Treprostinil (marketed under the trade names Remodulin for infusion and Tyvaso for inhalation) is a synthetic analog of prostacyclin (PGI₂).

Treprostinil sodium, Uniprost, LRX-15, U-62840, UT-15, BW-15AU, 15AU81, Remodulin

289480-64-4, 81846-19-7 (free acid

During the 1960s a U.K. research team, headed by Professor John Vane began to explore the role of prostaglandins in anaphylaxis and respiratory diseases. Working with a team from the Royal College of Surgeons, Vane discovered that aspirin and other oral anti-inflammatory drugs worked by inhibiting the synthesis of prostaglandins. This finding opened the door to a broader understanding of the role of prostaglandins in the body.

Vane and a team from the Wellcome Foundation had identified a lipid mediator they called “PG-X,” which inhibited platelet aggregation. PG-X, which later would become known as prostacyclin, was 30 times more potent than any other known anti-aggregatory agent.

By 1976, Vane and fellow researcher Salvador Moncada published the first paper on prostacyclin, in the scientific journal Nature. The collaboration produced a synthetic molecule which was given the name epoprostenol. But like native prostacyclin, the structure of the epoprostenol molecule proved to be unstable in solution, prone to rapid degradation. This presented a challenge for both in vitro experiments and clinical applications. To overcome this challenge, the research team that discovered prostacyclin was determined to continue the research in an attempt to build upon the success they had seen with the prototype molecule. The research team synthesized nearly 1,000 analogs.

Treprostinil has demonstrated a unique effect on PPAR gamma, a transcription factor important in vascular pathogenesis as a mediator of proliferation, inflammation and apoptosis. Through a complementary, yet cyclic AMP-independent pathway, treprostinil activates PPARs, another mechanism that contributes to the anti-growth benefits of the prostacyclin class.

Treprostinil is indicated for the treatment of pulmonary arterial hypertension in patients with NYHA Class II-IV symptoms to diminish symptoms associated with exercise.^[1] It may be administered as a continuous subcutaneous infusion or continuous intravenous infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream infections, continuous intravenous infusion should be reserved for patients who are intolerant of the subcutaneous route, or in whom these risks are considered warranted.

In patients with pulmonary arterial hypertension requiring transition from epoprostenol sodium (Flolan), treprostinil is indicated to diminish the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition.

The pharmacokinetics of continuous subcutaneous treprostinil are linear over the dose range of 1.25 to 125 ng/kg/min (corresponding to plasma concentrations of about 15 pg/mL to 18,250 pg/m) and can be described by a two-compartment model. Dose proportionality at infusion rates greater than 125 ng/kg/min has not been studied.

The major effects of treprostinil are vasodilation of arteries in the pulmonary (lung) and body. Treprostinil also inhibits platelet aggregation.

Treprostinil may be administered as a continuous subcutaneous infusion or continuous intravenous infusion via a small infusion pumpthat the patient must wear at all times. Treprostinil can be given subcutaneously by continuous infusion using an infusion set connected to an infusion pump, but also may be given intravenously via a central venous catheter if the patient is unable to tolerate subcutaneous administration because of severe site pain or reaction.

1. Remodulin Full Prescribing Information US Patent No. 5,153,222

2. UT_OpinVEvid_FEB09v.1

3. Cost-minimization analysis of treprostinil vs. epoprostenol as an alternate to oral therapy nonresponders for the treatment of pulmonary arterial hypertension L. Narine, L. K. Hague, J. H. Walker, C. Vicente, R. Schilz, O. Desjardins, T. R. Einarson and M. Iskedjian

…..

(+)-Treprostinil (also known as UT-15) is the active ingredient in Remodulin®, a commercial drug approved by FDA for the treatment of pulmonary arterial hypertension (PAH). It was first described in U.S. Pat. No. 4,306,075. Treprostinil is a stable analog of prostacyclin (PGI₂) belonging to a class of compounds known as benzindene prostacyclins, which are useful pharmaceutical compounds possessing activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition, and bronchodilation.

