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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......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 expands approval of Blincyto (blinatumomab) for treatment of a type of leukemia in patients who have a certain risk factor for relapse


Image result for blinatumomab

FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse

Blincyto (blinatumomab)

The U.S. Food and Drug Administration granted accelerated approval to Blincyto (blinatumomab) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). MRD refers to the presence of cancer cells below a level that can be seen under the microscope. In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse.Continue reading.

 

March 29, 2018

Release

The U.S. Food and Drug Administration granted accelerated approval to Blincyto (blinatumomab) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). MRD refers to the presence of cancer cells below a level that can be seen under the microscope. In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse.

“This is the first FDA-approved treatment for patients with MRD-positive ALL,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD.”

B-cell precursor ALL is a rapidly progressing type of cancer in which the bone marrow makes too many B-cell lymphocytes, an immature type of white blood cell. The National Cancer Institute estimates that approximately 5,960 people in the United States will be diagnosed with ALL this year and approximately 1,470 will die from the disease.

Blincyto works by attaching to CD19 protein on the leukemia cells and CD3 protein found on certain immune system cells. Bringing the immune cell close to the leukemia cell allows the immune cells to attack the leukemia cells better. The FDA first approved Blincyto under accelerated approval in December 2014 for the treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory positive B-cell precursor ALL. Full approval for this indication was granted in July 2017, and at that time, the indication was also expanded to include patients with Philadelphia chromosome-positive ALL.

The efficacy of Blincyto in MRD-positive ALL was shown in a single-arm clinical trial that included 86 patients in first or second complete remission who had detectable MRD in at least 1 out of 1,000 cells in their bone marrow. Efficacy was based on achievement of undetectable MRD in an assay that could detect at least one cancer cell in 10,000 cells after one cycle of Blincyto treatment, in addition to the length of time that the patients remained alive and in remission (hematological relapse-free survival). Overall, undetectable MRD was achieved by 70 patients. Over half of the patients remained alive and in remission for at least 22.3 months.

The side effects of Blincyto when used to treat MRD-positive B-cell precursor ALL are consistent with those seen in other uses of the drug. Common side effects include infections (bacterial and pathogen unspecified), fever (pyrexia), headache, infusion related reactions, low levels of certain blood cells (neutropenia, anemia), febrile neutropenia (neutropenia and fever) and low levels of platelets in the blood (thrombocytopenia).

Blincyto carries a boxed warning alerting patients and health care professionals that some clinical trial participants had problems with low blood pressure and difficulty breathing (cytokine release syndrome) at the start of the first treatment, experienced a short period of difficulty with thinking (encephalopathy) or other side effects in the nervous system. Serious risks of Blincyto include infections, effects on the ability to drive and use machines, inflammation in the pancreas (pancreatitis), and preparation and administration errors—instructions for preparation and administration should closely be followed. There is a risk of serious adverse reactions in pediatric patients due to benzyl alcohol preservative; therefore, the drug prepared with preservative free saline should be used for patients weighing less than 22 kilograms.

This new indication for Blincyto was approved under the accelerated approval pathway, 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 in randomized controlled trials is required to verify that achieving undetectable MRD with Blincyto improves survival or disease-free survival in patients with ALL.

The FDA granted this application Priority Review and it received Orphan Drugdesignation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Blincyto to Amgen Inc.

 

//////amgen, fda 2018,  Priority Review m  Orphan Drug designation, Blincyto, blinatumomab,

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BRUSH UP YOUR NMR, 4-(3,5-Dichloropyridin-4-yl)morpholine


str1

3,5-Dichloro-4-morpholinopyridine

Preparation of 4-(3,5-Dichloropyridin-4-yl)morpholine (5).(Pichowicz, M.Crumpler, S.McDonald, E.Blagg, J. Tetrahedron 2010662398DOI: 10.1016/j.tet.2010.01.101)

 5 as a light-orange solid.
1H NMR (CDCl3, 400 MHz): δ = 8.35 (2H, s), 3.84 (4H, m), 3.37 (4H, m);
13C NMR (CDCl3, 101 MHz): δ = 150.8, 149.3, 128.4, 67.4, 50.4;
HRMS–ESI+m/z [M + H]+ calcd for C9H11Cl2N2O+: 233.02429; found: 233.02446.
 1H NMR PREDICT
13C NMR PREDICT
DEPT PREDICT
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00009

/////////////

Clc2cncc(Cl)c2N1CCOCC1

Bedaquiline fumarate, ベダキリンフマル酸塩


Bedaquiline fumarate.png

Bedaquiline fumarate; Bedaquiline (fumarate); Cas 845533-86-0; UNII-P04QX2C1A5; P04QX2C1A5;

Bedaquiline fumarate

(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-naphthalen-1-yl-1-phenylbutan-2-ol;(E)-but-2-enedioic acid

  • R 207910
  • TMC 207
Molecular Formula: C36H35BrN2O6
Molecular Weight: 671.588 g/mol
Product
Formula
C32H31BrN2O2. C4H4O4
CAS

845533-86-0 FUMARATE
FREE FORM 843663-66-1
Mol weight
671.5769
2018/1/19  PMDA

JAPAN

APPROVED

Bedaquiline fumarate Sirturo Janssen Pharmaceutical

ベダキリンフマル酸塩
Bedaquiline Fumarate

C32H31BrN2O2▪C4H4O4 : 671.58
[845533-86-0]

FREE FORM

  1.  Saga, Yutaka; Journal of the American Chemical Society 2010, Vol132(23), Pg 7905-7907 , -168.0 ° Conc: 0.8 g/100mL; Solv:DMF; Wavlenght: 589.3 nm; Temp: 25 °C
  2.  Chandrasekhar, Srivari; European Journal of Organic Chemistry 2011, (11), PG 2057-2061, S2057/1-S2057/18  -165.2 °       Conc: 0.8 g/100mL; Solv: DMF ; Wavlenght: 589.3 nm; Temp: 25 °, MP 104 °C

EMA

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002614/WC500163215.pdf

The applicant Janssen-Cilag International N.V. submitted on 28 August 2012 an application for Marketing Authorisation to the European Medicines Agency (EMA) for SIRTURO, through the centralised procedure falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 21 July 2011. SIRTURO was designated as an orphan medicinal product EU/3/05/314 on 26 August 2005. SIRTURO was designated as an orphan medicinal product in the following indication: treatment of tuberculosis. The applicant applied for the following indication: SIRTURO is indicated in adults (≥ 18 years) as part of combination therapy of pulmonary tuberculosis due to multi-drug resistant Mycobacterium tuberculosis.

Disease to be treated About a third of the global population, more than 2 billion people, is infected with M. tuberculosis, of which the majority is latent. The life time risk to fall ill in overt TB is around 10% in general, but many times higher (around 10% annual risk) in untreated HIV-positive individuals. Tuberculosis is the leading cause of death in the latter population. It was estimated that a total of 8.8 million new TB cases occurred in 2010, including 1.1 million people co infected with HIV, and that about 1.45 million people died due to TB. During more recent years the burden of TB resistant to first line therapy has increased rapidly. Such multidrug resistant tuberculosis (defined later in this assessment report) has been reported in all regions of the world. Presently around 500.000 of new MDR cases are estimated to emerge every year, which is close to 5% of all new TB cases. China and India carried nearly 50% of the total burden of incident MDR-TB cases in 2008, followed by the Russian Federation (9%). The incidence of MDR-TB in US and EU was reported to be 1.1% and 2.4%, respectively. Within the EU, the incidence is much higher in certain Eastern European countries, with the largest burden in Romania, Latvia and Lithuania. MDR TB is an orphan disease in the EU, US and in Japan.

Current TB therapy and definitions Treatment of pulmonary drug susceptible TB typically takes 6 months resulting in cure rates in well over 90% of cases with good treatment adherence. The two most important drugs in this treatment are isoniazid (INH) and rifampicin (RIF). TB with resistance to at least both INH and RIF is called multidrug resistant (MDR) TB. The two most important “classes” of second-line TB drugs to be used in such cases are injectable drugs (the aminoglycosides amikacin and kanamycin, and the related agent capreomycin) and fluoroquinolones. Apart from these agents a number of miscellaneous drugs are used in addition, as part of combination therapy. The effectiveness of these latter miscellaneous drugs is generally lower, the tolerability is problematic and established breakpoints for resistance determination are lacking.

The term pre-XDR (pre-extensively drug resistant) TB is used when resistance is present also to one of the two main second-line class agents (injectables or any of the fluoroquinolones), and XDR-TB when resistance is present to INH+RIF + injectables + fluoroquinolones. The WHO standard treatment for MDR-TB is commonly divided into 2 phases: • a 4 to 6-month intensive treatment phase in which an injectable drug plus 3-4 other drugs, including a fluoroquinolone, • a continuation phase without the injectable drug and often without pyrazinamide (PZA) for a total duration of 18-24 months. Using this approach, cure rates in MDR-TB are much lower than those seen in DS-TB (ranging from less than 50% to around 75%), despite the higher number of agents and longer treatment duration. Hence, MDR TB is associated with a high mortality and is considered an important major threat to public health. More recent approaches to evaluate various MDR TB regimens have yielded somewhat more optimistic outcomes, despite shorter treatment durations. In these non-randomised studies (with low number of patients) cure rates in the range of 90% were achieved by including a fourth generation fluoroquinolone and by increasing the number of agents even further, to include up to 7 agents in the intensive phase, and still 4-5 agents in a second phase.

About the product SIRTURO (bedaquiline, formerly known as TMC 207) is a new agent of a unique class, specific for mycobacteria, and seemingly without cross-resistance to available TB agents. A large number of pre-clinical studies showed promising results for bedaquiline. For example, in animal models bedaquiline + pyrazinamide cured TB at a higher rate than the traditional first line combination, even when therapy was shortened for the former combination. The clinical program for bedaquiline has been aimed at treating MDR-TB, and data is now available from phase 2b studies of moderate size, both placebo-controlled and non-controlled studies. The treatments given in these studies were similar to those recommended by the WHO, although the number of agents used was slightly higher (five agents in the preferred background regimens). Bedaquiline (versus placebo in the controlled study) was added during the first (intensive) treatment phase, while the background regimens were generally unchanged throughout the complete course of therapy (18-24 months). On the basis of these studies, the applicant submitted an application for a conditional approval for bedaquiline, with the proposed indication: treatment of adult patients infected with pulmonary tuberculosis due to MDR M. tuberculosis, as part of combination therapy. In line with the approach in the phase 2 studies, Sirturo is only to be used during the first 6 months of therapy. However the planned pivotal study (as a specific obligation) will test for 40 weeks of bedaquiline treatment.

In 2009, the drug candidate was licensed to Global Alliance TB Drug Development by Tibotec worldwide for the treatment of tuberculosis.

Bedaquiline (INN) is chemically designated as (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4- (dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol with fumaric acid (1:1), and has the following structure:

str4

Bedaquiline fumarate is a white to almost white powder. It contains two asymmetric carbon atoms, C-1 (R), C-2 (S) and exhibits ability to rotate the orientation of linearly polarized light (optical rotation). The substance is non-hygroscopic. It is practically insoluble in aqueous media over a wide pH range and very slightly soluble in 0.01 N HCl. The substance is soluble in a variety of organic solvents. Due to the low solubility Log KD (log P) could not be determined experimentally. In Biopharmaceutics Classification System (BCS) bedaquiline is classified as a Class 2 compound (expressing low solubility and high permeability). Bedaquiline exists in only one non-solvated crystalline form: Form A. In addition 2 pseudopoly-morphs were found: Form B and Form C. The substance can also be made amorphous. Sufficient evidence was provided to demonstrate that Form A is obtained by the employed manufacturing process of the active substance. Particle size was considered a critical quality attribute of the active substance as bedaquiline is not dissolved in the dosage form. Therefore an appropriate test on particle size determination was included in the active substance specification. The acceptance criteria are based upon the capabilities of the milling process, batch and stability data, and the known impact of the particle size on manufacturability, in-vitro release, and in-vivo performance

Bedaquiline is a bactericidal antimycobacterial drug. Chemically it is a diarylquinoline. FDA approved on December 28, 2012.

Image result for Bedaquiline fumarate

Bedaquiline is indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB).

Bedaquiline, sold under the brand name Sirturo, is a medication used to treat active tuberculosis.[1] It is specifically used to treat multi-drug-resistant tuberculosis(MDR-TB) when other treatment cannot be used.[1][5] It should be used along with at least three other medications for tuberculosis.[1][5] It is used by mouth.[5]

Common side effects include nausea, joint pains, headaches, and chest pain.[1] Serious side effects include QT prolongation, liver dysfunction, and an increased risk of death.[1] While harm during pregnancy has not been found, it has not been well studied in this population.[6] It is in the diarylquinoline antimycobacterialclass of medications.[1] It works by blocking the ability of M. tuberculosis to make adenosine 5′-triphosphate (ATP).[1]

Bedaquiline was approved for medical use in the United States in 2012.[1] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] The cost for six months is approximately $900 USD in low income countries, $3,000 USD in middle income countries, and $30,000 USD in high income countries.[5]

SIRTURO (bedaquiline) for oral administration is available as 100 mg strength tablets. Each tablet contains 120.89 mg of bedaquiline fumarate drug substance, which is equivalent to 100 mg of bedaquiline. Bedaquiline is a diarylquinoline antimycobacterial drug.

Bedaquiline fumarate is a white to almost white powder and is practically insoluble in aqueous media. The chemical name of bedaquiline fumarate is (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4- (dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol compound with fumaric acid (1:1). It has a molecular formula of C32H31BrN2O2 · C4H4O4 and a molecular weight of 671.58 (555.50 + 116.07). The molecular structure of bedaquiline fumarate is the following:

SIRTURO (bedaquiline) Structural Formula Illustration

SIRTURO (bedaquiline) contains the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose 2910 15 mPa.s, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, purified water (removed during processing).

Medical uses

Its use was formally approved (Dec 2012) by the U.S. Food and Drug Administration (FDA) for use in tuberculosis (TB) treatment, as part of a Fast-Trackaccelerated approval, for use only in cases of multidrug-resistant tuberculosis, and the more resistant extensively drug resistant tuberculosis.[8]

As of 2013 Both the World Health Organization (WHO) and US Centers for Disease Control (CDC) have recommended (provisionally) that bedaquiline be reserved for patients with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed.[9][10]

Clinical trials

Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway.[11] It has been shown to improve cure rates of smear-positive multidrug-resistant tuberculosis, though with some concern for increased rates of death (further detailed in the Adverse effects section).[12]

Small studies have also examined its use as salvage therapy for non-tuberculous mycobacterial infections.[11]

It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid + moxifloxacin + pyrazinamide).[13][14]

Side effects

The most common side effects of bedaquiline in studies were nausea, joint and chest pain, and headache. The drug also has a black-box warning for increased risk of death and arrhythmias, as it may prolong the QT interval by blocking the hERG channel.[15] All patients on bedaquiline should have monitoring with a baseline and repeated ECGs.[16] If a patient has a QTcF of > 500ms or a significant ventricular arrythmia, bedaquiline and other QT prolonging drugs should be stopped.

There is considerable controversy over the approval for the drug, as one of the largest studies to date had more deaths in the group receiving bedaquiline that those receiving placebo.[17] 10 deaths occurred in the bedaquiline group out of 79, while 2 occurred in the placebo group, out of 81.[12] Of the 10 deaths on bedaquiline, 1 was due to a motor vehicle accident, 5 were judged as due to progression of the underlying tuberculosis and 3 were well after the patient had stopped receiving bedaquiline.[17] However, there is still significant concern for the higher mortality in patients treated with bedaquiline, leading to the recommendation to limit its use to situations where a 4 drug regimen cannot otherwise be constructed, limit use with other medications that prolong the QT interval and the placement of a prominent black box warning.[17][11]

Drug interactions

Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the hepatic enzyme responsible for oxidative metabolism of the drug.[16] Co-administration with rifampin, a strong CYP3A4 inducer, results in a 52% decrease in the AUC of the drug. This reduces the exposure of the body to the drug and decreases the antibacterial effect. Co-administration with ketoconazole, a strong CYP3A4 inhibitor, results in a 22% increase in the AUC, and potentially an increase in the rate of adverse effects experienced[16]

Since bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided.[9] Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones and clofazimine.

Mode of action

Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. ATP production is required for cellular energy production and its loss leads to cell death, even in dormant or nonreplicating mycobacteria.[18] It is the first member of a new class of drugs called the diarylquinolines.[18] Bedaquiline is bactericidal.[18]

Resistance

The specific part of ATP synthase affected by bedaquiline is subunit c which is encoded by the gene atpE. Mutations in atpE can lead to resistance. Mutations in drug efflux pumps have also been linked to resistance.[19]

History

Bedaquiline was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting, after the drug had been in development for over seven years.[20] It was discovered by a team led by Koen Andries at Janssen Pharmaceutica.[21]

Bedaquiline was approved for medical use in the United States in 2012.[1]

It is manufactured by Johnson & Johnson (J&J), who sought accelerated approval of the drug, a type of temporary approval for diseases lacking other viable treatment options.[22] By gaining approval for a drug that treats a neglected disease, J&J is now able to request expedited FDA review of a future drug.[23]

When it was approved by the FDA on the 28th December 2012, it was the first new medicine for TB in more than forty years.[24][25]

Bedaquiline, formally called (1R, 2S)-1-(6-Bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthyl)-1-phenyl-2-butanol in chemistry and known as Sirturo in commercial, is a new anti-mycobacterial medicine of diarylquinolines. It impinges on the
ATP synthesis of Mycobacterium tuberculosis by inhibiting the activity of proton pump on the cell’s ATP synthetase, and thereby eliminates M. tuberculosis (TB). It’s used for adult multi-drug resistant tuberculosis (MDR-PTB).

Image result for Bedaquiline fumarate

PATENT

US 20050148581

WO 2005117875

WO 2006125769

CA 2529265

WO 2006131519

JP 2011168519

CN 105017147

CN 105085395

CN 105198808

CN 105085396

WO 2016116076

WO 2016058564

WO 2016116075

WO 2016116073

WO 2016198031

CN 106866525

CN 106279017

CN 107602464

PATENT

WO 2017015793

The chemical name of beidaquinoline is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-dimethylamino-2-(1-naphthyl)-1 -Phenyl-2-butanol, the first drug developed by Johnson & Johnson in the United States to inhibit mycobacterium adenosine triphosphate (ATP) synthetase, was first introduced in the United States in December 2012 for the treatment of adult multidrug-resistant tuberculosis. The trade name is Sirturo. Beidaquinoline shows strong selectivity for Mycobacterium tuberculosis ATP synthase. Its novel mechanism of action makes it not cross-resistance with other anti-tuberculosis drugs, which will greatly reduce the drug resistance of Mycobacterium tuberculosis. It shows good activity against MDR-TB in macrophages, suggesting that it has the effect of shortening treatment time.

