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Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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, 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...... , 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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Every fifth FDA Warning Letter includes deficiencies regarding Equipment


Every fifth FDA Warning Letter includes deficiencies regarding Equipment

The considered period from 2012 until the first quarter of 2014 pertains to both companies in and outside of the United States.

None of the 19 mentioned warning letters is solely due to deficiencies regarding equipment. However, the big picture shows the lack of understanding of FDA requirements relative to used production equipment. In almost every case there are references

to violations against requirements defined in 21 CFR 211.67 (equipment cleaning and maintenance),

such as the absence of a maintenance system or a maintenance system that doesn’t fulfill the requirements.

In one case scratches and rust in production boilers were found. In another case the authority found

obvious defects with regard to the condition of the equipment, and in addition objected to the complete

lack of plans for maintenance and maintenance/cleaning of the production building.

The routine calibration was found to be insufficient in another case, and records of calibration work carried out were even missing completely.



GMP News: Endotoxin Testing Recommendations for Single-Use Intraocular Ophthalmic Devices



Endotoxin Testing Recommendations for Single-Use Intraocular Ophthalmic Devices

FDA published a draft Guideline on Endotoxin Testing Recommendations for Single-Use Intraocular Ophthalmic Devices. It is a result of FDAs activities to reduce the outbreaks of Toxic Anterior Segment Syndrome (TASS). Read more here.,9092,Z-MLM_n.html


Related to several outbreaks of Toxic Anterior Segment Syndrome (TASS) in the past, the U.S. Food and Drug Administration and other government and professional organizations started a collaboration to monitor rare eye condition associated with cataract surgery to help industry develop tools for improving safety of eye surgery medical devices. (see FDA News Release December 2011).

Now the FDA published a Draft Guidance for Industry and for Food and Drug Administration Staff on Endotoxin Testing Recommendations for Single-Use Intraocular Ophthalmic Devices. Because some of the national outbreaks of TASS have been associated with endotoxin, this guidance document was developed to notify manufacturers of the recommended endotoxin limit for the release of intraocular devices and single-use intraocular ophthalmic surgical instruments/accessories in an effort to mitigate future Toxic Anterior Segment Syndrome (TASS) outbreaks. The document provides recommendations for endotoxin limits as well as endotoxin testing to manufacturers and other entities involved in submitting premarket applications (PMAs) or premarket notification submissions [510(k)s] for different categories of intraocular devices to aid in the prevention of future outbreaks of TASS.

The recommendations made in this guidance are applicable to devices used within the eye, either as permanent implants or as single-use devices used in intraocular surgery. These include:

A. Intraocular Fluids (21 CFR 886.4275, Class III), including

  • Intraocular fluid (LWL)
  • Viscoelastic surgical aid (LZP)

B. Anterior Segment Solid Devices

1.Intraocular lenses (21 CFR 886.3600, Class III), including

  • Intraocular lenses (HQL)
  • Multifocal intraocular lenses (MFK)
  • Phakic intraocular lenses (MTA)
  • Toric intraocular lenses (MJP)
  • Accommodative intraocular lenses (NAA)
  • Implantable miniature telescope (NCJ)
  • Iris reconstruction lenses (NIZ)

2. Capsular tension ring devices (Class III), including

  • Endocapsular rings (MRJ)

3. Glaucoma devices

  • Aqueous shunts (21 CFR 886.3920, Class II), including
    – Eye valve implant (KYF)
  • Other glaucoma devices (Class III)
    – Intraocular pressure lowering implants (OGO)

4. Phacofragmentation systems (21 CFR 886.4670, Class II), specifically the accessories of irrigation/aspiration sleeves and tubing (HQC)

  • Posterior Segment Solid Devices (Class III)
  • Retinal prostheses (NBF)

Please be aware of the Endotoxin and Pyrogen Testing Conference – Part of PharmaLab 2014 on 19-20 November 2014 in Düsseldorf/Neuss, Germany

Final ICH M7 Guideline on Genotoxic Impurities published


GMP News: Final ICH M7 Guideline on Genotoxic Impurities published,8500,S-QSB_n.html


On on 15 July 2014, the ICH issued the guideline M7 “Assessment and Control of DNA reactive (mutagenic) Impurities in Pharmaceuticals to limit Potential Carcinogenic Risk” as Step 4 document. in In the last step of the ICH process (Step 5) this guideline now has to be implemented in the national regulations in the three ICH regions Europe, United States and Japan. The final M7 Guideline was published exactly 17 months after the release of the draft consensus guideline (Step 2) in February 2013, where it could be commented in a 6-month period.

The guideline comprises information, how impurities in pharmaceutical products relative to their genotoxic potential have to be evaluated with the analysis of structure-activity relationships and how the critical toxicological threshold (threshold of toxicological concern TTC) has to be determined. In the individual chapters, some highly complex issues and scenarios are covered – as, for instance, the question why potentially genotoxic substances with similar molecular structure and probably the same mechanism of action should still not be combined for the calculation of the TTC. Another problem the Guideline tries to clarify is the different values of the TTC, depending on the duration of the use of the medicinal product.

The last section of the document contains a statement of the ICH, that due to its complexity the guideline has to be implemented in the respective national rules and regulations after 18 months only. However, the following exceptions apply to some requests:

  • For the implementation of Ames tests the specifications of M7 have to be applied immediately. However, the Ames tests carried out before release of M7 need not be repeated.
  • The development programmes having started phase 2b/3 prior to publication of M7 can be continued. The requirements for the execution of two quantitative analyses of structure-activity relations (section 6), for impurity assessment (section 5) and for the documentation (section 9) do not have to be considered, though.
  • For a new marketing authorisation application which does not include the phase 2b/3 clinical trials, compliance with the aforementioned points is expected until 36 months after the publication of M7.

Compared to the previous Guideline version (Step 2) it now contains changes, clarifications and precisions in several parts. For a more detailed analysis of the new M7 Guideline please see one of our next newsletters.

The ECA will conduct the Impurities Forum 2014in Berlin, where a complete day will be dedicated to the implementation of Genotoxic Impurities ICH M7. On another day you will cover the implementation of Elemental Impurities ICH Q3D – whose finalisation is scheduled for September. The days can be booked separately or alternatively the entire 3 days of the Impurities Forum.

Deoxyribonucleic acid (DNA) synthesis

Deoxyribonucleic acid (DNA) synthesis is a process by which copies of nucleic acid strands are made. In nature, DNA synthesis takes place in cells by a mechanism known as DNA replication. Using genetic engineering and enzyme chemistry, scientists have developed man-made methods for synthesizing DNA. The most important of these is poly-merase chain reaction (PCR). First developed in the early 1980s, PCR has become a multi-billion dollar industry with the original patent being sold for $300 million dollars.

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DNA synthesis

From Wikipedia, the free encyclopedia

DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. The term DNA synthesis can refer to any of the following in various contexts:


DNA replication

In nature, such molecules are created by all living cells through the process of DNA replication, with replication initiator proteins splitting the existing DNA of the cell and making a copy of each split strand, with the copied strands then being joined together with their template strand into a new DNA molecule. Various means also exist to artificially stimulate the replication of naturally occurring DNA, or to create artificial gene sequences.

Polymerase chain reaction

polymerase chain reaction is a form of enzymatic DNA synthesis in the laboratory, using cycles of repeated heating and cooling of the reaction for DNA melting and enzymatic replication of the DNA.

Gene synthesis

Artificial gene synthesis is the process of synthesizing a gene in vitro without the need for initial template DNA samples. In 2010 J. Craig Venter and his team were the first to use entirely synthesized DNA to create a self-replicating microbe, dubbed Mycoplasma laboratorium.[1]

Oligonucleotide synthesis

Oligonucleotide synthesis is the chemical synthesis of sequences of nucleic acids. The process has been fully automated since the late 1970s and can be used to form desired genetic sequences as well as for other uses in medicine and molecular biology.

Base pair synthesis

Recent research has demonstrated the possibility of creating new nucleobase pairs in addition to the naturally occurring pairs, A-T (adenine – thymine) and G-C (guanine –cytosine). A third base pair could dramatically expand the number of amino acids that can be encoded by DNA, from the existing 20 amino acids to a theoretically possible 172.[1]


  1. Jump up to:a b Fikes, Bradley J. (May 8, 2014). “Life engineered with expanded genetic code”San Diego Union Tribune. Retrieved 8 May 2014.

FDA Grants breakthough therapy designation for InterMune’s pirfenidone 吡非尼酮 ピルフェニドン 吡非尼酮

Pirfenidone2DACS.svgMolecule of the Week: Pirfenidone

ピルフェニドン,  吡非尼酮

Esbriet (EU, US),  Pirespa (ピレスパ, Japan), Pirfenex (India), Etuary(China)

F647, S-7701,  AMR-69, Deskar

CAS Number:53179-13-8

FOR….  Idiopathic pulmonary fibrosis (IPF)


PMDA, OCT 16 2008 Pirespa®

EMA , FEB28 2011 Esbriet®)

FDA OCT 15 2014 Esbriet®)

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown origin. Drug companies have sought a treatment for IPF for many years. Several concentrated on developing pirfenidone, including InterMune of Brisbane, CA; Shionogi of Osaka, Japan; and GNI Group of Tokyo. The drug was first approved for treatment in China in 2008, followed by approvals in India in 2010, Europe in 2011, Canada in 2012, and the United States and Mexico in 2014.

In August 2014, before pirfenidone was approved by the US Food and Drug Administration, Roche (Basel, Switzerland) paid US$8.3 billion to acquire InterMune. The product is expected to add US$1.6 billion to Roche’s annual sales by 2020.

More about this molecule from CAS, the most authoritative and comprehensive source for chemical information.

REGULATORY….        US (NDA), EU (approved), China (approved), Japan (approved)
Originator:  Marnac, Inc.
Developer:  InterMune, Shionogi
Sales:$70.3 million (2013),$130−$140 million (expected 2014)

InterMune has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for its pirfenidone, an investigational treatment for adult patients with idiopathic pulmonary fibrosis (IPF).

