CA2058637A1 - Side-chain homologous vitamin d derivatives, process for their production, pharmaceutical preparations containing these derivatives and their use as pharmaceutical agents - Google Patents
Side-chain homologous vitamin d derivatives, process for their production, pharmaceutical preparations containing these derivatives and their use as pharmaceutical agentsInfo
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- CA2058637A1 CA2058637A1 CA002058637A CA2058637A CA2058637A1 CA 2058637 A1 CA2058637 A1 CA 2058637A1 CA 002058637 A CA002058637 A CA 002058637A CA 2058637 A CA2058637 A CA 2058637A CA 2058637 A1 CA2058637 A1 CA 2058637A1
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- hydroxy
- secochola
- tetraene
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- diol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
Abstract New side-chain homologous vitamin D derivatives of formula I
(I), are described, in which R1, R2, R3, R4, R5 and R6 have the meaning given in the description, B and D mean either 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 and X means an alkylene oxy radical -(CH2)nO- with n = 1 to 3 or A means a methylene bridge (-CH2-) between carbon atoms 20 and 22 and X means an alkylene radical -(CH2)n- or an alkylene oxy radical -(CH2)nO- with n = 1 to 3, or if A stands for a direct bond and B and D together stand for a second bond, means one of radicals -CH2-O-CH2-? -(CH2)2- or -(CH2)2 , and a process for their production, pharmaceutical preparations that contain this compound and their use for the production of pharmaceutical agents.
The new compounds have a proliferation-inhibiting and cell-differentiating effect.
(I), are described, in which R1, R2, R3, R4, R5 and R6 have the meaning given in the description, B and D mean either 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 and X means an alkylene oxy radical -(CH2)nO- with n = 1 to 3 or A means a methylene bridge (-CH2-) between carbon atoms 20 and 22 and X means an alkylene radical -(CH2)n- or an alkylene oxy radical -(CH2)nO- with n = 1 to 3, or if A stands for a direct bond and B and D together stand for a second bond, means one of radicals -CH2-O-CH2-? -(CH2)2- or -(CH2)2 , and a process for their production, pharmaceutical preparations that contain this compound and their use for the production of pharmaceutical agents.
The new compounds have a proliferation-inhibiting and cell-differentiating effect.
Description
Side-Chain Homologous Vitamin D Derivatives, Process for their Production, Pharmaceutical Preparations Containing these Derivatives and their Use as Pharmaceutical Agents This invention relates to side-chain homologous vitamin D
derivatives of formula I
,~ Y~
9`~ Il), ~.9 ~o
derivatives of formula I
,~ Y~
9`~ Il), ~.9 ~o
2 ~ 1 in which . -Rl 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 5 carbon atoms, a trifluoromethyl group or together a saturated, unsaturated or aromatic carbocyclic 3-, 4-, 5- or 6-member ring formed with the tertiary carbon atom or with the inclusion of 1 or 2 N, O or S
atoms a heterocyclic 3, 4, 5 or 6-member ring, 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 and X means an alkylene oxy radical -(CH2)nO- with n = 1 to 3 or A means a methylene bridge (-CH2-) between carbon atoms 20 and 22 and X means an alkylene radical -(CH2)n- or an alkylene oxy adical -(CH2)nO- with n = 1 to 3, or if A stands for a direct ~5 bond and B and D together stand for a second bond ~ 6 means one of radicals -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 radical~ Rl, R2 and within radicals R3 or R4 are derived in particular from saturated carboxylic acids or also from benzoic acid. Other suitable acyl radicals in Rl, R2, R3, R4 comprise those which are cyclic, acyclic, carboxyclic or heterocyclic -- all optionally also unsaturated. The preferred radicals are derived from Cl- to Cg-, preferably C2- to C5-, alkanecarboxyclic acids, such as, for example, acetyl, propionyl, butyryl.
If R5 and R6 form, together with the tertiary carbon atom, a saturated carboxylic ring, then the cyclopropyl or cyclohexyl ring is especially referred to. As alkyl groups for R5 and R6, those with 1 to 5 carbon atoms, which can be straight-chain or branched, are especially suitable. By way of example, there can be mentioned the methyl, ethyl, propyl and t-butyl group.
Preferred according to this invention are side-chain homologous vitamin D derivatives of general formula I, in which Rl, R3 or R4 stands 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-(l(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-(l(R)-hydroxy-3-methylbutyl)-9,10-secochola-SZ,7E,10(19),23E-tetraene-l(S),3(R3-diol, 24-(l(S)-hydroxy-3-methylbutyl)-9,10-secochola-SZ,7E,10(19),23E-tetraene-l(S),3(R)-diol, 24-(l(R)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19)-tri.ene-l(S),3(R)-diol, 24-(l(S)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19)-triene-l(S),3(R)-diol, 24-(l(R)-hydroxy-3-isopropoxypropyl)-9,10-secochola-SZ,7E,10(19),23E-tetraene-l(S),3(R)-diol, 24-(l(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-l(S),3(R),24(R)-triol, 24-isopropoxymethyl-9,10-secochola-SZ,7E,10(19),22E-tetraene-l(S),3(R),24(S)-triol, 24-(2-isopropoxyethyl)-9,10-secochola-5Z,7E,10(19),22E-tetraene-l(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),3tR),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 ~3 (cf. general formula V) are biologically inactive in and of themselves and are converted only after hydroxylation in 2-position in the liver or in l-position in the kidneys into their biologically active metabolites. The effect of vitamins D2 and ~3 consists in stabilizing the plasma Ca~ level and the plasma phosphate level; they counteract a decrease in the plasma Ca~+ level.
r~' ,~ H
p ~v H~)~ ~R~
ergocalciferol: Ra = Rb = H,~c = CH3, vitamin-D2 double bond C-22/23 cholecalciferol: Ra z Rb = Rc = H vitamin D3 25-hydroxycholecalciferol: Ra = Rc = H, Rb = OH
lalpha-hydroxycholecalciferol: Ra = OH, Rb = Rc = H
lalpha,25-dihydroxycholecalciferol:Ra = Rb = OH, Rc = H calcitriol Besides their pronounced effect on the calcium and phosphate metabolism, vitamins D2 and D3 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 24-position already follow from DE-A~-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 24-hydroxy vitamin D analogs described in international patent application W0 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 has already been briefly mentioned by De Luca. The in vitro bone absorption effect here is a direct measurement 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 of 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 by using a specific receptor protein from the intestine of rachitic chickens.
A binding protein containing a receptor is incubated with 3H-calcitriol (0.5 ng/ml) in a reaction volume of 0.575 ml in the absence and in the presence of the test substances for one 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 6uspension is fed to each test tube and incubated for 30 minutes at 22C. Then, the samples are centrifuged at 1,500 x g for 10 minutes at 4C. 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 concentrationsof the te~t ~ubstance 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-(1-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-SZ,7E,10(19),23E-tetraene-l(S),3(S)-diol (compound ~) 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 ~kin is removed, washed in an antibiotic-antimycotic solution and, with the dermal side facing down, incubated overnight at 4C
in dispase II solution (1.2 U/ml in tissue culture medium Ml99 +25 mmol/l HEPES + 15% fetal calf serum (~CS) + 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 ~etermined after trypan blue staining and the cells are sown in a density of 4x105 cells/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 37C, the cells are washed with phosphate-buffered saline solution (PBS) and incubated for another 24 hours in serum-free tissue culture medium (Ml99 ~ 50 U/ml of P/S + 0.5%
ethanol) with and without test substances at 32.5C. 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%
L~
trichloroacetic acid (TCA). The cells are washed with TCA and PBS, lysed by incubation in a proteinase K-solution (10 mmol/l of tris-HCl, 10 mmol/l of EDTA, 10 mmol/l of NaCl, 0.2% triton-X
100, pH 8.0, 50 micrograms/ml of protein kinase K) and the lysate 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. -Accordingly depending on the dose, calcitriol and compoundsA and B inhibit the 3H-thymidine incorporation in DNA with the following IC50 values:
calcitriol 2 x 10-9mol/l compound A 1 x 10 8mol/l compound B 3.2 x 10 9mol/l The effects of calcitriol and of the compounds according to the invention that stimulate the differentiation 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-s,lo-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 indicated below was performed:
NL 60 cells are cultivated in tissue culture medium (RPMl -10% fetal calf serum) at 37C in an atmosphere of 5% C02 in air.
To test the substance, the cells are separated by centrifuging and 2.8 x 105 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 100 microliters each 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 37C in s% Co2 in air, 100 microliters of an NBT-TPA solution (nitro blue tetrazolium (NBT), final concentration in the batch 1 mg/ml, tetradecanoyl~-phorbol myristate-13-acetate (TPA), final concentration in the batch 2 x 10-7 mol/l~ is pipetted into each indentation of the 96-hole plate into the cell suspension.
By incubation for 2 hours at 37C and 5% C02 in air, the NBT
is reduced to 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/l) and lO0 microliters of dimethyl sulfoxide are pipetted into each indentation and are exposed to ultrasonic waves for l minute. The concentration of formazan is measured by spectrophotometry at 650 nm.
The concentration of formazan formed is regarded as a measurement for the differentiation induction of the HL 60 cells into macrophages. The relative effectiveness of the test substance results from the quotient of ED50 test substance/EDso calcitriol.
According to this, calcitriol, compound C and compound D
have the ED50 values 1.8 x 10 9 mol/l, 2.2 x lo 9 mol/l or 2.5 x 10-9mol/l.
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 which are characterized by a hyperproliferation, e.g., hyperproliferative diseases of the skin (psoriasis) and malignant tumors (leukemia, colon cancer, breast cancer). In an especially preferred embodiment of the invention, calcitriol receptors are detected in the target organ before the treatment.
