AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

 PROCESS, SYNTHESIS  Comments Off on Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products
Jan 052016
 

 

Abstract Image

Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.

Two examples out of several in the publication discussed below……………

 

1  Diphenhydramine Hydrochloride

Figure
Scheme 1. Continuous Flow Synthesis of Diphenhydramine Hydrochloride
Diphenhydramine hydrochloride is the active pharmaceutical ingredient in several widely used medications (e.g., Benadryl, Zzzquil, Tylenol PM, Unisom), and its worldwide demand is higher than 100 tons/year.
In 2013, Jamison and co-workers developed a continuous flow process for the synthesis of 3minimizing waste and reducing purification steps and production time with respect to existing batch synthetic routes (Scheme 1). In the optimized process, chlorodiphenylmethane 1 and dimethylethanolamine 2 were mixed neat and pumped into a 720 μL PFA tube reactor (i.d. = 0.5 mm) at 175 °C with a residence time of 16 min. Running the reaction above the boiling point of 2and without any solvent resulted in high reaction rate. Product 3, obtained in the form of molten salt (i.e., above the melting point of the salt), could be easily transported in the flow system, a procedure not feasible on the same scale under batch conditions.
The reactor outcome was then combined with preheated NaOH 3 M to neutralize ammonium salts. After quenching, neutralized tertiary amine was extracted with hexanes into an inline membrane separator. The organic layer was then treated with HCl (5 M solution in iPrOH) in order to precipitate diphenhydramine hydrochloride 3 with an overall yield of 90% and an output of 2.4 g/h.

2 Olanzapine

Figure
Scheme 2. Continuous Flow Synthesis of Olanzapine
Atypical antipsychotic drugs differ from classical antipsychotics because of less side effects caused (e.g., involuntary tremors, body rigidity, and extrapyramidal effects). Among atypical ones, olanzapine 10, marketed with the name of Zyprexa, is used for the treatment of schizophrenia and bipolar disorders.
In 2013 Kirschning and co-workers developed the multistep continuous flow synthesis of olanzapine 10 using inductive heating (IH) as enabling technology to dramatically reduce reaction times and to increase process efficiency.(16) Inductive heating is a nonconventional heating technology based on the induction of an electromagnetic field (at medium or high frequency depending on nanoparticle sizes) to magnetic nanoparticles which result in a very rapid increase of temperature.As depicted in Scheme 2 the first synthetic step consisted of coupling aryl iodide 4 and aminothiazole 5 using Pd2dba3 as catalyst and Xantphos as ligand. Buchwald–Hartwig coupling took place inside a PEEK reactor filled with steel beads (0.8 mm) and heated inductively at 50 °C (15 kHz). AcOEt was chosen as solvent since it was compatible with following reaction steps. After quenching with distilled H2O and upon in-line extraction in a glass column, crude mixture was passed through a silica cartridge in order to remove Pd catalyst. Nitroaromatic compound 6 was then subjected to reduction with Et3SiH into a fixed bed reactor containing Pd/C at 40 °C. Aniline 7 was obtained in nearly quantitative yield, and the catalyst could be used for more than 250 h without loss of activity. The reactor outcome was then mixed with HCl (0.6 M methanol solution) and heated under high frequency (800 kHz) at 140 °C. Acid catalyzed cyclization afforded product 8 with an overall yield of 88%. Remarkably, the three step sequence did not require any solvent switch, and the total reactor volume is about 8 mL only.
The final substitution of compound 8 with piperazine 9 was carried out using a 3 mL of PEEK reactor containing MAGSILICA as inductive material and silica-supported Ti(OiPr)4 as Lewis acid. Heating inductively the reactor at 85 °C with a medium frequency (25 kHz) gave Olanzapine 10 in 83% yield.

SEE MORE IN THE PUBLICATION…………..

 

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00325
Publication Date (Web): November 26, 2015
Copyright © 2015 American Chemical Society
http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00325

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Maurizio Benaglia

Riccardo Porta

Riccardo Porta

 PhD Student

Alessandra Puglisi

Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy

Map of milan italy

 

 

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Synthesis of Phospholipopeptides

 SYNTHESIS  Comments Off on Synthesis of Phospholipopeptides
Jun 102015
 

thumbnail image: Synthesis of Phospholipopeptides

Synthesis of Phospholipopeptides

A crosslinking approach for the synthesis of phospholipopeptides under mild conditions

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http://www.chemistryviews.org/details/news/7984971/Synthesis_of_Phospholipopeptides.html

Bonan Li and Jun F. Liang, Stevens Institute of Technology, Hoboken, NJ, USA, report an approach to synthesize phospholipopeptides. They use a crosslinker with a thiol-reactive maleimide and an amine-reactive N-hydroxysuccinimide ester (pictured). Hence, the molecule is able to link the thiol group of the amino acid cystein in the peptide and the amine group of the phospholipid (phosphatidylamine).

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Synthesis of water-soluble β-NaYF4 nanocrystals in a green way

 nanotechnology  Comments Off on Synthesis of water-soluble β-NaYF4 nanocrystals in a green way
Jul 032014
 

Graphical abstract: Synthesis of water-soluble β-NaYF4 nanocrystals in a green way

http://pubs.rsc.org/en/Content/ArticleLanding/2014/CE/C4CE00643G?utm_medium=email&utm_campaign=pub-CE-vol-16-issue-29&utm_source=toc-alert#!divAbstract

Pure β-NaYF4 nanocrystals with a hexagonal phase were synthesized in a novel way at low temperature using sparingly soluble rare-earth salts as precursors and ethanol–water as the solvent. The phase of the products could be controlled by adjusting the water content. An up-converting aqueous colloidal solution and a transparent film were obtained through a simple post-treatment.

 

Synthesis of water-soluble β-NaYF4 nanocrystals in a green way

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*Corresponding authors
aMOE Key Laboratory of Bioinorganic and Synthetic Chemistry/State Key Laboratory of Optoelectronic Materials and Technology, Key Laboratory of Environment and Energy Chemistry of Guangdong Higher Education Institutes, School of Chemistry and Chemical Engineering, Sun Yat-Sen (Zhongshan) University, Guangzhou, PR China
E-mail: ceswmm@mail.sysu.edu.cn;
Fax: +86 20 84111038
bDepartment of Chemistry, University of Toronto, 80 St George Street, Toronto, Canada M5S 3H6
E-mail: gozin@chem.utoronto.ca
CrystEngComm, 2014,16, 6526-6529

DOI: 10.1039/C4CE00643G

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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-PGF1α 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

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock need help, email or call me

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I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

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SURAMIN HEXASODIUM

 Uncategorized  Comments Off on SURAMIN HEXASODIUM
Jan 082014
 

 

suramin

A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties.

A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. Suramin is manufactured by Bayer in Germany as Germanin®.

Also known as: Naphuride, Germanin, Naganol, Belganyl, Fourneau, Farma, Antrypol, Suramine, Naganin

8,8′-{Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]}di(1,3,5-naphthalenetrisulfonic acid) …FREE FORM

8,8′-[Ureylenebis[m-phenylenecarbonylimino(4-methyl-m-phenylene)carbonylimino]]di(1,3,5-naphthalenetrisulfonic acid) hexasodium salt

CAS  145-63-1 FREE FORM

129-46-4 of hexa sodium

LAUNCHED 1940 BAYER

Formula C51H40N6O23S6 
Mol. mass 1297.29

The molecular formula of suramin is C51H34N6O23S6. It is a symmetric molecule in the center of which lies urea, NH-CO-NH. Suramin contains eightbenzene rings, four of which are fused in pairs (naphthalene), four amide groups in addition to the one of urea and six sulfonate groups. When given as drug it usually contains six sodium ions that form a salt with the six sulfonate groups.

Suramin is a drug developed by Oskar Dressel and Richard Kothe of Bayer, Germany in 1916, and is still sold by Bayer under the brand nameGermanin.

Suramin sodium is a heparanase inhibitor that was first launched in 1940 by Bayer under the brand name Antrypol for the treatment of helminthic infection. It was later launched by Bayer for the treatment of trypanosomiasis (African sleeping sickness).

