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Synlett 2014; 25(10): 1443-1447
DOI: 10.1055/s-0033-1341258
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Early ADME Evaluation of a Novel Scaffold, Tetrahydro-6H-pyrido[3,2-b]azepin-6-one

Koen Muylaert
a   Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium   Fax: +32(9)2646221   Email: Chris.Stevens@UGent.be
,
Martyna Jatczak
a   Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium   Fax: +32(9)2646221   Email: Chris.Stevens@UGent.be
,
Benjamin Wuyts
b   Drug Delivery and Disposition, KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, O&N II, Herestraat 49 – Box 921, 3000 Leuven, Belgium
,
Laurens M. De Coen
a   Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium   Fax: +32(9)2646221   Email: Chris.Stevens@UGent.be
,
Kristof Van Hecke
c   XStruct, Department of Inorganic and Physical Chemistry, Faculty of Sciences, Ghent University, Krijgslaan 281, S3, 9000 Gent, Belgium
,
Hans Loones
a   Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium   Fax: +32(9)2646221   Email: Chris.Stevens@UGent.be
,
Janneke Keemink
b   Drug Delivery and Disposition, KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, O&N II, Herestraat 49 – Box 921, 3000 Leuven, Belgium
,
Daniel García
a   Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium   Fax: +32(9)2646221   Email: Chris.Stevens@UGent.be
,
Sven Mangelinckx
a   Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium   Fax: +32(9)2646221   Email: Chris.Stevens@UGent.be
,
Pieter Annaert
b   Drug Delivery and Disposition, KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, O&N II, Herestraat 49 – Box 921, 3000 Leuven, Belgium
,
Christian V. Stevens*
a   Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium   Fax: +32(9)2646221   Email: Chris.Stevens@UGent.be
› Author Affiliations
Further Information

Publication History

Received: 14 March 2014

Accepted after revision: 27 March 2014

Publication Date:
12 May 2014 (online)

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Abstract

The synthesis and preliminary ADME evaluation of ­novel 4-(trifluoromethyl)-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepin-6-ones is presented. The key step is a ring expansion of 4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-ones via a Beckmann rearrangement. The rearrangement opens up possibilities to access novel unexplored scaffolds for medicinal chemistry. The biopharmaceutical profiling revealed a strong structural dependency of the druglike properties.

Key words

bioorganic chemistry - fluorine - fused-ring systems - pyridines - ring expansion

Supporting Information

    for this article is available online at http://www.thieme-connect.com/products/ejournals/journal/ 10.1055/s-00000083.
  • Supporting Information
 

  • References and Notes

  • 1 Evans BE, Rittle KE, Bock MG, DiPardo RM, Freidinger RM, Whitter WL, Lundell GF, Veber DF, Anderson PS. J. Med. Chem. 1988; 31: 2235
    CrossrefPubMed
  • 2 Nicolaou KC, Pfefferkorn JA, Roecker AJ, Cao G.-Q, Barluenga S, Mitchell HJ. J. Am. Chem. Soc. 2000; 122: 9939
    Crossref
  • 3 Horton DA, Bourne GT, Smythe ML. Chem. Rev. 2003; 103: 893
    CrossrefPubMed
  • 4 Mason JS, Morize I, Menard PR, Cheney DL, Hulme C, Labaudiniere RF. J. Med. Chem. 1999; 42: 3251
    Crossref
  • 5 Costantino L, Barlocco D. Curr. Med. Chem. 2006; 13: 65
    Crossref
  • 6 Barrios V, Escobar C. Expert Rev. Cardiovasc. Ther. 2010; 8: 1653
    Crossref
  • 7 Lüscher B, Keller CA. Pharmacol. Ther. 2004; 102: 195
    Crossref
  • 8 Bioorganic and Medicinal Chemistry of Fluorine . Begue J.-P, Bonnet-Delpon D. John Wiley and Sons; Hoboken, NJ: 2008
    CrossrefGoogle Scholar
  • 9 Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
    CrossrefPubMed
  • 10 Hoyt SB, London C, Park M. Tetrahedron Lett. 2009; 50: 1911
    Crossref
  • 11 Hussenether T, Huebner H, Gmeiner P, Troschütz R. Bioorg. Med. Chem. 2004; 12: 2625
    CrossrefPubMed
  • 12 Setoi H, Ohkawa T, Zenkoh T, Hemmi K, Tanaka H. EP 620216A1, 1994
  • 13 Fisher MH, Wyvratt MJ, Schoen WR, Devita RJ. WO 9216524A1, 1992
  • 14 Paglietti G, Loriga M. J. Chem. Res., Synop. 1986; 284
  • 15 Bauer A, Weber KH, Unruh M. Arch. Pharm. (Weinheim, Ger.) 1972; 305: 557
    CrossrefPubMed
  • 16 Liu J, Guideen D. WO 2012015693A1, 2012
  • 17 Marfat A, Robinson RP. US 5811432A, 1998
  • 18 Robinson RP, Donahue KM, Son PS, Wagy SD. J. Heterocycl. Chem. 1996; 33: 287
    Crossref
  • 19 Robinson RP, Marfat A. EP 436333A2, 1991
  • 20 Kiyoto T, Ando J, Tanaka T, Tsutsui Y, Yokotani M, Noguchi H, Ushiyama F, Urabe H, Horikiri H. JP 2009149618A, 2009
  • 21 Kiyoto T, Ando J, Tanaka T, Tsutsui Y, Yokotani M, Noguchi T, Ushiyama F, Urabe H, Horikiri H. WO 2007138974A1, 2007
  • 22 Tsoung J, Panteleev J, Tesch M, Lautens M. Org. Lett. 2014; 16: 110
    Crossref
  • 23 Matsufuji T, Shimada K, Kobayashi S, Kawamura A, Fujimoto T, Arita T, Hara T, Konishi M, Abe-Ohya R, Izumi M, Sogawa Y, Nagai Y, Yoshida K, Takahashi H. Bioorg. Med. Chem. Lett. 2014; 24: 750
    Crossref
  • 24 Bracke ME, Vanhoecke BW. A, Derycke L, Bolca S, Possemiers S, Heyerick A, Stevens CV, De Keukeleire D, Depypere HT, Verstraete W, Williams CA, McKenna ST, Tomar S, Sharma D, Prasad AK, DePass AL, Parmar VS. Anti-Cancer Agents Med. Chem. 2008; 8: 171
    Crossref
  • 25 Rammeloo T, Stevens CV, De Kimpe N. J. Org. Chem. 2002; 67: 6509
    Crossref
  • 26 Rammeloo T, Stevens CV. Chem. Commun. 2002; 250
  • 27 Wauters I, De Blieck A, Muylaert K, Heugebaert TS. A, Stevens CV. Eur. J. Org. Chem. 2014; 1296
  • 28 Heugebaert T, Van Hevele J, Couck W, Bruggeman V, Van der Jeught S, Masschelein K, Stevens CV. Eur. J. Org. Chem. 2010; 1017
  • 29 Herbert B, Schumacher R, Dai G, Xie W. WO 2009055437A2, 2009
  • 30 Cyclohexane-1,3-dione (22.42 g, 200 mmol, 1 equiv) was dissolved in anhydrous toluene (250 mL) and NH4OAc (14.42 g, 200 mmol, 1 equiv) was added and refluxed under Dean–Stark conditions for 4 h.Compound 2: 1H NMR (300 MHz, CDCl3): δ = 1.99 (2H, tt, J = 6.1 Hz, J = 6.1Hz, CH2CH 2CH2), 2.30 (2 H, t, J = 6.1 Hz, CH 2CqNH2), 2.35 (2 H, t, J = 6.1Hz, CH 2CO), 4.59 (2 H, br. s, NH 2), 5.26 (1 H, CH). 13C NMR (75 MHz, CDCl3): δ = 21.8, 28.8, 35.9, 99.9, 167.2, 198.0.
  • 31 Volochnyuk DM, Pushechnikov AO, Krotko DG, Sibgatulin DA, Kovalyova SA, Tolmachev AA. Synthesis 2003; 1531
    Article in Thieme Connect
  • 32 3-Aminocyclohex-2-en-1-one (5 g, 1 equiv) was dissolved in AcOH (200 mL) and an appropriate 1-substituted 4,4,4-trifluoro-1,3-dione (1.5 equiv) was added and refluxed for 7 h.Compound 4a: 1H NMR (300 MHz, CDCl3): δ = 2.20 (2 H, tt, J = 6.1, 6.1 Hz, CH2CH 2CH2), 2.67 (3 H, s, CH3), 2.75 (2 H, t, J = 6.1Hz, CH 2CO), 3.20 (2 H, t, J = 6.1Hz, CH 2CqN), 7.45 (1 H, s, CH). 13C NMR (75 MHz, CDCl3): δ = 21.3, 25.1, 33.6, 39.8, 120.0, 122.5, 123.2, 137.3, 163.7, 165.4, 195.6. 19F NMR (282 MHz, CDCl3): δ = –61.7.
  • 33 Pyrko AN. Russ. J. Org. Chem. 2008; 44: 1215
    Crossref
  • 34 The appropriate 4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one (1 equiv) was dissolved in EtOH. To this solution, hydroxylamine hydrochloride (10 equiv) and pyridine (10 equiv) were added and refluxed for 4 h.Compound 5a: 1H NMR (400 MHz, CDCl3): δ = 1.89 (2 H, tt, J = 6.5Hz, 6.5Hz, CH2CH 2CH2), 2.62 (3 H, s, CH3), 2.88 (2 H, t, J = 6.5Hz, CH 2CqNO), 2.93 (2 H, t, J = 6.5Hz, CH 2CqN), 7.36 (1 H, s, CH), 8.45 (1H, br. s, OH). 13C NMR (100 MHz, CDCl3): δ = 20.2, 23.8, 24.3, 33.3, 119.6, 122.9, 122.9, 135.8, 152.4, 158.2, 162.2. 19F NMR (376.5 MHz, CDCl3): δ = –60.05.
  • 35 Yoshida Y, Shimonishi K, Sakakura Y, Okada S, Aso N. Synthesis 1999; 1633
    Article in Thieme Connect
  • 36 The appropriate 4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one oxime (1 equiv) was dissolved in MeCN. To this solution, p-toluenesulfonyl chloride (1.5 equiv), Et3N (1.5 equiv) and N,N,N′,N′-tetramethyl-1,3-propanediamine (0.1 equiv) were added and stirred overnight at r.t.Compound 6a: 1H NMR (400 MHz, CDCl3): δ = 1.88 (2H, tt, J = 6.5Hz, J = 6.5Hz, CH2CH 2CH2), 2.44 (3H, s, CH 3CqCHCH), 2.61 (3 H, s, CH 3CqN), 2.92 (2 H, t, J = 6.5Hz, CH2CNO), 2.96 (2 H, t, J = 6.5Hz, CH2CH2CH 2CqN), 7.33 (2 H, d, J = 7.7Hz, 2 × CH3CqCH); 7.34 (1 H, s, CF3CqCH), 7.88 (2 H, d, J = 7.7Hz, 2 × CH3CqCHCH). 13C NMR (100 MHz, CDCl3): δ = 19.7, 21.8, 24.6, 26.0, 33.5, 119.1, 119.5, 122.3, 129.2, 129.7, 132.3, 136.3, 145.2, 160.4, 160.9, 162.9. 19F NMR (376.5 MHz, CDCl3): δ = –60.2.
  • 37 Jössang-Yanagida A, Gansser C. J. Heterocycl. Chem. 1978; 15: 249
    Crossref
  • 38 The appropriate O-tosyl-4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one oxime (1 equiv) was dissolved in an EtOH–H2O mixture (6:4). KOAc (2.1–8.4 equiv) was added, and the mixture was refluxed until full conversion (1–8 d).Compound 7a: 1H NMR (400 MHz, CDCl3): δ = 2.32–2.42 (4 H, m, COCH 2CH 2), 2.62 (3 H, s, CH3), 3.08–3.14 (2 H, m, CH2CqN), 7.32 (1 H, s, CH), 7.99 (1 H, br. s, NH). 13C NMR (100 MHz, CDCl3): δ = 24.0, 27.2, 32.3, 33.0, 117.8, 122.4, 128.2, 129.7, 156.1, 157.0, 174.0. 19F NMR (376.5 MHz, CDCl3): δ = –63.2.Compound 8a: 1H NMR (400 MHz, CDCl3): δ = 1.38 (3 H, t, J = 7.1 Hz, CH 3CH2), 2.24–2.41 (4 H, m, COCH 2CH 2), 2.55 (3 H, s, CH3), 2.84 (2 H, t, J = 7.1 Hz, CH2CqN), 4.35 (2 H, q, J = 7.1 Hz, CH3CH 2), 7.25 (1 H, s, CH). 13C NMR (100MHz, CDCl3): δ = 14.0, 22.8, 29.0, 30.5, 33.1, 62.4, 117.9, 122.9, 129.8, 138.3, 152.2, 153.8, 168.1. 19F NMR (376.5 MHz, CDCl3): δ = –63.2.
  • 39 Opanasenko M, Shamzhy M, Lamač M, Čejka J. Catal. Today 2013; 204: 94
    Crossref
  • 40 Clarysse S, Brouwers J, Tack J, Annaert P, Augustijns P. Eur. J. Pharm. Sci. 2011; 43: 260
    Crossref
  • 41 Wuyts B, Brouwers J, Mols R, Tack J, Annaert P, Augustijns P. J. Pharm. Sci. 2013; 102: 3800
    Crossref
  • 42 Augustijns P, Wuyts B, Hens B, Annaert P, Butler J, Brouwers J. Eur. J. Pharm. 2014; 57: 322
    Crossref
  • 43 Brouwers J, Tack J, Augustijns P. Int. J. Pharm. 2007; 336: 302
    Crossref
  • 44 Matsson P, Pedersen JM, Norinder U, Bergström CA. S, Artursson P. Pharm. Res. 2009; 26: 1816
    Crossref
  • 45 Holmstock N, Annaert P, Augustijns P. Drug Metab. Dispos. 2012; 40: 1473
    Crossref
  • 46 Obach RS. Drug Metab. Dispos. 1999; 27: 1350
    PubMed