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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 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 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 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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FDA approves first cancer treatment for any solid tumor with a specific genetic feature


05/23/2017
The U.S. Food and Drug Administration today granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature (biomarker). This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated

May 23, 2017

Release

The U.S. Food and Drug Administration today granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature (biomarker). This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated.

Keytruda (pembrolizumab) is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs.

“This is an important first for the cancer community,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”

MSI-H and dMMR tumors contain abnormalities that affect the proper repair of DNA inside the cell. Tumors with these biomarkers are most commonly found in colorectal, endometrial and gastrointestinal cancers, but also less commonly appear in cancers arising in the breast, prostate, bladder, thyroid gland and other places. Approximately 5 percent of patients with metastatic colorectal cancer have MSI-H or dMMR tumors.

Keytruda works by targeting the cellular pathway known as PD-1/PD-L1 (proteins found on the body’s immune cells and some cancer cells). By blocking this pathway, Keytruda may help the body’s immune system fight the cancer cells. The FDA previously approved Keytruda for the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma.

Keytruda was approved for this new indication using the Accelerated Approvalpathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study is required to verify and describe anticipated clinical benefits of Keytruda, and the sponsor is currently conducting these studies in additional patients with MSI-H or dMMR tumors.

The safety and efficacy of Keytruda for this indication were studied in patients with MSI-H or dMMR solid tumors enrolled in one of five uncontrolled, single-arm clinical trials. In some trials, patients were required to have MSI-H or dMMR cancers, while in other trials, a subgroup of patients were identified as having MSI-H or dMMR cancers by testing tumor samples after treatment began. A total of 15 cancer types were identified among 149 patients enrolled across these five clinical trials. The most common cancers were colorectal, endometrial and other gastrointestinal cancers. The review of Keytruda for this indication was based on the percentage of patients who experienced complete or partial shrinkage of their tumors (overall response rate) and for how long (durability of response). Of the 149 patients who received Keytruda in the trials, 39.6 percent had a complete or partial response. For 78 percent of those patients, the response lasted for six months or more.

Common side effects of Keytruda include fatigue, itchy skin (pruritus), diarrhea, decreased appetite, rash, fever (pyrexia), cough, difficulty breathing (dyspnea), musculoskeletal pain, constipation and nausea. Keytruda can cause serious conditions known as immune-mediated side effects, including inflammation of healthy organs such as the lungs (pneumonitis), colon (colitis), liver (hepatitis), endocrine glands (endocrinopathies) and kidneys (nephritis). Complications or death related to allogeneic hematopoietic stem cell transplantation after using Keytruda has occurred.

Patients who experience severe or life-threatening infusion-related reactions should stop taking Keytruda. Women who are pregnant or breastfeeding should not take Keytruda because it may cause harm to a developing fetus or newborn baby. The safety and effectiveness of Keytruda in pediatric patients with MSI-H central nervous system cancers have not been established.

The FDA granted this application Priority Review designation, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The FDA granted accelerated approval of Keytruda to Merck & Co.

///////////Keytruda, pembrolizumab, BIO MARKER, MERCK, FDA 2017

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FDA approves first drug Actemra (tocilizumab) to specifically treat giant cell arteritis


Image result for actemra logo
05/22/2017
The U.S. Food and Drug Administration today expanded the approved use of subcutaneous Actemra (tocilizumab) to treat adults with giant cell arteritis. This new indication provides the first FDA-approved therapy, specific to this type of vasculitis.

May 22, 2017

Release

The U.S. Food and Drug Administration today expanded the approved use of subcutaneous Actemra (tocilizumab) to treat adults with giant cell arteritis. This new indication provides the first FDA-approved therapy, specific to this type of vasculitis.

“We expedited the development and review of this application because this drug fulfills a critical need for patients with this serious disease who had limited treatment options,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Giant cell arteritis is a form of vasculitis, a group of disorders that results in inflammation of blood vessels. This inflammation causes the arteries to narrow or become irregular, impeding adequate blood flow. In giant cell arteritis, the vessels most involved are those of the head, especially the temporal arteries (located on each side of the head). For this reason, the disorder is sometimes called temporal arteritis. However, other blood vessels, including large ones like the aorta, can become inflamed in giant cell arteritis. Standard treatment involves high doses of corticosteroids that are tapered over time.

The efficacy and safety of subcutaneous (injected under the skin) Actemra for giant cell arteritis were established in a double-blind, placebo-controlled study with 251 patients with giant cell arteritis. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined as the absence of symptoms of giant cell arteritis, normalization of inflammatory laboratory tests, and tapering the use of prednisone (a steroid drug). A greater proportion of patients receiving subcutaneous Actemra with standardized prednisone regimens achieved sustained remission from Week 12 through Week 52 as compared to patients receiving placebo with standardized prednisone regimens. The cumulative prednisone dose was lower in treated patients with Actemra relative to placebo.

The overall safety profile observed in the Actemra treatment groups was generally consistent with the known safety profile of Actemra. Actemra carries a Boxed Warning for serious infections. Patients treated with Actemra who develop a serious infection should stop that treatment until the infection is controlled. Live vaccines should be avoided during treatment with Actemra. Actemra should be used with caution in patients at increased risk of gastrointestinal perforation. Hypersensitivity reactions, including anaphylaxis and death, have occurred. Laboratory monitoring is recommended due to potential consequences of treatment-related changes in neutrophils (type of white blood cell), platelets, lipids and liver function tests.

Subcutaneous Actemra was previously approved for the treatment of moderate to severely active rheumatoid arthritis. Intravenous Actemra was also previously approved for the treatment of moderate to severely active rheumatoid arthritis, systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis. Intravenous administration is not approved for giant cell arteritis.

The FDA granted this application a Breakthrough Therapy designation and a Priority Review.

The FDA granted the supplemental approval of Actemra to Hoffman La Roche, Inc.

//////////Actemra, tocilizumab, fda 2017, Breakthrough Therapy designation, Priority Review,  supplemental approval, Hoffman La Roche, Inc.

FDA approves drug to treat ALS, Radicava (Edaravone) , эдаравон, إيدارافون , 依达拉奉 ,ラジカット,


Edaravone.svg

05/05/2017
The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

May 5, 2017

Release

The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This is the first new treatment approved by the FDA for ALS in many years, and we are pleased that people with ALS will now have an additional option.”

ALS is a rare disease that attacks and kills the nerve cells that control voluntary muscles. Voluntary muscles produce movements such as chewing, walking, breathing and talking. The nerves lose the ability to activate specific muscles, which causes the muscles to become weak and leads to paralysis. ALS is progressive, meaning it gets worse over time. The Centers for Disease Control and Prevention estimates that approximately 12,000-15,000 Americans have ALS. Most people with ALS die from respiratory failure, usually within three to five years from when the symptoms first appear.

Radicava is an intravenous infusion given by a health care professional. It is administered with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles consist of dosing on 10 of 14 days, followed by 14 days drug-free.

The efficacy of edaravone for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan. In the trial, 137 participants were randomized to receive edaravone or placebo. At Week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving a placebo.

The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising (contusion) and gait disturbance.

Radicava is also associated with serious risks that require immediate medical care, such as hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug. Sodium bisulfite may cause anaphylactic symptoms that can be life-threatening in people with sulfite sensitivity.

The FDA granted this drug orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Radicava to Mitsubishi Tanabe Pharma America, Inc,

ChemSpider 2D Image | Edaravone | C10H10N2O

1-Phenyl-3-methyl-5-pyrazolone
3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl- [ACD/Index Name]
89-25-8 [RN]
эдаравон [Russian]
إيدارافون [Arabic]
依达拉奉 [Chinese]
ラジカット,
MCI-186

Edaravone (brand name ラジカット, Radicut) is a nootropic and neuroprotective agent used for the purpose of aiding neurological recovery following acute brain ischemia and subsequent cerebral infarction.[1] It acts as a potent antioxidant and strongly scavenges free radicals, protecting against oxidative stress and neuronal apoptosis.[2][3][4] It has been marketed solely in Japan by Mitsubishi Pharma since 2001.[1] It is also marketed in India by Edinburgh Pharmaceuticals by the brand name Arone.

On June 26, 2015, Mitsubishi Tanabe Pharma Corporation announced it has received approval to market Radicut for treatment of ALS in Japan. The phase III clinical trial began in 2011 in Japan. The company was awarded Orphan Drug Designation for Radicut by the FDA and EU in 2015. Radicut is an intravenous drug and administrated 14 days followed by 14 days drug holiday.

The biotech company Treeway is developing an oral formulation of edaravone (TW001) and is currently in clinical development. Treeway was awarded orphan drug designation for edaravone by the EMA in November 2014 and FDA in January 2015.

Edaravone has been shown to attenuate methamphetamine– and 6-OHDA-induced dopaminergic neurotoxicity in the striatum and substantia nigra, and does not affect methamphetamine-induced dopamine release or hyperthermia.[5][6] It has also been demonstrated to protect against MPTP-mediated dopaminergic neurotoxicity to the substantia nigra, though notably not to the striatum.[7][8][9]

Image result for edaravone synthesis

Edaravone (CAS NO.: 89-25-8), with other name of 3-Methyl-1-phenyl-2-pyrazolin-5-one, could be produced through many synthetic methods.

Following is one of the synthesis routes: By direct cyclization of phenylhydrazine (I) with ethyl acetoacetate (II) in refluxing ethanol.

SYNTHESIS

Edaravone, chemical name: 3-methyl-1-phenyl-2-pyrazoline-5-one, of the formula: Formula: CiciHltlN2O, molecular weight: 174.20, the formula:

 

Figure CN101830852BD00031

[0004] Edaravone is a brain-protecting agent (free radical scavenger). Clinical studies suggest that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. In patients with acute cerebral infarction Edaravone suppressed reduce peri-infarct regional cerebral blood flow, so that the first concept of days after the onset of brain NAA glycerol content than the control group significantly increased. Preclinical studies suggest that rats after ischemia / reperfusion of ischemic intravenous edaravone, can prevent the progress of cerebral edema and cerebral infarction, and relieve the accompanying neurological symptoms, suppress delayed neuronal death. Mechanism studies suggest that edaravone can scavenge free radicals, inhibiting lipid peroxidation, thereby inhibiting brain cells, endothelial cells, oxidative damage nerve cells.

For the synthesis of edaravone reported some use of benzene and methyl ethyl ketone amide corpus obtained, but methyl ethyl ketone amide difficult to obtain and slow reaction, which now has basically been abandoned; some use benzene corpus and ethyl acetoacetate in ethanol (see US4857542A, Synthesis Example 1) or water (Dykhanov NN Ethyl and butyl acetoacetates, Med Prom SSSR, 1961,15 (1):. 42-45) refluxing the reaction of the reaction The resulting purity edaravone poor, and the yield is not high, only about 70%.

Edaravone, chemical name: 2,4_-dihydro-5-methyl-2-phenyl pyrazole -3H- – one, of the formula: CiciHltlN2O, molecular weight: 174.20, the formula:

Figure CN102285920BD00031

edaravone is a clear cerebral infarction harmful factors (free radicals), protection of new therapeutic agents for cerebral infarction nerve cells. Clinical studies have shown that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. When patients with acute cerebral infarction Edaravone, peri-infarct rCBF decrease has improved, and the first 28 days after the onset of brain NAA content was significantly higher than that in the control group glycerol. Mechanism studies suggest that edaravone can clear the brain is highly cytotoxic hydroxyl radicals, inhibiting the synthesis of lipids free radicals, which can suppress brain infarction after reperfusion edema, protecting brain from damage and improve nerve impairment symptoms, and the delayed neuronal death inhibition, to protect the brain.

 The first is by phenylhydrazine and methyl ethyl ketone amide (National API process compilation, 1980.737-739) condensation reaction in water at 50 ° C, a yield of up to 97%, but the raw material ketone amide ( CH3C0CH2C0NH2) are not readily available. Formula I

Edaravone synthetic route for the reaction:

Figure CN102285920BD00032

[0008] The second is to phenylhydrazine and ethyl acetoacetate in ethanol or water at reflux the reaction, sodium bisulfite as the preparation of the catalyst. From the perspective of the chemical reaction, acetyl ethyl ketone amide more than hydrazine reacted with benzene and ethyl acetoacetate more readily available, the price is cheaper, but lower reaction yield of about 70%. Formula 2 for the synthesis route Edaravone reaction formula:

Figure CN102285920BD00041

PATENT

https://www.google.com/patents/CN101830852B?cl=en

Figure CN101830852BD00041

1 Edaravone Synthesis Example [0023] Example

[0024] (1) Weigh benzene hydrochloride corpus 13. 5g (94mmol), was added to IOOml water, stirred for 0.5 hours, sodium hydroxide was added an equimolar 3. 76g, stirred for 0.5 hours; [0025] ( 2) To the reaction solution was added dropwise ethyl acetoacetate 11. 7g (90mmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 15. 5g;

[0026] (3) The crude product was added 30ml volume ratio of 2: 1 isopropanol – water, 2g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 14 a white crystalline powder. 8g, yield 90%, mpU9 ° C, with a purity of 99.9% 0

2 Edaravone Synthesis Example [0027] Example

[0028] (1) Weigh 15g of benzene hydrochloride corpus (I (Mmmol), was added to 120ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 4. 16g, stirred for 0.5 hours;

[0029] (2) To the reaction solution was added dropwise 13g of ethyl acetoacetate (lOOmmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 16. 7g;

(3) The crude product was added 40ml volume ratio of 2: 1 isopropanol – water, 2. 5g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature to precipitate a white solid, as a white crystalline powder 16. lg, a yield of 88.9%, mpU8 ° C, with a purity of 99.9% 0

3 Edaravone Synthesis Example [0031] Example

[0032] (1) Weigh 22g of benzene hydrochloride corpus (152mm0l), was added to 200ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 6. 08g, stirred for 0.5 hours;

[0033] (2) To the reaction solution was added dropwise 19g of ethyl acetoacetate (146mm0l), the reaction exotherm, the reaction was heated to reflux for 3 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 24. Sg;

[0034] (3) The crude product was added 50ml volume ratio of 2: 1 isopropanol – water, 3g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 23 a white crystalline powder. 2g, a yield of 87. 8%, mpU8 ° C, with a purity of 99.9% 0

[0035] Comparative Example

[0036] The ethyl acetoacetate 65g (0. 5mol) and 180ml of anhydrous ethanol mixed, with stirring at 50 ° C was added dropwise benzyl corpus 54g (0. 5mol) and a solution consisting of 30ml absolute ethanol, dropwise at reflux for 2 Bi hours, ethanol was distilled off 60ml, cooled, suction filtered, washed crystals with cold absolute ethanol twice, and dried in vacuo to give pale yellow crystals 70g. Recrystallized twice from absolute ethanol to give pale yellowish white crystals 56g (yield 65%).

PATENT

https://www.google.com/patents/CN102285920B?cl=en

Example 1: Preparation of phenylhydrazine edaravone.