More recently, the product has entered early clinical development at Ohio State University for the treatment of platinum-pretreated patients with stage IIIB/IV non-small cell lung cancer, in combination with docetaxel or gemcitabine.

The National Cancer Institute (NCI) is conducting phase II clinical studies for the treatment of glioblastoma multiforme and for the treatment of adrenocortical carcinoma.

According to the National Cancer Institute there are no active clinical trials (as of April 1, 2008). Completed and closed clinical trials are listed here:[1]

In addition to Germanin, the National Cancer Institute also lists the following “Foreign brand names”: 309 F or 309 Fourneau,[1] Bayer 205, Moranyl, Naganin, Naganine.

It is used for treatment of human sleeping sickness caused by trypanosomes.[2]

It has been used in the treatment of onchocerciasis.[3]

It has been investigated as treatment for prostate cancer.[4]

Also, suramin as treatment for autism is being evaluated. [5]

Suramin is administered by a single weekly intravenous injection for six weeks. The dose per injection is 1 g.

The most frequent adverse reactions are nausea and vomiting. About 90% of patients will get an urticarial rash that disappears in a few days without needing to stop treatment. There is a greater than 50% chance of adrenal cortical damage, but only a smaller proportion will require lifelongcorticosteroid replacement. It is common for patients to get a tingling or crawling sensation of the skin with suramin. Suramin will cause clouding of the urine which is harmless: patients should be warned of this to avoid them becoming alarmed.

Kidney damage and exfoliative dermatitis occur less commonly.

Suramin has been applied clinically to HIV/AIDS patients resulting in a significant number of fatal occurrences and as a result the application of this molecule was abandoned for this condition. http://www.ncbi.nlm.nih.gov/pubmed/3548350

Suramin is also used in research as a broad-spectrum antagonist of P2 receptors[6][7] and agonist of Ryanodine receptors.[8]

ChemSpider 2D Image | 8,8'-{Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]}di(1,3,5-naphthalenetrisulfonic acid) | C51H40N6O23S6suramin

Its effect on telomerase has been investigated.[9]

It may have some activity against RNA viruses.[10]

In addition to antagonism of P2 receptors, Suramin inhibits the acitivation of heterotrimeric G proteins in a variety of other GPCRs with varying potency. It prevents the association of heteromeric G proteins and therefore the receptors Guanine exchange functionality (GEF). With this blockade the GDP will not release from the Gα subunit so it can not be replaced by a GTP and become activated. This has the effect of blocking downstream G protein mediated signaling of various GPCR proteins including Rhodopsin, the A1 Adenosine receptor, and the D2 dopamine receptor.[11]

A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. Suramin is manufactured by Bayer in Germany as Germanin®.

8-1-2012
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  1.  The formula of suramin was kept secret by Bayer for commercial reasons. But it was elucidated and published in 1924 by Fourneau and his team of the Pasteur Institute, and it is only on this date that its exact chemical composition was known. (E. Fourneau, J. and Th. Tréfouël and J. Vallée (1924). “Sur une nouvelle série de médicaments trypanocides”, C. R. Séances Acad. Sci. 178: 675.)
  2. Darsaud A, Chevrier C, Bourdon L, Dumas M, Buguet A, Bouteille B (January 2004). “Megazol combined with suramin improves a new diagnosis index of the early meningo-encephalitic phase of experimental African trypanosomiasis”. Trop. Med. Int. Health 9 (1): 83–91.doi:10.1046/j.1365-3156.2003.01154.x. PMID 14728611.
  3.  Anderson J, Fuglsang H (July 1978). “Further studies on the treatment of ocular onchocerciasis with diethylcarbamazine and suramin”. Br J Ophthalmol 62 (7): 450–7.doi:10.1136/bjo.62.7.450. PMC 1043255. PMID 678497.
  4.  Ahles TA, Herndon JE, Small EJ, et al. (November 2004). “Quality of life impact of three different doses of suramin in patients with metastatic hormone-refractory prostate carcinoma: results of Intergroup O159/Cancer and Leukemia Group B 9480”. Cancer 101 (10): 2202–8.doi:10.1002/cncr.20655. PMID 15484217.
  5.  http://medicalxpress.com/news/2013-03-drug-treatment-autism-symptoms-mouse.html
  6.  Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA. (september 2006). “International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy”. Pharmacol Rev. 58 (3): 281–341.doi:10.1124/pr.58.3.3. PMID 16968944.
  7.  Khakh BS, Burnstock G, Kennedy C, King BF, North RA, Séguéla P, Voigt M, Humphrey PP. (march 2001). “International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits”. Pharmacol Rev. 53 (1): 107–118.PMID 11171941.
  8.  Wolner I, Kassack MU, Ullmann H, Karel A, Hohenegger M (October 2005). “Use-dependent inhibition of the skeletal muscle ryanodine receptor by the suramin analogue NF676”. Br. J. Pharmacol. 146 (4): 525–33. doi:10.1038/sj.bjp.0706359. PMC 1751178.PMID 16056233.
  9.  Erguven M, Akev N, Ozdemir A, Karabulut E, Bilir A (August 2008). “The inhibitory effect of suramin on telomerase activity and spheroid growth of C6 glioma cells”. Med. Sci. Monit. 14(8): BR165–73. PMID 18667993.
  10.  Mastrangelo E, Pezzullo M, Tarantino D, Petazzi R, Germani F, Kramer D, Robel I, Rohayem J, Bolognesi M, Milani M (2012) Structure-based inhibition of norovirus RNA-dependent RNA-polymerases. J Mol Biol
  11.  Beindl W, Mitterauer T, Hohenegger M, Ijzerman AP, Nanoff C, Freissmuth M. (August 1996).“Inhibition of receptor/G protein coupling by suramin analogues”. ol. Pharmacology. 50 (2): 415–23. PMID 8700151.
  12. Drugs Fut 1986, 11(10): 860
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SURAMIN

Enterovirus-71 (EV71) is one of the major causative reagents for hand-foot-and-mouth disease. In particular, EV71 causes severe central nervous system infections and leads to numerous dead cases. Although several inactivated whole-virus vaccines have entered in clinical trials, no antiviral agent has been provided for clinical therapy. In the present work, we screened our compound library and identified that suramin, which has been clinically used to treat variable diseases, could inhibit EV71 proliferation with an IC50 value of 40μM. We further revealed that suramin could block the attachment of EV71 to host cells to regulate the early stage of EV71 infection, as well as affected other steps of EV71 life cycle. Our results are helpful to understand the mechanism for EV71 life cycle and provide a potential for the usage of an approved drug, suramin, as the antiviral against EV71 infection.

 

  • Suramin Hexasodium
  • 129-46-4

Synonyms

  • 309 F
  • Antrypol
  • BAY 205
  • Bayer 205
  • CI-1003
  • EINECS 204-949-3
  • Fourneau 309
  • Germanin
  • Moranyl
  • Naganin
  • Naganine
  • Naganinum
  • Naganol
  • Naphuride sodium
  • NF060
  • NSC 34936
  • SK 24728
  • Sodium suramin
  • Suramin Hexasodium
  • Suramin sodium
  • Suramina sodica
  • Suramina sodica [INN-Spanish]
  • Suramine sodique
  • Suramine sodique [INN-French]
  • Suramine sodium
  • Suraminum natricum
  • Suraminum natricum [INN-Latin]
  • UNII-89521262IH

 

Suramin Sodium, is an anticancer agent with a wide variety of activities.

Recently suramin was shown to inhibit FSH binding to its receptor (Daugherty, R. L.; Cockett, A. T. K.; Schoen, S. R. and Sluss, P. M. “Suramin inhibits gonadotropon action in rat testis: implications for treatment of advanced prostate cancer” J. Urol. 1992, 147, 727-732).

This activity causes, at least in part, the decrease in testosterone production seen in rats and humans that were administered suramin(Danesi, R.; La Rocca, R. V.; Cooper, M. R.; Ricciardi, M. P.; Pellegrini, A.; Soldani, P.; Kragel, P. J.; Paparelli, A.; Del Tacca, M.; Myers, C. E, “Clinical and experimental evidence of inhibition of testosterone production by suramin.” J. Clin. Endocrinol. Metab. 1996, 81, 2238-2246).

