Synthesis of pyrimidine and condensed pyrimidine derivatives and their evaluation for anti-inflammatory activity

Article abstract of DOI:10.1007/s00044-010-9507-y

Condensation of various amines (Ia-c) with 4-isothiocyanato-4-methyl-2- pentanone (2a) at room temperature gave tetrahydropyrimidinethiones (3a-c) whereas condensation of 1a-e with 3-isothiocyanatobutanal at room temperature gave tetrahydropyrimidinethion

Full text of DOI:10.1007/s00044-010-9507-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:91–99
DOI 10.1007/s00044-010-9507-y
ORIGINAL RESEARCH
Synthesis of pyrimidine and condensed pyrimidine derivatives
and their evaluation for anti-inflammatory activity
•
Sham M. Sondhi Jaiveer Singh S. K. Agrawal
•
•
•
A. K. Saxena Partha Roy
Received: 27 February 2010 / Accepted: 4 November 2010 / Published online: 27 November 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Condensation of various amines (Ia–c) with
4-isothiocyanato-4-methyl-2-pentanone (2a) at room tem-
perature gave tetrahydropyrimidinethiones (3a–c) whereas
condensation of 1a–e with 3-isothiocyanatobutanal at
room temperature gave tetrahydropyrimidinethiones (4a–e).
Amines 1a, d, f–i on condensation with 4-isothiocyanato-4-
methyl-2-pentanone (2a) by heating under reflux for 8 h at
pH * 4 (for 1a, d) and at RT (for 1f–i) gave dihydropyr-
imidinethiones 5a–b and 5c–f, respectively. Condensation
of 1f with 3-isothiocyanatobutanal gave dihydropyimidin-
ethione 6. When isothiocyanate (2a) and phenylenediamine
derivatives 1g, h were heated under reflux at pH *4, tri-
cyclic compounds 7a, b were obtained in good yields.
Condensation of 3-isothiocyanatobutanal with o-phenylen-
ediamines 1h and 1j at pH * 5 by refluxing in methanol for
8 h gave products 8 and 9. All these compounds were
screened for anti-inflammatory activity. Compounds 3c, 4c
and 7a exhibited anti-inflammatory activity comparable to
standard drug ibuprofen.
Introduction
Major health problems faced by mankind are inflammatory
diseases and cancer. Any kind of health problem is asso-
ciated with pain and for the treatment of pain various
drugs, i.e. aspirin, phenylbutazone, ibuprofen and indo-
methacin are available in the market. Continuous used of
these drugs for long time can cause ulcer (a major side
effect) (Wolf 1981) and hence cannot be used permanently.
Pyrimidine and condensed pyrimidine derivatives exhibit a
broad spectrum of biological activities such as anticancer,
anti-inflammatory, COX inhibitor, antiallergic and anal-
gesic etc. (Breault and Pease 2000; Devesa et al., 2004;
Arai et al., 2004; Hogenkamp et al., 2001; Lee et al., 2000;
Kim et al., 2003). To reduce human health problems, there
is an urgent need to develop safer anti-inflammatory drugs
and search new potent molecules which can be developed
as anticancer agents. In continuation of our efforts in this
direction (Sondhi et al., 2007; 2009a, b, c, d) we have
synthesized a number of pyrimidine and condensed
pyrimidine derivatives and evaluated them for anti-
inflammatory activity which we wish to report in this
article.
Keywords Pyrimidine ꢀ Condensed pyrimidine ꢀ
Anti-inflammatory activity ꢀ Heterocyclic compounds
Results and discussion
S. M. Sondhi (&) ꢀ J. Singh
Department of Chemistry, Indian Institute of Technology,
Roorkee 247667, Uttarakhand, India
e-mail: sondifcy@iitr.ernet.in
4-Isothiocyanato-4-methyl-pentane-2-one (2a) (Mathes
et al., 1948) on condensation with 4-(aminomethyl)pyri-
dine, 1-(2-aminoethyl)pyrrolidine and 4-(2-aminoethyl)-
morpholine (1a–c) at room temperature using methanol as
solvent of reaction gave tetrahydropyrimidine derivatives
3a–c (Scheme 1). The structures assigned to 3a–c are fully
S. K. Agrawal ꢀ A. K. Saxena
Pharmacology Division, Indian Institute of Integrative Medicine,
Jammu 180001, India
P. Roy
Department of Biotechnology, Indian Institute of Technology,
Roorkee 247667, Uttarakhand, India
1
supported by IR, HNMR, GC–MS and elemental analysis
data reported in experimental section of this article.
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Med Chem Res (2012) 21:91–99
Scheme 1 Synthesis of
pyrimidine and condensed
pyrimidine derivatives
R
NH2
CH3
H3C
N
1a-e
CH3
N
For 1a-e
For 1a-c
CH3
O
C
S
C
S
H
O
2b
MeOH/RT/8h
MeOH/RT/8h
2a
H
CH3
CH3
H
N
S
CH3
N
S
R
R
N
N
HO
CH3
OH
H
4a-e
3a-c
H2
C
CH2
N
CH2
N
4a, R=
4c, R=
4e, R=
4b, R=
4d, R=
3a, R=
3b, R=
3c, R=
N
CH2
H2
C
H2
C
N
N
CH2
O
N
CH2
CH2
CH2
O
H2
C
H2
C
CH2
N
O
R
NH2
1a,d,f-i
CH3
H3C
N
CH3
H3C
N
For 1f-i
for 1a, d
CH3
O
C
S
CH3
MeOH/RT/8h
MeOH/Δ8h/pH~4
O
C
S
2a
2a
H
N
H
CH3
CH3
CH3
N
S
S
CH3
R
R
N
N
CH3
CH3
5c-f
5a,b
NC
H2
C
CH2
CH2
N
5c, R=
5e, R=
5d, R=
5f, R=
5a, R=
5b, R=
NH2
OH
N
H
H3C
Br
CH2
O
NH2
Condensation of 3-isothiocyanatobutanal Peretokin et al.
