Novel substituted naphthalen-1-yl-methanone derivatives as anti-hyperglycemic agents

Article abstract of DOI:10.1016/j.bmcl.2006.02.013

A series of aminoalkoxy phenyl-substituted naphthalene-1-yl-methanone was synthesized and tested for its anti-hyperglycemic activity in SLM and STZ-S rat models. Some compounds (3b, 4c and 4h) of the series were showing significant anti-hyperglycemic acti

Full text of DOI:10.1016/j.bmcl.2006.02.013

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2719–2723
Novel substituted naphthalen-1-yl-methanone derivatives
as anti-hyperglycemic agents
Atul Kumar,a,* S. R. Pathak,a Pervez Ahmad,a S. Ray,a P. Tewarib and A. K. Srivastavab
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
bBiochemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 28 November 2005; revised 25 January 2006; accepted 7 February 2006
Available online 24 February 2006
Abstract—A series of aminoalkoxy phenyl-substituted naphthalene-1-yl-methanone was synthesized and tested for its anti-hypergly-
cemic activity in SLM and STZ-S rat models. Some compounds (3b, 4c and 4h) of the series were showing significant anti-hyper-
glycemic activity in male Sprague–Dawley rats in sucrose-loaded model (SLM) as well as in streptozotocin-induced model (STZ-S).
Active compounds were also evaluated for relative binding affinity against glucagon receptor.
Ó 2006 Elsevier Ltd. All rights reserved.
Diabetes (type-2) is a disease characterised by insulin
resistance, hyperglycemia and hyperinsulinemia, leading
to impaired secretion of insulin in latter stages.1 Diabe-
tes is often associated with obesity, dyslipidemia and
hypertension, which are collectively known as syndrome
X or insulin resistance-associated disorders (IRAD).2
Current therapies for type-2 diabetes have inherent
problems of non-compliance, ineffectiveness and hypo-
glycemic episodes with insulin and sulfonyl ureas.3 Dif-
ferent types of peroxisome proliferator-activated
receptor (PPAR) agonists (glitazones and glitazars) have
been shown to have beneficial effects on the described
characteristic of type-2 diabetes. Glitazone type thera-
peutics are in market but some of them have been
reported to have hepatotoxicity.4 Therefore, there is a
greater need for more effective and better-tolerated oral-
ly active agents.
the lack of insulin-mediated suppression of glucagon
production in postprandial state contribute to the ele-
vated glucagon levels associated with the hyperglycemia
observed in the diabetic state. Therefore, reducing circu-
lating glucagon levels and inhibiting glucagon-immuno-
neutralization of endogenous glucagons with
monoclonal glucagons resulted in normalization of
hyperglycemic in streptozotocin diabetic rats.5
The study gives indication that glucagon receptor antag-
onists can be effectively used for the treatment of type-2
diabetes. The glucagon receptor is a seven transmem-
brane G-protein-coupled receptor (GPCR) belonging
to the secretin family.6
There are some peptide glucagon antagonists known
such as DesHIS1[Glu9]-glucagon amide, DesHIS1
DesPhe6 [Glu9]-glucagon amide and Nleu9Ala11,16-glu-
cagon amide.7 But oral availability and metabolic stabil-
ity of these peptide antagonists are question marked.
Although very few non-peptide glucagon antagonists
were reported in the literature, for example, CP-
99,711, NNC-92,1687 and I8 (Fig. 1). This prompted
us to design new non-peptide glucagon receptor
antagonists.
Glucagon is a 29-amino acid polypeptide produced in
the pancreatic a-cells and secreted in response to falling
glucose levels during the fasting period. Glucagon
increases glucose production by promoting glycogenoly-
sis and gluconeogenesis in the liver and attenuation of
the ability of insulin to inhibit these processes. The com-
bined action of glucagon and insulin is responsible for
maintaining glucose homeostasis in the body. Both in-
creased glucagon secretion during the fasting state and
We describe in this paper the design, synthesis and anti-
diabetic activities of (substituted aminoalkoxy phenyl)
naphthalen-1-yl-methanone derivatives.
Keywords: Anti-hyperglycemic activity; Naphthalen-1-yl-methanone;
Glucagon antagonists.
*
The design of naphthalen-1-yl-methanone nucleus was
mainly based on CP-99,711, NNC-92,1687 and the
Corresponding author. Tel.: +91 522 2612411; fax: +91 522
2623405; e-mail: dratulsax@gmail.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.02.013

2720
A. Kumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2719–2723
O
motif Ba was designed as side chain having substituted
alkylamino groups, as present in CP-99,711 (glucagon
antagonist). Interestingly similar side chains are also
present in rosiglitazone and adrenergic receptor b-3 ago-
nists. The phenolic group motif-Fa was taken from mo-
tifs-F/F1 of NNC-92,1687 and compound I. In the motif
Ea only the carbonyl hinge was kept as present in NNC-
92,1687 and Compound I. Whereas the main nucleus
(motif Aa) was selected as naphthalene moiety. The mo-
tifs A/A1 are having heterocyclic moieties, which were
changed into naphthalene moiety. The selection of
naphthalene nucleus was based on motif A2 of
compound I (Fig. 2). As Fa and Ba motifs together are
bulkier therefore, unsubstituted naphthalene (Aa) and
only carbonyl hinge (Ea) are selected from motifs E
and E1. The designed phenyl-substituted alkylamino
naphthalen-1-yl-methanone nucleus II (4a–k) is shown
in Figure 3.
NH
N
S
O
O
N
Rosiglitazone
Cl
Cl
N
N
N
N
CP-99-711
N
O
S
OH
N
H
OH
OH
NNC-92-1687
O
N
N
H
Cl
Synthesis of naphthalen-1-yl[4-(2/3-amino-1-yl-alkoxy)-
phenyl]methanone derivatives (4) was achieved starting
from 1-naphthoic acid (Scheme 1). Friedel Crafts acyla-
tion reaction of anisole with 1-naphthoic acid in the
presence of AlCl3 or polyphosphoric acid gave 4-meth-
oxy-phenyl naphthophenone (1). The reaction gave bet-
ter results, when polyphosphoric acid was used as
catalyst, which on reaction with pyridine hydrochloride
I
O
Figure 1.
recently reported compound I (Fig. 1). Our strategy here
was to merge the key pharmacophoric motifs of these
three series into a hybrid structure of type II (4a–k).
These molecules have three important motifs, which
are responsible for the biological activity (Fig. 2).
Whereas naphthalen-1-yl-methanone molecule has four
distinct motifs in which one motif Ba is taken from
CP-99,711, motif Aa is taken from I and other two mo-
tifs (Ea and Fa) are selected from two common motifs of
compound I and NNC-92,1687 (E,E1 and F,F1). The
Ba
Fa
R1
R2
Ea
O
N
n
O
Aa
II (4a-k)
A
B
Cl
Cl
N
N
N
Figure 3. General structure of synthesized compound [substituted
naphthalen-1-yl-methanone] II (4a–k).
N
HO
C
H3CO
HO
O
CP-99,711
O
O
(a)
(b)
E
O
N
S
A1
OH
OH
N
H
R1
2
1
NNC-92,1687
F
N
(C)
O
n
Cl
R2
O
E1
O
F1
OH
n
(d)
O
N N
H
O
A2
Cl
I
4
O
3
Figure 2. Three main motifs responsible for biological activity of CP-
99,711. A, heterocyclic moiety; B, alkyl amino chain; C, phenyl. NNC-
92,1687: F, phenolic moiety; E, linker and A1, heterocyclic moiety;
Compound I: A2, naphthalene; E1, linker; F1, phenolic moiety.
Scheme 1. Reagents and conditions: (a) anisole, (PPA) polyphosphoric
acid, 80 °C; (b) pyridine hydrochloride 120 °C or BBr3, 6 h stirring; (c)
acetone/K2CO3 reflux; (d) acetone/K2CO3 reflux or DMF/K2CO3,
80 °C.

A. Kumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2719–2723
2721
at 120 °C or boron tribromide at room temperature gave
demethylated product 4-hydroxy-phenyl naphthophe-
receptor binding affinity 4b: IC50 = 55 lM, 4h:IC50
=
17 lM, and 4k: IC50 = 35 lM). All compounds tested
were functionally competitive antagonists. Compound
4 h was showing quite comparable anti-hyperglycemic
activity with standard drugs (metformin, glibenclamide
and glyclazide) in STZ-S rat model (Table 1).
none (2). Boron tribromide gave better yield than pyri-
4-hydroxyl-phenyl
dine
hydrochloride.
The
naphthophenone (2) on Willimson O-alkylation reaction
with bromochloroalkanes in the presence of dry K2CO3
and acetone transformed into [(2/3-chloro alkoxy)-phen-
yl]naphthalen-1-yl methanone (3) which on treatment
with various aliphatic and aromatic amines in acetone/
K2CO3 under refluxing condition or in DMF/K2CO3/
DMAP at 80 °C under anhydrous conditions gave the
desired product as free base (4). Which on treatment
with oxalic acid in methanol gave [(2/3-substituted
aminoalkoxy phenyl]naphthalen-1-yl-methanone as
their oxalate salts (4a–k). The synthesized compounds
were tested for their anti-hyperglycemic activity and
are listed in Table 1.
Sucrose-loaded model. Compounds were tested for their
effect on glucose tolerance curve in rats of average
body weight 169 20 g, an indirect effect of measuring
anti-hyperglycemic activity. The blood glucose levels of
all animals were checked after an overnight fasting
(16 h) by glucostrip (Boehringer–Mannheim). Animals
showing blood glucose level between 60 and 80 (mg/
dl) (3.33–4.44/mM) were divided into two groups of
five to six animals each. Animals of experimental
groups were administered the suspension of the syn-
thetic compounds orally (made in 1.0% gum acacia)
at a dosage of 100 mg/kg body weight. Animals of con-
trol group were given an equal amount of 1.0% gum
acacia. A sucrose load (10.0 g/kg) was given to each
animal orally exactly after 30 min postadministration
of the test sample/vehicle. Blood glucose of each ani-
mal was determined at 30, 60, 90 and 120 min postad-
ministration of sucrose. Food but not water was
removed from the cages during the course of experi-
mentation. Quantitative glucose tolerance of each ani-
mal was calculated by area under curve (AUC)
method. The % fall in blood glucose level was calculat-
ed by comparing AUC of experimental and control
group. Samples showing significant inhibition
(p < 0.05) on postprandial hyperglycemia (AUC) were
considered as active samples.
All the synthesized compounds were evaluated for anti-
hyperglycemic activity in sucrose-loaded model (SLM)
using male Sprague–Dawley rats. Compounds showing
promising anti-hyperglycemic activity are 3b (22%), 4b
(17.2%), 4c (14.9%), and 4h 28.8%. But out of these,
only activity shown by 3b and 4h was significant at
p < 0.05. The most active compound in the series
(n = 1) as well as in (n = 2) have alkyl pyrrolidine as a
side chain. All the compounds then evaluated for anti-
hyperglycemic activity in sucrose charged streptozotocin
(STZ-S)-induced b-cell damaged diabetic model of Spra-
gue–Dawley strain male albino rat model. Compounds
3b and 4h were showing 17% and 27% glucose lowering
activity, respectively, at 100 mg/kg dose. It is interesting
to report here that compound having alkyl pyrrolidine
substitution in both the series [n = 1 (17%), n = 2
(27%)] was active and most potent compounds in entire
series. Whereas alkyl piperidine substitution is showing
moderate activity in n = 1 series (11.3%) but it is show-
ing insignificant activity in n = 2 (6.8%) series. Com-
pounds showing activity in SLM as well as STZ-S
models were assayed for competitive binding of 125I-glu-
cagon to the human glucagon receptor.9 Compounds
exhibited moderate activity against the human glucagon
Sucrose challenged streptozotocin-induced model. A cal-
culated amount of the fresh solution of streptozotocin
(STZ) dissolved in 100 mM citrate buffer (pH 4.5) was
injected to overnight fasted rats (60 mg/kg) intraperito-
neally. Blood was checked for glucose content 48 h later
by glucometer and animals showing blood glucose pro-
file between 150 and 250 mg/dl were selected and were
divided into different groups. Half an hour posttest
Table 1. Anti-hyperglycemic activity of aminoalkoxy naphthophenone derivatives 3 (a,b), 4 (a–k)10
Compound
n
R1
R2
% Anti-hyperglycemic activity
SLM
STZ-S
3a
3b
1
2
1
1
1
1
1
1
2
2
2
2
2
—
—
—
—
24
22
ND
8.5
4a
4b
Piperidine
Pyrrolidine
—
—
15.4
17.2
14.9
7.16
9.71
7.21
7.16
11.3
17
4c
4d
H
C6H5CH2
C6H11
4-OCH3C6H5
C2H5
5.6
H
Nil
9.2
4e
H
C2H5
4f
4g
Nil
6.8
Piperidine
Pyrrolidine
—
—
4h
4i
28.8 (p < 0.05 active)
27
7.5
H
H
H
C6H5CH2
C6H11
4-OCH3C6H5
8.06
11.16
16.17
12.9
33.7
40.4
4j
4k
Nil
12.6
19.1
29.0
27.7
Metformin
Glibenclamide
Glyclazide

2722
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
1. Ginsberg, H.; Plutzky, J.; Sobel, E. J. Cardiovasc. Risk
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

A. Kumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2719–2723
2723
NMR (CDCl3) d: 3.73 (s, 3H, OCH3), 4.15 (t, 2H, OCH2),
3.56 (t, 2H, NCH2),6.67 (d, 2H, ArH), 6.78 (d, 2H, ArH)
6.86 (d, 2H, ArH), 7.21–7.45 (m 4H, ArH), 7.7–7.93 (m,
5H, ArH). Anal. Calcd for C26H23NO3: C, 78.58; H, 5.79;
N, 3.52. Found: C, 78.14; H, 5.69; N, 3.72.
69.48; H, 6.0; N, 3.11. Found: C, 69.42; H, 5.87; N, 3.21.
[4-(2-Benzylamino-propoxy)-phenyl]-naphthalen-1yl-
methanone (4i). Yield 70%; mp 210 °C; IR (KBr):
1652 cmÀ1 (C@O), 1600 (Ar-H); MS (FAB) (M+1) 396,
1H NMR (CDCl3) d: 3.94 (t, 2H OCH2), 2.54 (t, 2H,
NCH2), 1.83 (m, 2H CH2 CH2 CH2) 3.86 (s, 1H,
C6H5CH2), 7.10–7.21 (m, 5H, ArH), 6.86 (d, 2H, Ar H)
7.82–8.12 (m, 5H, ArH), 7.21–7.47 (m, 4H, ArH). Anal.
Calcd for C27H25NO2: C, 82.02; H, 6.32; N, 3.54, Found:
C, 82.23; H, 6.22; N, 3.45.
[4-(2-Cyclohexylamino-propoxy)-phenyl]-naphthalen-1yl-
methanone (4j). Yield 60%; mp, 165 °C; IR
(KBr):1652 cmÀ1 (C@O), 1600 (Ar-H); MS (FAB)
(M++1) 477; 1H NMR (CDCl3) d: 4.14 (t, 2H, OCH2),
2.53 (t, 2H, NCH2), 2.46 (m,1H, NH-CH), 1.12–1.87
(m,10H, C6H10), 1.95 (m, 2H, CH2 CH2 CH2), 6.86 (d, 2H,
ArH), 7.21–7.44 (m 4H, ArH), 7.73–7.97 (m, 5H, ArH).
Anal. Calcd for C28H31NO6: C, 75.16; H, 6.4; N, 2.93.
Found: C, 75.23; H, 6.26; N, 3.10.
{4-[2-(4-Methoxybenzylamino-propoxy)-phenyl]-naphtha-
len-1yl-methanone} (4k). Yield 72%; mp 130 °C; IR (KBr)
1652 cmÀ1 (C@O), 1600 (Ar-H); MS (FAB) (M++1) 411;
1HNMR (CDCl3) d: 3.76 (s, 3H, OCH3), 4.14 (t, 2H,
OCH2), 3.56 (t, 2H, NCH2), 1.94 (m, 2H, CH2 CH2 CH2),
6.68 (d, 2H, ArH), 6.76 (d, 2H, ArH) 6.85 (d, 2H, ArH),
7.23–7.49 (m 4H, ArH), 7.72–7.97 (m, 5H, ArH). Anal.
Calcd for C27H25NO3: C, 78.83; H, 6.08; N, 3.40. Found:
C, 78.53; H, 6.48; N, 3.10.
[4-(2-Diethylamino-ethoxy)-phenyl]-naphthalen-1yl-meth-
anone (4f). Yield 80%; mp 171 °C; IR (KBr): 1652 cmÀ1
1
(C@O), 1600 (Ar-H); MS (FAB) (M++1) 437; H NMR
(CDCl3) d: 1.12 {t, 6H, CH2-(CH3)2}, 4.15 (t, 2H, OCH2),
2.5–2.96 (m, 6H, NCH2), 6.81–6.92 (d, 2H, ArH), 7.42–
7.56 (m, 4H, ArH), 7.83–8.24 (m, 5H, ArH). Anal. Calcd
for C25H27NO6: C, 68.64; H, 6.17; N, 3.40. Found: C,
66.72; H, 5.71; N, 3.29.
Naphthalen-1-yl-[4-(2-piperidin-1-yl-propoxy)-phenyl]-
methanone (4g). Yield 82%; mp 165 °C; IR (KBr): 1652
(cmÀ1) C@O, 1600 cmÀ1 ArH, 2929 (CH2-Str); MS (FAB)
(M++1) 463; 1H NMR (CDCl3) d: 4.24 (t, 2H, OCH2),
2.96 (t, 2H, NCH2), 2.73 (m, 4H, NCH2) 1.65 (m, 4H-
CH2) 1.24 (p, 4H, CH2 CH2 CH2). 6.86 (d, 2H, ArH),
7.21–7.46 (m, 4H, ArH), 7.73–7.98 (m, 5H, ArH). Anal.
Calcd for C27H29NO6 C, 69.9; H, 6.22; N, 3.02. Found: C,
69.56; H, 6.33; N, 3.37.
Naphthalen-1-yl-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-
methanone (4h). Yield 80%; mp 158 °C; IR (KBr): 1653
(C@O); MS (FAB) (M++1) 449; 1H NMR (CDCl3) d: 4.12
(t, 2H, OCH2), 2.11–2.53 (m, 6H, NCH2), 1.23–1.64 (m,
4H, CH2), 6.88 (d, 2H, ArH), 7.22–7.47 (m, 4H, ArH)
7.72–7.96 (m, 5H, ArH). Anal. Calcd for C26H27NO6: C,