IE58104B1 - Vitamin d derivatives, pharmaceutical compositions containing them and percursors thereof - Google Patents

Vitamin d derivatives, pharmaceutical compositions containing them and percursors thereof

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Publication number
IE58104B1
IE58104B1 IE244385A IE244385A IE58104B1 IE 58104 B1 IE58104 B1 IE 58104B1 IE 244385 A IE244385 A IE 244385A IE 244385 A IE244385 A IE 244385A IE 58104 B1 IE58104 B1 IE 58104B1
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compound according
carbon
hydrogen
compound
vitamin
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IE852443L (en
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Wisconsin Alumni Res Found
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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

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  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nutrition Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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 1 alpha ,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

This invention relates to novel 24-homovitamin D derivatives.
Vitamin D is known to regulate calcium and phosphorus 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 hydroxy lated derivatives. Thus vitamin is hydroxy la ted in vivo to 25-hydroxyvitamin in the liver which in turn is converted into 1o<,25-dihydroxyvitamin in tne kidneys. It is tne latter compound which is now recognized as being the circulating hormonal form of vitamin D.
Because of their biological activity in promoting calcium and phosphorus transport in tne 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.
New Derivatives of vitamin have now been found which express excellent vitamin D-like activity and which, therefore, could readily serve as a substitute for vitamin in known applications, such as tne treatment of various disease states manifesting calcium and phospnorus imbalance such as hypoparathyroidism, osteodystrophy, osteomalacia and osteoporosis.
These derivatives are 24-hcxnovitamins, particularly k<,z5dihydroxy-22E(orZ)-denydro-24-homovitamin D~ and 25-dinydroxy-24homovitamin D^.
The compounds of the present invention can be represented by the formula: where R^, and are each independently hydrogen, acyl having frcm 1 to 4 carbon atcms or benzoyl and and R^ each represent hydrogen atcms or taken together form a carbon to carbon bond.
The compounds of this invention can be prepared in accordance with the following schematic and detailed description where like numbers identify like compounds.
In accordance with the process of this invention: Bisnorcholenic acid acetate (a) was reduced with lithium aluminum hydride and subsequently oxidized with dichlorodicyanobenzoguinone 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 la, 2a-epoxide (1) in 41% yield. Reduction of (1) with lithium and anmonium chloride in liguid anmonia-tetrahydrofuran at -78°, and subsequent treatment with chlorcmethyl methyl ether provided the dimethyaxymethyl ether (MCMO) (2) in 38% yield. Removal of the THP group, followed by Swem oxidation gave the aldehyde (4) in 81% yield. This was reacted with vinylmagnesium bromide 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 methyImagnesium bromide to provide the alcohol (T) in 93% yield. Removal of MOM group, followed by acylation, e.g. acetylation gave (22E)-l0(,3B-diacetoxy25-hydroxy-24-hcmo-cholesta-5,22-diene (9) in 73% yield.
Allylic bromination of (9) with N-bromosuccinimide, followed by treatment with tetra-n-butylairmoniurn bromide and then with tetra-n-butylanrnonium fluoride gave the 5,7,22triene (10) as a main product in 24% yield. Ihe 5,7-diene (10) was irradiated with a medium pressure mercury lamp in benzene-ethanol for 5 min, subsequently refluxed for 1 hr, and then hydrolyzed to afford (22E)-la,25-dihydroxy-22-dehydro-24homovitamin (11) in 22% yield by analogous methods well known in the art other acylates or benzoates can be prepared which would be equally useful in the succeeding process steps.
The 5,22-diene (9) was selectively hydrogenated, e.g. using tetra n-butylanmonium fluoride, to provide the 5-ene (12) in 92% yield. This conpound was converted to la,25-dihydrcxy-24-homovitainin D3 d4) via the 5,7-diene (13) as described above in 12% overall yield.
In the following detailed description melting points were determined with a hot-stage microscope and were uncorrected. ^H-NMR spectra were taken with a Hitachi* R-24A (60 MHz) in CDC13 with Me^Si as an internal standard, unless otherwise noted. Mass spectra were obtained with a Shimadzu QP-IOOO mass spectrometer at 70 eV.
