4′-((5-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl-thio)-methyl)-4-fluorobiphenyl-2-carboxamide

Cas 1820758-44-8
C₂₄ H₁₈ F N₃ O₄ S
4′-((5-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl-thio)-methyl)-4-fluorobiphenyl-2-carboxamide



Glycogen synthase kinase-3 (GSK-3) is a constitutively active, ubiquitous serine/threonine kinase that takes part in a number of physiological processes ranging from glycogen metabolism to apoptosis. GSK-3 is a key mediator of various signaling pathways, such as the Wnt and the insulin/AKT signaling pathways.
Therefore, dysregulation of GSK-3 has been linked to various human diseases, such as cancer, diabetes, and neurodegenerative diseases.Two related isoforms of GSK-3 exist in mammals, GSK-3α and -β, which share a sequence identity within their catalytic domains of 98%.
Beyond the catalytic domains they show significant differences. Although these isoforms are structurally related, they are not functionally equivalent, and one cannot compensate for loss of the other.
The debate on the respective contributions of the isoforms GSK-3α and GSK-3β on the pathogenesis of different diseases is ongoing.
Various studies indicate that the therapies of certain diseases benefit from specific targeting of GSK-3α and GSK-3β. GSK-3α was recently identified as a differentiation target in acute myeloid leukemia (AML). AML is a hematopoietic malignancy defined by uncontrolled proliferation and disrupted myeloid differentiation. AML is the second most common form of leukemia in adults.
The current treatment of AML with conventional chemotherapy is very aggressive yet ineffective for the majority of patients with the disease.Thus, alternative targeted treatment approaches for AML are highly desirable. GSK-3α recently emerged as a potential target in this disease.

PAPER

The challenge for glycogen synthase kinase-3 (GSK-3) inhibitor design lies in achieving high selectivity for one isoform over the other. The therapy of certain diseases, such as acute myeloid leukemia (AML), may require α-isoform specific targeting. The scorpion shaped GSK-3 inhibitors developed by our group achieved the highest GSK-3α selectivity reported so far but suffered from insufficient aqueous solubility. This work presents the solubility-driven optimization of our isoform-selective inhibitors using a scorpion shaped lead. Among 15 novel compounds, compound 27 showed high activity against GSK-3α/β with the highest GSK-3α selectivity reported to date. Compound 27 was profiled for bioavailability and toxicity in a zebrafish embryo phenotype assay. Selective GSK-3α targeting in AML cell lines was achieved with compound 27, resulting in a strong differentiation phenotype and colony formation impairment, confirming the potential of GSK-3α inhibition in AML therapy

Evaluation of Improved Glycogen Synthase Kinase-3α Inhibitors in Models of Acute Myeloid Leukemia

Theresa Neumann^†, Lina Benajiba^‡, Stefan Göring^†, Kimberly Stegmaier^‡, and Boris Schmidt^*†

^† Clemens Schöpf Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287 Darmstadt, Germany

^‡ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, United States

J. Med. Chem., Article ASAP

DOI: 10.1021/acs.jmedchem.5b01200

Publication Date (Web): October 23, 2015

Copyright © 2015 American Chemical Society

*Phone: +49 6151 163075. Fax: +49 6151 163278. E-mail: Schmidt_boris@t-online.de.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01200

http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01200/suppl_file/jm5b01200_si_001.pdf

compound 27 as a colorless solid. HPLC: 96%, t_R = 6.93 min.

¹H NMR (DMSO-d₆, 500 MHz, 300 K): δ (ppm) = 4.32 (td, J = 5.2 Hz, J = 3.7 Hz, 4H), 4.60 (s, 2H), 7.05 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 9.1 Hz, J = 2.7 Hz, 1H), 7.31 (td, J = 8.6 Hz, J = 2.8 Hz, 1H), 7.38 (m, 3H), 7.41 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.4 Hz, J = 2.1 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H).

¹³C NMR (DMSO, 125 MHz, 300 K): δ (ppm) = 35.6, 64.1, 64.4, 114.3 (d, J_C–F = 21 Hz), 115.0, 115.9 (d, J_C–F = 21 Hz), 115.9, 118.1, 120.0, 128.6 (2C), 128.8 (2C), 132.0 (d, J_C–F = 8 Hz), 134.8, 135.5, 138.9, 139.0 (d, J_C–F = 7 Hz), 143.8, 146.7, 160.9 (d, J_C–F = 247 Hz), 162.7, 164.9, 169.5.

EI-MS: m/z = 463 (100, [M⁺]), 464 (26, [M⁺ + H]), 465 (7, [M⁺ + 2H].

ABOUT  Boris Schmidt

Boris Schmidt

Prof. Dr.

Technical University Darmstadt, Darmstadt · Clemens Schöpf-Institute of Chemistry and Biochemistry

• 
  Technical University Darmstadt

  Clemens Schöpf-Institute of Chemistry and Biochemistry

  Darmstadt, Hessen, Germany

  *Phone: +49 6151 163075. Fax: +49 6151 163278.

  E-mail: Schmidt_boris@t-online.de.

RESEARCH EXPERIENCE

• Mar 2002–present
  Technische Universität Darmstadt · Clemens Schöpf Institut für Organische Chemie und Biochemie
  Germany · Darmstadt
• May 1999–Feb 2002, Novartis, Novartis Pharma AG
  Switzerland · Basel
• May 1994–Apr 1999
  Leibniz Universität Hannover · Institute of Organic Chemistry
  Germany · Hannover

AWARDS & ACHIEVEMENTS

• Nov 2012
  Award: Hans AND Ilse Breuer Award Alzheimer Research

.................................................
ABOUT Theresa Neumann

Theresa Neumann

Technical University Darmstadt, Darmstadt · Clemens Schöpf-Institute of Chemistry and Biochemistry

• 
  Technical University Darmstadt

  Clemens Schöpf-Institute of Chemistry and Biochemistry

  Darmstadt, Hessen, Germany

////////

Analytical Characterization of new related impurities of Diltiazem, DTZ II (B)

 



........

.

NOTE DTZ (A) IS DILTIAZEM AND OTHER TWO ARE IMPURITIES


 

Structure elucidation of DTZ-II impurity In the positive mass spectra, the protonated [M+H]⁺ molecular ion was detected at m/z 370.1. The even m/z number of [M+H]⁺ ions suggest that DTZ-II contains odd number of nitrogen atoms (nitrogen rule). From these results the molecular ion of DTZ-II was found to be at m/z 369. The mass difference between Diltiazem and DTZ-II was found to be 45 amu less. The positive HR-MS spectrum showed protonated molecular ion at m/z 370.1131 corresponding to molecular formula C₂₀H₂₀NO₄S. When compared with the molecular formula of Diltiazem, there was a difference of C₂H₇N. The difference can be rationalized in terms of the loss of trimethyl amine moiety. The presence of additional aromatic signal at δ 7.55 ppm in ¹H NMR (Figure 9) and corresponding carbon signal at 131.741 ppm in ¹³C NMR (Figure 10). The correlation between the carbon and proton clearly observed in HSQC (Figure 11) and one methylene signal was observed in HSQC. The methylene proton at δ 4.38 and 4.71 ppm in ¹H NMR corresponding carbon signal at 99.41 ppm in ¹³C NMR. The aromatic methine proton at δ 7.55 ppm showed HMBC (Figure 12) correlations for carbon C5 and C7 positions at 140.808 and 165.121 ppm respectively (Figure 7). The aromatic methine proton at δ 7.55 ppm showed correlation with methylene proton at δ 4.38 and 4.71 ppm in COSY (Figure 13). NMR assignments are shown in Table 1. The above spectral data supports the assigned structure as 2-(4-methoxyphenyl)-4-oxo-5-vinyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl acetate (DTZ-II).

 

 

 


 


 



FOLLOW OTHERS IN .........http://www.orientjchem.org/vol31no3/analytical-characterization-of-two-new-related-impurities-of-diltiazem-by-high-resolution-mass-spectrometry-and-nmr-techniques/

Analytical Characterization of two new related impurities of Diltiazem by High Resolution Mass spectrometry and NMR techniques096

Volume 31, Number 3

Jagadeesh Narkedimilli^1,2,*, Y. Ravindrakumar¹ ,Sandeep Mohanty¹, T. Srinivasarao¹, A. Jayashree^2
1Dr. Reddy’s Laboratories Limited, API Plant-III, Medak District, Hyderabad 500072, Telangana, India.   ²Centre for chemical sciences & Technology, Institute of Science and Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad 500085, Telangana, India.   Corresponding author E-mail: jagadeeshn@drreddys.com
DOI : http://dx.doi.org/10.13005/ojc/310363
ABSTRACT: Diltiazem (DTZ) is an optically active calcium channel blocker having a benzodiazepine structure. Two impurities (referred as DTZ-I and DTZ-II) were detected with area percentages ranging from 0.1% to 0.15% during the impurity profile study of Diltiazem hydrochloride drug substance. A simple isocratic high performance liquid chromatographic method (HPLC) and liquid chromatography–mass spectrometry (LC–MS) were used for the detection. The impurities were isolated by preparative column chromatography. Analytical information from nuclear magnetic resonance and mass spectral data of the potential impurities revealed their structures as 2-(4-methoxyphenyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl acetate (DTZ-I) and 2-(4-methoxyphenyl)-4-oxo-5-vinyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl acetate (DTZ-II). Impurity identification, isolation and structure elucidation were discussed.
KEYWORDS: Diltiazem; Potential impurities; Isolation; characterization techniques

Copy the following to cite this article:

Jagadeesh N, Ravindrakumar Y, Mohanty S, Srinivasarao T, Jayashree A. Analytical Characterization of two new related impurities of Diltiazem by High Resolution Mass spectrometry and NMR techniques. Orient J Chem 2015;31(3).

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DILTIAZEM IS
































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