ZA200602385B - 1,3-Diacylated,26,27-alkyl/haloalkyl vitamin D3 compounds and methods of use thereof - Google Patents
1,3-Diacylated,26,27-alkyl/haloalkyl vitamin D3 compounds and methods of use thereof Download PDFInfo
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- ZA200602385B ZA200602385B ZA200602385A ZA200602385A ZA200602385B ZA 200602385 B ZA200602385 B ZA 200602385B ZA 200602385 A ZA200602385 A ZA 200602385A ZA 200602385 A ZA200602385 A ZA 200602385A ZA 200602385 B ZA200602385 B ZA 200602385B
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- South Africa
- Prior art keywords
- compound
- vitamin
- cholecalciferol
- acetyl
- cell
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Description
1,3-DIACLYATED, 26,27-ALKYL/HALCALKYL VITAMIN D; COMPOUNDS
AND METHODS OF USE THEREOF
This application claims priority to: U-S. provisional application Ser. No. 60/505,735, filed 24 September 2003; GB0322395.5, filed 24 September 2003; and
GB0404567.0, filed 01 March 2004. Each off the aforementioned applications is incorporated herein in its entirety by this refe=rence.
The importance of vitamin D (cholec alciferol) in the biological systems of h_igher animals has been recognized since its discov ery by Mellanby in 1920 (Mellanby, E. (1921) Spec. Rep. Ser. Med. Res. Council (G-B) SRS 61:4). It was in the interval of 1920-1930 that vitamin D officially became classified asa "vitamin" that was essential for the normal development of the skeleton zand maintenance of calcium and phosphorous homeostasis.
Studies involving the metabolism of ~vitamin Dj were initiated with the discovery and chemical characterization of the plasma metabolite, 25-hydroxyvitamin Dj [25(0H)D3] (Blunt, J.W. etal. (1968) Biochemistry 6:3317-3322) and the hormonally active form, 10,25(0H),Ds (Myrtle, J.F. et cal. (1970) J. Biol. Chem. 245:1190-119=6;
Norman, A.W. et al. (1971) Science 173:51—54; Lawson, D.EM. et al. (1971) Nattre 230:228-230; Holick, MF. (1971) Proc. Naml. Acad. Sci. USA 68:303-804). The formulation of the concept of a vitamin D ermdocrine system was dependent both up=-on appreciation of the key role of the kidney in producing la, 25(0OH),D3 in a carefully regulated fashion (Fraser, D.R. and Kodicek—, E (1970) Nature 288:764-766; Wong,. R.G. etal (1972) J. Clin. Invest. 51:1287-1291), and the discovery of a nuclear receptor for 10,25(0OH),D; (VD3R) in the intestine (Hausssler, MR. et al. (1969) Exp. Cell Res. 58:234-242; Tsai, H.C. and Norman, A.W. C1972) J. Biol. Chem. 248:5967-5975).
The operation of the vitamin D endoecrine system depends on the following: first, on the presence of cytochrome P450 enzymes in the liver (Bergman, T'. and Postlin-d, H. (1991) Biochem. J. 276:427-432; Ohyama, and Okuda, K. (1991) J. Biol. Chem. 266:8690-8695) and kidney (Henry, H.L. an_d Norman, AW. (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 Ds into biologically active metabolites such as 1a, 25(0H));D3 and 24R,25(0H),D3; second, on the existence of the plasma vitamin D binding protein (DBP) to effect the selective transport and delivery of these hydrophobic molecumles to the various tissue components of the vitamin 5D endocrine system (Van Baelen, H. etal. (1988) Arn 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 10,25(0H)2Ds to generate the requisite specific biological responses for this secosteroid hormone (Pike, J.W. (1991) Annu. Rev. Nutr. 1.1:1 89-216). To date, there is evidence that nuclear receptors for 1c,25(0H),D3 (VDR) exist in more than 30 tissues and cancer cell lines (Reichel, H. and Norman, A.W. (1989) Annu. Rev. Med. 40.71-78).
Vitamin Ds and its hormonally active forms are well-known regulators of calcium and phosphorous homeostas¥s. 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 €he kidneys. Furthermore, the discovery of the presence of specific vitamin D receptors in more than 30 tissues has led to the identification of vitamin Ds as a plur3potent regulator outside its classical role in calcium/bone homeostasis. A paracrine role for 1a,25(0H); D3 has been suggested by the combined presence of enzymes capable of oxidizing vitamin Ds into its active forms, e.g., 25-OHD-1a-hydroxylase, and specific receptors in several tissues such as bone, keratinocytes, placenta, and immune cells. Moreover, vitamin Ds 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 synttmetic analogs of these compounds. A large number of these analogs involve structural modifications in the A ring, B ring, C/D rings, and, primarily, the side chain (Bouillon, R.et al. , Endocrine Reviews 16(2):201-204).
Although a vast majority of the vitarmin Ds analogs developed to date involve structural modifications in the side chain, a fevw studies have reported the biological profile of A- ring diastereomers (Norman, A.W. er al. J. Biol. Chem. 268 (27): 20022-20030).
Furthermore, biological esterificatiom of steroids has been studied (Hochberg, R.B.,
(1998) Endocr Rev. 19(3): 33 1-348), and esters of vitamin Dj are known (WO 97/11053).
Moreover, despite much effort in developing synthetic analogs, clinical applications of vitamin D and its structural analogs 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 present inventiom is further described below with reference to the following non-limiting examples and with reference to the following figures, in which:
Figure 1 shows Percent Type 1 Diabetes Mellitus incidence for compound (2).
Figure 2 shows NOD mouse body weight (g) at two doses of compound (2).
Figure 3 shows the presence of vitamin D receptors (VDRs) on bladder cells.
Figure 4 shows calcitriol (the activated form of vitamin Ds) as effective in inhibiting the basal growth of bladder cells.
Figure 5 shows the evaluation of the effect of Vitamin Ds analogue (2) on bladder function in am in vivo model cyclophosphamide (CYP) induced chronic
IC in rats.
In one aspect, the inwention provides a vitamin D3 compound of formula I:
R
Ry 5
Riaz 6
ORg 1 Ry 1.
Xz X4
Nall
R> Ri wherein: A; is single or double bond; A; is a single, double or triple bond; X; and X; are each independently Ha or =CH, provided X, anc X are not both =CHy; R; and Rare each independently OC(0)C;-C, alkyl, OC(O)hgydroxyalkyl, or OC(O)haloalkyl; Rs, Rs and Rs are each independently hydrogen, C1-C4 salkyl, hydroxyalkyl, or haloalkyl, with the understanding that Rs is absent when A; isa triple bond, or R; and Rs taken together with Cy form Cs-Cs cycloalkyl; Re and Ry are esach independently alkyl or haloalkyl; and Rg is H, C(0)C1-C4 alkyl, C(O)hydroxyalky—1, or C(O)haloalkyl; provided that when
A, is a single bond, Rj is hydrogen and Ry is me=thyl, then A; is a double or triple bond; and pharmaceutically acceptable esters, salts, an_d prodrugs thereof.
In a preferred embodiment, the inventior provides vitamin D3; compounds of formula I-a: . 2 Rg i Ry OT a
Xa X4
R Ni l.-a 2 R4 wherein (in formula I above, Rs is H, Rs is metknyl, A; is a double bond,) Rs is H (or absent if A; is a triple bond), and Az, Xi, X2, Rm, Ra, Re, Ry, and Rs are previously described.
In another preferred embodiment, the invention provices vitamin D3 compounds of formula Ilo: : 2\ Re 1 R, OTe
H
Xa X4 : R 5 Rs I.-b wherein (in feormula I above, R; and Rs taken together with C_-20 form cyclopropyl), Rs is H (or absemt if Ag is a triple bond), and As, Az, Xi, Xz, Rim Ro, Re, R7, and Re are previously described.
In yet another aspect, the invention provides a pharmaceutical composition. The composition comprises an effective amount of a vitamin D3 compound of formula I, and a pharmaceutically acceptable carrier.
In a Further aspect, the method provides a method of ameliorating a deregulation of calcium and phosphate metabolism. The method include :s administering to a subject a therapeutically effective amount of a vitamin D3 compound of formula I, so as to ameliorate the deregulation of the calcium and phosphate ma etabolism.
In ammother aspect, the invention provides a method cof modulating the expression of an immuroglobulin-like transcript 3 (ILT3) surface mole=cule in a cell. The method includes cortacting the cell with a vitamin D3 compound of= formula I in an amount effective to modulate the expression of an immunoglobulin—like transcript 3 (ILT3) surface molecule in the cell.
In yest another aspect, the invention provides a meth- od of treating an ILT3- associated disorder in a subject. The method includes administering to the subject a vitamin Ds compound of formula I in an amount effective t=o modulate the expression of an ILT3 surface molecule, thereby treating the IL T3-associ_ated disorder in the subject.
In still another aspect, the invention provides a method of inducing immunological tolerance in a subject. The method include=s administering to the subject a vitamin D3 compound of formula I in an amount effective to modulate the expression of an ILT3 surface molecules, thereby inducing immunological tolerance in the subject.
In a further aspect, thhe invention provides a method of inhibiting transplant rejection in a subject. The nethod includes administering to the subject a vitamin Ds compound of formula I in an amount effective to modulate the expression of an ILT3 surface molecule, thereby irhibiting transplant rejection in the subject.
In still another embodiment, the invention provides amethod for preventing or treating bladder dysfunctior in a subject in need thereof by administering an effective amount of a vitamin Ds commpound thereby to prevent or treat bladder dysfunction in said subject. )
In yet another aspec=t, the invention provides a packaged formulation for use in the treatment of a vitamin ID; associated state. The packaged formulation includes a pharmaceutical composition comprising a vitamin D; compound of formula I and a pharmaceutically-acceptabMe carrier, packaged with instructions for use in the treatment of a vitamin Ds associated =state.
In another aspect, the invention provides a packaged formulation for use in the treatment of an [LT-3 associated disorder. The packed formulation includes a pharmaceutical composition comprising a vitamin Ds compound of formula I and a oT * pharmaceutically-acceptabTe carrier, packaged with instmctions for use in the treatment of anILT3-associated disomrder. ,
In a further aspect, ~the invention provides a method for modulating immunosuppressive activitzy by an antigen-presenting cell. The method includes contacting an antigen-presenting cell with a vitamin D3 compound of formula I in an amount effective to modulaate ILT3 surface molecule expression, thereby modulating thes immunosuppressive activit-y by the antigen-presenting cell.
Detailed Description of tae Invention 1. DEFINITIONS
Before further description of the present invention, and in order that the invention may be more rea_dily understood, certain terms are first defined and collected here for convenience. . :
The term “administration” or “administerinmg” includes routes of introducing the vitamin D; compound(s) to a subject to perform thmeir intended function. Examples of routes of administration which can be used includes injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), oral, irhalation, rectal and transdermal. The pharmaceutical preparations are, of course, given Wby forms suitable for each administration route. For example, these preparatisons are administered in tablets or capsule form, by injection, inhalation, eye lotion, sointment, suppository, etc. administration by injection, infusion or inhalation=; topical by lotion or ointment; and rectal by suppositories. Oral administration is pre=ferred. The injection can be bolus or can be continuous infusion. Depending on the route of administration, the vitamin Ds compound can be coated with or disposed in a seleected material to protect it from natural conditions which may detrimentally effect its abil .ity to perform its intended function.
The vitamin Ds compound can be administered al-one, or in conjunction with either another agent as described above or with a pharmszaceutically-acceptable carrier, or both.
The vitamin D3 compound can be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent.
Furthermore, the vitamin D3 compound can also toe administered in a proform which is converted into its active metabolite, or more activ-e metabolite in vivo.
The term "alkyl" refers to the radical of sa_turated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalksw1 substituted alkyl groups. The term alkyl further includes alkyl groups, which can furrther include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbonss of the hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorous atoms. Im preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carlibon atoms in its backbone (e.g., C1-Cso Co for straight chain, C5-Cso for branched chain), pre=ferably 26 or fewer, and more preferably 20 or fewer, and still more preferably 4% or 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 throughcout the specification and claims is intended to include both "unsubstituted alkyls" amad "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 subs-tituents can include, for example,
halogen, hydroxyl, alkycarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, camboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including al kylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhycryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, : sulfamoyl, sulfonamidam, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroareomatic 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. Cycloalky~lscan be further substituted, e.g., with the substituents described above. An "alkylaryl" mmoiety is an alkyl substituted with an aryl (e.g, phenylmethyl (benzyl)). 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 bord respectively.
Unless the num ber 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 omne 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 m-ethyl, ethyl, n-propyl, i-propyl, tert-butyl, hexyl, heptyl, octyl amd so forth. In preferred eembodiment, the term "ower alkyl" includes a straight chain alkyy] having 4 or fewer carbon atoms in its backbone, e.g., C;-Cq alkyl.
The terms "alkoxyalkyl," "polyaminoalkyl” and “thioalkoxyalkyl" refer to alkyl groups, as described atoove, which further include oxygen, nitrogen or sulfur atoms replacing one or more esarbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or : sulfur atoms.
The terms "alke=nyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length ancd possible substitution to the alkyls described above, but that contain at least one dotable or triple bond, respectively. For example, the invention contemplates cyano an~-d propargyl groups.
The term "antigeen" includes a substance which elicits an immune response. The= antigens of the inventicon to which tolerance is induced may or may not be exogenously= derived relative to the Bhost. For example, the method of the invention may be used to induce tolerance to an autoantigen.” An autoantigen is a normal constituent of the body that reacts with an autoantibody. The invention also includes inducing toler-ance to an “alloantigen.” Alloantigemn refers to an antigen found only in some members o-fa species, for example the blood group substances. An allograft is a graft to a genetically different member of the sames species. Allografts are rejected by virtue of the immunological response of I lymphocytes to histocompatibility antigens. The method of the invention also provide=s for inducing tolerance to a "xenoantigen.” Xenoartigens are substances that cause an immune reaction due to differences between differert species. Thus, a xenograft iss a graft from a member of one species to a member ofa different species. Xenografics are usually rejected within a few days by antibodie=s and cytotoxic T lymphocytes to Thistocompatibility antigens.
The language “antigeen-presenting cell” or “APC” includes a cell that is a_ble to present an antigen to, for ex ample, a T helper cell. Antigen-presenting cells inchkude B lymphocytes, accessory celks or non-lymphocytic cells, such as dendritic cells, .
Langerhans cells, and mononuclear phagocytes that help in the induction of an immune response by presenting antigen to helper T lymphocytes. The antigen-presentinzg cellof the present invention is preferably of myeloid origin, and includes, but is not linmited to, dendritic cells, macrophage=s, monocytes. APCs of the present invention may be= isolated from the bone marrow, bloedxd, thymus, epidermis, liver, fetal liver, or the spleerm.
The terms "antineoplastic agent" and "antiproliferative agent" are used interchangeably herein and. includes agents that have the functional property of inhibiting the proliferation of a vitamin D;-responsive cells, e.g., inhibit the development or progressiozn of a neoplasm having such a characteristic, particularly a hematopoietic neoplasm. : The term "aryl" as used herein, refers to the radical of aryl groups, incliading 5- 95 and 6-membered single-rirag aromatic groups that may include from zero to forar 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," "heteroarylss" or "heteroaromatics." The ar-omatic ring can be substituted at one or more ring peositions with such substituents as clescribed above, as for example, halogen, hydroxyl, alkoxy, : alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylatze, alkylcarbonyl, alkoxycarbonyl, aminocarbony], alkylthioca_rbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamiino, arylamino, diarylamino, and alkylarylamino), acylamino «(including alkylcarbeonylamino, arylcarbonylamino, carbamoyl and ureido), amidiro, imino, sulfhydryl., alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfarmoyl, sulfonami do, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylars~], or an aromatic or heteroa_romatic 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 language “autoimmune disease” or “autoimmune disorder” refers to the condition where the immune system attacks the host’s own tissue(s). Imm an autoimmune disease, the immune tolerance system of the patient fails to recognize s elf antigens and, asa consequence of this loss of tolerance, brings the force of the immu ne system to bear on tissuess which express the antigen. Autoimmune disorders include, Bbut are not limited to, type 1 insulin-dependent diabetes mellitus, adult respiratory distress syndrome, - 15 inflammamtory bowel disease, dermatitis, meningitis, thrombotic thromtoocytopenic purpura, “Sjogren's syndrome, encephalitis, uveitis, uveoretinitis, leuko=cyte adhesion deficienc=y, rheumatoid arthritis, rheumatic fever, Reiter's syndrome, psoriatic arthritis, ’ progressive systemic sclerosis, primary biliary cirrhosis, pemphigus, peemphigoid, necrotizi-ng vasculitis, myasthenia gravis, multiple sclerosis, lupus erythematosus, polymyossitis, sarcoidosis, granulomatosis, vasculitis, pernicious anem: ia, CNS inflammaatory disorder, antigen-antibody complex mediated diseases, sautoimmune haemolytic anemia, Hashimoto's thyroiditis, Graves disease, habitual sspontaneous abortionss, Reynard's syndrome, glomerulonephritis, dermatomyositis, chronic active hepatitis-, celiac disease, autoimmune complications of AIDS, atrophic gastritis, ankylosing spondylitis and Addison's disease. "Whe language "biological activities" of vitamin D; includes alll activities elicited by vitamin Ds compounds in a responsive cell. It includes genomic a_nd non-genomic activitie s elicited by these compounds (Gniadecki R. and Calverley M1]. (1998)
Pharma-cology & Toxicology 82: 173-176; Bouillon, R. et al. (1995) Endocrinology
Reviews 16(2):206-207; Norman A.W. etal. (1 992) J. Steroid Biochem Mol. Biol 41:231-—240; Baran D.T. et al. (1991) J. Bone Miner Res. 6:1269-12#75; Caffrey J.M. and
Farach-eCarson M.C. (1989) J. Biol. Chem. 264:20265-20274; Nemer-el. et al. (1984)
Endocrinology 115:1476-1483).
By “bladder dysfunction” is meant bladder co nditions associated with overactivity of the detrusor muscle, for example, clin ical BPH or overactive bladder. In the context of the present invention “bladder dysfunction” excludes bladder cancer.
The language "bone metabolism" includes direct or indirect effects in the formation or degeneration of bone structures, e.g. bosne formation, bone resorption, efc., which may ultimately affect the concentrations in ser~um of calcium and phosphate. This term is also intended to include effects of compounds of the invention in bone cells, e.g., osteoclasts and osteoblasts, that may in turn result in bone formation and degeneration.
The language "calcium and phosphate homeomstasis" refers to the careful balance of calcium and phosphate concentrations, intracellularly and extracellularly, triggered by fluctuations in the calcium and phosphate concentration in a cell, a tissue, an organ or a system. Fluctuations in calcium levels that result fro=m direct or indirect responses to compounds of the invention are intended to be included by these terms.
The term "carcinoma" is art recognized and reefers to malignancies of epithelial or endocrine tissues including respiratory system carecinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicralar carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, sand melanomas. Exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, bladder, breast, head and neck, colon and ovary. The term also includes carcinosarcomas, e.g., which include malignant tumors composed of carcineomatous and sarcomatous tissues.
An "adenocarcinoma" refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structure=s.
The term "chiral" refers to molecules which mave 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 im=ages of one another.
The term “effective amount” includes an amosunt effective, at dosages and for periods of time necessary, to achieve the desired resumlt, e.g., sufficient treat a vitamin Ds associated state or to modulate ILT3 expression in a «cell. An effective amount of vitamin D3 compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the vitamin 3 compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic responses. An effective amount is also one in which an™y toxic or detrimental effects (e.g., side effects) of the vitamin D3 compound are outweig=zhed by the therapeutically beneficial effects.
A therapeutically effective amount of vitamin D3 compounad (i.e., an effective dosage) may range from about 0.001 to 30 pg/kg body weight, pre=ferably about 0.01 to 25 pg/kg body weigzht, more preferably about 0.1 to 20 pg/kg body weight, and even more preferably abeout 1 to 10 pg/kg, 2 to 9 pg/kg, 3to 8 pgkg, 4 to 7 pgkg,or5t06 ) pg/kg body weight The skilled artisan will appreciate that certair factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or dissorder, previous treatments, the general health =and/or age of the subject, and other Cliseases present. Moreover, treatment of a subject with a therapeutically effe=ctive amount of a vitamin Dj compound can irclude a single treatment or, prefex=ably, can include a series of treatments. In ones example, a subject is treated with a vitarmain Ds compound in the range of between aboumt 0.1 to 20 pg/kg body weight, one time peer week for between about 1to 10 weeks, preferably between 2 to 8 weeks, more prefemrably between about 3 to 7 weeks, and even moore preferably for about 4, 5, or 6 weeks. Int will also be appreciated that the effective dosanage of a vitamin Ds compound used fo=r treatment may increase or decrease over the ccourse of a particular treatment.
The term "enantiomers" refers to two stereoisomers of a c=ompound which are non-superimposab le mirror images of one another. An equimolazr mixture of two enantiomers is callled a "racemic mixture" or a "racemate.”
The languamge "genomic" activities or effects of vitamin I is intended to include those activities me=diated by the nuclear receptor for lo, 25(0H)==Ds3 (VDsR), e.g, transcriptional activation of target genes.
The term “haloalkyl” is intended to include alkyl groups =as defined above that are mono-, di- or poolysubstituted by halogen, e.g., fluoromethyl and trifluoromethyl.
The term "halogen" designates -F, Cl, -Br or I.
The term "hydroxyl" means -OH.
The term "heteroatom" as used herein means an atom of aany element other than carbon or hydroge=n. Preferred heteroatoms are nitrogen, oxygemm, sulfur and phosphorus.
The term "homeostasis" is art-recognized to mean maintenance of static, or constant, conditiomns in an internal environment.
Wea 2005/030222 PCT/US2004/031412
The language "hormone secretion" is art-reco- gnized and includes activities of vitamin Dj compounds that control the transcription zand processing responsible for secretion of a given hormone e.g., a parathyroid hormone (PTH) of a vitamin D3 responsive cell (Bouillon, R. et al. (1995) Endocrine Reviews 16(2):235-237). 3 The language "hypercalcemia" or "hypercalcemic activity” is intended to have its accepted clinical meaning, namely, increases in calcium serum levels that are manifested in a subject by the following side effects, depression of central and peripheral nervous - system, muscular weakness, constipation, abdominal pain, lack of appetite and, depressed relaxation of the heart during diastole. Symptomatic manifestations of hypercalcemia are triggered by a stimulation of at least one of the following activities, intestinal calcium transport, bone calcium metabolisam and osteocalcin synthesis (reviewed in Boullion, R. et al. (1995) Endocrinolo_gy Reviews 16(2): 200-257).
The terms "hyperproliferative" and "neoplas&ic” are used interchangeably, and include those cells having the capacity for autonomous growth, i.e., an abnormal state or 1= condition characterized by rapidly proliferating cell growth. Hyperproliferative and neoplastic disease states may be categorized as pathologic, i.e., characterizing or constituting a disease state, or may be categorized a=s non-pathologic, i.e., a deviation from normal but not associated with a disease state. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly 2 O transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. "Pathologic hyperproliferative” cells occur in disease states characterized by malignant tumor growth. Examples of non-pathelogic hyperproliferative cells include proliferation of cells associated with woundl repair.
The language “immunoglobulin-like transcript 3” or “ILT3” refers to a cell surface molecule of the immunoglobulin superfamily, which is expressed by antigen- presenting cells (APCs) such as monocytes, macrophages and dendritic cells. ILT3 isa member of the immunoglobulin-like transcript (ILC) family and displays a long ' cytoplasmic tail containing putative immunoreceptor tyrosine-based inhibitory motifs (ITIMs). ILT3 has been shown to behave as an inhibitory receptor when cross-linked to a stimulatory receptor. A cytoplasmic component of the ILT3-mediated signaling pathway is the SH2-containing phosphatase SHP-1_, which becomes associated with
ILT3 upon cross-linking. ILT3 is also internalized and ILTS3 ligands are efficiently presented to specific T cells (see, e.g., Cella, M. et al. (1997) J. Exp. Med. 185 :1743).
