FIELD OF THE INVENTION The present invention relates to novel pharmacologically active vitamin D analogues as well as pharmaceutical preparations containing these compounds and dosage units of such preparations.

BACKGROUND OF THE INVENTION It has recently been shown that 1 a, 25-dihydroxyvitamin D3 (1, 25 (OH) 2D3) has an effect in relation to bone anabolism indicating the potential use of this compound in the treatment of osteoporosis and conditions characterized by an abnormal bone mineralisation. Erben et al. (Endocrinology, 139, 4319-4328 (1998)) have provided evidence for a direct anabolic effect of 1, 25 (OH) 2D3 on bone.

However, the therapeutic possibilities of 1, 25 (OH) 2D3 in such indications are severely limited by the well known potent effect of this hormone on calcium metabolism ; elevated blood concentra- tions will rapidly give rise to hypercalcemia. Thus, this compound is not completely satisfatory for use as a drug in the treatment of osteoporosis which may require prolonged administration of the drug in relatively high doses or in the treatment of other tissue specific diseases. Is is also well known that 1, 25 (OH) 2D3 has many other physiological effects in the human and mammal organism affecting a wide range of organs and tissues.

A number of thia-analogues of vitamin D3 are known. 1, 25-Dihydroxy-23-thiavitamin D3 is described in European Patent Application, publication number 78704. 23-Thia-aro-vitamin D analogues are described in G. Grue-Srensen, E. Binderup and L. Binderup in"Vitamin D. A Pluripotent Steroid Hormone : Structural Studies, Molecular Endocrinology and Clinical Applications", ed. by A. W. Norman, R. Bouillon and M. Thomasset, Walter de Gruyter, New York, 1994, pp. 75-76. 24-and 25-sulphonyl-analogues of 1, 25-dihydroxy-vitamin D3 have been described in G. H. Posner et al., J. Med. Chem., 42, 3425 (1999).

Some of these compounds may have advantages over 1, 25 (OH) 2D3, e. g. in having reduced calcium metabolism effects relative to 1, 25 (OH) 2D3. However, there is no report on a possible effect of these compounds in relation to bone anabolism.

Because of the serious medical implications for the affected individual, and the relatively limited numbers of drugs available for treatment of osteoporosis and the severity of the known side effects of 1, 25 (OH) 2D3, there is a continuing need for new vitamin D analogues with high pharmacological activity, such as bone anabolic activity, anti-cell proliferative and/or cell differentiation inducing activity, showing an acceptable combination of prolonged therapeutic

activity and minimum toxic effects compared to 1 a, 25 (OH) 2D3. It is an object of the present invention to provide such new compounds. Moreover, the bone anabolic activity of the novel compounds of the present invention is accompanied by a strengthening effect on the skeletal muscles. Thus rendering the compounds of the invention even more useful in various medical treatments, especially relating to treatment of osteoporosis.

The present inventors have found that the novel vitamin D analogues, represented by the general formula I herein, have shown bone anabolic effects in an in vivo model of osteoporosis and related bone disorders. Moreover, the bone anabolic activity of the analogues of the invention including the novel compounds is accompanied by a strengthening effect on the skeletal muscles.

Thus, the object of the present invention is achieved with the selected vitamin D analogues having the general formula I below.

SUMMARY OF THE INVENTION The present invention is directed to novel compounds represented by the general formula I wherein R'and R2, which may be the same or different, represent hydrogen or a residue after removal of 1 hydrogen atom from a straight, branched or cyclic, saturated or unsaturated, Ci-C6- hydrocarbon ; or R'and R2, together with the carbon atom to which they are attached (marked with an asterisk in formula 1), can form a C3-C8 carbocyclic ring ; Q represents a diradical residue after removal of 2 hydrogen atoms from a straight, branched or cyclic, saturated or unsaturated Ci-C8-hydrocarbon substituted with one or more chlorine or bromine atoms and/or substituted with one or more alkyl or alkoxy groups ; R', R2 and/or Q is optionally substituted with one or more fluorine atoms ; m is 0, 1 or 2 and n is 0 or 1.

DETAILED DESCRIPTION OF THE INVENTION Preferred compounds of formula I are compounds wherein R'and R2 taken together with the carbon atom (starred in formula 1) form a C3-C5 alkylen group ; and/or compounds of formula I wherein Q represents a C3-C5 alkylen group substituted with one or two chlorine atoms, or Q represents a phenylen group substituted with one bromine atom, one or two chlorine atoms, or one or two methyl or methoxy groups ; and compounds of formula I wherein and n is 1.

Examples of specific compounds useful in the invention are 1 (S), 3 (R)-Dihydroxy-20 (R)- (3, 3-dichloro-4-hydroxy-4-methyl)-1-pentylthiomethyl-9, 10- seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 101), 1 (S), 3 (R)-Dihydroxy-20 (R)- (3, 3-dichloro-4-hydroxy-4-methyl)-l-pentylsulphinylmethyl- 9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 102), 1 (S), 3 (R)-Dihydroxy-20 (R)-(2-chloro-5-(hydroxymethyl)) phenylthiomethyl-9, 10-seco- pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 103) (Compound 103), 1 (S), 3 (R)-Dihydroxy-20 (R)-(2-chloro-5-((1-hydroxy-1-methyl) ethyl)) phenylthiomethyl- 9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 104), 1 (S), 3 (R)-Dihydroxy-20 (R)-(3-chloro-4-((1-hydroxy-1-methyl) ethyl)) phenylthiomethyl- 9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 105), 1 (S), 3 (R)-Dihydroxy-20 (R)- (2-chloro-4- ( (l-hydroxy-1-methyl) ethyl)-5- methoxy) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 106), 1 (S), 3 (R)-Dihydroxy-20 (R)-(2-chloro-4-((1-hydroxy-1-methyl) ethyl)-6-methyl) phenylthio- methyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 107), 1 (S), 3 (R)-Dihydroxy-20 (R)-(2, 6-dichloro-4-((1-hydroxy-1-methyl) ethyl)) phenylthio- methyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 108), 1 (S), 3 (R)-Dihydroxy-20 (R)-(2-chloro-4-((1-hydroxy-1-methyl) ethyl)) phenylthiomethyl- 9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 112), 1 (S), 3 (R)-Dihydroxy-20 (R)- (2-bromo-4- ( (1-hydroxy-1-methyl) ethyl)) phenylthiomethyl- 9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 113), 1 (S), 3 (R)-Dihydroxy-20 (R)-(4-((1-hydroxy-1-methyl) ethyl)-3-methyl) phenylthiomethyi- 9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, (Compound 114), 1 (S), 3 (R)-Dihydroxy-20 (R)-(4-((1-hydroxy-1-methyl) ethyl)-2-methoxy) phenylthiomethyl- 9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 115), 1 (S), 3 (R)-Dihydroxy-20 (R)- (2, 6-dimethoxy-4- ( (1-hydroxy-1- methyl) ethyl)) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 116), and 1 (S), 3 (R)-Dihydroxy-20 (R)-(4-((1-hydroxy-1-methyl) ethyl)-2-methyl) phenylthiomethyl-

9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound 117).

It is preferred to use compounds of general formula I wherein R'and R2 each represents a C1- C2-alkyl group such as methyl and ethyl, methyl being more preferred, or wherein R'and R2 each represents hydrogen, and wherein Q is selected from the group consisting of 1, 3-propylene, 1, 4-phenylene and 1, 3-phenylene. It is also preferred that R1 = R2 "C3-C8 carbocyclic ring"includes the saturated cycloalkanes and unsaturated cyclic olefins, such as cycloalkenes having one endocyclic double bond, and having from 3-8 carbon atoms, and includes, for example, cyclopropyl, cyclopentyl, and cyclohexyl groups.

"Olefinic group"refers to a straight or branched acyclic hydrocarbon having one or more carbon- carbon double bonds of either E or Z stereochemistry where applicable, and having the number of carbon atoms specified. The term includes, for example, (C2-C15) olefinic group, preferably a (C2-C6) alkenyl ; (C3-C5) olefinic group, preferably an alkenyl such as allyl ; 1-butenyl ; 2-butenyl ; and 2-methyl-2-propenyl. Olefinic groups having only one carbon-carbon double bond, herein called alkenyl, are preferred.

