Chemotherapy of leishmaniasis. Part VII: Synthesis and bioevaluation of substituted terpenyl pyrimidines

Article abstract of DOI:10.1016/j.ejmech.2006.10.002

Some novel 4-N-substituted terpenyl pyrimidines 5(a-d) and 7(a-g) have been synthesized using novel synthetic methods. The compounds were screened for in vivo antileishmanial screening. When compared to 4-thiomethoxy substituted pyrimidine 2 4-N-substitut

Full text of DOI:10.1016/j.ejmech.2006.10.002

European Journal of Medicinal Chemistry 42 (2007) 1211e1217
http://www.elsevier.com/locate/ejmech
Original article
Chemotherapy of leishmaniasis. Part VII: Synthesis and
bioevaluation of substituted terpenyl pyrimidines*
a
a
a
b
S.N. Suryawanshi a, , B.A. Bhat , Susmita Pandey , Naveen Chandra , Suman Gupta
*
a Division of Medicinal Chemistry, Central Drug Research Institute, Chatter Manzil, Lucknow 226001, Uttar Pradesh, India
b Division of Parasitology, Central Drug Research Institute, Chatter Manzil, Lucknow 226001, Uttar Pradesh, India
Received 19 April 2006; received in revised form 30 September 2006; accepted 5 October 2006
Available online 11 May 2007
Abstract
Some novel 4-N-substituted terpenyl pyrimidines 5(aed) and 7(aeg) have been synthesized using novel synthetic methods. The compounds
were screened for in vivo antileishmanial screening. When compared to 4-thiomethoxy substituted pyrimidine 2 4-N-substituted terpenyl pyrim-
idines 5(aed) and 7(aeg) were found inactive.
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: b-Ionone; Terpenyl pyrimidines; Antileishmanial activity
1. Introduction
of novel compounds. DHFR has been quite successful as a
biochemical target in cancer [8] and malaria [9] and has
resulted in the development of clinically active molecules i.e.,
pyrimethamine, trimethoprim, cycloguanil and methotrexate.
However, these classical DHFR inhibitors showed very little
selectivity towards leishmanial and trypanosomal enzymes [7].
Relatively very little has been reported on the development
of specific inhibitors of leishmainal and trypanosome DHFR.
Coombs group [8,9] investigated some 5-substituted 2,4-
diaminopyrimidines that were good inhibitors of Leishmania
mexicana DHFR in in vitro model. However, in a mouse study
compounds were found toxic. Further studies by Sirawaraporn
et al. [10] on substituted 5-benzyl-2,4-diaminopyrimidines
were quite encouraging in the in vitro studies. In continuation
of our studies on terpene-substituted pyrimidines [11], we syn-
thesized some novel terpenyl pyrimidines and evaluated them
for in vivo biological profile and the results are reported in this
communication.
Leishmaniasis is an infection caused by protozoa of the
genus Leishmania presenting several forms of the disease
such as cutaneous (CL), mucocutaneous (MCL) and visceral
leishmaniasis (VL), which can be fatal when untreated. The
chemotherapy currently available for leishmaniasis is far from
satisfactory. Resistance to the pentavalent antimonials [1,2],
which have been recommended as drugs for the treatment of
both visceral (VL) and cutaneous leishmaniasis (CL) for more
than 50 years, is now widespread in India. Although new drugs
have become available in recent years for the treatment of VL
including amphotericin B lipid complex [3] and the oral drug
miltefosine [4], treatment problems remain. Natural products
are being explored to generate new leads in the chemotherapy
of leishmaniasis [5]. At the same time biochemical targets are
also under investigation to generate novel small molecules as
lead molecules [6]. Among the biochemical targets, dihydro-
folate reductase (DHFR) [7] is being evaluated in the design
2. Chemistry
*
CDRI communication no. 6952.
The ketene dithioacetal 1 was made available from
commercially available b-ionone in quantitative yield [12].
The reaction of ketene dithioacetal 1 with guanidine in dry
* Corresponding author. Tel.: þ91 0522 2212411-18; fax: þ91 0522
2223405/2223938/2229504.
E-mail address: shivajins@yahoo.co.in (S.N. Suryawanshi).