This invention thus also relates to pharmaceutical preparations that contain at least one compound according to 1~
general formula I together with a pharmaceutically compatible vehicle. 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 auxiliary agents such as, e.g., stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances.
The compounds are advantageously administered by injection or intravenous infusion of suitable sterile solutions or as oral dosage through 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 mg)/patient/day, preferably 1.0 microgram/patient/day - 500 micrograms/patient/day.
The compounds according to the invention are generally administered analogously to the administration of the known agent "calcipotriol" for the treatment of psoriasis.
Further, the invention relates to the use of the compounds according to formula I for the production of pharmaceutical ag~nts.
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
~X' Y ~
~ ~ I
~IV).
\~oa2 in which Rl 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 formula IVa ~Iv~
1~1 ~oR2 in which Rl, 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 XyR
OH R
H = ~ - ~
b~ <~OH: O-C~l R ` I\~OR~
1~
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 general formula II
~ ~ R5 y ~lI), oR2~' ~ R
in which Rl, R2, A, B, D, X and R5 and R6 have the meaning given in formula IIIa/IIIb, and then the latter, by the cleaving of existing hydroxy protecting groups and optionally by partial or complete esterification of the hydroxy groups r 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. Both the R and the S hydroxy isomer of general formula IIIa or IIIB
result during the reduction. Both isomers can be separated chromatographically.
Optionally, before reduction o~ the carbonyl function, the double bond in the side chain can be selectively hydrogenated.
As hydrogenation agent, lithium-tri-tert-butoxy-aluminum hydride in a polar solvent is suitable, among others.
The following conversion of a compound of general formula IIIa/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, rotating 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 by using tetra-n-butyl-ammonium 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.
1~
Production of the initial materials 1. l(S),3(R)-bis-(tert-Butyldimethylsilyloxy)-20(S)-formyl-9,10-secopregna-5E,7E,10(19)-triene 1:
The production of ~ is performed according to M.J.
Calverley, Tetrahydron 43, 4609 (1987); see also international patent application W0 87/00834. The production of the initial compound in which Rl is a hydrogen atom is also described there.
2. l(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 (1965) in 200 ml of THF is instilled at 25C
in 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 60C, cooled again to 25C and a solution of 6.2 g of 1 in 70 ml of THF is added drop by drop. It is stirred for 2 hours under reflux, the cooled reaction solution is then poured into water and extracted with ethyl acetate. After drying (Na2SO4) 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 l(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 0C slowly mixed with 20 ml of a 20%
solution of diisobutylaluminum hydride in toluene. After 30 minutes at 0C, the reaction solution is poured carefully into NH4Cl solution and extracted with ethyl acetate. After the usual working up, 4.88 g of l(S),3(R)-bis-(tert-~utyldimethylsilyloxy)-23-ethoxy-9,10-secochola-5E,7E,10(19),22-tetraen-24-ol is obtained as a colorless, oily isomer mixture that is used in the next step without further purification.
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 l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-24-hydroxy-9,lo-secochola-5E,7E,10,(19)-trien-23-one 5 is obtained as colorless oil.
IH-NMR (CDC13): = 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, lH, OH), 4.10 (dd, lH, H-24), 4.16 (m, lH, H-3), 4.21 (dd, lH, H-24), 4.39 (m, lH, H-1), 4.88, 4.93 (s;
lH, H-l9 each), 5.77, 6.39 (d, J=llHz; lH, 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 0C with 300 mg of sodium borohydride. It is stirred for 1.5 hours at 0C, the reaction mixture is then poured into NH4Cl solution and extracted 2~
with ethyl acetate. 1.75 g of l(S), 3(R)-bis-(tert-butyldimethylsilyloxy~-9,10-secochola-SE,7E,10,(19)-triene-23,24 diol 6 is obtained as a colorless, oily mixture of the 23-epimers 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 ~inutes, 1.0 g of Pb(OAC)4 is again added and it is stirred for another 15 minutes at +5 to +10C.
For the working upr it is mixed with NaHCO3 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 l(S~,3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-5E,7E,10,(19)-triene-21-carbaldehyde with a melting point of 101-104C is obtained.
The reaction of aldehyde 1 or 2 with a phosphorane of formula 0 ~5 ~3 ~ x ~ ~t leads to the compounds of general formula IV (Wittig reaction).
Production of the phosphorus ylides used:
1. Isobutylcarbonylmethylenetriphenyl phosphorane a. Bromomethylisobutyl ketone 50 ml of isobutylmethyl ketone in 240 ml of methanol is mixed at 0C with 20 ml of bromine and, after being added, is stirred for another 1.5 hours at +10C. After this, 360 ml of water is added and it is stirred for another 16 hours at room temperature.
For the working up, the reaction mixture is mixed with saturated common salt solution, the organic phase that precipitates is separated and the aqueous phase is extracted with ether. The combined organic phases are washed with 10% Na2C03 solution and dried on Na2S04. After filtration, the solvent is removed in the water jet vacuum and the residue is distilled.
The main fraction contains 53.7 g of bromomethylisobutyl ketone of bpl5 200f 67-69C.
b. Isobutylcarbonylmethyltriphenylphosphonium bromide Bromomethylisobutyl ketone (S3.6 g) and triphenylphosphine (78.5 g) are intimately mixed in a 500 ml round-bottom flask and, after the initially strong heat tonality subsides, are left for 12 hours under nitrogen at room temperature. After that, the solid reaction mass is taken up in 330 ml of methylene chloride and refluxed for 30 minutes. After adding 500 ml of ether, it is allowed to cool to room temperature and the product is isolated by filtration. After drying, 111.7 g of the phosphonium salt with a melting point of 244-245C is obtained.
c. Isobutylcarbonylmethylenetriphenyl phosphorane ~' 111.6 g of the phosphonium bromide obtained under b. is mixed successively with 1500 ml of methylene chloride and 1500 ml of 2N NaOH and stirred for 30 minutes at room temperature. The organic phase is separated, washed with water and dried on Na2S04. The solid residue obtained after concentration by evaporation is recrystallized from tert-butyl methyl ether and yields 72.2 g of the ylide with a melting point of 120-121C.
2. Isoamylcarbonylmethylenetriphenyl phosphorane The formation of the title compound is performed analogously to the process described under 1. by bromation of isoamylmethyl ketone, reaction of the bromide with triphenylphosphine to phosphonium salt and formation of the ylide with 2N NaOH.
After distillative purification, 54.68 g of l-bromo-S-methyl-hexan-2-one of bpl5-20of 80-86C is obtained from 50.0 ml of isoamylmethyl ketone and 18.2 ml of bromine.
91.6 g of the phosphonium salt with a melting point of 230-233C is obtained from 54.58 g of the bromide and 74.14 g of triphenylphosphine.
After treatment with NaOH and recrystallization of the crude product from methylene chloride/ester, 69.8 g of the title compound with a melting point of 64-67C is obtained from 91.6 g of phosphonium salt.
atoms a heterocyclic 3, 4, 5 or 6-member ring, 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 and X means an alkylene oxy radical -(CH2)nO- with n = 1 to 3 or A means a methylene bridge (-CH2-) between carbon atoms 20 and 22 and X means an alkylene radical -(CH2)n- or an alkylene oxy adical -(CH2)nO- with n = 1 to 3, or if A stands for a direct ~5 bond and B and D together stand for a second bond ~ 6 means one of radicals -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 radical~ Rl, R2 and within radicals R3 or R4 are derived in particular from saturated carboxylic acids or also from benzoic acid. Other suitable acyl radicals in Rl, R2, R3, R4 comprise those which are cyclic, acyclic, carboxyclic or heterocyclic -- all optionally also unsaturated. The preferred radicals are derived from Cl- to Cg-, preferably C2- to C5-, alkanecarboxyclic acids, such as, for example, acetyl, propionyl, butyryl.
If R5 and R6 form, together with the tertiary carbon atom, a saturated carboxylic ring, then the cyclopropyl or cyclohexyl ring is especially referred to. As alkyl groups for R5 and R6, those with 1 to 5 carbon atoms, which can be straight-chain or branched, are especially suitable. By way of example, there can be mentioned the methyl, ethyl, propyl and t-butyl group.
Preferred according to this invention are side-chain homologous vitamin D derivatives of general formula I, in which Rl, R3 or R4 stands 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-(l(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-(l(R)-hydroxy-3-methylbutyl)-9,10-secochola-SZ,7E,10(19),23E-tetraene-l(S),3(R3-diol, 24-(l(S)-hydroxy-3-methylbutyl)-9,10-secochola-SZ,7E,10(19),23E-tetraene-l(S),3(R)-diol, 24-(l(R)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19)-tri.ene-l(S),3(R)-diol, 24-(l(S)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19)-triene-l(S),3(R)-diol, 24-(l(R)-hydroxy-3-isopropoxypropyl)-9,10-secochola-SZ,7E,10(19),23E-tetraene-l(S),3(R)-diol, 24-(l(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-l(S),3(R),24(R)-triol, 24-isopropoxymethyl-9,10-secochola-SZ,7E,10(19),22E-tetraene-l(S),3(R),24(S)-triol, 24-(2-isopropoxyethyl)-9,10-secochola-5Z,7E,10(19),22E-tetraene-l(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),3tR),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 ~3 (cf. general formula V) are biologically inactive in and of themselves and are converted only after hydroxylation in 2-position in the liver or in l-position in the kidneys into their biologically active metabolites. The effect of vitamins D2 and ~3 consists in stabilizing the plasma Ca~ level and the plasma phosphate level; they counteract a decrease in the plasma Ca~+ level.
r~' ,~ H
p ~v H~)~ ~R~
ergocalciferol: Ra = Rb = H,~c = CH3, vitamin-D2 double bond C-22/23 cholecalciferol: Ra z Rb = Rc = H vitamin D3 25-hydroxycholecalciferol: Ra = Rc = H, Rb = OH
lalpha-hydroxycholecalciferol: Ra = OH, Rb = Rc = H
lalpha,25-dihydroxycholecalciferol:Ra = Rb = OH, Rc = H calcitriol Besides their pronounced effect on the calcium and phosphate metabolism, vitamins D2 and D3 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 24-position already follow from DE-A~-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 24-hydroxy vitamin D analogs described in international patent application W0 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 has already been briefly mentioned by De Luca. The in vitro bone absorption effect here is a direct measurement 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 of 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 by using a specific receptor protein from the intestine of rachitic chickens.
