IL97158A - Side-chain homologous vitamin D derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same - Google Patents

Abstract

The description relates to novel side-chain-homologous vitamin D derivatives of formula (I), in which R<1>, R<2>, R<3>, R<4>, R<5> and R<6> have the significance given in the description, B and D are either a hydrogen atom or together a second bond (E-configuration double bond) and either A is a direct bond between the carbon atoms 20 and 22 and X is an alkyloxy radical -(CH2)nO- with n = 1 to 3 or A is a methylene bridge (-CH2-) between the carbon atoms 20 and 22 and X is an alkylene radical -(CH2)n- or an alkylenoxy radical -(CH2)nO- with n = 1 to 3, or if A is a direct bond and B and D together are a second bond, (a) is one of the radicals (b) , -(CH2)2-= or -(CH2)2-=, and a process for their production, pharmaceutical preparations containing this compound and its use in making medicaments. The new compounds have proliferation-inhibiting and cell-differentiating effects.

Description

SIDE-CHAIN HOMOLOGOUS VITAMIN D DERIVATIVES, PROCESSES FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME IMK t !?" »n nmp >i>e>3ni nijDnij SIDE-CHAIN HOMOLOGOUS VITAMIN D DERIVATIVES PROCEGO FOR THEIR PRODUCTION, PHARMACEUTICAL PREPARATIONS CONTAINING TIIECE DERIVATIVES AND THEIR USE AS PHARMACEUTICAL AGENTS Background of the Invention This invention relates to side-chain homologous vitamin D derivatives of formula I means a hydrogen atom, a hydroxy or an acyloxy group with 1 to 9 carbon atoms, means a hydrogen atom or an acyl group with 1 to 9 carbon atoms, R3 or R4 means a hydroxy or acyloxy group with 1 to 9 carbon atoms, and the respective other substituent is a hydrogen atom or R3 and R4 together mean an oxygen ~- atom, R5 and R6, independently of one another, each mean a linear or branched alkyl radical with up to 4 carbon atoms, a trifluoromethyl group or together a saturated, unsaturated or aromatic carbocyclic or heterocyclic 3-, 4-, 5- or 6-member ring with the inclusion of 1 or 2 N, 0 or S atoms and formed with the tertiary carbon atom, B and D either mean a hydrogen atom each or together a second bond (E-configured double bond) and either A means a direct bond between carbon atoms 20 and 22 X means an alkylene oxy radical -(CH2)n0- with n = l to 3 or A means a methylene bridge (-CH2-) between carbons atoms 20 and 22 and X means an alkylene radical -(CH2)n- or an alkylene oxy radical -(CH2)nO- n = 1 to 3 or when A stands for a direct bond or when B and D together stand *s for a second bond, then -X-< means one of the groups -CH2-0-CH2-< , -(CH2)2-≡ or -(CH2)2-=, as well as a process for their production, pharmaceutical preparations that contain these compounds and their use for the production of pharmaceutical agents.

The acyloxy or acyl groups possible for radicals R1, R2 and within radicals R3 or R4 are derived in particular from saturated carboxylic acids or also from benzoic acid.

If R5 and R6 form, together with the tertiary carbon atom, a saturated carbocyclic ring, then the cyclopropyl or cyclohexyl ring is especially suitable. As alkyl groups.. for R5 and R6, those with 1 to 5 carbon atoms are especially suitable.

Preferred according to this invention are side-chain homologous vitamin D derivatives of general formula I, in which R1, R3 and R4 stand for a hydroxy group or R5 and R6 stand for a methyl group or, together with the tertiary carbon atom, for a cyclopropyl ring, R2 stands for a hydrogen atom and n is 1 or 2.

Between carbons atoms 22 and 23 (when A means a direct bond) or between carbon atoms 23 and 24 (when A means a methylene group) there is preferably- a double bond.