The company had submitted a new drug application to the FDA in May for pirfenidone and noted a target FDA review of six months under the Prescription Drug User Fee Act.

InterMune’s Esbriet (Pirfenidone), an orally active, anti-fibrotic agent that inhibits the synthesis of TGF-beta, is currently seeking approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with idiopathic pulmonary fibrosis (IPF), a progressive and eventually fatal lung disease. On May 27, 2014 Brisbane, California-based InterMune resubmitted its pirfenidone New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in response to a Complete Response Letter (CRL) received in May 2010.

On July 17, 2014, Pirfenidone was awardedbreakthrough therapy designation by the FDA. If the FDA approves it within six months, Pirfenidonecould be sold in the United States in the first quarter of 2015.

InterMune licensed pirfenidone from Marnac, Inc. and its co-licensor, KDL GmbH, in 2002 and in 2007 purchased from Marnac and KDL the rights to sell the compound in the United States, Europe and other territories except in Japan, Taiwan and South Korea where rights to the molecule were licensed by Marnac and KDL to Shionogi & Co. Ltd. of Japan.

Pirfenidone is the only commercially approved drug for the treatment of mild to moderate idiopathic pulmonary fibrosis(IPF) in the world and is now approved in the EU, Norway, Iceland, Canada, Japan, China, India, South Korea, Argentina and Mexico.

In Japan it is marketed as Pirespa (ピレスパ) by Shionogi & Co since 2008.

In 2011 it was approved for use in Europe for IPF under the trade nameEsbriet, where the drug is priced in the range of $33,000 to $47,000 per year, depending on the country.

In October 2010, the Indian Company Cipla launched it as Pirfenex.

In September 2011, the China Food and Drug Administration  (CFDA) granted Shanghai genomics (上海睿星基因技术有限公司), the wholly owned subsidiary of Japan-based GNI Group Ltd,  with approval of pirfenidone (F647) under the trade name Etuary (艾思瑞) in China. Etuary (pirfenidone, F647) was manufactured by GNI’s affiliate Beijing Continent Pharmaceuticals (北京康蒂尼药业有限公司).

The U.S. Food and Drug Administration (FDA) declined to approve pirfenidone in 2010 because InterMune’s two previous Phase III studies ( known as CAPACITY) of Esbriet brought mixed results, insisting on another Phase III trial after an advisory committee recommended approval of the drug, but by a 9–3 margin.

In February 2014, InterMune said its latest Esbriet the phase III “Ascend” study of 555 IPF patients showed strong and positive results. Pirfenidone improved lung function and slowed the progression of IPF — meeting its primary endpoint of reducing the risk of a meaningful decline in forced vital capacity compared to the placebo group from baseline at week 52.

Pirfenidone is still under investigation for the treatment of IPF in the United States and has not been approved by the FDA.

Esbriet (Pirfenidone) is the only product marketed by InterMune.  Revenue from the drug was about $70.3 million in 2013. The company recorded Esbriet sales of $30.3 million in the first quarter of 2014. Esbriet sales in 2014 are expected in the range of $130−$140 million.

Pirfenidone (INNBAN) is a drug developed by several companies worldwide, including InterMune Inc., Shionogi Ltd., and GNI Group Ltd., for the treatment of idiopathic pulmonary fibrosis (IPF). In 2008, it was first approved in Japan for the treatment of IPF after clinical trials, under the trade name of Pirespa by Shionogi & Co. In October 2010, the Indian Company Cipla launched it as Pirfenex. In 2011, it was approved for use in Europe for IPF under the trade name Esbriet.[2] The proposed trade name in the US is also Esbriet. In September 2011, the Chinese State Food and Drug Administration provided GNI Group Ltd with new drug approval of pirfenidone in China,[3] and later manufacture approval in 2013 under the trade name of Etuary.[4]

In 2014 it was approved in México under the name KitosCell LP, indicated for pulmonary fibrosis and liver fibrosis.[5] There is also a topical form created for the treatment of abnormal wound healing processes.[6]

Mechanism of action

Pirfenidone has well-established antifibrotic and anti-inflammatory properties in various in vitro systems and animal models offibrosis.[7] A number of cell-based studies have shown that pirfenidone reduces fibroblast proliferation,[8][9][10][11] inhibits TGF-βstimulated collagen production[8][9][12][13][14] and reduces the production of fibrogenic mediators such as TGF-β.[10][13] Pirfenidone has also been shown to reduce production of inflammatory mediators such as TNF-α and IL-1β in both cultured cells and isolatedhuman peripheral blood mononuclear cells.[15][16] These activities are consistent with the broader antifibrotic and anti-inflammatoryactivities observed in animal models of fibrosis.

Preclinical studies

Studies in models of fibrosis

In animal models, pirfenidone displays a systemic antifibrotic activity and has been shown to reduce biochemical and histopathological indices of fibrosis of the lung, liver, heart and kidney.[7]

Pirfenidone demonstrates a consistent antifibrotic effect in several animal models of pulmonary fibrosis.[17][18][19][20][21] Of these, the bleomycin model is the most widely used model of pulmonary fibrosis. In this model, bleomycin administration results in oxidative stress and acute inflammation, with the subsequent onset of pulmonary fibrosis in a number of animal species including the mouse and hamster.[7][19] Numerous studies have demonstrated that pirfenidone attenuates bleomycin-induced pulmonary fibrosis.[17][18][21][22][23][24] One study investigated the effect of pirfenidone over a 42-day period after repeated bleomycin administration.[18] Administration of pirfenidone minimised early lung oedema and pulmonary fibrosis when treatment was initiated concurrently with lung damage. This study evaluated pulmonary protein expression and found pirfenidone treatment normalised expression of pro-inflammatory and fibrogenic proteins. Similar reductions in pulmonary fibrosis were observed when pirfenidone treatment was delayed until pulmonary fibrosis was established and progressing,[17] i.e. when administered in a therapeutic as opposed to a prophylactic treatment regimen.

The antifibrotic effect of pirfenidone has been further established in animal models of cardiac,[25][26][27] renal,[28][29] and hepatic[8][30][31] fibrosis. In these models, pirfenidone demonstrated a consistent ability to reduce fibrosis and the expression of fibrogenic mediators.


Pirfenidone is administered orally. Though the presence of food significantly reduces the extent of absorption, the drug is to be taken after food, to reduce the nausea and dizziness associated with the drug. The drug is around 60% bound to plasma proteins, especially to albumin.[32] Up to 50% of the drug is metabolized by hepatic CYP1A2 enzyme system to yield 5-carboxypirfenidone, the inactive metabolite. Almost 80% of the administered dose is excreted in the urine within 24 hours of intake.[32]

Clinical trials in Idiopathic Pulmonary Fibrosis (IPF)

The clinical efficacy of pirfenidone has been studied in three Phase IIIrandomizeddouble-blindplacebo-controlled studies in patients with IPF.[33][34]

The first Phase III clinical trial to evaluate the efficacy and safety of pirfenidone for the treatment of patients with IPF was conducted in Japan. This was a multicentre, randomised, double-blind, trial, in which 275 patients with IPF were randomly assigned to receive pirfenidone 1800 mg/day (110 patients), pirfenidone 1200 mg/day (56 patients), or placebo(109 patients), for 52 weeks. Pirfenidone 1800 or 1200 mg/day reduced the mean decline in vital capacity from baseline to week 52 compared with placebo. Progression-free survival was also improved with pirfenidone compared with placebo.[33]

The CAPACITY (004 & 006) studies were randomizeddouble-blindplacebo-controlledPhase III trials in eleven countries across Europe, North America, and Australia.[34] Patients with IPF were randomly assigned to treatment with oral pirfenidone or placebo for a minimum of 72 weeks.[34] In study 004, pirfenidone reduced decline in forced vital capacity(FVC) (p=0.001). Mean change in FVC at week 72 was –8.0% (SD 16.5) in the pirfenidone 2403 mg/day group and –12.4% (SD 18.5) in the placebo group, a difference of 4.4% (95% CI 0.7 to 9.1). Thirty-five (20%) of 174 versus 60 (35%) of 174 patients, respectively, had an FVC decline of at least 10%. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0.501). Mean change in FVC at week 72 was –9.0% (SD 19.6) in the pirfenidone group and –9.6% (19.1) in the placebo group. The difference between groups in change in predicted FVC at week 72 was not significant (0.6%, 95% CI –3.5 to 4.7).[34]

In May, 2014, the results of ASCEND studies (Phase III) were published. ASCEND is a randomized, double-blind, placebo-controlled trial that enrolled 555 patients. The results confirmed observations from previous clinical studies that pirfenidone significantly reduced IPF disease progression as measured by change in percent predicted forced vital capacity (FVC) from Baseline to Week 52 (rank ANCOVA p<0.000001). In addition, significant treatment effects were shown on both of the key secondary endpoints of six-minute walk test distance change (p=0.0360) and progression-free survival (p=0.0001). A pre-specified analysis of the pooled population (N=1,247) from the combined ASCEND and CAPACITY studies (taking CAPACITY mortality data through Week 52) showed that the risk of all-cause mortality was reduced by 48% in the pirfenidone group compared to the placebo group (HR=0.52, log rank p=0.0107)[35] .

A review by the Cochrane Collaboration concluded that pirfenidone appears to improve progression-free survival and, to a lesser effect, pulmonary function in patients with IPF.[36]Randomised studies comparing non-steroid drugs with placebo or steroids in adult patients with IPF were included. Four placebo-controlled trials of pirfenidone treatment were reviewed, involving a total of 1155 patients. The result of the meta-analysis showed that pirfenidone significantly reduces the risk of disease progression by 30%. In addition, meta-analysis of the two Japanese studies confirmed the beneficial effect of pirfenidone on the change in VC from baseline compared with placebo.[36]


In Europe, pirfenidone is indicated for the treatment of mild-to-moderate idiopathic pulmonary fibrosis. It was approved by the European Medicines Agency (EMA) in 2011.[2] In October 2008, it was approved for use in Japan, in India in 2010, and in China in 2011 (commercial launch in 2014).

