AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Jun 262016
 

2016 Patent Expirations.

READ AT

http://lab.express-scripts.com/lab/insights/drug-options/2016-drug-pipeline-full-of-blockbuster-potential

CUBICIN OFF PATENT IN 2016 IN US

JAPAN 2016

Blopress

BARACLUDE IN JAPAN IN 2016

ENTECAVIR, BARACLUDE

Vfend (Voriconazole) IN UK





According to a report by DCAT, based on IMS analysis, the following are some of the key patent expiries between 2014 and 2018.

  1. Nexium (esomeprazole): This patent expired in May 2014. Innovator AstraZeneca granted a license to Teva (TEVA) to produce the generic form in the United States.
  2. Celebrex (celecoxib): This patent expired in 2014. Pfizer conceded the drug to generic drug makers Actavis (ACT) and Teva after a prolonged lawsuit.
  3. Symbicort (budesonide/formoterol fumarate dihydrate): Some of AstraZeneca’s 13 patents have expired, but all won’t expire until 2023. No generic version of the drug exists.
  4. Crestor (rosuvastatin): AstraZeneca will lose its patent protection for Crestor in 2016.
  5. Cialis (tadalafi): Eli Lilly (LLY) is set to lose patent protection in the United States and Europe in 2017.

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

Ranking (by highest sales forecasts for 2020)

Drug

Disease

Pharmaceutical Company

2020 Forecast Sales (US $ billions)

1

Obeticholic acid

Chronic liver diseases, primarily primary biliary cirrhosis

Intercept Pharmaceuticals and Sumitomo Dainippon Pharma

2.621

2

Emtricitabine + tenofovir alafenamide (F/TAF)

HIV-1 infection

Gilead Sciences and Japan Tobacco

2.006

3

Tenofovir alafenamide + emtricitabine + rilpivirine (R/F/TAF)

HIV-1 infection

Gilead Sciences and Janssen R&D

1.572

4

MK-5172A (grazoprevir + elbasvir)

HCV infection

Merck & Co

1.537

5

Venetoclax

Chronic lymphocytic leukemia

Abbvie

1.477

6

Nuplazid (pimavanserin)

Parkinson’s disease psychosis

ACADIA Pharmaceuticals

1.409

7

Uptravi (selexipag)

Pulmonary arterial hypertension

Nippon Shinyaku Co and Actelion

1.268

2016 DRUGS-TO-WATCH FORECAST SALES RANKINGS

Analysis based on data accessed on January 08, 2016.

(SOURCE: Thomson Reuters Cortellis)

 SOME SELECTED STRUCTURES

Obeticholic acid

Obeticholic acid.svg

2Grazoprevir

Grazoprevir.svg

 3 Venetoclax

Venetoclax.svg

 4

Pimavanserin

New Blockbuster Drugs to Watch in 2016

Each of these new drugs could rake in $2 billion in sales.

Blockbuster drugs, those medicines that bring in more than $1 billion in sales every year, are the holy grail of drug development. They can make a pharmaceutical company and send them to rock-star status among investors, as evidenced by the rise of Gilead Sciences after the launch of its hepatitis C treatments. This year’s slate of new drug launches features at least seven drugs expected to hit blockbuster status within the next five years, according to a study by Thomson Reuters.

The line-up also reveals key trends within the pharmaceutical industry for this year and beyond, including an increasing focus on rare diseases, the development of more convenient single-dose regimens, and more affordable treatments.

Here are the seven drugs set to launch this year and reach blockbuster status by 2020.

1. Intercept Pharmaceuticals and Sumitomo Dainippon Pharma

Drug: Obeticholic acid

Indication: Chronic liver diseases, primarily primary biliary cirrhosis

2020 Forecast Sales: $2.62 billion

Intercept Pharmaceuticals’ ICPT -7.35% obeticholic acid has proved very effective in treating non-alcoholic steatohepatitis, a type of liver inflammation caused by fat build-up in the organ. This condition has no approved treatment and a potentially large market, which is expected to push the drug to blockbuster status, if approved. About 2% to 3% of the global population has non-alcholoic steatohepatitis and the share will likely increase due to rising rates of pre-disposing factors like obesity and insulin resistance.

2. Gilead Sciences and Japan Tobacco

Drug: Emtricitabine and tenofovir alafenamide (F/TAF)

Indication: HIV-1 infection

2020 Forecast Sales: $2 billion

Gilead’s GILD -3.48% two HIV-1 infection drugs in development are both expected to be big money-makers, and the company is hoping the new daily single-dosage options will be able to replace sales of its existing HIV treatments that are set to lose patent protections in 2017. The new TAF-based therapies show evidence that they are potentially a safer replacement for some current therapies, including Gilead’s own Truvada.

3. Gilead Sciences and Janssen R&D

Drug: Tenofovir alafenamide and emtricitabine and rilpivirine (R/F/TAF)

Indication: HIV-1 infection

2020 Forecast Sales: $1.57 billion

Like the No. 2 drug on this list, Gilead’s secondary TAF-based combination therapy in partnership with Johnson & Johnson’s JNJ -1.49% Janssen unit is expected to improve renal and bone mineral density measurements compared with some existing drugs. Those results combined with the improved longevity of HIV patients and increasing numbers of those eligible for antiretroviral drugs means a large and lucrative market for the two new TAF-based drugs.

Tenofovir alafenamide structure.svg

Tenofovir alafenamide

4. Merck & Co.

Drug: MK-5172A

Indication: Hepatitis C virus

2020 Forecast Sales: $1.54 billion

Merck MRK -3.12% is getting ready to enter the heated market for hepatitis C treatments, going up against Gilead’s Harvoni and Abbvie’s Viekira Pak. Following a significant setback when theFood and Drug Administration withdrew its “breakthrough drug” status, Merck’s treatment could finally launch this year to give another safe and high-quality treatment for the disease. A recent warning by the FDA concerning Viekira Pak has dampened sales of Abbvie’s drug, which could give Merck a leg up when it eventually brings its hepatitis C drug to market. It could also pursue an aggressive pricing strategy to gain market share, given the currently high price tags on current treatments.

5. Abbvie

Drug: Venetoclax

Indication: Chronic lymphocytic leukemia

2020 Forecast Sales: $1.48 billion

Abbvie’s ABBV -2.37% Venetoclax is a potential oral treatment for cancer, primarily focused on a type of chronic lymphocytic leukemia that is resistant to chemotherapy. The drug was a leading therapy at last year’s annual meeting of the American Society of Hematology after a clinical trial showed an overall response rate of 79.4% in patients with relapsed chronic lymphocytic leukemia. The drug is also being tested as a potential treatment for other hematological cancers like non-Hodgkin’s lymphoma, as well as in combination with tamoxifen in patients with metastatic breast cancer.

6. ACADIA Pharmaceuticals

Drug: Nuplazid

Indication: Parkinson’s disease psychosis

2020 Forecast Sales: $1.41 billion

ACADIA’s ACAD -6.18% nuplazid could be the first and only drug on the market to help treat Parkinson’s disease psychosis, which affects up to 40% of Parkinson’s patients. Clinical trials have shown that the drug does not worsen motor symptoms, a vital factor for these patients, while improving night-time sleep, daytime wakefulness, and caregiver burden. Nuplazid may also work in other psychosis settings, such as schizophrenia and Alzheimer’s disease psychosis. The combination of those three diseases means ACADIA’s drug has a potentially massive and therefore lucrative market.

7. Nippon Shinyaku and Actelion

Drug: Uptravi

Selexipag

Indication: Pulmonary arterial hypertension

2020 Forecast Sales: $1.27 billion

Nippon Shinyaky’s Uptravi is able to both delay the progression of pulmonary arterial hypertension, a type of high blood pressure that affects arteries in the lungs and heart, as well as reduce the risk of hospitalization. The drug is the only one on this list that’s already available. It entered the market in the first week of January 2016 and is expected to bring in $189 million in its first year, with sales increasing to $1.27 billion by 2020. Uptravi is being promoted as an additional therapy once baseline treatment has been started. A massive clinical trial showed that Uptravi reduced the risk of death from pulmonary arterial hypertension by 39% versus placebo.

2015

  1. Opdivo, Bristol-Myers Squibb, $5.684 billion
  2. Praluent, Regeneron Pharmaceuticals and Sanofi, $4.414 billion
  3. LCZ-696, Novartis, $3.731 billion
  4. Ibrance, Pfizer, $2.756 billion
  5. Iumacaftor plus ivacaftor, Vertex Pharmaceuticals, $2.737 billion
  6. Viekira Pak, AbbieVie, $2.500 billion
  7. Evolocumab, Amgen and Astellas Pharma, $1.862 billion
  8. Gardasil 9, Merck & Co., $1.637 billion
  9. Brexpiprazole, Ostuka Pharmaceutical and Lundbeck, $1.353 billion
  10. Toujeo, Sanofi, $1.265 billion
  11. Cosentyx, Novartis, $1.082 billion

SOME MORE STRUCTURES

Rilpivirine.svgRilpivirine

Elbasvir.svgElbasvir

Opdivo

Quetiapine

The pharmaceuticals losing patent protection in 2016

 

A review of the drugs to watch in 2016 identifies several key areas of continued focus in the pharmaceutical industry: rare diseases, FDC regimens and pricing. The year ahead is anticipated to be a very interesting, and challenging, one for the pharmaceutical industry.

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

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Jun 242016
 
Abstract Image

The synthesis of hydroperoxymethyl oxazoles by oxidation of alkylideneoxazoles with molecular oxygen was implemented in a microstructured reactor for increased safety and larger-scale applications. Elaborate studies on the influence of pressure and temperature were performed, and the apparent activation energy for the oxidation reaction was determined. Elevated temperatures up to 100 °C and pressures up to 18 bar(a) led to a conversion rate of approximately 90% within 4 h of the reaction time, thus displaying the high potential and beneficial effect of using a microreactor setup with liquid recycle loop for this oxidation. The in situ reduction of the generated hydroperoxide functionality shows the capability of this setup for follow-up transformations.

Oxazole–hydroperoxide 3as a colorless solid. Rf (PE/EA 3:1 = 0.31).

1H NMR (30 MHz, CDCl3) δ = 4.98 (s, 2H), 7.12 (s, 1H), 7.49–7.29 (m, 3H), 7.88–7.75 (m, 2H), 10.16 (s, 1H). GC-MS (EI) m/z = 173.1 (M – OH), 144.1 (M – CH2OOH), 116.1 (M – C6H5 + 2H), 89.1.

 

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Safe and Fast Flow Synthesis of Functionalized Oxazoles with Molecular Oxygen in a Microstructured Reactor

Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,Germany
Institute of Chemical Process Engineering, Mannheim University of Applied Sciences, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany
§ Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), 21589 Jeddah, Saudi Arabia
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00118
*E-mail: t.roeder@hs-mannheim.de. Telephone: +49 621 292 6800.
Siegel
Organisch-Chemisches Institut                                    
Im Neuenheimer Feld 270
69120 Heidelberg
Germany
Institute of Chemical Process Engineering, Mannheim University of Applied Sciences, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany

Panorama picture of the Campus in July 2006

 

Thorsten Röder

Prof. Dr.
Professor (Full)

Research experience

  • Sep 2009–present
    Professor (Full)
    Hochschule Mannheim · Institute of Chemical Process Engineering
    Germany · Mannheim
  • Sep 2005–Aug 2009
    Laboratory Head
    Novartis · Chemical and Analytical Process Development
    Switzerland · Basel
  • Sep 1999–Aug 2004
    PhD Student
    Universität Paderborn · Department of Chemistry · Physical Chemistry Prof. Kitzerow
    Germany · Paderborn
 Teaching experience
  • Sep 2009–present
    Professor (Full)
    Hochschule Mannheim · Institute of Chemical Process Engineering
    Germany
    Lectures in: Chemical Reaction Engineering Thermodynamic Microreactors & Nanotechnology CFD Practical Course: Chemical Reaction Engineering

Education

  • Oct 1999–Oct 2004
    Universität Paderborn
    Physical Chemistry · Dr. rer. nat.
    Germany · Paderborn
  • Sep 1994–Sep 1999
    Universität Paderborn
    Chemistry · Diplom Chemiker
    Germany
Hashmi Stephen 160x200

Prof. Dr. A. Stephen K. Hashmi

E-Mail hashmi@hashmi.de

/////////Safe and Fast,  Flow Synthesis, Functionalized Oxazoles, Molecular Oxygen, Microstructured Reactor

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Jun 232016
 

STR1

Tenatoprazole.svg

Tenatoprazole

泰妥拉唑

Tenatoprazole; 113712-98-4; Ulsacare; Protop; TU 199; TU-199;
Molecular Formula: C16H18N4O3S
Molecular Weight: 346.40412 g/mol

5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine

2-[2-(3,5-Dimethyl)pyridylmethylsulfinyl]-5-methoxyimidazo[4,5-b]pyridine

Phase I

PHASE 1 FOR ………..A proton pump inhibitor potentially for the treatment of gastroesophageal reflux disease.

Research Code TU-199

CAS No. 113712-98-4

Mitsubishi Tanabe Pharma and was licensed to Negma Laboratories

Tenatoprazole is a proton pump inhibitor drug candidate that was undergoing clinical testing as a potential treatment for refluxoesophagitis and peptic ulcer as far back as 2003.[1] The compound was invented by Mitsubishi Tanabe Pharma and was licensed to Negma Laboratories (part of Wockhardt as of 2007[2]).[3]:22

Mitsubishi reported that tenatoprazole was still in Phase I clinical trials in 2007[4]:27 and again in 2012.[3]:17

Tenatoprazole has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors, and has a half-life about seven times longer than other PPIs.[5]

Tenatoprazole is a novel imidazopyridine derivative and has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors. It is activated more slowly than other proton pump inhibitor, but its inhibition is resistant to reversal.Tenatoprazole has an extended plasma half-life in comparison with those of all other proton pump inhibitors; this makes it more potent in the treatment of nocturnal acid breakthrough than esomeprazole, one of the most popular proton pump inhibitors.
Tenatoprazole belongs to the class of covalent proton pump inhibitors (PPIs), which is converted to the active sulfenamide or sulfenic acid by acid in the secretory canaliculus of the stimulated parietal cell of the stomach.This active species binds to luminally accessible cysteines of the gastric H+,K+-ATPase, resulting in disulfide formation and acid secretion inhibition.Tenatoprazole binds at the catalytic subunit of the gastric acid pump with a stoichiometry of 2.6 nmol mg−1 of the enzyme in vitro. In vivo, maximum binding of tenatoprazole was 2.9 nmol mg−1of the enzyme at 2 h after intravenous (IV) administration.

