DE4317415A1 - 25-Carboxylic acid derivatives in the vitamin D series having modifications in the 20-position, processes for their preparation, intermediates for these processes, pharmaceutical preparations containing these derivatives and their use for the production of medicaments - Google Patents

Abstract

The novel 25-carboxylic acid derivatives of the general formula I <IMAGE> in which R<19> and R<19a> each are a hydrogen atom or together are an exocyclic methylene group, R<21> and R<21a> independently of one another are a hydrogen atom, a chlorine or fluorine atom, an alkyl group having 1 to 4 carbon atoms, where, if R<19> and R<19a> together form a methylene group, R<21> cannot be a hydrogen atom and R<21a> cannot be a methylene group or conversely, are together a methylene group or, together with the quaternary carbon atom 20, are a 3-7-membered, saturated or unsaturated carbocyclic ring, and the other substituents have the meanings indicated in the description, and processes for their preparation are described. The novel compounds have vitamin D activity and proliferation-inhibiting and cell-differentiating action and are suitable for the production of medicaments.

Description

The present invention relates to 25-carboxylic acid derivatives of the general Formula I,

in which R 1 and R 3 independently of one another each represent a hydrogen atom, a straight-chain or branched-chain saturated alkanoyl group having 1 to 9 carbon atoms or an aroyl group,
R¹⁹ and R ^19a each represent a hydrogen atom or together an exocyclic methylene group,
A and B together are a keto oxygen atom or A is a group OR²⁴ and B is a hydrogen atom or A is a hydrogen atom and B is a group OR²⁴, where R²⁴ is a hydrogen atom or a straight or branched chain saturated alkanoyl group having up to 9 carbon atoms or an aroyl group, R²¹ and R ^21a independently of one another are a hydrogen atom, a chlorine or fluorine atom, an alkyl group having 1 to 4 carbon atoms, where if R¹⁹ and R ^19a together form a methylene group, R²¹ cannot stand for a hydrogen atom and R ^21a for a methyl group or vice versa, together one Methylene group, together with the quaternary carbon atom 20 a 3-7 membered, saturated or unsaturated carbocyclic ring,
R⁴ and R ^4a simultaneously represent a hydrogen atom, a chlorine or fluorine atom, a trifluoromethyl group, a straight or branched chain, saturated or unsaturated hydrocarbon radical with up to 4 carbon atoms or R⁴ and R⁴a together with the carbon atom 25 form a 3- to 7-membered group, saturated or unsaturated carbocyclic ring and Y one of the radicals CC (O) NR⁵R⁵ ′, - C (O) OR⁶, -C (O) SR⁶, -CN, where R⁵ and R⁵, independently of one another and R⁶ each for a hydrogen atom or a linear one or are branched alkyl or alkoxy groups with 1 to 8 carbon atoms,
and processes for their preparation, intermediates for this process, pharmaceutical preparations containing these compounds and their use for the production of medicaments.

Preferably each represents a hydrogen atom for the radicals R¹, R³ and R²⁴. The possible alkanoyl groups as radicals R¹, R³ and R²⁴ are of saturated Carboxylic acids, especially acetic acid, propionic acid, butyric acid, iso- Butyric acid, pivalic acid or valeric acid derived. The benzoyl radical should be mentioned primarily as the aroyl group.

The radicals R⁴ and R ^4a are preferably methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl and tert-butyl radicals.

Of the radicals R²¹ and R ^21a , one preferably also has one of these meanings and the other radical represents a methyl group.

R²¹ and R ^21a are further preferably preferably a methylene group or together with the tertiary carbon atom 20 they form a cyclopropyl ring.

The following preferred substitution patterns also apply:
R²¹ = F and R ^21a = methyl and R²¹ = methyl and R ^21a = F.

R⁴ and R ^4a also preferably together represent a methylene group or they form together with the tertiary carbon atom 25 a cyclopropyl, pentyl or hexyl ring.

A hydrogen atom is preferred for each of the radicals R⁵, R⁵ 'and R⁶.

In the radicals R⁵, R⁵ ′ and R⁶ the alkyl group is, for example, the methyl, Ethyl, n-propyl, n-butyl, i-propyl, i-butyl, tert-butyl or even a higher one contain straight or branched chain alkyl group.  

The following compounds are particularly preferred:

• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a- 5,7,10 (19), 22-tetraen-25-carboxylic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a- 5,7,10 (19), 22-tetraen-25-carboxylic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a- 5,7,10 (19), 22-tetraen-25-carboxylic acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a- 5,7,10 (19), 22-tetraen-25-carboxylic acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a- 5,7,10 (19), 22-tetraen-25-carboxylic acid propyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a- 5,7,10 (19), 22-tetraen-25-carboxylic acid propyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a- 5,7,10 (19), 22-tetraen-25-carboxylic acid isopropyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a- 5,7,10 (19), 22-tetraen-25-carboxylic acid isopropyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a- 5,7,10 (19), 22-tetraen-25-carboxylic acid butyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a- 5,7,10 (19), 22-tetraen-25-carboxylic acid butyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (1-9), 20,22- pentaen-25-carbonic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (1-9), 20,22- pentaen-25-carboxylic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (1-9), 20,22- pentaen-25-carboxylic acid ethyl ster
• (5Z, 7E, 22E) - (1S, 3R, 24S) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (1-9), 20,22- pentaen-25-carboxylic acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (1-9), 20,22- pentaen-25-carboxylic acid propyl ester
• (5 Z, 7E, 22E) - (1S, 3R, 24S) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19) -, 20,22- pentaen-25-carboxylic acid propyl ester
• (5Z, 7E, 22E) - (1S, 3R, 2 4R) -13,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 20,22-  pentaen-25-carboxylic acid isopropyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 2-0,22- pentaen-25-carboxylic acid isopropyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (1-9), 20,22- pentaen-25-carboxylic acid butyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (1-9), 20,22- pentaen-25-carboxylic acid butyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20,21-methylene-1,3,24-trihydroxy-9,10-secoch-olesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20,21-methylene-1,3,24-trihydroxy-9,10-secoch-olesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20,21-methylene-1,3,24-trihydroxy-9,10-secoch-olesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20,21-methylene-1,3,24-trihydroxy-9,10-secoch-olesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20,21-methylene-1,3,24-trihydroxy-9,10-secoch-olesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid propyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20,21-methylene-1,3,24-trihydroxy-9,10-secoch-olesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid propyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20,21-methylene-1,3,24-trihydroxy-9,10-secoch-olesta- 5,7,10 (19), 22-tetraen-2 5-carboxylic acid isopropyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20,21-methylene-1,3,24-trihydroxy-9,10-secoch-olesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid isopropyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20,21-methylene-1,3,24-trihydroxy-9,10-secoch-olesta- 5,7, 10 (19), 22-tetraen-25-carboxylic acid butyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20,21-methylene-1,3,24-trihydroxy-9,10-secoch-olesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid butyl ester

The natural vitamins D₂ and D₃ (cf. general formula Vit. D) are in themselves biologically inactive and are only in the liver after hydroxylation in 25-position or in 1-position in the kidney converted into its biologically active metabolites. The Effect of vitamins D₂ and D₃ is to stabilize the plasma Ca⁺⁺ and Plasma phosphate levels; they act to lower the plasma Ca⁺⁺ level opposite.  

In addition to their pronounced effect on calcium and phosphate metabolism Vitamin D₂ and D₃ and its synthetic derivatives also inhibit proliferation and cell differentiating effects (H. F. De Luca, The Metabolism and Function of Vitamin D in Biochemistry of Steroid Hormones, ed. H. L. J. Makin, 2nd Edition, Blackwell Scientific Publications 1984, pp. 71-116) When using vitamin D, overdose symptoms can occur (Hypercalcaemia).

1α-Cholecalciferols hydroxylated in the 24 position are already known from DE-A-25 26 981 emerged; they have a lower toxicity than the corresponding non-hydroxylated 1α- Cholecalciferol. The hydroxylated compounds show a selective activation of the intestinal calcium absorption and a weaker bone absorption effect than 1α- Cholecalciferol.

The 24-hydroxy- described in international patent application WO 87/00834 Vitamin D analogs can be used for the treatment of abnormal cell proliferation and / or cell differentiation caused disorders in humans and animals.

There is a dissociation for various 1,25-dihydroxy-homo-vitamin D derivatives  regarding the properties of bone absorption effect and HL-60 cell differentiation previously mentioned by De Luca. The in vitro bone absorption effect is a direct measure of calcium mobilization in vivo.

