Synthesis of variously 9,9-dialkylated octahydropyrimido [3,4-a]-s-triazines with potential antifungal activity

Article abstract of DOI:10.1016/S0014-827X(01)01181-8

9,9-Dialkyloctahydropyrimido[3,4-a]-s-triazines were synthesized by iminodimethylation reaction between a 5,5-dialkyl-6-aminopyrimidine-2,4(3H,5H)-dione, a substituted aniline and two moles of formaldehyde. The synthesis of 5,5-dialkyl-6-aminopyrimidinedione consisted of the condensation of urea with ethyl 2,2-dialkylcyanoacetates. 18 Octahydropyrimido[3,4-a]-s-triazines were synthesized and compounds resulting from a supplementary aminomethylation were also obtained. Most of these compounds were tested for antifungal activity in vitro. Only 9,9-dibutyl-6,8-dioxo-3(2-chlorophenyl)2,3,4,5,6,7,8,9-octahydropyrimido[3, 4-a]-s-triazine showed some activity against Microsporum canis.

Full text of DOI:10.1016/S0014-827X(01)01181-8

Il Farmaco 57 (2002) 109–116
www.elsevier.com/locate/farmac
Synthesis of variously 9,9-dialkylated octahydropyrimido
[3,4-a]-s-triazines with potential antifungal activity
Amar Ghaib, Sabine Me´nager, Philippe Ve´rite´, Olivier Lafont *
Laboratoire de Pharmacochimie, De´partement Chimie Organique, Faculte´ de Me´decine et Pharmacie, 22, boule6ard Gambetta,
76183 Rouen cedex 1, France
Received 24 July 2001; accepted 9 October 2001
Abstract
9,9-Dialkyloctahydropyrimido[3,4-a]-s-triazines were synthesized by iminodimethylation reaction between a 5,5-dialkyl-6-
aminopyrimidine-2,4(3H,5H)-dione, a substituted aniline and two moles of formaldehyde. The synthesis of 5,5-dialkyl-6-aminopy-
rimidinedione consisted of the condensation of urea with ethyl 2,2-dialkylcyanoacetates. 18 Octahydropyrimido[3,4-a]-s-triazines
were synthesized and compounds resulting from a supplementary aminomethylation were also obtained. Most of these compounds
were tested for antifungal activity in vitro. Only 9,9-dibutyl-6,8-dioxo-3(2-chlorophenyl)2,3,4,5,6,7,8,9-octahydropyrimido[3,4-a]-
´
s-triazine showed some activity against Microsporum canis. © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights
reserved.
Keywords: Iminodimethylation; Antifungal agents; Ethyl 2,2-dialkylcyanoacetates; 9,9-Dialkyloctahydropyrimido[3,4-a]-s-triazines
have already been synthesized and proved to be active
as antiparasitic [1,2] and antimicrobial agents [3].
1. Introduction
In this last area, a pharmacomodulation has been
The need for new pharmacophores which could be
performed only on the 9,9-diethylderivatives [4]
used to design new antifungal agents is still a concern
(Scheme 1).
for medicinal chemists.
Due to their structural relationship to both folic
acids and cycloguanil ring, compounds containing the
pharmacophore octahydropyrimido [3,4-a]-s-triazine
First of all, for n=0, R=H, the phenyl group has
been substituted by various substituents: Cl, NO2, CH3,
OCH3 in various positions. Preliminary antimicrobial
results showing that chlorine was the more efficient
substituent, the pharmacomodulation has been focussed
on variation of the position and the number of Cl
substituents on the phenyl group. The best antifungal
results were obtained (MIC=1 mml−1) against Trico-
phyton rubrum and Epidermophyton floccosum for chlo-
rine atom in position 3. In the case of bacteria a
moderate activity has been observed for Bacillus cereus,
when two chlorine atoms were introduced in positions 2
and 4 [4].
The alkylation of N7 by a methyl group, the replace-
ment of the oxygen atom in position 6 by a sulfur atom,
Scheme 1.
the introduction of methylene groups between N3 and
the phenyl group, did not increase antifungal activity
[4].
* Corresponding author.
E-mail address: olivier.lafont@univ-rouen.fr (O. Lafont).
´
0014-827X/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0014-827X(01)01181-8

110
A. Ghaib et al. / Il Farmaco 57 (2002) 109–116
Scheme 2.
The present work deals with the modulation of the
mole of sodium ethanolate and two moles of ethyl
bromide, the major product was ethyl monoethyl-
cyanoacetate (56%), but ethyl diethylcyanoacetate was
obtained with 35% yield (Scheme 3).
Despite this lack of selectivity, this method could be
used when a product dialkylated by the same alkyl
group (Bu or Pr) was needed. In the presence of
potassium hydroxide, the non-alkylated compound was
a salt, which was very soluble in water, and could then
be easily eliminated from the medium. For the
monoalkylcompound, its solubility was weaker but
substituents of the carbon atom in position 9, in order
to modify the lipophilicity of the compounds and to
test its influence on the antifungal activity. Taking
account of the results obtained with two ethyl groups in
position 9, the substituents chosen for the phenyl group
were one or two chlorine atoms, in various positions.
Trifluoromethyl group, which is considered similar to
chlorine from a pharmacological point of view, was
also selected.
