MXPA98001943A - Derivatives of calcitriol and its u - Google Patents

Abstract

A method for treating metabolic metabolic diseases such as osteoporosis, as well as other disease states treatable with vitamin D compounds, which comprises administering an effective amount of one or more modified vitamin D compounds. The modified compound contains a typical vitamin D core but with hydrolysable groups in vivo at one or more of the carbon positions 1, 3 and 25. The conversion time of the modified compound to its active form such as calcitriol can be regulated, for this way provide controlled release of the compound in vivo over time, by changing or modifying the hydrolysable groups

Description

CALCITRIOL DERIVATIVES AND THEIR USES Background of the Invention This invention relates to biologically active vitamin D compounds, and more particularly to vitamin D compounds with hydrolyzable groups in one or more of the carbon positions 1, 3 and 25, such as esters of the;, 25-dihydroxyvitamin D3 or esters of 1,25-dihydroxyvitamin D3 analogs and their use to regulate with time the function of l, 25 (OH) 2D3 (or of analogues of l, 25 (OH) 2D3 ) during the treatment of a variety of diseases such as osteoporosis, renal osteodystrophy, hypoparathyroidism or proliferative skin disorders. The lce-hydroxylated metabolites of vitamin D, most importantly the;, 25-dihydroxyvitamin D3, lar, 25-dihydroxyvitamin D2, - are known as highly potent regulators of calcium homeostasis in animals and humans. With the discovery of lar, 25-dihydroxyvitamin D3 as the active form of the vitamin, an intense investigation of analogs of this hormonal form of vitamin D has arisen with the intention of finding analogues that have selective biological activity. As a consequence, many structural analogs of these metabolites, such as compounds with different side chain structures, different hydroxylation patterns or different stereochemistry, have been prepared and tested. Important examples of these analogs are lar-dihydroxyvitamin D3, lar-dihydroxyvitamin D2, various fluorinated side chain derivatives of the;, 25-dihydroxyvitamin D3, 19-nor-vitamin D compounds, and homologous side chain analogs. Several of these known compounds exhibit highly potent activity in vivo or in vitro and some of these have been found to exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity provides these compounds with advantageous therapeutic activity profiles and thus some of these compounds are in use, or have been proposed for use, in the treatment of disease varieties such as renal osteodystrophy, vitamin D resistant rickets, osteoporosis, psoriasis and certain malignancies. Various forms of osteoporosis are known, for example post-menopausal, senile and steroid-induced osteoporosis, one of the characteristics of which is the loss of bone mass. Women at the time of menopause suffer a marked loss of bone mass eventually leading to osteopenia, which in turn leads to fractures with spontaneous crush of the vertebrae and fractures of the long bones. This disease is generally known as post-menopausal osteoporosis and presents a major medical problem, both in the United States and in most other countries where the average life of women reaches ages of at least 60 and 70 years. In general, the disease that is often accompanied by bone pain and decreased physical activity is diagnosed by one or two vertebral crush fractures, with evidence of decreased bone mass. It is known that this disease is accompanied by decreased ability to absorb calcium, decreased levels of sex hormones, especially estrogen and androgen, and a negative balance of calcium. Similar symptoms of bone loss characterize senile osteoporosis and osteoporosis induced by steroids, the latter being a recognized result of long-term glucocorticoid (cortico-steroid) therapy in certain disease states. The methods for treating osteoporosis have varied considerably, but to date there is still no satisfactory total treatment. A conventional treatment consists of administering a calcium supplement to the patient. However, the calcium supplement itself has not been successful in preventing or curing the disease. Another conventional treatment is the injection of sex hormones, especially estrogen, which has been reported to be effective in preventing the rapid loss of bone mass experienced in post-menopausal women. This technique however has been complicated by the fear of its possible carcinogenicity. Other treatments for which variable results have been reported have included a combination of vitamin D in large doses, calcium and fluoride. The main problem with this approach is that fluoride induces structurally non-firm bone called tissue bone and furthermore, produces a number of side effects, such as an increased incidence of fractures and gastrointestinal reaction to the large amounts of fluoride administered. Another suggested method is to block bone resorption by injecting calcitonin or providing phosphonates. The U.S. Patent No. 4,255,596 suggests the use of various vitamin D3 metabolites to increase the absorption and retention of calcium in the body of mammals that exhibit evidence of or have a physiological tendency to bone loss. The metabolites specifically named in that patent, namely lar-dihydroxyvitamin D3, lar-dihydroxyvitamin D2, the, 25-dihydroxyvitamin D3 (calcitriol), lar, 25-dihydroxyvitamin D2, and 1,25,25-trihydroxyvitamin D3 although are capable of the activity described and claimed in this patent, however, can also cause hypercalcemia, especially if they are used with the conventional calcium supplement. The treatment of calcitriol has been found to be effective in reducing bone loss in women with post-menopausal osteoporosis, by increasing the absorption of intestinal calcium and reducing bone resorption. Aloria et al. "Calcitriol in the Treatment of Postmenopausal Osteoporosis" (Calcitriol in the treatment of post-menopausal osteoporis), Amer. Jour. of Med., Volume 84, March, 1988. p. 401-408. Again, however, Aloria and colleagues oppose the use of oral doses of calcitriol due to the risk of hypercalcemia. Therefore, the use of calcitriol to treat osteoporosis has not been widely accepted. Another important consideration is that calcitriol in vivo is produced slowly and continuously by the kidney and is thus available during the day and night. When administered orally or by injection, large quantities are available to the tissues initially, but it is left soon after two or four hours due to metabolism and excretions. A process by which calcitriol may become available in vivo more slowly and more continuously would avoid peaks and valleys in the availability of