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ORGANIC SPECTROSCOPY

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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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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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  5. Jump up to:a b c d The selection and use of essential medicines: Twentieth report of the WHO Expert Committee 2015 (including 19th WHO Model List of Essential Medicines and 5th WHO Model List of Essential Medicines for Children) (PDF). World Health Organization. 2015. p. vii, 29. ISBN 9789241209946Archived(PDF) from the original on 20 December 2016. Retrieved 10 December 2016.
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  9. Jump up to:a b Centers for Disease Control and Prevention (2013-10-25). “Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis”. MMWR62 (RR-09): 1–12. ISSN 1545-8601PMID 24157696.
  10. Jump up^ WHO (2013). The use of bedaquiline in the treatment of multidrug-resistant tuberculosis : interim policy guidanceArchived from the original on 2017-09-10.
  11. Jump up to:a b c Field, Stephen K. (2015-07-01). “Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?”Therapeutic Advances in Chronic Disease6(4): 170–184. doi:10.1177/2040622315582325ISSN 2040-6223PMC 4480545Freely accessiblePMID 26137207Archived from the original on 2015-10-28.
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  13. Jump up^ BPaMZ @ TB Alliance Archived 2017-02-19 at the Wayback Machine.
  14. Jump up^ Two new drug therapies might cure every form of tuberculosis. Feb 2017 Archived 2017-02-20 at the Wayback Machine.
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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

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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

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

Elobixibat hydrate, エロビキシバット水和物


Elobixibat skeletal.svgChemSpider 2D Image | Elobixibat | C36H45N3O7S2Elobixibat.png

Elobixibat

  • Molecular FormulaC36H45N3O7S2
  • Average mass695.888 Da
 CAS 439087-18-0 [RN]
A3309
AZD7806
Glycine, N-[(2R)-2-[[2-[[3,3-dibutyl-2,3,4,5-tetrahydro-7-(methylthio)-1,1-dioxido-5-phenyl-1,5-benzothiazepin-8-yl]oxy]acetyl]amino]-2-phenylacetyl]-
N-{(2R)-2-[({[3,3-Dibutyl-7-(methylsulfanyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenylacetyl}glycine
A-3309
AJG-533
AZD-7806
A-3309; AJG-533; Goofice
Image result for Elobixibat

Elobixibat hydrate

Approved 2018/1/19 Japan pmda

TRADE NAME Goofice  to EA Pharma

エロビキシバット水和物

C36H45N3O7S2▪H2O : 713.9
[1633824-78-8] CAS OF HYDRATE

Image result for Goofice

Gooffice ® tablet 5 mg (hereinafter referred to as Gooffice ® ) is an oral chronic constipation remedy drug containing as active ingredient Erobi vat having bile acid transporter inhibitory action. It is the world’s first bile acid transporter inhibitor.

Elobixibat is an inhibitor of the ileal bile acid transporter (IBAT),[1] undergoing development in clinical trials for the treatment of chronic constipation and irritable bowel syndrome with constipation (IBS-C).

Mechanism of action

IBAT is the bile acid:sodium symporter responsible for the reuptake of bile acids in the ileum which is the initial step in the enterohepatic circulation. By inhibiting the uptake of bile acids, elobixibat increases the bile acid concentration in the gut, and this accelerates intestinal passage and softens the stool. Following several phase II studies, it is now undergoing phase III trials.[2]

Drug development

The drug was developed by Albireo AB, who licensed it to Ferring Pharmaceuticals for further development and marketing.[3] Albireo has partnered with Ajinomoto Pharmaceuticals, giving the Japan-based company the rights to further develop the drug and market it throughout Asia.[4]

  • OriginatorAstraZeneca
  • DeveloperAlbireo Pharma; EA Pharma
  • Class2 ring heterocyclic compounds; Amides; Carboxylic acids; Laxatives; Small molecules; Sulfides; Sulfones; Thiazepines
  • Mechanism of ActionSodium-bile acid cotransporter-inhibitors
  • Orphan Drug StatusNo
  • New Molecular EntityYes