2. Results and discussion
Table 1
5,5-Dialkyl-6-aminopyrimidine-2,4(3H,5H)-diones used as starting
materials
2.1. Chemistry
The synthesis of octahydropyrimido[3,4-a]-s-triazines
was performed via an iminodimethylation reaction of
5,5-dialkyl-6-aminopyrimidine-2,4(3H,5H)-dione, with
formaldehyde and variously substituted anilines
(Scheme 2). The 6-aminopyrimidinedione was under the
enamino form and the condensation was an extension
of the Mannich reaction [5].
1
R1
R2
Four
different
5,5-dialkyl-6-aminopyrimidine-
a
b
c
Bu
Pr
Bu
Pr
Bu
Pr
Et
Et
2,4(3H,5H)-diones (1a–d) were used as starting materi-
als (Table 1).
The first step of the synthesis consisted of the synthe-
sis of ethyl 2,2-dialkylcyanoacetates. According to an-
cient works, the alkylation of ethyl cyanoacetate was
performed by heating with alkyl halide and sodium
ethanolate in stoichiometric conditions to yield
monoalkylderivative, the second alkylation being ob-
tained by the reaction of this monoalkyl derivative with
a new molecule of alkylhalide in alkaline medium [6].
Unfortunately, under these conditions the result con-
sisted always of a mixture of monoalkyl, of dialkyl
derivatives and of starting material. Modifications of
the relative proportions of cyanoacetate, alkyl halide or
sodium ethanolate (1,1,1; 1,2,2; 1,1,2; 1,3,2) did not
lead to a unique compound. For example, with one
d
Scheme 3.

A. Ghaib et al. / Il Farmaco 57 (2002) 109–116
111
material was then constituted of a-chlorocarboxylic
acid, which was treated with sodium cyanide, leading to
monoalkylcyanoacetic acid, which was then submitted
to an esterification reaction. The second alkylation was
then obtained by treatment with an alkylhalide in the
presence of sodium ethanolate (Scheme 4).
The following step consisted of the condensation of
urea, with these ethyl dialkylcyanoacetates, in the pres-
ence of sodium ethanolate, according to the method
described by Conrad [8] (Scheme 5).
Scheme 4.
The structure of this kind of compound which could
undergo many kind of tautomerisms was studied by C.
Giraud et al. [9] and the dioxoenamino form was
proved to be predominant.
For the iminodimethylation reactions, these 6-
aminopyrimidinediones reacted in ethanol solution with
eight different anilines (1 mol) and formaldehyde (2
mol). These anilines were unsubstituted 2a or variously
substituted. Compounds 2b–d were, respectively, sub-
stituted by a chlorine atom in positions 2, 3 or 4.
Compound 2e was substituted by two chlorine atoms in
positions 2 and 4. Compounds 2f–h were, respectively,
substituted by a trifluoromethyl group in positions 2,3
or 4 (Table 2).
Scheme 5.
In each case, the product of the reaction was isolated
after precipitation.
Table 2
Substituted anilines
In most cases, octahydropyrimido[3,4-a]-s-triazines 3
were obtained. In sixteen cases, 3a–g, 3i–p, 3r, were the
only products of the reactions. In two cases the com-
pounds resulting from an iminodimethylation 3h and 3q
were accompanied, respectively, by 4a and 4b, resulting
from a supplementary aminomethylation of the nitro-
gen atom in position 7. In four cases, the compounds
4c, 4d, 4e and 4f resulting from both an iminodimethy-
lation and an aminomethylation were the only com-
pounds obtained (Table 3).
2
R3
R4
R5
a
b
c
d
e
f
H
Cl
H
H
H
Cl
H
H
H
CF3
H
H
H
H
Cl
Cl
H
H
CF3
All synthesized compounds (except 4a, 4e and 4f for
insolubility reasons) were tested against Tricophyton
H
Cl
CF3
H
mentagrophytes
(B70554),
Aspergillus
fumigatus
(B42928), Candida albicans (B59630 and B63195), Can-
dida glabrata (B63155), Candida crusei (B68404), Can-
dida parapsilosis (B66126), Candida kefyr (81/018),
Candida tropicalis (CDC44), Cryptococcus neoformans
(B66663) and Sporothrix schenckii (B64284).
Against Microsporum canis (B68128), two more com-
pounds 3a and 4d could not be essayed for insolubility
reason under the experimental conditions.
g
h
H
sufficient to allow a separation in alkaline medium.
Dialkylcompound could then be isolated from the or-
ganic phase with 44% yield.
Unfortunately when the expected product was un-
symmetrically dialkylated by two different alkyl groups,
this method could not be used because the best yield
after purification did not exceed 27%. Moreover, during
the separation step of the monoalkylderivative by disso-
lution in alkaline medium, a hydrolysis of the ester
group occurred, making it necessary to add a new
esterification step to the sequence.
In the case of Tricophyton rubrum (B68183), only 3d,
3h, 3o, 3q and 3r were soluble enough to be tested
under the experimental conditions.
All tested compounds failed to exhibit any antifungal
activity except 3b which presented a moderate activity
against Microsporum canis (0.4BMICB4×10−6
g
ml−1).