[0024] a. Weigh 5.1g phenylhydrazine (47mmol), was added under stirring to water containing 45mL round-bottom flask, take appropriate concentrated hydrochloric acid solution was adjusted to pH 6.0 with PH meter.

[0025] b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, was added 1.5g sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.

[0026] c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 85% yield, 99.2% purity 0

[0027] Example 2: Preparation of phenylhydrazine hydrochloride edaravone.

[0028] a. Weigh 6.8g phenylhydrazine hydrochloride (47mmol), was added under stirring to water containing 45mL round-bottomed flask, the pH of the solution adjusted to 6.0 with aqueous ammonia.

[0029] b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, 1.25g was added sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.

[0030] c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 84% yield, with a purity of 99.2%. [0031] Comparative Example:

Under the [0032] state of agitation will phenylhydrazine 10.2g (94mmol) added to a round bottom flask equipped with IOOmL water in an appropriate amount of concentrated hydrochloric acid was dubbed the volume ratio of 1: 1 aqueous hydrochloric acid, with a PH adjusting pH of the solution was measured 6.0. After weighing Ethylacetoacetate 11.7g (90mmol) added to the reaction mixture, the reaction was exothermic and cooling to room temperature, sodium bisulfite (NaHSO3), heated to 105 ° C under reflux for 3h, the hot solution Water was added into the beaker and mechanical stirring, cooling, filtration, and dried to give the yellow edaravone crude, 73% yield, with a purity of 99.1%.

Figure CN102285920BD00042

CLIP

http://www.rsc.org/suppdata/books/184973/9781849739634/bk9781849739634-chapter%204.2.3.pdf

Edaravone:

IR (KBr) max/cm-1 : 3431, 3129, 1602, 1599, 1580;

1 H NMR (300 MHz, CDCl3): δ 7.86 (d, J = 7.5 Hz, 2H, ArH), 7.40 (m, 2H, ArH), 7.18 (m, 1H, ArH), 3.41 (d, J =0.6 Hz, 2H, CH2), 2.19 (s, 3H, CH3);

13C NMR (75 MHz, CDCl3): 170.6, 156.4, 130.1, 128.8, 125.0, 118.9, 43.1, 17.0;

1 H NMR (300 MHz, DMSO-d6): δ 11.5 (bs, 1H, NH), 7.71 (m, 2H, ArH), 7.40 (m, 2H, ArH), 7.22 (m, 1H, ArH), 5.36 (s, 1H, CH), 2.12 (s, 3H, CH3);

13C NMR (75 MHz, DMSO-d6):171.7, 158.9, 148.7, 139.2, 138.6, 129.3,125.4, 124.8, 118.4, 43.5, 17.1, 14.2.

These values are in accordance with the previous published in literature1 .

In the carbon spectrum in DMSO presented in Figure SM 4.2.3.1.8 is evident the presence of the two major tautomeric structures of edaravone, signals are identified by different colours in both structures in the figure. Also in the IR analysis of the solid material (Figure SM 4.2.3.1.9) is possible to see either the NH form (max/cm-1, 3129), the OH form (max/cm- 1 , 3431) and the C=O (max/cm-1, 1599) of the enol and keto tautomeric forms of edaravone.

1. S. Pal, J. Mareddy and N. S. Devi, J.  Braz. Chem. Soc., 2008, 19, 1207.

CLIP

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532008000600023

We have shown that the short reaction time, in combination with good yields can make microwave assisted reaction of hydrazines with β-ketoesters ideal for a rapid entry to pyrazolones. All the compounds synthesized are characterized by spectroscopic (1H NMR, IR and MS) data. While determination of tautomeric composition of compound 3 is quite challenging as eight possible tautomeric forms need to be considered, interestingly, two major tautomeric forms of compound 3a was observed in two different solvents. For example, it exists as 1,2-dihydro pyrazolone (T-1Figure 2) in DMSO and 2,4-dihydro form (T-2Figure 2) in chloroform as indicated by 1H NMR spectra (Figure 3). The olefinic proton of T-1 appeared at 5.36 δ whereas the methylene hydrogens appeared at 3.43 δ in case of T-2. Additionally, the NH proton of T-1 at 11.40 δ was not observed incase of T-2 confirmed the absence of NH in the 2,4-dihydro form. Existence of two major tautomeric forms was also observed in case compound 3b (see 1H NMR data in the experimental section). However, X-ray study on single crystal of 2-(4-chlorophenyl)-5-methyl-1,2-dihydro pyrazol-3-one (3i) indicates that 2-aryl pyrazol-3-ones e.g. 3a-b3e-f and 3i exist as 1,2-dihydro form in crystal state. 27 It is mention worthy that the aryl ring of all these 2-aryl pyrazol-3-ones remain twisted with respect to the pyrazole plane as indicated by the crystallographic data of 3i [the dihedral angle between the pyrazole and benzene ring planes was found to be 15.81 (11)º].27

 

 

 

5-Methyl-2-phenyl-1,2-dihydro pyrazol-3-one (3a)

mp 125-127 ºC (lit21 126-130 ºC); 

IR (KBr) νmax/cm-1: 3127, 1597, 1525, 1498, 1454;

 1H NMR (400 MHz, DMSO-d6δ 11.40 (bs, 1H), 7.71-7.69 (m, 2H), 7.42-7.38 (m, 2H), 7.21-7.18 (m, 1H), 5.36 (s, 1H), 2.10 (s, 3H); 

13C NMR (50 MHz, DMSO-d6δ 170.6, 156.2, 138.1, 128.8 (2C), 124.9, 118.9 (2C), 43.1, 16.9; 

Mass (CI, m/z) 175 (M+1, 100).

1H NMR (400 MHz, CDCl3)δ 7.85 (d, J 8.3 Hz, 2H), 7.40-7.37 (m, 2H), 7.24-7.18 (m, 1H), 3.43 (s, 2H), 2.20 (s, 3H).

21. Makhija, M. T.; Kasliwal, R. T.; Kulkarni, V. M.; Neamati, N.; Bioorg. Med. Chem. 200412, 2317.         [ Links ]

CN101830852A Mar 22, 2010 Sep 15, 2010 海南美兰史克制药有限公司 Edaravone compound synthesized by new method
CN102060771A Nov 18, 2009 May 18, 2011 南京长澳制药有限公司 Edaravone crystal form and preparation method thereof
CN102180834A Mar 24, 2011 Sep 14, 2011 江苏正大丰海制药有限公司 Preparation method for edaravone

References

  1. ^ Jump up to:a b Doherty, Annette M. (2002). Annual Reports in Medicinal Chemistry, Volume 37 (Annual Reports in Medicinal Chemistry). Boston: Academic Press. ISBN 0-12-040537-7.
  2. Jump up^ Watanabe T, Tanaka M, Watanabe K, Takamatsu Y, Tobe A (March 2004). “[Research and development of the free radical scavenger edaravone as a neuroprotectant]”. Yakugaku Zasshi (in Japanese). 124 (3): 99–111. doi:10.1248/yakushi.124.99. PMID 15049127.
  3. Jump up^ Higashi Y, Jitsuiki D, Chayama K, Yoshizumi M (January 2006). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, for treatment of cardiovascular diseases”. Recent Patents on Cardiovascular Drug Discovery. 1 (1): 85–93. doi:10.2174/157489006775244191. PMID 18221078.
  4. Jump up^ Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N, Tada N (2006). “Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury”. CNS Drug Reviews. 12 (1): 9–20. doi:10.1111/j.1527-3458.2006.00009.x. PMID 16834755.
  5. Jump up^ Yuan WJ, Yasuhara T, Shingo T, et al. (2008). “Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons”. BMC Neuroscience. 9: 75. doi:10.1186/1471-2202-9-75. PMC 2533664Freely accessible. PMID 18671880.
  6. Jump up^ Kawasaki T, Ishihara K, Ago Y, et al. (August 2006). “Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum”. European Journal of Pharmacology. 542 (1-3): 92–9. doi:10.1016/j.ejphar.2006.05.012. PMID 16784740.
  7. Jump up^ Kawasaki T, Ishihara K, Ago Y, Baba A, Matsuda T (July 2007). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger, prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the substantia nigra but not the striatum”. The Journal of Pharmacology and Experimental Therapeutics. 322 (1): 274–81. doi:10.1124/jpet.106.119206. PMID 17429058.
  8. Jump up^ Yokoyama H, Takagi S, Watanabe Y, Kato H, Araki T (June 2008). “Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice”. Journal of Neural Transmission (Vienna, Austria : 1996). 115 (6): 831–42. doi:10.1007/s00702-008-0019-6. PMID 18235988.
  9. Jump up^ Yokoyama H, Yano R, Aoki E, Kato H, Araki T (September 2008). “Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice”. Metabolic Brain Disease. 23 (3): 335–49. doi:10.1007/s11011-008-9096-3. PMID 18648914.

External links

Edaravone
Edaravone.svg
Edaravone ball-and-stick model.png
Clinical data
Trade names Radicut
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • Rx-only (JP)
Identifiers
Synonyms MCI-186
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.001.719
Chemical and physical data
Formula C10H10N2O
Molar mass 174.20 g/mol
3D model (Jmol)
////////// Radicava, edaravone, fda 2017, Lou Gehrig’s disease, amyotrophic lateral sclerosis,  Mitsubishi Tanabe, orphan drug designation89-25-8, эдаравон, إيدارافون , 依达拉奉 ,ラジカット,
O=C1CC(=NN1c1ccccc1)C

FDA approves new combination treatment for acute myeloid leukemia, Rydapt (midostaurin)


MIDOSTAURIN

04/28/2017
The U.S. Food and Drug Administration today approved Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3, in combination with chemotherapy. The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

April 28, 2017

Release

The U.S. Food and Drug Administration today approved Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3, in combination with chemotherapy. The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of white blood cells in the bloodstream. The National Cancer Institute estimated that approximately 19,930 people would be diagnosed with AML in 2016 and 10,430 were projected to die of the disease.

“Rydapt is the first targeted therapy to treat patients with AML, in combination with chemotherapy,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “The ability to detect the gene mutation with a diagnostic test means doctors can identify specific patients who may benefit from this treatment.”

Rydapt is a kinase inhibitor that works by blocking several enzymes that promote cell growth. If the FLT3 mutation is detected in blood or bone marrow samples using the LeukoStrat CDx FLT3 Mutation Assay, the patient may be eligible for treatment with Rydapt in combination with chemotherapy.

The safety and efficacy of Rydapt for patients with AML were studied in a randomized trial of 717 patients who had not been treated previously for AML. In the trial, patients who received Rydapt in combination with chemotherapy lived longer than patients who received chemotherapy alone, although a specific median survival rate could not be reliably estimated. In addition, patients who received Rydapt in combination with chemotherapy in the trial went longer (median 8.2 months) without certain complications (failure to achieve complete remission within 60 days of starting treatment, progression of leukemia or death) than patients who received chemotherapy alone (median three months).

Common side effects of Rydapt in patients with AML include low levels of white blood cells with fever (febrile neutropenia), nausea, inflammation of the mucous membranes (mucositis), vomiting, headache, spots on the skin due to bleeding (petechiae), musculoskeletal pain, nosebleeds (epistaxis), device-related infection, high blood sugar (hyperglycemia) and upper respiratory tract infection. Rydapt should not be used in patients with hypersensitivity to midostaurin or other ingredients in Rydapt. Women who are pregnant or breastfeeding should not take Rydapt because it may cause harm to a developing fetus or a newborn baby. Patients who experience signs or symptoms of lung damage (pulmonary toxicity) should stop using Rydapt.

Rydapt was also approved today for adults with certain types of rare blood disorders (aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm or mast cell leukemia). Common side effects of Rydapt in these patients include nausea, vomiting, diarrhea, swelling (edema), musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, fever, headache and shortness of breath.

The FDA granted this application Priority Review, Fast Track (for the mastocytosis indication) and Breakthrough Therapy (for the AML indication) designations.

The FDA granted the approval of Rydapt to Novartis Pharmaceuticals Corporation. The FDA granted the approval of the LeukoStrat CDx FLT3 Mutation Assay to Invivoscribe Technologies Inc.

MIDOSTAURIN

(9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiamzonine-1-one

N-[(9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methylbenzamide

N-((9S,10R,11R,13R)-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo(1,2,3-gh:3′,2′,1′-lm)pyrrolo(3,4-j)(1,7)benzodiazonin-11-yl)-N-methyl-,

N-[(2R,4R,5R,6S)-5-methoxy-6-methyl-18-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14(28),15(19),20(27),21(26),22,24-nonaen-4-yl]-N-methylbenzamide hydrate

N-benzoyl staurosporine

NOVARTIS ONCOLOGY ORIGINATOR

Chemical Formula: C35H30N4O4

Exact Mass: 570.22671

Molecular Weight: 570.63710

Elemental Analysis: C, 73.67; H, 5.30; N, 9.82; O, 11.22

Tyrosine kinase inhibitors

PKC 412。PKC412A。CGP 41251。Benzoylstaurosporine;4′-N-Benzoylstaurosporine;Cgp 41251;Cgp 41 251.

120685-11-2 CAS

PHASE 3

  • 4′-N-Benzoylstaurosporine
  • Benzoylstaurosporine
  • Cgp 41 251
  • CGP 41251
  • CGP-41251
  • Midostaurin
  • PKC 412
  • PKC412
  • UNII-ID912S5VON

Midostaurin is an inhibitor of tyrosine kinase, protein kinase C, and VEGF. Midostaurin inhibits cell growth and phosphorylation of FLT3, STAT5, and ERK. It is a potent inhibitor of a spectrum of FLT3 activation loop mutations.

it  is prepared by acylation of the alkaloid staurosporine (I) with benzoyl chloride (II) in the presence of diisopropylethylamine in chloroform.Production Route of Midostaurin

Midostaurin is a synthetic indolocarbazole multikinase inhibitor with potential antiangiogenic and antineoplastic activities. Midostaurin inhibits protein kinase C alpha (PKCalpha), vascular endothelial growth factor receptor 2 (VEGFR2), c-kit, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) tyrosine kinases, which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors.

MIDOSTAURIN

Derivative of staurosporin, orally active, potent inhibitor of FLT3 tyrosine kinase (fetal liver tyrosine kinase 3). In addition Midostaurin inhibits further molecular targets such as VEGFR-1 (Vascular Endothelial Growth Factor Receptor 1), c-kit (stem cell factor receptor), H-and K-RAS (Rat Sarcoma Viral homologue) and MDR (multidrug resistance protein).

Midostaurin inhibits both wild-type FLT3 and FLT3 mutant, wherein the internal tandem duplication mutations (FLT3-ITD), and the point mutation to be inhibited in the tyrosine kinase domain of the molecule at positions 835 and 836.Midostaurin is tested in patients with AML.

Midostaurin, a protein kinase C (PKC) and Flt3 (FLK2/STK1) inhibitor, is in phase III clinical development at originator Novartis for the oral treatment of acute myeloid leukemia (AML).

Novartis is conducting phase III clinical trials for the treatment of aggressive systemic mastocytosis or mast cell leukemia. The National Cancer Institute (NCI) is conducting phase I/II trials with the drug for the treatment of chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS).

Massachusetts General Hospital is conducting phase I clinical trials for the treatment of adenocarcinoma of the rectum in combination with radiation and standard chemotherapy.

MIDOSTAURIN

Midostaurin (PKC412) is a multi-target protein kinase inhibitor being investigated for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus, and is active in patients with mutations of CD135 (FMS-like tyrosine kinase 3 receptor).[1]

After successful Phase II clinical trials, a Phase III trial for AML has started in 2008. It is testing midostaurin in combination with daunorubicin and cytarabine.[2] In another trial, the substance has proven ineffective in metastatic melanoma.[3]

Midostaurin has also been studied at Johns Hopkins University for the treatment of age-related macular degeneration (AMD), but no recent progress reports for this indication have been made available. Trials in macular edema of diabetic origin were discontinued at Novartis.

In 2004, orphan drug designation was received in the E.U. for the treatment of AML. In 2009 and 2010, orphan drug designation was assigned for the treatment of acute myeloid leukemia and for the treatment of mastocytosis, respectively, in the U.S. In 2010, orphan drug designation was assigned in the E.U. for the latter indication.

MIDOSTAURIN

References

  1.  Fischer, T.; Stone, R. M.; Deangelo, D. J.; Galinsky, I.; Estey, E.; Lanza, C.; Fox, E.; Ehninger, G.; Feldman, E. J.; Schiller, G. J.; Klimek, V. M.; Nimer, S. D.; Gilliland, D. G.; Dutreix, C.; Huntsman-Labed, A.; Virkus, J.; Giles, F. J. (2010). “Phase IIB Trial of Oral Midostaurin (PKC412), the FMS-Like Tyrosine Kinase 3 Receptor (FLT3) and Multi-Targeted Kinase Inhibitor, in Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome with Either Wild-Type or Mutated FLT3”. Journal of Clinical Oncology 28 (28): 4339–4345. doi:10.1200/JCO.2010.28.9678PMID 20733134edit
  2.  ClinicalTrials.gov NCT00651261 Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
  3.  Millward, M. J.; House, C.; Bowtell, D.; Webster, L.; Olver, I. N.; Gore, M.; Copeman, M.; Lynch, K.; Yap, A.; Wang, Y.; Cohen, P. S.; Zalcberg, J. (2006). “The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study”British Journal of Cancer 95 (7): 829–834. doi:10.1038/sj.bjc.6603331PMC 2360547PMID 16969355.
    1. Midostaurin product page, Fermentek
    2.  Wang, Y; Yin, OQ; Graf, P; Kisicki, JC; Schran, H (2008). “Dose- and Time-Dependent Pharmacokinetics of Midostaurin in Patients With Diabetes Mellitus”. J Clin Pharmacol 48 (6): 763–775. doi:10.1177/0091270008318006PMID 18508951.
    3.  Ryan KS (2008). “Structural studies of rebeccamycin, staurosporine, and violacein biosynthetic enzymes”Ph.D. Thesis. Massachusetts Institute of Technology.

Bioorg Med Chem Lett 1994, 4(3): 399

US 5093330

EP 0657164

EP 0711556

EP 0733358

WO 1998007415

WO 2002076432

WO 2003024420

WO 2003037347

WO 2004112794

WO 2005027910

WO 2005040415

WO 2006024494

WO 2006048296

WO 2006061199

WO 2007017497

WO 2013086133

WO 2012016050

WO 2011000811

8-1-2013
Identification of potent Yes1 kinase inhibitors using a library screening approach.
Bioorganic & medicinal chemistry letters
 
3-1-2013
Evaluation of potential Myt1 kinase inhibitors by TR-FRET based binding assay.
European journal of medicinal chemistry
2-23-2012
Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen.
Journal of medicinal chemistry
 
1-26-2012
VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia.
Journal of medicinal chemistry
1-1-2012
H2O2 production downstream of FLT3 is mediated by p22phox in the endoplasmic reticulum and is required for STAT5 signalling.
PloS one
10-27-2011
Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.
Journal of medicinal chemistry
 
6-1-2011
Discovery, synthesis, and investigation of the antitumor activity of novel piperazinylpyrimidine derivatives.
European journal of medicinal chemistry
3-1-2010
Colony stimulating factor-1 receptor as a target for small molecule inhibitors.
Bioorganic & medicinal chemistry
7-18-2012
Staurosporine Derivatives as Inhibitors of FLT3 Receptor Tyrosine Kinase Activity
6-13-2012
Crystal form of N-benzoyl-staurosporine
12-14-2011
COMPOSITIONS FOR TREATMENT OF SYSTEMIC MASTOCYTOSIS
7-6-2011
Staurosporine derivatives as inhibitors of flt3 receptor tyrosine kinase activity
7-6-2011
Staurosporine Derivatives for Use in Alveolar Rhabdomyosarcoma
12-10-2010
Pharmaceutical Compositions for treating wouds and related methods
11-5-2010
COMBINATIONS OF JAK INHIBITORS
7-23-2010
COMBINATIONS COMPRISING STAUROSPORINES
3-5-2010
COMBINATION OF IAP INHIBITORS AND FLT3 INHIBITORS
1-29-2010
ANTI-CANCER PHOSPHONATE ANALOGS
1-13-2010
Therapeutic phosphonate compounds
11-20-2009
Use of Staurosporine Derivatives for the Treatment of Multiple Myeloma
7-17-2009
KINASE INHIBITORY PHOSPHONATE ANALOGS
6-19-2009
Organic Compounds
3-20-2009
Use of Midostaurin for Treating Gastrointestinal Stromal Tumors
11-21-2008
PHARMACEUTICAL COMPOSITIONS COMPRISING A POORLY WATER-SOLUBLE ACTIVE INGREDIENT, A SURFACTANT AND A WATER-SOLUBLE POLYMER
11-19-2008
Anti-cancer phosphonate analogs
9-12-2008
Multi-Functional Small Molecules as Anti-Proliferative Agents
9-5-2008
Sensitization of Drug-Resistant Lung Caners to Protein Kinase Inhibitors
8-29-2008
Organic Compounds
8-27-2008
Kinase inhibitory phosphonate analogs
4-25-2008
Treatment Of Gastrointestinal Stromal Tumors With Imatinib And Midostaurin
12-28-2007
Pharmaceutical Uses of Staurosporine Derivatives
12-7-2007
Kinase Inhibitor Phosphonate Conjugates
8-17-2007
Combinations comprising staurosporines
10-13-2006
Staurosporine derivatives for hypereosinophilic syndrome
7-15-2005
Phosphonate substituted kinase inhibitors
10-20-2004
Staurosporin derivatives

MIDOSTAURIN HYDRATE

Midostaurin according to the invention is N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methylbenzamide of the formula (II):

Figure US20090075972A1-20090319-C00002

or a salt thereof, hereinafter: “Compound of formula II or midostaurin”.

Compound of formula II or midostaurin [International Nonproprietary Name] is also known as PKC412.

Midostaurin is a derivative of the naturally occurring alkaloid staurosporine, and has been specifically described in the European patent No. 0 296 110 published on Dec. 21, 1988, as well as in U.S. Pat. No.  5093330 published on Mar. 3, 1992, and Japanese Patent No. 2 708 047.

………………….

https://www.google.co.in/patents/EP0296110B1

The nomenclature of the products is, on the complete structure of staurosporine ([storage]-NH-CH ₃derived, and which is designated by N-substituent on the nitrogen of the methylamino group

Figure imgb0028

Example 18:

     N-Benzoyl-staurospor

  • A solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N, N-diisopropylethylamine in 2 ml of chloroform is added at room temperature with 0.035 ml (0.3 mmol) of benzoyl chloride and 10 stirred minutes.The reaction mixture is diluted with chloroform, washed with sodium bicarbonate, dried over magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent methylene chloride / ethanol 30:1), mp 235-247 ° with brown coloration.
  • cut paste may not be ok below

Staurosporine the formula [storage]-NH-CH ₃ (II) (for the meaning of the rest of [storage] see above) as the basic material of the novel compounds was already in 1977, from the cultures of Streptomyces staurosporeus AWAYA, and TAKAHASHI

O ¯

Figure imgb0003

MURA, sp. nov. AM 2282, see Omura, S., Iwai, Y., Hirano, A., Nakagawa, A.; awayâ, J., Tsuchiya, H., Takahashi, Y., and Masuma, R. J. Antibiot. 30, 275-281 (1977) isolated and tested for antimicrobial activity. It was also found here that the compound against yeast-like fungi and microorganisms is effective (MIC of about 3-25 mcg / ml), taking as the hydrochloride = having a LD ₅ ₀ 6.6 mg / kg (mouse, intraperitoneal). Stagnated recently it has been shown in extensive screening, see Tamaoki, T., Nomoto, H., Takahashi, I., Kato, Y, Morimoto, M. and Tomita, F.: Biochem. and Biophys. Research Commun. 135 (No. 2), 397-402 (1986) that the compound exerts a potent inhibitory effect on protein kinase C (rat brain)

…………………

https://www.google.co.in/patents/US5093330

EXAMPLE 18 N-benzoyl-staurosporine

0.035 ml (0.3 mmol) of benzoyl chloride is added at room temperature to a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N,N-diisopropylethylamine in 2 ml of chloroform and the whole is stirred for 10 minutes. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed on silica gel (eluant:methylene chloride/ethanol 30:1); m.p. 235

…………………….

Bioorg Med Chem Lett 1994, 4(3): 399

http://www.sciencedirect.com/science/article/pii/0960894X94800049

Full-size image (2 K)

……………………

http://www.google.com/patents/WO1998007415A2

A variety of PKC inhibitors are available in the art for use in the invention. These include bryostatin (U.S. Patent 4,560,774), safinogel (WO 9617603), fasudil (EP 187371), 7- hydoxystaurosporin (EP 137632B), various diones described in EP 657458, EP 657411 and WO9535294, phenylmethyl hexanamides as described in WO9517888, various indane containing benzamides as described in WO9530640, various pyrrolo [3,4-c]carbazoles as described in EP 695755, LY 333531 (IMSworld R & D Focus 960722, July 22, 1996 and Pharmaprojects Accession No. 24174), SPC-104065 (Pharmaprojects Accession No. 22568), P-10050 (Pharmaprojects Accession No. 22643), No. 4432 (Pharmaprojects Accession No. 23031), No. 4503 (Pharmaprojects Accession No. 23252), No. 4721 (Pharmaprojects Accession No. 23890), No. 4755 (Pharmaprojects Accession No. 24035), balanol (Pharmaprojects Accession No. 20376), K-7259 (Pharmaprojects Accession No. 16649), Protein kinase C inhib, Lilly (Pharmaprojects Accession No. 18006), and UCN-01 (Pharmaprojects Accession No. 11915). Also see, for example, Tamaoki and Nakano (1990) Biotechnology 8:732-735; Posada et al. (1989) Cancer Commun. 1:285-292; Sato et al. (1990) Biochem Biophys. Res. Commun. 173:1252-1257; Utz et al. (1994) Int. J. Cancer 57:104-110; Schwartz et al. (1993) J. Na . Cancer lnst. 85:402-407; Meyer et al. (1989) Int. J. Cancer 43:851-856; Akinaga et al. (1991) Cancer Res. 51:4888-4892, which disclosures are herein incorporated by reference. Additionally, antisense molecules can be used as PKC inhibitors. Although such antisense molecules inhibit mRNA translation into the PKC protein, such antisense molecules are considered PKC inhibitors for purposes of this invention. Such antisense molecules against PKC inhibitors include those described in published PCT patent applications WO 93/19203, WO 95/03833 and WO 95/02069, herein incorporated by reference. Such inhibitors can be used in formulations for local delivery to prevent cellular proliferation. Such inhibitors find particular use in local delivery for preventing rumor growth and restenosis.

N-benzoyl staurosporine is a benzoyl derivative of the naturally occurring alkaloid staurosporine. It is chiral compound ([a]D=+148.0+-2.0°) with the formula C35H30R1O4 (molecular weight 570.65). It is a pale yellow amorphous powder which remains unchanged up to 220°C. The compound is very lipophilic (log P>5.48) and almost insoluble in water (0.068 mg/1) but dissolves readily in DMSO.

……………………….

staurosporine

Staurosporine (antibiotic AM-2282 or STS) is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus. It was the first of over 50 alkaloids to be isolated with this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray analysis of a single crystal and the absolute stereochemical configuration by the same method in 1994.

Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive. The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment

Synthesis of Staurosporine

Staurosporine is the precursor of the novel protein kinase inhibitor midostaurin(PKC412). Besides midostaurin, staurosporine is also used as a starting material in the commercial synthesis of K252c (also called staurosporine aglycone). In the natural biosynthetic pathway, K252c is a precursor of staurosporine.

Indolocarbazoles belong to the alkaloid sub-class of bisindoles. Of these carbazoles the Indolo(2,3-a)carbazoles are the most frequently isolated; the most common subgroup of the Indolo(2,3-a)carbazoles are the Indolo(2,3-a)pyrrole(3,4-c)carbazoles which can be divided into two major classes – halogenated (chlorinated) with a fully oxidized C-7 carbon with only one indole nitrogen containing a β-glycosidic bond and the second class consists of both indole nitrogen glycosilated, non-halogenated, and a fully reduced C-7 carbon. Staurosporine is part of the second non-halogenated class.

The biosynthesis of staurosporine starts with the amino acid L-tryptophan in its zwitterionic form. Tryptophan is converted to an imineby enzyme StaO which is an L-amino acid oxidase (that may be FAD dependent). The imine is acted upon by StaD to form an uncharacterized intermediate proposed to be the dimerization product between 2 imine molecules. Chromopyrrolic acid is the molecule formed from this intermediate after the loss of VioE (used in the biosynthesis of violacein – a natural product formed from a branch point in this pathway that also diverges to form rebeccamycin. An aryl aryl coupling thought to be catalyzed by a cytochrome P450enzyme to form an aromatic ring system occurs

Staurosporine 2

This is followed by a nucleophilic attack between the indole nitrogens resulting in cyclization and then decarboxylation assisted by StaC exclusively forming staurosporine aglycone or K252c. Glucose is transformed to NTP-L-ristoamine by StaA/B/E/J/I/K which is then added on to the staurosporine aglycone at 1 indole N by StaG. The StaN enzyme reorients the sugar by attaching it to the 2nd indole nitrogen into an unfavored conformation to form intermediated O-demethyl-N-demethyl-staurosporine. Lastly, O-methylation of the 4’amine by StaMA and N-methylation of the 3′-hydroxy by StaMB leads to the formation of staurosporine

US4107297 * 28 Nov 1977 15 Aug 1978 The Kitasato Institute Antibiotic compound
US4735939 * 27 Feb 1987 5 Apr 1988 The Dow Chemical Company Insecticidal activity of staurosporine
ZA884238A * Title not available
////////FDA 2017, acute myeloid leukemia, Rydapt, midostaurin, Novartis Pharmaceuticals Corporation, LeukoStrat CDx FLT3 Mutation Assay,  Invivoscribe Technologies Inc, Priority Review, Fast Track, (for the mastocytosis indication, Breakthrough Therapy

FDA approves first treatment for a form of Batten disease, Brineura (cerliponase alfa)


Image result
04/27/2017
The U.S. Food and Drug Administration today approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.

