IE60921B1

IE60921B1 - Dehydrocholecalciferol derivatives

Info

Publication number: IE60921B1
Application number: IE15789A
Authority: IE
Original assignee: Hoffmann La Roche
Priority date: 1988-01-20
Filing date: 1989-01-19
Publication date: 1994-09-07
Also published as: FI890283A0; FI890283A; ES2033467T3; PT89486A; PT89486B; NO175429B; ATE74350T1; IL88989A0; DK169945B1; DK19789A; HU201007B; JPH0764806B2; GR3004786T3; FI90764B; YU47298B; FI90764C; BG60530B2; DK19789D0; IE890157L; MC1998A1

Abstract

The novel compounds of the formula in which R is hydrogen or hydroxyl and A is -C IDENTICAL C-; -C=CH- having the E-configuration or -CH2-CH2-, can be used as agents for the treatment of hyperproliferative skin diseases and as agents for the treatment of neoplastic diseases.

Description

Description The invention relates to compounds of the formula wherein R is hydrogen or hydroxy and A is -C=C-, -CH=CHwith the E-configuration or -CH2-CH2-, to pharmaceutical preparations containing one or more compounds of formula I and to the use of these compounds for the manufacture of such preparations useful in the treatment of hyperproliferative skin diseases such as psoriasis and for the treatment of neoplastic diseases such as leukaemia.

The invention also relates to a process for the manufacture of a medicament, whereby the active ingredient, namely one or more compounds of formula I, Is brought Into a form usable for therapeutic purposes together with a pharmaceutically suitable carrier material and further adjuvants, characterized by manufacturing a medicament for the treatment of hyperproliferative skin diseases and of neoplastic diseases consisting of the combination of a preparation containing one or more compounds of formula i and the information which is directly related to the treatment of the said diseases.

Examples of Ci.4-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Examples of aryl-Ci-4-alkyl groups are benzyl, phenethyl and phenylpropyl. Examples of aryl groups are phenyl and p-tolyl. Halogen denotes bromine, chlorine, fluorine or iodine.

The following compounds A to F fall under formula I: A: 1,25-dihydroxy-16-dehydrocholecalciferol; B: 25-hydroxy-16-dehydrocholecalciferol; G 1,25-dihydroxy-16,23E-bisdehydrocholecalciferol; D: 25-hydroxy-16,23E-bisdehydrocholecalciferol; E: 1,25-dihydroxy-16-dehydro-23-didehydrocholecalciferol; and F: 25-hydroxy-16-dehydro-23-didehydrocholecalciferol; with the 1,25-dihydroxylated compounds A, C and E being preferred.

The compounds of formula I, i.e. those of formulae la and lb, can be prepared as described in Schemes 1, 2 and 3 by reacting a corresponding compound of formula I which contains instead of two or three hydroxy groups two or three protected hydroxy groups of the formula -OSi(Ri,R2,R3) wherein Ri and R3 represent Ci.4-alkyl and R2 represents Ci-4-alkyl, aryl or aryl-Ci.4-alkyl, with an agent suitable for cleaving off the protecting groups.

Scheme 1 wherein A, R-ι, R2 and R3 have the above significance.

Scheme 2 wherein Ri, R2 and R3 have the above significances Scheme 3 XI·· wherein Rq, R2 and R3 have the above significances, X is chlorine, bromine or iodine and Ts is tosyl.

The intermediates of formula II, i.e. those of formulae Ila, lib and lie, are novel and are an object of the invention.

In Scheme I, a compound of formula II is converted into that of formula IVa or IVb by reaction with the corresponding compound of the formula wherein Ph is phenyl; R4 is hydrogen or -OSi(Ri, R2, R3) and Ri, R2 and R3 have the above significance.

The reaction is carried out at *60 to 90°C, preferably -75°C, in a polar, aprotic, organic solvent, e.g. dry ether or preferably dry tetrahydrofuran (THF), in the presence of a strong base, such as an alkyl lithium, e.g. butyl lithium.

The protecting groups in a compound of formula IVa or IVb are removed by reaction with a fluorine salt, e.g. tetrabutylammonium fluoride in a polar, organic solvent, e.g. ether or preferably THF. The corresponding compound of formula la or Ib is obtained.

In Scheme 2, the compound of formula V is oxidized to that of formula VI. For this purpose there is used e.g. 2,2’-bipyridinium chlorochromate or preferably pyridinium chlorochromate in an aprotic, organic solvent such as methylene chloride.

The compound of formula VI is converted into that of formula lib, e.g. by reacting with a trialkylsilylimidazole such as trimethylsilylimidazole in an aprotic, organic solvent such as THF or preferably methylene chloride.

The compound of formula V can also be partially hydrogenated to that of formula VII, e.g. by reaction with a reducing agent such as lithium aluminium hydride, preferably in the presence of an alkali metal alkoxide, e.g. sodium methoxide, in an aprotic, organic solvent, e.g. ether or preferably THF, at reflux temperature (about 68°C for THF). The reaction takes about 10-20 hours.