Highest Development Phases

  • RegisteredConstipation
  • DiscontinuedDyslipidaemias; Irritable bowel syndrome

Most Recent Events

Approved 2018/1/19 japan pmda

  • 24 Jan 2018Elobixibat is still in phase II trials for Constipation in Indonesia, South Korea, Taiwan, Thailand and Vietnam (Albireo pipeline, January 2018)
  • 24 Jan 2018Discontinued – Phase-II for Irritable bowel syndrome in USA and Europe (PO) (Alberio pipeline, January 2018)
  • 19 Jan 2018Registered for Constipation in Japan (PO) – First global approval
  • In 2012, the compound was licensed to Ajinomoto (now EA Pharma) by Albireo for exclusive development and commercialization rights in several Asian countries. At the same year, the product was licensed to Ferring by Albireo worldwide, except Japan and a small number of Asian markets, for development and marketing. However, in 2015, this license between Ferring and Albireo was terminated and Albireo is seeking partner for in the U.S. and Europe. In 2016, Ajinomoto and Mochida signed an agreement on codevelopment and comarketing of the product in Japan.

Elobixibat

albireo_logo_nav.svg

Elobixibat is an IBAT inhibitor approved in Japan for the treatment of chronic constipation, the first IBAT inhibitor to be approved anywhere in the world.  EA Pharma Co., Ltd., a company formed via a 2016 combination of Eisai’s GI business with Ajinomoto Pharmaceuticals and focused on the gastrointestinal disease space, is the exclusive licensee of elobixibat for the treatment of gastrointestinal disorders in Japan and other select countries in Asia (not including China) and is expected to co-market elobixibat in Japan with Mochida Pharmaceutical Co., Ltd., and to co-promote elobixibat in Japan with Eisai, under the trade name GOOFICE®.

We also believe that elobixibat has potential benefit in the treatment of NASH based on findings on relevant parameters in clinical trials of elobixibat that we previously conducted in patients with chronic constipation and in patients with elevated cholesterol and findings on other parameters relevant to NASH from nonclinical studies that we previously conducted with elobixibat or a different IBAT inhibitor. In particular, in a clinical trial in dyslipidemia patients, elobixibat given for four weeks reduced low-density lipoprotein (LDL) cholesterol, with the occurrence of diarrhea being substantially the same as the placebo group. Also, in other clinical trials in constipated patients, elobixibat given at various doses and for various durations reduced LDL-cholesterol and, in one trial, increased levels of glucagon-like peptide 1 (GLP-1). Moreover, A4250 (an IBAT inhibitor) showed significant improvement (p < 0.05) on the nonalcoholic fatty liver disease activity score in an established model of NASH in mice known as the STAM™ model and improvement in liver inflammation and fibrosis in another preclinical mouse model. We are considering conducting a Phase 2 clinical trial of elobixibat in NASH

These benzothiazepines possess ileal bile acid transport (IBAT) inhibitory activity and accordingly have value in the treatment of disease states associated with hyperlipidaemic conditions and they are useful in methods of treatment of a warm-blooded animal, such as man. The invention also relates to processes for the manufacture of said benzothiazepine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit IBAT in a warm-blooded animal, such as man.
It is well-known that hyperlipidaemic conditions associated with elevated
concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for cardiovascular atherosclerotic disease (for instance “Coronary Heart Disease: Reducing the Risk; a Worldwide View” Assman G., Carmena R. Cullen P. et al; Circulation 1999, 100, 1930-1938 and “Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals from the American Heart Association” Grundy S, Benjamin I., Burke G., et al; Circulation, 1999, 100, 1134-46). Interfering with the circulation of bile acids within the lumen of the intestinal tracts is found to reduce the level of cholesterol. Previous established therapies to reduce the concentration of cholesterol involve, for instance, treatment with HMG-CoA reductase inhibitors, preferably statins such as simvastatin and fluvastatin, or treatment with bile acid binders, such as resins. Frequently used bile acid binders are for instance cholestyramine and cholestipol. One recently proposed therapy (“Bile Acids and Lipoprotein Metabolism: a Renaissance for Bile Acids in the Post Statin Era” Angelin B, Eriksson M, Rudling M; Current Opinion on Lipidology, 1999, 10, 269-74) involved the treatment with substances with an IBAT inhibitory effect.
Re-absorption of bile acid from the gastro-intestinal tract is a normal physiological process which mainly takes place in the ileum by the IBAT mechanism. Inhibitors of EBAT can be used in the treatment of hypercholesterolaemia (see for instance “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolaemic properties”, Biochemica et Biophysica Acta, 1210 (1994) 255- 287). Thus, suitable compounds having such inhibitory IBAT activity are also useful in the treatment of hyperlipidaemic conditions.