(1985) with various amines 1a–e at room temperature
using methanol as solvent of reaction gave tetra-
hydropyrimidinethiones 4a–e (Scheme 1). Spectral data
and elemental analysis of 4a–e reported in experimental
section of this article fully support the structures assigned
to them.
Condensation of 4-(aminomethyl)pyridine (1a) and tet-
rahydrofurfurylamine (1d) with 2a by heating under reflux,
in methanol, after adjusting the pH of reaction mixture
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Med Chem Res (2012) 21:91–99
93
Scheme 1 continued
CH3
H
N
CH3
S
H2
C
MeOH/RT/8h
H2
C
CH2
NH2
N
CH2
N
C
S
H
O
2b
N
H
H
N
H
1f
6
S
CH3
H3C
N
R
N
NH
MeOH/Δ8h
R
NH2
CH3
N
CH3
O
pH~4
C
S
CH3
H
CH3
NH2
1g,h
2a
7a, R= CN 7b, R= Br
CH3
S
Br
Br
NH2
MeOH/Δ8h
N
H
NH
N
N
C
S
H
CH3
O
pH~5
NH2
H
1h
2b
8
S
CH3
CH3
CH3
N
NH
CH3
NH2
NH2
MeOH/Δ8h
N
N
pH~5
H
C
H
O
H
1j
S 2b
9
to *4 (by adding a few drops of 10% sulphuric acid in
methanol) gave products 5a and 5b, respectively. Struc-
tures assigned to 5a and 5b (Scheme 1) are fully supported
by spectral and analytical data reported in experimen-
tal section. Condensation of tryptamine (1f), 3,4-diam-
inobenzonitrile (1g), 4-bromo-1,2-diaminobenzene (1h)
and 2-amino-4-methyl phenol (1i) with 2a at room tem-
perature using methanol as solvent of reaction gave prod-
ucts 5c–f (Scheme 1), respectively. Structures assigned to
5c–f (Scheme 1) are fully supported by correct spectral and
analytical data reported in experimental section of this
article.
Scheme 1 indicates that amine 1a on condensation with
2a at room temperature gave tetrahydropyrimidine deriv-
ative 3a whereas condensation of 1a with 2a by refluxing
in methanol at pH * 4 gave dihydropyrimidine derivative
5a. Similarly, condensation of 1g and 1h with 2a at room
temperature gave dihydropyrimidine derivatives 5d, 5e
whereas condensation of 1g and 1h with 2a by refluxing in
methanol at pH * 4 gave tricyclic pyrimidine derivatives
7a and 7b, respectively. From the above observations it is
clear that the condensation of amines or diamines with
isothiocyanatoketones gave reaction products which are
reaction condition dependent. Further in the case of dia-
mines 1g, 1h and 1i condensation products are dictated by
inductive effect of groups already present on aromatic
system. Most basic amino group reacts first with isothio-
cyanato group followed by cyclization to give final con-
densation products.
Tryptamine on condensation with (R,S) 3-isothiocy-
anatobutanal (2b) at room temperature using methanol as
solvent of reaction gave product 6 (Scheme 1) in good
yield. Spectral and analytical data of 6 reported in exper-
imental section fully support the structure assigned to it.
Condensation of 3,4-diaminobezonitrile (1g), 4-bromo-1,2-
diaminobenzene (1h) with 2a and 4-bromo-1,2-diamino-
benzene (1h), 2,3-diaminotoluene (1j) with 2b by refluxing
in methanol for 8 h after adjusting the pH of reaction
contents to *4 or 5 (by adding a few drops of 10% sul-
phuric acid in methanol) gave tricyclic pyrimidine deriv-
atives 7a, 7b, 8 and 9 (Scheme 1), respectively. Structures
of 7a, 7b, 8 and 9 are fully supported by correct spectral
and analytical data reported in experimental section of this
article.
Compounds 3a–c, 4a–e, 5a–f, 6, 7a, b, 8 and 9 at
50 mg/kg p.o. were screened for anti-inflammatory activity
using carrageenan-induced paw oedema model (Winter
et al., 1962), and results are summarized in Table 1.
Compounds 3a–c, 4a–e, 5a–f, 6, 7a, b, 8 and 9 exhibited
27, 8, 35, 30, 30, 38, 18, 29, 25, 18, 30, 32, 31, 27, 25, 39,
24, 27 and 0% anti-inflammatory activity, respectively,
whereas standard drug ibuprofen exhibited 39% activity at
50 mg/kg p.o. It is observed that although all the com-
pounds contain pyrimidine moiety but compounds 3c, 4c
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Med Chem Res (2012) 21:91–99
General procedure for synthesis of pyrimidine
Table 1 Anti-inflammatory activity evaluation of compounds 3a–c,
4a–e, 5a–f, 6, 7a, b, 8 and 9 at 50 mg/kg p.o
derivatives
Comp.
tested
Anti-inflammatory
activity (%)
Comp.