Suramin is the only non-peptidic small molecule that has been reported to be an FSH receptor binding antagonist.

Figure US06200963-20010313-C00003

Suramin is 8,8′ – (carbonylbis(imino-3,1-phenylenecarbonylimino (4-methyl-3,1-phenylene) carbonylimino)) bis-1,3 ,5-naphthalenetrisulfonic acid (GB Patent No. 224849). This polyanionic compound has been used for many decades as a prophylactic and therapeutic agent for try- panosomiasis. It was subsequently shown that suramin is able to block the activity of a variety of proteins like cellular and viral enzymes and growth factors (Mitsuya, M. et al. Science 226 : 172 (1984), Hosang, M. J. Cell. Biochem. 29 : 265 (1985), De Clercq, E. Cancer Lett. 8 : 9 (1979)).

 

5-32-1977
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EP0183352A2 * Sep 27, 1985 Jun 4, 1986 THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce Use of suramin for clinical treatment of infection with any of the members of the family of human-t-cell leukemia (htvl) viruses including lymphadenopathy virus (lav)
EP0205077A2 * Jun 3, 1986 Dec 17, 1986 Bayer Ag Suramin sodium for use as an immunostimulant

 

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TAMOXIFEN, can treat and prevent one type of breast cancer, without the side effects of chemotherapy.

 GENERIC, PROCESS, Uncategorized  Comments Off on TAMOXIFEN, can treat and prevent one type of breast cancer, without the side effects of chemotherapy.
Nov 082013
 

TAMOXIFEN

10540-29-1 CAS

READ ABOUT TITLE AT……….http://www.rsc.org/chemistryworld/sites/default/files/CIIE_Tamoxifen.mp3

 

Molecular Formula: C26H29NO•C6H8O7
CAS Number: 54965-24-1
Brands: Nolvadex, TAMOXIFEN CITRATE

 

Chemically, NOLVADEX (tamoxifen citrate) is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2 hydroxy-1,2,3- propanetricarboxylate (1:1). The structural and empirical formulas are:

 

 

NOLVADEX (Tamoxifen Citrate) Structural Formula Illustration

 

Tamoxifen citrate has a molecular weight of 563.62, the pKa’ is 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL.

 

NDA021807 APPR2005-10-29 DARA BIOSCIENCES,

SOLTAMOX

US PATENT  6,127,425

US 6127425 APPROVED 1998-06-26 EXPIRY 2018-06-26

 

Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, and thus may be characterized as a mixed agonist/antagonist. Tamoxifen is the usual endocrine (anti-estrogen) therapy for hormone receptor-positive breast cancer in pre-menopausal women, and is also a standard in post-menopausal women although aromatase inhibitors are also frequently used in that setting.

Some breast cancer cells require estrogen to grow. Estrogen binds to and activates the estrogen receptor in these cells. Tamoxifen is metabolized into compounds that also bind to the estrogen receptor but do not activate it. Because of this competitive antagonism, tamoxifen acts like a key broken off in the lock that prevents any other key from being inserted, preventing estrogen from binding to its receptor. Hence breast cancer cell growth is blocked.

Tamoxifen was discovered by pharmaceutical company Imperial Chemical Industries (now AstraZeneca) and is sold under the trade names Nolvadex, Istubal, and Valodex. However, the drug, even before its patent expiration, was and still is widely referred to by its generic name “tamoxifen.

 

Breast cancer

Tamoxifen is currently used for the treatment of both early and advanced ER+ (estrogen receptor positive) breast cancer in pre- and post-menopausal women.Additionally, it is the most common hormone treatment for male breast cancer. It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease. It has been further approved for the reduction of contralateral (in the opposite breast) cancer.

In 2006, the large STAR clinical study concluded that raloxifene is equally effective in reducing the incidence of breast cancer, but after an average 4-year follow-up there were 36% fewer uterine cancers and 29% fewer blood clots in women taking raloxifene than in women taking tamoxifen, although the difference is not statistically significant.

Nolvadex (tamoxifen) 20 mg tablets

In 2005, the ATAC trial showed that after average 68 months following a 5 year adjuvant treatment, the group that received anastrozole (Arimidex) had significantly better results than the tamoxifen group in measures like disease free survival, but no overall mortality benefit. Data from the trial suggest that anastrozole should be the preferred medication for postmenopausal women with localized breast cancer that is estrogen receptor (ER) positive.Another study found that the risk of recurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to anastrozole.

 

 

Crystallographic structure of 4-hydroxy-tamoxifen (carbon = white, oxygen = red, nitrogen = blue) complexed with ligand binding domain of estrogen receptor alpha (cyan ribbon)

Tamoxifen

lTamoxifen was first developed in 1962 as a morning-after birth control pill that was successful in experiments with laboratory rats.
lTamoxifen (brand name Nolvadex) is the best-known hormonal treatment and the most prescribed anti-cancer drug in the world.
lUsed for over 20 years to treat women with advanced breast cancer, tamoxifen also is commonly prescribed to prevent recurrences among women with early breast cancer.
lIs a SERMs.
Anti-estrogens work by binding to estrogen receptors, blocking estrogen from binding to these receptors, stopping cell proliferation
lBreast-cancer prevention occurred in 1998 when the National Cancer Institute (NCI) announced results of a six-year study showing that tamoxifen reduced the incidence of breast cancer by 45 percent among healthy but high-risk women.
l13,388 healthy women considered at high risk for breast cancer were recruited
l85 developed breast cancer compared to 154 of those on the placebo or dummy pill.
lpotentially life-threatening side effects. There were 33 cases of endometrial cancer in the tamoxifen group
lThere were 30 cases of blood clots in major veins (deep-vein thrombosis)
lBecause these problems developed exclusively among postmenopausal women
–60-year-old, an age at which 17 out of every 1,000 women can be expected to develop breast cancer within five years
–ages of 35 and 59 were eligible to participate if their risks matched or exceeded those of a 60-year-old
lAlthough tamoxifen has been useful both in treating breast cancer patients and in decreasing the risk of getting breast cancer.
lSide effects arise from the fact that while tamoxifen acts as an antiestrogen that blocks the effects of estrogen on breast cells, it mimics the actions of estrogen in other tissues such as the uterus. Its estrogen-like effects on the uterus stimulate proliferation of the uterine endometrium and increase the risk of uterine cancer.

Adequate patent protection is required to develop an innovation in a timely manner. In 1962, ICI Pharmaceuticals Division filed a broad patent in the United Kingdom (UK) (Application number GB19620034989 19620913). The application stated, “The alkene derivatives of the invention are useful for the modification of the endocrine status in man and animals and they may be useful for the control of hormone-dependent tumours or for the management of the sexual cycle and aberrations thereof. They also have useful hypocholesterolaemic activity”.

This was published in 1965 as UK Patent GB1013907, which described the innovation that different geometric isomers of substituted triphenylethylenes had either oestrogenic or anti-oestrogenic properties. Indeed, this observation was significant, because when scientists at Merrell subsequently described the biological activity of the separated isomers of their drug clomiphene, they inadvertently reversed the naming. This was subsequently rectified.

Although tamoxifen was approved for the treatment of advanced breast cancer in post-menopausal women in 1977 in the United States (the year before ICI Pharmaceuticals Division received the Queen’s Award for Technological Achievement in the UK), the patent situation was unclear. ICI Pharmaceuticals Division was repeatedly denied patent protection in the US until the 1980s because of the perceived primacy of the earlier Merrell patents and because no advance (that is, a safer, more specific drug) was recognized by the patent office in the United States. In other words, the clinical development advanced steadily for more than a decade in the United States without the assurance of exclusivity. This situation also illustrates how unlikely the usefulness of tamoxifen was considered to be by the medical advisors to the pharmaceutical industry in general. Remarkably, when tamoxifen was hailed as the adjuvant endocrine treatment of choice for breast cancer by the National Cancer Institute in 1984, the patent application, initially denied in 1984, was awarded through the court of appeals in 1985. This was granted with precedence to the patent dating back to 1965! So, at a time when world-wide patent protection was being lost, the patent protecting tamoxifen started a 17 year life in the United States. The unique and unusual legal situation did not go uncontested by generic companies, but AstraZeneca (as the ICI Pharmaceuticals Division is now called) rightly retained patent protection for their pioneering product, most notably, from the Smalkin Decision in Baltimore, 1996. (Zeneca, Ltd. vs. Novopharm, Ltd. Civil Action No S95-163 United States District Court, D. Maryland, Northern Division, March 14, 1996.)