The synthesis of beidaquinoline has been reported in the literature. The specific synthesis route is as follows:

The patent WO2004011436 mentions the use of column chromatography to separate and purify the crude product, but this method is not conducive to industrialization; in addition, a method for isolating and purifying beraquinoline diastereomer A is disclosed in Step C of the Example of WO2006125769. . However, although the purity of the diastereomer A obtained by the separation and purification method disclosed in this patent is 82%, it is actually only possible to achieve the reaction conversion rate of more than 80%. The actual study found that due to the difficult control of the reaction conditions for the preparation of bedaquino, the control conditions for water, temperature, and drip rate are harsh and the reaction is unstable, and it cannot be ensured that the conversion rate reaches more than 80% per batch, and the conversion is usually When the rate is between 60-80%, the ratio of diastereomer B to diastereomer A obtained by this method is between 1:1 and 1:3, and the next step is chiral separation. It has an impact; even the conversion rate is sometimes as low as about 50%. When the conversion rate is as low as 50%, since the amount of the product in the reaction liquid is small, as in the method using patent WO 2006125769, the isolated product can hardly be purified even if the product is separated and purified by the purification method disclosed in this patent. The resulting diastereomer A is also of low purity.

Example 1
Reaction material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA (20g) reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 56%. After quenching the reaction, n-heptane (40 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 0° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 50% acetic acid aqueous solution to remove 3-dimethylamino-1-(naphthalene-5-yl)acetone as a raw material, and 15% hydrochloric acid aqueous solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by layering the filtrate, adjusted to alkaline with aqueous ammonia, extracted with toluene and free, and then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure to obtain a product that is not correct. Enantiomer A (4.9 g), purity 89%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetylene (40 ml), DMSO (4.9 ml), and R-binaphthol phosphate (2.62 g) were added to diastereomer A (4.9 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitates are separated out; at room temperature, the filter cake is washed with acetone and dried under vacuum at 50-60° C. to give a resolution salt (2.07 g);
Split salt (2.07g), toluene (37ml), potassium carbonate (1.51g) and water (13ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, organic layer was treated with 10% potassium carbonate aqueous solution ( (5ml) was washed once, at this time organic layer TLC monitoring; washed with purified water to neutral pH (20ml × 3 times); organic layer was concentrated under reduced pressure to give a colorless oil (1.5g); add toluene (1ml) to heat the whole Dissolve, add ethanol (12ml) and stir at room temperature for 0.5h. Precipitate the solid, and stir in ice water bath for 1h. Filter and wash the filter cake with ethanol. Dry it in vacuo at 50-60°C to give bedaquinoline (1.07g). The HPLC purity is >99%. .
Example 2
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 65%. After quenching the reaction, diisopropyl ether (160 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 5° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 10% aqueous formic acid to remove 3-dimethylamino-1-(naphthalene-5-yl)acetone as a raw material, and 5% aqueous sulfuric acid solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. Filtration, filtration of the filtrate, the product was transferred to the aqueous layer, the raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer, and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. The product was diastereoisomer A (5.7 g), purity 92%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (45 ml), DMSO (5.7 ml), and R-binaphthol phosphate (3.04 g) were added to diastereomer A (5.7 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. Cooling, precipitated salt precipitation; filtered at room temperature, washed with acetone cake, 50-60 ° C vacuum drying salt (2.6g);
The resolved salt (2.41 g), toluene (39 ml), potassium carbonate (1.58 g) and water (14 ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, the organic layer was treated with 10% aqueous potassium carbonate solution ( (5ml) was washed once, washed with purified water until the pH was neutral (20ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.6g); toluene was added (1ml) to heat the solution and ethanol was added (12ml) The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedalquinoline (1.19 g) with an HPLC purity of >99%.
Example 3
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 75%. After quenching the reaction, diisopropyl ether (400 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 2° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 60% aqueous solution of propionic acid to remove 3-dimethylamino-1-(naphthalen-5-yl)acetone as a raw material, and 40% methanesulfonic acid aqueous solution was added to the organic layer for stirring to make the product salified. Precipitated in the water layer. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (6.0 g), purity 94%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (48 ml), DMSO (6.0 ml), and R-binaphthol phosphate (3.09 g) were added to diastereomeric A (6.0 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give the resolved salt (2.59 g).
The resolved salt (2.59g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved; while hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5 ml) was washed once, washed with purified water until the pH was neutral (20 ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.7 g); toluene (1 ml) was added and heated to complete dissolution, and ethanol (12 ml) was added. The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedaquinoline (1.20 g) with an HPLC purity of >99%.
Example 4
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one step reaction to obtain the racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 70%. After quenching the reaction, petroleum ether (16 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 3° C. and filtered to remove diastereoisomer B. The obtained filtrate was washed with 30% acetic acid aqueous solution to remove 3-methylamino-1-(naphthalen-5-yl)acetone as a raw material, and 25% phosphoric acid aqueous solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be slightly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, and then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (5.72 g), purity 88%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetylene (45 ml), DMSO (5.7 ml), and R-binaphthol phosphate (3.04 g) were added to diastereomer A (5.72 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated out; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give a resolution salt (2.43 g);
Split salt (2.43g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5 ml) was washed once, washed with purified water until the pH was neutral (20 ml x 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.5 g); toluene (1 ml) was added for heating and ethanol was added (12 ml) The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, and the filter cake was washed with ethanol. Drying in vacuo at 50-60° C. gave bedaquinoline (1.16 g) with an HPLC purity of >99%.
Example 5
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one step reaction to obtain the racemic bedaquiline reaction solution. The conversion of this reaction was 80% by HPLC analysis. After quenching the reaction, n-hexane (80 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 1° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 40% aqueous acetic acid to remove 3-dimethylamino-1-(naphthalen-5-yl)acetone as starting material, and 20% aqueous hydrochloric acid solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (6.1 g), purity 96%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (48 ml), DMSO (6.1 ml), and R-binaphthol phosphate (3.09 g) were added to diastereomer A (6.1 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated out; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give the resolution salt (2.69 g).
The resolved salt (2.69g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved; while hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5ml) was washed once, washed with purified water until the pH was neutral (20ml×3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.8g); toluene (1ml) was added to heat to dissolve and ethanol (12ml) was added. The precipitated solid was stirred for 0.5 h at room temperature, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedalquinoline (1.28 g) with an HPLC purity of >99%.

PAPER

ACS Medicinal Chemistry Letters (2017), 8(10), 1019-1024

6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
 Medicinal Chemistry Department (Infectious Diseases), Janssen Pharmaceuticals, Campus de Maigremont, BP315, 27106 Val de Reuil Cedex, France
§ Global Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, United States
 Infectious Diseases BVBA, Janssen Pharmaceuticals, Beerse, Belgium
 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
ACS Med. Chem. Lett.20178 (10), pp 1019–1024
DOI: 10.1021/acsmedchemlett.7b00196
Publication Date (Web): September 22, 2017
Copyright © 2017 American Chemical Society

Abstract

Abstract Image

Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.

PAPER

Chinese Chemical Letters (2015), 26(6), 790-792

PAPER

Organic & Biomolecular Chemistry (2016), 14(40), 9622-9628.

http://pubs.rsc.org/en/content/articlelanding/2016/ob/c6ob01893a/unauth#!divAbstract

New synthetic approaches towards analogues of bedaquiline

Abstract

Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.

Graphical abstract: New synthetic approaches towards analogues of bedaquiline
http://www.rsc.org/suppdata/c6/ob/c6ob01893a/c6ob01893a1.pdf

PAPER

 Topics in Organometallic Chemistry (2011), 37(Bifunctional Molecular Catalysis), 1-30

PAPER

Saga, Yutaka; Journal of the American Chemical Society 2010, Vol132(23), Pg 7905-7907

Catalytic Asymmetric Synthesis of R207910

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
J. Am. Chem. Soc.2010132 (23), pp 7905–7907
DOI: 10.1021/ja103183r
Publication Date (Web): May 20, 2010
Copyright © 2010 American Chemical Society

Abstract

Abstract Image

The first asymmetric synthesis of a very promising antituberculosis drug candidate, R207910, was achieved by developing two novel catalytic transformations; a catalytic enantioselective proton migration and a catalytic diastereoselective allylation of an intermediate α-chiral ketone. Using 2.5 mol % of a Y-catalyst derived from Y(HMDS)3 and the new chiral ligand 9, 1.25 mol % of p-methoxypyridine N-oxide (MEPO), and 0.5 mol % of Bu4NCl, α-chiral ketone 3 was produced from enone 4 with 88% ee. This reaction proceeded through a catalytic chiral Y-dienolate generation via deprotonation at the γ-position of 4, followed by regio- and enantioselective protonation at the α-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu4NCl markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization. The second key catalytic allylation of ketone 3 was promoted by CuF•3PPh3•2EtOH (10 mol %) in the presence of KOtBu (15 mol %), ZnCl2 (1 equiv), and Bu4PBF4 (1 equiv), giving the desired diastereomer 2 in quantitative yield with a 14: 1 ratio without any epimerization at the α-stereocenter. It is noteworthy that conventional organometallic addition reactions did not produce the desired products due to the high steric demand and a fairly acidic α-proton in substrate ketone 3. This first catalytic asymmetric synthesis of R207910 includes 12 longest linear steps from commercially available compounds with an overall yield of 5%.

https://pubs.acs.org/doi/suppl/10.1021/ja103183r/suppl_file/ja103183r_si_001.pdf

1 in 62 % yield (6.5 mg, 0.012 mmol ). 1H NMR (500 MHz, CDCl3) : 1.91-1.95 (m, 1H), 1.98 (s, 6H), 1.99-2.10 (m, 2H), 2.52 (d, J = 14.1 Hz, 1H), 4.21 (s, 3H), 5.89 (s, 1H), 6.87-6.89 (m, 3H), 7.10-7.15 (m, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 8.5 Hz, 1H), 7.61 (t, J = 8.5 Hz, 1H), 7.63-7.67 (m, 2H), 7.72 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 2.2 Hz, 1H), 8.60 (d, J = 8.5 Hz, 1H), 8.89 (s, 1H); 13C NMR (126 MHz, CDCl3) : 29.7, 33.5, 44.7, 49.5, 54.2, 56.4, 82.6, 117.0, 124.5, 125.0, 125.1, 125.3, 125.8, 126.9, 127.1, 127.4, 127.9, 128.0, 128.1, 128.5, 129.8, 129.9, 131.9, 132.7, 133.3, 134.7, 138.8, 140.6, 141.8, 143.8, 161.4; IR (KBr, cm-1 ):  3443; MS (ESI) m/z 555 (M+H) + ; HRMS (FAB) calcd for C32H32N2O2Br (M+H) + 555.1647. Found 555.1644; [] 26 D – (c = 0.3, DMF).

PAPER

Gaurrand, Sandrine; Chemical Biology & Drug Design 2006, VOL 68(2), PG 77-84 

http://web.a.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=1&sid=fac0fcc3-2a10-4f5f-8e20-d057adf71ce9%40sessionmgr4006

str1 str2

PAPER

Chandrasekhar, Srivari; European Journal of Organic Chemistry 2011, (11), PG 2057-2061, S2057/1-S2057/18

Srivari Chandrasekhar

Dr.Chandrasekhar S
Director 
CSIR-Indian Institute of Chemical Technology                              
(Council of Scientific and Industrial Research)
Ministry of Science & Technology, Government of India
Tarnaka, Hyderabad-500007, Telangana, INDIA

Landline 27193030
Mobile 9440802787
Fax
Email ID director@iict.res.in
Alternate Email ID srivaric@iict.res.in
Alternate URL http://www.iictindia.org/staffprofiles/staffProfile.aspx?emp_id=iict1372

READ

http://www.iictindia.org/staffprofiles/staffprofile.aspx?qry=1372

(1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)- 2-(naphthalen-1-yl)-1-phenylbut-an-2-ol (3a): A solution of 16a and 16b (6.0 g, 10.2 mmol) in Me2NH (200 mL, 8.0 m in THF) was stirred at 45 °C for 24 h. The solution was filtered and the filtrate concentrated under reduced pressure to afford the crude product which on purification by silica gel column chromatography (eluent: ethyl acetate/hexane = 1:6) furnished 3a and 3b as white solids (4.8 g, 90%) (1:1 w/w).

3a: M.p. 104 °C. [α]D 25 = –165.2 (c = 0.8, DMF). (2S)- R207910 (3a)

1 H NMR (300 MHz, CDCl3): δ = 8.89 (s, 1 H, H4), 8.61 (d, J = 8.6 Hz, 1 H, H20), 7.96 (d, J = 2.0 Hz, 1 H, H5), 7.92 (d, J = 7.4 Hz, 1 H, H14), 7.87 (d, J = 8.1 Hz, 1 H, H17), 7.72 (d, J = 8.8 Hz, 1 H, H8), 7.68–7.56 (m, 3 H, H7, H16, H19), 7.48 (t, J = 7.6 Hz, 1 H, H18), 7.30 (t, J = 7.7 Hz, 1 H, H15), 7.17–7.10 (m, 2 H, H24), 6.93–6.83 (m, 3 H, H25, H26), 5.89 (s, 1 H, H11), 4.21 (s, 3 H, H30), 2.60–2.51 (m, 1 H, H27), 2.18–2.02 (m, 2 H, H27, H28), 1.99 (s, 6 H, H29), 1.95–1.85 (m, 1 H, H28) ppm.

13C NMR (75 MHz, CDCl3): δ = 161.3, 143.7, 141.6, 140.5, 138.7, 134.6, 131.9, 129.9, 129.8, 129.7, 128.4, 128.1, 127.8, 127.3, 127.1, 126.8, 125.7, 125.2, 125.1, 125.0, 124.4, 116.9, 82.4, 56.2, 54.1, 49.5, 44.6, 33.4, 29.6 ppm.

IR (KBr): ν˜ = 3441 cm–1.

HRMS (ESI) calcd. for C32H32BrN2O2 [M + H]+ 555.1642; found 555.1671.

(2R)-R207910

References[

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Bedaquiline
Bedaquiline.svg
Clinical data
Trade names Sirturo
Synonyms Bedaquiline fumarate,[1]TMC207,[2] R207910, AIDS222089
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration
by mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding >99.9% [4]
Metabolism Liver, by CYP3A4[3]
Biological half-life 5.5 months [3]
Excretion fecal[3]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C32H31BrN2O2
Molar mass 555.5 g/mol
3D model (JSmol)

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 2 (FDA Orange Book Patent ID)
Patent 8546428
Expiration Mar 19, 2029
Applicant JANSSEN THERAP
Drug Application N204384 (Prescription Drug: SIRTURO. Ingredients: BEDAQUILINE FUMARATE)
FDA Orange Book Patents: 2 of 2 (FDA Orange Book Patent ID)
Patent 7498343
Expiration Oct 2, 2024
Applicant JANSSEN THERAP
Drug Application N204384 (Prescription Drug: SIRTURO. Ingredients: BEDAQUILINE FUMARATE)
Patent ID

Patent Title

Submitted Date

Granted Date

US7498343 Mycobacterial inhibitors
2005-07-07
2009-03-03
US8546428 FUMARATE SALT OF (ALPHA S, BETA R)-6-BROMO-ALPHA-[2-(DIMETHYLAMINO)ETHYL]-2-METHOXY-ALPHA-1-NAPHTHALENYL-BETA-PHENYL-3-QUINOLINEETHANOL
2010-02-04

//////////////Bedaquiline, JAPAN 2018, R 207910, Sirturo, TMC 207, FDA 2012, EMA 2014, ベダキリンフマル酸塩

CN(C)CCC(C1=CC=CC2=CC=CC=C21)(C(C3=CC=CC=C3)C4=C(N=C5C=CC(=CC5=C4)Br)OC)O.C(=CC(=O)O)C(=O)O

Cafestol


Cafestol, a Bioactive Substance in Coffee, Has Antidiabetic Properties in KKAy Mice https://lnkd.in/e7BxMkg

Image result for Cafesterol

ChemSpider 2D Image | Cafesterol | C20H28O3

Image result for Cafesterol

Cafesterol

  • Molecular FormulaC20H28O3
  • Average mass316.435 Da
  • (1S,4S,12S,13R,16S,17R)-17-(Hydroxymethyl)-12-methyl-8-oxapentacyclo[14.2.1.01,13.04,12.05,9]nonadeca-5(9),6-dien-17-ol
    (1S,4S,12S,13R,16S,17R)-17-(Hydroxymethyl)-12-methyl-8-oxapentacyclo[14.2.1.01,13.04,12.05,9]nonadeca-5(9),6-dien-17-ol
    (1S,4S,12S,13R,16S,17R)-17-(Hydroxyméthyl)-12-méthyl-8-oxapentacyclo[14.2.1.01,13.04,12.05,9]nonadéca-5(9),6-dién-17-ol
    (3bS,5aS,7R,10aR,10bS)-7-(hydroxymethyl)-10b-methyl-3b,4,5,6,7,8,9,10,10a,10b,11,12-dodecahydro-5a,8-methanocyclohepta[5,6]naphtho[2,1-b]furan-7-ol
    [3bS-(3ba,5ab,7b,8b-10aa,10bb)]-3b,4,5,6,7,8,9,10,10a,10b,11,12-Dodecahydro-7-hydroxy-10b-methyl-5a,8-methano-5aH-cyclohepta[5,6]-naphtho[2,1-b]furan-7-methanol
    Cafesterol
    469-83-0 [RN]

Scientists identify health benefits of cafestol in coffee

Scientists have identified two compounds in coffee – cafestol and caffeic acid – that could someday lead to the development of new medications to better prevent and treat type 2 diabetes…

Drinking three to four cups of coffee per day has been shown to decrease the risk of developing type 2 diabetes.

Now, scientists report they have identified two compounds that contribute to this health benefit. Researchers say that this knowledge could someday help them develop new medications to better prevent and treat the disease.

Patients with type 2 diabetes become resistant to insulin, a hormone that helps turn glucose from food into energy. To overcome this resistance, the pancreas makes more insulin, but eventually, it just can’t make enough. High blood glucose levels can cause health problems, such as blindness and nerve damage.

Coffee’s cafestol has dual benefits

Several genetic and life style risk factors have been linked to the development of type 2 diabetes, but drinking coffee has been shown to help prevent its onset. Caffeine was thought to be responsible, but studies have shown it has only a short-term effect on glucose and insulin, and decaffeinated coffee has the same effect as the regular version of the drink. To investigate which of coffee’s many bioactive components are responsible for diabetes prevention, Søren Gregersen and colleagues tested the effects of different coffee substances in rat cell lines.

