EP1034178A1 - Phosphoethanolamin-konjugate von vitamin d- verbindungen - Google Patents

Phosphoethanolamin-konjugate von vitamin d- verbindungen

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Publication number
EP1034178A1
EP1034178A1 EP97948592A EP97948592A EP1034178A1 EP 1034178 A1 EP1034178 A1 EP 1034178A1 EP 97948592 A EP97948592 A EP 97948592A EP 97948592 A EP97948592 A EP 97948592A EP 1034178 A1 EP1034178 A1 EP 1034178A1
Authority
EP
European Patent Office
Prior art keywords
vitamin
methyl
hydrogen
formula
phosphocholine
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.)
Ceased
Application number
EP97948592A
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English (en)
French (fr)
Inventor
Andrew C. Peterson
Parvin T. Yazdi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clarion Pharmaceuticals Inc
Original Assignee
Clarion Pharmaceuticals Inc
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 Clarion Pharmaceuticals Inc filed Critical Clarion Pharmaceuticals Inc
Publication of EP1034178A1 publication Critical patent/EP1034178A1/de
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols

Definitions

  • the present invention relates to certain phosphoethanolamine conjugates of vitamin D compounds, pharmaceutically acceptable salts thereof, and to pharmaceutical compositions thereof.
  • novel compounds herein described possess anti-tumor, anti-psoriatic and anti-inflammatory activities.
  • Amidothiophosphates and glyceroamidothiophosphate derivatives of vitamin D 3 are known: S.D. Stamatov and S. Gronowitz, Lipids Vol. 25(3), pp. 149-151 (1990). Applicants are unaware of any phosphoethanolamine derivatives of vitamin D compounds.
  • Figure 1 is a graphical representation of results from an in vitro MDA-MB-231 Human Breast Cancer Cell inhibition assay of a compound of the invention, designated CPR 2005, in comparison with vitamin D 3 .
  • Figure 2 is a graphical representation of results from an in vitro HT-29 Human
  • Colon Cancer Cells inhibition assay of a compound of the invention designated CPR 2005, in comparison with vitamin D 3 .
  • Figure 3 is a graphical representation of results from an in vitro PAM-212 Mouse Keratinocytes inhibition assay of a compound of the invention, designated CPR 2005, in comparison with vitamin D 3 .
  • the present invention relates to novel phosphoethanolamine conjugates of vitamin D compounds, natural or synthetic, as represented by the general formula (I):
  • PEA together with the oxygen, bonded to both the PEA moiety and the vitamin D moiety, is phosphoethanolamine moiety of the formula: O
  • R 1 is hydrogen or methyl, provided that at least one R' is methyl;
  • R 2 represents hydrogen, mediyl, carbonyl or halogen (F, Cl, Br, I);
  • R 3 represents hydrogen or hydroxy
  • R" represents a radical of the formula:
  • A is hydrogen or methyl
  • C and D individually, are each hydrogen, C,.j alkyl, trifluoromethyl or cyclopropyl; C and D, together with the commonly bound carbon atom, is cyclopropyl; and E is hydrogen, methyl, methoxy, halogen (F, Cl, Br, I), trifluoromethoxy or, provided that either C or D is not hydrogen, hydroxy; and
  • the formula (I) compounds may be alternatively denoted as "R-O-PEA ", a vitamin D moiety conjugated at the 3-hydroxy position with the defined phosphoethanolamine moiety, wherein R represents the vitamin D moiety and -O-PEA represents the defined phosphoethanolamine moiety.
  • R represents the vitamin D moiety
  • -O-PEA represents the defined phosphoethanolamine moiety.
  • Vitamin D for example, .vitamins D,, D 2 , D ⁇ , and D 4 .
  • trivial names for each have been reported.
  • cholecalciferol or calciol also known as vitamin D 3
  • calciferol also known as vitamin D 2
  • calcitriol also known as la, 25-dihydroxyvitaminD 3
  • la, 25-dihydroxyvitaminD 3 is chemically denoted as (l ⁇ , 30, 5Z, 7E)-9,10-secochole_ta-5,7, 10(19)- trie ⁇ e-l,3,25-triol.