 

Title: Tamoxifen
CAS Registry Number: 10540-29-1
CAS Name: (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine
Additional Names: 1-p-b-dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene
Molecular Formula: C26H29NO
Molecular Weight: 371.51
Percent Composition: C 84.06%, H 7.87%, N 3.77%, O 4.31%
Literature References: Nonsteroidal estrogen antagonist.
Prepn: BE 637389 (1964 to ICI). Identification and separation of isomers: G. R. Bedford, D. N. Richardson, Nature 212, 733 (1966); BE 678807; M. J. K. Harper et al., US 4536516 (1966, 1985 both to ICI). Stereospecific synthesis: R. B. Miller, M. I. Al-Hassan, J. Org. Chem. 50, 2121 (1985). Review of chemistry and pharmacology: B. J. A. Furr, V. C. Jordan, Pharmacol. Ther. 25, 127-205 (1984). Reviews of clinical experience in treatment and prevention of breast cancer: I. A. Jaiyesimi et al., J. Clin. Oncol. 13, 513-529 (1995); C. K. Osborne, N. Engl. J. Med. 339, 1609-1618 (1998).
Properties: Crystals from petr ether, mp 96-98°.
Melting point: mp 96-98°
Derivative Type: Citrate
CAS Registry Number: 54965-24-1
Manufacturers’ Codes: ICI-46474
Trademarks: Kessar (Pharmacia); Nolvadex (AstraZeneca); Tamofène (Aventis); Zemide (Alpharma); Zitazonium (Servier)
Molecular Formula: C26H29NO.C6H8O7
Molecular Weight: 563.64
Percent Composition: C 68.19%, H 6.62%, N 2.49%, O 22.71%
Properties: Fine, white, odorless crystalline powder, mp 140-142°. Slightly sol in water; sol in ethanol, methanol, acetone. Hygroscopic at high relative humidities. Sensitive to uv light. LD50 in mice, rats (mg/kg): 200, 600 i.p.; 62.5, 62.5 i.v.; 3000-6000, 1200-2500 orally (Furr, Jordan).
Melting point: mp 140-142°
Toxicity data: LD50 in mice, rats (mg/kg): 200, 600 i.p.; 62.5, 62.5 i.v.; 3000-6000, 1200-2500 orally (Furr, Jordan)
Derivative Type: (E)-Form
CAS Registry Number: 13002-65-8
Properties: mp 72-74° from methanol.
Melting point: mp 72-74° from methanol
Derivative Type: (E)-Form citrate
Manufacturers’ Codes: ICI-47699
Properties: mp 126-128°.
Melting point: mp 126-128°
CAUTION: Tamoxifen is listed as a known human carcinogen: Report on Carcinogens, Eleventh Edition (PB2005-104914, 2004) p III-239.
Therap-Cat: Antineoplastic (hormonal).
Keywords: Antineoplastic (Hormonal); Antiestrogens; Selective Estrogen Receptor Modulator (SERM).
Synthesis of the E and Z isomers of the antiestrogen Tamoxifen. 
David W.Robertson and John A. Katzenellenbogen. 
Journal of Organic Chemistry 1982 , 47, Pages 2387-2393. 
An early synthesis of Tamoxifen : Production of non stereo specific products. 

 

 For easy of understanding the complete synthesis has been broken down into a number of steps.Step 1. 
 
Step 1.
 
This step shows use of a simple friedel-craft acylation involving Anisole(A) and Phenylacetic acid (B). The acylating agent in this process was a mixture of PCl5 / SnCl4. The ketone C was formed in a 78% yield.

 

Step 2.

 

 

 

Step 2.
 

Alkylation was promoted by treating the ketone C with Sodium hydride (NaH). This removed the acidic protons (located on the position alpha to the carbonyl group) to produce the enolate ion. This could be isolated as the sodium enolate of the ketone treatment of this with ethyl iodide resulted in the formation of compound (D) in a 94% yield. The Ethyl iodide was chosen as the acylating agent probably as it contains the iodide ion , which is an excellent leaving group. It can therefore facilitate an SN2 substitution reaction with relative easy.
 

 

 

Step 3.

 

 

 

Step 3.
  The phenol was deprotected using Lithium ethanthiolate in DMF ( Dimethyl This facilitated the removal of the methyl group and replaced it with a H to form a hydroxl group. Thus forming compound (E) in a 96% yield.

 

This is a key step as it has left a chink in the armour of the molecule. This can then be used to build up a characteristic part of the Tamoxifen molecule. (eg the (diemthylamino)ethyl group can be added easily from here)
 

 

Step 4.

 

 

 

 

Step 4.
 

Then product E can be alkylated by treatment with 2-(dimethylamino) ethy chloride. The most facile site of alklation is the OH group on the phenyl ring. This can be interpreted roughly by using HSAB theory. e.g Hard and Soft acid/base theory. The carbon adjacent to the chloride ion of the reactant 2-(dimethylamino)ethyl chloride is made slightly harder due to the process of symbiosis. This can rationalise the formation between the hard oxygen atom to the normally soft carbon atom. In this case the carbon atom has become slightly harder due to the presence of the hard chorine atom. Hence the interaction is favourable by HSAB theory. The above reaction gives product F via a SN2 substitution reaction in 70% yield.
 

 

Step 5.

 

 

Step5.
 

F on treatment with PhMgBr forms the tertiary alcohol (G).
 

Formation of the Grignard reagent can be achieved via reaction of PhBr + Mg —–> PhMgBr. The Grignard reagent has effectively formed a carbanion species eg C delta negative (-ve). This is due to the presence of the C-Mg bond. the fact that Magnesium is a more electropositive element thus making the Carbon atom the more electronegative element and hence acquiring a negative charge. As a result of the negative nature of the carbon atom it can now attack the delta positive (+ve) Carbon atom of the carbonyl group.
 

 

step 6.

 

 

 

 

Step 6.
The dehydration of F was initiated by treatment of methanoic hydrogen chloride. this gives the required structure of Tamoxifen. However it gives a racemic mixture of both cis and trans isomers.
 

The ratio of the Cis / Trans isomers was (1.3 / 1). These isomers of Tamoxifen can be separated by Silica gel thin layer chromatography with benzene / triethylamine (9:1) as the developing solvent. Analysis of this technique revealed that the Z (Trans) isomer was more mobile than the E (Cis) isomer.

Synthetic Route 2: A Stereospecific Approach.

 

Stereospecific Synthesis of (Z) – Tamoxifen via carbometalation of Alkynylsilanes.

Studied for historical reasons rather than synthetic brilliance. This synthesis was the first stereo specific synthesis of (Z) Trans Tamoxifen. Comparison between this synthesis and the previous route I believe can illustrate the development of synthetic approaches to large molecules. In particular the quest for stereo specific reactions. So starting from an alkynylsilane (A) and through a series of reactions we can generate only the (Z) – Trans isomer of Tamoxifen.

Again for ease of understanding the complete synthesis has been broken down into a number of steps.

Step1.

 

Step1.

 

 

This step contains the vital stereo specific step. Namely the carbometalation of the alkynylsilane.It is this step which establishes the stereochemistry about the double bond. The phenyl (trimethyl silyl) – acetylene was carbometalated with diethylaluminium chloride – titanocene dichloride reactant to produce an organometallic intermediate. This organometallic intermediate was then cleaved with N bromosucciniamide to produce the alkene (B) in 85% yield.

The stereochemistry was assigned as E (Cis) mechanistic evidence suggests that this is linked to some steric reasons.

(Earlier work dedicated to this reaction see : Miller, R.B. Al-Hassan.M.I J.Org.Chem. 1984, 49, 725)

Step2.

Step 2.

The second step shows the stereo specific replacement of the Br group by a phenyl group. This was achieved by use of Palladium – catalysed coupling of compound (B) with phenyl zinc chloride to form (C) the vinylsilane in a 95% yield.

Step3.

