DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR earlier GLENMARK LS Research centre as consultant,Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, [email protected]

FDA approves new diagnostic imaging agent FLUCICLOVINE F-18 to detect recurrent prostate cancer

FDA 2016, Uncategorized Comments Off

May 282016

FLUCICLOVINE F-18

Cyclobutanecarboxylic acid, 1-amino-3-(fluoro-¹⁸F)-, trans- [

Molecular FormulaC₅H₈¹⁸FNO₂
Average mass132.124 Da

Axumin (fluciclovine F 18)

fluciclovinum (¹⁸F)

GE-148

NMK36

trans-1-Amino-3-(¹⁸F)fluorcyclobutancarbonsäure [German] [ACD/IUPAC Name]

trans-1-Amino-3-(¹⁸F)fluorocyclobutanecarboxylic acid [ACD/IUPAC Name]

UNII-38R1Q0L1ZE

anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid

cas 222727-39-1

FDA approves new diagnostic imaging agent to detect recurrent prostate cancer

05/27/2016 11:27 AM EDT

The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.

May 27, 2016

Release

Prostate cancer is the second leading cause of death from cancer in U.S. men. In patients with suspected cancer recurrence after primary treatment, accurate staging is an important objective in improving management and outcomes.

“Imaging tests are not able to determine the location of the recurrent prostate cancer when the PSA is at very low levels,” said Libero Marzella, M.D., Ph.D., director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research. “Axumin is shown to provide another accurate imaging approach for these patients.”

Two studies evaluated the safety and efficacy of Axumin for imaging prostate cancer in patients with recurrent disease. The first compared 105 Axumin scans in men with suspected recurrence of prostate cancer to the histopathology (the study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. Radiologists onsite read the scans initially; subsequently, three independent radiologists read the same scans in a blinded study.

The second study evaluated the agreement between 96 Axumin and C11 choline (an approved PET scan imaging test) scans in patients with median PSA values of 1.44 ng/mL. Radiologists on-site read the scans, and the same three independent radiologists who read the scans in the first study read the Axumin scans in this second blinded study. The results of the independent scan readings were generally consistent with one another, and confirmed the results of the onsite scan readings. Both studies supported the safety and efficacy of Axumin for imaging prostate cancer in men with elevated PSA levels following prior treatment.

Axumin is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure to patients and healthcare providers during administration. Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended.

The most commonly reported adverse reactions in patients are injection site pain, redness, and a metallic taste in the mouth.

Axumin is marketed by Blue Earth Diagnostics, Ltd., Oxford, United Kingdom

Patent

http://www.google.com/patents/WO2014023775A1?cl=en

The non-natural amino acid [ F]-l-amino-3-fluorocyclobutane-l-carboxylic acid

([¹⁸F]-FACBC, also known as [¹⁸F]-Fluciclovine) is taken up specifically by amino acid transporters and has shown promise for tumour imaging with positron emission tomography (PET).

A known synthesis of [¹⁸F]-FACBC begins with the provision of the protected precursor compound 1 -(N-(t-butoxycarbonyl)amino)-3 –

[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-l-carboxylic acid ethyl ester. This precursor compound is first labelled with [¹⁸F]-fluoride:

II before removal of the two protecting groups:

IT III

EP2017258 (Al) teaches removal of the ethyl protecting group by trapping the [¹⁸F]- labelled precursor compound (II) onto a solid phase extraction (SPE) cartridge and incubating with 0.8 mL of a 4 mol/L solution of sodium hydroxide (NaOH). After 3 minutes incubation the NaOH solution was collected in a vial and a further 0.8 mL 4 mol/L NaOH added to the SPE cartridge to repeat the procedure. Thereafter the SPE cartridge was washed with 3 mL water and the wash solution combined with the collected NaOH solution. Then 2.2 mL of 6 mol/L HCl was then added with heating to 60°C for 5 minutes to remove the Boc protecting group. The resulting solution was purified by passing through (i) an ion retardation column to remove Na⁺ from excess NaOH and Cl^~ from extra HCl needed to neutralise excess of NaOH to get a highly acidic solution before the acidic hydrolysis step, (ii) an alumina column, and (iii) a reverse-phase column. There is scope for the deprotection step(s) and/or the

purification step in the production of [¹⁸F]-FACBC to be simplified.

Example 1: Synthesis of f FIFACBC

No-carrier- added [¹⁸F]fluoride was produced via the ¹⁸0(p,n)¹⁸F nuclear reaction on a GE PETtrace 6 cyclotron (Norwegian Cyclotron Centre, Oslo). Irradiations were performed using a dual-beam, 30μΑ current on two equal Ag targets with HAVAR foils using 16.5 MeV protons. Each target contained 1.6 ml of > 96% [¹⁸0]water (Marshall Isotopes). Subsequent to irradiation and delivery to a hotcell, each target was washed with 1.6 ml of [¹⁶0]water (Merck, water for GR analysis), giving approximately 2-5 Gbq in 3.2 ml of [¹⁶0]water. All radiochemistry was performed on a commercially available GE FASTlab™ with single-use cassettes. Each cassette is built around a one-piece-moulded manifold with 25 three-way stopcocks, all made of polypropylene. Briefly, the cassette includes a 5 ml reactor (cyclic olefin copolymer), one 1 ml syringe and two 5 ml syringes, spikes for connection with five prefilled vials, one water bag (100 ml) as well as various SPE cartridges and filters. Fluid paths are controlled with nitrogen purging, vacuum and the three syringes. The fully automated system is designed for single-step fluorinations with cyclotron-produced [¹⁸F]fluoride. The FASTlab was programmed by the software package in a step-by-step time-dependent sequence of events such as moving the syringes, nitrogen purging, vacuum, and temperature regulation. Synthesis of

[¹⁸F]FACBC followed the three general steps: (a) [¹⁸F]fluorination, (b) hydrolysis of protection groups and (c) SPE purification.

Vial A contained K₂₂₂ (58.8 mg, 156 μπιοΐ), K₂C0₃ (8.1 mg, 60.8 μπιοΐ) in 79.5% (v/v)

MeCN(a_q) (1105 μΐ). Vial B contained 4M HC1 (2.0 ml). Vial C contained MeCN

(4.1ml). Vial D contained the precursor (48.4 mg, 123.5 μιηοΐ) in its dry form (stored at -20 °C until cassette assembly). Vial E contained 2 M NaOH (4.1 ml). The 30 ml product collection glass vial was filled with 200 mM trisodium citrate (10 ml). Aqueous

[¹⁸F]fluoride (1-1.5 ml, 100-200 Mbq) was passed through the QMA and into the ¹⁸0-

