WO1987001705A1 - 26,26,26,27,27-PENTAFLUORO-1alpha-HYDROXY-27-METHOXYVITAMIN D3 - Google Patents

26,26,26,27,27-PENTAFLUORO-1alpha-HYDROXY-27-METHOXYVITAMIN D3 Download PDF

Info

Publication number
WO1987001705A1
WO1987001705A1 PCT/US1986/001301 US8601301W WO8701705A1 WO 1987001705 A1 WO1987001705 A1 WO 1987001705A1 US 8601301 W US8601301 W US 8601301W WO 8701705 A1 WO8701705 A1 WO 8701705A1
Authority
WO
WIPO (PCT)
Prior art keywords
vitamin
pentafluoro
compound
hydroxy
compounds
Prior art date
Application number
PCT/US1986/001301
Other languages
French (fr)
Inventor
Hector F. Deluca
Nobuo Ikekawa
Yoshiro Kobayashi
Yoko Tanaka
Original Assignee
Wisconsin Alumni Research Foundation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Wisconsin Alumni Research Foundation filed Critical Wisconsin Alumni Research Foundation
Priority to DE8686904523T priority Critical patent/DE3665867D1/en
Publication of WO1987001705A1 publication Critical patent/WO1987001705A1/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J9/00Normal 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 a compound which is characterized by vitamin D-like activity.
  • this invention relates to a derivative of vitamin D 3 , to a method for preparing such compounds and to novel intermediates generated during such process.
  • Vitamin D 3 is a well-known agent for the control of calcium and phosphorous homeostasis. In the normal animal or human this compound is known to stimulate intestinal calcium transport and bone-calcium mobilization and is effective in preventing rickets.
  • vitamin D 3 must be converted in vivo to its hydroxylated forms.
  • the vitamin is first hydroxylated in the liver to form 25-hydxoxy-vitamin D 3 and is further hydroxylated in the kidney to produce 1 ⁇ ,25-dihydroxy-vitam ⁇ in D 3 or 24,25-dihydroxyvitamin D 3 .
  • the 1 ⁇ -hydroxylated form of the vitamin is generally considered to be the physiologically active or hormonal form of the vitamin and to be responsible for what are termed the vitamin D-like activities, such as increasing intestinal absorption of calcium and phosphate, mobilizing bone mineral, and retaining calcium in the kidneys.
  • 3,741,996 directed to 1 ⁇ -hydroxycholecalciferol
  • 3,907,843 directed to 22-dehydro-25-hydroxycholecalciferol
  • 3,906,014 directed to 3-deoxy-1 ⁇ -hydroxycholecalciferol
  • 4,069,321 directed to the preparation of various side chain-fluorinated vitamin D 3 derivatives and side chain-fluorinated vitamin D 3 derivatives and side chain-fluorinated dihydrotachysterol analogs.
  • Certain fluoro derivatives of the accepted hormonal form of the vitamin, 1,25-dihydroxycholecalciferol (1,25- (OH) 2 D 3 ) are of particular interest because they are characterized by at least as great if not greater activity than 1,25-(OH) 2 D 3 .
  • These are, 24,24-difluoro-1,25-(OH) 2 D 3 (U.S. Patent No. 4,201,881) and 26,26,26,27,27,27-hexafluoro-1 ⁇ ,25-dihydroxycholecalciferol (U.S. Patent No. 4,358,406).
  • the derivative has been identified as 26,26,26,27,27pentafluoro-1 ⁇ -hydroxy-27- methoxyvitamin D 3 .
  • the compound is characterized by properties which are unexpected for a vitamin D 3 derivative in that it exhibits little activity in in vivo bone resorption (as measured by serum calcium concentration) while being substantially more active than 1 ⁇ -hydroxycholecalciferol (U.S. Patent No. 3,741,996) in binding to receptor sites.
