WO1986002078A1 - Vitamin d derivatives and methods for preparing same - Google Patents

Vitamin d derivatives and methods for preparing same Download PDF

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Publication number
WO1986002078A1
WO1986002078A1 PCT/US1985/001571 US8501571W WO8602078A1 WO 1986002078 A1 WO1986002078 A1 WO 1986002078A1 US 8501571 W US8501571 W US 8501571W WO 8602078 A1 WO8602078 A1 WO 8602078A1
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Prior art keywords
vitamin
gave
ethyl acetate
mmol
compounds
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PCT/US1985/001571
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French (fr)
Inventor
Hector F. Deluca
Nobuo Ikekawa
Yoko Tanaka
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Wisconsin Alumni Research Foundation
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Publication date
Application filed by Wisconsin Alumni Research Foundation filed Critical Wisconsin Alumni Research Foundation
Priority to NL8520265A priority Critical patent/NL8520265A/en
Publication of WO1986002078A1 publication Critical patent/WO1986002078A1/en
Priority to DK260086A priority patent/DK154290C/en
Priority to DK111188A priority patent/DK159389C/en
Priority to DK177489A priority patent/DK158989C/en
Priority to DK015290A priority patent/DK158990C/en
Priority to DK015390A priority patent/DK158991C/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • This invention relates to novel vitamin D derivatives.
  • this invention relates to 24-homovitamins.
  • this invention relates to hydroxylated 24-hom ovitamins.
  • Vitamin D is known to regulate calcium and phosphorous metabolism in animals and humans and it has now been firmly established that the biological efficacy of vitamin D depends upon its metabolic conversion, in vivo, to hydroxylated derivatives.
  • vitamin D 3 is hydroxylated in vivo to 25-hydroxyvitamin D 3 in the liver which in turn is converted into 1 ⁇ ,25-dihydroxyvitamin D 3 in the kidneys. It is the latter compound which is now recognized as being the circulating hormonal form of vitamin D.
  • vitamin D Because of their biological activity in promoting calcium and phosphorous transport in the intestine and the mobilization and mineralization of bone these forms of vitamin D are important pharmaceutical products which are eminently suitable for use in the treatment of various bone disorders.
  • Vitamin D derivatives and their preparation and application are discussed in many references in the patent and other literature.
  • U.S. Patent No. 3,565,924 is directed to 25-dihydroxycholecalciferol
  • U.S. Patent No. 3,697,559 is directed to 1,25-dihydroxycholecalciferol
  • U.S. Patent No. 3,741,996 is directed to 1 ⁇ -hydroxycholecalciferol
  • U.S. Patent No. 3,786,062 is directed to 22-dehydro-25-hydroxycholecalciferol
  • U.S. Patent No. 3,880,894 is directed to 1,25-dihydroxyergocalciferol
  • New derivatives of vitamin D 3 have now been found which express excellent vitamin D-like activity and which, for that reason, could readily serve as a substitute for vitamin D 3 , as well as various of its derivatives, in known applications, such as, for example the treatment of various disease states manifesting calcium and phosphorous imbalance as hyp ⁇ parathyroidism, osteodystrcphy, osteomalacia and osteoporosis.
  • These derivatives are 24-homovitamins and particularly 1 ⁇ ,25-dihydroxy-22E(orZ)-dehydro-24-homovitamin D 3 and 1 ⁇ ,25dihydroxy-24-homooitamin D 3 .
  • R 1 , R 2 and R 3 are each selected from the group consisting of hydrogen, an acyl group having from 1 to about 4 carbon atcms, and benzoyl and R 4 and R 5 each represent hydrogen atoms or taken together form a carbon to carbon double bond.
  • Bisnorcholenic acid acetate (a) was reduced with lithium aluminum hydride and subsequently oxidized with dichlorodicyanobenzoquinone to afford the 1,4,6-triene-3-one (b) in 47% yield.
  • the 22-THP-ether of b was treated with alkaline hydrogen peroxide to give the 1 ⁇ ,2 ⁇ -epoxide (1) in 41% yield.
  • Reduction of (1) with lithium and ammonium chloride in liquid a mm o nia-tetrahydrofuran at -78°, and subsequent treatment with chloromethyl methyl ether provided the dimethyoxyirethyl ether (2) in 38% yield.
  • the 5,22-diene (9) was selectively hydrogenated to provide the 5-ene (10) in 92% yield.
  • This compound was converted to 1 ⁇ ,25-dihydroxy-24-harovitamin D 3 (14) via the 5,7-diene (13) as described above in 12% overall yield.
  • Lithium (5.00g) was added in small portion to liquid airmonia (200 ml) at -78° under argon atmosphere during 30 min. After stirring for 1 hr at -78°, 1 ⁇ ,2 ⁇ -epoxy-22-tetrapyranyloxy-23,24-dinorchola-4,6-diene-3-one (1) (2.00g, 4.69 mmol) in dry THF (150ml) was added dropwise at -78° during 30 min, and this mixture was stirred for 1 hr at -78°. To this reaction mixture, anhydrous NH 4 Cl (60 g) was added in small portion at -78° during 1 hr.
  • the 22E stereo isomer, ccxrpound (6) can be readily converted to the 22Z stereo isomer by treatment with iodine.
  • treatment of compound (6) in ether with a catalytic amount of iodine (2%) of the amount of (6) while under diffuse daylight for 1 hr. results in a trans to cis isomerization which, after HPLC purification, (Zorbax-Sil column, 4.6 x 25 cm, 6% 2-propanol/hexane) yielded the 22Z stereo isomer.
  • the vitamin D 3 analogue (11) was determined as 100% by high performance liquid chromatography (a Shimadzu IC-3A; column, Zorbax ZIL normal phase, 4.6 mm i.d. x 15cm; solvent, MeOH-CH 2 Cl 2 , 1 : 49; flow rate, 3ml/min; retention time, 11.5 min).
