41294-56-8 Usage
Uses
Used in Pharmaceutical Industry:
Alfacalcidol is used as a treatment for various bone-related conditions, including osteoporosis, vitamin D-dependent rickets, and osteomalacia. It is effective in stimulating intestinal calcium absorption and bone mineral mobilization, making it a valuable vitamin D source for these applications.
Used in Renal Bone Disease Treatment:
Alfacalcidol is used as a treatment for renal bone diseases, which are conditions that affect the bones due to kidney problems. It helps regulate the calcium and phosphorus metabolism, thus maintaining normal calcium levels within the body.
Used in Poultry Feed Industry:
Alfacalcidol is used as a poultry feed additive to prevent tibial dyschondroplasia, a bone development disorder in chickens. It also increases the bioavailability of phytate, an essential nutrient for poultry.
Used in Immune System Regulation:
Alfacalcidol has significant effects on the immune system, particularly on regulatory T cells, which play a crucial role in maintaining immune homeostasis and preventing autoimmune diseases.
Physical and Chemical Properties
White crystal or crystalline powder, insoluble in water and hexane, soluble in methanol, ethanol, chloroform, methylene chloride, acetone or ether. Perishable in case of air and light .
Pharmacological effects
Alfacalcidol is quickly converted by the liver into 1,25-dihydroxyvitamin D3, regulates calcium balance in the body, because of the enhancing of 1,25-dihydroxyvitamin D3 levels in vivo circulating , thereby increases the calcium and phosphorus intestinal absorption, promotes bone mineralization, decreases parathyroid hormone levels in plasma and reduces calcium resorption, relieves bone, muscle pain and improves osteoporosis and menopause, aging and steroid-induced intestinal related calcium malabsorption.
Alfacalcidol increases the intestinal and renal tubular reabsorption of calcium and inhibit parathyroid hyperplasia, reduces parathyroid hormone synthesis and release, inhibits bone resorption. Promotes collagen and bone matrix protein synthesis.Regulates Calcium metabolism of muscles , promotes muscle cells differentiation, enhances muscle strength, increases neuromuscular coordination, tends to reduce falls. Suitable for the treatment of rickets and osteomalacia, renal osteodystrophy, osteoporosis and hypoparathyroidism. Youth are limited to young people with idiopathic osteoporosis and glucocorticoid-induced osteoporosis too.
The above information is edited by the lookchem of Tian Ye.
Pharmacodynamics
This product after oral administration, is rapidly absorbed into the bloodstream from the gut, 25-hydroxy enzyme of the liver microsomal make 25-hydroxy of side chain compound to generate 1α, 25-(OH) 2D3, distributed in the intestine and bone and other target tissues, upon binding to the receptor, it can promote intestinal absorption of calcium, causing a series of physiological activities, such as bone salt dissolving and bone formation . Rats removed of the kidney and rats deficient in vitamin D, are given this product experiments, which shows that the level of promoting intestinal absorption of calcium, elevates serum calcium.Due to renal completely removed in rats removed of the kidney , the majority of bone resorption and bone-like cavity layer, low-calcified layer next layer increases, give this product 30d to experiment, the bone freshmen is observed. Therefore alfacalcidol promotes bone formation. Elderly patients with osteoporosis given this product ,iliac bone biopsy is performed by electronic and optical microscope to find that active osteoblasts, osteocytes, bone calcification small chamber increases, improves bone tissue.
Indications
Symptoms alfacalcidol can be used to improve chronic renal insufficiency, hypoparathyroidism, vitamin D-dependent rickets, a softening of bone disease caused by vitamin D metabolism, such as hypocalcemia, hand, foot cramps, pain , bone disease and osteoporosis embolism.
Instructions
For osteoporosis, oral: initial amount of 0.5μg/d, maintenance dose of 0.25~0.50μg, qd.
Dialysis patients with chronic hypocalcemia, 0.5~3.0μg/d, divided 2 to 3 times daily.
Hypoparathyroidism, 0.25~3.00μg/d, divided 2 to 3 times daily.
Renal bone atrophy, the next day 0.25~3.00μg, divided 2 to 3 times daily.
Vitamin D-dependent rickets, 1μg/d, divided 2 to 3 times daily.
Familial hypophosphatemia, 2μg/d, divided 2 to 3 times daily.
Adverse reactions
Small amount alone is usually no more adverse reactions, long-term large doses of medication or in combination with calcium can cause hypercalcemia and hypercalciuria.patients in Long-term high doses and patients with renal impairment may be nausea, loss of appetite, dizziness, skin itching, rash, constipation, anorexia, vomiting, abdominal pain, high calcium signs ,it can be restored to normal after treatment. Vitamin D and its analogues allergies, hypercalcemia, vitamin D poisoning signs patients are banned. Early medication serum calcium levels should be determined weekly, when a stable dose, they are measured every 2 to 4 weeks, especially renal dysfunction serum calcium levels should be measured regularly. when hypercalcemia occurs, It Shall be discontinued and deal with hypercalcemia. After serum calcium returns to normal , the dose is dministered half of the last dose. Alfacalcidol combination with calcium can cause elevated serum calcium, when it combined with thiazide diuretics can cause the danger of hypercalcemia . When treated with digitalis drugs, care should be taken to develop the amount of this drug.The amount of Alfacalcidol should be increased when combined with barbiturates, anticonvulsants .
Precautions
If hypercalcemia occurs,it should be stopped taking until serum calcium returns to normal (about a week), and then press the last half dose administration. patients have Vitamin D symptoms or known allergy to vitamin D and its analogues is unfit for use. Patients Should avoid taking vitamin D drugs at the same time, so as not to cause vitamin D intoxication.
Drug Interactions
Using Alfacalcidol and magnesium formulation (magnesium oxide, magnesium carbonate, etc.) sometimes causes hypermagnesemia.
Using Alfacalcidol and Cardiac preparations may cause cardiac arrhythmia.
Using Alfacalcidol and vitamin D and its derivatives (calcitriol) , it is possible to cause hypercalcemia.
Using Alfacalcidol and calcium , Thiazide diuretics, digitalis drugs , can cause hypercalcemia.
And barbiturates, anti-seizure drugs may reduce the efficacy of the drug.
Gastrointestinal absorption inhibitors can reduce the absorption of the drug.
Combination with large doseas of Phosphorus compounds, can induce hyperphosphatemia.
When Alfacalcidol and calcium preparations (calcium lactate, calcium carbonate, etc.) are used together, there may be hypercalcemia.
Referrence
https://en.wikipedia.org/wiki/Alfacalcidol
https://www.drugbank.ca/drugs/DB01436
http://www.mhra.gov.uk
JD Ringe, H Faber, P Fahramand, E Schacht, Alfacalcidol versus plain vitamin D in the treatment of glucocorticoid/inflammation-induced osteoporosis, J. Rheumatol. Suppl., 2005, vol. 76, 33-40
Originator
One-Alpha ,Leo ,UK ,1978
Manufacturing Process
1. Preparation of 1,4-cyclized adduct of cholesta-1,5,7-trien-β-ol and 4-
phenyl-1,2,4-triazoline-3,5-dione: a solution of 400 mg of cholesta-1,5-7-
trien-3β-ol in 30 ml of tetrahydrofuran is cooled with ice, and 190 mg of 4-
phenyl-1,2,4-triazoline-3,5-dione is added little by little to the solution under
agitation. The mixture is agitated at room temperature for 1 hour and the
solvent is distilled under reduced pressure. The residue is purified by
chromatography using a column packed with silica gel. Fractions eluted with
ether-hexane (7:3 v/v) are collected and recrystallization from ether gives
550 mg of a 1,4-cyclized adduct of cholesta-1,5,7-trien-3β-ol and 4-phenyl-
1,2,4-triazoline-3,5-dione having a melting point of 178°C to 182°C.
2. Preparation of 1,4-cyclized adduct of cholesta-5,7-dien-3β-ol-1α-epoxide
and 4-phenyl-1,2,4-triazoline-3,5-dione: 1.25 g of the 1,4-cyclized adduct of
cholesta-1,5,7-trien-3β-ol and 4-phenyl-1,2,4-triazoline-3,5-dione is dissolved
in 50 ml of chloroform, and 560 mg of m-chloroperbenzoic acid is added to
the solution. The mixture is agitated for 20 hours at room temperature, and
200 mg of m-chloroperbenzoic acid is further added and the mixture is
agitated again for 20 hours. The reaction mixture liquid is diluted with
chloroform, washed with a 10% aqueous solution of potassium carbonate and
dried with magnesium sulfate. Then, the solvent is distilled under reduced
pressure. The residue is purified by silica gel chromatography, and first
effluent fractions eluted with ether are collected, and recrystallization from
methanol gives 680 g of a crystal melting at 172°C to 173°C. The second
ether effluent fractions are collected, and recrystallization from methanol gives
400 mg of a 1,4-cyclized adduct of cholesta-5,7-dien-3β-ol-1α,2α-epoxide and
4-phenyl-1,2,4-triazoline-3,5-dione having a melting point of 152°C to 154°C.
3. Preparation of cholesta-5,7-diene-1α,3β-diol: a solution of 500 mg of the
1,4-cyclized adduct of cholesta-5,7-dien-3β-ol-1α,2α-epoxide and 4-phenyl-
1,2,4-triazoline-3,5-dione in 40 ml of tetrahydrofuran is added dropwise under
agitation to a solution of 600 mg of lithium aluminum hydride in 30 ml of THF.
Then, the reaction mixture liquid is gently refluxed and boiled for 1 hour and
cooled, and a saturated aqueous solution of sodium sulfate is added to the
reaction mixture to decompose excessive lithium aluminum hydride. The
organic solvent layer is separated and dried, and the solvent is distilled. The residue is purified by chromatography using a column packed with silica gel.
Fractions eluted with ether-hexane (7:3 v/v) are collected, and
recrystallization from the methanol gives 400 mg of cholesta-5,7-diene-1α,3β-
diol.
4. Preparation of 1α,3β-dihydroxyprovitamin D3: a solution of 25 mg of
cholesta-5,7-diene-1α,3β-diol in 650 ml of ether is subjected to radiation of
ultraviolet rays for 14 minutes in an argon gas atmosphere by passing it
through a Vycor filter using a 200-W high pressure mercury lamp (Model
654A-36 manufactured by Hanobia). The solvent is distilled at room
temperature under reduced pressure. This operation is repeated twice, and 50
mg of the so obtained crude product is fractionated by chromatography using
a column packed with 20 g of Sephadex LH-20. The first effluent fractions
eluted with chloroform-hexane (65:35 v/v) give 13.5 mg of oily 1α,3β-
dihydroxyprovitamin D3. The composition exhibits a maximum ultraviolet
absorption at 260 nm in an ether solution.
5. Preparation of 1α-hydroxycholecalciferol: a solution of 13.5 mg of 1α,3β-
dihydroxyprovitamin D3 in 200 mi of ether is allowed to stand still in the dark
at room temperature in an argon gas atmosphere for 2 weeks. During this
period, the position of the maximum ultraviolet absorption is shifted from 260
nm to 264 nm, and the absorption intensity becomes 1.6 times as high as the
original intensity. The solvent is distilled at room temperature under reduced
pressure, and the residue is purified by chromatography using a column
packed with 10 g of Sephadex LH-20. The fractions eluted with chloroformhexane
(65:35 v/v) give 6.5 mg of oily 1α-hydroxycholecalciferol.
Therapeutic Function
Calcium regulator, Vitamin
Clinical Use
Vitamin D analogue:
Increase serum calcium levels
Suppression of PTH production
Drug interactions
Potentially hazardous interactions with other drugs
Carbamazepine, fosphenytoin, phenytoin,
phenobarbital and primidone may increase
metabolism of alfacalcidol, necessitating larger doses
than normal to produce the desired effect.
Metabolism
Alfacalcidol is hydroxylated in the liver by the
enzyme vitamin D 25-hydroxylase to form the active
1,25-dihydroxycolecalciferol (calcitriol). Calcitriol is
inactivated in both the kidney and the intestine, through
the formation of a number of intermediates including the
formation of the 1,24,25-trihydroxy derivatives. Vitamin
D compounds and their metabolites are excreted mainly
in the bile and faeces with only small amounts appearing
in urine; there is some enterohepatic recycling but it is
considered to have a negligible contribution to vitamin D
status.
Check Digit Verification of cas no
The CAS Registry Mumber 41294-56-8 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 4,1,2,9 and 4 respectively; the second part has 2 digits, 5 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 41294-56:
(7*4)+(6*1)+(5*2)+(4*9)+(3*4)+(2*5)+(1*6)=108
108 % 10 = 8
So 41294-56-8 is a valid CAS Registry Number.
InChI:InChI=1/C27H44O2/c1-18(2)8-6-9-19(3)24-13-14-25-21(10-7-15-27(24,25)5)11-12-22-16-23(28)17-26(29)20(22)4/h11-12,18-19,23-26,28-29H,4,6-10,13-17H2,1-3,5H3/b21-11+,22-12-/t19-,23+,24-,25?,26-,27-/m1/s1
41294-56-8Relevant articles and documents
Photoisomerization of alfa calcidol by a sensitized quantum chain reaction
Estruch, Gast?n A.,Aramendía, Pedro F.
, p. 769 - 773 (2012)
The production of vitamin D3 is a pharmaceutically relevant process, producing high added-value products. Precursors are extracts from vegetal origin but bearing mainly an E geometry in the 5,6 double bond. The synthesis of vitamin D3 (5-E-α-calcidol) wit
Improved preparation method of alfacalcidol
-
Paragraph 0028-0030; 0032-0034; 0036-0038, (2020/05/08)
The invention discloses an improved preparation method of alfacalcidol. The preparation method is characterized by comprising the following steps: starting from 1 alpha-OH-3,5-cyclized vitamin D3, directly carrying out ring-opening hydrolysis without an acetate intermediate to obtain alfacalcidol and a trans-isomer thereof, carrying out a Diels-Alder reaction, selectively reacting with the trans-isomer, and carrying out column chromatography separation or methyl formate recrystallization to obtain a pure alfacalcidol product. The method is simple and convenient to operate, mild in reaction condition and high in total yield, and is suitable for large-scale synthesis of products.
Refining method for alfacalcidol
-
Paragraph 0023; 0024; 0025; 0026, (2019/04/13)
The invention provides a refining method for alfacalcidol. The refining method comprises the following steps: firstly, converting a crude product of alfacalcidol into alfacalcidol sulphate; forming sodium alfacalcidol sulphate; re-crystallizing sodium alfacalcidol sulphate and then degreasing. The reaction equation is as follows. According to the refining method for alfacalcidol provided by the invention, the crude product of alfacalcidol is firstly converted into alfacalcidol sulphate, and then the sodium alfacalcidol sulphate is formed, and the sodium alfacalcidol sulphate is re-crystallizedand then is degreased; the refining efficiency is high, the cost is low and the production stability is high; the refining method can meet the requirement for volume production and has a bright application prospect.
Method for preparing high-purity 1 alpha-hydroxyvitamin D3
-
Paragraph 0025, (2018/03/01)
The invention discloses a method for preparing high-purity 1 alpha-hydroxyvitamin D3. The method comprises the following steps of (1) carrying out esterification; (2) carrying out cyclization; (3) carrying out oxidization; (4) carrying out ring opening; (5) carrying out photochemical isomerisation; (6) utilizing molecular sieve zeolite to carry out chiral purification and treatment on crude 1 alpha-hydroxyvitamin D3, and finally, carrying out recrystallization with an ethyl acetate-n-hexane system to obtain the high-purity 1 alpha-hydroxyvitamin D3. According to the method, by using a liposoluble solvent to replace pyridine and using an organic alkaline catalyst, under the condition with equivalent yield, the reaction temperature is changed from low temperature to room temperature, the reaction time is shortened, the pyridine with large pungent smell is avoided from using, and thus the economic practicability of the technology is greatly improved.
A modified synthesis of the antiosteoporosis drug alfacalcidol via a key photochemical transformation of 1α-5,6-Trans-Vitamin D3
Ding, Junyuan,Guo, Xianghai,Zeng, Zhouliangzi,Liu, Ningzhi
, p. 2606 - 2608 (2013/12/04)
Alfacalcidol (1α-hydroxyvitamin D3) is an important clinical drug for the treatment of osteoporosis. Its practical synthesis has been intensively pursued across academia. The difficulties of separating 5,6-cis and 5,6-trans isomers in the current process was avoided by photochemical transformation of the 5,6-trans isomer into the 5,6-cis isomer. Employing vitamin D3 as a starting material, alfacalcidol was obtained by a five-step reaction sequence of esterification, cyclization, oxidation, solvolysis ring-opening, and subsequent photochemical reaction. The overall yield has been greatly improved from 17% to 31%. Georg Thieme Verlag Stuttgart New York.
Continuous-flow synthesis of activated vitamin D3 and its analogues
Fuse, Shinichiro,Mifune, Yuto,Tanabe, Nobutake,Takahashi, Takashi
experimental part, p. 5205 - 5211 (2012/08/08)
An efficient, two-stage, continuous-flow synthesis of 1α,25-(OH) 2-vitamin D3 (activated vitamin D3) and its analogues was achieved. The developed method afforded the desired products in satisfactory yields using a high-intensity and economical light source, i.e., a high-pressure mercury lamp. In addition, our method required neither intermediate purification nor high-dilution conditions. The Royal Society of Chemistry 2012.
Pd-catalyzed carbocyclization-negishi cross-coupling cascade: A novel approach to 1α,25-dihydroxyvitamin D3 and analogues
Gomez-Reino, Clara,Vitale, Cristian,Maestro, Miguel,Mourino, Antonio
, p. 5885 - 5887 (2007/10/03)
(Chemical Equation Presented) A mild palladium-catalyzed cascade has been used for the synthesis of the hormone 1α,25-dihydroxyvitamin D3 (calcitriol, 1a) and its analogues 1b and 1c. This one-pot process involves two consecutive transformations at room temperature: An initial palladium-catalyzed 6-exo-cyclocarbopalladation of vinyl triflates followed by a Negishi cross-coupling reaction with an alkenyl zinc. This novel strategy opens new possibilities for the preparation of a variety of new vitamin D analogues of therapeutic potential, particularly with modifications at the triene and/or ring-A.
Treatment of inflammatory bowel disease with vitamin D compounds
-
, (2008/06/13)
A method of treating inflammatory bowel disease, particularly ulcerative colitis and Crohn's disease, is disclosed. The method involves administering a vitamin D compound in an amount effective to treat the disease. The administration of a vitamin D compound also prevents the development of or delays the onset of inflammatory bowel disease in susceptible individuals.
VITAMIN D DERIVATIVES AND PROCESS FOR PRODUCING THE SAME
-
, (2008/06/13)
A process for producing hydroxyvitamin D derivatives, characterized by converting a hydrogen atom or atoms at the 2-position, 24-position, 25-position and/or 26-position of a vitamin D into a hydroxyl group or groups in a solution containing a microorganism that belongs to the genus Nocardia, Streptomyces,Sphingomonas or Amycolata which has an ability to hydroxylate vitamin Ds or an enzyme produced by that microorganism, and optionally under the coexistence of a cyclodextrin; and novel vitamin D3 derivatives obtained by that process.
Synthesis and pharmacokinetics of 1α-hydroxyvitamin D3 tritiated at 22 and 23 positions showing high specific radioactivity
Kawase, Akira,Ichikawa, Fumihiko,Koike, Nobuo,Kamachi, Shinichi,Stumpf, Walter E.,Nishii, Yasuho,Kubodera, Noboru
, p. 215 - 219 (2007/10/03)
A novel synthesis of a radioactive compound of 1α-hydroxyvitamin D3 (1αOHD3) (1) and its pharmacokinetics are described. Radioactive 1αOHD3 tritiated at 22 and 23 positions ([22,23-3H4]1αOHD3) (5) was prepared via key reactions of the reduction of acetylenic side chain in the ketone (12) with tritium gas in the presence of palladium-charcoal and the subsequent Wittig reaction with the A-ring synthon (16). [22,23-3H4]1αOHD3 (5) showed high specific radioactivity (111.5 Ci/mmol) and was used successfully in pharmacokinetics studies with rats. In the pharmacokinetics studies, the plasma concentration level of the active form of vitamin D3, 1α,25- dihydroxyvitamin D3 [1α,25(OH)2D3], after oral or intravenous administration of [22,23-3H4]1αOHD3 (5), showed longer half-life, lower maximum concentration, and lower area under the curve than those after treatment of 1α,25(OH)2D3 tritiated at 26 and 27 positions (4). These results might suggest a beneficial therapeutic utility of 1αOHD1 (1) over the treatment of 1α,25(OH)2D3 (2).
