WO2007039322A1 - Use of vitamin d3 compounds for the treatment of uveitis - Google Patents

Use of vitamin d3 compounds for the treatment of uveitis Download PDF

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Publication number
WO2007039322A1
WO2007039322A1 PCT/EP2006/061415 EP2006061415W WO2007039322A1 WO 2007039322 A1 WO2007039322 A1 WO 2007039322A1 EP 2006061415 W EP2006061415 W EP 2006061415W WO 2007039322 A1 WO2007039322 A1 WO 2007039322A1
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compound
vitamin
formulation
kit
alkyl
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PCT/EP2006/061415
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French (fr)
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Luciano Adorini
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Bioxell Spa
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    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to novel uses and methods, and compounds for use therein.
  • Uveitis a condition comprising inflammation of the eye including the iris, ciliary body, and choroid, actually comprises a large group of diverse diseases affecting not only the uvea but also the retina, optic nerve and vitreous.
  • uveitis anterior, intermediate, posterior and panuveitis (total). Inflammation may be induced by trauma or toxic or infectious agents, but in most cases the mechanisms seem to be autoimmune in nature. Symptoms may be acute, sub-acute, chronic (greater than 3 months duration) and recurrent. The etiology is unknown in the majority of cases of endogenous uveitis. Uveitis is a major cause of severe visual impairment. Although the number of patients blinded from uveitis is unknown, it has been estimated that uveitis accounts for 10-15% of all cases of total blindness in the USA.
  • posterior uveitis focal, multifocal or diffuse choroiditis, chorioretinitis, retinochoroiditis, uveoretinitis or neurouveitis.
  • the condition is usually painless but is characterised by the presence of floaters, vision impairment (sudden or gradual) such as blurring of vision, etc., and vision loss.
  • Posterior uveitis may have several etiologies, and manifests itself in complex and sometimes misleading clinical conditions. There is growing evidence both in experimental models and clinically that endogenous posterior uveoretinitis is often characterised by an exaggerated immune response which causes tissue destruction.
  • treatment can be directed towards dampening the resulting inflammatory cascade and hopefully reducing tissue damage.
  • the mainstay of treatment is systemic corticosteroid and often this is given in combination with immunosuppressive agents, such as cyclosporin A or azathioprine.
  • immunosuppressive agents such as cyclosporin A or azathioprine.
  • High dose steroids are often required to control the disease and in addition to the disadvantages of the required longterm use and resistance in some patients, potentially serious side effects are often present.
  • weight gain particularly around the face, which can be cosmetically unacceptable.
  • Another important side effect of corticosteroids, particularly with reference to the eye is glaucoma resulting from increased intraocular pressure.
  • the present inventors have developed a new method of treating uveitis with a view to mitigating or alleviating the aforementioned disadvantages.
  • the method is based on the use of calcitriol and analogs thereof, collectively "vitamin D compounds”.
  • vitamin D cholesterol calcium and phosphorus homeostasis
  • the operation of the vitamin D endocrine system depends on the following: first, on the presence of cytochrome P450 enzymes in the liver (Bergman, T. and Postlind, H. (1991) Biochem. J. 276:427-432; Ohyama, Y and Okuda, K. (1991) J. Biol. Chem. 266:8690-8695) and kidney (Henry, H.L. and Norman, A.W. (1974) J. Biol. Chem. 249:7529-7535; Gray, R.W. and Ghazarian, J. G. (1989) Biochem. J.
  • Vitamin D 3 and its hormonally active forms are well-known regulators of calcium and phosphorus homeostasis. These compounds are known to stimulate, at least one of, intestinal absorption of calcium and phosphate, mobilization of bone mineral, and retention of calcium in the kidneys. Furthermore, the discovery of the presence of specific vitamin D receptors in more than 30 tissues has led to the identification of vitamin D 3 as a pluripotent regulator outside its classical role in calcium/bone homeostasis.
  • a paracrine role for 1 -alpha, 25(OH) 2 D 3 has been suggested by the combined presence of enzymes capable of oxidizing vitamin D 3 into its active forms, e.g., 25-OHD-1-alpha-hydroxylase, and specific receptors in several tissues such as bone, keratinocytes, placenta, and immune cells.
  • enzymes capable of oxidizing vitamin D 3 into its active forms e.g., 25-OHD-1-alpha-hydroxylase
  • specific receptors e.g., 25-OHD-1-alpha-hydroxylase
  • specific receptors e.g., 25-OHD-1-alpha-hydroxylase
  • specific receptors e.g., 25-OHD-1-alpha-hydroxylase
  • vitamin D 3 hormone and active metabolites have been found to be capable of regulating cell proliferation and differentiation of both normal and malignant cells (Reichel, H. et al. (1989) Ann. Rev. Med. 40: 71-78).
  • 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 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 (analogue V), inhibited 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 (IGF1). Moreover, the analogue induced bcl-2 protein expression, intracellular calcium mobilization, and apoptosis in both unstimulated and KGF-stimulated BPH cells.
  • KGF keratinocyte growth factor
  • IGF1 insulin-like growth factor
  • Topical administration of calcitriol has been said to inhibit Langerhans cell migration and corneal neovascularisation in ocular surface inflammation (Suzuki et al (2000) Curr. Eye Res. 20(2) 127-130) and calcitriol has been said to inhibit the P aeruginosa-induced expression of IL- 1b, IL-6 and IL-8 in human corneal epithelial cells (Xue et al (2002) Immunol. Cell Biol. 80(4) 340-5).
  • the cornea is a distinct part of the eye, separate from those internal and posterior parts of the eye which are treated according to the methods of the present invention.
  • the cornea is accessible by topical treatment (direct administration to the cornea) which would not be the route of choice in the context of the present invention (for which systemic administration would be especially suitable).
  • vitamin D compounds such as calcitriol and an analogue of calcitriol (“Compound A") can prevent experimental autoimmune uveoretinitis (EAU), an autoimmune disease mediated by Th 1 -type uveitogenic CD4+ T cells that serves as a model for human posterior uveitis.
  • EAU experimental autoimmune uveoretinitis
  • Th 1 -type uveitogenic CD4+ T cells that serves as a model for human posterior uveitis.
  • the invention provides the use of a vitamin D compound in the prevention or treatment of uveitis. Also provided is a method of treating a patient with uveitis by administering an effective amount of a vitamin D compound. Further provided is the use of a vitamin D compound in the manufacture of a medicament for the prevention or treatment of uveitis. Further provided is a vitamin D compound for use in the prevention or treatment of uveitis. Additionally provided is a pharmaceutical combination comprising a vitamin D compound and a further agent for the treatment or prevention of uveitis. Also provided is a kit comprising a vitamin D compound together with instructions directing administration of said compound to a patient in need of treatment or prevention of uveitis thereby to treat or prevent uveitis in said patient.
  • the invention provides a method of prevention or treatment of uveitis using a vitamin D compound.
  • the invention provides a method for preventing or treating uveitis in a subject, comprising administering to a subject in need thereof an effective amount of a vitamin D compound, such that the uveitis is prevented or treated in the subject.
  • the invention provides a method as described above, further comprising identifying a subject in need of prevention or treatment for uveitis. In another embodiment, the invention provides a method as described above, further comprising the step of obtaining the vitamin D compound. According to the methods described herein, the subject is typically a mammal, particularly a human. In another embodiment, the invention provides a method described herein wherein the vitamin D compound is formulated in a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier. In another aspect, the invention provides a pharmaceutical formulation comprising a vitamin D compound and a pharmaceutically acceptable carrier for use in the prevention or treatment of uveitis.
  • the invention provides a pharmaceutical formulation comprising a vitamin D compound and a pharmaceutically acceptable carrier packaged with instructions for use in the prevention or treatment of uveitis.
  • the invention provides a vitamin D compound for preventing or treating uveitis.
  • the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is administered separately, sequentially or simultaneously in separate or combined pharmaceutical formulations with a second medicament for the prevention or treatment of uveitis.
  • the vitamin D compound is not a compound represented by formula (I):
  • 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 3 , R 4 and R 5 are each independently hydrogen, CrC 4 alkyl, hydroxyalkyl, or haloalkyl, with the understanding that R 5 is absent when A 2 is a triple bond, 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 alkyl or haloalkyl; and
  • R 8 is H, C(O)C 1 -C 4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; provided that when A 1 is
  • the vitamin D compound is a compound of formula (I), as follows:
  • 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 (e.g.
  • R 1 and R 2 may each also independently represent OH;
  • R 3 , R 4 and R 5 are each independently hydrogen, CrC 4 alkyl, hydroxyalkyl, or haloalkyl, with the understanding that R 5 is absent when A 2 is a triple bond, 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 alkyl (e.g.
  • 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.
  • Particular compounds of formula (I) that may be mentioned for use in the context of the invention are those wherein A 1 is a single bond, R 3 is hydrogen, R 4 is methyl, and A 2 is a double or triple bond.
  • R 1 and R 2 are OH or OC(O)C 1 -C 4 alkyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 1 and R 2 are OAc.
  • the invention provides for use, method, formulation, compound or kit, wherein A 1 is single bond and A 2 is a single bond.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 3 and R 4 taken together with C 20 form C 3 -C 6 cycloalkyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 3 and R 4 taken together with C 20 form cyclopropyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 5 is hydrogen.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 6 and R 7 are each independently C 1-4 alkyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 6 and R 7 are each independently methyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 8 is H.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 1 and R 2 are OH or OAc, R 3 and R 4 taken together with C 20 form cyclopropyl, and R 6 and R 7 are each methyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein said vitamin D compound is a compound of the formula (II):
  • X is H 2 or CH 2
  • Ri is hydrogen, hydroxy or fluorine
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or methyl provided that when R 2 or R 3 is methyl, R 3 or R 2 must be hydrogen
  • R 4 is methyl, ethyl or trifluoromethyl
  • R 5 is methyl, ethyl or trifluoromethyl
  • A is a single or double bond
  • B is a single, E-double, Z-double or triple bond.
  • the invention provides for the use, method, formulation, compound, or kit, wherein in the compound of formula (II) each of R 4 and R 5 is methyl or ethyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is 1,3-Di-O-acetyl-1 ,25-dihydroxy-20- cyclopropyl-cholecalciferol (hereinafter sometimes referred to as "Compound A”) having the formula:
  • the vitamin D compound is not 1,3-Di-O-acetyl-1 ,25-dihydroxy- 20-cyclopropyl-cholecalciferol.
  • the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is I ⁇ S-dihydroxy ⁇ O ⁇ i ⁇ -cyclopropyl- cholecalciferol having the formula:
  • the vitamin D compound is not 1,3-Di-O-acetyl-1 ,25-dihydroxy- 20-cyclopropyl-cholecalciferol.
  • the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is 1-alpha-fluoro-25-hydroxy-16,23E-diene- 26,27-bishomo-20-epi-cholecalciferol, having the formula:
  • the invention provides for the use, method, formulation, compound or kit wherein the compound is calcitriol.
  • the invention provides for the use, method, formulation, compound or kit, wherein said uveitis is autoimmune uveitis.
  • the invention provides for the use, method, formulation, compound or kit, wherein said uveitis is posterior uveitis and in particular is uveoretinitis.
  • Figure 1 shows the experimental procedure used to treat experimental autoimmune uveoretinitis (EAU) with Compound A.
  • FIG. 2 shows the EAU disease score (quantitated between 0 and 4) at day 21.
  • Figure 3 shows the reduced antigen-specific delayed type hypersensitivity (DTH) responses to IRBP in mice.
  • DTH delayed type hypersensitivity
  • Figure 4 shows the in vitro assay of primed lymph node cells (LN) used to indicated that calcitriol and Compound A both appeared to be potent on T cell polarization.
  • LN primed lymph node cells
  • FIG. 5 shows that Ag driven chemokine release, such as MIP-Ia, Rantes and TARC, is inhibited by Vitamin D compounds.
  • uveitis conditions comprising inflammation of the eye, in particular the uveal tract (iris, ciliary body, choroid) with or without additional inflammation of the retina, optic nerve and vitreous, including but not limited to anterior, intermediate, posterior uveitis and panuveitis and in acute, sub-acute, chronic or recurrent forms.
  • the methods of the invention are applicable, for example, to the treatment of posterior uveitis including but not limited to focal, multifocal or diffuse choroiditis, chorioretinitis, retinochoroiditis uveretinitis or neurouveitis.
  • posterior uveitis including but not limited to focal, multifocal or diffuse choroiditis, chorioretinitis, retinochoroiditis uveretinitis or neurouveitis.
  • Such types of uveitis may by caused by an autoimmune response or a disordered immune response (for example where inflammation continues after infecting bacteria have been removed).
  • Most typically the posterior uveitits is uveoretinitis.
  • the vitamin D compounds may be used in human or veterinary medicine.
  • the terms “subject” and “patient” are used interchangeably, and are intended to include mammals, for example, humans. It is preferred that the vitamin D compound be used in the treatment of human patients.
  • 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 ocular delivery.
  • the pharmaceutical preparations are, of course, given by forms suitable for each administration route. For example, these preparations are administered in tablets or capsule form, by injection, infusion, inhalation, lotion, ointment, suppository, etc. Oral administration is preferred.
  • the injection can be bolus or can be continuous infusion.
  • the vitamin D compound can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally effect its ability to perform its intended function.
  • the vitamin D compound can be administered alone, or in conjunction with either another agent useful in the treatment of uveitis (for example corticosteroids), or with a pharmaceutically-acceptable carrier, or both.
  • the vitamin D compound can be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent (via the same or different routes).
  • the vitamin D compound can also be administered in a pro-form which is converted into its active metabolite, or more active metabolite in vivo.
  • 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 uveitis.
  • 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.
  • a therapeutically effective amount of vitamin D compound may range from about 0.001 to 30 ug/kg body weight, preferably about 0.01 to 25 ug/kg body weight, more preferably about 0.1 to 20 ug/kg body weight, and even more preferably about 1 to 10 ug/kg, 2 to 9 ug/kg, 3 to 8 ug/kg, 4 to 7 ug/kg, or 5 to 6 ug/kg body weight (for example, per day).
  • an effective dosage may range from about 0.001 to 30 ug/kg body weight, preferably about 0.01 to 25 ug/kg body weight, more preferably about 0.1 to 20 ug/kg body weight, and even more preferably about 1 to 10 ug/kg, 2 to 9 ug/kg, 3 to 8 ug/kg, 4 to 7 ug/kg, or 5 to 6 ug/kg body weight (for example, per day).
  • certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of
  • 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, one time 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.
  • alkyl refers to the radical of saturated aliphatic groups, including straight- chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • alkyl further includes alkyl groups, which can optionally further include (for example, in one embodiment alkyl groups do not include) oxygen, nitrogen, sulfur or phosphorus atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorus atoms.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., CrC 30 for straight chain, C 3 -C 30 for branched chain), preferably 26 or fewer, and more preferably 20 or fewer, especially 6 or fewer (for example 4 for fewer).
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, 6 or 7 carbons in the ring structure.
  • alkyl as used throughout the specification and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls,” the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, 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, sulfonamido, nitro, trifluoro
  • alkylaryl moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • aryl e.g., phenylmethyl (benzyl)
  • alkyl also includes 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 (i.e. alkenyl and alkynyl groups).
  • 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, propyl (n- propyl and i-propyl), butyl (tert-butyl, n-butyl and sec-butyl), pentyl, 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., d-C 4 alkyl.