The compound of formula VII obtained is oxidized to the compound of formula VIII as described above for the oxidation of V to VI.

The compound of formula VIII is converted into that of formula Ila by reaction with a trialkylsilylimidazole as described above for the conversion of VI to lib.

In Scheme 3, a compound of formula X is reacted in an ether, preferably THF, at reflux temperature with magnesium. The resulting Grignard solution is treated firstly with cuprous iodide and then with the compound of formula IX.

The compound of formula XI obtained is reacted with a fluoride, e.g. tetrabutylammonium fluoride in ether or preferably THF.

The compound of formula XII obtained can be oxidized as described above for the oxidation of V to VI.

The compound of formula XIII obtained is converted into that of formula lie by treatment with a trialkylsilylimidazole as described above for the conversion of VI into lib.

For the preparation of a compound of formula IX, a compound of the formula (Tetrahedron 40, 1984, 2283) is reacted with a tosylating agent 5 such as a p-toluenesulphonyl halide, e.g. the chloride, in an organic base, e.g. collidine or preferably pyridine. The resulting compound of the formula XV is then converted into that of formula IX by reaction of a trialkylsilyl chloride, e.g. trimethylsilyl chloride, in the presence of imidazole and in an aprotic organic solvent, e.g. THF or methylene chloride.

For the preparation of a compound of formula X, a compound of the formula X-CH2CH2COCH3 XVI is converted into that of the formula X-CH2CH2C(CH3)2-OH XVII wherein X has the above significance, by reaction with a methylGrignard reagent such as methylmagnesium bromide in ether. The compound of formula XVII is converted into one of formula X by reaction with a trialkylsilyl chloride as described above for the conversion of XV into IX.

For the preparation of a compound of formula V, a compound 5 of formula XV is reacted with a cyanide-forming agent, e.g. sodium cyanide, in an aprotic, organic solvent, e.g. dimethyl sulphoxide (DMSO), at a temperature between 80 and 100°C for 1-5 hours. There is obtained a compound of the formula This is converted into the compound of the formula by reaction with a reducing agent, e.g. diisobutylaluminium hydride, followed by hydrolysis, e.g. with a mineral acid such as hydrochloric acid. The reduction is conducted in an aprotic, organic solvent, e.g. methylene chloride, at about -10 to 10°C for 20 to 90 minutes. The compound of formula XIX is converted into that of the formula 1 Br C—Br HO XX by reaction with a mixture of triphenylphosphine, carbon tetrabromide and zinc dust in a aprotic, organic solvent, e.g. methylene chloride, for about 1 to 30 hours.

The compound of formula XX is converted into that of the formula HO XXI by reaction with a strong base, e.g. butyl lithium, in a polar aprotic solvent, e.g. THF, at about -80 to -70°C, for about 1 to 3 hours. The compound of formula XXI is converted into that of the formula Me3SIO XXII by reaction with trimethylsilylimidazole in an aprotic, organic solvent, e.g. THF or methylene chloride. This compound is converted into that of the formula 2 xxm by reaction with a strong base, e.g. butyl lithium, and then with acetone. The reaction is conducted in an aprotic, organic solvent, e.g. THF, at about -80 to -60°C. The compound of formula XXIII is converted into that of formula V (in Scheme 2) by reaction with a fluoride, e.g. tetrabutylammonium fluoride in an organic solvent, e.g. ether or THF.

The compounds of formula I stimulate the differentiation of and decrease the proliferation of human keratinocytes. io Accordingly, they can be used as medicaments for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders or keratinization and keratosis. The compounds of formula I are also useful as medicaments for the treatment of neoplastic diseases such as leukaemia.

