AZD 3264 an IKK2 Inhibitor from Astra Zeneca

New Drug Approvals

AZD 3264

MW 441.50

CAS 1609281-86-8

MF C₂₁ H₂₃ N₅ O₄ S

3-​Thiophenecarboxamide​, 2-​[(aminocarbonyl)​amino]​-​5-​[4-​(3,​5-​dimethyl-​4-​isoxazolyl)​-​2-​[(3S)​-​3-​pyrrolidinyloxy]​phenyl]​-

2-(Carbamoylamino)-5-[4-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(3S)-pyrrolidin-3-yloxy]phenyl]thiophene-3-carboxamide

Inhibition of IkB-kinase IKK2 has been identified as one of the novel pathways to treat inflammatory conditions such as asthma, chronic pulmonary obstructive disorder (COPD) and rheumatoid arthritis

Astrazeneca Ab,

……………………..

PATENT

WO 2003010158

https://www.google.com/patents/WO2003010158A1?cl=en

The synthesis began with the aromatic nucleophilic substitution reaction of 2-fluorobromobenzene (2) with (S)-N-Boc-3-pyrrolidinol 3 to give the bromo intermediate 4, which was borylated via halogen metal exchange using n-hexLi in THF followed by treatment with triisopropyl borate and acidic work-up to give the boronic acid intermediate 5. Suzuki coupling of the boronic acid 5 with bromothiophene 6(2)afforded the intermediate 7. Intermediate 7 was subjected to regioselective bromination using bromine in acetic acid. This reaction was nonregioselective and yielded 17% of the required…

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Elemental impurities – A database to facilitate the risk assessment of active ingredients and excipients

One of the main demands of the Guideline ICH Q3D is to carry out risk assessments on metallic impurities. A database with analytical data provides a valuable support. Learn more about the data sharing using the new elemental impurities database.

http://www.gmp-compliance.org/enews_04843_Elemental-impurities—A-database-to-facilitate-the-risk-assessment-of-active-ingredients-and-excipients_9263,9300,S-QSB_n.html

Released in December 2014, the ICH Q3D Guideline on Elemental Impurities contains extensive specifications for the control of a total of 24 elements (21 metals, 3 metalloids) that can be present as impurities in pharmaceutical products. Main sources can be

• Active ingredients
• Excipients (including water)
• Processing auxiliaries and catalysts
• Production equipment
• Container and closure systems

The Guideline ICH Q3D calls for a risk assessment with regard to the presence of metallic impurities in various dosage forms, taking into account the respective limit values. The main factors of influence are to be included (see fishbone diagram on p. 6 of the Guideline). The risks identified in a comprehensive analysis have then to be categorized in a meaningful and justifiable manner.

The data for the content of metallic impurities, e.g. in excipients (for this purpose there is a study conducted by the FDA) or of migratable impurities in container / closure systems (there exists a Literature review in the PDA journal of pharmaceutical science and technology) is rather thin. And the sources of information can only be found through extensive research. The greatest treasure of information is located in the databases of several pharmaceutical and API manufacturers which have carried out analytical studies already.

To merge these data and information and to make them available to all interested companies in the form of a database, representatives of eight major companies have joined forces to an “Elemental Impurities Pharma Consortium”. This group was formed in October 2013, after a Conference on “Elemental Impurities” conducted by the Joint Pharmaceutical Analysis Group (JPAG).

The database that is currently established under the auspices of the EI Pharma Consortium, now comprises analytical data on elemental impurities from over 100 different materials (pharmaceutical excipients, dyes, etc.), which were provided by other companies. These data are anonymized, so that interested users of the database can not recognize the specific origin of the information.

The benefit for the user increases to the same extent as the database grows, which basically means for the companies that have to implement one of the main requirements of the ICH Q3 Guideline – to carry out a risk assessment. The timeframe for this is tight: for medicinal products still to be approved the provisions of ICH Q3D need to be fulfilled by June 2016. Already approved products have to comply from December 2017 (see also our news “Industry Coalition” gives practical advice for the control of elemental impurities in active substances and excipients).

Note : At the Impurities Forum from 16-18 June 2015 in Prague you will receive more information about this topic. Andrew Teasdale, one of the initiators of the Consortium, will report about the database and the possibilities to use it.

 

 

ECA and PQG publish Chapter 6 of the interpretation of the ECA and PQG publish Chapter 6 of the interpretation of the EU GDP Guideline

The ECA Foundation and the Pharmaceutical Quality Group (PQG) have been working on the interpretation of different chapters of the EU GDP Guideline. Now the group has finalized the work on chapter 6 – Complaints, Returns, Suspected Falsified Medicinal Products & Medicinal Product Recalls. Read more about the GDP Guidance Chapter 6.

http://www.gmp-compliance.org/enews_04844_ECA-and-PQG-publish-Chapter-6-of-the-interpretation-of-the-EU-GDP-Guideline_9271,S-GDP_n.html

The ECA Foundation and the Pharmaceutical Quality Group (PQG) have been working on the interpretation of different chapters of the EU GDP Guideline. The interpretation of five chapters have been published already. The following 5 Guidance chapters on the EU GDP Guideline are available:

Chapter 1: Quality Management
Chapter 9: Transportation (also contains a template for a Technical Agreement)
Chapter 7: Outsourced Activities
Chapter 2: Personnel
Chapter 5: Operations

Now the group has finalized the work on chapter 6 – Complaints, Returns, Suspected Falsified Medicinal Products & Medicinal Product Recalls. Chapter 6 of the EU GDP Guideline requires that all complaints, returns, suspected falsified medicinal products and recalls must be recorded and handled carefully according to written procedures. Some returned medicinal products might be released for resale. The handling should be performed only after an assessment of the returned medicinal products. The approval should be made by the Responsible Person (RP). Also complaints must be handled based on a written procedure and all details of each complaint must be recorded. Finally, the identification and handling of Falisified Medicinal Products are also defined in chapter 6. The ECA/PQG Guidance document provides information on how to implement the requirements.

You will find chapter 6 and all other GDP Guidance chapters in the members area of the GDP Group Webpage. Membership is available at no costs

RG-1577, EVT 302

New Drug Approvals

RG-1577, EVT 302

Hoffmann La Roche

RG-1577, a selective and reversible monoamine oxidase B inhibitor, for treating AD (phase 2 clinical, as of May 2015).

Family members of the product case for RG-1577 (WO2004026825) hold protection in EU until 2023 and expire in US in 2024 with US154 extension. Follows on from WO2006097197, claiming a process for preparing RG-1577.

Alzheimer^‘s Disease is a brain disease that slowly destroys memory and thinking skills, up to loss of the ability to carry out the simplest tasks. It is the most common cause of dementia among older people. Mild Alzheimer^‘s Disease manifests itself in memory loss and small changes in other cognitive abilities, e.g getting lost, trouble handling money and managing daily tasks, having some mood and personality changes, etc. In the stage of Moderate Alzheimer^‘s Disease, the control of language, reasoning, sensory processing, and…

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