Synthesis and antimicrobial activities of hexahydroimidazo[1,5-a]pyridinium bromides with varying benzyl substituents

Article abstract of DOI:10.1016/j.ejmech.2011.04.012

Variously substituted benzyl bromides were employed to quaternize hexahydrobenzylimidazo[1,5-a]pyridine (A) and the resulting bromides (1-11) were evaluated for their in vitro antimicrobial activity against 10 pathogenic microorganisms: Staphylococcus aur

Full text of DOI:10.1016/j.ejmech.2011.04.012

European Journal of Medicinal Chemistry 46 (2011) 2895e2900
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antimicrobial activities of hexahydroimidazo[1,5-a]pyridinium
bromides with varying benzyl substituents
,
c
b
b
a
Hayati Türkmen a , Nur Ceyhan , N. Ülkü Karabay Yavas¸ oglu , Güven Özdemir , Bekir Çetinkaya
*
ꢀ
a Ege University, Department of Chemistry, 35100 Bornova-Izmir, Turkey
b Ege University, Department of Biology, 35100 Bornova-Izmir, Turkey
c Mugla University, Department of Biology, 48147 Mugla, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Variously substituted benzyl bromides were employed to quaternize hexahydrobenzylimidazo[1,5-a]
pyridine (A) and the resulting bromides (1e11) were evaluated for their in vitro antimicrobial activity
against 10 pathogenic microorganisms: Staphylococcus aureus, Staphylococcus epidermidis, Bacillus cereus,
Micrococcus luteus, Proteus vulgaris, Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia,
Received 13 October 2010
Received in revised form
15 March 2011
Accepted 4 April 2011
Available online 19 April 2011
Candida albicans and Candida krusei. Antimicrobial activities were surprisingly high (MIC: 0.78e400 mg/
mL) and the sensitivity of the salts tested has been found to depend strongly both on the benzyl
substituents and the microorganisms used. However, the correlation observed between antimicrobial
activity and calculated partition coefficient (ClogP) was poor. Acute toxicity assessment of these salts
showed LD50 of 757e2000 mg/kg, after oral administration in mice in 24 h.
Keywords:
Hexahydroimidazo[1,5-a]pyridinium
bromides
Imidazolinium salts
Antimicrobial activities
Acute toxicity
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
The most commonly used antibacterial reagents, benzalkonium
chloride and cetyl chloride, contain benzyl and pyridine moieties,
The chemistry of imidazole derivatives has attracted more
attention during recent years due to their reactivity and biological
activities. They have been shown to possess antihelmintic, anti-
fungal, antibacterial and anticancer activities [1]. Besides their
biological actions, diazol(in)ium salts find wide applications in the
preparation of N-heterocyclic carbenes (NHCs) and their metal
complexes [2e10], some of which have attracted important atten-
tion as potential pharmaceuticals [7]. Additionally, diazol(in)ium
salts, as potential antiseptics/disinfectants, have been the research
subject of several groups [11e30]. Our previous work in this area
has concerned the antimicrobial activity of substituted imidazoli-
nium, benzimidazolium and tetrahydropyrimidinium salts and
their metal complexes [31e35]. Studies have shown that annula-
tions at various positions of the imidazole scaffolds significantly
influence the stability of the carbene species [36]. Therefore, it can
be envisioned that such fusion(s) may be used as a tool for tuning
their biological properties. For example, 1-p-chlorophenylhexahy-
droimidazo[1,5-a]pyridines, containing fused piperidine moiety on
the N1eC5 atoms of the imidazoline (ring A) are hypotensive
agents [37].
respectively. On the other hand, more efficacious compounds can
be designed by joining two or more biologically active systems
together in a single molecular framework. In view of the above
mentioned facts and in continuation of our interest in the synthesis
of imidazoline moiety [31e35], we synthesized and evaluated the
antimicrobial activity of benzyl substituted hexahydroimidazo[1,
5-a]pyridinium bromides (1e11). It has been hoped that combi-
nation of these active groups in the new molecular design would
lead to better antimicrobial agents with less toxic properties.
