Iloprost (ciloprost) used to treat a serious heart and lung disorder called pulmonary arterial hypertension

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Iloprost (ciloprost)

6,9ALPHA-METHYLENE-11ALPHA,15S-DIHYDROXY-16-METHYL-PROSTA-5E,13E-DIEN-18-YN-1-OIC ACID

6,​9α-​methylene-​11α,​15S-​dihydroxy-​16-​methyl-​prosta-​5E,​13E-​dien-​18-​yn-​1-​oic acid

Iloprost Molecule

ILOPROST (Ventavis®) is used to treat a serious heart and lung disorder called pulmonary arterial hypertension. While iloprost inhalation solution will not cure this disorder, it is designed to improve symptoms and the quality of life. Generic iloprost inhalation solution is not yet available.

Iloprost is a second generation structural analog of prostacyclin (PGI) with about ten-fold greater potency than the first generation stable analogs, typified by carbaprostacyclin.1 Iloprost binds with equal affinity to the human recombinant IP and EP1 receptors with a Ki of 11 nM.2Iloprost constricts the isolated guinea pig ilium and fundus circular smooth muscle (an EP1 receptor preparation) as strongly as prostaglandin E2 (PGE2) itself.3 Iloprost inhibits the ADP, thrombin, and collagen-induced aggregation of human platelets with an ED50 of about 13 nM.1 In whole animals, iloprost acts as a vasodilator, hypotensive, antidiuretic, and prolongs bleeding time.4 It has been evaluated in several human clinical studies as a treatment for idiopathic pulmonary hypertension.5,6 In these studies, an aerosolized dose of 30 µg/day was effective, and doses as high as 150 µg/day for up to a year were well tolerated.

73873-87-7 CAS NO

78919-13-8 PHENACYL ESTER

Launched – 1992 bayer

Ilomedin®, Ventavis™

iloprost

An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of EPOPROSTENOL, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation.

BAY-q-6256 E-1030 SH-401 ZK-36374

Endoprost Ilomedin Ilomédine Ventavis Iloprost is a synthetic prostacyclin analog discovered and developed by Schering AG and Berlex which has been available for more than ten years as therapy for peripheral arterial occlusive disease (PAOD), including Raynaud’s phenomenon and Buerger’s disease.

Iloprost improves blood flow, relieves the pain associated with circulatory disturbances and improves the healing of ulcers, which can develop as a result of poor arterial blood flow. Iloprost also produces vasodilatation of the pulmonary arterial bed, with subsequent significant improvement in pulmonary artery pressure, pulmonary vascular resistance and cardiac output, as well as mixed venous oxygen saturation. In 2003, Schering AG received approval in the E.U. for an inhaled formulation of iloprost (Ventavis[R]) for the treatment of primary pulmonary hypertension and the following year, the product was launched in Germany and the U.K.

Introduction on the U.S. market took place in March 2005 by CoTherix for the same indication in patients with NYHA Class III or IV symptoms. Iloprost is also available for the treatment of pulmonary hypertension and peripheral vascular disease. CoTherix had been developing a dry powder for potential use in the treatment of pulmonary hypertension; however, no recent development has been reported for this research. In Japan, phase III clinical trials are ongoing for the treatment of pulmonary arterial hypertension. In 2003, CoTherix licensed exclusive rights from Schering AG to market iloprost in the U.S. for primary pulmonary hypertension while Schering AG retained rights to the product outside the U.S. In April 2005, CoTherix established a collaborative research and development agreement with Quadrant to develop an extended-release formulation of iloprost inhalation solution. Iloprost was designated as an orphan medicinal product for the treatment of pulmonary hypertension in December 2000 by the EMEA and will fall under orphan drug protection until 2013.

The FDA has assigned to iloprost several orphan drug designations. In 1989, iloprost solution for infusion was granted orphan drug designation for the treatment of Raynaud’s phenomenon secondary to systemic sclerosis followed by another orphan drug designation in 1990 for iloprost solution for injection for the treatment of heparin-associated thrombocytopenia. In 2004, an additional orphan drug designation for iloprost inhalation solution for the treatment of pulmonary arterial hypertension was assigned.

The status has also been assigned in the E.U. for this indication. In 2012, orphan drug designation was assigned in the U.S. for the treatment of purpura fulminans in combination with eptifibatide and for the treatment of pulmonary arterial hypertension. In 2007, Cotherix was acquired by Actelion.

ILOPROST

iloprost phenacyl ester

Ventavis (TN), Iloprost phenacyl ester, Iloprost-PE, Iloprost (INN), CHEMBL138694, CHEMBL236025, AC1O6009, DAP000273, CID5311181

2-oxo-2-phenylethyl 5-[(2Z)-5-hydroxy-4-[(1E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-octahydropentalen-2-ylidene]pentanoate

IMPORTANT PUBLICATIONS

Ciloprost Drugs Fut 1981, 6(11): 676

A carbohydrate approach for the formal total synthesis of the prostacyclin analogue (16S)-iloprost Tetrahedron Asymmetry 2012, 23(5): 388

