WO1984000550A1 - Novel vitamin d analogs - Google Patents
Novel vitamin d analogs Download PDFInfo
- Publication number
- WO1984000550A1 WO1984000550A1 PCT/US1983/000965 US8300965W WO8400550A1 WO 1984000550 A1 WO1984000550 A1 WO 1984000550A1 US 8300965 W US8300965 W US 8300965W WO 8400550 A1 WO8400550 A1 WO 8400550A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vitamin
- dihydroxyvitamin
- fluoro
- analogs
- compounds
- Prior art date
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
Definitions
- This invention relates to compounds characterized by vitamin D-like activity.
- this invention relates to fluorinated analogs of vitamin D 3 .
- vitamin D in regulating calcium and phosphate hemeostasis in animals and humans is dependent on metabolism of the vitamin in vivo to hydroxylated forms.
- this metabolic activation involves an initial hydroxylation at carbon 25 to yield 25-hydroxyvitamin D 3 , followed by another hydroxylation at carbon 1 to produce 1 ⁇ ,25-dihydroxyvitamin D 3 .
- This latter compound is generally considered the active form of vitamin D 3 , and as such is the agent directly responsible for stimulation of intestinal calcium transport and bone mineral mobilization in vivo.
- 1 ⁇ ,25-dihydroxyvitamin D 3 is, hcwever, itself subject to further metabolism in vivo, being converted for example to 1 ⁇ , 24,25-trihydroxyvitamin D 3 by enzymatic hydroxylation at C-24.
- This 24-hydroxylated form is, however, less active than 1 ⁇ ,25-dihydroxyvitamin D 3 itself, and 24-hydroxylation may represent indeed a step towards inactivation and degradation of the active form of the vitamin. Hence, to the extent that 24-hydroxylation occurs, it depletes the body stores of the physiologically most active metabolite, 1 ⁇ ,25-dihydroxyvitamin D 3 .
- the present invention relates to novel compounds possessing the desirable properties of high potency and a blocked C-24-position.
- An example of such a compound is 24-fluoro-1,25-dihydroxyvitamin D 3 , which may be represented by the following structure:
- the structure shown above is characterized by the presence of the activity-enhancing hydroxy groups at carbons 1 and 25, as they occur in the natural metabolite, and fluorine as a blocking substituent at carbon 24.
- the blocking substitutent interferes with the introduction, by in vivo metabolism, of the 24-hydroxy group. Because of the presence of a single fluoro substitutent, such compounds have the advantage over previously proposed 24-blocked analogs (U.S. Patents 4,201,881 and 4,196,133 supra) of being biologically and chemically more similar and closely related to the natural 1,25-dihydr ⁇ xy metabolite, and hence of being a more desirable substitute for the natural coirpound. Also, by virtue of this lesser fluorine substitution, the novel analog may be used advantageously and more broadly in treatments of bone disease and related calcium disorders, since in the practical pharmaceutical applications of drugs it is often desirable to avoid as far as possible, the introduction of unnatural foreign elements.
- 24-fluoro-1 ⁇ ,25-dihydroxyvitamin D 3 can be prepared by the in vitro enzymatic hydroxylation of 24-fluoro-25-hydroxy vitamin D 3 (U.S. Letters Patents No. 4,305,880) at carbon 1, using a h ⁇ togenate of kidney tissue obtained from vitamin D-deficient chickens. The required homogenate is obtained as follows: One day-old leghorn chickens are fed a vitamin D-deficient diet containing 1% calcium for one month (Omdahl et al, Biochemistry, 10, 2935-2940 (1971)).
- 24-fluoro-1 ⁇ ,25-dihydroxyvitamin D 3 the precursor compound, 24-fluoro-25-hydroxyvitamin D 3 is then incubated with this homogenate.
- the following procedure illustrates a small-scale incubation, but it should be understood that amounts can be scaled-up appropriately if desired.
- a sample (ca. 3 ⁇ g) of 24-fluoro-25-hydroxyvitamin D 3 (in 25 ⁇ l of 95% ethanol is added to an aliquote of the kidney h ⁇ togenate (prepared as described above and representing about 600 mg of kidney tissue) suspended in 4.5 ml of buffer solution (pH 7.4) which contains 0.19 M sucrose, 1.5 mM Tris-acetate, 1.9 mM magnesium acetate and 25 mM succinate. After shaking the mixture at 37°C for 2 hours, the reaction is stopped by adding a 2:1 mixture of methanol:CHCl 3 solvent. The organic phase of the resulting mixture is separated and evaporated and the residue containing the desired 24-fluoro 1 ⁇ ,25-dihydroxyvitamin D 3 is subjected to chromatography.
- a cteomatograph suitable for such purpose is a model ALC/GPC 204 high pressure liquid chromatograph (Waters Associates, Medford, MA) equipped with an ultraviolet detector operating at 254 nm.)
- the sample obtained as above is injected onto a silica gel column (Zorbax-SIL, 0.46 x 25 cm, manufactured by Dupont, Inc.) operating under a pressure of 1000 psi which produces a flow rate of about 2 ml/min.
- a silica gel column Zorbax-SIL, 0.46 x 25 cm, manufactured by Dupont, Inc.
- the sample is recycled twice through this column (by switching the instrument to its recycle mode) and then collected.
- Solvent is evaporated and the residue is further purified on a reversed-phase column [Zorbax-ODS (octadecylsilane bonded to a fine grained silica gel) 0.45 x 25 cm, a product of Dupont and Co.] using the same high pressure liquid chromatograph operating at a pressure of 3000 psi.
- the product is eluted with a solvent mixture of H 2 O/MeOH (1:3), recycled once and then collected.
- the collected fractions are evaporated and the residue is rechrcmatographed on the straight-phase silica gel column (Zorbax-SIL, 0.46 x 25 cm) using conditions exactly as described above.
- Acylated derivatives of both the above compounds which may be desired for certain applications are prepared by conventional methods, i.e. treatment of a solution of hydroxy co ⁇ pound with an acylating agent, such as an acyl anhydride or acyl chloride.
- an acylating agent such as an acyl anhydride or acyl chloride.
- Various procedures for such acylations are well known in the art, as are the required acylating reagents.
- treatment of 24-fluoro-1,25-dihydroxy vitamin D 3 with acetic anhydride in pyridine, or mixtures of pyridine and an inert co-solvent at temperatures below 50°C yields the corresponding 1,3-diacetate, whereas under more forcing conditions, e.g. 80-90°C, the 1,3,25-triacetate is obtained.
- acylates such as propionates, butyrates, benzoates, nitrobenzoates, hemisuccinates, hemiglutamates, hemiadipates, hemidiglycolates, etc. are prepared in an analogous fashion by reaction of the vitamin alcohol with the corresponding anhydrides or acyl chlorides. If desired, acyl groups in such acylated derivatives, are removed by conventional means, such as hydrolysis with mild base (KOH/MeOH or similar conditions). By means of selective acylation and/or deacylation, performed on 24-fluoro-1 ⁇ , 25-dihydroxyvitamin D 3 or its 5,6-trans-isomer, one can obtain compounds characterized by the structures below:
- each of R 1 , R 2 , and R 3 is hydrogen or acyl.
- acyl refers to an aliphatic acyl group of 1 to 6 carbons in all possible isomeric forms, such as acetyl, propionyl, butyryl, etc., or to conventional aromatic acyl groups, such as benzoyl, nitrdbenzoyl, haldbenzoyl, methylbenzoyl, etc. , or to a dicarboxylic acyl group of 2-6 atoms chain length, such as represented by oxalyl, malonyl, succinyl, glutaryl, adipyl, diglycolyl, etc.
- novel compounds of this invention similar to that of the natural hormone, 1,25-dihydroxyvitamin D 3 , strongly suggests their application as therapeutic agents for disorders involving calcium and phosphate metabolism with perhaps, better maintenance of the compound pool in vivo because of the interference with 24-hydroxylation.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
New fluorinated derivatives of vitamin D among which are 24-fluoro-alpha, 25-dihydroxyvitamin D3 and 24-fluoro-1alpha, 25-dihydroxy-5,6-trans-vitamin D3. The compounds should be a ready substitute for 1alpha,25-dihydroxyvitamin D where the need for vitamin D-like activity is indicated but should be more resistant to degradative 24-hydroxylation because of the presence of fluorine as a blocking substituent at C-24.
Description
Description
Novel Vitamin D Analogs
Technical Field
This invention relates to compounds characterized by vitamin D-like activity.
