Synthesis of some heterocycle containing urea derivatives and their anti-viral activity

Article abstract of DOI:10.3987/COM-05-10488

Some new isoindol heterocyclic ureas (6a-6i) have been synthesized using N-aminophthalimide (2) and ethyl N-monosubstituted/ethyl N,N-disubstituted carbamate (5a-5i). All the newly synthesized final compounds have been evaluated for their anti-viral activities against a variety of viruses. The compound (6f) with the methoxy substituent showed reasonably better activity as compared to the standard drugs against all the viruses (cf. Tables 1, 2 and 3). Further, all the products (6a-6i) were found to be active against Vesicular stomatitis virus, Coxsackie virus B4 and Respiratory syncytical virus (cf. Table 2) and the compounds (6h) and (6i) displayed better antiviral activity in comparison to Brivudin and (S)-DHPA (cf. Table 3).

Full text of DOI:10.3987/COM-05-10488

HETEROCYCLES, Vol. 68, No. 1, 2006
11
HETEROCYCLES, Vol. 68, No. 1, 2006, pp. 11 – 22. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd June, 2005, Accepted, 25th November, 2005, Published online, 29th November, 2005. COM-05-10488
SYNTHESIS OF SOME HETEROCYCLE CONTAINING UREA
DERIVATIVES AND THEIR ANTI-VIRAL ACTIVITY
a
a
b
Manjusha Verma, Krishna N. Singh,* and Erik D. Clercq
a
Department of Applied Chemistry, Institute of Technology, Banaras Hindu
University, Varanasi-221005, India.E-mail: knsinghbhu@yahoo.co.in
b
Katholieke University, Leuven, Rega Institute, Minderbroedersstraat 10,
B-3000 Leuven, Belgium
Abstract- Some new isoindol heterocyclic ureas (6a-6i) have been synthesized
using N-aminophthalimide (2) and ethyl N-monosubstituted/ethyl N,N-
disubstituted carbamate (5a-5i). All the newly synthesized final compounds
have been evaluated for their anti-viral activities against a variety of viruses.
The compound (6f) with the methoxy substituent showed reasonably better
activity as compared to the standard drugs against all the viruses (cf. Tables 1,
2
and 3). Further, all the products (6a-6i) were found to be active against
Vesicular stomatitis virus, Coxsackie virus B4 and Respiratory syncytical virus
cf. Table 2) and the compounds (6h) and (6i) displayed better antiviral
activity in comparison to Brivudin and (S)-DHPA (cf. Table 3).
(
INTRODUCTION
The urea functionality manifests neuroprotective activity and is also a key structural element of many
1
-5
biologically active substrates, such as enzyme inhibitors and peptidomimetics. Urea derivatives possess
biological activities such as anti-bacterial, anti-fungal, anti-neoplastic, hypocholesterolemic, anti-ulcer,
gastric protective activities, anti-acetylcholinesterase, anti-diabetic, anti-arrhythmic, hypo- and
6
-9
hypertensive, and plant growth regulating activities. Recently, cyclic ureas have gained importance as
HIV-1 protease inhibitors which are important components of many highly active anti-retroviral therapy
1
0-19
regimens.
compounds.
Urea undergoes a variety of chemical reactions to afford wide range of important
2
0-30
31
In addition, they have also been used as chiral auxiliaries for asymmetric synthesis.
Due to their broad spectrum applications, the synthesis of urea derivatives has received considerable
32-41
attention.
Extensive investigations have recently been carried out for the preparation of libraries of
4
2-47
urea compounds with potential biological activities.
been prepared as follows:
Mono- or N,N-disubstituted urea derivatives have

12
HETEROCYCLES, Vol. 68, No. 1, 2006
(
i).
By the reaction of unsubstituted urea with alkylamines or their hydrochloride salts and subsequent
4
8
loss of ammonia or ammonium halide, to yield the expected substituted ureas.
4
9,50
(
(
(
(
ii).
By the aminolysis of isonitriles or cyanamides.
5
1
iii). By the conversion of nitrourea into substituted urea by the action of amines.
5
2
iv). By the reaction of alkali metal cyanates with amines.
v). By the reductive alkylation, whereby the substituents may be introduced into urea.
5
3
Many of the above mentioned synthetic methodologies described for the preparation of ureas suffer from
drawbacks, such as long reaction times, harsh reaction conditions, low product yields, occurrence of side
products and lack of versatility. Further, some of the reagents employed are expensive and toxic. In view
of the above, we report herein a convenient method for the preparation of some novel heterocyclic ureas
employing N-aminophthalimide and ethyl N-monosubstituted/ethyl N,N-disubstituted carbamate.
RESULTS AND DISCUSSION
A facile synthesis of 1-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-substituted phenyl)ureas (6a-f) and 3-
(
1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-(4-substituted phenyl)-1-methylureas (6g-i) has been achieved
adopting the steps described in Scheme 1. Phthalimide (1) was initially allowed to react with hydrazine
hydrate (96%) in ethanol to afford N-aminophthalimide (2). Refluxing a mixture of p-substituted aniline
(
3) and methyl iodide in solvent methanol provided N-methyl p-substituted aniline (4). Equimolar
reaction of 3/4 with ethyl chloroformate in solvent ether furnished ethyl p-substituted phenylcarbamate
5a-f) or ethyl N-p-substituted phenyl, N-methylcarbamate (5g-i) in reasonably good yield. The
(
condensation of N-aminophthalimide (2) with the substrates (5a-f) and (5g-i) was finally carried out to
obtain the product 1-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-substituted phenyl)-urea / 3-(1,3-dioxo-
1
,3-dihydro-isoindol-2-yl)-1-(4-substituted phenyl)-1-methylurea (6). The products (6a-i) were
recrystallized using ethanol/benzene and were fully characterized based on their mp, elemental analysis
and spectral data.
All the isoindol urea derivatives (6a-i) were subsequently subjected to their in vitro anti-viral screening
against a number of viruses and the results were compared with standard drugs (Tables 1, 2 and 3).
Cytotoxicity and anti-viral activity of the compounds have been performed in HEL, HeLa and Vero cell
cultures. The anti-viral activity has been expressed in terms of minimum inhibitory concentration
(
μg/mL) which is the least concentration required to reduce cytopathogenicity by 50%. These compounds
have also been evaluated for their minimum cytotoxic concentration (μg/mL) which is required to cause a
microscopically detectable alteration of normal cell morphology.
As an outcome, the compounds (6d, 6f and 6g) are found to be more active than the standard drug
Ribavirin against Herpes simplex virus-1(KOS), Herpes simplex virus-2 (G), Vesicular stomatitis virus
-1
r
and Herpes simplex virus-1 TK KOS ACV .

