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Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with 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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Medivir AB :New Drug Application has been filed with FDA for Simeprevir (TMC435) for combination treatment of adult patients with genotype 1 chronic hepatitis C


03/28/2013| Medivir AB announced that a new drug application (NDA) has been filed with the U.S. Food and Drug Administration (FDA) seeking approval for simeprevir. The filing is based on phase III data in treatment-naïve and treatment-experienced patients with compensated liver disease.

The filing of a regulatory application in the US triggers a milestone payment of ?10m to Medivir.

Simeprevir is jointly developed by Medivir and Janssen Pharmaceuticals, Inc. (Janssen), and is an investigational NS3/4A protease inhibitor, administered as a 150 mg capsule once daily with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C in adult patients.

“The filing in the U.S. is a very important milestone for simeprevir, the hepatitis C patients and for Medivir as a company. In addition it triggers a ? 10m milestone payment to us, which strengthens our solid financial situation even more.” comments Maris Hartmanis, CEO of Medivir.

The regulatory submission for simeprevir is supported in part by data from three pivotal phase III studies: QUEST-1 and QUEST-2 in treatment-naïve patients and PROMISE in patients who have relapsed after prior interferon-based treatment. In each study, participants were treated with one 150 mg simeprevir capsule once daily for 12 weeks plus pegylated interferon and ribavirin for 24 or 48 weeks. Primary efficacy data from the phase III studies will be presented at different upcoming medical meetings.

About Simeprevir

Simeprevir, an investigational next generation NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB, is currently in late phase III studies as a once-daily capsule (150 mg) taken in combination with pegylated interferon and ribavirin for the treatment of genotypes 1 and 4 HCV.

Global phase III studies of simeprevir include QUEST-1 and QUEST-2 in treatment-naïve patients, PROMISE in patients who have relapsed after prior interferon-based treatment and ATTAIN in null-responder patients. In parallel to these trials, phase III studies for simeprevir are ongoing in treatment-naïve and treatment-experienced HIV-HCV co-infected patients, HCV genotype 4 patients and Japanese HCV genotype 1 patients. Janssen recently announced the submission of a new drug application for simeprevir in Japan for the treatment of genotype 1 hepatitis C.

Simeprevir is being studied in phase II interferon-free trials with and without ribavirin in combination with:

  • Janssen’s non-nucleoside inhibitor TMC647055 and ritonavir in treatment-naïve genotype 1a and 1b HCV patients;
  • Gilead Sciences, Inc.’s nucleotide inhibitor sofosbuvir (GS-7977) in treatment-naïve and previous null-responder genotype 1 HCV patients; and
  • Bristol-Myers Squibb’s NS5A replication complex inhibitor daclatasvir (BMS-790052) in treatment-naive and previous null-responder genotype 1 HCV patients.

In addition, Janssen has a non-exclusive collaboration with Vertex Pharmaceuticals to evaluate in a phase II study the safety and efficacy of an all-oral regimen of simeprevir and Vertex’s investigational nucleotide analogue polymerase inhibitor VX-135 for the treatment of HCV. As a first step, Janssen Pharmaceutical Inc. will conduct a drug-drug interaction (DDI) study with simeprevir and VX-135.

We also recently announced plans to initiate a phase II trial of an investigational interferon-free regimen with simeprevir, TMC647055 and Idenix’s IDX719, a once-daily, pan-genotypic NS5A inhibitor, with and without ribavirin.

About Hepatitis C

Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease and liver transplants, is a rapidly evolving treatment area with a clear need for innovative treatments. Approximately 150 million people are infected with hepatitis C worldwide, and 350,000 people per year die from the disease.

About Medivir AB

Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor in late phase III clinical development for hepatitis C that is being developed in collaboration with Janssen R&D Ireland.


Simeprevir (formerly TMC435) is an experimental drug candidate for the treatment of hepatitis C. It is being developed by Medivir and Johnson & Johnson’s pharmaceutical division Janssen Pharmaceutica and is currently in Phase III clinical trials.[1]

Simeprevir is a hepatitis C virus protease inhibitor.[2]

Simeprevir is being tested in combination regimens with pegylated interferon alfa-2a and ribavirin,[3] and in interferon-free regimens with other direct-acting antiviral agents including daclatasvir[4] and sofosbuvir [5]

  1.  “Medivir Announces That Simeprevir (TMC435) Data Will Be Presented at the Upcoming AASLD Meeting”. Yahoo News. October 1, 2012. Retrieved November 6, 2012.
  2.  Lin, TI; Lenz, O; Fanning, G; Verbinnen, T; Delouvroy, F; Scholliers, A; Vermeiren, K; Rosenquist, A et al. (2009). “In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor”. Antimicrobial agents and chemotherapy 53 (4): 1377–85. doi:10.1128/AAC.01058-08. PMC 2663092. PMID 19171797.
  3.  “Phase 3 Studies Show Simeprevir plus Interferon/Ribavirin Cures Most Patients in 24 Weeks”. December 27, 2012.
  4.  Medivir announces TMC435 in an expanded clinical collaboration. Medivir. 18 April 2012.
  5.  [ Results from a phase IIa study evaluating Simeprevir and Sofosbuvir in prior null responder Hepatitis C patients have been presented at CROI. 6 March 2013.

New Merck, Reviewed

As I mentioned last night, most Wall Street analysts are offering only moderately bullish estimates of Invokana®‘s peak 2017 sales, this early in the game. And I partially agree — it makes some sense to be conservative here, given the questions about other drug candidates in this new class.

On the other hand, it appears that Invokana will have a very clean FDA label (very few scary warnings — no black box warnings), and will be able to note the study results showing “off-target” weight-loss effects — in most patients on the drug. Given that obesity and this type of diabetis are closely associated, that may be a very powerful finding, for patient conversion — to this new class. It will be a once a day pill, and very convenient to take.

In addition, J&J’s Janssen unit is now saying that the wholesale price will be about…

View original post 390 more words

FDA Approves Canagliflozin, Invokana – First in New Class of Type 2 Diabetes Drugs


FRIDAY March 29, 2013

The first in a new class of type 2 diabetes drugs was approved Friday by the U.S. Food and Drug Administration.

Invokana (canagliflozin) tablets are to be taken, in tandem with a healthy diet and exercise, to improve blood sugar control in adults with type 2 diabetes.

Invokana belongs to a class of drugs called sodium-glucose co-transporter 2 (SGLT2) inhibitors. It works by blocking the reabsorption of glucose (sugar) by the kidney and increasing glucose excretions in urine, the FDA said in a news release.

Canagliflozin (Invokana) is drug for the treatment of type 2 diabetes developed by Johnson & Johnson.[1][2] In March 2013, canagliflozin became the first in a new class of drugs for diabetes treatment to be approved.[3] It is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter causes blood glucose to be eliminated through the urine

  1. New J&J diabetes drug effective in mid-stage study, Jun 26, 2010
  2.  Edward C. Chao (2011). “Canagliflozin”. Drugs of the Future 36 (5): 351–357. doi:10.1358/dof.2011.36.5.1590789.
  3.  “U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin”. Reuters. Mar 29, 2013. “U.S. health regulators have approved a new diabetes drug from Johnson & Johnson, making it the first in its class to be approved in the United States.”
  4. Prous Science: Molecule of the Month November 2007

The agency told drug maker Janssen Pharmaceuticals that it must conduct five post-approval studies of the drug to determine the risk of problems such as heart disease, cancer, pancreatitis, liver abnormalities and pregnancy complications.



Canagliflozin is a highly potent and selective subtype 2 sodium-glucose transport protein (SGLT2) inhibitor to CHO- hSGLT2, CHO- rSGLT2 and CHO- mSGLT2 with IC50 of 4.4 nM, 3.7 nM and 2 nM, respectively.

M.Wt: 444.52
CAS No: 842133-18-0

Canagliflozin Hemihydrate
(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hydrate (2:1)

Canagliflozin (INN, trade name Invokana) is a drug of the gliflozin class, used for the treatment of type 2 diabetes.[1][2] It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, a division of Johnson & Johnson.[3]
U.S. Patent No, 7,943,788 B2 (the ‘788 patent) discloses canagliflozin or salts thereof and the process for its preparation.
U.S. Patent Nos. 7,943,582 B2 and 8,513,202 B2 discloses crystalline form of 1 -(P-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate and process for preparation thereof. The US ‘582 B2 and US ‘202 B2 further discloses that preparation of the crystalline form of hemi-hydrate canagliflozin typically involves dissolving in a good solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005/012326 pamphlet, and adding water and a poor solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.
U.S. PG-Pub. No. 2013/0237487 Al (the US ‘487 Al) discloses amorphous dapagliflozin and amorphous canagliflozin. The US ‘487 Al also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1: 1 crystalline complex of canagliflozin with D-proline (Form CS2), 1 :1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4).
The US ‘487 Al discloses preparation of amorphous canagliflozin by adding its heated toluene solution into n-heptane. After drying in vacuo the product was obtained as a white solid of with melting point of 54.7°C to 72.0°C. However, upon repetition of the said experiment, the obtained amorphous canagliflozin was having higher amount of residual solvents. Therefore, the amorphous canagliflozin obtained by process as disclosed in US ‘487 Al is not suitable for pharmaceutical preparations.
The US ‘487 Al further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vapor sorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.
The canagliflozin assessment report EMA/718531/2013 published by EMEA discloses that Canagliflozin hemihydrate is a white to off-white powder^ practically insoluble in water and freely soluble in ethanol and non-hygroscopic. Polymorphism has been observed for canagliflozin and the manufactured Form I is a hemihydrate, and an unstable amorphous Form II. Form I is consistently produced by the proposed commercial synthesis process. Therefore, it is evident from the prior art that the reported amorphous form of canagliflozin is unstable and hygroscopic as well as not suitable for pharmaceutical preparations due to higher amount of residual solvents above the ICH acceptable limits.
Medical use

    1. Canagliflozin is an antidiabetic drug used to improve glycemic control in people with type 2 diabetes. In extensive clinical trials, canagliflozin produced a consistent dose-dependent reduction in HbA1c of 0.77% to 1.16% when administered as monotherapy, combination with metformin, combination with metformin & Sulfonyulrea, combination with metformin & pioglitazone and In combination with insulin from a baselines of 7.8% to 8.1%, in combination with metformin, or in combination with metformin and a sulfonylurea. When added to metformin Canagliflozin 100mg was shown to be non-inferior to both Sitagliptin 100mg and glimiperide in reductions on HbA1c at one year, whilst canagliflozin 300mg successfully demontrated statistical superiority over both Sitagliptin and glimiperide in HbA1c reductions. Secondary efficacy endpoint of superior body weight reduction and blood pressure reduction (versus Sitagliptin and glimiperide)) were observed as well. Canagliflozin produces beneficial effects on HDL cholesterol whilst increasing LDL cholesterol to produce no change in total cholesterol.[4][5]


      Canagliflozin has proven to be clinically effective in people with moderate renal failure and treatment can be continued in patients with renal impairment.

      Adverse effects

      Canagliflozin, as is common with all sglt2 inhibitors, increased (generally mild) urinary tract infections, genital fungal infections, thirst,[6] LDL cholesterol, and was associated with increased urination and episodes of low blood pressure.
      There are concerns it may increase the risk of diabetic ketoacidosis.[7]
      Cardiovascular problems have been discussed with this class of drugs.[citation needed] The pre-specified endpoint for cardiovascular safety in the canagliflozin clinical development program was Major Cardiovascular Events Plus (MACE-Plus), defined as the occurrence of any of the following events: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina leading to hospitalization. This endpoint occurred in more people in the placebo group (20.5%) than in the canagliflozin treated group (18.9%).
      Nonetheless, an FDA advisory committee expressed concern regarding the cardiovascular safety of canagliflozin. A greater number of cardiovascular events was observed during the first 30 days of treatment in canagliflozin treated people (0.45%) relative to placebo treated people (0.07%), suggesting an early period of enhanced cardiovascular risk. In addition, there was an increased risk of stroke in canagliflozin treated people. However none of these effects were seen as statistically significant. Additional cardiovascular safety data from the ongoing CANVAS trial is expected in 2015.[8]


      The drug may increase the risk of dehydration in combination with diuretic drugs.
      Because it increases renal excretion of glucose, treatment with canagliflozin prevents renal reabsorption of 1,5-anhydroglucitol, leading to artifactual decreases in serum 1,5-anhydroglucitol; it can therefore interfere with the use of serum 1,5-anhydroglucitol (assay trade name, GlycoMark) as a measure of postprandial glucose excursions.[9]

      Mechanism of action

      Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the renal glucose reabsorption (SGLT1 being responsible for the remaining 10%). Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine,[10] corresponding to 476 kilocalories. Additional water is eliminated by osmotic diuresis, resulting in a lowering of blood pressure.
      This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose) compared to other antidiabetic drugs such as sulfonylurea derivatives and insulin.[11]


      On July 4, 2011, the European Medicines Agency approved a paediatric investigation plan and granted both a deferral and a waiver for canagliflozin (EMEA-001030-PIP01-10) in accordance with EC Regulation No.1901/2006 of the European Parliament and of the Council.[12]
      In March 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States.[13]



Canagliflozin is an API that is an inhibitor of SGLT2 and is being developed for the treatment of type 2 diabetes mellitus.[0011] The IUPAC systematic name of canagliflozin is (25,,3/?,4i?,55′,6 ?)-2-{3-[5-[4-fluoro- phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, and is also known as (15)-l,5-anhydro-l-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4- methylphenyl]-D-glucitol and l-( -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene. Canagliflozin is a white to off-white powder with a molecular formula of C24H25F05S and a molecular weight of 444.52. The structure of canagliflozin is shown as compound B.

Compound B – Canagliflozin
[0012] In US 2008/0146515 Al, a crystalline hemihydrate form of canagliflozin (shown as Compound C) is disclosed, having the powder X-ray diffraction (XRPD) pattern comprising the following 2Θ values measured using CuKa radiation: 4.36±0.2, 13.54±0.2, 16.00±0.2, 19.32±0.2, and 20.80±0.2. The XRPD pattern is shown in Figure 24. A process for the preparation of canagliflozin hemihydrate is also disclosed in US 2008/0146515 Al.

Compound C – hemihydrate form of canagliflozin
[0013] In US 2009/0233874 Al, a crystalline form of canagliflozin is disclosed.


WO 2005/012326 pamphlet discloses a class of compounds that are inhibitors of sodium-dependent glucose transporter (SGLT) and thus of therapeutic use for treatment of diabetes, obesity, diabetic complications, and the like. There is described in WO 2005/012326 pamphlet 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene of formula (I):

Example 1 Crystalline 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene was prepared in a similar manner as described in WO 2005/012326.

(1) To a solution of 5-bromo-1-[5-(4-fluorophenyl)-2-thienylmethyl]-2-methylbenzene (1, 28.9 g) in tetrahydrofuran (480 ml) and toluene (480 ml) was added n-butyllithium (1.6M hexane solution, 50.0 ml) dropwise at −67 to −70° C. under argon atmosphere, and the mixture was stirred for 20 minutes at the same temperature. Thereto was added a solution of 2 (34.0 g) in toluene (240 ml) dropwise at the same temperature, and the mixture was further stirred for 1 hour at the same temperature. Subsequently, thereto was added a solution of methanesulfonic acid (21.0 g) in methanol (480 ml) dropwise, and the resulting mixture was allowed to warm to room temperature and stirred for 17 hours. The mixture was cooled under ice—water cooling, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with brine and dried over magnesium sulfate. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was triturated with toluene (100 ml)—hexane (400 ml) to give 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]-benzene (3) (31.6 g). APCI-Mass m/Z 492 (M+NH4).
(2) A solution of 3 (63.1 g) and triethylsilane (46.4 g) in dichloromethane (660 ml) was cooled by dry ice-acetone bath under argon atmosphere, and thereto was added dropwise boron trifluoride•ethyl ether complex (50.0 ml), and the mixture was stirred at the same temperature. The mixture was allowed to warm to 0° C. and stirred for 2 hours. At the same temperature, a saturated aqueous sodium hydrogen carbonate solution (800 ml) was added, and the mixture was stirred for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate twice. The organic layer was washed with water twice, dried over magnesium sulfate and treated with activated carbon. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 ml), and thereto were added diethyl ether (600 ml) and H2O (6 ml). The mixture was stirred at room temperature overnight, and the precipitate was collected, washed with ethyl acetate-diethyl ether (1:4) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (33.5 g) as colorless crystals.
mp 98-100° C. APCI-Mass m/Z 462 (M+NH4). 1H-NMR (DMSO-d6) δ 2.26 (3H, s), 3.13-3.28 (4H, m), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.3 Hz), 4.10, 4.15 (each 1H, d, J=16.0 Hz), 4.43 (1H, t, J=5.8 Hz), 4.72 (1H, d, J=5.6 Hz), 4.92 (2H, d, J=4.8 Hz), 6.80 (1H, d, J=3.5 Hz), 7.11-7.15 (2H, m), 7.18-7.25 (3H, m), 7.28 (1H, d, J=3.5 Hz), 7.59 (2H, dd, J=8.8, 5.4 Hz).
Anal. Calcd. for C24H25FO5S.0.5H2O: C, 63.56; H, 5.78; F, 4.19; S, 7.07. Found: C, 63.52; H, 5.72; F, 4.08; S, 7.00.
Figure US07943582-20110517-C00001

Example 2An amorphous powder of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (1.62 g) was dissolved in acetone (15 ml), and thereto were added H2O (30 ml) and a crystalline seed. The mixture was stirred at room temperature for 18 hours, and the precipitate was collected, washed with acetone—H2O (1:4, 30 ml) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (1.52 g) as colorless crystals. mp 97-100° C.


there are a significant number of other β-C-arylglucoside derived drug candidates, most of which differ only in the aglycone moiety (i.e., these compounds comprise a central 1-deoxy-glucose ring moiety that is arylated at CI). It is this fact that makes them attractive targets for a novel synthetic platform technology, since a single methodology should be able to furnish a plurality of products. Among β-C-arylglucosides that possess known SGLT2 inhibition also currently in clinical development are canagliflozin, empagliflozin, and ipragliflozin.

Dapagliflozin                             Canagliflozin

Ipragliflozin …………………Empagliflozin
[0007] A series of synthetic methods have been reported in the peer-reviewed and patent literature that can be used for the preparation of β-C-arylglucosides. These methods are described below and are referred herein as the gluconolactone method, the metalated glucal method, the glucal epoxide method and the glycosyl leaving group substitution method.
[0008] The gluconolactone method: In 1988 and 1989 a general method was reported to prepare C-arylglucosides from tetra-6>-benzyl protected gluconolactone, which is an oxidized derivative of glucose (see J. Org. Chem. 1988, 53, 752-753 and J. Org. Chem. 1989, 54, 610- 612). The method comprises: 1) addition of an aryllithium derivative to the hydroxy-protected gluconolactone to form a hemiketal (, a lactol), and 2) reduction of the resultant hemiketal with triethylsilane in the presence of boron trifluoride etherate. Disadvantages of this classical, but very commonly applied method for β-C-arylglucoside synthesis include:
1) poor “redox economy” (see J. Am. Chem. Soc. 2008, 130, 17938-17954 and Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN- 10: 0120594757); pg 38)— that is, the oxidation state of the carbon atom at CI, with respect to glucose, is oxidized in the gluconolactone and then following the arylation step is reduced to provide the requisite oxidation state of the final product. 2) due to a lack of stereospecificity, the desired β-C-arylglucoside is formed along with the undesired a-C-arylglucoside stereoisomer (this has been partially addressed by the use of hindered trialkylsilane reducing agents (see Tetrahedron: Asymmetry 2003, 14, 3243-3247) or by conversion of the hemiketal to a methyl ketal prior to reduction (see J. Org. Chem. 2007, 72, 9746-9749 and U.S. Patent 7,375,213)).
Oxidation Reduction

Glucose Gluconoloctone Hemiketal a-anomer β-anomer
R = protecting group
[0009] The metalated glucal method: U.S. Patent 7,847,074 discloses preparation of SGLT2 inhibitors that involves the coupling of a hydroxy-protected glucal that is metalated at CI with an aryl halide in the presence of a transition metal catalyst. Following the coupling step, the requisite formal addition of water to the C-arylglucal double bond to provide the desired C-aryl glucoside is effected using i) hydroboration and oxidation, or ii) epoxidation and reduction, or iii) dihydroxylation and reduction. In each case, the metalated glucal method represents poor redox economy because oxidation and reduction reactions must be conducted to establish the requisite oxidation states of the individual CI and C2 carbon atoms.
[0010] U.S. Pat. Appl. 2005/0233988 discloses the utilization of a Suzuki reaction between a CI -boronic acid or boronic ester substituted hydroxy-protected glucal and an aryl halide in the presence of a palladium catalyst. The resulting 1- C-arylglucal is then formally hydrated to provide the desired 1- C-aryl glucoside skeleton by use of a reduction step followed by an oxidation step. The synthesis of the boronic acid and its subsequent Suzuki reaction, reduction and oxidation, together, comprise a relatively long synthetic approach to C-arylglucosides and exhibits poor redox economy. Moreover, the coupling catalyst comprises palladium which is toxic and therefore should be controlled to very low levels in the drug substance.

R = protecting group; R’ = H or alkyl
[0011] The glucal epoxide method: U.S. Patent 7,847,074 discloses a method that utilizes an organometallic (derived from the requisite aglycone moiety) addition to an electrophilic epoxide located at C1-C2 of a hydroxy-protected glucose ring to furnish intermediates useful for SGLT2 inhibitor synthesis. The epoxide intermediate is prepared by the oxidation of a hydroxy- protected glucal and is not particularly stable. In Tetrahedron 2002, 58, 1997-2009 it was taught that organometallic additions to a tri-6>-benzyl protected glucal-derived epoxide can provide either the a-C-arylglucoside, mixtures of the a- and β-C-arylglucoside or the β-C-arylglucoside by selection of the appropriate counterion of the carbanionic aryl nucleophile (i.e., the
organometallic reagent). For example, carbanionic aryl groups countered with copper (i.e., cuprate reagents) or zinc (i.e., organozinc reagents) ions provide the β-C-arylglucoside, magnesium ions provide the a- and β-C-arylglucosides, and aluminum (i.e., organoaluminum reagents) ions provide the a-C-arylglucoside.

or Zn[0012] The glycosyl leaving group substitution method: U.S. Patent 7,847,074, also disclosed a method comprising the substitution of a leaving group located at CI of a hydroxy-protected glucosyl species, such as a glycosyl halide, with a metalated aryl compound to prepare SGLT2 inhibitors. U.S. Pat. Appl. 2011/0087017 disclosed a similar method to prepare the SGLT2 inhibitor canagliflozin and preferably diarylzinc complexes are used as nucleophiles along with tetra- >-pivaloyl protected glucosylbromide.

