Substituted acrylophenones and related mannich bases as possible spermicides and inhibitors of HIV envelope glycoprotein-CD4 interaction.

Article abstract of DOI:10.1016/S0223-5234(01)01292-2

Several appropriately substituted 4-(dialkylamino-alkyl)-substituted-styryl-alkyl ketones or acetophenones were prepared and subjected to the Mannich reaction to yield compounds that would incorporate both alpha,beta-unsaturated keto groups and a substituted aminomethyl function with or without another olefinic moiety at position 4. The spermicidal activity of the prepared compounds was evaluated. Several compounds 2d, 4a and 4e were found to possess spermicidal activity at 0.005% concentration, while compounds 2a, 2c, 2f, 3a and 4b were active at 0.01% concentration. Compounds 2a, 2c, 3a, 4a and 4e also inhibited the interaction between recombinant HIV Env and CD4. Out of these, compound 2c was found to be most active.

Full text of DOI:10.1016/S0223-5234(01)01292-2

European Journal of Medicinal Chemistry 37 (2002) 855Á864
/
www.elsevier.com/locate/ejmech
Original paper
Substituted acrylophenones and related mannich bases as possible
spermicides and inhibitors of HIV envelope glycoproteinÁCD4
interactionꢀ
/
Niharika Kumaria a, Anil Kumar Dwivedi a,*, Jagdamba Prasad Maikhuri b,
Gopal Gupta b, Saman Habib c, Janak Dulari Dhar b, Satyawan Singh a
a Division of Pharmaceutics, Central Drug Research Institute, CDRI, Chatter Manzil, PO Box 173, Lucknow 226 001, India
b Division of Endocrinology, Central Drug Research Institute, CDRI, Chatter Manzil, PO Box 173, Lucknow 226 001, India
c Division of Membrane Biology, Central Drug Research Institute, CDRI, Chatter Manzil, PO Box 173, Lucknow 226 001, India
Received 22 November 2000; received in revised form 12 November 2001; accepted 14 November 2001
Abstract
Several appropriately substituted 4-(dialkylamino-alkyl)-substituted-styryl-alkyl ketones or acetophenones were prepared and
subjected to the Mannich reaction to yield compounds that would incorporate both a,b-unsaturated keto groups and a substituted
aminomethyl function with or without another olefinic moiety at position 4. The spermicidal activity of the prepared compounds
was evaluated. Several compounds 2d, 4a and 4e were found to possess spermicidal activity at 0.005% concentration, while
compounds 2a, 2c, 2f, 3a and 4b were active at 0.01% concentration. Compounds 2a, 2c, 3a, 4a and 4e also inhibited the interaction
between recombinant HIV Env and CD4. Out of these, compound 2c was found to be most active.
´
# 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
Keywords: Spermicides; HIV EnvÁCD4 interaction; Mannich bases; 2-Dialkylaminomethyl-1-[4-(dialkylaminoalkoxy)phenyl]prop-2-en-1-one and
/
4-dialkylaminomethyl-1-[4-(dialkylaminoalkoxy)phenyl]penta-1,4-dien-3-one; 1-[4-(Dialkylaminoalkoxy)phenyl]-3-dialkylamino-propan-1-one; 5-
Dialkylaminoalkyl-1-[(4-dialkylaminoalkoxy)phenyl]pent-1-en-3-one
1. Introduction
A number of nuclear substituted styryl ketone-related
Mannich bases and allyl alcohols were found to show
anti-bacterial and anti-tumour activity [1,2]. Several
Mannich bases of formyl and other substituted phenols
[3,4], N-substituted a-amino alkyl acrylophenones and
related compounds [5], substituted quinotoxin deriva-
tives [6,7] exhibited spermicidal activity against human
spermatozoa. Several styryl ketones and their Mannich
bases, incorporating an a,b-unsaturated keto system,
were prepared and tested for their spermicidal potential
In a recent survey carried out on the acceptability of
different methods of contraception, it was found that
there is a growing trend towards the use of local
contraceptive agents and devices, particularly, new
spermicides possessing anti-human immuno-deficiency
virus (HIV), anti-fungal and anti-bacterial activity for
medicating condoms or in other barrier contraceptive
preparations.
Several a,b-unsaturated ketones have a wide spectrum
of biological activity, including anti-tumour activity that
has been attributed to reactivity towards cellular thiols.
against human spermatozoa in our laboratory [8Á11].
/
One of these compounds, 1-(4-methoxy-phenyl)-4-piper-
idyl-methyl-penta-1,4-dien-3-one [10,11], CDRI com-
pound no. 87/132, also inhibited the binding of HIV
envelope protein (HIV Env) with its receptor on
mammalian cells, the CD4 molecule. Encouraged by
these findings, it was considered of interest to prepare a
ꢀ CDRI Communication No. 6111.
* Correspondence and reprints
E-mail address: a_k_dwivedi@yahoo.com (A.K. Dwivedi).
´
0223-5234/02/$ - see front matter # 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
PII: S 0 2 2 3 - 5 2 3 4 ( 0 1 ) 0 1 2 9 2 - 2

856
N. Kumaria et al. / European Journal of Medicinal Chemistry 37 (2002) 855Á864
/
series of appropriately substituted styryl alkyl ketones
followed by their Mannich reaction to yield compounds
that would incorporate both a,b-unsaturated keto
groups and a substituted aminomethyl function with
and without another olefinic moiety at position 4.
3. Biological screening
3.1. Spermicidal activity
The spermicidal activity was determined using the
SanderÁCramer assay [12] using KrebsÁRinger bicar-
/
/
bonate buffer (pH 7.6). The minimum effective concen-
tration (MEC) is reported in % (wt./vol.) of test material
as determined with three individual human semen
samples. The compounds were dissolved in physiologi-
cal saline/DMSO at different concentrations. Semen and
test compound solutions were mixed in the ratio of 1:5
(about 5 s), and immediately examined under a phase
contrast microscope. The results were scored as positive
if 100% of spermatozoa became immotile within 20 s,
whereas even if only one or two spermatozoa showed
sluggish motility, the test concentration of the com-
pound was scored negative. The control slides were
prepared by adding physiological saline instead of test
solutions.
2. Chemistry
The hydroxy group of 4-acetyl-phenol or 1-(4-hydro-
xyphenyl)butan-1-en-3-one or 4-acetyl-2-isopropyl-5-
methyl-phenol was amino-alkylated with disubstituted-
aminoalkyl-halides in presence of a mild base like
potassium carbonate and catalytic amount of sodium
iodide to give 4-(dialkylaminoalkyloxy)acetophenone or
1-(4-(dialkylaminoalkyloxy)phenyl)butan-1-en-3-one or
4-(dialkylaminoalkyloxy)-5-isopropyl-2-methyl-aceto-
phenone in 40Á50% yield. Sodium salt of 4-acetyl-2-
/
isopropyl-5-methyl-phenol was also reacted with epi-
chlorohydrin in presence of sodium hydroxide and the
epoxide so formed was opened with a secondary amine
to get 4-[3-dialkylamino-2-hydroxy-propoxy]-5-isopro-
pyl-2-methyl-acetophenone.
The 4-dialkylaminoalkoxy acetophenone or 1-[4-(dia-
lkylaminoalkoxy)phenyl]buta-1-en-3-one or 4-[3-dialky-
lamino-2-hydroxy-propoxy]-5-isopropyl-2-methyl-acet-
ophenone were subjected to reaction with a secondary
amine in presence of excess of paraformaldehyde in
glacial acetic acid under gentle refluxing to yield 2-
dialkylaminomethyl-1-[4-(dialkylaminoalkoxy)phe-
nyl]prop-2-en-1-one or 4-dialkylaminomethyl-1-[4-(dia-
lkylaminoalkoxy)phenyl]penta-1,4-dien-3-one, or 2-
dialkylaminomethyl-1-[5-isopropyl-2-methyl-4-(2-hy-
droxy-3-dialkylaminopropoxy)phenyl]prop-2-en-1-one,
respectively.
3.2. Inhibition of HIV-1 EnvÁCD4 interaction
/
A quantitative bioassay to measure the fusion of cells
derived from cell lines HL2/3 and HLCD4-CAT in the
presence of test compounds was carried out [13]. The
HL2/3 line contains stably integrated copies of the HIV-
1 clone HXB2/3gpt and expresses high levels of HIV-1
proteins (Gag, Env, Tat, Rev and Nef) but no infectious
virus. Co-culture of HL2/3 cells with the CD4-expres-
sing cell line HLCD4-CAT results in efficient cell fusion
within 6Á12 h and activates CAT gene expression in
/
HLCD4-CAT. Fusion efficiency was quantitated by
assaying CAT activation using a colorimetric enzyme
immunoassay (Boehringer Mannheim, Germany). Fu-
sion in the presence or absence of test compounds was
measured with dextran sulphate as positive control for
inhibition.