calcitriol, thus providing an effective in vivo level of the compound over a longer period of time and also avoiding or substantially reducing episodes of hypercalcemia that often result from the sudden availability of excessive amounts of the substance. SUMMARY OF THE INVENTION The present invention provides a method for modulating and regulating the in vivo activity of biologically active vitamin D compounds, such as calcitriol or calcitriol analogue. More specifically, this invention provides modified vitamin D compounds that exhibit a convenient and highly advantageous pattern of biological activity in vivo, i.e. more gradual onset and longer duration of activity. As a consequence of these advantageous properties, these compounds represent novel therapeutic agents for the treatment of all diseases wherein the vitamin D compounds have been shown to be effective, such as metabolic bone diseases or proliferative skin disorders (psoriasis) and will have to demonstrate be especially useful for the treatment of diseases where bone formation is desired, such as osteoporosis (post-menopausal, senile or induced by steroids), osteomalacia or renal osteodystrophy. Structurally, the key feature of modified vitamin D compounds having these convenient biological attributes is that they are derivatives of lar, 25-dihydroxyvitamin D3 or derivatives of lar analogues, 25-dihydroxyvitamin D2, wherein a hydrolyzable group is connected to the hydroxy group at carbon 25 and optionally any other hydroxy groups present on the molecule. Depending on various structural factors -, for example the type, size, structural complexity - of the attached group, these derivatives are considered and hydrolyzed in lar, 25-dihydroxyvitamin D3 or a lar analogue, 25-dihydroxyvitamin D2, at different speeds in vivo, thus providing the "slow release" of the biologically active vitamin D compound (ie 1, 25-dihydroxyvitamin D3 or its analog 1, 25-dihydroxyvitamin D2) in the body. The "slow release" in in vivo activity profiles of these compounds can of course be further modulated by the use of mixtures of derivatives (eg mixtures of different derivatives of 1,25-dihydroxyvitamin D3 or different derivatives of analogues of 1.25- dihydroxyvitamin D2) or the use of mixtures consisting of one or more vitamin D derivatives together with non-derived vitamin D compounds. It is important to note that the critical structural characteristic of the vitamin derivatives identified above is the presence of a hydrolysable group connected to the hydroxy group on carbon 25 of the molecule. The presence of a hydrolysable group in that position imparts in the resulting derivatives the convenient "slow release" biological activity profile mentioned above. Other hydroxy functions that occur in the molecule (for example hydroxy functions in carbons 1 or 3) may be present as free hydroxy groups, or one or more of them may also be derived with a hydrolysable group. The fact that the introduction of a hydrolyzable group into carbon 25 of the vitamin D molecule markedly modulates the pattern of biological activity in vivo of the resulting derivative was not previously appreciated. Considering the importance of this specific modification and the demonstration of its marked and highly beneficial biological effects form the basis of this invention. The "hydrolyzable group" present in the aforementioned derivatives is preferably an acyl group, ie a group of the type Q1C0-, wherein Q1 represents hydrogen or a hydrocarbon radical of 1 to 18 carbon atoms which can be straight chain, cyclic, branched, saturated or unsaturated. Thus, for example, the hydrocarbon radical can be a straight or branched chain alkyl group, or a straight or branched chain alkenyl group with one or more double bonds, or it can be an optionally substituted cycloalkyl or cycloalkenyl group or an aromatic group , such as phenyl, benzyl or substituted or unsubstituted naphthyl. Especially preferred acyl groups are alkanoyl or alkenoyl groups, of which some typical examples are formyl, acetyl, propanoyl, hexanoyl, isobutyryl, 2-butenoyl, palmitoyl or oleyl. Another convenient type of hydrolyzable group is the hydrocarbyloxycarbonyl group ie a group of the type Q2-0-CO-, wherein Q2 is a hydrocarbon radical of 1 to 18 carbon atoms as defined above. Exemplary of these hydrocarbon radicals are methyl, ethyl, propyl and higher straight-chain or branched alkyl and alkenyl radicals, as well as aromatic hydrocarbon radicals such as phenyl or benzoyl. Among the modified vitamin D compounds having the convenient in vivo activity profile indicated above, a particularly important and preferred class are certain acyl ester derivatives of calcitriol, ie the calcitriol derivatives characterized by the following structural formula: wherein X1 and X2 independently represent hydrogen or an acyl group, and wherein X3 represents an acyl group as previously defined. Two other very important groups of modified vitamin D compounds are the corresponding acyl esters of the calcitriol side chain homologs, and the acyl derivatives of the 19-ñor-1, 25-dihydroxy vitamin D analogues. The present invention therefore provides a series of modified vitamin D compounds that are useful for the treatment of metabolic bone disease (such as various forms of osteoporosis, osteomalacia, osteodystrophy, etc.) or of differentiating diseases such as psoriasis or malignancies. More specifically, a method for treating these diseases comprises the administration of an effective amount of the aforementioned acyl ester derivatives of lar, 25-dihydroxyvitamin D3 or of the corresponding derivatives of lar analogs, 25-dihydroxyvitamin D2. The above compounds can be administered alone or in combination with other pharmaceutically acceptable agents. Doses of not less than about 0.5 μg per day to not more than about 10 μg per day of the individual compound per se, or in combinations, are generally effective. This method has the distinct advantage that it will retard bone mass due to the conversion of these compounds to calcitriol which has been shown to be effective in the treatment of osteoporosis. Furthermore, these compounds will be less likely to advantageously cause hypercalcemia or hypocalcemia after the non-derivatized compounds even if a compound is administered continuously on a daily basis, provided that the appropriate compounds and dosages are employed, it being understood that the compounds and the levels Dosage will be adjusted depending on the response of the subject as verified by methods known to those with skill in the specialty. The above method, which involves the administration of the indicated doses of these compounds is effective in restoring or maintaining bone mass, and thus provides a novel method for the treatment or prevention of various forms of osteoporosis such as post-menopausal osteoporosis, osteoporosis. senile and osteoporosis induced by steroids. It will be apparent that the method will find easy application for the prevention or treatment of disease states other than those named, where the loss of bone mass is an indication. Also, it will further be apparent that the method will find easy application for the prevention or treatment of hypercalcemia and hypocalcemia, since the conversion rate of these analogues, ie the hydroxylation process in vivo can be controlled and regulated in the manner described above. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph illustrating the activity of di- and tri-acetates of lar, 25-dihydroxyvitamin D3 in serum calcium and particularly illustrates the percent of milligrams of calcium found in blood with time; and Figure 2 is a graph similar to Figure 1, except that it illustrates the activity of 25-mono-acetate-lar, 25-dihydroxyvitamin D3 in serum calcium. Description of the Invention The present invention provides novel modified vitamin D compounds that are useful in the treatment of metabolic bone diseases, such as osteoporosis, as well as other disease states. These modified vitamin D compounds are hydrolysable in vivo to calcitriol, or calcitriol analogs, over a period of time after administration, and as a consequence regulate the availability in vivo of active calcitriol or calcitriol analogues, thus modulating their profile as well. of activity in vivo. The term "activity profile" refers to the biological response over time of vitamin D compounds, such as calcitriol or calcitriol analogs. Individual modified compounds or mixtures of these compounds can be administered for "fine-tuning" of a desired response course in time. As used here, the term "vitamin D compound" encompasses compounds having ring C, ring D and ring 3S-hydroxycyclohexane A of vitamin D, interconnected by the double bond system 5, 7 diene vitamin D together with any side chain connected to the D. ring. In other words, the vitamin D compounds encompassed herein include those having a "vitamin D" core comprising unsubstituted or substituted rings A-, C- and D- interconnected by a double bond system 5, 7 typical vitamin D diene together with a side chain connected to the D ring. As used herein, the term "modified vitamin D compounds" encompasses any vitamin D compound in which one or more of the hydroxy functions present in this compound are modified by derivatization with a hydrolysable group. A "hydrolysable group" is a hydroxy modifying group that can be hydrolyzed in vivo such that the free hydroxy functions are regenerated. In the context of this description, the term "hydrolyzable group" preferably includes acyl and hydrocarbyloxycarbonyl groups, ie groups of the type Q1C0- and Q2-0-C0, respectively, wherein Q1 and Q2 have the meanings given above. Structurally, the modified vitamin D compounds covered can be represented by the formula: wherein R5 and R6 each represent hydrogen, or together R5 and R6 represent a methylene group. The side chain group R in the structure shown above represents a steroid side chain of the following structure: wherein the stereochemical center (corresponding to C-20 in the steroid numbering) can have the R or S configuration, (ie already be the natural configuration with respect to carbon 20 or the opposite non-natural configuration) and where Z is chosen from Y, -OY, -CH20Y, -C = CY and -CH = CHY, where the double bond can have the cis geometry or trans and where Y is chosen from the radical of the structure: - (CH2) m wherein m and n independently represent the integers from 0 to 5, wherein R1 is chosen from hydrogen, OX4, fluorine, trifluoromethyl, and alkyl having 1 to 5 carbon atoms, which may be straight or branched chain and optionally contain a hydroxy substituent , and wherein R2 is selected from hydrogen, fluorine, trifluoromethyl, and alkyl having 1 to 5 carbon atoms, which may be straight or branched chain and optionally contain a hydroxy substituent, and wherein R3 and R4 independently represent trifluoromethyl or alkyl with 1 to 5 carbon atoms, which may be straight or branched chain and optionally contain a hydroxy substituent, and wherein R1 and R2 together represent an oxo group or an alkylidene group, = CR2R2, or = CR2R3 or the group - ( CH2) p-, where p in is an integer from 2 to 5 and where R3 and R4 together represent the group - (CH2) -, where q in is an integer from 2 to 5. In the structures shown above X1 , X2 and X4 independently represent hydrogen no, an acyl group or a hydrocarbyloxycarbonyl group, and X3 represent an acyl group or a hydrocarbyloxycarbonyl group, as previously defined herein. Some specific examples of these modified vitamin D compounds include calcitriol derivatives such as: lar, 25 (OH) 2-D3-l, 3, 25-Triacetate wherein X1 = X2 = X3 = CH3CO; lar, 25 (OH) 2-D3-l, 3,25-Trihexanoate wherein X1 = X2 = X3 = CH3 (CH2) 4CO; lar, 25 (OH) 2-D3-l, 3,25-Trinonanoate wherein X1 = X2 = X3 = CH3 (CH2) 7C0; lar, 25 (OH) 2-D3-l, 3,25-Acetate where X1 = X2 = H and X3 = CH3CO. The following examples, which are intended to be illustrative only, describe the process for the synthesis of modified vitamin D compounds. In these examples, specific compounds identified by the Arabic numerals (for example compounds 1, 2, 3, ... etc.) refer to the structures so numbered below. Additionally, examples are provided that are illustrative of the distinctive biological characteristics in the new compounds, these characteristics serve as a basis for the application of those compounds in the treatment of metabolic bone disease and other diseases responsive to vitamin D such as psoriasis.

