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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Hyderabad. India to Host Industrial Organic Chemistry Workshops in February 2018


 

Dr Will Watson, an expert in Chemical Development and related fields, from Scientific Update will be visiting India in February to deliver two important workshops for Industrial Process Chemists:

Chemical Development and Scale Up in the Fine Chemical and Pharmaceutical Industries, February 5th – 7th 2018, Hyderabad, India

Practical Crystallisation & Polymorphism, February 8th & 9th 2018, Hyderabad, India

Discounts are available for groups – please contact sciup@scientificupdate.com for more information.

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(+)-(S,S)-Reboxetine succinate, Esreboxetine succinate


Image result for (S,S)-Reboxetine succinateimg

Esreboxetine succinate

str1

(2S)-2-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine butanedioate (1:1)
(2S)-2-[(S)-(2-Ethoxyphenoxy)(phenyl)methyl]morpholine succinate (1:1)
(S,S)-reboxetine succinate
635724-55-9 [RN]
Esreboxetine succinate [USAN]
Morpholine, 2-[(S)-(2-ethoxyphenoxy)phenylmethyl]-, (2S)-, butanedioate (1:1)
Succinic acid – (2S)-2-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine (1:1)
UNII:XQO13W6OCH

Esreboxetine is a selective norepinephrine reuptake inhibitor which was under development by Pfizer for the treatment of neuropathic pain and fibromyalgia but failed to show significant benefit over currently available medications and was discontinued.[1][2][3][4] It is the (S,S)-(+)-enantiomer of reboxetine and is even more selective in comparison.[1][5]

However, recently it has been shown that esreboxetine could be effective in fibromyalgia patients.[6]

Figure

Reboxetine mesylate (1) and succinate (2).

Image result for (S,S)-Reboxetine succinate

Image result for (S,S)-Reboxetine succinate

CLIP

http://pubs.rsc.org/en/Content/ArticleHtml/2012/GC/c1gc15921f

The synthesis of (±)-reboxetine mesylate,4 the Active Pharmaceutical Ingredient (API) for Edronax™.

Scheme 1 The synthesis of (±)-reboxetine mesylate,4 the Active Pharmaceutical Ingredient (API) for Edronax™.

 

The conversion of (±)-reboxetine mesylate to (S,S)-reboxetine succinate.
Scheme 2 The conversion of (±)-reboxetine mesylate to (S,S)-reboxetine succinate.

 

The Pfizer early resolution route to (S,S)-reboxetine succinate.
Scheme 3 The Pfizer early resolution route to (S,S)-reboxetine succinate.

The Pfizer asymmetric synthesis for (S,S)-reboxetine intended for commercialisation.

Scheme 4 The Pfizer asymmetric synthesis for (S,S)-reboxetine intended for commercialisation.

CLIP

(S,S)-Reboxetine succinate (3) (Figure 1) has been under late-stage development at Pfizer for the medication of neuropathic and fibromyalgia pain.(16)

16.(a) HughesB.McKenzieI.StokerM. J. WO2006/000903, May 1, 2006.

(b) AllenA. J.Hemrick-LueckeS.SumnerC. R.WallaceO. B. WO2005/060949, July 7, 2005.

(c) KelseyD. K. WO2005/021095, Oct 3, 2005.

(d) AllenA. J.KelseyD. K. WO 2005/020976, Oct 3, 2005.

(e) SumnerC. R. WO2005/020975, Oct 3, 2005.

(f) HassanF. WO2004/016272, Feb 26, 2004.

(g) WongE. H. F. WO2004/002463, Jan 8, 2004.

PAPER

Process Development for (S,S)-Reboxetine Succinate via a Sharpless Asymmetric Epoxidation

http://pubs.acs.org/doi/abs/10.1021/op700007g?crel=US_AC_eAdv_Blog

Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, U.S.A.
Org. Process Res. Dev.200711 (3), pp 354–358
DOI: 10.1021/op700007g
Publication Date (Web): March 23, 2007
Copyright © 2007 American Chemical Society

Abstract

Abstract Image

Reboxetine mesylate is a selective norepinephrine uptake inhibitor (NRI) currently marketed as the racemate. The (S,S)-enantiomer of reboxetine is being evaluated for the treatment of neuropathic pain and a variety of other indications. (S,S)-Reboxetine has usually been prepared by resolution of the racemate as the (−)-mandelate salt, an inherently inefficient process. A chiral synthesis starting with a Sharpless asymmetric epoxidation of cinnamyl alcohol to yield (R,R)-phenylglycidol was developed. (R,R)-Phenylglycidol was reacted without isolation with 2-ethoxyphenol to give 4, which was isolated by direct crystallization. Key process variables for the asymmetric epoxidation were investigated. Conversion of (R,S)-4 to reboxetine parallels the racemic synthesis with streamlined and optimized processing conditions. (S,S)-Reboxetine free base was converted directly to the succinate salt without isolation as the mesylate salt.

(2S,3S)-Reboxetine Succinate (9).

mp 145.2−147.1 °C (lit. mp 148 °C).8 1H NMR (400.13 MHz, CDCl3) δ 1.41 (t, J = 7.0 Hz, 3H), 2.4 (s, 4H), 2.9−3.06 (m, 2H), 3.15−3.22 (m, 2H), 3.81−3.86 (m, 1H), 4.02−4.09 (m, 3H), 4.17−4.24 (m, 1H), 5.13 (d, J = 4.3 Hz), 6.66−6.90 (m, 4H), 7.26−7.39 (m, 5H). 13C NMR (100.62 MHz, CDCl3) δ 15.08, 31.89, 43.24, 44.84, 64.72, 76.91, 82.91, 113.94, 118.27, 121.1, 127.38, 128.66, 136.94, 149.8, 178.73. LRMS-APCI m/z calcd for C19H23NO3 (M + H)+:  314. Found:  m/z = 314 [M + 1]+. Anal. Calcd for C19H23NO3−C4H6O4:  C, 64.02; H, 6.77; N, 3.25. Found:  C, 63.99; H, 6.77; N, 3.16. [α]32.4D +17.24° (c 0.5, EtOH).

8)Zampieri, M.; Airoldi, A.; Martini, A. WO2003/106441, 12/24/03.

PAPER

Commercial Synthesis of (S,S)-Reboxetine Succinate: A Journey To Find the Cheapest Commercial Chemistry for Manufacture

http://pubs.acs.org/doi/abs/10.1021/op200181f

Chemical Research and Development, Pfizer Inc., Sandwich Laboratories, Sandwich, Kent, CT13 9NJ, United Kingdom
Org. Process Res. Dev.201115 (6), pp 1305–1314
DOI: 10.1021/op200181f
Publication Date (Web): August 18, 2011
Copyright © 2011 American Chemical Society

Abstract

Abstract Image

The development of a synthetic process for (S,S)-reboxetine succinate, a candidate for the treatment of fibromylagia, is disclosed from initial scale-up to deliver material for registrational stability testing through to commercial route evaluation and subsequent nomination. This entailed evaluation of several alternative routes to result in what would have been a commercially attractive process for launch of the compound.

(2S,3S)-2-[α-(2-Ethoxyphenoxy)benzyl]morpholine Succinate Salt (S,S)-Reboxetine Succinate

 (S,S)-reboxetine succinate (897 g, 82%) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 7.22–7.54 (m, 5H), 6.66–6.96 (m, 4H), 5.27 (d, J = 6.0 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.83 (m, 2H), 3.50 (m, 2H), 2.61–2.82 (m, 3H), 2.34 (br s, 4H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, d6-DMSO) δ 174.4, 149.0, 147.3, 137.8, 128.2, 127.3, 120.7, 116.7, 114.4, 80.8, 77.5, 65.9, 64.1, 45.8, 44.1, 39.7, 39.

References[edit]

  1. Jump up to:a b Matilda Bingham; Napier, Susan Jolliffe (2009). Transporters as Targets for Drugs (Topics in Medicinal Chemistry). Berlin: Springer. ISBN 3-540-87911-0.
  2. Jump up^ Rao SG (October 2009). “Current progress in the pharmacological therapy of fibromyalgia”Expert Opinion on Investigational Drugs18 (10): 1479–93. PMID 19732029doi:10.1517/13543780903203771.
  3. Jump up^ “Search of: esreboxetine – List Results – ClinicalTrials.gov”.
  4. Jump up^ “Musculoskeletal Report: Pfizer Stops Work on Esreboxetine for FM”.
  5. Jump up^ Fish, P. V.; MacKenny, M.; Bish, G.; Buxton, T.; Cave, R.; Drouard, D.; Hoople, D.; Jessiman, A.; Miller, D.; Pasquinet, C.; Patel, B.; Reeves, K.; Ryckmans, T.; Skerten, M.; Wakenhut, F. (2009). “Enantioselective synthesis of (R)- and (S)-N-Boc-morpholine-2-carboxylic acids by enzyme-catalyzed kinetic resolution: application to the synthesis of reboxetine analogs”. Tetrahedron Letters50 (4): 389. doi:10.1016/j.tetlet.2008.11.025.
  6. Jump up^ Arnold, L. M., Hirsch, I., Sanders, P., Ellis, A. and Hughes, B. (2012), Safety and efficacy of esreboxetine in patients with fibromyalgia: A fourteen-week, randomized, 

REFERENCES

1: Fujimori I, Yukawa T, Kamei T, Nakada Y, Sakauchi N, Yamada M, Ohba Y, Takiguchi M, Kuno M, Kamo I, Nakagawa H, Hamada T, Igari T, Okuda T, Yamamoto S, Tsukamoto T, Ishichi Y, Ueno H. Design, synthesis and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitor. Bioorg Med Chem. 2015 Aug 1;23(15):5000-14. doi: 10.1016/j.bmc.2015.05.017. Epub 2015 May 15. PubMed PMID: 26051602.

2: Shen F, Tsuruda PR, Smith JA, Obedencio GP, Martin WJ. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model. PLoS One. 2013 Sep 30;8(9):e74891. doi: 10.1371/journal.pone.0074891. eCollection 2013. PubMed PMID: 24098676; PubMed Central PMCID: PMC3787017.

3: Arnold LM, Hirsch I, Sanders P, Ellis A, Hughes B. Safety and efficacy of esreboxetine in patients with fibromyalgia: a fourteen-week, randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 2012 Jul;64(7):2387-97. doi: 10.1002/art.34390. PubMed PMID: 22275142.

4: Arnold LM, Chatamra K, Hirsch I, Stoker M. Safety and efficacy of esreboxetine in patients with fibromyalgia: An 8-week, multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. 2010 Aug;32(9):1618-32. doi: 10.1016/j.clinthera.2010.08.003. PubMed PMID: 20974319.

5: Klarskov N, Scholfield D, Soma K, Darekar A, Mills I, Lose G. Measurement of urethral closure function in women with stress urinary incontinence. J Urol. 2009 Jun;181(6):2628-33; discussion 2633. doi: 10.1016/j.juro.2009.01.114. Epub 2009 Apr 16. PubMed PMID: 19375093.

Esreboxetine
Esreboxetine.svg
Clinical data
Routes of
administration
Oral
ATC code
  • None
Legal status
Legal status
  • In general: uncontrolled
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C19H23NO3
Molar mass 313.391 g/mol
3D model (JSmol)

////////////(+)-(S,S)-Reboxetine, (S,S)-Reboxetine, Reboxetine, Esreboxetine succinate

CCOc1ccccc1O[C@H]([C@@H]2CNCCO2)c3ccccc3.OC(=O)CCC(=O)O

ESCITALOPRAM, S-(+)-Citalopram, эсциталопрам , إيسكيتالوبرام , 艾司西酞普兰 ,


ChemSpider 2D Image | Escitalopram | C20H21FN2OImage result for ESCITALOPRAM
Escitalopram
(+)-Citalopram
(1S)-1-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile [ACD/IUPAC Name]
(S)-citalopram
128196-01-0 [RN]
5-Isobenzofurancarbonitrile, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-, (1S)- [ACD/Index Name]
  • Molecular FormulaC20H21FN2O
  • Average mass324.392 Da
  • S-(+)-Citalopram
    эсциталопрам [Russian] [INN]
    إيسكيتالوبرام [Arabic] [INN]
    艾司西酞普兰 [Chinese] [INN]

Image result for ESCITALOPRAM

Lexapro® (escitalopram oxalate) is an orally administered selective serotonin reuptake inhibitor (SSRI). Escitalopram is the pure Senantiomer (single isomer) of the racemic bicyclic phthalane derivative citalopram. Escitalopram oxalate is designated S-(+)-1-[3(dimethyl-amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate with the following structural formula:

 

Lexapro® (escitalopram oxalate) Structural Formual Illustration

The molecular formula is C20H21FN2O • C2H2O4 and the molecular weight is 414.40.

Escitalopram oxalate occurs as a fine, white to slightly-yellow powder and is freely soluble in methanol and dimethyl sulfoxide (DMSO), soluble in isotonic saline solution, sparingly soluble in water and ethanol, slightly soluble in ethyl acetate, and insoluble in heptane.

Lexapro (escitalopram oxalate) is available as tablets or as an oral solution.

Lexapro tablets are film-coated, round tablets containing escitalopram oxalate in strengths equivalent to 5 mg, 10 mg, and 20 mg escitalopram base. The 10 and 20 mg tablets are scored. The tablets also contain the following inactive ingredients: talc, croscarmellose sodium, microcrystalline cellulose/colloidal silicon dioxide, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, and polyethylene glycol.