  • vitamin D in the term “vitamin D compound” or “vitamin D moiety” is used in the same broad context as set forth in said reference, to wit:
  • vitamin D should be used as a general term to describe all steroids that exhibit qualitatively the biological activity of calciol. The term should be used in derived terms such as vitamin D activity, vitamin D deficiency, vitamin D antagonist. "
  • R in formula (I) is derived from the corresponding vitamin D compound having a hydroxyl (-OH) in the 3-position, including all possible stereo isomeric and geometrically isomeric forms due to the asymmetric carbon atoms and the cis or trans configuration at double-bonds inherent in the vitamin D structure.
  • Said vitamin D compounds with a hydroxy in the 3-position constitute the starting materials (A) used in preparing the subject phosphoethanolamine conjugates of vitamin D. Representative starting materials are identified in the following Table 1.
  • the invention also comprehends salts of the formula (I) compounds and all isomeric forms thereof.
  • These salts include acid addition salts, such as, for example, those made with hydrochloric, hydrobromic, nitric, sulfiiric, phosphoric, carbonic, acetic, citric or lactic acids.
  • the salts may also include those made with bases, such as, for example, sodium hydroxide, potassium hydroxide or calcium hydroxide.
  • the salts of the invention are made by conventional methods well known to the skilled.
  • the salts for therapeutic use of the formula (I) compounds are pharmaceutically acceptable salts, as understood in the art.
  • the compounds of the present invention (I) may be prepared by the one-step procedure outlined in the following Reaction Scheme.
  • the symbols R 2 , R 3 , R 4 , R 5 and PEA are as previously defined.
  • the thus-obtained compounds in the Reaction Scheme may be purified by conventional methods of the art, e.g. chromatography, recrystallization, etc.
  • the compounds of formula (I) have asymmetric carbon atoms (Cl, C3, C13, C14, C17, C20, and C25 positions in the secocholestatriene backbone) and in carbon atoms within R 4 in their structure and consequently they may exist in the form of different stereo isomeric forms (diastereomers) or racemates.
  • Substantially pure forms of each diastereomer, or of each enantiomer of a particular diastereomer may be obtained, substantially free of the others by the application of art known resolution methodologies such as, for example, by selective crystallization or column chromatography, or by starting their preparation from the appropriate isomeric precursor.
  • the compounds of formula (A) are known in the literature or are obtainable by art recognized procedures, for example, Wolfgang, J. Synform 1987, 5(2), 41-122;Wolfgang, J. Synform 1986, 4 ⁇ 3), 131-250; Wolfgang, J. Synform 1987, 5(1), 1-86; Stork, G., Hutchinson, D. , Okabe, M., Parker, D., Choonsup, R., Ribereau, F, Suzuki, T., Zebovitz, T. Pure Appl. Chem. 1992, 64(12), 1806-1812; Posner, G, Johnson, N. J. Org. Chem. 1994, 59, 7855-7861; Posner, G.
  • the phosphoethanolamine moiety (PEA) is introduced into Compound (A) by the selective reaction of the 3-hydroxyl group in Compound (A) with 2-chloro-2-oxo-l,3,2- dioxaphospholane in an inert organic aprotic solvent, such as, for example, toluene (preferred), benzene, chloroform, diethyl ether, dioxane and the like, followed by reaction with an appropriate amine N(R') 3 , to yield the desired compound (I).
  • an inert organic aprotic solvent such as, for example, toluene (preferred), benzene, chloroform, diethyl ether, dioxane and the like
  • the compounds of the subject invention (I) and pharmaceutically acceptable salts thereof are useful chemopreventative and adjuvant agents in several aspects. They are advantageously administered to ameliorate conditions associated with vitamin D deficiency, for example, rickets in children and osteomalacia in adults. In addition, they are useful for the treatment of cancerous tumors and also for treating inflammation and hyperproliferative skin diseases such as psoriasis.
  • the subject compounds may be used alone for such indications or in combination with other compatible medicaments.
  • the following testing procedure using the identified human breast and human colon carcinoma cell lines in an in vitro assay, demonstrates the marked anti-tumor (or antineoplastic) activity of the subject compounds.
  • ATC American Type Culture Collection: a. MDA-MB-231 (ATCC HTB-26): an estrogen receptor negative human breast carcinoma cell line (attachment dependent); and b. HT-29 (ATCC HTB-38): a human colon carcinoma cell line (attachment dependent).
