This invention relates to a hitherto unknown class of compounds which shows an immunomodulating effect as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including cancer cells and skin cells, to pharmaceutical preparations containing these compounds, to dosage units of such prepa¬ rations, and to their use in the treatment and prophylaxis of autoimmune diseases, including diabetes mellitus, hyper¬ tension, inflammatory diseases such as rheumatoid arthritis and asthma as well as diseases characterized by abnormal cell differentiation and/or cell proliferation, and/or imbalance in the immune system. The compounds of the present invention are repre¬ sented by the general formula I

in which R 1 and R2 may be the same or different and stand for hydrogen, lower alkyl, lower cycloalkyl, or, taken together with the carbon atom (starred in formula I), bearing the groups X, R 1 and R2, can form a C~-C„ carbo-

cyclic ring; X stands for hydrogen or hydroxy, R3 and R4, which may be the same or different stand for hydrogen,- lower alkyl or halogen, n is 0, 1 or 2 and m is 0, 1 or 2.

In the context of this invention, the expression "lower alkyl" indicates a straight or branched saturated or unsaturated carbon chain containing from 1 to 5 carbon atoms, and the expression "lower cyclo-alkyl" indicates a saturated or unsaturated C -C„ carbocyclic ring.

As can be seen from formula I, depending on the meanings of X, R 1 and R2, the compounds of the invention can comprise several diastereoisomeric forms (e.g. R or configuration at the starred carbon atom). The invention covers all these diastereoisomers in pure form and also mixtures of diastereoisomers. In addition, derivatives of I in which one or more of the hydroxy groups are masked as groups which can be reconverted to hydroxy groups in vivo are also within the scope of the invention ( "bioreversible derivatives or prodrugs of I" ) .

The term "bioreversible derivatives or prodrugs of I" includes, but is not limited to, derivatives of the com¬ pounds of formula I in which one or more hydroxy groups have been transformed into -O-acyl or -O-glycosyl groups, or a phosphate ester, such masked groups being hydrolyzable in vivo. Compounds of formula I in which X is hydrogen are another type of prodrug. These compounds are relatively inactive in vitro, but are converted to active compounds of formula I (X = OH) by enzymatic hydroxylation after administration to the patient. It has recently been shown that lα,25-dihydroxy- vitamin D ₃ (1,25(OH) ₂ D^) influences the effects and/or production of interleukins, indicating the potential use of this compound in the treatment of diseases characterized by a dysfunction of the immune system, e.g. autoimmune diseases and rejection of transplants. In addition, other conditions characterized by an abnormal interleukin-1 production, e.g. inflammatory diseases such as rheumatoid arthritis may be treated with 1,25(0H) ₂ D ₃ -

It has also been shown that l,25(OH) ₂ D_ is able to stimulate the differentiation of cells and inhibit exces¬ sive cell proliferation, and it has been suggested that this compound might be useful in the treatment of diseases characterized by abnormal cell proliferation and/or cell differentiation such as cancer and psoriasis.

Also, the use of 1,25(0H) ₂ D ₃ for the treatment of hypertension and diabetes mellitus has been suggested.

However, the therapeutic possibilities in such indi- cations of 1,25(0H) ₂ D ₃ are severely limited by the well known potent effect of this hormone on calcium metabolism; elevated blood concentrations will rapidly give rise to hypercalcemia. Thus, this compound and its potent synthetic analogues are not completely satisfatory for use as drugs in the treatment of e.g. psoriasis, cancer or immune diseases which may require continuous administration of the drug in relatively high doses.

A number of oxa-analogues of vitamin D ₃ are known, lα,25-dihydroxy-20-oxa-21-norvitamin D ₃ and lα-hydroxy- -20-oxa-21-norvitamin D ₃ are described in N. Kubodera et al, Chem. Pharm. Bull., 34, 2286 (1986), lα,25-dihydroxy- -22-oxavitamin D_ and 25-hydroxy-22-oxavitamin D,-. are de¬ scribed in E. Murayama et al, Chem. Pharm. Bull., 34, 4410 (1986), J. Abe et al, FEBS LETTER, 226, 58 (1987) and European Patent Application, publication number 184 112, lα,25-dihydroxy-23-oxavitamin D ₃ is described in European Patent Application, publication number 78704, and a number of 22-oxa-analogues of vitamin D.-. are described in Inter¬ national Patent Applications Nos PCT/DK90/00037 and PCT/DK90/00036, both filed on February 13, 1990.

In vitro experiments indicate that some of these compounds may have advantages over l,25(OH) ₂ D^. Thus lα,25-dihydroxy-22-oxavitamin D- has only one 14th as much affinity as lα,25(OH) ₂ D ₃ for the chick intestinal cytosolic receptor, a weaker affinity than 1,25(0H) ₂ D ₃ for the recep¬ tor in a human myeloid leukemia cell line (HL-60), and a high activity as inducer of differentiation in HL-60 cells.

In contrast to the compounds of the present invention the above mentioned 22-oxa-compounds do not contain an aromatic ring.

The usefulness of a vitamin D analogue in the above mentioned indications is dependent not only upon a favour¬ able ratio of binding affinity to relevant receptors comp¬ ared to the intestinal receptor, but also upon the fate of the compound in the organism.