  • the vitamin D 3 analogue (11) had the following spectral data; U : 265 nm, : 228 nm, MS m/z: 428 (M + ), 410, 392 (base peak),
  • the 5,7-diene (13) (5.8 mg, 0.0113 mmol) was converted, as described for (11), to the vitamin D 3 analogue (14) (890 ⁇ g, 19%).
  • the retention time of (14) under the above-described HPLC condition was 11.0 min. : 265 nm, : 228 nm.
  • the compounds of this invention can be readily obtained in crystalline form by crystallization from suitable solvents, e.g. hexane, ethers, alcohols, or mixtures thereof as will be apparent to those skilled in the art.
  • suitable solvents e.g. hexane, ethers, alcohols, or mixtures thereof as will be apparent to those skilled in the art.
  • Bone calcium mobilization activity was assayed by measuring the rise in serum calcium levels in response to the compound administered.
  • Male, weanling rats (Holtzman Co., Madison, WI) were fed a lew-calcium, vitamin D deficient diet (Suda et al, J. Nutr. 1001049-1050, 1970) and water ad libitum for 3 weeks.
  • the rats were then divided into three groups of 5-6 rats each and were given intrajugularly either 1,25-(OH) 2 D 3 or the test compound dissolved in 0.05ml of 95% ethanol. Rats in the control group were given 0.05ml ethanol vehicle in the same manner. Eighteen hours after the dose, the rats were killed and their blood was collected and centrifuged to obtain serum. Serum calcium concentrations were determined with an atomic absorption spectrometer Model 403 (Perkin-Elmer Co., Nbrwalk, Conn.) in presence of 0.1% lanthanum chloride.
  • the compounds of this invention may be readily administered in sterile parenteral solutions by injection or intravenously or by alimentary canal in the form of oral dosages, or by suppository or even transcutaneously.
  • Doses of from about 0.1 ⁇ g to about 2.5 ⁇ g per day are effective in obtaining the physiological calcium balance responses characteristic of vitamin D-like activity with maintenance dosage of from about 0.1 ⁇ g to about 0.5 ⁇ g being suitable.
  • Dosage forms of the compounds can be prepared by combn ing them with a non-toxic pharmaceutically acceptable carrier as is well known in the art.
  • Such carriers may be either solid or liquid such as, for example, corn starch, lactose, sucrose, peanut oil, olive oil, sesame oil and water.
  • the dosage forms of the compounds of the invention may be tablets, capsules, powders, troches or lozenges. If a liquid carrier is used, soft gelatin capsules, or syrup or liquid suspensions, emulsions or solutions may be the dosage form.
  • the dosage forms may also contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, etc. They may also contain other therapeutically valuable substances.

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  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
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  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

New 24-homo-vitamin D compounds, methods for preparing the same and novel intermediate compounds. The compounds are characterized by vitamin D-like activity of the order of 1alpha,25-dihydroxyvitamin D3, the recognized circulating hormonal form of vitamin D, or various of its derivatives and are useful in the treatment of disease state characterized by calcium-phosphorous imbalances.

Description

Vitamin D Derivatives and Methods for Preparing Same
Technical Field
This invention relates to novel vitamin D derivatives.
More specifically, this invention relates to 24-homovitamins.
Still more specifically this invention relates to hydroxylated 24-hom ovitamins.
Vitamin D is known to regulate calcium and phosphorous metabolism in animals and humans and it has now been firmly established that the biological efficacy of vitamin D depends upon its metabolic conversion, in vivo, to hydroxylated derivatives. Thus vitamin D3 is hydroxylated in vivo to 25-hydroxyvitamin D3 in the liver which in turn is converted into 1α,25-dihydroxyvitamin D3 in the kidneys. It is the latter compound which is now recognized as being the circulating hormonal form of vitamin D.
Because of their biological activity in promoting calcium and phosphorous transport in the intestine and the mobilization and mineralization of bone these forms of vitamin D are important pharmaceutical products which are eminently suitable for use in the treatment of various bone disorders. Background Art
Vitamin D derivatives and their preparation and application are discussed in many references in the patent and other literature. For example, U.S. Patent No. 3,565,924 is directed to 25-dihydroxycholecalciferol; U.S. Patent No. 3,697,559 is directed to 1,25-dihydroxycholecalciferol; U.S. Patent No. 3,741,996 is directed to 1α-hydroxycholecalciferol; U.S. Patent No. 3,786,062 is directed to 22-dehydro-25-hydroxycholecalciferol; U.S. Patent No. 3,880,894 is directed to 1,25-dihydroxyergocalciferol; U.S. Patent No. 4,201,881 is directed to 24,24-difluoro-1α,25-dihydroxycholecalciferol; U.S. Patent No. 4,196,133 is directed to 24,24-difluoro-1α,25dihydroxycholecalciferol. Disclosure of Invention
New derivatives of vitamin D3 have now been found which express excellent vitamin D-like activity and which, for that reason, could readily serve as a substitute for vitamin D3, as well as various of its derivatives, in known applications, such as, for example the treatment of various disease states manifesting calcium and phosphorous imbalance as hypσparathyroidism, osteodystrcphy, osteomalacia and osteoporosis.
These derivatives are 24-homovitamins and particularly 1α,25-dihydroxy-22E(orZ)-dehydro-24-homovitamin D3 and 1α,25dihydroxy-24-homooitamin D3.
