US20060293291A1 - 2-Propylidene-19-nor-vitamin d compounds - Google Patents

2-Propylidene-19-nor-vitamin d compounds Download PDF

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US20060293291A1
US20060293291A1 US10/544,163 US54416304A US2006293291A1 US 20060293291 A1 US20060293291 A1 US 20060293291A1 US 54416304 A US54416304 A US 54416304A US 2006293291 A1 US2006293291 A1 US 2006293291A1
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hydroxypropylidene
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Hector Deluca
Rafal Sicinski
Agnieszka Glebocka
Lori Plum
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Definitions

  • the present invention relates to vitamin D compounds, and more particularly, to 2-alkylidene-19-nor-vitamin D analogs having a substituted propylidene moiety at carbon-2,pharmaceutical uses for such analogs, and a general method for chemically synthesizing such analogs.
  • the natural hormone 1 ⁇ ,25-dihydroxyvitamin D 3 and its analog in the ergosterol series i.e. 1 ⁇ ,25-dihydroxyvitamin D 2 are known to be highly potent regulators of calcium homeostasis in animals and humans, and more recently their activity in cellular differentiation has been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987).
  • Many structural analogs of these metabolites have been prepared and tested, including 1 ⁇ -hydroxyvitamin D 3 , 1 ⁇ -hydroxyvitamin D 2 , various side chain homologated vitamins and fluorinated analogs.
  • Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
  • a class of 1 ⁇ -hydroxylated vitamin D compounds not known heretofore are the vitamin D isomers having the A-ring exocyclic methylene moiety at C-10 removed and possessing an additional fragment, being a substituted propylidene group, attached to carbon-2.
  • the present invention is directed toward 2-alkylidene-19-nor-vitamin D analogs having a substituted propylidene moiety at carbon-2, various pharmaceutical uses for these analogs, and a general method for chemically synthesizing these analogs.
  • the present invention is directed toward the E-isomer and Z-isomer of (20R)-1 ⁇ ,25-dihydroxy-2-[3′-hydroxypropylidene]-19-norvitamin D 3 as well as the E-isomer and Z-isomer of (20S)-1 ⁇ ,25-dihydroxy-2-[3′-hydroxypropylidene]-19-norvitamin D 3 . Also disclosed is 2-[(3′-methoxymethoxy)propylidene]-19-nor-1 ⁇ ,25-(OH) 2 D 3 .
  • R can represent a saturated or unsaturated hydrocarbon radical of 1 to 35 carbons, that may be straight-chain, branched or cyclic and that may contain one or more additional substituents, such as hydroxy- or protected-hydroxy groups, fluoro, carbonyl, ester, epoxy, amino or other heteroatomic groups.
  • Preferred side chains of this type are represented by the structure below where the stereochemical center (corresponding to C-20 in steroid numbering) may have the R or S configuration, (i.e.
  • carbon 20 may have either the R or S configuration, i.e. the natural configuration (20R) or the unnatural 20-epi configuration (20S).
  • the wavy line to the carbon 1′ indicates possibility of two geometrical isomers of 2-propylidene unit (differing in the orientation of substituents of terminal carbon atoms in the A-ring 1,4-dimethylenecyclohexane fragment).
  • side chains with natural 20R-configuration are the structures represented by formulas (a), (b), (c), (d) and (e) below. i.e. the side chain as it occurs in 25-hydroxyvitamin D 3 (a); vitamin D 3 (b); 25-hydroxyvitamin D 2 (c); vitamin D 2 (d); and the C-24 epimer of 25-hydroxyvitamin D 2 (e).
  • novel 2-propylidene-19-nor vitamin D compounds of structure I exhibit a desired, and highly advantageous, pattern of biological activity.
  • These compounds are characterized by relatively high intestinal calcium transport activity, i.e. similar to that of 1 ⁇ ,25-dihydroxyvitamin D 3 , while also exhibiting relatively high activity, as compared to 1 ⁇ ,25-dihydroxyvitamin D 3 , in their ability to mobilize calcium from bone.
  • these compounds are highly specific in their calcemic activity.
  • Their preferential activity on intestinal calcium transport and calcium mobilizing activity allows the in vivo administration of these compounds for the treatment and prophylaxis of metabolic bone diseases where bone loss is a major concern.
  • these compounds would be preferred therapeutic agents for the treatment and prophylaxis of diseases where bone formation is desired, such as osteoporosis, especially low bone turnover osteoporosis, steroid induced osteoporosis, senile osteoporosis or postmenopausal osteoporosis, as well as osteomalacia and renal osteodystrophy.
  • the compounds may be administered transdermally, orally or parenterally.
  • the compounds may be present in a pharmaceutical composition in an amount from about 0.01 ⁇ g/gm to about 100 ⁇ g/gm of the composition, preferably from about 0.1 ⁇ g/gm to about 50 ⁇ g/gm of the composition, and may be administered in dosages of from about 0.01 ⁇ g/day to about 100 ⁇ g/day, preferably from about 0.1 ⁇ g/day to about 50 ⁇ g/day.
