[go: up one dir, main page]

WO2006035075A1 - Utilisation de composes de vitamine d pour la prevention ou le traitement de la prostatite chronique - Google Patents

Utilisation de composes de vitamine d pour la prevention ou le traitement de la prostatite chronique Download PDF

Info

Publication number
WO2006035075A1
WO2006035075A1 PCT/EP2005/054965 EP2005054965W WO2006035075A1 WO 2006035075 A1 WO2006035075 A1 WO 2006035075A1 EP 2005054965 W EP2005054965 W EP 2005054965W WO 2006035075 A1 WO2006035075 A1 WO 2006035075A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
vitamin
methyl
mmol
cholecalciferol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2005/054965
Other languages
English (en)
Inventor
Luciano Adorini
Giuseppe Penna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bioxell SpA
Original Assignee
Bioxell SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0508694A external-priority patent/GB0508694D0/en
Application filed by Bioxell SpA filed Critical Bioxell SpA
Publication of WO2006035075A1 publication Critical patent/WO2006035075A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate

Definitions

  • vitamin D analogues can treat and prevent chronic prostatitis, in particular non-bacterial chronic prostatitis, for example chronic auto-immune prostatitis.
  • vitamin D cholesterol calcium and phosphorus homeostasis
  • vitamin D and its structural analogues have been limited by the undesired side effects elicited by these compounds after administration to a subject for known indications/applications of vitamin D compounds.
  • vitamin D 3 The activated form of vitamin D, vitamin D 3 , and some of its analogues have been described as potent regulators of cell growth and differentiation. It has previously been found that vitamin D 3 , as well as an analogue (l,25-dihydroxy-16ene,23yne vitamin D 3 , also known as analogue V, referred to elsewhere herein as Compound B), inhibited Benign Prostatic Hyperplasia (BPH) cell proliferation and counteracted the mitogenic activity of potent growth factors for BPH cells, such as keratinocyte growth factor (KGF) and insulin-like growth factor (IGFl). Moreover, the analogue induced bcl-2 protein expression, intracellular calcium mobilization, and apoptosis in both unstimulated and KGF- stimulated BPH cells.
  • analogue induced Benign Prostatic Hyperplasia
  • FIG. 2 shows the protocol for treatment of established EAP.
  • Figure 3 shows the histological analysis and H&E staining of frozen sections.
  • Figure 4 shows a demonstration that VDR agonists treat established EAP without affecting serum calcium levels.
  • Figure 6 shows increased Foxp3 expression in prostate-draining lymph nodes from VDR agonist -treated NOD mice.
  • Figure 9 shows development of NOD autoimmune prostatitis.
  • Figure 10 shows prostate organ culture from NOD and NOD:SCID mice.
  • Figure 15 shows H&E staining of frozen sections of ganglia of the prostate peripheral nervous system.
  • Figure 20 shows the contractile responses in dorsal prostatic lobes.
  • Non inflammatory CP no evidence of leucocytes
  • CP is CP of category III (i.e. it does not include asymptomatic inflammatory prostatitis).
  • CPPS Chronic Pelvic Pain Syndrome
  • chronic prostatitis excludes Benign Prostatic Hyperplasia (BPH).
  • the vitamin D compound may be used to treat chronic prostatitis in males. Such males may concurrently suffer from BPH. Alternatively they may not suffer from BPH.
  • administration includes routes of introducing the vitamin D compound(s) to a subject to perform their intended function.
  • routes of administration include injection (subcutaneous, intravenous, parenterally, intraperitoneally), oral, inhalation, rectal, transdermal or via bladder instillation.
  • the pharmaceutical preparations are, of course, given by forms suitable for each administration route.
  • the preparations may be administered orally in tablets or capsule form, by injection, inhalation, topically as a lotion or ointment, rectally as a suppository etc.
  • Oral administration is preferred.
  • the injection can be bolus or can be continuous infusion.
  • an effective amount includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, i.e. sufficient to treat chronic prostatitis.
  • An effective amount of vitamin D compound may vary according to factors such as the disease state, age and weight of the subject, and the ability of the vitamin D compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the vitamin D compound are outweighed by the therapeutically beneficial effects.
  • the dose administered will also depend on the particular vitamin D compound used, the effective amount of each compound can be determined by titration methods known in the art.
  • treatment of a subject with a therapeutically effective amount of a vitamin D compound can include a single treatment or, preferably, can include a series of treatments.
  • a subject is treated with a vitamin D compound in the range of between about 0.1 to 20 ug/kg body weight, once per day for a duration of six months or longer, for example for life depending on management of the symptoms and the evolution of the condition.
  • an "on-off ' or intermittent treatment regime can be considered.
  • the effective dosage of a vitamin D compound used for treatment may increase or decrease over the course of a particular treatment.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six, and most preferably from one to four carbon atoms in its backbone structure, which may be straight or branched-chain.
  • lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, tert -butyl, hexyl, heptyl, octyl and so forth.
  • the term "lower alkyl” includes a straight chain alkyl having 4 or fewer carbon atoms in its backbone, e.g., C 1 -C 4 alkyl.
  • Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the invention contemplates cyano and propargyl groups.
  • thiol means -SH; the term “hydroxyl” means -OH.
  • haloalkyl is intended to include alkyl groups as defined above that are mono-, di- or polysubstituted by halogen, e.g., fluoroalkyl such as fluoromethyl and trifluoromethyl.
  • hydroxyalkyl is intended to include alkyl groups as defined above that are mono-, di- or polysubstituted by hydroxy, e.g., hydroxymethyl or 2-hydroxyethyl.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl,
  • vitamin D compound includes any compound that is capable of treating or preventing chronic prostatitis.
  • compounds which are ligands for the vitamin D receptor (VDR ligands) and which are capable of treating or preventing chronic prostatitis are considered to be within the scope of the invention.
  • Vitamin D compounds are preferably agonists of the vitamin D receptor.
  • vitamin D compounds are intended to include secosteroids. Examples of specific vitamin D compounds suitable for use in the methods of the present invention are further described herein.
  • a vitamin D compound includes vitamin D 2 compounds, vitamin D 3 compounds, isomers thereof, or derivatives/analogues thereof.
  • Preferred vitamin D compounds are vitamin D 3 compounds which are ligands of
  • vitamin D 3 The official IUPAC name for vitamin D 3 is 9,10-secocholesta-5,7,10(19)-trien-3B-ol.
  • a 6-s-trans conformer of l-alpha,25(OH) 2 D 3 is illustrated herein having all carbon atoms numbered using standard steroid notation.
  • a dotted line ( — ) indicating a substituent which is in the beta-orientation (i.e., above the plane of the ring)
  • a wedged solid line ( ⁇ ) indicating a substituent which is in the alpha-orientation (i.e., below the plane of the molecule)
  • a wavy line ( ⁇ ) indicating that a substituent may be either above or below the plane of the ring.
  • ring A it should be understood that the stereochemical convention in the vitamin D field is opposite from the general chemical field, wherein a dotted line indicates a substituent on Ring A which is in an alpha-orientation (i.e., below the plane of the molecule), and a wedged solid line indicates a substituent on ring A which is in the beta- orientation (i.e., above the plane of the ring).
  • X 1 and X 2 are defined as H 2 or CH 2 .
  • the invention provides the use of a vitamin D compound in the prevention or treatment of chronic prostatitis. It provides a vitamin D compound for use in the prevention or treatment of chronic prostatitis. Also provided is a method of treating a patient with chronic prostatitis or preventing chronic prostatitis by administering an effective amount of a vitamin D compound. More particularly, there is provided a method of prevention or treatment of chronic prostatitis in a patient in need thereof by administering an effective amount of a Vitamin D compound therebv to prevent or treat chronic prostatitis in said patient. Said method typically further comprises the step of obtaining or synthesising the Vitamin D compound.
  • the Vitamin D compound is usually formulated in a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier.
  • a vitamin D compound in the manufacture of a medicament for the prevention or treatment of chronic prostatitis.
  • the vitamin D compound for use in accordance with the invention comprises a compound of formula I:
  • R 1 and R 2 are hydrogen, C 1 -C 4 alkyl or 4-hydroxy-4-methylpentyl, wherein R 1 and R 2 are not both hydrogen;
  • X 1 is H 2 or CH 2 ;
  • a 2 is a single, a double or a triple bond
  • R 3 is C 1 -C 4 alkyl, hydroxyalkyl, or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl or trifluoromethyl
  • R 4 is C 1 -C 4 alkyl, hydroxyalkyl or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl or trifluoromethyl
  • the configuration at C 20 is R or S.
  • the vitamin D compound for use in accordance with the invention is a compound of the formula:
  • X is hydroxyl or fluoro.
  • the vitamin D compound for use in accordance with the invention is a compound having the formula:
  • R 1 and R 2 are each, independently, hydrogen, or alkyl, e.g., methyl;
  • R 3 is alkyl, e.g., methyl
  • R 4 is alkyl, e.g., methyl
  • the vitamin D compound for use in accordance with the invention is selected from the group consisting of:
  • the vitamin D compound for use in accordance with the invention is selected from the group of geminal compounds consisting of:
  • Xi is H 2 or CH 2 ;
  • a 2 is a single, a double or a triple bond
  • R 1 , R 2 , R 3 and R 4 are each independently Ci-C 4 alkyl, hydroxyalkyl, or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl or trifluoromethyl;
  • Xi is CH 2 .
  • a 2 is a single bond.
  • R 1 , R 2 , R 3 , and R 4 are each independently methyl or ethyl.
  • Z is -OH.
  • Xi is CH 2 ;
  • a 2 is a single bond;
  • R 1 , R 2 , R 3 , and R 4 are each independently methyl or ethyl; and
  • Z is -OH.
  • R 1 , R 2 , R 3 , and R 4 are each methyl.
  • the vitamin D compound for use in accordance with the invention is a geminal compound of the formula:
  • the chemical names of the compounds 2 and 3 mentioned above are: l,25-dihydroxy-21-(2R,3-dihydroxy-3-methyl-butyl)-20R-cholecalciferol; and l,25-dihydroxy-21-(2R,3-dihydroxy-3-methyl-butyl)-20S-cholecalciferol.
  • geminal compounds include the following vitamin D compounds for use in accordance with the invention. 1 , 25 -Dihydroxy-21 -(2R,3 -dihydroxy-3 -methyl-butyl)-20S- 19-nor-cholecalciferol:
  • the vitamin D compound for use in accordance with the invention is a compound of the formula:
  • R 3 and R 4 are each independently hydrogen, C 1 -C 4 alkyl, hydroxyalkyl or haloalkyl or R 3 and R 4 taken together with C 20 form C 3 -C 6 cycloalkyl;
