AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Sep 162016
 

Figure

ORM 10921

UNII-D26C95A960; D26C95A960; ORM-12741; ORM12741; ORM 12741; ORM-10921;

(1S,12bS)-1-(Methoxymethyl)-1-methyl-2,3,4,6,7,12b-hexahydro-1H-[1]benzofuro[2,3-a]quinolizine

(1S,12bS)-1-(methoxymethyl)-1-methyl-2,3,4,6,7,12b-hexahydro-[1]benzofuro[2,3-a]quinolizine

285.38, C18 H23 N O2

2H-​Benzofuro[2,​3-​a]​quinolizine, 1,​3,​4,​6,​7,​12b-​hexahydro-​1-​(methoxymethyl)​-​1-​methyl-​, (1S,​12bS)​-

cas 610782-82-6

Belle David Din, Reija Jokela, Arto Tolvanen,Antti Haapalinna, Arto Karjalainen, Jukka Sallinen, Jari Ratilainen
Applicant Orion Corporation

UNII-D26C95A960.png

 

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David Din Belle

David Din Belle

Senior research scientist at Orion Corporation

https://fi.linkedin.com/in/david-din-belle-a2594115

Jari Ratilainen

Jari Ratilainen

https://fi.linkedin.com/in/jari-ratilainen-6a566218

 

Image result for Reija Jokela

Reija Jokela

https://fi.linkedin.com/in/reija-jokela-06499a1a

 

The basic drug substance candidate ORM10921 (MW = 285.38),

IUPAC name [1R*,12bR*)-(−)-1,3,4,6,7,12b-hexahydro-1-methoxymethyl-1-methyl-2H-benzofuro [2,3-a]quinolizine],

and its hydrochloric salt were synthesized by Orion Pharma, Finland.

The absolute configuration was assigned by optical rotation and later by single-crystal X-ray diffraction (see Supporting Information). The optical purity of the material was >97%.

  • Originator Juvantia Pharma (CEASED); Orion
  • Class Neuropsychotherapeutics
  • Mechanism of Action Alpha 2c adrenergic receptor antagonists

Highest Development Phases

  • Discontinued Major depressive disorder; Schizophrenia

Most Recent Events

  • 10 May 2006 Discontinued – Phase-I for Schizophrenia in Finland (unspecified route)
  • 10 May 2006 Discontinued – Preclinical for Depression in Finland (unspecified route)
  • 15 Nov 2002 Preclinical trials in Schizophrenia in Finland (unspecified route)

Image result for ORM 10921

Figure 1: Chemical structure of the study compound. Molecular Formula: C18H23NO2 · HCl · ½ H2O; Molecular Weights: 285.39 (free base), 321.85 (hydrochloride) 330.86 (hydrochloride hemihydrate). ORM-10921 · HCl is a single stereoisomer with the (1R*,12bR*) configuration.

The alpha adrenergic receptors can be divided on a pharmacological basis into alphal- and alpha2-adrenoceptors, which can both be further divided into subtypes. Three genetically encoded subtypes, namely alpha2A-, alpha2B- and alpha2C-adrenoceptors, have been discovered in human. Accordingly, alpha2- adrenoceptors in humans have been subdivided into three pharmacological subtypes known as alpha2A-, alpha2B- and alpha2C-adrenoceptors. A fourth, pharmacologically defined subtype, alpha2D, is known in rodents and in some other mammals, and it corresponds to the genetically defined alpha2A-adrenoceptors.

The alpha2-adrenoceptor subtypes have distinct tissue distributions and functional roles. For instance, while alpha2A-adrenoceptors are widely expressed in various tissues, alpha2C-adrenoceptors are concentrated in the CNS, and they appear to play a role in the modulation of specific CNS-mediated behavioural and physiological responses. Compounds that are non-specific to any of the above-mentioned alpha2 subtypes, and compounds that are specific to certain alpha2 subtypes, are already known. For example, atipamezole is a non-specific alpha2 antagonist. Atipamezole has been described in, for example, EP-A-183 492 (cf. p.13, compound XV) and Haapalinna, A. et al., Naunyn-Schmiedeberg’s Arch. Pharmacol. 356 (1997) 570-582. U.S. Patent No. 5,902,807 describes compounds that are selective antagonists for the alpha2C subtype and may be used in the treatment of mental illness, e.g. mental disturbance induced by stress. Such compounds include, for example, MK-912 and BAM- 1303. Furthermore, WO-A-99 28300 discloses substituted imidazole derivatives having agonist-like activity for alpha2B- or 2B/2C-adrenoceptors. hi addition, WO 01/64645 relates to derivatives of quinoline useful as alpha2 antagonists, as well as to selective alpha2C antagonist agents. The disclosures of all documents cited above in this paragraph are incorporated by reference herein.

Several arylquinolizine derivatives and related compounds have been described in the literature, some of which possess valuable pharmaceutical effects. For example, U.S. Patents No. 4,806,545 and 4,044,012 describe 1,1-disubstituted indolo[2,3-«]quinolizidines useful as vasodilators and antihypoxic agents. Further, substituted arylquinolizine derivatives, described for example in U.S. Patent No. 4,686,226 possessing alpha2-adrenoceptor antagonistic activity are useful for example as antidepressant, antihypertensive, or antidiabetic agents or platelet aggregation inhibitors. In addition, U.S. Patent No. 3,492,303 relates to indolo[2,3- α]quinolizidines useful as central nervous system depressants.

 

PATENT

WO 2003082866

https://www.google.com/patents/WO2003082866A1?cl=en

 

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Sep 152016
 

 

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All participants of the GMP training course “Product Transfer” will receive a special version of the Guideline Manager CD including documents and templates useable for site change projects.

Click

http://www.gmp-compliance.org/eca_mitt_05359_15221,Z-PEM_n.html

According to the European GMP-Rules, written procedures for tranfser activities and their documentation are required. For example, a Transfer SOP, a transfer plan and a report are now mandatory and will be checked during inspections.

As participant of the GMP education course “Product Transfer” in Berlin, from 25-27 October 2016 you will receive a special version of the Guideline Manager CD with a special section concerning product transfers. This section contains, amongst others, a Transfer SOP and a template for a Transfer Plan. Both documents are in Word format and can immediately be used after adoption to your own situation.

Regulatory Guidance Documents like the WHO guideline on transfer of technology in pharmaceutical manufacturing and the EU/US Variation Guidelines, are also part of the Guideline Manager CD. Due to copyright reasons, this CD is not available for purchase and can only be handed out to participants of the Product Transfer course.

/////////Product Transfer

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Sep 152016
 

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Analytical Lifecycle: USP <1210> “Statistical Tools”, Analytical Target Profile and Analytical Control Strategy

The United States Pharmacopeia (USP) is currently undertaking further steps towards a comprehensive analytical lifecycle approach by publishing a draft of a new General Chapter <1210> Statistical Tools for Procedure Validation and two Stimuli Articles regarding Analytical Target Profile and Analytical Control Strategy in Pharmacopeial Forum. Read more about the life cycle concept for analytical procedures.

http://www.gmp-compliance.org/enews_05565_Analytical-Lifecycle–USP–1210–%22Statistical-Tools%22–Analytical-Target-Profile-and-Analytical-Control-Strategy_15438,15608,Z-PDM_n.html

Following the recently announced elaboration of a new general chapter <1220> “The Analytical Procedure Lifecycle” the United States pharmacopeia (USP) is now proceeding in its approach for a comprehensive analytical lifecycle concept. A further step towards this approach is the draft of a new USP General Chapter <1210> Statistical Tools for Procedure Validation which has been published in Pharmacopeial Forum (PF) 42(5) in September 2016. Comment deadline is November 30, 2016.

Additionally, two Stimuli Articles regarding “Analytical Control Strategy” and “Analytical Target Profile: Structure and Application Throughout The Analytical Lifecycle” appeared in the same issue of the PF.

In the draft chapter <1210> Statistical Tools for Procedure Validation, the USP Statistics Expert Committee presents a revision to the proposal of <1210> published in PF 40(5) [Sept.–Oct. 2014]. On the basis of the comments and feedback given by stakeholders, the committee has addressed their concerns about the narrow scope and details on methodology to be used. The chapter is proposed as a companion to general chapter <1225> Validation of Compendial Procedures with the purpose of providing statistical methods that can be used in the validation of analytical procedures. A revision of general chapter <1225>, including a new section on Lifecycle Management of Analytical Procedures, has been published for comment in PF 42(2) in March 2016.

