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GSK 2251052, Epetraborole, AN3365




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(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro- 2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gramnegative infections

(S)-3-aminomethylbenzoxaborole; ABX; AN-3365; GSK ‘052; GSK-052; GSK-2251052, GSK2251052, Epetraborole

[(S)-3-(aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy- 1,3-dihydro-2,1-benzoxaborole hydrochloride],

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride

1-Propanol, 3-(((3S)-3-(aminomethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborol-7-yl)oxy)-


MW 237.0614,

cas 1093643-37-8

Anacor Pharmaceuticals, Inc., INNOVATOR

Glaxosmithkline Llc DEVELOPER

Biomedical Advanced Research and Development Authority (BARDA)

GSK 2251052 • $38.5M over the 1st two years; up to $94M……..

Originally came from Anacor about ten years ago, then was picked up by GlaxoSmithKline, and it’s an oxaborole heterocycle that inhibits leucyl tRNA synthetase

GlaxoSmithKline recently announced a contract with the Biomedical Advanced Research and Development
Authority (BARDA), a US government preparedness organization ,  The award guarantees GSK $38.5 million over 2 years towards development of GSK2251052, a molecule co-developed with Anacor Pharma a few years back, as a counter-bioterrorism agent. The full funding amount may later increase to $94 million, pending BARDA’s future option.

The goal here is to develop “GSK ‘052”, as it’s nicknamed among med-chemists, into a new antibiotic against especially vicious and virulent Gram negative bacteria, such as the classic foes plague (Yersinia pestis) or anthrax (Bacillus anthracis).

Look closely at GSK’052 (shown above): that’s a boron heterocycle there! Anacor, a company specializing in boron based lead compounds, first partnered with GSK in 2007 to develop novel benzoxaborole scaffolds. This isn’t the first company to try the boron approach to target proteins; Myogenics (which, after several acquisitions, became Millennium Pharma) first synthesizedbortezomib, a boronic acid peptide, in 1995.

Stephen Benkovic (a former Anacor scientific board member) and coworkers at Penn State first discovered Anacor’s early boron lead molecules in 2001, with a screening assay. The molecules bust bacteria by inhibiting  leucyl-tRNA synthetase, an enzyme that helps bacterial cells to correctly tag tRNA with the amino acid leucine. Compounds with cyclic boronic acids “stick” to one end of the tRNA, rendering the tRNA unable to cycle through the enzyme’s editing domain. As a result, mislabeled tRNAs pile up, eventually killing the bacterial cell.

Inhibition of synthetase function turns out to be a useful mechanism to conquer all sorts of diseases.  Similar benzoxaborozoles to GSK ‘052 show activity against sleeping sickness (see Trypanosoma post by fellow Haystack contributor Aaron Rowe), malaria, and various fungi.

Boron-containing molecules such as benzoxaboroles that are useful as antimicrobials have been described previously, see e.g. “Benzoxaboroles – Old compounds with new applications” Adamczyk-Wozniak, A. et al., Journal of Organometallic Chemistry Volume 694, Issue 22, 15 October 2009, Pages 3533-3541 , and U.S. Pat. Pubs. US20060234981 and US20070155699. Generally speaking, a benzoxaborole has the following structure and substituent numbering system:

Figure imgf000003_0001

Certain benzoxaboroles which are monosubstituted at the 3-, 6-, or 7-position, or disubstituted at the 3-/6- or 3-/7- positions are surprisingly effective antibacterials, and they have been found to bind to the editing domain of LeuRS in association with tRNALeu Such compounds have been described in US7, 816,344. Using combinations of certain substituted benzoxaboroles with norvaline and/or other amino acid analogs and their salts to: (a) reduce the rate of resistance that develops; and/or (b) decrease the frequency of resistance that develops; and/or (c) suppress the emergence of resistance, in bacteria exposed to compounds

2D chemical structure of 1234563-15-5

Epetraborole R-mandelate


2D chemical structure of 1234563-16-6

Epetraborole hydrochloride

Image result for GSK 2251052


Anacor Pharmaceuticals is out to change that. The Palo Alto, Calif.-based biotechnology company is developing a family of boron-containing small-molecule drugs. And with the assistance of Naeja Pharmaceutical, a Canadian contract research organization, Anacor has licensed one of those molecules to GlaxoSmithKline and taken another one into Phase III clinical trials.

Anacor was founded in 2002 to develop technology created by Lucy Shapiro, a Stanford University bacterial geneticist, and Stephen J. Benkovic, a Pennsylvania State University organic chemist. Through a long-standing scientific collaboration, the two researchers had discovered boron-containing compounds that inhibited specific bacterial targets.

Lucy ShapiroLucy Shapiro is a Professor in the Department of Developmental Biology at Stanford University School of Medicine where she holds the Virginia and D. K. Ludwig Chair in Cancer Research and is the Director of the Beckman Center for Molecular and Genetic Medicine. She is a member of the Scientific Advisory Board of Ludwig Institute for Cancer Research and is a member of the Board of Directors of Pacific Biosciences, Inc. She founded the anti-infectives discovery company, Anacor Pharmaceuticals, and is a member of the Anacor Board of Directors.  Professor Shapiro has been the recipient of multiple honors, including: election to the American Academy of Arts and Sciences, the US National Academy of Sciences, the US Institute of Medicine, the American Academy of Microbiology, and the American Philosophical Society. She was awarded the FASEB Excellence in Science Award, the 2005 Selman Waksman Award from the National Academy of Sciences, the Canadian International 2009 Gairdner Award, the 2009 John Scott Award, the 2010 Abbott Lifetime Achievement Award, the 2012 Horwitz Prize and President Obama awarded her the National Medal of Science in 2012. Her studies of the control of the bacterial cell cycle and the establishment of cell fate has yielded valuable paradigms for understanding the bacterial cell as an integrated system in which the transcriptional circuitry is interwoven with the three-dimensional deployment of key regulatory and morphological proteins, adding a spatial dimension to the systems biology of regulatory networks.


Stephen J. Benkovic

Stephen J. Benkovic

  • Evan Pugh University Professor and Eberly Chair in Chemistry

414 Wartik Laboratory
University Park, PA 16802
(814) 865-2882



Naeja was a three-year-old contract research firm run by Ronald Micetich and his son Christopher Micetich. Based in Edmonton, Alberta, the firm is staffed by chemists and biologists from a variety of nations who have found Canada welcoming to highly educated immigrants.

GSK. Last July, the British firm paid Anacor $15 million and exercised its option to take over development of AN3365. David J. Payne, vice president of GSK’s antibacterial drug discovery unit, lauded the compound, now renamed GSK2251052, as having “the potential to be the first new-class antibacterial to treat serious hospital gram-negative infections in 30 years.” GSK chemists have since developed a stereospecific synthesis for commercial-scale production

David J. Payne, vice president of GSK’s antibacterial drug discovery unit

David J Payne Dr Payne holds a BSc in Biochemistry from Brunel University, UK, and a PhD and DSc from The Medical School, University of Edinburgh, UK. Dr Payne has 20 years of experience in antibacterial drug discovery and is currently Vice President and Head of the Antibacterial Discovery Performance Unit (DPU) within the Infectious Diseases Centre of Excellence in Drug Discovery (ID CEDD) where he is responsible for GSK’s antibacterial research effort from discovery to clinical proof of concept (up to Phase II clinical trials). At GSK, Dr Payne has played a leading role in redesigning the strategy for antibacterial research and has helped create long-term alliances with innovative biotechnology companies which has expanded GSK’s discovery pipeline. Furthermore, he has created industry-leading partnerships with the Wellcome Trust and the Defense Threat Reduction Agency (US Department of Defense) to accelerate GSK’s antibacterial programmes. To date, Dr Payne has been involved with the progression of a broad diversity of novel mechanism antibacterial agents into development. Dr Payne has authored more than 190 papers and conference presentations.





    General procedure for Chiral Synthesis of 3-aminomethylbenzoxaboroles

  • Figure US20090227541A1-20090910-C00108
    Figure US20090227541A1-20090910-C00109
      4-(3-Aminomethyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyramide acetate salt (A5)

    • Figure US20090227541A1-20090910-C00175

4-[2-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-3-formyl-phenoxy]-butyric acid ethyl ester

    • Figure US20090227541A1-20090910-C00176
    • A mixture of 4-(2-bromo-3-formyl-phenoxy)-butyric acid ethyl ester (5.50 g, 17.5 mmol), bis(neopentyl glucolato)diboron (6.80 g, 30.1 mmol), PdCl2(dppf).CH2Cl2 (1.30 g, 1.79 mmol), and KOAc (5.30 g, 54.1 mmol) in anhydrous THF (600 mL) was heated with stirring at 80° C. (bath temp) O/N under an atmosphere of N2. The mixture was then filtered through Celite and concentrated in vacuo to approximately one quarter of the original volume. The resulting precipitate was isolated by filtration. The precipitate was washed with THF and EtOAc and the combined filtrate was concentrated in vacuo to give an oily residue which was used directly in the next reaction without further purification.
    • 1H NMR (400 MHz, CDCl3) δ (ppm): 9.95 (s, 1H), 7.47-7.39 (m, 2H), 7.09-7.07 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 4.09-4.01 (m, 2H), 3.83 (s, 3H), 3.66 (s, 3H), 2.53 (t, J=8.0 Hz, 2H), 2.19-2.07 (m, 2H), 1.32-1.22 (m, 3H), 0.98 (s, 6H).

4-(1-Hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid ethyl ester

    • Figure US20090227541A1-20090910-C00177
    • MeNO2 (1.3 mL, 25 mmol) was added dropwise to a stirred solution of crude 4-[2-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-formyl-phenoxy]-butyric acid methyl ester (9.4 g), NaOH (1.0 g, 25 mmol) and H2O (35 mL) in MeCN (90 mL) at rt. The mixture was stirred at rt O/N and then acidified (pH 2) using 4 M HCl. The THF was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (10% to 30% EtOAc in hexane) to give the title compound as a yellow oil: yield 2.52 g (45% over 2 steps).
    • 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.04 (s, 1H), 7.46-7.42 (m, 1H), 7.07-7.05 (m, 1H), 6.88-6.86 (m, 1H), 5.87 (d, J=8.2 Hz, 1H), 5.69 (dd, J=9.2, 2.5 Hz, 1H), 5.29 (dd, J=13.3, 2.7 Hz, 1H), 4.14-3.94 (m, 5H), 2.55-2.44 (m, 2H), 2.02-1.88 (m, 2H), 1.16 (t, J=7.2 Hz, 3H); MS (ESI) m/z=322 (M−1, negative).

4-(1-Hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid

  • Figure US20090227541A1-20090910-C00178
  • A mixture of 4-(1-hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid ethyl ester (2.51 g, 7.78 mmol), 10% NaOH (17 mL), and 1:1 MeOH/H2O (70 mL) was stirred at rt for 5 h. The MeOH was removed in vacuo and the remaining aqueous layer was acidified to pH 1 using 2 M HCl. The aqueous layer was then extracted with EtOAc. The organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound as a pale yellow foam: yield 1.85 g (81%).
  • 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.08 (bs, 1H), 9.01 (bs, 1H), 7.46-7.41 (m, 1H), 7.06-7.04 (m, 1H) 6.89-6.87 (m, 1H), 5.70 (dd, J=7.0, 2.3 Hz, 1H), 5.30 (dd, J=13.3, 2.3 Hz, 1H), 4.55 (dd, J=13.6, 4.2 Hz, 1H), 4.03 (t, J=6.6 Hz, 2H), 2.40 (t, J=7.5 Hz, 2H), 1.95-1.89 (m, 2H); MS (ESI) m/z=296 (M+1, positive).
      3-Aminomethyl-6-(2-hydroxy-propoxy)-3H-Benzo[c][1,2]oxaborol-1-ol acetate salt (A31)

    • Figure US20090227541A1-20090910-C00261

4-(2-Benzyloxy propoxy-2-bromobenzaldehyde

    • Figure US20090227541A1-20090910-C00262
    • A mixture of 2-bromo-4-fluoro-benzaldehyde (30.0 g, 148 mmol), Na2CO3 (78.31 g, 738.8 mmol) and 2-benzyloxy propanol (24.56 g, 147.8 mmol) in anhydrous DMSO (300 mL) was heated with stirring at 130° C. (bath temp) for 72 h under N2. The reaction mixture was cooled to rt and diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexane to 30% EtOAc in hexane) to give the title compound: yield 3.84 g (7%).
    • 1H NMR (400 MHz, CDCl3) δ (ppm): 10.22 (s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.42-7.20 (m, 5H), 7.12 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.8, 2.2 Hz, 1H), 4.52 (s, 2H), 4.16 (t, J=6.2 Hz, 2H), 3.65 (t, J=6.1 Hz, 2H), 2.10 (q, J=6.2 Hz, 2H).

4-(2-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[/, 3, 2]dioxaborolan-2-yl)-benzaldehyde

    • Figure US20090227541A1-20090910-C00263
    • General procedure 5: 4-(2-benzyloxy propoxy-2-bromobenzaldehyde (4.84 g, 13.9 mmol), B2pin2 (5.27 g, 20.8 mmol), KOAc (4.08 g, 41.6 mmol), PdCl2(dppf).CH2Cl2 (811 mg, 8 mol %), and 1,4-dioxane (50 mL). Purification: Biotage (gradient from 2% EtOAc/hexane to 20% EtOAc/hexane): yield 4.0 g (70%).
    • 1H NMR (400 MHz, CDCl3) δ (ppm): 10.36 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.43-7.14 (m, 6H), 7.01 (dd, J=8.6, 2.7 Hz, 1H), 4.53 (s, 2H), 4.18 (t, J=6.2 Hz, 2H), 3.66 (t, J=6.1 Hz, 2H), 2.11 (q, J=6.1 Hz, 2H), 1.40 (s, 12H).


    • Figure US20090227541A1-20090910-C00264
    • General procedure 8: 4-(2-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.0 g, 7.6 mmol), MeNO2 (924 mg, 15.1 mmol), NaOH (605 mg, 15.1 mmol), and H2O (10 mL). Purification: flash chromatography (10% EtOAc/hexane to 40% EtOAc): yield 820 mg (30%).
    • 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.46 (bs, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.41-7.18 (m, 6H), 7.09 (dd, J=8.6, 2.3 Hz, 1H), 5.71 (dd, J=9.2, 2.5 Hz, 1H), 5.31 (dd, J=13.3, 2.7 Hz, 1H), 4.58-4.40 (m, 3H), 4.08 (t, J=6.2 Hz, 2H), 3.60 (t, J=6.2 Hz, 2H), 2.08-1.94 (m, 2H).

3-Aminomethyl-6-(2-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol acetate salt (A31)

  • Figure US20090227541A1-20090910-C00265
  • General procedure 13: 6-(2-benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (820 mg, 2.29 mmol), 20% Pd(OH)2 (850 mg, 1 equiv w/w), and AcOH (40 mL). Purification: preparative HPLC: yield 120 mg (22%).
  • 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.32 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.98 (bs, 1H), 4.04 (t, J=6.2 Hz, 2H), 3.56 (t, J=6.2 Hz, 2H), 3.03-2.85 (m, 1H), 2.61 (dd, J=12.9, 7.0 Hz, 1H), 1.89 (s, 3H), 1.97-1.67 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 97.44% (MaxPlot 200-400 nm), 97.77% (220 nm).
      • 7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)

      • Figure US20090227541A1-20090910-C00333


      • Figure US20090227541A1-20090910-C00334
      • NaH (2.95 g, 72.4 mmol) was added to an ice-cold solution of 2,3-dihydroxybenzaldehyde (5.0 g, 36 mmol) in anhydrous DMSO (45 mL). Benzyl-3-bromopropyl ether (6.45 mL, 36.2 mmol) was then added and the mixture was stirred at rt for 12 h. The mixture was neutralized using 1 N HCl and then extracted with EtOAc. The organic fraction was washed with H2O and concentrated in vacuo. The residue was purified by flash chromatography (8:2 hexane/EtOAc) to give the title compound as a brown oil: yield 8.40 g (81%).
      • [0891]
        1H NMR (400 MHz, CDCl3) δ (ppm): 9.93 (s, 1H), 7.36-7.23 (m, 6H), 7.20-7.16 (m, 2H), 6.98-6.91 (m, 1H), 4.53 (s, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.70 (t, J=6.1 Hz, 2H), 2.19-2.16 (m, 2H).

    3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[/, 3, 2]dioxaborolan-2-yl)-benzaldehyde

      • Figure US20090227541A1-20090910-C00335
      • [0893]
        General procedure 6: 3-(3-benzyloxy-propoxy)-2-hydroxy-benzaldehyde (7.6 g, 26 mmol), pyridine (3.42 mL, 42.5 mmol), Tf2O (4.60 mL, 27.9 mmol), and CH2Cl2 (200 mL): yield 8.60 g (77%).
      • [0894]
        1H NMR (400 MHz, CDCl3) δ (ppm): 10.23 (s, 1H), 7.54-7.47 (m, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.36-7.22 (m, 6H), 4.52 (s, 2H), 4.23 (t, J=6.3 Hz, 2H), 3.71 (t, J=6.1 Hz, 2H), 2.21-2.17 (m, 2H).
      • [0895]
        General procedure 5: trifluoro-methanesulfonic acid 2-(3-benzyloxy-propoxy)-6-formyl-phenyl ester (8.0 g, 19 mmol), B2pin2 (9.71 g, 38.2 mmol), KOAc (5.71 g, 57.4 mmol), PdCl2(dppf).CH2Cl2 (1.39 g, 1.89 mmol), and anhydrous dioxane (160 mL). Purification: flash chromatography (9:1 hexane/EtOAc): yield 4.80 g (43%)-some pinacol contamination, used without further purification.
      • [0896]
        1H NMR (400 MHz, CDCl3) δ (ppm): 9.93 (s, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.41-7.36 (m, 1H), 7.35-7.24 (m, 5H), 7.08 (d, J=7.8 Hz, 1H), 4.50 (s, 2H), 4.10 (t, J=6.3 Hz, 2H), 3.67 (t, J=6.3 Hz, 2H), 2.11 (quin, J=6.2 Hz, 2H), 1.43 (s, 12H).

    7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)

      • Figure US20090227541A1-20090910-C00336
      • General procedure 8: 3-(3-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (36 g, 91 mmol), MeNO2 (16.6 g, 273 mmol), NaOH (3.64 g, 83 mmol), H2O (180 mL), and THF (50 mL). Purification: flash chromatography (1:1 hexane/EtOAc). A47 was isolated as a light yellow oil: yield 15.9 g (50%).
      • 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.05 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.35-7.20 (m, 5H), 7.06 (d, J=7.4 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.70 (dd, J=9.4, 2.3 Hz, 1H), 5.29 (dd, J=13.7, 2.7 Hz, 1H), 4.53 (dd, J=13.3, 9.4 Hz, 1H), 4.45 (s, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.60 (t, J=6.3 Hz, 2H), 2.04-1.91 (m, 2H); MS (ESI): m/z=356 (M−1, negative); HPLC purity: 99.35% (MaxPlot 200-400 nm), 97.32% (220 nm).

    Alternative synthesis of 3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A46)

    • Figure US20090227541A1-20090910-C00337
    • General procedure 13: A47 (0.50 g, 1.4 mmol), 20% Pd(OH)2/C (0.5 g, 1:1 w/w), AcOH (20 mL), and H2O (0.24 mL). The filtrate was concentrated and treated with 4 N HCl to give the title compound as a colorless solid: yield 0.22 g (47%).
    • 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.42 (t, J=7.8 Hz, 1H), 6.97-6.90 (m, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.20 (dd, J=9.2, 2.5 Hz, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.54 (t, J=6.2 Hz, 2H), 3.40 (dd, J=13.3, 2.7 Hz, 1H), 2.68 (dd, J=13.1, 9.2 Hz, 1H), 1.88-1.78 (m, 2H); MS (ESI): m/z=238 (M+1, positive).



      3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A46)

    • Figure US20090227541A1-20090910-C00328

Synthesis of 3-(3-Benzyloxy-propoxy)-2-bromo-benzaldehyde (C)

    • Figure US20090227541A1-20090910-C00329
    • To a 5° C. solution of compound A (15.0 g, 0.075 mol), B (12.0 ml, 0.075 mol) and triphenylphosphine (19.6 g, 0.075 mol) in 200 ml of anhydrous THF was added DIAD (14.8 ml, 0.075 mol) drop by drop over a period of 15 minutes. The resulting solution was warmed to room temperature over a period of 5 h and the solvent was evaporated in vacuo. The residue was dissolved in 150 ml of EtOAc and the organic layer washed with water, brine and dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of hexane to 5% EtOAc/hexane) generating 13.0 g (50% yield) of C [3-(3-benzyloxy-propoxy)-2-bromo-benzaldehyde].
    • 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.41 (s, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.32-7.25 (m, 6H), 7.08 (d, J=8.0 Hz, 1H), 4.54 (s, 2H), 4.16 (t, J=6.0 Hz, 2H), 3.74 (t, J=5.8 Hz, 2H), 2.19-2.14 (m, 2H).

3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (D)

    • Figure US20090227541A1-20090910-C00330
    • Compound C (8.9 g, 0.025 mol), KOAc (7.5 g, 0.076 mol), and bis(pinacolato)diboron (12.9 g, 0.051 mol) were dissolved in 50 ml of dry DMF and degassed for 30 minutes. To this was added PdCl2(dppf).DCM (0.56 g, 0.76 mmol) and the contents were again degassed for 10 minutes and then heated to 90° C. for 4 h. An additional quantity of PdCl2(dppf).DCM (0.2 g, 0.27 mmol) was added and heating was continued for an additional 2 h. The reaction was cooled to RT, filtered through celite and the solvent evaporated in vacuo. The residue was dissolved in DCM, washed with brine and the organic layer dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of hexane to 5% EtOAc/hexane) provided 5.4 g (53% yield) of D [3-(3-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde].
    • 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.91 (s, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.32-7.27 (m, 5H), 7.06 (d, J=8.4 Hz, 1H), 4.49 (s, 2H), 4.08 (t, J=6.0 Hz, 2H), 3.67 (t, J=6.2 Hz, 2H), 2.11-2.08 (m, 2H), 1.44 (s, 12H). ESI+MS m/z, 397 (M+H)+.

7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (E)

  • Figure US20090227541A1-20090910-C00331
  • To an ice cold solution of NaOH (0.68 g, 0.017 mol) in 10 ml of water was added a solution of compound D (6.8 g, 0.017 mol) dissolved in 5 ml of THF. After 15 minutes, nitromethane (0.93 ml, 0.017 mol) was added drop by drop and the content stirred at RT overnight. The THF was evaporated under reduced pressure and the contents acidified to pH-3 with 2N HCl. The aqueous layer was extracted with EtOAc several times, and the combined ethyl acetate layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of 10% EtOAc/hexane to 30% EtOAc/hexane) provided 3.7 g (55% yield) of E [7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol] 3.7 g.
  • 1H NMR (400 MHz, DMSO-d6+D2O (0.01 ml)) δ (ppm) 7.49 (t, J=7.8 Hz, 1H), 7.34-7.25 (m, 5H), 7.08 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 5.23 (dd, J=13.2, 2.4 Hz, 1H), 4.58-4.53 (m, 1H), 4.47 (s, 2H), 4.12 (t, J=6.2 Hz, 2H), 3.63 (t, J=6.0 Hz, 2H), 2.04-2.00 (m, 2H). ESI-MS m/z, 356 [M−H]. HPLC purity: 97.12% (MaxPlot 200-400 nm).
    3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol (A46)

  • Figure US20090227541A1-20090910-C00332
  • Compound E (6.0 g, 0.016 mol) was dissolved in 50 ml of glacial acetic acid and to it was added Pd(OH)2 on Carbon (20% metal content, 50% weight-wet) (5.2 g) and the content set for hydrogenation in a Parr shaker at 45 psi for 2 h. The reaction was checked for completion and the contents were filtered through Celite. The solvent was evaporated under reduced pressure at ambient temperature to yield a gummy material. To this three times was added 15 ml of dry toluene and evaporated yielding a fluffy solid. Purification was accomplished by preparative HPLC (C18 column, using acetonitrile and 0.1% AcOH/water solution) provided 1.5 g (45% yield) of compound A46 [3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol] with 0.33 mol % acetic acid (by HNMR).
  • 1H NMR (400 MHz, DMSO-d6+D2O (0.01 ml)) δ (ppm) 7.52 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 5.29 (dd, J=9.2, 2.4, 1H), 4.12 (t, J=6.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.48 (dd, J=13.2, 2.8 Hz, 1H), 2.80-2.74 (m, 1H), 1.92 (t, J=6.2 Hz, 2H). ESI+MS m/z, 238 [M+H]+. HPLC purity: 95.67% (MaxPlot 200-400 nm) and 96.22% (220 single wavelength).


    (S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A49)
      (3-Benzyloxy)-1-bromo-propane (2)

    • Figure US20090227541A1-20090910-C00339
    • A solution of 1 (160 g, 962.58 mmol) and triphenylphosphine (277.72 g, 1.1 eq, 1058.83 mmol) was dissolved in dichloromethane (800 mL) and cooled to 0° C. (ice/water). A solution of carbon tetrabromide (351.16 g, 1.1 eq, 1058.83 mmol) in dichloromethane (200 mL) was added dropwise and the mixture was left to stir at rt for 18 h. The dichloromethane solvent was evaporated to obtain a white solid. The solid was treated with an excess of hexanes, stirred for 1 h, filtered off and the solvent was evaporated to yield a crude product. The crude product was purified by silica gel column chromatography using 5-10% ethyl acetate and hexane to obtain 2 (199 g, 91%) as a colorless liquid.

3-(3-Benzyloxy-propoxy)-2-hydroxy-benzaldehyde (4)

    • Figure US20090227541A1-20090910-C00340
    • To a solution of aldehyde 3 (27.47 g, 1 eq, 198.88 mmol) in 0.5 L of anhydrous DMSO was added sodium tertiary-butoxide (42.3 g, 2.2 eq, 440.31 mmol) portionwise. The reaction mixture was stirred at rt for 30 minutes. A brown color solution was formed. The reaction mixture was cooled to 0° C. and added bromide (56 g, 1.2 eq, 244.41 mmol) dropwise. The mixture was stirred at rt O/N. 90% of aldehyde 3 was converted to product. The reaction mixture was acidified to pH-3 and then extracted into EtOAc and washed with water. The organic layer was concentrated, the product was purified on silica gel column (EtOAc:hexane 80:20), to yield as compound 4 (48 g, 84.31% yield) (viscous oil).

Trifluoro-methanesulfonic acid 2-(3-benzyloxy-propoxy)-6-formyl-phenyl ester (5)

    • Figure US20090227541A1-20090910-C00341
    • To an ice cold solution of 4 (48 g, 1.0 eq, 167.72 mmol) in 200 mL of dry DCM was added pyridine (22 mL, 1.62 eq, 272.11 mmol). To the reaction mixture trifluoromethanesulfonic anhydride (33 mL, 1.16 eq, 196.14 mol) was added drop by drop. The mixture was stirred for 3 h at 0° C. The mixture was quenched with 500 mL of 1N HCl. The compound was then extracted into DCM (300 mL) and passed through a small silica gel column and concentrated to give compound 5 (57 g, 82% yield) as a pale yellow thick oil.

3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (6)

    • Figure US20090227541A1-20090910-C00342
    • Compound 5 (65 g, 1.0 eq, 155.5 mmol), bis(pinacolato)diboron (86.9 g, 2.2 eq, 342.11 mmol), KOAc (45.7 g, 3.0 eq, 466.5 mmol) were mixed together and 600 mL of dioxane was added. The mixture was degassed with N2 for 30 minutes and PdCl2(dppf).DCM (5.7 g, 0.05 eq, 7.77 mmol) was added. The resulting slurry was heated to 90° C. overnight. The solvent was evaporated, EtOAc was added and then filtered through a pad of Celite. The organic layer was then washed with water (2×150 mL) and the solvent was evaporated. Column chromatography using 15% EtOAc/hexanes gave compound 6 (37.1 g, 61% yield).

7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)

    • Figure US20090227541A1-20090910-C00343
    • A solution of compound 6 (36 g, 1.0 eq, 90.91 mmol) in 50 mL of THF was cooled to 0° C. Nitromethane (16.6 g, 3.0 eq, 272.72 mmol) was added, followed by an aqueous solution of NaOH (3.64 g in 180 mL of H2O). The reaction mixture was stirred at room temperature overnight. The starting material disappeared. The cyclization was afforded by adding 1N HCl until the solution was acidified and then extracted into EtOAc. The EtOAc was evaporated and the mixture was triturated with water and decanted. Column chromatography using 50% EtOAc/hexanes gave compound A47 (15.9 g, 50% yield).

(R) and (S) 7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol

    • Figure US20090227541A1-20090910-C00344
    • 4.82 g of (A47) was resolved via chiral HPLC using CHIRALPAK ADH column and CO2:methanol (86:14) as eluent (25° C. UV detection was monitored at 230 nm. Two peaks, (S)-7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol and (R)-7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol were collected and evaporated to yellow oils. Analysis of the pooled fractions using a CHIRALPAK ADH 4.6 mm ID×250 mm analytical column and the same mobile phase provided the (S) enantiomer [0.7 g (29% yield)] with a retention time of 6.11 min and a 98.2% ee. The (R) enantiomer [1.0 g (41% yield)] had a retention time of 8.86 min and a 99.6% ee.

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol (A49)

  • Figure US20090227541A1-20090910-C00345
  • (A47) (550 mg, 1.57 mmol) was dissolved in 15 mL of glacial acetic acid. 280 mg of 20 wt % palladium hydroxide on carbon (Pearlman’s catalyst) was added and the reaction mixture was flushed with hydrogen 3× and hydrogenated at 55 psi for 3.5 hours. The mixture was filtered through Celite to remove catalyst and rinsed with methanol. Acetic acid was evaporated to obtain the crude product. HPLC purification gave 128 mg of the acetate salt of (A49). The acetate salt was treated with 10 mL of 2N HCl and stirred for 3 hours. The material was lyophilized overnight to obtain 93 mg of the hydrochloride salt of (A49) (Yield 22%).
  • 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.48 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.4 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 5.27 (d, J=9.4 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 2.82 (dd, J=13.3, 9.0 Hz, 1H), 1.95-1.83 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 98.74% (MaxPlot 200-400 nm), 98.38% (220 nm); Chiral HPLC=95.14% ee.


    (R)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol (A50)

  • Figure US20090227541A1-20090910-C00346
  • (R)-7-(3-benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (0.70 g, 2.0 mmol) was dissolved in 20 mL of glacial acetic acid. 350 mg of 20 wt % palladium hydroxide on carbon (Pearlman’s catalyst) was added and the reaction mixture was flushed with hydrogen 3× and hydrogenated at 55 psi for 3.5 hours. The mixture was filtered through Celite to remove catalyst and rinsed with methanol. Acetic acid was evaporated to obtain the crude product. HPLC purification gave 65 mg of pure compound. After purification, this acetate salt was combined with material from another reaction. This product was treated with 2N HCl (10 mL) and stirred for 3 h at rt. The material was lyophilized overnight to obtain 74 mg of the hydrochloride salt of (A50) (Yield 14%).
  • 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.48 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.4 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 5.27 (d, J=9.4 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 2.83 (dd, J=13.3, 8.6 Hz, 1H), 1.94-1.82 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 99.12% (MaxPlot 200-400 nm), 98.74% (220 nm); Chiral HPLC=98.82% ee.


US20040203094 * Sep 20, 2002 Oct 14, 2004 Martinis Susan A. Eucyl-tRNA synthetases and derivatives thereof that activate and aminoacylate non-leucine amino acids to tRNA adaptor molecules
US20070155699 * Aug 16, 2006 Jul 5, 2007 Anacor Pharmaceuticals Boron-containing small molecules
US20090227541 * Jun 19, 2008 Sep 10, 2009 Anacor Pharmaceuticals, Inc. Boron-containing small molecules



BIG TEAM Hernandez, front row, fifth from left, poses during a research meeting at Naeja’s headquarters.Anacor

BIG TEAM Hernandez, front row, fifth from left, poses during a research meeting at Naeja’s headquarters.

Dr. R. G. Micetich’s research career began in 1963 as a Research Scientist with R & L Molecular Research Ltd. (established by Dr. R. U. Lemieux). This company later became Raylo Chemicals Ltd. Dr. Micetich served as the Research Director (Pharmaceutical Research) of Raylo. During the period from 1963 to 1980 Dr. Micetich’s group was involved in pharmaceutical research and process development work in antibiotics and in NSAI’s (non-steroidal anti-inflammatory agents). This work produced a drug “Mofezolac” – a NSAI which is now marketed in Japan by the Japanese company “Yoshitomi”. Market ~ U.S. $60 million.

In 1980, Dr. R. G. Micetich joined the Faculty of Pharmacy, University of Alberta as an Adjunct Professor working on projects for international big Pharma companies. The work with Taiho Pharmaceutical Company in Japan has produced another drug – a beta-lactamase inhibitor – “TAZOBACTAM” which is now marketed worldwide. This drug now produces annual sales of over US$ 1 billion.

In 1987, Dr. Micetich established a joint venture research company with Taiho, Japan called SynPhar. SynPhar had numerous patents worldwide in various therapeutic areas and many compounds and classes of compounds at various stages of development up to late preclinical.

In view of the significant growth opportunities for SynPhar and in response to the changing international market place for pharmaceuticals, Dr. Micetich acquired and transferred all the assets including intellectual property, equipment and fixtures from SynPhar to NAEJA Pharmaceutical Inc. in 1999. NAEJA is a private Albertan company, founded by the Micetich family which from an initial staff in August 1999 of 40, has grown to 130 and is still growing. NAEJA is a completely self-supporting private company with no venture capital, nor private, nor government funding. The majority of NAEJA employees hold Ph.D.’s. NAEJA has collaborative agreements with pharmaceutical companies around the world. Based on its own intellectual property, NAEJA also has a number of co-development agreements with biotech companies worldwide. Dr. Micetich laid the seeds of foundation for NAEJA and the company continues after his passing, building his legacy.

Dr. R. G. Micetich boasted over 100 publications in well know scientific journals and composed over 100 patents taken out in many countries…………..


RONALD G. MICETICH (1931-2006): A Scientific Career Ronald Micetich was born in Podanur, Coimbatore (South India). Following receipt of B.Sc. Honors (Chemistry, Loyola College, Madras) and M.A. (Chemistry, Madras University) degrees in India, Ron obtained a Ph.D. (Organic Chemistry, University of Saskatchewan, Canada) in 1962. Ron initiated his interest in microbiology while he was a postdoctoral fellow at the National Research Council of Canada. During the period 1963-1980, Ron held a number of industrial appointments where he rapidly advanced his industrial scientific career (research scientist → associate research director → acting research director → director pharmaceutical / agricultural research) at Raylo Chemicals in Edmonton, Alberta. In 1981 Ron joined the Faculty of Pharmacy & Pharmaceutical Sciences at the University of Alberta as an Adjunct Professor at which time a highly successful drug development program was established with Taiho Pharmaceuticals. This joint industrial collaboration led to the birth of SynPhar with Dr. Micetich as Chairman of the Board, President, CEO and Research Director (1987-1999). Ron, again as Chairman of the Board, CEO and Research Director, established NAEJA (North America, Europe, Japan, Asia) Pharmaceuticals in 1999 with a rollover of assets, including staff, equipment and intellectual property, from SynPhar Laboratories. What began as a full fledged pharmaceutical company with an extensive intellectual property portfolio and a proven track record evolved into an internationally respected pharmaceutical outsource service provider. NAEJA has carved a unique niche in the outsource industry offering extensive discovery experience and expertise. Today, NAEJA has over 120 staff that consists of over 90% scientists holding PhD degrees.,………….see link below

[PDF]RONALD G. MICETICH – University of Alberta – Journal …

Dr.Muhammed Majeed with Dr. Ronald Micetich, CEO, Naeja Pharmaceuticals, Edmonton Canada’.
Christopher Micetich
Christopher Micetich

Founder, President & CEO, Board Chairman

Fedora Pharmaceuticals Inc.

January 2012 – Present (3 years 10 months)Edmonton, Alberta, Canada

See us at:

Fedora Pharmaceuticals has developed a family of beta-lactamase inhibitors designed to have activity against pathogens containing all four classes of beta-lactamases. These promising novel beta-lactamase inhibitors, used in combination with various beta-lactam antibiotics to treat those antibiotic infections currently resistant to therapy, have recently been licensed to Swiss-based pharmaceutical giant, Hoffman La Roche Ltd. in what is being touted as one of the largest biotech licensing deals ever signed in Canadian history!

Fedora Pharmaceuticals in Canada and Meiji Seika in Japan, with shared world-wide rights, have teamed and jointly entered into this significant tripartite agreement with Roche. Under the terms of the agreement, Roche will obtain exclusive rights from both companies to develop and commercialize the agent worldwide excluding Japan. Fedora and Meiji will receive from Roche; an upfront payment, development, regulatory and sales event milestone payments in addition to royalties on sales of products. While the details of the amounts have not been disclosed a total deal value of US$750 Million in addition to royalties has been announced.

Fedora was founded in 2012 and is headquartered in Edmonton, Alberta, Canada.

President & CEO, Founder


August 1999 – Present (16 years 3 months)

NAEJA Pharmaceuticals Inc. is a privately controlled pharmaceutical CRO specializing in early stage drug discovery research with particular expertise in the area of Medicinal Chemistry. NAEJA employs highly skilled PhD scientists recruited from around the globe.

The company boasts a very long and successful track record of rapidly advancing drugs through discovery into the clinic. Several drugs in latter stages of clinical development and on the market today have originated from NAEJA. Most recently is Fedora Pharmaceuticals US $750M licensing deal to Hoffman La Roche Ltd that originated from the laboratories of NAEJA.

As a privately controlled company, NAEJA are very responsive to client’s needs offering many years of drug discovery experience to successfully find ways to advance research programs in a timely, cost effective and efficient manner. NAEJA’s longstanding track record is a testimony in itself!

////////////GSK 2251052, Epetraborole, Christopher Micetich, Ronald Micetich, Naeja Pharmaceuticals


1 Comment

  1. larryhbern says:

    Reblogged this on Leaders in Pharmaceutical Business Intelligence and commented:
    Using combinations of certain substituted benzoxaboroles with norvaline and/or other amino acid analogs and their salts to: (a) reduce the rate of resistance that develops; and/or (b) decrease the frequency of resistance that develops; and/or (c) suppress the emergence of resistance, in bacteria exposed to compounds

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