The activity of the compounds of formula I as agents for the treatment of hyperproliferative skin diseases can be demonstrated accordingly to methods known per se, e.g. as set forth in The Society for Investigative Dermatology 1986, 709-714. The effects of compounds A to F on the morphologic differentiation of cultured human keratinocytes compared with the effect of 1,25dihydroxycholecalciferol (compound X) are given in Tables 1 to 4 as the number (x104) of cultured human keratinocytes. A compound which induces the differentiation of basal cells to squamous cells and envelope cells is suitable for the treatment of skin diseases which are characterized by keratinization disorders, such as psoriasis. 3 Table. 1 Compound Dose (M) Number of cells (x104): Total number Basal cells Squamous Envelope cells cells Control 133±5 118±4 15±1 18±2 X 10-10 122±4 103±2 19±2 23±1 10-e 112±6 89±2 23±4 30±3 10-6 95±7 64±6 31±1 34±2 A 10-10 132±8 115±7 17±1 27±2 10-6 128±10 106±8 22±2 33±2 10-6 101±7 71±5 30±2 39±2 B 10-1° 133±6 115±5 18±1 25±1 10-6 131±4 109±2 22±2 29±2 IO*6 104±4 74±3 30±1 33±1 4 Table 2 Compound Dose Number of ceils (xIO4): (M) Total Basal Squamous Envelope number cells cells cells Control 123±7 105±6 18±1 74±7 X 10-10 116±9 95±8 21±1 91 ±4 10*® 101±10 75±8 26±2 122±11 IO-θ 83±5 57±4 26±1 146±16 c 10-1° 117±4 92±2 25±2 103±6 io-® 108±3 80±2 28±1 128±3 1 0*6 80±7 54±6 26±1 153±1 D 10-10 113±7 93±6 20±1 104±10 10-6 111±7 86±3 25±2 128±5 10-6 94±3 68±1 26±2 144±7 I F> y.ablo 3 Compound Dose Number of cells (x104): (M) Total Basal Squamous Envelope number cells cells cells Control 108±10 93±8 15±2 88±8 X 10-10 106±7 86±6 18±1 100±9 10-8 84±8 61±5 23±3 122±8 10-8 73±7 51 ±5 22±2 142±11 E 10-10 86±4 63±2 23±2 114±5 10-8 82±3 53±2 29±1 141 ±5 10-8 78±3 41 ±1 27±2 147±4 F 10-10 103±5 81 ±3 22±2 103±10 10-8 97±3 67±2 29±1 121 ±6 10-6 84±4 55±2 29±1 137±7 The activity of the compounds of formula I as agents for the treatment of hyperproliferative skin diseases can also be demonstrated by determining the number of human keratinocytes, envelope cells and squamous carcinoma cell lines (SCC-115) formed in the presence of said compounds.

The results are given in the Tables 4 and 5: β Table-4 Treatment Dose (M) Number of keratinocytes (x104) Number of envelope cells (x102) Control (0.1% ethanol) 189.49±22.3 858.28±185.70 Compound E 10-12 187.36±15.33 1136.63± 383.66 10--10 175.34±10.19 1444.87± 312.47 10-8 145.79±15.66 2113.62±1049.33 10 10-6 41.95± 7.53 1916.83± 887.66 Control (0.1% ethanol) 148.73±16.23 2193.7± 921.9 Compound A 10-12 114.91±10.95 1662.2± 420.1 10*1° 130.37±24.32 3973.8± 126.99 10-8 120.67±16.87 7235.2± 55.5 10-8 109.22±15.87 8323.5± 157.6 7 Table 5 Treatment Dose (M) Number of cell lines (SCC-15) (x10-5) Control 7.35±1.75 Compound E 10-12 6.98±1.68 10-10 5.89±1.58 10-8 5.76±1.53 10-8 0.40±0.98 Compound A 10-8 0.49±0.13 The above results show that the compounds of formula I induce the differentiation of skin cells and accordingly are usable in the treatment of hyperproliferative skin diseases such as psoriasis.

In order to demonstrate the activity of the compounds of formula I as agents for the treatment of neoplastic diseases, the antiproliferative (AP) and the differentiation-inducing (DI) effects of compounds A to F and the number of human promyelocytic HL-60 tumour cells were evaluated. In Table 6 the AP effect is given as the percentage reduction in the number of cells and as the concentration ID50 which reduced the number of cells by 50%. The DI effect is given as the percentage of differentiated cells and as the concentration ED50 of the compounds which induces a 50% differentiation of the cells. s Iabls_S Concentration (x10*8M) % Reduction in cell number IDso (x 10*®M) Differentiated cells (%) ED50 (x10'8M) Compound X 6 3 0.01 0.1 5 11 1 16 2 19 2 10 66 68 100 84 98 Compound A 0.01 10 3 0.1 33 16 1 84 0.2 92 0.2 10 85 97 100 85 98 Compound B 0.1 10 5 1 8 4 10 14 35 6 32 100 82 93 1000 95 95 l 9 Compound C 0.01 0.1 1 10 100 18 20 81 85 86 0.3 3 19 92 97 99 Compound D 0.1 12 1 1 12 2 10 17 150 17 100 46 31 1000 95 97 Compound E 0.01 6 9 0.1 59 50 1 80 0.07 96 10 81 98 Compound F 0.1 13 4 1 10 12 10 8 70 21 100 58 55 1000 95 91 0.3 200 0.1 These results show that the compounds of formula I inhibit 25 the proliferation of human promyelocytic cells in vitro and at the same time have no cell toxicity. Furthermore, the cells differentiate toward a more mature phenotype at the same dosages which inhibit proliferation. From these results it will be evident that these compounds can be used as medicaments for the treatment of neoplastic diseases such as leukaemia.

For the treatment of neoplastic diseases of for the treatment of hyperproliferative skin diseases, the compounds of formula I can be administered orally to warm-blooded animals which need such treatment, e.g. to an adult human, in a dosage in the range of about 0.1 to 10 pg per day.