In Mexico it has been approved on a gel[37] form for the treatment of scars and fibrotic tissue [38] and has proven to be effective in the treatment of skin ulcers, such as diabetic foot.

Other research done shows that Pirfenidone can be an effective anti-fibrotic treatment [39] for chronic liver fibrosis.[40]

Regulatory progress

In May 2010, the U.S. Food and Drug Administration declined to approve the use of pirfenidone for the treatment of idiopathic pulmonary fibrosis, requesting additional clinical trials.[41] In December 2010 an advisory panel to the European Medicines Agency recommended approval of the drug.[2] In February 2011, the European Commission (EC) has granted marketing authorisation in all 27 EU member states and China FDA granted approval in September, 2011. Afterwards, a randomised, Phase III trial (the ASCEND study) has been completed in the U.S. in 2014.[42] Application for the U.S. regulatory approval is expected in 2014.

In Mexico it has been approved in gel for the treatment of chronic wounds and skin injuries and the oral form it is approved for the treatment of Pulmonary Fibrosis and Liver fibrosis.

Pirfenidone is a non-peptide synthetic molecule with a molecular weight of 185.23 daltons. Its chemical elements are expressed as CI2HHNO, and its structure is known. The synthesis of pirfenidone has been worked out. Pirfenidone is manufactured and being evaluated clinically as a broad- spectrum anti-fibrotic drug. Pirfenidone has anti-fibrotic properties via: decreased TNF-α expression, decreased PDGF expression, and decreased collagen expression. Several pirfenidone Investigational New Drug Applications (INDs) are currently on file with the U.S. Food and Drug Administration. Phase II human investigations have been initiated or completed for pulmonary fibrosis, renal glomerulosclerosis, and liver cirrhosis. There have been other Phase II studies that used pirfenidone to treat benign prostate hypertrophy, hypertrophic scarring (keloids), and rheumatoid arthritis.

One important use of pirfenidone is known to be providing therapeutic benefits to patients suffering from fibrosis conditions such as Hermansky-Pudlak Syndrome (HPS) associated pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF). Pirfenidone demonstrates a pharmacologic ability to prevent or remove excessive scar tissue found in fibrosis associated with injured tissues including that of lungs, skin, joints, kidneys, prostate glands, and livers. Published and unpublished basic and clinical research suggests that pirfenidone may safely slow or inhibit the progressive enlargement of fibrotic lesions, remove pre-existing fibrotic lesions, and prevent formation of new fibrotic lesions following tissue injuries.

It is understood that one mechanism by which pirfenidone exerts its therapeutic effects is by modulating cytokine actions. Pirfenidone is a potent inhibitor of fibrogenic Attorney Docket: 30481/30033 A cytokines and TNF-α. It is well documented that pirfenidone inhibits excessive biosynthesis or release of various fibrogenic cytokines such as TGF-βl, bFGF, PDGF, and EGF. Zhang S et ah, Australian New Eng. J. OphthaL, 26:S74-S76 (1998). Experimental reports also show that pirfenidone blocks the synthesis and release of excessive amounts of TNF-α from macrophages and other cells. Cain et al., Int. J. Immunopharm. , 20:685-695 (1998).

Pirfenidone has been studied in clinical trials for use in treatment of IPF. Thus, there is a need for a synthetic scheme that provides pirfenidone having sufficient purity as an active pharmaceutical ingredient (API) and involves efficient and economical processes. Prior batches of pirfenidone were shown to have residual solvent traces of ethyl acetate (e.g., about 2 ppm) and butanol.

improved process for preparing pirfenidone. The process involves using a cuprous oxide catalyst to couple 5-methyl-2-pyridone and bromobenzene in an organic solvent. Without intending to be limited by any particular theory, it is believed that the purity of the bromobenzene is important, as amounts of a dibromobenzene impurity in the bromobenzene can lead to dimer-type byproducts, which can complicate the Attorney Docket: 30481/30033 A purification of the resulting pirfenidone.

These dimer-type byproducts cannot be in a product intended as to be marketed as an active pharmaceutical ingredient (API), and they are difficult to remove from the intended pirfenidone product. Thus, the bromobenzene used in the disclosed processes preferably have an amount of dibromobenzene of less than about 0.15% by weight or molar ratio, and more preferably less than about 0.1% by weight or molar ratio or less than 0.05% by weight or molar ratio.


Coupling of Bromobenzene and 5-Methyl-2-pyridone

5-Methyl-2-pyridone (1.0 equivalents), potassium carbonate (1.2 equivalents), copper(I) oxide (0.05 equivalents), bromobenzene (1.8 equivalents, with a purity of at least 98%, preferably at least 99%, or at least 99.8%), and dimethyl formamide (2.0 volume equivalents) were charged into an inert reactor. This mixture was heated to 125° C. for about 18 hours. A sample was collected and analyzed for reaction completion. If reaction completion was not satisfactory, the reaction was maintained at 125° C. for an additional 2 hours. The reaction mixture was then cooled to 25° C. to form a slurry.

The resulting slurry was filtered in a Nutsche filter in order to remove salts. The filter cake was rinsed twice with toluene. The mother liquor and process liquor were collected in Vessel (A). A sodium chloride solution (15%) was charged into the product solution. The pH was adjusted to greater than or equal to 11.5 using a 32% sodium hydroxide solution. The mixture was then agitated. After agitation was stopped, the mixture was allowed to settle for at least 30 minutes to allow the two phases to separate. The organic layer was separated and the aqueous layer was extracted with toluene. The toluene extraction was added to the organic layer. The combined organics were then washed with a 15% sodium chloride solution and agitated for at least 15 minutes. The agitation was stopped and the layers were allowed to settle for at least 30 minutes. The organic layer was separated from the aqueous layer, and then carbon treated by flowing it through Zeta Carbon filters for 2 hours at 20-25° C. The carbon treated solution was then concentrated under vacuum to remove all water and much of the toluene.

Heptanes were then added to the concentrated solution, and it was heated to about 80° C. The solution was slowly cooled to about 0° C. over at least 7 hours. The pirfenidone precipitated out of the solution, was collected by filtration and dried, using a Nutsche filter/drier. The pirfenidone cake was washed twice with a mixture of toluene and heptanes (at 0° C.), then vacuum dried at a temperature of about 42° C. The crude pirfenidone was formed in about 85% yield.

Crystallization of Pirfenidone

Pirfenidone, a 32% hydrochloride solution, and deionized water were charged in an inert reactor. The mixture was heated to about 45° C., then a 32% sodium hydroxide solution was titrated into the mixture until the pH was at least 11. The temperature of the mixture was maintained at about 45° C. during the titration. Upon reaching the pH of at least 11, the mixture was then cooled slowly to 5° C., over the course of at least 2 hours. The pirfenidone crystallized from this cooled solution and was isolated in a Nutsche filter/drier. The pirfenidone cake was washed twice with deionized water (at 5° C.). The pirfenidone was then vacuum dried in the filter/drier at a temperature of about 45° C. The pirfenidone was also milled through a loop mill in order to reduce the particle size to less than 150 μm.

The resulting pirfenidone was then analyzed and the only residual solvents observed were toluene and heptanes at about 10 to 13 ppm. No ethyl acetate or butanol was detected in the pirfenidone. The amount of bis-conjugate in the purified pirfenidone was 0.03% or less. All impurities of the purified pirfenidone were less than about 0.05%.


Idiopathic pulmonary fibrosis (IPF) is a rare disease of unknown etiology that is characterised by progressive fibrosis of the interstitium of the lung, leading to decreasing lung volume and progressive pulmonary insufficiency. IPF is a well-recognised and distinct interstitial lung disease with unique histopathologic, clinical and prognostic characteristics (American Thoracic Society/European CHMP assessment report EMA/CHMP/115147/2011 Page 6/84 Respiratory Society (ATS/ERS), 2000; ATS/ERS, 2002). IPF is most prevalent in middle aged and elderly patients, and usually presents between the ages of 40 and 70 years (ATS/ERS 2000). Many patients experience long periods of relative stability but acute episodes of rapid respiratory deterioration may result in death. Most patients die of respiratory failure. Median survival, as described across a range of studies, is only 2 to 5 years after diagnosis. Despite continued improvement in the understanding of the pathogenesis of IPF, there remain no approved therapies or medications in the European Union, nor has the prognosis been substantially altered over the last two decades.

Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is an immunosuppressant (ATC code L04AX05). The mechanism of action has not been fully established. However, existing data suggest that pirfenidone exerts both antifibrotic and anti-inflammatory properties.

Esbriet is presented as hard gelatin capsules containing 267 mg of pirfenidone as the active substance. The capsules have a blue opaque body and gold opaque cap imprinted with “InterMune 267 mg” in brown ink and contain a white to pale yellow powder.

Pirfenidone is chemically designated as 5-Methyl-1-phenyl-2-1(H)-pyridone and has the following structure: Pirfenidone is white to pale yellow powder. It is freely soluble in methanol, ethyl alcohol, acetone, and chloroform, sparingly soluble in 1.0 N HCl, water and 1.0 N NaOH. Dissolution in water is pH independent. Pirfenidone does not possess any chiral centres and therefore is not subject to stereoisomerism. The acid dissociation constant, pKa, was calculated to be (-0.2 ± 0.6) and is consistent with the observation that pirfenidone behaves as a neutral compound in aqueous environment. The substance is not hygroscopic. Melting range is between 106o C and 112o C. Pirfenidone primarily exists in a single stable crystalline form designated as Form A. Sufficient evidence was provided to prove that the form A is obtained by the utilised manufacturing process. Particle size distribution of the active substance is controlled

The drug substance specification includes tests for physical appearance, identification (IR and UV), water content (Karl Fisher), residue on ignition, sulphated ash, heavy metals, related substances (HPLC), assay (HPLC), loss on drying, particle size distribution and microbiological purity (total aerobic microbiological count, total combined yeast and mould count, specified microorganisms: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella spp.). ……….



 fibrotic diseases such as renal fibrosis and cirrhosis, myocardial fibrosis is a class of serious harm to human life and health of important diseases, as well as people living with global industrialization, changes in diet, the incidence of fibrotic diseases is gradually increased correspondingly, many domestic and foreign scholars fibrosis links from chemical compounds, natural compounds, biologics, gene therapy and other different areas of a large number of anti-fibrotic compounds studied. So far, the pyridone compound has been found that a class of effective antifibrotic compound.