Angewandte Chemie, 1981 ,  vol. 93,   12  pg. 1080 – 1081

Tetrahedron Letters, 1992 ,  vol. 33,   52  pg. 8055 – 8056

Helvetica Chimica Acta, 1986 ,  vol. 69,  7  pg. 1718 – 1727

Journal of Medicinal Chemistry, 1986 ,  vol. 29,  3  pg. 313 – 315

US5286494 A1

US 4474802

uS 2013184295

WO 1992014438

WO 1993007876

WO 1993015739

WO 1994008584

WO 2013040068

WO 2012174407

WO 2011047048

……………………………………

•  5,6,7-trinor-4,8-inter-m-phenylene prostaglandin 1₂derivatives.
• Prostaglandin I₂, hereinafter referred to as PGI₂, of

  

  was first found by J.R. Vane et.al. in 1976 and is biosynthe- sized from arachidonic acid via endoperoxide(PGH₂ or PGG₂) in the vascular wall. PGI₂ is well known to show potent activity to inhibit platelet aggregation and to dilate peripheral blood vessels(C & EN, Dec. 20, 1976, page 17 and S. Moncade et al., Nature, 263,633(1976)).

• [0003]
  Because of the unstable exo-enolether structure thereof, PGI₂ is extremely unstable even in a neutral aqueous solution and is readily converted to 6-oxo-PGF_1α which is almost physiologically inactive. Such instability of PGI₂ is a big obstacle to its use as a drug. Furthermore, PGI₂ is unstable in vivo as well and shows only short duration of action.
• The compounds of the present invention are novel PGI₂ derivatives in which the exo-enolether moiety characteristic of PGI₂ is transformed into “inter-m-phenylene” moiety. In this sense the compounds may be regarded as analogs of PGI₂.
• The compounds of the present invention feature much improved stability in vitro as well as in vivo in comparison with PGI₂. The compounds are highly stable even in an aqueous solution and show long duration of action in vivo. Further, the compounds have advantages over PGI₂ for pharmaceutical application because they exhibit more selective physiological actions than PGI₂, which has multifarious, inseperable biological activities.
• Some prostaglandin I₂ derivatives which have 5,6,7-tri- nor-4,8-inter-m-phenylene structure have already been described in publication by some of the present authors. (Kiyotaka Ohno, Hisao Nishiyama and Shintaro Nishio, U.S.P. 4,301,164 (1981)). But, the compounds of the present invention, which feature the presence of alkynyl side chain, have more potent physiological activities as well as decreased side effects than the already disclosed compounds analogous to those of the present invention.
• It is an object of this invention to provide novel prostaglandin I₂derivatives which are stable and possess platelet aggregation-inhibiting, hypotensive, anti-ulcer and other activities.

• 

  is named as 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI₂.

• Alternatively, the compound of the formula (II) may be named as a derivative of butyric acid by the more formal nomenclature. In such a case, the condensed ring moiety is named after the basical structure of 1H-cyclopenta[b]benzofuran of the following formula:

  

  The term “synthetic prostacyclins” as used herein can refer to any prostacyclin that can be prepared via synthetic organic chemistry, including those prostacyclins that are also naturally occurring, such as Prostacyclin (PGI₂):

   

  

  which is also known as Epopreostenol.

  Thus, examples of synthetic prostacyclins include, but are not limited to: Prosta

   

  

  lloprost, which has the structure:

   

  

  Trepro inil (also known as Rumodolin), which has the structure:

   

  

  Beraprost, which has the structure:

   

  

  as well as the esters, stereoisomers, and salts thereof, or other analogues or derivatives of the recited synthetic prostacyclins, such as compounds comprising other aliphatic linker groups linking the carboxylic acid group to the cyclic components of the synthetic prostacyclins, compounds containing additional alkene and/or alkyne bonds, and/or compounds containing additional substituents on the cyclic components of the synthetic prostacyclins.

  

   iloprost, in contrast to PGI.sub.2 a stable prostacyclin derivative, has been known since 1980 by European patent application EP 11591, no other prostacyclin derivative has previously been tested in this indication. It is therefore reasonable to assume that a spontaneous healing is involved in the published case.

  It has now been found, surprisingly, that iloprost is effective in the case of cerebral malaria.

  For salt formation of iloprost, inorganic and organic bases are suitable, as they are known to one skilled in the art for the formation of physiologically compatible salts. For example, there can be mentioned: alkali hydroxides, such as sodium and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.

  The β-cyclodextrin clathrate formation takes place according to EP 259468.

  The production of iloprost is described in detail in EP 11591.

  • Nileprost iloprost, and a process for preparing these compositions.
  • From EP 11 591 already carbacyclin derivatives of the cytoprotective effect on the gastric and intestinal mucosa, and the myocardial cytoprotection using carbacyclin derivatives is known.
  • It has now been found that iloprost (I) and Nileprost (II)

    

    and their salts with physiologically acceptable bases and cytoprotective effect in the kidney.

  • Forming salts of iloprost and Nileprost inorganic and organic bases are suitable, as are known to those skilled in the formation of physiologically compatible salts known. Examples which may be mentioned are: alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.
  • The production of iloprost and is described in detail in EP Nileprost 2234 and EP 11591.

  ………………..

  J. Med. Chem., 1986, 29 (3), pp 313–315

  DOI: 10.1021/jm00153a001

  http://pubs.acs.org/doi/pdf/10.1021/jm00153a001

see paper

THANKS AND REGARD’S

DR ANTHONY MELVIN CRASTO Ph.D GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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