For the treatment of hyperproliferative skin diseases, the compounds of formula I can also be administered topically to warm-blooded animal in a daily dosage of about 1 to 1000 pg/g of topical formulation.

For oral administration the compounds of formula I can be incorporated e.g. into capsules or tablets together with pharmaceutically acceptable carriers. Examples of such carriers for capsules are binders such as tragacanth, gums or gelatine; excipients such as dicalcium phosphate; disintegrating agents such as corn starch; lubricants such as magnesium stearate; sweetening agents such as sucrose; flavoring agents such as peppermint. Tablets can be coated with shellac, sugar or both. A syrup or elixir can contain a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring agent.

Topical dosage forms containing compounds of formula I are ointments and creams consisting of oleaginous, resorbable, water-soluble and emulsion-type bases such as lanolin and polyethylene glycols. Other topical dosage forms are gels, lotions, powders and aerosols. The topical preparations can also be used in the treatment of inflammations of the skin and mucous membranes, e.g. of the mouth or lower colon.

Lotions, i.e. liquid preparations such as solutions or hydroalcoholic preparations, which contain substance in powder form, can contain, in addition to the active ingredient, suspending or dispersing agents such as cellulose derivatives, e.g. ethyl or methyl cellulose; gelatine or gums, as well as a vehicle such as water, alcohol or glycerol. Gels are semi-solid preparations which are prepared from a solution or suspension of the active ingredient in a vehicle. The aqueous or anhydrous vehicles are treated with a gelling agent, e.g. carboxypolymethylene, and neutralized with a base, e.g. sodium hydroxide or an amine such as polyethylenecocoamine.

Examala .3 a) A mixture of 3.24 g of (1(R*),3aR*-(3ap,4a,7aa)]3a,4,5,6,7,7a-hexahydro-4-hydroxy-p,7a-dimethyl-3H-indene-1ethanol, 30 ml of pyridine and 3.51 g of p-toluenesulphonyl chloride is stirred at 0°C for 18 hours. After the addition of ice and dilution with water, the mixture is extracted with methylene chloride. The organic phase is washed with 1N H2SO4 and saturated NaHCO3, then dried and evaporated. The residue is chromatographed over silica gel with ethyl acetate-hexane (1:1:5). There are obtained 4.61 g (82%) of [1(R*),3aR*(3ap,4 b) To a solution of 4.61 g of the product of a) in 22 ml of DMSO are added 1.10 g of sodium cyanide and the mixture is heated at 90°C for 2 hours. After cooling to room temperature, the solvent is removed under reduced pressure. The mixture is diluted with water and then extracted with ether. The organic phase is washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with methylene chloride-hexane-ethyl acetate (86:7:7). There are obtained 2.52 g (91%) of (1(R*),3aR*-(3aP,4a,7a c) To a mixture of 6.85 mi of diisobutylaluminium hydride in hexane and 5.2 ml of methylene chloride at -6°C is added a solution of 0.430 g of the product of b) in 10 mi of methylene chloride. The mixture is stirred at -6°C for 55 minutes. After £2 the addition of saturated ammonium chloride, the mixture is hydrolyzed with 3N HCI-ether (2:1). The aqueous layer is extracted with ether. The organic layers are washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:2). There are obtained 260 mg (60%) of [1(R*),3aR*-(3ap,4a,7aa)]-3a,4,5,6,7, 7a-hexahydro-4-hydroxy-p,7a-dimethyl-3H-indene-1-propanal, [a]?+43.1° (c 0.32, CHCI3). d) A mixture of 1.77 g of triphenylphosphine, 2.23 g of carbon tetrabromide, 441 mg of zinc dust and 23 ml of methylene chloride is stirred at 25°C for 31 hours. To the mixture is added a solution of 0.430 g of the product of c) in 38 ml of methylene chloride and the mixture is stirred for 18 hours. The mixture is diluted with pentane and insoluble material is filtered off. The insoluble fraction is dissolved in methylene chloride and the solution is again diluted with pentane. After filtration, the combined filtrates are evaporated. The residue is purified on silica gel with 1:4 ethyl acetate-hexane. There is obtained 0.490 g (67%) of [1(R‘),3aR‘-(3ap,4a,7aa)]-1-(4,4-dibromo-1methyl-3-butenyl)-3a,4,5,6,7,7a-hexahydro-7a-methyl-3Hinden-4-ol, [a]?+14.4° (c 0.55, CHCI3). e) To a solution of 0.680 g of the product of d) in 31 ml of THF at -75°C are added dropwise 3.77 ml of a 1.6M solution of butyl lithium in hexane. The mixture is stirred at -75° for 1 hour and at 25°C for 1 hour. After the addition of saturated brine, the mixture is diluted with ether. The organic phase is washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:4). There is obtained 0.350 g (89%) of [1(R*),3aR‘-(3ap,4a,7aa)]-3a,4,5,6,7, 7a-hexahydro-7a-methyl-1-(1-methyl-3-butynyl)-3H-inden-4ol, [a]" +30.70 (C 0.42, CHCI3). f) To a solution of 1.29 g of the product of e) in 80 ml of methylene chloride are added 3.59 g of 1 -(trimethylsilyl)imidazole. The mixture is stirred for 3 hours. After adding 40 ml of water and stirring for 20 minutes, the mixture is extracted with ethyl acetate. The organic phase is washed with water and saturated brine, dried and evaporated. The residue is purified on silica gel with ethyl acetate-hexane (1:15). There are obtained 1.70 g (99%) of [1(R*),3aR*-(3ap,4a,7aa)]-3a,4,5,6,7, 7a-hexahydro-7a-methyl-1 -(1 -methyl-3-butynyl)-4-[(trimethylsilyl)oxy]-3H-indene, [aft+39.7° (c 0.30, CHCI3). g) To a solution of 1.70 g of the product of f) in 48 ml of THF at -75°C are added dropwise 6.01 ml of 1.6M butyl lithium in hexane. After stirring for 40 minutes, 3.05 ml of acetone are added and the mixture is stirred at -75°C for 20 minutes and at 25°C for 75 minutes. After the addition of 40 ml of a 1:1 mixture of 2M KHCO3 and 1M potassium sodium tartrate, the mixture is stirred for 20 minutes and then extraced with ethyl acetate. The organic phase is washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate hexane (1:5). There are obtained 1.62 g (89%) of [1 (R*),3aR*-(3ap,4a,7a h) To a solution of 1.62 g of the product of g) in 53 ml of THF are added 15.5 ml of 1M tetrabutylammonium fluoride in THF.