Especially preferred are the compounds 24- (1 (R) -Hydroxy-4-methylpentyl) -9 , 10-secochola-5Z , 7E,10(19) ,23E-tetraene-l(S) , 3 (R) -diol, 24- (1 (S) -hydroxy-4-methylpentyi) -9 , 10-secochola-5Z , 7E, 10(19) ,23E-tetraene-l(S) , 3(R)-diol, 24- (1 (R) -hydroxy-3-methylbutyl) -9 , lO-secochola-5Z , 7E, 10(19) ,23E-tetraene-l(S) , 3(R)-diol, 24 (1 (S) -hydroxy-3-methylbutyl) -9, 10-secochola-5Z,7E,10(19) ,23E-tetraene-l(S) ,3(R)-diol, 24- ( 1 (R) -hydroxy-3-methylbutyl) -9 , l0-secochola-5Z , 7E , 10 ( 19) -triene-1 (S) , 3 (R) -diol 24 (1(S) -hydroxy-3-methylbutyl) -9, 10-secochola-5Z, 7E, 10 (19) -triene-1 (S) , 3 (R) -diol , 24- ( 1 (R) -hydroxy-3-isopropoxypropyl) -9 , 10-secochola- 5Z,7E,10, (19) ,23E-tetraene-l(S) ,3(R)-diol, 24- ( 1 (S) -hydroxy-3-isopropoxypropyl) -9 , 10-secochola-5Z,7E,10, (19) ,23E-tetraene-l(S) ,3(R) -diol, 24-isopropoxymethyl-9, 10-secochola-5Z,7E, 10 (19) , 22E- tetraene-1 (S) , 3 (R) , 24 (R) -triol , 24-isopropoxymethyl-9,10-secochola-5Z,7E,10(19) , 22E- tetraene-l(S) ,3(R) , 24 (S) -triol, 24-(2-isopropoxyethyl)-9,10-secochola-5Z,7E,10(19) , 22E- tetraene-1 (S) , 3 (R) , 24 (R) -triol , 24- (2-isopropoxyethyl) -9, 10-secochola-5Z, 7E, 10 (19) , 22E- tetraene-l(S) , 3 (R) , 24 (S) -triol , 26, 27-cyclo-24a, 24b-dihomo-9, 10-secocholesta- 5Z,7E,10(19) , 23E-tetraene-l (S) , 3 (R) , 24a (R) -triol 26, 27-cyclo-24a, 24b-dihomo-9, 10-secocholesta- 5Z,7E,10(19) ,23E-tetraene-l(S) ,3(R) , 24a (S) -triol.

Natural vitamins D2 and D3 (see general formula V) are biologically inactive in and of themselves and are converted only after hydroxylation in the 25 position in the liver or in the 1 position in the kidneys into their biologically active metabolites. The effect of vitamins D2 and D3 consists in stabilizing the plasma Ca** level and the plasma phosphate level; they counteract a decrease in the plasma ergocalciferol: Ra = Rb = H,RC = CH3, vitamin D2 double bond C-22/23 cholecalciferol: Ra = Rb = Rc = H vitamin Dj 25-hydroxycholecalciferol: Ra = Rc = H, Rb = OH lalpha-hydroxycholecalciferol : Ra = OH, Rb =» Re » H lalpha, 25-dihydroxycholecalciferol :Ra = Rb = OH, Rc = H calcitriol Besides their pronounced effect on the calcium and........ phosphate metabolism, vitamin D2 and Dj and their synthetic derivatives also have proliferation-inhibiting and cell-differentiating effects (H.F. De Luca, The Metabolism and Function of Vitamin D in Biochemistry of Steroid Hormones, publisher H.L.J. Makin, 2nd Edition, Blackwell Scientific Publications 1984, pages 71-116).

But overdose phenomena can occur when using vitamin D (hypercalcemia) . lalpha-Cholecalciferols hydroxylated in the 24-position follow from DE-AS-25 26 981; they have a lower toxicity than the corresponding nonhydroxylated lalpha-cholecalciferol . The hydroxylated compounds show a selective activation of the intestinal calcium absorption and a weaker bone absorption effect than lalpha-cholecalciferol.

The 2 -hydroxy vitamin D analogs described in international patent application WO 87/00834 can be used for treating disorders caused by abnormal cell proliferation and/or cell differentiation in humans and animals.

For various 1, 25-dihydroxy-homo vitamin D derivatives, a dissociation with respect to the properties of the bone absorption effect and HL-60 cell differentiation have already been briefly mentioned by De Luca. The in vitro bone absorption effect here is a direct measure for the in vivo calcium mobilization.

It has now been found that the side-chain homologous vitamin D derivatives of general formula I according to the invention surprisingly exhibit a more favorable spectrum of action compared with the vitamin D derivative calcitriol (lalpha, 25-dihydroxycholecalciferol) . While the effects on the calcium and phosphate metabolism are clearly weakened (decrease in the side effects from overdosing or necessary higher dosage) , the proliferation-inhibiting and cell-differentiating effects are approximately maintained (dissociation) .

