BG60530B2 - Dehydrocholecalciferoles - Google Patents

Abstract

The compounds are used as an agent for the treatment of hyperproliferative skin diseases and as an agent for the treatment of neoplastic diseases. They have a formula where r is hydrogen or a hydroxyl group and a is -c=c-, -cn=cns configuration or -cn2-cn2-. 7 claims

Description

(54) DEHYDROCHOLECADCIFEROLS

The invention relates to compounds of formula

wherein R is hydrogen or a hydroxyl group and A is -C = C-, -CH = CH- with the E-configuration or -CH ₂ -CH ₂ -, a pharmaceutical composition containing one or more compounds of formula I, and the use of these compounds for the preparation of such preparations for the treatment of hyperproliferative skin diseases such as psoriasis and for the treatment of neoplastic diseases such as leukemia.

The invention also relates to a method for the preparation of medicaments in which the active ingredient, namely one or more compounds of formula I, together with a pharmaceutically acceptable carrier and other excipients, is formulated in a therapeutically acceptable form, to obtain a medicament for treatment of hyperproliferative skin diseases and neoplastic diseases, comprising a combination of a preparation containing one or more compounds of formula I and information in direct connection with the treatment of said this disease.

Examples of C-alkyl groups are methyl, stylish, propyl, isopropyl, butyl and tert-butyl. Examples of the aryl C _1-4 alkyl group are benzyl, phenethyl and phenylpropyl. Examples of aryl groups are phenyl and p-tolyl. Halogen means 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;

C: 1,25-dihydroxy-16,23E-bisdehydrochol is calcium cyferol;

D: 25-hydroxy-16,23 E-bisdehydrocholecal cyferol;

E: 1,25-dihydroxy-16-dihydro-23-didehydrocholecalciferol and

F: 25-hydroxy-16-dehydro-23-didehydrocholecalciferol, wherein 1,25-dihydroxylated compounds A, C and E are preferred.

The compounds of formula I, i. those of formulas 1a and 1b may be prepared as described in Schemes 1, 2 and 3 as the corresponding compound of formula I, which instead of two or three hydroxyl groups contains two or three protected hydroxyl groups of formula

-OSi (R, R ₂ , Rj) where R, u R ₃ denote a C ₄ -alkyl residue and R 1 represents a C _(4- alkyl, aryl or aryl-C ₄ -alkyl residue) reacted with a cleavable reagent of the protecting groups.

SCHEME 1

where A, R _r R ₂ and R ₃ have the above meanings

SCHEME 2

V

VII

where R _{| (} R ₂ and R ₃ have the above meanings

SCHEME 3

where R _p R ₂ and R ₃ have the above meanings, X is chlorine, bromine or iodine and Ts is a tosyl residue.

The intermediate is Formula II. for example, compounds of formula IIa, IIb and Ps are novel and object of the invention.

In Scheme 1, the compounds of formula II are converted to compounds of formula IVa or IVb by reaction with the corresponding compound of formula

h where Ph denotes a phenyl moiety, R ₄ denotes hydrogen or -OOSi (R _p R ₂ and R ₃ ) u R _p R ₂ and R ₃ have the above meanings.

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

The protecting groups in the compound of formula IVa or IVb may be removed with a fluorine salt, e.g., tetrabutylammonium fluoride, in a polar, organic solvent, e.g. ether or preferably tetrahydrofuran. The corresponding compound of formula Ia or Ib is obtained.

In Scheme 2, the compound of formula V is oxidized to a compound of formula VI. For this it 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 to a compound of formula IIb, e.g. by reaction with trialkylsilylimidazole, such as trimethylsilylimidazole, in an aprotic, organic solvent such as THF or preferably methylene chloride.

The compounds of formula V may also be hydrogenated to compounds of formula VII, e.g. by reaction with a reducing agent such as lithium aluminum hydride, preferably in the presence of alkali metal oxides, in an aprotic, organic solvent, e.g. ether, or preferably THF, at reflux temperature (about 68 ° C for THF), the reaction lasts for about 1020 h.

The resulting compound of formula VII can be oxidized to a compound of formula VIII, as described for the oxidation of compounds of formula V to compounds of formula VI.

The compounds of formula VIII can be converted to compounds of formula IIa by reaction with trialkylsilylimidazole, as described above, for the conversion of compounds of formula VI into compounds of formula IIb.

In Scheme 3, a compound of formula X is reacted with magnesium in ether, preferably THF, at reflux temperature. The resulting Grignard solution is first reacted with copper (I) iodide and then with a compound of formula IX.

The resulting compound of formula XI is reacted with fluoride, e.g. tetrabutylammonium fluoride in ether or preferably tetrahydrofuran.

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

The resulting compound of formula XIII can be converted to a compound of formula Pc by treatment with trialkylsilylimidazole, as described above for the conversion of a compound of formula VI to a compound of formula IIb.