Lexapro oral solution contains escitalopram oxalate equivalent to 1 mg/mL escitalopram base. It also contains the following inactive ingredients: sorbitol, purified water, citric acid, sodium citrate, malic acid, glycerin, propylene glycol, methylparaben, propylparaben, and natural peppermint flavor.

Escitalopram, also known by the brand names Lexapro and Cipralex among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children over 12 years of age with major depressive disorder (MDD) or generalized anxiety disorder (GAD). Escitalopram is the (S)-stereoisomer(Left-enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. Whether escitalopram exhibits superior therapeutic properties to citalopram or merely represents an example of “evergreening” is controversial.[2]

Medical uses

Escitalopram has FDA approval for the treatment of major depressive disorder in adolescents and adults, and generalized anxiety disorder in adults.[3] In European countries and Australia, it is approved for depression (MDD) and certain anxiety disorders: general anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder with or without agoraphobia.

Depression

Escitalopram was approved by regulatory authorities for the treatment of major depressive disorder on the basis of four placebo controlled, double-blind trials, three of which demonstrated a statistical superiority over placebo.[4]

Controversy exists regarding the effectiveness of escitalopram compared to its predecessor citalopram. The importance of this issue follows from the greater cost of escitalopram relative to the generic mixture of isomers citalopram prior to the expiration of the escitalopram patent in 2012, which led to charges of evergreening. Accordingly, this issue has been examined in at least 10 different systematic reviews and meta analyses. The most recent of these have concluded (with caveats in some cases) that escitalopram is modestly superior to citalopram in efficacy and tolerability.[5][6][7][8]

In contrast to these findings, a 2011 review concluded that all second-generation antidepressants are equally effective,[9] and treatment guidelines issued by the National Institute of Health and Clinical Excellence and by the American Psychiatric Association generally reflect this viewpoint.[10][11]

Anxiety disorder

Escitalopram appears to be effective in treating general anxiety disorder, with relapse on escitalopram (20%) less than placebo (50%).[12]

Other

Escitalopram as well as other SSRIs are effective in reducing the symptoms of premenstrual syndrome, whether taken in the luteal phase only or continuously.[13] There is no good data available for escitalopram for seasonal affective disorder as of 2011.[14] SSRIs do not appear to be useful for preventing tension headaches or migraines.[15][16]

Adverse effects

Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libidodelayed ejaculation, genital anesthesia,[17] and anorgasmia.[18][19]

An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications.[20][21][22] The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients.[23]

Escitalopram is not associated with significant weight gain. For example, 0.6 kg mean weight change after 6 months of treatment with escitalopram for depression was insignificant and similar to that with placebo (0.2 kg).[24] 1.4–1.8 kg mean weight gain was reported in 8-month trials of escitalopram for depression,[25] and generalized anxiety disorder.[26] A 52-week trial of escitalopram for the long-term treatment of depression in elderly also found insignificant 0.6 kg mean weight gain.[27] Escitalopram may help reduce weight in those treated for binge eating associated obesity.[28]

Citalopram and escitalopram are associated with dose-dependent QT interval prolongation[29] and should not be used in those with congenital long QT syndrome or known pre-existing QT interval prolongation, or in combination with other medicines that prolong the QT interval. ECG measurements should be considered for patients with cardiac disease, and electrolyte disturbances should be corrected before starting treatment. In December 2011, the UK implemented new restrictions on the maximum daily doses.[30][31] The U.S. Food and Drug Administration and Health Canada did not similarly order restrictions on escitalopram dosage, only on its predecessor citalopram.[32]

Escitalopram should be taken with caution when using Saint John’s wort.[33] Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole. The authors of this study suggested that this increase is unlikely to be of clinical concern.[34] Caution should be used when taking cough medicine containing dextromethorphan (DXM) as serotonin syndrome, liver damage, and other negative side effects have been reported.

Discontinuation symptoms

Escitalopram discontinuation, particularly abruptly, may cause certain withdrawal symptoms such as “electric shock” sensations[35] (also known as “brain shivers” or “brain zaps”), dizziness, acute depressions and irritability, as well as heightened senses of akathisia.[36]

Pregnancy

There is a tentative association of SSRI use during pregnancy with heart problems in the baby.[37] Their use during pregnancy should thus be balanced against that of depression.[37]

Overdose

Excessive doses of escitalopram usually cause relatively minor untoward effects such as agitation and tachycardia. However, dyskinesiahypertonia, and clonus may occur in some cases. Plasma escitalopram concentrations are usually in a range of 20–80 μg/L in therapeutic situations and may reach 80–200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolizers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.[38][39][40] Escitalopram seems to be less dangerous than citalopram in overdose and comparable to other SSRIs.[41]

Pharmacology

Mechanism of action

Binding profile[42]
Receptor Ki (nM)
SERT 2.5
NET 6,514
5-HT2C 2,531
α1 3,870
M1 1,242
H1 1,973

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market, escitalopram has the highest selectivity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET), making the side-effect profile relatively mild in comparison to less-selective SSRIs.[43] The opposite enantiomer, (R)-citalopram, counteracts to a certain degree the serotonin-enhancing action of escitalopram.[citation needed] As a result, escitalopram has been claimed to be a more potent antidepressant than the racemic mixture, citalopram, of the two enantiomers. In order to explain this phenomenon, researchers from Lundbeck proposed that escitalopram enhances its own binding via an additional interaction with another allosteric site on the transporter.[44] Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram,[45] and therefore the allosteric interaction cannot explain the observed counteracting effect. In the most recent paper, however, the same authors again reversed their findings and reported that (R)-citalopram decreases binding of escitalopram to the transporter.[46] Although allosteric binding of escitalopram to the serotonin transporter is of unquestionable research interest, its clinical relevance is unclear since the binding of escitalopram to the allosteric site is at least 1000 times weaker than to the primary binding site.

Escitalopram is a substrate of P-glycoprotein and hence P-glycoprotein inhibitors such as verapamil and quinidine may improve its blood-brain penetrability.[47] In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor enhanced its antidepressant-like effects.[47]

Interactions

Escitalopram, similarly to other SSRIs (with the exception of fluvoxamine), inhibits CYP2D6 and hence may increase plasma levels of a number of CYP2D6 substrates such as aripiprazolerisperidonetramadolcodeine, etc. As much of the effect of codeine is attributable to its conversion (10%) to morphine its effectiveness will be reduced by this inhibition, not enhanced.[48] As escitalopram is only a weak inhibitor of CYP2D6, analgesia from tramadol may not be affected.[49] Escitalopram can also prolong the QT interval and hence it is not recommended in patients that are concurrently on other medications that have the ability to prolong the QT interval. Being a SSRI, escitalopram should not be given concurrently with MAOIs or other serotonergic medications.[43]

History

Cipralex brand escitalopram 10mg package and tablet sheet

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the U.S. FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.[50] The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva.[51] On July 14 of that year, however, the U.S. District Court of Delaware decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.[52]

In 2006 Forest Laboratories was granted an 828-day (2 years and 3 months) extension on its US patent for escitalopram.[53] This pushed the patent expiration date from December 7, 2009 to September 14, 2011. Together with the 6-month pediatric exclusivity, the final expiration date was March 14, 2012.

Society and culture

Allegations of illegal marketing

In 2004, two separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers, one by a practicing physician named Joseph Piacentile, and the other by a Forest salesman named Christopher Gobble.[54] In February 2009, these two suits received support from the US Attorney for Massachusetts and were combined into one. Eleven states and the District of Columbia have also filed notices of intention to intervene as plaintiffs in the action. The suits allege that Forest illegally engaged in off-label promoting of Lexapro for use in children, that the company hid the results of a study showing lack of effectiveness in children, and that the company paid kickbacks to doctors to induce them to prescribe Lexapro to children. It was also alleged that the company conducted so-called “seeding studies” that were, in reality, marketing efforts to promote the drug’s use by doctors.[55][56] Forest responded to these allegations that it “is committed to adhering to the highest ethical and legal standards, and off-label promotion and improper payments to medical providers have consistently been against Forest policy.”[57] In 2010 Forest Pharmaceuticals Inc., agreed to pay more than $313 million to settle the charges over Lexapro and two other drugs, Levothroid and Celexa.[58]

Brand names

Escitalopram is sold under many brand names worldwide such as Cipralex.[1]

Image result for ESCITALOPRAM SYNTHESISImage result for ESCITALOPRAM SYNTHESIS

The Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III), which slowly rearranges to the benzophenone (IV). A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI), which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture. Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers. This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene.

A new method for the preparation of citalopram has been developed: The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (I) with refluxing SOCl2 gives the acyl chloride (II), which is condensed with 2-amino-2-methyl-1-propanol (III) in THF yielding the corresponding amide (IV). The cyclization of (IV) by means of SOCl2 affords the oxazoline (V), which is treated with 4-fluorophenylmagnesium bromide (VI) in THF giving the benzophenone (VII). This compound (VII), without isolation, is treated with 3-(dimethylamino)propylmagnesium chloride (VIII) in the same solvent, providing the cabinol (IX), which is cyclized by means of methanesulfonyl chloride and Et3N in CH2Cl2 yielding the isobenzofuran (X). Finally, this compound is treated with POCl3 in refluxing pyridine to generate the 5-cyano substituent of citalopram.

The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (XII) with refluxing SOCl2 gives the acyl chloride (XIII), which is condensed with 2-amino-2-methyl-1-propanol (XIV) in THF to yield the corresponding amide (XV). The cyclization of (XV) by means of SOCl2 affords the oxazoline (XVI), which is treated with 4-fluorophenylmagnesium bromide (XVII) in THF to give the benzophenone (XVIII). This compound (XVIII), without isolation, is treated with 3-(dimethylamino)propylmagnesium chloride (XIX) in the same solvent to provide the carbinol (XX), which is submitted to optical resolution with (+)- or (-)-tartaric acid, or (+)- or (-)-camphor-10-sulfonic acid (CSA) to give the desired (S)-enantiomer (XXI). Cyclization of (XXI) by means of methanesulfonyl chloride and TEA in dichloromethane yields the chiral isobenzofuran (XXII), which is finally treated with POCl3 in refluxing pyridine.

The Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III), which slowly rearranges to the benzophenone (IV). A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI), which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture. Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers. This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene

The Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III), which slowly rearranges to the benzophenone (IV). A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI), which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture. Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers. This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene.

Racemic 5-bromo-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (I) is submitted to optical resolution by chiral chromatography to give the corresponding (S)-isomer (II), which is treated with Zn(CN)2 and Pd(PPh3)4 to afford the target Escitalopram.

The esterification of racemic 1-[4-bromo-2-(hydroxymethyl)phenyl]-4-(dimethylamino)-1-(4-fluorophenyl)-1-butanol (I) with (S)-2-(6-methoxynaphth-2-yl)propionyl chloride (II) by means of TEA and DMAP in THF gives the corresponding ester (III) as a diastereomeric mixture that is separated by chiral chromatography over Daicel AD, the desired diastereomer (IV) is easily isolated. Finally, this ester is hydrolyzed and simultaneously cyclized by means of NaH in DMF to provide the target intermediate (V). Other acyl chlorides such as (S)-2-(4-isobutylphenyl)propionyl chloride, (S)-O-acetylmandeloyl chloride, (S)-benzyloxycarbonylprolyl chloride, (S)-2-phenylbutyryl chloride, (S)-2-methoxy-2-phenylacetyl chloride or (S)-N-acetylalanine can also be used in the preceding sequence.

Citalopram
Title: Citalopram
CAS Registry Number: 59729-33-8
CAS Name: 1-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile
Additional Names: 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-5-phthalancarbonitrile; nitalapram
Manufacturers’ Codes: Lu-10-171
Molecular Formula: C20H21FN2O
Molecular Weight: 324.39
Percent Composition: C 74.05%, H 6.53%, F 5.86%, N 8.64%, O 4.93%
Literature References: Selective serotonin reuptake inhibitor (SSRI). Prepn: K. P. Boegesoe, A. S. Toft, DE 2657013eidem, US4136193 (1977, 1979 both to Kefalas); A. J. Bigler et al., Eur. J. Med. Chem. – Chim. Ther. 12, 289 (1977). Prepn of enantiomers: K. P. Boegesoe, J. Perregaard, EP 347066eidemUS 4943590, reissued as US RE 34712 (1989, 1990, 1994 all to Lundbeck). Pharmacology: A. V. Christensen et al., Eur. J. Pharmacol. 41, 153 (1977). HPLC determn in plasma and urine: E. Oyehaug et al.,J. Chromatogr. 308, 199 (1984). Comparative biotransformation of enantiomers: L. L. Von Moltke et al., Drug Metab. Dispos. 29, 1102 (2001). Review of clinical pharmacokinetics: K. Brosen, C. A. Naranjo, Eur. Neuropsychopharmacol. 11, 275-283 (2001). Review of clinical experience in depression: M. B. Keller, J. Clin. Psychiatry 61, 896-908 (2000). Clinical trial of S-form in depression: W. J. Burke et al, ibid63, 331 (2002).
Properties: bp0.03 175-181°.
Boiling point: bp0.03 175-181°
Derivative Type: Hydrobromide
CAS Registry Number: 59729-32-7
Trademarks: Celexa (Forest); Cipramil (Lundbeck); Elopram (Recordati); Seropram (Lundbeck)
Molecular Formula: C20H21FN2O.HBr
Molecular Weight: 405.30
Percent Composition: C 59.27%, H 5.47%, F 4.69%, N 6.91%, O 3.95%, Br 19.71%
Properties: Crystals from isopropanol, mp 182-183°.
Melting point: mp 182-183°
Derivative Type: S-(+)-Form
CAS Registry Number: 128196-01-0
Additional Names: Escitalopram
Properties: [a]D +12.33° (c = 1 in methanol).
Optical Rotation: [a]D +12.33° (c = 1 in methanol)
Derivative Type: Escitalopram oxalate
CAS Registry Number: 219861-08-2
Manufacturers’ Codes: Lu-26-054-0
Trademarks: Cipralex (Lundbeck); Gaudium (Recordati); Lexapro (Forest)
Molecular Formula: C20H21FN2O.C2H2O4
Molecular Weight: 414.43
Percent Composition: C 63.76%, H 5.59%, F 4.58%, N 6.76%, O 19.30%
Properties: Fine white to slightly yellow powder. Crystals from acetone, mp 147-148°. [a]D +12.31° (c = 1 in methanol). Freely sol in methanol, DMSO; sol in isotonic saline; sparingly sol in water, ethanol; slightly sol in ethyl acetate. Insol in heptane.
Melting point: mp 147-148°
Optical Rotation: [a]D +12.31° (c = 1 in methanol)
Therap-Cat: Antidepressant.
Keywords: Antidepressant; Bicyclics; Serotonin Uptake Inhibitor.