Glucose Glucosyl bromide β-anomer
[0013] Methodology for alkynylation of 1,6-anhydroglycosides reported in Helv. Chim. Acta. 1995, 78, 242-264 describes the preparation of l,4-dideoxy-l,4-diethynyl^-D-glucopyranoses (a. La., glucopyranosyl acetylenes), that are useful for preparing but-l,3-diyne-l,4-diyl linked polysaccharides, by the ethynylating opening (alkynylation) of partially protected 4-deoxy-4-C- ethynyl-l,6-anhydroglucopyranoses. The synthesis of β-C-arylglucosides, such as could be useful as precursors for SLGT2 inhibitors, was not disclosed. The ethynylation reaction was reported to proceed with retention of configuration at the anomeric center and was rationalized (see Helv. Chim. Acta 2002, 85, 2235-2257) by the C3-hydroxyl of the 1,6- anhydroglucopyranose being deprotonated to form a C3-0-aluminium species, that coordinated with the C6-oxygen allowing delivery of the ethyne group to the β-face of the an oxycarbenium cation derivative of the glucopyranose. Three molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6-anhydroglucopyranose. The
ethynylaluminium reagent was prepared by the reaction of equimolar (i.e., 1:1) amounts of aluminum chloride and an ethynyllithium reagent that itself was formed by the reaction of an acetylene compound with butyllithium. This retentive ethynylating opening method was also applied (see Helv. Chim. Acta. 1998, 81, 2157-2189) to 2,4-di-<9-triethylsilyl- 1,6- anhydroglucopyranose to provide l-deoxy-l-C-ethynyl- -D-glucopyranose. In this example, 4 molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6- anhydroglucopyranose. The ethynylaluminium regent was prepared by the reaction of equimolar (i.e., 1: 1) amounts of aluminum chloride and an ethynyl lithium reagent that itself was formed by reaction of an acetylene compound with butyllithium.
[0014] It can be seen from the peer-reviewed and patent literature that the conventional methods that can be used to provide C-arylglucosides possess several disadvantages. These include (1) a lack of stereoselectivity during formation of the desired anomer of the C- arylglucoside, (2) poor redox economy due to oxidation and reduction reaction steps being required to change the oxidation state of CI or of CI and C2 of the carbohydrate moiety, (3) some relatively long synthetic routes, (4) the use of toxic metals such as palladium, and/or (5) atom uneconomic protection of four free hydroxyl groups. With regard to the issue of redox economy, superfluous oxidation and reduction reactions that are inherently required to allow introduction of the aryl group into the carbohydrate moiety of the previously mention synthetic methods and the subsequent synthetic steps to establish the required oxidation state, besides adding synthetic steps to the process, are particular undesirable for manufacturing processes because reductants can be difficult and dangerous to operate on large scales due to their flammability or ability to produce flammable hydrogen gas during the reaction or during workup, and because oxidants are often corrosive and require specialized handling operations (see Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN-10: 0120594757); pg 38 for discussions on this issue).
[0015] In view of the above, there remains a need for a shorter, more efficient and
stereoselective, redox economic process for the preparation of β-C-arylglucosides. A new process should be applicable to the industrial manufacture of SGLT2 inhibitors and their prodrugs,
EXAMPLE 22 – Synthesis of 2,4-di-0-feri-butyldiphenylsUyl-l-C-(3-((5-(4- fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside (2,4-di-6>-TBDPS- canagliflozin; (IVi”))

[0227] 2-(5-Bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (1.5 g, 4.15 mmol) and magnesium powder (0.33 g, 13.7 mmol) were placed in a suitable reactor, followed by THF (9 mL) and 1,2-dibromoethane (95 μί). The mixture was heated to reflux. After the reaction was initiated, a solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (2.5 g, 6.92 mmol) in THF (15mL) was added dropwise. The mixture was stirred for another 2 hours under reflux, and was then cooled to ambient temperature and titrated to determine the concentration. The thus prepared 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl magnesium bromide (0.29 M in THF, 17 mL, 5.0 mmol) and A1C13 (0.5 M in THF, 4.0 mL, 2.0 mmol) were mixed at ambient temperature to give a black solution, which was stirred at ambient temperature for 1 hour. To a solution of l ,6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl- -D-glucopyranose (0.64 g, 1.0 mmol) in PhOMe (3.0 mL) at ambient temperature was added rc-BuLi (0.4 mL, 1.0 mmol, 2.5 M solution in Bu20). After stirring for about 5 min the solution was then added into the above prepared aluminum mixture via syringe, followed by additional PhOMe (1.0 mL) to rinse the flask. The mixture was concentrated under reduced pressure (50 torr) at 60 °C (external bath temperature) to remove low-boiling point ethereal solvents, and PhOMe (6 mL) was then added. The remaining mixture was heated at 150 °C (external bath temperature) for 5 hours at which time HPLC assay analysis indicated a 68% yield of 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5- (4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside. After cooling to ambient temperature, the reaction was treated with 10% aqueous NaOH (1 mL), THF (10 mL) and diatomaceous earth at ambient temperature, then the mixture was filtered and the filter cake was washed with THF. The combined filtrates were concentrated and the crude product was purified by silica gel column chromatography (eluting with 1 :20 MTBE/rc-heptane) to give the product 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)- -D-glucopyranoside (0.51 g, 56%) as a white powder.
1H NMR (400 MHz, CDC13) δ 7.65 (d, J= 7.2 Hz, 2H), 7.55 (d, J= 7.2 Hz, 2H), 7.48 (dd, J= 7.6, 5.6 Hz, 2H), 7.44-7.20 (m, 16H), 7.11-6.95 (m, 6H), 6.57 (d, J= 3.2 Hz, IH), 4.25 (d, J= 9.6 Hz, IH), 4.06 (s, 2H), 3.90-3.86 (m, IH), 3.81-3.76 (m, IH), 3.61-3.57 (m, IH), 3.54-3.49 (m, 2H), 3.40 (dd, J= 8.8, 8.8 Hz, IH), 2.31 (s, 3H), 1.81 (dd, J= 6.6, 6.6 Hz, IH, OH), 1.19 (d, J= 4.4 Hz, IH, OH), 1.00 (s, 9H), 0.64 (s, 9H); 13C NMR (100 MHz, CDC13) δ 162.1 (d, J= 246 Hz, C), 143.1 (C), 141.4 (C), 137.9 (C), 136.8 (C), 136.5 (C), 136.4 (CH x2), 136.1 (CH x2), 135.25 (C), 135.20 (CH x2), 135.0 (CH x2), 134.8 (C), 132.8 (C), 132.3 (C), 130.9 (d, J= 3.5 Hz, C), 130.5 (CH), 130.0 (CH), 129.7 (CH), 129.5 (CH), 129.4 (CH), 129.2 (CH), 127.6 (CH x4), 127.5 (CH x2), 127.2 (CH x2), 127.1 (d, J= 8.2 Hz, CH x2), 127.06 (CH), 126.0 (CH), 122.7 (CH), 115.7 (d, J= 21.8 Hz, CH x2), 82.7 (CH), 80.5 (CH), 79.4 (CH), 76.3 (CH), 72.9 (CH), 62.8 (CH2), 34.1(CH2), 27.2 (CH3 x3), 26.7 (CH3 x3), 19.6, (C), 19.3 (CH3),19.2 (C); LCMS (ESI) m/z 938 (100, [M+NH4]+), 943 (10, [M+Na]+).
EXAMPLE 23 – Synthesis of canagliflozin (l-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)- 4-methylphenyl)- -D-glucopyranoside; (Ii))

[0228] A mixture of the 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5-(4-fluorophenyl)thiophen- 2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside (408 mg, 0.44 mmol) and TBAF (3.5 mL, 3.5 mmol, 1.0 M in THF) was stirred at ambient temperature for 4 hours. CaC03 (0.73 g), Dowex 50WX8-400 ion exchange resin (2.2 g) and MeOH (5mL) were added to the product mixture and the suspension was stirred at ambient temperature for 1 hour and then the mixture was filtered through a pad of diatomaceous earth. The filter cake was rinsed with MeOH and the combined filtrates was evaporated under vacuum and the resulting residue was purified by column chromatography (eluting with 1 :20 MeOH/DCM) affording canagliflozin (143 mg, 73%).

1H NMR (400 MHz, DMSO-J6) δ 7.63-7.57 (m, 2H), 7.28 (d, J= 3.6 Hz, 1H), 7.23-7.18 (m, 3H), 7.17-7.12 (m, 2H), 6.80 (d, J= 3.6 Hz, 1H), 4.93 (br, 2H, OH), 4.73 (br, 1H, OH), 4.44 (br,IH, OH), 4.16 (d, J= 16 Hz, 1H), 4.10 (d, J= 16 Hz, 1H), 3.97 (d, J= 9.2 Hz, 1H), 3.71 (d, J=I I.6 Hz, 1H), 3.47-3.43 (m, 1H), 3.30-3.15 (m, 4H), 2.27 (s, 3H);

13C NMR (100 MHz, DMSO- d6) δ 161.8 (d, J= 243 Hz, C), 144.1 (C), 140.7 (C), 138.7 (C), 137.8 (C), 135.4 (C), 131.0 (d, J= 3.1 Hz, C), 130.1 (CH), 129.5 (CH), 127.4 (d, J= 8.1 Hz, CH x2), 126.8 (CH), 126.7 (CH), 123.9 (CH), 116.4 (d, J= 21.6 Hz, CH x2), 81.8 (CH), 81.7 (CH), 79.0 (CH), 75.2 (CH), 70.9 (CH), 61.9 (CH2), 33.9 (CH2), 19.3 (CH3);

LCMS (ESI) m/z 462 (100, [M+NH4]+), 467 (3, [M+Na]+).

Example 1 – Synthesis of l,6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl- -D-glucopyranose (II”)

[0206] To a suspension solution of l,6-anhydro- -D-glucopyranose (1.83 g, 11.3 mmol) and imidazole (3.07 g, 45.2 mmol) in THF (10 mL) at 0 °C was added dropwise a solution of TBDPSC1 (11.6 mL, 45.2 mmol) in THF (10 mL). After the l,6-anhydro-P-D-gJucopyranose was consumed, water (10 mL) was added and the mixture was extracted twice with EtOAc (20 mL each), washed with brine (10 mL), dried (Na2S04) and concentrated. Column
chromatography (eluting with 1 :20 EtOAc/rc-heptane) afforded 2,4-di-6>-ieri-butyldiphenylsilyl- l,6-anhydro- “D-glucopyranose (5.89 g, 81%).
1H NMR (400 MHz, CDC13) δ 7.82-7.70 (m, 8H), 7.49-7.36 (m, 12H), 5.17 (s, IH), 4.22 (d, J= 4.8 Hz, IH), 3.88-3.85 (m, IH), 3.583-3.579 (m, IH), 3.492-3.486 (m, IH), 3.47-3.45 (m, IH), 3.30 (dd, J= 7.4, 5.4 Hz, IH), 1.71 (d, J= 6.0 Hz, IH), 1.142 (s, 9H), 1.139 (s, 9H); 13C NMR (100 MHz, CDCI3) δ 135.89 (CH x2), 135.87 (CH x2), 135.85 (CH x2), 135.83 (CH x2), 133.8 (C), 133.5 (C), 133.3 (C), 133.2 (C), 129.94 (CH), 129.92 (CH), 129.90 (CH), 129.88 (CH), 127.84 (CH2 x2), 127.82 (CH2 x2), 127.77 (CH2 x4), 102.4 (CH), 76.9 (CH), 75.3 (CH), 73.9 (CH), 73.5 (CH), 65.4 (CH2), 27.0 (CH3 x6), 19.3 (C x2).