The mixture is stirred for 50 minutes. After dilution with halfconcentrated NaHCO3, the mixture is evaporated to remove most of the solvent and extracted with ethyl acetate. The organic phase is washed with half-concentrated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:1). There are obtained 1.17 g (82%) of [1(R‘),3aR*-(3ap,4a,7aa)]-3a,4,5,6,7,7a-hexahydro-1-(1,5dimethyl-5-hydroxy-3-hexynyl)-7a-methyl-3H-inden-4-ol, m.p. 105-107°. i) To a solution of 0.720 g of the product of h) in 44 ml of methylene chloride are added 1.59 g of sodium acetate and 3.18 g of 2,2'-bipyridinium chlorochromate. The mixture is stirred for 2 hours. After the addition of 1.59 g of 2,2’bipyridinium chlorochromate, the stirring is continued for hours. After the addition of 6 ml of 2-propanol, the mixture is diluted with water and extracted with ether-ethyl acetate (1:1). The organic phase is washed with water, 1N H2SO4, saturated NaHC03 and saturated brine. The solution is evaporated and the residue is chromatographed on silica gel with ethyl acetatehexane (1:1). There is obtained 0.560 g (78%) of [1(R*),3aR*(3ap,7aa)]-3,3a,4,5,6,7,7a-hexahydro-1 -(5-hydroxy-1,5dimethyl-3-hexynyl)-7a-methyl-4H-inden-4-one, [aft+35.3° (c 0.36, CHCI3). j) To a solution of 0.552 g of the product of i) in 70 ml of methylene chloride are added 2.00 g of 1 -(trimethylsilyl)imidazole. After stirring for 17 hours and adding 22 ml of water, the mixture is extracted with ethyl acetate. The organic phase is washed with water and saturated brine, then dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:4). There is obtained 0.693 g (99%) of [1 (R*),3aR‘-(3ap,7aa)]-3,3a,4,5,6,7,7a-hexahydro-1 -(1,5dimethyl-5-[(trimethylsilyl)oxy]-3-hexynyl)-7a-methyl-4Hinden-4-one, [aft+29.5° (c 0.20, CHCI3). k) To a solution of 2.00 g of [3S-(1Z,3a,5p)]-[2-[3,5-bis[[(1,1dimethyl)dimethylsilyl]oxy]-2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide in 45 ml of THF at -75°C are added dropwise 1.87 ml of 1.6M butyl lithium in hexane. After stirring for 6 minutes, a solution of 0.693 g of the product of j) in 26 ml of THF is added dropwise. After stirring at -75°C for 70 minutes and adding a 1:1 mixture of 1M potassium sodium tartrate and 2M KHCO3, the mixture is extracted with ethyl acetate. The organic phase is washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:15). There are obtained 1.23 g (87%) of (1 α,3β,5Ζ,7Ε)-1,3-bis[[1,1 -dimethylethyl)dimethylsilyl]oxy]-25[(trimethylsilyl)oxy]-9,10-secocholesta-5,7,10(19),16-tetraen3-yne, [aft+47.1° (c 0.21, CHCI3).

I) To a solution of 0.228g of the product of k) in 11 ml of THF are added 1.92 ml of 1M tetrabutylammonium fluoride in THF.

