New Drug Approvals

Home » Posts tagged 'NDA' (Page 2)

Tag Archives: NDA


Blog Stats

  • 2,671,297 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,434 other followers

Follow New Drug Approvals on



Flag Counter


Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,434 other followers



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

Personal Links

Verified Services

View Full Profile →



Flag Counter

SUMATRIPTAN …Avanir files new drug application for migraine drug


1-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]- N-methyl-methanesulfonamide


Formula C14H21N3O2S 
Mol. mass 295.402 g/mol
CAS number 103628-46-2 
Melting point: mp 169-171°
Therap-Cat: Antimigraine.
Keywords: Antimigraine; Serotonin Receptor Agonist.
NDA 020626,GSK, IMITREX, 1997

Avanir Pharmaceuticals has filed a new drug application (NDA) with the US Food and Drug Administration (FDA) for approval of its new breath-powered investigational drug-device combination product, ‘AVP-825’, for the acute treatment of migraines.  click on title  Avanir files new drug application for migraine drug 

Sumatriptan moleculeSUMATRIPTAN


CAS Registry Number:
103628-48-4 ((1:1) salt), 103628-47-3 ((2:1) salt), 103628-46-2 (free base)
GlaxoSmithKline (Originator), Atrix (Formulation), Nastech (Formulation), NovaDel Pharma (Formulation)
Manufacturers’ Codes: GR-43175C
Trademarks: Imigran (GSK); Imitrex (GSK); Imiject (GSK)
Molecular Formula: C14H21N3O2S.C4H6O4
Molecular Weight: 413.49
Percent Composition: C 52.28%, H 6.58%, N 10.16%, O 23.22%, S 7.75%
Properties: mp 165-166°.
Melting point: mp 165-166°
Launched-1991, Acute Attacks of Migraine, Treatment of, Analgesic and Anesthetic Drugs, Antimigraine Drugs, 5-HT1B Agonists, 5-HT1D Agonists

AVP-825 is an investigational drug-device combination product consisting of low-dose sumatriptan powder delivered intranasally utilizing a novel Breath Powered delivery technology. If approved, AVP-825 would be the first and only fast-acting, dry-powder intranasal form of sumatriptan for the treatment of migraine.

The Breath Powered delivery technology is activated by user’s breath to propel medications deep into the nasal cavity where absorption is more efficient and consistent than through most other routes. A user exhales into the device, automatically closing the soft palate and sealing off the nasal cavity completely. Through a sealing nosepiece placed into the nostril, the exhaled breath carries medication from the device directly into one side of the nose. Narrow nasal passages are gently expanded and medication is dispersed deep into the nasal cavity reaching areas where it can be rapidly absorbed. As the medication is delivered, the air flows around to the opposite side of the nasal cavity and exits through the other nostril. Closure of the soft palate helps prevent swallowing or inhalation of sumatriptan powder into the lungs.

Canada 2469019 APPROVED 2005-09-13 EXP 2022-12-04
United States 6135979                  1997-03-21        2017-03-21
United States 5705520                  1994-12-10        2011-12-10
Canada 2098302                  2001-10-16        2011-12-10
Patent No PatentExpiry use code
5307953 Dec 2, 2012  
5307953*PED Jun 2, 2013  
5554639 Sep 10, 2013 U-232…METHOD OF TREATING MIGRAINE
5554639*PED Mar 10, 2014

Sumatriptan is a synthetic drug belonging to the triptan class, used for the treatment of migraine headaches. Structurally, it is an analog of the naturally occurring neuro-active alkaloids dimethyltryptamine (DMT), bufotenine, and 5-methoxy-dimethyltryptamine, with an N-methyl sulfonamidomethyl- group at position C-5 on the indole ring.[1]

Sumatriptan is produced and marketed by various drug manufacturers with many different trade names such as Sumatriptan, Imitrex, Treximet, Imigran, Imigran recovery.

Large doses of sumatriptan can cause sulfhemoglobinemia, a rare condition in which the blood changes from red to greenish-black, due to the integration of sulfur into the hemoglobin molecule.[2] If sumatriptan is discontinued, the condition reverses within a few weeks.

Serious cardiac events, including some that have been fatal, have occurred following the use of sumatriptan injection or tablets. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarctionventricular tachycardia, and ventricular fibrillation.

The most common side-effects[3] reported by at least 2% of patients in controlled trials of sumatriptan (25, 50, and 100 mg tablets) for migraine are atypical sensations (paresthesias and warm/cold sensations) reported by 4% in the placebo group and 5–6% in the sumatriptan groups, pain and other pressure sensations (including chest pain) reported by 4% in the placebo group and 6–8% in the sumatriptan groups, neurological events (vertigo) reported by less than 1% in the placebo group and less than 1% to 2% in the sumatriptan groups. Malaise/fatigue occurred in less than 1% of the placebo group and 2–3% of the sumatriptan groups. Sleep disturbance occurred in less than 1% in the placebo group to 2% in the sumatriptan group.


Sumatriptan is structurally similar to serotonin (5HT), and is a 5-HT (types 5-HT1D and 5-HT1B[4]agonist. The specific receptor subtypes it activates are present on the cranial arteries and veins. Acting as an agonist at these receptors, sumatriptan reduces the vascular inflammation associated with migraines.

The specific receptor subtype it activates is present in the cranial and basilar arteries. Activation of these receptors causes vasoconstriction of those dilated arteries. Sumatriptan is also shown to decrease the activity of the trigeminal nerve, which, it is presumed, accounts for sumatriptan’s efficacy in treating cluster headaches. The injectable form of the drug has been shown to abort a cluster headache within fifteen minutes in 96% of cases.[5]


Sumatriptan is administered in several forms; tablets, subcutaneous injection, and nasal spray. Oral administration (as succinate) suffers from poorbioavailability, partly due to presystemic metabolism—some of it gets broken down in the stomach and bloodstream before it reaches the target arteries. A new rapid-release tablet formulation has the same bioavailability, but the maximum concentration is achieved on average 10–15 minutes earlier. When injected, sumatriptan is faster-acting (usually within 10 minutes), but the effect lasts for a shorter time. Sumatriptan is metabolised primarily by monoamine oxidase A into an indole acetic acid analogue, part of which is further conjugated with glucuronic acid. These metabolites are excreted in the urine and bile. Only about 3% of the active drug may be recovered unchanged.

There is no simple, direct relationship between sumatriptan concentration (pharmacokinetics) per se in the blood and its anti-migraine effect (pharmacodynamics). This paradox has, to some extent, been resolved by comparing the rates of absorption of the various sumatriptan formulations, rather than the absolute amounts of drug that they deliver.[6][7]


Sumatriptan was the first clinically available triptan (in 1991). In the United States, it is available only by medical prescription. However, it can be bought over the counter in the UK and Sweden in 50 mg dosage. Several dosage forms for sumatriptan have been approved, including tablets, solution for injection, and nasal inhalers.

On April 15, 2008, the US FDA approved Treximet, a combination of sumatriptan and naproxen, an NSAID.[8] This combination has shown a benefit over either medicine used separately.[9]

In July 2009, the US FDA approved a single-use jet injector formulation of sumatriptan. The device delivers a subcutaneous injection of 6 mg sumatriptan, without the use of a needle.Autoinjectors with needles have been previously available in Europe and North America for several years.[10]

Phase III studies with a iontophoretic transdermal patch (Zelrix/Zecuity) started in July 2008.[11] This patch uses low voltage controlled by a pre-programmed microchip to deliver a single dose of sumatriptan through the skin within 30 minutes.[12][13]Zecuity was approved by the US FDA in January 2013.[14]


Sumatriptan vials 100 5509

On November 6, 2008, Par Pharmaceutical announced that it would begin shipping generic versions of sumatriptan injection (sumatriptan succinate injection) 4 mg and 6 mg starter kits and 4 mg and 6 mg pre-filled syringe cartridges to the trade immediately. In addition, Par anticipates launching the 6 mg vials early in 2009.[15]

Mylan Laboratories Inc., Ranbaxy, Sandoz, Dr. Reddy’s Pharmaceuticals and other companies have received FDA approval for generic versions of Imitrex tablets in 25-, 50-, and 100-milligram doses since 2009. The drug is available in U.S. and European markets, since Glaxo’s patent protections have expired in those jurisdictions. However, sales of a generic delivered via nasal spray are still restricted in the United States.

See also Sumavel DosePro (above).[10]


hydrogenation of nitrile with pd/c in presence of dimethyl amine


Sumatriptan synth.png

U.S. Patent 4,785,016

The diazotation of 4-amino-N-methylbenzenemethanesulfonamide (I) with NaNO2-HCl followed by reduction with SnCl2 gives the 4-hydrazino compound (II), which is condensed with (phenylthio)acetaldehyde (III) in ethanol yielding the ethylideneamino compound (IV). The cyclization of (IV) with HCl in ethanol affords N-methyl-3-(phenylthio)-1H-indole-5-methansulfonamide (V), which is desulfurized with RaNi in refluxing ethanol-water to give N-methyl-1H-indole-5-methanesulfonamide (VI). The reaction of (VI) with oxalyl chloride and dimethylamine yields the oxalyl derivative (VII), which is finally reduced with LiAlH4 in refluxing THF.