When 4-dialkylaminoalkoxy acetophenone or 1-[4-
(dialkylaminoalkoxy)phenyl]buta-1-en-3-one or 4-[3-
dialkylamino-2-hydroxy-propoxy]-5-isopropyl-2-meth-
yl-acetophenone were subjected to Mannich reaction in
absolute ethanol or in propan-1-ol in presence of a few
drops of concentrated hydrochloric acid under reflux,
the major products formed were 1-[4-(dialkylaminoalk-
oxy)phenyl]-3-dialkylamino-propan-1-one or 5-dialkyla-
minoalkyl-1-[(4-dialkylaminoalkoxy)phenyl]pent-1-en-
3-one or 3-(4-dialkylamino)-1-[5-isopropyl-2-methyl-4-
(2-dialkylaminoethoxy)phenyl]propan-1-one, respec-
tively along with 2-dialkylaminomethyl-1-[4-(dialkyla-
minoalkoxy)phenyl]prop-2-en-1-one or 4-
dialkylaminomethyl-1-[4-(dialkylaminoalkoxy)phe-
nyl]penta-1,4-dien-3-one, or 2-dialkylaminomethyl-1-[5-
isopropyl-2-methyl-4-(2-hydroxy-3-dialkylaminopro-
poxy)phenyl]prop-2-en-1-one formed in trace amounts
4. Results and discussion
1-(4-Methoxy-phenyl)-4-(piperidyl-methyl)penta-1,4-
dien-3-one [10,11], CDRI compound no. 87/132, is a
potent spermicide as well as a strong inhibitor of HIVÁ
/
CD4 interaction. A series of its analogues was prepared
by substituting methoxy group with dialkylamino-alkyl
group to increase water solubility. The criterion for
selection of the side chain were based on the observation
that the side chain of nonoxynol-9 has nine carbon
atoms at the para position of the phenyl ring. Therefore,
side chains having eight or nine carbon atoms with a
secondary amino group, to increase water solubility,
were selected.
The compounds listed in Table 1 were prepared and
tested for their spermicidal activity. Several compounds
(Fig. 1aÁc).
/

N. Kumaria et al. / European Journal of Medicinal Chemistry 37 (2002) 855Á
/
864
857
Fig. 1. Synthesis of different compounds reported.

858
N. Kumaria et al. / European Journal of Medicinal Chemistry 37 (2002) 855Á864
/
Table 1
Spermicidal efficacy of the compounds prepared against human spermatozoa
Compound
Spermicidal activity (% concentration)
Compound
Spermicidal activity (% concentration)
2a
2b
2c
2d
2e
2f
0.01
1.0
4c
4d
4e
4f
0.1
1.0
0.01
0.005
1.0
0.005
0.1
5a
5b
5c
6a
6b
6c
6d
6e
7a
7b
7c
7d
inactive
inactive
inactive
1.0
0.01
0.1
2g
2h
3a
3b
3c
3d
3e
3f
0.1
0.01
0.1
inactive
inactive
1.0
0.05
0.1
1.0
0.1
inactive
inactive
0.1
0.1
1.0
3g
4a
4b
0.005
0.01
0.1
Á/
Á/
showed 100% spermicidal activity at a concentration
range 1.0Á0.005%.
Two compounds, 4a and 2d, exhibiting high spermi-
cidal activity were also checked for their effect on fusion
of HL2/3 and HLCD4-CAT cells (Fig. 2). Both com-
pounds showed dose-dependent inhibition of HIV-1
/
The amino group in the ether linkage in the side chain
as well as in the amino methyl group played a very
important role. Piperidine and pyrrolidine derivatives
showed activity at higher dilution than morpholine or
N-methyl-piperazine derivatives. If the amino group
was morpholine, the compounds showed very marginal
activity or were inactive at 1.0% concentration.
All the compounds belonging to the series 1-[4-(3-
dialkylaminoalkoxy)phenyl]-3-dialkylamino-propan-1-
one were devoid of spermicidal activity at 1.0% con-
centration.
EnvÁCD4 interaction resulting in decreased CAT re-
/
porter gene expression.
5. Experimental
All the m.p.s were determined on a hot stage
apparatus and are uncorrected. IR spectra (cmꢀ1
)
were recorded on a PerkinÁElmer 881 spectrophot-
/
ometer as KBr discs or neat. 1H-NMR spectra were
recorded on a Bruker DPX-200 MHz or Bruker Avance
DRX-300 MHz FT NMR instrument using TMS as
internal standard and CDCl3 as a solvent unless stated
When a CHÄ/CH moiety was introduced between the
phenyl ring and the COCH2 group the 5-(4-dialkyla-
mino)-1-[4-(dialkylaminoalkoxy)phenyl]pent-1-en-3-
one, some compounds such as 6a, 6d, 6e showed
spermicidal activity at 1.0% concentration. Introduction
of a methylene group in the compounds mentioned in
Fig. 1, i.e. 4-(dialkylaminomethyl)-1-[4-(3-dialkylami-
noalkoxy)phenyl]pent-1,4-dien-3-one, led to sharp in-
crease in the spermicidal activity. One of these
compounds i.e. 3a was found to be active at 0.01%
concentration.
When a CHÄ
phenyl ring and the COCÄ
/
CH moiety was not present between the
CH2 group e.g. the 1-[4-(3-
/
dialkylamino-alkoxy)phenyl]-2-dialkylamino-methyl-
propan-2-en-1-one some compounds i.e. 2a, showed
spermicidal activity at 0.005% concentration.
The compounds derived from thymol and having
hydroxy group in the propyl side chain e.g. 4a, 4e
showed activity at lower concentration than the corre-
sponding compounds derived from 4-acetyl phenol
without hydroxy group in the propyl side chain.
Fig. 2. Inhibition of HIV EnvÁ
pounds.
/
CD4 interaction by different com-

N. Kumaria et al. / European Journal of Medicinal Chemistry 37 (2002) 855Á
/
864
859
otherwise. The mass spectra were recorded on JEOL-
JMS-D-300 mass spectrometer and elemental analyses
OÃ
/
CH2), 6.57Á
/
6.63 (d, 2H, CH Ä
/
CH), 6.87Á
/
6.99 (m,
H). Anal. Found:
2H, ArÃ
/
H), 7.40Á
/
7.50 (m, 2H, ArÃ
/
were carried out on CarloÁ
/
Erba 1108 analyser.
75.63; H, 9.05; N, 5.25. Calc. for C18H25NO2: C, 75.26;
H, 8.71; N, 4.87%.
5.1. General procedure for O-dialkylamino-alkylation of
4-acetyl-phenols or 4-hydroxybenzylidineacetones or 4-
acetyl-2-isopropyl-5-methyl-phenol
5.1.5. 4-{4-[2-(Pyrrolidin-1-yl)ethoxy]phenyl}but-3-en-
2-one (1e)
Yield: 35%. M.p. 78Á
/
79 8C. IR (cmꢀ1): n 1664, 1602,
1
4-Acetyl-phenols or 4-hydroxybenzylidineacetones or
4-acetyl-2-isopropyl-5-methyl-phenol (0.1 mol) was trea-
ted with dialkylamino-alkyl-halide-hydrohalide (0.15
mol), K2CO3 (0.21 mol), NaI (0.05 mol) in 50 mL of
C3H6O, the mixture was refluxed for 20 h [14], cooled,
filtered, C3H6O was distilled off and the resultant oily
liquid was purified on a column of neutral alumina
using C6H6 and methanolic C6H6 as eluent. Removal of
1512, 1250. EIMS: m/z 259 [Mꢁ]. H-NMR: d 1.71Á
/
1.82 (m, 4H, CH2), 2.17 (s, 3H, COÃ
(m, 4H, CH2ÃN), 2.89Á2.95 (t, 2H, NÃ
(t, 2H, OÃCH2), 6.56 (d, 1H, CHÄCH), 6.64 (d, 1H,
CH ÄCH), 6.82Á6.86 (m, 2H, ArÃH), 7.43Á7.46 (m, 3H,
ArÃH). Anal. Found: C, 73.88; H, 7.76; N, 5.11. Calc.
/
CH3), 2.26Á/2.64
/
/
/
CH2), 4.12Á/4.18
/
/
/
/
/
/
/
for C16H21NO2: C, 74.13; H, 8.10; N, 5.40%.
the solvent gave a viscous mass in 30Á
compounds synthesised by the above procedure are as
follows.
/
42% yield. The
5.1.6. 4-[4-(3-Diethylaminopropoxy)phenyl]but-3-en-2-
one (1f)
Yield: 32%. M.p. viscous. IR (cmꢀ1): n 1656, 1598,
1
1512, 1249. EIMS: m/z 247 [Mꢁ]. H-NMR: d 1.9Á
/
2.0
CH3, NÃ
CH2), 6.5Á6.6 (d,
H), 7.4Á7.8 (m, 2H,
H). Anal. Found: C, 72.62; H, 8.22; N, 5.01. Calc.
