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A. Kumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2719–2723
solution for 16 h. Reaction mixture was extracted with
ethyl acetate and recrystallized with methanol to yield
2.General method of O-alkylation: [4-(2-chloro-ethoxy)-
phenyl]-naphthalen-1-yl methanone (3a). (4-Hydroxy-
phenyl)-1-naphthlen-1-yl-methanone (1) (0.01 mol) and
bromochloro ethane (0. 015 mol) were refluxed in dry
acetone in the presence of baked K2CO3 (1.5 mmol) under
anhydrous conditions. After completion of the reaction
K2CO3 was filtered and acetone was distilled off, and the
product was crystallized from ethyl acetate/hexane to give
[4-(2-chloro-ethoxy)-phenyl]-naphthalene-1-yl-methanone
3a. Yield 82%. Mp 75–79 °C; MS (FAB) 311 (M+1); IR
(KBr): 1651 cmÀ1 (C@O), 2965 cmÀ1 (CH2–H Str);
1600 cmÀ1 (ArH); 1H NMR (CDCl3) d: 4.26 (t, 2H, O
CH2), 3.83 (t, 2H, CH2Cl), 6.84 (d, 2H, ArH), 7.42–7.54
(m, 4H, ArH), 7.82–8.15 (m, 5H, ArH).
[4-(3-Chloro-propoxy)-phenyl]-naphthalen-1-yl-meth-
anone (3b). Yield 85%; mp 60 °C; IR (KBr): 1651 cmÀ1
(C@O), 2965 cmÀ1 (CH2–H Str), 1600 cmÀ1 ArH); MS
(FAB) (M++1) 323; 1H NMR (CDCl3) d: 4.14 (t, 2H,
OCH2), 3.60 (t, 2H, Cl CH2), 2.13 (m, 2H, CH2 CH2 CH2),
6.82 (m, 2H, ArH), 7.20–7.41 (m, 4H, ArH), 7.72–7.95 (m,
5H, ArH).
sample treatment, a sucrose load of 2.5 g/kg body
weight was given to each rat. Blood-glucose levels were
again tested at 30, 60, 90, 120, 180, 240, 300 min, and
24 h posttest sample/drug administration. Food but
not water was withdrawn from the cages during the
experiment.
In conclusion, we have described a novel series of naph-
thalen-1yl-methanone, which is showing promising anti-
hyperglycemic activity in SLM and STZ-S rat models.
The most active compound 4h is showing 28.8% blood
sugar lowering activity in SLM model and 27% in
STZ-S model and it is also exhibiting glucagon antago-
nistic activity (IC50 = 17 lM). The work has generated a
new lead and further optimisation of lead is in progress.
Acknowledgment
We are thankful to CSIR (New Delhi) and Novo Nor-
disk (Denmark) for support.
General method of N-alkylation: naphthalen-1-yl-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methanone (4a). [4-(2-
Chloro-ethoxy)-phenyl]-naphthalen-1-yl-methanone (3a)
(10 mmol), piperidine (15 mmol) and K2CO3 (1.0 mol)
were taken in acetone (anhydrous) and the reaction
mixture was refluxed for 6 h. On completion of reaction,
as monitored by TLC. K2CO3 was filtered off, in the case
of acetone, reaction mixture was distilled off, poured into
water (60 ml) and extracted with ethyl acetate thrice. The
solvent was distilled off and chromatographed on basic
alumina using hexane and ethyl acetate to yield 4a. Which
on treatment with oxalic acid in methanol gave oxalate
References and notes
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1988, 5, 337.
2. Staels, B.; Dallongeville, J.; Auwerx, J.; Schoonjans, K.;
Leitensdrof, E.; Fruchart, J.-C. Circulation 1998, 98, 2088.
3. Meglasson, M. D.; Wilson, J. M.; Yu, J. H. J. Pharmacol.
Exp. Ther. 1993, 266, 1954.
4. Larsen, S. D.; Connell, M. A.; Cudahy, M. M.; Evans, B.
R.; May, P. D.; Meglasson, M. D.; O’Sullivan, T. J.;
Schostarez, H. J.; Si, J. C.; Stevens, F. C.; Tanis, S. P.;
Tegley, C. M.; Tucker, J. A.; Vaillancourt, V. A.; Vidmar,
T.; Watt, W.; Yu, J. H. J. Med. Chem. 2001, 44, 1217.
5. Brand, C. L.; Rolin, B.; Jorgensen, P. N.; Svendsen, I.;
Kristnsen, J. S.; Holst, J. J. Diabetologia 1994, 37, 985.
6. Jelinik, L. J.; Lok, S.; Rosenberg, G. B.; Smith, R. A.;
Grant, F.; Bigges, S.; Bensch, P. A., et al. Science 1993,
259, 1614.
7. (a) Post, S. R.; Rubinstein, P. G.; Tger, H. G. Proc. Natl.
Acad. Sci. U.S.A. 1993, 90, 1662; (a) Unson, C. G.; Wu, C.
R.; Fizpatrick, K. J.; Merrifield, R. B. J. Biol. Chem. 1994,
269, 12548.
8. (a) Collins, J. L.; Dambek, P. J.; Goldstein, S. W.; Faraci,
W. S. Bioorg. Med. Chem. Lett. 1992, 2, 915; (b) Athony, L.;
Michael, P., et al. Bioorg. Med. Chem. Lett. 2002, 12, 663.
9. (a) Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke,
B. R. J. Med. Chem. 2000, 43, 527; (b) Lok, S.; Kuijper, J.
L.; Jelink, L. J.; Kramar, J. M.; Whitmore, T. E.;
Sprecher, C. A.; Mattewes, S.; Grant, F. J.; Biggs, S. H.;
Rosenberg, G. B.; Sheppard, P. O.; O’Hara, P. J.; Foster,
D. C.; Kindsvogel, W. Gene 1994, 140, 203.
salt of 4a. Yield 83%; mp 125 °C; IR (KBr): 1652 (cmÀ1
)
C@O, 1600 cmÀ1 ArH, 2929 (CH2-Str); MS (FAB)
(M++1) 449; 1H NMR (CDCl3) d: 4.24 (t, 2H, OCH2),
2.91 (t, 2H, NCH2), 2.76 (m, 4H, NCH2) 1.62 (m, 4H-
CH2) 1.24 (p, 2H, CH2 CH2 CH2) 6.84 (d, 2H, ArH), 7.2–
7.4 (m, 4H, ArH) 7.7–7.9 (m, 5H, ArH). Anal. Calcd for
(4a) C26H27NO6: C, 69.48; H, 6.00; N, 3.11. Found: C,
69.17; H, 6.14; N, 3.21.
Naphthalen-1-yl-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-
methanone (4b). Yield 81%; mp 155 °C, IR (KBr): 1653
1
(C@O), MS (FAB) (M++1) 435, H NMR (CDCl3) d: 4.1
(t, 2H, OCH2), 2.0–2.5 (m, 6H, NCH2), 1.2–1.6 (m, 4H, H,
2,3), 6.8 (d, 2H, ArH), 7.2–7.4 (m, 4H, ArH) 7.7–7.9 (m,
5H, ArH). Anal. Calcd for C25H25NO6: C, 71.7; H, 6.20;
N, 3.21. Found: C, 71.5; H, 6.33; N, 3.39.
[4-(2-Benzylamino-ethoxy)-phenyl]-naphthalen-1yl-meth-
anone (4c). Yield 72%; mp 220 °C; IR (KBr): 1652 cmÀ1
(C@O), 1600 (Ar-H); MS (FAB) (M+1) 382; 1H NMR
(CDCl3) d: 3.97 (t, 2H OCH2), 2.54 (t, 2H, NCH2), 3.84 (s,
1H, C6H5CH2), 7.12–7.26 (m, 5H, ArH), 6.85 (d, 2H,
ArH) 7.28–7.52 (m 4H, ArH) 7.8–8.3 (m 5H, ArH). Anal.
Calcd for C26H25NO2: C, 81.80; H, 6.56; N, 3.57. Found:
C, 81.52; H, 6.32; N, 3.57.
10. (4-Methoxy-phenyl)naphthalen-1-yl-methanone (1).
A
[4-(2-Cyclohexylamino-ethoxy)-phenyl]-naphthalen-1yl-
methanone (4d). Yield 64%; mp 210 °C; (KBr): 1652 cmÀ1
mixture of 1-naphthoic acid (5 g, 28 mmol), anisole
(9 ml, 0.082 mol) and polyphosphoric acid (45 g) was
taken in rb flask. The reaction mixture was heated at 80 °C
for 8 h. Reaction mixture was poured on ice and extracted
with ethyl acetate. Organic layer was concentrated to give
(1). Which was recrystallised with benzene–hexane.(4-
Hydroxy-phenyl)naphthalen-1-yl-methanone (2). 4-Meth-
oxy-phenyl naphthophenone (2.5 g, 14 mmol) was taken
in dry dichloromethane (30 ml) and stirred for 15 min at
0 °C. Boron tribromide (5 ml, 1 M soln in CH2Cl2) was
slowly added to the reaction mixture and stirred the
1
(C@O), 1600 (Ar-H); MS (FAB) (M+ + 1) 463; H NMR
(CDCl3) d: 4.14 (t, 2H, OCH2), 2.53 (t, 2H, NCH2), 2.46
(m, 1H, NH–CH), 1.10–1.92 (m, 10H, C6H10), 6.84 (d, 2H,
ArH), 7.22–7.46 (m 4H, ArH), 7.71–7.97 (m, 5H, ArH).
Anal. Calcd for C27H29NO6: C, 69.90; H, 6.26; N, 3.00.
Found: C, 69.5; H, 5.87; N, 3.36.
4-[2-(4-Methoxy benzyl amino-ethoxy)-phenyl]-naphtha-
len-1yl-methanone (4e). Yield 70%; mp 140 °C; IR (KBr):
1
1652 cmÀ1 (C@O), 1600 (Ar); MS (FAB) (M++1) 397; H