U.S. Patent US3839346, US4052509A discloses a pyridone compound of structural formula are available (O) of the general formula 1 – mono-substituted phenyl-5 – methyl -2 (1H)-pyridone.

Image not available. View PDF Wherein the number of the substituent R is 0 or 1, R represents a nitro substituent species, a chlorine atom, an alkyl group, a methoxy group; such pyridones have anti-inflammatory, antipyretic, lower serum uric acid levels, pain and so on.

In addition, U.S. Patent (US3839346) discloses a process approach is to formula (IV), 5 – methyl -2 (1H)-pyridone as raw materials, and formula (V) monosubstituted phenyl iodide, the reaction and generating (O) type 1 – benzene substituted-5 – methyl -2 (1H) pyridone compound, the reaction process is as follows: Image not available. View PDF Chinese Patent (1086514A) discloses a process for preparing formula (IV) method is based on formula (IV) 1 – nitrile-1 – butene and (VII) formula 1,1 – bis dimethyl ether as amine starting material, the reaction of (VIII) Formula 1 – dimethylamine -2 – methyl-4 – cyano-1 ,3 – butadiene intermediates in acid conditions and then cyclized to generate ( IV ‘) formula and formula (IV) of the desired compound, the reaction process is as follows:Image not available. View PDF Although these methods to some of the previous methods were further improved, but there are still formula (VI) compound is unstable, prone to aggregation, (VII) is not easy to obtain the compound of formula shortcomings.

On the other hand, ORGANIC SYNTHESES Vol.78, 51 discloses the compound (II) Preparation of Compound (IV) method Image not available. View PDF

SUMMARY OF THE INVENTION For the above-mentioned disadvantages of the prior art, the present invention is one of the technical solution is to provide a class of anti-fibrosis effect, and organ and has a wide applicability antifibrotic pyridinone compound; technical solution of the present invention The second program is to provide an easy to use on the market too, and the starting material for production of stable molecules antifibrotic pyridone compound process method.


A Simple Synthesis of Pirfenidone (Esbriet,Pirespa,ピレスパ,Pirfenex, Etuary), InterMune's idiopathic pulmonary fibrosis Drug 特发性肺纤维化药物吡非尼酮(艾思瑞)的简单制备方法


By condensation of 5-methyl-2- (1H) -pyridone (I) with iodobenzene (II) by means of K2CO3 and Copper powder at reflux temperature.
Casta Lv r, J .; Blancafort, P .; Pirfenidone. Drugs Fut 1977, 2, 6,
 US 3839346; ZA 7309472

CA 1049411;. DE 2555411; US ​​3974281

WO2002085858A1 * Apr 19, 2002 Oct 31, 2002 Asahi Glass Co Ltd Process for producing purified piperidine derivative
WO2003014087A1 * Aug 6, 2002 Feb 20, 2003 Asahi Glass Co Ltd Process for preparation of 5-methyl-1-phenyl-2(1h) -pyridinone
WO2008147170A1 * May 29, 2008 Dec 4, 2008 Armendariz Borunda Juan Socorr New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same
1 * See also references of WO2010141600A2
2 * WU ET AL.: “Tissue distribution and plasma binding of a novel antifibrotics drug pirfenidone in rats“, ASIAN JOURNAL OF PHARMADYNAMIS AND PHARMACOKINETICS, vol. 6, no. 4, 2006, pages 351-356, XP002684997,
Hegde et al., “17. Pirfenidone (Idiopathic Pulmonary Fibrosis), Chapter 28 To Market, To Market-2008,” Ann Rep Med Chem, vol. 44 (2009).
2 Hegde et al., “17. Pirfenidone (Idiopathic Pulmonary Fibrosis), Chapter 28 To Market, To Market—2008,” Ann Rep Med Chem, vol. 44 (2009).
3 International Search Report from corresponding International Application No. PCT/US2010/037090, dated Mar. 1, 2011.
4 Ma et al., “Synthesis of pirfenidone,” Zhongguo Yiyao Gongye Zazhi, 37(6):372-373 as summarized in Liu et al., “Synthetic Approaches to the 2008 New Drugs,” Mini-Reviews in Medicinal Chemistry, 9:1655-75 (2009).
5 * Vogel, A., Practical Organic Chemistry, 3d ed., London, Longman Group, 1974, pp. 44-45 and 122-127.
6 Wu et al., Tissue distribution and plasma binding of a novel antifibrotics drug pifenidone in rats, Asian J. Pharmadynamics and Pharmacokinetics, 6(4):351-6 (2006).
7 Zhang et al., Pirfenidone reduces fibronectin synthesis by cultured human retinal pigment epithelial cells, Aust. N Z J Ophthalmol., 26 Suppl 1:S74-6 (1998).
WO2002085858A1 * Apr 19, 2002 Oct 31, 2002 Asahi Glass Co Ltd Process for producing purified piperidine derivative
WO2003014087A1 * Aug 6, 2002 Feb 20, 2003 Asahi Glass Co Ltd Process for preparation of 5-methyl-1-phenyl-2(1h) -pyridinone
WO2008147170A1 * May 29, 2008 Dec 4, 2008 Armendariz Borunda Juan Socorr New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same
1 * See also references of WO2010141600A2
2 * WU ET AL.: “Tissue distribution and plasma binding of a novel antifibrotics drug pirfenidone in rats“, ASIAN JOURNAL OF PHARMADYNAMIS AND PHARMACOKINETICS, vol. 6, no. 4, 2006, pages 351-356, XP002684997,


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Systematic (IUPAC) name
Clinical data
Trade names Esbriet; Pirespa; Etuary
AHFS/ International Drug Names
Licence data EMA:Link
Legal status POM (UK)
Routes Oral
Pharmacokinetic data
Protein binding 50–58%[1]
Metabolism Hepatic (70–80% CYP1A2-mediated; minor contributions from CYP2C9,CYP2C19CYP2D6 andCYP2E1)[1]
Half-life 2.4 hours[1]
Excretion Urine (80%)[1]
ATC code L04AX05
PubChem CID 40632
ChemSpider 37115
KEGG D01583 Yes
Chemical data
Formula C12H11NO 
Mol. mass 185.22 g/mol



Salix Pharmaceuticals and Pharming receive FDA approval for Ruconest


  • Ruconest® is the first recombinant human C1 esterase inhibitor (rhC1INH) approved for use in patients with HAE.
  • rhC1INH and plasma-derived C1INH have an identical amino acid sequence. 18

The in vitro inhibitory potency of rhC1INH toward target enzymes is comparable with that of plasma-derived C1INH. 1, 6, 19

Ruconest® is the first recombinant human C1 esterase inhibitor (rhC1INH) developed and approved for the treatment of acute angioedema attacks in HAE patients. Use of a well-controlled transgenic platform for the production of Ruconest® ensures that product supply is virtually unlimited and avoids the risk of transmission of human blood-borne infections.

fda …..July 17, 2014 approved

Salix Pharmaceuticals and Pharming receive FDA approval for Ruconest
Salix Pharmaceuticals and Pharming have announced US Food and Drug Administration (FDA) approval of Ruconest for treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE).

Salix Pharmaceuticals and Pharming receive FDA approval for Ruconest

Salix Pharmaceuticals and Pharming have announced US Food and Drug Administration (FDA) approval of Ruconest for treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE).

The FDA has approved the company’s biologics licence application for Ruconest, a C1 esterase inhibitor [recombinant], based on a Phase III trial (RCT) that included an open-label extension (OLE) phase and is supported by results of two additional RCTs and two additional OLE studies.


read at



Salix Pharmaceuticals, Ltd.SLXP -1.30% and Pharming Group NV today announced that the Food and Drug Administration has approved RUCONEST® (C1 Esterase Inhibitor [Recombinant]) 50 IU/kg for the treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE). Because of the limited number of patients with laryngeal attacks, effectiveness was not established in HAE patients with laryngeal attacks.


“We are pleased that RUCONEST® provides the HAE community with another FDA-approved option for treating painful and debilitating HAE attacks,” said Anthony Castaldo, President of the Hereditary Angioedema Association (US HAEA), a non-profit patient services and research organization with a membership of over 5,000 HAE patients in the United States.


RUCONEST® is a recombinant C1 esterase inhibitor that can be administered by the patient after receiving training by a healthcare provider. HAE attacks stem from a deficiency of the C1 inhibitor protein in the blood. HAE is a rare inherited genetic condition that is often not properly diagnosed until later in a patient’s life as the symptoms of an attack can mirror someone experiencing an allergic reaction. Severe, painful swelling can occur at any time, which means most people suffering from HAE deal with the constant fear of when their next attack might surface and how that might impair their lives and those around them.


“Results in the pivotal clinical trial demonstrate RUCONEST® is a safe and effective option for the treatment of acute hereditary angioedema attacks,” said Dr. Marc Riedl of the US HAEA Angioedema Center at the University of California – San Diego and primary investigator of the phase III study. “At the US HAEA Angioedema Center, we strive to better the lives of those suffering from hereditary angioedema and part of that is ensuring patients have access to advanced treatments that have been proven to work in clinical trials. RUCONEST is an important addition to those treatment options.”