These results show that an increase of lipophilicity
has a negative influence on antifungal activity, which
could be related to a decrease of water solubility.
Another process adapted from the synthesis of ethyl
cyanoacetate itself [7] had then to be used. The starting

112
A. Ghaib et al. / Il Farmaco 57 (2002) 109–116
1
3. Experimental section
lues. H NMR spectra were recorded on Bruker AC
200 spectrometer 200 MHz. A Hewlett Packard 5890
gas chromatograph equipped with a capillary column
was used for the GC analyses. The fused silica column
(25 m×0.2 mmID×0.11 mm film thickness) was
coated with crosslinked 5% phenylmethyl silicon gum.
The carrier gas was helium at an inlet pressure of 62
Kpa. Mass spectra were obtained on a GC–MS system.
The mass spectrometer (Hewlett Packard 5970 MSD)
was operating in electron impact mod (70 eV) and
directly interfaced with the gas chromatograph appara-
tus.
3.1. Chemistry
Melting points were determined on a Kofler appara-
tus and are uncorrected. Elemental analyses indicated
by symbols were within 90.4% of the theoretical va-
Table 3
Octahydropyrimido[3,4-a]-s-triazines
3.1.1. Synthesis of ethyl 2,2-dialkylcyanoacetates
3.1.1.1. Classical synthesis. The method used was des-
cribed by Traube [6]: sodium (23 g,1 mol) was dissolved
in 400 ml dry ethanol [10]. After cooling, distilled ethyl
cyanacetate (106 ml, 1 mol) was added, then alkylhalide
(1 mol) was added dropwise. The mixture was stirred at
room temperature for 3 h. After the solvent was evapo-
rated and the residue was dissolved in the minimal
volume of water, two phases were obtained. The
aqueous phase was extracted with diethyloxide (3×57
ml). The organic phase was dried, the solvent was
evaporated and the residue was purified by distillation
under reduced pressure. The different compounds were
quantified by GC–MS. For R=ethyl and with ethyl
bromide (2 mol), the yields were: ethyl monoethyl-
cyanoacetate 56%; ethyl diethylcyanoacetate 35%; non
alkylated ethylcyanoacetate 9%.
In order to obtain pure monoalkyl and dialkylderiva-
tives, the distillate was first washed with aliquot quanti-
ties of sodium hydroxide (20% in water) corresponding
to the amount on non-alkylated compound present in
the reaction medium. The aqueous phase was elimi-
nated. Then the organic residue was washed again with
aliquot quantities of sodium hydroxide corresponding
to the amounts of monoalkylated compound present.
Dialkylated compounds remained in the organic phase
and were separated by distillation under reduced pres-
sure. The aqueous phase was evaporated under va-
cuum, then the residue was dissolved with the minimal
amounts of water. Hydrochloric acid was added until
two phases appeared. The organic phase was consti-
tuted of monoalkylcyanoacetic acid. This acid was es-
terified with an excess of ethanol and ten drops of
sulfuric acid. The ethyl monoalkylcyanoacetate was
distilled under reduced pressure. Table 4 reports the
yields of these compounds.
Reactants
3
4
a
b
R1
R2
R3
R4
R5
1a+2a
1a+2b
1a+2c
1a+2d
1a+2g
1a+2h
1b+2a
1b+2b
1b+2c
1b+2d
1b+2e
1b+2f
1c+2a
1c+2c
1c+2d
1d+2a
1d+2b
1d+2c
1b+2g
1b+2h
1c+2e
1d+2d
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Bu
Bu
Bu
Bu
Bu
Bu
Pr
Pr
Pr
Pr
Pr
Bu
Bu
Bu
Bu
Bu
Bu
Pr
Pr
Pr
Pr
Pr
Pr
Et
Et
Et
Et
Et
Et
Pr
Pr
Et
Et
H
Cl
H
H
H
H
H
Cl
H
H
Cl
CF3
H
H
H
H
Cl
H
H
H
H
H
Cl
H
CF3
H
H
H
Cl
H
H
H
H
Cl
H
H
H
H
H
Cl
H
CF3
H
H
H
Cl
Cl
H
H
H
Cl
H
H
H
H
Pr
Bu
Bu
Bu
Pr
Pr
Pr
Pr
Pr
Bu
Pr
H
Cl
CF3
H
H
H
c
d
e
f
CF3
Cl
Cl
Cl
H
Table 4
Mono- and dialkylated ethyl cyanoacetates (yields and Ref.)
R1
R2
Yield (%)
Ref.
Et
Pr
Bu
Pr
Pr
Bu
Bu
H
H
H
Pr
Bu
Et
Et
18
27
22
16
22
83
78
[11]
[12]
[11]
[8]
[13]
[8]
3.1.1.2. Alternati6e synthesis of unsymmetrically dialky-
lated ethyl 2,2-dialkyl cyanoacetates from h-chlorocar-
boxylic acids. Synthesis of ethyl 2-alkylcyanoacetates
was realized according to the method described in
organic syntheses [7] for ethylcyanoacetate itself, using
[14]

A. Ghaib et al. / Il Farmaco 57 (2002) 109–116
113
2-chloroalkylcarboxylic acids instead of chloroacetic
acid.
The second alkylation was performed by the classical
method described in [6].
mido[3,4-a]-s-triazine 3 or 4 was filtered and then dried.