The mixture is stirred for 16 hours. After dilution with water, the mixture is extracted with ethyl acetate. The organic phase is washed with semi-saturated brine and saturated brine, dried and evaporated. The residue is purified on silica gel with ethyl acetate-hexane (3:1). There is obtained 0.126 g (96%) of 1,25dihydroxy-16-dehydro-23-didehydrocholecalciferol, [a]*+21.5 (c 0.20, MeOH).

Examcls_2 a) As described in Example 1k), but starting from 0.343 g of [5S-(1 Z)]-[2-[5-[[(1,1 -dimethylethyl)dimethylsilyl]oxy]-2methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.186 g of the product of Example 1j), there is obtained 0.205 g (80%) of (3p,5Z,7E)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]25-[(trimethy Isily l)oxy]-9,10-secocholesta-5,7,10(19),16tetraen-23-yne, MS m/e 580 (M+). b) By treating 0.248 g of the product of a) as described in Example 11) there is obtained 0.153 g (91%) of 25-hydroxy-16dehydro-23-didehydrocholecalciferol, [a]* + 99.6° (c 0.25), MeOH).

Example. 3 a) To a mixture of 0.146 g of lithium aluminium hydride, 0.211 g of sodium methoxide and 6.5 ml of THF at 0°C is added dropwise a solution of 0.180 g of the product of Example 1h) in 13 ml of THF. The mixture is heated at 68°C for 16 hours and then cooled to 0°C. After dilution with 13 ml of ether and the addition of 0.30 ml of water and 0.26 ml of 10% aqueous NaOH, the mixture is stirred at room temperature for 1 hour and filtered. The solids are mixed with ether and filtered. The combined filtrates are evaporated and chromatographed on silica gel with ethyl acetate-hexane (1:2) and there is obtained 0.179 g (99%) of [1(R*),1(3E),3ap,43). b) To a solution of 0.120 g of the product of a) in 10 ml of methylene chloride are added 0.500 g of pyridinium dichromate and 25 mg of pyridinium p-toluenesulphonate. The mixture is stirred for 135 minutes. After the addition of 40 ml of ether, the mixture is stirred for 5 minutes and filtered. The solids are mixed with ether and filtered. The combined filtrates are washed with saturated aqueous CUSO4, water, semi-saturated aqueous NaHCO3 and saturated brine. The organic phase is dried and evaporated. The residue is chromatographed on silica gel with % ethyl acetate-hexane. There are obtained 90 mg (76%) of [1(R‘),1(3E),(3ap,7aa)]-3,3a,5,6,7,7a-hexahydo-1-(5-hydroxy1,5-dimethyl-3-hexenyl)-7a-methyl-4H-inden-4-one, [a]" + 30.6° (c 0.17, CHCI3). c) By treating 0.099 g of the product of b) as described in Example 1j) there is obtained 0.111 g (89%) of [1(R‘),1(3E), (3ap,7aa)]-3,3a,5,6,7,7a-hexahydro-1 -(1,5-dimethyl-5[(trimethylsilyl)oxy]-3-hexenyl)-7a-methyl-4H-inden-4-one, [a]204 + 24.60 (c 0.22, CHCI3). d) As described in Example 1k), starting from 0.265 g of [3S20 (1Z,3a,5p)]-[2-[3,5-bis[[(1,1-dimethyl)dimethylsilyl]oxy]-2methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.095 g of the product of c) there is obtained 0.162 g (83%) of (1 β,3α,5Ζ,7Ε,23Ε)-1,3-bis[[(1,1 -dimethylethyl)dimethylsilyl]oxy25-[(tri methy Isily I) oxy]-9,10-secocholesta-5,7,10(19),16,2325 pentaene, MS m/e 712 (M+). e) By treating 0.159 g of the product of d) as described in Example 11) there is obtained 0.077 g (84%) of 1,25-dihydroxy16,23E-bisdehydrocholecalciferol, [a] + 46.5° (c 0.20, MeOH).

Example 4 a) As described in Example 1k), starting from 0.225 g of [5S(1 Z)]-[2-[5-[[(1,1 -dimethylethyl)dimethylsilyl]oxy]-2-methylenecyciohexylidene]ethyl]diphenylphosphine oxide and 0.110 g of the product of Example 3c) there is obtained 0.150 g (81%) of 2? (3β,5Ζ,7Ε,23Ε)-3-([(1,1-dimethylethyl)dimethylsilyl]oxy]-25[(trimethy Isily l)oxy]-9,1O-secocholesta-5,7,10(19),-16,23pentaene, [a]2o + 68.3° (c 0.18, CHCI3). b) By treatment of 0.144 g of the product of a) as described in Example 11) there is obtained 0.076 g (78%) of 25-hydroxy16,23E-bisdehydrocholecalciferol, [a]" + 62.5° (c 0.20, MeOH).