Sijmen de Vries, CEO of Pharming, said: “The approval of RUCONEST® in the US is a very significant milestone for Pharming. For many years we have strived to make RUCONEST® – the first recombinant replacement therapy for C1Inhibitor deficiency – available to the HAE patient community in the US, because we were aware of the great value and benefit this product adds to patients’ lives. Today we are proud to have achieved this goal in the US.”


“RUCONEST® is a much needed treatment option for patients suffering from acute attacks of hereditary angioedema. Until now, there hasn’t been an FDA approved recombinant C1 esterase inhibitor option to treat symptoms of HAE,” said Carolyn J. Logan, President and Chief Executive Officer of Salix. “The unpredictability of HAE can make patients feel uncertain about when their next attack might strike, which is why it is important to have a medicine that can be administered by the patient that resolves an attack. Salix is proud to make RUCONEST® available.”


The FDA approval of the Biologics License Application (BLA) for RUCONEST® for treatment of acute angioedema attacks in patients with HAE is based on a randomized, double-blind, placebo-controlled, phase III trial (RCT) which included an open-label extension (OLE) phase and is supported by the results of two additional RCTs and two additional OLE studies. The pivotal RCT and OLE studies analyzed the results from 44 subjects who experienced 170 HAE attacks. The primary efficacy endpoint was the time to beginning of symptom relief, assessed using patient-reported responses to two questions about the change in overall severity of their HAE attack symptoms after the start of treatment. These were assessed at regular time points for each of the affected anatomical locations for up to 24 hours. To achieve the primary endpoint, a patient had to have a positive response to both questions along with persistence of improvement at the next assessment time (i.e., the same or better response).


A statistically significant difference in the time to beginning of symptom relief was observed in the intent-to-treat population (n=75) between RUCONEST and placebo (p=0.031, log-rank test); the median time to beginning of symptom relief was 90 minutes for RUCONEST patients (n=44) and 152 minutes for placebo patients (n=31).


RUCONEST® is manufactured by Pharming Group NV in the Netherlands. Salix has licensed exclusive rights from Pharming to commercialize RUCONEST® in North America and market RUCONEST® for the treatment of acute HAE attack symptoms.


Salix currently plans on making RUCONEST® accessible to patients later in 2014.


RUCONEST® (C1 Esterase Inhibitor [Recombinant]) 50 IU/kgis an injectable medicine that is used to treat acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE). HAE is caused by a deficiency of the C1 esterase inhibitor protein, which is present in blood and helps control inflammation (swelling) and parts of the immune system. A shortage of C1 esterase inhibitor can lead to repeated attacks of swelling, pain in the abdomen, difficulty breathing and other symptoms. RUCONEST® contains C1 esterase inhibitor at 50 IU/kg.

When administered at the onset of HAE attack symptoms at the recommended dose, RUCONEST® works to return a patient’s C1-INH levels to normal range and quickly relieve the symptoms of an HAE attack with a low recurrence of symptoms.

RUCONEST® is the first and only plasma-free, recombinant C1-INH approval from the U.S. Food and Drug Administration (FDA) and was approved in July 2014.

About HAE

RUCONEST has been granted Orphan Drug designation by the FDA for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE). With RUCONEST now approved by the FDA, Salix believes this designation should provide seven years of marketing exclusivity in the United States.

Hereditary angioedema (HAE) is a genetic condition occurring between 1 in 10,000 to 1 in 50,000 people. Those with HAE experience episodes of swelling in their extremities, face and abdomen, with potentially life-threatening swelling of the airway. When it occurs in the abdomen, this swelling can be accompanied by bouts of nausea, vomiting and severe pain. Swelling in the face or extremities can be painful, disfiguring, and disabling.

HAE patients have a defect in the gene that controls production of a protein found in the blood vessels, called C1 inhibitor or C1-INH. When a person’s C1-INH levels are low, fluid from blood vessels can leak into nearby connective tissues, causing severe pain and swelling and, in rare cases, death from asphyxiation from airway swelling.

About Pharming Group NV

Pharming Group NV is developing innovative products for the treatment of unmet medical needs. RUCONEST® (conestat alfa) is a recombinant human C1 esterase inhibitor approved for the treatment of angioedema attacks in patients with HAE in the USA, Israel, all 27 EU countries plus Norway, Iceland and Liechtenstein. RUCONEST® is distributed in the EU by Swedish Orphan Biovitrum. RUCONEST® is partnered with Salix Pharmaceuticals Inc. SLXP -1.30% in North America. The product is also being evaluated for various follow-on indications. Pharming has a unique GMP compliant, validated platform for the production of recombinant human proteins that has proven capable of producing industrial volumes of high quality recombinant human protein in a more economical way compared to current cell based technologies. In July 2013, the platform was partnered with Shanghai Institute for Pharmaceutical Industry (SIPI), a Sinopharm Company, for joint global development of new products. Pre- clinical development and manufacturing will take place at SIPI and are funded by SIPI. Pharming and SIPI initially plan to utilize this platform for the development of rhFVIII for the treatment of Haemophilia A. Additional information is available on the Pharming website; .

About Salix Pharmaceuticals

Salix Pharmaceuticals, Ltd., headquartered in Raleigh, North Carolina, develops and markets prescription pharmaceutical products and medical devices for the prevention and treatment of gastrointestinal diseases. Salix’s strategy is to in-license late-stage or marketed proprietary therapeutic products, complete any required development and regulatory submission of these products, and commercialize them through the Company’s 500-member specialty sales force.

Salix markets XIFAXAN® (rifaximin) tablets 200 mg and 550 mg, MOVIPREP® (PEG 3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution, 100 g/7.5 g/2.691 g/1.015 g/5.9 g/4.7 g), OSMOPREP® (sodium phosphate monobasic monohydrate, USP, and sodium phosphate dibasic anhydrous, USP) Tablets, APRISO® (mesalamine) extended-release capsules 0.375 g, UCERIS® (budesonide) extended release tablets, for oral use, GIAZO® (balsalazide disodium) tablets, COLAZAL® (balsalazide disodium) Capsules, GLUMETZA® (metformin hydrochloride extended-release tablets) 500 mg and 1000 mg, ZEGERID® (omeprazole/sodium bicarbonate) Powder for Oral Suspension, ZEGERID® (omeprazole/sodium bicarbonate) Capsules, METOZOLV® ODT (metoclopramide hydrochloride), RELISTOR® (methylnaltrexone bromide) Subcutaneous Injection, FULYZAQ® (crofelemer) delayed-release tablets, SOLESTA®, DEFLUX®, PEPCID® (famotidine) for Oral Suspension, DIURIL® (chlorothiazide) Oral Suspension, AZASAN® (azathioprine) Tablets, USP, 75/100 mg, ANUSOL-HC® 2.5% (Hydrocortisone Cream, USP), ANUSOL-HC® 25 mg Suppository (Hydrocortisone Acetate), PROCTOCORT® Cream (Hydrocortisone Cream, USP) 1% and PROCTOCORT® Suppository (Hydrocortisone Acetate Rectal Suppositories) 30 mg, CYCLOSET® (bromocriptine mesylate) tablets, FENOGLIDE® (fenofibrate) tablets. UCERIS (budesonide) rectal foam, RELSITOR®, encapsulated bowel prep and rifaximin for additional indications are under development.



Chemical structure for CTK0H5262





BBR-2778 , CTK0H5262


  • Pixolti
  • Pixuvri
  • UNII-P0R64C4CR9


An immunosuppressant.

144510-96-3 [RN]





CTI BioPharma receives Israeli approval for aggressive B-cell non-Hodgkin’s lymphoma therapy

CTI BioPharma has obtained Israeli Ministry of Health’s approval for Pixuvri (pixantrone), as a monotherapy to treat adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma who have received up to three previous courses of treatment.

The company also announced that the Dutch Healthcare Authority and the College voor zorgverzekeringen of the Netherlands have approved funding for Pixuvri as an add-on drug for patients who need a third or fourth-line treatment option for aggressive B-cell lymphoma.

Tel Aviv University faculty of medicine Dr Abraham Avigdor said: “The approval of PIXUVRI in Israel provides patients with aggressive B-cell NHL who have failed second or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side-effects.


read at


CAS number  144510-96-3
PubChem 134019
ChemSpider 118174 Yes
KEGG D05522 Yes
ATC code L01DB11
Jmol-3D images Image 1
Molecular formula C17H19N5O2
Molar mass 325.365 g/mol
Appearance Blue solid
Routes of
9.5–17.5 hours
Excretion Fecal (main route of excretion) and renal (4–9%)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)

Pixantrone dimaleate [USAN]

CAS  144675-97-8

Molecular Formula

  • C17-H19-N5-O2.2C4-H4-O4

Molecular Weight

  • 441.4417
  • Benz(g)isoquinoline-5,10-dione, 6,9-bis((2-aminoethyl)amino)-, (2Z)-2-butenedioate (1:2)

On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin’s B-cell lymphoma (NHL). Pixantrone is a cytotoxic aza-anthracenedione that directly alkylates DNA-forming stable DNA adducts and cross-strand breaks. The recommended dose of pixantrone is 50 mg/m2 administered on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician’s best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects with pixantrone were bone marrow suppression (particularly of the neutrophil lineage) nausea, vomiting, and asthenia. This article summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (



Pixantrone (rINN; trade name Pixuvri) is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewertoxic effects on cardiac tissue.[1] It acts as a topoisomerase II poison and intercalating agent.[2][3] The code name BBR 2778 refers topixantrone dimaleate, the actual substance commonly used in clinical trials.[4]




Anthracyclines are important chemotherapy agents. However, their use is associated with irreversible and cumulative heart damage. Investigators have attempted to design related drugs that maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines.[5] Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.[1]