H₂0 recovery vial. The QMA was then flushed with MeCN and sent to waste. The trapped [¹⁸F]fluoride was eluted into the reactor using eluent from vial A (730 μΐ) and then concentrated to dryness by azeotropic distillation with acetonitrile (80 μΐ, vial C). Approximately 1.7 ml of MeCN was mixed with precursor in vial D from which 1.0 ml of the dissolved precursor (corresponds to 28.5 mg, 72.7 mmol precursor) was added to the reactor and heated for 3 min at 85°C. The reaction mixture was diluted with water and sent through the tC18 cartridge. Reactor was washed with water and sent through the tC18 cartridge. The labelled intermediate, fixed on the tC18 cartridge was washed with water, and then incubated with 2M NaOH (2.0 ml) for 5 min after which the 2M NaOH was sent to waste. The labelled intermediate (without the ester group) was then eluted off the tC18 cartridge into the reactor using water. The BOC group was hydrolysed by adding 4M HC1 (1.4 ml) and heating the reactor for 5 min at 60 °C. The reactor content with the crude [¹⁸F]FACBC was sent through the HLB and Alumina cartridges and into the 30 ml product vial. The HLB and Alumina cartridges were washed with water (9.1 ml total) and collected in the product vial. Finally, 2M NaOH (0.9 ml) and water (2.1 ml) was added to the product vial, giving a purified formulation of [¹⁸F]FACBC with a total volume of 26 ml. Radiochemical purity was measured by radio-TLC using a mixture of MeCN:MeOH:H₂0:CH₃COOH (20:5:5: 1) as the mobile phase. The radiochemical yield (RCY) was expressed as the amount of radioactivity in the [¹⁸F]FACBC fraction divided by the total used [¹⁸F]fluoride activity (decay corrected). Total synthesis time was 43 min.

The RCY of [¹⁸F]FACBC was 62.5% ± 1.93 (SD), n=4.

/////FDA, diagnostic imaging agent, recurrent prostate cancer, fda 2016, Axumin, marketed, Blue Earth Diagnostics, Ltd., Oxford, United Kingdom, fluciclovine F 18

C1[C@@](C[C@H]1[18F])(N)C(=O)O

Flow approach towards AZD 6906

flow synthesis, PROCESS Comments Off

May 272016

Scheme 1: Flow approach towards AZD6906 (65).

PIC CREDIT, The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry, Marcus Baumann and Ian R. Baxendale, Beilstein J. Org. Chem. 2015, 11, 1194–1219.,doi:10.3762/bjoc.11.134

In 2012 researchers from AstraZeneca (Sweden) reported upon a scale-up campaign for their gastroesophageal reflux inhibitor programme. Specifically, flow chemical synthesis was used to efficiently and reliably provide sufficient quantities of the target compound AZD6906 (65), which had been prepared previously in batch. From these earlier batch studies concerns had been raised regarding exothermic reaction profiles as well as product instability which needed to be addressed when moving to larger scale synthesis. Flow was identified as a potential way of circumventing these specific problems and so was extensively investigated. The developed flow route [1 ] started with the reaction of methyl dichlorophosphine (66) and triethyl orthoacetate (67), which in batch could only be performed under careful addition of the reagent and external cooling using dry ice/acetone. Pleasingly, a simple flow setup in which the two streams of neat reagents were mixed in a PTFE T-piece maintained at 25 °C was found effective in order to prepare the desired adduct 68 in high yield and quality showcasing the benefits of superior heat dissipation whilst also safely handling the toxic and pyrophoric methyl dichlorophosphine reagent (Scheme 1).

As the subsequent Claisen condensation step was also known to generate a considerable exotherm, a similar flow setup was used in order to allow the reaction heat to dissipate. The superiority of the heat transfer process even allowed this step to be performed on kilogram quantities of both starting materials (68, 69) at a reactor temperature of 35 °C giving the desired product 72 within a residence time of only 90 seconds. Vital to the successful outcome was the efficient in situ generation of LDA from n-BuLi and diisopropylamine as well as the rapid quenching of the reaction mixture prior to collection of the crude product. Furthermore, flow processing allowed for the reaction of both substrates in a 1:1 ratio (rather than 2:1 as was required in batch) as the immediate quenching step prevented side reactions taking place under the strongly basic conditions. Having succeeded in safely preparing compound 72 on kilogram scale, the target compound 65 was then generated by global deprotection and subsequent recrystallisation where batch was reverted to as the conditions had been previously devised and worked well.

Marcus

Dr Marcus Baumann
Postdoc

Marcus Baumann studied chemistry at the Philipps-University Marburg/Germany, from where he graduated in 2007. His studies involved a 6 month period as an Erasmus student at the Innovative Technology Centre at the University of Cambridge, UK (with Prof. Steven V. Ley and Dr Ian R. Baxendale), where he developed a new flow-based oxazole synthesis. He soon returned to Cambridge to pursue his doctoral studies with Prof. Steven V. Ley where he developed flow processes for Curtius rearrangements, different fluorination reactions as well as important heterocycle syntheses. Upon completion of his PhD in 2010 Marcus was awarded a Feodor Lynen Postdoctoral Fellowship (Alexander von Humboldt Foundation, Germany) allowing him to join the group of Prof. Larry E. Overman at UC Irvine, USA (2011-2013). During his time in California his research focused on the synthesis of naturally occurring terpenes as well as analogues of ETP-alkaloids. The latter project generated potent and selective histone methyltransferase inhibitors and opened routes towards new probes for epigenetic diseases which are currently under further investigation. In early 2013 Marcus returned to the UK and took up a postdoctoral position with Prof. Ian R. Baxendale at the University of Durham, where his interests concentrate on the development of flow and batch based strategies towards valuable compounds en route for regenerative medicines.

Prof. Ian R. Baxendale

Personal web page

Professor in the Department of Chemistry

Telephone: +44 (0) 191 33 42185

Member in the Centre for Sustainable Chemical Processes

(email at [email protected])

Research Interests

My general areas of interest are: Organic synthesis (natural products, heterocyclic and medicinal chemistry), Organometallic chemistry, Catalyst design and application, Meso flow chemistry, Microfluidics, Microwave assisted synthesis, Solid supported reagents and scavengers, and facilitated reaction optimisation using Robotics and Automation.

My primary research direction is the synthesis of biologically potent molecules which encompasses the design, development and integration of new processing techniques for their preparation and solving challenges associated with the syntheses of new pharmaceutical and agrochemical compounds. In our work we utilise the latest synthesis tools and enabling technologies such as microwave reactors, solid supported reagents and scavengers, enzymes, membrane reactors and flow chemistry platforms to facilitate the bond making sequence and expedite the purification procedure. A central aspect of our investigations is our pioneering work on flow chemical synthesis and microreactor technology as a means of improving the speed, efficiency, and safety of various chemical transformations. As a part of these studies we are attempting to devise new chemical reactions that are not inherently feasible or would be problematic under standard laboratory conditions. It is our further challenge to enhance the automation associated with these reactor devices to impart a certain level of intelligence to their function so that repetitive wasteful actions currently performed by chemists can be delegated to a machine; for example, reagent screening or reaction optimisation. We use these technologies as tools to enhance our synthetic capabilities but strongly believe in not becoming slaves to any methodology or equipment.

For those interested in our research and wishing to find out more we invite you to visit our website at: http://www.dur.ac.uk/i.r.baxendale/

Early scale-up work of a promising reflux inhibitor AZD6906 is described. Two steps of an earlier route were adapted to be performed in continuous flow to avoid issues related to batch procedures, resulting in a robust method with reduced cost of goods and improved product quality. Toxic and reactive reagents and starting materials could be handled in a flow regime, thereby allowing safer and more convenient reaction optimization and production.

Gustafsson, T.; Sörensen, H.; Pontén, F. Org. Process Res. Dev. 2012, 16, 925–929. doi:10.1021/op200340c

Development of a Continuous Flow Scale-Up Approach of Reflux Inhibitor AZD6906

Tomas Gustafsson, Henrik Sörensen, and Fritiof Pontén*

Medicinal Chemistry, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden

Org. Process Res. Dev., 2012, 16 (5), pp 925–929

DOI: 10.1021/op200340c

Publication Date (Web): February 21, 2012

*Telephone: +46 31 776 16 65. Email: [email protected].

This article is part of the Continuous Processes 2012 special issue.

One benefit of flow reactors is improved control over reaction temperature, due to reduced reaction volume at a given time, higher surface area, and the movement of the reaction mixture. This is particularly helpful for very exothermic reactions, which often require cryogenic cooling to prevent runaway reactions – this type of cooling is very expensive and resource-intensive on a large scale. One such reaction is described in a recent paper from AstraZeneca, in which a phosphinate anion adds into a glycine derivative. The product of this reaction is an intermediate in the synthesis of a gastroesophageal reflux inhibitor drug candidate called AZD6906.

////Flow synthesis, AZD 6906

Flow synthesis of Fluoxetine

Uncategorized Comments Off

May 272016

Scheme 1: Flow synthesis of fluoxetine (46).

One of the early published examples of industry-based research on multi-step flow synthesis of a pharmaceutical was reported in 2011 by scientists from Eli Lilly/UK and detailed the synthesis of fluoxetine 46, the API of Prozac[1]. In this account each step was performed and optimised individually in flow, with analysis and purification being accomplished off-line. The synthesis commences with the reduction of the advanced intermediate ketone 47 using a solution of pre-chilled borane–THF complex (48) to yield alcohol 49 (Scheme 1).

Conversion of the pendant chloride into iodide 51 was attempted via Finckelstein conditions, however, even when utilising phase-transfer conditions in order to maintain a homogeneous flow regime the outcome was not satisfactory giving only low conversions. Alternatively direct amination of chloride 49 utilising high temperature flow conditions (140 °C) allowed the direct preparation of amine 50 in excellent yield.

Flow processing using a short residence time (10 min) at the elevated temperature allowed for a good throughput; in addition, the handling of the volatile methylamine within the confines of the flow reactor simplifies the practical aspects of the transformation, however, extra precautions were required in order to address and remove any leftover methylamine that would pose a significant hazard during scaling up.

The final arylation of 50 was intended to be performed as a S_NAr reaction, however, insufficient deprotonation of the alcohol 50 under flow conditions (NaHMDS or BEMP instead of using a suspension of NaH as used in batch) required a modification to the planned approach. To this end a Mitsunobu protocol based on the orchestrated mixing of four reagent streams (50, 54 and reagents 52 and 53) was developed and successfully applied to deliver fluoxetine (46) in high yield.

Overall, this study is a good example detailing the intricacies faced when translating an initial batch synthesis into a sequence of flow steps for which several adaptations regarding choice of reagents and reaction conditions are mandatory in order to succeed.

Ahmed-Omer, B.; Sanderson, A. J. Org. Biomol. Chem. 2011, 9, 3854–3862. doi:10.1039/C0OB00906G
Paper

Preparation of fluoxetine by multiple flow processing steps

Batoul Ahmed-Omer^a and Adam J. Sanderson*^a

*Corresponding authors

^aEli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UK

Org. Biomol. Chem., 2011,9, 3854-3862

DOI: 10.1039/C0OB00906G

http://pubs.rsc.org/en/Content/ArticleLanding/2011/OB/c0ob00906g#!divAbstract

Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.

Graphical abstract: Preparation of fluoxetine by multiple flow processing steps

1 The general method set-up of flow process used for the synthesis of (±)- fluoxetine.

Scheme 1 Synthesis of (±)-fluoxetine in flow: (i) BH3·THF, r.t., 5 min (77%); (ii) NaI, toluene: water, 100 °C, 20 min (43%); (iii); MeNH2 (aq), …

//////////Flow synthesis, fluoxetine

SETIPIPRANT

Uncategorized Comments Off

May 272016

Setipiprant, KYTH-105

CAS 866460-33-5

2-(2-(1-naphthoyl)-8-fluoro-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)acetic acid

2-[8-fluoro-2-(naphthalene-1-carbonyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5-yl]acetic acid

5H-Pyrido(4,3-b)indole-5-acetic acid, 8-fluoro-1,2,3,4-tetrahydro-2-(1-naphthalenylcarbonyl)-

MF C24H19FN2O3

MW 402.4176632

IND FILED BY ALLERGAN FOR Alopecia

ACT-129968, a CRTH2 receptor antagonist, had been in phase II clinical trials at Actelion

Setipiprant; UNII-BHF20LA2GM; ACT-129968; 866460-33-5;

Setipiprant is a prostaglandin D2 (PGD2) antagonist. Essentially, it inhibits PGD2 receptor activity

KYTH-105 had previously been studied as a potential allergic inflammation treatment and had undergone eight clinical trials, resulting in a safety database of more than 1,000 patients. Treatment in all studies was well tolerated across all treatment groups.

Intellectual Property
KYTHERA acquired exclusive worldwide rights to KYTH-105, as well as certain patent rights covering the use of PGD2 receptor antagonists for the treatment of hair loss (often presenting as male pattern baldness, or androgenic alopecia).

Next Steps
KYTHERA plans to file an Investigational New Drug (IND) application and initiate a proof-of-concept study to establish the efficacy of KYTH-105 in male subjects with androgenic alopecia (AGA).

In 2015, Allergan acquired Kythera.

2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid

mp 224.0 °C.

LC(1)/ESI-MS t_R = 0.83 min; m/z [M + H⁺] = 403.09.

¹H NMR (DMSO-d₆), 65:35 mixture of two rotamers, δ: 8.02 (m, 2 H), 7.76 (d, J = 7.8 Hz, 0.65 H), 7.72 (m, 0.35 H), 7.49–7.64 (m, 3.35 H), 7.35–7.49 (m, 2.35 H), 6.98 (ddd, J_H–F = 9.3 Hz, J₁ = 9.3 Hz, J₂ = 2.4 Hz, 0.65 H), 6.88 (m, 0.65 H), 4.85–5.14 (m, 3.3 H), 4.42 (m, 0.35 H), 4.32 (m, 0.7 H), 4.06 (m, 0.35 H), 3.50 (t, J = 5.5 Hz, 1.3 H), 2.95 (m, 0.70 H), 2.68 (m, 0.65 H), 2.58 (m, 0.65 H).

¹³C NMR (DMSO-d₆) δ: 170.7, 169.2, 157.7 (d, J_C–F = 232 Hz), 157.4 (d, J_C–F = 233 Hz), 137.1, 136.2, 135.1, 134.9, 134.0, 133.8, 133.5, 129.6, 129.5, 129.4, 129.3, 128.9, 128.8, 127.5, 127.4, 127.0, 126.9, 126.0, 125.9, 125.7 (d, J_C–F = 10 Hz), 125.2, 125.1, 125.0, 124.1, 123.9, 110.9 (d, J_C–F = 10 Hz), 110.8 (m), 109.3 (d, J_C–F = 26 Hz), 109.1 (d, J_C–F = 26 Hz), 106.7 (m), 103.3 (d, J_C–F = 23 Hz), 103.0 (d, J_C–F = 23 Hz), 44.73, 44.70, 44.5, 44.4, 39.5, 39.3, 23.1, 22.3.

HRMS (ESI): m/zcalcd for C₂₄H₂₀N₂O₃F [M + H⁺] 403.1458, found 403.1458.

SYNTHERSIS

Setipiprant (INN) (developmental code names ACT-129,968, KYTH-105) is a drug originally developed by Actelion which acts as a selective, orally available antagonist of the prostaglandin D₂ receptor 2 (DP₂).^[1] It was initially researched as a treatment for allergies and inflammatory disorders, particularly asthma, but despite being well tolerated in clinical trials and showing reasonable efficacy against allergen-induced airway responses in asthmatic patients,^[2]^[3] it failed to show sufficient advantages over existing drugs and was discontinued from further development in this application.^[4]

However, following the discovery in 2012 that the prostaglandin D₂ receptor (DP/PGD₂) is expressed at high levels in the scalp of men affected by male pattern baldness,^[5] the rights to setipiprant were acquired by Kythera with a view to potentially developing this drug as a novel treatment for baldness, with a previously unexploited mechanism of action.^[6] While it is too early to tell whether setipiprant will be an effective treatment for this condition, the favorable pharmacokinetics and relative lack of side effects seen in earlier clinical trials mean that fresh clinical trials for this new application can be conducted fairly quickly.^[7]

Prostaglandin D2 is a known agonist of the thromboxane A2 (TxA2) receptor, the PGD2 (DP) receptor and the recently identified G-protein-coupled “chemoattractant receptor- homologous molecule expressed on Th2 cells” (CRTH2).

The response to allergen exposure in a previously sensitized host results in a cascade effect involving numerous cell types and release of a number of cytokines, chemokines, and multiple mediators. Among these critical initiators are the cytokines interleukin (IL)-4, IL-13, and IL-5, which play critical roles in Th2 cell differentiation, immunoglobulin (Ig)E synthesis, mast cell growth and differentiation, upregulation of CD23 expression, and the differentiation, recruitment, and activation of eosinophils. The stimulated release of the array of mediators, causes end-organ damage, including constriction and hyperresponsi- veness, vascular permeability, edema, mucous secretion, and further inflammation.

Because of the number of responses targeted, corticosteroids have proven to be the most effective therapy. Rather than antagonizing these specific responses in a directed way, another approach is to alter the immune response, that is, to change the nature of the immunological response to allergen. CRTH2 is preferentially expressed on Th2 cells and is a chemoattractant receptor for PGD2 that mediates PGD2-dependent migration of blood Th2 cells. Chemoattractants are responsible for the recruitment of both Th2 cells and other effector cells of allergic inflammation, which can provide the conceptual basis for the development of new therapeutic strategies in allergic conditions.

So far, few compounds having CRTH2 antagonistic activity have been reported in the patent literature. Bayer AG claims the use of Ramatroban ((3R)-3-(4-fluorobenzene- sulfonamido)-l,2,3,4-tetrahydrocarbazole-9-propionic acid) for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjuvatitis

(GB 2388540). Further, (2-tert.-butoxycarbonyl-l, 2, 3, 4-tetrahydro-pyrido[4,3-b]indol-5- yl)-acetic acid and (2-ethoxycarbonyl-l, 2, 3, 4-tetrahydro-pyrido[4,3-b]indol~5-yl)-acetic acid are disclosed by Kyle F. et al in two patent applications (US 5817756 and WO 9507294, respectively).

Furthermore, oral bioavailability of the Ramatroban and its ability to inhibit prostaglandin D2-induced eosinophil migration in vitro has been reported (Journal of Pharmacology and Experimental Therapeutics, 305(1), p.347-352 (2003)).

Description of the invention:

It has now been found that compounds of the general Formulae (I) and (II) of the present invention are CRTH2 receptor antagonists. These compounds are useful for the treatment of both chronic and acute allergic/immune disorders such as allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases, such as Churg-Strauss syndrome and sinusitis, basophil- related diseases, such as basophilic leukemia and basophilic leukocytosis.

The compounds of general Formulae (I) and (II), especially those mentioned as being preferred, display high selectivity towards the CRTH2 receptor. No antagonistic effects (IC₅₀ >10 μM) are observed on e.g. prostaglandin D2 receptor DPI; PGI2 receptor (IP), PGE2 receptors (EPl, EP2, EP3, EP4), PGF2 receptor (FP), thromboxane receptor A2 (TxA2), leukotriene receptors (CysLTl, CysLT2, LTB4), complement receptor (C5a), angiotensin receptors (ATI, AT2) or serotonin receptor 5HT2c.

The solubility of compounds of general Formulae (I) and (II) in buffer at pH 7 is generally >800 μg/ml.

In vitro assays with rat and dog liver microsomes, or with rat and human hepatocytes revealed high metabolic stability for compounds of general Foπnulae (I) and (II), especially for those compounds mentioned as being preferred.

The compounds of general Formulae (I) and (II), especially those mentioned as being preferred, do not interfere with cytochrome P-450 enzymes, e.g. they are neither degraded by, nor do they inhibit such enzymes.

Excellent pharmacokinetic profiles have been observed for compounds of general Formulae (I) and (II), especially for those compounds mentioned as being preferred, after oral administration (10 mg/kg) to rats and dogs (bioavailability 20-80%, T_max 30 min, C_max 2000- 6000 ng/ml, low clearance, T_{] 2}4-8 h). The compounds of general Formulae (I) and (II), especially those mentioned as being preferred, are efficacious in vitro, inhibiting PGD2-induced migration of eosinophils or other CRTH2 expressing cells in a cell migration assay. A number of techniques have been developed to assay such chemotactic migration (see, e.g., Leonard et al., 1995, “Measurement of α- and β-Chemokines”, in Current Protocols in Immunology, 6.12.1- 6.12.28, Ed. Coligan et al, John Wiley & Sons, Inc. 1995). The compounds of the present invention are tested using a protocol according to H. Sugimoto et al. (J Pharmacol Exp Ther. 2003, 305(1), 347-52), or as described hereinafter: Purified eosinophils are labeled with a fluorescent dye, i.e. Calcein-AM and loaded in BD Falcon FluoroBlock upper inserts. Test compounds are diluted and incubated with eosinophils in the BD Falcon

FluoroBlock upper inserts for 30 min at 37 °C in a humidified CO₂ incubator. A constant amount of PGD2 is added to BD Falcon FluoroBlock lower chamber, at a concentration known to have a chemotactic effect on CRTH2 cells. As a control, at least one aliquot in the upper well does not contain test compound. The inserts are combined with the chambers and are incubated for 30 min at 37 °C in a humidified CO₂ incubator. After an incubation period, the number of migrating cells on the lower chamber is counted using a fluorescent reader, i.e. an Applied Biosystems Cyto Fluor 4000 plate reader. The contribution of a test compound to the chemotactic activity of PGD2 is measured by comparing the chemotactic activity of the aliquots containing only dilution buffer with the activity of aliquots containing a test compound. If addition of the test compound to the solution results in a decrease in the number of cells detected in the lower chamber relative to the number of cells detected using a solution containing only PGD2, then there is identified an antagonist of PGD2 induction of chemotactic activity of eosinophils.

PAPER

Journal of Medicinal Chemistry (2013), 56(12), 4899-4911

http://pubs.acs.org/doi/abs/10.1021/jm400122f

Identification of 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid (Setipiprant/ACT-129968), a Potent, Selective, and Orally Bioavailable Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) Antagonist

Heinz Fretz*, Anja Valdenaire, Julien Pothier, Kurt Hilpert, Carmela Gnerre, Oliver Peter, Xavier Leroy, and Markus A. Riederer

Drug Discovery Unit, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland

J. Med. Chem., 2013, 56 (12), pp 4899–4911

DOI: 10.1021/jm400122f

Herein we describe the discovery of the novel CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 28 (setipiprant/ACT-129968), a clinical development candidate for the treatment of asthma and seasonal allergic rhinitis. A lead optimization program was started based on the discovery of the recently disclosed CRTh2 antagonist 2-(2-benzoyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 5. An already favorable and druglike profile could be assessed for lead compound 5. Therefore, the lead optimization program mainly focused on the improvement in potency and oral bioavailability. Data of newly synthesized analogs were collected from in vitro pharmacological, physicochemical, in vitro ADME, and in vivo pharmacokinetic studies in the rat and the dog. The data were then analyzed using a traffic light selection tool as a visualization device in order to evaluate and prioritize candidates displaying a balanced overall profile. This data-driven process and the excellent results of the PK study in the rat (F = 44%) and the dog (F = 55%) facilitated the identification of 28 as a potent (IC₅₀ = 6 nM), selective, and orally available CRTh2 antagonist.

PAtent

WO 2005095397

http://www.google.co.in/patents/WO2005095397A1?cl=en

Formula 6.

Scheme 1

Step a)

Step b)

Scheme 2

Formula (I).

References

Fretz H, Valdenaire A, Pothier J, Hilpert K, Gnerre C, Peter O, Leroy X, Riederer MA. Identification of 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (setipiprant/ACT-129968), a potent, selective, and orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonist. J Med Chem. 2013 Jun 27;56(12):4899-911. doi: 10.1021/jm400122f PMID 23721423
Sidharta PN, Diamant Z, Dingemanse J. Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects. Fundam Clin Pharmacol. 2014 Dec;28(6):690-9. doi: 10.1111/fcp.12079 PMID 24734908
Diamant Z, Sidharta PN, Singh D, O’Connor BJ, Zuiker R, Leaker BR, Silkey M, Dingemanse J. Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin Exp Allergy. 2014 Aug;44(8):1044-52. doi: 10.1111/cea.12357 PMID 24964348
Norman P. Update on the status of DP2 receptor antagonists; from proof of concept through clinical failures to promising new drugs. Expert Opin Investig Drugs. 2014 Jan;23(1):55-66. doi: 10.1517/13543784.2013.839658 PMID 24073896
Garza LA, et al. Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Science Translational Medicine, 21 March 2012; 4(126):126ra34. doi: 10.1126/scitranslmed.3003122
George Cotsarelis, Garret Fitzgerald, Luis Garza. Compositions and methods for regulating hair growth. US Patent application 2015/0072963
Pipeline KYTH-105 (setipiprant)
http://files.shareholder.com/downloads/AMDA-MFNLA/4023632629x0x817836/4E5AC47A-B9EE-4296-9D97-631C0F6B7C97/KYTH-105_setipiprant_.pdf

Patent ID	Date	Patent Title
US2015072963	2015-03-12	COMPOSITIONS AND METHODS FOR REGULATING HAIR GROWTH
US2014328861	2014-11-06	Combination of CRTH2 Antagonist and a Proton Pump Inhibitor for the Treatment of Eosinophilic Esophagitis
US2010234396	2010-09-16	Tetrhydropyridoindole Derivatives
US7714132	2010-05-11	Tetrahydropyridoindole derivatives

S etipiprant
Systematic (IUPAC) name

2-[8-fluoro-2-(naphthalene-1-carbonyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5-yl]acetic acid
Clinical data
Administration	Oral
Identifiers
CASRN	866460-33-5
ATC code	none
PubChem	CID 49843471
Chemical data
Formula	C₂₄H₁₉FN₂O₃
Molar mass	402.417 g/mol

///////Setipiprant, KYTH-105, 866460-33-5, ALLERGAN, Alopecia, KYTHERA

c15ccccc5cccc1C(=O)N(CC3)Cc2c3n(CC(O)=O)c(cc4)c2cc4F

Crisil rings warning bell for pharma on US slowdown

regulatory Comments Off

May 262016

Companies like Dr. Reddy’s Laboratories and Sun Pharma derive close to 60% of their revenue from exports to the US. Lupin too, gets 45% of its revenue from generic formulation sales to the US, while others like Cadila Healthcare, Torrent Pharma ……………

Crisil rings warning bell for pharma on US slowdown

////Crisil, warning bell, pharma, US slowdown

EU GMP Annex 1 Revision 2016 – what does the pharmaceutical industry expect?

regulatory Comments Off

May 262016

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote speech at the Pharma Congress 2016 about the revision of Annex 1 of the EU GMP Guide. Read here what the pharmaceutical industry expects form the new Annex 1.

http://www.gmp-compliance.org/enews_05326_EU-GMP-Annex-1-Revision-2016—what-does-the-pharmaceutical-industry-expect_15160,15266,15265,15432,Z-PEM_n.html

Europe’s biggest Pharma Congress of its kind took place in Düsseldorf on 12 and 13 April. With more than 1000 participants, 90 exhibitors and 10 GMP conferences this Congress 2016 has been the biggest since the first one 18 years ago. 50 lectures, almost exclusively case studies from pharmacuetical companies such as Pfizer, Novartis, Boehringer Ingelheim and many more were discussed. Special attention was paid to the keynotes at the beginning of each congress day.

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote speech about the revision of Annex 1 of the EU Guidelines to Good Manufacturing Practice. The first version dates already back to the year 1972. Dr Haefele stated that there had already been five revisions since this time but no fundamental review. This means the time has come to revise this fundamental document on the regulation of sterile manufacture in Europe.

Dr Haefele demonstrated the need for action on one hand by a comparison with the FDA Aseptic Guide and on the other hand by means of his own commenting. Friedrich Haefele said that priority should be given to harmonisation. He basically believes that Annex 1 should remain reserved for sterile parenteral products and that other sterile products or active pharmaceutical ingredients should be regulated in other documents or in specific annexes. He also wants a separation between aseptically manufactured and terminally sterilised products in the new Annex 1.

He considers DIN ISO 14644-1 to be a central document that is used for the classification of clean rooms in the European Guideline but also in the US Guide. Dr Haefele is not bothered by the fact that the limit for 5 µm particles has been deleted from the grade ISO 5 (ISO 4.8). According to him it should also be deleted from the European requirements. Deviations in the case of 0.5 and 5 µm particles occur essentially in parallel so that it should be possible to renounce to the limit for 5 µm particles.

Dr Haefele also proposed a simplification for the microbiological environmental monitoring. Settle plates as well as microbial air sampling are required in Europe at the moment. According to Dr Haefele only the microbial air sampling should be compulsory whereas the use of settle plates should be optional or additional. The use of average values in the microbiological monitoring in the clean room should be dismissed. With the use of isolators with validated decontamination cycles the microbiological monitoring could be reduced to the essential pursuant to ICH Q9 Quality Risk Management.

In contrast to the FDA Aseptic Guide the European Annex 1 contains requirements concerning the crimping process as well as a differentiation between aseptic and clean processes. For the latter Dr Haefele wants a clear definition of “Grade A Air Supply” that should be used for protection during the process according to Annex 1. Dr Haefele stated that the industry has its opinion concerning this but that it should also be recorded in the relevant official document. By this he meant the use of air filtered according to the requirements of grade A without considering the microbiological requirements.

There are important differences between Annex 1 and the Aseptic Guide in the area of sterilisation. The US document contains no indications for a terminal product sterilisation. It is contained in the EU document. Dr Haefele proposes to limit the requirement for a sterilisation with pure steam primariliy to the terminal product sterilisation and to also allow other methods e.g. sterilisation with ethylene oxide for example for so-called ready-to-use materials.

He sees further potential for improvement concerning the topic sterile filtration. He considers that the integrity testing after sterilisation immediately before filling can be omitted since the data of the filter validation and the integrity testing after filling give adequate security. To renounce to the obligatory integrity testing after sterilisation and before use, reduces the complexity of the aseptic set-up and when constructing facilities.

A further difference concerns the quality oversight. In Europe there is no requirement that the quality assurance (physically) must take place on-site during aseptic processes. But the Aseptic Guide requires a QC oversight and here, especially the media fill is mentioned. Dr Haefele invoked a harmonisation of the requirements, in order to strengthen the European philosophy, however. Quality assurance is a system and not an organisation. Mr. Haefele proposed a further change concerning the media fill in isolators. Here, interventions are carried out from the outside when carrying gloves. This means that they are “person-neutral”. The requirement that the qualification of interventions during the media fill has to be done person-specific should therefore be omitted for media fills in isolators.

As concerns the topic disinfection Mr. Haefele would prefer the admission of hydrogen peroxide for the decontamination of surfaces in isolators and material locks as well as the dispensation with the mandatory rotation when using disinfectants.
A further topic in Annex 1 is the monitoring of the integrity of containers containing sterile medicinal products. At the moment, the Annex requires a 100% integrity testing only for containers closed by fusion (glass ampoules and BFS containers). Dr Haefele would prefer more openness up to suitable controls for all packaging systems or pharmaceutical dosage forms.

Finally, he reaffirmed the use of modern barrier techniques for the aseptic manufacture as state-of-the-art and repeated his wish for a harmonisation of the requirements for sterile and aseptically produced medicinal products. MRA, mutual recognition agreements, could reduce the number of regulatory inspections at the companies.

Currently, the publication of the draft of the new EU GMP Annex 1 is planned for autumn 2016.

Source: Pharma Kongress 2016 (companies who wish to book a booth in 2017 can register here)
/////Dr Friedrich Haefele, Vice President, Fill & Finish Biopharma, Boehringer Ingelheim, EU GMP Annex 1 Revision 2016, pharmaceutical industry,

WHO issues revised Guideline on HVAC Systems

regulatory Comments Off

May 262016

The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems for the manufacture of non-sterile forms. As most guidelines on this topic address the requirements for sterile dosage forms, the previous version was gladly accepted by industry. Learn more about the revised guideline on HVAC systems.

http://www.gmp-compliance.org/enews_05358_WHO-issues-revised-Guideline-on-HVAC-Systems_15160,15221,15661,15612,Z-PEM_n.html

The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems used for the manufacture of non-sterile dosage forms. As most guidelines on this topic address the requirements for sterile forms, the previous version (TRS 961, Annex 1) from 2011 was gladly accepted by industry. Mentioned are non-sterile dosage forms as tablets, capsules, liquids or ointments, but also for the final steps in the manufacture of APIs. The WHO guideline means to provide guidance specifically for the areas design, installation, qualification and maintenance of ventilation systems. For the manufacture of highly potent materials the WHO refers to their Guideline TRS 961, Annex 3.

The biggest changes comprise:

The chapter “Premises” was moved to the front to emphasize its importance. The chapter now further comprises some sample layouts
The section “Commissioning, Qualification and Validation” was revised to match it with the WHO Guideline TRS 937, Annex 4 (Supplementary guidelines on good manufacturing practices: validation)
The part “Maintenance” was removed from the part “Commissioning, Qualification and Validation” and is now a separte chapter
In addition a number of comments were added, graphs revised, and the overall readability was improved

Due to the many references and the numerous and improved illustrations the document is a good source for the (exemplary) requirements in the manufacture of solid and non-sterile dosage forms.

To find out more please visit the WHO website where you will find the draft document SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS. The deadline for comments is the 12 July 2016. The results are expected to be discussed during the 51st WHO expert committee meeting in October.

///////////WHO, revised Guideline, HVAC Systems

CFI-402257

Uncategorized Comments Off

May 252016

CFI-402257

N-cyclopropyl-4-(7-((((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)amino)-5-(pyridin-2-yloxy)pyrazolo[1,5-a]pyridin-3-yl)-2-methylbenzamide

N-cyclopropyl-4-(7-( (((Is, 3s)-3-hydroxy-3-methylcyclobutyl)methyl)amino)-5- (pyridin-3-yloxy)pyrazolol 1 , 5-a ]pyrimidin-3-yl)-2-methylbenzamide

CAS 1610759-22-2 (free base); 1610677-37-6 (HCl)
MF: C29H31N5O3
MW: 497.2427

University Health Network

CFI-402257 is a highly potent and selective TTK (threonine tyrosine kinase) Inhibitor ((TTK Ki = 0.1 nM) with potential anticancer activity. TTK is an essential chromosomal regulator and is overexpressed in aneuploid tumors. High TTK levels correlate with a high tumor grade11 and poor patient outcomes. TTK inhibition are associated with a disabled mitotic checkpoint, resulting in chromosome segregation errors, aneuploidy, and cell death.

Synthesis

SYN OF INTERMEDIATE

SYNTHESIS COLOUR INDICATED

SYN OF INTERMEDIATES

IF YOU HAVE ENJOYED IT ………EMAIL ME [email protected], +919323115463, India

INDIA FLAG

DR ANTHONY CRASTO , WORLDDRUGTRACKER, HELPING MILLIONS, MAKING INDIA AND INDIANS PROUD

Protein kinases have been the subject of extensive study in the search for new therapeutic agents in various diseases, for example, cancer. Protein kinases are known to mediate intracellular signal transduction by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell.

Human TTK protein kinase (TTK), also known as tyrosine threonine kinase, dual specificity protein kinase TTK, Monopolar Spindle 1 (Mpsl) and Phosphotyrosine -Picked Threonine Kinase (PYT), is a conserved multispecific kinase that is capable of phosphorylating serine, threonine and tyrosine residues when expressed in E. coli (Mills et al., J. Biol. Chem. 22(5): 16000-16006 (1992)). TTK mRNA is not expressed in the majority of physiologically normal tissues in human (Id). TTK mRNA is expressed in some rapidly proliferating tissues, such as testis and thymus, as well as in some tumors (for example, TTK mRNA was not expressed in renal cell carcinoma, was expressed in 50% of breast cancer samples, was expressed in testicular tumors and ovarian cancer samples) (Id). TTK is expressed in some cancer cell lines and tumors relative to normal counterparts (Id.; see also WO 02/068444 Al).

Therefore, agents which inhibit a protein kinase, in particular TTK, have the potential to treat cancer. There is a need for additional agents which can act as protein kinase inhibitors, in particular TTK inhibitors.

In addition, cancer recurrence, drug resistance or metastasis is one of the major challenges in cancer therapies. Cancer patients who responded favorably to the initial anticancer therapy often develop drug resistance and secondary tumors that lead to the relapse of the disease. Recent research evidences suggest that the capability of a tumor to grow and propagate is dependent on a small subset of cells within the tumor. These cells are termed tumor-initiating cells (TICs) or cancer stem cells. It is thought that the TICs are responsible for drug resistance, cancer relapse and metastasis. Compounds that can inhibit the growth and survival of these tumor-initiating cells can be used to treat cancer, metastasis or prevent recurrence of cancer. Therefore, a need exists for new compounds that can inhibit the growth and survival of tumor- imitating cells.

PATENT

WO 2015070349

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015070349&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

A4: N-cyclopropyl-4-(7-( (((Is, 3s)-3-hydroxy-3-methylcyclobutyl)methyl)amino)-5- (pyridin-3-yloxy)pyrazolol 1 , 5-a ]pyrimidin-3-yl)-2-methylbenzamide hydrochloride and its free base

A). Through Boc deprotection: A mixture of tert-butyl (3- bromo-5-(pyridin-3-yloxy)pyrazolo[l,5-a]pyrimidin-7- yl)(((ls,3s)-3-((tert-butoxycarbonyl)oxy)-3- methylcyclobutyl)methyl)carbamate (0.23 g, 0.38 mmol), N- cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-

dioxaborolan-2-yl)benzamide (0.15 g, 0.49 mmol), PdC dppfDCM (0.15 g, 0.49 mmol), and 2M K₃P0₄ (0.57 mL, 1.14 mmol) in THF (4 mL) was charged with Ar and heated in the microwave at 130 °C for 3 h. Water and EtOAc were added to separate the phases and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over NaSC>4, filtered and concentrated. The crude product was purified by flash chromatography (gradient: EtOAc/hex 20-60%) to give a yellow oil.

The above intermediate was dissolved in DCM (10 mL) and treated with TFA (3 mL) at rt for 3 h. After reaction completion, solvent was removed in vacuo and the crude product was dissolved in MeOH (5 mL). The mixture was filtered and purified by prep-HPLC. The compound was passed through a PoraPak cartridge and triturated with Et₂0 to give the title compound as a free base (white solid). The free base was dissolved in MeOH (5 mL), and HC1 (1 M Et₂0, 2 equiv) was then added slowly. Solvent was removed in vacuo to give the title compound as a beige solid in HC1 salt (96 mg, 47% over 2 steps). ¾ NMR (400 MHz, CD₃OD) δ ppm 9.14 (br. s, 1H), 8.89-8.82 (m, 1H), 8.79-8.71 (m, 1H), 8.40 (s, 1H), 8.31-8.21 (m, 1H), 7.68 (s, 1H), 7.59 (d, J = 9.5 Hz, 1H), 7.23 (d, J= 8.0 Hz, 1H), 6.06 (s, 1H), 3.56 (d, J= 6.5 Hz, 2H), 2.88-2.79 (m, 1H),

2.40-2.31 (m, 1H), 2.29 (s, 3H), 2.26-2.18 (m, 2H), 1.99-1.89 (m, 2H), 1.37 (s, 3H),

0.85-0.76 (m, 2H), 0.63-0.53 (m, 2H); MS ESI [M + H]⁺ 499.3, calcd for [C^HsoNeOs +

H]⁺ 499.2. HPLC purity: 99.5% at 254 nm.

B). Through PMB deprotection: A mixture of N- cyclopropyl-4-(7-((((ls,3s)-3-hydroxy-3- methylcyclobutyl)methyl)(4-methoxybenzyl)amino)-5- (pyridin-3-yloxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2- methylbenzamide (9.6 g, 15.5 mmol), TFA (50 mL) in DCE

(70 mL) was heated in an oil bath at 50 °C for 4 h. After reaction completion, solvent was removed in vacuo and the crude product was dissolved in a mixture of MeOH/DCM (100 mL/25 mL). 2M Na₂CC (150 mL) was then added and the resulting mixture was stirred at rt for 30 min. The reaction mixture was diluted with DCM and the phases were separated. The aqueous phase was extracted with DCM and the combined organic extracts were washed with water, dried over MgSC , filtered and concentrated. The crude product was triturated and sonicated in a mixture of DCM/Et₂0 (10 mL/70 mL) to give the title compound as a off white solid in free base (5.9 g, 77%). Ti NMR (400 MHz, CD₃OD) δ ppm 8.58-8.53 (m, 1H), 8.50-8.46 (m, 1H), 8.36 (s, 1H), 7.86-7.80 (m, 1H), 7.76-7.72 (m, 1H), 7.61-7.55 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 5.92 (s, 1H), 3.52 (d, J = 6.8 Hz, 2H), 2.86-2.77 (m, 1H), 2.38-2.28 (m, 1H), 2.25 (s, 3H), 2.24-2.18 (m, 2H), 1.99-1.88 (m, 2H), 1.37 (s, 3H), 0.84-0.75 (m, 2H), 0.64-0.54 (m, 2H); MS ESI [M + H]⁺ 499.2, calcd for [CzsHsoNgOs + H]⁺ 499.2. HPLC purity: 96.1% at 235 nm.

PATENT

WO 2014075168

PAPER

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.5b00485

This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1¹/₂ type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK K_i = 0.1 nM), highly selective, orally bioavailable anticancer agent (CFI-402257) for IND enabling studies.

Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent

Yong Liu^†, Radoslaw Laufer^†, Narendra Kumar Patel^†, Grace Ng^†, Peter B. Sampson^†, Sze-Wan Li^†, Yunhui Lang^†,Miklos Feher^†, Richard Brokx^†, Irina Beletskaya^†, Richard Hodgson^†, Olga Plotnikova^†, Donald E. Awrey^†, Wei Qiu^‡, Nickolay Y. Chirgadze^‡, Jacqueline M. Mason^†, Xin Wei^†, Dan Chi-Chia Lin^†, Yi Che^†, Reza Kiarash^†, Graham C. Fletcher^†, Tak W. Mak^†, Mark R. Bray^†, and Henry W. Pauls^*^†

^† Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada

^‡ Campbell Family Cancer Research Institute, University Health Network, Princess Margaret Cancer Center, 610 University Avenue, Toronto, Ontario M5G 2C4, Canada

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.5b00485

*E-mail: [email protected]. Phone: 905-337-3446.

REFERENCES

Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent
Yong Liu, Radoslaw Laufer, Narendra Kumar Patel, Grace Ng, Peter B. Sampson, Sze-Wan Li, Yunhui Lang, Miklos Feher, Richard Brokx, Irina Beletskaya, Richard Hodgson, Olga Plotnikova, Donald E. Awrey, Wei Qiu, Nickolay Y. Chirgadze, Jacqueline M. Mason, Xin Wei, Dan Chi-Chia Lin, Yi Che, Reza Kiarash, Graham C. Fletcher, Tak W. Mak, Mark R. Bray, and Henry W. Pauls
Publication Date (Web): May 6, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.5b00485

////TTK inhibitors, CFI-402257, pyrazolo[1,5-a]pyrimidines, 1¹/₂ type inhibitors, 1610759-22-2, 1610677-37-6

C[C@]1(O)C[C@H](C1)CNc2cc(nc3c(cnn23)c5ccc(C(=O)NC4CC4)c(C)c5)Oc6cccnc6

Antimycobacterial Agents

PRECLINICAL, Uncategorized Comments Off

May 252016

Styryl Hydrazine Thiazole Hybrids

Will be updated………kindly email [email protected]

DATA

ABOUT Dehydrozingerone

Dehydrozingerone; Feruloylmethane; 1080-12-2; 4-(4-Hydroxy-3-methoxyphenyl)-3-buten-2-one; 4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one; Vanillalacetone;

http://pubs.acs.org/doi/abs/10.1021/np300465f

J. Nat. Prod., 2012, 75 (12), pp 2088–2093

DOI: 10.1021/np300465f

Dehydrozingerone (1) is a pungent constituent present in the rhizomes of ginger (Zingiber officinale) and belongs structurally to the vanillyl ketone class. It is a representative of half the chemical structure of curcumin (2), which is an antioxidative yellow pigment obtained from the rhizomes of turmeric (Curcuma longa). Numerous studies have suggested that 2 is a promising phytochemical for the inhibition of malignant tumors, including colon cancer. On the other hand, there have been few studies on the potential antineoplastic properties of 1, and its mode of action based on a molecular mechanism is little known. Therefore, the antiproliferative effects of1 were evaluated against HT-29 human colon cancer cells, and it was found that 1 dose-dependently inhibited growth at the G2/M phase with up-regulation of p21. Dehydrozingerone additionally led to the accumulation of intracellular ROS, although most radical scavengers could not clearly repress the cell-cycle arrest at the G2/M phase. Furthermore, two synthetic isomers of1 (iso-dehydrozingerone, 3, and ortho-dehydrozingerone, 4) were also examined. On comparing of their activities, accumulation of intracellular ROS was found to be interrelated with growth-inhibitory effects. These results suggest that analogues of 1 may be potential chemotherapeutic agents for colon cancer

PAPER

Series of styryl hydrazine thiazole hybrids inspired from dehydrozingerone (DZG) scaffold were designed and synthesized by molecular hybridization approach. In vitro antimycobacterial activity of synthesized compounds was evaluated against Mycobacterium tuberculosis H₃₇Rv strain. Among the series, compound 6o exhibited significant activity (MIC = 1.5 μM; IC₅₀ = 0.48 μM) along with bactericidal (MBC = 12 μM) and intracellular antimycobacterial activities (IC₅₀ = <0.098 μM). Furthermore, 6o displayed prominent antimycobacterial activity under hypoxic (MIC = 46 μM) and normal oxygen (MIC = 0.28 μM) conditions along with antimycobacterial efficiency against isoniazid (MIC = 3.2 μM for INH-R1; 1.5 μM for INH-R2) and rifampicin (MIC = 2.2 μM for RIF-R1; 6.3 μM for RIF-R2) resistant strains of Mtb. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for biological activity, suggesting the importance of molecular hybridization approach for the development of newer DZG clubbed hydrazine thiazole hybrids as potential antimycobacterial agents.

Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents

Girish A. Hampannavar^†, Rajshekhar Karpoormath^*^†, Mahesh B. Palkar^§^†, Mahamadhanif S. Shaikh^†, and Balakumar Chandrasekaran^†

^† Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa

^§ Department of Pharmaceutical Chemistry, K.L.E. University College of Pharmacy, Vidyanagar, Hubballi 580031, Karnataka, India

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.6b00088

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00088

*Phone: +27 31 260 7179. Fax: +27 (0) 31 260 7792. E-mail: [email protected].

///////Antimycobacterial activity, bactericidal, dehydrozingerone, NIAID, thiazole, PRECLINCAL

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FDA approved a switchover from batch to the new technology for production of HIV drug Prezista, Darunavir on a line at its plant in Gurabo, Puerto Rico

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May 232016

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FDA urges companies to get on board with continuous manufacturing

The FDA gave Johnson & Johnson’s ($JNJ) Janssen drug unit the thumbs up last week for the continuous manufacturing process that it has been working on for 5 years. The agency approved a switchover from batch to the new technology for production of HIV drug Prezista on a line at its plant in Gurabo, Puerto Rico……http://www.fiercepharma.com/manufacturing/fda-urges-companies-to-get-on-board-continuous-manufacturing

Darunavir

SEE……http://www.en-cphi.cn/news/show-29367.html

Just after opening a refurbished manufacturing facility in Cape Town, South Africa earlier this year, pharma giant Johnson & Johnson ($JNJ) recently opened the doors to its Global Public Health Africa Operations office there.

The company has invested $21 million (300 million rand) in the facilities. The global public health facility will focus on HIV, tuberculosis and maternal, newborn and child health, South Africa – The Good News reported.

“This (investment) tells us that South Africa has the capability to provide a facility for world-class manufacturing,” Rob Davies, minister of the Department of Trade and Industry told the publication.

Johnson & Johnson, which has operated in South Africa for more than 86 years, planned to close the Cape Town manufacturing plant by the end of 2008 but was persuaded to keep the facility open for local manufacturing to serve sub-Saharan business. By 2015, the plant was cited by J&J as the most-improved in cost competitiveness from 30 company plants worldwide.

Earlier this month, the FDA gave J&J’s Janssen drug unit the go-ahead to proceed with the continuous manufacturing process it’s been working on for 5 years. The agency approved a switchover from batch to the new technology for production of HIV drug Prezista, Darunavir on a line at its plant in Gurabo, Puerto Rico.