When 3 and 4 both precipitated (3h and 4a; 3q and
4b), they were dissolved in ethyl oxide and 4 was
precipitated by acetone.
Boiling points were in agreement with the literature.
N.B. When the compounds were chiral they were iso-
lated as racemates.
3.1.3.1. 9,9-Dibutyl-6,8-dioxo-3-phenyl-2,3,4,5,6,7,8,9-
octahydropyrimido[3,4-a]-s-triazine (3a). Yield: 71%;
m.p.: 149 °C, Anal. (C, H, N) C20H28N4O2. H NMR
1
3.1.2. Synthesis of
(CDCl3) l ppm: 0.7 (t, 6H, 2 CH3 butyl); 0.95 (m, 4H,
CH3CH2CH2CH2ꢀ); 1.15 (m, 4H, CH3CH2CH2CH2ꢀ);
1.85 (m, 4H, CH3CH2CH2CH2ꢀ); 5.0 (s, 2H, NꢀCH2ꢀ
N); 5.35 (s, 2H, CꢁOꢀNꢀCH2ꢀN); 6.95 (m, 3H, Ar);
7.25 (m, 2H, Ar); 8.2 (s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
5,5-dialkyl-6-aminopyrimidine-2,4(3H,5H)-diones
5,5-Dialkyl-6-aminopyrimidine-2,4(3H,5H)-diones
were prepared according to the standard method: con-
densation of urea with the appropriate ethyl 2,2-di-
alkylcyanoacetate in alkaline medium [7].
3.1.3.2. 9,9-Dibutyl-6,8-dioxo-3(2-chlorophenyl)-2,3,4,5,
6,7,8,9-octahydropyrimido[3,4-a]-s-triazine (3b). Yield:
80%; m.p.: 164 °C, Anal. (C, H, N) C20H27N4O2Cl. H
NMR (CDCl3) l ppm: 0.8 (t, 6H, 2 CH3 butyl); 1.2 (m,
8H, CH3CH2CH2CH2ꢀ), 1.9 (m, 4H, CH3CH2CH2-
CH2ꢀ); 4.95 (s, 2H, NꢀCH2ꢀN); 5.3 (s, 2H,
CꢁOꢀNꢀCH2ꢀN); 7.05 (m, 3H, Ar); 7.35 (d, 1H, Ar);
8.05 (s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
3.1.2.1. 6-Amino-5,5-dibutylpyrimidine-2,4(3H,5H)dione
(1a). Yield: 32%; m.p.\260 °C; Anal. (C, H, N)
C12H21N3O2. H-NMR (DMSO-d6) l ppm: 0.8 (t, 6H,
1
1
two CH3 butyl); 0.95 (m, 4H, CH3CH2CH2CH2); 1.15
(m,
4H,
CH3CH2CH2CH2ꢀ);
1.8
(t,
4H,
CH3CH2CH2CH2ꢀ); 7.65 (s, 1H, ech D2O, NH2); 7.95
(s, 1H,ech D2O, NH2); 10.5 (s, 1H, ech D2O,
CꢁOꢀNHꢀCꢁO).
3.1.3.3. 9,9-Dibutyl-6,8-dioxo-3(3-chlorophenyl)-2,3,4,5,
6,7,8,9-octahydropyrimido[3,4-a]-s-triazine (3c). Yield:
22%; m.p.: 132 °C, Anal. (C, H, N) C20H27N4O2Cl. H
NMR (CDCl3) l ppm: 0.75 (t, 6H, 2 CH3 butyl); 0.95
(m, 4H, CH3CH2CH2CH2ꢀ); 1.15 (m, 4H, CH3CH2-
CH2CH2ꢀ); 1.85 (m, 4H, CH3CH2CH2CH2ꢀ); 5.0 (s,
2H, NꢀCH2ꢀN); 5.35 (s, 2H, CꢁOꢀNꢀCH2ꢀN); 6.9 (m,
3H, Ar); 7.25 (m, 1H, Ar); 8.45 (s, 1H, ech D2O,
CꢁOꢀNHꢀCꢁO).
3.1.2.2. 6-Amino-5-,5-dipropylpyrimidine-2,4(3H,5H)-
dione (1b). Yield: 44%; m.p.\260 °C; Anal. (C, H, N)
C10H17N3O2. H NMR (DMSO-d6) l ppm: 0.8 (t, 6H,
two CH3 propyl); 1.05 (m, 4H, CH3CH2CH2ꢀ); 1.8 (m,
4H, CH3CH2CH2ꢀ); 7.9 (s, 1H, ech D2O,NH2); 8.35 (s,
1H,ech D2O, NH2); 10.6 (s, 1H, ech D2O,
CꢁOꢀNHꢀCꢁO).
1
1
3.1.2.3. 6-Amino-5-butyl-5-ethylpyrimidine-2,4(3H,5H)-
dione (1c). Yield: 47%; m.p.\260 °C; Anal. (C, H, N)
C10H17N3O2. H NMR (DMSO-d6) l ppm: 0.8 (t, 6H,
two CH3); 1.1 (m, 4H, CH3CH2CH2CH2ꢀ); 1.9 (m, 4H,
CH3CH2ꢀ and CH3CH2CH2CH2ꢀ); 8.0 (s,1H, ech D2O,
NH2); 8.46 (s, 1H, ech D2O, NH2); 10.1 (s, 1H, ech
D2O, CꢁOꢀNHꢀCꢁO).
