Home » Posts tagged 'organic chemistry' (Page 22)
Tag Archives: organic chemistry
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
.....FOR BLOG HOME CLICK HEREFlag and hits
ORGANIC SPECTROSCOPY
SUBSCRIBE
Subscribe in a reader
Enter your email address:
Delivered by FeedBurner
Subscribe to New Drug Approvals by Email
Recent Comments
 | shivkr2 on SPSR Excellence Award 2025 – S… |
 | Bonkasaurus on Infigratinib phosphate |
 | PALOVAROTENE | ORGAN… on Palovarotene |
| Pfizer just purchase… on Temanogrel | |
| Pfizer To Cash In On… on Temanogrel |
Citrus And Statins
bergamottin
Citrus And Statins. —Citrus And Statins “” “How Foods and Drugs Collide” provided my first knowledge that 5-geranoxy psoralen (bergamottin) had been identified as the active agent in grapefruit juice implicated in interfering with the so-called statin drugs
( C&ENCitrus And Statins, Sept. 27, page 55 William L. Stanley Carmel, Calif. /articles/88/i49/Citrus-Statins.html 20101206 88 49 /magazine/88/8849.html /departments/letters.html Citrus And Statins Letters Citrus And Statins Chemical & Engineering News Citrus And Statins ACS 2009 IRS Form 990 Available The American Chemical Society’s 2009 Form 990 is now available on ACS’s website.
Chemical & Engineering News, 88(49), December 06, 2010 [Letters] you will have to pay a fee or subscribe
free info from net
Bergamottin is a natural furanocoumarin found principally in grapefruit juice. It is also found in the oil of bergamot orange, from which it was first isolated and from which its name is derived. To a lesser extent, bergamottin is also present in the essential oils of other citrus fruits. Along with the chemically related compound 6′,7′-dihydroxybergamottin, it is believed to be responsible for thegrapefruit juice effect in which the consumption of the juice affects the metabolism of a variety of pharmaceutical drugs.[1]
Chemistry
Chemically, bergamottin and dihydroxybergamottin are linear furanocoumarins functionalized with side chains derived fromgeraniol. They are inhibitors of some isoforms of the cytochrome P450 enzyme, particularly CYP3A4.[2] This prevents oxidative metabolism of certain drugs by the enzyme, resulting in an elevated concentration of drug in the bloodstream.
Normally, the grapefruit juice effect is considered to be a negative interaction, and patients are often warned not to consume grapefruit or its juice when taking medication. However, some current research is focused on the potential benefits of cytochrome P450 inhibition.[3] Bergamottin, dihydroxybergamottin, or synthetic analogs may be developed as drugs that are targeted to increase the oral bioavailability of other drugs. Drugs that may have limited use because they are metabolized by CYP3A4 may become viable medications when taken with a CYP3A4 inhibitor because the dose required to achieve a necessary concentration in the blood would be lowered.[4]
Biosynthesis of bergamottin
Bergamottin is derived from components originating in the shikimate pathway.[5] The biosynthesis of this compound starts with the formation of the demethylsuberosin (3) product which is formed via the alkylation of the umbelliferone (2) compound.[6] The alkylation of the umbelliferone is initiated with the use of dimethylallyl pyrophosphate, more commonly known as DMAPP. The cyclization of an alkyl group occurs to form marmesin (4), which is done in the presence of NADPH and oxygen along with a cytochrome P450 monooxygenase catalyst.[7] This process is then repeated twice more, first to remove the hydroxyisopropyl substituent from marmesin (4) to form psoralen (5), and then to add a hydroxyl group to form bergaptol (6).[8] Bergaptol (6) is next methylated with SAM, S-Adenosyl methionine, to form bergapten (7). The final step in this biosynthesis is the attachment of a GPP, or geranyl pyrophosphate, to the newly methylated bergapten (7) to form the target molecule bergamottin (8).
References
- ^ David G. Bailey, J. Malcolm, O. Arnold, J. David Spence (1998). “Grapefruit juice-drug interactions”. Br J Clin Pharmacol 46 (2): 101–110. doi:10.1046/j.1365-2125.1998.00764.x.PMC 1873672. PMID 9723817.