  • the compounds of the invention are also especially suited for treatment and prophylaxis of human disorders which are characterized by an imbalance in the immune system, e.g. in autoimmune diseases, including multiple sclerosis, diabetes mellitus, lupus, host versus graft reaction, and rejection of transplants; and additionally for the treatment and prophylaxis of inflammatory diseases, such as rheumatoid arthritis, asthma, and inflammatory bowel diseases such as Crohn's disease or ulcerative colitis, as well as the improvement of bone fracture healing and improved bone grafts. It has also been discovered that these compounds increase breaking strength (cortical strength) as well as crushing strength (trabecular strength) of bones.
  • autoimmune diseases including multiple sclerosis, diabetes mellitus, lupus, host versus graft reaction, and rejection of transplants
  • inflammatory diseases such as rheumatoid arthritis, asthma, and inflammatory bowel diseases such as Crohn's disease or ulcerative colitis
  • these compounds increase breaking strength (cortical
  • these compounds could also be used in conjunction with bone replacement procedures such as hip replacements, knee replacements, and the like.
  • Acne, alopecia, skin conditions such as dry skin (lack of dermal hydration), undue skin slackness (insufficient skin firmness), insufficient sebum secretion and wrinkles, and hypertension are other conditions which may be treated with the compounds of the invention.
  • the above compounds are also characterized by high cell differentiation activity.
  • these compounds also provide therapeutic agents for the treatment of psoriasis, or as an anti-cancer agent, especially against leukemia, colon cancer, breast cancer, skin cancer and prostate cancer.
  • the compounds may be present in a composition to treat psoriasis in an amount from about 0.01 ⁇ g/gm to about 100 ⁇ g/gm of the composition, preferably from about 0.1 ⁇ g/gm to about 50 ⁇ g/gm of the composition, and may be administered topically, transdermally, orally or parenterally in dosages of from about 0.01 ⁇ g/day to about 100 ⁇ g/day, preferably from about 0.1 ⁇ g/day to about 50 ⁇ g/day.
  • E-isomer and Z-isomer of both the (20R) and (20S) isomers of 1 ⁇ ,25-dihydroxy-2-[3′-hydroxypropylidene]-19-norvitamin D 3 have been synthesized and their binding, transcriptional, calcemic (both intestinal calcium transport and bone calcium mobilization) and differentiation activities determined.
  • the E-isomer of this (20R) analog is characterized by the general formula Ia shown below and is referred to herein as “1AGR”: Structurally, the Z-isomer of this (20R) analog is characterized by the general formula Ib shown below and is referred to herein as “2AGR”: Structurally, the E-isomer of this (20S) analog is characterized by the general formula Ic shown below and is referred to herein as “1AGS”: Structurally, the Z-isomer of this (20S) analog is characterized by the general formula Id shown below and is referred to herein as “2AGS”:
  • Another 2-propylidene compound that has been synthesized is 2-[(3′-methoxymethoxy)propylidene]-19-nor-1 ⁇ ,25-dihydroxyvitamin D 3 , and its binding, transcriptional, calcemic (both intestinal calcium transport, and bone calcium mobilization) and differentiation activities were determined.
  • this analog is characterized by the general formula Ie shown below, and is referred to herein as “F-Wit”:
  • the invention also provides a novel synthesis for the production of the end products of formula I, and specifically of formulae Ia through Id.
  • this invention provides novel intermediate compounds formed during the synthesis of the end products. Structurally, these novel intermediates are characterized by the general formulae V, VI, VII, VIII, IX and X below where Y 1 , Y 2 , Y 3 , and Y 4 , which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, and X may be an alkyl, hydrogen, hydroxy-protecting group, hydroxyalkyl, alkoxyalkyl and aryloxyalkyl.
  • FIG. 1 is a graph illustrating the relative activity of 1 ⁇ ,25-dihydroxyvitamin D 3 as well as the herein described and claimed 2-[(3′-methoxymethoxy)propylidene]-19-nor-1 ⁇ ,25-(OH) 2 D 3 (F-Wit) in binding to the 1 ⁇ ,25-dihydroxyvitamin D pig intestinal nuclear receptor;
  • FIG. 2 is a graph illustrating the relative activity of 1 ⁇ ,25-dihydroxyvitamin D 3 as well as the herein described and claimed E-isomer of 2-(3′-hydroxypropylidene)-19-nor-1 ⁇ ,25-(OH) 2 D 3 (1AGR), the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-(20S)-1 ⁇ ,25-(OH) 2 D 3 (1AGS), the Z-isomer of 2-(3′-hydroxypropylidene)-19-nor-1 ⁇ ,25-(OH) 2 D 3 (2AGR), and the Z-isomer of 2-(3′-hydroxypropylidene)-19-nor-1 ⁇ ,25-(OH) 2 D 3 (2AGS);
  • FIG. 3 is a graph illustrating the percent HL-60 cell differentiation as a function of the concentration of 1 ⁇ ,25-dihydroxyvitamin D 3 , (20S)-2-methylene-19-nor-1 ⁇ ,25-dihydroxyvitamin D 3 (2MD) and the herein described and claimed 2-[(3′-methoxymethoxy)propylidene]-19-nor-1 ⁇ ,25-(OH) 2 D 3 (F-Wit), the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-1 ⁇ ,25-(OH) 2 D 3 (1AGR), and the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-(20S)-1 ⁇ ,25-(OH) 2 D 3 (1AGS);
  • FIG. 4 is a graph illustrating the transcriptional activity as a function of the, concentration of 1 ⁇ ,25-dihydroxyvitamin, (20S)-2-methylene-19-nor-1 ⁇ ,25-dihydroxyvitamin D 3 (2MD) and the herein described and claimed 2-[(3′-methoxytethoxy)propylidene]-19-nor-1 ⁇ ,25-(OH) 2 D 3 (F-Wit), the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-1 ⁇ ,25-(OH) 2 D 3 (1AGR), and the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-(20S)-1 ⁇ ,25-(OH)2D 3 (1AGS);
  • FIG. 5 is a bar graph illustrating the intestinal calcium transport activity of 2-[(3′-methoxymethoxypropylidene]-19-nor-1 ⁇ ,25-(OH) 2 D 3 (F-Wit), the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-1 ⁇ ,25-(OH) 2 D 3 (1AGR), and the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-(20S)-1 ⁇ ,25-(OH) 2 D 3 (1AGS) at various dosages as compared to control (vehicle) and (20S)-2-methylene-19-nor-1 ⁇ ,25-dihydroxyvitamin D 3 (2MD); and
  • FIG. 6 is a bar graph illustrating the bone calcium mobilization activity of 2-[(3′-methoxymethoxy)propylidene]-19-nor-1 ⁇ ,25-(OH) 2 D 3 (F-Wit), the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-1 ⁇ ,25-(OH) 2 D 3 (1AGR), and the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-(20S)-1 ⁇ ,25-(OH) 2 D 3 (1AGS) at various dosages as compared to control (vehicle) and (20S)-2-methylene-19-nor-1 ⁇ ,25-dihydroxyvitamin D 3 (2MD).
