GB2082588A - Anti-vitamin D compound - Google Patents
Anti-vitamin D compound Download PDFInfo
- Publication number
- GB2082588A GB2082588A GB8132031A GB8132031A GB2082588A GB 2082588 A GB2082588 A GB 2082588A GB 8132031 A GB8132031 A GB 8132031A GB 8132031 A GB8132031 A GB 8132031A GB 2082588 A GB2082588 A GB 2082588A
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- United Kingdom
- Prior art keywords
- vitamin
- methyl
- compound
- diene
- methyl vitamin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
- C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a novel anti-vitamin D derivative, 25-methyl vitamin D3 of formula <IMAGE> which is prepared by irradiating 3 beta - acetoxy-25-methylcholesta-5,7-diene and thermally isomerizing and saponifying the resulting previtamin.
Description
SPECIFICATION
Anti-vitamin D compound
This invention relates to compounds having anti-vitamin D activity and, in particular, to analogues of vitamin
D, which, when co-administered to an animal with vitamin D will inhibit or abolish the normal response of that animal to vitamin D.
The application of various of the vitamins to correct certain calcium metabolism disfunctions, e.g. rickets has long been known. More recently, various derivatives of vitamin D, such as 25-hydroxycholecalciferol (United States Letters No.3,565,924), la,-hydroxycholecalciferol (United States Letters No.3,741,996) and 1 ,25-dihydroxycholecalciferol (United States Letters No. 3,697,559) permit the treatment of other metabolic disorders involving the calcium and phosphorous balance (imbalance) in animals (see, for exampie, United
States Patent Nos. 3,646,204,3,639,596 and 3,879,548).
Other derivatives of vitamin D have now been found which are characterised by anti-vitamin D activity. In other words, such compounds, when co-administered with vitamin D tend to abolish the normal response of an animal to vitamin D, that is, they display an inhibitory action against the intestinal calcium transport and bone calcium mobilisation effects of vitamin D. Such activity suggests their application for correcting certain calcium disorders in animals such as hypercalcemia, hypervitaminosis D, hypersensitivity to vitamin D and metastatic calcification.
In our Application No. 11797/78 (Serial No 1 574685) we have described a class of compounds having the general formula
where X is
wherein each R1 is independently lower alkyl, R2 and R3 are each independently hydrogen, lower acyl, lower alkyl, or acryl and R is hydrogen, acyl of 1 to 6 carbon atoms or benzoyl. In particular the compound in which R is hydrogen,
where R2 and R3 are both methyl, referred to as 25-aza-vitamin D3, is described as having a good anti-vitamin
D effect and is, therefore, appropriate for use in reducing or reversing the biological effect of the D vitamins and in reducing hypercalcemia.
We have now found, according to the present invention, another specific compound of value for this utility. This compound is of the general formula in which R is hydrogen and
wherein R1 is methyl, referred to as 25-methyl vitamin D3.
25-Methyl vitamin D3 can be prepared according to the following reaction scheme:
Preparation of the 25-methyl analogue 14 can therefore be accomplished via a route similar to that used for the synthesis of 25-aza-vitamin D3. Thus the bromide 2 can be prepared as described in the above identified application. Thus the starting material 1 can be prepared from stigmasterol according to the procedure of Partrick etal (Helv. Chim. Acta 57,764(1974)) and the bromide obtained therefrom by reaction with powdered lithium bromide in acetonitrile. Reaction of bromide 2 in the THF with the lithium salt of 3,3-dimethylbutyne (generated with n-butyl lithium) gives the acetylenic intermediate 10.Hydrogenation of
10 (H2,10% Pd/C) affords 11 which by solvolysis in hot glacial acetic acid is converted to 25
methylcholesterol 3P-acetate (compound 12). This intermediate acid is allylically brominated and
dehydrobrominated to 5,7-diene 13. Irradiation of 13(3ss-acetoxy-25-methyl-cholesterol-5,7-diene) followed
by thermal isomerisation of the isolated previtamin derivative and saponification (KOH/MeOH) leads to
25-methyl vitamin D3 (14).
6ss-Methoxy-25-methyl-3a,5-cyclo-5a-cholest-23-yne (10).
25 ml of a 1.5 M solution of n-butyl lithium in hexane is added to a solution of 3 g of 3,3-dimethyl-1 -butyne in 120 ml of dioxane at 5". The mixture is stirred for 4 hours at room temperature, then 6 g (0.015 mol) of
bromide 2 is added and the mixture is refluxed for 3 days. Workup gives an oil which is purified on a column
of silica gel (500 g). This gives 5.5 g (90%) of alkyne 10 as an oil, sufficiently pure for subsequent steps.