0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.10.002

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S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 42 (2007) 1211e1217
isopropanol (steel bomb, 120e130 ꢀC, 24 h) furnished ter-
penyl pyrimidine 2 in 50% yield [11a] (Scheme 1). Direct re-
placement of 4-thiomethyl group in 2 with primary and
secondary amines proved least useful and even at steel bomb
condition starting material was recovered. We then thought
of oxidizing 4-thiomethyl group in 2 to sulfonylmethoxy as
in 3, in view to make it more facile to SN2 displacement reac-
tion with various amines. After exploring various oxidation re-
actions, oxone in THF was found to be more successful [13].
The reaction of terpenyl pyrimidine 2 with oxone in THF (rt,
4 h) furnished 3 in 50% yield, contaminated with epoxy com-
pound 4 as a side product in 25% yield.
2
R
N
N
NH2
5
d) R =
N
N
C6H5
a) R =
b) R =
NHNH2
NHCH2C6H5
c) R =
N
Scheme 2.
Terpenyl pyrimidine 2 reacted with hydrazine hydrate (D,
24 h) to furnish 5a as a crystalline compound in 66% yield
which melted at 250e251 ꢀC. The structure of 5a was con-
Having been successfully synthesized pyrimidines 7(aeg)
from S, N-acetals 6(aeg), we planned to synthesize 4-N-
substituted pyrimidines 9(aeb) from N, N-acetals 8(aeb)
(Scheme 4). The reaction of morpholine with ketene dithioace-
tal 1 at ethanol reflux temperature did not provide S,N-acetal
but furnished only N,N-acetal 8a in 60% yield as a crystalline
solid. Under identical reaction conditions ketene dithioacetal 1
reacted with piperazine to produce N, N-acetal 8b in 81%
yield.
1
firmed by H NMR and 13C NMR data. The terpenyl pyrimi-
dine 2 failed to react with benzyl amine at reflux conditions.
Extended reaction time and reflux conditions were of less
use. Even under steel bomb reaction conditions benzyl amine
failed to react with terpenyl pyrimidine 2. However, 4-sulfo-
nylmethoxy pyrimidine 3 reacted with benzyl amine (isopro-
panol, D, 24 h) to furnish 5b as a white crystalline solid in
25% yield. Under identical reaction conditions 5(ced) were
synthesized as shown in Scheme 2.
In a synthetic sequence as shown in Scheme 1, the oxida-
tion reaction with oxone was not a very clean reaction which
always furnished epoxide 4 as a side product. To overcome
this side product we visualized synthesis of 4-N-substituted
pyrimidines as shown in Scheme 3. The reaction of 1 with ar-
omatic amines furnished S, N-acetals 6(aeg) in good yields
(Table 1) [14]. Cyclohexyl amine also reacted with 1 under
identical reaction conditions to furnish 6f in good yield. Hav-
ing been successfully synthesized S, N-acetals 6(aeg) we sub-
jected them towards pyrimidine formation reaction as shown
in Scheme 3. To our expectations S,N-acetal 6a reacted with
guanidine in isopropanol (steel bomb, 130e140 ꢀC, 15 h) to
furnish pyrimidine 7a in 46% yield (Table 2). The structure
of 7a was confirmed on the basis of 1H and 13C NMR spectra.
Under identical reaction conditions 6(beg) were reacted with
guanidine in isopropanol to furnish 7(beg) as shown in
Scheme 3.
The reaction of N, N-acetals 8(aeb) with guanidine was not
found very satisfactory. For instance, N,N-acetal 8a on reac-
tion with guanidine in isopropanol (130e140 ꢀC, steel
bomb, 15 h) furnished 4-N-substituted pyrimidine 9a in 26%
yield as a crystalline solid which melted at 139e140 ꢀC.
1
The structure was confirmed by H and 13C NMR. However,
N,N-acetal 8b on reaction with guanidine under identical
reaction conditions furnished only 7% of the required com-
pound 9b.
3. Biological activities
The in vivo leishmanicidal activity was determined in golden
hamsters (Mesocricetus auratus) infected with HOM/IN/80/
DD8 strain of Leishmania donovani obtained through the cour-
tesy of P.C.C. Garnham, Imperial College, London (U.K.).
For in vivo evaluation of compounds, the method of Bever-
idge [15] as modified by Bhatnagar et al. [16] and Gupta et al.
[17] was employed. Male hamsters weighing 35e40 g were
NH
H2N NH2
Oxone,THF
SMe
SMe
SMe
OH, steel bomb
O
N
N
1
2
NH2
O
+
SO2CH3
SO2CH3
N
N
N
N
NH2
NH2
3
4
Scheme 1.

S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 42 (2007) 1211e1217
1213
1
SMe
NHR
O
NHR
N
N
6(a-g)
7(a-g)
NH2
F
a) R =
b) R =
e) R =
f) R =
OMe
c) R =
Cl
F
g) R =
N
d) R =
Scheme 3.
infected with 1 ꢁ 107 amastigotes and the intensity of infec-
tion after 20 days was assessed by spleen biopsy. Animals
with 2þ infections (5e15 amastigote/100 cell nuclei) were se-
lected for screening the compounds. The infected animals
were randomized into several groups on the basis of their par-
asitic burdens. Usually 4e6 animals were used for each com-
pound and the same numbers were kept as untreated controls.
The drug treatment was given intraperitoneally for five con-
secutive days at 50 mg/kg dose level. To assess the effect of
test compounds spleen biopsies were performed on each ani-
mal after 7 and 28 days of last drug administration and
amastigote counts were assessed by Giemsa staining. The per-
centage inhibition in amastigote multiplication was calculated
using the following formula
ANAT ꢁ 100
P:I: ¼ 100 ꢂ
INAT ꢁ TIUC
P.I. ¼ percent inhibition of amastigotes multiplication;
ANAT ¼actual number of amastigotes in treated animals;
INAT ¼ initial number of amastigotes in treated animals and
TIUC ¼ times increase of parasites in untreated control animals.
Table 1
Synthesis of S, N- and N, N-acetals
S. no.
Substrate
Amine
Reaction conditions
Product
S,N, %
N,N, %
1
2
3
4
1
1
1
1
Steel bomb, EtOH, 100e110 ꢀC, 9 h
EtOH, reflux, 15 h
6a, 59
6b, 87
6c, 90
6d, 42
e
H2N
H2N
H2N
H2N
e
e
e
OMe
Cl
Steel bomb, EtOH, 100e120 ꢀC, 20 h
Steel bomb, EtOH, 100e120 ꢀC, 22 h
F
F
5
6
1
1
EtOH, reflux, 40 h
EtOH, reflux, 20 h
6e, 30
6f, 43
e
e
H2N
H2N
7
1
EtOH, reflux, 20 h
6g, 68
e
HN
HN
NH
O
8
9
1
1
EtOH, reflux, 5 h
EtOH, reflux, 5 h
e
e
8a, 81
8b, 60
HN

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S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 42 (2007) 1211e1217
Table 2
Synthesis of 4-N-substituted terpenyl pyrimidine
Table 3
Antileishmanial activity of compounds against Leishmania donovani in
hamsters
S. no.
Substrate
Reaction conditions
Product
Yield
(%)
S. no.
Compound
Dose
(mg/kg)
In vivo inhibition (%)
1
2
3
4
5
6
7
8
9
a
6a
6b
6c
6d
6e
6f
Guanidine, isopropanol,
steel bomb, 15 h
7a
7b
7c
7d
7e
7f
46
67
64
71
55
88
70a
26a
7
Day-7
Day-28
1
2
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
66
ND
ND
NI
NI
NI
NI
31
NI
NI
NI
NI
NI
40
NI
NI
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Guanidine, isopropanol,
steel bomb, 15 h
2
3
3
4
Guanidine, isopropanol,
Steel bomb, 20 h
4
5a
5b
5c
5d
7a
7b
7c
7d
7e
7f
7g
9a
9b
5
Guanidine, isopropanol,
steel bomb, 25 h
6
7
Guanidine, isopropanol,
steel bomb, 25 h
8
9
Guanidine, isopropanol,
steel bomb, 15 h
10
11
12
13
14
15
16
6g
8a
8b
Guanidine, isopropanol,
steel bomb, 15 h
7g
9a
9b
Guanidine, isopropanol,
steel bomb, 15 h
Guanidine, isopropanol,
steel bomb, 15 h
Yield based on the basis of recovered starting.
replacement of thiomethoxy group in 2 by primary amines
as well as secondary amines as in 5(aed) and 7(aeg) resulted
in loss of in vivo antileishmanial activity profile.