The term"Halogen"when used herein means the same or different of fluoro, chloro, bromo, and iodo ; fluoro, chloro, and bromo being preferred.

Where the terms"comprise","comprises","comprised"or"comprising"are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.

As can be seen from formula 1, depending on the meanings of R'and R2, the compounds of the invention can comprise several diastereoisomeric forms (e. g. R or S configuration at the starred carbon atom). The invention covers all these diastereoisomers in pure form and also mixtures of diastereoisomers.

The compounds of formula I may conveniently be prepared from the vitamin D-derivative Compound (i), cf. Compound 5 in WO 91/15457, for example by the routes outlined in Scheme 1.

Photoisomerization of Compound (i) gives Compound (ii). Treatment of Compound (ii) with side chain building block HS-R under basic conditions gives the intermediate III (m=0), in which R is -(Q)-[C (R) (R2)] nOH or optionally a radical which can be converted to this at any convenient later stage. An alternative to this route involves treatment of Compound (i) under basic conditions with

a side chain building block HS-R, wherein R is as described above, to give the intermediate 11.

Thus R in compounds 11 and III does not necessarily have the same meaning along a particular synthetic sequence. The conversion of R to-(Q)-[C (R') (R2)] nOH may well involve several steps.

Apart from any necessary modification within the side chain (R), the conversion of 11 to I (in which m=0) involves a photoisomerisation step and a desilylation step, analogous to the steps used in the last stages of the synthesis of other vitamin D analogues (cf. European patent No. 0 227 826).

Compound (ii) may also be desilylated to Compound (iii), which is then treated with side chain building blocks R-SH under basic conditions to yield the vitamin D analogues I (in which m = 0).

The side chain building block HS-R is prepared by methods analogous to those used to prepare known compounds, such as 4-mercaptobenzoic acid (O. Paquatte, A. Fried and S.-C. Tu, Arch.

Biochem. Biophys. 264, 392-399 (1988)) or methyl 4-mercaptobenzoate (M. S. Newman and H. A.

Karnes, J. Org. Chem., 31, (1966) 3980-3984).

The compounds of formula I wherein m=1 or 2 may conveniently be prepared via oxidation of a corresponding compound (ii), II, iii or 1, for example with hydrogen peroxide and sodium tungstate in aqueous methanol. The diastereoisomeric sulphoxides (m = 1) may be separated chromato- graphically.

The following standard abbreviations are used throughout this disclosure : Dabco = 1, 4- diazabicyclo [2. 2. 2] octane ; DMF = N, N,-dimethylformamide ; DMSO = dimethylsulphoxide ; Et = ethyl ; HMPA = hexamethylphosphoric triamide ; Me = methyl ; TBA = tetrabutylammonium ; THF = tetrahydrofuran ; Ts = 4-toluenesulphonyl.

Scheme)

Notes to Scheme I a) Isomerization with hv-triplet sensitizer, e. g. anthracene or 9-acetylanthracene. b) Alkylation with the side chain building block RSH in the presence of a base (e. g. NaH) in solvent, e. g. DMF.

C) Optional functional group modification in the R-group, e. g. esterification of a carboxyl group with diazomethane or methanol and strong mineral acid, followed by reaction with alkyllithium, alkylmagnesium bromide or a reducing agent, such as sodium bis (2- methoxyethoxy) aluminium hydride. d) Optional oxidation of S in position 23 to the corresponding sulphoxides and sulphone with e. g. hydrogen peroxide and sodium tungstate as catalyst. e) Deprotection with TBAF or HF.

Scheme II Notes to Scheme II See notes to Scheme I.

It should be noted that although the shown intermediates may have hydroxyl groups protected as tert-butyl-dimethylsilyl ethers, the scope of the invention does not exclude the use of alternative hydroxyl protecting groups well known in the art (such as those described in T. W. Greene and P.

G. M. Wuts,"Protective groups in organic synthesis", 3d ed., Wiley, New York, 1999), together with alternative reactions for deprotection.

Some of the side chain building blocks R-SH may be prepared according to Scheme III, where the thiophenol ring, besides a 2-hydroxy-2-propyl substituent, is substituted with one or more of the following substituents : Cl, Br, methyl and/or methoxy.

Scheme Nf Notes to Scheme I I I Y'= H, Cl, Br, Me or OMe ; Y2 = Cl, Br, Me or OMe ; X = OMe or Me. f) Dimethylthiocarbamoyl chloride/Dabco/DMF/50°C/5 h g) 180-220°C/0. 5-2 h h) MeMgBr/ether/THF/0-25°C/0. 5-5 h i) NaOH/MeOH/water/20-60°C/0. 5-5 h The present invention provides a hitherto undisclosed series of vitamin D analogues related to the analogues disclosed in WO 91/15475, and which is characterised by the presence of additional halogen, alkyl or alkoxy groups in the side chain represented by the group Q in formula I herein.

Compared to the prior art vitamin D analogues, illustrated by 1 (S), 3 (R)-dihydroxy-20 (R)- (4- ( (1- hydroxy-1-methyl) ethyl) phenylthio-methyl)-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene (Compound

145 disclosed in WO 91/15475), the present new vitamin D analogues have precisely the properties which are demanded (Table 1) : Reduced calcemic activity (in the rat calciuric model, Ca* in Table 1 below) together with an only slightly reduced antiproliferative activity as shown in 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 ; wherein the VDR, HaCaT and Ca assays are described), is slightly higher than that of 1 (S), 3 (R)-dihydroxy-20 (R)- (4- ( (1-hydroxy-1- methyl) ethyl) phenylthio-methyl)-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene.

Table 1 Compound 1a, 25 (OH) 2D3 No. 101 No. 102 No. 104 Assav VDR#, rel. * 1 0. 75 0. 01 <0. 02 MCF-7, rel. * 1 131x 19x HaCaT, rel. * 1 <0. 8x 7x, 6x 16x Ca* 100% <0. 5% # Vitamin D receptor binding * Geometric mean of the ratios, relative to 1 a, 25 (OH) 2D3, from all experiments with the compound in question, in the assay concerned.

The present compounds are intended for use in the preparation of pharmaceutical compositions which are useful in the treatment of specific human and veterinary disorders as described above.

The amount required of a compound of formulae f (hereinafter referred to as the active compound or 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.

Moreover, the novel compounds are intended for use in pharmaceutical compositions which are useful in the local or systemic treatment or prophylaxis of human and veterinary disorders amenable to treatment with vitamin D or vitamin D analogues, such as e. g. psoriasis and other disturbances of keratinization, 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 erythema- tosus, diabetes mellitus and chronic dermatoses of autoimmune type, e. g. scleroderma and pemphigus vulgaris, 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, 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 osteomalacia.

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 antipsoriatic 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 treat- ment. 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 immunosuppressive/immunoregulating drugs or treatments, e. g. with cyclosporin A.

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 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 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 suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular 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 physi- cally 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 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.

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 microcrystalline form, for example, in the form of an aqueous microcrystalline 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 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.

The compositions may further contain other therapeutical 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 pathological conditions, said method consisting of administering to a patient in need of treatment an effective amount of one or more compounds of formula 1, alone or in combination with one or more other therapeutical 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. Preferred pathological conditions to be treated with the present compounds are osteoporosis and related bone disorders including skeletal muscle weakness.

In the systemic treatment daily doses of from 0. 001-100 ug per kilogram body weight, preferably from 0. 002-15 Rg/kg of mammal body weight, for example 0. 003-10 llg/kg of a compound of formula I are administered, typically corresponding to a daily dose for an adult human of from 0. 2 to 750 lAg. In the topical treatment of dermatological disorders, ointments, creams or lotions con- taining from 0. 1-2500 p9/9, and preferably from 0. 1-500, ug/g, of a compound of formula I are ad- ministered. For topical use in ophthalmology ointments, drops or gels containing from 0. 1-2500 g/g, and preferably from 0. 1-500 y9/9, of a compound of formula I are administered. The oral compositions are formulated, preferably as tablets, capsules, or drops, containing from 0. 05-250 , ug, preferably from 0. 1-125 9, of a compound of formula 1, per dosage unit.