Finally, EP-A 0 421 561 24-cycloalkylmethyl-substituted vitamin D Described derivatives that have a more favorable spectrum of activity than calcitriol. During their effects on calcium and phosphate metabolism compared to Calcitriol are significantly weakened, the proliferation-inhibiting and remain cell-differentiating effects approximately obtained.

Compared to these structurally related connections, the 25-carboxylic acid derivatives according to the invention in the vitamin D series in that they in terms of cell differentiation versus hypercalcaemic effects yet are more dissociated.

The vitamin D activity of the compounds according to the invention is determined by means of the calcitriol Receptor tests determined. It is made using a specific receptor protein carried out by young pigs from the intestine.

Binding protein containing the receptor is incubated with 3 H-calcitriol (5 × 10 ^-10 mol / l) in a reaction volume of 0.270 ml in the absence and in the presence of the test substances for two hours at 40 ° C. in a test tube. Charcoa 1-dextran absorption is carried out to separate free and receptor-bound calcitriol. For this purpose, 250 µl of a Charcoal dextran suspension are added to each test tube and incubated at 4 ° C for 20 minutes. The samples are then centrifuged at 10,000 × g for 5 minutes at 4 ° C. The supernatant is decanted and measured after 1 hour equilibration in Picofluor 15 TM in a β counter.

The with different concentrations of the test substance and the reference substance (un labeled calcitriol) at constant concentration of the reference substance (³H-calcitriol) competition curves obtained are related to each other and a Competition factor (KF) determined.

It is defined as the quotient of the concentrations of the respective test substance and the Reference substance required for 50% competition:

To determine the acute hypercalcemic effect of various calcitriol derivatives the test described below is carried out:

The effect of control (solution basis), reference substance (1,25 (OH) ₂-D₃ = Cal citriol) and test substance is administered in groups after a single subcutaneous application tested by 10 native male rats (140-170 g). The rats are kept during the Trial time in special cages to determine the excretion of water and Minerals kept. The urine is collected in 2 fractions (0-16 h and 16-22 h). Oral calcium load (0.1 mM calcium in 6.5% alpha hydroxypropyl cellulose, 5 ml / Animal) replaces the lack of calcium intake due to food withdrawal at 16 h. To At the end of the experiment, the animals are killed by decapitation and for the determination of the Bleeding serum calcium levels. For the primary screen examination in vivo, a single standard dose (200 µg / kg) tested. For selected substances that will Confirm the result by establishing a dose-response relationship.

A hypercalcaemic effect is shown in increased serum compared to the control Calcium level values.

The significance of differences between substance groups and controls as well as between test substance and reference substance are determined with suitable statistical Procedure secured. The result is called the dose relation DR (DR = factor test sub punch dose / reference substance dose for comparable effects).

The differentiation-stimulating effect of calcitriol analogs is also quantita tiv recorded.

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

HL 60 cells are grown in tissue culture medium (RPMI-10% fetal calf serum) at 37 ° C cultivated in an atmosphere of 5% CO₂ in air.

For substance testing, the cells are centrifuged off and 2.0 × 10⁵ cells / ml in phenol red-free tissue culture medium was added. The test substances are in ethanol dissolved and with tissue culture medium without phenol red to the desired concentration  diluted. The dilution levels with the cell suspension are in a ratio of Mixed 1:10 and 100 µl of this cell suspension mixed with substance in a well pipetting of a 96-hole plate. As a control, a cell suspension is used in the same way added to the solvent.

After incubation for 96 hours at 37 ° C in 5% CO₂ in air, 100 µl of an NBT-TPA solution (nitro blue tetrazolium (NBT), final concentration in the mixture 1 mg / ml) is added to the cell suspension in each well of the 96-well plate , Tetradecanoylphorbolmyristat-13-acetate (TPA), final concentration in the batch 2 × 10 ^-7 mol / l) pipetted.

By incubation for 2 hours at 37 ° C and 5% CO₂ in air is due to the intra cellular oxygen radical release, stimulated by TPA, into macrophages Differentiated NBT cells reduced to insoluble formazan.

To end the reaction, the wells of the 96-hole plate are suctioned off and the adhering cells fixed by adding methanol and dried after fixation. To dissolve the intracellular formazan crystals formed in each well Pipette 100 ul potassium hydroxide (2 val / l) and 100 ul dimethyl sulfoxide and 1 minute ultrasound. The concentration of formazan is determined spectrophotometrically at 650 nm measured.

As a measure of the induction of differentiation of HL 60 cells to macrophages Concentration of formazan formed. The result is also called the dose relation (DR = factor test substance dose / reference substance dose for comparable effects) specified.

The results of the calcitriol receptor test and the determination of the dose relation of the induction of differentiation of HL 60 cells and the dose relation for hypercalcaemia are summarized below:
Test connection:
(5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -carboxylic acid ethyl ester 6a

• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22- tetraen-25-carboxylic acid isopropyl ester 10a

Comparative compound

Calcitriol

Due to the reduced risk of hypercalcemia, the sub according to the invention are suitable punch in a special way for the manufacture of pharmaceuticals for the treatment of Diseases characterized by hyperproliferation, e.g. B. hyperprolife rative diseases of the skin (psoriasis) and malignant tumors (leukemia, colon carci nom, mammary carcinoma) and acne (J. Invest. Dermatol., Vol. 92 No. 3,1989). Also for Treatment and prophylaxis of disorders caused by an imbalance the immune system, such as autoimmune diseases, including diabetes mellitus and transplant rejection (WO-A-91/00855), the compounds according to the invention can be used. In a particularly preferred embodiment of the invention be prior to treatment Calcitriol receptors detected in the target organ.

Furthermore, it was surprisingly found that the inventions compounds according to the invention on the skin of mice, rats and guinea pigs an increased reddening of the skin and an increase in the thickness of the epidermis can be induced. The Increase in skin redness is based on the increase in quan with a colorimeter identifiable red value of the skin surface. The red value is after three times Substance application (dose 0.003%) at intervals of 24 hours typically around that Increased 1.5 times. The increase in epidermal thickness is seen in the histological specimen quantified. The number of proliferating epidermal cells (cells in the 5 phase of the Cell cycle) is determined by flow cytometry and is typically by a factor of 6 elevated.

These properties of the 25-carboxylic acid derivatives according to the invention in the vitamin D Series leaves them for therapeutic use in atrophic skin, as in natural Skin aging, premature skin aging due to increased exposure to light or drug-induced skin atrophy occurs through treatment with glucocorticoids,  seem suitable.

It can also be assumed that wound healing by topical application with the new connections can be accelerated.

The present invention thus also relates to pharmaceutical preparations which at least one compound according to general formula I together with a phar contain pharmaceutically acceptable carriers.

The compounds can be formulated as solutions in pharmaceutically acceptable union solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or carriers or as pills, tablets or capsules, which in contain solid carriers known per se. For a topical application who which the compounds advantageously as creams or ointments or in a similar, formulated for topical use suitable pharmaceutical form. Any such form lation can also contain other pharmaceutically acceptable and non-toxic auxiliaries ten such. B. stabilizers, antioxidants, binders, dyes, emulsifiers or Taste corrections. The compounds are advantageously made by injection or intravenous infusion of suitable sterile solutions or as an oral dosage via the Nutritional tract or topical in the form of creams, ointments, lotions or more suitable transdermal patch applied, as described in EP-A 0 387 077.

The daily dose is included

0.1 µg / patient / day - 1000 µg (1 mg) / patient / day,

preferably

1.0 µg / patient / day - 500 µg / patient / day.

The compounds of the invention are generally administered analogously to Administration of the known agent "calcipotriol" for the treatment of psoriasis.

The invention also relates to the use of the compounds of the formula I for Manufacture of drugs.  

The 25-carboxylic acid derivatives of the general formula I are prepared when R¹⁹ and R ^19a together form an exocyclic methylene group according to the invention in that a compound of the general formula II

wherein
R¹ 'and R³' are alkyl, aryl or mixed alkyl and aryl-substituted silyl groups, preferably the tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropyl silyl group,
A ′ and B ′ together represent a keto group or one of the two substituents represents a protected hydroxy group and the other represents a hydrogen atom (silyl protective group as defined above, tetrahydrofuranyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or trimethylsilylethoxymethyl group),
R¹⁹, R ^19a , R²¹, R ^21a , R⁴, and R ^{4a have} the meanings already described in the general formula I, and Y ′ are the same radicals as Y in the compound of the general formula I or, if Y in the compound of the formula - C (O) OR⁶ and R⁶ is to be hydrogen, optionally denotes a 2- (trimethylsilyl) ethyl-carboxylic acid ester group, by simultaneous or gradual elimination of the hydroxyl protective groups and, if appropriate, by partial, gradual or complete esterification of free hydroxyl groups and / or if then Y ′ represents a carboxyl radical -COOH, if desired by converting it into an amide radical-C (O) NRSRSa, converting it into a compound of the general formula I.