To obtain a compound of formula IX, a compound of formula

(Tetrahedron 40, 1984, 2283) interacts with a tosylating agent such as ptoluene sulfonyl halide e.g. organic chloride, e.g. colidine or preferably pyridine. The resulting compound of formula

e.g. methylene chloride at about -10 to 10C for 20 to 90 minutes. The compound of formula XIX is converted to a compound of formula then converted to a compound of formula IX by reaction with trialkylsilyl chloride, e.g. trimethylsilyl chloride, in the presence of imidazole and imidazole , an organic solvent, e.g. THF or methylene chloride.

For preparing a compound of of formula X, the compound of formula X-CH ₂ CH ₂ COCH ₃ XVI is converted to the compound of formula

X-CH ₂ CH ₂ C (CH ₃ ) ₂ -OH XVII where X has the above meanings by reaction with a methyl-Grignard reagent such as methylmagnesium bromide in ether. The compound of formula XVII can be converted to a compound of formula X by reaction with trialkylsilyl chloride as described for the conversion of a compound of formula XV to a compound of formula IX.

For the preparation of a compound of formula V, a compound of formula XV is reacted with a cyanide-forming agent, e.g. sodium cyanide, in an aprotic, organic solvent, for example dimethyl sulfoxide (DMSO), at a temperature between 80 and 100 ° C for 1-5 hours.

by reaction with a mixture of triphenylphosphine, tetrabromomethane and zinc powder, in an aprotic, organic solvent, e.g. methylene chloride for about 1 to 30 hours

The compound of formula XX can be converted to a compound of formula

by reacting with a strong base, for example butyllithium, in a polar, aprotic, organic solvent, e.g. THF, at about -80 to -70 ° C for about 1 to 3 hours. The compound of formula XXI is converted to the compound of formula

This compound is converted to a compound of formula

by reacting with trimethylsilylimidazole in an aprotic, organic solvent, e.g. THF or methylene chloride. This compound is converted to a compound of formula by reaction with a reducing agent, e.g. diisobutylaluminum hydride, followed by hydrolysis, e.g. with an inorganic acid such as hydrochloric acid. The reduction is carried out in aprotic, organic solvent,

by interacting with a strong base, e.g. butyl lithium and then with acetone.

The reaction is carried out in an aprotic, organic solvent, e.g. THF, at 80 ° to -60 ° C. The compound of formula XX111 is converted to a compound of formula V (in Scheme 2) by reaction with fluoride, e.g., -5 tetrabutylammonium fluoride, in an organic solvent, e.g. ether or THF.

The compounds of formula I stimulate differentiation and reduce the proliferation of human keratocytes. Therefore, they can be used as a treatment for hyperproliferative skin diseases such as psoriasis, basal cell carcinoma, disorders of keratinization and keratosis. The compounds of formula I can also be used as a treatment for neoplastic diseases such as leukemia.

The activity of the compounds of formula I as a treatment for hyperproliferative diseases can be demonstrated by known methods, e.g. as described in The Society for Investigative Dermatolgv 1986, 709714. The effects of compounds A to F on the morphological differentiation of cultured human keratocytes compared to the effect of 1,25-dihydroxycholecalciferol (compound X) are given in Tables 1 to 4 as a number (xyOH cultured human keratinocytes. A compound that induces the differentiation of basal cells to flat-footed cells and keratinized flat-footed cells is suitable for the treatment of skin diseases characterized by disorders of keratinization, such as psoriasis.

Table 1

Connect- opinion The dose (M) Number of cells (x10 ⁴ ): Total number Basal cells Flat-dish cells Keratinized squamous epithelial cells Cont- roll 133 ± 5 118 ± 4 15 ± 1 18 ± 2 X Yu Yu 122 ± 4 103 ± 2 19 + 2 23 ± 1 10 ⁸ 112 ± 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 ⁸ 128 ± 10 106 ± 8 22 + 2 33 ± 2 10 ⁶ 10 1 ± 7 71 ± 5 30 + 2 39 ± 2 IN 10 y 133 ± 6 115 ± 5 18 + 1 25 ± 1 10 ⁸ 13 1 ± 4 109 ± 2 22 ± 2 29 ± 2 10 ⁶ 104 ± 4 74 ± 3 30 ± 1 33 ± 1

Table 2

Connect- The dose singing (M) Total number Cell Number (x10 ⁴ ): Basal Flat Cells Epithelial Cells Keratinized squamous epithelial cells

Con- roll 123 7 105 ± 6 18 + 1 74 ± 7 X 10 ¹⁰ 116 ± 9 95 ± 8 21 + 1 91 ± 4 ⁸ 101 ± 10 75 ± 8 26 + 2 122 ± 11 10 ⁶ 83 ± 5 57 ± 4 26 + 1 146 ± 16 p 10 1 ° 117 + 4 92 ± 2 25 + 2 103 ± 6 10 ⁸ 108 ± 3 80 ± 2 28 + 1 128 ± 3 10 ⁶ 80 ± 7 54 ± 6 26 + 1 153 ± 1 D ¹⁰ 113 ± 7 93 ± 6 20 + 1 104 ± 10 y · ⁸ 111 ± 7 86 + 3 25 + 2 128 ± 5 10 ⁶ 94 ± 3 68 + 1 26 + 2 144 ± 7

Table 3 Compound Dose (M) number Common cells Basal cells Number of cells (x10 ⁴ ) Keratinized flat-dish cells

Cont- roll 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 ⁶ 73 ± 7 51 + 5 22 + 2 142 ± 11 Well 10 ¹⁰ 86 ± 4 63 ± 2 23 + 2 114 ± 5 10 ⁸ 82 ± 3 53 ± 2 29 + 1 141 + 5 10 ⁶ 78 ± 3 41 ± 1 27 + 2 147 + 4 F The 10th 103 ± 5 81 ± 3 22 + 2 103 ± 4 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 a treatment for hyperproliferative skin diseases can also be determined by the number of human keratocytes, keratinized squamous cells, and squamous cell carcinoma cell lines (SCC-115) that are formed in the presence of said compounds.