The researchers investigated different coffee compounds’ effects on cells in the lab. Cafestol and caffeic acid both increased insulin secretion when glucose was added. The team also found that cafestol increased glucose uptake in muscle cells, matching the levels of a currently prescribed antidiabetic drug. They say cafestol’s dual benefits make it a good candidate for the prevention and treatment of type 2 diabetes. However, because coffee filters eliminate much of the cafestol in drip coffee, it is likely that other compounds also contribute to these health benefits.

LINK….https://www.newfoodmagazine.com/news/21531/scientists-identify-health-benefits-of-cafestol-in-coffee/

Image result for Cafesterol

Cafestol
Cafestol.svg
Names
IUPAC name

(3bS,5aS,7R,8R,10aR,10bS)-3b,4,5,6,7,8,9,10,10a,10b,11,12-Dodecahydro-7-hydroxy-10b-methyl-5a,8-methano-5aH-cyclohepta[5,6]naphtho[2,1-b]furan-7-methanol
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
PubChem CID
UNII
Properties
C20H28O3
Molar mass 316.44 g·mol−1
Melting point 158 to 162 °C (316 to 324 °F; 431 to 435 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Cafestol
Structural Formula Vector Image
Title: Cafestol
CAS Registry Number: 469-83-0
CAS Name: [3bS-(3ba,5ab,7b,8b,10aa,10bb)]-3b,4,5,6,7,8,9,10,10a,10b,11,12-Dodecahydro-7-hydroxy-10b-methyl-5a,8-methano-5aH-cyclohepta[5,6]naphtho[2,1-b]furan-7-methanol
Additional Names: cafesterol
Molecular Formula: C20H28O3
Molecular Weight: 316.43
Percent Composition: C 75.91%, H 8.92%, O 15.17%
Literature References: Diterpenoid constituent of coffee. Isoln from green coffee oil: Slotta, Neisser, Ber. 71, 1991, 2342 (1938); C. Djerassi et al., J. Org. Chem. 18, 1449 (1953). Prepn and purification: R. Bertholet, US 4692534 (1987 to Nestec). Structure: C. Djerassi et al., J. Am. Chem. Soc. 81, 2386 (1959); R. A. Finnegan, C. Djerassi, ibid. 82, 4342 (1960). Stereochemical studies: R. A. Finnegan, J. Org. Chem. 26, 3057 (1961); A. I. Scott et al., J. Am. Chem. Soc. 84, 3197 (1962); A. I. Scott et al., Tetrahedron20, 1339 (1964). Stereospecific total synthesis of (±)-form: E. J. Corey et al., J. Am. Chem. Soc. 109, 4717 (1987).
Properties: Crystals from hexane, mp 158°-l60°. [a]D -101°. uv max: 222 nm (log e 3.78).
Melting point: mp 158°-l60°
Optical Rotation: [a]D -101°
Absorption maximum: uv max: 222 nm (log e 3.78)
Derivative Type: Acetate
Molecular Formula: C22H30O4
Molecular Weight: 358.47
Percent Composition: C 73.71%, H 8.44%, O 17.85%
Properties: Needles from petr ether, mp 167-168°. [a]D -89°. uv max: 222 nm (log e 3.80).
Melting point: mp 167-168°
Optical Rotation: [a]D -89°
Absorption maximum: uv max: 222 nm (log e 3.80)
Derivative Type: Tetrahydrocafestol
Molecular Formula: C20H32O3
Molecular Weight: 320.47
Percent Composition: C 74.96%, H 10.06%, O 14.98%
Properties: Crystals from dil methanol, mp 154.5-157°.
Melting point: mp 154.5-157°

//////////Cafesterol

CC12CCC3=C(C1CCC45C2CCC(C4)C(C5)(CO)O)C=CO3

Fosravuconazole L-lysine ethanolate, ホスラブコナゾール L-リシンエタノール付加物


Image result for Fosravuconazole L-lysine ethanolate

Image result for Fosravuconazole L-lysine ethanolate

C23H20F2N5O5PS▪C6H14N2O2▪C2H6O : 739.73
[914361-45-8]

[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butan-2-yl]oxymethyl dihydrogen phosphate;(2S)-2,6-diaminohexanoic acid;ethanol

L-Lysine [[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-yl]oxy]methyl dihydrogen phosphate ethanol

BFE-1224
BMS-379224
E-1224

ravuconazole prodrugs, ravuconazole methyl phosphate

fosravuconazole bis(L-lysine)

ホスラブコナゾール L-リシンエタノール付加物

Formula
C23H20F2N5O5PS. C6H14N2O2. C2H6O
CAS
914361-45-8
Mol weight
739.727

Antifungal, Ergosterol biosynthesis inhibitor

Fungal infection; Onychomycosis; Trypanosoma cruzi infection

PMDA JAPAN APPROVED

2018/1/19 PMDA APPROVED Fosravuconazole L-lysine ethanolate Nailin Sato Pharmaceutical

FOR

Tinea, nail (onychomycosis)

NOTE THIS STR

Image result for fosravuconazole

  • 4-[2-[(1R,2R)-2-(2,4-Difluorophenyl)-1-methyl-2-[(phosphonooxy)methoxy]-3-(1H-1,2,4-triazol-1-yl)propyl]-4-thiazolyl]benzonitrile
  • E 1224
  • Fosravuconazole
  • CAS  351227-64-0

Drugs for Neglected Diseases initiative (DNDi), under license from Eisai, is developing fosravuconazole for CD  and eumycetoma 

In February 2013, the drug was in phase II/III development by Seren Pharmaceuticals for onychomycosis in North America, Europe and Asia, including Japan,

In 2010, the product was licensed exclusively to Brain Factory (now Seren Pharma) for development, commercialization and sublicense in Japan for the treatment of fungal infections. In 2014, Seren Pharma signed an agreement with Sato Pharma, granting them the development and commercialization rights of the product in Japan

Sato Pharmaceutical Co., Ltd. has obtained marketing and manufacturing approval for the oral antifungal agent, Nailin capsules 100mg containing the active ingredient fosravuconazole L-lysine ethanolate (fosravuconazole) for the treatment of onychomycosis in Japan.

Sato Pharma conducted a phase III clinical study of the agent in patients with onychomycosis in Japan, and after confirming efficacy and safety of the agent in the study, the company applied for marketing and manufacturing authorization in January 2017.

Fosravuconazole, the active ingredient of Nailin capsules 100mg, is a new triazole class oral antifungal component discovered by Eisai.

Fosravuconazole, the active ingredient of Nailin capsules 100mg, is a new triazole class oral antifungal component discovered by Eisai. By providing Nailin capsules 100mg as a new option for the treatment of onychomycosis, Sato Pharma and Eisai will strive to fulfil the needs of onychomycosis patients and healthcare professionals.

Onychomycosis is a fungal infection of the toenails or fingernails that may involve any component of the nail unit, including the matrix, bed, or plate. With Sato Pharma now having obtained marketing and manufacturing approval for Nailin capsules 100mg, as an oral treatment for onychomycosis, this is the first new treatment for the disease in approximately 20 years.

Fosravuconazole is a prodrug of ravuconazole originated by Eisai. In 2018, the product was approved in Japan for the treatment of onychomycosis. Fosravuconazole is being tested in phase II clinical studies at Eisai and Drugs for Neglected Diseases Initiative (DNDi) for the treatment of american trypanosomiasis (Chagas disease)

Image result for Fosravuconazole L-lysine ethanolate WIKI

Onychomycosis due to Trichophyton rubrum, right and left great toe. Tinea unguium.
Image/CDC

Sato Pharmaceutical Co., Ltd. obtained marketing and manufacturing approval for the oral antifungal agent NAILIN Capsules 100mg containing the active ingredient fosravuconazole L-lysine ethanolate (fosravuconazole) for the treatment of onychomycosis in Japan on January 19, 2018.
Fosravuconazole, the active ingredient of NAILIN Capsules 100mg, is a new triazole class oral antifungal component discovered by Eisai. Sato Pharma conducted a Phase III clinical study of the agent in patients with onychomycosis in Japan, and after confirming efficacy and safety of the agent in the study, Sato Pharma applied for marketing and manufacturing authorization in January 2017.Sato Pharma and Eisai Co., Ltd. are jointly providing information on its proper use.

Onychomycosis is a fungal infection of the toenails or fingernails that may involve any component of the nail unit, including the matrix, bed, or plate.

Onychomycosis affects 1 in every 10 Japanese people, and there are an estimated approximately 11 million sufferers in Japan. With Sato Pharma now having obtained marketing and manufacturing approval for NAILIN Capsules 100mg, as an oral treatment for onychomycosis, this is the first new treatment for the disease in approximately 20 years.

Image result for Onychomycosis

Sato Pharmaceutical Co. Ltd., Eisai Co. Ltd., and Seren Pharmaceuticals Inc. announced that Sato Pharma and Eisai will co-promote a new triazole class oral antifungal agent (development code: BFE1224) containing the active ingredient fosravuconazole L-lysine ethanolate (fosravuconazole) in Japan, based on an agreement between the three companies. The agent is currently under regulatory review for the treatment of onychomycosis.

After receiving regulatory approval, Sato Pharma will begin distributing the agent, and Sato Pharma and Eisai will jointly provide information on its proper use.

Fosravuconazole is a new oral antifungal component developed by Eisai. In 2010, Eisai concluded a license agreement with Seren Pharma (formerly known as Brain Factory Co., Ltd.), granting them exclusive rights to develop, commercialize, and sublicense the agent in Japan.

In 2014, Seren Pharma concluded an agreement with Sato Pharma, granting them the development and commercialization rights, and both companies continued to develop the agent for treating onychomycosis. In January 2017, Sato Pharma applied for marketing authorization for the agent.

Sato Pharma, Eisai, and Serena Pharma will cooperate to maximize the value of fosravuconazole in order to fulfil the unmet medical needs of patients with fungal diseases.

Courtesy- techno.bigmir

PATENT

WO 2006118351

Journal of the American Chemical Society, 139(31), 10733-10741; 2017

PAPER

BMS-379224, a water-soluble prodrug of ravuconazole
42nd Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 27-30, San Diego) 2002, Abst F-817

PATENT

WO 2006118351

WO 2007072851

WO 2001052852

WO 2006026274

WO 2013082102

WO 2013157584

////////////ホスラブコナゾール L-リシンエタノール付加物, Fosravuconazole L-lysine ethanolate, Nailin, SATO, BFE-1224, BMS-379224, E-1224, JAPAN 2018, ravuconazole prodrugs, ravuconazole methyl phosphate, fosravuconazole bis(L-lysine), Drugs for Neglected Diseases initiative, DNDi

CCO.CC(C1=NC(=CS1)C2=CC=C(C=C2)C#N)C(CN3C=NC=N3)(C4=C(C=C(C=C4)F)F)OCOP(=O)(O)O.C(CCN)CC(C(=O)O)N

ELECLAZINE, элеклазин , إيليكلازين , 依来克秦 , REVISITED


Eleclazine.pngChemSpider 2D Image | eleclazine | C21H16F3N3O3

ELECLAZINE

GS-6615

Molecular Formula: C21H16F3N3O3
Molecular Weight: 415.372 g/mol

1443211-72-0

4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one

4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3,4,5- tetrahydro-1,4- benzoxazepin-5-one

7-(4-(Trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one

1,4-Benzoxazepin-5(2H)-one, 3,4-dihydro-4-(2-pyrimidinylmethyl)-7-[4-(trifluoromethoxy)phenyl]-

Eleclazine; UNII-PUY08529FK; 1443211-72-0; GS-6615; PUY08529FK; 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-on

элеклазин [Russian] [INN]
إيليكلازين [Arabic] [INN]
依来克秦 [Chinese] [INN]
  • Phase III Long QT syndrome
INGREDIENT UNII CAS
Eleclazine Hydrochloride 4R1JP3Q4HI 1448754-43-5

Eleclazine has been used in trials studying the treatment of LQT2 Syndrome, Long QT Syndrome, Ischemic Heart Disease, Ventricular Arrhythmia, and Long QT Syndrome Type 3, among others.

In 2015, orphan drug designation was assigned to the product by the FDA for the treatment of congenital long QT syndrome.

  • Originator Gilead Sciences
  • Class Antiarrhythmics; Ischaemic heart disorder therapies; Pyrimidines; Small molecules; Vasodilators
  • Mechanism of Action Sodium channel antagonists

Highest Development Phases

  • Phase III  Long QT syndrome
  • Phase II/III Hypertrophic cardiomyopathy
  • Phase II Ventricular arrhythmias
  • No development reported Ischaemic heart disorders

Most Recent Events

  • 15 Nov 2017 Gilead Sciences presents safety and adverse events data from a phase III trial in Long QT syndrome type 3 at the 90th Annual Scientific Sessions of the American Heart Association (AHA-2017)
  • 11 Nov 2017 Efficacy data from the phase II TEMPO trial in Ventricular arrthymmia presented at the 90th Annual Scientific Sessions of the American Heart Association
  • 17 Feb 2017 Gilead Sciences terminates a phase II/III trial in Hypertrophic cardiomyopathy in Australia, France, Germany, Israel, Italy, Netherlands, USA and United Kingdom (NCT02291237)
  • Gilead Sciences was developing eleclazine (GS-6615), a late sodium current inhibitor, for the potential oral (tablet) treatment of hypertrophic cardiomyopathy and arrhythmias including long QT-3 (LQT3) syndrome.

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Long QT syndrome

The late sodium current (INaL) is a component of the fast Na+ current of cardiac myocytes and neurons. Late sodium current in cardiac cells is small compared with the fast component, but it may make a large contribution to sodium loading during each cardiac cycle. Impaired sodium channel function contributes to pathologic increase of the late sodium current, sodium overload, and sodium-induced calcium overload by way of the sodium-calcium exchanger. Calcium overload causes impaired diastolic relaxation, which increases diastolic wall tension, increases myocardial oxygen demand, reduces myocardial blood flow and oxygen supply, microvascular perfusion, and worsens ischemia and angina. Many common neurological and cardiac conditions are associated with abnormal (INaL) augmentation, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals. Inhibiting the late sodium current can lead to reductions in elevated intracellular calcium levels, which, in turn, may lead to reduced tension in the heart wall and reduced oxygen requirements for the heart muscle. Inhibition of cardiac late sodium current is a strategy used to suppress arrhythmias and sodium -dependent calcium overload associated with myocardial i schemia and heart failures. Thus, compounds that selectively inhibit the iate sodium current (INaL) in mammals may be useful in treating such disease states.

Eleclazine (4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)pheny l)-3,4-dihydrobenzo[b]oxepin-5(2H)-one]; CAS # 144321 1-72-0) is an inhibitor of the late sodium current, Eleclazine is being investigated for the treatment of cardiomyopathy, specifically hypertrophic cardiomyopathy, as well as additional cardiovascular indications, including angina, heart failure, atrial fibrillation (AF), ischemic heart disorders, atrial premature beats (APBs), myocardial isch mia, and arrhythmias.

Eleclazine

Eleclazine shows a shortening of the QTc interval (the time interval between the start of the Q-wave and the end of T-wave in the electrical cycle of the heart) in patients with QT-3 (LQT3) sydrome. LQTS is a genetic disorder that prolongs the heart’s QTc interval and can cause life-threatening cardiac arrhythmias. Therefore, eleclazine is also being investigated for treatment of long QT syndrome.

Eleclazine may be metabolized in the liver and may be subject to extensive cytochrome P450-mediated oxidative metabolism. Eleclazine is metabolized predominantly by N-dealkylation, and elimination is principally in the bile and gastrointestinal tract. The primary metabolite of eleclazine is GS-623134

Adverse effects associated with eleclazine may include dizziness, dry mouth, nausea, weakness, ringing in ears, tremors, and the like. Additionally, some metabolites of eleclazine, particularly the metabolite GS 623134, may have undesirable side effects.

PATENT

PRODUCT, WO 2013112932, WO 2013006485

WO 2013006463

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013006463&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

WO 2013006463 , ( US8962610 ) hold protection in the EU states until 2032 and in US until 2033 with US154 extension.

PATENT

WO 2015017661

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015017661

Provided herein is a method for reducing the prolongation of the QT interval in a human patient, said method comprising administering to the patient an effective amount of Compound 1:

Example 1: 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4- dihydrobenzo[f][1,4]oxazepin-5(2H)-one (Compound 1)

To a solution of Compound 1-A (20 g, 0.083 mol, 1 eq.) and Compound 1-B (25 g, 0.15 mol, 1.8 eq.) in DMF (150 mL), NaOH solution (20 mL, 10 M, 5 eq.) was slowly added at room temperature (slightly exothermic) and stirred at r.t. for 10 min, followed by heating at 95 °C for 2 h. After cooling the reaction mixture, ethyl acetate (200 mL) was added and the organic layer was separated. The organics was washed with water (20 mL), brine, dried over sodium sulphate and concentrated.

The residue was dissolved in 1,4-dioxane (50 mL) and to this 4 N HCl in dioxane (50 mL) and cone. HCl ( 2 mL) was added and stirred at room temperature for 4 h, filtered the precipitate, washed with ethyl acetate and dried. Compound 1-C was obtained (30 g) as a light yellow solid.

To the bromide (15 g, 0.04 mol, 1 eq), boronic acid (12.5 g, 0.06 mol, 1.5 eq) and potassium carbonate (22 g, 0.16 mol, 4 eq) in a round bottom flask, solvent (150 mL, toluene/isopropanol/water : 2/1/1) was added and stirred under nitrogen for 10 min. To the above solution the palladium catalyst (1 g, 0.012 mol, 0.02 eq) was added and heated at 85 °C for 2h. The reaction mixture was diluted with ethyl acetate, separated the organic layer and filtered the organic layer through a plug of celite and silica gel and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided Compound 1 (13 g).

To a solution of Compound 1 (26 g) in 1,4-dioxane (25 mL), 4N HCl/dioxane (25 mL) was added followed by cone. HCl (2 mL) and stirred at room temperature for 4h. Solvent was distilled off, dichlorom ethane was added and distilled off and to the residue, ethyl acetate (150 mL) was added and stirred at room temperature overnight and filtered the precipitate, washed with ethyl acetate, hexane and dried under vacuum. Compound 1-HCl obtained (24.8 g) was a white solid.

1H-NMR (CDCl3) 5 8.72 (d, 2H, J= 5.2 Hz), 8.17 (d, 1H, J= 2.4 Hz), 7.59-7.63 (m, 3H), 7.26 (d, 2H, J= 3.2 Hz), 7.22 (t, 1H, J= 4.8 Hz), 7.10 (d, 1H, J= 8.4 Hz), 5.10 (s, 2H), 4.56 (t, 2H, J = 5.0 Hz), 3.77 (t, 2H, J= 5.0 Hz); MS m/z 416.1 (M+H).