  • hydroxy-protecting group signifies any group commonly used for the temporary protection of hydroxy functions, such as for example, alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafter referred to simply as “silyl” groups), and alkoxyalkyl groups.
  • Alkoxycarbonyl protecting groups are alkyl-O—CO— groupings such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl.
  • acyl signifies an alkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or a carboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl, succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, or a halo, nitro or alkyl substituted benzoyl group.
  • alkyl as used in the description or the claims, denotes a straight-chain or branched alkyl radical of 1 to 10 carbons, in all its isomeric forms.
  • Alkoxyalkyl protecting groups are groupings such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl.
  • Preferred silyl-protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl and analogous alkylated silyl radicals.
  • aryl specifies a phenyl-, or an alkyl-, nitro- or halo-substituted phenyl group.
  • a “protected hydroxy” group is a hydroxy group derivatised or protected by any of the above groups commonly used for the temporary or permanent protection of hydroxy functions, e.g. the silyl, alkoxyalkyl, acyl or alkoxycarbonyl groups, as previously defined.
  • hydroxyalkyl deuteroalkyl
  • fluoroalkyl refer to an alkyl radical substituted by one or more hydroxy, deuterium or fluoro groups respectively.
  • the term “24-homo” refers to the addition of one methylene group and the term “24-dihomo” refers to the addition of two methylene groups at the carbon 24 position in the side chain. Likewise, the term “trihomo” refers to the addition of three methylene groups. Also, the term “26,27-dimethyl” refers to the addition of a methyl group at the carbon 26 and 27 positions so that for example R 3 and R 4 are ethyl groups. Likewise, the term “26,27-diethyl” refers to the addition of an ethyl group at the 26 and 27 positions so that R 3 and R 4 are propyl groups.
  • 2-propylidene-19-nor-vitamin D compounds of structure I when the side chain is unsaturated are:
  • the double bond located between the 22 and 23 carbon atoms in the side chain may be in either the (E) or (Z) configuration. Accordingly, depending upon the configuration, the term “22,23(E)” or “22,23(Z)” could be included in each of the above named compounds. Also, it is common to designate the double bond located between the 22 and 23 carbon atoms with the designation “ ⁇ 22 ”. Thus, for example, the fourth named compound above could also be written as 2-(3′-hydroxypropylidene)-19-nor-24-homo-22,23(E)- ⁇ 22 -1,25-(OH) 2 D 3 where the double bond is the (E) configuration.
  • this compound could be written as 2-(3′-hydroxypropylidene)-19-nor-20(S)-24-homo-22,23(E)- ⁇ 22 -1,25-(OH) 2 D 3 .
  • 2-propylidene-19-nor-vitamin D compounds of structure I when the side chain is saturated are:
  • groups Y 1 , Y 2 , X and R represent groups defined above; Y 1 , Y 2 , and X preferably hydroxy-protecting groups, it being also understood that any functionalities in R that might be sensitive, or that interfere with the condensation reaction, be suitable protected as is well-known in the art.
  • the process shown above represents an application of the convergent synthesis concept, which has been applied effectively for the preparation of vitamin D compounds (e.g. Lythgoe et al., J. Chem. Soc. Perkin Trans. I, 590 (1978); Lythgoe, Chem. Soc. Rev. 9, 449 (1983); Toh et al., J. Org. Chem.
  • Hydrindanones of the general structure II are known, or can be prepared by known methods. Specific important examples of such known bicyclic ketones are the structures with the side chains (a), (b), (c) and (d) described above, i.e. 25-hydroxy Grundmann's ketone (e) [Baggiolini et al., J. Org. Chem, 51, 3098 (1986)]; Grundmann's ketone (f) [Inhoffen et al., Chem. Ber. 90, 664 (1957)]; 25-hydroxy Windaus ketone (g) [Baggiolini et al., J. Org. Chem., 51, 3098 (1986)] and Windaus ketone (h) [Windaus et al., Ann., 524, 297 (1936)]:
  • one of the two secondary hydroxy groups of 1 (equatorial hydroxyl at C-3) was selectively protected as t-butyldimethylsilyl ether (TBDMS) and the other was then oxidized with Dess-Martin periodinane reagent to the 4-ketone 3.
