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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Lifetime achievement award, WHC17, in Hyderabad, Telangana, India 22 Aug 2017

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Aug 252017
 

Lifetime achievement award ……..WORLD HEALTH CONGRESS 2017 in Hyderabad, 22 aug 2017 at JNTUH KUKATPALLY. HYDERABAD, TELANGANA, INDIA, Award given by Dr. M Sunitha Reddy Head of the Department, Centre for Pharmaceutical Sciences, Institute of Science &Technology, JNTU-H, Kukatpally, Hyderabad, India

Speaking at World health congress 2017….JNTUH Hyderabad 22 aug 2017



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Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

 spectroscopy, SYNTHESIS, Uncategorized  Comments Off on Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester
Dec 202016
 
str1
2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester
1-Piperazineacetic acid, 4-(4-chlorophenyl)-α,α-dimethyl-, ethyl ester
2-[4-(4-Chlorophényl)-1-pipérazinyl]-2-méthylpropanoate d‘éthyle
Ethyl 2-[4-(4-chlorophenyl)-1-piperazinyl]-2-methylpropanoate
Ethyl-2-[4-(4-chlorphenyl)-1-piperazinyl]-2-methylpropanoat
1206769-44-9
2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester (en)
AGN-PC-0JIRMK
AKOS016034964
ethyl 2-[4-(4-chlorophenyl)piperazin-1-yl]-2-methylpropanoate
MWt310.819
MFC16H23ClN2O2
Image result for MOM CAN TEACH YOU NMRNMR IS EASY
1H NMR PREDICT
 str0
ACTUAL VALUES……..1H NMR (400 MHz, CDCl3): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH2-CH3), 1.35 (s, 6H, 2 x CH3), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 4.20 (q, 2H, J = 7.2 Hz, -CH2-CH3), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).
str1
13C NMR PREDICT
str2
ACTUAL VALUES……..13C NMR (100 MHz, CDCl3): δ ppm 14.3 (CH3), 22.7 ((CH3)2), 46.6 (-CH2-N-CH2-), 49.7 (-CH2-N-CH2-), 60.5 (O-CH2), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).
str3
Paper

To a solution of 4-(4-chlorophenyl)piperazine dihydrochloride 1 (5.0 g, 0.0185 mol) in DMSO (30 ml), anhydrous cesium carbonate (30.0 g, 0.0925 mol), sodium iodide (1.39 g, 0.0093 mol) and ethyl 2-bromo-2-methylpropanoate 2 (3.97 g, 0.02 mol) were added. The resulting mixture was stirred at 25-30oC for 12 hours. The reaction mass was diluted with water (200 ml) and extracted with ethyl acetate (2 x 200 ml). The ethyl acetate layer was washed with water (2 x 100 ml), dried over anhydrous sodium sulfate (10.0 g) and concentrated under vacuum. The crude product thus obtained was purified by column chromatography (stationary phase silica gel 60-120 mesh; mobile phase 10% ethyl acetate in hexane). The title compound 3 was obtained as a white solid (4.73 g, 82 %).

Molbank 2009 m607 i001
Melting Point: 56oC.
EI-MS m/z (rel. int. %): 311 (100) [M+1]+, 236(40), 197(60), 154(45).
IR ν max (KBr) cm-1: 2839-2996 (C-H aliphatic); 1728 (C=O), 1595, 1505 (C=C aromatic), 1205 (C-O bending), 758 (C-Cl bending).
1H NMR (400 MHz, CDCl3): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH2-CH3), 1.35 (s, 6H, 2 x CH3), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH2-N-CH2-), 4.20 (q, 2H, J = 7.2 Hz, -CH2-CH3), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).
13C NMR (100 MHz, CDCl3): δ ppm 14.3 (CH3), 22.7 ((CH3)2), 46.6 (-CH2-N-CH2-), 49.7 (-CH2-N-CH2-), 60.5 (O-CH2), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).
Elemental analysis: Calculated for C16H23ClN2O2: C, 61.83%, H, 7.46%, N, 9.01%; Found: C, 61.90%, H, 7.44%, N, 8.98%.
Molbank 2009, 2009(3), M607; doi:10.3390/M607

Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

1Department of Chemistry, Sambalpur University, JyotiVihar-768019, Orissa, India
2Institute of Chemical Technology (ICT), Matunga, Mumbai-400019, Maharashtra, India
*Author to whom correspondence should be addressed.
Received: 17 May 2009 / Accepted: 30 June 2009 / Published: 27 July 2009
Bijay K Mishra

Professor at Sambalpur University, Chemistry Department

Abstract

The title compound was synthesized by N-alkylation of 4-(4-chlorophenyl)piperazine with ethyl 2-bromo-2-methylpropanoate and its IR, 1H NMR, 13C NMR and Mass spectroscopic data are reported.