The vitamin D activity of the compounds according to the invention is determined by the calcitriol receptor test. It is performed using a specific receptor protein from the intestine of rachitic chickens.

A binding protein containing the receptor is incubated with 3H-calcitriol (0.5 ng/ml) in a reaction volume of 0.575 ml in the absence and presence of the test substances for an hour in a test tube. To separate the free calcitriol from the calcitriol bound to the receptor, a charcoal-dextran absorption is performed. For this purpose, 200 microliters of a charcoal-dextran suspension is fed to each test tube and incubated for 30 minutes at 22°C- Then the specimens are centrifuged at 1,500 x g for 10 minutes at 4°C. The supernatant fluid is decanted and measured in a beta-counter after about 1 hour of equilibration in atom light.

The competition curves obtained with various concentrations of the test substance and of the reference substance (unlabeled calcitriol) with a constant concentration of the standard substance (3H-calcitriol) are placed in relation to one another and a competition factor (KF) is determined.

It is defined as the quotient of the concentrations of the respective test substance and of the reference substance that are necessary for 50% competition: concentration of the test substance at 50% competition KF = concentration of the reference substance at 50% competition According to this, 24- (l-hydroxy-3-methylbutyl) -9 , 10-secochola-5Z,7E, 10 (19) , 23E-tetraene-l (S) ,3(R)-diol (compound A) has a KF value of 2.0 and 24- (1-hydroxy-3-methylbutyl) -9 , 10-secochola-5Z , 7E, 10 (19) , 23E-tetraene-l (S) , 3 (S) -diol (compound B) has a KF-value of 3.6. .. .

To determine the antiproliferative power of the compounds according to the invention, the test described below is performed instead with compounds A and B as test substances: Keratinocytes of newborn mice are prepared and cultivated in a modification of the method of Yuspa, S. and Harris, C.C., "Altered differentiation of mouse epidermal cells treated with retinyl acetate in vitro," Exp. Cell Res. 86: 95-105, 1974.

Neonatal NMRI mice of both sexes are killed by decapitation, the skin is removed, washed in an antibiotic-antimycotic solution and, with the dermal side facing down, incubated overnight at 4°C in dispase II solution (1.2 U/ml in tissue culture medium M199 +25 mmol/1 HEPES + 15% fetal calf serum (FCS) + 50 U/ml of penicillin/streptomycin (P/S) (preparation medium, PM) . The epidermis is removed and a single-cell suspension is produced by trypsinization. After centrifuging, the cell sediment is resuspended, the number of living, small, round cells is determined after trypan blue staining and the cells are sown in a density of 4xl05 eelIs/cm2 in Primaria 24-hole plates in tissue culture medium (M199 + 15% FCS + 50 U/ml of P/S) . After 24 hours of incubation at 37°C, the cells are washed with phosphate-buffered saline solution (PBS) and incubated another 24 hours in serum-free tissue culture medium (M199 + 50 U/ml of P/S + 0.5% ethanol) with and without test substances at 32.5°C. Then 0.4 microcuries/50 microliters of 3H-methylthymidine (40 Ci/mmol) is added. After 4 hours, the medium is suctioned off and the reaction is ended by adding 500 microliters of ice-cold 10% trichloroacetic acid (TCA) .

The cells are washed with TCA and PBS, lyzed by incubation in a proteinase K-solution (10 mmol/1 of tris-HCl, 10 mmol/1 of EDTA, 10 mmol/1 of NaCl, 0.2% triton-X 100, pH 8.0, 50... micrograms/ml of protein kinase K) and the lyzate is clarified by centrifuging. In the supernatant fluid, the radioactivity is determined by scintillation photometry and, after specific staining of the DNA with diamidinophenylindole (DAPI) , the DNA concentration is determined by fluorescence photometry.

According to this, depending on the dose, calcitriol and compounds A and B inhibit the 3H-thymidine incorporation in DNA with the following IC50 values: calcitriol 2 x 10"9 mol/1 compound A 1 x 10"8 mol/1 compound B 3.2 x 10"9 mol/1 The effects of calcitriol that stimulate the differentiation effects and of the compounds according to the invention 26, 27-cyclo-24a, 24b-dihomo-9, 10-secocholesta-5Z,7E,10(19) ,23E-tetraene-l(S) ,3(R) ,24a(R)-triol (compound C) and 26, 27-cyclo-24a, 24b-dihomo-9, 10-secocholesta-5Z,7E,10(19) , 23E-tetraene-l(S) ,3(R) , 24a (S) -triol (compound D) practically do not differ.