U.S. Pat. No. 5,153,222 describes use of treprostinil for treatment of pulmonary hypertension. Treprostinil is approved for the intravenous as well as subcutaneous route, the latter avoiding potential septic events associated with continuous intravenous catheters. U.S. Pat. Nos. 6,521,212 and 6,756,033 describe administration of treprostinil by inhalation for treatment of pulmonary hypertension, peripheral vascular disease and other diseases and conditions. U.S. Pat. No. 6,803,386 discloses administration of treprostinil for treating cancer such lung, liver, brain, pancreatic, kidney, prostate, breast, colon and head-neck cancer. U.S. patent application publication No. 2005/0165111 discloses treprostinil treatment of ischemic lesions. U.S. Pat. No. 7,199,157 discloses that treprostinil treatment improves kidney functions. U.S. Pat. No. 7,879,909 discloses treprostinil treatment of neuropathic foot ulcers. U.S. publication No. 2008/0280986 discloses treprostinil treatment of pulmonary fibrosis, interstitial lung disease with treprostinil and asthma. U.S. Pat. No. 6,054,486 discloses treatment of peripheral vascular disease with treprostinil. U.S. patent application publication No. 2009/0036465 discloses combination therapies comprising treprostinil. U.S. publication No. 2008/0200449 discloses delivery of treprostinil using a metered dose inhaler. U.S. Pat. Nos. 7,417,070, 7,384,978 and 7,544,713 as well as U.S. publications Nos. 2007/0078095, 2005/0282901, and 2008/0249167 describe oral formulations of treprostinil and other prostacyclin analogs as well as their use for treatment of a variety of conditions. U.S. provisional application No. 61/354,949 filed Jun. 15, 2010 discloses the use of orally administered treprostinil for treatment of Raynaud’s phenomenon, systemic sclerosis and digital ischemic lesions.

Treprostinil and other prostacyclin derivatives have been prepared as described in Moriarty, et al in J. Org. Chem. 2004, 69, 1890-1902, Drug of the Future, 2001, 26(4), 364-374, U.S. Pat. Nos. 4,306,075, 6,441,245, 6,528,688, 6,700,025, 6,765,117, 6,809,223 and US Publication No. 2009/0163738. The entire teaching of these documents are incorporated herein by reference in their entirety. The methods described in these patent documents, however, do not describe a feasible production method for producing stereochemically pure treprostinil because, for example, the methods require the use of expensive reagents and tedious chromatographic purification techniques. Therefore, there is a need in the art for an economical, efficient and simplified method for preparing treprostinil and its synthetic intermediates.

NMR

The ¹HNMR and HPLC of the samples were compared with reference UT-15 and were identical; ¹H NMR (CDCl₃, 300 MHz) δ 0.90 (t, 3H, 6 Hz), 1.05-1.78 (m, 13H), 2.85-2.85-2.98 (m, 1H), 2.03 2.12 (m, 1H), 2.21-2.32 (m, 1H), 2.45-2.53 (m, 1H), 2.61-2.81 (m, 3H), 3.52 (br s, 1H), 3.58-3.69 (m, 1H), 4.62 (s, 2H), 6.69 (d, 1H, J=8 Hz), 6.78 (d, 1H, J=8 Hz), 7.04 (dd, 1H, J=8 Hz).

J. Org. Chem. 2004, 69, 1890-1902

mp 126−127 °C;

[α]²⁵_D +52.6 (c 0.453, MeOH), [α]²⁵_D + 34.0° (c 0.457, EtOH).

IR 3385, 2928, 2856, 1739, 1713, 1585, and 779 cm^–1;

¹H NMR (CDCl₃, 300 MHz) δ 0.87 (t, 3 H, J = 6 Hz), 1.21−1.86 (m, 13H), 2.02−2.44 (m, 4H), 3.42−3.76 (m, 3H), 3.81 (s, 2H), 3.82−3.94 (m, 1H), 4.63−4.68 (m, 1H), 4.88−4.92 (m, 1H), 4.94−4.98 (m, 1H), 4.99−5.02 (m, 1H), 5.60 (s, 1H), 5.92−6.06 (m, 1H), 6.85 (d, 1H, J = 6 Hz), 7.20−7.27 (m, 1H), 7.31−7.37 (m, 1H);

¹³C NMR (MeOH, 75 MHz) δ 13.1, 22.4, 25.1, 25.3, 28.3, 31.8, 32.7, 33.2, 34.7, 36.9, 40.7, 41.0, 51.3, 65.2, 71.6, 76.3, 109.5, 121.1, 125.8, 127.4, 140.8, 155.2, 171.5; UV, λ_max MeOH, 217 nm;

HPLC, Hypersil ODS column (4.6 × 250 mm²), 5 μm; flow rate 2.0 mL/min; mobile phase A, water (60%):acetonitrile (40%):trifluoroacetic acid (0.1%), and mobile phase B, water (22%):acetonitrile (78%):trifluoroacetic acid (0.1%); retention time, 15 min (purity 99.7%). Anal. Calcd for C₂₃H₃₄O₅:  C, 70.74; H, 8.78. Found:  C, 70.41; H, 8.83.