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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 AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, 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 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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Tafamidis skeletal.svgChemSpider 2D Image | Tafamidis | C14H7Cl2NO3


  • Molecular Formula C14H7Cl2NO3
  • Average mass 308.116 Da


2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
594839-88-0 [RN]
6-Benzoxazolecarboxylic acid, 2-(3,5-dichlorophenyl)-
Tafamidis meglumine
Familial amyloid polyneuropathy LAUNCHED PFIZER 2011 EU
ApprovedJapanese Pharmaceuticals and Medical Devices Agency in September 2013
PHASE 3, at  FDA, Amyloidosis, PFIZER
Image result for Vyndaqel tafamidis meglumine
Molecular Formula: C21H24Cl2N2O8
Molecular Weight: 503.329 g/mol

CAS 951395-08-7

Image result for Vyndaqel tafamidis meglumine

D-Glucitol, 1-deoxy-1-(methylamino)-, 2-(3,5-dichlorophenyl)-6-benzoxazolecarboxylate

Tafamidis (INN, or Fx-1006A,[1] trade name Vyndaqel) is a drug for the amelioration of transthyretin-related hereditary amyloidosis(also familial amyloid polyneuropathy, or FAP), a rare but deadly neurodegenerative disease.[2][3] The drug was approved by the European Medicines Agency in November 2011 and by the Japanese Pharmaceuticals and Medical Devices Agency in September 2013.[4]

In 2011 and 2012, orphan drug designation was assigned in Japan and the U.S., respectively, for the treatment of transthyretin amyloid polyneuropathy. This designation was assigned in the E.U. in 2012 for the treatment of senile systemic amyloidosis. In 2017, fast drug designation was assigned in the U.S. for the treatment of transthyretin cardiomyopathy.

Tafamidis is a novel specific transthyretin (TTR) stabilizer or dissociation inhibitor. TTR is a tetramer that is responsible in transporting the retinol-binding protein-vitamin A complex and minimally transporting thyroxine in the blood. In TTR-related disorders such as transthyretin familial amyloid polyneuropathy (TTR-FAP), tetramer dissociation is accelerated that results in unregulated amyloidogenesis and amyloid fibril formation. Eventually the failure of autonomic and peripheral nervous system is induced. Tafamidiswas approved by the European Medicines Agency (EMA) in 2011 under the market name Vyndaqel for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adult patients with early-stage symptomatic polyneuropathy to delay peripheral neurologic impairment. Tafamidis is an investigational drug under the FDA and in June 2017, Pfizer received FDA Fast Track Designation for tafamidis

Image result for TAFAMIDIS

The marketed drug, a meglumine salt, has completed an 18 month placebo controlled phase II/III clinical trial,[5][6] and an 12 month extension study[7] which provides evidence that tafamidis slows progression of Familial amyloid polyneuropathy.[8] Tafamidis (20 mg once daily) is used in adult patients with an early stage (stage 1) of familial amyloidotic polyneuropathy.[9][10]

Tafamidis was discovered in the Jeffery W. Kelly Laboratory at The Scripps Research Institute[11] using a structure-based drug design strategy[12] and was developed at FoldRx pharmaceuticals, a biotechnology company Kelly co-founded with Susan Lindquist. FoldRx was led by Richard Labaudiniere when it was acquired by Pfizer in 2010.

Tafamidis functions by kinetic stabilization of the correctly folded tetrameric form of the transthyretin (TTR) protein.[13] In patients with FAP, this protein dissociates in a process that is rate limiting for aggregation including amyloid fibril formation, causing failure of the autonomic nervous system and/or the peripheral nervous system (neurodegeneration) initially and later failure of the heart. Kinetic Stabilization of tetrameric transthyretin in familial amyloid polyneuropathy patients provides the first pharmacologic evidence that the process of amyloid fibril formation causes this disease, as treatment with tafamidis dramatically slows the process of amyloid fibril formation and the degeneration of post-mitotic tissue. Sixty % of the patients enrolled in the initial clinical trial have the same or an improved neurologic impairment score after six years of taking tafamidis, whereas 30% of the patients progress at a rate ≤ 1/5 of that predicted by the natural history. Importantly, all of the V30M FAP patients remain stage 1 patients after 6 years on tafamidis out of four stages of disease progression. [Data presented orally by Professor Coelho in Brazil in 2013][7]

The process of wild type transthyretin amyloidogenesis also appears to cause wild-type transthyretin amyloidosis (WTTA), also known as senile systemic amyloidosis (SSA), leading to cardiomyopathy as the prominent phenotype.[14] Some mutants of transthyretin — including V122I, which is primarily found in individuals of African descent — are destabilizing, enabling heterotetramer dissociation, monomer misfolding, and subsequent misassembly of transthyretin into a variety of aggregate structures [15] including amyloid fibrils[16]leading to familial amyloid cardiomyopathy.[17] While there is clinical evidence from a small number of patients that tafamidis slows the progression of the transthyretin cardiomyopathies,[18] this has yet to be demonstrated in a placebo-controlled clinical trial. Pfizer has enrolled a placebo-controlled clinical trial to evaluate the ability of tafamidis to slow the progression of both familial amyloid cardiomyopathy and senile systemic amyloidosis ( identifier: NCT01994889).

Regulatory Process

Tafamidis was approved for use in the European Union by the European Medicines Agency in November 2011, specifically for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). In September 2013 Tafamidis was approved for use in Japan by the Pharmaceuticals and Medical Devices Agency, specifically for the treatment of transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). Tafamidis is also approved for use in Brazil, Argentina, Mexico and Israel by the relevant authorities.[19] It is currently being considered for approval by the United States Food and Drug Administration (FDA) for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP.

In June 2012, the FDA Peripheral and Central Nervous System Drugs Advisory Committee voted “yes” (13-4 favorable vote) when asked if the findings of the pivotal clinical study with tafamidis were “sufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefit”. The Advisory Committee voted “no” 4-13 to reject the drug–in spite of the fact that both primary endpoints were met in the efficacy evaluable population (n=87) and were just missed in the intent to treat population (n=125), apparently because more patients than expected in the intent to treat population were selected for liver transplantation during the course of the trial, not owing to treatment failure, but because their name rose to the top of the transplant list. However, these patients were classified as treatment failures in the conservative analysis used.

Pfizer (following its acquisition of FoldRx ), under license from Scripps Research Institute , has developed and launched tafamidis, a small-molecule transthyretin stabilizer, useful for treating familial amyloid polyneuropathy.


 European Journal of Medicinal Chemistry, 121, 823-840; 2016



THE SCRIPPS RESEARCH INSTITUTE [US/US]; 10550 N Torrey Pines Road, La Jolla, CA 92037 (US)

KELLY, Jeffrey, W.; (US).
SEKIJIMA, Yoshiki; (US)

Image result for The Scripps Research Institute

Dr. Jeffery W. Kelly

Lita Annenberg Hazen Professor of Chemistry

Co-Chairman, Department of Molecular Medicine

Click here to download a concise version of Dr. Jeffery Kelly’s curriculum vitae.

Image result for The Scripps Research Institute



Example 5: Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors
Transthyretin’s two thyroxine binding sites are created by its quaternary structural interface. The tetramer can be stabilized by small molecule binding to these sites, potentially providing a means to treat TTR amyloid disease with small molecule drugs. Many families of compounds have been discovered whose binding stabilizes the tetrameric ground state to a degree proportional to the small molecule dissociation constants Km and Ka2. This also effectively increases the dissociative activation barrier and inhibits amyloidosis by kinetic stabilization. Such inhibitors are typically composed of two aromatic rings, with one ring bearing halogen substituents and the other bearing hydrophilic substituents. Benzoxazoles substituted with a carboxylic acid at C(4)-C(7) and a halogenated phenyl ring at C(2) also appeared to complement the TTR thyroxine binding site. A small library of these compounds was therefore prepared by dehydrocyclization of N-acyl amino-hydroxybenzoic acids as illustrated in Scheme 1.

Scheme 1: General Synthesis of Benzoxazoles
Reagents: (a) ArCOCl, THF, pyridine (Ar = Phenyl, 3,5-Difluorophenyl, 2,6-Difluorophenyl, 3,5-Dichlorophenyl, 2,6-Dichlorophenyl, 2-(Trifluoromethyl)phenyl, and 3-(Trifluoromethyl)phenyl); (b) TsOH*H2O, refluxing xylenes; (c) TMSCHN2, benzene, MeOH; (d) LiOH, THF, MeOH, H2O (8-27% yield over 4 steps).

The benzoxazoles were evaluated using a series of analyses of increasing stringency. WT TTR (3.6 μM) was incubated for 30 min (pH 7, 37 °C) with a test compound (7.2 μM). Since at least one molecule ofthe test compound must bind to each molecule of TTR tetramer to be able to stabilize it, a test compound concentration of 7.2 μM is only twice the minimum effective concentration. The pH was then adjusted to 4.4, the optimal pH for fibrilization. The amount of amyloid formed after 72 h (37 °C) in the presence ofthe test compound was determined by turbidity at 400 nm and is expressed as % fibril formation (ff), 100%) being the amount formed by TTR alone. Ofthe 28 compounds tested, 11 reduced fibril formation to negligible levels (jf< 10%; FIG. 7).
The 11 most active compounds were then evaluated for their ability to bind selectively to TTR over, all other proteins in blood. Human blood plasma (TTR cone. 3.6 -5.4 μM) was incubated for 24 h with the test compound (10.8 μM) at 37 °C. The TTR and any bound inhibitor were immunoprecipitated using a sepharose-bound polyclonal TTR antibody. The TTR with or without inhibitor bound was liberated from the resin at high pH, and the inhibitor: TTR stoichiometry was ascertained by HPLC analysis (FIG. 8). Benzoxazoles with carboxylic acids in the 5- or 6-position, and 2,6-dichlorophenyl (13, 20) or 2-trifluoromethylphenyl (11, 18) substituents at the 2-position displayed the highest binding stoichiometries. In particular, 20 exhibited excellent inhibitory activity and binding selectivity. Hence, its mechanism of action was characterized further.
To confirm that 20 inhibits TTR fibril formation by binding strongly to the tetramer, isothermal titration calorimetry (ITC) and sedimentation velocity experiments were conducted with wt TTR. ITC showed that two equivalents of 20 bind with average dissociation constants of Kdi = Kd2 = 55 (± 10) nM under physiological conditions. These are comparable to the dissociation constants of many other highly efficacious TTR
amyloidogenesis inhibitors. For the sedimentation velocity experiments, TTR (3.6 μM) was incubated with 20 (3.6 μM, 7.2 μM, 36 μM) under optimal fibrilization conditions (72 h, pH 4.4, 37 °C). The tetramer (55 kDa) was the only detectable species in solution with 20 at 7.2 or 36 μM. Some large aggregates formed with 20 at 3.6 μM, but the TTR remaining in solution was tetrameric.
T119M subunit inclusion and small molecule binding both prevent TTR amyloid formation by raising the activation barrier for tetramer dissociation. An inhibitor’s ability to do this is most rigorously tested by measuring its efficacy at slowing tetramer dissociation in 6 M urea, a severe denaturation stress. Thus, the rates of TTR tetramer dissociation in 6 M urea in the presence and absence of 20, 21 or 27 were compared (FIG. 9). TTR (1.8 μM) was completely denatured after 168 h in 6 M urea. In contrast, 20 at 3.6 μM prevented tetramer dissociation for at least 168 h (> 3 the half-life of TTR in human plasma). With an equimolar amount of 20, only 27% of TTR denatured in 168 h. Compound 27 (3.6 μM) was much less able to prevent tetramer dissociation (90% unfolding after 168 h), even though it was active in the fibril formation assay. Compound 21 did not hinder the dissociation of TTR at all. These results show that inhibitor binding to TTR is necessary but not sufficient to kinetically stabilize the TTR tetramer under strongly denaturing conditions; it is also important that the dissociation constants be very low (or that the off rates be very slow). Also, the display of functional groups on 20 is apparently optimal for stabilizing the TTR tetramer; moving the carboxylic acid from C(6) to C(7), as in 27, or removing the chlorines, as in 21, severely diminishes its activity.