HETEROCYCLES, Vol. 68, No. 1, 2006
13
NH
2
NH-CH
3
O
O
NH NH .H O
2
2
2
CH3I
NH
O
N NH2 ;
O
C H OH
2
5
1
2
R
1
R
4
1
3
R
1
=Cl, Br ,N O
2
3
/4 + Cl C OC H
R
1
N C OC H5
2
2
5
O
O
R
2
5
3
4
: R = F, Cl, Br, NO , COOH, OCH
1
2
3
5
a : R = F, R = H ; 5b : R1 = Cl , R2 = H
1 2
R2 = H
5
c : R = Br, R = H ;5d : R = NO , R = H
1 2 1 2 2
:R = Cl, Br, NO ; R = CH
3
1
2
2
5
5
5
e : R = COOH, R = H ;5f : R = OCH , R = H
1
2
1
3
2
g : R = Cl, R = CH ;
1
2
3 5h : R
2
= Br, R = CH
3
1
i : R = NO , R = CH
3
1
2
2
O
2
+ 5
N NH C
N
R
R
1
O
O
2
6
6
a : R = F, R = H ; 6b : R = Cl, R = H
1
2
1
2
6
c : R = Br, R = H ; 6d : R = NO R = H
1
2
1
2
2
6
6
6
e : R = COOH, R = H ; 6f : R = OCH , R = H
1
2
1
3
2
g: R = Cl, R = CH ; 6h : R = Br, R = CH
1
2
3
1
2
3
i : R = NO , R = CH
3
1
2
2
Scheme 1
Compound (6d) shows lesser activity than Ribavirin against Vaccinia virus, whereas compound (6f) and
(
6g) are comparable to Ribavirin against Vaccinia virus (cf. Table 1). The compounds (6d, 6f and 6g)
-1
have better activities than Brivudin against Vesicular stomatitis virus and Herpes simplex virus-1 TK
r
KOS ACV . The compounds (6a-c, 6e, 6h and 6i) and Brivudin show equal activities against Vesicular
-1
r
stomatitis virus and Herpes simplex virus-1 TK KOS ACV . Compounds (6d, 6f and 6g) are more active
than Acyclovir against Vaccinia virus and Vesicular stomatitis virus. Compounds (6f) and (6g) show
better activity than Ganciclovir against Vaccinia virus, while the compounds (6d, 6f and 6g) are better
than Ganciclovir against Vesicular stomatitis virus.

14
HETEROCYCLES, Vol. 68, No. 1, 2006
Table-1:
Cytotoxicity and anti-viral activity of the compounds (6a-i) in HEL cell cultures
2
Compound Minimum
Cytotoxic
Minimum Inhibitory Concentration (μg/mL)
Herpes
Herpes
simplex virus- simplex
Vaccinia
virus
Vesicular
stomatitis
virus
Herpes simplex
virus-1
Concentration
1
-
(
μg/mL)
1
(KOS)
virus-2 (G)
TK KOS
r
ACV
6
a
>400
>400
>400
400
>400
>400
>400
>80
>400
>400
>400
>80
>400
>400
>400
240
>400
>400
>400
>80
>400
>400
>400
>80
6b
6
c
6d
6
e
>400
400
>400
>80
>400
>80
>400
>80
>400
>80
>400
>80
6
f
6
g
400
>80
>80
>80
>80
>80
6
h
>400
>400
>400
>400
>400
>100
>400
>400
>400
>400
80
>400
>400
48
>400
>400
>400
240
>400
>400
>400
240
6
I
Brivudin
Ribavirin
0.0768
>400
240
80
Acyclovir
Ganciclovir
0.384
0.0064
0.384
0.096
>400
>100
>400
>100
9.6
0.48
1
2
Required to cause a microscopically detectable alteration of normal cell morphology.
Required to reduce virus-induced cytopathogenicity by 50%.
Table-2:
Cytotoxicity and anti-viral activity of the compounds (6a-i) in HeLa cell cultures
2
Compound Minimum Cytotoxic
Minimum Inhibitory Concentration (μg/mL)
1
Concentration
Vesicular stomatitis Coxsackie virus B4
virus
Respiratory
syncytical virus
(
μg/mL)
6
a
400
400
400
80
>80
>80
>80
>16
>80
>16
80
>80
>80
>80
>16
>80
>16
80
>80
>80
>80
>16
>80
>16
80
6b
6
c
6d
6
e
400
80
6
f
6
g
400
>80
400
>400
>400
>400
6h
>80
>80
>400
>400
48
>80
>80
>400
>400
48
>80
>80
>400
>400
16
6
i
Brivudin
(
S)-DHPA
Ribavirin
1
2
Required to cause a microscopically detectable alteration of normal cell morphology.
Required to reduce virus-induced cytopathogenicity by 50%.