In the case of the silyl protecting groups or the trimethylsilylethoxymethyl group tetrabutylammonium fluoride is used to split them off, Hydrofluoric acid or hydrofluoric acid / pyridine; in the case of the rest Ether groups these become under the catalytic action of acid, for example p-toluenesulfonic acid, pyridinium p-toluenesulfonate, acetic acid, Hydrochloric acid or an acidic ion exchanger separated.

If R⁶ in the general formula I is hydrogen, Y 'is in the general formula II preferably for a 2- (trimethylsilyl) ethyl carboxylic acid be ester group, which is cleaved with one of the fluorine reagents mentioned. The free carboxylic acid formed can, if appropriate, be carried out by customary processes by esterification or conversion into an amide radical -C (O) NR⁵R⁵ 'or Thioester -C (O) SR⁶ to be implemented further.

The preparation of the starting compounds for the general formula II starts of those in Tetrahedron 43, 4609 (1987) or in the international Patent application WO 87/00834 by M. Calverley et al. described (20S) - Formylsecopregnatrienes of the general formula III,

wherein R¹ 'and R³' have the meanings already described.

The compounds of general formula III are in the 20-modified analogs of the general formula IV

where R²¹ and R ^{21a have} the meanings already described, transferred.

For the synthesis of the compound of general formula V

which is derived from the general formula IV in that R²¹ and R ^21a each represent a methyl group, the compound of the general formula is deprotonated in with a base such as sodium hydride, potassium hydride, lithium diisopropylamide or potassium tert-butanolate and with an electrophilic, the Reagent providing methyl group such as CH₃X (X = Cl, Br, I, tosylate, mesylate) implemented.

The homologous alkyl groups R²¹ and R ^21a are introduced analogously by alkylation with a reagent supplying the homologous alkyl group. The introduction of a chlorine or fluorine atom in the 20 position is achieved by a-halogenation using standard methods.

To build the side chain, the compound of general formula V in a Wittig reaction with N-methoxy-N-methyl-2- (triphenylphosphoranylidene) acetamide (D.A. Evans et al. J. Am. Chem. Soc. 112, 7001 (1990)) or one other, similarly reacting phosphoranylides at elevated temperature to one Compound of the general formula VI

wherein R¹ 'and R³' have the meanings given, implemented.

The reaction preferably takes place at a temperature in the range between 90 and 120 ° C in a solvent such as. B. dimethyl sulfoxide (DMSO) or Toluene.

In the next reaction step, the compound is treated by treating the general formula VI with a reducing agent such as Diisobutyl aluminum hydride (DIBAH) or lithium aluminum hydride in one Solvents like tetrahydrofuran or another ether at deeper Temperature (-60 to -100 ° C) of the aldehyde of the general formula VII  

receive.

By adding a suitable nucleophilic component to the carbonyl Function of the aldehyde VH can now be the side chain, as in the end desired 25-carboxylic acid derivative of the general formula I should be present, build up. Under the influence of a strong base such as e.g. B. lithium diisopropylamide, Lithium diethylamide, lithium, sodium or potassium hexamethyl disilazide is initially a compound of the general formula VIII,

in which R⁴, R ^4a and Y 'have the meanings already described,
deprotonated in a solvent such as tetrahydrofuran or another ether at a temperature between -60 and -90 ° C. and then added to a compound of the general formula VII, a compound of the general formula IX

wherein R¹ ', R³', R⁴, R ^4a and Y 'have the meanings already given, obtained.

Both the 24α- and the 24β-hydroxyisomers are formed, which are based on have this or a later stage separated chromatographically. In the Subsequent reactions can therefore be separated as desired Diastereomers or the mixture can be used.

Should A and B in the ultimately desired connection of the general Formula I together mean a keto oxygen atom, the 24-hydroxy compound of the general formula IX at this stage with Braunstein, Pyridi nium chlorochromate, pyridinium dichromate, barium manganate or oxaiyl chloride / - Dimethyl sulfoxide oxidized to the 24-keto compound.

The conversion of a compound of general formula IX into the corresponding compound of the general formula II takes place, for. B. by Irradiation with ultraviolet light in the presence of a so-called "Triplet Sensitizers". Within the scope of the present invention, this Anthracene used. By cleaving the π bond of the 5,6 double bond, Rotation of the A-ring by 180 ° around the 5.6 single bond and re-establishment of the 5,6 double bond, the stereoisomerism on the 5,6 double bond is reversed. The 24-hydroxy group is then optionally with a protective group (Tetrahydrofuranyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethyl or trimethylsilylethoxymethyl group) among the usual, the expert common conditions. This procedure enables a clean one  Cleavage of the silyl protecting groups R¹ 'and R³'. Finally, if available, the 24-hydroxy protecting group in the last stage under the catalytic action an acidic agent (pyridinium p-toluenesulfonate [PPTS], p-toluenesulfonic acid, Acetic acid, hydrochloric acid, acidic ion exchanger) removed and the free Hydroxy groups optionally further implemented as already described.

To establish another C-20 modification, a compound of general formula X

generated, which is derived from the general formula IV in that R²¹ and R ^21a together form a methylene group and the isomerization of the triene system has already taken place.

For this purpose, the compound of the general formula III is analogous to that in WO 90/09991 described method in a compound of general formula XI

transferred.

By reaction with sulfur ylides, which consist of reagents of the type Me₃S⁺I⁻ or Me₃S⁺ (O) I⁻ by deprotonation with a base such as potassium tert-butanolate, Sodium hydride or potassium hydride are produced, a compound is obtained general formula XII

the stereochemistry at C-20 need not be uniform.

By rearrangement of the epoxides of the general formula III with bases such. B. Receives lithium diisopropylamide, lithium diethylamide or aluminum isopropylate the allyl alcohols of the general formula XIII,

which is analogous to that described above by photochemical isomerization of the Triensystems be converted into a compound of general formula XIV.

The conversion into a compound of the general formula X now takes place through Oxidation with an oxidizing agent such. B. manganese dioxide, pyridinium chloro chromate, pyridinium dichromate, barium manganate or oxalyl chloride / DMSO.

Another C-20 modification is made by implementing the compound of general formula XIV with an organometallic reagent of type I-CH₂- Zn-I, which is formed from Zn / Cu, Zn / Ag or Et₂Zn with CH₂I₂ (Simmons-Smith- Reaction), where a compound of the general formula XV

arises.

The alcohol function in XV is now with an oxidizing agent such. B. (Pyridinium chlorochromate, pyridinium dichromate or oxalyl chloride / DMSO) for Compound of general formula XVI

implemented,
which is derived from the general formula IV in that R²¹ and R ^21a together with the quaternary carbon atom C-20 form a cyclopropyl ring and the triene system is isomerized.

The compounds of general formulas X and XVI are now over the Intermediate stages XVII, XVIII and XIX

where R²¹ and R ^{21a have} the meanings described in the general formulas X and XVI, implemented analogously to the synthesis routes already described in a compound of general formula I.

The diastereomer separations or releases and derivatizations of the Hydroxy groups take place as already described. If desired, before the Deprotection, in turn, the 24-hydroxy group analogous as before described oxidized to the keto function.

The preparation of the 25-carboxylic acid derivatives of the general formula I, in which R¹⁹ and R ^19a each represent a hydrogen atom, is carried out according to the invention in that a compound of the general formula XX

wherein R¹ ′, R³ ′, R⁴, R ^4a , R²¹, R ^21a , A ′, B ′ and Y ′ have the meaning already described in the general formula II (also R²¹ = H, R ^21a = CH₃, R²¹ = CH₃, R ^21a = H), analogously to the reaction of the compounds of the general formula II (protective group cleavages) is converted into the target compounds.

For the synthesis of the compounds of general formula XX one uses the Aldehyde XXI

(H.H. Inhoffen et al., Chem. Ber. 91, 780 (1958), Chem Ber. 92, 1772 (1959); W, G. Dauben et al., Tetrahedron Lett. 30, 677 (1989)), wherein P is an acyl, alkyl or aryl-substituted silyl or tetrahydropyranyl, tetrahydrofuranyl or methoxymethyl or another alcohol protecting group.  

The structural modifications to the carbon atom 20 can be analogous to those for the vitamin D derivatives are described above, where Compounds of the general formula XXII

arise
wherein R²¹ and R ^21a each represent a methyl group, together a methylene group, together with the carbon 20 a cyclopropyl ring or R²¹ a fluorine and R ^21a a methyl group or R²¹ a methyl group and R ^21a a fluorine atom or R²¹ a hydrogen atom and R ^21a a methyl group or R²¹ is a methyl group and R ^{21a is} a hydrogen atom.

