Flupirtine, D 9998

2-amino-6-(4-fluoro-benzylamino)- pyridin-3-yl)-carbamic acid ethyl ester, is unique as a non-opioid, non-NSAID, non-steroidal analgesic with a favorable tolerability. It first became available in Europe in 1984, and was sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor

PHASE 2

MS

• Neuronal potassium channels (7)
• Membrane resting potential (6)
• NMDA receptor channels (indirectly)(14)

• Originally developed by Asta Medica (1) (4)
• Being developed and commercialized to treat fibromyalgia by Synthetic Biologics (1)

Flupirtine

75507-68-5 maleate
56995-20-1 (free base)

LAUNCHED

1986 NEUROPATHIC PAIN

Flupirtine maleate is the INN for 2-amino-3-ethylcarbamato-6- (4-fluoro-benzylamino) maleate, CAS: 75507-68-5, molar mass 420.40 g / mol, molecular formula C1 5 H17FN4O2 • C4H4O4, and corresponds to the structure of formula I.

Flupirtine maleate is used, for example, under the trade name Katadolon® as an analgesic.

PATENT
http://www.google.com/patents/CN103086963A?cl=en
FIG. 1 is flupirtine maleate 1H NMR.
[0021] FIG. 2 is flupirtine maleate A crystal X-ray diffraction pattern

Example 3
2-Amino-3-nitro-6-chloropyridine 246g, and 254g of triethylamine were added to 800ml of ethanol-necked flask and stirred under heating to reflux, fluorine was slowly added dropwise benzylamine 80g, reaction of 6 hours, the reaction was completed After the dropwise addition of purified water 500ml, cooled slowly with stirring to room temperature, filtered, dried to give 2-amino-3-nitro-6-p-fluoro-benzylamino-pyridine.
[0033] The ferric chloride hexahydrate was dissolved in purified water 41g 200ml, adding activated charcoal 20g, heated to 50 ° C, a saturated solution of sodium hydroxide was added 45g (24g of sodium hydroxide dissolved in 21ml water), 60 ° C with stirring I hours, cooled to room temperature, filtered, and dried to give ferric hydroxide / activated carbon catalyst.
[0034] A mixture of 2-amino-3-nitro-6-p-fluorobenzyl-aminopyridine 104.Sg, ferric hydroxide / activated carbon catalyst was added to 20g 2L reaction flask was added 95% ethanol 1200ml, heated with stirring to 90 ° C. Insulation 60% hydrazine hydrate was added dropwise 250g. Drops Bi insulation response to 3h. Completion of the reaction, the reaction solution is filtered hot with concentrated hydrochloric acid to 240ml and 95% ethanol IOOOml reaction flask. (TlO ° C crystallization I h, filtered, dried to give 2,3-amino-6-fluoro-benzyl-aminopyridine on
Hydrochloride.
[0035] A mixture of 2,3-diamino-6-p-fluoro-benzylamino-pyridine hydrochloride 132g, 800ml of isopropanol was added to a 2L reaction flask, the temperature control to 28 至 30 ° C, was slowly added dropwise acetic acid ester 39g. Stirred for 0.5 hours, was slowly added dropwise triethylamine 70g, after stirring for 0.5 hours, complement ethyl chloroformate 5g, stirred for 15 minutes, additional triethylamine remaining 10g. Continue stirring for I hour. The reaction solution was concentrated under reduced pressure to about 800ml of distillate was distilled out. The remaining reaction solution was poured into an aqueous solution of maleic acid with a good (39g of maleic acid was dissolved in purified water IlOOml), stirred for 30 minutes at room temperature, (T5 ° C was stirred for 5 ~ 8 hours, filtered, dried to give the maleic acid flupirtine crude.
[0036] The crude flupirtine maleate product 100g, 2000ml of ethanol into the reaction flask and heated to 70~80 ° C, was added 5g of activated carbon and dissolved, and incubated I hour, filtered hot, O~5 ° C CRYSTALLIZATION 3 hours, filtered and dried to give crude I. The crude product I 90g, 450ml of ethanol into the reaction flask and heated 20h, and then slowly cooled to room temperature, O~5 ° C for 2 hours, filtered, and dried to give crystal form A of flupirtine maleate product.













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paper

J Pharm Biomed Anal. 2014 Mar;90:27-34. doi: 10.1016/j.jpba.2013.11.015. Epub 2013 Nov 27.

Flupirtine maleate is a centrally acting, non-opioid, nonsteroidal antiinflammatory analgesic. During the manufacturing of flupirtine maleate, two unknown impurities present in the laboratory batches in the range of 0.05-1.0% along with the known impurities in HPLC analysis. These unknown impurities were obtained from the enriched mother liquor by column chromatography. Based on the complete spectral analysis (MS, (1)H, (13)C, 2D NMR and IR) and knowledge of the synthetic scheme of flupirtine maleate, these two new impurities were designated as diethyl 5-((4-fluorobenzyl)amino)-2-oxo-1H-imidazo[4,5-b]pyridine-1,3(2H)-dicarboxylate (impurity-I) and diethyl(6-((4-fluorobenzyl)amino)pyridine-2,3-diyl)dicarbamate (impurity-II). Impurity isolation, identification, structure elucidation and the formation of impurities were also discussed. Preparation and structure elucidation of impurity-III were also first reported in this paper.

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

journal of pharmaceutical and biomedical analysis, 90, 2014, 27-34

 

  1H NMR INTERPRETATIONS/PREDICTIONS

13C  NMR INTERPRETATIONS/PREDICTIONS

…….

PAPER

Helvetica Chimica Acta, , vol. 77, # 8 p. 2175 – 2190

AND GIVES PRODUCT

ALSO AN INTHelvetica Chimica Acta, , vol. 77, # 8 p. 2175 – 2190

…………..

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.

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.

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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