It has now been found that the compounds of the pre- sent invention show favourable selectivity with respect to receptor binding and at the same time show high bioavailab¬ ility as well as chemical and metabolic stability.

The selectivity of the compounds is illustrated by the fact that while they have high affinities for the receptor in tumour cells (similar to or much better than that of l,25(OH) ₂ D ₃ ) and the concentration needed to induce cell differentiation in a human monocytic tumour cell line is the same as or considerably lower than that needed of l,25(OH) ₂ D ₃ to give the same effect, their binding affinity for the intestinal receptor is lower than that of l,25(OH)_D ₃ . In vivo in rats the compounds are less active than 1,25(0H) ₂ D ₃ in inducing hypercalciuria and hyper¬ calcemia.

This renders the compounds of the invention espe- cially suited for both local and systemic treatment and prophylaxis of human and veterinary disorders which are characterized by abnormal cell proliferation and/or cell differentiation, such as certain dermatological disorders including psoriasis and acne, and certain cancer forms, e.g. leukemia and myelofibrosis, and diseases characterized by an imbalance in the immune system, e.g autoimmune dis¬ eases or AIDS, and to obtain desired immunosuppression as in transplantation procedures, as well as treatment of diabetes mellitus and hypertension and inflammatory dis- eases, such as rheumatoid arthritis and asthma. As the compounds of this invention may promote the differentiation of the hair follicle cells, these compounds may be used in the treatment of alopecia. Preliminary studies indicate

that the compounds of the invention may reverse the unat¬ tractive concomitants of skin ageing, e.g. on photoaged skin.

The compounds of formula I may conveniently be pre- pared from the vitamin D-derivative 1_ (or its 20R isomer) (Tetrahedron, 43, 4609 (1987)) by the routes outlined in Scheme 1. Oxidation of 1_ for example using the van Rheenen procedure (Tetrahedron Letters, 1969, 985) gives the ketone 2_, which is reduced to the 20R-alcohol 3. When a suitable chiral reducing agent is used 3 may be prepared with very high stereoselectivity, but 3_ is conveniently prepared by NaBH. reduction of 2 and separating the minor amount of corresponding 20S-alcohol chromatographically. O-Alkylation of 3 to give III is achieved by treatment under basic con- ditions with a side chain building block of general formula Z-R, in which Z is a leaving group such as a halogen (Cl, Br or I) or p-toluenesulphonyloxy or methanesulphonyloxy, and R is as defined in the notes to Scheme 1. Thus R in compounds III, IV, V and VI does not necessarily have the same meaning along a particular synthetic sequence, and the conversion of R to the side chain in I may well involve several steps. Apart from any necessary modification within the side chain (R), the conversion of III to I involves a photoisomerisation step and a desilylation step, analogous to the steps used in the last stages of the synthesis of other vitamin D analogues (see European patent No. 0 227 826).

The side chain building blocks, RZ, are either known compounds or may be prepared analogously to those described in PCT/DK89/00079. They may typically be prepared by the routes outlined in Scheme 2.

The following standard abbreviations are used throughout this disclosure: Me = methyl; Et = ethyl; Pr = n-propyl; Pr ¹ = isopropyl; Bu = tert-butyl; THP = tetra- hydro-4H-pyran-2-yl; THF = tetrahydrofuran: Ts = p-toluene- sulphonyl; TBA = tetra-(n-butyl)-ammonium.

Schβa* 1

V

Notes to Scheme 1

where Y is hydrogen or hydroxyl in which the hydroxyl group may optionally be protected by a protective groups, such as trialkylsilyl or THP. n, m, R 1, R2, R3, and R4 are as defined as above. a) Oxidation e.g. with 0 ₂ with Cu(AcO) ₂ , 2,2'-bipyridyl and l,4-diazabicyclo[2,2,2]octane as catalyst. b) Reduction (e.g. with NaBH. ). c) Alkylation with the side chain fragment R-Z in the presence of base (e.g. KOH, KOBu or KH, with or without catalyst (e.g. 18-Crown-6) in solvent, e.g.

THF. d) Optional functional group modification in the side chain. e) Isomerisation with h v - triplet sensitizer, e.g. anthracene. f) Deprotection with TBA F ^~ or HF. It should be noted that although the shown inter¬ mediates may have hydroxyl groups protected as tert-butyl- dimethylsilyl ethers, the scope of the invention does not exclude the use of alternative hydroxyl protecting groups well known in the art (such as those described in T.W. Greene, "Protective groups in organic synthesis", Wiley, New York, 1981), together with alternative reactions for deprotection.

Scheme 2

Examples of Routes for the Preparation of the Side Chain Fragment R-Z

Notes to Scheme 2 a) Grignard reaction with R 2MgBr or R2Mgl b) Silylation with Me ₃ SiCl + base c) Reaction with dihydropyran d) Acid hydrolysis

The present compounds are intended for use in pharma¬ ceutical compositions which are useful in the treatment of human and veterinary disorders as described above.

The amount required of a compound of formula I (here¬ inafter referred to as the active ingredient) for therapeu- tic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment. The compounds of the invention can be admini¬ stered by the parenteral, intra-articular, enteral or topi-

cal routes. They are well absorbed when given enterally and this is the preferred route of administration in the treat¬ ment of systemic disorders. In the treatment of dermatolo- gical disorders like psoriasis, topical or enteral forms are preferred.

