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D05928.pngStiripentol.pngChemSpider 2D Image | Stiripentol | C14H18O3Stiripentol structure.svg

Stiripentol

スチリペントール

STIRIPENTOL; Diacomit; 49763-96-4; BCX 2600; Estiripentol; Stiripentolum

CAS: 137767-55-6 49763-96-4

(E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-ol

Molecular Formula: C14H18O3
Molecular Weight: 234.295 g/mol

UNII

R02XOT8V8I, Diacomit
fda approval 2018/8/20

Stiripentol (marketed as Diacomit by Laboratoires Biocodex) is an anticonvulsant drug used in the treatment of epilepsy. It is approved for the treatment of Dravet syndrome, an epilepsy syndrome. It is unrelated to other anticonvulsants and belongs to the group of aromatic allylic alcohols.

Medical use

It is used in some countries as an add-on therapy with sodium valproate and clobazam for treating children with Dravet syndromewhose seizures are not adequately controlled.[1][2][3] As of 2017 it was not known whether stiripentol remains useful as children become adolescents nor as they become adults.[4]

Adverse effects

Very common (more than 10% of people) adverse effects include loss of appetite, weight loss, insomnia, drowsiness, ataxiahypotonia, and dystonia.[3]

Common (between 1% and than 10% of people) adverse effects include neutropenia (sometimes severe), aggressiveness, irritability, behavior disorders, opposing behavior, hyperexcitability, sleep disorders, hyperkinesias, nausea, vomiting, and elevated gamma-glutamyltransferase.[3]

Interactions

Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines.[3]

Pharmacology

As with most anticonvulsants, the precise mechanism of action is unknown. Regardless, stiripentol has been shown to have anticonvulsant effects of its own.

Stiripentol increases GABAergic activity. At clinically relevant concentrations, it enhances central GABA neurotransmission through a barbiturate-like effect, since it increases the duration of opening of GABA-A receptor channels in hippocampal slices.[5] It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and metabolism.[6] Specifically, it has been shown to inhibit lactate dehydrogenase, which is an important enzyme involved in the energy metabolism of neurons. Inhibition of this enzyme can make neurons less prone to fire action potentials, likely through activation of ATP-sensitive potassium channels.[7]

Stiripentol also improves the effectiveness of many other anticonvulsants, possibly due to its inhibition of certain enzymes, slowing the drugs’ metabolism and increasing blood plasma levels.[3]

Chemistry

Stiripentol is an α-ethylene alcohol; its chemical formula is 4,4-dimethyl-1-[3,4-(methylendioxy)-phenyl]-1penten-3-ol. It is chiral and is marketed as an equimolar racemic mixture. The R enantiomer appears to be around 2.5 times more active than the S enantiomer.[8]

Paper

Synthesis of the antiepileptic (R)-Stiripentol by a combination of lipase catalyzed resolution and alkene metathesis

The enantiopure (ee >99%) antiepileptic (R)-(+)-Stiripentol has been stereoselectively synthesized via cross metathesis of 5-vinylbenzo[d][1,3]dioxole 1 and (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2. A novel one-pot two-step pathway for the synthesis of 5-vinylbenzo[d][1,3]dioxole 1 starting from 3,4-dihydroxycinnamic acid has been introduced. A lipase catalyzed kinetic resolution access to enantiopure (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2 (ee >99%) has also been developed.

Image result for Stiripentol synthesis

Image result for Stiripentol synthesis

Stiripentol (CAS NO.: 49763-96-4), with other name of 4,4-Dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-penten-3-ol, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Stiripentol

The synthesis of [14]-labeled stiripentol has been published:The reaction of 3,4-methylenedioxybromobenzene (I) with 14CO2 by means of butyllithium in ether gives 3,4-methylenedioxybenzoic acid (II), which is reduced with LiAlH4 to the corresponding benzyl alcohol (III). Oxidation of (III) with CrO3-pyridine affords the aldehyde (IV), which is condensed with methyl tert-butyl ketone (V) by means of NaOH in refluxing ethanol to give the labeled pentanone (VI). Finally, this compound is reduced to [14C]-labeled stiripentol with NaBH4 in methanol

合成路线图解说明:The condensation of 3,4-methylenedioxybenzaldehyde (I) with 3,3-dimethyl-2-butanone (II) by means of NaOH in ethanol-water gives 4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-penten-3-one (III), which is reduced with NaBH4 in methanol.
合成路线图解说明:The synthesis of [14]-labeled stiripentol has been published: The reaction of 3,4-methylenedioxybromobenzene (I) with 14CO2 by means of butyllithium in ether gives 3,4-methylenedioxybenzoic acid (II), which is reduced with LiAlH4 to the corresponding benzyl alcohol (III). Oxidation of (III) with CrO3-pyridine affords the aldehyde (IV), which is condensed with methyl tert-butyl ketone (V) by means of NaOH in refluxing ethanol to give the labeled pentanone (VI). Finally, this compound is reduced to [14C]-labeled stiripentol with NaBH4 in methanol.

History

Stiripentol was discovered in 1978 by scientists at Biocodex and clinical trials started over the next few years.[8] It was originally developed for adults with focal seizures, but failed a Phase III trial.[4]

In December 2001 the European Medicines Agency (EMA) granted stiripentol orphan drug status (designation number EU/3/01/071) for the treatment of severe myoclonic epilepsy of infancy (SMEI, also known as Dravet’s syndrome) in children and in 2007, the EMA granted the drug a marketing authorisation for use of the drug as an add-on to other anti-seizure drugs.[3] It was approved in Canada for this use in 2012.[9] As of 2017 it was also approved for this use in Japan.[2]

As of 2014 it was not approved in the US, and parents of children with Dravets were paying around $1,000 for a month supply to obtain it from Europe.[10]

Stiripentol
Stiripentol structure.svg
Clinical data
Trade names Diacomit
AHFS/Drugs.com International Drug Names
License data
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • AU: Unscheduled
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ECHA InfoCard 100.051.329 Edit this at Wikidata
Chemical and physical data
Formula C14H18O3
Molar mass 234.30 g·mol−1
3D model (JSmol)

References

  1. Jump up^ Brigo, F; Igwe, SC; Bragazzi, NL (18 May 2017). “Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy”. The Cochrane Database of Systematic Reviews5: CD010483. doi:10.1002/14651858.CD010483.pub4PMID 28521067.
  2. Jump up to:a b Nickels, KC; Wirrell, EC (May 2017). “Stiripentol in the Management of Epilepsy”. CNS drugs31 (5): 405–416. doi:10.1007/s40263-017-0432-1PMID 28434133.
  3. Jump up to:a b c d e f “Diacomit (stiripentol) SPC” (PDF). EMA. 8 January 2014. Retrieved 1 October 2017. For updates see EMA index page
  4. Jump up to:a b Nabbout, R; Camfield, CS; Andrade, DM; Arzimanoglou, A; Chiron, C; Cramer, JA; French, JA; Kossoff, E; Mula, M; Camfield, PR (April 2017). “Treatment issues for children with epilepsy transitioning to adult care”. Epilepsy & Behavior69: 153–160. doi:10.1016/j.yebeh.2016.11.008PMID 28188045.
  5. Jump up^ Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H (2006). “Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels”Epilepsia47 (4): 704–16. doi:10.1111/j.1528-1167.2006.00497.xPMID 16650136.
  6. Jump up^ Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ (2005). “Stiripentol. A novel antiepileptic drug” (PDF). Pharmacological reports : PR57 (2): 154–60. PMID 15886413.
  7. Jump up^ Sada N, Lee S, Katsu T, Otsuki T, Inoue T (2015). “Targeting LDH enzymes with a stiripentol analog to treat epilepsy”Science347 (6228): 1362–67. doi:10.1126/science.aaa1299PMID 25792327.
  8. Jump up to:a b “Scientific evaluation” (PDF). EMA. 2007.
  9. Jump up^ “Stiripentol (Diacomit): For Severe Myoclonic Epilepsy in Infancy (Dravet Syndrome)” (PDF). Canadian Agency for Drugs and Technologies in Health. April 2015.
  10. Jump up^ Kossoff, E (January 2014). “Stiripentol for dravet syndrome: is it worth it?”Epilepsy Currents14 (1): 22–3. doi:10.5698/1535-7597-14.1.22PMC 3913306Freely accessiblePMID 24526870.

////////////Stiripentol, fda 2018, Diacomit, 49763-96-4, BCX 2600, Estiripentol, Stiripentolum

CC(C)(C)C(C=CC1=CC2=C(C=C1)OCO2)O

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DR ANTHONY CRASTO

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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 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 Open superstar 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 30 year tenure till date Dec 2017, Around 35 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, 50 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 19 lakh plus views on New Drug Approvals Blog in 216 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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