- ^ Basavaraj Girennavar, Shibu M. Poulose, Guddadarangavvanahally K. Jayaprakasha, Narayan G. Bhat and Bhimanagouda S. Patila (2006). “Furocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes”. Bioorganic & Medicinal Chemistry 14 (8): 2606–2612. doi:10.1016/j.bmc.2005.11.039. PMID 16338240.
- ^ E. C. Row, S. A. Brown, A. V. Stachulski and M. S. Lennard (2006). “Design, synthesis and evaluation of furanocoumarin monomers as inhibitors of CYP3A4”. Org. Biomol. Chem. 4(8): 1604–1610. doi:10.1039/b601096b. PMID 16604230.
- ^ Christensen, Hege; Asberg, Anders; Holmboe, Aase-Britt; Berg, Knut Joachim (2002). “Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers”. European Journal of Clinical Pharmacology 58 (8): 515–520. doi:10.1007/s00228-002-0516-8. PMID 12451428.
- ^ Dewick, P. Medicinal Natural Products:A Biosynthetic Approach, 2nd ed., Wiley&Sons: West Sussex, England, 2001, p 145.
- ^ Bisagni, E. Synthesis of psoralens and analogues. J. Photochem. Photobiol. B. 1992, 14, 23-46.
- ^ Voznesensky, A. I.; Schenkman, J. B. The cytochrome P450 2B4-NADPH cytochrome P450 reductase electron transfer complex is not formed by charge-pairing. J. Biol. Chem. 1992, 267, 14669-14676.
- ^ Kent, U. M.; Lin, H. L.; Noon, K. R.; Harris, D. L.; Hollenberg, P. F. Metabolism of bergamottin by cytochromes P450 2B6 and 3A5. J. Pharmacol. Exp. Ther. 2006, 318, 992-1005
Transform your life in 10 minutes with ancient ‘youthing’ practice
NaturalNews) If you need more zest and zip in your life, the secret to these states and more can be found in a set of simple (yet profound) yogic exercises known as the “Five Tibetans.” Developed by Buddhist monks and brought to the West in the 1930s, Tibetan yoga is a series of five movements that improve digestion and circulation while dispelling fatigue and depression. Advocates of the practice rave about the boundless energy, clarity and vitality the short daily sessions produce. And many also believe Tibetan yoga reverses the hands of time, promoting an ageless and disease free body.
Learn more: http://www.naturalnews.com/041813_transform_life_ancient_practice_youthing.html#ixzz2dL3zsuIL
Catalyst’s Firdapse Gets FDA ‘Breakthrough’ Designation
amifampridine
used as phosphate salt
Catalyst Pharmaceutical Partners Receives Breakthrough Therapy Designation From FDA for Firdapse(TM) for the Treatment of LEMS
CORAL GABLES, Fla., Aug. 27, 2013 (GLOBE NEWSWIRE) — Catalyst Pharmaceutical Partners, Inc. (Nasdaq:CPRX), a specialty pharmaceutical company focused on the development and commercialization of novel prescription drugs targeting rare (orphan) neuromuscular and neurological diseases, today announced that its investigational product
Firdapse(TM) (amifampridine phosphate) has received “Breakthrough Therapy Designation” by the U.S. Food and Drug Administration (FDA) for the symptomatic treatment of patients with Lambert-Eaton Myasthenic Syndrome (LEMS). Firdapse(TM) is Catalyst’s investigational therapy that is being evaluated for the treatment of the debilitating symptoms associated with LEMS, including muscle weakness.
read all ar
http://www.pharmalive.com/catalysts-firdapse-gets-fda-breakthrough-designation
3,4-Diaminopyridine (or 3,4-DAP) is an organic compound with the formula C5H3N(NH2)2. It is formally derived from pyridine by substitution of the 3 and 4 positions with an amino group.