X1 = X2 = X3 = H X1 = X = X3 = CH3CO XX = X2 = X3 = CH3 (CH2) 4CO X1 = X2 = X3 = CH3 (CH2) 7C0 X1 = X2 = (CH3) 2CHCO; X3 = H X1 = X = CH3 (CH2) 4CO, X3 = H X1 = X2 = (C6H5CO, X3 = H8: X1 = X2 = H, X3 = CH3CO EXAMPLE 1 Preparation of Mono-, Di- and Tri-Esters of the, 25 ( OH) 2-D3 Experimental Spectra are obtained in the following instruments: UV absorption spectrum (ultraviolet) were taken with the Perkin Elmer lambda 3B UV / vis spectrophotometer Spectrum nuclear magnetic resonance (NMR) were recorded at 400 or 500 MHz with a Bruker DMX spectrometer Chemical shifts (s) are reported downstream of Me4Si (s 0.00) Mass spectra are recorded at 70 eV in a Kratos MS-50 TC instrument equipped with a Kratos DS-55 data system. preparative thin layer (plc) is carried out with Merk silica gel plates 1-mm F-254 and E.Merk silica gel plates 0.25 mm F-254 General Procedure for the Preparation of Triesters: Preparation of larvae , 25 (OH) 2-D 3-1,3, 25-Acetate X1 »X2 = H and X3 = CH3CO. A solution of glacial acetic acid (0.05 mL, 0.87 mmol), trifluoroacetic anhydride (0.05 mL, 0.35 mmol) is stirred at room temperature 3.5 h. Then lar, 25 (OH) 2-D3 (1) (0.3 mg, 0.00072 mmol) in 0.4 mL dry THF is added to the above solution at 0 ° C. The reaction mixture is stirred at 0 ° C for 0.5 h and then at room temperature for 2 h. The solvent is removed under reduced pressure to give a crude product which is purified twice by preparative thin layer chromatography (p.l.c. 15% EtOAc / hexane) to give a pure compound (2) (0.122 mg, 31.3% yield). UV? Max 265 nm (EtOH). X H NMR (CDCl 3): O, 0.51 (s, 3 H, C-18-CH 3), 0.92 (d, J = 5.0 Hz, 3 H; C21-CH3), 1.42 (s, 6H, C26f27-CH3), 1.98, 2.04, 2.06 (s, 9H, CH3CO-), 5.04 (s, ÍH, C19 E, H), 5.18 (m, ÍH, C3- H), 5.31 (s, ÍH, C19 ZH), 5.48 (t, J = 6 Hz, C -H), 5.91 (6.35 (dd, J = 10 Hz, C6 / 7-H), MS: m / z 542 (M +) 482 (M + -60), 422 (M + -2 x 60), 362 (M + 3 x 60), lar, 25 (OH) 2-D3-l, 3,25-Trihexanoate (3) X1 = X2 = X3 = CH3 (CH2) 4CO To hexanoic acid (0.15 mL, 1.20 mmol) add trifluoroacetic anhydride (0.1 mL 0.71 mmol) The mixture is stirred at room temperature for 4 h (the solution is turned to pale brown) After lar, 25 (OH) 2-D3 (1) (0.4 mg, 0.00096 mmol) in 0.2 mL dry THF is added, the reaction mixture is stirred at room temperature for 2 h or until complete (as verified by thin layer chromatography) The product (3) (0.217 mg, 31.72% yield) is processed as the previous example and purified by plc (three times, 8% EtOAc / Skellysolve B). UV? max 265 nm 245nm (shoulder) (EtOH). X H NMR (CDCl 3): s, 0.51 (s, 3 H, C-18-CH 3), 0.89 (t, J = 6.3 Hz, 9 H; CH 3 CH 2) 4 CO), 0.92 (d, j = 6.3 Hz, 3 H C 21 -CH 3 ), 1.42, (S, 6H, C26 / 27CH3) / 5.14 (s, ÍH, C19 EH), . 18 (m, ÍH, C3-H), 5.32 (s, ÍH ,. C19 Z-H), 5.47 (t, J = 6.3 Hz, lH, C1-H), 5,916.34 (dd, J = 11.15 Hz, C6 / 7-H), MS: m / z 710 (M +) 594 (M + -116) ^ 5! COOH), 478 (M + -2 x 116), 362 (M + 3 x 116). la, 25 (OH) 2-D3-1,3,25-Trinonanoate (4) X1 = .X2 = X3 = CH3 (CH2) 7CO. To nonanoic acid (0.2 mL, 1145 mmol) trifluoroacetic anhydride (0.08 mL 0.566 mmol) is added, and the mixture is stirred at room temperature for 4 h. After lar, 25 (OH) 2-D3 (1) (0.4 mg, 0.00096 mmol) in 0.2 mL dry THF is added, the reaction mixture is stirred at room temperature for 4 h or until complete (as determined by TLC). . The usual processing of the product (4) (0.283mg, 35.2% yield). UV? Max 265.3 nm 243.9 nm (shoulder) (EtOH): lE NMR (CDCl3): C, 0.51 (s, 3H, C-18-CH3), 0.88 (t, J = 6.2 Hz, 9H; CH3 CH2) 7C0 -), 0.92 (d, j = 6.3 Hz, 3H C21-CH3), 1.42, (s, 6H, C26 / 27CH3), 5.04 (s, ÍH, C19 EH), 5.18 (m, ÍH, C3-H) , 5.32 (s, ÍH, C19 ZH), 5.49 (t, J = 6.2 Hz ^ H ^ -H), 5,916.34 (dd, J = 11.36 Hz, C6 | 7-H), MS: m / z 836 (M +) 678 (M + -158), CH 3 (CH 2) 7COOH), 520 (M + -2x158), 362 (M + -3 x 158). General Procedure for the Preparation of Diesters: Preparation of the, 25 (OH) 2-D 3-l, 3, -diisobutyrate (5) X1 = X2 = (CH3) 2 CHCO, and X3 = H; A solution of isobutyric acid (0.06 mL, 0.647 mmol), N, N-dicyclohexylcarbodimide (35.55 mg, 0.173 mmol) 4-pyrrolidinopyridine (6.12 mg, 0.04 mmol) and lar, 25 (OH) 2-D3 (1) (0.4 mg, 0.00096 mmol) in 0.15 mL of dry dichloromethane is stirred at room temperature overnight (12 h). The white precipitate formed was filtered and the residue was washed with dichloromethane. The combined organic solution is concentrated and the crude product is purified twice by (5_) (296mg, 55.33% yield). UV? Max 266.5 nm, 244 nm (shoulder); X H NMR (CDCl 3): s, 0.49 (s, 3 H, C-18-CH 3), 0.93 (d, J = 6.25 Hz, 3 H, C 21 -CH 3), 1.14 (t, J = 6.3 Hz, 12 H, CH 3) 2 CHCO-), 1.21 (s, 6H, C26 27-CH3), 5.05, (s, C19, E, H), 5.17 (m, ÍH, C3-H), 5.35 (s, ÍH, C19 ZH), 5.5 (t, J = 6.3 Hz, ÍH, C -.- H), 5.91 6.35 (dd, J = 11.35 Hz, 2H, C6 7-H), MS: m / z 556 (M +) 468 (M + -88 , CH3) 2CHCOOH), 380 (M + -2 x 88), 362 (M + -2 x 88 -H20). la, 25 (0H) 2-D 3-1,3, -dihexanoate (6) X - * - = X 2 = (CH 3) (CH 2) 4 CO, X 3 = H; A solution of n-hexanoic acid (0.15 mL, 1.19 mmol), N, N-dicyclohexylcarbodimide (73.66 mg, 0.358 mmol) 4-pyrrolidinopyridine (4.45 mg, 0.03 mmol) and lar, 25 (OH) 2-D3 (1) (0.5 mg, 0.00012 mmol) in 0.1 mL of dry dichloromethane is stirred at room temperature overnight (12 h).

After processing as in the preceding example, the crude product is purified by p.l.c. (3 times) to give a crude product 15% EtOAc / skellysolve B) (5) and (0.79 mg, 10.74% yield). UV? Max 263.6 nm, 240 nm (EtOH); lE NMR (CDCl 3): G, 0.51 (s, 3 H, C-18-CH 3), 0.89 (d, J = 6.4 Hz, 6 H, CH 3 (CH 2) 4-C 0), 0.93 (d, J = 6.25 Hz, 3H, C21-CH3), 1.21 (s, 6H, C26 / 27-CH3), 5.04, (s, ÍH C19, E, H), 5.18 (m, ÍH, C3-H), 5.30 (s, ÍH, C19 ZH), 5.49 (t, J = 6.2 Hz, ÍH, -H), 5.92 6.34 (dd, J = 11.26, 2H, C6 # 7-H), MS: m / z 612 (M +) 496 (M + - 116, CH3) (CH2) 4C00H), 478 (M + -116-H20), 380 (M + -2 x 116), 362, (M + -2 x 116-H20). lar, 25 (0H) 2-D 3-l, 3, -dibenzoate (7) X1 = X2 = C6H5C0, X3 = H.A; A solution of benzoic acid (15.53 mg, 0.127 mmol), N, N-dicyclohexylcarbodimide (42.64 mg, 0.206 mmol) 4-pyrrolidinopyridine (2.13 mg, 0.0144 mmol) and lar, 25 (OH) 2-D3 (1) (0.51 mg, 0.00123 mmol) in dry dichloromethane (0.4 mL) is stirred at room temperature for 12 h. After processing as before, the crude product is purified by p.l.c. (2 times) to give a pure product 8% EtOAc / skellysolve B) (7) and (0.123mg, 16.4% yield). UV? Max 265.4 nm, 230.5 nm (EtOH); X H NMR (CDCl 3): s, 0.28 (s, 3 H, C-18-CH 3), 0.91 (d, J = 5.0 Hz, C21-CH 3), 1.21 (s, 6 H, C26.27-CH3) < 5-13 '(s' 1H C19, E-H), 5.47 (m, ÍH, C19-Z-H), . 51 (m, ÍH, C3-H), 5.82 (t, J = 6.2 Hz, ÍH, Cx-H), 5.93 6.45 (dd, J = 10, C6 7-H), 7.41, 7.54, 8.04 (m, 10 H, Ar-H). MS: m / z 624 (M +) 606 (M + -H2 =) (M + -122, C6H5 COOH), 380 (M + -2 x 122), 362, (M + -2 x 122-H20). la, 25 (OH) 2-D 3-l, 3, -Acetate (8) X1 = X2 = H, X3 = CH3CO; lar, 25 (0H) 2-D3-l, 3,25-triacetate (2) (0.168 mg, 0.00031 mmol), is dissolved in 1 mL of 0.6% methanolic solution of potassium carbonate. After the mixture is stirred at room temperature for 2 h (or until complete by TLC) it is removed under reduced pressure. The crude product is purified by p.l.c. (50% EtOAc / hexane) to give a pure product (8) (0.056mg, 39.4% yield). UV? Max 265 nm, (EtOH); XH NMR (CDCl 3): C, 0.54 (s, 3H, C-18-CH 3), 0.92 (d, J = 5 Hz, C21-CH 3), 1.42 (s, 6H, C26 # 27-CH 3), 1.98, (s, 3H, CH3CO), 4.24 (m, ÍH, C3-H), 4.44 (t, J = 6 Hz, C? -H), 5.01 6.34 (s, ÍH, C19 EH), 5.34, (s, ÍH, C19 ZH) 6.02, 6.39 (dd, J = 10 Hz, 2H, C6 7-H), MS: m / z 458 (M +) 440 (M + H20), 422, (M + -2 x H20), 398 (M + -60, CH3COOH), 