The determination of whether the candidate vitamin D3 compound modulates the expression of the ILT3 surface molecule «an be accomplished, for example, by comparison of ILT3 surface molecule expression to a control, by measuring mRNA expression, or by measuring protein expression.
An “TLT3-associated disorder” includes a disease, disorder or condition whichm is associated with an ILT3 molecule. ILT3 associated disorders include disorders in wh ich
ILT3 activity is aberrant or in which a nosn-ILT3 activity that would benefit from modulation of an ILT3 activity is aberrarat. In one embodiment, the ILT3-associated : disorder is an immune disorder, e.g., an autoimmune disorder, such as type 1 insulin- dependent diabetes mellitus, adult respiratory distress syndrome, inflammatory bowel disease, dermatitis, meningitis, thrombot3c thrombocytopenic purpura, Sjogren's syndrome, encephalitis, uveitis, uveoretinitis, leukocyte adhesion deficiency, rheumatoid arthritis, rheumatic fever, Reiter's syndrosme, psoriatic arthritis, progressive systemic sclerosis, primary biliary cirrhosis, pempehigus, pemphigoid, necrotizing vasculitis, myasthenia gravis, multiple sclerosis, lupus erythematosus, polymyositis, sarcoidosis_, granulomatosis, vasculitis, pernicious anemia, CNS inflammatory disorder, antigen- antibody complex mediated diseases, aut-oimmune haemolytic anemia, Hashimoto's thyroiditis, Graves disease, habitual sporataneous abortions, Reynard's syndrome, glomerulonephritis, dermatomyositis, chronic active hepatitis, celiac disease, autoimmune complications of AIDS, atrophic gastritis, ankylosing spondylitis and
Addison's disease; or transplant rejectiom, such as GVHD. In certain embodiments off the invention, the ILT3 associated disorder is an immune disorders, such as transplant rejections, graft versus host disease and autoimmune disorders.
The term " immune response” includes T and/or B cell responses, e.g., cellular 95 and/or humoral immune responses. The claimed methods can be used to reduce both primary and secondary immune responses. The immune response of a subject can be- determined by, for example, assaying antibody production, immune cell proliferation, the release of cytokines, the expression of cell surface markers, cytotoxicity, and the like. )
The terms “immunological tolerance” or “tolerance to an antigen” or “immunee ' tolerance” include unresponsiveness to a-n antigen without the induction of a prolonge=d generalized immune deficiency. Consequently, according to the invention, a tolerant host is capable of reacting to antigens otkaer than the tolerizing antigen. Tolerance represents an induced depression in the response of a subject that, had it not been subjected to the tolerance-inducing procedeure, would be competent to mount an immune response to that antigen. In one embodimsent of the invention, immunological tolerance is induced in an antigen-presenting cell, e. g, an antigen-presenting cell derived from the myeloid or lymphoid lineage, dendritic ce 11s, monocytes and macrophages.
The language “immunosuppressivee activity” refers to the process of inhibiting a normal immune response. Included in this response is when T and/or B clones of lymphocytes are depleted in size or suppressed in their reactivity, expansion or differentiation. Immunosuppressive activ=ity may be in the form of inhibiting or blocking an immune response already in gprogress or may involve preventing the induction of an immune response. The fianctions of activated T cells may be inhibited by suppressing immune cell responses or by inducing specific tolerance, or both.
Immunosuppression of T cell responses i=s generally an active, non-antigen-specific, process that requires continuous exposure of the T cells to the suppressive agent.
Tolerance, which involves inducing non--Tesponsiveness or anergy in T cells, is distinguishable from immunosuppressior in that it is generally antigen-specific and persists after exposure to the tolerizing aggent has ceased. Operationally, tolerance can be demonstrated by the lack of a T cell reesponse upon re-exposure to specific antigen in the absence of the tolerizing agent.
The language "improved biological properties" refers to any activity inherentina ~ compound of the invention that enhances its effectiveness in vivo. In a preferred embodiment, this term refers to any qual itative or quantitative improved therapeutic property of a vitamin D3; compound, such as reduced toxicity, e.g. , reduced hypercalcemic activity.
The language "inhibiting the gro~wth" of the neoplasm includes the slowing, interrupting, arresting or stopping its growth and metastases and does not necessarily indicate a total elimination of the neoplaestic growth.
The phrase "inhibition of an impaune response” is intended to include decreases in T cell proliferation and activity, e.g., = decrease in IL, interferon-y, GM-CSF synthesis and secretion (Lemire, J. M. (W992) J. Cell Biochemistry 49:26-31, Lemire, J.
M. et al. (1994) Endocrinology 135 (6): 2813-2821; Bouillon, R. et al. (1995) Endocine
Review 16 (2):231-32).
The term "isomers" or "stereoisomers" refers to compounds whi- ch have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
The term "leukemia" is intended to have its clinical meaning, nemmely, a neoplastic disease in which white corpuscle maturation is arrested at a porimitive stage of "cell development. The disease is characterized by an increased numbe-T of leukemic blast cells in the borse marrow, and by varying degrees of failure to proeduce normal hematopoietic cells. The condition may be either acute or chronic. Letakemia's are further typically categorized as being either lymphocytic i.e., being chamreacterized by
TT 10 cells which have properties in common with normal lymphocytes, or myelocytic (or myelogenous), i.e., characterized by cells having some characteristics Of normal granulocytic cells. Acute lymphocytic leukemia ("ALL") arises in lymphoid tissue, and ordinarily first manifests its presence in bone marrow. Acute myelocystic leukemia ("AML") arises frorm bone marrow hematopoietic stem cells or their progeny. The term acute myelocytic leukemia subsumes several subtypes of leukemia: miweloblastic leukemia, promyelocytic leukemia, and myelomonocytic leukemia. In_ addition, leukemias with erythroid or megakaryocytic properties are considered myelogenous . leukemias as well. . The term "leukemic cancer" refers to all cancers or neoplasias cf the hemopoietic and immune systems (blood and lymphatic system). The acute and chmronic leukemias, together with the other types of tumors of the blood, bone marrow cell:s (myelomas), and lymph tissue (lymphomas), cause about 10% of all cancer deaths and aabout 50% of all cancer deaths in children and adults less than 30 years old. Chronic m—yelogenous leukemia (CML), a 1so known as chronic granulocytic leukemia (CGL)®, is a neoplastic disorder of the hematopoietic stem cell. The term "leukemia" is art recognized and refers to a progressive, malignant disease of the blood-forming organs_, marked by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow.
The term "modulate" refers to increases or decreases in the actSivity of a cell in response to exposure to a compound of the invention, e.g., the inhibition of proliferation and/or induction of differentiation of at least a sub-population of cells in an animal such that a desired end result is achieved, e.g., a therapeutic result. In preferred embodiments, this phrase is intended to include hyperactive conditions that result in pathological disorders.
The common medical meaning of the term "neoplasia" refers to "new cell ‘ growth" that results as a loss of responsiveness to normal growth controls, e.g. to neoplastic cell growth. A "hypemplasia” refers to cells undergoing an abnormally high : rate of growth. However, as useed herein, the terms neoplasia and hyperplasia can be used interchangably, as their con text will reveal, referring to generally to cells experiencing abnormal cell growth rates. Neoplasias and hyperplasias include "tumors," which may be either benign, prermalignant or malignant.
The language "non-genommic™ vitamin D; activities include cellular (e.g., calcium transport across a tissue) and sub cellular activities (e.g., membrane calcium transport opening of voltage-gated calciunm channels, changes in intracellular second messengers) elicited by vitamin D3 compound._s in a responsive cell. Electrophysiological and biochemical techniques for detecsting these activities are known in the art. An example of a particular well-studied non-g-enomic activity is the rapid hormonal stimulation of intestinal calcium mobilization, termed "transcaltachia" (Nemere I. et al. (1984)
Endocrinology 115:1476-1483; Laieberherr M. et al. (1989) J. Biol. Chem. 264:20403- 20406; Wali RK. et al. (1992) E-ndocrinology 131:1125-1133; Wali RK. et al. (1992)
Am. J, Physiol. 262:G945-G953; "Wali R.K. et al. (1990) J. Clin. Invest. 85:1296-1303;
Bolt M.J.G. et al. (1993) Biocher=n. J. 292:271-276). Detailed descriptions of : experimental transcaltachia are provided in Norman, A.W. (1993) Endocrinology 268(27):20022-20030; Yoshimoto, Y. and Norman, A.W. (1986)
Endocrinology118:2300-2304. Changes in calcium activity and second messenger systems are well known in the art and are extensively reviewed in Bouillion, R. et al. (1995) Endocrinology Review 16(22): 200-257; the description of which is incorporated herein by reference.
The phrases "parenteral ad-ministration" and "administered parenterally” as used herein means modes of administra_tion other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intra_sternal injection and infusion.
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. Bach of the rings of the polycycle can be substiteated with such substituents as described above, as for example, halogen, hydroxyl, alkxylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, ealkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, “phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, ary>lamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkwylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, triflueoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroar-omatic moiety.
The term “prodrug” includes compounds with nm cieties which can be metabolized in vivo. Generally, the prodrugs are metabeolized in vivo by esterases or by . other mechanisms to active drugs. Examples of prodrugzs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical. Salts", J. Pharm. Sci. 66:1-19).
The prodrugs can be prepared in situ during the final isc>lation and purification of the - compounds, or by separately reacting the purified compeound in its free acid form or : hydroxyl with a suitable esterifying agent. Hydroxyl greoups can be converted into esters a via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl esteer moieties, (e.g, propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino 1 ower-alky] esters (e.g. dimethylaminoethy] ester), acylamino lower alkyl esters (e.g, acetyloxymethy] ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e- g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, armides, lower-alkyl amides, di- lower alkyl amides, and hydroxy amides. Preferred prodrug moieties are propionoic acid esters and acyl esters. Prodrugs which are converted to active forms through other mechanisms in vivo are also included.
The language "a prophylactically effective anti-ne=oplastic amount" of a compound refers to an amount of a vitamin D3 compounci of the formula (I) or otherwise ; described herein which is effective, upon single or multipole dose administration to the patient, in preventing or delaying the occurrence of the onset of a neoplastiec disease state.
The term "psoriasis" is i mtended to have its medical meaning, namely, a disease which afflicts primarily the skims and produces raised, thickened, scaling, noenscarring lesions. The lesions are usually sharply demarcated erythematous papules ccovered with overlapping shiny scales. The sales are typically silvery or slightly opalescent.
Involvement of the nails frequently occurs resulting in pitting, separation of= the nail, thickening and discoloration. Psoriasis is sometimes associated with arthritis, and it may be crippling.
The language "reduced toxicity" is intended to include a reduction imma any undesired side effect elicited by a vitamin Ds compound when administered in vivo, e.g., a reduction in the hypercalcemic activity.
The term "sarcoma" is art recognized and refers to malignant tumors of © mesenchymal derivation.
The term "secosteroid” is art-recognized and includes compounds in - ‘which one of the cyclopentanoperhydro- phenanthrene rings of the steroid ring structure is broken. 10,,25(OH),D5 and analogs thereof are hormonally active secosteroids. In tEne case of vitamin Dj, the 9-10 carbon-carbon bond of the B-ring is broken, generating a seco-B- steroid. The official TUPAC name for vitamin Ds is 9,10-secocholesta-5,7,1CO(19)-trien- 3B-ol. For convenience, a 6-s-trcans conformer of 1c,25(OH)D; is illustrate=d herein having all carbon atoms numbered using standard steroid notation. . 2 24
S 50 2 OH @ 17 7
DE
> 3 g 15 6.1 4g A
Lf 9 5 OH
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 (—) or (+m) indicating a substituent which is in the= B-orientation (i.e. , above the plane of the ring), a wedged solid line («) indicating a sumbstituent which is in the a-orientation (ie. , below the plane of the molecule), or a wavy line (“indicating that a substituent ‘may be either above or below the plane of th ering. In regard to ring A, it should be understood that the stereochemical conventicon in the vitamin D field is opposite from the general chemical field, wherein a dotted Mine indicates a substituent on Ring A which is in an a-orientation (i.e. , below the plane cf the molecule), and a wedged solid line indicates a substituent on ring A which is in the B-orientation (i.e. , above the plane of the ring). As shown, the A ring of the hormaone 1a,25(0H),D; contains two asymmetric centers at carbons 1 and 3, each one containimng a hydroxyl group in well-characterized configurations, namely the 1a- and 3p- hydroxyl groups. In other words, carbons 1 and 3 of the A ring are said to be "chiral carbons" or "carbon centers.”
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) conformatio.-n whereas “E” refers to what is often referred to as a “trans” (opposite side) conformmation. Regardless, both configurations, cis/trans and/or Z/E are contemplated for the ecompounds for use in the present invention.
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:
Lo
I
RS" :Ry - wherein X; and X; are defined as H (or H; ) or— =CH,; or
. Xo 1 :
II
Ra" R1 whereinX, and X, are defined as Hor CHa. Although there doess not appear to be any set convention, it is clear that one of ordinary skill in the art unde=rstands either formula I or II to represent an A ring in which, for example, X, is =CHzanc1X; is defined as Ha, as follows:
R » [ Ri,
For purposes of the instant invention, formula I will be used in alll generic structures.
The term "sulfhydryl" or "thiol" means —SH.
The term “subject” includes organisms which are capable of suffering froma vitamin Ds associated state or who could otherwise benefit from the administration of a vitamin Ds; compound of the invention, such as human and non-hwuman animals.
Preferred human animals include human patients suffering from Or prone to suffering from a vitamin Ds associated state, as described herein. The term. "non-human animals" of the invention includes all vertebrates, e.g., , mammals, e.g., rodents, e.g., mice, and pon-mammals, such as non-human primates, sheep, dog, cow, chi_ckens, amphibians, : reptiles, etc.
The phrases "systemic administration," "administered systemically”, "peripheral administration” and "administered peripherally" as used herein mean the administration of a vitamin Ds compowund(s), drug or other material, such that it enters the patiemnt's system and, thus, is subject to metabolism and other like processes, for example, - subcutaneous administaration.
The language "€herapeutically effective anti-neoplastic amount!’ of a vitammin D3 +S compound of the invention refers to an amount of an agent which is effective, upon single or multiple dose administration to the patient, in inhibiting the growth of neoplastic vitamin Ds-responsive cells, or in prolonging the survivability of the patient with such neoplastic ce 1s beyond that expected in the absence of such treatment.
The language “transplant rejection” refers to an immune reaction directec against a transplanted organ(s) from other human donors (allografts) or from other specises such as sheep, pigs, or non-h_uman primates (xenografts). Therefore, the method of thee : invention is useful for preventing an immune reaction to transplanted organs frorm other human donors (allografts) or from other species (xenografts). Such tissues for transplantation include, but are not limited to, heart, liver, kidney, lung, pancreas, pancreatic islets, bone marrow, brain tissue, cornea, bone, intestine, skin, and hematopoietic cells. Al-so included within this definition is “graft versus host diseease” of “GVHD,” which isa condition where the graft cells mount an immune response against the host. Therefore, the method of the invention is useful in preventing gmraft versus host disease in camses of mismatched bone marrow or lymphoid tissue transsplanted for the treatment of acute leukemia, aplastic anemia, and enzyme or immune deficiencies, for examplee. The term “tfansplant rejection” also includes disease symptoms characterized by loss of organ function. For example, kidney rejection would be characterized by a risTing creatine level in blood. Heart rejection is characterize=d by an endomyocardial biopssy, while pancreas rejection is characterized by rising blomod : glucose levels. Liver rej ection is characterized by the levels of transaminases of 1-dver origin and bilirubin levels in blood. Intestine rejection is determined by biopsy, wshile
Tung rejection is determizned by measurement of blood oxygenation.
The term "VDR" is intended to include members of the type II class of steroid/thyroid superfamily of receptors (Stunnenberg, H.G. (1993) Bio Essays 15(5):309-15), which are able to bind and transactivate through the vitamin D respoonse element (VDRE) in the albsence of a ligand (Damm ez al. (1989) Nature 339:593-297,;
Sap et al. Nature 343:1777-180).
The term "VDRE" re= fers to DNA sequences composed of half-sites arranged as direct repeats. It is known ira the art that type TI receptors do not bind to their respoective binding site as homodimers ¥but require an auxiliary factor, RXR (e.g RXRat, ROXRB,
RXR) for high affinity bind ing Yu etal. (1991) Cell 67:1251-1266; Bugge et al~ (1992) EMBO J. 11:1409-14-18; Kliewer et al. (1992) Nature 355:446-449; Leid etal. (1992) EMBO J. 11:1419-14-35; Zhang et al. (1992) Nature 355:441-446).
The language “vitam-in Dj associated state” is a state which can be prevented, treated or otherwise ameliorated by administration of one or more compounds of —the invention. Vitamin Ds associated states include IL T3-associated disorders, disorcqers characterized by an aberrant activity of a vitamin Ds-responsive cell, disorders : characterized by a deregulation of calcium and phosphate metabolism, and other disorders or states described herein. .
The term "vitamin D=-responsive cell” includes any cell which is is capable of responding to a vitamin D3 ¢ ompound having the formula I or otherwise describead herein, or is associated with edisorders involving an aberrant activity of hyperproliferative skin cells, parathyroid cells, neoplastic cells, immune cells, ancd bone cells. These cells can respormd to vitamin Dj activation by triggering genomic and/or non-genomic responses that miltimately result in the modulation of cell proliferatiosn, differentiation survival, and/or other cellular activities such as hormone secretion Ina preferred embodiment, the ulltimate responses of a cell are inhibition of cell prolifeeration and/or induction of differentE ation-specific genes. Exemplary vitamin Ds respons=ive cells include immune cells, beone cells, neuronal cells, endocrine cells, neoplastic cells, epidermal cells, endodermal «cells, smooth muscle cells, among others.
With respect to the nomenclature of a chiral center, terms vd" and "1" configuration are as defined boy the TUPAC Recommendations. As to the use of time terms, diastereomer, racematee, epimer and enantiomer will be used in their normall context to describe the stereo-chemistry of preparations. 2, VITAMIN D3 COMPOUNDS OF THE INVENTION
A prominent feature oof the vitamin D3 compounds of the invention is acylation at the 1 and 3 positions on the Aw ring of the compounds. 1,3-diacyl vitamin D3 compounds are described in U.S. Patent 5,976,784 to DeLuca et al. However, any compounds= specifically disclosed in U.S. Patent 5,976,784 to DeLuca et al. are excluded from the scope the appended claims.
The acylated vitamin D3 compounds of formula I above exert a full spectrum of 1,25(0OH),D; biological activitie=s such as binding to the specific nuclear receptor VDR, suppression of the increased parsathyroid hormone levels in 5,6-nephrectomized rats, suppression of INF-y release in BVILR cells, stimulation of HL-60 leukemia cell differentiation and inhibition of solid tumor cell proliferation. It is well known that in vivo and in cellular cultures 1,258-(0OH),D; undergoes a cascade of metabolic modifications initiated by the in#fluence of 24R-hydroxylase enzyme. First 24R-hy- droxy metabolite is formed, whiech is oxydized to 24-keto intermediate, and then 23S- hydroxylation and fragmentatior produce the fully inactive calcitroic acid. ! ) It has been discovered th_at 1,3-diacylated compounds of the invention have unexpected and/or superior propeerties as compared to corresponding 1,3-dihydroxy compounds. For example, 1,3-IDi-O-acetyl-1 ,25-dihydroxy-16,23Z-diene-26,27- hexafluoro-19-nor-cholecalciferecl (2), 1,3-Di-O-acetyl-1,25-Dihydroxy-16-ene-23-yne- 26,27-hexafluoro-19-nor-cholec-alciferol (4) and 1,3,25-Tri-O-acetyl-1,25-Dihydroxy- 1 6-ene-23-yne-26,27-hexafluorc-19-nor-cholecalciferol (5) have a significantly higher maximum tolerated dose and im proved activity when compared with the corresponding dihydroxy compounds, 1,25-dih_ydroxy-1 6,23Z-diene-26,27-hexafluoro-19-nor- . 20 cholecalciferol (1) and 1,25-dihsydroxy-16-ene-23-yne-26,27-hexafluoro-19-nor- cholecalciferol (3).
Thus, in one aspect, the invention provides a vitamin Ds compound of formula I=
Be I°
RaaZ >~_R6
ORg . 1 Ry
Xz X4
RY R wherein:
A, is single or double bond;
A, is a single, double or triple bond;
X; and X; are each independently Ha or =CHp, provided X, and Xj are not both ~=CHy; ’
R, and R;are each independently OC(CO)C:-Cs alkyl, OC(O)hydroxyalkyl, or
OC(O)haloalkyl;
Rs. Ry and Rs are each independently Bhydrogen, C{-C, alkyl, hydroxyalkyl, or “haloalkyl, with the understanding that Rs is atosent when A; is a triple bond, or Rs and Res —taken together with Cz form Cs5-Cs cycloalkyl;
Rs and Rs are each independently alky~1 or haloalkyl; and
Rs is H, C(0)C;-Cs alkyl, C(O)hydrox=yalkyl, or C(O)haloalkyl; provided that when A, is single bond, “R; is hydrogen and Ry is methyl, then Az
His a double or triple bond; and gpharmaceutically acceptable esters, salts, and —prodrugs thereof.
In one embodiment of the invention, XX is Hz and Xj is =CHz. In another ecmbodiment, X; and X; are Hz. In another enmabodiment, A; is a single bond. In another e=mbodiment, A; is a double bond. In another embodiment, A; is a triple bond.
In a preferred embodiment, Rj is hydrogen and Ry is C1-Cs alkyl, preferably mmethyl. In another preferred embodiment, R3 and Ry, taken together with Cao, form Cs- &C; cycloalkyl. In a preferred embodiment, Rs and Rg, taken together with Cy, form cyclopropyl.
In a preferred embodiment, R; and R; are each independently OC(0)C;-C4 alkyl, preferably OC(O)CHs. :
In a preferred embodiment, Re and Ry are each independently alkyl or haloalkyl. preferably methyl, ethyl, or trifluoromethyl.
In a preferred embodiment, Rg is H or «C(0)C,-C, alkyl.
Certain embodiments fe the invention are directed to 1,3-acylated, 26,27- haloakly vitamin D; compouncis. Such compounds are represented by the formula I-c:
R
TPN
R3 9) Re
ORg 1 R7 l.-c ,
Xa Xq
R2 Ry wherein: : A. is single or double bond;
A is a single, double or triple bond,
X, and X; are each independently H; or CHa, provided X; and X; are not both
CH;
R, and R; are each inde=pendently OC(O)C;-Cs alkyl, OC(O)hydroxyalkyl, or
OC(O)haloalkyl;
Rs, R4 and Rs are each independently hydrogen, C,-C4 alkyl, hydroxyalkyl, or haloalkyl, or R3 and Ry taken teogether with Cz form C3-Cs cylcoalkyl;
Rs and Ry are each indespendently haloalkyl; and
Rs is H, OC(0)C;-C, alikyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof. In preferred embodiments, Rg and Ry are each independently trihaloalkyl, especially trifluoromethyl.
In another embodiment of the invention, Ry and Ry are OC(O)CH3 R3 is H, Ry is methyl, Rs is H (or absent if A; is a triple bond), as shown in formula I-a. 2 R6
IE
Xow | X41 l-a
HsC(0)CO™ OC(O)CHs
In a preferred embodiment, Aj is a double bond, and X; is =CH, and Xs is Hy.