The condensation of hydrazine (II) with 4,4-dimethoxy-N,N-dimethylbutylamine (VIII) by means of HCl in water gives the butylidenehydrazino compound (IX), which is cyclized with polyphosphate ester (PPE) in CHCl3.


Beilstein J. Org. Chem. 2011, 7, 442–495.

ref are below article


The neuroamine transmitter serotonin contains an indole ring, so it is not surprising that indoles are a recurring theme in many drugs affecting central nervous system (CNS) function including antidepressants, antipsychotics, anxiolytics and antimigraine drugs, as well as psychedelic agents. Indole is also one of the best represented heterocyclic motifs present in the top selling pharmaceuticals, being found in eight of the top 200 drugs, with five of these belonging to the triptan family of antimigraine treatments. The classical Fischer indole synthesis is usually reported as one of the first choice routes to prepare these scaffolds. Drugs such as GSK’s serotonin receptor modulators sumatriptan (49, Imitrex) and zolmitriptan (50, Zomig) use the Fischer indole synthesis at a late stage in order to form the desired compound albeit in only low to moderate yields (Scheme 9).

Scheme 9: Key steps in the syntheses of sumatriptan and zolmitriptan.

However, in sumatriptan the indole product resulting from the Fischer synthesis can still react further which leads to the formation of by-products and significantly reduced yields. One way to minimise this was to protect the nitrogen of the sulfonamide group prior to indole formation [11]. This leads not only to an increased yield in the indole forming step (to 50%) but also facilitates chromatographic purification. The dimethylamino group can be present from the beginning of the synthesis or can be introduced via displacement of chloride or reduction of a cyano moiety. Alternatively, the dimethyl ethylene amine side chain can be introduced in position 3 via a Friedel–Crafts-type acylation. The resulting acid chloride is transformed in situ to the corresponding amide which on reduction with lithium aluminium hydride affords sumatriptan (Scheme 10) [12].

Scheme 10: Introduction of the N,N-dimethylaminoethyl side chain.

In the standard Fischer indole synthesis a hydrazine, which is most commonly derived from the corresponding diazonium salt, is reacted with a suitable carbonyl compound. Alternatively, the Japp–Klingemann reaction can be used to directly couple the diazonium salt with a β-ketoester to obtain a hydrazone which can then undergo indole ring formation (Scheme 11) [13].

Scheme 11: Japp–Klingemann reaction in the synthesis of sumatriptan.

As can be seen from Scheme 11 the indole 59 prepared via the Japp–Klingemann reaction is substituted at position 2 by an ester group which prevents reaction with electrophiles, thereby reducing the amount of undesired by-products. A simple sequence of hydrolysis and decarboxylation then affords sumatriptan [14].

All the reported methods for the synthesis of sumatriptan begin with the sulfonamide group already present on the aromatic ring and several routes are possible to introduce this functional group. The scalable route to the sulfonamides inevitably involves the preparation of the sulfonyl chloride intermediate which is then trapped with the desired amine. The sulfonyl chloride can also be prepared from the corresponding hemithioacetal 61 by treatment with NCS in wet acetic acid (Scheme 12). This efficient oxidation produces only methanol and formaldehyde as by-products [15].

Scheme 12: Synthesis of the intermediate sulfonyl chlorides 62 and 63.
  1. 11. Pete, B.; Bitter, I.; Szántay, C., Jr.; Schön, I.; Töke, L. Heterocycles 1998, 48, 1139–1149. doi:10.3987/COM-97-8087
  2. 12…Oxford, A. W. Indole Derivative. U.S. Patent 5,037,845, Aug 6, 1991.
  3. 13…Japp, F. R.; Klingemann, F. Chem. Ber. 1887, 20, 2942–2944. doi:10.1002/cber.188702002165
  4. Pete, B.; Bitter, I.; Harsányi, K.; Töke, L. Heterocycles 2000, 53, 665–673. doi:10.3987/COM-99-8815
  5. Kim, D.-W.; Ko, Y. K.; Kim, S. H. Synthesis 1992, 12, 1203–1204. doi:10.1055/s-1992-26333


References for full article

  1.  The presence of the sulfonamide group in the molecule does not make sumatriptan a “sulfa drug”, since it does not have any anti-microbial properties.
  2.  “Patient bleeds dark green blood”BBC News. 8 June 2007. Retrieved 6 March 2010.
  3.  Tablets
  4.  Razzaque Z, Heald MA, Pickard JD, et al. (1999). “Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation”.Br J Clin Pharmacol 47 (1): 75–82. doi:10.1046/j.1365-2125.1999.00851.xPMC 2014192.PMID 10073743.
  5.  Treatment of acute cluster headache with sumatriptan. The Sumatriptan Cluster Headache Study Group. N Engl J Med 1991;325:322-6.
  6.  Fox, A. W. (2004). “Onset of effect of 5-HT1B/1D agonists: a model with pharmacokinetic validation”. Headache 44 (2): 142–147. doi:10.1111/j.1526-4610.2004.04030.x.PMID 14756852edit
  7.  Freidank-Mueschenborn, E.; Fox, A. (2005). “Resolution of concentration-response differences in onset of effect between subcutaneous and oral sumatriptan”. Headache 45 (6): 632–637. doi:10.1111/j.1526-4610.2005.05129a.xPMID 15953294edit
  8.  GSK press release – Treximet (sumatriptan and naproxen sodium) tablets approved by FDA for acute treatment of migraine
  9.  Brandes JL, Kudrow D, Stark SR, et al. (April 2007). “Sumatriptan-naproxen for acute treatment of migraine: a randomized trial”JAMA 297 (13): 1443–54.doi:10.1001/jama.297.13.1443PMID 17405970.
  10.  Brandes, J.; Cady, R.; Freitag, F.; Smith, T.; Chandler, P.; Fox, A.; Linn, L.; Farr, S. (2009). “Needle-free subcutaneous sumatriptan (Sumavel DosePro): bioequivalence and ease of use.”. Headache 49 (10): 1435–1444. doi:10.1111/j.1526-4610.2009.01530.x.PMID 19849720edit
  11. NCT00724815 The Efficacy and Tolerability of NP101 Patch in the Treatment of Acute Migraine (NP101-007)
  12.  SmartRelief -electronically assisted drug delivery (iontophoresis)
  13.  Pierce, M; Marbury, T; O’Neill, C; Siegel, S; Du, W; Sebree, T (2009). “Zelrix: a novel transdermal formulation of sumatriptan”. Headache 49 (6): 817–25. doi:10.1111/j.1526-4610.2009.01437.xPMID 19438727.
  14.  Zecuity Approved by the FDA for the Acute Treatment of Migraine
  15.  “PAR PHARMACEUTICAL BEGINS SHIPMENT OF SUMATRIPTAN INJECTION”Par Pharmaceutical. 2008-11-06. Retrieved 2008-11-25.
  16. Serotonin 5HT1-receptor agonist. Prepn: M. D. Dowle, I. H. Coates, DE 3320521eidem, US 4816470; A. W. Oxford, GB 2162522 (1983, 1989, 1986 all to Glaxo).
  17. Receptor binding studies: P. P. A. Humphrey et al., Br. J. Pharmacol.94, 1123 (1988); P. Schoeffter, D. Hoyer, Arch. Pharmacol. 340, 135 (1989).
  18. LC-MS determn in plasma: J. Oxford, M. S. Lant, J. Chromatogr. 496, 137 (1989).
  19. Clinical evaluations in migraine: A. Doenicke et al., Lancet 1, 1309 (1988);
  20. Subcutaneous Sumatriptan International Study Group, N. Engl. J. Med. 325, 316 (1991); in acute cluster headache: Sumatriptan Cluster Headache Study Group, ibid. 322.
  21. Review of pharmacology and clinical experience: S. J. Peroutka, Headache 30 (Suppl. 2), 554-560 (1990).
  22. Drugs Fut 1989,14(1),35
Noncardiotoxic pharmaceutical compounds
Fixed Combination Dosage Forms for the Treatment of Migraine
Patient controlled drug delivery device
Rapid dissolution of combination products
Indole derivative
Pharmaceutical formulations
Fuel and water homogenizer

Avanir Pharmaceuticals, Inc. is a biopharmaceutical company focused on bringing innovative medicines to patients with central nervous system disorders of high unmet medical need. As part of our commitment, we have extensively invested in our pipeline and are dedicated to advancing medicines that can substantially improve the lives of patients and their loved ones. For more information about Avanir, please visit

AVANIR® is a trademark or registered trademark of Avanir Pharmaceuticals, Inc. in the United States and other countries. All other trademarks are the property of their respective owners.

Avanir Pharmaceuticals, Inc. licensed exclusive rights for the development and commercialization of AVP-825, a novel Breath Powered intranasal system containing a low-dose sumatriptan powder from OptiNose Inc. of Yardley, PA.