5.1.1. 1-[4-(3-Piperidinopropoxy)phenyl]ethan-1-one
(1a)
(m, 2H, OÃ
CH2, COCH3), 4.0Á
2H, CH ÄCH), 6.8Á7.0 (m, 2H, ArÃ
ArÃ
/
CH2Ã
/
CH2), 2.1Á
/
2 (m, 11H, NÃ
/
/
/
4.1 (t, 2H, OÃ
/
/
Yield: 41%. M.p. viscous mass. IR (cmꢀ1): n 1674,
/
/
/
/
1
1600, 1573. EIMS: m/z 261 [Mꢁ]. H-NMR: d 1.3Á
/
1.8
CH2, COCH3),
4.2 (t, 2H, OÃCH2), 6.7Á
8.0 (m, 2H, ArÃH). Anal.
/
(m, 6H, CH2), 1.9Á
2.4Á2.5 (m, 6H, NÃ
7.0 (m, 2H, ArÃH), 7.7Á
/
2.3 (m, 5H, OÃ
/
CH2Ã
/
for C15H21NO2: C, 72.87; H, 8.50, N, 5.39%.
/
/
CH2), 3.9Á
/
/
/
/
/
/
5.1.7. 1-[5-Isopropyl-2-methyl-4-(3-
Found: C, 73.93; H, 9.18; N, 5.73. Calc. for C16H23NO2:
piperidinoethoxy)phenyl]ethan-1-one (1g)
Yield: 48%. M.p. viscous mass. IR (cmꢀ1): n 1668,
C, 73.56; H, 8.81; N, 5.36%.
1
1604, 1556, 1504. EIMS: m/z 302 [Mꢁ]. H-NMR: d
5.1.2. 1-[4-(2-Piperidinoethoxy)phenyl]ethan-1-one
(1b)
1.20Á
2.45Á
2.84 (t, 2H, NÃ
(t, 2H, OÃCH2), 6.75 (s, 1H, ArÃ
/
1.24 (m, 6H, CH(CH3)2), 1.44Á
2.55 (m, 10H, CH2ÃN, ArÃCH3, COCH3), 2.78Á
CH2), 3.23Á3.27 (d, 1H, CH), 4.12Á4.18
H), 7.70 (s, 1H, ArÃ
/
1.68 (m, 6H, CH2),
/
/
/
/
Yield: 40%. M.p. 58Á
/
60 8C. IR (cmꢀ1): n 1674, 1604,
/
/
/
1510, 1264. EIMS: m/z 247 [Mꢁ]. H-NMR: d 1.58Á
/
/
/
/
1
1.77 (m, 6H, CH2), 2.48Á
COCH3), 2.76Á2.87 (t, 2H, NÃ
(t, 2H, OÃCH2), 6.91Á7.00 (m, 2H, ArÃ
(m, 2H, ArÃ
/
2.55 (m, 7H, CH2Ã
/N,
H). Anal. Found: C, 75.86; H, 9.98; N, 4.98. Calc. for
/
/
CH2CH2O), 4.13Á
/
4.20
7.94
C19H29NO2: C, 75.49; H, 9.60; N, 4.63%.
/
/
/
H), 7.90Á
/
/
H). Anal. Found: C, 73.28; H, 8.89; N, 6.05.
Calc. for C15H21NO2: C, 72.89; H, 8.50; N, 5.66%.
5.2. General procedure for synthesis of 1-[5-isopropyl-2-
methyl-4-(2-hydroxy-3-
dialkylaminopropoxy)phenyl]ethan-1-one
5.1.3. 1-{4-[2-(Pyrrolidin-1-yl)ethoxy]phenyl}ethan-1-
one (1c)
4-Acetyl-2-isopropyl-5-methyl-phenol (0.1 mol) was
added to methanolic CH3ONa, prepared by dissolving
0.21 mol of Na in 100 mL of dry MeOH under stirring.
The resulting mixture was cooled and treated with
epichlorohydrin (0.1 mol). It was refluxed for 5 h. The
resulting mass so obtained was added gradually to ice-
Yield: 31%. M.p. Oil. IR (cmꢀ1): n 1674, 1600, 1508,
1260. EIMS: m/z 233 [Mꢁ]. 1H-NMR: d 1.71Á
/
1.86 (m,
N, COCH3), 2.86Á
4.27 (t, 2H, OÃCH2),
7.85 (m, 2H, ArÃH).
4H, CH2), 2.45Á
2.96 (d, 2H, NÃCH2CH2O), 4.07Á
6.92Á6.93 (m, 2H, ArÃH), 7.84Á
/
2.66 (m, 7H, CH2Ã
/
/
/
/
/
/
/
/
/
Anal. Found: C, 71.93; H, 7.97; N, 5.81. Calc. for
cold water, stirred and extracted with CHCl3 (3ꢂ25
/
C14H19NO2: C, 72.10; H, 8.15; N, 6.00%.
mL). The combined CHCl3 extract was washed with
water; organic layer was dried, concentrated to get a
viscous mass, which was purified by chromatography
over silica gel using C6H6 as an eluent.
3-(4-Acetyl-2-isopropyl-5-methyl-phenoxy)-1,2-ep-
oxy-propane (0.1 mol), as obtained above, in EtOH was
treated with (0.21 mol) secondary amine like piperidine,
morpholine or pyrrolidine. The mixture was heated
5.1.4. 4-[4-(3-Piperidinopropoxy)phenyl]but-3-en-2-one
(1d)
Yield: 45%. M.p. (Tartrate) 140Á
n 1681, 1658, 1598, 1512, 1263. EIMS: m/z 287 [Mꢁ].
1H-NMR: d 1.62Á
1.97 (m, 8H, CH2, OÃCH2ÃCH2),
2.32Á2.41 (m, 9H, NÃCH2, COCH3), 4.08Á4.18 (t, 2H,
/
141 8C. IR (cmꢀ1):
/
/
/
/
/
/

860
N. Kumaria et al. / European Journal of Medicinal Chemistry 37 (2002) 855Á864
/
under reflux for 6 h. Bulk of the solvent was distilled off
under reduced pressure. The viscous mass obtained was
treated with water (50 mL) extracted with CHCl3; the
CHCl3 layer washed with saline water, dried and
concentrated to a viscous liquid, which was purified by
column chromatography over neutral alumina.
chromatography over deactivated neutral alumina. The
compounds synthesised by the above procedure are as
follows.
5.3.1. 2-Piperidinomethyl-1-[4-(3-
piperidinopropoxy)phenyl]prop-2-en-1-one (2a)
Yield: 35%. M.p. (Tartrate) 134Á
/
135 8C. IR (cmꢀ1):
1
5.2.1. 1-{5-Isopropyl-2-methyl-4-[2-hydroxy-3-
piperidinopropoxy}phenyl]ethane-1-one (1h)
n 1651, 1571, 1508, 1255. EIMS: m/z 369 [Mꢁ]. H-
NMR: d 1.3Á
CH2ÃCH2), 2.3Á
OÃCH2), 5.5Á5.6 (s, 1H, Ä
6.7Á7.0 (m, 2H, ArÃH), 7.7Á
/
1.7 (m, 12H, CH2), 1.8Á
2.6 (m, 12H, NÃCH2), 3.9Á
CH2), 5.8Á5.9 (s, 1H, Ä
7.9 (m, 2H, ArÃH). Anal.
/
2.2 (m, 2H, OÃ
4.1 (t, 2H,
CH2),
/
Yield: 42%. M.p. semi solid. IR (cmꢀ1): n 1670, 1600,
/
/
/
/
1
1504, 1356. EIMS: m/z 333 [Mꢁ]. H-NMR: d 1.21Á
/
/
/
/
/
/
1.24 (d, 6H, CHÃ
2.53Á2.55 (d, 6H, ArÃ
6H, NÃCH2), 3.21Á3.24 (m, 1H, CH), 3.97Á
3H, OÃCH2, CHOH), 6.66Á6.73 (s, 1H, ArÃH), 7.69Á
7.74 (s, 1H, ArÃH). Anal. Found: C, 71.75; H, 9.69; N,
/
(CH3)2), 1.54Á
CH3, ArÃCOCH3), 2.67Á
4.14 (m,
/
1.74 (m, 6H, CH2),
/
/
/
/
/
/
/
/
2.87 (m,
Found: C, 75.08; H, 9.49; N, 7.82. Calc. for
/
/
/
C23H34N2O2: C, 74.79; H, 9.21; N, 7.58%.
/
/
/
/
/
5.3.2. 2-Morpholinomethyl-1-[4-(3-
piperidinopropoxy)phenyl]prop-2-en-1-one (2b)
4.55. Calc. for C20H31NO3: C, 72.0; H, 9.30; N, 4.20%.
Yield: 37%. M.p. (Tartrate) 110Á
/
111 8C. IR (cmꢀ1):
1
5.2.2. 1-{5-Isopropyl-2-methyl-4-[2-hydroxy-3-
morpholinopropoxy}phenyl]ethane-1-one (1i)
Yield: 34%. M.p. viscous mass. IR (cmꢀ1): n 1670,
n 1651, 1573, 1510, 1257. EIMS: m/z 373 [Mꢁ]. H-
NMR: d 1.5Á
CH2CH2), 2.4Á
OCH2), 4.04Á4.08 (t, 2H, OÃ
5.89 (s, 1H, ÄCH2), 6.8Á6.9 (m, 2H, ArÃ
2H, ArÃH). Anal. Found: C, 70.43; H, 8.22; N, 7.23.
/
1.6 (m, 6H, CH2), 1.9Á
2.5 (m, 12H, NCH2), 3.6Á
CH2), 5.63 (s, 1H, Ä
H), 7.7Á
/
2.0 (m, 2H, OÃ
/
/
/
3.7 (m, 4H,
1
1606, 1504, 1252. EIMS: m/z 335 [Mꢁ]. H-NMR: d
/
/
/CH2),
1.22Á
CH3, ArÃ
3.97Á4.36 (m, 6H, OÃ
6.66Á6.73 (s, 1H, ArÃH), 7.59Á
/
1.25 (d, 6H, CHÃ
COCH3), 3.05Á
CH2), 4.58 (m, 1H, CHOH),
7.78 (s, 1H, ArÃH).
/
(CH3)2), 2.43Á
/
2.55 (d, 6H, ArÃ
/
/
/
/
/7.9 (m,
/
/
3.28 (m, 7H, NÃ
/
CH2, CH),
/
/
/
Calc. for C22H32N2O3: C, 70.77; H, 8.57; N, 7.50%.
/
/
/
/
Anal. Found: C, 68.36; H, 8.96; N, 4.48. Calc. for
5.3.3. 2-Pyrrolidinomethyl-1-[4-(3-
piperidinopropoxy)phenyl]prop-2-en-1-one (2c)
C19H29NO4: C, 68.05; H, 8.65; N, 4.17%.
Yield: 30%. M.p. (Tartrate) 124Á
/
125 8C. IR (cmꢀ1):
1
5.2.3. 1-{5-Isopropyl-2-methyl-4-[2-hydroxy-3-
(pyrrolidin-1-yl)propoxy}phenyl]ethane-1-one (1j)
n 1651, 1598, 1508, 1255. EIMS: m/z 357 [Mꢁ]. H-
NMR: d 1.5Á
CH2ÃCH2), 2.4Á
2H, OÃCH2), 5.73 (s, 1H, Ä
6.90Á6.94 (m, 2H, ArÃH), 7.7Á
/
1.6 (m, 10H, CH2), 1.7Á
2.5 (m, 12H, NÃCH2), 4.03Á
CH2), 6.05 (s, 1H, Ä
7.8 (m, 2H, ArÃ
/
2.0 (m, 2H, OÃ
4.09 (t,
CH2),
H).
/
Yield: 42%. M.p. viscous. IR (cmꢀ1): n 1670, 1606,
/
/
/
/
1
1504, 1353. EIMS: m/z 319 [Mꢁ]. H-NMR: d 1.08Á
/
/
/
/
1.25 (d, 6H, (CH3)2CH), 2.01Á
2.68 (d, 6H, ArÃCH3, ArÃCOCH3), 2.72Á
NCH2, CH), 3.19Á3.30 (m, 1H, CHOH), 3.90Á
2H, OÃCH2), 6.67 (s, 1H, ArÃH), 7.72 (s, 1H, ArÃ
/
2.42 (m, 4H, CH2), 2.55Á
2.98 (m, 7H,
4.00 (t,
H).
/
/
/
/
/
/
/
/
Anal. Found: C, 74.50; H, 9.32; N, 8.23. Calc. for
C22H32N2O2: C, 74.15; H, 8.98; N, 7.86%.
/
/
/
/
/
Anal. Found: C, 71.86; H, 9.47; N, 4.75. Calc. for
C19H29NO3: C, 71.47; H, 9.09; N, 4.38%.
5.3.4. 2-Piperidinomethyl-1-[4-(2-
piperidinoethoxy)phenyl]prop-2-en-1-one (2d)
Yield: 22%. M.p. (Tartrate) 126Á
/
127 8C. IR (cmꢀ1):
1
5.3. General procedure for synthesis of 2-
dialkylaminomethyl-1-[4-
n 1648, 1600, 1520, 1308. EIMS: m/z 356 [Mꢁ] H-
NMR: d 1.27Á
NÃCH2), 3.97Á
CH2), 5.83 (s, 1H, Ä
7.71Á7.73 (m, 2H, ArÃ
/
1.41 (m, 12H, CH2), 2.56Á
4.09 (t, 2H, OÃCH2), 5.40 (s, 1H, Ä
CH2), 6.88Á6.92 (m, 2H, ArÃH),
H). Anal. Found: C, 73.78; H,
/
2.66 (m, 12H,
(dialkylaminoalkoxy)phenyl]prop-2-en-1-one and 4-
dialkylaminomethyl-1-[4-
/
/
/
/
/
/
/
(dialkylaminoalkoxy)phenyl]penta-1,4-dien-3-one
/
/
8.61; N, 7.48. Calc. for C22H32N2O2: C, 74.15; H, 8.98;
N, 7.86%.
Substituted 4-(dialkylaminoalkoxy)acetophenones or
1-[substituted-4-(dialkylamino-alkoxy)phenyl]buta-1-
en-3-one (0.1 mmol), paraformaldehyde (0.3 mmol),
secondary amine hydrochloride (0.12 mmol) in glacial
5.3.5. 2-Morpholinomethyl-1-[4-(2-
piperidinoethoxy)phenyl]prop-2-en-1-one (2e)
AcOH were heated under gentle reflux for 5Á
/6 h. Bulk
Yield: 20%. M.p. (Tartrate) 132Á
n 2940, 1662, 1602, 1522, 1218. EIMS: m/z 358 [Mꢁ].
1H-NMR: d 1.45Á
1.47 (m, 6H, CH2), 2.51Á2.83 (m,
12H, NCH2), 3.38Á3.70 (m, 4H, OÃCH2), 4.14Á4.20 (t,
2H, OÃCH2), 5.91 (s, 1H, ÄCH2), 6.05 (s, 1H, ÄCH2),
6.91Á6.95 (m, 2H, ArÃH), 7.79Á7.83 (m, 2H, ArÃH).
/
133 8C. IR (cmꢀ1):
of the solvent was distilled off under reduced pressure
and the residue taken in water, neutralised up to pH 7
with NaHCO3. The solution was extracted with CHCl3,
washed with water, dried over anhydrous Na2SO4 and
concentrated. The residual viscous mass was purified by
/
/
/
/
/
/
/
/
/
/
/
/

N. Kumaria et al. / European Journal of Medicinal Chemistry 37 (2002) 855Á
/
864
861
Anal. Found: C, 70.63; H, 8.62; N, 8.06. Calc. for
C21H30N2O3: C, 70.39; H, 8.37; N, 7.82%.
7.1Á
/
7.2 (m, 2H, ArÃ
/
H), 7.5Á
/
7.7 (m, 2H, ArÃ
/
H). Anal.
Found: C, 72.08; H, 8.25; N, 7.42. Calc. for
C24H34N2O2: C, 72.36; H, 8.54; N, 7.03%.
5.3.6. 2-Piperidinomethyl-1-[4-(2-
pyrrolidinoethoxy)phenyl]prop-2-en-1-one (2f)
Yield: 35%. M.p. (Tartrate) 110Á
/
111 8C. IR (cmꢀ1):
5.3.11. 4-(4-Methylpiperazin-1-yl)methyl-1-[4-(3-
piperidinopropoxy)phenyl]penta-1,4-dien-3-one (3c)
n 1654, 1600, 1506, 1256. EIMS: m/z 342 [Mꢁ]. H-
1
Yield: 28%. M.p. (Tartrate) 140Á
/
141 8C. IR (cmꢀ1):
NMR: d 1.25Á
CH2ÃN), 3.00Á
NÃCH2), 4.22Á
CH2), 6.09 (s, 1H, Ä
7.84Á7.85 (m, 2H, ArÃ
/
1.62 (m, 10H, CH2), 2.42Á
3.05 (t, 2H, NÃCH2), 3.32Á
4.28 (t, 2H, OÃCH2), 5.67 (s, 1H, Ä
CH2), 6.93Á6.97 (m, 2H, ArÃH),
H). Anal. Found: C, 73.92; H,
/2.576 (m, 8H,
n 1590, 1512, 1216. EIMS: m/z 411 [Mꢁ]. H-NMR: d
1
/
/
/
/3.44 (t, 2H,
/
/
/
/
1.25Á
2.75 (m, 16H, NÃ
(s, 1H, ÄCH2), 6.02 (s, 1H, Ä
CHÄCH), 7.07Á7.15 (d, 1H, CH Ä
2H, ArÃH), 7.54Á7.59 (m, 2H, ArÃH). Anal. Found: C,
/
1.78 (m, 8H, CH2), 2.23 (s, 3H, NÃ
CH2), 4.05Á4.11 (t, 2H, OÃ
CH2), 6.87Á6.92 (d, 1H,
CH), 7.35Á7.49 (m,
/
CH3), 2.42Á
/
/
/
/
/
/
/CH2), 5.89
/
/
/
/
/
9.11; N, 8.52. Calc. for C21H30N2O2: C, 73.68; H, 8.77;
N, 8.18%.
/
/
/
/
/
/
/
73.27; H, 8.79; N, 9.84. Calc. for C25H37N3O2: C, 72.99;
5.3.7. 2-Morpholinomethyl-1-[4-(2-
pyrolidinoethoxy)phenyl]prop-2-en-1-one (2g)
H, 9.00; N, 10.21%.
Yield: 39%. M.p. (Tartrate) 118Á
/
120 8C. IR (cmꢀ1):
n 1624, 1600, 1232. EIMS: m/z 344 [Mꢁ]. H-NMR: d
1
5.3.12. 4-Piperidinomethyl-1-[4-(2-
pyrrolidinoethoxy)phenyl]penta-1,4-dien-3-one (3d)
1.71Á
3.05Á
4.26Á
1H, Ä
2H, ArÃ
/
1.91 (m, 4H, CH2), 2.48Á
3.28 (m, 4H, NÃCH2), 3.65Á
4.32 (t, 2H, OÃCH2), 5.65 (s, 1H, Ä
CH2), 6.92Á6.97 (m, 2H, ArÃH), 7.79Á
H). Anal. Found: C, 69.47; H, 8.41; N, 8.38.
/
2.83 (m, 8H, CH2Ã
3.69 (t, 4H, OÃCH2),
CH2), 5.71 (s,
7.83 (m,
/N),
/
/
/
/
Yield: 15%. M.p. (Tartrate) 130Á
/
131 8C. IR (cmꢀ1):
/
/
/
n 1646, 1600, 1514, 1248. EIMS: m/z 368 [Mꢁ]. H-
1
/
/
/
/
NMR: d 1.41Á
CH2N), 2.89Á2.94 (t, 2H, NCH2), 3.28Á
CH2), 4.11Á4.19 (t, 2H, OCH2), 5.90 (s, 1H, Ä
6.11 (s, 1H, ÄCH2), 6.90Á6.95 (d, 1H, CHÄCH), 7.00Á
7.04 (d, 1H, CH ÄCH), 7.50Á7.54 (m, 2H, ArÃH), 7.58Á
7.61 (m, 2H, ArÃH). Anal. Found: C, 74.63; H, 8.31; N,
/
1.62 (m, 10H, CH2), 2.39Á
3.43 (t, 2H, NÃ
CH2),
/2.63 (m, 8H,
/
/
/
/
Calc. for C20H28N2O3: C, 69.76; H, 8.13; N, 8.13%.
/
/
/
/
/
/
5.3.8. 2-[4-Methylpiperazin-1-yl]-1-[4-(2-
pyrolidinoethoxy)phenyl]prop-2-en-1-one (2h)
Yield: 35%. M.p. viscous mass. IR (cmꢀ1): n 1636,
/
/
/
/
/
7.21. Calc. for C23H32N2O2: C, 75.0; H, 8.69; N, 7.60%.
1
1604, 1508, 1248. EIMS: m/z 357 [Mꢁ]. H-NMR: d
1.66Á
CH3), 4.14Á
5.65 (s, 1H, Ä
7.83 (m, 2H, ArÃ
/
1.75 (m, 4H, CH2), 2.57Á
4.23 (t, 2H, OÃCH2), 5.56 (s, 1H, Ä
CH2), 7.01Á7.06 (m, 2H, ArÃH), 7.79Á
H). Anal. Found: C, 70.95; H, 9.02; N,
/
2.89 (m, 19H, NCH2, NÃ
/
/
/
/
CH2),
5.3.13. 4-Morpholinomethyl-1-[4-(2-
pyrrolidinoethoxy)phenyl]penta-1,4-dien-3-one (3e)
/
/
/
/
/
Yield: 11%. M.p. (Tartrate) 116Á
/
117 8C. IR (cmꢀ1):
11.52. Calc. for C21H31N3O2: C, 70.58; H, 8.68; N,
11.76%.
n 1664, 1502, 1246. EIMS: m/z 370 [Mꢁ]. H-NMR: d
1
1.87 (bs, 4H, CH2), 2.43Á
3.04 (t, 2H, NÃCH2), 3.62Á
4.24 (t, 2H, OÃCH2), 5.92 (s, 1H, Ä
CH2), 6.67Á6.75 (d, 2H, CH ÄCH), 6.91Á
ArÃH), 7.50Á7.55 (m, 2H, ArÃH). Anal. Found: C,
/
2.85 (m, 8H, NÃ
3.72 (m, 4H, OÃ
CH2), 6.13 (s, 1H, Ä
6.95 (m, 2H,
/
CH2), 2.98Á
CH2), 4.19Á
/
/
/
/
/
5.3.9. 4-Piperidinomethyl-1-[4-(3-
piperidinopropoxy)phenyl]penta-1,4-dien-3-one (3a)
/
/
/
161 8C. IR (cmꢀ1):
/
/
/
Yield: 36%. M.p. (Tartrate) 160Á
/
n 1652, 1593, 1512, 1251. EIMS: m/z 396 [Mꢁ]. H-
1
/
/
/
71.75; H, 7.98; N, 7.76. Calc. for C22H30N2O3: C, 71.35;
H, 8.10; N, 7.56%.
NMR: d 1.6Á
CH2ÃCH2), 2.4Á
OCH2), 5.90 (s, 1H, Ä
(d, 2H, CH ÄCH), 7.1Á
2H, ArÃ
/
1.8 (m, 12H, CH2), 1.9Á
2.7 (m, 12H, NÃCH2), 3.9Á
CH2), 6.20 (s, 1H, ÄCH2), 6.9Á
7.2 (m, 2H, ArÃH), 7.5Á
/
2.1 (t, 2H, OÃ
/
/
/
/
/
4.2 (t, 2H,
/
/
/7.0
/
/
/
/7.7 (m,
/
H). Anal. Found: C, 75.38; H, 8.72; N, 6.69.
5.3.14. 4-(4-Methylpiperazin-1-yl)methyl-1-[4-(2-
pyrrolidinoethoxy)phenyl]penta-1,4-dien-3-one (3f)
Calc. for C25H36N2O2: C, 75.75; H, 9.09; N, 7.07%.
Yield: 17% M.p. (Tartrate) 180Á
1590, 1530, 1226. EIMS: m/z 383 [Mꢁ]. H-NMR: d
1.66Á1.69 (m, 4H, CH2), 2.50Á2.84 (m, 19H, NÃCH2,
NÃCH3), 4.10Á4.16 (t, 2H, OÃCH2), 6.05 (s, 1H, Ä
CH2), 6.28 (s, 1H, ÄCH2), 6.94 (d, 1H, CHÄCH), 6.99
(d, 1H, CH ÄCH), 7.60Á7.63 (d, 2H, ArÃH), 7.65Á7.69
(m, 2H, ArÃH). Anal. Found: C, 71.75; H, 8.29; N,
/
181 8C. IR 1664,
1
5.3.10. 4-Morpholinomethyl-1-[4-(3-
piperidinopropoxy)phenyl]penta-1,4-dien-3-one (3b)
161 8C. IR (cmꢀ1):
/
/
/
Yield: 49%. M.p. (Tartrate) 160Á
/
/
/
/
/
n 1652, 1593, 1512, 1251. EIMS: m/z 399 [Mꢁ]. H-
/
/
1
NMR: d 1.6Á
CH2ÃCH2ÃCH2), 2.4Á
(m, 4H, CH2ÃO), 4.0Á4.1 (t, 2H, OÃ
CH2), 6.15 (s, 1H, ÄCH2), 6.8Á7.0 (d, 2H, CH Ä
/
1.8 (m, 6H, CH2), 1.9Á
2.8 (m, 12H, NÃ
CH2), 5.80 (s, 1H,
CH),
/
2.1 (t, 2H, OÃ
/
/
/
/
/
/
/
/
/
CH2), 3.6Á3.8
/
/
/
/
/
10.60. Calc. for C23H33N3O2: C, 72.06; H, 8.61; N,
Ä
/
/
/
/
10.96%.

862
N. Kumaria et al. / European Journal of Medicinal Chemistry 37 (2002) 855Á864
/
5.3.15. 4-Piperidinomethyl-1-[4-(3-
dimethylaminopropoxy)phenyl]penta-1,4-dien-3-one
(3g)
ArÃ
(m, 8H, OÃ
5.68 (s, 1H, Ä
ArÃH), 7.21 (d, 1H, ArÃ
/
CH3), 2.28Á
CH2), 4.03Á
CH2), 5.96 (s, 1H, Ä
H). Anal. Found: C, 67.63; H,
/
2.68 (m, 13H, NÃ
4.16 (m, 3H, OÃ
CH2), 6.66 (d, 1H,
/
CH2, CH), 3.70Á
/
3.75
/
/
/CH2, CHOH),
/
/
Yield: 34%. M.p. (Tartrate) 120Á
/
121 8C. IR (cmꢀ1):
/
/
n 1656, 1596, 1512, 1255. EIMS: m/z 356 [Mꢁ]. H-
8.90; N, 6.62. Calc. for C25H38N2O5: C, 67.26; H, 8.52;
N, 6.27%.
1
NMR: d 1.2Á
CH2CH2CH2), 2.3Á
2H, OÃCH2), 6.0 (s, 1H, Ä
7.0 (d, 2H, CH ÄCH), 7.1Á
(m, 2H, ArÃH). Anal. Found: C, 73.78; H, 8.63; N, 7.49.
/
1.7 (m, 6H, CH2), 2.0Á
2.6 (m, 14H, NCH2), 4.0Á
CH2), 6.2 (s, 1H, ÄCH2), 6.9Á
7.2 (m, 2H, ArÃH), 7.5Á7.6
/
2.1 (m, 2H, OÃ
/
/
/
4.2 (t,
/
/
/
/
5.3.20. 2-Piperidinomethyl-1-[5-isopropyl-2-methyl-4-
(2-hydroxy-3-pyrrolidinopropoxy)phenyl]prop-2-en-1-
one (4e)
/
/
/
/
/
Calc. for C22H32N2O2: C, 74.15; H, 8.98; N, 7.86%.
Yield: 15%. M.p. (Tartrate) 118Á
/
120 8C. IR (cmꢀ1):
n 1743, 1606, 1220, 1112. EIMS: m/z 428 [Mꢁ]. H-
1
5.3.16. 2-Piperidinomethyl-1-[5-isopropyl-2-methyl-4-
(2-hydroxy-3-piperidinopropoxy)phenyl]prop-2-en-1-one
(4a)
NMR: d 1.1Á
CH2), 2.1Á2.3 (s, 3H, ArÃ
CH2, CH), 3.9Á4.3 (m, 3H, OÃ
1H, ÄCH2), 6.1 (s, 1H, ÄCH2), 6.7 (d, 1H, ArÃ
(d, 1H, ArÃH). Anal. Found: C, 73.24; H, 9.70; N, 6.91.
/
1.3 (m, 6H, (CH3)2CH), 1.4Á
CH3), 2.4Á3.3 (m, 13H, NÃ
CH2, CHOH), 6.0 (s,
H), 7.3
/2.0 (m, 10H,
/
/
/
/
166 8C. IR (cmꢀ1):
/
/
Yield: 33%. M.p. (Tartrate) 164Á
/
n 1739, 1612, 1502, 1251. EIMS: m/z 441 [Mꢁ]. H-
1
/
/
/
/
NMR: d 1.0Á
CH2), 2.3Á2.4 (s, 3H, ArÃ
CH2, CH), 3.9Á4.4 (m, 3H, OÃ
(s, 1H, ÄCH2), 6.1Á6.2 (s, 1H, Ä
ArÃH), 7.2Á7.3 (m, 1H, ArÃH). Anal. Found: C, 73.15;
/
1.3 (d, 6H, (CH3)2CH), 1.4Á
CH3), 2.5Á3.3 (m, 13H, NÃ
CH2, CHOH), 5.9Á6.0
CH2), 6.6Á6.7 (m, 1H,
/
2.2 (m, 12H,
Calc. for C26H40N2O3: C, 72.89; H, 9.34; N, 6.54%.
/
/
/
/
/
/
/
/
/
/
/
5.3.21. 2-Morpholinomethyl-1-[5-isopropyl-2-methyl-4-
(2-hydroxy-3-pyrrolidinopropoxy)phenyl]prop-2-en-1-
one (4f)
/
/
/
H, 9.18; N, 5.98. Calc. for C27H42N2O3: C, 73.46; H,
9.52; N, 6.34%.
Yield: 18%. M.p. (Tartrate) 170Á
/
174 8C. IR (cmꢀ1):
n 1744, 1682, 1532, 1220. EIMS: m/z 430 [Mꢁ]. H-
1
5.3.17. 2-Morpholinomethyl-1-[5-isopropyl-2-methyl-4-
(2-hydroxy-3-piperidinopropoxy)phenyl]prop-2-en-1-one
(4b)
NMR: d 1.14Á
CH2), 2.08 (s, 3H, ArÃ
CH2), 3.22Á3.34 (m, 1H, CH), 3.68Á
CH2), 4.12Á4.20 (m, 3H, OÃCH2, CHOH), 5.93 (s, 1H,
CH2), 6.20 (s, 1H, ÄCH2), 6.68Á6.72 (d, 1H, ArÃH),
7.20Á7.26 (d, 1H, ArÃH). Anal. Found: C, 70.07; H,
/
1.25 (m, 6H, (CH3)2), 1.70Á
CH3), 2.33Á2.69 (m, 12H, NÃ
3.72 (m, 4H, OÃ
/
1.77, (m, 4H,
/
/
/
/
/
/
Yield: 27.0%. M.p. (Tartrate) 186Á
(cmꢀ1): n 1736, 1602, 1254. EIMS: m/z 444 [Mꢁ]. H-
NMR: d 1.19 (bs, 6H, (CH3)2CH), 1.82Á1.92 (m, 6H,
CH2), 2.3 (s, 3H, ArÃCH3), 3.09Á3.63 (m, 13H, NÃ
CH2, CH), 4.01Á4.19 (m, 7H, OÃCH2, CHOH), 6.31
(s, 1H, ÄCH2), 6.68 (s, 1H, ÄCH2), 6.94 (s, 1H, ArÃH),
7.31 (s, 1H, ArÃH). Anal. Found: C, 70.58; H, 9.31; N,
/
188 8C. IR
/
/
1
Ä
/
/
/
/
/
/
/
/
/
/
9.15; N, 6.85. Calc. for C25H38N2O4: C, 69.76; H, 8.83;
/
/
N, 6.51%.
/
/
/
/
6.68. C26H40N2O4: C, 70.27; H, 9.00; N, 6.30%.
5.4. General procedure for the synthesis of 1-[4-
(dialkylaminoalkoxy)phenyl]-3-dialkylamino-propan-1-
one or 5-dialkylaminoalkyl-1-[(4-
5.3.18. 2-Piperidinomethyl-1-[5-isopropyl-2-methyl-4-
(2-hydroxy-3-morpholinopropoxy)phenyl]prop-2-en-1-
one (4c)
dialkylaminoalkoxy)phenyl]pent-1-en-3-one
Yield: 39%. M.p. (Tartrate) 138Á
/
139 8C. IR (cmꢀ1):
Substituted 4-dialkylamino-alkoxy acetophenone or
substituted 1-(4-dialkylamino-alkoxy-phenyl)buta-1-en-
3-one (0.1 mol), paraformaldehyde (0.2 mol), and
secondary amine hydrochloride (0.2 mol) in absolute
EtOH or in propan-1-ol (20 mL) were heated to reflux
temperature. Concentrated HCl was added until pH 3
was reached. The mixture was heated under reflux for 9
h. The solvent was then removed in vacuum, residue
dissolved in water (50 mL), 5% aq. solution of NaHCO3
was added to bring the pH upto 7.5. The solution was
extracted with CHCl3, washed with water, dried over
anhydrous Na2SO4 and concentrated. The residual
viscous mass was purified by chromatography over
n 2944, 1740, 1512, 1242. EIMS: m/z 444 [Mꢁ]. H-
1
NMR: d 1.15Á
6H, CH2), 2.00Á
13H, NÃCH2, CH), 3.69Á
4.16 (m, 3H, OÃCH2, CHOH), 5.79 (s, 1H, Ä
(s, 1H, ÄCH2), 7.06 (d, 1H, ArÃH), 7.45 (d, 1H, ArÃ
/
1.20 (m, 6H, (CH3)2CH), 1.25Á
2.08 (s, 3H, ArÃCH3), 2.37Á2.67 (m,
3.74 (m, 4H, OÃCH2), 4.05Á
CH2), 5.95
H).
/
1.57 (m,
/
/
/
/
/
/
/
/
/
/
/
/
Anal. Found: C, 69.89; H, 8.65; N, 5.99. Calc. for
C26H40N2O4: C, 70.27; H, 9.00; N, 6.30%.
5.3.19. 2-Morpholinomethyl-1-[5-isopropyl-2-methyl-4-
(2-hydroxy-3-morpholinopropoxy)phenyl]prop-2-en-1-
one (4d)
Yield: 43%. M.p. (Tartrate) 179Á
/
182 8C. IR (cmꢀ1):
deactivated neutral alumina using C6H6/C6H6ÁMeOH
/
n 1740, 1610, 1516, 1216. EIMS: m/z 446 [Mꢁ]. H-
mixture as the eluent. The following compounds were
synthesised by the above procedure.
1
NMR: d 1.16Á
/
1.25 (m, 6H, (CH3)2CH), 2.08 (s, 3H,

N. Kumaria et al. / European Journal of Medicinal Chemistry 37 (2002) 855Á
/
864
863
5.4.1. 1-[4-(3-Piperidinopropoxy)phenyl]3-pyrrolidin-1-
ylpropan-1-one (5a)
5.4.6. 5-(4-Methylpiperazin-1-yl)-1-[4-(3-
piperidylpropoxy)phenyl]pent-1-en-3-one (6c)
Yield: 17%. M.p. (Tartrate) 110Á
n 1743, 1668, 1604, 1514. EIMS: m/z 345 ([Mꢁ]ꢁ
1H-NMR: d 1.4Á
1.9 (m, 10H, CH2), 2.0Á2.1 (m, 4H,
COCH2, OÃCH2ÃCH2), 2.2Á2.6 (m, 12H, NÃCH2),
4.0Á4.2 (t, 2H, OÃCH2), 6.9Á7.0 (d, 2H, ArÃH), 7.9Á
8.0 (d, 2H, ArÃH). Anal. Found: C, 73.45; H, 9.66; N,
/
111 8C. IR (cmꢀ1):
1).
Yield: 15%. M.p. (Tartrate) 124Á
/
125 8C. IR (cmꢀ1):
1
/
n 1652, 1596, 1512, 1170. EIMS: m/z 399 [Mꢁ]. H-
/
/
NMR: d 1.43Á
CH2ÃCH2), 2.28 (s, 3H, NÃ
CH2), 2.7Á2.8 (m, 4H, NÃCH2, COÃ
2H, OÃCH2), 6.5Á6.6 (s, 1H, ArÃCHÄ
2H, ArÃH), 7.41Á7.48 (m, 3H, ArÃH, CH Ä
/
1.59 (m, 6H, CH2), 1.94Á
CH3), 2.3Á2.5 (m, 14H, NÃ
CH2), 4.01Á4.07 (t,
CH), 6.6Á6.7 (d,
CHÃCO).
/
1.97 (t, 2H, OÃ
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
7.88. Calc. for C21H32N2O2: C, 73.25; H, 9.30; N, 8.13%.
/
/
/
/
/
Anal. Found: C, 72.54; H, 9.62; N, 10.84. Calc. for
C24H37N3O2: C, 72.18; H, 9.27; N, 10.52%.
5.4.2. 1-[4-(3-Piperidinopropoxy)phenyl]3-morpholin-
1-ylpropan-1-one (5b)
Yield: 18%. M.p. (Tartrate) 153Á
n 1728, 1672, 1600, 1512. EIMS: m/z 361 ([Mꢁ]ꢁ
1H-NMR: d 1.4Á
1.7 (m, 6H, CH2), 1.9Á2.1 (m, 4H,
COCH2, OÃCH2ÃCH2), 2.2Á2.6 (m, 12H, NÃCH2),
3.6Á3.8 (m, 4H, CH2ÃO), 4.0Á4.1 (t, 2H, OÃCH2), 6.9Á
7.0 (d, 2H, ArÃH), 7.9Á8.0 (d, 2H, ArÃH). Anal.
/
154 8C. IR (cmꢀ1):
1).
5.4.7. 5-(3-Methyl-piperidyl)-1-[4-(3-
piperidinopropoxy)phenyl]pent-1-en-3-one (6d)
/
Yield: 15%. M.p. (Tartrate) 182Á
n 1598, 1512, 1217, 1172, 1039. EIMS: m/z 398 [Mꢁ].
1H-NMR: d 0.85Á
0.88 (d, 3H, CHÃCH3), 1.43Á1.59
(m, 10H, CH2), 1.94Á1.97 (d, 2H, OÃCH2ÃCH2), 2.35Á
2.50 (m, 10H, CH2N, COCH2), 2.72Á
CH2, CH ÃCH3), 4.01Á4.07 (t, 2H, OÃ
(s, 2H, ArÃCH ÄCH, ArÃH), 7.45Á7.49 (m, 3H, ArÃ
CHÄCH Ã
/
183 8C. IR (cmꢀ1):
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
2.86 (m, 5H, NÃ
/
Found: C, 70.31; H, 9.27; N, 8.16. Calc. for
C21H32N2O3: C, 70.0; H, 8.88; N, 7.77%.
/
/
/
CH2), 6.58Á6.62
/
/
/
/
/
/
H,
/
/CO). Anal. Found: C, 75.71; H, 9.92; N, 7.27.
5.4.3. 1-[4-(3-Piperidinopropoxy)phenyl]3-(4-
methylpiperazin-1-yl)propan-1-one (5c)
Calc. for C25H38N2O2: C, 75.37; H, 9.54; N, 7.03%.
Yield: 14%. M.p. (Tartrate) 98Á
/
99 8C. IR (cmꢀ1): n
5.4.8. 5-(4-Methylpiperidyl)-1-[4-(3-piperidino-
propoxy)phenyl]pent-1-en-3-one (6e)
1672, 1600, 1512. EIMS: m/z 373 [Mꢁ]. H-NMR: d
1
1.4Á
2.28 (s, 3H, NÃ
2.87 (d, 2H, CH2Ã
(t, 2H, OÃCH2), 6.9Á
2H, ArÃH). Anal. Found: C, 71.15; H, 9.0; N, 11.66.
/
1.5 (m, 6H, CH2), 1.9Á
CH3), 2.4Á2.5 (m, 14H, NÃ
N), 3.0Á3.1 (d, 2H, CH2Ã
6.94 (d, 2H, ArÃH), 7.90Á
/
2.0 (d, 2H, OÃ
CH2), 2.83Á
O), 4.0Á4.1
7.94 (d,
/
CH2Ã
/
CH2),
Yield: 18%. M.p. (Tartrate) 108Á
n 1741, 1654, 1596, 1217, 1170. EIMS: m/z 398 [Mꢁ].
1H-NMR: d 0.90Á
0.93 (d, 3H, CHÃCH3), 1.44Á1.59
(m, 10H, CH2), 1.94Á1.98 (d, 2H, OÃCH2ÃCH2), 2.35Á
2.51 (m, 8H, NÃCH2), 2.77Á2.92 (m, 5H, NÃCH2, CH Ã
CH3), 4.0Á4.07 (t, 2H, OÃCH2), 6.80 (s, 1H, ArÃCH Ä
CH), 6.84Á6.91 (m, 2H, ArÃH), 7.44Á7.49 (m, 3H, ArÃ
H, CHÄCH ÃCO). Anal. Found: C, 75.10; H, 9.81; N,
/
109 8C. IR (cmꢀ1):
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
Calc. for C22H35N3O2: C, 70.77; H, 9.38; N, 11.26%.
/
/
/
/
/
/
/
/
5.4.4. 5-(Piperidyl)-1-[4-(3-
piperidinopropoxy)phenyl]pent-1-en-3-one (6a)
/
/
6.66. Calc. for C25H38N2O2: C, 75.37; H, 9.54; N, 7.03%.
Yield: 16%. M.p. (Tartrate) 120Á
/
122. IR (cmꢀ1): n
1654, 1596, 1512. EIMS: m/z 384 [Mꢁ]. H-NMR: d
1
5.4.9. 3-Morpholinyl-1-[5-isopropyl-2-methyl-4-(2-
hydroxy-3-piperidino-propoxy)phenyl]propan-1-one (7a)
1.5Á
CH2), 2.3Á
COÃCH2), 4.0Á
1H, ArÃCH ÄCH), 6.62Á
(m, 3H, ArÃH, CHÄCH Ã
/
1.7 (m, 12H, CH2), 1.95Á
2.5 (m, 12H, NÃCH2), 2.7Á
4.06 (t, 2H, OÃCH2), 6.54Á
6.65 (s, 2H, ArÃH), 7.3Á
CO). Anal. Found: C, 74.61;
/
1.98 (d, 2H, OÃ
2.8 (d, 2H,
6.57 (s,
7.4
/
CH2Ã
/
/
/
/
Yield: 12.0%. M.p. (Tartrate) 112Á115 8C. IR
/
(cmꢀ1): n 1670, 1608, 1554, 1512, 1363. EIMS: m/z
/
/
/
/
1
432 [Mꢁ]. H-NMR: d 1.21Á
/
1.25 (m, 6H, CH(CH3)2),
2.82 (m, 17H, CH2, NÃ
CH3), 3.09 (m, 1H, CH), 3.68Á3.73 (m,
CH2, CH ÃOH), 4.02Á4.06 (t, 2H, OÃCH2), 6.67
(s, 1H, ArÃH), 7.56 (s, 1H, ArÃH). Anal. Found: C,
/
/
/
/
/
/
/
/
1.52Á
COCH2, ArÃ
5H, OÃ
/
1.68 (m, 16H, CH2), 2.36Á
/
/
H, 9.76; N, 7.62. Calc. for C24H36N2O2: C, 75.0; H, 9.37;
N, 7.29%.
/
/
/
/
/
/
/
/
5.4.5. 5-(Morpholinyl)-1-[4-(3-
piperidinopropoxy)phenyl]pent-1-en-3-one (6b)
69.83; H, 9.08; N, 6.62. Calc. for C25H40N2O4: C, 69.44;
H, 9.25; N, 6.48%.
Yield: 14%. M.p. (Tartrate) 123Á
/
124 8C. IR (cmꢀ1):
n 1652, 1596, 1512, 1172. EIMS: m/z 386 [Mꢁ]. H-
5.4.10. 3-(Morpholinyl)-1-[5-isopropyl-2-methyl-4-(2-
piperidinoethoxy)phenyl]propan-1-one (7b)
Yield: 21%. M.p. (Tartrate) 180 8C. IR (cmꢀ1): n
1670, 1606, 1556, 1502, 1359, 1309, 1064. Mass: m/z 402
1
NMR: d 1.4Á
CH2ÃCH2), 2.3Á
NÃCH2ÃCO), 3.6Á
2H, OÃCH2), 6.5Á6.6 (s, 1H, ArÃ
2H, ArÃH), 7.46Á7.49 (m, 3H, ArÃ
/
1.5 (m, 6H, CH2), 1.95Á
2.5 (m, 10H, NÃCH2), 2.7Á
3.7 (t, 4H, OÃCH2), 4.01Á
CH ÄCH), 6.8Á
H, CHÄCH Ã
/
1.98 (d, 2H, OÃ
2.8 (m, 4H,
4.07 (t,
7.0 (s,
CO).
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
[Mꢁ]. 1H-NMR: d 1.16Á
1.48Á
2.60 (m, 12H, CH2Ã
CH2), 3.05Á3.09 (m, 1H, CH), 3.68Á
/
1.23 (m, 6H, CH(CH3)2),
1.50 (m, 6H, CH2), 2.03 (s, 3H, ArÃCH3), 2.47Á
N, COCH2), 2.78Á2.83 (d, 2H, NÃ
3.73 (m, 4H, OÃ
/
/
/
/
/
/
/
/
Anal. Found: C, 71.12; H, 8.42; N, 6.87. Calc. for
C23H34N2O3: C, 71.50; H, 8.80; N, 7.25%.
/
/
/
/
/
/

864
N. Kumaria et al. / European Journal of Medicinal Chemistry 37 (2002) 855Á864
/
CH2), 4.03Á
7.56 (s, 1H, ArÃ
/
4.09 (t, 2H, OÃ
/
CH2), 6.75 (s, 1H, ArÃ
/
H),
H). Anal. Found: C, 72.01; H, 9.82; N,
inhibition assay described for compounds mentioned in
this paper.
/
7.33. Calc. for C24H38N2O3: C, 71.64; H, 9.45; N, 6.96%.
5.4.11. 3-(4-Methylpiperazin-1-yl)-1-[5-isopropyl-2-
methyl-4-(2-piperidinoethoxy)phenyl]propan-1-one (7c)
Yield: 19%. M.p. (Tartrate) 90 8C. IR (cmꢀ1): n
References
1672, 1606, 1556, 1502, 1353, 1309, 1251. Mass: m/z 415
[1] J.R. Dimmock, W.G. Taylor, J. Pharm. Sci. 63 (i) (1974) 69Á
/
74.
49.
1
[Mꢁ]. H-NMR: 1.23Á
/
1.25 (m, 6H, CH(CH3)2), 1.46Á
CH3), 2.31 (s, 3H,
N, COCH2), 2.78Á
CH2), 3.26 (m, 1H, CH), 4.14Á4.20 (t,
CH2), 6.56 (s, 1H, ArÃH), 7.56 (s, 1H, ArÃH).
/
[2] J.R. Dimmock, W.G. Taylor, J. Pharm. Sci. 64 (2) (1975) 41Á
/
1.93 (m, 6H, CH2), 2.17 (s, 3H, ArÃ
NÃCH3), 2.46Á2.63 (m, 14H, CH2Ã
2.88 (d, 4H, NÃ
2H, OÃ
/
[3] S.C. Sharma, R. Prasad, A.K. Goel, N.M. Khanna, Indian J.
Chem. 20 (13) (1981) 1010Á1013.
/
/
/
/
/
[4] N.M. Khanna, V.K. Shukla, A.K. Dwivedi, B.S. Setty, V.P.
Kamboj, Indian Patent No. 173757.
[5] R.C. Gupta, P. Nautiyal, A.C. Jhingran, V.P. Kamboj, B.S. Setty,
/
/
/
/
/
Anal. Found: C, 72.59; H, 10.26; N, 10.56. Calc. for
N. Anand, Indian J. Chem. 20 (B) (1981) 303Á307.
/
C25H41N3O2: C, 72.28; H, 9.97; N, 10.12%.
[6] N.M. Khanna, V.K. Shukla, A.K. Dwivedi, V.S. Setty, V.P.
Kamboj, Indian Patent No. 173760.
[7] N.M. Khanna, V.K. Shukla, A.K. Dwivedi, V.S. Setty, V.P.
Kamboj, Indian Patent No. 174013.
5.4.12. 3-(4-Methylpiperidyl)-1-[5-isopropyl-2-methyl-
4-(2-piperidinoethoxy)phenyl]propan-1-one (7d)
[8] N.M. Khanna, A.K. Dwivedi, R. Pal, S. Singh, B.S. Setty, V.P.
Kamboj, Indian Patent Application No. 2629/DEL/96 dated
29.11.96.
Yield: 17%. M.p. (Tartrate) 128Á
n 1668, 1604, 1556, 1504, 1307, 1215. Mass: m/z 414
[Mꢁ]. 1H-NMR: d 1.20Á
1.24 (m, 6H, CH(CH3)2),
1.45Á1.67 (m, 16H, CH2, ArÃCH3, CHÃCH3), 2.43Á
2.55 (m, 12H, CH2ÃN, COCH2), 2.80Á2.86 (t, 2H, NÃ
CH2) 3.23Á3.30 (m, 1H, CH), 4.13Á4.19 (t, 2H, OÃ
CH2), 6.76 (s, 1H, ArÃH), 7.70 (s, 1H, ArÃH). Anal.
/
130 8C. IR (cmꢀ1):
/
[9] A.K. Dwivedi, V.K. Shukla, K. Bhandari, B.S. Setty, V.P.
Kamboj, N.M. Khanna, Indian J. Chem. Sect. B 30 (1991)
/
/
/
/
281Á285.
/
/
/
/
[10] N.M. Khanna, V.K. Shukla, A.K. Dwivedi, J.P.S. Sarin, B.S.
Setty, V.P. Kamboj, Indian Patent Application No. 1134/DEL/88.
[11] N.M. Khanna, A.K. Dwivedi, R. Pal, S. Singh, B.S. Setty, V.P.
Kamboj, Indian Patent Application No. 2629/DEL/96.
/
/
/
/
/
Found: C, 75.75; H, 9.74; N, 6.54. Calc. for
C26H42N2O2: C, 75.36; H, 10.14; N, 6.78%.
[12] F.V. Sander, S.D. Crammer, Hum. Fertil. (1941) 134.
[13] V. Ciminale, B.K. Felber, M. Campbell, G.N. Pavlakis, AIDS
Res. Hum. Retroviruses 6 (11) (1990) 1281Á
[14] N. Bodor, B.K. Sloan, J.J. Kaminski, C. Shih, S. Pogany, J. Org.
Chem. 48 (1983) 5280Á5284.
/
1287.
Acknowledgements
/
Authors are thankful to Dr A.P., National Cancer
Research Institute, USA, for advice on the cell fusion