Example 5 a) To a solution of 6.25 g of ethyl 3-bromopropionate in 26 ml of THF at -20°C are added 28.8 ml of 2.8M methylmagnesium bromide in ether. The mixture is stirred at room temperature for 170 minutes. After the addition of 15 ml of saturated aqueous ammonium chloride and 42 ml of 1N HCl, the organic phase is separated and the aqueous phase is extracted with ether. The organic extracts are washed with saturated brine, dried and evaporated. The residue is chromatographed on silica gel with 30% ethyl acetate-hexane. There are obtained 2.57 g (45%) of 4bromo-2-methyl-2-butanol, MS m/e 151 (M+-CH3). b) To a solution of 2.56 g of 4-bromo-2-methyl-2-butanol and 4.86 g of imidazole in 15 ml of Ν,Ν-dimethylformamide at 0°C are added 6.48 g of chlorotriethylsilane. The mixture is stirred at room temperature for 200 minutes. After adding ice, the mixture is diluted with water and extracted with pentane. The organic phase is washed with water and saturated brine, dried and evaporated. The residue is chromatographed on silica gel with pentane. There are obtained 4.02 g (93%) of (3-bromo-1,1dimethylpropoxy)triethyls»lane, MS m/e 265 (M+-CH3). c) To a solution of 0.930 g of [1(Π*),3βΠ*(33β,4α,73α)]3a,4,5,6,7,7a-hexahydro-4-hydroxy^,7a-dimethyl-3H-indene-1ethanol 4-methyl-benzenesulphonate and 1.10 g of imidazole in 73 ml of methylene chloride at 0°C is added 0.580 g of chlorotriethylsilane. The mixture is stirred at room temperature for 1.5 hours. After adding ice, the mixture is diluted with water and stirred for 20 minutes. The organic layer is extracted with 2H methylene chloride. The extracts are washed with water, 1N N2SO4, saturated, aqueous NaHCO3 and saturated brine. After drying and evaporation, the residue is purified on silica gel with ethyl acetate-hexane (1:5). There are obtained 1.22 g (100%) of [1 (R*),3aR*-(3ap,4a,7aa)]-3a,4,5,6,7,7a-hexahydro-4-[(triethylsilyl)oxy]-p,7a-dimethyl-3H-indene-1 -ethanol 4-methylbenzenesulphonate, [a]" +46.1° (c 0.31, CHCI3). d) To a solution of 3.08 g of (3-bromo-1,1-dimethylpropoxy)triethylsilane in 31 ml of THF is added 0.282 g of magnesium.

The mixture is heated at 68°C for 3.5 hours. Then, a mixture of 0.686 g of cuprous iodide together with the above-mentioned Grignard solution stirred at 3°C for 30 minutes. A solution of 1.02 g of the product of c) is added and the mixture is stirred at room temperature for 40 minutes. After adding a mixture of ice and water, the mixture is extracted with ether. The organic phase is washed with 1N H2SO4 and saturated aqueous NaHCO3, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:15). There are obtained 1.80 g of [1 (R‘),3aR*-(3ap,4a,7aa)]-3a,4,5,6,7,7a-hexahydro-1 -[1,520 dimethyl-5-[(triethylsilyl)oxy]hexyl]-4-[(triethylsilyl)oxy]-7amethyl-3H-indene, MS m/e 479 (M+-Et). e) To a solution of 1.60 g of the product of d) in 5 ml of THF are added 2.00 ml of 1M tetrabutylammonium fluoride in THF.

The mixture is heated at 68°C for 50 minutes. After cooling to room temperature, the mixture is diluted with water and extracted with methylene chloride. The organic phase is washed with brine, dried and evaporated. The residue is purified on silica gel with ethyl acetate-hexane (1:1). There is obtained 0.420 g (79%) of [1(R*),3aR*-(3ap,4aa,7aa)]-3a,4,5,6,7,7a-hexahydro-43θ hydroxy-a,201 +12.0° (c 0.25, CHCI3). f) To a solution of 0.210 g of the product of e) in 18 ml of methylene chloride is added 0.870 g of pyridinium dichromate and 44 mg of pyridinium p-toluenesulphonate. The mixture is qc stirred for 175 minutes. After the addition of 50 ml of ether I the mixture is stirred for 5 minutes and filtered. The solids are washed with saturated aqueous CuSO< solution, water, semisaturated aqueous NaHCO3 and saturated brine. The organic phase is dried and evaporated. The residue is chromatographed on silica gel with 35% ethyl acetate-hexane. There is obtained 0.175 g (84%) of [1 (R*),3aR*-(3ap,7aa)]-3,3a,5,6,7,7a-hexahydro-1-(5hydroxy-1,5-dimethylhexyl)-7a-methyl-4H-inden-4-one, [aft +28.20 (c 0.22, CHCI3). g) By treating 0.168 g of the product of f) as described in Example 1j) there is obtained 0.211 g (100%) of [1(R‘),3aR*(3ap,7aa)]-3,3a,4,5,6,7,7a-hexahydro-1 -(1,5-dimethyl-5[(trimethylsilyl)oxy]hexyl)-7a-methyl-4H-inden-4-one, [a]20° +21.90 (c 0.27, CHCI3). h) As described in Example 1k), but starting from 0.581 g of [3S-(1Z,3a,5p]-[2-[3,5-bis[[(1,1-dimethyl)dimethylsilyl]oxy]-2methylenecyclohexylidene]ethyl]diphenylphosphine oxide and 0.210 g of the product of g), there is obtained 0.358 g (83%) of (1α,3β,5Ζ,7Ε)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-25[(trimethylsilyl)oxy]-9,10-secocholesta-5,7,10(19),16-tetraene, MS m/e 714 (M+). i) Treatment of 0.350 g of the product of h) as described in Example 11) gives 0.168 g (83%) of 1,25-dihydroxy-16-dehydrocholecalciferol, [aft +40.0° (c 0.17, MeOH).

Example 6 a) As described in Example 1k), starting from 0.383 g of [5S(1 Z)]-[2-[5-[[(1,1 -dimethylethyl)dimethylsilyl]oxy]-2-methylenecyclohexlidene]ethyl]diphenylphosphine oxide and 0.188 g of the product of Example 5g) there is obtained 0.245 g (78%) of (3a,5Z,7E)-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-25[trimethylsilyl)oxy]-9,10-secocholesta-5,7,10(19),16-tetraene, [aft+67.5° (c 0.20, CHCI3). b) Treatment of 0.239 g of the product of a) as described in Example 11) gives 0.135 g (83%) of 25-hydroxy-16-dehydrocholecalciferol, [aft +75.4° (c .13, MeOH).

The composition of soft gelatine capsules for oral 5 administration and of a topical cream is given in Examples A and B hereinafter: Example A mqZcattsule Compound E 0.0001-0.010 Butylated hydroxytoluene 0.016 Butylated hydroxyanisole 0.016 Fractionated coconut oil 160.0 Example B ma/α of cream Compound E 0.001-1.0 Cetyl alcohol 1.5 Stearyl alcohol 2.5 Sorbitan monostearate Glyceryl monostearate and polyoxyethylene 2.0 20 glycol stearate 4.0 Polysorbate 60 1.0 Mineral oil 4.0 Propylene glycol 5.0 Propylparaben 0.05 25 Butylated hydroxyanisole 0.05 Sorbitol solution 2.0 Edetate disodium salt 0.01 Methylparaben 0.18 Distilled water q.s. to 100 g 1

Claims

Claims 1.25- dihydroxy-16,23E-bisdehydrocholecalciferol and 1.25- Dihydroxy-16-dehydro-23-didehydrocholecaiciferol,

1. A compound of the formula wherein R is hydrogen or hydroxy and A is -CsC-,

2. A compound in accordance with claim 1 from the following group:

3. 3

4. A compound in accordance with claim 1 or 2 for use as a therapeutically active substance, especially for the treatment of hyperproliferative skin diseases, particularly of psoriasis, or for the treatment of neoplastic diseases, particularly of 5. And exemplified.

5. A process for the preparation of a compound according to claim 1 or 2, characterized by reacting a corresponding compound of formula I which contains instead of two or three hydroxy groups two or three protected hydroxy groups of the io formula -OSi(Ri,R2,R3) wherein Ri and R3 are Ci-4-alkyl and R2 is Ci-4-alkyl, aryl or aryl-Ci-4-alkyI, with a reagent suitable for removing the protecting groups. 15

6. A medicament, especially for the treatment of hyperproliferative skin diseases, particularly of psoriasis, or for the treatment of neoplastic diseases, particularly leukaemia, comprising an effective amount of a compound according to claim 1 or 2 and a pharmaceutical carrier material, especially for oral 20 or topical administration. 5 leukaemia. 5 -CH-CH- with the E-configuration or -CH2-CH2-.

7. The use of a compound in accordance with claim 1 or 2 for the manufacture of a medicament for the treatment of hyperproliferative skin diseases, particularly of psoriasis, or for the treatment of neoplastic diseases, particularly of leukaemia.

8. A compound according to claim 1, substantially as hereinbefore described and exemplified.

9. A process for the preparation of a compound according to claim 1, substantially as hereinbefore described

10. A compound according to claim 1, whenever prepared by a process claimed in a preceding claim. 10 1,25-dihydroxy-16-dehydrocholecalciferol. wherein A is -CH=CH- with the E-configuration, -CH2-CH2 or especially -CsC- and Ri and R3 are independently C1.4alkyl, especially methyl, and R2 is Ci.4-alkyl, especially methyl, aryl or aryl-Ci.4-alkyl.

11. A medicament according to claim 6, substantially as hereinbefore described and exemplified.