  • TDMMS t-butyldimethylsilyl ether
  • the tertiary 1-hydroxyl was acetylated and the resulted acetoxy ketone 4 subjected to the Wittig reaction with an ylide generated from the appropriate phosphonium salt.
  • the choice of the phosphonium salt used for this purpose should be made considering the structure of the final 19-norvitamin D.
  • 2-methylene-19-nor-vitamin D compounds may be synthesized using the A-ring synthons 17a,b and 18a,b and the appropriate Windaus-Grundmann ketones having the desired side chain structure.
  • Wittig-Horner coupling of the lithium phosphinoxy carbanion generated from 17a and phenyllithium with the protected 25-hydroxy Grundmann's ketone 19a (SCHEME III), prepared according to published procedure [Sicinski et al., J. Med. Chem. 37, 3730 (1994)], gave the expected protected-vitamin compound 20.
  • UV absorption spectra were recorded with a Perkin-Elmer Lambda 3B UV-VIS spectrophotometer in ethanol.
  • 1 H nuclear magnetic resonance (NMR) spectra were recorded at 400 and 500 MHz with a Bruker Instruments DMX-400 and DMX-500 Avance console spectrometers in deteriochloroform.
  • 13 C nuclear magnetic resonance (NMR) spectra were recorded at 125 MHz with a Bruker Instruments DMX-500 Avance console spectrometer in deuteriochloroform. Chemical shifts ( ⁇ ) are reported downfield from internal Me 4 Si ( ⁇ 0.00).
  • Electron impact (EI) mass spectra were obtained with a Micromass AutoSpec (Beverly, Mass.) instrument.
  • High-performance liquid chromatography (HPLC) was performed on a Waters Associates liquid chromatograph equipped with a Model 6000A solvent delivery system, a Model U6K Universal injector, and a Model 486 tunable absorbance detector. ThF was freshly distilled before use from sodium benzophenone ketyl under argon.
  • keto lactone 4 was obtained from commercial ( ⁇ )-quinic acid as described in the Example I (a-c).
  • n-BuLi 2.0 M in cyclohexane, 1.50 mL, 3.00 mmol
  • the orange-red mixture was cooled to 45° C. and siphoned during 15 min to a solution of keto acetate 4 (700 mg, 2.13 mmol) in anhydrous ThF (24 mL).
  • the reaction mixture was stirred at ⁇ 40° C. for 2 h and stopped by addition of brine cont. 1% HCl.
  • Protected 19-norvitamin D 3 compounds 23a and 23b were obtained by Wittig-Horner coupling of protected 25-hydroxy Grundmann's ketone 19b with the phosphine oxides 18a and 18b performed analogously to the process described above for the preparation of (20R)-isomers 22a and 22b.
  • the protected vitamins were purified on a silica column, using hexane/ethyl acetate (99.5:0.5) solvent system, and they were obtained in ca. 47% yield.
  • Analytical sample of the protected vitamin 23a was obtained by HPLC (10 mm ⁇ 25 cm Zorbax-Sil column, 4 mL/min) purification using hexane/ethyl acetate (99.7:0.3) solvent system. Pure compound 23a was eluted at R V 25 mL as a colorless oil.
  • Vitamins 25a and 25b were obtained by hydrolysis of the silyl protecting groups in the 19-norvitamin derivatives 23a and 23b performed analogously to the process described above for the preparation of (20R)-isomers 24a and 24b.
  • the residue was purified by HPLC (10 mm ⁇ 25 cm Zorbax-Sil column, 4 mL/min) using hexane/2-propanol (8:2) solvent system. Pure mixture of 19-norvitamin 25a and 25b (95% yield) was collected at R V 36.5 mL.
  • novel compounds of this invention defined by formula I may be formulated for pharmaceutical applications as a solution in innocuous solvents, or as an emulsion, suspension or dispersion in suitable solvents or carriers, or as pills, tablets or capsules, together with solid carriers, according to conventional methods known in the art. Any such formulations may also contain other pharmaceutically-acceptable and non-toxic excipients such as stabilizers, anti-oxidants, binders, coloring agents or emulsifying or taste-modifying agents.
  • the compounds may be administered orally, topically, parenterally or transdermally.
  • the compounds are advantageously administered by injection or by intravenous infusion or suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal, or in the form of creams, ointments, patches, or similar vehicles suitable for transdermal applications.
  • Doses of from 0.01 ⁇ g to 100 ⁇ g per day of the compounds, preferably from about 0.1 ⁇ g/day to about 50 ⁇ g/day, are appropriate for treatment purposes, such doses being adjusted according to the disease to be treated, its severity and the response of the subject as is well understood in the art.
  • each may be suitably administered alone, or together with graded doses of another active vitamin D compound—e.g. 1 ⁇ -hydroxyvitamin D 2 or D 3 , or 1 ⁇ ,25-dihydroxyvitamin D 3 —in situations where different degrees of bone mineral mobilization and calcium transport stimulation is found to be advantageous.