The role ofthe substituents in 20 is evident from its co-crystal stracture with TTR (FIG. 10). Compound 20 orients its two chlorine atoms near halogen binding pockets 2 and 2′ (so-called because they are occupied by iodines when thyroxine binds to TTR). The 2,6 substitution pattern on the phenyl ring forces the benzoxazole and phenyl rings out of planarity, optimally positioning the carboxylic acid on the benzoxazole to hydrogen bond to the ε-NH3+ groups of Lys 15/15′. Hydrophobic interactions between the aromatic rings of 20 and the side chains of Leu 17, Leu 110, Ser 117, and Val 121 contribute additional binding energy.


ChemMedChem (2013), 8(10), 1617-1619.

Nature Reviews Drug Discovery (2012), 11(3), 185-186


Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV
J Med Chem 2011, 54(2): 510



Novel crystalline forms of tafamidis methylglucamine (designated as Form E), processes for their preparation and compositions comprising them are claimed. Also claimed is their use for treating familial amyloid neuropathy. Represents first PCT filing from Crystal Pharmatech and the inventors on this API.;jsessionid=2C2DC88BD4DC90B179C38EC5283D0941.wapp2nA?docId=WO2017190682&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText


Image result for TAFAMIDIS

2-(3, 5-Dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis)

m.p. = 200.4–202.7 °C; Rf = 0.37 (petroleum ether/ethyl acetate/acetic acid = 6:1:0.01).

IR (cm-1 , KBr): 3383, 1685, 1608, 1224, 769;

1H NMR (DMSO-d6, 400 MHz) (ppm) 8.27 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 8.04–8.02 (m, 1H), 7.94 (s, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 6.8 Hz, 5.2 Hz, 1H);

13C NMR (DMSOd6, 100 MHz) (ppm) 167.2, 162.1, 150.1, 145.0, 137.8, 133.7, 131.4, 128.6, 126.8, 124.3, 120.5, 112.6.

Data was consistent with that reported in the literature. [27]Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet, J.; Yamaguchi, J.; Itami, K. Chem. Eur. J. 2011, 17, 10113.


Image result for TAFAMIDIS


Proc Natl Acad Sci U S A. 2012 Jun 12; 109(24): 9629–9634.
Published online 2012 May 29. doi:  10.1073/pnas.1121005109


The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A–retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (Kds ∼2 nM and ∼200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.

4-Amino-3-hydroxybenzoic acid (AHBA) is reacted with HCl (3 to 6 M equivalents) in methanol (8 to 9 L/kg). Methyl t-butyl ether (TBME) (9 to 11 L/kg) is then added to the reaction mixture. The product, methyl 4-amino-3-hydroxybenzoate hydrochloride salt, is isolated by filtration and then reacted with 3,5-dichlorobenzoyl chloride (0.95 to 1.05 M equivalents) in the presence of pyridine (2.0 to 2.5 M equivalents) in dichloromethane (DCM), (8 to 9 L/kg) as a solvent. After the distillation of DCM, acetone and water are added to the reaction mixture, producing methyl 4-(3,5-dichlorobenzoylamino)-3- hydroxy-benzoate. This is recovered by filtration and reacted with p-toluenesulfonic acid monohydrate (0.149 to 0.151 M equivalents) in toluene (12 to 18 L/kg) at reflux with water trap. Treatment with charcoal is then performed. After the distillation of toluene, acetone (4-6 L/kg) is added. The product, methyl 2-(3,5-dichlorophenyl)-benzoxazole-6- carboxylate, is isolated by filtration and then reacted with LiOH (1.25 to 1.29 M equivalents) in the presence of tetrahydrofuran (THF) (7.8 to 8.2 L/kg) and water (7.8 to 8.2 L/kg) at between 40 and 45 °C. The pH of the reaction mixture is adjusted with aqueous HCl to yield 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, the free acid of tafamidis. This is converted to the meglumine salt by reacting with N-methyl-Dglucamine (0.95 to 1.05 M equivalents) in a mixture of water (4.95 to 5.05 L/kg)/isopropyl alcohol (19.75 to 20.25 L/kg) at 65-70 °C. Tafamidis meglumine (dglucitol, 1-deoxy-1-(methylamino)-,2-(3,5-dichlorophenyl)-6-benzoxazole carboxylate) is then isolated by filtration.

2 The following fragments were identified from electrospray ionization mass spectra acquired in positive-ion mode: meglumine M+ (C7H18NO5+, m/z = 196.13), M (carboxylate form) +2H (C14H6Cl2NO3, m/z = 308.13), M (salt) + H (C21H24Cl2N2O8, m/z = 504.26). 1 H-nuclear magnetic resonance spectra were acquired on a 700 MHz Bruker AVANCE II spectrometer in acetone:D2O (~8:2). Data were reported as chemical shift in ppm (δ), multiplicity (s = singlet, dd = double of doublets, m = multiplet), coupling constant (J Hz), relative integral and assignment: δ = 8.14 (m, JH2-H5 = 0.6 and JH2-H6 = 1.5, 1H, H2), 8.02 (dd, JH9-H11 = 1.9 and JH13-H11 = 1.9, 2H, H9 and H13), 7.97 (dd, JH6-H5 = 8.25, 1H, H6), 7.67 (dd, JH5-H2 = 0.6 and JH5-H6 = 8.25, 1H, H5), 7.58 (m, JH11-H9 = 1.9 and JH11-H13 = 1.9, 1H, H11), 4.08 (m, JH16-H17 = 4.9, 1H, H16), 3.79 (dd, JH17-H18 = 2.2, 1H, H17), 3.73 (dd, JH19-H20 = 3.2, 1H, H20), 3.69 (m, JH19-H20 = 3.2, 1H, H19), 3.61 (m, JH18-H19 = 12.25, 1H, H18), 3.58 (m, JH19-H20′ = 5.8 and JH20-H20′ = 11.7, 1H, H20′ ), 3.19 (m, JH15-H15′ = 12.9 and JH15′-H16 = 9.25 and JH15-H16 = 3.5, 2H, H15).


Concise Synthesis of Tafamidis (Scheme 8)

4-(6-Benzoxazoyl)morpholine (8)


A mixture of 4-amino-3-hydroxybenzoic acid (1.53 g, 10 mmol) and trimethyl orthofomate (3 mL) was heated at 100 ºC for 5 h. After cooling to room temperature, trimethyl orthofomate was removed under reduced pressure. To a solution of benzoxazole 6-carboxylic acid in CH2Cl2 (10 mL) were added DMF (0.1 mL) and oxalyl chloride (1.8 mL, 20 mmol) and the resultant mixture was stirred at room temperature for 12 h. After cooling to room temperature, DMF and oxalyl chloride were removed under reduced pressure to yield the corresponding acid chloride as a solid. Thus-generated acid chloride and morpholine (2.2 mL) were stirred at room temperature for 3 h. After removing solvents under reduced pressure, the mixture was treated with saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with brine (20 mL), dried with anhydrous magnesium sulfate, and the solvent removed under reduced pressure. Purification of the resulting oil by flash column chromatography on silica (5% methanol in CHCl3 as eluent) afforded heteroarene 8 (1.30 g, 56%) as a white solid. Rf = 0.47 (MeOH/CHCl3 = 1:20). 1 H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.71 (s, 1H) 7.44 (d, J = 7.6 Hz, 1H), 4.00–3.25 (br, 8H). 13C NMR (150 MHz, CDCl3) δ 169.52, 153.87, 149.67, 141.24, 132.90, 123.79, 120.76, 110.48, 66.81. HRMS (DART) m/z calcd for C12H13N2O3 [MH]+ : 233.0926, found 233.0926.

4-(3,5-Dichlorophenyl 6-benzoxazoyl)morpholine

To a 20-mL glass vessel equipped with J. Young® O-ring tap containing a magnetic stirring bar were added Ni(cod)2 (13.9 mg, 0.05 mmol), 2,2’-bipyridyl (7.8 mg, 0.05 mmol), LiOt-Bu (60 mg, 0.75 mmol), 8 (174.2 mg, 0.5 mmol), 3,5-dichloroiodobenzene (9: 203.9 mg, 0.75 mmol), followed by dry 1,2-dimethoxyethane (2.0 mL). The vessel was sealed with an O-ring tap and then heated at 100 °C in an 8-well reaction block with stirring for 24 h. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica gel pad (EtOAc). The filtrate was concentrated and the residue was subjected to preparative thin-layer chromatography (5% methanol in CHCl3 as eluent) to afford SI-2 (139.6 mg, 74 %) as a white foam. Rf = 0.70 (MeOH/CHCl3 = 1:20). 1 H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 2.0 Hz, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 4.00–3.25 (br, 8H). 13C NMR (150 MHz, CDCl3) δ 169.38, 161.78, 150.40, 142.90, 135.82, 132.95, 131.61, 129.26, 125.91, 124.23, 120.41, 110.26, 66.77. HRMS (DART) m/z calcd for C18H15Cl2N2O3 [MH]+ : 377.0460 found 377.0465.

Tafamidis[19  ] Razavi, H.; Palaninathan, S. K.; Powers, E. T.; Wiseman, R. L.; Purkey, H. E.; Mohamedmohaideen, N. N.; Deechongkit, S.; Chiang, K. P.; Dendle, M. T. A.; Sacchettini, J. C.; Kelly, J. W. Angew. Chem. Int. Ed. 2003, 42, 2758.]

HF·pyridine (0.5 mL) was added to a stirred solution of SI-2 (32 mg, 0.09 mmol) in THF (0.5 mL) at 70 ºC for 12 h. After cooling the reaction mixture to room temperature, the mixuture was diluted with EtOAc and washed sequentially with sat.NaHCO3, 2N HCl and brine. The organic layer was concentrated and the residue was subjected to preparative thin-layer chromatography (1% acetic acid, 5% methanol in CHCl3 as eluent) to afford tafamidis (24.7 mg, 94%) as a white foam.

1 H NMR (600 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.08 (d, J = 1.4 Hz, 2H), 8.00 (d, J = 8.3 Hz, 1H), 7.88 (m, 2H).

13C NMR (150 MHz, DMSO-d6) δ 166.6, 162.0, 150.0, 144.6, 135.1, 131.7, 129.1, 128.7, 126.5, 125.8, 120.0, 112.2.

HRMS (DART) m/z calcd for C14H8Cl2NO3 [MH]+ : 307.9881, found 307.9881.