UV spectra were obtained in ethanol solution with a Shimadzu UV-200 double beam spectrophotometer. Column Chromatography was effected using silica gel (E. Merck*, Kieselgel 60, 70-230 nesh). Preparative thin layer chromatography was carried out on precoated plates of silica gel (E. Merck , Kieselgel 60 U II F^r,, 0.25 nm thickness). The usual work-up refers to 254 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; THF 15 tetrahydrofuran; ether - diethyl ether, MeOH - methanol, MOM methoxymethyl. Tenperatures are in ° centigrade. 22-Hydroxy-23,24-dinorchola-l,4,6-triene-3-one (b) Ito a solution of 3p-acetoxydinorcholenic acid (a) (7.0 g, 18.04 nmole) in THF (20 mL) 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). Ihis in dioxane (140 mL) was treated with dichlorodicyanobenzoquinone (11.7 g, 51.54 nmole) under reflux for 14 h. After cooling to room temperature the reaction mixture 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 (b) (2.8 g, 47%) mp 156-157° (ether) UVXEt0H nm (ε): 299 (13000), 252 (9200), 224 (12000), H-NMR (CDCl^O: 0.80 (3H, s, 18-H3), 1.04 (3H, d, J=6 Hz, 21-H.p , 1.21 (3H, ε, 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 (IH, d, J=1O Hz, 1-H), MS m/z: 326 (M+), 311, 308, 293, 267, 112. la, 2a-Epoxy-22-tetrahydropyranyloxy-23,24-dinorchola-4,6-dien. * Registered Trade Mark 3- one (1) The alcohol (b) (2.7 g, 8.28 nmole) in dichloromethane (50 mL) was treated with dihydropyrane (1.5 mL, 16.42 nmole) and p-toluenesulfonic acid (50 mg) at rocm tenperature for 1 h. The usual work-up (ethyl acetate for extraction) gave a crude product. To a solution of this product in MeOH (70 mL), 30% Η2Ο2 (4.8 iriL) and 10% NaOH/MeOH (0.74 mL) were added and this mixture was stirred at rocm tenperature 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) UVA^^nm (e): η TTIclX 290 (22000), ΤΊ—NMR (CDC13)6: 0.80 (3H, s, 18-H.j), 1.07 (3H, d, J=6 Hz, 21-H3), 1.18 (3H, s, 19-H3), 3.38 (IH, dd, J=4 and 1.5 Hz, 1-H), 3.55 (IH, d, J=4 Hz, 2-H), 3.30-4.10 (4H, m, 22-H2 and THP), 4.50 (IH, m, THP), 5.58 (IH, d, J=1.5 Hz, 4- H) , 6.02 (2H, s, 6-H and 7-H) , MS m/z: 342 (M+ - DHP) , 324 (M+ - THPOH), 309, 283, 85. la, 3 β-Diirethoxyme thoxy-23,24-dinorchol-5-en-22-tetrahydropyranyl ether (2) Lithium (5.00 g) was added in small portion to liquid arrrronia (200 ml) at -78° under argon atmosphere during 30 min. After stirring for 1 hr at -78°, la,2a-epoxy-22-tetrapyranyloxy-23,24-dinorchola-4,6-diene-3-one (1) (2.00 g, 4.69 m mol) in dry THF (150 ml) was added dropwise at -78° during 30 min, and this mixture was stirred for 1 hr at -78°. To this reaction mixture, anhydrous NH^Cl (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 arrmonia was removed by' bubbling argon. The usual work-up (ether was used as a solvent) gave a crude product. This was treated with chloro-methyl methyl ether (2.0 ml, 26.34 m mol) and Ν,Ν-diethy Icy clohexy lamine (4.6 ml, 24.93 m mol) 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) (922 