The U.S. Food and Drug Administration today approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.

“The FDA is committed to approving new and innovative therapies for patients with rare diseases, particularly where there are no approved treatment options,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Approving the first drug for the treatment of this form of Batten disease is an important advance for patients suffering with this condition.”

CLN2 disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), collectively referred to as Batten disease. CLN2 disease is a rare inherited disorder that primarily affects the nervous system. In the late infantile form of the disease, signs and symptoms typically begin between ages 2 and 4. The initial symptoms usually include language delay, recurrent seizures (epilepsy) and difficulty coordinating movements (ataxia). Affected children also develop muscle twitches (myoclonus) and vision loss. CLN2 disease affects essential motor skills, such as sitting and walking. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. Batten disease is relatively rare, occurring in an estimated two to four of every 100,000 live births in the United States.

Brineura is an enzyme replacement therapy. Its active ingredient (cerliponase alfa) is a recombinant form of human TPP1, the enzyme deficient in patients with CLN2 disease. Brineura is administered into the cerebrospinal fluid (CSF) by infusion via a specific surgically implanted reservoir and catheter in the head (intraventricular access device). Brineura must be administered under sterile conditions to reduce the risk of infections, and treatment should be managed by a health care professional knowledgeable in intraventricular administration. The recommended dose of Brineura in pediatric patients 3 years of age and older is 300 mg administered once every other week by intraventricular infusion, followed by an infusion of electrolytes. The complete Brineura infusion, including the required infusion of intraventricular electrolytes, lasts approximately 4.5 hours. Pre-treatment of patients with antihistamines with or without antipyretics (drugs for prevention or treatment of fever) or corticosteroids is recommended 30 to 60 minutes prior to the start of the infusion.

The efficacy of Brineura was established in a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients with CLN2 disease and compared to 42 untreated patients with CLN2 disease from a natural history cohort (an independent historical control group) who were at least 3 years old and had motor or language symptoms. Taking into account age, baseline walking ability and genotype, Brineura-treated patients demonstrated fewer declines in walking ability compared to untreated patients in the natural history cohort.

The safety of Brineura was evaluated in 24 patients with CLN2 disease aged 3 to 8 years who received at least one dose of Brineura in clinical studies. The safety and effectiveness of Brineura have not been established in patients less than 3 years of age.

The most common adverse reactions in patients treated with Brineura include fever, ECG abnormalities including slow heart rate (bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma (abnormal collection of blood outside of a blood vessel), headache, irritability, increased CSF white blood cell count (pleocytosis), device-related infection, feeling jittery and low blood pressure.

Brineura should not be administered to patients if there are signs of acute intraventricular access device-related complications (e.g., leakage, device failure or signs of device-related infection such as swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device). In case of intraventricular access device complications, health care providers should discontinue infusion of Brineura and refer to the device manufacturer’s labeling for further instructions. Additionally, health care providers should routinely test patient CSF samples to detect device infections. Brineura should also not be used in patients with ventriculoperitoneal shunts (medical devices that relieve pressure on the brain caused by fluid accumulation).

Health care providers should also monitor vital signs (blood pressure, heart rate, etc.) before the infusion starts, periodically during infusion and post-infusion in a health care setting. Health care providers should perform electrocardiogram (ECG) monitoring during infusion in patients with a history of slow heart rate (bradycardia), conduction disorder (impaired progression of electrical impulses through the heart) or structural heart disease (defect or abnormality of the heart), as some patients with CLN2 disease can develop conduction disorders or heart disease. Hypersensitivity reactions have also been reported in Brineura-treated patients. Due to the potential for anaphylaxis, appropriate medical support should be readily available when Brineura is administered. If anaphylaxis occurs, infusion should be immediately discontinued and appropriate treatment should be initiated.

The FDA will require the Brineura manufacturer to further evaluate the safety of Brineura in CLN2 patients below the age of 2 years, including device related adverse events and complications with routine use. In addition, a long-term safety study will assess Brineura treated CLN2 patients for a minimum of 10 years.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Brineura also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is also receiving a Rare Pediatric Disease Priority Review Voucherunder a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the tenth rare pediatric disease priority review voucher issued by the FDA since the program began.

The FDA granted approval of Brineura to BioMarin Pharmaceutical Inc.

////////Brineura, cerliponase alfa, fda 2017, Batten disease, BioMarin Pharmaceutical Inc, Priority Review,  Breakthrough Therapy designations, Orphan Drug designation,

FDA approves new drug to treat multiple sclerosis Ocrevus (ocrelizumab)


03/29/2017
On March 28, the U.S. Food and Drug Administration approved Ocrevus (ocrelizumab) to treat adult patients with relapsing forms of multiple sclerosis (MS) and primary progressive multiple sclerosis (PPMS). This is the first drug approved by the FDA for PPMS. Ocrevus is an intravenous infusion given by a health care professional.

On March 28, the U.S. Food and Drug Administration approved Ocrevus (ocrelizumab) to treat adult patients with relapsing forms of multiple sclerosis (MS) and primary progressive multiple sclerosis (PPMS). This is the first drug approved by the FDA for PPMS. Ocrevus is an intravenous infusion given by a health care professional.

“Multiple sclerosis can have a profound impact on a person’s life,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This therapy not only provides another treatment option for those with relapsing MS, but for the first time provides an approved therapy for those with primary progressive MS.”

MS is a chronic, inflammatory, autoimmune disease of the central nervous system that disrupts communication between the brain and other parts of the body. It is among the most common causes of neurological disability in young adults and occurs more frequently in women than men. For most people with MS, episodes of worsening function (relapses) are initially followed by recovery periods (remissions). Over time, recovery may be incomplete, leading to progressive decline in function and increased disability. Most people experience their first symptoms of MS between the ages of 20 and 40.

PPMS is characterized by steadily worsening function from the onset of symptoms, often without early relapses or remissions. The U.S. Centers for Disease Control and Prevention estimates that approximately 15 percent of patients with MS have PPMS.

The efficacy of Ocrevus for the treatment of relapsing forms of MS was shown in two clinical trials in 1,656 participants treated for 96 weeks. Both studies compared Ocrevus to another MS drug, Rebif (interferon beta-1a). In both studies, the patients receiving Ocrevus had reduced relapse rates and reduced worsening of disability compared to Rebif.

In a study of PPMS in 732 participants treated for at least 120 weeks, those receiving Ocrevus showed a longer time to the worsening of disability compared to placebo.

Ocrevus should not be used in patients with hepatitis B infection or a history of life-threatening infusion-related reactions to Ocrevus. Ocrevus must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Ocrevus can cause infusion-related reactions, which can be serious. These reactions include, but are not limited to, itchy skin, rash, hives, skin redness, flushing, low blood pressure, fever, tiredness, dizziness, headache, throat irritation, shortness of breath, swelling of the throat, nausea, and fast heartbeat. Additionally, Ocrevus may increase the risk for malignancies, particularly breast cancer. Delay Ocrevus treatment for patients with active infections. Vaccination with live or live attenuated vaccines is not recommended in patients receiving Ocrevus.

In addition to the infusion-related reactions, the most common side effect of Ocrevus seen in the clinical trials for relapsing forms of MS was upper respiratory tract infection. The most common side effects in the study of PPMS were upper respiratory tract infection, skin infection, and lower respiratory tract infection.

The FDA granted this application breakthrough therapy designation, fast track designation, and priority review.

The FDA granted approval of Ocrevus to Genentech, Inc.

//////multiple sclerosis, Ocrevus, ocrelizumab, fda 2017, genentech,

FDA approves new eczema drug Dupixent (dupilumab)


03/28/2017 11:14
The U.S. Food and Drug Administration today approved Dupixent (dupilumab) injection to treat adults with moderate-to-severe eczema (atopic dermatitis). Dupixent is intended for patients whose eczema is not controlled adequately by topical therapies, or those for whom topical therapies are not advisable. Dupixent can be used with or without topical corticosteroids.

The U.S. Food and Drug Administration today approved Dupixent (dupilumab) injection to treat adults with moderate-to-severe eczema (atopic dermatitis). Dupixent is intended for patients whose eczema is not controlled adequately by topical therapies, or those for whom topical therapies are not advisable. Dupixent can be used with or without topical corticosteroids.

“FDA’s approval of Dupixent demonstrates our commitment to approving new and innovative therapies for patients with skin disease,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Eczema can cause significant skin irritation and discomfort for patients, so it is important to have a variety of treatment options available to patients, including those patients whose disease is not controlled by topical therapies.”

Atopic dermatitis, a chronic inflammatory skin disease, is often referred to as “eczema,” which is a general term for several types of inflammation of the skin. Atopic dermatitis is the most common of the many types of eczema; onset typically begins in childhood and can last through adulthood. The cause of atopic dermatitis is a combination of genetic, immune and environmental factors. In atopic dermatitis, the skin develops red, scaly and crusted bumps, which are extremely itchy. Scratching leads to swelling, cracking, “weeping” clear fluid, and finally, coarsening and thickening of the skin.

Dupixent is administered as an injection under the skin. Dupixent’s active ingredient is an antibody (dupilumab) that binds to a protein [interleukin-4 (IL-4) receptor alpha subunit (IL-4Ra)], that causes inflammation. By binding to this protein, Dupixent is able to inhibit the inflammatory response that plays a role in the development of atopic dermatitis.

The safety and efficacy of Dupixent were established in three placebo-controlled clinical trials with a total of 2,119 adult participants with moderate-to-severe atopic dermatitis not adequately controlled by topical medication(s). Overall, participants who received Dupixent achieved greater response, defined as clear or almost clear skin, and experienced a reduction in itch after 16 weeks of treatment.

Dupixent can cause side effects such as serious allergic reactions and eye problems, such as pink eye (conjunctivitis) and inflammation of the cornea (keratitis). If patients experience new or worsening eye symptoms such as redness, itching, pain or visual changes, they should consult a health care provider. The most common side effects include injection site reactions; cold sores in the mouth or on the lips; and eye and eyelid inflammation, including redness, swelling and itching.

The safety and efficacy of Dupixent have not been established in the treatment of asthma. Patients who also have asthma should not adjust or stop their asthma treatment without talking to their physicians.

The FDA granted the application for Dupixent Priority Review and Breakthrough Therapy designation.

The FDA granted the approval of Dupixent to Regeneron Pharmaceuticals, Inc.

FDA approves first treatment Bavencio (avelumab)for rare form of skin cancer


 Image result for avelumab
str1
03/23/2017
The U.S. Food and Drug Administration today granted accelerated approval to Bavencio (avelumab) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC), including those who have not received prior chemotherapy. This is the first FDA-approved treatment for metastatic MCC, a rare, aggressive form of skin cancer.

March 23, 2017

Release

The U.S. Food and Drug Administration today granted accelerated approval to Bavencio (avelumab) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC), including those who have not received prior chemotherapy. This is the first FDA-approved treatment for metastatic MCC, a rare, aggressive form of skin cancer.

“While skin cancer is one of the most common cancers, patients with a rare form called Merkel cell cancer have not had an approved treatment option until now,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “The scientific community continues to make advances targeting the body’s immune system mechanisms for the treatment of various types of cancer. These advancements are leading to new therapies—even in rare forms of cancer where treatment options are limited or non-existent.”

According to the National Cancer Institute, approximately 1,600 people in the United States are diagnosed with MCC every year. While the majority of patients present with localized tumors that can be treated with surgical resection, approximately half of all patients will experience recurrence, and more than 30 percent will eventually develop metastatic disease. In patients with metastatic MCC, the cancer has spread beyond the skin into other parts of the body.

Bavencio targets the PD-1/PD-L1 pathway (proteins found on the body’s immune cells and some cancer cells). By blocking these interactions, Bavencio may help the body’s immune system attack cancer cells.

Bavencio received an Accelerated Approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need using clinical trial data that is thought to predict a clinical benefit to patients. Further clinical trials are required to confirm Bavencio’s clinical benefit and the sponsor is currently conducting these studies.

Today’s approval of Bavencio was based on data from a single-arm trial of 88 patients with metastatic MCC who had been previously treated with at least one prior chemotherapy regimen. The trial measured the percentage of patients who experienced complete or partial shrinkage of their tumors (overall response rate) and, for patients with a response, the length of time the tumor was controlled (duration of response). Of the 88 patients who received Bavencio in the trial, 33 percent experienced complete or partial shrinkage of their tumors. The response lasted for more than six months in 86 percent of responding patients and more than 12 months in 45 percent of responding patients.

Common side effects of Bavencio include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reactions, rash, decreased appetite and swelling of the limbs (peripheral edema). The most common serious risks of Bavencio are immune-mediated, where the body’s immune system attacks healthy cells or organs, such as the lungs (pneumonitis), liver (hepatitis), colon (colitis), hormone-producing glands (endocrinopathies) and kidneys (nephritis). In addition, there is a risk of serious infusion-related reactions. Patients who experience severe or life-threatening infusion-related reactions should stop using Bavencio. Women who are pregnant or breastfeeding should not take Bavencio because it may cause harm to a developing fetus or a newborn baby.

The FDA granted this application Priority Review and Breakthrough Therapydesignation. Bavencio also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted accelerated approval of Bavencio to EMD Serono Inc.

Image result for avelumab

Image result for avelumab

Avelumab
Monoclonal antibody
Type ?
Source Human
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG

Avelumab (MSB0010718C) is a fully human monoclonal PD-L1 antibody of isotype IgG1, currently in development by Merck KGaA, Darmstadt, Germany & Pfizer for use in immunotherapy, especially for treatment of Non-small-cell lung carcinoma (NSCLC) .[1]

Mechanism of action

Avelumab binds to the PD ligand 1 and therefore inhibits binding to its receptor programmed cell death 1 (PD-1). Formation of a PD-1/PD-L1 receptor/ligand complex leads to inhibition of CD8+ T cells, and therefore inhibition of an immune reaction. Immunotherapy aims at ceasing this immune blockage by blocking those receptor ligand pairs. In the case of avelumab, the formation of PD-1/PDL1 ligand pairs is blocked and CD8+ T cell immune response should be increased. PD-1 itself has also been a target for immunotherapy.[2] Therefore, avelumab belongs to the group of Immune checkpoint blockade cancer therapies.

Clinical trials

As of May 2015, according to Merck KGaA, Darmstadt, Germany & Pfizer, avelumab has been in Phase I clinical trials for bladder cancer, gastric cancer, head and neck cancer, mesothelioma, NSCLC, ovarian cancer and renal cancer. For Merkel-cell carcinoma, Phase II has been reached and for NSCLC there is also a study already in Phase III.[1]

Merkel-cell carcinoma

On March 23, 2017, the U.S. Food and Drug Administration granted accelerated approval to avelumab (BAVENCIO, EMD Serono, Inc.) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC).