A binding protein containing a receptor is incubated with 3H-calcitriol (0.5 ng/ml) in a reaction volume of 0.575 ml in the absence and in the presence of the test substances for one 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 6uspension is fed to each test tube and incubated for 30 minutes at 22C. Then, the samples are centrifuged at 1,500 x g for 10 minutes at 4C. 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 concentrationsof the te~t ~ubstance 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-(1-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-SZ,7E,10(19),23E-tetraene-l(S),3(S)-diol (compound ~) 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 ~kin is removed, washed in an antibiotic-antimycotic solution and, with the dermal side facing down, incubated overnight at 4C
in dispase II solution (1.2 U/ml in tissue culture medium Ml99 +25 mmol/l HEPES + 15% fetal calf serum (~CS) + 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 ~etermined after trypan blue staining and the cells are sown in a density of 4x105 cells/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 37C, the cells are washed with phosphate-buffered saline solution (PBS) and incubated for another 24 hours in serum-free tissue culture medium (Ml99 ~ 50 U/ml of P/S + 0.5%
ethanol) with and without test substances at 32.5C. 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%
L~
trichloroacetic acid (TCA). The cells are washed with TCA and PBS, lysed by incubation in a proteinase K-solution (10 mmol/l of tris-HCl, 10 mmol/l of EDTA, 10 mmol/l of NaCl, 0.2% triton-X
100, pH 8.0, 50 micrograms/ml of protein kinase K) and the lysate 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. -Accordingly depending on the dose, calcitriol and compoundsA and B inhibit the 3H-thymidine incorporation in DNA with the following IC50 values:
calcitriol 2 x 10-9mol/l compound A 1 x 10 8mol/l compound B 3.2 x 10 9mol/l The effects of calcitriol and of the compounds according to the invention that stimulate the differentiation 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-s,lo-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 indicated below was performed:
NL 60 cells are cultivated in tissue culture medium (RPMl -10% fetal calf serum) at 37C in an atmosphere of 5% C02 in air.
To test the substance, the cells are separated by centrifuging and 2.8 x 105 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 100 microliters each 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 37C in s% Co2 in air, 100 microliters of an NBT-TPA solution (nitro blue tetrazolium (NBT), final concentration in the batch 1 mg/ml, tetradecanoyl~-phorbol myristate-13-acetate (TPA), final concentration in the batch 2 x 10-7 mol/l~ is pipetted into each indentation of the 96-hole plate into the cell suspension.
By incubation for 2 hours at 37C and 5% C02 in air, the NBT
is reduced to 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/l) and lO0 microliters of dimethyl sulfoxide are pipetted into each indentation and are exposed to ultrasonic waves for l minute. The concentration of formazan is measured by spectrophotometry at 650 nm.
The concentration of formazan formed is regarded as a measurement for the differentiation induction of the HL 60 cells into macrophages. The relative effectiveness of the test substance results from the quotient of ED50 test substance/EDso calcitriol.
According to this, calcitriol, compound C and compound D
have the ED50 values 1.8 x 10 9 mol/l, 2.2 x lo 9 mol/l or 2.5 x 10-9mol/l.
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 which are characterized by a hyperproliferation, e.g., hyperproliferative diseases of the skin (psoriasis) and malignant tumors (leukemia, colon cancer, breast cancer). In an especially preferred embodiment of the invention, calcitriol receptors are detected in the target organ before the treatment.
This invention thus also relates to pharmaceutical preparations that contain at least one compound according to 1~
general formula I together with a pharmaceutically compatible vehicle. 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 auxiliary agents such as, e.g., stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances.
The compounds are advantageously administered by injection or intravenous infusion of suitable sterile solutions or as oral dosage through 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 mg)/patient/day, preferably 1.0 microgram/patient/day - 500 micrograms/patient/day.
The compounds according to the invention are generally administered analogously to the administration of the known agent "calcipotriol" for the treatment of psoriasis.
Further, the invention relates to the use of the compounds according to formula I for the production of pharmaceutical ag~nts.
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
~X' Y ~
~ ~ I
~IV).
\~oa2 in which Rl 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 formula IVa ~Iv~
1~1 ~oR2 in which Rl, 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 XyR
OH R
H = ~ - ~
b~ <~OH: O-C~l R ` I\~OR~
1~
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 general formula II
~ ~ R5 y ~lI), oR2~' ~ R
in which Rl, R2, A, B, D, X and R5 and R6 have the meaning given in formula IIIa/IIIb, and then the latter, by the cleaving of existing hydroxy protecting groups and optionally by partial or complete esterification of the hydroxy groups r 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. Both the R and the S hydroxy isomer of general formula IIIa or IIIB
result during the reduction. Both isomers can be separated chromatographically.
Optionally, before reduction o~ the carbonyl function, the double bond in the side chain can be selectively hydrogenated.
As hydrogenation agent, lithium-tri-tert-butoxy-aluminum hydride in a polar solvent is suitable, among others.
The following conversion of a compound of general formula IIIa/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, rotating 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 by using tetra-n-butyl-ammonium 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.
1~
Production of the initial materials 1. l(S),3(R)-bis-(tert-Butyldimethylsilyloxy)-20(S)-formyl-9,10-secopregna-5E,7E,10(19)-triene 1:
The production of ~ is performed according to M.J.
Calverley, Tetrahydron 43, 4609 (1987); see also international patent application W0 87/00834. The production of the initial compound in which Rl is a hydrogen atom is also described there.
2. l(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 (1965) in 200 ml of THF is instilled at 25C
in 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 60C, cooled again to 25C and a solution of 6.2 g of 1 in 70 ml of THF is added drop by drop. It is stirred for 2 hours under reflux, the cooled reaction solution is then poured into water and extracted with ethyl acetate. After drying (Na2SO4) 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 l(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 0C slowly mixed with 20 ml of a 20%
solution of diisobutylaluminum hydride in toluene. After 30 minutes at 0C, the reaction solution is poured carefully into NH4Cl solution and extracted with ethyl acetate. After the usual working up, 4.88 g of l(S),3(R)-bis-(tert-~utyldimethylsilyloxy)-23-ethoxy-9,10-secochola-5E,7E,10(19),22-tetraen-24-ol is obtained as a colorless, oily isomer mixture that is used in the next step without further purification.
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 l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-24-hydroxy-9,lo-secochola-5E,7E,10,(19)-trien-23-one 5 is obtained as colorless oil.
IH-NMR (CDC13): = 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, lH, OH), 4.10 (dd, lH, H-24), 4.16 (m, lH, H-3), 4.21 (dd, lH, H-24), 4.39 (m, lH, H-1), 4.88, 4.93 (s;
lH, H-l9 each), 5.77, 6.39 (d, J=llHz; lH, 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 0C with 300 mg of sodium borohydride. It is stirred for 1.5 hours at 0C, the reaction mixture is then poured into NH4Cl solution and extracted 2~
with ethyl acetate. 1.75 g of l(S), 3(R)-bis-(tert-butyldimethylsilyloxy~-9,10-secochola-SE,7E,10,(19)-triene-23,24 diol 6 is obtained as a colorless, oily mixture of the 23-epimers 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 ~inutes, 1.0 g of Pb(OAC)4 is again added and it is stirred for another 15 minutes at +5 to +10C.
For the working upr it is mixed with NaHCO3 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 l(S~,3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-5E,7E,10,(19)-triene-21-carbaldehyde with a melting point of 101-104C is obtained.
The reaction of aldehyde 1 or 2 with a phosphorane of formula 0 ~5 ~3 ~ x ~ ~t leads to the compounds of general formula IV (Wittig reaction).
Production of the phosphorus ylides used:
1. Isobutylcarbonylmethylenetriphenyl phosphorane a. Bromomethylisobutyl ketone 50 ml of isobutylmethyl ketone in 240 ml of methanol is mixed at 0C with 20 ml of bromine and, after being added, is stirred for another 1.5 hours at +10C. After this, 360 ml of water is added and it is stirred for another 16 hours at room temperature.
For the working up, the reaction mixture is mixed with saturated common salt solution, the organic phase that precipitates is separated and the aqueous phase is extracted with ether. The combined organic phases are washed with 10% Na2C03 solution and dried on Na2S04. After filtration, the solvent is removed in the water jet vacuum and the residue is distilled.
The main fraction contains 53.7 g of bromomethylisobutyl ketone of bpl5 200f 67-69C.
b. Isobutylcarbonylmethyltriphenylphosphonium bromide Bromomethylisobutyl ketone (S3.6 g) and triphenylphosphine (78.5 g) are intimately mixed in a 500 ml round-bottom flask and, after the initially strong heat tonality subsides, are left for 12 hours under nitrogen at room temperature. After that, the solid reaction mass is taken up in 330 ml of methylene chloride and refluxed for 30 minutes. After adding 500 ml of ether, it is allowed to cool to room temperature and the product is isolated by filtration. After drying, 111.7 g of the phosphonium salt with a melting point of 244-245C is obtained.
c. Isobutylcarbonylmethylenetriphenyl phosphorane ~' 111.6 g of the phosphonium bromide obtained under b. is mixed successively with 1500 ml of methylene chloride and 1500 ml of 2N NaOH and stirred for 30 minutes at room temperature. The organic phase is separated, washed with water and dried on Na2S04. The solid residue obtained after concentration by evaporation is recrystallized from tert-butyl methyl ether and yields 72.2 g of the ylide with a melting point of 120-121C.
