One pot synthesis of pyrimidine and bispyrimidine derivatives and their evaluation for anti-inflammatory and analgesic activities

Article abstract of DOI:10.1016/j.bmc.2007.03.028

A number of pyrimidine derivatives (1-10) have been synthesized by condensation of 4-isothiocyanato-4-methylpentan-2-one with furfurylamine, histamine, 1-(3-aminopropyl)imidazole, 1-(3-aminopropyl)-2-pyrrolidinone, 2-aminobenzonitrile and 3-isothiocyanato

Full text of DOI:10.1016/j.bmc.2007.03.028

Bioorganic & Medicinal Chemistry 15 (2007) 3334–3344
One pot synthesis of pyrimidine and bispyrimidine derivatives
and their evaluation for anti-inflammatory and analgesic activities
Sham M. Sondhi,a,* Shubhi Jain,a Monica Dinodia,a Rakesh Shuklab and Ram Raghubirb
aDepartment of Chemistry, Indian Institute of Technology–Roorkee (IIT R), Roorkee 247667, UA, India
bDepartment of Pharmacology, Central Drug Research Institute (CDRI), Lucknow 226001, India
Received 23 January 2007; revised 7 March 2007; accepted 8 March 2007
Available online 13 March 2007
Abstract—A number of pyrimidine derivatives (1–10) have been synthesized by condensation of 4-isothiocyanato-4-methylpentan-2-
one with furfurylamine, histamine, 1-(3-aminopropyl)imidazole, 1-(3-aminopropyl)-2-pyrrolidinone, 2-aminobenzonitrile and 3-isoth-
iocyanatobutanal with 1-(3-aminopropyl)-2-pyrrolidinone and 2-hydrazinopyridine under different reaction conditions. Various
bispyrimidine derivatives (11–15) were obtained by condensation of 4-isothiocyanato-4-methylpentan-2-one with 2,4,8,10-tetraoxaspi-
ro[5,5]undecane3,9-dipropamine (110), 1,4-bis(3-aminopropyl)piperazine (130), 3,5-diamino 1,2,4-triazole (150) and 3-isothiocyanatobut-
anal with 2,4,8,10-tetraoxaspiro[5,5]undecane 3,9-dipropamine, 1,4-bis(3-aminopropyl)piperazine. All these compounds were
characterized by correct FT-IR, 1H NMR, MS and elemental analysis. These compounds were screened for anti-inflammatory and anal-
gesic activities. Anti-inflammatory activity of 3 is comparable while analgesic activity was found to be better than that of standard drug.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
temperature for 2 days and then solvent was removed
at room temperature. To the semisolid residue left be-
hind were added little diethyl ether and ethyl acetate
and the reaction contents were scratched. Solid product
separated out was filtered and washed thoroughly with
cold ethyl acetate to give pure condensed product 3-(fur-
an-2-yl methyl)-4-hydroxy-4,6,6-trimethyl tetrahydro-
pyrimidine-2(1H) thione (1; Scheme 1). 1H NMR
(500 MHz; CDCl3) of 1 shows signals at d 1.24 (s, 3H,
CH3); 1.39 (s, 3H, CH3); 1.67 (s, 3H, CH3); 2.02–2.05
(d, 1H, J = 15 Hz, one H of pyrimidine CH2); 2.10–
2.13 (d, 1H, J = 15 Hz, one H of pyrimidine CH2);
2.96 (br s, 1H, OH, exch); 4.85–4.88 (d, 1H, J = 15 Hz,
one H of CH2); 5.84–5.87 (d, 1H, J = 15 Hz, one H of
CH2); 6.34 (dd, 1H, J = 2 and 3.5 Hz, Ar); 6.53 (dd,
1H, J = 1 and 3.5 Hz, Ar); 6.57 (br s, 1H, NH exch);
7.35 (dd, 1H, J = 1 and 2 Hz, Ar). GC–MS did not show
M+ ion peak but gave M+–H2O peak at m/z 236
(40.48%). This can be due to tert-OH being very labile
and undergoing elimination very fast. FT-IR spectra
show absorption bands at 3423 and 3233 (–OH, –NH–),
and 1534 (Ar) cmꢀ1. Spectral data of compound 1 fully
support the structure assigned to it. Formation of 1 can
be explained by nucleophilic attack of –NH2 of 1a on
isothiocyanato group of 1b giving a non-isolable interme-
diate thiourea 10 (Scheme 1) and further nucleophilic
attack by –NH– to >C@O group giving a ring cyclized
hydrated product 1 (Scheme 1).
Pain is associated with any kind of health problem and for
the management of pain, there is an urgent need of safer
anti-inflammatory drugs. Pyrimidine derivatives possess-
ing anti-inflammatory and analgesic activities have been
reported in the literature.1–7 In addition to above-men-
tioned activities, pyrimidine derivatives possessing antitu-
mour,8 antimicrobial,9 antibacterial,10 antifungal11 and
antiinfective12 activities have also been reported in the lit-
erature. In continuation of our efforts13–23 in search of po-
tential anti-inflammatory and analgesic molecules we
have synthesized a number of pyrimidine and bispyrimi-
dine derivatives and evaluated them for biological activi-
ties which we wish to report in this paper.
2. Results and discussion
2.1. Chemistry
Furfurylamine (1a; Scheme 1) and 4-isothiocyanato-4-
methylpentane-2-one24 (1b) were dissolved in methanol.
The reaction contents were allowed to stand at room
Keywords: Ketoisothiocynate; Pyrimidine; Bispyrimidine; Anti-inflam-
matory; Analgesic.
*
Corresponding author. Tel.: +91 1332 285811; fax: +91 1332
273650; e-mail: sondifcy@iitr.ernet.in
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.03.028

S. M. Sondhi et al. / Bioorg. Med. Chem. 15 (2007) 3334–3344
3335
H3C
CH3
H
H
CH3
CH3
CH3
CH3
S
N
S
N
N
MeOH
RT
CH2NH2
H2C N
C
H2C NH
H3C
O
CH3
O
O
O
S
1b
OH
H3C
O
1a
1
1'
MeOH / H+
pH-4
MeOH
pH-4
H
CH3
CH3
S
N
H
H
CH3
CH3
CH3
S
N
-H2O
S
N
-H+
H2C N
CH3
H
O
H2C N
H2C N
OH2
H3C
O
O
2'
2''
H3C
2
CH3
H
N
CH3
CH3
S
H3C
N
CH3
H2 H2
MeOH
RT
N
CH2CH2NH2
N
C
C
N
C
CH3
N
O
H3C
OH
H
N
S
H
3
3a
1b
N
H
CH3
CH3
S
N
N
H2 H2
H2C C C
MeOH
RT
N
H3C OH
H3C
CH3
4
N
N
C
S
MeOH
pH-4
/ H
N
CH3
O
CH2CH2CH2NH2
N
MeOH
1b
H
4a
CH3
CH3
S
N
N
H2 H2
C C
N
H2C
CH3
5
Scheme 1.
When compound 1 was heated in methanol under reflux
for 8 h at pH ꢁ4, dehydrated product, that is, 1-(furan-
2-yl methyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-
2(1H)thione (2; Scheme 1) was obtained in good yield.
1H NMR (500 MHz; DMSO-d6) of 2 shows signals d
1.02 (s, 6H, 2· CH3); 1.92 (s, 3H, CH3); 4.72 (s, 1H,
@CH–); 5.30 (s, 2H, –CH2–); 6.12–6.13 (d, 1H, Ar);
6.27–6.30 (q, 1H, Ar); 7.44–7.47 (d, 1H, Ar); 8.63 (s, 1H,
NH, exch). GC–MS gave M+ ion peak at m/z 236
(30.34%). FT-IR spectra show absorption bands at 3221
(–NH–) and 1521 (Ar) cmꢀ1. Spectral data of 2 are in
complete agreement with the structure assigned to it.