Approval was based on data from an open-label, single-arm, multi-center clinical trial (JAVELIN Merkel 200 trial) demonstrating a clinically meaningful and durable overall response rate (ORR). All patients had histologically confirmed metastatic MCC with disease progression on or after chemotherapy administered for metastatic disease.

ORR was assessed by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The ORR was 33% (95% confidence interval [CI]: 23.3, 43.8), with 11% complete and 22% partial response rates. Among the 29 responding patients, the response duration ranged from 2.8 to 23.3+ months with 86% of responses durable for 6 months or longer. Responses were observed in patients regardless of PD-L1 tumor expression or presence of Merkel cell polyomavirus.

Safety data were evaluated in 1738 patients who received avelumab, 10 mg/kg, every 2 weeks. The most common serious adverse reactions to avelumab are immune-mediated adverse reactions (pneumonitis, hepatitis, colitis, adrenal insufficiency, hypo- and hyperthyroidism, diabetes mellitus, and nephritis) and life-threatening infusion reactions. Among the 88 patients enrolled in the JAVELIN Merkel 200 trial, the most common adverse reactions were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema. Serious adverse reactions that occurred in more than one patient in the trial were acute kidney injury, anemia, abdominal pain, ileus, asthenia, and cellulitis.

The recommended dose and schedule of avelumab is 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks. All patients should receive premedication with an antihistamine and acetaminophen prior to the first four infusions of avelumab.

Full prescribing information for avelumab is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf

References

  1. ^ Jump up to:a b Merck-Pfizer Alliance. “Merck-Pfizer Alliance Avelumab Fact Sheet” (PDF). Retrieved 2 December 2015.
  2. Jump up^ Hamid, O; Robert, C; Daud, A; Hodi, F. S.; Hwu, W. J.; Kefford, R; Wolchok, J. D.; Hersey, P; Joseph, R. W.; Weber, J. S.; Dronca, R; Gangadhar, T. C.; Patnaik, A; Zarour, H; Joshua, A. M.; Gergich, K; Elassaiss-Schaap, J; Algazi, A; Mateus, C; Boasberg, P; Tumeh, P. C.; Chmielowski, B; Ebbinghaus, S. W.; Li, X. N.; Kang, S. P.; Ribas, A (2013). “Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma”. New England Journal of Medicine. 369 (2): 134–44. doi:10.1056/NEJMoa1305133. PMC 4126516Freely accessible. PMID 23724846.

//////////fda 2017, Bavencio, avelumab, EMD Serono Inc., Priority Review,  Breakthrough Therapy designation.  Orphan Drug designation, skin cancer

FDA approves drug Xadago (Safinamide, сафинамид , سافيناميد , 沙非胺 , ) to treat Parkinson’s disease


ChemSpider 2D Image | Safinamide | C17H19FN2O2

Safinamide

  • Molecular Formula C17H19FN2O2
  • Average mass 302.343 Da
(2S)-2-[[[4-[(3-Fluorophenyl)methoxy]phenyl]methyl]amino]propanamide
133865-89-1 ,
сафинамид ,
سافيناميد 
沙非胺 
EMD-1195686, ZP-034, FCE-28073(R-isomer), PNU-151774E, NW-1015, FCE-26743
CAS   202825-46-5 (mesylate) SEE BELOW

str1

(+)-(S)-2-[[p-[(m-fluorobenzyl)oxy]benzyl]amino]propionamide monomethanesulfonate

Propanamide, 2-[[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino]-, (2S)-, methanesulfonate

Molecular Weight 398.45
Formula C17H19FN2O2 ● CH4O3S

CAS 202825-46-5 (Safinamide Mesylate)

Safinamide is a white to off-white, non-hygroscopic crystalline solid. It shows pH dependent solubility in aqueous buffers due to the secondary amine moiety, being soluble at acidic pH and practically insoluble at neutral pH.

It is freely soluble in de-ionized water, methanol and DMSO but practically insoluble in non-polar organic solvents.

Safinamide is chiral and possesses a single stereogenic centre.

Three crystalline forms are known. The anhydrous form selected for commercialisation is the most thermodynamically stable form, whilst the others are either not physiologically relevant or have very similar dissolution profiles. SOURCE EMA

Safinamide methanesulfonate was approved by European Medicine Agency (EMA) on Feb 22, 2015. It was developed by Newron and Zambon, then marketed as Xadago® by Zambon in EU.

FDA approved March 21, 2017

Safinamide is a unique molecule with a novel dual mechanism of action based on the enhancement of the dopaminergic function (through potent reversible inhibition of MAO-B and of dopamine uptake) and inhibition of the excessive release of glutamate. It is indicated for the treatment of Parkinson’s disease (PD).

Xadago® is available as film-coated tablet for oral use, containing Eq. 50 mg/100 mg of free Safinamide. The recommended dose is 50 mg or 100 mg once daily.

SYNTHESIS WILL BE UPDATED…………..
03/21/2017
The U.S. Food and Drug Administration today approved Xadago (safinamide) tablets as an add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. An “off” episode is a time when a patient’s medications are not working well, causing an increase in Parkinson’s symptoms, such as tremor and difficulty walking.

March 21, 2017, Release

The U.S. Food and Drug Administration today approved Xadago (safinamide) tablets as an add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. An “off” episode is a time when a patient’s medications are not working well, causing an increase in Parkinson’s symptoms, such as tremor and difficulty walking.

“Parkinson’s is a relentless disease without a cure,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to helping make additional treatments for Parkinson’s disease available to patients.”

An estimated 50,000 Americans are diagnosed with Parkinson’s disease each year, according to the National Institutes of Health, and about one million Americans have the condition. The neurological disorder typically occurs in people over age 60, though it can occur earlier, when cells in the brain that produce a chemical called dopamine become impaired or die. Dopamine helps transmit signals between the areas of the brain that produce smooth, purposeful movement – such as eating, writing, and shaving. Early symptoms of the disease are subtle and occur gradually. In some people, Parkinson’s disease progresses more quickly than in others.

The efficacy of Xadago in treating Parkinson’s disease was shown in a clinical trial of 645 participants who were also taking levodopa and were experiencing “off” time. Those receiving Xadago experienced more beneficial “on” time, a time when Parkinson’s symptoms are reduced, without troublesome uncontrolled involuntary movement (dyskinesia), compared to those receiving a placebo. The increase in “on” time was accompanied by a reduction in “off” time and better scores on a measure of motor function assessed during “on” time than before treatment.

In another clinical trial of 549 participants, the participants adding Xadago to their levodopa treatment had more “on” time without troublesome uncontrolled involuntary movement compared to those taking a placebo, and also had better scores on a measure of motor function assessed during “on” time than before treatment.

Certain patients should not take Xadago. These include patients who have severe liver problems, or who take a medicine used to treat a cough or cold called dextromethorphan. It also should not be taken by patients who take another medicine called a monoamine oxidase inhibitor (MAOI) because it may cause a sudden severe increase in blood pressure, or by those who take an opioid drug, St. John’s wort, certain antidepressants (such as serotonin-norepinephrine reuptake inhibitors, tricyclics, tetracyclics, and triazolopyridines), or cyclobenzaprine, because it may cause a life-threatening reaction called serotonin syndrome.

The most common adverse reactions observed in patients taking Xadago were uncontrolled involuntary movement, falls, nausea, and trouble sleeping or falling asleep (insomnia).

Serious, but less common, risks include the following: exacerbated high blood pressure (hypertension); serotonin syndrome when used with MAOIs, antidepressants, or opioid drugs; falling asleep during activities of daily living; hallucinations and psychotic behavior; problems with impulse control/compulsive behaviors; withdrawal-emergent hyperpyrexia (fever) and confusion; and retinal pathology.

The FDA granted approval of Xadago to Newron Pharmaceuticals.

Safinamide (INN; brand name Xadago) is a drug indicated for the treatment of Parkinson’s disease with monoamine oxidase B inhibiting and other methods of action.[2] It was approved in Europe in February 2015,[3] and in the United States on March 21, 2017[4]. It has also been tested for the use in patients with restless legs syndrome (RLS), but no study results have been published.

Image result for SAFINAMIDE SYNTHESIS

Medical uses

Safinamide has been approved by the European Medicines Agency for the treatment of adult patients with idiopathic Parkinson’s disease as add-on therapy to a stable dose of levodopa (L-dopa) alone or in combination with other Parkinson drugs in patients with mid-to-late-stage fluctuating disease.[5]

Contraindications

Safinamide is contraindicated in patients with severe liver impairment, with albinism, retinitis pigmentosa, severe diabetic neuropathy, uveitis and other disorders of the retina. Combination with other monoamine oxidase (MAO) inhibitors and pethidine is also contraindicated.[6]

Adverse effects

Common adverse events in clinical trials (in more than 1% of patients) included nausea, dizziness, tiredness, sleeplessness, orthostatic hypotension (low blood pressure), and headache. There was no significant difference in the occurrence of these effects between safinamide and placebo treated patients.[6][7]

In experiments with rats (but not in those with monkeys), retinopathies have been observed.[1][8]

Overdose

Expected overdose effects are hypertension (high blood pressure), orthostatic hypotension, hallucinations, psychomotor agitation, nausea, vomiting, and dyskinesia. In studies, a singe patient was suspected to have overdosed for a month; symptoms were confusion, drowsiness and mydriasis (dilation of the pupils) and subsided completely after the drug was discontinued. No specific antidote is available.[6]

Interactions

As a MAO inhibitor, safinamide can theoretically cause hypertensive crises, serotonin syndrome and other severe side effects when combined with other MAO inhibitors or with drugs that are known to interact with MAO inhibitors, such as pethidine, dextromethorphan, selective serotonin reuptake inhibitors (SSRIs), serotonin–noradrenaline reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants. An interaction with tyramine, a substance found in various foods, could be expected by the same reasoning but has been excluded in studies.[6]

Another theoretical interaction is with drugs with affinity to the transporter protein ABCG2 (also known as BCRP), such as pitavastatin, pravastatin, ciprofloxacin, methotrexat, and diclofenac; a study with the latter has shown no clinical relevance.[9] A study testing possible interactions with amidase inhibitors is part of the post-authorisation development plan.[1] There are no relevant interactions related to cytochrome P450 (CYP) liver enzymes, although one inactivation pathway of safinamide seems to be mediated by CYP3A4.[6]

Pharmacology

Mechanisms of action

Like the older antiparkinson drugs selegiline and rasagiline, safinamide is a selective monoamine oxidase B inhibitor, reducing degradation of dopamine; in contrast to the other two, its action is reversible. Safinamide also inhibits glutamate release[7][10] and dopamine reuptake.[11] Additionally, it blocks sodium and calcium channels,[10][12] the relevance of which for its antiparkinson action is however unknown.[6]

Pharmacokinetics

Safinamide is absorbed quickly and nearly completely from the gut and reaches highest blood plasma concentrations after 1.8 to 2.8 hours. There is no relevant first-pass metabolism; total bioavailability is 95%. The substance is bound to plasma proteins to 88–90%.[6]

The metabolism is not well understood. The principal step is mediated by amidases which have not been identified, and produces safinamide acid (NW-1153). Other relevant metabolites are O-debenzylated safinamide (NW-1199),[9] the N-dealkylated amine which is then oxidized to a carboxylic acid (NW-1689), and the glucuronide of the latter.[6][13] In tests with liver microsomes, dealkylation seemed to be mediated by CYP3A4, but other CYP enzymes appear to be involved as well. Safinamide acid binds to the organic anion transporter 3 (OAT3), but this has probably no clinical relevance. Safinamide itself transiently binds to ABCG2. No other transporter affinities have been found in preliminary studies.[6]

Safinamide is eliminated, mainly (>90%) in form of its metabolites, via the kidney, with an elimination half-life of 20 to 30 hours. Only 1.5% are found in the stool.[6]

Metabolism pathways of safinamide.[9][13] Enzymes: CYP = cytochrome P450, MAO-A = monoamine oxidase A, ALDH = aldehyde dehydrogenases, UGT = UDP-glucuronosyltransferases. Gluc = acyl glucuronide.

History

The compound was originally discovered at Farmitalia-Carlo Erba, which was acquired by Pharmacia in 1993. In 1995, Pharmacia merged with Upjohn. Safinamide was first disclosed in 1998.[14] In the course of a major restructuring in the same year, all rights for safinamide were transferred to the newly formed company Newron Pharmaceuticals, which developed the drug until it was sold to Merck KGaA in 2006.[15]

In 2007, a Phase III clinical trial was started, scheduled to run until 2011.[16] In October 2011 Merck, now Merck-Serono, announced that they would give all rights to develop the compound back to Newron because they wanted to prioritise other projects and had corrected their estimates for safinamide’s market potential downwards.[17]

The US Food and Drug Administration (FDA) refused to file Newron’s application in 2014 on formal grounds.[18] Newron re-applied in December 2014.[19] In spring 2015, the European Medicines Agency (EMA) approved the drug. Safinamide is the first antiparkinson medication to be approved for ten years.[8]

Research

Potential additional uses might be restless legs syndrome (RLS) and epilepsy.[20] They were being tested in Phase II trials in 2008, but no results are available.

str1

(+)-(S)-2-[[p-[(m-fluorobenzyl)oxy]benzyl]amino]propionamide monomethanesulfonate

Propanamide, 2-[[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino]-, (2S)-, methanesulfonate

Molecular Weight 398.45
Formula C17H19FN2O2 ● CH4O3S

CAS 202825-46-5 (Safinamide Mesylate)

Safinamide is a white to off-white, non-hygroscopic crystalline solid. It shows pH dependent solubility in aqueous buffers due to the secondary amine moiety, being soluble at acidic pH and practically insoluble at neutral pH.

It is freely soluble in de-ionized water, methanol and DMSO but practically insoluble in non-polar organic solvents.

Safinamide is chiral and possesses a single stereogenic centre.

Three crystalline forms are known. The anhydrous form selected for commercialisation is the most thermodynamically stable form, whilst the others are either not physiologically relevant or have very similar dissolution profiles.SOURCE EMA

Safinamide methanesulfonate was approved by European Medicine Agency (EMA) on Feb 22, 2015. It was developed by Newron and Zambon, then marketed as Xadago® by Zambon in EU.

FDA approved March 21, 2017

Safinamide is a unique molecule with a novel dual mechanism of action based on the enhancement of the dopaminergic function (through potent reversible inhibition of MAO-B and of dopamine uptake) and inhibition of the excessive release of glutamate. It is indicated for the treatment of Parkinson’s disease (PD).

Xadago® is available as film-coated tablet for oral use, containing Eq. 50 mg/100 mg of free Safinamide. The recommended dose is 50 mg or 100 mg once daily.