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 compressing, 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 moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent.

In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e. g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.

The invention will now be further described in the following non-limiting Preparations and Examples : Preparations and Examples General The exemplified compounds of formula I are listed in Table 2. The intermediates of Scheme I, Il and III referred to in the Preparations are to be identified by numbers with the corresponding formulae in Table 3 and 4. These are used to illustrate typical syntheses of the exemplified compounds 1.

For 1 H nuclear magnetic resonance spectra (300 MHz) chemical shift values (8) are quoted in ppm for deuteriochloroform solutions (except where otherwise stated) relative to internal tetramethylsilane (â = 0) or chloroform (8 = 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). For 13C nuclear magnetic resonance spectra (75. 5 MHz) chemical shift values (8) are quoted in ppm for deuteriochloroform solutions (except where otherwise stated) relative to internal tetramethylsilane (8 = 0) or chloroform (8 = 76. 81).

Ether is diethyl ether, and was dried over sodium. THF was dried over sodium-benzophenone.

Petroleum ether refers to the pentane fraction. If not specified, % means v/v%. Reactions were run at room temperature unless otherwise noted. The work-up procedure referred to involves di- lution with the specified solvent (otherwise the organic reaction solvent), wash with water and then brine, drying over anhydrous MgS04, and concentration in vacuo to give a residue.

Chromatography was performed on silica gel.

Table 2 : Examples of Compounds of formula I wherein n=1. Details are provided for compounds where an Example No. is given ; other compounds may be prepared using analogous reaction sequences from known starting materials.

Compound Example m Q R1 R2 No. No.

101 1 0 CH2CH2CCl2 Me Me 102 2 1 CH2CH2CCl2 Me Me 103 3 0 1, 3- (6-chloro) phenylene H H 104 4 0 1, 3- (6-chloro) phenylene Me Me 105 5 0 1, 4- (3-chloro) phenylene Me Me 106 6 0 1, 4- (2-chloro-5- Me Me methoxy) phenylen 107 7 0 1, 4-(2-chloro-6- Me Me methyl) phenylene 108 8 0 1, 4- (2, 6- Me Me dichloro) phenylen 109* 9 1 1, 4- (3-chloro) phenylene Me Me 110** 10 1 1, 4- (3-chloro) phenylene Me Me 111 11 2 1, 4-(3-chloro)phenylene Me Me 112 15 0 1, 4- (2-chloro) phenylene Me Me 113 16 0 1, 4- (2-bromo) phenylene Me Me 114 17 0 1, 4-(3-methyl)phenylene Me Me 115 18 0 1, 4- (2-methoxy) phenylene Me Me 116 19 0 1, 4- (2, 6- Me Me dimethoxy) phenylen 117 20 0 1, 4- (2-methyl) phenylene Me Me * Isomer with Compound 110 Isomer with Compound 109

Table 3 Intermediate compounds prepared according to Preparations 9 to 24 below. Details are provided for compounds where a Preparation No. is given ; other compounds may be prepared using analogous reaction sequences from known starting materials.

Compound Preparation Type m R Formula number number (See Scheme I) 13 9 11 0 CH2CH2CCI2C (OSiEt3) Me2 14 10 11 0 2-CI-5- (C (OH) H2)-C6H3 15 11 Il 0 2-CI-5- (C (OH) Me2)-C6H3 16 12 Ill 0 CH2CH2CCl2C(OSiEt3) Me2 17 13 III 0 2-CI-5- (C (OH) H2)-C6H3 18 14 Ill 0 2-Cl-5-(C (OH) Me2)-C6H3 19 15 111 0 3-CI-4- (MeOOC)-C6H3 20 16 III 0 3-CI-4- (C (OH) Me2)-C6H3 21 17 Ill 0 2-Cl-4-(MeOOC)-5-(MeO)-C6H2 22 18 Ill 0 2-CI-4- (C (OH) Me2)-5- (MeO)-C6H2 23 19 Ill 0 2-Cl-4-(MeOOC)-6-Me-C6H2 24 20 Ill 0 2-Cl-4-(C (OH) Me2)-6-Me-C6H2 25 21 Ill 0 2, 6-CI2-4-(MeOOC)-C6H2 26 22 lit 0 2, 6-CI2-4- (C (OH) Me2)-C6H2 27 24 Ill 2 3-CI-4- (C (OH) Me2)-C6H3 28* 23 Ill 1 3-CI-4- (C (OH) Me2)-C6H3 29** 23 Ill 1 3-CI-4- (C (OH) Me2)-C6H3 Isomer with Compound 29 ** Isomer with Compound 28

Table 4 Intermediate and final side chain building blocks according to Scheme III and Preparations 26 to 53 below. Details are provided for compounds where a Preparation No. is given ; other compounds may be prepared using analogous reaction sequences from known starting materials.

Compound Preparation Type X Y1 Y2 number number (See Scheme 111) 30 26 V OMe H 3-CI 31 27 VI OMe H 3-Cl 32 28 Vll - H 3-Cl 33 29 R-SH-H 3-CI 34 30 V OMe H 3-Br 35 31 Vi OMe H 3-Br 36 32 Vll - H 3-Br 37 33 R-SH-H 3-Br 38 34 V Me H 2-Me 39 35 Vl Me H 2-Me 40 36 Vl l-H 2-Me 41 37 R-SH-H 2-Me 42 38 V Me H 3-OMe 43 39 V) Me H 3-OMe 44 40 Vll - H 3-OMe 45 41 R-SH-H 3-OMe 46 42 V OMe 3-OMe 5-OMe 47 43 VI OMe 3-OMe 5-OMe 48 44 Vll - 3-Ome 5-OMe 49 45 R-SH-3-OMe 5-OMe 50 46 V Me H 3-Me 51 47 Vi Me H 3-Me 52 48 Vll - H 3-Me 53 49 R-SH-H 3-Me 54 50 V OMe 3-Cl 5-Cl 55 51 V) OMe 3-Cl 5-Cl 56 52 Vll - 3-Cl 5-Cl 57 53 R-SH-3-Cl 5-Cl General Procedure 1 : Isomerization of Compound (i) to Compound (ii) and of Compound Il to the corresponding Compound III

A solution of the compound (i) or compound 11 (ca. 0. 2 g), anthracene (200 mg) and triethylamine (0. 3 ml) in dichloromethane (15 ml) under nitrogen in a Pyrex flask was irradiated with light from a high pressure ultraviolet lamp, type TQ718Z2 (Hanau) at about 10°C for 30 minutes. The reaction mixture was filtered, concentrated in vacuo and purified by chromatography to give the compound (ii) or compound III, respectively.

General Procedure 2 : Isomerization of Compound (i) to Compound (ii) and of Compound II to the corresponding Compound III A solution of compound (i) or compound 11 (5 g), 9-acetylanthracene (160 mg) and triethylamine (5. 5 mL) in toluene (200 mL) under argon in a Pyrex flask was irradiated with light from a high pressure ultraviolet lamp, type TQ718Z2 (Hanau), 700 W, at about 10°C for 105 minutes. Solvent was removed in vacuo to give compound (ii) or compound 111, respectively, which were used without further purification.

General Procedure 3 : Reaction of Compound (i), Compound (ii) or Compound (iii) with the side chain building block R-SH to Compound II, Compound III or Compound I, respectively.

Sodium hydride dispersion (55% in oil, 179 mg) was washed with petroleum ether (3 x 2 mL) under an atmosphere of argon. A mixture of R-SH (1. 2 mmol) in DMF (1. 5 mL) was added and the mixture was stirred for 10-60 min. Compound (i), Compound (ii) or Compound (iii) (ca. 0. 7 mmol) in DMF (1. 5 mL) was added and stirred. The temperature was kept between 20 and 80°C for 0. 5 to 10 h. At room temperature, water (8 mL) was added. If the R-group contained a carboxy group, pH was adjusted to 4. 3 with dilute hydrochloric acid. The mixture was worked up with ether.