IMITREX Tablets contain sumatriptan succinate, a selective 5-HT1B/1D receptor agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole- 5-methanesulfonamide succinate (1:1), and it has the following structure:

IMITREX Tablets contain sumatriptan succinate, a selective 5-HT1B/1Dreceptor agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole- 5-methanesulfonamide succinate (1:1), and it has the following structure:

IMITREX (sumatriptan succinate) Structural Formula Illustration

The empirical formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline.

Each IMITREX Tablet for oral administration contains 35, 70, or 140 mg of sumatriptan succinate equivalent to 25, 50, or 100 mg of sumatriptan, respectively. Each tablet also contains the inactive ingredients croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium bicarbonate. Each 100-mg tablet also contains hypromellose, iron oxide, titanium dioxide, and triacetin.

New Drug Application for Belinostat in Relapsed or Refractory PTCL Submitted to the FDA

Copenhagen, December 10, 2013
Topotarget announces the submission of a New Drug Application (NDA) for belinostat for the treatment of relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) to the US Food and Drug Administration (FDA). The NDA has been filed for Accelerated Approval with a request for Priority Review. Response from the FDA regarding acceptance to file is expected within 60 days from the FDA receipt date.
read all this here





Belinostat (PXD101)

Belinostat (PXD101) is a novel HDAC inhibitor with IC50 of 27 nM, with activity demonstrated in cisplatin-resistant tumors.

Belinostat inhibits the growth of tumor cells (A2780, HCT116, HT29, WIL, CALU-3, MCF7, PC3 and HS852) with IC50 from 0.2-0.66 μM. PD101 shows low activity in A2780/cp70 and 2780AD cells. Belinostat inhibits bladder cancer cell growth, especially in 5637 cells, which shows accumulation of G0-G1 phase, decrease in S phase, and increase in G2-M phase. Belinostat also shows enhanced tubulin acetylation in ovarian cancer cell lines. A recent study shows that Belinostat activates protein kinase A in a TGF-β signaling-dependent mechanism and decreases survivin mRNA.

MW 318.07
Molecular Formula: C15H14N2O4S

414864-00-9  cas no


A novel HDAC inhibitor



Tiny Biotech With Three Cancer Drugs Is More Alluring Takeover Bet Now
The drug is one of Spectrum’s two drugs undergoing phase 3 clinical trials. Allergan paid Spectrum $41.5 million and will make additional payments of up to $304 million based on achieving certain milestones. So far, Raj Shrotriya, Spectrum’s chairman,





Belinostat (PXD101) is experimental drug candidate under development byTopoTarget for the treatment of hematological malignancies and solid tumors. It is a histone deacetylase inhibitor.[1]

In 2007 preliminary results were released from the Phase II clinical trial of intravenous belinostat in combination with carboplatin and paclitaxel for relapsedovarian cancer.[2] Final results in late 2009 of a phase II trial for T cell lymphomawere encouraging.[3] Belinostat has been granted orphan drug and fast trackdesignation by the FDA.[4]


  1.  Plumb, Jane A.; Finn, Paul W.; Williams, Robert J.; Bandara, Morwenna J.; Romero, M. Rosario; Watkins, Claire J.; La Thangue, Nicholas B.; Brown, Robert (2003). “Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101″. Molecular Cancer Therapeutics 2 (8): 721–728. PMID 12939461.
  2.  “CuraGen Corporation (CRGN) and TopoTarget A/S Announce Presentation of Belinostat Clinical Trial Results at AACR-NCI-EORTC International Conference”. October 2007.
  3.  Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma, December 2009
  4.  “Spectrum adds to cancer pipeline with $350M deal.”. February 2010.





(E)-N-hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide, also known as PXD101 and Belinostat®, shown below, is a well known histone deacetylate (HDAC) inhibitor. It is being developed for treatment of a range of disorders mediated by HDAC, including proliferative conditions (such as cancer and psoriasis), malaria, etc.

Figure US20100286279A1-20101111-C00001

PXD101 was first described in WO 02/30879 A2. That document describes a multi-step method of synthesis which may conveniently be illustrated by the following scheme.

Figure US20100286279A1-20101111-C00002
Figure US20100286279A1-20101111-C00003



Figure US20100286279A1-20101111-C00034





Durata Therapeutics Announces FDA’s Acceptance for Priority Review of NDA for Dalvance (dalbavancin hydrochloride)

CAS No. 171500-79-1
Chemical Name: Dalbavancin
Synonyms: MDL 63397;Dalbavancin
CBNumber: CB41028737
Molecular Formula: C88H100Cl2N10O28
Formula Weight: 1816.71

CHICAGO, Nov 26, 2013 (GLOBE NEWSWIRE via COMTEX) — Durata Therapeutics, Inc. DRTX +6.48% today announced that the New Drug Application (NDA) for its investigational drug, Dalvance (dalbavancin hydrochloride) for injection, has been accepted for priority review by the U.S. Food and Drug Administration (FDA) with an action date of May 26, 2014. Durata is seeking FDA approval of Dalvance(TM) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive microorganisms, including MRSA (methicillin resistant Staphylococcus aureus

Dalbavancin, V-Glycopeptide, VER-001, BI-397 factor B0, BI-397
Vicuron Pharmaceuticals (Originator)
5,31-Dichloro-38-de(methoxycarbonyl)-7-demethyl-19-deoxy-56-O-[2-deoxy-2-(10-methylundecanamido)-beta-D-glucopyranuronosyl]-38-[N-[3-(dimethylamino)propyl]carbamoyl]-42-O-alpha-D-mannopyranosyl-N15-methylristomycin A aglycone; (3S,15R,18R,34R,35S,48S,50aR
Dalbavancin, which is also referred to in the scientific literature as BI397 or VER001, is a semi=synthetic glycopeptide mixture, the properties of which have been reported in U.S. Pat. Nos. 5,606,036, 5,750,509, 5,843,679, and 5,935,238.
U.S. Publication No. 20040224908;
J Antibiot1995,48,(8):869
Drugs Fut1999,24,(8):839

Dalbavancin is prepared by chemical modification of the natural glycopeptide complex A-40,926 as described in Malabarba and Donadio (1999) Drugs of the Future 24(8):839-846. The predominant component of dalbavancin is Factor Bo, which accounts for >75% of the whole complex.

[0042] The amount of each of the components present in a dalbavancin composition is dictated by a variety of factors, including, for example, the fermentation conditions employed in the preparation of the natural glycopeptide complex A-40926, which is the precursor to dalbavancin (see, e.g., U.S. Pat. No.5,843,679), the conditions employed to recover A-40926 from the fermentation broth, the chemical reactions employed to selectively esterify the caxboxyl group of the sugar moiety of A-40926, the conditions employed to amidate the peptidyl carboxyl group, the conditions employed to saponify the ester of the carboxyl group of the N-acylaminoglucuronic acid function, the conditions employed to recover dalbavancin from the synthetic mixture, and the like.

the semisynthetic glycopeptide dalbavancin was synthesized from the natural antibiotic A 40926, originally isolated from an Actinomadura culture (Malabarba et al., 1998, U.S. Pat. No. 5,750,509). Dalbavancin has shown greater efficacy against various bacterial strains than vancomycin or the antibiotic linezolid and represents a promising new treatment for skin and soft tissue infections (see, e.g., Jabés et al., 2004, Antimicrob. Agents Chemother. 48:1118-1123). According to U.S. Pat. No. 5,750,509, dalbavancin is a glycopeptide antibiotic with a monomethyl moiety at its N15 amino (see FIG. 1 for numbering), and this N15-monomethyl amino could be free (i.e. —NHCH3) or protected with an amino protecting group such as t-butoxycarbonyl, carbobenzyloxy, arylalkyl or benzyl. The method for making certain of the dalbavancin components reported in the ‘509 patent also produced N15,N15-dialkyl analogs of dalbavancin in minor-quantities, but these molecules were not characterized.