mg, 38%) as an oil. ’’h-NMR 6 0.70 (3H, s, 18-H3) , 1.02 (3H, s, 19-H.j) , 1.04 (3H, d, J=6 Hz, 21-H3), 3.34 (3H, s, -O-CH3), 3.37(3H, s, -O-CH3),4.63 (2H, ABq, J=7 Hz, ΔΑΒ=11 Hz, la-O-CH2-O-), 4.64 (2H, s, 3β-Ο-<2Ι2-0-) , and 5.50 (1H, m, 6-H). la, 35-Diirethoxyinethoxy-23,24-dinorchol-5-en-22-ol (3) The THP ether (2) (922 mg, 1.77 mmol) in 1HF (8 ml) and IfeCH (8 ml) was treated with 2M HCl (1 ml) 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 (40 g). Elution with hexane-ethyl acetate (2 ; 1) gave the alcohol (3) (678 mg, 88%) as an amorphous solid. ^Ή-NMR δ 0.70 (3H, s, 18-H3), l.O2(3H,s,19-H3), 1.04 (3H, d, J=6 Hz, 21-H3), 3.34 (3H, s, -O-CH3), 3.38 (3H, s, -O-CH-j), 4.65 (2H, ABq, J=7 Hz, ΔΑΒ = 11 Hz, la-O-CH2-O-) , 4.66 (2H,s,38-O-CH2-O-), 5.53 (lH,m,6-H) . la, 36-Dimethoxyrnethoxy-23,24-dinorchol-5-en-22-al (4) To a solution of oxalyl chloride (0.27 ml, 3.09 mmol) in dichloromethane (8 ml) dimethyl sulphoxide (0.44 ml, 6.21 nmol) was added at -78°C under argon. The mixture was stirred at -78°C for 10 min. To the solution the alcohol (3) (660 mg, 1.51 nmol) in dichlorcmethane (5 ml) was added at -78°C.
After stirring for 15 min, triethylamine (1.89 ml, 13.6 nmol) 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) (607 mg, 92%) as a crystal, np 71-72°C (hexane), ^-0 6 0.74 (3H, s, 18-H.p , 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 (1Ή, m, 1β-Η) , 4.65 (2H, ABq, J=7 Hz, ΔΑΒ = 11 Hz, la-C-CH—O-), 4.66 (2H, s, 3β-Ο-θΗ-Ο-), 5.52 (IH, m, 6-H), and 9.61 (IH, d, J=3 Hz, -CHO), Anal. Calcd for C2gH42°5: C' 71:85; H, 9.74. Found: C, 71.71; H, 9.68. la, 3B-Dimethoxyinethoxychola-5,23-dien-22-ol (5) To magnesium (70 mg, 2.92 mmol) in THF (3 ml) 50% solution of vinyl bromide in THF (0.42 ml, 2.98 rrmol) was added. The mixture was stirred at room temperature under argon for 30 min. To the resulting Grignard reagent the aldehyde (4) (595 mg, 1.37 mmol) in THF (6 ml) was added at rocm 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 alcohol (5) (595 mg, 94%) as an amorphous solid. ^H-NMR δ: 0.70 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 3.35 (3H, s, -0-0^), 3.38 (3H, s, -O-CH3), 3.69 (IH, m, 1β-Η), 4.20 (IH, m, 22-H), 4.64 (2H, ABq, J=7 Hz, ΔΑΒ = 11 Hz, la-O-CH2-O-) , 4.65 (2H, s, 3β-Ο-<Ή2-Ο-), 5.52 (IH, m, 6-H), 4.90-6.0 (3H, m, 23-H and 24-H2). (22E) -Ια, 3β-Ρίιη£ί±ΐ!θχνιη6-ΰιοχγ-27-ηοΓοΗο1θ5ΐ^-5,22-dien-26oic acid ethyl ester (6) A solution of the allylic alcohol {5) (590 mg, 1.28 rrmol), triethyl orthoacetate (1.0 ml, 5.46 mmol) , propionic 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) (630 mg, 93%) as an oil. ^I-NMR 5: 0.68 (3H, s, 18-H3) , 0.97 (3H, d, J=6 Hz, 21-H3), 1.03 (3H, s, 19-H3), 1.24 (3H, t, J=7 Hz, -CO2CH2CH3) , 3.35 (3H, s, -O-€H3), 3.39 (3H, s, -O-CH^) , 3.70 (IH, m, 1β-Η), 4.11 (2H, q, J=7 Hz, -ΟγΤ^σ^) , 4.64 (2H, ABq, J=7 Hz, MB = 11 Hz, lct-O-O^-O-) , 4.65 (2H, s, 3β-0-012-0-) , 5.29 (2H, m, 22-H and 23-H), 5.52 (LH, m, 6-H).