  • alkyl examples include CrC 6 alkyl or Ci-C 4 alkyl (such as methyl or ethyl).
  • hydroxyalkyl examples include C r C 6 hydroxyalkyl or C r C 4 hydroalkyl (such as hydroxy methyl).
  • alkoxyalkyl refers to alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • aryl refers to the radical of aryl groups, including 5- and 6- membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as
  • aryl heterocycles "heteroaryls” or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydr ⁇ l, alkylthio, ar ⁇ lthio, thio
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogueous 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.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • diastereomers refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.
  • enantiomers refers to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • An equimolar mixture of two enantiomers is called a “racemic mixture” or a “racemate.”
  • halogen designates -F, -Cl, -Br or -I; the term “sulfhydryl” or “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., C r6 haloalkyl or C r4 haloalkyl such as fluoromethyl and trifluoromethyl.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • polycyclyl or “polycyclic radical” refer to the radical of two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • 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,
  • isomers or “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • an isolated vitamin D compound is at least 75% pure, especially at least 85% pure, in particular at least 95% pure and preferably at least 99% pure on a w/w basis, said purity being by reference to compounds with which the vitamin D compound is naturally associated or else chemically associated in the course of chemical synthesis.
  • the terms “isolated” or “substantially purified” also refer to preparations of a chiral compound which substantially lack one of the enantiomers; i.e., enantiomerically enriched or non-racemic preparations of a molecule.
  • isolated epimers or “isolated diastereomers” refer to preparations of chiral compounds which are substantially free of other stereochemical forms.
  • isolated or substantially purified vitamin D 3 compounds include synthetic or natural preparations of a vitamin D 3 enriched for the stereoisomers having a substituent attached to the chiral carbon at position 3 of the A-ring in an alpha-configuration, and thus substantially lacking other isomers having a beta-configuration. Unless otherwise specified, such terms refer to vitamin D 3 compositions in which the ratio of alpha to beta forms is greater than 1 :1 by weight.
  • an isolated preparation of an a epimer means a preparation having greater than 50% by weight of the alpha-epimer relative to the beta stereoisomer, more preferably at least 75% by weight, and even more preferably at least 85% by weight.
  • the enrichment can be much greater than 85%, providing "substantially epimer-enriched" preparations, i.e., preparations of a compound which have greater than 90% of the alpha-epimer relative to the beta stereoisomer, and even more preferably greater than 95%.
  • the term "substantially free of the beta stereoisomer" will be understood to have similar purity ranges.
  • vitamin D compound includes any compound being an analogue of vitamin D that is capable of treating or preventing uveitis.
  • compounds which are ligands for the Vitamin D receptor (VDR ligands) and which are capable of treating or preventing uveitis 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.
  • vitamin D compounds are vitamin D 3 compounds which are ligands of (more preferably are agonists of) the vitamin D receptor.
  • the vitamin D compound e.g., the vitamin D 3 compound
  • Vitamin D 1 compounds, vitamin D 2 compounds and vitamin D 3 compounds include, respectively, vitamin D 1 , D 2 , D 3 and analogues thereof.
  • the vitamin D compound may be a steroid, such as a secosteroid, e.g., calciol, calcidiol or calcitriol.
  • certain preferred vitamin D compounds in accordance with the invention include those described in U.S. Patent No. 6,492,353 and published international application WO2005/030222, which are incorporated herein by reference.
  • the term "obtaining” includes purchasing, synthesizing, isolating or otherwise acquiring one or more of the the vitamin D compounds used in practicing the invention.
  • the term "secosteroid" is art-recognized and includes compounds in which one of the cyclopentanoperhydro-phenanthrene rings of the steroid ring structure is broken.
  • 1-alpha,25(OH) 2 D 3 and analogues thereof are hormonally active secosteroids.
  • vitamin D 3 the 9-10 carbon-carbon bond of the B-ring is broken, generating a seco-B-steroid.
  • 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 1-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). Furthermore the indication of stereochemistry across a carbon-carbon double bond is also opposite from the general chemical field in that "Z” refers to what is often referred to as a "cis” (same side) conformation whereas “E” refers to what is often referred to as a "trans” (opposite side) conformation. Regardless, both configurations, cis/trans and/or Z/E are contemplated for the compounds for use in the present invention.
  • the A ring of the hormone 1-alpha,25(OH) 2 D 3 contains two asymmetric centers at carbons 1 and 3, each one containing a hydroxyl group in well-characterized configurations, namely the 1 -alpha- and 3-beta- hydroxyl groups.
  • carbons 1 and 3 of the A ring are said to be "chiral carbons" or "carbon centers.”
  • the vitamin D compound is a compound of formula
  • X is hydroxyl or fluoro
  • Y is H 2 or CH 2 ;
  • Z 1 and Z 2 are H or a substituent represented by formula (IV), provided Z 1 and Z 2 are different (preferably Z 1 and Z 2 do not both represent formula (IV)):
  • Z 3 represents the above-described formula (III);
  • Ri, R 2 , and Z 4 are each, independently, hydrogen, alkyl, or a saturated or unsaturated carbon chain represented by formula (V), provided that at least one of Ri, R 2 , and Z 4 is the saturated or unsaturated carbon chain represented by formula (V) and provided that all of Ri, R 2 , and Z 4 are not saturated or unsaturated carbon chain represented by formula (V):
  • Z 5 represents the above-described formula (IV); A 2 is a single bond, a double bond, or a triple bond; and A 3 is a single bond or a double bond; and
  • R 3 , and R 4 are each, independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl; and R 5 is H 2 or oxygen. R 5 may also represent hydrogen or may be absent.
  • the vitamin D compound is a compound of formula (Vl):
  • Xi and X 2 are H 2 or CH 2 , wherein X 1 and X 2 are not CH 2 at the same time;
  • A is a single or double bond
  • a 2 is a single, double or triple bond
  • a 3 is a single or double bond
  • Ri and R 2 are hydrogen, C r C 4 alkyl or 4-hydroxy-4-methylpentyl, wherein R 1 and R 2 are not both hydrogen;
  • R 5 is H 2 or oxygen, R 5 may also represent hydrogen or may be absent;
  • R 3 is CrC 4 alkyl, hydroxyalkyl or haloalkyl, eg., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl; and
  • R 4 is CrC 4 alkyl, hydroxyalkyl or haloalkyl, eg., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl.
  • the vitamin D compound is a compound of formula (VII):
  • Xi and X 2 are H 2 or CH 2 , wherein X 1 and X 2 are not CH 2 at the same time;
  • A is a single or double bond
  • a 2 is a single, double or triple bond
  • a 3 is a single or double bond
  • R 1 and R 2 are hydrogen, C 1 -C 4 alkyl, wherein R 1 and R 2 are not both hydrogen;
  • R 5 is H 2 or oxygen, R 5 may also represent hydrogen or may be absent;
  • R 3 is C 1 -C 4 alkyl, hydroxyalkyl or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl; and
  • R 4 is C 1 -C 4 alkyl, hydroxyalkyl haloalkyl, e.g., or fluoroalkyl, e.g., fluoromethyl and trifluoromethyl.
  • the vitamin D compound is a "geminal" compound of formula
  • a 2 is a single, a double or a triple bond
  • R 3 is CrC 4 alkyl, hydroxyalkyl, or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl;
  • R 4 is CrC 4 alkyl, hydroxyalkyl or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl; and the configuration at C 20 is R or S.
  • An example geminal compound of formula (VIII) is 1 ,25-dihydroxy-21-(3-hydroxy-3- methylbutyl)-19-nor-cholecalciferol:
  • the vitamin D compound is a compound of formula (IX):
  • A is a single or double bond
  • Ri and R 2 are each, independently, hydrogen, alkyl (for example methyl);
  • R 3 , and R 4 are each, independently, alkyl
  • X is hydroxyl or fluoro.
  • the vitamin D compound is a compound having formula (X):
  • Ri 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 is selected from the group consisting of:
  • the vitamin D compound is selected from the group consisting of:
  • the vitamin D compound is selected from the group of geminal compounds consisting of:
  • the vitamin D compound is a geminal compound of formula (Xl):
  • a 1 is a single or double bond
  • a 2 is a single, a double or a triple bond
  • R 3 and R 4 are each independently CrC 4 alkyl, d-C 4 deuteroalkyl, hydroxyalkyl, or haloalkyl;
  • R 5 , R 6 and R 7 are each independently hydroxyl, OC(O)Ci -C 4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl; the configuration at C 20 is R or S;
  • R 5 , R 6 and R 7 are hydroxyl. In other embodiments, R 6 and R 7 are each acetyloxy.
  • Z is hydrogen when at least one of Ri and R 2 is CrC 4 deuteroalkyl and at least one of R 3 and R 4 is haloalkyl or when at least one of Ri and R 2 is haloalkyl and at least one of R 3 and R 4 is d-C 4 deuteroalkyl;
  • Z is - OH.
  • Still other embodiments of of formula (Xl) include those wherein X 1 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.
  • X 1 is H 2 ; A 2 is a single bond; R 1 , R 2 , R 3 , and R 4 are each independently methyl or ethyl; the configuration at C 20 is S; and Z is -OH.
  • X 1 is H 2 ;
  • a 2 is a single bond;
  • R 1 , R 2 , R 3 , and R 4 are advantageously each methyl.
  • the haloalkyl is fluoroalkyl.
  • fluoroalkyl is fluoromethyl or trifluoromethyl.
  • Additional embodiments of of formula (Xl) include compounds X 1 is H 2 ; A 2 is a triple bond; R 1 and R 2 are each C 1 -C 4 deuteroalkyl; R 3 and R 4 are each haloalkyl; and Z is hydrogen.
  • X 1 is CH 2 ; A 2 is a triple bond; R 1 and R 2 are each C 1 -C 4 deuteroalkyl; R 3 and R 4 are each haloalkyl; and Z is hydrogen.
  • R 1 and R 2 are advantageously each deuteromethyl and R 3 and
  • R 4 are advantageously each trifluoromethyl.
  • the vitamin D compound is a geminal compound of formula (XII):
  • a 2 is a single, a double or a triple bond
  • 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.
  • X 1 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 is a geminal compound of the formula:
  • the vitamin D compound is a compound of formula (XIII):
  • Ri and R 2 are each independently, hydroxyl, OC(O)CrC 4 alkyl, OC(O)hydroxyalkyl, OC(O)fluororalkyl;
  • R 3 and R 4 are each independently hydrogen, d-C 4 alkyl, hydroxyalkyl or haloalkyl, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cylcoalkyl; and
  • R 5 and R 6 are each independently CrC 4 alkyl and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • R 3 and R 4 are each independently hydrogen, C r
  • R 5 and R 6 are each independently C r C 4 alkyl.
  • R 5 and R 6 are each independently haloalkyl e.g., C r C 4 fluoroalkyl.
  • R 3 and R 4 are taken together with C20 to form C 3 -C 6 cycloalkyl, an example is cyclopropyl.
  • Xi and X 2 are each H 2 .
  • R 3 is hydrogen and R 4 is CrC 4 alkyl.
  • 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.
  • Ri and R 2 are each independently hydroxyl or OC(O)CrC 4 alkyl.
  • Ri and R 2 are each OC(O)CrC 4 alkyl. In another preferred embodiment, Ri and R 2 are each acetyloxy.
  • I .S-O-diacetyl-i ⁇ -dihydroxy-i ⁇ -ene ⁇ -keto-i ⁇ - nor-cholecalciferol having the following structure:
  • the vitamin D compound for use in accordance with the invention is 2-methylene-19-nor-20(S)-1 -alpha, 25-hydroxyvitamin D 3 :
  • the vitamin D compound is a compound of the formula (XIV):
  • a 1 is single or double bond
  • a 2 is a single, double or triple bond
  • R 3 , R 4 and R 5 are each independently hydrogen, C r 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 -4 alkyl or haloalkyl; and R 8 is H, -COCrC 4 alkyl (e.g. Ac), -CO hydroxyalkyl or -COhaloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • R 8 is H, -COCrC 4 alkyl (e.g. Ac), -CO hydroxyalkyl or -COhaloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • R 6 and R 7 are each independently haloalkyl.
  • R 8 may suitably represent H or Ac.
  • a 1 is a single bond and A 2 is a single bond, E or Z double bond, or a triple bond.
  • 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.
  • 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 C 1- 4 alkyl. In another set of example compounds R 6 and R 7 are each independently haloalkyl. In another embodiment, R 6 and R 7 are each independently methyl, ethyl or fluoroalkyl. In a preferred embodiment, R 6 and R 8 are each trifluoroalkyl, e.g., trifluoromethyl.
  • R 5 represents hydrogen
  • vitamin D compounds for use in accordance with the invention are represented by formula (XV):
  • a 1 is single or double bond
  • a 2 is a single, double or triple bond;
  • Ri and R 2 are each independently OH, OC(O)CrC 4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl;
  • R 3 , R 4 and R 5 are each independently hydrogen, C r 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 haloalkyl; and
  • R 8 is H, C(O)CrC 4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • An example compound of the above-described formula (XV) which is one of the preferred compounds in the context of the present invention is 1,3-di-O-acetyl-1 ,25-dihydroxy- I ⁇ SZ-diene ⁇ Z-hexafluoro-i ⁇ -nor-cholecalciferol:
  • the compound is one of formula (XVI), wherein 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:
  • vitamin D compounds for use in accordance with the invention are represented by the formula (XVII):
  • vitamin D compounds for use in accordance with the invention are represented by the formula (XVIII):
  • Xi CH 2 and X 2 is H 2 .
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • X 1 and X 2 are each H 2 .
  • a 1 is a single bond
  • a 2 is a triple bond, it is preferred that R 8 is H or C(O)CH 3 , and R 6 and R 7 are alkyl or haloalkyl. It is preferred that the alkyl group is methyl, and the haloalkyl group is trifluoroalkyl, preferably trifluoromethyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are haloalkyl, preferably trifluoroalkyl, preferably trifluoromethyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • a preferred compound of formula (XVIII) is 1,3-di-O-acetyl-1 ,25-dihydroxy-20- cyclopropyl-23E-ene-26,27-hexafluoro-19-nor-cholecalciferol:
  • Compound A I .S-Di-O-acetyl-i ⁇ -dihydroxy ⁇ O-cyclopropyl- cholecalciferol (referred to as "Compound A" in examples herein) having the formula:
  • esters and salts of Compound A 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.
  • Another compound is 1 ,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol having the formula:
  • esters and salts of 1 ,25-dihydroxy-20,21,28- cyclopropyl-cholecalciferol include pharmaceutically acceptable labile esters that may be hydrolysed in the body to release 1 ,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol.
  • Salts of 1,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol 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.
  • 1 ,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol may be administered as a pharmaceutically acceptable salt or ester thereof, preferably it is employed as is i.e., it is not employed as an ester or a salt thereof.
  • vitamin D compounds for use in the invention are compounds of the formula (XIX):
  • X is H 2 or CH 2 ;
  • Ri is hydrogen, hydroxy or fluorine
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or methyl, though when R 2 or R 3 is methyl, the other of R 3 or R 2 must be hydrogen;
  • R 4 is methyl, ethyl or trifluoromethyl
  • R 5 is methyl, ethyl or trifluoromethyl
  • A is a single or double bond
  • B is a single, E-double, Z-double or triple bond.