SYNTHESIS

Safinamide has been obtained by reductocondensation of 4-(3-fluorobenzyloxy)benzaldehyde (I) with L-alaninamide (II) by means of sodium cyanoborohydride in methanol.EP 0400495; EP 0426816; JP 1992500215; US 5236957; US 5391577; US 5502079; WO 9014334

CLIP

http://pubs.rsc.org/en/content/articlehtml/2016/sc/c6sc00197aImage result for SAFINAMIDE SYNTHESIS

image file: c6sc00197a-s2.tif

Scheme 2 Synthesis and isolation of [18F]safinamide, [18F]FMT, and [18F]mFBG.

PATENT

WO2009074478A1

Safinamide (NW- 1015, FCE-26743A, PNU- 151774E) is a sodium channel blocker, a calcium channel modulator, a monoamino oxidase B (MAO-B) inhibitor, a glutamate release inhibitor and a dopamine metabolism modulator. Safinamide is useful in the treatment of CNS disorders, in particular of epilepsy, Parkinson’s disease, Alzheimer’s disease, depression, restless legs syndrome and migraine (WO 90/ 14334, WO 2004/089353, WO 2005/ 102300 and WO 2004/062655). Ralfinamide (NW- 1029, FCE-26742A, PNU-0154339E) is a sodium channel blocker useful in the treatment of pain conditions, including chronic pain and neuropathic pain, migraine, bipolar disorders, depressions, cardiovascular, inflammatory, urogenital, metabolic and gastrointestinal disorders (WO 99/35125, WO 03/020273, WO 2004/062655, WO 2005/018627, WO 2005/070405, WO 2005/ 102300).

In particular, safinamide is specifically described in WO 90/ 14334. Safinamide, its R-enantiomer, their racemic mixture and their salts with pharmaceutically acceptable acids and the use thereof for the preparation of pharmaceutical compositions active as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic and/or hypnotic agents are specifically claimed in WO 90/ 14334. Ralfinamide is specifically described in WO 90/ 14334. Ralfinamide, its R- enantiomer, their racemic mixture and their salts with pharmaceutically acceptable acids and their use thereof for the preparation of pharmaceutical compositions active as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic and/or hypnotic agent are comprised by the claims of WO 90/ 14334.

Moreover, the use as analgesics of safinamide, ralfinamide, the respective R-enantiomers, the respective racemic mixtures and their salts with pharmaceutically acceptable acids is claimed in WO 99/035125. WO 2006/027052 A2 specifically discloses and claims the use of the single R-enantiomer of ralfinamide i.e., (R)-2-[4-(2- fluorobenzyloxy)benzylamino]propanamide (I’b), and its salts with pharmaceutically acceptable acids as a selective sodium and calcium channel modulator for the selective treatment of pathological affections wherein sodium or calcium channel mechanism(s) play(s) a pathological role, including pain, migraine, inflammatory processes affecting all body systems, disorders affecting skin and related tissue, disorders of the respiratory system, disorders of the immune and endocrinological systems, gastrointestinal, and urogenital disorders, wherein the therapeutical activity of said compound is substantially free from any MAO inhibitory side effect or exhibits significantly reduced MAO inhibitory side effect.

It has now been discovered that the large scale preparations of safinamide and ralfinamide according to the methods described in the prior art, contain two undesired impurities, i.e., respectively, (S)-2-[3-(3- fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide (Ha) and (S)- 2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide (lib), and their salt, in particular the respective methanesulfonates (lie) and (Hd)

Figure imgf000004_0001

(Ha) (lib)

The same situation occurs with the preparation according the prior art methods for the R-enantiomers (I’a) and (I’b) of, respectively, safinamide and ralfinamide, the respective racemic mixtures (Ia, I’a) and (Ib, I’b), and the salts thereof with pharmaceutically acceptable acids, (I’c), (I’d) and the respective racemic mixtures (Ic, I’c) and (Id, I’d) in particular the methanesulfonates, which result to be contaminated by the respective R isomers (Il’a), (Il’b), (II’c), and (Il’d) of the above identified impurities (Ha), (lib), (lie) and (Hd) or the respective racemic mixtures (Ha, Il’a), (lib, Il’b), (Hc, II’c) and (Hd, Il’d).

PATENT

WO2014178083A1.

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by bradykinesia, rigidity, resting tremor, and ataxia. These symptoms are caused by decreased dopamine release in the striatum. Clinically, PD is defined by presence of Lewy bodies, intracellular neuronal inclusions in the substantia nigra and at other sites in the brain. Estimated prevalence of this disease is 100 to 200 per 100,000 population including males and females across the entire age group. Current treatment for PD comprises dopaminergic medications that include levodopa, dopamine agonists (DAs), monoamine oxidase-B (MAO-B) inhibitors. Figure 1 provides few examples of pharmaceutically important benzyloxy-benzylamine derivatives. Many of these benzyl oxy-benzylamines with various amine functions were studied and has been patented as sodium channel blockers. Among them, safinamide ((5)-N2– {4-[3- fluorobenzyl)oxy] benzyl}- alaninamide methanesulfonate) is a noted example which is under phase III clinical trials for treatment of Parkinson’s disease. Its mechanism of action is manifold which comprise MAO-B and dopamine uptake inhibition. Further, safinamide is believed to block voltage-dependent sodium channels, modulates calcium channels and reduction of glutamate release in the central nervous system. WOl 998003472 discloses serinamide, glycinamide, alaninamide and phenylalaninamide derivatives of a compound (I). These compounds (I) are useful for the treatment of neurological diseases.

EP2474521 discloses high purity degree (S)-2-[4-(3-fluorobenzyloxy)- benzylamino]propanamide (safinamide) or (S)-2-[4-(2-fluorobenzyloxy)- benzylamino]propanamide (ralfinamide) or a salt thereof with a pharmaceutically acceptable acid with a content of the respective impurity (S)-2-[3-(3-fluorobenzyl)-4-(3- fluorobenzyloxy)-benzylamino]propanamide or (S)-2-[3-(2-fluorobenzyl)-4-(2- fluorobenzyloxy)-benzylamino]propanamide.

US2009149544 relates to novel alpha- aminoamide derivatives, their pharmaceutically acceptable salts, solvates, and hydrates thereof. The application also provides compositions comprising a compound and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an inhibitor of monoamine oxidase type B (MAO-B) and/or a sodium (Na.sup.+) channel blocker, and/or a calcium (Ca.sup.2+) channel modulator.

The strategy employed in the art to prepare benzyloxy-benzylamine derivatives including safinamide or its analogue ralfinamide is chiral pool approach starting from L-alaniriamide and reductively aminating with 4-(3-fluorobenzyloxy) benzaldehyde. Although this method is very simple and straightforward, it suffers from several serious drawbacks, such as need to use toxic reagents such as sodium cyanoborohydride and further formation of toxic by-products such as hydrogen cyanide and sodium cyanide and other toxic impurities in large-scale production Importantly, the possibility of generating a range of safinamide analogues by means of the chiral-pool approach is limited in terms of the structure and stereochemistry of the products because of inadequacies in the availability of D-alaninamide and its analogues

Hence, the developments of newer methods for the preparation of compounds of formula (I) comprising safinamide and related analogues are highly desirable

Example 2: Synthesis of (R)-l-(benzyIoxy)propan-2-ol [(R)-compound 3]

To a solution of (7? benzyl glycidyl ether [fR)-compound 2] (4 g, 24.4 mmol) in dry THF (10 mL) at 0 °C, a pre-cooled solution of lithium aluminium hydride (1.4 g, 36.6 mmol) in anhydrous THF (10 mL) was added slowly with stirring under nitrogen. After 60 min, the reaction mixture was quenched with 1 ml of water and 1 ml of 15 % NaOH solution and the content was stirred for 15 min. The inorganic precipitate was filtered, washed with ethyl acetate and the solvent evaporated under reduced pressure. The residue was purified by a short filtration column to afford (-fl)-compound 3 as a colorless oil (3.8 g, 95%); [a]22D = -14.5 (c 2, CHC13); IR (CHC13): vmax3418, 3087, 3063, 3030, 2963, 2924, 1952, 1873, 1600, 1495, 1454, 1363, 1244, 1099, 1028, 918, 808, 698 cm“1; Ή NMR (200 MHz, CDC13): δΗ 1.13 (d, J = 6.3 Hz, 3H), 2.5 (bs, 1H), 3.23-3.32 (dd, J = 9.8, 1.3 Hz, 1H), 3.43-3.49 (dd, J = 9.45, 3.2 Hz, 1H), 3.91-4.03 (m, 1H), 4.55 (s, 2H), 7.25-7.37 (m, 5H); I3C NMR (50 MHz, CDC13): 5C 137.8 (C), 128.3 (CH, 2 carbons), 127.7 (CH, 3 carbons), 75.7 (CH2), 73.2 (CH2), 66.4 (CH), 18.6 (CH3); MS: m/z 189 [M+Na]+.

Example 3: Synthesis of (S)-((2-azidopropoxy)methyl)benzene [(S)- compound 4]

To a stirred solution of secondary alcohol ( )-compound 3 (3 g, 18.1 mmol) in dry dichloromethane (25 mL), Et3N (3.1 mL, 21.7 mmol) at 0 °C was added, followed by drop wise addition of mesyl chloride (1.8 mL, 21.7 mmol). The reaction mixture was stirred at 0°C for 2 hours, subsequently at room temperature for 3 hours under a nitrogen atmosphere. After completion of the reaction (indicated by TLC), the reaction mixture was diluted with dichloromethane and washed with a saturated solution of sodium bicarbonate (30 mL) and water (2 x 10 mL). The organic layer was separated, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the O-mesyl compound (4.3 g; crude).

To a solution of the crude 0-mesyl compound (4 g, 16.37 mmol) in dry DMF (10 mL), sodium azide (1.6 g, 24.55 mmol) was added and the reaction mixture was heated at 60°C for 6 hours under nitrogen atmosphere. After completion of the reaction (indicated by TLC), water (10 mL) was added to the reaction mixture, then extracted with ethyl acetate (2 x 15 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 95:5) to yield (¾)-compound 4 as a colorless oil. (2.8 g; 89%); [a]22D = +6.1 (c 1.3, CHC13); IR (CHC13): vmax 3394, 3032, 2977, 2864, 2500, 2104, 1724, 1641 , 1496, 1454, 1363, 1269, 1 101 , 913, 698 αη ‘,Ή NMR (200 MHz, CDC13): δΗ 1.20 (d, J = 6.7 Hz, 3H), 3.39-3.54 (m, 2H), 3.61-3.77 (m, 1H), 4.57 (s, 2H), 7.25-7.39 (m, 5H); 13C NMR (50 MHz, CDC13): 5C 137.8 (C), 128.4 (CH, 2 carbons), 127.7 (CH), 127.5 (CH, 2 carbons), 73.7 (CH2), 73.2 (CH2), 56.9 (CH), 16.1 (CH3);MS: m/z 214 [M+Na]+.

Example 4: Synthesis of (S)-N-(l-hydroxypropan-2-yl)-2-nitrobenzenesulfonamide [(S)- compound 5]

To a solution of ^-compound 4 (2.5 g, 13.1 mmol) in methanol (15 mL), trifluoroacetic acid (2 mL) and palladium hydroxide on activated carbon (0.05 g, 10-20 wt %) were added and the reaction mixture was stirred under hydrogen (60 psi) for 8 hours. After completion of the reaction (indicated by TLC), the catalyst was filtered over a plug of celite and the solvent was evaporated under reduced pressure to half of its volume which was basified with 2.5 M methanolic NaOH. Evaporation of the remaining solvent under reduced pressure was done followed by filtration of the residue through a short bed of basic alumina (eluent; MeOH) to obtain the amino alcohol as a pale brown oil (0.94 g, crude) which was subjected to the next reaction without further purification.

To a solution of amino alcohol (0.9 g, 1 1.98 mmol) in dry dichloromethane (5 mL), 2-nitrobenzenesulfonylchloride (3.2 g, 14.37 mmol) in dichloromethane (8 mL) and triethylamine (2.6 mL, 17.97 mmol) at 0 °C were slowly added under nitrogen atmosphere. The solution was stirred for 2 hours. After completion of the reaction (indicated by TLC), water (10 mL) was added to the reaction mixture, then extracted with dichloromethane (2 x 15 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 60:40) to yield (S)- compound 5 as a pale yellow oil (2.33 g, 75% ); [a]22D = +80.2 (c 2.1, CHClj); IR (CHC13): vmax 3546, 3367, 3022, 2883, 2401, 1594, 1542, 1412, 1362, 1216, 1170, 1 125, 1059, 971, 854, 668 cm“1; ]H NMR (200 MHz, CDC13): δΗ 1.13 (d, J = 6.5 Hz, 3H), 2.16 (bs, 1H), 3.45-3.70 (m, 3H), 5.61 (d, J = 6.6 Hz, 1H), 7.73-7.80 (m, 2H), 7.86-7.91 (m, 1H), 8.13-8.22 (m, 1H); 13C NMR (50 MHz, CDC13): 5C 147.8 (C), 134.4 (C), 133.7 (CH), 133.0 (CH), 130.9 (CH), 125.5 (CH), 66.2 (CH2), 52.5 (CH), 17.8 (CH3); MS: m/z 283 [M+Na]+.

Example 5: Synthesis of l-fluoro-3-(iodomethyl)benzene ( compound 7)

To a stirred solution of triphenyl phosphine (4.15 g, 15.85 mmol), imidazole (1.1 g, 15.85 mmol) in dry dichloromethane (20 mL), iodine (4.8 g, 19.02 mmol) at 0°C was added and the solution was stirred for 5 min. To this, 3-fluoro benzyl alcohol (compound 6) (2 g, 15.85 mmol) dissolved in dichloromethane (5 mL) was added drop wise over 10 min and the stirring was continued for 1 hour with exclusion of light. After completion of the reaction (indicated by TLC), the reaction mixture was quenched by addition of an aqueous Na2S203 solution (15 mL), then extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 95:5) to yield compound 7 as a colorless oil (3.5 g, 95% ); (IR (CHC13): vmax 3460, 3060, 2965, 1695, 1613, 1593, 1482, 1446, 1259, 1 156, 1068, 944, 871, 782, 736, 686 cm“1 ; Ή NMR (200 MHz, CDC13): δΗ 4.42 (s, 2H), 6.89-6.99 (m, 1H), 7.05-7.17 (m, 2H), 7.21-7,29 (m, 1H); 13C NMR (50 MHz, CDC13): 6C 165.0 (C), 141.6 (C), 130.2 (CH), 124.4 (CH), 1 15.9 (CH), 1 14.7 (CH), 3.9 (C¾).

Example 6: Synthesis of (4-((3-flurobenzyl)oxy)phenyl)methanol (compound 8)

To a stirred solution of 4-(hydroxymethyl)phenol (1.57 g, 12.7 mmol) and K2C03 (8.8 g, 63.55 mmol) in dry acetonitrile (25 mL), compound 7 (3 g, 12.7 mmol) in acetonitrile was slowly added and the reaction mixture was heated at 70°C for 6 hours. After completion of the reaction (indicated by TLC), water (20 mL) was added to the reaction mixture, then extracted with ethylacetate (3 x 20 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 70:30) to yield compound 8 as a colorless solid (2.7 g, 91% ); mp 63-65 °C; IR (CHC13): vmax 3422, 3017, 1612, 1512, 1489, 1381, 1216, 1 174, 1020, 829, 668 cm“1; Ή NMR (200 MHz, CDC13): δΗ 4.61 (s, 2H), 5.06 (s, 2H), 6.91-6.98 (m, 2H), 7.00-7.06 (m, 1H), 7.12-7.20 (m, 2H), 7.25-7.37 (m, 3H); 13C NMR (50 MHz, CDC13): 5C 165.4 (C), 160.5 (C), 158.0 (C), 139.6 (C), 133.5 (CH), 130.2 (CH), 128.7 (CH, 2 carbons), 122.7 (CH), 1 14.8 (CH, 2 carbons), 1 13.9 (CH), 69.1 (CH2), 64.9 (CH2); MS: m/z 255 [M+Na]+.

Example 7: Synthesis of l-fluoro-3-((4-(iodomethyl)phenoxy)methyI)benzene (compound 9)

To a stirred solution of triphenyl phosphine (2.82 g, 10.8 mmol), imidazole (0.73 g, 10.76 mmol) in dry dichloromethane (20 mL), iodine (3.27 g, 12.9 mmol) at 0 °C was added and the solution was stirred for 5 min. To this, compound 8 (2.5 g, 10.8 mmol) dissolved in dichloromethane (5 mL) was added drop wise over 10 min and the stirring was continued for 1 hour with exclusion of light. After completion of the reaction (indicated by TLC), the reaction mixture was quenched by addition of an aqueous Na2S203 solution (15 mL), then extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 95:5) to yield compound 9 as a colorless oil (3.4 g, 93%); IR (CHC13): vmax 3503, 3033, 2925, 2089, 1607, 1509, 1488, 1381, 1301, 1250, 1 155, 1079, 944, 869, 776, 684 cm“1; 1H NMR (200 MHz, CDC13): δΗ 4.47 (s, 2H), 5.04 (s, 2H), 6.85-6.91 (m, 2H), 6.96-7.02 (m, 1H), 7.05-7.12 (m, 1H), 7.16-7.20 (m, 1H), 7.29-7.40 (m, 3H).

,3C NMR (50 MHz, CDC13): 6C 165.4 (C), 160.5 (C), 158.1 (C), 131.9 (C), 130.2 (CH), 130.1 (CH, 2 carbons), 122.7 (CH), 1 15.1 (CH, 2 carbons), 1 14.7 (CH), 1 13.9 (CH), 69.2 (CH2), 6.33 (CH2).

Example 8: Synthesis of (S)-N-(4-((3-flurobenzyl)oxy)benzyl)-N-(l-hydroxypropan-2-yl)-2-nitrobenzenesulfonamide [(S)-compound 10]

To a stirred solution of (^-compound 5 (1 g, 3.8 mmol) and K2C03 (2.65 g, 19.2 mmol) in dry acetonitrile (25 mL), compound 9 (1.84 g, 5.4 mmol) in acetonitrile was slowly added and the reaction mixture was heated at 70°C for 72 hours. After completion of the reaction (indicated by TLC), water (20 mL) was added to the reaction mixture, then extracted with ethylacetate (3 15 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 80:20) to yield (¾)-compound 10 as a colorless oil (1.46 g, 80% ); [a]22D = +5.4 (c 1.5, CHC13); IR (CHC13): vmax 3445, 3020, 2928, 2400, 1613, 1544, 1512, 1453, 1371, 1216, 1 162, 1029, 852, 668 cm“1; 1H NMR (200 MHz, CDC13): δΗ 1.07 (d, J = 6.9 Hz, 3H), 1.91 (t, J = 5.2 Hz, 1H), 3.41-3.53 (m, 2H), 4.05-4.22 (m, 1H), 4.37-4.57 (m, 2H), 5.02 (m, 2H), 6.87 (d, J = 8.53 Hz, 2H), 6.97-7.12 (m, 2H), 7.20 (d, J = 7.2 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.47-7.67 (m, 3H), 7.89 (d, J = 8.09 Hz, 1H); 13C NMR (50 MHz, CDC13): 6C 165.5 (C), 160.6 (C), 158.4 (C), 147.7 (C), 139.6 (C), 134.1 (C), 133.4 (CH), 131.6 (CH), 131.4 (CH), 130.3 (CH), 129.7 (CH, 2 carbons), 124.1 (CH), 122.8 (CH), 115.1 (CH), 114. 9 (CH, 2 carbons), 114.0 (CH), 69.2 (CH2), 64.3 (CH2), 56.2 (CH), 46.9 (CH2), 15.4 (CH3); MS: m/z 497 [M+Na]+.

Example 9: Synthesis of (S)-2-(N-(4-((3-fluorobenzyl)oxy)benzyl)-2-nitrophenylsulfonamido) propanoic acid [(S)-compound 11]

A mixture of (S compound 10 (1.25 g, 2.6 mmol), TEMPO (0.028 g, 0.18 mmol), acetonitrile (20 mL), and sodium phosphate buffer (16 mL, 0.67 M, pH 6.7) was heated to 35°C. Next, sodium chlorite (0.47 g dissolved in 2 mL water, 7.9 mmol) and diluted bleach (4-6%, 0.09 mL diluted in 1 mL water) were added simultaneously over 1 hour. The reaction mixture was stirred at 35°C until the reaction was complete (3 hours, TLC), then cooled to room temperature. Water (30 mL) was added and the pH adjusted to 8 with 2 M NaOH. The reaction was quenched by pouring it into ice cold Na2S03 solution maintained at <20°C. After stirring for 30 min at room temperature, ethyl acetate (20 mL) was added and the stirring was continued for an additional 15 min. The organic layer was separated and discarded. More ethyl acetate (20 mL) was added, and the aqueous layer was acidified with 1 M HC1 to pH 3-4. The organic layer was separated, washed with water (2 x 15 mL), brine and concentrated under reduced pressure to afford the carboxylic acid (S -compound 1 1 (1.1 g, 85%); [ ]22ο = -20.4 (c 1.1, CHC13); IR (CHC13): vmax 3398, 3095, 1718, 1612, 1591, 1543, 1512, 1489, 1457, 1371, 1303, 1251, 1163, 1059, 900, 852, 831 , 778, 684 cm“1; 1H NMR (200 MHz, CDC13): 8H 1.44 (d, J = 7.3 Hz, 3H), 4.23 (d, J = 15.6 Hz, 1H), 4.64 (d, J = 15.6 Hz, 1H), 4.82-4.90 (q, J = 7.4 Hz, 1H), 4.92 (s, 2H), 6.68 (d, J = 8.6 Hz, 2H), 6.89-7.01 (m, 2H), 7.07-7.13 (m, 3H), 7.18-7.33 (m, 2H), 7.43-7.55 (m, 3H), 8.81 (bs, 1H); 13C NMR (50 MHz, CDC13): 5C 176.5 (CO), 165. 0 (C), 158.0 (C), 147.4 (C), 139.4 (C), 134.1 (C), 133.2 (CH), 131.4 (CH), 130.3 (CH), 129.9 (CH, 2 carbons), 128.4 (C), 124.1

(CH), 122.6 (CH), 1 15.0 (CH), 114.6 (CH, 2 carbons), 1 14.3 (CH), 1 13.8 (CH) 69.1 (CH2), 56.1 (CH), 49.0 (CH2), 16.8 (CH3); MS: m/z 51 1 [M+Na .

Example 10: Synthesis of (S)-2-(N-(4-((3-fluorobenzyI)oxy)benzyl)-2-nitrophenylsulfonamido) propanamide [(S)- compound 12]

To a solution of carboxylic acid (¾)-compound 1 1 (1 g, 2.04 mmol) and triethyl amine (0.34 mL, 2.4 mmol) in dry THF (20 mL), ethyl chloroformate (0.21 mL, 2.2 mmol) at 0 °C was added under nitrogen atmosphere. After 1 hour, ammonium hydroxide (25% w/v aqueous solution, 1.4 mL, 10.2 mmol) was added and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, potassium carbonate (0.29 g, 2.1 mmol) was added and the reaction mixture was filtered, and washed with ethylacetate. The solvent was removed under reduced pressure and the crude product was subjected to column chromatography (silica gel, petroleum ether/EtOAc, 50:50) to obtain sulfonamide (Sj-compound 12 as a colorless oil (0.9 g, 91%); [a]22D = -32.1 (c 1.2, CHC13); IR (CHC13): vmax 3472, 1961 , 161 1, 1592, 1542, 1511, 1449, 1371, 1304, 1243, 1 163, 1060, 1029, 895, 852, 684 cm“1; Ή NMR (200 MHz, CDC13): δΗ 1.43 (d, J = 7.1 Hz, 3H), 4.44 (d, J = 15.4 Hz, 1H), 4.59 (d, J = 15.5 Hz, 1H), 4.60-4.71 (q, J= 7.0 Hz, 1 H), 5.01 (s, 2H), 5.50 (bs, 1H), 6.31 (bs, 1H), 6.78 (d, J = 8.71 Hz, 2H), 6.98-7.1 1 (m, 2H), 7.15-7.22 (m, 3H), 7.31-7.45 (m, 2H), 7.59-7.64 (m, 3H);13C NMR (50 MHz, CDC13): 5C 172.3 (CO), 165.5 (C), 158.2 (C), 147.5 (C), 139.6 (C), 139.4 (C), 133.6 (CH), 131.7 (CH), 130.5 (CH, 2 carbons),130.3 (CH), 128.1 (C), 124.2 (CH), 122.7 (CH), 1 15.1 (CH), 1 14.7 (CH, 2 carbons),1 14.4 (CH), 1 13.9 (CH), 69.0 (CH2), 55.7 (CH), 48.3 (CH2), 14.9 (CH3); MS: m/z 510 [M+Na]+.

Example 11: Synthesis of (S)-2-((4-((3-fluorobenzyl)oxy) benzyl) amino) propanamide [(S)-compound of formula I]

To a solution of sulfonamide (S)- compound 12 (0.8 g, 1.64 mmol), potassium carbonate (0.56 g, 4.9 mmol) in dry DMF (10 mL), thiophenol (0.2 mL, 1.9 mmol) was added. The reaction mixture was vigorously stirred for 6 hours. After completion of the reaction (indicated by TLC), water (10 mL) was added to the reaction mixture, then extracted with ethylacetate (2 x 20 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 60:40) to yield (S) -compound of formula I as a colorless solid (0.43 g, 86% ); mp 207-09 °C; [a]22D = +3.89 (c 1.55, CHC13); IR (CHC13): vmax 3341, 2970, 2927, 2853, 1648, 1592, 1512, 1489, 1445, 1406, 1384, 1254, 1176, 1 137, 1030, 953, 928, 829, 680 cm“1; Ή NMR (200 MHz, CDC13): δΗ 1.34 (d, J = 6.9 Hz, 3H), 2.49 (bs, 2H), 3.19-3.30 (q, J = 6.8 Hz, 1H), 3.63-3.78 (dd, J = 19.4, 3.9 Hz, 2H), 5.05 (s, 2H), 5.85 (bs, 1H), 6.95 (d, J = 8.7 Hz, 2H), 7.00-7.06 (m, 1H), 7.13-7.24 (m, 4H), 7.29-7.40 (m, 1H). 13C NMR (50 MHz, CDC13): 8C 178.3 (CO), 165.4 (C), 157.7 (C), 139.6 (C), 132.1 (C), 130.2 (CH), 129.3 (CH, 2 carbons), 122.7 (CH), 1 14.9 (CH, 2 carbons), 1 14.6 (CH), 1 13.9 (CH), 69.2 (CH2), 57.5 (CH), 51.9 (CH2), 19.6 (CH3); MS: m/z 302 [M]+, 325 [M+Na]+.

Example 12: Synthesis of (S)-Safinamide mesylate

To a stirred solution of (^-compound of formula I (0.1 g, 0.33 mmol) in ethylacetate (3 mL) at 70°C, methanesulfonic acid (0.02 mL, 0.33 mmol) was added and the reaction mixture was stirred for 2 hours. Subsequently, the temperature was lowered to 35°C and the stirring was continued for additional 1 hour. The solvent was evaporated under reduced pressure and the residue was filtered through a short bed of basic alumina [eluent: EtOAc/MeOH; (95:5)] to obtain safinamide mesylate as a white solid (0.11 g, 90%); mp 209-10 °C [lit.7mp 210]; [a]22D = +9.6 (c 1.1, AcOH); {lit.7 [a] D = +12.9 (c 1.1, AcOH)} ee >98% [The ee of safinamide mesylate was determined by chiral HPLC analysis; Chiralcel OD-RH (150 x 4.6 mm) column; eluent:

Methanol/ Acetonitrile/Buffer-TEAP, pH 3 (20: 10:70); flow rate 0.5 mL/min (780 psi); detector: 224 nm] [f¾)-isomer tR = 1 1.55 min, (SJ-isomer tR = 12.94 min].

PAPERS

Synthesis2014, 46, 1751-1756.

N2-{4-[(3-Fluorobenzyl)oxy]benzyl}-L-alaninamide [(S)-14] BASE FORM
PhSH (0.2 mL, 1.9 mmol) was added to a solution of sulfonamide (S)-13 (0.8 g, 1.64 mmol) and K2CO3 (0.56 g, 4.9 mmol) in anhyd DMF (10 mL), and the mixture was vigorously stirred for 6 h. When the reaction was complete (TLC), H2O (10 mL) was added and the mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (2 × 10), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography [silica gel, PE–EtOAc(60:40)] to give a colorless solid; yield: 0.43 g (86%); mp 207–09 °C;

[α]D22 +3.89 (c 1.55, CHCl3).
IR (CHCl3): 3341, 2970, 2927, 2853, 1648, 1592, 1512, 1489, 1445,1406, 1384, 1254, 1176, 1137, 1030, 953, 928, 829, 680 cm–1.

1H NMR (200 MHz, CDCl3): δH = 1.34 (d, J = 6.9 Hz, 3 H), 2.49 (brs, 2 H), 3.19–3.30 (q, J = 6.8 Hz, 1 H), 3.71 (dd, J = 19.4, 3.9 Hz, 2H), 5.05 (s, 2 H), 5.85 (br s, 1 H), 6.95 (d, J = 8.7 Hz, 2 H), 7.00–7.06 (m, 1 H), 7.13–7.24 (m, 4 H), 7.29–7.40 (m, 1 H).

13C NMR (50 MHz, CDCl3): δC = 178.3 (CO), 165.4 (C), 157.7 (C),139.6 (C), 132.1 (C), 130.2 (CH), 129.3 (CH, 2 C), 122.7 (CH), 114.9 (CH, 2 C), 114.6 (CH), 113.9 (CH), 69.2 (CH2), 57.5 (CH),51.9 (CH2), 19.6 (CH3).

MS: m/z = 302 [M]+, 325 [M + Na]+.