The side chains are introduced as for the vitamin D derivatives above described, the intermediates of the general formulas XXIII, XXIV and XXV

wherein R²¹, R ^21a , R⁴, R ^4a and Y have the meanings already mentioned, are run through.

The separation of the diastereomeric alcohols or secondary compounds can be done on any  any level.

For the synthesis of the compounds of general formula XX, the free hydroxy group protected, a compound of the general formula XXVI

is formed.

P ′ can be a tetrahydropyranyl, tetrahydrofuranyl or methoxymethyl group, if P is an acyl, alkyl or aryl substituted silyl group or P ′ can be an acyl, be alkyl or aryl substituted silyl group if P is a tetrahydropyranyl or tetrahydro furanyl or methoxymethyl group to differentiate the protecting groups to reach.

You split off P according to standard conditions and get a connection of general formula XXVII

Now the free hydroxyl group is oxidized (according to common procedures with pyridinium chlorochromate, pyridium dichromate, with barium manganate or under Swern conditions gen), wherein a compound of the general formula XXVIII

receives.

By reacting this compound with that by a base such as n-butyllithium (n-BuLi) or lithium diisopropylamide (LDA) generated anion of the known phosphine oxi of the general formula XXIX (H.F. DeLuca, Tetrahedron Lett 32, 7663 (1991)), in which R ′ and R³ ′ are alkyl- or aryl-substituted silyl groups,

a compound of the general formula XX is obtained.

The following examples serve to explain the invention in more detail.

example 1 (5E, 7E) - (1S, 3R) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20-fo-rmyl-20-methyl-9,10-secopregna-5, 7.10 (19) -triene 2

140 mg (4.5 mmol) of sodium hydride (80%) in 20 ml of tetrahydrofuran are initially introduced and removes the oxygen by repeated degassing in a vacuum and flushing with argon. Now at 0 ° C 2.5 g (3.0 mmol) (5E, 7E) - (1S, 3R) -1,3-bis [[1,1- dimethylethyl (diphenyl) silyl] oxy] -20-formyl-9,10-secopregna-5,7,10 (1-9) -triene 1 (M. Calverley Tetrahedron 43 4609 (1987), WO 87/00834, tert.- Butyldimethylsilyl protecting groups) in 20 ml of tetrahydrofuran and then 1.87 g (13.5 mmol) of methyl iodide were added dropwise. Stir overnight Room temperature, then pour the reaction mixture onto sodium chloride Solution, extracted with ethyl acetate, the organic phase washes with sodium chloride Solution, dries over sodium sulfate, removes the solvent and cleans the Crude product by chromatography on silica gel with hexane / ethyl acetate as Mobile phase, whereby 2.0 g of the title compound is obtained as a colorless foam.

1 H-NMR (CDCl₃): δ = 0.52 ppm (s, 3H, H-18); 0.96 u. 0.98 (2x s, 9H each, Si-t butyl); 1.13 u. 1.15 (2x s, 3H, H-21 and C-20-Me each); 4.29 (m, 1H, H -3); 4.64 (m, 1H, H-1); 4.73 u. 4.90 (2x s, 1H each, H-19); 5.62 u. 6.38 (2x d, J = 11 Hz, each 1H, H-6 u. H-7); 7.22-7.68 (m, 20H, Si-phenyl); 9.68 (s, 1H, H-22)

Example 2 (5E, 7E, 22E) - (1S, 3R) -bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20, N-dimethyl-N-methoxy-9,10-secochola-5,7 , 10 (19), 22-tetraen-24-amide 3

2.0 g (2.44 mmol) of 2 and 5.2 g (14.6 mmol) of N-methoxy-N-methyl-2- are stirred (triphenylphosphoranylidene) acetamide (D.A. Evans et al. J. Am. Chem. Soc. 112, 7001 (1990)) in 100 ml of toluene under argon for 48 hours at 80 ° C. After this Cooling, the solution is concentrated and the residue is chromatographed Silica gel with hexane / ethyl acetate, 880 mg of the title compound being colorless Foam remain.  

1 H-NMR (CDCl₃): δ = 0.53 ppm (s, 3H, H-18); 0.99 (s, 18H, Si-t-butyl); 1.16 u. 1.18 (2x s, 3H, H-21 and C-20-Me each); 3.27 (s, 3H, N-Me); 3.70 (s, 3H, N-OMe); 4.29 (m, 1H, H -3); 4.60 (m, 1H, H-1); 4.68 u. 4.88 (2x s, 1H each, H-19); 5.60 u. 6.38 (d, J = 11 Hz, each 1H, H-6 and H-7); 6.30 (d, J = 16 Hz, 1H, H-23); 7.19 (d, J = 16 Hz, 1H, H-22); 7.23-7.70 (m, 20H, Si-phenyl)

Example 3 (5E, 7E, 22E) - (1S, 3R) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -2-0-methyl-9,10-secopregna-5,7, 10 (19), 22-tetraen-24-al 4

880 mg (0.96 mmol) 3 are dissolved in 15 ml of tetrahydrofuran under argon, cooled to -78 ° C. and 4.2 ml (5 mmol) of DIBAH solution (1.2 M in toluene) are added dropwise. After 2 Hours at -78 ° C, 0.3 ml of methanol is added and the mixture is stirred for 1 hour at room temperature to. Then the precipitate is filtered off, the filtrate is concentrated and the residue is purified by chromatography, 690 mg of the title compound obtained as a colorless foam.

1 H-NMR (CDCl₃): δ = 0.51 ppm (s, 3H, H-18); 0.98 (s, 18H, Si-t-butyl); 1.16 u. 1.20 (2x s, 3H, H-21 and C-20-Me each); 4.30 (m, 1H, H-3); 4.61 (m, 1H, H-1); 4.70 u. 4.88 (2x s, 1H each, H-19); 5.61 u. 6.37 (2x d, J = 11 Hz, each 1H, H-6 and H-7); 6.07 (dd, J = 16.8 Hz, 1H, H-23); 7.04 (d, J = 16 Hz, 1H, H-22); 7.22 - 7.68 (m, 20H, Si phenyl); 9.57 (d, J = 8 Hz, 1H, H-24)

Example 4 (5E, 7E, 22E) - (1S, 3R) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -2-4-hydroxy-20-methyl-9,10-secocholesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid ethyl ester 5

From 180 mg (1.8 mmol) diisopropylamine and 1.1 ml (1.7 mmol) n-butyllithium (1.6 M in hexane) in 30 ml of tetrahydrofuran is prepared under argon and LDA -78 ° C cooled. 200 mg (1.7 mmol) of ethyl isobutyrate are then added and the mixture is stirred 30 min at -78 ° C and then add 590 mg (0.68 mmol) 4 in 3 ml Tetrahydrofuran. The mixture is stirred at -78 ° C for 2 hours and then open  Poured sodium chloride solution. After extraction with ethyl acetate, wash the organic phase with sodium chloride solution, drying over sodium sulfate and Removing the solvent, the residue is purified by chromatography, whereby 480 mg of the title compound are obtained as a colorless foam (1: 1- Diastereomers with respect to C-24).

1 H-NMR (CDCl₃): δ = 0.53 ppm (s, 3H, H-18); 0.95 (s, 18H, Si-t-butyl); 1.05 / 1.07, 1.10 / 1.12, 1.17, 1.18 (4x s, each 3H, H-21, C-20-Me, H-26 and H-27); 1.28 (t, 3 = 7 Hz, 3H, COOEt); 2.57 (d, J = 5 Hz, 1H, OH); 4.15 (q, 3 = 7 Hz, 2H, COOEt); 4.18 (m, 1H, H-24); 4.28 (m, 1H, H-3); 4.63 (m, 1H, H-1); 4.72 u. 4.90 (2x s, each 1H, H-19); 5.32 (dd, J = 15.5, 7.5 Hz, H-23); 5.89 / 5.90 (d, J = 15.5 Hz, 1H, H-22); 5.60 u. 6.38 (2x d, J = 11 Hz, each 1H, H-6 and H-7); 7.20-7.68 (m, 20H, Si-phenyl)

Example 5 (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -carboxylic acid ethyl ester 6a and (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22 -tetraen-25-carboxylic acid ethyl ester 6b

480 mg (0.5 mmol) of S are stirred with 65 mg (0.77 mmol) of dihydropyran and one Spatula tip pyridinium p-toluenesulfonate in 5 ml methylene chloride under argon for 24 hours at room temperature. The organic phase is treated with sodium chloride Washed solution, dried over sodium sulfate, the solvent removed and the The residue is purified by chromatography on silica gel with hexane / ethyl acetate, where 480 mg of the diastereomer mixture remain as a colorless foam. This Product is dissolved in 80 ml of toluene and in the presence of 100 mg (0.55 mmol) Anthracene and 0.1 ml triethylamine in a Pyrex immersion reactor with a High pressure mercury lamp (Philips HPK 125) under nitrogen for 15 min. irradiated. The solvent is removed and the crude product is 708 mg (2.25 mmol) tetrabutylammonium fluoride in 10 ml tetrahydrofuran under argon stirred at 60 ° C for 1 hour. It is then poured into sodium chloride solution, extracted with ethyl acetate, washes with sodium chloride solution, dries over sodium sulfate and removes the solvent. The residue is dissolved in 5 ml of methanol / methylene chloride (9: 1) and stirred under argon with 500 mg of Amberlite (activated) for 24 hours.  