PATENT

WO-2018048977

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018048977&redirectedID=true

Novel deuterated analogs of a substituted oxazepin compounds, particularly eleclazine and their salts, esters, prodrugs and solvates and compositions and combinations comprising them are claimed. Also claim is their use for treating a late sodium current-mediated disorder, such as acute coronary syndrome, angina, congestive heart disease, myocardial infraction, diabetes, ischemic heart disorders, inflammatory diseases and cancers.

EXAMPLE 1- COMPARATIVE

[00297] 4-(pyrimidin-2-ylmethyl)-7-[4-(trifluorome4hoxy)phenyl]-2,3,4,5-tetrahydro-l,4- benzoxazepin-5-one [Eleclazine]

[00299] To a solution of 5-bromo-2-hydroxybenzoate (10 g, 43.28 mmol, 1.00 equiv) in DMA (100 ml.) was added potassium carbonate (9 g, 65, 12 mmol, 1.50 equiv) and 2-chloroacetonitrile (3.4 mL, 1.25 equiv). The resulting suspension was stirred overnight. The solids were filtered out. The filtrate was washed with water. The resulting solution was extracted with ethyl acetate (3 x 50 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1 1 g (94%) of methyl 5-bromo-2-(cyanomethoxy)benzoate as a white solid, LC-MS: m/z = 270 [M+H]+.

[00300] Step 2: 7-bromo-2,3,4,5-tetrahydro-l,4-benzoxazepin-5-one

[00301] To a solution of 5-bromo-2-(cyanomethoxy)benzoate [Example 1 , Step 1 ] (4 g, 14.81 mmol, 1.00 equiv) in methanol (50 mL) was added saturated aq. NIL (4 mL) and Raney-Ni (2 mL) under a H2 atmosphere. The resulting solution was stirred overnight at room temperature. The catalyst was filtered out. The filtrate was concentrated under vacuum. The residue was purifsed by SiCte chromatography eluted with ethyl acetate/petroleum ether (1 : 1 ) to afford 530 mg (15%) of 7-bromo-2,3,4,5-tetrahydro-l,4-benzoxazepin-5-one as a yellow solid. LC-MS: m/z = 242 [M+H]+.

[00302] Step 3 : 7-bromo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydro-l,4-benzoxazepin-5- one

[00303] To a solution of 7-bromo-2,3,4,5-tetrahydro- l ,4-benzoxazepin-5-one [Example 1, Step 2] (530 mg, 2.19 mmol, 1.00 equiv) and 2-(chloromethyl)pyrimidine hydrochloride (650 mg, 3.96 mmol, 1.80 equiv) in DMF (10 mL), was slowly added a NaOH solution (0.55 mL, 10 M, 2.50 equiv), which was stirred at room temperature for 10 min. Then the mixture was stirred at 95°C for 2 h. After cooling the reaction mixture, ethyl acetate (30 mL) was added and the organic layer was separated. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford 600 mg (82%) of 7-bromo- 4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydro-l,4-benzoxazepin-5-one as light yellow oil . LC-MS: m/z = 334 [M+H]+.

[00304] Step 4: 4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3,4,5-tetrahydro- 1 ,4-benzoxazepin-5-one

[00305] To a solution of 7-bromo-4-(pyriraidin-2-ylmethyl)-2,3,4,5-tetrahydro-l,4- benzoxaze- pin-5-one [Example 1, Step 3] (277 mg, 0.83 mmol, 1.00 equiv) in Toluene/iPrOH/thO (2: 1 : 1, 4 mL) was added potassium carbonate (459 mg, 3.32 mmol, 4.00 equiv) and [4-(trifluoromethoxy)phenyl]boronic acid (257 mg, 1.25 mmol, 1.50 equiv). The mixture was stirred for 10 min at room temperature. Then Pd(dppf)Ch (12 mg, 0.02 equiv) was added to the solution. The mixture was stirred at 85°C for 2 h. After cooling the reaction mixture, ethyl acetate (30 mL) was added, and the organic layer was separated. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, Sum, 19*150mm; mobile phase, Water (10 mmol/L NH4HCO3) and CH3CN (50,0% CH3CN up to 52.0% in 7 min); Detector, UV 254, 220nra to afford 190 mg (55%) of 4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3,4,5- tetrahydro-1,4- benzoxazepin-5-one as a white solid. LC-MS: m/z = 416 [M+H]+

[00306] 1H NMR (400 MHz, Chloroform-t/) δ 8.75-8.74 (m, 2H), 8.20-8. 19 (m, IH), 7.66- 7,61 (m, 3H), 7,29-7,28 (m, IH), 7.27-7.26 (m, IH), 7.24-7.23 (m, I H), 7.13-7.1 1 (m, IH), 5.12 (s, 2H), 4.60-4.57 (m, 2H), 3.81 -3.78 (m, 2H).

PAPER

Journal of Medicinal Chemistry (2016), 59(19), 9005-9017

Abstract Image

Late sodium current (late INa) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Nav 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia–ventricular fibrillation (VT–VF). We will describe structure–activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late INa inhibitor 1(ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S–T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC50values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late INainhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties

Medicinal Chemistry, Drug Metabolism, §Drug Safety Evaluation, Formulation and Process Development, and Structural Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
# Biology, Gilead Sciences Inc., 7601 Dumbarton Circle, Fremont, California 94555, United States
J. Med. Chem.201659 (19), pp 9005
7-(4-(Trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one 4
Compound 4 HCl obtained (24.8 g) was obtained as a white solid. Anal. HPLC 100% (6.78 min).
 
 1H NMR (CDCl3) δ 8.72 (d, 2H, J = 5.2 Hz), 8.17 (d, 1H, J = 2.4 Hz), 7.59–7.63 (m, 3H), 7.26 (d, 2H, J = 3.2 Hz), 7.22 (t, 1H, J = 4.8 Hz), 7.10 (d, 1H, J = 8.4 Hz), 5.10 (s, 2H), 4.56 (t, 2H, J = 5.0 Hz), 3.77 (t, 2H, J = 5.0 Hz). LCMS m/z 416.1 (M + H).
HRMS-ESI+: [M + H]+ calcd for C21H16F3N3O3, 416.1217; found, 416.1215.
PAPER
Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions
Scientific Reports (2017), 7, (1), 1-11.
PATENT
US 20180064726
PATENTS
Patent ID

Patent Title

Submitted Date

Granted Date

US9126989 COMPOUND AND METHODS FOR TREATING LONG QT SYNDROME
2014-07-31
2015-02-05
US9193694 FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS
2013-09-26
2014-05-15
US9125916 METHODS OF TREATING HYPERTROPHIC CARDIOMYOPATHY
2014-07-28
2015-02-05
US2016332976 PROCESSES FOR PREPARING FUSED HETEROCYCLIC ION CHANNEL MODULATORS
2016-05-02
US2015283149 METHODS OF TREATING PATIENTS HAVING IMPLANTABLE CARDIAC DEVICES
2015-03-20
2015-10-08
Patent ID

Patent Title

Submitted Date

Granted Date

US2015045305 COMBINATION THERAPIES USING LATE SODIUM ION CHANNEL BLOCKERS AND POTASSIUM ION CHANNEL BLOCKERS
2013-01-25
2015-02-12
US2016332977 PROCESSES FOR PREPARING FUSED HETEROCYCLIC ION CHANNEL MODULATORS
2016-05-02
US9598435 FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS
2015-10-01
2016-04-07
US2015225384 PROCESSES FOR PREPARING FUSED HETEROCYCLIC ION CHANNEL MODULATORS
2015-02-13
2015-08-13
US9273038 SOLID FORMS OF AN ION CHANNEL MODULATOR
2015-02-12
2015-08-13
Patent ID

Patent Title

Submitted Date

Granted Date

US9676760 FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS
2016-05-11
US8697863 Fused heterocyclic compounds as ion channel modulators
2013-03-07
2014-04-15
US8586732 Fused heterocyclic compounds as ion channel modulators
2012-06-29
2013-11-19
US2017007617 INTRAVENOUS FORMULATIONS OF A LATE SODIUM CURRENT INHIBITOR
2016-07-06
US2014329755 COMBINATION THERAPY FOR THE TREATMENT OF ARRHYTHMIAS OR HEART FAILURE
2014-04-30
2014-11-06

/////////////////ELECLAZINE, GS-6615, GS 6615, элеклазин إيليكلازين 依来克秦 Phase III,  Long QT syndrome, orphan drug designation, Long QT syndrome

C1COC2=C(C=C(C=C2)C3=CC=C(C=C3)OC(F)(F)F)C(=O)N1CC4=NC=CC=N4

Baloxavir marboxil, バロキサビルマルボキシル , балоксавир марбоксил , بالوكسافير ماربوكسيل , 玛巴洛沙韦 ,


Image result for japan animated flag

str1

1985606-14-1.pngBaloxavir marboxil.png

Image result for XofluzaChemSpider 2D Image | baloxavir marboxil | C27H23F2N3O7S

Baloxavir marboxil

バロキサビルマルボキシル

балоксавир марбоксил [Russian] [INN]

بالوكسافير ماربوكسيل [Arabic] [INN]
玛巴洛沙韦 [Chinese] [INN]

Carbonic acid, [[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-3,4,6,8,12,12a-hexahydro-6,8-dioxo-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxy]methyl methyl ester

({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate

  1. (((12aR)-12-((11S)-7,8-Difluoro-6,11-dihydrodibenzo(b,E)thiepin-11-yl)-6,8-dioxo-3,4,6,8,12,12ahexahydro-1H-(1,4)oxazino(3,4-C)pyrido(2,1-F)(1,2,4)triazin-7-yl)oxy)methyl methyl carbonate
  2. Carbonic acid, (((12aR)-12-((11S)-7,8-difluoro-6,11-dihydrodibenzo(b,E)thiepin-11-yl)-3,4,6,8,12,12a-hexahydro-6,8-dioxo-1H-(1,4)oxazino(3,4-C)pyrido(2,1-F)(1,2,4)triazin-7-yl)oxy)methyl methyl ester

Antiviral

In Japan the product is indicated for treatment influenza types A and B in adults and children

RG-6152

UNII-505CXM6OHG

  • Originator Shionogi
  • Developer Roche; Shionogi
  • Class Antivirals; Dibenzothiepins; Esters; Pyridines; Small molecules; Triazines
  • Mechanism of Action Endonuclease inhibitors

Highest Development Phases

  • Marketed Influenza A virus infections; Influenza B virus infections
  • Phase III Influenza virus infections
  • Preclinical Influenza A virus H5N1 subtype
Xofluza (TN)
Antiviral
Formula
C27H23F2N3O7S
Cas
1985606-14-1
Mol weight
571.5492
2018/2/23 PMDA JAPAN APPROVED Baloxavir marboxil Xofluza Shionogi

Image result for japan animated flag

バロキサビル マルボキシル
Baloxavir Marboxil

C27H23F2N3O7S : 571.55
[1985606-14-1]

Image result for ShionogiImage result for Xofluza

2D chemical structure of 1985606-14-1

https://chem.nlm.nih.gov/chemidplus/sid/1985606141

Baloxavir marboxil (trade name Xofluza, compound code S-033188/S-033447) is a medication being developed by Shionogi Co., a Japanese pharmaceutical company, for treatment of influenza A and influenza B. The drug was in late-stage trials in Japan and the United States as of early 2018, with collaboration from Roche AG.[1].

It was approved for sale in Japan on February 23, 2018.[2]

Baloxavir marboxil is a medication developed by Shionogi Co., a Japanese pharmaceutical company, for treatment of influenza A and influenza B. The drug was approved for use in Japan in February 2018 and is in late phase trials in the United States as of early 2018. Roche, which makes Tamiflu, has acquired the license to sell Xofluza internationally, but it may not be until 2019 that it could be available in the United States [7]. Interestingly, a study has determined that administering Baloxavir marboxil with neuraminidase inhibitors leads to a synergistic effect in influenza treatment

Image result for Xofluza

It is an influenza therapeutic agent (cap-dependent endonuclease inhibitor), characterized by only taking one dose. Unlike neuraminidase inhibitors such as oseltamivir (Tamiflu) and zanamivir (Relenza) that inhibit the action of neuraminidase, which liberates viruses from the infected cells surface, baloxavir marboxil may prevent replication by inhibiting the cap-dependent endonuclease activity of the viral polymerase.[3]

In October 2015, the Japanese Ministry of Health, Labour and Welfare granted Sakigake status to Shionogi’s baloxavir marboxil for A type or B -type influenza virus infection . In October 2015, the drug was designated for Priority Review by the Ministry of Health, Labour and Welfare, presumably for the treatment of A type or B -type influenza virus infection .

This drug is a CAP endonuclease inhibitor [1]. The influenza endonuclease is an essential subdomain of the viral RNA polymerase enzyme. CAP endonuclease processes host pre-mRNAs to serve as primers for viral mRNA and therefore has been a common target for studies of anti-influenza drugs.

Viral gene transcription is primed by short-capped oligonucleotides that are cleaved from host cell pre mRNA by endonuclease activity. Translation of viral mRNAs by the host ribosome requires that they are capped at the 5′ end, and this is achieved in cells infected with influenza virus by a “cap-snatching” mechanism, whereby the endonuclease cleaves 5′ caps from host mRNA which then act as primers for transcription.The N-terminal domain of PA subunit (PAN) has been confirmed to accommodate the endonuclease activity residues, which is highly preserved among subtypes of influenza A virus and is able to fold functionally [4]. Translation of viral mRNAs by the host ribosome requires that they are capped at the 5′ end, and this is achieved in cells infected with influenza virus by a “cap-snatching” mechanism, whereby the endonuclease cleaves 5′ caps from host mRNA which then act as primers for transcription. The endonuclease domain binds the N-terminal half of PA (PAN) and contains a two-metal (Mn2+) active site that selectively cleaves the pre-mRNA substrate at the 3′ end of a guanine [3].

The administration of a CAP endonuclease inhibitor, such as Baloxavir marboxil, prevents the above process from occurring, exhibiting its action at the beginning of the pathway before CAP endonuclease may exert its action

Image result for Xofluza

It achieves this by inhibiting the process known as cap snatching[4], which is a mechanism exploited by viruses to hijack the host mRNA transcription system to allow synthesis of viral RNAs.

Image result for Xofluza

Shionogi, in collaboration with licensee Roche (worldwide except Japan and Taiwan), have developed and launched baloxavir marboxil

In March 2018, Shionogi launched baloxavir marboxil for the treatment of influenza types A and B in Japan . In September 2017, Shionogi was planning to file an NDA in the US; in February 2018, the submission remained in preparation

By September 2016, baloxavir marboxil had been awarded Qualified Infectious Disease Product (QIDP) designation in the US

In March 2017, a multicenter, randomized, double-blind, parallel-group, phase III study (NCT02954354; 1601T0831; CAPSTONE-1) was initiated in the US, Canada and Japan to compare a single dose of baloxavir marboxil versus placebo or oseltamivir bid for 5 days in influenza patients aged from 12 to 64 years of age (n = 1494). The primary endpoint was the time to alleviation of symptoms (TTAS).

PATENTS

JP 5971830

Kawai, Makoto; Tomita, Kenji; Akiyama, Toshiyuki; Okano, Azusa; Miyagawa, Masayoshi

PATENTS

WO 2017104691

Shishido, Takao; Noshi, Takeshi; Yamamoto, Atsuko; Kitano, Mitsutaka

In Japanese Patent Application No. 2015-090909 (Patent No. 5971830, issued on Aug. 17, 2016, Registered Publication), a compound having a CEN inhibitory action and represented by the formula:
[Chemical Formula 2]

is described. Anti-influenza agents of six mechanisms are enumerated as drugs that can be used together with the above compounds. However, no specific combinations are described, nor is it disclosed nor suggested about the combined effect.

Synthesis Example 2
[formula 39]

Compound III-1 (1.00g, 2.07mmol) to a suspension of DMA (5 ml) of chloromethyl methyl carbonate (0.483 g, 3.10 mmol) and potassium carbonate (0 .572 g, 4.14 mmol) and potassium iodide (0.343 g, 2.07 mmol) were added, the temperature was raised to 50 ° C. and the mixture was stirred for 6 hours. Further, DMA (1 ml) was added to the reaction solution, and the mixture was stirred for 6 hours. The reaction solution was cooled to room temperature, DMA (6 ml) was added, and the mixture was stirred at 50 ° C. for 5 minutes and then filtered. 1 mol / L hydrochloric acid water (10 ml) and water (4 ml) were added dropwise to the obtained filtrate under ice cooling, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure at 60 ° C. for 3 hours to obtain compound II-4 (1.10 g, 1.93 mmol, yield 93%).
1 H-NMR (DMSO-D 6) δ: 2.91-2.98 (1 H, m), 3.24-3.31 (1 H, m), 3.44 (1 H, t, J = 10.4 Hz) J = 10.8, 2.9 Hz), 4.06 (1 H, d, J = 14.3 Hz), 4.40 (1 H, dd, J = 11.5, 2.8 Hz), 3.73 (3 H, s), 4.00 , 5.67 (1 H, d, J = 6.5 Hz), 5.72 (1 H, d, J = 11.8 Hz), 4.45 (1H, dd, J = 9.9, 2.9 Hz), 5.42 J = 8.0, 1.1 Hz), 7.14 – 7.18 (1 H, m ), 7.23 (1 H, d, J = 7.8 Hz), 7.37 – 7.44 (2 H, m)

PATENTS

JP 6212678

PATENTS

JP 6249434

JP 5971830

SYNTHESIS OF KEY INTERMEDIATE

SYNTHESIS OF KEY INTERMEDIATE

SYNTHESIS OF FINAL PRODUCT

Japan’s New Drug: One Pill May Stop The Flu in Just One Day

 Opinions expressed by Forbes Contributors are their own.

Isao Teshirogi, president and chief executive officer of Shionogi & Co., speaks during an interview in Tokyo, Japan. Photographer: Kiyoshi Ota/Bloomberg

One day, you may be able to stop flu viruses in your body in just one day with just one pill. Based on an announcement yesterday, that day may be someday very soon in May in Japan.

On Friday, Japanese pharmaceutical company Shionogi announced that the flu medication that they have developed, Xofluza, otherwise known as baloxavir marboxil (which sounds a bit like a Klingon General), has been approved to be manufactured and sold in Japan. Beginning in October 2015, the medication underwent priority review by Japan’s Ministry of Health, Labor, and Welfare. Shionogi filed for approval in the autumn of 2017. Compared to Tamiflu, which requires two doses each day for five days, apparently only a single dose of Xofluza will be needed to treat the flu. Even though Xofluza has received approval, people will have to wait until the Japanese national insurance sets a price for the medication, which according to Preetika Rana writing for the Wall Street Journal, may not occur until May.

Xofluza works via a different mechanism from neuroaminidase inhibitors like Tamiflu (oseltamivir) and Relenza (zanamivir). Flu viruses are like squatters in your home that then use the furniture and equipment in your home to reproduce. Yes, I know, that makes for a lovely picture. A flu infection begins when flu viruses reach your lungs. Each flu virus will enter a cell in your lungs and then use your cell’s genetic material and protein production machinery to make many, many copies of itself. In order to do this, the flu virus uses “cap-snatching”, which has nothing to do with bottle caps or Snapchat. The virus employs an endonuclease enzyme to clip off and steal the caps or ends of your messenger RNA and then re-purposes these caps to reproduce its own genetic material. After the virus has made multiple copies of itself, the resulting viruses implement another enzyme called a neuroaminidase to separate themselves from parts of the host cell and subsequently spread throughout the rest of your body to cause havoc. While Tamiflu, Relenza, and other neuroaminidase inhibitors try to prevent the neuroaminidase enzyme from working, Xofluza acts at an earlier step, stopping the “cap-snatching” by blocking the endonuclease enzyme.

In a clinical trial, Xofluza stopped an infected person from shedding flu virus sooner than Tamiflu. (Photo Illustration by Ute Grabowsky/Photothek via Getty Images)

By acting at an earlier step before the virus has managed to replicate, Xofluza could stop a flu virus infection sooner than neuroaminidase inhibitors. The results from Shionogi’s Phase III CAPSTONE-1 clinical trial compared Xofluza (then called Cap-dependent Endonuclease Inhibitor S-033188, which doesn’t quite roll off the tongue) with oseltamivir and placebo, with results being published in Open Forum Infectious Diseases. The study found that baloxavir marboxil (or Xofluza) stopped an infected person from shedding flu virus earlier (median 24 hours) than oseltamivir (median 72 hours). Those taking baloxavir marboxil also had lower measured amounts of viruses than those taking oseltamivir throughout the first 3 days of the infection. Baloxavir marboxil also seemed to shorten the duration of flu symptoms (median 53.7 hours compared to a median of 80.2 hours for those taking placebo). Since symptoms are largely your body’s reaction to the flu virus, you can begin shedding virus before you develop symptoms, and symptoms can persist even when you are no longer shedding the virus.

The key with any of these flu medications is early treatment, especially within the first 24 to 48 hours of infection, which may be before you notice any symptoms. Once the virus has replicated and is all over your body, your options are limited. The vaccine still remains the best way to prevent an infection.

In the words of Alphaville, this new drug could be big in Japan. While Xofluza won’t be available in time to help with the current flu season, this year’s particularly harsh flu season has highlighted the need for better ways to treat the flu. But will the United States see Xofluza anytime soon? Similar to Pokemon, Xofluza may need a year or two to reach the U.S. market. But one day, one pill and one day may be a reality in the U.S.

http://www.shionogi.co.jp/en/company/news/2018/pmrltj0000003nx1-att/e180223.pdf

XOFLUZA TM (Baloxavir Marboxil) Tablets 10mg/20mg Approved for the Treatment of Influenza Types A and B in Japan Osaka, Japan, February 23, 2018 – Shionogi & Co., Ltd. (Head Office: Osaka; President & CEO: Isao Teshirogi, Ph.D.; hereafter “Shionogi”) announced that XOFLUZATM (generic name: baloxavir marboxil) tablets 10mg/20mg was approved today by the Ministry of Health, Labour and Welfare for the treatment of Influenza Types A and B. As the cap-dependent endonuclease inhibitor XOFLUZATM suppresses the replication of influenza viruses by a mechanism different from existing anti-flu drugs, XOFLUZATM was designated for Sakigake procedure with priority review by the Ministry of Health, Labour, and Welfare of Japan in October 2015. Shionogi filed for approval to manufacture and sell XOFLUZATM in October 25, 2017. As the treatment with XOFLUZATM requires only a single oral dose regardless of age, it is very convenient, and is expected to improve adherence. XOFLUZATM is expected to be a new treatment option that can improve the quality of life in influenza patients. Shionogi will launch the product immediately after the National Health Insurance (NHI) price listing. Shionogi’s research and development targets infectious disease as one of its priority areas, and Shionogi have positioned “protecting people from the threat of infectious diseases” as one of its social mission targets. Shionogi strives constantly to bring forth innovative drugs for the treatment of infectious diseases, to protect the health of patients we serve.

References

  1. Jump up^ Rana, Preetika (10 February 2018). “Experimental Drug Promises to Kill the Flu Virus in a Day”. Wall Street Journal.
  2. Jump up^ “XOFLUZA (Baloxavir Marboxil) Tablets 10mg/20mg Approved For The Treatment Of Influenza Types A And B In Japan”. 23 February 2018 – via http://www.publicnow.com.
  3. Jump up^ Dias, Alexandre; Bouvier, Denis; Crépin, Thibaut; McCarthy, Andrew A.; Hart, Darren J.; Baudin, Florence; Cusack, Stephen; Ruigrok, Rob W. H. (2009). “The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit”. Nature458(7240): 914–918. doi:10.1038/nature07745ISSN 0028-0836.
  4. Jump up^ “Cap snatching”.
Baloxavir marboxil
Baloxavir marboxil.svg
Identifiers
CAS Number
PubChem CID
UNII
KEGG
Chemical and physical data
Formula C27H23F2N3O7S
Molar mass 571.55 g·mol−1
3D model (JSmol)

Shionogi & Company, Limited(塩野義製薬株式会社 Shionogi Seiyaku Kabushiki Kaisha) is a Japanesepharmaceutical company best known for developing Crestor. Medical supply and brand name also uses Shionogi (“シオノギ”).

Shionogi has business roots that date back to 1878, and was incorporated in 1919. Among the medicines produced are for hyperlipidaemiaantibiotics, and cancer medicines.

In Japan it is particularly known as a producer of antimicrobial and antibiotics. Because of antibiotic resistance and slow growth of the antibiotic market, it has teamed up with US based Schering-Plough to become a sole marketing agent for its products in Japan.

Shionogi had supported the initial formation of Ranbaxy Pharmaceuticals, a generic manufacturer based in India. In 2012 the company became a partial owner of ViiV Healthcare, a pharmaceutical company specialising in the development of therapies for HIV.[3]

The company is listed on the Tokyo Stock Exchange and Osaka Securities Exchange and is constituent of the Nikkei 225 stock index.[4]

Medicines
Media
  • Shionogi has a close relationship with Fuji Television Network, Inc., because Shionogi is the sponsor of “Music Fair” (as of 2018, aired on 17 TV stations including TV Oita System Co.) started in 1964.
  • Shionogi was a main sponsor of Team Lotus during the age 1991/1994.[5]
References
  1. “Shionogi Company Profile”. Retrieved March 18, 2014.
  2. “Shionogi Annual Report 2013” (PDF). Retrieved March 18, 2014.
  3. “Shionogi and ViiV Healthcare announce new agreement to commercialise and develop integrase inhibitor portfolio”. viivhealthcare.com. Retrieved 18 March 2014.
  4. “Components:Nikkei Stock Average”Nikkei Inc. Retrieved March 11,2014.
  5. Perry, Alan. “Sponsor Company Profiles”. Retrieved 25 April 2012.
External links

/////////Baloxavir marboxil, バロキサビルマルボキシル, JAPAN 2018,  Xofluza,  S-033188, S-033447, RG-6152, Qualified Infectious Disease Product, Priority Review, SAKIGAKE, балоксавир марбоксил بالوكسافير ماربوكسيل 玛巴洛沙韦 Shionogi, roche

COC(=O)OCOC1=C2C(=O)N3CCOCC3N(N2C=CC1=O)C4C5=C(CSC6=CC=CC=C46)C(=C(C=C5)F)F

Eating Nuts may dramatically improve Colon Cancer outcomes — ClinicalNews


Eating Nuts may dramatically improve Colon Cancer outcomes Those who regularly consumed at least two, one-ounce servings of nuts each week demonstrated a 42% improvement in disease-free survival and a 57% improvement in overall survival. Nut Consumption and Survival in Patients With Stage III Colon Cancer: Results From CALGB 89803 (Alliance). Journal of Clinical […]

via Eating Nuts may dramatically improve Colon Cancer outcomes — ClinicalNews

Pralatrexate プララトレキサート


10-Propargyl-10-deazaaminopterin.pngPralatrexate.pngChemSpider 2D Image | Pralatrexate | C23H23N7O5

Pralatrexate (JAN/USAN/INN);
10-Propargyl-10-deazaaminopterin;
Folotyn (TN)

Antineoplastic

Product

CAS:
FOLOTYN (Allos Therapeutics)
146464-95-1
Formula
C23H23N7O5
Exact mass
477.1761

Image result for Difolta

  • (2S)-2-((4-((1RS)-1-((2,4-diaminopteridin-6-yl)methyl)but-3-ynyl)benzoyl)amino)pentanedioic acid
  • (2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl}amino)pentanedioic acid
  • 10-Propargyl-10-deazaaminopterin
  • N-(4-(1-((2,4-Diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-L-glutamic acid
  • PDX
  • UNII:A8Q8I19Q20

Japan approved 2017

2017/7/3 PMDA JAPAN Pralatrexate Difolta Mundipharma NME

Image result for DifoltaImage result for Difolta

EMA 2012

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002096/WC500129886.pdf

The molecule contains two asymmetric carbon centres (C10) and (C19). The C10 position exists in the RS-configuration (approx. 50:50 ratio) on the link between the two aryl groups. The C19 position is contained in the glutamic acid moiety and predominantly exists in the S-configuration. Pralatrexate is an off-white to yellow crystalline material, soluble in aqueous solutions at pH 6.5 or higher and practically insoluble in chloroform, and ethanol. It predominantly exists as a single polymorph (form A).

Pralatrexate, chemically known as “(2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl- ]-amino]pentanedioic acid”, also known as “10-Propargyl-10-deazaminopterin” or “PDX”, is a compound which has been tested and found useful in the treatment of cancer. In its racemic form, 2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]a- mino]-pentanedioic acid has been approved by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory peripheral T-cell lymphoma.

Pralatrexate,  was first disclosed in Journal of Medicinal Chemistry. 36: 2228-2231 (1993) by DeGraw et al., and subsequently in U.S. Pat. No. 5,374,726 and U.S. Pat. No. 5,354,741.

Pralatrexate is an antimetabolite for the treatment of relapsed or refractory peripheral T-cell lymphoma. It is more efficiently retained in cancer cells than methotrexate. FDA approved on September 24, 2009.

Pralatrexate (brand name Folotyn) is an anti-cancer therapy.[1] It is the first drug approved as a treatment for patients with relapsed or refractory peripheral T-cell lymphoma, or PTCL[2] — a biologically diverse group of aggressive blood cancers that have a poor prognosis.[2]

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Approval

Folotyn was approved by the U.S. Food and Drug Administration (FDA) in September 2009 under the FDA’s accelerated approval,[2] which allows for earlier approval of drugs that meet unmet medical needs.[3] Pralatrexate injection is marketed in the U.S. under the name Folotyn by Spectrum Pharmaceuticals.[2] Clinical trials are currently underway to explore the potential of Folotyn in other blood related cancers and solid tumors.[4]

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Mechanism

Pralatrexate is an antifolate (a folate analogue metabolic inhibitor) designed to accumulate preferentially in cancer cells.[1] Based on preclinical studies, researchers believe that pralatrexate selectively enters cells expressing reduced folate carrier type 1 (RFC-1), a protein that is overexpressed on certain cancer cells compared to normal cells.[1]

Antifolates, such as pralatrexate, are part of a group of compounds known as antimetabolites with structural similarity to naturally occurring molecules involved in DNA synthesis.[5] Cancer cells mistake antimetabolites for normal metabolites[5] allowing the compound to stop or slow critical enzymes involved in DNA synthesis which then triggers cell death.[1] Because of their primary effect on DNA synthesis, the antimetabolites are most effective against actively dividing cells and are largely cell-cycle phase specific.[5]

The selectivity of pralatrexate for cancer cells is based upon the observation that cancer cells generally have an overexpression of reduced folate carrier protein-1 (RTC-1) compared to normal somatic cells. This carrier protein allows the entrance of pralatrexate into the cell. Upon entering the cell, folypolyglutamate synthase FPGS catalyzes the polyglutamination of pralatrexate so that it is retained inside the cell.
Once inside, pralatrexate competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. Subsequent depletion of thymidine monophosphate (TMP) occurs so that the cancer cell is unable to synthesize DNA and RNA. As a result, the cancer cell cannot proliferate and is forced to undergo apoptosis. Pralatrexate is more effective against cells that are actively dividing.

Biological Activity

Pralatrexate (Folotyn) is an antifolate, and structurally a folate analog. It acts as an inhibitor of dihydrofolate reductase. It is selective for the reduced folate carrier type 1. Its IC50 is < 300 nM in some cell lines.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Discovery

Research on this class of drugs began in the 1950s at SRI International, where scientists were focused on developing new chemotherapies and antifolates that would be effective against tumor cells.[1]

In the late 1970s, researchers at Memorial Sloan Kettering Cancer Center discovered that cancerous cells take in natural folate through a protein identified as plasma membrane transporter (now referred to as “reduced folate carrier type 1” or “RFC-1”). Further research showed that when normal cells evolve into cancerous cells they often overproduce RFC-1 to ensure they get enough folate.[6]

A subsequent scientific collaboration was ultimately formed among SRI International, Memorial Sloan Kettering Cancer Center, and the Southern Research Institute with the intention of developing an antifolate with greater therapeutic selectivity – an agent that could be more effectively internalized into tumors (transported into the cells through RFC-1) and would be more toxic to cancer cells than normal cells.[6]

This collaboration, supported by the National Cancer Institute,[7] led to the identification of pralatrexate in the mid-1990s. Pralatrexate was later licensed to Allos Therapeutics in 2002 for further development.[8] Allos Therapeutics, Inc. was acquired by Spectrum Pharmaceuticals, Inc. on September 5, 2012. Allos is now a wholly owned subsidiary of Spectrum.[9]

Pralatrexate, is a 10-deazaaminopterin derivative which has been developed for the potential treatment of malignancies. Pralatrexate is an antifolate, structurally a folate analog inhibitor of dihydrofolate reductase (DHF ) exhibiting high affinity for reduced folate carrier- 1 (RFC- 1) and iolylpolyglutamate synthetase (FPGS). with antineoplastic and immunosuppressive activities, resulting in extensive internalization and accumulation in tumour cells. Pralatrexate selectively enters cells expressing RFC- 1. Intracellularly, this agent is highly polyglutamylated and competes for the folate binding site of DHFR, blocking tetrahydrofolate synthesis, which may result in depletion of nucleotide precursors; inhibition of DNA. RNA and protein synthesis; and apoptotic tumor cell death. Efficient intracellular polyglutamylation of pralatrexate results in higher intracellular concentrations compared to non-polyglutamylated pralatrexate, which is more readily effuxed by the MRP (multidrug resistance protein) drug efflux pump. RFC- 1, an oncofetal protein expressed at highest levels during embryonic development, may be over expressed on the cell surfaces of various cancer cell types. Pralatrexate is the first and only drug approved by the Food and Drug Administration as a treatment for relapsed or refractory peripheral T-cell lymphoma, demonstrating the ability to reduce tumor size, but not to prolong life.

Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules the synthesis of which depends on single carbon transfer.

US 200510267117 discloses that T cell lymphoma is treated by administering to a patient suffering from T cell lymphoma a therapeutically effective amount of IO-propargyl-10- deazaaminopterin. Remission is observed in human patients, even with drug resistant T cell lymphoma at weekly dosages levels as low as 30 mg/m2. In general, the 10-propargyl-lO- deazaaminopterin is administered in an amount of from 30 to 275 mg/m2 per dose.

US 2011/0190305 discloses diastereomers of 10-propargyl-l 0-deazaminopterin, compositions comprising optically pure diastereomers of 10-propargyl-l 0-deazaminopterin, in particular the two (R,S) diastereomers about the C 10 position, method of preparation of the diastereomers and method of treatment of conditions related to inflammatory disorders and cancer.

US005354751 discloses heteroaroyl-10-deazaaminopterins and 10-alkenyl or 10-alkynyl-lO- deazaaminopterins having pronounced anti-inflammatory activity, anti-leukemic and anti- tumorigenic activity, as well as a method for treatment of inflammatory diseases, leukemia and tumors. Pharmaceutical compositions containing these heteroaroyl-lO-deazaaminopterin compounds are also disclosed. The invention further concerns a process for preparation of these compounds. A method for preparation of I0-propargyl-10-deazaaminopterin compound is also disclosed in this document.

Journal publication Bioorganic and Medicinal Chemistry (19) 2011, page 1151, synthetic approaches to the 2009 new drugs, also discloses a method for synthesis of Pralatrexate. The method comprises alkylating dimethyl homotrephthalate with propargyl bromide in the presence of KH in THF and then with 2,4-diamino-6-(bromomethyl)pteridine hydrobromide in the presence of KH in D F to afford crude product. Subsequent hydrolysis of the diester with aqueous NaOH, followed by acidification with acetic acid to give crude carboxylic acid, followed by thermally induced decarboxylation in D SO to give 10-deazapteroic acid derivative. Activation of carboxylic acid as a mixed anhydride using t-butyl chioroformate prior to coupling with diethyl L-glutamate hydrochloride in the presence of Et3 in DMF to give lO-propargyl-IO-deaza-aminopterin diethyl ester. Finally, saponification of diethyl ester with aqueous NaOH in 2-methoxyethanol, followed by acidifying with AcOH giving Pralatrexate.

Methods of preparing Pralatrexate known in the prior art are not only complicated but preparation of Pralatrexate using the methods disclosed in the prior art also result in very high manufacturing cost. Therefore, there is a need for an improved, simple and cost effective method for preparation of Pralatrexate which can be used for industrial scale preparation of this compound.

PATENT

 scheme- 1 .

Figure imgf000006_0001

Scheme-1

Figure imgf000008_0001

Scheme 2

Figure imgf000009_0001

Scheme 3

scheme 4.

Figure imgf000010_0001

https://patents.google.com/patent/WO2013164856A1/en

PATENT

https://patents.google.com/patent/WO2014016740A2/en

Pralatrexate, chemically known as “(25)-2-[[4-[(lR5)-l-[(2,4-diaminopteridin-6- yl)methyl]but-3-ynyl]benzoyl]- amino] pentanedioic acid”, also known as “10-Propargyl- 10-deazaminopterin” or “PDX”, is a compound which has been tested and found useful in the treatment of cancer. In its racemic form, 2S)-2-[[4-[(lRS)-l-[(2,4-diaminopteridin-6- yl)methyl]but-3-ynyl]benzoyl]amino]- pentanedioic acid has been approved by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory peripheral T-cell lymphoma.

Pralatrexate, represented by Formula (I), was first disclosed in Journal of Medicinal Chemistry. 36: 2228-2231 (1993) by DeGraw et al., and subsequently in US 5374726 and US 5354741.

Figure imgf000003_0001

DeGraw et al, publication, US 5374726 and US 5354741 disclose method for the synthesis of Pralatrexate of Formula (I), comprising alkylation of homoterephthalic acid dimethyl ester with propargyl bromide using Potassium Hydride, which is further coupled with 2,4-diamino-6-bromomethylpteridine in presence of Potassium Hydride followed by hydrolysis in presence of NaOH in 2-methoxyethanol-water mixture and decarboxylation at high temperature in DMSO and subsequent coupling with L-glutamic acid diethyl ester using t-butyl chloroformate and a base, and finally hydrolysis of the product with NaOH in 2-methoxyethanol-water mixture to give Pralatrexate of Formula (I). The process is outlined below as synthetic Scheme- 1.

Figure imgf000004_0001
Figure imgf000004_0002

Scheme- 1

The methods disclosed in DeGraw et al., publication, US 5374726 and US 5354741 suffer from the following disadvantages, which are outlined below:

(i) Use of pyrophoric Potassium hydride in the initial alkylation step and the subsequent coupling step.

(ii) Amide formation in the penultimate step by use of a hazardous chloroformate reagent.

(iii) The final product has a purity of -95% and is contaminated with the 10- deazaminopterin impurity to the level of 4%, which affects the final quality of Active Pharmaceutical ingredient (API) and does not meet the Pharmacopeial specifications. Use of 2-methoxyethanol in the last step which is classified under guideline of International Conference on Harmonisation of Pharmaceutical for Human USE (ICH) as a Class-2 solvent, with a maximum daily exposure limit of 50 ppm. Extensive use of column chromatography during the method adding to the cost of manufacture.

(vi) Low yield of the final Pralatrexate (-5.5 %).

US 6028071 discloses a process for the preparation of Pralatrexate of Formula (I) comprising coupling of homoterephthalic acid dimethyl ester with propargyl bromide using NaH in THF, further coupling of the product with 2,4-diamino-6- bromomethylpteridine using NaH in DMF, followed by hydrolysis with a base in 2- methoxyethanol-water mixture, and decarboxylation at elevated temperatures at 115- 120°C in DMSO, and finally coupling of the product with L-glutamic acid dimethyl ester using benzotriazole-l-yloxytris(dimethylamino) phosphonium hexafluorophosphate (BOP) and triethylamine in DMF, and finally hydrolysis with NaOH in methanol-water mixture to yield Pralatrexate. The process is outlined below as synthetic Scheme-2.

Figure imgf000005_0001

3, R = CH3

4 ■■ H

Figure imgf000005_0002

Scheme-2 The process disclosed in US 6028071 suffer from the following disadvantages outlined below

(i) Use of sodium hydride in the initial alkylation step and the subsequent coupling step.

(ii) Using benzotriazole-l-yloxytris(dimethylamino) phosphonium hexafluoro phosphate (BOP) in coupling reaction that liberates Hexamethylphosphoramide (HMPA), which is carcinogenic

(iii) Extensive column chromatography during the process adding to the cost of manufacture

(iv) Quality of the API obtained by this process is only -98%.

(v) Low yield of Pralatrexate is obtained (2.06%).

(vi) In the propargylation step the ratio of oc-monopropargyl homoterephthalic acid dimethyl ester to oc-monopropargyl homoterephthalic acid dimethyl ester is not less than 75:25.

US 20110190305 relates to optically pure diastereomers of 10-propargyl-lO- deazaminopterin, in particular the two ( ,S) diastereomers about the CIO position. None of the prior art discloses a process for preparing substantially pure Pralatrexate. When the present inventors practiced the invention disclosed in US 6028071 to ascertain the purity of Pralatrexate, they found the content of individual diastereomers at the CIO position to be 50+3.66%.

Example- 11

10-Propar gyl- 10-deazaminopterin (Pralatrexate)

To aqueous NaOH (11.6 g NaOH in 472 mL DM water) and Methanol (944 mL), 10- Propargyl-10-deazaminopterin Dimethyl Ester (59.0 g) was added at 20-25°C and stirred the reaction mass for 8 hours. After completion of reaction which was monitored by HPLC, pH of the reaction mass was adjusted to 6.6 with acetic acid. Excess methanol was evaporated under reduced pressure below 40° C and DM water (1298mL) was added to the residual solution. The pH of the residual solution was adjusted to 4.5 with dilute acetic acid. The reaction mass was stirred for 30 minutes at 20-25° C and filtered the solid precipitated. The solid was furthered purified with DM water (590 mL) by stirring at 20- 25°C for 30-35 minutes. The solid was filtered and dried under vacuum at 35-40° C to give 39 g (70 %) of the title compound.

Purity: 99.56 %

Water content = 4.8 % (w/w)

*H NMR (DMSO-d6; 400MHz): δ 1.91 (m, 1H), 2.05 (m, 1H), 2.33 (t, J=7.2 Hz, 2H), 2.59 (bm, 2H), 2.78 (s, 1H), 3.14-3.20 (bm, 1H), 3.28 (dd, J=14.4 Hz & 6.4 Hz, 1H), 3.64 (quintet, J=7.2 Hz), 4.35 (bm, 1H), 6.30 (bs, 2H, NH2), 7.39 (d, J=8.0 Hz, 2H), 7.61 & 7.63 (2xbs, 2H, NH2), 7.73 (d, J=8.0Hz, 2H), 8.39 (bs, 1H), 8.50 (d, J=7.6 Hz, 1H, NH), 12.20 (bs, 2H, 2xC02H).

13C NMR (DMSO-d6; 100MHz): δ 24.84 (CH2), 25.94 (CH2), 30.46 (CH2), 39.08 (CH2), 43.05 (CH), 51.93 (CH), 72.90 (CH), 82.57 (C), 121.51 (C), 127.35 (2xCH), 127.35 (2xCH), 132.22 (C), 146.69 (C), 147.20 (C), 150.56 (CH), 154.17 (C), 162.41 (C), 162.77 (C), 166.42 & 166.46 (CONH), 173.54 (C02H), 173.94 (C02H).

MS (ES+) m/z: 478 [M+H]+.

IR (KBr, cm-1): 1540, 1557, 1639, 1704, 3300, 3420.

XRD (°2Theta; Cu): 8.47, 10.85, 12.28, 14.34, 15.00, 15.78, 18.90, 21.79, 24.20, 27.5, 28.92, 34.28.

Example- 12 discloses the preparation of Pralatrexate according to US 6028071.

Example-12

To 10-Propargyl-lO-deazaminopterin dimethyl ester (3.0 g) in methanol (181.8 mL), aqueous sodium hydroxide (0.52 g of sodium hydroxide in 13.1 mL demineralized water) was added at 20-25°C accompanied by stirring. The reaction mixture was stirred for 2h at 20-25°C, kept for further 8 hours at the same temperature and diluted with demineralized water (181.8 mL). methanol was recovered under vacuum below 40°C and the residue was left at 20-25°C for 24 hrs. The reaction was monitored by HPLC and acidified with acetic acid (7.5 mL). The solid obtained was filtered, washed with demineralized water (15 mL) and suck-dried for 2-3 hrs. The product was dried under vacuum at 50-55°C for 12 hours.

Weight : 2.5

Yield (%) : 89.2

Purity by HPLC (%) : 99.61

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013096800&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Pralatrexate, (2S)-2-[[4-[(1 RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentandioic acid, also referred to as 10-propargyl-10-deaza-aminopterin, is an anti-cancer drug having the following formula:

Pralatrexate is approved for a treatment for patients with relapsed or refractory peripheral T-cell lymphoma. It is an antifolate and acts as an inhibitor of

dihydrofolate reductase.

[0004] Pralatrexate is disclosed in several documents such as DeGraw et al., (J. Med. Chem, 1993, 36, 2228), US 6,028,071, US 5,354,751, EP 0944389, EP 1891957 and WO 98/02163. US 6,028,071 discloses Pralatrexate and a preparation thereof, as described in the following reaction scheme:

EXAMPLES

Reference examples:

[0099] Pt-MADES (compound 5) and Pt-MADAC (compound 6) may be prepared according to procedures disclosed in US 6,028,071, example 1.

Example 1 : Decarboxylation of Pt-MADAC (compound 6)

[00100] Pt-MADAC (compound 6) (17 g, 43.3 mmol, containing 1.4% of impurity hydro-Pt-MADAC (compound 6a) according to HPLC analysis) was added to N-methyl-2-pyrrolidone (170 mL, 10 Vol.) pre-heated at 120°C. Upon dissolution of the solid, N, N-diisopropylethyl amine (5.6 mL, 32.1 mmol) was added. The reaction mixture was stirred at 120 °C for 0.5 h, then cooled down to room temperature and poured into water (1700 mL, 100 Vol.). The pH was adjusted to 4.5 by addition of aq. HCl (16% w/w). A precipitate formed and was isolated by filtration. The collected solid was dried in a drying oven at 45 °C for 18 h to provide Pt-MADEC (compound 7) as a yellow solid (14.6 g, 97% yield, purity 87.1%), containing 7.5% of Pt-lactone (compound 7b) and 1.4% of hydro-Pt-MADEC (compound 7a) according to HPLC analysis.

Example 2: Decarboxylation of Pt-MADAC (Compound 6) without use of a base

[00101] Pt-MADAC (compound 6) (2 g, 5.10 mmol, containing 1.4% of impurity hydro-Pt-MADAC (compound 6a) according to HPLC analysis) was added to N-methyl-2-pyrrolidone (20 mL, 10 Vol.) pre-heated at 120 °C. The reaction mixture was stirred at 120 °C for 1 h, then cooled down to room temperature and poured into water (200 mL, 100 Vol.). The pH was adjusted to 4.5 by addition of aq. HCl (16% w/w) and the precipitate that formed was isolated by filtration. Drying in a drying oven at 45 °C for 18 h furnished Pt-MADEC (compound 7) as a yellow solid (1.65 g, 93% yield, purity 85.8%), containing 6.9% of Pt-lactone (compound 7b) and 1.4% of hydro-Pt-MADEC (compound 7a) according to HPLC analysis.

Example 3: Purification of Pt-MADEC 7 by precipitation of the corresponding potassium salt

[00102] Pt-MADEC (compound 7) (4 g, corresponding to 9.9 mmol of product considering the residual solvent content, prepared according to example 1) was added to aqueous KOH (12.9 mmol of KOH in 40 mL of water, 10 Vol.). The solid dissolved rapidly, and after 0.5 h, the formation of a precipitate started. After 0.5 h at room temperature the reaction mixture was cooled to 0 °C. After 1 h at 0 °C, the precipitate that had formed was isolated by filtration. Drying in a drying oven at 45 °C for 18 h furnished K-Pt-MADEC (compound 11) as a pale yellow solid (2.5 g, 65% yield, purity 99.5%), containing 0.3% of K-Pt-lactone-open (compound 11b) and 0.1% of hydro-K-Pt-MADEC (compound 11a) according to HPLC analysis.

Example 4: Purification of Pt-MADEC 7 derived from Pt-MADAC containing Pt-NADAC (5%) and Pt-lactone as impurities

[00103] Pt-MADAC (compound 6) (10 g) containing 5% of impurity Pt-NADAC (compound 6c) (according to HPLC analysis) was subjected to the decarboxylation conditions described in Example 1. The isolated Pt-MADEC (compound 7) (8.7 g, 87% yield, purity 83.4%) contained 6.2% of Pt-lactone (compound 7b), 1.6% of Pt- NADEC (compound 7c) and 3.4% of unreacted Pt-NADAC (compound 6c) according to HPLC analysis.

[00104] The compound was subjected to the purification conditions described in Example 3, furnishing K-Pt-MADEC (compound 11) (5.3 g, 55% yield, purity 98.5%), containing 0.3% of K-Pt-lactone-open (compound lib), 0.88% of K-Pt-NADEC (compound 11c) and 0.18% of K-Pt-NADAC (compound 1 Id) according to HPLC analysis.

Example 5: Purification of Pt-MADEC 7 by precipitation of the corresponding sodium salt

[00105] Pt-MADEC (compound 7) (2 g, corresponding to 4.95 mmol of product considering the residual solvent content) was added to aqueous NaOH (6.44 mmol of NaOH in 20 mL of water, 10 Vol.). The solid dissolved rapidly, then after 5 minutes the formation of a precipitate started. After 0.5 h at room temperature, the reaction mixture was cooled to 0 °C. After 1 h at 0 °C the precipitate that had formed was isolated by filtration. The collected solid was then dried in a drying oven at 45 °C for 18 h to provide the Na-Pt-MADEC (compound 12) as a pale yellow solid (1.6 g, 75% yield, purity 96.6%), containing 1.8% of Na-Pt-lactone-open (compound 12b) and 0.3% of hydro-Na-Pt-MADEC (compound 12a) according to HPLC analysis.

Example 6: Purification of Pt-MADEC 7 by precipitation of the corresponding lithium salt

[00106] Pt-MADEC (compound 7) (2 g, corresponding to 4.27 mmol of product, considering the residual solvent content), was added to aqueous LiOH (5.55 mmol of LiOH, in 20 mL of water, 10 Vol.). The solid dissolved rapidly, and after 15 minutes the formation of a precipitate started. After 0.5 h at room temperature the reaction mixture was cooled to 0 °C. After 1 h at 0 °C the precipitate that had formed was isolated by filtration. The collected solid was then dried in a drying oven at 45 °C for 18 h to provide Li-Pt-MADEC (compound 13) as a pale yellow solid (1.1 g, 73% yield, purity 97.7%), containing 0.6% of Li-Pt-lactone-open (compound 13b) and 0.9% of hydro-Li-Pt-MADEC (compound 13a) according to HPLC analysis.

Example 7: Synthesis of Pt-lactone

[00107] To a suspension of Pt-MAD AC (compound 6) (12.2 g, 31.2 mmol) in acetonitrile (122 mL, 10 Vol.), copper (I) iodide (595 mg, 3.12 mmol) and N,N-diisopropylethyl amine (10.9 mL, 62.2 mmol) were added. The reaction mixture was heated to reflux and stirred at reflux for 48 h., and then cooled to room temperature. The resulting precipitate was filtered and washed with acetonitrile (24 mL, 2 Vol.). The collected solid was then dried in a drying oven at 45 °C for 18 h to provide Pt-lactone (compound 7b) as a brown solid (12.3 g, >100% yield, purity 94.1%).

Example 8: Purification of Pt-MADES by formation of the corresponding DMF solvate

[00108] Pt-MADES (compound 5) (40 g, purity 94.7%) was added to DMF (400 mL, 10 Vol.), pre-heated at 120 °C. After dissolution of the product, the reaction mixture was kept at 120°C for 0.5 h, and then cooled to room temperature. The

resulting precipitate was filtered and washed with acetone (2 x 200 mL, 2 x 5 Vol.). Drying in a drying oven at 45 °C for 18 h furnished Pt-MADES (compound 5) as a pale yellow solid (36.4 g, 91% yield, purity 97.5%).

Example 9: purification of Pt-MADES

[00109] Pt-MADES (compound 5) (30 g, purity 94.7%) was suspended in a mixture of MeOH (300 mL, 10 Vol.) and formamide (150 mL, 5 Vol.). The suspension was heated at 60-65 °C for 2 h, then cooled to room temperature. Upon stirring at room temperature for 15 h, the resulting precipitate was filtered and washed with methanol (2 x 30 mL, 2 x 1 Vol.). Drying in a drying oven at 50 °C for 18 h furnished Pt-MADES (compound 5) as a pale yellow solid (22.5 g, 75% yield, purity 98.0%).

Example 10: purification of Pt-MADAC

[00110] Pt-MADAC (compound 6) (50 g, purity 94.0%) was suspended in a mixture of MeOH (150 mL, 3 Vol.) and formamide (50 mL, 1 Vol.). The suspension was heated at 60-65 °C for 2 h, and then cooled to room temperature. Upon stirring at room temperature for 15 h, a precipitate formed and was filtered and washed with methanol (2 x 50 mL, 2 x 1 Vol.). The collected precipitate was then dried in a drying oven at 50°C for 18 h. The thus-produced Pt-MADES was then suspended in MeOH (500 mL, 10 Vol.). This suspension was heated at reflux for 1 h, and then cooled to 0°C. The resulting precipitate was filtered and washed with methanol (2 x 50 mL, 2 x 1 Vol.). Drying in a drying oven at 50 °C for 18 h furnished Pt-MADAC (compound 6) as a pale yellow solid (41 g, 82% yield, purity 96.3%).

Example 11: Preparation of Pralatrexate, sodium salt (PLT-Na) (Compound 10a) by hydrolysis of Pralatrexate ethyl ester (PLT-ES) (Compound 9B)

[00111] A reactor was charged with EtOH (195 mL) and aqueous NaOH (3.75 M, 19.5 mL, 73 mmol). The mixture was then cooled down to 10 °C. 10-Propargyl-10-

deazaaminopterin ethyl ester (PLT-ES, Compound 9B, 13 g, 24.4 mmol) was added, and the temperature was increased to 25 °C over 0.5 h. The resulting suspension was then stirred at 25 °C for 17 h. The solid in the suspension was then isolated by filtration and washed with EtOH (65 mL). The collected solid was then dried in a drying oven at 45 °C for 18 h to provide (2S)-2-[[4-[(1 RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid disodium salt (Na-PLT; compound 10a) as a pale yellow solid (10.9 g, 86% yield, purity 99.6%).

Example 12: Preparation of Pralatrexate (Compound 10)

[00112] (2S)-2-[[4-[(1 RS)-1-[(2,4-Diaminopteridin-6-yl)methyl]but-3-ynyl]benzo-yl]amino]pentanedioic acid disodium salt (Na-PLT, Compound 10a, 10.9 g, 20.9 mmol) was dissolved in water (109 mL). The pH of the solution was adjusted to 4.5 by addition of aqueous HCl 1N. A precipitate formed and was isolated by filtration and washed with water (54 mL). The collected solid was then dried in a drying oven at 45 °C for 17 h to provide Pralatrexate (Compound 10) as a white solid (9.4 g, 81% yield, and purity 99.7%).