The results are given in Tables 4 and 5. 5

Table 4

Treatment The dose (M) Number of keratinocytes (x! 0 ') Number of keratinized squamous cells (x10 ⁴ Control (0.1% etho- zero) 189.49 ± 22.3 858.28 ± 185.70 Comp. Well 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 ⁶ 41.95 ± 7.53 1916.83 ± 887.66

Control (0.1% etho- zero) 148.73 16,23 2193,7 921,9 Comp. A 10 ¹² 114.91 ± 10.95 1662.2 ± 420.1 10 ¹⁰ 130.37 ± 24.32 3973.8 ± 126.99 10 ⁸ 120.67 ± 16.87 7235.2 ± 55.5 10 ⁶ 109.22 ± 15.87 8323.5 ± 157.6

Table 5 Treatment The dose Number of cell lines (M) (SCC-15) (x10 ⁵ ) Control 7.35 ± 1.75 Comp. Well 10 ¹² 6.98 ± 1.68 10 ¹⁰ 5.89 ± 1.58 10 ⁸ 5.76 ± 1.53 10 ⁶ 0.40 ± 0.98 Comp. A 10 ⁶ 0.49 ± 0.13

The above results indicate that the compounds of formula I induce skin cell differentiation and can therefore be used to treat hyperproliferative skin diseases such as psoriasis.

To demonstrate the activity of the compounds of formula I as a treatment for neoplastic diseases, the antiproliferative (AP) and differentially induced <D1) effect of the compounds A to F, as well as the number of human promyelocytic tumor cells HL-60, were established. Table 6 shows the AP effect as a percentage reduction in cell count and concentration

An ID that reduces the number of cells by 50%. DI-sfektat is given as the percentage of differentiated cells and as the concentration of ED _J0 compounds which osigurya10 watt 50% differentiation of the cells.

Table 6

Concentration ^ED 50 (HJ M) % reduction in cell count cells (x10 ⁸ M) Differentiated % ed ₅ o (xlO'M Compound X 0.01 6 3 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 Compound C 0.01 18 3 0.1 20 19 1 81 0.3 92 0.3 10 85 97 100 86 99 Compound D 0.1 12 1 1 12 2 10 17 150 17 200 100 46 31 1000 95 97 Compound E 0.01 6 9 0.1 59 50

1 80 0.07 96 0.1 10 81 98 Compound F 0.1 13 4 1 10 12 10 8 70 21 70 100 58 55 1000 95 91

These results indicate that the compounds of Formula I suppress in vitro proliferation of human promyelocytic cells, and thus exhibit no cellular toxicity. The cells later differentiate to the mature phenotype at the same doses that inhibit proliferation. It follows from these results that these compounds can be used as a treatment for neoplastic diseases such as leukemia.

The compounds of formula I may be administered orally for the treatment of neoplastic diseases or for the treatment of hyperproliferative skin diseases in warm-blooded patients requiring the same treatment, e.g. in adults at a dosage in the range of 0.110 mg per day.

For the treatment of hyperproliferative skin diseases, the compounds of formula I may also be administered topically in warm blood at a daily dose of about 1 to 1000 mg / g topical formulation.

For oral administration, the compounds of formula I can be prepared, e.g. such as capsules or tablets, together with a pharmaceutically acceptable carrier. Examples of such capsule carriers are binders such as tragacanth, gum or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch; glidants such as magnesium stearate; sweeteners such as sucrose; flavoring agents such as mint. The tablets may be coated with shellac, sugar or both components. The syrup or elixir may contain a sweetener, methyl and propyl paraben as a preservative, colorant and flavoring agent.

Topical dosage forms containing the compounds of formula I are ointments and creams consisting of oily, absorbable, water-soluble and emulsion-like bases such as lanolin and polyethylene glycol. Other dosage forms for topical administration are goals, lotions, powders and aerosols. Topical formulations can be used to treat inflammation of the skin and mucous membranes, e.g. the oral cavity or the large intestine.

Lotions, ie liquid preparations such as solutions, for example aqueous or hydroalcoholic preparations, which contain the substance in powder form may also contain suspending or dispersing agents such as cellulose derivatives, e.g. ethyl or methylcellulose, gelatin or gums, and a carrier such as water, alcohol or glycerol in addition to the active ingredient. Gels are semi-solid preparations which are prepared from a solution or suspension of the active substance in a carrier. Water or water-free media are treated with a gelling agent, e.g. carboxypolymethylene and neutralized with a base, e.g. sodium hydroxide or amine such as polyethylene cocoamine.