FIG. 1:
X-ray powder diffraction pattern of the crystalline of hemihydrate of the compound of formula (I).
FIG. 2:
Infra-red spectrum of the crystalline of hemihydrate of the compound of formula (I).
FIGS. 3 and 4 provide the XRPD pattern and IR spectrum, respectively, of amorphous canagliflozin.
Systematic (IUPAC) name
Clinical data
Trade names Invokana
AHFS/ entry
  • US:C (Risk not ruled out)
Legal status
Routes of
Pharmacokinetic data
Bioavailability 65%
Protein binding 99%
Metabolism Hepaticglucuronidation
Biological half-life 11.8 (10–13) hours
Excretion Fecal and 33% renal
CAS Registry Number 842133-18-0 Yes
ATC code A10BX11
PubChem CID: 24812758
DrugBank DB08907 Yes
ChemSpider 26333259 
UNII 6S49DGR869 
ChEBI CHEBI:73274 
Synonyms JNJ-28431754; TA-7284; (1S)-1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol
Chemical data
Formula C24H25FO5S
Molecular mass 444.52 g/mol


  1. “U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin”. Reuters. Mar 29, 2013. U.S. health regulators have approved a new diabetes drug from Johnson & Johnson, making it the first in its class to be approved in the United States.
WO2005012326A1 Jul 30, 2004 Feb 10, 2005 Tanabe Seiyaku Co Novel compounds having inhibitory activity against sodium-dependant transporter
WO2013064909A2 * Oct 30, 2012 May 10, 2013 Scinopharm Taiwan, Ltd. Crystalline and non-crystalline forms of sglt2 inhibitors
CN103655539A * Dec 13, 2013 Mar 26, 2014 重庆医药工业研究院有限责任公司 Oral solid preparation of canagliflozin and preparation method thereof
US7943582 Dec 3, 2007 May 17, 2011 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyransoyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene hemihydrate
US7943788 Jan 31, 2005 May 17, 2011 Mitsubishi Tanabe Pharma Corporation Glucopyranoside compound
US8513202 May 9, 2011 Aug 20, 2013 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate
US20130237487 Oct 30, 2012 Sep 12, 2013 Scinopharm Taiwan, Ltd. Crystalline and non-crystalline forms of sglt2 inhibitors
WO2008002824A1 * Jun 21, 2007 Jan 3, 2008 Squibb Bristol Myers Co Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes
US6774112 * Apr 8, 2002 Aug 10, 2004 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
US20090143316 * Apr 4, 2007 Jun 4, 2009 Astellas Pharma Inc. Cocrystal of c-glycoside derivative and l-proline
US20110087017 * Oct 14, 2010 Apr 14, 2011 Vittorio Farina Process for the preparation of compounds useful as inhibitors of sglt2
US20110098240 * Aug 15, 2008 Apr 28, 2011 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor in combination with a dpp-iv inhibitor
Citing Patent Filing date Publication date Applicant Title
WO2014195966A2 * May 30, 2014 Dec 11, 2014 Cadila Healthcare Limited Amorphous form of canagliflozin and process for preparing thereof
US9006188 May 23, 2014 Apr 14, 2015 Mapi Pharma Ltd. Co-crystals of dapagliflozin







CAS 1672658-93-3
C24 H25 F O6 S, 460.52
D-Glucopyranose, 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-
CAS 1809403-04-0
C24 H25 F O6 S, 460.52
D-Glucose, 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-


(2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one    12

From the FT-IR spectra of 12 contain a signal at 1674 cm–1, this signal is strongly indicative of a carbonyl ketone being present in 12

In 13C NMR and HMBC correlations spectra, the chemical shift at 199.75 ppm was observed. Analysis of the NMR data  confirmed that the structure of 12 is a ring-opened keto form

Synthesis of (2R,3S,4R,5R)-1-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one 12

title compound 12 (84.23% yield) and having 99.4% purity by HPLC;
DSC: 160.84–166.44 °C;
Mass: m/z 459 (M+–H);
IR (KBr, cm–1): 3313, 2982, 1674.7, 1601, 1507.5, 1232.7;
1H NMR (600 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.80 (dd, J = 1.8 Hz, 1H), 7.61–7.58 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.21–7.18 (m, 2H), 6.84 (d, J = 3.6 Hz, 1H), 5.17 (dd, J = 3.6, 3.0 Hz, 1H), 5.02 (d, J = 6.6 Hz, 1H), 4.57 (d, J = 4.8 Hz, 1H), 4.43–4.39 (m, 3H), 4.22 (s, 2H), 4.02–4.01 (m, 1H), 3.53–3.51 (m, 3H), 3.38–3.37 (m, 1H), 2.35 (s, 3H);
13C NMR (101 MHz, DMSO-d6) δ 199.7, 162.6, 160.2, 142.8, 142.1, 140.5, 138.8, 133.3, 130.5, 130.4, 130.4, 129.3, 127.2, 127.0, 127.0, 126.7, 123.5, 116.0, 115.8, 75.2, 72.3, 71.8, 71.3, 63.2, 33.2, 19.2.
HRMS (ESI): calcd m/zfor [C24H25FO6S + Na]+ = 483.1248, found m/z 483.1244.
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00281


FDA Approves New Drug Application (NDA) for Teva’s Quartette (levonorgestrel/ethinyl estradiol and ethinyl estradiol) Tablets for the Prevention of Pregnancy


ethinyl estradiol

Quartette™ Represents the Next Generation of Extended Regimen Oral Contraceptives


Teva Pharmaceutical Industries Ltd. today announced that the U.S. Food and Drug Administration (FDA) has approved Quartette™ (levonorgestrel/ethinyl estradiol and ethinyl estradiol) tablets for the prevention of pregnancy. Quartette™ represents the next generation of extended regimen oral contraceptives to be approved by the FDA, and was designed to minimize breakthrough bleeding (BTB) between scheduled periods. The approval of Quartette™ demonstrates Teva’s continued commitment to the development and production of an innovative range of pharmaceutical products that support the health of women around the world.

“Breakthrough bleeding can be experienced with any birth control pill, especially during the first few months, and is one of the reasons a large number of women discontinue extended regimens,” said Dr. James A. Simon, clinical professor of Obstetrics and Gynecology at the George Washington University School of Medicine. “The estrogen in Quartette™ increases at specific points and provides four short light periods a year. Breakthrough bleeding decreases over time, which might help encourage patient adherence.”

The approval was based on a development program that included results from Phase I, Phase II and Phase III clinical trials designed to evaluate the safety and efficacy of Quartette™. The Phase III clinical trial, which involved more than 3,000 women, found that Quartette™ was 97 percent effective at preventing pregnancy. Data further demonstrated that the most common adverse reactions (≥2%) in the Phase III clinical trial were headaches, heavy/irregular vaginal bleeding, nausea/vomiting, acne, dysmenorrhea, weight increased, mood changes, anxiety/panic attack, breast pain and migraines. The primary clinical trial that evaluated the efficacy of Quartette™ also assessed BTB. BTB and unscheduled spotting decreased over successive 91 day cycles.1

Quartette™ features a unique 91-day oral regimen, whereby the dose of estrogen increases at three distinct points over the first 84 days and the amount of progestin remains consistent; this is followed by seven days of 10 mcg of ethinyl estradiol.

“Teva is the leader in the pharmaceutical industry in the marketing and development of extended regimen oral contraceptives, and Quartette™ represents the next generation of these contraceptives. It is a uniquely differentiated product and is based on Teva’s research into when breakthrough bleeding is most likely to occur with these regimens,” said Jill DeSimone, senior vice president & general manager, Global Teva Women’s Health. “Quartette™ is the newest product in our global women’s health franchise and is an example of our dedication to providing a variety of contraceptive and family planning options that fit women’s lifestyles.”

The US FDA has cleared Eisai’s ACIPHEX Sprinkle (rabeprazole sodium) as 12-week gastroesophageal reflux disease (GERD) therapy for use in children between one to eleven years age

28 MAR 2013


The US FDA has cleared Eisai’s ACIPHEX Sprinkle (rabeprazole sodium) as 12-week gastroesophageal reflux disease (GERD) therapy for use in children between one to eleven years age.

The approval was based on positive data from multicenter, double-blind trial conducted in 127 pediatric patients between one to 11 years of age with GERD.

Eisai president and CEO Lonnel Coats said, “We are proud to offer a new treatment option for young children who suffer from GERD.”

The parallel-group study comprised a treatment period of 12 weeks and an extension period of two dose levels of rabeprazole for 24 weeks.

Healing was achieved in 81% of patients during the treatment period and 90% retained healing during the extension period.

The active ingredient in ACIPHEX Delayed-Release Tablets is rabeprazole sodium, a substituted benzimidazole that inhibits gastric acid secretion. Rabeprazole sodium is known chemically as 2-[[[4-(3methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H–benzimidazole sodium salt. It has an empirical formula of C18H20N3NaO3S and a molecular weight of 381.43. Rabeprazole sodium is a white to slightly yellowish-white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform and ethyl acetate and insoluble in ether and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions. The structural formula is:

Figure 1

ACIPHEX® (rabeprazole sodium) Structural Formula Illustration

ACIPHEX is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of rabeprazole sodium.

Inactive ingredients of the 20 mg tablet are carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, propylene glycol, sodium hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron oxide yellow is the coloring agent for the tablet coating. Iron oxide red is the ink pigment.


FDA accepts Merck BLA for investigational allergy immunotherapy tablet

Allergen Immunotherapy Tablets


28 MAR 2013

The US FDA has accepted Merck’s biologics license application (BLA) for an investigational allergy immunotherapy tablet (AIT), Timothy grass pollen (Phleum pratense).

The application includes safety and efficacy data of the investigational sublingual dissolvable tablet from Phase III trials including a long-term, multi-season trial.

Merck Research Laboratories senior vice president, global scientific strategy, franchise head, infectious diseases and interim franchise head, respiratory & immunology Jeffrey Chodakewitz said, “We are pleased to have achieved this important milestone in the development of our investigational grass pollen AIT, which, if approved, would represent a potential new option for allergy specialists to offer appropriate allergic rhinitis patients.”

The grass pollen (Phleum pratense) AIT is designed to generate an immune response targeting the root cause of allergic rhinitis.

The company has collaborated with ALK-Abello for grass pollen (Phleum pratense) AIT development in North America.

Europe grants conditional OK to Pfizer’s Bosulif

Good News For Pfizer’s Orphan Drug Bosulif (Bosutinib) in Europe



mar 28,2013

Regulators in Europe have given a partial green light to Pfizer ‘s leukaemia drug Bosulif.

The European Commission has granted conditional marketing authorisation for Bosulif (bosutinib) for the treatment of adults with chronic, accelerated or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukaemia (CML). The drug can be given to patients previously treated with one or more tyrosine kinase inhibitors ie Novartis’ Gleevec (imatinib) and Tasigna (nilotinib) or Bristol-Myers Squibb’s Sprycel (dasatinib).

The European Medicines Agency’s  (EMA) Committee for Medicinal Products for Human Use (CHMP) on January 17, 2013, adopts a positive opinion, recommending a conditional marketing authhorization for Pfizer’s orphan drug Bosulif (Bosutinib) for Chronic Leukemia (CML).  Bosutinib receives orphan designation from the European Commission (EC) on August 4, 2010, for CML.

Pfizer receives FDA approval on September 4, 2012, for orphan drug Bosulif (Bosutinib) for CML. Pfizer receives on February 24, 2009, FDA Orphan Drug Designation (ODD) for Bosutinib for CML.


Bosutinib (rINN/USAN; codenamed SKI-606, marketed under the trade name Bosulif) is atyrosine kinase inhibitor undergoing research for use in the treatment of cancer. [1] [2]Originally synthesized by Wyeth, it is being developed by Pfizer.

Some commercial stocks of bosutinib (from sources other than the Pfizer material used for clinical trials) have recently been found to have the incorrect chemical structure, calling the biological results obtained with them into doubt.[3]

Bosutinib received US FDA approval on September 5, 2012 for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+)chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.[4][5][6]

  1. Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A, Ahmed S, Redaelli S, Piazza R, Magistroni V, Andreoni F, Scapozza L, Formelli F, Gambacorti-Passerini C. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 2006 Dec 1;66(23):11314-22. Epub 2006 Nov 17.
  2. Vultur A, Buettner R, Kowolik C, et al. (May 2008). “SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells”.Mol. Cancer Ther. 7 (5): 1185–94. doi:10.1158/1535-7163.MCT-08-0126.PMC 2794837PMID 18483306.
  3.  Derek Lowe, In The Pipeline (blog), “Bosutinib: Don’t Believe the Label!”
  4. Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24.
  5. Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicus L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial. J Clin Oncol. 2012 Sep 4. [Epub ahead of print]
  6. “Bosulif Approved for Previously Treated Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia”. 05 Sep 2012.