  • each of R 4 and R 5 is methyl or ethyl, for example 1-alpha- fluoro ⁇ S-hydroxy-i ⁇ E-diene ⁇ Z-bishomo ⁇ O-epi-cholecalciferol having the formula:
  • B is single, double, or triple bond
  • Xi and X 2 are each independently H 2 or CH 2 , provided Xi and X 2 are not both CH 2 ;
  • R 4 and R 5 are each independently alkyl or haloalkyl.
  • Examples of compounds of formula (XX) include the following:
  • vitamin D compound of the invention is 1 ,25-dihydroxy-21(3-hydroxy-3- trifluoromethyM-trifluoro-butynyl ⁇ Z-hexadeutero-i ⁇ -nor ⁇ OS-cholecalciferol.
  • a 1 is a double bond
  • Xi CH 2 and X 2 is H 2 .
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl or haloalkyl. It is preferred that the alkyl group is methyl and the haloalkyl group is trifluoroalkyl, preferably trifluoromethyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl. It is also preferred that R 6 and R 7 are independently alkyl and haloalkyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • a 1 is a double bond
  • X 1 and X 2 are each H 2 .
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl or haloalkyl. It is preferred that the alkyl group is methyl or ethyl and the haloalkyl group is trifluoroalkyl, preferably trifluoromethyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are haloalkyl, preferably trifluoroalkyl, preferably trifluoromethyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • Ri and R 2 are OC(O)CH 3
  • a 1 is a single bond
  • a 2 is a single, double or triple bond, except that when R 3 is H and R 4 is methyl, A 2 is a double or triple bond.
  • R 3 is H
  • R 4 is methyl
  • R 5 is absent
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • Preferred compounds of the present include the following: 1,3-Di-O-acetyl-1 ,25- dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor-cholecalciferol, 1 ,3-Di-O-acetyl-1 ,25- Dihydroxy-i ⁇ -ene ⁇ S-yne ⁇ e ⁇ Z-hexafluoro-i ⁇ -nor-cholecalciferol, 1,3,25-Tri-O-acetyl-1 ,25- Dihydroxy-16-ene-23-yne-26,27-hexafluoro-19-nor-cholecalciferol, 1,3-Di-O-acetyl-1 ,25- dihydroxy-i ⁇ -ene ⁇ S-yne-cholecalciferol, 1,3-Di-O-acetyl-1,25-dihydroxy-16,23E-diene- cholecalciferol, 1 ,3-Di-O-ace
  • vitamin D compounds for use in accordance with the invention include those having formula (XXII):
  • 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 ;
  • Ri and R 2 are each independently OH, OC(O)CrC 4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl;
  • R 3 , R 4 and R 5 are each independently hydrogen, d-C 4 alkyl, hydroxyalkyl, or haloalkyl, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cylcoalkyl; R 6 and R 7 are each independently haloalkyl; and
  • R 8 is H, C(O)CrC 4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • R 6 and R 7 are each independently trihaloalkyl, especially trifluoromethyl.
  • a vitamin D compound of particular interest is calcitriol.
  • vitamin D receptor agonists include paricalcitol (ZEMPLARTM) (see US Patent 5,587,497), tacalcitol (BONALFATM) (see US Patent 4,022,891), doxercalciferol (HECTOROLTM) (see Lam et al. (1974) Science 186, 1038), maxacalcitol (OXAROLTM) (see US Patent 4,891,364), calcipotriol (DAIVONEXTM) (see US Patent 4,866,048), and falecalcitriol (FULSTANTM).
  • ZEMPLARTM paricalcitol
  • BONALFATM tacalcitol
  • HECTOROLTM doxercalciferol
  • OFECTOROLTM maxacalcitol
  • OXAROLTM calcipotriol
  • DAIVONEXTM see US Patent 4,866,048)
  • falecalcitriol FULSTANTM
  • the structures of some of the compounds of the invention include asymmetric carbon atoms. Accordingly, it is to be understood that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and/or by stereochemically controlled synthesis.
  • 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,” W.J. 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 compounds of the invention may be administered via ocular delivery, for example, through an ocular device suitable for direct implantation into the eye.
  • Such devices of the present invention are surprisingly found to provide sustained controlled release of various compositions to treat the eye without risk of detrimental local and systemic side effects.
  • An object of the present ocular method of delivery is to maximize the amount of drug contained in an intraocular device while minimizing its size in order to prolong the duration of the implant. See, e.g., U.S. Patents 5,378,475; 5,773,019; 6,001,386; 6,217,895, 6,375,972, and 6,756,058 and U.S. Publications 2005/0096290 and 2005/01269448.
  • Other methods of delivery include: an ocular delivery system that could be applied to an intra-ocular lens to prevent inflammation or posterior capsular opacification, an ocular delivery system that could be inserted directly into the vitreous, under the retina, or onto the sclera, and wherein inserting can be achieved by injecting the system or surgically implanting the system, a sustained release drug delivery system, and a method for providing controlled and sustained administration of an agent effective in obtaining a desired local or systemic physiological or pharmacological effect comprising surgically implanting a sustained release drug delivery system at a desired location.
  • a sustained release drug delivery system comprising an inner reservoir comprising an effective amount of an agent effective in obtaining a desired local or systemic physiological or pharmacological effect, an inner tube impermeable to the passage of said agent, said inner tube having first and second ends and covering at least a portion of said inner reservoir, said inner tube sized and formed of a material so that said inner tube is capable of supporting its own weight, an impermeable member positioned at said inner tube first end, said impermeable member preventing passage of said agent out of said reservoir through said inner tube first end, and a permeable member positioned at said inner tube second end, said permeable member allowing diffusion of said agent out of said reservoir through said inner tube second end; a method for administering a compound of the invention to a segment of an eye, the method comprising the step of implanting a sustained release device to deliver the compound of the invention to the vitreous of the eye or an implantable, sustained release device for administering a compound of the invention to a segment of
  • Still other methods of delivery include ointments or drops for topical application to the eye.
  • Such formulations are especially appropriate for the treatment of uveitis in the anterior portion of the eye.
  • the methods are particularly suitable for treating ocular conditions related to uveitis.
  • the devices are also particularly suitable for use as an ocular device in treating subjects suffering from ocular conditions wherein the device is surgically implanted within the vitreous of the eye.
  • 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 uveitis, 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.
  • 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) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • 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.
  • materials which can serve as pharmaceutically- acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide
  • wetting agents such as sodium laur ⁇ l 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, vaginal, 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, 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 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • 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.
  • a compound may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example,
  • 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 they release 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.
  • 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 isostear ⁇ l alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostear ⁇ l alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of the invention for rectal or vaginal 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 or vaginal cavity 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 or vaginal cavity and release the active agent.
  • compositions of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • 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.
  • 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, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons 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 (Tweens, 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.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms 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.
  • antibacterial and antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • 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.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • 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.
  • kits for treatment or prevention of a disease or disorder or symptoms thereof associated withuveitis includes an effective amount of a compound in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to uveitis, wherein the effective amount of compound is less than 500 mg of the compound.
  • the kit comprises a sterile container which contains the compound; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister- packs, or other suitable container form known in the art.
  • sterile container which contains the compound; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister- packs, or other suitable container form known in the art.
  • Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
  • the instructions will generally include information about the use of the compound for treatment of a disease or disorder or symptoms thereof associated with uveitis; in preferred embodiments, the instructions include at least one of the following: description of the compound; dosage schedule and administration for treatment of uveitis or symptoms thereof; precautions; warnings; indications; counter-indications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references.
  • the instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
  • vitamin D compound(s) When administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically-acceptable carrier.
  • 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
  • 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 vitamin D compound of the present invention is administered at a concentration of about 0.001 ug to about 100 ug per kilogram of body weight, about 0.001 to about 10 ug/kg or about 0.001 ug to about 100 ug/kg of body weight. Ranges intermediate to the above-recited values are also intended to be part of the invention.
  • the vitamin D compound may be administered separately, sequentially or simultaneously in separate or combined pharmaceutical formulations with a second medicament for the treatment of uveitis (for example a second vitamin D compound of the present invention).
  • 0.0797 g of 1 ,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 organic layer was washed with 3x10 ml. of water, once with 5 ml. of saturated sodium hydrogen carbonate, once with 3 ml.
  • vitamin D compound eg VDR agonists such as Vitamin D3 analogues can have an effect on uveitis has been proven in an in vivo model.
  • EAU an autoimmune disease mediated by TM -type uveitogenic CD4+ T-cells, serves as a model for human posterior uveitis.
  • E ⁇ AU-susceptible B10.RIII mice were immunized with an uveitogenic regimen of 8 ug of interphotoreceptor retinoid-binding protein (IRBP) in CFA and treated orally with calcitriol or with Compound A, before or after EAU induction.
  • IRBP interphotoreceptor retinoid-binding protein
  • Figure 2 shows the EAU disease score (quantitated between 0 and 4) at day 21.
  • calcitriol at 0.5 ug/kg and Compound A at 10 ⁇ g/kg can prevent EAU, when administered from day -6 to 2.
  • Compound A but not calcitriol could inhibit EAU development when treatment was started 7 days after immunization.
  • protected mice had reduced antigen-specific delayed type hypersensitivity (DTH) responses to IRBP. It can be concluded that delayed hypersensitivity to IRBP in treated mice is correlated with disease severity.
  • LN primed lymph node cells
  • IFN-gamma is a signature cytokine for Th1 cells
  • IL-7 is a signature cytokine of pathogenic T cells. Both of these cytokines have been found to be produced by pathogenic T-cells in TM- type autoimmune diseases. That there is apparently no effect on IL-4 which is a Th2 cell signature cytokine implies a selectivity in the treatment for effect on a TM response over a Th2 response.
  • Vitamin D 3 derivatives as shown in Figure 5.
  • Vitamin D compounds eg VDR agonists
  • the inventors have demonstrated that natural Vitamin D 3 (calcitriol) effectively prevents E ⁇ AU whilst a synthetic vitamin D compound (a VDR agonist) Compound A, is capable of preventing as well as treating EAU.
  • Compound B a Vitamin D compound (1 ⁇ -Fluoro-25-hydroxy-16-ene- 23-yne-20-cyclopropyl-cholecalciferol) was found to be ineffective in inhibiting EAU in this model.
  • IRPB interphotoreceptor retinoid binding protein
  • CFA Complete Freund's adjuvant
  • TARC T-cell activation regulatory chemokine
  • EAU experimental autoimmune uveoretinitis LN - lymph nodes Incorporation by Reference

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Abstract

The invention provides for the use of vitamin D compounds in the prevention or treatment of uveitis.

Description

USE OP VITAMIN D3 COMPOUNDS FOR THE TREATMENT OF UVEITIS
Related Applications
This application claims the benefit of U.S. provisional patent application no. 60/718,766, filed September 19 2005, the contents of which are hereby incorporated by reference.
Field of the Invention
The present invention relates to novel uses and methods, and compounds for use therein.
Background of the Invention
Uveitis, a condition comprising inflammation of the eye including the iris, ciliary body, and choroid, actually comprises a large group of diverse diseases affecting not only the uvea but also the retina, optic nerve and vitreous. According to the International Uveitis Study Group, there are several classifications of uveitis: anterior, intermediate, posterior and panuveitis (total). Inflammation may be induced by trauma or toxic or infectious agents, but in most cases the mechanisms seem to be autoimmune in nature. Symptoms may be acute, sub-acute, chronic (greater than 3 months duration) and recurrent. The etiology is unknown in the majority of cases of endogenous uveitis. Uveitis is a major cause of severe visual impairment. Although the number of patients blinded from uveitis is unknown, it has been estimated that uveitis accounts for 10-15% of all cases of total blindness in the USA.
A variety of conditions can be described as posterior uveitis: focal, multifocal or diffuse choroiditis, chorioretinitis, retinochoroiditis, uveoretinitis or neurouveitis. The condition is usually painless but is characterised by the presence of floaters, vision impairment (sudden or gradual) such as blurring of vision, etc., and vision loss. Posterior uveitis may have several etiologies, and manifests itself in complex and sometimes misleading clinical conditions. There is growing evidence both in experimental models and clinically that endogenous posterior uveoretinitis is often characterised by an exaggerated immune response which causes tissue destruction.
When no apparent infectious or neoplastic aetiology is found, treatment can be directed towards dampening the resulting inflammatory cascade and hopefully reducing tissue damage.
The mainstay of treatment is systemic corticosteroid and often this is given in combination with immunosuppressive agents, such as cyclosporin A or azathioprine. High dose steroids are often required to control the disease and in addition to the disadvantages of the required longterm use and resistance in some patients, potentially serious side effects are often present. In young people a common side effect is weight gain, particularly around the face, which can be cosmetically unacceptable. Another important side effect of corticosteroids, particularly with reference to the eye is glaucoma resulting from increased intraocular pressure.
Furthermore, systemic treatment with corticosteroids is often inefficient in treating the macular edema that can complicate posterior uveitis. This inefficiency can be partially overcome by intravitreal administration of such drugs, though this route of administration has the obvious drawback of patient comfort and, despite the localisation of the administration, poor drug penetration into ocular tissues often occurs.
Therefore a strong need exists for more selective and specific treatments of uveitis. For example, it would be advantageous to develop uveitis immunotherapy that is amenable to systemic administration and which is free of the well recognised disadvantages of the current treatments.
Summary of the Invention
The present inventors have developed a new method of treating uveitis with a view to mitigating or alleviating the aforementioned disadvantages. The method is based on the use of calcitriol and analogs thereof, collectively "vitamin D compounds".
The importance of vitamin D (cholecalciferol) in the biological systems of higher animals has been recognized since its discovery by Mellanby in 1920 (Mellanby, E. (1921) Spec. Rep. Ser. Med. Res. Council (GB) SRS 61 A). It was in the interval of 1920-1930 that vitamin D officially became classified as a "vitamin" that was essential for the normal development of the skeleton and maintenance of calcium and phosphorus homeostasis.
Studies involving the metabolism of vitamin D3 were initiated with the discovery and chemical characterization of the plasma metabolite, 25-hydroxyvitamin D3 [25(OH) D3] (Blunt, J.W. et al. (1968) Biochemistry 6:3317-3322) and the hormonally active form, 1- alpha,25(OH)2D3 (Myrtle, J.F. et al. (1970) J. Biol. Chem. 245:1190-1196; Norman, A.W. et al. (1971) Science 173:51-54; Lawson, D.E.M. et al. (1971) Nature 230:228-230; Holick, M. F. (1971) Proc. Natl. Acad. Sci. USA 68:803-804). The formulation of the concept of a vitamin D endocrine system was dependent both upon appreciation of the key role of the kidney in producing 1-alpha,25(OH)2D3 in a carefully regulated fashion (Fraser, D. R. and Kodicek, E (1970) Nature 288:764-766; Wong, R.G. et al. (1972) J. Clin. Invest. 51 :1287-1291), and the discovery of a nuclear receptor for 1-alpha,25(OH)2D3 (VD3R) in the intestine (Haussler, M. R. et al. (1969) Exp. Cell Res. 58:234-242; Tsai, H.C. and Norman, A.W. (1972) J. Biol. Chem. 248:5967-5975).