With the International Nonproprietary Name amifampridine, it is used as a drug, predominantly in the treatment of a number of rare muscle diseases. In Europe, the phosphate salt of amifampridine has been licenced as Firdapse (BioMarin Pharmaceutical) in 2010 as an orphan drug
GLENMARK-A new way for a new world
http://www.glenmarkpharma.com/GLN_NWS/homepage.aspx?res=P_GLN
http://www.glenmark-generics.com/
| Type | Public |
|---|---|
| Traded as | BSE: 532296NSE: GLENMARK) |
| Industry | Pharmaceuticals, Drugs &Healthcare |
| Founded | 1977 |
| Founder(s) | Gracias Saldanha |
| Headquarters | Mumbai, Maharashtra[1], India |
| Key people | Glenn Saldanha, MD & CEO [2] |
| Products | Medicines and Vaccines |
| Revenue |  1031.10 crore(US$160 million) (2009–2010)[3] |
| Employees | 7,000 [4] |
| Subsidiaries | Glenmark Generics Ltd[5] |
| Website | www.glenmarkpharma.com |
Glenmark Pharmaceuticals is a pharmaceutical company headquartered in Mumbai, India. [6] It manufactures and markets generic formulation products and active pharmaceutical ingredients (API), both in the domestic and international markets. In the formulation business, its business spans segments such as Dermatology, Internal Medicine, Paediatrics, Gynaecology, ENT andDiabetes.
It has four manufacturing facilities for formulations and additional three facilities for APIs. These manufacturing facilities are located in the states of Maharashtra, Goa, Himachal Pradesh and Gujarat in India.
It operates in 95 countries through its subsidiaries, Glenmark Pharmaceuticals USA, Glenmark Pharmaceuticals UK. Glenmark Pharmaceuticals SA. [7]
HEAD OFFICE AT ANDHERI MUMBAI INDIA
- http://www.glenmarkpharma.com/UITemplate/HtmlContainer.aspx?res=P_GLN_CONTACT
- “If I were FM | Glenn Saldanha, managing director and CEO, Glenmark Pharmaceuticals – Economy and Politics”. livemint.com. 2009-07-01. Retrieved 2010-09-30.
- “BSE Plus”. Bseindia.com. Retrieved 2010-09-30.
- Glenmark Pharmaceuticals Ltd. (2529483): Stock Quote & Company Profile – BusinessWeek”. Investing.businessweek.com. Retrieved 2010-09-30.
- “Glenmark Pharmaceuticals | TopNews”. Topnews.in. Retrieved 2010-09-30.
- “about Glenmark Pharmaceuticals”. http://www.ibef.org. Retrieved 2010-09-30.
- “Glenmark Pharmaceuticals acquires Bouwer Bartlett, South Africa”. domain-b.com. 2005-12-26. Retrieved 2010-09-30.
WORLD-CLASS CAPABILITIEIS: Glenn Saldanha (left), Managing Director and CEO, along with Dr. Michael Buschle, President Biologics, Glenmark Pharmaceuticals at a press conference in Mumbai on Monday. Photo: Paul Noronha
RESEARCH CENTRE AT MAHAPE INDIA
Glenmark Pharma – The persevering innovator
Every Tuesday, unmindful of the gridlocked traffic, Glenn Saldanha, the 43-year-old Chairman of Glenmark Pharmaceuticals Ltd, or GPL, makes it a point to visit his research centre at Mahape in Navi Mumbai. It is the hub of Glenmark’s focus on creating new chemical entities, or NCEs, R&Dspeak for original drugs. Leading the innovation for Saldanha are his lab coat-clad scientists and researchers peering into the test tubes, burettes and pipettes at the Mahape facility.
“Almost 30 to 40 per cent of my time spent on business goes into issues relating to innovation,” he says. That includes thinking about research strategy, deciding on which chemical targets to focus on and which therapeutic segments to chase, and even hiring key R&D talent. Today, out of Glenmark’s 600-odd scientists, 400 are involved in NCE research.
The past 13 years have convinced the ardent admirer of Steve Jobs, the iconic former CEO of Apple, that the future lies in innovation. “If you look at how some of the largest corporations of the world were built, it is clear you need to have innovative products,” says Saldanha, a pharmacist by training, who voraciously reads scientific journals to stay updated on current scientific thought and trends. “Look at what Apple has created… that is the way to build a mega corporation, and that is the key reason why, despite our setbacks, we believe so heavily in innovation.”
Creating an NCE has been the Holy Grail for Indian pharma companies, including giants such as Dr Reddy’s Laboratories and Ranbaxy Laboratories (now owned by Daiichi Sankyo of Japan), but without any major success so far. These companies have reviewed their focus on NCE research and some branched into related activities like differentiated products. So has Glenmark, but it also soldiers on with drug discovery as its key focus area. With five molecules currently undergoing trials in various phases, the company now leads the charge of the Indian drug research industry.
