92
P. K. Halen et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 88–94
in formulating parenteral and ophthalmic dosage forms
of these NSAIDs.
1.59 (d, 3H), 2.51 (s, 6H), 3.20 (m, 2H), 3.91 (s, 3H), 3.93 (m, CH),
4
1
6
.54 (t, 2H), 7.12 (m, 2H), 7.36 (d, 1H), 7.68 (m, 3H) and 12.50 (brs,
H), Anal. calc. for C18 : C 63.99; H 7.16; N 4.15. Found: C
3.68; H 7.56; N 3.88%.
H24Cl NO
3
The synthesized ester derivatives cannot be classified
as prodrugs since they possess the intrinsic anticholiner-
gic activity prior to being hydrolyzed to the respective
parent drugs. The novel properties (anticholinergic/
reduced gastric secretions) of these new anti-inflamma-
tory derivatives make them useful lead molecules as new
anti-inflammatory agents with greatly improved thera-
peutic index for long-term oral anti-inflammatory ther-
apy.
2
-Diethylaminoethyl 2-(6-methoxy-2-naphthyl)
propanoate hydrochloride 4d
M.p. 118–1208C, yield 58.6%, UV (MeOH): kmax 232 nm (log e
–
1
1
4.73), IR (cm ): 1733 (C=O stretching), H-NMR: d (ppm) (CDCl ):
3
1.30 (t, 6H), 1.57 (d, 3H), 3.13 (m, 6H), 3.84 (m, 1H), 3.91 (s, 3H),
4
1
6
.50 (t, 2H), 7.11 (m, 2H), 7.39 (d, 1H), 7.67 (m, 3H) and 10.40 (brs,
H). Anal. calc. for C20 : C 65.65; H 7.71; N 3.83; Found: C,
5.55; H, 7.72; N, 3.47%.
H28ClNO
3
We acknowledge the financial support provided by All India
Council for Technical Education New Delhi, India, in the form
of a research project under the Thrust Area Program in Techni-
cal Education (TAPTEC).
2
-(1-Piperidino)ethyl 2-(6-methoxy-2-naphthyl)
propanoate hydrochloride 4e
M.p. 161–1638C, yield 57.3%, UV (MeOH): kmax 232 nm (log e
4.73), IR (cm ): 1733 (C=O stretching), H-NMR: d (ppm) (CDCl ):
-
1
1
3
1
.41 to 1.60 (m, 2H), 1.56 (d, 3H), 1.83 (m, 4H), 2.32 (m, 2H), 3.14
(
(
m, 2H), 3.27 (m, 2H), 3.81 (q, 1H), 3.90 (s, 3H), 4.51 (m, 2H), 7.11
m, 2H), 7.42 (d, 1H), 7.70 (m, 3H) and 11.06 (brs, 1H). Anal. calc.
Experimental
3
for C21H28ClN O : C 66.74; H 7.47; N 3.71; Found: C 66.58; H 7.84;
N 3.51%.
Parent drug 4a was obtained from Ranbaxy Ltd., India as a gift
sample. Lambda (Type IV) carrageenan and the aminoalcohols
were purchased from Sigma Aldrich. Tropinol was prepared in
the laboratory by the basic hydrolysis (methanol/potassium
hydroxide) of atropine. Distilled water was used in preparation
of buffer solutions. Anhydrous sodium sulphate was used as dry-
ing agent. Melting points were taken in open capillaries and are
uncorrected. The IR spectra were recorded on a Shimadzu-8300
FT-IR using KBr disc. Absorbance was measured on a Shimadzu
2-(1-Pyrrolidino)ethyl 2-(6-methoxy-2-naphthyl)
propanoate hydrochloride 4f
M.p. 136–1388C, yield 63.3%, UV (MeOH): kmax 232 nm (log e
– 1
1
4
1
3
7
3
.77), IR (cm ): 1732 (C=O stretching), H-NMR: d (ppm) (CDCl ):
.60 (d, 3H), 1.83 (m, 4H), 2.06 (m, 1H), 2.34 (m, 1H), 3.70 (m, 1H),
.19 (m, 1H), 3.41 (m, 2H), 3.92 (s, 3H), 4.58 (m, 2H), 7.14 (m, 2H),
.36 (d, 1H), 7.70 (m, 3H) and 12.50 (brs, 1H). Anal. calc. for
1
UV-1601 spectrophotometer. H-NMR spectra were recorded on a
20 3
C H26ClNO : C 66.02; H 7.20; N 3.85; Found: C 66.49; H 7.50; N
3
300 MHz instrument for solutions in CDCl .
3
.62%.
General method for the synthesis of ester derivatives
2
-(4-Morpholino)]ethyl 2-(6-methoxy-2-naphthyl)
4
c–h and 5c–h
propanoate hydrochloride 4g
M.p. 155–1578C, yield 63.5%, UV (MeOH): kmax 232 nm (log e
Solution of respective NSAID 4a and 5a (9 mmol) and thionyl
chloride (27 mmol) in dry toluene (20 mL) was heated at 100 for
-1
1
4
1
2
2
3
.72), IR (cm ): 1735 (C=O stretching), H-NMR: d (ppm) (CDCl ):
2
hours. The excess of thionyl chloride and solvent was removed
.60 (d, 3H), 2.17 (brs, 1H), 2.40 (brs, 1H), 2.97 (m, 2H), 3.10 (m,
H), 3.39 (m, 2H), 3.87 (m, 3H), 3.93 (s, 3H), 4.60 (m, 2H), 7.15 (m,
H), 7.36 (d, 1H), 7.71 (m, 3H) and 13.10 (brs, 1H). Anal. calc. for
under vacuum to obtain the acid chloride. The acid chloride was
further dissolved in freshly distilled chloroform (30 mL) and
anhydrous potassium carbonate (3.0 g) was added. Appropriate
N,N-disubstituted aminoalcohol (27 mmol) was dissolved in
freshly distilled chloroform (10 mL) and added drop wise to the
well-stirred acid chloride solution at room temperature fol-
lowed by refluxing on a water bath for 3 hours. The reaction mix-
ture was further diluted with chloroform to 200 mL and filtered.
The organic layer was washed with ice-cold water to remove the
excess of aminoalcohol. The organic layer was dried and the sol-
vent removed under vacuum to give oily ester product. The oily
base was dissolved in dry iso-propyl ether and dry hydrogen
chloride was passed through the solution to give white solid pre-
cipitate of the ester hydrochloride. The salt so obtained was fil-
tered and crystallized from acetone-iso-propyl ether system. All
the derivatives 4c–h and 5c–h were synthesized by this method.
20 4
C H26ClNO : C 63.24, H 6.90, N 3.69; Found: C 63.01; H 7.13; N
3
.54%.
8
-Methyl-8-azabicyclo[3.2.1]octan-3yl 2-(6-methoxy-2-
naphthyl)propanoate hydrochloride 4h
M.p. 220–2238C, yield 40.5%, UV (MeOH): kmax 232 nm (log e
4.43), IR (cm ): 1727 (C=O stretching), H-NMR: d (ppm) (CDCl ):
3
1.56 (m, 8H), 2.28 (s, 3H), 3.07 (brs, 1H), 3.22 (brs, 1H), 3.81 (m,
1H), 3.92 (s, 3H), 4.95 (m, 1H), 7.11 (m, 2H), 7.34 (d, 1H) and 7.68
–
1
1
(m, 3H). Anal. calc. for C22
Found: C 67.49, H 7.39, N 3.38%.
3
H28ClNO : C 67.77, H 7.24, N 3.59;
2
-Dimethylaminoethyl 6-methoxy-2-naphtylacetate
hydrochloride 5c
2
-Dimethylaminoethyl 2-(6-methoxy-2-naphthyl)-
M.p. 158–1618C, yield 53.3%, UV (MeOH): kmax 230 nm (log e
–
1
1
propanoate hydrochloride 4c
M.p. 150–1538C, yield 61.4%, UV (MeOH): kmax 232 nm (log e
4.94), IR (cm ): 1746 (C=O stretching), H-NMR: d (ppm) (CDCl ):
3
2.64–66 (brs, 6H), 3.24 (m, 2H), 3.85 (s, 2H), 3.90 (s, 3H), 4.55 (m,
2H), 7.13 (m, 2H), 7.37 (d, 1H), 7.69 (m, 3H) and 12.55 (brs, 1H).
–
1
1
4.88), IR (cm ): 1725 (C=O stretching), H-NMR: d (ppm) (CDCl
3
):
i
2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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