tested
Anti-inflammatory
activity (%)
Synthesis of 4-hydroxy-4,6,6-trimethyl-3-(pyridin-4-
ylmethyl)-tetrahydropyrimidine-2(1H)-thione (3a)
3a
3b
3c
4a
4b
4c
4d
4e
5a
5b
27
08
35
30
30
38
18
29
25
18
5c
30
32
31
27
25
39
24
27
00
39
5d
4-(Aminomethyl)pyridine 1a (0.22 ml, 2 mmole) was
taken in methanol (10 ml) and to it was added 4-iso-
thiocyanato-4-methyl-pentane-2-one (Mathes et al., 1948)
2a (0.31 ml, 2 mmole). The reaction contents were allowed
to stand at room temperature for 8 h. The reaction contents
were saturated under reduced pressure and allowed to stand
at room temperature for crystallization, it was filtered and
air dried to give pure product 3a. Yield: 0.482 g (91%);
mp: 170°C; IR(KBr) mmax: 3451 (OH), 3250 (NH), 1608
5e
5f
6
7a
7b
8
9
Ibuprofen
1
and 1524 (Ar) cm-1. H NMR (500 MHz, DMSO-d6) d:
1.24 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.34 (s, 3H, CH3),
2.03 (s, 2H, [CH2), 4.896–4.930 (d, 1H, J = 17 Hz, one H
of CH2), 5.495–5.529 (d, 1H, J = 17 Hz, one H of CH2),
6.12 (s, 1H, OH exch.), 7.25 (s, 2H, Ar), 8.45 (s, 3H, 2H of
Ar ? 1H of NH exch.). GC–MS m/z 265 [M]?, 30.13%,
Anal. Calcd for C13H19N3OS C, 58.86; H, 7.17; N, 15.85;
S, 12.07 Found C, 58.93; H, 7.48; N, 15.65; S, 12.18.
Similarly were synthesized compounds 3b and 3c.
and 7a showed good anti-inflammatory activity at 50 mg/
kg p.o., this is because 3c and 4c contains morpholin group
directly attached to first position N atom of pyrimidine ring
and compound 7a contains –CN group attached to tricyclic
system, presence of these groups may be making these
compounds favourable electronically and stereochemically
for interaction with the active site and thus showing good
anti-inflammatory activity.
4-Hydroxy-4,6,6-trimethyl-3-(2-(pyrrolidin-1-yl)ethyl)-
tetrahydropyrimidine-2(1H)-thione (3b)
Conclusion
Solvent of crystallization: MeOH; Yield: 77%; mp: 148°C;
IR(KBr) mmax: 3416 and 3232 (OH and NH), 1635 ([C=N–),
1538 and 1448 (Ar) cm-1. 1H NMR (500 MHz, DMSO-d6)
d: 1.14 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.43(s, 3H, CH3),
1.69 (s, 4H, 29 CH2), 1.843–1.871 (d, 1H, J = 14 Hz, one
H of CH2), 1.946–1.974 (d, 1H, J = 14 Hz, one H of CH2),
2.38–2.45 (t, 3H, one H of CH2 ? CH2), 2.63 (s, 2H, one H
of CH2), 3.02 (s, 1H, one H of CH2), 3.62 (s, 1H, one H of
CH2), 4.400–4.427 (d, 1H, J = 13.5 Hz,one H of CH2),
7.38 (brs, 1H, OH exch.), 8.16 (s, 1H, NH exch.). 13C NMR
(500 MHz, DMSO-d6) d: 23.603, 28.809, 30.552, 30.627,
45.413, 47.552, 49.539, 54.060, 55.301, 81.720, 176.863.
GC–MS m/z 271 [M]?, 4.51%, Anal.Calcd for C13H25
N3OS C, 57.56; H, 9.22; N, 15.49; S, 11.81 Found C,
57.46; H, 9.20; N, 15.55; S, 11.90.
A number of pyrimidine and condensed pyrimidine deriv-
atives, i.e. 3a–c, 4a–e, 5a–f, 6, 7a, b, 8 and 9 have been
synthesized using different reaction conditions. On
screening for anti-inflammatory activity compounds 3c, 4c
and 7a exhibited anti-inflammatory activity comparable to
standard drug ibuprofen.
Experimental
Melting points (mps) were determined on a JSGW appa-
ratus and are uncorrected. IR spectra were recorded using a
Perkin Elmer 1600 FT spectrometer. 1H NMR spectra were
recorded on a Bruker WH-500/400 spectrometer at a ca
5–15% (w/v) solution in DMSO-d6 (TMS as internal
standard). GC–MS was recorded on Perkin Elmer Clarus
500 mass spectrometer. Elemental analysis was carried out
on a Vario EL III elementor. Thin layer chromatography
(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 using Qualigen’s silica gel for column
chromatography (60–120 mesh).
4-Hydroxy-4,6,6-trimethyl-3-(2-(morpholinoethyl)-
tetrahydropyrimidine-2(1H)-thione (3c)
Solvent of crystallization: MeOH; Yield: 83%; mp: 154°C;
IR(KBr) mmax: 3476 and 3222 (OH and NH), 1613, 1540
(Ar) cm-1. 1H NMR (500 MHz, DMSO-d6) d: 1.15 (s, 3H,
CH3), 1.27 (s, 3H, CH3), 1.44 (s, 3H, CH3),1.865–1.893 (d,
1H, J = 14 Hz, one H of pyrimidine –CH2–), 1.964–1.994
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Med Chem Res (2012) 21:91–99
95
(dd, 1H, J1 = 2 Hz, J2 = 14 Hz, one H of pyrimidine
–CH2–), 2.36–2.42 (m, 3H, aliphatic), 2.57–2.59 (t, 2H,
aliphatic), 2.80–2.85 (m, 1H, aliphatic), 3.56–3.58 (t, 4H,
aliphatic), 3.70–3.76 (m, 1H, aliphatic), 4.24-4.29 (m, 1H,
aliphatic), 6.86 (s, 1H, OH exch.), 8.21 (s, 1H, NH exch.).
2.331–2.356 (d, 1H, J = 12.5 Hz, one H of CH2), 2.476 (s,
2H, one H of CH2), 2.700–2.714 (d, 2H, J = 2.8 Hz, CH2),
2.95–3.00 (m 1H, one H of CH2), 3.30–3.40 (m, 1H, one H
of CH2 after D2O exch.), 3.50–3.55 (m, 1H, one H of CH2),
4.53–4.56 (m, 1H, one H of CH2), 4.82 (s, 1H, one H of
CH2), 7.99 (bs, 1H, OH exch.), 8.16 (s, 1H, NH exch.).
GC–MS m/z 243 [M]?, 1.95%), Anal. Calcd for
C11H21N3OS C, 54.32; H, 8.64; N, 17.28; S, 13.17 Found
C, 54.38; H, 8.62; N, 17.61; S, 13.22.
GC–MS does not show M? ion peak at m/z 287 but gave
H
N
S
H2
C
fragment peaks at m/z 183 (
, 2.73%). Anal.
H2C
N
Calcd for C13H25N3O2S C, 54.35; H, 8.71; N, 14.63; S,
11.15 Found C, 54.30; H, 8.75; N, 14.58; S, 11.20.
4-Hydroxy-6-methyl-3-(2-morpholinoethyl)-
tetrahydropyrimidine-2(1H)-thione (4c)
Synthesis of 4-hydroxy-6-methyl-3-(pyridin-4-ylmethyl))-
tetrahydropyrimidine-2(1H)-thione (4a)
Solvent of elution: CHCl3:MeOH (9:1); Yield: 67%; mp:
158°C; IR(KBr) mmax: 3471 and 3221 (OH and NH), 1637
([C=N–), 1511 and 1446 cm-1 1H NMR (500 MHz,
.
4-(Aminomethyl)pyridine 1a (0.11 ml, 1 mmole) was taken
in methanol (10 ml), and 3-isothiocyanatobutanal (Pereto-
kin et al., 1985) (0.13 ml; 1 mmole) was added to it. The
reaction contents were allowed to stand at room temperature
for 10 h. The reaction contents were saturated under
reduced pressure, and the residue left behind was dissolved
in methanol (3 ml). The resulting solution was adsorbed
over silica gel and subjected to column chromatography
over silica gel. Elution with EtOAc:CHCl3 (4:1) removed
side products and further elution with EtOAc gave pure
product 4a. Yield: 0.111 g (47%); mp: 179°C; IR(KBr)
DMSO-d6 ? D2O) d: 1.103–1.116 (d, 3H, J = 6.5 Hz,
CH3), 1.39–1.45 (m, 1H, one H of CH2), 1.87–1.90 (m, 1H,
one H of CH2), 2.335–2.361 (m, 3H, one H of CH2 ?CH2),
2.61–2.71(m, 3H, one H of CH2 ?CH2), 3.48–3.58 (m, 6H,
29 CH2), 4.323–4.353 (d, 1H, J = 15 Hz, one H of CH2),
N
CH
4.794–4.804 (t, 1H, J = 2.5 Hz,
). GC–MS does
O
not give M? ion peak at m/z 259 but gave fragmentation
peaks at m/z 241 ([M]?-18, 1.39%), Anal. Calcd for
C11H21N3O2S C, 50.96; H, 8.11; N, 16.22; S, 12.35 Found
C, 50.93; H, 8.11; N, 16.28; S, 12.41.
m
max: 3460 and 3215 (OH and NH), 1638 ([C=N–), 1604
1
and 1546 (Ar) cm-1. H NMR (400 MHz, DMSO-d6) d:
1.173–1.189 (d, 3H, J = 6.4 Hz, CH3), 1.52–1.59 (m, 1H,
one H of CH2), 1.885–1.919 (dd, 1H, J1 = 1.6 Hz,
J2 = 12 Hz, one H of CH2), 3.58–3.64 (m, 1H, one H of
CH2), 4.581–4.623 (d, 1H, J = 16.8 Hz, one H of CH2),
4.67–4.70 (m, 1H, one H of CH2), 5.661–5.702 (d, 1H,
J = 16.4 Hz, one H of CH2), 6.48 (s, 1H, OH exch.),
7.220–7.235 (d, 2H, J = 6 Hz, Py), 8.44 (s, 1H, NH exch.),
8.481–8.496 (dd, 2H, J = 1.6 Hz, J = 4.5 Hz, Py). 13C
NMR (500 MHz, DMSO-d6) d: 20.418, 36.929, 42.559,
52.425, 76.195, 122.503, 188.093, 149.886, 178.176. GC–
MS does not give M? ion peak but gave fragmentation
peaks at m/z 219 ([M]? -18, 46.04%), Anal. Calcd for
C11H15N3OS C, 55.69; H, 6.33; N, 17.72; S, 13.50 Found C,
55.62; H, 6.36; N, 17.81; S, 13.53.
4-Hydroxy-6-methyl-3-((2-tetrahydrofuran-2-yl)methyl)-
tetrahydropyrimidine-2(1H)-thione (4d)
Solvent of elution: CHCl3:EtOAc (9.5:0.5); Yield: 50%;
mp: 148°C; IR(KBr) mmax: 3396 and 3253 (OH and NH),
1635 ([C=N–), 1540 and 1504 (Ar) cm-1 1H NMR
.