Compounds possessing such IBAT inhibitory activity have been described, see for instance the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/50051 and EP 0 864 582.
A further aspect of this invention relates to the use of the compounds of the invention in the treatment of dyslipidemic conditions and disorders such as hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In addition, these compounds are expected to be useful for the prevention and treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart diseases, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurisms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocytes, monocytes and/or macrophage infiltration, intimal thickening, medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischaemic attacks.

PATENTS

WO 2002050051

https://patentscope.wipo.int/search/en/detail.jsf%3Bjsessionid=4E054324A28B9E2E7C3C73102D1560EC.wapp1?docId=WO2002050051&recNum=237&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22A61K%22%26fq%3DPAF_M%3A%22ASTRAZENECA+AB%22&sortOption=Relevance&maxRec=655

STARKE, Ingemar; (SE).
DAHLSTROM, Mikael; (SE).
BLOMBERG, David; (SE)

ASTRAZENECA 

SYNTHESIS

WO 2002050051, WO 1996016051

STR1

PATENT

WO 2003051821

WO 2003020710

TW I291951

WO 2013063512

WO 2013063526

US 20140323412

EP 3012252

PATENT

WO 2003020710

https://patents.google.com/patent/WO2003020710A1/und

STR1

PATENT

WO 2014174066 

WO 02/50051 discloses the compound 1 ,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(/V-{(R)-1 ‘-phenyl-1 ‘- [/V-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,5-benzothiazepine (elobixibat; lUPAC name: /V-{(2R)-2-[({[3,3-dibutyl-7-(methylthio)-1 ,1 -dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenyl-ethanolyl}glycine). This compound is an ileal bile acid transporter (I BAT) inhibitor, which can be used in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases. According to the experimental section of WO 02/50051 , the last synthetic step in the preparation of elobixibat consists of the hydrolysis of a ie f-butoxyl ester under acidic conditions. The crude compound was obtained by evaporation of the reaction mixture under reduced pressure and purification of the residue by preparative HPLC using acetonitrile/ammonium acetate buffer (50:50) as eluent (Example 43). After freeze drying the product, no crystalline material was identified.

Example 1

Preparation of crystal modification I

Toluene (1 1 .78 L) was charged to a 20 L round-bottom flask with stirring and 1 ,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(/V-{(R)-1 ‘-phenyl-1 ‘-[/\/’-(i-butoxycarbonylmethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,5-benzothiazepine (2.94 kg) was added. Formic acid (4.42 L) was added to the reaction mass at 25-30 °C. The temperature was raised to 1 15-120 °C and stirred for 6 hours. The reaction was monitored by HPLC to assure that not more than 1 % of the starting material remained in the reaction mass. The reaction mass was cooled to 40-43 °C. Purified water (1 1 .78 L) was added while stirring. The reaction mass was further cooled to 25-30 °C and stirred for 15 min.

The layers were separated and the organic layer was filtered through a celite bed (0.5 kg in 3 L of toluene) and the filtrate was collected. The celite bed was washed with toluene (5.9 L), the filtrates were combined and concentrated at 38-40 °C under vacuum. The reaction mass was then cooled to 25-30 °C to obtain a solid.