It is now filtered, the filtrate is washed with sodium hydrogen carbonate solution and Sodium chloride solution, dries over sodium sulfate, removes the solvent and purifies the residue chromatographically. The separation of the diastereomers now takes place via HPLC (reversed phase conditions, acetonitrile / water as Eluent, whereby one consecutively 5 mg 6b and 6 mg 6a as colorless foams receives.

1 H-NMR (CD₂Cl₂): 6a: δ = 0.58 ppm (s, 3H, H-18); 1.03, 1.07, 1.12 (3x s, 3H, 3H, 6H, H-21, C-20-Me, H-26 and. H-27); 1.27 (t, J = 7 Hz, 3H, COOEt); 4.10 (m, 1H, H-24); 4.12 (q, J = 7 Hz, 2H, COOEt); 4.18 (m, 1H, H-3); 4.38 (m, 1H, H-1); 4.97 u. 5.30 (2x s, 1H each, H-19); 5.31 (dd, J = 15.5, 7 Hz, 1H, H-23); 5.86 (d, J = 15.5 Hz, 1H, H-22); 5.99 u. 6.35 (2x d, J = 11 Hz, each 1H, H-6 and H-7) 6b: δ = 0.58 ppm (s, 3H, H-18); 1.01, 1.09, 1.12 (3x s, 3H, 3H, 6H, H-21, C-20- Me, H-26 u. H-27); 1.27 (t, J = 7 Hz, 3H, COOEt); 4.10 (m, 1H, H-24); 4.11 (q, J = 7 Hz, 2H, COOEt); 4.18 (m, 1H, H-3); 4.38 (m, 1H, H-1); 4.96 u. 5.30 (2x s, 1H each, H-19); 5.30 (dd, J = 15.5, 7 Hz, 1H, H-23); 5.88 (d, J = 15.5 Hz, 1H, H-22); 5.99 u. 6.35 (2x d, J = 11 Hz, each 1H, H-6 and H-7)  

Example 6 (5E, 7E, 22E) - (1S, 3R) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -2-4-hydroxydy-20-methyl-9,10-secocholesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid propyl ester 7

From 217 mg (2.2 mmol) diisopropylamine and 1.23 ml (2 mmol) n-butyllithium (1.6 M in hexane) in 30 ml of tetrahydrofuran is prepared under argon and LDA -78 ° C cooled. 256 mg (2 mmol) of propyl isobutyrate are then added and the mixture is stirred 30 min at -78 ° C and then add 690 mg (0.8 mmol) 4 in 3 ml of tetrahydrofuran. The mixture is stirred at -78 ° C for 2 hours and then on sodium chloride solution poured. After extraction with ethyl acetate, wash the organic phase with Sodium chloride solution, drying over sodium sulfate and removing the The residue is purified by chromatography using solvent, 550 mg the title compound are obtained as a colorless foam (1: 1 diastereomers with respect to C-24).

1 H-NMR (CDCl₃): δ = 0.53 ppm (s, 3H, H-18); 0.95 (t, J = 7 Hz, 3H, COOPr); 0.97 u. 0.98 (2x s, 9H each, Si-t-butyl); 1.07 / 1.08, 1.10 / 1.12, 1.18 u. 1.19 (4x s, 3H each, H- 21, C-20-Me, H-26 u. H-27); 1.68 (hex, J = 7 Hz, 2H, COOPr); 2.53 (d, J = 7 Hz, 1H, OH); 4.08 (q, J = 7 Hz, 2H, COOPr); 4.15 (m, 1H, H-24); 4.28 (m, 1H, H-3); 4.62 (m, 1H, H-1); 4.72 u. 4.89 (2x s, 1H each, H-19); 5.33 (dd, J = 15.5, 7 Hz, H-23); 5.90 / 5.91 (d, J = 15.5 Hz, 1H, H-22); 5.60 u. 6.39 (2x d, J = 11 Hz, each 1H, H-6 and H- 7); 7.22-7.65 (m, 20H, Si-phenyl)

Example 7 (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secochoiest-a-5,7,10 (19), 22-tetraen-25 -carboxylic acid propyl ester 8a and (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22 -tetraen-25-carboxylic acid propyl ester 8b

540 mg (0.55 mmol) 2 are stirred with 76 mg (0.90 mmol) dihydropyran and one Spatula tip pyridinium p-toluenesulfonate in 7 ml methylene chloride under argon for 24 hours at room temperature. The organic phase is treated with sodium chloride Washed solution, dried over sodium sulfate, the solvent removed and the  The residue is purified by chromatography on silica gel with hexane / ethyl acetate, where 525 mg of the diastereomer mixture remain as a colorless foam. This Product is dissolved in 80 ml of toluene and in the presence of 100 mg (0.55 mmol) Anthracene and 0.1 ml triethylamine in a Pyrex immersion reactor with a High pressure mercury lamp (Philips HPK 125) under nitrogen for 15 min. irradiated. The solvent is removed and the crude product is mixed with 1.5 g (4.8 mmol) of tetrabutylammonium fluoride in 20 ml of tetrahydrofuran under argon 60 ° C stirred for 1 hour. It is then poured into sodium chloride solution, extracted with Ethyl acetate, washes with sodium chloride solution, dries over sodium sulfate and removes the solvent. The residue is dissolved in 10 ml of methanol / methylene chloride (9: 1) dissolved and stirred under argon with 688 mg of Amberlite (activated) for 24 hours. Man filter now, wash the filtrate with sodium hydrogen carbonate solution and Sodium chloride solution, dries over sodium sulfate, removes the solvent and purifies the residue chromatographically. The separation of the diastereomers now takes place via HPLC (reversed phase conditions, acetonitrile / water as Eluent, whereby one consecutively 34 mg 8b and 24 mg 8a as colorless foams receives.

1 H-NMR (CD₂Cl₂): 8a: δ = 0.58 ppm (s, 3H, H-18); 0.95 (t, J = 7 Hz, 3H, COOPr); 1.04, 1.08, 1.22 (3x s, 3H, 3H, 6H, H-21, C-20-Me, H-26 and H-27); 1.67 (hex, J = 7 Hz, 3H, COOPr); 4.02 (t, J = 7 Hz, 2H, COOPr); 4.10 (m, 1H, H-24); 4.18 (m, 1H, H-3); 4.38 (m, 1H, H-1); 4.96 u. 5.29 (2x s, 1H each, H-19); 5.31 (dd, J = 15.5, 7 Hz, 1H, H-23); 5.86 (d, J = 15.5 Hz, 1H, H-22); 6.00 u. 6.36 (2x d, J = 11 Hz, each 1H, H-6 u. H-7)

8b: δ = 0.58 ppm (s, 3H, H-18); 0.95 (t, J = 7 Hz, 3H, COOPr); 1.00, 1.09, 1.22 (3x s, 3H, 3H, 6H, H-21, C-20-Me, H-26 and. H-27); 1.68 (hex, J = 7 Hz, 3H, COOPr); 4.02 (t, J = 7 Hz, 2H, COOPr); 4.10 (m, 1H, H-24); 4.18 (m, 1H, H-3); 4.38 (m, 1H, H-1); 4.96 u. 5.29 (2x s, 1H each, H-19); 5.32 (dd, J = 15.5, 7 Hz, 1H, H-23); 5.89 (d, J = 15.5 Hz, 1H, H-22); 6.00 u. 6.36 (2x d, J = 11 Hz, each 1H, H-6 and H-7)  

Example 8 (5E, 7E, 22E) - (1S, 3R) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -2-4-hydroxy-20-methyl-9,10-secocholesta- 5,7,10 (19), 22-tetraen-25-carboxylic acid isopropyl ester 9

From 192 mg (1.9 mmol) diisopropylamine and 1.1 ml (1.7 mmol) n-butyllithium (1.6 M in hexane) in 30 ml of tetrahydrofuran is prepared under argon and LDA -78 ° C cooled. 221 mg (1.7 mmol) of isobutyric acid isopropyl ester are now added, stir for 30 min at -78 ° C and then add 440 mg (0.51 mmol) 4 in 3 ml Tetrahydrofuran. The mixture is stirred for 3 hours at -78 ° C and then open Poured sodium chloride solution. After extraction with ethyl acetate, wash the organic phase with sodium chloride solution, drying over sodium sulfate and Removing the solvent, the residue is purified by chromatography, where 390 mg of the title compound are obtained as a colorless foam (1: 1- Diastereomers with respect to C-24).