Compounds of the present invention can be conveniently represented by the formula:
Figure imgf000004_0001
where R1, R2 and R3 are each selected from the group consisting of hydrogen, an acyl group having from 1 to about 4 carbon atcms, and benzoyl and R4 and R5 each represent hydrogen atoms or taken together form a carbon to carbon double bond. Best Mode for Carrying Out the Invention
The compounds of this invention can be prepared in accordance with the process shown in the following schematic and process description. In the schematic and detailed description of the process like numbers identify like compounds.
Figure imgf000005_0001
In accordance with the process of this invention:
Bisnorcholenic acid acetate (a) was reduced with lithium aluminum hydride and subsequently oxidized with dichlorodicyanobenzoquinone to afford the 1,4,6-triene-3-one (b) in 47% yield. The 22-THP-ether of b was treated with alkaline hydrogen peroxide to give the 1α,2α-epoxide (1) in 41% yield. Reduction of (1) with lithium and ammonium chloride in liquid a mm o nia-tetrahydrofuran at -78°, and subsequent treatment with chloromethyl methyl ether provided the dimethyoxyirethyl ether (2) in 38% yield. Removal of the THP group, followed by Swern oxidation gave the aldehyde (4) in 81% yield. This was reacted with vinylmagnesium brαtiide to provide the allylalcohol (5) in 94% yield. This alcohol was heated in refluxed xylene with triethyl orthoacetate and a catalytic amount of propionic acid, to afford the ester (6) in 93% yield. Then, the ester (6) was reacted with irethylmagnesium branide to provide the alcohol (7) in 93% yield. Removal of MOM group, followed by acetylation gave (22E)-1α,3β-diacetoxy-25-hydroxy24-homo-cholesta-5,22-diene (9) in 73% yield.
Allylie bromination of (9) with N-brom succinimide, followed by treatment with tetra-n-butylammonium bromide and then with tetra-n-butylammonium fluoride gave the 5,7,22triene (10) as a main product in 24% yield. The 5,7-diene (10) was irradiated with a medium pressure mercury lamp in benzene-ethanol for 5 min, si±isequently refluxed for 1 hr, and then hydrolyzed to afford (22E)-1α,25-dihydroxy-22-dehydro-24homovitamin D3 (11) in 22% yield.
The 5,22-diene (9) was selectively hydrogenated to provide the 5-ene (10) in 92% yield. This compound was converted to 1α,25-dihydroxy-24-harovitamin D3 (14) via the 5,7-diene (13) as described above in 12% overall yield. Detailed Description of Process
In the following detailed description of the process of this invention melting points were determined with a hot-stage microscope and were uncorrected. 1H-NKR spectra were taken with a Hitachi R-24A (60MHz) in CDCl3 with Me4Si as an internal standard, unless otherwise noted. Mass spectra were obtained with a Shimadzu QP-1000 mass spectrometer at 70 eV. UV spectra were obtained in ethanol solution with a Shimadzu UV-200 double beam spactrophotometer. Column Chromatography was effected using silica gel (E. Merck, Kieselgel 60, 70-230 mesh). Preparative thin layer chrcmatography was carried out on precoated plates of silica gel (E. Merck, Kieselgel 60
F254, 0.25mm thickness). The usual work-up refers to dilution with water, extraction with an organic solvent indicated in parenthesis, washing the extract to neutrality, drying over anhydrous magnesium sulphate, filtration, and removal of the solvent under reduced pressure. The following abbreviations are used; THP - tetrahydropyranyl; THFtetrahydrofuran; ether - diethyl ether, MeOH - methanol, MOMirethoxyirethyl. Temperatures are in ° centigrade. 22-Hydroxy-23,24-dinorchola-1,4,6-triene-3-one (b)
To a solution of 3β-acetoxydinorcholenic acid (a) (7.0g, 18.04 mmole) in THF (20mL) lithium aluminum hydride (3.0 g, 78.95 mmole) was added. This mixture was stirred at 60°C for 14 h. To this reaction mixture water and ethyl acetate were carefully added. Filtration and removal of the solvent gave the residue (5.2 g). This in dioxane (140mL) was treated with dichlorodicyanobenzoquinone (11.7 g, 51.54 mmole) under reflux for 14 h. After cooling to room temperature the reaction irriLxture.was filtered and the filtrate was evaporated to leave the residue, which was applied to a column of alumina (200 g). Elution with dichloromethane provided the trienone H
(b) (2.8 g, 47%) mp 156-157° (ether) UV ran (ε) : 299
Figure imgf000007_0001
(10300), 252 (9200), 224 (12000), 1H-NMR (CDCl3)δ: 0.80 (3H, s, 18-H3), 1.04 (3H, d, J=6 Hz, 21-H3), 1.21 (3H, s, 19-H3), 3.10-3.80 (3H, m, 22-H2 and OH), 5.90-6.40 (4H, m, 2-H, 4-H,6-H, and 7-H), 7.05 (1H, d, J=10Hz, 1-H), MS m/z: 326 (M+), 311, 308, 293, 267, 112. 1α, 2α-Epoxy-22-tetrahydropyranyloxy-23,24-dinorchola-4,6-dien 3-one (1)
The alcohol (b) (2.7g, 8.28 rrtnole) in dichloromethane (50 mL) was treated with dihydropyrane (1.5 mL, 16.42 irmole) and p-toluenesulfonic acid (50 mg) at room temperature for 1 h. The usual work-up (ethyl acetate for extraction) gave a crude product. To a solution of this product in EeOH (70 mL), 30% H2O2 (4.8 mL) and 10% NaOH/MeOH (0.74 mL) were added and this mixture was stirred at room temperature for 14 h. The usual work-up (ethyl acetate for extraction) gave a crude product, which was applied to a column of silica gel (50 g). Elution with benzene-ethyl acetate (100 : 1) provided the epoxide (1) (1,.45 g, 41%): mp 113-115° (hexane)
Figure imgf000008_0001
(ε):
290 (22000), 1H-NMR (CDCl3)δ: 0.80 (3H, s, 18-H3), 1.07 (3H, d, J=6Hz, 21-H3), 1.18 (3H, s, 19-H3), 3.38 (1H, dd, J=4 and 1.5Hz, 1-H), 3.55 (1H, d, J=4Hz, 2-H), 3.30-4.10 (4H, m, 22-H2 and THP), 4.50 (1H, m, THP), 5.58 (1H, d, J=1.5Hz, 4-H), 6.02 (2H, s, 6-H and 7-H) , MS m/z: 342 (M+ - DHP), 324
(M+ - THPOH), 309, 283, 85.