4. Results and discussion
In earlier studies by us [11a,b,18] and others [19] have
shown that pyrimidines attached to a suitable hydrophobic ter-
pene handle form a unique pharmacophore and show antimi-
crobial and antileishmanial profile. We visualized that the
terpene plays as good hydrophobic handle and activity profile
is displayed by the pyrimidine ring. In view of this we under-
took modification on the pyrimidine ring. 4-O-Substituted ter-
penyl pyrimidines displayed moderate antileishmanial activity
profile [11a] and we visualized that they might be acting
through immunostimulation. Therefore, we decided to intro-
duce another nitrogen function at the 4-position which is re-
quired for the DHFR inhibition and we synthesized
compounds via two different synthetic routes as shown in
Schemes 2 and 3. The compound 2 displayed 66% inhibition
on 50 mg/kg in a hamster model [11a]. The replacement of
SMe by nitrogen substitution as in 5(aed) resulted in the
loss of in vivo biological activity. To our surprise, even sub-
stitution of variously substituted anilines at 4-position as in
7(aeg) did not show in vivo biological profile. Substitution
of secondary amines as in 9(aeb) also has no effect and
compounds were found inactive (Table 3). In conclusion,
5. Experimental
The reported melting points (ꢀC) are the uncorrected ones.
The infrared spectra were recorded in KBr on a PerkineElmer
model 881. NMR spectra were obtained in CDCl3 (with Me4Si
as internal standard, Aldrich) and are reported in parts per mil-
lion downfield from Me4Si. Proton and carbon NMR spectra
were recorded on Bruker Advance DRX 2000 instrument.
Electron impact (EI) mass spectra were recorded on a Jeol
JMS-D-300 spectrometer with the ionization potential of
70 eV. Elemental analyses were carried out on a Carlo-Erba
EA 1108 instrument.
5.1. 4-Methanesulfonyl-6-[2-(2,6,6-trimethyl-cyclohex-1-
enyl)-ethenyl]-pyrimidin-2-ylamine (3)
To a solution of 2 (0.578 g, 2 mmol) in THF (20 ml) was
added oxone (3.690 g, 6 mmol) in water (20 ml) at 0 ꢀC and
stirred the reaction mixture for 4 h at room temperature. The
reaction mixture was concentrated in vacuo and extracted
1
R
R
O
R
N
N
8(a-b)
N
9(a-b)
NH2
a) R =
b) R =
a) R =
b) R =
N
O
O
N
N
NH
NH
Scheme 4.

S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 42 (2007) 1211e1217
1215
with ethylacetate (50 ml ꢁ 2). The ethylacetate extract was
washed with brine (50 ml), dried (Na2SO4) and solvent was re-
moved in vacuo. The crude product was column chromato-
graphed (SiO2, 60e120 mesh). Elution with 30%
ethylacetate in hexane furnished 3 as a pale yellow foam
(0.30 g, 50%). IR (neat, cmꢂ1) 3421, 2131, 1730, 1608,
133.709 (d), 137.630 (s), 162.873 (s), 163.251 (s), 163.965
(s); MS: (m/e) 326 (Mþ), 311 (Mþ ꢂ CH3).
6.3. 4-(4-Phenyl-piperazin-1-yl)-6-[2-(2,6,6-trimethyl-
cyclohex-1-enyl)-ethenyl]-pyrimidin-2-ylamine (5d)
1
1568; H NMR (CDCl3, 200 MHz) d 1.00 (s, 6H), 1.50 (m,
Yield 50%. M.p. 120e123 ꢀC; IR (KBr, cmꢂ1) 3327,
3205, 2916; 1H NMR (CDCl3, 200 MHz) d 1.05 (s, 6H),
1.50 (m, 2H), 1.65 (m, 2H), 5.90 (s, 1H), 6.20 (d,
J ¼ 16.00 Hz, 1H), 6.90 (m, 3H), 7.30 (m, 3H); 13C NMR
(CDCl3, 200 MHz) d 19.63 (t), 22.24 (q), 2 ꢁ 29.44 (q),
33.65 (t), 34.67 (s), 40.12 (t), 2 ꢁ 44.30 (t), 2 ꢁ 49.56 (t),
92.46 (d), 2 ꢁ 116.83 (t), 120.62 (d), 2 ꢁ 129.63 (d), 131.90
(d), 134.24 (s), 137.62 (s), 151.57 (s), 163.31 (s), 164.23 (s);
MS: (m/e) 403 (Mþ).
2H), 1.60 (m, 2H), 1.80 (s, 3H), 2.10 (m, 2H), 3.20 (s, 3H),
5.45 (m, 2H), 6.35 (d, J ¼ 16.00 Hz, 1H), 7.50 (d,
J ¼ 16.00 Hz, 1H); MS: (m/e) 321 (Mþ), 306 (Mþ ꢂ CH3).