The operation of the vitamin D endocrine system depends on the following: first, on the presence of cytochrome P450 enzymes in the liver (Bergman, T. and Postlind, H. (1991) Biochem. J. 276:427-432; Ohyama, Y and Okuda, K. (1991) J. Biol. Chem. 266:8690-8695) and kidney (Henry, H.L. and Norman, A.W. (1974) J. Biol. Chem. 249:7529-7535; Gray, R.W. and Ghazarian, J. G. (1989) Biochem. J. 259:561-568), and in a variety of other tissues to effect the conversion of vitamin D3 into biologically active metabolites such as 1-alpha,25(OH)2D3 and 24R,25(OH)2D3; second, on the existence of the plasma vitamin D binding protein (DBP) to effect the selective transport and delivery of these hydrophobic molecules to the various tissue components of the vitamin D endocrine system (Van Baelen, H. et al. (1988) Ann NY Acad. Sci. 538:60-68; Cooke, N.E. and Haddad, J.G. (1989) Endocr. Rev. 10:294-307; Bikle, D.D. et al. (1986) J. Clin. Endocrinol. Metab. 63:954-959); and third, upon the existence of stereoselective receptors in a wide variety of target tissues that interact with the agonist 1-alpha,25(OH)2D3 to generate the requisite specific biological responses for this secosteroid hormone (Pike, J.W. (1991) Annu. Rev. Nutr. 11 :189-216). To date, there is evidence that nuclear receptors for 1- alpha,25(OH)2D3 (VD3R) exist in more than 30 tissues and cancer cell lines (Reichel, H. and Norman, A.W. (1989) Annu. Rev. Med. 40:71-78), including the normal eye (Johnson J.A. et al. Curr. Eye Res. 1995 Feb; 14(2): 101-8).
Vitamin D3 and its hormonally active forms are well-known regulators of calcium and phosphorus homeostasis. These compounds are known to stimulate, at least one of, intestinal absorption of calcium and phosphate, mobilization of bone mineral, and retention of calcium in the kidneys. Furthermore, the discovery of the presence of specific vitamin D receptors in more than 30 tissues has led to the identification of vitamin D3 as a pluripotent regulator outside its classical role in calcium/bone homeostasis. A paracrine role for 1 -alpha, 25(OH)2 D3 has been suggested by the combined presence of enzymes capable of oxidizing vitamin D3 into its active forms, e.g., 25-OHD-1-alpha-hydroxylase, and specific receptors in several tissues such as bone, keratinocytes, placenta, and immune cells. Moreover, vitamin D3 hormone and active metabolites have been found to be capable of regulating cell proliferation and differentiation of both normal and malignant cells (Reichel, H. et al. (1989) Ann. Rev. Med. 40: 71-78).
Given the activities of vitamin D3 and its metabolites, much attention has focused on the development of synthetic analogues of these compounds. A large number of these analogues involve structural modifications in the A ring, B ring, C/D rings, and, primarily, the side chain (Bouillon, R. et al. (1995) Endocrine Reviews 16(2) :201-204). Although a vast majority of the vitamin D3 analogues developed to date involve structural modifications in the side chain, a few studies have reported the biological profile of A-ring diastereomers (Norman, A.W. et al. (1993) J. Biol. Chem. 268 (27): 20022-20030). Furthermore, biological esterification of steroids has been studied (Hochberg, R.B., (1998) Endocr. Rev. 19(3): 331-348), and esters of vitamin D3 are known (WO 97/11053).
Moreover, despite much effort in developing synthetic analogues, clinical applications of 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.
The activated form of vitamin D, vitamin D3, and some of its analogues have been described as potent regulators of cell growth and differentiation. It has previously been found that vitamin D3 as well as an analogue (analogue V), inhibited 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 (IGF1). Moreover, the analogue induced bcl-2 protein expression, intracellular calcium mobilization, and apoptosis in both unstimulated and KGF-stimulated BPH cells.
Topical administration of calcitriol has been said to inhibit Langerhans cell migration and corneal neovascularisation in ocular surface inflammation (Suzuki et al (2000) Curr. Eye Res. 20(2) 127-130) and calcitriol has been said to inhibit the P aeruginosa-induced expression of IL- 1b, IL-6 and IL-8 in human corneal epithelial cells (Xue et al (2002) Immunol. Cell Biol. 80(4) 340-5). However, the cornea is a distinct part of the eye, separate from those internal and posterior parts of the eye which are treated according to the methods of the present invention. In particular the cornea is accessible by topical treatment (direct administration to the cornea) which would not be the route of choice in the context of the present invention (for which systemic administration would be especially suitable).
As described in the Examples herein, the inventors have found that vitamin D compounds such as calcitriol and an analogue of calcitriol ("Compound A") can prevent experimental autoimmune uveoretinitis (EAU), an autoimmune disease mediated by Th 1 -type uveitogenic CD4+ T cells that serves as a model for human posterior uveitis.
Thus, in one aspect, the invention provides the use of a vitamin D compound in the prevention or treatment of uveitis. Also provided is a method of treating a patient with uveitis by administering an effective amount of a vitamin D compound. Further provided is the use of a vitamin D compound in the manufacture of a medicament for the prevention or treatment of uveitis. Further provided is a vitamin D compound for use in the prevention or treatment of uveitis. Additionally provided is a pharmaceutical combination comprising a vitamin D compound and a further agent for the treatment or prevention of uveitis. Also provided is a kit comprising a vitamin D compound together with instructions directing administration of said compound to a patient in need of treatment or prevention of uveitis thereby to treat or prevent uveitis in said patient.
In one aspect, the invention provides a method of prevention or treatment of uveitis using a vitamin D compound.
In another aspect, the invention provides a method for preventing or treating uveitis in a subject, comprising administering to a subject in need thereof an effective amount of a vitamin D compound, such that the uveitis is prevented or treated in the subject.
In one embodiment, the invention provides a method as described above, further comprising identifying a subject in need of prevention or treatment for uveitis. In another embodiment, the invention provides a method as described above, further comprising the step of obtaining the vitamin D compound. According to the methods described herein, the subject is typically a mammal, particularly a human. In another embodiment, the invention provides a method described herein wherein the vitamin D compound is formulated in a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier. In another aspect, the invention provides a pharmaceutical formulation comprising a vitamin D compound and a pharmaceutically acceptable carrier for use in the prevention or treatment of uveitis. In yet another aspect, the invention provides a pharmaceutical formulation comprising a vitamin D compound and a pharmaceutically acceptable carrier packaged with instructions for use in the prevention or treatment of uveitis. In another aspect, the invention provides a vitamin D compound for preventing or treating uveitis. In one embodiment, the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is administered separately, sequentially or simultaneously in separate or combined pharmaceutical formulations with a second medicament for the prevention or treatment of uveitis.
In certain embodiments, the vitamin D compound is not a compound represented by formula (I):
Figure imgf000007_0001
wherein: A1 is single or double bond; A2 is a single, double or triple bond; Xi and X2 are each independently H2 or =CH2, provided Xi and X2 are not both =CH2; R1 and R2 are each independently OC(O)C1 -C4alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl; R3, R4 and R5 are each independently hydrogen, CrC4alkyl, hydroxyalkyl, or haloalkyl, with the understanding that R5 is absent when A2 is a triple bond, or R3 and R4 taken together with C20 form C3-C6cycloalkyl; R6 and R7 are each independently alkyl or haloalkyl; and R8 is H, C(O)C1 -C4alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; provided that when A1 is a single bond, R3 is hydrogen and R4 is methyl, then A2 is a double or triple bond; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
In other embodiments, the vitamin D compound is a compound of formula (I), as follows:
Figure imgf000007_0002
wherein: A1 is single or double bond; A2 is a single, double or triple bond; X1 and X2 are each independently H2 or =CH2, provided X1 and X2 are not both =CH2; R1 and R2 are each independently OC(O)C1 -C4alkyl (e.g. OAc), OC(O)hydroxyalkyl, or OC(O)haloalkyl; R1 and R2 may each also independently represent OH; R3, R4 and R5 are each independently hydrogen, CrC4alkyl, hydroxyalkyl, or haloalkyl, with the understanding that R5 is absent when A2 is a triple bond, or R3 and R4 taken together with C20 form C3-C6cycloalkyl; R6 and R7 are each independently alkyl (e.g. C1-4 alkyl) or haloalkyl; and R8 is H, C(O)C1 -C4alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof. Particular compounds of formula (I) that may be mentioned for use in the context of the invention are those wherein A1 is a single bond, R3 is hydrogen, R4 is methyl, and A2 is a double or triple bond.
Further particular sets of compounds of formula (I) for use in the invention are provided in which R1 and R2 are OH or OC(O)C1-C4 alkyl. In yet another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein R1 and R2 are OAc. In still another embodiment, the invention provides for use, method, formulation, compound or kit, wherein X1 is =CH2 and X2 is H. In still another embodiment, the invention provides for use, method, formulation, compound or kit, wherein A1 is single bond and A2 is a single bond. In another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein R3 and R4 taken together with C20 form C3-C6 cycloalkyl. In still another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein R3 and R4 taken together with C20 form cyclopropyl. In yet another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein R5 is hydrogen. In still another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein R6 and R7 are each independently C1-4alkyl. In another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein R6 and R7 are each independently methyl. In still another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein R8 is H. In another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein R1 and R2 are OH or OC(O)C1-C4 alkyl, X1 is =CH2 and X2 is H, A1 is single bond, A2 is a single bond, R3 and R4 taken together with C20 form C3-C6 cycloalkyl, R5 is hydrogen, R6 and R7 are each independently C1-4alkyl, and R8 is H. In yet another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein R1 and R2 are OH or OAc, R3 and R4 taken together with C20 form cyclopropyl, and R6 and R7 are each methyl.
In one embodiment, the invention provides for the use, method, formulation, compound or kit, wherein said vitamin D compound is a compound of the formula (II):
Figure imgf000008_0001
wherein:
X is H2 or CH2
Ri is hydrogen, hydroxy or fluorine
R2 is hydrogen or methyl R3 is hydrogen or methyl provided that when R2 or R3 is methyl, R3 or R2 must be hydrogen
R4 is methyl, ethyl or trifluoromethyl
R5 is methyl, ethyl or trifluoromethyl
A is a single or double bond B is a single, E-double, Z-double or triple bond.
In another embodiment, the invention provides for the use, method, formulation, compound, or kit, wherein in the compound of formula (II) each of R4 and R5 is methyl or ethyl.
In another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is 1,3-Di-O-acetyl-1 ,25-dihydroxy-20- cyclopropyl-cholecalciferol (hereinafter sometimes referred to as "Compound A") having the formula:
Figure imgf000009_0001
In another embodiment, the vitamin D compound is not 1,3-Di-O-acetyl-1 ,25-dihydroxy- 20-cyclopropyl-cholecalciferol.
In another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is I^S-dihydroxy^O^i ^δ-cyclopropyl- cholecalciferol having the formula:
Figure imgf000010_0001
In another embodiment, the vitamin D compound is not 1,3-Di-O-acetyl-1 ,25-dihydroxy- 20-cyclopropyl-cholecalciferol.
In another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is 1-alpha-fluoro-25-hydroxy-16,23E-diene- 26,27-bishomo-20-epi-cholecalciferol, having the formula:
Figure imgf000010_0002
In another embodiment, the invention provides for the use, method, formulation, compound or kit wherein the compound is calcitriol.
In still another embodiment, the invention provides for the use, method, formulation, compound or kit, wherein said uveitis is autoimmune uveitis.
Most suitably, the invention provides for the use, method, formulation, compound or kit, wherein said uveitis is posterior uveitis and in particular is uveoretinitis.
Brief Description of the Drawings
Figure 1 shows the the experimental procedure used to treat experimental autoimmune uveoretinitis (EAU) with Compound A.
Figure 2 shows the EAU disease score (quantitated between 0 and 4) at day 21. Figure 3 shows the reduced antigen-specific delayed type hypersensitivity (DTH) responses to IRBP in mice.
Figure 4 shows the in vitro assay of primed lymph node cells (LN) used to indicated that calcitriol and Compound A both appeared to be potent on T cell polarization.
Figure 5 shows that Ag driven chemokine release, such as MIP-Ia, Rantes and TARC, is inhibited by Vitamin D compounds.
Detailed Description of the Invention
1. DEFINITIONS
Before further description of the present invention, and in order that the invention may be more readily understood, certain terms are first defined and collected here for convenience.
By "uveitis" it is meant conditions comprising inflammation of the eye, in particular the uveal tract (iris, ciliary body, choroid) with or without additional inflammation of the retina, optic nerve and vitreous, including but not limited to anterior, intermediate, posterior uveitis and panuveitis and in acute, sub-acute, chronic or recurrent forms.
The methods of the invention are applicable, for example, to the treatment of posterior uveitis including but not limited to focal, multifocal or diffuse choroiditis, chorioretinitis, retinochoroiditis uveretinitis or neurouveitis. Such types of uveitis may by caused by an autoimmune response or a disordered immune response (for example where inflammation continues after infecting bacteria have been removed). Most typically the posterior uveitits is uveoretinitis.
Those skilled in the art will recognise that the vitamin D compounds may be used in human or veterinary medicine. Thus, in accordance with the invention, the terms "subject" and "patient" are used interchangeably, and are intended to include mammals, for example, humans. It is preferred that the vitamin D compound be used in the treatment of human patients.
The term "administration" or "administering" includes routes of introducing the vitamin D compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally), oral, inhalation, rectal, transdermal, or ocular delivery. The pharmaceutical preparations are, of course, given by forms suitable for each administration route. For example, these preparations are administered in tablets or capsule form, by injection, infusion, inhalation, lotion, ointment, suppository, etc. Oral administration is preferred. The injection can be bolus or can be continuous infusion. Depending on the route of administration, the vitamin D compound can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally effect its ability to perform its intended function. The vitamin D compound can be administered alone, or in conjunction with either another agent useful in the treatment of uveitis (for example corticosteroids), or with a pharmaceutically-acceptable carrier, or both. The vitamin D compound can be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent (via the same or different routes). Furthermore, the vitamin D compound can also be administered in a pro-form which is converted into its active metabolite, or more active metabolite in vivo.
The term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, i.e. sufficient to treat uveitis. 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.
A therapeutically effective amount of vitamin D compound (i.e., an effective dosage) may range from about 0.001 to 30 ug/kg body weight, preferably about 0.01 to 25 ug/kg body weight, more preferably about 0.1 to 20 ug/kg body weight, and even more preferably about 1 to 10 ug/kg, 2 to 9 ug/kg, 3 to 8 ug/kg, 4 to 7 ug/kg, or 5 to 6 ug/kg body weight (for example, per day). The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. In addition, 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. Moreover, 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. In one example, a subject is treated with a vitamin D compound in the range of between about 0.1 to 20 ug/kg body weight, one time 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.
Also, as with other chronic treatments an "on-off" or intermittent treatment regime can be considered. It will also be appreciated that the effective dosage of a vitamin D compound used for treatment may increase or decrease over the course of a particular treatment. The term "alkyl" refers to the radical of saturated aliphatic groups, including straight- chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which can optionally further include (for example, in one embodiment alkyl groups do not include) oxygen, nitrogen, sulfur or phosphorus atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorus atoms. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., CrC30 for straight chain, C3-C30 for branched chain), preferably 26 or fewer, and more preferably 20 or fewer, especially 6 or fewer (for example 4 for fewer). Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, 6 or 7 carbons in the ring structure.
Moreover, the term alkyl as used throughout the specification and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. Cycloalkyls can be further substituted, e.g., with the substituents described above. Suitably, an alkyl moiety is unsubstituted.
An "alkylaryl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). Unsubstituted alkyl (including cycloalkyl) groups or groups substituted by halogen, especially fluorine, are generally preferred over other substituted groups. The term "alkyl" also includes 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 (i.e. alkenyl and alkynyl groups).
Unless the number of carbons is otherwise specified, "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. Examples of lower alkyl groups include methyl, ethyl, propyl (n- propyl and i-propyl), butyl (tert-butyl, n-butyl and sec-butyl), pentyl, hexyl, heptyl, octyl and so forth. In preferred embodiment, the term "lower alkyl" includes a straight chain alkyl having 4 or fewer carbon atoms in its backbone, e.g., d-C4alkyl.
Thus specific examples of alkyl include CrC6alkyl or Ci-C4alkyl (such as methyl or ethyl). Specific examples of hydroxyalkyl include CrC6hydroxyalkyl or CrC4hydroalkyl (such as hydroxy methyl).
The terms "alkoxyalkyl," "polyaminoalkyl" and "thioalkoxyalkyl" refer to alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
The term "aryl" as used herein, refers to the radical of aryl groups, including 5- and 6- membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like.
Those aryl groups having heteroatoms in the ring structure may also be referred to as
"aryl heterocycles", "heteroaryls" or "heteroaromatics." The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydrγl, alkylthio, arγlthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. 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).
The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogueous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. For example, the invention contemplates cyano and propargyl groups.
The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. The term "diastereomers" refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.
The term "enantiomers" refers to two stereoisomers of a compound which are non- superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or a "racemate."
As used herein, the term "halogen" designates -F, -Cl, -Br or -I; the term "sulfhydryl" or "thiol" means -SH; the term "hydroxyl" means -OH.
The term "haloalkyl" is intended to include alkyl groups as defined above that are mono- , di- or polysubstituted by halogen, e.g., Cr6haloalkyl or Cr4haloalkyl such as fluoromethyl and trifluoromethyl.
The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
The terms "polycyclyl" or "polycyclic radical" refer to the radical of two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. 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, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety.
The term "isomers" or "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
The terms "isolated" or "substantially purified" are used interchangeably herein and refer to vitamin D3 compounds in a non-naturally occurring state. The compounds can be substantially free of cellular material or culture medium when naturally produced, or chemical precursors or other chemicals when chemically synthesized. In one embodiment of the invention an isolated vitamin D compound is at least 75% pure, especially at least 85% pure, in particular at least 95% pure and preferably at least 99% pure on a w/w basis, said purity being by reference to compounds with which the vitamin D compound is naturally associated or else chemically associated in the course of chemical synthesis.
In certain preferred embodiments, the terms "isolated" or "substantially purified" also refer to preparations of a chiral compound which substantially lack one of the enantiomers; i.e., enantiomerically enriched or non-racemic preparations of a molecule.
Similarly, the terms "isolated epimers" or "isolated diastereomers" refer to preparations of chiral compounds which are substantially free of other stereochemical forms. For instance, isolated or substantially purified vitamin D3 compounds include synthetic or natural preparations of a vitamin D3 enriched for the stereoisomers having a substituent attached to the chiral carbon at position 3 of the A-ring in an alpha-configuration, and thus substantially lacking other isomers having a beta-configuration. Unless otherwise specified, such terms refer to vitamin D3 compositions in which the ratio of alpha to beta forms is greater than 1 :1 by weight. For instance, an isolated preparation of an a epimer means a preparation having greater than 50% by weight of the alpha-epimer relative to the beta stereoisomer, more preferably at least 75% by weight, and even more preferably at least 85% by weight. Of course the enrichment can be much greater than 85%, providing "substantially epimer-enriched" preparations, i.e., preparations of a compound which have greater than 90% of the alpha-epimer relative to the beta stereoisomer, and even more preferably greater than 95%. The term "substantially free of the beta stereoisomer" will be understood to have similar purity ranges.
As used herein, the term "vitamin D compound" includes any compound being an analogue of vitamin D that is capable of treating or preventing uveitis. Generally, compounds which are ligands for the Vitamin D receptor (VDR ligands) and which are capable of treating or preventing uveitis are considered to be within the scope of the invention. Vitamin D compounds are preferably agonists of the vitamin D receptor. Thus, 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 D2 compounds, vitamin D3 compounds, isomers thereof, or derivatives/analogues thereof. Preferred vitamin D compounds are vitamin D3 compounds which are ligands of (more preferably are agonists of) the vitamin D receptor. Preferably the vitamin D compound (e.g., the vitamin D3 compound) is a more potent agonist of the vitamin D receptor than the native ligand (i.e., the vitamin D, e.g., vitamin D3). Vitamin D1 compounds, vitamin D2 compounds and vitamin D3 compounds include, respectively, vitamin D1, D2, D3 and analogues thereof. In certain embodiments, the vitamin D compound may be a steroid, such as a secosteroid, e.g., calciol, calcidiol or calcitriol. Non-limiting examples of certain preferred vitamin D compounds in accordance with the invention include those described in U.S. Patent No. 6,492,353 and published international application WO2005/030222, which are incorporated herein by reference.
As used herein, the term "obtaining" includes purchasing, synthesizing, isolating or otherwise acquiring one or more of the the vitamin D compounds used in practicing the invention.
The term "secosteroid" is art-recognized and includes compounds in which one of the cyclopentanoperhydro-phenanthrene rings of the steroid ring structure is broken. For example, 1-alpha,25(OH)2D3 and analogues thereof are hormonally active secosteroids. In the case of vitamin D3, the 9-10 carbon-carbon bond of the B-ring is broken, generating a seco-B-steroid. The official IUPAC name for vitamin D3 is 9,10-secocholesta-5,7,10(19)-trien-3B-ol. For convenience, a 6-s-trans conformer of 1-alpha,25(OH)2 D3 is illustrated herein having all carbon atoms numbered using standard steroid notation.
Figure imgf000017_0001
In the formulas presented herein, the various substituents on ring A are illustrated as joined to the steroid nucleus by one of these notations: 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), or a wavy line ( ^^^ ) indicating that a substituent may be either above or below the plane of the ring. In regard to 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). Furthermore the indication of stereochemistry across a carbon-carbon double bond is also opposite from the general chemical field in that "Z" refers to what is often referred to as a "cis" (same side) conformation whereas "E" refers to what is often referred to as a "trans" (opposite side) conformation. Regardless, both configurations, cis/trans and/or Z/E are contemplated for the compounds for use in the present invention.
As shown, the A ring of the hormone 1-alpha,25(OH)2D3 contains two asymmetric centers at carbons 1 and 3, each one containing a hydroxyl group in well-characterized configurations, namely the 1 -alpha- and 3-beta- hydroxyl groups. In other words, carbons 1 and 3 of the A ring are said to be "chiral carbons" or "carbon centers."
With respect to the nomenclature of a chiral center, terms "d" and "I" configuration are as defined by the IUPAC Recommendations. As to the use of the terms, diastereomer, racemate, epimer and enantiomer will be used in their normal context to describe the stereochemistry of preparations.
Also, throughout the patent literature, the A ring of a vitamin D compound is often depicted in generic formulae as any one of the following structures:
Figure imgf000018_0001
wherein X1 and X2 are defined as H or =CH2; or
Figure imgf000018_0002
wherein X1 and X2 are defined as H2 or CH2. Although there does not appear to be any set convention, it is clear that one of ordinary skill in the art understands either formula (A) or (B) to represent an A ring in which, for example, Xi is =CH2and X2 is defined as H2 , as follows:
Figure imgf000019_0001
For purposes of the instant invention, formula (B) will be used in all generic structures.
In one embodiment of the invention, the vitamin D compound is a compound of formula
(III):
Figure imgf000019_0002
wherein:
X is hydroxyl or fluoro; Y is H2 or CH2;
Z1 and Z2 are H or a substituent represented by formula (IV), provided Z1 and Z2 are different (preferably Z1 and Z2 do not both represent formula (IV)):
Figure imgf000019_0003
wherein:
Z3 represents the above-described formula (III);
A is a single bond or a double bond; Ri, R2, and Z4, are each, independently, hydrogen, alkyl, or a saturated or unsaturated carbon chain represented by formula (V), provided that at least one of Ri, R2, and Z4 is the saturated or unsaturated carbon chain represented by formula (V) and provided that all of Ri, R2, and Z4 are not saturated or unsaturated carbon chain represented by formula (V):
Figure imgf000020_0001
wherein:
Z5 represents the above-described formula (IV); A2 is a single bond, a double bond, or a triple bond; and A3 is a single bond or a double bond; and
R3, and R4, are each, independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl; and R5 is H2 or oxygen. R5 may also represent hydrogen or may be absent.
Thus, in the above structure of formula (V) (and in corresponding structures below), when A2 represents a triple bond R5 is absent. When A2 represents a double bond R5 represents hydrogen. When A2 represents a single bond R5 represents a carbonyl group or two hydrogen atoms.
In another embodiment of the invention, the vitamin D compound is a compound of formula (Vl):
Figure imgf000020_0002
wherein:
Xi and X2 are H2 or CH2, wherein X1 and X2 are not CH2 at the same time;
A is a single or double bond;
A2 is a single, double or triple bond; A3 is a single or double bond;
Ri and R2 are hydrogen, CrC4 alkyl or 4-hydroxy-4-methylpentyl, wherein R1 and R2 are not both hydrogen;
R5 is H2 or oxygen, R5 may also represent hydrogen or may be absent; R3 is CrC4 alkyl, hydroxyalkyl or haloalkyl, eg., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl; and
R4 is CrC4 alkyl, hydroxyalkyl or haloalkyl, eg., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl.
In yet another embodiment of the invention, the vitamin D compound is a compound of formula (VII):
Figure imgf000021_0001
wherein:
Xi and X2 are H2 or CH2, wherein X1 and X2 are not CH2 at the same time;
A is a single or double bond; A2 is a single, double or triple bond;
A3 is a single or double bond;
R1 and R2 are hydrogen, C1-C4 alkyl, wherein R1 and R2 are not both hydrogen;
R5 is H2 or oxygen, R5 may also represent hydrogen or may be absent;
R3 is C1-C4 alkyl, hydroxyalkyl or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl; and
R4 is C1-C4 alkyl, hydroxyalkyl haloalkyl, e.g., or fluoroalkyl, e.g., fluoromethyl and trifluoromethyl.
An example of the above structure of formula (VII) is 1,25-dihydroxy-16-ene-23-yne cholecalciferol.
In yet another embodiment, the vitamin D compound is a "geminal" compound of formula
(VIII):
Figure imgf000022_0001
wherein:
Figure imgf000022_0002
A2 is a single, a double or a triple bond; R3 is CrC4 alkyl, hydroxyalkyl, or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl;
R4 is CrC4 alkyl, hydroxyalkyl or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl; and the configuration at C20 is R or S.
Compounds of this type may be referred to as "geminal" or "gemini" vitamin D3 compounds due to the presence of two alkyl chains at C20.
An example geminal compound of formula (VIII) is 1 ,25-dihydroxy-21-(3-hydroxy-3- methylbutyl)-19-nor-cholecalciferol:
Figure imgf000022_0003
In another embodiment, the vitamin D compound is a compound of formula (IX):
Figure imgf000023_0001
wherein:
A is a single or double bond;
Ri and R2 are each, independently, hydrogen, alkyl (for example methyl);
R3, and R4, are each, independently, alkyl, and
X is hydroxyl or fluoro.
In a further embodiment, the vitamin D compound is a compound having formula (X):
Figure imgf000023_0002
wherein:
Ri and R2, are each, independently, hydrogen, or alkyl, e.g., methyl;
R3 is alkyl, e.g., methyl,
R4 is alkyl, e.g., methyl; and
X is hydroxyl or fluoro. In specific embodiments of the invention, the vitamin D compound is selected from the group consisting of:
Figure imgf000024_0001
In other specific embodiments of the invention, the vitamin D compound is selected from the group consisting of:
Figure imgf000025_0001
In further specific embodiments of the invention, the vitamin D compound is selected from the group of geminal compounds consisting of:
Figure imgf000026_0001
In still further specific embodiments of the invention, the vitamin D compound is a geminal compound of formula (Xl):
Figure imgf000027_0001
wherein: A1 is a single or double bond;
A2 is a single, a double or a triple bond;
Ri> F?2, R3 and R4 are each independently CrC4alkyl, d-C4 deuteroalkyl, hydroxyalkyl, or haloalkyl;
R5, R6 and R7 are each independently hydroxyl, OC(O)Ci -C4alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl; the configuration at C20 is R or S;
Figure imgf000027_0002
Z is hydrogen when at least one of Ri and R2 is CrC4 deuteroalkyl and at least one of R3 and R4 is haloalkyl or when at least one of Ri and R2 is haloalkyl and at least one of R3 and R4 is CrC4 deuteroalkyl; or Z is -OH, =0, -SH, or -NH2; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
Various embodiments of this aspect of the invention include individual compounds of formula (Xl) wherein: A1 is a single bond; A2 is a single bond; A2 is a triple bond; Ri, R2, R3, and R4 are each independently methyl or ethyl; R1, R2, R3, and R4 are each independently C1-C4 deuteroalkyl or haloalkyl; R5 is hydroxyl; R6 and R7 are hydroxyl; R6 and R7 are each OC(O)C1- C4 alkyl; X1 is H2; X1 is CH2; Z is hydrogen; or Z is =0.
In certain embodiments of formula (Xl), R5, R6 and R7 are hydroxyl. In other embodiments, R6 and R7 are each acetyloxy. In yet other embodiments of formula (Xl), Z is hydrogen when at least one of Ri and R2 is CrC4 deuteroalkyl and at least one of R3 and R4 is haloalkyl or when at least one of Ri and R2 is haloalkyl and at least one of R3 and R4 is d-C4 deuteroalkyl; Z is -OH, =0, -SH, or -NH2 when X1 is CH2; Z is -OH, =0, -SH, or -NH2 when X1 is H2 and the configuration at C20 is S; or Z is =0, -SH, or -NH2 when X1 is H2 and the configuration at C20 is R. In one embodiment, Z is - OH.
Still other embodiments of of formula (Xl) include those wherein X1 is CH2; A2 is a single bond; R1, R2, R3, and R4 are each independently methyl or ethyl; and Z is -OH. In one embodiment, X1 is CH2; A2 is a single bond; R1, R2, R3, and R4 are each independently methyl or ethyl; and Z is =0. In one embodiment, X1 is H2; A2 is a single bond; R1, R2, R3, and R4 are each independently methyl or ethyl; the configuration at C20 is S; and Z is -OH. In another embodiment, X1 is H2; A2 is a single bond; R1, R2, R3, and R4 are each independently methyl or ethyl; and Z is =0. In these embodiments, R1, R2, R3, and R4 are advantageously each methyl.
In certain embodiments, the haloalkyl is fluoroalkyl. Advantageously, fluoroalkyl is fluoromethyl or trifluoromethyl.
Additional embodiments of of formula (Xl) include compounds X1 is H2; A2 is a triple bond; R1 and R2 are each C1-C4 deuteroalkyl; R3 and R4 are each haloalkyl; and Z is hydrogen. In other embodiments, X1 is CH2; A2 is a triple bond; R1 and R2 are each C1-C4 deuteroalkyl; R3 and R4 are each haloalkyl; and Z is hydrogen.
In these embodiments, R1 and R2 are advantageously each deuteromethyl and R3 and
R4 are advantageously each trifluoromethyl.
In still further specific embodiments of the invention, the vitamin D compound is a geminal compound of formula (XII):
Figure imgf000028_0001
wherein:
Figure imgf000029_0001
A2 is a single, a double or a triple bond;
Ri, R2, R3 and R4 are each independently d-C4 alkyl, hydroxyalkyl, or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl; Z is -OH, Z may also be =0, -NH2 or -SH; and the configuration at C20 is R or S, and pharmaceutically acceptable esters, salts, and prodrugs thereof.
