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Definitions

• This invention relates to vitamin D compounds, and more particularly to 2-methylene-(l 7Z)- 17(20)-dehydro-l 9,21-dinor- vitamin D analogs and their pharmaceutical uses.
• the natural hormone, l ⁇ ,25-dihydroxyvitamin D3 and its analog in ergosterol series, i.e. l ⁇ ,25-dihydroxyvitamin D2 are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987).
• vitamin D analogs i.e. the so called 19-nor-vitamin
• Chugai group as potential drugs for osteoporosis and as antitumor agents. See also Okano et al., Biochem. Biophys. Res. Commun. 163, 1444 (1989).
• Other 2- substituted (with hydroxyalkyl, e.g., ED- 120, and fluoroalkyl groups) A-ring analogs of l ⁇ ,25-dihydroxyvitamin D3 have also been prepared and tested
• 17-ene vitamin D compounds as well as vitamin D compounds having a double bond in the side chain thereof are also known, and have been proposed for various pharmacological uses. Bone diseases such as osteoporosis, skin disorders such as psoriasis, cancers such as leukemia and cosmetic conditions such as wrinkles are just some of the applications proposed for such compounds. 17-ene compounds are described in U.S. Patents 5,545,633; 5,929,056 and 6,399,797 while 2-alkylidene compounds having a side chain with a double bond therein are described in, for example, U.S. Patent 5,843,928.
• the present invention is directed toward 2-methylene-( 17Z)- 17(20)- dehydro-19,21-dinor-vitamin D analogs, their biological activity, and various pharmaceutical uses for these compounds.
• These new vitamin D compounds not known heretofore are the 19-nor- vitamin D analogs having a methylene group at the 2-position (C-2), a double bond located between carbon atoms 17 and 20, the replacement of the methyl group typically located at the 21 position (C-21) in the side chain with a hydrogen atom, and the side chain attached at the 17-position (C- 17) in its Z-configuration.
• the preferred vitamin D analog is 2-methylene-(17Z)- 17(20)dehydro-19,21-dinor-l ⁇ ,25-dihydroxyvitamin D 3 (hereinafter referred to as "Vit II Z").
• Xj , X 2 and X 3 which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group.
• the preferred analog is 2-methylene-(17Z)- 17(20)-dehydro-19,21-dinor-l ⁇ ,25-dihydroxyvitamin D 3 which has the following formula Ia:
• the above compounds I, particularly Ia exhibit a desired, and highly advantageous, pattern of biological activity. These compounds are characterized by relatively high binding to vitamin D receptors, which is only slightly lower potency than that of the natural hormone l ⁇ ,25-dihydroxy vitamin D 3 . These compounds also have the ability to promote intestinal calcium transport in vivo, in a dose dependent manner, and they would be classified as having about the same or equal intestinal calcium transport activity, as compared to that of l ⁇ ,25-dihydroxyvitamin D 3 . These compounds I, and particularly Ia, also have the ability to mobilize calcium from bone and they would be classified as having about the same or equal bone calcium mobilizing activity, as compared to l ⁇ ,25-dihydroxyvitamin D 3 .
• these compounds can be characterized as having significant calcemic activity. It is undesirable to raise serum calcium to supraphysiologic levels when suppressing the preproparathyroid hormone gene (Darwish & DeLuca, Arch. Biochem. Biophys. 365, 123-130, 1999) and parathyroid gland proliferation. These analogs having calcemic activity while also very active on differentiation and transcription are expected to be useful as a therapy for suppression of secondary hyperparathyroidism of renal osteodystrophy. [0010]
• the compounds I, particularly Ia, of the invention have also been discovered to be especially suited for treatment and prophylaxis of human disorders which are characterized by an imbalance in the immune system, e.g.
• autoimmune diseases including multiple sclerosis, lupus, diabetes mellitus, host versus graft rejection, and rejection of organ transplants; and additionally for the treatment of inflammatory diseases, such as rheumatoid arthritis, asthma, and inflammatory bowel diseases such as celiac disease, ulcerative colitis and Crohn's disease.
• inflammatory diseases such as rheumatoid arthritis, asthma, and inflammatory bowel diseases such as celiac disease, ulcerative colitis and Crohn's disease.
• Acne, alopecia and hypertension are other conditions which may be treated with the compounds of the invention.
• the above compounds I, and particularly Ia are also characterized by relatively high cell differentiation activity and in promoting transcription.
• these compounds also provide a therapeutic agent for the treatment of psoriasis, or as an anti-cancer agent, especially against leukemia, colon cancer, breast cancer, skin cancer and prostate cancer.
• these compounds due to their relatively high cell differentiation activity, provide a therapeutic agent for the treatment of various skin conditions including wrinkles, lack of adequate dermal hydration, i.e. dry skin, lack of adequate skin firmness, i.e. slack skin, and insufficient sebum secretion. Use of these compounds thus not only results in moisturizing of skin but also improves the barrier function of skin.
• the compounds of the invention of formula I, and particularly formula Ia are also useful in preventing or treating obesity, inhibiting adipocyte differentiation, inhibiting SCD-I gene transcription, and/or reducing body fat in animal subjects. Therefore, in some embodiments, a method of preventing or treating obesity, inhibiting adipocyte differentiation, inhibiting SCD-I gene transcription, and/or reducing body fat in an animal subject includes administering to the animal subject, an effective amount of one or more of the compounds or a pharmaceutical composition that includes one or more of the compounds of formula I. Administration of one or more of the compounds or the pharmaceutical compositions to the subject inhibits adipocyte differentiation, inhibits gene transcription, and/or reduces body fat in the animal subject.
• One or more of the compounds may be present in a composition to treat the above-noted diseases and disorders in an amount from about O.Ol ⁇ g/gm to about 1000 ⁇ g/gm of the composition, preferably from about O.l ⁇ g/gm to about 500 ⁇ g/gm of the composition, and may be administered topically, transdermally, orally, rectally, nasally, sublingually or parenterally in dosages of from about O.Ol ⁇ g/day to about 1000 ⁇ g/day, preferably from about O.l ⁇ g/day to about 500 ⁇ g/day.
• Figures 1-5 illustrate various biological activities of 2-methylene-
• Figure 1 is a graph illustrating the relative activity of Vit II Z and
• Figure 2 is a graph illustrating the percent HL-60 cell differentiation as a function of the concentration of Vit III Z and 1,25(OH) 2 D 3 ;
• Figure 3 is a graph illustrating the in vitro transcription activity of
• Figure 4 is a graph illustrating the bone calcium mobilization activity of 1,25(OH) 2 D 3 as compared to Vit II Z;
• Figure 5 is a graph illustrating the intestinal calcium transport activity of 1,25(OH) 2 D 3 as compared to Vit IIZ.
• vitamin D analog seemed an interesting target because the relatively small methylene group at the C-2 position should not interfere with binding to the vitamin D receptor.
• this 19- nor analog is characterized by the general formula Ia previously illustrated herein, and its pro-drug (in protected hydroxy form) is characterized by general formula I previously illustrated herein.
• groups X 1 , X 2 and X 3 are hydroxy-protecting groups, preferably t-butyldimethylsilyl, it being also understood that any functionalities that might be sensitive, or that interfere with the condensation reaction, be suitably 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.
• the hydrindanone of the general structure II is not known. It can be prepared by the method shown in the Scheme herein (see the preparation of compound Vit II Z).
• 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.
• the terms "hydroxyalkyl”, “deuteroalkyl” and “fluoroalkyl” refer to an alkyl radical substituted by one or more hydroxy, deuterium or fluoro groups respectively.
• the protected vitamin 16 (8.4 mg, 11.4 ⁇ mol) was dissolved in anhydrous THF (500 ⁇ L) and treated with TBAF (0.115 mL, 30 mg, 114 ⁇ mol) and stirred at rt in dark for overnight. The solvent was removed in vaccuo and residue was applied on Sep-Pak cartridge, and eluted with 30% ethyl acetate/hexane to get the deprotected vitamin 17.
• the vitamin was further purified by HPLC (9.4-mm x 25-cm Zorbax-Sil column, 3 mL/min) using hexane/IPA (90/10) as solvent system.
• FIG. 5 shows that Vit II Z has significant ability to increase intestinal calcium transport activity in vivo, in a dose dependent manner, and it clearly has about the same or equal activity as compared to that of 1,25- dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), the natural hormone, in stimulating intestinal calcium transport. Vit II Z stimulated intestinal calcium transport as potently as 1,25(OH) 2 D 3 .
• FIG. 4 demonstrates that Vit II Z also has significant bone calcium mobilization activity, as compared to 1,25(OH) 2 D 3 . Vit II Z has about the same or equal bone calcium mobilization activity compared to 1,25(OH) 2 D 3 .
• Figures 4 and 5 thus illustrate that Vit II Z may be characterized as having significant calcemic activity.
• FIG. 2 illustrates that Vit II Z is about 25 times more potent than
• 1,25(OH) 2 D 3 on HL-60 cell differentiation i.e. causing the differentiation of HL-60 cells into monocytes, making it an excellent candidate for the treatment of psoriasis and cancer, especially against leukemia, colon cancer, breast cancer, skin cancer and prostate cancer.
• this compound provides a therapeutic agent for the treatment of various skin conditions including wrinkles, lack of adequate dermal hydration, i.e. dry skin, lack of adequate skin firmness, i.e. slack skin, and insufficient sebum secretion. Use of this compound thus not only results in moisturizing of skin but also improves the barrier function of skin.
• Figure 3 illustrates that in bone cells the compound Vit II Z is one log, i.e. 10 times, more potent than 1,25(OH) 2 D 3 in increasing transcription of the 24-hydroxylase gene .
• Vit II Z will be very effective in psoriasis because it has direct cellular activity in causing cell differentiation, gene transcription, and in suppressing cell growth.
• Vit II Z may have significant activity as an anti-cancer agent, especially against leukemia, colon cancer, breast cancer, skin cancer and prostate cancer.
• Vit II Z The strong activity of Vit II Z on HL-60 differentiation suggests it will be active in suppressing growth of parathyroid glands and in the suppression of the preproparathyroid gene.
• the first system was a nickel affinity resin that utilizes the C-terminal histidine tag on this protein.
• the protein that was eluted from this resin was further purified using ion exchange chromatography (S- Sepharose Fast Flow). Aliquots of the purified protein were quick frozen in liquid nitrogen and stored at -80 0 C until use.
• the protein was diluted in TEDK 50 (50 mM Tris, 1.5 mM EDTA, pH7.4, 5 mM DTT, 150 mM KCl) with 0.1% Chaps detergent.
• the receptor protein and ligand concentration were optimized such that no more than 20% of the added radiolabeled ligand was bound to the receptor.
• Radiolabeled ligand ( 3 H- 1,25(OH) 2 D 3 , -159 Ci/mmole) was added in ethanol at a final concentration of 1 nM.
• Radiolabeled and unlabeled ligands were added to 100 mcl of the diluted protein at a final ethanol concentration of ⁇ 10%, mixed and incubated overnight on ice to reach binding equilibrium. The following day, 100 mcl of hydroxylapatite slurry (50%) was added to each tube and mixed at 10-minute intervals for 30 minutes. The hydroxylapaptite was collected by centrifugation and then washed three times with Tris-EDTA buffer (50 mM Tris, 1.5 mM EDTA, pH
• the study drugs were dissolved in ethanol and the concentrations determined using UV spectrophotometry. Serial dilutions were prepared so that a range of drug concentrations could be tested without changing the final concentration of ethanol ( ⁇ 0.2%) present in the cell cultures.
• HL60 Human promyelocytic leukemia
• HL60 cells were plated at 1.2 x 10 5 cells/ml. Eighteen hours after plating, cells in duplicate were treated with drug. Four days later, the cells were harvested and a nitro blue tetrazolium reduction assay was performed (Collins et al., 1979; J. Exp. Med. 149:969-974). The percentage of differentiated cells was determined by counting a total of 200 cells and recording the number that contained intracellular black-blue formazan deposits. Verification of differentiation to monocytic cells was determined by measuring phagocytic activity (data not shown).
• Vit II Z might not only be useful in the treatment of the above listed diseases, but also in the prevention of the above listed diseases.
• VDR binding VDR binding, HL60 cell differentiation, and transcription activity.
• Vit II Z will be very effective in psoriasis because it has direct cellular activity in causing cell differentiation, gene transcription, and in suppressing cell growth.
• Vit II Z will have significant activity as an anti-cancer agent, especially against leukemia, colon cancer, breast cancer, skin cancer and prostate cancer, as well as against skin conditions such as dry skin (lack of dermal hydration), undue skin slackness (insufficient skin firmness), insufficient sebum secretion and wrinkles.
• Vit II Z is an excellent candidate for numerous human therapies as described herein, and that it may be particularly useful in a number of circumstances such as suppression of secondary hyperparathyroidism of renal osteodystrophy, autoimmune diseases, cancer, numerous types of skin conditions, and psoriasis.
• Vit II Z is an excellent candidate for treating psoriasis because: (1) it has significant VDR binding, transcription activity and cellular differentiation activity; (2) it has little hypercalcemic liability at relatively low doses, unlike 1,25(OH) 2 D 3 ; and (3) it is easily synthesized.
• Vit II Z has significant binding activity to the vitamin D receptor, but has relatively low potency to raise blood serum calcium, it may also be particularly useful for the treatment of secondary hyperparathyroidism of renal osteodystrophy.
• the compound Vit II Z of the invention may be 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, lupus, diabetes mellitus, host versus graft rejection, and rejection of organ transplants; and additionally for the treatment of inflammatory diseases, such as rheumatoid arthritis, asthma, and inflammatory bowel diseases such as celiac disease, ulcerative colitis and Crohn's disease. Acne, alopecia and hypertension are other conditions which may be treated with the compound Vit II Z of the invention.
• the compounds of the invention of formula I, and particularly formula Ia are also useful in preventing or treating obesity, inhibiting adipocyte differentiation, inhibiting SCD-I gene transcription, and/or reducing body fat in animal subjects. Therefore, in some embodiments, a method of preventing or treating obesity, inhibiting adipocyte differentiation, inhibiting SCD-I gene transcription, and/or reducing body fat in an animal subject includes administering to the animal subject, an effective amount of one or more of the compounds or a pharmaceutical composition that includes one or more of the compounds of formula I. Administration of the compound or the pharmaceutical compositions to the subject inhibits adipocyte differentiation, inhibits gene transcription, and/or reduces body fat in the animal subject.
• the animal may be a human, a domestic animal such as a dog or a cat, or an agricultural animal, especially those that provide meat for human consumption, such as fowl like chickens, turkeys, pheasant or quail, as well as bovine, ovine, caprine, or porcine animals.
• the compounds of this invention defined by formula I, particularly Vit II Z 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 of formula I and particularly Vit II Z may be administered orally, topically, parenterally, rectally, nasally, sublingually or transdermally.
• the compound is 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.
• a dose of from 0.0 l ⁇ g to 1000 ⁇ g per day of the compounds I, particularly Vit II Z, preferably from about 0. l ⁇ g to about 500 ⁇ g per day, is appropriate for prevention and/or treatment purposes, such dose 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. l ⁇ - hydroxyvitamin D j or D3, or l ⁇ ,25-dihydroxyvitamin D3 ⁇ 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. l ⁇ - hydroxyvitamin D j or D3, or l ⁇ ,25-dihydroxyvitamin D3 ⁇ in situations where different degrees of bone mineral mobilization and calcium transport stimulation is found to be advantageous.
• compositions for use in the above-mentioned treatments comprise an effective amount of the compounds I, particularly Vit II Z, as defined by the above formula I and Ia as the active ingredient, and a suitable carrier.
• An effective amount of such compound for use in accordance with this invention is from about 0.01 ⁇ g to about 1000 ⁇ g per gm of composition, preferably from about 0.1 ⁇ g to about 500 ⁇ g per gram of composition, and may be administered topically, transdermally, orally, rectally, nasally, sublingually, or parenterally in dosages of from about O.Ol ⁇ g/day to about 1000 ⁇ g/day, and preferably from about 0.1 ⁇ g/day to about 500 ⁇ g/day.
• the compounds I, particularly Vit II Z may be formulated as creams, lotions, ointments, topical patches, pills, capsules or tablets, suppositories, aerosols, 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 I, particularly Vit II Z may be 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.
• the formulations 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 nasal administration, inhalation of powder, self-propelling or spray formulations.
• a nebulizer or an atomizer can be used for nasal administration, inhalation of powder, self-propelling or spray formulations.
• the formulations, when dispensed, preferably have a particle size in the range of 10 to lOO ⁇ .
• formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy.
• dosage unit is meant 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.

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