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Sertindole2DACS.svg.

 

SERTINDOLE

Sertindole_synthesis

Sertindole (brand names: Serdolect, and Serlect) is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company H. Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative.

Sertindole is not approved for use in the United States.

 

Medical Uses

Sertindole appears effective as an antipsychotic in schizophrenia.[4]

 

Safety and status

USA

Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996,[10] but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation.[11] In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths.[12] Lundbeck cites the results of the Sertindole Cohort Prospective (SCoP) study of 10,000 patients to support its claim that although sertindole does increase the QTc interval, this is not associated with increased rates of cardiac arrhythmias, and that patients on sertindole had the same overall mortality rate as those on risperidone.[13] Nevertheless in April 2009 an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe.[14] As of October 2010, the drug has not been approved by the FDA for use in the USA.[15]

Europe

In Europe, sertindole was approved and marketed in 19 countries from 1996,[12] but its marketing authorization was suspended by the European Medicines Agency in 1998[16] and the drug was withdrawn from the market. In 2002, based on new data, the EMA’s CHMP suggested that Sertindole could be reintroduced for restricted use in clinical trials, with strong safeguards including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirement before and during treatment.[17][18]

Synthesis

Sertindole synthesis:[19]

PAPER

Identification and synthesis of impurities formed during sertindole preparation

I. V. Sunil Kumar1Email of corresponding author, G. S. R. Anjaneyulu1 and V. Hima Bindu2
1Research and Development Centre, Aptuit Laurus Private Limited, ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad-500078, India
2Institute of Science and Technology, JNTU, Hyderabad-500072, India
Email of corresponding author Corresponding author email
Associate Editor: N. Sewald

Sertindole is designated chemically as 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinone. Its literature synthesis (Scheme 1) [1-5] involves the copper catalyzed N-arylation of 5-chloroindole (11) with 4-fluorobromobenzene (12). The product, 5-chloro-1-(4-fluorophenyl)indole (13), on treatment with 4-piperidinone hydrochloride monohydrate (14) under acidic conditions affords 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole hydrochloride (15). Reduction of 15 in the presence of platinum oxide yields 5-chloro-1-(4-fluorophenyl)-3-(4-piperdinyl)-1H-indole (9) which on condensation with 1-(2-chloroethyl)imidazolidinone (16) in the presence of a base gives sertindole (1).

[1860-5397-7-5-i1]
Scheme 1: Reagents and conditions: i) K2CO3, CuBr, ethylenediamine, DMF 130–135 °C; ii) CH3COOH, CF3COOH, 100–110 °C; iii) PtO2/H2, methanol, 30–35 °C; iv) K2CO3, KI, methylisobutyl ketone (MIBK),110–115 °C.

During the laboratory optimization of sertindole (1), many process related impurities were identified. The guidelines recommended by ICH state that the acceptable levels for a known and unknown compound (impurity) in the drug should be less than 0.15 and 0.10%, respectively [6]. In order to meet the stringent regulatory requirements, the impurities present in the drug substance must be identified and characterized. Literature reports [5,7-9] include impurities formed due to either over reduction (e.g., 2, 3 and 6) [5,7], incomplete reduction (e.g., 4 and 5) [5,8] or due to incomplete alkylation (e.g., 9 and 10) [5,7]. However, no synthetic details have been reported. In this context, the present study describes identification, synthesis and characterization of impurities formed during sertindole synthesis.

References

 

Perregaard, J.; Arnt, J.; Boegesoe, K. P.; Hyttel, J.; Sanchez, C. (1992). “Noncataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles”. Journal of Medicinal Chemistry 35 (6): 1092. doi:10.1021/jm00084a014.

 

Sertindole
Sertindole2DACS.svg
Sertindole ball-and-stick model.png
Systematic (IUPAC) name
1-[2-[4-[5-chloro-1-(4-fluorophenyl)-indol-3-yl]-1-piperidyl]ethyl]imidazolidin-2-one
Clinical data
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • AU: C
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 75%[1]
Protein binding 99.5%[1]
Metabolism Hepatic (mostly via CYP2D6 and CYP3A4)[2][3]
Biological half-life 3 days[2]
Excretion Faecal (the majority), Renal (4% metabolites; 1% unchanged)[2]
Identifiers
CAS Registry Number 106516-24-9 Yes
ATC code N05AE03
PubChem CID: 60149
IUPHAR/BPS 98
DrugBank DB06144 Yes
ChemSpider 54229 Yes
UNII GVV4Z879SP Yes
KEGG D00561 Yes
ChEBI CHEBI:9122 Yes
ChEMBL CHEMBL12713 Yes
Chemical data
Formula C24H26ClFN4O
Molecular mass 440.941

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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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