  1. Jump up^ Bulawa, C.E.; Connelly, S.; DeVit, M.; Wang, L. Weigel, C.;Fleming, J. Packman, J.; Powers, E.T.; Wiseman, R.L.; Foss, T.R.; Wilson, I.A.; Kelly, J.W.; Labaudiniere, R. “Tafamidis, A Potent and Selective Transthyretin Kinetic Stabilizer That Inhibits the Amyloid Cascade”. Proc. Natl. Acad. Sci., 2012 109, 9629-9634.
  2. Jump up^ Ando, Y., and Suhr, O.B. (1998). Autonomic dysfunction in familial amyloidotic polyneuropathy (FAP). Amyloid, 5, 288-300.
  3. Jump up^ Benson, M.D. (1989). “Familial Amyloidotic polyneuropathy”. Trends in Neurosciences, 12.3, 88-92, PMID 2469222doi:10.1016/0166-2236(89)90162-8.
  4. Jump up^
  5. Jump up^ Clinical trial number NCT00409175 for “Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis” at
  6. Jump up^ Coelho, T.; Maia, L.F.; Martins da Silva, A.; Cruz, M.W.; Planté-Bordeneuve, V.; Lozeron, P.; Suhr, O.B.; Campistol, J.M.; Conceiçao, I.; Schmidt, H.; Trigo, P. Kelly, J.W.; Labaudiniere, R.; Chan, J., Packman, J.; Wilson, A.; Grogan, D.R. “Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial”. Neurology, 2012, 79, 785-792.
  7. Jump up to:a b Coelho, T.; Maia, L.F.; Martins da Silva, A.; Cruz, M.W.; Planté-Bordeneuve, V.; Suhr, O.B.; Conceiçao, I.; Schmidt, H. H. J.; Trigo, P. Kelly, J.W.; Labaudiniere, R.; Chan, J., Packman, J.; Grogan, D.R. “Long-term Effects of Tafamidis for the Treatment of Transthyretin Familial Amyloid Polyneuropathy”. J. Neurology, 2013 260, 2802-2814.
  8. Jump up^ Ando, Y.; Sekijima, Y.; Obayashi, K.; Yamashita, T.; Ueda, M.; Misumi, Y.; Morita, H.; Machii, K; Ohta, M.; Takata, A; Ikeda, S-I. “Effects of tafamidis treatment on transthyretin (TTR) stabilization, efficacy, and safety in Japanese patients with familial amyloid polyneuropathy (TTR-FAP) with Val30Met and non-Varl30Met: A phase III, open-label study”. J. Neur. Sci., 2016 362, 266-271, doi:10.1016/j.jns.2016.01.046.
  9. Jump up^ Andrade, C. (1952). “A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves”. Brain: a Journal of Neurology, 75, 408-427.
  10. Jump up^ Coelho, T. (1996). “Familial amyloid polyneuropathy: new developments in genetics and treatment”. Current Opinion in Neurology, 9, 355-359.
  11. Jump up^ Razavi, H.; Palaninathan, S.K. Powers, E.T.; Wiseman, R.L.; Purkey, H.E.; Mohamadmohaideen, N.N.; Deechongkit, S.; Chiang, K.P.; Dendle, M.T.A.; Sacchettini, J.C.; Kelly, J.W. “Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation and Mechanism of Action”. Angew. Chem. Int. Ed., 2003, 42, 2758-2761.
  12. Jump up^ Connelly, S., Choi, S., Johnson, S.M., Kelly, J.W., and Wilson, I.A. (2010). “Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses”. Current Opinion in Structural Biology, 20, 54-62.
  13. Jump up^ Hammarstrom, P.; Wiseman, R. L.; Powers, E.T.; Kelly, J.W. “Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics”. Science, 2003, 299, 713-716
  14. Jump up^ Westermark, P., Sletten, K., Johansson, B., and Cornwell, G.G., 3rd (1990). “Fibril in senile systemic amyloidosis is derived from normal transthyretin”. Proc Natl Acad Sci U S A, 87, 2843-2845.
  15. Jump up^ Sousa, M.M., Cardoso, I., Fernandes, R., Guimaraes, A., and Saraiva, M.J. (2001). “Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates”. The American Journal of Pathology, 159, 1993-2000.
  16. Jump up^ Colon, W., and Kelly, J.W. (1992). “Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro”. Biochemistry 31, 8654-8660.
  17. Jump up^ Jacobson, D.R., Pastore, R.D., Yaghoubian, R., Kane, I., Gallo, G., Buck, F.S., and Buxbaum, J.N. (1997). “Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans”. The New England Journal of Medicine, 336, 466-473.
  18. Jump up^ Maurer, M.S.; Grogan, D.R.; Judge, D.P.; Mundayat, R.; Lombardo, I.; Quyyumi, A.A.; Aarts, J.; Falk, R.H. “Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes.” Circ. Heart. Fail. 2015 8, 519-526.
  19. Jump up^
Patent ID

Patent Title

Submitted Date

Granted Date

US2016185739 Solid Forms Of A Transthyretin Dissociation Inhibitor
US9770441 Crystalline solid forms of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole
Patent ID

Patent Title

Submitted Date

Granted Date

US9771321 Small Molecules That Covalently Modify Transthyretin
Patent ID

Patent Title

Submitted Date

Granted Date

US8703815 Small molecules that covalently modify transthyretin
US8653119 Methods for treating transthyretin amyloid diseases
Patent ID

Patent Title

Submitted Date

Granted Date

US7214695 Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US7214696 Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
US7560488 Methods for treating transthyretin amyloid diseases
US8168663 Pharmaceutically acceptable salt of 6-carboxy-2-(3, 5 dichlorophenyl)-benzoxazole, and a pharmaceutical composition comprising the salt thereof
Tafamidis skeletal.svg
Clinical data
Trade names Vyndaqel
License data
Routes of
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
CAS Number
PubChem CID
Chemical and physical data
Formula C14H7Cl2NO3
Molar mass 308.116 g/mol
3D model (JSmol)

//////////////TTAFAMIDIS, Fx-1006A, PF-06291826, Orphan Drug, SCRIPP, PFIZER




“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Novartis obtains European approval for Cosentyx to treat psoriasis

Novartis obtains European approval for Cosentyx to treat psoriasis
Swiss drug-maker Novartis has received approval from the European Commission (EC) for its Cosentyx (secukinumab, formerly known as AIN457) to treat moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy.SEE



Secukinumab is a human monoclonal antibody designed for the treatments of uveitis, rheumatoid arthritis, ankylosing spondylitis, and psoriasis. It targets member A from the cytokine family of interleukin 17.[1][2] At present, Novartis Pharma AG, the drug’s developer, plans to market it under the trade name “Cosentyx.” [3] It is highly specific to the human immunoglobulin G1k (IgG1k) subclass.[2]

In July 2014 secukinumab established superiority to placebo and to etanercept for the treatment of chronic plaque psoriasis in Phase III clinical trials.[4] In October 2014, the FDA Dermatologic and Ophthalmic Drugs Advisory Committee unanimously voted to recommend the drug for FDA approval, although this vote in and of itself does not constitute an approval. However, the FDA typically follows recommendations from these committees.[5] In October 2014, Novartis announced that the drug had achieved a primary clinical endpoint in two phase III clinical trials for ankylosing spondylitis.[6] As of 28 October, the relevant FDA committee had not yet responded to these results. In early November 2014, Novartis also released the results of a Phase 3 study on Psoriatic Arthritis that yielded very promising results.[7]

Although the drug was originally intended to treat rheumatoid arthritis, phase II clinical trials for this condition yielded disappointing results.[8] Similarly, while patients in a phase II clinical trial for [psoriatic arthritis] did show improvement over placebo, the improvement did not meet adequate endpoints and Novartis is considering whether to do more research for this condition.[9] Novartis has said that it is targeting approval and release in early 2015 for plaque psoriasis and ankyloding spondylitis indications.

It is also in a phase II clinical trial for Multiple Sclerosis [10] as it has exhibited efficacy in treating experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

CAS registry numbers

  • 875356-43-7 (heavy chain)
  • 875356-44-8 (light chain)


  1. “Statement On A Nonproprietary Name Adopted By The USAN Council: Secukinumab”. American Medical Association.
  2.  Hueber, W.; Patel, D. D.; Dryja, T.; Wright, A. M.; Koroleva, I.; Bruin, G.; Antoni, C.; Draelos, Z.; Gold, M. H.; Psoriasis Study, P.; Durez, P. P.; Tak, J. J.; Gomez-Reino, C. S.; Rheumatoid Arthritis Study, R. Y.; Foster, C. M.; Kim, N. S.; Samson, D. S.; Falk, D.; Chu, Q. D.; Callanan, K.; Nguyen, A.; Uveitis Study, F.; Rose, K.; Haider, A.; Di Padova, F. (2010). “Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis”. Science Translational Medicine 2 (52): 52ra72.doi:10.1126/scitranslmed.3001107. PMID 20926833. edit
  4.  Langley RG, Elewski BE, Mark Lebwohl M, et al., for the ERASURE and FIXTURE Study Groups (July 24, 2014). “Secukinumab in Plaque Psoriasis — Results of Two Phase 3 Trials”. N Engl J Med 371: 326–338. doi:10.1056/NEJMoa1314258.
  5.  committees.[dead link]
Monoclonal antibody
Type Whole antibody
Source Human
Target IL17A
Clinical data
Legal status
  • Investigational
CAS number  Yes
ATC code L04AC10
DrugBank DB09029
Synonyms AIN457
Chemical data
Formula C6584H10134N1754O2042S44 
Molecular mass 147.94 kDa

EMA grants orphan drug designations to Alnylam’s ALN-AT3 for haemophilia treatment



EMA grants orphan drug designations to Alnylam’s ALN-AT3 for haemophilia treatment
Biopharmaceutical company Alnylam Pharmaceuticals has received orphan drug designations for ALN-AT3 from the European Medicines Agency (EMA) Committee to treat haemophilia A and B





May 13,2014

Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, announced today positive top-line results from its ongoing Phase 1 trial of ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD). These top-line results are being presented at the World Federation of Hemophilia (WFH) 2014 World Congress being held May 11 – 15, 2014 in Melbourne, Australia. In Part A of the Phase 1 study, human volunteer subjects received a single subcutaneous dose of ALN-AT3 and, per protocol, the maximum allowable level of AT knockdown was set at 40%. Initial results show that a single, low subcutaneous dose of ALN-AT3 at 0.03 mg/kg resulted in an up to 28-32% knockdown of AT at nadir that was statistically significant relative to placebo (p < 0.01 by ANOVA). This led to a statistically significant (p < 0.01) increase in peak thrombin generation, that was temporally associated and consistent with the degree of AT knockdown. ALN-AT3 was found to be well tolerated with no significant adverse events reported. With these data, the company has transitioned to the Multiple Ascending Dose (MAD) Part B of the study in moderate-to-severe hemophilia subjects. Consistent with previous guidance, the company plans to present initial clinical results from the Phase 1 study, including results in hemophilia subjects, by the end of the year. These human study results are the first to be reported for Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency, durability, and a wide therapeutic index. Further, these initial clinical results demonstrate a greater than 50-fold potency improvement with ESC-GalNAc conjugates relative to standard template chemistry conjugates.

“We are excited by these initial positive results for ALN-AT3 in the human volunteer ‘Part A’ of our Phase 1 study. Indeed, within the protocol-defined boundaries of single doses that provide no more than a 40% knockdown of AT in normal subjects, we were able to demonstrate a statistically-significant knockdown of AT of up to 28-32% and an associated increase in thrombin generation. Remarkably, this result was achieved at the lowest dose tested of 0.03 mg/kg, demonstrating a high and better than expected level of potency for ALN-AT3, our first ESC-GalNAc conjugate to enter clinical development,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “With these results in hand, we are now proceeding to ‘Part B’ of the study, where we will administer multiple ascending doses to up to 18 patients with moderate-to-severe hemophilia A or B. Patients will receive three weekly doses, and we fully expect to achieve robust levels of AT knockdown as we dose escalate. In addition, we will aim to evaluate a once-monthly dosing regimen in future clinical studies, as we believe this could provide a highly attractive prophylactic regimen for patients. We look forward to sharing our detailed Phase 1 results, including data in hemophilia subjects, later this year, consistent with our original guidance.”

“There are several notable implications of these exciting initial results with ALN-AT3. First, ALN-AT3 now becomes the fourth program in our ‘Alnylam 5×15’ pipeline to demonstrate clinical activity. As such, these results increase our confidence level yet further across the entirety of our pipeline efforts, where we remain focused on genetically defined, liver-expressed disease targets with a modular and reproducible delivery platform. Moreover, these results with ALN-AT3 establish human proof of concept for our ESC-GalNAc conjugate technology, extending and broadening the human results we have previously shown with ALN-TTRsc which employs our standard template chemistry. Our ESC-GalNAc conjugate technology enables subcutaneous dosing with increased potency and durability and a wide therapeutic index, and has now become our primary approach for the delivery of RNAi therapeutics,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “Finally, the achievement of target knockdown at such a low dose of 0.03 mg/kg is unprecedented. Based on our evaluation of datasets from non-human primate (NHP) and human studies, these results demonstrate a 10-fold improved potency for ALN-AT3 as compared with NHP and a 50-fold improved potency in humans as compared with ALN-TTRsc. Based on data we announced earlier this week at TIDES, we believe that this increased potency is the combined result of enhanced stability for ESC-GalNAc conjugates and an attenuated nuclease environment in human tissue compared with other species. If these results extend to other ESC-GalNAc-siRNA conjugates, such as those in our complement C5 and PCSK9 programs, we believe we can expect highly potent clinical activities with very durable target knockdown effects.”