380 (M + -60-H2O), 362 (M + -60-2 x H20). EXAMPLE 2 This example illustrates the serum calcium response of rats over time to three compounds, namely lar25 (OH) 2D3-1, 3, 25-triacetate, lar25 (OH) 2D3-1, 3-diacetate and lar25 ( OH) 2D3 (not esterified). In this biological test, rats were fed a diet containing calcium (0.47% calcium) deficient in vitamin D for a period of 8 weeks to deplete vitamin D. Each was given a single oral dose of 1,000 pmol or 1 nanomole of each of the compounds, and serum calcium was determined by drawing blood from the rats at various times as illustrated in Table 1. Figure 1 is a graph illustrating the data in Table 1. Because Calcium is present in the diet and therefore in your intestine, the rise or increase of calcium in the serum represents substantial absorption of intestinal calcium. The results clearly show that 1,3-diacetate and the non-esterified calcitriol produce essentially the same response course in times, illustrating that the acetylation of hydroxy groups C-1 and C-5 does not significantly alter the biological response, supposedly due to that the acyl groups in these positions are rapidly removed, for example by digestive enzymes. In marked contrast, the triacetate does not begin to show a response until 12 to 18 hours after the dose reaching a peak at 24 hours. In this way, the 25-acetate group is probably intact over a longer period and then hydrolyzed slowly within the body. In this way, the triacetate clearly retards the use of calcitriol indicating that the activity profile of the main calcitriol in vivo can be changed very markedly by oscillation of the C-25 hydroxy group.

TABLE 1 (A) (B) Time Control 1.25 (OH "D, Diacetate 0 Hours 4.3 ± 0.07 8 Hours 6.06 + 0.89 5.42 ± 0.90 12 Hours 7.39 + 0.10 6.50 + 0.13 18 Hours 6.97 + 0.51 6.24 + 0.51 24 Hours 6.45 ± 0.50 5.98 + 0.43 48 Hours 4.43 ± 0.18 5.59 ± 0.80 5.11 + 0.48 TABLE 1 (Cont) (O Time Control Triacetate 0 Hours 4.3 + 0.07 8 Hours 4.06 ± 0.38 12 Hours 4.70 ± 0.12 18 Hours 5.91 + 0.30 24 Hours 6.7 + 0.54 48 Hours 4.43 ± 0.18 5.10 + 0 .43 All data = average + SD (A) of (B), NS Dif. (A) of (C), at 8 hours, 12 hours, p < 0.001 EXAMPLE 3 This example illustrates the serum calcium response of rats over time to two compounds ie 25 (OH) 2D3 (unesterified) and lar25 (OH) 2D3-25-acetate, administered by three different methods, that is, orally (orally), intramuscularly (IM), and subcutaneously (Sub Cu.) In this test, a nanomole of each compound is administered to rats deficient in vitamin D, which is dosed 0.47% calcium, 0.3% P of diet in 0.1 ml of 95% propylene glycol / 5% ethanol There were at least 4 rats per group Calcium serum was determined at various times illustrated in Table 2 after a single dose administered r the indicated route. Figure 2 is a graph illustrating the data of Table 2. The results are in agreement with those of Example 2. Irrespective of the administration route lar25 (OH) 2D3-25-acetate shows a more gradual onset of activity in vivo and a delayed peak of activity. In this way, 25-monoacetate clearly retards the use of calcitriol, confirming that the presence of a C-25-O-acyl group has a pronounced effect on the activity pattern and the course of response time of a biologically active vitamin D compound active.TABLE 2 Serum calcium response to lar25 (0H) 2D3 and its 25-acetate Calcium in Serum (mcr / 100 ml) Compound Route Administration Day 1 Day 3 None 5.9 + 0.34 - (Control) 1.25- Oral 9.33 + 0.41 - (0H) 2D3 1.25- Oral 7.70 ± 0.11 8.87 + 0.6 (OH) 2D3 25-Acetate 1.25-I.M. 8.10 ± 0.24 9.17 + 0.53 (OH) 2D3 25-Acetate 1.25- Sub. Cu, 7.78 + 0.28 9.00 + 0.28 (OH) 2D3 25-Acetate TABLE 2 (Cont) Calcium response in Serum to lar25 (OH) 2D3 and its 25-acetate Calcium in Serum (mcr / 100 ml) Compound Route Administration Day 6 Day 10 None 5.7 + 0.34 5.2 + 0.63 (Control) 1.25- Oral 8.6 + 0.52 7.15 + 0.68 (OH) 2D3 1.25- Oral 8.54 + 0.15 8.83 ± 0.71 (OH) 2D3 25-Acetate 1.25-I.M. 9.77 + 0.3 (OH) 2D3 25-Acetate 1.25- Sub. Cu. 9.84 + 0.39 (OH) 2D3 25-Acetate The modified vitamin D compound or combinations thereof can be easily administered as sterile paraenterior solutions by injection or intravenously, or by alimentary canal in the oral or transdermal dosage form or by suppository. Dose of about 0.5 microgram to about 10 micrograms per day of the modified vitamin D compound per se, or in combination with other modified vitamin D compounds, the proportions of each of the compounds in the combination depend on the particular disease state that is It serves and the degree of bone mineralization and / or bone mobilization desired, are generally effective in practicing the present invention. In all cases, sufficient amounts of the compound should be used to restore bone mass. Amounts exceeding approximately 10 micrograms per day of the modified vitamin D compound or the combination of that compound with other modified vitamin D compounds, generally unnecessary to achieve the desired results, may result in hypercalcemia, and may not be economically reasonable. In practice, higher doses are used where the therapeutic treatment of a disease state is the desired end while the lower doses, in general, are used for prophylactic purposes with the understanding that the specific dose administered in any given case will be adjusted in accordance with the specific compounds administered, the disease to be treated, the condition of the subject and other relevant medical facts that may modify the activity of the drug or the response of the subject, as is well known to those skilled in the art. In general, either a single daily dose or divided daily doses may be employed, as is well known in the art. Dosage forms of the various compounds can be prepared by combining them with pharmaceutically acceptable non-toxic carriers to make either immediate-release or slow-release formulations, as is well known in the art. These carriers can be solid or liquid such as for example corn starch, lactose, sucrose, peanut oil, olive oil, sesame oil and propylene glycol. If a solid carrier is employed, the dosage form of the compounds may be tablets, capsules, powders, troches or lozenges. If a liquid carrier is employed, the dosage form may be soft gelatin capsules, or liquid syrups or suspensions, emulsions or solutions. The dosage form may also contain adjuvants, such as preservatives, stabilizers, humectants or emulsifiers, solution promoters, etc. They may also contain other therapeutically valuable substances. The modified vitamin D compounds may also include any of the following compounds wherein one or more hydroxy functions that may be present are modified by derivatization with a hydrolysable group in vivo.

P represents hydrogen, alkyl or acyl; X represents part of the side chain of vitamin D or one of its established analogues; Y and Y ', which may be the same or different, represent hydrogen or alkyl or when taken together represent an alkylidene group, or form a carbocyclic ring; - VI and VI ', which may be the same or different, represent hydrogen or alkyl or when taken together represent an alkylidene group, or form a carbocyclic ring; One of the carbon atoms of the central part corresponding to positions 14, 13, 17 or 20, together with the substituents R and R 'connected thereto, can be replaced by an oxygen (0), sulfur (S) or nitrogen that it has a substituent R and (NR). R and R '(ie, R, R1 # R2, R'3, R4, R'4, R5, R'5): ° when located at a relative position 1.3 on the central chain, such as R? and R3 or R'3, R2 or R'2 and R4 or R'4, R3 or R'3 and R5 or R'5, taken together with three adjacent atoms of the central chain corresponding to positions 8, 14, 13 or 14, 13, 17 or 13, 17, 20 respectively, can form a saturated, unsaturated, carbocyclic or heterocyclic 3-, 4-, 5-, 6- or 7- membered ring. also including cases in which R and R 'substituted gemimals taken together form a cyclic unsaturated bond, under the condition that when R and R'3 form a carbocyclic ring of 6 members of the following nature (1) unsubstituted and saturated, (2) monosubstituted at C-ll or (3) with a double bond between C-9 and C-ll, R2 and R4 do not form a 5-membered carbocyclic ring when R3 is methyl, ethyl or ethenyl. ° when they are located in a relative position 1,1 (ie neighborhood) on the central chain such as R-, ^ and R2 or R'2, R2 or R'2 and R3 or R'3, R3 or R'3 and R4 or R'4, R4 or R'4 and R5 or R'5 and when it is not part of a ring as described above, are taken together with two adjacent atoms of the central chain, corresponding to positions 8, 14, or 14, 13 or 13, 17 or 17, 20 respectively, can form a 3-, 4-, 5-, 6- or 7- membered, saturated or unsaturated, carbocyclic or heterocyclic ring, which also includes cases in those R and R 'substituted gemals taken together form a cyclic unsaturated bond. ° When they are located in a relative position 1.1 (ie geminal) on the central chain such as R2 and R'2 and R2 or R3 and R'3 or R4 and R'4 or R5 and R'5 and when not are part of a ring as described above, taken together with the carbon containing the R and R 'substituents, can form either a 3-, 4-, 5-, 6- carbocyclic or a saturated or unsaturated heterocyclic ring. Which may be the same or different, and when they do not form a ring or a bond as described above, represent hydrogen or a lower alkyl group, or when taken together in the case of geminal substitution, they represent a lower alkylidene group. In the context of the invention, the term "lower alkyl group" denotes a straight or branched saturated or unsaturated carbon chain containing from 1 to 7 carbon atoms, and "lower alkylidene group" indicates a saturated or unsaturated carbon chain , straight or branched containing 1 to 7 carbon atoms which is connected to one of the main chain atoms 14, 13 and / or 20 through a double bond. In the context of the invention, part of the side chain of vitamin D or one of its established analogues represents an alkyl chain substituted with 2 to 15 carbon atoms, especially as presented in D2 (C-22 to C-28) or D3 (C-22 to C-27) or partially modified as illustrated below with the numbering of vitamin D, especially: hydroxyl substituent in one or more positions, for example 24, 25 and / or 26 and / or - methyl or ethyl substituent in one or more positions, for example 24, 26 and / or 27 and / or one or more halogen substituents in a or more positions, for example perfluorinated in the positions 26 and / or 27 or difluorinated at position 24 and / or - one or several additional carbon atoms especially C-24 between positions 24 and 25, with the same aforementioned substitution pattern and / or ester derivatives of one or more hydroxyl substituents mentioned above and / or changing one or more carbon atoms by an oxygen, nitrogen or sulfur atom for example at positions 22, 23 or 24 and / or cyclized between carbon atoms 26 and 27 by a bond (cyclopropane ) or by the intermediary of 1 to 4 carbon atoms, the ring may be saturated, unsaturated or aromatic and may optionally be substituted in any or any "possible positions with the aforementioned and / or cyclized substituent between the carbon atoms 26 and 27 by the 4 carbon atoms to form a heterocyclic ring, including aromatic, which may optionally be substituted in any possible position with the abovementioned substituent When unsaturated and / or unsaturated with one or more double or triple CC bonds, these unsaturated chains can be substituted in any possible position by the aforementioned substituents and / or epoxide function can be present between carbon atoms 22, 23 or 23, 24 or 24, 25 or 25, 26; these epoxidized chains can be saturated or unsaturated and can be substituted in any possible positions with the aforementioned substituents and / or two or more of the carbon atoms of the side chain can be linked by a single bond or by the intermediary from 1 to 5. carbon or oxygen atoms, nitrogen or sulfur atoms, to form a carbocyclic or heterocyclic ring including aromatic, saturated or unsaturated of 3 to 7 members, which can optimally be substituted in any possible position, by substituents mentioned above and / or substituted in one or more positions by a saturated, unsaturated heterocyclic or aromatic carbocyclic ring which may be substituted in any or any possible positions with the aforementioned substituents, isomeric forms of the substituted chain. Therefore the invention relates to a series of analogs with widely varying structures. More often, the compounds of the invention are represented by one of the formulas: nde: X, Y, Y ', W and W have the same meaning as before: Z represents a saturated or unsaturated hydrocarbon chain consisting of zero (therefore Z represents a bond between two carbon atoms 1, 3 related of the central chain) one, two, three or four atoms, which may then be substituted and / or replaced by a heteroatom such as oxygen, sulfur and nitrogen. Rl, R, R 2 1 31 R 3 / R 4 / R 4 / R 5/5 ° which may be the same or different, represent hydrogen or lower alkyl such as methyl, ethyl or n-propyl. Among those preferred cyclic derivatives of the type: where: n is an integer equal to 2 or 3; X represents one of the following side chain portions of vitamin D: (4-hydroxy-4-methyl) pentyl, (R) - or (S) - (3-hydroxy-4-methyl) pentyl, (3'-hydroxy) -3'-methyl) butyloxy, (4-hydroxy-4-ethyl) hexyl, (4-hydroxy-4-methyl) -2-pentyl, (4'-hydroxy-4'-ethyl) hexyloxy; 4,5-epoxy, 4-methyl-2-pentynyl; 4-hydroxy-4-ethyl-2-hexinyl; (3-methyl-2, 3-epoxy) -butyloxy; (3-hydroxy-3-ethyl) -pentyloxy; (4-hydroxy-4-ethyl) -hexyloxy Y, Y ', W and W are the same and represent hydrogen or together represent a methylene group = CH2; R1 # R2, R'2, R3, R'3, R4, R'4, R5, R'5 which may be the same or different, represent hydrogen or methyl.