Dalbavancin (INN, trade name Zeven) is a novel second-generation lipoglycopeptideantibiotic. It belongs to the same class as vancomycin, the most widely used and one of the few treatments available to patients infected with methicillin-resistant Staphylococcus aureus (MRSA).[1]

Dalbavancin (BI397) is a novel semisynthetic lipoglycopeptide that was designed to improve upon the natural glycopeptides currently available, vancomycin and teicoplanin.[2]

It possesses in vitro activity against a variety of Gram-positive pathogens[3][4] includingMRSA and MRSE.[5] It is a once-weekly, two-dose antibiotic that Pfizer acquired when it bought Vicuron Pharmaceuticals in 2005.[6]

Dalbavancin has undergone a phase III clinical trial for adults with complicated skin infections, but in Dec 2007 the FDA said more data was needed before approval.[6] On September 9, 2008, Pfizer announced that it will withdraw all marketing applications in order to conduct another Phase 3 clinical trial.[7] Durata Therapeutics acquired the rights to dalbavancin in December 2009 and has initiated two new Phase III clinical trials for treatment of acute bacterial skin and skin structure infections.[8] Preliminary results in Dec 2012 looked good.[9]

  1.  Vicuron Pharmaceuticals Submits New Drug Application for Dalbavancin to U.S. Food and Drug Administration
  2.  Scheinfeld NS. (May 2006). “Dalbavancin: A review for dermatologists.”. Dermatology Online Journal 12 (6). Unknown parameter |numero= ignored (helpPMID 17083861
  3.  Chen AY, Zervos MJ, Vazquez JA (2007). “Dalbavancin: a novel antimicrobial”. Int. J. Clin. Pract. 61 (5): 853–63. doi:10.1111/j.1742-1241.2007.01318.xPMC 1890846.PMID 17362476.
  4.  Das B, Sarkar C, Biswas R, Pandey S (2008). “Review: dalbavancin-a novel lipoglycopeptide antimicrobial for gram positive pathogens”. Pak J Pharm Sci 21 (1): 78–88. PMID 18166524.
  5.  Dalbavancin: A Novel Lipoglycopeptide Antibacterial
  6.  UPDATE 1-Pfizer says US FDA wants more data on antibiotic. Dec 2007
  7.  “Pfizer Will Withdraw Global Marketing Applications for Dalbavancin to Conduct a New Trial” (Press release). Pfizer Inc. 2008-09-09. Retrieved 2008-09-11.
  8.  Durata Begins Dalbavancin Study Enrollment. Drug Discovery & Development – October 05, 2011.
  9.  Durata Therapeutics Announces Phase 3 Clinical Trial Results for Dalbavancin in the Treatment of ABSSSI



Aeterna Zentaris Submits New Drug Application to FDA for Macimorelin Acetate (AEZS-130) for Evaluation of AGHD


CAS  381231-18-1

Chemical Formula: C26H30N6O3

Exact Mass: 474.23794

Molecular Weight: 474.55480

Elemental Analysis: C, 65.80; H, 6.37; N, 17.71; O, 10.11

945212-59-9 (Macimorelin acetate)


USAN (ab-26)

Diagnostic agent for adult growth hormone deficiency (AGHD)
1. D-Tryptophanamide, 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-, acetate (1:1)
2. N2-(2-amino-2-methylpropanoyl-N1-[(1R)-1-formamido-2-(1H-indol-3-yl)ethyl]- D-tryptophanamide acetate


Aeterna Zentaris GmbH
D-87575, EP 1572, ARD 07

Macimorelin (also known as AEZS-130, EP-1572) is a novel synthetic small molecule, acting as a ghrelin agonist, that is orally active and stimulates the secretion of growth hormone (GH). Based on results of Phase 1 studies, AEZS-130 has potential applications for the treatment of cachexia, a condition frequently associated with severe chronic diseases such as cancer, chronic obstructive pulmonary disease and AIDS. In addition to the therapeutic application, a Phase 3 trial with AEZS-130 as a diagnostic test for growth hormone deficiencies in adults has been completed.

QUEBEC, Nov. 5, 2013 /PRNewswire/ – Aeterna Zentaris Inc. (the “Company”) today announced that it has submitted a New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) for its ghrelin agonist, macimorelin acetate (AEZS-130). Phase 3 data have demonstrated that the compound has the potential to become the first orally-approved product that induces growth hormone release to evaluate adult growth hormone deficiency (“AGHD”), with accuracy comparable to available intravenous and intramuscular testing procedures.  read at

macimorelin (JMV 1843), a ghrelin-mimetic growth hormone secretagogue in Phase III for adult growth hormone deficiency (AGHD)

Macimorelin, a growth hormone modulator, is currently awaiting registration in the U.S. by AEterna Zentaris as an oral diagnostic test of adult growth hormone deficit disorder. The company is also developing the compound in phase II clinical trials for the treatment of cancer related cachexia. The compound was being codeveloped by AEterna Zentaris and Ardana Bioscience; however, the trials underway at Ardana were suspended in 2008 based on a company strategic decision. AEterna Zentaris owns the worldwide rights of the compound. In 2007, orphan drug designation was assigned by the FDA for the treatment of growth hormone deficit in adults.

New active series of growth hormone secretagogues
J Med Chem 2003, 46(7): 1191

WO 2001096300

WO 2007093820


J Med Chem 2003, 46(7): 1191

Abstract Image


Synthetic Pathway for JMV 1843 and Analoguesa

a Reagents and conditions:  (a) IBCF, NMM, DME, 0 °C; (b) NH4OH; (c) H2, Pd/C, EtOH, HCl; (d) BOP, NMM, DMF, Boc-(d)-Trp-OH; (e) Boc2O, DMAP cat., anhydrous CH3CN; (f) BTIB, pyridine, DMF/H2O; (g) 2,4,5-trichlorophenylformate, DIEA, DMF; (h) TFA/anisole/thioanisole (8:1:1), 0 °C; (i) BOP, NMM, DMF, Boc-Aib-OH; (j) TFA/anisole/thioanisole (8:1:1), 0 °C; (k) RP preparative HPLC.

TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO (7). 6 (1 g, 1.7 mmol) was dissolved in a mixture of trifluoroacetic acid (8 mL), anisole (1 mL), and thioanisole (1 mL) for 30 min at 0 °C. The solvents were removed in vacuo, the residue was stirred in ether, and the precipitated TFA, H-Aib-(d)-Trp-(d)-gTrp-CHO was filtered. 7 was purified by preparative HPLC and obtained in 52% yield. 1H NMR (400 MHz, DMSO-d6) + correlation 1H−1H:  δ 1.21 (s, 3H, CH3 (Aib)), 1.43 (s, 3H, CH3 (Aib)), 2.97 (m, 2H, (CH2)β), 3.1 (m, 2H, (CH2)β), 4.62 (m, 1H, (CH)αA and (CH)αB), 5.32 (q, 0.4H, (CH)α‘B), 5.71 (q, 0.6H, (CH)α‘A), 7.3 (m, 4H, H5 and H6 (2 indoles)), 7.06−7.2 (4d, 2H, H2A and H2B (2 indoles)), 7.3 (m, 2H, H4 or H7 (2 indoles)), 7.6−7.8 (4d, 2H, H4A and H4B or H7A and H7B), 7.97 (s, 3H, NH2 (Aib) and CHO (formyl)), 8.2 (d, 0.4H, NH1B (diamino)), 8.3 (m,1H, NHA and NHB), 8.5 (d, 0.6H, NH1A (diamino)), 8.69 (d, 0.6H, NH2A (diamino)), 8.96 (d, 0.4H, NH2B (diamino)), 10.8 (s, 0.6H, N1H1A (indole)), 10.82 (s, 0.4H, N1H1B (indole)), 10.86 (s, 0.6H, N1H2A (indole)), 10.91 (s, 0,4H, N1H2B (indole)). MS (ES), m/z:  475 [M + H]+, 949 [2M + H]+. HPLC tR:  16.26 min (conditions A).


The inventors have now found that the oral administration of growth hormone secretagogues (GHSs) EP 1572 and EP 1573 can be used effectively and reliably to diagnose GHD.

EP 1572 (Formula I) or EP 1573 (Formula II) are GHSs (see WO 01/96300, Example 1 and Example 58 which are EP 1572 and EP 1573, respectively) that may be given orally.

EP 1572 and EP 1573 can also be defined as H-Aib-D-Trp-D-gTrp-CHO and H-Aib-D-Trp-D-gTrp-C(O)NHCH2CH3. Wherein, His hydrogen, Aib is aminoisobutyl, D is the dextro isomer, Trp is tryptophan and gTrp is a group of Formula III:


H-Aib-D-Trp-D-gTrp-CHO: Figure US06861409-20050301-C00007


Example 1 H-Aib-D-Trp-D-gTrp-CHO

Total synthesis (percentages represent yields obtained in the synthesis as described below):


Z-D-Trp-OH (8.9 g; 26 mmol; 1 eq.) was dissolved in DME (25 ml) and placed in an ice water bath to 0° C. NMM (3.5 ml; 1.2 eq.), IBCF (4.1 ml; 1.2 eq.) and ammonia solution 28% (8.9 ml; 5 eq.) were added successively. The mixture was diluted with water (100 ml), and the product Z-D-Trp-NH2 precipitated. It was filtered and dried in vacuo to afford 8.58 g of a white solid.


C19H19N3O3, 337 g.mol−1.

Rf=0.46 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

1H NMR (250 MHZ, DMSO-d6): δ 2.9 (dd, 1H, Hβ, Jββ′=14.5 Hz; Jβα=9.8 Hz); 3.1 (dd, 1H, Hβ′, Jβ′β=14.5 Hz; Jβ′α=4.3 Hz); 4.2 (sextuplet, 1H, Hα); 4.95 (s, 2H, CH2 (Z); 6.9-7.4 (m, 11H); 7.5 (s, 1H, H2); 7.65 (d, 1H, J=7.7 Hz); 10.8 (s, 1H, N1H).