Compounds without a carboxy group were purified by chromatography to give compound I (Ethyl acetat as eluant) or 11 or III (ether/petroleum ether 1 : 3 as eluant). Compounds II or III with a carboxy group were used in the next step without further purification.

General Procedure 4 : Esterification of Compounds II or III containing a carboxy group to the corresponding methyl esters.

To an etheral solution (35 mL) of compound 11 or 111 (0. 7 mmol), containing a carboxy group, was added a etheral solution of diazomethane until a yellow colour persisted. The reaction mixture was concentrated in vacuo, and the residue was chromatographed (ether/petroleum ether 1 : 3 as eluant) to give the desired methyl ester.

General Procedure 5 : Reaction of side chain methyl esters with methyllithium.

To a solution of compound 11 or III, containing a methoxycarbonyl group in the side chain, (0. 13 mmol) in dry THF (1. 5 mL) under argon at 0°C was added a solution of methyllithium in ether (1. 6 M, 0. 24 mL). After stirring for 30 minutes, water (15 mL) was added, and the reaction mixture was

worked up with ether. Purification by chromatography (ether/petroleum ether 1 : 3 as eluant) gave the corresponding tertiary alcohol 11 or 111.

General Procedure 6 : Reaction of side chain methyl esters with sodium bis (2- methoxyethoxy) aluminum hydride.

To a solution of compound 11 or 111, containing a methoxycarbonyl group in the side chain, (0. 13 mmol) in toluene (0. 4 mL) under argon was added a solution of sodium bis (2- methoxyethoxy) aluminum hydride in toluene (3. 4 M, 0. 041 mL). After stirring at 50°C for 30 minutes, water (10 mL) was added, and the reaction mixture was worked up with ethyl acetate.

Purification by chromatography (ether/petroleum ether 1 : 4 as eluant) gave the corresponding primary alcohol 11 or iii.

General Procedure 7 : Oxidation of compound I, II or III (m = 0) to the corrresponding isomeric sulphoxides (m = 1).

A mixture of compound I, II or III (m = 0) (0. 85 mmol), sodium hydrogencarbonate (100 mg), methanol (4 mL), chloroform (4 mL), a 2% (w/v) aqueous solution of sodium tungstate dihydrate (0. 10 mL) and 30% hydrogen peroxide (0. 24 mL) was stirred at room temperature for 3 h. Water (100 mL) was added and the mixture was worked up with dichloromethane. The residue was chromatographed with ethyl acetate to give the desired products.

General Procedure 8 : Oxidation of compound 11 or III (m=0) to the corrresponding sulphone (m=2).

A mixture of compound 11 or III (m = 0) (0. 85 mmol), sodium hydrogencarbonate (100 mg), methanol (4 mL), chloroform (4 mL), a 2% (w/v) aqueous solution of sodium tungstate dihydrate (0. 10 mL) and 30% hydrogen peroxide (0. 48 mL) was stirred at 50°C for 3 h. Water (100 mL) was added and the mixture was worked up with dichloromethane. The residue was chromatographed with ethyl acetate to give the desired product.

General Procedure 9 : Deprotection of compound III to the corresponding compound I by desilylation with TBAF.

A solution of compound 111 (0. 3 mmol) and TBAF trihydrate (1. 2 mmol) in THF (10 mL) under argon was stirred at 65°C for 1 h. The reaction mixture was worked up with ethyl acetate.

Purification by chromatography (ethyl acetate as eluant) gave compound 1.

General Procedure 10 : Deprotection of compound (ii) or III to the corresponding compound (iii) or I by desilylation with HF.

The compound ii or III (ca. 0. 3 mmol) was dissolved in ethyl acetate (0. 6 mL) and acetonitrile (8 mL) was added under stirring. A solution of 5% hydrofluoric acid in acetonitrile/water 8 : 1 (4. 0 mL) was added, and the mixture was stirred under argon at room temperature for 90 minutes. Excess

4 M aqueous NaOH was added, and the reaction mixture was worked up with ethyl acetate. The residue was purified by recrystallization from ethyl acetate to give compound (iii) or by chromatography (ethyl acetate as eluant) to give a compound of formula 1.

General Procedure 11 : Preparation of O-aryl dimethylthiocarbamates IV.

Method : M. S. Newman and H. A. Karnes, J. Org. Chem., 31, (1966) 3980-3984 (see preparation of 0-2-carbomethoxyphenyl dimethylthiocarbamate).

General Procedure 12 : Preparation of S-aryl dimethylthiocarbamates V.

Method : M. S. Newman and H. A. Karnes, J. Org. Chem., 31, (1966) 3980-3984 (see pyrolysis experiments).

General Procedure 13 : Preparation of 2-aryl-2-propanol compounds Vi.

A compound of the general formula V (1 mmol) was dissolved in dry THF at 0°C and methylmagnesium bromide (3 mmol when X = OMe ; 2 mmol when X = Me ; 3. 0 M in ether) was added. The temperature was raised to r. t. and after 2 h the reaction mixture was acidified with dilute hydrochloric acid worked up with ether. The compound was purified by gradient chromatography starting with toluene and ending with toluene/acetone 90 : 10 (v/v).

General Procedure 14 : Preparation of mercapto compounds R-SH.

Method : M. S. Newman and H. A. Karnes, J. Org. Chem., 31, (1966) 3980-3984 (see preparation of thiophenols).

Preparation 1 : Compound (ii) Method : General Procedure 2.

Starting material : Compound (i).

A sample not containing 9-acetylanthracene was obtained by chromatography (ether/petroleum ether 1 : 9 as eluat).

13 C NMR : 8 = 148. 1, 144. 4, 139. 9, 135. 2, 133. 1, 129. 5, 127. 7, 122. 8, 118. 0, 111. 0, 74. 1, 71. 8, 67. 3, 55. 7, 52. 2, 45. 8, 45. 1, 44. 6, 39. 6, 35. 2, 28. 5, 26. 6, 25. 6, 25. 6, 23. 1, 21. 7, 21. 4, 18. 0, 17. 9, 16. 5, 12. 1,-4. 9,-5. 0,-5. 3.

Preparation 2 : Compound 1, S-Acetyl-3, 3-dichloro-1-mercapto-4-methyl-4- (triethylsilyloxy) pentane.

To an ice-cold solution of 3, 3-dichloro-2-methyl-5-hexen-2-ol (1. 2 g) (cf. W094/07851) in dichloromethane (10 mL) was added triethylsilyltrifluorosulfonate (1. 6 mL) followed by 2, 6-lutidine.

After 2 h water was added and the mixture was worked up with dichloromethane.

Chromatography gave 4, 4-dichloro-5-methyl-5-(triethylsilyloxy)-1-hexene (Compound 2)'H NMR : 8= 6. 11 (m, 1 H), 5. 25 (m, 1 H), 5. 19 (m, 1 H), 2. 99 (m, 2H), 1. 53 (s, 6H), 0. 95 (t, 9H), 0. 63 (q, 6H).

This compound was treated with ozone followed by sodium borohydride as described in preparation 16 in W094/07851 to give 3, 3-dichloro-4-methyl-4- (triethylsilyloxy)-pentan-1-ol (Compound 3) 13C NMR : 8 = 100. 2, 80. 3, 60. 1, 44. 0, 25. 7, 6. 8, 6. 3.

This compound (0. 6 g) in THF (5 mL) was added at-78°C to a mixture of triphenylphosphine (0. 86 g), THF (5 mL), diisopropylazodicarboxylate (0. 62 mL) and thioacetic acid (0. 24 mL). After stirring at-78°C for 1 h and at room temperature over night the mixture was concentrated to dryness in vacuo. Chromatography with 1-10% ether in petroleum ether gave S-acetyl-3, 3- dichloro-1-mercapto-4-methyl-4- (triethylsilyloxy) pentane (Compound 1).