Example 1

a) Oizot3ZDD [1 (R *), ZAK * - Ga β, 4a, 7aa)] 3a, 4,5,6,7,7a-hexahydro-4-hydroxy), 7a-dimethyl-3H-indene-1 ethanol, 30 ml pyridine and 3.51 g p-toluenesulfonyl chloride were stirred for 18 hours at 0 ° C. After the addition of ice and dilution with water, the mixture was extracted with methylene chloride. The organic phase was washed with 1 N H ₂ SO ₄ and saturated NaHCO ₃ solution. it is then dried and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate-hexane (1: 1.5). 4.61 g (82%) of [1 (R *), 3aR * - (3a / R, 4a, 7aa) J3a, 4,5,6,7a-hexahydro-4-hydroxy- / 1, 7a- are obtained. dimethyl-3H-inden-1-ethanol-4-methylbenzenesulfonate, [α ²¹ ] _at + 31.9 ° (c 0.53, CHCl ₃ ).

c) To a solution of 4.61 g of product a) in 22 ml of dimethylsulfoxide was added 1.10 g of sodium cyanide and the mixture was heated at 90 ° C for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The mixture was diluted with water and then extracted with ether. The organic phase was washed with saturated sodium chloride solution, dried and evaporated. The residue was chromatographed on silica gel eluting with methylene chloride; hexane: ethyl acetate (86: 7: 7). 2.52 g (91%) [KR], 3aR * - (3a D 4α, 7aa)] - 3a, 4, 5, 6, 7, 7a-hexahydro-4-hydroxy-, 7a-dimethyl- 3H-indene-1-propanenitrile, [α ²¹ ] _D + 29.2 ° (c 0.65, CHCl ₃ ).

c) To a mixture of 6.85 ml of diisobutylaluminum hydride in hexane and 5.2 ml of methylene chloride was added at -6 ° C a solution of 0.430 g of product c) in 10 ml of methylene chloride. The mixture was stirred for 55 min at -6 ° C. After the addition of saturated ammonium chloride, the mixture was hydrolyzed with 3N HCl (2: 1). The aqueous layer was extracted with ether. The organic layers were washed with saturated sodium chloride solution, dried and evaporated. The residue was chromatographed on silica gel with ethyl acetate: hexane (1: 2). Obtained 260 mg (60%) [1 (R *), 3aR »- (3a) 3, 4α, 7aa)] - 3a, 4, 5, 6, 7, 7a-hexahydro-4hydroxy-β, 7a-dimethyl -H-indene-1 propanol, [α ²² ] _D + 43.1 ° (c 0.32, CHCl ₃ ).

d) A mixture of 1.77 g of triphenylphosphine, 2.23 g of tetrabromomethane, 441 mg of zinc powder and 23 ml of methylene chloride was stirred at 25 ° C for 31 h. A solution of 0.430 g of product c) in 38 ml of methylene chloride was added to the mixture and the mixture was stirred for 18 hours. The mixture was diluted with pentane and the insoluble product filtered. The insoluble fraction was dissolved with methylene chloride and the solution was diluted once again with pentane. After filtration, the combined filtrates were evaporated. The residue was purified on silica gel with 1: 4 ethyl acetate: hexane. 0.490 g (67%) of [1 (R *), 3aR * - (3a β, 4α, lafi)] - 1- (4,4-dibromo-1-methyl-3-butenyl) -3a, 4 are obtained. 5, 6, 7, 7a-hexahydro-7a-methyl 3 H -inden-4-ol, [α ²¹ ] _D + 14.4 ° (c 0.55, CHCl ₃ ).

e) To a solution of 0,680 g of product

d) 3.77 ml of a 1.6M solution of butyllithium in hexane was added dropwise at 31 ΙΤΧΦηΙΤΧΦ at -75 ° C. The mixture was stirred for 1 h at -75 ° and 1 h at 25 ° C. After the addition of saturated sodium chloride solution, the mixture was diluted with saturated aqueous NaHCO ₃ solution and extracted with ether. The organic phase was washed with saturated sodium chloride solution, dried and evaporated. The residue was chromatographed on silica gel with ethyl acetate: hexane (1: 4).

0.350 g (89%) of [HR *), 3aR &apos; -methyl-3-butynyl-3H-inden-4-ol, [cc ²² ] _L + 30.7 &quot; (with 0.42. CHCl _{3 was obtained} ).

f) To a solution of 1.29 g of product c) in 80 ml of methylene chloride was added 3.59 g of 1 (trimethylsilyl) imidazole. The mixture was stirred for 3 hours. After the addition of 40 ml of water and stirring for 20 min, the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried and evaporated. The residue was purified on silica gel with ethyl acetate: hexane (1:15). Obtained 1.70 g (99%) [1 (R 1), 3aR 1 - (3a / 3, 4α, 7aa)] - 3a, 4, 5, 6, 7, 7a-hexahydro-7a-methyl-1 - (1-methyl-3-butynyl) -4 - [(trimethylsilyl) oxy] -3H-indene, [α ²⁰ ] _at + 39.7 ° (c 0.30, CHCl ₃ ).