(400 MHz, DMSO-d6) d: 1.127–1.143 (d, 3H, J = 6.4 Hz,
CH3), 1.43–1.46 (m, 1H, one H of CH2), 1.57–1.61 (m, 1H,
one H of CH2), 1.80–1.91 (m, 4H, 29 CH2), 3.52–3.57 (m,
1H, one H of CH2), 3.64–3.69 (m, 1H, one H of CH2),
3.76–3.84 (m, 2H, CH2), 4.007–4.053 (dd, 1H, J1 = 4 Hz,
J2 = 14 Hz, one H of CH2), 4.13–4.18 (m, 1H, one H of
CH2), 4.94–4.96 (m, 1H, one H of CH2), 6.03 (s, 1H, OH
exch.), 8.20 (s, 1H, NH exch.). GC–MS m/z 230 [M]?,
16.36%. Anal. Calcd for C10H18N2O2S C, 52.17; H, 7.83;
N, 12.17; S, 13.91 Found C, 52.19; H, 7.88; N, 12.23; S,
13.95.
Similarly were synthesized compounds 4b–e.
4-Hydroxy-6-methyl-3-(2-(pyrollidin-1-yl)ethyl)-
tetrahydropyrimidine-2(1H)-thione (4b)
4-Hydroxy-6-methyl-3-(2-(pipridin-1-yl)ethyl)-
tetrahydropyrimidine-2(1H)-thione (4e)
Solvent of elution: CHCl3:MeOH (9.5:0.5); Yield: 68%;
mp: 150°C; IR(KBr) mmax: 3415 and 3216 (OH and NH),
1639 ([C=N–), 1526 and 1448 (Ar) cm-1 1H NMR
.
Solvent of elution: CHCl3:MeOH (9.5:0.5); Yield: 58%;
mp: 198°C; IR(KBr) mmax: 3449 (OH), 3235 (NH), 1634
([C=N–), 1533 and 1506 (Ar) cm-1. 1H NMR (400 MHz,
DMSO-d6) d: 1.121–1.137 (d, 3H, J = 6.4 Hz, CH3),
(500 MHz, DMSO-d6) d: 1.128–1.141 (d, 3H, J = 6.5 Hz,
CH3), 1.40–1.46 (m, 1H, one H of CH2), 1.73 (s, 4H, 29
CH2), 1.871–1.897 (d, 1H, J = 13 Hz, one H of CH2),
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Synthesis of 1-(2-(H-indol-3-yl)ethyl)-4,4,6-trimethyl-3,4-
dihydropyrimidine-2(1H)-thione (5c)
1.38–1.54 (m, 7H, aliphatic), 1.86–1.91 (m, 1H, aliphatic),
2.22–2.27 (m, 3H, aliphatic), 2.62–2.70 (m, 3H, aliphatic),
3.38–3.54 (m, 2H, aliphatic), 4.46–4.51 (m, 1H, aliphatic),
4.78–4.79 (m, 1H, aliphatic), 7.94 (s, 1H, OH exch.), 8.12
(s, 1H, NH exch.). GC–MS does not give M? ion peak at
m/z 257 but gave fragmentation peaks at m/z 239 ([M]?-18,
0.89%). Anal. Calcd for C12H23N3OS C, 56.03; H, 8.95; N,
16.34; S, 12.45 Found C, 56.10; H, 8.92; N, 16.41; S,
12.47.
Tryptamine 1f (0.160 g, 1 mmole) was taken in methanol
(10 ml) and to it was added 4-isothiocyanato-4-methyl-
pentane-2-one 2a (0.16 ml, 1 mmole). The reaction con-
tents were allowed to stand at room temperature for 8 h.
The reaction contents were saturated under reduced pres-
sure and allowed to stand at room temperature for crys-
tallization, the solid residue left behind was filtered and air
dried to give crude product, which was purified by column
chromatography over silica gel. Elution with CHCl3
removed side products and further elution with CHCl3:
MeOH (8.5:1.5) gave pure product 5c. Yield: 0.191 g
(64%); mp: 265°C; IR(KBr) mmax: 3467, 3260 (NH, NH),
1533 and 1502 (Ar) cm-1. 1H NMR (500 MHz, DMSO-d6)
d: 0.97 (s, 3H, CH3), 1.30(s, 3H, CH3), 1.66 (s, 3H, CH3),
2.174–2.201 (d, 1H, J = 13.5 Hz, aliphatic), 2.395–2.423
(d, 1H, J = 14 Hz, aliphatic), 2.637–2.674 (dd, J1 =
3.5 Hz, J2 = 15.5 Hz, 1H, aliphatic), 2.71–2.77 (m, 1H,
aliphatic), 5.583–5.618(dd, 1H, J = 4.5 Hz, J = 13 Hz, =
CH–), 6.962–6.991 (t, 1H, J = 7 Hz, Ar), 7.047–7.077
(t, 1H, J = 7.5 Hz, Ar), 7.300–7.316(d, 1H, J = 8 Hz, Ar),
7.396–7.412 (d, 1H, J = 8 Hz, Ar), 8.27 (s, 1H, NH exch.)
10.95 (s, 1H, NH exch.), one proton was buried under
signal of water at d 3.38. 13C NMR (500 MHz, DMSO-d6)
d: 21.110, 27.274, 29.846, 30.317, 43.897, 46.174, 49.701,
56.008, 106.188, 111.599, 118.415, 119.095, 121.497,
126.667, 136.375, 139.517, 177.693. GC–MS m/z 299
[M]?, 94.96%. Anal. Calcd for C17H21N3S C, 68.22; H,
7.02; N, 14.04; S, 10.70 Found C, 68.45; H, 7.18; N, 14.02;
S, 10.72.