The ongoing Phase 1 trial of ALN-AT3 is being conducted in the U.K. as a single- and multi-dose, dose-escalation study comprised of two parts. Part A – which has now been completed – was a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, intended to enroll up to 24 healthy volunteer subjects. The primary objective of this part of the study was to evaluate the safety and tolerability of a single dose of ALN-AT3, with the potential secondarily to show changes in AT plasma levels at sub-pharmacologic doses. This part of the study evaluated only low doses of ALN-AT3, with a dose-escalation stopping rule at no more than a 40% level of AT knockdown. Based on the pharmacologic response achieved in this part of the study, only the lowest dose cohort (n=4; 3:1 randomization of ALN-AT3:placebo) was enrolled. Part B of the study is an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate-to-severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses, specifically three doses, of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3; thrombin generation is known to be a biomarker for bleeding frequency and severity in people with hemophilia (Dargaud, et al., Thromb Haemost; 93, 475-480 (2005)). In this part of the study, dose-escalation will be allowed to proceed beyond the 40% AT knockdown level.

In addition to reporting positive top-line results from the Phase 1 trial with ALN-AT3, Alnylam presented new pre-clinical data with ALN-AT3. First, in a saphenous vein bleeding model performed in hemophilia A (HA) mice, a single subcutaneous dose of ALN-AT3 that resulted in an approximately 70% AT knockdown led to a statistically significant (p < 0.0001) improvement in hemostasis compared to saline-treated HA mice. The improved hemostasis was comparable to that observed in HA mice receiving recombinant factor VIII. These are the first results in what can be considered a genuine bleeding model showing that AT knockdown with ALN-AT3 can control bleeding. Second, a number of in vitro studies were performed in plasma from hemophilia donors. Stepwise AT depletion in these plasma samples was shown to achieve stepwise increases in thrombin generation. Furthermore, it was shown that a 40-60% reduction of AT resulted in peak thrombin levels equivalent to those achieved with 10-15% levels of factor VIII in HA plasma and factor IX in hemophilia B (HB) plasma. These levels of factor VIII or IX are known to significantly reduce bleeding in hemophilia subjects. As such, these results support the hypothesis that a 40-60% knockdown of AT with ALN-AT3 could be fully prophylactic. Finally, a modified Activated Partial Thromboplastin Time (APTT) assay – an ex vivomeasure of blood coagulation that is significantly prolonged in hemophilia – was developed, demonstrating sensitivity to AT levels. Specifically, depletion of AT in HA plasma led to a shortening of modified APTT. This modified APTT assay can be used to routinely and simply monitor functional activity of AT knockdown in further ALN-AT3 clinical studies.

“The unmet need for new therapeutic options to treat hemophilia patients remains very high, particularly in those patients who experience multiple annual bleeds such as patients receiving replacement factor ‘on demand’ or patients who have developed inhibitory antibodies. Indeed, I believe the availability of a safe and effective subcutaneously administered therapeutic with a long duration of action would represent a marked improvement over currently available approaches for prophylaxis,” said Claude Negrier, M.D., head of the Hematology Department and director of the Haemophilia Comprehensive Care Centre at Edouard Herriot University Hospital in Lyon. “I continue to be encouraged by Alnylam’s progress to date with ALN-AT3, including these initial data reported from the Phase 1 trial showing statistically significant knockdown of antithrombin and increased thrombin generation, which has been shown to correlate with bleeding frequency and severity in hemophilia. I look forward to the advancement of this innovative therapeutic candidate in hemophilia subjects.”

About Hemophilia and Rare Bleeding Disorders

Hemophilias are hereditary disorders caused by genetic deficiencies of various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major internal organs. Hemophilia A is defined by loss-of-function mutations in Factor VIII, and there are greater than 40,000 registered patients in the U.S. and E.U. Hemophilia B, defined by loss-of-function mutations in Factor IX, affects greater than 9,500 registered patients in the U.S. and E.U. Other Rare Bleeding Disorders (RBD) are defined by congenital deficiencies of other blood coagulation factors, including Factors II, V, VII, X, and XI, and there are about 1,000 patients worldwide with a severe bleeding phenotype. Standard treatment for hemophilia patients involves replacement of the missing clotting factor either as prophylaxis or on-demand therapy. However, as many as one third of people with severe hemophilia A will develop an antibody to their replacement factor – a very serious complication; these ‘inhibitor’ patients become refractory to standard replacement therapy. There exists a small subset of hemophilia patients who have co-inherited a prothrombotic mutation, such as Factor V Leiden, antithrombin deficiency, protein C deficiency, and prothrombin G20210A. Hemophilia patients that have co-inherited these prothrombotic mutations are characterized as having a later onset of disease, lower risk of bleeding, and reduced requirements for Factor VIII or Factor IX treatment as part of their disease management. There exists a significant need for novel therapeutics to treat hemophilia patients.

About Antithrombin (AT)

Antithrombin (AT, also known as “antithrombin III” and “SERPINC1″) is a liver expressed plasma protein and member of the “serpin” family of proteins that acts as an important endogenous anticoagulant by inactivating Factor Xa and thrombin. AT plays a key role in normal hemostasis, which has evolved to balance the need to control blood loss through clotting with the need to prevent pathologic thrombosis through anticoagulation. In hemophilia, the loss of certain procoagulant factors (Factor VIII and Factor IX, in the case of hemophilia A and B, respectively) results in an imbalance of the hemostatic system toward a bleeding phenotype. In contrast, in thrombophilia (e.g., Factor V Leiden, protein C deficiency, antithrombin deficiency, amongst others), certain mutations result in an imbalance in the hemostatic system toward a thrombotic phenotype. Since co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, inhibition of AT defines a novel strategy for improving hemostasis.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This delivery platform is being employed in several of Alnylam’s genetic medicine programs, including programs in clinical development.

About RNAi

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company’s “Alnylam 5x15TM” product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; and other programs yet to be disclosed. As part of its “Alnylam 5×15” strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. Alnylam is also developing ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as NatureNature MedicineNature BiotechnologyCell, the New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit

Eisai’s lenvatinib 兰伐替尼 レンバチニブ to get speedy review in Europe

Lenvatinib skeletal.svg


For the treatment of patients with progressive radioiodine-refractory, differentiated thyroid cancer (RR-DTC).

CAS  417716-92-8,
 CAS 857890-39-2 (lenvatinib mesylate)
E 7080, ER-203492-00, E7080, E 7080,
Molecular Formula: C21H19ClN4O4
Molecular Weight: 426.85296
Eisai Co., Ltd INNOVATOR

European regulators have agreed to undertake an accelerated assessment of Eisai’s lenvatinib as a treatment for progressive radioiodine-refractory, differentiated thyroid cancer.

The drug, which carries Orphan Status in the EU, is to be filed “imminently” and could become the first in a new class of tyrosine kinase inhibitors, the drugmaker said.

Read more at:

Lenvatinib was granted Orphan Drug Designation for thyroid cancer by the health authorities in Japan in 2012, and in Europe and the U.S in 2013. The first application for marketing authorization of lenvatinib in the world was submitted in Japan on June 2014. Eisai is planning to submit applications for marketing authorization in Europe and the U.S. in the second quarter of fiscal 2014.

Lenvatinib is an oral multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor receptors (VEGFR), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor receptors (FGFR), the platelet-derived growth factor (PDGF) receptor PDGFRalpha, KIT and RET that are involved in tumor proliferation. This potentially makes lenvatinib a first-in-class treatment, especially given that it simultaneously inhibits the kinase activities of FGFR as well as VEGFR.

Eisai's lenvatinib to get speedy review in Europe




Systematic (IUPAC) name
Clinical data
Legal status Prescription only
CAS number
ATC code None
PubChem CID 9823820
ChemSpider 7999567 Yes
UNII EE083865G2 Yes
Chemical data
Formula C21H19ClN4O4 
Mol. mass 426.853 g/mol

Lenvatinib (E7080) is a multi-kinase inhibitor that is being investigated for the treatment of various types of cancer by Eisai Co. It inhibits both VEGFR2 and VEGFR3 kinases.[1]

The substence was granted orphan drug status for the treatment of various types of thyroid cancer that do not respond toradioiodine; in the US and Japan in 2012 and in Europe in 2013[2] and is now approved for this use.

Clinical trials

Lenvatinib has had promising results from a phase I clinical trial in 2006[3] and is being tested in several phase II trials as of October 2011, for example against hepatocellular carcinoma.[4] After a phase II trial testing the treatment of thyroid cancer has been completed with modestly encouraging results,[5] the manufacturer launched a phase III trial in March 2011.[6]

Chemical structure for Lenvatinib

Lenvatinib Mesilate

Molecular formula: C21H19ClN4O4,CH4O3S =523.0.

CAS: 857890-39-2.

UNII code: 3J78384F61.

About the Lenvatinib (E7080) Phase II Study
The open-label, global, single-arm Phase II study of multi-targeted kinase inhibitor lenvatinib (E7080) in advanced radioiodine (RAI)-refractory differentiated thyroid cancer involved 58 patients with advanced RAI refractory DTC (papillary, follicular or Hurthle Cell) whose disease had progressed during the prior 12 months. (Disease progression was measured using Response Evaluation Criteria in Solid Tumors (RECIST).) The starting dose of lenvatinib was 24 mg once daily in repeated 28 day cycles until disease progression or development of unmanageable toxicities.

2.   About Thyroid Cancer
Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat or near the trachea. It affects more women than men and usually occurs between the ages of 25 and 65.
The most common types of thyroid cancer, papillary and follicular (including Hurthle Cell), are classified as differentiated thyroid cancer and account for 95 percent of all cases. While most of these are curable with surgery and radioactive iodine treatment, a small percentage of patients do not respond to therapy.

3.   About Lenvatinib (E7080)
Lenvatinib is multi-targeted kinase inhibitor with a unique receptor tyrosine kinase inhibitory profile that was discovered and developed by the Discovery Research team of Eisai’s Oncology Unit using medicinal chemistry technology. As an anti-angiogenic agent, it inhibits tyrosine kinase of the VEGF (Vascular Endothelial Growth Factor) receptor, VEGFR2, and a number of other types of kinase involved in angiogenesis and tumor proliferation in balanced manner. It is a small molecular targeting drug that is currently being studied in a wide array of cancer types.

4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (additional name: 4-[3-chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide) is known to exhibit an excellent angiogenesis inhibition as a free-form product, as described in Example 368 of Patent Document 1. 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is also known to exhibit a strong inhibitory action for c-Kit kinase (Non-Patent Document 1, Patent Document 2).

However, there has been a long-felt need for the provision of a c-Kit kinase inhibitor or angiogenesis inhibitor that has high usability as a medicament and superior characteristics in terms of physical properties and pharmacokinetics in comparison with the free-form product of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.

[Patent Document 1] WO 02/32872

[Patent Document 2] WO 2004/080462

[Non-Patent Document 1] 95th Annual Meeting Proceedings, AACR (American Association for Cancer Research), Volume 45, Page 1070-1071, 2004




Examples will now be described to facilitate understanding of the invention, but the invention is not limited to these examples.

Example 1Phenyl N-(2-chloro-4-hydroxyphenyl)carbamate

After suspending 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) and adding pyridine (23.4 mL) while cooling on ice, phenyl chloroformate (23.2 ml) was added dropwise below 20° C. Stirring was performed at room temperature for 30 minutes, and then water (400 mL), ethyl acetate (300 mL) and 6N HCl (48 mL) were added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. The solvent was removed to give 46 g of the title compound as a solid.

1H-NMR (CDCl3): 5.12 (1h, br s), 6.75 (1H, dd, J=9.2, 2.8 Hz), 6.92 (1H, d, J=2.8 Hz), 7.18-7.28 (4H, m), 7.37-7.43 (2H, m), 7.94 (1H, br s)

Example 21-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea

After dissolving phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL), cyclopropylamine (22.7 mL) was added while cooling on ice and the mixture was stirred overnight at room temperature. Water (400 mL), ethyl acetate (300 mL) and 6N HCl (55 mL) were then added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. Prism crystals obtained by concentrating the solvent were filtered and washed with heptane to give 22.8 g of the title compound (77% yield from 4-amino-3-chlorophenol).