  • another active vitamin D compound e.g. 1 ⁇ -hydroxyvitamin D 2 or D 3 , or 1 ⁇ ,25-dihydroxyvitamin D 3
  • compositions for use in the above-mentioned treatment of psoriasis and other malignancies comprise an effective amount of one or more 2-propylidene-19-nor-vitamin D compound as defined by the above formula I as the active ingredient, and a suitable carrier.
  • An effective amount of such compounds for use in accordance with this invention is from about 0.01 ⁇ g to about 100 ⁇ g per gm of composition, preferably from about 0.1 ⁇ g/gm to about 50 ⁇ g/gm of the composition, and may be administered topically, transdermally, orally or parenterally in dosages of from about 0.01 ⁇ g/day to about 100 ⁇ g/day, preferably from about 0.1 ⁇ g/day to about 50 ⁇ g/day.
  • the compounds may be formulated as creams, lotions, ointments, topical patches, pills, capsules or tablets, or in liquid form as solutions, emulsions, dispersions, or suspensions in pharmaceutically innocuous and acceptable solvent or oils, and such preparations may contain in addition other pharmaceutically innocuous or beneficial components, such as stabilizers, antioxidants, emulsifiers, coloring agents, binders or taste-modifying agents.
  • the compounds are advantageously administered in amounts sufficient to effect the differentiation of promyelocytes to normal macrophages. Dosages as described above are suitable, it being understood that the amounts given are to be adjusted in accordance with the severity of the disease, and the condition and response of the subject as is well-understood in the art.
  • compositions of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients.
  • the carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
  • Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and carrier such as cocoa butter, or in the form of an enema.
  • Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops; or as sprays.
  • a nebulizer or an atomizer can be used for asthma treatment.
  • dosage unit a unitary, i.e. a single dose which is capable of being administered to a patient as a physically and chemically stable unit dose comprising either the active ingredient as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
  • Modified vitamin D compounds that exhibit a desirable and highly advantageous pattern of biological activity in vivo, namely, the more gradual onset and more prolonged duration of activity, may also be used herein.
  • the key feature of the modified vitamin D compounds having these desirable biological attributes is that they are derivatives of 2-propylidene-19-nor-vitamin D analogs, in which a hydrolyzable group is attached to the hydroxy group at carbon 25 and, optionally, to any other of the hydroxy groups present in the molecule.
  • these derivatives hydrolyze to the active 2-propylidene-19-nor-vitamin D analog, at different rates in vivo, thus providing for the “slow release” of the biologically active vitamin D compound in the body.
  • the “slow release” in vivo activity profiles of such compounds can, of course, be further modulated by the use of mixtures of derivatives or the use of mixtures consisting of one or more vitamin D derivative together with underivatized vitamin D compounds.
  • the critical structural feature of the vitamin derivatives identified above is the presence of a hydrolyzable group attached to the hydroxy group at carbon 25 of the molecule.
  • a hydrolyzable group at that position imparts on the resulting derivatives the desirable “slow-release” biological activity profile mentioned above.
  • Other hydroxy functions occurring in the molecule e.g. hydroxy functions at carbons 1 or 3 may be present as free hydroxy groups, or one or more of them may also be derivatised with a hydrolyzable group.
  • the “hydrolyzable group” present in the above-mentioned derivatives is preferably an acyl group, i.e. a group of the type Q 1 CO—, where Q 1 represents hydrogen or a hydrocarbon radical of from 1 to 18 carbons that may be straight chain, cyclic, branched, saturated or unsaturated.
  • the hydrocarbon radical may be a straight chain or branched alkyl group, or a straight chain or branched alkenoyl group with one or more double bonds, or it may be an optionally substituted cycloalkyl or cycloalkenyl group, or an aromatic group, such as substituted or unsubstituted phenyl, benzyl or naphthyl.
  • acyl groups are alkanoyl or alkenoyl groups, of which some typical examples are formyl, acetyl, propanoyl, hexanoyl, isobutyryl, 2-butenoyl, palmitoyl or oleoyl.
  • Another suitable type of hydrolyzable group is the hydrocarbyloxycarbonyl group, i.e. a group of the type Q 2 -O—CO—, where Q 2 is a C 1 to C 18 hydrocarbon radical as defined above.
  • hydrocarbon radicals are methyl, ethyl, propyl, and higher straight chain or branched alkyl and alkenoyl radicals, as well as aromatic hydrocarbon radicals such as phenyl or benzoyl.
  • modified vitamin D compounds are hydrolyzable in vivo to the active analog over a period of time following administration, and as a consequence regulate the in vivo availability of the active analog, thereby also modulating their activity profile in vivo.
  • activity profile refers to the biological response over time of vitamin D compounds. Individual modified compounds, or mixtures of such compounds, can be administered to “fine tune” a desired time course of response.
  • modified vitamin D compound encompasses any vitamin D compound in which one or more of the hydroxy functions present in such a compound are modified by derivatization with a hydrolyzable group.
  • a “hydrolyzable group” is a hydroxy-modifying group that can be hydrolyzed in vivo, so as to regenerate the free hydroxy functions.
  • hydrolyzable group preferably includes acyl and hydrocarbyloxycarbonyl groups, i.e. groups of the type Q 1 CO— and Q 2 -O—CO, respectively, where Q 1 and Q 2 have the meaning defining earlier.