  • DMEM Dulbecco's Modified Eagle's Medium
  • FBS Fetal Bovine Serum
  • DMEM/F12 1:1 DMEM and Ham's F-12 (DMEM/F12) plus 10% FBS.
  • Methodology a. After cell passage, count cells with a hemacytometer; b. Adjust cell concentration to approximately 5,000 cells per 100 ⁇ L; c. Pipette 100 ⁇ L cell suspension into each well of a standard 96-well microtiter plate; d. Preincubate 24 hours to allow cells to attach; e. Add test compound d ssolved in phosphate buffered saline (PBS), or in DMSO for the comparative compound, vitamin D 3 , for final concentration levels ranging from 0 to 100 ⁇ M; f. Adjust volume to 200 ⁇ L per well by adding culture media without FBS; and g. Incubate 48 hours under standard culture conditions and determine end point.
  • PBS phosphate buffered saline
  • DMSO DMSO
  • End Point a. Remove media and add 100 ⁇ L per well of cold (4°C) 10% (w/v) trichloroacetic acid (TCA) in water; b. After 1 hour at 4 C C, remove TCA and rinse cells 5 times with tap water; c. Air-dry plates; d. Add 50 ⁇ L per well of 0.4% (w/v) sulforhoda ine B (SRB) in 1 % (v/v) acetic acid in water; e. After 30 minutes at room temperature, rinse cells 4 times with 1 % (v/v) acetic acid in water to remove residual stain; f. Air-dry plates; g. Dissolve stain by adding 100 ⁇ L per well of unbuffered Tris base, pH 10.5; h. Read absorbance at 562 n using ' a standard 96-well microtiter plate reader.
  • Absorbance readings are linear with dye concentrations below 1.8 absorbance units. To reduce absorbance, decrease wavelength at which measurements are taken; i. Data Analysis: single point reading: the higher the absorbance, the higher the cell number; control - no test compound present in culture medium; background - no cell present, no test compound present in culture medium; initial control cell number (ICCN) - no test compound present in culture medium, end point was determined at the time of treatment; final control cell number (FCCN) - no test compound present in culture medium, end point was determined at 72 hours after treatment; final cell number (FCN) - test compound present in culture medium, end point was determined at 48 hours after treatment; calculate:
  • ICCN A(control, zero hour)-A(background)
  • FCCN A(control, 48 hours)-A(background)
  • FCCN - ICCN where A is absorbance
  • Results are represented in Figures 1 and 2, which illustrate the marked inhibition of MDA- MB-231 cell growth at 100 ⁇ M and HT-29 cell growth at concentrations above 30 ⁇ M by
  • Anti-tumor activity is to be expected against a wide spectrum of mammalian (including human) tumors and cancerous growths such as cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, hver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, colon, breast, cervix, uteri, corpus endomet ⁇ um, ovary, prostate, testes, bladder, kidney and other urinary tissues, eye, brain and central nervous system, thyroid and other endocrine glands, leukemias (lymphocytic, granulacytic, monocytic), Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, etc.
  • tumors include cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), e
  • the instant invention thus provides a method of treating a tumor in a mammal afflicted with same comprising administering to said mammal an effective anti-tumor amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides pharmaceutical compositions comprising an effective anti-tumor amount of a Formula (I) compound or such salt and a pharmaceutically acceptable carrier.
  • Psoriasis is a chronic inflammatory dermatosis characterized, in part, by hyper- proliferation of keratinocytes and release of pro-inflammatory cytokines. Compounds that reduce hype ⁇ roliferation of keratinocytes in vitro are likely to have utility in the control of psoriasis. As will be shown, using the assay described below with the illustrative compound CPR-2005, the compounds of Formula (I) markedly inhibit proliferation of these cells in vitro, thus indicating that these compounds are useful in ameliorating psoriasis.
  • Cell line PAM-212 murine keratinocyte cell line isolated and cultivated from newborn
  • mice see S. H. Yuspa et al., Cancer Research, Vol. 40, pp. 4694-4703, December, 1980) that appears to retain many characteristics of normal keratinocytes.
