TreprostinilSodium

Description

Treprostinil sodium has been launched for the treatment of pulmonary hypertension. This synthetically designed tricyclic benzindene analog of the natural potent vasodilator prostacyclin has been developed for subcutaneous infusion. Treprostinil sodium can be prepared in a 15 step stereoselective process. It has been suggested that treprostinil sodium acts via the prostacyclin receptor since the agent could only increase CAMP in human embryonic kidney cells transiently transfected with the human prostacyclin receptor. In a conscious spontaneously hypertensive rat model, treprostinil sodium reduced hypoxia-induced increases in pulmonary arterial pressure and pulmonary vascular resistance in a dose-related manner. At higher doses, the test compound reduced systemic arterial pressure and systemic vascular resistance. In patients with primary pulmonary arterial hypertension, a one year therapy with treprostinil improved hemodynamics parameters: a 22% improvement in cardiac output, a 24% significant decrease in peripheral vascular resistance, a decrease in mean pulmonary arterial pressure (55 vs. 58 mmHg at baseline) and an improvement in NYHA functional class were observed. In addition, 6-min walk distance was significantly improved (463 vs. 399 m at baseline). A larger study conducted in 470 patients with pulmonary arterial hypertension has demonstrated the same type of result. In patients with severe intermittent claudication, infusion of treprostinil was well tolerated and increased the blood flow in most of the peripheral arteries of the lower limb. Treprostinil is eliminated in a biphasic distribution with a terminal half-life of 2-4 h. Approximately 79% of the administrated dose is excreted in the urine. Thus, treprostinil, in contrast to the currently available epoprostenol remains biologically active for a longer time and is not sensitive to light and temperature. Moreover, the subcutaneous administration avoids the epoprostenol systemic side effects due to continuous surgically implanted intravenous infusion. Treprostinil is well tolerated by patients and the main adverse effects currently observed are injection site reaction and injection site pain.

Originator

Pharmacia/ GSK (USA)

Uses

Treprostinil Sodium is a potent agonist of DP1, EP2 and IP receptors.

brand name

Remodulin

Synthesis

The synthesis of treprostinil starts from commercially available 3-methoxybenzyl alcohol (213). The hydroxyl group in 213 was protected as a t-butyldimethylsilyl ether via reaction with TBDMS chloride in DCM at rt. A regiospecific introduction of the allylic chain and deprotection of the silyl group in situ provided alcohol 216 in 36% yield in a three-step sequence. Swern oxidation of alcohol 216 using oxalyl chloride/DMSO furnished aldehyde 217 in 86% yield. Acetylene 218 was first treated with magnesium ethyl bromide and then reacted with aldehyde 217 to provide adduct 219 in 52% yield. The alcohol functional group in 219 was then transformed into a carbonyl group in 220 via a PCC-mediated oxidation. Ketone 220 was then reduced again using chiral boron reagent to give the chiral alcohol which was protected with TBDMS chloride in situ (221). Optically pure intermediate 221 underwent cobalt-mediated Pauson-Khand reaction to furnish tricyclic compound 222 in excellent yield. Catalytic hydrogenation was employed to reduce the double bond and the hydroxyl moiety to give ketone 223. Sodium borohydride mediated reduction of the carbonyl group in 223 gave single diastereomer 224. The THP and methyl ether protecting groups were then removed in a two-step process to give triol 226. The more reactive hydroxyl group on the phenyl ring was then reacted with chloroacetonitrile to furnish nitrile 227. A base mediated hydrolysis of the nitrile provided free acid, treprostinil (228), which was converted to its sodium salt 26 by titration with sodium hydroxide (no yield reported).