Specifically, the revision clarifies the accuracy and precision calculations while removing specific linearity requirements. Linearity may be inferred from accuracy or other statistical methods as deemed appropriate. The chapter discusses all of the following analytical performance characteristics from a statistical perspective:

  • accuracy,
  • precision,
  • range,
  • detection limit,
  • quantitation limit,
  • and linearity.

Additional related topics that are discussed in the draft include statistical power, two one-sided tests of statistical equivalence, tolerance intervals, and prediction intervals.

Furthermore, up to now, four Stimuli Articles regarding the analytical lifecycle have been published:

and new in PF 42(5)

  • “Analytical Control Strategy”, and
  • “Analytical Target Profile: Structure and Application Throughout The Analytical Lifecycle”.

The Analytical Target Profile (ATP) is the focal point of the lifecycle approach. It is comparable to the Quality Target Product Profile (QTPP) which is defined in ICH Q8. The Stimuli Article emphasizes “that the current approach to development, validation, verification, and transfer of analytical procedures has served the industry well.” The lifecycle approach – comprised of the development (design, stage 1), qualification (stage 2), and monitoring of the performance of analytical procedures (control strategy, stage 3) – is an extension of the current guidance, taking advantage of the learnings from ICH Q8 – quality by design (QbD) concepts. The Article considers in particular the following questions (and provides examples):

  • What is an ATP, and why is it useful?
  • How can the ATP criteria be established?
  • How can an ATP be applied during the three stages of the procedure lifecycle?

According to the article, “an additional advantage of using an ATP is that it can drive the development of a robust control strategy, resulting in better, more consistent performance of an analytical procedure throughout its lifecycle.”

In the Stimuli Article on the Analytical Control Strategy (ACS), the following questions are discussed:

  • What is the ACS?
  • What is the relationship between the ACS and the ATP?
  • What is the quality risk management (QRM) process and how can it be applied to an analytical procedure?
  • How does the ACS apply to the product lifecycle?

Additionally, examples of the following are provided:

  • How to develop an ACS using the QRM process, and
  • How to develop and apply a risk-based replicate strategy to minimize variability.

The USP Expert Panel would appreciate any feedback on the suggested approaches, as well as any alternative approaches for consideration.
Following your registration on the USP Pharmacopeial Forum website you can get to the proposal for general chapter <1210> and the complete stimuli articles. Because of the importance of the new USP chapter <1220>, ECA and USP join forces and organise the first joint event “Lifecycle Approach of Analytical Procedures“, in Prague, Czech Republic, from 8 to 9 November 2016.

 

/////////Analytical Lifecycle,  USP <1210> “Statistical Tools”,  Analytical Target Profile, Analytical Control Strategy

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Sep 132016
 

The importance of Quality by Design (QbD) is being realized gradually, as it is gaining popularity among the generic companies. However, the major hurdle faced by these industries is the lack of common guidelines or format for performing a risk-based assessment of the manufacturing process. This article tries to highlight a possible sequential pathway for performing QbD with the help of a case study. The main focus of this article is on the usage of failure mode and effect analysis (FMEA) as a tool for risk assessment, which helps in the identification of critical process parameters (CPPs) and critical material attributes (CMAs) and later on becomes the unbiased input for the design of experiments (DoE). In this case study, the DoE was helpful in establishing a risk-based relationship between critical quality attributes (CQAs) and CMAs/CPPs. Finally, a control strategy was established for all of the CPPs and CMAs, which in turn gave rise to a robust process during commercialization. It is noteworthy that FMEA was used twice during theQbD: initially to identify the CPPs and CMAs and subsequently after DoE completion to ascertain whether the risk due to CPPs and CMAs had decreased.

 

 

 

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Image result for Quality by Design in Action 1: Controlling Critical Quality Attributes of an Active Pharmaceutical Ingredient

Quality by Design in Action 1: Controlling Critical Quality Attributes of an Active Pharmaceutical Ingredient

CTO-III, Dr. Reddy’s Laboratories Ltd, Plot 116, 126C and Survey number 157, S.V. Co-operative Industrial Estate, IDA Bollaram, Jinnaram Mandal, Medak District, Telangana 502325, India
Department of Chemistry, Osmania University, Hyderabad, Telangana 500007, India
Org. Process Res. Dev., 2015, 19 (11), pp 1634–1644
*Telephone: +919701346355. Fax: + 91 08458 279619. E-mail: amrendrakr@drreddys.com (A.K.R.)., *E-mail:sripabba85@yahoo.co.in (P.S.).

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////// QbD, DoE, FMEA, ANOVA, Design space.
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Sep 132016
 

 

REGIOMER OF BESIFLOXACIN

 

 

 

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Abstract: In this paper (R)-7-(azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1 was isolated and identified as the N-substituted regioisomer of besifloxacin, which has been synthesized from the reaction of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 3 with (R)-tert-butyl 3-aminoazepane-1-carboxylate 2 in acetonitrile as solvent in 37% yield. The chemical structure of compound 1 was established on the basis of 1H-NMR, 13C-NMR, mass spectrometry data and elemental analysis.

Structural Characterization
1H-NMR (500 MHz, DMSO-d6): δ ppm: 14.73 (H-23, s, 1H), 9.72 (H-14, s, 2H), 8.69 (H-7, s, 1H),7.79 (H-1, d, J = 13.1 Hz, 1H), 6.20 (H-11, d, J = 9.1 Hz, 1H), 4.37 (H-12 and H-19, m, 2H), 3.38(H-13, m, 2H), 3.23 (H-15, m, 1H), 3.09 (H-15, m, 1H), 2.14 (H-18, m, 1H), 1.94 (H-16 and H-18, m,2H), 1.84 (H-16 and H-17, m, 2H), 1.60 (H-17, m, 1H), 1.23 (H-20 or H-21, m, 2H), 1.03 (H-20 orH-21, m, 2H).
13C-NMR(125 MHz, DMSO-d6): δ ppm: 175.6 (C-9), 165.4 (C-22), 151.7 (C-7), 150.6 (C-2), 148.7(C-3), 139.0 (C-5), 137.3 (C-4), 117.8 (C-10), 110.3 (C-1), 107.0 (C-8), 52.9 (C-12), 50.1 (C-13), 46.2(C-15), 41.3 (C-19), 34.0 (C-18), 24.9 (C-16), 21.6 (C-17), 10.9 (C-20 or C-21).
FAB-MS, m/z = 394.1 (M+).
Elemental analysis: Calculated for C19H21ClFN3O3.HCl: C, 53.03%; H, 5.15%; N, 9.77%; found: C,52.82%; H, 5.39%; N, 9.50%.

 

1H-NMR (500 MHz, DMSO-d6): δ ppm: 14.73 (H-23, s, 1H), 9.72 (H-14, s, 2H), 8.69 (H-7, s, 1H), 7.79 (H-1, d, J = 13.1 Hz, 1H), 6.20 (H-11, d, J = 9.1 Hz, 1H), 4.37 (H-12 and H-19, m, 2H), 3.38 (H-13, m, 2H), 3.23 (H-15, m, 1H), 3.09 (H-15, m, 1H), 2.14 (H-18, m, 1H), 1.94 (H-16 and H-18, m,2H), 1.84 (H-16 and H-17, m, 2H), 1.60 (H-17, m, 1H), 1.23 (H-20 or H-21, m, 2H), 1.03 (H-20 orH-21, m, 2H).

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13C-NMR(125 MHz, DMSO-d6): δ ppm: 175.6 (C-9), 165.4 (C-22), 151.7 (C-7), 150.6 (C-2), 148.7(C-3), 139.0 (C-5), 137.3 (C-4), 117.8 (C-10), 110.3 (C-1), 107.0 (C-8), 52.9 (C-12), 50.1 (C-13), 46.2(C-15), 41.3 (C-19), 34.0 (C-18), 24.9 (C-16), 21.6 (C-17), 10.9 (C-20 or C-21).