3C NMR : 8 = 195. 1, 100. 8, 80. 2, 41. 2, 30. 3, 25. 9, 25. 4, 6. 8, 6. 3.

Preparation 3 : Compound 4, 4-chloro-3-mercapto-benzylalcohol.

A solution of 4-chloro-3- (chlorosulphonyl) benzoic acid (4. 8 g) in acetic acid (60 mL) was stirred in the dark with 56% hydriodic acid (18 mL) for 22 h. A solution of sodium thiosulphate (26. 0 g) in water (260 mL) was added. The crystalline product was isolated, washed with water and dried in vacuo to give bis (5-carboxy-2-chlorophenyl) disulfide (Compound 5). This compound (1. 7 g) was refluxed with methanol (40 mL) and conc. sulphuric acid (0. 25 mL) for 5 h. After addition of chloroform (10 mL) a water containing azeotrope (ca. 10 mL) was distilled. Reflux was continued for 3 h. Solvent was removed in vacuo, the residue was dissolved in dichloromethane and "filtered"through silica gel to give bis (5-methoxycarbonyl-2-chlorophenyl) disulfide (Compound 6).

This compound (1. 0 g) was dissolved in THF and slowly added (exothermic reaction) under argon to a mixture of lithium aluminumhydride (0. 48 g) in THF (5 mL). After the reaction had reached room temperature the mixture was acidified with dilute hydrochloric acid. Work up with ether and purification by chromatography (dichloromethane/ethyl acetate 1 : 1 as eluant) gave 4-chloro-3- mercapto-benzylalcohol (Compound 4).

CNMR : 8 =140. 2, 132. 0, 130. 7, 129. 7, 127. 9, 124. 9, 64. 1.

Preparation 4 : Compound 7 2- (4-chloro-3-mercapto-phenyl) propan-2-ol.

Bis (5-methoxycarbonyl-2-chlorophenyl) disulfide) (Compound 6) (see preparation 3) (1. 0 g) was mixed with THF (5 mL) under argon and lithium tri (tert-butoxy) aluminiumhydride in THF (1. 25 M, 20 mL) was slowly added and the mixture was stirred for 20 minutes. After acidification with dilute hydrochloric acid the mixture was worked up with ether. Purification by chromatography (dichloromethane as eluant) gave methyl 4-chloro-3-mercapto-benzoate (Compound 8). This compound (0. 82 g) was dissolved in ether (15 mL) and slowly added to methyl magnesium iodide (20 mmol) in ether (15 mL). After stirring for 20 min the mixture was acidified with dilute hydrochloric acid and worked up with ether. Purification by chromatography (dichloromethane/ethyl acetate 1 : 1 as eluant) gave 2- (4-chloro-3-mercapto-phenyl) propan-2-ol (Compound 7).

1H NMR : 8= 7. 48 (d, 1 H), 7. 29 (t, 1 H), 7. 16 (dd, 1 H), 3. 92 (s, 1 H), 1. 54 (s, 6H).

Preparation 5 : Compound 9 2-chloro-4-mercapto-benzoic acid.

Method : O. Paquatte, A. Fried and S.-C. Tu, Arch. Biochem. Biophys., 264 (1988) 392-399.

Starting material : 4-amino-2-chloro-benzoic acid.

3C NMR (acetone-d6) : 3=166. 1, 140. 5, 134. 8, 133. 1, 130. 5, 127. 4, 127. 2.

Preparation 6 : Compound 10 5-chloro-4-mercapto-2-methoxy-benzoic acid.

Method : O. Paquatte, A. Fried and S.-C. Tu, Arch. Biochem. Biophys., 264 (1988) 392-399.

Starting material : 4-amino-5-chloro-2-methoxy-benzoic acid.

3C NMR (DMSO-d6) : 8 = 165. 3, 157. 5, 138. 0, 131. 6, 122. 2, 122. 0, 112. 0, 56. 3.

Preparation 7 : Compound 11 5-chloro-4-mercapto-3-methyl-benzoic acid.

Method : O. Paquatte, A. Fried and S.-C. Tu, Arch. Biochem. Biophys., 264 (1988) 392-399.

Starting material : 4-amino-5-chloro-3-methyl-benzoic acid.

3C NMR (DMSO-d6) : ô= 166. 6, 146. 7, 130. 1, 128. 4, 122. 2, 118. 0, 116. 1, 18. 1.

Preparation 8 : Compound 12 3, 5-dichloro-4-mercapto-benzoic acid.

Method : O. Paquatte, A. Fried and S.-C. Tu, Arch. Biochem. Biophys., 264 (1988) 392-399.

Starting material : 4-amino-3, 5-dichloro-benzoic acid.

13C NMR (pyridine-d5) : 8 = 167. 4, 145. 7, 130. 3, 121. 0, 118. 5.

Preparation 9 : Compound 13 Method : General Procedure 3.

Starting materials : Compound (i) and S-acetyl-3, 3-dichloro-1-mercapto-4-methyl-4- (triethylsilyloxy) pentane.

Reaction conditions : room temperature/4 h.

DMF was replaced by THF/HMPA 20 : 1 as solvent. R-SH = 3, 3-Dichloro-1-mercapto-4-methyl-4- (triethylsilyloxy) pentane was prepared in situ from the S-acetyl compound by using 10 equivalents of sodium hydride.

'H NMR : 8 =6. 44 (d, 1 H), 5. 82 (d, 1H), 4. 97 (s, 1 H), 4. 95 (s, 1 H), 4. 52 (m, 1 H), 4. 21 (t, 1H), 2. 95- 2. 80 (m, 3H), 2. 60-2. 25 (m, 5H), 1. 51 (s, 6H), 2. 05-0. 90 (m, 15), 0. 99 (d, 3H), 0. 96 (t, 9H), 0. 91 (s, 9H), 0. 86 (s, 9H), 0. 64 (q, 6H), 0. 56 (s, 3H), 0. 05 (s, 12H).

Preparation 10 : Compound 14 Method : General Procedure 3.

Starting materials : Compound (i) and 4-chloro-3-mercapto-benzylalcohol.

Reaction conditions : room temperature/2 h.

CNMR : 8 = 153. 4, 142. 6, 139. 7, 137. 1, 135. 4, 132. 2, 129. 4, 126. 4, 124. 3, 121. 4, 116. 5, 106. 5, 70. 1, 67. 0, 64. 4, 56. 0, 55. 5, 45. 7, 43. 7, 40. 1, 39. 5, 36. 4, 34. 8, 28. 7, 26. 8, 25. 7, 25. 6, 23. 3, 21. 8, 18. 9, 18. 1, 17. 9, 12. 4,-5. 0,-5. 1,-5. 1.

Preparation 11 : Compound 15 Method : General Procedure 3.

Starting materials : Compound (i) and 2- (4-chloro-3-mercapto-phenyl) propan-2-ol.

Reaction conditions : room temperature/0. 5 h.

CNMR : 5 = 153. 4, 148. 0, 142. 6, 136. 3, 135. 4, 131. 8, 129. 1, 125. 0, 122. 5, 121. 4, 116. 4, 106. 5, 72. 1, 70. 0, 67. 0, 56. 0, 55. 6, 45. 6, 43. 7, 40. 1, 39. 8, 36. 4, 35. 0, 31. 6, 28. 6, 26. 8, 25. 7, 25. 6, 23. 3, 21. 8, 18. 8, 18. 0, 17. 9, 12. 4,-5. 0,-5. 1,-5. 1.

Preparation 12 : Compound 16 Method : General Procedure 1.

Starting material : Compound 13.

13C NMR : 8 = 148. 1, 140. 4, 135. 0, 122. 9, 117. 9, 111. 0, 101. 3, 80. 2, 71. 9, 67. 3, 56. 0, 55. 6, 45. 9, 45. 5, 44. 6, 41. 8, 40. 3, 39. 2, 35. 7, 28. 7, 26. 9, 25. 9, 25. 7, 25. 6, 23. 3, 21. 8, 18. 6, 18. 0, 17. 9, 12. 3, 6. 8, 6. 4,-4. 9,-5. 0,-5. 3.