g) To a solution of product f) 1.6M butyllithium in hexane was added dropwise into 48 ml THF at -75 ° C. After 40 minutes of stirring, 3.05 ml of acetone was added and the mixture was stirred for 20 minutes at -75 ° C and 75 minutes at 25 ° C. After adding 40 ml of a 1: 1 mixture of 2M KHCO ₃ and 1M potassium tartrate, the mixture was stirred. was stirred for 20 minutes and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried and evaporated. The residue was chromatographed on silica gel with ethyl acetate: hexane (1: 5). 1.62 g (89%) of [1 (R1), 3aR1 - (3a / S, 4α, 7aa)) - 6 (3a, 4, 5, 6, 7, 7a-hexahydro-7a-methyl) are obtained. -4 - [(trimethylsilyl) oxy] -3H-inden-1-yl) -2-methyl-3heptin-1-ol, [α ²⁰ ] _D + 39.7 ° (c 0.30, CHCl ₃ ).

h) To a solution of 1.62 g of product g) in 53 ml of tetrahydrofuran was added 15.5 ml of 1M tetrabutylammonium fluoride in THF. The mixture was stirred for 50 min. After dilution with semi-concentrated NaHCO ₃ , the mixture was evaporated to remove most of the solvent and extracted with ethyl acetate. The organic phase was washed with semi-concentrated sodium chloride solution, dried and evaporated. The residue was chromatographed on silica gel with ethyl acetate: hexane (1: 1). 1.17 g (82%) of [1 (R 1), 3aR * - (3a / S, 4α, 7aa)] - 3a, 4, 5, 6, 7, 7a-hexahydro-1 (1.5 -dimethyl-5-hydroxy-3-hexynyl) -7a-methyl-3H-inden-4-ol, mp 105-107 ° C.

i) To a solution of 0.720 g of product h) in 44 ml of methylene chloride was added 1.59 g of sodium acetate and 3.18 g of 2,2'-bipyridinium chlorochromate. The mixture was stirred for 2 h. After the addition of 1.59 g of 2,2'-bipyridinis chlorochromate, stirring was continued for 2 h. After the addition of 6 ml of 2-propanol, the mixture was diluted with water and extracted with ether: ethyl acetate (1: 1). The organic phase was washed with water, INH ₂ SO ₄ , saturated NaHCO ₃ solution and saturated sodium chloride solution. The solution was evaporated and the residue was chromatographed on silica gel with ethyl acetate: hexane (1: 1). 0.560 g (78%) of [1 (R *), 3aR * - (3a0, 7aa)] - 3, 3a, 5, 6, 7, 7a-hexahydro-1- (5-hydroxy-1,5- dimethyl-3-hexynyl) -7a-methyl-4Ninden-4-one, [a ^a1 ] _O +35,3 (c 0.36, CHCl ₃ ).

j) To a solution of 0.552 g of product i) in 70 ml of methylene chloride was added 2.00 g of 1 (trimethylsilyl) imidazole. After stirring for 17 h and adding 22 ml of water, the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, then dried and evaporated. The residue was chromatographed on silica gel with ethyl acetate: hexane (1: 4). 0.693 g (99%) (1 (R *), 3aR * - (3a / R, 7aa)] - 3, 3a, 5, 6, 7, 7a-hexahydro-1- (1,5-dimethyl- 5 [(trimethylsilyl) -oxy] -3-hexynyl) -7a-methyl-4H-inden-4-one, [a ²⁰ ] _D +29.5 (c0.20, CHCl ₃ ).

k) To a solution of 2.00 g [3s- (1Z, 3α, 5β)] [2- [3,5-bis- [[(1,1-dimethylethyl) dimethylsilyl] oxy] -2-methylenecyclohexylidene] ethyl] diphenylphosphine oxide in 45 ml THF at 75 ° C was added 1.87 ml of 1.6M butyllithium in hexane. After stirring for 6 min, a solution of 0.693 g of product j) in 26 ml of THF was added dropwise. After 70 min stirring at -75 ° C and adding a 1: 1 mixture of 1M potassium sodium tartrate and 2M KHCO ₃ , the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried and evaporated. The residue was chromatographed on silica gel with ethyl acetate: hexane (1:15). 1.23 g (87%) are obtained (Ια, 3β, 5Ζ, 7Ε) -

1,3 bis [[(1,1-dimethylethyl) dimethylsilyl] oxy] -25- [(trimethylsilyl) -oxy] -9,10-secolesta-5, 7, 10 (19), 16-tetraen-3-yn , [α ¹ '] D + 47.1 ^O (c 0.21, CHCl 3).

l) To a solution of 0.228 g of product k) in 11 ml of THF was added 1.92 ml of 1M tetrabutylammonium fluoride in THF. The mixture was stirred for 16 h. After dilution with water, the mixture was extracted with ethyl acetate. The organic phase was washed with semi-saturated sodium chloride solution and saturated sodium chloride solution, dried and evaporated. The residue was purified on silica gel with ethyl acetate: hexane (3: 1). 0.126 g (96%) of 1,25-dihydroxy-16-dihydro-23-didehydrochatecatecifer 1, [α ²¹ ], + 21.5 (with 0.20, MHOH) is obtained.

