NOVEL VITAMIN D ANALOGUES

Abstract: The present invention relates to compounds of formula (I), in which formula R represents hydrogen, or R represents (C1-C6)alkyl, phenyl, or (C7-C9)aralkyl, optionally substituted with one or more groups selected from (C1-C3)alkyl, F, and phenyl; n is an integer having the value 0, 1, or 2; and X represents hydroxy or halogen.

Description: NOVEL VITAMIN D ANALOGUES FIELD OF THE INVENTION This invention relates to a hitherto unknown class of compounds that show strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including skin cells and cancer cells, as well as immunomodulating and antiinflammatory effects, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and/or prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation. BACKGROUND OF THE INVENTION A number of vitamin D analogues have been described that show some degree of selectivity in favour of the cell differentiation inducing/cell proliferation inhibiting activity in vitro as compared to the effects on calcium metabolism in vivo (as measured in increased serum calcium concentration and/or increased urinary calcium excretion), which adversely limit the dosage that can safely be administered to patients. One of the first of these to appear, calcipotriol (INN) or calcipotriene (USAN), has been developed on the basis of this selectivity and is now recognized worldwide as an effective and safe drug for the topical treatment of psoriasis. A study with another vitamin D analogue, seocalcitol, selected on this basis supports the concept that systemically administered vitamin D analogues may inhibit breast cancer cell proliferation in vivo at sub-toxic doses (Colston, K.W. et al., Biochem. Pharmacol. 44, 2273-2280 (1992)). Another vitamin D analogue, CB1093 (20-epi-22-ethoxy-23-yne-24a, 26a, 27a, tr/shomo-lα,25(OH)2D3 vitamin D3) (Calverley M. J. et al. In: Vitamin D, Proceedings of the Ninth Workshop on Vitamin D, Orlando, Florida, Walter de Gruyter, Berlin, 1994, pp 85-86; and disclosed in WO 93/19044) has been shown to possess potent activity in an in vitro assay on inhibiting the invasiveness of human carcinoma cells (Hansen C. M. et al. In: Vitamin D, Proceedings of the Ninth Workshop on Vitamin D, Orlando, Florida, Walter de Gruyter, Berlin, 1994, pp 508-509). CB1093 has also been demonstrated to have potent inhibitory activity on the prolifera- tion of, and stimulatory activity on the differentiation and apoptosis of, different types of cancer cells, such as, brain glial tumour cells in vitro ( Baudet , C. et al. , Cancer Lett.. 1996, 100, 3); MCF-7 breast cancer cells in vitro and in vivo (Colston, K. W., et al., In: Vitamin D, Proceedings of the Tenth Workshop on Vitamin D, Strasbourg, France, 1997, University of California, Riverside, 1997, pp 443-450; Danielsson, C. et al., In: Vitamin D, Proceedings of the Tenth Workshop on Vitamin D, Strasbourg, France, 1997, University of California, Riverside, 1997, pp 485-486.; Danielsson, C. et al., J. Cellular Biochem., 1997, 66, 552); NB4 acute promyelocytic leukemia cells in vitro (Elstner, E., et al., J. Clin. Invest, 1997, 99, 349); HL-60 and de novo human acute myeloid leukemia cells in vitro (Pakkala, I. et al., Blood 1995, 86(10, Suppl.), 775a; Pakkala, I. et al., Leukemia Research 1997, 21, 321); and MG-63 human osteosarcoma cells in vitro (Ryhanen, S., et al., J. Cellular Biochem. 1998, 70, 414). CB 1093 also significantly decreased plasma PTH and phosphate levels in chronically uraemic rats with secondary hyperparathyroidism (Hruby,M. et al., Nephrol. Dial. Transplant. 1996, 11, 1781). The classical calcemic vitamin D activity of CB1093, as determined by the urinary excretion of calcium in rats, has been determined to 27% of that of lα,25(OH)2D3 and the calcemic activity of seocalcitol in the same assay has been determined to 50% (Danielsson, C. et al., J. Cellular Biochem., 1997, 66, 552). In an in vivo experiment treating rats with mammary tumours with CB1093 (1 μg/kg body weight for 28 days) there was a 49% reduction of the initial tumour volume, but there was still a slight increase in the serum calcium concentration (ibid.). This indicates that the therapeutic window may still be rather narrow, and concern about possible induced increases in serum calcium levels cannot yet be excluded. Another problem using vitamin D analogues in the non-topical treatment of hyperproli- ferative diseases, such as cancer, is metabolic stability in vivo. This stability has to be above a certain minimum level, for a compound to be used in practical therapy. As shown in table 1, the stability of CB1093 in an in tro-model of metabolic stability, using rat liver homogenate "S-9" (Kissmeyer, A.-M. et al., Biochem. Pharmacol., 1997, 53, 1087) is quite low compared to seocalcitol (TV 2 1.3 hr) and lα,25(OH) 2 D3 (TV2 2.5 hr). There is therefore a continuing need for new vitamin D analogues with high anti-cell proliferative and/or cell differentiation inducing activity showing an acceptable combination of prolonged therapeutic activity and minimum toxic effects compared to lα,25(OH)2D3. The purpose of the present invention is to provide such new compounds, which purpose is achieved with the novel compounds having the general formula I herein. SUMMARY OF THE INVENTION The compounds of the invention constitute a novel class of vitamin D analogues represented by the general formula I: in which formula R represents hydrogen, or (C^-C jalkyl, phenyl, or (C7-Cg)aralkyl optionally substituted with one or more of (Cι-C3)alkyl, F, or phenyl; n is an integer having the value 0, 1, or 2; and X represents hydroxy or halogen. DETAILED DESCRIPTION OF THE INVENTION Preferred embodiments of the invention. Preferred compounds of formula I are compounds wherein R represents methyl, ethyl, propyl, isopropyl, benzyl, and ortho methylbenzyl, meta methylbenzyl, and para methylbenzyl. More preferably R represents methyl or ethyl, n is preferably 0 or 1; 1 being more preferred. Preferably X represents OH, F, or Cl. Most preferably X represents F or X most preferably represents OH or Cl. The compounds of the invention can comprise more than one diastereoisomeric form; that is both R and S configurations at the carbon atoms marked 22, 25 and 26 in formula I. The invention covers all these diastereoisomers in pure form and also mixtures there- of. Preferred isomers are compounds having the configurations 22(S),25(S),26(S) and 22(S),25(S),26(R). In addition, prodrugs of compounds of formula I in which one or more of the hydroxy groups are masked as groups that can be reconverted to hydroxy groups in vivo could also be envisaged. The compounds I may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or recrystallisation from an organic solvent or mixture of said solvent and a co-solvent which may be organic or inorganic, such as water. The crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all crystalline modifications and forms and also mixtures thereof. Exemplary compounds of the invention are l(S),3(R)-Dihydroxy-20(R)-(5-ethyl-l(S),5(S),6(S)-trihydroxy-2-heptyn-l-yl)-9,10- secopregna-5(Z),7(E),10(19)-triene (Compound 101), l(S),3(R)-Dihydroxy-20(R)-(5(S),6(S)-dihydroxy-5-ethyl-l(S)-methoxy-2-heptyn-l- yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 102), l(S),3(R)-Dihydroxy-20(R)-(5(S),6(S)-dihydroxy-l(S)-ethoxy-5-ethyl-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 103), l(S),3(R)-Dihydroxy-20(R)-(5(S),6(S)-dihydroxy-5-ethyl-l(S)-(l-propyloxy)-2-heptyn- l-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 104), l(S),3(R)-Dihydroxy-20(R)-(l(S)-benzylyloxy-5(S),6(S)-dihydroxy-5-ethyl-2-heptyn-l- yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 105), l(S),3(R)-Dihydroxy-20(R)-(5(R),6(S)-dihydroxy-l(S)-ethoxy-5-ethyl-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 106), l(S),3(R)-Dihydroxy-20(R)-(5(R),6(R)-dihydroxy-l(S)-ethoxy-5-ethyl-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 107), l(S),3(R)-Dihydroxy-20(R)-(5(S),6(R)-dihydroxy-l(S)-ethoxy-5-ethyl-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 108), (S),3(R)-Dihydroxy-20(R)-(4-ethyl-l(S),4(S),5(S)-trihydroxy-2-hexyn-l-yl)-9,10- secopregna-5(Z),7(E),10(19)-triene (Compound 109), (S),3(R)-Dihydroxy-20(R)-(4(S),5(S)-dihydroxy-l(S)-ethoxy-4-ethyl-2-hexyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 111), l(S),3(R)-Dihydroxy-20(R)-(4-ethyl-l(S),4(R),5(S)-trihydroxy-2-hexyn-l-yl)-9,10- secopregna-5(Z),7(E),10(19)-triene (Compound 114), l(S),3(R)-Dihydroxy-20(R)-(4(R),5(S)-dihydroxy-l(S)-ethoxy-4-ethyl-2-hexyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-triene (Compound 116), l(S),3(R)-Dihydroxy-20(R)-(l(S)-ethoxy-5-ethyl-6(S)-fluoro-5(S)-hydroxy-2-heptyn-l- yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (compound 149), and l(S),3(R)-Dihydroxy-20(R)-(l(S)-ethoxy-5-ethyl-6(R)-fluoro-5(S)-hydroxy-2-heptyn-l- yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (compound 150). l(S),3(R)-Dihydroxy-20(R)-(l(S),5(R/S)-dihydroxy-5-ethyl-6(S)-fluoro-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-triene (compound 157) l(S),3(R)-Dihydroxy-20(R)-(l(S)-ethoxy 5-ethyl-6(S)-fluoro-2-heptyn-5(R/S)-hydroxy l-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene (compound 158) l(S),3(R)-Dihydroxy-20(R)-(l(S),5(R/S)-dihydroxy-5-ethyl-6(R)-fluoro-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-triene (compound 159) l(S),3(R)-Dιhydroxy-20(R)-( l(S)-ethoxy 5-ethyl-6(R)-fluoro-2-heptyn-5(R/S)-hydroxy l-yl)-9,10-secopregna-5(Z),7(E),10(19)-tπene (compound 160) As used in the specification the following terms have the meaning indicated : "Alkyl" refers to any univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom, and includes the subclasses of normal alkyl (n-alkyl), and primary, secondary and tertiary alkyl groups respectively, and having the number of carbon atoms specified, including for example (C 1 -C 3 )alkyl, (C 1 -C 6 )alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl. Alkane refers to an acyclic straight or branched hydrocarbon having the general formula c n H 2n+2 anc * therefore consisting entirely of hydrogen atoms and saturated carbon atoms. "(C -Cg)aralkyl" refers to any alkyl group substituted with an aromatic group, such as phenyl, and having the total number of carbon atoms specified, preferred are (Cy-Cg)- aralkyl groups. Examples are benzyl, 2-phenyl-ethyl, ortho methylbenzyl, meta methylbenzyl, and para methylbenzyl. "Halogen" means the same or different of fluoro, chloro, bromo, and lodo. The present invention provides a hitherto undisclosed series of vitamin D analogues which is characterised by the presence of an additional hydroxy group or halogen atom in the 26 position of the side chain. Compared to the prior art vitamin D analogues, illustrated by CB1093, the present new vitamin D analogues have precisely the properties which are demanded (Table 1) : Half or less the calcemic activity (in the rat calciuπc model) and much higher metabolic stability (in the S-9 rat liver homogenate model), together with an only slightly reduced antiprohferative activity (in two different cancer assays: The U937 leukemia cell assay (Kissmeyer, A.