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Acitretin

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Acitretin Basic information

Product Name:
Acitretin
Synonyms:
  • (all-e)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraen
  • 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid
  • (ALL-E)-9-(4-METHOXY-2,3,6-TRIMETHYLPHENYL)-3,7-DIMETHYL-2,4,6,8-NONATETRAENOIC ACID
  • ACITRETIN
  • SORIATANE
  • NEOTIGASON
  • Neotigason, Soriatane
  • Acritretin
CAS:
55079-83-9
MF:
C21H26O3
MW:
326.43
EINECS:
259-474-4
Product Categories:
  • Inhibitors
  • API
  • Aromatics
  • Soriatane
  • Active Pharmaceutical Ingredients
  • Various Metabolites and Impurities
  • Intermediates & Fine Chemicals
  • Metabolites & Impurities
  • Pharmaceuticals
  • Retinoids
  • Intracellular receptor
Mol File:
55079-83-9.mol
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Acitretin Chemical Properties

Melting point:
228-230°C
Boiling point:
404.46°C (rough estimate)
Density 
1.1348 (rough estimate)
refractive index 
1.4700 (estimate)
storage temp. 
2-8°C
solubility 
Practically insoluble in water, sparingly soluble in tetrahydrofuran, slightly soluble in acetone and in ethanol (96 per cent), very slightly soluble in cyclohexane.
form 
powder
pka
4.72±0.33(Predicted)
λmax
352nm(MeOH)(lit.)
Merck 
14,112
Stability:
LIGHT SENSITIVE
CAS DataBase Reference
55079-83-9(CAS DataBase Reference)
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Safety Information

Hazard Codes 
T,N
Risk Statements 
61-36/38-50/53
Safety Statements 
53-26-45-60-61-37/39
RIDADR 
UN 3077 9/PG 3
WGK Germany 
3
RTECS 
RA8460000
8-10-21
HazardClass 
9
PackingGroup 
III
HS Code 
2918992090
Hazardous Substances Data
55079-83-9(Hazardous Substances Data)
Toxicity
LD50 i.p. in mice (mg/kg): >4000 (1 day), 700 (10 days), 700 (20 days) (Bollag, 1978)

MSDS

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Acitretin Usage And Synthesis

Description

Acitretin is the free acid form of etretinate useful in the treatment of severe psoriasis and other disorders of keratinization. Although the two compounds have virtually the same efficacy and teratogenic side-effects, acitretin is advantageous for child-bearing women, as its shorter half-life reduces the necessary contraception period from two years to only one month after treatment ceases.

Chemical Properties

Crystalline Solid

Originator

Hoffmann-La Roche (Switzerland)

Uses

A synthetic retinoid which is the major metabolite of etretinate (E938000).

Uses

antipsoriatic;binds to nuclear receptors that regulate gene transcription

Indications

Unlike isotretinoin, acitretin (Soriatane) is not primarily sebosuppressive. Rather, it promotes normalization of dysregulated keratinocyte proliferative activity in the epidermis and is also antiinflammatory. Oral absorption is optimal when acitretin is taken with a fatty meal; peak levels are reached approximately 3 hours after ingestion, while steady-state plasma levels are achieved after approximately 3 weeks of daily dosing. The mean terminal elimination half-life of the parent compound is 49 hours. However, when consumed with ethanol, acitretin may be transesterified to form etretinate, a retinoid that is stored in adipose tissue, resulting in a much longer half-life (3–4 months or longer).

Manufacturing Process

228 g of 5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1- triphenylphosphonium bromide was added under nitrogen to 910 ml of dimethylformamide and treated at 5-10°C within 20 min. with 17.5 g of a suspension of sodium hydride (about 50% by weight) in mineral oil. The mixture was stirred for 1 hour at about 10°C, then 61.8 g of 3-formylcrotonic acid butyl ester was added dropwise at 5-8°C, a mixture was heated for 2 hours at 65°C, subsequently introduced into 8 L of ice-water, then was added 300 g of sodium chloride, and the mixture thoroughly extracted with a total 18 L of hexane. The extract was washed 5 times with 1 L of methanol/water (6:4 parts by volume) each time and 2 times with 1.5 L water each time, dried over sodium sulphate and evaporated under reduced pressure to leave 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester, m.p. 80-81°C.
125.8 g of this ester was introduced into 2 L of abs. ethanol and treated with a solution of 125.6 g of hydroxide in 195 ml of water. The mixture was heated to boiling under nitrogen gassing for 30 minutes, then cooled, introduced into 10 L of ice-water and, after the addition of about 240 ml of conc. hydrochloric acid (pH 2-4), thoroughly extracted with total 9 L methylene chloride. Extract is washed with about 6 L water to neutrality, dried over calcium chloride and evaporated under reduced pressure. The residue is taken up in 700 ml of hexane. The precipitated 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethylnona- 2,4,6,8-tetraen-1-oic acid melts at 228-230°C.

brand name

Soriatane (Connetics);Neotigason (r) 10;Neotigason roche 10 mg;Neotigason sauter kapsein 25 mg.

Therapeutic Function

Antipsoriatic

World Health Organization (WHO)

Acitretin, a retinol derivative, was introduced in 1989 for the treatment of severe psoriasis. By the end of 1990, acitretin was confirmed to be metabolized in part to etretinate. Marketing authorization was suspended temporarily in France while the product information was modified to conform to the recommendations issued by the Committee for Proprietary Medicinal Products of the European Communities. Acitretin remains registered in several countries. See also WHO comment for etretinate.

Mechanism of action

Acitretin (Soriatane) is a synthetic derivative of vitamin A that is particularly effective in treating the pustular and erythrodermic forms of psoriasis. It is the main metabolite of etretinate; ingestion of alcohol with acitretin increases the amount of detectable etretinate. It is accumulated in fatty tissue with a prolonged elimination half-life of approximately 120 days. Most patients show improvement within 2 to 4 weeks, although some patients may need as long as 6 months of therapy before a response is noted.

Pharmacology

Like other systemic retinoids, acitretin is a serious teratogen and should not be prescribed for women of childbearing potential unless no acceptable alternative is available and the patient has acknowledged in writing that she understands the need to use two effective forms of contraception during therapy and for 3 years following discontinuation of therapy. Because of the much longer half-life of etretinate, which may be formed when ethanol is ingested with acitretin, female patients of childbearing potential must also agree not to ingest alcohol during treatment and for 2 months following its discontinuation. Other toxicities are similar to those of isotretinoin; they include cutaneous irritation and inflammation, bone and joint pain, hyperlipidemia, hepatic enzyme elevation, and tendinous and ligamentous calcifications.Alopecia (hair loss) may also occur in some patients.

Clinical Use

Acitretin is most useful for the treatment of severe psoriasis, particularly the pustular and erythrodermic variants. Psoriatic nail changes and arthritis also may respond. Combining the drug with ultraviolet light therapy (Re-UVB, in the case of ultraviolet B radiation, or Re-PUVA, with psoralen plus ultraviolet A radiation) permits the use of lower doses of both acitretin and ultraviolet radiation. Other conditions for which the drug may be especially useful include congenital and acquired hyperkeratotic disorders, such as the ichthyoses and palmoplantar keratodermas, and severe lichen planus.

Side effects

Side effects are dose dependent and include elevation of triglycerides, hepatitis, hair loss, thinning of the nails, cheilitis, xerosis, and stickiness of the skin. Gemfibrozil (300 mg b.i.d.) corrects elevated lipid levels on this therapy.

Veterinary Drugs and Treatments

Acitretin may be useful in the treatment of canine lamellar ichthyosis, solar-induced precancerous lesions in Dalmatians or bull Terriers, actinic keratoses, squamous cell carcinomas, and intracutaneous cornifying epitheliomas (multiple keratoacanthomas).
While the drug has provided effective treatment of idiopathic seborrhea (particularly in cocker spaniels), it is not effective in treating the ceruminous otitis that may also be present. Results have been disappointing in treating idiopathic seborrheas seen in basset hounds and West Highland terriers.
Acitretin’s usage in cats is very limited, but etretinate has shown some usefulness in treating paraneoplastic actinic keratosis, solarinduced squamous cell carcinoma and Bowen’s Disease in this species.

Acitretin Preparation Products And Raw materials

Raw materials

AcitretinSupplier

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