It is known from the literature (Mangelsdorf, D.J. et al, J. Cell. Biol. 98: 391-398 (1984)) that the in vitro treatment of human leukemia cells (promyelocytic cell line HL 60) with calcitriol induces the differentiation of the cells into macrophages.

To quantify the differentiation-stimulating effect of calcitriol analogs, the test given below was performed: HL-60 cells are cultivated in tissue culture medium (RPM1 - 10% fetal calf serum) at 37°C in an atmosphere of 5% C02 in air.

To test the substance, the cells are separated by centrifuging and 2.8 x 10s cells/ml are taken up in phenol red-free tissue culture medium. The test substances are dissolved in ethanol and diluted with tissue culture medium without phenol red to the desired concentration. The dilution stages are mixed with the cell suspension in a ratio of 1:10 and in each case 100 microliters of this cell suspension mixed with substance is pipetted into an indentation of a 96-hole plate. As a control, a cell suspension is mixed analogously with the solvent.

After incubation for 96 hours at 37°C in 5% C02 in air, 100 microliters of an NBT-TPA solution (nitro blue tetrazolium (NBT) final concentration in the preparation 1 mg/ml, tetradecanoyl phorbol myristate-13-acetate (TPA) , final concentration in the preparation 2 x 10"7 mol/1) is pipetted into each indentation of the 96-hole plate into the cell suspension.

By incubation for 2 hours at 37°C and 5% C02 in air, the NBT becomes an insoluble formazan because of the intracellular oxygen radical release, stimulated by TPA, in the cells differentiated into macrophages.

To end the reaction, the indentations of the 96-hole plate are drained and the adhering cells are fixed by adding methanol and dried after fixation.

To dissolve the intracellular formazan crystals formed, 100 microliters of potassium hydroxide (2 val/1) and 100 microliters of dimethyl sulfoxide are pipetted into each indentation and are exposed to ultrasonic waves for one minute. The concentration of formazan is measured by spectral photometry at 650 nm.

The concentration of formazan formed is valid as a measure for the differentiation induction of the HL 60 cells into macrophages. The relative effectiveness of the test substance results from the quotient ED50 test substance/ED50 calcitriol .

According to this, calcitriol, compound C and compound D have the ED50 values 1.8 x 10*9 mol/1, 2.2 x 10"9 mol/1 or 2.5 x 10*9 mol/1.

Because of the reduced risk of hypercalcemia, the substances according to the invention are especially suited for the production of pharmaceutical agents for treating diseases characterized by a hyperproliferation, e.g., hyperproliterative diseases of the skin (psoriasis) and malignant tumors (leukemia, colon cancer, breast cancer) . A prerequisite for a successful treatment is proof of calcitriol receptors in the target organ.

This invention thus relates to pharmaceutical preparations that contain at least one compound according to general formula I together with a pharmaceutically compatible vehicles. The compounds can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles or as pills, tablets or capsules that contain solid vehicles in the way known in the art. For a topical use, the compounds are advantageously formulated as creams or ointments or in a similar pharmaceutical agent form suitable for topical use. Each such formulation can also contain other pharmaceutically compatible and nontoxic inactive ingredients such as, e.g., stabilizers, antioxidants, binders, dyes, emulsifiers or taste corrigents. The compounds are advantageously administered by injection or intravenous infusion of suitable sterile solutions or as oral doses by the alimentary tract or topically in the form of creams, ointments, lotions or suitable transdermal plasters, as described in EP-A-0387 077.

The daily dose is 0.1 microgram/patient/day - 1,000 micrograms (1 m<3) /patient/day, preferably 1.0 microgram/patient/day - 500 micrograms/patient/day.

Further, the invention relates to the use of the compounds according to formula I for the production of pharmaceutical agents.