1α,3β-Dimethoxymethόxy-23,24-dinorchol-5-en-22-tetrahydropyranyl ether (2)
Lithium (5.00g) was added in small portion to liquid airmonia (200 ml) at -78° under argon atmosphere during 30 min. After stirring for 1 hr at -78°, 1α,2α-epoxy-22-tetrapyranyloxy-23,24-dinorchola-4,6-diene-3-one (1) (2.00g, 4.69 mmol) in dry THF (150ml) was added dropwise at -78° during 30 min, and this mixture was stirred for 1 hr at -78°. To this reaction mixture, anhydrous NH4Cl (60 g) was added in small portion at -78° during 1 hr. After 1.5 hr the cooling bath was removed and most of the airmonia was removed by bubbling argon. Ihe usual work-up (ether was used as a solvent) gave a crude product. This was treated with chloro-methyl methyl ether (2.0ml, 26.34 m mol) and N,N-diethylcyclohexylamine
(4.6ml, 24.93 mmol) in dioxane (20 ml) at 45° for 24 hr. The usual work-up (ethyl acetate) gave a crude product, which was applied to a column of silica gel (40 g). Elution with. hexane-ethyl acetate (5 : 1) provided the dimethoxymethyl ether (2) (922mg, 38%) as an oil. 1 H-NMR δ 0.70 (3H, s, 18-HJ, 1.02 (3H, s, 19-H3), 1.04 (3H, d, J=6Hz, 21-H3), 3.34 (3H, s, -C-CH3), 3.37 (3H, s, -O-CH3),4.63 (2H, ABq, J=7Hz, ΔAB=11Hz, 1α-O-CH2-O-), 4.64 (2H, s, 3β-O-CB2-O-), and 5.50 (1H, m, 6-H). 1α,3β-D_imethoxymethoxy-23,24-dinorchol-5-en-22-ol (3)
The THP ether (2) (922mg, 1.77 mmol) in THF (8ml) and MeOH (8 ml) was treated with 2M HCl (1ml) at room temperature for 2 h. The usual work-up (ethyl acetate) gave a crude product, which was applied to a column of silica gel (40g). Elution with hexane-ethyl acetate (2 : 1) gave the alcohol (3) (678mg, 88%) as an amorphous solid. 1H-NMR δ 0.70 (3H, s, 18-H3), 1.02(3H,s,19-H3), 1.04 (3H, d, J=6 Hz, 21-H3), 3.34 (3H, s, -O-CH3), 3.38 (3H, s, -O-CH3), 4.65 (2H, ABq, J=7 Hz, ΔAB = 11 Hz, 1α-O-CH2-O-), 4.66 (2H,s,3β-O-CH2-O-), 5.53 (1H,m,6-H). 1α,3β-D-_methoxymethoxy-23,24-dinorchol-5-en-22-al (4)
To a solution of oxalyl chloride (0.27ml, 3.09 mmol) in dichlororrethane (8ml) dimethyl sulphoxide (0.44ml, 6.21 iπxol) was added at -78°C under argon. The mixture was stirred at -78°C for 10 min. To the solution the alcohol (3) (660mg, 1.51 mmol) in dichloromethane (5 ml) was added at -78°C. After stirring for 15 min, triethylamine (1.89 ml, 13.6 mmol) was added. The mixture was stirred at -78°C under argon for 5 min, and warmed up to room temperature. The usual work-up (ether) gave a crude product, which was applied to a column of silica gel (30 g). Elution with hexane-ethyl acetate (4 : 1) gave the aldehyde (4) (607mg, 92%) as a crystal, up 71-72°C (hexane), 1H-NMR δ 0.74 (3H, s, 18-H3) , 1.04 (3H, s, 19-H3), 1.12 (3H, d, J=6 Hz, 21-H3), 3.35 (3H, s, -O-CH3) , 3.39 (3H, s, -O-CH3), 3.7 (1H, m, 1β-H), 4.65 (2H, ABq, J=7Hz, ΔAB = 11 Hz, 1α-O-CH2-O-), 4.66 (2H, s, 3β-O-CH-O-), 5.52 (1H, m, 6-H), and 9.61 (1H, d, J=3 Hz, -CHO), Anal. Ceiled for C26 H42O5:C, 71:85; H, 9.74. Found: C, 71.71; H, 9.68. 1α,3β-Dimethoxymetho_x_ychola-5,23-dien-22-ol (5)
To magnesium (70mg, 2.92mmol) in THF (3ml) 50% solution of vinyl bromide in THF (0.42ml, 2.98 mmol) was added. The mixture was stirred at room temperature under argon for 30 min. To the resisting Grignard reagent the aldehyde (4) (595mg, 1.37 mmol) in THF (6 ml) was added at room temperature. The mixture was stirred at room temperature for 1 h. The usual work-up (ether) gave a crude product, which was applied to a column of silica gel (30 g). Elution with hexane-ethyl acetate (3 : 1) gave the allylic aloohol (5) (595mg, 94%) as an amorphous solid. 1H-NMR 6: 0.70 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 3.35 (3H, s, -O-CH3) , 3.38 (3H, s, -O-CH3), 3.69 (1H, m, 1β-H), 4.20 (1H, m, 22-H), 4.64 (2H, ABq, J=7Hz, ΔAB = 11 Hz, 1α-O-CH2-O-), 4.65 (2H, s, 3β-O-CH2-O-), 5.52 (1H, m, 6-H), 4.90-6.0 (3H, m, 23-H and 24-H2).