More specifically, this invention relates to fluorinated analogs of vitamin D3. Background Art
It is by now well established that the action of vitamin D in regulating calcium and phosphate hemeostasis in animals and humans is dependent on metabolism of the vitamin in vivo to hydroxylated forms. In the case of vitamin D3, this metabolic activation involves an initial hydroxylation at carbon 25 to yield 25-hydroxyvitamin D3, followed by another hydroxylation at carbon 1 to produce 1α,25-dihydroxyvitamin D3. This latter compound is generally considered the active form of vitamin D3, and as such is the agent directly responsible for stimulation of intestinal calcium transport and bone mineral mobilization in vivo. 1α,25-dihydroxyvitamin D3 is, hcwever, itself subject to further metabolism in vivo, being converted for example to 1α, 24,25-trihydroxyvitamin D3 by enzymatic hydroxylation at C-24. This 24-hydroxylated form is, however, less active than 1α,25-dihydroxyvitamin D3 itself, and 24-hydroxylation may represent indeed a step towards inactivation and degradation of the active form of the vitamin. Hence, to the extent that 24-hydroxylation occurs, it depletes the body stores of the physiologically most active metabolite, 1α ,25-dihydroxyvitamin D3. For this reason, 24,24-difluoro compounds have recently been proposed as pharmacologically desirable analogs and substitutes, because the presence of the 24-difluoro substituents blocks the activity-attenuating 24-hydroxylation
reactions. Indeed, such compounds have been shown to possess activites at least equivalent, and generally superior, to the corresponding non-fluorinated metabolite (see U.S. Letters Patents Nos. 4,196,133 and 4,201,881; Tanaka et al, J. Biol. Chem. 254, 7163 (1979); Tanaka et al, Arch. Biochem. Biophys. 199, 473 (1980)). Disclosure of Invention
The present invention relates to novel compounds possessing the desirable properties of high potency and a blocked C-24-position. An example of such a compound is 24-fluoro-1,25-dihydroxyvitamin D3, which may be represented by the following structure:
The structure shown above is characterized by the presence of the activity-enhancing hydroxy groups at carbons 1 and 25, as they occur in the natural metabolite, and fluorine as a blocking substituent at carbon 24. The blocking substitutent interferes with the introduction, by in vivo metabolism, of the 24-hydroxy group. Because of the presence of a single fluoro substitutent, such compounds have the advantage over previously proposed 24-blocked analogs (U.S. Patents 4,201,881 and 4,196,133 supra) of being biologically and chemically more similar and closely related to the natural
1,25-dihydrαxy metabolite, and hence of being a more desirable substitute for the natural coirpound. Also, by virtue of this lesser fluorine substitution, the novel analog may be used advantageously and more broadly in treatments of bone disease and related calcium disorders, since in the practical pharmaceutical applications of drugs it is often desirable to avoid as far as possible, the introduction of unnatural foreign elements.
24-fluoro-1α,25-dihydroxyvitamin D3 can be prepared by the in vitro enzymatic hydroxylation of 24-fluoro-25-hydroxy vitamin D3 (U.S. Letters Patents No. 4,305,880) at carbon 1, using a hαtogenate of kidney tissue obtained from vitamin D-deficient chickens. The required homogenate is obtained as follows: One day-old leghorn chickens are fed a vitamin D-deficient diet containing 1% calcium for one month (Omdahl et al, Biochemistry, 10, 2935-2940 (1971)). The chickens are then killed, their kidneys are removed, and a 20% (w/v) homogenate is prepared in ice-cold 0.19 M sucrose solution containing 15 mM Tris-acetate (trihydroxymethylaminoethane acetate) pH 7.4) and 1.9 mM magnesium acetate. (Omdahl, J. , et al, Biochemistry , 10, 2935-2940 (1971) and Tanaka, Y. , et al, Arch. Biochem. Biophys. 171, 521-526 (1975)).
To produce the desired analog, 24-fluoro-1α,25-dihydroxyvitamin D3, the precursor compound, 24-fluoro-25-hydroxyvitamin D3 is then incubated with this homogenate. The following procedure illustrates a small-scale incubation, but it should be understood that amounts can be scaled-up appropriately if desired.
A sample (ca. 3 μg) of 24-fluoro-25-hydroxyvitamin D3 (in 25 μl of 95% ethanol is added to an aliquote of the kidney hαtogenate (prepared as described above and representing about 600 mg of kidney tissue) suspended in 4.5 ml of buffer solution (pH 7.4) which contains 0.19 M sucrose, 1.5 mM Tris-acetate, 1.9 mM magnesium acetate and 25 mM succinate. After shaking the mixture at 37°C for 2 hours, the reaction is
stopped by adding a 2:1 mixture of methanol:CHCl3 solvent. The organic phase of the resulting mixture is separated and evaporated and the residue containing the desired 24-fluoro 1α,25-dihydroxyvitamin D3 is subjected to chromatography.
Initial purification of the product is readily accomplished by chromatography on small Sephadex LH-20 (Pharmacia Corp. , Piscataway, N.J.) columns, using solvent systems such as CHCl3:hexane (65:35, v/v) or hexane:CHCl3:MeOH (9:1:1, v/v) , but most advantageously the product is purified by high pressure liquid chromatography. (A cteomatograph suitable for such purpose is a model ALC/GPC 204 high pressure liquid chromatograph (Waters Associates, Medford, MA) equipped with an ultraviolet detector operating at 254 nm.) The sample obtained as above is injected onto a silica gel column (Zorbax-SIL, 0.46 x 25 cm, manufactured by Dupont, Inc.) operating under a pressure of 1000 psi which produces a flow rate of about 2 ml/min. Using a solvent system containing 9% of 2-propanol in hexane, the sample is recycled twice through this column (by switching the instrument to its recycle mode) and then collected. Solvent is evaporated and the residue is further purified on a reversed-phase column [Zorbax-ODS (octadecylsilane bonded to a fine grained silica gel) 0.45 x 25 cm, a product of Dupont and Co.] using the same high pressure liquid chromatograph operating at a pressure of 3000 psi. The product is eluted with a solvent mixture of H2O/MeOH (1:3), recycled once and then collected. The collected fractions are evaporated and the residue is rechrcmatographed on the straight-phase silica gel column (Zorbax-SIL, 0.46 x 25 cm) using conditions exactly as described above. After recycling twice, the sample is collected, and after evaporation of the solvent, pure product (24-fluoro-1α,25-dihydroxyvitamin D3) is obtained, and characterized and quantitated by its ultraviolet absorption maximum at 264 nm, and its characteristic mass spectral pattern (MW=434) .
From the 24-fluorcι-1α,25-dihydroxyvitamin D3 the corresponding 5 ,6-trans-isomer is readily prepared by iodine-catalyzed isomerization according to the general procedure of Verloop et al, Rec. Trav. Chim. Rays-Bas 78 , 1004 (1969). Thus treatment of 24-fluoro-1α,25-dihydroxyvitamin D3 in ether solution containing a drop of pyridine, with a solution of iodine in hexane (ca. 0.5 mg/ml) over 15 minutes, followed by addition of an aqueous solution of sodium thiosulfate, separation of the organic phase, and evaporation of solvent yields a residue, from which the desired 24-fluoro-1α,25-dihydroxy-5,6-transvitamin D3 is isolated by a combination of reversed-phase and straight-phase high performance liquid chromatography (HPLC) using the systems described above, or by thin layer chromatography (TLC) on silica gel using ethylacetate/hexane solvent mixtures.
Acylated derivatives of both the above compounds which may be desired for certain applications are prepared by conventional methods, i.e. treatment of a solution of hydroxy coπpound with an acylating agent, such as an acyl anhydride or acyl chloride. Various procedures for such acylations are well known in the art, as are the required acylating reagents. Thus, for example, treatment of 24-fluoro-1,25-dihydroxy vitamin D3 with acetic anhydride in pyridine, or mixtures of pyridine and an inert co-solvent, at temperatures below 50°C yields the corresponding 1,3-diacetate, whereas under more forcing conditions, e.g. 80-90°C, the 1,3,25-triacetate is obtained. Other acylates, such as propionates, butyrates, benzoates, nitrobenzoates, hemisuccinates, hemiglutamates, hemiadipates, hemidiglycolates, etc. are prepared in an analogous fashion by reaction of the vitamin alcohol with the corresponding anhydrides or acyl chlorides. If desired, acyl groups in such acylated derivatives, are removed by conventional means, such as hydrolysis with mild base (KOH/MeOH or similar conditions). By means of selective acylation and/or deacylation, performed on 24-fluoro-1α,
25-dihydroxyvitamin D3 or its 5,6-trans-isomer, one can obtain compounds characterized by the structures below:
wherein each of R1, R2, and R3, and which may be the same or different, is hydrogen or acyl.
In this description, and in the claims, the term acyl refers to an aliphatic acyl group of 1 to 6 carbons in all possible isomeric forms, such as acetyl, propionyl, butyryl, etc., or to conventional aromatic acyl groups, such as benzoyl, nitrdbenzoyl, haldbenzoyl, methylbenzoyl, etc. , or to a dicarboxylic acyl group of 2-6 atoms chain length, such as represented by oxalyl, malonyl, succinyl, glutaryl, adipyl, diglycolyl, etc.
The high vitamin D-like activity of the novel compounds of this invention, similar to that of the natural hormone, 1,25-dihydroxyvitamin D3, strongly suggests their application as therapeutic agents for disorders involving calcium and phosphate metabolism with perhaps, better maintenance of the compound pool in vivo because of the interference with 24-hydroxylation.
Claims
1. Compounds having the structure
2. Compounds according to Claim 1 wherein each of R1, R2 and R3 is selected from the group consisting of hydrogen, acetyl and benzoyl.
3. 24-fluorc)-1α,25-dihydroxyvitamin D3.
4. 24-fluoro-1α,25-dihydroxy-5,6-trans-vitamin D3.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP83502455A JPS59501314A (en) | 1982-07-26 | 1983-06-22 | Novel vitamin D analogs |
| NL8320218A NL8320218A (en) | 1982-07-26 | 1983-06-22 | NEW VITAMIN D ANALOGS. |
| DK1614/84A DK161484D0 (en) | 1982-07-26 | 1984-03-21 | VITAMIN D ANALOGICAL COMPOUNDS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US40199782A | 1982-07-26 | 1982-07-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1984000550A1 true WO1984000550A1 (en) | 1984-02-16 |
Family
ID=23590116
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1983/000965 WO1984000550A1 (en) | 1982-07-26 | 1983-06-22 | Novel vitamin d analogs |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS59501314A (en) |
| AU (1) | AU1821383A (en) |
| CH (1) | CH661047A5 (en) |
| DE (1) | DE3390125T1 (en) |
| DK (1) | DK161484D0 (en) |
| IL (1) | IL69061A0 (en) |
| NL (1) | NL8320218A (en) |
| WO (1) | WO1984000550A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3590020C2 (en) * | 1984-01-30 | 1995-03-09 | Wisconsin Alumni Res Found | 1-Hydroxy-vitamin-D compounds which are unsaturated in the side chain |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3847955A (en) * | 1973-07-16 | 1974-11-12 | Wisconsin Alumni Res Found | 1,24,25-trihydroxycholecalciferol |
| US4229357A (en) * | 1978-07-26 | 1980-10-21 | Wisconsin Alumni Research Foundation | Fluorovitamin D compounds and processes for their preparation |
| US4305880A (en) * | 1980-09-22 | 1981-12-15 | Wisconsin Alumni Research Foundation | Process for preparing 24-fluoro-25-hydroxycholecalciferol |
-
1983
- 1983-06-22 AU AU18213/83A patent/AU1821383A/en not_active Abandoned
- 1983-06-22 WO PCT/US1983/000965 patent/WO1984000550A1/en active Application Filing
- 1983-06-22 NL NL8320218A patent/NL8320218A/en unknown
- 1983-06-22 DE DE19833390125 patent/DE3390125T1/en not_active Withdrawn
- 1983-06-22 JP JP83502455A patent/JPS59501314A/en active Pending
- 1983-06-22 CH CH1547/84A patent/CH661047A5/en not_active IP Right Cessation
- 1983-06-23 IL IL69061A patent/IL69061A0/en unknown
-
1984
- 1984-03-21 DK DK1614/84A patent/DK161484D0/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3847955A (en) * | 1973-07-16 | 1974-11-12 | Wisconsin Alumni Res Found | 1,24,25-trihydroxycholecalciferol |
| US4229357A (en) * | 1978-07-26 | 1980-10-21 | Wisconsin Alumni Research Foundation | Fluorovitamin D compounds and processes for their preparation |
| US4305880A (en) * | 1980-09-22 | 1981-12-15 | Wisconsin Alumni Research Foundation | Process for preparing 24-fluoro-25-hydroxycholecalciferol |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59501314A (en) | 1984-07-26 |
| DE3390125T1 (en) | 1984-09-20 |
| AU1821383A (en) | 1984-02-23 |
| DK161484A (en) | 1984-03-21 |
| DK161484D0 (en) | 1984-03-21 |
| CH661047A5 (en) | 1987-06-30 |
| IL69061A0 (en) | 1983-10-31 |
| NL8320218A (en) | 1984-06-01 |
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