WO2003088977A1 - (20S)-1α-HYDROXY-2α-METHYL AND 2β-METHYL-19-NOR-VITAMIN D3 AND THEIR USES - Google Patents

(20S)-1α-HYDROXY-2α-METHYL AND 2β-METHYL-19-NOR-VITAMIN D3 AND THEIR USES Download PDF

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WO2003088977A1
WO2003088977A1 PCT/US2003/008423 US0308423W WO03088977A1 WO 2003088977 A1 WO2003088977 A1 WO 2003088977A1 US 0308423 W US0308423 W US 0308423W WO 03088977 A1 WO03088977 A1 WO 03088977A1
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vitamin
methyl
hydroxy
administered
day
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French (fr)
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Hector F. Deluca
Rafal R. Sicinski
Pawel K. Grzywacz
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Wisconsin Alumni Research Foundation
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Wisconsin Alumni Research Foundation
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Priority to DE60324909T priority Critical patent/DE60324909D1/de
Priority to MXPA04010428A priority patent/MXPA04010428A/es
Priority to HK06100719.4A priority patent/HK1080728B/xx
Priority to EP03714261A priority patent/EP1496914B1/en
Priority to JP2003585729A priority patent/JP4511838B2/ja
Priority to CA002483409A priority patent/CA2483409A1/en
Priority to KR10-2004-7017019A priority patent/KR20040102156A/ko
Priority to NZ536421A priority patent/NZ536421A/en
Application filed by Wisconsin Alumni Research Foundation filed Critical Wisconsin Alumni Research Foundation
Priority to AU2003218267A priority patent/AU2003218267B2/en
Priority to BR0309405-7A priority patent/BR0309405A/pt
Publication of WO2003088977A1 publication Critical patent/WO2003088977A1/en
Priority to IL16468804A priority patent/IL164688A0/xx
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/417—Saturated compounds containing a keto group being part of a ring polycyclic
    • C07C49/423—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system
    • C07C49/427—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system having two rings
    • C07C49/433—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system having two rings the condensed ring system containing seven carbon atoms
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/417—Saturated compounds containing a keto group being part of a ring polycyclic
    • C07C49/423—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system
    • C07C49/427—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system having two rings
    • C07C49/443—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system having two rings the condensed ring system containing eight or nine carbon atoms

Definitions

  • This invention relates to vitamin D compounds, and more particularly to the pro-drugs (20S)-1 -hydroxy-2 ⁇ -methyl and 2 ⁇ -methyl-19-nor-vitamin D 3 and their pharmaceutical uses.
  • the natural hormone, 1 ⁇ ,25-dihydroxyvitamin D3 and its analog in ergosterol series, i.e. 1 ⁇ ,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, 1 ⁇ -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 as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
  • vitamin D analogs which are 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 revealed a selective activity profile with high potency in inducing cellular differentiation, and very low calcium mobilizing activity.
  • these compounds are potentially useful as therapeutic agents for the treatment of malignancies, or the treatment of various skin disorders.
  • the present invention is directed toward the pro-drugs (20S)-1 ⁇ -hydroxy- 2 ⁇ -methyl-19-nor-vitamin D 3 (formula la below) and (20S)-1 ⁇ -hydroxy-2 ⁇ -methyl- 19-nor-vitamin D 3 (formula lb below), their biological activity, and various pharmaceutical uses for these compounds.
  • the above two compounds exhibit a desired, and highly advantageous, pattern of biological activity. These compounds do not bind or bind poorly to the vitamin D receptor.
  • the 2 ⁇ -methyl compound has greater intestinal calcium transport activity, as compared to that of 1 ⁇ ,25-dihydroxyNitamin D3, and has greater ability to mobilize calcium from bone, as compared to 1 ⁇ ,25- dihydroxyvitamin D 3 .
  • the 2 ⁇ -methyl compound has intestinal calcium transport activity and bone calcium mobilization activity about the same as 1 ⁇ ,25- dihydroxyvitamin D 3 .
  • these compounds can be characterized as having very potent calcemic activity, and are highly specific in their calcemic activity.
  • these compounds have activity on mobilizing calcium from bone and either high or normal intestinal calcium transport activity allows the in vivo administration of these compounds for the treatment of metabolic bone diseases where bone loss is a major concern. Because of their activity on bone, these compounds would be preferred therapeutic agents for the treatment 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.
  • osteoporosis especially low bone turnover osteoporosis, steroid induced osteoporosis, senile osteoporosis or postmenopausal osteoporosis, as well as osteomalacia.
  • the compounds 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, lupis, diabetes mellitus, host versus graft reaction, 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 and Crohns disease. Acne, alopecia and hypertension are other conditions which may be treated with the compounds of the invention.
  • the above compounds are also characterized by high or significant cell differentiation activity.
  • 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 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 may be present in a composition to treat the above- noted diseases and disorders in an amount from about 0.01 ⁇ g/gm to about 100 ⁇ 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.
  • Figure 1 is a graph illustrating the relative activity of (20S)-1 ⁇ -hydroxy-2 ⁇ - methyl-19-nor-vitamin D 3 , (20S)-1 ⁇ -hydroxy-2 ⁇ -methy 1-19-nor-vitamin D 3 , and 1 ⁇ ,25-dihydroxyvitamin D 3 to compete for binding of [ 3 H]-1 ,25-(OH) 2 -D 3 to the vitamin D pig intestinal nuclear receptor; and
  • Figure 2 is a graph illustrating the percent HL-60 cell differentiation as a function of the concentration of (20S)-1 ⁇ -hydroxy-2 ⁇ -methyl-19-nor-vitamin D 3 , (20S)-1 ⁇ -hydroxy-2 ⁇ -methyl-19-nor-vitamin D 3 , and of 1 ,25-dihydroxyvitamin D 3 .
  • (20S)-1 ⁇ -Hydroxy-2 -methyl-19-nor-vitamin D 3 and (20S)-1 ⁇ -hydroxy-2 ⁇ - methy 1-19-nor-vitamin D 3 were synthesized and tested. Structurally, these 19-nor analogs are characterized by the formula la and lb, respectively, previously illustrated herein.
  • the preparation of (20S)-1 ⁇ -hydroxy-2 ⁇ -methyl- and (20S)-1 ⁇ -hydroxy- 2 ⁇ -methyl-19-nor-vitamin D 3 having structures la and lb can be accomplished by a common general method, i.e.
  • Y- j and Y2 are hydroxy-protecting groups, preferably tBuMe 2 Si groups, 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. Chem.
  • a hydrindanone of the structure II is a new compound that can be prepared from commercial vitamin D 2 by modification of known methods.
  • the starting alcohol 1 was prepared from commercial vitamin D 2 in 3 steps (Scheme 1).
  • the resulting C-22 alcohol 1 was oxidized to the aldehyde 2, which then was equilibrated at C-20.
  • the mixture of (20R)- and (20S)-aldehydes was reduced and (20R)-alcohol 3 was isolated by chromatography. This, in turn, was tosylated and the tosylate 4 coupled with the Grignard reagent 5 in the presence of dilithium tetrachlorocuprate.
  • the obtained hydrindanol 6 was oxidized to the new (20S)-Grundmann ketone analog II.
  • the final step of the process is the selective homogeneous catalytic hydrogenation of the exomethylene unit at carbon 2 in the vitamin V performed efficiently in the presence of tris(triphenylphosphine)rhodium(l) chloride [Wilkinson's catalyst, (Ph 3 P) 3 RhCI].
  • the isolated material is an epimeric mixture (ca. 1 :1) of 2-methyl-19-nor-vitamins la and lb differing in configuration at C-2.
  • the mixture can be used without separation or, if desired, the individual 2 ⁇ - and 2 ⁇ -isomers can be separated by an efficient HPLC system.
  • the starting alcohol 1 was prepared from commercial vit-unin D 2 in 70% yield, according to the procedure published by J. C. Hanekamp, R. B. R ⁇ okhuizen, H. J. T. Bos, L. Brandsma Tetrahedron, 1992, 48 , 9283-9294.
  • Ozone was passed through a solution of vitamin D 2 (3 g, 7.6 mmol) in methanol (250 mL) and pyridine (2.44 g, 2.5 mL, 31 mmol) for 50 min at -78 °C.
  • the reaction mixture was then flushed with an oxygen for 15 min to remove the residual ozone and the solution was treated with NaBH (0.75 g, 20 mmol).
  • the second portion of N-1BH 4 (0.75 g, 20 mmol
  • the third portion of NaBH 4 (0.75 g, 20 mmol) was then added and the reaction mixture was stirred for 18 h.
  • the aldehyde 2 (1.36 g, 4.3 mmol) was dissolved in CH 2 C1 2 (15 mL) and a 40% aq. n-Bu NOH solution (5.6 mL, 5.57 g, 8.6 mmol) was added. The resulting mixture was stirred at room temperature for 16 h, diluted with methylene chloride (30 mL), washed with water, dried (Na 2 SO 4 ) and concentrated under reduced pressure. A residue was chromatographed on silica gel with hexane/ethyl acetate (95:5) to afford a mixture of aldehyde 2 and its 2Q-epimer (730 mg, 53% yield) in ca. 1:1.7 ratio (by 1H NMR).
  • Tris(triphenylphosphine)rhodium (I) chloride (3.5 mg, 3.8 ⁇ mol) was added to dry benzene (2.5 mL) presaturated with hydrogen. The mixture was stirred at room temperature until a homogeneous solution was formed (ca. 45 min). A solution of vit-imin V (1.8 mg, 4.5 ⁇ mol) in dry benzene (400+400 ⁇ L) was then added and the reaction was allowed to proceed under a continuous stream of hydrogen for 3 h. Benzene was removed under vacuum, the residue was redissolved in hexane/ethyl acetate (1:1) and applied on a Waters silica Sep-Pak cartridge (2 g).
  • Figure 2 illustrates (20S)-1 ⁇ -hydroxy-2 ⁇ -methyl-19-nor- vitamin D 3 is almost as potent as 1,25-(OH) 2 D 3 on HL-60 differentiation, making it an excellent candidate for the treatment of psoriasis and cancer, especially against leukemia, colon cancer, breast 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.
  • the 2 ⁇ derivative is 100 times less active than 1 ,25(OH) 2 D 3 making it less effective in these areas.
  • (20S)-1 ⁇ -hydroxy-2 ⁇ -methyl-19-nor-vitamin D 3 has significant bone calcium mobilization activity, and its activity is about the same as 1 ,25-(OH) 2 D 3 .
  • (20S)-1 ⁇ -hydroxy-2 ⁇ -methyl-19- nor-vitamin D 3 may be characterized as having significant and very potent calcemic activity which is greater than 1 ,25-(OH) 2 D 3 , and that (20S)-1 ⁇ -hydroxy- 2 ⁇ -methyl-19-nor-vitamin D 3 also has significant and very potent calcemic activity that is about the same as 1 ,25-(OH) 2 D 3 .
  • Intestinal calcium transport was determined as described by Perlman et al. (Biochemistry 29, 190-196, 1990).
  • the compounds la and lb exhibit a desired, and highly advantageous, pattern of biological activity. These compounds are characterized by relatively high intestinal calcium transport activity, as compared 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. Hence, these compounds are highly specific in their calcemic activity. Their activity on mobilizing calcium from bone and either high or normal intestinal calcium transport activity allows the in vivo administration of these compounds for the treatment of metabolic bone diseases where bone loss is a major concern.
  • these compounds would be preferred therapeutic agents for the treatment 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.
  • (20S)-1 ⁇ -Hydroxy-2 ⁇ -methyl-19-nor-vitamin D 3 and (20S)-1 ⁇ -hydroxy-2 ⁇ - methyl-19-nor-vitamin D 3 are much less active than 1 ,25(OH) 2 D 3 in binding to the vitamin D receptor ( Figure 1 ), and they are both also only slightly less active than 1 ,25-(OH) 2 D 3 in causing differentiation of the promyelocyte, HL-60, into the monocyte ( Figure 2).
  • (20S)-1 ⁇ -hydroxy-2 ⁇ -methyl-19-nor-vitamin D 3 and (20S)-1 ⁇ -hydroxy-2 ⁇ -methyl-19-nor-vitamin D 3 are both excellent candidates for numerous human therapies and that they may be useful in a number of circumstances in addition to cancer and psoriasis such as autoimmune diseases.
  • the compounds of this invention defined by formula la 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 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 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. Since the compounds exhibit specificity of action, each may be suitably administered alone, or together with graded doses of another active vitamin D compound - e.g. 1 ⁇ - hydroxyvitamin D 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 (20S)-1 ⁇ -hydroxy-2 ⁇ -methyl-19-nor-vitamin D 3 or (20S)- 1 ⁇ -hydroxy-2 ⁇ -methyl-19-nor-vitamin D 3 as defined by the above formula la 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 100 ⁇ g per gm of composition, and may be administered topically, transdermally, orally or parenterally in dosages of from about 0.01 ⁇ g/day to about 100 ⁇ 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.
  • 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 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.

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PCT/US2003/008423 2002-04-22 2003-03-20 (20S)-1α-HYDROXY-2α-METHYL AND 2β-METHYL-19-NOR-VITAMIN D3 AND THEIR USES Ceased WO2003088977A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
KR10-2004-7017019A KR20040102156A (ko) 2002-04-22 2003-03-20 (20Ｓ)-1α-히드록시-2α-메틸 및2β-메틸-19-노르-비타민 Ｄ₃ 및 그의 용도
HK06100719.4A HK1080728B (en) 2002-04-22 2003-03-20 (20s)-1alpha-hydroxy-2alpha-methyl, and 2beta-methyl-19-nor-vitamin d3 and their uses
EP03714261A EP1496914B1 (en) 2002-04-22 2003-03-20 (20S)-1alpha-HYDROXY-2alpha-METHYL AND 2beta-METHYL-19-NOR-VITAMIN D3 AND THEIR USES
JP2003585729A JP4511838B2 (ja) 2002-04-22 2003-03-20 （２０Ｓ）−１α−ヒドロキシ−２α−メチル及び２β−メチル−１９−ノル−ビタミンＤ３及びそれらの使用
CA002483409A CA2483409A1 (en) 2002-04-22 2003-03-20 (20s)-1.alpha.-hydroxy-2.alpha.-methyl and 2.beta.-methyl-19-nor-vitamin d3 and their uses
DE60324909T DE60324909D1 (de) 2002-04-22 2003-03-20 (20s)-1alpha-hydroxy-2alpha-methyl und 2beta-methyl-19-nor vitamin d3 und ihre verwendung
BR0309405-7A BR0309405A (pt) 2002-04-22 2003-03-20 Compostos e métodos de tratamento da psorìase de doença selecionada do grupo que consiste em leucemia, câncer de cólon, câncer de peito ou câncer de próstata, de doença autoimune, de doença inflamatória, de condição de pele e de doença metabólica do osso
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