3.1.3.4. 9,9-Dibutyl-6,8-dioxo-3(4-chlorophenyl)-2,3,4,5,
6,7,8,9-octahydropyrimido[3,4-a]-s-triazine (3d). Yield:
81%; m.p.: 142 °C, Anal. (C, H, N) C20H27N4O2Cl. H
NMR (CDCl3) l ppm: 0.75 (t, 6H, 2 CH3 butyl); 1.0
(m, 4H, CH3CH2CH2CH2ꢀ); 1.15 (m, 4H, CH3CH2-
CH2CH2ꢀ); 1.9 (m, 4H, CH3CH2CH2CH2ꢀ); 5.05 (s,
2H, NꢀCH2ꢀN); 5.45 (s, 2H, CꢁOꢀNꢀCH2ꢀN); 6.95 (d,
2H, Ar); 7.25 (d, 1H, Ar); 8.45 (s, 1H, ech D2O,
CꢁOꢀNHꢀCꢁO).
1
1
3.1.2.4. 6 - Amino - 5 - ethyl - 5 - propylpyrimidine - 2,4(3H,
5H)dione (1d). Yield: 41%; m.p.\260 °C; Anal. (C, H,
1
N) C9H15N3O2. H NMR (DMSO-d6) l ppm: 0.65 (t,
3H, CH3 propyl); 0.8 (t, 3H, CH3 ethyl); 1.05 (m, 2H,
CH3CH2CH2ꢀ); 1.9 (m, 4H, CH3CH2ꢀ and
CH3CH2CH2); 7.95 (s, 1H, ech D2O, NH2); 8.45 (s,
1H,ech D2O, NH2); 10.6 (s, 1H, ech D2O,
CꢁOꢀNHꢀCꢁO).
3.1.3.5. 9,9 - Dibutyl - 6,8 - dioxo - 3(3 - trifluoromethyl-
phenyl)-2,3,4,5,6,7,8,9 octahydropyrimido[3,4-a]-s-tria-
zine (3e). Yield: 15%; m.p.: 135 °C, Anal. (C, H, N)
1
C21H27N4O2F3. H NMR (CDCl3) l ppm: 0.7 (t, 6H, 2
CH3 butyl); 0.85 (m, 4H, CH3CH2CH2CH2ꢀ); 1.1 (m,
4H, CH3CH2CH2CH2ꢀ); 1.9 (m, 4H, CH3CH2-
CH2CH2ꢀ); 5.05 (s, 2H, NꢀCH2ꢀN); 5.4 (s, 2H,
CꢁOꢀNꢀCH2ꢀN); 7.15 (m, 3H, Ar); 7.4 (t, 1H, Ar);
9.15 (s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
3.1.3. Synthesis of 9,9-dialkyloctahydro-
pyrimido[3,4-a]-s-triazines
5,5-Dialkyl-6-aminopyrimidine-2,4(3H,5H)-dione
(0.015 mol) was added to formaldehyde (0.03 mol) and
variously substituted anilines (0.015 mol) in 10 ml
absolute ethanol. The mixture was stirred at reflux of
ethanol for 30 min. After cooling, the octahydropyri-
3.1.3.6. 9,9 - Dibutyl - 6,8 - dioxo - 3(4 - trifluoromethyl-
phenyl)-2,3,4,5,6,7,8,9-octahydropyrimido[3,4-a]-s-tria-
zine (3f). Yield: 2%; m.p.: 129 °C, Anal. (C, H, N)

114
A. Ghaib et al. / Il Farmaco 57 (2002) 109–116
1
1
C21H27N4O2F3. H NMR (CDCl3) l ppm: 0.65 (t, 6H,
two CH3 butyl); 0.85 (m, 4H, CH3CH2CH2CH2ꢀ); 1.05
(m, 4H, CH3CH2CH2CH2ꢀ); 1.8 (m, 4H, CH3CH2-
CH2CH2ꢀ); 5.05 (s, 2H, NꢀCH2ꢀN); 5.35 (s, 2H,
CꢁOꢀNꢀCH2ꢀN); 7.05 (d, 2H, Ar); 7.5 (d, 2H, Ar); 8.4
(s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
C19H23N4O2F3. H NMR (CDCl3) l ppm: 0.85 (t, 6H,
two CH3 propyl); 1.2 (m, 4H, CH3CH2CH2ꢀ); 1.9 (m,
4H, CH3CH2CH2ꢀ); 4.85 (s, 2H, NꢀCH2ꢀN); 5.1 (s, 2H,
CꢁOꢀNꢀCH2ꢀN); 7.1 (d, 1H, Ar); 7.25 (t,1H, Ar); 7.45
(t, 1H, Ar); 7.65 (d,1H, Ar); 8.1 (s, 1H, ech D2O,
CꢁOꢀNHꢀCꢁO).