When A; is a triple bond, it is preferred that Rs is H or C(O)CH3, and Re and Ry are alkyl or haloalkyl. It is preferred that the alkyl group is methyl and the haloalkyl group is triflucroalkyl, preferably trifluoxromethyl. When Az isa double bond, it is preferred that Rg is H or C(O)CHs, and Rs amd Ry are alkyl, preferably methyl. 1t is also preferred that Rg and R; are independently alkyl and haloalkyl. When Az isa single bond, it is preferred that Rs is H or C(O)CHs and Re and Rj are alkyl, preferably methyl.
In a preferred embodiment, A; isa double bond, and X; and X; are each Ha.
When A; is a triple bond, it is preferred that Rs is H or C(O)CHs, and Rg and Ry are alkyl or haloalkyl. It is preferred that the alkyl group is methyl or ethyl and the haloalkyl group is trifluoroalkyl, preferably trifluoromethyl. When Az is a double bond, it is preferred that Rg is H or C(O)€CH3, and Re and Rs are haloalkyl, preferably trifluoroalky’], preferably trifluorormethyl. When A: is a single bond, it is preferred that
Rs is H or C(O)CHj, and Rg and R~ are alkyl, preferably methyl.
In another embodiment of t-he invention of formula (I), R; and R; are OC(0)CHs,
A, is a single bond, and A; is a sin gle, double or triple bond, except that when R3 is H and R, is methyl, A; is a double or triple bond. In a preferred embodiment, Rs isH, Ry is methyl, R 5 is absent, Rs is H or C(O)CH3, and Rs and R; are alkyl, preferably methyl.
Preferred compounds of thes present invention are summarized in Table 1 and include the following: 1,3-Di-O-ac-etyl-1,25-dihydroxy-16,23 Z-diene-26,27-hexafluoro- 19-nor-cholecalciferol (2), 1,3-Di-O-acetyl-1,25-Dihydroxy-16-ene-23-yne-26,27- hexaflucro-19-nor-cholecalciferol 4), 1,3,25-Tri-O-acetyl-1,25-Dihydroxy-16-ene-23- yne-26,27-hexafluoro-19-nor-cholescalciferol (5), 1,3-Di-O-acetyl-1,25-dihydroxy-16-
ene-23-yne-cholecalciferol (7), 1,3-Di-O-acetyl-1,25-dihydroxy-16,23E-diene- cholecalciferol (9), 1,3-Di-O-acetyl-1,25-dihydroxy—16-ene-cholecalciferol (11), 1,3,25-
Tri-O-acetyl-1,25 _dihydroxy-16-cne-23-yne-26,27-Eaexafluoro-cholecalciferol (13), 1,3-
Di-O-acetyl-1,25-dihydroxy-16-ene-23-yne-26,27-h_exafluoro-cholecalciferol (14), 1,3- .
Di-O-acetyl-1,25-dihydroxy-16,23E-diene-25R,26-txrifluoro-cholecalciferol (16), 1,3-Di-
O-acetyl-1,25-dihydroxy-16-ene-19-nor-cholecalcifeerol (18), 1,3-Di-O-Acetyl-1,25- dihydroxy-16-ene-23-yne-1 9-nor-cholecalciferol (2€0), 1,3-Di-O-acetyl-1,25-dihydroxy- 16-ene-23-yne-26,27-bishomo-1 9-nor-cholecalcifersol (22) and 1,3-Di-O-acetyl-1,25- dihydroxy-23-yne-~cholecalciferol (41).
Table 1 / 2\ Re 1 fr, ORe
I:
Xo | Xq l-a
H3C(0)CO" OC(O)CHam
ET a CR LL Lo @ [mm |= |= [& [oh [H @® [mm |= [= (0k [om [H © (mm |= |= [0k [Oh [COCK @ [om m |= [= [0% [cB |H © [Om [m= [= |[O& [cB [H an [Om | | — [— [C& [Om [H a [Ck |B |= |= [Or [CB [COG
I a EE HL a [om |B |= [= [on [om [H a [mm |= |— [& [a JH ey (mm |= [= [Ch Jom [H @) [W |R |= [= [CHCRJCERCGRHIH
TCC nc OE cB 3 Z olefin
In another embod_.iment of the invention, Ry and R; are each COC(O)CH;, and Rs and Ry, taken together with Cy form cyclopropyl, and Rs is H (or abssent if A; is a triple bond), as shown in form=ala I-b. 2\ Re 1 R,ORs
IE
Xa Xi } I-b
H3C(O=)CO' OC(O)CH3 .
In a preferred embodiment, X; is =CHzand Xz is H,. When «A, is a single bond, and Aj is a triple bond, it is preferred that Rg is H or C(O)CH3, and FR and Ry are alkyl, preferably methyl. Wher A, is a single bond, and Az is a single boned, it is preferred that
RgisH or C(O)CHs, and Rs and Ry are alkyl, preferably methyl. Wen A; is a double bond, and A, is a single bwond, it is preferable that Rs is H or C(O)CHH3, and Rs and Ry are alkyl, preferably metinyl. I
In another preferreed embodiment, X; and X; are each H,. When A, is a single bond, and A; is a triple bond, it is preferred that Rg is H or C(O)CHij.,, and Rg and Ry are alkyl or haloalkyl. Itis prreferred that the alkyl group is methyl, and the haloalkyl group is trifluorcalkyl, preferably trifluoromethyl. When A, isa single bornd, and A; is a double bond, it is preferresd that Rg is H or C(O)CHs, Rg and R; are baaloalkyl, preferably triflucroalkyl, preferably trifluoromethyl. When A, isa double bonc, and A. is a single bond, it is preferred that Rg is H or C(O)CHj, Rs and Ry are alkyl, pr-eferably methyl.
Preferred compounds of the present invention are summarize=d in Table 2 and include the following: 1,3-Dj-0-acetyl-1,25-dihydroxy-20-cyclopropoyl-23-yne-19-nor- cholecalciferol (24), 1,3,25-Tri-O-acetyl-1,25-dihydroxy-20-cyclopr-opyl-23-yne-26,27- hexafluoro-1 9_nor-cholec=alciferol (26), 1,3-Di-O-acetyl-1,25 -dihydr-oxy-20- cyclopropyl-23-yne-26,27-hexafluoro-1 9-nor-cholecalciferol (27), 1-,3-Di-O-acetyl- 1,25-dihydroxy-20-cyclogpropyl-23-yne-cholecalciferol (29), 1,3-Di-eO-acetyl-1,25- dihydroxy-20-cyclopropy-1-23E-ene-26,27-hexafluoro-19-nor-cholec -alciferol 31), 1,3-
Di-O-acetyl-1,25-dihydrawxy-20-cyclopropyl-23Z-ene-26,27-hexafluaoro-19-nor-
cholec-alciferol (33), 1,3-Di-O-acetyl-1,25-dihydroxy-20-cyclopropeyl-cholecalciferol (35), M,3-Dj-O-acetyl-1a,25-dihydroxy-16-ene-20-cyclopropyl-1 9—~nor-cholecalciferol (37), amd 1,3-Di-O-acetyl-1a.,25-hydroxy-16-ene-20-cyclopropyl-c=holecalciferol (39).
Table 2 2\ 6 1 R,ORe
Xz | X4 g Ib
H5C(0)CO' OC(O)CHs .
Fe aE LE Cr LT a Lo ei» mm | [= [CR [CH [BH
Cie J TN ES ES 2
EC a El El WO ©» [om[m | — [= [Ok [Ch [H
Gi» [mm | — |= [Ck [CB [H wr mm | |= [Oh [Oh JH
Ge mm | [— [ok [om [wm om (mm |= [— [Ob [CH= [H
FT ce EE ec Co LB ® Z ole=fin.
The structures of some of the compounds of the invention iinclude asymmetric carborm atoms. Accordingly, the isomers arising from such asymm etry (e.g., all enanti-omers and diastereomers) are included within the scope of tie invention, unless indicated otherwise. Such isomers can be obtained in substantially. pure form by classic=al separation techniques and/or by stereochemically controlled synthesis.
Naturally occurring or synthetic isomers can be separated i-n several ways known inthe art. Methods for separating a racemic mixture of two enanti .omers include
: chromatography using a chiral stationary phase (see, e.g, "Chiral Liquid
Chromatography," SW.J. Lough, Ed. Chapman and Hall, New York (19889).
Enantiomers can alsso be separated by classical resolution techniques. Eor example, formation of diastereomeric salts and fractional crystallization can be umsed to separate 5S enantiomers. For thme separation of enantiomers of carboxylic acids, thes diastereomeric salts can be formed by addition of enantiomerically pure chiral bases si ach as brucine, quinine, ephedrine, strychnine, and the like. Alternatively, diasterecome=ric esters can be formed with epantiomerically pure chiral alcohols such as menthol, fol Towed by separation of the diastereomeric esters and hydrolysis to yield the free, enantiomerically enriched carboxylic acid. For separation of the optical isomers of amiro compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonics acid, tartaric acid, mandelic acid,. or lactic acid can result in formation of the diasteresomeric salts. 3. USES OF TEE VITAMIN D; COMPOUNDS OF THE INVENTION
In another embodiment, the invention also provides methods fo: x treating a subject for a vitamirm Ds associated state, by administering to the subject an effective amount of a vitamimm D3 compound of formula I or otherwise described herein. Vitamin
Ds associated states include disorders involving an aberrant activity of a vitamin Dj- responsive cell, e.g. neoplastic cells, hyperproliferative skin cells, paramthyroid cells, immune cells and bone cells, among others. Vitamin Dj associated stattes also include [LT3-associated diseorders. In certain embodiments, the subject is a mamrnmal, e.g., a primate, e.g., a human.
In certain enmbodiments, the methods of the invention include aiministering to a subject a therapeutically effective amount of a vitamin D3 compound iro combination with another pharmaceutically active compound. Examples of pharmaccuetically active compounds include compounds known to treat autoimmune disorders, e«.£., immunosuppressant agents such as cyclosporin A, rapamycin, desoxysgpergualine, FK 506, steroids, azathJoprine, anti-T cell antibodies and monoclonal antitoodies to T cell subpopulations. Other pharmaceutically active compounds that may be= used can be found in Harrison's Principles of Internal Medicine, Thirteenth Editiorm, Eds. T.R.
Harrison ef al. McGraw-Hill N.Y., NY; and the Physicians Desk Refere=nce 50th Edition 1997, Oradell New Wersey, Medical Economics Co., the complete conte=nts of which are expressly incorporat=ed herein by reference. The vitamin Ds; compound and the pharmaceutically active compound may be administered to the subject in the same pharmaceutical compositiora or in different pharmaceutical compositions (at the ssame time or at different times).
A. Hyvperprolife=rative Conditions
In another aspect, th_e present invention provides a method of treating a subject for a disorder characterized by aberrant activity of a vitamin Ds-responsive cell. "The method involves administer—ing to the subject an effective amount of a pharmaceutical composition of a vitamin D= compound of formula I or otherwise described hereimn such that the activity of the cell i=s modulated.
In certain embodime=nts, the cells to be treated are hyperproliferative cells . As described in greater detail b=elow, the vitamin D3 compounds of the invention can be. used to inhibit the proliferation of a variety of hyperplastic and neoplastic tissues. In accordance with the present= invention, vitamin D3 compounds of the invention ca_n be used in the treatrment of botlh pathologic and non-pathologic proliferative conditicons characterized by unwanted garowth of vitamin Ds-responsive cells, e.g., hyperproliferative skin cellss, immune cells, and tissue having transformed cells, e=.g,, such as carcinomas, sarcom_as and leukemias. In other embodiments, the cells to be treated are aberrant secretory cells, e.g., parathyroid cells, immune cells.
The use of vitamin ID compounds in treating hyperproliferative conditions: has been limited because of their hypercalcemic effects. Thus, vitamin D; compounds of the invention can provide a lesss toxic alternative to current methods of treatment.
In one embodiment, the invention features a method for inhibiting the proliferation and/or inducin_g the differentiation of a hyperproliferative skin cell, e.g, an epidermal or an epithelial cell, e.g., a keratinocytes, by contacting the cells with ao vitamin D3; compound of thes invention. In general, the method includes a step of contacting a pathological or- non-pathological hyperproliferative cell with an effective amount of such vitamin Ds ecompound to promote the differentiation of the hyperproliferative cells The present method can be performed on cells in culture,. e.g., invitro or ex vivo, or can bes performed on cells present in an animal subject, e.g., as part of an in vivo therapeutic prowtocol. The therapeutic regimen can be carried outon a human or any other animal ssubject.
The vitamin Ds comgpounds of the present invention can be used to treat a hyperproliferative skin disorder. Exemplary disorders include, but are not limited to, psoriasis, basal cell carcinorma, keratinization disorders and keratosis. Additional examples of these disorders include eczema; lupus associated skin lesions; psoriatic arthritis; rheumatoid arthritis that involves hyperproliferation and inflammation of epithelial-related cells lining the joint capsule; dermatitides such as seborrheic dermati tis and solar dermatitis; keratoses such as seborrheic keratosis, senile keratosis, actinic keratosis. photo-induced ke=ratosis, and keratosis follicularis; acne vulgaris; keloids an«d prophylaxis against keloid Formation; nevi; warts including verruca, condyloma or condyloma acuminatum, amd human papilloma viral (HPV) infections such as venereal warts; leukoplakia; lichen planus; and keratitis.
In an illustrative example, vitamin Ds compounds of the invention can be used to inhibit the hyperproliferation of keratinocytes in treating diseases such as psoriasis by” administering an effective amount of these compounds to a subject in need of treatment.
The term "psoriasis is inte=nded to have its medical meaning, namely, a disease whicka afflicts primarily the skin aand produces raised, thickened, scaling, nonscarring lesions.
The lesions are usually sharply demarcated erythematous papules covered with overlapping shiny scales. "The scales are typically silvery or slightly opalescent. ~
Involvement of the nails fi-equently occurs resulting in pitting, separation of the nail, thickening and discoloration. Psoriasis is sometimes associated with arthritis, and it may be crippling. Hyperproliferation of keratinocytes is a key feature of psoriatic epidermal hyperplasia alorg with epidermal inflammation and reduced differentiatiom1 of keratinocytes. Multiple m_echanisms have been invoked to explain the keratinocyte hyperproliferation that chemracterizes psoriasis. Disordered cellular immunity has also been implicated in the pathogenesis of psoriasis.
The invention also- features methods for inhibiting the proliferation and/or reversing the transformed phenotype of vitamin Dy-responsive hyperproliferative celLls by contacting the cells wi€h a vitamin D3; compound of formula I or otherwise described herein. In general, the me=thod includes a step of contacting pathological or non- pathological hyperprolifer-ative cells with an effective amount of a vitamin D; compeound of the invention for promoting the differentiation of the hyperproliferative cells. The present method can be performed on cells in culture, e.g., in vitro or ex vivo, or can be performed on cells present in an animal subject, e.g, as part of an in vivo therapeutic protocol. The therapeutic regimen can be carried out on a human or other subject.
The vitamin Ds compounds of formula I or otherwise described herein can be tested initially in vitro for their inhibitory effects in the proliferation of neoplastic cells.
Examples of cell lines that can be used are traansformed cells, e.g., the human promyeloid leukemia cell line HL-60, and the human myeloid leukemia U-937 cell line (Abe E. et al. (1981) Proc. Natl. Acad. Sci. LSA 78:4990-4994; Song L.N. and Cheng T. (1992) Biochem Pharmacol 43:2292-2295; ZZhou 1.Y. et al. (1989) Blood 74:82-93; U.S.
Pat. Nos. 5,401,733, U.S. 5,087,619). Altern atively, the antitumoral effects of vitamin
D; compounds of the invention can be tested in vivo using various animal models known in the art and summarized in Bouillon, R. et eal. (1995) Endocrine Reviews 16(2):233 (Table E); which is incorporated by reference herein. For example, SL mice are routinely used in the art to test vitamin D cormpounds as models for MI myeloid : leukemia (Honma et al. (1983) Cell Biol. 80 201-204; Kasukabe T. et al. (1987) Cancer
Res. 47:567-572); breast cancer studies can be performed in, for example, nude mice models for human MX1 (ER) (Abe J. et al. (71991) Endocrinology 129:832-837; other cancers, e.g., colon cancer, melanoma osteossarcoma, can be characterized in, for : example, nude mice models as describe in (Eisman J. A. et al. (1987) Cancer Res. 47:21-25; Kawaura A. ef al. (1990) Cancer E ett 55:149-152; Belleli A. (1992)
Carcinogenesis 13:2293-2298; Tsuchiya H. eet al. (1993) J. Orthopaed Res. 11:122-1 30).
The subject method may also be used to inhibit the proliferation of hyperplastic/neoplastic cells of hematopoietic origin, e.g, arising from myeloid, lymphoid or erythroid lineages, or precursor cells thereof. For instance, the present invention contemplates the treatment of varieous myeloid disorders including, but not limited to, acute promyeloid leukemia (APMIEL), acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) (reviewed in Vaickus, L. (1991) Crit Rev. in
Oncol./Hemotol. 11:267-97). Lymphoid malignancies which may be treated by the subject method include, but are not limited two acute lymphoblastic leukemia (ALL) which includes B-lineage ALL and T-lineagee ALL, chronic lymphocytic leukemia y (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) and Waldenstrom's macroglobulinemia (WM). Additional form_s of malignant lymphomas contemplated by the treatment method of the present invention include, but are not limited to non-
Hodgkin lymphoma and vvariants thereof, peripheral T cell lymphomas, adult T ceAl leukemia/lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), large granular lymphocytic leukemia (1.GF) and Hodgkin's disease.
In certain embodiments, the vitamin Ds compounds of the invention can bes used in combinatorial therapy with conventional cancer chemotherapeutics. Conventiosnal treatment regimens for lesukemia and for other tumors include radiation, drugs, or a "combination of both. In addition to radiation, the following drugs, usually in combinations with each anther, are often used to treat acute leukemias: vincristine, prednisone, methotrexates, mercaptopurine, cyclophosphamide, and cytarabine. Im chronic leukemia, for ex:ample, busulfan, melphalan, and chlorambucil can be use=d in combination. All ofthe conventional anti-cancer drugs are highly toxic and tendl to make patients quite ill w~hile undergoing treatment. Vigorous therapy is based on the premise that unless ever=y leukemic cell is destroyed, the residual cells will multioly and cause a relapse.
The subject methnod can also be useful in treating malignancies of the various organ systems, such as am ffecting lung, breast, lymphoid, gastrointestinal, and gen: ito- urinary tract as well as a_denocarcinomas which include malignancies such as mo=st colon cancers, renal-cell carcirnoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, c-ancer of the small intestine, cancer of the esophagus, andl bladder cancer.
According to the= general paradigm of vitamin Dj; involvement in differenstiation of transformed cells, exemplary solid tumors that can be treated according to the method of the present invention include vitamin Ds-responsive phenotypes of sarcomas aand carcinomas such as, but not limited to: fibrosarcoma, myxosarcoma, liposarcomam, chondrosarcoma, osteogzenic sarcoma, chordoma, angiosarcoma, endotheliosarco=1ma, lymphangiosarcoma, lyrmphangioendotheliosarcoma, synovioma, mesothelioma,
Ewing's tumor, leiomyo:sarcoma, rhabdomyosarcoma, colon carcinoma, pancreat=ic cancer, breast cancer, ovarian cancer, prostate cancer, bladder cancer, squamous cell carcinoma, basal cell cazxrcinoma, adenocarcinoma, sweat gland carcinoma, sebaceeous gland carcinoma, papilleary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bmronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocsarcinoma, seminoma, embryonal carcinoma, Wilms' tum_or, cervical cancer, testicul=ar tumor, lung carcinoma, small cell lung carcinoma, blacider carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharsa/ngioma, ependymoma, pinealoma, hemangiowblastoma, acoustic neuroma, oligodendrcoglioma, meningioma, melanoma, peuroblastoma, and retinoblastoma.
Determination of a therapeutically effective anti-mneoplastic amount or a prophylactically effective anti-neoplastic amount of the =vitamin Ds; compound of the invention, can be readily made by the physician or veterinarian (the "attending clinician™),. as one skilled in the art, by the use of known_ techniques and by observing results obt=ained under analogous circumstances. The dosages may be varied depending upon the re=quirements of the patient in the judgment of ®&he attending clinician, the severity of ~ the'condition being treated and the particular compound being employed. In determining the therapeutically effective antineoplastic zamount or dose, and the prophylact=ically effective antineoplastic amount or dose=, a number of factors are considered by the attending clinician, including, but not limited to: the specific hyperplastJic/neoplastic cell involved; pharmacodynamic characteristics of the particular agent and ts mode and route of administration; the desi-rder time course of treatment; the speciess of mammal; its size, age, and general health ; the specific disease involved; the degree : of or involvement or the severity of the diseamse; the response of the individual patient; thee particular compound administered; the mod_e of administration; the ‘ bioavailabwility characteristics of the preparation adminis=stered; the dose regimen selected; sthe kind of concurrent treatment (i.e., the inte-raction of the vitamin Ds compounds of the invention with other co-administeredl therapeutics); and other relevant circumstances. U.S. Patent 5,427,916, for example, desscribes method for predicting the effectivensess of antineoplastic therapy in individual patients, and illustrates certain methods vwhich can be used in conjunction with the treamtment protocols of the instant invention. :
Trecatment can be initiated with smaller dosagess which are less than the optimum dose of thee compound. Thereafter, the dosage should bee increased by small increments until the osptimum effect under the circumstances is reacched. For convenience, the total daily dosamge may be divided and administered in portions during the day if desired. A therapeuti_cally effective antineoplastic amount and a prophylactically effective anti- neoplastic= amount of a vitamin Ds compound of the imw/ention is expected to vary from about 0.1 milligram per kilogram of body weight per dzay (mg/kg/day) to about 100 mg/kg/day.
Compounds which are cetermined to be effective for the prevention or treatment of tumors in animals, e.g, dogss, rodents, may also be useful in treatment of tumors in humans. Those skilled in the a:rt of treating tumors in humans will know, based upon the data obtained in animal stuedies, the dosage and route of administration of the compound to humans. In general, the dosage and route of administration in humans is expected to be similar to that ir animals.
The identification Of theose patients who are in need of prophylactic treatment for hyperplastic/neoplastic disease= states is well within the ability and knowledge of one skilled in the art. Certain of th_e methods for identification of patients which are at risk of developing neoplastic disea=se states which can be treated by the subject method are appreciated in the medical arts ., such as family history of the development of a particular disease state and the presence sof risk factors associated with the development of that disease state in the subject patient. A clinician skilled in the art can readily identify such : candidate patients, by the use cof, for example, clinical tests, physical examination and medical/family history.
C. Immuniolo gical Activity
Healthy individual s preotect themselves against foreign invaders using many different mechanisms, includimng physical barriers, phagocytic cells in the blood and tissues, a class of immune cellls known as lymphocytes, and various blood-bom molecules. All of these m echzanisms participate in defending individuals from a potentially hostile environtnerat. Some of these defense mechanisms, known as natural or innate immunity, are present in an individual prior to exposure to infectious microbes or other foreign macromolecu_les, are not enhanced by such exposures, and do not discriminate among most fore-ign substances. Other defense mechanisms, known as acquired or specific inmunity~, are induced or stimulated by exposure of foreign substances, are exquisitely” specific for distinct macromolecules, and increase in magnitude and defensive Capabilities with each successive exposure to a particular macromolecule. Substances that induce a specific immune response are known as antigens (see, e.g., Abbas, A. ef al., Cellular and Molecular Immunology, W.B.
Saunders Company, Philadelphia, 1991; Silverstein, A.M. A history of Immunology,
San Diego, Academic Press, M989; Unanue A. ef al., Textbook of Immunology, 2 ed.
Williams and Wilkens, Baltinmore, 1984).
One of the most remarkable properties of the immune system is its abJlity to } distinguish between forezign antigens and self-antigens. Therefore, the lymphuocytes in each individual are able to recognize and respond to many foreign antigens bwat are normally unresponsive to the potentially antigenic substances present in the individual.
