estra-1,3,5(10)-triene-3,17beta-diol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate)

Originator

Estracyt,Bastian Werk,W. Germany,1973

Background

A nitrogen mustard linked to estradiol, usually as phosphate; used to treat prostatic neoplasms; also has radiation protective properties.

Definition

ChEBI: A steroid phosphate which is the 17-O-phospho derivative of estramustine.

Manufacturing Process

A solution in dry benzene of 82 grams of bis(β-chloroethyl)amine freshly liberated from its hydrochloride is added gradually to a solution of 36 grams of carbonyl chloride (phosgene) in benzene at a temperature below 10°C. The mixture is mechanically stirred for 3 hours, the precipitate of bis(β- chloroethyl)amine hydrochloride is removed by filtration and the benzene is distilled off on a water bath. The residue is distilled in vacuo and the Nchloroformyl-bis(β-chloroethyl)amine is obtained as a pale yellow oil with a BP of 114° to 116°C at 1 mm Hg.
To a solution of 16.35 grams of estradiol in 75 ml of dry pyridine, 21.00 grams of the abovementioned chloroformyl-bis(β-chloroethyl)amine are added while stirring and cooling with ice-water.
The reaction mixture is allowed to stand at room temperature for 60 to 70 hours under the exclusion of air humidity. Then the excess of the chloroformyl compound is hydrolyzed with crushed ice. Ethyl acetate is added and after shaking, the ethyl acetate solution is separated and washed with water, dried over sodium sulfate and evaporated in vacuo to dryness.
The residue is the 3-N-bis(beta-chloroethyl)carbamate of estradiol. The compound melts at 101° to 103°C after recrystallization from isopropyl ether plus hexane (1:1).
To a solution of 2.3 ml of phosphorus oxychloride in 50 ml of dry pyridine is added a solution of 2.2 grams of 3-N-bis(β-chloroethyl)carbamate of estradiol while stirring and at a temperature of about -10°C. The reaction mixture is allowed to stand at about 0°C for 1? hours, whereupon it is hydrolyzed by pouring it into ice-water. The main part of the pyridine is evaporated in vacuo, whereupon the residue is poured into 100 ml of cold 3.5 N hydrochloric acid with stirring. The precipitate thus obtained is isolated and washed with 0.1 N hydrochloric acid and water.
The compound, which consists of the 17-phosphate of estradiol-3-N-bis(β- chloroethyl)carbamate, melts under decomposition at about 155°C. It is soluble in an aqueous solution of alkali.

Therapeutic Function

Cancer chemotherapy

Clinical Use

Alkylating agent:
Prostate cancer

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid concomitant use with clozapine (increased risk of agranulocytosis).
Bisphosphonates: concentration increased by sodium clodronate

Metabolism

Not Available

Metabolism

Estramustine sodium phosphate is absorbed from the gastrointestinal tract and rapidly dephosphorylated in the intestine and prostate to estramustine and its oxidised isomer estromustine. Some hydrolysis of the carbamate linkage occurs in the liver, releasing estradiol, estrone, and the normustine group. Estramustine and estromustine are excreted with their metabolites mainly in the faeces.