  • R 5 and R 6 are each independently C 1 -C 4 alkyl, hydroxyalkyl or haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • R 3 and R 4 will preferably each be independently selected from hydrogen and C 1 -C 4 alkyl.
  • R 5 and R 6 are each independently C 1 -C 4 alkyl.
  • R 5 and R 6 are each independently haloalkyl e.g., C 1 -C 4 fluoroalkyl.
  • R 3 and R 4 are taken together with C 20 to form C 3 -C 6 cycloalkyl, an example is cyclopropyl.
  • X 1 and X 2 are each H 2 .
  • R 3 is hydrogen and R 4 is C 1 -C 4 alkyl. In a preferred embodiment R 4 is methyl.
  • R 5 and R 6 are each independently methyl, ethyl, fluoromethyl or trifluoromethyl. In a preferred embodiment, R 5 and R 6 are each methyl.
  • the vitamin D compound for use in accordance with the invention is 2-methylene-19-nor-20(S)-l-alpha-hydroxyvitamin D3:
  • a 1 is single or double bond
  • a 2 is a single, double or triple bond
  • X 1 and X 2 are each independently H 2 or CH 2 , provided X 1 and X 2 are not both CH 2 ;
  • R 1 and R 2 are each independently OC(O)C 1 -C 4 alkyl (including OAc), OC(O)hydroxyalkyl or OC(O)haloalkyl;
  • R 3 , R 4 and R 5 are each independently hydrogen, C 1 -C 4 alkyl, hydroxyalkyl, or haloalkyl, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cycloalkyl; R 6 and R 7 are each independently Ci ⁇ alkyl or haloalkyl; and
  • R 8 is H, -COC 1 -C 4 alkyl (eg Ac), -COhydroxyalkyl or -COhaloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • a 1 is a single bond and A 2 is a single bond, E or Z double bond, or a triple bond. In another embodiment, A 1 is a double bond and A 2 is a single bond, E or Z double bond, or a triple bond.
  • R 5 is absent.
  • X 1 and X 2 are each H. In another embodiment, X 1 is CH 2 and X 2 is H 2 .
  • R 3 is hydrogen and R 4 is C 1 -C 4 alkyl. In a preferred embodiment R 4 is methyl.
  • R 1 and R 2 both represent OAc.
  • R 6 and R 7 are each independently Ci ⁇ alkyl.
  • R 6 and R 7 are each independently haloalkyl.
  • R 6 and R 7 are each independently methyl, ethyl or fluoroalkyl.
  • R 6 and R 7 are each trifluoroalkyl, e.g., trifluoromethyl.
  • R 5 represents hydrogen
  • vitamin D compounds for use in accordance with the invention are represented by formula I-a:
  • a 1 is single or double bond
  • a 2 is a single, double or triple bond
  • R 1 and R 2 are each independently OC(O)C 1 -C 4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl;
  • R 8 is H, C(O)C 1 -C 4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • R 1 and R 2 are each OAc; A 1 is a double bond; A 2 is a triple bond; and R 8 is either H or Ac for example the following compound:
  • vitamin D compounds for use in accordance with the invention are represented by the formula I-b:
  • the vitamin D compounds for use in accordance with the invention are represented by the formula I-c:
  • vitamin D compounds for use in accordance with the invention are compounds of the formula:
  • R 1 is hydrogen, hydroxy or fluorine
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or methyl, when R 2 or R 3 is methyl, R 3 or R 2 must be hydrogen;
  • R 4 is methyl, ethyl or trifluoromethyl
  • A is a single or double bond
  • esters include pharmaceutically acceptable labile esters that may be hydrolysed in the body to release Compound A.
  • Salts of Compound A include adducts and complexes that may be formed with alkali and alkaline earth metal ions and metal ion salts such as sodium, potassium and calcium ions and salts thereof such as calcium chloride, calcium malonate and the like.
  • Compound A may be administered as a pharmaceutically acceptable salt or ester thereof, preferably Compound A is employed as is i.e., it is not employed as an ester or a salt thereof.
  • X 1 and X 2 are each independently H 2 or CH 2 , provided X 1 and X 2 are not both CH 2 ;
  • vitamin D compounds of the invention is l,25-dihydroxy-21(3-hydroxy-3- trifluoromethyl-4-trifluoro-butynyl)-26,27-hexadeutero-19-nor-20S-cholecalciferol.
  • Further vitamin D 3 compounds of the invention have the formula:
  • B is single, double, or triple bond
  • R 2 , R 3 and R 6 are each independently hydrogen, C 1 -C 4 alkyl, hydroxyalkyl, or haloalkyl, with the understanding that R 6 is absent when B is a triple bond, or R 2 and R 3 taken together with C 20 form C 3 -C 6 cycloalkyl;
  • R 4 and R 5 are each independently alkyl or haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • Compound F (l,3-Di-O-acetyl-l,25-dihydroxy-16-ene-24-keto-19-nor-cholecalciferol) having the structure:
  • vitamin D compound of use in the present invention is Compound D (1 -alpha- fluoro-25- hydroxy- 16-ene-23 -yne-20-cyclopropyl-cholecalciferol) :
  • Naturally occurring or synthetic isomers can be separated in several ways known in the art. Methods for separating a racemic mixture of two enantiomers include chromatography using a chiral stationary phase (see, e.g., "Chiral Liquid Chromatography,” WJ. Lough, Ed. Chapman and Hall, New York (1989)). Enantiomers can also be separated by classical resolution techniques. For example, formation of diastereomeric salts and fractional crystallization can be used to separate enantiomers.
  • the diastereomeric salts can be formed by addition of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and the like.
  • diastereomeric esters can be formed with enantiomerically pure chiral alcohols such as menthol, followed by separation of the diastereomeric esters and hydrolysis to yield the free, enantiomerically enriched carboxylic acid.
  • the invention also provides a pharmaceutical composition, comprising an effective amount of a vitamin D compound as described herein and a pharmaceutically acceptable carrier.
  • the effective amount is effective to treat chronic prostatitis, as described previously.
  • the vitamin D compound is administered to the subject using a pharmaceutically-acceptable formulation, e.g., a pharmaceutically-acceptable formulation that provides sustained delivery of the vitamin D compound to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.
  • these pharmaceutical compositions are suitable for topical or oral administration to a subject.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intrarectally, for example, as a suppository, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes
  • parenteral administration for example, by subcutaneous, intramuscular or intravenous injection as, for
  • pharmaceutically acceptable refers to those vitamin D compounds of the present invention, compositions containing such compounds, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier includes pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • compositions containing a vitamin D compound(s) include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, aerosol and/or parenteral administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 to about 99.5 per cent e.g. from about 1 per cent to about 99 percent of active ingredient or else from about 0.5 per cent to about 90 per cent, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent by weight.
  • compositions include the step of bringing into association a vitamin D compound(s) with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a vitamin D compound with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a vitamin D compound(s) as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical- formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro -encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the vitamin D compound(s) include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solub
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active vitamin D compound(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of the invention for rectal administration may be presented as a suppository, which may be prepared by mixing one or more vitamin D compound(s) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum and release the active agent.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum and release the active agent.
  • Dosage forms for the topical or transdermal administration of a vitamin D compound(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active vitamin D compound(s) may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to vitamin D compound(s) of the present invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a vitamin D compound(s), excipients such as lactose, talc, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons or hydrofluoroalkanes such as HFAl 34a or HFA227 and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the vitamin D compound(s) can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A nonaqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically-acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • Transdermal patches have the added advantage of providing controlled delivery of a vitamin D compound(s) to the body.
  • dosage forms can be made by dissolving or dispersing the agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the active ingredient across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active ingredient in a polymer matrix or gel.
  • compositions of the invention suitable for parenteral administration comprise one or more vitamin D compound(s) in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutan
  • Injectable depot forms are made by forming microencapsule matrices of vitamin D compound(s) in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the vitamin D compound(s), which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • An exemplary dose range is from 0.1 to 300 ug per day.
  • An exemplary dose range of Compound A is from 0.1 to 300 ug per day, for example 50-150 ug per day e.g., 75 or 150 ug per day.
  • a unit dose formulation preferably contains 50-150 ug e.g., 75 or 150 ug and is preferably administered once per day.
  • a preferred dose of the vitamin D compound for the present invention is the maximum that a patient can tolerate and not develop hypercalcemia.
  • the invention also includes a packaged formulation including a pharmaceutical composition comprising a vitamin D compound and a pharmaceutically acceptable carrier packaged with instructions for use in the prevention and/or treatment of chronic prostatitis.
  • Exemplary methods of synthesis include the photochemical ring opening of a 1 - hydroxy lated side chain-modified derivative of 7-dehydrocholesterol which initially produces a previtamin that is easily thermolyzed to vitamin D 3 in a well known fashion (Barton, D.H.R. et al. (1973) J. Am. Chem. Soc. 95:2748-2749; Barton, D.H.R. (1974) JCS Chem. Comm. 203- 204); phosphine oxide coupling method developed by (Lythgoe, et al. ( 1978) JCSPerkin Trans.
  • Examples of the compounds of use in this invention having a saturated side chain can be prepared according to the general process illustrated and described in U.S. Patent No.
  • Examples of compounds of the invention having an unsaturated side chain can be prepared according to the general process illustrated and described in U.S. Patent No. 4,847,012.
  • Examples of compounds of the invention wherein R groups at position C20 together represent a cycloalkyl group can be prepared according to the general process illustrated and described in U.S. Patent No. 4,851,401.
  • the starting material l,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor-cholecalciferol can be prepared as described in US Patent 5,428,029 to Doran et al.. 3 mg of 1,25-dihydroxy- 16,23Z-diene-26,27-hexafluoro-19-nor-cholecalciferol was dissolved in 0.8 ml of pyridine, cooled to ice-bath temperature and 0.2 ml of acetic anhydride was added and maintained at that temperature for 16 h.