The production of side-chain homologous vitamin D derivatives of formula I is performed according to the invention in that a compound of general formula IV in which R1' means a hydrogen atom or a protected hydroxy group and R2' means a hydroxy protecting group and A, X and R5 and R6 have the meaning given in formula I, optionally after selective hydrogenation of the double bond in the side chain, is converted into a compound of general in which R1', R2', A, X and R5 and R6 have the meaning given in formula IV and optionally, after reduction of the carbonyl function and optionally after separation of the mixture of the epimeric hydroxy compounds of general formulas IIIA and IIIB formed by the reduction in which R , R2, A, X and R5 and R6 have the meaning given in formula IV and B and D have the meaning given in formula I, by irradiation with ultraviolet light with reversal of the stereoisomerism at the 5,6 double bond is converted into a compound of gener in which R1', R2', A, B, D, X and R5 and R6 have the meaning given in formula Illa/IIIb and then the latter, by the cleaving of existing hydroxy protecting groups and optionally by partial or complete esterification of the hydroxy groups is converted into a compound of general formula I.

The reduction of the side-chain carbonyl function in the compound of general formula IV is performed for example with cerium(III) chloride/sodium borohydride in a polar solvent. The R and the S hydroxy isomers of general formula Ilia or IIIB result from the reduction. Both isomers can be separated chromatographically .

Optionally, before reduction of the carbonyl function, the double bond in the side chain can be selectively hydrogenated . As hydrogenation agent, lithium-tri-tert-butoxy-alu inum hydride in a polar solvent is suitable, among others.

The following conversion of a compound of general formula Illa/IIIb into a compound of general formula II is performed, e.g., by irradiation with ultraviolet light in the presence of a so-called "triplet sensitizer." In the framework of this invention, anthracene is used for this purpose. By cleaving the pi-bond of the 5,6 double bond, rotation of the A ring by 180° around the 5,6 single bond and reestablishing the 5,6 double bond, the stereoisomerism at the 5,6 double bond is reversed.

Then available hydroxy protecting groups are cleaved, preferably using tetra-n-butyl-anunonium fluoride and optionally the free hydroxy groups are esterified according to current processes partially or completely with the corresponding carboxylic acid halide (halide =» chloride, bromide) or carboxylic acid anhydride.

Production of the starting materials 1. 1(S) , 3( )-bis-(tert-Butyldimethylsilyloxy)-20(S)-formyl-9 , 10-secopregna-5E, 7E, 10 (19) -triene 1: The production of 1 is performed according to M.J.

Calverley, Tetrahydron 43., 4609 (1987) ; see also international patent application WO 87/00834. The production of the starting compound in which R1' is a hydrogen atom is also described there. 2. 1 (S) , 3 (R) -bis- (tert-Butyldimethylsilyloxy) -20 (R) -methyl-9 , 10-secopregna-5E, 7E, 10 (19) -triene-21-carbaldehyde 2 Aldehyde 2 is produced according to a new process. a. A solution of 15.57 g of diethyl phosphonoethoxy ethyl acetate (produced according to W. Grell and H.

Machleidt, Liebigs Ann. Chem. 699. 53 (1966) in 200 ml of THF is instilled at 25°C to a suspension of 1.8 g of sodium hydride (80% in oil) in 70 ml of abs. THF. After adding, it is stirred another 90 minutes at 60°C, cooled again to 25°C and a solution of 6.2 g of 1 in 70 ml of THF is instilled. It is stirred for 2 hours under reflux, the cooled reaction solution is then poured into water and extracted with ethyl acetate. After drying (Na2S04) and concentration by evaporation, the crude product obtained is chromatographed on silica gel with hexane/ethyl acetate. The main fraction yields 5.2 g of 1 (S) , 3 (R) -bis- (tert-butyldimethylsilyloxy) -23- (ethoxy-9 , 10-secochola-5E , 7E , 10 ( 19 ) -tetraene-24-acid ethyl ester as an oily mixture of the C-22 double bond isomers . b. 5.2 g of the product obtained under a. is dissolved in 120 ml of toluene and at 0°C slowly mixed with 20 ml of a 20% solution of diisobutylaluminum hydride in toluene.

