118292-40-3

Avage,Allergan

An acetylenic retinoid prodrug converted to the active metabolite, Tazarotenic acid, with selective affinity for retinoic acid receptors RAR?and RAR. Antiacne; antipsoriatic. Used in treatment of photodamaged skin

anticholelithic

Tazarotene is a prescription topical retinoid sold as a cream or gel. This medication is approved for treatment of psoriasis, acne, and sun damaged skin (photodamage). It is commonly sold in two concentrations: 0.05% and 0.1%. In addition to tretinoin, wh

Used to treat psoriasis, acne and sun damaged skin.

ChEBI: The ethyl ester of tazarotenic acid. A prodrug for tazarotenic acid, it is used for the treatment of psoriasis, acne, and sun-damaged skin.

Like other retinoids, tazarotene (Tazorac) acts by binding to RARs and altering gene expression. Tazarotene appears to be particularly selective for the retinoid receptors RAR-β and RAR-γ, but the clinical significance of this observation is unknown.

A mixture of 14.91 g (135.324 mmol) of thiophenol and 5.5 g (137.5 mmol) of NaOH in 100 ml acetone was heated at reflux for 2.5 h and then treated dropwise with a solution of 20 g (134.19 mmol) of 1-bromo-3-methyl-2- butene in 20 ml acetone. This solution was refluxed for 40 h and then stirred at room temperature for 24 h. Solvent was then removed in vacuo, the residue taken up in water, and extracted with 3 times 50 ml ether. Ether extracts were combined and washed with 3 times 30 ml of 5% NaOH solution, then water, saturated NaCl solution and dried. Solvent was then removed in vacuo and the residue further purified by kugelrohr distillation (80°C, 0.75 mm) to give the phenyl-3-methylbut-2-enylsulfide as a pale yellow oil.
To a solution of 15.48 g (86.824 mmol) of phenyl-3-methylbut-2-enylsulfide in 160 ml benzene were added successively 12.6 g (88.767 mmol) of phosphorus pentoxide and 11 ml of 85% phosphoric acid. This solution was refluxed with vigorous stirring under argon for 20 h, then cooled to room temperature. The supernatant organic layer was decanted and the syrupy residue extracted with 3 times 50 ml ether. Organic fractions were combined and washed with water, saturated NaHCO3 and saturated NaCl solution and then dried. Solvent was removed in vacuo and the residue purified by kugelrohr distillation (80°C, 0.5 mm) to give the 4,4-dimethylthiochroman as a pale yellow oil.
A solution of 14.3 g (80.21 mmol) of 4,4-dimethyl thiochroman and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 h, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 h. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5 times 50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried. The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150°C, 0.7 mm) to give the 4,4-dimethyl-6-acetylthiochroman as a pale yellow oil.
To a solution of 1.441 g (14.2405 mmol) of diisopropylamine in 30 ml dry tetrahydrofuran under argon at -78°C was added dropwise 9 ml of 1.6 M (14.4 mmol) n-butyl lithium in hexane. After stirring this solution at -78°C for 1 h, it was treated dropwise with a solution of 2.95 g (13.389 mmol) of 4,4- dimethyl-6-acetylthiochroman in 5 ml of dry tetrahydrofuran. After another hour of stirring at -78°C, the solution was treated with 2.507 g (14.53 mmol) of diethyl chlorophosphate and brought to room temperature, where it was stirred for 3.75 h. This solution was then transferred using a double ended needle to a solution of lithium diisopropylamide (prepared as above using 2.882 g (28.481 mmol) of diisopropylamine and 18 ml of 1.6 M (28.8 mmol) n-butyl lithium in hexane) in 60 ml dry tetrahydrofuran at -78°C. The cooling bath was removed and the solution stirred at room temperature for 15 h, then quenched with water and acidified to pH 1 with 3 N hydrogen chloride. The mixture was stirred at room temperature for 12 h, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 h. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5 times 50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried. The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150°C, 0.7 mm) to give the 4,4-dimethyl-6-ethynylthiochroman as a pale yellow oil.
A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol) ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 g dimethylaminopyridine in 200 ml methylene chloride was heated at reflux for 2 h. The mixture was allowed to cool, solvent removed in vacuo and residue subjected to flash chromatography to give the ethyl 6-chloronicotinate as a low-melting white solid.
2 Methods of preparation of the ethyl 6-[2-(4,4-dimethylthiochroman-6- yl)ethynyl]nicotinate.
1. Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 465.7 mg (2.3019 mmol) of 4,4-dimethyl-6- ethynyl-thiochroman in 4 ml of dry tetrahydrofuran at 0°C was added dropwise 1.5 ml of 1.6 M (2.4 mmol) n-butyl lithium in hexane. This was stirred at 0°C for 10 min and at room temperature for 10 min, cooled again to 0°C and then treated with a solution of 330 mg (2.4215 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter the solution was stirred at 0°C for 30 min, then at room temperature for 10 min. A solution of 426.3 mg (2.2967 mmol) of ethyl 6-chloronicotinoate in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 430 mg (0.37 mmol) of tetrakistriphenylphosphine palladium in 4 ml dry tetrahydrofuran and stirred at room temperature for 10 min, then treated by double ended needle with the solution of the alkynylzinc prepared above. This mixture was stirred at room temperature for 18 h, then quenched with 100 ml water. Product was recovered by extraction with 3 times 75 ml ether. Ether fractions were combined and washed with saturated NaCl solutions and dried. Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate.
2. A solution of 15.4 g (76.2 mmol) of 4,4-dimethyl-6-ethynylthiochroman and 14.0 g (75.5 mmol) of ethyl-6-chloronicotinate in 35 ml of freshly distilled triethylamine was degassed and then treated under nitrogen with a finely powdered mixture of 1 g (5.25 mmol) of high purity cuprous iodide and 2 g (2.85 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was heated under nitrogen at 55°C for 20 h and then cooled to room temperature. The triethylamine was then removed under vacuum and the residue was diluted with 200 ml of a 1:4 mixture of ethyl acetate and hexanes. This mixture was filtered through silica and the filtrate concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel; 15% ethyl acetate in hexanes) and recrystallized from a mixture of ethyl acetate and hexanes to give the ethyl 6-[2-(4,4-dimethylthiochroman-6- yl)ethynyl]nicotinate as a pale yellow solid.

Avage (Allergan); Tazorac (Allergan).

Keratolytic

Tazarotene induces the expression of tazarotene-induced gene 3 (TIG3), a tumor suppressor gene. It is a prodrug of tazarotenic acid, which specifically activates RARb and RARg, only weakly activates RARa, and is inactive at retinoid X receptors (RXRs). In psoriasis, tazarotene normalizes abnormal keratinocyte differentiation and reduces their hyperproliferation.

In the United States, tazarotene has been approved for topical treatment of psoriasis (involving up to 20% body surface area) and mild to moderate facial acne. Application site burning, stinging, and desquamation are common side effects, especially with acne. Tazarotene is contraindicated in women who are pregnant.

Tazorac is a category X drug and must be avoided in pregnancy. This drug can be irritating and should be avoided in patients with sensitive skin or seborrheic dermatitis.

Retinoid prodrug, converted to active form, the carboxylic acid of tazarotene by rapid de-esterification. This drug binds to all three retinoic acid receptors with some increased affinity for the β and γ receptors.