6ss-Methoxy-25-methyl-3a,5-cyclo-5a-cholestane 01 1).
A mixture of 5.1 g (0.13 mol) of 10,75 ml dioxane, 1.0 g of sodium bicarbonate and 0.1 g of 10% Pd/C is
stirred under 1 atm of H2 until 2 equivalents of gas are consumed. The solids are then removed by filtration
and the filtrate is concentrated in vacuo to yield an oil which after purification on a column of silica gel (400 g) yields the 25-methyl derivative 11(4.75 g, 90%).
Solvolysis of compound 12: Formation of 25-methylcholesterol 3ss-acetate (12).
3,5-cyclosteroid 12 (2 mmole), dissolved in 50 ml glacial acetic acid, is heated to 70 for 18 hours. After
cooling, the mixture is neutralised with 10% aqueous NaOH and extracted 3 times with ethyl acetate (75 ml
each). The organic extracts are combined and washed with 10% aqueous NaOH (3 x 50 ml), then with
saturated salt solution and water. Evaporation of the organic solvent then gives compound 12 as an
amorphous solid in 85-90% yield, in sufficient purity for subsequent reaction steps.
3ss-Acetoxy-25-methylcholesta-5,7-diene (13).
Cholesterol derivative 12 (1 mmole) in 40 ml of CC14 is treated with 600 mg NaHCO3 and 170 mg of
1,3-dibromo-5,5-dimethyl hydantoin, and the mixture is refluxed under N2 for 3 hours. After cooling to 0 C the solid.hydantoin is removed by filtration. The filtrate is evaporated, the residue is redissolved in 5 ml
xylene at 140"C. After 1.5 hours under N2 at this temperature the mixture is cooled to room temperature,
diluted with benzene, and washed with 5% HCl, 4% NaHCO3 and saturated NaCI solution. After drying (using
Na2SO4) the solvent is evaporated and the residue is chromatographed on Ag NO3 - impregnated thin layer
plates developed with ethyl acetate/Skellysolve B (1 :4).This yields pure 5,7-diene (13) of molecular weight
440 and exhibiting the typical 5,7-diene ultraviolet spectrum.
25-Methylvitamin D3 (14), The 5,7-diene 13(0.02 mmoles, in 100 ml diethyl ether), is irradiated under N2 and in an ice bath for 3
minutes with vigorous stirring, using a water-cooled quartz irradiation apparatus and a low-pressure
mercury arc lamp with a Vycor filter. The solvent is then evaporated and the residue is purified by
preparative thin layer chromatography (ethyl acetate/hexane). The previtamin derivative is recovered and
subjected to hydrolysis in 0.1 M KOH/MeOH, at 70 " over 3 hours. This step accomplishes both the removal of
acetate and the isomerisation of the previtamin skeleton to the vitamin compound. The basic medium is
diluted with H2O and extracted with ethyl acetate. After evaporation of the organic solvent, the product is
purified on ARNO3 impregnated silica gel plates (ethyl acetate/Skellysolve B). This yields the vitamin analogue, 25-methyl-vitamin D3 (compound 14) in pure form and exhibiting the expected physical properties (molecular weight 398; uitraviolet maximum at 265 nm).
Claims (6)
1. 25-Methyl vitamin D3.
2. Process for preparing 25-methyl vitamin D3 which comprises irradiating 3p-acetoxy-25- methylcholesta-5,7-diene and thermally isomerising and saponifying the resulting previtamin.
3. Process according to claim 2 substantially as hereinbefore described.
4. 25-Methyl vitamin D3 whenever prepared by a process as claimed in claim 2 or 3.
5. A pharmaceutical composition which comprises 25-methyl vitamin D3 as claimed in claim 1 or4 and a
pharmaceutically acceptable carrier or diluent.
6. 25-Methyl vitamin D3 for use in treating a calcium disorder in an animal.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8132031A GB2082588B (en) | 1978-05-19 | 1981-10-23 | Anti-vitamin d compound |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/907,893 US4217288A (en) | 1977-03-24 | 1978-05-19 | Anti-vitamin D compounds |
GB8132031A GB2082588B (en) | 1978-05-19 | 1981-10-23 | Anti-vitamin d compound |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2082588A true GB2082588A (en) | 1982-03-10 |
GB2082588B GB2082588B (en) | 1983-03-30 |
Family
ID=26281057
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8132031A Expired GB2082588B (en) | 1978-05-19 | 1981-10-23 | Anti-vitamin d compound |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2082588B (en) |
-
1981
- 1981-10-23 GB GB8132031A patent/GB2082588B/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB2082588B (en) | 1983-03-30 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |