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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Telacebec


ChemSpider 2D Image | Telacebec | C29H28ClF3N4O2
Image result for Telacebec
Image result for Telacebec

Telacebec

  • Molecular FormulaC29H28ClF3N4O2
  • Average mass557.006 Da

Telacebec, IAP6, CAS No. 1334719-95-7телацебек [Russian] [INN]تيلاسيبيك [Arabic] [INN]特雷贝克105731334719-95-7[RN]55G92WGH3X
6-Chloro-2-ethyl-N-(4-{4-[4-(trifluoromethoxy)phenyl]-1-piperidinyl}benzyl)imidazo[1,2-a]pyridine-3-carboxamide
Imidazo[1,2-a]pyridine-3-carboxamide, 6-chloro-2-ethyl-N-[[4-[4-[4-(trifluoromethoxy)phenyl]-1-piperidinyl]phenyl]methyl]-Q203Q-203T56 AN DNJ C2 HG BVM1R D- AT6NTJ DR DOXFFF

Qurient Therapeutics and Russia licensee Infectex are developing telacebec, an oral formulation which targets QcrB subunit of the cytochrome bc1 complex, for treating multi drug resistant or extensively drug resistant Mycobacterium tuberculosis infection. Qurient is also investigating telacebec for treating buruli ulcer (an infection caused by Mycobacterium ulcerans ). In January 2021, a global phase II trial was expected to begin by December 2021 for the treatment of buruli ulcer.

syn

Angewandte Chemie, International Edition, 57(4), 1108-1111; 2018

PATENT

WO-2021018387

Novel crystalline forms of telacebec , processes for their preparation and compositions comprising them are claimed. Also claimed is their use for treating bacterial infection.

Different forms of 6-chloro-2-ethyl-AT-(4-(4-(4- (trifluoromethoxy)phenvDpiperidine-i-vDbenzvDimidazolT.2-alpyridine- 3-carboxamide

The present invention relates to different forms of the compound 6-chloro-2-ethyl-lV-(4-(4-(4-(trifhioromethoxy)phenyl)piperidine-i-yl)benzyl)imidazo[i,2-a]pyridine-3-carboxamide and to methods of making such forms/compounds. The present invention furthermore relates to mono-acid addition salts thereof, to methods of making such mono-acid addition salts and to pharmaceutical compositions comprising any of the aforementioned compounds. Furthermore, the present invention relates to uses of any of these compounds.

Tuberculosis as a disease continues to result in millions of deaths each year. Inadequate use of chemotherapy has led to an increasing number of drug resistant cases. This situation is likely to worsen with the emergence of extremely resistant strains to all currently known drugs. Current chemotherapy consists of compounds that directly target Mycobacterium tuberculosis, either by neutralizing general information pathways and critical processes such as RNA polymerization and protein synthesis inhibition or by interfering with mycobacterial specific cell envelop synthesis. The most widely used dedicated anti-tubercular drugs isoniazid, ethionamide, and pyriazin amide are pro-drugs that first require activation. They are administered to a patient for a course of several months. Patients infected with multi-drug resistant strains of M. tuberculosis may have to undergo combination therapies for extended periods of time.

WO 2011/113606 describes various anti-tubercular compounds and their use in the treatment of bacterial infections, including compound“Q203” which chemically is 6-chloro-2-ethyl-!V-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-i-yl)benzyl)imidazo[i,2-a]pyridine-3-carboxamide. In a publication by Pethe et al. (Nature Medicine, 19, 1157-1160 (2013), this compound is reported to be active against tuberculosis by interfering with the bacterial energy metabolism, inhibiting cytochrome bci activity which is an essential component of the electron transport chain required for synthesis of ATP.

Whilst the compound shows promise for future therapy of tuberculosis and related infections, there continues to be a need for forms thereof that are particularly suitable for pharmaceutical administration. In particular there is a need to provide forms that are showing an improved solubility in comparison to the free base of this compound. Furthermore, there is a need in the art to provide for forms that show an improved stability.

In a first aspect the present invention relates to a compound 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-i-yl)benzyl)imidazo[i,2-a]pyridine-3-carboxamide ditosylate having the structure

PATENT

WO2011113606 .

WO 2017049321

WO 2012143796

PAPER

Scientific reports (2019), 9(1), 8608.

Angewandte Chemie, International Edition (2018), 57(4), 1108-1111.

European journal of medicinal chemistry (2017), 136, 420-427.

European Journal of Medicinal Chemistry (2017), 136, 420-427.

 European journal of medicinal chemistry (2017), 125, 807-815.

Nature communications (2016), 7, 12393.

Nature medicine (2013), 19(9), 1157-60

PAPER

Journal of Medicinal Chemistry (2014), 57(12), 5293-5305.

https://pubs.acs.org/doi/10.1021/jm5003606J. Med. Chem. 2014, 57, 12, 5293–5305

Publication Date:May 28, 2014
https://doi.org/10.1021/jm5003606

Abstract Image

A critical unmet clinical need to combat the global tuberculosis epidemic is the development of potent agents capable of reducing the time of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis therapy. In this paper, we report on the optimization of imidazo[1,2-a]pyridine amide (IPA) lead compound 1, which led to the design and synthesis of Q203 (50). We found that the amide linker with IPA core is very important for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA series play a critical role in improving in vitro and in vivo efficacy and pharmacokinetic profile. The optimized IPAs 49 and 50 showed not only excellent oral bioavailability (80.2% and 90.7%, respectively) with high exposure of the area under curve (AUC) but also displayed significant colony-forming unit (CFU) reduction (1.52 and 3.13 log10 reduction at 10 mg/kg dosing level, respectively) in mouse lung.

6-Chloro-2-ethyl-N-(4-{4-[4-(trifluoromethoxy)phenyl]piperidin-1-yl}benzyl)imidazo[1,2-a]pyridine-3-carboxamide (50)

Mp = 164.0 °C; 1H NMR (400 MHz, CDCl3) δ 1.37 (t, J = 7.6 Hz, 3H), 1.82–1.97 (m, 4H), 2.64–2.70 (m, 1H), 2.80–2.87 (m, 2H), 2.93 (q, J = 7.6 Hz, 2H), 3.80–3.83 (m, 2H), 4.61 (d, J = 5.2 Hz, 2H), 6.00 (br t, J = 5.2 Hz, 1H), 6.96–6.99 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.24–7.30 (m, 5H), 7.52 (dd, J = 9.6, 0.8 Hz, 1H), 9.53 (dd, J = 2.0, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.3, 23.6, 33.4, 42.0, 43.3, 50.4, 115.4, 117.0, 121.2, 121.6, 121.9, 126.3, 128.2, 128.3, 128.7, 128.9, 144.5, 144.7, 147.7, 151.4, 151.5, 161.2; 19F NMR (376 MHz, CDCl3) δ 58.31 (s, 3F); LC/MS (ESI) m/z 557 [M + H]+; HRESIMS calcd for C29H29ClF3N4O2 [M + H]+ 557.1926, found 557.1918.

str1
str2
str3

19F NMR (376 MHz, CDCl3) δ 58.31 (s, 3F); 

13C NMR (100 MHz, CDCl3) δ 13.3, 23.6, 33.4, 42.0, 43.3, 50.4, 115.4, 117.0, 121.2, 121.6, 121.9, 126.3, 128.2, 128.3, 128.7, 128.9, 144.5, 144.7, 147.7, 151.4, 151.5, 161.2; 

1H NMR (400 MHz, CDCl3) δ 1.37 (t, J = 7.6 Hz, 3H), 1.82–1.97 (m, 4H), 2.64–2.70 (m, 1H), 2.80–2.87 (m, 2H), 2.93 (q, J = 7.6 Hz, 2H), 3.80–3.83 (m, 2H), 4.61 (d, J = 5.2 Hz, 2H), 6.00 (br t, J = 5.2 Hz, 1H), 6.96–6.99 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.24–7.30 (m, 5H), 7.52 (dd, J = 9.6, 0.8 Hz, 1H), 9.53 (dd, J = 2.0, 0.8 Hz, 1H);

CLIP

June 3, 2019.  Qurient press release:

SEONGNAM-SI, South Korea–(BUSINESS WIRE)– Qurient Co. Ltd. today announced positive results from the Phase 2a EBA (early bactericidal activity) clinical trial for telacebec (Q203), a first-in-class, orally-available antibiotic for the treatment of tuberculosis (TB). Telacebec is a selective inhibitor with high specificity for the cytochrome bc1 complex of Mycobacterium tuberculosis. This complex is a critical component of the electron transport chain, and inhibition disrupts the bacterium’s ability to generate energy.

The EBA trial assessed the pharmacokinetics, safety, and activity of telacebec in three dose strength (100 mg, 200 mg and 300 mg) in the treatment of adult patients with pulmonary TB. Telacebec met the primary objective of rate of change in the time to positivity (TTP) in sputum over days 0 to 14. Telacebec was safe and well tolerated throughout the different dose strengths. Full results from EBA trial are expected to be presented at future scientific meetings.


Phase 2. EBA began July 2018 in South Africa.  As of March 2019, study is active, not enrolling.


June 2018. Q203 has a non-proprietary name assigned: telacebec. USAN: -cebec Cytochrome bc1 complex inhibitors in Mycobacterium tuberculosis.


Phase 1. Description from clinicaltrials.gov:  Randomized, double-blind, placebo-controlled, dose-escalation study in healthy male and female volunteers. Subjects randomly assigned to 1 of 7 treatment cohorts (Cohorts 1 – 7) of 8 subjects each, receiving either Q203 or placebo (6 active treatment : 2 placebo) in a fasting state. Dose escalation to the next cohort may be considered when at least 6 out of 8 subjects, in a cohort, completes all procedures and none of the subjects has a clinically significant adverse event (AE) that is being followed, or at the discretion of the PI if no drug-related serious adverse events (SAEs) have occurred. A food effect cohort will be enrolled to test administration of Q203 in a fed state, at 100 mg dose level (this dose level may change based on PK analysis results). Subjects who received 100mg dose in a fasting state will return and receive the second dose, with food. Subjects will be followed up for AEs, SAE or pregnancy for 30 days postdrug administration.

Related Links


Qurient Press Release. June 2019.Kalia NP et al. 2017. Exploiting the synthetic lethality between terminal respiratory oxidases to kill M. tuberculosis and clear host infection.. PNAS.114.7426

Related Links


//////////////Telacebec,  IAP6, 1334719-95-7, PHASE 2, QURIENT, TUBERCULOSIS, телацебек , تيلاسيبيك , 特雷贝克 , Q 203

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