(22E) -1α,3β-Dimethoxymethoxy-27-norcholesta-5,22-dien-26oic acid ethyl ester (6)
A solution of the allylic alcohol (5) (590 mg, 1.28 mmol), triethyl orthoacetate (1.0ml, 5.46 mmol), prcpionic acid (4 drops), and xylene (8 ml) was refluxed under argon for 2 h. Removal of the solvent under reduced pressure gave the residue, which was applied to a column of silica gel (30 g). Elution with hexane-ethyl acetate (4 : 1) gave the ester (6) (630mg, 93%) as an oil. 1Η-NMR δ: 0.68 (3H, s, 18-H3), 0.97 (3H, d, J=6Hz, 21-H3), 1.03 (3H, s, 19-H3), 1.24 (3H, t, J=7 Hz, -CO2CH2CH3), 3.35 (3H, s, -O-CH3), 3.39 (3H, s, -O-CH3), 3.70 (1H, m, 1β-H), 4.11 (2H, q, J=7Hz, -CO2CH2CH3), 4.64 (2H, ABq, J=7Hz, ΔAB = 11Hz, 1α-O-CH2-O-), 4.65 (2H, s, 3β-C-CH2-O-), 5.29 (2H, m, 22-H and 23-H), 5.52 (1H, m, 6-H).
If desired the 22E stereo isomer, ccxrpound (6), can be readily converted to the 22Z stereo isomer by treatment with iodine. Thus, treatment of compound (6) in ether with a catalytic amount of iodine (2%) of the amount of (6) while under diffuse daylight for 1 hr. results in a trans to cis isomerization which, after HPLC purification, (Zorbax-Sil column, 4.6 x 25 cm, 6% 2-propanol/hexane) yielded the 22Z stereo isomer. (22E) -1α,3β-Dimethoxymethoxy-24-homo-cholesta-5,22-diene-25-ol
(7)
To a solution of the ester (6) (605mg, 1.14 mmol) in THF (6ml) 1M solution of methylmagnesium bromide in THF (4.5ml, 4.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 h. The usual work-up (ether) gave a crude product, which was applied to a column of silica gel (30 g). Elution with hexane-ethyl acetate (3 : 1) gave the alcohol (7) (548 mg, 93%) as an oil. 1H-NMR δ: 0.68 (3H, s, 18-H3), 0.97 (3H, d, J=6 Hz, 21-H3), 1.01 (3H, s, 19-H3), 1.21 (6H, s, 26-H3 and 27-H3), 3.33 (3H, s, -O-CH3), 3.38 (3H, s, -O-CH3), 3.70 (1H, m, 1β-H), 4.64 (2H, AEq, J=7 Hz, ΔAB = 11Hz, 1α-O-CH2-O-), 4.65 (2H, s, 3β-O-CH2-O-), 5.29 (2H, m, 22-H and 23-H), and 5.50 (1H, m, 6-H). (22E) -24-Homocholesta-5,22-diene-1α,3β,25-triol (8)
A solution of the dimethoxymethyl ether (7) (540mg, 1.04 mmol) in THF (15ml) was treated with 6M HCl (3ml) at 50°C for 2.5 h. The usual work-up (ethyl acetate) gave a crude product, which was applied to a column of silica gel (20 g). Elution with hexane-ethyl acetate (1 : 1) gave the triol (8) (428mg, 95%) as a crystal, mp 164-166°C (hexane-ethyl acetate), 1H-NMR δ: 0.68 (3H, s, 18-H3), 0.95 (3H, s, J=6Hz, 21-H3), 1.00 (3H, s, 19-H3), 1.20 (6H, s, 26-H3 and 27-H3), 3.80 (1H, m, 1β-H), 3.92 (1H, m, 3α-H), 5.30 (2H, m, 22-H and 23-H), and 5.53 (1H, m, 6-H). (22E) -1α,3β-Diacetoxy-25-hydroxy-24-homocholesta-5,22-diene
(9)
A solution of the triol (8) (395mg, 0.919 mmol) in pyridine (2ml) was treated with acetic anhydride (1ml) at room temperature for 16 h. The usual work-up (ethyl acetate) gave a crude product, which was applied to a column of silica gel (20g). Elution with hexane-ethyl acetate (2 : 1) gave the diacetate (9) (361 mg, 77%) as an oil. 1H-NMR δ: 0.67 (3H, s, 18-H3), 0.97 (3H, d, J=6 Hz, 21-H3), 1.07 (3H, s, 19-H3), 1.21 (6H, s, 26-H3 and 27-H3), 2.01 (3H, s, acetyl), 2.04 (3H, s, acetyl), 4.98 (1H, m, 3α-H) , 5.05 (1H, m, 1β-H), 5.31 (2H, m, 22-H and 23-H), and 5.52 (1H, m, 6-H). (22E)-1α,3β-Diacetoxy-25-hydroxy-24-homocholesta-5,7,22-triene
(10)
A solution of the 5-ene (9) (51 mg, 0.0992 mmol) and N-bromo-succinimide (21mg, 0.118 mmol) in carbontetrachloride
(3ml) was refluxed under argon for 20 min. After the mixture had been cooled to 0°C, the resulting precipitate was filtered off. The filtrate was concentrated below 40°C to leave the residue. This in THF (5ml) was treated with a catalytic amount of tetra-n-butylammonium bromide at room temperature for 50 min. Then, the mixture was treated with a solution of tetra-n-butylammonium fluoride in THF (3.5 ml, 3.5 mmol) at room temperature for 30 min. The usual work-up (ethyl acetate) gave a crude product, which was submitted to preparative thin layer chromatography (hexane-ethyl acetate, 4
: 1, developed five times). The band of Rf value 0.48 was scraped off and eluted with ethyl acetate. Removal of the solvent provided the 5,7-diene (10) 12.5mg, 24%), :
Figure imgf000012_0001
293, 282, and 271.