Ospemifene ….EMA accepts MAA submission of Shionogi’s ospemifene for the treatment of VVA


CAS Number: 128607-22-7

OSPHENA is indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause

Also known as:
  • CCRIS 9205
  • Deamino-hydroxytoremifene
  • Fc-1271
  • FC-1271a
  • Ospemifene
  • Osphena

Molecular Formula: C24H23ClO2
Molecular Weight: 378.89 g.mol-1

Ospemifene, FC-1271a
Orion Corp. (Originator), Hormos (Codevelopment) 

Marja Sodervall, Maire Eloranta, Arja Kalapudas, Brian Kearton, Michael McKenzie, “METHODS FOR THE PREPARATION OF FISPEMIFENE FROM OSPEMIFENE.” U.S. Patent US20080214860, issued September 04, 2008.



Patent No


PatentExpireyDate patent use code
6245819 Jul 21, 2020 U-1369
8236861 Aug 11, 2026 U-1369
8236861 Aug 11, 2026 U-1370
Exclusivity Code ExclusivityDate
NCE Feb 26, 2018


Date of issue ofmarketing authorisation valid throughout the European Union 15/01/2015



Ospemifene appears as a white to almost white, non-hygroscopic crystalline powder. It is insoluble in water, soluble in ethanol and propanol, very slightly soluble in isopropanol. The partition coefficient was found 4.43 and the pKa was calculated 14.26. The molecule has two geometrical isomeric forms. The active substance ospemifene is the Z-isomer. Polymorphism was not observed.

The chemical name of the active substance ospemifene is Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl) phenoxy]ethanol, corresponding to the molecular formula C24H23O2Cl and has a relative molecular mass of 378.9.

Ospemifene is a new selective non-hormonal estrogen receptor modulator (SERM) that is used for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. FDA approved on February 26, 2013.

Bone Diseases, Treatment of, ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Hormone Replacement Therapy, METABOLIC DRUGS, Treatment of Osteoporosis, Treatment of Postmenopausal Syndrome , Selective Estrogen Receptor Modulators (SERM)



Article 27 March 2013

Shionogi Limited, the London-based European subsidiary of Shionogi & Co., Ltd announced today that on 26th March 2013 the European Medicines Agency (EMA) accepted its Marketing Authorisation Application (MAA) submission for ospemifene for the treatment of vulvar and vaginal atrophy (VVA) in post-menopausal women.

this is already approved by FDA

“We are pleased to announce the MAA submission for ospemifene to the EMA following the US Food and Drug Administration (FDA) approval last month. The acceptance of the MAA submission for ospemifene not only represents an important step forward in expanding the treatment options for women living in Europe with this condition, but it is also an important milestone for Shionogi as it continues to build its business in Europe” said Takashi Takenoshita, CEO of Shionogi Limited.

Osphena (ospemifene) to treat women experiencing moderate to severe dyspareunia (pain during sexual intercourse), a symptom of vulvar and vaginal atrophy due to menopause.

Dyspareunia is a condition associated with declining levels of estrogen hormones during menopause. Less estrogen can make vaginal tissues thinner, drier and more fragile, resulting in pain during sexual intercourse.

Osphena, a pill taken with food once daily, acts like estrogen on vaginal tissues to make them thicker and less fragile, resulting in a reduction in the amount of pain women experience with sexual intercourse.

“Dyspareunia is among the problems most frequently reported by postmenopausal women,” said Victoria Kusiak, M.D., deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Osphena provides an additional treatment option for women seeking relief.”

Osphena’s safety and effectiveness were established in three clinical studies of 1,889 postmenopausal women with symptoms of vulvar and vaginal atrophy. Women were randomly assigned to receive Osphena or a placebo. After 12 weeks of treatment, results from the first two trials showed a statistically significant improvement of dyspareunia in Osphena-treated women compared with women receiving placebo. Results from the third study support Osphena’s long-term safety in treating dyspareunia.

Common side effects reported during clinical trials included hot flush/flashes, vaginal discharge, muscle spasms, genital discharge and excessive sweating.

Osphena is marketed by Florham Park, N.J.-based Shionogi, Inc.

  • Shionogi Files a New Drug Application for Ospemifene Oral Tablets 60mg for the Treatment of Vulvar and Vaginal Atrophy – May 9, 2012

OSPHENA is an estrogen agonist/antagonist. The chemical structure of ospemifene is shown in Figure 1.

Figure 1: Chemical structure

OSPHENA® (ospemifene) Structural Formula Illustration

The chemical designation is Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethanol, and has the empirical formula C24H23ClO2, which corresponds to a molecular weight of 378.9. Ospemifene is a white to off-white crystalline powder that is insoluble in water and soluble in ethanol.

Each OSPHENA tablet contains 60 mg of ospemifene. Inactive ingredients include colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.


Ospemifene (commercial name Osphena produced by Shionogi) is an oral medication indicated for the treatment of dyspareunia – pain during sexual intercourse – encountered by some women, more often in those who are post-menopausal. Ospemifene is aselective estrogen receptor modulator (SERM)[1] acting similarly to an estrogen on thevaginalepithelium, building vaginal wall thickness which in turn reduces the pain associated with dyspareunia. Dyspareunia is most commonly caused by “vulval and vaginal atrophy.”[2]

The medication was approved by the FDA in February 2013.[3]

Ospemifene is used to treat dyspareunia. It is available as a 60 mg tablet that is taken by mouth once a day. The fact that ospemifene can be taken orally is an advantage over other products that are used to treat dyspareunia, because these are generally in a topical dosage form and have to be applied locally.[2] The oral dosage form is much easier and more convenient for patients to administer.

It is “an agonist/antagonist that makes vaginal tissue thicker and less fragile resulting in a reduction in the amount of pain women experience with sexual intercourse.”[2] This drug should be used for the shortest amount of time possible due to associated adverse effects.[2]

Approval process

Hormos Medical Ltd., which is a part of QuatRx Pharmaceuticals, filed a patent on January 19, 2005 for a solid dosage form of ospemifene.[5] In March of 2010, QuatRX Pharmaceuticals licensed ospemifene to Shionogi & Co., Ltd. for them to develop it into a product and put it on the market.[6] A New Drug Application (NDA) was submitted to the FDA on April 26, 2012.[7] Amendments to the NDA were submitted in June, July, August, October, and November 2012, and January and February of 2013.[7] It was ultimately approved by the FDA on February 26, 2013.[6]

Preclinial and clinical trials

Preclinical trials were performed in ovariectomized rats to model menopause.[8] Oral ospemifene was compared with raloxifene (another SERM), its metabolites 4-hydroxy ospemifene and 4′-hydroxy ospemifene, estradiol, and ospemifene administered as an intravaginal suppository.[8] Estradiol was used as a positive control and raloxifene was used because it is in the same drug class as ospemifene.[8]Multiple doses of oral ospemifene were tested.[8] 10 mg/kg/day of Ospemifene was found to cause a greater increase in vaginal weight and vaginal epithelial height than 10 mg/kg/day of raloxifene.[8] Vaginal weight had a 1.46x increase after a two week treatment of 10mg/kg/day of ospemifene.[8] The number of progesterone receptors was increased in the vaginal stroma and epithelium, which indicates that ospemifene has “estrogenic activity.”[8]

A binding assay was also performed to measure the affinity of ospemifene for the estrogen receptor (ERα and ERβ).[8] The study showed that ospemifene bound ERα and ERβ with similar affinity.[8] Ospemifene bound the estrogen receptors with a lower affinity than estradiol.[8] Ospemifene was shown to be an antagonist of “ERE-mediated transactivation on MCF-7 cells,” which the authors concluded indicates “anti-estrogenic activity in breast cancer cells.”[8]

Two 12 week phase 3 clinical trials were performed for ospemifene.[9] To evaluate the efficacy of the drug, 4 signs and symptoms of dyspareunia were measured. These included the “change in percent parabasal cells,” “change in percent superficial cells,” “change in vaginal pH,” and “change in most bothersome symptom (vaginal dryness and vaginal pain associated with sexual activity.”[9]Ospemifene was more effective than placebo in all four of these categories.[9] A dose-response was also seen in the trial; ospemifene 60 mg had greater efficacy than ospemifene 30 mg.[9] Safety was also evaluated in these phase 3 trials. There was a 5.2% increase in the incidence of hot flushes, 1.6% increase in urinary tract infections, and 0.5% increase in the incidence of headache with ospemifene over placebo.[9] One of the phase 3 trials was double-blinded and randomized and involved 826 women who were post-menopausal.[10]The women in the study were required to have one or more vulvovaginal atrophy (VVA) symptom that was moderate or severe in nature, no more than 5% of cells that were superficial when given a vaginal smear, and have a vaginal pH of at least 5.0.[10] Another phase 3 trial involved 605 women who were between the ages of 40 and 80, were diagnosed with VVA, and whose worst symptom was dyspareunia.[11]


In the first half of the 2013 fiscal year, Osphena® generated 0.1 B yen in revenue, which is probably roughly equivalent to $974, 944 U.S. dollars.[12] When Osphena® was put onto the market, it was predicted to earn $495 million in 2017.[13]

OSPHENA is an estrogen agonist/antagonist. The chemical structure of ospemifene is shown in Figure 1.

Figure 1: Chemical structure

OSPHENA™ (ospemifene) Structural Formula Illustration

The chemical designation is Z-2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethanol, and has the empirical formula C24H23ClO2, which corresponds to a molecular weight of 378.9. Ospemifene is a white to off-white crystalline powder that is insoluble in water and soluble in ethanol.

Each OSPHENA tablet contains 60 mg of ospemifene. Inactive ingredients include colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.

“SERM”s (selective estrogen receptor modulators) have both estrogen-like and antiestrogenic properties (Kauffman & Bryant, 1995). The effects may be tissue-specific as in the case of tamoxifen and toremifene which have estrogen-like effects in the bone, partial estrogen-like effect in the uterus and liver, and pure antiestrogenic effect in breast cancer.

Raloxifene and droloxifen are similar to tamoxifen and toremifene, except that their antiestrogenic properties dominate. Based on the published information, many SERMs are more likely to cause menopausal symptoms than to prevent them. They have, however, other important benefits in elderly women: they decrease total and LDL cholesterol, thus deminishing the risk of cardiovascular diseases, and they may prevent osteoporosis and inhibit breast cancer growth in postmenopausal women.

Ospemifene is the Z-isomer of the compound of formula (I)

Figure imgb0001

and it is one of the main metabolites of toremifene, is known to be an estrogen agonist and antagonist (Kangas, 1990; International patent publications WO 96/07402 and WO 97/32574 ). The compound is also called (deaminohydroxy)toremifene and it is also known under the code FC-1271a. Ospemifene has relatively weak estrogenic and antiestrogenic effects in the classical hormonal tests (Kangas, 1990). It has anti-osteoporosis actions and it decreases total and LDL cholesterol levels in both experimental models and in human volunteers (International patent publications WO 96/07402 and WO 97/32574 ). It also has antitumor activity in an early stage of breast cancer development in an animal breast cancer model.