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PAPER

Molbank 2013, 2013(2), M801; doi:10.3390/M801
Short Note
(R)-7-(Azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid Hydrochloride
Supplementary File 3:Support Information (PDF, 340 KB)
Download PDF [188 KB, 27 May 2013; original version 22 May 2013]
R&D Center, Jiangsu Yabang Pharmaceutical Group, Changzhou 213200, China
In this paper (R)-7-(azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1was isolated and identified as the N-substituted regioisomer of besifloxacin, which has been synthesized from the reaction of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 3 with (R)-tert-butyl 3-aminoazepane-1-carboxylate 2in acetonitrile as solvent in 37% yield. The chemical structure of compound 1 was established on the basis of 1H-NMR, 13C-NMR, mass spectrometry data and elemental analysis

REGIOMER OF BESIFLOXACIN

 

Besifloxacin.pngBESIFLOXACIN

 

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 Zaixin Chen *
R&D Center, Jiangsu Yabang Pharmaceutical Group, Changzhou 213200, China
* Author to whom correspondence should be addressed;

E-Mail: zaixin_chen@163.com.

Zai-Xin Chen

Director of R&D Center at Jiangsu Yabang Pharmaceutical Group Co., Ltd

https://cn.linkedin.com/in/zai-xin-chen-45074179

https://www.researchgate.net/profile/Zai_Xin_Chen

 

 

///////N-substituted regioisomer of besifloxacin, besifloxacin

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Sep 122016
 

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DDD 107498, DDD 498

PATENT WO 2013153357,  US2015045354

6-Fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide

6-Fluoro-2-[4-(4-morpholinylmethyl)phenyl]-N-[2-(1-pyrrolidinyl)ethyl]-4-quinolinecarboxamide

4-​Quinolinecarboxamide​, 6-​fluoro-​2-​[4-​(4-​morpholinylmethyl)​phenyl]​-​N-​[2-​(1-​pyrrolidinyl)​ethyl]​-

CAS 1469439-69-7

CAS 1469439-71-1 SUCCINATE

MF C27H31FN4O2
MW 462.559043 g/mol
      6-fluoro-2-[4-(morpholin-4-ylmethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide
  • Originator Medicines for Malaria Venture; University of Dundee
  • Class Small molecules
  • Mechanism of Action Protein synthesis inhibitors

Highest Development Phases

  • No development reported Malaria

Most Recent Events

  • 16 Jul 2016 No recent reports of development identified for preclinical development in Malaria in United Kingdom
  • 01 Apr 2015 DDD 498 licensed to Merck Serono worldwide for the treatment of Malaria
Inventors Ian Hugh Gilbert, Neil Norcross, Beatriz Baragana Ruibal, Achim Porzelle
Original Assignee University Of Dundee

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Prof Ian Gilbert:

Head of Biological Chemistry and Drug Discovery

BCDD, College of Life Sciences, University of Dundee, DD1 5EH, UK
Tel: +44 (0) 1382-386240

 

University of Dundee

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SCHEMBL15322600.pngDDD498

 

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Merck Serono and MMV sign agreement to develop potential antimalarial therapy

Agreement further diversifies MMV’s partner base, strengthening our antimalarial research and development portfolio

01 April 2015

Photo © Merck Serono

Merck Serono, the biopharmaceutical business of Merck, and MMV announced today that an agreement has been signed for Merck Serono to obtain the rights to the investigational antimalarial compound DDD107498 from MMV. This agreement underscores the commitment of Merck Serono to provide antimalarials for the most vulnerable populations in need.

“This agreement strengthens our Global Health research program and our ongoing collaboration with Medicines for Malaria Venture,” said Luciano Rossetti, Executive Vice President, Global Head of Research & Development at Merck Serono. “MMV is known worldwide for its major contribution to delivering innovative antimalarial treatments to the most vulnerable populations suffering from this disease, and at Merck Serono we share this goal.”

DDD107498 originated from a collaboration between MMV and the University of Dundee Drug Discovery Unit, led by Prof. Ian Gilbert and Dr. Kevin Read. The objective of the clinical program is to demonstrate whether the investigational compound exerts activity on a number of malaria parasite lifecycle stages, and remains active in the body long enough to offer potential as a single-dose treatment against the most severe strains of malaria.

While development and commercialization of the compound is under Merck Serono’s responsibility, MMV will provide expertise in the field of malaria drug development, including its clinical and delivery expertise, and provide access to its public and private sector networks in malaria-endemic countries.

Merck Serono has a dedicated Global Health R&D group working to address key unmet medical needs related to neglected diseases, such as schistosomiasis and malaria, with a focus on pediatric populations in developing countries. Its approach is based on public-private partnerships and collaborations with leading global health institutions and organizations in both developed and developing countries.

“Working with partners like Merck Serono is critical to the progress of potential antimalarial compounds, like DDD107498, through the malaria drug pipeline,” said Dr. Timothy Wells, Chief Scientific Officer at MMV. “Their Global Health Program is gaining momentum and we need more compounds to tackle malaria, a disease that places a huge burden on the world’s most vulnerable populations. DDD107498 holds great promise and we look forward to working with the Merck Serono team through the development phase.”

According to the World Health Organization, there were an estimated 198 million cases of malaria worldwide in 2013, and an estimated 584,000 deaths, primarily in young children from the developing world. The launch of the not-for-profit research foundation, MMV, in 1999 and a number of collaborations and partnerships, including those with Merck Serono, has contributed to reducing the major gap in malaria R&D investment and subsequent dearth of new medicines.

“It’s hugely encouraging to see the German pharmaceutical industry increasing their engagement in the development of novel antimalarials,” said global malaria expert Prof. Dr. Peter Kremsner, Director of the Institute for Tropical Medicine at the University of Tübingen, Germany. “The Merck Serono and MMV collaboration to develop DDD107498 is a great step. It’s a compound that offers lots of promise so I’m excited to see how it progresses.

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Scots scientists in ‘single dose’ malaria treatment breakthrough

An antimalarial drug that could treat patients was discovered by Dundee university scientists

Scientists have discovered an antimalarial compound that could treat malaria patients in a single dose and help prevent the spread of the disease from infected people.

The compound DDD107498 also has the potential to treat patients with malaria parasites resistant to current medications, researchers say.

Scientists hope it could lead to treatments and protection against the disease, which claimed almost 600,000 lives amid 200 million reported cases in 2013.

The compound was identified through a collaboration between the University of Dundee’s drug discovery unit (DDU) and the Medicines for Malaria Venture (MMV), a separate organisation.

The compound is now undergoing further safety testing with a view to entering human clinical trials within the next year.

Details of the discovery have been published in the journal Nature.

Professor Ian Gilbert, head of chemistry at the DDU, who led the team that discovered the compound, said: “The publication describes the discovery and profiling of this exciting new compound.

“It reveals that DDD107498 has the potential to treat malaria with a single dose, prevent the spread of malaria from infected people and protect a person from developing the disease in the first place.

“There is still some way to go before the compound can be given to patients. However, we are very excited by the progress that we have made.”

The World Health Organisation reports that there were 200 million clinical cases of malaria in 2013, with 584,000 people dying from the disease. Most of these deaths were children under the age of five and pregnant women.

MMV chief executive officer Dr David Reddy said: “Malaria continues to threaten almost half of the world’s population – the half that can least afford it.

“DDD107498 is an exciting compound since it holds the promise to not only treat but also protect these vulnerable populations.

“The collaboration to identify and progress the compound, led by the drug discovery unit at the University of Dundee, drew on MMV’s network of scientists from Melbourne to San Diego.”The publication of the research is an important step and a clear testament to the power of partnership.”

MMV selected DDD107498 to enter preclinical development in October 2013 following the recommendation of its expert scientific advisory committee.

Since then, with MMV’s leadership, large quantities of the compound have been produced and it is undergoing further safety testing with a view to entering human clinical trials within the next year.

Merck Serono has recently obtained the right to develop and, if successful, commercialise the compound, with the input of MMV’s expertise in the field of malaria drug development and access and delivery in malaria-endemic countries.

Dr Michael Chew from the Wellcome Trust, which provides funding for the DDU and MMV, said: “The need for new antimalarial drugs is more urgent than ever before, with emerging strains of the parasite now showing resistance against the best available drugs.

“These strains are already present at the Myanmar-Indian border and it’s a race against time to stop resistance spreading to the most vulnerable populations in Africa.

“The discovery of this new antimalarial agent, which has shown remarkable potency against multiple stages of the malaria lifecycle, is an exciting prospect in the hunt for viable new treatments.”

PAPER

 

Abstract Image

Figure

Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy

Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, U.K.
Cell and Molecular Biology, Department of Life Sciences, Imperial College, London, SW7 2AZ, U.K.
§ School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
Eskitis Institute, Griffith University, Brisbane Innovation Park, Nathan Campus, Brisbane, QLD 4111, Australia
Swiss Tropical and Public Health Institute, Swiss TPH, Socinstrasse 57, 4051 Basel, Switzerland
#University of Basel, CH-4003 Basel, Switzerland
Medicines for Malaria Venture, International Centre Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland
J. Med. Chem., Article ASAP
DOI: 10.1021/acs.jmedchem.6b00723
*K.D.R.: phone, +44 1382 388 688; e-mail, k.read@dundee.ac.uk., *I.H.G.: phone, +44 1382 386 240; e-mail,i.h.gilbert@dundee.ac.uk.
Figure
Conditions: (a) morpholine, Et3N, DCM, 16 h, 72% yield; (b) MeMgBr, toluene, reflux, 4 h and then a 10% aqueous HCl, reflux, 1 h, 70% yield; (c) NBS, benzoyl peroxide, dichlorobenzene, 140 °C, 16 h, 70% yield; (d) morpholine, K2CO3, acetonitrile, 40 °C, 16 h, 64% yield; (e) 5-fluoroisatin, KOH, EtOH, 120 °C, microwave, 20 min, 30–76% yield; (f) amine, CDMT, N-methylmorpholine, DCM, 20–61% yield.

 

A single-dose treatment against malaria worked in mice to cure them of the disease. The drug also worked to block infection in healthy mice and to stop transmission, according to a study published in Nature today. The fact that the drug can act against so many stages of malaria is pretty new, but what’s even more exciting is the compound’s mode of action: it kills malaria in a completely new way, researchers say. The feature would make it a welcome addition to our roster of antimalarials — a roster that’s threatened by drug resistance.

RESEARCHERS SIFTED THROUGH A LIBRARY OF ABOUT 4,700 COMPOUNDS TO FIND THIS ONE

Malaria is an infectious disease that’s transmitted through mosquito bites; it’s also a leading cause of death in a number of developing countries. Approximately 3.4 billion people live in areas where malaria poses a real threat. As a result, there were 207 million cases of malaria in 2012 — and 627,000 deaths. There are drugs that can be used to prevent malaria, and even treat it, but drug resistance is halting the use of certain treatments in some areas.

A long search

Searching for a new drug is all about trial and error. To find this particular compound, researchers sifted through a library of about 4,700 compounds, testing them to see if they were capable of killing the malaria parasite in a lab setting. When they found something that worked, they tweaked the drug candidate to see if it could perform more effectively. “We went through a lot of these cycles of testing and designing new compounds,” says Ian Gilbert, a medicinal chemist at the University of Dundee in the UK, and a co-author of the study. “Eventually we optimized to the compound which is the subject of the paper.” For now, that compound’s unwieldy name is DDD107498.

To make sure DDD107498 really had potential, the researchers tested it on mice that had already been infected with malaria. A single dose was enough to provoke a 90 percent reduction in the number of parasites in their blood. The scientists also gave the compound to healthy mice that were subsequently exposed to malaria. DDD107498 helped the mice evade infection with a single dose, but it’s unclear how long that effect would last in humans. Finally, the researchers looked at whether the compound could prevent the transmission from an infected mouse to a mosquito. A day after receiving the treatment, mice were put in contact with mosquitoes. The scientists noted a 91 percent reduction in infected mosquitoes.

“IT HAS THE ABILITY TO BE A ONE-DOSE [DRUG], IN COMBINATION WITH ANOTHER MOLECULE.”

“What’s exciting about this molecule is obviously the fact that it has the ability to be a one-dose [drug], in combination with another molecule to cure blood stage malaria,” says Kevin Read, a drug researcher also at the University of Dundee and a co-author of the study. The fact that the compound has the ability to block transmission and protect against infection is equally thrilling. But the way in which DDD107498 kills malaria might be its most interesting feature. It halts the production of proteins — which are necessary for the parasite’s survival. No other malaria drug does that right now, Read says. “So, in principle, there’s no resistance out there already to this mechanism.”

The drug hasn’t been tested in humans yet, so it may not be nearly as good in the field. But Read says DDD107498 looks promising. “From all the pre-clinical or non-clinical data we’ve generated, it is comparable or better than any of the current marketed anti-malarials in those studies.” And at $1 per treatment, the price of the drug should fall “within the range of what’s acceptable,” he says.

“It looks like an excellent study, and the results look very important,” says Philip Rosenthal, a malaria drug researcher at The University of California-San Francisco who didn’t participate in the study. This is a big shift for Rosenthal’s field. Five years ago, “we had very little going on in anti-malarial drug discovery,” he says. Now, there’s quite a bit going on for malaria researchers, and a number of promising compounds are moving along. DDD107498 “is another player, and it’s got a number of positive features,” he says.

OTHER TREATMENTS HAVE TO BE TAKEN FOR A FEW DAYS

One of the features is the drug’s potency. It’s very active against cultured malaria parasites, Rosenthal says. But what’s perhaps most intriguing about DDD107498 is that the drug works against the mechanism that enables protein synthesis the malaria parasite’s cells. No other malaria drug does that right now, Read says. “Considering challenges of treating malaria, which is often in rural areas and developing countries, a single dose would be a big plus,” he says. “In addition, because of it’s long half life, it may also work to prevent malaria with once a week dosing, which is also a benefit.”

Still, no drug is perfect. The data suggests that DDD107498 doesn’t kill malaria as quickly as some other drugs, Rosenthal says. And when the researchers tested it to see how long it might take for resistance to develop, the results weren’t as promising as he would like. The parasites figured out a way to become resistant to the compound “relatively easily,” he says. That shouldn’t be “deal-killer,” however. “Its slow onset of action probably means it should be combined with a faster-acting drug,” he says.

BUT IT’S SLOW-ACTING

The compound is going through safety testing now. If everything goes well, it should hit human trials within the next year, Read says. Chances are, it will have to be used in combination with other malaria drugs, Gilbert says. “All anti-malarials are given in combination because it slows down resistance.”

“When you’re treating infectious diseases, you know that drug resistance is always a potential problem, so having a number of choices to treat malaria is a good thing,” Rosenthal says. In this case, the drug’s new mode of action may hold lead to an entirely new weapon against malaria. “Obviously it’s got a long way to go,” Read says. But the compound is “very exciting,” nonetheless.

PATENT
str1 str2 str3 str4
Example 16-Fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide, Example compound 1 in Scheme 2
str1
In a sealed microwave tube, a suspension of 2-chloro-6-fluoro-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide (preparation 4) (2.00 g, 6 mmol), [4-(morpholinomethyl)phenyl]boronic acid, hydrochloride, available from UORSY, (3.20 g, 12 mmol), potassium phosphate (2.63 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.19 mmol) in DMF/Water 3/1 (40 ml) was heated at 130° C. under microwave irradiation for 30 min. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (150 ml) and washed twice with NaHCO3 saturated aqueous solution (2×100 ml). The organic layer was separated, dried over MgSO4 and concentrate to dryness under reduced pressure. The reaction crude was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A, followed by a 30 min ramp to 10% B, and then 15 min hold at 10% B. The fractions containing product were pooled together and concentrated to dryness under vacuum to obtain the desired product as an off-white solid (1 g). The product was dissolved in methanol (100 ml) and 3-mercaptopropyl ethyl sulfide Silica (Phosphonics, SPM-32, 60-200 uM) was added. The suspension was stirred at room temperature over for 2 days and then at 50° C. for 1 h. After cooling to room temperature, the scavenger was filtered off and washed with methanol (30 ml). The solvent was removed under reduced pressure and the product was further purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired product as a white solid (0.6 g, 1.3 mmol, Yield 20%).
1H NMR (500 MHz; CDCl3) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J=5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J=5.4 Hz, J=11.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J=8.2 Hz), 8.21 (dd, 1H, J=5.5 Hz, J=9.2 Hz) ppm. 19F NMR (407.5 MHz; CDCl3) δ−111.47 ppm.
Purity by LCMS (UV Chromatogram, 190-450 nm) 99%, rt=5.7 min, m/z 463 (M+H)+ HRMS (ES+) found 463.2501 [M+H]+, C27H32F1N4O2 requires 463.2504.
Example 26-Fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide; fumaric acid salt, compound (IB) in Scheme 2
str1
The starting free base (example 1) (0.58 g, 1 mmol) was dissolved in dry ethanol (10 ml) and added dropwise to a stirred solution of fumaric acid (0.15 g, 1 mmol) in dry ethanol (9 ml). The mixture was stirred at room temperature for 1 h. The white precipitate was filtered, washed with ethanol (20 ml) and then dissolved in 10 ml of water and freeze dried to obtain the desired salt as a white solid (0.601 g, 1 mmol, Yield 82%).
1H NMR (500 MHz; d6-DMSO) δ 1.83-1.86 (m, 4H), 2.41 (brs, 4H), 2.94 (brs, 4H), 3.03 (t, 2H, J=6.2 Hz), 3.57 (s, 2H), 3.60-3.65 (m, 6H), 6.47 (s, 2H), 7.51 (d, 2H, J=8.25), 7.74-7.78 (m, 1H), 8.06 (dd, 1H, J=2.9 Hz, J=10.4 Hz), 8.17 (dd, 1H, J=5.7 Hz, J=9.3 Hz), 8.24-8.26 (m, 3H), 9.24 (t, 1H, J=5.5 Hz) ppm. 19F NMR (407.5 MHz; d6-DMSO) δ-112.30 ppm.
Purity by LCMS (UV Chromatogram, 190-450 nm) 99%, rt=5.3 min, m/z 463 (M+H)+
Example 1AAlternative synthesis of 6-fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide, Example compound 1A in Scheme 4
str1
To a stirred suspension of 6-fluoro-2-[4-(morpholinomethyl)phenyl]quinoline-4-carboxylic acid (preparation 7) (2.20 g, 6 mmol) in DCM (100 ml) at room temperature, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (1.26 g, 7 mmol) and 4-methylmorpholine (NMO) (1.33 ml, 12 mmol) were added. The reaction mixture was stirred at room temperature for 1 h and then 2-pyrrolidin-1-ylethanamine (0.77 ml, 6 mmol) was added and stirred at room temperature for further 3 h. The reaction mixture was washed with NaHCO3 saturated aqueous solution (2×100 ml) and the organic phase was separated, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was absorbed on silica gel and purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 2 min hold 100% A followed by a 30 min ramp to 10% B and then 15 min hold at 10% B. The desired fractions were concentrated to dryness under vacuum to obtain the crude product as a yellow solid (95% purity by LCMS). The sample was further purified by a second column chromatography using a 40 g silica gel cartridge, eluting with DCM (Solvent A) and 10% NH3-MeOH in DCM (Solvent B) and the following gradient: 2 min hold 100% A, followed by a 10 min ramp to 23% B and then 15 min hold at 23% B. The desired fractions were concentrated to dryness under vacuum to obtain product as a white solid (1 g). Re-crystallisation form acetonitrile (18 ml) yielded the title compound as a white solid (625 mg, 1.24 mmol, 20%).
1H NMR (500 MHz; CDCl3) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J=5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J=5.4 Hz, J=11.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J=8.2 Hz), 8.21 (dd, 1H, J=5.5 Hz, J=9.2 Hz) ppm.
1H NMR (500 MHz; d6-DMSO) δ 1.72-1.75 (m, 4H), 2.41 (brs, 4H), 2.56 (brs, 4H), 2.67 (t, 2H, J=6.6 Hz), 3.49-3.52 (m, 2H), 3.56 (s, 2H), 3.60-3.61 (m, 4H), 7.52 (d, 2H, J=8.3 Hz), 7.73-7.77 (m, 1H), 8.07 (dd, 1H, J=2.9 Hz, J=10.4 Hz), 8.18-8.21 (m, 2H), 8.26 (d, 2H, J=8.3 Hz), 8.85 (t, 1H, J=6.6 Hz) ppm.
13C NMR (125 MHz; d6-DMSO3) δ 23.2, 38.4, 53.2, 53.5, 54.5, 62.1, 66.2, 109.0, 109.1, 117.3, 120.1, 120.3, 124.1, 124.2, 127.1, 129.4, 132.2, 132.3, 136.8, 139.9, 142.8, 145.2, 155.3, 159.0, 161.0, 166.1 ppm.
19F NMR (500 MHz; d6-DMSO) δ-112.47 ppm.
Purity by LCMS (UV Chromatogram, 190-450 nm) 99%, rt=5.0 min, m/z 463 (M+H)+
PATENT
WO 2016033635
Patent
WO 2013153357

SCHEME 1

Figure imgf000018_0001

SCHEME 2

Figure imgf000019_0001

Preparation 4Yield: 54% Preparation 3

Yield: 27%

Figure imgf000019_0002

SCHEME 4 B

Figure imgf000021_0001

Yield: 72% Yield: 70% Preparation 6

Figure imgf000021_0002

Example 1 : 6-Fluoro-2-r4-(morpholinomethyl)phenyll-N-(2-pyrrolidin-1-ylethyl)quinoline- 4-carboxamide, Example compound 1 in Scheme 2

Figure imgf000050_0002

In a sealed microwave tube, a suspension of 2-chloro-6-fluoro-N-(2-pyrrolidin-1- ylethyl)quinoline-4-carboxamide (preparation 4) (2.00 g, 6 mmol), [4- (morpholinomethyl)phenyl]boronic acid, hydrochloride, available from UORSY, (3.20 g, 12 mmol), potassium phosphate (2.63 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.19 mmol) in DMF/Water 3/1 (40 ml) was heated at 130°C under microwave irradiation for 30 min. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (150 ml) and washed twice with NaHC03 saturated aqueous solution (2 x 100 ml). The organic layer was separated, dried over MgS04and concentrate to dryness under reduced pressure. The reaction crude was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A, followed by a 30 min ramp to 10 % B, and then 15 min hold at 10% B. The fractions containing product were pooled together and concentrated to dryness under vacuum to obtain the desired product as an off-white solid (1 g). The product was dissolved in methanol (100 ml) and 3-mercaptopropyl ethyl sulfide Silica (Phosphonics, SPM-32, 60- 200 uM) was added. The suspension was stirred at room temperature over for 2 days and then at 50°C for 1 h. After cooling to room temperature, the scavenger was filtered off and washed with methanol (30 ml). The solvent was removed under reduced pressure and the product was further purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired product as a white solid (0.6 g, 1.3 mmol, Yield 20%).

1 H NMR (500 MHz; CDCI3) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J = 5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J = 5.4 Hz, J = 1 1.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1 H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J = 8.2 Hz), 8.21 (dd, 1 H, J = 5.5 Hz, J = 9.2 Hz) ppm . 19 F NMR (407.5 MHz; CDCI3) δ -11 1.47 ppm. Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.7 min, m/z 463 (M+H)+ HRMS (ES+) found 463.2501 [M+H]+, C27H32F1 N402 requires 463.2504.

Example 2: 6-Fluoro-2-[4-(morpholinomethyl)phenyl1-N-(2-pyrrolidin-1-ylethyl)quinoline- 4-carboxamide; fumaric acid salt, compound (IB) in Scheme 2

Figure imgf000051_0001

The starting free base (example 1) (0.58 g, 1 mmol) was dissolved in dry ethanol (10 ml) and added dropwise to a stirred solution of fumaric acid (0.15 g, 1 mmol) in dry ethanol (9 ml). The mixture was stirred at room temperature for 1 h. The white precipitate was filtered, washed with ethanol (20 ml) and then dissolved in 10 ml of water and freeze dried to obtain the desired salt as a white solid (0.601 g, 1 mmol, Yield 82%).

1 H NMR (500 MHz; d6-DMSO) δ 1.83-1.86 (m, 4H), 2.41 (brs, 4H), 2.94 (brs, 4H), 3.03 (t, 2H, J = 6.2 Hz), 3.57 (s, 2H), 3.60-3.65 (m, 6H), 6.47 (s, 2H), 7.51 (d, 2H, J = 8.25), 7.74-7.78 (m, 1 H), 8.06 (dd, 1 H, J = 2.9 Hz, J = 10.4 Hz), 8.17 (dd, 1 H, J = 5.7 Hz, J = 9.3 Hz), 8.24-8.26 (m, 3H), 9.24 (t, 1 H, J = 5.5 Hz) ppm. 19 F NMR (407.5 MHz; d6- DMSO) δ -112.30 ppm.

Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.3 min, m/z 463 (M+H)+

Example 1A: Alternative synthesis of 6-fluoro-2-[4-(morpholinomethyl)phenyl1-N-(2- pyrrolidin-1-ylethyl)quinoline-4-carboxamide, Example compound 1A in Scheme 4

Figure imgf000052_0001

To a stirred suspension of 6-fluoro-2-[4-(morpholinomethyl)phenyl]quinoline-4-carboxylic acid (preparation 7) (2.20 g, 6 mmol) in DCM (100 ml) at room temperature, 2-chloro- 4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.26 g, 7 mmol) and 4-methylmorpholine (NMO) (1.33 ml, 12 mmol) were added. The reaction mixture was stirred at room temperature for 1 h and then 2-pyrrolidin-1-ylethanamine (0.77 ml, 6 mmol) was added and stirred at room temperature for further 3 h. The reaction mixture was washed with NaHC03 saturated aqueous solution (2x 100 ml) and the organic phase was separated, dried over MgS04 and concentrated under reduced pressure. The resulting residue was absorbed on silica gel and purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 2 min hold 100% A followed by a 30 min ramp to 10 %B and then 15 min hold at 10%B. The desired fractions were concentrated to dryness under vacuum to obtain the crude product as a yellow solid (95% purity by LCMS). The sample was further purified by a second column chromatography using a 40 g silica gel cartridge, eluting with DCM (Solvent A) and 10% NH3-MeOH in DCM (Solvent B) and the following gradient: 2 min hold 100% A, followed by a 10 min ramp to 23 % B and then 15 min hold at 23% B. The desired fractions were concentrated to dryness under vacuum to obtain product as a white solid (1 g). Re-crystallisation form acetonitrile (18 ml) yielded the title compound as a white solid (625 mg, 1.24 mmol, 20%).

1 H NMR (500 MHz; CDCI3) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J = 5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J = 5.4 Hz, J = 1 1.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1 H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J = 8.2 Hz), 8.21 (dd, 1 H, J = 5.5 Hz, J = 9.2 Hz) ppm .

1 H NMR (500 MHz; d6-DMSO) δ 1.72-1.75 (m, 4H), 2.41 (brs, 4H), 2.56 (brs, 4H), 2.67 (t, 2H, J = 6.6 Hz), 3.49-3.52 (m, 2H), 3.56 (s, 2H), 3.60-3.61 (m, 4H), 7.52 (d, 2H, J = 8.3 Hz), 7.73-7.77 (m, 1 H), 8.07 (dd, 1 H, J = 2.9 Hz, J = 10.4 Hz), 8.18-8.21 (m, 2H), 8.26 (d, 2H , J = 8.3 Hz), 8.85 (t, 1 H, J = 6.6 Hz) ppm.

13C NMR (125 MHz; d6-DMS03) 5 23.2, 38.4, 53.2, 53.5, 54.5, 62.1 , 66.2, 109.0, 109.1 , 1 17.3, 120.1 , 120.3, 124.1 , 124.2, 127.1 , 129.4, 132.2, 132.3, 136.8, 139.9, 142.8, 145.2, 155.3, 159.0, 161 .0, 166.1 ppm.

19 F NM R (500 MHz; d6-DMSO) δ -1 12.47 ppm.

Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.0 min, m/z 463 (M+H)+

PAPER
A Quinoline Carboxamide Antimalarial Drug Candidate Uniquely Targets Plasmodia at Three Stages of the Parasite Life Cycle
Angewandte Chemie, International Edition (2015), 54, (46), 13504-13506
original image

Putting a stop to malaria: Phenotypic screening against malaria parasites, hit identification, and efficient lead optimization have delivered the preclinical candidate antimalarial DDD107498. This molecule is distinctive in that it has potential for use as a single-dose cure for malaria and shows a unique broad spectrum of activity against the liver, blood, and mosquito stages of the parasite life cycle.

 Prof. P. M. O’Neill Department of Chemistry, University of Liverpool Liverpool, L69 7ZD (UK) E-mail: pmoneill@liverpool.ac.uk Prof. S. A. Ward Liverpool School of Tropical Medicine, Pembroke Place Liverpool, L3 5QA (UK)
 str1

Professor Ian Gilbert FRSC

Design and synthesis of potential therapeutic agents
Position:
Professor of Medicinal Chemistry and Head of the Division of Biological Chemistry and Drug Discovery
Address:
College of Life Sciences, University of Dundee, Dundee
Full Telephone:
+44 (0) 1382 386240, int ext 86240

Dr Neil Norcross

Position:
Medicinal Chemist
Address:
College of Life Sciences, University of Dundee, Dundee
Full Telephone:
(0) , int ext
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La investigadora asturiana Beatriz Baragaña, en La Pola. / PABLO NOSTI
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Achim Porzelle

REFERENCES

///////////DDD107498, DDD 107498, PRECLINICAL, DUNDEE, MALARIA, DDD 498, Achim Porzelle, Ian Gilbert, MERCK SERENO, Beatriz Baragaña, Medicines for Malaria Venture,  University of Dundee, Neil Norcross, 1469439-69-7, 1469439-71-1 , SUCCINATE

Fc1ccc2nc(cc(c2c1)C(=O)NCCN1CCCC1)-c1ccc(cc1)CN1CCOCC1

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Abstract Image

The transamination-chemistry-based process for sitagliptin is a through-process, which challenges the crystallization of the active pharmaceutical ingredient (API) in a batch stream composed of multiple components. Risk-assessment-based design of experiment (DoE) studies of particle size distribution (PSD) and crystallization showed that the final API PSD strongly depends on the seeding-point temperature, which in turn relies on the solution composition.

To determine the solution composition, near-infrared (NIR) methods had been developed with partial least squares (PLS) regression on spectra of simulated process samples whose compositions were made by spiking each pure component, either sitagliptin free base (FB), water, isopropyl alcohol (IPA), dimethyl sulfoxide (DMSO), or isopropyl acetate (IPAc), into the process stream according to a DoE. An additional update to the PLS models was made by incorporating the matrix difference between simulated samples in lab and factory batches.

Overall, at temperatures of 20–35 °C, the NIR models provided a standard error of prediction (SEP) of less than 0.23 wt % for FB in 10.56–32.91 wt %, 0.22 wt % for DMSO in 3.77–19.18 wt %, 0.32 wt % for IPAc in 0.00–5.70 wt %, and 0.23 wt % for water in 11.20–28.58 wt %. After passing the performance qualification, these on-line NIR methods were successfully established and applied for the on-line analysis of production batches for compositions prior to the seeding point of sitagliptin crystallization.

 

 

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Application of On-Line NIR for Process Control during the Manufacture of Sitagliptin

Global Science, Technology and Commercialization, Merck Sharp & Dohme Corporation P.O. Box 2000, Rahway, New Jersey 07065, United States
Org. Process Res. Dev., 2016, 20 (3), pp 653–660
DOI: 10.1021/acs.oprd.5b00409

////////On-Line NIR,  Process Control, Sitagliptin

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Nina Sharma
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M Pharm, PhD ( IIT, BHU)PGDMM ( UK)

Recruitment Services –  Standard terms

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Managing Director

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Advanced Diploma in HR Management   (ABE UK) 2008

Advanced Diploma in Business Management (ABE, UK) 2009

(Top Paper Prize Global Award for two papers)

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FORMULATIONS EXPERT

Experienced in top level R&D Operations of Formulation Development, Global Portfolio and ­Resource management with successful  projects completion and Formulation launches   in   various therapeutic categories, for OTC, ANDA and 505(b) (2), NCE and Biosimilars in reputed organizations with repeated track record of achievement

High level Formulation Development skill for LVP.SVP.Tablets, Capsules,Dry Syrup,Liquids, Semisolids for domestic and International markets, QA and Regulatory for USFDA , MCA and semi-regulated markets

Formulation development ,Technology transfer and Production operations ,Quality and compliance expert with track record of successful new products launches  , portfolio expansion, Claims substantiation and Regulatory support, Tech transfer and supply chain transition management ,Project and team leadership to drive successful product launches within time and budget.

In  recent   roles  as Senior Director with Johnson and Johnson ( J&J )  have led  10 million USD  Formulation R &D project  for Early developmentand Late Development ANDA ,manufacturing of clinical supplies  for advanced market  and Integrated drug product development for Emerging markets of China ,Korea, Taiwan and Mexico; Director Technical and Scientific Affairs with Teva Pharma  Assignments with Novartis Healthcare Private Limited as R & D Head India – Global Research & Development Lab for OTC and Pfizer as Director (Head) for Formulation development Global R&D Center for Vet Medicine   were successful   projects in leadership position of Formulation R&D. Expertise in FMCG Sector as Head of Oral care Technology in India Global Formulation R&D Center, Procter and Gamble as R&D Manager Healthcare and Generics in Ranbaxy, Lupin and Searle.

Have published twenty research publications including four in international journals, US andEuropeanPatent holder across the illustrious career path.

Distinction of launching new products in conventional dosage forms, solids, liquids, sterile and semisolids and New Drug delivery systems covering full span of therapeutic area for infectious, psychiatry, cardiology, virology and biotechnology, pain and HIV, well versed with NDDS and Containment strategies.

An effective communicator   with excellent people management/ training skills and strong analytical, problem solving & organizational abilities   with proven track record of efficiently working with global partners.

 

CAREER HIGHLIGHTS

July 2015 to Present: Managing Director Shamisha Resources Management, Ahmedabad and Mumbai

WEBSITE……http://www.shamisha.in/

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Sept 2013 to July 2015– Director Technical Services and Production operation for   Teva Pharma ( Procter &Gamble Teva Joint Venture PGT Healthcare )  , leading a team of 18 Managers /supervisors and Production staff of about 430 by end of 2014, handling commercialization of green field project of 600 crores.

Jan 2012 onwards Gresen Lehmann Group (GLG Singapore) consultant –successfully completed consultancy for Mckinsey, BCG on Pharmaceutical Development

July 2011 to Sep 2011 Senior VP Avesthagen Limited

July 2010 to July 2011 Senior Director Pharmaceutical Development and July 2008 to Feb   2010 Global Formulation   R&D Center at Johnson and Johnson

The responsibilities included set up and start up of Pharmaceutical development organization for Chem Pharm , Global NCE  Pre formulation and Late development for EU and US  and support emerging markets of India , China , Brazil , Mexico .

Asia Drug product development strategy and capability calculations for three Sites, project allocation and transition plan, global SOP, s and processes.

Creating   Road Map of Pharmaceutical Development till 2012 and integration

Since Sept 2005 Jan 2008 Novartis Healthcare Private Limited as Formulation R&D Head India – Global OTC Research &Development

Notable Deliverables

  • Led the effort in setting up the India Lab from Start up to operational build the team through recruitment and training
  • Head count increased to 47, established functions like Product development , Analytical, QA , Regulatory-CMC, Documentation ,CSV , I T   Clinical operations , Facility Management , EHS ,Purchase and administration
  • The Stability centre having 18 chambers can cater to all the four zones including Brazil.
  • Use of LIMS, Empower, SAS and fully validated 21 CFR compliant systems.
  • Product design and submissions for ANDA in advanced market domain.
  • Clinical operations (Phase III) through CRO (Siro, Lotus, and Reliance Life Sciences) in the area of Generic OTC molecules for advanced market. Studies executed by  Protocol preparation , approval ,quality audits and effective relation management , periodic reporting to global Clinical operations at Nyon ( Switzerland )
  • Played a key role in introducing Standard procedures (283 new) to make India Lab compliant with Global Quality operations standard and obtained USFDA Registration   for the Site. The standards introduced by India Site are adopted by two other global sites. Data generation as per USFDA , EMEA , ANVISA and MCA
  • Efficiently led the Information Security and Safety Audits with successful outcome.
  • Distinction of leading the Group Quality Audit which is a tough internal standard to meet and India is the only compliant Lab so far.
  • Planning and control of Revenue and Capital budget for India Site

 

HOLDS THE MERIT OF

  • US FDA Registration ,Twenty eight Pharmaceutical development and Stability testing projects in the area  Conventional Solids , Liquids semi solids and NDDS , Patches
  • Clinical operations, Technical writing, CMC Head count expansions within short time of lab operations.

Instrumental in collaborating with other Global Sites and local management to drive superior results.

  • Conducted successful studies on major global brands like Excedrin, Vibrocil, Theraflu, and Buckleys & Benefiber and applied the Project Management tools, innovative research based on market feedback. Milestones on delivery of Projects completed on time. Global project teams technical resource on global brands like Benefiber, Theraflu
  • Established a successful R&D Centre with high productivity and GMP within short time.

Apr 2004- August 20 05           Pfizer India Limited as Director

  • Planning and budgeting  for new research center in Formulations and API , won 9 million dollar investment (first ever for the Thane Site )
  • Awarded four NCE Enhancement projects in Liquids and solids from Sandwich through bidding process for US and Europe market.
  • Formed the core team of R&D Scientists and Managers
  • Conducted early development studies for NCE molecules, coordinated pharmacokinetic studies on anthelmentics, Doramectin pour on, Selamectin with Praziquantel spot on formulations.
  • Technical liaison with Indian Regulatory Authorities for fast approvals of import of API and formulations.
  • Led the effort in establishing the Organization and formulating plans for expansion
  • Pivotal in establishing linkages across Pfizer, organization processes for reporting and communication, Project management and control systems, and people development.

 Feb1999-March 2004        Colgate Palmolive India Ltd., General Manager-Oral Care

 Notable Deliverables

  • Technical business support for driving growth in India, Pakistan, Africa and Middle East through new products launches in Oral care technology
  • Managed and coordinated largest Anti caries Clinical trials on Oral formulation with Triclosan and Fluoride conducted in India on 6000 children over a period of 24 months through Dentists
  • Managed and coordinated Multicentre Clinical trials on Whitening Oral care formulations conducted in India for Indian and Australian market
  • Managed and coordinated Clinical trials on formulations with different polishing agents
  • Managed and coordinated Clinical trials on Toothpowder and toothbrushes
  • Effective coordination with Global Research centre for Protocol preparation, approval, servicing of sample, reporting to Global
  • Efficiently liasioned with Government bodies for strategic partnership on future specifications for RM and Finished products pertaining to Oral care.
  • Led the effort to design, develop and Re launch major flagship brands Colgate Dental cream five times, Colgate toothpowder three times and Fresh Energy Gel two variants re-launched three times each to claim back the lost market shares (approximately 900 crores business). Regained the lost market share by nine point
  • Launching of Low cost formula with Cibaca brand name which resulted in increase in 7% Market share, formulation developed indigenously
  • Entry to medium price segment by launching Colgate Herbal
  • Led the efforts in the development of several innovative forms of Oral care including stripe formulations, innovative affordable oral care formulation.
  • Initiated several cost saving projects and implemented margin improvement programs on formulations.
  • Successfully obtained Ayurvedic classification to support pain claim for Herbal dentifrice due for launch.
  • Conducted several training programs for management team of manufacturing locations on Quality as certified trainer.
  • Spearheaded functions for entry into Low and medium price segments retaining the Colgate Global standards, to compete in emerging markets dominated by local players.
  • Herbal segment through launch of Herbal toothpaste
  • Pivotal in designing Consumer qualified products to enter new market segment
  • Efficiently executed Quality improvement programs for raw material across six manufacturing locations in India and Nepal
  • Margin improvement programs on all the major brands like Colgate Dental cream, toothpowder and Gel formulations thereby resulting in huge savings viz. common base Technology for to drive margins, new crystal structure development for Calcium carbonate, process improved for Triclosan manufacture, introduction of liquid form of Sodium lauryl sulphate, powder form of Sodium silicate, use of Natural calcium carbonate in liquid dentifrice
  • Developed self-preservation technique for liquid dentifrice named as Gold standard by Piscataway Research center
  • Merit of introducing Quality standards and Guidelines in India Technology center
  • Participated in designing new plant for toothpaste manufacture
  • Designing Specifications for Bureau of Indian Standards for Toothpaste, toothpowder, Sorbitol and Calcium carbonate
  • Filed one patent on Coated Natural Calcium Carbonate Oral Care Toothpowder Composition
  • Distinction of being committee member on three BIS Committees for PCD 19 for 4 years
  • Received Colgate YCMAD Award for innovation four times
  • Nominated  team members and direct subordinates to win the award 19 times.

Sept ’1997-Jan1999   Searle India Ltd., Senior Manager (Pharmaceutical Development)

Notable Deliverables

·Instrumental in developing, reformulating & launching 12 products within fourteen months. Pivotal in developing

  • New products in area of conventional and specialized delivery system in therapeutic segment of cardiovascular, anti diabetic, gastrointestinal, anti-infective, neurological and biotechnology products.
  • Dosage forms like tablets, capsules, chewable, sustained release, dry syrups, liquid orals, suspensions using resin technology and injectables.
  • Played a key role in setting up a new department for international regulatory submissions, dossiers submitted for twenty molecules to contribute to export business.

July 1994 – Aug 1997   Lupin Laboratories Ltd as Senior Manager (Development)

Notable Deliverables

  • Led the effort in launching New Products Division ,  by developing & launching 8 new Herbal products through a new division of ethically promoted Natural products with 50 Sales personnel
  • Limited Phase III Clinicals for Anxiolytic and Appetite Stimulant formulation managed and coordinated through Clininvent
  • Periodontical Clinicals conducted and managed in Governmental dental College Mumbai
  • Claim support Clinicals on Ayurvedic Uterine tonic (U-Sedate) conducted at KEM Hospital Mumbai and Pune
  • Launched products like natural appetite stimulant, oral care, arthritis, rejuvenation, laxatives and digestive
  • Developed personal care products for export market, shampoos, hair oils, oral rinses, anti ageing cream all herbal/natural in nature
  • Successfully introduced bulk actives for exports, filed international patent on novel process for extraction of Hydroxyl Citric Acid from Garcinia.

 

Dec1991-June 1994 Ranbaxy Laboratories Ltd., as Product Development Manager

Notable Deliverables

  • Successfully developed and launched several conventional and specialty dosage forms as tablets, liquid oral, injectables, creams and led the team of product development scientists for India, Semi regulated markets of CIS , Indonesia , Malyasia and also Europe.
  • Managed and coordinated several BA/BE Studies for anti-infective in Ranbaxy and also Therapeutic Drug Monitoring Lab Mumbai.
  • Pivotal in supporting export market through regulatory submissions, product development and launch in the designated countries.
  • Significantly contributed in documentation for MCA approval.

March 1985-Nov 1991, Procter & Gamble India Ltd., as Research and Development Manager

  • Efficiently developed and launched indigenously developed Herbal products in OTC Category in

candy and syrup base

  • Actively participated in Clinical trials for OTC products (cough syrup)
  • Joining position Research Executive, promoted to Asstt. Manager, further promoted to Manager

Aug 80 -Dec ’84       Indian Institute of Technology, Benares Hindu University as Lecturer

Nov ’78-July ’80       Hamdard College of Pharmacy, University of Delhi as Lecturer

Academic Distinctions

Received Best Girl Student award in High School, University

Merit scholarship National Scholarship CSIR Scholarship –not availed

Memberships : Beureu of Indian Standards 2000-2004, IPA Life Member, CIM Member

Contact details  nina1sharma@gmail.com, 9820733290,9974672915,07940321865,02225797954

Address

Shamisha Resource Management  331-332 Sobo Centre South Bopal Ahmedabad

Ahmedabad  A92 Shaligram 3 Prahladnagar Ahmedabad

Mumbai  1104, Sovereign Hiranandani Gardens Powai Mumbai 400076

////////////Shamisha Resource Managment, Experts in Recruitment, Pharmaceutical ,  FMCG Consulting, NINA SHARMA

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Sep 092016
 

Image result for ECA's Visual Inspection Group

The ECA’s Visual Inspection Group has developed a new document with answers to frequently asked questions. This new Q&A document is now available for download on the Group’s website. Read more about frequently asked questions in the visual inspection.

http://www.gmp-compliance.org/enews_05500_New-Q-A-Document-on-the-Visual-Inspection-of-Parenterals-available_15266,15265,15221,15662,Z-PEM_n.html

The Visual Inspection Group, an Interest Group of the ECA Foundation, has developed a new document with frequently asked questions. The new Q&A document, which was compiled by the Group’s Board, is now available for a free of charge download on the website.

For compiling the document the members of the Group were asked to provide their questions in February. These questions were then evaluated and answered by the Board Members.

The new document is structured as follows:

  • Manual Inspection
  • Automated Inspection
  • Qualification / Validation
  • Test sets
  • Re-Qualification
  • AQL-Tests
  • Defect Categorisation
  • Specific Products
  • Regulatory Affairs
  • Process Control / SPC

Some examples for the questions and the respective answers:

The grey portion of fully automatic control is often checked manually, to return not clearly or fully tested products back to the inspection process. Is it allowed to carry out this testing with the automated inspection machine? From a GMP view, there are no restrictions. It is also important here that at the end a yield calculation and evaluation in the batch record appears. And there are also automated inspection systems that have already integrated the double inspection with multiple cameras.
In highly automated manufacturing lines for LVP flexible containers, the visual inspection process may/cannot comply to the standard visual inspection criteria e.g.: 5 sec inspection time, agitation of the container etc. Is this a compliance problem? The requirements like 5 sec inspection time required by pharmacopoeias are addressing manually performed visual inspection. If the visual inspection is performed automatically, it is the company’s responsibility to ensure that the inspection via camera systems is as effective as a manual visual inspection via a validation (e.g. Knapp Test).

 

Should the AQL be inspected by QC or production AQL manual inspection may be carried out by production staff (to avoid setting up a separate visual inspection team in QC) under a quality oversight or the quality unit. If performed by production operators, the AQL test should not be done by members of the team that was performing the 100 % visual inspection of the batch.

 

The new Q&A document is available for members in the members’ area on the Visual Inspection Group website free of charge. Membership in the Group is also free of charge and merely requires a registration.

The Good Practice Guide “Visual Inspection of medicinal products for parenteral use”, was also revised. The new Version 3.0 will be introduced at the ECA Conference Particles in Parenterals in Barcelona, Spain, from 28-29 September 2016. All delegates of the conference will receive a free copy.

///////// ECA,  Visual Inspection Group, parenteral use, Particles in Parenterals

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Sep 092016
 

The FDA has set the focus of its inspections on data integrity for quite some time already. The most recent Warning Letter addressed to a Chinese API manufacturer dated August 2016 clearly concentrates on the topic data integrity. Please find out more about the current FDA Warning Letter in this News.

http://www.gmp-compliance.org/enews_05557_New-Warning-Letter-of-the-FDA-with-the-Focus-on-%22Data-Integrity%22_15488,15844,Z-QCM_n.html

Again, the focus of FDA’s Warning Letter for the Chinese API manufacturer Zhejiang Medicine Co. Ltd. dated 4th August 2016 is on the lack of data integrity. Among other things, records of activities were made not at the time when they have been performed. Moreover, original data have been deleted. A number of alarming findings were discovered in the course of the FDA inspection in June 2015.

The FDA is now expecting concrete measures (“Data Integrity Remediation”) from the company. For this, the FDA expressly recommended to retain qualified, external consultants. Among the measures to be taken:

A – A comprehensive investigation of the extent of incorrect data
1. An extensive plan for the execution of the investigation
2. Interviews of current and former employees to clarify the root cause of incorrect data
3. An assessment of the extent of data integrity deficits.
4. A comprehensive retrospective assessment of the performance of analytical testing.

B – A current risk assessment of the possible effects of the deficiencies identified on the quality of the medicinal products, up to the risk to patients!

C – A management strategy for the implementation of CAPA plans.

All in all, there were great concerns about the authenticity and reliability of the data produced in that company.

To find out more access the complete Warning Letter for Zhejiang Medicine Co. Ltd.

Image result for Zhejiang Medicine Co. Ltd,

//////////Zhejiang Medicine Co. Ltd, Warning Letter,  FDA, Data Integrity

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