteoporosis, renal osteodystrophy, osteomalacia or Paget's disease. The therapeutic dose of 14-epi-19-nor-22- oxa-1α,25-(OH)₂D₃ (i.e. compound 5 of example 1 ) will be adapted for other species of mammals, including human beings, starting from the above observations in rats, based on well known guidance for calculating the human equivalent dose.

Comparative example 5

The compound of example 43 of U.S. Patent No. 6,017,907 (hereinafter referred as KS 532) was tested for bone effects in the same tests as described herein above. Table 3 below shows that this compound exhibits no selectivity for bone effects. This compound was found to have significant increased or decreased serum calcium levels together with significant decreased femur calcium levels compared to the vehicle treated animals. No animal at any of the doses tested was able to demonstrate significant increase on femur calcium levels, compared to the vehicle treated animals. The biological profile of this known vitamin D₃ analogue is therefore unfavourable for a therapeutic use in bone disorders.

Table 3

* p < 0.05

Claims

1. The compound 14-epi-19-nor-22-oxa-1α,25-(OH)₂D₃ according to the structural formula below:

2. The compound of claim 1 , being characterized by chemical shifts of proton nuclear magnetic resonance at 6.25 (1 H, d), 6.04 (1 H, d), 4.1 1 (1 H, m), 4.08 (1 H, m), 3.81 (1 H, td), 3.59-3.49 (2 H, m), 2.70 (1 H, dd), 2.49 (2 H, m), 2.28 (2 H, m), 2.18 (1 H, dd), 2.10-1.40 (14 H, m), 1.27 (3 H, s), 1.25 (3 H, s), 1.12 (3 H, d) and 0.94 (3 H, s) ppm.

3. The compound of claim 1 , being characterized by chemical shifts of carbon nuclear magnetic resonance at 142.6, 131.4, 123.9, 119.0, 76.3, 70.6, 67.5, 67.2, 65.1 , 57.0, 54.8, 45.4, 44.8, 42.1 , 41.8, 37.3, 36.5, 29.8, 28.7, 24.4, 23.6, 23.1 , 20.5, 18.0 and 14.2 ppm.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of claims 1 to 3, and one or more pharmaceutically acceptable excipients.

5. A pharmaceutical composition according to claim 4, in the form of a dose comprising from 0.O01 mg to 1 ,000 mg of said compound.

6. Use of the compound of claim 1 for the manufacture of a medicament for the treatment or prevention of bone disorders in a mammal.

7. The use of claim 6, wherein said bone disorder is selected from the group consisting of Paget's disease, renal osteodystrophy, osteomalacia and osteoporosis.

8. A method of prevention or treatment of a bone disorder in a mammal, comprising the administration to said mammal of a therapeutically effective amount of a compound according to any of claims 1 to 3.

9. A method of prevention or treatment according to claim 8, wherein said bone disorder is selected from the group consisting of Paget's disease, renal osteodystrophy, osteomalacia and osteoporosis.

10. A method of prevention or treatment according to claim 8 or claim 9, wherein said mammal is a human being, and wherein said therapeutically effective amount is within a range from about 2 to 20 μg per day and per kg body weight of said mammal.

11. A method of prevention or treatment according to any of claims 8 to 10, wherein said mammal is selected from the group consisting of postmenopausal women, postoophorectomy women, men with androgen deficiency, and elderly people at risk of osteoporotic fractures.

12. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound according to any of claims 1 to 3, and

(b) a therapeutically effective amount of at least one drug effective as a biologically active agent with respect to a bone disorder selected from the group consisting of osteoporosis, osteomalacia and Paget's disease.

13. A pharmaceutical composition according to claim 12, wherein said compound (a) and said at least one drug (b) are present in said composition in respective proportions such as to provide a synergistic effect against said bone disorder.

14. A pharmaceutical composition according to claim 12 or claim 13, wherein the weight proportion of said compound (a) with respect to said at least one drug (b) is within the range of 5% to 95%.

15. A pharmaceutical composition according to any of claims 12 to 14, wherein said drug (b) is selectyed from the group consisting of alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, neridronate, risedronate, zoledronic acid, incadronate, minodronate, olpadronate, and selective estrogen receptor modulators.

16. A compound selected from the group consisting of (1 S₁SaSJaR)-I -((1 S)- 1-(3-hydroxy-3-methylbutoxy)ethyl)-7a-methyIoctahydro-4/-/-inden-4-one and (1 R,3R)-5-((E)-2-((1 S,3aS,7aR)-1 -((1 S)- 1 -(3-hydroxy-3-methylbutoxy)ethyl)- 7a-methyloctahydro-4/-/-inden-4-ylidene)ethylidene)-1 ,3-bis(te/if-butyldimethyl- silyloxy)cyclohexane.

17. Use of a compound according to claim 16 for the preparation of the compound of claim 1.