2. Isoamylcarbonylmethylenetriphenyl phosphorane The formation of the title compound is performed analogously to the process described under 1. by bromation of isoamylmethyl ketone, reaction of the bromide with triphenylphosphine to phosphonium salt and formation of the ylide with 2N NaOH.
After distillative purification, 54.68 g of l-bromo-S-methyl-hexan-2-one of bpl5-20of 80-86C is obtained from 50.0 ml of isoamylmethyl ketone and 18.2 ml of bromine.
91.6 g of the phosphonium salt with a melting point of 230-233C is obtained from 54.58 g of the bromide and 74.14 g of triphenylphosphine.
After treatment with NaOH and recrystallization of the crude product from methylene chloride/ester, 69.8 g of the title compound with a melting point of 64-67C is obtained from 91.6 g of phosphonium salt.
3. Isopropoxymethylcarbonylmethylenetriphenyl phosphorane 2.43 g of sodium is dissolved in 150 ml of isopropanol.
After adding 20.0 g of chloromethylcarbonylmethylenetriphenyl phosphorane ketone (R. F. Hudson et al., J. Org. Chem. 28 2446, 1963) dissolved in 200 ml of isopropanol, is refluxed for 8 hours.
The cooled reaction mixture is poured into a common salt solution and extracted with ethyl acetate. The oily residue obtained after concentration by evaporation is chromatographed on silica gel with ethyl acetate. 9.53 g of the title compound with -a melting point of 134C is obtained.
After adding 20.0 g of chloromethylcarbonylmethylenetriphenyl phosphorane ketone (R. F. Hudson et al., J. Org. Chem. 28 2446, 1963) dissolved in 200 ml of isopropanol, is refluxed for 8 hours.
The cooled reaction mixture is poured into a common salt solution and extracted with ethyl acetate. The oily residue obtained after concentration by evaporation is chromatographed on silica gel with ethyl acetate. 9.53 g of the title compound with -a melting point of 134C is obtained.
4. (2-Isopropoxyethyl)-carbonylmethylenetriphenyl phosphorane a. l-Bromo-4-isopropoxy-butan-2-one A solution of 68.2 g of 4-isopropoxy-2-butanone (F.B. Hasan et al., J. Biolog. Chem. 256, 7781, 1981) in 315 ml of methanol is mixed by instillation at oC with 26.9 ml of bromine and then stirred for 1.5 hours at +10C. Then 470 ml of water is instilled in the reaction solution and it is stirred for 16 hours at room temperature. For working up, it is poured into saturated common salt solution and extracted with ether. Distillation of the crude product yields 78.07 g of the bromine derivative of bpl5-20of 95C.
b. 4-Isopropoxy-2-oxo-butyl-triphenylphosphonium bromide According to the process described under 1, 133.35 g of phosphonium salt with a melting point of 183C is obtained from 78.0 g of the bromide obtained under a. and 97.85 g of triphenylphosphine.
c. (2~Isopropoxyethyl)-carbonylmethylenetriphenyl phosphorane The phosphonium bromide (1~3.2 g) obtained under b. is treated as described under 1. with 2N NaOH in methylene chloride.
After recrystallization of the crude product from ethyl acetate, 64.38 g of the title compound with a melting point of 97C is obtained.
b. 4-Isopropoxy-2-oxo-butyl-triphenylphosphonium bromide According to the process described under 1, 133.35 g of phosphonium salt with a melting point of 183C is obtained from 78.0 g of the bromide obtained under a. and 97.85 g of triphenylphosphine.
c. (2~Isopropoxyethyl)-carbonylmethylenetriphenyl phosphorane The phosphonium bromide (1~3.2 g) obtained under b. is treated as described under 1. with 2N NaOH in methylene chloride.
After recrystallization of the crude product from ethyl acetate, 64.38 g of the title compound with a melting point of 97C is obtained.
5. (l-Ethylpropoxymethyl)-carbonylmethylenetriphenyl phosphorane A solution of 3.04 g of sodium in 100 ml of 3-pentanol is reacted with 25.0 g of chloromethylcarbonylmethylenetriphenyl phosphorane analogously to the production of --isopropoxymethylcarbonylmethylenetriphenyl phosphorane. The title compound is obtained as crystallized oil with a melting point of 66-70C.
6. Cyclopropylmethoxymethylcarbonylmethylenetriphenyl phosphorane A solution of 5.58 g of sodium in 25.0 g of cyclopropylmethanol and 200 ml of toluene is reacted with 30.0 g of chloromethylcarbonylmethylenetriphenyl phosphorane analogously to the production of isopropoxymethylcarbonylmethylenetriphenyl phosphorane. The title compound is obtained as solid with a melting point of 121C.
7. (3-Butinyl)-carbonylmethylenetriphenyl phosphorane 20.0 g of methylcarbonylmethylenetriphenyl phosphorane is dissolved in 628 ml of tetrahydrofuran and mixed by instillation at -78C with 41.3 ml of butyllithium (1.6 molar solution in hexane)O Then, 5.0 ml of propargyl bromide is instilled. The reaction mixture is added to an ice/common salt solution after heating to room temperature, and the mixture is extracted with ethyl acetate. ~fter drying the organic phase with sodium sulfate, 23.4 g of solid is obtained. Column chromatographic purification (silica gel/ethyl acetate) yields 15.4 g of the title compound with a melting point of 135-136C.
8. (3-Butenyl)-carbonylmethylenetriphenyl phosphorane By reaction of 15.0 g of methylcarbonylmethylenetriphenyl phosphorane in 471 ml of tetrahydrofuran with 31.0 ml of butyllithium and 4.28 ml of allyl bromide analogously-to 7, the title compound is obtained as crystallized oil with a melting point of 92-93C.
By varying the keto component used for the production of the Wittig reagent, other phosphoranes, which can be reacted with aldehyde 1 or 2 analogously to other compounds of general formula IV as described below, can be obtained in a similar way.
EXAMPLE ~
A solution of 1.6 g of l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-SE,7E,10,(19)-triene-21-carbaldehyde in 50 ml of toluene is stirred for 16 hours at 80C under argon after adding 3.02 g of isoamylcarbonylmethylenetriphenyl phosphorane. Then, the solvent is removed under reduced pressure and the residue is chromatographed on silica gel with hexane/ethyl acetate. The main fraction yields 1.15 g of tl(S~,3(R)-bis-(tert- -butyldimethylsilyloxy~-9~lo-secochola-5E~7E~lo~(l9)~23(E) tetraen-24-yl]-4-methyl-pentan-1-one as colorless oil.
IH-NMR (CDC13): ~ = 0.01 ppm (s,12H,Si-CH3), 0.56 (s,3H,H-18), 0.87 (s,18H,Si-t.-butyl); 0.88 (d,J=7Hz,6H,C-(CH3)2), 0.95 (d,J=7Hz,3H,H-21); 4.25 (m,lH,H-3); 4.55 (m,lH,H-1); 4.94 and 5.00 (s; lH, H-19 each); 5.82 and 6.46 (d,J=llHz; lH, H-6, H-7 each); 6.10 (d,J=16Hz,lH,H-24); 6.80 (m,lH,H-23).
572 mg of cerium(III)-chloride-heptahydrate is dissolved in 10 ml of methanol and the compound (1.10 g) produced according to example 1 dissolved in 5 ml of methanol is added. After adding 61 mg of sodium borohydride, it is stirred for 30 minutes at 0C.
For the working up, it is poured into water, extracted with dichloromethane, dried (Na2S04) and concentrated by evaporation.
The mixture of diastereomeric alcohols thus obtained is separated by chromatography on silica gel with hexane/ethyl acetate. In the elution sequence, 290 mg of l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-24-(1-hydroxy-4-methylpentyl)-9~10-seco-5E,7E,10(19),23(E)-cholate-traene (epimer A) and 120 mg of epimer B are obtained. The epimers show identical NMR spectra.
IH-NMR (CDC13): S = 0.01 ppm (s,12H,Si-CH3), 0.49 (s,3H,H-18), 0.86 (s,18H,Si-t.-butyl); 0.86 (d,J-7Hz,6H,C-(CH3)2); 0.88 (d,J=7Hz,3H,H-21); 4.16 (m,lH,H-3); 4.48 (m,lH,H-l); 4.88 and 4.93 (s; lH, H-l9 each); 5.40 (dd,J=15.5 and 7Hz,lH,H-24~; 5.55 (m,lH,H-23~; 5.77 and 6.40 (d,J=llHz; lH, H-6, H-7 each).
A solution of 290 mg of the product (epimer A) obtained under example 2 in 80 ml of toluene is irradiated in a pyrex immersion reactor by a high pressure mercury vapor lamp (Philips HPK 125) after adding 44 mg of anthracene and 0.01 ml of triethylamine. The irradiation time is 3.5 minutes, the thorough mixing of the solution is guaranteed by introducing a nitrogen stream. After concentration by evaporation and chromatography on silica gel with hexane/ethyl acetate, 241 mg of l(S),3(R)-bis(tert-butyldimethylsilyloxy)-24-(1-hydroxy-4-methylpentyl)-
By varying the keto component used for the production of the Wittig reagent, other phosphoranes, which can be reacted with aldehyde 1 or 2 analogously to other compounds of general formula IV as described below, can be obtained in a similar way.