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Cited texts

Further reading

External links

Escitalopram
Escitalopram.svg
Escitalopram-from-xtal-3D-balls.png
Clinical data
Pronunciation About this sound pronunciation 
Trade names Cipralex, Lexapro and many others[1]
AHFS/Drugs.com Monograph
MedlinePlus a603005
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 80%
Protein binding ~56%
Metabolism Liver, specifically the enzymes CYP3A4 and CYP2C19
Biological half-life 27–32 hours
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
Formula C20H21FN2O
Molar mass 324.392 g/mol
(414.43 as oxalate)
3D model (JSmol)

///////////////////S-(+)-Citalopram, эсциталопрам إيسكيتالوبرام 艾司西酞普兰 , CITALOPRAM

http://shodhganga.inflibnet.ac.in/bitstream/10603/101297/15/15_chapter%206.pdf

Amantadine Hydrochloride, アダマンタン-1-アミン , تادين ,Амантадин , 金刚烷胺 , アマンタジン


Amantadine.svg

ChemSpider 2D Image | Amantadine | C10H17N

Amantadine

  • Molecular Formula C10H17N
  • Average mass 151.249 Da
[768-94-5]
1-ADAMANTAMINE
1-adamantanamine; 1-adamantylamine; 1-aminoadamantane; Amantidine; Aminoadamantane
1-Adamantylamine
1-Aminotricyclo(3.3.1.1(sup 3,7))decane
2204333 [Beilstein]
31377-23-8 [RN]
40933-03-7 [RN]
4-pyridinecarboxylic acid, compd. with tricyclo[3.3.1.13,7]decan-1-amine (1:1)
Journal of the American Chemical Society, 91, p. 6457, 1969 DOI: 10.1021/ja01051a047
Synthesis, p. 457, 1976
Amantadine Hydrochloride - API

AMANTADINE HYDROCHLORIDE

  • Molecular FormulaC10H18ClN
  • Average mass187.710 Da
CAS 665-66-7
SPECTROSCOPY BASE
13 C NMR
RAMAN
MASS
Image result for Amantadine NMR
1H NMR
IR

Amantadine (trade name Symmetrel, by Endo Pharmaceuticals) is a drug that has U.S. Food and Drug Administration approval for use both as an antiviral and an antiparkinsonian drug. It is the organic compound 1-adamantylamine or 1-aminoadamantane, meaning it consists of an adamantane backbone that has an amino group substituted at one of the four methyne positions. Rimantadineis a closely related derivative of adamantane with similar biological properties.

Apart from medical uses, this compound is useful as a building block in organic synthesis, allowing the insertion of an adamantyl group.

According to the U.S. Centers for Disease Control and Prevention (CDC) 100% of seasonal H3N2 and 2009 pandemic flu samples tested showed resistance to adamantanes, and amantadine is no longer recommended for treatment of influenza in the United States. Additionally, its effectiveness as an antiparkinsonian drug is undetermined, with a 2003 Cochrane Review concluding that there was insufficient evidence in support of or against its efficacy and safety.[2]

Medical uses

Parkinson’s disease

Amantadine is used to treat Parkinsons disease, as well as parkinsonism syndromes.[3] A 2003 Cochrane review concluded evidence was inadequate to support the use of amantadine for Parkinson’s disease.[2]

An extended release formulation is used to treat dyskinesia, a side effect of levodopa which is taken by people who have Parkinsons.[4]

Influenza

Amantadine is no longer recommended for treatment of influenza A infection. For the 2008/2009 flu season, the CDC found that 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes.[5] The CDC issued an alert to doctors to prescribe the neuraminidase inhibitors oseltamivir and zanamivir instead of amantadine and rimantadine for treatment of flu.[6][7] A 2014 Cochrane review did not find benefit for the prevention or treatment of influenza A.[8]

Fatigue in multiple sclerosis

Amantadine also seems to have moderate effects on multiple sclerosis (MS) related fatigue.[9]

Adverse effects

Amantadine has been associated with several central nervous system (CNS) side effects, likely due to amantadine’s dopaminergic and adrenergic activity, and to a lesser extent, its activity as an anticholinergic. CNS side effects include nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure disorders and psychiatric symptoms in patients with schizophrenia or Parkinson’s disease. The usefulness of amantadine as an anti-parkinsonian drug is somewhat limited by the need to screen patients for a history of seizures and psychiatric symptoms.

Rare cases of severe skin rashes, such as Stevens-Johnson syndrome,[10] and of suicidal ideation have also been reported in patients treated with amantadine.[11][12]

Livedo reticularis is a possible side effect of amantadine use for Parkinson’s disease.[13]

Influenza

The mechanisms for amantadine’s antiviral and antiparkinsonian effects are unrelated. The mechanism of amantadine’s antiviral activity involves interference with the viral protein, M2, a proton channel.[14][15] After entry of the virus into cells via endocytosis, it is localized in acidic vacuoles; the M2 channel functions in transporting protons with the gradient from the vacuolar space into the interior of the virion. Acidification of the interior results in disassociation of ribonucleoproteins, and the initiation of viral replication. Amantadine and rimantadine function in a mechanistically identical fashion in entering the barrel of the tetrameric M2 channel, and blocking pore function (i.e., proton translocation). Resistance to the drug class is a consequence of mutations to the pore-lining residues of the channel, leading to the inability of the sterically bulky adamantane ring that both amantadine and rimantadine share, in entering in their usual way, into the channel.[citation needed]

Influenza B strains possess a structurally distinct M2 channels with channel-facing side chains that fully obstruct the channel vis-a-vis binding of adamantine-class channel inhibitors, while still allowing proton flow and channel function to occur; this constriction in the channels is responsible for the ineffectiveness of this drug and rimantadine towards all circulating Influenza B strains.

Parkinson’s disease

Amantadine is a weak antagonist of the NMDA-type glutamate receptorincreases dopamine release, and blocks dopamine reuptake.[16] Amantadine probably does not inhibit MAO enzyme.[17] Moreover, the mechanism of its antiparkinsonian effect is poorly understood.[citation needed] The drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be a weak NMDA receptor antagonist[18][19] as well as an anticholinergic, specifically a nicotinic alpha-7 antagonist like the similar pharmaceutical memantine.

In 2004, it was discovered that amantadine and memantine bind to and act as agonists of the σ1 receptor (Ki = 7.44 µM and 2.60 µM, respectively), and that activation of the σ1receptor is involved in the dopaminergic effects of amantadine at therapeutically relevant concentrations.[20] These findings may also extend to the other adamantanes such as adapromine, rimantadine, and bromantane, and could explain the psychostimulant-like effects of this family of compounds.[20]

History

Amantadine was approved by the U.S. Food and Drug Administration in October 1966 as a prophylactic agent against Asian influenza, and eventually received approval for the treatment of influenzavirus A[21][22][23][24] in adults. In 1969, the drug was also discovered by accident upon trying to help reduce symptoms of Parkinson’s disease, drug-induced extrapyramidal syndromes, and akathisia.

In 2017, the U.S. Food and Drug Administration approved the use of amantadine in an extended release formulation developed by Adamas Pharma for the treatment of dyskinesia, an adverse effect of levodopa, that people with Parkinson’s experience.[25]

Veterinary misuse

In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza.[26] In Western countries and according to international livestock regulations, amantadine is approved only for use in humans. Chickens in China have received an estimated 2.6 billion doses of amantadine.[26] Avian flu (H5N1) strains in China and southeast Asia are now resistant to amantadine, although strains circulating elsewhere still seem to be sensitive. If amantadine-resistant strains of the virus spread, the drugs of choice in an avian flu outbreak will probably be restricted to the scarcer and costlier oseltamivir and zanamivir, which work by a different mechanism and are less likely to trigger resistance.

On September 23, 2015, the US Food and Drug Administration announced the recall of Dingo Chip Twists “Chicken in the Middle” dog treats because the product has the potential to be contaminated with amantadine.[27]

Image result for Amantadine SYNTHESIS

Image result for Amantadine SYNTHESIS

Image result for Amantadine SYNTHESIS

PAPER

An Improved Synthesis of Amantadine Hydrochloride

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00242

 Vietnam Military Medical University, No. 160, Phung Hung str., Phuc La ward, Ha Dong district, Hanoi, Vietnam
 School of Chemical Engineering, Hanoi University of Science and Technology, No.1, Dai Co Viet str., Bach Khoa ward, Hai Ba Trung district, Hanoi, Vietnam
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00242
Abstract Image

Amantadine hydrochloride 1 is an antiviral drug used in the prevention and treatment of influenza A infections. It has also been used for alleviating early symptoms of Parkinson’s disease. Several methods for the preparation of 1 have been reported. These procedures started with adamantane 2 using as many as four reaction steps to produce amantadine hydrochloride with overall yields ranging from 45% to 58%. In this article, we describe a two-step procedure for the synthesis of 1from 2 via N-(1-adamantyl)acetamide 4 with an improved overall yield of 67%. The procedure was also optimized to reduce the use of toxic solvents and reagents, rendering it more environment-friendly. The procedure can be considered as suitable for large-scale production of amantadine hydrochloride. The structure of amantadine hydrochloride was confirmed by 1H NMR, 13C NMR, IR, and MS.

Amantadine Hydrochloride (1)

 1. Yield: 232 g (82%). Rf = 0.5 (CHCl3/MeOH/25% aqueous NH3 = 6:1:1).
Purity (GC): 99.22%, tR 10.10 min; mp 360 °C.
1H NMR (CDCl3, 500 MHz): δ 8.28 (br, s, 3H), 2.15 (s, 3H), 2.04 (s, 6H); 1.69 (s, 6H).
13C NMR (CDCl3, 125 MHz): δ 52.95, 40.56, 35.38, 28.97.
IR (KBr): cm–1 3331.73–3185.17 (N–H); 3054.60–2917.82 (C–H); 1363.50 (C–N).
MS: m/z = 151.9 [M + 1]+, 135.0 [M–NH2 – 1]+.
IR spectrum of amantadine hydrochloride (1)
MS spectrum of amantadine hydrochloride
1H-NMR spectrum of amantadine hydrochloride (1) in CDCl3
13C-NMR spectrum of amantadine hydrochloride (1) in CDCl3
Amantadine
Title: Amantadine
CAS Registry Number: 768-94-5
CAS Name: Tricyclo[3.3.1.13,7]decan-1-amine
Additional Names: 1-adamantanamine; 1-aminoadamantane; 1-aminodiamantane (obsolete); 1-aminotricyclo[3.3.1.13,7]decane
Molecular Formula: C10H17N
Molecular Weight: 151.25
Percent Composition: C 79.41%, H 11.33%, N 9.26%
Literature References: NMDA-receptor antagonist; also active vs influenza A virus. Prepn: H. Stetter et al., Ber. 93, 226 (1960); W. Haaf, ibid. 97, 3234 (1964); P. Kovacic, P. D. Roskos, Tetrahedron Lett. 1968, 5833. Antiviral activity: W. L. Davies et al.,Science 144, 862 (1964). GC determn in biological samples and pharmacodynamics: W. E. Bleidner et al., J. Pharmacol. Exp. Ther. 150, 484 (1965). Pharmacology and toxicology: V. G. Vernier et al., Toxicol. Appl. Pharmacol. 15, 642 (1969). Comprehensive description: J. Kirschbaum, Anal. Profiles Drug Subs. 12, 1-36 (1983). Review of use vs influenza A: R. L. Tominack, F. G. Hayden, Infect. Dis. Clin. North Am. 1, 459-478 (1987); of pharmacokinetics: F. Y. Aoki, D. S. Sitar, Clin. Pharmacokinet. 14, 35-51 (1988). Review of NMDA receptor binding and neuroprotective properties: J. Kornhuber et al., J. Neural Transm. 43, Suppl., 91-104 (1994). Series of articles on clinical experience in Parkinson’s disease: ibid. 46, Suppl., 399-421 (1995).
Properties: Crystals by sublimation, mp 160-190° (closed tube) (Stetter). Also reported as mp 180-192° (Haaf). pKa: 10.1. Sparingly sol in water.
Melting point: mp 160-190° (closed tube) (Stetter); mp 180-192° (Haaf)
pKa: pKa: 10.1

Derivative Type: Hydrochloride

CAS Registry Number: 665-66-7
Manufacturers’ Codes: EXP-105-1; NSC-83653
Trademarks: Adekin (Desitin); Lysovir (Alliance); Mantadan (Boehringer, Ing.); Mantadine (Endo); Mantadix (BMS); Symmetrel (Endo); Virofral (Novo)
Molecular Formula: C10H17N.HCl
Molecular Weight: 187.71
Percent Composition: C 63.99%, H 9.67%, N 7.46%, Cl 18.89%
Properties: Crystals from abs ethanol + anhydr ether, mp >360° (dec). Freely sol in water (at least 1:20); sol in alcohol, chloroform. Practically insol in ether. LD50 orally in mice, rats: 700, 1275 mg/kg (Vernier).
Melting point: mp >360° (dec)
Toxicity data: LD50 orally in mice, rats: 700, 1275 mg/kg (Vernier)
Derivative Type: Sulfate
CAS Registry Number: 31377-23-8
Trademarks: PK-Merz (Merz)
Molecular Formula: C10H17N.½H2SO4
Molecular Weight: 200.29
Percent Composition: C 59.97%, H 9.06%, N 6.99%, S 8.00%, O 15.98%
Therap-Cat: Antiviral; antiparkinsonian.
Keywords: Antidyskinetic; Antiparkinsonian; Antiviral.
Amantadine
Amantadine.svg
Amantadine ball-and-stick model.png
Clinical data
Trade names Symmetrel
Synonyms 1-Adamantylamine
AHFS/Drugs.com Monograph
MedlinePlus a682064
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 86–90%[1]
Protein binding 67%[1]
Metabolism Minimal (mostly to acetyl metabolites)[1]
Biological half-life 10–31 hours[1]
Excretion Urine[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.011.092
Chemical and physical data
Formula C10H17N
Molar mass 151.249 g/mol
3D model (JSmol)

References

  1. Jump up to:a b c d e “SYMMETREL® (amantadine hydrochloride)” (PDF). TGA eBusiness Services. NOVARTIS Pharmaceuticals Australia Pty Limited. 29 June 2011. Retrieved 24 February2014.
  2. Jump up to:a b Crosby, Niall J; Deane, Katherine; Clarke, Carl E (2003). Clarke, Carl E, ed. “Amantadine in Parkinson’s disease”. Cochrane Database of Systematic Reviewsdoi:10.1002/14651858.CD003468.
  3. Jump up^ “Amantadine – FDA prescribing information,”Drugs.com. Retrieved 2017-08-28.
  4. Jump up^ “Amantadine extended release capsules” (PDF). FDA. August 2017. For label updates, see FDA index page for NDA 208944
  5. Jump up^ CDC weekly influenza report – week 35, cdc.gov
  6. Jump up^ “CDC Recommends against the Use of Amantadine and Rimantadine for the Treatment or Prophylaxis of Influenza in the United States during the 2005–06 Influenza Season”CDC Health AlertCenters for Disease Control and Prevention. 2006-01-14. Archived from the original on 3 May 2008. Retrieved 2008-05-20.
  7. Jump up^ Deyde, Varough M.; Xu, Xiyan; Bright, Rick A.; Shaw, Michael; Smith, Catherine B.; Zhang, Ye; Shu, Yuelong; Gubareva, Larisa V.; Cox, Nancy J.; Klimov, Alexander I. (2007). “Surveillance of Resistance to Adamantanes among Influenza A(H3N2) and A(H1N1) Viruses Isolated Worldwide”. Journal of Infectious Diseases196 (2): 249–257. PMID 17570112doi:10.1086/518936.
  8. Jump up^ Alves Galvão, MG; Rocha Crispino Santos, MA; Alves da Cunha, AJ (21 November 2014). “Amantadine and rimantadine for influenza A in children and the elderly.”. The Cochrane database of systematic reviews11: CD002745. PMID 25415374doi:10.1002/14651858.CD002745.pub4.
  9. Jump up^ Braley, TJ; Chervin, RD (Aug 2010). “Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment.”Sleep33 (8): 1061–7. PMC 2910465Freely accessiblePMID 20815187.
  10. Jump up^ Singhal, KC; Rahman, SZ (2002). “Stevens Johnson Syndrome Induced by Amantadine”. Rational Drug Bulletin12 (1): 6.
  11. Jump up^ “Symmetrel (Amantadine) Prescribing Information” (PDF). Endo Pharmaceuticals. May 2003. Retrieved 2007-08-02.
  12. Jump up^ Cook, PE; Dermer, SW; McGurk, T (1986). “Fatal overdose with amantadine”. Canadian Journal of Psychiatry31 (8): 757–8. PMID 3791133.
  13. Jump up^ Vollum, DI; Parkes, JD; Doyle, D (June 1971). “Livedo reticularis during amantadine treatment”Br Med J2 (5762): 627–8. PMC 1796527Freely accessiblePMID 5580722doi:10.1136/bmj.2.5762.627.
  14. Jump up^ Wang C, Takeuchi K, Pinto LH, Lamb RA (1993). “Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block”Journal of Virology67 (9): 5585–94. PMC 237962Freely accessiblePMID 7688826.
  15. Jump up^ Jing X, Ma C, Ohigashi Y, et al. (2008). “Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel”Proc. Natl. Acad. Sci. U.S.A105 (31): 10967–72. PMC 2492755Freely accessiblePMID 18669647doi:10.1073/pnas.0804958105.
  16. Jump up^ Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. p. 3962. ISBN 978-3-85200-181-4.
  17. Jump up^ Strömberg, U.; Svensson, T. H. (November 1971). “Further Studies on the Mode of Action of Amantadine”wiley.comActa Pharmacologica et Toxicologica, Nordic Pharmacological Society. 30 (3–4): 161–171. doi:10.1111/j.1600-0773.1971.tb00646.x.
  18. Jump up^ Kornhuber, J; Bormann, J; Hübers, M; Rusche, K; Riederer, P (1991). “Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study”. Eur. J. Pharmacol. Mol. Pharmacol. Sect206: 297–300. doi:10.1016/0922-4106(91)90113-v.
  19. Jump up^ Blanpied, TA; Clarke, RJ; Johnson, JW (2005). “Amantadine inhibits NMDA receptors by accelerating channel closure during channel block”. Journal of Neuroscience25 (13): 3312–22. PMID 15800186doi:10.1523/JNEUROSCI.4262-04.2005.
  20. Jump up to:a b Peeters, Magali; Romieu, Pascal; Maurice, Tangui; Su, Tsung-Ping; Maloteaux, Jean-Marie; Hermans, Emmanuel (2004). “Involvement of the sigma1 receptor in the modulation of dopaminergic transmission by amantadine”. European Journal of Neuroscience19 (8): 2212–2220. ISSN 0953-816XPMID 15090047doi:10.1111/j.0953-816X.2004.03297.x.
  21. Jump up^ Hounshell, David A.; Kenly Smith, John (1988). Science and Corporate Strategy: Du Pont R&D, 1902–1980. Cambridge University Press. p. 469.
  22. Jump up^ “Sales of flu drug by du Pont unit a ‘disappointment'”The New York Times. Wilmington, Delaware. October 5, 1982. Retrieved May 19, 2008.
  23. Jump up^ Maugh, T. (1979). “Panel urges wide use of antiviral drug”. Science206 (4422): 1058–60. PMID 386515doi:10.1126/science.386515.
  24. Jump up^ Maugh, T. H. (1976). “Amantadine: an Alternative for Prevention of Influenza”. Science192 (4235): 130–1. PMID 17792438doi:10.1126/science.192.4235.130.
  25. Jump up^ Bastings, Eric. “NDA 208944 Approval Letter” (PDF).
  26. Jump up to:a b Sipress, Alan (2005-06-18). “Bird Flu Drug Rendered Useless”Washington Post. pp. A01. Retrieved 2007-08-02.
  27. Jump up^ “Enforcement Report – Week of September 23, 2015”FDA.gov. US Food and Drug Administration, US Department of Health & Human Services.

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Synthesis of isosorbide: an overview of challenging reactions


Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC01912B, Tutorial Review
C. Dussenne, T. Delaunay, V. Wiatz, H. Wyart, I. Suisse, M. Sauthier
This review gives an overview of the catalysts and technologies developed for the synthesis of isosorbide, a platform molecule derived from biomass (sorbitol and cellulose).

Synthesis of isosorbide: an overview of challenging reactions

 Author affiliations

Abstract

Isosorbide is a diol derived from sorbitol and obtained through dehydration reactions that has raised much interest in the literature over the past few decades. Thus, this platform chemical is a biobased alternative to a number of petrosourced molecules that can find applications in a large number of technical specialty fields, such as plasticizers, monomers, solvents or pharmaceuticals. The synthesis of isosorbide is still a technical challenge, as several competitive reactions must be simultaneously handled to promote a high molar yield and avoid side reactions, like degradation and polymerization. In this purpose, many studies have proposed innovative and varied methods with promising results. This review gives an overview of the synthesis strategies and catalysts developed to access this very attractive molecule, pointing out both the results obtained and the remaining issues connected to isosorbide synthesis.

STR1 STR2

Up to now, isosorbide has been used to access a large panel of molecules with relevant applicative properties and industrial reality (Scheme 2).12 Isosorbide dinitrate is used since several decades as vasodilator.13, 14 The dimethyl isosorbide is for example used as solvent in cosmetics15-17 and isosorbide diesters18-22 are actually industrially produced and commercialized as surfactants23-27 and PVC plasticizer28, 29 . The rigid scaffold associated to the bifunctionality of the molecule has attracted a strong interest in the field of polymers chemistry. Isosorbide and derivatives have thus been shown as suitable monomers for the industrial production of polycarbonates30, 31, polyesters32-41 or polyamides42-44, with attractive applicative properties. For example, isosorbide allows the increase of Tg, improves the scratch resistance and gives excellent optical properties to polymers. Polyesters and polycarbonates containing isosorbide have now commercial developments in food packaging, spray container, automotive, material for electronic devices … .

Conclusions

Isosorbide is a versatile platform molecule that shows key features to make it a credible alternative to petro-based products. The molecule is already available on large industrial scale (tens of thousands tons per years), which allows its development in commercial products such as active pharma ingredient, additive for cosmetic, speciality chemicals and polymers (ex: polycarbonates – polyesters). The development of more selective and higher yields syntheses of isosorbide are greatly needed to consolidate isosorbide production in view of a large expansion of its uses. Sorbitol conversion to isosorbide, relying on a starch route, is already a tough challenge. In a farther future, development of a credible path to isosorbide relying on cellulose source could even be thought of, provided that very versatile innovative catalysts will be developed in the next years. In all cases, a key issue is to develop catalysts that will avoid the massive production of “oligomeric/polymeric” by-products in order to access more sustainable processes by limiting the amounts of wastes produced during the synthesis. For this purpose, more selective homogeneous catalysts than the conventional Brønsted acids or alternative reaction conditions would be of strong interest. Selective and recyclable heterogeneous catalysts would be even more profitable as they would allow the continuous production of catalyst free isosorbide. This latter approach faces strong limitations due to the need of high reaction temperatures that often result in high amounts of side-products and the need of frequent and often tedious catalyst regeneration. Innovation concerning isosorbide synthesis is still an open field on which the design of efficient and robust catalysts, either homogeneous or heterogeneous, is a key issue. Such developments would pave the way to high scale effective processes considering altogether synthesis and purification of isosorbide.

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Image result for ISOSORBIDE SYNTHESIS

Image result for ISOSORBIDE SYNTHESIS

Isosorbide is a heterocyclic compound that is derived from glucose. Isosorbide and its two isomers, namely isoidide and isomannide, are 1,4:3,6-dianhydrohexitols. It is a white solid that is prepared from the double dehydration of sorbitol. Isosorbide is a non-toxic diolproduced from biobased feedstocks, that is biodegradable and thermally stable. It is used in medicine and has been touted as a potential biofeedstock.

Production

Hydrogenation of glucose gives sorbitol. Isosorbide is obtained by double dehydration of sorbitol:

(CHOH)4(CH2OH)2 → C6H10O2(OH)2 + 2 H2O

An intermediate in the dehydration is the monocycle sorbitan.[1]

Application

Isosorbide is used as a diuretic, mainly to treat hydrocephalus, and is also used to treat glaucoma.[2] Other medications are derived from isosorbide, including isosorbide dinitrate and isosorbide mononitrate, are used to treat angina pectoris. Other isosorbide-based medicines are used as osmotic diuretics and for treatment of esophageal varices. Like other nitric oxide donors (see biological functions of nitric oxide), these drugs lower portal pressure by vasodilation and decreasing cardiac output. Isosorbide dinitrate and hydralazineare the two components of the anti-hypertensive drug isosorbide dinitrate/hydralazine (Bidil).

Isosorbide is also used as a building block for bio based polymers such as polyesters.[3]

References

  1. Jump up^ M. Rose, R. Palkovits (2012). “Isosorbide as a Renewable Platform chemical for Versatile Applications—Quo Vadis?”. ChemSusChem5 (1): 167–176. PMID 22213713doi:10.1002/cssc.201100580.
  2. Jump up^ CID 12597 from PubChem
  3. Jump up^ Bersot J.C. (2011). “Efficiency Increase of Poly (ethylene terephthalate‐co‐isosorbide terephthalate) Synthesis using Bimetallic Catalytic Systems”. Macromol. Chem. Phys212 (19): 2114–2120. doi:10.1002/macp.201100146.
Isosorbide
Isosorbide.svg
Names
Other names

D-Isosorbide; 1,4:3,6-Dianhydro-D-sorbitol; 1,4-Dianhydrosorbitol
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.010.449
KEGG
PubChem CID
UNII
Properties
C6H10O4
Molar mass 146.14 g·mol−1
Appearance Highly hygroscopic white flakes
Density 1.30 at 25 °C
Melting point 62.5 to 63 °C (144.5 to 145.4 °F; 335.6 to 336.1 K)
Boiling point 160 °C (320 °F; 433 K) at 10 mmHg
in water (>850 g/L), alcoholsand ketones
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

From the net

STR1

Image result for ISOSORBIDE SYNTHESIS

 

 

1H Nuclear magnetic resonance (NMR) spectra of PTMG, isosorbide, HDI, and polyurethane.HDI: hexamethylene diisocyanate; PTMG: poly(tetramethylene glycol).

1H Nuclear magnetic resonance (NMR) spectra of PTMG, isosorbide, HDI, and polyurethane.HDI: hexamethylene diisocyanate; PTMG: poly(tetramethylene glycol).

 

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REF

http://www.rsc.org/suppdata/gc/c4/c4gc01822b/c4gc01822b1.pdf

Synthesis of five- and six-membered heterocycles by dimethyl carbonate with catalytic amount of nitrogen bicyclic bases

http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01822b#!divAbstract

F. Aricò, a,*S. Evaristoa and P. Tundoa,*

Catalytic amount of a nitrogen bicyclic base, i.e., DABCO, DBU and TBD is effective for the one-pot synthesis of heterocycles from 1,4-, 1,5-diols and 1,4-bifunctional compounds via dimethyl carbonate chemistry under neat conditions. Nitrogen bicyclic bases, that previously showed to enhance the reactivity of DMC in methoxycarbonylation reaction by BAc2 mechanism, are herein used for the first time as efficient catalysts for cyclization reaction encompassing both BAc2 and BAl2 pathways. This synthetic procedure was also applied to a large scale synthesis of cyclic sugars isosorbide and isomannide starting from D-sorbitol and D-mannitol, respectively. The resulting anhydro sugar alcohols were obtained as pure crystalline compounds that did not require any further purification or crystallization.

Image result for ISOSORBIDE SYNTHESIS

Larger scale synthesis of isosorbide: In a round bottom flask equipped with a reflux condenser, D-sorbitol (0.05 mol, 1.00 mol. eq.), DMC (0.44 mol, 8.00 mol. eq.), DBU (2.70 mmol, 0.05 mol. eq.) and MeOH (20.00 mL) were heated at reflux while stirring. The progress of the reaction was monitored by NMR. After 48 hours the reaction was stopped, cooled at room temperature and the mixture was filtered over Gooch n°4. Finally, DMC was evaporated under vacuum and the product was obtained as pure in 98% yield (7.90 g, 0.05 mol). Characterization data were consistent with those obtained for the commercially available compound.

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File:Isosorbide dinitrate synthesis.png

 

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FDA clears first 7T magnetic resonance imaging device


FDA clears first 7T magnetic resonance imaging device

Today, the U.S. Food and Drug Administration cleared the first seven tesla (7T) magnetic resonance imaging (MRI) device, more than doubling the static magnetic field strength available for use in the United States. The Magentom Terra is the first 7T MRI system cleared for clinical use in the United States. Continue reading.

 JTV 519, K 201, 


JTV-519.svg

JTV-519

  • Molecular FormulaC25H32N2O2S
  • Average mass424.599 Da
  • 145903-06-6 CAS

ChemSpider 2D Image | JTV-519 hydrochloride salt | C25H33ClN2O2S

JTV-519 hydrochloride salt

  • Molecular FormulaC25H33ClN2O2S
  • Average mass461.060 Da
3-(4-Benzyl-1-piperidinyl)-1-(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1-propanonhydrochlorid (1:1)
4-[3-(4-benzylpiperidin-1-yl)propanoyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride
JTV-519 hydrochloride salt
1038410-88-6 [RN]
  1. UNII-0I621Y6R4Q
  2. K201
  3. 1038410-88-6
  4. K 201
  5. SCHEMBL194018
  6. CHEMBL2440857
  7. DTXSID90146108
  8. 0I621Y6R4Q
  9. LS-193564

Image result for Andrew Marks, JAPAN TOBACCO

JAPAN TOBACCO

Acute Myocardial Infarction, Treatment of Cardiovascular Diseases (Not Specified)
Antiarrhythmic Drugs

JTV-519 (K201) is a 1,4-benzothiazepine derivative that interacts with many cellular targets.[1] It has many structural similarities to diltiazem, a Ca2+ channel blocker used for treatment of hypertensionangina pectoris and some types of arrhythmias.[2] JTV-519 acts in the sarcoplasmic reticulum (SR) of cardiac myocytes by binding to and stabilizing the ryanodine receptor (RyR2) in its closed state.[3][4]It can be used in the treatment of cardiac arrhythmias, heart failurecatecholaminergic polymorphic ventricular tachycardia (CPVT) and store overload-induced Ca2+ release (SOICR).[2][3][4] Currently, this drug has only been tested on animals and its side effects are still unknown.[5] As research continues, some studies have also found a dose-dependent response; where there is no improvement seen in failing hearts at 0.3 μM and a decline in response at 1 μM.[4]

K-201 (JTV-519; 1,4-benzothiazepine derivative) is an antiarrhythmic drug, had been in phase II clinical development at Japan Tobacco and Sequel Pharmaceuticals for the intravenous treatment of atrial fibrillation; however no recent developments have been reported and Sequel Pharmaceuticals has ceased operations.

In 2006, NovaCardia acquired rights from Aetas to develop the product in Europe and US for cardiovascular disorders. Sequel acquired the compound, which has a unique multi-ion channel profile, from NovaCardia following its acquisition by Merck & Co.

Treatment with JTV-519 involves stabilization of RyR2 in its closed state, decreasing its open probability during diastole and inhibiting a Ca2+ leak into the cell’s cytosol.[3][4] By decreasing the intracellular Ca2+ leak, it is able to prevent Ca2+ sparks or increases in the resting membrane potential, which can lead to spontaneous depolarization (cardiac arrhythmias), and eventually heart failure, due to the unsynchronized contraction of the atrial and ventricular compartments of the heart.[2][3][4] When Ca2+ sparks occur from the SR, the increase in intracellular Ca2+ contributes to the rising membrane potential which leads to the irregular heart beat associated to cardiac arrhythmias.[3] It can also prevent SOICR in the same manner; preventing opening of the channel due to the increase of Ca2+ inside the SR levels beyond its threshold.[2]

Molecular problem

In the closed state, N-terminal and central domains come into close contact interacting to cause a “zipping” of domains. This leads to conformational constraints that stabilize the channel and maintain the closed state.[1] Most RyR2 mutations are clustered into three regions of the channel, all affecting the same domains that interact to stabilize the channel.[1] Any of these mutations can lead to “unzipping” of the domains and a decrease in the energy barrier required for opening the channel (increasing its open probability).[1]This channel “unzipping” allows for an increase in protein kinase A phosphorylation and calstabin2 dissociation. Phosphorylation of RyR2 increases the channel’s response to Ca2+, which usually binds the RyR2 to open it.[1] If the channel become phosphorylated, this can lead to an increase in Ca2+ sparks due to an increase in Ca2+ sensitivity.

Some researchers believe that the depletion of calstabin2 from the RyR2 causes the calcium leak.[3] The depletion of calstabin2 can occur in both heart failure and CPVT.[3]Calstabin2 is a protein that stabilizes RyR2 in its closed state, preventing Ca2+ leakage during diastole. When calstabin2 is lost, the interdomain interactions of RyR2 become loose, allowing the Ca2+ leak.[3] However, the role of calstabin2 has been controversial, as some studies have found it necessary for the effect of JTV-519,[3] whereas others have found the drug functions without the stabilizing protein.[2]

Molecular mechanism

JTV-519 seems to restore the stable conformation of RyR2 during the closed state.[1][4] It is still controversial whether or not calstabin2 is necessary for this process, however, many studies believe that JTV-519 can act directly on the channel and by binding, prevents conformational changes.[2] This stabilization of the channel decreases its open probability resulting in fewer leaks of Ca2+ into the cytosol and fewer Ca2+ sparks to occur.[3][4] Researchers who believe that calstabin2 is necessary for JTV-519 effect, found that this drug may function by inducing the binding of calstabin2 back to the channel or increasing calstabin2’s affinity for the RyR2 and thus increasing its stability.[2][3]

SYNTHESIS

PATENT

US 20050186640

https://www.google.com/patents/US20050186640

Inventors Andrew MarksDonald LandryShi DengZhen Cheng
Original Assignee Marks Andrew R.Landry Donald W.Deng Shi X.Cheng Zhen Z.

PATENT

WO 9212148

https://www.google.co.in/patents/WO1992012148A1?cl=en

Inventors Noboru KanekoTatsushi OosawaTeruyuki SakaiHideo Oota
Applicant Noboru Kaneko

PATENT

US 2014121368

2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines are important compounds because of their biological activities, as disclosed, for example, in U.S. Pat. Nos. 5,416,066 and 5,580,866 and published US Patent Applications Nos. 2005/0215540, 2007/0049572 and 2007/0173482.

Synthetic procedures exist for the preparation of 2-oxo-, 3-oxo-, 5-oxo- and 3,5-dioxo-1,4-benzothiazepines and for 2,3-dihydro-1,4-benzothiazepines. However, relatively few publications describe the preparation of 2,3,4,5-tetrahydrobenzo-1,4-thiazepines that contain no carbonyl groups, and most of these involve reduction of a carbonyl group or an imine. Many of the routes described in the literature proceed from an ortho-substituted arene and use the ortho substituents as “anchors” for the attachment of the seven-membered ring. Essentially all the preparatively useful syntheses in the literature that do not begin with an ortho-substituted arene employ a modification of the Bischler-Napieralski reaction in which the carbon of the acyl group on the γ-amide becomes the carbon adjacent the bridgehead and the acyl substituent becomes the 5-substituent. Like earlier mentioned syntheses, the Bischler-Napieralski synthesis requires reduction of an iminium intermediate.

It would be useful to have an intramolecular reaction for the direct construction of 2,3,4,5-tetrahydrobenzo[1,4]thiazepines that would allow more flexibility in the 4- and 5-substituents and that would avoid a separate reduction step. The Pictet Spengler reaction, in which a β-arylethylamine such as tryptamine undergoes 6-membered ring closure after condensation (cyclization) with an aldehyde, has been widely used in the synthesis of 6-membered ring systems over the past century and might be contemplated for this purpose. The Pictet Spengler reaction, however, has not been generally useful for 7-membered ring systems such as 1,4-benzothiazepines. A plausible explanation is that the failure of the reaction for typical arenes was due to the unfavorable conformation of the 7-membered ring. There are two isolated examples of an intramolecular Pictet-Spengler-type reaction producing a good yield of a benzothiazepine from the addition of formaldehyde. In one case, the starting material was a highly unusual activated arene (a catechol derivative) [Manini et al. J. Org. Chem. (2000), 65, 4269-4273]. In the other case, the starting material is a bis(benzotriazolylmethyl)amine that cyclizes to a mono(benzotriazolyl)benzothiazole [Katritzky et al. J. Chem. Soc. Pl (2002), 592-598].

PATENT

US 20050186640

WO 2015031914

US 20040229781

US 20090292119

US 7704990

PAPER

Journal of Medicinal Chemistry (2013), 56(21), 8626-8655

http://pubs.acs.org/doi/full/10.1021/jm401090a

PAPER

Synthesis of 2,3,4,5-Tetrahydrobenzo[1,4]thiazepines via N-Acyliminium Cyclization

 ARMGO Pharma, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, United States
 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00260
Publication Date (Web): September 28, 2017
Copyright © 2017 American Chemical Society
*Phone: (914)-425-0000. E-mail: sbelvedere@armgo.com.

Abstract

Abstract Image

We report an efficient and scalable synthesis of 7-methoxy-2,3,4,5-tetrahydrobenzo[1,4]thiazepine, the core structure of biologically active molecules like JTV-519 and S107. This synthetic route, starting with 4-methoxythiophenol and proceeding via acyliminum cyclization, gives the target product in four steps and 68% overall yield and is a substantial improvement over previously published processes. Nine additional examples of tetrahydrobenzo[1,4]thiazepine synthesis via acyliminium ring closure are also presented.

References

  1. Jump up to:a b c d e f Oda, T; Yano, M; Yamamoto, T; Tokuhisa, T; Okuda, S; Doi, M; Ohkusa, T; Ikeda, Y; et al. (2005). “Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure”. Circulation111 (25): 3400–10. PMID 15967847doi:10.1161/CIRCULATIONAHA.104.507921.
  2. Jump up to:a b c d e f g Hunt, DJ; Jones, PP; Wang, R; Chen, W; Bolstad, J; Chen, K; Shimoni, Y; Chen, SR (2007). “K201 (JTV519) suppresses spontaneous Ca2+ release and 3Hryanodine binding to RyR2 irrespective of FKBP12.6 association”The Biochemical Journal404 (3): 431–8. PMC 1896290Freely accessiblePMID 17313373doi:10.1042/BJ20070135.
  3. Jump up to:a b c d e f g h i j k Wehrens, XH; Lehnart, SE; Reiken, SR; Deng, SX; Vest, JA; Cervantes, D; Coromilas, J; Landry, DW; Marks, AR (2004). “Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2”. Science304 (5668): 292–6. PMID 15073377doi:10.1126/science.1094301.
  4. Jump up to:a b c d e f g Toischer, K; Lehnart, SE; Tenderich, G; Milting, H; Körfer, R; Schmitto, JD; Schöndube, FA; Kaneko, N; et al. (2010). “K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum”Basic research in cardiology105 (2): 279–87. PMC 2807967Freely accessiblePMID 19718543doi:10.1007/s00395-009-0057-8.
  5. Jump up^ Viswanathan, MN; Page, RL (2009). “Pharmacological therapy for atrial fibrillation: Current options and new agents”. Expert Opinion on Investigational Drugs18 (4): 417–31. PMID 19278302doi:10.1517/13543780902773410.
JTV-519
JTV-519.svg
Names
IUPAC name

3-(4-Benzyl-1-piperidinyl)-1-(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1-propanone
Other names

K201
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
Properties
C25H32N2O2S
Molar mass 424.60 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////////JTV-519K201, JTV 519, K 201, 

Phytomenadione, Phytonadione, фитоменадион ,فيتوميناديون ,


Vitamin K1.png

ChemSpider 2D Image | Phylloquinone | C31H46O2

Phytomenadione,

PHYTONADIONE, Phylloquinone

Molecular Formula: C31H46O2
Molecular Weight: 450.707 g/mol
[R-[R*,R*-(E)]]-2-Methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-1,4-naphthalenedione
1,4-Naphthalenedione, 2-methyl-3-((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecenyl)-
2′,3′-trans-Vitamin K1
фитоменадион [Russian] [INN]
فيتوميناديون [Arabic] [INN]
2-methyl-3-[(2E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-yl]naphthalene-1,4-dione
 CAS 84-80-0[RN]
Antihemorrhagic vitamin
Aqua mephyton
AQUAMEPHYTON
Combinal K1
Kativ N
Kephton
Kinadion
K-Ject
KONAKION
Mono-kay
Phyllochinonum
Phylloquinone (8CI)
Optical Rotatory Power -0.28 ° Solv: 1,4-dioxane (123-91-1); Wavlen: 589.3 nm; Temp: 25 °CKarrer, P.; Helvetica Chimica Acta 1944, VOL 27, PG317-19

 

MASS

 

1H NMR

400 MHZ CDCL3

 

13C NMR

  1. Murahashi, Shun-ichi; European Journal of Organic Chemistry 2011, VOL2011(27), P5355-5365 
  2. Huang, Zhihong; Advanced Synthesis & Catalysis 2007, VOL349(4+5), PG539-545 

IR LIQ FILM

 

Phylloquinone is a family of phylloquinones that contains a ring of 2-methyl-1,4-naphthoquinone and an isoprenoid side chain. Members of this group of vitamin K 1 have only one double bond on the proximal isoprene unit. Rich sources of vitamin K 1 include green plants, algae, and photosynthetic bacteria. Vitamin K1 has antihemorrhagic and prothrombogenic activity.

Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin found in food and used as a dietary supplement.[1][2] As a supplement it is used to treat certain bleeding disorders.[2] This includes in warfarin overdosevitamin K deficiency, and obstructive jaundice.[2] It is also recommended to prevent and treat hemorrhagic disease of the newborn.[2] Use is typically recommended by mouth or injection under the skin.[2] Use by injection into a vein or muscle is recommended only when other routes are not possible.[2] When given by injection benefits are seen within two hours.[2]

Common side effects when given by injection include pain at the site of injection and altered taste.[2] Severe allergic reactions may occur with injected into a vein or muscle.[2] It is unclear if use during pregnancy is safe; however, use is likely okay during breastfeeding.[3] It works by supplying a required component for making a number of blood clotting factors.[2] Found sources include green vegetables, vegetable oil, and some fruit.[4]

Phytomenadione was first isolated in 1939.[5] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[6] The wholesale cost in the developing world is about 0.11 to 1.27 USD for a 10 mg vial.[7]In the United States a course of treatment costs less than 25 USD.[8] In 1943 Edward Doisy and Henrik Dam were given a Nobel Prizefor its discovery.[5]

Terminology

Phytomenadione is often called phylloquinone or vitamin K,[9] phytomenadione or phytonadione. Sometimes a distinction is made between phylloquinone, which is considered to be a natural substance, and phytonadione, which is considered to be a synthetic substance.[10]

stereoisomer of phylloquinone is called vitamin k1 (note the difference in capitalization).

Chemistry

Vitamin K is a fat-soluble vitamin that is stable in air and moisture but decomposes in sunlight. It is a polycyclic aromatic ketone, based on 2-methyl1,4-naphthoquinone, with a 3-phytyl substituent. It is found naturally in a wide variety of green plants, particularly in leaves, since it functions as an electron acceptor during photosynthesis, forming part of the electron transport chain of photosystem I.

Phylloquinone is an electron acceptor during photosynthesis, forming part of the electron transport chain of Photosystem I.

The best-known function of vitamin K in animals is as a cofactor in the formation of coagulation factors II (prothrombin), VII, IX, and X by the liver. It is also required for the formation of anticoagulant factors protein C and S. It is commonly used to treat warfarin toxicity, and as an antidote for coumatetralyl.

Vitamin K is required for bone protein formation.

SYN

e-EROS Encyclopedia of Reagents for Organic Synthesis, 1-2; 2001

WO2016060670

 

PAPERS

Helvetica Chimica Acta (1944), 27, 317-19.

PATENT

US 2683176

CN 105399615

WO 2016060670

References

  1. Jump up^ Watson, Ronald Ross (2014). Diet and Exercise in Cystic Fibrosis. Academic Press. p. 187. ISBN 9780128005880.
  2. Jump up to:a b c d e f g h i j “Phytonadione”. The American Society of Health-System Pharmacists. Retrieved 8 December 2016.
  3. Jump up^ “Phytonadione Use During Pregnancy”Drugs.com. Retrieved 29 December 2016.
  4. Jump up^ “Office of Dietary Supplements – Vitamin K”ods.od.nih.gov. 11 February 2016. Retrieved 30 December 2016.
  5. Jump up to:a b Sneader, Walter (2005). Drug Discovery: A History. John Wiley & Sons. p. 243. ISBN 9780471899792.
  6. Jump up^ “WHO Model List of Essential Medicines (19th List)” (PDF). World Health Organization. April 2015. Retrieved 8 December 2016.
  7. Jump up^ “Vitamin K1”International Drug Price Indicator Guide. Retrieved 8 December 2016.
  8. Jump up^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 229. ISBN 9781284057560.
  9. Jump up^ Haroon, Y.; Shearer, M. J.; Rahim, S.; Gunn, W. G.; McEnery, G.; Barkhan, P. (June 1982). “The content of phylloquinone (vitamin K1) in human milk, cows’ milk, and infant formula foods determined by high-performance liquid chromatography”J. Nutr112 (6): 1105–1117. PMID 7086539.
  10. Jump up^ “Vitamin K”. Retrieved 2009-03-18.
Phytomenadione
Vitamin K1.png
Clinical data
Trade names Mephyton, others
Synonyms Vitamin K1, phytonadione, phylloquinone
AHFS/Drugs.com Monograph
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
by mouth, subQ, IM, IV
ATC code
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
ECHA InfoCard 100.001.422
Chemical and physical data
Formula C31H46O2
Molar mass 450.70 g/mol
3D model (JSmol)

/////////////PHYTONADIONE, фитоменадион ,فيتوميناديون PHYTONADIONE, Phylloquinone

PHYSICAL AND CHEMICAL PROPERTIES
MELTING POINT : Yellow viscous oil (Ref. 0001)


REFRACTIVE INDEX : n20D=1.5263(Ref. 0010)

OPTICAL ROTATION : [a]25D=-28deg(Ref. 0001)Optical rotation
[Table ] (Ref. 0010)

SOLUBILITY : Insol in water. Sparingly sol in methanol; sol in ethanol, acetone, benzene, petr ether, hexane, dioxane, chloroform, ether, other fat solvents and in vegetable oils(Ref. 0001)
SPECTRAL DATA
UV SPECTRA : Uv max (petr ether) 242, 248, 260, 269, 325 nm (E1%1cm396, 419, 383, 387, 68) (Ref. 0001). Uv max (ethanol) 243, 248, 262, 270, 330 nm (Ref. 0002).
(UV Ref. 0010)Em at 248 nm (EtOH) =18,900 (Ref. 0002/0006).

IR SPECTRA : (liquid) : 6.05m (CO), 6.21, 6.28m (aromatic nucleus) (Ref. 0008)
(IR Ref. 0010)
[Table 0002] (Ref. 0010)

NMR SPECTRA : at 60 MHz in CDCl3, i nternal standard Si(CH3)4: multiplet at 453-486 Hz (4 aromatic H), triplet at 302 Hz (J=7 Hz) (olefinic H at C2. , doublet at 201 Hz ) (J=7 Hz) (CH2.-1), singlet at 130 Hz (CH3-2), signal at 107 Hz (trans-methyl group at C3. .(Ref. 0008)
( NMR Ref. 0010) Proton magnetic resonance data

MASS SPECTRA : [Spectrum  (Ref. 0005)
REFERENCES

[0001]

AUTHOR : Anonym. (1989) Vitamin K1 in The Merck Index , 11th edition (Budavari, S., O’Neil, M. J., Smith, A., and Heckelman, P.E., eds), pp1580, Merck & Co., Inc., Rahway, N. J.
TITLE :
JOURNAL :
VOL : PAGE : – ()

[0002]

AUTHOR : Dunphy,P.J., and Brodie,A.F.
TITLE : The structure and function of quinones in respiratory metabolism.
JOURNAL : Methods in Enzymology
VOL : 18 PAGE : 407 -461 (1971)

[0005]

AUTHOR : Di Mari, S. J., Supple, J. H., and Rapoport, H.
TITLE : Mass spectra of naphthoquinones. Vitamin K1(20) PubMed ID:5910960
JOURNAL : J Am Chem Soc.
VOL : 88 PAGE : 1226-1232 (1966)

[0006]

AUTHOR : Suttie,W.J. (1991) Vitamin K, in Handbook of Vitamins (2nd ed., Machlin,L.J., ed) , pp145-194, Marcel Dekker, Inc., New York
TITLE :
JOURNAL :
VOL : PAGE : – ()

[0007]

AUTHOR : Kodaka,K., Ujiie,T.,Ueno,T., and Saito,M.
TITLE : Contents of Vitamin K1 and Chlorophyll in Green Vegetables.
JOURNAL : J Jpn Soc Nutr Food Sci
VOL : 39 PAGE : 124 -126 (1986)

[0008]

AUTHOR : Mayer,H., and Isler,O .
TITLE : Synthesis of Vitamin K.
JOURNAL : Methods in Enzymology
VOL : 18 PAGE : 491 -547 (1971)

[0009]

AUTHOR : Naruta,Y., and Maruyama,K.
TITLE : Regio- and sterocontrolled polyprenylation of quinones. A new synthetic method of vitamin K series.
JOURNAL : Chemistry Lett
VOL : PAGE : 881 -884 (1979)

[0010]

AUTHOR : Sommer,P., and Kofler,M.
TITLE : Physicochemical Properties and Methods of Analysis of Phylloquinones, Menaquinones, Ubiquinones, and Related Compounds. PubMed ID:5340867
JOURNAL : Vitamins and Hormones
VOL : 24 PAGE : 349 -399 (1966)

[0011]

AUTHOR : Bristol, J. A., Ratcliffe, J. V., Roth, D. A., Jacobs, M. A., Furie, B. C., and Furie, B.
TITLE : Biosynthesis of prothrombin: intracellular localization of the vitamin K-dependent carboxylase and the sites of gamma-carboxylation PubMed ID:8839851
JOURNAL : Blood.
VOL : 88 PAGE : 2585-2593 (1996)

[0022]

AUTHOR : Usui, Y., Nishimura, N., Kobayashi, N., Okanoue, T., Kimoto, M., and Ozawa, K.
TITLE : Measurement of vitamin K in human liver by gradient elution high-performance liquid chromatography using platinum-black catalyst reduction and fluorimetric detection PubMed ID:2753953
JOURNAL : J Chromatogr.
VOL : 489 PAGE : 291-301 (1989)

 

//////////////

ELAMIPRETIDE


Elamipretide.pngimg

Elamipretide

Elamipretide biologic depiction

H-D-Arg-Tyr(2,6-diMe)-Lys-Phe-NH2

D-arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-phenylalaninamide

(2S)-6-amino-2-[[(2S)-2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]hexanamide

CAS 736992-21-5

Chemical Formula: C32H49N9O5

Molecular Weight: 639.8

  • A free radical scavenger and antioxidant that localizes in the inner mitochondrial membrane.
  • Mitochondrial Protective Agent to Improve Cell Viability
  1. Elamipretide
  2. bendavia
  3. UNII-87GWG91S09
  4. 736992-21-5
  5. MTP 131
  6. RX 31
  7. SS 31
  8. 87GWG91S09
  9. L-Phenylalaninamide, D-arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-
  10. SS-31 peptide
  11. Arg-Dmt-Lys-Phe-NH2
  12. D-Arg-Dmt-Lys-Phe-NH2
  13. SS31 peptide
  14. Elamipretide [USAN:INN]
  15. MTP-131
  16. Elamipretide (USAN/INN)
  17. arginyl-2,’6′-dimethyltyrosyl-lysyl-phenylalaninamide
  18. CHEMBL3833370
  19. SCHEMBL15028020
  20. CTK2H1007

Elamipretide is a cardiolipin peroxidase inhibitor and mitochondria-targeting peptide, Improves Left Ventricular and Mitochondrial Function. In vitro: Elamipretide significantly increases enzymatic activities of both complexes to near normal levels.

Background Information

Elamipretide is a cardiolipin peroxidase inhibitor and mitochondria-targeting peptide, Improves Left Ventricular and Mitochondrial Function. In vitro: Elamipretide significantly increases enzymatic activities of both complexes to near normal levels. long-term therapy with elamipretide reduces ROS formation, attenuated mPTP openings, and significantly decreases the levels of cytosolic cytochrome c and active caspase-3, thus suppressing a major signaling pathway for apoptosis. Elamipretide represents a new class of compounds that can improve the availability of energy to failing heart and reduce the burden of tissue injury caused by excessive ROS production. [1] In vivo: Fourteen dogs with microembolization-induced HF are randomized to 3 months monotherapy with subcutaneous injections of elamipretide (0.5 mg/kg once daily. Elamipretide has been shown to enhance ATP synthesis in multiple organs, including heart, kidney, neurons, and skeletal muscle. [1] ……by MedChemexpress Co., Ltd.

Elamipretide (also known as SS-31 and Bendavia)[1][2] is a small mitochondrially-targeted tetrapeptide (D-Arg-dimethylTyr-Lys-Phe-NH2) that appears to reduce the production of toxic reactive oxygen species and stabilize cardiolipin.[3]

Stealth Peptides, a privately held company, was founded in 2006 to develop intellectual property licensed from several universities including elamipretide; it subsequently changed its name to Stealth BioTherapeutics.[4][5]

Acute coronary syndrome; Age related macular degeneration; Cardiac failure; Corneal dystrophy; Diabetic macular edema; Lebers hereditary optic atrophy

  • Originator Stealth Peptides
  • Developer Stealth BioTherapeutics
  • Class Eye disorder therapies; Ischaemic heart disorder therapies; Oligopeptides; Peptides; Small molecules
  • Mechanism of Action Free radical scavengers; Mitochondrial permeability transition pore inhibitors
  • Phase II/III Barth syndrome
    • Phase II Acute kidney injury; Corneal disorders; Heart failure; Leber’s hereditary optic atrophy; Mitochondrial disorders; Reperfusion injury
    • Phase I/II Diabetic macular oedema; Dry age-related macular degeneration; Mitochondrial myopathies
    • Phase I Age-related macular degeneration
    • No development reported Chronic heart failure; Diabetes mellitus; Eye disorders; Neurodegenerative disorders

    Most Recent Events

    • 29 Jun 2017 Initial efficacy and adverse events data from phase II MMPOWER-2 trial in Mitochondrial-myopathies released by Stealth
    • 02 Jun 2017 Stealth BioTherapeutics completes a phase II trial in Heart failure in Germany and Serbia (SC) (NCT02814097)
    • 01 May 2017 Phase-II/III clinical trials in Barth syndrome (In children, In adolescents, In adults, In the elderly) in USA (SC) (NCT03098797)

Novel crystalline salt (eg hydrochloride, mesylate and tosylate salts) forms of D-Arg-Dmt-Lys-Phe-NH2 (referred to as MTP-131 or elamipretide ) and composition comprising them are claimed. See WO2016190852 , claiming therapeutic compositions including chromanyl compounds, variants and analogues and uses thereof. Stealth BioTherapeutics (formerly known as Stealth Peptides) is developing elamipretide, which targets mitochondria, for the potential iv/sc treatment of cardiac reperfusion injury, acute coronary syndrome, acute kidney injury, mitochondrial myopathy, skeletal muscle disorders and congestive heart failure.

Also, the company is developing an oral formulation of elamipretide , which targets mitochondria and reduces the production of excess reactive oxygen species, for treating chronic heart failure. In January 2015, a phase II trial was ongoing . In July 2016, a phase II trial was initiated in Latvia, Spain and Hungary .

Further, the company is developing an ophthalmic formulation of elamipretide , a mitochondria targeting peptide, for treating ocular diseases including diabetic macular edema, age-related macular degeneration and fuchs’ corneal endothelial dystrophy and Leber’s hereditary optic neuropathy.

In April 2016, a phase II trial was initiated for LHON . Family members of the product case of elamipretide ( WO2007035640 ) hold protection in the EU until 2026 and expires in the US in 2027 with US154 extension.

Acute coronary syndrome; Age related macular degeneration; Cardiac failure; Corneal dystrophy; Diabetic macular edema; Lebers hereditary optic atrophy

SYNTHESIS

NEXT………………………

PATENT 2

ELAMIPRETIDE BY STEALTH

WO-2017156403

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017156403&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription


; MTP-131; D-Arg-Dmt-Lys-Phe-Nth). Compound

1 has been shown to affect the mitochondrial disease process by helping to protect organs from oxidative damage caused by excess ROS production and to restore normal ATP production.

PATENT

US 20110082084

WO 2011091357

WO 2012129427

WO 2013059071

WO 2013126775

US 20140378396

US 20140093897

WO 2015134096

WO 2015100376

WO 2015060462

US 20150010588

PATENNT

WO 2015197723

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015197723

PROCESS FOR PREPARING

D-ARGINYL-2,6-DIMETHYL-L-TYROSYL-L-LYSYL-L-PHENYLALANINAMIDE

TECHNICAL FIELD

The invention relates to a process for solution-phase synthesis of D- Arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-phenylalaninamide (abbreviated H-D-Arg-(2,6-Dimethyl)Tyr-L-Lys-L-Phe-NH2, development code SS-31 , MTP-131 , X-31) of Formula (I), an active ingredient developed by Stealth BioTherapeutics under the investigational drug brand names Bendavia® and Ocuvia®, for both common and rare diseases including a mitochondrial targeted therapy for ischemia reperfusion injury.

Formula (I)

BACKGROUND

The product belongs to the class of so-called “Szeto-Schiller peptides”. Szeto-Sciller peptides or “SS peptides” are small, aromatic-cationic, water soluble, highly polar peptides, such as disclosed in US 6703483 and US 7576061 , which can readily penetrate cell membranes. The aromatic-cationic peptides include a minimum of two amino acids, and preferably include a minimum of four amino acids, covalently joined by peptide bonds. The maximum number of amino acids is about twenty amino acids covalently joined by peptide bonds. As described by EP 2012/2436390, optimally, the number of amino acids present in the SS peptides is four.

Bendavia® is being tested for the treatment of ischemia reperfusion injury in patients with acute myocardial infarction (AMI), for the treatment of acute kidney injury (AKI) and renal microvascular dysfunction in hypertension, for the treatment of skeletal muscle dysfunction, for the treatment of mitochondrial myopathy and for the treatment of chronic heart failure. Trials are ongoing to assess the Ocuvia’s potential to treat Leber’s Hereditary Optic Neuropathy (LHON) a devastating inherited disease that causes sudden blindness, often in young adults.

Mitochondria are the cell’s powerhouse, responsible for more than 90% of the energy our bodies need to sustain life and support growth. The energetics from mitochondria maintains healthy physiology and prevents disease. In many common and rare diseases, dysfunctional mitochondria are a key component of disease progression.

D-Arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-phenylalaninamide is a cell-permeable and mitochondria-targeted peptide that showed antioxidant activity and was concentrated in the inner mitochondrial membrane. Compound (< 1 nM) significantly reduced intracellular reactive oxygen species, increased mitochondrial potential and prevented tBHP-induced apoptosis in both N2A and SH-SY5Y neuronal cell lines. In rats, intraperitoneal treatment (1 and 3 mg/kg) 1 day prior to unilateral ureteral obstruction and every day thereafter for 14 days significantly decreased tubular damage, macrophage infiltration and interstitial fibrosis. Compound (3 mg/kg i.p. qd for 2 weeks) also prevented apoptosis and insulin reduction in mouse pancreatic islets caused by streptozotocin.

Further studies performed in a G93A mouse model of amyotrophic lateral sclerosis (ALS) demonstrated that the compound (5 mg/kg/day i.p. starting at 30 days of age) led to a significant delay in disease onset.

Potentially useful for the treatment of ALS and may be beneficial in the treatment of aging and diseases associated with oxidative stress.

In the last few years the peptide H-D-Arg-(2,6-Dimethyl)Tyr-L-Lys-L-Phe-NH2, shown in Fig 1 , and its therapeutic activity have been disclosed and

claimed by in several patent applications.

EP 2436390, US 201 10245182 and US 201 10245183 claim topical anesthetic compositions for application to the skin for pain management or anti-skin aging agents, respectively, comprising Szeto-Schiller peptides; SS-31 is specifically claimed as active ingredient. Sequence of solid-phase synthesis is indicated as the preferred preparation process.

US 7718620 claims a process of treating or preventing ischemia-reperfusion injury of the kidney in a mammal by administrating an effective amount of an aromatic-cationic peptide. SS-31 is specifically claimed as active ingredient.

WO2005/001023 discloses a generical process and carrier complexes for delivering molecules to cells comprising a molecule and an aromatic cationic peptide of type D-Arg-Dmt-Lys-Phe-NH2. The tetrapeptide SS-31 is

specifically claimed as product useful for the process at claim 18.

WO2012/1741 17 and WO2014/210056 claim therapeutic compositions based on SS peptides and the aromatic-cationic peptide D-Arg-Dmt-Lys-Phe-NH2 as active agent.

WO 2013/086020, WO 2004/070054 and WO 2005/072295 provide processes for preventing mithochondrial permeability transition and reducing oxidative damage in a mammal, a removed organ, or a cell in need thereof and specifically claims the process wherein the peptide does not have mu-opioid receptor agonist activity, i.e., D-Arg-Dmt-Lys-Phe-NH2.

WO 2009/108695 discloses a process for protecting a kidney from renal injury which may be associated with decreased or blocked blood flow in the subject’s kidney or exposure to a nephrotoxic agent, such as a radiocontrast dye. The processes include administering to the subject an effective amount of an aromatic-cationic peptide to a subject in need thereof and one of the selected peptide is D-Arg-Dmt-Lys-Phe-NH2.

US 6703483 discloses a detailed procedure for the preparation of novel analogs of DALDA [H-Tyr-D-Arg-Phe-Lys-NH2], namely H-Dmt-D-Arg-Phe-Lys-NH2 using the solid-phase techniques and /?-methylbenzhydrylamine

resin and protocols that have been extensively used by inventor’s laboratory.

Most prior art processes for preparing the compound typically comprise conventionally performed peptide solid-phase synthesis with further purification by chromatography in order to obtain the requested purity for therapeutic use.

It is well known that solid-phase synthesis followed by chromatographic purification is time consuming, very expensive and very difficult to be scaled up on industrial scale, so the need of developing a process for large scale production is obvious. The compound is isolated as organic acid salt, as acetate or trifluoro acetate.

eddy et al., Adv. Exp. Med. Biol, 2009, 61 1 , 473 generally describes the liquid-phase synthesis of antioxidant peptides of Figure 1 and similar others (SS-02, SS-20), involving routinely used side chain protecting groups for amino acid building blocks. The guanidine group was protected with NO2 and the ε-ΝΗ2 of Lys was protected by Cbz or 2-Cl-Cbz. These peptides were

synthesized using Boc/Cbz chemistry and BOP reagent coupling. Starting with the C-terminal Lys residue protected as H-Lys(2-Cl-Cbz)-NH2, (prepared

from the commercially available Boc-Lys(2-Cl-Cbz)-OH in two steps by amidation with NH4HCO3 in the presence of DCC/HOBt following a literature procedure [Ueyama et all, Biopolymers, 1992, 32, 1535, PubMed: 1457730], followed by exposure to TFA). Selective removal of the 2-Cl-Cbz in the

presence of the NO2 group was accomplished using catalytic transfer hydrogenolysis (CTH) [Gowda et al., Lett. Pept. Sci., 2002, 9, 153].

A stepwise procedure by standard solution peptide synthesis for preparation of potent μ agonist [DmtJDALDA and its conversion into a potent δ antagonist H-Dmt-Tic-Phe-Lys(Z)-OH by substitution of D-Arg with Tic to enhance the δ opioid agonist activity is described by Balboni et al., J. Med.

Chem., 2005, 48, 5608. A general synthetic procedure for a similar tetrapeptide ([Dmt-D-Arg-Phe-Lys-NH2 is described by Ballet et al., J. Med.

Chem. 2011, 54, 2467.

Similar DALDA analog tetrapeptides were prepared by the manual solid-phase technique using Boc protection for the a-amino group and DIC/HOBt or HBTU/DIEA as coupling agent [Berezowska et al., J. Med. Chem., 2009, 52, 6941 ; Olma et al., Acta Biochim. Polonica, 2001, 48, 4, 1 121 ; Schiller at al., Eur. J. Med. Chem., 2000, 35, 895].

Despite the high overall yield in the solid-phase approach, it has several drawbacks for the scale-up process such as:

a. the application of the highly toxic and corrosive hydrogen fluoride for cleavage of the peptide from the resin,

b. low loading (0.3-0.35 mmol/g of resin) proved necessary for successful end-step, and

c. use of excess amounts of reagents (3-fold of DIC, 2.4-fold of HOBt, etc.) on each step [ yakhovsky et al., Beilstein J. Org. Chem., 2008, 4(39), 1 , doi: 10.376/bjoc.4.39]

SUMMARY

The invention relates to a more efficient process avoiding either solid-phase synthesis or chromatographic purification, more suitable for large scale production. The process of the invention is described in Scheme A.

The following abbreviations are used:

Dmt = 2,6-dimethyl tyrosine; Z= benzyloxycarbonyl; MeSO3H = methane sulphonic acid; Boc = Tert-butyloxycarbonyl; NMM = N-methyl morpholine; TBTU= N,N,N’,N’-Tetramethyl-O-(benzotriazol- l-yl)uronium tetrafluoroborate; DMF = dimethyl formamide; TFA = trifluoroacetic acid

Scheme A shows the process for the solution phase synthesis of peptide

1 for assembly of the tetrapeptide backbone using O-Benzyl (Bzl) group and benzyloxycarbonyl (Z) group respectively, as the temporary protection for amino acids’ N-termini (Scheme Figure 2), followed by a final catalytic hydrogenolysis. The final product is isolated as organic acid salt, for example, acetic acid salt.

H-Phe-NH 2 + Boc-Lys(Z)-OH

Boc-Lys(Z)-Phe-NH 2

(IV)

(V) I MeS03H/CH2CI2

Boc-DMTyr(Bzl)-OH + MeS03H.H-Lys(Z)-Phe-NH 2

(

Boc-DMTyr(Bzl)-Lys(Z)-Phe-NH 2

(VIII)

I MeS03H/CH2CI2

Z-D-Arg-ONa + H-DMTyr(Bzl)-Lys(Z)-Phe-NH 2.MeS03H

(X) (IX)

TBTU/NMM/DMF

Z-D-Arg-DMTyr(Bzl)-Lys(Z)-Phe-NH

(XI)

I H2, Pd/C

X ACOH

H-D-Arg-DMTyr-Lys-Phe-NH

(I)

Scheme A

This process is a notable improvement with respect to the prior art and its advantages can be summarized as follows:

• The synthesis is performed in liquid phase allowing the scale up on industrial scale without need of special equipment; · The selection of the protecting group in the building blocks allows a straightforward synthesis with very simple deprotection at each step and minimize the formation of undesired by-product;

• Each intermediate can be crystallized allowing removal of impurities which are not transferred to the following step;

· The purity of each intermediate is very high and usually close to

99%.

EXAMPLES

Example 1: Preparation of Boc-Lys(Z)-Phe-NH2

Charge 200 mL of DMF, 44 g of Boc-Lys(Z)-OH and 15.6 g of H-Phe-NH2 in a flask. Stir the mixture at room temperature for 10 min. Add 19.2 g of

N-methylmorpholine and 32.1 g of TBTU successively at room temperature. Stir the mixture at room temperature for 1 h. Add 500 mL of water into the reaction mixture to precipitate the product at room temperature. Filter the mixture to isolate the solid product and wash the filter cake with water.

Transfer the filter cake into a flask containing 360 mL of ethyl acetate and heat the mixture at 50°C till all the solid is dissolved. Separate the organic phase of product and discard the small aqueous phase. Concentrate the organic phase at 40~45°C and under vacuum to remove the solvent till lots of solid is formed. Filter the residue to isolate the solid product. Transfer the filter cake into a flask containing 2000 mL of MTBE and heat the mixture at refluxing for 20 min. Then, cool down the mixture to room temperature. Filter the mixture to isolate the solid product. Dry the filter cake at 30 °C and under vacuum to give 35 g of solid product.

Example 2: Preparation of H-Lys(Z)-Phe-NH2.MeSC>3H

Charge 26.3 g of Boc-Lys(Z)-Phe-NH2, 200 mL of methylene chloride

and 9.6 g of methanesulfonic acid. Stir the mixture at 15-20 °C for 18 h. Add 100 mL of MTBE into the mixture and stir at 15-20 °C for 1 h. Filter the mixture to isolate the solid product. Dry the wet cake in air at room temperature to give 26.4 g of white solid product.

Example 3: Preparation of Boc-DMeTyr(Bzl)-Lys(Z)-Phe-NH2

Charge 8.4 g of Boc-DMeTyr(Bzl)-OH, 1 1 g of H-Lys(Z)-Phe-NH2.MeSO3H, 7.4 g of TBTU and 80 mL of THF in a flask. Stir the mixture

at room temperature for 15 min, and then cool down to 10°C. Add 6.36 g of N-methylmorpholine and stir the mixture at 20-25°C for 3 h. Add the reaction mixture into a flask containing 240 mL of water. Add 32 mL of methylene chloride into the mixture obtained in the previous operation of. Stir the resultant mixture at room temperature for 20 min. Filter the mixture to isolate the solid product and wash the filter cake with acetone (300 mL X 2). Dry the filter cake in air at room temperature to give 14.3 g of white solid product.

Example 4: Preparation of H-DMeTyr(Bzl)-Lys(Z)-Phe-NH2.MeS03H

Charge 14 g of Boc-BMeTyr(Bzl)-Lys(Z)-Phe-NH2, 280 mL of methylene chloride and 3.3 g of methanesulfonic acid in a flask. Stir the mixture at 18 ~ 22 °C for 10 h. Add 560 mL of heptanes into the mixture and stir the mixture at room temperature for 30 min. Filter the mixture to isolate the solid product. Dry the wet cake in air at room temperature to give 14 g of white solid product.

Example 5: Preparation of Z-D-Arg-DMeTyr(Bzl)-Lys(Z)-Phe-NH2

Charge 6.34 g of Z-D-Arg-ONa, 100 mL of DMF and 2.0 g of methanesulfonic acid in a flask. Stir the mixture at room temperature till a clear solution was formed. Add 14 g of H-DMeTyr(Bzl)-Lys(Z)-Phe-NH2.MeSO3H and cool down the mixture to 10°C. Add 6.15 g of TBTU and

9.67 g of N-methylmorpholine successively. Stir the mixture at room temperature for 4 h. Add aqueous solution of LiOH prepared by dissolving 2.9 g of LiOH.L O in 8 mL of water. Stir the mixture for 30 min. Add the resultant mixture slowly into a flask containing 420 mL of water under stirring. Add 56 mL of methylene chloride into the mixture. Filter the mixture to isolate the solid product. Transfer the filter cake into a flask containing 150 mL of acetic acid, and heat the mixture at 35-40 °C till most of the solid was dissolved. Add 450 mL of MTBE into the mixture and cool down the mixture under stirring to room temperature. Filter the mixture to isolate the solid product. Dry the filter cake in air at room temperature to give 17.3 g of the white solid product.

Example 6 Preparation of H-D-Arg-DMeTyr-Lys-Phe-NH2.3AcOH

Charge 2.0 g of Z-D-Arg-DMeTyr(Bzl)-Lys(Z)-Phe-NH2, 20 mL of acetic acid and 5% Pd/C catalyst (which is obtained by washing 5.0 g of 5% Pd/C containing 60% of water with 30 mL of acetic acid) in a flask. Change the atmosphere of the flask with hydrogen. Stir the mixture at room temperature and pressure of 1 atm of hydrogen for 2 h. Filter the mixture to remove the Pd/C catalyst and wash the filter cake with 10 mL of acetic acid. Combine the filtrate and washing solution and concentrate the solution at 20°C and under vacuum to remove most the solvent. Add 100 mL of acetonitrile into the residue and stir the mixture at room temperature for 20 min. Filter the mixture to isolate the solid product. Dry the filter cake at room temperature and under vacuum to give 0.7 g of the white product.

PATENT

WO 2016001042

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016001042&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

References

  1. Jump up^ “Recommended INN List 75” (PDF). WHO Drug Information30 (1): 111. 2016.
  2. Jump up^ “Elamipretide”. AdisInsight. Retrieved 24 April 2017.
  3. Jump up^ Kloner, RA; Shi, J; Dai, W (February 2015). “New therapies for reducing post-myocardial left ventricular remodeling.”Annals of translational medicine3 (2): 20. PMC 4322169Freely accessiblePMID 25738140.
  4. Jump up^ Valigra, Lori (April 9, 2012). “Stealth Peptides sees positive results from Bendavia”Boston Business Journal.
  5. Jump up^ Dolgin, Elie (11 February 2016). “New drugs offer hope for mitochondrial disease”STAT.
Patent ID

Patent Title

Submitted Date

Granted Date

US2017152289 PROCESS FOR THE PRODUCTION OF D-ARGINYL-2, 6-DIMETHYL-L-TYROSYL-L-LYSYL-L-PHENYLALANINAMIDE 2015-06-24
Patent ID

Patent Title

Submitted Date

Granted Date

US2014294796 AROMATIC-CATIONIC PEPTIDES AND USES OF SAME 2012-12-05 2014-10-02
US2016264623 TETRAPEPTIDE COMPOUND AND METHOD FOR PRODUCING SAME 2014-10-23 2016-09-15
US2017081363 PHARMACEUTICALLY RELEVANT AROMATIC-CATIONIC PEPTIDES 2014-12-23
US2016340389 PHARMACEUTICALLY RELEVANT AROMATIC-CATIONIC PEPTIDES 2014-12-23
US2017129920 Process for Preparing D-Arginyl-2, 6-Dimethyl-L-Tyrosyl-L-Lysyl-L-Phenylalaninamide 2015-06-24

REFERENCES

1: Alam NM, Mills WC 4th, Wong AA, Douglas RM, Szeto HH, Prusky GT. A mitochondrial therapeutic reverses visual decline in mouse models of diabetes. Dis Model Mech. 2015 Jul 1;8(7):701-10. doi: 10.1242/dmm.020248. Epub 2015 Apr 23. PubMed PMID: 26035391; PubMed Central PMCID: PMC4486862.

2: Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther. 2014 Dec;96(6):672-83. doi: 10.1038/clpt.2014.174. Epub 2014 Sep 4. Review. PubMed PMID: 25188726; PubMed Central PMCID: PMC4267688.

3: Dai W, Shi J, Gupta RC, Sabbah HN, Hale SL, Kloner RA. Bendavia, a mitochondria-targeting peptide, improves postinfarction cardiac function, prevents adverse left ventricular remodeling, and restores mitochondria-related gene expression in rats. J Cardiovasc Pharmacol. 2014 Dec;64(6):543-53. PubMed PMID: 25165999.

4: Eirin A, Ebrahimi B, Zhang X, Zhu XY, Woollard JR, He Q, Textor SC, Lerman A, Lerman LO. Mitochondrial protection restores renal function in swine atherosclerotic renovascular disease. Cardiovasc Res. 2014 Sep 1;103(4):461-72. doi: 10.1093/cvr/cvu157. Epub 2014 Jun 19. PubMed PMID: 24947415; PubMed Central PMCID: PMC4155472.

5: Liu S, Soong Y, Seshan SV, Szeto HH. Novel cardiolipin therapeutic protects endothelial mitochondria during renal ischemia and mitigates microvascular rarefaction, inflammation, and fibrosis. Am J Physiol Renal Physiol. 2014 May 1;306(9):F970-80. doi: 10.1152/ajprenal.00697.2013. Epub 2014 Feb 19. PubMed PMID: 24553434.

6: Brown DA, Hale SL, Baines CP, del Rio CL, Hamlin RL, Yueyama Y, Kijtawornrat A, Yeh ST, Frasier CR, Stewart LM, Moukdar F, Shaikh SR, Fisher-Wellman KH, Neufer PD, Kloner RA. Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia. J Cardiovasc Pharmacol Ther. 2014 Jan;19(1):121-32. doi: 10.1177/1074248413508003. Epub 2013 Nov 28. PubMed PMID: 24288396; PubMed Central PMCID: PMC4103197.

7: Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014 Apr;171(8):2017-28. doi: 10.1111/bph.12468. PubMed PMID: 24134698; PubMed Central PMCID: PMC3976619.

8: Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014 Apr;171(8):2029-50. doi: 10.1111/bph.12461. Review. PubMed PMID: 24117165; PubMed Central PMCID: PMC3976620.

9: Zhao WY, Han S, Zhang L, Zhu YH, Wang LM, Zeng L. Mitochondria-targeted antioxidant peptide SS31 prevents hypoxia/reoxygenation-induced apoptosis by down-regulating p66Shc in renal tubular epithelial cells. Cell Physiol Biochem. 2013;32(3):591-600. doi: 10.1159/000354463. Epub 2013 Sep 6. PubMed PMID: 24021885.

10: Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, Beyer RP, Crispin DA, Shulman NJ, Szeto HH, Tian R, MacCoss MJ, Rabinovitch PS. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013 Sep 1;6(5):1067-76. doi: 10.1161/CIRCHEARTFAILURE.113.000406. Epub 2013 Aug 9. PubMed PMID: 23935006; PubMed Central PMCID: PMC3856238.

/////////////////////Elamipretide,  SS-31,  Bendavia, PEPTIDE

CC1=CC(=CC(=C1CC(C(=O)NC(CCCCN)C(=O)NC(CC2=CC=CC=C2)C(=O)N)NC(=O)C(CCCN=C(N)N)N)C)O

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