Ospemifene is also the first SERM which has been shown to have beneficial effects in climacteric syndromes in healthy women. The use of ospemifene for the treatment of certain climacteric disorders in postmenopausal women, namely vaginal dryness and sexual dysfunction, is disclosed in WO 02/07718 . The published patent application WO 03/103649 describes the use of ospemifene for inhibition of atrophy and for the treatment or prevention of atrophyrelated diseases or disorders in women, especially in women during or after the menopause.


credit chemdrug
The condensation of desoxybenzoin (I) with 2-(benzyloxy)ethyl bromide (II) by means of aqueous 48% NaOH containing triethylbenzylammonium chloride (TEBAC) gives 4-(benzyloxy)-1,2-diphenyl-1-butanone (III), which by reaction with the Grignard reagent (IV) – prepared from 4-(tetrahydropyranyloxy)phenyl bromide (V) and Mg in THF – yields the triphenylbutanol derivative (VI). Elimination of the THP-protecting group of compound (VI) by means of H2SO4 in ethanol/water at room temperature affords the triphenylbutanol derivative (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the butane-1,4-diol derivative (VIII). Cyclization of the butane-1,4-diol (VIII) by means of H2SO4 in hot ethanol/water gives 2-(4-hydroxyphenyl)-2,3-diphenyltetrahydrofuran (IX), which is treated with 48% HBr in refluxing AcOH to yield a mixture of (E)- and (Z)-4-(4-hydroxyphenyl)-3,4-diphenyl-3-buten-1-ol (X), which is separated by chemical work up. The phenolic OH group of the desired (Z)-isomer (X) is condensed with 2-(benzyloxy)ethyl bromide (II) by means of NaOH and tetrabutylammonium bromide in refluxing toluene/ water to afford the benzyloxyethyl ether (XII). Reaction of the aliphatic OH group of ether (XII) with PPh3 and CCl4 in acetonitrile provides the corresponding chloro derivative (XIII), which is finally debenzylated with H2 over Pd/C in ethyl acetate/ethanol.
Sorbera, L.A.; Castar, J.; Bay
Ospemifene. Drugs Fut 2004, 29, 1, 38


US 4996225; US 5491173,
WO 9732574, WO 9607402,
The condensation of desoxybenzoin (I) with tetrahydropyranyl ether (II) in aq. 48% NaOH containing TEBAC gives 1,2-diphenyl-4-(tetrahydropyranyloxy)-1-butanone (III), which by a Grignard condensation with 4-methoxyphenylmagnesium bromide (IV) in THF yields the monoprotected triphenylbutanediol (V). The deprotection of (V) with H2SO4 in ethanol/water at room temperature affords the triphenylbutane-1,4-diol (VI), which is cyclized with H2SO4 in hot ethanol/water to provide 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran (VII). The reaction of (VII) with 48% HBr in refluxing acetic acid gives a mixture of (E)- and (Z)-4-(4-hydroxyphenyl)-3,4-diphenyl-1-butanol that is separated by chemical working up to obtain the desired (Z)-isomer (VIII). The condensation of the phenolic OH of (VIII) with benzyl protected 2-bromoethanol (IX) by means of NaOH and tetrabutylammonium bromide in refluxing toluene/water gives the benzyloxyethyl ether (X). The reaction of the aliphatic OH group of (X) with PPh3 and CCl4 in acetonitrile yields the corresponding chloro derivative (XI), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethyl acetate/ethanol.


Ospemifene simple structure, its point is to control the synthesis of the product cis-trans isomerization of the double bond. Chloride 1 and benzene ( 2 ) occurs pay – acylation reaction 3 . Ester4 aluminum trichloride under the action of Fries rearrangement of 5 , 5 on the propylene oxide under alkaline conditions to obtain 6 , 6 and 3 McMurry coupling occurs directly generated Ospemifene.



  • Ospemifene is the Z-isomer of the compound of formula (Ib)

    Figure imgb0006
  • The common starting material in the syntheses of (Ib), namely compound (II), is previously known (Toivola, 1990; EP 0095875 ). According to a method disclosed in EP 095875 , this compound was prepared by dealkylation of a corresponding ether to give (II). The method may be used to produce a mixture of isomers of compounds (Ib), but most preferably is used to prepare the pure E- and Z-isomers of this compound.
  • Particularly in case the Z-isomer of the compound (Ib) is desired, a preferable method for the synthesis of compound (II) is a McMurry reaction of commercially available starting materials, 4-hydroxybenzophenone with 3-chloropropiophenone. The McMurry reaction is a well-known reductive coupling of ketones involving two steps: (1) a single electron transfer to the carbonyl groups from an alkali metal, followed by (2) deoxygenation of the 1,2-diol with low-valent titanium to yield the alkene. This reaction produces mainly the Z-isomer of compound (II)
  • Figure imgb0011
  • The alkylation in step a) is carried out in an organic solvent, preferably carried out in tetrahydrofuran. It is also preferable to add a base to the solvent, most preferably sodium hydride
        EXAMPLE 14-(4-Chloro-1,2-diphenyl-but-1-enyl)phenol (Compound II)

      • Zinc (15.0 g, 0.23 mol) and tetrahydrofuran (THF) (180 ml) was added to the reaction vessel and cooled to -10 °C. Titan tetrachloride was added dropwise to the mixture (21.6 g, 0.114 mol) at about -10 °C. After the addition was completed the mixture was refluxed for two hours. Then the mixture was cooled to 40 °C and 4-hydroxybenzophenone (7.68 g, 0.039 mol) and 3-chloropropiophenone (6.48 g, 0.039 mol) dissolved in THF (75 ml) were added to the mixture. Refluxing was continued for additional 3.5 hours. The cooled reaction mixture was poured in aqueous potassium carbonate solution (21 g K2CO3 + 210 ml water) and allowed to stand overnight at the ambient temperature. The mixture was filtered and the precipitate was washed with THF. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water. Ethyl acetate phase was evaporated to dryness and the residue was crystallized first from methanol-water (8:2) and then from methanol-water (9:1). Yield 5.4 g.
      • Z-isomer:1H NMR (CDCl3): 2.92 (t, 2H, =CH2CH2Cl), 3.42 (t, 2H, =CH2CH2 Cl), 6.48 (d, 2H, aromatic proton ortho to hydroxy), 6.75 (d, 2H, aromatic proton meta to hydroxy), 7.1-7.4 (m, 10H, aromatic protons)


2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethanol (Compound Ib)

      • 4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenol (0.23 g, 0.689 mmol) was dissolved in tetrahydrofuran (3 ml) under nitrogen atmosphere. Sodium hydride (0.025 g, 1.03 mmol) was added to the solution and the mixture was stirred at room temperature for an hour. 2-(2-iodo-ethoxy)-tetrahydropyran (0.3 g, 1.17 mmol) was added and the mixture was refluxed for 2 hours. Additional portions of 2-(2-iodo-ethoxy)-tetrahydro-pyran (0.5 g, 2 mmol) were added to the mixture during seven hours. After cooling and adding water, THF was evaporated and the mixture was extracted three times with ethyl acetate. The organic phase was washed with 2 N aqueous sodium hydroxide and water, dried with sodium sulphate and evaporated to dryness. The residue (which is Compound (IV) where Pr is tetrahydropyranyl) was dissolved in ethanol and acidified with 2 N aqueous hydrogen chloride solution. The mixture was stirred at room temperature over night, evaporated and extracted with dichloromethane. After washing with water the organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography with dichloromethane/methanol 9.5/0.5 as eluent. Yield 0.17 g, 59 %.
      • Z-isomer, 1H NMR (CDCl3): 2.92 (t, 2H, =CH2CH2Cl), 3.42 (t, 2H, =CH2CH2 Cl), 3.85-3.89 (m, 4H, OCH2CH2), 6.56 (d, 2H, aromatic proton ortho to hydroxy), 6.80 (d, 2H, aromatic proton meta to hydroxy), 7.1-7.43 (m, 10H, aromatic protons).


2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethanol (Compound Ib)

  • The compound was prepared by the same method as described in Example 2 using 2-(2-iodo-ethoxymethyl)-benzene as a reagent and removing the benzylic protecting group using the method described in Example (e) ofUS Patent No. 6,891,070 B2 . Briefly, the removal is carried out under a nitrogen atmosphere, in the presence of Zn powder and acetyl chloride.
      EXAMPLE 5

2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethanol (Compound Ib)

  • [4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-acetic acid ethyl ester (Example 4) was dissolved in tetrahydrofuran at room temperature under nitrogen atmosphere. Lithium aluminium hydride was added to the solution in small portions until the reaction was complete. The reaction was quenched by adding saturated ammonium chloride solution to the mixture. The product was extracted into toluene, which was dried and evaporated in vacuo. The yield 100 mg, 43 %.
  • 1H NMR (CDCl3): 2.92 (t, 2H, =CH2CH2Cl), 3.42 (t, 2H, =CH2CH2 Cl), 3.85-3.89 (m, 4H, OCH2CH2), 6.56 (d, 2H, aromatic proton ortho to hydroxy), 6.80 (d, 2H, aromatic proton meta to hydroxy), 7.1-7.43 (m, 10H, aromatic protons).


e) 2-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethoxy}ethanol:

Z-1-{4-[2-(2-Benzyloxy-ethoxy)ethoxy]phenyl}-4-chloro-1,2-diphenyl-but-1-ene (3.8 g, 7.4 mmol) is dissolved in ethyl acetate under nitrogen atmosphere, Zn powder (0.12 g, 1.85 mmol) and acetyl chloride (1.27 g, 16.3 mmol) are added and the mixture is stirred at 50° C. for 3 h (Bhar, 1995). The reaction mixture is cooled to room temperature, water (10 ml) is added and stirring is continued for additional 10 min. The aqueous layer is separated and the organic phase is washed with 1 M aqueous hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in methanol (16 ml) and water (4 ml). The acetate ester of the product is hydrolysed by making the mixture alkaline with sodium hydroxide (1 g) and stirring the mixture at room temperature for 1 h. Methanol is evaporated, water is added and the residue is extracted in ethyl acetate and washed with 1 M hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in toluene (25 ml), silica gel (0.25 g) is added and mixture is stirred for 15 min. Toluene is filtered and evaporated to dryness.

The residue is crystallised from heptane-ethyl acetate (2:1). The yield is 71%.

Z-isomer: 1H NMR (CDCl3): 2.92 (t, 2H), 3.41 (t, 2H), 3.58-3.63 (m, 2H), 3.69-3.80 (m, 4H), 3.96-4.01 (m, 2H), 6.56 (d, 2H), 6.78 (d, 2H), 7.10-7.40 (m, 10H).

E-2-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethoxy}ethanol is prepared analogously starting from E-1-{4-[2-(2-benzyloxy-ethoxy)ethoxy]phenyl}-4-chloro-1,2-diphenyl-but-1-ene. The product is purified by flash chromatography with toluene-methanol (10:0.5) as eluent.

E-isomer: 1H NMR (CDCl3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.79 (m, 4H), 3.85-3.90 (m, 2H), 4.13-4.17 (m, 2H), 6.85-7.25 (m, 2H).

Debenzylation of 1-{4-[2-(2-benzyloxy-ethoxy)ethoxy]phenyl}-4-chloro-1,2-diphenyl-but-1-ene is also carried out by hydrogenation with Pd on carbon as a catalyst in ethyl acetate-ethanol solution at room temperature.


EXAMPLE 5. Preparation of (Z)-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)- phenoxy]ethanol (ospemifene) by base hydrolysis of pivaloyl-groiip
; . (Z)-2-(4-(4-Chloro- l ,2-diphenylbut-l-en- l-yl)phenqxy)ethyl pivalate ( 1 g, 2.16 mmol) was dissolved in THF (8 ml) followed by addition of MeOH (1 ml) and water (1 ml). Sodium hydroxide (0.1 g, 2.5 mmol) was added in orie portion and the reaction was stirred at room temperature for 12 h. After completion of the reaction the mixture was partitioned between water (20 ml) and EtOAc (20 ml). Organic phase was washed with water (20 ml) and brine (20 ml); dried (Na2S04), filtered, and concentrated: The residue was crystallized from -PrOH yielding ospernifene (0:29 g, 35 %) as a white solid.