This immunological unresponsiveness is referred to as immune tolerance (sec, e.g, Burt
RX et al. (2002) Blood ©9:768; Coutinho, A. et al. (2001) Immunol. Rev. 182=:39;
Schwartz, RH (1990) Science 248:1349; Miller, JF. et al. (1989) Immunology Today 10:53). " Selfitolerance is an acquired process that has to be learned by the lymphocytes of "10 each individual. Tt cccumrs in part because lymphocytes pass through a stage mntheir development when an encounter with antigen presented by antigen-presentin_g cells (APCs) leads to their death or inactivation in a process known as positive ancl negative selection (see, e.g., Debsatin KM (2001) Ann. Hematol. 80 Suppl 3:B29; Abb as, A. : (1991), supra). Thus, potentially self-recognizing lymphocytes come into contact with self-antigens at this stagze of functional immaturity and are prevented from desveloping to a stage at which they weould be able to respond to self-antigens. Autoimmunity arises when abnormalities in the induction or maintenance of self-tolerance occur that result in a loss of tolerance to a poarticular antigen(s) and a subsequent attack by the haost’s immune system on the Thost’s tissues that express the antigen(s) (see, e.g., BOyton RJ ef al. (2002) Clin. Exp. hremunol. 127:4; Hagiwara E. (2001) Ryumachi 41:888 ; Burt RK et al. (2992) Blood 99.7683).
The ability of th_e immune system to distinguish between self and for-eign antigens also plays a critical role in tissue transplantation. The success of a @ransplant depends on preventing ®he immune system of the host recipient from recogn=izing the transplant as foreign and, in some cases, preventing the graft from recognizimng the host tissues as foreign. For ezxample, when a host receives a bone marrow transpMant, the transplanted bone marrow may recognize the new host as foreign, resulting #n graft versus host disease (GVHD). Consequently, the survival of the host dependss on preventing both the rejesction of the donor marrow as well as rejection of the host by the graft immune reaction (see, e.g., Waldmann H et al. (2001) Int. Arch. Allerg—y Immunol. . 126:11) .
Currently, deleterious immune reactions that result in autoimmune diseases and transplant rejections are= prevented or treated using agents such as steroids, a==zathioprine,
anti-T cell antibodies, and more recently, morxoclonal antibodies to Tecell subpopulations. Immunosuppressive drugs stxch as cyclosporin A (CsA), rapamycin, desoxyspergualine and FK-506 are also wideBy used.
Nonspecific immune suppression agers, such as steroids and antibodies to lymphocytes, put the host at increased risk forr opportunisitc infection and development of tumors. Moreover, many immunosuppresssive drugs result in bone demineralization within the host (see, e.g., Chhajed PN et al. (22002) Indian J. Chest Dis. Allied 44:31;
Wijdicks EF (2001) Liver Transpl. 7:937; Ka_ramehic J et al. (2001) Med. Arh. 55:243;
U.S. Patent No. 5,597,563 issued to Beschorrer, WE and U.S. Patent No. 6,071,897 issued to DeLuca HF et al.). Because of the mmajor drawbacks associated with existing immunosuppressive modalities, there is a nee=d for a new approach for treating immune disorders, e.g., for inducing immune toleranc ein a host.
Thus, in another aspect, the invention provides a method for modulating the activity of an immune cell by contacting the ecell with a vitamin Ds compound of formula I or otherwise described herein.
In one embodiment, the present invermtion provides a method for suppressing immune activity in an immune cell by contacting a pathological or non-pathological immune cell with an effective amount of 2 vi_tamin D3 compound of the invention to thereby inhibit an immune response relative @to the cell in the absence of the treatment.
The present method can be performed on cells in culture, e.g., in vitro or ex vivo, or can be performed on cells present in an animal scabject, e.g., as part of an in vivo therepeutic protocol. In vivo treatment can be carried ou—ton a human or other animal subject.
The vitamin D3; compounds of the invention can be tested initially in vitro for their inhibitory effects on T cell proliferation: and secretory activity, as described in
Reichel, H. et al, (1987) Proc. Natl. Acad. S=ci. USA 84:3385-3389; Lemire, J. M. etal. (1985) J. Immunol 34:2032-2035. Alternatively, the immunosuppressive effects can be tested in vivo using the various animal modeIls known in the art and summarized by
Bouillon, R. ez al. (1995) Endocine Reviews 16(2) 232 (Tables 6 and 7). For example, animal models for autoimmune disorders, .£=., lupus, thyroiditis, encephalitis, diabetes and nephritis are described in (Lemire J.M. ( 1992) J. Cell Biochem. 49:26-31; Koizumi
T. et al. (1985) Int. Arch. Allergy Appl. Imme=snol. 77:396-404; Abe J. et al. (1990)
Calcium Regulation and Bone Metabolism 1=46-151; Fournier C. et al. (1990) Clin.
Immunol Immunopathol. 54:53-63; Lemire JM. and Archer D.C. (1991) J. Clin. Invest. -3.9-
87:1103-1107); Lemire, J. ML. et al., (1994) Endocrinology 135 (6):2818-2821; Inaba M. et al. (1992) Metabolism 41 :631-635; Mathieu C. et al. 1992) Diabetes 41:1491-1495;
Mathieu C. et al. (1994) Diabetologia 37:552-558; Lille-vang S.T. et al. (1992) Clin.
Exp. Immunol. 88:301-306, among others). Models for «characterizing immunosuppressuve activity during organ transplantation, e.g., skin graft, cardiac graft, islet graft, are described in Jordan S.C. ef al. (1988) v H errath D (eds) Molecular,
Cellular and Clinical Endocrinology 346-347; Veyron IP. et al. (1993) Transplant
Immunol. 1:72-76; Jordan S.C. (1988) v Herrath D (eds) Molecular, Cellular and
Clinical Endocrinology 334-335; Lemire JM. et al. (1992) T ransplantation 54:762-763;
Mathieu C. et al. (1994) Transplant Proc. 26:3128-3129).
After identifying certain test compounds as effesctive suppresors of an immune response in vitro, these compounds can be used in vivo as part of a therapeutic protocol.
Accordingly, another aspect of the invention provides a method of suppressing an immune response, comprising administering to a subject a pharmaceutical preparation of a vitamin Ds compounds of the invention, so as to inbibit immune reactions such as graft rejection, autoimmune disorders and inflammation.
In one embodiment, the invention provides a method for treating a subject for a : vitamin Ds associated state, wherein the vitamin Ds associated state is an ILT3- associated disorder, by administering to the subject an effective amount of 2 vitamin Ds compound of the invention. In one embodiment, the thme IL T3-associated state is an immune disorder. In certain embodiments, the immune disorder is an autoimmune disorder. In a specific embodiment, the immune disorder is Type 1 diabetes mellitus. In other embodiments, the immune disorder is transplant mrejection.
For example, the subject vitamin D; cormpound of the invention can be used to inhibit responses in clinical situations where it is desirable to downmodulate T cell responses. For example, in graft-versus-host disease, cases of transplantation, autoimmune diseases (including, for example, diabetes mellitus, arthritis (including rheumatoid arthritis, juvenile rheumatoid arthritis, oste=oarthritis, psoriatic arthritis), multiple sclerosis, encephalomyelitis, diabetes, myastimenia gravis, systemic lupus erythematosis, autoimmune thyroiditis, dermatitis (incBuding atopic dermatitis and eczematous dermatitis), psoriasis, Sjdgren’s Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulc er, iritis, conjunctivitis,
keratoconjunctivitis, wulcerative colitis, asthma, allergic asthma, cutaneous Lupus erythematosus, sclerc>derma, vaginitis, proctitis, drug eruptions, leprosy reveersal reactions, erythema nmodosum leprosum, autoimmune uveitis, allergic encepohalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearingz loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, poolychondritis, Wegener's granulomatosis, chronic actiwwe hepatitis,
Stevens-Johnson syneirome, idiopathic sprue, lichen planus, Crohn's diseas-e, Graves ophthalmopathy, sarc=oidosis, primary biliary cirrhosis, uveitis posterior, ard interstitial lung fibrosis). Downemodulation of immune activity will also be desirable in cases of allergy such as, atopi- c allergy.
Another aspecst of the invention provides a method of modulating tie expression of an immunoglobuli-n-like transcript 3 (ILT3) surface molecule in a cell. ~The method includes contacting tlhe cell with a compound of formula I in an amount efffectiveto modulate the express:ion of an immunoglobulin-like transcript 3 (ILT3) sur—face molecule 1S in the cell. In one enxbodiment, cell is within a subject a subject. In anotheer emobidment the modulation is upregulation of expression. In other embodiment, the modulation is downreegulation of expression.
A related aspeect of the invention provides a method of treating an TLT3- associated disorder ir a subject. The method includes administering to the= subject a compound of formula I in an amount effective to modulate the expression - of an ILT3 surface molecule, thereby treating the ILT3-associated disorder in the subj- ect.
In certain emBbodiments, the present invention provides methods aad compositions for treating immune disorders, such as, for example, autoimr—xune disorders and transplant rejections, such as graft versus host disease (GVHD). These embodiments of the invention are based on the discovery that vitamin D3; c=ompounds of the invention are able= to modulate the expression of immunoglobulin-like —transcript 3 (ILT3) on cells, e.g., antigen-presenting cells.
Accordingly, another aspect of the invention provides a method for— inhibiting transplant rejection imn a subject. The method includes administering to the= subject a compound of formulaa I in an amount effective to modulate the expression ofan ILT3 surface molecule, thesreby inhibiting transplant rejection in the subject. In one embodiment, the trarmsplant is an organ transplant. In another embodiment=, the transplant is a pancreatic islet transplant. In yeat another embodiment, the transplant is a bone rmarrow transplant.
As described before, determination of a therapeutical'y effective immumnosuppressive amount can be readily made by the atten _ding clinician, as one skilleA in the art, by the use of known techniques and by observing results obtained under analogous circumstances. Compounds which are deter~mined to be effective in animals, e.g, dogs, rodents, may be extrapolated accordingly= to humans by those skilled inthe art. Starting dose/regimen used in animals can be estirnated based on prior studie=s. For example, doses of vitamin Ds compounds of the= invention to treat autoimmune disorders in rodents can be initially estimated inm the range of 0.1 g/kg/day to 1 gr7kg/day, administered orally or by injection.
Those skilled in the art will know based upon the dat=a obtained in animal studies, the dowsage and route of administration in humans is expectecd to be similar to that in anima ls. Exemplary dose ranges to be used in humans are fr-om 0.25 to 10 pg/day, prefer.ably 0.5 to 5 pg/day per adult (U.S. Pat. No. 4,341,774).
D. Calcium and Phosphate Homeostasis
The present invention also relates to a method of treating in a subject a disorder ) characterized by deregulation of calcium metabolism. This ruoethod comprises contacting a pathological or non-pathological vitamin Ds resgponsive cell with an effective amount of a vitamin D3; compound of the invention to thereby directly or indiresctly modulate calcium and phosphate homeostasis. Techniques for detecting calciu—m fluctuation ir vivo or in vitro are known in the art.
Exemplary Catt homeostasis related assays include =assays that focus on the intesti-ne where intestinal 43Ca2+ absorption is determined either 1) in vivo (Hibberd
K.A.and Norman'A.W. (1969) Biochem. Pharmacol. 18:23487-2355; Hurwitz S. et al. (1967) J. Nutr. 91:319-323; Bickle D.D. et al. (1984) Endocrinology 114:260-267), or 2) in v=itro with everted duodenal sacs (Schachter D. ef al. (1961) Am. J. Physiol 200:12263-1271), or 3) on the genomic induction of calbindin_-D gk in the chick or of calbin-din-Dgy in the rat (Thomasset M. ef al. (1981) FEBS Lett. 127 :13-16; Brehier A. and TBhomasset M. (1990) Endocrinology 127:580-587). The bone-oriented assays includ_e: 1) assessment of bone resorption as determined via t-he release of Ca2t from bone 71 vivo (in animals fed a zero Ca2+ diet) (Hibberd K.A. and Norman A.W. (1969)
Biochezm. Pharmacol. 18:2347-2355; Hurwitz S. et al. (1967) J. Nutr. 91:319-323), or from bone explants in vitro (Bouillon R. et al. (1992) J. Biol. Cheam. 267:3044-3051), 2) mueasurement of serum osteocalcin levels [osteocalcin is an osteotlast-specific protein ®hat after its synthesis is largely incorporated into the bone matrix, but partially released finto the circulation (or tissue culture medium) and thus represents a good market of bone formation or tumover] (Bouillon R. ez al. (1992) Clin. Chem. 38:22055-2060), or 3) bone zsh content (Norman A.W. and Wong R.G. (1972) J. Nutr. 102: 12709-1718). Only one
Kcidney-oriented assay has been employed. In this assay, urinary C a2 excretion is cletermined (Hartenbower D.L. et al. (1977) Walter de Gruyter, Beerlin pp 587-589); this =ssay is dependent upon elevations in the serum Ca2+ level and may reflect bone Ca2t mobilizing activity more than renal effects. Finally, there is a "soft tissue calcification” assay that can be used to detect the consequences of administratio=n of a compound of
She invention. In this assay a rat is administered an intraperitonea_1 dose of 43Ca2™,
Followed by seven daily relative high doses of a compound of the invention; in the event of onset of a severe hypercalcemia, soft tissue calcification can bes assessed by cletermination of the 45Ca2+ level. In all these assays, vitamin D= compounds of the finvention are administered to vitamin D-sufficient or -deficient armimals, as a single dose or chronically (depending upon the assay protocol), at an appropriate time interval
Before the end point of the assay is quantified.
In certain embodiments, vitamin D3 compounds of the inveention can be used to rmnodulate bone metabolism. The language "bone metabolism" is Lntended to include direct or indirect effects in the formation or degeneration of bone =structures, e.g., bone formation, bone resorption, etc., which may ultimately affect the concentrations in sserum of calcium and phosphate. This term is also intended to include effects of vitamin
ID; compounds in bone cells, e.g. osteoclasts and osteoblasts, that may in turn result in tone formation and degeneration. For example, it is known in thes art, that vitamin Dj compounds exert effects on the bone forming cells, the osteoblastss through genomic and ron-genomic pathways (Walters MLR. et al. (1982) J. Biol. Chem. 257:7481-7484;
Yurutka P.W. et al. (1993) Biochemistry 32:8184-8192; Mellon W _S. and DeLuca H.F. (1980) J. Biol. Chem. 255:4081-4086). Similarly, vitamin D3 concapounds are known in tahe art to support different activities of bone resorbing osteoclasts such as the stimulation of differentiation of monocytes and mononuclear phagocytes into osteoclasts (Abe E. er al. (1988) J. Bone Miner Res. 3:635-645; Takahashi N. et al. (1988)
Eendocrinology 123:1504-1510; Udagawa N. ef al. (1990) Proc. Neatl. Acad. Sci. USA
87:7260-7264). Accordingly, vitamin D3 compounds of the invention that modulate the production of bone cells can influence bone fosrmation and degeneration.
The present invention provides a metheod for modulating bone cell metabolism by contacting a pathological or a non-pathologzical bone cell with an effective amount of avitamin Ds compound of the invention to thesreby modulate bone formation and degeneration. The present method can be performed on cells in culture, e.g., in vitro or ex vivo, or can be performed in cells present ir an animal subject, e.g., cells in vivo.
Exemplary culture systems that can be used imclude osteoblast cell lines, e.g., ROS 17/2.8 cell line, monocytes, bone marrow cult-ure system (Suda T. et al. (1990) Med.
Res. Rev. 7:333-366; Suda T. er al. (1992) J. Cell Biochem. 49:53-5 8) among others.
Selected compounds can be further tested in v ivo, for example, animal models of osteopetrosis and in human disease (Shapira =. (1993) Clin. Orthop. 294:34-44).
In a preferred embodiment, a method fFor treating osteoporosis is provided, comprising administering to a subject a pharmaceutical preparation of a vitamin Ds compound of the invention to thereby ameliorate the condition relative to an untreated subject.
Vitamin D3 compounds of the invention can be tested in ovarectomized animals, e.g., dogs, rodents, to assess the changes in bone mass and bone formation rates in both normal and estrogen-deficient animals. Cliniczal trials can be conducted in humans by attending clinicians to determine therapeutically effective amounts of the vitamin D3 compounds of the invention in preventing anc] treating osteoporosis.
In other embodiments, therapeutic applications of the vitamin D; compounds of the invention include treatment of other disea. ses characterized by metabolic calcium and phosphate deficiencies. Exemplary of such d—iseases are the following: osteoporosis, osteodystrophy, osteomalacia, rickets, osteitis fibrosa cystica, renal osteodystrophy, osteosclerosis, anti-convulsant treatment, osteopenia, fibrogenesis-imperfecta ossium, secondary hyperparathyrodism, hypoparathyr-oidism, hyperparathyroidism, cirrhosis, obstructive jaundice, drug induced metabolisrm, medullary carcinoma, chronic renal disease, hypophosphatemic VDRR, vitamin TD-dependent rickets, sarcoidosis, glucocorticoid antagonism, malabsorption symdrome, steatorrhea, tropical sprue, idiopathic hypercalcemia and milk fever. -4e4 -
E. Hormone Secretion
In yet another aspect, the present invention provides a method for modulating hormones secretion of a vitamin Ds- responsive cell, e.g., an endocrine cell. Hormone secretior includes both genomic and non-genomic activities of v=itamin D3 compounds
S ofthe in_vention that control the transcription and processing resgponsible for secretion of a given Faormone e.g., parathyroid hormone (PTH), calcitonin, imsulin, prolactin (PRL) and TRH in a vitamin D; responsive cell (Bouillon, R. et al. (19995) Endocrine Reviews 16(2):23+5-237). “Whe present method can be performed on cells in culture, e.g. in vitro or ex vivo, or on cells present in an animal subject, e.g., invivo. Vitamin D3 compounds of the inventiomn can be initially tested in vitro using primary cultures o f parathyroid cells.
Other sy-stems that can be used include the testing by prolactin secretion in rat pituitary tumor cells, e.g., GHACI cell line (Wark J.D. and Tashjian Jr. A. .H. (1982)
Endocrimwlogy 111:1755-1757; Wark J. D. and Tashjian Jr. AH . (1983) J. Biol. Chem. 258:211=8-2121; Wark JD. and Gurtler V. (1986) Biochem. J. 233:513-518) and TRH secretior in GH4C1 cells. Alternatively, the effects of vitamin ID; compounds of the inventiomn can be characterized in vivo using animals models as dllescribed in Nko M. et al. (1982) Miner Electrolyte Metab. 5:67-75; Oberg FE. et al. (19993) J. Immunol. 150:348=7-3495; Bar-Shavit Z. et al. (1986) Endocrinology 118:6579-686; Testa U. et al. (1993) J= Immunol. 150:2418-2430; Nakamaki T. et al. (1992) 4_nticancer Res. 12:1331- 1337; Weinberg J.B. and Larrick J.W. (1987) Blood 70:994-10022; Chambaut-Guérin
A.M. aned Thomopoulos P. (1991) Eur. Cytokine New. 2:355; Yoshida M. et al. (1992)
Anticancer Res. 12:1947-1952; Momparler R.L. et al. (1993) Leakemnia 7:17-20; Eisman 1.A. (1934) Kanis JA (eds) Bone and Mineral Research 2:45-76;_ Veyron P. et al. (1993)
Transplant Immunol. 1:72-76; Gross ML. et al. (1986) J Bone Mireier Res. 1:457-467;
Costa B.TM. et al. (1985) Endocrinology 117:2203-2210; Koga MA. er al. (1988) Cancer
Res. 48:22734-2739; Franceschi R.T. et al. (1994) J. Cell Physiol_. 123:401-409; Cross
H.S. et axl. (1993) Naunyn Schmiedebergs Arch. Pharmacol. 347 :105-110; Zhao X. and .
Feldman: D. (1993) Endocrinology 132:1808-1814; Skowronski R.J. et al. (1993)
Endocririology 132:1952-1960; Henry FLL. and Norman A.W. (21975) Biochem.
Biophys. Res. Commun. 62:781-788; Wecksler W.R. er al. (1980) Arch. Biochem.
Biophys. 201:95-103; Brumbaugh PF. ef al. (1975) Am. J. PhysFal. 238:384-388;
Oldham SB. et al. (1979) Endocrinology 104:248-254; Chertow~ B.S. et al. 1975) J.
WO) 2005/030222 PCT/US2004/031412
Clin Invest. 56:668-678; Canterbury IM. et al. (1978) J. Clin. Invest. 61:1375-1383;
Quesad J.M. et dl. (1992) J. Clin. Endocrinol. Metab. 758:494-501. : In certain embodiments, the vitamin D3 compourds of the present invention can be used to inhibit parathyroid hormone (PTH) processing, e.g., transcriptional,
S translational processing, and/or secretion of a parathyroid cell as part of a therapeutic protocol. Therapeutic methods using these compounds «can be readily applied to all diseases, involving direct or indirect effects of PTH activity, e.g., primary or secondary responses.
Accordingly, therapeutic applications for the viteamin D3 compounds of the invention include treating diseases such as secondary hy-perparathyroidism of chronic renal failure (Slatopolsky E. et al. (1990) Kidney Int. 38 141-847; Brown A.J. et al. (1989) J. Clin. Invest. 84:728-732). Determination of therapeutically affective amounts and dose regimen can be performed by the skilled artisan using the data described in the art. . E. Protection Against Neuronal Loss
In yet another aspect, the present invention prov-ides a method of protecting against neuronal loss by contacting a vitamin Ds respon_sive cell, e.g, a neuronal cell, with a vitamin D3 compound of the invention to preven® or retard neuron loss. The 2€@ language "protecting against" is intended to include pre—vention, retardation, and/or termination of deterioration, impairment, or death of a meurons.
Neuron loss can be the result of any condition o=f a neuron in which its normal function is compromised. Neuron deterioration can be tthe result of any condition which compromises neuron function which is likely to lead to neuron loss. Neuron function 2-5 can be compromised by, for example, altered biochemisstry, physiology, or anatomy of a neuron. Deterioration of a neuron may include membrane, dendritic, or synaptic changes which are detrimental to normal neuronal functioning. The cause of the neuron deterioration, impairment, and/or death may be unknown. Alternatively, it may be the result of age- and/or disease-related changes which occur in the nervous system of a 3¢Q subject.
When neuron loss is described herein as "age-re=lated”, it is intended to include peuron loss resulting from known and unknown bodily changes of a subject which are associated with aging. When neuron loss is described Inerein as "disease-related", it is intended to include neuron loss resulting from known sand unknown bodily changes of 2 subject which are associated with disease. It should bes understood, however, that these terms are not mutually exclusive and that, in fact, manzy conditions that result in the loss of neurons are both age- and disease-related.
Exemplary age-related diseases associated withm neuron loss and changes in neuronal morphology include, for example, Alzheimer's Disease, Pick's Disease,
Parkinson's Disease, Vascular Disease, Huntington's Disease, and Age-Associated
Memory Impairment. In Alzheimer's Disease patients, neuron loss is most notable in the hippocampus, frontal, parietal, and anterior temporal cortices, amygdala, and the olfactory system. The most prominently affected zone=s of the hippocampus include the
CA region, the subiculum, and the entorhinal cortex. Memory loss is considered the earliest and most representative cognitive change beca-use the hippocampus is well known to play a crucial role in memory. Pick's Disease is characterized by severe neuronal degeneration in the neocortex of the frontal a nd anterior temporal lobes which is sometimes accompanied by death of neurons in the striatum. Parkinson's Disease can be identified by the loss of neurons in the substantia ni gra and the locus ceruleus.
Huntington's Disease is characterized by degeneration of the intrastriatal and cortical cholinergic neurons and GABA-ergic neurons. Parkin son's and Huntington's Diseases are usually associated with movement disorders, but o—ften show cognitive impairment (memory loss) as well.