  • Methodology is the same as that described in part 4 of the assay protocol for anti-tumor activity, except that, with reference to part 4(b) of the assay protocol for anti-tumor activity, cell concentration in this case is adjusted to 1,000 cells per 100 ⁇ L (rather than 5,000 cells per 100 ⁇ L).
  • the instant invention thus provides a method of treating psoriasis in a mammal inflicted with same comprising administering to said mammal an effective anti-psoriatic amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. It also provides pharmaceutical compositions comprising an effective anti-psoriatic amount of a compound of Formula (I) or such salt and a pharmaceutically acceptable carrier.
  • Inflammation is a complex process, involving a variety of cell types including macrophages, for example, see S.L. Kunkel, "Inflammatory Cytokines", pp. 1-15, in Manual of Vascular Mediators, P.A. Ward, Editor, produced by the publishers of Hospital Practice. References relative to macrophages are numerous, including, for example, J. Immunology Vol. 119, pp. 950-954
  • Macrophages are activated by infection and by a wide variety of non-infectious irritants and proinflammatory agents. Upon activation, macrophages participate in a variety of reactions. They may phagocytize bacteria and kill them by either oxygen-dependent or -independent pathways. With respect to the oxygen-dependent pathways, activation of macrophages induces them to increase oxygen consumption and produce reactive oxygen species (for example, radicals such as superoxide). Production of reactive oxygen species by activated macrophages is associated with inflammatory responses. In addition, on activation, macrophages release a variety of inflammatory cytokines, including several interleukins and tumor necrosis factor a (TNF ⁇ ). Inhibition of any of these activation-related processes can lead to reduced inflammation.
  • TNF ⁇ tumor necrosis factor a
  • the RAW 264.7 cell line (available from the ATCC under accession no. TIB 71) is a murine monocyte/macrophage line the cells of which show many of the differentiative functions of a macrophage. Like macrophages, the cells are capable of phagocytosis and undergo an oxidative burst (increased oxygen consumption) and production of oxygen radicals (e.g., superoxide) in response to appropriate signals.
  • Oxionionase oxygen radicals
  • Agents that inhibit the activation of these cells in vitro, so as to inhibit the respiratory burst and corresponding production of oxygen radicals associated with the activation are therefore inhibitors of macrophage activation and critical steps in inflammatory processes.
  • the respiratory burst and corresponding production of oxygen radicals that accompany macrophage activation can be measured in a variety of ways, including chemiluminescence based on the reaction of the oxygen radicals with luminol added to the culture medium (see M.A. Trush et al., 1978, "The Generation of Chemiluminescence by Phagocytic Cells.” Methods in Enzymology 57: 462-494). Indeed, chemiluminescence generated from luminol in the culture medium of macrophage cell lines is recognized in the art as a marker of macrophage activation.
  • EDTA (1 ⁇ M in ca-MG free Hank's balanced salt solution); at a 1:4 to 1:5 split; b. All procedures are performed aseptically in a class II biological safety cabinet using standard BL-2 containment procedures. In order to prevent genetic drift in stock cell lines, fresh cultures are prepared at approximately monthly intervals with cells thawed from liquid nitrogen storage.
  • Methodology a. After cell passage, count cells with a hemacytometer; b. Adjust cell concentration to approximately 1,000,000 cells per mL; c. Suspend cells in DMEM lacking phenol red and without FBS; d. Pipette 1 mL of cell suspension into a standard luminometer cuvet (12 x 75), commercially obtainable from Analytical Luminescence Laboratories, San Diego,
  • Results are represented in Table 1, which indicates the marked inhibition of luminescence by CPR 2005 at concentrations above 1 ⁇ M.
  • mice Male CD-I , 21-24 g (Product Number 3002) obtainable from Harlan Sprague
  • mice Dawley, Indianapolis, IN, USA; 2. Methodology: a. Prepare 0.01 % (w/v) PMA in a mixture of equal volumes of acetone and ethanol; b. Prepare 0.01% (w/v) PMA and 5% (w/v) test compound in a mixture of equal volumes of acetone and ethanol; c. Divide 9 mice into 3 groups of 3 mice each; d. Leave one group of mice untreated; e. Treat the second group of mice by applying 20 ⁇ L of PMA solution to both ears using a micropipetter; f. Treat the third group of mice by applying 20 ⁇ L of PMA solution to the right ear and 20 ⁇ L of PMA/test compound solution to the left ear; g. Wait 6 hours and euthanize the mice in a CC_ chamber h. Cut the ears and punch out circles of 6-mm diameter; and
  • Results are represented in Table 2, which shows the marked inhibition of PMA-induced inflammation in mouse ear by CPR 2005.
  • the subject compounds are useful in the treatment of acute and chronic inflammatory diseases, such as, for example, dermatitis, conjunctivitis, bursitis, rheumatoid arthritis and the like.
  • the instant invention thus provides a method of treating inflammation in a mammal afflicted with same comprising administering to said mammal an effective anti-inflammatory amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. It also provides pha ⁇ naceuticai compositions containing an effective anti-inflammatory amount of a Formula (I) compound or such salt and a pharmaceutically acceptable carrier.
  • compositions of the present invention comprise an active compound, i.e., a Formula (I) compound or a pharmaceutically acceptable salt thereof, together with an acceptable carrier for it and optionally other therapeutically active ingredients.
  • the carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal or parenteral (including subcutaneous, intramuscular, intrader al and intravenous), nasal, or bronchial administration. Preferred are those suitable for oral or parenteral administration. Topical formulations are also included, for example, for anti-psoriatic usage.
  • Formula (I) compounds typically decompose on heating above 200°C. This characteristic may need to be taken into consideration in, for example, preparing tablets on a commercial scale where the heat of compression may be a factor.
  • the Formula (I) compounds are also rather insoluble in water and, accordingly, liquid formulations which account for this factor may be made according to art-recognized pharmaceutical techniques.
  • Examples of these techniques include an injection wherein the active compound is dissolved in a suitable solvent or co-solvent such as an appropriate polyethylene glycol, or a propylene glycol or the like; a sealed gelatin capsule enclosing an oily solution of the active compound; a suppository of the active compound in a conventional suppository base such as cocoa butter; or a liposome formulation, for example, the active compound and a glycerophospholipid such as phosphatidylcholine.
  • a suitable solvent or co-solvent such as an appropriate polyethylene glycol, or a propylene glycol or the like
  • a sealed gelatin capsule enclosing an oily solution of the active compound
  • a suppository of the active compound in a conventional suppository base such as cocoa butter
  • a liposome formulation for example, the active compound and a glycerophospholipid such as phosphatidylcholine.
  • the aforementioned characteristics of the Formula (I) compounds are
  • formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include die step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid or solid carrier and then, if necessary, shaping the product into desired unit dosage form.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units sucb as capsules, cachets, tablets, boluses or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or in liquid form, e.g.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, surface active or dispersing agents.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.
  • Formulations suitable for parenteral administration conveniently comprise a sterile preparation of the active compound in, for example, a polyethylene glycol 200 or propylene glycol solution which is preferably isotonic with the blood of the recipient.
  • Useful formulations also comprise concentrated solutions or solids containing the compound of Formula (I) which upon dilution with an appropriate solvent give a solution suitable for parenteral administration.
  • Preparations for topical or local applications which are, for example, conventional for anti-psoriatic usage, comprise aerosol sprays, lotions, gels, ointments, etc. and pharmaceutically acceptable vehicles therefore such as, for example, lower aliphatic alcohols, polyglycerols such as glycerol, polyethyleneglycerol, esters of fatty acids, oils and fats, silicones, and other conventional topical carriers.
  • pharmaceutically acceptable vehicles therefore such as, for example, lower aliphatic alcohols, polyglycerols such as glycerol, polyethyleneglycerol, esters of fatty acids, oils and fats, silicones, and other conventional topical carriers.
  • the compounds of Formula (I) are preferably utilized at concentrations of from about 0.1 % to about 5.0% percent by weight.
  • the formulations of this invention may further include one or more optional accessory ingredients(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
  • the compounds of Formula (I) and salts thereof of the invention are intended to be administered under the guidance of a physician or veterinarian.
  • the amount of compound of Formula (I) or salt thereof required to be effective for each of the herein indicated activities will, of course, vary with the individual mammal being treated and is ultimately at the discretion of the medical or veterinary practitioner.
  • the factors to be considered include the condition being treated, the route of administration, the nature of the composition, the mammal's species and sex, the mamma s body weight, surface area, age and general condition, and the particular compound or salt to be administered.