Mass Spectrometry (Electrospray), m/z 338 [M+H]+, 360 [M+Na]+, 675 [2M+H]+, 697 [2M+Na]+.


Z-D-Trp-NH2 (3 g; 8.9 mmol; 1 eq.) was dissolved in DMF (100 ml). HCl 36% (845 μl; 1.1 eq.), water (2 ml) and palladium on activated charcoal (95 mg, 0.1 eq.) were added to the stirred mixture. The solution was bubbled under hydrogen for 24 hr. When the reaction went to completion, the palladium was filtered on celite. The solvent was removed in vacuo to afford HCl, H-D-Trp-NH2 as a colorless oil.

In 10 ml of DMF, HCl, H-D-Trp-NH2 (8.9 mmol; 1 eq.), Boc-D-Trp-OH (2.98 g; 9.8 mmol; 1.1 eq.), NMM (2.26 ml; 2.1 eq.) and BOP (4.33 g; 1.1 eq.) were added successively. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to afford 4.35 g of Boc-D-Trp-D-Trp-NH2 as a white solid.


C27H31N5O4, 489 g.mol−1.

Rf=0.48 {Chloroform/Methanol/Acetic Acid (85/10/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.28 (s, 9H, Boc); 2.75-3.36 (m, 4H, 2 (CH2)β; 4.14 (m, 1H, CHα); 4.52 (m, 1H, CHα′); 6.83-7.84 (m, 14H, 2 indoles (10H), NH2, NH (urethane) and NH (amide)); 10.82 (d, 1H, J=2 Hz, N1H); 10.85 (d, 1H, J=2 Hz, N1H).

Mass Spectrometry (Electrospray), m/z 490 [M+H]+, 512 [M+Na]+, 979 [2M+H]+.


Boc-D-Trp-D-Trp-NH2 (3 g; 6.13 mmol; 1 eq.) was dissolved in acetonitrile (25 ml).

To this solution, di-tert-butyl-dicarbonate (3.4 g; 2.5 eq.) and 4-dimethylaminopyridine (150 mg; 0.2 eq.) were successively added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.53 g of Boc-D-(NiBoc)Trp-D-(NiBoc)Trp-NH2 as a white solid.


C37H47N5O8, 689 g.mol−1.

Rf=0.23 {ethyl acetate/hexane (5/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.25 (s, 9H, Boc); 1.58 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.4 (m, 4H, 2 (CH2)β); 4.2 (m, 1H, CHα′); 4.6 (m, 1H, CHα); 7.06-8 (m, 14H, 2 indoles (10H), NH (urethane), NH and NH2 (amides)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]+, 712 [M+Na]+, 1379 [2M+H]+, 1401 [2M+Na]+.


Boc-D-(NiBoc)Trp-D-(NiBoc)Trp-NH2 (3 g; 4.3 mmol; 1 eq.) was dissolved in the mixture DMF/water (18 ml/7 ml). Then, pyridine (772 μl; 2.2 eq.) and Bis(Trifluoroacetoxy)IodoBenzene (2.1 g; 1.1 eq.) were added. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and aqueous saturated sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. Boc-D-NiBoc)Trp-D-g(NiBoc)Trp-H was used immediately for the next reaction of formylation.

Rf=0.14 {ethyl acetate/hexane (7/3)}.

C36H47N5O7, 661 g.mol−1.

1H NMR (200 MHZ, DMSO-d6): δ 1.29 (s, 9H, Boc); 1.61 (s, 18H, 2 Boc); 2.13 (s, 2H, NH2 (amine)); 3.1-2.8 (m, 4H, 2 (CH2)β); 4.2 (m, 1H, CHα′); 4.85 (m, 1H, CHα); 6.9-8 (m, 12H, 2 indoles (10H), NH (urethane), NH (amide)).

Mass Spectrometry (Electrospray), m/z 662 [M+H]+, 684 [M+Na]+.


Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-H (4.3 mmol; 1 eq.) was dissolved in DMF (20 ml). Then, N,N-diisopropylethylamine (815 μl; 1.1 eq.) and 2,4,5-trichlorophenylformate (1.08 g; 1.1 eq.) were added. After 30 minutes, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane {5/5} to afford 2.07 g of Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-CHO as a white solid.


C37H47N5O8, 689 g.mol−1.

Rf=0.27 {ethyl acetate/hexane (5/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.28 (s, 9H, Boc); 1.6 (s, 9H, Boc); 1.61 (s, 9H, Boc); 2.75-3.1 (m, 4H, 2 (CH2)β); 4.25 (m, 1H, (CH)αA&B); 5.39 (m, 0.4H, (CH)α′B); 5.72 (m, 0.6H, (CH)α′A); 6.95-8.55 (m, 14H, 2 indoles (10H), NH (urethane), 2 NH (amides), CHO (formyl)).

Mass Spectrometry (Electrospray), m/z 690 [M+H]+, 712 [M+Na]+, 1379 [2M+H]+.


Boc-D-(NiBoc)Trp-D-g(NiBoc)Trp-CHO (1.98 g; 2.9 mmol; 1 eq.) was dissolved in a -mixture of trifluoroacetic acid (16 ml), anisole (2 ml) and thioanisole (2 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-D-Trp-D-gTrp-CHO was filtered.

TFA, H-D-Trp-D-gTrp-CHO (2.9 mmol; 1 eq.), Boc-Aib-OH (700 mg; 1 eq.), NMM (2.4 ml; 4.2 eq.) and BOP (1.53 g; 1.2 eq.) were successively added in 10 ml of DMF. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (200 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to afford 1.16 g of Boc-Aib-D-Trp-D-gTrp-CHO as a white solid.


C31H38N6O5, 574 g.mol−1.

Rf=0.26 {Chloroform/Methanol/Acetic Acid (180/10/5)}.

1H NMR (200 MHZ, DMSO-d6): δ 1.21 (s, 6H, 2 CH3(Aib)); 1.31 (s, 9H, Boc); 2.98-3.12 (m, 4H, 2 (CH2)β); 4.47 (m, 1H, (CH)αA&B); 5.2 (m, 0.4H, (CH)α′B); 5.7 (m, 0.6H, (CH)α′A); 6.95-8.37 (m, 15H, 2 indoles (10H), 3 NH (amides), 1 NH (urethane) CHO (formyl)); 10.89 (m, 2H, 2 N1H (indoles)).

Mass Spectrometry (Electrospray), ml/z 575 [M+H]+, 597 [M+Na]+, 1149 [2M+H]+, 1171 [2M+Na]+.


Boc-Aib-D-Trp-D-gTrp-CHO (1 g; 1.7 nmmol) was dissolved in a mixture of trifluoroacetic acid (8 ml), anisole (1 ml) and thioanisole (1 ml) for 30 minutes at 0° C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-Aib-D-Trp-D-gTrp-CHO was filtered.

The product TFA, H-Aib-D-Trp-D-gTrp-CHO was purified by preparative HPLC (Waters, delta pak, C18, 40×100 mm, 5 μm, 100 A).


C26H30N6O3, 474 g.mol−1.

1H NMR (400 MHZ, DMSO-d6)+1H/1H correlation: δ 1.21 (s, 3H, CH3 (Aib)); 1.43 (s, 3H, CH3 (Aib)); 2.97 (m, 2H, (CH2)β); 3.1 (m, 2H, (CH2)β′); 4.62 (m, 1H, (CH)αA&B); 5.32 (q, 0.4H, (CH)α′B); 5.71 (q, 0.6H, (CH)α′A); 7.3 (m, 4H5 and H6 (2 indoles)); 7.06-7.2 (4d, 2H, H2A et H2B (2 indoles)); 7.3 (m, 2H, H4 or H7 (2 indoles)); 7.6-7.8 (4d, 2H, H4A and H4B or H7A et H7B); 7.97 (s, 3H, NH2 (Aib) and CHO (Formyl));8.2 (d, 0.4H, NH1B (diamino)); 8.3 (m,1H, NHA&B); 8.5 (d, 0.6H, NH1A (diamino)); 8.69 (d, 0.6H, NH2A (diamino)); 8.96 (d, 0.4H, NH2B (diamino)); 10.8 (s, 0.6H, N1H1A (indole)); 10.82 (s, 0.4H, N1H1B (indole)); 10.86 (s, 0.6H, N1H2A (indole)); 10.91 (s, 0.4, N1H2B (indole)).

Mass Spectrometry (Electrospray), m/z 475 [M+H]+, 949 [2M+H]+.



Aeterna Zentaris NDA for Macimorelin Acetate in AGHD Accepted for Filing by the FDA

Quebec City, Canada, January 6, 2014 – Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZS) (the “Company”) today announced that the U.S. Food and Drug Administration (“FDA”) has accepted for filing the Company’s New Drug Application (“NDA”) for its ghrelin agonist, macimorelin acetate, in Adult Growth Hormone Deficiency (“AGHD”). The acceptance for filing of the NDA indicates the FDA has determined that the application is sufficiently complete to permit a substantive review.