  • the compound because it evidences sore vitamin D-like properties, would find application in the treatment of mineral (calcium and phosphous in particular) imbalance conditions as manifested, for example, in hypqparathyroidism, renal osteodystr ⁇ phy, ostecmalacia, etc. in man, in milk fever disease in dairy cattle and in the thinning of egg shells in fowl. Best Mode for Carrying out the Invention
  • the oxalyl diester of 1 ⁇ ,3 ⁇ -diacetoxychol-5-en-24-o1 (Y. Kobayashi, T. Taguchi, S. Mitsuhashi, T. Eguchi, E. Oshima and N. Ikekawa, Chem., Pharm. Bull., 30, 4297 (1982)) was oxidized with dimethylsulfoxide to give the 24-aldehyde (1). Condensation with 2,2,4,4-tetratris (trifluoromethyl) -1,3-dithiethane provided the hexafluoro-24-ene (2) in good yield. The 24double bond was reduced with sodium borohydride to give the hexafluorocholesterol derivative (3).
  • the C-7 double bond was introduced with N-bromo succinimide as a usual procedure.
  • the diacetate was hydrolyzed with KOH-MeOH, one fluorine atom at C-27 position was replaced with a methoxy group to give the diene (4). This replacement was confirmed by the mass spectral data.
  • the diene (4) was then subjected to
  • Mass spectra were obtained with a HITACHI double focusing mass spectromenter RMU-7L.
  • Column chromatography was effected with silica gel (Merck, 70-23 mesh).
  • Preparative thin layer chromatography was carried out on precoated plates of silica gel (Merck, silica gel 60 F 25 4 ).
  • the usual work-top refers to dilution with water, extraction with an organic solvent, washing to neutrality, drying over magnesium sulfate, filtration, and removal of the solvent under reduced pressure.
  • THF tetrahydrofuran
  • ether diethyl ether
  • HMPA hexamethylphosphoramide
  • TsOH p-toluenesulfonic acid
  • THP tetraphdropyranyl
  • s singlet
  • d doublet
  • t triplet
  • q quatraplet
  • m multiplet
  • bs broaden singlet. All temperates are in °C.
  • blocking groups other than the acetate group can be utilized in the starting material.
  • acyl groups having frcm 1 to about 4 carbon atoms can be readily utilized as well as other blocking groups which will be evident to those skilled in the art.
  • the 26,26,26,27,27,27-pentafluoro-1 ⁇ -hydroxy-27-methoxyvitamin D 3 (5) can, if desired, be readily obtained in crystalline form by crystallization from suitable solvents such as, hexane, ethers and alcohols (absolute or aqueous) and mixtures thereof as will be evident and well known to those skilled in the art.
  • the 26,26,26,27,27-pentafluoro-1 ⁇ -hydroxy-27-methoxyvitamin D 3 compound of this invention may be readily administered as sterile parenteral solutions by injection or .intravenously or by alimentary canal in the form of oral dosages, or by suppository. Doses of from about 0.1 ⁇ g to about 10 ⁇ g per day would be effective in obtaining the physiological calcium balance responses described and which are characteristic of vitamin D-like activity, with maintenance doses of about 0.25 ⁇ g being suitable.
  • Dosage form of the compounds can be prepared by combining them with a non-toxic pharmaceutically acceptable carrier as is well known in the art.
  • a non-toxic pharmaceutically acceptable carrier 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.

Abstract

New derivative of vitamin D3, 26,26,26,27,27-pentafluoro-1alpha-hydroxy-27-methoxy-cholecalciferol and a process for preparing the same. The compound is characterized by some vitamin D-like activity except that it exhibits negligible activity in mobilizing bone. This characteristic indicates that the compound would find ready application in the treatment of disease or physiological states which evince loss of bone mass and application in other situations where metabolic calcium imbalances are found.

Description

26,26,26,27,27-Pentafluoro-1α-Hydroxy-27Methoxyvitamin D3
Technical Field
This invention relates to a compound which is characterized by vitamin D-like activity.
More specifically this invention relates to a derivative of vitamin D3, to a method for preparing such compounds and to novel intermediates generated during such process.
Vitamin D3 is a well-known agent for the control of calcium and phosphorous homeostasis. In the normal animal or human this compound is known to stimulate intestinal calcium transport and bone-calcium mobilization and is effective in preventing rickets.
It is also now well known that to be effective, vitamin D3 must be converted in vivo to its hydroxylated forms. The vitamin is first hydroxylated in the liver to form 25-hydxoxy-vitamin D3 and is further hydroxylated in the kidney to produce 1α,25-dihydroxy-vitamιin D3 or 24,25-dihydroxyvitamin D3. The 1α-hydroxylated form of the vitamin is generally considered to be the physiologically active or hormonal form of the vitamin and to be responsible for what are termed the vitamin D-like activities, such as increasing intestinal absorption of calcium and phosphate, mobilizing bone mineral, and retaining calcium in the kidneys. Background Art
Since the discovery of biologically active metabolites of vitamin D there has been much interest in the preparation of structural analogs of these metabolities, because such ccrnpounds nay represent useful therapeutic agents for the treatment of diseases resulting from calcium metabolism disorders. A variety of vitamin D-like compounds have been synthesized. See, for example, U.S. Patent Nos. 3,741,996 directed to 1α-hydroxycholecalciferol; 3,907,843 directed to 22-dehydro-25-hydroxycholecalciferol; 3,906,014 directed to 3-deoxy-1α-hydroxycholecalciferol; and 4,069,321 directed to the preparation of various side chain-fluorinated vitamin D3 derivatives and side chain-fluorinated vitamin D3 derivatives and side chain-fluorinated dihydrotachysterol analogs.
Certain fluoro derivatives of the accepted hormonal form of the vitamin, 1,25-dihydroxycholecalciferol (1,25- (OH)2D3) are of particular interest because they are characterized by at least as great if not greater activity than 1,25-(OH)2D3. These are, 24,24-difluoro-1,25-(OH)2D3 (U.S. Patent No. 4,201,881) and 26,26,26,27,27,27-hexafluoro-1α,25-dihydroxycholecalciferol (U.S. Patent No. 4,358,406).
Also of interest is the 26,26,26,27,27,27-hexafluoro derivative of 25-hydroxycholecalciferol (see U.S. Patent No. 4,248,791) which exhibits greater vitamin D-like activity than 25-hydroxycholecalciferol. Disclosure of the Invention
A new derivative of vitamin D3 has now been prepared.
The derivative has been identified as 26,26,26,27,27pentafluoro-1α-hydroxy-27- methoxyvitamin D3. The compound is characterized by properties which are unexpected for a vitamin D3 derivative in that it exhibits little activity in in vivo bone resorption (as measured by serum calcium concentration) while being substantially more active than 1α-hydroxycholecalciferol (U.S. Patent No. 3,741,996) in binding to receptor sites.
These unusual properties suggest that the compound would be eminently suitable in applications where it is desired to enhance new bone formation (mineralization) and to that end would be highly suitable for administration in conjunction or combination with vitamin D or a derivative thereof which displays traditional vitamin D-like activity, i.e. both bone resorption and bone mineralization. Disease states for which such conjunctive or combinative administration would be of particular value are those where there is a tendency toward or evidence of loss of bone mass, such as, for example, postmenopausal osteoporosis, senile osteoporosis and osteopenia. Analagously, disease states in animals which cause loss of bone mass or which are evidenced by inadequate bone mineralization such as, leg weakness condition in turkeys, chickens and poults or other domesticated animals would benefit from the administration of the compound of this invention either alone or in conjunction or combination with vitamin D or other vitamin D derivatives.
Also, the compound, because it evidences sore vitamin D-like properties, would find application in the treatment of mineral (calcium and phosphous in particular) imbalance conditions as manifested, for example, in hypqparathyroidism, renal osteodystrαphy, ostecmalacia, etc. in man, in milk fever disease in dairy cattle and in the thinning of egg shells in fowl. Best Mode for Carrying out the Invention
The compounds of this invention can be readily synthesized in accordance with the following schematic and description, in the schematic and the description like compounds are identified by like numbers.
The oxalyl diester of 1α,3β-diacetoxychol-5-en-24-o1 (Y. Kobayashi, T. Taguchi, S. Mitsuhashi, T. Eguchi, E. Oshima and N. Ikekawa, Chem., Pharm. Bull., 30, 4297 (1982)) was oxidized with dimethylsulfoxide to give the 24-aldehyde (1). Condensation with 2,2,4,4-tetratris (trifluoromethyl) -1,3-dithiethane provided the hexafluoro-24-ene (2) in good yield. The 24double bond was reduced with sodium borohydride to give the hexafluorocholesterol derivative (3). The C-7 double bond was introduced with N-bromo succinimide as a usual procedure. When the diacetate was hydrolyzed with KOH-MeOH, one fluorine atom at C-27 position was replaced with a methoxy group to give the diene (4). This replacement was confirmed by the mass spectral data. The diene (4) was then subjected to
Figure imgf000006_0001
UV-irradiation and pentafluoro-1α-hydroxy-27-methyoxyvitamin D3 (5) was recovered.
Synthesis
The physico-chemical data set forth in the following detailed description of the synthesis of the compounds of this invention were obtained as indicated below.
Melting points were determined on a hot stage microscope and were uncorrected. U.V. spectra were obtained in ethanol solution with a Shimadzu UV-200 double beam spectrophotcmeter. IR spectra were taken with a JEJOL IRA-1 diffraction grating infrared spectrophotαreter. 1H-NMR spectra were run on a Varian EM-390 spectrometer for solutions in CDCl3 unless otherwise stated, with tetramethylsilane as an internal reference. 19F-NMR spectra were recorded on a Varian EM-360L spectrometer in CDCI3 solution, with benzotrifluoride as an internal reference (a plus means high field). Mass spectra were obtained with a HITACHI double focusing mass spectromenter RMU-7L. Column chromatography was effected with silica gel (Merck, 70-23 mesh). Preparative thin layer chromatography was carried out on precoated plates of silica gel (Merck, silica gel 60 F25 4). The usual work-top refers to dilution with water, extraction with an organic solvent, washing to neutrality, drying over magnesium sulfate, filtration, and removal of the solvent under reduced pressure.
The following abbreviations were used: THF, tetrahydrofuran; ether, diethyl ether; HMPA, hexamethylphosphoramide; TsOH, p-toluenesulfonic acid; THP, tetraphdropyranyl; s, singlet; d, doublet; t, triplet; q, quatraplet; m, multiplet; bs, broaden singlet. All temperates are in °C.
1a,3β-Diacetoxychol-5-en-24-o1 (1)
To a solution of oxalyl chloride (0.32 ml, 3.69 mmol) in dichloro-methane (12 ml) was added dimethylsulfoxide (0.52 ml,
7.38 nmol) at -78° under Argon atmosphere and the mixture was stirred at 78° for 10 rain. Then 1α,3β-diacetoxychol-5-en-24 ol (Chem. Pharm. Bull., 30, 4297 (1982)) (850 mg, 1.85 mmol) in dichloro-methane (7 ml) was added and the solution was further stirred. After 15 min, triethylamine (2.05 ml, 14.76 mmol) was added and the mixture was stirred for 5 min, then warmed to room temperature. The usual work-up (ether) gave a crude product, which was chromatographed on silica gel (74 g). Elution with hexane-ethyl acetate (4 : 1) gave the aldehyde (1) (750 mg, 89%), amorphous solid. 1H-NMR (CDCl3) δ: 0.65(3H, s, 18-H3), 1.04 (3H, S, 19-H3), 1.94 (3H, s, acetyl), 1.97 (3H, s, acetyl), 4.82 (1H, m, 3α-H), 4.95 (1H, m, 1β-H), 5.41(1H, m, 6-H), 9.58(1H, t, J=1.6 Hz, 24-H).
It is to be understood that in the foregoing procedure blocking groups other than the acetate group can be utilized in the starting material. For example, acyl groups having frcm 1 to about 4 carbon atoms can be readily utilized as well as other blocking groups which will be evident to those skilled in the art.
1α-Acetoxy, 26,26,26,27,27,27-hexafluorocholesterol 3β-acetate (3)
To a solution of 1α,3β-diacetoxychol-5-en-22-al (1) (134 mg, 0.29 irarol) and triphenylphosphine (1.024g, 3.9 mmol) in ether (50 ml) was added 2,2,4,4-tetratris(trifluoromethyl)-1, 3-dithiethane (760 mg, 2.1 mmol) at -78°C (dry ice-acetone) and the reaction mixture was stirred for 16 hr. After removal of the solvent under reduced pressure, the residue was chrαnatographed on silica gel (n-hexane-ethyl acetate 5 : 1) to give a mixture of the hexafluoride (2) and triphenylphosphine sulfide (394 mg, molar ratio 1:1.77), H-nmr (CDCl3) δ 0.68(3H, s, 18-H3), 0.95(3H, d, J=6Hz, 21-H3), 1.08 (3H, s, 19-H3), 2.02 (3H, s, acetyl), 2.05 (3H, s, Acetyl), 4.95 (1H, m, 3-H), 5.β2(1H, m, 1-H), 5.58 (1H, m, 6-H), 6.80(1H, m, 24-H).
This mixture (350 mg) was treated with sodium borohydride (100 mg) in THF (15 ml) and t-butanol (7.5 ml) at room temperature for 22 hr. After the usual work-up [ether-ethyl acetate (1 : 1) for extraction], the extracts were purified on a column of silica gel (40 g) eluted with n-hexane-ethyl acetate (10 : 1) to give the crude hexafluorocholesterol (3), which was further purified on a column of silica gel (20 g). Elution of n-hexane-ethyl acetate (20 : 1) provided the pure hexafluorocholesterol derivative (3) (69 mg, 51%) as amorphous. (6): 1H-nmr(CDCl3) δ .68 (3H, s, 18-H3), 0.92 (3H, d, J=6Hz, 21-H3), 1.10(3H, s, 19-H3), 2.03 (3H, s, acetyl), 2.07 (3H, s, acetyl), 5.00(1H, m, 3-H), 5.10(1H, m, 1-H), 5.58 (1H, m, 6-H). 19F-nmr(CDCl3) -3.3 (3F,d, J=10.3 Hz), -4.1 (3F, d, J=10.9Hz). MS m/e 454 (M+ -2AcOH -HF), 440, 335, 253. High resolution MS calcd. for CH27H35F5, 454.2656. Found: 454.2539.
26,26,26,27,27-Pentafluoro-1α,3β-dihydroxy-27-methoxycholesta5,7-diene (4)
A mixture of 26,26,26,27,27,27-hexafluoro-1α,3β-diacetoxycholest-5-ene (3) (26 mg, 0.044 mmol) and N-Bromosuccinimide (11 mg, 0.062 mmol) in carbontetrachloride (2 ml) wasrefluxed under argon atmosphere for 25 min. After cooling to 0°, the resulting precipitate was filtered off. The filtrate was concentrated below 40° to leave the residue. This in xylene (2 ml) was added dropwise to a refluxing solution of collidine (0.5 ml) and xylene (1.5 ml) and refluxing was ∞ntinued for 20 min. The usual work-up (ethyl acetate for extraction gave the crude diene. This in THF (5 ml) was treated with 5% KOH-MeOH (7.5 ml) for 60 min. The usual work up (ethyl acetate for extraction) gave a crude product, which was submitted to preparative TLC (benzene-ethyl acetate, 1 : 1, developed three times). The band of Rf 0.41 was scraped off and eluted with ethyl acetate. Removal of the solvent provided the 5,7-diene (4.5 mg, 20%); UV : 293,
Figure imgf000009_0001
282, 272 nm. MS m/z :520 (M+) , 500, 482, 466, 287, 269, 251, 233. From the mass spectral data, one fluorine at C-27 was exchanged to methoxy group during the hydrolysis procedure with KOH-MeOH. 26,26,26,27,27-Pentafluoro-1α-hydroxy-27-methoxyvitamin D3 (5)
A solution of the 5,7-diene (4) (4.5 mg, 8.86 μmol) in benzene (90 ml) and ethanol (40 ml) was irradiated with a medium pressure mercury lamp through a Vycor filter with ice cooling under argon atmosphere for 5 min. Then, the reaction mixture was refluxed for 1 hr under argon atmosphere. Removal of the solvent under reduced pressure gave a crude product, which was submitted to preparative TLC (benzene-ethyl acetate, 1 : 1, developed three times). The band of Rf 0.50 was scraped off and eluted with ethyl acetate. Removal of the solvent provided the vitamin D3 analogue (5) (0.67 mg, 15%), UV
Figure imgf000010_0001
^ : 265 nm, 228 nm; MS m/z: 50(M+-HF), 482, 466,
Figure imgf000010_0002
3β5, 287, 269, 251, 233, 213, 152, 134. The band of Rf 0.43 was scraped off and eluted with ethyl acetate. Removal of the solvent recovered the 5,7-diene (1.3 mg, 29%).
The 26,26,26,27,27,27-pentafluoro-1α-hydroxy-27-methoxyvitamin D3 (5) can, if desired, be readily obtained in crystalline form by crystallization from suitable solvents such as, hexane, ethers and alcohols (absolute or aqueous) and mixtures thereof as will be evident and well known to those skilled in the art.
The 26,26,26,27,27-pentafluoro-1α-hydroxy-27-methoxyvitamin D3 compound of this invention may be readily administered as sterile parenteral solutions by injection or .intravenously or by alimentary canal in the form of oral dosages, or by suppository. Doses of from about 0.1 μg to about 10 μg per day would be effective in obtaining the physiological calcium balance responses described and which are characteristic of vitamin D-like activity, with maintenance doses of about 0.25 μg being suitable.
Dosage form 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 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, as well as other factors known to those skilled in the art in the therapeutic use of such medicinal agents.
Biological Activity
The biological activity of 26,26,26,27,27-pentafluoro1α-hydroxy-27-methoxyvitamin D3 was established through appropriate-assays as described following:
Bone Calcium Mobilization
Weanling male rats (Holtzman Co., Madison, Wis.) were fed a low calcium vitamin D deficient diet (Suda et al, J. Nutrition (1970) 100, 1049) for three weeks. At the end of that time they were divided into three groups, one of which was given 650 pmols of 1α-hydroxyvitamin D3 (1α-OHD3) dissolved in 0.05 ml of 95% EtOH, one of which was given 650 pmols of 1α-hydroxy-26,26,26,27,27-pentafluoro-27-methoxy vitamin D3 (1αOH-26,26,26,27,27-F5-27OCH3-D3) in the sane vehicle as the 1α-hydroxy vitamin D3 and the last of which was given the vehicle alone. The administrations were made intrajugularly 16 hours prior to sacrifice. The blood was collected and centrifuged to obtain the serum. 0.1 ml of serum in each case was mixed with lanthanum chloride solution and the calcium concentration was measured with an atonic absorption spectrophotometer (Perkin-ELrer Model 214). Since intake of calcium from the diet is negligibly low, the increase in serum calcium concentration reflects the bone mobilization activity of the compounds tested. Results are shown in Table I below:
Figure imgf000012_0001
Receptor Binding
Displacement of radiolabeled 1,25-dihydroxy vitamin D3
(1,25-(OH)2D3) from the chick intestinal receptor was measured for 1α-OHD3 and 1αOH-26,26,26,27,27-F5-27-OCH3-D3 in accordance with the method of Shepard et al (Biochem. J. (1978) 182, 55-69). The results obtained, which are shown in Figure 1, demonstrate that the pentafluoro compound is about three times more potent than 1α-OHD3 in displacing radiolabeled 1,25-(OH)2D3 from the receptor, which is evidence of the vitamin D-like activity of these compounds in calcium intestinal transport and bone mineralization.

Claims

Claims
1. Compounds having the formula
Figure imgf000013_0002
Figure imgf000013_0003
where R and R1 are selected from the group consisting of hydrogen and an acyl group having from 1 to about 4 carbon atoms.
2. The compounds of claim 1 in crystalline form.
3; A pharmaceutical composition comprising at least one compound of claim 1 together with at least one pharmaceutically acceptable excipient.
4. 26,26,26,27,27-pentafluoro-1α-hydroxy-27-methoxyvitamin D3.
5. A pharmaceutical composition comprising the compound of claim 4 together with at least one pharmaceutically acceptable excipient.
6. The compound of claim 4 in crystalline form.
7. Compounds having the formula
Figure imgf000013_0001
where R and R1 are selected from the group consisting of hydrogen and an alkyl group having from 1 to about 4 carbon atoms
R2 is selected from the group consisting of hydrogen and -OCH3, and the dotted line represents a carbon to carbon bond when R2 is -OCH3.
8. 1α,3β-dihydroxy-26,26,26,27,27-pentafluoro-27-methoxycholesta-5,7-diene.
PCT/US1986/001301 1985-09-16 1986-06-16 26,26,26,27,27-PENTAFLUORO-1alpha-HYDROXY-27-METHOXYVITAMIN D3 WO1987001705A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE8686904523T DE3665867D1 (en) 1985-09-16 1986-06-16 26,26,26,27,27-PENTAFLUORO-1-ALPHA-HYDROXY-27-METHOXYVITAMIN D3

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US776,342 1985-09-16
US06/776,342 US4619920A (en) 1985-09-16 1985-09-16 26,26,26,27,27-pentafluoro-1α-hydroxy-27-methoxyvitamin D3

Publications (1)

Publication Number Publication Date
WO1987001705A1 true WO1987001705A1 (en) 1987-03-26

Family

ID=25107119

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1986/001301 WO1987001705A1 (en) 1985-09-16 1986-06-16 26,26,26,27,27-PENTAFLUORO-1alpha-HYDROXY-27-METHOXYVITAMIN D3

Country Status (5)

Country Link
US (1) US4619920A (en)
EP (1) EP0236346B1 (en)
JP (1) JPS63500940A (en)
DE (1) DE3665867D1 (en)
WO (1) WO1987001705A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0264880A1 (en) * 1986-10-20 1988-04-27 Sumitomo Pharmaceuticals Company, Limited Fluorine derivatives of vitamin D3 and process for producing the same

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5316770A (en) * 1989-02-16 1994-05-31 University Of Georgia Research Foundation, Inc. Vitamin D derivative feed compositions and methods of use
WO1990009179A1 (en) * 1989-02-16 1990-08-23 University Of Georgia Research Foundation, Inc. Treatment of tibial dyschondroplasia
US5366736A (en) * 1989-02-16 1994-11-22 University Of Georgia Research Foundation, Inc. Vitamin D derivative feed compositions and methods of use
US5605949A (en) * 1994-10-11 1997-02-25 Basf Corporation Latex composition employing specifically defined alcohol ethoxylate surfactant and hydrophobic defoaming agent
IL118156A (en) * 1995-05-09 2001-08-26 Duphar Int Res Vitamin d compounds, their preparation and pharmaceutical compositions containing them
US5716946A (en) * 1996-02-13 1998-02-10 Wisconsin Alumni Research Foundation Multiple sclerosis treatment
WO2000028982A2 (en) 1998-11-19 2000-05-25 The Board Of Trustees For The University Of Arkansas Increasing bone strength with selected bisphosphonates
US6479474B2 (en) * 1999-07-08 2002-11-12 Wisconsin Alumni Research Foundation Dietary calcium as a supplement to vitamin D compound treatment of multiple sclerosis
EA201691980A1 (en) 2009-01-27 2017-07-31 БЕРГ ЭлЭлСи WAYS TO REDUCE SIDE EFFECTS ASSOCIATED WITH CHEMOTHERAPY
WO2011019617A2 (en) 2009-08-14 2011-02-17 Cytotech Labs, Llc Vitamin d3 and analogs thereof for treating alopecia
SG10201709894RA (en) 2013-05-29 2018-01-30 Berg Llc Preventing or mitigating chemotherapy induced alopecia using vitamin d

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4358406A (en) * 1981-07-27 1982-11-09 Wisconsin Alumni Research Foundation 26,26,26,27,27,27-Hexafluoro-1α,25-dihydroxycholecalciferol and process for preparing same
US4411833A (en) * 1982-05-26 1983-10-25 Wisconsin Alumni Research Foundation Method for preparing 26,26,26,27,27,27-hexafluoro-1α,25-dihydroxycholesterol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4358406A (en) * 1981-07-27 1982-11-09 Wisconsin Alumni Research Foundation 26,26,26,27,27,27-Hexafluoro-1α,25-dihydroxycholecalciferol and process for preparing same
US4411833A (en) * 1982-05-26 1983-10-25 Wisconsin Alumni Research Foundation Method for preparing 26,26,26,27,27,27-hexafluoro-1α,25-dihydroxycholesterol

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0264880A1 (en) * 1986-10-20 1988-04-27 Sumitomo Pharmaceuticals Company, Limited Fluorine derivatives of vitamin D3 and process for producing the same
US4853378A (en) * 1986-10-20 1989-08-01 Sumitomo Chemical Company, Limited Fluorine derivatives of vitamin D3 and process for producing the same

Also Published As

Publication number Publication date
EP0236346A1 (en) 1987-09-16
JPS63500940A (en) 1988-04-07
DE3665867D1 (en) 1989-11-02
EP0236346B1 (en) 1989-09-27
US4619920A (en) 1986-10-28
EP0236346A4 (en) 1987-08-24

Similar Documents

Publication Publication Date Title
US5532391A (en) Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives
US4358406A (en) 26,26,26,27,27,27-Hexafluoro-1α,25-dihydroxycholecalciferol and process for preparing same
US4689180A (en) 1α,25-dihydroxy-22Z-dehydroxyvitamin D compound
US4552698A (en) 23,23-Difluoro-1α,25-dihydroxy-vitamin D3
US4248791A (en) 25-Hydroxy-26,26,26,27,27,27-hexafluorocholecalciferol
US4588528A (en) 1,24-dihydroxy-Δ22 -vitamin D3 and process for preparing same
US4619920A (en) 26,26,26,27,27-pentafluoro-1α-hydroxy-27-methoxyvitamin D3
US4505906A (en) Hydroxyvitamin D2 isomers
JPH0651624B2 (en) Drugs for prevention of bone loss or treatment or prevention of regenerative disorders
AU582789B2 (en) Vitamin d derivatives and methods for preparing same
US4500460A (en) 23,23-Difluoro-25-hydroxy-vitamin D3 and process for preparing same
US5036061A (en) Process for the preparation of 1 alpha,25-dihydroxylated vitamin D2 and related compounds
AU587174B2 (en) 1a, 25-dihydroxy-22z-dehydrovitamin d compound
KR20050055784A (en) Vitamin d analogues, compositions comprising said analogues and their use
US4564474A (en) 23,23-Difluoro-25-hydroxy-vitamin D3 and process for preparing same
IE850520L (en) 1ó-hydroxy vitamin d2 analogues
GB2145091A (en) Vitamin D3 derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): DE GB JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 1986904523

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1986904523

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWG Wipo information: grant in national office

Ref document number: 1986904523

Country of ref document: EP