(S)-Safinamide Mesylate (1)
MsOH (0.02 mL, 0.33 mmol) was added to a stirred solution of sulfonamide (S)-14 (0.1 g, 0.33 mmol) in EtOAc (3 mL) at 70 °C, and the mixture was stirred for 2 h. The temperature was then lowered to 35 °C, and the mixture was stirred for an additional 1 h. The solvent was evaporated under reduced pressure and the residue was filtered
through a short bed of basic alumina with elution by EtOAc–MeOH; (95:5) to give a white solid; yield: 0.11 g (90%);

mp 209–210 °C [Lit.7a 210 °C];

[α]D22 +9.6 (c 1.1, AcOH); {Lit.7 [α]D22+12.9 (c 1.1, AcOH)}.
Chiral HPLC: column: Chiralcel OD-RH (150 × 4.6 mm); eluent:MeOH–MeCN–buffer-TEAP (pH 3) (20:10:70); flow rate: 0.5mL/min (780 psi); detector: 224 nm [(R)-isomer: tR = 11.55 min;
(S)-isomer: tR = 12.94 min]; ee >98%.

7a) Pevarello, P.; Bonsignori, A.; Dostert, P.;
Heidempergher, F.; Pinciroli, V.; Colombo, M.; McArthur,
R. A.; Salvati, P.; Post, C.; Fariello, R. G.; Varasi, M. J. Med.
Chem. 1998, 41, 579.

PAPER

Chin. J. Pharmas.2012, 43, 161-163.

…………….BASE

…………MESYLATE

PAPER

J. Med. Chem. 2007, 50, 4909-4916.

(S)-2-[6-(3-Fluorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-propionamide (21). The title compound was obtained using the same procedure described for the synthesis of (R)-2-[6-(3-fluorobenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]propionamide, starting from 6-(3-fluorobenzyloxy)-1,2,3,4-tetrahydroisoquinoline (0.24 g, 0.95 mmol) and (R)-2-amino-1-methyl-2-oxoethyl-2-nitrobenzenesulfonate (0.52 g, 1.9 mmol). After column chromatography
purification using 99:1 DCM/MeOH as eluent, 0.075 g (24% yield) of the title compound was obtained as a pure white solid. Mp 153- 154 °C. 1H NMR (CDCl3) ä 1.35 (d, 3H, J ) 7.0), 2.67-2.97 (m, 4H), 3.28 (q, 1H, J ) 7.0), 3.64 (d, 1H, J ) 14.2), 3.77 (d, 1H, J ) 14.2), 5.05 (s, 2H), 5.36 (br, 1H), 6.74 (d, 1H, J ) 2.5), 6.79 (dd, 1H, J ) 8.5, 2.5), 6.97 (d, 1H, J ) 8.5), 6.99-7.06 (m, 1H), 7.06-7.24 (m, 3H), 7.30-7.40 (m, 1H).

J. Med. Chem.1998, 41, 579-590.

Molecules 21 00793 g001 1024

References

  1. “Summary of the risk management plan (RMP) for Xadago (safinamide)” (PDF). European Medicines Agency. January 2015.
  2.  Fariello, RG (2007). “Safinamide”. Neurotherapeutics. 4 (1): 110–116. doi:10.1016/j.nurt.2006.11.011. PMID 17199024.
  3.  “EPAR Summary for the Public for Xadago” (PDF). European Medicines Agency. February 2015.
  4.  “After an odyssey of setbacks, FDA finally green-lights Newron’s Parkinson’s drug Xadago”. endpts.com. Retrieved 2017-03-21.
  5.  Lawrence, Janna (2015-01-19). “Safinamide recommended for approval as Parkinson’s disease therapy”. The Pharmaceutical Journal. Royal Pharmaceutical Society. Retrieved 2015-01-19.
  6.  Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  7.  H. Spreitzer (14 April 2014). “Neue Wirkstoffe – Safinamid”. Österreichische Apothekerzeitung (in German) (8/2014): 30.
  8. Klement, A (18 July 2016). “Xadago”. Österreichische Apothekerzeitung (in German) (15/2016): 10.
  9.  “Summary of Product Characteristics for Xadago” (PDF). European Medicines Agency. 24 February 2015.
  10. ^ Jump up to:a b Caccia, C; Maj, R; Calabresi, M; Maestroni, S; Faravelli, L; Curatolo, L; Salvati, P; Fariello, RG (2006). “Safinamide: From molecular targets to a new anti-Parkinson drug”. Neurology. 67 (7 Suppl 2): S18–23. doi:10.1212/wnl.67.7_suppl_2.s18. PMID 17030736.
  11.  Merck Serono: Vielversprechende Daten zur kognitiven Wirkung von Safinamid bei Parkinson im Frühstadium. (German) 8 June 2007.
  12.  Pevarello, P; Bonsignori, A; Caccia, C; Amici, R; Salvati, P; Fariello, RG; McArthur, RA; Varasi, M (1999). “Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsants”. Bioorganic & Medicinal Chemistry Letters. 9 (17): 2521–2524. doi:10.1016/s0960-894x(99)00415-1.
  13. ^ Jump up to:a b Krösser, Sonja; Marquet, Anne; Gallemann, Dieter; Wolna, Peter; Fauchoux, Nicolas; Hermann, Robert; Johne, Andreas (2012). “Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects”. Biopharmaceutics & Drug Disposition. 33 (9): 550. doi:10.1002/bdd.1822. PMID 23097240.
  14. Jump up^ Pevarello, P; Bonsignori, A; Dostert, P; Heidempergher, F; Pinciroli, V; Colombo, M; McArthur, RA; Varasi, M (1998). “Synthesis and Anticonvulsant Activity of a New Class of 2-[(Arylalkyl)amino]alkanamide Derivatives”. Journal of Medicinal Chemistry. 41 (4): 579–590. doi:10.1021/jm970599m. PMID 9484507.
  15. Jump up^ “Wichtigste Ergebnisse der Langzeitstudie mit Safinamid als Begleittherapie zu Levodopa bei Parkinson im fortgeschrittenen Stadium” [Major results from the long-term study of safinamide as add-on to levodopa for late-stage Parkinson] (in German). Merck KGaA. 4 November 2010.
  16. Jump up^ Study of Safinamide in Early Parkinson’s Disease as Add-on to Dopamine Agonist (MOTION)
  17. Jump up^ Merck Returns Rights for Safinamide to Newron, 21 October 2011.
  18. Jump up^ “Information about FDA Refusal to File” (PDF). Newron. 29 July 2014.
  19.  “Information about FDA re-application” (PDF). Newron. 29 December 2014.
  20.  Chazot, PL (2007). “Drug evaluation: Safinamide for the treatment of Parkinson’s disease, epilepsy and restless legs syndrome”. Current Opinion in Investigational Drugs. 8 (7): 570–579. PMID 17659477.
Safinamide
Safinamide.svg
Clinical data
Trade names Xadago
AHFS/Drugs.com UK Drug Information
Pregnancy
category
  • Fetal malformations in animal studies[1]
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • UK:POM (Prescription only)
Pharmacokinetic data
Bioavailability 95%
Protein binding 88–90%
Metabolism Amidases, glucuronidation
Biological half-life 20–30 hrs
Excretion 76% renal, 1.5% faeces
Identifiers
Synonyms EMD-1195686, PNU-15774E;
(2S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl] methylamino]propanamide
CAS Number
PubChemCID
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.120.167
Chemical and physical data
Formula C17H19FN2O2
Molar mass 302.34 g/mol
3D model (Jmol)

//////////Xadago, safinamide,  Newron Pharmaceuticals, FDA 2017, Parkinson’s disease, 133865-89-1 , сафинамид , سافيناميد沙非胺, EMD-1195686, ZP-034, FCE-28073(R-isomer), PNU-151774E, NW-1015, FCE-26743

C[C@H](NCC1=CC=C(OCC2=CC=CC(F)=C2)C=C1)C(N)=O

Novartis Kisqali® (ribociclib, LEE011) receives FDA approval as first-line treatment for HR+/HER2- metastatic breast cancer in combination with any aromatase inhibitor


Novartis logo: a global healthcare company

  • Approved based on a first-line Phase III trial that met its primary endpoint of progression-free survival (PFS) at interim analysis due to superior efficacy compared to letrozole alone[1]
  • At this interim analysis, Kisqali plus letrozole reduced risk of disease progression or death by 44% over letrozole alone, and demonstrated tumor burden reduction with a 53% overall response rate[1]
  • Kisqali plus letrozole showed treatment benefit across all patient subgroups regardless of disease burden or tumor location[1]
  • At a subsequent analysis with additional follow-up and progression events, a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole alone was observed[2]

Basel, March 13, 2017 The US Food and Drug Administration (FDA) has approved Kisqali®(ribociclib, formerly known as LEE011) in combination with an aromatase inhibitor as initial endocrine-based therapy for treatment of postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer.

Kisqali is a CDK4/6 inhibitor approved based on a first-line Phase III trial that met its primary endpoint early, demonstrating statistically significant improvement in progression-free survival (PFS) compared to letrozole alone at the first pre-planned interim analysis[1]. Kisqali was reviewed and approved under the FDA Breakthrough Therapy designation and Priority Review programs.

“Kisqali is emblematic of the innovation that Novartis continues to bring forward for people with HR+/HER2- metastatic breast cancer,” said Bruno Strigini, CEO, Novartis Oncology. “We at Novartis are proud of the comprehensive clinical program for Kisqali that has led to today’s approval and the new hope this medicine represents for patients and their families.”

The FDA approval is based on the superior efficacy and demonstrated safety of Kisqali plus letrozole versus letrozole alone in the pivotal Phase III MONALEESA-2 trial. The trial, which enrolled 668 postmenopausal women with HR+/HER2- advanced or metastatic breast cancer who received no prior systemic therapy for their advanced breast cancer, showed that Kisqali plus an aromatase inhibitor, letrozole, reduced the risk of progression or death by 44 percent over letrozole alone (median PFS not reached (95% CI: 19.3 months-not reached) vs. 14.7 months (95% CI: 13.0-16.5 months); HR=0.556 (95% CI: 0.429-0.720); p<0.0001)[1].

More than half of patients taking Kisqali plus letrozole remained alive and progression free at the time of interim analysis, therefore median PFS could not be determined[1]. At a subsequent analysis with additional 11-month follow-up and progression events, a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole alone was observed[2]. Overall survival data is not yet mature and will be available at a later date.

“In the MONALEESA-2 trial, ribociclib plus letrozole reduced the risk of disease progression or death by 44 percent over letrozole alone, and more than half of patients (53%) with measurable disease taking ribociclib plus letrozole experienced a tumor burden reduction of at least 30 percent. This is a significant result for women with this serious form of breast cancer,” said Gabriel N. Hortobagyi, MD, Professor of Medicine, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center and MONALEESA-2 Principal Investigator. “These results affirm that combination therapy with a CDK4/6 inhibitor like ribociclib and an aromatase inhibitor should be a new standard of care for initial treatment of HR+ advanced breast cancer.”

Kisqali is taken with or without food as a once-daily oral dose of 600 mg (three 200 mg tablets) for three weeks, followed by one week off treatment. Kisqali is taken in combination with four weeks of any aromatase inhibitor[1].

Breast cancer is the second most common cancer in American women[3]. The American Cancer Society estimates more than 250,000 women will be diagnosed with invasive breast cancer in 2017[3]. Up to one-third of patients with early-stage breast cancer will subsequently develop metastatic disease[4].

Novartis is committed to providing patients with access to medicines, as well as resources and support to address a range of needs. The Kisqali patient support program is available to help guide eligible patients through the various aspects of getting started on treatment, from providing educational information to helping them understand their insurance coverage and identify potential financial assistance options. For more information, patients and healthcare professionals can call 1-800-282-7630.

The full prescribing information for Kisqali can be found at https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kisqali.pdf(link is external).

About Kisqali® (ribociclib)
Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About the MONALEESA Clinical Trial Program
Novartis is continuing to assess Kisqali through the robust MONALEESA clinical trial program, which includes two additional Phase III trials, MONALEESA-3 and MONALEESA-7, that are evaluating Kisqali in multiple endocrine therapy combinations across a broad range of patients, including premenopausal women. MONALEESA-3 is evaluating Kisqali in combination with fulvestrant compared to fulvestrant alone in postmenopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy. MONALEESA-7 is investigating Kisqali in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in premenopausal women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy.

About Novartis in Advanced Breast Cancer
For more than 25 years, Novartis has been at the forefront of driving scientific advancements for breast cancer patients and improving clinical practice in collaboration with the global community. With one of the most diverse breast cancer pipelines and the largest number of breast cancer compounds in development, Novartis leads the industry in discovery of new therapies and combinations, especially in HR+ advanced breast cancer, the most common form of the disease.

Kisqali® (ribociclib) Important Safety Information
Kisqali® (ribociclib) can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Patients should tell their healthcare provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. Kisqali can cause serious liver problems. Patients should tell their healthcare provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking Kisqali and may result in infections that may be severe. Patients should tell their healthcare provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking Kisqali, patients should tell their healthcare provider if they are pregnant, or plan to become pregnant as Kisqali can harm an unborn baby. Females who are able to become pregnant and who take Kisqali should use effective birth control during treatment and for at least 3 weeks after the last dose of Kisqali. Do not breastfeed during treatment with Kisqali and for at least 3 weeks after the last dose of Kisqali. Patients should tell their healthcare provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with Kisqali. Patients should avoid pomegranate or pomegranate juice, and grapefruit or grapefruit juice while taking Kisqali. The most common side effects (incidence >=20%) of Kisqali when used with letrozole include white blood cell count decreases, nausea, tiredness, diarrhea, hair thinning or hair loss, vomiting, constipation, headache, and back pain. The most common grade 3/4 side effects in the Kisqali + letrozole arm (incidence >2%) were low neutrophils, low leukocytes, abnormal liver function tests, low lymphocytes, and vomiting. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Please see the Full Prescribing Information for Kisqali, available at https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kisqali.pdf(link is external).

About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

Novartis is on Twitter. Sign up to follow @Novartis and @NovartisCancer at http://twitter.com/novartis(link is external) and http://twitter.com/novartiscancer (link is external)
For Novartis multimedia content, please visit www.novartis.com/news/media-library
For questions about the site or required registration, please contact media.relations@novartis.com

References
[1] Kisqali (ribociclib) Prescribing information. East Hanover, New Jersey, USA: Novartis Pharmaceuticals Corporation; March 2016.
[2] Novartis Data on File
[3] American Cancer Society. How Common Is Breast Cancer? Available at https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html(link is external). Accessed January 23, 2017.
[4] O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. The Oncologist. 2005;10(Suppl 3):20-29.

Ribociclib skeletal.svg

рибоциклиб ريبوسيكليب 瑞波西利

Ribociclib « New Drug Approvals

////////////////Novartis,  Kisqali®, ribociclib, LEE011,  FDA 2017, HR+/HER2- metastatic breast cancer, рибоциклиб ريبوسيكليب 瑞波西利

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