Dehydration will occur through non-isolable intermedi-
ates 20 and 200 (Scheme 1).
to a double bond and is sp2 hybridized and thus does
not affect –CH2– attached to furan ring and hence shows
1
a singlet in H NMR, whereas in case of compound 1
C6-carbon of pyrimidine ring is sp3 hybridized and is
attached to one methyl and one hydroxyl group due to
the effect of C6–OH group which is in close vicinity of
–CH2– of furan ring both the protons becoming differ-
ent and giving geminal coupling and hence appearing
as two doublets. Direct condensation of 1a with 1b using
methanol as solvent and adjusting pH to ꢁ4 and heating
under reflux, on usual work up, gave compound 2
(Scheme 1). The yield of product 2 obtained by direct
condensation was slightly less than what was obtained
by dehydration of 1 and 2.
1
A comparison of H NMR of 1 and 2 indicates absence
Condensation of histamine (3a) with 4-isothiocyanato-4-
methylpentan-2-one(1b) inmethanol atroomtemperature
gave 6-hydroxy-1[2-(1H imidazo-4-yl)-ethyl]-4,4,6-tri-
methyl tetrahydropyrimidine-2-thione (3; Scheme 1).
The structure of compound 3 is fully supported by spec-
tral data reported in the Section 4 of this paper.
Condensation of 1-(3-aminopropyl) imidazole 4a with
1b at room temperature using methanol as solvent gave
of signals at d 2.02–2.05 (d, 1H one H of –CH2– of
pyrimidine ring), 2.10–2.13 (d, 1H, one H of CH2 1of
pyrimidine) and 2.96 (br s, 1H, OH, exch) in the H
NMR of 2 and presence of a signal at d 4.72 (s, 1H,
@CH–). These observations confirm elimination of
H2O from 1 leading to the formation of 2. In case of
compound 2 C6-carbon of pyrimidine ring is attached

3336
S. M. Sondhi et al. / Bioorg. Med. Chem. 15 (2007) 3334–3344
H
N
CH3
CH3
S
O
N
H2C
N
C
C
MeOH / RT
H2 H2
OH
H3C
6
H3C
N
CH3
MeOH
pH-4
H
C
N
O
CH3
O
S
CH2CH2CH2NH2
MeOH
pH-4
H
1b
7a
H
N
CH3
CH3
S
O
N
H2C
N
C
C
H2 H2
CH3
7
CH3
H
S
N
MeOH
CH3
O
N
C
S
N
RT
N
O
H2C
N
C
C
H
O
H2 H2
CH2CH2CH2NH2
OH
7a
1c
8
H
N
CH3
CH3
S
CH3
H3C
NH2
N
C
S
MeOH
6hrs
N
O
CH3
CH3
CN
CN
9
1b
9a
CH3
H
CH3
S
N
MeOH
N
C
S
H
N
N
/ 10hrs
N
O
H
NHNH2
N
OH
10
10a
1c
Scheme 1. (continued)
1-(3-(1H-imidazol-1-yl) propyl)-6-hydroxy-4,4,6-trimethyl
tetrahydro pyrimidine-2(1H)-thione (4; Scheme 1). Spec-
tral data of 4 reported in the experimental section of this
paper are in agreement with the structure assigned to it.
Compound 4 when heated under reflux in methanol after
adjusting pH of the reaction mixture to ꢁ4 undergoes
dehydration to give product 1-(3-(1H-imidazol-1-yl)pro-
pyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H) thi-
one (5; Scheme 1).The structure of compound 5 is fully
supported by spectral data reported in experimental sec-
tion of this paper. EI-MS of 5 gave M+ ion peak at m/z
264 (M+, 53%). Interestingly, compound 5 gave all the
fragmentation peaks which are also shown by compound
4 after loss of H2O molecule, that is, m/z 264 (M+ꢀH2O;
58.3). Fragmentation pattern of compound 4 is explained
in Figure 1. Compound 5 was also obtained by direct con-
densation of 4a and 1b by refluxing in methanol for eight
hours and then purifying the product by column chroma-
tography. The yield obtained for 5 by conversion of 4 to 5
was much better than the product 5 obtained by direct
condensation of 4a and 1b. Condensation of 1-(3-amino-
propyl)-2-pyrrolidinone 7a and 4-isothiocyanato-4-
methylpentan-2-one (1b) at room temperature using
methanol as solvent of reaction gave condensed product
6, that is, 1-(3-(6-hydroxy-4,4,6-trimethyl-2-thioxo-tetra-
hydropyrimidine-1(2H)-yl) propyl) pyrrolidin-2-one.
When compound 6 was heated under reflux using metha-
nol as solvent and adjusting the pH of reaction mixture to
ꢁ4 (by adding a few drops of 10% sulfuric acid in metha-
nol) compound 6 undergoes dehydration to give 1,3-
(4,4,6-trimethyl-2-thioxo-3,4-dihydropyrimidine-1(2H)-
propyl)pyrrolidin-2-one (7) in good yield. The structures
assigned to compounds 6 and 7 are in full agreement
with their spectral data reported in experimental section
of this paper. Direct condensation of 7a and 1b by
refluxing in methanol and adjusting the pH to ꢁ4
gave lower yield of 7 than obtained from conversion of
6 to 7.

S. M. Sondhi et al. / Bioorg. Med. Chem. 15 (2007) 3334–3344
3337
N
H
CH3
CH3
N
S
N
H2C
N
C
C
H2 H2
N
OH
-SH
H
N
CH3
S
4
N
m/z 282 (4.4%)
H2C
N
C
C
N
H2 H2
CH3
CH3
N
CH3
N
-H2O
m/z 249 (5.1%)
H2C
N
C
C
-CH3
H2 H2
OH
CH3
m/z 249 (5.1%)
-H2O
N
d
CH3
CH3
H
S
N
N
b
a
c
H2C
N
C
C
H2 H2
(a)
CH3
m/z 264 (58.3%)
-SH
N
N
CH3
CH3
N
N
(b)
N
H2
C
CH2
H2C
H2C
N
C
C
H2 H2
m/z 109 (22.5%
-C2H4
CH3
m/z 231 (7.0%)
-H
N
N
N
N
N
H2C CH2
N
CH2
m/z 81 (50.6%)
m/z 95 (38.4%)
-H
H2C
C CH2
H
m/z 108(27.5%)
-C2H2
N
N
CH2
HC
m/z 94 (8.3%)
N
N
CH3
m/z 82 (84%)
Figure 1.
Pyrrolidinone 7a on condensation with 3-isothiocyanato-
butanal25 (1c; Scheme 1) at room temperature gave
product 8, that is, 1-(3-(6-hydroxy-4-methyl-2-thioxo-tet-
rahydropyrimidine-1(2H)-yl)-propyl)pyrrolidin-2-one.
Spectral data of 8 reported in experimental section of this
paper fully support the structure assigned to it. 2-Amin-
obenzonitrile (9a; Scheme 1) on condensation with
4-isothiocyanato-4-methylpentan-2-one (1b; Scheme 1)
by refluxing for 6 h, using methanol as solvent, gave con-
densation product 2-(4,4,6-trimethyl-2-thioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)benzo-nitrile (9; Scheme 1) in good
yield. Condensation of 2-hydrazinopyridine - (10a) with
3-isothiocyanatobutanal (1c; Scheme 1) by refluxing in
methanol for 10 h and then purifying the crude product
by column chromatography over silica gel (elution CHCl3
EtOA, 1:1) gave 4-hydroxy-6-methyl-3(pyridin-2-ylami-
no)-tetrahydropyrimidine-2(1H)thione (10; Scheme 1).