2. Results and discussion
2.1. Chemistry
The target salts (1e11) shown in Scheme 1 have been obtained by
quaternization of 1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridine (A),
by variously substituted benzyl bromides. 2-Benzyl-1,5,6,7,
8,8a-hexahydroimidazo[1,5-a]pyridin-2-ium bromide (1), 2-(2,4,
6-tetramethylbenzyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrid-
in-2-ium bromide (4), 2-(2,3,5,6-tetramethylbenzyl)-1,5,6,7,8,8a-
hexahydroimidazo[1,5-a]pyridin-2-ium bromide (5), 2-(pentam-
ethylbenzyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridin-2-ium
bromide (6) are known in the literature [38,39]. The other salts
* Corresponding author.
E-mail address: hayatiturkmen@hotmail.com (H. Türkmen).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.04.012

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H. Türkmen et al. / European Journal of Medicinal Chemistry 46 (2011) 2895e2900
Br
+
N
Ar
N
A
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Br-
N
N
Br-
Br-
Br-
Br-
Br-
Cl
Br-
Br-
Br-
Br-
Br-
F
F
F
F
F
Cl
Cl
CN
11
CH3
3
C(CH3)3
2
CF3
10
5
4
6
7
9
8
1
Scheme 1. Synthesis and formula of the salts used for antimicrobial and acute toxicity tests.
were prepared according to the published procedure. The purity
of the salts was checked by TLC with Merck Kieselgel GF 254
Plates, elemental analyses and 1H and 13C NMR (Varian Mercury
AS 400).
substituted salts, such as 3e6. This observation suggests poor
correlation between lipophilicity and MIC values. Thus, other
factors, such as steric and electronic might be influential. For
example, inhibitory activity increases in going from electron-rich to
electron-poor benzyls. This may indicate that the negatively
charged walls of the microorganism prefer a more positive cation to
bind.
2.2. Calculated logP
For theoretically calculated logarithms of 1-octanol/water parti-
tion coefficient parameter (ClogP) MarvinSketch v 5.3.5 e Calculator
Plugin was used [40,41].
In agreement with this the electron-withdrawing substituents
(Cl, CN, CF3) at the p-position of the phenyl ring also increases the
positive charge density on the imidazolinium cation. The salt 10,
bearing two Cl atoms on the 2,4-position of the benzyl ring, shows
a generally improved activity when compared to the mono chlor-
obenzyl bromide, 9. However, acute toxicity of 10 is slightly higher
than 9. However, pentafluorobenzyl derivative (7) was less active
and less toxic than 8.
The position of the annulation seemed to be important. There-
fore, related literature data [31] and data from this work were
compiled in Table 2. Comparison of the antimicrobial activity of 1,
5- and 4,5-annulated imidazolinium salts (12, 13) suggests that
1,5-annulation enhances the antimicrobial activity against SA, SE,
EC and CE.
2.3. Pharmacology
2.3.1. Antimicrobial activity
The in vitro antibacterial screening of the compounds (1e11)
against Staphylococcus aureus, Staphylococcus epidermidis, Bacillus
cereus, Micrococcus luteus, Proteus vulgaris, Escherichia coli, Salmo-
nella typhimurium, Klebsiella pneumoniae and the antifungal
screening against Candida albicans and Candida krusei was carried
out by the MIC method. The MIC values together with ClogP and
LD50 values are given in Table 1. 1-Octanol/water partition coeffi-
cient (logP) is indicative of the lipophilicity of the compounds and it
is accepted that more lipophilic molecules cross the cell membrane
more easily. Gentamycin and nystatin were used as reference
compounds as a comparison and a check on the reliability of the
method used.
It is worth noting that among the tested compounds, 8e11 and 2
showed a very good antifungal activity against C. albicans (ATCC
10231) and C. krusei (ATCC 6258) with MICs 0.78
were better than the values obtained for standard drug nystatin
(6.25 and 3.12 g/mL, respectively). In this study, compounds 8e11
mg/mL, which
m
All of these salts showed remarkable selectivities and effective
activities against tested microorganisms (>400e0.78 mg/mL).
However, among these compounds tested, unsubstituted benzyl
derivative (1) affords the lowest inhibitory activity (MIC: >400
are generally more effective on the bacteria than the other
compounds, which were comparable with that for gentamycin.
E. coli (ATCC 8739), S. typhimurium (CCM 5445) and K. pneumoniae
(CCM 2318) are highly pathogenic to humans. Indeed, the bacte-
rium K. pneumoniae showed a lower microbial susceptibility
compared to the other tested microorganisms. This is probably due
to its capsular material surrounding the microorganism. The
compounds tested here generally showed lower antimicrobial
activities against Gram-negative bacteria. The antimicrobial activ-
ities against Gram-positive bacteria and fungus may depend on the
differences between the cell structures of these microorganisms.
Whether differences in antimicrobial activities are due to differ-
ential uptake or different intramolecular interactions requires
further investigation.
m
g/mL) against Gram-positive B. cereus (CCM 99), Gram-negative
bacteria and two yeasts. The antimicrobial mechanism of cationic
biocides has been believed to involve their destructive interaction
with cell wall and/or cytoplasmic membranes leading to the death
of the microorganism and this interaction is known to be enhanced
by hydrophobic moieties bonded to the nitrogen of the imidazole
nitrogen. It is also known that the chain length of the alkyl
substituent on the N atom enhances the antibacterial activity [14].
CH3 groups therefore, have been added incrementally to the benzyl
ring with the intention of increasing lipophilicity and as a conse-
quence improving the activity. The bromide 2, bearing one CH3 at
C-4 of the benzyl substituent displayed a very good activity against
all microorganism (except S. typhimurium). Despite their increasing
ClogP values, this change was accompanied by significant reduc-
tions in the antimicrobial activity of multi methylated benzyl
2.3.2. Acute toxicity
Despite their promising properties, less attention has been paid
to the possible use of ionic liquids in pharmaceutical formulation
and processing, presumably due to lack of information on their

Table 1
ClogP, LD50 and in vitro MIC values for hexahydroimidazo[1,5-a]pyridinium bromides.
Ar
N
+
N
Br-
Salt
Ar
ClogP
LD50 (mg/kg)
MIC (
mg/mL)
Gram-positive bacteria
Gram-negative bacteria
Yeasts
CA
SA
SE
BC
ML
PV
EC
ST
KP
CK
1
2
3
ꢀ1.35
0.14
907
838
100
50
>400
3.12
>400
>400
>400
>400
>400
>400
100
100
200
12.5
50
200
100
50
200
25
50
ꢀ0.85
>2000
3.12
1.56
<0.78
6.25
6.25
6.25
0.78
0.78
3.12
0.78
4
5
6
7
0.17
0.68
758
1946
1106
978
50
50
25
25
200
100
50
200
100
200
200
50
50
12.5
6.25
12.5
6.25
50
50
50
6.25
3.12
3.12
1.19
3.12
0.78
12.5
12.5
6.25
12.5
12.5
50
F
F
ꢀ0.72
3.12
6.25
0.78
12.5
25
25
12.5
12.5
F
F
F
8
9
ꢀ0.47
ꢀ0.72
824
1.56
1.56
0.78
0.78
3.12
3.12
0.78
0.78
6.25
6.25
0.78
0.78
12.5
12.5
0.78
0.78
0.78
CF3
Cl
>2000
3.12
3.12
0.78
0.78
0.78
0.78
Cl
10
11
ꢀ0.08
ꢀ0.53
1891
0.78
1.56
0.78
1.56
3.12
0.78
0.78
1.56
12.5
12.5
0.78
0.78
Cl
>2000
3.12
6.25
6.25
0.78
0.78
3.12
0.78
6.25
0.78
CN
Gentamycin
Nystatin
3.12
1.56
1.56
25
e
e
e
e
e
e
e
e
e
e
6.25
3.12
Abbreviations: ClogP: calculated logarithm of 1-octanol/water partition coefficient: LD50: the dose that kills half of the mice tested; MIC: minimum inhibitory concentration;
SA: Staphylococcus aureus; SE: Staphylococcus epidermidis; BC: Bacillus cereus; ML: Micrococcus luteus; PV: Proteus vulgaris; EC: Escherichia coli; ST: Salmonella typhimurium;
KP: Klebsiella pneumoniae; CA:Candida albicans; and CK: Candida krusei.

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H. Türkmen et al. / European Journal of Medicinal Chemistry 46 (2011) 2895e2900
Table 2
organic solid which was recrystallized from methanol/diethyl ether
(3 mL/20 mL).
Comparison of hexahydroimidazo[1,5-a]pyridinium bromides (1 and 4) with
4,5-annulated salts (12 and 13).
4.1.1. 2-(4-tert-Butylbenzyl)-1,5,6,7,8,8a-hexahydroimidazolo[1,5-a]
pyridin-2-ium bromide, 2
Yield: 4.6 g, 96%, m.p.: 112e115 ꢂC. 1H NMR (CDCl3,
d, ppm): 9.98
Mes
Ar
Mes
Mes
(s, 1 H, NCH), 7.39 (d, J ¼ 2.1 Hz, 2 H, CH2C6H4C(CH3)3), 7.34 (d,,
J ¼ 2.1 Hz, 2 H, CH2C6H4C(CH3)3), 4.82 (s, 2 H, CH2C6H4C(CH3)3),
4.33e4.18 (m, 2 H, piperidin-H), 3.96 (m, 1 H, piperidin-H), 3.34 (m,
2 H, NCH2CH), 2.00e1.53 (m, 6 H, piperidin-H), 1.29 (s, 9 H,
N
N
N
+
N
+
+
N
Me
N
Cl-
Cl-
Br-
CH2C6H4C(CH3)3). 13C NMR (CDCl3,
d, ppm): 155.9 (NCH), 152.3,
Ar = Ph(1); Mes(4)
12
13
129.8, 128.8, 126.3 (CH2C6H4C(CH3)3), 59.6 (NHCH2CH), 53.7
(CH2C6H4C(CH3)3), 51.9, 46.1, 34.8, 31.7, 31.4, 25.6, 22.4 (piperidin-C,
CH2C6H4C(CH3)3). Anal. Calc. for C15H18N3Br (M: 320.23): C, 61.54;
H, 7.75; N, 7.97. Found: C, 61.60; H, 7.65; N, 8.01%.
Mes = C6H2-2,4,6-Me
MIC (mg/mL)
SA
SE
EC
CA
1
4
12
13
100
50
1600
100
50
25
1600
1600
>400
200
1600
1600
>400
50
1600
1600
4.1.2. 2-(4-Methylbenzyl)-1,5,6,7,8,8a-hexahydroimidazolo[1,5-a]
pyridin-2-ium bromide, 3
Yield: 4.2 g, 90%, m.p.: 101e103 ꢂC. 1H NMR (CDCl3,
d, ppm): 9.97
(s,1 H, NCH), 7.30 (d, J ¼ 2.0 Hz, 2 H, CH2C6H4CH3), 7.17 (d, J ¼ 1.9 Hz,
2 H, CH2C6H4CH3), 4.81 (s, 2 H, CH2C6H4CH3), 4.28 (m, 2 H, piper-
idin-H), 3.97 (m, 1 H, piperidin-H), 3.52 (m, 2 H, NCH2CH), 2.33 (s, 3
toxicity [42]. Some of the salts tested here for their antimicrobial
activity displayed a very efficient performance. Hence, they were all
assayed for acute toxicity which is one of the basic requirements in
drug development. Acute toxicity results, LD50 values, were shown
in Table 1. No lethality was observed among mice treated with
2000 mg/kg oral doses of imidazole derivates 2, 10 and 11 on the
limit test. LD50 values of other salts after oral administration in mice
in 24 h showed low toxicity according to EPA and WHO.
H, CH2C6H4CH3), 1.98e1.49 (m, 6 H, piperidin-H). 13C NMR (CDCl3,
d,
ppm): 155.8 (NCH), 139.0, 130.0, 129.8, 128.9 (CH2C6H4CH3), 59.6
(NHCH2CH), 53.6 (CH2C6H4CH3), 51.9, 46.1, 31.8, 25.6, 22.3, 21.4
(piperidin-C, CH2C6H4CH3). Anal. Calc. for C15H21N2Br (M: 309.24):
C, 58.26; H, 6.84; N, 9.06. Found: C, 58.31; H, 6.85; N, 9.08%.