Preparation 13 : Compound 17 Method : General Procedure 1.

Starting material : Compound 14.

CNMR : 8= 148. 1, 140. 2, 139. 7, 137. 1, 135. 1, 132. 2, 129. 4, 126. 4, 124. 3, 122. 8, 118. 0, 111. 0, 71. 8, 67. 3, 64. 4, 55. 9, 55. 5, 45. 8, 45. 5, 44. 6, 40. 2, 39. 5, 34. 8, 28. 6, 26. 8, 25. 7, 25. 6, 23. 3, 21. 7, 18. 9, 18. 0, 18. 0, 12. 3,-4. 9,-5. 0,-5. 3.

Preparation 14 : Compound 18 Method : General Procedure 1.

Starting material : Compound 15.

CNMR : 8 =148. 1, 148. 0, 140. 3, 136. 3, 135. 1, 131. 8, 129. 1, 125. 0, 122. 8, 122. 5, 117. 9, 111. 0, 72. 1, 71. 8, 67. 3, 55. 9, 55. 7, 45. 8, 45. 5, 44. 6, 40. 2, 39. 8, 35. 0, 31. 6, 28. 6, 26. 8, 25. 7, 25. 6, 23. 2, 21. 7, 18. 8, 18. 0, 18. 0, 12. 3,-4. 9,-5. 0,-5. 3.

Preparation 15 : Compound 19 Method : General Procedure 3 (reaction conditions : room temperature/1 h) and 4.

Starting material : Compound 9.

1 3C N M R : 8 = 165. 4, 148. 2, 145. 2, 140. 0, 135. 2, 134. 4, 131. 6, 128. 4, 125. 3, 124. 6, 122. 8, 118. 1, 111. 0, 71. 8, 67. 3, 55. 9, 55. 5, 52. 1, 45. 8, 45. 5, 44. 6, 40. 3, 39. 1, 34. 8, 28. 6, 26. 8, 25. 7, 25. 6, 23. 2, 21. 7, 18. 8, 18. 0, 17. 9, 12. 4,-4. 9,-5. 0,-5. 3.

Preparation 16 : Compound 20 Method : General Procedure 5.

Starting material : Compound 19 13C NMR : S= 148. 1, 141. 7, 140. 2, 138. 0, 135. 1, 131. 4, 130. 5, 127. 0, 126. 8, 122. 8, 118. 0, 111. 0, 72. 7, 71. 8, 67. 3, 65. 6, 55. 9, 55. 5, 45. 8, 45. 5, 44. 6, 40. 3, 35. 1, 29. 3, 28. 6, 26. 8, 25. 6, 25. 6, 23. 2, 21. 7, 18. 7, 18. 0, 17. 9, 15. 0, 12. 3,-4. 9,-5. 0,-5. 3.

Preparation 17 : Compound 21 Method : General Procedure 3 (reaction conditions : 40°C/18 h) and 4.

Starting materials : Compound (ii) and Compound 10.

3C NMR : 8 = 164. 8, 157. 9, 148. 1, 144. 2, 139. 9, 135. 3, 131. 9, 123. 2, 122. 7, 118. 1, 116. 6, 111. 0, 110. 2, 71. 8, 67. 3, 56. 2, 55. 8, 55. 7, 51. 8, 45. 8, 45. 5, 44. 6, 40. 3, 39. 1, 34. 8, 28. 5, 26. 8, 25. 6, 25. 6, 23. 2, 21. 7, 18. 9, 18. 0, 17. 9, 12. 4,-4. 9,-5. 0,-5. 3.

Preparation 18 : Compound 22 Method : General Procedure 5.

Starting material : Compound 21.

13C NMR : 8 = 155. 3, 148. 2, 140. 1, 135. 4, 135. 2, 135. 0, 126. 8, 122. 8, 118. 0, 112. 5, 111. 0, 80. 4, 71. 9, 71. 8, 67. 3, 55. 9, 55. 7, 55. 6, 45. 8, 45. 5, 44. 6, 40. 3, 40. 2, 35. 2, 29. 3, 28. 6, 26. 9, 25. 7, 25. 6, 23. 2, 21. 8, 18. 8, 18. 0, 17. 9, 12. 3,-4. 9,-5. 0,-5. 3.

Preparation 19 : Compound 23 Method : General Procedure 3 and 4.

Starting materials : Compound (ii) and Compound 11.

Preparation 20 : Compound 24 Method : General Procedure 5.

Starting material : Compound 23.

Preparation 21 : Compound 25 Method : General Procedure 3 and 4.

Starting materials : Compound (ii) and Compound 12

Preparation 22 : Compound 26 Method : General Procedure 5.

Starting material : Compound 25.

Preparation 23 : Compounds 28 and 29 Method : General Procedure 7.

Starting material : Compound 20.

Preparation 24 : Compound 27 Method : General Procedure 8.

Starting material : Compound 20.

Preparation 25 : Compound (iii) Method : General Procedure 10.

Starting material : Compound (ii).

13C NMR (DMSO-d6) : 8 =149. 4, 144. 8, 139. 5, 136. 0, 132. 3, 130. 0, 127. 5, 122. 3, 117. 7, 109. 9, 74. 1, 68. 5, 65. 0, 55. 2, 51. 5, 44. 9, 44. 8, 43. 1, 38. 8, 34. 5, 28. 1, 26. 0, 22. 8, 21. 5, 21. 0, 16. 3, 11. 9.

Preparation 26 : Compound 30 Method : General Procedure 11.

Starting material : Methyl 3-chloro-4-hydroxybenzoate.

3C NMR : 8=185. 6, 165. 4, 153. 4, 131. 6, 129. 1, 128. 9, 128. 1, 125. 3, 52. 5, 43. 5, 39. 0.

Preparation 27 : Compound 31 Method : General Procedure 12.

Starting material : Compound 30.

3C NMR : 8 =165. 5, 164. 2, 139. 2, 137. 7, 134. 0, 132. 3, 130. 8, 127. 8, 52. 5, 37. 1.

Preparation 28 : Compound 32 Method : General Procedure 13.

Starting material : Compound 31.

3C NMR : 8 =165. 5, 152. 7, 139. 4, 138. 0, 126. 4, 126. 1, 123. 5, 72. 1, 37. 0, 31. 6.

Preparation 29 : Compound 33 Method : General Procedure 14.

Starting material : Compound 32.

13C NMR : 8 =148. 3, 131. 8, 129. 6, 126. 0, 123. 6, 72. 0, 31. 7.

Preparation 30 : Compound 34 Method : General Procedure 11.

Starting material : Methyl 3-bromo-4-hydroxybenzoate.

13C NMR : 8=185. 5, 165. 2, 154. 6, 134. 7, 129. 6, 129. 2, 125. 3, 117. 3, 52. 5, 43. 5, 39. 0.

Preparation 31 : Compound 35 Method : General Procedure 12.

Starting material : Compound 34.

13C NMR : 8 =165. 3, 164. 3, 137. 6, 136. 2, 134. 1, 132. 1, 129. 8, 128. 4, 52. 5, 37. 1.

Preparation 32 : Compound 36 Method : General Procedure 13.

Starting material : Compound 35.

13C NMR : 8 =165. 5, 152. 6, 137. 9, 130. 5, 129. 7, 128. 4, 124. 2, 72. 1, 37. 0, 31. 6.

Preparation 33 : Compound 37 Method : General Procedure 14.

Starting material : Compound 36.

3C NMR : 8 =148. 3, 131. 9, 129. 4, 129. 3, 124. 3, 122. 2, 72. 0, 31. 7.

Preparation 34 : Compound 38 Method : General Procedure 11.

Starting material : 2-Methyl-4-hydroxyacetophenone.

3C NMR : 8=200. 2, 187. 0, 155. 9, 141. 0, 134. 9, 130. 9, 126. 2, 120. 1, 43. 3, 38. 8, 29. 5, 21. 9.

Preparation 35 : Compound 39 Method : General Procedure 12.

Starting material : Compound 38.

13C NMR : # =201. 2, 166. 0, 138. 9, 138. 6, 137. 9, 132. 6, 129. 5, 37. 0, 29. 6, 21. 4.

Preparation 36 : Compound 40 Method : General Procedure 13.

Starting material : Compound 39.

13C NMR : 8 =167. 1, 147. 0, 139. 5, 136. 7, 132. 9, 126. 8, 126. 0, 73. 5, 36. 9, 30. 7, 22. 1.

Preparation 37 : Compound 41 Method : General Procedure 14.

Starting material : Compound 40.

13C NMR : 8 =

Preparation 38 : Compound 42 Method : General Procedure 11.

Starting material : 3-Methoxy-4-hydroxyacetophenone.

13C NMR : 8 =196. 9, 187. 0, 151. 9, 146. 8, 135. 8, 124. 1, 121. 8, 111. 7, 56. 1, 43. 4, 38. 9, 26. 5.

Preparation 39 : Compound 43 Method : General Procedure 12.

Starting material : Compound 42.

3C NMR : 8 =197. 5, 165. 2, 159. 9, 139. 4, 137. 7, 123. 3, 121. 2, 109. 9, 56. 3, 37. 0, 26. 7.

Preparation 40 : Compound 44 Method : General Procedure 13.

Starting material : Compound 43.

13C NMR : 8 =166. 5, 160. 0, 153. 3, 137. 7, 117. 2, 114. 7, 108. 1, 72. 6, 56. 1, 37. 0, 31. 7.

Preparation 41 : Compound 45 Method : General Procedure 14.

Starting material : Compound 44.

13C NMR : 8 = 154. 6, 147. 9, 128. 8, 118. 3, 116. 9, 107. 1, 72. 2, 55. 7, 31. 6.

Preparation 42 : Compound 46 Method : General Procedure 11.

Starting material : Methyl 3, 5-dimethoxy-4-hydroxybenzoate.

3C NMR : 8 =187. 0, 166. 5, 152. 5, 135. 8, 127. 9, 106. 6, 56. 5, 52. 3, 43. 5, 38. 8.

Preparation 43 : Compound 47 Method : General Procedure 12.

Starting material : Compound 46.

3C NM R : 8 =166. 6, 164. 8, 161. 1, 132. 9, 110. 7, 105. 3, 56. 6, 52. 4, 37. 1.

Preparation 44 : Compound 48 Method : General Procedure 13.

Starting material : Compound 47.

Preparation 45 : Compound 49 Method : General Procedure 14.

Starting material : Compound 48.

Preparation 46 : Compound 50 Method : General Procedure 11.

Starting material : 3-Methyl-4-hydroxyacetophenone.

Preparation 47 : Compound 51 Method : General Procedure 12.

Starting material : Compound 50.

Preparation 48 : Compound 52 Method : General Procedure 13.

Starting material : Compound 51.

Preparation 49 : Compound 53 Method : General Procedure 14.

Starting material : Compound 52.

Preparation 50 : Compound 54 Method : General Procedure 11.

Starting material : Methyl 3, 5-dichloro-4-hydroxybenzoate.

3C NMR : 8 =183. 8, 164. 4, 150. 1, 130. 2, 129. 8, 129. 1, 52. 7, 43. 6, 39. 1.

Preparation 51 : Compound 55 Method : General Procedure 12.

Starting material : Compound 54.

13C NMR : 8=164. 5, 162. 8, 142. 0, 133. 7, 132. 8, 129. 1, 52. 8, 37. 2.

Preparation 52 : Compound 56 Method : General Procedure 13.

Starting material : Compound 55.

3C NMR : 8=164. 0, 153. 4, 141. 6, 126. 1, 125. 1, 72. 0, 37. 1, 31. 4.

Preparation 53 : Compound 57 Method : General Procedure 14.

Starting material : Compound 56.

C NMR : 8 = 147. 7, 132. 0, 130. 6, 124. 5, 71. 9, 31. 6.

Example 1 : 1 (S), 3 (R)-Dihydroxy-20 (R)- (3, 3-dichloro-4-hydroxy-4-methyl)-1-pentylthiomethyl-9, 10- seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 101 Method : General Procedure 9.

Starting material : Compound 16.

13C NMR : 8= 147. 7, 142. 6, 133. 3, 124. 8, 117. 3, 111. 8, 102. 4, 78. 2, 70. 8, 66. 8, 56. 1, 55. 7, 45. 8, 45. 3, 42. 9, 42. 2, 40. 4, 39. 4, 35. 8, 29. 0, 28. 7, 26. 9, 25. 1, 23. 5, 22. 1, 18. 8, 12. 6.

Example 2 : 1 (S), 3 (R)-Dihydroxy-20 (R)- (3, 3-dichloro-4-hydroxy-4-methyl)-1-pentylsulphinylmethyl- 9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 102 Method : General Procedure 7.

Starting material : Compound 101.

13 NMR : 8 = 142. 1, 133. 5, 124. 7, 117. 5, 111. 8, 78. 3, 70. 8, 66. 8, 60. 4, 56. 3, 48. 1, 45. 8, 45. 3, 42. 9, 40. 4, 31. 9, 28. 9, 25. 1, 23. 4, 22. 0, 19. 5, 14. 2, 12. 8.

Example 3 : 1 (S), 3 (R)-Dihydroxy-20 (R)- (2-chloro-5- (hydroxymethyl)) phenylthiomethyl-9, 10-seco- pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 103 Method : General Procedure 10.

Starting material : Compound 17.

13C NMR : 8 = 147. 6, 142. 6, 139. 9, 137. 2, 133. 2, 132. 4, 129. 6, 126. 7, 124. 9, 124. 6, 117. 3, 111. 8, 70. 8, 66. 8, 64. 6, 56. 1, 55. 7, 45. 9, 45. 3, 42. 9, 40. 2, 39. 7, 35. 0, 29. 0, 26. 9, 23. 5, 22. 1, 19. 1, 12. 6.

Example 4 : 1 (S), 3 (R)-Dihydroxy-20 (R)-(2-chloro-5-((1-hydroxy-1-methyl) ethyl)) phenylthiomethyl- 9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 104 Method : General Procedure 10.

Starting material : Compound 18.

C NMR : 8= 148. 2, 147. 6, 142. 6, 136. 4, 133. 2, 132. 1, 129. 3, 125. 3, 124. 9, 122. 8, 117. 3, 111. 8, 72. 3, 70. 8, 66. 8, 56. 1, 55. 8, 45. 8, 45. 3, 42. 9, 40. 3, 40. 0, 35. 2, 31. 8, 29. 0, 26. 9, 23. 5, 22. 1, 19. 0, 12. 6.

Example 5 : 1 (S), 3 (R)-Dihydroxy-20 (R)-(3-chloro-4-((1-hydroxy-1-methyl) ethyl)) phenylthiomethyl- 9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 105 Method : General Procedure 10.

Starting material : Compound 20.

13C NMR : 8 = 147. 7, 142. 5, 138. 2, 133. 3, 130. 8, 127. 2, 127. 0, 124. 8, 117. 3, 111. 8, 80. 5, 72. 9, 70. 8, 66. 8, 56. 1, 55. 7, 45. 8, 45. 3, 42. 9, 40. 5, 40. 3, 35. 2, 29. 5, 29. 0, 26. 9, 23. 5, 22. 1, 18. 9, 12. 5.

Example 6 : 1 (S), 3 (R)-Dihydroxy-20 (R)-(2-chloro-4-((1-hydroxy-1-methyl) ethyl)-5- methoxy) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, compound 106

Method : General Procedure 10.

Starting material : Compound 22.

CNMR : 8=155. 5, 147. 7, 142. 3, 135. 5, 135. 2, 133. 5, 127. 1, 126. 2, 124. 7, 117. 4, 112. 8, 111. 8, 72. 2, 70. 7, 66. 8, 56. 1, 55. 9, 55. 8, 45. 8, 45. 3, 42. 9, 40. 4, 40. 3, 35. 4, 29. 5, 28. 9, 27. 0, 23. 5, 22. 1, 19. 0, 12. 6.

Example 7 : 1 (S), 3 (R)-Dihydroxy-20 (R)-(2-chloro-4-((1-hydroxy-1-methyl) ethyl)-6- methyl) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, compound 107 Method : General Procedure 10.

Starting material : Compound 24.

Example 8 : 1 (S), 3 (R)-Dihydroxy-20 (R)-(2, 6-dichloro-4-((1-hydroxy-1- methyl) ethyl)) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 108 Method : General Procedure 10.

Starting materials : Compound 26.

CNMR : 8=151. 6, 147. 7, 142. 7, 141. 0, 133. 1, 132. 1, 125. 0, 124. 9, 117. 2, 111. 8, 72. 0, 70. 8, 66. 8, 56. 1, 55. 7, 45. 7, 45. 3, 42. 9, 42. 5, 40. 3, 36. 2, 31. 5, 29. 0, 27. 1, 23. 6, 22. 1, 18. 9, 12. 2.

Example 9 1 (S), 3 (R)-Dihydroxy-20 (R)-(3-chloro-4-((1-hydroxy-1- methyl) ethyl)) phenylsulphinylmethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 109 (Stereoisomer with Compound 110) Method : General Procedure 10.

Starting material : Compound 28 sulphoxide of Compound 20.

Example 10 1 (S), 3 (R)-Dihydroxy-20 (R)- (3-chloro-4- ( (1-hydroxy-1- methyl) ethyl)) phenylsulphinylmethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 110 (Stereoisomer with Compound 109) Method : General Procedure 10.

Starting material : Compound 29.

Example 11 1 (S), 3 (R)-Dihydroxy-20 (R)-(3-chloro-4-((1-hydroxy-1- methyl) ethyl)) phenylsulphonylmethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 111 Method : General Procedure 10.

Starting material : Compound 27.

Example 12 Capsules containing Compound 105 Compound 105 was dissolved in arachis oil to a final concentration of 1 gag Compound 105/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 p, t of the Compound 105 in oil solution, such that each capsule contained 0. 1, ug Compound 105.

Example 13 Drop preparations containing Compound 105 1) Drop preparation containing Compound 105 in the form of an oil solution 0. 1 g of Compound 105 and 0, 5 g of D, L-alpha-tocopherole (as an antioxidant) are dissolved in Medium Chain Triglycerides (Ph. Eur) to obtain 100 L (= 94. 5 kg). The preparation is filtered, and the solution is transferred to brown bottles provided with a suitable dropper plug or drop-insert to enable dripping off of 1 ml of solution which is divided into 25 drops.

1 ml of solution contains 1 microgram of Compound 105 and 0. 04 microgram of Compound 145 per drop. The bottle is closed with a suitable screw cap made of polypropylene.

2) Drop preparation containing compound 105 in the form of a solubilised aqueous solution A) 0. 2 g of Compound 105 and 2 g of D, L-alpha-tocopherole are dissolved in a stainless steel container in 10. 2 kg (14 L) of ethanol 99. 9%, and 2 kg of Cremophor RH40 (R) (Polyoxyl 40 hydrogenated castor oil).

B) 54 kg of Purified water, 0. 015 kg of citric acid monohydrate, 0. 950 kg of sodium citrate, 45 kg of Sorbitol, and 0. 150 kg of methylparaben are dissolved at heating in a separate container.

Following cooling to below 25°C solution B is slowly poured into solution A while stirring the mixture. Cremophor RH40 hereby forms a micellar solution wherein the water insoluble Compound 105 and D, L-alpha-tocopherole remains in solution in the preparation. Finally, purified water is added to the preparation to obtain 113 kg (=100 L) of preparation of a pH in the range (6. 5-7. 5). The preparation is filtered and bottled in brown bottles provided with a suitable dropper plug or drop insert and a matching screw cap.

1 ml of the preparation contains 2 microgram of Compound 105 to be divided into, e. g., 20 drops each corresponding to 0. 1 microgram of Compound 105.

Example 14 Injection Fluid Containing Compound 105 Compound 105 (active substance) 10 ug 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 105 is dissolved in the solution obtained. The solution is subjected to sterile filtration and is autoclaved at an appropriate time-temperature condition.

Example 15 1 (S), 3 (R)-Dihydroxy-20 (R)-(2-chloro-4-((1-hydroxy-1- methyl) ethyl)) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 112 Method : General Procedure 3.

Starting materials : Compound (iii) and Compound 33.

13C NMR : 8 = 148. 0, 147. 7, 142. 6, 134. 9, 133. 6, 133. 3, 128. 6, 126. 0, 124. 8, 123. 3, 117. 3, 111. 8, 72. 1, 70. 8, 66. 8, 56. 1, 55. 8, 45. 8, 45. 3, 42. 9, 40. 3, 39. 9, 35. 2, 31. 7, 29. 0, 27. 0, 23. 6, 22. 1, 19. 1, 12. 5.

Example 16 1 (S), 3 (R)-Dihydroxy-20 (R)- (2-bromo-4- ( (1-hydroxy-1- methyl) ethyl)) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 113 Method : General Procedure 3.

Starting materials : Compound (iii) and Compound 37.

C NMR : 8 = 148. 0, 147. 7, 142. 5, 136. 9, 133. 3, 129. 3, 128. 2, 124. 8, 124. 0, 123. 8, 117. 3, 111. 8, 71. 9, 70. 8, 66. 8, 56. 1, 55. 9, 45. 8, 45. 3, 42. 9, 40. 3, 35. 1, 31. 7, 29. 0, 27. 0, 23. 6, 22. 1, 19. 1, 12. 5.

Example 17 1 (S), 3 (R)-Dihydroxy-20 (R)-(4-((1-hydroxy-1-methyl) ethyl)-3- methyl) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 114 Method : General Procedure 3.

Starting materials : Compound (iii) and Compound 41.

13C NMR : 8 = 147. 4, 143. 1, 142. 4, 136. 3, 135. 7, 133. 0, 132. 6, 125. 7, 125. 6, 124. 6, 117. 0, 111. 6, 73. 2, 70. 6, 66. 6, 55. 9, 55. 6, 45. 6, 45. 0, 42. 7, 40. 4, 40. 1, 35. 2, 30. 7, 28. 8, 26. 7, 23. 3, 21. 9, 18. 7, 12. 3.

Example 18 1 (S), 3 (R)-Dihydroxy-20 (R)-(4-((1-hydroxy-1-methyl) ethyl)-2- methoxy) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 115 Method : General Procedure 3.

Starting materials : Compound (iii) and Compound 45.

C NMR : 8 =157. 3, 148. 6, 147. 7, 142. 6, 133. 3, 129. 3, 124. 8, 123. 6, 117. 3, 117. 0, 111. 8, 107. 1, 72. 5, 70. 8, 66. 8, 56. 1, 55. 9, 55. 8, 45. 8, 45. 3, 42. 9, 40. 3, 39. 1, 35. 4, 31. 8, 29. 0, 27. 0, 23. 6, 22. 1, 19. 0, 12. 4.

Examples 19 1 (S), 3 (R)-Dihydroxy-20 (R)- (2, 6-dimethoxy-4- ( (1-hydroxy-1- methyl) ethyl)) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 116 Method : General Procedure 3.

Starting materials : Compound (iii) and Compound 49.

Example20 1 (S), 3 (R)-Dihydroxy-20 (R)- (4- ( (l-hydroxy-1-methyl) ethyl)-2- methyl) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 117 Method : General Procedure 3.

Starting materials : Compound (iii) and Compound 53.

Example 21 1 (S), 3 (R)-Dihydroxy-20 (R)-(2, 6-dichloro-4-((1-hydroxy-1- methyl) ethyl)) phenylthiomethyl-9, 10-seco-pregna-5 (Z), 7 (E), 10 (19)-triene, Compound 108 Method : General Procedure 3.

Starting materials : Compound (iii) and Compound 57.