The Company’s NDA, submitted on November 5, 2013, seeks approval for the commercialization of macimorelin acetate as the first orally-administered product that induces growth hormone release to evaluate AGHD. Phase 3 data have demonstrated the compound to be well tolerated, with accuracy comparable to available intravenous and intramuscular testing procedures. The application will be subject to a standard review and will have a Prescription Drug User Fee Act (“PDUFA”) date of November 5, 2014. The PDUFA date is the goal date for the FDA to complete its review of the NDA.

David Dodd, President and CEO of Aeterna Zentaris, commented, “The FDA’s acceptance of this NDA submission is another significant milestone in our strategy to commercialize macimorelin acetate as the first approved oral product for AGHD evaluation. We are finalizing our commercial plan for this exciting new product. We are also looking to broaden the commercial application of macimorelin acetate in AGHD for use related to traumatic brain injury victims and other developmental areas, which would represent significant benefit to the evaluation of growth hormone deficiency, while presenting further potential revenue growth opportunities for the Company.”

About Macimorelin Acetate

Macimorelin acetate, a ghrelin agonist, is a novel orally-active small molecule that stimulates the secretion of growth hormone. The Company has completed a Phase 3 trial for use in evaluating AGHD, and has filed an NDA to the FDA in this indication. Macimorelin acetate has been granted orphan drug designation by the FDA for use in AGHD. Furthermore, macimorelin acetate is in a Phase 2 trial as a treatment for cancer-induced cachexia. Aeterna Zentaris owns the worldwide rights to this novel patented compound.

About AGHD

AGHD affects about 75,000 adults across the U.S., Canada and Europe. Growth hormone not only plays an important role in growth from childhood to adulthood, but also helps promote a hormonally-balanced health status. AGHD mostly results from damage to the pituitary gland. It is usually characterized by a reduction in bone mineral density, lean mass, exercise capacity, and overall quality of life.

About Aeterna Zentaris

Aeterna Zentaris is a specialty biopharmaceutical company engaged in developing novel treatments in oncology and endocrinology. The Company’s pipeline encompasses compounds from drug discovery to regulatory approval.

home business

back to home for more updates



MOBILE-+91 9323115463

Cubist Pharmaceuticals, Inc. announced that it has submitted a NDA to the U.S. FDA for approval of its investigational antibiotic tedizolid phosphate (TR-701).

PRONUNCIATION ted” eye zoe’ lid
THERAPEUTIC CLAIM Treatment of complicated skin and skin structure infections
1. 2-Oxazolidinone, 3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5- [(phosphonooxy)methyl]-, (5R)-
2. [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxooxazolidin-5- yl]methyl hydrogen phosphate

TRADEMARK None as yet
SPONSOR Trius Therapeutics
Note: This adoption statement supersedes the USAN torezolid phosphate (N09/81), which is hereby rescinded and replaced by the USAN tedizolid phosphate (N10/118).

Cubist Announces Submission of New Drug Application for Investigational Antibiotic Tedizolid for Treatment of Serious Skin Infections

LEXINGTON, Mass.–(BUSINESS WIRE)– Cubist Pharmaceuticals, Inc. today announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of its investigational antibiotic tedizolid phosphate (TR-701). Cubist is seeking approval of tedizolid phosphate for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Tedizolid phosphate is a once daily oxazolidinone being developed for both intravenous (I.V.) and oral administration for the treatment of serious Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA).

Emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating bacterial infections. One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have reviewed novel approaches to developing new antibiotics. However, the development of new antibacterial agents is a challenging task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have reviewed the challenges in the discovery of antibacterial agents.

Several antibacterial agents have been described in the prior art (for example, see PCT International Application Nos. PCT/US2010/060923, PCT/EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/EP2009/056178 and PCT/US2009/041200). However, there remains a need for potent antibacterial agents for preventing and/or treating bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.

my old article cut paste

ChemSpider 2D Image | Torezolid | C17H15FN6O3

Tedizolid, 856866-72-3


  • Molecular Formula: C17H15FN6O3
  • Average mass: 370.337799


Torezolid (also known as TR-701 and now tedizolid[1]) is an oxazolidinone drug being developed by Trius Therapeutics (originator Dong-A Pharmaceuticals) for complicated skin and skin-structure infections (cSSSI), including those caused by Methicillin-resistantStaphylococcus aureus (MRSA).[2]

As of July 2012, tedizolid had completed one phase III trial, with another one under way. [3]Both trials compare a six-day regimen of tedizolid 200mg once-daily against a ten-day regimen of Zyvox (linezolid) 600mg twice-daily.

The prodrug of tedizolid is called “TR-701″, while the active ingredient is called “TR-700″.[4][5]

March 5 2013

Trius Therapeutics will soon be reporting data from its second phase III trial (ESTABLILSH-2) and the recently announced publication of the data from its first phase III trial (ESTABLISH-1) in the Journal of the American Medical Association (JAMA)

  1. “Trius grows as lead antibiotic moves forward”. 31 Oct 2011.
  2. “Trius Completes Enrollment In Phase 2 Clinical Trial Evaluating Torezolid (TR-701) In Patients With Complicated Skin And Skin Structure Infections”. Jan 2009.
  4. PMID 19528279 In vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent.
  5. PMID 19218276 TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens.

Monoclonal antibody (mAbs) 2013

2013——-29 monoclonal antibody (mAbs) drugs are in Phase III clinical development.

While around 350 therapeutic mAbs are currently in clinical development globally, only 28 had entered active Phase 2/3 or Phase 3 studies as of January 2013,  Additionally one mAb mixture was under evaluation in Phase III.

Historically, mAbs that target antigens relevant to cancer have comprised approximately 50% of the mAb clinical pipeline,

but in 2013 the picture has changed: 66% or 19 of the antibodies to watch in 2013 are for non-cancer indications.

The non-cancer mAbs include alirocumab (Regeneron; Sanofi, hypercholesterinemia);

AMG 145 (Amgen, hypercholesterinemia),

epratuzumab (UCB, SLE),

gantenerumab (Roche; Alzheimer’s disease),

gevokizumab (Xoma/Servier, Non-infectious uveitis),

itolizumab (Biocon, Plaque psoriasis), ixekizumab (Eli Lilly and Co., psoriasis),

lebrikizumab (Roche/Genentech, rheumatoid arthritis),

mepolizumab (GSK, Asthma, COPD etc.),

ocrelizumab (Roche/Genentech, multiple sclerosis),

reslizumab (Teva, Eosinophilic asthma), romosozumab (Amgen, Postmenopausal osteoporosis),

sarilumab (Regeneron; Sanofi, rheumatoid arthritis),

secukinumab (Novartis, rheuma, psoriasis),

sirukumab (Janssen R&D LLC, rheumatoid arthritis),

solanezumab (Eli Lilly and Co., Alzheimer’s disease),

tabalumab (Eli Lilly and Co., rheuma, SLE)


vedolizumab (Millenium, Ulcerative colitis; Crohn disease).

The mixture of actoxumab and bezlotoxumab (MK-3415A, Merck & Co.) is being evaluated in two Phase 3 studies as a treatment for Clostridium difficile infection.

The ten cancer mAbs are:

elotuzumab (Bristol-Myers Squibb, Abbott, multiple myeloma),

farletuzumab (Morphotek, ovarian cancer),

inotuzumab ozogamicin (Pfizer; UCB, ALL, NHL),

naptumomab estafenatox (Active Biotech, renal cell carcinoma),

necitumumab (ImClone LLC, NSCL),

nivolumab (Bristol-Myers Squibb, NSCL, renal cell carcinoma),

obinutuzumab (Roche/Genetech, Diffuse large B cell lymphoma, CLL, NHL),

onartuzumab (Roche/Genetech, NSCL cancer; gastric cancer),

racotumomab (CIMAB; Laboratorio Elea S.A.C.I.F. y A, NSCL),

and ramucirumab (ImClone LLC, Gastric; liver, breast, colorectal, NSCL cancers).

Gilead Submits New Drug Application to U.S. FDA for Idelalisib for the Treatment of Indolent Non-Hodgkin’s Lymphoma


SEPT 2013

Gilead Submits New Drug Application to U.S. FDA for Idelalisib for the Treatment of Indolent Non-Hodgkin’s Lymphoma

FOSTER CITY, Calif.–(BUSINESS WIRE)–Sep. 11, 2013– Gilead Sciences, Inc. today announced that the company has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of idelalisib, an investigational, targeted, oral inhibitor of PI3K delta, for the treatment of indolent non-Hodgkin’s lymphoma (iNHL). The data submitted in this NDA support the use of idelalisib for patients with iNHL that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy.

read all at

January 2013 updated

Idelalisib ….US FDA Accepts NDA for Gilead’s Idelalisib for the Treatment of Refractory Indolent Non-Hodgkin’s Lymphoma




An antineoplastic agent and p110delta inhibitor


Icos (Originator)

  • CAL-101
  • GS-1101
  • Idelalisib
  • UNII-YG57I8T5M0

M.Wt: 415.43
Formula: C22H18FN7O

CAS No.: 870281-82-6
CAL-101 Solubility: DMSO ≥80mg/mL Water <1.2mg/mL Ethanol ≥33mg/mL



Idelalisib (codenamed GS-1101 or CAL-101) is a drug under investigation for the treatment of chronic lymphocytic leukaemia. It is in Phase III clinical trials testing drug combinations with rituximab and/or bendamustine as of 2013. The substance acts as aphosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase.[1][2]

GDC-0032 is a potent, next-generation beta isoform-sparing PI3K inhibitor targeting PI3Kα/δ/γ with IC 50 of 0.29 nM/0.12 nM/0.97nM,> 10 fold over Selective PI3K [beta].