Random screening at the US National Cancer Institute of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant anti-tumor activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone, which also exhibited marked anti-tumor activity[5] Mitoxantrone was considered as an analog of doxorubicin with less structural complexity but with a similar mode of action. In clinical studies, mitoxantrone was shown to be effective against numerous types of tumors with less toxic side effects than those resulting from doxorubicin therapy. However, mitoxantrone was not totally free of cardiotoxicity. A number of structurally modified analogs of mitoxantrone were synthesized and structure-activity relationship studies made.[5] BBR 2778 was originally synthesized by University of Vermont researchers Miles P. Hacker and Paul A. Krapcho[5] and initially characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the Boehringer Mannheim Italia Research Center, Monza, and University of VermontBurlington.[4]Other studies have been completed at the University of Texas M. D. Anderson Cancer CenterHouston, the Istituto Nazionale Tumori,Milan, and the University of Padua.[2][6][4] In the search for novel heteroanalogs of anthracenediones, it was selected as the most promising compound. Toxicological studies indicated that BBR 2778 was not cardiotoxic, and US patents are held by the University of Vermont. An additional US patent application was completed in June 1995 by Boehringer Mannheim, Italy.[5]

Novuspharma, an Italian company, was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-La Roche, and BBR 2778 was developed as Novuspharma’s leading anti-cancer drug, pixantrone.[7] A patent application for the injectable preparation was filed in May 2003.[8]

In 2003, Cell Therapeutics, a Seattle biotechnology company, acquired pixantrone through a merger with Novuspharma.[9]

Clinical trials

Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics.[10] phase III clinical trials of pixantrone have been completed.[11][12] Pixantrone is being studied as an antineoplastic for different kinds of cancer, including solid tumors and hematological malignancies such as non-Hodgkin lymphomas.

Animal studies demonstrated that pixantrone does not worsen pre-existing heart muscle damage, suggesting that pixantrone may be useful in patients pretreated with anthracyclines. While only minimal cardiac changes are observed in mice given repeated cycles of pixantrone, 2 cycles of traditional anthracyclines doxorubicin or mitoxantrone result in marked or severe heart muscle degeneragion.[1]

Clinical trials substituting pixantrone for doxorubicin in standard first-line treatment of patients with aggressive non-Hodgkin’s lymphoma, had a reduction in severe side effects when compared to patients treated with standard doxorubicin-based therapy. Despite pixantrone patients receiving more treatment cycles, a three-fold reduction in the incidence of severe heart damage was seen as well as clinically significant reductions in infections and thrombocytopenia, and a significant reduction in febrile neutropenia. These findings could have major implications for treating patients with breast cancer, lymphoma, and leukemia, where debilitating cardiac damage from doxorubicin might be prevented.[13]Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.[14]

The completed phase II RAPID trial compared the CHOP-R regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab to the same regimen, but substituting Doxorubicin with Pixantrone. The objective was to show that Pixantrone was not inferior to Doxorubicin and less toxic to the heart.[15]

Pixantrone was shown to have potentially reduced cardiotoxicity and demonstrated promising clinical activity in these phase II studies in heavily pretreated non-Hodgkin lymphomapatients.[14]

The pivotal phase III EXTEND (PIX301) randomized clinical trial studied pixantrone to see how well it works compared to other chemotherapy drugs in treating patients with relapsed non-Hodgkin’s lymphoma.[16] The complete response rate in patients treated with pixantrone has been significantly higher than in those receiving other chemotherapeutic agents for treatment of relapsed/refractory aggressive non-Hodgkin lymphoma.[14]


It can be administered through a peripheral vein rather than a central implanted catheter as required for other similar drugs.[8][14]

Regulatory approval

U.S. Food and Drug Administration

The FDA granted fast track designation for pixantrone in patients who had previously been treated two or more times for relapsed or refractory aggressive NHL. Study sponsor Cell Therapeutics announced that Pixantrone achieved the primary efficacy endpoint. The minutes of the Oncologic Drugs Advisory Committee meeting of March 22, 2010[17]show that this had not in fact been achieved with statistical significance and this combined with major safety concerns lead to the conclusion that the trial was not sufficient to support approval. In April 2010 the FDA asked for an additional trial.[18]

European Medicines Agency

On May 5, 2009, Pixantrone became available in Europe on a Named-Patient Basis. A named-patient program is a compassionate use drug supply program under which physicians can legally supply investigational drugs to qualifying patients. Under a named-patient program, investigational drugs can be administered to patients who are suffering from serious illnesses prior to the drug being approved by the European Medicines Evaluation Agency. “Named-patient” distribution refers to the distribution or sale of a product to a specific healthcare professional for the treatment of an individual patient. In Europe, under the named-patient program the drug is most often purchased through the national health system.[19] In 2012 pixantrone received conditional marketing authorization in the European Union as Monotherapy to Treat Adult Patients with Multiply Relapsed or Refractory Aggressive Non-Hodgkin B-Cell Lymphomas.


Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis.[20] Pixantrone has a similar mechanism of action as mitoxantrone on the effector function of lymphomonocyte B and T cells in experimental allergic encephalomyelitis but with lower cardiotoxicity. Pixantrone inhibits antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production.[21] Clinical trials are currently ongoing in Europe.

Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats,[22] and in vitro cell viability experiments indicated that Pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity, a mechanism implicated in Alzheimer’s disease.[23]

3,4-Pyridinedicarboxylic acid (I) was converted to the cyclic anhydride (II) upon heating with acetic anhydride. Friedel-Crafts condensation of anhydride (II) with p-difluorobenzene (III) in the presence of AlCl3 gave rise to a mixture of two regioisomeric keto acids, (IV) and (V). Cyclization of this mixture in fuming sulfuric acid at 140 C generated the benzoisoquinoline (VI) (1,2). Subsequent displacement of the fluorine atoms of (VI) with ethylenediamine ( VII) in pyridine provided the target bis (2-aminoethylamino) derivative, which was finally converted to the stable dimaleate salt. Alternatively, ethylenediamine (VII) was protected as the mono-N-Boc derivative (VIII) by treatment with Boc2O. Condensation of the difluoro compound (VI) with the protected ethylenediamine (VIII) furnished (IX). The Boc groups of (IX) were then removed by treatment with trifluoroacetic acid. After adjustment of the pH to 4.2 with KOH, treatment with maleic acid provided BBR-2778.

J Med Chem1994,37, (6): 828



  1.  Cavalletti E, Crippa L, Mainardi P, Oggioni N, Cavagnoli R, Bellini O, Sala F. (2007). “Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone”. Invest New Drugs. 25 (3): 187–95. doi:10.1007/s10637-007-9037-8PMID 17285358.
  2. De Isabella P, Palumbo M, Sissi C, Capranico G, Carenini N, Menta E, Oliva A, Spinelli S, Krapcho AP, Giuliani FC, Zunino F. (1995). “Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives”. Mol Pharmacol. 48 (1): 30–8.PMID 7623772.
  3.  Evison BJ, Mansour OC, Menta E, Phillips DR, Cutts SM (2007). “Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent”Nucleic Acids Res. 35 (11): 3581–9. doi:10.1093/nar/gkm285PMC 1920253.PMID 17483512.
  4.  Krapcho AP, Petry ME, Getahun Z, Landi JJ Jr, Stallman J, Polsenberg JF, Gallagher CE, Maresch MJ, Hacker MP, Giuliani FC, Beggiolin G, Pezzoni G, Menta E, Manzotti C, Oliva A, Spinelli S, Tognella S (1994). “6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5,10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: synthesis and antitumor evaluations”. J Med Chem. 37 (6): 828–37. doi:10.1021/jm00032a018PMID 8145234.
  5.  US patent 5587382, Krapcho AP, Hacker MP, Cavalletti E, Giuliani FC, “6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity”, issued 1996-12-24, assigned to Boehringer Mannheim Italia, SpA
  6.  Zwelling LA, Mayes J, Altschuler E, Satitpunwaycha P, Tritton TR, Hacker MP. (1993). “Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II”. Biochem Pharmacol. 46 (2): 265–71. doi:10.1016/0006-2952(93)90413-QPMID 8394077.
  7.  Borchmann P, Reiser M (May 2003). “Pixantrone (Novuspharma)”. IDrugs 6 (5): 486–90. PMID 12789604.
  8.  EP patent 1503797, Bernareggi A, Livi V, “Injectable Pharmaceutical Compositions of an Anthracenedione Derivative with Anti-Tumoral Activity”, published 2003-11-27, issued 2008-09-29, assigned to Cell Therapeutics Europe S.R.L.
  9.  Pollack, Andrew (2003-06-17). “Company News; Cell Therapeutics Announces Plan To Buy Novuspharma”The New York Times. Retrieved 2010-05-22.
  10. Jump up^ Mosby’s Medical Dictionary, 8th edition. © 2009, Elsevier. “definition of antineoplastic antibiotic”. Free Online Medical Dictionary, Thesaurus and Encyclopedia. Retrieved 2012-01-31.
  11. Jump up^ “NCT00088530”BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). Retrieved 2012-01-31.
  12.  “NCT00551239”Fludarabine and Rituximab With or Without Pixantrone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma. 2012-01-31. Retrieved 2012-01-31.
  13. “Pixantrone Combination Therapy for First-line Treatment of Aggressive Non-Hodgkin’s Lymphoma Results in Reduction in Severe Toxicities Including Heart Damage When Compared to Doxorubicin-based Therapy”Press Release. Retrieved 2012-01-31.
  14. Jump up to:a b c d Engert A, Herbrecht R, Santoro A, Zinzani PL, Gorbatchevsky I (September 2006). “EXTEND PIX301: a phase III randomized trial of pixantrone versus other chemotherapeutic agents as third-line monotherapy in patients with relapsed, aggressive non-Hodgkin’s lymphoma”. Clin Lymphoma Myeloma 7 (2): 152–4.doi:10.3816/CLM.2006.n.055PMID 17026830.
  15. Jump up^ “NCT00268853”A Trial in Patients With Diffuse Large-B-cell Lymphoma Comparing Pixantrone Against Doxorubicin. Retrieved 2012-01-31.
  16. Jump up^ “NCT00101049”BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). Retrieved 2012-01-31.
  17. Jump up^ Vesely N, Eckhardt SG (2010-03-22). “NDA 022-481 PIXUVRI (pixantrone dimaleate) injection” (pdf). Summary Minutes of the Oncologic Drugs Advisory Committee. United States Food and Drug Administration. Retrieved 2012-01-31.
  18. Jump up^ “Cell Therapeutics Formally Appeals FDA’s Nonapprovable Ruling for Pixantrone”. GEN News. 2010-12-03.
  19. Jump up^ “Pixantrone Now Available in Europe on a Named-Patient Basis”. Retrieved 2012-01-31.
  20. Jump up^ Gonsette RE, Dubois B (August 2004). “Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity”. J. Neurol. Sci. 223(1): 81–6. doi:10.1016/j.jns.2004.04.024PMID 15261566.
  21. Jump up^ Mazzanti B, Biagioli T, Aldinucci A, Cavaletti G, Cavalletti E, Oggioni N, Frigo M, Rota S, Tagliabue E, Ballerini C, Massacesi L, Riccio P, Lolli F (November 2005). “Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis”. J. Neuroimmunol. 168 (1-2): 111–7.doi:10.1016/j.jneuroim.2005.07.010PMID 16120465.
  22. Jump up^ Ubiali F, Nava S, Nessi V, Longhi R, Pezzoni G, Capobianco R, Mantegazza R, Antozzi C, Baggi F (February 2008). “Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats”. J. Immunol. 180 (4): 2696–703. PMID 18250482.
  23. Jump up^ Colombo R, Carotti A, Catto M, Racchi M, Lanni C, Verga L, Caccialanza G, De Lorenzi E (April 2009). “CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity”. Electrophoresis 30(8): 1418–29. doi:10.1002/elps.200800377PMID 19306269.



