NOVEL VITAMIN D ANALOGUES

Abstract: The invention relates to compounds of formula (I) in which formula X is hydrogen or hydroxy; R<1> and R<2> stand for hydrogen or a C1-C6 hydrocarbyl radical; or taken together with the carbon atom bearing the group X, can form a C3-C8 carbocyclic ring; R<3> stands for hydrogen or a C1-C10 hydrocarbyl radical or for YR<4>, in which Y stands for the radicals -CO-, -CO-O-, -CO-S-, -CS-, -CS-O-, -CS-S-, -SO- or -SO2-, and R<4> stands for hydrogen or a C1-C10 hydrocarbyl radical; Q is a single bond or a C1-C8 hydrocarbylene diradical. R<1>, R<2>, R<3> and/or Q may be optionally substitued with one or more deuterium or fluorine atoms. The compounds show an antiinflammatory and immunomodulating effect as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells.

Description: NOVEL VITAMIN D ANALOGUES This invention relates to a hitherto unknown class of compounds which shows antunflammatory and immunomodulating effects as well as strong activity in inducing differenti¬ ation and inhibiting undesirable proliferation of certain cells, including cancer cells and skin cells, to pharma¬ ceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treat¬ ment and prophylaxis of hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal fail¬ ure, and a number of disease states including diabetes mellitus, hypertension, acne, alopecia, skin ageing, imbal¬ ance in the immune system, inflammatory diseases such as rheumatoid arthritis and asthma as well as diseases charac¬ terized by abnormal cell differentiation and/or cell pro¬ liferation such as e.g. psoriasis and cancer, and for pro¬ moting osteogenesis and treating osteoporosis. The compounds of the invention constitute a novel class of vitamin D analogues and are represented by the general formula I in which formula X is hydrogen or hydroxy; R 1 and R2, which may be the same or different, stand for hydrogen or a C. -C fi hydrocarbyl radical; or R and R , taken together with the carbon atom (starred in formula I) bearing the 3 group X Λ can form a C -C 8 carbocyclic ring; R stands for hydrogen or a C, -C, π hydrocarbyl radical or for YR , in which Y stands for the radicals -CO-, -C0-0-, -CO-S-, 4 -CS-, -CS-0-, -CS-S-, -SO- or -S0 2 ~, and R stands for hydrogen or a C, -C, n hydrocarbyl radical; Q is a single 1 2 3 bond or a C,-C R hydrocarbylene diradical. R Λ R , R and/or Q may be optionally substituted with one or more deuterium or fluorine atoms. In the context of this invention, the expression hydrocarbyl radical (hydrocarbylene diradical) indicates the residue after removal of 1 (2) hydrogen atom(s) from a straight, branched or cyclic saturated or unsaturated hy¬ drocarbon. Examples of R 1 and R2 when taken separately include (apart from hydrogen), but are not limited to, methyl, tri- fluoromethyl, ethyl, vinyl, normal-, iso- and cyclo-propyl, and 1-methylvinyl. Examples of R 1 and R2 when taken together include di-, tri-, tetra- and penta-methylene. Examples of R 3 and R4 include (apart from hydrogen), but are not limited to, methyl, trifluoromethyl, ethyl, propyl, normal-, iso- and cyclopropyl, normal-, iso-, sec-, and tert-butyl, normal- and iso-pentyl, phenyl and benzyl. Examples of Q include a single bond, methylene, di-, tri- and tetra-methylene, -CH 2 -CH=CH-, -CI -C≡C-, -CH=CH-CH 2 - Λ -C=C-CH 2 - Λ phenylene (CgH.; ortho, meta, para), -CH 2 -(CgH.)- (ortho, meta, para), and -(C 5 H.)-CH 2 - (ortho, meta, para). As can be seen from formula I, depending on the meanings of R 1, R2, -R3, Q and X the compounds of the inven¬ tion can comprise several diastereoisomeric forms (e.g. R or £ configuration at the starred carbon atom). The inven¬ tion covers all these- diastereoisomers in pure form as well as mixtures of diastereoisomers. In particular, both diastereoisomers having the two possible configurations at the carbon atom marked "22" are included. In addition, prodrugs 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. Compounds of formula I in which X is hydrogen also may act as prodrugs, as these compounds are relatively in- active in vitro, but are converted to active compounds of formula I by enzymatic hydroxylation after administration to the patient. It has recently been shown that lα,25-dihydroxy- -vitamin D 3 (1,25(0H) 2 D 3 ) influences the effects and/or production of interleukins (Muller, K. et al, Immunol. Lett. 12, 361-366 (1988)), indicating the potential use of this compound in the treatment of diseases characterized by a dysfunction of the immune system, e.g. autoimmune dis¬ eases, AIDS, host versus graft reactions, and rejection of transplants or other conditions characterized by an abnor¬ mal interleukin-1 production, e.g. inflammatory diseases such as rheumatoid arthritis and asthma. It has also been shown that 1,25(0H) 2 D 3 is able to stimulate the differentiation of cells and inhibit excess- ive cell proliferation (Abe, E. et al, Proc. Natl. Acad. Sci., U.S.A. 2£L, 4990-4994 (1981)), and it has been sug¬ gested that this compound might be useful in the treatment of diseases characterized by abnormal cell proliferation and/or cell differentiation such as leukemia, myelofibrosis and psoriasis. Also, the use of 1,25(0H) 2 D 3 , or its pro-drug lα-0H-D 3 , for the treatment of hypertension (Lind, L. et al, Acta Med. Scand. 222, 423-427 (1987)) and diabetes mellitus (Inomata, S. et al, Bone Mineral __, 187-192 (1986)) has been suggested. Another indication for 1,25(0H) 2 D 3 is suggested by the recent observation of an association between hereditary vitamin D resistance and alopecia: treatment with l,25(OH) 2 D 3 may promote hair growth (Editorial, Lancet, March 4, 1989, p. 478). Also, the fact that topical application of 1,25(0H) 2 D 3 reduces the size of sebaceous glands in the ears of male Syrian hamsters suggests that this compound might be useful for the treatment of acne (Malloy, V.L. et al., the Triconti- nental Meeting for Investigative Dermatology, Washington, 1989). However, the therapeutic possibilities in such indi¬ cations of l,25(OH) 2 D 3 are severely limited by the well known potent effect of this hormone on calcium metabolism; elevated blood concentrations wili rapidly give rise to hypercalcemia. Thus, this compound and its potent synthetic analogues are not completely satisfactory for use as drugs in the treatment of e.g. psoriasis, leukemia or immune dis- eases which may require continuous administration of the drug in relatively high doses. A number of vitamin D analogues have recently been described which show some degree of selectivity in favour of the cell differentiation inducing/cell proliferation inhibiting activity as compared with the effect on calcium metabolism. Thus, the vitamin D„ analogue, MC 903, containing a 22,23-double bond, a 24-hydroxy group and in which the car¬ bon atoms 25, 26 and 27 are incorporated in a three mem- bered ring, is a potent inducer of cell differentiation and inhibitor of cell proliferation which shows only moderate activity on calcium metabolism ia vivo (Binderup, L. and Bramm, E., Biochem. Pharmacol. 2Z, 889-895 (1988)). However, this selectivity is not paralleled by in vitro studies, which show that MC 903 binds equally well as 1,25(0H) 2 D 3 to the intestinal vitamin D receptor. Possibly, the low in vivo activity on calcium metabolism of MC 903 is due to a rapid metabolism of the compound, thus limiting the potential of this compound for systemic use. 24-Homo-l,25-dihydroxyvitamin D 3 and 26-homo-l,25- dihydroxyvitamin D 3 (together with their 22,23-didehydro- analogues) (Ostrem, V.K.; Tanaka, Y. ; Prahl, J. ; DeLuca, H.F.; and Ikekawa, N.; Proc. Natl. Acad. Sci. USA 84, 2610-14 (1987)) have been claimed to have the same binding affinity as 1,25(0H) 2 D 3 to both the rat and chicken intes¬ tinal receptor and the receptor in a human myeloid leukemia cell line (HL-60), and yet to be 10-fold more potent than 1,25(0H) 2 D 3 in inducing differentiation of HL-60 cells in vitro. In yivo, these compounds are respectively "signifi¬ cantly less potent" and "more potent" than l,25(OH) 2 D in calcium metabolism assessments. 26,27-Dimethyl-lα,25-dihydroxyvitamin D„ has been synthesized, but the published information regarding its biological activities is contradictory. (Sai, H. ; Takatsuto, S.; Hara, N.; and Ikekawa, N.; Chem. Pharm. Bull. ___[, 878-881 (1985) and Ikekawa, N.; Eguchi, T.; Hara, N.; Takatsuto, S.; Honda, A.; Mori, Y.; and Otomo, S.; Chem. Pharm. Bull. __l, 4362-4365 (1987)). The closely related 26,27-diethyl-lα,25-dihydroxyvitamin D 3 is also reported by these authors; in this case as having "almost no vitamin D activity" (i.e. calcium metabolism effects) while being 10-fold more potent than 1,25(0H) 2 D 3 in induc- ing cell differentiation. US Patent 4,804,502 discloses compounds containing a triple bond in the side chain of Vitamin D, and these com¬ pounds are claimed to be useful in the treatment of disease states characterized by metabolic calcium deficiencies. The fact that there are only small structural differ¬ ences between the compounds of the prior art referred to above indicates that the present state of knowledge does not allow prediction of the structure of vitamin D ana¬ logues which will show a favourable degree of selectivity, as reflected by a higher cell differentiating activity in vitro compared to the binding affinity for intestinal vit¬ amin D receptor in vitro. Furthermore, the matter is com¬ plicated by the observation that receptor binding affini¬ ties in vitro are not always paralleled by in vivo studies, probably reflecting a pharmacokinetic difference between the compounds. The compounds of the present invention differ struc¬ turally from the above vitamin D analogues, some of which have been reported to have potent effects on cell differen¬ tiation/proliferation in the configuration of the methyl group at carbon-20. This "unnatural" configuration present in the compounds I (and also in compounds according to our previous international patent application number PCT/DK90/00156, filing date 19th June, 1990, publication number WO 91/00271, and international patent application number PCT/DK91/00200, filing date 11th July, 1991, publi¬ cation number WO 92/03414), has surprisingly been found to have a profound and advantageous biological significance. Thus a particular compound of formula I, when compared to the corresponding compound containing the "natural" C-20 configuration (methyl and hydrogen radicals exchanged), is observed to show one or more of the following advantages:- (a) more potent effects on cell differentiation/proli¬ feration (b) a greater selectivity in favour of the potent effects on cell differentiation/proliferation contra the effects on calcium metabolism; (c) more potent effects on the production and action of interleukins; (d) a greater selectivity in favour of the effects on interleukin production and action contra the e fects on calcium metabolism. The compounds of the invention are therefore es¬ pecially suited for both local and systemic treatment and prophylaxis of human and veterinary disorders which are characterized by 1) abnormal cell proliferation and/or cell differentiation, such as certain dermatological disorders including psoriasis and certain cancer forms, 2) an imbal¬ ance in the immune system, e.g. in autoimmune diseases, in¬ cluding diabetes mellitus, host versus graft reaction, and rejection of transplants; and additionally for the treat¬ ment of inflammatory diseases, such as rheumatoid arthritis and asthma. Acne, alopecia, and hypertension are other con¬ ditions which may be treated with the compounds of the in¬ vention. Finally, as thickening of the skin is observed after topical treatment with the compounds of the in- vention, these compounds may be useful for treatment or prevention of skin ageing, including photo-ageing. Because of the low tendency of the compounds to pro¬ duce hypercalcemia on continued administration they are expected to be valuable for the long term treatment of hy¬ perparathyroidism (particularly secondary hyperparathyroid¬ ism associated with renal failure) and for promoting oste- ogenesis and treating osteoporosis. For these indications the presently described compounds have a higher therapeu- tic ratio than the prior art compounds (see US 4,948,789 and EP 0385446 A2). The present compounds may be used in combination with other pharmaceuticals. In the prevention of graft re¬ jection and graft versus host reaction, a treatment with the present compounds may advantageously be combined with e.g. a cyclosporin treatment. Compounds I can be prepared from the vitamin D- -derived aldehyde compound __ (Scheme 1); a synthesis of 0 which has been reported [M.J.. Calverley, Tetrahedron 43, 4609 (1987)], for example by the routes outlined in Scheme 1. The following standard abbreviations are used throughout this disclosure: Me = methyl; Et = ethyl; Bu = n-butyl; i-Pen = isopentyl; Ph = phenyl; Bn = benzyl; Ac = acetyl; Piv = pivaloyl; THP = tetrahydro-4H-pyran-2-yl; TMS = trimethylsilyl; DMAP = 4-dimethylaminopyridine; PPTS = pyridinium p-toluenesulfonate; pet.ether = petroleum ether; THF = tetrahydro uran; TBAF = tetra-(n-butyl)-ammonium fluoride; b.p. = boiling point; PLC = preparative thin-lay- er chromatography. Scheme 1 Synthesis of Compounds I of the Invention X 1 = H, OH, OR 5 5 R = alcohol protective group, e.g. tri(loweralkyl)- silyl or THP R 1, R2, R3 and Q have the above meanings. Notes to Scheme 1 a) (i) Compound 1 is reacted with the anion R ~ , derived from the side chain building block, RH, of general formula V, with a suitable base. (ii) The resulting mixture of the two C-22-epimers, IIA 3 and IIB (R = H), is separated. b) Optional alkylation of the C-22-hydroxy compounds 3 (R = H) of type II or III to the corresponding 3 compound II or III, where R = C ι -C ι0 hydrocarbyl. c) Optional acylation of the C-22-hydroxy compound 3 (R = H) of type II or III to the corresponding 3 4 4 compound II or III, where R = YR ; Y and R hav¬ ing the above meanings. d) Optional functional group modification in the side chain. e) Isomerization of Compounds II or IV to the corre¬ sponding compound III or I, by means of UV-light in the presence of a triplet sensitizer, e.g. anthracene. f) Deprotection of Compounds II or III to the corre¬ sponding compound IV or I, e.g. by HF or by TBAF followed by PPTS. The side chain building blocks RH of general formula V are either known compounds, or they can be prepared by standard methods known to the specialist. In particular, this applies to the side chain build¬ ing blocks RH necessary for the preparation of the exemplified compounds (101-149). The procedures according to Scheme 1 can be used analogously to the specific preparations and examples men¬ tioned in the following. As a nonlimiting illustration, the preparation of some compounds of the general formula V where Q = (CH 2 ) , X 1 = OR 5 and R 5 = -Si(CH 3 ) 3 or THP (n = 0-3) is outlined in Scheme 2, but similar compounds of formula V with other Q and/or X may be prepared by analogous methods. Some spe¬ cific side chain building blocks RH are listed in Table 1 and their syntheses are described in the preparations. Scheme 2 Synthesis of some Side Chain Building Blocks V HC≡C-CH Br HC=C-(CH 2 ) 2 -COOEt VII Notes to Scheme 2 1 2 1 __. (i) Al, (ii) R R C=0; &. Grignard reagent R MgBr or R Mgl; ς_. Me 3 SiCl/base; .&. dihydropyran/acid; Q.. acetyl- ene/Na/liq.NH 3 ; £_. (i) MeOH/acid, (ii) dihydropyran/acid. Table 1 Some Side Chain Building Blocks. RH of General Formula V (Q = (CH i ? 2- Λ )n-'. n = 0-3. R 1 = R 2 = CHg or C^ R 5 =SiMe 3 or THP) Intermediates for the preparation of the side chain build¬ ing blocks, RH of Table 1, are either known compounds or can e.g. be prepared from the compounds listed in Table 2. The syntheses of these compounds are described in the Prep¬ arations. Table 2 Some Intermediaties for the Synthesis of the RH (V) of Table 1 The reaction of the aldehyde 1 with the side chain building blocks, RH = H-C≡C-Q-C(R 1 )(R 2 )0R 5 , can be per- formed by standard methods of nucleophilic addition of acetylenic anions ( ~ ) to carbonyl compounds; i.e. by treating the RH with a suitable base, such as n-BuLi, in a suitable anhydrous solvent, such as THF, then adding ]__ . , to 3 give II (R = H) after usual aqueous work-up (which is nor- mally implied in all the reactions of Schemes I and II). 3 In general the reaction product II (R = H) is a mix¬ ture of the two possible C-22-epimers, here designated IIA and IIB. It is usually preferable to separate the IIA and IIB epimers which can conveniently be done by chromatogra- phy. Nonlimiting illustrations of such compounds of for- 3 mula II (R = H) are given in Table 3. In this table thes« compounds are described as separate 22-epimers IIA or IIB (preparations 11, 12, 13, 21, 22 and 23). The compounds IIA are chromatographically less polar than the corresponding IIB epimers (see general procedure 7), and usually the IIA epimers are formed in higher yields than the corresponding IIB epimers. Furthermore, there is usually a difference in the chemical shift of the H-NMR signals of the C-21 methyl group which in the IIA epimers occur in the range of circa δ 1.04-1.02 (d, 3H), whereas for the IIB epimers the corre¬ sponding signals are found at slightly higher field (circa 6 1.00-0.97). The optional alkylation or acylation of the C-22- 3 hydroxy compounds (R = H) of general formula II or III to 3 yield the corresponding compound where R is C. -C- 0 hydro¬ carbyl or YR can be performed by standard methods well known to the specialist. Illustrative, but non limiting, compounds of this sort are listed in Table 3. Table 3 also contains the other examples of photoisomerized compounds of general formula III along with references to the prepara¬ tion of each compound. In the alkylation reaction use is preferably made of 3 an alkylating agent R Z, in which Z stands for a good leav¬ ing group, such as for example C1-, Br-, I-, CHgSOg-, p-CH 3 -C β H.-S0 3 - or CF 3 S0 3 ~; the R Z being allowed to react with the anion of the appropriate compound II or III (R H), derived therefrom by means of a suitable strong base, such as an alkali-metal alkoxide, alkyl alkali-metal or alkali-metal hydride. A useful method is described in Gen¬ eral Procedure 8, and in more detail in the included prep¬ arations; a suitable crown ether may be added as a phase transfer agent to accelerate the alkylation process. In the acylation reaction producing compounds II or III where R = YR , use may advantageously be made of stan¬ dard acylation procedures, such as reaction of the alcohol 3 (II or III, R = H) with an acid chloride or acid anhydride (R 4YCl or (R4Y) 0), or by forming the acylating agent in situ from the corresponding acid R 4YOH and a dehydrating or condensing agent, such as e.g. a carbodiimide or an assist- ing acid anhydride, forming an intermediary mixed anhydride. Furthermore, the addition of a suitable base, such as a tertiary amine, may often be profitably applied during the acylation; in many cases addition of a special heterocyclic amine like DMAP may accelerate the acylation process considerably. Examples of acylation procedures are given in General Procedure 9 and illustrated in more detail in the included preparations. Exemplified Compounds I of the invention are listed in Table 4, the numbered examples giving reference to il¬ lustrative methods of synthesis, together with spectro- scopic data for those same compounds of the examples. It should be noted that the preparations and examples of Schemes 1 and 2 are illustrative only, the particular synthesis of each step and the order in which each step is performed can be varied greatly. Furthermore, the radical R: -C≡C-Q-C(R 1)(R )(X1) may optionally be a radical which can be converted to this at any convenient later stage (or over several stages). Thus R in compounds II, III and IV does not necessarily have the same meaning along a particu¬ lar synthetic sequence. The conversion of R to -C≡C-Q-C(R 1)(R2)X1 may well involve several steps and pos¬ sibly involve a temporary protection of the sensitive triene system of the molecule. Apart from any necessary 3 modification of R or within the side chain (R), the con¬ version of II to I involves a photoisomerisation step and a deprotection step, analogous to the steps used in the last stages of the synthesis of other vitamin D analogues (see European patent No. 0 227 836). Table 3. . Intermediates of formulas II and III; Q = ( H ? ) Table 3 (continued): Intermediates of formulas II and III; Q - (CH 2 ) Table 3 (continued): Table 3 (continued): Intermediates of formulas II and III; Q = ( CH 2^n V Table 4: Exemplified Compounds of General Formula I. Q = (CH 2 ) Table 4 (continue ): Exemplified Compounds of General Formula I, Q = (CH 2 ) t Table 4 (continued): Exemplified Compounds of General Formula I. Q = ^ CH 2^n Table 4 (continued): Exemplified Compounds of General Formula I, Q = ( H 2 ) (R) configuration at starred carbon atom ++ (5.) configuration at starred carbon atom 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 thera¬ peutic effect will, of course, vary both with the particu¬ lar compound, the route of administration and the mammal under treatment. The compounds of the invention can be ad¬ ministered by the parenteral, intra-articular, enteral or topical routes. They are well absorbed when given enterally and this is the preferred route of administration in the treatment of systemic disorders. In the treatment of derma- tological disorders like psoriasis or eye diseases 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 0.1 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 car¬ riers. 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 in¬ gredient for both intra-articular and ophthalmic adminis- tration. Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. For asthma treatment inhalation of powder, self-pro¬ pelling or spray formulations, dispensed with a spray can, a nebulizer or an atomizer can be used. The formulations, 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 suspen¬ sion. 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, -Cg-alkyl hydrocarbons or mixtures thereof; chlorinated and fluorinated C, -Cg-alkyl hydrocarbons are especially preferred. Generally, the pro¬ pellant constitutes 45 to 99.9% w/w of the formulation whilst the active ingredient constitutes 0.1 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 ad¬ ditional ingredients such as diluents, buffers, flavour¬ ing agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (in¬ cluding 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 con¬ taining from 0.1-500 μg/g, and preferably from 0.1-100 μg/9 / of a compound of formula I are administered. For top¬ ical use in ophthalmology ointments, drops or gels contain- ing from 0.1-500 μg/g, and preferably from 0.1-100 μg/g, of a compound of formula I are administered. The oral composi¬ tions are formulated, preferably as tablets, capsules, or drops, containing from 0.05-50 μg, preferably from 0.1-25 μg, of a compound of formula I, per dosage unit. The invention will now be further described in the following non-limiting General Procedures, Preparations and Examples: General Procedures. Preparations and Examples General The exemplified compounds I are listed in Table 4. 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 (_l) 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 MgS0 4 , and con¬ centration in vacuo to give a residue. Chromatography was performed on silica gel. General Procedures General Procedure 1: Protection of tertiary alcohols V or VII to give the corresponding trimethylsilyl compounds V or VI (Scheme 2. Table 1) (Preparation 1) To a solution of the appropriate compound V or VII (0.043 mol) in dichloromethane (60 ml) was added N-ethyl- diisopropylamine (6.1 g) and chlorotrimethylsilane (5.1 g) and the mixture was stirred at 20°C for one hour. Phosphate buffer (pH 6.5, 0.07M, 60 ml) was added and after separa- tion the organic phase was washed with saturated aqueous sodium chloride solution, dried and evaporated in vacuo to yield the title compound of the preparation. General Procedure 2: Protection of tertiary alcohols V or VII to give the corresponding 2- tetrahydropyranyl compounds V or VI (Scheme 2 , Table 1) (Preparations 2. 4. 6. 8) A mixture of the appropriate compound V or VII (0.01 mol), 3,4-dihydro-2H-pyran (1.26 g), PPTS (0.25 g) and dry dichloromethane (25 ml) was stirred under argon for 4 hours at 20 β C. To the reaction mixture was added 100 ml of ether and 50 ml of semi-saturated aqueous sodium chloride solu- tion. The organic phase was separated, dried and evaporated in vacuo to yield a crude product which was purified by chromatography (mixture of ether and pet.ether as eluant) to yield the title compound of the preparation. General Procedure 3: Reaction of ketones R 1R2C=0 with organometallic reagent prepared from nropargylbromide and aluminium to give the corresponding tertiary alcohol V (Scheme 2. Table 2) (Preparation 3) A mixture of aluminium scales (3.6 g), mercuric chloride (0.1 g) and dry THF (20 ml) was stirred at 20"C for 20 minutes, under argon. A solution of propargyl bro- mide (23.8 g) in dry THF (20 ml) was added with stirring during 40 minutes, keeping the temperature at 25-30°C by intermittent cooling. The reaction mixture was stirred at 40-45°C, heating as necessary, for 30 minutes. After cool¬ ing to about 25°C, a solution of the appropriate ketone, (0.2 mol) in dry ether (25 ml) was added during one hour, with stirring, cooling slightly to keep the tempera¬ ture at about 25°C. Stirring was continued for a further half hour at 30-35°C, after which the reaction mixture was worked up (ether). The residue was purified by distillation in vacuo through a 50 cm Podbielniak column to yield the title compound of the preparation as an oil. -I General Procedure 4: Reaction of 4-pentinoic acid ethyl ester with Grignard reagents r R 1MσX2, to give the corresponding tertiary alcohol V (Scheme 2. Table. 2) (Preparations 5 and 7) (X 2 = Cl, Br, I) To 1.1 g magnesium turnings (Grignard quality) in a dry flask, was added dropwise with stirring a solution of the appropriate alkyl halide R 1X2 (0.045 mol) in dry ether (20 ml). The reaction took place under argon, with stirring, and with reflux, and lasted 20 minutes. Stirring and reflux was continued for a further 10 minutes. This Grignard reagent was transferred to an addition funnel, under argon, and added dropwise with stirring and cooling to about -20°C, to a solution of 4-pentinoic acid ethyl ■ - ester (1.9 g) in dry ether (20 ml). The addition lasted 15 minutes, and after that stirring was continued for 20 minutes at -20°C and for one hour at 30"C. The reaction mixture was poured into a mixture of 100 g ice/water and 4N hydrochloric acid (15 ml) under stirring. After addition of aqueous sodium bicarbonate sol¬ ution to render a pH of circa 5, the mixture was extracted twice with ether (25 ml each). The combined organic phases were washed with water and saturated aqueous sodium chlor¬ ide solution, dried and evaporated in vacuo to yield a crude product. This was purified either by distillation in vacuo or by chromatography (mixture of ether and pet. ether as eluant) to yield the title compound of the preparation. an equimolar amount of a different lower alkyl .ester, e.g. the methyl or propyl ester may be used instead of the ethyl ester. General Procedure 5: Conversion of TMS-protected alco¬ hols of types V or VI to the corre¬ sponding THP-protected compound of type V or VI (Scheme 2. Table 2) (Preparation 9) To a solution of the appropriate TMS-protected terti¬ ary alcohol V or VI (0.02 mol) in methanol (25 ml) was added 5 drops of 6M hydrogen chloride in methanol and the mixture was stirred for 15 minutes at 20°C. The reaction mixture was evaporated until the methanol was removed, and the residue was redissolved in dichloromethane (40 ml) . To this solution was added 3,4-dihydro-2-H-pyran (3.3 g) and PPTS (0.16 g) in portions under stirring and cooling in an ice-bath. After that, the mixture was stirred at 20°C for three hours and then diluted with ether (200 ml). The ether phase was extracted with saturated aqueous sodium bicarbon¬ ate, water and saturated aqueous sodium chloride, dried and evaporated in vacuo to yield a crude product. This was purified by chromatography (mixture of ether and pet.ether as eluant) to yield the title compound of the preparation as an oil. General Procedure 6: Conversion of compounds VI. with a terminal bromine atom, to the corresponding compound V. with a terminal ethinyl group (Scheme 2. Table 1) (Preparation 3-Q) Through dry liquid ammonia (circa 75 ml) dry acetyl¬ ene was bubbled at a rate of about 200 ml per minute with stirring. At the same time sodium (0.5 g) was added in small pieces during 5, minutes. After about 5 minutes more, the flow of acetylene was discontinued, and the appropriate bromo-co pound VI (3 mmol) was added during 5 minutes; stirring at room temperature was continued until all of the ammonia had evaporated (2.to 4 hours). Pet.ether (100 ml) and ice/water (100 g) was added under stirring. The organic phase was separated, washed several times with water until neutral, dried and evaporated in vacuo to yield a crude product. This was purified by chromatography (dichlorometh¬ ane or mixture of dichloromethane and pet.ether as eluants) to yield the title compound of the preparation. General Procedure 7: Reaction of Compound 1 with side chain building blocks V (RH) to yield Compounds IIA and IIB (Scheme 1, Table 3) (Preparations 11-13 and 21-23) To a solution of the appropriate compound V (2.5 mmol) in dry THF (5 ml), cooled to -70°C and stirred under argon, was added dropwise, during 2 minutes, a solution of n-butyllithium (1.6 mM in hexane; 1.2 ml). Stirring was continued at -70 C C for 10 minutes and then at 20°C for one hour. The mixture was again cooled to -70°C, and a solution of the aldehyde, compound 1 (0.57 g; 1 mmole) in dry THF (5 ml) was added dropwise, during 4 minutes, and after that, stiring was continued at -70°C for 15 minutes. The reaction mixture was worked up (ether) to yield a crude product con- taining compounds IIA and IIB which were separated and purified by chromatography (mixture of ether and pet.ether as eluant) to yield the title compounds of the preparation. (If necessary, repeated chromatography of selected frac¬ tions were performed, if convenient, in the form of PLC or on a Waters Prep-500 machine) . General Procedure 8: Alkylation of C-22-hydroxy-com- pounds (R 3 =H) of type II or III to the corresponding compound II or 3 III where R = C. -C.. Q hydrocarbyl (Scheme 1 f Table 3) (Preparations 14-18 and 44-45) To a solution of the appropriate compound II or III (R 3 = H) (0.5 mmol) in dry THF (5 ml) was added, while stirring at 20°C under argon, a 20% suspension of potassium hydride in mineral oil (0.2 ml) followed by an alkylating 3 agent, R Z (1.5 mmol). Then, a solution of 18-Crown-6 (0.13 g) in dry THF (2 ml) was added, during 5 minutes. Stirring at 20°C was continued for two hours, after which the reac¬ tion mixture was worked up (ether) . The crude product was purified by chromatography (mixture of ether and pet.ether as eluant) to yield the title compound of the preparation. General Procedure 9: Acylation of C-22-hydroxy-com- 3 pounds (R =H) of type II or III to the corresponding compound II or III where R 3 = YR 4 (Scheme 1. Table 3) (Preparations 19-20 and 26-27) To a solution of the appropriate compound II or III (R = H) (0.25 mmol) in a suitable dry solvent, e.g. di¬ chloromethane, was added, while stirring at 20"C under 4 4 4 argon, an acylating reagent (R YCl, (R Y) 2 ° or R YOH), pre¬ ferably accompanied by one or two suitable bases, such as triethylamine, pyridine and/or DMAP. In the case where an acid, R YOH, was used, the addition of a dehydrating or condensing agen such as e.g.. dicyclohexyl carbodiimide was desirable. The reaction mixture was then stirred at a suit¬ able temperature (from room temperature up to the boiling point of the solvent) for a sufficient time (typically for 1 to 4 hours). After a suitable work-up the crude product was purified by chromatography to yield the title compound of the preparation. General Procedure 10: Isomerization of Compounds II or TV to the corresponding compound III or I (Scheme 1. Table 3) (Prepara¬ tions 24-25. 28-43 and 46-47) A solution of the appropriate compound II or IV (0.3 mmol), anthracene (70 mg) and triethylamine (0.05 ml) in dichloromethane (20 ml) under argon in a Pyrex flask was irradiated with UV-light from a high pressure ultraviolet lamp, type TQ760Z2 (Hanau) at about 10°C for 20 minutes under stirring. The reaction mixture was concentrated in vacuo and treated with pet.ether (2x5 ml). After filtering the filtrate was concentrated in vacuo and purified by chromatography (mixture of ether and pet.ether as eluant) to yield the title compound of the preparation or example. General Procedure 11: Deprotection of Compounds II or III to the corresponding Compound IV or I by treatment with HF (Scheme 1 , Table 4) (Examples 1-7 and 11-22) To a solution of the appropriate compound II or III (0.07 mmol) in ethyl acetate (0.2 ml) was added aceto- nitrile (2 ml) followed by a 5% solution of hydrofluoric acid in acetonitrile:water, 7:1 (1.2 ml) under argon and with stirring. Stirring was continued for 45 minutes at 20°C. Saturated aqueous sodium bicarbonate solution (10 ml) was added, and the reaction mixture was worked up (ethyl acetate) The residue was purified by chromatography (ethyl acetate or a mixture of ethyl acetate and hexane or pentane as eluant) to yield the title compound of the preparation or example. General Procedure 12: Deprotection of Compounds II or III to the corresponding Compounds IV or I by treatment with tetra-n-but- ylammoniumfluoride followed by pyridine-p-toluenesulfonate (Scheme 1. Table 4) (Examples 8-10) To a solution of the appropriate compound II or III (0.16 mmol) in THF (5 ml) was added a solution of tetra-n- -butylammonium fluoride (300 mg) in THF (5 ml) while stir¬ ring at 60°C under argon. Stirring was continued for one hour at 60°C, and the reaction mixture was worked up (ethyl acetate with an additional extraction with aqueous sodium hydrogen carbonate). The residue after evaporation was purified by chromatography (50% to 0% pet. ther in ethyl acetate as eluant) and then dissolved in absolute ethyl alcohol (2 ml). PPTS (2 mg) was added, and the mixture was stirred for one hour at 50°C under argon. After work-up - ~ - or in the reverse order (ethyl acetate with an additional aqueous sodium bicarbon¬ ate extraction) the residual crude product was purified by chromatography (50% to 0% pet.ether in ethyl acetate as eluant) to yield the title compound of the preparation or example. Preparations Preparation 1: Compound 2 Method: General Procedure 1. Starting material V: 3-Ethyl-l-pentyn-3-ol. NMR: δ = 0.17 (s, 9H), 0.95 (t, 6H), 1.63 (q, 4H), 2.42 (s, IH). Preparation 2: Compound 3 Method: General Procedure 2. Starting material V: l-Methyl-4-pentyn-2-ol. Chromatography eluant: 5% ether in petroleum ether. NMR: δ = 1.34 (s, 3H), 1.35 (s, 3H), 1.51 (m, 4H), 1.67 (m, IH), 1.84 (m, IH), 2.00 (t, IH), 2.44 (m, 2H), 3.45 (m, IH), 3.97 (m, IH), 4.81 (m, IH). Preparation 3: Compound 4 Method: General Procedure 3. Starting material: Diethyl ketone. B.p. of Compound 4: 71-72°C/30 mbar. NMR: δ = 0.90 (t, 6H), 1.60 (m, 4H), 1.75 (s, IH), 2.05 (t, IH), 2.35 (m, 2H). Preparation 4: Compound 5 Method: General Procedure 2. Starting material V: Compound 4. Chromatography eluant: 0% to 5% ether in pet.ether. NMR: δ = 0.90 (m, 6H), 1.45-1.92 (m, 10H), 1.96 (t, IH), 2.46 (d, 2H), 3.47 (m, IH), 3.98 (m, IH), 4.81 (m, IH). Preparation 5: o oun 6 Method: General Procedure 4. Starting material: Methyl magnesium iodide. Purification by distillation in vacuo. B.p. of compound £: 58-59"C/12 mmHg. NMR: δ = 1.24 (s, 6H), 1.69 (s, IH), 1.75 (t, 2H), 1.98 (t, IH), 2.31 (m, 2H). Preparation 6: ompoun 7 Method: General Procedure 2. Starting material V: Compound £. Chromatography eluant: 0% to 5% ether in pet. ether. NMR: δ = 1.21 (s, 3H), 1.23 (s, 3H), 1.51 (m, 4H), 1.64 (m, IH), 1.78 (t, 2H), 1.83 (m, IH), 1.92 (t, IH), 2.29 (m, 2H), 3.45 (m, IH), 3.93 (m, IH), 4.73 (m, IH). Preparation 7: Compound 8 Method: General Procedure 4. Starting material: Ethyl magnesium bromide. Chromatography eluant: 25% ether in pet. ether. NMR: δ = 0.87 (t, 6H), 1.48 (m, 4H), 1.71 (m, 2H), 1.97 (t, 2H), 2.26 (m, 2H). Preparation 8: Compound 9 Method: General Procedure 2. Starting material V: Compound 8_. Chromatography eluant: 0% to 5% ether in pet. ether. NMR: δ = 0.84 (m, 6H), 1.40-1.90 (m, 12H), 1.92 (t, IH), 2.25 (m, 2H), 3.45 (m, IH), 3.94 ( , IH), 4.69 (m, IH). Preparation 9: Compound 10 Method: General Procedure 5. Starting material VI: l-Bromo-4-ethyl-4-trimethyl- silyloxyhexane. Chromatography eluant: 10% ether in pet.ether. NMR: δ = 0.83 (m, 6H), 1.45-2.05 (m, 14H), 3.43 (t, 2H), 3.45 (m, IH), 3.94 (m, IH), 4.68 (m, IH). Preparation 10: Compound 11 Method: General Procedure 6. Starting material VI: Compound __ζ_. Chromatography eluant: Dichloromethane. NMR: δ = 0.83 (t, 6H), 1.54 (q, 4H), 1.45-1.90 (m, 10H), 1.95 (t, IH), 2.17 (m, 2H), 3.44 (m, IH), 3.95 (m, IH), 4.69 ( , IH). Preparation 11: Compounds 12 and 13 Method: General Procedure 7. Starting material V: Compound _ . Chromatography eluant: 10% to 20% ether in pet.ether. NMR 12: δ = 0.06 (m, 12H), 0.16 (s, 9H), 0.55 (s, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 0.94 (t, 6H), 1.04 (d, 3H), 1.30-2.00 (m, 18H), 2.06 (bt, IH), 2.31 (bd, IH), 2.55 (dd, IH), 2.88 (dd, IH), 4.21 (m, IH), 4.52 (m, IH), 4.66 (m, IH), 4.94 (m, IH), 4.98 (m, IH), 5.83 (d, IH), 6.45 (d, IH). NMR ___ : δ = 0.06 (m, 12H), 0.18 (s, 9H), 0.56 (s, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 0.96 (t, 6H), 1.00 (d, 3H), 1.20-2.10 (m, 19H), 2.30 (bd, IH), 2.55 (dd, IH), 2.87 (bd, IH), 4.22 (m, IH), 4.52 (m, IH), 4.67 (m, IH), 4.94 (m, IH), 4.98 (m, IH), 5.82 (d, IH), 6.44 (d, IH). Preparation 12: Compound 14 Method: General Procedure 7. Starting material V: Compound 2.. Chromatography eluant: 20% to 25% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.54 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.03 (d, 3H), 1.31 (s, 3H), 1.32 (s, 3H), 1.25-1.97 (m, 20H), 2.05 (bt, IH), 2.33 (bd, IH), 2.45 (m, 2H), 2.54 (dd, IH), 2.87 (dd, IH), 3.44 (m, IH), 3.94 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4.60 (m, IH), 4.79 (m, IH), 4.93 (m, IH), 4.98 (m, IH), 5.82 (d, IH), 6.44 (d, IH). Preparation 13: Compounds 15 and 16 Method: General Procedure 7. Starting material V: Compound ϋL- Chromatography eluant: 20% to 33% ether in pet.ether. NMR 15 . : δ = 0.05 (m, 12H), 0.54 (s, 3H), 0.85 (s, 9H), 0.86 (m, 6H), 0.89 (s, 9H), 1.02 (d, 3H), 1.25-1.97 (m, 24H), 2.04 (bt, IH), 2.30 (bd, IH), 2.46 (m, 2H), 2.54 (dd, IH), 2.87 (dd, IH), 3.45 (m, IH), 3.96 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4.57 (m, IH), 4.80 (m, IH), 4.93 (m, IH), 4.97 (m, IH), 5.82 (d, IH), 6.44 (d, IH). NMR 1£: δ = 0.05 (m, 12H), 0.55 (s, 3H), 0.85 (s, 9H), 0.88 (m, 6H), 0.89 (s, 9H), 0.98 (d, 3H), 1.30-1.97 (m, 24H), 2.02 (bt, IH), 2.30 (bd, IH), 2.49 (m, 2H), 2.54 (dd, IH), 2.87 (dd, IH), 3.45 ( , IH), 3.95 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4.61 (m, IH), 4.80 (m, IH), 4.93 (m, IH), 4.97 (m, IH), 5.82 (d, IH), 6.44 (d, IH). Preparation 14: Compound 17 Method: General Procedure 8. Starting material IIA: Compound 15. 3 Alkylating agent: R Z: Methyl iodide. Chromatography eluant: 0% to 10% ether in pet.ether. NMR: δ ' = 0.05 (m, 12H), 0.53 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 0.90 (m, 6H), 1.01 (d, 3H), 1.25-1.98 (m, 23H), 2.04 (bt, IH), 2.31 (bd, IH), 2.48 (m, 2H), 2.55 (dd, IH), 2.87 (m, IH), 3.33 (s, 3H), 3.45 (m, IH), 3.96 (m, IH), 4.09 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4.80 (m, IH), 4.93 (m, IH), 4.97 (m, IH), 5.81 (d, IH), 6.44 (d, IH). Preparation 15: Compound 18 Method: General Procedure 8. Starting material IIA: Compound 15. 3 Alkylating agent: R Z: Ethyl bromide. Chromatography eluant: 0% to 10% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.53 (s, 3H), 0.85 (s, 9H), 0.87 (t, 6H), 0.89 (s, 9H), 1.01 (d, 3H), 1.17 (t, 3H), 1.25-1.98 (m, 23H), 2.04 (bt, IH), 2.30 (bd, IH), 2.47 (m, 2H), 2.55 (dd, IH), 2.87 (dd, IH), 3.28 (m, IH), 3.45 (m, IH), 3.74 (m, IH), 3.96 ( , IH), 4.15 ( , IH), 4.21 (m, IH), 4.52 (m, IH), 4.80 (m, IH), 4.93 (m, IH), 4.97 (m, IH), 5.81 (d, IH), 6.44 (d, IH). Preparation 16: Compound 19 Method: General Procedure 8. Starting material IIA: Compound 15. 3 Alkylating agent: R Z: n-Butyl bromide. Chromatography eluant: 0% to 10% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.52 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 0.85-0.95 (m, 9H), 1.01 (d, 3H), 1.20-1.98 (m, 27H), 2.03 (bt, IH), 2.30 (bd, IH), 2.47 (m, 2H), 2.55 (dd, IH), 2.87 (m, IH), 3.21 (m, IH), 3.44 (m, IH), 3.68 (m, IH), 3.96 (m, IH), 4.12 (m, IH), 4.21 (m, IH), 4.53 (m, IH), 4.80 (m, IH), 4.93 (m, IH), 4.98 (m, IH), 5.81 (d, IH), 6.45 (d, IH). Preparation 17: Compound 20 Method: General Procedure 8. Starting material IIA: Compound 15. 3 Alkylating agent: R Z: l-Bromo-3-methylbutane. Chromatography eluant: 0% to 10% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.52 (s, 3H), 0.86 (s, 9H), 0.88 (t, 6H), 0.90 (s, 9H), 0.90 (d, 6H), 1.00 (d, 3H), 1.15-1.97 (m, 26H), 2.03 (bt, IH), 2.30 (bd, IH), 2.47 (m, 2H), 2.55 (dd, IH), 2.87 (dd, IH), 3.23 (m, IH), 3.44 (m, IH), 3.72 (m, IH), 3.97 (m, IH), 4.11 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4. ' 80 (m, IH), 4.93 (m, IH), 4.98 (m, IH), 5.81 (d, IH), 6.45 (d, IH). Preparation 18: Compound 21 Method: General Procedure 8. Starting material IIA: Compound 15. 3 Alkylating agent: R Z: Benzyl bromide. Chromatography eluant: 0% to 10% ether in pet.ether. NMR: δ = 0.06 (m, 12H), 0.53 (s, 3H), 0.86 (s, 9H), 0.90 (s, 9H), 0.91 (t, 6H), 1.07 (d, 3H), 1.15-1.97 (m, 23H), 2.02 (bt, IH), 2.30 (bd, IH), 2.51 (m, 2H), 2.55 (dd, IH), 2.84 (bd, IH), 3.45 (m, IH), 3.97 (m, IH), 4.21 (m, IH), 4.28 (m, IH), 4.38 (d, IH), 4.53 (m, IH), 4.78 (d, IH), 4.82 (m, IH), 4.93 (m, IH), 4.98 (m, IH), 5.81 (d, IH), 6.44 (d, IH), 7.23-7.40 (m, 5H). Preparation 19: Compound 22 Method: General Procedure 9. Starting material IIA: Compound 15. Acylating reagent: Acetic anhydride (0.2 ml). Base: DMAP (30 mg). Solvent: Dichloromethane (20 ml). Reaction temperature: 40°C. Reaction time: 3 hours. Work up: Concentration in vacuo. Chromatography eluant: 0% to 20% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.52 (s, 3H), 0.85 (s, 9H), 0.87 (m, 6H), 0.89 (s, 9H), 1.07 (d, 3H), 2.05 (s, 3H), 1.10-2.10 ( , 24H), 2.29 (bd, . IH), 2.45 (m, 2H), 2.54 (dd, IH), 2.86 (dd, IH), 3.43 (m, IH), 3.94 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4.77 ( , IH), 4.93 (m, IH), 4.97 (m, IH), 5.35 (m, IH), 5.81 (d, IH), 6.43 (d, IH). Preparation 20: Compound 23 Method: General Procedure 9. Starting material IIA: Compound 15. Acylating reagent: Pivaloyl chloride (150 mg). Bases: Triethylamine (200 mg), DMAP (30 mg). Solvent: Dichloromethane (10 ml). Reaction temperature: 40°C. Reaction time: 1.5 hours. Work up: Ether. Chromatography eluant: 0% to 20% ether in pet. ther. NMR: δ = 0.05 (m, 12H), 0.54 (s, 3H), 0.85 (s, 9H), 0.87 (t, 6H), 0.89 (s, 9H), 1.10 (d, 3H), 1.20 (s, 9H), 1.05-2.07 (m, 24H), 2.29 (bd, IH), 2.44 (bs, 2H), 2.55 (dd, IH), 2.86 (dd, IH), 3.44 (m, " IH), 3.94 (m, IH), 4.21 (m, IH ) , 4. 52 (m, IH ) , 4.77 ( m, IH ) , 4.93 ( m, IH ) , 4. 97 ( m, IH ) , 5.31 (m, IH ) , 5. 81 ( d, IH ) , 6. 43 ( d, IH ) . Preparation 21: Compounds 24 and 25 Method: General Procedure 7. Starting material V: Compound 2- Chromatography eluant: 15% to 33% ether in pet.ether. NMR 21: δ = 0.05 (m, 12H), 0.54 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.02 (d, 3H), 1.19 (s, 3H), 1.21 (s, 3H), 1.30-1.98 (m, 22H), 2.04 (bt, IH), 2.17-2.40 (m, 3H), 2.54 (dd, IH), 2.87 (dd, IH), 3.43 (m, IH), 3.93 (m, IH), 4.21 (m, IH), 4.53 (m, IH), 4.57 (m, IH), 4.70 (m, IH), 4.93 (m, IH), 4.97 (m, IH), 5.82 (d, IH), 6.44 (d, IH) . NMR 25.: δ = 0.05 ( , 12H), 0.54 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 0.97 (d, 3H), 1.20 (s, 3H), 1.23 (s, 3H), 1.17-1.98 (m, 22H), 2.04 (bt, IH), 2.20-2.44 (m, 3H), 2.55 (dd, IH), 2.87 (dd, IH), 3.44 (m, IH), 3.92 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4.57 (m, IH), 4.71 (m, IH), 4.93 (m, IH), 4.97 (m, IH), 5.82 (d, IH), 6.44 (d, IH). Preparation 22: Compounds 26 and 27 Method: General Procedure 7. Starting material V: Compound 9_. Chromatography eluant: 15% to 33% ether in pet.ether. NMR 6: δ = 0.05 (m, 12H), 0.55 (s, 3H), 0.82 (t, 6H), 0.85 (s, 9H), 0.89 (s, 9H), 1.02 (d, 3H), 1.25-1.98 (m, 26H), 2.05 (bt, IH), 2.12-2.38 (m, 3H), 2.54 (dd, IH), 2.87 (dd, IH), 3.44 (m, IH), 3.93 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4.57 (m, IH), 4.68 (m, IH), 4.93 (m, IH), 4.98 (m, IH), 5.82 (d, IH), 6.44 (d, IH). NMR 21: δ = 0.04 (m, 12H), 0.54 (s, 3H), 0.82 (t, 6H), 0.85 (s, 9H), 0.88 (s, 9H), 0.97 (d, 3H), 1.10-1.97 (m, 26H), 2.03 (bt, IH), 2.12-2.42 (m, 3H), 2.54 (dd, IH), 2.86 (dd, IH), 3.44 (m, IH), 3.93 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4.56 (m, IH), 4.67 (m, IH), 4.93 (m, IH), 4.97 (m, IH), 5.82 (d, IH), 6.44 (d, IH). Preparation 23: Compounds 28 and 29 Method: General Procedure 7. Starting material V: Compound 11. Chromatography eluant: 15% to 20% ether in pet.ether. NMR 23.: δ = 0.05 (m, 12H), 0.54 (s, 3H), 0.81 (t, 6H), 0.85 (s, 9H), 0.89 (d, 9H), 1.02 (d, 3H), 1.27-1.98 (m, 28H), 2.05 (bt, IH), 2.17 (m, 2H), 2.30 (bd, IH), 2.54 (dd, IH), 2.87 (dd, IH), 3.44 (m, IH), 3.94 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4.57 (m, IH), 4.70 (m, IH), 4.93 (m, IH), 4.97 (m, IH), 5.82 (d, IH), 6.44 (d, IH). NMR 2 : δ = 0.05 (m, 12H), 0.55 (s, 3H), 0.82 (t, 6H), 0.85 (s, 9H), 0.89 (d, 9H), 0.98 («d, 3H), 1.25-2.10 ( , 29H), 2.22 ( , 2H), 2.29 (bd, IH), 2.55 (dd, IH), 2.87 (dd, IH), 3.44 (m, IH), 3.94 (m, IH), 4.21 (m, IH), 4.52 (m, IH), 4.59 (m, IH), 4.71 (m, IH), 4.93 (m, IH), 4.97 (m, IH), 5.82 (d, IH), 6.44 (d, IH). Preparation 24: Compound 30 Method: General Procedure 10. Starting material IIA: Compound 12. Chromatography eluant: 10% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.16 (s, 9H), 0.54 (s, 3H), 0.86 (s, 9H), 0.87 (s, 9H), 0.94 (m, 6H), 1.03 (d, 3H), 1.20-1.95 (m 18H), 2.01 (bt, IH), 2.21 (dd, IH), 2.44 (dd, IH), 2.82 (m, IH), 4.18 (m, IH), 4.36 (m, IH), 4.66 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 25: Compound 31 Method: General Procedure 10. Starting material IIB: Compound 13. Chromatography eluant: 0% to 12% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.18 (s, 9H), 0.55 (s, 3H), 0.87 (s, 18H), 0.96 (m, 6H), 0.99 (d, 3H), 1.10-2.10 (m, 19H), 2.20 (dd, IH), 2.44 (dd, IH), 2.82 (m, IH), 4.18 (m, IH), 4.35 (m, IH)., 4.67 (d, IH), 4.85 (d, IH), 5.17 (d, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 26: Compound 32 Method: General Procedure 9. Starting material IIIA: Compound 30. Acylating reagent: Acetic acid (0.02 ml). Dehydrating agent: Dicyclohexyl carbodiimide (66 mg). Base: DMAP (7 mg). Solvent: Dichloromethane (3 ml). Reaction temperature: 20°C. Reaction time: 4 hours. Work up: Filtration, concentration of the filtrate in vacuo. Chromatography eluant: 10% ether in pet.ether. NMR: δ = 0.05 ( , 12H), 0.14 (s, 9H), 0.52 (s, 3H), 0.86 (s, 18H), 0.92 (t, 6H), 1.08 (d, 3H), 1.05-2.05 (m, 18H), 2.05 (s, 3H), 2.20 (dd, IH), 2.43 (dd, IH), 2.82 (m, IH), 4.18 (m, IH), 4.36 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 5.42 (d, IH), 6.00 (d, IH), 6.21 (d, IH). Preparation 27: om oun 33 Method: General Procedure 9. Starting material IIIA: Compound 30. Acylating reagent: Phenyl chlorothionoformate (125 mg). Base: Pyridine (0.2 ml). Solvent: Dichloromethane (5 ml). Reaction temperature: 20 °C. Reaction time: 3 hours. Work up: Dichloromethane. Chromatography eluant: 4% ether in pet. ther. NMR: δ = 0.06 (m, 12H), 0.18 (s, 9H), 0.56 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 0.96 (t, 6H), 1.16 (d, 3H), 1.10-2.10 (m, 18H), 2.21 (dd, IH), 2.44 (dd, IH), 2.84 (m, IH), 4.19 (m, IH), 4.37 (m, IH), 4.86 (m, IH), 5.18 (m, IH), 5.78 (d, IH), 6.02 (d, IH), 6.23 (d, IH), 7.08 (m, 2H), 7.28 (m, IH), 7.42 (m, 2H). Preparation 28: Compound 34 Method: General Procedure 10. Starting material IIA: Compound 14. Chromatography eluant: 20% to 25% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.53 (s, 3H), 0.87 (s, 18H), 1.02 (d, 3H), 1.31 (s, 3H), 1.32 (s, 3H), 1.15-1.94 (m, 20H), 2.00 (bt, IH), 2.20 (dd, IH), 2.44 (dd, IH), 2.45 (m, 2H), 2.82 (dd, IH), 3.44 (m, IH), 3.95 (m, IH), 4.18 (m, IH), 4.36 (m, IH), 4.60 (m, IH), 4.80 (m, IH), 4.85 (m, IH), 5.17 ( , IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 29: Compound 35 Method: General Procedure 10. Starting material IIA: Compound 15. Chromatography eluant: 20% to 25% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.53 (s, 3H), 0.87 (s, 18H), 0.90 (m, 6H), 1.01 (d, 3H), 1.15-1.94 (m, 24H), 1.99 (bt, IH), 2.20 (dd, IH), 2.44 (dd, IH), 2.46 (m, 2H), 2.81 (dd, IH), 3.43 (m, IH), 3.95 (m, IH), 4.17 (m, IH), 4.36 (m, IH), 4.57 (m, IH), 4.80 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 30: Compound 36 Method: General Procedure 10. Starting material IIB: Compound 16. Chromatography eluant: 15% to 25% ether in pet.ether. NMR: δ - 0.05 (m, 12H), 0.54 (s, 3H), 0.87 (s, 18H), 0.89 (m, 6H), 0.97 (d, 3H), 1.15-1.92 (m, 24H), 1.97 (bt, IH), 2.20 (dd, IH), 2.44 (dd, IH), 2.49 (m, 2H), 2.81 (dd, IH), 3.45 (m, IH), 3.96 (m, IH), 4.17 (m, IH), 4.36 (m, IH), 4.61 (m, IH), 4.81 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 31: Compo n 37 Method: General Procedure 10. Starting material IIA: Compound 17. Chromatography eluant: 5% to 10% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.52 (s, 3H), 0.87 (s, 18H), 0.89 (m, 6H), 1.00 (d, 3H), 1.20-1.93 (m, 23H), 1.99 (bt, IH), 2.20 (dd, IH), 2.44 (dd, IH), 2.48 (m, 2H ) , 2.82 (m, IH), 3.33 (s, 3H), 3.44 (m, IH), 3.96 (m, IH), 4.10 (m, IH), 4.18 (m, IH), 4.36 (m, IH), 4.80 (m, IH), 4.85 ( , IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 32: Compound 38 Method: General Procedure 10. Starting material IIA: Compound 18.. Chromatography eluant: 0% to 10% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.51 (s, 3H), 0.86 (s, 18H), 0.88 (m, 6H), 1.00 (d, 3H), 1.18 (t, 3H), 1.25-1.92 (m, 23H), 1.99 (bt, IH), 2.20 (dd, IH), 2.43 (dd, IH), 2.46 (m, 2H), 2.82 (dd, IH), 3.28 (m, IH), 3.44 (m, IH), 3.75 (m, IH), 3.97 (m, IH), 4.15 (m, IH), 4.18 (m, IH), 4.36 (m, IH), 4.80 (m, IH), 4.86 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 33: Compound 39 Method: General Procedure 10. Starting material IIA: Compound 19. Chromatography eluant: 5% to 10% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.51 (s, 3H), 0.87 (s, 18H), 0.85-0.95 (m, 9H), 1.00 (d, 3H), 1.20-1.93 (m, 27H), 1.98 (bt, IH), 2.20 (dd, IH), 2.44 (dd, IH), 2.47 (m, 2H), 2.82 (m, IH), 3.21 (m, IH), 3.44 (m, IH), 3.68 (m, IH), 3.96 (m, IH), 4.12 (m, IH), 4.18 (m, IH), 4.36 (m, IH), 4.81 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.23 (d, IH). Preparation 34: com ound 4Q Method: General Procedure 10. Starting material IIA: Compound 20. Chromatography eluant: 0% to 5% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.51 (s, 3H), 0.86 (s, 18H), 0.88 (m, 12H), 0.99 (d, 3H), 1.15-1.92 (m, 26H), 1.98 (bt, IH), 2.20 (dd, IH), 2.43 (dd, IH), 2.47 (m, 2H), 2.82 (bd, IH) , 3.22 (m, IH) , 3.44 (m, IH) , 3.71 (m, IH) , 3. 96 ( m, IH ) , 4. 11 (m, IH) , 4.17 (m, IH ) , 4.36 (m, IH ) , 4. 80 ( m, IH) , 4. 85 (m, IH) , 5. 17 (m, IH ) , 6.00 ( d, IH ) , 6. 22 ( d, IH ) . Preparation 35: Compound 1 Method: General Procedure 10. Starting material IIA: Compound 21- Chromatography eluant: 0% to 10% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.51 (s, 3H), 0.86 (s, 18H), 0.90 ( , 6H), 1.05 (d, 3H), 1.15-1.90 (m, 23H), 1.97 (bt, IH), 2.20 (dd, IH), 2.43 (dd, IH), 2.51 ( , 2H), 2.79 (bd, IH), 3.45 (m, IH), 3.96 ( , IH), 4.18 (m, IH), 4.27 (m, IH), 4.36 (m, IH), 4.38 (d, IH), 4.77 (d, IH), 4.82 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.00 (d, IH), 6.22 (d, IH), 7.34 (m, 5H). Preparation 36: Compound 42 Method: General Procedure 10. Starting material IIA: Compound 22. Chromatography eluant: 0% to 20% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.51 (s, 3H), 0.86 (s, 18H), 0.83-0.92 (m, 6H), 1.07 (d, 3H), 1.00-1.91 (m, 23H), 1.96 (bt, IH), 2.05 (s, 3H), 2.20 (dd, IH), 2.43 (dd, IH), 2.46 (m, 2H), 2.81 (dd, IH), 3.43 (m, IH), 3.94 (m, IH), 4.17 (m, IH), 4.36 (m, IH), 4.78 (m, IH), 4.84 (m, IH), 5.16 (m, IH), 5.34 (m, IH), 6.00 (d, IH), 6.21 (d, IH). Preparation 37: Compound 43 Method: General Procedure 10. Starting material IIA: Compound 23. Chromatography eluant: 0% to 20% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.52 (s, 3H), 0.86 (s, 18H), 0.82-0.90 (m, 6H), 1.09 (d, 3H), 1.20 (s, 9H), 1.00-1.90 (m,.23H), 1.94 (bt, IH), 2.18 (dd, IH), 2.43 (dd, IH), 2.44 (bs, 2H), 2.81 (dd, IH), 3.43 (m, IH), 3.94 (m, IH), 4.17 (m, IH), 4.35 (m, IH), 4.76 (m, IH), 4.84 (m, IH), 5.16 (m, IH), 5.31 (m, IH), 6.00 (d, IH), 6.21 (d, IH). Preparation 38: Compound 44 Method: General Procedure 10. Starting material IIA: Compound 24. Chromatography eluant: 15% to 25% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.53 (s, 3H), 0.86 (s, 18H), 1.01 (d, 3H), 1.18 (s, 3H), 1.21 (s, 3H), 1.73 (t, 2H), 1.15-1.98 (m, 20H), 1.99 (bt, IH), 2.20 (dd, IH), 2.29 (m, 2H), 2.43 (dd, IH), 2.82 (dd, IH), 3.45 (m, IH), 3.92 (m, IH), 4.17 (m, IH), 4.36 (m, IH), 4.57 (m, IH), 4.70 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 39: Compound 45 Method: General Procedure 10. Starting material IIB: Compound 23.. Chromatography eluant: 20% to 25% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.53 (s, 3H), 0.86 (s, 18H), 0.96 (d, 3H), 1.20 (s, 3H), 1.23 (s, 3H), 1.75 (t, 2H), 1.12-1.92 (m, 20H), 1.99 (bt, . IH), 2.20 (dd, IH), 2.31 (m, 2H), 2.43 (dd, IH), 2.82 (dd, IH), 3.44 (m, IH), 3.92 (m, IH), 4.19 (m, IH), 4.36 (m, IH), 4.57 (m, IH), 4.70 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 40: Compound 46 Method: General Procedure 10. Starting material IIA: Compound 26. Chromatography eluant: 20% to 25% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0. ' 53 (s, 3H), 0.82 (m, 6H), 0.86 (s, 18H), 1.01 (d, 3H), 1.72 (t, 2H), 1.25-1.93 (m, 24H), 2.00 (bt, lH), n 2.20 (dd, IH), 2.23 (m, 2H), 2.43 (d, IH), 2.82 (dd, IH), 3.44 ( , IH), 3.93 (m, IH), 4.18 (m, IH), 4.36 (m, IH), 4.57 (m, IH), 4.67 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 41: Compound 47 Method: General Procedure 10. Starting material IIB: Compound 27. Chromatography eluant: 20% to 25% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.53 (s, 3H), 0.83 (t, 6H), 0.86 (s, 18H), 0.96 (d, 3H), 1.12-1.93 (m, 26H), 1.98 (bt, IH), 2.10-2.40 (m, 3H), 2.43 (dd, IH), 2.81 (dd, IH), 3.44 (m, IH), 3.93 (m, IH), 4.18 (m, IH), 4.35 (m, IH), 4.57 (m, IH), 4.67 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 42: Compound 48 Method: General Procedure 10. Starting material IIA: Compound 28. Chromatography eluant: 0% to 20% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.53 (s, 3H), 0.81 (t, 6H), 0.86 (s, 18H), 1.02 (d, 3H), 1.25-1.93 (m, 28H), 2.00 (bt, IH), 2.18 (m, 2H), 2.20 (dd, IH), 2.43 (dd, IH), 2.82 (dd, IH), 3.43 ( , IH), 3.94 (m, IH), 4.18 (m, IH), 4.36 (m, IH), 4.57 (m, IH), 4.70 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 43: Compound 49 Method: General Procedure 10. Starting material IIB: Compound 29. Chromatography eluant: 0% to 20% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.54 (s, 3H), 0.82 (t, 6H), 0.86 (s, 18H), 0.97 (d, 3H), 1.15-2.05 (m, 29H), 2.20 (dd, IH), 2.21 (m, IH), 2.43 (dd, IH), ' 2.82 (dd, IH), 3.44 (m, IH), 3.94 (m, IH), 4.18 (m, IH), 4.35 (m, IH), 4.59 ( , IH), 4.71 (m, IH), 4.85 (m, IH), 5.17 (m, IH), 6.01 (d, IH), 6.22 (d, IH). Preparation 44: Compound 50 Method: General Procedure 8. Starting material IIA: Compound 12. 3 Alkylating agent: R Z: Methyl iodide. Chromatography eluant: 0% to 10% ether in pet.ether. NMR: δ = 0.06 (m, 12H), 0.17 (s, 9H), 0.54 (s, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 0.96 (dt, 6H), 1.03 (d, 3H), 1.64 (q, 4H), 1.15-2.12 (m, 14H), 2.31 (bd, IH), 2.55 (dd, IH), 2.87 (m, IH), 3.36 (s, 3H), 4.17 (d, IH), 4.21 (m, IH), 4.53 (m, IH), 4.93 (m, IH), 4.98 (m, IH), 5.82 (d, IH), 6.45 (d, IH). Preparation 45: Compound 51 Method: General Procedure 8. Starting material IIA: Compound 12. 