Spectral data of 9 and 10 reported in Section 4 of this

3338
S. M. Sondhi et al. / Bioorg. Med. Chem. 15 (2007) 3334–3344
N
H
H
N
d
b
S
a
S
CH3
CH3
N
CH3
CH3
N
(b)
(d)
c
N
N
H2C
C
C
H2C
H2 H2
CH3
CH3
m/z 264 (58.3 %)
(c)
m/z 169 (4.8%)
(a)
H
H
N
S
S
CH3
CH3
N
CH3
CH3
H
S
N
CH3
CH3
N
N
H2C
C
C
H2
H2
N
CH3
CH3
m/z 155 (17.1%)
H2C
C
H2
m/z 197 (4.8%)
CH3
m/z 183 (30.7%)
-H
H
S
N
CH3
CH3
-H
N
H2C
C
H
CH3
m/z 182 (10.8%)
H
S
N
CH3
CH3
H
S
CH3
N
- CH3
N
H2C
C C
H
H2
N
CH3
m/z 196 (20.5%)
H2C
C C
H
H2
CH3
m/z 181 (100%)
Figure 1. (continued)
paper fully support the structures assigned to them.
2,4,8,10-Tetraoxaspiro[5,5]undecane 3,9-dipropamine
(110; Scheme 2) on condensation with 4-isothiocyanato-4-
methylpentan-2-one (1b; Scheme 2) at room temperature
using methanol as a solvent gave condensed product
1-(3-(9-(3-((4,6,6,-trimethyldihydro pyrimidine-2(1H)thi-
one)-4-ene-3yl)propyl)2,4,8,10-tetraoxaspiro[5,5]undecan-
3-yl)propyl)-4,4,6-trimethyldihydro pyrimidine-2(1H)thi-
(q, 4H, C13,C21,C19b and C23b); 4.73 (s, 2H, 2· @CH–);
7.52 (s, 2H, 2· NH, exch). IR (KBr) tmax 3178 (NH)
cmꢀ1. FAB-MS of 11 gave MH+ ion peak at m/z 553
(50%). The structure of 11 is fully supported by IR,
1H NMR, elemental analysis and FAB-MS spectral
data. During condensation of 3-isothiocyanatobutanal
(1c; Scheme 2) with 110 at room temperature using
methanol as a solvent pure condensed product, that is,
1-(3-(9-(3-((4-hydroxo-6-methyl tetrahydro pyrimidin-
2(1H)thione)3yl)propyl)-2,4,8,10-tetraoxaspiro[5,5]und-
ecan-3-yl)propyl)-6-hydroxo-4-methyltetrahydropyrimi-
dine-2(1H)thione (12; Scheme 2), was obtained only
after chromatographic separation of the crude product.
Yield of the pure condensed product 12 was 36%. Struc-
ture assigned to 12 is in complete agreement with its
spectral data reported in Section 4 of this paper.
1
one (11; Scheme 1) in 50% yield. While interpreting H
NMR of 11 peak positions were assigned with the help of
1H NMR of starting material, that is (110). It is considered
that dioxane ring starting with C13 is in the plane and
dioxane ring starting with C21 is out of plane.
1H NMR (200 MHz; DMSO-d6) d 1.20–1.22 (2s, look-
ing like a doublet, 12H, 4· CH3 i.e., C5C6C32C33);
1.63–1.65 (m, 4H, 2· CH2; C11C25); 1.71–1.76 (m, 4H,
2· CH2; C12C24); 1.93 (s, 6H, 2· CH3; C1C29), 3.33–
3.37 (t, 2H, C19a and C23a), 3.52–3.58 (t, 4H, 2· CH2;
C10C26); 4.09–4.27 (m, 4H, 2· CH2; C17,C15); 4.49–4.57
When 1,4-bis(3-aminopropyl) piperazine (130; Scheme 2)
and 4-isothiocyanato-4-methylpentan-2-one (1b; Scheme
2) dissolved in methanol were kept at room temperature
S
S
34
7
18
20
19
17
32
CH3
NH
31
O
HN
O
5
35
9
8
10 11 12
CH2 CH2 CH2
24 25 26
CH2 CH2 CH2
27
H3C
4
21
13
O
N
N
16
23
33
CH3
H3C
28
H3C
29
O
22
6
30
3
2
15
14
CH3
1
11

S. M. Sondhi et al. / Bioorg. Med. Chem. 15 (2007) 3334–3344
3339
S
S
N
NH
O
O
HN
O
O
CH3
CH3
H3C
H3C
(CH2)3
H3C
(CH2)3
N
11
CH3
CH3
H3C
N
C
MeOH
RT
7 days
CH3
O
S1b
O
O
O
H2N(H2C)3
(CH2)3NH2
O
11'
CH3
MeOH
RT, 10 days
N
C
S
O
H
Ic
S
S
O
HN
O
NH
N
(CH2)3
CH3
H3C
(CH2)3
N
O
O
HO
OH
12
13
S
S
HN
NH
CH3
CH3
H3C
H3C
N (CH2)3
CH3
N
N (CH2)3
N
H3C
OH
OH
CH3
H3C
N
C
S1b
Abs. MeOH
RT
1 day
CH3
O
N
(CH2)3NH2
H2N(H2C)3
N
CH3
13'
N
C
S 1c
MeOH
O
H
16 hrs
S
S
HN
NH
N (CH2)3
N
H3C
N (CH2)3
HO
N
CH3
HO
14
S
NH2
NH
CH3
H3C
CH3
CH3
MeOH
8 hrs
N
N
N
C
S
N
N
S
N
CH3
O
NH2
N
CH3
HN
N
H
H3C
H3C
N
H
15'
1b
CH3
15
Scheme 2.
for one day, solid product separated out which on filtra-
tion and washing with chilled methanol gave pure product
13 in 50% yield. Structure assigned to 13, that is, 4-hydro-
xy-3-(3-(4-(3-(6-hydroxy-4,4,6-trimethyl-2-thioxotetra-
hydropyrimidin1(2H)yl)propyl) piperazin-1-yl)propyl)-
4,4,6-trimethyl tertahydropyrimidin-2-(1H)-thione, is
completely supported by spectral data reported in Section
4 of this paper. Condensation of 1,4-bis(3-aminopro-
pyl)piperazine (130; Scheme 2) with 3-isothiocyanatobut-
anal (1c; Scheme 2) at room temperature using methanol
as a solvent gave complex mixture which was difficult to
separate and hence the same reaction was carried out by
refluxing the reaction mixture for 16 h. Removal of sol-
vent and recrystallization of the crude product from ethyl
acetate methanol (1:1) gave condensed product 4-hydro-
xy-3-(3-(4-(3-(6-hydroxy-4-methyl-2-thioxo-tetrahydro
pyrimidin-1(2H)-yl)propyl)piperazin-1-yl)propyl)-6-methyl-
tetrahydropyrimidine-2(1H)-thione (14; Scheme 2) in 50%
yield. Spectral data of 14 reported in experimental section
of this paper are in complete agreement with the structure as-
signed to it. 3,5-Diamino-1,2,4-triazole (150) on reaction with
4-isothiocyanato-4-methylpentan-2-one (1b) at room tem-
perature gave complex mixture but the same reaction on
heating under reflux in methanol gave crude product which

3340
S. M. Sondhi et al. / Bioorg. Med. Chem. 15 (2007) 3334–3344
was purified by column chromatography over silica gel.
