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WO1996030338A1 - Analogues de la vitamine d3 substitues en position 1 - Google Patents

Analogues de la vitamine d3 substitues en position 1 Download PDF

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Publication number
WO1996030338A1
WO1996030338A1 PCT/US1996/003626 US9603626W WO9630338A1 WO 1996030338 A1 WO1996030338 A1 WO 1996030338A1 US 9603626 W US9603626 W US 9603626W WO 9630338 A1 WO9630338 A1 WO 9630338A1
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Prior art keywords
mmol
nmr
vitamin
hexane
cdcl
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PCT/US1996/003626
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English (en)
Inventor
Gary H. Posner
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The Johns-Hopkins University
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Publication of WO1996030338A1 publication Critical patent/WO1996030338A1/fr

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    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/532—Cycloaliphatic phosphine oxides or thioxides

Definitions

  • the present invention relates to novel biologically active vitamin D 3 analogues which include at least one hydroxyalkyl substituent on the A-ring (e.g. in the 1-position). More
  • the present invention relates to hybrid compounds YB, JK 276-1, JK 276-2, JK 277-1 and JK 277-2 which are vitamin D 3 analogues each of which includes both a hydroxyalkyl substituent in the 1-position and a modified D-ring side chain.
  • These compounds are potent anti-proliferative vitamin D 3 analogues but have a very low ( ⁇ 10 -3 relative to calcitriol) binding affinity to the calf thymus vitamin D 3 receptor (VDR).
  • Vitamin D 3 analogues have been recognized as having important biological activities. It is known, for example, that vitamin D 3 analogues can be used to control calcium and phosphate
  • vitamin D 3 produces 1 ⁇ ,25-dihydroxy-vitamin D 3 (calcitriol) which is a potent regulator of cell differentiation and proliferation as well as intestinal calcium and phosphorus absorption and bone calcium mobilization.
  • Calcitriol is also known to affect the immune system and this compound, as well as a variety of synthetic vitamin D 3 derivatives have been used in practical, clinical chemotherapy of such diverse human illnesses as osteoporosis, cancer, immunodeficiency syndromes and skin disorders such as dermatitis and psoriasis.
  • major research efforts are underway in an effort to prepare vitamin D 3 analogues as drugs in which calcitropic activity is effectively separated from cell growth regulation.
  • Calcitriol may be structurally represented as follows:
  • the upper and lower ring portions of calcitriol may be called, for ease of reference, the C/D-ring and A-ring, respectively.
  • 1 ⁇ -hydroxyl group have also been prepared, e.g. the 1 ⁇ -hydroxyl , 1 ⁇ -fluoro and the 1- -unfunctionalized (i.e. 25-hydroxyvitamin D 3 ).
  • the present invention is based on the unexpected finding that the A-ring portion of vitamin D 3 analogues can be modified without negatively affecting the biological activity of the resulting compounds.
  • the invention provides vitamin D 3 analogues which include at least one hydroxyalkyl substituent on the ring-A.
  • this hydroxyalkyl substituent may be placed on the 1, 2, 3- and/or 4- positions of the A-ring.
  • the preferred embodiment of the invention is the vitamin D 3 analogue wherein the 1 ⁇ -hydroxy group is replaced by a hydroxyalkyl group of, for example, 1-6 carbon atoms.
  • R being straight or branched alkyl of 1 to
  • R 1 is hydrogen and R 2 represents the substituents completing a vitamin D 3 analogue.
  • corresponding analogues which include one or more hydroxyalkyl substituents in the 2,3- and/or 4- position in lieu of, or in addition to, the hydroxyalkyl in the 1-position of the ring-A.
  • the D-ring may include the conventional D 3 substitution or any other known modification thereof. See, for example
  • the preferred compound according to the invention is 1-hydroxymethyl-25-hydroxyvitamin D 3 represented by the formula:
  • a particularly preferred compound of the present invention is the compound YB represented by the formula:
  • Compound YB includes a hydroxyalkyl substituent in the 1-position and a modified D- ring side chain. As a result, compound YB demonstrates potent anti-proliferative activity comparable to that of calcitriol but has a VDR binding affinity of ⁇ 10 -3 relative to that of calcitriol.