3 Alkylating agent: R Z: Ethyl bromide. Chromatography eluant: 0% to 10% ether in pet.ether. NMR: δ = 0.06 (m, 12H), 0.16 (s, 9H), 0.53 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 0.95 (t, 6H), 1.03 (d, 3H), 1.18 (t, 3H), 1.63 (q, 4H), 1.10-2.15 (m, 14H), 2.31 (bd, IH), 2.55 (dd, IH), 2.88 (m, IH), 3.30 (m, IH), 3.77 (m, IH), 4.21 (d, IH), 4.21 (m, IH), 4.53 (m, IH), 4.93 (m, IH), 4.98 (m, IH), 5.82 (d, IH), 6.45 (d, IH). Preparation 46: Compound 52 Method: General Procedure 10. Starting material IIA: Compound 50. Chromatography eluant: 0% to 20% ether in pet.ether. NMR: δ = 0.06 (m, 12H), 0.17 (s, 9H), 0.53 (s, 3H), 0.87 (s, 18H), 0.96 (dt, 6H), 1.02 (d, 3H), 1.63 (q, 4H), 1.15-2.10 (m, 14H), 2.21 (dd, IH), 2.45 (dd, IH), 2.82 (m, IH), 3.36 (s, 3H), 4.16 (d, IH), 4.19 (m, IH), 4.38 (m, IH), 4.86 (m, IH), 5.18 (m, IH), 6.01 (d, IH), 6.23 (d, IH). Preparation 47: Compound 53 Method: General Procedure 10. Starting material IIA: Compound 51. Chromatography eluant: 0% to 10% ether in pet.ether. NMR: δ = 0.05 (m, 12H), 0.16 (s, 9H), 0.52 (s, 3H), 0.87 (s, 18H), 0.95 (t, 6H), 1.02 (d, 3H), 1.18 (t, 3H), 1.63 (q, 4H), 1.12-2.10 (m, 14H), 2.21 (dd, IH), 2.44 (dd, IH), 2.82 (bd, IH), 3.30 (m, IH), 3.77 (m, IH), 4.18 (m, IH) , 4.21 ( d, IH) , 4.37 (d, IH ) , 4.86 ( , IH ) , 5.17 (m, IH) , 6.01 (d, IH) , 6.23 ( d, IH ) . Examples Example 1: 1(S) .3(R)-Dihvdroxy-20(R)-(1. -dihydr- oxy-4-ethyl-2-hexyn-l-yl)-9.10-seπn- pregna-5(Z).7(E) .10(19)-triene: is mer A (Compound 101) Method: General Procedure 11. Starting material IIIA: Compound 20.. Chromatography eluant: Ethyl acetate. NMR: δ = 0.56 (S, 3H), 1.03 (t, 6H), 1.03 (d, 3H), 1.20-2.07 (m, 22H), 2.32 (dd, IH), 2.60 (dd, IH), 2.84 (m, IH), 4.23 (m, IH), 4.44 (m, IH), 4.65 (m, IH), 5.00 (m, IH), 5.33 (m, IH), 6.02 (d, IH), 6.38 (d, IH). Example 2: 1(S) .3(R)-Dihydroxy-20(R)-(1.4-dihydr- oxy-4-ethyl-2-hexyn-l-yl)-9 r 10-seco-pre- gnβ-5(Z).7(E).10(19)-triene: isomer B (Compound 102) Method: General Procedure 11. Starting material IIIB: Compound 31. Chromatography eluant: Ethyl acetate. NMR: δ = 0.57 (s, 3H), 0.99 (d, 3H), 1.05 (t, 6H), 1.15-2.15 (m, 22H), 2.32 (dd, IH), 2.60 (dd, IH), 2.83 (m, IH), 4.24 (m, IH), 4.44 (m, IH), 4.66 (m, IH), 5.00 (m, IH), 5.33 (m, IH), 6.02 (d, IH), 6.37 (d, IH). Example 3: 1(S).3(R)-Dihvdroxy-20(R)-(1-acetoxy- -4-ethyl-4-hvdroxy-2-hexyn-l-yl)- .10- seco-pregna-5(Z) .7(E) .10(19)-triene: isomer A (Compound 103) Method: General Procedure 11. Starting material IIIA: Compound 32. Chromatography eluant: Ethyl acetate. NMR: δ = 0.53 (s, 3H), 1.00 (t, 6H), 1.07 (d, 3H), 1.10-2.10 (m, 21H), 2.07 (s, 3H), 2.30 (dd, IH), 2,58 (dd, IH), 2.82 (m, IH), 4.22 (m, IH), 4.42 (m, IH), 4.98 (m, IH ) , 5.32 ( m, IH ) , 5.38 ( d, IH ) , 6.01 ( d, IH ) , 6.35 ( d, IH ) . Example 4: 1(S) .3(R)-Dihydroxy-20(R)-(4-ethyl-4- -hydroxy-2-phenoxythiocarbonyloxy-2- hexyn-l-yl)-9 r 10-seco-pregna- 5(Z).7(E).10(19)-triene: isomer A (Compound 104) Method: General Procedure 11. Starting material IIIA: Compound 33. Chromatography eluant: Ethyl acetate. NMR: δ = 0.58 (s, 3H), 1.04 (t, 6H), 1.15 (d, 3H), 1.20-2.10 (m, 21H), 2.31 (dd, IH), 2.59 (bd, IH), 2.84 (bd, IH), 4.23 (m, IH), 4.43 (m, IH), 5.00 (m, IH), 5.33 (m, IH), 5.74 (d, IH), 6.03 (d, IH), 6.37 (d, IH), 7.08 (m, 2H), 7.30 (m, IH), 7.43 (m, 2H). Example 5: 1(S).3(R)-Dihydroxy-20(R)-(1.5-dihydr- oxy-5-methyl-2-hexyn-l-yl)-9 r 10-seco- pregna-5(Z) .7(E) .10(19)-triene: isomer A (Compound 105) Method: General Procedure 11. Starting material IIIA: Compound 34. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.57 (s, 3H), 1.04 (d, 3H), 1.25 (s, 6H), 1.20-2.10 (m, 14H), 2.28 (dd, IH), 2.33 (m, 2H), 2.51 (dd, IH), 2.86 (dd, IH), 3.44 (s, IH), 3.63 (d, IH), 3.88 (d, IH), 3.92 (d, IH), 4.16 (m, IH), 4.40 (m, IH), 4.55 (m, IH), 4.87 (m, IH), 5.32 (m, IH), 6.09 (d, IH), 6.29 (d, IH). Example 6: 1(S) .3(R)-Dihvdroxy-20( )-(1.5-dihvdr- oxy-5-ethyl-2-heptyn-l-yl)-9.10-seco- pregna-5(Z) .7(E) .10(19)-triene: isomer A (Compound 106) Method: General Procedure 11. Starting material IIIA: Compound 2_ϊ. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.55 (s, 3H), 0.89 (t, 6H), 1.02 (d, 3H), 1.15-2.40 (m, 22H), 2.31 (dd, IH), 2.37 (m, 2H), 2.58 (dd, IH), 2.83 (dd, IH), 4.22 (m, IH), 4.43 (m, IH), 4.59 (m, IH), 4.99 ( , IH), 5.33 (m, IH), 6.03 (d, IH), 6.36 (d, IH). Example 7: 1(S) .3(R)-Dihydroxy-20(R)-(1.5-dihydr- oxy-5-ethyl-2-heptyn-l-yl)-9.10-seco- pregna-5(Z) .7(E) r 10(19)-triene: isomer B (Compound 107) Method: General Procedure 11. Starting material IIIB: Compound 36. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.57 (s, 3H), 0.91 (t, 6H), 0.99 (d, 3H) 1.15-2.45 (m, 23H), 2.41 (m, 2H), 2.60 (dd, IH), 2.83 (dd, IH), 4.23 (m, IH), 4.44 (m, IH), 4.65 (m, IH), 5.00 (m, IH), 5.33 (m, IH), 6.02 (d, IH), 6.37 (d, IH). Example 8: 1(S) .3(R)-Dihydroxy-20(R)-(5-ethyl-5- hydroxy-l-methoxy-2-heptvn-l-yl)-9.10- seco-pregna-5(Z) .7(E) .10( 19 )-triene: isomer A (Compound 108) Method: General Procedure 12. Starting material IIIA: Compound ___.. NMR: δ = 0.55 (s, 3H), 0.91 (t, 6H), 1.02 (d, 3H), 1.20-2.10 (m, 21H), 2.29 (dd, IH), 2.40 (m, 2H), 2.59 (dd, IH), 2.84 (m IH), 3.35 (s, 3H), 4.11 (m, IH), 4.22 (m, IH), 4.43 ( , IH), 5.00 (m, IH), 5.33 (m, IH), 6.02 (d, IH), 6.37 (d, IH). Example 9: 1(S) .3(R)-Dihydroxy-20(R)-(l-ethoxy-5- -ethyl-5-hydroxy-2-heptyn-l-vl)-9.10- seco-pregna-5(Z) .7(E) .10(19)-triene: isomer A (Compound 1Q9) Method: General Procedure 12. Starting material IIIA: Compound 23.. NMR: δ = 0.55 (s, 3H), 0.90 (t, 6H), 1.02 (d, 3H), 1.20 (t, 3H), 1.15-2.10 (m, 21H), 2.31 (dd, IH), 2.39 (m, 2H), 2.59 (dd, IH), 2.83 (dd, IH), 3.31 (m, IH), 3.75 (m, IH, 4.17 (m, IH), 4.22 (m, IH), 4.43 (m, IH), 5.00 (m, IH), 5.33 (m, IH), 6.02 (d, IH), 6.37 (d, IH). Example 10: 1(S) .3(R)-Dihvdroxy-20(R)-(1-butoxy- 5-ethyl-5-hydroxv-2-heptyn-l-vl)-9.10- seco-pregna-5(Z).7(E) .10(19)-triene: isomer A (Compound 110) Method: General Procedure 12. Starting material IIIA: Compound 39. NMR: δ = 0.54 (s, 3H), 0.90 (t, 6H), 0.92 (t, 3H) 1.01 (d, 3H), 1.20-2.10 (m, 25H), 2.31 (dd, IH), 2.39 (m, 2H), 2.60 (dd, IH), 2.84 (dd, IH), 3.24 (m, IH), 3.68 (m, IH, 4.13 (m, IH), 4.23 (m, IH), 4.43 (m, IH), 5.00 (m, IH), 5.33 (m, IH), 6.02 (d, IH), 6.38 (d, IH). Example 11: 1(S).3(R)-Dihydroxy-20(R)-(5-ethyl-5- -hydroxy-l-(3-methylbutyloxy)-2-heptyn- 1-vl)-9.10-seco-pregna-5(Z) .7(E) .10(19)- triene: isomer A (Compound 111) Method: General Procedure 11. Starting material IIIA: Compound 40. Chromatography <eluant: 50% to 0% hexane in ethyl acetate. NMR: δ = 0.54 (s, 3tf), 0.90 (t, 6H), 0.91 (d, 6H) 1.01 (d, 3H), 1.20-2.05 (m, 24H), 2.31 (dd, IH), 2.39 ( , 2H), 2.59 (dd, IH), 2.84 (dd, IH), 3.25 (m, IH), 3.71 (m, IH, 4.13 (m, IH), 4.23 (m, IH), 4.43 (m, IH), 5.00 ( , IH), 5.33 (m, IH), 6.02 (d, IH), 6.38 (d, IH). Example 12: 1 (S) .3(R)-Dihvdroxv-20(R)-(1-bβnzyl- nxy-5-ethyl-5-hydroxy-2-heptyn-l-yl)- Q.lO-seco-pregna-5(Z) .7(E) .10(19)- triene: isomer A (Compound 112) Method: General Procedure 11. Starting material IIIA: Compound ____. Chromatography eluant: 50% to 0% hexane in ethyl acetate. NMR: δ = 0.54 (s, 3H), 0.91 (t, 6H) 1.06 (d, 3H), 1.15-2.05 (m, 21H), 2.30 (dd, IH), 2.42 (m, 2H), 2.57 (dd, IH), 2.81 (bd, IH), 4.21 (m, IH), 4,29 (m, IH), 4,41 ( , IH), 4,41 (d, IH), 4.77 (d, IH), 4.99 (m, IH), 5,32 (m, IH), 6.01 (d, IH), 6.36 (d, IH), 7.23-7.40 (m, 5H). Example 13: 1(S).3(R)-Dihydroxy-20(R)-(1-acetoxy- -5-ethyl-5-hvdroxy-2-heptvn-l-yl)-9.10- seco-pregna-5(Z).7(E).10(19)-triene isomer A (Compound 113) Method: General Procedure 11. Starting material IIIA: Compound 42. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.55 (s, 3H), 0.88 (t, 6H), 1.08 (d, 3H), 2.08 (s, 3H), 1.05-2.10 (m, 21H), 2.33 (dd, IH), 2.36 (m, 2H), 2.59 (dd, IH), 2.83 (dd, IH), 4.22 (m, IH), 4.43 (m, IH), 4.99 (m, IH), 5.33 (m, IH), 5.34 (m, IH), 6.02 (d, IH), 6.36 (d, IH). Example 14: 1(S).3(R)-Dihydroxy-20(R)-(5-ethyl-5- -hydroxy-l-pivaloyloxy-2-heptyn-l-yl)- 9 r 10-seco-pregna-5(Z) .7(E) .10(19)- triene: isomer A (Compound 114) Method: General Procedure 11. Starting material IIIA: Compound 43. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.56 (s, 3H), 0.87 (m, 6H), 1.11 (d, 3H), 1.22 (s, 9H), 1.05-2.10 (m, 21H), 2.32 (dd, IH), 2.34 (m. 2H), 2.59 (dd, IH), 2.83 (dd, IH), 4.23 (m, IH), 4.42 (m, IH), 4.99 (m, IH), 5.31 (m, IH), 5.33 (m, IH), 6.02 (d, IH), 6.36 (d, IH). Example 15: 1(S) .3(R)-Dihydroxv-20(R)-(1.6-dihvdr- oxy-6-methyl-2-heptvn-l-yl)-9.10-seπo- pregna-5(Z).7(E).10(19)-triene: isomer A (Compound 115) Method: General Procedure 11. Starting material IIIA: Compound 44. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.56 (s, 3H), 1.01 (d, 3H), 1.17 (s, 6H), 1.25-2.10 (m, 16H), 2.28 (m, 3H), 2.50 (dd, IH), 2.87 (dd, IH), 3.36 (bs, IH), 3.72 (m, IH), 3.87 (d, IH), 3.94 (d, IH), 4,17 (m, IH), 4.40 (m, IH), 4.51 (m, IH), 4.87 (m, IH), 5.32 (m, IH), 6.09 (d, IH), 6.29 (d, IH). Example 16: 1(S).3(R)-Dihydroxy-20(R)-(1.6-dihydr- oxy-6-methyl-2-heptvn-l-yl)-9.10-seco- pregna-5(Z).7(E).10(19)-triene: isomer B (Compound 116) Method: General Procedure 11. Starting material IIIB: Compound _3. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.58 (s, 3H), 0.98 (d, 3H), 1.18 (s, 6H), 1.15-2.10 (m, 16H), 2.31 (m, 3H), 2.50 (dd, IH), 2.86 (dd, IH), 3.32 (s, IH), 3.66 (d, IH), 3.91 (d, IH), 4.01 (d, IH), 4.16 (m, IH), 4.40 (m, IH), 4.57 (m, IH), 4.87 (m, IH), 5.32 (m, IH), 6.10 (d, IH), 6.29 (d, IH). Example 17: 1(S) , fR)-Pihydrpxy-2Q(R -(1 ,6-dihydr- oxy-6-ethyl-2-octyn-l-yl)-9.10-seco- pregna-5(Z) .7(E),10(19)-triene: isomer A (Compound 117) Method: General Procedure 11. Starting material IIIA: Compound ____. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.56 (s, 3H), 0.84 (t, 6H), 1.01 (d, 3H), 1.45 (q, 4H), 1.25-2.10 (m, 16H), 2.23 (m, 2H), 2.29 (dd, IH), 2.51 (dd, IH), 2.86 (dd, IH), 3.09 (bs, IH), 3.71 (bs, IH), 3.87 (d, IH), 3.94 (bd, IH), 4,17 (m, IH), 4.40 (m, IH), 4.50 (m, IH), 4.87 (m, IH), 5.32 (m, IH), 6.09 (d, IH), 6.29 (d, IH) Example 18: 1(S).3(R)-Dihydroxy-20(R)-(1.6-dihydr- oxy-6-ethyl-2-octyn-l-yl)-9.10-seco- pregna-5(Z).7(E).10(19)-triene: isomer B (Compound 118) Method: General Procedure 11. Starting material IIIB: Compound 47. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.58 (s, 3H), 0.85 (t, 6H), 0.98 (d, 3H), 1.46 (q, 4H), 1.25-2.10 (m, 16H), 2.28 (m, 3H), 2.50 (dd, IH), 2.86 (dd, IH), 3.07 (s, IH), 3.66 (d, IH), 3.91 (d, IH), 4.02 (d, IH), 4,17 (m, IH), 4.40 (m, IH), 4.57 (m, IH), 4.86 ( , IH), 5.32 (m, IH), 6.09 (d, IH), 6.29 (d, IH). Example 19: 1(S).3(R)-Dihydrox -20(R)-(1.7-dihydr- oxy-7-ethyl-2-nonyn-l-yl)-9.10-seco- pregna ^ 5(Z).7(E).10(19)-triene: isomer A (Compound 1X9) • Method: General Procedure 11. Starting material IIIA: Compound 48. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.55 (s, 3H), 0.86 (t, 6H), 1.03 (d, 3H), 1.47 (q, 4H), 1.10-2.10 ( , 22H), 2.23 (m, 2H), 2,31 (dd, IH), 2.60 (bd, IH), 2.84 (bd, IH), 4.23 (m, IH), 4.43 (m, IH), 4.58 (m, IH), 5.00 (m, IH), 5.33 (m, IH), 6.02 (d, IH), 6.37 (d, IH). Example 20: 1(S).3(R)-Dihydroxy-20(R)-(1.7-dihydr- nxy-7-ethyl-2-nonyn-l-vl)-9.10-SRΠO- pregna-5(Z).7(E).10(19)-triene: isomer B (Compound 120) Method: General Procedure 11. Starting material IIIB: Compound 49. Chromatography eluant: 25% to 0% hexane in ethyl acetate. NMR: δ = 0.58 (s, 3H), 0.86 (t, 6H), 0.99 (d, 3H), 1.45 (q, 4H), 1.35-2.10 (m, 18H), 2.22 (m, 2H), 2.28 (dd, IH), 2.50 (dd, IH), 2.85 (m, IH), 2.91 (s, IH), 3.66 (d, IH), 3.91 (d, IH), 4.02 (d, IH), 4.16 (m, IH), 4.40 (m, IH), 4.60 (m, IH), 4.87 (m, IH), 5.32 (m, IH), 6.10 (d, IH), 6.29 (d, IH). Example 21: 1(S).3(R)-Dihvdroxy-20(R)-(1- ethoxy- -4-hydroxy-4-ethyl-2-hexyn-l-yl)-9.10- -seco-pregna-5(Z).7(E) .10(19)-triene: isomer A (Compound 130) Method: General Procedure 11. Starting material IIIA: Compound 52. Chromatography eluant: Ethyl acetate. NMR: δ = 0.55 (s, 3H), 1.02 (d, 3H), 1.05 (t, 6H), 1.68 (m, 4H), 1.20-2.10 (m, 17H), 2.32 (dd, IH), 2.60 (dd, IH), 2.84 (m, IH), 3.36 (s, 3H), 4.16 (d, IH), 4.23 (m, IH), 4.43 (m, IH), 5.00 (m, IH), 5.33 (m, IH), 6.02 (d, IH), 6.38 (d, IH). Example 22 : 1( S ) .3 ( R ) -Dihvdroxy-20( R ) -( 1-ethoxy- -4-hvdroxy-4-ethyl-2-hexyn-l-yl)-9,10- -seco-pregna-5(Z) ,7(E) ,10(19)-triene: isomer A (Compound 135) Method: General Procedure 11. Starting material IIIA: Compound 53. Chromatography eluant: Ethyl acetate. NMR: δ = 0.55 (s, 3H), 1.03 (d, 3H), 1.04 (t, 6H), 1.20 (t, 3H), 1.12-2.20 (m, 21H), 2.31 (dd, IH), 2.59 (bd, IH), 2.83 (m, IH), 3.31 (m, IH), 3.76 (m, IH), 4.22 (m, 2H), 4.42 (m, IH), 5.00 (m, IH), 5.33 (m, IH), 6.02 (d, IH), 6.38 (d, IH). Example 23 Capsules containing Compound 109 Compound 109 was dissolved in arachis oil to a final concentration of 1 μg of Compound 109/ml oil. 10 Parts by weight of gelatine, 5 parts by weight glycerine, 0.08 parts by weight potassium sorbate, and 14 parts by weight distilled water were mixed together with heating and formed into soft gelatine capsules. These were then filled each with 100 μl of Compound 109 in oil solution, such that each capsule contained 0.1 μg of Compound 109. Example 24 Dermatological Cream Containing Compound 109 In 1 g almond oil was dissolved 0.05 mg of Compound 109. To this solution was added 40 g of mineral oil and 20 g of self-emulsifying beeswax. The mixture was heated to liquify. After the addition of 40 ml hot water, the mixture was mixed well. The resulting cream contains approximately 0.5 μg of Compound 109 per gram of cream.

Claims: WHAT WE CLAIM IS: A compound of the formula I in which formula X is hydrogen or hydroxy; R 1 and R2, which may be the same or different, stand for hydrogen or a C,-Cg hydrocarbyl radical; or R 1 and R2, taken together with the carbon atom (starred in formula I) bearing the 3 group X, can form a Cg-Co carbocyclic ring; R stands for hydrogen or a C.-C. Q hydrocarbyl radical or for YR , in which Y stands for the radicals -CO-, -C0-0-, -C0-S-, 4 -CS- -CS-0-, -CS-S-, -SO- or -SO j -, and R stands for hydrogen or a C,-C. n hydrocarbyl radical; Q is a single bond or a C.-Cg hydrocarbylene diradical; R 1, R2, R3 and/or Q may be optionally substituted with one or more deuterium or fluorine atoms. 2. A diastereoisomer of a compound according to claim 1, in pure form; or a mixture of diastereoisomers of a compound according to claim 1. 3. A compound according to claim 1 which is 1(S ) , 3(R)-Dihydroxy-20( R)-( 1, 5-dihydroxy-5-ethyl-2-heptyn- -l-yl )-9 , 10-seco-pregna-5( Z ) , 7(E ) , 10( 19 )-triene; isomer A, 1(S),3(R)-Dihydroxy-20(R)-(5-ethyl-5-hydroxy-l-methoxy-2- -he tyn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A, l(S),3(R)-Dihydroxy-20(R)-(l-ethoxy-5-ethyl-5-hydroxy-2- -heptyn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A, 1(S),3(R)-Dihydroxy-20(R)-(l-methoxy-4-hydroxy-4-ethyl-2- -hexyn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A, or l(S),3(R)-Dihydroxy-20(R)-(l-ethoxy-4-hydroxy-4-ethyl-2- -hexyn-1-yl)-9,10-seco-pregna-5(Z),7(E),10(19)-triene; isomer A. 4. A method for producing a compound of formula I: in which formula X is hydrogen or hydroxy; R 1 and R2, which may be the same ' or different, stand for hydrogen or a C.-Cg hydrocarbyl radical; or R 1 and R2, taken together with the carbon atom (starred in formula I) bearing the group X, can form a C~-C 8 carbocyclic ring; Rι « J stands for hydrogen or a C,-C, 0 hydrocarbyl radical or for YR , in which Y stands for the radicals -CO-, -C0-0-, -CO-S, 4 -CS-, -CS-0-, -CS-S-, -SO- or -S0 2 ~, and R stands for hydrogen or a C.-C, n hydrocarbyl radical; Q is a single bond or a C 1 -Cg hydrocarbylene diradical; R 1, R2, R3 and/or Q may be optionally substituted with one or more deuterium or fluorine atoms, in which a) 1(S),3(R)-bis-(iert-butyldimethylsilyloxy)-20(R)- -formyl-9,10-seco-pregna-5(E),7(E),10(19)-triene is reacted with the anion R~, derived from the side chain building block, RH, of formula V V: RH, R being -C≡C-Q - X in which X 1 is H, OH or OR5, R5 being an alcohol pro¬ tective group, e.g. tri(loweralkyl)silyl or THP, and RR 1 1,, RR22 aanndd QQ hhaavvee tthhee aabboovvee mmeeaanniinnggss,, wwiitthh aa ssuuiittaabb]le base, to form ai mnixture of two C-22-epimers IIA and 3 IIIIBB,, iinn which R stands for H, and R have the above meaning IIA/IIB which epimers are separated; b) a compound of formula IIA or IIB of step a), where 3 R = H, is optionally alkylated to the corresponding compound IIA or IIB, in which R ,3" is C,-C. Q hydro- carbyl or optionally acylated to the corresponding compound IIA or IIB, where R 3 = YR4, Y and R having the above meanings; c) a compound of formula IIA or IIB of step a) or step b) is isomerized to the corresponding compound IIIA or IIIB by means of UV-light in the presence of a triplet sensitizer, e.g. anthracene, IIIA/IIIB 3 in which R and R have the above meanings; d) a compound of formula IIIA or IIIB is deprotected to the corresponding compound of the general formula I, e.g. by hydrofluoric acid or by tetra-(n-butyl)- ammonium fluoride followed by pyridinium p-toluene- sulfonate. 5. A method according to claim 4 in which steps b) and c) are performed in the reverse order. 6. A pharmaceutical composition containing an effective amount of one or more of the compounds of claim 1, together with pharmaceutically acceptable, non-toxic carriers and/or auxiliary agents. 7. A pharmaceutical composition according to claim 6 in dosage unit form. 8. A dosage unit according to claim 7 containing from 0.1 ppm to 0.1% by weight of the dosage unit of a compound of formula I. 9. A method for the treatment and prophylaxis of a number of disease states including hyperparathyroidism and auto- immune diseases (including diabetes mellitus), hyperten¬ sion, acne, alopecia, skin ageing (including photo-ageing), imbalance in the immune system, inflammatory diseases such as rheumatoid arthritis and asthma as well as diseases characterized by abnormal cell differentiation and/or cell proliferation, and for promoting osteogenesis and treating osteoporosis, using a composition according to any one of claims 6-8. 10. A method according to claim 9 for the treatment or prophylaxis of cancer. 11. A method according to claim 9 for the treatment or prophylaxis of psoriasis. 12. The use of a compound of claim 1 in the manufacture of a medicament for the treatment and prophylaxis of a num¬ ber of disease states including hyperparathyroidism and autoimmune diseases (including diabetes mellitus), hyper¬ tension, acne, alopecia, skin ageing (including photo- -ageing), imbalance in the immune system, inflammatory dis¬ eases such as rheumatoid arthritis and asthma as well as diseases characterized by abnormal cell differentiation and/or cell proliferation, and for promoting osteogenesis and treating osteoporosis. 13. The use according to claim 12 for the treatment and prophylaxis of cancer. 14. The use according to claim 12 for the treatment and prophylaxis of psoriasis.

Inventors: BRETTING CLAUS AAGE SVENSGAARD, GRUE-SOERENSEN GUNNAR, BRETTING, CLAUS, AAGE, SVENSGAARD, GRUE-SOERENSEN, GUNNAR
Applicants: LEO PHARM PROD LTD, LEO PHARMACEUTICAL PRODUCTS LTD. A/S (LOEVENS KEMIS
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, A61P3, A61P9, A61P11, A61P29, A61P35, A61P37, A61P43, C07C401