-M. et al., Biochem. Pharmacol., 1997, 53, 1087) and the MCF-7 mammary cancer cell assay (Danielsson, C. et al., J. Cellular Biochem., 1997, 66, 552)). Moreover the activity of the present Compounds I in the HaCaT assay, a psoriasis model (Kissmeyer, A.-M. et al., Biochem. Pharmacol., 1997, 53, 1087), is slightly higher than that of CB1093. The advantageous properties of the 26-hydroxy or 26-halogen vitamin D analogues of the present invention are entirely unexpected, as it is known that a similar introduction of a 26-hydroxy group in seocalcitol results in compounds with drastically reduced activities in both the U937 and the HaCaT assays. All the four possible 26-hydroxy-seocalcιtoi analogues have been shown to be natural metabolites of seocalcitol in vitro and in vivo in rats and in vitro in humans (Binderup, E., et al., In : Vitamin D, Proceedings of the Tenth Workshop on Vitamin D, Strasbourg, France, 1997, University of California, Riverside, 1997, pp 89-90; Kissmeyer, A.-M. et al., Biochem. Pharmacol., 1997, 53, 1087). Table 1 Compound lα,25(OH) 2 D 3 No. 103 5 No. 108 5 CB1093 S,$ 25/26-Configur. 25(S), 26(S) 25(5), 26(R) (No 26-OH) Assav U937, -log IC 5u 7.5 ± 0.3 9.0 ± 0.2 8.9 ± 0.2 9.5 ± 0.1 U937, rel.* 1.0 36 49 74 MCF-7, -log IC 50 7.7 ± 0.3 9.9 ± 0.1 9.8 ± 0.2 10.2 ± 0.3 MCF-7, rel.* 1.0 153 89 311 HaCaT, -log IC50 7.4 ± 0.3 9.0 ± 0.3 8.8 ± 0.2 8.7 ± 0.9 HaCaT, rel.* 1.0 38 30 18 S-9,metab./π vitr. # 0.43 0.29 0.02 Calcem.;/n vivo* 1.0 0.11 0.16 0.27 Notes to Table 1 : § R = Ethyl, n = 1 and 22(S)-configuration $ Reference compound : No 26-OH-group; otherwise the same structure as Compound 103/108 * Geometric mean of the ratios, relative to lα,25(OH)2 3, from all experiments with the compound in question, in the assay concerned; the higher the value, the more potent the compound # Fraction left after 1 hour incubation The following standard abbreviations are used throughout this disclosure: AcOH = acetic acid 18C6 = 18-Crown-6 b.p. = boiling point Bn = benzyl Bu = n-butyl Comp = Compound No. DMAP = 4-dimethylaminopyridine DMF = N,N-dimethylformamide Et = ethyl EtOAc = ethyl acetate Exam = Example No. eqv = equivalent (molar) Ether = diethyl ether G.P. = General Procedure No. Hal = Cl, Br or l h = hour Me = methyl m.p. = melting point Ms = methanesulfonate PG = Protective Group Ph = phenyl Pr = n-propyl Prep = Preparation No. PPTS = pyridinium p-toluenesulfonate Py = pyridine TBAF = tetra-n-butylammonium fluoride TBS = tert-butyldimethylsilyl Tf = trifluromethanesulfonyl THF = tetrahydrofuran THP = tetrahydro-4H-pyran-2-yl TMS = trimethylsilyl Tol = toluene Ts = 4-toluenesulfonyl Compounds of formula I, as illustrated in Table 4, may be prepared by the general method of Scheme 1 : 1 Notes to Scheme 1 : General : X 1 = O-PG 2 , F, Cl, Br, or I PG and PG = Hydrogen or Protective Groups: the same or different, or a combined bifunctional group. Q = H or Me 3 Sι; n = 1,2 or 3. (a) CH3NH-OCH3, HCI; EtMgBr (3 eqv) (b) 1) Q-C≡C-(CH 2 ) n -Met; (Met = -Li, -MgHal ; -AlBr 2 , -Br + Sml 2 ) . if it is desired (only for Q = H) that: PG 1 = TMS and X 1 = O-PG 2 = O-TBS and Q = H : 11) Me 3 SιCI/Et 3 N/CH 2 CI 2 /DMAP, or, if it is desired that: PG 1 -PG 2 = -C(CH 3 ) 2 -, i.e. X = O-PG 2 (-PG 1 -), and Q = H : 11) TBAF/THF, (→PG 1 = PG 2 = Q = H) III ) CH 2 =C(CH 3 )-0-CH 3 or (CH 3 ) 2 C(OCH 3 ) 2 /TsOH or, if it is desired that: PG 1 = TMS and X 1 = F: Compounds 509 or 510 (e.g. prepared as in Scheme la) replace compounds 503 and 504 of Scheme 1; or, if it is desired that: PG 1 = TMS and X 1 = F, Cl, Br, or I and Q = H : 11) TBAF/THF, (→PG 1 = PG 2 = Q = H, i.e. X 1 = OH) iϋ) Conversion of X (= OH) to X = F, Cl, Br, or I, for example as shown in Scheme 2; iv) optional conversion of PG 1 - H to PG 1 = TMS, e.g. with Me 3 SιCI/Et 3 N/CH 2 CI 2 /DMAP (c) 1) II + BuLi; 11) 1; in) optional alkylation of 22-OH with RZ/base (Z = Good leaving group, e.g. Hal, Ms, Ts, or Tf) (d) 1) Triplet sensitized photo-isomeπzation of the vitamin D tnene, 5(6)(E) to 5(6)(Z); 11) optional alkylation of 22-OH with RZ/base (e) 1) Deprotection with HF/CH 3 CN/EtOAc or TBAF/THF, optionally followed by or preceded by PPTS/EtOH. Scheme 1a Notes to Scheme la: (a) KF, HCONH 2 , 70°C (method of Fπtz-Langhals, E. et al, Tetr.Lett. 1993, 34, 293) (b) CH3NH-OCH3, HCI, EtMgBr (3 eqv) Compounds I can be prepared from the vitamin D-deπved aldehyde compound 1, a synthesis of which has been reported (Calverley, M. J., Tetrahedron, 1987, 43, 4609.), for example by the routes outlined in Scheme 1, by reaction with an organometallic derivative of the side chain building blocks of general formula II. The Compounds II to be used for making the Compounds I where X - OH can be synthesized as follows: L(-)Ethyl lactate or D( + )ethyl lactate (or the corresponding methyl ester) is protected by silylation with tert-butyldimethylsilyl chloride to give the corresponding ethyl TBS-lactate (501, 502). This is converted, in a direct procedure with ethyl magnesium bromide, to the corresponding ethylketone, (503, 504), via the intermediary Λ/-methoxy-Λ/-methylamιdes, by the method of Williams, J. M. et al. (Tetr.Lett., 1995, 36, 5461). The ketone 503 or 504 is converted to the partially protected side chain synthon of general formula II by reaction with an organometallic reagent of the type Q- G≡C-(CH 2 ) n -Met; (Met = -Li, -MgHal; -AIBr 2 .-Hal + e.g. Sml 2 ; Q = H or Me 3 Sι; n = 1, 2 or 3). In the case of Q-C≡C-(CH 2 ) n -Hal + e.g. Sml 2 , a Barbier type reaction between a halide, a ketone, and a metal/metal salt is referred to. A mixture of two diastereoisomers is usually formed: The R and the S isomer at the carbon atom marked (25) in Scheme 1, that is the carbon atom which ends up being the carbon atom C(25) in the final compound of formula I. If desired, the two diastereoisomers may be separated at this stage, or later during the synthesis of the side chain synthons II, if this is more convenient. The following steps in the synthesis of the fully protected side chain synthons II are: 1) If Q is tπmethylsilyl, Q is converted into hydrogen by deprotection, e.g. by means of a base. 2) The unprotected hydroxy group at the carbon atom marked (25) is protected, e.g. by silylation with TMS-CI ; such that PG 1 = TMS (and PG 2 =TBS). 2 Alternatively the TBS group (PG ) of compound II may be removed, e.g. by TBAF (if Q = TMS, this is converted to H at the same time). The two hydroxy groups at the carbon atoms marked (25) and (26), respectively, can then be protected in one step, by conversion into a cyclic acetal or ketal, e.g. an acetonide (isopropylidene ketal), e.g. by means of e.g. 2-methoxypropene or 2,2-dιmethoxypropane and an acid, such that PG 2 and PG are connected into one group: -C(CH 3 ) 2 -. Other methods of protection of 1,2- diols are described in the literature, e.g. in : Greene, T. W. and Wuts, P. G. M., "Protective Groups in Organic Synthesis", Sec. Ed., John Wiley and Sons, New York 1991, pp 118-142. An advantage of using cyclic acetals or ketals, such as acetonides, as protective groups of compounds II is that they are particularly well suited for establish- mg the stereochemistry at carbons (25) and (26) by way of Nuclear Overhauser Enhancement (NOE) NMR spectroscopy. The Compounds II to be used for making the Compounds I where X = F may be synthesized from ketone 509 or 510, using the method of Scheme la and the intermediates of Table la: Table la Fluoπnated Side Chai n Bu i ld i ng Blocks of Scheme la P Prreepp C Coommpp G G..PP.. C C(26) 42 505 11 R 43 506 11 S 44 507 12 S 45 508 12 R 46 509 la S 47 510 la R The Compounds II to be used for making the Compounds I where X is Cl, Br, or I are preferably made (and for X = F may be made) from the corresponding Compounds II 1 7 1 where O-PG and O-PG (= X ) are both OH, for example as shown in Scheme 2: Scheme 2 Note to Scheme 2 The compounds II where X = Cl or I can be converted to each other or converted to the corresponding compounds where X = F or Br by standard methods, e.g. as described in: R. C. Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, N.Y., USA, 1989, pp. 337 - 339 hereby incorporated by reference. 1 l 0 13 Table 2 Side Chain Bui ld i ng Blocks of Genera l Formu la II (Scheme 1 ) Prep Comp G.P. Q n C(25) C(26) PGl PG2 4 201 2 H 1 S S H TBS 5 202 4 H 1 S S H H 6 203 5 H 1 s S -C(CH 3 ) 2 - 7 204 6 H 1 s Ξ TMS TBS 8 205 2 H 1 R S H TBS 9 206 4 H 1 R S H H 10 207 5 H 1 R S -C(CH 3 ) 2 - 11 208 6 H 1 R S TMS TBS 12 209 2 H 1 R R H TBS 13 210 6 H 1 R R TMS TBS 14 211 2 H 1 S R H TBS 15 212 6 H 1 S R TMS TBS 16 213 3 H 0 S S H TBS 17 214 3a TMS 0 S S H TBS 18 215 4 H 0 S S H H 19 216 5a H 0 S S -C(CH 3 ) 2 - 16 217 3 H 0 R S H TBS 17 218 3a TMS 0 R S H TBS 18 219 4 H 0 R S H H 20 220 5a H 0 R S -C(CH 3 ) 2 - Note to Table 2: X 1 ^ O-PG 2 Table 2a Fluoπnated Side Chain Building Blocks of General Formula II (Scheme 1) Prep Comp G.P. Q n C(25) C(26) PG 1 X 1 48 221 2a H 1 R/S S H F 49 222 6 H 1 R/S S TMS F 50 223 2a H 1 R/S R H F 51 224 6 H 1 R/S R TMS F The reaction of the aldehyde 1 with the organometallic reagents derived from the side chain building blocks II, can be performed by standard methods of nucleo- philic addition of organometallic reagents to carbonyl compounds; i.e. by reacting the alkyne intermediate II with a Gπgnard reagent, such as ethyl magnesium bromide, or an alkyl lithium, such as butyl lithium (General Procedure 7) in a suitable anhydrous solvent, such as ether and/or THF, to generate the metal acetylide, then adding 1, to give III after usual aqueous work-up (which is normally implied in all the reactions of Scheme 1. In general the reaction product III is a mixture of the two possible C-22 epimers, here designated IIIA and IIIB. It is usually preferable to separate the IIIA and IIIB epimers which can conveniently be done by chromatography. Nonlimiting illustrations of such compounds of formula III are given in Tables 3 and 3a. Compounds IIIA are formed in much higher yields than the