If desired the 22E stereo isomer, carpound (6) , can be readily converted to the 22Z stereo iscmer 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 iO isomerization which, after KPLC purification, (Zorbax-Sil column, 4.6 x 25 cm, 6% 2-propanol/hexane) yielded the 22Z stereo isomer. (22E) -la, 3p-Dimethoxymethoxy-24-homo-cholesta-5,22-diene-25-ol (7) To a solution of the ester (6) (605 mg, 1.14 mmol) in THF (6 ml) IM solution of rrethylmagnesium bromide in THF (4.5 ml, 4.5 nmol) was added at rocm temperature. The mixture was stirred at rocm 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. ^Ή-NMR 6: 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-ay , 3.38 (3H, s, -O-CH3), 3.70 (IH, m, Ιβ-H) , 4.64 (2H, ABq, J=7 Hz, ΔΑΒ = 11 Hz, la-Q-CH2-O-) , 4.65 (2H, ε, ββ-ΟΟ^-Ο-), 5.29 (2H, m, 22-H and 23-H), and 5.50 (IH, m, 6-H). (22E) -24-Homocholesta-5,22-diene-lct, 3S, 25-triol (8) A solution of the dimethoxyrnethyl ether (T) (540 mg, 1.04 mmol) in THF (15 ml) was treated with 6M HCl (3 ml) 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_) (428 mg, 95%) as a crystal, mp 164-166°C (hexane-ethyl acetate), ^H-NMR 6: 0.68 (3H, s, 18-H3), 0.95 (3H, s, J=6 Hz, 21-H3), 1.00 (3H, s, 19-H3), 1.20 (6H, s, 26-H3 and 27-H3), 3.80 (IH, m, 1β-Η), 3.92 (IH, m, 3a-H), 5.30 (2H, m, 22-H and 23-H), and 5.53 (IH, m, 6-H). (22E) -la, 36-Diacetoxy-25-hydroxy-24-homochoIesta-5,22-diene (9) A solution of the triol (8) (395 mg, 0.919 mmol) in pyridine (2 ml) was treated with acetic anhydride (1 ml) at rocxn temperature for 16 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 (2 : 1) gave the diacetate (9) (361 mg, 77%) as an oil. ^Ή-NMR δ: 0.67 (3H, s, 18-Hg), 0.97 (3H, d, J=6 Hz, 21-Hg), 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 (IH, m, 3a-H), 5.05 (IH, m, Ιβ-H), 5.31 (2H, m, 22-H and 23-H), and 5.52 (IH, m, 6-H). (22E) -lot, 3p-Diacetoxy-25-hydroxy-24-hcmocholesta-5,7,22-triene (10) A solution of the 5-ene (9) (51 mg, 0.0992 mmol) and N-bromo-succinimide (21 mg, 0.118 mmol) in carbontetrachloride (3 ml) was refluxed under argon for 20 min. After the mixture had been cooled to O°C, the resulting precipitate was filtered off. The filtrate was concentrated below 40°C to leave the residue. This in 1HF (5 ml) vras 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 TKF (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) 12.5 mg, 24%) , 293, 282, and 271. la, 25-Dihydroxy-22E-dehydro-24-homovitamin (11) A solution of the 5,7-diene (10) (7.3 mg, 0.0143 irmol) in benzene (90 ml) and ethanol (40 ml) was irradiated with with a medium pressure mercury lamp through a Vycol filter at O°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 chromatography (hexane-ethyl acetate, 4 : 1, developed five times). The band of Rf value 0.38 was scraped off and eluted with ethyl acetate. Removal of the solvent gave the vitamin D3 diacetate (1.8 mg, 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) (2.1 mg, 29%).
