Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/50—Organo-phosphines
  • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
  • C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/50—Organo-phosphines
  • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
  • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/14—All rings being cycloaliphatic
  • C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane

Definitions

• This invention relates to vitamin D compounds, and more particularly to
• the natural hormone, 1 ⁇ ,25-dihydroxyvitamin D3 and its analog in the ergosterol series, i.e. 1 ⁇ ,25-dihydroxy vitamin 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 ⁇ - hydroxy vitamin D3, 1 ⁇ -hydroxy vitamin 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.
• diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporos
• 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 some 19-nor-analogs e.g., 1 ⁇ ,25-dihydroxy-19-nor-vitamin D3 revealed a selective activity profile with high potency in inducing cellular differentiation, and reduced calcium mobilizing activity.
• these compounds are potentially useful as therapeutic agents for the treatment of malignancies, or the treatment of various skin disorders.
• Two different methods of synthesis of such 19-nor- vitamin D analogs have been described (Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), and DeLuca et al, U.S. Pat. No. 5,086,191).
• Patent 6,579,861 and 1 ⁇ -hydroxy-2 -methylene- 19-nor-bishomopregnacalciferol is described in U.S. 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 1 ⁇ ,25-dihydroxy vitamin D3. 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 aimed at vitamin D compounds characterized by the transposition of the A-ring exocyclic methylene group from carbon 10 (C-10) to carbon 2 (C- 2) (e.g., 2-methyIene-19-norvitamin D analogs). These analogs also lack a 3 ⁇ -OH group, but are characterized by the presence of a 1 ⁇ -OH group, that is important for biological activity.
• the present invention is directed toward 3-desoxy-2-methylene-19-nor-vitamin D analogs, and their pharmaceutical uses, and more specifically toward (20S)-3-desoxy-2- methylene- 1 ⁇ ,25-dihydroxy-19-norvitamin D3, its biological activity, and various pharmaceutical uses for this compound as well as (20R)-3-desoxy-2-methylene-1 ⁇ ,25- dihydroxy-19-nor-vitamin D3, its biological activity, and various pharmaceutical uses for this compound.
• R may be hydrogen, an alkyl, hydroxyalkyl or fluoroalkyl group, or R may represent a side chain of the formula:
• stereochemical center at carbon 20 may have the R or S configuration, and where Z in the above side chain structure is selected from Y, -OY, -CH2OY, -C ⁇ CY and
• -CH CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, -COR 5 and a radical of the structure:
• R 1 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C 1-5 -alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected- hydroxy substituent
• each of R 3 , R 3 and R 4 independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C 1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent
• side chains are the structures represented by formulas (a), (b), (c), (d) and (e) below with natural 20R-configuration, i.e., the side chain as it occurs in 25-hydroxyvitamin D3 (a); vitamin D3 (b); 25-hydroxyvitamin D 2 (c); vitamin D 2 (d); and the C-24 epimer of 25-hydroxyvitamin D 2 (e).
• side chains are the structures represented by formulas (a), (b), (c), (d) and (e) below having the 20-epi or (20S)-configuration, i.e., the side chain as it occurs in (20S)-25-hydroxyvitamin D 3 (a); (20S)-vitamin D 3 (b); (20S)-25- hydroxyvitamin D 2 (c); (20S)-vitamin D 2 (d); and the C-24 epimer of (20S)-25- hydroxyvitamin D 2 (e).
• carbon 20 may have either the R or S configuration.
• the preferred analogs are (20S)-3-desoxy-2-methylene-1 ⁇ ,25-dihydroxy-1 - nor-vitamin D3 (referred to herein as "3-desoxy-2MD”) which has the following formula 1 ⁇ :
• 3D-MJ (20R)-3-desoxy-2-methylene-1 ⁇ ,25-dihydroxy-19-nor-vitamin D3 which has the following formula lb:
• 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, i.e. they bind with about the same affinity as 1 ⁇ ,25-dihydroxyvitamin D3, and in bone cells their in vitro transcription activity is also substantially the same as 1 ⁇ ,25-dihydroxyvitamin D3 in causing 24- hydroxylase gene transactivation.
• They are either about the same or slightly more potent causing differentiation of HL-60 cells into monocytes than 1,25(OH)2D3. They also exhibit either about the same or slightly more activity in their ability to mobilize calcium from bone, and similar or only slighltly less activity in their ability to promote intestinal calcium transport, as compared to 1 ⁇ ,25-dihydroxy vitamin D3.
• the above compounds I, and particularly la and lb have relatively high binding affinity, are characterized by relatively high cell differentiation activity, and high bone calcium mobilization activity, but have slightly lower intestinal calcium transport activity.
• these compounds have potential as anti-cancer agents and provide therapeutic agents for the prevention or treatment of osteosarcoma, leukemia, colon cancer, breast cancer, skin cancer and prostate cancer.
• 3-desoxy-2MD and 3D-MJ might also be useful in treatment of bone diseases, such as senile osteoporosis, postmenopausal osteoporosis, steroid- induced osteoporosis, low bone turnover osteoporosis, osteomalacia, and renal osteodystrophy.
• One or more of the compounds may be present in a composition to treat or prevent the above-noted diseases in an amount from about 0.0 ⁇ g/gm to about 1000 of the composition, preferably from about O. ⁇ 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 0.0 ⁇ g/day to about 1000 ⁇ g/day, preferably from about 0.1 ⁇ g/day to about 500 ⁇ g day.
• Figures 1-5 illustrate various biological activities of (20S)-3-desoxy-2- methylene-1 ⁇ ,25-dihydroxy-19-nor-vitamin D3, hereinafter referred to as "3-desoxy-2MD,” as compared to the native hormone 1 ⁇ ,25-dihydroxyvitamin D3, hereinafter " 1,25(OH)2D3.”
• Figure 1 is a graph illustrating the relative activity of 3-desoxy-2MD 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 3-desoxy-2MD and 1,25(OH) 2 D3;
• Figure 3 is a graph illustrating the in vitro transcription activity of 1,25(OH) 2 D 3 as compared to 3-desoxy-2MD;
• Figures 4A and 4B are bar graphs illustrating the bone calcium mobilization activity of 1,25(OH) 2 D3 as compared to 3-desoxy-2MD.
• Figures SA and SB are bar graphs illustrating the intestinal calcium transport activity of 1,25(OH)2D3 as compared to 3-desoxy-2MD.
• Figures 6-10 illustrate various biological activities of (20R)-3-desoxy-2- methylene-1 ⁇ ,25-dihydroxy-19-nor-vitamin D3, hereinafter referred to as "3D-MJ,” as compared to the native hormone 1 ⁇ ,25-dihydroxyvitamin D3, hereinafter "1,25(OH) 2 D 3 .”
• Figure 6 is a graph illustrating the relative activity of 3D-MJ and 1 ,25(OH) 2 D 3 to compete for binding with [ 3 H]-1,25-(OH)2-D3 to the full-length recombinant rat vitamin D receptor;
• Figure 7 is a graph illustrating the percent HL-60 cell differentiation as a function of the concentration of 3D- J and 1,25(OH) 2 D3;
• Figure 8 is a graph illustrating the in vitro transcription activity of 1,25(OH) 2 D 3 as compared to 3D-MJ;
• Figure 9 is a bar graph illustrating the bone calcium mobilization activity of 1,25(OH) 2 D3 as compared to 3D-MJ.
• Figure 10 is a bar graph illustrating the intestinal calcium transport activity of 1,25(OH) 2 D 3 as compared to 3D-MJ.
• 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.
• 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.
• alkylidene refers to a radical having the general formula CiJt k -where k is an integer.
• substituents X and R represent the groups defined above; X being preferably a hydroxy-protecting group, 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. 48, 1414 (1983); Baggiolini et al, J. Org.
• Hydrindanones of the general structure ⁇ 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 (f) [Baggiolini et al, J. Org. Chem, 51, 3098 (1986)]; Grundmann's ketone (g) [Inhoffen et al, Chem. Ber, 90, 664 (1957)]; 25-hydroxy Windaus ketone (h) [Baggiolini et al, J. Org. Chem, 51, 3098 (1986)] and Windaus ketone (i) [Windaus et al, Ann, 524, 297 (1936)]:
• the introduced secondary hydroxyl was silylated and the protected compound 3 was subjected to the Wittig reaction with an ylide generated from methyltriphenylphosphonium bromide and n-butyllithium.
• the carbonyl group was deprotected in the reaction with the Lewis acid (FeCb) and the formed cyclohexanone S was subjected to a Peterson reaction leading to the mixture of ⁇ , ⁇ -unsaturated esters 6 and 7.
• the separation of the geometric isomers was more easily achieved (by column chromatography) after the reduction step, providing the E- and Z-allylic alcohols 8 and 9, respectively.
• the Z-isomer 9 was next transformed in the three-step procedure into the corresponding phosphine oxide 10.
• Wittig- Homer coupling of the known Grundmann ketone 11 [see Sicinski et al., J. Med. Chem., 41, 4662 (1998)] with the lithium phosphinoxy carbanion generated from the phosphine oxide 10 was subsequently carried out, producing the protected 19-norvitamin D compound, which after hydroxyls deprotection with tetrabutylammonium fluoride provided the desired (20S)-3- desoxy-2-methylene-1 ⁇ ,25-dihydroxy-19-nor-vitamin D3 (12, 3-desoxy-2MD).
• This synthetic path is described in EXAMPLE I herein.
• Butyldiphenylsilyl)oxy]-4-methylene-cyclohexanone (5) To a solution of ketal 4 (160 mg, 0.392 mmol) in methylene chloride (11 mL) at room temperature FeCl 3 x 6H 2 0 (547 mg, 2.02 mmol) was added. The resulting dark yellow suspension was stirred for 50 min and quenched by the addition of water. The aqueous layer was extracted with methylene chloride, the combined organic layers were dried (MgS0 4 ) and concentrated under reduced pressure. Column chromatography on silica of the resulting yellow residue using hexane/ethyl acetate (95:5) yielded ketone 5 (141 mg, 99%) as a colorless oil.
• keto compound 5 (63 mg, 172.8 umol) in anhydrous THF (300 ⁇ L + 80 ⁇ L) was added dropwise. The solution was stirred at -78 °C for 2 hours, and the reaction was quenched with saturated NH4CI, poured into brine and extracted with ethyl acetate. The combined organic extracts were dried (MgS0 4 ) and evaporated. The residue was dissolved in hexane and applied on a silica Sep- Pak cartridge. Elution with hexane/ethyl acetate (98:2) gave unsaturated esters 6 and 7 (65 mg, 90%) as a colorless oil.
• Butyldiphenylsilyl)oxy]-4'-methylene-cyclohexylidene]ethanols (8 and 9).
• Diisobutylaluminium hydride (1.5 M in toluene; 1.9 mL, 2.85 mmol) was slowly added to a stirred solution of allylic esters 6 and 7 (165 mg, 0.392 mmol) in toluene:methylene chloride (2:1; 8 mL) at -78 °C under argon. Stirring was continued at -78 °C for 1 h and at -40 °C for 30 min.
• Butyldiphenylsilyl)oxy]-4'-methylene-cyclohexylidene]ethyl]diphenyl phosphine oxide (10).
• n-BuLi 2.5 M in hexanes; 24 ⁇ , 60 umol
• argon at 0 °C.
• a solution of a freshly recrystallized tosyl chloride (11.2 mg, 61 umol) in anhydrous THF (110 ⁇ L) was then added to the allylic alcohol - n-BuLi solution.
• FIGS 5 A and 5B show that 3-desoxy-2MD has relatively low activity as compared to that of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the natural hormone, in stimulating intestinal calcium transport. 3-desoxy-2MD is at least one half log less potent than 1,25(OH) 2 D 3 in promoting active calcium transport across the gut.
• Figures 4A and 4B demonstrate that 3-desoxy-2MD has relatively high bone calcium mobilization activity, as compared to 1,25(OH)2D3- 3-desoxy-2MD is at least 10 times more potent than the native hormone in releasing bone calcium stores.
• Figure 2 illustrates that 3-desoxy-2MD is about 3 times more potent than 1,25(OH 2 D 3 on HL-60 cell differentiation, making it an excellent candidate for the treatment of a cancer, especially for the prevention or treatment of osteosarcoma, leukemia, colon cancer, breast cancer, skin cancer and prostate cancer.
• Figure 3 illustrates that the compound 3-desoxy-2MD has about the same transcriptional activity as 1 ⁇ ,25-dihydroxyvitamin D3 in bone cells.
• 3-desoxy- 2MD is as potent as 1,25(OH) 2 D3 in increasing transcription of the 24-hydroxylase gene. This result, together with the cell differentiation activity of Figure 2, suggests that 3-desoxy- 2MD will be very effective in treating the above referred to cancers because it has direct cellular activity in causing cell differentiation, gene transcription, and in suppressing cell growth.
• 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°C until use.
• the protein was diluted in TEDK 5 0 (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.
• 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 promyelocytic 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% C0 2 .
• HL60 cells were plated at 1.2 x 10 s 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).
• VDR binding HL60 cell differentiation, and transcription activity. 3-desoxy-
• 3-desoxy-2MD will have significant activity as an anti-cancer agent, especially for preventing or treating osteosarcoma, leukemia, colon cancer, breast cancer, skin cancer and prostate cancer because it has direct cellular activity in causing cell differentiation and in suppressing cell growth.
• 3-desoxy-2MD is an excellent candidate for numerous human therapies as described herein.
• 3-desoxy-2MD is an excellent candidate for treating a cancer because: (1) it has significant VDR binding, transcription activity and cellular differentiation activity; (2) it has relatively low intestinal calcium absorption liability unlike 1,25(OH)2D3; and (3) it is easily synthesized. Because of its selective activity in the bone and increased potency on cellular differentiation, 3-desoxy-2MD might also be useful in treatment of bone diseases, such as senile osteoporosis, postmenopausal osteoporosis, steroid- induced osteoporosis, low bone turnover osteoporosis, osteomalacia, and renal osteodystrophy.
• bone diseases such as senile osteoporosis, postmenopausal osteoporosis, steroid- induced osteoporosis, low bone turnover osteoporosis, osteomalacia, and renal osteodystrophy.
• Figure 10 shows that 3D-MJ has relatively high activity in stimulating intestinal calcium transport. 3D-MJ has about the same potency as 1,25(OH)2D3 in promoting active calcium transport across the gut.
• Figure 9 demonstrates that 3D-MJ has relatively high bone calcium mobilization activity, as compared to 1,25(OH)2D3. 3D-MJ has about the same potency as the native hormone in releasing bone calcium stores.
• FIG. 7 illustrates that 3D-MJ has about the same potency as 1,25(OH)2D3 on
• FIG. 8 illustrates that the compound 3D-MJ has about the same transcriptional activity as 1 ⁇ ,25-dihydroxyvitamin D3 in bone cells.
• 3D-MJ is as potent as 1,25(OH)2D3 in increasing transcription of the 24-hydroxylase gene. This result, together with the cell differentiation activity of Figure 7, suggests that 3D-MJ will be very effective in treating the above referred to cancers because it has direct cellular activity in causing cell differentiation, gene transcription, and in suppressing cell growth.
• VDR binding HL60 cell differentiation, and transcription activity. 3D-MJ
• 3D-MJ will have significant activity as an anti-cancer agent, especially for preventing or treating osteosarcoma, leukemia, colon cancer, breast cancer, skin cancer and prostate cancer because it has direct cellular activity in causing cell differentiation and in suppressing cell growth.
• 3D-MJ is an excellent candidate for numerous human therapies as described herein.
• 3D-MJ is an excellent candidate for treating a cancer because: (1) it has significant VDR binding, transcription activity and cellular differentiation activity; and (2) it is easily synthesized. Because of its selective activity in the intestine and bone and increased potency on cellular differentiation, 3D-MJ might also be useful in treatment of bone diseases, such as senile osteoporosis, postmenopausal osteoporosis, steroid-induced osteoporosis, low bone turnover osteoporosis, osteomalacia, and renal osteodystrophy.
• bone diseases such as senile osteoporosis, postmenopausal osteoporosis, steroid-induced osteoporosis, low bone turnover osteoporosis, osteomalacia, and renal osteodystrophy.
• the compounds of this invention defined by formula I, 1 ⁇ , and lb 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 3-desoxy-2MD of formula 1 ⁇ and 3D-MJ of formula lb 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 0.01 ⁇ g to 1000 ⁇ g per day of the compounds I, particularly 3-desoxy-2MD and 3D-MJ, preferably from about 0.1 ⁇ g to about S00 ⁇ 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. 1 ⁇ -hydroxyvitamin D2 or D3, or 1 ⁇ ,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. 1 ⁇ -hydroxyvitamin D2 or D3, or 1 ⁇ ,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 3-desoxy-2MD and 3D-MJ, as defined by the above formula I, 1 ⁇ , and lb, 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 0.0 ⁇ g/day to about 1000 ⁇ g /day, and preferably from about 0.1 ⁇ g/day to about 500 ⁇ g/day.
• the compounds I 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 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 100 ⁇ .
• 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

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• 2012
  • 2012-06-13 CA CA2824870A patent/CA2824870C/en not_active Expired - Fee Related
  • 2012-06-13 WO PCT/US2012/042225 patent/WO2012174095A1/en not_active Ceased
  • 2012-06-13 EP EP12729302.5A patent/EP2721004B1/en not_active Not-in-force
  • 2012-06-13 US US13/495,548 patent/US8993547B2/en active Active
  • 2012-06-13 AU AU2012271759A patent/AU2012271759B2/en not_active Ceased
  • 2012-06-13 JP JP2014515955A patent/JP6035331B2/ja not_active Expired - Fee Related

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