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Definitions

• This invention relates to vitamin D compounds, and more particularly to
• 17,20(E)-dehydro vitamin D analogs and their pharmaceutical uses and especially 17(E)-l ⁇ ,25-dihydroxy-17(20)-dehydro-2-methylene-19-norvitamin D 3 , its biological activities, and its pharmaceutical uses.
• the natural hormone, l ⁇ ,25-dihydroxyvitamin D3 and its analog in the 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). Many structural analogs of these metabolites have been prepared and tested, including 1 ⁇ -hydroxyvitamin D3, l ⁇ -hydroxyvitamin D2, 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.
• Another class of vitamin D analogs i.e. the so called 19-nor- vitamin D compounds, is characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms.
• Biological testing of such 19-nor-analogs e.g., l ⁇ ,25-dihydroxy-19-nor-vitamin D3 revealed a selective activity profile with high potency in inducing cellular differentiation, and very low calcium mobilizing activity.
• Patent 6,627,622 All three of these compounds have relatively high binding activity to vitamin D receptors and relatively high cell differentiation activity, but little if any calcemic activity as compared to l ⁇ ,25-dihydroxyvitamin D 3 . Their biological activities make these compounds excellent candidates for a variety of pharmaceutical uses, as set forth in the '352, '861 and '622 patents.
• the present invention is directed toward 17,20(E)-dehydro vitamin D analogs, and their pharmaceutical uses, and more specifically toward 17(E)-I ⁇ ,25-dihy droxy- 17(20)-dehydro-2-methylene-19-norvitamin D 3 , their biological activity, and various pharmaceutical uses for these compounds.
• Y 1 and Y 2 which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, where Rn and Ri 2 are each hydrogen or taken together are a methylene group
• 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, fiuoro, carbonyl, ester, epoxy, amino or other heteroatomic groups.
• Preferred side chains of this type are represented by the structure below
• m and n independently, represent the integers from 0 to 5, where R* is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and Ci_ 5 - alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R ⁇ , R ⁇ , and R ⁇ , independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C ⁇ .5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected- hydroxy substituent, and where R* and R ⁇ , taken together, represent an oxo group, or an alkylidene group having a general formula C k H 2k - where k is an integer, the group and R % taken together, represent an oxo group, or the group -(CH2)q-, where q is an integer from 2 to 5, and where R ⁇ represents hydrogen,
• the preferred analog is 17(E)-I ⁇ ,25-dihydroxy-17(20)-dehydro-2-methylene- 19- norvitamin D 3 which has the following formula Ia:
• the above compounds of formula I exhibit a desired, and highly advantageous, pattern of biological activity.
• These compounds are characterized by relatively high binding to vitamin D receptors, but very low intestinal calcium transport activity, as compared to that of l ⁇ ,25 -dihydroxy vitamin D3, and have very low ability to mobilize calcium from bone, as compared to l ⁇ ,25-dihydroxyvitamin D 3 .
• these compounds can be characterized as having little, if any, 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 little or no calcemic activity while being very active on cell differentiation are also expected to be useful as a therapy for suppression of secondary hyperparathyroidism of renal osteodystrophy.
• the compounds I, and 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. 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 compounds of the invention.
• autoimmune diseases including multiple sclerosis, lupus, diabetes mellitus, host versus graft rejection, and rejection of organ transplants
• 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
• the above compounds I, and particularly Ia are also characterized by relatively 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.
• these compounds provide therapeutic agents 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 differentiations, 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 differentiations, 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, and in particular the compound of formula Ia.
• 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 or prevent 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 lOOO ⁇ g/day, preferably from about O. l ⁇ g/day to about 500 ⁇ g/day.
• Figures 1-5 illustrate various biological activities of 17(E)-I ⁇ ,25-dihydroxy- 17(20)-dehydro-2-methylene-19-norvitamin D 3 , hereinafter referred to as "VIT-III," as compared to the native hormone l ⁇ ,25-dihydroxyvitamin D 3 , hereinafter " 1,25(OH) 2 D 3 .”
• Figure 1 is a graph illustrating the relative activity of VIT-III and 1,25(OH) 2 D 3 to compete for binding with [ 3 H]- 1,25-(OH) 2 -D 3 to the full-length recombinant rat vitamin D receptor;
• Figure 2 is a graph illustrating the percent HL-60 cell differentiation as a function of the concentration of VIT-III and 1,25(OH) 2 D 3 ;
• Figure 3 is a graph illustrating the in vitro transcription activity of 1,25(OH) 2 D 3 as compared to VIT-III;
• Figure 4 is a bar graph illustrating the bone calcium mobilization activity of 1,25(OH) 2 D 3 as compared to VIT-III;
• Figure 5 is a bar graph illustrating the intestinal calcium transport activity of 1,25(OH) 2 D 3 as compared to VIT-III.
• 17,20(E)-dehydro vitamin D analogs having the structure I can be accomplished by a common general method, i.e. the condensation of a bicyclic Windaus-Grundmann type ketone II with the allylic phosphine oxide III to the corresponding 17,20(E)-dehydro vitamin D analog IV followed by deprotection at C-I and C-3 to provide I:
• groups Y ( and Y 2 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. 48, 1414 (1983); Baggiolini et al, J. Org.
• hydrindanones of the general structure II are not known. They can be prepared by the method shown in the Schemes herein (see the preparation of compound VIT-III).
• 17,20(E)-dehydro vitamin D ⁇ analogs are those encompassed by general formula I wherein carbon-2 on the A-ring is substituted with an alkylidene group or an alkyl group, or are hydrolyzable slow release compounds (whether substituted at carbon-2 or not substituted at carbon-2).
• Y j , Y2, Ri 1 , R 12 and Z are as previously defined herein, and Rg and R9, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group -(CH2) X — where x is an integer from 2 to 5.
• R 1O is selected from the group consisting of alkyl, hydroxyalkyl and fluoroalkyl.
• 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 17,20(E)-dehydro-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 17,20(E)-dehydro-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. It is important to stress that 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. The presence of 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 derivatived 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 alkenyl 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 Ci to Cj 8 hydrocarbon radical as defined above.
• hydrocarbon radicals are methyl, ethyl, propyl, and higher straight chain or branched alkyl and alkenyl 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.
• modified vitamin D compounds encompassed may be represented by the formula VII shown below:
• Y 1 , Y 2 , R 11 , R] 2 , R 6 , R 7 and Z 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- substituted derivatives such as:
• VIT-III 17(E)- 1 ⁇ ,25-dihydroxy- 17(20)-dehydro-2-methylene- 19-nor- vitamin D 3 (referred to herein as VIT-III) was synthesized and tested. Structurally, this 19-nor analog is characterized by the general formula Ia previously illustrated herein.
• the preparation of 17(E)-I ⁇ ,25-dihydroxy-l 7(20)-dehydro-2-methylene-19-nor- vitamin D 3 having the structure Ia can be accomplished by the condensation of a bicyclic Windaus-Grundmann type ketone Ha with the allylic phosphine oxide IHa to the corresponding 17(20)-dehydro- vitamin D analog IVa followed by deprotection at C-I and C-3 to provide Ia:
• groups Y ⁇ and Y2 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 a specific application of the convergent synthesis concept, which was referred to previously herein and has been applied effectively for the preparation of vitamin D compounds
• hydrindanone of the general structure Ha is not known. It can be prepared by the method shown in the Schemes herein (see the preparation of compound VIT-III).
• 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.
• Alkoxy refers to any alkyl radical which is attached by oxygen, i.e. an alkyl-o-group.
• 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.
• An “alkylidene” refers to a radical having the general formula C k H 2k -where k is an integer. More specifically, reference should be made to the following description as well as to the Schemes herein for a detailed illustration of the preparation of compound VIT- III.
• Des-A,B-23,24-dinorcholan-8/?,22-diol (2) A flame dried 1000 mL two necked flask was charged with ergocalciferol 1 (5 g, 12.6 mmol), pyridine (5 mL), and anhydrous MeOH (400 mL). The solution was cooled to -78 0 C in an argon atmosphere. O 3 was bubbled through the solution until a deep blue color developed and persisted (about Ih). The solution was treated with O 2 until the blue color faded (15 min). Then NaBH 4 (1.5 g, 39.7 mmol) was added. After 15 min.
• Des-A,B-22-(p-toluenesulfonyloxy)-23,24-dinorcholan-8yff-ol (3) A solution of diol 2 (1 g, 4.71 mmol) in anhydrous pyridine (12 mL) was cooled to -25 0 C and a precooled solution of tosyl chloride (1.08 g, 5.66 mmol) in anhydrous pyridine (2mL) was added dropwise. The reaction mixture was stirred at that temperature for 4 h and allowed to warm to 0 0 C and stirred at that temperature for additional 20 h.
• hydroxyl tosylate 3 1.5 g, 4.09 mmol
• anhydrous DMF 20 mL
• 2,6-lutidine 0.580 mL, 0.52 g, 4.92 mmol
• TBSOTf (1.13 mL, 1.3Og, 4.92 mmol
• Des-A,B-8 ⁇ -[( ⁇ r/-butyldimethylsilyl)oxy]-23,24-dinorcholan-22-al (5) A solution of 4 (1.9 g, 3.96 mmol) in DMSO (5 mL) was added to a suspension OfNaHCO 3 (1.5 g, 17.9 mmol) in DMSO (20 mL) at rt. The mixture was heated to 150 0 C under argon for 15 min and cooled to rt. Water (50 mL) followed by ethyl acetate (50 mL) were added and aqueous phase was extracted with ethyl acetate (3 x 30 mL).
• Des-A,B-8/H(ter/-butyldimethylsilyl)oxy]-pregnan-20-one (6) A flame dried flask was charged with J-BuOK (1.55 g, 13.9 mmol) and anhydrous t-BuOH (30 mL) at room temperature. O 2 was bubbled through the solution for 15 min. A solution of aldehyde 5 (0.9 g, 2.78 mmol) in anhydrous t-BuOH (15 mL) was added to the reaction mixture and O 2 was bubbled through the solution for additional 10 min. The reaction was quenched with water (15 mL) and extracted with ether (3 x 30 mL). The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated.
• the olefin mixture without further purification was dissolved in methanol (20 mL) and />-Toluenesulfonic acid monohydrate (p-TSA) (0.10Og) was added at 0 0 C.
• the reaction mixture was stirred at room temperature for 3 days [Additional amounts ofp-TSA were successively added (100 mg, 24h; 75 mg, 36h; 50 mg, 48h)].
• Methanol was evaporated and residue was diluted with ethyl acetate (30 mL).
• the organic phase was washed with saturated aqueous NaHCO 3 solution (20 mL) water (20 mL), dried (Na 2 CO 3 ) and evaporated.
• the residue was purified on column chromatography to yield 0.284 g (79%) of a mixture of olefin alcohols 14a, 14b, 15a, 15b, 16.
• the olefin alcohols were separated on HPLC.
• the protected vitamin 19a (7.7 mg, 10.2 ⁇ mol) was dissolved in anhydrous THF (500 ⁇ L) and treated with TBAF (0.102 mL, 26.7 mg, 102 ⁇ 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 20a.
• 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.
• the mixture was stirred under argon atmosphere at -78 0 C for 3h and at 0 0 C for 18h.
• Ethyl acetate was added and organic phase was washed with brine, dried (Na 2 SO 4 ) and evaporated.
• the residue was applied on a Sep-Pak cartridge, and eluted with 1% ethyl acetate/hexane to give the 19-nor protected vitamin derivative.
• the vitamin was further purified by HPLC (9.4-mm x 25-cm Zorbax-Sil column, 4ml/min) using hexane/IPA (99.95:0.05) solvent system.
• the protected vitamin 19b (12.8 mg, 16.9 mmol) was dissolved in anhydrous THF (500 ⁇ L) and treated with TBAF (170 ⁇ L, 44.2 mg, 169 ⁇ 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.
• the vitamin was further purified by HPLC (9.4-mm x 25-cm Zorbax-Sil column, 4ml/min) using hexane/IPA (85/15) as solvent system.
• Figure 5 shows that VIT-III has little 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.
• Figure 4 demonstrates that VIT-III has very little bone calcium mobilization activity, as compared to 1,25(OH) 2 D 3 .
• FIGS 4-5 thus illustrate that VIT-III may be characterized as having little, if any, calcemic activity.
• FIG. 2 illustrates that VIT-III is as potent as 1,25(OH) 2 D 3 on HL-60 cell differentiation, 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 the compound VIT-III has about the same transcriptional activity as l ⁇ ,25-dihydroxyvitamin D 3 in bone cells. This result, together with the cell differentiation activity of Figure 2, suggests that VIT-III will be very effective in psoriasis because it has direct cellular activity in causing cell differentiation and in suppressing cell growth. These data also indicate that VIT-III may have significant activity as an anti ⁇ cancer agent, especially against leukemia, colon cancer, breast cancer, skin cancer and prostate cancer. The strong activity of VIT-III on HL-60 differentiation suggests it will be active in suppressing growth of parathyroid glands and in the suppression of the preproparathyroid gene.
• Full-length recombinant rat receptor was expressed in E. coli BL21 (DE3) Codon Plus RIL cells and purified to homogeneity using two different column chromatography systems.
• 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 KCI) with 0.1% Chaps detergent.
• the receptor protein and ligand concentration was optimized such that no more than 20% of the added radiolabeled ligand was bound to the receptor. Study Drugs
• 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 7.4) containing 0.5% Titron X-100.
• Tris-EDTA buffer 50 mM Tris, 1.5 mM EDTA, pH 7.4
• the pellets were transferred to scintillation vials containing 4 ml of Biosafe II scintillation cocktail, mixed and placed in a scintillation counter. Total binding was determined from the tubes containing only radiolabeled ligand.
• 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 promyelocyte leukemia (HL60) cells were grown in RPMI- 1640 medium containing 10% fetal bovine serum. The cells were incubated at 37°C in the presence of 5% CO 2 .
• 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).
• Antagonism was tested by adding a combination of 1,25(OH) 2 D 3 and the compound in the same well keeping the final ethanol concentration the same.
• Antagonism was tested by administering a combination of 1,25(OH) 2 D 3 and the compound to the animal simultaneously.
• VIT-III will be very effective in psoriasis because it has direct cellular activity in causing cell differentiation and in suppressing cell growth.
• VIT-III 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-III 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, and psoriasis.
• VIT-III is an excellent candidate for treating psoriasis because: (1) it has significant VDR binding, transcription activity and cellular differentiation activity; (2) it is devoid of hypercalcemic liability unlike 1,25(OH) 2 D 3 ; and (3) it is easily synthesized. Since VIT-III has significant binding activity to the vitamin D receptor, but has little ability to raise blood serum calcium, it may also be particularly useful for the treatment of secondary hyperparathyroidism of renal osteodystrophy.
• the compound VIT-III 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-III of the invention.
• autoimmune diseases including multiple sclerosis, lupus, diabetes mellitus, host versus graft rejection, and rejection of organ transplants
• 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
• a method of preventing or treating obesity, inhibiting adipocyte differentiations, 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.
• 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 and Ia 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-III of formula Ia 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 lOOO ⁇ g per day of the compounds I, particularly VIT-III, preferably from about O.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. Since the compound exhibits specificity of action, each may be suitably administered alone, or together with graded doses of another active vitamin D compound — e.g. l ⁇ -hydroxyvitamin D2 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 D2 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-III, 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-III 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-III 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.
• 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 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 ⁇ .
• the 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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