Vitamin D analogue

1 Vitamin D Analogues - A patent covering the photochemical conversion of the diene (112) into the triene (113) within what is called a microreactor has been published. The microreactor system is a zeolite with the appropriate size of the cavity to provide stereochemical control of the reaction. The use of the 2,7-dimethyl-3,6-diazacyclohepta-1,6-diene tetrafluoroborate/biphenyl filter solution has allowed the double wavelength irradiation (290-300 nm and X. 330 nm) of procalcitriol as a route to la,25-dihydroxycholecalciferol. A study of the control that can be exercised upon the reaction by changes in temperature was carried out. The results of a study of the influence of intensity on the picosecond laser irradiation of provitamin D have been published. Other research has been aimed at the examination of the photochemical behaviour of previtamin 03.  

1 Vitamin D Analogues - The analogues (151) of pre-vitamin D3 have been synthesised and their irradiation in THF solution at wavelengths around 3(X) nm brings about cisArans-isomerism Cyclization to (152) is also observed and in this process there is a wavelength and excited state dependence. Thus with 

Photochemical transformations of previtamin D at low temperatures (90 K) has shown that there are slight differences in the rate of ring opening of (153) into (154) dependent upon the wavelength used. Further irradiation of the triene (154) leads to the formation of the more stable conformer (155). A detailed study of this isomerization has shown that the methyl group and the hydroxyl function 

The propellaprismane (156) has been synthesized by the intramolecular (2+2)-photocycloaddition of the diene (157). Interest in the synthesis of cage compounds such as (158) continues. This particular example is produced on irradiation of the triene (159) through quartz in a mixture of acetone and benzene. The reaction is chemically efficient and the product is formed in 80% yield. 

The copper(I) catalysed photo-cycloaddition reactions of the dienes (160) have been studied. This process provides an efficient route to the (2+2) cycloadducts (160a) in the ratios and yields shown under the appropriate structures. These adducts are key components in an approach to the synthesis of A -capnellene. Copper triflate controlled photocycloadditions have also been used as a key step in the synthesis of some cyclopentanes. The reaction involves the cyclization of the dienes (161) under the copper(I) controlled conditions into the adducts (162) and this is followed by thermal reactions that bring about rearrangement and ring opening. 

Gleiter et al. have demonstrated that Dewar-benzene derivatives such as (118) undergo efficient conversion into prismanes on irradiation at X 280 nm in ether solution. The reactions of these systems are substituent dependent and derivatives such as (119) are unreactive. 

Several examples of isomerism of heavily substituted dienes into cyclobutenes have been reported. The reactions are brought about by the use of quartz filtered light. The reactions are quite efficient and, for example, the bicyclo[4.4.1]undeca-dienes (130) can be converted efficiently into the isomeric products (131) and (132) in the yields shown below the appropriate structure. Ring strain does not adversely affect the reaction since it is also possible to bring about ring closure of the bicyclo[4.2.1]nonadienes (133) to afford the tricyclic products (134) and (135). The (2+2)-photocycloaddition of the lambertianate derivative (136) results in the formation of the cyclobutane adduct (137). ° 

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Vitamin rarely occurs in plants. However, Solanumglaucophjllum Solanum malacoyyhn Cestrum diumum and TrinetumJlavescens have been shown to contain water-soluble glycosides of vitamin D analogues with 1 a,25-dihydroxy-vitarnin D activity (16—22). The vitamin D content in various plant and animal materials is shown in Table 3. Vitamin D occurs naturally in all animals (24). 

Vitamin D analogues (calcipotriol, calcitriol, and tacalcitol) are also frequently selected as initial pharmacotherapy in the management of mild to moderate psoriasis.2 These inhibit keratinocyte differentiation and proliferation and maybe antiinflammatory.2 Unlike corticosteroids, tachyphylaxis does not occur with prolonged use. Clearance of lesions should occur after 4 to 6 weeks of treatment.2 Lack of response by 8 weeks... 

Salusky IB Are new vitamin D analogues in renal bone disease superior to calcitriol Pediatr Nephrol 2005 20 393. [PMID 15690188]... 

Scheme 8C.20. Symmetry -assisted enantiospecific synthesis of A-ring of Vitamin D analogues based on asymmetric ene cyclization.

Avenell A, Gillespie WJ, Gillespie LD, O Connell DL. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. 2005 CD000227. 

Van de Kerkhof, P.C.M., Biological activity of vitamin D analogues in the skin, with special reference to antipsoriatic mechanisms, Br. J. Dermatol., 132, 675, 1995. 

Griffiths, C.E.M. Retinoids vitamin D analogues action on nuclear transcription, Hasp. Med., 59,... 

Two new vitamin D analogues, maxacalcitol [29] and hexafluorocalcitriol [30] (Fig. 2.5) were designed to separate the antiproliferative effects of the natural hormone from its role in calcium and phosphate mobilization. There had not been... 

The first line of treatment is usually the application of topical products, ranging from over-the-counter products to topical steroids. Emollients may be used to reduce dryness and scaling, as well as reducing the hyperproliferation associated with plaque psoriasis. The use of vitamin D analogues, tazarotene, dithranol or coal tar preparations aims to lessen or remove the patient s scaly plaques. However, excess use can irritate the skin and their use is not recommended for the more irritant forms of psoriasis. Tar baths and tar shampoos (containing coal tar) may help with managing the condition. Treatment, if nonirritating, should be continued for 4-6 weeks and thereafter assessed. Emollients... 

L13. Lucia, M. S., Anzano, M. A., Slayter, M. V., Anver, M. R., Green, D. M., etal., Chemopreventive acitvity of tamoxifen, N-(4-hydroxyphenyl)retamide, and the vitamin D analogue Ro24-5531 for andorgen-promoted carcinomas of the rat seminal vesicle and prostate. Cancer Res. 55, 5621-5627 (1995). 

The immunosuppressive effects of 1,25-(OH)2D3 in such diseases as diabetes in non-obese diabetic (NOD) mice [375], and the autoimmune diseases murine lupus [376] and encephalomyelitis [377] reveal potentially important and novel uses for vitamin D treatment. However, it is clear that noncalce-mic immunopotent vitamin D analogues will have to be employed to prevent hypercalcaemia caused by 1,25-(OH)2D3. 

Brown AJ (2001) Therapeutic uses of vitamin D analogues. American Journal of Kidney Disease 38, S3-S19. 

Such is the versatility of DAST and related reagents that many fluorinated derivatives of natural products, including steroids, carbohydrates, nucleosides, prostaglandins and vitamin D analogues, amongst others, have been successfully synthesised [10, 16, 17] (Table 3.5). 

As discussed in Sect. 2, a-selanylalkyllithiums, generated from selenoacetals, can react with various electrophilic reagents, i. e. chloromethyl isopropyl ether for the synthesis of la-hydroxy vitamin D analogues [25] and with propargylic chloride derivatives for the preparation of alkynols [26]. A synthesis of vinyl-cyclopropane derivatives from l,4-dichloro-but-2-ene was achieved with trans stereoselectivity (>93%) in 68-89% yield. This one-pot cyclization, via an intramolecular allylic substitution, required the presence of two equivalents of u-BuLi [26] (Scheme 23). 

Calcipotriol and tacalcitol are vitamin D analogues available as creams or ointments for the treatment of psoriasis (p. 313). 

Topical calcipotriol (a vitamin D analogue) is an effective and safe treatment for mild to moderate psoriasis vulgaris. Its mode of action is identical to that of 1,25-dihydroxycolecalciferol (calcitriol). 

There is controversy about whether the long-term use of Cl-hydroxylated vitamin D analogues in non-dialysed patients with chronic renal insufficiency is associated with an impairment of glomerular filtration rate (SEDA-9, 639) (49). Treatment with these drugs should be restricted to patients with severe renal osteodystrophy. A proper dose should be administered in order to avoid a deleterious effect on renal function. Serum calcium and creatinine concentrations should be monitored carefully. The treatment should be withdrawn if hypercalcemia develops. 

Of 19 chronic hemodialysis patients taking a combination of alfacalcidol and calcitriol for 12 months, six had increased bone resorption, six had reduced bone resorption, and seven had no change. Histologically documented aggravation of hyperparathyroidism was associated with a statistically significant increase in plasma concentrations of phosphate and parathyroid hormone. The administration of vitamin D analogues may therefore be either beneficial or noxious depending on whether or not induced hyperphosphatemia is adequately prevented (55). 

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