  • reaction mixture was diluted with 1 ml of water, stirred for 10 min in the ice bath and distributed between 5 ml of water and 20 ml of ethyl acetate.
  • the organic layer was washed with 3 x 5 ml of water, once with 5 ml of saturated sodium hydrogen carbonate, once with 3 ml of brine then dried (sodium sulfate) and evaporated.
  • the oily residue was taken up in 1 :6 ethyl acetate - hexane and flash-chromatographed using a stepwise gradient of 1:6, 1 :4 and 1 :2 ethyl acetate - hexane.
  • the starting material l,25-dihydroxy-16-ene-23-yne-26,27-hexafluoro-19-nor-cholecalciferol can be prepared as described in US Patents 5,451,574 and 5,612,328 to Baggiolini et al.. 314 mg (0.619 mmole) of l,25-dihydroxy-16-ene-23-yne-26,27-hexafluoro-19-nor-cholecalciferol was dissolved in 1.5 ml of pyridine, cooled to ice-bath temperature, and 0.4 ml of acetic anhydride was added. The reaction mixture was kept at room temperature for 7 hours and then for 23 hours in a refrigerator.
  • 0.0468 g of l ⁇ S-Dihydroxy-l ⁇ E-diene-cholecalciferol was dissolved in 1.5 mL of pyridine. This solution was cooled in an ice bath then refrigerated overnight, diluted with 10 mL of water while still immersed in the ice bath, stirred for 10 min and transferred to a separatory funnel with the aid of 10 mL of water and 40 mL of ethyl acetate. The organic layer was washed with 4x20 mL of water, 10 mL of brine passed through a plug of sodium sulfate and evaporated.
  • 0.0774 g of l ⁇ S-Dihydroxy-l ⁇ -ene-cholecalciferol was dissolved in 1.5 mL of pyridine. This solution was cooled in an ice bath then 0.3 mL of acetic anhydride was added. The solution was stirred, refrigerated overnight then diluted with 1 mL of water, stirred for 1 h in the ice bath and diluted with 30 mL of ethyl acetate and 15 mL of water. The organic layer was washed with 4x15 mL of water, once with 5 mL of brine then dried (sodium sulfate) and evaporated.
  • 0.0291 g of l,25-dihydroxy-16-ene-23-yne-26,27-hexafluoro-cholecalciferol was dissolved in 1.5 mL of pyridine. This solution was cooled in an ice bath then 0.25 mL of acetic anhydride was added. The solution was stirred for 20 min and kept in a freezer overnight. The cold solution was diluted with 15 mL of water, stirred for 10 min, and diluted with 30 mL of ethyl acetate. The organic layer was washed with 4x15 mL of water, once with 5 mL of brine then dried (sodium sulfate) and evaporated.
  • 1.5 mL of l,25-dihydroxy-16,23E-diene-25R,26-trifluoro-cholecalciferol was dissolved in 1.5 mL of pyridine, cooled to ice-bath temperature and 0.4 mL of acetic anhydride was added. The mixture was then refrigerated. After two days the mixture was diluted with 1 mL of water, stirred for 10 min in the ice bath then distributed between 10 mL of water and 30 mL of ethyl acetate. The organic layer was washed with 4x15 mL of water, once with 5 mL of brine then dried (sodium sulfate) and evaporated.
  • 0.0726 g of l,25-dihydroxy-16-ene-23-yne-26,27-bishomo-19-nor-cholecalciferol was dissolved in 0.8 mL of pyridine, cooled to ice-bath temperature and 0.2 mL of acetic anhydride was added. The solution was stirred in the ice-bath then refrigerated overnight. The solution was then diluted with 1 mL of water, stirred for 10 min in the ice bath and distributed between 10 mL of water and 25 mL of ethyl acetate.
  • 0.282 g of l,25-Dihydroxy-20-cyclopropyl-23-yne-19-nor-cholecalciferol was dissolved in 0.8 mL of pyridine, cooled to ice-bath temperature and 0.2 mL of acetic anhydride was added and the mixture was refrigerated overnight, then diluted with 1 mL of water, stirred for 10 min in the ice bath and distributed between 5 mL of water and 20 mL of ethyl acetate. The organic layer was washed with 3x5 mL of water, once with 5 mL of saturated sodium hydrogen carbonate, once with 3 mL of brine then dried (sodium sulfate) and evaporated.
  • 0.0369 g of l,25-dihydroxy-20-cyclopropyl-23-yne-cholecalciferol was dissolved in 0.8 mL of pyridine, cooled to ice-bath temperature and 0.2 mL of acetic anhydride was added and the mixture was refrigerated overnight, then diluted with 1 mL of water, stirred for 10 min in the ice bath and distributed between 5 mL of water and 20 mL of ethyl acetate. The organic layer was washed with 3x5 mL of water, once with 5 mL of saturated sodium hydrogen carbonate, once with 3 mL of brine then dried (sodium sulfate) and evaporated.
  • 0.0429 g of l,25-dihydroxy-20-cyclopropyl-23Z-ene-26,27-hexafluoro-19-nor-cholecalciferol was dissolved in 0.8 mL of pyridine, cooled to ice-bath temperature and 0.2 mL of acetic anhydride was added. The solution was refrigerated overnight. The solution was then diluted with 1 mL of water, stirred for 10 min in the ice bath and distributed between 7 mL of water and 25 mL of ethyl acetate.
  • 0.0797 g of l,25-dihydroxy-20-cyclopropyl-cholecalciferol was dissolved in 0.8 mL of pyridine, cooled to ice-bath temperature and 0.2 mL of acetic anhydride was added. The solution was refrigerated overnight. The solution was then diluted with 1 mL of water, stirred for 10 min in the ice bath and distributed between 10 mL of water and 25 mL of ethyl acetate.
  • the mixture was diluted with methanol (20 mL), stirred for 3 min, then ice (20 g) was added, stirred for 2 min and the supernatant decanted into a mixture containing saturated ammonium chloride (50 mL).
  • the residue was repeatedly washed with small amounts of tetrahydrofuran that was also added to the salt solution, which was then equilibrated with ethyl acetate (80 mL).
