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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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ATORVASTATIN SYNTHESIS
atorvastatin
Atorvastatin (INN) /əˌtɔrvəˈstætən/, marketed by Pfizer as a calcium salt under the trade name Lipitor,[1] is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms. Like all statins, atorvastatin works by inhibitingHMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body.
Atorvastatin was first synthesized in 1985 by Bruce Roth of Parke-Davis Warner-Lambert Company (since acquired by Pfizer). The best selling drug in pharmaceutical history, sales of Lipitor since it was approved in 1996 exceed US$125 billion, and the drug has topped the list of best-selling branded pharmaceuticals in the world for nearly a decade.[2] When Pfizer’s patent on Lipitor expired on November 30, 2011,[3] generic atorvastatin became available in the United States, initially manufactured only by generic drugmakers Watson Pharmaceuticals and India’s Ranbaxy Laboratories. Prices for the generic version did not drop to the level of other generics—$10 or less for a month’s supply—until other manufacturers were able to supply the drug in May 2012.[4]
| Atorvastatin calcium, YM-548, CI-981, Prevencor, Tahor, Lipibec, Torvast, Sortis, Lipitor | |
| (3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxyheptanoic acid calcium salt (2:1) | |
| 134523-03-8, 134523-00-5 (free acid), 110862-48-1 (free acid (R*,R*)-isomer) | |
| 2-C33-H34-F-N2-O5.Ca | |
| 1155.35 | |
| Alzheimer’s Dementia, Treatment of , Cardiovascular Drugs, Cognition Disorders, Treatment of, Immunologic Neuromuscular Disorders, Treatment of, Lipoprotein Disorders, Treatment of , Metabolic Drugs, Multiple Sclerosis, Agents for, Neurologic Drugs, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HMG-CoA Reductase Inhibitors, TNFSF6 Expression Inhibitors | |
| Launched-1997 | |
| Jouveinal (Originator), Pfizer (Originator), Almirall Prodesfarma (Licensee), Syncro (Licensee), Yamanouchi (Licensee), Stanford University (Codevelopment) |
| SYNTHESISTrans-6-[2-(3- or 4-carboxamido-substd. pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis | |
| Roth, B.D. (Pfizer Inc.) | |
| EP 0247633; US 4681893 | |
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1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl 2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 C in acetic anhydride giving 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX), which is finally treated first with NaOH in methanol/water, and then with CaCl2 or calcium acetate. |
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- “Pfizer product promotion page (Liptor)”. Retrieved 2011-12-05.
- “Lipitor becomes world’s top-selling drug”. Crain’s New York Business. 2011-12-28.
- CNN Wire Staff (November 30, 2011). “Lipitor loses patent, goes generic”. CNN. Retrieved November 18, 2012.
- NeLM, June 2012: Price to UK National Health Service for 28 tablets from £3.25 (10mg) to £10.00 (80mg).
- “Atorvastatin Calcium”. Drugs.com. Retrieved 3 April 2011.
Further reading
- “Highlights of prescribing information” (pdf). Lipitor (atorvastatin calcium) Tablets for oral administration. Pfizer. 2009-06-01. Retrieved 2011-10-26.
- Maggon K (June 2005). “Best-selling human medicines 2002-2004”. Drug Discov. Today 10 (11): 739–42. doi:10.1016/S1359-6446(05)03468-9. PMID 15922927.
- Roth BD (2002). “The discovery and development of atorvastatin, a potent novel hypolipidemic agent”. Prog Med Chem. Progress in Medicinal Chemistry 40: 1–22. doi:10.1016/S0079-6468(08)70080-8. ISBN 978-0-444-51054-9. PMID 12516521.
- Simons J (2003-01-20). “The $10 Billion Pill Hold the fries, please. Lipitor, the cholesterol-lowering drug, has become the bestselling pharmaceutical in history. Here’s how Pfizer did it”. Fortune. Retrieved 2011-10-26.
- Winslow R (2000-01-24). “The Birth of a Blockbuster: Lipitor’s Route out of the Lab”. The Wall Street Journal. Retrieved 2011-10-26.
- “Ann Arbor chemist wins national award for drug discovery”. ScienceBlog. American Chemical Society. 2003-03-01. Retrieved 2011-10-26.
- Rowe A (2008-08-20). “Meet the Guy Who Invented Lipitor”. Wired Science. Wired.com. Retrieved 2011-10-26.
- Bernstein M (2008-08-16). “Chemical Society To Honor ‘Heroes Of Chemistry’ During National Meeting”. Medical News Today. Retrieved 2011-10-26.
- He L (2003-09-27). “Bruce D. Roth, Pfizer Inc, USA”. Chinese Academy of Sciences·Institute of Process Engineering. Retrieved 2011-10-26.
External links
- Atorvastatin bound to proteins in the PDB
- Lipitor.com – manufacturer’s site
- MedlinePlus Drug information: Atorvastatin (Systemic) – information from USP DI Advice for the Patient
- U.S. National Library of Medicine: Drug Information Portal – Atorvastatin
| An improved synthesis of 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for atorvastatin synthesis | |
| Radl, S.; et al. | |
| Tetrahedron Lett 2002,43(11),2087 | |
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The 6-cyanohexanoic ester (VII), intermediate in the synthesis of 180072 (see intermediate (XLI) in scheme no. 18007204a) has been obtained as follows: the reaction of 1,6-heptadien-4-ol (I) with BuLi, CO2, and I2 in THF gives the cyclic carbonate (II), which is treated with Ts-OH in acetone to yield the acetonide (III). The reaction of the iodine atom of (III) with KCN in hot DMSO affords the nitrile (IV), which is oxidized at the terminal double bond with OsO4 and NaIO4, or O3 and Me2S, to provide the carbaldehyde (V). The oxidation of (V) with CrO3/H2SO4 in acetone gives the carboxylic acid (VI), which is finally esterified with tert-butanol by means of DCC and DMAP in dichloromethane, yielding the target ester intermediate (VII). |
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Lipitor industrial production shown below (TL, 1985, 2951; TL, 1992, 2279; 2283)
Divided into two fragments. Primary amine fragment iso-ascorbic acid as a starting material (stereoisomer of vitamin C) in the system. 1,4 – dione as a starting material isobutyrylacetanilide fragment, obtained by the Stetter reaction, the reaction of benzoin conjugated version Michael addition. Diketone related primary amine with a substituted pyrrole ring obtained five, after deprotection and salt formation Lipitor.
Atorvastatin of IC50-0.025μM, its RR configuration is as high IC50-0.007μM (SS configuration IC50-0.44μM).
Initially synthesized as shown above (JMC, 1991, 357).
Which polysubstituted pyrrole ring by the Munchnone of 1,3-dipolar [3 +2] cycloaddition get.
Oncopeptides Testing Melflufen in Europe
Oncopeptides AB, a company working to enhance oncology therapies, announced that the first patient has been dosed as part of a phase 2 study in multiple myeloma patients with its drug candidate melflufen (previously called J1). The trial is an open-label phase 2 study, designed to determine the level of efficacy of melflufen in combination with dexamethasone, for late stage, relapsing or relapsing/refractory patients
read all at
Diabetes Drug Trial Moves to Israel
Oramed Pharmaceuticals Inc., a developer of oral drug delivery systems, announced that it has initiated patient recruitment for a new clinical trial of its orally ingestible insulin capsule, ORMD-0801 for patients with type 1 diabetes mellitus (T1DM) in Israel.
Biotech portfolio update – 2012 summary and 2013 outlook
read all here
http://www.orf-blog.com/biotech-portfolio-update-%E2%80%93-2012-summary-and-2013-outlook/
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ANTHELMINTIC ACTIVITY OF THE LEAVES OF MORUS ALBA LINN
桑 Morus alba Linn.
Abstract
Present study was carried out to scientifically evaluate the anthelmintic potential of the methanolic extract of leaves of the plant morus alba(L) as it is used by the tribal community of different states and this is also highlighted in traditional uses of the plant.
Activity was performed using adult earthworms and albendazole was used as a standard. Various doses (2.5, 5, 10 mg/ml) of methanolic extracts of leaves were used for the study.
From results of the study it is clear that potency of the extracts is inversely proportional to the time taken for paralysis and death of worms.
All the tested doses showed significant activity (P<0.01) compared to the standard and activity also confirms dose dependant nature of the extracts.
read all at
http://www.pharmatutor.org/articles/anthelmintic-activity-leaves-of-morus-alba-linn
桑 Morus alba Linn.
The US Food and Drug Administration (FDA) has approved the GlaxoSmithKline vaccine Flulaval Quadrivalent, used to treat seasonal influenza.
FDA backs second GSK flu vaccine
The US Food and Drug Administration (FDA) has approved the GlaxoSmithKline vaccine Flulaval Quadrivalent, used to treat seasonal influenza.