Age-Associated Memory Impairment (AAMI) is another age-associated disorder that is characterized by memory loss in healthy, elderlsy individuals in the later decades of life. Crook, T. ef al. (1986) Devel. Neuropsych. 2(=4).261-276. Presently, the neural basis for AAMI has not been precisely defined. Howe=ver, neuron death with aging has been reported to occur in many species in brain regions implicated in memory, including cortex, hippocampus, amygdala, basal ganglia, cholinergic basal forebrain, locus ceruleus, raphe nuclei, and cerebellum. Crook, T. ef a. (1986) Devel. Neuropsych. 2(4):261-276.
Vitamin D; compounds of the invention can pr-otect against neuron loss by genomic or non-genomic mechanisms. Nuclear vitamin D3 receptors are well known to exist in the periphery but have also been found in the rain, particularly in the hippocampus and neocortex. Non-genomic mechanisms may also prevent or retard neuron loss by regulating intraneuronal and/or peripheral calcium and phosphate levels. -
Furthermore, vitamin Ds compounds of the invention may prot-ect against neuronal loss by acting indirectly, e.£., by modulating serum PTH levels. For example, a positive * correlation has been demonstrated between serum PTH levels sand cognitive decline in
Alzheimer's Disease.
The present method can be performed on cells in cultumre, e.g. in vitro or ex vivo, or on cells present in an animal subject, €.£., in vivo. Vitamin Ds compounds of the invention can be initially tested in vitro using neurons from embryonic rodent pups {See e.g. U.S. Patent No. 5,179,109-fetal rat tissue culture), or other mammalian (See e.g.
U.S. Patent No. 5,089,517-fetal mouse tissue culture) or non-ryammalian animal models. These culture systems have been used to characterize the protection of peripheral, as well as, central nervous system neurons in animmal or tissue culture models of ischemia, stroke, trauma, nerve crush, Alzheimer’s Disease , Pick's Disease, and
Parkinson's Disease, among others. Examples of in vitro systems to study the prevention of destruction of neocortical neurons include using in vitro cultures of fetal mouse neurons and glial cells previously exposed to various glutamate agonists, such as kainate, NMDA, and o-amino-3-hydroxy-5-methyl-4-isoxazOlepronate (AMPA). U.S.
Patent No. 5,089,517. See also U.S. Patent No. 5,170,109 (treatment of rat cortical/hippocampal neuron cultures with glutamate prior to treatment with neuroprotective compound); U.S. Patent Nos. 5,163,196 and 5,196,421 (neuroprotective excitatory amino acid receptor antagonists inhibit glycine, ka_inate, AMPA receptor binding in rats). ‘
Alternatively, the effects of vitamin Ds compounds off the invention can be characterized in vivo using animals models. Neuron deterior=ation in these model systems is often induced by experimental trauma or intervention (e.g. application of 95 toxins, nerve crush, interruption of oxygen supply).
G. Smooth Muscle Cells
In yet another aspect, the present invention provides =a method of modulating the activity of a vascular smooth muscle cell by contacting a vit=amin Da-responsive smooth muscle cell with a vitamin D3 compound of the invention to activate or, preferably, inhibit the activity of the cell. The language "activity of a smanooth muscle cell” is intended to include any activity of a smooth muscle cell, suc=h as proliferation, migration, adbesion and/or metabolism.
In certain embodiments, the vitamin ID»; compounds of the invention can be used to treat diseases and conditions associated with aberreant activity of a vitamin Ds- responsive smooth muscle cell. For example, the pressent invention can be used in the treatment of hyperproliferative vascular diseases, such as hypertension induced vascular remodeling, vascular restenosis and atherosclerosis. Mn other embodiments, the compounds of the present invention can be used in treating disorders characterized by aberrant metabolism of a vitamin Ds-responsive smooth muscle cell, e.g., arterial hypertension.
The present method can be performed on cellss in culture, e.g. in vitro or ex vivo, or on cells present in an animal subject, e.g., 72 vivo. Vitamin Ds compounds of the invention can be initially tested in vitro as described &n Catellot et al. (1982), J. Biol.
Chem. 257(19): 11256. 4. SUPPRESSION OF RENIN EXPRES. SION
The compounds of the present invention contx=ol blood pressure by the suppression of rennin expression and are useful as antihypertensive agents. Renin- angiotensin regulatory cascade plays a significant roles in the regulation of blood pressure, electrolyte and volume homeostasis (Y.C. Li, Abstract, DeLuca Symposium on
Vitamin Ds, Tauc, New Mexico, June 15 - June 19, 2€02, p. 18). Thus, the invention provides a method of treating a subject for a vitamin 1D; associated state, wherein the vitamin Ds associated state is a disorder characterized by an aberrant activity of a cell that expresses renin. The method includes administexring to the subject an effective amount of a compound of formula I, such that renin e=xpression by the cell is suppressed, and the subject is thereby treated for hypertension. 5. BLADDER DYSFUNCTION
Morphological bladder changes, including a perogressive de-nervation and hypertrophy of the bladder wall are frequent histological findings in patients with different bladder disorders leading to overactive bladder such as bladder disorders associated with, for example, clinical benign prostaticc hyperplasia (BPH) and spinal cord injury.
The increase in tension and/or strain or the bladder observed in these conditions has been shown to be associated with cellular and molecular alterations,
e.g., in cytoskeletal and contractile proteins, in mitochondrial funct=ion, and in various enzyme activities of the smooth muscle cells. The hypertrophy of t=he bladder wall also involves alterations in its extracellular matrix and non-smooth musecle components.
These changes in the bladder are associated with the storages (irritative) symptoms, in particular frequency, urgency, urge incontinence and nocturia. These symptoms affect the social, psychological, domestic, occupational, physical and sexual lives of the patients leading to a profound negative impact on their quality of life.
At the present time, an ideal treatment of these symptoms h_as not been found.
Each of the therapeutic options available (for example, anti-muscarxinics or alpha- blockers) is associated with disadvantages relating to their mechanTism of action, which is based only on the management of symptoms and not on the treatment of the etiology of the condition. In fact, the clinical utility of some of the availablee agents has been limited by poor efficacy and lack of universal patient acceptance due toa number of significant side effects.
As a consequence there is a need for new treatments that pr—ovide improved clinical effectiveness by targeting the underlying etiological factor... the abnormal growth and consequent dysfunction of bladder smooth muscle cells.
As described herein, it has now surprisingly been found tha_t vitamin D analogues can treat and prevent bladder dysfunction in disorders associated with bladder hypertrophy, such as bladder overactivity and clinical BPH. Overactive bladder, also known as detrusor overactivity or detrusor instability... involves involuntary bladder spasms. A hyperactive detrusor muscle can case overactive bladder. Although the underlying cause of overactive bladder can toe neurological disease (e.g., multiple sclerosis, Parkinson's disease, stroke, spinal « cord lesions), nerve damage caused by abdominal trauma, pelvic trauma, or surgery, str—oke, multiple sclerosis, infection, bladder cancer, drug side effects or enlarged prostate (BPH), in many cases the cause is idiopathic, i.e. of unknown cause. :
In addition, such vitamin D related compounds have an appelication in the treatment of irritative voiding symptoms associated with BPH. BPH is associated not only with enlargement of the gland leading to bladder outlet obstru-ction (BOO) and symptoms secondary to this, but also to morphological bladder cha-nges, including a hypertrophy of the bladder wall and progressive de-nervation. The=se changes lead to increased functional demands and dissruption of the coordination within the b' adder smooth muscle cells. 6. PHARMACEUTICAL. COMPOSITIONS
The invention also provides a “pharmaceutical composition, comprisimg an effective amount of a vitamin D3 compound of formula I or otherwise described herein and a pharmaceutically acceptable carrier. In a further embodiment, the effective amount is effective to treat a vitamin MD; associated state, as described previoeusly.
In an embodiment, the vitamir D3 compound is administered to the swubject using a pharmaceutically-acceptable formul ation, e.g., a pharmaceutically-acceptatble formulation that provides sustained deslivery of the vitamin D3 compound to =a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three v=veeks, or four weeks after the pharmaceutically=-acceptable formulation is administereed to the subject.
In certain embodiments, these: pharmaceutical compositions are suita_ble for topical or oral administration to a sub, ject. In other embodiments, as describeed in detail below, the pharmaceutical compositions of the present invention may be spe=cially formulated for administration in solidll or liquid form, including those adaptead for the following: (1) oral administration, for= example, drenches (aqueous or non-acjueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) par—enteral administration, for example, by subciataneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for exarmple, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectal. ly, for example, as a pessary, cream or foam_; or (5) aerosol, for example, as an aqueecous aerosol, liposomal preparation or solid particles containing the compound.
The phrase "pharmaceutically~ acceptable” refers to those vitamin D3 compounds of the present invention, compositionss containing such compounds, and/or d_osage forms which are, within the scope of sound zmedical judgment, suitable for use in contact with the tissues of human beings and anim als without excessive toxicity, irritatior=, 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 v-ehicle, such as a liquid or solid filler, d:iluent,
. excipient, solvent or encapsulating material, involved ira 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 sensse 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-acceptatole 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 tragacanthh; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wamxes; (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 glycerim, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate ard ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (187) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) othe=r non-toxic compatible substances employed in pharmaceutical formulations.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatzives 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-solutole 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), ssorbitol, tartaric acid, phosphoric acid, and the like.
Compositions containing a vitamin Ds compound(s) include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The compositions may conweniently be presented in unit dosage form and may be prepared by any methods we=11 known in the art of pharmacy.
The amount of active ingredient which can be combirmed with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particzular mode of administration. The amount of activee ingredient which can be combdined with a carrier material to produce a single dossage form will generally be that amount of the compound which produces a therapeutic «effect. Generally, out of one hund_xed per cent, this amount will range from about 1 peer cent to about ninety-nine ) 5 percent of active ingredient, preferably from about 5 pexx cent to about 70 per cent, most : prefe=rably from about 10 per cent to about 30 per cent.
Methods of preparing these compositions includlle the step of bringing into association a vitamin Ds 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 D3 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 forma of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and z:acacia or tragacanth), powders, granules, or as a solution or a suspension in an aque=ous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as ar 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 lik—e, each containing a predetermined amount of a vitamin D; compound(s) as an active ingredient. A comppound may also be administered as a bolus, electuamry or paste.
In solid dosage forms of the invention for oral amdministration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sod jum citrate or dicalcium phoss phate, and/or any of the following: (1) fillers or ex tenders, such as starches, lactose, sucrose, glhicose, mannitol, and/or silicic acid; (2) bindeers, such as, for example, carbeoxymethylcellulose, aiginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) lnumectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbeonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) seolution retarding agents, such as paraffin; (6) absomption accelerators, such as quatesmary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcokhol and glycerol monostearate; (8) absorbents, sucha as kaolin and bentonite clay; (9) lubri_cants, such a talc, calcium stearate, magnesium stesarate, solid polyethylene glycols, sodivam lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capswules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed ass fillers in soft and hard-fillead gelatin capsules using such excipients as lactose or milk sugars, as well as high mole=cular 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 birder (for example, gelatin or= hydroxypropylmethyl cellulose), lubricant, inert diluent, pmreservative, disintegreant (for example, sodium starch glycolate or cross-linked sos=dium carboxymmethy] cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistene=d with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutiecal compositions of the prese=nt invention, such as dragees, capsules, pills and granules, ray optionally be scored one prepared with coatings and shells, such as enteric coatingss and other coatings well knoswn in the pharmaceutical-formulating art. They may also bee formulated so as to provide sslow or controlled release of the active ingredient therein ussing, for example, hydroxy —propylmethyl cellulose in varying proportions to provide th_e desired release profile, other polymer matrices, liposomes and/or microspheres. Theey may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizirag agents in the form of sterile solid compositions which camn be dissolved in sterile water, or some other sterile injectable medium immediately Boefore use. These compos&itions may also optionally contain opacifying agents and maay be ofa composition that they release the active ingredient(s) only, or preferxentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner=. Examples of embedding compositions which can be used include polymeric subzstances and waxes.
The active ingredient can also be in micro-encapsulated form, if appropriate, withone or more of= the above-described excipients. “Liquid dosage forms for oral administration of the vitamin TID; compound(s) include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups sand elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for exampole, water or other solvents, solubilizing agents and emulsifiers, such as eths/1 alcohol _, isopropyl alcohol, ethyl czarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butyleme glycol, oils (in particular, cottonseed, groundnut, corn, ge=rm, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethy~lene glycols and fatty acid esters of sorbitan, and mixtures thereof.
In addition to inert diluents, the oral compositiors can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perSfuming and preservative agents.
Suspensions, in addition to the active vitamin D— compound(s) may contain susgpending agents as, for example, ethoxylated isostear—y1 alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bermtonite, agar-agar and tragacanth, and mixtures thereof.
Pharmaceutical compositions of the invention for rectal or vaginal administration ma=y be presented as a suppository, which may be prepared by mixing one or more vitamin D3 compound(s) with one or more suitable non irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a saliicylate, and which is solid at room temperature, but Hiquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
Compositions of the present invention which aree suitable for vaginal administration also include pessaries, tampons, creams. gels, pastes, foams or spray formmulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a vitamin Ds cormpound(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, pat=ches and inhalants. The active vitamin Ds; compounci(s) may be mixed under sterile corditions with a pharmaceutically-acceptable carrier, sand with any preservatives, buf=fers, or propellants which may be required.
The ointments, pastes, creams and gels may coratain, in addition to vitamin Ds cormpound(s) of the present invention, excipients, such as animal and vegetable fats, oilss, waxes, paraffins, starch, tragacanth, cellulose deri~vatives, polyethylene glycols, sili=cones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to za vitamin Ds compound(s), excipients such as lactose, talc, silicic acid, aluminum Exydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sp-rays can additionally contain cusstomary propellants, such as chlorofluorohydrocarbosns and volatile unsubstituted hydrocarbons, such as butane and propane.
The vitamin Ds compound(s) can be alternatively admini=stered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid : particzles containing the compound. A nonaqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are preferred becausse they minimize expo-sing the agent to shear, which can result in degradation of tEne compound.
Ordinarily, an aqueous aerosol is made by formulating arn aqueous solution or suspeension of the agent together with conventional pharmaceuticcally-acceptable carriers and s=stabilizers. The carriers and stabilizers vary with the requiresments of the particular compound, but typically include nonionic surfactants (Tweens, IPluronics, or polyethylene glycol), innocuous proteins like serum albumin, scOtbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or suigar alcohols. Aerosols generally are prepared from isotonic solutions.
Transdermal patches have the added advantage of provieding controlled delivery of a vitamin Ds compound(s) to the body. Such dosage forms can be made by diss olving or dispersing the agent in the proper medium. Absorption enhancers can also be umsed to increase the flux of the active ingredient across the sIkin. The rate of such flux can be controlled by either providing a rate controlling membramne or dispersing the acti-ve ingredient in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solu—tions and the like, are . 20 als contemplated as being within the scope of the invention.
Pharmaceutical compositions of the invention suitable For parenteral administration comprise one or more vitamin D; compound(s) : in combination with one or nore 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 thickenings agents.
Examples of suitable aqueous and nonaqueous carriers which may be employed in tthe pharmaceutical compositions of the invention include water, ethanol, polyols (suech as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectab Je organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, b=y 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. Prewention of the action of microorganisms may be ensured by the inclusion of vaarious antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol seorbic 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 ofthe 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 off a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuss cular injection. This may be accomplished by the use of a liquid suspension of crys=stalline or amorphous material having poor water solubility. The rate of absorption o=f 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-adoministered drug form is accomplished by dissolving or suspending the drug in_ an oil vehicle. : Injectable depot forms are made by forming nmmicroencapsule matrices of vitamin
D3 compound(s) in biodegradable polymers such as poolylactide-polyglycolide.
Depending on the ratio of drug to polymer, and the na: ture of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydridlles). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. }
When the vitamin D3; compound(s) are admini=stered as pharmaceuticals, to humans and animals, they can be given per se or as a gpharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically-acceptable ca rrier.
Regardless of the route of administration selec=ted, the vitamin D3 compound(s), which may be used in a suitable hydrated form, and/onc the pharmaceutical compositions of the present invention, are formulated into pharmacesutically-acceptable dosage forms by conventional methods known to those of skill in thee art.
Actumal dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be vari_ed so as to obtain an amount of tne 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 10 mg per day.
A preferred dose of the vitamin Ds compound for the pre=sent invention is the maximum t8at a patient can tolerate and not develop serious hypercalcemia. Preferably, the vitamin 1D; compound of the present invention is administere=d at a concentration of about 0.001 pg to about 100 pg per kilogram of body weight, at>out 0.001 — about 10 pg/kg or abe out 0.001 pg — about 100 pg/kg of body weight. Ranges intermediate to the above-recite=d values are also intended to be part of the inventiomn.
Exemplific. ation of the Invention
The invention is further illustrated by the following exarmples which should in no way should be construed as being further limiting.
Synthesis osf Compounds of the Invention
Experiment=al .
All eoperations involving vitamin D; analogs were condumcted in amber-colored glassware imn a nitrogen atmosphere. Tetrahydrofuran was distil _led from sodium- benzophenone ketyl just prior to its use and solutions of solutes were dried with sodium sulfate. Me=lting points were determined on a Thomas-Hoover capillary apparatus and are uncorreacted. Optical rotations were measured at 25 °C. 1H] T™NMR spectra were recorded at 400 MHz in CDCl; unless indicated otherwise. TLC was carried out on silica gel pl. ates (Merck PF-254) with visualization under short-——wavelength UV light or by sprayingz the plates with 10% phosphomolybdic acid in methanol followed by heating. Flsash chromatography was carried out on 40-65 um ma: esh silica gel.
Preparative HPLC was performed on a 5x5 0 cm column and 15=-30 um mesh silica gel at a flow rawte of 100 mVmin. The results are summarized in Table 1 for examples 1-10 and 19 (Czo.-natural), and Table 2 for examples 11-18 (C2o-cycloopropyl).
EXAMPEE 1
Synthesis of 1,3-Di-O-acetyl-1,25-dilyydroxy—1 6,23Z-diene-26,27-hexafluoro-19-nor- cholecalciferol (2)
H } , ol Fs wn FF es a — Ju
Ho OH
Ac OAC 1 2
The starting material 1,25-dihydroxy-16,23Z-dE iene-26,27-hexafluoro-19-nor- cholecalciferol (1) can be prepared as describead in US Patent 5,428,029 to Doran et al.. 3mgof 1,25-dihydroxy-16,23Z-diene-26,27-heexafluoro-19-nor-cholecalciferol (1) was dissolved in 0.8 ml of pyridine, cooled to ice-b ath temperature and 0.2 m1 of acetic anhydride was added and maintained at that texruperature for 16 h. Then the reaction mixture was diluted with 1 ml of water, stirred for 10 min in the ice bath and distributed between 5 ml of water and 20 ml of ethyl acetemte. The organic layer was washed with 3 x 5 ml of water, once with 5 ml of saturated sodium hydrogen carbonate, once with 3 ml ofbrine then dried (sodium sulfate) and evapor-ated. The oily residue was taken up in 1:6 ethyl acetate — hexane and flash-chromatogeraphed using a stepwise gradient of 1:6, 1:4 and 1:2 ethyl acetate - hexane. The columm chromatography was monitored by TLC (1:4 ethyl acetate — hexane, spot visualization with phosphomolybdic acid spray), the appropriate fractions were pooled, evaporated, the residue taken up in methyl formate, filtered, then evaporated again to give 23.8 mg of the title compound (2) as a colorless syrup; 400 MHz '"H NMR 6 0.66 (3H, s), 0.90 &(1H, m), 1.06 (3H, 4, J=7.2 Hz), 1.51 (1H, m), 1.72-1.82 (3H,m), 1.9-2.1 (3H, m), 1.99 (3H, s) 2.04 (3H,s), 2.2-2.3 3 m), 2.44-2.64 (6H, m), 2.78 (1H, m), 3.01 (1H, 5), =5.10 (2H, m). 5.38 (1H, m), 5.43 (1H, 4,
J=12 Hz), 5.85 (1H, d, J=11.5 Hz), 5.97 (1H, d-t,J=12 and 7.3 Hz), 6.25 (1H, d,7=11.5
Hz).
EXAMPLE 2
Synthesis of ~ 1,3-Di-O-acetyl-1,25-Dihydroxy-1 6-ene-23-yne-26_,27-hexafluoro-1 9-nor- cholecalcaiferol (4) and 1 ,3,25-Tri-O-acetyl-1 \25-Dikydroxy-= 6-ene-23-yne-26,27- hexafluoro-19-nor-cholecalciferol 4)
Fa h fa Fa a FoC OH I. 5 RC + 5 Fa AC
HOY~"YoH AcOSN"Y0Ae AcON"YoAc 3 4 5
The startings material 1,25-dihydroxy-16-ene-23-yne-26,27-hexzafluoro-19-nor- cholecalcife=rol (3) can be prepared as described in US Patents 5-,451,574 and 5,612,328 to Baggioliriet al.. 314 mg (0.619 mmole) of 1,25-dihydroxy-A 6-ene-23-yne-26,27- hexafluoro- 19-nor-cholecalciferol (3) was dissolved in 1.5 ml o f pyridine, cooled to ice- bath temper—ature, and 0.4 ml of acetic anhydride was added. Tkne reaction mixture was kept at roonm temperature for 7 hours and then for 23 hours in a refrigerator. It was then diluted witte 10 ml water and extracted with 30 m! of ethyl acetzate. The organic extract was washec with water and brine, dried over sodium sulfate ani evaporated. The residue wass FLASH chromatographed on a 10 x 140 mm colur—n with 1:6 and 1:4 ethyl acetate-hex-ane as the mobile phase to give 126 mg of 1,3-Di-O--acetyl-1,25-Dihydroxy- 16-ene-23-sy/ne-26,27-hexafluoro-1 9-nor-cholecalciferol (4), aned 248 mg of 1,3,25-Tri-
O-acetyl-1,=25-Dihydroxy-16-ene-23-yne-26,27-hexafluoro-19--nor-cholecalciferol A).
EXAMPLE 3
Synthezsis of 1,3-Di-O-acetyl-1,25-dihydroxy-1 6-ene-23-yme-cholecalciferol (7) \ \
Ee OH Ta OH
Ho OH Aco™ OAc 6 7
A 10-mL round-bottom flask was charged with =<40 mg of 1,25-dihydroxy-16-ene-23- yne-cholecalciferol (6). This material was dissoslved in 1 mL of pyridine. This solution was cooled in an ice bath then 0.3 mL of acetic manhydride was added. The solution was stirred for 30 min, then refrigerated overnight, d iluted with water and transferred to a separatory funnel with the aid of 10 mL of water and 40 mL of ethyl acetate. The organic layer was washed with 4 x 20 mL of water, 10 mL of brine passed through a plug of sodium sulfate and evaporated. The light brown, oily residue was taken up in 1:9 ethyl acetate - hexane then flash chromatographed on a 10x130 mm column using 1:9 ethyl acetate - hexane as mobile phase for fractions 1-5, 1:6 for fractions 6-13 and 1:4 ethyl acetate - hexane for fractions 14-20 (18 mL fractions). Fractions 14-19 contained the main band with Rf0.15 (TLC 1:4) . Those fractions were pooled and evaporated to a colorless oil, 0.044 g. The mate-rial was taken up in methyl formate, filtered and evaporated to give a colorless, stick~y foam, 0.0414 g of the title compound -O.
EXAMPLE 4
Synthesis of 1,3-Di-O-acetyl-1,25-dihydro=cy-1 6,23E-diene-cholecalciferol (9) 20 . B
ABN ,
H H
Ho OH aco™ OAc 8 . 9 0.0468 g of 1,25-Dihydroxy-16,23E-diene-cholecalciferol (8) was dissolved in 1.5 mL of pyridine. This solution was cooled in an ice bath then refrigerated overnight, diluted with 10 mL of water while still immersed in the ice bath, stirred for 10 min and transferred to a separatory funnel with the aid of 10 mL of water and 40 mL of ethyl acetate. The organic layer was washed with 4x220 mL of water, 10 mL of brine passed through a plug of sodium sulfate and evaporated. The light brown, oily residue was taken up in 1:9 ethyl acetate - hexane then flash chromatographed on a 10x130 mm column using 1:9 ethyl acetate - hexane as mobile phase for fractions 1-3 (20 mL fractions),s 1:6 for fractions 6-8 and 1:4 ethyl acetate - hexane for fractions 9-17 (18 mL each). Frzactions 11-14 contained the main band with Rf 0.09 (TLC 1:4). Those fractions wwere pooled and evaporated to a colorless oil, 0.63153 g. This material was taken up Mn methyl formate, filtered and evaporated, to give 0.014 g of the title .5 compouned (9).
Symmthesis of 1,3-Di-0-acetyl-1 25-dihydroxy-16-ere_e-cholecalciferol (11)
H H )
Bh — I
I
Ho OH aco OAc 10 il ‘0.0774 gz of 1,25-Dihydroxy-16-ene-cholecalciferol (10) was dissolved in 1.5 mL of pyridine_. This solution was cooled in an ice bath then 0.73 mL of acetic anhydride was added. he solution was stirred, refrigerated overnight tlhen diluted with 1 mL of water, stirred for 1 h in the ice bath and diluted with 30 mL of e=thyl acetate and 15 mL of water. The organic layer was washed with 4x15 mL of vvater, once with 5 mL of brine then drie=d (sodium sulfate) and evaporated. The light br-own, oily residue was taken up in 1:9 etThyl acetate - hexane then flash chromatographed on a 10x130 mm column using 1:9 ethy~1 acetate - hexane as mobile phase for fraction 1 (20 mL fractions), 1:6 for fractionss 2-7 and 1:4 ethyl acetate - hexane for fractions 8-13. Fractions 9-11 contained the mair band with Rf 0.09 (TLC 1:4 ethyl acetate - hex=ane). Those fractions were pooled and evaporated to a colorless oil, 0.0354 g. This material was taken up in methyl formate, filtered and the solution evaporated, 0.027 g colorless film, the title compound (1).
EXAMPLE 6
Synthesis of 1 ,3,25-Tri-O-acetyl-1,25-dihycroxy-1 6-ene-23-yne-26,27-hexafluoro- cholecalciferol (13) and 1,3-Di-0-acetyl—1,25-dikydroxy-1 6-ene-23-yne-26,27- hexafluoro-chole=calciferol 14) u, , , \ \ \
CF3 Fs Fs
CCAIR GR + Yn reH
I
Ho™ OH AS OAc aco OAc 12 13 14 0.0291 gof ] 25-dihydroxy-16-ene-23-yne—26,27-hexafluoro-cholecalciferol (12) was dissolved in 1.5 mL of pyridine. This solut-ion was cooled in an ice bath then 0.25 mL of acetic anhydride was added. The solutiosn was stirred for 20 min and kept in a freezer overnight. The cold solution was diluted with 15 mL of water, stirred for 10 min, and diluted with 30 mL of ethyl acetate. The omrganic layer was washed with 4x15 mL of water, once with 5 mL of brine then dried (sodium sulfate) and evaporated. The light brown, oily residue was taken up in 1:6 ethyl acetate - hexane then flash chromatographed on a 10x110 mm columm using 1:6 ethyl acetate - hexane as mobile phase. Fractions 2-3 gave 72.3461 - 72.3285 = 0.0176 g. Evaporation of fractions 6-7 gave 0.0055 g. The residue of fractions 2 — 3 was taken up in methyl formate, filtered and evaporated to give 0.0107 g of the title= triacetate (13). The residue of fractions 6-7 was taken up in methyl formate, filtered arad evaporated to give 0.0049 g of diacetate (14).
030222 PCT/US2004/031412 ’ EXAMPLE 7
Synthe=sis of 1,3-Di-0-acetyl-1,25 -dihydroxy-1 6,23 E-alliene-25R,26-trifluoro~ : cholecalciferol (16) “NaF [crs
H H
A - I
Ho ~"VoH aco OAc 15 16 1.5 mL of 1,25-dihydroxy-16,23E-diene-25R,26-trifluoro—cholecalciferol (15) was dissolved in 1.5 mL of pyridine, cooled to ice-bath tempemrature and 0.4 mL of acetic anhydrides was added. The mixture was then refrigerated. After two days the mixture was dilutesd with 1 mL of water, stirred for 10 min in the ice bath then distributed between M0 mL of water and 30 mL of ethyl acetate. The= organic layer was washed with 4x15 mL of water, once with 5 mL of brine then dried (sodium sulfate) and evaporate=d. The light brown, oily residue was taken up imn 1:6 ethyl acetate - hexane then flasta chromatographed on a 10x130 mm column using 1:6 ethyl acetate - hex ane as mobiles phase. Fractions 4-6 (TLC, 1:4) contained the main band (see TLC) These fractions were evaporated and gave 0.0726 g. This residwae was taken up in methyl formate, filtered and evaporated, to give 0.0649 g of calorless foam, the title compound (16).
EXAMPLE 8
Synthe=sis of 1,3-Di-0-acetyl-1,25-dihydroxy-1 6-ene-M 9-nor-cholecalciferol (18)
H H
J & — J # l
Ho™ OH aco™ OAc 17 18
0.0535 g of 1,25-Dihydroxy-16-ene-~19-nor-cholecal ciferol (17) was dissolved in 1.5 mL of pyridine, cooled to ice-bath temperature and 0.3 ml of acetic anhydride was added and the mixture was refrigerated overnight. The solmution was diluted with 1 mL of water, stirred for 10 min in the ice bath then distribu_ted between 10 mL of water and 30 mL of ethyl acetate. The organic layer was washed —with 4x15 mL of water, once with 5 mL of brine then dried (sodium sulfate) and evaporamted. The nearly colorless, oily residue was taken up in 1:6 ethyl acetate - hexane ass mobile phase for fractions 1-6 then 1:4 ethyl acetate - hexane was used. Fractions 9-19 (TLC, 1:4 ethyl acetate - hexane, Rf 0.09, see below) were pooled, evaporated, to give 00306 g, which was taken up in methyl formate, filtered, then evaporated. It gave 0..0376 of the title compound (18).
EXAMPLE 9»
Synthesis of 1,3-Di-0-Acetyl-1,25-dihydroxy-1 6—ene-23-yne-19-nor-cholecalciferol (20) \ A 4 OH TH OH
Ho OH Acco OAc 19 20 50 mg of 1,25-dihydroxy-16-ene-23-yne-19-nor-ch:olecalciferol (19) was dissolved in 0.8 mL of pyridine, cooled to ice-bath temperature and 0.2 mL of acetic anhydride was added. The mixture was refrigerated for 3 days the=n diluted with 1 mL of water, stirred for 10 min in the ice bath and distributed between S mL of water and 20 mL of ethyl acetate. The organic layer was washed with 4x5 m_L of water, once with 3 mL of brine then dried (sodium sulfate) and evaporated. The nearly colorless, oily residue was taken up in 1:6 ethyl acetate - hexane then flash chromatographed on a 15x120 mm column using 1:6 ethyl acetate - hexane as mobile phase fo-r fractions 1-6, 1:4 for fractions 9-12, 1:3 for fractions 13-15 and 1:2 ethyl acetate - hexamne for the remaining fractions.
Fractions 11-16 (TLC, 1:4 ethyl acetate - hexane, JR0.09, see below) were pooled,
evaporated 76.1487 - 76.1260 = 0.0227 g, taken up in methyl formate, filtered, then evaporated. It gave 0.0186 g ofthe title compound (20).
EXAMPLE 10
Synthesis of 1,3-Di-O-acetyB-1 25-dihydroxy-16-ene-23-yne-26,2 7-~bishomo-19-r10r- cholecalciferol (22) \ =
B OH EE OH
I no OH ao™ OAc 21 22
C10 0.0726 g of 1,25-dihydroxy-L. 6-ene-23-yne-26,27-bishomo-19-nor-ctholecalciferol 1) was dissolved in 0.8 mL of pyridine, cooled to ice-bath temperature =and 0.2 mL of acetic anhydride was added. The solution was stirred in the jce-bath then refrigerated overnight. The solution was ~then diluted with 1 mL of water, stirred for 10 min in the ice bath and distributed betweeen 10 mL of water and 25 mL of ethyl acetate. The » organic layer was washed with 3x10 mL of water, once with 5 mL o=f saturated sodium ’ hydrogen carbonate, once wi-th 3 mL of brine then dried and evaporaated, 33.5512 - 33.4654 = 0.0858 g of a tan Oily residue that was flash-chromatogragphed on a 153120 mm column using 1:6 as mobile phase. Fractions 7-11 (20 mL each) were pooled (TLC 20 . 1:4 ethyl acetate - hexane, R=f 0.14) and evaporated, 67.2834 - 67.26.54 = 0.018 g. This residue was taken up in methyl formate, filtered and evaporated. It ggave 0.0211 g of the title compound (22). .
EXAMPLE 11
Synthesis of 1,3-Di-O-acetyl-1 25-dihkydroxy-20-cyclcopropyl-23-yne-19-nor- cholecalciferol (24) ° wH N\ wH AN % OH ——> % H
Ho OH aco™ OAC . 23 24 0.282 gof 1,25-Dihydroxy-20-cyclopropyl-23-yne-19-nor-ccholecalciferol (23) was dissolved in 0.8 mL of pyridine, cooled to ice-bath tempera—ture and 0.2 mL of acetic anhydride was added and the mixture was refrigerated over—night, then diluted with 1 mL of water, stirred for 10 min in the ice bath and distributed beetween 5 mL of water and 20 mL of ethyl acetate. The organic layer was washed with 3x5 mL of water, once with 5 mL of saturated sodium hydrogen carbonate, once with 3 nL of brine then dried . (sodium sulfate) and evaporated. The oily residue was take=n up in 1:6 ethyl acetate - ) hexane then flash chromatographed on a 15x110 mm colur=in using 1:6 ethyl acetate - hexane as mobile phase for fractions 1-4, 1:4 for fractions 5-12, 1:3 for fractions 13-15 ethyl acetate - hexane for the remaining fractions. Fractionas 7-12 (TLC, 1:4 ethyl acetate - hexane, Rf 0.13) were pooled, evaporated, the resiidue taken up in methyl formate, filtered, then evaporated to give 0.023 g of the title compound (24).
EXAMPLE 12
Synthesis of 1,3,25-Tri-O-acetyl-1,25-dihydroxy-20-cxpclopropyl-23-yne-26,2 7- hexafluoro-19-nor-cholecalciferol (26) and 1 ,3-Di-0-aacetyl-1,25-dihydroxy-20- cyclopropyl-23-yne-26,27-hexafluoro-1 9-nor-c.holecalciferol (27) wH \ 0, AN wH N
CF, CFs Fs i IE FC OH __. I # Fo OH I & Fs OAc
Ho OH Aco™ OAc aco OAc 25 27 26
0.1503 g of 1,25-dihycAroxy-20-cyclopropyl-23-yne-26,27-hexafl -uoro-19-nor- cholecalciferol 25) was dissolved in 0.8 mL of pyridine, cooled to ice-bath temperature and 0.2 mL of acetic anhydride was added. The mixture was reficigerated overnight then diluted with 1 mL of vvater, stirred for 10 min in the ice bath and_. distributed between 5 mL of water and 20 m_L of ethyl acetate. The organic layer was —washed with 3x5 mL of water, once with 5 mI. of saturated sodium hydrogen carbonate, once with 3 mL of brine then dried (sodium su Yfate) and evaporated. The oily residue wans taken up in 1:6 ethyl acetate - hexane then “flash chromatographed on a 15x150 mm column using 1:6 ethyl acetate - hexane as mobile phase for fractions 1-5, 1:4 for the remmaining fractions.
Fractions 3-4 and 6-7 were pooled, evaporated, then taken up in methyl formate, filtered, and evaporated to giv-e 0.0476 g of the title triacetate (26) and 004670 g of the title diacetate (27).
EXAMPLE 13
Synthesis of 1,3-Di—0-acetyl-1 25-dihydroxy-20-cyclopropyl—23-yne-cholecalciferol 29) wH AN wh N
IE HOT IE H
Ho OH Aco™ OA 28 29 } 0.0369 g of 1,25-dihw/droxy-20-cyclopropyl-23 -yne-cholecalcifZerol (28) was dissolved in 0.8 mL of pyridines, cooled to ice-bath temperature and 0.2 nL of acetic anhydride was added and the mixture was refrigerated overnight, then dili_xted with 1 mL of water, stirred for 10 min in whe ice bath and distributed between 5 mL. of water and 20 mL of ethyl acetate. The or-ganic layer was washed with 3x5 mL of w~ater, once with 5 mL of saturated sodium hyc3rogen carbonate, once with 3 mL of brine then dried (sodium sulfate) and evaporated. The oily residue was taken up in 1:6 e=thyl acetate - hexane then flash-chromatograph €d on a 13x110 mm column using 1:6 ethyes1 acetate - hexane as mobile phase for fracctions 1-7, 1:4 ethyl acetate - hexane for th-€ remaining fractions.
Fractions 9—11 (TLC, 1:4 ethyl acetate - hexane) were pooled, evapoprated, taken up in methyl formate, filtered, then evaporated, to give 0.0099 g of the titlle compound (29).
EXAMPLE 14
Synthesis of 1,3-Di-O-acetyl-1,25-dlihydroxy-20-cyclopropyl-=23E-ene-26,27- hexafluoro-19-nor-cholecalciferol (31) wH = a wH == Fs
Fc OH L Fsac OH
H —_— I # :
Ho OH Aco™ OAC 30 3 0.0328 g off 1,25-dihydroxy-20-cyclopropyl-23E-ene-26,27-hexaflumoro-19-nor- cholecalcifeerol (30) 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 refrigzerated overnight.
The soluticon was then diluted with 1 mL. of water, stirred for 10 mimn in the ice bath and distributed between 5 mL of water and 20 mL of ethyl acetate. (Extraction of the aqueous layer gave no phosphomolybdic acid-detectable material). The organic layer was washe=d with 3x5 mL of water, once with 5 mL of saturated socdium hydrogen carbonate, once with 3 mL of brine then cIried (sodium sulfate) and . evaporated, the residue shows Rf 0.25 as the only spot. The oily residue was taken _ up in 1:6 ethyl acetate - he=xane then flash-chromato-graphed on a 13.5x110 mm ceolumn using 1:6 ethyl acetate - he=xane as mobile phase for fractions 1-10. Fractions 4-9 wwere pooled and evaporated, the residue taken up in methy/1 formate, filtered, then ewwaporated to give 0.0316 g ofthe title compound (31).
EXAMPLE 1S
Synthesis of 1,3-Di-0-acetyl-1,25-dihydroxy —20-cyclopropyl-23Z-ene-26,27- hexafluoro-19-nor-cholec=alciferol (33)
FoC, OH Fc OMe 3 3 wH = nH = - i - # J © )
Ho OH Aco™ OAc
Co 32 33 0.80429 g of 1,25-dibydroxy-20-cyclopropyl-23 Z-eme-26,27-hexafluoro-19-nor- chmolecalciferol (32) was dissolved in 0.8 mL of pymridine, cooled to ice-bath temperature amd 0.2 mL of acetic anhydride was added. The scelution was refrigerated overnight.
The solution was then diluted with 1 mL of water, stirred for 10 min in the ice bath and distributed between 7 mL of water and 25 mL of egthyl acetate. The organic layer was weashed with 3x5 mL of water, once with § mL of saturated sodium hydrogen carbonate, ommce with 3 mL of brine then dried (sodium sulfate=, TLC (1:4 ethyl acetate - hexane sheows mostly one spot) and evaporated, flash-chroamatographed on a 15x120 mm co lumn using 1:6 as mobile phase. Fractions 3-6 (20 mL each) were pooled and ev aporated. The residue was taken up in methyl fosrmate, filtered and evaporated, to giwe 0.0411 g of the title compound (33). :
EXAMPLE 1.6
Synthesis of 1,3-Di-O-acetyl-1,25-dihydroxy-2 «-cyclopropyl-cholecalciferol (35) wid vH
OH OH
TW — IE
Ho OH AO OAc 34 35 . 0.03797 g of 1,25-dihydroxy-20-cyclopropyl-cholec alciferol (34) 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 solutior was then diluted with 1 mL of water, stirred for 10 min in the ice bath and distributec 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 witch 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. Fractioms 9-16 (20 mL each) were pooled (TLC 1:4 ethyl acetate - hexane, Rf 0.13) and evapor=ated. This residue was taken up in methyl formate, filtered and evaporated to give ©.0581 g of the title compound (35).
EXAMPLE 17
Synthesis of 1,3-Di-0O-acetyl-1 a,25-dihydroxy-1 6-ene— 20-cyclopropyl-19-nor- cholecalciferol (37)
OH OH
Gi Ac0 1 H pyridine
HO™ OH Acco OAc : 36 a7
To the solution of 1c25-Dihydroxy-16-ene-20-cyclopropy B-19-nor-cholecalciferol 36) (94mg, 0.23 mmol) in pyridine (3mL) at 0°C, acetic anhydride (0.5 mL, 5.3 mmol) was added. The mixture was stirred for 1h, refrigerated for 15h. and then was stirred for additional 8h. Water (10 mL) was added and after stirring £for 15 min. the reaction mixture was extracted with AcOEt : Hexane 1:1 (25 mL), vesashed with water (4x25 mL) and brine (20 mL), dried over Na;SOs. The residue (120 mg) after evaporation of the solvent was purified by FC (15g, 30% AcOEt in hexane) tos give the titled compound (37) (91 mg, 0.18 mmol, 80%). [o]*%= +14.4 c 0.34, EtOE]L UV Amax (EtOH): 242nm (¢ 34349), 250 nm (g 40458), 260 nm (e 27545); HNMR (CDCl): 6.25 (1H, 4, J=11.1
Hz), 5.83 (1H, d, J=11.3 Hz), 5.35 (1H, m), 5.09 (2H, m), 2.82-1.98 (7H, m), 2.03 (3H, 5), 1.98 (3H, s), 2.00-1.12 (15H, m), 1.18 (6H, 5), 0.77 BH, s ),0.80-0.36 (4H, m); Bc : 300 NMR (CDCl): 170.73(0), 170.65(0), 157.27(0), 142.55(0)., 130.01(0), 125.06(1),
1223.84(1), 115.71(1), 71.32(0), 70.24(1), 69.99(1), 559.68(1), 50.40(0), 44.08(2), 41 40(2), 38.37(2), 35.96(2), 35.80(2), 32.93(2), 29_48(3), 29.31(2), 28.71(2), 23.71(2), 228 50(2), 21.56(3), 21.51(0), 21.44(3), 18.013), 12.93(2), 10.53(2); MS HRES
Calculated for CsHagOs M+Na 521.3237. Obserwed M+Na 521.3233.
EXAMPLE 18
Synthesis of 1,3-Di-O-acetyl-1 a,25-hydroxy-1 6-aene-20-cyclopropyl-cholecalciferol 0 G9
OH OH a Ac,O 0 oyrdne
HO™ "0H AcO™ OAc 38 39 )
TT othe solution of 1ot,25-Dihydroxy-16-ene-20-cysclopropyl-cholecalciferol (38) (100 pg, 0.23 mmol) in pyridine (3mL) at 0°C, acetic zanhydride (0.5 mL, 5.3 mmol) was amdded. The mixture was stirred for 2h and then reffrigerated for additional 15h. Water (10 mL) was added and after stirring for 15 min. tine reaction mixture was extracted with
AACOEt : Hexane 1:1 (25 mL), washed with water 4x 25 mL), brine (20 mL) and dried
Over Na;SOs. The residue (150mg) after evaporati on of the solvent was purified by FC (C 15g, 30% AcOEt in hexane) to give the titled concapound (39) (92 mg, 0.18 mmol, 78 4). [v= -14.9 ¢ 0.37, EtOH. UV Amax (EtOH): 208 nm (g 15949), 265 nm (¢
MW 5745); "HNMR (CDCl): 6.34 (1H, 4, J=11.3 H=), 5.99 (1H, d, J=11.3 Hz), , 5.47
C 1H, m), 5.33 (1H, m), 5.31 (1H, 5), 5.18 (1H, m), 5.04 (1H, s), 2.78 (1H, m), 2.64 (1H, rm), 2.40-1.10 (18H, m), 2.05 (3H, 5), 2.01 3H, 5), 1.18 (6H, s), 0.76 (3H, 5 ),0.66-0.24
C 4H, m); *C NMR (CDCl): 170.76(0), 170.22(0)», 157.18(0), 143.02(0), 142.40(0), ~131.94(0), 125.31(1), 125.101), 117.40(1), 115.22(2), 72.97(1), 71.32(0), 69.65(1), =59.71(1), 50.57(0), 44.07(2), 41.73(2), 38.36(2), 37.10(2), 35.80(2), 29.45(3), 29.35(2)= 729.25(3), 28.92(2), 23.80(2), 22.48(2), 21.55(3), >1.50(3), 21.35(0), 17.90(3), 12.92(2) = 10.54(2); MS HRES Calculated for Cs2HysOs M+=Na 533.3237. Observed M+Na 533.3236.
EXAMPLE 19
Synthesis of 1 3-Di-O-acetyl-1,25-dihydroxy-238-yne-cholecalciferol 41) (a AN oH N - OH = OH
Bn — | =H l
Ho" OH AcO™" OAc sS 40 4 0.2007g of 40(0.486 mmol) was dissolved in 2 mL of pyridine. This solution was cooled in an ice bath and 0.6 mL of acetic anhydride was adde=d. The solution was kept in an ice bath for 45 h then diluted with 10 mL of water, stirred for 10 min and equilibrated with 1 0 10mL of water and 40 mL of ethyl acetate. The organ-ic layer was washed with 4x20 mL of water, 10 mL of brine, dried (sodium sulfate) ard evaporated. The brown, oily residue was flash chromatographed using 1:19, 1:9, an d 1:4 ethyl acetate — hexane as stepwise gradient. The main band with Rf 0.16 (TLC H :4 acetate ~hexane) was evaporated to give 1,3-di-O-acetyl-1,25-dihydroxy-23 —yne- cholecalciferol (41) a 1.5 colorless foam, 0.0939 g.
Biological Assays and Data
As described in the following examples, the In_ventors’ finding that calcitriol and
Vitamin D; analogues can have an effect on the growt=h and fimction of bladder cells has been proven in in vitro models by culturing human str-omal bladder cells and has been confirmed in a preclinical in vivo validated model.
EXAMPLE 20
Determination of Maximum Tolercated Dose (MTD)
The maximum tolerated dose of the vitamin D®3 compounds of the invention were determined in eight week-old female C57BL/6 mice (C3 mice/group) dosed orally (0.1 mV/mouse) with various concentrations of Vitamin Dsg analogs daily for four days. Analowgs ~30 were formulated in miglyol for a final concentration ©£0.01, 0.03, 0.1 0.3, 1, 3, 10, 30, 1GD0 and 300 pg/kg whem given at 0.1 mi/mouse p.o. daily. Blood for se=rum calcium assay was drawn by tail bleed on day five, the final day of the study. Serum c=alcium levels were determined using a colorimetric assay (Sigma Diagnostics, procedumre no. 597). The highest dose of analog tolerated without inducing hypercalcemia (s» eram calcium >10.7 mg /dl) was taken as th e maximum tolerated dose (MID). Table 3 shows the relative MTD for various vitamin Dj compounds. Notably, compound (2) has an IMTD that is more than 300 times greater than compound (1). Similarly, compounds (4) and (5) also have a MTD that is considerably greater than their parent compound (3).