EXAMPLE ~
A solution of 1.6 g of l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-SE,7E,10,(19)-triene-21-carbaldehyde in 50 ml of toluene is stirred for 16 hours at 80C under argon after adding 3.02 g of isoamylcarbonylmethylenetriphenyl phosphorane. Then, the solvent is removed under reduced pressure and the residue is chromatographed on silica gel with hexane/ethyl acetate. The main fraction yields 1.15 g of tl(S~,3(R)-bis-(tert- -butyldimethylsilyloxy~-9~lo-secochola-5E~7E~lo~(l9)~23(E) tetraen-24-yl]-4-methyl-pentan-1-one as colorless oil.
IH-NMR (CDC13): ~ = 0.01 ppm (s,12H,Si-CH3), 0.56 (s,3H,H-18), 0.87 (s,18H,Si-t.-butyl); 0.88 (d,J=7Hz,6H,C-(CH3)2), 0.95 (d,J=7Hz,3H,H-21); 4.25 (m,lH,H-3); 4.55 (m,lH,H-1); 4.94 and 5.00 (s; lH, H-19 each); 5.82 and 6.46 (d,J=llHz; lH, H-6, H-7 each); 6.10 (d,J=16Hz,lH,H-24); 6.80 (m,lH,H-23).
572 mg of cerium(III)-chloride-heptahydrate is dissolved in 10 ml of methanol and the compound (1.10 g) produced according to example 1 dissolved in 5 ml of methanol is added. After adding 61 mg of sodium borohydride, it is stirred for 30 minutes at 0C.
For the working up, it is poured into water, extracted with dichloromethane, dried (Na2S04) and concentrated by evaporation.
The mixture of diastereomeric alcohols thus obtained is separated by chromatography on silica gel with hexane/ethyl acetate. In the elution sequence, 290 mg of l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-24-(1-hydroxy-4-methylpentyl)-9~10-seco-5E,7E,10(19),23(E)-cholate-traene (epimer A) and 120 mg of epimer B are obtained. The epimers show identical NMR spectra.
IH-NMR (CDC13): S = 0.01 ppm (s,12H,Si-CH3), 0.49 (s,3H,H-18), 0.86 (s,18H,Si-t.-butyl); 0.86 (d,J-7Hz,6H,C-(CH3)2); 0.88 (d,J=7Hz,3H,H-21); 4.16 (m,lH,H-3); 4.48 (m,lH,H-l); 4.88 and 4.93 (s; lH, H-l9 each); 5.40 (dd,J=15.5 and 7Hz,lH,H-24~; 5.55 (m,lH,H-23~; 5.77 and 6.40 (d,J=llHz; lH, H-6, H-7 each).
A solution of 290 mg of the product (epimer A) obtained under example 2 in 80 ml of toluene is irradiated in a pyrex immersion reactor by a high pressure mercury vapor lamp (Philips HPK 125) after adding 44 mg of anthracene and 0.01 ml of triethylamine. The irradiation time is 3.5 minutes, the thorough mixing of the solution is guaranteed by introducing a nitrogen stream. After concentration by evaporation and chromatography on silica gel with hexane/ethyl acetate, 241 mg of l(S),3(R)-bis(tert-butyldimethylsilyloxy)-24-(1-hydroxy-4-methylpentyl)-
9,10-secochola-5Z,7E,10(19),23(E)-tetraene is obtained as colorless oil.
[ ~X ]D20+ 49.6 (CHC13, c=0.425).
Analogous treatment of 120 mg of the polar isomer (epimer B) obtained according to example 2 yields 113 mg as colorless oil.
[~ ]D20+ 41.4 (CHC13, c=0.285) A solution of 225 mg of the product obtained according to example 3 from epimer A in 5 ml of THF is stirred for 60 minutes at 60C after adding 1.31 ml of a lM solution of tetrabutylammonium fluoride in THF. After cooling, it is poured into a saturated common salt solution and extracted with ethyl acetate. The crude product is chromatographed on silica gel with hexane/ethyl acetate and yields 85 mg of 24~ hydroxy-4-methylpentyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-l(S),3(R)-diol as white foam.
IH-NMR (CDC13): ~ = 0.57 ppm (s,3H,H-18), 0.84 (d,J=7Hz,3H,H-21); 0.92 (d,J=7Hz,6H,C-(CH3)2); 4.03 (m,lH,H-25);
4.23 (m,lH,H-3); 4.43 (m,lH,H-l); 5.00 and 5.33 (s; lH, H-l9 each); 5.45 (dd,J=15.5 and 7Hz,lH,H-24); 5.60 (m,lH,H-23); 6.02 and 6.38 (d,J=lHz; llH, H-6, H-7 each).
Analogous treatment of the product (95 mg) obtained according to example 3 from epimer B yields 35 mg of the epimeric triol as colorless oil. The NMR spectra of the epimers are identical.
Analogously to the process described under example 1, 2.05 g of l(S~,3(R)-bis-(tert-butyldimethylsilyloxy)-20-(R)-methyl-9,10-secopregna-5E,7E,10(19)-triene-21-carbaldehyde in 53 ml of toluene is reacted with 3.4 g of isobutylcarbonylmethylenetriphenyl phosphorane. After ~9 chromatographic purification, [l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-secochola-5E,7E,10(19),23(E)-tetraen-24-yl3-3-methyl-butan-1-one with a melting point of 79-81C is obtained (from ethanol).
[C~]D20 + 52.6 (CHC13, c=0.500) By reduction of 1.75 g of the product obtained under example 5 under the conditions of example 2, l(S~,3(R)-bis~tert-butyldimethylsilyloxy)-24-(1(R,S)-hydroxy-3-methylbutyl)-9,10-secochola-5E,7E,10(19),23E-tetraene is obtained as an oily mixture of the epimers. By chromatography on silica gel with hexane/ethyl acetate, 780 mg of epimer A and 600 mg of epimer B
are obtained in the elution sequence as colorless oils, which cannot be differentiated by NMR spectroscopy.
By triplet-sensitized photoisomerization analogously to example 3 and subsequent silylether cleavage analogously to example 4, 240 mg of 24-(1-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19),23(E)-tetraene-l(S),3(R)-diol (compound A) with a decomposition interval of 119-125C, is obtained from 700 mg of epimer A produced according to example 6 [ ~ ~D20+ 38.8 (methanol, c=0.505).
Analogous treatment of 330 mg of epimer B yields 129 mg of 24-(1-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19j,23(E)-^ ~) tetraene-l(S),3~S)-diol (compound B) with a decomposition interval of 139-145C, [C~ )D20+ 54.8 (methanol) c=0.5G5).
A solution of 170 mg of the product obtained according to example 5 in 5 ml of THF is stirred for 90 minutes at room temperature after adding 200 mg of lithium-tri-tert-butoxy-aluminum hydride. For working up, it is mixed with 0.8 ml of saturated NH4Cl solution, filtered and the filtrate is concentrated by evaporation. Chromatography of the crude product on A12O3 (Merck, neutral, step III) yields 108 mg of 1-[l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-secochola-5~,7E,10(19)-trien-24-yl]-3-methyl-butan-1-one as colorless oil.
IH-NMR (CDC13): ~ = 0.53 ppm (s,3H,H-18); 4.22 tm,lH,H-3);
4.54 (m,lH,H-1); 4.93 and 4.98 (m; lH, H-19 each); 5.8Z and 6.46 (d,J=llHz; lH, H-6, H-7 each).
From 100 mg of the product of example 8, photochemical double bond isomerization analogously to example 3 and silylether cleavage analogously to example 4 yield 50 mg of 1-[l(S),3(R)-dihydroxy~9,10-secochola-5Z,7E,10(19)-trien-24-yl]-3-methyl-butan-1-one.
W (methanol): = 212 nm ( ~ =14 300), 265 (15 860).
The reaction of 1.6 g of l(S),3~R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-5E,7E,10(19)-triene-21-carbaldehyde with (2-isopropoxyethyl)-carbonylmethylenetriphenyl phosphorane analogously to example 1 yields 1.15 g of 1-[l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-secochola-5E,7E,10(19),23(E)-tetraen-24-yl]-3-isopropoxy-propan-l-one as colorless oil~ -IH-NMR (CDC13): ~ = 0.01 ppm (s,12H,Si-CH3), 0.55 (s,3H,H-18), 0.86 and 0.90 (s; 9H, Si-t.-butyl each); 0.96 (d, J=7Hz,3H,H-21); 1.15 (d,J=7Hz,6H,C(CH3)2); 3.60(m,1H,CH-0); 3.73 (t,J=7Hz,2H,CH2-0); 4.23 (m,lH,H-3); 4.55 (m,lH,H-l); 4.95 and 5.00 (m; lH, H-l9 each); 5.83 and 6.46 (d,J=ll Hz; lH, H-6, H-7 each); 6.11 (d,J=15.5Hz,lH,H-24); 6.87 (m,lH,H-23).
By reduction analogously to example 2, photoisomerization analogously to example 3 and silylether cleavage analogously to example 4, 143 mg of 24-1l(R,S) hydroxy-3-isopropoxypropyl)-9,10-secochola-5Z,7E,10(19),23-tetraene-l(S),3(R)-diol is obtained from 1.05 g of the product produced according to example 10 as a 1:1 mixture of the diastereomers that are separated by high-pressure liquid chromatography. The isomers exhibit identical NMR spectra.
IH-NMR (CDC13): ~ = 0.57 ppm (s,3H,H-18),0.94 (d,J-7Hz,3H,H-213; 1.15 (d,J=7Hz,6H,C(CH3)2), 4.17 (m,lH,H-3);
3~
4.21 (m,lH,H-25); 4.38 (m,lH,H-l); 4.98 and 5.29 (m; lH, H-l9 each); 5.45 (dd,J=15.5 and 7Hz,lH,H-24); 5.63 (m,lH,H-23); 6.02 and 6.38 (d,J=llHz; lH, H-6, H-7 each).