  • the pharmaceutical compositions of this invention contain from about 0.5 to about 500 mg and, preferably, from about 5 to about 350 mg of the active ingredient, preferably in a unit dosage form, for each of the indicated activities.
  • a suitable effective dose is in the range of about 0.1 to about 200 mg/kg body weight per day, preferably in the range of about 1 to about 100 mg/kg per day, calculated as the non-salt form of Formula (I).
  • the total daily dose may be given as a single dose, multiple doses, e.g., two to six times per day, or by intravenous infusion for a selected duration Dosages above or below the range cited above are within the scope of the present invention and may be administered to the individual patient if desired and necessary.
  • a dose range would be about 7.5 to about 1500 mg per day, and a typical dose would be about 800 mg per day. If discrete multiple doses are indicated, treatment might typically be 200 mg of a compound of Formula (I) given 4 times per day.
  • Solutions of the subject compounds (I) in PBS have characteristics indicative of the presence of liposomes. These preparations require sonication in order to form uniform, cloudy suspensions. The requirement for sonication and the cloudy appearance of the suspensions are some known properties of liposomal preparations. Additionally, foam generation, which is associated with miceliar suspensions, is not a property of these preparations. Hence, unlike vitamin D 3 , the subject compounds are capable of forming liposomes.
  • Neat 4-chloro-2-oxo-l,3,2-dioxaphospholane(0.81 g, 5.72 mmol) is added in one portion to a stirred, mixture of (5Z,7E)-(3S)-9, 10-secocholesta-5,7, 10(19)-trien-3-ol (2.0 g, 5.2 mmol), commercially obtained from Spectrum Chemical Manufacturing Corp., Gardena, California, and triethylamine (0.84 mL, 5.76 mmol) in anhydrous toluene (80 mL) at room temperature under a nitrogen atmosphere. The resultant mixture is stirred at room temperature for four days. The white solid which precipitates is filtered off and washed wi ⁇ dry toluene.
  • the toluene filtrate is concentrated in vacuo to leave a viscous residue which is further dried under high vacuum. Then, a mixture of tiimethylamine (6.24 g) in acetonitrile (dried by distillation over phosphorus pentoxide, 65 mL) is added to the residue. The flask which contains the residue and tiimethylamine in acetonitrile is sealed by tightly connecting glass stoppers with wire and is then heated with stirring to 60-70°C for 24 hours. Upon cooling, a white solid precipitates. The mixture is put into a refrigerator for 24 hours to further crystallize. The white solid is filtered from the cold solution and is washed sequentially with dry acetonitrile and then acetone.
  • Example 1 The procedure of Example 1 is followed, except that an equivalent amount of each vitamin D compound in Table 1, from 2 to 7, is used as the starting material to yield, as respective products, the corresponding 3-phosphocholine derivative of formula (I):

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP97948592A 1997-11-24 1997-11-24 Phosphoethanolamin-konjugate von vitamin d- verbindungen Ceased EP1034178A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1997/021931 WO1999026953A1 (en) 1997-11-24 1997-11-24 Phosphoethanolamine conjugates of vitamin d compounds

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EP1034178A1 true EP1034178A1 (de) 2000-09-13

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BR102016008247A2 (pt) * 2016-04-13 2017-10-17 Acolli S.A. Food supplement based on 2-aminoethanol dihydrogenophosphate and synthesis process

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AU614372B2 (en) * 1988-04-21 1991-08-29 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Novel vitamin d analogues
GB8904153D0 (en) * 1989-02-23 1989-04-05 Leo Pharm Prod Ltd Chemical compounds
DE4334154C2 (de) * 1993-10-01 1997-05-22 Schering Ag 2-Halogeno-1,25-dihydroxy-cholecalciferole und pharmazeutische Zusammensetzungen
US5691328A (en) * 1996-02-02 1997-11-25 Clarion Pharmaceuticals Inc. Phosphoethanolamine conjugates of vitamin D compounds
US5661138A (en) * 1996-10-03 1997-08-26 Clarion Pharmaceutical, Inc. (o-Acyl-p-N-acylamino-phenyl)-O-phosphoethanolamines

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Title
See references of WO9926953A1 *

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