EXAMPLE 21
Immunological Assay
Immature dendritic cells (DC) were prepared as described i'nRomani, N. et al. (Romani, N. et al. 1996) J. Immunol. Meth. 196:137). IFN~y production by allogeneic T cell activation in thme mixed leukocyte response (MLR) was determ_ined as described in
Penna, G., et al., J _mmunol, 164: 2405-2411 (2000).
Briefly, peripheral blood mononuclear cells (PBMC) were - separated from buffy coats by Ficoll gradient and the same number (3x10°) of allogeneicc PBMC from 2 different donors were co-cultured in 96-well flat-bottom plates. The vitamimn Ds compounds were added to each of time cultures. After 5 days, [FN-y production in th ie MLR assay was measured by ELIS_A and the results expressed as amount (oM) of test compound required to induce 50% inhibitJion of IFN-y production (ICso). The results are summarized in Table 3.
Table 3
Compound MTD (mice) INF-y pg/kg ICs pM
Ee | on | 0 cPolecalciferol (1, hexafluoro—19-nor-cholecalciferol (2 colecalciferol (3 7,3-Di-O-acetyl-1,2_5-Dihydroxy-16-ene-23-yne-26,27- 525.0 hexafluoro—19-nor-cholecalciferol (4 1,3,25-Tri-O-acetyl-1_,25-Dihydroxy-16-ene-23-yne-26,27- hexaftuoro—19-nor-cholecalciferol (5,
cholecalciferol (7, cholecalciferol (9 1.3-Di-O-acetyl-1,25-dihydroxy-16-ene-cholecalciferol 11 hexafluoro-cholecalciferol (13 7.3-Di-O-acetyl-1,25-dikydroxy-16-ene-23-yne-26,27- EERE hexafluoro-cholecalciferol (14,
Cl : oro-cholecalciferol (16, 1,3-Di-O-acetyl-1,25-dikydroxy-16-ene-19-nor- 3 3.0 cholecalciferol (18) i 1,3-Di-0-Acetyl-1,25-dilydroxy-16-ene-23-yne-19-nor- EERE cholecalciferol (20, 1,3-Di-O-acetyl-1,25-dikydroxy-16-ene-23-yne-26,27- 25.3 bishomo-19-nor-cholecalciferol (22) 1,3-Dt-O-acetyl-1,25-dihydroxy-20-cyclopropyl-23-yne-19- | 802.0 nor-cholecalciferol (24, 1,3,25-Tri-O-acetyl-1,25-dihydroxy-20-cyclopropyl-23- 922.0 ne-26,27-hexafluoro-19-nor-cholecalciferol (26; ae |W 0 * 26,27-hexafluoro-19-nor-cholecalciferol (2 1,3-Di-0-acetyl-1,25-dikydroxy-20-cyclopropyl-23-yne- 30 7.8 cholecalciferol (29) 1,3-Di-0-acetyl-1,25-dihydroxy-20-cyclopropyl-23E-ene- : 0.3 26,27-hexaftuoro-19-nor-cholecalciferol (31) . 1,3-Di-O-acetyl-1,25-dihydroxy-20-cyclopropyl-23Z-ene- 0 0 26,27-hexafluoro-19-nor-cholecalciferol (33 cholecalciferol (35) 1,3-Di-O-acetyl-1a,25-dihydroxy-16-ene-20-cyclopropyl- 10 68.0 19-nor-cholecalciferol (37) 1,3-Di-0-acewl-1a,25-hydroxy-16-ene-20-cyclopropyl- 3 45.0 cholecalciferol (39) 1,3-Di-0-acetyl-1,25-dikydroxy-23-yne-cholecalciferol | 1 [see 41
EXAMPLE 222
Proliferation Assay using Bladde=r Cancer Cell Lines
Bladder cancer cell lines (T24, RT112, HTM 376 and RT4 are human blaaccider cancer cell lines; NHEK are normal human keratinaocytes) were obtained from thhe
European Collection of Cell Cultures (Salisbury, UK). Cells were plated at 3 x ML03 per well, in flat bottomed 96-well plates imm 100 ul of DMEM medium containing: 5% Fetal
Clone I, 50 ug/l gentamicin, 1 mM soclium pyruvate and 1% non-essential amino acids.
After culturing for 24 h at 37 °C in 5% CO2, to allow cells to adhere to the plates., VDR ligands (compounds (2), (4), (5) and other vitamin Dj analogs as shown in Table —4) were added at concentrations ranging from 100 pM to 0.3 pM in 100 pl of above-ment—ioned complete medium. After a further 72 “hoof culture , cell proliferation was measure=d using a fluorescence-based proliferation assay kit. (CyQuant Cell Proliferation Assay Kit,
Molecular Probes, Eugene, OR, USAYD. The IC50 was calculated from the regres -sion curve of the titration data. The results are shown in Table 4.
Table 4.
Et SE : pM) pM) pM) pM) 7s aparece | 546 | 19 | 50 | 45 | 49 hexaflugro-19-nor-cholecalciferol (1 1,3-Di-O-acetyl-1,25-dihydroxy-16,23Z- 55 1 100 20 diene-26,27-hexafluoro-19-nor- cholecalciferol (2, 1,3-Di-0-acetyl-1,25-Dikydroxy-16-ene- 29 15 >100 23-yne-26,27-hexafluoro-19-nor- ’ cholecalciferol (4, ene-23-yne-26,27-hexafluoro-19-nor- cholecalciferol (5
Kr Wl I Mal NL NL 23-yne-cholecalciferol yo diene-cholecalciferol (9, cholecalciferol (11 ene-23-yne-26,27-hexafluoro- cholecalciferol (13 1,3-Di-O-acetyl-1,25-dikydroxy-16-ene- >100 26 >100 19 0.98 23-yne-26,2 7-hexafluoro-cholecaiciferol 14
Ed NNER 16,23E-diene-25R,26-trifluoro- cholecalciferol (16 (sr ll RN NA NL ene-19-nor-cholecalciferol (18, [rl Ml all I NI : 23-yne-19-nor-cholecalciferol (20, 1,3-Di-0-acetyl-1,25-dihydroxy-16-ene- 81.7 7 >100 4.7 23-yne-26,27-bishomo-19-nor- bi cholecalciferol (22, 1,3-Di-O-acetyl-1, ,25-dihydroxy-20- 21.5 18 >100 7 cyclopropyl-23-yne-19-nor- cholecalciferol (24, )
cyclopropyl-23-yne-26,27-hexaflbuoro- 19-nor-cholecalciferol (26, cyclopropyl-23-yne-26,27-hexafluoro- 19-nor-cholecalciferol (2
Berit ll I MA LI Wi opropyl-23-yne-cholecalciferol (29 1,3-Di-O-acetyl-1,25-dihydroxy-20- 243 7 cyclopropyl-23E-ene-26,27-hexafluoro- 19-nor-cholecalciferol (31
Ev a RR cyclopropyl-23Z-ene-26,27-hexafluoro- 19-nor-cholecalciferol (33,
Bert al I EA clopropyl-cholecalciferol (35, 1,3-Di-O-acetyl-1a,25-dihydroxy-16- 17.4 3 ene-20-cyclopropyl-19-nor- cholecalciferol (3 eee | To 20-cyclopropyl-cholecalciferol (39, ee | vw | § cholecalciferol (41
EXAMPLE 23
Inhibition of type 1 diabetes developmerat by VDR ligand administra=tion
The non-obese (NOD)/Lt mice used for the experiments were purchased from
Charles River Laboratories (Calco, Italy). All m ice were kept under specific pathogen- free conditions. Glucose levels in the tail venouss blood were quantified using a
EUROFlash (Lifescan, Issy les Moulineaux, Framnce). A diagnosis of diabete=s was after two sequential glucose measurements higher than 200 mg/dl. 1,3-Di-O-acetyl-1,25-dihydroxy-16,23Z- diene-26,27-hexafluoro-19-rmor- : cholecalciferol (2) was dissolved in ethanol (1 mm g/ml) and then diluted in migglyol 812. = NOD/LLt. female mice were dosed orally with veThicle (miglyol 812) alone or —vehicle containing (2) (0.1 mg/Kg body weight or 0.2 m:g/Kg body weight per os) Sx. /week from 8 to 16 weeks of age and glycemia levels were nonitored until 27 weeks of a_ge. The incidence of disease was significantly lower in nice treated with compound (C2) compared to controls, and the higher dose (0.2 mg/Kg) was the most effectivee as shown in Figure 1 and in Table 5. About 70% of vehicle-treated controls were diabestic by 27 weeks of age compared to only 30% (at the 0.1 r=ng/Kg dose) and 40% (at the= 0.2 mg/Kg dose) of mice treated with compound (2) from 8 to 16 weeks of age. As shovovn in
Figure 2 and Table 6, compound (2), when given at the 0.1 mg/Kg or 0.2 mg/Kg dose, did not affect body weight, which suggests a lack of obvious toxic effects.
Table 5. Percent Type 1 Diabetes Mellitms incidence for compound (2).
Miglyol | Cmpd (2), 0.1 ug/kg p-o. | Cmpd (2), 0.2 ng/kg p.o- —s TT 3 | ___ _=2 tr :
I HE SE EE
—a Ts | 2 t 7 SN I SA EN EE —% | 20 | 2 | 1 —e 1 20 | 2 tt —7 20 | fo | 1 —s 20 | 10 | 4 —s 1 20 |__| 1 —0 | 40 |__| do — 1 eo | 2 | 10 —52 eo | ___ s [10 —33 | eo | __ s0 | 20 —3¢ 60 |__| 20 —2 | eo | _ 4 20 —2 | eo | ___ 40 | 0 —r 70 1 40 | 30
Table 6 NOD mouse body weight (g) at two doses of compound (2).
Cmpd (2) 0.1 ug/kg p.o. | Cmpd 0.2 ug/kg p.o. "5 owe | mor | mas 5 pe | me | mss
ENP TT rT
TI | pas | me | mes
EXPT ET ET
EN rT EYE
ENP ET EE
5 | eur | awe | msm
ENP TE
ENP ET ET
EAP rT ET
ENP ET ETE
ENP rT Er
EXPT ra
ERP ET rT
ENF ET rT
EAP EY Er | mes | ar | ors
EAP rT rT
EXAMPLE 24
The activity of Calcitriol and Vitamin Ds asalogues on the growth and function of bladder cells 5 The Inventors’ finding that calcitriol asad Vitamin D3 analogues can have ar effect on the growth and function of bladder ceells has been proven in in vitro models by culturing human stromal bladder cells. The Imventors confirmed the presence of vitamin
D receptors (VDRs), as previously reported im the literature, on these cells (see bel ow in
Figure 3).
In these models, calcitriol (the activatesd form of vitamin Ds) and other vita_min
D; analogues have been shown to be effectives in inhibiting the basal (Fig 4) growt=h of bladder cells. This activity, never reported be=fore, is dose dependent with an ICsop of 9.8 +7x10™" for calcitriol (1,25-dihydroxycholec- alciferol) (on basal cells).
A similar investigation was performed on a number of other vitamin D compounds and the results (expressed as -Logg ICs ) are shown in the table below_ Data in the table refers to inhibitors effect of the compound on basal human, bladder cel 1 . growth in cells which are not stimulated with testosterone or (in one case) are stimulated. The maximum tolerated dose (MID) in rats is also listed for each compound (Table 7).
Table? ‘ ec dF g/kg 26,27-hexafluoro-19-nor-cholecalcifero cholecalciferol (7) * cholecalciferol (9)*
STO.
Fond id cholecalciferol (11)* 26,27-hexafluoro-cholecalciferol (14)* cholecalciferol (18)* 19-nor-cholecalciferol (20 cyclopropyl-23-yne-26,27-hexafluoro-1 9-nor- cholecalciferol (26, 23-yne-26,27-hexafluoro-1 9-nor-cholecalciferol’ 27)* 23-yne-cholecalciferol (29, 23E-ene-26,27-hexafluoro-19-nor- cholecalciferol (31)* 1,3-Di-O-acetyl-1,25-dihydroxy-20-cyclopropyl- 6.70.36 10
Ed cholecalciferol (33 cholecalciferol (35, cholecalciferol (41
Compounds marked in the table with an asterisk (*)) are those which are of particular interest in the context of the invention (these having the highest —LogICso values for unstimulated cells).
EXAMPLE 25
Ewvaluation of the effect of Vitamin Ds analogues on ladder function in an in vivo model —cyclophosphamide (CYP) induced” chronic IC in rats ’ The rat model of chemical cystitis induced by inEyaperitoneal injection of CYP has been well accepted. CYP is used in clinical practice in the treatment of a number of mal ignant tumors. One of its metabolites, acrolein, is excreted in urine in large conscentrations causing hemorrhagic cystitis associated wvith symptoms of urinary freqquency, urgency and pelvic pain. The inflammatory porocess is characterized by charges in gross histology of bladder, increase in numbe=r and distribution of infl- ammatory cell infiltrates (mast cells, macrophage, PEMNS), cyclo-oxygenase-2 experession and prostaglandin production, growth factor and cytokine production. The rat -model of chemical cystitis closely resembles interstiwtial cystitis, a chronic, painful utirary bladder syndrome and has been used for the tes®ing of therapeutic agents in the pas=t.
This model was used to test the effects of 1,25 -Aihydroxyvitamin Dj analogue in ratss with CYP-induced cystitis. The effects of the treatment on the cystometric par-ameters in a conscious freely moving rat with CYP-@induced cystitis were monitored.
The following cystomefric parameters were recorded im each animal: bladder capacity, fillSing pressure (pressure at the beginning of the bladder filling), threshold pressure (blaadder pressure immediately prior to micturition), milicturition pressure (the maximal bla_dder pressure during micturition), presence or abserce of non-voiding bladder cortractions (increases in bladder pressure of at least 10 cm H,0 without release of urimne), and amplitude of non-voiding bladder contraction.
Animals: Wistar rats weighing 125-175g were —used. Two groups of animals had a tabe implanted into the urinary bladder for intravesical pressure recording. Following rec=overy all animals received three intraperitoneal injections of CYP and subsequently we=re divided into the treatment and sham control groupos.
Treatment group: Rats treated with oral 1,25-diThydroxyvitamin D3 analogue 1,3- di O-acetyl-1,25-dihydroxy-16,23Z-diene-26,27-hexaf Tuoro-19-nor-cholecalciferol 2) for- 14 days (daily dose of 0.1pg/kg)
*e, FC pers
IH
AcO™ OAc
Control group: Rats treated with oral vehiculum (miglyol) in the dose identical to 5 that delivered in the treatment group &Cystometry was performed 24 hours following the last dose of the drug or, vehicul 1m on awake freely moving animals. There were four Sham contreo] animals and three Treated animals.
Method=s Implant=ation of the polyethylene tubing into the urinary bladder:
A lower midline abdominal incision was performed under general inhalation anesthesia (isoflurine with O;) and polyethylene tubing (PE-50, Clay Adams,
Parsippaany, NJ) with the end flared by heat was inserted into the dome of —the bladder and secmured in place with a 6-0 prolene purse string suture. The distal endl of the tubing was heaat-sealed, tunneled subcutaneously and externalized at the back of he neck, out of the amnimal’s reach. Abdominal and neck incisions were closed with 4-C nylon sutures.
Intraperitoneal injection of cyclophosphamide:
Following recovery (5 days) subject animals underwent three intraperitoneal injectiomns of CYP (Sigma Chemical, St. Louis, MO; 75 mg/kg each, intraperitoneal) over thes period of nine days. On the tenth day following the first CYP injection the sham control animals received the vehicle only, whereas the experimental group> were treated with thes 1,25-dihydroxyvitamin Ds analogue 1,3-di-O-acetyl-1,25-dihydroxy-16,23Z- diene-2+6,27-hexafluoro-19-nor-cholecalciferol (delivered using gavage). TEwo weeks followimg the initiation of the treatment animals underwent a conscious cy~stometrogram to assess the function of the urinary bladder.
Cystometrogram:
An animal vwas placed unrestrained in a cage and the catheter was connected via aT-tubetoa pressure transducer (Grass® Model PT300, West Warwick, RI) and microinjection pump (Harvard Apparatus 22, South Natick, MA). A 0.9%c» saline solution was infuse«d at room temperature into the bladder at 2 rate of 10 mh.
Intravesical pressure was recorded continuously using a Neurodata Acquisition System (Grass® Model 15, Astro-Med, Inc, West Warwick, RI). Atleast three reproducible micturition cycles wvere recorded after the initial stabilization period of 25 =-30 min. }
Timeline of an expesriment:
CC La A
Tc SE CN
CYP treatment (€hree doses of 75mg/kg i.p. every 11-17
Fil
CC CR Lc
Results
The data an alysis is summarized in Tables 8 and 9 and Figure 5.
Table 8: Cystometric parameters for the control group
Bl. Cap. #of NVBC | Amplitude
Sl al =
IE FL CN EN
IE LC A LA LI LC EL
I NC J EL EN ES
IE 2 J J ECA
EN LE EC LC LN A
IE EN L.A EE LU
I EN J LJ LA
Fl LE LR EL LB LN
IE LN LA A J CAS LO
OSL LN I CN LL
BI. Cap = bladder capacity (ml), FP = filling pressure (cmH;0), TP = threshold pressure (cmH;0), MP = micturition pressure (cmH:0), # of NVBC = number of non-voiding bladder contractions, amplitude of NVBC = amplitude of non-voiding bladder contraction s
Table 9:Cystometric paramete=rs for the treatment group amplitude
J FO FP a
Eo LC CN I ELI LA LI
IE CN LJ LL. LAN EPS LN
IE CE LA AS CA
Ec LE LC A LN LA LN
OE LJ LN LN LL CO LLIN
IEC A EAN LA LL
Ea EN LN LJ LN CA CI
SE LN LL LN LB CAN CI
IEC RC LN LL CN CN
Changes were noted in a number of c5/stometric parameters. Dramatic reductions in both the number and amplitude of non-voiding bladder contractions were observed in the drug treated animals. Less preonounced but still statistically significant reductions in the filling and threshold pressutres were also recorded. The treatment did not result in a change of the bladder capacity -
Bladder overactivity associated with achronic cystitis manifests itself in frequent contractions of the bladder wall associated with irritative often painful urinary symptoms. The fact that non-voiding bladde=r contractions were reduced both in their frequency and amplitude strongly suggest thaat if the effects on the bladder function in patients with interstitial cystitis will be simil:ar, treatment (c.g. oral treatment) with vitamin D; analogues has a potential to relieve these debilitating symptoms. Reducticon in filling and threshold pressures is significant from a clinical standpoint because the= increased intravesical pressure assoc iated with interstitial cystitis is a condition potentially jeopardizing the upper ur-inary tract. } 5 This example provides a further demonstration that a vitamin Ds analogue, 13- di-O-acetyl-1 25-dihydroxy-16,23Z—diene-26,27-hexafluoro-19-nor-cholecalciferol <Q), . has the ability to treat bladder dysfumction.
Abbreviations
T testosterone
DHT dihydrotestosterone
GF growth factor
BPH benign prostatic hyp<erplasia
BOO Bladder Outlet Obstaruction
AR Androgen receptors
PSA Prostate Specific An tigen
VDR Vitamin D receptor hBC human bladder cells
KGF keratinocyte growth factor
EXAMPLE 26
Effects on BPH cells in vitro
MATERIALS AND METHODS
Materials
Minimum Essential Medium_ (MEM), DMEM-F12 1:1 mixture, Ham's F12 medium, phosphate buffered saline: (PBS), bovine serum albumin (BSA) fraction W, . glutamine, geneticine, collagenase type IV, calcitriol, testosterone (T), dihydrotestosterone (DHT), cypro®erone acetate, and a kit for measuring calcemia.. were purchased from Sigma (St. Louis, MO). Plastic ware for cell cultures was purchas-ed from Falcon (Oxnard, CA). Disposable filtration units for growth media preparatieon were purchased from PBI International (Milan, Italy).
BPH cells
Human BPH cells, prepared , maintained and used as previously described im
Crescioli C, et al. Journal of Clin#cal and Endocrinology Metabolism (2000) 85 pw 2576- 2583, were obtained from prostat-e tissues derived from 5 patients, who underwert suprapubic adenomectomy for BPH, after informed consent and approval by the Local . Ethical Committee. Patients did not receive any pharmacological treatment inthe 3 months preceding surgery.
BPH cell proliferation assay
For all cell proliferation assays, 4x10* BPH cells were seeded onto 12-well plates in their growth medium, starved in re d- and serum-free medium containing 0.1% BSA for 24 h, and then treated with specific stimuli for 48 h. Cells in phenol red- and serum- free medium containing 0.1% BSA were used as controls. Thereafter, cells were trypsinized, and each experimental p oint was derived from hemocytometer counting, averaging at least six different fields for each well, as previously reported (see Crescioli
C, et al. Journal of Clinical and Endocrinology Metabolism (2000) 85 p 2576-2583).
Experiments were performed Lising increasing concentrations (1 0'%-10"M) of calcitriol or vitamin-D analogs with or without a fixed concentration of T (10 nM), KGF or Des(1-3)IGF-I (10 ng/ml). Growth assays were also carried out using a fixed concentration of androgens (10 nM) with or without vitamin-D analogs (1 nM, 10 nM) . or the anti-androgens finasteride (F, 1 nM) and cyproterone acetate (Cyp, 100 aM).
Growth assays were also performed using a fixed concentration of T (10 nM) or GFs (10 ng/ml) with or without the vitamin—D analogs. (10 nM).
In the same experiment, each. experimental point was repeated in triplicate or quadruplicate and experiments were performed 3 times. Results are expressed as % variation (meantSEM) over the maximal T or GF-induced stimulation.
Results
BPH cell proliferation was significantly increased by testosterone (T). When cell growth was stimulated for 48 h with T the inhibitory effects of vitamin-D analogs were even more pronounced (Table 10).
Table 10. Inhibition of testosterone-induced humman BPH cell proliferation by vitamin D analogs expressed as -LogIC50. The= maximum tolerated dose (MTD) of each compound (i.e. the highest non-hypercalc emic dose) in mice is shown.
Compound MTD in CD1 Mouse
Rail — 0 | wwe | 0 [wwe | wT]
IC cd IE
I I EL
I I A RL
I SN
Tw | mwes | T
EXAMPLEE 27
Soft Gelatin Capsule alormulation I
Item Ingredients ng/Capsule 1 Compound (2) from Example 1 10.001-0.02 2 Butylated Hydroxytoluene (BHT) 0.016 3 Butylated Hydroxyanisole (BHA) 0.016 4 Miglyol 812 gs. 160.0
Manufacturing Procedure: 1. BHT and BHA is suspended in Migly~ol 812 and warmed to about 50 °C with stirring, until dissolved. 2. 1,3-Di-O-acetyl-1,25-dihydroxy-16,2=3 Z-diene-26,27-hexafluoro-19-nor- cholecalciferol is dissolved in the solution from step 1 at 50 °C. 3. The solution from Step 2 is cooled at= room temperature. 4. The solution from Step 3 is filled int soft gelatin capsules.
Note: All manufacturing steps are performed under an. nitrogen atmosphere and protected from light.
EXAMPLE 28
Soft Gelatin Capsule Fornmulation LI ;
Item Ingredients mg/Capsule } 1 Compound (2) from Example 1 10.001-0.02 2 di-.alpha.-Tocopherol 0.016 3 Miglyol 812 gs. 160.0
Manufacturing Procedure: 1. Di-a-Tocopherol is suspended in Miglyolll 812 and warmed to about 50 °C with sstiring, until dissolved. 2. 1,3-Di-O-acetyl-1,25-dihydroxy-16,23Z-iene-26,27-hexafluoro-19-nor- chole=calciferol is dissolved in the solution from step 1at 50 °C. 3. The solution from Step 2 is cooled at roo—m temperature. 4. The solution from Step 3 is filled into soft gelatin capsules.