Starting fron aldehyde 1 and isopropoxymethylcarbonylmethylenetriphenyl phosphorane, isomer B
(5Z,7E,22E-l(S),3(R),24(S)-9,10-seco-24a,24b-dihomo-24b- -oxacholesta-5,7,10(19),22-tetraene-1,3,24-triol) with a melting point of 131-132C is obtained analogously to the sequence of examples 1-4.
Starting fron aldehyde 1 and (2-isopropoxyethyl)-carbonylmethylenetriphenyl phosphorane, isomer B (5Z,7E,22E-l(S3,3(R),24(S)-9,10-seco-24a,24b,24c-trihomo-24c-oxacholesta-5,7,10(19),22-tetraene-1,3,24-triol) with a melting point of 125-126C is obtained analogously to the sequence of examples 1-4.
Analogously to example 1, 0.85 g of l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-5E,7E,10(19)-triene-21-carbaldehyde is reacted with 4.5 g of cyclopropylmethylcarbonyltriphenyl phosphorane. After chromatographic purification on silica gel with hexane/ethyl acetate, 500 mg of l(S),3(R3-bis-(tert-butyldimethylsilyloxy)-26,27-cyclo-24a,24b-dihomo-s,lO-secocholesta-5E,7E,10(19),23E-tetraen-24a-one is obtained as colorless foam.
IH-NMR (CDCl3): ~ = 0.01 ppm (s,12H,Si-CH3); 0.09 and 0.50 (m; 2H, H-26 and H-27 each); 0.50 (s,3H,H-18); 0.83 and 0.85 (8;
9H, Si-t.-butyl each); 0.91 (d,J=7.3Hz,3H,H-21); 0.96 (m,lH,H-25); 2.47 (d,J=6Hz,2H,H-24b); 4.16 (m,lH,H-3); 4.47(m,1H,H-l);
4.89 and 4.93(~; lH, H-l9 each); 5.77 and 6.40 (d,J=llHz; lH, H-6 and H-7 each); 6.08~d,J=15.SHz,H-24);
6.75(ddd,J=15.5,9,6.5Hz,lH,H-23).
Reduction of the product obtained under example 14 analogously to example 2 yields 200 mg of l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5E,7E,10(19),23E-tetraen-24a(R,S)-ol as an oily mixture of the epimers that cannot be differentiated by NMR
spectroscopy.
IH-NMR (CDCl3): ~ = 0.01 ppm (s,12H,Si-CH3); 0.09 and 0.40 (m; 2H, H-26 and H-27 each); 0.50 (s,3H,H-18); 0.68 (m,lH,H-25);
0.81 and 0.86(s; 9H, Si-t.-butyl each); 0.88 (d,J=7Hz,3H,H-21);
1.40 (t,J=7Hz,H-24b); 4.13 (m,lH,H-24a); 4.17 (m,lH,H-3); 4.49 (m,lH,H-l); 4.88 and 4.93 (s; lH, H-l9 each); 5.45 (dd,J=15.5, 6.5Hz,lH,H-24); 5.59 (ddd,J=15.5, 7, 6.5Hz,lH,H-23); 5.77 and 6.40 (d,J=llHz; lH, H-6 and H-7 each).
Analogously to example 3, by triplet-sensitized photoisomerization and cleavage of the protecting groups analogously to example 4, 86 mg of 26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19~,23E-tetraene-l(S),3(R),24a(R,S)-triol is obtained from 190 mg of the compound described under example 15 as a 1:1 mixture of the diastereomers that are separated by high-pressure liquid chromatography. The NMR
spectra of both diastereomers are identical.
IH-NMR (CDC13): J = o. og and 0.49 (m; 2H, H-26 and H-27 each); 0.53 (s,3H,H-18); 0.70(m,1H,H-253; 0.93 (d,J=7Hz,3H,H-21);
4.18 (m,lH,H-24a); 4~22 (m,lH,H-3); 4.43 (m,lH,H-l); S.00 and 5.32 (s; lH, H-19 each); 5.50 (dd,J=15.5, 6.5Hz,H-24); 5.64 (ddd,J=15.5, 7, 6.5Hz,lH,H-23); 6.02 and 6.38 (d,J=llHz; lH, H-6 and H-7 each).
Starting from aldehyde 1 and (l-ethylpropoxymethyl)-carbonylmethylenetriphenyl phosphorane, isomer B (5Z,7E,22E-l(S),3(~),24(S)-26,27-dimethyl-24a,24b-dihomo-24b-oxa-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol) with a melting point of 103-105C is obtained analogously to the sequence of examples 1-4.
Starting from aldehyde 1 and cyclopropylmethoxymethylcarbonylmethylenetriphenyl phosphorane, isomer B (5Z,7E,22E-l(S),3(R),24(S)-26,27-cyclo-24a,24b,24c-trihomo-24b-oxa-9~lo-secocholesta-5~7~lo(l9)~22-tetraene-l~3~24 triol) is obtained analogously to the sequence of examples 1-4.
IH-NMR (DMS0-~): S=0.16 ppm (m,2H); 0.43 (m,2H); 0.53 (S,3H); 1.00 (d,J-6Hz,3H); 3.21 (m,4H); 4.00 (m,2H); 4.19 (m,lH);
4.51 (d,J=5Hz,lH); 4.70 (d,J=5~z,lH); 4.75 (m,lH); 4.82 (d,J=5Hz,lH); 5.21 (m,lH); 5.39 (m,2H); 5.98 (d,J=llhz,lH); 6.18 (d,J=llhz,lH).
Starting from aldehyde 1 and (3-butinyl)-carbonylmethylenetriphenyl phosphorane, isomer B (5Z,7E,22E-l(S),3(R),24(S)-24-(3-butinyl)-9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol) with a melting point of 115-118C is obtained analogously to the sequence of examples 1-4.
Starting from aldehyde 1 and (3-butenyl)-carbonylmethylenetriphenyl phosphorane, isomer B (5Z,7E,22E-l(S),3(R),24(S)-24-(3-butenyl)-9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol) with a melting point of 146-147C is obtained analogously to the sequence of examples 1-4.
[ ~X ]D20+ 49.6 (CHC13, c=0.425).
Analogous treatment of 120 mg of the polar isomer (epimer B) obtained according to example 2 yields 113 mg as colorless oil.
[~ ]D20+ 41.4 (CHC13, c=0.285) A solution of 225 mg of the product obtained according to example 3 from epimer A in 5 ml of THF is stirred for 60 minutes at 60C after adding 1.31 ml of a lM solution of tetrabutylammonium fluoride in THF. After cooling, it is poured into a saturated common salt solution and extracted with ethyl acetate. The crude product is chromatographed on silica gel with hexane/ethyl acetate and yields 85 mg of 24~ hydroxy-4-methylpentyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-l(S),3(R)-diol as white foam.
IH-NMR (CDC13): ~ = 0.57 ppm (s,3H,H-18), 0.84 (d,J=7Hz,3H,H-21); 0.92 (d,J=7Hz,6H,C-(CH3)2); 4.03 (m,lH,H-25);
4.23 (m,lH,H-3); 4.43 (m,lH,H-l); 5.00 and 5.33 (s; lH, H-l9 each); 5.45 (dd,J=15.5 and 7Hz,lH,H-24); 5.60 (m,lH,H-23); 6.02 and 6.38 (d,J=lHz; llH, H-6, H-7 each).
Analogous treatment of the product (95 mg) obtained according to example 3 from epimer B yields 35 mg of the epimeric triol as colorless oil. The NMR spectra of the epimers are identical.
Analogously to the process described under example 1, 2.05 g of l(S~,3(R)-bis-(tert-butyldimethylsilyloxy)-20-(R)-methyl-9,10-secopregna-5E,7E,10(19)-triene-21-carbaldehyde in 53 ml of toluene is reacted with 3.4 g of isobutylcarbonylmethylenetriphenyl phosphorane. After ~9 chromatographic purification, [l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-secochola-5E,7E,10(19),23(E)-tetraen-24-yl3-3-methyl-butan-1-one with a melting point of 79-81C is obtained (from ethanol).
[C~]D20 + 52.6 (CHC13, c=0.500) By reduction of 1.75 g of the product obtained under example 5 under the conditions of example 2, l(S~,3(R)-bis~tert-butyldimethylsilyloxy)-24-(1(R,S)-hydroxy-3-methylbutyl)-9,10-secochola-5E,7E,10(19),23E-tetraene is obtained as an oily mixture of the epimers. By chromatography on silica gel with hexane/ethyl acetate, 780 mg of epimer A and 600 mg of epimer B
are obtained in the elution sequence as colorless oils, which cannot be differentiated by NMR spectroscopy.
By triplet-sensitized photoisomerization analogously to example 3 and subsequent silylether cleavage analogously to example 4, 240 mg of 24-(1-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19),23(E)-tetraene-l(S),3(R)-diol (compound A) with a decomposition interval of 119-125C, is obtained from 700 mg of epimer A produced according to example 6 [ ~ ~D20+ 38.8 (methanol, c=0.505).
Analogous treatment of 330 mg of epimer B yields 129 mg of 24-(1-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19j,23(E)-^ ~) tetraene-l(S),3~S)-diol (compound B) with a decomposition interval of 139-145C, [C~ )D20+ 54.8 (methanol) c=0.5G5).
A solution of 170 mg of the product obtained according to example 5 in 5 ml of THF is stirred for 90 minutes at room temperature after adding 200 mg of lithium-tri-tert-butoxy-aluminum hydride. For working up, it is mixed with 0.8 ml of saturated NH4Cl solution, filtered and the filtrate is concentrated by evaporation. Chromatography of the crude product on A12O3 (Merck, neutral, step III) yields 108 mg of 1-[l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-secochola-5~,7E,10(19)-trien-24-yl]-3-methyl-butan-1-one as colorless oil.