Example 2.

a) As described in Example 1 k) but starting from 0.343 g [5S- (1Z)] - [2- [5 [[(1,1-dimethylethyl) dimethylsilyl] oxy] -2methylene cyclohexylidene] ethyl] diphenylphosphine oxide and 0.186 g of the product of Example lj) gave 0.205 g (80%) (3/3, 5Ζ, 7E) -3 - [[(1,1 dimethylethyl) dimethylsilyl] oxy] -25- [(trimethylsilyl) -oxy] - 9,10-secolesterol-5, 7, 10 (19), 16-tetraen-23-yn, MS m / e 580 (M +).

b) Treatment of 0.248 g of product a) as described in Example 11) gave 0.153 g (91%) of 25-hydroxy-16-dehydro-23-didehydrohalecalciferol, [a ²¹ ] _at + 99.6 ° (c 0.25, MeOH).

Example 3.

a) To a mixture of 0.146 g of lithium aluminum hydride, 0.211 g of sodium methoxide and 6.5 ml of THF at 0 ° C was added a solution of 0.180 g of product lh) in 13 ml of THF. The mixture was heated at 68 ° C for 16 h and then cooled to 0 ° C. After diluting with 13 ml of ether and adding 0.30 ml of water and 0.26 ml of 10% aqueous sodium hydroxide, the mixture was stirred for 1 h at room temperature and filtered. The solid was stirred with ether and filtered. The combined filtrates were evaporated and chromatographed on silica gel with ethyl acetate: hexane (1: 2) to give 0.179 g (99%) [1 (R *), 3E), 3ζβ, 4a, 7aa)] - (3a. 4. 5, 6, 7, 7a) -hexahydro-1- (5-hydroxy-1,5-dimethyl-3-hexenyl) -7a-methyl-1H-inden-4ol, [a ²¹ ] _D + 11.5 ° (c 0.33, CHCl ₃ ).

b) To a solution of 0,120 g of the product a) in 10 ml of methylene chloride was added 0,500 g of pyridinium dichromate and 25 mg of pyridinium ptoluene sulfonate. The mixture was stirred for 135 min. After the addition of 40 ml of ether, the mixture was stirred for 5 min and filtered. The solid was stirred with ether and filtered. The combined filtrates were washed with saturated aqueous CuSO ₄ , water, semi-saturated aqueous NaHCO ₃ solution and saturated sodium chloride solution. The organic phase is dried and evaporated. The residue was chromatographed on silica gel with 35% ethyl acetate-hexane. Obtained 90 mg (76%) [1 (R *), KCE), (3ζβ, 7aa) -3,

For, 5, 6, 7, 7a-hexahydro-1- (5-hydroxy-1,5-dimethyl-3-hexenyl) -7a-methyl-4H-inden-4-one, [a ²⁵ ], + 30,6 ° (c 0.17, CHCl3.

c) Treatment of 0.099 g of product b), as described in example lj), yields 0.11 lg (89%) (1 (R *), KZE), (3b, 7aa)] 3, 3a, 5, 6, 7, 7a-hexahydro-1- (1,5-dimethyl-

5- [(trimethylsilyl) oxy] -3-hexenyl) -7a-methyl-4H-inden-4-one, [α ²⁴ ] _O + 26.4 ° (c 0.22, CHCl ₃ ).

d) As described in Example 1k), starting from 0.265 g [3S- (1Z, 3a, 5β)) - (2 [3,5-bis [[(1,1-dimethylethyl) dimethylsilyl] oxy] - 2-methylenecyclohexylidene] ethyl] diphenylphosphinoxide and 0.095 g of product c), 0.162 g (83%) ((β, 3a, 5Ζ, 7Ε, 23Ε) 1, 3bis [[(1,1-dimethylethyl) dimethylsilyl] is obtained oxy] -25- [(trimethylsilyl] oxy] -9,10-secolesta-5, 7, 10 (19), 16, 23-pentaene, MS m / e 712 (M +).

e) Treatment of 0.159 g of product d) as described in Example 11) gave 0.077 g (84%) of 1,25-dihydroxy-16,23E-bisdehydrocholecalciferol, [α ²ⁱ ] _D + 46.5 ° (c 0.20, MeOH).

Example 4.

a) As described in Example 1k) starting from 0.225 g of [5S- (1Z)] - [2- [5 - [[(1, dimethylethyl) dimethylsilyl] oxy] -2-methylenecyclohexylidene] ethyl] dimethylphosphine oxide and 0.110g of product 3c), 0.150g (81%) (3β, 5Ζ, 7Ε, 23Ε) -3 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -25- [(trimethylsilyl) oxy] - 9,10-secolesterol-5, 7, 10 (19), 16, 23-pentaene, [α ²⁴ ] _with + 68.3 ° (e 0.18, CHCl ₃ ).

b) Treatment of 0.144 g of product a) as described in example 11) gave 0.076 g (78%) of 25-hydroxy-16,23bis-dehydrocholecalciferol, [α ²² ) ₀ +62,5 (by 0.20) , Meon).