1H-NMR (CDCl3): 0.72-0.77 (2H, m), 0.87-0.95 (2H, m), 2.60-2.65 (1H, m), 4.89 (1H, br s), 5.60 (1H, br s), 6.71 (1H, dd, J=8.8, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.24-7.30 (1H, br s), 7.90 (1H, d, J=8.8H)

Example 34-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

To dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloro-quinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), followed by heating and stirring at 70° C. for 23 hours. After the reaction mixture was allowed to cool down to room temperature, water (50 mL) was added, and the produced crystals were collected by filtration to give 1.56 g of the title compound (88% yield).

1H-NMR (d6-DMSO): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J=5.6 Hz)

Example 44-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

In a reaction vessel were placed 7-methoxy-4-chloro-quinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethylsulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) in that order, under a nitrogen atmosphere. After stirring at 20° C. for 30 minutes, the temperature was raised to 65° C. over a period of 2.5 hours. After stirring at the same temperature for 19 hours, 33% (v/v) acetone water (5.0 L) and water (10.0 L) were added dropwise over a period of 3.5 hours. Upon completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours, and 33% (v/v) acetone water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or higher over a period of 1 hour. After then stirring at 40° C. for 16 hours, the precipitated crystals were collected by filtration using a nitrogen pressure filter, and the crystals were washed with 33% (v/v) acetone water (33.3 L), water (66.7 L) and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum drier to give 7.78 kg of the title compound (96.3% yield).










EX 368

Figure US07253286-20070807-C00838

Example 368


The title compound (22.4 mg, 0.052 mmol, 34.8%) was obtained as white crystals from phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (70 mg, 0.15 mmol) and cyclopropylamine, by the same procedure as in Example 11.

1H-NMR Spectrum (DMSO-d6) δ (ppm): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J=5.6 Hz).

The starting material was synthesized in the following manner.

Production Example 368-1Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate

The title compound (708 mg, 1.526 mmol, 87.4%) was obtained as light brown crystals from 4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.745 mmol), by the same procedure as in Production Example 17.

1H-NMR Spectrum (CDCl3) δ (ppm): 4.14 (3H, s), 5.89 (1H, br), 6.50 (1H, d, J=5.6 Hz), 7.16 (2H, dd, J=2.4, 8.8 Hz), 7.22–7.30 (4H, m), 7.44 (2H, m), 7.55 (1H, s), 7.81 (1H, br), 8.31 (1H, d, J=8.8 Hz), 8.68 (1H, d, J=5.6 Hz), 9.27 (1H, s).



Preparation Example 1

Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (1)

Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5 g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature. To the mixture was added water (1.75 L), and the mixture was stirred. Precipitated crude crystals were filtered off, washed with water, and dried at 70° C. for 50 min. To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature. Precipitated crystals was filtered off and dried under vacuum, and then further dried at 70° C. for 8 hours to give the titled crystals (12.91 g; 80.2%).

Preparation Example 2Preparation of 4-(3-cloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (2)

(1) Preparation of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate

To a suspension of 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) was added pyridine (23.4 mL) while cooling in an ice bath, and phenyl chloroformate (23.2 mL) was added dropwise below 20° C. After stirring at room temperature for 30 min, water (400 mL), ethyl acetate (300 mL), and 6N-HCl (48 mL) were added and stirred. The organic layer was separated off, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give 46 g of the titled compound as a solid.

  • 1H-NMR Spectrum (CDCl3) δ(ppm): 5.12 (1H, br s), 6.75 (1H, dd, J=9.2, 2.8 Hz), 6.92 (1H, d, J=2.8 Hz), 7.18-7.28 (4H, m), 7.37-7.43 (2H, m), 7.94 (1H, br s).
    (2) Preparation of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea

To a solution of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL) was added cyclopropylamine (22.7 mL) while cooling in an ice bath, and the stirring was continued at room temperature overnight. Water (400 mL), ethyl acetate (300 mL), and 6N-HCl (55 mL) were added thereto, and the mixture was stirred. The organic layer was then separated off, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give prism crystals, which were filtered off and washed with heptane to give 22.8 g of the titled compound (yield from 4-amino-3-chlorophenol: 77%).

  • 1H-NMR Spectrum (CDCl3) δ(ppm): 0.72-0.77 (2H, m), 0.87-0.95 (2H, m), 2.60-2.65 (1H, m), 4.89 (1H, br s), 5.60 (1H, br s), 6.71 (1H, dd, J=8.8, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.24-7.30 (1H, br s), 7.90 (1H, d, J=8.8 Hz)
    (3) Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70° C. for 23 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added, and the resultant crystals were then filtered off to give 1.56 g of the titled compound (yield: 88%).

Preparation Example 3Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (3)

7-Methoxy-4-chloroquinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethyl sulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea 5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) were introduced in this order into a reaction vessel under a nitrogen atmosphere. The mixture was stirred for 30 min at 20° C., and the temperature was raised to 65° C. over 2.5 hours. The mixture was stirred at the same temperature for 19 hours. 33% (v/v) acetone-water (5.0 L) and water (10.0 L) were added dropwise over 3.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 2 hours. 33% (v/v) acetone-water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or more over 1 hour. After stirring at 40° C. for 16 hours, precipitated crystals were filtered off using a nitrogen pressure filter, and was washed with 33% (v/v) acetone-water (33.3 L), water (66.7 L), and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum dryer to give 7.78 kg of the titled compound (yield: 96.3%).

1H-NMR chemical, shift values for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamides obtained in Preparation Examples 1 to 3 corresponded to those for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide disclosed in WO 02/32872.

Example 5

A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A)

(Preparation Method 1)

In a mixed solution of methanol (14 mL) and methanesulfonic acid (143 μL, 1.97 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (700 mg, 1.64 mmol) at 70° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, the reaction mixture was cooled to room temperature over 5.5 hours, further stirred at room temperature for 18.5 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (647 mg).

(Preparation Method 2)

In a mixed solution of acetic acid (6 mL) and methanesulfonic acid (200 μL, 3.08 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.41 mmol) at 50° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, ethanol (7.2 mL) and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) (12 mg) were added in this order to the reaction mixture, and ethanol (4.8 mL) was further added dropwise over 2 hours. After the addition was completed, the reaction mixture was stirred at 40° C. for 1 hour then at room temperature for 9 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (545 mg).

Example 6A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form B)

A crystalline form of the acetic acid solvate of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form I) (250 mg) obtained in Example 10 was dried under aeration at 30° C. for 3 hours and at 40° C. for 16 hours to give the titled crystals (240 mg)…………MORE IN PATENT



According to the present invention 4- (3-chloro-4- (cyclopropylamino-carbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide amorphous is excellent in solubility in water.

Example 1 4- (3-chloro-4- (cyclopropylamino-carbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide manufacture of amorphous amide
4- (3-chloro-4- (cyclopropylamino-carbonyl) amino phenoxy) -7-methoxy-6-quinolinecarboxamide B-type crystals (Patent Document 2) were weighed to 300mg, is placed in a beaker of 200mL volume, it was added tert- butyl alcohol (tBA) 40mL. This was heated to boiling on a hot plate, an appropriate amount of tBA to Compound A is dissolved, water was added 10mL. Then, the weakened heated to the extent that the solution does not boil, to obtain a sample solution. It should be noted, finally the solvent amount I was 60mL. 200mL capacity eggplant type flask (egg-plant shaped flask), and rotated in a state of being immersed in ethanol which had been cooled with dry ice. It was added dropwise a sample solution into the interior of the flask and frozen. After freezing the sample solution total volume, to cover the opening of the flask in wiping cloth, and freeze-dried. We got an amorphous A of 290mg.

Patent Document 2: US Patent Application Publication No. 2007/0117842 Patent specification

Amorphous A 13 C-solid state NMR spectrum in Figure 2, the chemical shifts and I are shown in Table 3.
[Table 3] *: peak of t- butyl alcohol



ACS Medicinal Chemistry Letters (2015), 6(1), 89-94



Journal of Pharmaceutical and Biomedical Analysis (2015), 114, 82-87

KEEP WATCHING WILL BE UPDATED………….most of my posts are updated regularly


  1. Matsui, J.; Funahashi, Y.; Uenaka, T.; Watanabe, T.; Tsuruoka, A.; Asada, M. (2008). “Multi-Kinase Inhibitor E7080 Suppresses Lymph Node and Lung Metastases of Human Mammary Breast Tumor MDA-MB-231 via Inhibition of Vascular Endothelial Growth Factor-Receptor (VEGF-R) 2 and VEGF-R3 Kinase”. Clinical Cancer Research 14 (17): 5459–65.doi:10.1158/1078-0432.CCR-07-5270. PMID 18765537.
  2. “Phae III trial shows lenvatinib meets primary endpoint of progression free surival benefit in treatment of radioiodine-refactory differentiated thyroid cancer”. Eisai. 3 February 2014.
  3. Glen, H; D. Boss; T. R. Evans; M. Roelvink; J. M. Saro; P. Bezodis; W. Copalu; A. Das; G. Crosswell; J. H. Schellens (2007). “A phase I dose finding study of E7080 in patients (pts) with advanced malignancies”. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I 25 (18S): 14073.
  4. NCT00946153 Study of E7080 in Patients With Advanced Hepatocellular Carcinoma (HCC)
  5. Gild, M. L.; Bullock, M.; Robinson, B. G.; Clifton-Bligh, R. (2011). “Multikinase inhibitors: A new option for the treatment of thyroid cancer”. Nature Reviews Endocrinology 7 (10): 617–624.doi:10.1038/nrendo.2011.141. PMID 21862995. edit
  6. NCT01321554 A Trial of E7080 in 131I-Refractory Differentiated Thyroid Cancer



Martin Schlumberger et al. A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib(E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT). 2014 ASCO Annual Meeting. Abstract Number:LBA6008. Presented June 2, 2014. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr LBA6008). Clinical trial information: NCT01321554.

Bando, Masashi. Quinoline derivative-​containing pharmaceutical composition. PCT Int. Appl. (2011), WO 2011021597 A1

Tomohiro Matsushima, four Nakamura, Kazuhiro Murakami, Atsushi Hoteido, Yusuke Ayat, Naoko Suzuki, Itaru Arimoto, Pinche Hirose, Masaharu Gotoda.Has excellent characteristics in terms of physical properties (particularly, dissolution rate) and pharmacokinetics (particularly, bioavailability), and is extremely useful as an angiogenesis inhibitor or c-Kit kinase inhibitor. US patent number US7612208  Also published as: CA2426461A1, CA2426461C, CN1308310C, CN1478078A, CN101024627A, DE60126997D1, DE60126997T2, DE60134679D1, DE60137273D1, EP1415987A1, EP1415987A4, EP1415987B1, EP1506962A2, EP1506962A3, EP1506962B1, EP1777218A1, EP1777218B1 , US7612092, US7973160, US8372981, US20040053908, US20060160832, US20060247259, US20100197911, US20110118470, WO2002032872A1, WO2002032872A8.Publication date: Aug 7, 2007 Original Assignee: Eisai Co., Ltd

Funahashi, Yasuhiro et al.Preparation of urea derivatives containing nitrogenous aromatic ring compounds as inhibitors of angiogenesis. US patent number US7253286, Also published as:CA2426461A1, CA2426461C, CN1308310C, CN1478078A, CN101024627A, DE60126997D1, DE60126997T2, DE60134679D1, DE60137273D1, EP1415987A1, EP1415987A4, EP1415987B1, EP1506962A2, EP1506962A3, EP1506962B1, EP1777218A1, EP1777218B1, US7612092, US7973160, US8372981, US20040053908, US20060160832, US20060247259, US20100197911, US20110118470, WO2002032872A1, WO2002032872A8.Publication date:Aug 7, 2007. Original Assignee:Eisai Co., Ltd

Sakaguchi, Takahisa; Tsuruoka, Akihiko. Preparation of amorphous salts of 4-​[3-​chloro-​4-​[(cyclopropylaminocarbonyl)​amino]​phenoxy]​-​7-​methoxy-​6-​quinolinecarboxamide as antitumor agents.  PCT Int. Appl. (2006), WO2006137474 A1 20061228.

Naito, Toshihiko and Yoshizawa, Kazuhiro. Preparation of urea moiety-containing quinolinecarboxamide derivatives. PCT Int. Appl., WO2005044788, 19 May 2005

Itaru Arimoto et al. Crystal of salt of 4-​[3-​chloro-​4-​(cyclopropylaminocarbonyl)​amino-​phenoxy]​-​7-​methoxy-​6-​quinolinecarboxamide or solvate thereof and processes for producing these. PCT Int. Appl. (2005), WO2005063713 A1 20050714.

Medicinal Composition
Nitrogen-containing aromatic derivatives
Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
Nitrogen-containing aromatic derivatives
Use of sulfonamide-including compounds in combination with angiogenesis inhibitors
c-Kit kinase inhibitor
Nitrogen-Containing Aromatic Derivatives
Urea derivative and process for preparing the same
US7253286 * 18 Apr 2003 7 Aug 2007 Eisai Co., Ltd Nitrogen-containing aromatic derivatives
US20040053908 18 Apr 2003 18 Mar 2004 Yasuhiro Funahashi Nitrogen-containing aromatic derivatives
US20040242506 9 Aug 2002 2 Dec 2004 Barges Causeret Nathalie Claude Marianne Formed from paroxetine hydrochloride and ammonium glycyrrhyzinate by precipitation, spray, vacuum or freeze drying, or evaporation to glass; solid or oil; masks the bitter taste of paroxetine and has a distinctive licorice flavor; antidepressants; Parkinson’s disease
US20040253205 10 Mar 2004 16 Dec 2004 Yuji Yamamoto c-Kit kinase inhibitor
US20070004773 * 22 Jun 2006 4 Jan 2007 Eisai R&D Management Co., Ltd. Amorphous salt of 4-(3-chiloro-4-(cycloproplylaminocarbonyl)aminophenoxy)-7-method-6-quinolinecarboxamide and process for preparing the same
US20070078159 22 Dec 2004 5 Apr 2007 Tomohiro Matsushima Has excellent characteristics in terms of physical properties (particularly, dissolution rate) and pharmacokinetics (particularly, bioavailability), and is extremely useful as an angiogenesis inhibitor or c-Kit kinase inhibitor
US20070117842 * 22 Apr 2004 24 May 2007 Itaru Arimoto Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same
EP0297580A1 30 Jun 1988 4 Jan 1989 E.R. SQUIBB & SONS, INC. Amorphous form of aztreonam
JP2001131071A Title not available
JP2005501074A Title not available
JPS6422874U Title not available
WO2002032872A1 19 Oct 2001 25 Apr 2002 Itaru Arimoto Nitrogenous aromatic ring compounds
WO2003013529A1 9 Aug 2002 20 Feb 2003 Barges Causeret Nathalie Claud Paroxetine glycyrrhizinate
WO2004080462A1 10 Mar 2004 23 Sep 2004 Eisai Co Ltd c-Kit KINASE INHIBITOR
WO2004101526A1 22 Apr 2004 25 Nov 2004 Itaru Arimoto Polymorphous crystal of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-qunolinecarboxamide and method for preparation thereof
WO2005044788A1 8 Nov 2004 19 May 2005 Eisai Co Ltd Urea derivative and process for producing the same
WO2005063713A1 22 Dec 2004 14 Jul 2005 Itaru Arimoto Crystal of salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)amino-phenoxy)-7-methoxy-6-quinolinecarboxamide or of solvate thereof and processes for producing these
WO2006030826A1 14 Sep 2005 23 Mar 2006 Eisai Co Ltd Medicinal composition




hplc real len real nmr


European Medicines Agency recommends 39 medicines for human use for marketing authorisation in first half of 2014


European Medicines Agency recommends 39 medicines for human use for marketing authorisation in first half of 2014

Thirty-nine medicines for human use were recommended for marketing authorisationby the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in the first half of 2014, compared with 44 in first half of 2013 and 33 in first half of 2012.

This figure includes a number of new innovative medicines with the potential to meet unmet medical needs, treat diseases for which no treatments were previously available or bring significant added benefit to patients over existing therapies. Among these medicines are the anticancer medicines Mekinist (trametinib) and Gazyvaro (obinutuzumab), the anti-inflammatory* Entyvio (vedolizumab), the anti-infective Daklinza (daclatasvir), as well as Translarna (ataluren) and Sylvant (siltuximab), which are both intended for the treatment of rare conditions.

In parallel, the number of medicines recommended for approval via the European Union centralised procedure based on generic or informed consent applications has decreased compared with the first half of 2013 (6 versus 13).

More than two in three applicants received scientific advice from the CHMP during the development phase of their medicine, and for innovative medicines four in five applicants received such advice. This is a significant increase compared with the first half of 2013 (when one in two applicants received scientific advice), and mirrors the growing number of requests for scientific advice received by the Agency.

Confirming the trend observed in the past few years, the number of new medicines intended for the treatment of rare diseases is steadily increasing, providing treatments for patients who often have only few or no options. In the first half of 2014, eight medicines were recommended for the treatment of rare diseases. This number includes three medicines for which the CHMP recommended conditional approval but whose applications were withdrawn by the sponsor prior to a final decision by the European CommissionExternal link icon **.

Conditional approval is one of the Agency’s mechanisms to provide early patient access to medicines that fulfill unmet medical needs or address life-threatening diseases. The CHMP also used this mechanism for the recommendation of the first treatment for Duchenne muscular dystrophy (Translarna), a life-threatening condition.


The CHMP granted two positive opinions after an accelerated assessment for the medicines Sylvant and Daklinza; this mechanism aims to speed up the assessment of medicines that are expected to be of major public health interest particularly from the point of view of therapeutic innovation.

The CHMP also gave an opinion on the use of a new combination product in the treatment of hepatitis C virus (HCV) infection in a compassionate use programme (ledipasvir and sofosbuvir). These programmes are intended to give patients with a life-threatening, long-lasting or seriously disabling disease access to treatments that are still under development. The treatment paradigm of hepatitis C is currently shifting rapidly, with the development of several new classes of direct-acting antivirals. By recommending the conduct of three compassionate use programmes and the marketing authorisation of three new medicines for HCV infection over the past eight months, the Agency is actively supporting this shift which is expected to bring significant added benefit to patients.


Committee for Medicinal Products for Human Use (CHMP) opinions - First half 2014


* On Friday 11 July 2014 at 11:00 the statement, ‘the anti-infectives Entyvio (vedolizumab) and Daklinza (daclatasvir)’ was corrected to ‘the anti-inflammatory Entyvio (vedolizumab), the anti-infective Daklinza (daclatasvir)’.

** The CHMP had recommended a conditional approval for Vynfinit (vintafolide) and its companion diagnostics Folcepri (etarfolatide) and Neocepri (folic acid). After authorisation, the company was to provide confirmatory data from an ongoing study with Vynfinit. However, before the authorisation process could be completed by the European Commission, preliminary data from this study became available which showed that the study could not confirm the benefit of Vynfinit in ovarian cancer patients. Therefore, the company terminated the study and decided to withdraw the applications.


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BI launches COPD drug Striverdi, olodaterol in UK and Ireland



BI-1744-CL (hydrochloride) marketed as drug

Boehringer Ingelheim Pharma  innovator


Olodaterol (trade name Striverdi) is a long acting beta-adrenoceptor agonist used as an inhalation for treating patients with chronic obstructive pulmonary disease (COPD), manufactured by Boehringer-Ingelheim.[1]

see……….           ……… synfacts

Olodaterol is a potent agonist of the human β2-adrenoceptor with a high β12 selectivity. Its crystalline hydrochloride salt is suitable for inhalation and is currently undergoing clinical trials in man for the treatment of asthma. Oloda­terol has a duration of action that exceeds 24 hours in two preclinical animal models of bronchoprotection and it has a better safety margin compared with formoterol.

Olodaterol hydrochloride [USAN]

Bi 1744 cl
Olodaterol hydrochloride
Olodaterol hydrochloride [usan]

868049-49-4 [RN] FREE FORM

CAS 869477-96-3 HCL SALT


2H-1,4-Benzoxazin-3(4H)-one, 6-hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)- 1,1-dimethylethyl)amino)ethyl)-, hydrochloride (1:1)

2H-1,4-benzoxazin-3(4H)-one, 6-hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)- 1,1-dimethylethyl)amino)ethyl)-, hydrochloride (1:1)

6-Hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)-1,1-dimethylethyl)amino)ethyl)- 2H-1,4-benzoxazin-3(4H)-one hydrochloride

clinical trials

Boehringer Ingelheim has launched a new chronic obstructive pulmonary disease drug, Striverdi in the UK and Ireland.
Striverdi (olodaterol) is the second molecule to be licenced for delivery via the company’s Respimat Soft Mist inhaler, following the COPD blockbuster Spiriva (tiotropium). The drug was approved in Europe in November based on results from a Phase III programme that included more than 3,000 patients with moderate to very severe disease.

Olodaterol hydrochloride is a drug candidate originated by Boehringer Ingelheim. The product, delivered once-daily by the Respimat Soft Mist Inhaler, was first launched in Denmark and the Netherlands in March 2014 for the use as maintenance treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. In 2013, approval was obtained in Russia and Canada for the same indication, and in the U.S, the product was recommended for approval. Phase III clinical trials for the treatment of COPD are ongoing in Japan.

ChemSpider 2D Image | Olodaterol | C21H26N2O5
Systematic (IUPAC) name
Clinical data
Trade names Striverdi
AHFS/ UK Drug Information
Pregnancy cat. No experience
Legal status POM (UK)
Routes Inhalation
CAS number 868049-49-4; 869477-96-3 (hydrochloride)
ATC code R03AC19
PubChem CID 11504295
ChemSpider 9679097
Synonyms BI 1744 CL
Chemical data
Formula C21H26N2O5 free form
C21 H26 N2 O5 . Cl H; of hcl salt
Mol. mass 386.44 g/mol free form; 422.902 as hyd salt

BI launches COPD drug Striverdi in UK and Ireland

Medical uses

Olodaterol is a once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD including chronic bronchitis and/or emphysema, and is administered in an inhaler called Respimat Soft Mist Inhaler.[2][3][4][5][6][7]

As of December 2013, olodaterol is not approved for the treatment of asthma. Olodaterol monotherapy was previously evaluated in four Phase 2 studies in asthma patients. However, currently there are no Phase 3 studies planned for olodaterol monotherapy in patients with asthma.

In late January 2013, Olodaterol CAS# 868049-49-4 was the focus of an FDA committee reviewing data for the drug’s approval as a once-daily maintenance bronchodilator to treat chronic obstructive pulmonary disease (COPD), as well as chronic bronchitis and emphysema. The FDA Pulmonary-Allergy Drugs Advisory Committee recommended that the clinical data from the Boehringer Ingelheim Phase III studies be included in their NDA.

Also known as the trade name Striverdi Respimat, Olodaterol is efficacious as a long-acting beta-agonist, which patients self-administer via an easy to use metered dose inhaler. While early statistics from clinical trials of Olodaterol were encouraging, a new set of data was released earlier this week, which only further solidified the effectual and tolerable benefits of this COPD drug.

On September 10, 2013 results from two Phase 3 studies of Olodaterol revealed additional positive results from this formidable COPD treatment. The conclusion from these two 48 week studies, which included over 3,000 patients, showed sizable and significant improvements in the lung function of patients who were dosed with Olodaterol. Patients in the aforementioned studies were administered either a once a day dosage of Olodaterol via the appropriate metered-dose inhaler or “usual care”. The “usual care” included a variety of treatment options, such as inhaled corticosteroids (not Olodaterol), short and long acting anticholinergics, xanthines and beta agonists, which were short acting. The clinical trial participants who were dosed with Olodaterol displayed a rapid onset of action from this drug, oftentimes within the first five minutes after taking this medication. Additionally, patients dispensed the Olodaterol inhaler were successfully able to maintain optimum lung function for longer than a full 24 hour period. The participants who were given Olodaterol experienced such an obvious clinical improvement in their COPD symptoms, and it quickly became apparent that the “usual care” protocol was lacking in efficacy and reliability.

A staggering 24 million patients in the United States suffer from chronic obstructive pulmonary disease, and this patient population is in need of an effectual, safe and tolerable solution. Olodaterol is shaping up to be that much needed solution. Not only have the results from studies of Olodaterol been encouraging, the studies themselves have actually been forward thinking and wellness centered. Boehringer Ingelheim is the first company to included studies to evaluate exercise tolerance in  patients with COPD, and compare the data to those patients who were dosed with Olodaterol. By including exercise tolerance as an important benchmark in pertinent data for Olodaterol, Boehringer Ingelheim has created a standard for COPD treatment expectations. The impaired lung function for patients with COPD contributes greatly to their inability to exercise and stay healthy. Patients who find treatments and management techniques to combat the lung hyperinflation that develops during exercise have a distinct advantage to attaining overall good health.

– See more at:

Data has demonstrated that Striverdi, a once-daily long-acting beta2 agonist, significantly improved lung function versus placebo and is comparable to improvements shown with the older LABA formoterol. The NHS price for the drug is £26.35 for a 30-day supply.

Boehringer cited Richard Russell at Wexham Park Hospital as saying that the licensing of Stirverdi will be welcomed by clinicians as it provides another option. He added that the trial results showing improvements in lung function “are particularly impressive considering the study design, which allowed participants to continue their usual treatment regimen. This reflects more closely the real-world patient population”.

Significantly, the company is also developing olodaterol in combination with Spiriva, a long-acting muscarinic antagonist. LAMA/LABA combinations provide the convenience of delivering the two major bronchodilator classes.

Olodaterol is a novel, long-acting beta2-adrenergic agonist (LABA) that exerts its pharmacological effect by binding and activating beta2-adrenergic receptors located primarily in the lungs. Beta2-adrenergic receptors are membrane-bound receptors that are normally activated by endogenous epinephrine whose signalling, via a downstream L-type calcium channel interaction, mediates smooth muscle relaxation and bronchodilation. Activation of the receptor stimulates an associated G protein which then activates adenylate cyclase, catalyzing the formation of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA). Elevation of these two molecules induces bronchodilation by relaxation of airway smooth muscles. It is by this mechanism that olodaterol is used for the treatment of chronic obstructive pulmonary disease (COPD) and the progressive airflow obstruction that is characteristic of it. Treatment with bronchodilators helps to mitigate associated symptoms such as shortness of breath, cough, and sputum production. Single doses of olodaterol have been shown to improve forced expiratory volume in 1 sec (FEV1) for 24 h in patients with COPD, allowing once daily dosing. A once-a-day treatment with a LABA has several advantages over short-acting bronchodilators and twice-daily LABAs including improved convenience and compliance and improved airflow over a 24-hour period. Despite similarities in symptoms, olodaterol is not indicated for the treatment of acute exacerbations of COPD or for the treatment of asthma.

Adverse effects

Adverse effects generally were rare and mild in clinical studies. Most common, but still affecting no more than 1% of patients, were nasopharyngitis (running nose), dizziness and rash. To judge from the drug’s mechanism of action and from experiences with related drugs, hypertension (high blood pressure), tachycardia (fast heartbeat), hypokalaemia (low blood levels of potassium), shaking, etc., might occur in some patients, but these effects have rarely, if at all, been observed in studies.[1]


Based on theoretical considerations, co-application of other beta-adrenoceptor agonists, potassium lowering drugs (e. g. corticoids, many diuretics, and theophylline), tricyclic antidepressants, and monoamine oxidase inhibitors could increase the likelihood of adverse effects to occur. Beta blockers, a group of drugs for the treatment of hypertension (high blood pressure) and various conditions of the heart, could reduce the efficacy of olodaterol.[1] Clinical data on the relevance of such interactions are very limited.


Mechanism of action

Like all beta-adrenoceptor agonists, olodaterol mimics the effect of epinephrine at beta-2 receptors (β₂-receptors) in the lung, which causes the bronchi to relax and reduces their resistance to airflow.[3]

Olodaterol is a nearly full β₂-agonist, having 88% intrinsic activity compared to the gold standard isoprenaline. Its half maximal effective concentration (EC50) is 0.1 nM. It has a higher in vitro selectivity for β₂-receptors than the related drugs formoterol and salmeterol: 241-fold versus β₁- and 2299-fold versus β₃-receptors.[2] The high β₂/β₁ selectivity may account for the apparent lack of tachycardia in clinical trials, which is mediated by β₁-receptors on the heart.


Once bound to a β₂-receptor, an olodaterol molecule stays there for hours – its dissociation half-life is 17.8 hours –, which allows for once-a-day application of the drug[3] like with indacaterol. Other related compounds generally have a shorter duration of action and have to be applied twice daily (e.g. formoterol, salmeterol). Still others (e. g. salbutamol, fenoterol) have to be applied three or four times a day for continuous action, which can also be an advantage for patients who need to apply β₂-agonists only occasionally, for example in an asthma attack.[8]



On 29 January 2013 the U.S. Food and Drug Administration (FDA) Pulmonary-Allergy Drugs Advisory Committee (PADAC) recommended that the clinical data included in the new drug application (NDA) for olodaterol provide substantial evidence of safety and efficacy to support the approval of olodaterol as a once-daily maintenance bronchodilator treatment for airflow obstruction in patients with COPD.[9]

On 18 October 2013 approval of olodaterol in the first three European countries – the United Kingdom, Denmark and Iceland – was announced by the manufacturer.[10]


Figure  Chemical structures of salmeterol, formoterol, inda- caterol, and emerging once-daily long-acting β2-agonists



Synthetic approaches to the 2013 new drugs – ScienceDirect

Science Direct

Synthesis of olodaterol hydrochloride (XVI).


Olodaterol hydrochloride was approved for long-term, once-daily maintenance treatment of chronic
obstructive pulmonary disease (COPD) in 2013 in the following countries: Canada, Russia, United
Kingdom, Denmark, and Iceland.142, 143 The drug has been recommended by a federal advisory panel for
approval by the FDA.142, 143 Developed and marketed by Boehringer Ingelheim, olodaterol is a longacting
β2-adrenergic receptor agonist with high selectivity over the β1- and β3-receptors (219- and 1622-fold, respectively).144 Upon binding to and activating the β2-adrenergic receptor in the airway, olodaterol
stimulates adenyl cyclase to synthesize cAMP, leading to the relaxation of smooth muscle cells in the
airway. Administered by inhalation using the Respimat®
Soft Mist inhaler, it delivers significant
bronchodilator effects within five minutes of the first dose and provides sustained improvement in
forced expiratory volume (FEV1) for over 24 hours.143 While several routes have been reported in the
patent and published literature,144-146 the manufacturing route for olodaterol hydrochloride disclosed in
2011 is summarized in Scheme 19 below.147
Commercial 2’,5’-dihydroxyacetophenone (122) was treated with one equivalent of benzyl bromide
and potassium carbonate in methylisobutylketone (MIBK) to give the 5’-monobenzylated product in
76% yield. Subsequent nitration occurred at the 4’-position to provide nitrophenol 123 in 87% yield.
Reduction of the nitro group followed by subjection to chloroacetyl chloride resulted in the construction
of benzoxazine 124 in 82% yield. Next, monobromination through the use of tetrabutylammonium
tribromide occurred at the acetophenone carbon to provide bromoketone 125, and this was followed by
asymmetric reduction of the ketone employing (−)-DIP chloride to afford an intermediate bromohydrin,
which underwent conversion to the corresponding epoxide 126 in situ upon treatment with aqueous
NaOH. This epoxide was efficiently formed in 85% yield and 98.3% enantiomeric excess. Epoxide
126 underwent ring-opening upon subjection to amine 127 to provide amino-alcohol 128 in in 84-90%
yield and 89.5-99.5% enantiomeric purity following salt formation with HCl. Tertiary amine 127 was
itself prepared in three steps by reaction of ketone 129 with methylmagnesium chloride, Ritter reaction
of the tertiary alcohol with acetonitrile, and hydrolysis of the resultant acetamide with ethanolic
potassium hydroxide. Hydrogenative removal of the benzyl ether within 128 followed by
recrystallization with methanolic isopropanol furnished olodaterol hydrochloride (XVI) in 63-70%
yield. Overall, the synthesis of olodaterol hydrochloride required 10 total steps (7 linear) from
commercially available acetophenone 122.

142. Gibb, A.; Yang, L. P. H. Drugs 2013, 73, 1841.

144. Bouyssou, T.; Hoenke, C.; Rudolf, K.; Lustenberger, P.; Pestel, S.; Sieger, P.; Lotz, R.; Heine,
C.; Buettner, F. H.; Schnapp, A.; Konetzki, I. Bioorg. Med. Chem. Lett. 2010, 20, 1410.
145. Trunk, M. J. F.; Schiewe, J. US Patent 20050255050A1, 2005.
146. Lustenberger, P.; Konetzki, I.; Sieger, P. US Patent 20090137578A1, 2009.
147. Krueger, T.; Ries, U.; Schnaubelt, J.; Rall, W.; Leuter, Z. A.; Duran, A.; Soyka, R. US Patent
20110124859A1, 2011.



WO 2004045618 or



Figure imgb0006


To a solution of 3.6 g 1,1-dimethyl-2-(4-methoxyphenyl)-ethylamine in 100 mL of ethanol at 70 ° C. 7.5 g of (6-benzyloxy-4H-benzo [1,4] oxazin-3-one )-glyoxal added and allowed to stir for 15 minutes. Then within 30 minutes at 10 to 20 ° C. 1 g of sodium borohydride added. It is stirred for one hour, with 10 mL of acetone and stirred for another 30 minutes. The reaction mixture is diluted with 150 mL ethyl acetate, washed with water, dried with sodium sulfate and concentrated. The residue is dissolved in 50 mL of methanol and 100 mL ethyl acetate and acidified with conc. Hydrochloric acid. After addition of 100 mL of diethyl ether, the product precipitates. The crystals are filtered, washed and recrystallized from 50 mL of ethanol. Yield: 7 g (68%; hydrochloride), mp = 232-234 ° C.


6.8 g of the above obtained benzyl compound in 125 mL of methanol with the addition of 1 g of palladium on carbon (5%) was hydrogenated at room temperature and normal pressure. The catalyst is filtered and the filtrate was freed from solvent. Recrystallization of the residue in 50 mL of acetone and a little water, a solid is obtained, which is filtered and washed.
Yield: 5.0 g (89%; hydrochloride), mp = 155-160 ° C.

The (R) – and (S)-enantiomers of Example 3 can be obtained from the racemate, for example, by chiral HPLC (for example, column: Chirobiotic T, 250 x 1.22 mm from the company Astec). As the mobile phase, methanol with 0.05% triethylamine and 0.05% acetic acid. Silica gel with a grain size of 5 microns, to which is covalently bound the glycoprotein teicoplanin can reach as column material used. Retention time (R enantiomer) = 40.1 min, retention time (S-enantiomer) = 45.9 min. The two enantiomers can be obtained by this method in the form of free bases. According to the invention of paramount importance is the R enantiomer of Example 3




WO 2005111005

Scheme 1.


Figure imgf000013_0001


Figure imgf000013_0003
Figure imgf000013_0002


Figure imgf000013_0004

Scheme 1:

Example 1 6-Hydroxy-8-{(1-hydroxy-2-r2-(4-methoxy-phenyl) – 1, 1-dimethyl-ethylamino]-ethyl)-4H-benzor 41oxazin-3-one – Hvdrochlorid


Figure imgf000017_0001

a) l-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone

To a solution of 81.5 g (0.34 mol) l-(5-benzyloxy-2-hydroxy-phenyl)-ethanone in 700 ml of acetic acid are added dropwise under cooling with ice bath, 18 mL of fuming nitric acid, the temperature does not exceed 20 ° C. increases. The reaction mixture is stirred for two hours at room temperature, poured onto ice water and filtered. The product is recrystallized from isopropanol, filtered off and washed with isopropanol and diisopropyl ether. Yield: 69.6 g (72%), mass spectroscopy [M + H] + = 288

b) l-(3-Amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone

69.5 g (242 mmol) of l-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone are dissolved in 1.4 L of methanol and in the presence of 14 g of rhodium on carbon (10%) as catalyst at 3 bar room temperature and hydrogenated. Then the catalyst is filtered off and the filtrate concentrated. The residue is reacted further without additional purification. Yield: 60.0 g (96%), R f value = 0.45 (silica gel, dichloromethane).

c) 8-acetyl-6-benzyloxy-4H-benzoπ .4] oxazin-3-one

To 60.0 g (233 mmol) of l-(3-Amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone and 70.0 g (506 mmol) of potassium carbonate while cooling with ice bath, 21.0 ml (258 mmol) of chloroacetyl chloride added dropwise. Then stirred overnight at room temperature and then for 6 hours under reflux. The hot reaction mixture is filtered and then concentrated to about 400 mL and treated with ice water. The precipitate is filtered off, dried and purified by chromatography on a short silica gel column (dichloromethane: methanol = 99:1). The product-containing fractions are concentrated, suspended in isopropanol, diisopropyl ether, and extracted with

Diisopropyl ether. Yield: 34.6 g (50%), mass spectroscopy [M + H] + = 298

d) 6-Benzyloxy-8-(2-chloro-acetyl)-4H-benzoFl, 4] oxazin-3-one 13.8 g (46.0 mmol) of 8-benzyloxy-6-Acetyl-4H-benzo [l, 4] oxazin -3-one and 35.3 g (101.5 mmol) of benzyltrimethylammonium dichloriodat are stirred in 250 mL dichloroethane, 84 mL glacial acetic acid and 14 mL water for 5 hours at 65 ° C. After cooling to room temperature, treated with 5% aqueous sodium hydrogen sulfite solution and stirred for 30 minutes. The precipitated solid is filtered off, washed with water and diethyl ether and dried. Yield: 13.2 g (86%), mass spectroscopy [M + H] + = 330/32.

e) 6-Benzyloxy-8-((R-2-chloro-l-hydroxy-ethyl)-4H-benzori ,41-oxazin-3-one The procedure is analogous to a procedure described in the literature (Org. Lett ., 2002, 4, 4373-4376).

To 13:15 g (39.6 mmol) of 6-benzyloxy-8-(2-chloro-acetyl)-4H-benzo [l, 4] oxazin-3-one and 25.5 mg (0:04 mmol) Cρ * RhCl [(S, S) -TsDPEN] (Cp * = pentamethylcyclopentadienyl and TsDPEN = (lS, 2S)-Np-toluenesulfonyl-l ,2-diphenylethylenediamine) in 40 mL of dimethylformamide at -15 ° C and 8 mL of a mixture of formic acid and triethylamine (molar ratio = 5: 2) dropwise. It is allowed for 5 hours at this temperature, stirring, then 25 mg of catalyst and stirred overnight at -15 ° C. The reaction mixture is mixed with ice water and filtered. The filter residue is dissolved in dichloromethane, dried with sodium sulfate and the solvent evaporated. The residue is recrystallized gel (dichloromethane / methanol gradient) and the product in diethyl ether / diisopropyl ether. Yield: 10.08 g (76%), R f value = 00:28 (on silica gel, dichloromethane ethanol = 50:1).

f) 6-Benzyloxy-8-(R-oxiranyl-4H-benzo [“L4] oxazin-3-one 6.10 g (30.1 mmol) of 6-benzyloxy-8-((R)-2-chloro-l-hydroxy- ethyl)-4H-benzo [l, 4] oxazin-3-one are dissolved in 200 mL of dimethylformamide. added to the solution at 0 ° C with 40 mL of a 2 molar sodium hydroxide solution and stirred at this temperature for 4 hours. the reaction mixture is poured onto ice water, stirred for 15 minutes, and then filtered The solid is washed with water and dried to give 8.60 g (96%), mass spectroscopy [M + H] + = 298..

g) 6-Benyloxy-8-{(R-l-hydroxy-2-r2-(4-methoxy-phenyl)-dimethyl-ll-ethvIaminol-ethyl)-4H-benzo-3-Tl A1oxazin

5.25 g (17.7 mmol) of 6-benzyloxy-8-(R)-oxiranyl-4H-benzo [l, 4] oxazin-3-one and 6.30 g (35.1 mmol) of 2 – (4-methoxy-phenyl 1, 1 – dimethyl-ethyl to be with 21 mL

Of isopropanol and stirred at 135 ° C for 30 minutes under microwave irradiation in a sealed reaction vessel. The solvent is distilled off and the residue chromatographed (alumina, ethyl acetate / methanol gradient). The product thus obtained is purified by recrystallization from a mixture further Diethylether/Diisopropylether-. Yield: 5:33 g (63%), mass spectroscopy [M + H] + = 477 h) 6-Hydroxy-8-{(R)-l-hydroxy-2-[2 – (4-methoxy-phenyl)-l, l-dimethyl-ethylamino] – ethyl}-4H-benzo [1, 4, 1 oxazin-3-one hydrochloride

A suspension of 5:33 g (11.2 mmol) of 6-Benyloxy-8-{(R)-l-hydroxy-2-[2 – (4-methoxy-phenyl)-l, l-dimethyl-ethylamino]-ethyl}-4H -benzo [l, 4] oxazin-3-one in 120 mL of methanol with 0.8 g of palladium on carbon (10%), heated to 50 ° C and hydrogenated at 3 bar hydrogen pressure. Then the catalyst is filtered off and the filtrate concentrated. The residue is dissolved in 20 mL of isopropanol, and 2.5 mL of 5 molar hydrochloric acid in isopropanol. The product is precipitated with 200 mL of diethyl ether, filtered off and dried. Yield: 4.50 g (95%, hydrochloride), mass spectroscopy [M + H] + = 387



WO 2007020227



WO 2008090193




Discovery of olodaterol, a novel inhaled beta(2)-adrenoceptor agonist with a 24h bronchodilatory efficacy
Bioorg Med Chem Lett 2010, 20(4): 1410

The discovery of the β2-adrenoceptor agonist (R)-4p designated olodaterol is described. The preclinical profile of the compound suggests a bronchoprotective effect over 24 h in humans.

Full-size image (4 K)








Click to access 203108Orig1s000ChemR.pdf

NDA 203108
Striverdi® Respimat® (olodaterol) Inhalation Spray
Boehringer Ingelheim Pharmaceuticals, Inc.


  1. Striverdi UK Drug Information
  2. Bouyssou, T.; Casarosa, P.; Naline, E.; Pestel, S.; Konetzki, I.; Devillier, P.; Schnapp, A. (2010). “Pharmacological Characterization of Olodaterol, a Novel Inhaled  2-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models”. Journal of Pharmacology and Experimental Therapeutics 334 (1): 53–62. doi:10.1124/jpet.110.167007. PMID 20371707. edit
  3. Casarosa, P.; Kollak, I.; Kiechle, T.; Ostermann, A.; Schnapp, A.; Kiesling, R.; Pieper, M.; Sieger, P.; Gantner, F. (2011). “Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol”. Journal of Pharmacology and Experimental Therapeutics 337 (3): 600–609. doi:10.1124/jpet.111.179259. PMID 21357659. edit
  4. Bouyssou, T.; Hoenke, C.; Rudolf, K.; Lustenberger, P.; Pestel, S.; Sieger, P.; Lotz, R.; Heine, C.; Büttner, F. H.; Schnapp, A.; Konetzki, I. (2010). “Discovery of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24h bronchodilatory efficacy”. Bioorganic & Medicinal Chemistry Letters 20 (4): 1410–1414. doi:10.1016/j.bmcl.2009.12.087. PMID 20096576. edit
  5. Joos G, Aumann JL, Coeck C, et al. ATS 2012 Abstract: Comparison of 24-Hour FEV1 Profile for Once-Daily versus Twice-Daily Treatment with Olodaterol, A Novel Long-Acting ß2-Agonist, in Patients with COPD[dead link]
  6. Van Noord, J. A.; Smeets, J. J.; Drenth, B. M.; Rascher, J.; Pivovarova, A.; Hamilton, A. L.; Cornelissen, P. J. G. (2011). “24-hour Bronchodilation following a single dose of the novel β2-agonist olodaterol in COPD”. Pulmonary Pharmacology & Therapeutics 24 (6): 666–672. doi:10.1016/j.pupt.2011.07.006. PMID 21839850. edit
  7. van Noord JA, Korducki L, Hamilton AL and Koker P. Four Weeks Once Daily Treatment with BI 1744 CL, a Novel Long-Acting ß2-Agonist, is Effective in COPD Patients. Am. J. Respir. Crit. Care Med. 2009; 179: A6183[dead link]
  8. Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
  9. Hollis A (31 January 2013). “Panel Overwhelmingly Supports Boehringer COPD Drug Striverdi”. FDA News/Drug Industry Daily.
  10. “New once-daily Striverdi (olodaterol) Respimat gains approval in first EU countries”. Boehringer-Ingelheim. 18 October 2013.

External links

The active moiety olodaterol is a selective beta2-adrenergic bronchodilator. The drug substance, olodaterol hydrochloride, is chemically described as 2H-1,4- Benzoxazin-3H(4H)-one, 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]-amino]ethyl]-, monohydrochloride. Olodaterol hydrochloride is a white to off-white powder that is sparingly-slightly soluble in water and slightly soluble in ethanol. The molecular weight is 422.9 g/mole (salt): 386.5 g/mole (base), and the molecular formula is C21H26N2O5 x HCl as a hydrochloride. The conversion factor from salt to free base is 1.094.

The structural formula is:

STRIVERDI® RESPIMAT® (olodaterol) Structural Formula Illustration

The drug product, STRIVERDI RESPIMAT, is composed of a sterile, aqueous solution of olodaterol hydrochloride filled into a 4.5 mL plastic container crimped into an aluminum cylinder (STRIVERDI RESPIMAT cartridge) for use with the STRIVERDI RESPIMAT inhaler.

Excipients include water for injection, benzalkonium chloride, edetate disodium, and anhydrous citric acid. The STRIVERDI RESPIMAT cartridge is only intended for use with the STRIVERDI RESPIMAT inhaler. The STRIVERDI RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow-moving aerosol cloud of medication from a metered volume of the drug solution. The STRIVERDI RESPIMAT inhaler has a yellow-colored cap.

When used with the STRIVERDI RESPIMAT inhaler, each cartridge containing a minimum of 4 grams of a sterile aqueous solution delivers the labeled number of metered actuations after preparation for use. Each dose (1 dose equals 2 actuations) from the STRIVERDI RESPIMAT inhaler delivers 5 mcg olodaterol in 22.1 mcL of solution from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).


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Organic spectroscopy should be brushed up and you get confidence

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Organic chemists from Industry and academics to interact on Spectroscopy techniques for Organic compounds ie NMR, MASS, IR, UV Etc. email me ………..  is the link

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EU approves Takeda’s bowel drug Entyvio

EU approves Takeda's bowel drug Entyvio

Hot on the heels of an approval in the US, regulators in Europe have now also given Takeda’s Entyvio (vedolizumab) the nod for two inflammatory bowel diseases. The European Commission has granted Marketing Authorisation for use of the gut-selective humanised monoclonal antibody to treat adults with moderately to severely active ulcerative colitis (UC) and adults with moderately to severely active Crohn’s disease (CD).

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Europe approves Pierre Fabre’s Hemangiol

Europe approves Pierre Fabre's Hemangiol

Regulators in Europe have given the green light to Pierre Fabre’s Hemangiol for the treatment of proliferating infantile haemangioma.

The European Commission has granted the French company authorisation to market Hemangiol, an oral solution of the beta-blocker propranolol specially developed for paediatric use. The thumbs-up follows an approval in the USA in March; it will be launched across the Atlantic as Hemangeol next month.

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Kevin Grogan

Kevin Grogan is the World News Online Editor for PharmaTimes and has been writing about the industry since 1997, having previously worked as a journalist on rock/pop music publications, while contributing articles to the likes of The Independent and the Manchester Evening News on football. He specialises in the business developments of the pharmaceutical industry – financial results, mergers and acquisitions, alliances, legal tussles – and has a particular interest in emerging markets and the prospects for biotech.

Newly approved drugs: EMA presents figures

In the EU, the number of approved drugs is rising with a new active ingredient; however, stagnated, the number of newly approved generics.

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