GS-1101 is a novel, orally available small molecule inhibitor of phosphatidylinositol 3-kinase delta (PI3Kdelta) develop by Gilead and is waiting for registration in U.S. for the treatment of patients with indolent non-Hodgkin’s lymphoma that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy and for the treatment of chronic lymphocytic leukemia. The compound is also in phase III clinical evaluation for the treatment of elderly patients with previously untreated small lymphocytic lymphoma (SLL) and acute myeloid leukemia. Clinical trials had been under way for the treatment of inflammation and allergic rhinitis; however, no recent development has been reported. Preclinical studies have shown that GS-1101 has desirable pharmaceutical properties. The compound was originally developed by Calistoga Pharmaceuticals, acquired by Gilead on April 1, 2011.

clinical trials, click link

FOSTER CITY, Calif.–(BUSINESS WIRE)–Jan. 13, 2014– Gilead Sciences, Inc. (Nasdaq: GILD) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the company’s New Drug Application (NDA) for idelalisib, a targeted, oral inhibitor of PI3K delta, for the treatment of refractory indolent non-Hodgkin’s lymphoma (iNHL). FDA has granted a standard review for the iNHL NDA and has set a target review date under the Prescription Drug User Fee Act (PDUFA) of September 11, 2014.

The NDA for iNHL, submitted on September 11, 2013, was supported by a single arm Phase 2 study (Study 101-09) evaluating idelalisib in patients with iNHL that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy. Following Gilead’s NDA submission for iNHL, FDA granted idelalisib a Breakthrough Therapy designation for relapsed chronic lymphocytic leukemia (CLL). The FDA grants Breakthrough Therapy designation to drug candidates that may offer major advances in treatment over existing options. Gilead submitted an NDA for idelalisib for the treatment of CLL on December 6, 2013.

About Idelalisib

Idelalisib is an investigational, highly selective oral inhibitor of phosphoinositide 3-kinase (PI3K) delta. PI3K delta signaling is critical for the activation, proliferation, survival and trafficking of B lymphocytes and is hyperactive in many B-cell malignancies. Idelalisib is being developed both as a single agent and in combination with approved and investigational therapies.

Gilead’s clinical development program for idelalisib in iNHL includes Study 101-09 in highly refractory patients and two Phase 3 studies of idelalisib in previously treated patients. The development program in CLL includes three Phase 3 studies of idelalisib in previously treated patients. Combination therapy with idelalisib and GS-9973, Gilead’s novel spleen tyrosine kinase (Syk) inhibitor, also is being evaluated in a Phase 2 trial of patients with relapsed or refractory CLL, iNHL and other lymphoid malignancies.

Additional information about clinical studies of idelalisib and Gilead’s other investigational cancer agents can be found at Idelalisib and GS-9973 are investigational products and their safety and efficacy have not been established.

About Indolent Non-Hodgkin’s Lymphoma

Indolent non-Hodgkin’s lymphoma refers to a group of largely incurable slow-growing lymphomas that run a relapsing course after therapy and can lead ultimately to life-threatening complications such as serious infections and marrow failure. Most iNHL patients are diagnosed at an advanced stage of disease, and median survival from time of initial diagnosis for patients with the most common form of iNHL, follicular lymphoma, is 8 to 10 years. The outlook for refractory iNHL patients is significantly poorer.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

The delta form of PI3K is expressed primarily in blood-cell lineages, including cells that cause or mediate hematologic malignancies, inflammation, autoimmune diseases and allergies. By specifically inhibiting only PI3K delta, a therapeutic effect is exerted without inhibiting PI3K signalling that is critical to the normal function of healthy cells. Extensive studies have shown that inhibition of other PI3K forms can cause significant toxicities, particularly with respect to glucose metabolism, which is essential for normal cell activity.

In 2011, orphan drug designation was assigned to GS-1101 in the U.S. for the treatment of CLL. In 2013, several orphan drug designations were assigned to the compound in the E.U. and U.S.: for the treatment of follicular lymphoma, for the treatment of mucosa-associated lymphoid tissue lymphoma (MALT), for the treatment of nodal marginal zone lymphoma, for the treatment of splenic marginal zone lymphoma, and for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma. Orphan drug designation was also assigned in the U.S. for the treatment of lymphoplasmacytic lymphoma with or without Walenstom’s macroglobulinemia and, in the E.U., for the treatment of Waldenstrom’s macroglobulinemia (lymphoplasmacytic lymphoma).

Later in 2013, some of these orphan drug designations were withdrawn in the E.U.; for the treatment of chronic lymphocytic leukemia / small lymphocytic lymphoma, for the treatment of extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), for the treatment of of nodal marginal-zone lymphoma and for the treatment of splenic marginal-zone lymphoma. In 2013, the FDA granted a breakthrough therapy designation for the treatment of chronic lymphocytic leukemia.

  1.  H. Spreitzer (13 May 2013). “Neue Wirkstoffe – Ibrutinib und Idelalisib”. Österreichische Apothekerzeitung (in German) (10/2013): 34.
  2.  Wu, M.; Akinleye, A.; Zhu, X. (2013). “Novel agents for chronic lymphocytic leukemia”.Journal of Hematology & Oncology 6: 36. doi:10.1186/1756-8722-6-36.PMC 3659027PMID 23680477.


CAL-101 is an Oral Delta Isoform-Selective PI3 Kinase Inhibitor.

CAL-101 (GS 1101) is a potent PI3K p110δ inhibitor with an IC50 of 65 nM. PI3K-delta inhibitor CAL-101 inhibits the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), preventing the activation of the PI3K signaling pathway and thus inhibiting tumor cell proliferation, motility, and survival. Unlike other isoforms of PI3K, PI3K-delta is expressed primarily in hematopoietic lineages. The targeted inhibition of PI3K-delta is designed to preserve PI3K signaling in normal, non-neoplastic cells. [3][4]
[3] Blood 2011, 117, 591-594.
[4] Blood, 2010, 116, 2078-2088.
5. WO 2005113556
6. WO 2005113554
7. WO 2010057048
8. WO 2011156759
9. WO 2012125510
10. WO 2013134288
11. US 2013274198
12. J Med Chem. 2013 Mar 14;56(5):1922-39. doi: 10.1021/jm301522m
US7932260 4-27-2011 Quinazolinones as Inhibitors of Human Phosphatidylinositol 3-Kinase Delta
WO2005113556A1 * 12 May 2005 1 Dec 2005 Icos Corp Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
WO2005117889A1 * 12 Nov 2004 15 Dec 2005 Didier Bouscary Methods for treating and/or preventing aberrant proliferation of hematopoietic
WO2005120511A1 * 4 Jun 2005 22 Dec 2005 Joel S Hayflick Methods for treating mast cell disorders
WO2006089106A2 * 16 Feb 2006 24 Aug 2006 Icos Corp Phosphoinositide 3-kinase inhibitors for inhibiting leukocyte accumulation
US20060106038 * 25 May 2005 18 May 2006 Icos Corporation Methods for treating and/or preventing aberrant proliferation of hematopoietic cells

The synthesis of a compound in accordance with formula I is first exemplified using steps A-E below, which provide a synthetic procedure for compound 107, the structure of which is shown below.

Figure imgf000150_0001

(107) is idelalisib


Synthesis of 2-fluoro-6-nitro-N-phenyl-benzamide (108)

Step A: A solution of 2-fluoro-6- nitrobenzoic acid (100 g, 0.54 mol) and dimethylformamide (5 mL) in dichloromethane (600 mL) was treated dropwise with oxalyl chloride (2 M in dichloromethane, 410 mL, 0.8 mol, 1.5 eq) over 30 min. After stirring 2 h at room temperature, the reaction was concentrated to an orange syrup with some solids present. The syrup was dissolved in dry dioxane (80 mL) and slowly added to a suspension of aniline (49 mL, 0.54 mol, 1 eq) and sodium bicarbonate (90 g, 1.08 mol, 2 eq) in a mixture of dioxane (250 mL) and water (250 mL) at 6 0C. The temperature reached 27°C at the end of the addition. After 30 min, the reaction mixture was treated with water (1.2 L). The precipitate was collected by vacuum filtration, washed with water (300 mL) , air dried in the funnel, and dried in vacuo at 50°C for 24 h to afford an off-white solid product (139 g, 99%). 1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, IH), 8.12 (d, J = 7.7 Hz, IH), 7.91-7.77 (m, 2H), 7.64 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.15 > (t, J = 7.4 Hz, IH), ESI-MS m/z 261 (MH+). The reaction described above and compound 108 are shown below.