Example 5.

a) To a solution of 6.25 g of 3-bromoethylpropionate in 28 ml of THF at -20 ° C was added 28.8 ml of 2.8M methylmagnesium bromide in ether. The mixture was stirred for 170 min at room temperature. After the addition of 15 ml of saturated aqueous ammonium chloride solution and 42 ml of IN HCl, the organic phase was separated and the aqueous phase was extracted with ether. The organic extract was washed with saturated sodium chloride solution, dried and evaporated. The residue was chromatographed on silica gel with 30% ethyl acetate-hexane. 2.57 g (45%) of 4bromo-2-methyl-2-butanol, MS m / e 151 (M + CH ₃ ) are obtained.

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 dimethylformamide, 6.48 g of chlorotriethylsilane was added at 0 ° C. The mixture was stirred for 200 min at room temperature. After the addition of ice, the mixture was diluted with water and extracted with pentane. The organic phase was washed with water and saturated sodium chloride solution, dried and evaporated. The residue was chromatographed on silica gel with pentane. 4.02 g (93%) (3-bromo-1,1-dimethylpropoxy) triethylsilane, MS m / e 265 (M + -CH ₃ ) are obtained.

c) To a solution of 0.930 g [1 (R *), 3aR * (3a ?, 4a, 7aa)] - 3a, 4, 5, 6, 7, 7a-hexahydro-4-hydroxy-N, 7a- dimethyl-3H-inden-1-ethanol-4-methyl-benzosulfonate and 1.10 g of imidazole in 73 ml of methylene chloride at 0 ° C was added 0.580 g of chlorotriethylsilane. The mixture was stirred for 1.5 h at room temperature. After the addition of ice, the mixture was diluted with water and stirred for 20 min. The organic layer was extracted with methylene chloride. The extract was washed with water, INH ₂ SO ₄ , saturated aqueous NaHCO ₃ and saturated sodium chloride solution. After drying and evaporation, the residue was purified on silica gel with ethyl acetate: hexane (1: 5). 1.22 g (100%) of [1 (R *), 3aR * - (3a β, 4a, 7acr)] - 3a, 4, 5, 6, 7, 7a-hexahydro-4- [(triethylsilyl) are obtained oxy] -, 7adimethyl-3H-inden-1-ethanol-4-methyl-benzosulfonate [a ²⁰ ] _c + 46.1 ° (c 0.31, CHCl ₃ ).

d) To a solution of 3.08 g (3-bromo-1,1-dimethylpropoxy) -triethylsilane in 31 ml THF was added 0.282 g of magnesium. The mixture was heated at 68 ° C for 3.5 h. Then a mixture of 0.686 g of copper (1) -iodide was stirred together with the aforementioned Grignard solution for 30 min at 3 ° C. A solution of 1.02 g of product c) was added and the mixture was stirred for 40 min at room temperature. After adding a mixture of ice and water, the mixture was extracted with ether. The organic phase was washed with 1N sulfuric acid, saturated aqueous NaH ₃ CO ₃ , dried and evaporated. The residue was chromatographed on silica gel with ethyl acetate: hexane (1:15). 1.80 g of [1 (R *), 3aR * (3ζβ, 4α, 7aa)] - 3a, 4, 5, 6, 7, 7a-hexahydro 1- [1,5-dimethyl-5- [(triethylsilyl) are obtained ) oxy] -hexyl] -4 - [(triethylsilyl) oxy] -7a-methyl-3H15 indene, MS m / c 479 (M + -Et).

e) To a solution of 1.60 g of product d) in 5 ml of THF was added 2.00 ml of 1M tetrabutylammonium fluoride in THF. The mixture was heated at 68 ° C for 50 min. After cooling to room temperature, the mixture was diluted with water and extracted with methylene chloride. The organic phase was washed with brine, dried and evaporated. The residue was purified on silica gel with ethyl acetate: hexane (1: 1). 0.420 g (79%) of [1 (R *), 3aR * - (3a / l, 4aa, 7aa) j-3a, 4, 5, 6, 7, 7a-hexahydro-4hydroxy-a, a, - ε, 7a-tetramethyl-1H-inden-1pentanol, [α ²¹ ] _D + 12.0 ° (c 0.25, CHCl ₃ ).

f) To a solution of 0.210 g of the product f) 0.870 g of pyridinium dichromate and 44 mg of pyridinium ptoluenesulfonate are added in 18 ml of methylene chloride. The mixture was stirred for 175 min. After the addition of 50 ml of ether, the mixture was stirred for 5 min and filtered. The solid was washed with saturated aqueous CuSO ₄ , water, semi-saturated aqueous NaHCO ₃ and saturated sodium chloride. The organic phase is dried and evaporated. The residue was chromatographed on silica gel with 35% ethyl acetate-hexane. 0.175 g (84%) of [(R *), 3aR * - (3a £, 7aa,)] - 3, 3a, 5, 6, 7, 7a-hexahydro-1- (5-hydroxy-1,5dimegitecate are obtained ) -7a-megyl-4H-icden-4-one, [N, 4, + 28.2 ^O (c 0.22, CHCl ₃ ).