4.1.3. 2-(Pentafluorobenzyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]
pyridin-2-ium bromide, 7
Yield: 5.19 g, 90%, m.p.: 142e144 ꢂC. 1H NMR (CDCl3,
d, ppm):
3. Conclusions
9.75 (s, 1 H, NCH), 5.10 (s, 2 H, CH2C6F5), 4.32 (m, 2 H, piperidin-H),
4.11 (m, 1 H, piperidin-H), 3.37 (m, 2 H, NCH2CH), 2.03e1.49 (m, 6 H,
As a fused, reduced pyridine at the N1eC5 positions of the imi-
dazolinium ring resulted in compounds which in general were
more active than simple imidazol(in)ium salts. For example, the
least active compounds of this group, unsubstituted benzyl
piperidin-H). 13C NMR (CDCl3,
d, ppm): 156.3 (NCH), 139.9, 138.7,
129.0, 124.9 (CH2C6F5), 59.5 (NHCH2CH), 53.7 (CH2C6F5), 46.8, 45.8,
32.1, 26.1, 22 (piperidin-C). Anal.Calc. for C14H14N2F5Br (M: 385.17):
C, 43.66; H,3.66; N,7.27. Found: C, 43.60; H, 3.59; N, 7.34%.
bromide (1) exhibited
a higher activity than the analogous
1,3-dibenzylbenzimidazolinium chloride [31]. However, the data
indicate that hydrophobic properties of the bromides, character-
ized by ClogP, are of minor importance for the in vitro antimicrobial
activity. Therefore, factors other than lipophilicity such as elec-
tronic and/or steric might be in operation.
4.1.4. 2-[4-(Trifluoromethyl)benzyl]-1,5,6,7,8,8a-hexahydroimidazolo
[1,5-a]pyridin-2-ium bromide, 8
Yield: 5.0 g, 92%. 1H NMR (CDCl3,
d, ppm): 9.94 (s, 1 H, NCH), 7.56
(q, J ¼ 2.1 Hz 4 H, CH2C6H4CF3), 4.95 (s, 2 H, CH2C6H4CF3), 4.15 (m, 2
The MICs of the most active derivatives (2, 8, 9, 10 and 11) were
shown to be as low as 0.78 mg/mL against Gram-negative, Gram-
H, piperidin-H), 3.95 (m, 1 H, piperidin-H), 3.10 (m, 2 H, NCH2CH),
1.93e1.47 (m, 6 H, piperidin-H). 13C NMR (CDCl3,
d, ppm): 156.3
positive bacteria and fungi. A simple inspection of Table 1 indicates
that the presence of electron-withdrawing groups (Cl, CF3 and CN,
and in certain cases CH3) at C-4 of the benzyl ring is mandatory for
the broad-spectrum antimicrobial activity and with the exception
of P. vulgaris, the resulting activity is superior to the standards
gentamycin and nystatin. It is worth mentioning that the salts 2, 10
and 11 with LD50 > 2000 mg/kg offer great potential for further
development of new antimicrobials and our efforts are continuing
along these lines.
(NCH), 137.2, 131.4, 129.6, 126.3, 126.2, (CH2C6H4CF3), 59.8
(NHCH2CH), 53.8 (CH2C6H4CF3), 51.5, 46.2, 31.6, 25.5, 22.3 (piper-
idin-C). Anal. Calc. for C15H18N2F3Br (M: 363.22): C, 46.60; H, 5.00;
N, 7.71. Found: C, 46.63; H, 5.05; N, 7.77%.
4.1.5. 2-(4-Chlorobenzyl)-1,5,6,7,8,8a-hexahydroimidazolo[1,5-a]
pyridin-2-ium bromide, 9
Yield: 4.7 g, 96%, m.p.: 89e91 ꢂC. 1H NMR (CDCl3,
d, ppm): 10.08
(s, 1 H, NCH), 7.27 (dd, J ¼ 0.6 Hz 2 H, CH2C6H4Cl), 7.18 (dd,
J ¼ 0.6 Hz, 2H, CH2C6H4Cl), 4.75 (s, 2 H, CH2C6H4Cl), 4.05 (m, 2 H,
piperidin-H), 3.84 (m, 1 H, piperidin-H), 3.18 (m, 2 H, NCH2CH),
4. Experimental
1.86e1.33 (m, 6 H, piperidin-H). 13C NMR (CDCl3,
d, ppm): 156.5
4.1. General procedure for the preparation of salts
(NCH), 134.9, 131.7, 130.5, 129.4, (CH2C6H4Cl), 59.6 (NHCH2CH), 53.5
(CH2C6H3Cl), 51.2, 46.0, 31.8, 25.6, 22.3 (piperidin-C). Anal. Calc. for
C14H18N2ClBr (M: 329.66): C, 51.01; H, 5.50; N, 8.50. Found: C, 51.10;
H, 5.60; N, 8.47%.
All chemicals used in this study were purchased from E. Merck,
Aldrich, Fluka or Alfa Aesar.
Variously substituted benzyl bromides (15 mmol) and
compound A (1.86 g; 15 mmol) were refluxed in toluene (5 mL) for
4 h. The mixture was cooled to room temperature, diethyl ether
(15 mL) was added and vigorously shaken and then decanted. The
solid residue was washed with Et2O (3 ꢁ 20 mL) to obtain an
4.1.6. 2-(2,4-Dichlorobenzyl)-1,5,6,7,8,8a-hexahydroimidazolo[1,5-a]
pyridin-2-ium bromide, 10
Yield: 5.0 g, 92%, m.p.: 156e158 ꢂC. 1H NMR (CDCl3,
d, ppm):
10.16 (s, 1 H, NCH), 7.28 (m, 1 H, CH2C6H3Cl2), 7.18 (m, 2 H,

H. Türkmen et al. / European Journal of Medicinal Chemistry 46 (2011) 2895e2900
2899
CH2C6H4Cl2), 7.06 (m, 1 H, CH2C6H3Cl2), 4.94 (s, 2 H, CH2C6H3Cl2),
4.19 (m, 2 H, piperidin-H), 3.94 (m, 1 H, piperidin-H), 3.25 (m, 2 H,
administered in increasing doses to groups of 10 male and 10
female animals. Mortalities were recorded within a given period,
and the LD50 was determined with the aid of statistical calculations
(Probit analyses in SPSS for Windows 10.0). In the tests, male and
female Swiss albino mice weighing 20e30 g were used [48,49].
NCH2CH), 1.91e1.44 (m, 6 H, piperidin-H). 13C NMR (CDCl3,
d, ppm):
157.0 (NCH), 135.9, 135.0, 129.8, 129.5, 128.4, 125.4 (CH2C6H3Cl2),
59.7 (NHCH2CH), 53.9 (CH2C6H3Cl2), 48.7, 46.2, 31.9, 25.7, 22.3
(piperidin-C). Anal.Calc. for C14H17N2Cl2Br (M: 364.11): C, 46.18; H,
4.71; N, 7.69. Found: C, 46.19; H, 4.68; N, 7.77%.
Acknowledgement
4.1.7. 2-(4-Cyanobenzyl)-1,5,6,7,8,8a-hexahydroimidazolo[1,5-a]
Financial supports from The Turkish Academy of Sciences
(TUBA) are gratefully acknowledged. We also thank to Hüseyin
Istanbullu at Ege University Pharmacy Department, for his assis-
pyridin-2-ium bromide, 11
Yield: 4.5 g, 94%, m.p.: 82e84 ꢂC. 1H NMR (CDCl3,
d, ppm): 10.03
_
(s, 1 H, NCH), 7.64 (s, 4 H, CH2C6H4CN), 5.07 (s, 2 H, CH2C6H4CN),
4.19 (m, 2 H, piperidin-H), 3.96 (m, 1 H, piperidin-H), 3.33 (m, 2 H,
tance for calculation of logP.
NCH2CH), 1.98e1.49 (m, 6 H, piperidin-H). 13C NMR (CDCl3,
d, ppm):
References
156.6 (NCH), 138.5, 133.2, 129.9, 118.4, 113.1 (CH2C6H4CN), 59.8
(NHCH2CH), 53.9 (CH2C6H4CN), 51.6, 46.3, 31.6, 25.4, 22.4 (piper-
idin-C). Anal. Calc. for C15H18N3Br (M: 320.23): C, 56.26; H, 5.67; N,
13.12. Found: C, 56.30; H, 5.65; N, 13.14%.
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