After 30 minutes at 0°C, the reaction solution is poured carefully into NHAC1 solution and extracted with ethyl acetate. After the usual working up, 4.88 g of 1(S),3(R)-bis- (tert-butyldimethylsilyloxy) -23-ethoxy-9 , 10-secochola-5E,7E, 10(19) , 22-tetraen-24-ol is obtained as a colorless, oily isomer mixture that is used without further purification in the next step. c. The compound produced under b. (4.88 g) is stirred in a mixture of 55 ml of dichloromethane and 55 ml of a 70% aqueous acetic acid for 4 hours at room temperature. Then it is neutralized by adding NH3 solution and extracted with dichloromethane. The crude product is chromatographed on silica gel with hexane/ethyl acetate. In this way 2.02 g of 1 (S) ,3 (R) -bis- (tert-butyldimethylsilyloxy) -24-hydroxy-9 , 10-secochola-5E, 7E, 10, (19) -trien-23-one 5 is obtained as a colorless oil. 1H-NMR (CDC13) : 6 = 0.01 ppm (s, 12H, Si-CH3) , 0.52 (s, 3H, H-18), 0.81 and 0.84 (s; 9H, Si-t-butyl each), 0.90 (d, J = 7HZ, 3H, H-21), 3.09 (t, J-5Hz, 1H, OH), 4.10 (dd, 1H, H-24), 4.16 (m, 1H, H-3) , 4.21 (dd, 1H, H-24) , 4.39 (m, 1H, H-1) , 4.88, 4.93 (s; 1H, H-19 each), 5.77, 6.39 (d, J=llHz; 1H, H-6, H-7 each) . d. The product obtained under c. (2.02 g) is dissolved in 25 ml of methanol and 25 ml of THF and mixed at 0°C with 300 mg of sodium borohydride. It is stirred for 1.5 hours at 0°C, the reaction mixture is then poured into NH4C1 solution and extracted with ethyl acetate. 1.75 g of 1(S), 3 (R) , bis- (tert-butyldimethylsilyloxy) -9 , 10-secochola- 5E, 7E, 10, (19) -triene-23 , 24-diol £ is obtained as a colorless, oily mixture of the 23 epimer that is used as such in the next reaction. e. 1.75 g of the product obtained under d. is dissolved in 40 ml of toluene and 1.23 g of lead tetraacetate is added in portions with ice water cooling. It is stirred for 30 minutes, 1.0 g of Pb(OAc)4 is again added and it is stirred another 15 minutes at +5 to +10°C.

For the working up, it is mixed with NaHC03 solution, the resulting suspension is filtered over cellite and the filtrate is extracted with ethyl acetate. The crude product is chromatographed on silica gel with hexane/ethyl acetate. After crystallization of the main fraction from ethanol, 560 mg of 1 (S) ,3 (R) -bis- (tert-butyldimethylsilyloxy) -20 (R) -methy1

Claims (14)

WHAT IS CLAIMED IS:

1. Side-chain homologous vitamin D derivatives formula I in which R1 means a hydrogen atom, a hydroxy or an acyloxy group with 1 to 9 carbon atoms, R2 means a hydrogen atom or an acyl group with 1 to 9 carbon atoms , R3 or R4 means a hydroxy or acyloxy group with 1 to 9 carbon atoms, and the respective other substituent is a hydrogen atom or R3 and R4 together mean an oxygen atom, R5 and R6, independently of one another, each mean a linear or branched alkyl radical with up to 4 carbon atoms, a trifluoromethyl group or together a saturated, unsaturated or aromatic carbocyclic or heterocyclic 3-, 4-, 5- or 6- member ring with the inclusion of 1 or 2 N, O or S atoms and formed with the tertiary carbon atom, B and D either mean a hydrogen atom each or together a second bond (E-configured double bond) and either A means a direct bond between carbon atoms 20 and 22 X means an alkylene oxy radical -(CH2)nO- with n = 1 to 3 or when A stands for a direct bond or when B and D together stand for a second bond, then -X-< means one of the groups -CH2-0-CH2-< , -(CH2)2-≡ or -(CH2)2-=, A means a methylene bridge (-CH2-) between carbons atoms 20 and 22 and X means an alkylene radical -(CH2)n- or an alkylene oxy radical -(CH2)n0- n = 1 to 3.

2. Vitamin D derivatives according to claim 1, in which R1 stands for a hydroxy group.

3. Vitamin D derivatives according to claim 1, in which R2 stands for a hydrogen atom.

4. Vitamin D derivatives according to claim 1, in which A means a direct bond between carbon atom 20 and carbon atom 22.

5. Vitamin D derivatives according to claim 1, in which A means a methylene bridge.

6. Vitamin D derivatives according to claim 1, in which B and D together mean a second bond.

7. Vitamin D derivatives according to claim 1, in which R3 or R4 means a hydroxy group.

8. Vitamin D derivatives according to claim 1, in which n in X is 1 or 2.

9. Vitamin D derivatives according to claim 1, in which R5 and R6 stand for methyl groups.

10. Vitamin D derivatives according to claim 1, in which R5 R6 and the tertiary carbon atom together stand for a cyclopropyl ring.