 

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CCOC(=O)C(N1CCN(CC1)c1ccc(cc1)Cl)(C)C

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Innogen summit India 2016, 18-19 Aug, Mumbai, India

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Aug 192016
 

 

i1Innogen summit India 2016, 18-19 Aug, Mumbai, India, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd………topic is Supergenerics, Innovation in Generics, commercialization, regulatory, other insights,

 

A0 a1

Dr. Ashok Kumar, President – Centre for Research & Development, Ipca Laboratories Ltd, at Innogen summit India 2016, 18-19 Aug, Mumbai, India,, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd — with DR ASHOK KUMAR OF IPCA at Holiday Inn-Mumbai Intl Airport.

 

A2

PANEL DISCUSSION, Dr. Ashok Kumar, President – Centre for Research & Development, Ipca Laboratories Ltd , Dr. Nilima A. Kshirsagar, National Chair Clinical Pharmacology, ICMR Government of India, Yugal Sikri, Chairman – Pharmaceutical Management, School of Business Management, SVKM’s Narsee Monjee Institute of Management Studies — with Yugal Sikri,, Nilima A. Kshirsagarand ASHOK KUMAR OF IPCA at Holiday Inn-Mumbai Intl Airport.

ashit

Ashit sikka, Koji nakamura, Uttam kumar, allfdron TERUMO, AT Innogen summit India 2016, 18-19 Aug, Mumbai, India,, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd — with Koji nakamura of terumo, Ashit Sikka and UTTAM KUMAR OF TERUMO at Holiday Inn-Mumbai Intl Airport.

 

INNO1 INNO3

ROHAN, RIDDHI AND PALLAVI OF INVENTICON

INNO4 S2

DR NIDHI SAPKAL OF ZIMLABS

S3

ALKA LUTHRA OF LUBRIZOL

 

SEEMA1

 

DR SEEMA SINGH, VP AND HEAD,-LEGAL AND IPM, MACLOEDS PHARMA, Innogen summit India 2016, 18-19 Aug, Mumbai, India,, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd — withSeema Singh.

 

lupin cadila

standing Mr Rajeev patil, Sr VP reg affairs Lupin and Mr Sushrut kulkarni Sr VP Zydus cadila, Head, Pharma tech cemtre — with sushrut kulkarni andrajeev patil.

Thanks to

STR1

Rohan Jagtap

Program Manager – Pharma & Lifesciences

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http://inventiconasia.com/About-Us.aspxgards,

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New Drug Approvals blog by Dr Anthony Crasto hits ten lakh views in 211 countries

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Dec 282015
 

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New Drug Approvals hits ten lakh views in 211 countries

http://newdrugapprovals.org/

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463
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ORGANIC SPECTROSCOPY INTERNATIONAL HAS 2 LAKH VIEWS

 spectroscopy  Comments Off on ORGANIC SPECTROSCOPY INTERNATIONAL HAS 2 LAKH VIEWS
Aug 032015
 

 

 

 

 

ORGANIC SPECTROSCOPY INTERNATIONAL HAS 2 LAKH VIEWS

 

Read by one and all in academics and industry

link is ……http://orgspectroscopyint.blogspot.in/

 

I get minimum 1000 hits in a day and all across the world

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ANTHONY CRASTO VENTURES INTO CHINA…..MY KAIXIN BLOG 开心网 ON MEDICINAL CHEMISTRY

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Feb 232015
 

KAIXIN


 

 

MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878

 

CHINA

 

 

 

MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878

 

MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878

 

MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878\

 

 

 

 

 

 

 

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Anthony crasto’s blog New drug approvals touches 3 lakh views…….Helping millions

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Jul 162014
 

link is http://newdrugapprovals.org/

 

All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Helping millions, 7 million hits on google, pushing boundaries, one lakh plus connections worldwide, 3 lakh plus VIEWS on this blog in 193 countries

 

 

 

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

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Market Opportunities Report on Poorly Soluble and Poorly Permeable Drugs

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Jul 162014
 
AZoNano - The A to Z of Nanotechnology
Published on July 14, 2014 at 6:04 AM IN AZANO

Poor bioavailability is a major reason for compounds to fail in preclinical development. Technology Catalysts International (TCI), a leading global pharmaceutical consulting firm, has compiled and analyzed technical and market information pertaining to the delivery of poorly water soluble or poorly permeable pharmaceutical compounds.

http://www.azonano.com/news.aspx?newsID=30615

To download a complimentary excerpt of this report, go to:

http://www.technology-catalysts.com/pdf/psd7_bro.pdf

Source: http://www.technology-catalysts.com/

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

 orphan status  Comments Off on Iloprost (ciloprost) used to treat a serious heart and lung disorder called pulmonary arterial hypertension
Jan 132014
 

http://chem.sis.nlm.nih.gov/chemidplus/RenderImage?maxscale=30&width=300&height=300&superlistid=0078919138

Iloprost (ciloprost)

MF C22H32O4
Formula Wgt 360.5

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.pngiloprost

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

  • BAY Q6256
  • Ciloprost
  • Iloprost
  • Iloprostum
  • Iloprostum [Latin]
  • UNII-AHG2128QW6
  • UNII-JED5K35YGL
  • Ventavis
  • ZK 00036374
  • 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

Molecular Formula: C30H38O5   Molecular Weight: 478.61972

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 2013253049

uS 2013184295

WO 1992014438

WO 1993007876

WO 1993015739

WO 1994008584

WO 2013040068

WO 2012174407

WO 2011047048

EP0011591A1 * Oct 18, 1979 May 28, 1980 Schering Aktiengesellschaft Prostane derivatives, their production and pharmaceutical compositions containing them
EP0084856A1 * Jan 19, 1983 Aug 3, 1983 Toray Industries, Inc. 5,6,7-Trinor-4, 8-inter-m-phenylene prostaglandin I2 derivatives
EP0099538A1 * Jul 11, 1983 Feb 1, 1984 Schering Aktiengesellschaft Carbacyclines, process for their preparation and their use as medicines

……………………………………

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

    Figure imgb0001

    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 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.

 

  • Figure imgb0004

    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:

    Figure imgb0005

    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):

     

    Figure imgf000025_0001

    which is also known as Epopreostenol.

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

     

    Figure imgf000025_0002

    lloprost, which has the structure:

     

    Figure imgf000025_0003

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

     

    Figure imgf000025_0004

    Beraprost, which has the structure:

     

    Figure imgf000026_0001

    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.

    Figure imgf000031_0001

     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)

      Figure imgb0001

      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

see paper

………………………………..
The formal total synthesis of the synthetic and stable analogue of prostacyclin, (16S) iloprost is described via a convergent synthesis starting from readily available d-glucose. Julia olefination and the aldol reaction are the key steps involved in the synthesis.
Full-size image (18 K)
……………………………………
  • Used as the starting material for the method described above ketone of general formula II can be prepared by reacting an alcohol of the formula IV

    Figure imgb0006

    (EJCorey et al., J. Amer. Chem. 93, 1490 (1971)) transformed with dihydropyran in the presence of catalytic amounts of p-toluenesulfonic acid in the tetrahydropyranyl ether V.

    Figure imgb0007
  • [0026]
    Lactone V with Diisobatylauminiumnydrid reduced at -70 ° C to the lactol VI, which is converted by Wittiereaktion Triphenylphosphoniummethylen with the olefin VII. After conversion to the tosylate with p-toluenesulfonyl chloride in the presence of pyridine is obtained by reaction with potassium nitrite in the dimethylsulfoxide 9SS-configured alcohol IX, which is converted with p-toluenesulfonyl chloride in the presence of pyridine in the tosylate X. Reaction with Malonsäurediäthylester in presence of potassium tert-butoxide gives the diester XI, which is converted by decarbalkoxylation with sodium cyanide in dimethyl sulfoxide in the ester XII.

    Figure imgb0008
  • [0027]
    Oxidative cleavage of the double bond in the compound XII with Hatrium p j o dat it out in the presence of catalytic amounts of osmium tetroxide to give the aldehyde XIII, which is oxidized with Jones reagent to the acid XIV which is then esterified with diazomethane to the compound XV. By Dieckmann condensation of XV with potassium tert-butoxide in tetrahydrofuran is obtained a mixture of isomers of the ketocarboxylic acid ester XVI and XVII, which by means of a decarbalkoxylation with 1,4-diazabicyclo [2,2,2] octane in xylene converted into ketone XVIII as the only reaction product is.

    Figure imgb0009
  • [0028]
    The removal of the Tetrahydropyranylätherschutzgruppe delivers the alcohol XIX, which is esterified with benzoyl chloride in the presence of pyridine to give the ester XX.

    Figure imgb0010
  • [0029]
    Benzyläthers hydrogenolytic cleavage of a catalytic amount of acid gives the alcohol XXI, which is according to ketalization compound XXII oxidized with Collins reagent to aldehyde XXIII.
  • [0030]
    This aldehyde XXIV with a phosphonate of the general formula

    Figure imgb0011

    wherein D, E and R 2 have the meanings given above is reacted in a Olefinicrungsreaktion to a ketone of the formula XXV.

    Figure imgb0012
  • [0031]
    After reduction of the 15-keto group with zinc borohydride or sodium borohydride or reaction with alkylmagnesium bromide or alkyllithium and. Epimerentrennung obtain the 15α-alcohols XXVI (PG numbering).

    Figure imgb0013
  • [0032]
    After hydrolysis of the ester group, for example with potassium carbonate in methanol and ketal cleavage with aqueous acetic acid yields the ketone of the formula XXVII,

    Figure imgb0014
……………………………………
ANTHONY MELVIN CRASTO

THANKS AND REGARD’S

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

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