IH-NMR (CDC13): ~ = 0.53 ppm (s,3H,H-18); 4.22 tm,lH,H-3);
4.54 (m,lH,H-1); 4.93 and 4.98 (m; lH, H-19 each); 5.8Z and 6.46 (d,J=llHz; lH, H-6, H-7 each).
From 100 mg of the product of example 8, photochemical double bond isomerization analogously to example 3 and silylether cleavage analogously to example 4 yield 50 mg of 1-[l(S),3(R)-dihydroxy~9,10-secochola-5Z,7E,10(19)-trien-24-yl]-3-methyl-butan-1-one.
W (methanol): = 212 nm ( ~ =14 300), 265 (15 860).
The reaction of 1.6 g of l(S),3~R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-5E,7E,10(19)-triene-21-carbaldehyde with (2-isopropoxyethyl)-carbonylmethylenetriphenyl phosphorane analogously to example 1 yields 1.15 g of 1-[l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-secochola-5E,7E,10(19),23(E)-tetraen-24-yl]-3-isopropoxy-propan-l-one as colorless oil~ -IH-NMR (CDC13): ~ = 0.01 ppm (s,12H,Si-CH3), 0.55 (s,3H,H-18), 0.86 and 0.90 (s; 9H, Si-t.-butyl each); 0.96 (d, J=7Hz,3H,H-21); 1.15 (d,J=7Hz,6H,C(CH3)2); 3.60(m,1H,CH-0); 3.73 (t,J=7Hz,2H,CH2-0); 4.23 (m,lH,H-3); 4.55 (m,lH,H-l); 4.95 and 5.00 (m; lH, H-l9 each); 5.83 and 6.46 (d,J=ll Hz; lH, H-6, H-7 each); 6.11 (d,J=15.5Hz,lH,H-24); 6.87 (m,lH,H-23).
By reduction analogously to example 2, photoisomerization analogously to example 3 and silylether cleavage analogously to example 4, 143 mg of 24-1l(R,S) hydroxy-3-isopropoxypropyl)-9,10-secochola-5Z,7E,10(19),23-tetraene-l(S),3(R)-diol is obtained from 1.05 g of the product produced according to example 10 as a 1:1 mixture of the diastereomers that are separated by high-pressure liquid chromatography. The isomers exhibit identical NMR spectra.
IH-NMR (CDC13): ~ = 0.57 ppm (s,3H,H-18),0.94 (d,J-7Hz,3H,H-213; 1.15 (d,J=7Hz,6H,C(CH3)2), 4.17 (m,lH,H-3);
3~
4.21 (m,lH,H-25); 4.38 (m,lH,H-l); 4.98 and 5.29 (m; lH, H-l9 each); 5.45 (dd,J=15.5 and 7Hz,lH,H-24); 5.63 (m,lH,H-23); 6.02 and 6.38 (d,J=llHz; lH, H-6, H-7 each).
Starting fron aldehyde 1 and isopropoxymethylcarbonylmethylenetriphenyl phosphorane, isomer B
(5Z,7E,22E-l(S),3(R),24(S)-9,10-seco-24a,24b-dihomo-24b- -oxacholesta-5,7,10(19),22-tetraene-1,3,24-triol) with a melting point of 131-132C is obtained analogously to the sequence of examples 1-4.
Starting fron aldehyde 1 and (2-isopropoxyethyl)-carbonylmethylenetriphenyl phosphorane, isomer B (5Z,7E,22E-l(S3,3(R),24(S)-9,10-seco-24a,24b,24c-trihomo-24c-oxacholesta-5,7,10(19),22-tetraene-1,3,24-triol) with a melting point of 125-126C is obtained analogously to the sequence of examples 1-4.
Analogously to example 1, 0.85 g of l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-secopregna-5E,7E,10(19)-triene-21-carbaldehyde is reacted with 4.5 g of cyclopropylmethylcarbonyltriphenyl phosphorane. After chromatographic purification on silica gel with hexane/ethyl acetate, 500 mg of l(S),3(R3-bis-(tert-butyldimethylsilyloxy)-26,27-cyclo-24a,24b-dihomo-s,lO-secocholesta-5E,7E,10(19),23E-tetraen-24a-one is obtained as colorless foam.
IH-NMR (CDCl3): ~ = 0.01 ppm (s,12H,Si-CH3); 0.09 and 0.50 (m; 2H, H-26 and H-27 each); 0.50 (s,3H,H-18); 0.83 and 0.85 (8;
9H, Si-t.-butyl each); 0.91 (d,J=7.3Hz,3H,H-21); 0.96 (m,lH,H-25); 2.47 (d,J=6Hz,2H,H-24b); 4.16 (m,lH,H-3); 4.47(m,1H,H-l);
4.89 and 4.93(~; lH, H-l9 each); 5.77 and 6.40 (d,J=llHz; lH, H-6 and H-7 each); 6.08~d,J=15.SHz,H-24);
6.75(ddd,J=15.5,9,6.5Hz,lH,H-23).
Reduction of the product obtained under example 14 analogously to example 2 yields 200 mg of l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5E,7E,10(19),23E-tetraen-24a(R,S)-ol as an oily mixture of the epimers that cannot be differentiated by NMR
spectroscopy.
IH-NMR (CDCl3): ~ = 0.01 ppm (s,12H,Si-CH3); 0.09 and 0.40 (m; 2H, H-26 and H-27 each); 0.50 (s,3H,H-18); 0.68 (m,lH,H-25);
0.81 and 0.86(s; 9H, Si-t.-butyl each); 0.88 (d,J=7Hz,3H,H-21);
1.40 (t,J=7Hz,H-24b); 4.13 (m,lH,H-24a); 4.17 (m,lH,H-3); 4.49 (m,lH,H-l); 4.88 and 4.93 (s; lH, H-l9 each); 5.45 (dd,J=15.5, 6.5Hz,lH,H-24); 5.59 (ddd,J=15.5, 7, 6.5Hz,lH,H-23); 5.77 and 6.40 (d,J=llHz; lH, H-6 and H-7 each).
Analogously to example 3, by triplet-sensitized photoisomerization and cleavage of the protecting groups analogously to example 4, 86 mg of 26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19~,23E-tetraene-l(S),3(R),24a(R,S)-triol is obtained from 190 mg of the compound described under example 15 as a 1:1 mixture of the diastereomers that are separated by high-pressure liquid chromatography. The NMR
spectra of both diastereomers are identical.
IH-NMR (CDC13): J = o. og and 0.49 (m; 2H, H-26 and H-27 each); 0.53 (s,3H,H-18); 0.70(m,1H,H-253; 0.93 (d,J=7Hz,3H,H-21);
4.18 (m,lH,H-24a); 4~22 (m,lH,H-3); 4.43 (m,lH,H-l); S.00 and 5.32 (s; lH, H-19 each); 5.50 (dd,J=15.5, 6.5Hz,H-24); 5.64 (ddd,J=15.5, 7, 6.5Hz,lH,H-23); 6.02 and 6.38 (d,J=llHz; lH, H-6 and H-7 each).
Starting from aldehyde 1 and (l-ethylpropoxymethyl)-carbonylmethylenetriphenyl phosphorane, isomer B (5Z,7E,22E-l(S),3(~),24(S)-26,27-dimethyl-24a,24b-dihomo-24b-oxa-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol) with a melting point of 103-105C is obtained analogously to the sequence of examples 1-4.
Starting from aldehyde 1 and cyclopropylmethoxymethylcarbonylmethylenetriphenyl phosphorane, isomer B (5Z,7E,22E-l(S),3(R),24(S)-26,27-cyclo-24a,24b,24c-trihomo-24b-oxa-9~lo-secocholesta-5~7~lo(l9)~22-tetraene-l~3~24 triol) is obtained analogously to the sequence of examples 1-4.
IH-NMR (DMS0-~): S=0.16 ppm (m,2H); 0.43 (m,2H); 0.53 (S,3H); 1.00 (d,J-6Hz,3H); 3.21 (m,4H); 4.00 (m,2H); 4.19 (m,lH);
4.51 (d,J=5Hz,lH); 4.70 (d,J=5~z,lH); 4.75 (m,lH); 4.82 (d,J=5Hz,lH); 5.21 (m,lH); 5.39 (m,2H); 5.98 (d,J=llhz,lH); 6.18 (d,J=llhz,lH).
Starting from aldehyde 1 and (3-butinyl)-carbonylmethylenetriphenyl phosphorane, isomer B (5Z,7E,22E-l(S),3(R),24(S)-24-(3-butinyl)-9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol) with a melting point of 115-118C is obtained analogously to the sequence of examples 1-4.
Starting from aldehyde 1 and (3-butenyl)-carbonylmethylenetriphenyl phosphorane, isomer B (5Z,7E,22E-l(S),3(R),24(S)-24-(3-butenyl)-9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol) with a melting point of 146-147C is obtained analogously to the sequence of examples 1-4.
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Side-chain homologous vitamin D derivatives of formula I
(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 5 carbon atoms, a trifluoromethyl group or together a saturated, unsaturated or aromatic carbocyclic 3-, 4-, 5- or 6-member ring formed with the tertiary carbon atom or with the inclusion of 1 or 2 N, O or S
atoms a heterocyclic 3, 4, 5 or 6-member ring, 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 and X means an alkylene oxy radical -(CH2)nO- with n = 1 to 3 or A means a methylene bridge (-CH2-) between carbon atoms 20 and 22 and X means an alkylene radical -(CH2)n- or an alkylene oxy radical -(CH2)nO- with n = 1 to 3, or if A stands for a direct bond and B and D together stand for a second bond, means one of radicals -CH2-O-CH2-?, -(CH2)2- or -(CH2)2-.
(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 5 carbon atoms, a trifluoromethyl group or together a saturated, unsaturated or aromatic carbocyclic 3-, 4-, 5- or 6-member ring formed with the tertiary carbon atom or with the inclusion of 1 or 2 N, O or S
atoms a heterocyclic 3, 4, 5 or 6-member ring, 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 and X means an alkylene oxy radical -(CH2)nO- with n = 1 to 3 or A means a methylene bridge (-CH2-) between carbon atoms 20 and 22 and X means an alkylene radical -(CH2)n- or an alkylene oxy radical -(CH2)nO- with n = 1 to 3, or if A stands for a direct bond and B and D together stand for a second bond, means one of radicals -CH2-O-CH2-?, -(CH2)2- or -(CH2)2-.
2. Vitamin D derivatives according to claim 1, in which R2 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 R3 or R4 means a hydroxy group.
5. Vitamin D derivatives according to claim 1, in which n in X is 1 or 2.
6. Vitamin D derivatives according to claim 1, in which R5 and R6 stand for methyl groups.
7. Vitamin D derivatives according to claim 1, in which R5, R6 and the tertiary carbon atom together stand for a cyclopropyl ring.
8. 24-(l(R)-Hydroxy-4-methylpentyl)-9,10-secochola-5Z, 7E,10(19),23E-tetraene-l(S), 3(R)-diol, 24-(l(S)-hydroxy-4-methylpentyl)-9,10-secochola-5Z, 7E,10(19),23E-tetraene-l(S),3(R)-diol, 24-(l(R)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-l(S),3(R)-diol, 24-(l(S)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-l(S),3(R)-diol, 24-(l(R)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19)-triene-l(S),3(R)-diol, 24 (l(S)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19)-triene-l(S),3(R)-diol, 24-(l(R)-hydroxy-3-isopropoxypropyl)-9,10-secochola-5Z,7E,10,(19),23E-tetraene-l(S),3(R)-diol, 24-(l(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-l(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-l(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.
9. Process for the production of side-chain homologous vitamin D derivatives of formula I
(I), in which R1, R2, R3, R4, R5, and R6 and A, B, D, and X have the meaning given in claim 1, characterized in that a compound of general formula IV
(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 formula IVa (IVa).
in which R1', R2', A, X and R5 and R6 have the meaning indicated 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 (IIIa) ?OH = .alpha.-OH
IllIbl ?OH = .beta.-OH
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, is converted into a compound of general formula II
(II), in which R1', R2', A, B, D, X and R5 and R6 have the meaning given in formula IIIa/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.
(I), in which R1, R2, R3, R4, R5, and R6 and A, B, D, and X have the meaning given in claim 1, characterized in that a compound of general formula IV
(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 formula IVa (IVa).
in which R1', R2', A, X and R5 and R6 have the meaning indicated 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 (IIIa) ?OH = .alpha.-OH
IllIbl ?OH = .beta.-OH
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, is converted into a compound of general formula II
(II), in which R1', R2', A, B, D, X and R5 and R6 have the meaning given in formula IIIa/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.
10. Pharmaceutical preparations, wherein they contain at least one compound according to claims 1 to 8 and a pharmaceutically compatible vehicle.
11. Use of the compounds according to claims 1 to 8 for the production of pharmaceutical agents.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4003854A DE4003854A1 (en) | 1990-02-06 | 1990-02-06 | New vitamin=D derivs. - are cell differentiators and proliferation inhibitors useful for treating psoriasis and malignant tumours |
| DEP4003854.8 | 1990-02-06 | ||
| DE19904034730 DE4034730A1 (en) | 1990-10-30 | 1990-10-30 | New vitamin=D derivs. with modified side chain |
| DEP4034730.3 | 1990-10-30 |
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| Publication Number | Publication Date |
|---|---|
| CA2058637A1 true CA2058637A1 (en) | 1991-08-07 |
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|---|---|---|---|
| CA002058637A Abandoned CA2058637A1 (en) | 1990-02-06 | 1991-02-06 | Side-chain homologous vitamin d derivatives, process for their production, pharmaceutical preparations containing these derivatives and their use as pharmaceutical agents |
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| EP (1) | EP0441467B1 (en) |
| JP (1) | JPH05501718A (en) |
| CN (1) | CN1029400C (en) |
| AT (1) | ATE106391T1 (en) |
| AU (1) | AU652739B2 (en) |
| CA (1) | CA2058637A1 (en) |
| CZ (1) | CZ280203B6 (en) |
| DE (1) | DE59101738D1 (en) |
| DK (1) | DK0441467T3 (en) |
| ES (1) | ES2055521T3 (en) |
| FI (1) | FI100598B (en) |
| HU (1) | HUT59665A (en) |
| IE (1) | IE70239B1 (en) |
| IL (1) | IL97158A (en) |
| NO (1) | NO300209B1 (en) |
| PT (1) | PT96679B (en) |
| WO (1) | WO1991012238A1 (en) |
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| US5532228A (en) * | 1990-02-06 | 1996-07-02 | Schering Aktiengesellschaft | Side-chain homologous vitamin D derivatives, process for their production, pharmaceutical preparations containing these derivatives and their use as pharmaceutical agents |
| DE4221961A1 (en) * | 1992-06-30 | 1994-01-05 | Schering Ag | 22-en-25-oxa derivatives in the vitamin D series, processes for their preparation, pharmaceutical preparations containing these derivatives and their use as medicines |
| GB9223061D0 (en) * | 1992-11-04 | 1992-12-16 | Leo Pharm Prod Ltd | Chemical compounds |
| TW267161B (en) * | 1992-11-20 | 1996-01-01 | Hoffmann La Roche | |
| DE4343694C2 (en) * | 1993-12-16 | 1997-02-13 | Schering Ag | Process for the homologation of protected C-22 vitamin D aldehydes and process intermediates |
| GB9524812D0 (en) * | 1995-12-05 | 1996-02-07 | Leo Pharm Prod Ltd | Chemical compounds |
| CA2296145A1 (en) * | 1997-07-17 | 1999-01-28 | F. Hoffmann-La Roche Ag | Dihomo-seco-cholestanes with two unsaturated bonds in the side chain |
| DE19935771A1 (en) | 1999-07-23 | 2001-02-01 | Schering Ag | New vitamin D derivatives with cyclic substructures in the side chains, processes and intermediates for their manufacture and their use in the manufacture of pharmaceuticals |
| JP2005257271A (en) * | 2002-02-25 | 2005-09-22 | Chugai Pharmaceut Co Ltd | Method of detecting bond between vitamin d 3 derivative and vitamin d 3 receptor |
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| US4225596A (en) * | 1978-10-13 | 1980-09-30 | Wisconsin Alumni Research Foundation | Method for treating calcium imbalance and improving calcium absorption in mammals |
| US4588528A (en) * | 1984-05-31 | 1986-05-13 | Wisconsin Alumni Research Foundation | 1,24-dihydroxy-Δ22 -vitamin D3 and process for preparing same |
| JPH07100685B2 (en) * | 1985-08-02 | 1995-11-01 | レオ・ファ−マシュ−ティカル・プロダクツ・リミテッド・エイ／エス（レ−ベンス・ケミスケ・ファブリック・プロデュクチオンスアクチ−セルスカブ） | Novel vitamin D analog |
-
1991
- 1991-02-06 EP EP91250032A patent/EP0441467B1/en not_active Expired - Lifetime
- 1991-02-06 ES ES91250032T patent/ES2055521T3/en not_active Expired - Lifetime
- 1991-02-06 WO PCT/DE1991/000104 patent/WO1991012238A1/en active IP Right Grant
- 1991-02-06 DE DE59101738T patent/DE59101738D1/en not_active Expired - Lifetime
- 1991-02-06 DK DK91250032.9T patent/DK0441467T3/en active
- 1991-02-06 CN CN91101506A patent/CN1029400C/en not_active Expired - Fee Related
- 1991-02-06 PT PT96679A patent/PT96679B/en not_active IP Right Cessation
- 1991-02-06 CZ CS91281A patent/CZ280203B6/en not_active IP Right Cessation
- 1991-02-06 AU AU72161/91A patent/AU652739B2/en not_active Ceased
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- 1991-02-06 CA CA002058637A patent/CA2058637A1/en not_active Abandoned
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Also Published As
| Publication number | Publication date |
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| NO300209B1 (en) | 1997-04-28 |
| ES2055521T3 (en) | 1994-08-16 |
| FI100598B (en) | 1998-01-15 |
| EP0441467A1 (en) | 1991-08-14 |
| IL97158A (en) | 1994-12-29 |
| CS28191A3 (en) | 1992-04-15 |
| AU7216191A (en) | 1991-09-03 |
| DK0441467T3 (en) | 1994-10-03 |
| HU913475D0 (en) | 1992-05-28 |
| CN1054588A (en) | 1991-09-18 |
| WO1991012238A1 (en) | 1991-08-22 |
| DE59101738D1 (en) | 1994-07-07 |
| EP0441467B1 (en) | 1994-06-01 |
| PT96679A (en) | 1991-10-31 |
| CZ280203B6 (en) | 1995-11-15 |
| IL97158A0 (en) | 1992-05-25 |
| HUT59665A (en) | 1992-06-29 |
| IE910389A1 (en) | 1991-08-14 |
| CN1029400C (en) | 1995-08-02 |
| ATE106391T1 (en) | 1994-06-15 |
| JPH05501718A (en) | 1993-04-02 |
| PT96679B (en) | 1998-07-31 |
| AU652739B2 (en) | 1994-09-08 |
| FI914677A0 (en) | 1991-10-04 |
| NO913913L (en) | 1991-12-05 |
| IE70239B1 (en) | 1996-11-13 |
| NO913913D0 (en) | 1991-10-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |