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Ximelagatran

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Ximelagatran

192939-46-1, EXANTA

N-​[(1R)-​1-​cyclohexyl-​2-​[(2S)-​2-​[[[[4-​[(hydroxyamino)iminomethyl]phenyl]methyl]amino]carbonyl]-​1-​azetidinyl]-​2-​oxoethyl]-​glycine,​ ethyl ester

C24H35N5O5
MW 473.6

CAS 260790-58-7 (Monohydrate)
CAS 260790-59-8 (MonoHBr)
CAS 260790-60-1 (Monomethanesulfonate)

ASTRAZENECA INNOVATOR

Ximelagatran (Exanta or Exarta, H 376/95) is an anticoagulant that has been investigated extensively as a replacement forwarfarin[1] that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports ofhepatotoxicity (liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).[2]

Ximelagatran is an ester prodrug of melagatran, a potent, direct, and reversible thrombin inhibitor (Ki = 1.2 nM). While melagatran has poor oral bioavailability, ximelagatran displays good bioavailability resulting, in part, from rapid absorption at the gastrointestinal tract, as well as rapid onset of action.Ximelagatran is converted to melagatran by reduction and hydrolysis at the liver and other tissues. It is used as an anticoagulant in a variety of situations, including thromboembolic disorders, stroke prevention in atrial fibrillation, and therapy in vein thrombosis

Method of action

Ximelagatran, a direct thrombin inhibitor,[3] was the first member of this class that can be taken orally. It acts solely by inhibiting the actions of thrombin. It is taken orally twice daily, and rapidly absorbed by the small intestine. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran. This conversion takes place in the liver and many other tissues throughdealkylation and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).

Uses

Ximelagatran was expected to replace warfarin and sometimes aspirin and heparin in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and complications of atrial fibrillation such as stroke. The efficacy of ximelagatran for these indications had been well documented,[4][5][6] except for non valvular atrial fibrillation.

An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin and heparin, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time (PTT), respectively. A disadvantage recognised early was the absence of an antidote in case acute bleeding develops, while warfarin can be antagonised by vitamin K and heparin by protamine sulfate.

Side-effects

Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5-6%) developed elevated liver enzymelevels, which prompted the FDA to reject an initial application for approval in 2004. The further development was discontinued in 2006 after it turned out hepatic damage could develop in the period subsequent to withdrawal of the drug. According to AstraZeneca, a chemically different but pharmacologically similar substance, AZD0837, is undergoing testing for similar indications.[2]

Melagatran synthesis

Melagatran.png

 

Sobrera, L. A.; Castaner, J.; Drugs Future, 2002, 27, 201.

SYNTHESIS

SYNTHESIS

SYNTHESIS

 

 

……

WO 1997023499/http://www.google.com/patents/EP0869966A1?cl=en

…………

 

References

  1.  Hirsh J, O’Donnell M, Eikelboom JW (July 2007). “Beyond unfractionated heparin and warfarin: current and future advances”. Circulation 116 (5): 552–560.doi:10.1161/CIRCULATIONAHA.106.685974. PMID 17664384.
  2. “AstraZeneca Decides to Withdraw Exanta” (Press release). AstraZeneca. February 14, 2006. Retrieved 2012-07-16.
  3.  Ho SJ, Brighton TA (2006). “Ximelagatran: direct thrombin inhibitor”. Vasc Health Risk Manag 2 (1): 49–58. doi:10.2147/vhrm.2006.2.1.49. PMC 1993972.PMID 17319469.
  4.  Eriksson, H; Wahlander K; Gustafsson D; Welin LT; Frison L; Schulman S; THRIVE Investigators (January 2003). “A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I”. Journal of Thrombosis and Haemostasis 1 (1): 41–47. doi:10.1046/j.1538-7836.2003.00034.x. PMID 12871538.
  5.  Francis, CW; Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW Jr; EXULT A Study Group (October 2003). “Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement”. New England Journal of Medicine 349 (18): 1703–1712.doi:10.1056/NEJMoa035162. PMID 14585938.
  6.  Schulman, S; Wåhlander K; Lundström T; Clason SB; Eriksson H; THRIVE III investigators (October 2003). “Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran”. New England Journal of Medicine 349 (18): 1713–1721. doi:10.1056/NEJMoa030104. PMID 14585939.

 

 

 

Ximelagatran
Ximelagatran.svg
Systematic (IUPAC) name
ethyl 2-[[(1R)-1-cyclohexyl-2-
[(2S)-2-[[4-(N’-hydroxycarbamimidoyl)
phenyl]methylcarbamoyl]azetidin-1-yl]-
2-oxo-ethyl]amino]acetate
Clinical data
Pregnancy
category
  • uncategorised
Legal status
  • Rx only/POM
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 20%
Metabolism None
Biological half-life 3-5h
Excretion Renal (80%)
Identifiers
CAS Registry Number 192939-46-1 
ATC code B01AE05
PubChem CID: 9574101
IUPHAR/BPS 6381
DrugBank DB04898 Yes
ChemSpider 7848559 Yes
UNII 49HFB70472 Yes
KEGG D01981 Yes
ChEMBL CHEMBL522038 Yes
Chemical data
Formula C24H35N5O5
Molecular mass 473.57 g·mol−1 (429 g/mol after conversion)

 

See full gatran series at………………http://apisynthesisint.blogspot.in/p/argatroban.html

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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 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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