1α,25-D_ihydroxy-22E-dehydro-24-homovitamin D3 (11)
A solution of the 5,7-diene (10) (7.3mg, 0.0143 mmol) in benzene (90ml) and ethanol (40ml) was irradiated with with a medium pressure mercury lamp through a Vycol filter at 0°C under argon for 5 min. The reaction mixture was refluxed under argon for 1 h. Removal of the solvent under reduced pressure gave a crude product, which was submitted to preparative thin layer chrcrratcgraphy (hexane-ethyl acetate, 4 : 1, developed five times). The band of Rf value 0.38 was scraped off and eluted with ethyl acetate. Resroval of the solvent gave the vitamin D3 diacetate (1.8mg, 25%). The band of Rf value 0.43 was scraped off and eluted with ethyl acetate. Removal of the solvent recovered the 5,7-diene (10)
(2.1mg, 29%).
The vitamin D3 diacetate (1.8mg, 2.15 μmol) in THF (4 ml) was treated with 5% KOH/MeOH (1 ml) at room temperature for 20 min. The usual work-up (ethyl acetate) gave a crude product, which was submitted to preparative thin layer chrcmatography (hexane-ethyl acetate, 1 : 2, developed three times). The band of Rf value 0.43 was scraped off and eluted with ethyl acetate. Removal of the solvent gave the vitaminD3 analogue (11) (1.4 mg, 90%) . The purity of the product
(11) was determined as 100% by high performance liquid chromatography (a Shimadzu IC-3A; column, Zorbax ZIL normal phase, 4.6 mm i.d. x 15cm; solvent, MeOH-CH2Cl2, 1 : 49; flow rate, 3ml/min; retention time, 11.5 min). The vitamin D3 analogue (11) had the following spectral data; U : 265
Figure imgf000013_0002
nm,
Figure imgf000013_0001
: 228 nm, MS m/z: 428 (M+), 410, 392 (base peak),
374, 287, 269, 251, 152, 134, 123, 59, 1H-NMR (360MHz) δ:
0.55 (3H, s, 18-H3), 1.02 (3H, d, J=6.6Hz, 21-H3), 1.22 (6H, s, 26-H3 and 27-H3), 2.32 (1H, dd, J=13.2 and 6.7Hz), 2.60
(1H, dd, J=13.0 and 3.0Hz), 2.83 (1H, dd, J=12.0 and 3.0Hz), 4.23 (1H, m, W1/2) = 18.4Hz, 3α-H), 4.43 (1H, m, W 1 /2 = 16.9 Hz, 1β-H), 5.00 (1H, bs, W1/2 = 3.2Hz, 19-H), 5.30 (1H, dd, J=15.0 and 7.1Hz, 22-H or 23-H), 5.33 (1H, bs, W1/2 = 3.2Hz, 19-H), 5.37 (1H, dd, J=15.0 and 5.8Hz, 22-H or 23-H), 6.01
(IH, d, J=11.0Hz, 7-H), 6.32 (1H, d, J=11.0Hz, 6-H). 1α,3β-Diacetoxy-24-homocholest-5-en-25-ol (12)
A mixture of the 5,22-diene (9) (40mg, 0.0778 mmol) and 10% Pd-C (4mg) in ethyl acetate (2ml) was stirred at room temperature under hydrogen for 3 h. The Pd catalyst was filtered off and the filtrate was concentrated to leave the residue, which was applied to a column of silica gel (5 g). Elution with hexane-ethyl acetate (4 : 1) gave the 5-ene (12)
(37 mg, 92%) as an oil. 1Η-NMR δ: 0.66 (3H, s, 18-H3) , 1.08
(3H, s, 19-H3), 1.20 (6H, s, 26-H3 and 27-H3), 2.02 (3H, s, acetyl), 2.05 (3H, s, acetyl), 4.97 (1H, m, 3α-H) , 5.07 (1H, m, 1β-H), 5.53 (1H, m, 6-H).
1α,3β-Diacetoxy-24-homoc_holesta-5,7-dien-25-ol (13)
The 5-ene (12) (19 mg, 0.037 mmol) was converted, as described for (10), to the 5,7-diene (13) (5.8 mg, 31%). EtCH 293, 282, 271 nm.
Figure imgf000014_0001
1α,25-Dihydroxy-24-homovitamin D3 (14)
The 5,7-diene (13) (5.8 mg, 0.0113 mmol) was converted, as described for (11), to the vitamin D3 analogue (14) (890 μg, 19%). The retention time of (14) under the above-described HPLC condition was 11.0 min. : 265
Figure imgf000014_0002
nm, : 228 nm. MS m/z 430 (M+), 412, 394 (base peak,
Figure imgf000014_0003
376, 287, 269, 251, 152, 134, 59.
If desired, the compounds of this invention can be readily obtained in crystalline form by crystallization from suitable solvents, e.g. hexane, ethers, alcohols, or mixtures thereof as will be apparent to those skilled in the art.
Biological Activity Bone calcium mobilization activities of 1α,25-(OH)2-24-homo-D_3 compounds.