Tenatoprazole, or (+)-5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} imidazo-[4,5-b] pyridine, is described in Patent No. EP 254,588. It belongs to the group of drugs considered as proton pump inhibitors, which inhibit the secretion of gastric acid and are useful in the treatment of gastric and duodenal ulcers. It can also be used to treat gastro-oesophageal reflux, digestive bleeding and dyspepsia, because of its relatively long elimination half-life, as described in the application for French patent No. FR 02. 13113.

The first known derivative of this series of proton pump inhibitors was omeprazole, described in Patent No. EP 001,529, which is endowed with properties which inhibit the secretion of gastric acid and is widely employed as an anti-ulcerative in human therapeutics.

In addition to omeprazole, other proton pump inhibitors are well known, and particular mention can be made of rabeprazole, pantoprazole and lansoprazole, which all exhibit structural analogy and lansoprazole, which all exhibit structural analogy and belong to the group of pyridinyl methyl sulfinyl benzimidazoles. These compounds are sulfoxides presenting with asymmetry at the level of the sulphur atom, and therefore generally take the form of a racemic mixture of two enantiomers.

Like omeprazole and other sulfoxide with an analogue structure, tenatoprazole has an asymmetric structure and may therefore be present in the form of a racemic mixture or of its enantiomers. Thus it may exist in the form of its two enantiomers with R and S configurations, or (+) or (−), respectively.

Recent studies have shown that, unlike all the other proton pump inhibitors such as, for example, omeprazole or lansoprazole, and unexpectedly, tenatoprazole is endowed with a markedly prolonged duration of action, resulting from a plasma half-life which is about seven times longer. Thus the clinical data collected have shown that tenatoprazole enables a degree of symptom relief and healing of gastric lesions which is superior to that achieved by other drugs belonging to the same therapeutic category of proton pump inhibitors, which thus allows its effective use in the treatment of atypical and oesophageal symptoms of gastro-oesophageal reflux, digestive bleeding and dyspepsia, as indicated above.

Studies performed by the application have made it possible to show that the two enantiomers contribute differently to the properties of tenatoprazole, and that the two enantiomers, (+) and (−) exhibit significantly different pharmacokinetic properties. Thus it is possible to prepare medicinal products with specific activity by isolating the enantiomers, and these enantiomers themselves exhibit a different pharmacokinetic profile from that of the known racemic mixture. It then becomes possible to use each of these enantiomers more effectively in precise indications for the treatment of perfectly identified pathologies.

Tenatoprazole.png

Anti-ulcer drug
tenatoprazole (tenatoprazole) is a new proton pump inhibitor, by the Japanese company Tokyo Tanabe, Japan’s Mitsubishi Corporation and Japan’s Hokuriku pharmaceutical companies jointly developed, has passed Phase II clinical trials. It acts on gastric parietal cells, reducing treatment of gastric ulcer, duodenal ulcer, reflux wall cell H + / K + -ATP activity, inhibition of gastric acid secretion, and H. pylori antibacterial activity, mainly for esophagitis and Zhuo – Ellison syndrome and gastric acid secretion disorders related diseases. Compared with the same types of drugs, Tenatoprazole suppress H + / K + -ATP enzyme activity is stronger, more stable, its efficacy than similar products currently widely used in clinical omeprazole strong 7 times. It has not been in the domestic market, nor ratified the production, with broad market prospects and development potential.
Proton pump inhibitors (proton pump inhibitors) for the treatment of acid-related diseases, the past ten years a wide range of clinical applications, better effect of the drug. It can quickly pass through the stomach wall membrane, gathered in a strongly acidic secretory tubules, and H + / K + -ATP enzyme (proton pump) thiol groups covalently bonded to form a disulfide bond, proton pump inactivation, inhibition of the enzyme H + / K + transport, so as to achieve the effect of acid suppression. Proton pump inhibitors and conventional clinical application of gastric acid suppression drugs H2 receptor antagonists compared with different sites of action and have different characteristics, namely acid-suppressing effect at night is good, rapid onset of acid inhibition strong and long time, easy to take these drugs can quickly and efficiently inhibit gastric acid secretion and clearance of Helicobacter pylori, it is widely used gastric ulcer, duodenal ulcer, reflux esophagitis and Zhuo – Ellison syndrome and other diseases treatment. Currently, proton pump inhibitors has been listed on the main omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole.
Physical and

chemical properties ofwhite or white crystalline powder, melting point 174 ~ 175 ℃. Soluble in chloroform, insoluble in alcohol and water.
This product and other proton pump inhibitors as compared to chemically stable. China had 34 omeprazole preparations from Portugal, Brazil, India, China and other 13 countries, the stability of the measurements were made. The results showed that only six products (18%) during the trial showing good physical and chemical stability of. 27 products (79%) less (including Chinese product), the active ingredient a significant chemical decomposition, color and physical properties such as dissolution, are also a corresponding change. The results of a stability test designed to compare the various proton pump inhibitors show investigated eight days at 60 ℃, relative humidity of 75%, after omeprazole decomposition only 3% of the active ingredient, the tenatoprazole 77% of the data, said Alpha pantoprazole stability far superior to omeprazole, is already developed similar products in the most promising products.

Synthesis 

 

Matsuishi, N.; Takeda, H.; Iizumi, K.; Murakami, K.; Hisamitsu, A. US Patent 4,808,596, 1989

Synthesis of Tenatoprazole 1 commences with the coupling of 2-mercapto-5-methoxyimidazo[4,5-b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 in the presence of potassium hydroxide affords 4 with 73% yield in ethanol and chloroform.  The oxidation of the penultimate sulfide intermediate4 with m-CPBA in chloroform (100 vol) afforded 1

STR1

 

Syn 2

Org. Process Res. Dev., 2009, 13 (4), pp 804–806
DOI: 10.1021/op800173u

synthesis of begins with the solvent-free condensation of 2-mercapto-5-methoxyimidazo[4,5-b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 to deliver the sulfide intermediate4 with 98% yield.

The final step of the synthesis is the oxidation of the sulfide intermediate with m-CPBA to form tenatoprazole 1. The sulfide intermediate 4 on treatment with 0.9 equiv of m-chloroperbenzoic acid (m-CPBA) at −10 to −15 °C afforded the crude tenatoprazole which was isolated as its sodium salt. The sodium salt of tenatoprazole 5 was purified by recrystallsation using dimethyl formamide and ethyl acetate (2:1 ratio) to yield the pure crystalline tenatoprazole sodium 5. Treatment of tenatoprazole sodium 5 with dil. HCl in the presence of acetone and water afforded the pure tenatoprazole 1

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PATENT

CN 1861600

CN 1982311

WO 2009116072

CN 101429192

WO 2010043601

IN 2010CH00462

IN 251400

CN 102304127

WO 2012004802

CN 102703922

IN 2009DE01392

WO 2014111957

IN 2013MU00181

IN 2014CH01419

PAPER

Dai, Liyan; Synthetic Communications 2008, V38(4), P576-582

Advanced Materials Research (Durnten-Zurich, Switzerland) (2011), 233-235(Pt. 1, Fundamental of Chemical Engineering), 160-164.

Organic Process Research & Development (2013), 17(10), 1293-1299

Enantiomeric separation of proton pump inhibitors on new generation chiral columns using LC and supercritical fluid chromatography
Journal of Separation Science (2013), 36, (18), 3004-3010………http://onlinelibrary.wiley.com/doi/10.1002/jssc.201300419/abstract

PATENT

CN 102304127

https://www.google.com/patents/CN102304127A?cl=en

Tenatoprazole is a new type of gastric H + / K + -ATP enzyme inhibitors (proton pump inhibitor PPI), the chemical name 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-methylsulfinyl) imidazole and W, 5-b] pyridine, useful in the treatment of gastric ulcer, duodenal ulcer, reflux esophagitis and Zhuo – Ai syndrome and gastric acid secretion disorders related diseases. The drug was developed by Japan’s Tokyo Tanabe, Japan’s Mitsubishi Corporation and Japan’s Hokuriku pharmaceutical companies. Compared with other varieties of the same type, which inhibit H + / K + -ATP enzyme activity is stronger, ulcers of various tests are effective, and significantly improve the stability compared with other proton pump inhibitors.

 US patent US4808596 “hidazo [4,5_b] pyridine compounds and pharmaceutical compositions containing same)) synthesis process disclosed Tenatoprazole the below formula:

 

Figure CN102304127AD00031

By  The route of 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride with 2-mercapto-5-methoxy-imidazole, 5-b] pyridine under basic conditions condensation of Intermediate 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5-b] pyridine, and then oxidizing the Thai duly omeprazole. This route for the synthesis of pull azole classic line, many pull azoles such as omeprazole can be synthesized by a similar route, this route mild condition, simple operation. But the route condensation, oxidation treatment after use of large amounts of toxic solvent chloroform, is not conducive to industrial scale; lower oxidation yields, the resulting Tenatoprazole containing unreacted starting materials 2- [2_ (3,5 – dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5-b] pyridine, further comprising a sulfone by-product, N- oxide, N- oxide sulfone, These by-products may interfere with purification of tenatoprazole.

Japanese Patent invention Wo 丨 J JP05222038 “5_methoxy-2- [[(4_methoxy-3, 5-dimethyl-2-pyridyl) methyl] thio] imidazo [4,5 ~ b] pyridine and intermediates)) male

Synthesis open Tenatoprazole the below formula:

 

Figure CN102304127AD00041

 4-chloro-2-chloromethyl-3,5-dimethylpyridine -N- oxide 2_ mercapto _5_ methoxy-imidazo – [4, 5-b] pyridine in alkaline under condensation of Intermediate 5-Methoxy-2- (4-chloro-3,5-dimethyl-2-methylthio Bi) imidazo W, 5-b] pyridine-oxide -N- ( yield 82%), then refluxed in a solution of sodium methoxide in methanol to give 5-methoxy-2- (4-oxo-3,5-dimethyl-2-methyl sulfide) imidazo W , 5-b] pyridine -N- oxide (income ¥ 71%), and then at room temperature in methylene chloride, phosphorus trichloride treated with deoxy (yield 95%), and finally oxidation in Tenatoprazole (income Rate not reported). The novel synthetic route, mild reaction conditions, simple operation, the yield of each step is higher, but the route is too long resulting in a total yield is not high, prolonged and rising production costs.

Reaction route is as follows:

 

Figure CN102304127AD00051

Example 1:

] a) 2- [2- (3,5-dimethyl) -4-methoxy-picolyl thioether _5_ methoxy] imidazo [4,5_b] pyridine:

 To a reaction flask was added 2-mercapto-5-methoxy-imidazole, 5-b] pyridine 18. lg, 12g of sodium hydroxide and water 144. 8g, stirred and dissolved at 25 ° C, was added dropwise within Ih 20g of the 2-chloromethyl-dimethyl-4-methoxy _3,5- pyridine hydrochloride and 60g of water were mixed solution dropwise at 25 ° C the reaction 2h, the reaction is completed, filtered, washed with water 144. 8g, 36. 2mL ethanol and washed to obtain a wet powder; wet powder was dried at 50 ° C in vacuo to constant weight to give 2- [2_ (3,5-dimethyl) -4-methoxy-pyridylmethyl sulfide -5 – methoxy] imidazo [4,5-b] pyridine 32. Og;

 2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5-b] pyridine 30g, dichloromethane 300g, methanol 15g, and dissolved with stirring; cooled to -10 ° C, was added dropwise the 15g and 485g m-chloroperbenzoic acid in methylene chloride mixed solution, dropwise addition the reaction temperature was controlled at -10 ° C, the dropping time of the pool; the dropwise addition, the temperature control at -10 ° C, the reaction 30min; completion of the reaction, at 10 ° C by the dropwise addition of lithium hydroxide and 135g water 15g mixed solution, drip complete, insulation stirred Ih; filtered cake was washed with acetone 60mL, get wet powder; wet powder was dried at 35 ° C under vacuum to constant weight to give Tenatoprazole lithium salt ^ g;

 3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, acetone 63mL, water IOOmL, cooling M0 ° C, dropping lmol within lh / L hydrochloric pH7 0, drops. Albert, stirring 30min; the filter cake washed with water 50mL, washed with acetone and 50mL, wet powder was dried at 35 ° C under vacuum to constant weight to give Tenatoprazole 19. Sg.

 Example 2:

 a) 2- [2- (3,5-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5_b] pyridine (4) Preparation: To the reaction flask was added 2-mercapto-5-methoxy-imidazo 44,5-b] pyridine 18. lg, 11. 2g of potassium hydroxide and water 217mL, stirred and dissolved at! 35 ° C, was added dropwise within 2h by the 33. 3g of 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride and 133. 2mL water mixed solution, dropwise at 35 ° C the reaction 4h, the reaction is completed, filtration, water 217mL, 72. 4mL ethanol and washed to obtain a wet powder; wet powder was dried at 60 ° C in vacuo to constant weight to give 2- [2- (3,5-dimethyl) -4-methoxy-pyridylmethyl sulfide -5-methoxy-yl] imidazo W, 5-b] pyridine 33. Ig;

 2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazole and W, 5-b] pyridine 30g, dichloromethane 400mL, methanol 50mL, stirring to dissolve; cooled to _15 ° C, was added drop by the m-chloroperoxybenzoic acid 16g of mixed solution of dichloromethane and 400mL , the process reactor temperature control was added dropwise at -20 ° C, the dropping time 2. 5h; the dropwise addition, the temperature control _15 ° C, the reaction 35min; completion of the reaction, at 15 ° C by the dropwise addition of 20g of hydrogen Lithium oxide and 200mL water mixed solution, drip completed, insulation mixing 1. 5h; filtration, the filter cake washed with acetone 90mL, get wet powder; wet powder was dried at 40 ° C under vacuum to constant weight to give Tenatoprazole lithium salt 28. 6g;

 3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, ethanol 75mL, water 150mL, cooled to 10 ° C, dropping 6mol / L hydrochloric pH8 0 within 2h,. drops Albert, stirring 40min; the filter cake washed with water 100mL, washed with acetone IOOmL, wet powder was dried at 40 ° C under vacuum to constant weight, yield powder was Tenatoprazole 19. 5g.

Example 3:

 a) 2- [2- (3,5-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5_b] pyridine (4) Preparation: To the reaction flask was added 2-mercapto-5-methoxy-imidazo 44,5-b] pyridine 18. lg, 8.4g of lithium hydroxide and water 180ml, stirred and dissolved at 30 ° C, was added dropwise within 1. 5h by the Guang .6g 2-chloro-3,5-dimethyl-4-methoxy-pyridine hydrochloride and 90mL water mixed solution, drop end at 30 ° C reaction 3h, the reaction is complete, filtration, water 217mL , washed with 85mL ethanol to obtain a wet powder; wet powder was dried at 55 ° C in vacuo to constant weight to give 2- [2- (3,5-dimethyl) -4-methoxy-5-pyridylmethyl sulfide oxy] imidazo [4,5-b] pyridine 32. 4g;

2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazole and W, 5-b] pyridine 30g, dichloromethane 600mL, methanol 60mL, stirring to dissolve; cooled to -20 ° C, was added drop by the m-chloroperoxybenzoic acid 18g of mixed solution of dichloromethane and 600mL , dropwise addition the reaction temperature is controlled at _20 ° C, the dropping time of the pool; the dropwise addition, the temperature control at _20 ° C, the reaction 40min; completion of the reaction, at 20 ° C by the dropwise addition of lithium hydroxide and 300mL 30g water mixed solution, drip complete insulation mixing tank; filter, the filter cake washed with acetone and 120mL, get wet powder; wet powder was dried at 40 ° C under vacuum to constant weight to give Tenatoprazole lithium salt 28. 7g;

 3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, methanol 75mL, water 120mL, cooled to 5 ° C, dropping dilute hydrochloric acid within 1 5h tune pH7 5,.. drops Albert, stirring 35min; the filter cake washed with water 75mL, 75mL acetone washed, wet powder was dried at 40 ° C under vacuum to constant weight, yield powder was Tenatoprazole 19. 6g.

Example 4:

 a) 2- [2- (3,5-dimethyl) -4-methoxy-picolyl thioether _5_ methoxy] imidazo [4,5_b] pyridine ⑷ Preparation of: To a solution The reaction flask was added 2-mercapto-5-methoxy imidazole -½, 5-b] pyridine 18. lg, IOg sodium hydroxide and water 150ml, stirred and dissolved at 30 ° C, the 1. 5h dropwise added from 21 . 5g of 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride and 90mL water mixed solution, dropwise at 30 ° C the reaction 3h, completion of the reaction, was filtered, washed with water 217mL, The wet powder was washed with ethanol to give 85mL; wet powder was dried at 55 ° C in vacuo to constant weight to give 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide ] imidazo [4,5-b] pyridine 32. 3g;

 2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazole and W, 5-b] pyridine 30g, dichloromethane 500mL, methanol 60mL, stirring to dissolve; cooled to -20 ° C, was added drop by the m-chloroperoxybenzoic acid 18g of mixed solution of dichloromethane and 500mL , the process reactor temperature control was added dropwise at -20 ° C, the dropping time pool; the dropwise addition, the temperature control in -20 ° C, the reaction 40min; completion of the reaction, at 20 ° C by the dropwise addition of lithium hydroxide 30g and 300mL water mixed solution, drip complete insulation mixing tank; filter, the filter cake washed with acetone and 120mL, get wet powder; wet powder was dried at 40 ° C under vacuum to constant weight to give Tenatoprazole lithium salt 28. 6g;

 3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, isopropanol 75mL, water 120mL, cooled to 5 ° C, dropping 3mol / L hydrochloric within 1 5h. . pH7 5, drops Albert, stirring 35min; the filter cake washed with water 75mL, 75mL acetone washed, wet powder was dried at 40 ° C under vacuum to constant weight, yield powder was Tenatoprazole 19. 7g.

PAPER

An Improved Synthesis of Antiulcerative Drug: Tenatoprazole

http://pubs.acs.org/doi/full/10.1021/op800173u

Department of Research and Development, Srini Pharmaceuticals Ltd., Plot No. 10, Type-C, Road No. 8, Film Nagar, Jubilee Hills, Hyderabad-500033, Andhra Pradesh, India, Department of Chemistry, Osmania University, Tarnaka, Hyderabad-500007, Andhra Pradesh, India and Research and Development, Integrated Product Development Organization, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupally, Qutubullapur, R. R. Dist. 500 072, Andhra Pradesh, India
Org. Process Res. Dev., 2009, 13 (4), pp 804–806
DOI: 10.1021/op800173u
Publication Date (Web): November 12, 2008
Copyright © 2008 American Chemical Society
* To whom correspondence should be addressed. Telephone: +91 9490783736. E-mail: drkvr_ou@yahoo.com;kvgr1951@rediffmail.com., †Srini Pharmaceuticals Ltd.
, ‡Osmania University.
, §Dr. Reddy’s Laboratory Ltd.
Abstract Image

An efficient, cost-effective and multikilogram-scale process for the synthesis of tenatoprazole 1, an antiulcerative drug, is described. The key steps in this synthesis involve the coupling of 2-mercapto-5-methoxyimidazo[4,5-b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 to yield 4 and its subsequent oxidation with m-CPBA to produce sulfoxide 1. The process has been scaled up for the multikilogram-scale of compound 1 with an overall yield of 72%. The new process requires no purification process and affords the target compound 1 with 99.8% purity by HPLC.

2-[2-(3,5-dimethyl)pyridylmethylsulfinyl]-5-methoxyimidazo[4,5-b]pyridine (1, 15.5 kg, 74%). Purity by HPLC 99.8%; 1H NMR (200 MHz, DMSO) δ 2.2 (s, 6H), 3.8 (s, 6H), 4.8 (s, 2H), 6.6 (d, 1H), 7.8 (d, 1H), 8.2 (s, 1H), 13.0 (s, 1H).

PATENT

http://www.google.co.in/patents/US7507746

the (+) enantiomer of tenatoplazole can be obtained by using chloroform, an industrially acceptable solvent, in accordance with the method proposed by Umemura et al. (J. Org. Chem. 1993, 58, 4592) as follows:

Figure US07507746-20090324-C00001

Example 1 (−)-5-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-imidazo[4,5-b]pyridineThe conditions for preparative chromatography, shown as an example, are as follows:

Column: 265×110 mm ChiralPak®

Chiral Stationary Phase selector of the Amylose tris type [(S)-a methylbenzylcarbamate]

Flow rate: 570 ml/min

Detection: UV 240 nm

Temperature: Ambient temperature

These conditions are implemented on a liquid preparative chromatography apparatus.

Introduce approximately 2 g of the racemic mixture if tenatoprazole exhibiting purity higher than 99.5%. The (−) enantiomer is identified by measuring the angle of optical rotation, which must be laevogyre. This measurement can be performed directly on the column, the product being dissolved in the solvent (acetonitrile).

Example 2 (+)-5-methoxy-2-{(4-methoxy-3, 5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-imidazo[4,5-b]pyridine(R)-(+)-binaphthol 85 g (0.311 mol, 0.2 equivalence), ortho titanic acid isopropyl 42 g (0.148 mol, 0.1 equivalence), water 55 g (3.06 mol) and chloroform 7.5 L were stirred for 1 hour at room temperature. To the resultant, 5-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio}imidazo[4,5-b]pyridine (MPI), 0.5 kg, was added and stirred for 0.5 hours at room temperature. The thus-prepared mixture was cooled to 5° C. and then 70% aqueous solution of tert-butylhydroperoxide, 0.4 L (approx. 3.0 mol, 2.0 equivalence) was added and stirred for 72 hours at the same temperature as above. After the reaction endpoint was confirmed by HPLC, an aqueous solution of sodium hydroxide was added thereto to separate the aqueous layer, thus removing foreign matter. Then, the resultant was concentrated. Ethyl acetate was added to concentrated residues, which were then heated and suspended. The thus-prepared crude crystalline substances were dissolved in water and neutralized to pH 6.8 with a diluted sulfuric acid solution which was chilled with ice. Deposited crystals were filtered, dried and recrystallized by addition of ethanol to obtain (+)-5-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-imidazo[4,5-b]pyridine {(+)-TU-199}

Yield: 77%

Optical purity: 96.6% ee

Chemical purity: 94.5%

Melting point: 135° C.

Optical rotation: +184° (conditions: C=1.0, N,N-dimethylformaldehyde solution)

Ultraviolet absorption spectrum: (10 μg/mL)λmax (nm): 316, 273, 206

When measurements were carried out, for a solubility of (+), (−) forms and a racemic form (±) of tenatoprazole in relation to water, it was found that the (+) form dissolved almost 3 times greater than the racemic body and (−) form dissolved over 2 times greater than the racemic form, exhibiting favorable physical properties in preparing drugs (refer to Table 2 below).

TABLE 2
(+) form (−) form (±)racemic form
Solubility (water) μg/mL 93.0 74.4 34.6

CLIPS

Tenatoprazole is a pyridinylmethylsulfinyl imidazopyridine compound, which is a weak base. This compound has three pKas. One is the pyridine pKa of pyridinylmethyl moiety and the others are the imidazole pKa and the pyridine pKa of the imidazopyridine moiety. The pyridine pKa1 enables tenatoprazole accumulation in the acidic canaliculus of the parietal cell. Protonation of the imidazopyridine ring enhances electron deficiency at the C-2 position, allowing intramolecular rearrangement to the active form. The active form is the sulfenic acid and/or cyclic sulfonamide, and reacts with luminal cysteine thiols of the enzyme to inhibit the enzyme activity

Synthesis route
from 2-mercapto-5-methoxy-imidazo [4,5-b] pyridine (2) and 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride ( 3) by nucleophilic substitution synthesis of 2- (4-methoxy-3,5-dimethyl-2-methylthio) -5-methoxy-imidazo [4,5-b] pyridine (4) the oxidation of 4 1. Figure 1 is a synthesis route of tenatoprazole
Scheme of tenatoprazole

References

  1. DataMonitor. March 2003. Gastrointestinal Disease Update: Digestive Disease Week 2003
  2. Economic Times. 3 March, 2011. Investors unwilling to forgive Wockhardt, promoter for failings
  3. Mitsubishi Tanabe Pharma State of New Product Development (as of May 8, 2012)
  4. Mitsubishi Tanabe Pharma FY2007 Interim Financial Results
  5. Li H et al. H+/K+-ATPase inhibitors: a patent review. Expert Opin Ther Pat. 2013 Jan;23(1):99-111. PMID 23205582
US4808596 * 24 Jul 1987 28 Feb 1989 Tokyo Tanabe Company, Ltd. Imidazo[4,5-b]pyridine compounds and pharmaceutical compositions containing same
US5753265 * 7 Jun 1995 19 May 1998 Astra Aktiebolag Multiple unit pharmaceutical preparation
US5798120 * 6 Oct 1994 25 Aug 1998 Tokyo Tanabe Company Limited Enteric granule-containing tablets
EP0124495A2 28 Feb 1984 7 Nov 1984 Aktiebolaget Hässle Omeprazole salts
EP0254588A1 24 Jul 1987 27 Jan 1988 Tokyo Tanabe Company Limited Imidazo[4,5-b] pyridine compounds, process for preparing same and pharmaceutical compositions containing same
Reference
1 * Andersson et al., Pharmacology & Therapeutics, 2005, vol. 108, pp. 294-307.
2 * Anon et al., Drugs in R&D, 2002, vol. 3, pp. 276-277.
3 Kakinoki et al., Methods and Findings in Experimental and Clinical Pharmacology, 21(3): 179-187 (1999).
4 Komatsu et al., J. Org. Chem., 58(17): 4529-4533 (1993).
5 Uchiyama et al., Journal of Pharmacy and Pharmacology, 51(4): 457-464 (1999).
6 Uchiyama et al., Methods and Findings in Experimental and Clinical Pharmacology, 21(2): 115-122 (1999).
Citing Patent Filing date Publication date Applicant Title
US20120220623 * 30 Aug 2012 Mitsubishi Tanabe Pharma Corporation The enantiomer of tenatoprazole and the use thereof in therapy
CN1453278A * May 10, 2002 Nov 5, 2003 中国人民解放军军事医学科学院放射医学研究所 Omprazole compound and its prepn and application
CN1861600A * Jun 14, 2006 Nov 15, 2006 浙江大学 Preparation process of taytrolazole
Reference
1 * 《Organic Process Research & Development》 20081112 Somaiah Sripathi et al. An Improved Synthesis of Antiulcerative Drug:Tenatoprazole 第804-806页 1-6 第13卷,
2 * 《Synthetic Communication》 20080101 Liyan Dai et al. Improved Synthetic Approach to Tenatoprazole 第576-582页 1-6 第38卷,
3 * 《中国药物化学杂志》 20061231 赵冬梅等 抗溃疡药泰妥拉唑的合成 第360-362页 1-6 第16卷, 第6期
Tenatoprazole
Tenatoprazole.svg
Systematic (IUPAC) name
5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine
Clinical data
Routes of
administration
Oral
Pharmacokinetic data
Metabolism Hepatic (CYP2C19-mediated)
Biological half-life 4.8 to 7.7 hours
Identifiers
CAS Number 113712-98-4 Yes
ATC code none
PubChem CID 636411
ChemSpider 552196 Yes
UNII RE0689TX2K Yes
Chemical data
Formula C16H18N4O3S
Molar mass 346.405 g/mol
Chirality Racemic mixture

テナトプラゾール
Tenatoprazole

C16H18N4O3S : 346.4
[113712-98-4]

/////////////Tenatoprazole, 113712-98-4, TU-199, proton pump inhibitor,  treatment of gastroesophageal reflux disease, Mitsubishi Tanabe Pharma,  Negma Laboratories, PHASE 1, テナトプラゾール

CC1=CN=C(C(=C1OC)C)CS(=O)C2=NC3=C(N2)C=CC(=N3)OC

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ViridisChem, Inc.