5.2. 4-Hydrazino-6-[2-(2,6,6-trimethyl-cyclohex-1-enyl)-
ethenyl]-pyrimidin-2-ylamine (5a)
Compound 2(0.578 g, 2 mmol) in neat hydrazine hydrate
was refluxed for 24 h to furnish 5a as crystalline solid in quan-
titative yield 66%. M.p. 250e251 ꢀC; IR (KBr, cmꢂ1) 3322,
2924, 1590, 1410; 1H NMR (CDCl3, 200 MHz) d 1.10 (s,
6H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (s, 3H), 2.00 (m, 2H),
4.95 (m, 2H), 6.00 (s, 1H), 6.20 (d, J ¼ 16.00 Hz, 1H), 6.30
(m, 3H), 7.30 (d, J ¼ 16.00 Hz, 1H); 13C NMR (CDCl3,
200 MHz) d 19.50 (t), 23.37 (q), 2 ꢁ 28.98 (q), 33.60 (s),
34.58 (t), 40.27 (t), 91.57 (d), 131.25 (s), 132.25 (d), 134.59
(s), 137.41 (d), 163.11 (s), 167.04 (s); MS: (m/e) 273 (Mþ),
258 (Mþ ꢂ CH3), 243 (Mþ ꢂ NHCH3).
7. General procedure for the synthesis of 6(aeg) and
8(aeb)
To a solution of ketene dithioacetal 1 in absolute alcohol
(60 ml) were added various amines (20 mmol) and refluxed/
or in steel bomb for 5e40 h to furnish S, N-acetals 6(aeg)
and N, N-acetals 8(aeb) in good yields as shown in Table 1.
8. General procedure for the synthesis of 4-N-phenyl-6-
[2-(2,6,6-trimethyl-cyclohex-1-enyl)-ethenyl]-
pyrimidine-2,4-diamine (7a)
6. General procedure for the synthesis of 5(bed)
To a solution of 3 (0.64 g, 2 mmol) in isopropanol (30 ml)
were added various amines to furnish N-substituted terpenyl
pyrimidines 5bed in quantitative yield.
To a solution of sodium isopropoxide (prepared by dissolv-
ing sodium metal 0.23 g in 20 ml of dry isopropanol) was
added guanidine hydrochloride (0.95 g, 10 mmol) and stirred
the reaction mixture for 3 h at room temperature. The white
solid was filtered off. To the filtrate was added 6a (3.86 g,
10 mmol) and the reaction mixture was heated in steel bomb
at 120e130 ꢀC for 15 h. It was concentrated in vacuo and ex-
tracted with ethylacetate (50 ml ꢁ 4). Combined extract was
washed with water (25 ml ꢁ 2), brine solution (50 ml), dried
(Na2SO4) and the solvent was removed in vacuo. The crude
product was column chromatographed (SiO2, 60e120 mesh).
Elution with 15% ethylacetate in hexane furnished 7a as
a thick liquid (3.07 g, 46%). IR (neat, cmꢂ1) 3408, 2927,
6.1. 4-N-Benzyl-6-[2-(2,6,6-trimethyl-cyclohex-1-enyl)-
ethenyl]-pyrimidine-2,4-diamine (5b)
Yield 25%. M.p. 81e83 ꢀC; IR (KBr, cmꢂ1) 3193, 2925,
1
1575; H NMR (CDCl3, 200 MHz) d 1.20 (s, 6H), 1.50 (m,
2H), 1.75 (m, 4H), 1.80 (s, 3H), 2.10 (m, 2H), 4.60 (d, 2H),
4.80 (m, 2H), 5.00 (m, 2H), 5.80 (s, 1H), 6.20 (d,
J ¼ 18.00 Hz, 1H), 7.40 (m, 4H); 13C NMR (CDCl3,
200 MHz) d 164.629 (s), 163.317 (s), 139.059 (s), 137.505
(s), 134.407 (d), 132.011 (s), 131.399 (d), 129.104 (d),
4 ꢁ 127.79 (d), 92.783 (d), 45.745 (t), 40.164 (t), 34.634 (s),
33.629 (t), 2 ꢁ 29.362 (q), 22.163 (q), 19.583 (t); MS: (m/e)
348 (Mþ), 333 (Mþ ꢂ CH3).
1
1600, 1550, 1500, 1400; H NMR (CDCl3, 200 MHz) d 1.10
(s, 6H), 1.50 (m, 2H), 1.65 (m, 2H), 1.80 (s, 3H), 2.05 (m,
2H), 5.00 (bs, 2H), 6.10 (s, 1H), 6.15 (d, J ¼ 16.00 Hz, 1H),
7.30 (m, 6H); 13C NMR (CDCl3, 200 MHz) d 19.541 (t),
22.152 (q), 2 ꢁ 29.319 (q), 33.653 (s), 34.221 (t), 40.152 (t),
93.410 (d), 2 ꢁ 122.880 (d), 124.670 (d), 2 ꢁ 129.663 (d),
130.993 (d), 132.437 (s), 135.084 (d), 137.429 (s), 139.252
(s), 163.007 (s), 163.259 (s), 163.772 (s); MS: (m/e) 335
(Mþ þ 1), 320 (Mþ ꢂ CH3).
6.2. 4-Piperidin-1-yl-6-[2-(2,6,6-trimethyl-cyclohex-
1-enyl)-ethenyl]-pyrimidin-2-ylamine (5c)
Yield 28%. M.p. 112e113 ꢀC; IR (KBr, cmꢂ1) 3479, 3286,
3165, 3000, 1573, 1521, 1411, 980; 1H NMR (CDCl3,
200 MHz) d 1.20 (s, 6H), 1.70 (m, 10H), 1.90 (s, 1H), 2.10
(m, 2H), 3.60 (m, 4H), 4.70 (d, 2H), 6.00 (s, 1H), 6.20 (d,
J ¼ 20.00 Hz, 1H), 7.30 (d, J ¼ 20.00 Hz, 1H); 13C NMR
(CDCl3, 200 MHz) d 19.585 (t), 22.161 (q), 25.173 (t),
2 ꢁ 26.015 (t), 2 ꢁ 29.363 (q), 33.577 (s), 34.607 (t), 40.153
(t), 2 ꢁ 45.445 (t), 92.439 (d), 131.555 (s), 131.949 (d),
8.1. 4-N-(4-Methoxyphenyl)-6-[2-(2,6,6-trimethyl-
cyclohex-1-enyl)-ethenyl]-pyrimidine-2,4-diamine (7b)
Yield 67%. M.p. 74e76 ꢀC; IR (KBr, cmꢂ1) 3400, 3000,
1
1600, 1568, 1506, 1240; H NMR (CDCl3, 200 MHz) d 1.10
(s, 6H), 1.40 (m, 2H), 1.50 (m, 2H), 1.75 (s, 3H), 2.00 (m, 2H),

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S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 42 (2007) 1211e1217
3.80 (s, 3H), 5.30 (m, 2H), 5.95 (s, 1H), 6.10 (d, J ¼ 16.00 Hz,
1H), 6.80 (d, J ¼ 8.00 Hz, 2H), 7.20 (d, J ¼ 8.00 Hz, 2H), 7.20
(d, 1H), 7.95 (m, 1H); 13C NMR (CDCl3, 200 MHz) d 19.539
(t), 22.137 (q), 2 ꢁ 29.299 (q), 33.607 (t), 35.078 (s), 40.119
(t), 55.821 (q), 92.761 (d), 2 ꢁ 114.908 (d), 126.022 (d),
131.370 (s), 131.933 (d), 132.126 (s), 134.554 (d), 137.434
(s), 157.409 (s), 163.435 (s), 163.641 (s), 163.995 (s); MS:
(m/e) 365 (Mþ þ 1).
1.30 (m, 10H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (s, 3H),
2.00 (m, 2H), 3.60 (m, 1H), 4.80 (d, 1H), 4.90 (m, 2H), 5.75
(s, 1H), 6.15 (d, J ¼ 16.00 Hz, 1H), 7.30 (d, J ¼ 16.00 Hz,
1H); 13C NMR (CDCl3, 200 MHz) d 19.566 (t), 22.134 (q),
2 ꢁ 25.173 (q), 25.670 (t), 2 ꢁ 29.333 (q), 29.727 (t),
2 ꢁ 33.642 (t), 34.607 (s), 40.145 (t), 50.00 (d), 95.749 (d),
131.431 (d), 131.815 (d), 134.226 (d), 137.558 (s), 162.865
(s), 163.256 (s), 163.713 (s); MS: (m/e) 340 (Mþ), 320
(Mþ ꢂ CH3).
8.2. 4-N-(4-Chlorophenyl)-6-[2-(2,6,6-trimethyl-
cyclohex-1-enyl)-ethenyl]-pyrimidine-2,4-diamine (7c)
8.6. 4-N-Ethyl-N-4-phenyl-6-[2-(2,6,6-trimethyl-
cyclohex-1-enyl)-ethenyl]-pyrimidine-2,4-diamine (7g)
Yield 64%. M.p. 55e56 ꢀC; IR (KBr, cmꢂ1) 3310, 2928,
1570, 1491, 1398; 1H NMR (CDCl3, 200 MHz) d 1.10 (s,
6H), 1.50 (m, 2H), 1.65 (m, 2H), 1.70 (s, 3H), 2.10 (m, 2H),
5.95 (s, 2H), 6.15 (s, 1H), 6.20 (d, J ¼ 16.00 Hz, 1H), 7.30
(d, 2H), 7.40 (d, J ¼ 16.00 Hz, 1H), 7.85 (d, 2H), 8.75 (s,
1H); 13C NMR (CDCl3, 200 MHz) d 20.321 (t), 22.459 (q),
2 ꢁ 29.783 (q), 34.169 (t), 35.292 (s), 40.840 (t), 96.180 (d),
2 ꢁ 122.635 (d), 127.376 (s), 2 ꢁ 129.711 (d), 132.275 (s),
132.709 (d), 134.390 (d), 138.321 (s), 141.040 (s), 163.501
(s), 163.710 (s), 164.628 (s); MS: (m/e) 369 (Mþ þ 1).
Yield 88%. IR (neat, cmꢂ1) 3415, 2927, 1581, 1215; H
1
NMR (CDCl3, 200 MHz) d 1.15 (s, 6H), 1.30 (s, 3H), 1.50
(m, 2H), 1.70 (m, 2H), 1.80 (s, 3H), 2.10 (m, 2H), 2.95 (m,
2H), 3.60 (m, 2H), 5.00 (m, 2H), 5.80 (s, 1H), 6.15 (d,
J ¼ 16.00 Hz, 1H), 7.30 (m, 6H); 13C NMR (CDCl3,
200 MHz) d 19.586 (t), 22.184 (q), 2 ꢁ 29.371 (q), 30.110
(q), 33.639 (s), 34.638 (t), 40.168 (t), 42.930 (t), 93.00 (d),
126.924 (d), 2 ꢁ 129.046 (d), 2 ꢁ 129.181 (d), 131.221 (d),
132.042 (s), 134.453 (d), 137.537 (s), 139.302 (s), 162.00
(s), 163.165 (s), 164.462 (s); MS: (m/e) 363 (Mþ þ 1).
8.3. 4-N-(4-Fluorophenyl)-6-[2-(2,6,6-trimethyl-
cyclohex-1-enyl)-ethenyl]-pyrimidine-2,4-diamine (7d)
8.7. 4-Morpholin-4-yl-6-[2-(2,6,6-trimethyl-cyclohex-1-
enyl)-ethenyl]-pyrimidin-2-ylamine (9a)
Yield 71%. M.p. 105e106 ꢀC; IR (KBr, cmꢂ1) 3412, 2928,
Yield 26%. IR (neat, cmꢂ1) 2922, 1643, 1484, 1446, 1392,
1
1574, 1507, 1405, 1217; H NMR (CDCl3, 200 MHz) d 0.89
1
1228, 980; H NMR (CDCl3, 200 MHz) d 1.20 (s, 6H), 1.50
(s, 6H), 1.40 (m, 2H), 1.50 (m, 2H), 1.65 (s, 3H), 1.90 (m,
2H), 5.70 (m, 2H), 5.95 (s, 1H), 6.00 (d, J ¼ 16.00 Hz, 1H),
6.90 (m, 2H), 7.25 (d, J ¼ 16.00 Hz, 1H), 7.60 (m, 2H), 8.50
(s, 1H); 13C NMR (CDCl3, 200 MHz) d 20.292 (t), 22.376
(q), 2 ꢁ 29.738 (q), 34.122 (t), 35.283 (s), 40.839 (t), 95.794
(d), 115.992 (d), 116.435 (d), 122.119 (d), 123.270 (d),
132.093 (s), 132.788 (d), 134.147 (d), 138.365 (s), 157.032
(s), 161.787 (s), 163.445 (s), 163.724 (s), 164.615 (s); MS:
(m/e) 353 (Mþ þ 1).
(m, 2H), 1.80 (s, 3H), 2.10 (m, 3H), 3.60 (m, 4H), 3.75 (m,
4H), 4.90 (d, 2H), 5.45 (m, 1H), 5.90 (s, 1H), 6.10 (d,
J ¼ 16.00 Hz, 1H), 6.60 (d, J ¼ 16.00 Hz, 1H); 13C NMR
(CDCl3, 200 MHz) d 17.572 (q), 25.173 (t), 2 ꢁ 26.362 (q),
33.577 (s), 36.607 (t), 40.153 (t), 2 ꢁ 54.426 (t), 2 ꢁ 70.335
(t), 92.439 (d), 128.858 (d), 131.949 (d), 133.709 (d),
137.630 (d), 162.873 (d), 168.262 (d), 171.654 (d); MS:
(m/e) 329 (Mþ þ 1).
8.4. 4-N-(3-Fluorophenyl)-6-[2-(2,6,6-trimethyl-
8.8. 4-Piprazine-1-yl-6-[2-(2,6,6-trimethyl-cyclohex-1-
cyclohex-1-enyl)-ethenyl]-pyrimidine-2,4-diamine (7e)
enyl)-ethenyl]-pyrimidin-2-ylamine (9b)
Yield 55%. M.p. 51e52 ꢀC; IR (KBr, cmꢂ1) 3414, 3306,
2932, 1572, 1444; 1H NMR (CDCl3, 200 MHz) d 1.02 (s,
6H), 1.50 (m, 2H), 1.60 (m, 2H), 1.70 (s, 3H), 2.00 (m, 2H),
5.60 (m, 2H), 6.10 (s, 1H), 6.15 (d, J ¼ 16.00 Hz, 1H), 6.80
(m, 1H), 7.00e7.40 (m, 4H), 8.20 (m, 1H); 13C NMR
(CDCl3, 200 MHz) d 19.497 (t), 22.114 (q), 2 ꢁ 29.261 (q),
33.671 (s), 34.580 (t), 40.113 (t), 94.073 (d), 110.897 (d),
117.158 (d), 117.212 (d), 130.272 (d), 130.473 (d), 132.895
(s), 135.622 (d), 137.319 (s), 141.122 (s), 141.334 (s),
161.104 (s), 165.972 (s), 178.578 (s); MS: (m/e) 353 (Mþ þ 1).
Yield 7%. IR (neat, cmꢂ1) 3344, 2925, 1581, 1417, 1356;
1H NMR (CDCl3, 200 MHz) d 1.20 (s, 6H), 1.55 (m, 2H),
1.70 (s, 3H), 2.10 (m, 3H), 3.50 (m, 4H), 3.85 (m, 4H), 4.95
(d, 2H), 5.45 (m, 1H), 5.90 (s, 1H), 6.20 (d, J ¼ 16.00 Hz,
1H), 6.50 (d, J ¼ 16.00 Hz, 1H); 13C NMR (CDCl3,
200 MHz) d 17.560 (q), 25.173 (t), 2 ꢁ 26.362 (q), 34.658
(s), 38.656 (t), 42.852 (t), 52.450 (t), 54.426 (t), 70.335 (t),
74.457 (t), 92.439 (d), 129.866 (d), 132.957 (d), 134.799 (d),
139.434 (d), 161.762 (d), 168.262 (d), 170.275 (d); MS:
(m/e) 328 (Mþ þ 1).
8.5. 4-N-Cyclohexyl-6-[2-(2,6,6-trimethyl-cyclohex-1-
Acknowledgements
enyl)-ethenyl]-pyrimidine-2,4-diamine (7f)
Financial support to B.A. Bhat by NOVA-NORDIX, S.P.
and N.C. by MOH (India) and technical support by Mrs.
Manju are gratefully acknowledged.
Yield 88%. M.p. 75e76 ꢀC; IR (KBr, cmꢂ1) 3415, 2931,
1579, 1215; 1H NMR (CDCl3, 200 MHz) d 1.10 (s, 6H),

S.N. Suryawanshi et al. / European Journal of Medicinal Chemistry 42 (2007) 1211e1217
1217
(b) Naveen Chandra, Ramesh, Ashutosh, Neena Goyal,
S.N. Suryawanshi, Suman Gupta, Eur. J. Med. Chem. 40 (2005)
552e556.
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