Bone calcium mobilization activity was assayed by measuring the rise in serum calcium levels in response to the compound administered. Male, weanling rats (Holtzman Co., Madison, WI) were fed a lew-calcium, vitamin D deficient diet (Suda et al, J. Nutr. 1001049-1050, 1970) and water ad libitum for 3 weeks. The rats were then divided into three groups of 5-6 rats each and were given intrajugularly either 1,25-(OH)2D3 or the test compound dissolved in 0.05ml of 95% ethanol. Rats in the control group were given 0.05ml ethanol vehicle in the same manner. Eighteen hours after the dose, the rats were killed and their blood was collected and centrifuged to obtain serum. Serum calcium concentrations were determined with an atomic absorption spectrometer Model 403 (Perkin-Elmer Co., Nbrwalk, Conn.) in presence of 0.1% lanthanum chloride.
Results obtained are shown in the following Table:
Figure imgf000015_0001
b) from a) and d) from c) P<0.001
It can be concluded from the foregoing data that in the vitamin D responsive systems of vitamin D-deficient animals the compounds of this invention exhibited the same activity as 1α,25-hydroxyvitamin D3, the circulating hormonal form of the vitamin, although, in the case of the 22-dehydro derivative the dosage was significantly higher.
The compounds of this invention may be readily administered in sterile parenteral solutions by injection or intravenously or by alimentary canal in the form of oral dosages, or by suppository or even transcutaneously. Doses of from about 0.1 μg to about 2.5 μg per day are effective in obtaining the physiological calcium balance responses characteristic of vitamin D-like activity with maintenance dosage of from about 0.1 μg to about 0.5 μg being suitable. Dosage forms of the compounds can be prepared by combn ing them with a non-toxic pharmaceutically acceptable carrier as is well known in the art. Such carriers may be either solid or liquid such as, for example, corn starch, lactose, sucrose, peanut oil, olive oil, sesame oil and water. If a solid carrier is used the dosage forms of the compounds of the invention may be tablets, capsules, powders, troches or lozenges. If a liquid carrier is used, soft gelatin capsules, or syrup or liquid suspensions, emulsions or solutions may be the dosage form. The dosage forms may also contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, etc. They may also contain other therapeutically valuable substances.
It should be understood that although dosage ranges are given the particular dose to be administered to a host will depend upon the specific disease state being treated, the end results being sought in a particular case, the physical size of the host, as well as other factors known to those skilled in the art in the therapeutic use of such medicinal agents.

Claims

Claims
1. Compounds having the formula
Figure imgf000017_0001
where R1, R2 and R3 are each selected frcm the group consisting of hydrogen, an acyl group having from 1 to about 4 carbon atoms and benzoyl and R4 and R5 each represent hydrogen atoms or taken together form a carbon to carbon double bond.
2. A compound according to claim 1 wherein R1, R2 and R3 are hydrogen and R4 and R5 are hydrogen atoms.
3. The compound of claim 2 in crystalline form.
4. The compound of claim 2 together with a pharmaceutically acceptable excipient.
5. A compound according to claim 1 wherein R1, R2 and R3 are hydrogen and R4 and R5 together represent a carbon to carbon double bond.
6. The compound of claim 5 in crystalline form.
7. A compound according to claim 4 together with a pharmaceutically acceptable excipient.
8. A compound according to claim 4 wherein the Δ22 bond is in the E configuration.
9. A compound according to claim 4 v.herein the Δ22 bond is in the Z configuration.
10. Ccitpounds having the formula
Figure imgf000017_0002
where R is selected from the group consisting of hydrogen, an acyl group having from 1 to about 4 carbon atoms, benzoyl and methoxymethyl.
11. Compounds having the formula
Figure imgf000018_0001
where R is selected frcm the group consisting of an acyl group having from about 1 to about 4 carbon atoms and benzoyl and R4 and R5 represent hydrogen atoms or taken together form a carbon to carbon double bond.
PCT/US1985/001571 1984-10-04 1985-08-19 Vitamin d derivatives and methods for preparing same WO1986002078A1 (en)

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NL8520265A NL8520265A (en) 1984-10-04 1985-08-19 DERIVATIVES OF VITAMIN D AND METHODS FOR PREPARING THE SAME
DK260086A DK154290C (en) 1984-10-04 1986-06-03 VITAMIN-D DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE
DK111188A DK159389C (en) 1984-10-04 1988-03-02 CHOLESTAGE STAGE OR TRIEND DERIVATIVES THAT MAY BE USED AS INTERMEDIATES FOR USE IN THE PREPARATION OF 24-HOMOVITAMIN-D3 DERIVATIVES
DK177489A DK158989C (en) 1984-10-04 1989-04-13 CHOLESTA STAGE DERIVATIVES THAT MAY BE USED AS INTERMEDIATE FOR USE IN THE PREPARATION OF HOMOVITAMIN-D3 DERIVATIVES
DK015290A DK158990C (en) 1984-10-04 1990-01-19 CHOLESTA STAGE DERIVATIVES THAT MAY BE USED AS INTERMEDIATE FOR USE IN THE PREPARATION OF HOMOVITAMIN-D3 DERIVATIVES
DK015390A DK158991C (en) 1984-10-04 1990-01-19 CHOLE STAGE DERIVATIVES THAT MAY BE USED AS INTERMEDIATES FOR USE IN THE PREPARATION OF HOMOVITAMIN-D3 DERIVATIVES