  • the invention is not to be viewed as limited to these compounds as other hybrid analogues involving the attachment of one or more additional hydroxyalkyl groups on the ring-A, with various other modifications as substituents in the ring-D, are contemplated.
  • Figure 1 shows the growth inhibition of keratinocyte cell line PE by 1,25-dihydroxy vitamin D 3 and 1-hydroxymethyl homologues at 3 ⁇ M.
  • Figure 2A shows the inhibition of TPA-induced ornithine decarboxylase activity by pretreatment with 1,25-dihydroxy vitamin D 3 and 1- hydroxymethyl homologues.
  • Figure 2B shows a dose-response curve for the inhibition of TPA-induced ODC activity with the 1-hydroxymethyl vitamin D 3 diastereomers (-)-2 and (+)-3.
  • Figure 3 shows a first example of the dose-response effects of calcitriol, compound YA and compound YB on keratinocyte proliferation.
  • N 0 represents the number of cells at zero hours and N 1 represents the number of cells at 96 hours.
  • Figure 4 shows a second example of the dose-response effects of calcitriol, compound YA and compound YB on keratinocyte proliferation.
  • Figure 5 shows a comparison of the effects of 1,25(OH) 2 D 3 (calcitriol), compound YA and compound YB on the proliferation of RWLeu-4 human chronic myelogenous leukemic cells as a function of dose.
  • MCW-II5-y-A is compound YA and MCW-II5-y-B is compound YB.
  • Figure 6 shows a comparison of the effects of 1,25(OH) 2 D 3 (filled squares), YA (filled circles) and YB (filled triangles) on thymidine incorporation by human breast cancer cell lines MDA 468 ( Figure 6A) and SKBr 3 ( Figure 6B).
  • Figure 7 shows a comparison of the effects of calcitriol (filled circles), JK 276-1 (open triangles), JK 276-2 (filled triangles), JK 277-1 (open squares), and JK 277-2 (filled
  • Figure 8 shows a comparison of the inhibitory effects of YA, YB, JK 276-1, JK 276-2 JK 277-1 and JK 277-2 on growth of HL-60 cells.
  • YA and YB were at concentrations of 10 -7 M; the other compounds were at concentrations of 10 -6 M.
  • halogen-free bicyclic lactone product is the synthetic equivalent of the product derived from 2-pyrone itself cycloadding to acrolein, a Diels-Alder reaction that requires high pressures and that cannot be accomplished simply by heating because of loss of CO 2 from the lactone bridge.
  • dienoate esters 10 were reduced, chlorinated, converted into the corresponding phosphines, and finally oxidized to give ring-A phosphine oxides 11 as two enantiomers (11a and 11b) having almost equal but opposite specific rotations of approximately 54°.
  • (+)-8 from (+)-6a: [ ⁇ ] 0 23°C -47.1o (c 0.100, CH 2 CI 2 , d.e. 98.8%)
  • a borosilicate test tube was charged with 141.1 mg (0.31 mmol) of dienoate E-10, 9.3 mg of 9-fluorenone, and 9.0 mL of tert-butyl methyl ether. The tube was sealed with a rubber septum, placed in a solution of 2 M sodium orthovanadate and irradiated with a medium pressure mercury arc lamp for 16 hours.
  • DIBAL-H diisobutylaluminum hydride
  • reaction mixture was quenched with 0.5 mL of 2 N sodium potassium tartrate, diluted with methylene chloride, separated, and the organic portion dried over an hydrous magnesium sulfate. Purification by PTLC (2 ⁇ 1000 ⁇ ), (2 elutions) 10% ethyl
  • tetrahydrofuran evaporated, diluted with 10 mL of methylene chloride, 6 drops of 30% hydrogen peroxide were added, and then rapidly stirred for 10 minutes. This was diluted with methylene chloride, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated.
  • the C,D ring ketone 12 was also
  • the 1-hydroxymethyl derivatives of the invention have been compared with calcitriol for biological activity.
  • the compounds were tested for growth inhibition of murine keratinocyte cells (cell line PE) and for the inhibition of
  • the cell line PE was derived from a papilloma induced in female SENCAR mice by a standard skin initiation/promotion protocol
  • the PE cell line culture medium used in the tests consisted of Eagle's minimal essential medium without calcium chloride supplemented with 8% chelexed fetal calf serum and 1% antibiotic-antimycotic and the addition of CaCl 2 to 0.05 mM Ca ++ .
  • 1,25D3 (calcitriol) that are among the most active inducers of leukemic cell differentiation are shown below.
  • Table 1 shows the results of further investigations into the effect of the D-ring side chains on the inhibition of proliferation (Anzano et al., Cancer Research, 54: 1653-1656, 1994;
  • Hydroxy aldehyde 4 obtained from 520 mg of diol 3 (as described above) and contaminated with trace amounts of unidentified ruthenium
  • O 2 was bubbled through a solution of KO-t-Bu (0.43 mL, 0.43 mmol) in dry t-BuOH (0.942 mL, freshly distilled from CaH 2 ) for 10-15 min.
  • a solution of O-silylated aldehyde 5 (28.5 mg, 0.088 mmol) in 0.54 mL of t-BuOH was added and O 2 was bubbled through the solution for an additional 10 min. followed by N 2 for 15 min.
  • O-Silylated Ketone Ether 11 A flame dried 25 mL round bottomed flask equipped with a magnetic stirring bar was charged with 143 mg (0.28 mmol) of O-silylated ether 8, 7 mL THF, 20 mg of 4 angstrom powdered molecular sieves (oven-dried), and 510 mg (1.9 mmol, 7 equiv.) of tetrabutylammonium fluoride hydrate (TBAF). TBAF was added portionwise at room temperature and the progress of the reaction was monitored closely by TLC.
  • TBAF tetrabutylammonium fluoride hydrate
  • TMS-imidazole 0.32 mol, 2.2 mmol, 15 eguiv.
  • Racemic phosphine oxide 14 (60.4 mg, 0.1 mmol, 1.4 equiv.) was dissolved in 1 mL freshly distilled anhydrous THF and cooled to -78°C under an Ar atmosphere. To this was added 0.062 ml (0.112 mmol, 1.1 equiv.) of PhLi (1.8 M in Et 2 O) dropwise over 5 min. during which time a deep red-orange color developed and persisted. The mixture was allowed to stir an addition 7-8 min.
  • reaction mixture was immediately quenched at -78°C with 0.3 mL of 2N sodium potassium tartrate followed by addition of dilute aqueous potassium carbonate. After warming to room temperature, the reaction was extracted with EtOAc (3 ⁇ 20 mL), the organic portion was dried over MgSO 4 , filtered, concentrated, and purified by silica gel column chromatography (7% EtOAc/hexane) to afford 49.1 mg (0.063 mmol) of the crude coupled product in 90% yield from C-D ring (-)-11. This was immediately placed in a flame-dried 25 mL round bottomed flask and dissolved in 10 ml of freshly distilled anhydrous THF under argon.
  • bottomed flasks were equipped with magnetic stir bars, oven dried for 12 h, cooled in a desiccator, rinsed with benzene and evaporated on a rotary evaporator (3X), and held under high vacuum for 5- 6 h.
  • a 10 mL round bottomed flask was charged with 60.4 mg (0.1 mmol) of racemic phosphine oxide 14 (synthesized as previously reported 5 ) which was azeotropically dried with benzene (3 X), sealed with a rubber septum, kept under high vacuum for 5-6h, re-azeotroped with benzene added via syringe through the septum, and kept under high vacuum (0.05 mm Hg) overnight (approximately 12 h).
  • a 10 mL round bottomed flask was charged with 26.4 mg (0.07 mmol) of C-D ring (-)11 which was dried by the procedure described for racemic phosphine oxide 14.
  • 1,25(OH) 2 D 3 which has been proposed as a possible candidate for development as an anticancer agent and/or a drug for the treatment of immune related diseases is 20-epi-23-oxa-24a,24b-dihomo-1 ⁇ ,25-dihydroxyvitamin D3, also called MC 1357:
  • Tetrahydrofuran (THF) and diethyl ether (Et 2 O) were distilled from benzophenone ketyl prior to use.
  • Methylene chloride (CH 2 Cl 2 ) and triethylamine (NEt 3 ) were distilled from calcium hydride prior to use.
  • Commercially available anhydrous solvents were used in other instances. All reagents were purchased from Aldrich Chemical Co (Milwaukee, WI) and were used as received without further
  • FT-IR spectra were recorded using a Perkin-Elmer Model 1600 FT-IR spectrophotometer.
  • the 1 H and 13 C NMR spectra were recorded on a
  • GS 1500 antiproliferative and low calcemic activity, designated GS 1500 (see Grue-Sorensen et al., in Vitamin D, A Pluripotent Steroid Hormone:
  • Compounds JK 277-1 and JK 277-2 are further structural modifications of 1,25(OH) 2 D 3 , having a hydroxymethyl group in the 1-position and the side chain of compound GS 1500 attached to the D ring.
  • the structures of compound JK 277-1 and JK 277-2 are represented by the formulas:
  • the growth inhibition test was carried out as follows:
  • a mitochondrial dehydrogenase reduces MTT to a blue formazan product with an absorbance maximum of 505 nm in DMSO; the number of viable cells can thus be determined spectrophotometrically.
  • PE cells were seeded at a density of 5,000 cells/well in 50 ⁇ l medium into 96-well microtiter plates. Twelve hours later, the medium was removed, and cells were treated with 100 ⁇ l fresh medium into which the appropriate amount of vitamin D 3 or derivative dissolved in dimethyl sulfoxide (DMSO) had been added, with the
  • the A 505 was then determined and cell number calculated from
  • results from the MTT assay for the inhibition of cell growth were independently confirmed by treating 100 cm 2 dishes of cells in an analogous manner for 96 hours, whereupon the cells were harvested by trypsinization and counted. Further, the
  • the medium was removed and the dishes washed with ice cold phosphate-buffered saline (PBS).
  • PBS ice cold phosphate-buffered saline
  • the excess PBS was then removed and the dishes rinsed with an ice cold solution of pyridoxal phosphate in PBS (50 ⁇ g/ml).
  • the excess liquid was removed, and the dishes were frozen at -80°C.
  • the dishes were scraped into Eppendorf tubes while still partially frozen, and the cells further lysed by freeze-thawing for generation of the 12,000 x g cytosol.
  • Figure 1 graphically shows the growth inhibition of keratinocyte cell line PE by vitamin D 3 and 1-hydroxymethyl homologues at 3 ⁇ M. The values shown represent the mean from 12 wells + S.D. Arrows indicate administration of fresh medium into which the compounds dissolved in DMSO had been added. Control cells were treated with DMSO alone (0.1% in culture medium). The-treated values are significantly different from the solvent control at 72 and 96 hours (p ⁇ 0.001, Student's t-test).
  • FIGS. 2A and 2B illustrate the inhibition of TPA-induced ornithine decarboxylase activity by pretreatment with vitamin D 3 and
  • Fig. 2A shows
  • Fig. 2B shows a dose-response curve for the inhibition of TPA-induced ODC activity with the
  • ODC decarboxylase
  • This enzyme can be induced rapidly and dramatically by many growth stimuli, including the tumor promoter TPA (Annu. Rev. Biochem.,
  • TPA TPA to induce ODC
  • Figure 2A shows the effects of vitamin D 3 and its 1-hydroxymethyl derivatives on the TPA-stimulated ODC activity in vi tro .
  • the potency of the three compounds as inhibitors of the effects of TPA on this enzyme were not
  • FIG. 2B illustrates the similar dose-response
  • VDR 1,25(OH) 2 -vitamin D 3 receptor
  • VDR binding assay was performed according to the procedure of Reinhardt, T.A., Horst, R.L., Orf, J.W., Hollis, B.W., J . Clin . Endocrin .
  • Compound YB is designated MCW-II-5yb in Table 3. These results show the amount of each compound that results in 50% displacement of [ 3 H]- 1,25(OH) 2 D 3 from the calf thymus VDR. Compound YB bound about 1300 times less strongly than
  • Figures 3 and 4 are separate examples showing the effects of various concentrations of the compound YB and calcitriol on cell
  • the calcium channel opening assay was performed according to the procedure of
  • compound YB is a potent anti-proliferative and differentiation inducing analogue of vitamin D 3 with both anti-proliferative and differentiation inducing activity comparable to that of calcitriol. Additional confirmation of the anti- proliferative activity of compound YB is shown in Figure 5. Treatment of RWLeu-4 human CML cell line with compound YB resulted in an anti- proliferative effect comparable to or slightly greater than that of calcitriol, even at 50 nM.
  • Compound YB is designated as MCW-II5-Y-B and calcitriol as 1,25-(OH) 2 -D 3 in Table 4. These results show that compound YB is similar to calcitriol in its ability to open calcium channels in an instantaneous non-genomic fashion.
  • Figures 6A and 6B provide data on the ability of compounds YA and YB to inhibit growth in human breast cancer cells, as evidenced by suppression of thymidine incorporation. It can be seen in this regard that YB is very comparable to
  • YB like 1,25(OH) 2 D 3 , is effective in inducing cell differentiation at a concentration of 10 -8 M, whereas YA is inactive at 10 -7 M.
  • compound YB is a vitamin D 3 analogue having a hydroxyalkyl substituent in the 1-position and a modified D-ring side chain. This novel compound exhibits a wide spread between the ratings for proliferation inhibition plus
  • compositions of this invention should prove valuable as therapeutic agents in diseases such as psoriasis and cancer wherein regulation of cell proliferation is an important aspect of treatment.

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Abstract

On décrit des analogues de la vitamine D3 qui comprennent un substituant hydroxyalkyle dans la position 1, ainsi qu'une chaîne latérale à noyau D modifié. Ces nouveaux composés constituent des substances antiprolifératives puissantes possédant une activité comparable à celle du calcitriol, mais avec un taux de fixation au récepteur de la vitamine D3 qui est approximativement de l'ordre de 10-3 par rapport à celui du calcitriol.
PCT/US1996/003626 1995-03-31 1996-03-28 Analogues de la vitamine d3 substitues en position 1 WO1996030338A1 (fr)

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US08/413,729 1995-03-31

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999011272A1 (fr) * 1997-09-02 1999-03-11 Johns Hopkins University School Of Medicine Formulations polymeres chargees en analogues de vitamine d3 destinees au traitement du cancer et des troubles neurodegeneratifs
ES2714628A1 (es) * 2017-11-29 2019-05-29 Univ Santiago Compostela Compuestos derivados de la vitamina D

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5274142A (en) * 1992-03-12 1993-12-28 The Johns Hopkins University Vitamin D3 analogues

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5274142A (en) * 1992-03-12 1993-12-28 The Johns Hopkins University Vitamin D3 analogues

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, Volume 3, No. 9, issued 1993, MARTIN J. CALVERLEY et al., "Synthesis and Biological Evaluation of MC 1357, A New 20-Epi-23-Oxa-1alpha,25-Dihydroxy-Vitamin D3 Analogue with Potent Non-Classical Effects", pages 1845-1848. *
PROCEEDINGS OF THE NINTH WORKSHOP ON VITAMIN D, issued 1994, GUNNER GRUE-SORENSEN, "Chemistry and Biology of 23-Oxa-Aro- and 23-Thia-Aro-Vitamin D Analogues with High Antiproliferative and Low Calcemic Activity", pages 75-76. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999011272A1 (fr) * 1997-09-02 1999-03-11 Johns Hopkins University School Of Medicine Formulations polymeres chargees en analogues de vitamine d3 destinees au traitement du cancer et des troubles neurodegeneratifs
ES2714628A1 (es) * 2017-11-29 2019-05-29 Univ Santiago Compostela Compuestos derivados de la vitamina D

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