correspond- ing IIIB epimers, typically in the ratio of about 95 to 5. Compounds IIIA, IVA and IA have 22(S) stereochemistry, and the corresponding compounds with the suffix B have 22(R) stereochemistry. Compounds IA are the preferred ones. The optional alkylation of the 22-hydroxy compounds of general formula III or IV to yield the corresponding compound III or IV where R is (C-^-CgJalkyl, phenyl, or (Cy-Cg)aralkyl can be performed by standard methods well known to the specialist. Illustrative, but non limiting, compounds of this sort are listed in Table 3. In the alkylation reaction use is preferably made of an alkylating agent RZ, in which Z stands for a good leaving group, such as for example Hal, Ms, Ts, Tf; the RZ being allowed to react with the anion of the appropriate compound III or IV WO 01 /l 0829 PCT/DKOO/00389 15 ( R = H ) , derived therefrom by means of a su itable strong base, such as a n al kal i- metal al koxide, al kyl a l kal i- metal or a lka l i- metal hyd ride . A su ita ble crown ether may be added as a phase transfer agent to accelerate the alkylation process. A usefu l method is descri bed i n Genera l Procedure 9. The photo-isomeπzation of the vitamin D tπene, 5(6)(E), Compounds III of Scheme 1, to 5(6)(Z), Compounds IV of Scheme 1, is performed by means of UV-hght in the presence of a triplet sensitizer, e.g. anthracene; useful methods are described in General Procedure 8 and and 8a. Nonlimiting illustrations of such compounds of general formula IV a re g iven in Ta bles 3 a nd 3a, a long with references to the prepa ration of each compound . The triplet sensitized photo-isomeπzation of the vitamin D tπene, 5(6)(E), Compounds III, to 5(6)(Z), Compounds IV, and the (optional) alkylation of the 22-OH-group with RHal/base, to form a 22-O-R compound where R ≠ H, may be performed in arbitrary order, according to what is most convenient in each case. The final step in the synthesis of Compounds I of the present invention, examples of which are listed in Table 4, is one or more deprotection procedures to remove all protec- tive groups of the compounds of general formula IV of Scheme 1. The deprotection may for example be performed either with TBAF to remove silyl groups, like TMS or TBS groups (General Procedure 4), or with HF which removes both silyl groups and acid- sensitive protective groups, such as isopropylidene (ketal) groups (General Procedure 10). Alternatively, if both types of protective groups are to be removed, two different selective procedures may be used in sequence, e.g. as described in W097/46522 (G.P. 7) : The silyl groups are removed with TBAF, followed by the use of PPTS which selectively removes acid-sensitive protective groups; (or in the reverse order). Table 3 Intermediates of General Formulas III and IV f Scheme 1 ) Type Prep Comp G. P. R n C(25) C(26) PG 1 PG 2 IIIA 21 301 7 H 1 Ξ S TMS TBS IIIB 21 302 7 H 1 S S TMS TBS IVA 22 401 8 H 1 S S TMS TBS IVA 23 402 9 Me 1 S S TMS TBS IVA 24 403 9 Et 1 s S TMS TBS IVA 25 404 9 Pr 1 s S TMS TBS IVA 26 405 9 Bn 1 s S TMS TBS IIIA 27 303 7 H 1 R S TMS TBS IVA 28 406 8 H 1 R S TMS TBS IVA 29 407 9 Et 1 R S TMS TBS IIIA 30 304 7 H 1 R R TMS TBS IVA 31 408 8 H 1 R R TMS TBS IVA 32 409 9 Et 1 R R TMS TBS IIIA 33 305 7 H 1 S R TMS TBS IVA 34 410 8 H 1 S R TMS TBS IVA 35 411 9 Et 1 S R TMS TBS IIIA 36 306 7a H 0 S S ■ c( CH 3>2 " IVA 37 412 8 H 0 S S • c( CH 3)2- IVA 38 413 9 Et 0 S S ■ c( CH 3)2 " IIIA 39 307 7a H 0 R S • c( CH 3)2- IVA 40 414 8 H 0 R S C(CH 3>2 " IVA 41 415 9 Et 0 R S C( CH 3)2- Note to Table 2 : X 1 = O- ■ PG 2 WO 1 /l 0829 PCT/DKOO/00389 17 Table 3a Fluoπnated Intermediates of General Formulas III and IV (Scheme 1) Type Prep Comp G.P. R n C(25) C C(26) PG 1 X IIIA 52 308 7 H 1 R/S S TMS F IVA 53 416 8a H 1 R/S S TMS F IVA 54 417 9 Et 1 R/S S H F IIIA 55 309 7 H 1 R/S R TMS F IVA 56 418 8a H 1 R/S R TMS F IVA 57 419 9 Et 1 R/S R H F Exemplified Compounds I of the invention are listed in Table 4, the numbered examples giving reference to illustrative methods of synthesis, together with spectroscopic data for the exemplified compounds. The Compounds, 110, 112-113, 115 and 117-156 are made in a sequence of synthetic steps which is analogous to the sequence used for the preparations of Compounds, 101-109, 111, 114, 116 and 157-160, Examples 1-12 and 16-19: Compound 1 and the appropriate side chain building blocks of General Formula II, H-C^C-(CH 2 ) n -C(C 2 H 5 )(OPG 1 )-CH(X 1 )CH 3 , are reacted, according to General Procedure 7 (G.P. 7), to give the corresponding compound of formula III. If not mentioned in Tables 2 or 2a, the compounds II in question can be prepared by similar methods to those applied for the synthesis of the compounds II listed in Tables 2 or 2a. The compound of formula III is photoisomeπzed, according to G.P. 8 or 8a, to give the corresponding compound of formula IV. Optionally, the compound of formula IV and the appropriate alkylating agent RZ are reacted, according to G.P. 9, to give the corresponding compound of formula IV where R ≠ H. The photoisomeπzation step and alkylation step may be performed in the reverse order, if desired. I I As the last step, the compou nd of formula IV is deprotected , accord ing to either G. P. 4 or G . P. 10 to g ive the Compound I i n question . Table 4 Compounds of General Formu la I Type Exam Comp G. P. R n X C(25) C(26) IA 1 101 4 H 1 OH S S IA 2 102 4 Me 1 OH S S IA 3 103 4 Et 1 OH S S IA 4 104 4 Pr 1 OH S S IA 5 105 4 Bn 1 OH S S IA 6 106 4 Et 1 OH R S IA 7 107 4 Et 1 OH R R IA 8 108 4 Et 1 OH S R IA 9 109 10 H 0 OH S S IA 110 10 Me 0 OH S S IA 10 111 10 Et 0 OH S S IA 112 10 Pr 0 OH S S IA 113 10 Bn 0 OH S S IA 11 114 10 H 0 OH R S IA 115 10 Me 0 OH R S IA 12 116 10 Et 0 OH R S IA 117 10 Pr 0 OH R S IA 118 10 H 0 OH R R IA 119 10 Et 0 OH R R IA 120 10 H 0 OH S R IA 121 10 Me 0 OH S R IA 122 10 Et 0 OH S R IA 123 10 Pr 0 OH S R IA 124 10 H 1 OH R S IA 125 10 Me 1 OH R S IA 124 10 H 1 OH R R IA 125 10 Me 1 OH R R IA 126 10 H 1 OH S R IA 127 10 Me 1 OH S R IA 128 10 Pr 1 OH S R IA 129 10 Bn 1 OH S R 1. ) Type Exam Comp G.P. R n X C(25) C(26) IA 131 10 H 2 OH S S IA 132 10 Me 2 OH S S IA 133 10 Et 2 OH S S IA 134 10 Pr 2 OH S S IA 135 10 Bn 2 OH S s IA 136 10 Et 2 OH R s IA 137 10 Et 2 OH R R IA 138 10 H 2 OH S R IA 139 10 Me 2 OH S R IA 140 10 Et 2 OH S R IA 141 10 Pr 2 OH S R IB 142 10 Et 1 OH S S IA 143 10 Me 0 F S S IA 144 10 Me 0 F S R IA 145 10 Et 0 F S S IA 146 10 Et 0 F S R IA 147 10 Me 1 F S S IA 148 10 Me 1 F S R IA 149 10 Et 1 F S S IA 150 10 Et 1 F S R IA 151 10 Et 2 F S S IA 152 10 Me 0 Cl S S IA 153 10 Et 0 Cl s S IA 154 10 Me 1 Cl s S IA 155 10 Et 1 Cl s S IA 156 10 Et 1 Cl s R IA 16 157 10 H 1 F R/S S IA 17 158 10 Et 1 F R/S S IA 18 159 10 H 1 F R/S R IA 19 160 10 Et 1 F R/S R The present compounds are intended for use in pharmaceutical compositions which are useful in the local or systemic treatment or prophylaxis of human and veterinary disorders, such as e.g. psoriasis (including pustulosis palmoplantaris, acrodermatitis continua and nail psoriasis) and other disturbances of keratinization, HIV-associated dermatoses, wound healing, various cancer forms, such as leukemia, mammary cancer, brain glial tumours, osteosarcoma, myelofibrosis, melanoma, other skin cancers, and of diseases of, or imbalances in, the immune system, such as host versus graft and graft versus host reaction and transplant rejection, and autoimmune diseases, such as discoid and systemic lupus erythematosus, diabetes mel tus and chronic dermatoses of autoimmune type, e.g. scleroderma and pemphigus vulgaπs, and inflammatory diseases, such as asthma and rheumatoid arthritis, as well as a number of other disease states including hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure, cognitive impairment or senile dementia (Alzheimers disease) and other neurodegenerative diseases, hypertension, acne, alopecia, skin atrophy, e.g. steroid induced skin atrophy, skin ageing, including photo-ageing, and to their use for promoting osteogenesis and treating/preventing osteoporosis and osteomalaαa. The present compounds may be used in combination with other pharmaceuticals or treatment modalities. In the treatment of psoriasis the present compounds may be used in combination with other antipsonatic drugs, e.g steroids, or with other treatments e.g. light- or UV-light-treatment or the combined PUVA-treatment. In the treatment of cancer the present compounds may be used in combination with other anti-cancer drugs or anti-cancer treatments, such as radiation treatment. In the prevention of graft rejection and graft versus host reaction, or in the treatment of auto-immune diseases, the present compounds may advantageously be used in combination with other immunosuppres- sive/immunoregulating drugs or treatments, e.g. with cyclospoπn A. The amount required of a compound of formula I (hereinafter referred to as the active ingredient) for therapeutic 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 administered 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 dermatological disorders like psoriasis or eye diseases topical or enteral forms are 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. The formulations, both for veterinary and for human medical use, of the present invention thus comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ιngredιent(s). The carrιer(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 suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articuiar and topical, nasal or buccal administration. 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, remaining 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 may conveniently be presented in dosage unit form and may be pre- pared 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-m-water emulsion or a water-m-oil emulsion. The active ingredient may also be administered in the form of a bolus, electuary or paste. Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier, 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. Transdermal formulations may be in the form of a plaster. Formulations suitable for intra-articular or ophthalmic administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystallme form, for example, in the form of an aqueous microcrystallme suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra-articular and ophthalmic administration. Formulations suitable for topical or ophthalmic administration include liquid or sem- i-liquid preparations such as liniments, lotions, gels, applicants, oil-m-water or water-m-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. Formulations suitable for administration to the nose or buccal cavity include powder, self-propelling and spray formulations, such as aerosols and atomizers. In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients, such as diluents, binders, preservatives etc. The compositions may further contain other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions, such as other immunosuppressants in the treatment of immunological diseases, or steroids in the treatment of dermatological diseases. The present invention further concerns a method for treating patients suffering from one of the above pathological 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 conditions. The treatment with the present compounds and/or with further therapeutically active compounds may be simultaneous or with intervals. In the systemic treatment daily doses of from 0.001-2 μg per kilogram body weight, preferably from 0.002-0.3 μg/kg of mammal body weight, for example 0.003-0.2 μg/kg of a compound of formula I are administered, typically corresponding to a daily dose for an adult human of from 0.2 to 15 μg. In the topical treatment of dermatological disorders, ointments, creams or lotions containing from 0.1-500 μg/g, and preferably from 0.1-100 μg/g, of a compound of formula I are administered. For topical use in ophthalmology ointments, drops or gels containing from 0.1-500 μg/g, and preferably from 0.1-100 μg/g, of a compound of formula I are administered. The oral compositions 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 is further illustrated by the following General Procedures, Preparations and Examples: EXAMPLES General Procedures. Preparations and Examples General : THF was dried over 4A molecular sieves. Reactions were routinely run under an argon atmosphere unless otherwise noted. In the standard work-up procedure, the reaction mixture was poured into water and extracted three times with a suitable organic solvent. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the product, which was purified by chromatography on silica gel (40 - 63 μrm), by crystallisation, or by distillation. For H nuclear magnetic resonance spectra (300 MHz) and 13 C NMR (75.6 MHz) chemical shift values (δ) (in ppm) are quoted, for deuteriochloroform solutions, except where noted, relative to internal tetramethylsilane (δ = 0.00) or chloroform (δ = 7.25) or deuteriochloroform (δ = 76.81 for 13 C NMR). The value for a multiplet, either defined (doublet (d), triplet (t), quartet (q)) or not (m) at the approximate midpoint is given unless a range is quoted (s = singlet, b = broad). General Procedures General Procedure 1 Synthesis of ketones 503 and 504 To a solution/suspension of the appropriate silylated ethyl lactate, compound 501 or 502, (23.2 g, 0.1 mol) and /v^O-dimethyl hydroxyl amine hydrochloride (12.2 g, 0.125 mol) in dry THF (800 ml) was added a 3.0 molar solution of ethyl magnesium bromide in ether (167 ml, 0.5 mol), during one hour, while stirring and cooling to -5°C. Stirring was continued for 18 hours at 25°C, after which the reaction mixture was hydrolyzed by pouring it into a solution of ammonium chloride (160 g) in water (1.2 I). After work up with ether, the crude product was purified by chromatography (eluant: 0% to 1% ether in petroleum ether) to give the desired compound. Variation : General Procedure la Synthesis of ketones 509 and 510 To a solution/suspension of the appropriate R or S, methyl or ethyl, 2-fluoropropionate (0.1 mol) and Λ^O-di methyl hydroxy la mine hydrochloride (10.7 g, 0.11 mol) in dry THF (300 ml) was added a 3.0 molar solution of ethylmagnesium bromide in ether (107 ml, 0.32 mol), during one hour, while stirring and cooling to 0 to -5°C. Stirring was continued for 4 hours at 0°C and 16 hours at 25°C, after which the reaction mixture was 24 hydrolyzed by addition of 25% aqueous ammonium chloride (300 ml) with vigourous stirring. The temperature rose to about 35°C and was kept there by means of a hot water bath; the pH was monitored with a pH-meter (pH about 8). After 15 minutes the pH was adjusted to 3 with 4N aqueous hydrochloric acid and stirring was continued for 15 minutes. The resulting two-phase mixture was separated and the aqueous phase was extracted twice with ether (50 ml). The combined organic phases were extracted twice with saturated sodium chloride solution (25 ml) and dried over anhydrous sodium sulfate. The solution of crude material was concentrated by distilling off the ether and some of the THF at atmospheric pressure through an an efficient still (1/16" Dixon gauze rings packed in a 7 cm column) . The residue (about 200 g) was fractionated through a 15 cm Vigreux- column connected to a dry-ice cooled condenser and receiver. By gradually lowering the pressure to 0.25 bar fractions consisting of THF and an increasing part of the title compound were collected (leaving a residue of higher boiling intermediate- and side-products). If desired, the first fractions may be concentrated by redestil- lation. The pure title compounds have a b. p. of about 45°C/27 mbar; fractions mixed with THF were, however, usable in the next synthetic step, when dried and the percen ¬ tage of title compound determined by NMR. General Procedure 2 Synthesis of tertiary proparoylic alcohols. Compounds II A mixture of aluminium scales (0.45 g), mercury(II) chloride (12 mg) and dry THF (10 ml) was stirred for 20 minutes. A solution of propargyl bromide (1.88 ml, 2.97 g, 25 mmol) in dry THF (5 ml) was added, with stirring, during 20 minutes, at 25° - 30°C. Stirring was continued for 30 minutes at 40°C. A solution of the appropriate ketone, Compound 503 or 504, (5.0 g, 23 mmol) in dry THF (10 ml) was added, during 10 minutes, at 25°C; the reaction mixture was stirred for a further IV2 hours at 25°C and then worked up with ether. The crude product was purified by chromatography, with 1 % ether in petroleum ether as eluant, which procedure was repeated twice, with suitable combination of fractions, to give each of the two isomeπc title compounds in a pure state. Variation : General Procedure 2a Synthesis of fluoπnated tertiary proparoylic alcohols. Compounds II A 1.5 M solution of allenylmagnesium bromide in ether ( 13 mi, about 20 mmol) (L.Brandsma, "Preparative Acetylenic Chemistry", 2 nd Ed., Elsevier, Amsterdam 1988, pp. 35-36) was cooled to -40°C, and a dry solution of the ketone 509 or 510 (16 mmol) in THF (20 ml) was added with stirring, during 30 minutes, followed by stirring for 10 minutes, while cooling to-30°C - -40°C. The reaction mixture was poured into 25% aqueous ammonium chloride (50 ml), while stirring and cooling in ice. The aqueous phase was extracted with ether (20 ml) and the combined organic phases were dried with magnesium sulfate and concentrated in vacuo to give the title compound as an oil. This product consisted of the two epimers in a ratio of about 3 : 1 and was used in the next synthetic step without further purification. General Procedure 3 Synthesis of tertiary acetylenic alcohols, Compounds II To a stirred suspension of lithium acetylide, ethylenediamine complex (5.3 g, 58 mmol) in dry THF (250 ml) was added a solution of the appropriate ketone, Compound 503 or 504, (12.5 g, 58 mmol) in dry THF (50 ml), during 20 minutes, at 35°C. Stirring was continued for 4 hours at 25°C, after which the reaction mixture was hydrolyzed by pouring it into a solution of sodium chloride (70 g) in water (200 ml). After work up with ether, the crude product was purified by chromatography (eluant: 0% to 2% ether in petroleum ether) to give the two isomeric title compounds as an only partially separable, but otherwise pure, mixture. This mixture was used as such in the next step, the removal of the silyl protection group, after which the two isomeric 25,26-diols could be separated by means of chromatography. General Procedure 3a Synthesis of tertiary thmethylsilyl acetylenic alcohols. Compounds II To a stirred solution of trimethylsilylacetylene (0.25 ml, 0.177 g, 1.8 mmol) in dry THF(6 ml) was added a 1.6 molar solution of butyl lithium in hexane (0.83ml, 1.3 mmol), during 10 minutes, at -60°C. Stirring was continued for 10 minutes at -60°C and at 25 C C for 30 minutes. The resulting solution of lithium trimethylsilylacetylide was again cooled to -60°C and a solution of the appropriate ketone, Compound 503 or 504, (0.3 g, 1.4 mmol) in dry THF (1 ml), was added during 2 minutes. Stirring was continued for 3 hours at -60°C, after which the reaction mixture was hydrolyzed by pouring it into a solution of ammonium chloride (2 g) in water (20 ml). After work up with ether, the crude product was purified by chromatography (eluant: 0% to 1% ether in petroleum ether) to give the two isomeric title compounds as an inseparable mixture. This was used as such in the next step, the removal of both silyl protection groups, after which the two isomeric 25,26-diols could be separated by means of chromatography. General Procedure 4 Deprotection of silyl-protected compounds with TBAF To a solution of the appropriate mono-silyl protected compound(s) (0.4 mmol), or di-silyl protected compound(s) (0.2 mmol), or tetra-silyl protected compound(s) (0.1 mmol) in THF (10 ml) was added TBAF tπhydrate (0.32 g, 1.0 mmol), (i.e. 2.5 mol of TBAF for each molar equivalent of silyl protection group), and the mixture was heated to reflux for one hour with stirring. After addition of 1M sodium hydrogen carbonate (10 ml), the mixture was worked up with ether or ethyl acetate. The residue was purified by chromatography to yield the desired compound(s). General Procedure 5 Protection of 25,26-diols II as acetonides, using 2-methoxypropene A solution of an unprotected 25,26-dιol, Compound II, (0.35 mmol ), 2-methoxypropene (50 mg, 0.7 mmol) and p-toluenesulfonic acid ( 1 mg) in dry DMF (2 ml), containing 3 A molecular sieves (1/16 " rods, about 0.1 g) was heated to 70°C, with stirring, for 30 minutes. After work up with ether, the crude product was purified by chromatography with 5% ether in petroleum ether as eluant to give the pure acetonide, Compound II. General Procedure 5a Protection of 25.26-dιols II as acetonides. using 2,2-dιmethoxypropane A solution of an unprotected 25,26 -diol, Compound II, (2.0 mmol ), 2,2-dιmethoxy- propane (2ml, 1.7 g, 16 mmol) and p-toluene sulfonic acid (38 mg) in dry acetone (10 ml) was stirred at 25 °C 2 hours. Tπethyiamine (1 ml) was added and the reaction mixture was concentrated to about 2 ml, using a short (about 3 cm) Vigreux column, at about b.p. 30°C /0.4 bar. Water (2 ml) and 1M sodium hydrogen carbonate (1 ml) were added, and the mixture was extracted with ether (3 x 8 ml). The combined ether extracts were dried with magnesium sulfate, and concentrated to about 0.5 ml (as above). The crude product was purified by chromatography with 5% ether in petroleum ether as eluant . After concentration (as above) of the appropriate combined fractions the pure acetonide, Compound II, was obtained. General Procedure 6 Protection of 25-monohydroxy Compounds II by trimethylsilylation Tπmethylchlorosilane (1.08 g, 10 mmol) was added during 10 minutes, at 0°C, to a stirred solution of a 25-hydroxy-26-tert-butyldιmethylsιlyloxy- (or 26-fluoro-) compound II (5.0 mmol), tπethylamine (1.51 g, 15 mmol) and DMAP (5 mg) in dry dichloro- methane (10 ml). Stirring was continued for 48 hours at 25°C. After work up (with ether) the crude product was purified by chromatography with petroleum ether as eluant to give the pure 25-trιmethylsιiyloxy-26-tert-butyldιmethylsιlyloxy- (or 26-fluoro-) compound II. General Procedure 7 Synthesis of Compounds III from Compound 1 and side chain building block II To a solution of the appropriate side chain building block, Compound II, (3.0 mmol) in dry THF (5 ml), cooled to -78°C and stirred under argon, was added dropwise, during 2 minutes, a solution of n-butyl lithium (1.6 M in hexane; 1.5 ml). Stirring was continued at -78°C for 15 minutes and at 20°C for another 15 minutes. The mixture was again cooled to -78°C, and a solution of the aldehyde, compound 1, ( 1.5 mmol) in dry THF (5 ml) was added dropwise during 4 minutes; after that stirring was continued at -78°C for 30 minutes. The reaction mixture was worked up (ether) to yield a crude product containing the isomeric 22-hydroxy compounds A (less polar) and B (more polar). These were separated by chromatography (mixture of ethyl acetate and petroleum ether as eluant) to yield the pure compounds III. Variation: General Procedure 7a The procedure of G.P. 7 was followed, except that 1.87 ml of n-butyl lithium (1.6M) and 3 mmol of compound 1 was used. General Procedure 8 Photoisomerisation of Compound HI to Compound IV A solution of the appropriate compound III (0.28 mmol), anthracene (0.1 g) and triethylamine (0.20 ml, 1.4 mmol) in dichloromethane (16 ml) in a 25 ml round- bottomed Pyrex flask was irradiated at about 10°C with UV-light from a high pressure ultraviolet lamp, type TQ760Z2 (Hanau), at 700 W, for 30 minutes (15 minutes at 0.08 mmol scale) while stirring. The reaction mixture was evaporated in vacuo, and the residue was treated with petroleum ether (2 x 2 ml) and filtered. The filtrate was concentrated and purified by chromatography to afford the desired compound IV. Variation : General Procedure 8a A solution of the appropriate compound III (0.13 mmol), 9-acetylanthracene (23 mg) and triethylamine (0.10 ml, 0.7 mmol) in toluene (5 ml) in a 10 ml round-bottomed Pyrex tube was irradiated at about 10°C with UV-light from a high pressure ultraviolet lamp, type TQ150Z2 (Hanau) (150 W) for 60 minutes. The reaction mixture was cooled to -20°C and filtered. The filtrate was evaporated in vacuo, and the residue was purified by chromatography to afford the desired compound IV, together with some 9-acetylanthracene which was removed after the final (deprotection) step. General Procedure 9 Alkylation of C-22-hvdroxy-compound III or IV To a solution of the appropriate 22-hydroxy compound (R=H) (0.5 mmol) in dry THF (5 WO 01 /l 0829 PCT/DKOO/0 28 ml) was added, while stirring at 20°C under argon, a 20% suspension of potassium hydride in mineral oil (0.2 mi) followed by an aikylating agent, RZ (1.5 mmol) and, finally, during 5 minutes, a solution of 18-Crown-6 (0.13 g) in dry THF (2 ml). Stirring at 25°C was continued for two hours, after which the reaction mixture was worked up (ether). The crude product was purified by chromatography (mixture of ether and petroleum ether as eluant) to yield the desired alkoxy compound III or IV. General Procedure 10 Synthesis of Compound I by deprotection of Compound IV with HF To a stirred solution of the appropriate Compound IV (0.25 mmol) in ethyl acetate (3 ml) was added acetonitπle (6 ml) followed by a 5% solution of hydrofluoric acid in acetonιtπie-H2θ 7: 1 (4 ml). After stirring for 2 hours at 25°C ethyl acetate (40 ml) and 1M sodium hydrogen carbonate (20 ml) was added, and the reaction mixture was worked up (ethyl acetate). The residue was purified by chromatography to give the desired compound I. General Procedure 11 Synthesis of lactic ester mesylates A solution of methanesulfonyl chloride (18.6 ml; 27.5 g; 0.24 mol) in tert-butyl methyl ether (100 ml) was added during one hour to a stirred solution of the appropriate R or S, methyl or ethyl, lactate (0.20 mol), triethylamine (28.3 g; 0.28 mol) and DMAP (0.24 g; 0.002 mol) in tert-butyl methyl ether (200 ml), while cooling in an ice bath. Stirring was continued for Vi hour in the ice bath a followed by 2 hours at 25°C. The reaction mixture was again cooled in an ice bath, and water (250 ml) was added slowly, keeping the temperature below 10°C . After stirring for 20 minutes more, the phases were separated, and the aqueous phase was extracted twice with ether (100 ml). The combined organic phases were extracted with : 1 N sulfuπc acid (100 ml), water ( 100 ml), 1 M sodium hydrogen carbonate (100 ml), water (2 x 100 ml) and saturated aqueous sodium chloride (100 ml). After drying with sodium suifate the solution was concen- trated (at 35°C and 0.2 bar), and the residue fractionated in vacuo through a 45 cm Podbielniak-type column to give the desired title compound . General Procedure 12 Synthesis of R or S. methyl or ethyl, 2-fluoropropιonate A solution of the appropriate lactic ester mesylate (0.125 mol) was added, during about one hour, to a solution/suspension of (freeze-dπed) potassium fluoride (29 g; 0.5 mol) in formamide (70 ml) which was stirred and heated in an oil bath at 60°C, in a vacuum of about 27 mbar. The flask was equipped with a Claisen-type side arm which was connected to a dry-ice cooler and a dry-ice cooled receiver, in which was condensed the 2-fiuoropropionic acid ester that was destilled continuously from the reaction. Stirring at 60°C and 20 mm Hg was continued until no more distillate was condensed, this took 4 - 5 hours. The distillate (which contained some water) was diluted with ether (40 ml), dried with magnesium sulfate and purified by distillation in a setup similar to the one used for the above preparation, keeping the bath temperature fairly constant at 50 - 60°C and gradually lowering the pressure, until the pure title compound was collected in the receiver. Preparation 1 Compound 502 A solution of (- )-ethyl D-lactate (R-isomer, unnatural) (5.2 g, 44 mmol), imidazole (13.6 g) and tert-butyl dimethylsilylchloride (15 g) in dry DMF (50 ml) was stirred at 25°C for 1 hour. Ethyl acetate (200 ml) was added and the organic solution was extracted with water (2x100 ml), 3M CaCI 2 (2x100 ml), water (100 mi) and 35% NaCI (100 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography with 1% ether in petroleum ether as eluant to give Compound 502 as an oil. [α] D 20 +30.5° (c 2.14, CHCI 3 ) 13 C NMR δ 173.9, 68.3, 60.5, 25.5, 21.1, 18.1, 14.0, -5.1, -5.5 Preparation 2 Compound 503 Method: General Procedure 1 Starting material : Ethyl (S)-(-)-0-tert-butyldimethylsilyllactate (Compound 501) Chromatography eluant: 0% to 5% ether in petroleum ether [α] D 20 -10.8° (c 2.17, CHCI3) 13 C NMR δ 214.7, 74.6, 29.9, 25.5, 20.8, 17.8, 7.1, -4.9, -5.3 Preparation 3 Compound 504 Method : General Procedure 1 Starting material : Compound 502 Chromatography eluant: 0% to 5% ether in petroleum ether. 13 C NMR δ 214.7, 74.6, 29.9, 25.5, 20.8, 17.8, 7.1, -4.9, -5.3 Preparation 4 Compound 201(4- Compound 205) Method : General Procedure 2 Starting material : Compound 503 Chromatography eluant: 1% ether in petroleum ether. 13 C NMR δ 1 NMR d 81.1, 75.6, 71.3, 70.0, 26.5, 25.8, 25.6, 17.8, 17.1, 7.4, -4.3, -5.2 Preparation 5 Compound 202 Method: General Procedure 4 Starting material : Compound 201 Chromatography eluant: 25% to 50% ether in petroleum ether. 13 C NMR δ 80.7, 75.5, 71.2, 71.1, 27.1, 26.0, 17.1, 7.6 Preparation 6 Compound 203 Method : General Procedure 5 Starting material : Compound 202 Chromatography eluant: 5 % ether in petroleum ether. 13 C NMR δ 106.8, 82.4, 80.2, 78.2, 70.8, 28.3, 26.7, 25.6, 25.0, 14.6, 7.2 Preparation 7 Compound 204 Method : General Procedure 6 Starting material : Compound 201 Chromatography eluant: petroleum ether. [α] D 20 -4.4° (c 1.8, CHCI 3 ) 1 C NMR δ 82.2, 80.1, 71.4, 70.3, 28.8, 25.8, 24.9, 17.9, 17.3, 7.5, 2.4, -4.4, -4.9 Preparation 8 Compound 205 (+ Compound 201) Method : General Procedure 2 Starting material : Compound 503 Chromatography eluant: 1% ether in petroleum ether. 13 C NMR δ 80.8, 75.1, 72.3, 70.2, 27.8, 25.6, 24.4, 17.8, 17.6, 7.4, -4.3, -5.2 Preparation 9 Compound 206 Method : General Procedure 4 Starting material : Compound 205 Chromatography eluant: 25 to 50 % ether in petroleum ether. 13 C NMR δ 80.8, 75.2, 71.6, 71.1, 29.1, 24.7, 17.0, 7.4 Preparation 10 Compound 207 Method : General Procedure 5 Starting material : Compound 206 Chromatography eluant: 5 % ether in petroleum ether. l 3 C NMR δ 106.9, 83.1, 81.0, 76.8, 70.1, 28.4, 28.2, 26.5, 24.5, 14.5, 8.1 Preparation 11 Compound 208 Method : General Procedure 6 Starting material : Compound 205 Chromatography eluant: petroleum ether. [α] D 20 +6.9° (c 1.6, CHCI 3 ) 13 C NMR δ 82.0, 79.8, 72.7, 70.5, 27.9, 27.0, 25.8, 25.7, 17.6, 8.3, 2.5, -4.4, -5.0 Preparation 12 Compound 209 (+ Compound 211) Method : General Procedure 2 Starting material : Compound 504 Chromatography eluant: 1 - 2% ether in petroleum ether. 13 C NMR δ 81.1, 75.6, 71.3, 70.0, 26.5, 25.8, 25.6, 17.8, 17.1, 7.4, -4.3, -5.2 Preparation 13 Compound 210 Method : General Procedure 6 Starting material : Compound 209 Chromatography eluant: petroleum ether. [ ] D 20 +4.1° (c 2.1, CHCI 3 ) 13 C NMR δ 82.2, 80.1, 71.4, 70.3, 28.8, 25.8, 25.0, 17.9, 17.3, 7.5, 2.4, -4.4, -4.9 Preparation 14 Compound 211 (+ Compound 209) Method : General Procedure 2 Starting material : Compound 504 Chromatography eluant: 1% to 2% ether in petroleum ether. 13 C NMR δ 80.8, 75.1, 72.3, 70.2, 27.8, 25.6, 24.4, 17.8, 17.6, 7.4, -4.3, -5.2 Preparation 15 Compound 212 Method : General Procedure 6 Starting material : Compound 211 Chromatography eluant: petroleum ether. [α] D 20 -7.0° (c 1.2, CHCI3) 13 C NMR δ 82.0, 79.8, 72.8, 70.5, 27.9, 27.0, 25.7, 17.8, 17.6, 8.3, 2.5, -4.4, -5.0 Preparation 16 Compound 213 + Compound 217 Method : General Procedure 3 Starting material : Compound 503 Chromatography eluant: 0% to 2% ether in petroleum ether. Compound 213 ! H NMR δ 3.70 (q,lH), 2.51 (s,lH), 1.80 (m,lH), 1.64 (m, lH), 1.25 (d,3H), 0.98 (t,3H), 0.88 (s,9H), 0.20 (s,6H) Compound 217 13 C NMR δ 83.9, 74.7, 73.3, 73.1, 31.0, 25.6, 25.5, 18.6, 8.1, -4.3, -5.1 Preparation 17 Compound 214 + Compound 218 Method : General Procedure 3a Starting material : Compound 503 Chromatography eluant: 0% to 1% ether in petroleum ether. Compound 214 13 C NMR δ 105.9, 89.2, 74.6, 73.5, 30.9, 25.7, 18.7, 17.2, 8.3, -0.3, -4.5, -4.9 Compound 218 13 C NMR δ 105.9, 89.6, 75.1, 73.4, 30.9, 25.7, 25.6, 18.7, 8.3, -0.3, -4.2, -5.0 Preparation 18 Compound 215 + Compound 219 Method : General Procedure 4 Starting material : Compound 213 + Compound 217, or Compound 214 + Compound 218 Chromatography eluant: a) 40% ether in petroleum ether, b) 33% ether in petroleum ether Compound 215 ! H NMR δ 3.84 (lH,q), 2.49 (lH,s), 1.74 (lH,m), 1.61 (lH,m), 1.27 (3H,d), 1.09 (3H,t) Compound 219 Crystallised from ether/n-heptane, m.p. 52° - 53°. 1 NMR δ 3.65 (q,lH), 2.46 (s,lH), 1.65 (m,2H), 1.31 (d,3H), 1.08 (t,3H) Preparation 19 Compound 216 Method : General Procedure 5a Starting material : Compound 219 Chromatography eluant: 5% ether in petroleum ether. 13 C NMR δ 108.6, 83.9, 79.3, 79.2, 72.8, 29.3, 28.3, 26.0, 13.6, 8.2 Preparation 20 Compound 220 Method : General Procedure 5a Starting material : Compound 215 Chromatography eluant: 5% ether in petroleum ether. 13 C NMR δ 108.6, 82.8, 81.3, 78.4, 75.1, 31.3, 27.6, 27.1, 15.8, 8.8 Preparation 21 Compound 301 + Compound 302 Method : General Procedure 7 Starting material : Compound 204 Chromatography eluant: 0% to 10% ether in petroleum ether. Compound 301 13 C NMR δ 153.4, 142.8, 135.3, 121.5, 116.4, 106.5, 83.2, 82.9, 80.3, 71.6, 70.1, 67.0, 64.6, 56.0, 51.4, 45.5, 43.8, 41.0, 39.6, 36.4, 29.0, 28.7, 26.4, 25.8, 25.7, 25.6, 25.2, 23.2, 21.9, 18.1, 17.9, 17.9, 17.3, 13.0, 12.4, 7.6, 2.5, -4.3, -5.0, -5.1 Compound 302 l 3 C NMR δ 152.5, 141.9, 134.3, 120.5, 115.4, 105.5, 82.3, 82.0, 79.3, 70.7, 69.1, 66.0, 64.7, 55.1, 51.1, 44.6, 42.8, 41.5, 39.2, 35.5, 28.0, 27.7, 26.0, 24.9, 24.7, 24.6, 24.4, 22.3, 21.0, 17.1, 17.0, 16.9, 16.4, 12.4, 10.8, 6.6, 1.5, -5.3, -5.8, -5.9 Preparation 22 Compound 401 Method: General Procedure 8 Starting material : Compound 301 Chromatography eluant: 0% to 2% ether in petroleum ether. 13 C NMR δ 148.2, 140.4, 135.0, 122.9, 117.9, 111.0, 83.1, 82.9, 80.3, 71.8, 71.6, 67.3, 64.6, 55.9, 51.4, 45.8, 45.3, 44.6, 41.0, 39.7, 29.0, 28.6, 26.5, 25.8, 25.7, 25.6, 25.2, 23.2, 21.8, 18.0, 17.9, 17.3, 13.0, 12.3, 7.6, 2.5, -4.3, -4.9, -5.0, -5.3 Preparation 23 Compound 402 Method: General Procedure 9 Starting material : Compound 401 Alkylating agent: Methyl iodide Chromatography eluant: 0% to 1% ether in petroleum ether. 13 C NMR δ 148.2, 140.6, 134.9, 122.9, 117.8, 111.0, 83.9, 80.8, 80.4, 73.6, 71.8, 71.7, 67.4, 56.0, 55.8, 51.4, 45.8, 45.3, 44.6, 40.4, 39.4, 29.1, 28.7, 26.5, 25.9, 25.7, 25.6, 25.3, 23.3, 21.8, 19.2, 18.0, 18.0, 17.4, 13.8, 12.4, 7.6, 2.5, -4.4, -4.9, -5.0, -5.3 Preparation 24 Compound 403 Method: General Procedure 9 Starting material: Compound 401 Alkylating agent: Ethyl bromide Chromatography eluant: 0% to 1% ether in petroleum ether. 13 C NMR δ 148.2, 140.7, 134.8, 123.0, 117.7, 111.0, 83.3, 81.4, 80.4, 72.0, 71.8, 71.7, 67.4, 63.8, 55.9, 51.4, 45.8, 45.4, 44.6, 40.3, 39.3, 29.1, 28.7, 26.4, 25.9, 25.7, 25.6, 25.3, 23.3, 21.8, 18.1, 18.0, 17.4, 15.0, 13.9, 12.4, 7.6, 2.5, -4.4, -4.9, -5.0, -5.3 Preparation 25 Compound 404 Method : General Procedure 9 Starting material : Compound 401 Alkylating agent: Propyl bromide Chromatography eluant: 0% to 1% ether in petroleum ether. 13 C NMR δ 148.2, 140.8, 134.8, 123.0, 117.7, 111.0, 83.3, 81.5, 80.5, 72.1, 71.8, 71.7, 70.1, 67.4, 55.9, 51.4, 45.8, 45.4, 44.6, 40.4, 39.5, 29.1, 28.7, 26.3, 25.9, 25.7, 25.6, 25.3, 23.3, 22.9, 21.8, 18.0, 18.0, 17.3, 13.9, 12.4, 10.7, 7.6, 2.5, -4.4, -4.9, -5.0, -5.3 Preparation 26 Compound 405 Method : General Procedure 9 Starting material: Compound 401 Alkylating agent: Benzyl bromide Chromatography eluant: 0% to 1% ether in petroleum ether. 13 C NMR δ 148.2, 140.7, 138.5, 134.9, 128.2, 128.0, 127.6, 127.4, 127.1, 122.9, 117.7, 111.0, 84.1, 81.0, 80.4, 71.8, 71.7, 70.1, 67.4, 55.8, 51.4, 45.8, 45.4, 44.6, 40.4, 39.4, 29.2, 28.7, 26.3, 25.9, 25.7, 25.6, 25.3, 23.2, 21.8, 18.0, 18.0, 17.4, 14.0, 12.4, 7.7, 2.5, -4.4, -4.8, -4.9, -5.0, -5.3 Preparation 27 Compound 303 Method: General Procedure 7 Starting material : Compound 208 Chromatography eluant: 0% to 5% ether in petroleum ether. 13 C NMR δ 153.4, 142.8, 135.3, 121.5, 116.4, 106.5, 83.1, 82.9, 80.0, 77.0, 72.9, 70.1, 67.0, 64.6, 56.0, 51.4, 45.5, 43.8, 41.0, 39.6, 36.4, 28.7, 28.0, 27.2, 26.4, 25.8, 25.7, 25.7, 25.6, 23.2, 21.9, 18.1, 17.9, 17.7, 13.0, 12.4, 8.4, 2.5, -4.4, -5.0, -5.1, -5.1 Preparation 28 Compound 406 Method : General Procedure 8 Starting material : Compound 303 Chromatography eluant: 0% to 5% ether in petroleum ether. 13 C NMR δ 148.2, 140.5, 135.0, 122.9, 117.9, 111.0, 83.1, 82.9, 80.0, 72.9, 71.8, 67.3, 64.6, 55.9, 51.4, 45.8, 45.3, 44.6, 41.0, 39.7, 28.6, 28.0, 27.2, 26.5, 25.8, 25.7, 25.7, WO 01 /l 0829 PCT/DKOO/00389 36 25.6, 23.2, 21.8, 18.0, 17.9, 17.9, 17.7, 13.0, 12.3, 8.4, 2.5, -4.4, -4.9, -4.9, -5.0, -5.3 Preparation 29 Compound 407 Method: General Procedure 9 Starting material : Compound 406 Alkylating agent: Ethyl bromide Chromatography eluant: 0% to 2% ether in petroleum ether. 13C NMR δ 148.2, 140.8, 134.8, 123.0, 117.7, 111.0, 83.1, 81.4, 80.1, 72.9, 71.9, 71.8, 67.4, 63.8, 55.9, 51.4, 45.8, 45.4, 44.6, 40.4, 39.4, 28.7, 28.0, 27.2, 26.5, 25.8, 25.7, 25.6, 23.3, 21.8, 18.0, 18.0, 17.9, 17.7, 15.0, 13.9, 12.4, 8.3, 2.4, -4.4, -4.9, -4.9, - 5.0, -5.3 Preparation 30 Compound 304 Method : General Procedure 7 Starting material : Compound 210 Chromatography eluant: 5% ether in petroleum ether. 13 C NMR δ 153.4, 142.8, 135.3, 121.5, 116.4, 106.5, 83.2, 82.9, 80.3, 71.6, 70.1, 67.0, 64.6, 56.0, 51.4, 45.5, 43.8, 41.0, 39.6, 36.4, 28.9, 28.7, 26.4, 25.8, 25.7, 25.6, 25.2, 23.2, 21.9, 18.1, 18.0, 17.9, 17.3, 13.0, 12.4, 7.6, 2.5, -4.3, -4.9, -5.0, -5.1, -5.1 Preparation 31 Compound 408 Method : General Procedure 8 Starting material : Compound 304 Chromatography eluant: 5% ether in petroleum ether. 1 C NMR δ 148.2, 140.4, 135.0, 122.9, 117.9, 111.0, 83.1, 83.0, 80.3, 71.8, 71.6, 67.3, 64.6, 55.9, 51.4, 45.8, 45.3, 44.6, 41.0, 39.7, 28.9, 28.6, 26.5, 25.8, 25.7, 25.7, 25.6, 25.2, 23.2, 21.8, 18.0, 17.9, 17.3, 13.0, 12.3, 7.6, 2.5, -4.3, -4.9, -5.0, -5.3 Preparation 32 Compound 409 Method : General Procedure 9 Starting material : Compound 408 Alkylating agent: Ethyl bromide Chromatography eluant: 1% ether in petroleum ether. 13 C NMR δ 148.2, 140.7, 134.8, 123.0, 117.7, 111.0, 83.4, 81.4, 80.4, 72.0, 71.8, 71.7, 37 67.8, 67.4, 63.8, 55.9, 51.3, 45.8, 45.4, 44.6, 40.3, 39.3, 29.0, 28.7, 26.3, 25.8, 25.7, 25.6, 25.4, 25.3, 23.3, 21.8, 18.0, 18.0, 17.4, 15.0, 14.0, 12.4, 7.6, 2.5, -4.4, -4.9, -5.0, -5.3 Preparation 33 Compound 305 Method : General Procedure 7 Starting material: Compound 212 Chromatography eluant: 3% ether in petroleum ether. 13 C NMR δ 263.2, 153.4, 142.8, 135.3, 121.5, 116.4, 106.5, 82.9, 80.0, 72.9, 70.1, 67.0, 64.7, 56.0, 51.4, 45.5, 43.8, 41.0, 39.6, 36.4, 28.7, 28.0, 27.2, 26.4, 25.7, 25.7, 25.6, 23.2, 21.9, 18.1, 17.9, 17.6, 13.0, 12.4, 8.4, 2.5, -4.4, -5.0, -5.1 Preparation 34 Compound 410 Method: General Procedure 8 Starting material : Compound 305 Chromatography eluant: 3% ether in petroleum ether. 13 C NMR δ 148.2, 140.5, 135.0, 122.9, 117.9, 111.0, 83.1, 82.9, 80.0, 72.9, 71.8, 67.3, 64.7, 55.9, 51.4, 45.8, 45.3, 44.6, 41.0, 39.7, 28.7, 28.0, 27.2, 26.5, 25.7, 25.7, 25.6, 23.2, 21.8, 18.1, 18.0, 17.9, 17.6, 13.0, 12.3, 8.4, 2.5, -4.4, -4.9, -4.9, -5.0, -5.3 Preparation 35 Compound 411 Method : General Procedure 9 Starting material : Compound 410 Chromatography eluant: 1% ether in petroleum ether. 13 C NMR δ 148.2, 140.8, 134.8, 123.0, 117.7, 111.0, 83.0, 81.4, 80.1, 72.9, 72.0, 71.8, 67.4, 63.8, 55.9, 51.4, 45.8, 45.4, 44.7, 40.3, 39.3, 28.7, 28.0, 27.2, 26.4, 25.8, 25.7, 25.6, 23.3, 21.8, 18.0, 18.0, 17.9, 17.6, 15.0, 14.0, 12.4, 8.4, 2.5, -4.4, -4.9, -4.9, -5.0, -5.3 Preparation 36 Compound 306 Method: General Procedure 7a Starting material : Compound 216 Chromatography eluant: 0 % to 20 % ether in petroleum ether. 13 C NMR δ 153.4, 142.7, 135.4, 121.5, 116.4, 108.1, 106.5, 85.6, 84.8, 79.3, 78.9, 70.1, 67.0, 64.4, 55.9, 51.2, 45.5, 43.8, 40.6, 39.5, 36.4, 28.7, 28.2, 28.0, 26.2, 25.9, 25.7, 25.6, 23.2, 21.9, 18.1, 17.9, 13.5, 13.1, 12.4, 8.2, -5.0, -5.1, -5.1 Preparation 37 Compound 412 Method : General Procedure 8 Starting material : Compound 306 Chromatography eluant: 10% ether in petroleum ether. 13 C NMR δ 148.1, 140.3, 135.0, 122.9, 117.9, 111.0, 108.1, 85.6, 84.7, 79.3, 78.9, 71.9, 67.3, 64.4, 55.8, 51.2, 45.8, 45.3, 44.6, 40.6, 39.5, 28.6, 28.2, 28.0, 26.2, 25.9, 25.7, 25.6, 23.1, 21.8, 18.0, 17.9, 13.5, 13.1, 12.4, 8.2, -4.9, -5.0, -5.3 Preparation 38 Compound 413 Method : General Procedure 9 Starting material : Compound 412 Alkylating agent: Ethyl bromide Chromatography eluant: 0% to 2% ether in petroleum ether. ! H NMR δ 6.22 (d,lH), 6.00 (d,lH), 5.17 (d,lH), 4.85 (d,lH), 4.36 (m,lH), 4.30 (q,lH), 4.20 (d,lH), 4.16 (m,lH), 3.72 (m,lH), 3.30 (m,lH), 2.82 (dd,lH), 2.43 (dd,lH), 2.20 (dd,lH), 1.99 (t,lH), 2.0 - 0.8 (m, 15H), 1.44 (s,3H), 1.40 (s,3H), 1.26 (d,3H), 1.18 (t,3H), 1.07 (t,3H), 1.00 (d,3H), 0.87 (s,18H), 0.51 (s,3H), 0.05 (s,12H) Preparation 39 Compound 307 Method: General Procedure 7a Starting material : Compound 220 Chromatography eluant: 0% to 20% ether in petroleum ether. 13 C NMR δ 153.4, 142.7, 135.3, 121.5, 116.4, 108.2, 106.5, 87.9, 83.8, 81.2, 78.4, 70.1, 67.0, 64.4, 55.9, 51.3, 45.4, 43.8, 40.7, 39.5, 36.4, 31.3, 28.7, 27.6, 26.8, 26.3, 25.7, 25.6, 23.2, 21.9, 18.1, 17.9, 15.8, 13.1, 12.4, 8.7, -5.0, -5.1, -5.1 Preparation 40 Compound 414 Method: General Procedure 8 Starting material : Compound 307 No Chromatography: Crude product used in the next step 13 C NMR δ 6.22 (lH,d), 6.01 (lH,d), 5.17 (lH,d), 4.85 (lH,d), 4.67 (lH,s), 4.36 (lH,m), 4.17 (lH,m), 3.85 (lH,q),2.82 ( lH,dd), 2.43 ( lH,dd), 2.21 (lH,dd), 1.89 (lH,t), 1.85 - 1.00 (13H,m), 1.68 (2H,q), 1.51 (3H,s), 1.35 (3H,d), 1.33 (3H,s), 1.06 (3H,t), 1.04 (3H,d), 0.87 (18H,s), 0.53 (3H,s), 0.05 (12H,s) Preparation 41 Compound 415 Method : General Procedure 9 Starting material : Compound 414 Alkylating agent: Ethyl bromide Chromatography eluant: 0% to 2% ether in petroleum ether. 13 C NMR δ 148.1, 140.7, 134.9, 122.9, 117.8, 111.0, 108.1, 86.5, 84.2, 81.3, 78.5, 71.9, 71.8, 67.3, 63.9, 55.9, 51.4, 45.9, 45.4, 44.6, 40.2, 39.3, 31.4, 28.7, 27.5, 26.9, 26.3, 25.7, 25.6, 23.3, 21.8, 18.0, 18.0, 15.8, 15.0, 14.0, 12.4, 8.8, -4.9, -5.0, -5.3 Preparation 42 Compound 505 Method: General Procedure 11 Starting material : Methyl (R)-(+)-lactate Purification: Distillation; b.p. 94°C/1.3mbar; [α] D 20 + 54.4° (c 2.29, CHCI 3 ) 13 C NMR δ 170.0, 74.1, 52.8, 39.1, 18.4 Preparation 43 Compound 506 Method : General Procedure 11 Starting material : Ethyl (S)-(-)-lactate Purification : Distillation; b.p. 98°C/1.5mbar; [α] D 20 - 53.1° (c 2.03, CHCI3), (litt. : Breitschuh, R. et al. Synthesis , 1992, 1170: [α] D 20 - 54.6°(c 4.36. CHCI3)) Preparation 44 Compound 507 Method : General Procedure 12 Starting material : Compound 505 Purification: Distillation; b.p. 39°C/53 mbar; [α] D 20 - 2.8° (c 2.21, CHCI3) 1 NMR δ 5.02 (dq,lH), 3.80 (s,3H), 1.58 (dd,3H) WO 01 /l 0829 PCT/DKOO/00389 40 Preparation 45 Compound 508 Method : General Procedure 12 Starting material : Compound 506 Purification : Distillation; b.p. 34°C/27 mbar; [α] D 20 + 3.8° (c 2.32, CHCI 3 ) 13 C NMR δ 170.5, 85.7, 61.5, 18.3, 14.1 Preparation 46 Compound 509 Method : General Procedure la Starting material : Compound 507 o n Purification : Distillation; b.p. about 45°C/27 mbar; [α] D -51.6° (approx.) (c 2.1, CHCI 3 :THF 4: 1) 1 NMR δ 4.88 (dq, IH); 2.64 (m, 2H); 1.47 (dd, 3H); 1.08 (t, 3H) Preparation 47 Compound 510 Method: General Procedure la Starting material : Compound 508 Purification : Distillation; b.p. about 45°C/27 mbar; [α] D 20 +43.3° (approx.) (c 2.0, CHCI 3 :THF 7:3) 13 C NMR δ 210.8, 92.6, 30.7, 17.7, 6.8 Preparation 48 Compound 221 Method: General Procedure 2a Purification: None Starting material : Compound 509 13 C NMR δ Major 93.4, 79.6, 74.3, 71.3, 27.8, 25.0, 14.8, 7.4 Minor 93.0, 80.0, 74.6, 71.0, 27.0, 25.4, 14.7, 7.2 Preparation 49 Compound 222 Method : General Procedure 6 Starting material: Compound 221 Chromatography eluant: petroleum ether Preparation 50 Compound 223 Method: General Procedure 2a Starting material: Compound 210 Purification: None 13 CNMRδ Major: 93.4, 79.7, 74.3, 71.4, 27.8, 25.0, 14.8, 7.4 Minor: 93.0, 80.0, 74.8, 71.0, 27.0, 25.4, 14.7, 7.2 Preparation 51 Compound 224 Method: General Procedure 6 Starting material: Compound 223 Chromatography eluant: petroleum ether. l3 C NMRδ Major: 93.2, 80.4, 78.3, 70.5, 28.1, 25.9, 14.9, 7.7, 2.1 Minor: 92.5, 80.6, 78.2, 70.3, 27.9, 25.1, 14.6, 7.2, 2.1 Preparation 52 Compound 308 Method: General Procedure 7 Starting materials: Compound 1 and Compound 222 Chromatography eluant: 0% to 20% ether in petroleum ether Preparation 53 Compound 416 Method: General Procedure 8a Starting material: Compound 308 Chromatography eluant: 50% dichloromethane in petroleum ether Preparation 54 Compound 417 Method: General Procedure 9 Starting material: Compound 416 Alkylating agent: Ethyl bromide Chromatography eluant: 0% to 10% ether in petroleum ether Preparation 55 Compound 309 Method : General Procedure 7 Starting materials: Compound 1 and Compound 224 Chromatography eluant: 0% to 20% ether in petroleum ether. 13 C NMR δ 153.4, 142.7, 135.4, 121.5, 116.4, 106.5, 93.3, 83.1, 81.5, 78.5, 70.1, 67.0, 64.6, 55.9, 51.4, 45.5, 43.8, 41.2, 40.9, 39.6, 36.4, 28.9, 28.7, 28.3, 27.5, 26.3, 25.7, 25.6, 23.2, 22.4, 21.9, 20.2, 19.2, 18.1, 17.9, 15.1, 14.8, 14.1, 13.0, 12.4, 11.2, 7.8, 2.2, -5.0, -5.1, -5.1 Preparation 56 Compound 418 Method : General Procedure 8a Starting material : Compound 309 Chromatography eluant: 50% dichloromethane in petroleum ether. !H NMR δ 6.22 (d,lH), 6.02 (d,lH), 5.17 (d,lH), 4.85 (d,lH), 4.62 (dq,lH), 4.60 (m,lH), 4.37 (m,lH), 4.18 (m,lH), 2.83 (d,lH), 2.50-0.80 (m,24H), 1.31 (dd,3H), 1.01 (d,3H), 0.85 (s,18H), 0.83 (d,3H), 0.12 (s,9H), 0.06 (d,12H) Preparation 57 Compound 419 Method : General Procedure 9 Starting material : Compound 418 Alkylating agent: Ethyl bromide Chromatography eluant: 0% to 10% ether in petroleum ether. 13 C NMR δ 148.1, 140.6, 134.9, 122.9, 117.8, 111.0, 93.4, 82.6, 80.5, 74.3, 71.9, 67.3, 64.0, 55.8, 51.3, 45.9, 45.4, 44.6, 40.1, 39.3, 28.7, 27.8, 26.2, 25.7, 25.6, 25.0, 23.3, 21.8, 18.0, 17.9, 14.7, 14.0, 12.4, 7.2, 2.2, -4.9, -5.0, -5.3 Examples Example 1 : l(S).3(R)-Dihvdroxy-20(R)-(5-ethyl-l(S),5(S) .6(S)-trihvdroxy-2-heptvn-l- yl)-9,10-secopreona-5(Z),7(E), 10( 19)-triene Compound 101 Method : General Procedure 4 Starting material : Compound 401 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. 13 C NMR (CD 3 OD) δ 149.8, 142.5, 135.8, 124.9, 119.0, 112.1, 84.3, 82.4, 77.1, 71.6, 71.5, 67.4, 65.5, 57.3, 52.7, 46.9, 46.2, 43.7, 42.4, 40.9, 30.1, 28.5, 27.0, 26.2, 24.5, 23.2, 17.3, 14.0, 13.1, 7.9 Example 2: l(S) .3(R)-Dihvdroxy-20(R)-(5(S) ,6(S)-dihvdroxy-5-ethyl- l(S)-methoxy-2- heptvn-l-yn-9, 10-secopregna-5(Z ,7(E), 10( 19)-thene Compound 102 Method : General Procedure 4 Starting material : Compound 402 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. 13 C NMR δ 147.7, 142.9, 133.1, 124.9, 117.2, 111.8,82.4, 82.0, 75.6, 73.8, 71.3, 70.9, 66.8, 56.4, 56.0, 51.5, 45.7, 45.3, 42.9, 40.3, 39.4, 29.1, 27.2, 26.5, 26.4, 23.5, 22.1, 17.1, 14.1, 12.6, 7.7 Example 3 : l(S) .3(R -Dihvdroxy-20(R)-(5(S),6(S)-dihvdroxy-l(S)-ethoxy-5-ethyl-2- heptvn-l-yl)-9.10-secopregna-5(Z).7(E) .10(19)-thene Compound 103 Method : General Procedure 4 Starting material : Compound 403 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. 13 C NMR δ 147.7, 142.9, 133.2, 124.8, 117.2, 111.8, 82.6, 81.9, 75.6, 72.3, 71.3, 70.8, 66.8, 64.2, 56.0, 51.5, 45.8, 45.3, 42.8, 40.2, 39.3, 29.1, 27.2, 26.4, 26.3, 23.5, 22.2, 17.1, 15.2, 14.2, 12.7, 7.7 Example 4: l(S).3(R)-Dihvdroxy-20(R)-(5(S) .6(S -dihvdroxy-5-ethyl-l(S)-(l-n- propyloxy)-2-heptvn-l-yl)-9,10-secopregna-5(Z),7(E).10(19)-thene Compound 104 Method : General Procedure 4 Starting material : Compound 404 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. 13 C NMR δ 147.7, 143.0, 133.0, 125.0, 117.1, 111.8, 82.9, 81.7, 75.6, 72.4, 71.3, 70.9, 70.5, 66.9, 56.0, 51.5, 45.8, 45.3, 42.9, 40.3, 39.5, 29.1, 27.2, 26.5, 26.3, 23.5, 23.1, 22.2, 17.1, 14.2, 12.7, 10.9, 7.7 Example 5 : l(S),3(R)-Dιhvdroxy-20(R)-( l(S)-benzyloxy-5(S) .6(S)-dιhvdroxy-5-ethyl-2- heptvn-l-yl)-9, 10-secopreqna-5(Z),7(E), 10(19 -trιene Compound 105 Method : General Procedure 4 Starting material : Compound 405 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. 13 C NMR δ 147.7, 142.9, 138.5, 133.1, 128.2, 127.7, 127.4, 124.9, 117.1, 111.8, 82.6, 82.2, 75.6, 71.9, 71.3, 70.8, 70.4, 66.8, 56.0, 51.5, 45.8, 45.3, 42.9, 40.3, 39.4, 29.0, 27.2, 26.4, 26.3, 23.5, 22.1, 20.8, 17.1, 12.7, 7.7 Example 6: l(S ,3(R)-Dιhvdroxy-20fR)-(5(R ,6(S -dιhvdroxy- l(S)-ethoxy-5-ethyl-2- heptvn-l-yl)-9,10-secopreqna-5(Z),7(E) , 10(19)-trιene Compound 106 Method : General Procedure 4 Starting material : Compound 407 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. 13 C NMR δ 147.7, 142.8, 133.2, 124.8, 117.2, 111.8, 82.9, 81.9, 75.4, 72.3, 71.2, 70.8, 66.8, 64.2, 56.0, 51.5, 45.8, 45.2, 42.9, 40.2, 39.3, 29.2, 29.1, 26.2, 25.1, 23.5, 22.2, 17.1, 15.2, 14.2, 12.7, 7.5 Example 7 : l(S),3(R)-Dιhvdroxy-20(R)-(5(R) ,6(R)-dιhvdroxy-l (S)-ethoxy-5-ethyl-2- heptvn- l-yl)-9 r 10-secopregna-5(Z),7(E) , 10( 19)-trιene Compound 107 Method : General Procedure 4 Starting material : Compound 409 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. 13 C NMR δ 147.7, 142.9, 133.2, 124.9, 117.2, 111.8, 82.6, 81.9, 75.6, 72.3, 71.3, 70.8, 66.8, 64.2, 56.0, 51.5, 45.8, 45.2, 42.8, 40.2, 39.3, 29.1, 27.2, 26.4, 26.3, 23.5, 22.1, 17.1, 15.2, 14.2, 12.7, 7.7 Example 8: l(S),3(R)-Dιhvdroxy-20(R)-(5(S),6(R)-dιhvdroxy-l(S)-ethoxy-5-ethyl-2- heptvn-l-yl)-9,10-secopregna-5(Z),7(E),10(19)-trιene Compound 108 Method : General Procedure 4 Starting material: Compound 411 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. 13 C NMR δ 147.7, 142.8, 133.2, 124.8, 117.2, 111.8, 83.0, 81.9, 75.4, 72.3, 71.2, 70.8, 66.8, 64.2, 56.0, 51.5, 45.8, 45.2, 42.9, 40.2, 39.3, 29.3, 29.1, 26.3, 25.1, 23.5, 22.1, 17.1, 15.2, 14.2, 12.7, 7.5 Example 9 : l(S),3(R)-Dihvdroxy-20(RW4-ethyl- l(S ,4(S).5(S)-trihvdroxy-2-hexyn-l- yl)-9.10-secopregna-5(Z).7(E).10(19)-triene Compound 109 Method : General Procedure 10 Starting material : Compound 412 Chromatography eluant: ethyl acetate. *H NMR (CD 3 OD) δ 6.32(d,lH), 6.08 (d,lH), 5.28 (d, IH), 4.90 (d,lH),4.57 (d,lH), 4.35 (t,lH), 4.12 (m,lH), 3.63 (q,lH),2.86 (dd,lH), 2.55(dd,lH), 2.25 (dd, lH), 2.0-1.0 (m,16H), 1.27 (d,3H), 1.23 (d,3H), 1.05 (t,3H), 0.56 (s,3H) Example 10: l(S) .3(R)-Dihvdroxy-20(R)-(4(S) .5(S)-dihvdroxy-l(S)-ethoxy-4-ethyl-2- hexyn-l-yl)-9,10-secopregna-5(Z) ,7(E , 10(19)-triene Compound 111 Method : General Procedure 10 Starting material : Compound 413 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. ! H NMR δ 6.37 (d,lH), 6.01 (d,lH), 5.32 (t,lH), 5.00 (d,lH), 4.42 (t, lH),4.41 (m,2H), 3.81 (q,lH), 3.73 (m,lH), 3.31 (rπ,lH), 2.83 (dd,lH), 2.59 (dd,lH), 2.31 (m,2H), 2.1 - 1.0 (m, 14H), 1.25 (d,3H), 1.21 (t,3H), 1.08 (t,3H), 1.02 (d,3H), 0.55 (s,5H) Example 11 : l(S),3(R)-Dihvdroxy-20(R)-(4-ethyl-l(S).4(R).5(S)-trihvdroxy-2-hexyn-l- yl)-9,10-secopregna-5(Z).7(E) .10(19)-triene Compound 114 Method : General Procedure 10 Starting material: Compound 414 Chromatography eluant: ethyl acetate. 13 C NMR δ (CD 3 OD)149.9, 142.4, 135.8, 130.2, 124.9, 119.1, 112.1, 73.5, 71.5, 67.4, 65.3, 61.6, 57.3, 52.7, 46.9, 46.2, 43.8, 42.2, 40.9, 32.1, 30.1, 27.1, 24.6, 23.2, 18.3, 14.5, 14.0, 13.0, 9.0 Example 12: l(S).3(R)-Dihvdroxy-20(R -(4(R) ,5(S)-dihvdroxy-l(S)-ethoxy-4-ethyl-2- hexyn-l-vn-9,10-secopregna-5(Z),7(E),10(19)-triene Compound 116 Method : General Procedure 10 Starting material: Compound 415 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. 13 C NMRδ 147.6, 142.9, 133.0, 125.0, 117.1, 111.9, 85.8, 85.3, 75.5, 73.2, 72.0, 70.9, 66.9, 64.3, 56.0, 51.5, 45.7, 45.3, 42.9, 40.2, 39.4, 31.0, 29.1, 26.4, 23.5, 22.1, 18.5, 15.2, 14.2, 12.7, 8.3 Example 13: Capsules containing Compound 103 Compound 103 was dissolved in arachis oil to a final concentration of 1 μg of Compound 103/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 103 in oil solution, such that each capsule contained 0.1 μg of Compound 103. Example 14: Dermatological Cream Containing Compound 102 In 1 g almond oil was dissolved 0.05 mg of Compound 102. To this solution was added 40 g of mineral oil and 20 g of self-emulsifying beeswax. The mixture was heated to liquefy. After the addition of 40 ml hot water, the mixture was mixed well. The resulting cream contains approximately 0.5 μg of Compound 102 per gram of cream. Example 15: Imection Fluid Containing Compound 108 Compound 108 (active substance) 10 μ g Disodium phosphate dihydrate (buffer) 15.4 mg Sodium dihydrogen phosphate dihydrate (buffer) 2 mg Sodium chloride 0.8 mg Sodium ascorbate (antioxidant) 5 mg Solutol® HS 15 from BASF (solubilizer) 5 mg Water for injection ad 1 ml Solutol® HS 15 is dissolved in the water for injection by heating it to a temperature of at the most 80°C. A cover of nitrogen is applied. The buffer substances and the sodium chloride are added and then the solution is cooled to at the most 30°C. Then sodium ascorbate is added and, finally, compound 108 is dissolved in the solution obtained. The solution is subjected to sterile filtration and is autoclaved at an appropriate time- temperature condition. WO 01 /l 0829 PCT/DKOO/00389 47 Example 16 : l(S).3(R)-Dihvdroxy-20(R)-(l(S) .5(R/S)-dihvdroxy-5-ethyl-6(S)-fluoro-2- heptvn-l-yl)-9,10-secopregna-5(Z),7(E),10(19)-triene Compound 157 Method : General Procedure 10 Starting material : Compound 416 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. Example 17 : l(S) .3(R)-Dihvdroxy-20(R)-( l(S)-ethoxy 5-ethyl-6(S)-fluoro-2-heptvn- 5(R/S)-hvdroxy l-yl)-9, 10-secopregna-5(Z),7(E).10(19)-triene Compound 158 Method : General Procedure 10 Starting material : Compound 417 Chromatography eluant: 50% petroleum ether in ethyl acetate. Example 18: l(S).3(R)-Dihvdroxy-20(R)-(l(S),5(R/S)-dihvdroxy-5-ethyl-6(R)-fluoro-2- heptvn-l-yl)-9,10-secopreqna-5(Z),7(E),10(19)-triene Compound 159 Method : General Procedure 10 Starting material : Compound 418 Chromatography eluant: 50% to 0% petroleum ether in ethyl acetate. 13 C NMR δ 147.7, 142.7, 133.2, 124.9, 117.3, 111.8, 93.4, 84.2, 80.5, 74.5, 70.9, 66.9, 64.8, 56.0, 51.5, 45.7, 45.3, 42.9, 41.0, 39.6, 29.0, 28.0, 26.4, 25.3, 23.4, 22.1, 14.9, 13.3, 12.6, 7.5 Example 19 : l(S).3(R)-Dihvdroxy-20(R)-(l(S -ethoxy 5-ethyl-6(R)-fluoro-2-heptvn- 5(R/S)-hvdroxy l-yl)-9,10-secopregna-5(Z),7(E .10(19)-triene Compound 160 Method : General Procedure 10 Starting material : Compound 419 Chromatography eluant: 50% petroleum ether in ethyl acetate. *H NMR δ 6.37 (d,lH), 6.02 (d,lH), 5.33 (s,lH), 5.00 (s,lH), 4.68 (dq,lH), 4.43 (m,lH), 4.23 (m,lH), 4.13 (s,lH), 3.73 (m,lH), 3.30 (m, lH), 2.84 (dd,lH), 2.58 (m,2H), 2.40 (dd,lH), 2.31 (dd,lH), 2.05-1.20 (m,19H), 1.38 (dd,3H), 1.20 (t,3H), 1.01 (d,3H), 0.96 (t,3H), 0.54 (s,3H)

Claims: CLAIMS 1 . A compound of the formula I wherein R represents hydrogen, or R represents (Cι-C5)alkyl, phenyl, or (C7-Cg)aralkyl, optionally substituted with one or more groups selected from (Cι-C3)alkyl, F, and phenyl; n is an integer having the value 0, 1, or 2; and X represents hydroxy or halogen; including any one of the possible diastereoisomers of formula I in pure form and any mixture of diastereoisomers of formula I. 2. A compound according to claim 1 wherein R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, benzyl, ortho methylbenzyl, meta methylbenzyl, and para methylbenzyl. 3. A compound according to any one of the preceding claims wherein n is 0 or 1, preferably n is 1. 4. A compound according to any one of the preceding claims wherein X represents a substituent selected from the group consisting of OH, F, and Cl. 5. A compound according to any one of the preceding claims having the configuration 22(S),25(S),26(S) or 22(S),25(S),26(R). 6. A compound according to claim 1 selected from the group consisting of l(S),3(R)-Dihydroxy-20(R)-(5-ethyl-l(S),5(S),6(S)-trihydroxy-2-heptyn-l-yl)-9,10- secopregna-5(Z),7(E), 10( 19)-triene (Compound 101), l(S),3(R)-Dιhydroxy-20(R)-(5(S),6(S)-dιhydroxy-5-ethyl-l(Ξ)-methoxy-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-tπene (Compound 102), l(S),3(R)-Dιhydroxy-20(R)-(5(S),6(S)-dιhydroxy-l(S)-ethoxy-5-ethyl-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-tπene (Compound 103), l(S),3(R)-Dιhydroxy-20(R)-(5(S),6(S)-dιhydroxy-5-ethyl-l(S)-( l-propyloxy)-2-heptyn- l-yl)-9,10-secopregna-5(Z),7(E),10(19)-trιene (Compound 104), l(S),3(R)-Dιhydroxy-20(R)-(l(S)-benzylyloxy-5(S),6(S)-dιhydroxy-5-ethyl-2-heptyn-l- yl)-9, 10-secopregna-5(Z),7(E), 10(19)-trιene (Compound 105), l(S),3(R)-Dιhydroxy-20(R)-(5(R),6(S)-dιhydroxy-l(S)-ethoxy-5-ethyl-2-heptyn-l-yl)- 9, 10-secopregna-5(Z),7(E),10(19)-trιene (Compound 106), l(S),3(R)-Dιhydroxy-20(R)-(5(R),6(R)-dιhydroxy-l(S)-ethoxy-5-ethyl-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-trιene (Compound 107), l(S),3(R)-Dιhydroxy-20(R)-(5(S),6(R)-dιhydroxy-l(S)-ethoxy-5-ethyl-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-tπene (Compound 108), (S),3(R)-Dιhydroxy-20(R)-(4-ethyl-l(S),4(S),5(S)-tπhydroxy-2-hexyn-l-yl)-9,10- secopregna-5(Z),7(E),10(19)-trιene (Compound 109), (S),3(R)-Dιhydroxy-20(R)-(4(S),5(S)-dιhydroxy-l(S)-ethoxy-4-ethyl-2-hexyn-l-yl)- 9,10-secopregna-5(Z),7(E), 10(19)-tπene (Compound 111), l(S),3(R)-Dιhydroxy-20(R)-(4-ethyl-l(S),4(R),5(S)-trιhydroxy-2-hexyn-l-yl)-9,10- secopregna-S(Z), 7(E), 10(19)-trιene (Compound 114), l(S),3(R)-Dιhydroxy-20(R)-(4(R),5(S)-dιhydroxy-l(S)-ethoxy-4-ethyl-2-hexyn-l-yl)- 9,10-secopregna-5(Z),7(E), 10(19)-tπene (Compound 116), l(S),3(R)-Dιhydroxy-20(R)-(l(S)-ethoxy-5-ethyl-6(S)-fluoro-5(S)-hydroxy-2-heptyn-l- yl)-9,10-secopregna-5(Z),7(E),10(19)-trιene (compound 149), and l(S),3(R)-Dιhydroxy-20(R)-(l(S)-ethoxy-5-ethyi-6(R)-fluoro-5(S)-hydroxy-2-heptyn-l- yl)-9,10-secopregna-5(Z),7(E),10(19)-trιene (compound 150). l(S),3(R)-Dιhydroxy-20(R)-(l(S),5(R/S)-dιhydroxy-5-ethyl-6(S)-fluoro-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-trιene (compound 157) l(S),3(R)-Dιhydroxy-20(R)-(l(S)-ethoxy 5-ethyl-6(S)-fluoro-2-heptyn-5(R/S)-hydroxy l-yl)-9, 10-secopregna-5(Z), 7(E), 10(19)-trιene (compound 158) l(S),3(R)-Dιhydroxy-20(R)-(l(S),5(R/S)-dιhydroxy-5-ethyl-6(R)-fluoro-2-heptyn-l-yl)- 9,10-secopregna-5(Z),7(E),10(19)-tπene (compound 159) l(S),3(R)-Dιhydroxy-20(R)-(l(S)-ethoxy 5-ethyl-6(R)-fluoro-2-heptyn-5(R/S)-hydroxy l-yl)-9,10-secopregna-5(Z),7(E),10(19)-trιene (compound 160) 7. A method for producing a compound of formula I of claim 1 characterized in a) reacting l(S),3(R)-bιs-(tert-butyldιmethylsιlyloxy)-20(R)-formyl-9,10- secopregna-5(E),7(E),10(19)-tπene, with an organometal lic reagent derived from the side cha i n bu ilding block HC≡C-(CH2) n -C(C 2 H 5 )(0-PG 1 )(CHX 1 -CH 3 ), wherein n 1 2 and R have the meani ngs specified above; X represents O-PG , fluorine, chlorine, 1 7 bromine, or iodine; PG and PG both represent the same or different group selected from tπmethylsilyl and tert-butyl-dimethylsilyl; or PG and PG together form one bifunctional isopropy dene ketal protective group; to form a compound of formula III, and b) optionally separating from diastereoisomers the compound formed in step a), c) subjecting the compound formed in step a) or step b) to triplet-sensitized photo- isomeπzation to the 5(Z) isomer, d) optionally alkylating the compound formed in step c) at the 22-hydroxy group with a (Cι-C5)alkyl or (C7-Cg)aralkyl bromide or iodide in the presence of a base and a phase transfer catalyst, and e) deprotectmg the compound formed in step c) or step d) to form a compound of formula I. 8. A pharmaceutical composition containing an effective amount of one or more of the compounds of claims 1-9, together with pharmaceutically acceptable, non-toxic carriers and/or auxiliary agents. 9. A method for the treatment and/or prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation, such as e.g. psoriasis including pustulosis palmoplantaπs, acrodermatitis continua and nail psoriasis and other disturbances of keratinization; HIV-associated dermatoses; wound healing; and various cancer forms, such as leukemia, mammary cancer, brain glial tumours, osteosarcoma, myelofibrosis, melanoma, other skin cancers; diseases of, or imbalances in, the immune system, such as host versus graft and graft versus host reactions; transplant rejection; autoimmune diseases including discoid and systemic lupus erythematosus; diabetes mellitus; and chronic dermatoses of autoimmune type, e.g. scleroderma and pemphigus vulgaπs; and inflammatory diseases, such as asthma and rheumatoid arthritis; as well as a number of other disease states including hyperparathyroidism, particularly secondary hyperpara- thyroidism associated with renal failure; cognitive impairment or senile dementia (Alzheimers disease) and other neurodegenerative diseases; hypertension; acne; alopecia; skin atrophy, e.g. steroid induced skin atrophy; skin ageing, including photo- ageing; and to their use for promoting osteogenesis and treating or preventing osteoporosis and osteomalacia, consisting in administering to a patient in need thereof a pharmaceutical composition according to claim 8. 10. The use of a compound according to any one of claims 1-6 in the manufacture of a medicament for the treatment and/or prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation, such as e.g. psoriasis including pustulosis palmoplantaris, acrodermatitis continua and nail psoriasis and other disturbances of keratinization; HIV-associated dermatoses; wound healing; and various cancer forms, such as leukemia, mammary cancer, brain glial tumours, osteosarcoma, myelofibrosis, melanoma, other skin cancers;diseases of, or imbalances in, the immune system, such as host versus graft and graft versus host reactions; transplant rejection; autoimmune diseases including discoid and systemic lupus erythematosus; diabetes mellitus; and chronic dermatoses of autoimmune type, e.g. scleroderma and pemphigus vulgaris; and inflammatory diseases, such as asthma and rheumatoid arthritis; as well as a number of other disease states including hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure; cognitive impairment or senile dementia (Alzheimers disease) and other neurodegenerative diseases; hypertension; acne; alopecia; skin atrophy, e.g. steroid induced skin atrophy; skin ageing, including photo- ageing; and to their use for promoting osteogenesis and treating or preventing osteoporosis and osteomalacia.

Inventors: BRETTING CLAUS AAGE SVENSGAARD, BRETTING, CLAUS, AAGE, SVENSGAARD
Applicants: BRETTING CLAUS AAGE SVENSGAARD, LEO PHARM PROD LTD, BRETTING, CLAUS, AAGE, SVENSGAARD, LEO PHARMACEUTICAL PRODUCTS LTD. A/S (LOEVENS KEMISKE FABRIK PRODUKTIONSAKTIESELSKAB)
Application year: 2000
Main classification: C07C401
IPC codes: A61K31, A61P3, A61P9, A61P11, A61P17, A61P19, A61P25, A61P29, A61P35, A61P37, C07C401