Figure imgf000151_0001


Synthesis of(S) – [1- (2-fluoro-6-nitro-benzoyl) -phenyl-aminocarbonyl] – propyl-carbamic acid tert-butyl ester (109)

Step B: A suspension of compound 108 (0.5 mol) and dimethylformamide (5 mL) in thionyl chloride (256 mL, 2.5 mol, 5 eq) was stirred at 85°C for 5 hours. The reaction mixture was concentrated in vacuo to a brown syrup. The syrup was dissolved in dichloromethane (200 mL) and was slowly added to a solution of N-BOC-L-2-aminobutyric acid (112 g, 0.55 mol, 1.1 eq) and triethylamine (77 mL, 0.55 mol, 1.1 eq) in dichloromethane (600 mL) at 10 0C. After stirring at room temperature for 3 h, salts were removed by filtration, and the solution was washed with 100 mL of water, saturated sodium bicarbonate, water, 5% citric acid, and saturated sodium chloride. The organic phase was dried with magnesium sulfate and concentrated to a red syrup. The syrup was dissolved in dichloromethane (450 mL) and purified by flash chromatography on a silica gel plug (15 x 22 cm, 4 L dry silica) eluted with hexanes/ethyl acetate (10%, 8 L; 15%, 8 L; 20%, 8 L; 25%, 4 L) to yield the compound 109 as an off-white solid (147 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 8.13 (d, J = 8.0 Hz, IH), 7.84 (t, J = 8.6 Hz, IH), 7.78- 7.67 (m, IH), 7.65-7.49 (m, 3H), 7.40-7.28 ( m, 2H), 7.19 (d, J = 7.5 Hz, IH), 4.05 (broad s, IH), 1.75- 1.30 (m, 2H), 1.34 (s, 9H), 0.93 (broad s, 3H). ESI- MS m/z 446.3 (MH+) . The reaction described above and compound 109 are shown below.

Figure imgf000152_0001

Synthesis of(S) – [1- (5-fluoro-4-oxo-3-phenyl-3 , 4-dihydro-quinazolin-2- yl) -propyl] -carbamic acid tert-butyl ester (110)

Step C: A solution of compound 109 (125 mmol, 1 eq) in acetic acid (500 mL) was treated with zinc dust (48.4 g, 740 mmol, 6 eq) added in 3 portions, and the reaction mixture was allowed to cool to below 35°C between additions. After stirring for 2 h at ambient temperature, solids were filtered off by vacuum filtration and washed with acetic acid (50 mL) . The filtrate was concentrated in vacuo, dissolved in EtOAc (400 mL) , washed with water (300 mL) , and the water layer was extracted with EtOAc (300 mL) . The combined organic layers were washed with water (200 mL) , sat’d sodium bicarbonate (2 x 200 mL) , sat’d NaCl (100 mL) , dried with MgSO4, and concentrated to a syrup. The syrup was dissolved in toluene (200 mL) and purified by flash chromatography on a silica gel plug (13 x 15 cm, 2 L dry silica) eluted with hexanes/ethyl acetate (10%, 4 L; 15%, 4 L; 17.5%, 8 L; 25%, 4 L) to yield compound 110 as an off-white foamy solid (33.6 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (td, J = 8.2, 5.7 Hz, IH), 7.64-7.48 (m, 5H), 7.39 (broad d, J = 7.6 Hz, IH), 7.30 (dd, J = 8.3 Hz, IH), 7.23 (d, J = 7.6 Hz, IH), 4.02-3.90 (m, IH), 1.76-1.66 (m, IH), 1.62-1.46 (m, IH), 1.33 (s, 9H), 0.63 (t, J= 7.3 Hz, 3H). ESI-MS m/z 398.3 (MH+). The reaction described above and compound 110 are shown below.

Figure imgf000153_0001


Syn of (S) -2- (1-amino-propyl) -5-fluoro-3-phenyl-3H-quinazolin-4- one (111)

Step D: A solution of compound 110 (85 mmol) in dichloromethane (60 mL) was treated with trifluoroacetic acid (60 mL) . The reaction mixture was stirred for 1 h, concentrated in vacuo, and partitioned between dichloromethane (150 mL) and 10% K2CO3 (sufficient amount to keep the pH greated than 10) . The aqueous layer was extracted with additional dichloromethane (100 raL) , and the combined organic layers were washed with water (50 mli) and brine (50 mL) . After drying with Mg SO4, the solution was concentrated to provide compound 111 as an off-white solid (22 g, 88%) . 1H NMR (300 MHz,

CDCl3) δ 7.73-7.65 (m, IH), 7.62-7.49 (m, 4H), 7.32- 7.22 (m, 2H), 7.13-7.06 (m, IH), 3.42 (dd, J= 7.5, 5.2 Hz, IH), 1.87-1.70 (m, IH), 1.58-1.43 (m, IH), 0.80 (t, J = 7.4 Hz, 3H) . ESI-MS m/z 298.2 (MH+) . The reaction described above and compound 111 are shown below.

Figure imgf000154_0001


syn of (S) -5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -propyl] – 3H-quinazolin-4-one (107)

Step E: A suspension of compound 111(65.6 mmol, 1 eq) , 6-bromopurine (14.6 g, 73.4 mmol, 1.1 eq) , and DIEA (24.3 mL, 140 mmol, 2 eq) in tert- butanol (40 mL) was stirred for 24 h at 800C. The reaction mixture was concentrated in vacuo and treated with water to yield a solid crude product that was collected by vacuum filtration, washed with water, and air dried. Half of the obtained solid crude product was dissolved in MeOH (600 mL) , concentrated onto silica gel (300 mL dry) , and purified by flash chromatography (7.5 x 36 cm, eluted with 10 L of 4% MeOH/CH2Cl2) to yield a solid product. The solid product was then dissolved in EtOH (250 mL) and concentrated in vacuo to compound 107 idelalisib as a light yellow solid (7.2 g, 50%).

1H NMR (300 MHz, 80 0C, DMSO-d5) δ 12.66 (broad s, IH), 8.11 (s, IH), 8.02 (broad s, IH), 7.81-7.73 (m, IH),7.60-7.42 (m, 6H), 7.25-7.15 (m, 2H), 4.97 (broad s, IH), 2.02-1.73 (m, 2H), 0.79 (t, J= 7.3 Hz, 3H).

ESI-MS m/z 416.2 (MH+).

C, H, N elemental analysis (C22Hi8N7OF-EtOH- 0.4 H2O).

Chiral purity 99.8:0.2 (S:R) using chiral HPLC (4.6 x 250 mm Chiralpak ODH column, 20 °C, 85:15 hexanes : EtOH, 1 rnL/min, sample loaded at a concentration of 1 mg/mL in EtOH) . The reaction described above and compound 107 idelalisib are shown below.

Figure imgf000155_0001
WO2001030768A1 * 26 Oct 2000 3 May 2001 Gustave Bergnes Methods and compositions utilizing quinazolinones
WO2001081346A2 * 24 Apr 2001 1 Nov 2001 Icos Corp Inhibitors of human phosphatidyl-inositol 3-kinase delta
WO2003035075A1 * 27 Aug 2002 1 May 2003 Icos Corp Inhibitors of human phosphatidyl-inositol 3-kinase delta
WO2005016348A1 * 13 Aug 2004 24 Feb 2005 Jason Douangpanya Method of inhibiting immune responses stimulated by an endogenous factor
WO2005016349A1 * 13 Aug 2004 24 Feb 2005 Thomas G Diacovo Methods of inhibiting leukocyte accumulation
WO2005067901A2 * 7 Jan 2005 28 Jul 2005 Carrie A Northcott Methods for treating and preventing hypertension and hypertension-related disorders
Identification of potent Yes1 kinase inhibitors using a library screening approach.
Bioorganic & medicinal chemistry letters
Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors.
Journal of medicinal chemistry
PI3Kδ and PI3Kγ as targets for autoimmune and inflammatory diseases.
Journal of medicinal chemistry

Share this:

Access 4,000+ profiles of new drugs in development!



Sign up for a 5-day trial and learn why the Drugs in Clinical Trials Database is a cost-effective way to find detailed information on new drug therapies in hundreds of disease conditions worldwide, monitor drug performance, track competitors and find study opportunities.

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.


FDA Approves Investigational MS Trial

The stem cell research division of the Tisch MS Research Center of New York announced that the U.S. Food and Drug Administration (FDA) approved autologous, mesenchymal stem cell-derived neural progenitor cells (MSC-NPs) as an Investigational New Drug (IND) for an open label, phase 1 clinical trial in the treatment of multiple sclerosis.


%d bloggers like this: