Design, synthesis, structure-activity relationship and antibacterial activity series of novel imidazo fused quinolone carboxamides

Article abstract of DOI:10.1016/j.ejmech.2008.07.024

A series of novel 7,8 and 1,8 imidazo fused quinolone carboxamides are synthesized and evaluated against antibacterial activity. 1,8 Imidazo fused quinolones exhibit moderate antibacterial activity. Molecular modeling studies were carried out to optimize

Full text of DOI:10.1016/j.ejmech.2008.07.024

European Journal of Medicinal Chemistry 44 (2009) 1570–1578
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis, structure–activity relationship and antibacterial activity series
of novel imidazo fused quinolone carboxamides
,
b
G. Venkat Reddy a, S. Ravi Kanth a, D. Maitraie a, B. Narsaiah a, P. Shanthan Rao a , K. Hara Kishore ,
*
U.S.N. Murthy b, B. Ravi c, B. Ashok Kumar d, T. Parthasarathy d
a Fluoroorganic Division, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Andhrapradesh 500007, India
b Biology Division, Indian Institute of Chemical Technology, Hyderabad, India
c Chemical Engineering, NITS, JNTU, Hyderabad, India
d Department of Chemistry, Drug Theoretics and Cheminformatics Lab, Nizam College, O.U., Hyderabad, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 7,8 and 1,8 imidazo fused quinolone carboxamides are synthesized and evaluated
against antibacterial activity. 1,8 Imidazo fused quinolones exhibit moderate antibacterial activity.
Molecular modeling studies were carried out to optimize the pharmacophore.
Received 21 December 2007
Received in revised form 4 April 2008
Accepted 18 July 2008
Available online 26 July 2008
O
O
F
CONHCH3
F
CONHCH3
O
N
Keywords:
Quinolines
Imidazo fused
QSAR
F
CONHCH3
H3C
N
Et
N
H3C
H3C
N
N
R
N
H
N
N
Et
Ar
N
Ar
Diamine
6 a-i
9a-i
10a-g
Ó 2008 Elsevier Masson SAS. All rights reserved.
1. Introduction
activity than ciprofloxacin in vitro [15]. Seman et al. and Chang et al.
[16] has reported the synthesis of imidazo [4,5,1-ij] quinolones as
antiallergic agents. We have synthesized 1,8 and 7,8 hetero ring
fused tricyclic quinolones retaining the well accepted functional-
ities in the system at appropriate positions.
Synthetic fluoroquinolones are widely accepted, useful and
indispensable antibacterial agents. The structure–activity rela-
tionship of antibacterial quinolones has been extensively investi-
gated, the optimum functionalities are found to be carboxyl group
at C-3, carbonyl functionality at C-4, fluorine at C-6, a secondary
amino group at C-7 position and an alkyl or aryl groups on N-1
position [1]. These include norfloxacin [2], perfloxacin [3], ofloxacin
[4], ciprofloxacin [5] and enoxacin [6], etc. Though the fluo-
roquinolones captured the market as antibacterials, some of them
are showing resistance to certain bacterial infections [7]. To over-
come this problem, hetero-fused tricyclic quinolones are synthe-
sized as a new class of compounds for their bio-evaluation and
some of them are found to be as potent as ciprofloxacin. Among
tricyclic compounds, imidazo [8–10], thiazolo [11], pyrazolo [12]
pyrazino [13,14] and triazolo [10] fused non-fluorinated quinolones
at 5,6 or 6,7 positions were reported by several research groups.
Thiazolo fused quinolone at 2,3 positions has shown 10 times more
2. Chemistry
We aimed to synthesize novel 7,8 and 1,8 hetero ring fused
tricyclic fluoroquinolones of general structural formula A, B.
O
O
F
COR
F
COR
R'
N
Et
R'
N
N
N
H
N
N
R"
R''
B
A
Retrosynthetic analysis of A and B shows the requirement of an
important synthon 7,8-diamino-4-hydroxy quinoline. The latter is
prepared from the condensation of 3-chloro-4-fluoroaniline 1 with
* Corresponding author. Tel.: þ91 40 27193171; fax: þ91 40 27193185.
E-mail address: shanthanpp@yahoo.co.in (P. Shanthan Rao).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.07.024

G. Venkat Reddy et al. / European Journal of Medicinal Chemistry 44 (2009) 1570–1578
1571
EMME and followed by its cyclisation under thermal conditions
produces 7-chloro-6-fluoro-4-hydroxy quinoline-3-carboxylic acid
ethyl ester 2. Nitration of the intermediate 2 with H2SO4/HNO3
mixture to afford 7-chloro-6-fluoro-4-hydroxy-8-nitro-quinoline-3-
carboxylic acid ethyl ester 3 as an exclusive product [17]. The
nitrocompound 3 is subjected to ethylation using ethyl iodide in
DMF in the presence of K2CO3 on heating at 80–90 ꢀC for 15 h and
found that the reaction was not proceed and recovered the starting
material which is not been clearly understood. As an alternate
strategy instead of alkylation, amination was attempted to get the
amine/amide compound. Thus the compound 3 is reacted with
excess of methyl amine solution at room temperature, undergone
nucleophlic substitution at C-7 and carboxylic ester was trans-
formed to N-carboxamide in a single step to give 6-fluoro-7-meth-
ylamino-8-nitro-4-hydroxy quinoline-3-N-methyl carboxamide 4
and reporting here for the first time. Reduction of C-8 nitro group of
compound 4 using Pd and H2 gave the desired 8-amino-6-fluoro-4-
hydroxy-7-methylamino-quinoline-3-carboxylic acid methylamide
5 as the intermediate diamine (Scheme 1).
The 8-amino-6-fluoro-4-hydroxy-7-methylamino-quinoline-3-
carboxylic acid methylamide 5 is further used as a synthon in
preparing tricyclic quinolone derivatives. Quinoline diamine 5 is
reacted with 4-fluorobenzaldehyde in equimolar proportions
under acidic conditions to result a mixture of two compounds 6d,
7d in 1:6 ratio, respectively. The reaction is expected to go through
the initial formation of Schiff’s base and in situ cyclisation to give
the tricyclic quinolone/quinoline. It may be more likely and well
accepted observation that the ring fusion to a single ring is more
facile than fusion with two rings, as a result 7,8 fused product was
major in the product formation. This reaction has been extended to
other aromatic aldehydes and obtained 1,8 fused quinolones 6a–i
and 7,8 fused quinolines 7a–i in each case. This study confirms not
only the versatility of the reaction but also opens for the conden-
sation of various carbonyl compounds with active synthon
(Scheme 2).
This reaction has been extended to quinoline diamine 5 with
various aliphatic aldehydes in equimolar proportions under acidic
conditions resulted exclusively a single compound. The formation
of 1,8 fused product is not observed. The possible reason for the
exclusive formation of 7,8 fused product could be the aromatic
aldehydes are prone to more nucleophilic attack than aliphatic
aldehydes. The 7,8 imidazo fused compounds 7,8 are further alky-
lated with ethyl iodide under basic conditions resulted 2-aryl-9-
ethyl-4-fluoro-3-methyl-6-oxo-6,9-dihydro-3H-imidazo[4,5-h]qui
noline-7-carboxylic acid methylamide 9a–i and 2-alkyl-9-ethyl-4-
fluoro-3-methyl-6-oxo-6,9-dihydro-3H-imidazo[4,5-h]quinoline-7
-carboxylic acid methylamide 10a–g, respectively (Scheme 3).
3. In vitro antibacterial activity
A number of imidazo fused tricyclic quinolones are prepared
retaining the well accepted functionalities for their activity study
and tested in vitro against representatives of Gram positive and
Gram negative bacteria. The minimum inhibitory concentrations
(MIC) are presented in Tables 1–3. In general 2-arylimidazo[4,5-l-ij
]-6-oxo-8-fluoro-9-N-methylamino-3,6-dihydro quinolone-5-N-m
ethyl carboxamide 6a–i are fairly active than 2-aryl-3-methyl-
imidazo[4,5-h]-4-fluoro-6-oxo-6,9-dihydro-9-ethylquinoline-7-N-
methyl carboxamide 9a–i and 2-alkyl-3-methylimidazo[4,5-h]-4-fl
uoro-6-oxo-6,9-dihydro-9-ethyl quinoline-7-methyl carboxamide
10a–g. Among all the imidazo fused quinolones the compound
containing furyl group as in 6a showed moderate activity against
Gram positive organisms (Bacillus subtilis and Staphylococcus
aureus). When the aryl group is phenyl 6b it was fairly active
against S. aureus and the presence of electron releasing groups in
the phenyl ring such as 6e, 6f, 6g were also showed moderate
activity against Pseudomonas aeruginosa, respectively. However, all
the compounds 6a–i and 9a–i are inactive against P. aeruginosa. The
compounds 9a–i are inactive against Klebsiella aerogenes, 9b, 9c, 9e,
and 9g–i are inactive against Chromobacterium violaceum and 9e–h
are inactive against B. subtilis and Bacillus sphaericus. The
compound 10a is inactive against all Gram positive and Gram
negative microorganisms and 10d, 10e and 10g are inactive against
Gram positive microorganisms. The activity of the synthesis
Further it has been observed that the aldehydes containing
electron withdrawing group resulted 1,8 fused compound (6h)
slightly higher yield than electron releasing substituents in
aromatic aldehydes.
OH
O
OH
F
Cl
F
EMME
F
COOEt
OEt
HNO3 / H2SO4
NH2
Cl
N
Cl
N
NO2
1
2
3
EtI/ K2CO3
DMF
O
N
O
F
OEt
Cl
NO2 C2H5
OH
OH
N
OH
N
F
COOEt
CH3NH2
H3C
F
CONHCH3
Pd/C
F
CONHCH3
Cl
N
N
H
H3C
N
H
NO2
3
NO2
NH2
5
4
Scheme 1.

1572
G. Venkat Reddy et al. / European Journal of Medicinal Chemistry 44 (2009) 1570–1578
OH
OH
O
F
F
ArCHO
AcOH,
NHCH3
H3C
N
H
N
H3C
NH
N
NH2
N=CHAr
5
O
OH
F
CONHCH3
F
CONHCH3
H3C
N
N
H
+
H3C
N
N
N
Ar
N
Ar
6a-i
7a-i
Ar: a = furyl; b=Ph; c = 4-Cl-Ph; d = 4-F-Ph; e = 4-Me -Ph;
f = 4-OMe -Ph; g = 4-N,N-dimethyl-Ph; h = 4-NO2 -Ph; i = 4-OH-Ph.
Scheme 2.
compounds was compared with standard drug ciprofloxacin under
similar experimental conditions. The results are tabulated in Tables
1–3.
ꢀ
ꢁ.ꢀ
ꢁ
MR ¼ n2 ꢁ 1
n2 þ 2 ꢂ MW=d
where MW/d is the volume, (n2 ꢁ1)/(n2 þ 2) is the probability
correction factor.
Relationship between antibacterial activity, expressed as log(1/
IC50) (from IC50 values) and the physicochemical parameters Xi
(Qlog P and MR) was analyzed statistically by fitting the data to
correlation equations consisting of various combinations of these
parameters.
3.1. Molecular modeling studies
A series of quinolone derivatives tested for antibacterial activity
were selected for the present study and the program of Windows
ChemSW [18] was adopted for molecular modeling studies. The
molecules were generated and energy minimization was carried
out by using Molecular Modeling Pro. Numerous physicochemical
properties and structural parameters have been devised earlier for
QSAR studies [19–25]. Appropriate descriptors or parameters for
the compounds, Qlog P and MR were correlated to the observed
antibacterial activity. The regression models are the QSAR molec-
ular models that were used to predict and design a compound with
best possible antibacterial property. The lipophilicity factor P is the
most used property where P is defined by 1-octanol/water partition
coefficient.
X
logð1=IC50Þ ¼
aiXi þ constant:
The statistical optimization is used to propose the best corre-
lation model. The constant and the correlation coefficient, ai for
each term were determined by the least squares method.
The antibacterial activities of quinolone derivatives against S.
aureus (Table 1) were quantitatively analyzed in terms of
physicochemical parameters by regression analysis. In the
present study the quantitative structure–activity relationship
(QSAR) technique was applied to arrive at
pharmacophore. model equation to correlate antibacterial
activity with the physicochemical properties was generated and
a best possible
A
All the Qlog P values used were calculated as per Bodor and
Buchwald method in ChemSW. Steric Factor (MR): MR is the molar
refractivity, the measure of steric factor, bulkiness of the molecule.
It is molar volume corrected by the refractive index.
the structural features of
discussed.
a
projected lead compound are
OH
O
F
CONHCH3
EtI
F
CONHCH3
H3C
H3C
N
N
Et
N
N
Base
N
7
N
9a-i
Ar
Ar
OH
O
N
F
CONHCH3
F
CONHCH3
AcOH
EtI
Base H3C
5+RCHO
H3C
N
N
R
N
R
N
N
Et
10a-g
8
R: a = ethyl; b = propyl; c = isopropyl; d = n-butyl; e = isobutyl; f = pentyl; g = hexyl
Scheme 3.

G. Venkat Reddy et al. / European Journal of Medicinal Chemistry 44 (2009) 1570–1578
1573
Table 1
Antibacterial assay: minimum inhibitory concentration of compounds 6a–i
Compounds
Microorganisms
Gram positive
Gram negative
Bacillus subtilis Bacillus sphaericus Staphylococcus aureus Pseudomonas aeruginosa Klebsiella aerogenes Chromobacterium violaceum
6a (R ¼ furyl)
6.25
12.5
25
25
25
25
25
25
12.5
12.5
25
12.5
25
6.25
6.25
25
25
12.5
25
12.5
12.5
25
12.5
12.5
25
25
6.25
6.25
6.25
–
–
–
–
–
–
–
–
25
–
–
6.25
12.5
6.25
6.25
6.25
25
12.5
25
6b (R ¼ phenyl)
6c (R ¼ 4’-chlorophenyl)
6d (R ¼ 4’-fluorophenyl)
6e (R ¼ 4’-methoxy phenyl) 25
6f (R ¼ 4’-methyl phenyl)
6g (R ¼ 4’-hydroxy phenyl)
6h (R ¼ 4’-nitro phenyl)
6i (R ¼ 4’-N(CH3)2 phenyl)
Ciprofloxacin
12.5
25
12.5
12.5
0.78
25
0.39
0.78
0.39
0.78
0.78
Negative control (DMSO) – no activity.
Values are indicated in mg/ml.
Table 2
Antibacterial assay: minimum inhibitory concentration of compounds 9a–i
Compounds
Microorganisms
Gram positive
Gram negative
Bacillus subtilis Bacillus sphaericus Staphylococcus aureus Pseudomonas aeruginosa Klebsiella aerogenes Chromobacterium violaceum
9a (R ¼ furyl)
25
25
25
25
–
–
–
–
12.5
25
25
25
–
–
–
12.5
25
25
25
–
–
–
–
–
–
–
–
–
25
–
–
25
–
25
–
9b (R ¼ phenyl)
–
–
–
–
–
–
–
–
9c (R ¼ 4’-chlorophenyl)
9d (R ¼ 4’-fluorophenyl)
9e (R ¼ 4’-methoxy phenyl)
9f (R ¼ 4’-methyl phenyl)
9g (R ¼ 4’-hydroxy phenyl)
9h (R ¼ 4’-nitro phenyl)
9i (R ¼ 4’-N(CH3)2 phenyl)
Ciprofloxacin
–
–
–
25
25
25
–
–
25
0.78
0.78
0.39
0.78
0.78
0.39
Negative control (DMSO) – no activity.
Values are indicated in g/ml.
m
Table 5 presents a correlation matrix between the parameters
Qlog P and MR. The matrix shows a good correlation between
Qlog P and MR. The term close to unity indicates high colinearity
while the value less than 0.5 indicates that non-colinearity exists
between two parameters. The perusal of correlation matrix
indicates either Qlog P or MR is the indicative parameter. The
regression technique was applied through the origin using these
two explainable parameters. Monoparametric and biparametric
QSAR equations were generated with Qlog P and MR. The results
of regression analysis were presented in Table 6. Eq. (1) (Table 6)
shows that the correlation between activity and Qlog P is
moderate and percent explainable is 81.2%. The equation is
found to be statistically fit. Eq. (2) represents the correlation
4. Results and discussion
The basic quinolone pharmacophore used in the present study is
depicted below. Their structural details, activity data log (1/IC50
and physicochemical parameter (Qlog P, MR) are shown in Table 4.
)
O
F
CONHCH3
H3C
N
N
H
N
Ar
6a-i
Table 3
Antibacterial assay: minimum inhibitory concentration of compounds 10a–g
Compounds
Microorganisms
Gram positive
Bacillus subtilis
Gram negative
Bacillus sphaericus
Staphylococcus aureus
Pseudomonas aeruginosa
Klebsiella aerogenes
Chromobacterium violaceum
10a (R ¼ ethyl)
10b (R ¼ propyl)
10c (R ¼ isopropyl)
10d(R ¼ butyl)
10e(R ¼ isobutyl)
10f (R ¼ pentyl)
10g (R ¼ hexyl)
Ciprofloxacin
–
–
–
–
25
50
12.5
25
25
50
0.78
–
12.5
50
–
25
12.5
25
25
25
25
0.39
12.5
12.5
–
–
25
–
50
25
–
–
50
–
25
50
–
–
25
–
25
12.5
12.5
50
0.78
0.78
0.39
0.78
Negative control (DMSO) – no activity.
Values are indicated in g/ml.
m

1574
G. Venkat Reddy et al. / European Journal of Medicinal Chemistry 44 (2009) 1570–1578
Table 4
Table 5
Antibacterial activity and physicochemical parameters of quinolone derivatives
Correlation matrix
Compounds No.
Activity
Qlog P
MR
96.0213
Activity
Qlog P
MR
6a
6b
6c
6d
6e
6f
6g
6h
6i
1.2041
0.6021
0.6021
0.6021
0.9031
0.6021
0.9031
0.9031
0.6021
2.4427
2.8852
2.6035
2.9378
2.4657
2.3382
2.4264
1.9621
1.1434
Activity Pearson correlation
Sig (2-tailed)
1.000
–
ꢁ0.685
ꢁ0.615
100.826
96.2377
101.0625
102.4845
110.4499
103.346
97.7154
88.262
0.042
0.078
Qlog P Pearson correlation
Sig (2-tailed)
–
1.000
–
0.576
0.104
MR Pearson correlation
Sig (2-tailed)
–
–
1.000
–
field from internal tetra methyl silane. The mass spectra were
measured on a VG micro mass 7070-H mass spectrometer. Elemental
analysis was carried on vario EL, Elemental instrument.
between activity and MR and its percent explainable in 90.4%. It
is also found to be statistically fit. Eq. (3) is the biparametric
analysis. It is statistically unfit because the probability factor of
Qlog P is more than 50% of its coefficient. Both Eqs. (4) and (5)
are found to be statistically valid. Eq. (5) is the most accepted
equation. The predictive ability of the modeled equations was
cross validated [19–25]. The quadratic form of this equation
indicates the optimal value of MR decides the highest activity. In
order to get optimal value, the activity was differentiated that
respect to MR and equated to zero. The optimal value of MR is
computed as 62.878 for its highest activity. Though molecules
having this range of MR are not available in the data set, but 6a
is the furyl unsubstituted analogue found to be the highest
activity and their MR values close to maximal value (62.878).
Therefore, the size of the substitutent at position-2 is important
in deciding the activity. As the size of the substituent increases,
the activity decreases (Table 4). The ligands with smaller size of
substituent of 2-aryl substituted tricyclic quinolones may suit-
ably pit in the receptor site of the enzyme responsible for
activity. The high antibacterial activity of the ligands, which
efficiently inhibit the enzyme activity, may suitably bind to the
receptor site.
5.1. 6-Fluoro-4-hydroxy-7-methylamino-8-nitro-quinoline-3-
carboxylic acid methylamide (4)
5.1.1. General procedure
Methyl amine (140 ml, 40%) was slowly added to 7-chloro-6-
fluoro-4-hydroxy-8-nitroquinoline-3-carboxylic acid ethyl ester 3
(10 g, 31 mmol) and kept stirring for 24 h at 30 ꢀC. The reaction
mixture was neutralized with acetic acid while cooling and the
separated solid was filtered, washed repeatedly with water till it is
neutral to pH and dried to give the desired compound (8.7 g).
Mp: >300 ꢀC, Yield: 92% IR (KBr)
n .
: 3490, 3272, 1669, 1511 cmꢁ1
1H NMR (TFA)
d: 3.12 (d, 3H, –CH3, J ¼ 9.1 Hz), 3.62 (d, 3H, –CH3,
J ¼ 9.1 Hz), 8.32 (d, 1H, Ar–H, JH–F ¼ 6 Hz), 8.65 (d, 1H, –NH–), 9.25
(br s, 1H, –NH–), 9.3 (s, 1H, ]CH–). Mass (EI m/z): 294 (Mþ), 264,
237.
5.2. 8-Amino-6-fluoro-4-hydroxy-7-methylamino-quinoline-3-
carboxylic acid methylamide (5)
5.2.1. General procedure
6-Fluoro-7-methyl
amino-8-nitro-4-hydroxy-quinoline-3-N-
methyl carboxamide 4 (5 g, 17 mmol) was dissolved in dimethyl
5. Experimental
formamide (250 ml) and added 10% Pd/C (300 mg) and hydrogen
gas at atmospheric pressure for 20 h maintaining temperature at
30 ꢀC. The catalyst was removed by filtration and filtrate was
distilled to leave the residue. The residue was washed with water,
filtered and dried to give 3.5 g of the title compound.
All the reagents were obtained from commercial sources. Melting
points were determined in open glass capillaries using Fisher-Johns
melting point instrument and was uncorrected. IR spectra were
recorded on FT-IR, Perkin–Elmer 1310 infrared spectrometer. 1H
NMR spectra were recorded on Varian Gemini (200 MHz) in CDCl3/
DMSO-d6/TFA as solvent. Chemical shifts are expressed in ppm down
Mp: >300 ꢀC, Yield: 78%. IR (KBr)
1648 cmꢁ1. 1H NMR (DMSO-d6)
: 2.94 (d, 3H, –CH3, J ¼ 9.3 Hz), 3.22
(d, 3H, –CH3, J ¼ 9 Hz); 5.74 (s, 2H, –NH2); 7.32 (d, 1H, Ar–H, JH–
n: 3406, 3300–3210,
d

G. Venkat Reddy et al. / European Journal of Medicinal Chemistry 44 (2009) 1570–1578
1575
Table 6
Model equations for the quinolone derivatives.
Eq. no.
1
Modeled eq.
R
R2
R2a
SEE
F
Activity ¼ 0.325 (0.055) Qlog P
0.901
0.812
0.789
0.399
34.583
75.613
52.339
66.794
69.108
PRESS ¼ 1.2766, q2 ¼ ꢁ1.5364
cv
2
3
4
5
Activity ¼ 0.00828 (0.001) MR
0.951
0.968
0.975
0.976
0.904
0.937
0.950
0.952
0.892
0.789
0.936
0.938
0.285
0.919
0.219
0.216
PRESS ¼ 0.650, q2 ¼ ꢁ0.291
cv
Activity ¼ ꢁ0.355 (0.185) Qlog P + 0.0162 (0.004) MR
PRESS ¼ 0.4495, q2 ¼ 0.106
cv
Activity ¼ ꢁ0.377 (0.086) Qlog P2 + 1.281 (0.219) Qlog P
PRESS ¼ 0.3383, q2 ¼ 0.327
cv
Activity ¼ ꢁ0.00033 (0.000) MR2 + 0.0415 (0.013) MR
PRESS ¼ 0.3290, q2 ¼ 0.346
cv
¼ 62 Hz); 8.10 (d, 1H, –NH–); 8.32 (br s, 1H, –NH–); 8.53 (s, 1H,
(br s, 1H, –NH–). Mass (EI m/z): 368 (Mþ), 309, 281. Analysis Calcd.
for C19H14F2N4O2: C, 61.95%; H, 3.83%; N, 15.21%. Found: C, 61.90%;
H, 3.73%; N, 15.24%.
F
]CH–). Mass (EI m/z): 264 (Mþ), 233.
5.3. Procedure for the preparation of imidazo [4,5-h]/imidazo
[4,5,1-ij], aryl substituted quinolines (6 and 7)
5.3.5. 8-Fluoro-9-methylamino-6-oxo-2-p-tolyl-6H-imidazo[4,5,1-
ij]quinoline-5-carboxylic acid methylamide (6e)
Mp: 291–292 ꢀC, Yield: 5.1%. IR (KBr) : 3190, 1670 cmꢁ1 1H
n .
A mixture of diamine 5 (10 mmol) and aromatic aldehyde
(10 mmol) was taken in acetic acid (10 ml) and refluxed for 4 h.
The reaction mixture was cooled and poured on to crushed ice. The
resulted solid was filtered, washed with water and dried. The
filtrate was neutralized with ammonia solution but additional solid
was not obtained. The separated solid was passed through column
on silica gel using chloroform to get the 1,8 fused compound and
methanol as eluent to isolate the 7,8 fused compound.
NMR (CDCl3)
d
: 2.22 (s, 3H, –CH3); 3.04 (d, 3H, –CH3, J ¼ 9.4 Hz);
3.41 (d, 3H, –CH3, J ¼ 9.2 Hz); 7.62 (d, 2H, phenyl, J ¼ 6.3 Hz); 7.84
(d, 1H, Ar–H, JH–F ¼ 6.1 Hz); 7.94 (d, 2H, phenyl, J ¼ 6.3 Hz); 8.93 (br
s,1H, –NH–); 9.47 (s,1H, Ar–H); 9.63 (br s,1H, –NH–). Mass (EI m/z):
364 (Mþ), 305, 277. Analysis Calcd. for C20H17FN4O2: C, 65.92%; H,
4.70%; N, 15.37%. Found: C, 65.91%; H, 4.75%; N, 15.40%.
5.3.6. 8-Fluoro-2-(4-methoxy-phenyl)-9-methylamino-6-oxo-6H-
imidazo[4,5,1-ij]quinoline-5-carboxylic acid methylamide (6f)
5.3.1. 8-Fluoro-2-furan-2-yl-9-methylamino-6-oxo-6H-
Mp: 295–297 ꢀC, Yield: 7.5%. IR (KBr) : 3212, 1675 cmꢁ1 1H
n .
imidazo[4,5,1-ij]quinoline-5-carboxylic acid methylamide (6a)
Mp: 285–287 ꢀC, Yield: 8.1%. IR (KBr) : 3197, 1672 cmꢁ1. 1H NMR
n
NMR (CDCl3)
d: 3.17 (d, 3H, –CH3, J ¼ 9.2 Hz); 3.47 (d, 3H, –CH3,
J ¼ 9.3 Hz); 4.07 (s, 3H, –OCH3); 7.2 (d, 2H, phenyl, J ¼ 6.2 Hz); 7.73
(d, 1H, Ar–H, JH–F ¼ 6.5 Hz); 7.96 (d, 2H, phenyl, J ¼ 6.4 Hz); 8.92
(br s, 1H, –NH–); 9.44 (s, 1H, Ar–H); 9.60 (br s, 1H, –NH–). Mass
(EI m/z): 380 (Mþ), 323, 295. Analysis Calcd. for C20H17FN4O3:
C, 63.15%; H, 4.50%; N, 14.72%. Found: C, 63.20%; H, 4.45%; N,
14.84%.
(CDCl3)
d
: 3.02 (d, 3H, –CH3, J ¼ 9.4 Hz); 3.45 (d, 3H, –CH3,
J ¼ 9.2 Hz); 6.78 (d, 1H, furyl, J ¼ 6.5 Hz); 7.24 (m, 1H, furyl,
J ¼ 6.7 Hz); 7.74 (d, 1H, Ar–H, JH–F ¼ 6.2 Hz); 7.89 (d, 1H, furyl,
J ¼ 6.8 Hz); 8.92 (br s, 1H, –NH–); 9.48 (s, 1H, Ar–H); 9.68 (br s, 1H,
–NH–). Mass (EI m/z): 340 (Mþ), 281, 253. Analysis Calcd. for
C17H13FN4O3: C, 60.01%; H, 3.85%; N, 16.46%. Found: C, 60.20%; H,
3.80%; N, 16.34%.
5.3.7. 2-(4-Dimethylamino-phenyl)-8-fluoro-9-methylamino-6-
oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxylic acid methylamide
(6g)
5.3.2. 8-Fluoro-9-methylamino-6-oxo-2-phenyl-6H-imidazo[4,5,1-
ij]quinoline-5-carboxylic acid methylamide (6b)
Mp: 289–290 ꢀC, Yield: 9.1%. IR (KBr) : 3212, 1680 cmꢁ1 1H
n .
Mp: >300 ꢀC, Yield: 10%. IR (KBr)
(CDCl3)
n .
: 3202, 1680 cmꢁ1 1H NMR
d
: 3.02 (d, 3H, –CH3, J ¼ 9.4 Hz); 3.17 (s, 6H, –N(CH3)2); 3.42
NMR (CDCl3)
d
: 3.08 (d, 3H, –CH3, J ¼ 9.4 Hz); 3.45 (d, 3H, –CH3,
(d, 3H, –CH3, J ¼ 9.2 Hz); 6.70 (d, 2H, phenyl, J ¼ 6.1 Hz); 6.91 (d, 1H,
Ar–H, JH–F ¼ 6.4 Hz); 7.80 (d, 2H, phenyl, J ¼ 6.3 Hz); 8.81 (br s, 1H,
–NH–); 9.54 (s, 1H, Ar–H); 9.72 (br s, 1H, –NH–). Mass (EI m/z): 393
(Mþ), 334, 306. Analysis Calcd. for C21H20FN5O2: C, 64.11%; H, 5.12%;
N, 17.80%. Found: C, 64.20%; H, 5.20%; N, 17.91%.
J ¼ 9.1 Hz); 7.67 (m, 3H, phenyl); 7.79 (d, 1H, Ar–H, JH–F ¼ 6.3 Hz);
7.93 (m, 2H, phenyl); 8.92 (m, 1H, –NH–); 9.48 (s, 1H, Ar–H); 9.65
(m, 1H, –NH–). Mass (EI m/z): 350 (Mþ), 320, 293, 265. Analysis
Calcd. for C19H15FN4O2: C, 65.13%; H, 4.31%; N, 15.99%. Found: C,
65.20%; H, 4.30%; N, 15.94%.
5.3.8. 8-Fluoro-9-methylamino-2-(4-nitro-phenyl)-6-oxo-6H-
imidazo[4,5,1-ij]quinoline-5-carboxylic acid methylamide (6h)
5.3.3. 2-(4-Chloro-phenyl)-8-fluoro-9-methylamino-6-oxo-6H-
imidazo[4,5,1-ij]quinoline-5-carboxylic acid methylamide (6c)
Mp: >300 ꢀC, Yield: 13%. IR (KBr) : 3252, 1690 cmꢁ1. 1H NMR
n
Mp: >300 ꢀC, Yield: 9.2%. IR (KBr) : 3216, 1680 cmꢁ1. 1H NMR
n
(CDCl3)
d
: 3.1 1 (d, 3H, –CH3, J ¼ 9.1 Hz); 3.53 (d, 3H, –CH3,
(CDCl3)
d
: 3.05 (d, 3H, –CH3, J ¼ 9.3 Hz); 3.44 (d, 3H, –CH3,
J ¼ 9.5 Hz); 7.83 (d, 1H, Ar–H, JH–F ¼ 6.2 Hz); 8.2 (d, 2H, phenyl,
J ¼ 6.2 Hz); 8.60 (d, 2H, phenyl, J ¼ 6.3 Hz); 9.27 (br s, 1H, –NH–);
9.53 (s, 1H, Ar–H); 9.72 (br s, 1H, –NH–). Mass (EI m/z): 395 (Mþ),
336, 308. Analysis Calcd. for C19H14FN5O4: C, 57.72%; H, 3.56%; N,
17.71%. Found: C, 57.65%; H, 3.40%; N, 17.84%.
J ¼ 9.1 Hz); 7.62 (d, 2H, phenyl, J ¼ 6.5 Hz); 7.74 (d, 1H, Ar–H, JH–
¼ 6.2 Hz); 7.93 (d, 2H, phenyl, J ¼ 6.4 Hz); 8.90 (br s, 1H, –NH–);
F
9.41 (s, 1H, Ar–H); 9.64 (br s, 1H, –NH–). Mass (EI m/z): 384 (Mþ),
325, 297. Analysis Calcd. for C19H14ClFN4O2: C, 59.37%; H, 3.6%; N,
14.56%. Found: C, 59.20%; H, 3.50%; N, 14.64%.
5.3.9. 8-Fluoro-2-(4-hydroxy-phenyl)-9-methylamino-6-oxo-6H-
imidazo[4,5,1-ij]quinoline-5-carboxylic acid methylamide (6i)
5.3.4. 8-Fluoro-2-(4-fluoro-phenyl)-9-methylamino-6-oxo-6H-
imidazo[4,5,1-ij]quinoline-5-carboxylic acid methylamide (6d)
Mp: >300 ꢀC, Yield: 5.6%. IR (KBr) : 3400–3252, 1681 cmꢁ1. 1H
n
Mp: 287–288 ꢀC, Yield: 8.9%. IR (KBr) : 3221, 1681 cmꢁ1 1H
n .
NMR (CDCl3)
d
: 3.02 (d, 3H, –CH3, J ¼ 9.4 Hz); 3.42 (d, 3H, –CH3,
NMR (CDCl3)
d
: 3.04 (d, 3H, –CH3, J ¼ 9.3 Hz); 3.44 (d, 3H, –CH3,
J ¼ 9.5 Hz); 7.65 (d, 2H, phenyl, J ¼ 6.1 Hz); 7.75 (d, 1H, Ar–H, JH–
J ¼ 9.1 Hz); 7.32 (m, 2H, phenyl); 7.74 (d, 1H, Ar–H, JH–F ¼ 6.1 Hz);
¼ 6.5 Hz); 7.94 (d, 2H, phenyl, J ¼ 6.7 Hz); 8.95 (br s, 1H, –NH–);
7.95 (m, 2H, phenyl); 8.92 (br s, 1H, –NH–); 9.42 (s, 1H, Ar–H); 9.67
F

1576
G. Venkat Reddy et al. / European Journal of Medicinal Chemistry 44 (2009) 1570–1578
9.43 (s, 1H, Ar–H); 9.61 (b, 1H, –NH–); 10.12 (br s, 1H, –OH). Mass
(EI m/z): 366 (Mþ), 307, 279. Analysis Calcd. for C19H15FN4O3:
C, 62.29%; H, 4.12%; N, 15.29%. Found: C, 62.20%; H, 4.20%;
N, 15.40%.
5.3.17. 4-Fluoro-6-hydroxy-3-methyl-2-(4-nitro-phenyl)-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (7h)
Mp: >300 ꢀC, Yield: 50%. IR (KBr) : 3350–3250, 1690 cmꢁ1. 1H
n
NMR (DMSO-d6)
d
: 3.05 (d, 3H, –CH3, J ¼ 9.5 Hz); 4.15 (s, 3H, –CH3);
7.62 (d, 2H, phenyl, J ¼ 6.5 Hz); 7.78 (d, 1H, Ar–H, JH–F ¼ 6.1 Hz); 8.74
(d, 2H, phenyl, J ¼ 6.2 Hz); 9.33 (s,1H, Ar–H); 10.01 (br s,1H, –NH–);
13.06 (br s, 1H, –OH). Mass (FAB): 396 (Mþ þ 1), 365, 337.
5.3.10. 4-Fluoro-2-furan-2-yl-6-hydroxy-3-methyl-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (7a)
Mp: >300 ꢀC, Yield: 60%. IR (KBr) : 3350–3250, 1660 cmꢁ1. 1H
n
NMR (DMSO-d6)
d
: 3.04 (d, 3H, –CH3, J ¼ 9.5 Hz); 4.16 (s, 3H, –CH3);
5.3.18. 4-Fluoro-6-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (7i)
6.71 (d, 1H, furyl, J ¼ 6.4 Hz); 7.25 (m, 1H, furyl); 7.62 (d, 1H, furyl,
J ¼ 6.7 Hz); 8.08 (d, 1H, Ar–H, JH–F ¼ 6.1 Hz); 8.76 (s, 1H, Ar–H);
10.04 (br s, 1H, –NH–); 13.03 (br s, 1H, –OH). Mass (FAB): 341
(Mþ þ 1), 310, 282.
Mp: >300 ꢀC, Yield: 59%. IR (KBr) : 3370–3250, 1680 cmꢁ1. 1H
n
NMR (DMSO-d6)
d
: 3.01 (d, 3H, –CH3, J ¼ 9.4 Hz); 4.16 (s, 3H, –CH3);
7.42 (d, 2H, phenyl, J ¼ 6.6 Hz); 7.78 (d, 2H, phenyl, J ¼ 6.4 Hz); 7.92
(d, 1H, Ar–H, JH–F ¼ 6.2 Hz); 8.84 (s, 1H, Ar–H); 10.07 (br s, 1H, –NH–
); 12.51 (br s, 1H, –OH); 13.06 (br s, 1H, –OH). Mass (FAB): 367
(Mþ þ 1), 336, 308.
5.3.11. 4-Fluoro-6-hydroxy-3-methyl-2-phenyl-3H-imidazo[4,5-
h]quinoline-7-carboxylic acid methylamide (7b)
Mp: >300 ꢀC, Yield: 60.4%. IR (KBr) : 3350–3250, 1680 cmꢁ1. 1H
n
NMR (DMSO-d6)
d
: 3.05 (d, 3H, –CH3, J ¼ 9 Hz); 4.14 (s, 3H, –CH3);
5.3.19. 2-Ethyl-4-fluoro-6-hydroxy-3-methyl-3H-imidazo[4,5-
h]quinoline-7-carboxylic acid methylamide (8a)
7.43 (m, 3H, phenyl); 7.74 (m, 2H, phenyl); 7.90 (d, 1H, Ar–H, JH–
Mp: >300 ꢀC, Yield: 65%. IR (KBr) : 3175, 1654 cmꢁ1 1H NMR
n .
¼ 6.1 Hz); 8.81 (s, 1H, Ar–H); 10.03 (m, 1H, –NH–); 13.02 (br s, 1H,
F
–OH). Mass (FAB): 351 (Mþ þ 1), 320, 292.
(DMSO-d6)
d
: 1.54 (m, 3H, –CH3); 2.93 (t, 2H, –CH2, J ¼ 9.2 Hz); 3.04
(d, 3H, –CH3, J ¼ 9.6 Hz); 4.03 (s, 3H, –CH3); 8.02 (d, 1H, Ar–H, JH–
5.3.12. 2-(4-Chloro-phenyl)-4-fluoro-6-hydroxy-3-methyl-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (7c)
¼ 6.2 Hz); 8.78 (s, 1H, Ar–H); 10.01 (br s, 1H, –NH–); 13.03 (br s,
F
1H, –OH). Mass (FAB): 303 (Mþ þ 1), 272, 244.
Mp: >300 ꢀC, Yield: 61%. IR (KBr) : 3350–3250, 1685 cmꢁ1. 1H
n
NMR (DMSO-d6)
d
: 3.04 (d, 3H, –CH3, J ¼ 9.5 Hz); 4.13 (s, 3H,
5.3.20. 4-Fluoro-6-hydroxy-3-methyl-2-propyl-3H-imidazo[4,5-
h]quinoline-7-carboxylic acid methylamide (8b)
–CH3); 7.41 (d, 2H, phenyl, J ¼ 6.5 Hz); 7.73 (d, 2H, phenyl,
J ¼ 6.4 Hz); 7.91 (d, 1H, Ar–H, JH–F ¼ 6.2 Hz), 8.75 (s, 1H, Ar–H);
10.08 (br s, m, 1H, –NH–); 13.01 (br s, 1H, –OH). Mass (FAB): 385
(Mþ þ 1), 354, 326.
Mp: >300 ꢀC, Yield: 62%. IR (KBr) : 3169, 1652.5 cmꢁ1. 1H NMR
n
(DMSO-d6)
d
: 1.22 (t, 3H, CH3, J ¼ 9.6 Hz); 2.04 (m, 2H, –CH2); 2.86
(t, 2H, –CH2, J ¼ 9.7 Hz); 3.02 (d, 3H, –CH3, J ¼ 9.6 Hz); 4.07 (s, 3H,
–CH3); 8.03 (d, 1H, Ar–H, JH–F ¼ 6.1 Hz); 8.77 (s, 1H, Ar–H); 10.06 (br
s, 1H, –NH–); 13.07 (br s, 1H, –OH). Mass (FAB): 327 (Mþ þ 1), 296,
268.
5.3.13. 4-Fluoro-2-(4-fluoro-phenyl)-6-hydroxy-3-methyl-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (7d)
Mp: >300 ꢀC, Yield: 59%. IR (KBr) : 3350–3250, 1687 cmꢁ1. 1H
n
NMR (DMSO-d6)
d
: 3.02 (d, 3H, –CH3, J ¼ 9.2 Hz); 4.16 (s, 3H, –CH3);
5.3.21. 4-Fluoro-6-hydroxy-2-isopropyl-3-methyl-3H-imidazo[4,5-
h]quinoline-7-carboxylic acid methylamide (8c)
7.44 (m, 2H, phenyl); 7.73 (m, 2H, phenyl); 7.92 (d, 1H, Ar–H, JH–
Mp: >300 ꢀC, Yield: 63%. IR (KBr) : 3165, 1652 cmꢁ1 1H NMR
n .
¼ 6.4 Hz); 8.82 (s, 1H, Ar–H); 10.03 (br s, 1H, –NH–); 13.01 (br s,
F
1H, –OH). Mass (FAB): 369 (Mþ þ 1), 338, 310.
(DMSO-d6) d: 1.26 (m, 6H, CH3); 1.92 (m, 2H, –CH2); 2.88 (m, 1H,
–CH–); 3.03 (d, 3H, –CH3, J ¼ 9.5 Hz); 4.04 (s, 3H, –CH3); 8.05 (d, 1H,
Ar–H, JH–F ¼ 6.1 Hz); 8.72 (s,1H, Ar–H); 10.07 (br s,1H, –NH–); 13.05
(br s, 1H, –OH). Mass (FAB): 327 (Mþ þ 1), 296, 268.
5.3.14. 4-Fluoro-6-hydroxy-3-methyl-2-p-tolyl-3H-imidazo[4,5-
h]quinoline-7-carboxylic acid methylamide (7e)
Mp: >300 ꢀC, Yield: 63%. IR (KBr) : 3350–3250, 1663 cmꢁ1. 1H
n
NMR (DMSO-d6)
d
: 2.24 (s, 3H, –CH3); 3.06 (d, 3H, –CH3, J ¼ 9.2 Hz);
5.3.22. 2-Butyl-4-fluoro-6-hydroxy-3-methyl-3H-imidazo[4,5-
h]quinoline-7-carboxylic acid methylamide (8d)
4.13 (s, 3H, –CH3); 7.48 (d, 2H, phenyl, J ¼ 6.5 Hz); 7.72 (d, 2H,
phenyl, J ¼ 6.5 Hz); 7.91 (d, 1H, Ar–H, JH–F ¼ 6.2 Hz); 8.85 (s, 1H, Ar–
H); 10.03 (br s, 1H, –NH–); 13.04 (br s, 1H, –OH). Mass (FAB): 365
(Mþ þ 1), 334, 306.
Mp: >300 ꢀC, Yield: 61%. IR (KBr) : 3164, 1654 cmꢁ1 1H NMR
n .
(DMSO-d6) d: 1.2–1.14 (m, 5H, CH3); 1.93 (m, 2H, –CH2); 2.88 (t, 2H,
–CH2, J ¼ 9.5 Hz); 3.04 (d, 3H, –CH3, J ¼ 9.3 Hz); 4.08 (s, 3H, –CH3);
8.03 (d, 1H, Ar–H, JH–F ¼ 6.4 Hz); 8.77 (s, 1H, Ar–H); 10.03 (br s, 1H,
–NH–); 13.09 (br s, 1H, –OH). Mass (FAB): 341 (Mþ þ 1), 310, 282.
5.3.15. 4-Fluoro-6-hydroxy-2-(4-methoxy-phenyl)-3-methyl-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (7f)
Mp: >300 ꢀC, Yield: 61%. IR (KBr) : 3350–3250, 1680 cmꢁ1. 1H
n
5.3.23. 4-Fluoro-6-hydroxy-2-isobutyl-3-methyl-3H-imidazo[4,5-
h]quinoline-7-carboxylic acid methylamide (8e)
NMR (DMSO-d6)
d
: 3.02 (d, 3H, –CH3, J ¼ 9.2 Hz); 3.93 (s, 3H,
Mp: >300 ꢀC, Yield: 61%. IR (KBr) : 3163, 1651 cmꢁ1 1H NMR
n .
–OCH3); 4.14 (s, 3H, –CH3); 7.43 (d, 2H, phenyl, J ¼ 6.5 Hz); 7.75 (d,
2H, phenyl, J ¼ 6.6 Hz); 7.91 (d, 1H, Ar–H); 8.86 (s, 1H, Ar–H); 10.01
(br s, 1H, –NH–); 13.01 (br s, 1H, –OH). Mass (FAB): 381 (Mþ þ 1),
350, 322.
(DMSO-d6) d: 1.24–1.13 (m, 6H, CH3); 1.98 (m,1H, –CH–); 2.73 (d, 2H,
–CH2, J ¼ 9.5 Hz); 3.05 (d, 3H, –CH3, J ¼ 9.4 Hz); 4.04 (s, 3H, –CH3);
8.07 (d, 1H, Ar–H, JH–F ¼ 6.2 Hz); 8.72 (s, 1H, Ar–H); 10.09 (br s, 1H,
–NH–); 13.03 (br s, 1H, –OH). Mass (FAB): 341 (Mþ þ 1), 310, 282.
5.3.16. 2-(4-Dimethylamino-phenyl)-4-fluoro-6-hydroxy-3-
methyl-3H-imidazo[4,5-h]quinoline-7-carboxylic acid methylamide
(7g)
Mp: >300 ꢀC, Yield: 58%. IR (KBr)
NMR (DMSO-d6)
4.17 (s, 3H, –CH3); 7.43 (d, 2H, phenyl, J ¼ 6.6 Hz); 7.72 (d, 2H,
phenyl, J ¼ 6.5 Hz); 7.96 (d, 1H, Ar–H, JH–F ¼ 6.4 Hz); 8.84 (s, 1H, Ar–
H); 10.08 (br s, 1H, –NH–); 13.02 (br s, 1H, –OH). Mass (FAB): 394
(Mþ þ 1), 363, 335.
5.3.24. 4-Fluoro-6-hydroxy-3-methyl-2-pentyl-3H-imidazo[4,5-
h]quinoline-7-carboxylic acid methylamide (8f)
n
: 3350–3250, 1675 cmꢁ1. 1H
Mp: >300 ꢀC, Yield: 60%. IR (KBr) : 3300–3145, 1644 cmꢁ1. 1H
n
d: 2.95 (s, 6H, –CH3); 3.05 (d, 3H, –CH3, J ¼ 9.4 Hz);
NMR (DMSO-d6) d: 1.26–1.33 (m, 7H, –CH2CH2CH3); 1.97 (m, 2H,
–CH2); 2.85 (t, 2H, –CH2, J ¼ 9.4 Hz); 3.03 (d, 3H, –CH3, J ¼ 9.3 Hz);
4.04 (s, 3H, –CH3); 8.08 (d, 1H, Ar–H, JH–F ¼ 6.4 Hz); 8.75 (s, 1H, Ar–
H); 10.02 (br s, 1H, –NH–); 13.07 (br s, 1H, –OH). Mass (FAB): 355
(Mþ þ 1), 324, 297.

G. Venkat Reddy et al. / European Journal of Medicinal Chemistry 44 (2009) 1570–1578
1577
5.3.25. 4-Fluoro-2-hexyl-6-hydroxy-3-methyl-3H-imidazo[4,5-
h]quinoline-7-carboxylic acid methylamide (8g)
Mp: >300 ꢀC, Yield: 60%. IR (KBr) : 3300–3145, 1643 cmꢁ1. 1H
NMR (DMSO-d6) : 1.25–1.35 (m, 9H, –CH2CH2CH2CH3); 1.96 (m,
2H, –CH2); 2.82 (t, 2H, –CH2, J ¼ 9.2 Hz); 3.01 (d, 3H, –CH3,
J ¼ 9.3 Hz); 4.05 (s, 3H, –CH3); 8.02 (d, 1H, Ar–H, JH–F ¼ 6.4 Hz); 8.78
(s, 1H, Ar–H); 10.03 (br s, m, 1H, –NH–); 13.06 (br s, 1H, –OH). Mass
(FAB): 369 (Mþ þ 1), 338, 311.
5.4.5. 9-Ethyl-4-fluoro-3-methyl-6-oxo-2-p-tolyl-6,9-dihydro-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (9e)
Mp: >300 ꢀC, Yield: 83%. IR (KBr) : 3196, 1651, 1619 cmꢁ1
NMR (CDCl3)
: 1.63 (t, 3H, –CH3, J ¼ 9.4 Hz); 2.42 (s, 3H, –CH3); 3.07
n
n
.
1H
d
d
(d, 3H, –CH3, J ¼ 9.3 Hz); 4.24 (s, 3H, –CH3); 5.21 (q, 2H, –CH2–,
J ¼ 9.5 Hz); 7.45 (d, 2H, phenyl, J ¼ 6.5 Hz); 7.66 (d, 2H, phenyl,
J ¼ 6.2 Hz); 8.14 (d, 1H, Ar–H, JH–F ¼ 6.1 Hz); 8.73 (s, 1H, Ar–H);
10.08 (br s, 1H, –NH–). Mass (EI m/z): 392 (Mþ), 361, 335, 307.
Analysis Calcd. for C22H21FN4O2: C, 67.33%; H, 5.39%; N, 14.27%.
Found: C, 67.40%; H, 5.50%; N, 14.2%.
5.4. Procedure for the ethylation of aryl/alkyl substituted imidazo
[4,5-h]hydroxy quinolines (9a–i and 10a–i)
5.4.6. 9-Ethyl-4-fluoro-2-(4-methoxy-phenyl)-3-methyl-6-oxo-6,9-
dihydro-3H-imidazo[4,5-h]quinoline-7-carboxylic acid
methylamide (9f)
A mixture of aryl/alkyl substituted imidazo [4,5-h]hydroxy
quinolines 7/8 (0.6 mmol) potassium carbonate (1.5 mmol), ethyl
iodide (3 mmol) in DMF (5 ml) was heated at 80–90 ꢀC with stirring
for 15 h. The mixture was evaporated to dryness by distilling DMF
and extracted the residue with chloroform. The CHCl3 layer was
washed with water, dried over sodium sulphate, concentrated to
half the volume and purified by passing through column chroma-
tography using silica gel to give the N-ethylated products 9 & 10,
respectively.
Mp: >300 ꢀC, Yield: 81%. IR (KBr)
NMR (CDCl3)
n
: 3226, 1660, 1622 cmꢁ1. 1H
d
: 1.64 (t, 3H, –CH3, J ¼ 9.2 Hz); 3.03 (d, 3H, –CH3,
J ¼ 9.4 Hz); 3.97 (s, 3H, –CH3); 4.21 (s, 3H, –CH3); 5.26 (q, 2H, –CH2–,
J ¼ 9.5 Hz); 7.14 (d, 2H, phenyl, J ¼ 6.4 Hz); 7.78 (d, 2H, phenyl,
J ¼ 6.5 Hz); 8.15 (d, 1H, Ar–H, JH–F ¼ 6.4 Hz); 8.79 (s, 1H, Ar–H);
10.08 (br s, 1H, –NH–). Mass (FAB): 409 (Mþ þ 1), 377, 349. Analysis
Calcd. for C22H21FN4O3: C, 64.69%; H, 5.18%; N, 13.71%. Found: C,
64.54%; H, 5.30%; N, 13.62%.
5.4.1. 9-Ethyl-4-fluoro-2-furan-2-yl-3-methyl-6-oxo-6,9-dihydro-
3H-imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (9a)
5.4.7. 2-(4-Dimethylamino-phenyl)-9-ethyl-4-fluoro-3-methyl-6-
oxo-6,9-dihydro-3H-imidazo[4,5-h]quinoline-7-carboxylic acid
methylamide (9g)
Mp: 287–288 ꢀC, Yield: 78%. IR (KBr) : 3193, 1659, 1620 cmꢁ1
n .
1H NMR (CDCl3)
d
: 1.69 (t, 3H, –CH3, J ¼ 9.1 Hz); 3.01 (d, 3H, –CH3,
J ¼ 9.3 Hz); 4.34 (s, 3H, –CH3); 5.27 (q, 2H, –CH2–, J ¼ 9.3 Hz); 6.72
(d, 1H, furyl, J ¼ 6.3 Hz); 7.25 (m, 1H, furyl); 7.76 (d, 1H, furyl,
J ¼ 6.3 Hz); 8.17 (d, 1H, Ar–H, JH–F ¼ 6 Hz); 8.73 (s, 1H, Ar–H); 10.08
(br s, 1H, –NH–). Mass (FAB): 369 (Mþ þ 1), 338, 310. Analysis Calcd.
for C22H21FN4O3: C, 64.69%; H, 5.18%; N,13.71%. Found: C, 64.54%; H,
5.30%; N, 13.62%.
Mp: >300 ꢀC, Yield: 81%. IR (KBr)
NMR (CDCl3)
n
: 3206, 1659, 1620 cmꢁ1. 1H
d: 1.66 (t, 3H, –CH3, J ¼ 9 Hz); 2.94 (s, 6H, –N(CH3)2);
3.03 (d, 3H, –CH3, J ¼ 9 Hz); 4.21 (s, 3H, –CH3); 5.26 (q, 2H, –CH2–,
J ¼ 9 Hz); 6.84 (d, 2H, phenyl, J ¼ 6.5 Hz); 7.63 (d, 2H, phenyl,
J ¼ 6.5 Hz); 8.07 (d, 1H, Ar–H, JH–F ¼ 6 Hz); 8.72 (s, 1H, Ar–H); 10.05
(br s, 1H, –NH–). Mass (FAB): 422 (Mþ þ 1), 391, 363. Analysis Calcd.
for C23H24FN5O2: C, 65.54%; H, 5.73%; N, 16.61%. Found: C, 65.44%;
H, 5.70%; N, 16.62%.
5.4.2. 9-Ethyl-4-fluoro-3-methyl-6-oxo-2-phenyl-6,9-dihydro-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (9b)
Mp: 293–294 ꢀC, Yield: 85%. IR (KBr)
n
: 3297,1672 cmꢁ1. 1H NMR
5.4.8. 9-Ethyl-4-fluoro-3-methyl-2-(4-nitro-phenyl)-6-oxo-6,9-
dihydro-3H-imidazo[4,5-h]quinoline-7-carboxylic acid
methylamide (9h)
(CDCl3)
d
: 1.65 (t, 3H, –CH3, J ¼ 9.5 Hz); 3.03 (d, 3H, –CH3,
J ¼ 9.3 Hz); 4.27 (s, 3H, –CH3); 5.21 (q, 2H, –CH2–, J ¼ 9.7 Hz); 7.69
(m, 3H, phenyl); 7.82 (m, 2H, phenyl, J ¼ 6.5 Hz); 8.17 (d, 1H, Ar–H,
JH–F ¼ 6.3 Hz); 8.73 (s, 1H, Ar–H); 10.04 (br s, m, 1H, –NH–). Mass
(FAB): 379 (Mþ þ 1), 348, 326. Analysis Calcd. for C21H19FN4O2: C,
66.65%; H, 5.06%; N, 14.80%. Found: C, 66.60%; H, 5.0%; N, 14.84%.
Mp: >300 ꢀC, Yield: 80%. IR (KBr)
NMR (CDCl3)
J ¼ 9.3 Hz); 4.24 (s, 3H, –CH3); 5.27 (q, 2H, –CH2–, J ¼ 9.7 Hz); 7.66
(d, 2H, phenyl, J ¼ 6.3 Hz); 7.83 (d, 2H, phenyl, J ¼ 6.5 Hz); 8.27 (d,
1H, Ar–H, JH–F ¼ 6.2 Hz); 8.85 (s, 1H, Ar–H); 10.09 (br s, 1H, –NH–).
Mass (EI m/z): 423 (Mþ), 366, 338. Analysis Calcd. for C21H18FN5O4:
C, 59.57%; H, 4.28%; N,16.54%. Found: C, 59.54%; H, 4.30%; N,16.62%.
n
: 3336, 1672, 1627 cmꢁ1. 1H
: 1.66 (t, 3H, –CH3, J ¼ 9.4 Hz); 3.01 (d, 3H, –CH3,
d
5.4.3. 2-(4-Chloro-phenyl)-9-ethyl-4-fluoro-3-methyl-6-oxo-6,9-
dihydro-3H-imidazo[4,5-h]quinoline-7-carboxylic acid
methylamide (9c)
Mp: >300 ꢀC, Yield: 87%. IR (KBr)
NMR (CDCl3)
n
: 3216, 1661, 1623 cmꢁ1. 1H
5.4.9. 2-(4-Ethox-phenyl)-9-ethyl-4-fluoro-3-methyl-6-oxo-6,9-
dihydro-3H-imidazo[4,5-h]quinoline-7-carboxylic acid
methylamide (9i)
d
: 1.63 (t, 3H, –CH3, J ¼ 9.4 Hz); 3.04 (d, 3H, –CH3,
J ¼ 9.2 Hz); 4.26 (s, 3H, –CH3); 5.27 (q, 2H, –CH2–, J ¼ 9.4 Hz); 7.62
(d, 2H, phenyl, J ¼ 6.3 Hz); 7.86 (d, 2H, phenyl, J ¼ 6.6 Hz); 8.24 (d,
1H, Ar–H, JH–F ¼ 6.1 Hz); 8.86 (s, 1H, Ar–H); 10.07 (br s, m, 1H, –NH–
). Mass (FAB): 413 (Mþ þ 1), 383, 355. Analysis Calcd. for
C21H18ClFN4O2: C, 61.09%; H, 3.41%; N, 13.57%. Found: C, 61.06%; H,
3.30%; N, 13.54%.
Mp: >300 ꢀC, Yield: 80%. IR (KBr)
NMR (CDCl3)
4.25 (m, 5H, –CH3, –CH2–); 5.21 (q, 2H, –CH2–, J ¼ 9.2 Hz); 7.01 (d,
2H, phenyl, J ¼ 6.2 Hz); 7.71 (d, 2H, phenyl, J ¼ 7.4 Hz); 8.11 (d, 1H,
Ar–H, JH–F ¼ 6.3 Hz); 8.71 (s, 1H, Ar–H); 10.02 (br s, 1H, –NH–). Mass
(FAB): 423 (Mþ þ 1), 392, 364. Analysis Calcd. for C23H23FN4O3: C,
63.95%; H, 5.87%; N, 14.20%. Found: C, 63.84%; H, 5.8 0%; N, 14.32%.
n
: 3213, 1658, 1620 cmꢁ1. 1H
: 1.64 (m, 6H, –CH3); 3.05 (d, 3H, –CH3, J ¼ 9.4 Hz);
d
5.4.4. 9-Ethyl-4-fluoro-2-(4-chloro-phenyl)-3-methyl-6-oxo-6,9-
dihydro-3H-imidazo[4,5-h]quinoline-7-carboxylic acid
methylamide (9d)
5.4.10. 2,9-Diethyl-4-fluoro-3-methyl-6-oxo-6,9-dihydro-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (10a)
Mp: 290–292 ꢀC, Yield: 85%. IR (KBr)
n .
: 3206, 1663, 1624 cmꢁ1
1H NMR (CDCl3)
d: 1.65 (t, 3H, –CH3, J ¼ 9.3 Hz); 3.02 (d, 3H, –CH3,
Mp: 281–283 ꢀC, Yield: 81%. IR (KBr) : 3193, 1659, 1620 cmꢁ1
n .
J ¼ 9.4 Hz); 4.23 (s, 3H, –CH3); 5.27 (q, 2H, –CH2–, J ¼ 9.4 Hz); 7.35
(m, 2H, phenyl, J ¼ 6.5 Hz); 7.86 (m, 2H, phenyl, J ¼ 6.6 Hz); 8.14 (d,
1H, Ar–H, JH–F ¼ 6.3 Hz); 8.82 (s, 1H, Ar–H); 10.07 (br s, m, 1H, –NH–
). Mass (EI m/z): 396 (Mþ), 339, 311, 296. Analysis Calcd. for
C21H18F2N4O2: C, 63.63%; H, 4.57%; N, 14.13%. Found: C, 63.60%; H,
4.50%; N, 14.2%.
1H NMR (CDCl3)
d
: 1.52 (m, 6H, CH3); 2.95 (t, 2H, –CH2, J ¼ 9.2 Hz);
3.04 (d, 3H, –CH3, J ¼ 9.4 Hz); 4.04 (s, 3H, –CH3); 5.01 (q, 2H, –CH2–,
J ¼ 9.7 Hz); 8.04 (d, 1H, Ar–H, JH–F ¼ 6.2 Hz); 8.73 (s, 1H, Ar–H);
10.04 (br s, 1H, –NH–). Mass (EI m/z): 330 (Mþ), 273, 245. Analysis
Calcd. for C17H19FN4O2: C, 61.80%; H, 5.79%; N, 16.95%. Found: C,
61.70%; H, 5.72%; N, 16.82%.

1578
G. Venkat Reddy et al. / European Journal of Medicinal Chemistry 44 (2009) 1570–1578
5.4.11. 9-Ethyl-4-fluoro-3-methyl-6-oxo-2-propyl-6,9-dihydro-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (10b)
–CH3, J ¼ 9.5 Hz); 1.9 (m, 2H, –CH2); 2.8 (t, 2H, –CH2, J ¼ 9.5 Hz); 3.0
(d, 3H, –CH3, J ¼ 9.6 Hz); 4.0 (s, 3H, –CH3); 5.0 (q, 2H, –CH2–,
J ¼ 9.4 Hz); 8.0 (d, 1H, Ar–H, JH–F ¼ 6.2 Hz); 8.7 (s, 1H, Ar–H); 10.0
(br s, m, 1H, –NH–). Mass (FAB): 387 (Mþ þ 1), 356, 328. Analysis
Calcd. for C21H27FN4O2: C, 65.26%; H, 7.04%; N, 14.49%. Found: C,
65.40%; H, 7.20%; N, 14.32%.
Mp: 287–288 ꢀC, Yield: 80%. IR (KBr) : 3183, 1659, 1620 cmꢁ1
n .
1H NMR (CDCl3)
d
: 1.23 (t, 3H, CH3, J ¼ 9.2 Hz); 1.57 (t, 3H, –CH3,
J ¼ 9.5 Hz); 2.07 (m, 2H, –CH2); 2.80 (t, 2H, –CH2, J ¼ 9.7 Hz); 3.07
(d, 3H, –CH3, J ¼ 9.5 Hz); 4.06 (s, 3H, –CH3); 5.02 (q, 2H, –CH2–,
J ¼ 9.4 Hz); 8.04 (d, 1H, Ar–H, JH–F ¼ 6.1 Hz); 8.74 (s, 1H, Ar–H);
10.02 (br s, 1H, –NH–). Mass (EI m/z): 344 (Mþ), 287, 259. Analysis
Calcd. for C18H21FN4O2: C, 62.77%; H, 6.14%; N, 16.26%. Found: C,
62.70%; H, 6.20%; N, 16.32%.
5.5. Antibacterial activity procedure
The minimum inhibitory concentration was done by broth
dilution method (NCCLS1982). A set of sterilized test tubes with
nutrient broth medium capped with cotton plugs 1–9. The test
compound is dissolved in suitable solvent and concentration of
5.4.12. 9-Ethyl-4-fluoro-2-isopropyl-3-methyl-6-oxo-6,9-dihydro-
3H-imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (10c)
Mp: 285–286 ꢀC, Yield: 84%. IR (KBr) : 3179, 1659, 1620 cmꢁ1. 1H
n
NMR (CDCl3)
d
: 1.20 (m, 6H, CH3); 1.54 (t, 3H, –CH3, J ¼ 9.2 Hz); 1.92
100 mg/ml of the test compound is added in the first test tube,
(m, 2H, –CH2); 2.87 (m, 1H, –CH–); 3.02 (d, 3H, –CH3, J ¼ 9.3 Hz);
4.06 (s, 3H, –CH3); 5.04 (q, 2H, –CH2–, J ¼ 9.4 Hz); 8.04 (d, 1H, Ar–H,
JH–F ¼ 6.2 Hz); 8.73 (s, 1H, Ar–H); 10.08 (br s, 1H, –NH–). Mass (EI m/
z): 344 (Mþ), 287, 259. Analysis Calcd. for C18H21FN4O2: C, 62.77%; H,
6.14%; N, 16.26%. Found: C, 62.69%; H, 6.10%; N, 16.12%.
which is serially diluted from 1 to 9. A fixed volume of 0.5 ml
overnight culture is added in all the test tubes and are incubated
at 37 ꢀC for 24 h. After 24 h, these tubes were measured for
turbidity.
5.4.13. 2-Butyl-9-ethyl-4-fluoro-3-methyl-6-oxo-6,9-dihydro-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (10d)
References
Mp: 291–293 ꢀC, Yield: 76%. IR (KBr) : 3178, 1659, 1620 cmꢁ1. 1H
n
[1] R. Filler, et al. (Eds.), Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications (1993), pp. 165–207.
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1358–1363.
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Antimicrob. Agents Chemother 22 (1982) 548.
[5] R. Wise, J.M. Andrews, L.J. Edwards, Antimicrob. Agents Chemother 23 (1983)
559.
NMR (CDCl3)
d: 1.2–1.1 (m, 5H, –CH2CH3); 1.5 (t, 2H, –CH3, J ¼ 9.2 Hz);
1.9 (m, 2H, –CH2); 2.8 (t, 2H, –CH2, J ¼ 9.4 Hz); 3 (d, 3H, –CH3,
J ¼ 9.7 Hz); 4.0(s,3H, –CH3);5.04(q,2H,–CH2–, J ¼ 9.3 Hz);8.05(d,1H,
Ar–H, JH–F ¼ 6.4 Hz); 8.73 (s,1H, Ar–H); 10.05 (br s,1H, –NH–). Mass(EI
m/z): 358 (Mþ), 327, 301, 273, 43. Analysis Calcd. for C19H23FN4O2: C,
63.67%; H, 6.46%; N, 15.63%. Found C, 63.50%; H, 6.40%; N, 15.42%.
[6] J.M. Domagala, C.L. Heifetz, M.P. Hutt, T.F. Mich, J.B. Nichols, M. Solomon,
D.F. Worth, J. Med. Chem. 31 (1988) 991–1001.
[7] D.C. Hooper, J.S. Wolfson, Quinolone Antimicrobial Agents, second ed. (1993).
[8] I. Saito, M. Yamanaka, T. Kanazawa, M. Sato, Japan Patent Kokai (1979) 54
(144), 398.
5.4.14. 9-Ethyl-4-fluoro-2-isobutyl-3-methyl-6-oxo-6,9-dihydro-
3H-imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (10e)
Mp: 282–284 ꢀC, Yield: 77%. IR (KBr) : 3159,1649,1610 cmꢁ1. 1H
n
[9] O. Takeki, K. Maliko, N. Yoichi, N. Michio, J. Pharm. Dynamics 2 (1979) 397.
[10] M. Fujita, H. Egawa, M. Kataoka, T. Miyamoto, J. Nakano, J. Matsumoto, Chem.
Pharm. Bull. 43 (1995) 2123–2132.
[11] T. Kametani, K. Kigasawa, M. Hiiragi, K. Wakisaka, O. Kusama, H. Sugi,
K. Kawasaki, J. Heteroatom. Chem. 14 (1977) 1175–1182.
[12] R.G. Glushkov, L.N. Dronova, A.S. Elina, Khim-Farm. Zh. 24 (1990) 33.
[13] J. Salon, V. Milata, N. Pronayova, J. Lesko, Monat. Chem. 131 (2000) 293.
[14] N.P. Peet, L.E. Baugh, S. Sunder, J.E. Lewis, J. Med. Chem. 28 (1985)
298–302.
NMR (CDCl3)
d
: 1.26–1.13 (m, 6H, CH3); 1.52 (t, 3H, –CH3, J ¼ 9.2 Hz);
1.92 (d, 2H, –CH2, J ¼ 9.7 Hz); 2.75 (m, 1H, –CH–); 3.04 (d, 3H, –CH3,
J ¼ 9.6 Hz); 4.06 (s, 3H, –CH3); 5.02 (q, 2H, –CH2–, J ¼ 9.5 Hz); 8.01
(d, 1H, Ar–H, JH–F ¼ 6.2 Hz); 8.71 (s, 1H, Ar–H); 10.02 (br s, 1H, –NH–
). Mass (EI m/z): 358 (Mþ), 301, 273, 43. Analysis Calcd. for
C19H23FN4O2: C, 63.67%; H, 6.46%; N, 15.63%. Found: C, 63.60%; H,
6.40%; N, 15.52%.
[15] V. Milata, D. Ilavsky, J. Lesko. Coll. Czech. Chem. Commun. 53 (1988) 1068.
[16] (a) M. Seman, A. Belicova, V. Milata, D. Ilavsky, Ceskaslov. Farm. 46 (1997) 226;
(b) Z. Wei-Chang, L. Qing, X. Zhen-Yu, Y. Ai-Zhen, Z. Xin- Ping, J. Chin. Pharm.
Sci. 7 (1998) 62–68.
5.4.15. 9-Ethyl-4-fluoro-3-methyl-6-oxo-2-pentyl-6,9-dihydro-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (10f)
Mp: 287–289 ꢀC, Yield: 74%. IR (KBr) : 3149,1619,1590 cmꢁ1. 1H
n
[17] L. Pogliani, J. Phys. Chem. (1996) 100.
[18] Chem software available from chem.Sw. Inc; 420 F Executive Ct.North, Fair-
feild, CA 94585. Consult. Available from: http://www.Chemsw.com.
[19] T. Yakaiah, B.P.V. Lingaiah, B. Narsaiah, B. Shireesha, S. Gururaj, B. Ashok
Kumar, T. Parthasarathy, K. Ravi Kumar, B. Sridhar, Bioorg. Med. Chem. Lett. 17
(2007) 3445–3453.
[20] B. Ashok Kumar, D. Ramasree, T. Parthasarathy, V. Uma, J. Teach Res. Chem. 11
(2004) 20.
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Lett. 13 (2005) 1873–1878.
NMR (CDCl3) d: 1.22–0.91 (m, 7H, –CH2CH2CH3); 1.52 (t, 3H, –CH3,
J ¼ 9.4 Hz); 1.95 (m, 2H, –CH2); 2.82 (t, 2H, –CH2, J ¼ 9.3 Hz); 3.04 (d,
3H, –CH3, J ¼ 9.2 Hz); 4.05 (s, 3H, –CH3); 5.06 (q, 2H, –CH2–,
J ¼ 9.7 Hz); 8.03 (d, 1H, Ar–H, JH–F ¼ 6.1 Hz); 8.71 (s, 1H, Ar–H);
10.02 (br s, 1H, –NH–). Mass (EI m/z): 372 (Mþ), 315, 287, 43.
Analysis Calcd. for C20H25FN4O2: C, 64.49%; H, 6.76%; N, 15.04%.
Found: C, 64.40%; H, 6.50%; N, 15.32%.
[22] A. Sirisha Madhuritha, B. Ashok Kumar, T. Parthasarathy, V. Uma, C. Eur. J.
Chem. 2 (2004) 696.
[23] N. Rameshwar, K. Krishna, B. Ashok Kumar, T. Parthasarathy, Bioorg. Med.
Chem. Lett. 14 (2006) 319–325.
[24] N. Bodor, P. Buchwald, J. Phys. Chem. B 101 (1997) 3404.
[25] V.N. Viswanadhan, A.K. Ghose, G.R. Revakar, Robins, J. Chem. Inf. Comput. Sci.
29 (1998) 163.
5.4.16. 9-Ethyl-4-fluoro-2-hexyl-3-methyl-6-oxo-6,9-dihydro-3H-
imidazo[4,5-h]quinoline-7-carboxylic acid methylamide (10g)
Mp: 286–287 ꢀC, Yield: 73%. IR (KBr) : 3145, 1630, 1592 cmꢁ1
n .
1H NMR (CDCl3)
d: 1.2–0.9 (m, 9H, –CH2CH2CH2 CH3); 1.5 (t, 3H,