READ ALL AT
http://www.pharmaceutical-technology.com/news/newsfda-backs-second-gsk-flu-vaccine?WT.mc_id=DN_News
Trace Metals Debate-Contentious new guidelines on pharmaceutical impurities will force the drug industry to change testing strategies.
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In 1905, the U.S. Pharmacopeial Convention, the nonprofit standards-setting organization known as USP, introduced a method to check for heavy metals in U.S. pharmaceuticals. More than 100 years later, drug manufacturers still use the same chemistry to determine whether the level of 10 metal impurities is acceptable in their products.
read all at
Serving The Chemical, Life Sciences & Laboratory Worlds . the link is
http://cen.acs.org/articles/91/i33/Trace-Metals-Debate.html
Supernus Announces Final FDA Approval and Upcoming Launch of Trokendi XR
Topiramate
ROCKVILLE, Md., Aug. 19, 2013 (GLOBE NEWSWIRE) — Supernus Pharmaceuticals, Inc., a specialty pharmaceutical company, received final approval from the Food & Drug Administration (the “FDA”) for Trokendi XR, a novel once-daily extended release formulation of topiramate for the treatment of epilepsy. The company expects to launch the product and for it to be available in pharmacies over the next few weeks.
The approval letter states that the FDA has completed its review of the application and that Trokendi XR is approved effective August 16, 2013 for use as recommended in the agreed-upon labeling. The FDA granted a waiver for certain pediatric study requirements and a deferral for submission of post-marketing pediatric pharmacokinetic assessments that are due in 2019 followed by clinical assessments in 2025.
“We are very excited about the approval of Trokendi XR and its upcoming launch. This is excellent news for Supernus, its shareholders, and patients with epilepsy. We remain committed to the epilepsy community and very much look forward to now having two products, Trokendi XR and Oxtellar XR, available to patients,” said Jack Khattar, Chief Executive Officer, President and Director of Supernus.
About Trokendi XR
Trokendi XR is a novel once- daily extended release formulation of topiramate. Trokendi XR is an antiepileptic drug (AED) indicated for initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures; adjunctive therapy in patients 6 years of age and older with partial onset or primary generalized tonic-clonic seizures, and adjunctive therapy in patients 6 years of age and older with seizures associated with Lennox-Gastaut syndrome. The product will be available in 25mg, 50mg, 100mg and 200mg extended-release capsules.
About Supernus Pharmaceuticals, Inc.
Supernus Pharmaceuticals, Inc. is a specialty pharmaceutical company focused on developing and commercializing products for the treatment of central nervous system, or CNS, diseases. The Company has one marketed product for epilepsy, Oxtellar XR (extended-release oxcarbazepine), and one approved product for epilepsy, Trokendi XR (extended-release topiramate). The Company is also developing several product candidates in psychiatry to address large market opportunities in ADHD, including ADHD patients with impulsive aggression. These product candidates include SPN-810 for impulsive aggression in ADHD and SPN-812 for ADHD
OTHER
Topiramate (brand name Topamax) is an anticonvulsant (antiepilepsy) drug. It was most recently approved for weight loss by the FDA in combination with phentermine. It has been used off-label for this purpose before FDA approval was obtained. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. It was also recently approved in a combination medication used for weight loss in late 2012. This medication was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil Pharmaceutical. Topiramate was first approved by the US FDA in 1996. Generic versions are available in Canada and these were approved by the Food and Drug Administration (FDA) in September 2006. Mylan Pharmaceuticals was recently granted final approval for generic topiramate 25, 100, and 200 mg tablets and sprinkle capsules by the FDA for sale in the United States. 50 mg tablets were granted tentative approval. The last patent for topiramate in the U.S. was for pediatric use; this patent expired on February 28, 2009.
Environmental toxins and poor health: pharmaceuticals are part of the toxic stew we live in
I consider my illness and that of many with protracted psychiatric drug withdrawal syndromes to be, in large part, one of environmental toxicity…drugs and all the crap in the air and processed foods we eat…etc…leading to chronic illness, yes. Pharmaceuticals put me seriously over the edge…but this can happen to people who’ve not taken massive doses of prescribed neurotoxins too. I have come to know a lot about those with chronic illness through my networking online. Pharmaceuticals often make people’s issues much more complicated.
This is why I write so much about food and the environment. This is how we are deeply holistic and part of the ecosystem and all that which is around us. Like I like to say, everything matters.
There was an important article in Scientific American interviewing Linda Birnbaum
How much of human disease is due to environmental exposures?The estimates vary, and it depends on…
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New Drug Approvals 