 

Neelam Vaidya

Neelam Vaidya

Experienced executive with passion to bring most needed solutions to market.

VP Product Management

ViridisChem, Inc.
LINKEDIN https://www.linkedin.com/in/neelamvaidya

Experienced executive with over 25 years of experience in both high-tech and bio-tech industries. Extensive experience in business development, contract negotiation, risk management and managing cross-functional global teams. Specific expertise includes delivering high performance, high security software infrastructures in multi-domain WEB environment, building and managing Cloud/SaaS based products with high traffic demands; and successfully building and launching pharma-centric products for the benefit for scientific community worldwide.
Extensive experience in product commercialization including infrastructure planning, pricing, positioning, branding, distribution, launch plans, etc. Extensive experience in product marketing using social, online and in-person techniques.

 

 

 

ViridisChem offers a suite of software products that provide critical information scientists would need to define environmentally-friendly product development processes. Utilizing its internal proprietary chemical database with full chemical and toxicological profiles of over 60 million compounds, and supporting citation and reaction databases that provide related citations and reactions, the products help scientists understand the toxicological implications about the decision they have to make during day-to-day research without having to go through any training.

ViridisChem Inc, is an innovative company with a mission to provide relevant green chemistry data and tools that will allow drug development, biochemical, agrochemical and petrochemical companies to move towards environmentally friendly processes, be compliant with government standards, and reduce pollution.

We offer first-in-market comprehensive “green database” and applications that enable in-depth analysis of development and manufacturing processes during product development and product optimization. This unique offering includes automatic evaluation of development and manufacturing process description, drill-down analysis of multi-step synthesis, as well as waste, energy usage projections during scale-up, so that scientists can make environmentally conscious smart decisions right from early development stage.

STR1

ViridisChem offers software solutions that help scientists define environmentally friendly product development processes that are greener, safer, and economical. Our goal is to offer a suite of products that provide the most relevant information and analysis within a matter of few clicks without extra efforts from the scientists, so the scientists can make environmentally friendly choices without spending extra time and efforts.

GREEN POCKET

  • Full chemical profiles of over 60 million chemicals at your fingertips
  • Visual charts for quick comparison among chemicals
  • Endpoint scores weighted for job-specific needs
  • Identifies US and international regulatory concerns
  • Data available any-time, any-where, on any device

SEE OTHERS AT

https://www.viridischem.com/products-and-services/

 

ViridisChem Team

ACS National Fall Symposium, 2015, Boston, MA (August 16-18, 2015)

Soon after the product launch of Green Pocketbook in May 2015, this was the major event we show-cased the products at. Our team was in New Jersey, Massachusetts area for many days prior to the event and were able to meet many prospective customers. As anticipated, the trip and the event were great success and we have received lot of feedback on both Green Pocketbook and Green analyzer products. We sincerely thank everyone we met for the insightful feedback and tremendous support they have provided, and look forward to building long term mutually beneficial relationship with them.

NEELAM VAIDYA IN CENTER

TRULY HER PASSION SPEAKS

Experienced executive with passion to bring most needed solutions to market

Green Analyzer – ViridisChem, Inc.

www.viridischem.com

What can ViridisChem do for you

 

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The advisory board of ECA’s Interest Group for Visual Inspection is working on a revision of a document with frequently asked questions with regard to visual inspection of parenterals.

see

http://www.gmp-compliance.org/enews_05379_ECA-Visual-Inspection-Groups-works-on-new-FAQ-Document_15266,15265,15221,15160,Z-PEM_n.htmlregard to visual inspection of parenterals.

 

The webpage of ECA’s Interest Group for Visual Inspection contains several sources for giving advice in the field of visual inspection of parenterals. Besides the practical guidance paper, it contains an online discussion forum and a document with frequently asked questions. It has become clear though, that many of the questions in the forum recur and that these questions have already been answered in the FAQ document. It was therefore decided to restructure the FAQ document:  the questions will now be sorted by topic to make the document easier to read. Also, in a group survey in February 2016 everybody was asked to send additional questions. The advisory board is now working on selected new questions which will be added to the restructured questions & answers document. The revised document will contain the following elements:

  • Manual inspection
  • Automated inspection
  • Qualification/Validation
  • Test sets
  • Requalification
  • AQL Testing
  • Defect categorisation
  • Special products
  • Regulatory affairs

It is planned to finish the document in summer 2016, but at the latest during a face-to-face meeting at the next group event in September 2016 in Barcelona. It will be made available to all group members afterwards.

 

//////////ECA Visual Inspection Groups,  FAQ Document, visual inspection of parenterals,

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ROXADUSTAT

ASP1517; ASP 1517; ASP-1517; FG-4592; FG 4592; FG4592; Roxadustat.

CAS 808118-40-3
Chemical Formula: C19H16N2O5
Exact Mass: 352.10592

Fibrogen, Inc.

THERAPEUTIC CLAIM, Treatment of anemia

Roxadustat nonproprietary drug name

CHEMICAL NAMES

(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycine

1. Glycine, N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl)carbonyl]-

2. N-[(4-hydroxy-1-methyl-7-phenoxyisoquinolin-3-yl)carbonyl]glycine

MF C19H16N2O5
MW  352.3
SPONSOR FibroGen
CODE FG-4592; ASP1517
CAS 808118-40-3
WHO NUMBER 9717

Roxadustat, also known as ASP1517 and FG-4592, is an HIF α prolyl hydroxylase inhibitor in a cell-free assay. It stabilizes HIF-2 and induces EPO production and stimulates erythropoiesis. Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin

FG-4592 (also known as ASP1517), 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid,
 is a potent small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH),
an enzyme up-regulating the expression of endogenous human erythropoietin (Epo).
It is currently being investigated as an oral treatment for anemia associated with chronic kidney disease (CKD).
Unlike other anemia treating agents, erythropoiesis-stimulating agents (ESAs),
FG-4592 inhibits HIF, through a distinctive mechanism, by stabilization of HIF. According to previous studies,
FG-4592 is capable of correcting and maintaining hemoglobin levels in CKD patients not
receiving dialysis and in patients of end-stage renal disease
who receives dialysis but do not need intravenous iron supplement.
Reference
1. Luis Borges. Different modalities of erythropoiesis stimulating agents.
 Port J Nephrol Hypert 2010; 24(2): 137-145
2. “FibroGen and Astellas announce initiation of phase 3 trial of FG-4592/ASP1517 for treatment 
of anemia of chronic kidney disease” Fibrogen Press Release. Dec 11 2012
3. “FibroGen announces initiation of phase 2b studies of FG-4592, 
an oral HIF prolyl hydroxylase inhibitor, for treatment of anemia”
  • Originator FibroGen
  • Developer Astellas Pharma; AstraZeneca; FibroGen
  • Class Amides; Antianaemics; Carboxylic acids; Isoquinolines; Small molecules
  • Mechanism of Action Basic helix loop helix transcription factor modulators; Hypoxia-inducible factor-proline dioxygenase inhibitors
  • Phase III Anaemia
  • Discontinued Sickle cell anaemia

Most Recent Events

  • 09 Jun 2016 Phase-III clinical trials in Anaemia in Japan (PO)
  • 20 May 2016 In collaboration with FibroGen, Astellas Pharma plans a phase III trial for Anaemia (In chronic kidney disease patients undergoing peritoneal dialysis) in Japan (PO) (NCT02780726)
  • 19 May 2016 In collaboration with FibroGen, Astellas Pharma plans a phase III trial for Anaemia (In erythropoiesis stimulating agent-naive, chronic kidney disease patients undergoing haemodialysis) in Japan (PO) (NCT02780141)

 

 

 

Roxadustat (FG-4592) is a novel new-generation oral hypoxia-induciblefactor (HIF) prolyl hydroxylase inhibitor (PHI) for the treatment of ane-mia in patients with chronic kidney disease (CKD). HIF is a cytosolic tran-scription factor that induces the natural physiological response to lowoxygen conditions, by stimulating erythropoiesis and other protectivepathways. Roxadustat has been shown to stabilize HIF and induce ery-thropoiesis. Consequently, it corrects anemia and maintains hemoglo-bin levels without the need for intravenous iron supplementation in CKDpatients not yet receiving dialysis and in end-stage renal disease pa-tients receiving dialysis. There are many concerns about the use of ery-thropoiesis-stimulating agents (ESA) to treat anemia as they causesupra-physiologic circulating erythropoietin (EPO) levels and are asso-ciated with adverse cardiovascular effects and mortality. Available clin-ical data show that modest and transient increases of endogenous EPOinduced by HIF-PHI (10- to 40-fold lower than ESA levels) are sufficientto mediate erythropoiesis in CKD patients. Evidence suggests that rox-adustat is well tolerated and, to date, no increased risk of cardiovascu-lar events has been found. This suggests that roxadustat provides adistinct pharmacological and clinical profile that may provide a saferand more convenient treatment of CKD anemia

 

FG-4592 is a new-generation hypoxia-inducible factor prolyl hydroxylase inhibitor in early clinical trials at FibroGen for the oral treatment of iron deficiency anemia and renal failure anemia. Preclinical studies are ongoing for the treatment of sickle cell anemia.

The investigational therapy is designed to restore balance to the body’s natural process of erythropoiesis through mechanisms including: natural EPO production, suppression of the effects of inflammation, downregulation of the iron sequestration hormone hepcidin, and an upregulation of other iron genes, ensuring efficient mobilization and utilization of the body’s own iron stores. In April 2006, FG-4592 was licensed to Astellas Pharma by originator FibroGen in Asia, Europe and South Africa for the treatment of anemia. FibroGen retains rights in the rest of the world. In 2007, the FDA put the trial on clinical hold due to one case of death by fulminant hepatitis during a phase II clinical trial for patients with anemia associated with chronic kidney disease and not requiring dialysis. However, in 2008, the FDA informed the company that clinical trials could be resumed. Phase II/III clinical trials for this indication resumed in 2012. In 2013, the compound was licensed to AstraZeneca by FibroGen for development and marketing in US, CN and all major markets excluding JP, Europe, the Commonwealth of Independent States, the Middle East and South Africa, for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD).
PATENTS
WO 2004108681
WO 2008042800
WO 2009058403
WO 2009075822
WO 2009075824
WO 2012037212
WO 2013013609
WO 2013070908

 

STR1

PATENT

CN 104892509

MACHINE TRANSLATED

Connaught orlistat (Roxadustat) by the US company Phibro root (FibroGen) R & D, Astellas AstraZeneca and licensed by a hypoxia-inducible factor (HIF) prolyl hydroxylase small molecule inhibitors, codenamed FG-4592.As a first new oral drug, FG-4592 is currently in Phase III clinical testing stage, for the treatment of chronic kidney disease and end-stage renal disease related anemia. Because the drug does not have a standard Chinese translation, so the applicant where it is transliterated as “Connaught Secretary him.”

Connaught orlistat (Roxadustat, I) the chemical name: N_ [(4- hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl) carbonyl] glycine, its structural formula is:

 

Figure CN104892509AD00031

The original research company’s international patent W02004108681 Division provides a promise he was prepared from the intermediate and intermediate Connaught Secretary for his synthetic route:

 

Figure CN104892509AD00032

 Zhejiang Beida company’s international patent W02013013609 preparation and acylation of core intermediate was further optimized synthesis route is:

 

Figure CN104892509AD00041

n PhO. eight XOOH

 

 original research company’s international patent W02014014834 and W02014014835 also provides another synthetic route he Connaught Secretary prepared:

 

Figure CN104892509AD00042

Analysis of the above synthetic route, although he continued to Connaught Division to improve and optimize the synthesis, but its essence rings manner that different form quinoline ring is basically the same mother. Especially methyl isoquinoline replaced either by way of introducing the Suzuki reaction catalyzed by a noble metal element, either through amine reduction achieved. Moreover, the above reaction scheme revelation raw materials are readily available, many times during the reaction need to be protected and then deprotected. Clearly, the preparation process is relatively complicated, high cost, industrial production has brought some difficulties.

Figure CN104892509AD00052

Example One:

tyrosine was added to the reaction flask and dried (18. lg, 0.1 mmol) and methanol 250mL, cooling to ice bath 0_5 ° C, was added dropwise over 1 hour a percentage by weight of 98% concentrated sulfuric acid 10g. Drops Albert, heating to reflux. The reaction was stirred for 16-20 hours, TLC the reaction was complete. Concentrated under atmosphere pressure, the residue was added water 100mL, using 10% by weight sodium hydroxide to adjust the pH to 6. 5-7.0, precipitated solid was filtered, washed with methanol and water chloro cake (I: 1) and dried in vacuo tyrosine methyl ester as a white solid (11) 15.38, yield 78.5% out 1–] \ ^ 111/2: 196 [] \ 1 + 1] +!.

Example Two:

[0041] a nitrogen atmosphere and ice bath, was added to the reaction flask tyrosine methyl ester (II) (9. 8g, 50mmol), potassium methoxide (3. 5g, 50mmol) and methanol 50mL, until no gas generation after, was heated to reflux, the reaction was stirred for 2 hours. Concentrated under atmosphere pressure to remove the solvent, the residue was added dimethylsulfoxide 25mL, freshly prepared copper powder (0.2g, 3. Lmmol), was slowly warmed to 150-155 ° C, for about half an hour later, a solution of bromobenzene ( 7. 9g, 50mmol), continue to heat up to 170-175 ° C, the reaction was stirred for 3 hours, TLC detection of the end of the reaction. Was cooled to 60 ° C, and methanol was added to keep micro-boiling, filtered while hot, the filter cake washed three times with hot ethanol, and the combined organic phases, was cooled to square ° C, filtered, and dried in vacuo to give a white solid of 2-amino-3- ( 4-phenoxyphenyl) propanoate (111) 8 11.5, yield 84.9% as 1 -] \ ^ 111/2:! 272 [] \ 1 + 1] +.

 Example Three:

 in the reaction flask was added 2-amino-3- (4-phenoxyphenyl) propionic acid methyl ester (III) (10. 8g, 40mmol), 40% by weight acetaldehyde (20g, 0. 2mol ) and the percentage by weight of 35% concentrated hydrochloric acid 50mL, refluxed for 1 hour. Continue 40% by weight was added acetaldehyde (10g, 0.1mol), and the percentage by weight of 35% concentrated hydrochloric acid 25mL, and then the reaction was refluxed for 3-5 hours. Was cooled to 4-7 ° C, ethyl acetate was added, and extracted layers were separated. The aqueous layer was adjusted with sodium hydroxide solution to pH 11-12, extracted three times with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid of 1-methyl-3-carboxylate -7- phenoxy-1,2,3,4-tetrahydroisoquinoline (IV) 8 4g, 70.7% yield; Mass spectrum (EI): EI-MS m / z: 298 [M + H] + .

 Example Four:

Under ice bath, the reaction flask was added methyl 3-carboxylate I- -7- phenoxy-1,2, 3,4-tetrahydro-isoquinoline (IV) (5. 9g, 20mmol) and dichloromethane 100mL, 0 ° C and under stirring added potassium carbonate (13. 8g, 0. lmol), p-toluenesulfonyl chloride (11. 4g, 60mmol), the addition was completed, the ice bath was removed and stirred at room temperature 3 hour. Water was added 30mL, after stirring standing layer, the organic phase was washed with dilute hydrochloric acid, water and saturated brine, and concentrated, the resulting product was added a 30% by weight sodium hydroxide solution (8. 0g, 60mmol) and dimethyl sulfoxide 60mL, gradually warming to 120-130 ° C, the reaction was stirred for 2-4 hours to complete the reaction by TLC. Cooled to room temperature, water was added lOOmL, extracted three times with ethyl acetate, the combined organic phase was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated, the resulting oil was treated with ethyl acetate and n-hexane (1: 3) recrystallization, vacuum dried to give an off-white solid 1-methyl-3-carboxylate 7-phenoxyheptanoic isoquinoline (V) 5. 25g, yield 89. 6%; EI-MS m / z: 294 [M + H] VH NMR (DMS0-d6) δ 2. 85 (s, 3H), 3 · 97 (s, 3H), 7 · 16-7. 24 (m, 3H), 7 · 49-7. 60 (m, 4Η), 8 · 35 (d, J = 9 · 0,1Η), 8 · 94 (s, 1Η).

Example five:

[0047] added 1-methyl-3-carboxylic acid methyl ester 7-phenoxyheptanoic isoquinoline (V) (2. 93g, IOmmol) and glacial acetic acid 50mL reaction flask, stirring solution of 30% by weight hydrogen peroxide 5mL, warmed to 60-70 ° C, was slowly added dropwise within 10 hours the percentage by weight of a mixture of 30% hydrogen peroxide 2mL and 12mL of glacial acetic acid, a dropping was completed, the reaction was continued for 20-24 hours. Concentrated under reduced pressure, ethanol was added, distillation is continued to be divisible remaining glacial acetic acid. The residue was dissolved with dichloromethane, washed with 5% by weight of sodium bicarbonate, the organic phase was separated, dried over anhydrous sodium sulfate. Filtered and the resulting solution was added p-toluenesulfonyl chloride (3. 8g, 20mmol), was heated to reflux, the reaction was stirred for 3-4 hours, TLC detection completion of the reaction. The solvent was distilled off under reduced pressure, cooled to room temperature, methanol was added, the precipitated solid, cooled to square ° C, allowed to stand overnight. Filtered, the filter cake washed twice with cold methanol and vacuum dried to give an off-white solid 1- methyl-3-methyl-4-hydroxy-phenoxy-isoquinoline -7- (VI) I. 86g, yield 60.2 %; EI-MS m / z:.. 310 [M + H] +, 1H NMR (DMS0-d6) δ 2.90 (s, 3H), 4.05 (s, 3H), 7 17-7 26 (m, 3H ), 7. 49-7. 61 (m, 4H), 8. 38 (d, J = 9. 0,1H), 11. 7 (s, 1H) 〇

 Example VI:

 in the reaction flask with magnetic stirring and pressure to join I- methyl-3-methyl-4-hydroxy-7-phenoxyheptanoate isoquinoline (VI) (1.55g, 5mmol), glycine (I. 13g, 15mmol) and sodium methoxide (3. 25g, 6mmol) in methanol (30mL).Sealed, slowly heated to 120 ° C, the reaction was stirred for 8-10 hours to complete the reaction by TLC. Cooled to room temperature, solid precipitated. Filtration, and the resulting solid was recrystallized from methanol, acetone and then beating the resulting solid was dried under vacuum to give a white solid Connaught orlistat 1.40g, yield 79.5%;

EI-MS m / z: 353 [M + H] +,

1H NMR (DMS0-d6) S2.72 (s, 3H), 3 · 99 (d, J = 6 · 0, 2H), 7 · 18-7. 28 (m, 3H), 7 · 49-7. 63 (m, 4H), 8 · 31 (d, J = 8 · 8,1H), 9 · 08 (s, lH), 13.41 (brs, lH).

PATENT

WO 2014014835

Example 10. Preparation of Compound A

a) 5-Phenoxyphthalide

Figure imgf000056_0001

[0200] A reactor was charged with DMF (68 Kg), and stirring was initiated. The reactor was then charged with phenol (51 Kg), acetylacetone (8 Kg), 5-bromophthalide (85 Kg), copper bromide (9 Kg), and potassium carbonate (77 Kg). The mixture was heated above 85 °C and maintained until reaction completion and then cooled. Water was added. Solid was filtered and washed with water. Solid was dissolved in dichloromethane, and washed with aqueous HCl and then with water. Solvent was removed under pressure and methanol was added. The mixture was stirred and filtered. Solid was washed with methanol and dried in an oven giving 5- phenoxyphthalide (Yield: 72%, HPLC: 99.6%). b) 2-Chloromethyl-4-phenoxybenzoic acid methyl ester

Figure imgf000056_0002

[0201] A reactor was charged with toluene (24 Kg), and stirring was initiated. The reactor was then charged with 5-phenoxyphthalide (56 Kg), thionyl chloride (41 Kg), trimethyl borate (1

Kg), dichlorotriphenylphosphorane (2.5 Kg), and potassium carbonate (77 Kg). The mixture was heated to reflux until reaction completion and solvent was removed leaving 2-chloromethyl-4- phenoxybenzoyl chloride. Methanol was charged and the mixture was heated above 50 °C until reaction completion. Solvent was removed and replaced with DMF. This solution of the product methyl 2-chloromethyl-4-phenoxybenzoic acid methyl ester in DMF was used directly in the next step (HPLC: 85%). c) 4-Hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (la)

Figure imgf000057_0001

[0202] A reactor was charged with a solution of 2-chloromethyl-4-phenoxybenzoic acid methyl ester (~68 Kg) in DMF, and stirring was initiated. The reactor was then charged with p- toluenesulfonylglycine methyl ester (66 Kg), potassium carbonate (60 Kg), and sodium iodide (4 Kg). The mixture was heated to at least 50 °C until reaction completion. The mixture was cooled. Sodium methoxide in methanol was charged and the mixture was stirred until reaction completion. Acetic acid and water were added, and the mixture was stirred, filtered and washed with water. Solid was purified by acetone trituration and dried in an oven giving la (Yield from step b): 58%; HPLC: 99.4%). 1H NMR (200 MHz, DMSO-d6) δ 11.60 (s, 1 H), 8.74 (s, 1H),

8.32 (d, J = 9.0 Hz, 1 H), 7.60 (dd, J = 2.3 & 9.0 Hz, 1H), 7.49 (m, 3 H), 7.24 (m, 3 H), 3.96 (s, 3 H); MS-(+)-ion M+l = 296.09 d) Methyl l-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

(lb)

Figure imgf000057_0002

[0203] A flask was charged with la (29.5 g) and acetic acid (44.3 g ± 5%), and then stirred. Bis-dimethylaminomethane (12.8 g ± 2%) was slowly added. The mixture was heated to 55 ± 5 °C and maintained until reaction completion. The reaction product was evaluated by MS, HPLC and 1H NMR. 1H NMR (200 MHz, DMSO-d6) δ 11.7 (s, 1 H), 8.38 (d, J = 9.0 Hz, 1 H), 7.61 (dd, J = 9.0, 2.7 Hz, 1 H), 7.49 (m, 3 H), 7.21 (m, 3 H), 5.34 (s, 2 H), 3.97 (s, 3 H), 1.98 (s, 3 H); MS-(+)-ion M+l = 368.12. e) Methyl l-((acetoxy)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (lc)

Figure imgf000058_0001

[0204] The solution of lb from a) above was cooled below 25 °C, at which time acetic anhydride (28.6 g ± 3.5 %) was added to maintain temperature below 50 °C. The resulting mixture was heated to 100 ± 5 °C until reaction completion.

[0205] The solution of lc and Id from above was cooled to less than 65 ± 5 °C. Water (250 mL) was slowly added. The mixture was then cooled to below 20 ± 5 °C and filtered. The wet cake was washed with water (3 x 50 mL) and added to a new flask. Dichloromethane (90 mL) and water (30 mL) were added, and the resulting mixture was stirred. The dichloromethane layer was separated and evaluated by HPLC.

[0206] The organic layer was added to a flask and cooled 5 ± 5 °C. Morpholine was added and the mixture was stirred until reaction completion. Solvent was replaced with acetone/methanol mixture. After cooling, compound lc precipitated and was filtered, washed and dried in an oven (Yield: 81%, HPLC: >99.7%). 1H NMR (200 MHz, DMSO-d6) δ 11.6 (S, 1 H), 8.31 (d, J = 9.0 Hz, 1 H), 7.87 (d, J = 2.3 Hz, 1 H), 7.49 (m, 3 H), 7.24 (m, 3 H), 3.95 (s, 3 H), 3.68 (s, 2H), 2.08 (s, 6 H); MS-(+)-ion M+l = 357.17. f) Methyl 4-hydroxy-l-methyl-7-phenoxyisoquinoline-3-carboxylate (le)

Figure imgf000058_0002

[0207] A reactor was charged with lc (16.0 g), Pd/C (2.08 g), anhydrous Na2C03 (2.56 g) and ethyl acetate (120 mL). The flask was vacuum-purged with nitrogen (3X) and vacuum-purged with hydrogen (3X). The flask was then pressurized with hydrogen and stirred at about 60 °C until completion of reaction. The flask was cooled to 20-25 °C, the pressure released to ambient, the head space purged with nitrogen three times and mixture was filtered. The filtrate was concentrated. Methanol was added. The mixture was stirred and then cooled. Product precipitated and was filtered and dried in an oven (Yield: 90%, HPLC: 99.7%). g) [(4-Hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid

(Compound A)

Figure imgf000059_0001

[0208] A pressure flask was charged with le (30.92 g), glycine (22.52 g), methanol (155 mL), sodium methoxide solution (64.81 g) and sealed (as an alternative, sodium glycinate was used in place of glycine and sodium methoxide). The reaction was heated to about 110 °C until reaction was complete. The mixture was cooled, filtered, washed with methanol, dried under vacuum, dissolved in water and washed with ethyl acetate. The ethyl acetate was removed and to the resulting aqueous layer an acetic acid (18.0 g) solution was added. The suspension was stirred at room temperature, filtered, and the solid washed with water (3 x 30 mL), cold acetone (5-10 °C, 2 x 20 mL), and dried under vacuum to obtain Compound A (Yield: 86.1%, HPLC: 99.8%). Example 11. Biological Testing

[0209] The solid forms provided herein can be used for inhibiting HIF hydroxylase activity, thereby increasing the stability and/or activity of hypoxia inducible factor (HIF), and can be used to treat and prevent HIF-associated conditions and disorders (see, e.g., U.S. Patent No. 7,323,475, U.S. Patent Application Publication No. 2007/0004627, U.S. Patent Application Publication No. 2006/0276477, and U.S. Patent Application Publication No. 2007/0259960, incorporated by reference herein).

SYNTHESIS……..

http://zliming2004.lofter.com/post/1cc9dc55_79ad5d8

FG-4592 - zliming2004 - zliming2004的博客

Condensation of 5-bromophthalide (I) with phenol (II) in the presence of K2CO3, CuBr and acetylacetone in DMF gives 5-phenoxyphthalide (III), which upon lactone ring opening using SOCl2, Ph3PCl2, B(OMe)3 and K2CO3 in refluxing toluene yields 2-chloromethyl-4-phenoxybenzoyl chloride (IV). Esterification of acid chloride (IV) with MeOH at 50 °C furnishes the methyl ester (V), which is then condensed with methyl N-tosylglycinate (VI) in the presence of K2CO3 and NaI in DMF at 50 °C to afford N-substituted aminoester (VII). Cyclization of the intermediate diester (VII) using NaOMe in MeOH leads to methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (VIII), which is submitted to Mannich reaction with bis-dimethylaminomethane (IX) in the presence of AcOH at 57 °C to provide the dimethylaminomethyl compound (X). Treatment of amine (X) with Ac2O at 103 °C, followed by selective hydrolysis of the phenolic acetate with morpholine leads to methyl 1-acetoxymethyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XI). Hydrogenolysis of the benzylic acetate (XII) in the presence of Pd/C and Na2CO3 in EtOAc yields methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboylate (XII), which finally couples with glycine (XIII) in the presence of NaOMe in MeOH at 110 °C to afford the target roxadustat (1-3).

FG-4592 - zliming2004 - zliming2004的博客

Cyclization of 4-phenoxyphthalic acid (I) with glycine (II) at 215 °C gives the phthalimide (III), which upon esterification with MeOH and H2SO4 at reflux yields methyl ester (IV). Subsequent rearrangement of phthalimidoacetate (IV) by means of Na in BuOH at 97 °C, followed by flash chromatography provides the isoquinoline-2-carboxylate (V). Bromination of intermediate (V) using POBr3 and NaHCO3 in acetonitrile leads to butyl 8-bromo-3-hydroxy-6-phenoxy-isoquinoline-2-carboxylate (VI), which upon hydrolysis with NaOH in refluxing H2O/EtOH furnishes carboxylic acid (VII). Substitution of bromine in intermediate (VII) using MeI and BuLi in THF at -78 °C, followed by alkylation with PhCH2Br in the presence of K2CO3 in refluxing acetone affords the 2-methyl isoquinoline (VIII). Ester hydrolysis in intermediate (VIII) using KOH in MeOH gives the corresponding carboxylic acid (IX), which is then activated with i-BuOCOCl and Et3N in CH2Cl2, followed by coupling with benzyl glycinate hydrochloride (X) to yield benzylated roxadustat (XI). Finally, debenzylation of intermediate (XI) with H2 over Pd/C in EtOAc/MeOH provides the title compound (1).

FG-4592 - zliming2004 - zliming2004的博客

Condensation of 4-nitro-ortho-phthalonitrile (I) with phenol (II) in the presence of K2CO3 in DMSO gives 4-phenoxy-ortho-phthalonitrile (III) (1), which upon hydrolysis with NaOH (1) or KOH (2) in refluxing MeOH yields 4-phenoxyphthalic acid (IV) (1,2). Dehydration of dicarboxylic acid (IV) using Ac2O and AcOH at reflux furnishes the phthalic anhydride (V), which is then condensed with methyl 2-isocyanoacetate (VI) using DBU in THF to provide oxazole derivative (VII). Rearrangement of intermediate (VII) with HCl in MeOH at 60 °C leads to isoquinoline derivative (VIII), which is partially chlorinated by means of POCl3 at 70 °C to afford 1-chloro-isoquinoline derivative (IX). Substitution of chlorine in intermediate (IX) using Me3B, Pd(PPh3)4 and K2CO3 in refluxing dioxane gives methyl 4-hydroxy-1-methyl-7-phenoxy-3-carboxylate (X), which is then hydrolyzed with aqueous NaOH in refluxing EtOH to yield the carboxylic acid (XI). Coupling of carboxylic acid (XI) with methyl glycinate hydrochloride (XII) by means of PyBOP, (i-Pr)2NH and Et3N in CH2Cl2 yields roxadustat methyl ester (XII), which is finally hydrolyzed with aqueous NaOH in THF to afford the target roxadustat (1).

CLIPS

SAN FRANCISCO, Nov 12, 2013 (BUSINESS WIRE) — FibroGen, Inc. (FibroGen), today announced that data from a China-based Phase 2 study of roxadustat (FG-4592), a first-in-class oral compound in late stage development for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD), were presented in an oral session at the 2013 American Society of Nephrology (ASN) Kidney Week in Atlanta, Georgia.
Roxadustat is an orally administered, small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase. HIF is a protein that responds to oxygen changes in the cellular environment and meets the body’s demands for oxygen by inducing erythropoiesis, the process by which red blood cells are produced and iron is incorporated into hemoglobin (Hb).
The randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy, safety, and tolerability of roxadustat in the correction of anemia in patients (N=91) with chronic kidney disease who had not received dialysis treatment, were not receiving erythropoiesis-stimulating agents (ESAs), and had Hb levels less than 10 g/dL. The correction study randomized patients 2:1 between roxadustat and placebo for 8 weeks of dosing, and included a low-dose cohort (n=30) and high-dose cohort (n=31). Intravenous (IV) iron was not allowed. The study also evaluated iron utilization, changes in serum lipids, and other biomarkers during treatment with roxadustat.
Data from this study suggest that roxadustat effectively corrected hemoglobin levels in anemic CKD patients in a dose-dependent manner as compared to placebo, and did so in the absence of IV iron supplementation regardless of degree of iron repletion at baseline. At the end of the 8-week treatment period, subjects showed mean maximum Hb increases from baseline of 2.6 g/dL in the high dose cohort and 1.8 g/dL in the low dose cohort, as compared to 0.7 g/dL in the placebo group (p < 0.0001) from mean baseline Hb of 8.8 g/dL, 8.8 g/dL, and 8.9 g/dL in the high dose, low dose, and placebo groups, respectively. 87% of patients in the high-dose cohort, 80% of patients in the low-dose cohort, and 23% of patients in the placebo group experienced a hemoglobin increase of 1 g/dL or greater from baseline (p < 0.0001). Similarly, 71% of patients in the high-dose cohort, 50% of patients in the low-dose cohort, and 3% of patients in the placebo group achieved target hemoglobin of 11 g/dL or greater (p < 0.0001). Serum iron levels remained stable in subjects randomized to roxadustat while the subjects underwent brisk erythropoiesis.
Study data also suggest that roxadustat may lower cholesterol. Dyslipidemia is highly prevalent in chronic kidney disease patients and a major cardiovascular risk factor in this population. Patients treated with roxadustat experienced a statistically significant reduction in total cholesterol (p <0.0001) and low-density lipoprotein (LDL) cholesterol (p <0.0001) at the end of the treatment period. The relative proportion of high density lipoprotein (HDL) cholesterol to LDL cholesterol increased significantly (p <0.02). Overall LDL cholesterol levels declined by a mean of 26% and median of 23% from a mean baseline value of 103 mg/dL.
Roxadustat was well tolerated by patients in the study with incidence of adverse events similar across all groups. In contrast to the exacerbation of hypertension observed in studies in which patients received currently available ESA therapies, subjects who received roxadustat in the present study showed small decreases in blood pressure that were similar to blood pressure changes in the placebo group. No cardiovascular serious adverse events were reported in patients treated with roxadustat.
The efficacy and safety of roxadustat are currently being investigated in a global pivotal Phase 3 development program.
“There is a global need for effective, safe, and accessible anemia therapies,” said Thomas B. Neff, Chief Executive Officer of FibroGen. “Side effects associated with current treatments include exposure to supra-physiological levels of erythropoietin and depletion of iron stores. Preliminary clinical findings show that oral administration of roxadustat (FG-4592) is able to correct anemia and maintain hemoglobin levels in patients with chronic kidney disease, to do so with peak erythropoietin levels within physiological range, and to achieve these effects without the administration of intravenous iron. These results suggest roxadustat, as an oral agent, has the potential to overcome the treatment barriers and inconveniences of current ESA therapies, including administration by injection and IV iron supplementation, in treating anemia in CKD patients.”
About Chronic Kidney Disease (CKD) and Anemia
Diabetes, high blood pressure, and other conditions can cause significant damage to the kidneys. If left untreated, those can result in chronic kidney disease and progress to kidney failure. Such deterioration can lead to patients needing a kidney transplant or being placed on dialysis to remove excess fluid and toxins that build up in the body. The progression of CKD also increases the prevalence of anemia, a condition associated with having fewer of the red blood cells that carry oxygen through the body, and/or lower levels of hemoglobin, the protein that enables red blood cells to carry oxygen. As hemoglobin falls, the lower oxygen-carrying capacity of an anemic patients’ blood results in various symptoms including fatigue, loss of energy, breathlessness, and angina. Anemia in CKD patients has been associated with increased hospitalization rates, increased mortality, and reduced quality of life.
Chronic kidney disease is a worldwide critical healthcare problem that affects millions of people and drives significant healthcare cost. In the US, prevalence of CKD has increased dramatically in the past 20 years, from 10 percent of the adult population (or approximately 20 million U.S. adults) as stated in the National Health and Nutrition Evaluation Survey (NHANES) 1988-1994, to 15 percent (or approximately 30 million U.S. adults) in NHANES 2003-2006. In 2009, total Medicare costs for CKD patients were $34 billion. China has an estimated 145 million CKD patients, or approximately five times the number of CKD patients in the U.S. (Lancet April 2012).
About Roxadustat / FG-4592
Roxadustat (FG-4592) is an orally administered small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity, in development for the treatment of anemia in patients with chronic kidney disease (CKD). HIF is a protein transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis (the process by which red blood cells are produced) and other protective pathways. Roxadustat has been shown to correct anemia and maintain hemoglobin levels without the need for supplementation with intravenous iron in CKD patients not yet receiving dialysis and in end-stage renal disease patients receiving dialysis. An Independent Data Monitoring Committee has found no signals or trends to date to suggest that treatment with roxadustat is associated with increased risk of cardiovascular events, thrombosis, or increases in blood pressure requiring initiation or intensification of antihypertensive medications.
About FibroGen
FibroGen is a privately-held biotechnology company focused on the discovery, development, and commercialization of therapeutic agents for treatment of fibrosis, anemia, cancer, and other serious unmet medical needs. FibroGen’s FG-3019 monoclonal antibody is in clinical development for treatment of idiopathic pulmonary fibrosis and other proliferative diseases, including pancreatic cancer and liver fibrosis. Roxadustat (FG-4592), FibroGen’s small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase, is currently in clinical development for the treatment of anemia. FibroGen is also currently pursuing the use of proprietary recombinant human type III collagens in synthetic corneas for treatment of corneal blindness. For more information please visit: www.fibrogen.com .

References

1: Besarab A, Provenzano R, Hertel J, Zabaneh R, Klaus SJ, Lee T, Leong R, Hemmerich S, Yu KH, Neff TB. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant. 2015 Oct;30(10):1665-73. doi: 10.1093/ndt/gfv302. Epub 2015 Aug 3. PubMed PMID: 26238121; PubMed Central PMCID: PMC4569392.

2: Forristal CE, Levesque JP. Targeting the hypoxia-sensing pathway in clinical hematology. Stem Cells Transl Med. 2014 Feb;3(2):135-40. doi: 10.5966/sctm.2013-0134. Epub 2013 Dec 26. PubMed PMID: 24371328; PubMed Central PMCID: PMC3925058.

3: Bouchie A. First-in-class anemia drug takes aim at Amgen’s dominion. Nat Biotechnol. 2013 Nov;31(11):948-9. doi: 10.1038/nbt1113-948b. PubMed PMID: 24213751.

4: Flight MH. Deal watch: AstraZeneca bets on FibroGen’s anaemia drug. Nat Rev Drug Discov. 2013 Oct;12(10):730. doi: 10.1038/nrd4135. PubMed PMID: 24080688.

5: Beuck S, Schänzer W, Thevis M. Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis. Drug Test Anal. 2012 Nov;4(11):830-45. doi: 10.1002/dta.390. Epub 2012 Feb 24. Review. PubMed PMID: 22362605.

6: Cases A. The latest advances in kidney diseases and related disorders. Drug News Perspect. 2007 Dec;20(10):647-54. PubMed PMID: 18301799.

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Racecadotril2DCSD.svg

 

Racecadotril;

CAS 81110-73-8;

Acetorphan; Benzyl 2-(3-(acetylthio)-2-benzylpropanamido)acetate; Tiorfan; CADOTRIL;

benzyl 2-[[2-(acetylsulfanylmethyl)-3-phenylpropanoyl]amino]acetate

Molecular Formula: C21H23NO4S
Molecular Weight: 385.47662 g/mol

 

Racecadotril.png

LAUNCHED  1993 BIOPROJET IN FRANCE

2010 IN CHINA

Racecadotril, also known as acetorphan, is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor.[2] Unlike other opioid medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect—it reduces the secretion of water and electrolytes into the intestine.[3] It is available in France (where it was first introduced in ~1990) and other European countries (including Germany, Italy, the UK and Spain) as well as most of South America and some South East Asian countries (including China, India and Thailand), but not in the United States. It is sold under the tradenames Hidrasec or, in France, Tiorfan.[4] In Italy it is sold under the tradename Tiorfix.[4]

Thiorphan is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinase.[5]

Racecadotril, also known as acetorphan, is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor. Unlike other medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect—it reduces the secretion of water and electrolytes into the intestine. It is available in India (It was first introduced in 1993 and is widely used in France) and other European countries, as well as most of South America and some South East Asian countries, but not in the United States. It is sold under the tradenames Hidrasec or, in France, Tiorfan. In Italy it is sold under the tradename Tiorfix.

In india trade names  REDOTTIL, ZEDOTT .

A small randomized controlled trial found racecadotril to significantly reduce the duration and volume of watery diarrhea in children when given as an adjunct to oral rehydration therapy.

Racecadotril, also known as acetorphan, is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor. Unlike other medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect—it reduces the secretion of water and electrolytes into the intestine. It is available in India (It was first introduced in 1993 and is widely used in France) and other European countries, as well as most of South America and some South East Asian countries, but not in the United States. It is sold under the tradenames Hidrasec or, in France, Tiorfan. In Italy it is sold under the tradename Tiorfix.

In india trade names  REDOTTIL, ZEDOTT .

A small randomized controlled trial found racecadotril to significantly reduce the duration and volume of watery diarrhea in children when given as an adjunct to oral rehydration therapy.

Indication & Dosage      

Acute diarrhoea

Adult: 100 mg tid, up to 7 days.

Administration – May be taken with or without food.

Special Precautions  –    Renal insufficiency, pregnancy, lactation.

Adverse Drug Reactions –  Vomiting, nausea, constipation, abdominal pain, thirst, vertigo and headache.

Mechanism of Action

Racecadotril increases the availability of endogenous opioids (enkephalins) by inhibiting the membrane-bound enkephalinase. These enkephalins activate δ-opioid receptors in the GI tract. This leads to a reduction in cAMP mucosal levels, resulting in a reducted secretion of water and electrolytes in the intestinal lumen.  Onset: Within 30 min.

Foreign Names

Racecadotrilum (Latin)

Racecadotril (German)

Racécadotril (French)

Racecadotrilo (Spanish)

 

Brand Names

AD             –  Hetero, India

Aquasec    –  Micro Nova, India

Cadotril    – Medifarma, Peru

Diarfix      –  CristerS, France

Dirasec     –  Abbott, India

Du La Bao  –  Baili Pharmaceutical, China

Enuff          –  Hetero, India

Feng Hai Ting – Zhengda Fenghai Pharmaceutical, China

Hidrasec   – Abbott, China;       Abbott, Philippines;                 Bagó, Ecuador;                Ferrer, Costa Rica; Ferrer, Dominican Republic;          Ferrer, Guatemala;            Ferrer, Honduras;                     Ferrer, Mexico; Ferrer, Nicaragua;    Ferrer, Panama;     Ferrer, El Salvador;    Fournier, Bulgaria;    Fournier, Romania; Galenica, Greece;     Laboratoire Sophartex, Vietnam;      Leti, Venezuela;      Silesia, Chile;

Solvay, Thailand

Hidrasec Children (pediatric) –  Fournier, Bulgaria

Hidrasec Infants (pediatric)-Fournier, Bulgaria

Hydral     –  Alembic, India

Lomorest   –  Zuventus, India

Mo Ni Ka   –  Hailing, China

Mold       –  Aversi, Georgia

Pedidot    –  Elder, India

Racaril    -East West, India

Racedot    –  Macleods, Georgia

Race-F     –  Bestochem, India

Racotil    –  Cipla, India

Racy       –  Abbott, India

Redotil    –  Dr. Reddy’s, India

Resorcal Lactantes/Ninos (pediatric) – Andromaco, Chile

Resorcal   – Andromaco, Chile

Tiorfan    – Abbott, Germany; Bago, Brazil; Bioproject, Tunisia; Bioprojet, France; CPH, Portugal; Ferrer, Peru; Ferrer Farma, Spain

Tiorfan Infantil – CPH, Portugal

Tiorfan Niños (pediatric) – Ferrer, Peru

Tiorfan nourrissons (pediatric) – Bioproject, Tunisia

Tiorfanor  – Bioprojet, France

Tiorfast   – Bioprojet, France

Tiorfix    – Costanzafarma, Italy

Zomatril   –  FDC, India

See also

  • Ecadotril, the (S)-enantiomer of racecadotril

Racecadotril (CAS NO.: 81110-73-8), with its systematic name of Glycine, N-(2-((acetylthio)methyl)-1-oxo-3-phenylpropyl)-, phenylmethyl ester, (+-)-, could be produced through many synthetic methods.

Following is one of the synthesis routes: 2-Benzylacrylic acid (I) reacts with SOCl2 in hot toluene to afford the acyl chloride (II), which is condensed with N-tosylglycine benzyl ester (III) in the presence of TEA in toluene to yield the corresponding amide (IV). Finally, this compound is condensed with thioacetic acid by heating at 80 °C to afford the target acylthio compound.

Racecadotril is a neutral endopeptidase inhibitor used as antidiarrheal in the treatment of chronic cardiac insufficiency and is available under the brand names Hidrasec and Tiorfan. Racecadotril is chemically known as N-[2-[(acetylthio) methyl]- l-oxo-3-phenylpropyl] glycine phenyl methyl ester, (herein after referred by its generic name racecadotril) and represented by the formula (I).

U.S. Patent No. US 4,513,009 describes amino acid derivatives including racecadotril, a pharmaceutical composition and a method of treatment.

The US’009 patent also discloses a process for the preparation of racecadotril which is illustrated by below scheme:

U.S. Patent No. US 6,835,851 B2 discloses a process for the preparation of racecadotril which is illustrated by scheme below:

European Patent No. EP 0501870B 1 discloses a process for the preparation of racec

Racecadotril

The use of coupling agents like hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) generally induces the formation of side products such as dicyclohexylurea. These side products do lead to major problems, wherein purification by chromatography may be contemplated, but the side products are extremely difficult to remove on an industrial scale.

Consequently, efforts have been made to replace the peptidic coupling step

so as to avoid the formation of side products associated with the use of the coupling agents. Thus, it appears that, even if the preparation of N-(mercaptoacyl)amino acid derivatives from .alpha.-substituted acrylic acids by Michael addition of a thio acid and conversion of acid to acid chloride by using thionyl chloride and then coupling of an amino ester may be advantageous on a laboratory scale, such reactions are difficult to adapt on an industrial use.

The aforementioned processes described above involves expensive reagents such as hydroxyl benzotriazole (HOBT) and dicyclohexyl amine carbodiimide (DCC) and hazardous reagent like thionyl chloride thus rendering the processes expensive and not feasible on industrial scale.

SYNTHESIS BY WORLDDRUGTRACKER

STR1

Patent

https://www.google.com/patents/WO2013098826A1?cl=en

EXAMPLES

Example-1: Preparation of Racecadotril (I):

Step A) Preparation of 2-acetyIsulfanyI methyI-3-phenyI propionic acid (IV)

16.2 g of 2-benzylacrylic acid and 12.3 ml of thioacetic acid were were charged into a clean and dry R.B.flask and stirred at about 30°C for about 1 hour. The reaction mixture was heated to about 60°C and stirred for about 4 hours.The excess of thioacetic acid was distilled off completely to afford the title compound as residue. Yield: 23.8 g. Step B) Preparation of Racecadotril crude (la)

23.8 g. of 2-acetyl sulfanylmethyl-3-phenyl-propionic acid (IV), 200ml of methylene chloride and 16.7 ml of triethylamine were charged into a clean and dry R.B.flask. 10. 5 ml of ethylchloroformate was added at about -5°C. The resultant reaction mixture was stirred at about 0°C for about 30 min. 33.7 g of glycine benzyl ester p-tosyalte (II), 14 ml of triethylamine and 100ml of methylene chloride was added as a mixture to the reaction mass at about 0°C. Then the resultant reaction mixture was stirred at about 0°C for about 1 hr. followed by at about 30°C for about 30 min. After completion of the reaction as determined by TLC, the reaction mass was washed with 65 ml of distilled water, 65 ml 4% sodium bicarbonate solution and followed by 65 ml distilled water. The organic and aqueous phases were separated and the solvent was distilled completely, 2 x 50 ml Isopropyl alcohol was charged and again distilled off the solvent completely to give residue. The residue

obtained was triturated with a mixture of isopropyl alcohol 4 ml) and n-hexane (94 ml) at about 5°C to the title compound as crude. Yield: 34 g.

ExampIe-2: Purification of Racecadotril (Crude):

34 g. of crude Racecadotril and 35 ml of 20 % v/v aqueous .methanol were charged in a clean and dry R.B.flask and heated to about 65°C. 3g. of SP.carbon was charged and stirred at about 65°C for about 10 min. The reaction suspension was stirred at about 65°C for about 10 min. The reaction suspension was filtered on hyflow bed (diatomous earth) and washed the hyflow bed with 30 ml of aqueous methanol. The filtrate obtained was cooled to about 0°C for about 30 min. The solid separated was filtered and the solid obtained washed with 60 ml of precooled aqueous methanol to afford the pure racecadotril (I).

Yield: 29 g.; Purity by HPLC: 99.5 area %; The overall yield is 75.3%.

PATENT

https://www.google.com/patents/CN104356036A?cl=en

Example 1

The 40. 0g Racecadotril dissolved in 200ml of absolute ethanol and water bath heated to 40 ° C, and stir until the whole solution, stirring was stopped, the solution was placed in 15 ° C water bath was allowed to stand, when starting When there is precipitation of crystals, and then placed under the 0 ° C crystallization, after filtration, to 45 ° C under hot air drying cycle 6 hours to obtain 29. 2g, purity 99.6% of Racecadotril a polymorph crystals.

  reflection angle X-ray powder diffraction pattern 20 at 4.3 °, 8.7 °, 13.2 °, 16.8 °, 17.8 ° and 20.0 ° at the show X-ray powder diffraction peaks. In 1135. 19CHT1,1551. 46CHT1,1644. 73CHT1,1687. 57CHT1, 1731. 35CHT1 and 3289. 20CHT1 displayed at an infrared absorption peak.

Clips

US 20020055645

PATENT

CN 104356036 A

Racecadotril, chemical name N_ [(R, S) -3- acetyl-mercapto-2-benzyl-propionyl)] glycine benzyl ester, is a neprilysin inhibitor, selectively, reversible inhibition of neprilysin, so that the inner protection from degradation of endogenous enkephalins, prolong the physiological activity of endogenous enkephalins in the digestive tract, mainly used in clinical treatment of children and adults with acute diarrhea. Its structural formula is as follows:

Figure CN104356036AD00031

 Racecadotril as enkephalinase inhibitors, developed in France in 1993 Bioprojet listed acute diarrhea treatment, trade name Tiorfan.

In W02011116490A1, US5945548 and CN101768095A and other documents, documented racecadotril the synthesis process, but did not report the crystal form; therefore the present inventors have not reported Racecadotril crystalline polymorph conduct further

Example 1

[0032] The 40. 0g Racecadotril dissolved in 200ml of absolute ethanol and water bath heated to 40 ° C, and stir until the whole solution, stirring was stopped, the solution was placed in 15 ° C water bath was allowed to stand, when starting When there is precipitation of crystals, and then placed under the 0 ° C crystallization, after filtration, to 45 ° C under hot air drying cycle 6 hours to obtain 29. 2g, purity 99.6% of Racecadotril a polymorph crystals.

[0033] reflection angle X-ray powder diffraction pattern 20 at 4.3 °, 8.7 °, 13.2 °, 16.8 °, 17.8 ° and 20.0 ° at the show X-ray powder diffraction peaks. In 1135. 19CHT1,1551. 46CHT1,1644. 73CHT1,1687. 57CHT1, 1731. 35CHT1 and 3289. 20CHT1 displayed at an infrared absorption peak.

research.

References

http://www.frontiersin.org/files/Articles/27281/fphar-03-00093-HTML/image_m/fphar-03-00093-g001.jpg

 

CN101103960A * Jul 14, 2006 Jan 16, 2008 海南盛科生命科学研究院 Dry mixed suspension containing racecadotril and preparation method thereof
CN101768095A * Dec 26, 2008 Jul 7, 2010 山东齐都药业有限公司 Preparation method of racecadotril
WO2001097803A1 * Jun 20, 2001 Dec 27, 2001 Laboratoire Glaxosmithkline Pharmaceutical preparations comprising racecadotril (acetorphan)
WO2013098826A1 * Dec 26, 2011 Jul 4, 2013 Symed Labs Limited “a process for the preparation of n-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof”
Reference
CN101103960A * Jul 14, 2006 Jan 16, 2008 海南盛科生命科学研究院 Dry mixed suspension containing racecadotril and preparation method thereof
CN101768095A * Dec 26, 2008 Jul 7, 2010 山东齐都药业有限公司 Preparation method of racecadotril
WO2001097803A1 * Jun 20, 2001 Dec 27, 2001 Laboratoire Glaxosmithkline Pharmaceutical preparations comprising racecadotril (acetorphan)
WO2013098826A1 * Dec 26, 2011 Jul 4, 2013 Symed Labs Limited “a process for the preparation of n-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof”
1 * 金庆平 等: “神经内肽酶抑制剂消旋卡多曲(Racecadotril)的合成工艺研究“, 《中国现代应用药学杂志》, vol. 20, no. 7, 31 August 2003 (2003-08-31)
US6013829 * Feb 4, 1997 Jan 11, 2000 Societe Civile Bioprojet Process for the asymmetric synthesis of S-acyl derivatives of 2-mercaptomethyl -3- phenyl propanoic acid, application to the synthesis of N-(mercaptoacyl) amino acid derivatives
US20040009956 * Apr 29, 2003 Jan 15, 2004 Dehua Pei Inhibition of protein tyrosine phosphatases and SH2 domains by a neutral phosphotyrosine mimetic
1 * MOHAMED A.O. ET AL.: ‘Stability-indicating methods for the determination of racecadotril in the presence of its degradation products‘ BIOSCIENCE TRENDS vol. 3, no. 6, 2009, pages 247 – 252, XP055074337
CN104356036A * Nov 7, 2014 Feb 18, 2015 山东齐都药业有限公司 Alpha crystal form of racecadotril and preparation method of alpha crystal form
Racecadotril
Racecadotril2DCSD.svg
Systematic (IUPAC) name
(RS)-Benzyl N-[3-(acetylthio)-2-benzylpropanoyl]glycinate
Clinical data
Trade names Hidrasec, Tiorfan
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Protein binding 90% (active thiorphan metabolite)[1]
Metabolism Liver-mediated[1]
Biological half-life 3 hours[1]
Excretion Urine (81.4%), feces (8%)[1]
Identifiers
CAS Number 81110-73-8 Yes
ATC code A07XA04 (WHO)
PubChem CID 107751
ChemSpider 96913 
UNII 76K53XP4TO 
ChEMBL CHEMBL2103772 
Synonyms Benzyl 2-[3-(acetylthio)-2-benzylpropanamido]acetate
Chemical data
Formula C21H23NO4S
Molar mass 385.47662 g/mol
Chirality Racemic mixture

/////////Racecadotrilacetorphanantidiarrheal drug

CC(=O)SCC(CC1=CC=CC=C1)C(=O)NCC(=O)OCC2=CC=CC=C2

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H3D

 

UCT’s H3D is a center of excellence for research and innovation with an already strong track record in malaria drug  discovery. The vision of H3D is to be the leading organization for integrated drug discovery and development on the African continent.

ABOUT H3D

H3D is Africa’s first integrated drug discovery and development centre. The Centre was founded at the University of Cape Town in April 2011 and pioneers world-class drug discovery in Africa.

Our Vision

To be the leading organisation for integrated drug discovery and development from Africa, addressing global unmet medical needs.

Our Mission

To discover and develop innovative medicines for unmet medical needs on the African continent and beyond, by performing state-of-the-art research and development and bridging the gap between basic science and clinical studies.

We embrace partnerships with local and international governments, pharmaceutical companies, academia, and the private sector, as well as not-for-profit and philanthropic organisations, while  training scientists to be world experts in the field.

The H3D collaboration with the Medicines for Malaria Venture (MMV) focuses on delivering potential agents against malaria that will be affordable and safe to use. In line with the global aim to eradicate malaria, projects are pursued that not only eliminates blood-stage Plasmodium falciparum and Plasmodium vivax infection, but also acts against liver stages and blocks transmission of the infection. The projects embrace multidisciplinary activities to optimise hit compounds from screening libraries through the drug discovery pipeline and deliver clinical candidates.

Merck Serono Announces Recipients of the Second Annual €1 Million Grant for Multiple Sclerosis Innovation

Darmstadt, Germany, September 12, 2014 – Merck Serono, the biopharmaceutical division of Merck, today announced the recipients of the second annual Grant for Multiple Sclerosis Innovation (GMSI) at MS Boston 2014, the joint meeting of the Americas Committee for Treatment and Research in MS (ACTRIMS) and European Committee for Treatment and Research in MS (ECTRIMS), taking place September 10-13 in Boston, U.S.A.

Merck signed a research agreement with the University of Cape Town (UCT), South Africa, to co-develop a new R&D platform. It aims at identifying new lead programs for potential treatments against malaria, with the potential to expand it to other tropical diseases. It combines Merck’s R&D expertise and the drug discovery capabilities of the UCT Drug Discovery and Development Centre, H3D.
UCT’s H3D is a center of excellence for research and innovation with an already strong track record in malaria drug  discovery. The vision of H3D is to be the leading organization for integrated drug discovery and development on the African continent. They say that working with partners like Merck is critical to build up a comprehensive pipeline to tackle malaria and related infectious diseases.

Journal Publications:

  1. Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization C. Soares de Melo, T-S. Feng, R. van der Westhuyzen, R.K. Gessner, L. Street, G. Morgans, D. Warner, A. Moosa, K. Naran, N. Lawrence, H. Boshoff, C. Barry, C. Harris, R. Gordon, K. Chibale. Biorg. Med. Chem. 2015, 23, 7240-7250.
  2. A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum- Infected Mouse Models from Structure−Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines. C. Le Manach, T. Paquet, C. Brunschwig, M. Njoroge, Z. Han, D. Gonzàlez Cabrera, S. Bashyam, R. Dhinakaran, D. Taylor, J. Reader, M. Botha, A. Churchyard, S. Lauterbach, T. Coetzer, L-M. Birkholtz, S. Meister, E. Winzeler, D. Waterson, M. Witty, S. Wittlin, M-B. Jiménez-Díaz, M. Santos Martínez, S. Ferrer, I. Angulo-Barturen, L. Street, and K. Chibale, J. Med. Chem. 2015, XX, XXXX
  3. Structure−Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines. D. Gonzàlez Cabrera, F. Douelle, C. Le Manach, Z. Han, T. Paquet, D. Taylor, M. Njoroge, N. Lawrence, L. Wiesner, D. Waterson, M. Witty, S. Wittlin, L. Street and K. Chibale. J Med Chem. 2015, 58, 7572-7579.
  4. Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 2. Le Manach, T. Paquet, D. Gonzalez Cabrera, Y. Younis, D. Taylor, L. Wiesner, N. Lawrence, S. Schwager, D. Waterson, M.J. Witty, S. Wittlin, L. Street, and K. Chibale. J. Med. Chem. 2014, 57, 8839−8848.
  5. Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 1. Le Manach, D. González Cabrera, F. Douelle, A.T. Nchinda, Y. Younis, D. Taylor, L. Wiesner, K. White, E. Ryan, C. March, S. Duffy, V. Avery, D. Waterson, M. J. Witty, S. Wittlin; S. Charman, L. Street, and K. Chibale. J. Med. Chem. 2014, 57, 2789-2798.
  6. 2,4-Diamino-thienopyrimidines as Orally Active Antimalarial Agents. D. González Cabrera, C. Le Manach, F. Douelle, Y. Younis, T.-S. Feng, T. Paquet, A.T. Nchinda, L.J. Street, D. Taylor, C. de Kock, L. Wiesner, S. Duffy, K.L. White, K.M. Zabiulla, Y. Sambandan, S. Bashyam, D. Waterson, M.J. Witty, A. Charman, V.M. Avery, S. Wittlin, and K. Chibale. J. Med. Chem. 2014,57, 1014-1022.
  7. Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension. Burger, T.L. Reudelhuber, A. Mahajan, K. Chibale,E.D. Sturrock, R.M. Touyz. Clin. Sci. (Lond). 2014, 127(1), 57-63.
  8. Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor. Denti, S.K. Sharp, W.L. Kröger, S.L. Schwager, A. Mahajan, M. Njoroge, L. Gibhard, I. Smit, K. Chibale, L. Wiesner, E.D. Sturrock, N.H. Davies. Eur. J. Pharm. Sci.2014, 56, 113-119.
  9. Fragment-based design for the development of N-domain-selective angiotensin-1-converting enzyme inhibitors. R.G. Douglas, R.K. Sharma, G. Masuyer, L. Lubbe, I. Zamora, K.R. Acharya, K. Chibale, E.D. Sturrock. Sci. (Lond). 2014, 126(4),305-313.
  10. Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum. Le Manach, C. Scheurer, S. Sax, S. Schleiferböck, D. González Cabrera, Y. Younis, T. Paquet, L. Street, P.J. Smith, X. Ding, D. Waterson, M.J. Witty, D. Leroy, K. Chibale and S. Wittlin*. Malaria Journal, 2013, 12, 424.
  11. Structure-Activity-Relationship Studies Around the 2-Amino Group and Pyridine Core of Antimalarial 3,5-Diarylaminopyridines Lead to a Novel Series of Pyrazine Analogues with Oral in vivo Activity. Y. Younis, F. Douelle, González Cabrera, C. Le Manach, A.T. Nchinda, T. Paquet, L.J. Street, K.L. White, K. M. Zabiulla, J.T. Joseph,  S. Bashyam, D. Waterson, M.J. Witty, S. Wittlin, S.A. Charman, and K. Chibale*   J. Med. Chem. 2013, 56, 8860−8871.
  12. Cell-based Medicinal Chemistry Optimization of High Throughput Screening (HTS) Hits for Orally Active Antimalarials-Part 2: Hits from SoftFocus Kinase and other Libraries. Y. Younis, L. J. Street, D. Waterson, M.J. Witty, and K. Chibale. J. Med. Chem. 2013, 56, 7750−7754.
  13. Structure-Activity Relationship Studies of Orally active Antimalarial 3,5-Substituted 2-Aminopyridines. D. González Cabrera, F. Douelle, Y. Younis, T.-S. Feng, C. Le Manach, A.T. Nchinda, L.J. Street, C. Scheurer, J. Kamber, K. White, O. Montagnat, E. Ryan, K. Katneni, K.M. Zabiulla, J. Joseph, S. Bashyam, D. Waterson, M.J. Witty, S. Charman, S. Wittlin, and K. Chibale* J. Med. Chem. 2012, 55, 11022– 11030.
  14. 3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential. Y. Younis, F. Douelle, T.-S. Feng, D. González Cabrera, C. Le Manach, A.T. Nchinda, S. Duffy, K.L. White, M. Shackleford,  J. Morizzi, J. Mannila, K. Katneni, R. Bhamidipati, K. M. Zabiulla, J.T. Joseph,  S. Bashyam, D. Waterson, M.J. Witty, D. Hardick, S. Wittlin, V. Avery, S.A. Charman, and K. Chibale*.  J. Med. Chem.  2012, 55, 3479−3487.
  15. Novel Orally Active Antimalarial Thiazoles. D. González Cabrera, F. Douelle, T.-S Feng, A.T. Nchinda, Y. Younis, K.L. White, Wu,E. Ryan, J.N. Burrows,D. Waterson, M.J. Witty,S. Wittlin,S.A. Charman and K. Chibale.  J. Med. Chem. 2011, 54, 7713–7719.
  16. Synthesis and molecular modeling of a lisinopril-tryptophan analogue inhibitor of angiotensin I-converting enzyme. A.T. Nchinda, K. Chibale, P. Redelinghuys and E.D. Sturrock. Med. Chem. Lett. 2006, 16(17), 4616-4619.

Patents

  1. Anti-Malarial Agents. Y. Younis, K. Chibale, M.J. Witty, D. Waterson. (2016) US9266842 B2.
  2. New Anti-Malarial Agents. D. Waterson, M.J. Witty, K. Chibale, L. Street, D. González Cabrera, T. Paquet. EP patent application (2015), No. 15 176 514.6.
  3. Preparation of aminopyrazine compounds as antimalarial agents for treatment of malaria. Y. Younis, K. Chibale, M.J. Witty, D. Waterson. PCT Int Appl. (2013), WO 2013121387 A1 20130822.
  4. Preparation of peptides as angiotensin I-​converting enzyme (ACE) inhibitors. E.D. Sturrock, A.T. Nchinda, K. Chibale. PCT Int. ppl. (2006), WO 2006126087 A2 20061130.
  5. Preparation of peptides as angiotensin I-​converting enzyme (ACE) inhibitors, E.D. Sturrock, A.T. Nchinda, K. Chibale. PCT Int. ppl. (2006), WO 2006126086 A2 20061130.

Head Office, Medicinal Chemistry Unit

Physical Address:
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North Lane off Ring Road
Upper Campus, University of Cape Town
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Postal Address:
University of Cape Town
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South Africa

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Map of P. D. Hahn Bldg, Rondebosch, Cape Town, 7700, South Africa
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//////H3D, Africa,  integrated drug discovery and development centre,  University of Cape Town 

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Jun 202016
 

Thumbnail image of graphical abstract

Acting on actin: The mechanism of action of amphidinolide X and amphidinolide J, two relatively small cytotoxic macrolides, has been elucidated. They do not target microtubules and intermediate filaments. The effects observed in A549 and PtK2 cells and the in vitro interaction with actin monomer (G-actin) indicate that these macrolides behave as actin-assembly inhibitors.

Mechanism of Action of the Cytotoxic Macrolides Amphidinolide X and J

  1. Chiara Trigili1,
  2. Benet Pera1,
  3. Dr. Marion Barbazanges2,
  4. Prof. Dr. Janine Cossy2,
  5. Dr. Christophe Meyer2,
  6. Dr. Oriol Pineda3,
  7. Dr. Carles Rodríguez-Escrich3,
  8. Prof. Fèlix Urpí3,
  9. Prof. Dr. Jaume Vilarrasa3,*,
  10. Dr. J. Fernando Díaz1,* and
  11. Dr. Isabel Barasoain1,*

DOI: 10.1002/cbic.201100042

Author Information

  1. 1Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid (Spain), Fax: (+34) 915360432
  2. 2Laboratoire de Chimie Organique, ESPCI, CNRS, 75231 Paris 05 (France)
  3. 3Departament de Química Orgànica, Facultat de Química, Universitat de Barcelona, Diagonal 647, 08028 Barcelona (Spain)

*Departament de Química Orgànica, Facultat de Química, Universitat de Barcelona, Diagonal 647, 08028 Barcelona (Spain)

Trigili, C., Pera, B., Barbazanges, M., Cossy, J., Meyer, C., Pineda, O., Rodríguez-Escrich, C., Urpí, F., Vilarrasa, J., Díaz, J. F. and Barasoain, I. (2011), Mechanism of Action of the Cytotoxic Macrolides Amphidinolide X and J. ChemBioChem, 12: 1027–1030. doi: 10.1002/cbic.201100042

 

Others

Total Synthesis by Alkene Metathesis: Amphidinolide X (Urpí /Vilarrasa),

To assemble the framework of the cytotoxic macrolide Amphidinolide X (3), Fèlix Urpí and Jaume Vilarrasa of the Universitat de Barcelona devised (Org. Lett. 2008, 10, 5191. DOI: 10.1021/ol8021676) the ring-closing metathesis of the alkenyl silane 1. No Ru catalyst was effective, but the Schrock Mo catalyst worked well.

 

Total Synthesis of Amphidinolide X & Y

Fürstner

A. Fürstner, E. Kattnig, O. Lepage, J. Am. Chem. Soc. 2006, 128, 9194-9204.

DOI: 10.1021/ja061918e

Another pair of amphidinolides in the bag, Fürstner et al. have completed the synthesis of X (the only member of the series with an even-numbered macrocycle) and Y using a powerful iron catalysed process. Both products (as with most of the family) are cytotoxic, and contain the heavily functionalised THF moiety. This allowed the group to create an intermediate common to both campaigns, starting from a simple epoxide produced from an Sharpless epoxidation.

Treatment of this with n-propyl grignard and catalytic quantities of the iron catalyst generated the allene in a 8:1 dr (this system has been used by the group in other work; see: DOI: 10.1246/cl.2005.624, DOI: 10.1021/ja027190t, DOI: 10.1002/anie.200460504, plus further examples cited in the paper). The allene was then cyclised with silver nitrate and calcium carbonate, returning the DHP, which was augmented to the desired THF via bromoesterification.

This portion of the natural product was coupled using an alkyl Suzuki reaction to the rest of the molecule in both cases, along with macrolactonisation to furnish the major ring system. In amphidinolide Y, a boron-mediated aldol reaction was used to create the 1,4 anti relationship between a pair of hydroxyls in the C1 – C12 fragment, in a 4:1 dr. Inseparable at this point, they carried the mixture through to a diastereoselective methyl grignard addition.

The desired aldol product reacted diastereoselectively with the grignard following the 1,2-anti chelate-cram model, whereas the undesired aldol product reacted with far less control. This section of the synthesis is quite intriguing, and is discussed in far more detail in the paper, which is a truly excellent read.

 

Figure 1: Scheme 1. (A) Sharpless asymmetric epoxidation of allylic alcohols 1 mediated by Ti(IV)-diethyltartrate (DET) catalyst with alkyl hydroperoxide as terminal oxidant leading to enantioenriched epoxides 2. (B) Preferential attack of the oxygen atom as a function of the stereochemistry of the DET chiral ligand. (C) Schematic representation of the dimeric active catalytic species 3.

 

Figure 10: Scheme 10. Structure of amphidinolide X 35 and details of the SAE step.

 

PAPER

http://onlinelibrary.wiley.com/doi/10.1002/anie.200900865/abstract

STR1

STR1

 

STR1

PAPER

 

http://onlinelibrary.wiley.com/doi/10.1002/chem.200802069/abstract

////////////Cytotoxic Macrolides,  Amphidinolide X and J

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Jun 202016
 

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Metal Synergy in a Potential Anti-Cancer Drug

Ruthenium teams up with platinum in a promising anticancer drug

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http://www.chemistryviews.org/details/ezine/9407491/Metal_Synergy_in_a_Potential_Anti-Cancer_Drug.html?elq_mid=10181&elq_cid=1558306

/////////Ruthenium, anticancer drug, platinum

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