Example 13: Preparation of Pralatrexate ethyl ester (PLT-ES) (compound 9B)

[00113] A reactor was charged with potassium 10-propargyl-4-deoxy-4-amino-10-deazapteroate (K-Pt-MADEC, compound 11, 11.1 g, 28.7 mmol). DCM (82 ml) and 1-methyl-2-pyrrolidinone (16.7 ml) were added to obtain a suspension. 1-Hydroxy-benzotriazole hydrate (HOBt, 0.77 g, 5.74 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC, 6.60 g, 34.4 mmol) and (L)-glutamic acid

diethyl ester hydrochloride (7.98 g, 34.4 mmol) were sequentially added. The resulting mixture was stirred at room temperature until HPLC analysis showed reaction completion. DCM was removed under reduced pressure and MeOH (22.2 mL) was added. The reaction mixture was poured into water pre-acidified with aqueous HCl 16% (w/w, 16.9 mL). The pH was adjusted to 4.5 by addition of aqueous NaOH, resulting in the precipitation of the PLT-ES. The solid precipitate was isolated by filtration and dried in oven at 55 °C for 18 h to provide PLT-ES as a pale yellow solid (13 g, 85% yield, and purity 99.0%).

Example 14: Preparation of crystalline Pralatrexate ethyl ester (compound 9B)

[00114] PLT-ES (Compound 9B, lg) was dissolved in EtOH (15 ml). After a few minutes a precipitate started to form, and the precipitate was isolated by filtration after 45 minutes (0.5g, yellow solid, amorphous form). The mother liquor was left at room temperature overnight, resulting in the precipitation of a yellow solid which was isolated by filtration (0.3g, crystalline form, PXRD is shown on Figure 7).

Example 15: Hydrolysis of Pralatrexate ethyl ester (compound 9B)

[00115] A reactor was charged with MeOH (48 mL), aqueous NaOH (3.75 M, 18.0 mL, 67.5 mmol), and water (6 mL), and the mixture was cooled down to 10 °C. PLT-ES 9B (12 g, 22.5 mmol) was added and the temperature was increased to 25 °C over 1 h. The resulting suspension was stirred at 25 °C for 1 h, and then EtOH (168 mL) was added, resulting in the formation of a precipitate. After stirring for an additional 24 h the solid precipitate was isolated by filtration and washed with EtOH (120 mL).

The collected solid was then dried in a drying oven at 60 °C for 18 h to provide Na-PLT 10a (10.5 g, 90% yield, purity 99.8%) as a pale yellow solid.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014068599

Pralatrexate is chemically, N-(4-{ 1-[(2,4-diaminopteridin-6-yl)methyl]but-3-yn-1 -yl}benzoyl)-L-glutamic acid and has the structural formula:

Pralatrexate is an anti-cancer therapy. It is the first drug approved as a treatment for patients with relapsed or refractory peripheral T-cell lymphoma, or PTCL – a biologically diverse group of aggressive blood cancers. Pralatrexate is currently marketed under the trade name FOLOTYN® by Alios.

Pralatrexate was disclosed in U.S. patent nos. 5,354,751 and 6,028,071.

According to the ‘071 patent, alpha-propargylhomoterephthalic acid dimethyl ester substantially free of homoterephthalic acid dimethyl ester was obtained by chromatographing alpha-propargylhomoterephthalic acid dimethyl ester residue obtained as part of the reaction between homoterephthalic acid dimethyl ester and propargyl bromide in the presence of

tetrahydrofuran and sodium hydride on silica gel using cyclohexane and ethyl acetate (8:1) for the elution.

Pralatrexate was also reported in J. Med. Chem, 1993, 36, 2228-2231. According to the paper, pralatrexate is prepared by crystallizing pralatrexate diethyl ester in a mixture of 2-methoxyethanol and water in the presence of sodium hydroxide.

International patent application publication no. WO 2012/061469 (‘469 patent) disclosed crystalline Form A, Form B and Form C of pralatrexate. According to the ‘469 patent, crystalline pralatrexate Form A can be prepared by crystallizing amorphous pralatrexate in formamide.

According to the ‘469 patent, crystalline pralatrexate Form B can be prepared by crystallizing amorphous pralatrexate in methanol or water.

According to the ‘469 patent, crystalline pralatrexate Form C can be prepared by crystallizing amorphous pralatrexate in a mixture of methanol and water.

Alpha-propargylhomoterephthalic acid dimethyl ester is a key staring material for the preparation of pralatrexate.

Example 1 :

Preparation of Alpha-propargylhomoterephthalic acid dimethyl ester

Sodium hydride (60 gm; 60%) was added to tetrahydrofuran (1500 ml) at room temperature and then cooled to 10 to 15°C. To the solution was added a solution of homoterephthalic acid dimethyl ester (250 gm) in tetrahydrofuran (250 ml) slowly for 15 minutes. The reaction mass was then cooled to 0 to -5°C and then added propargyl bromide (130 gm) in tetrahydrofuran (125 ml) slowly for 15 minutes at 0 to -5°C. The reaction mass was maintained for 2 hours at 0 to -5°C and then added methanol (50 ml). The temperature of the reaction mass was raised to room temperature and then added water (1500 ml) and diisopropyl ether (2500 ml), and then the layers were separated. The organic layer were dried with sodium sulfate and then concentrated to obtain 275 gm of alpha-propargylhomoterephthalic acid dimethyl ester.

Chromatographic purity of alpha-propargylhomoterephthalic acid dimethyl ester: 62.0%; Content of homoterephthalic acid dimethyl ester: 12.0%.

Example 2:

Purification of Alpha-propargylhomoterephthalic acid dimethyl ester

Alpha-propargylhomoterephthalic acid dimethyl ester (275 gm; HPLC Purity: 62.0%) as obtained in example 1 was dissolved in a mixture of hexane (1200 ml) and diisopropyl ether (65 ml) at room temperature. The solution was stirred for 15 hours at room temperature and filtered. The solid obtained was dried to obtain 175 gm of alpha-propargylhomoterephthalic acid dimethyl ester.

Chromatographic purity of alpha-propargylhomoterephthalic acid dimethyl ester: 74.6%; Content of homoterephthalic acid dimethyl ester: 0.4%.

Example 3:

Preparation of 10-propargyl-10-deazaminopterin diethyl ester

Step-I: Preparation oƒ 10-proparsyl-10-carbomethoxy-4-deoxy-4-amino-10-deazapteroic acid methyl ester

Sodium hydride (120 gm; 60%) was added to dimethylformamide (750 ml) at room temperature and then cooled to 0 to -5°C. To the solution was added a solution of alpha-propargylhomoterephthalic acid dimethyl ester (250 gm) in dimethylformamide (750 ml)

slowly for 15 minutes. The reaction mixture was maintained for 30 minutes at 0 to -5 C and then cooled to -20 to -25°C. To the reaction mixture was added 6-bromomethyl-pteridine-2,4-diamine (300 gm) in dimethylformamide (1500 ml) slowly for 30 minutes. The reaction mass was maintained for 2 hours at -20 to -25°C and then added methanol (300 ml). The temperature of the reaction mass was raised to room temperature and then added water (15000 ml) and diisopropyl ether (1500 ml). The contents were stirred for 2 hours at room temperature and filtered. The solid obtained was dried to obtain 198 gm of 10-propargyl-10-carbomethoxy-4-deoxy-4-amino-10-deazapteroic acid methyl ester.

Step-II: Preparation oƒ 10-proparsyl-10-carboxy-4-deoxy-4-amino-10-deazapteroic acid

2-Methoxyethanol (775 gm) was added to 10-propargyI-10-carbomethoxy-4-deoxy-4-amino-10-deazapteroic acid methyl ester (155 gm) at room temperature and then cooled to 15 to 20°C. To the reaction mixture was added a solution of sodium hydroxide (120 gm) in water (930 ml) and maintained for 4 hours at room temperature. The pH of the reaction mass was adjusted to 4.5 to 4.6 with acetic acid (50%) and then added water (3100 ml). The reaction mass was stirred for 2 hours, filtered and then dried to obtain 125 gm of 10-propargyl-10-carboxy-4-deoxy-4-amino-10-deazapteroic acid.

Step-III: Preparation oƒ 10-proparsyl-4-deoxy-4-amino-10-deazapteroic acid

10-Propargyl-10-carboxy-4-deoxy-4-amino-10-deazapteroic acid (135 gm) was added to dimethyl sulfoxide (1350 ml) at 120 to 125°C and maintained for 45 minutes at 120 to 125°C. The reaction mass was poured into water (3000 ml), maintained for 24 hours at room temperature and filtered to obtain a wet solid. To the wet solid was basified and then acetified, and maintained for 2 hours at room temperature. The separated solid was filtered and then dried to obtain 56 gm of 10-propargyl-4-deoxy-4-amino-10-deazapteroic acid.

Step-IV: Preparation oƒ 10-propargyl-10-deazaminopterin diethyl ester

Dimethylformamide (1 12 ml) was added to 10-propargyl-4-deoxy-4-amino-10-deazapteroic acid (14 gm) and stirred for 15 minutes. To the reaction mixture was added triethylamine (14 ml) and then cooled to 0 to -5°C. A solution of (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (21 gm) in dimethylformamide (28 ml) was added to the reaction mixture and maintained for 1 hour at 0 to -5°C. To the

reaction mixture was added L-glutamic acid diethyl ester (10 gm) in dimethylformamide (28 ml) slowly, maintained for 2 hours at -10 to -15°C and filtered. The pH of the filtrate obtained was adjusted with sodium hydroxide solution and then added water (700 ml) slowly for 45 minutes. The reaction mass was maintained for 2 hours at room temperature, filtered and then dried to obtain 14 gm of 10-propargyl-10-deazaminopterin diethyl ester.

Example 4:

Preparation of pralatrexate

10-Propargyl-10-deazaminopterin diethyl ester (40 gm) was dissolved in tetrahydrofuran (320 ml) at room temperature. The solution was then cooled to 15 to 20°C and added a solution of sodium hydroxide (24 gm) in water (400 ml) slowly for 15 minutes. The reaction mass was maintained for 45 minutes at 15 to 20°C and then added a mixture of tetrahydrofuran (200 ml) and ethyl acetate (200 ml). The layers were separated and to the aqueous layer was added water (80 ml). The separated aqueous layer was then concentrated and pH was adjusted to 4.7 to 4.8 with acetic acid (10%). The contents were stirred for 1 hour at room temperature and filtered. The solid obtained was then dried to obtain 28 gm of pralatrexate.

Chromatographic purity of pralatrexate: 98.5%;

Content of 10-propargyl-4-deoxy-4-amino-10-dezapteroic acid: 0.3%;

Content of 10-deazaaminopterin: 0.5%;

Example 5:

Purification of pralatrexate

The pralatrexate (28 gm: HPLC Purity: 98.5%) as obtained in example 4 was dissolved in tetrahydrofuran (400 ml) and then heated to 60°C. To the contents were added water (200 ml) at 60°C and then cooled to 5 to 10°C. The contents were stirred for 2 hours 30 minutes at 5 to 10°C, filtered and then dried to obtain a solid. The solid was dissolved in dimethyl sulfoxide (138 ml) and then stirred to obtain a clear solution. The solution was filtered through celite bed and then added ethanol (690 ml) slowly for 1 hour. The contents were stirred for 1 hour at room temperature, filtered and then dried to obtain 20 gm of pure pralatrexate.

Chromatographic purity of pralatrexate: 99.5%;

Content of 10-propargyl-4-deoxy-4-amino-10-dezapteroic acid: 0.06%; Content of 10-deazaaminopterin: 0.08%.

PAPER

Nonpolyglutamatable Antifolate N-alpha-(4 amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine”, JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 45, no. 8, 1 January 2002 (2002-01-01), pages 1690 – 1696, XP002291409, ISSN: 0022-2623, DOI: 10.1021/JM010518T *

Abstract Image

Details are disclosed for the synthesis of Nα-[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]-Nδ-hemiphthaloyl-l-ornithine (2) and Nα-[4-[5-(2,4-diaminoteridin-6-yl)pent-1-yn-4-yl]benzoyl]-Nδ-hemiphthaloyl-l-ornithine (6) as analogues of Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine (1, PT523), a nonpolyglutamatable antifolate currently in advanced preclinical development. In a 72 h growth inhibition assay against cultures of CCRF-CEM human leukemic lymphoblasts, the IC50 of 2 and 6 was 0.69 ± 0.044 nM and 1.3 ± 0.35 nM, respectively, as compared with previously reported values 4.4 ± 0.10 nM for aminopterin (AMT) and 1.5 ± 0.39 nM for PT523. In a spectrophotometric assay of dihydrofolate reductase (DHFR) inhibition using dihydrofolate and NADPH as the cosubstrates, the previously unreported compounds and the mixed 10R and 10S diastereomers of 6 had Ki values of 0.21 ± 0.05 pM and 0.60 ± 0.02 pM, respectively, as compared with previously reported values of 3.70 ± 0.35 pM for AMT and 0.33 ± 0.04 pM for PT523. Thus, while they were comparable to 1 and several of its previously studied analogues in their ability to bind to DHFR and inhibit the growth of CCRF-CEM cells, 2 and the mixed diastereomers of 6 were several times more active than AMT despite the fact that they cannot form γ-polyglutamylated metabolites of the type formed in cells from AMT and other classical antifolates with a glutamate side chain.

Synthesis and In Vitro Antitumor Activity of New Deaza Analogues of the Nonpolyglutamatable Antifolate Nα-(4-Amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine (PT523)

Dana-Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115
J. Med. Chem.200245 (8), pp 1690–1696
DOI: 10.1021/jm010518t
PAPER
Journal of Medicinal Chemistry (1993), 36(15), 2228-31
lO-Propargyl-10-deazaaminopte~n Diethyl Ester (6). A solution of the acid (6) (100 mg, 0.29 mmol) in dry DMF (5 mL) wastreatedwithtriethylamine(O.28mL,2.Ommol). Afterstirring at room temperature for 20 min, the solution was treated with isobutyl chloroformate (0.075 mL, 0.57 mmol). The mixture was stirred at room temperature for 1 h and then treated with L-glutamic acid diethyl ester hydrochloride (0.14 g, 0.57 mmol) and stirred for 2 h. The additions of isobutyl chloroformate and glutamate ester were repeated twice with one-quarter quantities of these reagents, and the final mixture was stirred for 15 h. The reaction was concentrated under high vacuum, and the residue was diesolved in CHCb (10 mL) and washed with dilute NgOH and then water. The organic layer was dried over N&O, and concentrated in vacuo. The residue was chromatographed on 10 g of flash silica gel (2% MeOH in CHCh). Following chromatography, an aliquot was saponified; HPLC analysis indicated 93 % purity. The product was obtained as a yellow foam 85 mg (55%): mass spectrum mle 534 (M + H); lH NMR (CDCh) 8.5 (8, lH, 7-H), 7.75 (d, 2H, C&), 7.28 (d, 2H), 7.0 (br s, lH, NH), 5.35 (br 8, lH, NH), 4.77 (m, lH, NHCH), 4.10 and 4.25 (q,4H, OCHd, 3.46 (m, 2H, C-SCHz), 3.23 (m, lH, C-lOH), 2.62 (m, 2H, WCHd, 2.46 (m, 2H,CH&OOEt), 2.15and2.32(m,2H,glu-3CH~),2.04(brs,lH,C=CH),1.22and 1.29 (t, 6H, CHaCHa).
10-Propargyl-10-deazaaminopterin (7). The diethyl ester (6) (83 mg, 0.16 -01) was dissolved in 2-methoxyethanol (2 mL), and the solution was treated with water (1 mL) and then 10% NaOH (1 mL). The solution was stirred for 2 h at room temperature. The reaction mixture was diluted with 10 mL of H20, neutralized to pH 5 with HOAc to give a precipitate which was collected, and dried to leave 45 mg (61%) of a pale yellow solid; HPLC analysis indicated 95 % purity; mass spectrum mle 765 (as the (TMS)a) derivative); W (0.1 N NaOH) A mas 256 nm (c 29 800), 372 (7000). Anal. Calcd for CmHaN,Oa.2.5HzO: C, H, N

PATENT

https://patents.google.com/patent/CN107488112A/zh

PATENT

US 20150183789

https://patents.google.com/patent/US9440979B2/en

PATENT

Publication numberPriority datePublication dateAssigneeTitle
WO2014020553A1 *2012-08-032014-02-06Fresenius Kabi Oncology Ltd.Salts of pralatrexate
CN103588775A *2013-11-122014-02-19连云港恒运医药科技有限公司普拉曲沙降解杂质及其制备方法
WO2014016740A3 *2012-07-232014-03-20Fresenius Kabi Oncology Ltd.Improved process for the preparation of pralatrexate
CN104418859A *2013-09-092015-03-18上海医药工业研究院普拉曲沙的晶型、含其的药物组合物及其制备方法和应用
WO2014068599A3 *2012-11-022015-03-19Hetero Research FoundationProcess for pralatrexate
CN104628727A *2013-11-072015-05-20正大天晴药业集团股份有限公司一种普拉曲沙的晶型及其制备方法
CN105272983A *2014-06-122016-01-27连云港润众制药有限公司一种高纯度普拉曲沙固体及其制备方法
US5354741A1993-05-071994-10-11American Cyanamid CompanyDiaryl (pyridinio and isoquinolinio) boron insecticidal and acaricidal agents
US5374726A1992-03-031994-12-20Degraw; Joseph I.Process for preparing 10-deazaaminopterins and 5,10-and 8,10-dideazaaminopterins from pteroic dicarboxylic acid diesters
US6028071A1996-07-172000-02-22Sloan-Kettering Institute For Cancer ResearchPurified compositions of 10-propargyl-10-deazaaminopterin and methods of using same in the treatment of tumors
US20110190305A12010-02-022011-08-04Allos Therapeutics, Inc.Optically Pure Diastereomers of 10-Propargyl-10-Deazaaminopterin and Methods of Using Same
Family To Family Citations
EP2794610B1 *2011-12-212016-03-09Plus Chemicals SAProcesses and intermediates for preparing pralatrexate
DEGRAW JOURNAL OF MEDICINAL CHEMISTRY vol. 36, 1993, pages 2228 – 2231