 

Step3.

This step during the synthesis was reported to be tricky and several approaches were attempted before a successful technique was discovered.

 

The objective of this step was to replace the trimethyl Silyl group by a suitable halogen atom (e.g. Bromine or Iodine)

However a facile reaction was reported when (C) was treated with bromine – sodium methoxide at -78�C to produce the vinyl bromide (D) in a yield of 85%

 

Step 4.

 

Step 4.

The vinyl bromide (D) coupled well with a Zinc organometallic species to produce (E) the ethyl triaryl olefin in a yield of 84%.

Step 5.

 

Step 5.

The formation of (F) Tamoxifen was achieved by demethylation with sodium ethylthoilate in refluxing dimethyl formamide. then reaction of the phenoxide ion with 2-( dimethylamino)ethyl chloride via a SN2 substitution.

Purification of the crude product was achieved via it’s hydrochloride salt ( via a reaction with HCl (g)) then F was regenerated by treatment with dilute base this produced the stereospecific (Z)- Trans isomer in an overall yield of 60%.

a synthesis

Palladium-Catalyzed Fluoride-Free Cross-Coupling of Intramolecularly ActivatedAlkenylsilanes and Alkenylgermanes: Synthesis of Tamoxifen as a Synthetic Application (pages 642–650)Kenji Matsumoto and Mitsuru ShindoArticle first published online: 23 FEB 2012 | DOI: 10.1002/adsc.201100627

Thumbnail image of graphical abstract

 

 

http://pubs.rsc.org/en/content/articlelanding/2011/cs/c0cs00129e#!divAbstract

 

 

 

 

EP 0883587 A1  WO1997026234A1)

 

Preparation of Z isomer of Tamoxifen

A solution of bromobenzene (3.92g, 25mmol) in ether (5ml) containing a crystal of iodine was added dropwise to a suspension of magnesium turnings (0.63g, 26mmol) in ether (5ml) at reflux, under nitrogen. After the addition was complete, the reaction mixture was cooled to room temperature and a solution of l- [ 4- ( 2- chloroethoxy)phenyl]-2-phenyl-l-butanone (3.75g, 12.4mmol) in ether (15ml) was added over 1 hour. The resulting mixture was refluxed for 16 hours, then poured into dilute hydrochloric acid (50ml) and extracted with ether (3x40ml) . The combined ether layers were concentrated, the residual oil was dissolved in ethanol (10ml) and refluxed with concentrated hydrochloric acid (5ml) for 4 hours. The organic phase was separated, dried (Na2S04) and evaporated to dryness to give a yellow oil. Η NMR (see Figures 1 to 4 and discussion below) showed this to be a 2:1 mixture of the Z and E isomers. The oil was then dissolved in warm methanol (about 40°C) and allowed to cool to room temperature. The colourless crystals formed proved to be pure Z isomer of 2-chloroethoxy tamoxifen (4.12g, 11.4mmol, 92% yield) . M.p. 107-109°C, m/z 362/364 (chlorine atom present), <SH 0.92 (3H, t, J = 7.33 Hz, CH3) , 2.46 (2H, q, J = 7.33 Hz, CH2CH3) , 3.72 (2H, t, J = 5.86 Hz, 0CH2CH2C1) , 4.09 (2H, t, J = 5.86 Hz, 0CH2CH2C1) , 6.55 (2H, d, J = 8.79 Hz, aromatic protons ortho to 0CH2CH2C1) , 6.79 (2H, d, J = 8.79 Hz, aromatic protons meta to 0CH2CH2C1) , 7.10-7.38 (10H, m, the two remaining C6H5 ,s) (see Figure 5) . The 2-chloroethoxy tamoxifen was reacted with dimethylamine in ethanol, under reflux, to produce the desired Z isomer of tamoxifen.

Analysis of Η NMR data

Figures 1 to 4 represent a mixture of the E- and Z- forms of compound XI described above.

The expansion of the region ό* 0.80 to 1.05 shows two overlapping triplets corresponding to the CH3 groups in the

Z- and E- derivatives respectively. The critical point is the ratio of the heights of the peaks at 0.92 (for the Z) and 0.94 (for the E) , which is approximately 2:1. The expansion of the 4.00 to 4.35 region reveals similar information where ratios are 10:6.4 and 5.56:3.43.

Similarly expansion of the region 3.6 to 3.9 shows the ratio to be 2.46:1. All of these measurements suggest an approximate 2:1 ratio.

Referring to Figure 5, this shows almost pure Z- isomer. It should be noted that there is 660 mg of this from an original mixture of a 2:1 ratio mixture of 780 mg which would contain only 520 mg of the Z-isomer.

 

 

 

Z isomer of tamoxifen and 4-hydroxytamoxi en include stereoselective syntheses (involving expensive catalysts) as described in J. Chem. Soc, Perkin Trans I 1987, 1101 and J. Org. Chem. 1990, 55, 6184 or chromatographic separation of an E/Z mixture of isomers as described in J. Chem. Res., 1985 (S) 116, (M) 1342, 1986 (S) 58, (M) 771.

(Z)-tamoxifen (1) as a white solid, mp: 95.8-96.3 ºC. 1H-NMR (500 MHz, CDCl3) d 0.92 (3H, t, J 7.3 Hz), 2.29 (6H, s), 2.45 (2H, q, J 7.3 Hz), 2.65 (2H, t, J 5.8 Hz), 3.93 (2H, t, J 5.8 Hz), 6.68 (2H, d, J 9.5 Hz), 6.78 (2H, d, J 9.5 Hz), 7.08-7.28 (10H, m).13C-NMR (125 MHz, CDCl3) d 13.6 (CH3), 29.0 (CH2), 45.8 (CH3), 58.2 (CH2), 65.5 (CH2), 113.4 (C), 126.0 (C), 126.5 (CH), 127.8 (CH), 128.1 (C), 129.7 (C), 131.8 (CH), 135.6 (CH), 138.2 (CH), 141.3 (CH), 142.4 (CH), 143.8 (C), 156.7 (C). IR (KBr film) nmax/cm-1: 3055, 2979, 2925, 2813, 2769, 1606, 1509, 1240, 1035, 707. GC–MS (EI) m/z 371(5%), 58(100%).

 

(Z)-tamoxifen (1) and (E)-tamoxifen (2) in 52% yield. 1H-NMR (300 MHz, CDCl3) d 0.91 (Z isomer. 3H, t, J 7.3 Hz), 0.94 (E isomer. 3H, t, J 7.3 Hz), 2.28 (Z isomer. 6H, s), 2.34 (E isomer. 6H, s), 2.42-2.52 (Z and Eisomers. 4H, m), 2.63 (Z isomer. 2H, t, J 5.9 Hz), 2.74 (E isomer. 2H, t, J 5.9 Hz), 3.94 (Z isomer. 2H, t, J 5.9 Hz), 4.07 (E isomer. 2H, t, J 5.9 Hz), 6.68 (Z isomer. 2H, d, J 9.7 Hz), 6.76 (E isomer. 2H, d, J 9.3 Hz), 6.86-7.36 (Z and E isomers. 10H, m). IR (KBr film) nmax/cm-1: 3081, 3056, 2974, 2826, 2770, 1611, 1509, 1238, 1044. GC–MS (EI) m/z: Z isomer, 371(4%), 72 (24%), 58(100%); E isomer, 371(3%), 72 (24%), 58(100%). (the diastereoisomeric ratio was determined by capillary GC analysis and the configuration of the major diastereoisomer established by comparison of the NMR data of the synthetic mixture with an authentic sample of (Z)-tamoxifen (1).

 

 

nmr

 

 

ir

FTIR

shows the typical spectra’s of pure tamoxifen citrate, PCL, a physical mixture of tamoxifen citrate and PCL and drug-loaded implants. The spectrum of tamoxifen citrate shows characteristic absorption bands at 3027 cm−1 (=C-H stretching), 1507 and 1477 (C=C ring stretching) and 3180 cm -1 (-NH2). PCL displays a characteristic absorption band at strong bands such as the carbonyl stretching mode around 1727 cm−1 (C=O), asymmetric stretching 2949 cm−1 (CH 2 ) symmetric stretching 2865 cm−1 (CH 2 ). No changes in the spectrum of the physical mixture and drug-loaded microspheres were evident by FTIR spectroscopy. The strong bands such as the carbonyl peak were clear at all points.