1 H-NMR (CDCl₃): δ = 0.53 ppm (s, 3H, H-18); 0.95 u. 0.97 (2x s, each 9H, Si-t butyl); 1.05 / 1.07, 1.09 / 1.11, 1.17 u. 1.18 (4x s, 3H, H-21, C-20-Me, H-26 and H- 27); 1.28 (d, J = 7 Hz, 6H, COOiPr); 4.12 (m, 1H, H-24); 4.28 (m, 1H, H-3); 4.64 (m, 1H, H-1); 4.72 u. 4.90 (2x s, 1H each, H-19); 5.24 (hept, J = 7 Hz, 1H, COOiPr); 5.33 (dd, J = 15.5, 7 Hz, H-23); 5.90 / 5.91 (d, J = 15.5 Hz, 1H, H-22); 5.61 u. 6.38 (2x d, J = 11 Hz, each 1H, H-6 u. H-7); 7.22-7.65 (m, 20H, Si-phenyl)

Example 9 (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -carboxylic acid isopropyl ester 10a and (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22 -tetraen-25-carboxylic acid isopropyl ester 10b

385 mg (0.39 mmol) 2 are stirred with 108 mg (1.56 mmol) dihydropyran and one Spatula tip pyridinium p-toluenesulfonate in 5 ml methylene chloride under argon for 24 hours at room temperature. The organic phase is treated with sodium chloride Washed solution, dried over sodium sulfate, the solvent removed and the  The residue is purified by chromatography on silica gel with hexane / ethyl acetate, where 490 mg of the diastereomer mixture remain as a colorless foam. This Product is dissolved in 80 ml of toluene and in the presence of 100 mg (0.55 mmol) Anthracene and 0.1 ml triethylamine in a Pyrex immersion reactor with a High pressure mercury lamp (Philips HPK 125) under nitrogen for 15 min. irradiated. The solvent is removed and the crude product is 1.23 g (3.9 mmol) tetrabutylammonium fluoride in 20 ml tetrahydrofuran under argon 60 ° C stirred for 1 hour. It is then poured into sodium chloride solution, extracted with Ethyl acetate, washes with sodium chloride solution, dries over sodium sulfate and removes the solvent. The residue is dissolved in 10 ml of methanol / methylene chloride (9: 1) dissolved and stirred under argon with 475 mg of Amberlite (activated) for 24 hours. Man filter now, wash the filtrate with sodium hydrogen carbonate solution and Sodium chloride solution, dries over sodium sulfate, removes the solvent and purifies the residue chromatographically. The separation of the diastereomers now takes place via HPLC (reversed phase conditions, acetonitrile / water as Mobile phase, one after the other 12 mg 10b and 11 mg 10a as colorless Receives foams.

1 H-NMR (CD₂Cl₂): 10a δ = 0.58 ppm (s, 3H, H-18); 1.03, 1.06, 1.12 (3x s, 3H, 3H, 6H, H-21, C-20-Me, H-26 and. H-27); 1.28 (d, J = 7 Hz, 6H, COOiPr); 4.09 (m, 1H, H-24); 4.18 (m, 1H, H-3); 4.38 (m, 1H, H-1); 4.96 u. 5.30 (2x s, 1H each, H-19); 4.98 (hept, J = 7 Hz, 1H, COOiPr); 5.31 (dd, J = 15.5, 7 Hz, H-23); 5.85 (d, J = 15.5 Hz, 1H, H-22); 5.99 u. 6.36 (2x d, J = 11 Hz, each 1H, H-6 and H-7)

1 H-NMR (CD₂Cl₂): 10b: δ = 0 59 ppm (s, 3H, H-18); 1.02, 1.11, 1.12 (3x s, 3H, 3H, 6H, H-21, C-20-Me, H-26 and. H-27); 1.27 (d, J = 7 Hz, 6H, COOiPr); 4.09 (m, 1H, H-24); 4.18 (m, 1H, H-3); 4.38 (m, 1H, H-1); 4.96 u. 5.30 (2x s, 1H each, H-19); 4.99 (hept, J = 7 Hz, 1H, COOiPr); 5.31 (dd, J = 15.5, 7 Hz, H-23); 5.88 (d, J = 15.5 Hz, 1H, H-22); 6.00 u. 6.36 (2x d, J = 11 Hz, each 1H, H-6 and H-7)  

Example 10 (5E, 7E) - (1S, 3R, 2OR) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -2-0,21-epoxy-20-methyl-9,10- secopregna-5,7,10 (19) -triene 11

3.1 g (3.84 mmol) (5E, 7E) - (1S, 3R) -Bis [[(1,1-dimethylethyl) diphenylsilyl] oxy] - 9,10-seco-pregna-5,7,10 (19) -trien-20-one (bis-TBDMS ether see WO 90/09991, Leo Pharmaceutical Products) are in 70 ml of dimethylformamide under argon dissolved and mixed with 1.06 g (5.2 mmol) trimethylsulfonium iodide. You cool down 0 ° C and added in portions 0.51 g (5.2 mmol) of potassium tert-butoxide. After 15 Min. At 0 ° C saturated sodium chloride solution is added, with ethyl acetate extracted and the organic phase several times with sodium chloride solution washed. After drying over sodium sulfate, the solvent and purifies the residue on silica gel with hexane / ethyl acetate, 2.2 g of the The title compound is obtained as a colorless foam.

1 H-NMR (CDCl₃): δ = 0.58 ppm (s, 3H, H-18); 0.89 u. 0.94 (2x s, each 9H, Si-t butyl); 1.32 (s, 3H, H-21); 2.31 u. 2.50 (2x d, J = 5 Hz, each 1H, H-22); 4.19 (m, 1H, H-3); 4.59 (t, J = 5.5 Hz, 1H, H-1); 4.70 u. 4.82 (2x s, 1H each, H-19); 5.57 u. 6.31 (2x d, J = 11 Hz, each 1H, H-6 u. H-7); 7.12-7.68 (m, 20H, Si-phenyl)

Example 11 (5E, 7E) - (1S, 3R) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20-methylene-9,10-secopregna-5,7,10 ( 19) -triene-21-ol 12

0.28 g (3.8 mmol) of diethylamine is dissolved in 35 ml of diethyl ether and under argon adds 2.4 ml (3.8 mmol) n-butyllithium solution (1.6 M in hexane) at 0 ° C. To At this temperature for 30 min, 0.72 g (0.88 mmol) 11 in 5 ml is added dropwise Diethyl ether and stirred for 1 hour at 0 ° C and 1 hour at room temperature. Then sodium chloride solution is added and the mixture is extracted with ethyl acetate and the organic phase is washed with sodium chloride solution. After drying Concentrate over sodium sulfate and chromatograph the residue Silica gel with hexane / ethyl acetate, where 360 mg of the title compound as colorless foam in addition to 280 mg of the starting product.  

1 H-NMR (CDCl₃): δ = 0.45 ppm (s, 3H, H-18); 0.99 u. 1.00 (2x s, 9H each, Si-t butyl); 4.08 u. 4.17 (2x d, J = 14.5 Hz, 1H each, H-22); 4.29 (m, 1H, H -3); 4.65 (m, 1H, H-1); 4.75 u. 4.90 (2x s, 1H each, H-19); 5.03 u. 5.23 (2x s, 1H each, H-21); 5.67 u. 6.39 (2x d, J = 11 Hz, each 1H, H-6 and H-7); 7.20-7.62 (m, 20H, Si-phenyl)

Example 12 (5Z, 7E) - (1S, 3R) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20-methylene-9,10-secopregna-5,7,10 ( 19) -triene-21-ol 13

500 mg (0.61 mmol) 12 are dissolved in 80 ml of toluene, and 80 mg (0.44 mmol) are added. Anthracene and 15 µl triethylamine and irradiated for 18 min in the under 5. described apparatus. After working up and cleaning, 450 mg are obtained the title compound as a colorless foam.