  • the modified vitamin D compounds encompassed may be represented by the formula XI shown below: where Y 1 , Y 2 , and R are as previously defined herein with respect to formula I with the exception that R 5 in the side chain is —OY 3 and Y 3 is an acyl group or a hydrocarbyloxycarbonyl group, as previously defined herein.
  • modified vitamin D compounds include 2-propylidene-19-nor vitamin D derivatives such as:
  • FIGS. 1 and 2 Competitive VDR Binding
  • FIG. 3 EL-60 Cell Differentiation
  • FIG. 4 Transcription Activation
  • Transcriptional activity was measured in ROS 17/2.8 (bone) cells that were stably transfected with a 24-hydroxylase (24OHase) gene promoter upstream of a luciferase reporter gene (Arbour et al., 1998). Cells were given a range of doses. Sixteen hours after dosing the cells were harvested and luciferase activities were measured using a luminometer.
  • 24OHase 24-hydroxylase
  • RLU in FIG. 4 refers to relative luciferase units.
  • FIGS. 5 and 6 Intestinal Calcium Transport and Bone Calcium Mobilization
  • FIG. 1 illustrates the relative activity of 2-[(3′-methoxymethoxy)propylidene]-19-nor-1 ⁇ ,25-(OH) 2 D 3 (also herein referred to as “F-Wit”) and 1 ⁇ ,25-dihydroxyvitamin D 3 in binding to the 1 ⁇ ,25-dihydroxyvitamin D pig intestinal nuclear receptor.
  • F-Wit 2-[(3′-methoxymethoxy)propylidene]-19-nor-1 ⁇ ,25-(OH) 2 D 3
  • F-Wit 1 ⁇ ,25-dihydroxyvitamin D 3 in binding to the 1 ⁇ ,25-dihydroxyvitamin D pig intestinal nuclear receptor.
  • FIGS. 1 and 2 illustrates the relative activity of the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-1 ⁇ ,25-(OH) 2 D 3 (also herein referred to as “1AGR”), the Z-isomer of 2-(3′-hydroxypropylidene)-19-nor-1 ⁇ ,25-(OH) 2 D 3 (also herein referred to as “2AGR”), the E-isomer of 2-(3′-hydroxypropylidene)-19-nor-(20S)-1 ⁇ ,25-(OH) 2 D 3 (also herein referred to as “1AGS”), the Z-isomer of 2-(3′-hydroxypropylidene)-19-nor-(20S)-1 ⁇ ,25-(OH) 2 D 3 (also herein referred to as “2AGS”), and 1 ⁇ ,25-dihydroxyvitamin D 3 in binding to the 1 ⁇ ,25-dihydroxyvitamin D pig intestinal nuclear receptor.
  • FIGS. 1 and 2
  • the 2-propylidene-19-nor compounds of this invention exhibit a pattern of biological activity having high potency in promoting the differentiation of malignant cells, relatively high intestinal calcium transport activity and a relatively high ability to mobilize calcium from bone. This is illustrated by the biological assay results obtained for F-Wit, 1AGR, 2AGR, 1AGS and 2AGS which is summarized in FIGS. 3 through 6 .
  • FIG. 1AGR, 2AGR, 1AGS and 2AGS which is summarized in FIGS. 3 through 6 .
  • FIG. 3 shows a comparison of the activity of the known active metabolite 1 ⁇ ,25-dihydroxyvitamin D 3 as well as the analog 2-methylene-19-nor-(20S)-1,25(OH) 2 D 3 (also herein referred to as “2MD”) and the presently claimed F-Wit, 1AGR and 1AGS analogs in inducing the differentiation of human leukemia cells (HL-60 cells) in culture to monocytes.
  • Differentiation activity was assessed by a standard differentiation assay, abbreviated as NBT reduction (nitroblue tetrazolium reduction).
  • NBT reduction nitrogenblue tetrazolium reduction
  • the assay was conducted according to known procedures, as given, for example, by DeLuca et al U.S. Pat. No. 4,717,721 and Ostrem et al, J. Biol. Chem. 262, 14164, 1987.
  • the differentiation activity of the test compounds is expressed in terms of the percent of HL-60 cells having differentiated to normal cells in response
  • FIG. 4 illustrates that F-Wit, 1AGR and 1AGS all have significant transcriptional activity in bone cells.
  • This result together with the cell differentiation activity of FIG. 3 , suggests that the presently claimed 2-propylidene compounds of structure I, and particularly F-Wit, 1AGR and 1AGS, will be very effective in psoriasis because they have direct cellular activity in causing cell differentiation and in suppressing cell growth.
  • the presently claimed 2-propylidene compounds of structure I, and particularly F-Wit, 1AGR and 1AGS may have significant activity as an anti-cancer agent, especially against leukemia, colon cancer, breast cancer, skin cancer and prostate cancer.
  • FIGS. 5 and 6 show a comparison of the calcemic activity of the known active 19-nor analog 2MD and the presently claimed F-Wit, 1AGR and 1AGS analogs.
  • FIG. 5 shows that F-Wit, 1AGR and 1AGS all have relatively high intestinal calcium transport activity, and are more active than 2M in intestinal calcium transport activity.
  • FIG. 6 shows that F-Wit, 1AGR and 1AGS all have significant ability to mobilize calcium from bone, and are less active in this regard than 2MD.