1H-NMR (400 MHz, CDC13) δ (ppm): 7.37 (2H, t, 7=8Hz, ArH), 7.29 (3Η, t, J=7.2Hz, ArH), 7.20 (2Η, t,7=7.6Hz, ArH), 7.16-7.13 (3Η, m, ArH), 6.80 (2Η, d, J=8.8Hz, ArH), 6.57 (2Η, d, 7=8.8Hz, ArH), 3.94 (2Η, t, y=4.4Hz, ArOCH2CH2OH), 3.87 (2H, m, ArOCH2CH OH), 3.42 (2H, t, J=7.2Hz, C1CH2CH2), 2.92 (2H, t, 7=7.2Hz, C1CH2CH2), 1.95 (1Η, t, 7=6.4Hz, OH).  

13C- NMR (100 MHz, CDC13) δ (ppm): 157.2, 143.2, 142.1 , 141.3, 2 x 135.7, 132.2, 130.0, 129.8, 128.8, 128.7, 127.4, 127.0, 113.9, 69.3, 61.8, 43.3, 39.0.

EXAMPLE 6. Preparation of (Z)-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)- phenoxy]ethanol (ospernifene) by reductive cleavage of pivaloyl-grou
(Z)-2-(4-(4-Chloro- 1 ,2-diphenylbut- 1 -en- 1 -yl)phenoxy)ethyl pivalate (3.5 g, 7.56 mmol) was dissolved in toluene (35 ml) and stirred under nitrogen for 5 min at room temperature. Lithium aluminium hydride solution (1 M in THE) (7.56 ml, 7.56 n mbi) was added dropwise to the reaction and the mixture was stirred at room temperature for 30 min. After HPLC indicated completion, the reaction was quenched by addition of saturated NH4Cl-sblution (75 ml). Additional amount of toluene (30 ml) was added and the phases were separated. The organic phase was washed with water (50 ml), brine (50 ml), dried (Na2S04), filtered and concentrated in vacuo. The residue was crystallized from 90 % MeOH yielding ospernifene (1 ,75 g, 61 9c) as a white solid.




  1.  Rutanen EM, Heikkinen J, Halonen K, Komi J, Lammintausta R, Ylikorkala O (2003). “Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial”. Menopause10 (5): 433–9.doi:10.1097/01.GME.0000063609.62485.27.PMID14501605.
  2.  Tanzi MG (April 2013). “Ospemifene: New treatment for postmenopausal women.”Pharmacy Today. American Pharmacists Association.
  3. “FDA approves Osphena for postmenopausal women experiencing pain during sex”FDA News Release (U.S. Food and Drug Administration). 2013-02-26.
  4. “Ospemifene: Indications, Side Effects, Warnings”.
  5. EP application 2286806, Lehtola V-M, Halonen K, “Solid formulations of ospemifene”, published 2011-02-23, assigned to Hormos Medical Ltd.
  6. “Shionogi Files a New Drug Application for Ospemifene Oral Tablets 60mg for the Treatment of Vulvar and Vaginal Atrophy”.
  7.  Kusiak V (2013-02-13). “NDA Approval” (PDF). U.S. Food and Drug Administration.
  8.  Unkila M, Kari S, Yatkin E, Lammintausta R (November 2013). “Vaginal effects of ospemifene in the ovariectomized rat preclinical model of menopause”. J. Steroid Biochem. Mol. Biol.138: 107–15.doi:10.1016/j.jsbmb.2013.04.004PMID23665515.
  9.  Center for Drug Evaluation and Research (2013-02-26). “Clinical Pharmacology and Biopharmaceutics Review Application Number 203505Orig1s000” (PDF). Office of Clinical Pharmacology Review. U.S. Food and Drug Administration.
  10.  Bachmann GA, Komi JO (2010). “Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study”. Menopause17 (3): 480–6.doi:10.1097/gme.0b013e3181c1ac01PMID20032798.
  11.  Portman DJ, Bachmann GA, Simon JA (June 2013). “Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy”. Menopause20 (6): 623–30.doi:10.1097/gme.0b013e318279ba64PMID23361170.
  12. First Half of Fiscal 2013 Financial Results. Nov. 1, 2013.
  13. ThePharmaLetter


Method for enhancing the bioavailablity of ospemifene
Novel oral formulations of ospemifene
Formulations of fispemifene
Methods for the inhibition of atrophy or for treatment or prevention of atrophy-related symptoms in women
Methods for the inhibition of atrophy or for treatment or prevention of atrophy-related symptoms in women
Solid formulations of ospemifene
Method for treatment or prevention of osteoporosis in individuals with high bone turnover
Triphenylalkene derivatives and their use as selective estrogen receptor modulators
Triphenylalkene derivatives and their use as selective estrogen receptor modulators
Method for the treatment of vaginal dryness and sexual dysfunction in women during or after the menopause

Phase 2 , Sarepta, shows eteplirsen for Duchenne muscular dystrophy


27 MAR 2013

The clock is ticking for Sarepta Therapeutics , a multitude of biotech investors and the boys who suffer from Duchenne muscular dystrophy.

Armed with promising Phase IIb data from a small study of eteplirsen involving only 12 patients with the lethal disease, Sarepta CEO Chris Garabedian is completing one of the most closely-watched high wire acts in the industry. At a time most companies would be focused solely on organizing a pivotal late-stage study, there’s intense speculation that the biotech will shoot for an accelerated approval with the data in hand. And it all comes down to their sit-down with the FDA to review mid-stage data.

Eteplirsen, also called AVI-4658, is an experimental drug, currently in clinical trials. It is designed for treatment of some mutations which cause Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease. Eteplirsen is a product of Sarepta Therapeutics Inc.

The drug is a Morpholino antisense oligomer which triggers excision of exon 51 during pre-mRNA splicing of the dystrophin RNA transcript. Skipping exon 51 changes the downstream reading frame of dystrophin;[1] giving eteplirsen to a healthy person would result in production of dystrophin mRNA which would not code for functional dystrophin protein but, for DMD patients with particular frameshifting mutations, giving eteplirsen can restore the reading frame of the dystrophin mRNA and result in production of functional (though internally-truncated) dystrophin.[2] Eteplirsen is given by intravenous infusion for systemic treatment of DMD.

Several clinical trials have been conducted to test eteplirsen, one in the UK involving local injection to the foot,[3][4] one in the UK involving systemic injection at low doses[5][6] and one in the USA at higher systemic doses[7] that progressed to a rollover extension study.[8]

  1.  “Exon Skipping Quantification by qRT-PCR in Duchenne Muscular Dystrophy Patients Treated with the Antisense Oligomer Eteplirsen”. Hum Gene Ther Methods. 17 Oct 2012.
  2.  “Morpholinos and Their Peptide Conjugates: Therapeutic Promise and Challenge for Duchenne Muscular Dystrophy.”. Biochim Biophys Acta. 1798 (12): 2296–303. 17 Feb 2010.
  3.  Gary Roper/Manager Clinical Research Governance Organisation, Imperial College London. “Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy”. US Government, NIH. Retrieved 30 October 2012.
  4.  Lancet Neurol. 8 (10): 918–28. 25 Aug 2009.
  5. Professor Francesco Muntoni, University College of London Institute of Child Health. “Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients”. US Government, NIH. Retrieved 30 October 2012.
  6.  “Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.”. Lancet. 378 (9791): 595–605. 23 Jul 2011.
  7.  Sarepta Therapeutics. “Efficacy Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients”. US Government, NIH. Retrieved 30 October 2012.
  8. Sarepta Therapeutics. “Efficacy, Safety, and Tolerability Rollover Study of Eteplirsen in Subjects With Duchenne Muscular Dystrophy”. US Government, NIH. Retrieved 30 October 2012.

Lundbeck, Otsuka reach agreement to develop and commercialize Lu AE58054

Lu AE58054


C20H19F5N2O, 398.37


1H-​Indole-​3-​ethanamine, 6-​fluoro-​N-​[[3-​(2,​2,​3,​3-​tetrafluoropropoxy)​phenyl]​methyl]​-


CAS No: 467458-02-2  hydrochloride, M.Wt: 434.83
Lu AE58054 Hydrochloride Formula: C20H20ClF5N2O


H. Lundbeck A/S (Lundbeck) and Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced a license and development agreement for Lu AE58054, a selective 5HT6receptor antagonist currently in development for the treatment of Alzheimer’s disease. Under the terms of the agreement, Lundbeck will grant Otsuka co-development and co-commercialization rights to Lu AE58054 in the U.S., Canada, East Asia including Japan, major European countries and Nordic countries.

Lu AE58054 is a potent and selective 5-HT6 receptor antagonist under development byLundbeck as an augmentation therapy for the treatment of cognitive deficits associated with Alzheimer’s disease and schizophrenia.[1][2]

Phase III trials recently began for Lu-AE58054, a novel 5-HT6 antagonist for Alzheimer’s disease (AD) from H Lundbeck and Otsuka. Lu-AE58054 already demonstrated significant improvement of cognitive function in an earlier phase II trial when administered with Aricept.


This orally available drug is an antagonist of the serotonin 6 (5-HT6) receptor. This receptor subtype is expressed primarily in the brain, particularly in the cerebral cortex and hippocampus, where it has been proposed to play a role in cognitive impairments associated with schizophrenia and Alzheimer’s disease.  The 5-HT6 receptor antagonists are thought to enhance cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission. Apart from some affinity for adrenergic receptors, Lu AE58054 has been reported to be highly selective over other G-protein coupled receptors. The compound enters the brain and dose-dependently reversed deficits in a rat model of cognitive impairment (Upton et al., 2008Arnt et al., 2010).

Lu AE58054 is being developed as a symptomatic adjunct to cholinesterase inhibitor treatment in Alzheimer’s disease. Lu AE58054 was originally discovered by Lilly, which licensed it to the biotechnology company Saegis for the development of cognitive impairment in thinking disorders such as schizophrenia. In 2006, Saegis was acquired by Lundbeck, which in October 2013 launched a global Phase 3 program in AD. This program consists of four trials planned to enroll a total of about 3,000 patients (see company press release).

No Phase 1 trials on this drug are listed in publicly available databases. In 2005, Saegis conducted a Phase 2a trial in 20 schizophrenia patients in the United States, evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of giving this drug as an add-on to Risperidone (see company press release). In 2009 and 2010, Lundbeck conducted a Phase 2 trial in Europe and Asia to evaluate the compound as an adjuct to Risperidone for its effect on cognitive deficits in 124 patients with schizophrenia. Results were not published in the peer-reviewed literature, but development of Lu AE58054 for cognitive deficits in schizophrenia appears to have ended.

In 2010 and 2011, Lundbeck evaluated Lu AE58054 in a Phase 2 study in 278 patients with probable Alzheimer’s disease. Conducted in Australia, Canada, and Europe, the trial compared the effects of a six-month course of an undisclosed dose of Lu AE58054 with 10 mg/day of Donepezil to the same dose of placebo. In June 2012, the company announced that the trial had met its primary cognition endpoint as measured by the ADAS-cog. On secondary endpoints, such as measures of global status and activities of daily living, Lu AE58054 treatment showed trends for a benefit but fell short of achieving statistical significance (see Jun 2012 news story).