Publication numberPriority datePublication dateAssigneeTitle

WO2014068599A3 *2012-11-022015-03-19Hetero Research FoundationProcess for pralatrexate
US5354751A1992-03-031994-10-11Sri InternationalHeteroaroyl 10-deazaamino-pterine compounds and use for rheumatoid arthritis
WO1998002163A1 *1996-07-171998-01-22Sloan-Kettering Institute For Cancer ResearchPurified compositions of 10-propargyl-10-deazaaminopterin and methods of using same in the treatment of tumors
US20050267117A12004-05-302005-12-01O’connor Owen ATreatment of T-cell lymphoma using 10-propargyl-10-deazaaminopterin
US20110190305A12010-02-022011-08-04Allos Therapeutics, Inc.Optically Pure Diastereomers of 10-Propargyl-10-Deazaaminopterin and Methods of Using Same
BIOORGANIC AND MEDICINAL CHEMISTRY, no. 19, 2009, pages 1151
CHITRA M VAIDYA ET AL: “synthesis and in vitro Antitumor Activity of New Deaza Analogues of the Nonpolyglutamatable Antifolate N-alpha-(4 amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine”, JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 45, no. 8, 1 January 2002 (2002-01-01), pages 1690 – 1696, XP002291409, ISSN: 0022-2623, DOI: 10.1021/JM010518T *
DEGRAW J I ET AL: “SYNTHESIS AND ANTITUMOR ACTIVITY OF 10-ALKYL-10-DEAZAMINOPTERINS. A CONVENIENT SYNTHESIS OF 10-DEAZAMINOPTERIN”, JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 25, 1 January 1982 (1982-01-01), pages 1227 – 1230, XP001135116, ISSN: 0022-2623, DOI: 10.1021/JM00352A026 *
KEVIN K-C LIU ET AL: “Synthetic approaches to the 2009 new drugs”, BIOORGANIC & MEDICINAL CHEMISTRY, PERGAMON, GB, vol. 19, no. 3, 16 December 2010 (2010-12-16), pages 1136 – 1154, XP028133979, ISSN: 0968-0896, [retrieved on 20101224], DOI: 10.1016/J.BMC.2010.12.038 *
TAGHAVI-MOGHADAM ET AL: “A new, general and regioselective method for the synthesis of 2,6-disubstituted 4-aminopteridines”, TETRAHEDRON LETTERS, PERGAMON, vol. 38, no. 39, 29 September 1997 (1997-09-29), pages 6835 – 6836, XP005258825, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(97)01619-5 *

References

  1. Jump up to:a b c d e [1], Allos Therapeutics Press Release, “Allos Therapeutics’ Pralatrexate Demonstrates Anticancer Activity in Multiple Cancer Cell Lines”.
  2. Jump up to:a b c d [2], Allos Therapeutics Press Release, “Allos Therapeutics’ FOLOTYN(TM) First and Only FDA-Approved Therapy for Relapsed or Refractory Peripheral T-cell Lymphoma”.
  3. Jump up^ [3], FDA, “Fast Track, Accelerated Approval and Priority Review”.
  4. Jump up^ [4], Allos Therapeutics, “Allos Therapeutics, Inc. Q1 2010 Earnings Call Transcript”.
  5. Jump up to:a b c [5], Psychiatric Times, “Principles of Oncologic Pharmacotherapy”.
  6. Jump up to:a b [6], Memorial Sloan Kettering Cancer Center Press Release, “FDA Approves Lymphoma Drug Developed at Memorial Sloan Kettering”.
  7. Jump up^ [7], National Cancer Institute “NCI Cancer Bulletin: The Next Steps in Drug Development at NCI”.
  8. Jump up^ “FDA Approves Pralatrexate for Treatment of Peripheral T-Cell Lymphoma” (Press release). SRI International. 2009-09-25. Retrieved 2013-07-10.
  9. Jump up^ Avery, Greg (2012-09-07). “Purchase of Allos Therapeutics is completed”Denver Business Journal. Retrieved 2013-07-10.

External links

Pralatrexate
Pralatrexate.png
Pralatrexate ball-and-stick.png
Clinical data
Trade names Folotyn
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • D
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
ECHA InfoCard 100.205.791
Chemical and physical data
Formula C23H23N7O5
Molar mass 477.47 g/mol
3D model (JSmol)

////////////プララトレキサート , japan 2017, Pralatrexate

NC1=NC2=NC=C(CC(CC#C)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)N=C2C(N)=N1

Nusinersen sodium, ヌシネルセンナトリウム


ヌシネルセンナトリウム
Nusinersen Sodium

C234H323N61Na17O128P17S17 : 7500.89
[1258984-36-9 , ヌシネルセン]

Nusinersen sodium

C234H323N61O128P17S17.17Na, 7500.8854

UNII 4CHB7QQU1Q

ISIS 396443

Nusinersen sodium was approved by the US Food and Drug Administration (FDA) on Dec 23, 2016, and approved by the European Medicines Agency’s (EMA) on May 30, 2017, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on July 3, 2017.

JAPAN APPROVAL

2017/7/3 Nusinersen sodium Spinraza Biogen Japan

An antisense oligonucleotide that induces survival motor neuron (SMN) protein expression, it was approved by the U.S. FDA in December, 2016 as Spinraza for the treatment of children and adults with spinal muscular atrophy (SMA). It is adminstrated as direct intrathecal injection.Nusinersen sodium colored.svg

FREE FORM CAS: 1258984-36-9

Image result for nusinersen

CAS1258984-36-9

MFC234H340N61O128P17S17

ISIS-396443, ISIS-SMNRx, IONIS-SMNRx

RNA, (2′-0-(2-methoxyethyi))(p-thio)(m5u-c-a-c-m5u-m5u-m5u-c-a-m5ua- a-m5 u-g-c-m5u-g-g)

RNA, (2′-0-(2-METHOXYETHYI))(P-THIO)(M5U-C-A-C-M5U-M5U-M5U-C-A-M5UA- A-M5 U-G-C-M5U-G-G)

All-P-ambo-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioguanylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioguanylyl-(3’¨5′)-2′-O-(2-methoxyethyl)guanosine

ISIS-SMNRx is a drug that is designed to modulate the splicing of the SMN2 gene to significantly increase the production of functional SMN protein. The US regulatory agency has granted Orphan Drug Designation with Fast Track Status to nusinersen for the treatment of patients with SMA. The European regulatory agency has granted Orphan Drug Designation to nusinersen for the treatment of patients with SMA.

Nusinersen,[1] marketed as Spinraza,[3] is a medication used in treating spinal muscular atrophy (SMA),[4] a rare neuromuscular disorder. In December 2016, it became the first approved drug used in treating this disorder. Nusinersen has orphan drugdesignation in the United States and the European Union.[5]

Image result for nusinersen

FDA

FDA approves first drug for spinal muscular atrophy

New therapy addresses unmet medical need for rare disease

The U.S. Food and Drug Administration today approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.

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For Immediate Release

December 23, 2016

The U.S. Food and Drug Administration today approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.

“There has been a long-standing need for a treatment for spinal muscular atrophy, the most common genetic cause of death in infants, and a disease that can affect people at any stage of life,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “As shown by our suggestion to the sponsor to analyze the results of the study earlier than planned, the FDA is committed to assisting with the development and approval of safe and effective drugs for rare diseases and we worked hard to review this application quickly; we could not be more pleased to have the first approved treatment for this debilitating disease.”

SMA is a hereditary disease that causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. There is wide variability in age of onset, symptoms and rate of progression. Spinraza is approved for use across the range of spinal muscular atrophy patients.

The FDA worked closely with the sponsor during development to help design and implement the analysis upon which this approval was based. The efficacy of Spinraza was demonstrated in a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose. Patients were randomized to receive an injection of Spinraza, into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick). Twice the number of patients received Spinraza compared to those who underwent the mock procedure. The trial assessed the percentage of patients with improvement in motor milestones, such as head control, sitting, ability to kick in supine position, rolling, crawling, standing and walking.

The FDA asked the sponsor to conduct an interim analysis as a way to evaluate the study results as early as possible; 82 of 121 patients were eligible for this analysis. Forty percent of patients treated with Spinraza achieved improvement in motor milestones as defined in the study, whereas none of the control patients did.

Additional open-label uncontrolled clinical studies were conducted in symptomatic patients who ranged in age from 30 days to 15 years at the time of the first dose, and in presymptomatic patients who ranged in age from 8 days to 42 days at the time of first dose. These studies lacked control groups and therefore were more difficult to interpret than the controlled study, but the findings appeared generally supportive of the clinical efficacy demonstrated in the controlled clinical trial in infantile-onset patients.

The most common side effects found in participants in the clinical trials on Spinraza were upper respiratory infection, lower respiratory infection and constipation. Warnings and precautions include low blood platelet count and toxicity to the kidneys (renal toxicity). Toxicity in the nervous system (neurotoxicity) was observed in animal studies.

The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a rare pediatric disease priority review voucher under 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 eighth rare pediatric disease priority review voucher issued by the FDA since the program began.

Spinraza is marketed by Biogen of Cambridge, Massachusetts and was developed by Ionis Pharmaceuticals of Carlsbad, California.

Medical use

The drug is used to treat spinal muscular atrophy associated with a mutation in the SMN1 gene. It is administered directly to the central nervous system (CNS) using intrathecal injection.[2]

In clinical trials, the drug halted the disease progression. In around 60% of infants affected by type 1 spinal muscular atrophy, the drug also significantly improved motor function.[2]

Image result for Nusinersen sodium

Side effects

Like other antisense drugs, there is a risk of abnormalities in blood clotting and a reduction in platelets as well as a risk of kidney damage.[2]

In clinical trials, people treated with nusinersen had an increased risk of upper and lower respiratory infections and congestion, ear infections, constipation, pulmonary aspiration, teething, and scoliosis. One infant in a clinical trial had severe lowering of salt levels and several had rashes. There is a risk that growth of infants and children might be stunted. In older clinical trial subjects, the most common adverse events were headache, back pain, and adverse effects from the spinal injection.[2]

Some people may develop antibodies against the drug; as of December 2016 it was unclear what effect this might have on efficacy or safety.[2]

Pharmacology

Spinal muscular atrophy is caused by loss-of-function mutations in the SMN1 gene which codes for survival motor neuron (SMN) protein. Patients survive owing to low amounts of the SMN protein produced from the SMN2 gene. Nusinersen modulates alternate splicing of the SMN2 gene, functionally converting it into SMN1 gene, thus increasing the level of SMN protein in the CNS.[6]

The drug distributes to CNS and to peripheral tissues.[2]

The half-life is estimated to be 135 to 177 days in CSF and 63 to 87 days in blood plasma. The drug is metabolized via exonuclease (3’- and 5’)-mediated hydrolysis and does not interact with CYP450 enzymes.[2] The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites.[2]

Chemistry

Nusinersen is an antisense oligonucleotide in which the 2’-hydroxy groups of the ribofuranosyl rings are replaced with 2’-O-2-methoxyethyl groups and the phosphate linkages are replaced with phosphorothioate linkages.[2][6]

History

Nusinersen was discovered in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals (formerly called Isis Pharmaceuticals).[7][8][9][10] Partial work was done at the University of Massachusetts Medical School funded by Cure SMA.[11]

Starting in 2012, Ionis partnered with Biogen on development and in 2015 Biogen acquired an exclusive license to the drug for a US$75 million license fee, milestone payments up to US$150 million, and tiered royalties thereafter; Biogen also paid the costs of development subsequent to taking the license.[12] The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor Laboratory and University of Massachusetts.[13]

In November 2016, the new drug application was accepted under the FDA’s priority review process on the strength of the Phase III trial and the unmet need, and was also accepted for review at the European Medicines Agency (EMA) at that time.[14][15] It was approved by the FDA in December 2016 and by EMA in May 2017 as the first drug to treat spinal muscular atrophy.[16][17] Subsequently, nusinersen was approved to treat SMA in Canada (July 2017),[18] Japan (July 2017),[19] Brasil (August 2017)[20] and Switzerland (September 2017).[21]

Controversy

Spinraza list price is US$125,000 per injection which puts the treatment cost at US$750,000 in the first year and US$375,000 annually after that. According to the New York Times, this places Spinraza “among the most expensive drugs in the world”.[15]

As of October 2017, Spinraza is reimbursed by health insurance providers in the United States and by the public healthcare systems in France (SMA type 1 and 2 patients only), Germany (all patients), Iceland (all patients), Italy (all patients) and Japan (SMA type 1 only).[3]

In October 2017, the authorities in Denmark recommended Spinraza for use only in a small subset of patients with SMA type 1 (young babies) and refused to offer it as a standard treatment in all other SMA patients quoting an “unreasonably high price” compared to the clinical effect.[22] Norwegian authorities rejected the funding in October 2017 because the price of the medicine was “unethically high”.[23] In February 2018 the funding was approved for patients under 18 years old.[23]

In January 2018 public funding of Spinraza was approved in Israel.

Nusinersen (formerly, IONIS-SMNRx, ISIS-SMNRx), intended to be marketed as Spinraza,[1] is an investigational drug for spinal muscular atrophy developed by Ionis Pharmaceuticals and Biogen with financial support from SMA Foundation and Cure SMA. It is a proprietary antisense oligonucleotide that modulates alternate splicing of the SMN2 gene, functionally converting it into SMN1 gene.

The drug is administered directly to the central nervous system using intrathecal injection once every 3–4 months.

Nusinersen has orphan drug designation in the United States and the European Union.[2]

In August 2016, a phase III trial in type 1 SMA patients was ended early due to positive efficacy data, with Biogen deciding to file for regulatory approval for the drug.[3]Consequently, the company submitted a New Drug Application to the FDA in September 2016[4] and a marketing authorisation application to the European Medicines Agency, under the centralised procedure,[5] in the following month. The company also announced an expanded access programme of nusinersen in type 1 SMA in selected countries.

In November 2016, a phase III clinical trial in type 2 SMA patients was halted after an interim analysis indicated the drug’s efficacy also in this SMA type.[6]

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P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

References

  1. Jump up to:a b “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74” (PDF). World Health Organization. pp. 413–14. Retrieved 13 March 2017.
  2. Jump up to:a b c d e f g h i j k “Nusinersen US Label” (PDF). FDA. December 2016. For updates see FDA index page for NDA 209531
  3. Jump up to:a b “Nusinersen”. AdisInsight. Retrieved 1 January 2017.
  4. Jump up^ Ottesen, Eric W. (2017-01-01). “ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy”Translational Neuroscience8 (1): 1–6. doi:10.1515/tnsci-2017-0001ISSN 2081-6936PMC 5382937Freely accessiblePMID 28400976.
  5. Jump up^ “Nusinersen”. UK Specialist Pharmacy Service. Retrieved 31 December 2016.
  6. Jump up to:a b Zanetta, C; Nizzardo, M; Simone, C; Monguzzi, E; Bresolin, N; Comi, GP; Corti, S (1 January 2014). “Molecular Therapeutic Strategies for Spinal Muscular Atrophies: Current and Future Clinical Trials”. Clinical Therapeutics36 (1): 128–40. doi:10.1016/j.clinthera.2013.11.006PMID 24360800.
  7. Jump up^ Garber, K (11 October 2016). “Big win possible for Ionis/Biogen antisense drug in muscular atrophy”. Nature Biotechnology34 (10): 1002–1003. doi:10.1038/nbt1016-1002PMID 27727217.
  8. Jump up^ Wadman, Meredith (23 December 2016). “Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease”Science.
  9. Jump up^ Offord, Catherine (December 1, 2016). “Oligonucleotide Therapeutics Near Approval”The Scientist.
  10. Jump up^ Tarr, Peter (24 December 2016). “CSHL FDA approval of life-saving SMA drug is hailed by its researcher-inventor at CSHL”Cold Spring Harbor Laboratory.
  11. Jump up^ “Therapeutic Approaches”http://www.curesma.org. Cure SMA. Retrieved 1 January 2017.
  12. Jump up^ “Biogen Shells Out $75M to Develop Ionis’ Nusinersen after Positive Phase III Results”Genetic Engineering News, August 1, 2016
  13. Jump up^ “Press release: Biogen and Ionis Pharmaceuticals Report Nusinersen Meets Primary Endpoint at Interim Analysis of Phase 3 ENDEAR Study in Infantile-Onset Spinal Muscular Atrophy | Biogen Media”Biogen. August 1, 2016.
  14. Jump up^ “Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU”. BioNews Services, LLC. Retrieved 2016-11-15.
  15. Jump up to:a b Katie Thomas (December 30, 2016). “Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval”New York Times.
  16. Jump up^ Grant, Charley (2016-12-27). “Surprise Drug Approval Is Holiday Gift for Biogen”Wall Street JournalISSN 0099-9660. Retrieved 2016-12-27.
  17. Jump up^ “Spinraza (nusinersen)”European Medicines Agency. Retrieved 2017-10-27.
  18. Jump up^ “Biogen’s SPINRAZA™ (nusinersen) Receives Notice of Compliance from Health Canada for the Treatment of 5q Spinal Muscular Atrophy (SMA)”Cision. 2017-07-04.
  19. Jump up^ “Biogen to launch Spinraza in Japan soon”. 2017-07-10.
  20. Jump up^ “Remédio inédito para atrofia muscular espinhal é liberado” (in Portuguese). 2017-08-25.
  21. Jump up^ “Spinraza – Zulassung nun auch in der Schweiz” (in German). SMA Schweiz. 2017-09-30.
  22. Jump up^ Medicinrådet siger nej til lægemiddel til børn med muskelsvind: ‘Urimeligt’ dyrt Retrieved October 13 2017.
  23. Jump up to:a b Dette er uforståelig og utrolig urettferdig

Further reading

  • Finkel, Richard S; Chiriboga, Claudia A; Vajsar, Jiri; Day, John W; Montes, Jacqueline; De Vivo, Darryl C; Yamashita, Mason; Rigo, Frank; Hung, Gene; Schneider, Eugene; Norris, Daniel A; Xia, Shuting; Bennett, C Frank; Bishop, Kathie M (2016). “Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study”. The Lancet388 (10063): 3017. doi:10.1016/S0140-6736(16)31408-8.
Nusinersen
Nusinersen sodium colored.svg
Clinical data
Trade names Spinraza
Synonyms IONIS-SMNRx, ISIS-SMNRx
AHFS/Drugs.com Multum Consumer Information
License data
Routes of
administration
Injection into cerebrospinal fluid
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Exonuclease (3’- and 5’)-mediated hydrolysis
Biological half-life 135–177 days (in CSF), 63–87 days (in plasma)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C234H323N61Na17O128P17S17[2]
Molar mass 7501 Da[2]
3D model (JSmol)

////////////////Nusinersen sodium, Spinraza, ヌシネルセンナトリウム, FDA 2016, EU 2017, JAPAN 2017

CC1=CN(C(=O)NC1=O)C2C(C(C(O2)CO)OP(=S)(O)OCC3C(C(C(O3)N4C=C(C(=NC4=O)N)C)OCCOC)OP(=S)(O)OCC5C(C(C(O5)N6C=NC7=C6N=CN=C7N)OCCOC)OP(=S)(O)OCC8C(C(C(O8)N9C=C(C(=NC9=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=CN=C2N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=CN=C2N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=CN=C2N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=C(NC2=O)N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=O)(OCC1C(C(C(O1)N1C=NC2=C1N=C(NC2=O)N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=C(NC2=O)N)OCCOC)O)S)OCCOC

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