  • the 2-propylidene-19-nor-analogs of structure I and particularly F-Wit, 1AGR and 1AGS, show a selective activity profile combining high potency in inducing the differentiation of malignant cells, relatively high intestinal calcium transport activity and moderate bone calcium mobilization activity.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100179344A1 (en) * 2004-04-09 2010-07-15 Wisconsin Alumni Research Foundation 2-Alkylidene-18,19-Dinor-Vitamin D Compounds

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004092118A2 (en) * 2003-04-10 2004-10-28 Wisconsin Alumni Research Foundation 2-propylidene-19-nor-vitamin d compounds
AU2006213722B2 (en) * 2005-02-11 2011-09-22 Wisconsin Alumni Research Foundation 2-methylene-19-nor-(20S-24epi)-1alpha,25-dihydroxyvitamin-D2
MX2007009726A (es) * 2005-02-11 2007-09-26 Wisconsin Alumni Res Found 2-metilen-19-nor-(20s-24s)-1a, 25-dihidroxivitamina-d2.
US8114393B2 (en) 2005-09-14 2012-02-14 Wisconsin Alumni Research Foundation Methods and compositions for phosphate binding
AU2007235386A1 (en) * 2006-04-05 2007-10-18 Wisconsin Alumni Research Foundation 1.Alpha.-hydroxy-2-(3'-hydroxypropylidene)-19-nor-vitamin D compounds and methods of making and use thereof
US20090281340A1 (en) * 2006-04-05 2009-11-12 Deluca Hector F 1alpha-hydroxy-2-(3'-hydroxypropylidene)-19-nor-vitamin d compounds and methods of making and treatment thereof
JP2009532458A (ja) * 2006-04-06 2009-09-10 ウイスコンシン アラムニ リサーチ ファンデーション ２−メチレン−１α−ヒドロキシ−１９，２１−ジノルビタミンＤ３類縁体およびその使用
AU2007298651A1 (en) * 2006-04-06 2008-03-27 Wisconsin Alumni Research Foundation 2-methylene-1 alpha-hydroxy-18,19,21-trinorvitamin D3 analogs and uses thereof
NZ570815A (en) * 2006-04-06 2012-01-12 Wisconsin Alumni Res Found 19-nor-vitamin D analogs with 1,2,or 3,2 heterocyclic ring
AU2007298673A1 (en) 2006-04-06 2008-03-27 Wisconsin Alumni Research Foundation 2- substituted-1alpha, 25-dihydroxy-19,26,27-trinor vitamin D analogs and uses thereof
NZ571773A (en) * 2006-04-06 2011-11-25 Wisconsin Alumni Res Found 2-Methylene-1alpha,25-dihydroxy-18,19,21-trinorvitamin D3 and uses thereof
JP2010505739A (ja) * 2006-04-06 2010-02-25 ウイスコンシン アラムニ リサーチ ファンデーション ２−メチレン−１α，２５−ジヒドロキシ−１９，２１−ジノルビタミンＤ３類縁体およびその使用
EP2004597B1 (en) * 2006-04-10 2011-01-26 Wisconsin Alumni Research Foundation 1alpha-hydroxy-2-(3'-hydroxypropylidene)-19-nor-vitamin d compounds with a 1,1-dimethylpropyl side chain

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4666634A (en) * 1984-12-05 1987-05-19 Chugai Seiyaku Kabushiki Kaisha vitamin D3 derivatives having a substituent at 2-position
US5086191A (en) * 1991-05-28 1992-02-04 Wisconsin Alumni Research Foundation Intermediates for the synthesis of 19-nor vitamin D compounds
US5237110A (en) * 1989-03-09 1993-08-17 Wisconsin Alumni Research Foundation 19-nor-vitamin d compounds
US5246925A (en) * 1989-03-09 1993-09-21 Wisconsin Alumni Research Foundation 19-nor-vitamin D compounds for use in treating hyperparathyroidism
US5428029A (en) * 1993-11-24 1995-06-27 Hoffmann-La Roche Inc. Vitamin D3 fluorinated analogs
US5484782A (en) * 1993-11-03 1996-01-16 Wisconsin Alumni Research Foundation (E)-20(22)-dehydrovitamin D compounds
US5536713A (en) * 1993-04-05 1996-07-16 Wisconsin Alumni Research Foundation 19-Nor-vitamin D3 compounds with substitutent at 2-position
US5817648A (en) * 1995-05-09 1998-10-06 Duphar International Research B.V. Vitamin D3 analogues having an unsaturated side chain
US5843927A (en) * 1994-11-21 1998-12-01 Wisconsin Alumni Research Foundation 18,19-dinor-vitamin D compounds
US5843928A (en) * 1997-03-17 1998-12-01 Wisconsin Alumni Research Foundation 2-alkylidene-19-nor-vitamin D compounds
US5877168A (en) * 1995-02-10 1999-03-02 Chugai Seiyaku Kabushiki Kaisha Vitamin D derivative with substituent at the 2β-position
US5945410A (en) * 1997-03-17 1999-08-31 Wisconsin Alumni Research Foundation 2-alkyl-19-nor-vitamin D compounds
US6392071B1 (en) * 1997-03-17 2002-05-21 Wisconsin Alumni: Research Foundation 26,27-homologated-20-EPI-2-alkylidene-19-nor-vitamin D compounds
US6806262B2 (en) * 2000-05-31 2004-10-19 Wisconsin Alumni Research Foundation 2-ethyl and 2-ethylidene-19-nor-vitamin D compounds