In July 2013, a Phase 1 study evaluating pharmacokinetics of single and multiple ascending doses in 42 healthy volunteers was added, and in October 2013, the first of four planned Phase 3 studies began. This study is set to enroll 930 patients with mild to moderate Alzheimer’s disease who are already taking a stable dose of 10 mg/day of Donepezil. The trial compares a six-month course of once-daily 30 or 60 mg capsules of drug to placebo for added benefit on cognition as measured by the ADAS-cog. Secondary outcomes will assess various aspects of global clinical function and behavior. No biomarkers are embedded in this trial, which is expected to last until September 2015. For all listed trials on Lu AE58054,

Description: IC50 Value: 0.83 nm [1] Lu AE58054 is an in-vitro potency and selectivity, in-vivo binding affinity and effect of the 5-HT (6) R antagonist in vitro:. Lu AE58054 displayed high affinity to the human 5-HT (6) receptor (5-HT (6) R) with a Ki of 0.83 nm. In a 5-HT (6) GTPgammaS efficacy assay Lu AE58054 showed no agonist activity, but demonstrated potent inhibition of 5-HT- . mediated activation Besides medium affinity to adrenergic alpha (1A) – and alpha (1B)-adrenoreceptors, Lu AE58054 demonstrated> 50-fold selectivity for more than 70 targets examined [1] in vivo: Orally administered Lu AE58054 potently inhibited striatal in. -vivo binding of the 5-HT (6) antagonist radioligand [(3) H] Lu AE60157, with an ED (50) of 2.7 mg / kg. Steady-state modelling of an acute pharmacokinetic/5-HT (6) R occupancy time-course experiment indicated a plasma EC (50) value of 20 ng / ml. Administration of Lu AE58054 in a dose range (5-20 mg / kg po) leading to above 65% striatal 5-HT (6) R binding occupancy in vivo, reversed cognitive impairment in a rat novel object recognition task induced after subchronic treatment for 7 d with phencyclidine (PCP 2 mg / kg bid, ip for 7 d, followed by 7 d drug free). The results indicate that Lu AE58054 is a selective antagonist of 5-HT (6) Rs with good oral bioavailability and robust efficacy in a rat model of cognitive impairment in schizophrenia [1] Clinical trial:. Lu-AE58054 Added to Donepezil for the Treatment for Moderate Alzheimer’s Disease Phage2.

Dementia is a clinical syndrome characterized by deficits in multiple areas of cognition that cannot be explained by normal aging, a noticeable decline in function, and an absence of delirium. In addition, neuropsychiatric symptoms and focal neurological findings are usually present, Dementia is further classified based on etiology. Alzheimer’s disease (AD) is the most common cause of dementia, followed by mixed AD and vascular dementia, vascular dementia, Lewy body dementia (DLB), and fronto- temporal dementia.

The incidence of Alzheimer’s disease is expected to increase through the year 2050 with an estimated prevalence of 1 1 to 16 million cases. Currently, two classes of medications are FDA approved for managing symptoms of AD – acetylcholinesterase inhibitors (AChEIs) and an N-methyl-D-aspartase (NMDA) receptor antagonist. AChEIs are commonly used as initial treatment on diagnosis. The AChEIs – donepezil, rivastigmine, galantamine, and tacrine – are indicated for mild-to-moderate AD; only donepezil is approved for the severe stage.

Despite the available therapies, there are no treatments to cure AD or to prevent or stop disease progression. Acetylcholinesterase inhibitors do not help everyone who has AhJieimers disease and in fact are not efficacious in many patients. Considering that AChEIs and memantine have only a modest symptomatic effect, and cannot prevent AD decline and slow disease progression, mere is a high unmet need for more effective symptomatic treatments and for a disease modifying/slowing therapies. The use of selective 5-HTe receptor antagonists to treat cognitive dysfunction has been suggested and is based on several lines of reasoning. For example, selective 5-HT« receptor antagonists have been shown to modulate cholinergic and glutamatergic neuronal function. The activity of selective 5-HT6 receptor antagonists has been demonstrated in animal models of cognitive function. Since the disclosure of the first selective 5-HT4 receptor antagonists, there have been several reports on the activity of these selective compounds in in-vivo models of cognitive function, N*(2-(6-fluoro-lH-indol-3-yI)ethyI)-3- (2,2,3,3-tetrafluoropropoxy)benzylamine (herein referred to as “Compound Γ) is a potent and selective1

RECTIFIED SHEET RULE 91 ISA/EP 5-HT6 receptor antagonist which has been in clinical development for treating cognition impairment associated with schizophrenia and as a treatment for AD.

Figure imgf000003_0001

In November 2008, a multi-centre, randomised, double-blind, fixed-dose study (120 mg/day BID) was initiated to explore the efficacy and safety of Compound I as adjunctive treatment to risperidone in patients with schizophrenia. Overall improvement in schizophrenia symptoms was assessed by using the Positive and Negative Syndrome Scale (PANSS) total score. Compound I did not offer any treatment advantage over placebo as measured by the PANSS total score. In 2010, it was announced that there did not appear to be any treatment advantage over placebo in improving patients’ overall neurocognitive performance as assessed using the BACS composite Z-score and the PANSS cognitive subscale scores.

In 2012, it was reported that a randomized, double blind, placebo controlled trial conducted in Europe, Canada and Australia met its primary endpoint in the treatment of AD. Data demonstrated that Compound I plus 10 mg/day of donepezil significantly improved cognitive function in 278 patients with Alzheimer’s disease compared to placebo plus donepezil, when measured by Alzheimer’s Disease Assessment Scale-cognitive sub-scale (ADAS-cog). Compound I showed positive results in secondary endpoints including measures of global impression and daily living activities compared to donepezil treated patients.

The daily dose of 90 mg of Compound I in the AD study was administered three times daily (3 x 30 mg) to overcome the relative short half-life observed in subjects in previous clinical studies. An issue for that dose selection was to ensure that the maximum exposure level fell under the maximum exposure limit which had been established from non-clinical toxicology studies. Accordingly, a fixed dose of three times in the study was introduced.

As the 5-HT6 receptor is a novel target predominately localized in the brain, a key problem in the development is to determine the amount of receptor occupancy and the correlation with plasma exposure. With CNS targets, further challenges exist that revolve around whether a drug will pass the blood brain barrier and whether it will reach the target at a suitable concentration and for a sufficient length of receptor occupancy. Direct brain measures of 5 -HT6 receptor occupancy may be valuable to many decision-making processes during the development of centrally acting drugs targeted at 5-HT6 to ensure adequate proof-of-concept testing and to optimize dosing regimens. In humans, tools such as positron emission tomography (PET) with specific radiolabeled ligands have been used to quantitatively assess in-vivo occupancy of a number of neurotransmitter receptors, including those for dopamine, serotonin, and benzodiazepines (Talbot, et al., European Neuropsychopharmacology, 2002, 12, 503-511).

An effective PET ligand, [nC]-LuPET was developed and has since been successfully evaluated for human use. The ligand was subsequently used to determine the 5-HT6 receptor occupancy following multiple dose ranges of Compound I. In the assessment for receptor occupancy, human subjects were administered the compound for at least three days at several dosage regimens.

The inventors discovered that high receptor occupancies were observed after multiple dosages of Compound I and that receptor occupancy was maintained 24 hrs post dose. Data generated from a separate Phase I P study in the elderly and data generated from the above AD study have shown that the elimination half life of Compound I in the elderly population was longer (about 19 hours) compared to young healthy subjects (about 12 hours).

With these convergent discoveries, the inventors have identified improved methods of treating AD by introducing a new and improved dosage regime comprising once daily administration in a novel dosage range. Based on the findings described herein, the dose range contemplated is expected to be efficacious while providing exposure levels below the NOAEL, thus improving the safety ratio.


WO 2009073118

General Synthetic Scheme

Figure imgf000041_0001

MeOH (-H2O); NaBH4 BoC2O

Figure imgf000041_0002
Figure imgf000041_0003
Figure imgf000042_0001


WO 2002078693

Example 402 N-(2-(6-Fluoro-lH-indol-3-yl)ethyl)-3-(2.2,3,3-tetrafluoropropoxy)benzylamine

Figure imgf000107_0001

Combine 6-fluorotryptamine hydrochloride (90 g, 0.419 mol) and water (900 ml). Add an aqueous solution of NaOH (2N, 230 ml) and dichloromethane (900 ml). After 1 hour, separate the organic layer, extract the aqueous layer with dichloromethane, combine the organic layers, wash water, dry over MgSO , and evaporate to a residue. Combine the residue and toluene (200 ml) and evaporate to give 78.45 g of a brown oil. Combine the above 78.45 g with another 41.4 g batch to provide 6-fluorotryptamine. Combine 6- fluorotryptamine (119.85) and ethanol (3.325 L), add 2,2,3,3- tetrafluoropropylbenzaldehyde (176 g, 0.745 moles, 1.2 equiv.) and 150 g of molecular sieve 3A. Heat to reflux. After 2 hours, cool to RT room temperature and add NaBH4 (35.2 g, 0.93 mol, 1.5 equiv.). After 1 hour, filter through celite and wash with 500 ml of ethanol. Evaporate the filtrate under reduced pressure to give an oily residue. Partition the residue between water and dichloromethane. Separate the layers, extract the aqueous later with dichloromethane, combine organic layers, wash with brine and dry over MgSO4. Filter and evaporate under reduced pressure to give the title compound. The HCI salt is formed as follows: Combine N-(2-(6-fluror-lH-indol-3-yl)ethyl)-

3-(2,2,3,3-tetrafluoropropyl)benzylamine (387 g, 0.97 moles) and diethyl ether (3.95 L) of at room temperature. Add dropwise a solution of HCl/Et2O (298 ml) over 15 minutes until the pH is about 3 to give a solid. Stir for 1 hour and collect the solid, wash with ether, and dry under reduced pressure for at 40°C to give the title compound as the hydrochloride.


Compound 6, also known as 2-(6-fluoro-1H-indol-3-yl)-N-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)ethanamine,

Figure US20130210829A1-20130815-C00008
Example 402 N-(2-(6-Fluoro-1-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine
Figure US08044090-20111025-C00051


Combine 6-fluorotryptamine hydrochloride (90 g, 0.419 mol) and water (900 ml). Add an aqueous solution of NaOH (2N, 230 ml) and dichloromethane (900 ml). After 1 hour, separate the organic layer, extract the aqueous layer with dichloromethane, combine the organic layers, wash water, dry over MgSO4, and evaporate to a residue. Combine the residue and toluene (200 ml) and evaporate to give 78.45 g of a brown oil. Combine the above 78.45 g with another 41.4 g hatch to provide 6-fluorotryptamine. Combine 6-fluorotryptamine (119.85) and ethanol (3.325 L), add 2,2,3,3-tetrafluoropropoxybenzaldehyde (176 g, 0.745 moles, 1.2 equiv.) and 150 g of molecular sieve 3A. Heat to reflux. After 2 hours, cool to RT room temperature and acid NaBH(35.2 g, 0.93 mol, 1.5 equiv.). After 1 hour, filter through celite and wash with 500 nil of ethanol. Evaporate the filtrate under reduced pressure to give an oily residue. Partition the residue between water and dichloromethane. Separate the layers, extract the aqueous later with dichloromethane, combine organic layers, wash with brine and dry over MgSO4. Filter and evaporate under reduced pressure to give the title compound.

The HCl salt is formed as follows: Combine N-(2-(6-fluoror-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropyl)benzylamine (387 g, 0.97 moles) and diethyl ether (3.95 L) of at room temperature. Add dropwise a solution of HCl/Et2O (298 ml) over 15 minutes until the pH is about 3 to give a solid. Stir for 1 hour and collect the solid, wash with ether, and dry under reduced pressure for at 40° C. to give the title compound as the hydrochloride.


  1.  “U.S. Development Programs. – Lundbeck”.
  2.  “Search of: Lu AE58054 – List Results –”.
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  4. WO 2009073118
  5. Novel and Potent 5-Piperazinyl Methyl-N1-aryl Sulfonyl Indole Derivatives as 5-HT6 Receptor Ligands
    ACS Medicinal Chemistry Letters (2010), 1(7), 340-344,
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  7. WO 2013055386
  8.  US 20130210829
  9. WO 2014037532

References on Lu AE58054 Hydrochloride:

[1]. Arnt J, Bang-Andersen B, Grayson B, Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol. 2010 Sep;13(8):1021-33.

[2]. Witten L, Bang-Andersen B, Nielsen SM, Characterization of [?H]Lu AE60157 ([?H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) binding to 5-hydroxytryptamine? (5-HT?) receptors in vivo.Eur J Pharmacol. 2012 Feb 15;676(1-3):6-11.

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