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DRUG SPOTLIGHT–Treprostinil

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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.

File:Treprostinil2.png

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.

Figure US20120197041A1-20120802-C00001

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

IR 3385, 2928, 2856, 1739, 1713, 1585, and 779 cm1;

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, λmax 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.

 


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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