Ethanol (3.7 L) was charged to a clean round-bottom flask with stirring, and the solid obtained in the previous step was added. The reaction mass was heated to 40-43 °C and stirred at this temperature for 30 min. The reaction mass was then cooled to 25-30 °C over a period of 30 min., and then further cooled to 3-5 °C over a period of 2 h, followed by stirring at this temperature for 14 h. Ethanol (3.7 L) was charged to the reaction mass with stirring, while maintaining the temperature at 0-5 °C, and the reaction mass was then stirred at this temperature for 1 h. The material was then filtered and washed with ethanol (1 .47 L), and vacuum dried for 30 min. The material was dried in a vacuum tray dryer at 37-40 °C for 24 h under nitrogen atmosphere. The material was put in clean double LDPE bags under nitrogen atmosphere and stored in a clean HDPE drum. Yield 1 .56 kg.

Crystal modification I has an XRPD pattern, obtained with CuKal -radiation, with

characteristic peaks at °2Θ positions: 3,1 ± 0.2, 4,4 ± 0.2, 4,9 ± 0.2, 5,2 ± 0.2, 6,0 ± 0.2, 7,4 ± 0.2, 7,6 ± 0.2, 7,8 ± 0.2, 8,2 ± 0.2, 10,0 ± 0.2, 10,5 ± 0.2, 1 1 ,3 ± 0.2, 12,4 ± 0.2, 13,3 ± 0.2, 13,5 ± 0.2, 14,6 ± 0.2, 14,9 ± 0.2, 16,0 ± 0.2, 16,6 ± 0.2, 16,9 ± 0.2, 17,2 ± 0.2, 17,7 ± 0.2, 18,0 ± 0.2, 18,3 ± 0.2, 18,8 ± 0.2, 19,2 ± 0.2, 19,4 ± 0.2, 20,1 ± 0.2, 20,4 ± 0.2, 20,7 ± 0.2, 20,9 ± 0.2, 21 ,1 ± 0.2, 21 ,4 ± 0.2, 21 ,8 ± 0.2, 22,0 ± 0.2, 22,3 ± 0.2, 22,9 ± 0.2, 23,4 ± 0.2, 24,0 ± 0.2, 24,5 ± 0.2, 24,8 ± 0.2, 26,4 ± 0.2,27,1 ± 0.2 and 27,8 ± 0.2. The X-ray powder diffractogram is shown in FIG. 4.

PATENT

WO 2014174066

エロビキシバット水和物
Elobixibat Hydrate

C36H45N3O7S2▪H2O : 713.9
[1633824-78-8]

References

  1. Jump up^ “INN for A3309 is ELOBIXIBAT”. AlbireoPharma. Archived from the original on 18 January 2012. Retrieved 5 December 2012.
  2. Jump up^ Acosta A, Camilleri M (2014). “Elobixibat and its potential role in chronic idiopathic constipation”Therap Adv Gastroenterol7 (4): 167–75. doi:10.1177/1756283X14528269PMC 4107709Freely accessiblePMID 25057297.
  3. Jump up^ Grogan, Kevin. “Ferring acquires rights to Albireo’s bowel drug”PharmaTimes. Retrieved 23 March 2017.
  4. Jump up^ “Ajinomoto Pharmaceuticals and Albireo Announce Japan and Asia License Agreement for Elobixibat”. Albireo. Retrieved 5 December2012.[permanent dead link]
Elobixibat
Elobixibat skeletal.svg
Clinical data
Routes of
administration
Oral
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C36H45N3O7S2
Molar mass 695.89 g/mol
3D model (JSmol)

//////////Elobixibat hydrate, japan 2018, A-3309, AJG-533, Goofice, A 3309, AJG 533, AZD 7806

CCCCC1(CN(C2=CC(=C(C=C2S(=O)(=O)C1)OCC(=O)NC(C3=CC=CC=C3)C(=O)NCC(=O)O)SC)C4=CC=CC=C4)CCCC

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