Figure 2: Transmission FTIR spectra of (a) tamoxifen-loaded implant, (b) physical mixture of drug+PCL, (c) pure PCL, (d) pure tamoxifen citrate

enlarged view

Figure 2: Transmission FTIR spectra of (a) tamoxifen-loaded implant, (b) physical mixture of drug+PCL, (c) pure PCL, (d) pure tamoxifen citrate

FTIR spectra of A) tamoxifen citrate; B) PLGA; C) mixture of drug and excipients; D) freshly prepared nanoparticles in the formulation (BS-3HS).

 

FTIR spectra of A) tamoxifen citrate; B) PLGA; C) mixture of drug and excipients; D) freshly prepared nanoparticles in the formulation (BS-3HS).

Mentions: The pure drug tamoxifen citrate, PLGA-85:15, PVA, a mixture of PLGA and PVA, and a mixture of tamoxifen citrate, PLGA, and PVA; and a freshly prepared formulation were mixed separately with IR grade KBr in the ratio of 1:100 and corresponding pellets were prepared by applying 5.5 metric ton pressure with a hydraulic press. The pellets were scanned in an inert atmosphere over a wave number range of 4000–400 cm−1 in Magna IR 750 series II, FTIR instrument (Nicolet, Madison, WI, USA).

 

dsc

Figure 3: DSC thermograms of pure tamoxifen (a), pure PCL (b), physical mixture of drug+PCL (c) and (d) drug-loaded implant. The experiment was carried with crimped aluminum pans and a heating rate of 10ºC/min

 

DSC thermograms of pure tamoxifen (a), pure PCL (b), physical mixture of drug+PCL (c) and (d) drug-loaded implant. The experiment was carried with crimped aluminum pans and a heating rate of 10ºC/min

 

 

xrd

Figure 4: X-ray diffraction studies of pure drug (a), pure PCL (b), physical mixture of drug+PCL (c) and (d) drug-loaded implant

X-ray diffraction studies of pure drug (a), pure PCL (b), physical mixture of drug+PCL (c) and (d) drug-loaded implant

 

synthesis

J.Chem. Research,1985(S) 116, (M) 1342 and 1986 (S) 58, (M) 0771.

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Pfizer 2013 and beyond

 companies  Comments Off on Pfizer 2013 and beyond
Oct 252013
 

Pfizer

Pfizer gets a lot of coverage in the financial papers–even if some of it turns out to be misguided.

For example, Pfizer got the media coverage all drug companies desire on May 4 from Seeking Alpha, http://seekingalpha.com/article/560531-pfizer-alzheimers-drugs-will-carry-stock-to-new-highs-in-2013

a stock market blog that provides free stock market analysis. A piece entitled “Pfizer: Alzheimer’s Drugs Will Carry Stock To New Highs In 2013” had a subheading “strong pipeline.”

Turns out that was too optimistic, as Pfizer’s Alzheimer’s drug–along with Johnson and Johnson’s–both failed to produce. But many stock analysts still hold hope that Pfizer has a new ‘cash cow’ coming down the pipeline.

Daily Finance http://www.dailyfinance.com/2012/09/07/a-peek-at-pfizers-pipeline/

notes that Pfizer currently has 87 drugs in its pipeline. While its true that most are in the early stages, 11 are ready to be reviewed by the FDA.

That number puts it ahead of most of its rivals, with Eli Lilly, a close second, having 63 drugs in Phases 1-3, plus one currently being reviewed. Bristol-Myers Squibb has 46 drugs in development, 7 under review, Merck has 35 drugs in Phase 2 or 3 with two under review, and Johnson and Johnson has 18 drugs that are already in Phase 3 clinical trials or up for FDA approval.

But, of course, as the journal points out, “Quality trumps quantity. . . . One or two blockbusters can be better than several lower-revenue drugs.”

So what does Pfizer have up its sleeve that might begin to fill the very big shoes of Lipitor?

Well, the company has diversified the therapeutic areas under research, with 26% of R&D efforts going toward oncology treatments, 20% to neuroscience and pain, 17% to cardiovascular and metabolic diseases, 14% to inflammation and immunology, 5% to vaccines, and 18% toward ‘other.’

Pfizer has several medicines for diabetes alone coming up, in Phase I and Phase II trials, almost all meant to treat type 2 diabetes.

But, notes Seeking Alpha,http://seekingalpha.com/article/560531-pfizer-alzheimer-s-drugs-will-carry-stock-to-new-highs-in-2013

its blockbuster potential in this area is limited by the existing treatments of Merck and Sanofi. 10% of Sanofi’s total sales come from Lantus,

Lantus

a diabetes drug useful for both types 1 and 2, and Merck made $1.3 billion off its Januvia

januvia

franchise in the first quarter of this year alone.

So hopes are pinned on Pfizer’s tofacitinib, currently under FDA review, as the treatment with the potential to earn $1 billion or more in sales, easing the gaping wound left by Lipitor. Tofacitinib prompts such high hopes because it might possibly treat rheumatoid arthritis, psoriasis, and irritable bowel syndrome. Some analysts have pinned this as the cash cow Pfizer so badly needs to replace treatments lost to the patent cliff.

Tofacitinib

http://seekingalpha.com/article/812981-pfizers-success-with-its-jak-inhibitor

If it gets approved, Tofacitinib would be first treatment for rheumatoid arthritis (RA) in a new class of medicines (known as Jenus kinase, or JAK, inhibitors), and the first JAK inhibitor approved for rheumatoid arthritis.

Tofacitinib showed statistically significant improvement compared to placebo in decreasing the symptoms of RA (as measured by 20% improvement in the American College of Rheumatology scale), in improving physical function (as measured by mean change in Health Assessment Questionnaire-Disability Index), and in leading to remission (as measured by Disease Activity Score 28 ESR).

Joel Kremer, MD, chief of medicine at Albany Medical College in N.Y., after analyzing the data, commented, “Tofacitinib appears to reduce the signs and symptoms of rheumatoid arthritis very quickly. We hope that after carefully considering the benefit/risk equation, this compound will provide an additional valuable treatment option for patients who have experienced inadequate response to prior treatments.”

Pfizer also believes its blood thinner Eliquis, which it is developing with Bristol-Myers Squibb (see below) could be a big money-maker.

apixaban, eliquis

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AltheRx obtains US patent for solabegron combination therapy for OAB treatment

 phase 2, Uncategorized  Comments Off on AltheRx obtains US patent for solabegron combination therapy for OAB treatment
Oct 212013
 

solabegron

AltheRx Pharmaceuticals has received a notice of allowance for its patent application from the US Patent and Trademark Office (USPTO) for the use of solabegron, a beta 3-adrenergic receptor agonist, in combination with antimuscarinics at both therapeutic and sub-therapeutic doses, for the treatment of overactive bladder (OAB).

AltheRx obtains US patent for solabegron combination therapy for OAB treatment

http://www.pharmaceutical-technology.com/news/newsaltherx-obtains-us-patent-for-solabegron-combination-therapy-for-oab-treatment?WT.mc_id=DN_News

 

Solabegron (GW-427,353) is a drug which acts as a selective agonist for the β3 adrenergic receptor. It is being developed for the treatment of overactive bladder andirritable bowel syndrome.[1][2][3] It has been shown to produce visceral analgesia by releasing somatostatin from adipocytes.,[4][5]

Solabegron was discovered by GlaxoSmithKline and acquired by AltheRx in March 2011. Solabegron relaxes the bladder smooth muscle by stimulating beta-3 adrenoceptors, a novel mechanism compared to older established drug treatments for overactive bladder syndrome such as the anticholinergic agents. Astellas Pharma have developed the first commercially available β3 adrenergic receptor, mirabegron, which is now licensed in Japan[6] and the US[7] for overactive bladder. Mirabegron is not licensed for irritable bowel syndrome.

A Phase II study of Solabegron for overactive bladder (OAB) looked at 258 patients with moderate to severe incontinence experiencing an average of 4.5 wet episodes per day. Results demonstrated a statistically significant improvement with Solabegron as compared to placebo, as measured by the percent reduction of the number of wet episodes and the absolute number of daily voids.