Elution with ethyl acetate chloroform (1:1) gave conden-
sation product 4,4,6-trimethyl-1-(5-(4,4,6-trimethyl-2-
thioxo-3,4-dihydropyrimidin-1(2H)-yl)-2H-1,2,4-triazol-
3-yl)-3,4-dihydropyrimidine-2(1H)thione (15; Scheme 2)
in 30% yield. Low yield of the product could be due to
the ring nitrogen of triazole making both the amino
groups less reactive. Structure of 15 is derived from its cor-
rect spectral data reported in Section 4 of this paper.
3 and 8 exhibited good anti-inflammatory and analgesic
activities, whereas 4, 6 and 14 exhibited good anti-
inflammatory activity. Compound 3 exhibited anti-
inflammatory activity comparable to ibuprofen and
analgesic activity better than ibuprofen.
4. Experimental
Melting points (mp) were determined on a JSGW appa-
ratus and are uncorrected. IR spectra were recorded
using a Perkin-Elmer 1600 FT spectrometer. H NMR
2.2. Biological results
1
Anti-inflammatory activity26 evaluation of 1–6, 8, 9, 11–
15 was carried out using carrageenin-induced paw oede-
ma assay and results are summarized in Table 1. Com-
pounds 3, 4, 6, 9, 11, 12, 15 at 100 mg/kg po; and
compounds 1, 2, 5, 8, 13, 14 at 50 mg/kg po exhibited
65%, 35%, 40.3%, 0.0%, 31.8%, 0.0%, 0.0% and 10.3%,
15.1%, 32.5%, 36.3%, 31.6%, 38.6% activity, respec-
tively, whereas ibuprofen exhibited 66.8% anti-inflam-
matory activity at 100 mg/kg po. Analgesic activity27
evaluation of 1–6, 8, 9, 11–15 was carried out using phe-
nyl quinone writhing assay and results are summarized
in Table 1. Compounds 3, 4, 6, 9, 11, 12, 15 at
100 mg/kg po; and compounds 1–5, 8, 9, 11, 13, 14 at
50 mg/kg po exhibited 100%, 50%, 34%, 25%, 75%,
0.0%, 0.0% and 15%, 8.5%, 25%, 25%, 40%, 50%,
0.0%, 25%, 10.0%, 40.0% analgesic activity, respectively,
whereas ibuprofen exhibited 75% and 50% analgesic
activity at 100 mg and 50 mg/kg po, respectively. A look
at Table 1 indicates that compounds 3, 4, 6, 8, 14 exhib-
ited good anti-inflammatory activity, whereas com-
pounds 3 and 8 exhibited good analgesic activity.
spectra were measured on a Bruker WH-500, 300 and
200 spectrometer at a ca. 5–15% (w/v) solution in
DMSO-d6 or CDCl3 (TMS as internal standard).
FAB-MS was recorded on JEOL SX-120 (FAB) spec-
trometer. GC–MS was recorded on Perkin-Elmer Clarus
500 mass spectrometer. Elemental analysis was carried
out on Vario EL III elementor. Thin layer chromatogra-
phy (TLC) was performed on silica gel G for TLC
(Merck) and spots were visualized by iodine vapour or
by irradiation with ultraviolet light (254 nm). Column
chromatography was performed by using Qualigen‘s sil-
ica gel for column chromatography (60–120 mesh).
4.1. General procedure for room temperature reactions
4.1.1. Synthesis of 3-(furan-2-yl methyl)-4-hydroxy-4,6,6-
trimethyltetrahydro pyrimidine-2(1H)-thione (1). Furfu-
ryl amine (0.20 ml; 2 mmol) was taken in methanol
(10 ml) and to it was added 4-isothiocyanato-4-methylp-
entan-2-one (0.30 ml; 2 mmol). The reaction contents
were allowed to stand at room temperature for two
days. Solvent was allowed to evaporate at room temper-
ature and the semisolid residue left behind was scratched
with chilled ethyl acetate diethyl ether (1:1) (5 ml). The
solid separated out was filtered and washed with chilled
ethyl acetate to give pure condensed product 1. Yield
3. Conclusion
A number of pyrimidine (1–10) and bispyrimidine (11–
15) derivatives have been synthesized and screened for
anti-inflammatory and analgesic activities. Compounds
1
0.290 g (57%), mp 95 ꢁC IR and H NMR data has al-
ready been reported in Section 2. GC–MS (m/z; relt
Table 1. Anti-inflammatory and analgesic activity evaluation of compounds 1–6, 8, 9, 11–15
Compound
Dose mg/kg po
Anti-inflammatory activity %
Dose mg/kg po
Analgesic activity %
1
2
3
50
50
10.3
15.1
65
50
50
15
8.5
100
50
100
100
75
50
25
25
12.5
50
4
100
35
100
50
25
40
5
6
8
9
50
100
50
32.5
40.3
36.3
0.0
50
100
50
34
50
100
100
50
25
0.0
75
11
100
31.8
100
50
25
12
13
100
50
0.0
31.6
38.6
0.0
100
50
0.0
10.0
40.0
0.0
75
14
15
50
50
100
100
100
100
50
Ibuprofen
66.8
50

S. M. Sondhi et al. / Bioorg. Med. Chem. 15 (2007) 3334–3344
3341
int %) 236 (40.48%), 221 (6.06%), 155 (5.72%), 96
(3.23%), 81 (100%).
1.75–1.80 (m, 1H, one H of CH2); 1.90–2.00 (m, 4H,
2· CH2); 2.00–2.10 (m, 1H, one H of CH2); 2.12–2.15
(t, 2H, –CH2–); 3.19 (m, 2H, CH2); 3.45 (m, 2H,
CH2); 3.68 (m, 2H, CH2); 5.90 (s, 1H, –OH, exch);
8.03 (s, 1H, NH, exch). TOF MS ES m/z 282.0582
(MH+ꢀH2O, 100%). Anal. Calcd for C14H25N3O2S C,
56.18; H, 8.36; N, 14.09; S, 10.70; found C, 55.91; H,
7.87; N, 13.59; S, 10.39.
Anal. Calcd for C12H18N2O2S C, 56.96; H, 7.08; N, 11.02;
S, 12.59; found C, 56.81; H, 7.32; N, 11.00; S, 12.91.
Similarly, 6-hydroxy-1[2-(1H imidazol-4-yl)-ethyl]-4,4,6-
trimethyl-tetrahydro pyrimidine-2-thione (3, at room
temperature for
3 days; product separated out,
washed with chilled methanol), 1-(3-(1H-imidazol-1-
yl)propyl)-6-hydroxy-4,4,6-trimethyl tetrahydropyrimi-
dine-2(1H)thione (4; at room temperature, for one day;
product separated out, washed with chilled methanol),
1-(3-(6-hydroxy-4,4,6-trimethyl-2-thioxo-tetrahydropyrim-
idine-1(2H)-yl)propyl)pyrrolidin-2-one (6; at room temper-
ature, for 1 day; product separated out, washed with
chilled methanol), and 1-(3-(6-hydroxy-4-methyl-2-thi-
oxo-tetrahydropyrimidin-1(2H)-yl)propyl)pyrrolidin-2-one
(8; at room temperature for 3 days, remove solvent at
room temperature, residue left behind was scratched
with ethyl acetate ethanol (9:1) and solid separated out
was washed with chilled methanol) were synthesized.