The vitamin diacetate (1.8 mg, 2.15 pmol) in THF (4 ml) was treated with 5% KOH/MeQH (1 ml) at rocm temperature for 20 min. The usual work-up (ethyl acetate) gave a crude product, which was submitted to preparative thin layer chromatography (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 vitamin analogue (11) (1.4 mg, 90%). The purity of the product (11) was determined as 100% by high performance liquid chromatography (a Shimadzu LC-3A; column, Zorbax ZIL normal phase, 4.6 nm i.d. x 15 cm; solvent, MeQH-CI^C^, 1 : 49; flew rate, 3 ml/min; retention time, 11.5 min). The vitamin D_ EtOH analogue (11) had the following spectral data; ; 265 nm, : 228 nm, MS m/z: 428 (M+), 410, 392 (base peak), 374, 287, 269, 251, 152, 134, 123, 59, ^-NCdR (360 MHz) 6: 0.55 (3H, s, 18-H3), 1.02 (3H, d, J=6.6 Hz, 21-H3), 1.22 (6H, s, 26-H3 and 27-H3), 2.32 (IH, dd, J=13.2 and 6.7 Hz), 2.60 (IH, dd, J=13.O and 3.0 Hz), 2.83 (IH, dd, J=12.O and 3.0 Hz), 4.23 (IH, m, W1/2) = 18.4 Hz, 3α-Η), 4.43 (IH, m, W1/2 = 16.9 Hz, 1β-Η), 5.00 (IH, bs, W1/2 = 3.2 Hz, 19-H), 5.30 (IH, dd, J=15.O and 7.1 Hz, 22-H or 23-H), 5.33 (IH, bs, W1/2 = 3.2 Hz, 19-H), 5.37 (IH, dd, J=15.0 and 5.8 Hz, 22-H or 23-H), 6.01 (1Ή, d, J=11.0 Hz, 7-H), 6.32 (IH, d, J=11.0 Hz, 6-H). la,3p-Diacetoxy-24-homocholest-5-en-25-ol (12) A mixture of the 5,22-diene (9) (40 mg, 0.0778 nmol) and 10% Pd-C (4 mg) in ethyl acetate (2 ml) was stirred at room tenperature 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. ^-NMR 6: 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-Η), 5.07 (1H, m, 1β-Η), 5.53 (IH, m, 6-H). Ια , 3g-Diacetoxy-2 4-homocholesta-5,7-dien-25-ol (13) The 5-ene (12) (19mg, 0.037 mmol) was converted, as described for (10), to the 5,7-diene (13) (5.8 mg, 31%).
UVXEt0H : 293, 282, 271 nm. max la,25-Dihydroxy-24-homovitamin (14) The 5,7-diene (13) (5.8 mg, 0.0113 mmol) was converted, as described for (11) , to the vitamin analogue (14) (890 pg, 19%). The retention time of (14) under the EtOH above—described HPLC condition was 11.0 min. UVA : 265 max nm, : 228 nm. MS m/z 430 (M+) , 412, 394 (base peak, 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.
Also if desired the compounds may be acylated according to the standard methods to yield the corresponding partially or completely hydroxy-protected products where each of , R2 and is hydrogen or acyl. For example, treatment of the trihydroxy product with acetic anhydride at room temperature in pyridine yields the 1,3-diacetyl compound whereas at elevated temperatures (75°-100°C) the 1,3,25triacetyl compound is obtained. By analogous methods fully or partially hydroxy-protected derivatives, i.e. derivatives with other acyl groups such as benzoyl, can be obtained.
A partially acylated derivative, e.g. 1,3-diacyl may also be further acylated, e.g. at C-25, by a different acyl group to obtain derivatives carrying mixed hydroxy-protecting functions. Selected removal of protecting groups can also readily be accomplished by selective hydrolysis (e.g. 10% KOH/MeOH at room temperature) of a 1,3, 25-tri-0-acyl derivatives, to yield 1,3-dihydroxy-25-0-acyl compound. Different protecting groups can then be introduced at the free hydroxy-positions and it is thus obvious that a combination of selective protection/deprotection steps will yield derivatives with any desired combination of hydroxyprotecting groups in the product.
Bone calcium mobilization activities of la ,25-(OH)2-24-homo-D2 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 low-calcium, vitamin D deficient diet (Suda et al, J. Nutr. 1OO 1049-1050, 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 0.05 ml of 95% ethanol. Rats in the control group were given 0.05 ml 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 ;5 403 (Perkin-Elmer Co., Norwalk, Conn.) in presence of 0.1% lanthanum chloride.