A Phase II study for irritable bowel syndrome (IBS) evaluated 102 patients with IBS. Solabegron demonstrated significant reduction in pain associated with the disorder and a trend for greater improvement in the quality of life, compared to placebo.

Both Phase II studies indicated a tolerability profile for Solabegron that was similar to placebo. The OAB patients did not suffer from dry mouth, constipation, increase in heart rate or cognitive issues.

AltheRx is currently preparing to advance Solabegron into a large clinical study in OAB.

Synthesis

Solabegron scheme.png

  1.  Hicks A, McCafferty GP, Riedel E, Aiyar N, Pullen M, Evans C, Luce TD, Coatney RW, Rivera GC, Westfall TD, Hieble JP. GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog. Journal of Pharmacology and Experimental Therapeutics. 2007 Oct;323(1):202-9.doi:10.1124/jpet.107.125757 PMID 17626794
  2.  Grudell AB, Camilleri M, Jensen KL, Foxx-Orenstein AE, Burton DD, Ryks MD, Baxter KL, Cox DS, Dukes GE, Kelleher DL, Zinsmeister AR. Dose-response effect of a beta3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health.American Journal of Physiology. Gastrointestinal and Liver Physiology. 2008 May;294(5):G1114-9. PMID 18372395
  3.  Kelleher DL, Hicks KJ, Cox DS, et al. Randomized, double-blind, placebo (PLA)-controlled, crossover study to evaluate efficacy and safety of the beta 3-adrenergic receptor agonist solabegron (SOL) in patients with irritable bowel syndrome (IBS). Neurogastroenterol Motil 2008;20 (Suppl 2):131.
  4.  Cellek S, Thangiah R, Bassil AK, Campbell CA, Gray KM, Stretton JL, Lalude O, Vivekanandan S, Wheeldon A, Winchester WJ, Sanger GJ, Schemann M, Lee K. Demonstration of functional neuronal beta3-adrenoceptors within the enteric nervous system. Gastroenterology. 2007 Jul;133(1):175-83.
  5. Schemann M, Hafsi N, Michel K, Kober OI, Wollmann J, Li Q, Zeller F, Langer R, Lee K, Cellek S. The beta3-adrenoceptor agonist GW427353 (solabegron) decreases excitability of human enteric neurons via release of somatostatin.Gastroenterology 2009 Sep 25. [Epub ahead of print]
  6.  http://www.ncbi.nlm.nih.gov/pubmed/22384458
  7.  http://chembl.blogspot.co.uk/2012/07/new-drug-approvals-2012-pt-xiv.html
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CILNIDIPINE 西尼地平

 GENERIC, Uncategorized  Comments Off on CILNIDIPINE 西尼地平
Oct 032013
 

 

cilnidipine

西尼地平

CAS 132203-70-4

  • (E) – (±) 1 ,4 a dihydro-2 ,6 – dimethyl-4 – (3 – nitrophenyl) -3,5 – pyridinedicarboxylic acid, 2 – methoxy- ethyl butylester 3 – phenyl – 2 – propenyl ester FRC-8653 Cinalong
  • More FRC 8653 1,4-Dihydro-2 ,6-dimethyl-4-(3-nitrophenyl) 3 ,5-pyridinedicarboxylic acid 2-methoxyethyl (2E)-3-phenyl-2-propenyl ester
  • Molecular formula:C 27 H 28 N 2 O 7
  • Molecular Weight:492.52
CAS Name: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyethyl (2E)-3-phenyl-2-propenyl ester
Additional Names: (±)-(E)-cinnamyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate
Manufacturers’ Codes: FRC-8653
Trademarks: Atelec (Morishita); Cinalong (Fujirebio); Siscard (Boehringer, Ing.)
Molecular Formula: C27H28N2O7
Molecular Weight: 492.52
Percent Composition: C 65.84%, H 5.73%, N 5.69%, O 22.74%
Properties: Crystals from methanol, mp 115.5-116.6°. LD50 in male, female mice, rats (mg/kg): ³5000, ³5000, ³5000, 4412 orally;³5000 all species s.c.; 1845, 2353, 441, 426 i.p. (Wada).
Melting point: mp 115.5-116.6°
Toxicity data: LD50 in male, female mice, rats (mg/kg): ³5000, ³5000, ³5000, 4412 orally; ³5000 all species s.c.; 1845, 2353, 441, 426 i.p. (Wada)
 Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.

 

Cilnidipine (INN) is a calcium channel blocker. It is sold as Atelec in Japan, asCilaheart, Cilacar in India, and under various other trade names in East Asian countries.

Cilnidipine is a dual blocker of L-type voltage-gated calcium channels in vascular smooth muscle and N-type calcium channels in sympathetic nerve terminals that supply blood vessels. However, the clinical benefits of cilnidipine and underlying mechanisms are incompletely understood.

Clinidipine is the novel calcium antagonist accompanied with L-type and N-type calcium channel blocking function. It was jointly developed by Fuji Viscera Pharmaceutical Company, Japan and Ajinomoto, Japan and approved to come into market for the first time and used for high blood pressure treatment in 1995. in india j b chemicals & pharmaceuticals ltd and ncube pharmaceutical develope a market of cilnidipine.

Hypertension is one of the most common cardiovascular disease states, which is defined as a blood pressure greater than or equal to 140/90 mm Hg. Recently, patients with adult disease such as hypertension have rapidly increased. Particularly, since damages due to hypertension may cause acute heart disease or myocardial infarction, etc., there is continued demand for the development of more effective antihypertensive agent.

Meanwhile, antihypertensive agents developed so far can be classified into Angiotensin II Receptor Blocker (ARB), Angiotensin-Converting Enzyme Inhibitor (ACEI) or Calcium Chanel Blocker (CCB) according to the mechanism of actions. Particularly, ARB or CCB drugs manifest more excellent blood pressure lowering effect, and thus they are more frequently used.

However, these drugs have a limit in blood pressure lowering effects, and if each of these drugs is administered in an amount greater than or equal to a specific amount, various side-effects may be caused. Therefore, there have been many attempts in recent years to obtain more excellent blood pressure lowering effect by combination therapy or combined preparation which combines or mixes two or more drugs.

Particularly, since side-effect due to each drug is directly related to the amount or dose of a single drug, there have been active attempts to combine or mix two or more drugs thereby obtaining more excellent blood pressure lowering effect through synergism of the two or more drugs while reducing the amount or dose of each single drug.

For example, US 20040198789 discloses a pharmaceutical composition for lowering blood pressure combining lercanidipine, one of CCB, and valsartan, irbesartan or olmesartan, one of ARB, etc. In addition, a combined preparation composition which combines or mixes various blood pressure lowering drugs or combination therapy thereof has been disclosed.

cilnidipine Compared with other calcium antagonists, clinidipine can act on the N-type calcium-channel that existing sympathetic nerve end besides acting on L-type calcium-channel that similar to most of the calcium antagonists. Due to its N-type calcium-channel blocking properties, it has more advantages compared to conventional calcium-channel blockers. It has lower incidence of Pedal edema, one of the major adverse effects of other calcium channel blockers. Cilnidipine has similar blood pressure lowering efficacy as compared to amlodipine. One of the distinct property of cilnidipine from amlodipine is that it does not cause reflex tachycardia.

In recent years, cardiovascular disease has become common, the incidence increased year by year, about a patient of hypertension in China. 3-1. 500 million, complications caused by hypertension gradually increased, and more and more young patients with hypertension technology. In recent years, antihypertensive drugs also have great development, the main first-line diuretic drug decompression 3 – blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, ar blockers and vascular angiotensin II (Ang II) receptor antagonist.

In the anti-hypertensive drugs, calcium antagonists are following a – blockers after another rapidly developing cardiovascular drugs, has been widely used in clinical hypertension, angina and other diseases, in cardiovascular drugs in the world, ranked first.

Cilnidipine for the long duration of the calcium channel blockers, direct relaxation of vascular smooth muscle, dilation of peripheral arteries, the peripheral resistance decreased, with lower blood pressure, heart rate without causing a reflex effect.

Cilnidipine is a dihydropyridine CCB as well as an antihypertensive. Cilnidipinehas L- and N-calcium channel blocking actions. Though many of the dihydropyridine CCBs may cause an increase in heart rate while being effective for lowering blood pressure, it has been confirmed that cilnidipine does not increase the heart rate and has a stable hypotensive effect. (Takahiro Shiokoshi, “Medical Consultation & New Remedies” vol. 41, No. 6, p. 475-481)

  • http://www.mcyy.com.cn/e-product2.asp
  • Löhn M, Muzzulini U, Essin K, et al. (May 2002). “Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C”. J. Hypertens. 20 (5): 885–93. PMID 12011649.

 

Cilnidipine (CAS NO.: 132203-70-4), with its systematic name of (+-)-(E)-Cinnamyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate, could be produced through many synthetic methods.

Following is one of the synthesis routes: By cyclization of 2-(3-nitrobenzylidene)acetocetic acid cinnamyl ester (I) with 2-aminocrotonic acid 2-methoxyethyl ester (II) by heating at 120 °C.

 

MORE

 

NMR

CARBOHYDRATE POLYMERS 90 PG 1719-1724 , YR2012

Numerous peaks were found in the spectrum of cilnidipine: 2.3555 (3H, s, CH3), 2.3886(3H, s, CH3), 3.2843(CD3OD), 3.3292(3H, s, OCH3), 3.5255–3.5623(2H, m, CH3OCH2CH2 ), 4.1224–4.1597(2H, m, CH3OCH2CH2 ), 4.6695–4.7293(2H, m, CH2 CH CH ), 4.8844(D2O), 5.1576(1H, s, CH), 6.2609(1H, dt, CH2 CH CH ), 6.5518(1H, d, CH2 CH CH ), 7.2488–7.3657(6H, m, ArH), 7.7002(1H, dd, ArH), 7.9805(1H, dd, ArH), 8.1548(1H, s, ArH)

CILNIDIPINE FT IR

 

CILNIDIPINE NMR

 

References:

Dihydropyridine calcium channel blocker. Prepn: T. Kutsuma et al., EP 161877; eidem, US 4672068(1985, 1987 both to Fujirebio).

Pharmacology: K. Ikeda et al., Oyo Yakuri 44, 433 (1992).

 

Mechanism of action study: M. Hosonoet al., J. Pharmacobio-Dyn. 15, 547 (1992).

LC-MS determn in plasma: K. Hatada et al., J. Chromatogr. 583, 116 (1992). Clinical study: M. Ishii, Jpn. Pharmacol. Ther. 21, 59 (1993).

Acute toxicity study: S. Wada et al., Yakuri to Chiryo 20, Suppl. 7, S1683 (1992), C.A. 118, 32711 (1992).

 

U.S Patent No. 4,572,909 discloses amlodipine; U.S Patent No. 4,446,325 discloses aranidipine; U.S Patent No. 4,772,596 discloses azelnidipine; U.S Patent No. 4,220,649 discloses barnidipine; U.S Patent No. 4,448,964 discloses benidipine; U.S Patent No. 5,856,346 discloses clevidipine; U.S Patent No. 4,466,972 discloses isradipine; U.S Patent No. 4,885,284 discloses efonidipine; and U.S Patent No. 4,264,61 1 discloses felodipine.

U.S Patent No. 5,399,578 discloses Valsartan; European Patent No. 0 502 314 discloses Telmisartan; U.S Patent No. 5,138,069 discloses Losartan; U.S Patent No. 5,270,317 discloses Irbesartan; U.S Patent No. 5,583,141 and 5,736,555 discloses Azilsartan; U.S Patent No. 5,196,444 discloses Candesartan; U.S Patent No. 5,616,599 discloses Olmesartan; and U.S Patent No. 5,185,351 discloses Eprosartan.

U.S Patent No. 4,374,829 discloses enalapril; U.S Patent No. 4,587,258 discloses ramipril; U.S Patent No. 4,344,949 discloses quinapril; U.S Patent No. 4,508,729 discloses perindopril; U.S Patent No. 4,374,829 discloses lisinopril; U.S Patent No. 4,410,520 discloses benazepril; U.S Patent No. 4,508,727 discloses imidapril; U.S Patent No. 4,316,906 discloses zofenopril; U.S Patent Nos. 4,046,889 and 4,105,776 discloses captopril; and U.S Patent No. 4,337,201 discloses fosinopril.

 

  • Planar chemical structures of these calcium blockers of formula (I) are shown below.

    Figure 00070001
    Figure 00070002
    Figure 00070003
    Figure 00070004
    Figure 00070005
    Figure 00080001
    Figure 00080002
    Figure 00080003
    Figure 00080004
  • Amlodipine is 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine disclosed in USP 4,572,909, Japanese patent publication No. Sho 58-167569 and the like.
  • Aranidipine is 3-(2-oxopropoxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,446,325 and the like.
  • Azelnidipine is 2-amino-3-(1-diphenylmethyl-3-azetidinyloxycarbonyl)-5-isopropoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,772,596, Japanese patent publication No. Sho 63-253082 and the like.
  • Barnidipine is 3-(1-benzyl-3-pyrrolidinyloxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,220,649, Japanese patent publication No. Sho 55-301 and the like.
  • Benidipine is 3-(1-benzyl-3-piperidinyloxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine and is described in the specifications of U.S. Patent No. 4,501,748, Japanese patent publication No. Sho 59-70667 and the like.
  • Cilnidipine is 2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-4-(3-nitrophenyl)-3-(3-phenyl-2-propenyloxycarbonyl)-1,4-dihydropyridine disclosed in USP 4,672,068, Japanese patent publication No. Sho 60-233058 and the like.
  • Efonidipine is 3-[2-(N-benzyl-N-phenylamino)ethoxycarbonyl]-2,6-dimethyl-5-(5,5-dimethyl-1,3,2-dioxa-2-phosphonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,885,284, Japanese patent publication No. Sho 60-69089 and the like.
  • Elgodipine is 2,6-dimethyl-5-isopropoxycarbonyl-4-(2,3-methylenedioxyphenyl)-3-[2-[N-methyl-N-(4-fluorophenylmethyl)amino]ethoxycarbonyl]-1,4-dihydropyridine disclosed in USP 4,952,592, Japanese patent publication No. Hei 1-294675 and the like.
  • Felodipine is 3-ethoxycarbonyl-4-(2,3-dichlorophenyl)-2,6-dimethyl-5-methoxycarbonyl-1,4-dihydropyridine disclosed in USP 4,264,611, Japanese patent publication No. Sho 55-9083 and the like.
  • Falnidipine is 2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-3-(2-tetrahydrofurylmethoxycarbonyl)-1,4-dihydropyridine disclosed in USP 4,656,181, Japanese patent publication (kohyo) No. Sho 60-500255 and the like.
  • Lemildipine is 2-carbamoyloxymethyl-4-(2,3-dichlorophenyl)-3-isopropoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine disclosed in Japanese patent publication No. Sho 59-152373 and the like.
  • Manidipine is 2,6-dimethyl-3-[2-(4-diphenylmethyl-1-piperazinyl)ethoxycarbonyl]-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,892,875, Japanese patent publication No. Sho 58-201765 and the like.
  • Nicardipine is 2,6-dimethyl-3-[2-(N-benzyl-N-methylamino)ethoxycarbonyl]-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,985,758, Japanese patent publication No. Sho 49-108082 and the like.
  • Nifedipine is 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,485,847 and the like.
  • Nilvadipine is 2-cyano-5-isopropoxycarbonyl-3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,338,322, Japanese patent publication No. Sho 52-5777 and the like.
  • Nisoldipine is 2,6-dimethyl-3-isobutoxycarbonyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,154,839, Japanese patent publication No. Sho 52-59161 and the like.
  • Nitrendipine is 3-ethoxycarbonyl-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,799,934, Japanese patent publication (after examination) No. Sho 55-27054 and the like.
  • Pranidipine is 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-(3-phenyl-2-propen-1 -yloxycarbonyl)-1,4-dihydropyridine disclosed in USP 5,034,395, Japanese patent publication No. Sho 60-120861 and the like.
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