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL67153A (en) 1981-11-02 1986-12-31 Res Inst Medicine Chem Intermediates in the production of vitamin d analogues and method for their production
GB8904154D0 (en) 1989-02-23 1989-04-05 Leo Pharm Prod Ltd Chemical compounds
NZ232734A (en) 1989-03-09 1991-11-26 Wisconsin Alumni Res Found 19-nor vitamin d derivatives and pharmaceutical compositions
AU649057B2 (en) 1990-08-24 1994-05-12 Wisconsin Alumni Research Foundation Methods and compositions containing vitamin D compounds for improvement of skin conditions
ATE173401T1 (de) 1990-09-07 1998-12-15 Wisconsin Alumni Res Found Neue verwendung von 1-alpha-hydroxylierten-19-nor-vitamin-d-verbind ngen zur behandlung von psoriasis
AU650751B2 (en) 1991-05-28 1994-06-30 Wisconsin Alumni Research Foundation Novel synthesis of 19-nor vitamin D compounds
JP3213092B2 (ja) * 1991-11-01 2001-09-25 中外製薬株式会社 ２β位に置換基を有するビタミンＤ誘導体
WO1996001811A1 (en) * 1994-07-11 1996-01-25 The Johns-Hopkins University 2-substituted 1,25-dihydroxyvitamin d3 derivatives
GB9915839D0 (en) * 1999-07-06 1999-09-08 Textron Automotive U K Valve assembly for vehicle washing system
EP1524264A3 (en) * 2000-05-31 2010-01-20 Wisconsin Alumni Research Foundation 2-ethylidene-19-nor-vitamin D compounds
US6846811B2 (en) * 2002-04-22 2005-01-25 Wisconsin Alumni Research Foundation (20S) 1α-hydroxy-2α-methyl and 2β-methyl-19-nor-vitamin D3 and their uses
WO2004092118A2 (en) * 2003-04-10 2004-10-28 Wisconsin Alumni Research Foundation 2-propylidene-19-nor-vitamin d compounds
US7053075B2 (en) * 2003-11-25 2006-05-30 Deluca Hector F Methods for reducing body fat using vitamin D compounds

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4666634A (en) * 1984-12-05 1987-05-19 Chugai Seiyaku Kabushiki Kaisha vitamin D3 derivatives having a substituent at 2-position
US5237110A (en) * 1989-03-09 1993-08-17 Wisconsin Alumni Research Foundation 19-nor-vitamin d compounds
US5246925A (en) * 1989-03-09 1993-09-21 Wisconsin Alumni Research Foundation 19-nor-vitamin D compounds for use in treating hyperparathyroidism
US5587497A (en) * 1989-03-09 1996-12-24 Wisconsin Alumni Research Foundation 19-nor-vitamin D compounds
US5086191A (en) * 1991-05-28 1992-02-04 Wisconsin Alumni Research Foundation Intermediates for the synthesis of 19-nor vitamin D compounds
US5536713A (en) * 1993-04-05 1996-07-16 Wisconsin Alumni Research Foundation 19-Nor-vitamin D3 compounds with substitutent at 2-position
US5484782A (en) * 1993-11-03 1996-01-16 Wisconsin Alumni Research Foundation (E)-20(22)-dehydrovitamin D compounds
US5428029A (en) * 1993-11-24 1995-06-27 Hoffmann-La Roche Inc. Vitamin D3 fluorinated analogs
US5843927A (en) * 1994-11-21 1998-12-01 Wisconsin Alumni Research Foundation 18,19-dinor-vitamin D compounds
US5877168A (en) * 1995-02-10 1999-03-02 Chugai Seiyaku Kabushiki Kaisha Vitamin D derivative with substituent at the 2β-position
US5817648A (en) * 1995-05-09 1998-10-06 Duphar International Research B.V. Vitamin D3 analogues having an unsaturated side chain
US5843928A (en) * 1997-03-17 1998-12-01 Wisconsin Alumni Research Foundation 2-alkylidene-19-nor-vitamin D compounds
US5936133A (en) * 1997-03-17 1999-08-10 Wisconsin Alumni Research Foundation 2-alkylidene-19-nor-vitamin D compounds
US5945410A (en) * 1997-03-17 1999-08-31 Wisconsin Alumni Research Foundation 2-alkyl-19-nor-vitamin D compounds
US6392071B1 (en) * 1997-03-17 2002-05-21 Wisconsin Alumni: Research Foundation 26,27-homologated-20-EPI-2-alkylidene-19-nor-vitamin D compounds
US20020087015A1 (en) * 1997-03-17 2002-07-04 Wisconsin Alumni Research Foundation Of Madison 26,27-homologated-20-EPI-2-alklidene-19-nor-vitamin D compounds
US6806262B2 (en) * 2000-05-31 2004-10-19 Wisconsin Alumni Research Foundation 2-ethyl and 2-ethylidene-19-nor-vitamin D compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100179344A1 (en) * 2004-04-09 2010-07-15 Wisconsin Alumni Research Foundation 2-Alkylidene-18,19-Dinor-Vitamin D Compounds

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CA2516233A1 (en) 2004-10-28
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