Results obtained are shown in the following Table: Table 1 Increase of serum calcium concentration in response to a ccnpound administered Conpound Administered Amount Administered (pmol/rat) Serum calcium Concentration (mg/100 ml) Exp. I Ethanol -.la,25-(OH)9D 650 la,25-(OH)2-24- 650 hamo-D^ Exp. II Ethanol -la,25-(OH)?D 325 la,25-(OH)2~22E- 650 dehydro- 24-homo3.6 J 0.3 4.9 - 0.2 4.4 + 0.2 a) * * b) b) 4.2 * 0.1 5.0* 0.5 5.0- 0.5 c) d) d) p< 0.001 * Standard deviation fran the means significantly different b) from a) and d) fran c) It can be concluded frcm the foregoing data that in the vitamin D responsive systems of vitamin D-deficient animals the ccmpounds of this invention exhibited the same activity as la, 25-hydroxyvitamin D^, the circulating hormonal form of the vitamin, although, in the case of the 22-dehydro derivative the dosage was significantly higher.
The carpounds 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, for example. Doses of fran, say, 0.1 pg to about 2.5 pg per day are generally effective in obtaining the physiological calcium balance responses characteristic of Vitamin D-like activity with maintenance dosage of frcm, say, 0.1 pg to about 0.5 pg being suitable.
Dosage forms of the compounds can be prepared by combining them with a non-toxic pharmaceutically acceptable carrier as is well known in the art. Such carriers may be either solid or liquid such 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 e.g. tablets, capsules, powders, troches or lozenges. If a liquid carrier is used, soft gelatin capsules or syrup or liquid suspensions, enulsions or solutions are typicallly the dosage form. The dosage forms may also contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents or solution promoters. 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. ί 7

Claims (7)

1.CLAIMS A compound aving the formula where R^ , R^ and R^ are each independently hydrogen, acyl 5 having from 1 to 4 carbon atoms or benzoyl and R^ and R_ each represent hyaroaen or taken together form a o carbon to carbon bond.
2. A compound according to claim 1 where in R l' R 2 and R^ are hydrogen and R^ and R_ 0 are hyd: rogen.
3. A compound according to claim 1 wherein V R 2 and R^ are hydrogen and R^ and R_ 0 togethe: r repress nt a carbon to carbon bond.
4. The compound of claim . 2 or 3 in crystall ine form . 5. A compound according to claim 3 where in the Δ22 bond is in the Ξ configurat :ior 1.
5. A compound according to claim 3 wherein the Δ22 bond is in the Z configuration. 7. A pharmaceutical composition which comprises at 20 least one compound as claimed in any one of the preceding claims and a pharmaceutically acceptable excipient . 1 8 wherein each R is independently hydrogen, acyl having from 1 to 4 carbon atoms, benzoyl or methoxymethyl. 5 - 9. A compound according to claim 8 wherein each R is methoxymethyl. io: A compound according to claim 8 wherein each R is hydrogen. 1 1 . A compound according to claim 8 wherein each 10 R is acetyl. i 2 . A compound having the formula wherein R^, R 2 and R 3 are each independently hydrogen, acyl having from 1 to 4 carbon atoms or benzoyl and R^ and R^ represent 15 hydrogen atoms or taken together form a carbon to carbon bond . i 2 13. A compound according to claim 12 wherein R^ and R 2 are each independently acyl having from 1 to 4 carbon atoms or benzoyl. 14. A compound according to claim 12 wherein and R 2 are both acetyl and R-j is hydrogen. A compound according to any one of claims 12 to 14 wherein R^ and R^ together form a carbon to carbon bond. 1
6. A compound according to any one of claims 12 to 14 wherein R^ and R^ represent hydrogen atoms. 1
7. Process for converting a OH side chain of a steroid nucleus to a OH 15 side chain which comprises reacting the starting material with triethyl orthoacetate to provide the ester side chain co 2 st and reacting the ester with a methyl magnesium halide. 1y. Process according to claim 17 wherein the 2. Q halide is methylmagnesium bromide. .19. Process according to claim 17 cr 18 wherein the reaction with triethyl orthoacetate is carried out in the presence of propionic acid, as catalyst. 20. Process according to claim 17' substantially as hereinbefore described.
IE244385A 1984-10-04 1985-10-04 Vitamin d derivatives, pharmaceutical compositions containing them and percursors thereof IE58104B1 (en)

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US5030772A (en) * 1990-02-14 1991-07-09 Deluca Hector F Process for preparing vitamin D2 compounds and the corresponding 1 α-hydroxylated derivatives
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