1 H-NMR (CDCl₃): δ = 0.43 ppm (s, 3H, H-18); 0.95 u. 1.00 (2x s, 9H each, Si-t butyl); 4.05 u. 4.15 (2x d, J = 14.5 Hz, 1H each, H-22); 4.25 (m, 1H, H -3); 4.55 (m, 1H, H-1); 4.83 (s, 1H, H-19); 5.00 (s, 1H, H-21); 5.08 (s, 1H, H-19 '); 5.21 (s, 1H, H-21 ′); 6.02 u. 6.10 (2x d, J = 11 Hz, each 1H, H-6 and H-7); 7.15-7.68 (m, 20H, Si phenyl)

Example 13 (5Z, 7E) - (1S, 3R) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20-fo-rmyl-9,10-secopregna-5,7,10 ( 19), 20-tetraene 14

2.8 g (3.36 mmol) of L3 are dissolved in 100 ml of methylene chloride and 11.6 g (133 mmol) of manganese dioxide. The mixture is stirred at room temperature for 1 hour and then suctioned off through Celite. After removing the solvent you get 2.5 g of the title compound as a colorless foam.  

1 H-NMR (CDCl₃): δ = 0.35 ppm (s, 3H, H-18); 0.92 u. 0.99 (2x s, 9H each, Si-t butyl); 4.23 (m, 1H, H -3); 4.55 (m, 1H, H-1); 4.83 u. 5.10 (2x s, 1H each, H-19); 6.02 u. 6.09 (2x d, J = 11 Hz, 1H each, H-6 and H-7); 6.11 u. 6.32 (2x s, 1H each, H-21); 7.23- 7.69 (m, 20H, Si-phenyl); 9.58 (s, 1H, H-22)

Example 14 (5Z, 7E, 22E) - (1S, 3R) -Bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -N-methoxy-N-methyl-9,10-secocliola-5,7, 10 (19), 20,22-pentaen-24-amide 15

1.2 g (1.4 mmol) of 14 and 3.75 g (9 mmol) of N-methoxy-N-methyl-2- are stirred (triphenylphosphoranylidene) acetamide (D.A. Evans et al. J. Am. Chem. Soc. 112, 7001 (1990)) in 50 ml of toluene under argon for 48 hours at 80 ° C. After this Cooling, the solution is concentrated and the residue is chromatographed Silica gel with hexane / ethyl acetate, 1.07 g of the title compound being colorless Foam remain.

1 H-NMR (CDCl₃): δ = 0.39 ppm (s, 3H, H-18); 0.93 u. 0.99 (2x s, 9H each, Si-t butyl); 3.28 (s, 3H, N-Me); 3.75 (s, 3H, N-OMe); 4.25 (m, 1H, H -3); 4.55 (m, 1H, H-1); 4.84 u. 5.10 (2x s, 1H each, H-19); 5.32 u. 5.57 (2x s, 1H each, H-21); 6.04 u. 6.10 (d, J = 11 Hz, each 1H, H-6 and H-7); 6.65 (d, J = 15.5 Hz, 1H, H-23); 7.23-7.70 (m, 21H, Si-phenyl and the like. H-22)

Example 15 (5Z, 7E, 22E) - (1S, 3R) -Bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -9.10-secochola-5,7,10 (19), 20,22- pentaen-24-al 16

750 mg (0.8 mmol) of 15 are dissolved in 10 ml of tetrahydrofuran under argon, the mixture is cooled to -78 ° C. and 3.3 ml (4 mmol) of DIBAH solution (1.2 M in toluene) are added dropwise. After 2 Hrs at -78 ° C, 2.3 ml of methanol are added and the mixture is stirred for 1 h at room temperature to. Then the precipitate is filtered off, the filtrate is concentrated and the residue is purified by chromatography, 500 mg of the title compound being obtained  obtained as a colorless foam.

1 H-NMR (CDCl₃): δ = 0.40 ppm (s, 3H, H-18); 0.92 u. 1.00 (2x s, 9H each, Si-t butyl); 4.22 (m, 1H, H -3); 4.56 (m, 1H, H-1); 4.82 u. 5.10 (2x s, 1H each, H-19); 5.51 u. 5.68 (2x s, 1H each, H-21); 6.02 u. 6.10 (2x d, J = 11 Hz, each 1H, H-6 and H-7); 6.36 (dd, J = 16.8 Hz, 1H, H-23); 7.18 (d, J = 16 Hz, 1H, H-22); 7.22 - 7.68 (m, 20H, Si phenyl); 9.60 (d, J = 8 Hz, 1H, H-24)

Example 16 (5Z, 7E, 22E) - (1S, 3R, 2OR) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] ox-y] -24-hydroxy-9,10-secocholesta-5, 7,10 (19), 20,22-pentaen-25-carboxylic acid isopropyl ester 17a (5Z, 7E, 22E) - (1S, 3R, 20S) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -24-hydroxy-9,10-secocholesta-5,7, 10 (19), 20,22-pentaen-25-carboxylic acid isopropyl ester 17b

From 385 mg (3.8 mmol) diisopropylamine and 2.2 ml (3.4 mmol) n-butyllithium (1.6 M in hexane) in 30 ml of tetrahydrofuran is prepared under argon and LDA -78 ° C cooled. 442 mg (3.4 mmol) of isobutyric acid isopropyl ester are now added, stir for 30 min at -78 ° C and then add 650 mg (0.76 mmol) 16 in 5 ml Tetrahydrofuran. The mixture is stirred for 3 hours at -78 ° C and then open Poured sodium chloride solution. After extraction with ethyl acetate, wash the organic phase with sodium chloride solution, drying over sodium sulfate and Removing the solvent, the residue is separated by chromatography, where 207 mg of the title compound 17b and 160 mg of the Title compound 17a is obtained as colorless foams.

1 H-NMR (CD₂Cl₂): 17a: δ = 0.37 ppm (s, 3H, H-18); 0.94 u. 0.96 (2x s, 9H each, Si t-butyl); 1.13 u. 1.14 (2x s, 3H, H-26 and H-27 each); 1.22 (d, J = 7 Hz, 6H, COOiPr); 4.14 (m, 1H, H-24); 4.24 (m, 1H, H-3); 4.54 (m, 1H, H-1); 4.81 u. 5.17 (2x s, 1H each, H-19); 4.98 (hept, J = 7 Hz, 1H, COOiPr); 4.99 u. 5.07 (2x s, 1H each, H-21); 5.77 (dd, J = 15.5, 6 Hz, H-23); 6.02 u. 6.12 (2x d, J = 11 Hz, each 1H, H-6 and H-7); 6.24 (d, J = 15.5 Hz, 1H, H-22); 7.22-7.65 (m, 20H, Si-phenyl)
1 H NMR (CD₂Cl₂): 17b; δ = 0 37 ppm (s, 3H, H-18); 0.94 u. 0.96 (2x s, 9H each, Si t-butyl); 1.15 u. 1.18 (2x s, 3H, H-26 and H-27 each); 1.23 (d, J = 7 Hz, 6H, COOiPr); 4.14 (m, 1H, H-24); 4.24 (m, 1H, H-3); 4.54 (m, 1H, H-1); 4.82 u. 5.19 (2x s, 1H each, H-19); 4.99 (hept, J = 7 Hz, 1H, COOiPr); 5.00 u. 5.08 (2x s, 1H each, H-21); 5.81 (dd, J = 15.5, 6 Hz, H-23); 6.02 u. 6.12 (2x d, J = 11 Hz, each 1H, H-6 and H-7); 6.29 (d, J = 15.5 Hz, 1H, H-22); 7.22-7.65 (m, 20H, Si-phenyl)

Example 17 (5Z, 7E, 22E) - (1S, 3R, 2OR) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (1-9), 20,22-pentaen-25-carboxylic acid isopropyl ester 18a

160 mg (0.16 mmol) 17a are stirred with 162 mg (1.6 mmol) dihydropyran and a spatula tip of pyridinium p-toluenesulfonate in 5 ml of methylene chloride Argon for 24 hours at room temperature. Then with sodium chloride solution washed, dried over sodium sulfate, the solvent removed and the The residue is purified by chromatography. The diastereoinere mixture thus obtained is dissolved in 20 ml of tetrahydrofuran and with 408 mg (1.3 mmol) Tetrabutylammonium fluoride stirred at 60 ° C under argon. You pour on Sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride Solution and constricts. The residue is now in with 420 mg Amberlite (activated) 5 ml of methanol / methylene chloride (9: 1) stirred at room temperature. Subsequently is filtered, the filtrate is washed with sodium hydrogen carbonate solution and Sodium chloride solution, dries over sodium sulfate and removes the solvent. The The crude product is purified by chromatography on silica gel with hexane / ethyl acetate, whereby 23 mg of the title compound is obtained as a colorless foam.

1 H-NMR (CD₂Cl₂): 18a: δ = 0.42 ppm (s, 3H, H-18); 1.11 u. 1.12 (2x s, 3H each, H- 26 u. H-27); 1.22 (d, J = 7 Hz, 6H, COOiPr); 4.15 (m, 2H, H-24 and H-3); 4.37 (m, 1H, H-1); 4.95 u. 5.30 (2x s, 1H each, H-19); 4.97 (hept, J = 7 Hz, 1H, COOiPr); 5.00 u. 5.17 (2x s, 1H each, H-21); 5.78 (dd, J = 15.5, 6 Hz, H-23); 6.03 u. 6.34 (2x d, J = 11 Hz, 1H each, H-6 u. H-7); 6.22 (d, J = 15.5 Hz, 1H, H-22)  

Example 18 (5Z, 7E, 22E) - (1S, 3R, 20S) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (1-9), 20,22-pentaen-25-carboxylic acid isopropyl ester 18b

207 mg (0.21 mmol) of 17b are stirred with 226 mg (2.7 mmol) of dihydropyran and a spatula tip of pyridinium p-toluenesulfonate in 5 ml of methylene chloride Argon for 24 hours at room temperature. Then with sodium chloride solution washed, dried over sodium sulfate, the solvent removed and the The residue is purified by chromatography. The mixture of diastereomers thus obtained is dissolved in 20 ml of tetrahydrofuran and with 566 mg (1.8 mmol) Tetrabutylaminonium fluoride stirred at 60 ° C under argon. You pour on Sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride Solution and constricts. The residue is now in with 500 mg Amberlite (activated) 5 ml of methanol / methylene chloride (9: 1) stirred at room temperature. Subsequently is filtered, the filtrate is washed with sodium hydrogen carbonate solution and Sodium chloride solution, dries over sodium sulfate and removes the solvent. The The crude product is purified by chromatography on silica gel with hexane / ethyl acetate, whereby 28 mg of the title compound is obtained as a colorless foam.

1 H-NMR (CD₂Cl₂): 17b: δ = 0.42 ppm (s, 3H, H-18); 1.12 u. 1.15 (2x s, 3H each, H- 26 u. H-27); 1.22 (d, J = 7 Hz, 6H, COOiPr); 4.14 (m, 2H, H-24 and H-3); 4.36 (m, 1H, H-1); 4.95 u. 5.30 (2x s, 1H each, H-19); 4.96 (hept, J = 7 Hz, 1H, COOiPr); 4.98 u. 5.16 (2x s, 1H each, H-21); 5.80 (dd, J = 15.5, 6 Hz, H-23); 6.03 u. 6.34 (2x d, J = 11 Hz, 1H each, H-6 u. H-7); 6.25 (d, J = 15.5 Hz, 1H, H-22).

Claims (16)

1. 25-carboxylic acid derivatives of the general formula I, in which R 1 and R 3 independently of one another each represent a hydrogen atom, a straight-chain or branched-chain saturated alkanoyl group having 1 to 9 carbon atoms or an aroyl group,
R¹⁹ and R ^19a each represent a hydrogen atom or together an exocyclic methylene group,
A and B together represent a keto oxygen atom or A a group OR²⁴ and B a hydrogen atom or A a hydrogen atom and B a group OR²⁴, where R²⁴ is a hydrogen atom or a straight or branched chain saturated alkanoyl group with up to 9 carbon atoms or an aroyl group,
R²¹ and R ^21a independently of one another represent a hydrogen atom, a chlorine or fluorine atom, an alkyl group having 1 to 4 carbon atoms, wherein when R¹⁹ and R ^19a together form a methylene group, R²¹ cannot represent a hydrogen atom and R ^21a cannot represent a methyl group or vice versa , together a methylene group, together with the quaternary carbon atom 20 a 3-7 membered, saturated or unsaturated carbocyclic ring,
R⁴ and R ^4a are each a hydrogen atom, a chlorine or fluorine atom, a trifluoromethyl group, a straight or branched chain, saturated or unsaturated hydrocarbon radical with up to 4 carbon atoms or R⁴ and R ^4a together with the carbonoin 25 a 3- to 7-membered , saturated or unsaturated carbocyclic ring and Y one of the radicals -C (O) NR⁵R⁵ ', -C (O) OR⁶, -C (O) SR⁶, -CN, where R⁵ and R⁵' independently of one another and R⁶ each for a hydrogen atom or represent a linear or branched alkyl or alkoxy group having 1 to 8 carbon atoms. 2. Compounds of general formula I according to claim 1, wherein R¹, R³ and R²⁴ each represent a hydrogen atom. 3. Compounds of general formula I according to claim 1, wherein R¹, R³ and R²⁴ each for an acetyl, propionyl, n-butyryl, iso-butyryl, pivaloyl or valeryl radical stand. 4. Compounds of general formula I according to claim 1, wherein R¹, R³ and R²⁴ each stand for a benzoyl residue. 5. Compounds of general formula I according to claim 1, wherein R⁴ and R ^4a
each represent a methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl or tert-butyl radical. 6. Compounds of general formula I according to claim 1, wherein the substituent R²¹ or R ^21a for a methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl or tert-butyl radical stand and the other substituent stands for a methyl group. 7. Compounds of general formula I according to claim 1, wherein R 21 and R ^21a together with the tertiary carbon atom 20 form a cyclopropyl ring. 8. Compounds of general formula I according to claim 1, wherein R²¹ and R ^21a together represent a methylene group. 9. Compounds of general formula I according to claim 1, wherein R²¹ is a fluorato and R ^{21a is} a methyl group or R²¹ is a methylene group and R ^{21a is} a fluorine atom. 10. Compounds of general formula I according to claim 1, wherein R⁴ and R ^4a together represent a methylene group or together with the tertiary carbon atom 25 form a cyclopropyl, pentyl or hexyl ring. 11. Compounds of general formula I according to claim 1, wherein R⁵ and R⁵ ' Are hydrogen atoms. 12. Compounds of general formula I according to claim 1, wherein R⁶ a Is hydrogen atom. 13. Compounds of general formula I according to claim 1, wherein R⁵ and R⁵ 'or R⁶ a methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl or tert-butyl group is. 14. Compounds of the general formula I, namely

• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -carboxylic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -carboxylic acid remethylester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -carboxylic acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -carbon acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -propyl carboxylate
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -car propyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -isopropyl carboxylate
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen -25 -isopropyl carboxylate
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -butyl carboxylate
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20-methyl-1,3,24-trihydroxy-9,10-secocholest-a-5,7,10 (19), 22-tetraen-25 -butyl carboxylate
• (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 20,22-pentaen-25-carboxylic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 20,22-pentaen-25-carboxylic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 20,22-pentaen-25-carboxylic acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 20,22-pentaen-25-carboxylic acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 20,22-pentaen-25-carboxylic acid propyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 20,22-pentaen-25-carboxylic acid propyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 20,22-pentaen-25-carboxylic acid isopropyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -1,3,24 -Trihydroxy-9,10-secocholesta- 5,7,10 (19), 20,22-pentaen-25-carboxylic acid isopropyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 20,22-pentaen-25-carboxylic acid butyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -1,3,24-trihydr oxy-9,10-secocholesta-5,7,10 (19), 20,22-pentaen-25-carboxylic acid butyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20,21-methylene-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraen-25 -carboxylic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20,21-methyl n-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraen 25-carboxylic acid methyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20,21-methylene-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraen-25 -carboxylic acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) 20,21-methylene-1,3,24-trihydroxy-9,10-secocholesta- 5,7,10 (19), 22-tetraen-25- carboxylic acid ethyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20,21-methylene-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraen-25 -Carboxylic acid propyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20,21-methylene-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraen-25 -propyl carboxylate
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20.21-methylene-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraen-25 -isopropyl carboxylate
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20,21-methylene-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraen-25 -isopropyl carboxylate
• (5Z, 7E, 22E) - (1S, 3R, 24R) -20,21-methylene-1,3,2 4-trihydroxy-9,10-secocholesta-5,7,10 (1 9), 22-tetraene -25-carboxylic acid butyl ester
• (5Z, 7E, 22E) - (1S, 3R, 24S) -20,21-methylene-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraen-25 -butyl carboxylate.

15. Pharmaceutical preparations containing at least one compound of the general Formula I according to one of claims 1 to 14 and a pharmaceutical compatible carrier. 16. Use of the compounds of general formula I according to claims 1 to 14 for the manufacture of pharmaceuticals.