4.1.5. Synthesis of 1-3-(6-hydroxy-4-methyl-2-thioxo-tet-
rahydropyrimidine-1(2H)-ylpropyl)-pyrrolidin-2-one (8).
Solvent of crystallization: THF, Yield 50%, mp 175 ꢁC,
IR (KBr) tmax 3452 and 3273 (–OH, NH), 1652
1
(>C@O). H NMR (500 MHz, DMSO-d6) d 1.20–1.22
(d, 3H, CH3); 1.51–1.55 (m, 1H, one H of CH2);
1.85–2.20 (m, 5H, 4H, 2· CH2) + (1H one H of –CH2–);
2.32–2.38 (t, 2H, –CH2–); 3.40–3.49 (m, 4H, 2·CH2);
3.62–3.71 (m, 2H, CH2); 3.90–3.97 (m, 1H,); 4.86–4.87
(t, 1H,); 6.41–6.42 (d, 1H, OH, exch); 7.36 (s, 1H, NH,
exch). FAB-MS m/z 272 (MH+, 40%); 254 (MH+ꢀH2O,
100%). Anal. Calcd for C12H21N3O2S C, 53.13; H, 7.74;
N, 15.49; S, 11.80; found C, 52.82; H, 7.72; N, 15.75; S, 11.78.
4.1.2. Synthesis of 6-hydroxy-1-[2-(1H-imidazol-4-
yl)ethyl]-4,4,6-trimethyl-tetrahydropyrimidine-2-thione
(3). Solvent of crystallization: methanol, yield 55% mp
180 ꢁC, IR (KBr) tmax 3395 and 3191(–OH, NH), 1533
(Ar). 1H NMR (200 MHz, CDCl3) d 1.07 (s, 3H,
CH3); 1.37 (s, 3H, –CH3); 1.81 (br s, 1H, –OH, exch);
1.86 (s, 3H, CH3); 2.45 (d, 1H, J = 14.5 Hz, 1H of
pyrimidine CH2); 2.55 (d, 1H, J = 14.5 Hz, 1H of pyrim-
idine CH2) 2.82–3.14 (m, 2H, CH2); 3.47–3.62 (m, 1H,
one H of CH2); 5.64–5.74 (m, 1H, one H of CH2);
6.80 (s, 1H, Ar); 6.87 (s, 1H, NH, exch); 7.48 (s, 1H,
Ar). FAB-MS m/z 251 (MH+ꢀH2O; 25%). Anal. Calcd
for C12H20N4OS C, 53.73; H, 7.46; N, 20.89; S, 11.94;
found C, 53.99; H, 7.05; N, 21.03; S, 12.01.
4.2. General procedure for pH adjusted reactions
4.2.1. Synthesis of 1-(furan-2-yl methyl)-4,4,6-trimethyl-
3,4-dihydropyrimidine-2(1H)-thione (2). Compound 1
(254 mg; 1 mmol) was dissolved in methanol (10 ml)
and pH of the reaction mixture was adjusted to ꢁ4 by
adding a few drops of 10% H2SO4 in methanol. The
reaction contents were heated under reflux for eight
hours, solvent was removed under reduced pressure
and the residue left behind was treated with 10% sodium
bicarbonate solution. The solid product so separated
was filtered, washed with water and recrystallized from
chloroform to give pure product 2. Yield 0.165 g
1
(70%). Mp 115 ꢁC IR and H NMR data have already
been reported in Section 2. GC–MS m/z 236 (M+,
30.34%), 221 (4.51%), 155 (4.62%), 81 (100%). Anal.
Calcd for C12H16N2OS C, 61.01; H, 6.77; N, 11.86; S,
13.56; found C, 60.87; H, 7.10; N, 12.13; S, 13.37.
4.1.3. Synthesis of 1-(3-(1H-imidazol-1-yl)propyl)-6-
hydroxy-4,4,6-trimethyl-tetrahydropyrimidine-2(1H)-thi-
one (4). Solvent of crystallization: methanol, yield 70%,
mp 170 ꢁC, IR (KBr) tmax 3250 and 3177 (OH, NH)
1
1525 (Ar). H NMR28 (400 MHz, DMSO-d6) d 1.14 (s,
Similarly, 1-(3-(1H-imidazol-1-yl)propyl)-4,4,6-trimethyl-
3,4-dihydropyrimidine-2(1H)-thione (5) and 1-(3-(4,4,6-
trimethyl-2-thioxo-3,4-dihydropyrimidine-1(2H)-yl)pro-
pyl)pyrrolidin-2-one (7) were synthesized.
3H, CH3); 1.23 (s, 3H, CH3); 1.37 (s, 3H, –CH3); 1.88
(d, 1H, J = 14 Hz, 1H of pyrimidine CH2); 1.94 (d, 1H,
J = 14 Hz, 1H of pyrimidine CH2); 2.02 (m, 1H, one H
of CH2); 2.34 (m, 1H, one H of CH2); 3.65–3.67 (m, 2H,
–CH2–); 3.96–3.99 (m, 2H, –CH2–); 5.91 (s, 1H, OH,
exch); 6.89 (s, 1H, Ar); 7.17 (s, 1H, Ar); 7.63 (s, 1H, Ar);
8.13 (s, 1H, NH, exch). EI-MS (m/z; relt int %) 282 (M+,
4.4%); 264 (58.3%); 249 (5.1%); 231 (7.0); 197 (4.8%);
196 (20.5%); 183 (30.7%); 182 (10.8%); 181 (100%); 169
(4.8%); 155 (17.1%); 109 (22.5%); 108 (27.5%); 95
(38.4%); 94 (8.3%); 82 (84%); 81 (50.6%). Anal. Calcd
for C13H22N4OS C, 55.31; H, 7.80; N, 19.85; S, 11.34;
found C, 55.63; H, 7.40; N, 19.51; S, 11.29.
4.2.2. Synthesis of 1-(3-(1H-imidazol-1-yl)propyl)-4,4,6-
trimethyl-3,4-dihydropyrimidine-2(1H)-thione (5). Solvent
of recrystallization: CHCl3 EA (1:1). Yield 25%; mp
120 ꢁC, IR (KBr) tmax 3203 (NH) 1637 (C@N) 1526
1
(Ar). H NMR (400 MHz, DMSO-d6) d 1.08 (s, 3H,
CH3); 1.12 (s, 3H, CH3); 1.77 (s, 3H, CH3); 1.99 (m, 2H,
–CH2–); 4.00–4.14 (m, 4H, 2· CH2); 4.78 (s, 1H, @CH–);
6.87 (s, 1H, Ar); 7.19 (s, 1H, Ar); 7.64 (s, 1H, Ar); 8.55
(s, 1H, NH, exch). EI-MS m/z 264 (M+, 53%). Anal. Calcd
for C13H20N4S C, 59.09; H, 7.57; N, 21.21; S, 12.12; found
C, 59.38; H, 7.41; N, 21.65; S, 12.01.
4.1.4. Synthesis of 1-3-(6-hydroxy-4,4,6-trimethyl-2-thi-
oxo-tetrahydropyrimidine-1(2H)-ylpropyl)-pyrrolidin-2-
one (6). Solvent of crystallization: methanol, yield 70%
mp 175 ꢁC, IR (KBr) tmax 3324 and 3204 (–OH, NH),
4.2.3. Synthesis of 1-3-(4,4,6-trimethyl-2-thioxo-3,4-dihy-
dropyrimidine-1(2H)-propyl)pyrrolidin-2-one (7). Solvent
of recrystallization: methanol. Yield 69%, mp 120 ꢁC, IR
(KBr) tmax 3449 (–NH), 1678 (>C@O). 1H NMR
1
1655 (>C@O). H NMR (500 MHz, DMSO-d6) d 1.10
(s, 3H, CH3); 1.20 (s, 3H, CH3); 1.40 (s, 3H, CH3);

3342
S. M. Sondhi et al. / Bioorg. Med. Chem. 15 (2007) 3334–3344
(500 MHz; DMSO-d6) d 1.12 (s, 9H, 3· CH3); 1.73 (m, 2H,
CH2); 1.88 (m, 4H, 2· CH2); 2.34 (m, 2H, CH2); 2.97 (m,
2H, CH2); 3.96 (m, 2H, CH2); 4.79 (s, 1H, @CH–); 8.50
(s, 1H, NH, exch). GC–MS m/z 281 (M+, 9.23%); 266
(8.51%); 248 (38.19%); 197 (1.27%); 196 (4.07%); 183
(4.89%); 155 (21.82%); 126 (100.0%); 98 (40.57%). Anal.
Calcd for C14H23N3OS C, 59.78; H, 8.18; N, 14.93; S,
11.39; found C, 60.01; H, 8.48; N, 14.59; S, 11.73.
pressure and the crude product so obtained was recrystal-
lized from methanol to give pure product 9. Yield 0.360 g
(70%). Mp 215 ꢁC, IR (KBr) tmax 3181 (NH), 2227 (CN),
1
1537 (Ar). H NMR (200 MHz; DMSO-d6) d 1.37–1.53
(3s, 9H, 3· CH3); 4.92 (s, 1H, @CH–); 7.33 (s, 1H, NH,
exch); 7.44–7.52 (m, 2H, Ar); 7.63–7.73 (m, 2H, Ar).
FAB-MS m/z 258 (MH+, 100%). Anal. Calcd for
C14H15N3S C, 65.36; H, 5.83; N, 16.15; S, 12.45; found
C, 65.02; H, 6.11; N, 16.32; S, 12.19.
4.3. Second procedure
4.5. Synthesis of 4-hydroxy-6-methyl-3-(pyridin-2-yl
amino)-pyrimidine-2(1H)-thione (10)
4.3.1. Synthesis of 1-(furan-2-yl methyl)-4,4,6-trimethyl-
3,4-dihydropyrimidine-2(1H)-thione (2). Furfurylamine
(0.20 ml; 2 mmol) was taken in methanol (10 ml) and to
it was added 4-isothiocyanato-4-methyl pentan-2-one
(0.30 ml; 2 mmol). The pH of reaction contents was ad-
justed to ꢁ4 by adding few drops of 10% H2SO4 in meth-
anol. The reaction mixture was heated under reflux for 6 h
and then solvent was removed under reduced pressure.
The residue left behind was treated with 10% sodium
bicarbonate solution and the solid obtained was filtered,
washed with water and recrystallized from methanol to
give pure product 2. Yield 0.329 g (70%). mp 115 ꢁC, IR
3-Isothiocyanatobutanal (0.26 ml; 2 mmol) and 2-
hydrazinopyridine (0.220 g; 2 mmol) were taken in
methanol (20 ml). The reaction contents were heated un-
der reflux for 10 h and then solvent was removed under
reduced pressure. The crude product so obtained was
purified by column chromatography over silica gel. Elu-
tion with CHCl3 removed side products and further elu-
tion with ethyl acetate chloroform (1:1) gave pure
product 10. Yield 0.100 g (20%). Mp 120 ꢁC, IR (KBr)
tmax 3454 and 3190 (OH, NH), 1531 (Ar) cmꢀ1 1H
.
1
(KBr) tmax 3221 (NH), 1521 (Ar). H NMR (500 MHz;
NMR (300 MHz; DMSO-d6) d 1.27–1.29 (d, 3H,
CH3), 1.96–2.17 (m, 2H, CH2), 3.76–3.86 (m, 1H,
DMSO-d6) d 1.02 (s, 6H, 2· CH3); 1.92 (s, 3H, CH3);
4.73 (s, 1H, @CH–); 5.30 (s, 2H, –CH2–); 6.12–6.13 (d,
1H, Ar); 6.27–6.30 (q, 1H, Ar); 7.44–7.47 (d, 1H, Ar);
8.63 (s, 1H, NH, exch). GC–MS m/z 236 (M+, 30.34%),
221 (4.51%), 155 (4.62%), 81 (100%). Similarly, com-
pound 7 was synthesized (yield 60%; recrystallization
MeOH). Compounds 2 and 7 obtained by route (i) and
(ii) were found to be same.
C
H
CH3
), 4.87–4.88 (t, 1H,), 6.65–6.68 (d, 1H, Ar),
6.77 (s, 1H, NH, exch), 6.82–6.86 (t, 1H, Ar), 7.52–
7.55 (t, 2H, 1H exch NH + 1H Ar), 8.21–8.22 (d, 1H,
Ar). FAB-MS. No M+ ion peak but (MH+ꢀH2O) ion
peak at m/z 221 (50%) was observed. Anal. Calcd for
C10H14N4SO C, 50.42; H, 5.88; N, 23.52; S, 13.44; found
C, 50.73; H, 5.66; N, 23.19; S, 13.72.
4.3.2. Synthesis of 1-(3-(1H-imidazol-1-yl)propyl)-4,4,6-
trimethyl-3,4-dihydropyrimidine-2(1H)-thione (5). 1-(3-
Aminopropyl)imidazole (0.25 ml; 2 mmol) was taken in
absolute methanol (10 ml) and to it was added 4-isothio-
cyanato-4-methylpentan-2-one (0.32 ml; 2 mmol). The
reaction mixture was heated under reflux for 8 h and then
the solvent was removed under reduced pressure. The
semisolid residue left behind was subjected to column
chromatography over silica gel. Elution with ethyl acetate
chloroform (1:1) gave condensed product 5. Yield 0.132 g
(25%). Mp 120 ꢁC, IR (KBr) tmax 3203 (NH) 1637 (C@N)
1526 (Ar). 1H NMR (400 MHz; DMSO-d6) d 1.08 (s, 3H,
CH3); 1.12 (s, 3H, CH3); 1.77 (s, 3H, CH3); 1.99 (m, 2H, –
CH2–); 4.00–4.14 (m, 4H, 2· CH2); 4.78 (s, 1H, @CH–);
6.87 (s, 1H, Ar); 7.19 (s, 1H, Ar); 7.64 (s, 1H, Ar); 8.55
(s, 1H, NH, exch). EI-MS m/z 264 (M+, 53%). All other
prominent fragmentation peaks obtained were same as
in case of compound 4. Compound 5 obtained by above
method and obtained by dehydration of 4 was found to
be same. Anal. Calcd for C13H20N4S C, 59.09; H, 7.57;
N, 21.21; S, 12.12; found C, 59.38; H, 7.41; N, 21.65; S,
12.01.
4.6. Synthesis of 1-(3-(9-(3-((4,6,6,-trimethyldihydropyr-
imidine-2(1H)thione)-4-ene-3yl)propyl)2,4,8,10-tetraoxa-
spiro[5,5]undecan-3-yl)propyl)-4,4,6-trimethyldihydro
pyrimidine-2(1H)thione (11)
2,4,8,10-Tetraoxaspiro[5,5]undecane3,9-dipropanamine
(274 mg; 1 mmol) was dissolved in methanol (5 ml) and
to it was added 4-isothiocyanato-4-methyl-pentan-2-one
(0.32 ml; 2 mmol). The reaction contents were allowed
to stand at room temperature for 7 days and then fil-
tered to give condensed product which was washed with
chilled methanol to give pure product 11. Yield 0.276 g
(50%), mp 190 ꢁC. Spectral data of compound 11 has al-
ready been reported in Section 2. Anal. Calcd for
C27H44N4S2O4 C, 58.69; H, 7.97; N, 10.14; S, 11.60;
found C, 58.27; H, 8.01; N, 10.31; S, 11.38.
4.7. Synthesis of 1-(3-(9-(3-((4-hydroxo-6-methyl tetra-
hydro pyrimidin-2(1H)thione)-3yl)propyl)-2,4,8,10-tetra-
oxaspiro[5,5]undecan-3-yl)propyl)-6-hydroxo-4-methyl-
tetrahydropyrimidine-2(1H)thione (12)
4.4. Synthesis of 2-(4,4,6-trimethyl-2-thioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)benzo-nitrile (9)
2,4,8,10-Tetraoxaspiro[5,5]undecane3,9-dipropanamine
(274 mg; 1 mmol) and 3-isothiocyanatobutanal (0.26 ml;
2 mmol) were taken in methanol (10 ml). Reaction con-
tents were allowed to stand at room temperature for 10
days. No solid product separated out. Solvent of the
reaction mixture was removed under reduced pressure
and the residue left behind was purified by column
4-Isothiocyanato-4-methylpentan-2-one (0.32 ml; 2 mmol)
and anthranilonitrile(236 mg; 2 mmol) were takenin 10 ml
methanol and the reaction mixture was heated under
reflux for 6 h. Solvent was removed under reduced

S. M. Sondhi et al. / Bioorg. Med. Chem. 15 (2007) 3334–3344
3343
chromatography over silica gel. Elution with ethyl ace-
tate:methanol (1:1) gave condensed product 12. Yield
0.192 g (36%); mp 130 ꢁC, IR (KBr) tmax 3444 (OH), 1H
NMR (200 MHz, DMSO-d6 + D2O) d 1.25–1.28 (d, 6H,
2· CH3), 1.56–1.91 (m, 12H, 6· CH2), 3.32–3.36 (d,
2H), 3.45–3.65 (m, 5H), 3.86–3.91 (t, 3H), 4.02 (m, 1H),
4.51–4.54 (t, 4H, 2· CH2), 4.90–4.95 (m, 1H), 5.94–5.97
(t, 1H), 6.37–6.47 (t, 1H), FAB-MS m/z 533 (MH+,
10%) Anal. Calcd for C23H40N4O6S2 C, 51.87; H, 7.51;
N, 10.52; S, 12.03; found C, 52.01; H, 7.39; N, 10.68;S, 11.87.
methyl pentan-2-one (0.64 ml; 4 mmol). The reaction
contents were heated under reflux for eight hours and then
solvent was removed under reduced pressure to give
crude product which was purified by column chromatog-
raphy over silica gel. Elution with CHCl3 removed side
products and further elution with chloroform ethyl
acetate (1:1) gave pure product 15. Yield 0.226 g (30%);
1
mp 240 ꢁC, IR (KBr) tmax 3194 (NH) 1546 (Ar). H
NMR (200 MHz; DMSO-d6 + CDCl3) d 1.35 (s, 12H,
4· CH3), 1.70 (s, 6H, 2· CH3), 4.79 (s, 2H, 2· @CH–),
8.22 (s, 2H, 2· NH, exch). FAB-MS m/z 378 (MH+,
80%). Anal. Calcd for C16H23N7S2 C, 50.92; H, 6.10; N,
25.99; S, 16.97; found C, 51.07; H, 5.97; N, 25.71; S, 17.13.
4.8. Synthesis of 4-hydroxo-3-(3-(4-(3-(6-hydroxy-4,4,6-
trimethyl-2-thioxo-tetrahydropyrimidin-1(2H)-yl)propyl)-
piperazin-1-yl)propyl)-4,6,6-trimethyl-tetrahydropyrimi-
dine-2(1H)-thione (13)
4.11. Anti-inflammatory activity evaluation
4-Isothiocyanato-4-methyl
pentan-2-one
(0.32 ml;
Anti-inflammatory activity evaluation26 was carried out
using carrageenin-induced paw oedema in albino rats.
Oedema in one of the hind paws was induced by injec-
tion of carrageenin solution (0.1 ml of 1%) into planter
aponeurosis. The volume of the paw was measured ple-
thysmographically immediately after and three hours
after the injection of the irritant. The difference in vol-
ume gave the amount of oedema developed. Percent
inhibition of the oedema between the control group
and compound-treated groups was calculated and com-
pared with the group receiving a standard drug. Anti-
inflammatory activity of compounds 1–6, 8, 9, 11–15
screened is reported in Section 2.
2 mmol) was added to a solution of 1,4-bis(3-aminopro-
pyl) piperazine (0.20 ml; 1 mmol) in absolute methanol
(5 ml). The reaction contents were allowed to stand at
room temperature for 1 day. Solid product separated
out was filtered, washed with methanol to give pure con-
densed product 13; Yield 0.267 g (50%); mp 210 ꢁC. IR
(KBr) tmax 3400 + 3312 (–OH, NH), 1H NMR
(400 MHz; DMSO-d6) d 1.15 (s, 6H, 2· CH3), 1.24 (s,
6H, 2· CH3), 1.44 (s, 6H, 2· CH3), 1.68 (m, 2H), 1.91
(q, 4H, 2· CH2), 2.10 (m, 2H), 2.24–2.35 (m, 10H,
5· CH2); 3.16–3.17 (q, 2H, CH2); 3.74–3.76 (t, 4H,
2· CH2), 6.16 (s, 2H, 2· OH, exch), 8.01 (s, 2H, 2· NH,
exch). TOF MS ES m/z 515.3203 (MH+, 100%) calculated
for C24H47N6O2S2 m/z 515.3202. Anal. Calcd for
C24H46N6O2S2 C, 56.03; H, 8.94; N, 16.34; S, 12.45; found
C, 55.81; H, 8.73; N, 16.51; S, 12.19.
4.12. Analgesic activity evaluation
Analgesia was measured by the writhing assay27 using
Swiss mice (15–20 g). Female mice were screened for
writhing on day-1 by injecting intraperitoneally 0.2 cm3
of 0.02% aqueous solution of phenylquinone. They were
kept on flat surface and the number of writhes of each
mouse was recorded for 20 min. The mice showing signif-
icant writhes (>10) were sorted out and used for analgesic
assay on the following day. The mice consisting of five in
each group and showing significant writhing were given
orally a 25 or 50 or 100 mg/kg po dose of the test com-
pounds 15 min prior to phenylquinone challenge. Writh-
ing was again recorded for each mouse in a group and a
percentage protection was calculated using the following
formula:
4.9. Synthesis of 4-hydroxo-3-(3-(4-(3-(6-hydroxy-4-methyl-
2-thioxo-tetrahydropyrimidin-1(2H)-yl)propyl)piperazin-
1-yl)propyl)-6-methyl-tetrahydropyrimidine-2(1H)-thione
(14)
1,4-Bis(3-aminopropyl) piperazine (0.20 ml; 1 mmol) was
taken in methanol (10 ml) and to it was added 3-isothiocy-
anatobutanal (0.26 ml; 2 mmol). The reaction contents
were heated under reflux for 16 h and then solvent was re-
moved under reduced pressure. The crude product so ob-
tained was scratched with ethyl acetate:methanol (1:1).
Solid product separated out was filtered and washed with
cold ethyl acetate. The crude product so obtained was
recrystallized from ethyl acetate; Yield 0.230 g (50%).
Protection ¼ 100 ꢀ ½ðNo: of writhings for treated miceÞ=
ðNo: of writhings for untreated miceÞ ꢂ 100ꢃ:
1
Mp 100 ꢁC; IR (KBr) tmax 3350, 3212 (OH, NH), H
NMR (200 MHz; DMSO-d6 + CDCl3) d 1.23–1.30 (dd,
6H, 2· CH3), 1.40–2.30 (m, 6H), 2.30–2.90 (m, 16H),
3.25–3.80 (m, 4H), 4.10–4.20 (m, 1H), 4.45–4.55 (m,
1H), 4.90–5.00 (m+s, 2H), 6.80–6.90 (2s, 2H, 2· NH,
exch). FAB-MS m/z 459 (MH+, 100%). Anal. Calcd for
C20H38N6O2S2 C, 52.40; H, 8.29; N, 18.34; S, 13.97; found
C, 52.11; H, 8.37; N, 18.12; S, 14.03.
This was taken as a percent of analgesic response and
was averaged in each group of mice. Percent of animals
exhibiting analgesia was determined with each dose.
Compounds 1–6, 8, 9, and 11–15 were screened for anal-
gesic activity and results are reported in Section 2.
4.10. Synthesis of 4,4,6-trimethyl-1-(5-(4,4,6-trimethyl-2-
thioxo-3,4 dihydro pyrimidin-1(2H)-yl)-2H-1,2,4-triazol-
3-yl)-3,4-dihydropyrimidine-2(1H)thione (15)
Acknowledgments
We are thankful to technical staff of the Chemistry
Department, I.I.T, Roorkee, for spectroscopic studies
and elemental analysis. Ms Shubhi Jain is thankful to
3,5-Diamino-1,2,4-triazole(200 mg;2 mmol)wasdissolved
inmethanol(20 ml)andtoitwasadded4-isothiocyanato-4-

3344
S. M. Sondhi et al. / Bioorg. Med. Chem. 15 (2007) 3334–3344
14. Sondhi, S. M.; Sharma, V. K.; Singhal, N.; Verma, R. P.;
Shukla, R.; Raghubir, R.; Dubey, M. P. Phosphorus,
Sulfur Silicon Relat. Elem. 2000, 156, 21.
MHRD, Govt of India, and Ms Monica Dinodia (SRF)
to UGC, Delhi, for financial assistance.
15. Sondhi, S. M.; Johar, M.; Singhal, N.; Dastidar, S. G.;
Shukla, R.; Raghubir, R. Monatshefte fuer Chemie 2000,
131, 511.
References and notes
16. Sondhi, S. M.; Johar, M.; Singh, N.; Shukla, R.; Raghu-
bir, R.; Dastidar, S. G. Indian J. Chem., Sect B 2002, 41B,
2659.
17. Sondhi, S. M.; Bhattacharjee, G.; Jameel, R. K.;
Shukla, R.; Lozach, O.; Meijer, L. Cent. Eur. J. Chem.
2004, 2, 1.
18. Sondhi, S. M.; Bhattacharjee, G.; Jameel, R. K.; Kumar,
A.; Bajaj, K. Indian J. Chem., Sect A 2005, 44A, 232.
19. Sondhi, S. M.; Singh, N.; Lahoti, A. M.; Bajaj, K.;
Kumar, A.; Lozach, O.; Meijer, L. Bioorg. Med. Chem.
2005, 13, 4291.
20. Sondhi, S. M.; Verma, R. P.; Singhal, N.; Shukla, R.;
Raghubir, R.; Dubey, M. P. Indian Drugs 1999, 36, 50.
21. Sondhi, S. M.; Singhal, N.; Johar, M.; Reddy, B. S. N.;
Lown, J. W. Curr. Med. Chem. 2002, 9, 1045.
22. Sondhi, S. M.; Rajvanshi, S.; Singh, N.; Jain, S.; Lahoti,
A. M. Cent. Eur. J. Chem. 2004, 2, 141.
23. Sondhi, S.M.; Dinodia, M.; Singh, J.; Rani, R., Curr.
Bioactive Compounds, in press.
24. Mathes, R. A.; Stewart, F. D.; Frank, S., Jr. J. Am. Chem.
Soc. 1948, 70, 1452.
25. Peretokin, A. V.; Shutalev, A. D.; Chupin, V. V.;
Mergenova, A. M.; Ignatova, L. A.; Malina, Y. F.;
Unkovskii, B. V. Zhurnal Organicheskoi Khimii 1985, 21,
1004; . Chem. Abstr. 1986, 104, 108981.
1. Hill, M. R.; Holland, S. J.; Pearson, S. L.; Yeates, K. T. PCT
Int. Appl. WO 2004048344 Chem. Abstr. 2004, 141, 38626.
2. Carter, M. C.; Naylor, A.; Payne, J. J.; Pegg, N. A. PCT Int.
Appl. WO 2003014091 Chem. Abstr. 2003, 138, 187783.
3. Agarwal, S. K.; Tadiparthi, R.; Aggarwal, P; Shivakumar,
S. PCT Int. Appl. WO 2003084936, Chem. Abstr. 2003,
139, 323529.
4. Bahekar, S. S.; Shinde, D. B. Bioorg. Med. Chem. Lett.
2004, 14, 1733.
5. Liu, L.; Lopez, P.; Bajpai, M.; Siegmund, A. C. U.S. Pat.
Appl. Publ. US 2004-923067 Chem. Abstr. 2005, 142,
261550.
6. Clare, M.; Hagen, T. J.; Houdek, S. C.; Lennon, P. J.;
Weier, R. M.; Xu, X., PCT Int. Appl. WO 2005040133
Chem. Abstr. 2005, 142, 463736.
7. Eatherton, A. J.; Giblin, G. M. P.; Mitchell, W. L.;
Naylor, A.; Rawlings, D. A.; Wall, I. D. PCT Int. Appl.
WO 2005075440 Chem. Abstr. 2005, 143, 211924.
8. Gangjee, A.; Jain, H. D.; Phan, J.; Lin, X.; Song, X.;
McGuire, J. J.; Kisliuk, R. L. J. Med. Chem. 2006, 49, 1055.
9. Alam, O.; Imran, M.; Khan, S. A. Indian J. Heterocycl.
Chem. 2005, 14, 293.
10. Hazarika, J.; Kataky, J. C. S. Indian J. Chem., Sect B
2001, 40B, 255.
11. Buurman, E. T.; Blodgett, A. E.; Hull, K. G.; Carcanague,
D. Antimicrob. Agents Chemother. 2004, 48, 313.
12. Kidwai, M.; Saxena, S.; Rastogi, S.; Venkataramanan, R.
Curr. Med. Chem.: Anti-Infect. Agents 2003, 2, 269.
13. Sondhi, S. M.; Singhal, N.; Verma, R. P.; Raghubir, R.;
Goel, A. K.; Patnaik, G. K. Indian J. Chem., Sect B 1997,
36B, 620.
26. Winter, C. A.; Risley, E. A.; Nuss, G. W. Proc. Soc. Exp.
Biol. Med. 1962, 111, 544.
27. Singh, P. P.; Junnarkar, A. V.; Seshagiri Rao, C.; Verma,
R. K.; Shridhar, D. R. Methods Find. Exp. Clin. Pharma-
col. 1983, 5, 601.
28. Charles, J. P.; Jacqlynn, B. The Aldrich Library of 13C and
1H FT NMR spectra, 1993, 3, 81B.