3.1.3.7. 9,9-Dipropyl-6,8-dioxo-3-phenyl-2,3,4,5,6,7,8,9-
octahydropyrimido[3,4-a]-s-triazine (3g). Yield: 67%;
m.p.: 184 °C, Anal. (C, H, N) C18H24N4O2. H NMR
3.1.3.13. 9-Butyl-9-ethyl-6,8-dioxo-3-phenyl-2,3,4,5,6,7,
8,9-octahydropyrimido[3,4-a]-s-triazine (3m). Yield:
19%; m.p.: 168 °C, Anal. (C, H, N) C18H24N4O2. H
1
1
(CDCl3) l ppm: 0.75 (t, 6H, two CH3 propyl); 1.1 (m,
4H, CH3CH2CH2ꢀ); 1.85 (m, 4H, CH3CH2CH2ꢀ); 5.0
(s, 2H, NꢀCH2ꢀN); 5.35 (s, 2H, CꢁOꢀNꢀCH2ꢀN); 7.0
(t,2H, Ar); 7.3 (m., 2H, Ar); 8.75 (s, 1H, ech D2O,
CꢁOꢀNHꢀCꢁO).
NMR (CDCl3) l ppm: 0.7 (t, 6H, 2 CH3); 1.0 (m, 4H,
CH3CH2CH2CH2ꢀ); 2.0 (t, 4H, CH3CH2ꢀ and
CH3CH2CH2CH2ꢀ); 5.2 (s, 2H, NꢀCH2ꢀN); 5.6 (s, 2H,
CꢁOꢀNꢀCH2ꢀN); 7.4 (m, 5H, Ar); 8.4 (s, 1H, ech D2O,
CꢁOꢀNHꢀCꢁO).
3.1.3.8.
9,9-Dipropyl-6,8-dioxo-3-(2-chlorophenyl)-
3.1.3.14. 9-Butyl-9-ethyl-6,8-dioxo-3-(3-chlorophenyl)-
2,3,4,5,6,7,8,9-octahydropyrimido [3,4-a]-s-triazine (3n).
Yield: 51%; m.p.: 152 °C, Anal. (C, H, N)
2,3,4,5,6,7,8,9-octahydropyrimido[3,4-a]-s-triazine (3h).
Yield: 13%; m.p.: 215 °C, Anal. (C, H, N)
C18H23N4O2Cl. H NMR (CDCl3) l ppm: 0.85 (t, 6H,
1
1
C18H23N4O2Cl. H NMR (CDCl3) l ppm: 0.7 (t, 6H, 2
two CH3 propyl); 1.2 (m, 4H, CH3CH2CH2ꢀ); 1.95 (m,
4H, CH3CH2CH2ꢀ); 5.0 (s, 2H, NꢀCH2ꢀN); 5.3 (s, 2H,
CꢁOꢀNꢀCH2ꢀN); 7.1 (m, 2H, Ar); 7.2 (m, 1H, Ar);
7.45 (d, 1H, Ar); 8.45 (s, 1H, ech D2O,
CꢁOꢀNHꢀCꢁO).
CH3); 1.1 (m, 4H, CH3CH2CH2CH2ꢀ); 1.9 (t, 4H,
CH3CH2ꢀ and CH3CH2CH2CH2ꢀ); 5.1 (s, 2H,
NꢀCH2ꢀN); 5.4 (s, 2H, CꢁOꢀNꢀCH2ꢀN); 7.4 (m, 4H,
Ar); 8.4 (s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
3.1.3.15. 9-Butyl-9-ethyl-6,8-dioxo-3-(4-chlorophenyl)-
2,3,4,5,6,7,8,9-octahydropyrimido [3,4-a]-s-triazine (3o).
Yield: 24%; m.p.: 138 °C, Anal. (C, H, N)
3.1.3.9.
9,9-Dipropyl-6,8-dioxo-3-(3-chlorophenyl)-
2,3,4,5,6,7,8,9-octahydropyrimido[3,4-a]-s-triazine (3i).
Yield: 45%; m.p.: 156 °C, Anal. (C, H, N)
1
C18H23N4O2Cl. H NMR (CDCl3) l ppm: 0.7 (t, 6H, 2
1
C18H23N4O2Cl. H NMR (CDCl3) l ppm: 0.75 (t, 6H,
CH3); 0.95 (m, 2H,CH3CH2CH2CH2ꢀ); 1.1 (m,
2H,CH3CH2CH2CH2ꢀ); 1.9 (t, 4H, CH3CH2ꢀ and
CH3CH2CH2CH2ꢀ); 5.0 (s, 2H, NꢀCH2ꢀN); 5.3 (dd,
2H, CꢁOꢀNꢀCH2ꢀN); 6.9 (d, 2H, Ar); 7.2 (d, 2H, Ar);
9.35 (s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
two CH3 propyl); 1.05 (m, 4H, CH3CH2CH2ꢀ); 1.85 (m,
4H, CH3CH2CH2ꢀ); 4.95 (s, 2H, NꢀCH2ꢀN); 5.3 (s, 2H,
CꢁOꢀNꢀCH2ꢀN); 6.9 (m, 3H, Ar); 7.15 (m, 1H, Ar);
8.8 (s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
3.1.3.10.
9,9-Dipropyl-6,8-dioxo-3-(4-chlorophenyl)-
3.1.3.16. 9-Ethyl-9-propyl-6,8-dioxo-3-phenyl-2,3,4,5,6,
7,8,9-octahydropyrimido [3,4-a]-s-triazine (3p). Yield:
19%; m.p.: 164 °C, Anal. (C, H, N) C17H22N4O2. H
NMR (CDCl3) l ppm: 0.8 (t, 6H, 2 CH3); 1.0 (m,
2H,CH3CH2CH2ꢀ); 1.9 (t, 4H, CH3CH2ꢀ and
CH3CH2CH2ꢀ); 5.2 (s, 2H, NꢀCH2ꢀN); 5.6 (s, 2H,
CꢁOꢀNꢀCH2ꢀN); 7.3 (m, 5H, Ar); 9.4 (s, 1H, ech D2O,
CꢁOꢀNHꢀCꢁO).
2,3,4,5,6,7,8,9-octahydropyrimido[3,4-a]-s-triazine (3j).
Yield: 66%; m.p.: 169 °C, Anal. (C, H, N)
C18H23N4O2Cl. H NMR (CDCl3) l ppm: 0.75 (t, 6H,
two CH3 propyl); 1.05 (m, 4H, CH3CH2CH2ꢀ); 1.85 (m,
4H, CH3CH2CH2ꢀ); 4.95 (s, 2H, NꢀCH2ꢀN); 5.35 (s,
2H, CꢁOꢀNꢀCH2ꢀN); 6.9 (d, 2H, Ar); 7.2 (d, 2H, Ar);
8.6 (s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
1
1
3.1.3.11. 9,9-Dipropyl-6,8-dioxo-3-(2,4-dichlorophenyl)-
2,3,4,5,6,7,8,9-octahydropyrimido [3,4-a]-s-triazine (3k).
Yield: 3%; m.p.: 175 °C, Anal. (C, H, N)
3.1.3.17.
9-Ethyl-9-propyl-6,8-dioxo-3-(2-chloro-
phenyl)-2,3,4,5,6,7,8,9-octahydropyrimido [3,4-a]-s-tria-
zine (3q). Yield: 32%; m.p.: 175 °C, Anal. (C, H, N)
C17H21N4O2Cl. H NMR (CDCl3) l ppm: 0.8 (t, 6H, 2
1
1
C18H22N4O2Cl2. H NMR (CDCl3) l ppm: 0.8 (t, 6H,
two CH3 propyl); 1.1 (m, 4H, CH3CH2CH2ꢀ); 1.9 (m,
4H, CH3CH2CH2ꢀ); 4.9 (s, 2H, NꢀCH2ꢀN); 5.25 (s, 2H,
CꢁOꢀNꢀCH2ꢀN); 6.85 (d, 1H, Ar); 7.1 (dd,1H, Ar); 7.4
(d,1H, Ar); 8.05 (s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
CH3); 1.1 (m, 2H,CH3CH2CH2ꢀ); 1.9 (t, 4H, CH3CH2ꢀ
and CH3CH2CH2ꢀ); 4.95 (s, 2H, NꢀCH2ꢀN); 5.35 (s,
2H, CꢁOꢀNꢀCH2ꢀN); 7.0 (m, 1H, Ar); 7.2 (m, 2H, Ar);
7.4 (d, 1H, Ar); 9.25 (s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
3.1.3.12. 9,9-Dipropyl-6,8-dioxo-3-(2-trifluoromethyl-
phenyl)-2,3,4,5,6,7,8,9-octahydropyrimido[3,4-a]-s-tria-
zine (3l). Yield: 28%; m.p.: 176 °C, Anal. (C, H, N)
3.1.3.18.
9-Ethyl-9-propyl-6,8-dioxo-3-(3-chloro-
phenyl)-2,3,4,5,6,7,8,9-octahydropyrimido [3,4-a]-s-tria-
zine (3r). Yield: 56%; m.p.: 144 °C, Anal. (C, H, N)

A. Ghaib et al. / Il Farmaco 57 (2002) 109–116
115
C17H21N4O2Cl. 1H NMR (CDCl3) l ppm: 0.8 (m,
6H, 2 CH3); 1.0 (m, 2H,CH3CH2CH2ꢀ); 1.9 (m, 4H,
CH3CH2ꢀ and CH3CH2CH2ꢀ); 5.0 (s, 2H, NꢀCH2ꢀN);
5.3 (s, 2H, CꢁOꢀNꢀCH2ꢀN); 6.9 (m, 3H, Ar); 7.15 (m,
1H, Ar); 9.15 (s, 1H, ech D2O, CꢁOꢀNHꢀCꢁO).
NꢀCH2ꢀN); 5.25 (s, 2H, CꢁOꢀNꢀCH2ꢀN); 5.4 (m, 3H,
NꢀCH2ꢀNH, and 1H, ech D2O, NH); 6.65–7.35 (m,
8H, Ar).
3.1.3.24. 9 - Ethyl - 9 - propyl - 6,8 - dioxo - 3 - (4 - chloro-
phenyl)-7-[(4-chlorophenyl)
8,9-octahydropyrimido[3,4-a]-s-triazine (4f). Yield: 1%;
Anal. (C, H, N) C24H27N5O2Cl2. H NMR (CDCl3) l
ppm: 0.4 (t, 3H, CH3 propyl); 0.6 (m, 5H, CH3 propyl
and CH3CH2CH2); 1.7 (m, 4H, CH3CH2CH2ꢀ and
CH3CH2CH2ꢀ); 4.9 (s, 2H, NꢀCH2ꢀN); 5.25 (s, 2H,
CꢁOꢀNꢀCH2ꢀN); 5.6 (m, 3H, NꢀCH2ꢀNH, and 1H,
ech D2O, NH); 6.85 (m, 4H, Ar); 7.2 (m, 4H, Ar).
aminomethyl]-2,3,4,5,6,7,
3.1.3.19. 9,9-Dipropyl-6,8-dioxo-3-(3-trifluoromethyl-
phenyl)-7-[(3-trifluoromethyphenyl)
aminomethyl]-
1
2,3,4,5,6,7,8,9-octahydropyrimido[3,4-a]-s-triazine (4c).
Yield: 46%; m.p.: 176 °C, Anal. (C, H, N)
1
C27H29N5O2F6. H NMR (CDCl3) l ppm: 0.6 (t, 6H, 2
CH3 propyl); 0.75 (m, 4H, CH3CH2CH2ꢀ); 1.75 (m, 4H,
CH3CH2CH2ꢀ); 5.0 (m, 3H, NꢀCH2ꢀN and 1H, ech
D2O, NH); 5.35 (s, 4H, NꢀCH2ꢀNH and
CꢁOꢀNꢀCH2ꢀN); 6.95–7.35 (m, 8H, Ar).
3.2. Biology
3.1.3.20. 9,9-Dipropyl-6,8-dioxo-3-(2-chlorophenyl)-7-
[(2 - chlorophenyl)aminomethyl] - 2,3,4,5,6,7,8,9 - octa-
hydropyrimido[3,4-a]-s-triazine (4a). Yield: 47%; m.p.:
127 °C, Anal. (C, H, N) C25H29N5O2Cl2. 1H NMR
(CDCl3) l ppm: 0.7 (t, 6H, two CH3 propyl); 0.85–1.05
(m, 4H, CH3CH2CH2ꢀ); 1.9 (m, 4H, CH3CH2CH2ꢀ);
4.9 (s, 2H, NꢀCH2ꢀN); 5.25 (s, 2H, CꢁOꢀNꢀCH2ꢀN);
5.4 (m, 3H, NꢀCH2ꢀNH and 1H, ech D2O, NH);
6.7–6.9 (m, 2H, Ar); 7.05 (m, 4H, Ar); 7.2–7.4 (m, 2H,
Ar).
All compounds (except 4c, 4e and 4f) have been
submitted to an automated pharmatical screening.
Acknowledgements
We thank Janssen-Cilag laboratory for the auto-
mated pharmatical screening.
3.1.3.21. 9,9-Dipropyl-6,8-dioxo-3-(4-trifluoromethyl-
References
phenyl)-7-[(4-trifluoromethyphenyl)
aminomethyl]-
2,3,4,5,6,7,8,9-octahydropyrimido[3,4-a]-s-triazine (4d).
Yield: 10%; m.p.: 182 °C, Anal. (C, H, N)
C27H29N5O2F6. H NMR (CDCl3) l ppm: 0.6 (t, 6H,
two CH3 propyl); 0.75 (m, 4H, CH3CH2CH2ꢀ); 1.75 (m,
4H, CH3CH2CH2ꢀ); 5.0 (s, 2H, NꢀCH2ꢀN); 5.05 (m,
1H, ech D2O, NH); 5.35 (s, 4H, NꢀCH2ꢀNH and
CꢁOꢀNꢀCH2ꢀN); 6.8–7.0 (dd, 4H, Ar); 7.4–7.5 (dd,
4H, Ar).
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1
3.1.3.22. 9 - Butyl - 9 - ethyl - 6,8 - dioxo - 3 - (2,4 - dichloro-
phenyl)-7-[(2,4-dichlorophenyl)
aminomethyl]-2,3,4,5,
6,7,8,9-octahydropyrimido[3,4-a]-s-triazine (4e). Yield:
1
13%; m.p.: 122 °C, Anal. (C, H, N) C25H27N5O2Cl4. H
NMR (CDCl3) l ppm: 0.75 (dt, 6H, CH3); 0.85 (m, 2H,
CH3CH2CH2CH2); 1.1 (m, 2H, CH3CH2CH2CH2ꢀ); 1.9
(m, 4H, CH3CH2CH2CH2ꢀ and CH3CH2ꢀ); 4.85 (s, 2H,
NꢀCH2ꢀN); 5.25 (s, 2H, CꢁOꢀNꢀCH2ꢀN); 5.4 (m, 3H,
NꢀCH2ꢀNH and 1H, ech D2O, NH); 6.8–7.4 (m, 6H,
Ar).
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aminomethyl]-2,3,4,5,6,7,
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15%; m.p.: 104 °C, Anal. (C, H, N) C24H27N5O2Cl2. H
NMR (CDCl3) l ppm: 0.6 (t, 3H, CH3 propyl); 0.7 (t,
3H, CH3 ethyl); 0.9 (m, 2H, CH3CH2CH2ꢀ); 1.85 (m,
4H, CH3CH2CH2ꢀ and CH3CH2ꢀ); 4.9 (s, 2H,
1

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