Incomrporation by Reference
The contents of all references (includlling literature references, issued patermts, published patent applications, and co-pendimng patent applications) cited throu ghout this application are hereby expressly inceorporated herein in their entireties by reference. )
Equivalents
Those skilled in the art will recognizee, or be able to-ascertain using no : more= than routine experimentation, many equivalents of the specific embodiments of the inveration described herein. Such equivalents are in—tended with be encompassed by the follo—wing claims.
Claims (1)
1. A vitamin D3 compound of formula I: NG ~~ 6 ORs 1 R7 Pr Xz X4 RY Ry wherein: ) A, is single or double bond; A, is a single, double or triple bond; X; and X, are each independently H; or =CHo, provided X, and X; are not both =CHpy; R, and R, are each independently OC(0)C1-Cs alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl; Rs, Ry and Rs are each independently hydrogen, C1-Cy alkyl, hydroxyalkyl, or haloalkyl, with the understanding that Rs is absent when A; isa triple bond, or R; and Ry taken together with Cp form C3-Cs cycloalkyl; Rs and Ry are each independently alkyl or haloalkyl; and ; Rj; is H, C(0)C;-C, alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; provided that when A, is single bond, Rs is hydrogern and Ry is methyl, then A; is a double or triple bond; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
2. The compound of claim 1, wherein X, is Hy =and X; is =CHa.
3. The compound of claim 1, wherein X; and XZ, are H,.
4, The compound of any preceding claim, wherein A, is a single bond.
S. The compound of any preceding claim, wherein A, is a double bond.
6. The compound of any preceding claim, wherein A; is a single bond.
7. The compound of any preceding claim, wherein A; is a double bond.
8. The compound of any preceding claim, wherein Az is triple bond.
9. The compound of any preceding claim, wherein Rs is hydrogen.
10. The compound of any preceding claim, wherein Ry is Ci-Cq alkyl. 11 The compound of any preceding claim, wherein Ra and Ry, taken together with Capp, form C;-Cs cycloalkyl.
12. The compound of any preceding claim, wherein Rs and Ry, taken together with Cy, form cyclopropyl. :
20 .
13. The compound of any preceding claim, wherein Ry and Rare each independently OC(O)C,;-Cs alkyl.
14. The compound of any preceding claim, wherein R; and Rare each OC(O)CHs.
15. The compound of any preceding claim, wherein Rg and Ryare each independently alkyl or haloalkyl.
16. The compound of any predecing claim, wherein Rs and Ry are each independently methyl or trifluoromethyl.
17. The compound of any predecing claim, w@herein Re and R; are each methyl.
18. The compound of any predecing claim, wherein Rg and Rj are each ethyl.
19. The compound of any preceding claim, wherein Re and R; are each trifluoromethyl.
20. The compound of claim 9, wherein Rg is mmethyl and Ry is trifluoromethyl. ) 10 .
21. The compound of any preceding claim, wherein Rg is H or C(0)C1-C4 alkyl.
22. The compound of any preceding claim, wherein Rs is H.
23. The compound of any preceding claim, wherein Rs is C(O)CHs. 24, The compound of claim 4, wherein Az is a double bond.
25. The compound of claim 4, wherein A; is - a triple bond.
26. The compound of any of claims 24-25, w-herein Rs is H and R, is C,-Cy alkyl.
27. The compound of any of claims 24-26, wherein Ry is methyl.
28. The compound of claim 1 ha-ving formula I-a } 2\ Re OR Ry © J A Xa Xq l-a HzC(0)CO" OC (O)CH3 ' 29. The compound of claim 28, wherein X; is =CH, and Xa is Hb.
30. The compound of claim 28, wherein X; and Xj are each Ha.
31. The compound of any of claims 28-30, wherein A, is a double bond.
32. The compound of any of claizms 28-31, wherein Az is a single bond.
33. The compound of any of claimms 28-31, wherein A; is a double bond.
34. © The compound of any of claiams 28-31, wherein A; is triple bond.
35. The compound of any of claiums 28-30, wherein A, is a single bond and A; is a double bond.
36. The compound of any of claims 28-30, wherein Aj is a single bond and A, is a triple bond.
37. "The compound of any of claims 28-36, wherein Rg is H or C(O)CH; .
38. The compound of any of claixns 28-37, wherein Rs and Ry are alkyl.
. -on2-
39. The compound of any preceding claim 2=8-38, wherein Rg and Ry are methyl.
40. The compound of any of claims 28-38, vevherein Rs and Ry are ethyl.
41. The compound of any of claims 28-37, wvherein Re and Ry are haloalkyl.
42. The compound of claim 41, wherein Rs sand Ry are trifluoroalkyl.
43. The compound of claim 41 or 42, wherein Re and Ry are trifluoromethyl. 44, The compound of any of claims 28-37, wherein Rg is trifluoromethyl ani R7 is methyl.
45. The compound of claim 28, wherein saicl compound is 1,3-Di-O-acetyl- 1,25-Dihydroxy-16-ene-23-yne-26,27-hexafluoro-19-neor-cholecalciferol: N oh => O i FaC : AcO™ OAc
46. The compound of claim 28, wherein saicd compound is 1,3,25-Tri-O- acetyl-1,25-Dihydroxy-1 6-ene-23-yne-26,27-hexafluorco-19-nor-cholecalciferol: Nt CF, = OAC AcO™ OAc
47. The compound of claim 28, wherein said compound is 1,3-Di-O-acetyl- 1,25-dilydroxy-16-ene-19-nor-cholecalciferol: , OH I AcO™ OAC 48 The compound of claim 28, wherein said compound is 1,3-Dj-O-acetyl- 1,25-dilydroxy-16-ene-23-yne-19-nor-cholecalciferol: \ > H II H AcO™ OAc
49. The compound of claim 28, wherein said compound is 1,3-Di-O-acetyl- 1,25-diaydroxy-16,23Z-diene-26,27-hexafluoro-1 9-nor--cholecalciferol:
OH . F3C CFs lw AcO™ OAC
50. The compound of claim 28, wheerein said compound is 1,3-Di-O-acetyl ~ 1,25-dihydroxy-16-ene-23-yne-26,27-bishomos-19-nor-cholecalciferol: Nt = OH H Aco OAC SL The compound of claim 28, wheerein said compound is 1,3-Di-O-acetyR- 1,25-dihydroxy-16-ene-23-yne-cholecalciferol : N\ - OH I H Aco™ OAC
52. The compound of claim 28, wh-erein said compound is 1,3-Di-O-acetyH- 1,25-dihydroxy-16,23E-diene-cholecalciferol: . , \ OH
I . AcO™ OAc
53. The compound of claim 28, whemrein said compound is 1,3-Di-O-acetyl- 1,25-dihydroxy-16-ene-cholecalciferol: OH I = Aco OAc
54. The compound of claim 28, whe=rein said compound is 1,3-Di-O-acetyl- 1,25-dihydroxy-16-ene-23-yne-26,27-hexafluomro-cholecalciferol: A CFs - OH H FsC Aco" OAc
58. The compound of claim 1, wherein said compound is 1,3-Di-O-acetyl- 1,25-dihydroxy-16,23E-diene-25R-26-trifluoram-cholecalciferol: _ CF, OH I ® AcO™ OAC
56. The compound of claim 28, wherein said compound is 1,3,25-Tri-O- acetyl-1,25-dilhydroxy-16-ene-23-yne-26,27-hexafluoro-chole -calciferol: N Fa H FsC OAc . Aco™ OAc
57. The compound of claim 28, wherein said compound is 1,3-Di-O-acetyl- 1,25-dihydrox=y-23-yne-cholecalciferol: wH AN — OH j H : AcO™ OAc
S58. The compound of claim 1having formula I-b 2\ Re ORL A X X 2; 1 . Ib
©. HsC(O)CO OC(O)CH3
59. The compound of claim 58, wherein A, is a sirgle bond.
60. The compound of claim 58, wherein A, is a dosuble bond.
© 61. The compound of any claims 58-60, wherein amd A; is a single bond.
62. The compound of any claims 58-60, wherein Aa, is double bond.
63. The compound of any of claims 58-60, whereim A; is a triple bond.
64. The compound of any of claims 58-63, whereimn X; is =CH,and X; is H.
65._ The compound of claims 58-63, wherein X, amd X; are each H. 66 The compound of any of claims 58-65, whereim Rs is H or C(O)CH, . 67~ The compound of any of claims 58-65 whereir Rg is H. 68- The compound of any of claims 58-67, wherein Rs and Ry are alkyl. 69_ The compound of any of claims 58-67, wherein Rs and R; are methyl. 70_— The compound of any of claims 58-67, wherein Re and Ry are haloalkyl.
71. The compound of any of claims 58-67, whereCn Rs and R; are trifluoroalkyl.
72. The compound of any of claims 58-67, wherefin Rg and R; are trififleoromethyl.
73. The compound of claim 58, wherein said compowund is 1,3-Di-O-acetyl- 1,25-dihydreoxy-20-cyclopropyl-23-yne-19-nor-cholecalciferol: wH > OH :
H . WN AcO’ OAc
74. The compound of claim 58, wherein said compound is 1,3,25-Tri-O- acetyl-1,25—dihydroxy-20-cyclopropyl-23-yne-26,27-hexafluorc>-19-nor-cholecalciferol: wH Sra £4 OAc H FC AcO™ OAC
75. The compound of claim 58, wherein said compound is 1,3-Di-O-acetyl- 1,25-dihydroxy-20-cyclopropy}-23-yne-26,27-hexafluoro-19-neor-cholecalciferol: weil AN CF; = OH ’ ww FaC Aco" OAc
76. The compound of claim 58, wherein said c=ompound is 1,3-Di-O-acetyl- 1,25-dihydroxy-20-cyclopropyl-23-yne-cholecalciferol: wH AN = OH H AcO™ OAc .
77. The compound of claim 58, wherein said « compound is 1,3-Di-O-acetyl- 1,25-dRihydroxy-20-cyclopropyl-cholecalciferol: oH OH I Aco" OAC
78. The compound of claim 58, wherein said compound is 1,3-Di-O-acetyl- 1,25-Clihydroxy-20-cyclopropyl-23E-ene-26,27-hexaflucro-19-nor-cholecalciferol: N<CF. ' wl 3 FsC OH I H Re) AcO’ OAc
PCT/US2004/031-412 :
79. The compound of claim 58, wherein said compound is 1,3-Di-O-acetyl- 1,25-dihydroxy-20-cyclopropyi-23Z-en €-26,27-hexafluoro-19-nor-cholecalciferol: c oH - FaC\LcFs nH . lH Aco™ OAc :
80. The compound of claim 58, wherein said compound is 1,3-Di-O-acetyl- 1,25-dihydroxy-16-ene-20-cyclopropyl-19-nor-cholecalciferol: -
(I. oo AcQ’ OAc 2«) 81. : The compound of claim 5 8, wherein said compound is 1,3-Di-O~acetyl- 1,25-dihydroxy-16-ene-20-cyclopropyl-cholecalciferol: H j = neo OAC
82. Use of a vitamin D3; compound of any one of claims 1-81 in the manufacture of a preparation for treat-ing a subject for a vitamin D; associated state. -101 - . AMENDED SHEET
PCT/US2004/031412 ’ 83. Use of claim 82, ~wherein said vitamin Dj; associated state is an ILT3- associated disorder.
84. Use of claim 83, wherein said ILT3-associated disorder is an immune disorder.
85. Use of claim 84, wherein said immune disorder is an autoimmune disorder.
86. Use of claim 85, wherein said autoimmune disorder is selected from the group consisting of type 1 imsulin-dependent diabetes mellitus, adult respiratory distress syndrome, inflammator=y bowel disease, dermatitis, meningitis, thrombotic thrombocytopenic purpura, Sjogzren’s syndrome, encephalitis, uveitis, uveoretinitis, leukocyte adhesion deficiency, rheumatoid arthritis, theumatic fever, Reiter’s syndrome, psoriatic arthritis, progressive systemic sclerosis, primary biliary cirrhosis, pemphigus, pemphigoid, necrotmzing vasculitis, myasthenia gravis, multiple sclerosis, lupus erythematosus, polymyositis, sarcoidosis, granulomatosis, vasculitis, pernicious anemia, CNS inflammatory disorder, antigen-antibody complex mediated diseases, autoimmune haemolytic anemia_, Hashimoto’s thyroiditis, Graves disease, habitual spontaneous abortions, Reynard_’s syndrome, glomerulonephritis, dermatomyositis, chronic active hepatitis, celiac dlisease, autoimmune complications of AIDS, atrophic gastritis, ankylosing spondylitis and Addison’s disease.
87. Use of claim 84, wherein said immune disorder is transplant rejection.
88. Use of claim 86, wherein said autoimmune disorder is type I insulin dependent diabetes mellitus.
89. Use of claim 82, wherein said vitamin Dj associated state is a disorder characterized by an aberrant act-ivity of a vitamin D;-responsive cell. -102 - AMENDED SHEET
PCT/US2004/03141 2 ‘ 90. Use of claim 89, whnerein said disorder comprises an aberrant activity of a hyperproliferative skin cell.
91. Use of claim 90, whnerein said disorder is selected from psoriasis, basal cell carcinoma and keratosis.
92. Use of claim 89, wherein said disorder comprises an aberrant activity of an endocrine cell.
93. Use of claim 92, wherein said endocrine cell is a parathyroid cell and the aberrant activity is processing and/or secretion of parathyroid hormone.
94. Use of claim 93, wherein said disorder is secondary hyperparathyroidism.
9s. Use of claim 89, wherein said disorder comprises an aberrant activity of a bone cell.
96. Use of claim 95, whe erein said disorder is selected from osteoporosis, osteodystrophy, senile osteoporosis, osteomalacia, rickets, osteitis fibrosa cystica, ancl renal osteodystrophy.
97. Use of claim 89, wh erein said disorder is cirrhosis or chronic renal disease.
98. Use of claim 82, wherein said preparation is administrable in combination with a pharmaceutical ly acceptable carrier.
99. Use of a compound of any one of claims 1 to 81 in the manufacture of a preparation for ameliorating a deregulation of calcium and phosphate metabolism im a subject. -103 - AMENDED SHEET
PCT/US2004/031412 ) 100. Use of claim 99, wherein the deregu:lation of the calcium and phosphate metabolism leads to osteoporosis.
101. Use of a compound of any one of claaims 1-81 in the manufacture of a preparation for modulating the expression of an im=rnunoglobulin-like transcript 3 (ILT3) surface molecule in a cell.
102. Use of claim 101, wherein said cell is within a subject.
103. Use of a compound of any one of cl.aims 1-81 in the manufacture of a preparation for treating an ILT3-associated disorde=r in a subject by modulating the expression of an ILT3 surface molecule.
104. Use of claim 103, wherein said ILT3-associated disorder is an immune disorder.
105. Use of claim 104, wherein said immune disorder is an autoimmune disorder.
106. Use of claim 105, wherein said autcoimmune disorder is type insulin dependent diabetes mellitus.
107. Use of a compound of any one of cl_aims 1-81 in the manufacture of a preparation for inducing immunological tolerance =in a subject by modulating the expression of an ILT3 surface molecule.
108. Use of claim 107, wherein said immunological tolerance is induced in an antigen-presenting cell.
109. Use of claim 108, wherein said anti gen-presenting cell is selected from the group consisting of dendritic cells, monocytes, and macrophages. -104 - AMENDED SHESET
PCT/US2004/031412 ’ 110. Use of a compound of any one of claims 1-81 in the manufacture of a preparation for inhibiting transplant rejection in a subject by modulating the expression of an 1ILT3 surface molecule.
111. Use of claim 110, wherein said transplant is a solid organ transplant.
112. Use of claim 110, wherein said transplant is a pancreatic islet transplant.
113. Use of claim 110, wherein said transplant is a bone marrow transplant. 114, Use of any one of claims 99, 101, 103, 107, or 110, wherein said preparation is administrable by using a ptwarmaceutically-acceptable formulation.
115. Use of claim 114, wherein said pharmaceutically-acceptable formulation provides sustained delivery o f'said vitamin D3; compound to a subject for at least four weeks after administration of” the pharmaceutically-acceptable formulation.
116. Use of a compound of any one of claims 1-81 in the manufacture of a preparation for modulating immunosuppressive activity by an antigen-presenting cell by modulating ILT3 surface molecule expression.
117. Use of any one of claims 99, 102, 103, 107, or 110, wherein said subject is a mammal.
118. Use of claims 101 or 116, wherein said cell is an antigen-presenting cell. 3 119. Use of claim 118, wherein said antigen-presenting cell is selected from the group consisting of dendritic cells, monocytes, and macrophages. - 105 - AMENDED SHEET
PCT/US2004/031412 ) 120. Use of any one of claims 101, 103 , 107, or 110, wherein the expression of said immunoglobulin-like transcript 3 (ILT3) surface molecule is upregulated.
121. Use of any one of claims 82,99, 1 01, 103, 107, or 110, wherein said S preparation is administrable orally.
122. Use of any one of claims 82, 99, 1 01, 103, 107, or 110, wherein said preparation is administrable intravenously.
123. Use of any one of claims 82, 99, 1 01, 103, 107, or 110, wherein said preparation is administrable topically.
124. Use of any one of claims 82, 99, 1 01, 103, 107, or 110, wherein said preparation is administrable parenterally.
125. Use of any one of claims 82, 99, 1 01, 103, 107, or 110, wherein said preparation is effective when administered at a concentration of 0.001 ng/kg of body weight.
126. Use of claim 125, wherein said preparation is 1,3-Di-O-acetyl-1,25- dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor-cholecalciferol (2).
127. Use of claim 125, wherein said preparation is 1,3-Di-O-acetyl-1,25- Dihydroxy-16-ene-23-yne-26,27-hexafluoro-19-mor-cholecalciferol (4).
128. Use of claim 125, wherein said preparation is 1,3,25-Tri-O-acetyl- 1,25-Dihydroxy-16-ene-23-yne-26,27-hexafluoro-19-nor-cholecalciferol (5).
129. Use of claim 89, wherein the disowrder is hypertension.
130. Use of claim 129, wherein the preparation suppresses expression of rennin, thereby treating the subject for hypertension. -106 - AMENDED SHIEET
PCT/US2004/031412
131. Use of claim 89, wherein the disord_er is benign prostate hypertrophy.
132. Use of claim 89, wherein the disord er is neoplastic disease.
133. Use of claim 132, wherein the neop lastic disease is selected from the group consisting of leukemia, lymphoma, melanoma, osteosarcoma, colon cancer, rectal cancer, prostate cancer, bladder cancer, and analignant tumors of the lung, breast, gastrointestinal tract, and genitourinary tract. 1 34. Use of claim 133, wherein the neop lastic disease is bladder cancer. 1 3S. Use of claim 89, wherein the disorder is neuronal loss. 1 36. Use of claim 135, wherein the disor-der is selected from the group consisting of Alzheimer’s disease, Pick’s Disease, Parkinson’s Disease, Vascular Disease, Huntington’s Disease, and Age-Associateed Memory Impairment.
137. Use of claim 89, wherein the disorder is characterized by an aberrant activity of a vitamin Dj-responsive smooth muscles cell.
138. Use of claim 137, wherein the disorder is hyperproliferative vascular ddsease selected from the group consisting of hypertension-induced vascular remodeling, vascular restenosis, and atherosclerosis.
139. Use of claim 137, wherein the disorder is arterial hypertension. 1-40. Use of a compound of any of claims 1-81 in the manufacture of a preparation for preventing or treating bladder dysfunction. 1-41. Use of a compound of formula I: -107 - AMENDED SHEET
PCT/US2004/031412
Be . ® Raz >~_-Rs Rg 1 R7
I. 5S Xs X4 RY R wherein: 4A, is single or double bond; A, is a single, double or triple bond; X; and X; are each independently H, or =CH,, provided X; and X; are not both =CH,; R, and R; are each independently 0C(0)C,;-C, alkyl, OC(O hydroxyalkyl, or OC(O)haloalkyl; Rs, Rs and R; are each independently hydrogen, C,-C, alkyl, hydroxyalkyl, or haloalkyl, with the understanding that Rj is absent when Aj isatrip le bond, or R; and Ry taken together with Co form Cs-Cs cycloalkyl; Rg and Ry are each independently alkyl or haloalkyl; and Rg is H, C(0)C,-C, alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl ; and pharmaceutically acceptable esters, salts, and prodrugs thereof; in the manufactumre of a preparation for preventing or treating bladder dysfunction.
142. Use of claim 140 or 141 wherein the preparatior is formulated in a pharmaceutical composition together with a pharmaceutically aacceptable diluent or carrier.
143. Use of any one of claims 140-142, wherein said compound is a Vitamin D receptor agonist. ;
144. Use of any one of claims 140-143, wherein said bladder dysfunction is characterized by the presence of bladder hypertrophy. -108 - . AMENDED SHEET
PCT/US2004/031412 ) 145. Use of any one of claims 140-144, wherein said bladder dysfunction is overactive bladder.
146. Use of any one of claims 140-145, wherein the subject is male.
147. Use of claim 140-146, wherein the male is «concurrently suffering from
BPH.
148. Use of any one of claims 140-147, wherein the subject is female.
149. Use of any of claims 82-147, wherein the stbject is a mammal.
150. Use of any of claims 82-149, wherein the seabject is human. 16 ISL A pharmaceutical composition, comprising an effective amount of a compound of any one of claims 1-81 and a pharmaceutically acceptable diluent or carrier .
152. The pharmaceutical composition of claim 1 52, wherein said effective amoumtis effective to treat a vitamin Dj associated state.
153. The pharmaceutical composition of claim 1 51, wherein said vitamin D; associated state is an [LT3-associated disorder.
154. The pharmaceutical composition of claim 1 52, wherein said vitamin D; associated state is a disorder characterized by an aberrant activity of a vitamin Ds- respon sive cell.
155. The pharmaceutical composition of claim 1 52, wherein said vitamin D; associated state is bladder dysfunction. -109 - AMENDED SHEET
PCT/US2004/031412 ) ® 156. A packaged formulation feor use in the treatment of a vitamin Dj associated state, comprising a pharmaceutical composition comprising a compound of any one of claims 1-81 and instructions for use in the treatment of a vitamin Ds associated state.
157. The package formulation «of claim 156, wherein said vitamin D3 associated state is an ILT3-associated disorder.
158. The packaged formulatior of claim 156, wherein said vitamin Ds associated state is a disorder characterize=d by an aberrant activity of a vitamin Ds- responsive cell.
159. The packaged formulatiom of claim 156, wherein said vitamin D; associated state is bladder dysfunction.
160. A method of modulating the expression of an immunoglobulin-like transcript 3 (ILT3) surface molecule in a cell, comprising contacting said cell with a compound of any one of claims 1-81 in aan amount effective to modulate the expression of an immunoglobulin-like transcript 3 (ILT3) surface molecule in said cell
161. A method for modulating immunosuppressive activity by an antigen- presenting cell, comprising contacting am antigen-presenting cell with a compound of any one of claims 1-81 in an amount effesctive to modulate ILT3 surface molecule expression, thereby modulating said immunosuppressive activity by said antigen- presenting cell.
162. A compound according tow any one of claims 1 to 81, substantially as herein described with reference to and ass illustrated in any of the examples.
163. Use according to any one of claims 82 to150, substantially as herein described with reference to and as illustrzated in any of the examples. - 110 - AMENDED SHEET
PCT/US2004/031412 . @
164. A composition according to any one ofS claims 151 to 155, substantially as herein described with reference to and as illustrated in any of the examples.
165. A formulation according to any one of claims 156 to 159, substantially as herein described with reference to and as illustrated in any of the examples.
166. A method according to claim 160 or clzaim 161, substantially as herein described with reference to and as illustrated in any of the examples. -111- AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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