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989010352A1 (en) * 1988-04-29 1989-11-02 Wisconsin Alumni Research Foundation SIDE CHAIN UNSATURATED 1alpha-HYDROXYVITAMIN D HOMOLOGS
WO1989010353A1 (en) * 1988-04-29 1989-11-02 Wisconsin Alumni Research Foundation Compounds effective in inducing cell differentiation
WO1989010351A1 (en) * 1988-04-21 1989-11-02 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemis Novel vitamin d analogues
DE4011061A1 (en) * 1989-04-05 1990-10-11 Chugai Pharmaceutical Co Ltd USE OF VITAMIN D DERIVATIVES FOR TREATING HYPERPARATHYREOIDISM
EP0421561A2 (en) * 1989-10-02 1991-04-10 Schering Aktiengesellschaft 24-D-homo-vitamin D-derivatives, a process for their production, pharmaceutical compositions containing them and their use as medicines
WO1991012239A1 (en) * 1990-02-14 1991-08-22 Wisconsin Alumni Research Foundation HOMOLOGATED VITAMIN D2 COMPOUNDS AND THE CORRESPONDING 1α-HYDROXYLATED DERIVATIVES
US5414098A (en) * 1990-02-14 1995-05-09 Wisconsin Alumni Research Foundation Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives
WO1998014195A1 (en) * 1996-10-04 1998-04-09 Wisconsin Alumni Research Foundation Use of vitamin d analogs for the treatment of arthritic disease
WO2006051106A1 (en) 2004-11-12 2006-05-18 Bioxell Spa Combined use of vitamin d derivatives and anti-proliferative agents for treating bladder cancer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4225596A (en) * 1978-10-13 1980-09-30 Wisconsin Alumni Research Foundation Method for treating calcium imbalance and improving calcium absorption in mammals
US4448721A (en) * 1982-09-20 1984-05-15 Wisconsin Alumni Research Foundation Hydroxyvitamin D2 compounds and process for preparing same

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3833622A (en) * 1969-03-17 1974-09-03 Upjohn Co Crystalline 25-hydroxycholecalciferol hydrate and structurally related compounds
US3880894A (en) * 1974-05-24 1975-04-29 Wisconsin Alumni Res Found 1,25-Dihydroxyergocalciferol
AU527805B2 (en) * 1978-07-27 1983-03-24 Research Institute For Medicine And Chemistry Inc. 1alpha, 1beta dihydroxy steroid-5-enes
US4508651A (en) * 1983-03-21 1985-04-02 Hoffmann-La Roche Inc. Synthesis of 1α,25-dihydroxyergocalciferol
CH665834A5 (en) * 1983-05-09 1988-06-15 Wisconsin Alumni Res Found METHOD FOR PRODUCING 1ALPHA, 25-DIHYDROXYLATED VITAMIN D (2) AND RELATED COMPOUNDS.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4225596A (en) * 1978-10-13 1980-09-30 Wisconsin Alumni Research Foundation Method for treating calcium imbalance and improving calcium absorption in mammals
US4448721A (en) * 1982-09-20 1984-05-15 Wisconsin Alumni Research Foundation Hydroxyvitamin D2 compounds and process for preparing same

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989010351A1 (en) * 1988-04-21 1989-11-02 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemis Novel vitamin d analogues
WO1989010353A1 (en) * 1988-04-29 1989-11-02 Wisconsin Alumni Research Foundation Compounds effective in inducing cell differentiation
FR2630740A1 (en) * 1988-04-29 1989-11-03 Wisconsin Alumni Res Found COMPOUNDS DERIVED FROM VITAMIN D3, PROCESS FOR THEIR PREPARATION AND THEIR USE
FR2630739A1 (en) * 1988-04-29 1989-11-03 Wisconsin Alumni Res Found VITAMIN D UNSATURATED SIDE CHAIN APPROVALS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME, AND THEIR USE
WO1989010352A1 (en) * 1988-04-29 1989-11-02 Wisconsin Alumni Research Foundation SIDE CHAIN UNSATURATED 1alpha-HYDROXYVITAMIN D HOMOLOGS
DE4011061A1 (en) * 1989-04-05 1990-10-11 Chugai Pharmaceutical Co Ltd USE OF VITAMIN D DERIVATIVES FOR TREATING HYPERPARATHYREOIDISM
DE4011061C2 (en) * 1989-04-05 1999-08-05 Chugai Pharmaceutical Co Ltd Use of vitamin D derivatives to treat hyperparathyroidism
US5665716A (en) * 1989-10-02 1997-09-09 Schering Aktiengesellschaft 24-homo vitamin D derivatives, process for their production and pharmaceutical preparations obtained therefrom
EP0421561A2 (en) * 1989-10-02 1991-04-10 Schering Aktiengesellschaft 24-D-homo-vitamin D-derivatives, a process for their production, pharmaceutical compositions containing them and their use as medicines
EP0421561A3 (en) * 1989-10-02 1991-06-12 Schering Ag 24-d-homo-vitamin d-derivatives, a process for their production, pharmaceutical compositions containing them and their use as medicines
CN1053103C (en) * 1989-10-02 2000-06-07 舍林股份公司 Pharmaceutical use of 24-homo-vitamin-D-derivative
WO1991012239A1 (en) * 1990-02-14 1991-08-22 Wisconsin Alumni Research Foundation HOMOLOGATED VITAMIN D2 COMPOUNDS AND THE CORRESPONDING 1α-HYDROXYLATED DERIVATIVES
US5750746A (en) * 1990-02-14 1998-05-12 Wisconsin Alumni Research Foundation Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives
US5532391A (en) * 1990-02-14 1996-07-02 Wisconsin Alumni Research Foundation Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives
US5414098A (en) * 1990-02-14 1995-05-09 Wisconsin Alumni Research Foundation Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives
WO1998014195A1 (en) * 1996-10-04 1998-04-09 Wisconsin Alumni Research Foundation Use of vitamin d analogs for the treatment of arthritic disease
US5891865A (en) * 1996-10-04 1999-04-06 Wisconsin Alumni Research Foundation Treatment of arthritic disease induced by infectious agents
WO2006051106A1 (en) 2004-11-12 2006-05-18 Bioxell Spa Combined use of vitamin d derivatives and anti-proliferative agents for treating bladder cancer

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