Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT1A and 5-HT2A receptors

Article abstract of DOI:10.1016/S0014-827X(02)01274-0

Synthesis applied to prepare compounds 5-15 and 17-22 discussed in this paper has been presented in Scheme 1. Multi-stage preparation techniques were used to obtain 4-aryl-hexahydro 1-4 and (R,R) and (S,S) 4-aryl-octahydropyrido[1,2-c]pyrimidine-1,3-dione

Full text of DOI:10.1016/S0014-827X(02)01274-0

Il Farmaco 57 (2002) 959ꢁ971
/
www.elsevier.com/locate/farmac
Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine
derivatives with an arylpiperazine moiety as ligands for 5-HT1A and
5-HT2A receptors
Franciszek Herold a,ꢀ, Jerzy Kleps a, Irena Wolska b, Gabriel Nowak c,d
a Department of Drug Technology, Faculty of Pharmacy, The Medical University of Warsaw, Banacha 1, 02-970 Warsaw, Poland
b Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan´, Poland
c Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krako´w, Poland
˛
d Laboratory of Radioligand Research, Collegium Medicum, Jagiellonian University, Medyczna 9, 30-688 Krako´w, Poland
Received 5 June 2001; accepted 3 March 2002
Abstract
Synthesis applied to prepare compounds 5ꢁ
preparation techniques were used to obtain 4-aryl-hexahydro 1ꢁ
1,3-dione (16) derivatives, being the starting compounds for further modification. N-Alkylation of the imide group in compounds
1ꢁ4 and 16 followed, using 1,4-dibromobutane to yield monobromobutyl derivatives 5ꢁ8 and 17. Subsequent condensation of those
compounds with appropriate 1-aryl or 1-heteroarylpiperazine led to the final hexahydro- 9ꢁ15 and octahydro- 18ꢁ22 pyrido[1,2-
/
15 and 17ꢁ/22 discussed in this paper has been presented in Scheme 1. Multi-stage
/4 and (R,R) and (S,S) 4-aryl-octahydropyrido[1,2-c]pyrimidine-
/
/
/
/
c]pyrimidine-1,3-dione derivatives. The final products were subjected to screening test to elucidate the affinity to 5-HT1A and 5-
HT2A receptors.
´
# 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety; Ligands for 5-HT1A and 5-HT2A receptors
1. Introduction
Serotonin exerts its pharmacological effects through
activation of membrane receptors located in different
structures of the brain. The 5-HT receptors have been
Serotonin (5-HT, 5-hydroxytryptamine) is one of the
most important and universal neurotrasmitters in verte-
brates. It is implicated in numerous physiological and
psychological functions that vary from cardiovascular
and respiratory activity and platelet aggregation to
various mood states and neuroendocrine processes.
Furthermore, serotoninergic dysfunction is reported to
be involved in several pathophysiological processes.
Numerous studies have shown that aberrant central 5-
HT neurotransmission is associated with several psy-
chiatric disorders, such as depression, anxiety, beha-
divided into seven main classes (5-HT1ꢁ5-HT7) on the
/
basis of the receptor binding profiles, common second
messenger coupling, amino acid sequences and the
functional activity of ligands. Each of these classes has
been subdivided further into several subtypes. The 5-
HT1 receptor class consists of five different subtypes,
termed: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F
[9ꢁ14].
/
5-HT1A receptors have been of particular interest
because they appear to be involved in the regulation of
emotional and affective behavior. Both clinical and
preclinical investigations into the 5-HT1A receptor
confirmed its role in a variety of psychiatric disorders
vioral disturbances [1ꢁ8]. Taking into account highly
/
complex pharmacology of the 5-HT system, one must
consider the widespread distribution of the 5-HT
innervation and various subpopulations of 5-HT.
including anxiety and depression [15ꢁ19].
/
Several groups of ligands for the 5-HT1A receptor
have been reported in the literature. Arylpiperazines
(e.g. buspirone, ipsapirone, gepirone) are one of such
ligand groups that has been shown to have agonist
ꢀ Corresponding author
´
0014-827X/02/$ - see front matter # 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S 0 0 1 4 - 8 2 7 X ( 0 2 ) 0 1 2 7 4 - 0

960
F. Herold et al. / Il Farmaco 57 (2002) 959ꢁ971
/
The arylpiperazines are a relatively new class of
psychotherapeutic drugs which posses high affinity for
the 5-HT1A receptor site, however with low selectivity
[22,23].
Buspirone along with other structurally related pyr-
imidinylpiperazine compounds, such as ipsapirone and
gepirone, binds with particular affinity to the 5-HT1A
receptors, and also displays pronounced affinity to other
receptor types. Buspirone as the first drug of this class
has reached wide acceptance, and is used in the
treatment of psychotic disorders accompanied by anxi-
ety. Nevertheless, a need for agents with even greater
selectivity still exist [19].
The aim of the present study was to synthesize the
new analogues of buspirone with hypothetically higher
affinity and selectivity to 5-HT1A receptors. In this study
buspirone was the key structure to which certain
modifications were made, namely by introducing the
pyrido[1,2-c]pyrimidine-1,3-dione residue with different
substituents into the imide part. Other modifications
were made by introducing different substituents at the
piperazine ring nitrogen. Thus, we designed and synthe-
sized a number of new arylpiperazinylalkyl derivatives
9ꢁ
/
15 and 18ꢁ22. These derivatives contain a fragment
/
of hexahydro- and octahydro-pyrido[1,2-c]pyrimidine-
1,3-dione ring system in which the imide group is
incorporated (Fig. 2). The obtained compounds were
tested for their affinity towards 5-HT1A, 5-HT2A and a1
adrenergic receptors, using radioligand binding assay.
Fig. 1.
2. Chemistry
properties at 5-HT1A receptors (Fig. 1). These com-
pounds are partial agonists with high affinity for the 5-
HT1A binding sites. All arylpiperazine molecules contain
the arylpiperazinyl group attached to the imide or amide
The compounds described in this paper (5ꢁ
17ꢁ22) were obtained as shown in Scheme 1.The
substrate for the synthesis were 4-aryl-hexahydro- 1ꢁ
/
15 and
/
/
4
moiety [20ꢁ23].
/
and (R,R) and (S,S) 4-aryl-octahydropyrido[1,2-c]pyr-
imidine-1,3-dione (16) derivatives, obtained as final
products of the several stages synthesis [39,40].
Analysis of 5-HT1A receptor ligand structures sug-
gests that affinity for the mentioned receptor depends on
the presence of two characteristic structural elements,
namely: arylpiperazinylalkyl and the imide or amide
Then the imide group of the above-described com-
4 and 16 was N-alkylated by the 1,4-
pounds 1ꢁ
/
[24ꢁ32]. However, opinions of authors on this subject
/
matter differ.
The role of arylpiperazinyl substituent is probably
connected with the ligand activity, but the precise role of
the imide group is still not fully established. According
to the latest literature, high affinity of the ligand for the
5-HT1A receptor is connected with a high lipophilicity of
the imide group and a lesser lipophilicity to the a
adrenergic receptor [25]. Other authors suggest an
important role of the steric factor [31ꢁ33]. Moreover,
/
numerous publications describe relationship between the
moiety containing the imide group and stability of the 5-
HT1A receptorꢁ
/
ligand complex, through a pꢁp dipole
/
interaction [34ꢁ38].
/
Fig. 2.