McLean Hospital study finds herbal extract may curb binge drinking – kudzu


18 May 2012

Belmont, MA – An extract of the Chinese herb kudzu dramatically reduces drinking and may be useful in the treatment of alcoholism and curbing binge drinking, according to a new study by McLean Hospital and Harvard Medical School researchers.

“Our study is further evidence that components found in kudzu root can reduce alcohol consumption and do so without adverse side effects,” said David Penetar, PhD, of the Behavioral Psychopharmacology Research Laboratory at McLean Hospital, and the lead author of the study. “Further research is needed, but this botanical medication may lead to additional methods to treat alcohol abuse and dependence.”

In the study, published in the current issue of Drug and Alcohol Dependence, researchers in the Behavioral Psychopharmacology Research Laboratory at McLean Hospital looked at one of the major components of the kudzu root—the isoflavone puerarin—to determine whether it would reduce alcohol consumption in a laboratory simulation…

View original post 389 more words

Decernotinib … JAK inhibitor for the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis.

Figure imgf000061_0003



Chemical structure for Decernotinib




(R)-2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2- trifluoroethyl)butanamide

Vertex Pharmaceuticals Inc

Vertex Pharma,

UNII-MZK2GP0RHK,  VX-509, VRT-831509, cas 944842-54-0
Molecular Formula: C18H19F3N6O
Molecular Weight: 392.37827


In phase 3  for the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis.

Figure US08163917-20120424-C00370DECERNOTINIB


The Janus kinases (JAK) are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3, and TYK2. The JAKs play a critical role in cytokine signaling. The down-stream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as psoriasis. Moreover, JAK kinases represent an established therapeutic target for this disease.

For example, JAK kinases are an established therapeutic target for treating psoriasis. Stump K. L., et al., Arthritis Res. Ther. (201 1) 13:R68; Fridman J.S., et al., J Immunol. (2010) 184:5298-5307; West K., Curr. Op. Investig. Drugs (2009) 10:491-504; Kremer J. M. et al., Arthritis Rheumatism (2009) 60(7):1895- 1905; Xiong, W. et al., Ther Adv Musculoskelet Dis. (201 1) 3(5): 255-266; Panes, J. et al. 19th Ann. Eur. Gastroenterology Week (Oct 22-26, 2011) Stockholm, SE, PI 456; and Drugs in R & D “Tofacitinib” (2010) 10(4):271-84.

Compounds described as kinase inhibitors, particularly the JAK family kinases, are disclosed in WO 2005/095400 and WO 2007/084557. Also disclosed in these publications are processes and intermediates for preparing these compounds

Decernotinib ( VX-509 ) is an oral selective JAK3 inhibitor being evaluated for the treatment of rheumatoid arthritis ( RA ). This was a 24-week, randomized, placebo-controlled, double-blind, phase 2 study of four dosing regimens of Decernotinib, administered to patients with RA with inadequate response to Methotrexate ( MTX ).

The aim of the study was to assess the efficacy and safety of four dosing regimens of VX-509 administered to patients with rheumatoid arthritis on stable background Methotrexate therapy.

Patients with active rheumatoid arthritis ( C-reactive protein [ CRP ] greater than ULN, greater than or equal to 6 swollen joints [ of 66 ], and greater than or equal to 6 tender joints [ of 68 ] ) taking stable doses of MTX were randomized 1:1:1:1:1 to receive placebo or one of four dosing regimens of Decernotinib ( 100 mg QD, 150 mg QD, 200 mg QD, or 100 mg BID ) for a duration of 24 weeks.

The primary efficacy endpoints at week 12 were met and have previously been reported; 24-week efficacy and safety results are now reported.

A total of 358 patients were randomized and received greater than or equal to 1 dose of study drug; 81% of patients were female, with a mean age of 53 years.
At baseline, the mean tender joint count was 23.8, the mean swollen joint count was 16.1, and the average disease duration was 7.3 years.

After 24 weeks of treatment the proportion of patients achieving ACR20, ACR50, ACR70, DAS28 ( CRP ) less than 2.6 and DAS28 ( ESR ) less than 2.6 and the decrease from baseline in DAS28 ( CRP ) were statistically significantly greater in each of the Decernotinib dose groups than in the placebo group.

Over 24 weeks, the percentage of patients with any adverse event was higher in the Decernotinib group ( all Decernotinib dose groups combined ) ( 59.9% ) relative to placebo ( 42.3% ) and led to study discontinuation in 9.1% and 8.5% of patients in the Decernotinib and placebo groups, respectively.
The most common adverse reactions in the Decernotinib group were headache ( 8.7% ), hypercholesterolemia ( 5.2% ), and diarrhea ( 4.5% ).
Serious adverse reactions occurred in similar proportions of patients receiving Decernotinib ( 7.3% ) or placebo ( 5.6% ), but there were more serious infections in the Decernotinib group ( 3.5% ) compared with placebo ( 1.4% ).
Through 24 weeks there were two serious adverse effects that resulted in death; one was cardiac failure in the Decernotinib 100 mg BID group ( previously reported ) and one was pancytopenia in a patient with pneumonia in the Decernotinib 200 mg QD group.
Elevations in transaminase levels and decreases in median neutrophil and lymphocyte counts were observed in the Decernotinib groups and were generally mild.

Safety profiles were comparable across groups receiving Decernotinib.

In conclusion, all tested doses of Decernotinib significantly improved signs and symptoms of rheumatoid arthritis versus placebo when administered in combination with stable background Methotrexate therapy for 24 weeks.
Decernotinib was associated with small increases in adverse reactions rates, serious infections, and mostly minor laboratory abnormalities. ( Xagena )

Source: EULAR Meeting – van Vollenhoven R et al, Ann Rheum Dis 2014;73(Suppl2)


WO 2007084557


WO 2013006634

Figure imgf000060_0002


Formula I is:


Figure imgf000061_0003

The present invention provides a process for preparing (R)-2-(2-(lH-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide of Formula la:

Figure imgf000074_0001


comprising the steps of:

ivb) reacting lH-pyrrolo[2,3-b]pyridine (5a) with p-toluenesulfonyl chloride in the presence of an organic solvent to generate l-tosyl-lH-pyrrolo[2,3-b]pyridine (9a)

Figure imgf000074_0002

5a 9a

vb) reacting l-tosyl-lH-pyrrolo[2,3-b]pyridine (9a) in an organic solvent with N-bromosuccinimide to generate 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (7a)


Figure imgf000074_0003

vi) reacting 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (7a) with triisopropyl borate in the presence of a strong lithium base in an organic solvent to generate

l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a) 0H

Figure imgf000074_0004


vii) esterifying l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a) with pinacolate alcohol in an organic solvent to generate

3 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 -tosyl- 1 H-pyrrolo[2,3 -bjpyridine (la) :

Figure imgf000075_0001

viiib) reacting 2,4-dichloropyrimidine (11a) with a hydrochloride salt of D-isovaline (15a) under coupling condition to generate a compound of Formula 2a


Figure imgf000075_0002

11a 2a

ixb) reacting the compound of Formula 2a with HC1 to generate the hydrochloride salt of the compound of Formula 2a;

i) reacting the compound of Formula la with the compound of Formula 2a with in the presence of water, an organic solvent, an inorganic base, and a transition metal catalyst to generate a compound of Formula 3a,


Figure imgf000075_0003

ii) deprotecting the compound of Formula 3a under basic conditions to generate a compound of Formula 4a


Figure imgf000075_0004

4a ; and iii) reacting the compound of Formula 4a with 2,2,2-trifluoroethylamine in the presence of a coupling agent and an organic solvent to generate the compound of Formula la.


Figure imgf000093_0002

Figure imgf000094_0001

– l13C415N2]


Figure imgf000094_0002
Figure imgf000095_0001


WO 2013070606


patent WO2014074471

WO2014074471 claiming use of heterocyclic compound (preferably decernotinib) for treating psoriasis. Vertex is developing decernotinib, an oral JAK 3 inhibitor, for the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis. As of July 2014, the drug is Phase 3 trials.

Table 1:


Example 1: Analytical Methods Used

[0260] (A) HPLC on C18 column. Mobile phase was acetonitrile/water/TFA (60:40:0.1). Flow rate was 1.0 mL/min. Detection at wavelength of 230 nm. Run time was 25-26 minutes.