In a further embodiment of formula (XII), Xi is CH2. In another embodiment, A2 is a single bond. In another, R1, R2, R3, and R4 are each independently methyl or ethyl. In a further embodiment, Z is -OH. In another, X1 is CH2; A2 is a single bond; R1, R2, R3, and R4 are each independently methyl or ethyl; and Z is -OH. In an even further embodiment, R1, R2, R3, and R4 are each methyl.
In a further embodiment of the invention, the vitamin D compound is a geminal compound of the formula:
Figure imgf000029_0002
33 50
The chemical names of compounds 33 and 50 mentioned above are 1 ,25-dihydroxy-21- (2R,3-dihydroxy-3-methyl-butyl)-20R-cholecalciferol and 1 ,25-dihydroxy-21-(2R,3-dihydroxy-3- methyl-butyl)-20S-cholecalciferol respectively.
Additional embodiments of geminal compounds include the following vitamin D compounds for use in accordance with the invention:
Figure imgf000030_0001
(1 J25-Dihydroxy-21-(2R,3-dihydroxy-3-nnethyl-butyl)-20S-19-nor-cholecalciferol);
Figure imgf000030_0002
(1 ,25-Dihydroxy-20S-21 -(3-hydroxy-3-methyl-butyl)-24-keto-1 θ-nor-cholecalciferol);
Figure imgf000030_0003
(1 ,25-Dihydroxy-20S-21-(3-hydroxy-3-methyl-butyl)-24-keto-cholecalciferol);
Figure imgf000031_0001
(I ^S-Dihydroxy^^a-hydroxy-S-trifluoronnethyl^-trifluoro-butynyl^θ^Z-hexadeutero- 1 θ-nor^OS-cholecalciferol)
and
Figure imgf000031_0002
(I ^S-Dihydroxy^^S-hydroxy-S-trifluoronnethyl^-trifluoro-butynyl^θ^Z-hexadeutero- 20S-cholecalciferol).
In certain embodiments of the invention, the vitamin D compound is a compound of formula (XIII):
Figure imgf000031_0003
wherein:
Xi and X2 are each independently H2 or =CH2, provided Xi and X2 are not both =CH2; Ri and R2 are each independently, hydroxyl, OC(O)CrC4 alkyl, OC(O)hydroxyalkyl, OC(O)fluororalkyl; R3 and R4 are each independently hydrogen, d-C4 alkyl, hydroxyalkyl or haloalkyl, or R3 and R4 taken together with C20 form C3-C6 cylcoalkyl; and R5 and R6 are each independently CrC4 alkyl and pharmaceutically acceptable esters, salts, and prodrugs thereof.
Suitably in compounds of formula (XIII), R3 and R4 are each independently hydrogen, Cr
C4 alkyl, or R3 and R4 taken together with C20 form C3-C6 cylcoalkyl.
In one example set of compounds of formula (XIII) R5 and R6 are each independently Cr C4 alkyl.
In another example set of compounds of formula (XIII) R5 and R6 are each independently haloalkyl e.g., CrC4 fluoroalkyl.
When R3 and R4 are taken together with C20 to form C3-C6 cycloalkyl, an example is cyclopropyl.
In one embodiment of formula (XIII), Xi and X2 are each H2. In another embodiment, R3 is hydrogen and R4 is CrC4 alkyl. In a preferred embodiment R4 is methyl.
In another embodiment of formula (XIII), R5 and R6are each independently methyl, ethyl fluoromethyl or trifluoromethyl. In a preferred embodiment, R5 and R6 are each methyl.
In yet another embodiment of formula (XIII), Ri and R2 are each independently hydroxyl or OC(O)CrC4 alkyl.
In a preferred embodiment of formula (XIII), Ri and R2 are each OC(O)CrC4 alkyl. In another preferred embodiment, Ri and R2 are each acetyloxy.
An example of such a compound is I .S-O-diacetyl-i ^δ-dihydroxy-iθ-ene^-keto-iθ- nor-cholecalciferol, having the following structure:
Figure imgf000033_0001
In another embodiment of the invention the vitamin D compound for use in accordance with the invention is 2-methylene-19-nor-20(S)-1 -alpha, 25-hydroxyvitamin D3:
Figure imgf000033_0002
The synthesis of this and related compounds is described in WO02/05823 and
US5,536,713 which are herein incorporated in their entirety by reference.
In certain embodiments of the invention, the vitamin D compound is a compound of the formula (XIV):
Figure imgf000033_0003
wherein:
A1 is single or double bond; A2 is a single, double or triple bond;
Xi and X2 are each independently H or =CH2, provided Xi and X2 are not both =CH2; Ri and R2 are each independently OH, OC(O)CrC4 alkyl (for example OAc),
OC(O)hydroxyalkyl, OC(O)haloalkyl;
R3, R4 and R5 are each independently hydrogen, CrC4 alkyl, hydroxyalkyl, or haloalkyl, or R3 and R4 taken together with C20 form C3-C6 cycloalkyl; and
R6 and R7 are each independently Ci-4alkyl or haloalkyl; and R8 is H, -COCrC4alkyl (e.g. Ac), -CO hydroxyalkyl or -COhaloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
When R3 and R4 are taken together with C20 to form C3-C6 cycloalkyl an example is cyclopropyl.
Suitably R6 and R7 are each independently haloalkyl. R8 may suitably represent H or Ac.
In one embodiment of formula (XIV), A1 is a single bond and A2 is a single bond, E or Z double bond, or a triple bond. In another embodiment, A1 is a double bond and A2 is a single bond, E or Z double bond, or a triple bond. One of ordinary skill in the art will readily appreciate that when A2 is a triple bond, R5 is absent
In one embodiment of formula (XIV), X1 and X2 are each H. In another embodiment, X1 is CH2 and X2 is H2. In another embodiment, R3 is hydrogen and R4 is C1-C4 alkyl. In a preferred embodiment R4 is methyl.
In another example set of compounds of formula (XIV), R1 and R2 both represent OAc.
In one set of example compounds of formula (XIV) R6 and R7 are each independently C1- 4alkyl. In another set of example compounds R6 and R7 are each independently haloalkyl. In another embodiment, R6 and R7 are each independently methyl, ethyl or fluoroalkyl. In a preferred embodiment, R6 and R8 are each trifluoroalkyl, e.g., trifluoromethyl.
Suitably R5 represents hydrogen.
Thus, in certain embodiments, vitamin D compounds for use in accordance with the invention are represented by formula (XV):
Figure imgf000035_0001
wherein:
A1 is single or double bond;
A2 is a single, double or triple bond; Xi and X2 are each independently H or =CH2, provided Xi and X2 are not both =CH2;
Ri and R2 are each independently OH, OC(O)CrC4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl;
R3, R4 and R5 are each independently hydrogen, CrC4 alkyl, hydroxyalkyl, or haloalkyl, or R3 and R4 taken together with C20 form C3-C6 cycloalkyl; R6 and R7 are each independently haloalkyl; and
R8 is H, C(O)CrC4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
In certain preferred embodiments of formula (XV), when A1 is single bond, R3 is hydrogen, and R4 is methyl, then A2 is a double or triple bond.
An example compound of the above-described formula (XV) which is one of the preferred compounds in the context of the present invention is 1,3-di-O-acetyl-1 ,25-dihydroxy- IΘ^SZ-diene^θ^Z-hexafluoro-iθ-nor-cholecalciferol:
Figure imgf000035_0002
In another preferred embodiment the compound is one of formula (XVI), wherein R1 and R2 are each OAc; A1 is a double bond; A2 is a triple bond; and R8 is either H or Ac:
Figure imgf000036_0001
In certain embodiments of the above-represented formula (XV), vitamin D compounds for use in accordance with the invention are represented by the formula (XVII):
Figure imgf000036_0002
Other example compounds of the above-described formula (XVII) include:
1 ,3-di-0-acetyl-1 ^S-dihydroxy^S-yne-cholecalciferol;
1 ,3-di-0-acetyl-1 ^δ-dihydroxy-iβ-ene^S-yne-cholecalciferol; 1 ,3-di-0-acetyl-1 ,25-dihydroxy-i 6,23E-diene-cholecalciferol;
1 ,3-di-0-acetyl-1 ^S-dihydroxy-iθ-ene-cholecalciferol;
1 ,3,25-Tri-O-acetyl-1 ,25-dihydroxy-16-ene-23-yne-26,27-hexafluoro-cholecalciferol:
I .S-di-O-acetyl-I ^S-dihydroxy-iθ-ene^S-yne^θ^Z-hexafluoro-cholecalciferol; i ^-Di-O-acetyl-I ^S-dihydroxy-iβ^aE-diene^SR^e-trifluoro-cholecalciferol; 1 ,3-Di-0-acetyl-1 ^S-Dihydroxy-iβ-ene^a-yne^e^Z-hexafluoro-iθ-nor-cholecalciferol; i .a^S-Tri-O-acetyl-I^S-Dihydroxy-iβ-ene^S-yne^e^Z-hexafluoro-iθ-nor- cholecalciferol;
1 ,3-di-0-acetyl-1 ^S-dihydroxy-iβ-ene-iθ-nor-cholecalciferol;
1 ,3-Di-O-acetyl-1 ,25-dihydroxy-16-ene-23-yne-19-nor-cholecalciferol; I .S-Di-O-acetyl-I ^S-dihydroxy-iβ-ene^S-yne^β^Z-bishomo-iθ-nor-cholecalciferol.
In certain other embodiments, the vitamin D compounds for use in accordance with the invention are represented by the formula (XVIII):
Figure imgf000037_0001
. (XViIi)
In a preferred embodiment, Xi is =CH2and X2 is H2. When A1 is a single bond, and A2 is a triple bond, it is preferred that R8 is H or C(O)CH3, and R6 and R7 are alkyl, preferably methyl. When A1 is a single bond, and A2 is a single bond, it is preferred that R8 is H or C(O)CH3, and R6 and R7 are alkyl, preferably methyl. When A1 is a double bond, and A2 is a single bond, it is preferable that R8 is H or C(O)CH3, and R6 and R7 are alkyl, preferably methyl.
In another preferred embodiment, X1 and X2 are each H2. When A1 is a single bond, and
A2 is a triple bond, it is preferred that R8 is H or C(O)CH3, and R6 and R7 are alkyl or haloalkyl. It is preferred that the alkyl group is methyl, and the haloalkyl group is trifluoroalkyl, preferably trifluoromethyl. When A1 is a single bond, and A2 is a double bond, it is preferred that R8 is H or C(O)CH3, R6 and R7 are haloalkyl, preferably trifluoroalkyl, preferably trifluoromethyl. When A1 is a double bond, and A2 is a single bond, it is preferred that R8 is H or C(O)CH3, R6 and R7 are alkyl, preferably methyl.
Other example compounds of the above-described formula (XVIII) include:
1 ,3-Di-O-acetyl-1 ,25-dihydroxy-20-cyclopropyl-23-yne-19-nor-cholecalciferol:
I .S^S-tri-O-acetyl-I ^S-dihydroxy^O-cyclopropyl^S-yne^e^Z-hexafluoro-iθ-nor- cholecalciferol;
I .S-di-O-acetyl-I ^S-dihydroxy^O-cyclopropyl^S-yne^β^Z-hexafluoro-iθ-nor- cholecalciferol;
1 ,3-di-O-acetyl-1 ,25-dihydroxy-20-cyclopropyl-23-yne-cholecalciferol;
I .S-di-O-acetyl-I ^S-dihydroxy^O-cyclopropyl^SZ-ene^e^Z-hexafluoro-iθ-nor- cholecalciferol;
1 ,3-di-0-acetyl-1 ,25-dihydroxy-20-cyclopropyl-cholecalciferol; 1 ,3-di-O-acetyl-1 ,25-dihydroxy-16-ene-20-cyclopropyl-19-nor-cholecalciferol; and I .S-Di-O-acetyl-I ^S-dihydroxy-iθ-ene^O-cyclopropyl-cholecalciferol.
A preferred compound of formula (XVIII) is 1,3-di-O-acetyl-1 ,25-dihydroxy-20- cyclopropyl-23E-ene-26,27-hexafluoro-19-nor-cholecalciferol:
Figure imgf000038_0001
An example of a preferred compound is I .S-Di-O-acetyl-i ^δ-dihydroxy^O-cyclopropyl- cholecalciferol (referred to as "Compound A" in examples herein) having the formula:
Figure imgf000038_0002
"Compound A"
Such compounds are described in WO2005/030222, the contents of which are herein incorporated by reference in their entirety. The invention also embraces use of esters and salts of Compound A. 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. However, although 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.
Another compound is 1 ,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol having the formula:
Figure imgf000039_0001
The compound is described in U.S. 6,492,353, the contents of which are herein incorporated by reference in their entirety.
The invention also embraces use of esters and salts of 1 ,25-dihydroxy-20,21,28- cyclopropyl-cholecalciferol. Esters include pharmaceutically acceptable labile esters that may be hydrolysed in the body to release 1 ,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol. Salts of 1,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol 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. However, although 1 ,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol may be administered as a pharmaceutically acceptable salt or ester thereof, preferably it is employed as is i.e., it is not employed as an ester or a salt thereof.
In a further embodiment, vitamin D compounds for use in the invention are compounds of the formula (XIX):
Figure imgf000039_0002
wherein:
X is H2 or CH2;
Ri is hydrogen, hydroxy or fluorine;
R2 is hydrogen or methyl; R3 is hydrogen or methyl, though when R2 or R3 is methyl, the other of R3 or R2 must be hydrogen;
R4 is methyl, ethyl or trifluoromethyl;
R5 is methyl, ethyl or trifluoromethyl;
A is a single or double bond; and
B is a single, E-double, Z-double or triple bond.
In preferred compounds, each of R4 and R5 is methyl or ethyl, for example 1-alpha- fluoro^S-hydroxy-iβ^E-diene^β^Z-bishomo^O-epi-cholecalciferol having the formula:
Figure imgf000040_0001
Such compounds are described in US 5,939,408 and EP808833, the contents of which are herein incorporated by reference in their entirety.
Other preferred vitamin D compounds for use in accordance with the invention include those having formula (XX):
Figure imgf000040_0002
wherein:
B is single, double, or triple bond;
Xi and X2 are each independently H2 or CH2, provided Xi and X2 are not both CH2; and
R4 and R5 are each independently alkyl or haloalkyl. Examples of compounds of formula (XX) include the following:
1 ,25-Dihydroxy-16-ene-23-yne-20-cyclopyl-cholecalciferol:
Figure imgf000041_0001
1 ,25-Dihydroxy-16-ene-23-yne-20-cyclopropyl-19-nor-cholecalciferol:
Figure imgf000041_0002
1 ,25-Dihydroxy-16-ene-20-cyclopropyl-23-yne-26,27-hexafluoro-19-nor-cholecalciferol:
Figure imgf000041_0003
1 ,25-Dihydroxy-16-ene-20-cyclopropyl-23-yne-26,27-hexafluoro-cholecalciferol:
Figure imgf000042_0001
1 ,25-Dihydroxy-16,23E-diene-20-cyclopropyl-26,27-hexafluoro-1 θ-nor-cholecalciferol:
Figure imgf000042_0002
I^S-Dihydroxy-IΘ^SE-diene^O-cyclopropyl^θ^Z-hexafluoro-cholecalciferol:
Figure imgf000042_0003
1 ,25-Dihydroxy-i 6,23Z-diene-20-cyclopropyl-26,27-hexafluoro-1 θ-nor-cholecalciferol:
Figure imgf000043_0001
,25-Dihydroxy-16,23Z-diene-20-cyclopropyl-26,27-hexafluoro-cholecalciferol:
Figure imgf000043_0002
,25-Dihydroxy-16-ene-20-cyclopropyl-19-nor-cholecalciferol:
Figure imgf000043_0003
,25-Dihydroxy-16-ene-20-cyclopropyl-cholecalciferol:
Figure imgf000044_0001
Another vitamin D compound of the invention is 1 ,25-dihydroxy-21(3-hydroxy-3- trifluoromethyM-trifluoro-butynyl^θ^Z-hexadeutero-iθ-nor^OS-cholecalciferol.
Still other preferred vitamin D compounds for use in accordance with the invention include those having formula (XXI):
Figure imgf000044_0002
In a preferred embodiment, A1 is a double bond, and Xi is =CH2 and X2 is H2. When A2 is a triple bond, it is preferred that R8 is H or C(O)CH3, and R6 and R7 are alkyl or haloalkyl. It is preferred that the alkyl group is methyl and the haloalkyl group is trifluoroalkyl, preferably trifluoromethyl. When A2 is a double bond, it is preferred that R8 is H or C(O)CH3, and R6 and R7 are alkyl, preferably methyl. It is also preferred that R6 and R7 are independently alkyl and haloalkyl. When A2 is a single bond, it is preferred that R8 is H or C(O)CH3, and R6 and R7 are alkyl, preferably methyl.
In a preferred embodiment, A1 is a double bond, and X1 and X2 are each H2. When A2 is a triple bond, it is preferred that R8 is H or C(O)CH3, and R6 and R7 are alkyl or haloalkyl. It is preferred that the alkyl group is methyl or ethyl and the haloalkyl group is trifluoroalkyl, preferably trifluoromethyl. When A2 is a double bond, it is preferred that R8 is H or C(O)CH3, and R6 and R7 are haloalkyl, preferably trifluoroalkyl, preferably trifluoromethyl. When A2 is a single bond, it is preferred that R8 is H or C(O)CH3, and R6 and R7 are alkyl, preferably methyl. In another embodiment of the invention of formula (XX), Ri and R2 are OC(O)CH3, A1 is a single bond, and A2 is a single, double or triple bond, except that when R3 is H and R4 is methyl, A2 is a double or triple bond. In a preferred embodiment, R3 is H, R4 is methyl, R5 is absent, R8 is H or C(O)CH3, and R6 and R7 are alkyl, preferably methyl.
Preferred compounds of the present include the following: 1,3-Di-O-acetyl-1 ,25- dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor-cholecalciferol, 1 ,3-Di-O-acetyl-1 ,25- Dihydroxy-iβ-ene^S-yne^e^Z-hexafluoro-iθ-nor-cholecalciferol, 1,3,25-Tri-O-acetyl-1 ,25- Dihydroxy-16-ene-23-yne-26,27-hexafluoro-19-nor-cholecalciferol, 1,3-Di-O-acetyl-1 ,25- dihydroxy-iθ-ene^S-yne-cholecalciferol, 1,3-Di-O-acetyl-1,25-dihydroxy-16,23E-diene- cholecalciferol, 1 ,3-Di-O-acetyl-1 ,25-dihydroxy-16-ene-cholecalciferol , 1 ,3,25-Tri-O-acetyl-1 ,25- dihydroxy-iθ-ene^S-yne^θ^Z-hexafluoro-cholecalciferol , 1 ,3-Di-O-acetyl-1 ,25-dihydroxy-16- ene-23-yne-26,27-hexafluoro-cholecalciferol , 1 ,3-Di-O-acetyl-1 ,25-dihydroxy-16,23E-diene- 25R,26-trifluoro-cholecalciferol , 1,3-Di-O-acetyl-1 ,25-dihydroxy-16-ene-19-nor-cholecalciferol , 1 ,3-Di-O-Acetyl-1 ^S-dihydroxy-iβ-ene^S-yne-iθ-nor-cholecalciferol, 1 ,3-Di-O-acetyl-1 ,25- dihydroxy-16-ene-23-yne-26,27-bishomo-19-nor-cholecalciferol and 1,3-Di-O-acetyl-1 ,25- dihydroxy-23-yne-cholecalciferol.
These compounds can be prepared, e.g., as described in PCT Publication WO2005/030222.
Yet further preferred vitamin D compounds for use in accordance with the invention include those having formula (XXII):
Figure imgf000045_0001
wherein:
A1 is single or double bond;
A2 is a single, double or triple bond,
X1 and X2 are each independently H2 or CH2, provided X1 and X2 are not both CH2; Ri and R2 are each independently OH, OC(O)CrC4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl;
R3, R4 and R5 are each independently hydrogen, d-C4 alkyl, hydroxyalkyl, or haloalkyl, or R3 and R4 taken together with C20 form C3-C6 cylcoalkyl; R6 and R7 are each independently haloalkyl; and
R8 is H, C(O)CrC4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
In preferred embodiments, R6 and R7 are each independently trihaloalkyl, especially trifluoromethyl.
These compounds can be prepared, e.g., as described in PCT Publication
WO2005/030222, the contents of which are incorporated herein by reference.
The use of compounds having the structures given above is extended to pharmaceutically acceptable esters, salts, and prodrugs thereof.
A vitamin D compound of particular interest is calcitriol.
Other example compounds of use in the invention which are vitamin D receptor agonists include paricalcitol (ZEMPLAR™) (see US Patent 5,587,497), tacalcitol (BONALFA™) (see US Patent 4,022,891), doxercalciferol (HECTOROL™) (see Lam et al. (1974) Science 186, 1038), maxacalcitol (OXAROL™) (see US Patent 4,891,364), calcipotriol (DAIVONEX™) (see US Patent 4,866,048), and falecalcitriol (FULSTAN™).
Other compounds include ecalcidene, calcithiazol and tisocalcitate.
Other compounds include atocalcitol, lexacalcitol and seocalcitol.
Another compound of possible interest is secalciferol ("OSTEO D").
Other non-limiting examples of vitamin D compounds that may be of use in accordance with the invention include those described in published international applications: WO2005/082375, WO2005/030223, WO2005/030222, WO2005/027923, WO2004/098522, WO2004/098507, WO98/49138, WO 01/40177, WO0010548, WO0061776, WO0064869, WO0064870, WO0066548, WO0104089, WO0116099, WO0130751, WO0140177, WO0151464, WO0156982, WO0162723, WO0174765, WO0174766, WO0179166, WO0190061, WO0192221 , WO0196293, WO02066424, WO0212182, WO0214268, WO03004036, WO03027065, WO03055854, WO03088977, WO04037781 , WO04067504, WO8000339, WO8500819, WO8505622, WO8602078, WO8604333, WO8700834, WO8910351, WO9009991, WO9009992, WO9010620, WO9100271, WO9100855, WO9109841, WO9112239, WO9112240, WO9115475, WO9203414, WO9309093, WO9319044, WO9401398, WO9407851, WO9407852, WO9408958, WO9410139, WO9414766, WO9502577, WO9503273, WO9512575, WO9527697, WO9616035, WO9616036, WO9622973, WO9711053, WO9720811 , WO9737972, WO9746522, WO9818759, WO9824762, WO9828266, WO9841500, WO9841501, WO9849138, WO9851663, WO9851664, WO9851678, WO9903829, WO9912894, WO9915499, WO9918070, WO9943645, WO9952863, those described in U.S. Patent Nos.: US3856780, US3994878, US4021423, US4026882, US4028349, US4225525, US4613594, US4804502, US4898855, US5039671, US5087619, US5145846, US5247123, US5342833, US5428029, US5451574, US5612328, US5747479, US5804574, US5811414, US5856317, US5872113, US5888994, US5939408, US5962707, US5981780, US6017908, US6030962, US6040461, US6100294, US6121312 , US6329538, US6331642, US6392071, US6452028, US6479538, US6492353, US6537981, US6544969, US6559138, US6667298, US6683219, US6696431, US6774251, and those described in published US Patent Applications: US2001007907, US2003083319, US2003125309, US2003130241 , US2003171605, US2004167105.
It will be noted that the structures of some of the compounds of the invention include asymmetric carbon atoms. Accordingly, it is to be understood that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and/or by stereochemically controlled synthesis.
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," W.J. 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. For the separation of enantiomers of carboxylic acids, the diastereomeric salts can be formed by addition of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and the like. Alternatively, 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. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. The compounds of the invention may be administered via ocular delivery, for example, through an ocular device suitable for direct implantation into the eye. Such devices of the present invention are surprisingly found to provide sustained controlled release of various compositions to treat the eye without risk of detrimental local and systemic side effects. An object of the present ocular method of delivery is to maximize the amount of drug contained in an intraocular device while minimizing its size in order to prolong the duration of the implant. See, e.g., U.S. Patents 5,378,475; 5,773,019; 6,001,386; 6,217,895, 6,375,972, and 6,756,058 and U.S. Publications 2005/0096290 and 2005/01269448.
Other methods of delivery include: an ocular delivery system that could be applied to an intra-ocular lens to prevent inflammation or posterior capsular opacification, an ocular delivery system that could be inserted directly into the vitreous, under the retina, or onto the sclera, and wherein inserting can be achieved by injecting the system or surgically implanting the system, a sustained release drug delivery system, and a method for providing controlled and sustained administration of an agent effective in obtaining a desired local or systemic physiological or pharmacological effect comprising surgically implanting a sustained release drug delivery system at a desired location.
Examples include, but are not limited to the following: a sustained release drug delivery system comprising an inner reservoir comprising an effective amount of an agent effective in obtaining a desired local or systemic physiological or pharmacological effect, an inner tube impermeable to the passage of said agent, said inner tube having first and second ends and covering at least a portion of said inner reservoir, said inner tube sized and formed of a material so that said inner tube is capable of supporting its own weight, an impermeable member positioned at said inner tube first end, said impermeable member preventing passage of said agent out of said reservoir through said inner tube first end, and a permeable member positioned at said inner tube second end, said permeable member allowing diffusion of said agent out of said reservoir through said inner tube second end; a method for administering a compound of the invention to a segment of an eye, the method comprising the step of implanting a sustained release device to deliver the compound of the invention to the vitreous of the eye or an implantable, sustained release device for administering a compound of the invention to a segment of an eye; a sustained release drug delivery device comprising: a) a drug core comprising a therapeutically effective amount of at least one first agent effective in obtaining a diagnostic effect or effective in obtaining a desired local or systemic physiological or pharmacological effect; b) at least one unitary cup essentially impermeable to the passage of said agent that surrounds and defines an internal compartment to accept said drug core, said unitary cup comprising an open top end with at least one recessed groove around at least some portion of said open top end of said unitary cup; c) a permeable plug which is permeable to the passage of said agent, said permeable plug is positioned at said open top end of said unitary cup wherein said groove interacts with said permeable plug holding it in position and closing said open top end, said permeable plug allowing passage of said agent out of said drug core, through said permeable plug, and out said open top end of said unitary cup; and d) at least one second agent effective in obtaining a diagnostic effect or effective in obtaining a desired local or systemic physiological or pharmacological effect; or a sustained release drug delivery device comprising: an inner core comprising an effective amount of an agent having a desired solubility and a polymer coating layer, the polymer layer being permeable to the agent, wherein the polymer coating layer completely covers the inner core.
Still other methods of delivery include ointments or drops for topical application to the eye. Such formulations are especially appropriate for the treatment of uveitis in the anterior portion of the eye.
The methods are particularly suitable for treating ocular conditions related to uveitis. The devices are also particularly suitable for use as an ocular device in treating subjects suffering from ocular conditions wherein the device is surgically implanted within the vitreous of the eye.
The invention also provides a pharmaceutical composition, comprising an effective amount of a vitamin D compound as described herein and a pharmaceutically acceptable carrier. In a further embodiment, the effective amount is effective to treat uveitis, as described previously.
In an embodiment, 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.
In certain embodiments, these pharmaceutical compositions are suitable for topical or oral administration to a subject. In other embodiments, as described in detail below, 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) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
The phrase "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.
The phrase "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. Some examples of materials which can serve as pharmaceutically- acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
Wetting agents, emulsifiers and lubricants, such as sodium laurγl 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.
Examples of pharmaceutically-acceptable antioxidants 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.
Compositions containing a vitamin D compound(s) include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, 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, 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 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
Methods of preparing these compositions include the step of bringing into association a vitamin D compound(s) with the carrier and, optionally, one or more accessory ingredients. In general, 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. A compound may also be administered as a bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical 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, such as dragees, capsules, pills and granules, 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. They 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 they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of 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. In addition to the active ingredient, 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.
In addition to inert diluents, 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 isostearγl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Pharmaceutical compositions of the invention for rectal or vaginal 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 or vaginal cavity and release the active agent.
Compositions of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
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, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons 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.
Ordinarily, 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 (Tweens, 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. Such 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.
Pharmaceutical 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.
Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention 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. 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. These 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. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
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 invention also provides kits for treatment or prevention of a disease or disorder or symptoms thereof associated withuveitis. In one embodiment, the kit includes an effective amount of a compound in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to uveitis, wherein the effective amount of compound is less than 500 mg of the compound.
In preferred embodiments, the kit comprises a sterile container which contains the compound; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister- packs, or other suitable container form known in the art. Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
The instructions will generally include information about the use of the compound for treatment of a disease or disorder or symptoms thereof associated with uveitis; in preferred embodiments, the instructions include at least one of the following: description of the compound; dosage schedule and administration for treatment of uveitis or symptoms thereof; precautions; warnings; indications; counter-indications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references. The instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
When the vitamin D compound(s) are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically-acceptable carrier.
Regardless of the route of administration selected, 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
A preferred dose of the vitamin D compound for the present invention is the maximum that a patient can tolerate and not develop hypercalcemia. Preferably, the vitamin D compound of the present invention is administered at a concentration of about 0.001 ug to about 100 ug per kilogram of body weight, about 0.001 to about 10 ug/kg or about 0.001 ug to about 100 ug/kg of body weight. Ranges intermediate to the above-recited values are also intended to be part of the invention.
The vitamin D compound may be administered separately, sequentially or simultaneously in separate or combined pharmaceutical formulations with a second medicament for the treatment of uveitis (for example a second vitamin D compound of the present invention).
Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps. Synthesis of Compounds of the Invention
The syntheses of compounds of the invention have been described in the art, for example in WO2005/082375, WO2005/030223, WO2005/030222, WO2005/027923, WO2004/098522, WO2004/098507, and U.S. 6,492,353, the contents of which are incorporated herein by reference in their entirety.
EXEMPLIFICATION OF THE INVENTION
The present invention will now be described with reference to the following non-limiting examples.
Synthetic Examples
All operations involving vitamin D3 analogs were conducted in amber-colored glassware in a nitrogen atmosphere. Tetrahydrofuran was distilled from sodium-benzophenone ketyl just prior to its use and solutions of solutes were dried with sodium sulfate. Melting points were determined on a Thomas-Hoover capillary apparatus and are uncorrected. Optical rotations were measured at 25 0C. 1H NMR spectra were recorded at 400 MHz in CDCI3 unless indicated otherwise. TLC was carried out on silica gel plates (Merck PF-254) with visualization under short-wavelength UV light or by spraying the plates with 10% phosphomolybdic acid in methanol followed by heating. Flash chromatography was carried out on 40-65 urn mesh silica gel. Preparative HPLC was performed on a 5x50 cm column and 15-30 urn mesh silica gel at a flow rate of 100 ml/min.