F. Herold et al. / Il Farmaco 57 (2002) 959ꢁ
/971
961
Scheme 1. Reagents: (i) Br(CH2)4Br, K2CO3, acetone, D; (ii) 1-aryl or heteroarylpiperazine, K2CO3, acetonitrile, D.
dibromobutane, yielding the monobromobutyl deriva-
tives 5ꢁ8 and 17.
The final products in the series of hexahydro- 9ꢁ
and octahydro- 18ꢁ22 derivatives were obtained by the
condensation of the appropriate 1-aryl or 1-heteroar-
ylpiperazine with the above-described bromobutyl deri-
ring adopts a chair conformation with the nitrogens N19
and N16 above and below the plane formed by
piperazine ring carbons. The piperidine ring adopts a
boat conformation; this ring is fused with the almost
planar uracil moiety.
/
/
15
/
vatives 5ꢁ8 and 17.
/
The obtained bases, after purification, were trans-
formed into the hydrochloride and were submitted to
primary screening tests for the affinity to 5-HT1A, 5-
HT2A and a1 receptors.
3. Pharmacology
The selected compounds 10ꢁ
/
15 and 18ꢁ21 were tested
/
All new compounds 5ꢁ
/
15 and 17ꢁ22 were identified
/
for their potency to inhibit binding of labelled ligands to
serotonin 5-HT1A and 5-HT2A receptors and to a1
adrenoceptors using in vitro radioligand binding assays
in rat cerebral cortical tissue. The following labelled
and proven by the IR and elemental analysis (Table 1),
1H (Table 2) and 13C NMR (Table 3).
Moreover, COSY, HETCOR, HMBC and GHMQC
ligands were used: 5-HT1A receptors*
DPAT; 5-HT2A receptors*
[3H]Ketanserin; a1 re-
ceptors*
[3H]Prazosin. Data were analyzed using itera-
/
[3H]8ꢀ
/
OHꢀ
/
experiments of the starting bromoderivatives 5ꢁ
/
8, 17
and the final targets 9ꢁ15 and 18ꢁ22 were carried out in
/
/
/
order to assign all the protons and carbons of these new
structures as well as to define the configuration at C4,
C4a chiral centers to constitute (R,R) and (S,S) pair for
/
tive curve fitting routines (GraphPAD/Prism, v. 3.0-San
Diego, CA, USA) to obtain IC50 values (i.e. the
concentration of the compound required to occupy
50% of receptors). These values were used to calculate
17ꢁ22 [40]. XRD experiments were carried out for
/
compound 9. The ORTEP view of the molecule is shown
in Fig. 3. The phenyl ring is planar and the piperazine
inhibition constants (Ki) according to the ChengꢁPrus-
/

962
F. Herold et al. / Il Farmaco 57 (2002) 959ꢁ971
/
Table 1
Physical, analytical and IR spectroscopic data of compounds 5ꢁ
/
15 and 17ꢁ
/22
No.
R
Ar
Yield (%) Base/hydrochloride m.p. (8C)
Formula
Analysis Calc./Found IR (CꢁO)
C
H
N
5
H
ꢁ
/
79.8
72.3
55.9
43.4
91.0
60.0
93.0
74.2
87.5
58.3
50.6
66.6
53.5
56.2
106ꢁ
100.0ꢁ
85.5ꢁ86.5
115ꢁ118
/
107
C18H21BrN2O2
C18H20BrFN2O2
C18H20BrClN2O2
C19H23BrN2O3
C29H36N4O2
57.29 5.61 7.42
57.32 5.57 7.34
54.68 5.10 7.08
54.72 5.02 7.12
52.50 4.90 6.80
52.45 4.80 6.87
56.01 5.69 6.87
56.19 5.69 6.89
1679, 1628
1692, 1645
1694, 1643
1689, 1659
6
F
ꢁ/
/
100.5
7
Cl
OCH3
H
ꢁ/
/
8
ꢁ/
/
9
2-toyl
126.5ꢁ
/
127
243.8
73.70 7.68 11.85 1670, 1610
73.62 7.68 11.73
243.5ꢁ
/
10
11
12
H
2-pyrimidinyl
2-pyridyl
120-121
241.2-242
118-119
C
C
26H32N6O2+2HCl
58.54 6.42 15.75 1690. 1640
58.61 6.34 15.70
H
27H33N5O2+2HCl+H2O
58.91 6.77 12.72 1680, 1620
59.01 6.74 12.81
219-219.5
140-141
F
2-pyrimidinyl
2-pyrimidinyl
2-pyridyl
C26H31FN6O2+2HCl
26H31ClN6O2+2HCl
56.63 6.03 15.23 1685, 1630
56.60 6.10 15.14
246.5-247
161.7-162.0
234.4-235.9
139.3-140.0
253.6-255.3
106-110
13 Cl
14 Cl
C
54.99 5.86 14.79 1693, 1637
55.07 5.98 14.80
C27H32ClN5O2+2HCl+0.5H2O
C27H34N6O3+2HCl+1.25H2O
C18H23BrN2O2
56.21 6.12 12.13 1690, 1637
56.28 5.91 12.26
15 OCH3 2-pyrimidinyl
55.39 6.54 14.35 1691, 1636
55.60 6.45 14.40
248.4-249
83.9-85.5
17
18
19
20
21
22
H
H
H
H
H
H
ꢁ/
56.98 6.11 7.38
56.89 6.03 7.41
1710, 1662
2-pyridyl
128.4-130.4
226.4-228.8
147.8-149.2
172.1-175.9
131.0-131.7
158.0-162.5
115.0-118.4
105.7-108.5
123.1-124.1
128.5-131.2
C
27H35N5O2+2HCl+0.25H2O
C26H34N6O2+2HCl+0.5H2O
28H35ClN4O2+HCl+H2O
C28H35FN4O2+2HCl+3H2O
29H38N4O2+2HCl+2.25H2O
60.22 6.93 12.99 1697, 1667
60.12 6.62 12.99
2-pyrimidinyl
57.35 6.85 15.43 1698, 1668
57.42 6.78 15.43
2-chlorophenyl 50.2
2-fluorophenyl 92.0
C
61.20 6.97 10.19 1700, 1660
61.52 6.88 10.22
55.54 7.16 9.25
55.42 7.20 9.19
59.18 7.71 9.51
59.25 7.29 9.47
1700, 1661
2-tolyl
60.0
C
1700, 1662
off formula [41]. The obtained Ki values are presented in
Table 4.
erally known, those receptors play a significant role in
regulating behavioral processes. Being an agonist of the
5-HT1A receptors, buspirone inhibits central activity
related with the 5-HT area of the brain. Its anxiolythic
action (without anticonvulsive and muscle relaxant
activity) extremely valuable and moreover, does not
lead to distinct drug dependence, does not impair
memory and, may also be used in treatment of alcohol
dependence due to its ability to inhibit the ‘augmenta-
tion’ system. In turn, undesired effects are quite
infrequent and have minor intensities. Thus, all these
features of the drug compared with classic anxiolythics
4. Results and discussion
The search for new substances based on buspirone as
the model drug seems fully justified in light of its
interesting pharmacological properties. Buspirone is
one of the ‘new’ anxiolythic drugs, unaffecting the
GABAꢁ
/
benzodiazepine receptors, whose action is re-
lated with 5-HT subgroup 5-HT1A receptors. As gen-

Table 2
1H NMR chemical shifts (d, ppm, deuteriochloroform) and coupling constants (Hz) of hexahydropyrido[1,2-c]pyrimidine derivatives: 5ꢁ
22 (B)
/
15 (A) and octahydropyrido[1,2-c]pyrimidine derivatives 17ꢁ
/
a
Comp. C-5H2
C-6H2
C-7H2
C-8H2
C-1xH2
C-2xH2
C-3xH2
C-4xH2
Ca H2
Cb H2
Aromatic rings
5
2.53 (t, 2H), 1.69 (q, 2H),
3Jꢂ6.5 3Jꢂ6.5
1.91 (m, 3.93 (t, 2H), 4.03 (t,
4H)ꢃC- 3Jꢂ6.5
1.84 (m, 2H)
3.44 (t, 2H),
3Jꢂ7.0
7.39 (m, 2H, C-2?H, C-
6?H), 7.32 (m, 1H, C-
4?H), 7.19 (m, C-3?H,
C-5?H), 3Jo ꢂ6.5,
Jm ꢂ1.0
2H),
3Jꢂ7.0
2xH2
6
7
8
2.50 (m, 2H), 1.72 (m, 2H),
2Jꢂ17.5,
1.93 (m, 3.94 (m,
4H)ꢃC- 2H),
4.04 (t,
2H),
1.84 (m, 2H)
1.85 (m, 2H)
1.84 (m, 2H)
3.44 (t, 2H),
3Jꢂ6.5
7.31ꢁ
6?H), 7.16ꢁ
/
7.37 (m, 1H, C-
7.25 (m,
2Jꢂ13.0,
/
3Jꢂ6.0
3Jꢂ6.5
2xH2
2Jꢂ14.0,
3Jꢂ6.0
1.92 (m, 3.93 (m,
3Jꢂ6.5
2H, C-4?H, C-5?H),
7.12 (m, 1H, C-3?H)
7.46 (m, 1H, C-6?H),
7.30 (m, 2H, C-4?H, C-
5?H), 7.20 (m, 1H, C-
3?H)
7.33 (m, 1H, C-4?H),
7.11 (m, 1H, C-6?H),
6.99 (m, 1H, C-5?H),
6.95 (d, 1H, C-3?H,
Jo ꢂ8.5), 3.78 (s, 3H,
OCH3)
2.40 (m, 2H), 1.71 (m, 2H),
2Jꢂ17.0,
4.04 (m,
2H),
3Jꢂ7.5
3.44 (m, 2H),
3Jꢂ6.5
2Jꢂ13.5,
4H)ꢃC- 2H),
3Jꢂ6.5
3Jꢂ6.5
2xH2
2Jꢂ14.0,
3Jꢂ6.0
1.92 (m, 3.92 (m,
2.43 (t, 2H), 1.69 (m, 2H),
3Jꢂ7.0
4.03 (t,
2H),
3Jꢂ7.0
3.44 (m, 2H),
3Jꢂ6.5
2Jꢂ13.5,
4H)ꢃC- 2H),
3Jꢂ7.0
2xH2
2Jꢂ14.0,
3Jꢂ7.0
9
2.53 (t, 2H), 1.69 (q, 2H)
3Jꢂ6.5
1.92 (q,
2H),
3Jꢂ7.0
3.94 (t, 2H) 4.04 (t,
2H),
1.74 (m, 2H)
1.61 (m, 2H)
2.46 (t, 2H),
3Jꢂ7.5
2.61 (bs, 4H) 2.94 (pt,
4H),
7.39 (m, 2H, C-2?H, C-
6?H), 7.32 (m, 1H, C-
4?H), 7.19 (m, 2H, C-
3?H, C-5?H), 7.15 (m,
2H, C-3ƒH, C-5ƒH),
7.02 (pd, 1H, C-4ƒH),
6.96 (m, 1H, C-6ƒH),
2.29 (s, 3H, CH3)
3Jꢂ7.5
3Jꢂ4.5
10
2.41 (t, 2H), 1.70 (q, 2H),
3Jꢂ7.5
1.92 (q,
2H),
3.94 (t, 2H), 4.04 (t,
3Jꢂ6.5
1.73 (q, 2H),
3Jꢂ7.0
1.60 (q, 2H),
3Jꢂ7.0
2.53 (t, 2H),
3Jꢂ5.0
2.49 (t, 4H), 3.82 (t,
3Jꢂ5.0
8.30 (d, 2H, C-4ƒH, C-
6ƒH, 3Jo ꢂ5.0), 7.40 (t,
2H, C-3?H, C-5?H,
3Jo ꢂ7.5), 7.33 (tt, 1H,
C-4?H, 3Jo ꢂ7.5,
3Jꢂ7.0
2H),
3Jꢂ7.0
4H),
3Jꢂ5.0
3Jꢂ6.5
4Jm ꢂ1.0), 7.19 (m,
2H, C-2?H, C-6?H,
3Jo ꢂ7.0), 6.47 (t, 1H,
C-5ƒH, 3Jo ꢂ4.5)
11
2.54 (m,
6H)ꢃCa H2
1.69 (q, 2H)
1.92 (q,
2H),
3Jꢂ6.5
3.94 (t, 2H), 4.04 (t,
3Jꢂ6.5
1.73 (m, 2H)
1.61 (m, 2H)
2.42 (pt, 2H)
2.54 (m,
3.53 (pt,
8.18 (m, 1H, C-6ƒH),
7.46 (m, 1H, C-4ƒH),
7.39 (m, 2H, C-3?H, C-
5?H), 7.32 (m, 1H, C-
4?H), 7.19 (m, 2H, C-
2?H, C-6?H), 6.61 (m,
2H, C-3ƒH, C-5ƒH)
2H),
3Jꢂ7.5
6H)ꢃC-5H2 4H)

Table 2 (Continued)
Comp. C-5H2
C-6H2
1.67ꢁ1.82 (m,
C-7H2
C-8H2
C-1xH2
C-2xH2
C-3xH2
C-4xH2
2.38ꢁ2.60 (m,
8H)ꢃC-5H2ꢃCa
H2
Ca H2
2.38ꢁ2.60
Cb H2
Aromatic rings
12
2.38ꢁ
/
2.60
(m, 8H)ꢃC- 4H)ꢃC-2xH2
4xH2ꢃCa H2
/
1.94 (q,
2H),
3Jꢂ6.5
3.94 (m,
2H),
4.04 (t,
2H),
3Jꢂ7.5
1.67ꢁ/1.82 (m,
1.62 (m, 2H)
/
/
3.84 (bs,
8.29 (d, 2H, C-4ƒH, C-
6ƒH, 3Jo ꢂ4.5), 7.34
(m, 1H, C-5ƒH), 7.20
(m, 2H, C-4?H, C-6?H),
7.11 (pt, 1H, C-3?H),
6.47 (pt, 1H, C-5?H)
8.29 (d, 2H, C-4ƒH, C-
6ƒH, 3Jo ꢂ4.5), 7.46
(m, 1H, C-3?H), 7.30
(m, 2H, C-4?H, C-5?H),
7.20 (m, 1H, C-6?H),
6.46 (t, 1H, C-5ƒH,
3Jo ꢂ5.0)
4H)ꢃC-6H2
(m, 8H)ꢃC- 4H)
5H2ꢃC-
2Jꢂ14.0,
3Jꢂ6.5
4xH2
13
2.34ꢁ
/
2.47
1.66ꢁ
/
1.79 (m,
1.93 (q,
2H),
3Jꢂ6.0
3.93 (m,
2H),
4.04 (t,
2H),
3Jꢂ7.5
1.66ꢁ/1.79 (m,
1.61 (q, 2H),
3Jꢂ7.0
2.34ꢁ/2.47 (m,
2.50 (pt, 4H) 3.83 (pt,
4H)
(m, 4H)ꢃC- 4H)ꢃC-2xH2
4H)ꢃC-6H2
4H)ꢃC-5H2
4xH2
2Jꢂ14.0,
3Jꢂ6.0
14
15
2.34ꢁ
/
2.46
1.64ꢁ
/
1.79 (m,
1.93 (m, 3.93 (m,
2H),
4.04 (t,
2H),
1.64ꢁ
4H)ꢃC-6H2
/
1.79 (m,
1.60 (m, 2H)
2.34ꢁ
4H)ꢃC-5H2
/
2.46 (m,
2.54 (t, 4H), 3.53 (t,
3Jꢂ5.0
8.18 (m, 1H, C-6ƒH),
7.46 (m, 2H, C-4ƒH, C-
3?H), 7.30 (m, 2H, C-
4?H, C-5?H), 7.20 (m,
1H, C-6?H), 6.61 (m,
2H, C-3ƒH, C-5ƒH)
8.29 (m, 2H, C-4ƒH, C-
6ƒH), 7.32 (m, 1H, C-
4?H), 7.10 (d, 1H, C-
6?H), 6.99 (t, 1H, C-
5?H), 6.64 (dd, 1H, C-
3?H, 3Jo ꢂ8.5), 6.46 (t,
1H, C-5ƒH, 3Jo ꢂ4.5),
3.77 (s, 3H, OCH3)
(m, 4H)ꢃC- 4H)ꢃC-2xH2
2H)
4H),
3Jꢂ5.0
4xH2
2Jꢂ14.5,
3Jꢂ7.5
3Jꢂ6.0
2.42 (m,
4H)ꢃC-4xH2 4H)ꢃC-2xH2
1.63ꢁ
/
1.78 (m,
1.91 (q,
2H),
3Jꢂ6.5
3.92 (m,
2H),
2Jꢂ13.5,
3Jꢂ6.7,
3Jꢂ6.5
4.03 (t,
2H),
3Jꢂ7.5
1.63ꢁ
/
1.78 (m,
1.60 (m, 2H)
2.42 (m, 4H)ꢃC- 2.49 (t, 4H), 3.82 (t,
5H2
4H)ꢃC-6H2
3Jꢂ5.0
4H)
C-4H
C-4aH
C-5Ha ,
C-6Ha
C-5He , C- C-6He /C- C-7Ha , C-3xH2
C-8Ha
C-8He
C-1xH2/C-
4xH2
Ca H2/Cb Aromatic rings
H2
2xH2
7He
b
c
d
17
18
3.57 (d, 1H), 3.45 (m, 1H)
,
1.35 (m, 1.64 (m,
2H) 21H)
1.84 (m,
3H)ꢃC-
1.52 (m, 1H),
2J7a ꢁ 7e ꢂ13.0,
2.75 (m, 1H)
,
4.44 (m, 1H)
,
3.87 (m,
2H) e/3.39
(t, 2H),
7.28ꢁ7.38 (m, 3H, C-
/
3J4 ꢁ 4aꢂ7.5
3J4a ꢁ 5a ꢂ11.0,
3J4a ꢁ 4ꢂ7.5,
3J4a ꢁ 5e ꢂ3.0
2J8a ꢁ 8e ꢂ13.0,
3J8a ꢁ 7a ꢂ13.0,
3J8a ꢁ 7e ꢂ3.0
2J8e ꢁ 8a ꢂ13.0,
3J8e ꢁ 7a ꢂ4.5,
3J8e ꢁ 7e ꢂ2.5,
3J8e ꢁ 6a ꢂ2.5
3?H, C-4?H, C-5?H),
7.20 (m, 2H, C-2?H, C-
6?H, 3Jo ꢂ7.0,
3xH2/1.73 3J7a ꢁ 8a ꢂ13.0,
(m,
3H)ꢃC-
2xH2
3J7a ꢁ 6a ꢂ13.0,
3J7a ꢁ 8e ꢂ4.0,
3J7a ꢁ 6e ꢂ4.0
1.54 (m, 3H)
3Jꢂ6.5
4Jm ꢂ1.5)
b
,
c
,
d
,
3.57 (d, 1H), 3.45 (m, 1H)
3Jꢂ8.0
1.40 (m, 1.62 (m,
2H) 3H)
1.84 (m,
1H)/1.75
(m, 1H)
2.75 (m, 1H)
4.45 (m, 1H)
2J8e ꢁ 8a ꢂ13.5,
3J8e ꢁ 7a ꢂ4.0,
3J8e ꢁ 7e ꢂ2.5,
4J8e ꢁ 6a ꢂ2.5
3.88 (m,
2.54 (bs,
4H)/3.55
(bs, 4H)
8.18 (m, 1H, C-6ƒH),
7.46 (m, 1H, C-4ƒH),
3J4a ꢁ 5a ꢂ11.0,
2J8a ꢁ 8e ꢂ13.0,
3J8a ꢁ 7a ꢂ13.0,
3J8a ꢁ 7e ꢂ3.0
2H)
e
,
3J4a ꢁ 4ꢂ8.0,
3J4a ꢁ 5e ꢂ3.0
2Jꢂ11.5,
3Jꢂ3.0/2.42
(bs, 2H)
7.28ꢁ7.39 (m, 3H, C-
/
3?H, C-4?H, C-5?H),
7.21 (m, 2H, C-2?H, C-
6?H), 6.62 (m, 2H, C-
3ƒH, C-5ƒH)

Table 2 (Continued)
C-4H
C-4aH
C-5Ha ,
C-6Ha
C-5He , C- C-6He /C- C-7Ha , C-3xH2
C-8Ha
C-8He
C-1xH2/C-
4xH2
Ca H2/Cb Aromatic rings
H2
2xH2
7He
b
c
d
19
3.57 (d, 1H), 3.44 (m, 1H)
,
1.35 (m, 1.62 (m,
2H) 3H)
1.84 (m,
1H)/1.75
(m, 1H)
1.52 (m, 3H)
2.74 (m, 1H)
,
4.44 (m, 1H)
,
3.88 (m,
2H)
2.46 (t,
4H),
8.29 (d, 2H, C-4ƒH, C-
3Jꢂ8.0
3J4a ꢁ 5a ꢂ11.0,
3J4a ꢁ 4ꢂ8.0,
3J4a ꢁ 5e ꢂ3.0
2J8a ꢁ 8e ꢂ13.0,
3J8a ꢁ 7a ꢂ13.0,
3J8a ꢁ 7e ꢂ3.0
2J8e ꢁ 8a ꢂ13.0,
3J8e ꢁ 7a ꢂ4.0,
3J8e ꢁ 7e ꢂ2.0,
4J8e ꢁ 6a ꢂ2.0
,
6ƒH, 3Jꢂ4.5), 7.35 (t,
2H, C-3?H, C-5?H),
7.31 (t, 1H, C-4?H),
7.20 (m, 2H, C-2?H, C-
6?H), 6.46 (t, 1H, C-
5ƒH, 3Jꢂ4.5)
e
2Jꢂ12.0,
3Jꢂ5.0/
3Jꢂ2.5/2.38 3.81 (t,
(t, 2H),
3Jꢂ7.5
4H),
3Jꢂ5.0
b
,
c
,
d
,
20
3.58 (d, 1H), 3.45 (m, 1H)
3Jꢂ8.0
1.35 (m, 1.63 (m,
2H) 3H)
1.84 (m,
1H)/1.75
(m, 1H)
1.54 (m, 3H)
2.75 (m, 1H)
4.45 (m, 1H)
2J8e ꢁ 8a ꢂ13.0,
3J8e ꢁ 7a ꢂ4.0,
3J8e ꢁ 7e ꢂ2.0,
4J8e ꢁ 6a ꢂ2.0
3.88 (m,
2.64 (bs,
4H)/3.09
(bs, 4H)
7.28ꢁ7.38 (m, 4H, C-
/
3J4a ꢁ 5a ꢂ11.0,
2J8a ꢁ 8e ꢂ13.0,
3J8a ꢁ 7a ꢂ13.0,
3J8a ꢁ 7e ꢂ2.5
2H)
3?H, C-4?H, C-5?H, C-
2?H), 7.21 (m, 3H, C-
3ƒH, C-5ƒ, C-6?H), 7.04
(dd, 1H, C-6ƒH), 6.96
(td, 1H, C-4ƒH,
e
,
3J4a ꢁ 4ꢂ8.0,
3J4a ꢁ 5e ꢂ3.0
2Jꢂ11.5,
3Jꢂ3.0/2.46
(t, 2H),
3Jꢂ7.0
3Jo ꢂ7.8, 4Jm ꢂ2.0)
7.33 (m, 3H, C-3?H, C-
4?H, C-5?H), 7.21 (m,
2H, C-2?H, C-6?H),
b
,
c
,
d
,
21
22
3.57 (d, 1H), 3.45 (m, 1H)
3Jꢂ8.0
1.35 (m, 1.62 (m,
2H) 3H)
1.84 (m,
1H)/1.75
(m, 1H)
1.53 (m, 3H)
2.75 (m, 1H)
4.45 (m, 1H)
2J8e ꢁ 8a ꢂ13.0,
3J8e ꢁ 7a ꢂ4.5,
3J8e ꢁ 7e ꢂ2.0,
4J8e ꢁ 6a ꢂ2.0
3.88 (m,
2.62 (bs,
4H)/3.11
(bs, 4H)
3J4a ꢁ 5a ꢂ11.0,
3J4a ꢁ 4ꢂ8.0,
3J4a ꢁ 5e ꢂ3.0
2J8a ꢁ 8e ꢂ13.0,
3J8a ꢁ 7a ꢂ13.0,
3J8a ꢁ 7e ꢂ2.5
2H)
e
,
2Jꢂ11.5,
3Jꢂ3.0/2.43
(t, 2H),
6.98ꢁ
3ƒH, C-5ƒH), 6.89ꢁ
(m, 2H, C-4ƒH, C-6ƒH)
7.28ꢁ7.38 (m, 3H, C-
/
7.07 (m, 2H, C-
/
6.97
3Jꢂ6.5
b
,
c
d
,
3.57 (d, 1H), 3.44 (m, 1H)
3Jꢂ7.5
1.35 (m, 1.62 (m,
2H) 3H)
1.84 (m,
1H)/1.75
(m, 1H)
1.53 (m, 3H)
2.74 (m, 1H)
2J8a -8e ꢂ12.5,
,
4.45 (m, 1H)
2J8e ꢁ 8a ꢂ12.5,
3J8e ꢁ 7a ꢂ4.0,
3J8e ꢁ 7e ꢂ2.0,
4J8e ꢁ 6a ꢂ2.0
3.88 (m,
2H)
2.57 (bs,
4H)/2.92
(t, 4H),
/
3J4a ꢁ 5a ꢂ11.0,
3?H, C-4?H, C-5?H),
7.21 (m, 2H, C-2?H, C-
6?H), 7.15 (t, 2H, C-
3ƒH, C-5ƒH), 7.02 (d,
1H, C-6ƒH), 6.96 (td,
1H, C-4ƒH, 3Jo ꢂ8.0),
2.29 (s, 3H, CH3)
e
,
3J4a ꢁ 4ꢂ7.5,
3J4a ꢁ 5e ꢂ3.0
3J8a ꢁ 7e ꢂ13.0,
3J8a ꢁ 7e ꢂ2.5
2Jꢂ12.0,
3Jꢂ3.0/2.42 3Jꢂ4.5
(t, 2H),
3Jꢂ8.0
a
b
c
d, doublet; pd, pseudodoublet; bs, broad singlet; o, ortho; m, meta; m, multiplet; t, triplet; a, axial; e, equatorial.
Multiplet seven lines.
Multiplet six lines.
Multiplet 10 lines.
Multiplet six lines.
d
e

966
F. Herold et al. / Il Farmaco 57 (2002) 959ꢁ971
/
Table 3
13C NMR spectral data of compounds 9ꢁ
a
/
15 and 18ꢁ
/
22 (A) and bromobutyl derivatives 5ꢁ
/8, 17 (B)
9
10
11
12
13
14
15
18
19
20
21
22
C-1
C-3
151.7
162.0
112.5
151.5
26.7
151.7
162.0
112.5
149.7
26.7
151.7
162.0
112.5
149.6
26.7
151.7
161.7
106.1
150.9
26.5
151.8
161.7
110.1
150.4
26.4
151.8
161.2
110.2
150.4
26.4
152.0
161.7
108.6
150.0
26.3
153.5
169.5
53.9
153.5
169.5
53.8
153.6
169.5
53.8
153.6
169.5
53.8
153.6
169.5
53.9
C-4
C-4a
C-5
57.1
32.0
57.1
32.0
57.1
32.0
57.1
32.0
57.1
32.0
b
C-6
C-7
18.6
21.8
18.6
21.8
18.6
21.8
18.4
21.8
18.5
21.8
18.5
21.9
18.5
21.9
23.8
24.5
23.8
24.5
23.8
24.5
23.8
24.5
23.8
24.5
C-8
42.6
42.6
42.6
43.5
43.6
43.0
42.8
45.5
45.6
45.6
45.6
45.6
b
b
b
b
b
b
C-1?
C-2?
C-3?
C-4?
C-5?
C-6?
C-1x
C-2x
C-3x
C-4x
C-a
C-b
C-1ƒ
C-2ƒ
C-3ƒ
C-4ƒ
C-5ƒ
C-6ƒ
R
133.4
128.5
130.8
127.7
130.8
128.4
41.6
133.3
128.5
130.7
127.7
130.7
128.5
41.6
133.4
128.5
130.8
127.7
130.8
128.5
41.6
120.9
160.5
115.8
130.0
124.2
133.0
41.5
132.5
135.1
132.6
129.7
127.1
129.5
41.4
132.5
135.1
129.5
129.7
127.1
132.6
41.5
122.2
157.4
111.1
129.5
120.8
132.4
41.5
136.4
128.9
128.5
127.9
128.5
128.9
41.1
136.4
128.9
128.5
128.0
128.5
128.9
41.2
136.4
128.9
128.5
127.9
128.5
128.9
41.2
136.4
128.9
128.5
127.9
128.5
128.9
41.2
136.4
128.9
128.6
127.9
128.6
128.9
41.3
25.7
24.3
25.7
24.3
25.7
24.4
25.6
21.8
25.7
24.2
25.7
24.3
25.7
24.3
26.4
24.0
26.5
24.1
26.5
24.0
26.4
24.0
26.5
24.2
58.4
53.7
58.5
53.1
58.4
53.1
58.4
53.1
58.4
53.1
58.4
53.1
58.5
53.1
58.3
52.9
58.4
53.1
58.2
53.3
58.2
53.2
58.4
53.7
51.6
43.7
45.2
42.9
43.0
45.2
43.7
45.5
43.6
51.0
50.4
51.7
b
b
b
b
b
b
149.6
132.6
126.5
123.0
131.0
119.0
17.9
149.3
128.8
130.6
123.6
127.6
120.4
140.1
155.7
116.1
122.4
118.9
124.4
151.6
132.6
126.5
123.0
131.0
119.0
17.9
161.6
159.6
107.0
137.4
113.2
148.0
161.4
161.2
159.6
107.0
137.4
113.2
148.0
161.7
159.5
107.0
137.4
113.3
148.0
161.7
157.7
109.7
157.7
157.7
109.8
157.7
157.7
109.8
157.7
157.7
109.7
157.7
55.6
157.7
109.7
157.7
b
5
6
7
8
17
C-1
C-3
C-4
C-4a
C-5
C-6
C-7
C-8
C-1?
C-2?
C-3?
C-4?
C-5?
C-6?
C-1x
C-2x
C-3x
C-4x
R
151.6
161.9
112.3
149.9
26.7
151.7
161.4
106.1
151.0
26.5
151.7
161.1
110.0
150.6
26.4
151.9
161.7
108.7
150.1
26.5
153.4
169.5
53.7
57.1
32.0
b
18.5
21.7
18.4
21.7
18.4
21.8
18.5
21.9
23.7
24.5
42.6
42.9
43.0
43.0
45.7
b
b
b
b
b
b
133.3
128.4
130.7
127.7
130.7
128.4
40.7
120.7
160.4
115.8
130.0
124.2
132.9
40.8
132.4
135.1
132.6
129.7
127.1
129.5
40.5
122.1
157.4
111.2
129.5
120.8
132.3
40.6
136.3
128.9
128.5
127.9
128.5
128.9
40.3
26.4
30.2
26.4
30.2
26.4
30.1
26.4
30.3
33.2
30.1
33.3
33.2
33.3
33.3
55.6
27.1
Coupling constants n J(13Cꢁ19F) (Hz) for compounds 6 1J2?-Fꢂ246.0, 2J3?-Fꢂ21.9, 2J1?-Fꢂ16.5, 3J4?-Fꢂ8.3, 3J6?-Fꢂ8.3, 4J5?-Fꢂ3.7, 5J5-Fꢂ1.8;
2 3 3 5 1 2 2 3 3
/
1
2
12 J2?-Fꢂ241.8, J3?-Fꢂ22.5, J1?-Fꢂ16.5, J4?-Fꢂ8.3, J6?-Fꢂ2.8, J5?-Fꢂ1.9; 21 J2ƒ-Fꢂ245.8, J3ƒ-Fꢂ20.6, J1ƒ-Fꢂ8.2, J4ƒ-Fꢂ4.2, J6ƒ-
4
Fꢂ3.6, J5ƒ-Fꢂ3.3; 15 1Jꢂ1.4 Hz (13Cꢁ17
/
O).
13C chemical shifts of the ipso carbon atoms of the pyridopyrimidine and phenyl rings are given in bold numbers (d, ppm), in
deuteriochloroform, TMS as the internal standard.
a
b
Appear as doublet.
justify the search for new derivatives within the primary
chemical structure. Also, generation of derivatives with
distinctly pronounced agonistic properties in respect to
serotonic 5-HT1A receptors or inhibition of effects
resulting from their effect on the a1 adrenergic receptor
could further increase their value.
The newly generated compounds discussed in this
paper have been investigated for their ability of binding

F. Herold et al. / Il Farmaco 57 (2002) 959ꢁ
/971
967
Table 5
Crystal data, data collection and structure refinement of 9
Molecular formula
Molecular weight
Temperature (K)
C29H36N4O2
472.62
293(2)
1.54178
triclinic
P-1
˚
Wavelength (A)
Crystal system
Space group
Unit cell dimensions
˚
a (A)
7.679(2)
10.332(2)
16.808(3)
84.72(3)
79.53(3)
82.95(3)
1298.1(5)
2
˚
b (A)
˚
c (A)
Fig. 3. ORTEP view of compound 9 with 50% probability of thermal
ellipsoids.
a (8)
b (8)
g (8)
3
V (A )
with the serotonergic type 5-HT1A and 5-HT2A recep-
tors, as well as the a1 adrenergic receptor. Special
attention should be given to derivatives containing a 2-
pyrimidinylpiperazinylbutyl substituent at position 2 of
the hexahydropyrido[1,2-c]pyrimidine ring system 10,
12, 13, 15. Such compounds have manifested moderate
affinities to the 5-HT1A receptor, and weak affinities to
the 5-HT2A and a1 adrenergic receptors (see Table 4).
Binding affinity to the 5-HT1A receptor depends in this
case on substituents present in position 2 of the benzene
ring associated with the hexahydropyrido[1,2-c]pyrimi-
dine ring. Binding affinity towards 5-HT1A receptor
˚
Z
Dcalc (Mg/m3)
1.209
0.606
508
Absorption coefficient (/mm)
F(000)
u Range for data collection (8)
Index ranges
4.32ꢁ60.0
/
ꢄ85h 58, ꢄ115k 511,
05l 518
3829
Reflections collected
Independent reflections
Data/restraints/parameters
Final R indices [I ꢀ2s(I)]
R indices (all data)
3752 [Rintꢂ0.0155]
3752/0/317
R1ꢂ0.0599, wR2ꢂ0.1651
R1ꢂ0.1325, wR2ꢂ0.1878
1.002
Goodness-of-fit on F2
Largest difference peak and hole 0.310 and ꢄ0.231
decreases in the following sequence: 10ꢀ
/
H; 15ꢀ
/
CH3O;
3
˚
(e/A )
12ꢀF; 13ꢀCl. The highest affinity was reported for
/
/
compound 18 (Table 4). Compound 15 has manifested
lower affinity to the 5-HT1A receptor, but at the same
time this compound shows lower affinity in relation to
the 5-HT2A receptor and decisively lower affinity in
relation to the a1 adrenergic receptor.
Similar investigations for receptor affinities were
performed for octahydropyrido[1,2-c]pyrimidine deriva-
tive 19 containing an unsubstituted phenyl. Results
show that the highest binding affinity to the receptor
is manifested by the analog hexahydropyrido[1,2-c]pyr-
imidine derivative 10. It is worth mentioning that
derivative 10 manifested higher 5-HT1A binding affinity
than compound 19. Further tests were made on
hexahydropyrido[1,2-c]pyrimidine derivatives marked
11 and 14, as well as on octahydropyrido[1,2-c]pyrimi-
dine derivative 18, with 2-pyridylpiperazinylbutyl sub-
stituent in position 2. The highest binding affinity to the
5-HT1A receptor was obtained for the compound 18
(analog to compound 11). All three compounds, i.e. 11,
14 and 18 had relatively low selectivity towards 5-HT2A
and a1 adrenergic receptors.
In summary, it may be concluded that of the 10 newly
synthesized and tested compounds 10ꢁ
special attention should be given to compound marked
as 15. Its parameters are: 5-HT1A/5-HT2A 15.4, 5-
/
15 and 18ꢁ21,
/
ꢂ
/
Table 4
Binding affinities data for 5-HT1A, 5-HT2A and a1 receptors in compounds 10ꢁ
/
15 and 18ꢁ21
/
Comp. Ki (nM)9SEM
5-HT1A [3H]8ꢀOHꢀDPAT
45.697.9
Selectivity versus 5-HT1A receptor Ki ratio
5-HT2A [3H]Ketanserin
a1 [3H]Prazosin
5-HT2A
a1
10
11
12
13
14
15
18
19
20
21
3369169
10291.7
12029457
94.1915.4
742917
6429133
114940.7
15979586
68.598.1
559926
7.4
1.3
5.4
7.7
0.9
15.4
2.6
2.2
0.9
3.1
26.4
1.2
79.2920.0
69.2919.4
78.7910.0
33.4915.3
56.497.1
27.3914.5
99.8927.4
38.9926.4
37.9914.3
374940.3
6079121
31.3911.4
8719306
69.7923.1
22094.1
10.7
8.2
3.4
28.3
2.5
5.6
0.5
35.993.5
117959.2
17.795.3
20.695.3
0.5

968
F. Herold et al. / Il Farmaco 57 (2002) 959ꢁ971
/
Table 6 (Continued)
Table 6
˚
Selected bond lengths (A) and angles (8) for compound 9
Bond lengths
C(22)ꢀN(19)ꢀC(18)
C(22)ꢀN(19)ꢀC(20)
C(18)ꢀN(19)ꢀC(20)
N(19)ꢀC(20)ꢀC(21)
N(16)ꢀC(21)ꢀC(20)
C(27)ꢀC(22)ꢀC(23)
C(27)ꢀC(22)ꢀN(19)
C(23)ꢀC(22)ꢀN(19)
114.2(3)
115.7(2)
109.6(3)
110.2(3)
111.5(3)
119.0(3)
121.8(3)
199.2(3)
Bond lengths
C(1)ꢀO(10)
C(1)ꢀN(2)
C(1)ꢀN(9)
N(2)ꢀC(3)
N(2)ꢀC(12)
C(3)ꢀO(11)
C(3)ꢀC(4)
C(4)ꢀC(4a)
C(4)ꢀC(1?)
C(4a)ꢀN(9)
C(4a)ꢀC(5)
C(5)ꢀC(6)
1.215(4)
1.372(4)
1.375(4)
1.389(4)
1.466(3)
1.224(3)
1.439(4)
1.350(4)
1.489(4)
1.374(4)
1.500(4)
1.507(5)
1.501(5)
1.486(5)
1.472(4)
1.482(5)
1.532(4)
1.473(5)
1.471(4)
1.433(4)
1.435(4)
1.524(4)
1.433(4)
1.432(4)
1.451(4)
HT1A/a1ꢂ
/
28.3; Kiꢂ
/
56.4 nM relative to 5-HT1A recep-
C(6)ꢀC(7)
C(7)ꢀC(8)
C(8)ꢀN(9)
tor.
The newly synthesized compound 15 showed highest
selectivity and high affinity towards the serotonergic
type 5-HT1A receptor.
C(12)ꢀC(13)
C(13)ꢀC(14)
C(14)ꢀC(15)
C(15)ꢀN(16)
N(16)ꢀC(17)
N(16)ꢀC(21)
C(17)ꢀC(18)
C(18)ꢀN(19)
N(19)ꢀC(22)
N(19)ꢀC(20)
5. Experimental
5.1. Chemistry
The IR spectra (potassium bromide pellets) were
Bond angles
recorded on either a Bio-Rad FTS-135 or a Perkinꢁ
/
O(10)ꢀC(1)ꢀN(2)
O(10)ꢀC(1)ꢀN(9)
N(2)ꢀC(1)ꢀN(9)
C(1)ꢀN(2)ꢀC(3)
C(1)ꢀN(2)ꢀC(12)
C(3)ꢀN(2)ꢀC(12)
O(11)ꢀC(3)ꢀN(2)
O(11)ꢀC(3)ꢀC(4)
N(2)ꢀC(3)ꢀC(4)
C(4a)ꢀC(4)ꢀC(3)
C(4a)ꢀC(4)ꢀC(1?)
C(3)ꢀC(4)ꢀC(1?)
C(4)ꢀC(4a)ꢀN(9)
C(4)ꢀC(4a)ꢀC(5)
N(9)ꢀC(4a)ꢀC(5)
C(4a)ꢀC(5)ꢀC(6)
C(4a)ꢀC(5)ꢀH(5A)
C(6)ꢀC(5)ꢀH(5A)
C(4a)ꢀC(5)ꢀH(5B)
C(6)ꢀC(5)ꢀH(5B)
H(5A)ꢀC(5)ꢀH(5B)
C(7)ꢀC(6)ꢀC(5)
122.7(3)
121.5(3)
115.8(3)
124.7(2)
118.0(2)
117.2(3)
119.4(3)
124.5(3)
116.1(3)
119.7(3)
123.2(2)
117.1(2)
120.7(2)
125.6(3)
113.6(3)
110.8(3)
109.5
Elmer FT-IR spectrometer Spectrum 1000, PE Auto
IMAGE System. The NMR spectra were recorded on a
1
UNITY plus 500 MHz spectrometer (500 MHz for H,
125 MHz for 13C, respectively). Two-dimensional NMR
1Hꢁ1
/
H COSY and 1Hꢁ13
C HETCOR and GHMQC
/
experiments were performed on a Varian UNITY plus
500 MHz spectrometer. For the 2D experiments, the
pulse sequences, acquisition and processing parameters
were taken from standard Varian software library. The
crystals suitable for X-ray analysis were grown from
C7H16 solution by slow evaporation. Data were col-
lected on a kappa-geometry KM4 KUMA diffract-
ometer [42], with graphite monochromated Cu Ka
radiation. The accurate unit cell dimensions were
obtained by the least-squares fit of setting angles of 29
109.5
109.5
reflections (11B
/
2u B
/
488). The u ꢁ2u scan method and
/
109.5
108.1
a variable scan speed, depending on reflection intensity,
were used. Two control reflections were measured after
every 100 reflections and showed no systematic changes
during data collection. Intensity data were corrected for
Lp effects [42]. The structure was solved by direct
methods with the SHELXL-97 [43] program and refined
by the full-matrix least-squares method with the
SHELXL-97 [44] program. Refinement was carried out
for reflections with positive values of F2 and one of them
was excluded from reflection files due to their large
111.8(3)
114.9(3)
112.8(3)
122.7(3)
119.1(2)
118.0(2)
113.4(3)
110.5(3)
111.8(3)
114.9(3)
109.2(3)
112.4(3)
110.7(3)
111.7(3)
110.4(3)
C(8)ꢀC(7)ꢀC(6)
C(7)ꢀC(8)ꢀN(9)
C(4a)ꢀN(9)ꢀC(1)
C(4a)ꢀN(9)ꢀC(8)
C(1)ꢀN(9)ꢀC(8)
N(2)ꢀC(12)ꢀC(13)
C(12)ꢀC(13)ꢀC(14)
C(15)ꢀC(14)ꢀC(13)
N(16)ꢀC(15)ꢀC(14)
C(17)ꢀN(16)ꢀC(21)
C(17)ꢀN(16)ꢀC(15)
C(21)ꢀN(16)ꢀC(15)
N(16)ꢀC(17)ꢀC(18)
N(19)ꢀC(18)ꢀC(17)
2
2
(jFoj ꢄ
/
jFcj ) differences. Scattering factors incorporated
2
2 2
in SHELXL-97 were used. The function a w(jFoj ꢄjFcj )
/
was minimized with wꢄ1ꢂ
Pꢂ(Fo2 ꢃ2Fc2)=3:
/
[s2(Fo)2ꢃ(0.1254P)2], where
/
/

F. Herold et al. / Il Farmaco 57 (2002) 959ꢁ
/971
969
All non-hydrogen atoms were refined with anisotropic
thermal parameters. The coordinates of the hydrogen
atoms were calculated from the geometry and refine-
ment as a riding model with their thermal parameters
calculated as 1.2 (1.5 for methyl group) times Ueq of the
bonded atom. An empirical extinction correction was
5.1.2. General procedure for the synthesis of 2-[4-[4-aryl
or heteroaryl-1-piperazinyl]butyl]-4-aryl-hexahydro-
1H,3H- and (R,R) and (S,S) octahydropyrido[1,2-
c]pyrimidine-1,3-diones (9ꢁ
The 5 mmol of the appropriate bromobutyl deriva-
tives 5ꢁ8, 17 was added under stirring to a mixture
/
15 and 18ꢁ
/
22)
/
composed of 80 ml MeCN and 5 mmol at the piperazine
derivatives, 20 mmol of K2CO3 and 0.5 mmol of
potassium iodate. The mixture was refluxed under
stirring for about 25 h. The time of the reaction was
controlled by TLC. The reaction mixture was cooled,
filtered and the filtrate was evaporated to dryness. The
residue was purified by flash chromatography (with
also applied according to the formula F? ꢂkFc[1ꢃ
c
(0:001xFc2l3=sin 2u)ꢄ1=4]; and the extinction coefficient
x was equal to 0.0029(8) [44].
Crystal data together with the data collection and
structure refinement details are listed in Table 5.
Selected bond lengths and angles are listed in Table 6.
The displacement ellipsoid representations of the mole-
cule, together with the atomic numbering scheme is
shown in Fig. 3 [45]. All geometric and thermal
parameters are given in Section 6.
CH2Cl2ꢁ
solid. The purified compounds were crystallized from:
9ꢁ11 from EtOH; 12, 13, 14, 20, 21, 22 from C7H16; 15,
/MeOH, 98:3 v/v) to afford the product as white
/
18 from C6H14 and 19 from MeCN.
The flash column chromatography was carried out on
The reaction yields, m.p.s, the result of elemental
analysis and IR data are given in Table 1. The results
obtained by NMR are collected in Table 2 (1H NMR)
and Table 3 (13C NMR).
Merck Kieselgel 60 (230ꢁ400 mesh). TLC was per-
/
formed on the plates DC-Platten Kieselgel 60 F254 of
Merck, using a mobile phase dioxan, C6H5CH3, EtOH
and 25% NaOH and visualized using a UV long or dyed
with C6H6 solution of p-chloranil.
5.2. Pharmacology
M.p.s were determined on a Laboratory Devices
MEL-TEMP† 3.0 (Bransted/Thermolyne; USA) instru-
ment without corrections.
5.2.1. 5-HT1A binding assay
Frozen Wistar rat cortices stored at ꢄ
used for radioligand binding assay. Tissues were thawed
in 50 volumes of ice-cold 50 mM TrisꢁHCl buffer, pH
7.4, homogenized and centrifuged at 20,000ꢅg for 20
min (i.e. washed). Tissue pellets were washed once more.
Assay (plates MAFCNOB 10, MultiScreen†-FC, Milli-
/
80 8C were
Microanalytical data were obtained on a Perkinꢁ
/
/
Elmer Analyzer CHN 2400 in the Department of
Chemistry, Technical University of Warsaw.
The starting materials, 4-aryl-hexahydro- and (R,R)
and (S,S) 4-aryl-octahydropyrido[1,2-c]pyrimidine-1,3-
/
pore) contained membrane suspension (ꢁ
/0.15 mg of
diones 1ꢁ/4 and 16 were prepared by the reported
protein), 1.0 nM [3H]8ꢀ
/
OHꢀDPAT (219 Ci/mmol,
/
procedure 1ꢁ/4 [39] and 16 [40].
Amersham) and buffer and/or 10 mM serotonin (non-
specific binding defining drug) or nine concentrations of
testing compound in a final volume of 0.3 ml. Assay
contained 10 mM pargyline, 5.7 mM CaCl2 and 0.1%
ascorbic acid. The mixture was incubated for 30 min at
37 8C. The incubation was terminated by rapid filtra-
tion (over Glass Fiber Type C Filter) using a Vacuum
Manifold (Millipore). The filters were then washed twice
with 0.1 ml ice-cold buffer and placed in scintillation
vials with liquid scintillation cocktail. Radioactivity was
measured in a Beckman LS 6500 liquid scintillation
counter. All assays were done in duplicates [46].
5.1.1. General procedure for the synthesis of 2-(4-
bromobutyl)-4-aryl-1H,3H-hexahydro- and (R,R) and
(S,S) octahydropyrido[1,2-c]pyrimidine-1,3-diones (5ꢁ
8, 17)
/
To the mixture of 0.04 mol of appropriate imide 1ꢁ4,
/
16 and 70 ml of C3H6O was added, while stirring 0.06
mol of K2CO3 and 0.12 mol of 1,4-dibromobutane. The
obtained mixture was stirred under reflux. The time of
the reaction was monitored by the TLC (ꢁ25 h). After
/
cooling the mixture was filtered and the filtrate was
5.2.2. 5-HT2A binding assay
evaporated to dryness. The obtained residue was
Frozen Wistar rat cortices stored at ꢄ
used for radioligand binding assay. Tissues were thawed
in 50 volumes of ice-cold 50 mM TrisꢁHCl buffer, pH
7.4, homogenized and centrifuged at 20,000ꢅg for 20
min (i.e. washed). Tissue pellets were washed once more.
Assay (plates MAFCNOB 10, MultiScreen†-FC, Milli-
/
80 8C were
purified by flash chromatography (with CH2Cl2ꢁ
/
MeOH, 97:2 v/v) to provide compounds 5ꢁ8 and 17 as
/
/
colorless solids. The compounds were crystallized: 5
from EtOH, 6 and 8 from C6H14, 7 from C7H16 and 17
from ligroine. The reaction yields, m.p.s, analytical and
/
1
IR data are given in Table 1. The results of H NMR
analysis are collected in Table 2 and of 13C NMR in
pore) contained membrane suspension (ꢁ0.15 mg of
/
protein), 0.6 nM [3H]Ketanserin (60 Ci/mmol, NEN)
Table 3.
and buffer and/or 1 mM mianserin (non-specific binding

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Filter) using a Vacuum Manifold (Millipore). The filters
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/
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buffer and/or 1 mM phentolamine (non-specific binding
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