  • the aqueous layer was re-extracted once with ethyl acetate (20 mL), the combined extracts were washed with brine (10 mL) then dried and evaporated.
  • aqueous phase was re-extracted with ethyl acetate (2x20 mL), the combined extracts were washed with water (5 mL) and brine (10 mL), then 1:1 brine - saturated sodium hydrogen carbonate solution and dried.
  • ketone 58 0.0763 g, 91 %: 1 H NMR: 0.63 (3H, s), 1.19, 1.21 and 1.23 (6H, s each, Me 2 COH), 1.25, 1.36, 1.38 (6H, m,s,s, 5,5- dimethyloxolane diastereomer), 1.1-1.9 (18H, m), 1.9-2.1 (3H, m), 2.1-2.4 (2H, m), 2.45 (IH, m), 3.66 (IH, m), 3.802 and 3.805 (3H, s each), 5.78 and 5.95 (IH, s each, major and minor acetal diastereomer), 6.89 (2H, m), 7.39 (2H, m).
  • the ketone 58 was stirred in a 1 N oxalic acid solution in 90 % methanol. The mixture became homogeneous after a few min. TLC (ethyl acetate) suggested complete reaction after 75 min (Rf 0.24 for 59). Thus, calcium carbonate (0.60 g) was added and the suspension stirred overnight, then filtered.
  • the deprotection reaction of 63 was carried out in IM solution of tetrabutylammonium fluoride in tetrahydrofuran to give 62.
  • the mixture was diluted with brine after 25 h, stirred for 5 min and then equilibrated with ethyl acetate and water.
  • the aqueous layer was re-extracted once with ethyl acetate, the combined extracts were washed with water and brine, and then dried and evaporated.
  • the residue was flash-chromatographed to give a residue that was taken up in methyl formate and evaporated to yield 62.
  • Claisen adapter with rubber septum and nitrogen sweep was charged with 1.6872 g (2.238 mmol) of sulfone 69 and 40 mL of methanol. Then 1.25 g (51.4 mmol) of magnesium was added to the stirred solution in two equal portions, in a 30 min time interval. The suspension was stirrd for 70 min then another 0.17 g of magnesium and ca. 5 mL of methanol was added and stirring continued 1 h. The mixture was then diluted with 100 mL of hexane and 50 mL of 1 M sulfuric acid was added dropwise to give two liquid phases. The aqueous layer was neutral.
  • the aqueous layer was re-extracted once with 25 mL of 1 : 1 dichloromethane - hexane.
  • the organic layers were combined then washed once with 15 mL of brine, dried and evaporated.
  • the resulting material was chromatographed on silica gel using hexane, 1 :39, 1:19 and 1 :9 ethyl acetate - hexane as stepwise gradients.
  • the main band was eluted with 1 :9 ethyl acetate - hexane to provide 1.2611 g of 70 as a colorless syrup.
  • the column was eluted with dichloromethane followed by 1 : 1 ethyl acetate - hexane until no solute was detectable in the effluent.
  • the effluent was evaporated and the colorless oil.
  • This oil was then chromatographed on a silica gel using 1:4, 1:3, 1:2, 1:1 and 2:1 ethyl acetate - hexane as stepwise gradients to furnish 0.2077 g of the diketone 73.
  • This material was chromatographed on a flash column, 15x150 mm using hexane and 1:100 ethyl acetate - hexane as stepwise gradients to yield 0.1572 g of the title compound 75 as a colorless syrup.
  • the light -tan solution was the diluted with 5 mL of brine, stirred for 5 min and transferred to a separatory funnel with 50 mL of ethyl acetate and 5 mL of water then re-extraction with 5 mL of ethyl acetate.
  • the organic layers were combined, washed with 5x10 mL of water, 10 mL of brine, dried and evaporated.
  • Compound 77 was prepared as described for 75 in Example 44 but by reacting 74 with [(2Z)-2- [(3S,5R)-3,5-bis(tert-butyldimethylsilanyloxy) methylenecyclohexylidene]- ethyljdiphenylphosphine oxide.
  • mice are genetically susceptible to experimentally-induced autoimmune prostatitis (EAP).
  • EAP experimentally-induced autoimmune prostatitis
  • a single prostate homogenate or prostatic antigen injection induces EAP in 100% of NOD male mice resulting in a florid leukocyte infiltrate in the prostate.
  • the course of EAP in this model is shown in Figure 1.
  • EAP is induced in mice for 14 days prior to “treatment” with vehicle (Miglyol 812) or VDR agonists (Vitamin D 3 analogues) up to day 30.
  • vehicle Miglyol 812
  • VDR agonists Vitamin D 3 analogues
  • VDR agonists as exemplified by Compound A (1 -alpha- fluoro-25-hydroxy- 16,23E-diene-26,27-bishomo-20-epi-cholecalciferol), Compound C (l 5 3-di-G-acetyl-l,25- dihydroxy- 16,23Z-diene ⁇ 26,274iexafluoro ⁇ 19 ⁇ i ⁇ f -eholeealciferol) and Compound D (I -alpha- fluoro-25-hydroxy- 16-ene-23 -yne-20-cyclopropyl-cholecalciferol), treat established EAP without affecting serum calcium levels. Histological evidence for this is shown in Figure 5.
  • Figure 6 shows increased Foxp3 expression in prostate-draining lymph nodes from VDR agonist -treated NOD mice.
  • Foxp3 is a transciption factor, an increase in which indicates an increase in T regulatory cells, in turn showing that inflammation may subside.
  • Figure 7 shows decreased inducible nitric oxide synthese (iNOS) expression in peritoneal macrophages from VDR agonist -treated NOD mice. A decrease in iNOS expression normally leads to a decrease in inflammation.
  • iNOS inducible nitric oxide synthese
  • VDR agonists have clear efficacy in EAP at non-hypercalcemic doses (as shown by histology score, increased Foxp3 and decreased iNOS expression).
  • Treatment with Compound A reduces by 80% the histological score in established EAP, suggesting its use in the treatment of human non-bacterial chronic prostatitis, in particular chronic autoimmune prostatitis
  • the NOD mouse represents a good model of autoimmune prostatitis, because the disease develops spontaneously.
  • Figure 8 shows prostate sections in a 34 week-old NOD mouse whilst Figure 9 shows development of NOD autoimmune prostatitis.
  • splenocyte cells from NOD mice treated with a VDR agonist in this case compound A, 1 -alpha- fluoro-25-hydroxy- 16,23E-diene-26,27-bishomo-20-epi- cholecalciferol
  • NOD mice a VDR agonist
  • Prostate infiltrating T-cells CD4 and CD8
  • diabetes and levels of NO, CCL2, IL-6 are measured.
  • Figure 10 shows the results of such analysis after prostate organ culture from NOD and NOD: SCID mice
  • Figure 11 shows decreased T cell infiltrate in the prostate of NOD: SCID recipients transferred with splenocytes from CmpdA-treated NOD mice.
  • Figure 12 shows that autoimmune diabetes is absent in NOD: SCID recipients transferred with splenocytes from CmpdA-treated NOD mice.
  • VDR agonists are active in spontaneous autoimmune prostatitis (as shown by inhibition of NO, CCL2, IL-6; reduced CD4 and CD8 prostatic cell infiltrate and reduced autoimmune diabetes upon transfer in NOD: SCID recipients). This further suggests the use of VDR agonists in the treatment of human non ⁇ bacterial chronic prostatitis, in particular chronic autoimmune prostatitis.
  • EXAMPLE 55 Treatment of EAP with ADR agonists in comparison to dexamethasone treatment
  • EAP was induced in non obese diabetic (NOD) mice, a strain genetically prone to develop different autoimmune diseases, by injection of mouse prostate homogenate in complete Freund's adjuvant (CFA).
  • CFA complete Freund's adjuvant
  • This protocol is known to induced EAP in 100% of NOD male mice, characterized by a florid leukocyte infiltrate into the prostate (Rivero et al., 1998, J Autoimmun 11, 603-610).
  • T cells specific for prostate antigen are IFN- ⁇ - producing ThI cells, that have an essential role in disease induction as shown using MHC class II-deficient NOD mice (Rivero et al., 2002, Clin Immunol 105, 176-184).
  • Cmpd A (1-alpha- fluoro-25-hydroxy-16,23E-diene-26,27-bishomo-20-epi-cholecalciferol) was administered orally 5 d/week at 100 ug/Kg from day 14 to 28 post immunization.
  • dexamethasone at 0.25 mg/Kg was administered daily (5 d/week) from day 14 to 28 post immunization.
  • mice received vehicle only (miglyol).
  • Dexamethasone is a clinically-used glucocorticoid. This class of compounds binds to a nuclear receptor in the same general family as the Vitamin D Receptor, and exerts in part similar activity. Therefore, it was of interest to compare the anti- inflammatory effects of dexamethasone and VDR agonists in the EAP model.
  • mice with established EAP treated with vehicle only numerous leukocyte infiltrates are observed adjacent to the ganglia of the prostate peripheral nervous system, whereas the ganglia are mostly free of infiltrating cells in mice treated with Cmpd A (Figure 15). This finding suggests an effect of Cmpd A on the pain component of autoimmune prostatitis.
  • Immunohistological analysis carried out on the same sections shows a marked reduction of all infiltrating cell types examined, an effect superior to dexamethasone treatment (Figure 16).
  • immunohistological analysis has demonstrated decreased cell proliferation, assessed by reduced expression of the proliferation marker Ki 67, and increased apoptosis, shown by increased staining revealed by the TUNEL assay.
  • EXAMPLE 57 VDR agonists restore nerve-induced contractions in EAP mice
  • EAP autoimmune prostatitis
  • CFA complete Freund's adjuvant
  • Cmpd A was administered orally 5 days/week at 100 ug/Kg from day 14 to 28 post immunization. Mice were then sacrificed by carbon monoxide asphyxiation. The abdomen was accessed through a lower midline incision whereafter the symphysis was opened.
  • prostate was carefully dissected free, and immediately placed in chilled Krebs solution. Body weight and whole prostate weight were used to calculate prostate/body percent weight. Under a dissection microscope, prostates were microsurgically dissected in ventral and dorsal lobe strips, and prepared for functional experiments in tissue baths.
  • BHT Butylated Hydroxytoluene
  • BHA Butylated Hydroxyanisole
  • BHT and BHA is suspended in Miglyol 812 and warmed to about 50 0 C with stirring, until dissolved.
  • the solution from Step 2 is cooled at room temperature. 4.
  • the solution from Step 3 is filled into soft gelatin capsules.
  • a capsule for oral administration is formulated under nitrogen in amber light: 150ug of Compound A in 150 mg of fractionated coconut oil (Miglyol 812), with 0.015 mg butylated hydroxytoluene (BHT) and 0.015 mg butylated hydroxyanisole (BHA), filled in a soft gelatin capsule.
  • Fr15 mg butylated hydroxytoluene (BHT) and 0.015 mg butylated hydroxyanisole (BHA) filled in a soft gelatin capsule.
  • a capsule for oral administration is formulated under nitrogen in amber light: 75ug of Compound A in 150 mg of fractionated coconut oil (Miglyol 812), with 0.015 mg butylated hydroxytoluene (BHT) and 0.015 mg butylated hydroxyanisole (BHA), filled in a soft gelatin capsule.
  • Fr15 mg butylated hydroxytoluene (BHT) and 0.015 mg butylated hydroxyanisole (BHA) filled in a soft gelatin capsule.
  • Item Ingredients mg/Capsule 1 l-alpha-fluoro ⁇ S-hydroxy-l ⁇ SE-diene ⁇ T-bishomo ⁇ O-epi-cholecalciferol 10.001-0.02
  • the solution from Step 2 is cooled at room temperature. 4.
  • the solution from Step 3 is filled into soft gelatin capsules.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un composé de vitamine D pour la prévention ou le traitement de la prostatite chronique ainsi que des méthodes, des formulations pharmaceutiques et des trousses associées.
PCT/EP2005/054965 2004-09-30 2005-09-30 Utilisation de composes de vitamine d pour la prevention ou le traitement de la prostatite chronique Ceased WO2006035075A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US61449804P 2004-09-30 2004-09-30
US60/614,498 2004-09-30
GB0508694A GB0508694D0 (en) 2005-04-29 2005-04-29 Novel methods
GB0508694.7 2005-04-29

Publications (1)

Publication Number Publication Date
WO2006035075A1 true WO2006035075A1 (fr) 2006-04-06

Family

ID=35478665

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/054965 Ceased WO2006035075A1 (fr) 2004-09-30 2005-09-30 Utilisation de composes de vitamine d pour la prevention ou le traitement de la prostatite chronique

Country Status (1)

Country Link
WO (1) WO2006035075A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2057463A1 (fr) * 1991-12-11 1993-06-12 David Rowland Composition vitaminique/minerale
US5939408A (en) * 1996-05-23 1999-08-17 Hoffman-La Roche Inc. Vitamin D3 analogs
US20010051184A1 (en) * 1999-05-20 2001-12-13 Madalene C.Y. Heng Method for using soluble curcumin to inhibit phosphorylase kinase in inflammatory diseases
US20040023934A1 (en) * 1993-09-10 2004-02-05 Bone Care International, Inc. Method of treating prostatic diseases using active vitamin D analogues

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2057463A1 (fr) * 1991-12-11 1993-06-12 David Rowland Composition vitaminique/minerale
US20040023934A1 (en) * 1993-09-10 2004-02-05 Bone Care International, Inc. Method of treating prostatic diseases using active vitamin D analogues
US5939408A (en) * 1996-05-23 1999-08-17 Hoffman-La Roche Inc. Vitamin D3 analogs
US20010051184A1 (en) * 1999-05-20 2001-12-13 Madalene C.Y. Heng Method for using soluble curcumin to inhibit phosphorylase kinase in inflammatory diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CRESCIOLI C ET AL: "INHIBITION OF PROSTATE CELL GROWTH BY BXL-628, A CALCITRIOL ANALOGUE SELECTED FOR A PHASE II CLINICAL TRIAL IN PATIENTS WITH BENIGN PROSTATE HYPERPLASIA", EUROPEAN JOURNAL OF ENDOCRINOLOGY, SCANDINAVIAN UNIVERSITY PRESS, NO, vol. 150, no. 4, April 2004 (2004-04-01), pages 591 - 603, XP009043025, ISSN: 0804-4643 *
DANIELS NICHOLAS A ET AL: "Correlates and prevalence of prostatitis in a large community-based cohort of older men.", UROLOGY. NOV 2005, vol. 66, no. 5, November 2005 (2005-11-01), pages 964 - 970, XP005158354, ISSN: 1527-9995 *

Similar Documents

Publication Publication Date Title
RU2126384C1 (ru) Аналоги витамина д, способ их получения, промежуточное соединение, фармацевтическая композиция, способ подавления болезненных состояний
RU2114825C1 (ru) Производные витамина d
JP2002505668A (ja) 環状エーテルビタミンＤ３化合物、１α（ＯＨ）３−エピ−ビタミンＤ３化合物及びそれらの使用法
JP2002506429A (ja) ３−エピビタミンｄ２化合物及びその使用法
EP1737468A2 (fr) Methodes permettant de traiter la cystite interstitielle et composes et compositions connexes
RO120338B1 (ro) Derivaţi analogi ai vitaminei d
BRPI0609666A2 (pt) uso de um composto de vitamina d, método para prevenir e /ou tratar endometriose, formulação farmacêutica, composto de vitamina d, e, kit
WO2011088209A2 (fr) Analogues 1-désoxy de composés apparentés à la vitamine d
US20070054887A1 (en) Methods for treating bladder dysfunction
JP4512490B2 (ja) ビタミンｄ類似体、該類似体を含んで成る組成物およびその使用
EP0944592B1 (fr) Derives de vitamine d3
US20080280860A1 (en) Use of Vitamin D Compounds to Treat Endometriosis
WO2006035075A1 (fr) Utilisation de composes de vitamine d pour la prevention ou le traitement de la prostatite chronique
US20080293647A1 (en) Combined Use Of Vitamin D Derivatives And Anti-Proliferative Agents For Treating Bladder Cancer
US20090298799A1 (en) Methods of Treating Osteoporosis and Secondary Hyperparathyroidism Using 20-Methyl, Gemini Vitamin D3 Compounds
RU2261244C2 (ru) Новые аналоги витамина d
ZA200602097B (en) Methods for treating bladder dysfunction
ZA200606720B (en) Treatment of interstitial cystitis with vitamin D compounds
US20100009949A1 (en) Novel method
AU2007306292A1 (en) Novel method of treatment of male sub-fertility
JPWO2004067525A1 (ja) ビタミンｄ３ラクトン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase