Calcipotriene Chemical Properties

Melting point:

166-168°C

Boiling point:

582.0±50.0 °C(Predicted)

Density 

1.12±0.1 g/cm3(Predicted)

storage temp. 

Desiccate at -20°C

solubility 

DMSO: soluble15mg/mL, clear

pka

14.29±0.20(Predicted)

form 

powder

InChIKey

LWQQLNNNIPYSNX-HCHVWAPNSA-N

CAS DataBase Reference

112965-21-6(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38

Safety Statements 

26

RIDADR 

UN 2811 6.1 / PGIII

WGK Germany 

3

HS Code 

2906195000

MSDS

• Language:English Provider:Calcipotriene

Calcipotriene Usage And Synthesis

Description

Calcipotriol is a topical vitaminD₃ derivative effective in the treatment of psoriasis vulgaris. The drug acts by binding to vitamin D₃ receptors in the skin keratinocytes, producing an elevation in cell differentiation and a reduction in cell proliferation. Although its efficacy is comparable to calcitriol, calcipotriol exhibits at least 100 times less effect on calcium metabolism in rats.

Chemical Properties

White Crystalline Solid

Originator

Leo Denmark (Denmark)

Uses

An antipsoriatic. A vitamin D3 analogue with low calcemic activity

Uses

antipsoriatic;viamin D receptor (VDR) affinity

Uses

A labelled antipsoriatic. A vitamin D3 analogue with low calcemic activity.

Indications

Calcipotriene (Dovonex), a synthetic vitamin D3 derivative, is indicated for the treatment of moderate plaque psoriasis. Its mechanism of action is unknown, although it competes for calcitriol receptors on keratinocytes and normalizes differentiation. It also has a variety of immunomodulatory effects in the skin. Although the drug can cause local irritation, the most serious toxicities are hypercalciuria and hypercalcemia, which are usually reversible.

Manufacturing Process

(1S,3R)-Bis-(t-butyldimethylsilyloxy)-(20S)-formyl-9,10-secopregna(5E,7E,10 (19))triene (Calverley Tetrahedron 43.4609 (1967) and (cyclopropyl)(tri-phenylphoshoranylidene)ketone are stirred in dimethyl sulfoxide under nitrogen. The reaction mixture is then diluted at room temperature with ethyl acetate and washed with common salt solution. The organic phase is dried on sodium sulfate and filtered. After removal of the solvent, the residue is filtered with toluene through silica gel. Evaporation of the solvent and gradient chromatography (toluene/hexane (1:1)-toluene) of the residue on silica gel yield (5E,7E,22E),(1S,3R)-1,3-bis-(t-butyldimethylsilyloxy)-24-cyclopropyl- 9,10-secochola-5,7,10(19),22-tetraene-24-one.
(5E,7E,22E),(1S,3R)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl-9,10- secochola-5,7,10(19),22-tetraene-24-one in tetrahydrofuran and methanol are mixed with a 0.4 M methanol CeCl3·7H2O solution. Sodium borohydride is added by portions under nitrogen with ice cooling. The suspension is stirred with ice cooling and then put into ice/common salt solution. The aqueous phase is extracted with ethyl acetate, the organic phase is washed neutral with water and dried on sodium sulfate. Filtration and removal of the solvent yield oil. By chromatography on silica gel with ethyl acetate/hexane (1:9). The (5E,7E,22E),(1S,3R,24S)-1,3-bis-(t-butyldimethylsilyloxy)-24-cyclopropyl- 9,10-secochola-5,7,10(19),22-tetraene-24-ol is obtained.
(5E,7E,22E),(1S,3R,24S)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl- 9,10-secochola-5,7,10(19),22-tetraene-24-ol is dissolved in toluene and after addition of anthracene and 1 drop of triethylamine it is radiated at room temperature with a high pressure mercury vapor lamp (Heraeus TQ 150) through Pyrex glass. The reaction mixture is concentrated by evaporation and the residue a mixture of (5Z,7E,22E),(1S,3R,24S)-1,3-bis-(t-butyldimethylsilyloxy)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene- 24-ol and anthracene - is directly reacted with tetrabutylammonium fluoride.
(5Z,7E,22E),(1S,3R,24S)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl- 9,10-secochola-5,7,10(19),22-tetraene-24-ol in tetrahydrofuran is kept with a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran under nitrogen. For working up, the cooled reaction mixture is poured into cold sodium bicarbonate solution and then extracted with ethyl acetate. After drying of the organic phase on sodium sulfate, filtration and evaporation of the solvent yields a resin-like residue. Chromatography on silica gel with ethyl acetate/hexane (2:1) yields (5Z,7E,22E),(1S,3R,24S)-24-cyclopropyl-9,10- secochola-5,7,10(19),22-tetraene-1,3,24-triol.

brand name

Dovonex (Leo);Daivonex.

Therapeutic Function

Antipsoriatic

Biological Activity

Vitamin D 3 analog that displays minimal effects on calcium homeostasis. Regulates cell differentiation and proliferation; exhibits antiproliferative activity against human HL-60, HL60/MX2, MCF-7, T47D, SCC-25 and mouse WEHI-3 cancer cell lines.

Biochem/physiol Actions

Calcipotriol, a synthetic derivative of calcitriol or Vitamin D, is used in the treatment of psoriasis and marketed under the trade name Dovonex. It has comparable affinity with calcitriol (Vit. D) for the Vitamin D receptor (VDR), while being less than 1% as active as the calcitriol in regulating calcium metabolism. VDR belongs to the steroid/thyroid receptor superfamily, and is found on the cells of many different tissues including the thyroid, bone, kindney, and T cells of the immune system. Binding of calcipotriol to the VDR modulates the T cells gene transcription of cell differentiation and proliferation-related genes.

Pharmacology

Calcipotriene (Dovonex) enhances the effectiveness of ultraviolet B (UVB) but also increases photosensitivity in UVB-treated patients. Ultraviolet light, 6% salicylic acid, 12% lactic acid, hydrocortisone valerate 0.2% ointment, and tazarotene (Tazorac) gel degrade calcipotriene (Dovonex). Halobetasol ointment and 5% tar gel are compatible with Calcipotriene (Dovonex). A British study found calcipotriene (Dovonex) to be safe and effective in a pediatric population over the age of 3, although it is not approved by the FDA.

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