Synthesis of 4,4,6-trimethyl-1-(pyridin-4-ylmethyl)-3,4-
dihydropyrimidine-2(1H)-thione (5a)
4-(Aminomethyl)pyridine 1a (0.11 ml, 1 mmole) was
taken in methanol (10 ml) and to it was added 4-iso-
thiocyanato-4-methyl-pentane-2-one
2a
(0.16 ml,
1 mmole) and a few drops of 10% H2SO4 in methanol to
adjust the pH of reaction mixture to *4. The reaction
contents were heated under reflux for 8 h. The solvent was
removed under reduced pressure, and the residue left
behind was treated with 10% sodium bicarbonate aqueous
solution (5 ml). The solid product so obtained was filtered,
washed with water and dried under vacuum. Crude product
so obtained was dissolved in methanol, and the resulting
solution was adsorbed on silica gel and subjected to col-
umn chromatography over silica gel. Elution with CHCl3
removed side products and further elution with CHCl3:
EtOAc (4:1, v/v) gave pure product 5a. Yield: 0.163 g
(66%); mp: 162°C; IR(KBr) mmax: 3471 (NH), 1600 and
1
1532 (Ar) cm-1. H NMR (500 MHz, DMSO-d6 ? D2O)
d: 1.22 (s, 6H, CH3 ? CH3), 1.71 (s, 3H, CH3), 4.87 (s,
1H, [C=CH–), 5.52 (s, 2H, [CH2), 6.196–6.206 (d, 2H,
J = 5 Hz, Py), 8.47–8.48 (m, 2H, Py). GC–MS m/z 247
[M]?, 38.38%. Anal.Calcd for C13H17N3S C, 63.15; H,
6.88; N, 17.00; S, 12.95 Found C, 63.21; H, 6.78; N, 17.15;
S, 12.90.
Similarly were synthesized compounds 5d–f.
4-Amino-3-(4,4,6-trimethyl-2-thioxo-3,4-dihydropyrimidin-
1(2H)-yl)benzonitrile (5d)
Similarly was synthesized compound 5b.
Solvent of crystallization: MeOH; Yield: 67%; mp: 246°C;
IR(KBr) mmax: 3386 and 3302 (NH2), 3186 (NH), 2213
1
(C:N), 1568 and 1512 (Ar) cm-1. H NMR (500 MHz,
4,4,6-Trimethyl-1-((tetrahydrofuran-2-yl)methyl)-3,4-
dihydropyrimidine-2(1H)-thione (5b)
DMSO-d6) d: 1.28 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.42
(s, 3H, CH3), 4.88 (s, 1H, [C=CH–), 5.88–5.93 (bs, 2H,
NH2 exch.), 6.74–6.77 (q, 1H, Ar), 7.31–7.34 (m, 1H, Ar),
7.38–7.40 (m, 1H, Ar), 8.91 (s, 1H, NH exch.). GC–MS
m/z 272 [M]?, 6.48%. Anal. Calcd for C14H16N4S C,
61.76; H, 5.88; N, 20.59; S, 11.76 Found C, 61.75; H,
5.93 N, 20.57; S, 11.78.
Solvent of elution: CHCl3:EA (9.5:0.5); Yield: 76%; mp:
110°C; IR(KBr) mmax: 3416 (NH), 1526 (Ar) cm-1
.
1H
NMR (500 MHz, DMSO-d6) d: 1.15(s, 3H, CH3), 1.17 (s,
3H, CH3), 1.54–1.59 (m, 1H, aliphatic), 1.78–1.92 (m ? s,
6H, 3H aliphatic ? 3H CH3), 3.61–3.65 (m, 1H, aliphatic),
3.72–3.77 (m, 1H, aliphatic), 3.85 (s, 1H, aliphatic),
4.08–4.10 (m, 1H, aliphatic), 4.42 (m, 1H, aliphatic), 4.79
(s, 1H, [C=CH–), 8.57 (s, 1H, NH exch.). GC–MS m/z 240
[M]?,6.12%. Anal.Calcd for C12H20N2OS C, 60.00; H,
8.33; N, 11.67; S, 13.33 Found C, 60.10; H, 8.40; N, 11.62;
S, 13.25.
1-(2-Amino-5-bromophenyl)-4,4,6-trimethyl-3,4-
dihydropyrimidine-2(1H)-thione (5e)
Solvent of crystallization: MeOH; Yield: 77%; mp: 185°C;
IR(KBr) mmax: 3377 and 3299 (NH2) 3194 (NH), 1621 and
123

Med Chem Res (2012) 21:91–99
97
1532 (Ar) cm-1. 1H NMR (500 MHz, DMSO-d6) d: 1.23(s,
3H, CH3), 1.28 (s, 3H, CH3), 1.41 (s, 3H, CH3), 4.88 (s,
1H, [C=CH–), 5.03–5.06 (s, 2H, NH2 exch.), 6.67–6.71
(m, 1H, Ar), 6.768–6.783 (d, 1H, J = 7.5 Hz, Ar),
6.890–6.901 (d, 1H, J = 5.5 Hz, Ar), 8.81 (s, 1H, NH
exch.). GC–MS m/z 327 [M]? Br81, 10.64%, 325 [M]?
Br79, 10.76%, Anal. Calcd for C13H16N3SBr C, 47.85; H,
4.91; N, 12.88; S, 9.82 Found C, 47.86; H, 4.88 N, 12.94;
S, 9.85.
NH exch.). 13C NMR (500 MHz, DMSO-d6) d: GC–MS m/
z 271 [M]?, 0.57%, Anal. Calcd for C15H17N3S C, 66.42;
H, 6.27; N, 15.49; S,11.81 Found C, 66.51; H, 6.26; N,
15.48; S, 11.86.
Synthesis of 4,4a,5-tetrahydro-3,3a,13-trimethyl-8-
cyanopyrimido[1,6-a]benzimidazol-1(2H)-thione (7a)
3,4-Diaminobezonitrile (1g) (0.13 ml, 1 mmole) was taken
in methanol (10 ml) and to it was added 4-isothiocyanato-
4-methyl-pentane-2-one 2a (0.16 ml, 1 mmole) and a few
drops of 10% H2SO4 in methanol to adjust the pH of
reaction mixture to *4. The reaction contents were heated
under reflux for 8 h. The solvent was removed under
reduced pressure, and the residue left behind was treated
with 10% sodium bicarbonate solution (5 ml). The solid
product so obtained was filtered, washed with water, dried
under vacuum and then crude product so obtained was
dissolved in methanol. The resulting solution was adsorbed
on silica gel and subjected to column chromatography over
silica gel. Elution with CHCl3 removed side products and
further elution with CHCl3:EtOAc (8.5:1.5) gave pure
product 7a. Yield: 0.207 g (76%); mp: 252°C; IR(KBr)
1-(2-Hydroxy-5-methylphenyl)- 4,4,6-trimethyl-3,4-
dihydropyrimidine-2(1H)-thione (5f)
Solvent of crystallization: MeOH; Yield: 75%; mp: 186°C;
1
IR(KBr) mmax: 3186 (NH), 1615 and 1539 (Ar) cm-1. H
NMR (500 MHz, DMSO-d6) d: 1.24–1.26 (2s, 6H,
CH3 ? CH3), 1.39 (s, 3H, CH3), 2.17 (s, 3H, CH3), 4.83 (s,
1H, [C=CH–), 6.71–6.75 (m, 1H, Ar), 6.801–6.805 (d, 1H,
J = 2 Hz, Ar), 6.912–6.932 (dd, 1H, J1 = 2 Hz, J2 =
8.5 Hz, Ar), 8.60 (s, 1H, OH exch.) 9.39 (s, 1H, NH exch.).
13C NMR (500 MHz, DMSO-d6) d: 25.213, 29.265,
33.126, 47.462, 51.550, 80.772, 97.402, 108, 045, 117.880,
120.940, 130.619, 131.959, 145.702, 172.786. GC–MS m/z
262 [M]?, 60.87%, Anal. Calcd for C14H18N2OS C, 64.12;
H, 6.87; N, 10.69; S,12.21 Found C, 64.17; H, 6.85; N,
10.73; S, 12.28.
m
max: 3212 (NH) 2214 (C:N) 1604 and 1505 (Ar) cm-1
.
1H NMR (500 MHz, DMSO-d6) d: 1.27–1.32 (2s, 6H,
CH3 ? CH3), 1.49 (s, 3H, CH3), 2.132–2.159 (d, 1H,
J = 13.5 Hz, one H of [CH2), 2.798–2.425 (d, 1H,
J = 13.5 Hz, one H of [CH2) 6.575–6.591 (d, 1H,
J = 8 Hz, Ar), 7.281–7.301 (q, J1 = 1.5 Hz, J2 = 8 Hz,
J3 = 9.5 Hz, 1H, Ar), 7.74 (s, 1H, NH exch.), 8.73 (s, 1H,
NH exch.), 8.897–8.899 (d, 1H, J = 1 Hz, Ar). GC–MS m/
z 272 [M]?, 22.17%. Anal. Calcd for C14H16N4S C, 61.76;
H, 5.88; N, 20.59; S,11.76 Found C, 61.72; H, 5.90; N,
20.65; S, 11.71.
Synthesis of 1-(2-(1H-indol-3-yl)ethyl)-4-methyl-3,4-
dihydropyrimidine-2(1H)-thione (6)
Tryptamine 1f (0.160 g, 1 mmole) was taken in methanol
(10 ml) and to it was added 3-isothiocyanatobutanal
(0.13 ml; 1 mmole). The reaction contents were allowed to
stand at room temperature for 10 h. The reaction contents
were saturated under reduced pressure, and the residue left
behind was dissolved in methanol. The resulting solution
was adsorbed on silica gel and subjected to column chro-
matography over silica gel. Elution with CHCl3:MeOH
(9:1) removed side products and further elution with
CHCl3:MeOH (4:1) gave pure product 6. Yield: 0.241 g
(89%); mp: 255°C; IR(KBr) mmax: 3397, 3194 (NH, NH),
Similarly was synthesized compound 7b.
4,4a,5-Tetrahydro-3,3a,13-trimethyl-8-
bromopyrimido[1,6-a]benzimidazol-1(2H)-thione (7b)
Solvent of elution: CHCl3:EtOAc (9:1); Yield: 86%; mp:
256°C; IR(KBr) mmax: 3179 (NH), 1594 and 1497 (Ar)
cm-1 1H NMR (500 MHz, DMSO-d6) d: 1.25 (s, 3H,
.
1618, 1537 and 1501 (Ar) cm-1 1H NMR (400 MHz,
.
CH3), 1.30 (s, 3H, CH3), 1.41 (s, 3H, CH3), 2.071–2.099 (d,
1H, J = 14 Hz, one H of [CH2), 2.367–2.394 (d, 1H,
J = 13.5 Hz, one H of [CH2) 6.667–6.671 (d, 1H,
J = 2 Hz, Ar), 6.718–6.739 (dd, 1H, J1 = 2 Hz,
J2 = 8.5 Hz, Ar), 6.85 (s, 1H, NH exch.), 8.44 (s, 1H, NH
exch.), 8.52–8.54 (d, 1H, Ar). 13C NMR (500 MHz,
DMSO–d6) d: 19.894, 20.419, 31.160, 51.863, 109.274,
116.279, 127.573, 128.548, 129.763, 132.118, 132.449,
151.964, 177.039. GC–MS m/z 327 [M]? Br81, 32.06%,
325 [M]? Br79, 31.91%. Anal. Calcd for C13H16N3SBr C,
DMSO-d6) d: 1.215–1.232 (d, 3H, J = 6.8 Hz, CH3),
1.98–2.05 (m, 1H, aliphatic), 2.33–2.38 (m, 1H, aliphatic),
2.66–2.76 (m, 2H, aliphatic), 3.16–3.23 (m, 1H, [CH–
CH3), 3.38–3.42 (m, 1H, =CH–CH–CH3), 4.90–4.94 (m,
1H, N–CH=C), 5.575–5.616 (dd, 1H, J1 = 4 Hz,
J2 = 11.6 Hz, =NH–CH=), 6.97–7.00 (m, 1H, Ar), 7.05–
7.09 (m, 1H, Ar), 7.315–7.335 (d, 1H, J = 8 Hz, Ar),
7.410–7.429 (dd, 1H, J1 = 2.8 Hz, J2 = 5 Hz, Ar),
8.291–8.299 (d, 1H, J = 3.2 Hz, NH exch.), 10.95 (s, 1H,
123

98
Med Chem Res (2012) 21:91–99
47.85; H, 4.91; N, 12.88; S, 9.82 Found C, 47.87; H,
4.95 N, 12.93; S, 9.84.
Anti-inflammatory activity
Paw oedema inhibition test was used on albino rats of
Charles Foster by adopting the method of Winter et al.
(1962). Groups of five animals of both sexes (body weight
120–160 g), excluding pregnant females, were given a dose
of test compound. 30 min later, 0.20 ml of 1% freshly
prepared carrageenan suspension in 0.9% NaCl solution
was injected subcutaneously into the planter aponeurosis of
the hind paw, and the volume was measured by a water
plethysmometer apparatus and then measured again 1–3 h
later. The mean increase of paw volume at each interval
was compared with that of control group (five rats treated
with carrageenan but not with test compound) at the same
intervals and percent inhibition value calculated by the
formula given below.
Synthesis of 3,4,4a,5-tetrahydro-3-methyl-8-
bromopyrimido[1,6-a]benzimidazol-1(2H)-thione (8)
4-Bromo-1,2-diaminobenzene 1h (0.187 g, 1 mmole) was
taken in methanol (10 ml) and to it was added 3-isothio-
cyanatobutanal 2b (0.13 ml; 1 mmole) and a few drops of
10% H2SO4 in methanol to adjust the pH of reaction
mixture to *5. The reaction contents were heated under
reflux for 8 h. The solvent was removed under reduced
pressure, and the residue left behind was treated with 10%
sodium bicarbonate solution (5 ml). The solid product so
obtained was filtered, washed with water and dried under
vacuum. Crude product so obtained was dissolved in
methanol, and the resulting solution was adsorbed on silica
gel and subjected to column chromatography over silica
gel. Elution with CHCl3 removed side products and further
elution with CHCl3:EtOAc (8.5:1.5) gave pure product 8.
Yield: 0.215 g (72%); mp: 187°C; IR(KBr) mmax: 3378,
% anti-inflammatory activity ¼ ½1 ꢁ Dt=Dcꢂ ꢃ 100
Dt and Dc are paw volumes of oedema in tested and control
groups, respectively. Compounds 3a–c, 4a–e, 5a–f, 6, 7a,
b, 8 and 9 were screened for anti-inflammatory activity,
and results are summarized in Table 1.
3230 (NH, NH), 1492 and 1445 (Ar) cm-1
(500 MHz, DMSO-d6) d: 1.18–1.21 (d ? m, 4H, 3 for
CH3 ? one for [CH–), 1.66–1.72 (m, 1H, one
.
1H NMR
Acknowledgments We are thankful to technical staff of the
Chemistry Department, I. I. T. Roorkee, for spectroscopic studies and
elemental analysis. One of the authors Mr. Jaiveer Singh (SRF-NET)
is thankful to CSIR, New Delhi, for financial assistance.
H
of [CH2), 2.172–2.177 (d, 1H, J = 2.5 Hz, one H
of [CH2) 4.707–4.717 (t, 1H, J = 2.5 Hz, [CH–),
6.712–6.735 (q, 1H, J1 = 3 Hz, J2 = 8 Hz, J3 = 11.5 Hz,
Ar), 6.87–6.89 (t, 2H, Ar), 8.31 (s, 1H, NH exch.), 9.20 (s,
1H, NH, exch.). GC–MS m/z 299 [M]? Br81, 1.76%, 297
[M]? Br79, 3.16%. Anal. Calcd for C11H12N3SBr C, 44.29;
H, 4.03; N, 14.09; S, 10.74 Found C, 44.35; H, 4.02; N,
14.39; S, 10.76.
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mp: 190°C; IR(KBr) mmax: 3189 (NH), 1614, 1574 and
1536 (Ar) cm-1 1H NMR (500 MHz, DMSO-d6) d:
.
1.25–1.29 (q ? d, 4H, 3H of CH3 ? 1H of [CH–), 2.51 (s,
3H, CH3), 3.02–3.07 (m, 1H, one H of [CH2), 3.30–3.34
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6.44; N, 18.03; S, 13.73 Found C, 61.83; H, 6.42; N, 18.08;
S, 13.82.
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123