11. 24- (1 (R) -Hydroxy-4-methylpentyl) -9, 10-secochola-5Z, 7E, 10(19) , 23E-tetraene-l(S) , 3(R)-diol, 24- ( 1 (S) -hydroxy-4-methylpentyl) -9 , 10-secochola-5Z , 7E,10(19) ,23E-tetraene-l(S) , 3 (R) -diol, 24- (1 (R) -hydroxy-3-methylbutyl) -9, 10-secochola-5Z, 7E,10(19) ,23E-tetraene-l(S) , 3(R)-diol, 24 (1 (S) -hydroxy-3-methylbutyl) -9, 10-secochola- 5Z,7E, 10(19) ,23E-tetraene-l(S) , 3 (R) -diol, 24- ( 1 (R) -hydroxy-3-methylbutyl) -9 , 10-secochola-5Z , 7E , 10 (19 ) -triene-1 (S) , 3 (R) -diol 24 ( 1 (S) -hydroxy-3-methylbutyl) -9 , 10-secochola-5Z , 7E , 10 ( 19 ) -triene-1 (S) , 3 (R) -diol , 24- (1 (R) -hydroxy-3-isopropoxypropyl) -9, 10-secochola-5Z,7E, 10, (19) ,23E-tetraene-l(S) ,3(R)-diol, 24- ( 1 (S) -hydroxy-3-isopropoxypropyl) -9 , 10-secochola-5Z,7E, 10, (19) ,23E-tetraene-l(S) ,3(R)-diol, 24-isopropoxymethyl-9 , 10-secochola-5Z , 7E, 10 (19) , 22E-tetraene-1 (S) , 3 (R) , 24 (R) -triol , 24-isopropoxymethyl-9, 10-secochola-5Z,7E, 10 (19) , 22E-tetraene-l(S) , 3 (R) , 24 (S) -triol, 24- (2-isopropoxyethyl) -9, 10-secochola-5Z , 7E, 10 (19) , 22E-tetraene-1 (S) , 3 (R) , 24 (R) -triol , 24- (2-isopropoxyethyl) -9 , 10-secochola-5Z , 7E, 10 (19) , 22E-tetraene-l(S) ,3(R) , 24 (S) -triol , 26 , 27-cyclo-24a, 24b-dihomo-9 , 10-secocholesta- 5Z,7E,10(19) ,23E-tetraene-l(S) , 3 (R) , 24a (R) -triol 26, 27-cyclo-24a, 24b-dihomo-9, 10-secocholesta- 5Z,7E,10(19) ,23E-tetraene-l(S) , 3 (R) , 24a (S) -triol .

12. Process for the production of side-chain homologous vitamin D derivatives of formula I in which R1, R2, R3, R4, R5, R6 and A, B, D, and X have the meaning given in claim 1, characterized in that a compound of general formula IV in which R1' means a hydrogen atom or a protected hydroxy group and R2' means a hydroxy protecting group and A, X and R5 and R6 have the meaning given in formula I, is converted, optionally after selective hydrogenation of the double bond in the side chain into a compound of general IVa in which R1' , R2', A, X and R5 and R6 have the meaning given in formula IV and optionally after reduction of the carbonyl function and optionally after separation of the mixture of the epimeric hydroxy compounds formed by the reduction of general formulas Ilia and Illb 97158/2 in which R1', R2', A, X and R5 and R6 have the meaning given in formula IV and B and D have the meaning given in formula I by irradiation with ultraviolet light with reversal of the stereoisomerism at the 5,6 double bond into a compound of general formu in which R1', R2', A, B, D, X and R5 and R6 have the meaning given in formula Illa/IIIb and then the latter, by cleaving existing hydroxy protecting groups and optionally by partial or complete esterification of the hydroxy groups, is converted into a compound of general formula I.

13. Pharmaceutical preparations, wherein they contain at least one compound according to claims 1 to 11 and a pharmaceutically compatible vehicle.

14. Use of the compounds according to claims 1 to 11 for the production of pharmaceutical agents, as described in the specification. for the Applicant: WOLFF, BREGMAN AND GOLLER