Even one successful launch, say that of revamilast (for asthma and rheumatoid arthritis), which has potential peak sales of $2 billion worldwide, could change the fortunes of the company, though one can never be sure till it actually happens. Next year, Glenmark is likely to have half a dozen compounds in Phase II human trials. Saldanha hopes to hit the market with one or more of his drugs between 2015 and 2017. This potential upside is precisely why Glenmark is in this listing of Tomorrow’s Goliaths, and not any of the other bigger or faster-growing companies.
Undiminished zest
“Every year we expect two more molecules to get into clinical trials,” says Saldanha, his zest undiminished by past failures. “In 2008, in a span of one or two quarters, our entire pipeline pretty much got wiped out, but we never lost our commitment and passion.” At that time its most advanced molecule, oglemilast, used for treating patients with chronic obstructive pulmonary disease, had to be abandoned when its Phase IIb trials produced unsatisfactory results. It also had to suspend clinical development of GRC 6211, a compound for treating osteoarthritis pain, because of side effects.
Unlike other companies that reduced NCE development efforts when faced with similar situations, Glenmark persevered. “We never downsized our research team and did not cut back on budgets,” says Saldanha. “We did not even cut travel and our scientists continued to participate in major global conferences.” It is hardly surprising that his core R&D team has stayed put. Consider Neelima Joshi, 48, Senior Vice President and Head of NCE R&D, who was part of the dozen-odd people who set up the Mahape facility in 2000.
Even then, she says, Glenmark’s management was clearly focused on innovation and the move was in anticipation of the product patent regime that was to come in 2005. It was the impending change in India’s patent law that shaped the mind of the 29-year-old Saldanha in 1998, when he returned to India after working with Eli Lilly and PricewaterhouseCoopers to run his father Gracias Saldanha’s formulations business. After India became a signatory to General Agreement on Tariffs and Trade, it changed its patent law in 2005 from a process patent, which encouraged creation of copies of blockbuster original drugs with minor process changes, to a product patent, where the original drug’s patent itself is recognised in India, thereby prohibiting the creation of copies. This key change, and Saldanha’s passion for research, convinced him to steer Glenmark the NCE way.
However, not everyone agrees with Glenmark’s approach to NCE development, especially of giving away a promising molecule in the early stages to big multinational companies for further R&D. The argument: outlicensing a molecule at a later stage can give a company better valuations. The alternative is to do what Piramal Healthcare wants to – not outlicense. “We believe in taking the drug from the bench to market,” says Dr Swati A. Piramal, Vice Chairperson of Piramal Healthcare, which hopes to deploy the funds it got from sale of its formulations business to Abbott for its R&D efforts. “We are now at the end of the 10 years, having begun in 2002, and we hope between 2012 and 2015, we will hit the market with a new drug.”
While Piramal’s approach is a bench-to-market one, others such as Sun Pharma have developed a different model. Sun Pharma has created a separate research entity called Sun Pharma Advanced Research Centre, better known as SPARC, whose sustainability is built by making differentiated and innovative “generic-plus” products (in simple language, the risk is less, as the basic ingredient is known, but the company is developing a patented technology and a better-targeted product with intellectual property built in). What is more, the returns from this are to help fund the research programme.
On the other hand, Hyderabadbased Dr Reddy’s, one of the pioneers of India’s drug discovery journey, has today rationalised its research programme. It had, in fact, tried out a unique model of creating the country’s first integrated drug development company, Perlecan Pharma, which had equity capital commitments from ICICI Venture and other investors. But it soon saw the outside investors exit and brought back Perlecan into the Dr Reddy’s fold after delays in progress of candidates were not acceptable to some partners who had wanted early monetisation.
Beyond NCEs
Dr Reddy’s has now widened its scope beyond NCEs to differentiated products and formulations where improvements are made on existing products that have limited competition in the market. Its only Phase III candidate, balaglitazone, a diabetes drug, has yet to deliver the goods; the asset class it belongs to, glitazone, has had to deal with an overhang of safety concerns, especially in cases where there is a prolonged use of the drug. Yet, Dr Reddy’s sees sense in Glenmark’s model. “It is a viable model and a right strategy for a small company as Indian companies do not have the capacity to take the drug on their own to the market,” says Satish Reddy, Chief Operating Officer and Managing Director of Dr Reddy’s. “They will need to depend on upfront and milestone payments, and royalties.”
Analysts are cautiously optimistic as Glenmark will have some six compounds in Phase II only next year. Plus the fact that Glenmark has still not hit the market with a new drug weighs it down. “It has had no material success so far; they may make it big but it is difficult to say right now,” says a Mumbai-based analyst.
On his part, Saldanha argues that he has already recovered his R&D investments. “Till date, we have spent about $120 million in innovation research; against that we have got around $200 million as upfront and milestone payments.”
Says Nomura Financial Advisory and Securities in a recent report: “Glenmark has generated outlicensing income every year from 2004/05 to 2011/12 – except 2008/09. Average licensing income has been Rs 1 billion over the eightyear period. With seven development assets in the pipeline, we believe Glenmark will be able to continue to book licensing income, although the quantum and timing cannot be predicted.”
With standalone revenues of Rs 1,154.63 crore and consolidated revenues of almost Rs 3,000 crore, Glenmark hopes to hit the $1-billion mark soon. And if one of the NCEs sails through, the impact on the topline will be significant – a huge distance travelled for a company that clocked less than Rs 100 crore in the late 1990s. Certainly, Saldanha’s long drives on the Mumbai roads to his R&D headquarters are proving worthwhile.
WATCH A VIDEO
…
WATCH A VIDEO
Small molecule, API biz to be growth drivers for company: Kiran Mazumdar Shaw, Biocon
“We have focused on creating key growth drivers and have structured the company along those growth drivers,” says Kiran Mazumdar Shaw. (BCCL)…………. owner BIOCON
MY, DR AMC COMMENTS- BIOCON GREAT PERFORMANCE, U ARE EVERYWHERE
Kiran Mazumdar Shaw: We have focused on creating key growth drivers and have structured the company along those growth drivers. These growth drivers are beginning to deliver very strongly for us.
The first is our small molecule business vertical, which is about our historic statins and immunosuppressant’s API business. This particular vertical going forward is envisioned to go up the value chain along an ANDA path and we believe that will improve the quality of earnings in this particular vertical, which for a long time was under pressure because of commoditisation of statins.http://economictimes.indiatimes.com/opinion/interviews/small-molecule-api-biz-to-be-growth-drivers-for-company-kiran-mazumdar-shaw-biocon/articleshow/21975113.cms
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 | |
 |
|
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. |
|
- “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 | |
 |
|
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). |
|
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.
Big boost for Incyte as Jakafi shines in PhII
ruxolitinib
Top-line results from a Phase II trial showed that its JAK inhibitor Jakafi (ruxolitinib), in combination with Roche’s Xeloda (capecitabine), improved survival in some patients with recurrent or treatment refractory advanced pancreatic cancer
http://www.pharmatimes.com/Article/13-08-
22/Big_boost_for_Incyte_as_Jakafi_shines_in_PhII.aspx
Ruxolitinib (trade names Jakafi and Jakavi, by Incyte Pharmaceuticals and Novartis) is a drug for the treatment of intermediate or high-risk myelofibrosis, a type of bone marrow cancer.It is also being investigated for the treatment of other types of cancer (such as lymphomas and pancreatic cancer), for polycythemia vera, and for plaque psoriasis.
The phase III Controlled Myelofibrosis Study with Oral JAK Inhibitor-I (COMFORT-I) and COMFORT-II trials showed significant benefits by reducing spleen size, relieving debilitating symptoms, and improving overall survival.
Mechanism of action
Ruxolitinib is a Janus kinase inhibitor with selectivity for subtypes 1 and 2 of this enzyme.
Side effects
Immunologic side effects have included herpes zoster (1.9%) and case reports of opportunistic infections.[10] Metabolic side effects have included weight gain (7.1%). Laboratory abnormalities have included alanine transaminase (ALT) abnormalities (25.2%), aspartate transaminase (AST) abnormalities (17.4%), and elevated cholesterol levels (16.8%).
Legal status
In November 2011, ruxolitinib was approved by the USFDA for the treatment of intermediate or high-risk myelofibrosis based on results of the COMFORT-I and COMFORT-II Trials.
Some analysts believe this to be a potential blockbuster drug.[3] As of the end of March 2012, and according to an Incyte spokesman, approximately 1000 physicians had prescribed the drug in the United States, out of a total 6500 hematologists and oncologists nationwide.
The US Food and Drug Administration had approved Incyte’s Jakafi (ruxolitinib) to treat patients with the bone marrow disease myelofibrosis (MF). Jakafi is the first and only drug granted license specifically for the treatment of the rare blood cancer.
Jakafi approved by FDA to treat rare bone marrow disease
Posted By Edward Su On November 17th, 2011
MF is a rare, potentially life-threatening blood cancer with limited treatment methods. Patients with the bone marrow disoder, characterized by bone marrow failure, enlarged spleen (splenomegaly), suffer from the symptoms of fatigue, night sweats and pruritus, poor quality of life, weight loss and shortened survival. The US drug firm Incyte estimates the disease affects about 16,000-18,500 people in the USA. Currently, the disease is treated with chemotherapy or bone marrow transplant.
Incyte’s Jakafi, the first drug to reach market from the Wilmington-based drug company, was approved by the FDA as a twice-a-day pill for the treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF. The US regulators reviewed Jakafi under its priority review program for important new therapies.
The approval of Jakafi was based on the results from two clinical studies involved 528 patients with the disease. Patients in the Jakafi treatment arm experienced a significant reduction in the size of their spleen as well as a 50 percent decrease in symptoms, including pain, discomfort and night sweats.
Jakafi, generically known as ruxolitinib, works by blocking JAK1 and JAK2 enzymes associated with the disease. The company has co-developed the drug with Novartis as part of their collaboration signed in 2009. The Swiss drug firm has the rights to market Jakafi in other countries.
“The availability of Jakafi is a significant medical advancement for people living with myelofibrosis, a debilitating disease,” said Paul A. Friedman, M.D., President and Chief Executive Officer of Incyte. “This milestone marks a tremendous achievement for Incyte because a scientific discovery from our research laboratories has become the first JAK inhibitor to reach the market and provide a clinical benefit to patients.”
Richard Pazdur, director of the Office of Hematology and Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said that Jakafi “represents another example of an increasing trend in oncology where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways”.
Incyte says Jakafi will be available next week, and the drug will cost $7,000 per month, or $84,000 for a year’s supply for insured patients. The company plans to provide Jakafi free to uninsured patients and will offer co-pay assistance to patients with financial need.
(JAK1, JAK2) inhibitor, developed by the Incyte Corporation, trade name Jakafi.
Ruxolitinib synthetic route as shown below. 4 – bromo-pyrazole ( 1 ) with ethyl vinyl ether ( 2 ) to protect, and then with a Grignard reagent to a halogen – exchanged with isopropyl magnesiumpinacol ester ( 3 ) quenching to obtain 4 . Compound 5 is obtained consisting of hydrogen is protected 6 , and then with a boronic acid ester 4 Suzuki coupling occurs under acidic conditions after removal of the protecting group pyrazolyl 7 , 7 and α, β-unsaturated aldehyde 8 chiral catalyst 9 of under the catalysis of asymmetric Michael addition to give ( R ) -10 (90% EE). ( R) -10 , after reaction with ammonia to obtain an imine oxidation with iodine nitrile 11 , respectively, with different conditions for the final removal of the protecting group to afford Ruxolitinib.
FDA Accepts Nuvo’s New Drug Application for Review
Nuvo Research Inc. announced that its U.S. licensee for PENNSAID@ (diclofenac sodium topical solution) 1.5% w/w and PENNSAID 2% (diclofenac sodium topical solution) 2% w/w,
Mallinckrodt has advised that the U.S. Food and Drug Administration has accepted for filing and review the New Drug Application (NDA) for PENNSAID 2% submitted by Mallinckrodt on August 7, 2013.
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.
Ajay Piramal’s 20-20 game planThree years after selling its generics business to Abbott, the group is ready with a new strategy on becoming a $20-billion company by 2020
Twenty is an important number for Ajay Piramal, founder of thePiramal Group. Whether it is the target of 20 per cent annual growth or the goal of taking market capitalisation to $20 billion by 2020, the number is key in his scheme of things.
READ ALL AT
New Drug Approvals 