HETEROCYCLES, Vol. 68, No. 1, 2006
15
A perusal of Table 2 indicates that all the compounds (6a-i) are more active (lesser MIC) than standard
drugs Brivudin and (S)-DHPA against Vesicular stomatitis virus, Coxsackie virus B4 and Respiratory
synctial virus. The compounds (6d) and (6f) are even better than Ribavirin against Vesicular stomatitis
virus and Coxsackie virus B4.
Table-3:
Cytotoxicity and anti-viral activity of compounds (6a-i) in Vero cell cultures
2
Compound Minimum
Cytotoxic
Minimum Inhibitory Concentration (μg/mL)
Parainf-
luenza-3
virus
Reovirus-1 Sindbis virus Coxsackie
virus B4
Punta Toro
virus
1
Concentration
(
μg/mL)
6
a
>400
>400
>400
>400
>400
400
>400
>400
>400
>400
>400
>80
>400
>400
>400
>400
>400
>80
>400
>400
>400
>400
>400
>80
>400
>400
>400
>400
>400
>80
>400
>400
>400
>400
>400
>80
6b
6
c
6d
6
e
6
f
6
g
>400
400
>400
>80
>400
>80
>400
>80
>400
>80
>400
>80
6h
6
i
400
>80
>80
>80
>80
>80
Brivudin
>400
>400
>400
>400
>400
48
>400
>400
48
>400
>400
240
>400
>400
>400
>400
>400
48
(
S)-DHPA
Ribavirin
1
2
Required to cause a microscopically detectable alteration of normal cell morphology.
Required to reduce virus-induced cytopathogenicity by 50%.
It is evident from Table 3 that the compounds (6f, 6h and 6i) have better anti-viral activity than Brivudin
and (S)-DHPA against Parainfluenza-3 virus, Reovirus-1, Sindbis virus, Coxsackie virus B4 and Punta
Toro virus. The compounds (6f, 6h and 6i) are found to be more active than Ribavirin against Sindbis
virus and Coxsackie virus B4. Thus, the synthesized compounds (6a-i) are found to possess potential anti-
viral activity against a number of viruses and the compound (6f) has been concluded to be the most
promising compound possessing a broad spectrum of anti-viral activity.
EXPERIMENTAL
The melting points were measured in open capillaries and are uncorrected. IR spectra were recorded on a
JASCO FT/IR-5300 spectrophotometer. NMR spectra were run on a JEOL FT-NMR spectrometer FX-
9
0Q and the chemical shifts are expressed as δ/ppm, downfield to TMS as internal reference.
5
4
Synthesis of N-aminophthalimide (2)
9
6% Hydrazine hydrate (4.1 mL, 0.081 mol), ethyl alcohol (80 mL) and powdered phthalimide (1, 11.9 g,

16
HETEROCYCLES, Vol. 68, No. 1, 2006
0
.081 mol) were placed in a round bottom flask fitted with a reflux condenser. The mixture was then
shaken for 2 min at rt and the resulting spongy mass was quickly heated and refluxed for 3 min. Water
50 mL) was then quickly added to it and the clear solution obtained was poured into a large volume of
(
water (200 mL). The resulting N-aminophthalimide (2) was filtered, dried and recrystallised from ethyl
alcohol. The aqueous filtrate on acidification also gave 2 which was recrystallised.
54
-1
Yield 5.8 g (44.2%); mp 200-203°C (lit., 200-205°C); IR cm (KBr) 3390, 1775, 1752, 1606, 1388,
1
1
309, 1052, 718, 536; H-NMR (DMSO-d
6
2
), δ/ppm: 5.0 (s, 2H, NH ), 7.7-8.1 (m, 4H, ArH).
5
5
Preparation of N-methyl p-substituted aniline (4)
A mixture of p-substituted aniline (3, 0.025 mol) and MeI (0.6 mL, 0.01 mol) was refluxed in methanol
25 mL) for 10 h. The reaction mixture was cooled and made alkaline by adding 20% KOH. A solution of
ZnCl (1.50 g, 0.011 mol) in H O (1.5 mL) was added. The mixture was cooled to 5°C, stirred and
filtered at the suction pump. The thick paste was extracted several times with petroleum ether (bp 60-
0°C). The combined petroleum ether extracts were successively washed with water and 25% ammonia
(
2
2
8
solution and dried over anhydrous MgSO . The solvent was removed at rotary evaporator and the residue
4
was recrystallized with ethanol.
N-Methyl-p-chloroaniline:
5
6
-1
Yield 2.52 g (71.2%); bp 239°C (lit., 240°C); IR cm (neat) 3480, 2942, 1618, 1495, 1325, 1287, 1181,
1
1
088, 822, 642, 506; H-NMR (DMSO-d ), δ/ppm 2.8 (d, J= 1.1 Hz, 3H, CH ), 4.0 (br s, 1H, NH), 6.4 (d,
6
3
J= 9.3 Hz, 2H, Ar-H), 7.0 (d, J= 9.3 Hz, 2H, Ar-H).
N-Methyl-p-bromoaniline:
-1
Yield 2.03 g (43.9%); mp > 300°C; IR cm (KBr) 3455, 2941, 1611, 1593, 1488, 1472, 1373, 1288, 1180,
1
1
068, 828, 818, 505; H-NMR (DMSO-d
6
3
), δ/ppm 2.8 (d, J= 1.1 Hz, 3H, CH ), 4.0 (br s, 1H, NH), 6.3 (d,
J= 9.3 Hz, 2H, Ar-H), 7.2 (d, J= 9.3 Hz, 2H, Ar-H). Anal. Calcd for C H NBr C, 45.18; H, 4.30; N, 7.53.
7
8
Found C, 45.08; H, 4.42; N, 7.41.
N-Methyl-p-nitroaniline:
5
7
-1
Yield 1.58 g (41.1%); mp 150°C (lit., 152°C); IR cm (KBr) 3349, 2941, 1634, 1580, 1480, 1473, 1372,
1
1
6
327, 1298, 1118, 841, 693; H-NMR (DMSO-d
6
3
), δ/ppm 2.8 (d, J= 1.0 Hz, 3H, CH ), 4.0 (br s, 1H, NH),
.7 (d, J= 9.2 Hz, 2H, Ar-H), 8.0 (d, J= 9.2 Hz, 2H, Ar-H)
Preparation of ethyl p-substituted phenylcarbamate or ethyl N-p-substituted phenyl, N-
58
methylcarbamate (5)
In a three necked round bottom flask fitted with a condenser and magnetic stirrer and cooled by an ice-
salt mixture, was added ether (25 mL) and p-substituted aniline (3) (0.0206 mol) / N-methyl-p-substituted
aniline (4) (0.0206 mol). The mixture was stirred continuously while maintaining the temperature below
5
°C. Ethyl chloroformate (1.9 mL, 0.0206 mol) was subsequently added dropwise under 5°C. When half
of the ethyl chloroformate was added to the reaction mixture, a cold aq 20% solution of equimolar NaOH