Claims (49)

1. CLAIMS 1.- A vitamin D derivative that provides the in vivo gradual release of a biologically active vitamin D compound and thus regulates the in vivo availability and activity profile of the biologically active vitamin D compound, the vitamin D derivative has the structure: wherein each of R5 and R6 represents hydrogen, or together R5 and R6 represent a methylene group, and wherein R is represented the structure: where the stereochemical center at carbon 20 of the side chain can have the configuration R or ¡§¡, and where Z is chosen from Y, -OY, -CH20Y, -C = CY and -CH = CHY, where the double bond can have the cis or trans stereochemical configuration and where Y is chosen from the radical of the structure:
2. (CH2) n wherein m and n independently represent the integers from 0 to 5, wherein R1 is selected from the group consisting of hydrogen, OX4, fluorine, trifluoromethyl, and alkyl having 1 to 5 carbon atoms, which may be straight or branched chain and optionally containing a hydroxy substituent, and wherein R2 is selected from the group consisting of hydrogen, fluorine, trifluoromethyl, and alkyl having 1 to 5 carbon atoms, which may be straight or branched chain and optionally contain a hydroxy substituent, and wherein each of R 3 and R 4 of trifluoromethyl and C 1 -C 5 alkyl, which may be straight or branched chain and optionally contain a hydroxy substituent, and wherein R 1 and R 2 together represent an oxo group or an alkylidene group , = CR2R2, or = CR2R3 or the group - (CH2) p-, where p in is an integer from 2 to 5 and where R3 and R4 together represent the group - (CH2) -, where q is an integer from 2 to 5 and where X1, X2 and X4 each are hydrogen, an ac group ilo or a hydrocarbyloxycarbonyl group, and wherein X 3 represents an acyl group or a hydrocarbyloxycarbonyl group. 2. - A vitamin D derivative according to claim 1, characterized in that it exhibits a biologically active profile in vivo, with a delayed onset or longer duration of activity.
3. 3. - A derivative of calcitriol that promotes the gradual release of active calcitriol in vivo, the derivative has the formula: wherein X1 and X2 independently represent hydrogen, an acyl group or a hydrocarbyloxycarbonyl group and wherein X3 is an acyl group or hydrocarbyloxycarbonyl group.
4. 4. A compound according to claim 3, characterized in that the acyl group is an alkanoyl group with 1 to 18 carbon atoms.
5. 5. - A compound according to claim 3, characterized in that X3 is an acyl group selected from the group consisting of acetyl, propanoyl and butanoyl.
6. 6. - A compound according to claim 3, characterized in that X1 and X2 both represent hydrogen.
7. 7. A compound according to claim 6, characterized in that X3 represents an alkanoyl group with 1 to 8 carbon atoms.
8. 8.- Iar25-dihydroxyvitamin D3-l, 3, 25-Triacetate.
9. 9.- lar25-dihydroxyvitamin D3-l, 3,25-Trihexanoate.
10. 10.- the25-dihydroxyvitamin D3-l, 3,25-Trinonanoate.
11. 11.- lo? 2S-dihydroxyvitamin D3-25-Acetate.
12. 12.- lc25-dihydroxyvitamin D3-25-format.
13. 13. - A method for providing the regulated in vivo release of an active form of a vitamin D compound having the hydroxy group on carbon 25, which comprises modifying the vitamin D compound by derivatizing the hydroxy group at carbon 25 with an acyl group or a hydrocarbyloxycarbonyl group to obtain a vitamin D derivative having the formula: wherein each of R5 and R6 represents hydrogen, or together R5 and R6 represent a methylene group, and wherein R is represented the structure: wherein the stereochemical center at carbon 20 of the side chain may have the R or S configuration, and wherein Z is chosen from Y, -OY, -CH20Y, -C = CY and -CH = CHY, wherein the double link can have the cis or trans stereochemical configuration and where Y is chosen from the radical of the structure: R \? / - (CH2) m- C- (CH2) .r-c-OX3 R / Wherein m and n independently represent the integers from 0 to 5, wherein R 1 is selected from the group consisting of hydrogen, OX 4, fluorine, trifluoromethyl, and alkyl having 1 to 5 carbon atoms, which may be straight chain or branched and optionally containing a hydroxy substituent, and wherein R 2 is selected from the group consisting of hydrogen, fluorine, trifluoromethyl, and 5-carbon alkyl, which may be straight or branched chain and optionally contain a substituent 10 hydroxy, and wherein each of R3 and R4 is selected from trifluoromethyl and alkyl having 1 to 5 carbon atoms, which may be straight or branched chain and optionally contain a hydroxy substituent, and wherein R1 and R2 together represent a oxo group or an alkylidene group, = CRR2, or 15 = CR2R3 or the group - (CH2) p-, where p in is an integer from 2 to 5 and where R3 and R4 together represent the group - (CH2) -, where q is an integer of 2 a = and wherein X1, X2 and X4 each are hydrogen, an acyl group or a hydrocarbyloxycarbonyl group, and wherein X3 represents a group Acyl or a hydrocarbyloxycarbonyl group.
14. 14. The method according to claim 13, characterized in that X1, X2, X3 and 44 independently represent an acyl group or a hydrocarbyloxycarbonyl group.
15. 15. - The method according to claim 13, characterized in that X3 is acyl or a hydrocarbyloxycarbonyl group and X1, X2 and X4 each represents hydrogen.
16. 16. The method according to claim 13, characterized in that X1, X2 and X4 are each hydrogen or an acyl group and X3 is an acyl group.
17. 17. The method according to claim 16, characterized in that the acyl group is acetyl.
18. 18. The method according to claim 16, characterized in that the acyl group is propanoyl, butanoyl or hexanoyl.
19. 19. - The method according to claim 16, characterized in that each of X1, X2, X3 and X4 is acetyl.
20. 20. The method according to claim 16, characterized in that each of X1, X2 and X4 is hydrogen and X3 is an acyl group.
21. 21. The method according to claim 20, characterized in that X3 is acetyl.
22. 22. The method according to claim 13, characterized in that the derivatized vitamin D compound has the formula: wherein X1 and X2 independently represent hydrogen, an acyl group or a hydrocarbyloxycarbonyl group and wherein X3 represents an acyl group or a hydrocarbyloxycarbonyl group.
23. 23. - The method according to claim 22, characterized in that X3 each are hydrogen or an acyl group and X3 is an acyl group.
24. 24. The method according to claim 23, characterized in that the acyl group is acetyl.
25. 25.- In a method to treat disease states resulting from disorders in calcium metabolism, which involves the administration of an active form of a vitamin D compound with a hydroxy group at carbon 25, the improvement characterized in that it comprises regulating the in vivo release of the active form of vitamin D compound by derivatizing the hydroxy group on carbon with an acyl group or a hydrocarbyloxycarbonyl group to obtain a vitamin D derivative having the formula: wherein each of R5 and R6 represents hydrogen, or together R5 and R6 represent a methylene group, and wherein R is represented the structure: wherein the stereochemical center at carbon 20 of the side chain may have the R or S configuration, and wherein Z is chosen from Y, -OY, -CH2OY, -C = CY and -CH = CHY, wherein the double link can have the cis or trans stereochemical configuration and where Y is chosen from the radical of the structure: (CH2) m wherein m and n independently represent the esters of 0 to 5, wherein R1 is selected from the group consisting of hydrogen, OX4, fluorine, trifluoromethyl, and alkyl with 1 to 5 carbon atoms, which may be straight or branched chain and optionally contain a hydroxy substituent, and wherein R2 is selected from the group consisting of hydrogen, fluorine, trifluoromethyl, and alkyl having 1 to 5 carbon atoms, which may be straight chain or branched and optionally containing a hydroxy substituent, and wherein each of R3 and R4 is selected from trifluoromethyl and alkyl having 1 to 5 carbon atoms, which may be straight or branched chain and optionally contain a hydroxy substituent, and wherein R1 and R2 together represent an oxo group or an alkylidene group, = CR2R2, or = CR2R3 or the group - (CH2) -, where p in is an integer from 2 to 5 and wherein R3 and R4 together represent the group - ( CH2) -, where q is an integer from 2 to 5 and wherein X1, X2 and X4 are each hydrogen, an acyl group or a hydrocarbyloxycarbonyl group, and wherein X3 represents an acyl group or a hydrocarbyloxycarbonyl group and administer effective dose of the vitamin D derivative to a subject.
26. 26. The method according to claim 25, characterized in that the derivatized compound is combined with a non-toxic pharmaceutically acceptable carrier and administered in liquid form.
27. 27. The method according to claim 26, characterized in that the derivatized compound is administered by injection.
28. 28. The method according to claim 26, characterized in that the derivatized compound is administered intravenously.
29. 29. The method according to claim 26, characterized in that the derivatized compound is administered orally.
30. 30. The method according to claim 25, characterized in that the derivatized compound is combined with a non-toxic pharmaceutically acceptable carrier and administered in solid form.
31. 31. The method according to claim 30, characterized in that the derivatized compound is administered by suppository.
32. 32. The method according to claim 30, characterized in that the derivatized compound is administered topically.
33. 33. - The method according to claim 30, characterized in that the derivatized compound is administered orally.
34. 34. - The method according to claim 25, characterized in that the disease is selected from the group consisting of renal osteodystrophy, hypoparathyroidism, pseudohypoparathyroidism, hypocalcemia, osteomalacia, vitamin D deficient rickets, post-menopausal osteoporosis, osteoporosis lacking estrogen, Senile osteoporosis, osteoporosis induced by steroids and psoriasis.
35. 35.- The method according to claim 25, characterized in that the modified vitamin D compound is administered in an amount of about 0.5 μg / day to about 10 μg / day.
36. 36. The method according to claim 25, characterized in that at least two derivatized vitamin D compounds are administered to the subject to provide a spectrum of activity.
37. 37. The method according to claim 36, characterized in that one of the two derivatized vitamin D compounds is at least calcitriol, wherein the hydroxy group in carbon 25 is derivatized with an acyl group.
38. 38. - A method for modifying the activity profile in vivo of a biologically active vitamin D compound having hydroxy groups at carbons 1, 3, and 25 and optionally at other carbon positions, which comprises derivatizing the hydroxy group at carbon 25 and optionally one or more of the hydroxy groups on the carbons 1, 3 or the other positions in the molecule, with an acyl group or a hydrocarbyloxycarbonyl group.
39. 39.- The method according to claim 38, characterized in that the active vitamin D compound is derivatized with an acyl group.
40. 40. The method according to claim 38, characterized in that one or more acyl groups are CH3C0.
41. 41. The method according to claim 38, characterized in that one or more acyl groups are CH3 (CH2) 4C0.
42. 42. The method according to claim 38, characterized in that one or more acyl groups is formyl.
43. 43. The method according to claim 38, characterized in that the activity profile in vivo is modified to produce a more gradual onset or a longer duration of the biological response of the active vitamin D compound.
44. 44.- A method for regulating the in vivo availability of calcitriol, which comprises derivatizing the 25-hydroxyl group with a hydrolysable group in vivo.
45. 45. The method according to claim 44, characterized in that the hydrolysable group is an acyl group.
46. 46. The method according to claim 44, characterized in that the hydrolysable group is CH3CO.
47. 47. The method according to claim 44, characterized in that the hydrolysable group is CH3 (CH2) 4CO.
48. 48. The method according to claim 44, characterized in that the hydrolysable group is CH3 (CH2) 7CO.
49. 49. The method according to claim 44, characterized in that the hydrolysable group is a hydrocarbyloxycarbonyl group.