[0261] (B) HPLC on C18 column. Mobile phase was acetonitrile/water/TFA (90: 10:0.1). Flow rate was 1.0 mL/min. Detection at wavelength of 230 nm.

[0262] (C) HPLC on a Waters XBridge Phenyl column, 4.6 x 150 mm, 3.5 μπι. Mobile phase A was water/1 M ammonium formate, pH 4.0 (99: 1). Mobile phase B was

acetonitrile/water/ 1M ammonium formate, pH 4.0 (90:9:1). Gradient 5 % to 90 % B in 15 minutes. Total run time 22 minutes. Flow rate 1.5 mL/min. Detection at UV, 245 nm.

T = 25 °C.

[0263] (D) HPLC on a Waters XBridge Phenyl column, 4.6 x 150 mm, 3.5 μπι. Mobile phase A was water/1 M ammonium formate, pH 4.0 (99: 1). Mobile phase B was

acetonitrile/water/ 1M ammonium formate, pH 4.0 (90:9: 1). Gradient 15% to 90 % B in 15 minutes. Total run time 22 minutes. Flow rate 1.5 mL/min. Detection at UV, 220 nm.

T = 35 °C.

[0264] Example 2: Preparation of Compounds of Formula I [0265] General Synthetic Scheme


[0266] The Boc-protected amino acid starting material (1) undergoes amidation in the presence of an activating agent, a coupling reagent, and the acid salt of the amine HNR7R17 to generate the Boc-protected amide intermediate (2). The amide intermediate (2) is

deprotected under acidic conditions and reacted with the halogenated heteroaryl (3) to generate the aminoheteroaryl intermediate (4). Boronated azaindole (5) is coupled with the aminoheteroaryl intermediate (4) under cross-coupling condition to generate the compound of Formula I.




346 M+H393.20 RT 1.60 (DMSO-d6, 300 MHz) 11.95 (bs, 1H), 8.7 (d,
1H), 8.25 (m, 2H), 8.12 (d, 1H), 8.02 (d, 1H),
7.28 (s, 1H), 7.13 (dd, 1H), 6.38 (bd, 1H), 3.75
(m, 2H), 2.06 (m, 1H), 1.83 (m, 1H), 1.46 (s,
3H), 0.8 (t, 3H);

Figure US08163917-20120424-C00370

Example 1 Preparation of Compounds of the Invention

General Synthetic Scheme


Figure US08163917-20120424-C00430

Step 1


To a stirred solution of Boc-valine (1; Ris Me; 3.8 g, 0.02 mol), EDC (4.63 g, 0.024 mol), HOBt (4.0 g, 0.026 mol), DIEA (10.5 mL, 0.06 mol) in 100 mL of DCM is added trifluoroethylamine HCl (2.92 g, 0.022 mol). The reaction mixture is stirred for 16 h. It is concentrated to dryness and redissolved in EtOAc, washed successively with 0.5N HCl, saturated aqueous solution of NaHCOand brine. The organic layer is dried (Na2SO4) and concentrated in vacuo to give 5.4 g (98%) of 2 as a white solid.

Step 2

Compound 2 (5.32 g, 0.0197 mol) is deprotected with a 1:1 mixture of DCM/TFA at rt for 45 min. Concentration to dryness gives the intermediate amine that is used directly for the next step. A mixture of 5-fluoro-2,4-dichloropyrimidine (3; R is F; 3.28 g, 0.0197 mol), the crude amine TFA salt (5.25 g, 0.0197 mol) and DIEA (10.27 mL, 0.059 mol) are stirred in isopropanol at rt for 16 h. The reaction mixture is concentrated in vacuo and redissolved in EtOAc, washed successively with 0.5N HCl, saturated aqueous solution of NaHCOand brine. The organic layer is dried (Na2SO4) and concentrated in vacuo to give a crude oil that is subjected to chromatography (50% EtOAc/50% hexanes) to yield the desired compound 4.

Step 3

A mixture of 5 (30 mg, 0.075 mmol; prepared according to WO 2005/095400), 4 (23 mg, 0.075 mmol), Pd (Ph3P)(9 mg, 0.0078 mmol) and sodium carbonate 2M (115 uL, 0.23 mmol) in 1 mL of DME is microwaved at 150° C. for 10 minutes. The reaction mixture is filtered through a short pad of silica gel with 30% EtOAc-70% hexanes as eluent to provide, after concentration to dryness, the crude intermediate that is used directly for the next step.

The crude intermediate is dissolved in 1 mL of dry methanol and 200 uL of sodium methoxide in methanol 25% was added. The reaction mixture is stirred at 60° C. for 1 h and quenched with 6N HCl (154 uL). The mixture is dried under a flow of nitrogen and purified by reverse phase HPLC (10-60 MeCN/water w/0.5% TFA) to provide the desired material of formula 6a.

Compounds of formulae 6b and 6c may be prepared in an analogous manner using the appropriate starting reagents. For instance, a compound of formula 6b may generally be made by substituting Cert-butyl 2-(2,2,2-trifluoroethylcarbamoyl)pyrrolidine-1-carboxylate for compound 1, while a compound of formula 6c may generally be made by substituting tert-butyl 2-(2,2,2-trifluoroethylcarbamoyl)propan-2-ylcarbamate for compound 1.

Example 2 Analytical Results

Tables 4, 5 and 6 below depicts exemplary 1H-NMR data (NMR) and liquid chromatographic mass spectral data, reported as mass plus proton (M+H), as determined by electrospray, and retention time (RT) for certain compounds of the present invention, wherein compound numbers in Tables 4, 5 and 6 correspond to the compounds depicted in Tables 1, 2 and 3, respectively (empty cells indicate that the test was not performed):





Azaindoles Useful as Inhibitors of Janus Kinases
Azaindoles useful as inhibitors of janus kinases

new patent


US8450489 * Mar 1, 2012 May 28, 2013 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of janus kinases
US8530489 * May 22, 2012 Sep 10, 2013 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
US8686143 * Oct 25, 2011 Apr 1, 2014 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of Janus kinases
US20120157429 * Oct 25, 2011 Jun 21, 2012 Wannamaker Marion W Compounds useful as inhibitors of janus kinases
US20120165307 * Mar 1, 2012 Jun 28, 2012 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of janus kinases
US20120309963 * May 22, 2012 Dec 6, 2012 Vertex Pharmaceuticals Incorporated 5-cyano-4- (pyrrolo [2,3b] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors
US20130237516 * Apr 25, 2013 Sep 12, 2013 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of janus kinases
WO2013173506A2 May 15, 2013 Nov 21, 2013 Rigel Pharmaceuticals, Inc. Method of treating muscular degradation


WO2005095400A1 Mar 30, 2005 Oct 13, 2005 Vertex Pharma Azaindoles useful as inhibitors of jak and other protein kinases
WO2007084557A2 Jan 17, 2007 Jul 26, 2007 Vertex Pharma Azaindoles useful as inhibitors of janus kinases
WO2013070606A1 * Nov 6, 2012 May 16, 2013 Vertex Pharmaceuticals Incorporated Methods for treating inflammatory diseases and pharmaceutical combinations useful therefor

Glenmark Pharmaceuticals to set up a new manufacturing facility in the US


Glenmark Pharmaceuticals to set up a new manufacturing facility in the US

• The facility will be situated in Monroe, North Carolina, USA
• The facility will manufacture oral solids, injectables and topicals over a five year period
Mumbai, India; July 17, 2014: Glenmark Pharmaceuticals Ltd; a research-driven, global, integrated pharmaceutical company plans to set up a new manufacturing facility in the US. The company plans to set up this manufacturing facility at Monroe Corporate Center, North Carolina, USA. The facility will be spread over 100,000 sq. feet (around 15 acre plot) and the company will first begin work on an oral solid unit and thereafter set up manufacturing units for injectables and topicals.





NEW DELHI: Glenmark Pharmaceuticals plans to set up its first manufacturing facility in the US at an estimated investment of over Rs 500 crore to cater to the North American market.

The proposed facility would house three units to produce oral solids, injectables and topicals and begin production by the end of the current fiscal.


Glenmark Pharmaceuticals Ltd has informed BSE regarding a Press Release dated July 17, 2014, titled ‘Glenmark Pharmaceuticals to set up a new manufacturing facility in the US”. Glenmark Pharmaceuticals plans to set up a new manufacturing facility in the US. The company plans to set up this manufacturing facility at Monroe Corporate Center, North Carolina, USA.Source : BSE Read all announcements in Glenmark To read the full report click hereRead more at:

“The US is a key strategic market for Glenmark and it is important for us to have a manufacturing base here to serve our growing business in the country,” Glenmark Pharmaceuticals Chairman and MD Glenn Saldanha said in a statement.

The plan to set up a manufacturing facility in the US underlines the fast paced growth the company has witnessed in a short span of eight years in the US market, he added.

The company will first begin work on an oral solid unit and thereafter set up manufacturing units for injectables and topicals, the Mumbai-based firm said.

“Over the next five years, we will make significant investments in this proposed facility and set up three units which will produce oral solids, injectables and topicals,” Saldanha said.

According to industry sources, the company plans to invest over Rs 500 crore on the facility.

With the setting up of a new facility in the US the company would further enhance its manufacturing footprint making it truly global in every sense of the term, he added.

The proposed facility at Monroe, North Carolina, will cater only to the US market and is the company’s first manufacturing facility in North America adding to its list of 14 plants in four countries – India, Brazil, Argentina and Czech Republic.

The company, which operates in North America through its subsidiary Glenmark Generics Inc, has a fast growing business with a robust portfolio of over 90 products authorised for distribution in the US in niche segments like dermatology, hormones, controlled substances and oncology.

Glenmark has nearly 70 abbreviated new drug applications (ANDAs) pending for approval with the US Food and Drug Administration.


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