HETEROCYCLES, Vol. 68, No. 1, 2006
17
(
1.2 mL, 0.0206 mol) was added gradually along with the rest of the ethyl chloroformate at such a rate so
that the last portions of the two solutions were added simultaneously. After stirring for 1 h, the ether layer
was separated and the aqueous phase was extracted with ether (2×20 mL). The combined ether extract
2 3
was dried with K CO , filtered and evaporated at rotary evaporator to afford the product (5a-i).
Ethyl p-fluorophenylcarbamate (5a):
-1
Yield 2.89 g (76.5%); mp 47°C (Recrystallised with EtOH); IR cm (KBr) 3402, 2985, 1700, 1574, 1555,
1
1
429, 1350, 1259, 1192, 1089, 1022, 799; H-NMR (DMSO-d
6
3
), δ/ppm 1.3 (t, J= 6.8 Hz, 3H, CH ), 4.1
(
q, J= 6.8, 13.1 Hz, 2H, CH
2
), 6.9 (d, J= 9.5 Hz, 2H, Ar-H), 7.6 (d, J= 9.5 Hz, 2H, Ar-H), 8.0 (s, 1H, NH).
Anal. Calcd for C
9
H10NO
2
F; C, 59.01; H, 5.46; N, 7.65. Found; C, 58.96; H, 5.55; N, 7.78.
Ethyl p-chlorophenylcarbamate (5b):
-1
Yield 2.01 g (49.0%); mp 59°C (Recrystallised with EtOH); IR cm (KBr) 3321, 2961, 1699, 1535, 1404,
1
1
305, 1261, 1094, 1024, 800, 680; H-NMR (DMSO-d ), δ/ppm: 1.3 (t, J= 6.8 Hz, 3H, CH ), 4.1 (q, J=
6
3
6
.8, 13.2 Hz, 2H, CH
Cl; C, 54.14; H, 5.01; N, 7.01. Found; C, 54.31; H, 4.88; N, 6.93.
Ethyl p-bromophenylcarbamate (5c):
2
), 7.2 (d, J= 9.3 Hz, 2H, Ar-H), 7.6 (d, J= 9.3 Hz, 2H, Ar-H), 8.0 (s, 1H, NH). Anal.
9 2
Calcd for C H10NO
-1
Yield 4.00 g (79.7%); mp 82°C (Recrystallised with EtOH); IR cm (KBr) 3300, 2933, 1705, 1590, 1570,
1
1
2
440, 1100, 1026, 570; H-NMR (DMSO-d
6
), δ/ppm: 1.3 (t, J= 6.8 Hz, 3H, CH
3
), 4.1 (q, J= 6.8, 13.2 Hz,
H, CH
2
), 7.4 (d, J= 9.3 Hz, 2H, Ar-H), 7.5 (d, J= 9.3 Hz, 2H, Ar-H), 8.0 (s, 1H, NH). Anal. Calcd for
Br; C, 44.28; H, 4.10; N, 5.74. Found; C, 44.41; H, 3.95; N, 5.88.
Ethyl p-nitrophenylcarbamate (5d):
9 2
C H10NO
5
4
-1
Yield 4.27 g (97.8%); mp 127°C (Recrystallised with EtOH) (lit., 129°C); IR cm (KBr): 3379, 2990,
1
1
739, 1599, 1551, 1514, 1416, 1333, 1265, 1219, 1109, 1059, 852, 748, 665; H-NMR (DMSO-d
6
),
δ/ppm 1.3 (t, J= 6.8 Hz, 3H, CH ), 4.1 (q, J= 6.8, 13.1 Hz, 2H, CH ), 7.9 (d, J= 9.2 Hz, 2H, Ar-H), 8.0 (s,
3
2
1
H, NH), 8.1 (d, J= 9.2 Hz, 2H, Ar-H).
Ethyl p-carboxyphenylcarbamate (5e):
-1
Yield 4.05 g (94.1%); mp 156°C (Recrystallised with EtOH); IR cm (KBr) 3333, 2998, 1711, 1668,
1
1
597, 1535, 1416, 1319, 1294, 1230, 1179, 1062, 945, 864, 841, 773; H-NMR (DMSO-d
6
), δ/ppm 1.3 (t,
J= 6.6 Hz, 3H, CH
3
), 4.1 (q, J= 6.7, 13.2 Hz, 2H, CH
2
), 7.8 (d, J= 9.2 Hz, 2H, Ar-H), 8.0 (s, 1H, NH), 8.1
; C, 57.41; H, 5.26; N, 6.69.
(
d, J= 9.2 Hz, 2H, Ar-H), 11.0 (s, 1H, COOH). Anal. Calcd for C10H11NO
4
Found; C, 57.30; H, 5.41; N, 7.06.
Ethyl p-methoxyphenylcarbamate (5f):
-1
Yield 3.47 g (86.4%); mp 53°C (Recrystallised with EtOH); IR cm (KBr) 3319, 2839, 1701, 1601, 1537,
1
1
442, 1415, 1315, 1238, 1186, 1074, 1028, 825, 775; H-NMR (DMSO-d
6
), δ/ppm 1.3 (t, J= 6.6 Hz, 3H,
CH
3
), 3.7 (s, 3H, OCH
3
), 4.1 (q, J= 6.7,13.1 Hz, 2H, CH
2
), 6.7 (d, J= 8.9 Hz, 2H, Ar-H), 7.5 (d, J= 8.9 Hz,

18
HETEROCYCLES, Vol. 68, No. 1, 2006
2
6
H, Ar-H), 8.0 (s, 1H, NH). Anal. Calcd for C10
.75; N, 7.12.
3
H13NO ; C, 61.53; H, 6.66; N, 7.17. Found; C, 61.47; H,
Ethyl p-chlorophenylmethylcarbamate (5g):
-1
Yield 1.37 g (31.2%); bp >250°C; IR cm (neat) 2898, 1677, 1580, 1560, 1433, 1379, 1190, 1150, 1008,
1
6
2
5
84; H-NMR (DMSO-d
6
), δ/ppm 1.3 (t, J=6.6 Hz, 3H, CH
), 7.2 (d, J= 9.2 Hz, 2H, Ar-H), 7.6 (d, J= 9.2 Hz, 2H, Ar-H). Anal. Calcd for C10
6.21; H, 5.62; N, 6.55. Found; C, 56.09; H, 5.67; N, 6.68.
3
), 2.8 (s, 3H, N-CH
3
), 4.1 (q, J= 6.5,13.1 Hz,
H, CH
2
H12NO
2
Cl; C,
Ethyl p-bromophenylmethylcarbamate (5h):
-1
Yield 3.65 g (60.7%); mp >250°C (Recrystallised with EtOH); IR cm (KBr) 2933, 1695, 1558, 1440,
1
1
189, 1149, 1007, 569; H-NMR (DMSO-d ), δ/ppm 1.3 (t, J= 6.6 Hz, 3H, CH ), 2.8 (s, 3H, N-CH ), 4.1
6
3
3
(
q, J= 6.5, 13.1 Hz, 2H, CH
2
), 7.4 (d, J= 9.3 Hz, 2H, Ar-H), 7.5 (d, J= 9.3 Hz, 2H, Ar-H). Anal. Calcd for
10 2
C H12NO Br; C, 46.52; H, 4.65; N, 5.42. Found; C, 46.40; H, 4.71; N, 5.58.
Ethyl p-nitrophenylmethylcarbamate (5i):
5
9
-1
Yield 1.59 g (34.2%); mp 45°C (Recrystallised with EtOH) (lit., 45°C); IR cm (KBr) 2900, 1723, 1600,
1
1
550, 1188, 1197, 1006, 1370, 1210; H-NMR (DMSO-d
6
), δ/ppm 1.3 (t, J= 6.6 Hz, 3H, CH
), 7.9 (d, J= 9.2 Hz, 2H, Ar-H), 8.1 (d, J= 9.2 Hz, 2H, Ar-H).
Preparation of 1-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-(4-substituted phenyl)urea and 3-(1,3-dioxo-
,3-dihydroisoindol-2-yl)-1-(4-substituted phenyl)-1-methylurea (6)
3
), 2.8 (s, 3H,
3 2
N-CH ), 4.1 (q, J= 6.5, 13.1 Hz, 2H, CH
1
Equimolar quantities of N-aminophthalimide (2) (1.14 g, 0.007 mol) and ethyl p-substituted
phenylcarbamate / ethyl N-p-substituted phenyl, N-methylcarbamate (5) (0.007 mol) were dissolved in
ethanol (30 mL). The reaction mixture was refluxed for 1-2 h. After the completion of the reaction as
checked by TLC, the solvent was removed at rotary evaporator and the residue was treated twice with
diethyl ether (2x20 mL). The combined ether extract was dried over anhydrous sodium sulphate and then
evaporated to afford the product (6a-i), which was recrystallised from ethanol/benzene and characterized.
1
-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(4-fluorophenyl)urea (6a):
-1
Yield 1.41 g (67.7%); mp >245°C (Recrystallised with EtOH); IR cm (KBr) 3344, 3012, 1700, 1699,
1
1
4
3
1
650, 1574, 1555, 1429, 1380, 800; H-NMR (DMSO-d
6
), δ/ppm 6.9 (d, J= 9.4 Hz, 2H, Ar-H), 7.6 (m,
H, Ar-H), 8.1 (d, J= 9.4 Hz, 2H, Ar-H), 8.3-8.5 (m, 2H, NH); Anal. Calcd for C15
.37; N, 14.04. Found; C, 60.00; H, 3.30; N, 14.00.
10 3 3
H N O F; C, 60.20; H,
-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(4-chlorophenyl)urea (6b):
-1
Yield 1.90 g (86.2%); mp >250°C (Recrystallised with EtOH); IR cm (KBr) 3358, 3012, 1697, 1639,
1
1
7
5
593, 1537, 1493, 1404, 831, 771, 682; H-NMR (DMSO-d ), δ/ppm 7.2 (d, J= 9.3 Hz, 2H, Ar-H), 7.4-
6
10 3 3
.7 (m, 4H, Ar-H), 8.1 (d, J= 9.4 Hz, 2H, Ar-H), 8.3-8.5 (m, 2H, NH); Anal. Calcd for C15H N O Cl; C,
7.07; H, 3.19; N, 13.31. Found; C, 57.00; H, 3.00; N, 13.49.

HETEROCYCLES, Vol. 68, No. 1, 2006
19
1
-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(4-bromophenyl)urea (6c):
-1
Yield 1.84 g (73.1%); mp 250°C (decomp) (Recrystallised with EtOH); IR cm (KBr) 3322, 3013, 1690,
1
1
629, 1525, 1440, 802, 592; H-NMR (DMSO-d ), δ/ppm 7.4-7.7 (m, 6H, Ar-H), 8.1 (d, J= 9.3 Hz, 2H,
6
10 3 3
Ar-H), 8.3-8.5 (m, 2H, NH); Anal. Calcd for C15H N O Br; C, 50.02; H, 2.80; N, 11.67. Found; C,
4
9.90; H, 2.60; N, 11.79.
-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(4-nitrophenyl)urea (6d):
1
-1
Yield 2.13 g (76.2%); mp 118-122°C (Recrystallised with benzene); IR cm (KBr) 3380, 3010, 1739,
1
1
4
5
1
600, 1557, 1530, 1450, 1423, 1344, 803; H-NMR (DMSO-d ), δ/ppm 7.7-7.9 (m, 4H, Ar-H), 8.1 (m,
6
H, Ar-H), 8.3-8.5 (m, 2H, NH); Anal. Calcd for C15
5.30; H, 3.30; N, 17.10.
10 4 5
H N O ; C, 55.22; H, 3.09; N, 17.17. Found; C,
-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(4-carboxyphenyl)urea (6e):
-1
Yield 2.20 g (96.8%); mp 215°C (Recrystallised with EtOH); IR cm (KBr) 3342, 3012, 3000, 1721,
1
1
4
1
1
675, 1600, 1570, 1550, 1427, 1289, 769; H-NMR (DMSO-d
6
), δ/ppm 7.7-7.8 (m, 4H, Ar-H), 8.1 (m,
H, Ar-H), 8.3-8.5 (m, 2H, NH), 11.0 (s, 1H, COOH); Anal. Calcd for C16
2.92. Found; C, 59.32; H, 3.65; N, 12.66.
11 3 5
H N O ; C, 59.08; H, 3.41; N,
-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-3-(4-methoxyphenyl)urea (6f):
-1
Yield 0.78 g (35.9%); mp >260°C (Recrystallised with EtOH); IR cm (KBr): 3329, 3017, 1770, 1715,
1
1
600, 1580, 1500, 1450, 1250, 1058, 803; H-NMR (DMSO-d
6
3
), δ/ppm: 3.7(s, 3H, OCH ), 6.7 (d, J= 9.0
Hz, 2H, Ar-H), 7.5-7.7 (m, 4H, Ar-H), 8.1 (d, J= 8.9 Hz, 2H, Ar-H), 8.3-8.5 (m, 2H, NH); Anal. Calcd for
; C, 61.73; H, 4.20; N, 13.50. Found; C, 60.92; H, 4.58; N, 13.74.
-(1,3-Dioxo-1,3-dihydroisoindol-2yl)-1-(4-chlorophenyl)-1-methylurea (6g):
16 13 3 4
C H N O
3
-1
Yield 1.31 g (57%); mp 155°C (Recrystallised with EtOH); IR cm (KBr) 3300, 3015, 1697, 1639, 1593,
1
1
537, 1493, 1404, 831, 803, 682; H-NMR (DMSO-d
6
3
), δ/ppm 2.8 (s, 3H, N-CH ), 7.2 (d, J= 9.0 Hz, 2H,
Ar-H), 7.6-7.7 (m, 4H, Ar-H), 8.1 (d, J= 9.1 Hz, 2H, Ar-H), 8.4 (s, 1H, NH); Anal. Calcd for
Cl; C, 58.28; H, 3.67; N, 12.74. Found; C, 58.00; H, 3.89; N, 12.87.
-(1,3-Dioxo-1,3-dihydroisoindol-2yl)-1-(4-bromophenyl)-1-methylurea (6h):
16 12 3 3
C H N O
3
-
1
Yield 0.86 g (33.2%); mp 240-241°C (Recrystallised with EtOH); IR cm (KBr) 3290, 3016, 2954, 1770,
1
1
710, 1590, 1570, 1440, 803, 570; H-NMR (DMSO-d
6
3
), δ/ppm 2.8 (s, 3H, N-CH ), 7.4-7.7 (m, 6H, Ar-
12 3 3
H), 8.1 (d, J= 9.3 Hz, 2H, Ar-H), 8.4 (s, 1H, NH) Anal. Calcd for C16H N O
Br; C, 51.36; H, 3.23; N,
1
1.23. Found; C, 51.42; H, 3.40; N, 11.00.
-(1,3-Dioxo-1,3-dihydro-isoindol-2yl)-1-(4-nitrophenyl)-1-methylurea (6i):
3
-1
Yield 1.67 g (70%); mp 105°C (Recrystallised with EtOH); IR cm (KBr) 3371, 3012, 2920, 1750, 1723,
1
1
570, 1531, 1458, 1393, 1250 800; H-NMR (DMSO-d
6
3
), δ/ppm 2.8 (s, 3H, N-CH ), 7.7-7.9 (m, 4H, Ar-
12 4 5
H), 8.1 (m, 4H, Ar-H), 8.4 (s, 1H, NH); Anal. Calcd for C16H N O
; C, 56.47; H, 3.55; N, 16.46. Found;

20
HETEROCYCLES, Vol. 68, No. 1, 2006
C, 56.40; H, 3.78; N, 16.66.
Anti-viral Screening
The final products (6a-i) were tested in vitro against a variety of viruses (Herpes simplex virus-1(KOS),
-1
Herpes simplex virus-2 (G), Vaccinia virus, Vesicular stomatitis virus, Herpes simplex virus-1 TK KOS
r
ACV , Coxsackie virus B4, Respiratory syncytical virus, Parainfluenza-3 virus, Reovirus-1, Sindbis virus
and Punta Toro virus) and the results were compared with standard drugs (cf. Table 1, 2 and 3).
Cytotoxicity and anti-viral activity of the compounds have been performed in HEL, HeLa and Vero cell
6
0
culture adopting a standard methodology.
ACKNOWLEDGEMENTS
The authors are thankful to Council of Scientific and Industrial Research, New Delhi, for financial
support. One of the authors (M Verma) is grateful for financial assistance as SRF from University Grant
Commission.
REFERENCES
1
.
C. P. Decicco, J. L. Seng, K. E. Kennedy, M. B. Covington, P. K. Welch, E. C. Arner, R. L.
Magolda, and D. J. Nelson, Bioorg. Med. Chem. Lett., 1997, 7, 2331.
2
3
.
.
J. A. W. Kruijtzer, D. J. Lefeber, and R. M. J. Liskamp, Tetrahedron Lett., 1997, 38, 5335.
F. Bohme, Ch. Kunert, H. Komber, D. Voigt, P. Friedel, M. Khodja, and H. Wilde,
Macromolecules, 2002, 35, S. 4233.
4
5
6
7
.
.
.
.
R. Di Fabio, N. Conti, E. De Magistris, A. Feriani, S. Provera, F. M. Sabbatini, A. Reggiani, and L.
Rovatti, and R. J.Barnaby, J. Med. Chem., 1999, 42, 3486.
P. Boden, J. M. Eden, J. Hodgson, D. C. Horwell, M. C. Pritchard, J. Raphy, and N. Suman-
Chauhan, Bioorg. Med. Chem. Lett., 1995, 5, 1773.
J. W. Newman, C. Morisseau, T. R. Harris, and B. D. Hammock, Proc. Natl. Acad. Sci. U. S. A.,
2
003, 100, 1558.
C. F. Purchase, A. D. White, M. K. Anderson, T. M. A. Bocan, R. F. Bousley, K. L. Hamelehle, R.
Homan, B. R. Krause, P. Lee, S. B. Mueller, C. Speyer, R. L. Stanfield, and J. F. Reindel, Bioorg.
Med. Chem. Lett., 1996, 6, 1753.
8
9
1
.
M. Jansen, H. Potschka, C. Brandt, W. Loescher, and G. Dannhardt, J. Med. Chem., 2003, 46, 64.
X.-Y, Xiao, K. Ngu, C. Chao, and D. V. Patel, J. Org. Chem., 1997, 62, 6968.
A. Ranise, S. Schenone, O. Bruno, F. Bondavalli, W. Filippelli, G. Falcone, and B. Rivaldi,
Farmaco, 2001, 56, 647.
.
0.
1
1.
M. C. Schroeder, J. M. Hamby, C. J. C. Connolly, P. J. Grohar, R. T. Winters, M. R. Barvian, C.
W. Moore, S. L. Boushelle, S. M. Crean, A. J. Kraker, D. L. Driscoll, P. W. Vincent, W. L. Elliott,
G. H. Lu, B. L. Batley, T. K. Dahring, T. C. Major, R. L. Panek, A. M. Doherty, and H. D. H.
Showalter, J. Med. Chem., 2001, 44, 1915.

HETEROCYCLES, Vol. 68, No. 1, 2006
21
1
1
1
2.
3.
4.
A. R. Katritzky, A. Oliferenko, A. Lomaka, and M. Karelson, Bioorg. Med. Chem. Lett., 2002, 12,
453.
3
H. Andreas, F. Romy, W. Michael, and W. H. Frank, Journal of Computer-Aided Molecular
Design, 1999, 13, 233.
P. Y. S. Lam, P. K. Jadhav, C. J. Eyermann, C. N. Hodge, Y. Ru, L. T. Bacheler, J. L. Meek, M. J.
Otto, M. M. Rayner, Y. N. Wong, C-H. Chang, P. C. Weber, D. A. Jackson, T. R. Sharpe, and S.
Erickson-Viitanen, Science, 1994, 263, 380.
1
1
1
5.
6.
7.
K. L. Mardis, R. Luo, and M. K. Gilson, J. Mol. Biol., 2001, 309, 507.
G. Guillena and C. Najera, Tetrahedron: Asymmetry, 1998, 9, 1125.
C. Palomo, M. Oiarbide, A. Gonzalez, J. M. Garcia, and F. Berree, Tetrahedron Lett., 1996, 37,
4
565.
1
1
8.
9.
H. Kubota, A. Kubo, M. Takahashi, R. Shimizu, T. Date, K. Okamura, and K. Nunami, J. Org.
Chem., 1995, 60, 6776.
R. F. Kaltenbach III, G. Trainor, D. Getman, G. Harris, S. Garber, B. Cordova, L. Bacheler, S.
Jeffrey, K. Logue, P. Cawood, R. Klabe, S. Diamond, M. Davies, J. Saye, J. Jona, and S.
Erickson-Viitanen, Antimicrobial Agents and Chemotherapy, 2001, 45, 3021.
Z. Tetere, D. Zicane, I. Ravina, M. Petrova, and E. Gudriniece, Chem. Heterocycl. Compd., 2002,
2
2
0.
1.
3
8, 1448.
S. M. Bromidge, S. Dabbs, D. T. Davies, S. Davies, D. M. Duckworth, I. T. Forbes, A. Gadre, P.
Ham, G. E. Jones, F. D. King, D. V. Saunders, K. M. Thewlis, D. Vyas, T. P. Blackburn, V.
Holland, G. A. Kennett, G. J. Riley, and M. D. Wood, Bioorg. Med. Chem., 1999, 7, 2767.
M. Gutschow, T. Hecker, and K. Eger, Synthesis, 1999, 410.
2
2
2
2
2.
3.
4.
5.
L. Ferris, D. Haigh, and C. J. Moody, J. Chem. Soc., Perkin Trans. 1, 1996, 2885.
N. C. Mathur, S. K. Wong, and H. Shechter, Tetrahedron Lett., 2003, 44, 5141.
K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd, S. Moreland, A. Hedberg, and B. C.
OReilly, J. Med. Chem., 1991, 34, 806.
2
2
2
6.
7.
8.
L. M. Deck and E. P. Papadopoulos, J. Heterocycl. Chem., 2000, 37, 675.
B. Koenig, M. Pelka, M. Subat, I. Dix, and P. G. Jones, Eur. J. Org. Chem., 2001, 1943.
L. Lemoucheux, J. Rouden, M. Ibazizene, F. Sobrio, and M.-C. Lasne, J. Org. Chem., 2003, 68,
7
289.
2
3
9.
0.
S. N. Shah and N. K. Chudgar, Molecules, 2000, 5, 657.
P. Phiasivongsa, J. Gallagher, C.-N. Cheng, P. R. Jones, V. V. Samoshin, and P. H. Gross, Org.
Lett., 2002, 4, 458727.
3
3
1.
2.
L. M. Deck and E. P. Papadopoulos, J. Heterocycl. Chem., 2000, 37, 675.
A. F. Hegarty and L. J. Drennan, In Comprehensive Organic Functional Group Transformations,
ed. by T. L. Gilchrist, Pergamon Press, Oxford, 1995, 6, 499.
3
3
3.
4.
A. R. Katritzky, N. Kirichenko, and B. V. Rogovoy, Arkivoc, 2003, 8, 8.
L. Lemoucheux, J. Rouden, M. Ibazizene, F. Sobrio, and M.-C. Lasne, J. Org. Chem., 2003, 68,
7
289.
3
5.
G. Ling, J. Chen, and S. Lu, J. Chem. Res., Synopses, 2003, 442.

22
HETEROCYCLES, Vol. 68, No. 1, 2006
3
3
3
6.
7.
8.
Y. Ichikawa, T. Nishiyama, and M. Isobe, J. Org. Chem., 2001, 66, 4200.
G. Haufe, U. Rolle, E. Kleinpeter, J. Kivikoski, and K. Rissanen, J. Org. Chem., 1993, 58, 7084.
O. Adetchessi, D. Desor, I. Forfar, C. Jarry, J. M. Leger, M. Laguerre, and A. Carpy, J. Heterocycl.
Chem., 1997, 34, 429.
3
4
4
9.
0.
1.
N. Risch, U. Westerwelle, J. Kiene, and R. Keuper, J. Prakt. Chem., 1999, 341, 616.
D. Scholz, P. Hecht, H. Schmidt, and A. Billich, Monatsh. Chem., 1999, 130, 1283.
S. M. Abdul Hai, S. Perveen, R. A. Khan, K. M. Khan, and N. Afza, Natural Product Research,
2
003, 17, 351.
4
2.
J. W. Nieuwenhuijzen, P. G. M. Conti, H. C. J. Ottenheijm, and J. T. M. Linders, Tetrahedron
Lett., 1998, 39, 7811.
4
4
4
4
3.
4.
5.
6.
C. W. Phoon and M. M. Sim, Synlett, 2001, 697.
K.-T. Huang and C.-M. Sun, Bioorg. Med. Chem. Lett., 2001, 11, 271.
B. Raju, J. M. Kassir, and T. P. Kogan, Bioorg. Med. Chem. Lett., 1998, 8, 3043.
M. A. Scialdone, S. W. Shuey, P. Soper, Y. Hamuro, and D. M. Burns, J. Org. Chem., 1998, 63,
4
802.
4
4
4
5
5
7.
8.
9.
0.
1.
B. A. Dressman, U. Singh, and S. W. Kaldor, Tetrahedron Lett., 1998, 39, 3631.
L. F. Cavalieri, V. E. Blair, and G. B. Brown, J. Am. Chem. Soc., 1948, 70, 1240.
H. Sawai and T. Takizawa, Tetrahedron Lett., 1972, 4263.
J. Schreiber and B. Witkop, J. Am. Chem. Soc., 1964, 86, 2441.
F. Yoneda, K. Tanaka, H. Yamato, K. Moriyama, and T. Nagamatsu, J. Am. Chem. Soc.,1989, 111,
9
199.
5
5
5
5
2.
3.
4.
B. B. Kehm and C. W. Whitehead, Org. Synth., Coll. Vol., 1963, IV, 515.
D. Xu, L. Ciszewski, T. Li, O. Repic, and T. J. Blacklock, Tetrahedron Lett., 1998, 39, 1107.
H. D. K. Drew and H. H. Hatt, J. Chem. Soc., 1937, 16.
5. B. S. Furniss, A. J. Hannaford, V. Rogers, P. W. G. Smith, and A. R. Tatchell, Vogel’s Textbook of
Practical Organic Chemistry, ELBS/Logman, Essex, England, 1978, 4th edn., 670, (reprinted
1
984).
6. Dictionary of organic compounds, 4 edn., Eyre and Spottiswoode Ltd., London, 1965, Vol. 2, p.
46.
th
5
6
5
5
5
6
7.
8.
9.
0.
Lit. 56, Vol. 4, p. 2249.
W. H. Hartman and M. R. Brethen, Org. Synth., Coll. Vol., 1950, II, 278.
Lit. 56, Vol. 3, p. 1407.
T. C. Rosen, E. D. Clercq, J. Balzarini, and G. Haufe, Org. Biomol. Chem., 2004, 229.