Example 1
Synthesis of 1,3-Di-O-acetyl-1,25-dihydroxy-20-cyclopropyl-cholecalciferol
(Compound A)
Figure imgf000057_0001
Compound A
0.0797 g of 1 ,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 organic layer was washed with 3x10 ml. of water, once with 5 ml. of saturated sodium hydrogen carbonate, once with 3 ml. of brine then dried and evaporated, to give 0.1061 g of a tan oily residue that was flash-chromatographed on a 15x120 mm column using 1 :6 as mobile phase. Fractions 9-16 (20 ml. each) were pooled (TLC 1 :4 ethyl acetate - hexane, Rf 0.13) and evaporated. This residue was taken up in methyl formate, filtered and evaporated to give 0.0581 g of the title compound (Compound A).
Biological Examples
As described in the following examples, the Inventors' finding that vitamin D compound eg VDR agonists such as Vitamin D3 analogues can have an effect on uveitis has been proven in an in vivo model.
Example 2
Capacity of Calcitriol and Vitamin D Analogues to Inhibit Experimental Autoimmune Uveoretinitis (EAU)
EAU, an autoimmune disease mediated by TM -type uveitogenic CD4+ T-cells, serves as a model for human posterior uveitis. Following the experimental procedure shown in Figure 1 , EΞAU-susceptible B10.RIII mice were immunized with an uveitogenic regimen of 8 ug of interphotoreceptor retinoid-binding protein (IRBP) in CFA and treated orally with calcitriol or with Compound A, before or after EAU induction. EAU development was followed by funduscopy and confirmed by histopathology on eyes collected 21 days after immunization. Figure 2 shows the EAU disease score (quantitated between 0 and 4) at day 21.
The Inventors found that calcitriol at 0.5 ug/kg and Compound A at 10 μg/kg can prevent EAU, when administered from day -6 to 2. In addition, Compound A but not calcitriol, could inhibit EAU development when treatment was started 7 days after immunization. As shown in Figure 3, protected mice had reduced antigen-specific delayed type hypersensitivity (DTH) responses to IRBP. It can be concluded that delayed hypersensitivity to IRBP in treated mice is correlated with disease severity. As shown in Figure 4, in vitro assay of primed lymph node cells (LN) from treated mice indicated that calcitriol and Compound A both appeared to be potent not just on the inhibition of specific T-cell proliferation, but also on T cell polarization.
Preventive treatment remarkably diminished both IFN-gamma and IL-17 production by LN. IFN- gamma is a signature cytokine for Th1 cells and IL-7 is a signature cytokine of pathogenic T cells. Both of these cytokines have been found to be produced by pathogenic T-cells in TM- type autoimmune diseases. That there is apparently no effect on IL-4 which is a Th2 cell signature cytokine implies a selectivity in the treatment for effect on a TM response over a Th2 response.
Therapeutic administration with Compound A markedly inhibited IL-17 but not IFN-g production. Combined data indicated that IL-17 releasing profile was more consistent to the histology measurement rather than IFN-g. In consistency with disease amelioration, antigen driven chemokine release, such as MIP-Ia, Rantes and TARC, is inhibited by Vitamin D3 derivatives as shown in Figure 5. The further mechanism(s) involved in inhibition of EΞAU by vitamin D compounds (eg VDR agonists) are being investigated. In conclusion, the inventors have demonstrated that natural Vitamin D3 (calcitriol) effectively prevents EΞAU whilst a synthetic vitamin D compound (a VDR agonist) Compound A, is capable of preventing as well as treating EAU.
It was noted that Compound B, a Vitamin D compound (1α-Fluoro-25-hydroxy-16-ene- 23-yne-20-cyclopropyl-cholecalciferol) was found to be ineffective in inhibiting EAU in this model.
References
M. Mohri, et al Suppression of the TNF-lnduced Increase in IL-1 Expression by Hypochlorite in Human Corneal Epithelial Cells. IOVS (2002) Vol. 43, No.10.
H: Yamagami, et al The Effects of Proinflammatory Cytokines on Cytokine-Chemokine Gene Expression Profiles in the Human Corneal Endothelium. IOVS, (2003) Vol. 44, No. 2.
S. Narayanan, et al The effect of interleukin-1 on cytokine gene expression by human corneal epithelial cells. Experimental Eye Research 80 (2005) 175-183.
M. Xue, et al. 1α,25-Dihydroxyvitamin D3 inhibits pro-inflammatory cytokine and chemokine expression in human corneal epithelial cells colonized with Pseudomonas aeruginosa. Immunology and Cell Biology (2002) 80, 340-345.
Abbreviations
IRPB - interphotoreceptor retinoid binding protein CFA - Complete Freund's adjuvant TARC - T-cell activation regulatory chemokine EAU - experimental autoimmune uveoretinitis LN - lymph nodes Incorporation by Reference
The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Equivalents
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

I . A method of prevention or treatment of uveitis using a vitamin D compound.
2. A method for preventing or treating uveitis in a subject, comprising administering to a subject in need thereof an effective amount of a vitamin D compound, such that uveitis is prevented or treated in said subject.
3. The method of claim 2, further comprising identifying a subject in need of prevention or treatment for uveitis.
4. The method according to claim 2, further comprising the step of obtaining the vitamin D compound.
5. The method of claim 3, wherein the subject is a mammal.
6. The method of claim 5, wherein the subject is a human.
7. The method according to claim 2, wherein the vitamin D compound is formulated in a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier.
8. The use of a vitamin D compound in the manufacture of a medicament for the prevention or treatment of uveitis.
9. A pharmaceutical formulation comprising a vitamin D compound and a pharmaceutically acceptable carrier for use in the prevention and/or treatment of uveitis.
10. A pharmaceutical formulation comprising a vitamin D compound and a pharmaceutically acceptable carrier packaged with instructions for use in the prevention and/or treatment of uveitis.
I I . A vitamin D compound for preventing and/or treating uveitis.
12. A kit containing a vitamin D compound together with instructions directing administration of said compound to a patient in need of treatment and/or prevention of uveitis thereby to treat and/or prevent uveitis in said patient.
13. The use, method, formulation, compound or kit according to any one of claims 1 to 12, wherein the vitamin D compound is administered separately, sequentially or simultaneously in separate or combined pharmaceutical formulations with a second medicament for the treatment of uveitis.
14. The use, method, formulation, compound or kit of any one of claims 1 to 12, wherein said vitamin D compound is a compound of the formula:
Figure imgf000062_0001
wherein: A1 is single or double bond;
A2 is a single, double or triple bond;
Xi and X2 are each independently H or =CH2, provided Xi and X2 are not both =CH2; Ri and R2 are each independently OH, OC(O)CrC4 alkyl (eg OAc), OC(O)hydroxyalkyl, OC(O)haloalkyl; R3, R4 and R5 are each independently hydrogen, CrC4 alkyl, hydroxyalkyl, or haloalkyl, with the understanding that R5 is absent when A2 is a triple bond, or R3 and R4 taken together with C20 form C3-C6 cycloalkyl; and
R6 and R7 are each independently alkyl (eg Ci_4alkyl) or haloalkyl; and R8 is H, -COCrC4alkyl, -COhydroxyalkyl or -COhaloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
15. The use, method, formulation, compound or kit of claim 14, wherein R1 and R2 are OH or OC(O)C1-C4 alkyl.
16. The use, method, formulation, compound or kit of claim 15, wherein R1 and R2 are OAc.
17. The use, method, formulation, compound or kit of claim 15, wherein R1 and R2 are OH.
18. The use, method, formulation, compound or kit of claim 14, wherein X1 is =CH2 and X2 is H.
19. The use, method, formulation, compound or kit of claim 14, wherein A1 is single bond and A2 is a single bond.
20. The use, method, formulation, compound or kit of claim 14, wherein R3 and R4 taken together with C20 form C3-C6 cycloalkyl.
21. The use, method, formulation, compound or kit of claim 20, wherein R3 and R4 taken together with C20 form cyclopropyl.
22. The use, method, formulation, compound or kit of claim 14, wherein R5 is hydrogen.
23. The use, method, formulation, compound or kit of claim 14, wherein R6 and R7 are each independently C1-4alkyl.
24. The use, method, formulation, compound or kit of claim 23, wherein R6 and R7 are each independently methyl.
25. The use, method, formulation, compound or kit of claim 14, wherein R8 is H.
26. The use, method, formulation, compound or kit of claim 14, wherein R1 and R2 are OH or OC(O)C1-C4 alkyl, X1 is =CH2 and X2 is H, A1 is single bond, A2 is a single bond, R3 and R4 taken together with C20 form C3-C6 cycloalkyl, R5 is hydrogen, R6 and R7 are each independently C1-4alkyl, and R8 is H.
27. The use, method, formulation, compound or kit of claim 26, wherein R1 and R2 are OH or OAc, R3 and R4 taken together with C20 form cyclopropyl, and R6 and R7 are each methyl.
28. The use, method, formulation, compound or kit of any one of claims 1 to 12, wherein said vitamin D compound is a compound of the formula:
Figure imgf000064_0001
wherein: X is H2 or CH2
Ri is hydrogen, hydroxy or fluorine R2 is hydrogen or methyl
R3 is hydrogen or methyl provided that when R2 or R3 is methyl, R3 or R2 must be hydrogen
R4 is methyl, ethyl or trifluoromethyl R5 is methyl, ethyl or trifluoromethyl A is a single or double bond
B is a single, E-double, Z-double or triple bond.
29. The use, method, formulation, compound, or kit according to claim 26, wherein each of R4 and R5 is methyl or ethyl.
30. The use, method, formulation, compound or kit of any one of claims 1 to 13, wherein said vitamin D compound is I.S-Di-O-acetyl-i ^δ-dihydroxy^O-cyclopropyl- cholecalciferol having the formula:
Figure imgf000064_0002
31. The use, method, formulation, compound or kit of any one of claims 1 to 13, wherein said vitamin D compound is 1,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol having the formula:
Figure imgf000065_0001
32. The use, method, formulation, compound or kit of any one of claims 1 to 13, wherein said vitamin D compound is 1-alpha-fluoro-25-hydroxy-16,23E-diene-26,27-bishomo- 20-epi-cholecalciferol, having the formula:
Figure imgf000065_0002
33. The use, method, formulation, compound or kit of any one of claims 1 to 13 wherein said compound is calcitriol.
34. The use, method, formulation, compound or kit of any one of claims 1 to 13 wherein said compound is a compound of formula (I):
Figure imgf000065_0003
wherein:
A1 is single or double bond;
A2 is a single, double or triple bond;
Xi and X2 are each independently H2 or =CH2, provided Xi and X2 are not both =CH2;
Ri and R2 are each independently OC(O)CrC4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl;
R3, R4 and R5 are each independently hydrogen, CrC4 alkyl, hydroxyalkyl, or haloalkyl, with the understanding that R5 is absent when A2 is a triple bond, or R3 and R4 taken together with C20 form C3-C6 cycloalkyl;
R6 and R7 are each independently alkyl or haloalkyl; and R8 is H, C(O)CrC4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; provided that when A1 is a single bond, R3 is hydrogen and R4 is methyl, then A2 is a double or triple bond; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
35. The use, method, formulation, compound or kit of any one of claims 1 to 13 wherein said compound is not a compound of formula (I):
Figure imgf000066_0001
wherein:
A1 is single or double bond;
A2 is a single, double or triple bond;
X1 and X2 are each independently H2 or =CH2, provided X1 and X2 are not both =CH2;
R1 and R2 are each independently OC(O)C1-C4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl;
R3, R4 and R5 are each independently hydrogen, C1-C4 alkyl, hydroxyalkyl, or haloalkyl, with the understanding that R5 is absent when A2 is a triple bond, or R3 and R4 taken together with C20 form C3-C6 cycloalkyl; R6 and R7 are each independently alkyl or haloalkyl; and R8 is H, C(O)CrC4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; provided that when A1 is a single bond, R3 is hydrogen and R4 is methyl, then A2 is a double or triple bond; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
36. The use, method, formulation, compound or kit of any one of claims 1 to 35, wherein said uveitis is autoimmune u vert is.
37. The use, method, formulation, compound or kit of claim 36 wherein said uveitis is posterior uvertis.
38. The use, method, formulation, compound or kit of claim 37, wherein said posterior uveitis is uveoretinitis.
PCT/EP2006/061415 2005-09-19 2006-04-06 Use of vitamin d3 compounds for the treatment of uveitis WO2007039322A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013026557A1 (en) * 2011-08-19 2013-02-28 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Vasoconstrictor-containing agent for combination therapy
WO2019164222A1 (en) * 2018-02-20 2019-08-29 Chong Kun Dang Pharmaceutical Corp. Compositions for preventing or treating uveitis
US11571426B2 (en) 2017-11-24 2023-02-07 Chong Kun Dang Pharmaceutical Corp. Compositions for preventing or treating lupus

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0815862A1 (en) * 1995-03-20 1998-01-07 Katsuhiko Mukai Ophthalmological composition comprising activated vitamin d
EP1059085A1 (en) * 1998-02-26 2000-12-13 Chugai Seiyaku Kabushiki Kaisha Langerhans cell migration inhibitors
US20040167105A1 (en) * 1997-09-08 2004-08-26 Manchand Percy Sarwood 1,3-dihydroxy-20,20-dialkyl-vitamin D3 analogs
WO2005030222A1 (en) * 2003-09-24 2005-04-07 Bioxell S.P.A. 1,3-diaclyated,26,27-alkyl/haloalkyl vitamin d3 compounds and methods of use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0815862A1 (en) * 1995-03-20 1998-01-07 Katsuhiko Mukai Ophthalmological composition comprising activated vitamin d
US20040167105A1 (en) * 1997-09-08 2004-08-26 Manchand Percy Sarwood 1,3-dihydroxy-20,20-dialkyl-vitamin D3 analogs
EP1059085A1 (en) * 1998-02-26 2000-12-13 Chugai Seiyaku Kabushiki Kaisha Langerhans cell migration inhibitors
WO2005030222A1 (en) * 2003-09-24 2005-04-07 Bioxell S.P.A. 1,3-diaclyated,26,27-alkyl/haloalkyl vitamin d3 compounds and methods of use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BECKER M D ET AL: "Management of sight-threatening uveitis: New therapeutic options", DRUGS 2005 NEW ZEALAND, vol. 65, no. 4, 2005, pages 497 - 519, XP009070079, ISSN: 0012-6667 *
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, vol. 150, no. 4, April 2004 (2004-04-01), pages 591 - 603, XP002392301, ISSN: 0804-4643 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013026557A1 (en) * 2011-08-19 2013-02-28 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Vasoconstrictor-containing agent for combination therapy
US11571426B2 (en) 2017-11-24 2023-02-07 Chong Kun Dang Pharmaceutical Corp. Compositions for preventing or treating lupus
WO2019164222A1 (en) * 2018-02-20 2019-08-29 Chong Kun Dang Pharmaceutical Corp. Compositions for preventing or treating uveitis
RU2757273C1 (en) * 2018-02-20 2021-10-12 Чонг Кун Данг Фармасьютикал Корп. Compositions for prevention or treatment of uveitis

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