In the treatment of respiratory diseases like asthma an aerosol is preferred.

While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. Conveniently, the active ingredient comprises from 1 ppm to 0.1% by weight of the formulation.

By the term "dosage unit" is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, re¬ maining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers. The formulations, both for veterinary and for human medical use, of the present invention comprise an active ingredient in association with a pharmaceutically accept¬ able carrier therefore and optionally other therapeutic ingredient(s). The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.

The formulations include e.g. those in a form suit¬ able for oral, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intra-articular and topical administration.

The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided

solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be administered in the form of a bolus, electuary or paste..

A tablet may be made by compressing or moulding the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by com- pressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by mould¬ ing, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent.

Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.

Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Formulations suitable for intra-articular administra¬ tion may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystal¬ line suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra-articular and ophthalmic adminis¬ tration.

Formulations suitable for topical administration,

including eye formulations, include liquid or semi-liquid preparations such as liniments, lotions, applicants, oil- -in-water or water-in-oil emulsions such as creams, oint¬ ments, including eye ointments, pastes; or solutions or suspensions such as drops, including eye-drops.

For asthma treatment inhalation of powder, self- propelling or spray formulations, dispensed with a spray can, a nebulizer or an atomizer can be used. The formu¬ lations, when dispensed, preferably have a particle size in the range of 10 to 100 μ.

Such formulations are most preferably in the form of a finely comminuted powder for pulmonary administration from a powder inhalation device or self-propelling powder- dispensing formulations. In the case of self-propelling solution and spray formulations, the effect may be achieved either by choice of a valve having the desired spray char¬ acteristics (i.e. being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled particle size. These self-propelling formulations may be either pow¬ der-dispensing formulations or formulations dispensing the active ingredient as droplets of a solution or suspension. Self-propelling powder-dispensing formulations pref¬ erably comprise dispersed particles of solid active ingre- dients, and a liquid propellant having a boiling point below 18°C at atmospheric pressure. The liquid propellant may be any propellant known to be suitable for medicinal administration and may comprise one or more C.-C _fi -alkyl hydrocarbons or halogenated C.-C-.-alkyl hydrocarbons or mixtures thereof; chlorinated and flourinated C--C _fi -alkyl hydrocarbons are especially preferred. Generally, the propellant constitutes 45 to 99.9% w/w of the formulation whilst the active ingredient constitutes 1 ppm to 0.1% w/w, of the formulation. In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavour¬ ing agents, binders, surface active agents, thickeners,

lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like. The compositions may further contain other therapeu- tically active compounds usually applied in the treatment of the above mentioned pathological conditions.

The present invention further concerns a method for treating patients suffering from one of the above patholog¬ ical conditions, said method consisting of administering to a patient in need of treatment an effective amount of one or more compounds of formula I, alone or in combination with one or more other therapeutically active compounds usually applied in the treatment of said pathological con¬ ditions. The treatment with the present compounds and/or with further therapeutically active compounds may be simul- taneous or with intervals.

In the treatment of systemic disorders daily doses of from 0.1-100 μg, preferably from 0.2-25 μg, of a compound of formula I are administered. In the topical treatment of dermatological disorders, ointments, creams or lotions containing from 1-1000 μg/g, and preferably from 10-500 μg/g, of a compound of formula I are administered. The oral compositions are formulated, preferably as tablets, capsules, or drops, containing from 0.1-50 μg, preferably from 0.2-25 μg, of a compound of formula I, per dosage unit.

The invention will now be further described in the following non-limiting Preparations and Examples:

Preparations and Examples General

The exemplified compounds I are listed in Table 1. The intermediates of Scheme I referred to in the Prepara¬ tions are to be identified by numbers with the correspond¬ ing formulae in Table 2. For nuclear magnetic resonance spectra (300 MHz) chemical shift values (δ) are quoted for deuteriochloroform solutions relative to internal tetramethylsilane (δ = 0) or chloroform (δ = 7.25). The value for a multiplet, either

defined (doublet (d), triplet (t), quartet (q)) or not (m) at the approximate mid point is given unless a range is quoted (s - singlet, b = broad). Coupling constants (J) are given in Hertz, and are sometimes approximated to the nearest unit.

Ether is diethyl ether, and was dried over sodium. THF was dried over sodium-benzophenone. Petroleum ether refers to the pentane fraction. Reactions were run at room temperature unless otherwise noted. The work-up procedure referred to involves dilution with the specified solvent (otherwise the organic reaction solvent), extraction with water and then brine, drying over anhydrous MgSO,, and concentration in vacuo to give a residue.

Table 1 Exemplified Compounds I

Tabel 2

Preparations of formula III or IV

(See Scheme 1)

Preparation 1; Compound 2

To a solution of 1(S),3(R)-bis-(tert-butyldimethyl- silyloxy)-20(S)-formyl-9,10-secopregna-5(E),(7E),10(19)- -triene (3.44 g, 6 mmol) in N,N-dimethylformamide (150 ml), l,4-diazabicyclo[2.2.2]octane (600 mg, 5.3 mmol), cupric acetate, monohydrate (90 mg, 0.45 mmol) and 2,2'-bipyridyl (72 mg, 0.45 mmol) were added. Air was bubbled through the well stirred solution for 6 days at 40°C.

The reaction mixture was diluted with ethyl acetate (500 ml), extracted with water (2 x 100 ml) and saturated aqueous sodium chloride (3 x 50 ml) and dried over MgSO.. Ethyl acetate was evaporated off, and the solid residue was purified by chromatography (silica gel, 10% ether in petroleum ether as eluant) to give the title compound. NMR: δ = 0.037 (s, 3H), 0.043 (s, 3H), 0.056 (s, 6H), 0.49 (s, 3H), 0.84 (s, 9H), 0.89 (s, 9H), 1.5-2.30 (m, 13H), 2.13 (s, 3H), 2.55 (dd, 1H), 2.70 (t, 1H), 2.89 (bd, 1H), 4.21 ( , 1H), 4.52 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.83 (d, 1H), 6.43 (d, 1H) ppm.

Preparation 2: Compound 3 and its 20S-isomer Compound 2 (Prep. 1) (3.10 g, 5.5 mmol) was dissolved in tetrahydrofuran (140 ml) and sodium borohydride (0.35 g, 3.3 mmol) was added. Methanol (100 ml) was then added drop- wise over 15 minutes. The reaction blend was stirred for 20 minutes, then diluted with ethyl acetate (560 ml). The solution was extracted with water (5 x 150 ml) and saturat¬ ed aqueous sodium chloride (150 ml), dried over MgSO. and evaporated to give a colourless oil. The oily residue was purified by chromatography (silica gel, 15% ethyl acetate in petroleum ether as eluant). The first eluted isomer (3A) was dissolved in methanol (3 ml). Upon scratching a crys¬ talline product precipitated. The suspension was stirred for 1 h at room temperature and 1 h in an ice bath. The crystals were collected on a filter and dried in a desic¬ cator over the week-end. Mp. 131 - 146°C. NMR: δ = 0.05 (m, 12H), 0.62 (s, 3H), 0.86 (s, 9H),

0.89 (s, 9H), 1.10-2.10 (m, 14H), 1.15 (d, 3H), 2.30 (bd, 1H), 2.53 (dd, 1H), 2.89 (m, 1H), 2.89 (m, 1H), 3.71 (m, 1H), 4.21 (m, 1H), 4.52 ( , 1H), 4.93 (m, 1H), 4.98 (m, 1H), 5.81 (d, 1H), 6.45 (d, 1H) ppm. The fractions containing the more polar 20S-isomer were evaporated to give a colourless residue.

NMR: δ = 0.052 (bd, 12H), 0.54 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.22 (d, 3H), 1.20-2.10 (m, 14H), 2.30 (bd, 1H), 2.55 (dd, 1H), 2.87 (m, 1H), 3.72 (m, 1H), 4.21 (m, 1H), 4.52 (m, 1H), 4.94 (bs, 1H), 4.98 (m, 1H), 5.82 (d, 1H), 6.44 (d, 1H) ppm.

A sample of the residue was dissolved in methanol. Upon scratching a crystalline product was formed. The sus¬ pension was placed in the refrigerator over the week-end. The crystals were collected on a filter and dried in a desiccator.

M.p. 58 - 63°C.

Preparation 3: 2-[2-(3-Bromomethylphenyl)-2-prop- yl-oxy]-tetrahydro-4H-pyran

To a stirred, ice-cooled solution of methyl 3-bromo- methyl-benzoate (6.12 g, 27 mmol) in dried ether (20 ml) was added dropwise over 30 minutes a filtered solution of a Grignard reagent, prepared from magnesium (1.47 g, 60 mmol) and methyl iodide (4.0 ml, 64 mmol) in dried ether (40 ml). After a further 20 minutes in the ice-bath, water (40 ml) was slowly poured onto the reaction mixture. The phases were separated, and the aqueous phase was extracted with ether (3 x 50 ml). The combined ether phases were consecu- tively extracted with water (3 x 50 ml) and saturated aqueous sodium chloride (50 ml), dried with MgSO. and con¬ centrated in vacuo to yield a dark oil.

The crude oil was then purified by chromatography (silica gel, 25% ether in petroleum ether as eluant) to yield the intermediate 2-(3-bromomethylphenyl)-propan-2-ol as a yellow oil.

The intermediate was dissolved in methylene chloride (100 ml), 3,4-dihydro-2H-pyran (2.4 ml, 26 mmol) and

pyridinium p-toluene sulfonate (0.43 g, 1.7 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ether (150 ml) and extracted with water (3 x 50 ml) and saturated aqueous sodium chloride (50 ml), dried and concentrated in vacuo. The product was then purified by chromatography (silica gel, 10% ether in petroleum ether as eluant) to give a colourless oil.

NMR: δ = 1.52 (s, 3H), 1.67 (s, 3H), 1.35-1.75 (m, 5H), 1.85 (m, IH), 3.39 (m, IH), 3.95 (m, IH), 4.43 (dd, IH), 4.51 (AB quartet, 2H), 7.28 (m, 2H), 7.38 (m, IH), 7.49 (m, IH) ppm.

Preparation 4: Compound 4 (R = 3-[2-(tetrahydro- -4H-pyran-2-yl)-oxy-propyl-2]-phenyl-

-methyl) To a solution of compound 3 (841 mg, 1.5 mmol) in dry tetrahydrofuran (10 ml), potassium hydride (1.0 ml, 20% suspension in oil) and 2-[2-(3-bromomethylphenyl)-2-prop- yl]tetrahydro-4H-pyran (2.01 ml), 6.75 mmol) were added, and the reaction mixture stirred vigorously. 18-Crown-6 (650 mg, 5.8 mmol) was dissolved in dry tetrahydrofuran (5 ml) and added dropwise over 20 minutes. After a further 90 minutes stirring, water (40 ml) was carefully added to the reaction mixture. After the reaction had subsided, the reaction mixture was diluted with ether (100 ml), and the organic phase consecutively extracted with water (3 x 50 ml) and aqueous saturated sodium chloride (50 ml). After drying and the removal of the solvent in vacuo, the product was purified by chromatography (silica gel, 10% ether in petroleum ether as eluant) to give the desired compound as a colourless oil.

NMR: δ = 0.06 (bs, 12H), 0.52 and 0.54 (2s, 3H), 0.85 (S, 9H), 0.89 (s, 9H), 1.17 (d, 3H), 1.49 (bs, 3H), 1.65 (bs, 3H), 1.10-1.98 (m, 17H), 2.04 (m, IH), 2.22 (m, IH), 2.31 (bd, IH), 2.54 (dd, IH), 2.86 (bd, IH), 3.37 (m, IH), 3.45 (m, IH), 3.94 (m, IH), 4.21 (m, IH), 4.34 (d, J = 11.3, IH), 4.39 (m, IH), 4.53 (m, IH), 4.60 (d, J = 11.3,

IH ) , 4. 93 (m, IH ) , 4. 98 (m, IH ) , 5.80 ( d, J = 11.4, IH ) , 6 .45 ( d, J = 11 .4 , IH) , 7.20 ( bd, IH ) , 7. 28 ( t, IH ) , 7 , 36 ( bd, IH ) , 7 .44 ( bs , IH ) ppm.

Preparation 5: Compound 5 (R = 3-[2-(tetrahydro-4H-

-pyran-2-yl)-oxy-propyl-2]-phenyl- -methyl) A solution of compound 4 (Prep. 4) (800 mg, 1.0 mmol), anthracene (800 mg, 4.5 mmol) and triethylamine (1 drop) in dichloromethane (60 ml) under nitrogen in a Pyrex flask was irradiated with light from a high pressure ultra- -violet lamp, type TQ 718-Z2 (Hanau), at room temperature for 35 minutes. The solution was filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 10% ether in petroleum ether as eluant) to give the desired compound as a colourless oil.

NMR: δ = 0.05 (bs, 12H), 0.50 and 0.53 (2s, 3H), 0.87 (s, 18H), 1.16 (d, 3H), 1.48 (bs, 3H), 1.65 (bs, 3H), 1.10-1.93 (m, 17H), 2.00 (t, IH), 2.20 (m, 2H), 2.44 (m, IH), 2.81 (bd, IH), 3.38 (m, IH), 3.45 (m, IH), 3.95 (m, IH), 4.18 (m, IH), 4.34 (d, J = 11.4, IH), 4.40 (m, 2H), 4.59 (d, J = 11.4, IH), 4.85 (m, IH), 5.16 (m, IH), 5.99 (d, J = 11.1, IH), 6.23 (d, J = 11.1, IH), 7.19 (bd, IH), 7.28 (t, IH), 7,36 (bd, IH), 7.44 (bd, IH) ppm.

Preparation 6: 2-[2-(4-Bromomethylphenyl)-2-propyl-

-oxy]-tetrahydro-4H-pyran By following the procedure of Preparation 3 and substituting methyl 4-bromomethyl-benzoate for methyl 3-bromomethyl-benzoate, the title compounds was prepared. NMR: δ = 1.50 (s, 3H), 1.66 (s, 3H), 1.35-1.70 (m, 5H), 1.85 (m, IH), 3.40 (m, IH), 3.95 (m, IH), 4.44 (m, IH), 4.50 (s, 2H), 7.37 (m, 4H).

Preparation 7: Compound 6 (R = 4-[2-(tetrahydro-4H-

-pyran-2-yl)-oxy-propyl-2]-phenyl- -methyl) This compound was prepared by following the procedure

of Preparation 4 and substituting 2-[2-(4-bromomethyl- phenyl)-2-propyl]-tetrahydro-4H-pyran for 2-[2-(3-bromό- methylphenyl)-2-propyl]-tetrahydro-4H-pyran.

NMR: δ = 0.06 (bs, 12H), 0.52 and 0.53 (2s, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 1.17 (d, 3H), 1.49 (bs, 3H), 1.66 (bs, 3H), 1.10-1.97 (m, 17H), 2.05 (m, IH), 2.16 (m, IH), 2.31 (bd, IH), 2.54 (dd, IH), 2.87 (bd, IH), 3.37 (m, IH),

3.45 (m, IH), 3.95 (m, IH), 4.21 (m, IH), 4.36 (d, J = 11.2, IH), 4.40 (m, IH), 4.52 (m, IH), 4.57 d, J =11.2, IH), 4.93 (m, IH), 4.98 (m, IH), 5.80 (d, J = 11.4, IH),

6.46 (d, J = 11.4, IH), 7.30 (d, 2H), 7.40 (bs, 2H) ppm.

Preparation 8: Compound 7 (R = 3-[2-(tetrahydro-4H-

-pyran-2-yl)-oxy-propyl-2]-phenyl- -methyl)

This compound was prepared by following the procedure of Preparation 5 and substituting compound 5 (Prep. 7) for compound 5 (Prep. 4).

NMR: δ = 0.06 (bs, 12H), 0.50 and 0.52 (2s, 3H), 0.87 (bs, 18H), 1.16 (d, 3H), 1.49 (bs, 3H), 1.66 (bs, 3H),

1.00-1.92 (m, 17H), 2.00 (bt, IH), 2.20 (m, 2H), 2,45 (dd, IH), 2.82 (bd, IH), 3.40 (m, 2H), 3.95 (m, IH), 4.18 ( , IH), 4.37 (m, IH), 4.56 (d, J = 11.3, IH), 4.86 (πt, IH), 5.17 (m, IH), 5.99 (d, J = 11.0, IH), 6.23 (d, J = 11.0, IH), 7.30 (d, 2H), 7.41 (d, 2H) ppm.

Preparation 9: 2-[3-(3-Bromomethylphenyl)-3-pentyl-

-oxy]-tetrahydro-4H-pyran The compound was prepared according to the procedure described in Preparation 3, except that methyl magnesium iodide was substituted with ethyl magnesium bromide.

NMR: δ = 0.63 (t, 3H), 0.77 (t, 3H), 1.42-1.75 (m, 5H), 1.77-2.15 (m, 5H), 3.43 (m, IH), 4.00 (m, IH), 4.52 (AB q, 2H), 4.58 (m, IH), 7.20-7.38 (m, 3H), 7.45 (bs,,lH) ppm.

Preparation 10: Compound 8 (R = 3-[3-(tetrahydro-4H-

-pyran-2-yl)-oxy-pentyl-3]-phenyl- -methyl) The compound was prepared according to the procedure described in Preparation 4, except that 2-[2-(3-bromometh- ylphenyl)-2-propyl-oxy]-tetrahydro-4H-pyran was substituted with 2-[3-(3-bromomethylphenyl)-3-pentyl-oxy]-tetrahydro- -4H-pyran.

NMR: δ = 0.06 (m, 12H), 0.53 (s, 0.5x3H), 0.54 (s, 0.5x3H), 0.59 (t, 3H), 0.76 (dt, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 1.17 (d, 3H), 1.10-2.12 (m, 22H), 2.19 (bd, IH), 2.30 (bd, IH), 2.54 (dd, IH), 2.85 (bd, IH), 3.44 (m, 2H), 3.97 (m, IH), 4.21 (m, IH), 4.33 (d, IH), 4.57 (m, 3H), 4.93 (m, IH), 4.98 (m, IH), 5.80 (d, IH), 6.45 (d, IH), 7.10-7.45 (m, 4H) ppm.

Preparation 11: Compound 9 (R = 3-[3-(tetrahydro-4H-

-pyran-2-yl)-oxy-pentyl-3] -phenyl- -methyl) The compound was prepared according to the procedure described in Preparation 5, except that the compound 4 prepared in Preparation 4 was substituted with the compound 8 prepared in Preparation 10.

NMR: δ = 0.05 (m, 12H), 0.51 (s, 0.5x3H), 0.52 (s, 0.5x3H), 0.59 (t, 3H), 0.76 (dt, 3H), 0.87 (s, 18H), 1.16 (d, 3H), 1.05-2.10 (m, 22H), 2.20 (m, 2H), 2.44 (dd, IH), 2.80 (bd, IH), 3.43 (m, 2H), 3.97 (m, IH), 4.18 (m, IH), 4.32 (d, IH), 4.36 (m, IH), 4.56 (m, 2H), 4.85 (m, IH), 5.17 (m, IH), 5.98 (d, IH), 6.23 (d, IH), 7.18 (d, IH), 7.27 (t, IH), 7.34 (d, IH), 7.39 (bd, IH) ppm.

Preparation 12: 2-[l-(2-Chloromethylphenyl)-2-methyl-

-2-propyl-oxy]-tetrahydro-4H-pyran The compound is prepared according to the procedure described in Preparation 3, except that methyl 3-bromometh¬ yl-benzoate is substituted with methyl 2-chloromethyl- phenylacetate.

Preparation 13: Compound 10 (R ^■***■* 2-[2-(tetrahydro-

-4H-pyran-2-yl)-oxy-2-methyl-propyl]- -phenylmethyl) The compound is prepared according to the procedure described in Preparation 4, except that 2-[2-(3-bromometh- yl-phenyl)-2-propyl-oxy]-tetrahydro-4H-pyran is substi¬ tuted with 2-[2-(2-chloromethylphenyl)-2-methyl-2-propyl- -oxy]-tetrahydro-4H-pyran.

Preparation 14: Compound 11 (R = 2-[2-(tetrahydro-

-4H-pyran-2-yl)-oxy-2-methyl-propyl]- -phenylmethyl) The compound is prepared according to the procedure described in Preparation 5, except that the compound 4 prepared in Preparation 4 is substituted with the compound 10 prepared in Preparation 13.

Preparation 15: 2-[2-(3-Chloromethyl-4-methyl-phen- yl)-2-propyl-oxy]-tetrahydro-4H-pyran The compound is prepared according to the procedure described in Preparation 3, except that methyl 3-bromometh¬ yl-benzoate is substituted with methyl 3-chloromethyl-4- -methyl-benzoate.

Preparation 16: Compound 12 (R = 3-[2-(tetrahydro-

-4H-pyran-2-yl)-oxy-propyl-2]-6-meth- yl-phenylmethyl) The compound is prepared according to the procedure described in Preparation 4, except that 2-[2-(3-bromometh- ylphenyl)-2-propyl-oxy]-tetrahydro-4H-pyran is substituted with 2-[2-(3-chloromethyl-4-methyl-phenyl)-2-propyl-oxy]- -tetrahydro-4H-pyran.

Preparation 17: Compound 13 (R = 3-[2-(tetrahydro-4H- -pyran-2-yl)-oxy-propyl-2]-6-methyl-

-phenylmethyl) The compound is prepared according to the procedure described in Preparation 5, except that the compound 4

prepared in Preparation 4 is substituted with the compound 12 prepared in Preparation 16.

Preparation 18: 2-[4-(2-(2-bromoethyl)-phenyl)-4- -heptyl-oxy]-tetrahydro-4H-pyran

The compound is prepared according to the procedure described in Preparation 3, except that methyl 3-bromo¬ methyl-benzoate is substituted with methyl 2-(2-bromoeth¬ yl)-benzoate and methyl magnesium iodide is substituted with n-propyl magnesium bromide.

Preparation 19: Compound 14 (R = 2-[2-[4-tetrahydro-

-4H-pyran-2-yl)-oxy-4-heptyl]-phen¬ yl)-ethyl The compound is prepared according to the procedure described in Preparation 4, except that 2-[2-(3-bromometh- ylphenyl)-2-propyl-oxy]-tetrahydro-4H-pyran is substituted with 2-[2-(2-bromoethyl)-phenyl)-4-heptyl-oxy]-tetrahydro- -4H-pyran.

Preparation 20: Compound 15 (R = 2-(2-[4-tetrahydro-

-4H-pyran-2-yl)-oxy-4-heptyl]-phen¬ yl)-ethyl The compound is prepared according to the procedure described in Preparation 5, except that the compound 4 prepared in Preparation 4 is substituted with the compound 14 prepared in Preparation 19.

Preparation 21: Methyl 2-(2-bromoethyl )-benzoate 2-(2-Bromoethyl)-benzoic acid (11.4 g, 50 mmol) is added to a solution of diazomethan in ether at 0°C. The reaction mixture is concentrated ±n vacuo, and the residue purified by chromatography to give the desired compound as a colourless oil.

Preparation 22: 2-[2-(4-Bromomethyl-3-fluoro-phenyl)-

-2-propyl-oxy]-tetrahydro-4H-pyran The compound is prepared according to the procedure

described in Preparation 3, except that methyl 3-bromometh¬ yl-benzoate is substituted with ethyl 4-bromomethyl-3- -fluoro-benzoate.

Preparation 23: Compound 16 (R = 4-[2-(tetrahydro-

-4H-pyran-2-yl)-oxy-propyl-2]-2- -fluoro-phenylmethyl The compound is prepared according to the procedure described in Preparation 4, except that 2-[2-(3-bromometh- ylphenyl)-2-propyl-oxy]-tetrahydro-4H-pyran is substituted with 2-[2-(4-bromomethyl-3-fluoro-phenyl)-2-propyl-oxy]- -tetrahydro-4H-pyra .

Preparation 24: Compound 17 (R = 4-[2-(tetrahydro- -4H-pyran-2-yl)-oxy-propyl-2]-2-

-fluoro-phenylmethyl The compound is prepared according to the procedure described in Preparation 5, except that the compound 4 prepared in Preparation 4 is substituted with the compound 16 prepared in Preparation 23.

Example 1; 1(S),3(R)-Dihydroxy-20(R)-(3-(2-hydr- oxy-2-propyl)-phenylmethyloxy)-9,10- -seco-pregna-5(Z),7(E),10(19)-triene (Compound 101

The compound prepared in Preparation 5 (700 mg, 0.88 mmol) was dissolved in ethyl acetate (1.0 ml). Acetonitrile (24 ml) was added under vigorous stirring. A solution of 5% hydrofluoric acid in acetonitrile/water 8:1 (10.6 ml) was added, and the reaction mixture stirred under nitrogen at room temperature for 45 minutes. Ethyl acetate (150 ml) was added, and the reation mixture consecutively extracted with saturated aqueous sodium hydrogen carbonate (60 ml), water (3 x 60 ml) and saturated aqueous sodium chloride (50 ml), dried with magnesium sulphate and concentrated in vacuo.

The residue was purified by chromatography (silica gel, 20% pentane in ethyl acetate as eluant) to give the title compound.