g) Treatment of 0.168 g of product f) as described in Example 1 j) gave 0.211 g (100%) [1 (R *), 3aR * - (3a / ?, 7aa)] 3, , 5, 6, 7, 7a-Hexahydro- (1,5-dimethyl-5 [(trimethylsilyl) oxy] -7a-methyl-4H-inden-4one, [a ²⁰ ] _O + 21.9 (c 0.27 , CHC1 ₃ ).

h) As described in Example 1k) but starting from 0.581 g [3S- (1Z, 3α, 5β)] - [2 [3,5-bis [[(1,1-dimethylethyl) dimethylsilyl] oxy] -2-methylcyclohexylidene] ethyl] diphenylphosphine oxide and 0.210 g of product g), 0.588 g (83%) (1a, 3β, 5Ζ, 7Ε) -1,3bis [[(1,1-dimethylethyl) dimethylsilyl] oxy] is obtained 25 - [(trimethylsilyl) oxy] -9,10-secolesta-5, 7, 10 (19), 16-tetraene, MS m / e 714 (M +).

i) Treatment of 0.350 g of product h) as described in example 11) gave 0.168 g (83%) of 1,25-dihydroxy-16-dehydrocholecal cyferol, [α ²⁰ ] _D + 40.0 ° (c 0 , 17, MEON).

Example 6

a) As described in Example 1k) starting from 0.383 g of [5S- (1Z)] - [2- [5 - [[(1-dimethylethyl) dimethylsilyl] oxy] -2-methylenecyclohexylidene] ethyl] diphenylphosphine oxide and 0.188 g from the product of Example 5g) gave 0.245 g (78%) (3α, 5Z, 7E) -3- [[(1.1d methylethyl) dimethylsilyl] oxy] -25 - [(trimethylsilyl)] oxy] - 9. 10-secolssta-5, 7, 10 (19), 16-tetraene, [a ²⁴ ] _with + 67.5 ° (with 0.20, CHCl ₃ ).

b) Treatment of 0.239 g of product a) as described in Example 11 gave 0.135 g (83%) of 25-hydroxy-16-dehydrocholecalciferol, [α ²³ ] _O + 75.4 ° (by 0.13, Meon).

The following Examples A and B show the composition of soft gelatin capsules for oral use and topical cream:

Example A mg / capsule

Compound E 0,0001-0,010 Butylhydroxytoluene 0.016 Butylhydroxyanisole 0.016 Fractionated coconut butter 160,0 Example B mg / g cream Compound E 0,001-1,0 Cetyl alcohol 1.5 Stearyl alcohol 2.5 Sorbitan monostearate 2.0 Glyceryl monostearate and polyoxy-ethylene- glycol stearate 4.0 Polysorbate 60 1.0 Mineral oil 4.0 Propylene glycol 5.0 Propyl paraben 0.05 Butylhydroxyanisole 0.05 Sorbitol solution 2.0 EDTA-disodium salt 0.01 Methylparaben 0.18 Distilled water up to 100 g

Claims (6)

Patent claims 1. Compound with formula where R represents hydrogen or a hydroxyl group and A represents -C=C-, -CH=CH- with E-configuration or -CH ₂ -CH ₂ -. 2. A compound according to claim 1 of the group 1.25-dihydroxy-16-dehydro-23-didehydrocholecalciferol, 1,25-dihydroxy-16,23E-bisdehydrocholecalciferol and 1.25-dihydroxy-16-dehydrocholecalciferol. 3. Compound with formula where A denotes -CH=CH- with E-configuration, _{-CH2- CH2-} or especially -CeCl2 R1 and _R3 independently of one another denote a C1-4-alkyl residue, especially methyl, and _R2 denotes a _C1-4- alkyl residue, especially methyl, an aryl residue or an aryl-C1-4-alkyl residue. 4. Use of a compound according to claim 1 or 2 as a therapeutically active substance, in particular for the treatment of 5 proliferative skin diseases, especially psoriasis, or for the treatment of neoplastic diseases, especially leukemia. 5. A method for preparing a compound according to claim 1 or 2, characterized in that 10 with the proviso that a corresponding compound of formula I which instead of two or three hydroxyl groups contains two or three protected hydroxyl groups of formula 15 -OSi (R1, _R2 , _R3 ) where R1 and _R3 represent a _C1-4- alkyl residue and _R2 represents a C1-4-alkyl residue, an aryl residue or an aryl- _C1-4 -alkyl residue, reacts with a reagent cleaving the protecting groups. 6. A means, in particular for the treatment of hyperproliferative skin diseases, especially psoriasis, or for the treatment of neoplasia 25 tic diseases, especially leukemia, characterized in that it contains an effective amount of a compound according to claim 1 or 2 and a pharmaceutical carrier, in particular for oral or topical use. 30 7. Use of a compound according to claim 1 or 2 for the preparation of medicaments for the treatment of hyperproliferative skin diseases, especially psoriasis, or for the treatment of neoplastic diseases, 35 especially leukemia.