RILUZOLE

Riluzole (Rilutek) is a drug used to treat amyotrophic lateral sclerosis and is marketed by Sanofi-Aventis. It delays the onset ofventilator-dependence or tracheostomy in selected patients and may increase survival by approximately two to three months.^[2]

NMR.........http://file.selleckchem.com/downloads/nmr/S161403-Riluzole-NMR-Selleck.pdf

RILUTEK® (riluzole) is a member of the benzothiazole class. Chemically, riluzole is 2-amino-6-(trifluoromethoxy)benzothiazole. Its molecular formula is C₈H₅F₃N₂OS and its molecular weight is 234.2. Its structural formula is as follows:

Riluzole is a white to slightly yellow powder that is very soluble in dimethylformamide, dimethylsulfoxide and methanol, freely soluble in dichloromethane, sparingly soluble in 0.1 N HCl and very slightly soluble in water and in 0.1 N NaOH. RILUTEK (riluzole) is available as a capsule-shaped, white, film-coated tablet for oral administration containing 50 mg of riluzole. Each tablet is engraved with “RPR 202” on one side.

Mechanism

Riluzole preferentially blocks TTX-sensitive sodium channels, which are associated with damaged neurons.^[12][13] Riluzole has also been reported to directly inhibit the kainateand NMDA receptors.^[14] However, the action of riluzole on glutamate receptors has been controversial, as no binding of the drug to any known sites has been shown for them.^[15][16] In addition, as its antiglutamatergic action is still detectable in the presence of sodium channel blockers, it is also uncertain whether or not it acts via this way. Rather, its ability to stimulate glutamate uptake seems to mediate many of its effects.^[17][18] In addition to its role in accelerating glutamate clearance from the synapse, Riluzole may also prevent glutamate release from presynaptic terminals.^[19] These effects combined could significantly reduce glutamate signaling and cause indirect antagonism without acting at glutamate receptors themselves.

Synthesis

Riluzole synthesis: U.S. Patent 4,826,860

References[edit]

1. ^ Jump up to:^{a b c d e f g h i} "PRODUCT INFORMATION RILUTEK® (riluzole) Tablets" (PDF). TGA eBusiness Services. sanofi-aventis australia pty ltd. 6 January 2009. Retrieved 18 February2014.
2. ^ Jump up to:^a b Miller, RG; Mitchell, JD; Moore, DH (14 March 2012). "Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)." (PDF). The Cochrane Database of Systematic Reviews 3: CD001447. doi:10.1002/14651858.CD001447.pub3.PMID 22419278.
3. Jump up^ van Kan, HJ; Groeneveld, GJ; Kalmijn, S; Spieksma, M; van den Berg, LH; Guchelaar, HJ (March 2005). "Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis." (PDF). British Journal of Clinical Pharmacology 59(3): 310–3. doi:10.1111/j.1365-2125.2004.02233.x. PMC 1884790. PMID 15752377.
4. Jump up^ Review of the Use of the Glutamate Antagonist Riluzole in Psychiatric Disorders and a Description of Recent Use in Childhood Obsessive-Compulsive Disorder. J Child Adolesc Psychopharmacol. 2010 August; 20(4): 309–315.
5. Jump up^ Zarate CA, Jr; Payne, JL; Quiroz, J; Sporn, J; Denicoff, KK; Luckenbaugh, D; Charney, DS; Manji, HK (January 2004). "An open-label trial of riluzole in patients with treatment-resistant major depression.". The American Journal of Psychiatry 161 (1): 171–4.doi:10.1176/appi.ajp.161.1.171. PMID 14702270.
6. Jump up^ Coric, V; Taskiran, S; Pittenger, C; Wasylink, S; Mathalon, DH; Valentine, G; Saksa, J; Wu, YT; Gueorguieva, R; Sanacora, G; Malison, RT; Krystal, JH (1 September 2005). "Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial.". Biological Psychiatry 58 (5): 424–8. doi:10.1016/j.biopsych.2005.04.043.PMID 15993857.
7. Jump up^ Mathew, SJ; Amiel, JM; Coplan, JD; Fitterling, HA; Sackeim, HA; Gorman, JM (December 2005). "Open-label trial of riluzole in generalized anxiety disorder.". The American Journal of Psychiatry 162 (12): 2379–81. doi:10.1176/appi.ajp.162.12.2379.PMID 16330605.
8. Jump up^ "Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering". Proceedings of the National Academy of Sciences of the United States of America. Retrieved 18 January 2015.
9. Jump up^ "Glutamatergic Dysfunction in Cognitive Aging: Riluzole in Mild Alzheimers Disease".rucares.org. Retrieved 12 March 2015.
10. Jump up^ "Rilutek (riluzole) dosing, indications, interactions, adverse effects, and more".Medscape Reference. WebMD. Retrieved 18 February 2014.
11. ^ Jump up to:^a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. edit
12. Jump up^ Song, JH; Huang, CS; Nagata, K; Yeh, JZ; Narahashi, T (August 1997). "Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels."(PDF). The Journal of Pharmacology and Experimental Therapeutics 282 (2): 707–14.PMID 9262334.
13. Jump up^ Bellingham, MC (February 2011). "A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade?". CNS Neuroscience & Therapeutics 17 (1): 4–31. doi:10.1111/j.1755-5949.2009.00116.x. PMID 20236142.
14. Jump up^ Debono MW, Le Guern J, Canton T, Doble A, Pradier L (April 1993). "Inhibition by riluzole of electrophysiological responses mediated by rat kainate and NMDA receptors expressed in Xenopus oocytes". Eur. J. Pharmacol. 235 (2-3): 283–9. doi:10.1016/0014-2999(93)90147-a. PMID 7685290.
15. Jump up^ Wokke, J (21 September 1996). "Riluzole.". Lancet 348 (9030): 795–9.doi:10.1016/S0140-6736(96)03181-9. PMID 8813989.
16. Jump up^ Kretschmer BD, Kratzer U, Schmidt WJ (August 1998). "Riluzole, a glutamate release inhibitor, and motor behavior". Naunyn Schmiedebergs Arch. Pharmacol. 358 (2): 181–90.doi:10.1007/pl00005241. PMID 9750003.
17. Jump up^ Azbill, RD; Mu, X; Springer, JE (July 2000). "Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes". Brain Res. 871 (2): 175–80.doi:10.1016/S0006-8993(00)02430-6. PMID 10899284.
18. Jump up^ Dunlop, J; Beal McIlvain, H; She, Y; Howland, DS (1 March 2003). "Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis". J Neurosci. 23 (5): 1688–96. PMID 12629173.
19. Jump up^ Wang, S.-J (January 2004). "Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes)". Neuroscience 125 (1): 191–201. doi:10.1016/j.neuroscience.2004.01.019.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

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ELETRIPTAN

ELETRIPTAN

Eletriptan, UK-116044-04(HBr salt), UK-116044, Relpax

143322-58-1  CAS OF FREE BASE

143577-61-1 (hemisuccinate), 179041-30-6 (monofumarate), 177834-92-3 (monoHBr salt), 180637-87-0 (monosuccinate)

(R)-3-[(-1-methylpyrrolidin-2-yl)methyl]-5-(2-phenylsulfonylethyl)- 1H-indole

Eletriptan hydrobromide was first disclosed in U.S. patent 5,545,644 (1996), assigned to Pfizer, New York, claiming the product “eletriptan” and its pharmaceutically acceptable salts thereof. ]. 

However, a detailed study on the profile of the impurities present and their synthesis has not yet been cited anywhere, except for in the case of some metabolites . Eletriptan hydrobromide  is a second-generation drug serotonin (5-HT1) agonist  used in the management of sensations of tightness, pain, pressure and heaviness in the precordium, throat and jaws. 

Eletriptan is more lipophilic than other triptans and absorbed more quickly than sumatriptan in the intestinal absorption. Eletriptan is more effective than sumatriptan in reducing the blood vessels surrounding the brain, which cause the swelling that is associated with the headache pain of a migraine attack, by blocking the release of substances from the nerve endings that causes more pain.

1H NMR PREDICT

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13C NMR



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WO2010049952A2

5-Bromoindole under Heck reaction conditions is coupled with phenyl vinyl sulfone followed by acylation with Cbz-Proline acid chloride to obtain a compound of Formula IV which on reduction in presence of a hydride agent provide Eletriptan.

1H NMR CDCI3 δ= 8.10 (bs, NH), 7.92-7.99 5 (m, 2H), 7.62-7.69 (m, 1H), 7.53-7.61 (m, 2H), 7.30 (s, 1H), 7.22 (d, 1H), 7.03 (s, 1H), 6.93 (dd, 1 H), 3.38-3.45 (m, 2H), 3.09-3.21 (m, 4H), 2.45-2.55 (m, 2H), 2.45 (s, 3H), 2.20-2.30 (m, 1H), 1.50-1.90 (m, 4H).

ESI Mass (M+H) 383.69

...........

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann,  Ian R. Baxendale, Steven V. Ley and Nikzad Nikbin

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK

Editor-in-Chief: J. Clayden

Beilstein J. Org. Chem. 2011, 7, 442–495.

http://beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-7-57

Eletriptan (87, Relpax) is yet another indole-containing antimigraine drug. A process route for the synthesis of eletriptan published by Pfizer starts from a preformed bromo-indole 88 [28] (Scheme 20). In order to perform the acylation of the indole ring on larger scale, ethylmagnesium bromide and the corresponding acid chloride 89 are added concurrently from two different sides of the reactor to stop these reagents reacting with each other. This method of adding the reagents circumvents the necessity to isolate the magnesium salt of the indole and increases the yield from 50 to 82%. The carbonyl group of the proline side chain is then reduced simultaneously with the complete reduction of the Cbz-group to a methyl group with lithium aluminium hydride. Finally, the sulfonate side chain is introduced via a Heck-type coupling similar to that of naratriptan (Scheme 15), followed by hydrogenation of the double bond to afford eletriptan (Scheme 20).

A rather ingenious Mitsunobu coupling reaction has been used to create a highly functionalised substrate 96 for an intramolecular Heck reaction resulting in a very short and succinct synthesis of eletriptan and related analogues 97 [29] (Scheme 21).

Scheme 21: Heck coupling for the indole system in eletriptan.

Interestingly, it was found that the most obvious approach, the direct Fischer indole synthesis, to prepare the core of eletriptan as shown in Scheme 22 is not successful [30]. This is believed to be due to the instability of the phenyl hydrazine species 98 under the relatively harsh reaction conditions required to promote the cyclisation.

Scheme 22: Attempted Fischer indole synthesis of elatriptan.

However, this problem could be avoided by using an acid-labile oxalate protected hydrazine 104 as depicted in Scheme 23. The yield of this step can be further improved up to 84% if the corresponding calcium oxalate is used.

Scheme 23: Successful Fischer indole synthesis for eletriptan.

• Macor, J. E.; Wythes, M. J. Indole Derivatives. U.S. Patent 5,545,644, Aug 13, 1996.
• Perkins, J. F. Process for the Preparation of 3-Acylindoles. Eur. Patent 1088817A2, April 4, 2001.
• Ashcroft, C. P. Modified Fischer Indole Synthesis for Eletriptan. WO Patent 2005/103035, Nov 3, 2005.
• Bischler, A. Chem. Ber. 1892, 25, 2860–2879. doi:10.1002/cber.189202502123

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.................

Synthesis of compounds related to the anti-migraine drug eletriptan hydrobromide

Suri Babu Madasu1,2, Nagaji Ambabhai Vekariya1, M. N. V. D. Hari Kiran1, Badarinadh Gupta1, Aminul Islam1, Paul S. Douglas2 and Korupolu Raghu Babu2

1Chemical Research and Development, Aurobindo Pharma Ltd., Survey No. 71 & 72, Indrakaran (V), Sangareddy (M), Medak Dist-502329, Andhra Pradesh, India
2Engineering Chemistry Department, AU College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India

Associate Editor: J. Aube

Beilstein J. Org. Chem. 2012, 8, 1400–1405.

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-8-162

Synthetic route of eletriptan hydrobromide. Reagents and conditions: (i) Acetic anhydride, TEA, DMF, 90–100 °C; (ii) palladium acetate, tri-(o-tolyl)phosphine, TEA, DMF, 90–100 °C; (iii) methanol, K2CO3, acetonitrile, H2O, 5–10 °C; (iv) palladium on carbon, acetone, H2O, aqueous hydrobromic acid, IPA, 25–30 °C.

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Org. Process Res. Dev., 2011, 15 (1), pp 98–103

DOI: 10.1021/op100251q

http://pubs.acs.org/doi/full/10.1021/op100251q

aReagents and conditions: (a) EtMgBr, Et2O. (b) 3, DCM, 50% from 1. (c) LiAlH4, THF, 72%. (d) Ac2O, TEA, DMF. (e) Phenyl vinyl sulfone (PVS), Pd(OAc)2, P(°Tol)3, TEA, DMF, 80% from 5. (f) H2, Pd/C, MeSO3H, acetone, 95%. (g) K2CO3, MeOH, 92%. (h) HBr, acetone 73%.

1H NMR (CDCl3): δ = 1.51−1.85 (m, 4H), 2.22−2.28 (m, 1H), 2.43−2.49 (m, 4H), 2.56−2.62 (m, 1H), 3.11−3.18 (m, 4H), 3.42−3.46 (m, 2H), 6.91−6.93 (s, 1H), 7.01 (s, 1H), 7.23−7.27 (d, 1H), 7.31 (s, 1H), 7.56−7.60 (m, 2H), 7.65−7.68 (m, 1H), 7.96−7.98 (d, 2H), 8.14 (s, 1H); LC/MS: Rt = 2.30 min; m/z 383 [MH]+

..............................

ELETRIPTAN HYDROBROMIDE MONOHYDRATE

http://www.sumobrain.com/patents/wipo/Eletriptan-hydrobromide-monohydrate/WO2000032589.html

'H-NMR (400MHz, ds-DMSO): delta = 10.90 (1H, d, J=2.2Hz), 9.35 (1 H, br s), 7.95 (2H, d, J=7.5Hz), 7.76 (1 H, t, J=7.5Hz), 7.66 (2H, t, J=7.5Hz), 7.38 (1 H, s), 7.24 (1 H, d, J=8.3Hz), 7.23 (1 H, d, J=2.2Hz), 6.92 (1 H, dd, J=8.3,1.4Hz), 3.63 (2H, m), 3.58 (2H, br m), 3.24 (1 H, m), 3.06 (1 H, m), 2.95 (2H, m), 2.86 (1 H, m), 2.83 (3H, s), 2.00 (1 H, m), 1.90 (2H, m), 1.70 (1 H, m).

Found: C, 54.85; H, 6.03; N, 5.76. C22H29N203SBr requires C, 54.87; H, 6.08; N, 5.82%.
1H NMR

13C PREDICT

COSYPREDICT

SYNTHESIS

Reference:

KANSAL, Vinod Kumar; MISTRY, Dhirenkumar N.; PATEL, Rakesh Ravjibhai; PANDEY, Saurabh Patent: US2009/299077 A1, 2009 ; Location in patent: Page/Page column 8 ;

USV Limited B.S.D. Mar Patent: US2012/71669 A1, 2012 ; Location in patent: Page/Page column 11 ;

US2012/71669 A1, ;

US2011/166364 A1, ;
WO2011/4391 A2, ;
WO2012/4811 A1, ;

US2008/287519 A1, ; Page/Page column 10 ;

WO2011/4391 A2, ; Page/Page column 19 ;
US2008/287519 A1, ; Page/Page column 8 ;