NMR: δ = 0.54 (s, 3H), 1.18 (d, 3H), 1.57 (s, 6H), 1.12-2.06 (m, 15H), 2.22 (bd, IH), 2.30 (dd, IH), 2.59 (dd, IH), 2.82 (m, IH), 3.45 (m, IH), 4.22 (bm, IH), 4.35 (d, J = 11.3, IH), 4.42 (bm, IH), 4.61 (d, J = 11.3, IH), 4.99 (m, IH), 5.32 (m, IH), 5.99 (d, J = 11.3, IH), 6.38 (d, J = 11.3, IH), 7.20 (bd, IH), 7.30 (t, IH), 7.40 (bd, IH), 7.50 (bd, IH), ppm.

Example 2: 1(S),3(R)-Dihydroxy-20(R)-(4-(2-hydr- oxy-2-propyl)-phenylmethyloxy)-9,10-

-seco-pregna-5(Z) ,7(E) ,10(19)-triene (Compound 102) This compound was prepared by following the procedure of Example 1 and substituting the compound prepared in Preparation 8 for the compound prepared in Preparation 5. NMR: δ = 0.54 (s, 3H), 1.16 (d, 3H), 1.58 (s, 6H), 1.10-2.10 (m, 15H), 2.17 (m, IH), 2.32 (dd, IH), 2.60 ( m, IH), 2.83 (m, IH), 3.43 (m, IH), 4.23 (m, IH), 4.35 (d, J = 11.3, IH), 4.43 (m, IH), 4.57 (d, J = 11.3, IH), 5.00 (m, IH), 5.32 ( , IH), 6.00 (d, J = 11.2, IH), 6.39 (d, J = 11.2, IH), 7.32 (d, 2H), 7.45 (d, 2H) ppm.

Example 3: 1(S),3(R)-Dihydroxy-20(R)-(3-(3-hydr- oxy-3-pentyl)-phenylmethyloxy) -9.10- -seco-pregna-5(Z),7(E),10(19)-triene

(Compound 103) This compound was prepared by following the procedure of Example 1 and substituting the compound 9 prepared in Preparation 11 for the compound 5 prepared in Preparation 5.

NMR: δ = 0.54 (s, 3H), 0.74 (t, 6H), 1.17 (d, 3H), 1.10-2.10 (m, 19H), 2,19 (bd, IH), 2.31 (dd, IH), 2.59 (dd, IH), 2.81 (bd, IH), 3.45 (m, IH), 4.22 (m, IH), 4.33 (d, IH), 4.42 (m, IH), 4.62 (d, IH), 5.00 (m, IH), 5.32 (m, IH), 5.99 (d, IH), 6.38 (d, IH), 7.18 (m, IH), 7.27 (m, 2H), 7.38 (bs, IH) ppm.

Example 4 : 1 ( S ) , 3 ( R ) -Dihydroxy-20( R ) - ( 2- ( 2-hydr- oxy-2-methy1-propyl)-phenylmethyl- -oxy)-9,lO-seco-pregna-5(Z),7(E),- 10(19)-triene (Compound 104) This compound is prepared by following the procedure of Example 1 and substituting the compound 11 prepared in Preparation 14 for the compound 5 prepared in Preparation 5.

Example 5: 1(S),3(R)-Dihydroxy-20(R)-(3-(2-hydr-

-oxy-propyl-2)-6-methyl-phenylmethyl- oxy)-9,10-seco-pregna-5(Z),7(E),- 10(19)-triene (Compound 105) This compound is prepared by following the procedure of Example 1 and substituting the compound 13 prepared in Preparation 17 for the compound 5 prepared in Preparation 5.

Example 6: 1(S),3(R)-Dihydroxy-20(R)-(2-(2-(4- -hydroxy-4-heptyl)-phenyl)-ethyloxy)-

-9,10-seco-pregna-5(Z),7(E),10(19)- -triene (Compound 106) This compound is prepared by following the procedure of Example 1 and substituting the compound 15 prepared in Preparation 20 for the compound 5 prepared in Preparation 5.

Example 7: 1(S),3(R)-Dihydroxy-20(R)-(4-(2-

-hydroxy-propyl-2)-2-fluoro-phenyl- methyloxy-9,10-seco-pregna-5(Z),-

7(E),10(19)-triene (Compound 107) This compound is prepared by following the procedure of Example 1 and substituting the compound 17 prepared in Preparation 24 for the compound 5 prepared in Preparation 5.

Example 8: Capsules containing Compound 101 101 is dissolved in arachis oil to a final concen-

tration of 1 μg 101/ml oil. 10 Parts by weight of gelat¬ ine, 5 parts by weight glycerine, 0.08 parts by weight potassium sorbate, and 14 parts by weight distilled water are mixed together with heating and formed into soft gela- tine capsules. These are then filled each with 100 μl of the 101 in oil solution, such that each capsule contains 0.1 μg 101.

Example 9: Dermatological Cream Containing Compound 101

In 1 g almond oil is dissolved 0.05 mg 101. To this solution is added 40 g of mineral oil and 20 g of self- -emulsifying beeswax. The mixture is heated to liquify. After the addition of 40 ml hot water, the mixture is mixed well. The resulting cream contains approximately 0.5 μg of 101 per gram of cream.