A catalyst- and solvent-free multicomponent synthesis and docking study of some new antiproliferative: N 5-allyl-quinolylpyrido[2,3- b] [1,4]benzodiazepinone precursors

Article abstract of DOI:10.1039/c5nj03280f

A multicomponent reaction has been developed by incorporating quinoline-3-carbaldehyde, 1,3-cyclohexanedione and 2,3-diaminopyridine into some new quinolylpyrido[2,3-b][1,4]benzodiazepinone assemblies under catalyst- and solvent-free conditions at 120 °C. Further reaction of the resulting intermediates with allyl bromide led to the formation of the corresponding N₅-allylated products, in situ, with higher yields in the same pot. Many candidates of this new class revealed noticeable activities against the representative human solid tumour cell lines A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast) and WiDr (colon). The most active compounds resemble the standard drug etoposide in antiproliferative activity against HeLa, T-47D and WiDr cell lines. Docking studies in the active site of MDM2 led us to consider this protein a plausible target for the antiproliferative effects of the compounds.

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A catalyst− and solvent−free multicomponent synthesis and
docking study of some new antiproliferative N5-allyl-
quinolylpyrido[2,3-b][1,4]benzodiazepinone precursors
Received 00th January 20xx,
Accepted 00th January 20xx
Hitesh A. Barad,a Tushar R. Sutariya,a Gaurangkumar C. Brahmbhatt,a Narsidas J. Parmar,a* Irene Lagunes,b José M. Padrón,b
DOI: 10.1039/x0xx00000x
Prashant Murumkar,c Mayank Kumar Sharma,c Mange Ram Yadavc
www.rsc.org/
A multicomponent reaction has been developed incorporating quinoline-3-carbaldehyde, 1,3-cyclohexanedione and 2,3-
diaminopyridine into some new quinolylpyrido[2,3-b][1,4]benzodiazepinone assemblies under catalyst− and solvent−free
conditions at 120 °C. Further reaction of the resulting intermediates with allyl bromide led to the formation of the
corresponding N5–allylated products, in situ, with higher yields in the same pot. Many candidates of this new class
revealed noticeable activities against the representative human solid tumour cell lines A549 (lung), HBL-100 (breast), HeLa
(cervix), SW1573 (lung), T-47D (breast) and WiDr (colon). The most active compounds resemble the standard drug
etoposide in antiproliferative activity against HeLa, T-47D and WiDr cell lines. Docking studies in the active site of MDM2
led us to consider this protein a plausible target for the antiproliferative effects of the compounds.
interest. Pyridodiazepine fusion conferred the resulting
heterocyclic frameworks with a notable neuroleptic property.6
The prototypical privileged substructure pyridobenzodizepine,
known to exhibit high pharmacological properties,7 is present
in the natural product (-)–auranthine (III), isolated from
Penicillium aurantiogriseum. Therapeutic drugs of this group
Introduction
Heterocycles with a diazepine nucleus incorporated as one
of their fused-ring systems represent noteworthy bioactive
molecular assemblies, and so remained highly perused
synthetic targets since their introduction in the early 1960s,1 in
both drug discovery and pharmacological investigations. The
diazepine nucleus fused with imidazole, pyrazol, pyrimidine,
thiazol, pyrrol, indol, benzopyran and triazol units is known to
confer a wide variety of biological properties on the resulting
heterocycles (Fig. 1).2 Chlordiazepoxide and diazepam,
effective in anxiety;3 chlozapines, useful in schizophrenia;
pirenzepine, a muscarinic receptor M1 antagonist; and finally
(Fig. 2) include pirenzepine
(IV) (the first M1–selective
muscarinic receptor antagonist),8 rispenzepine, propizepine (
V
)
9
and norepinephrine reuptake inhibitor tampramine (VI
)
AF–
.
DX 116 (VII) is a selective inhibitor of cardiac muscarinic
receptor M2 and has 10–fold higher in vitro affinity over M1
receptor.10 The clozapine–like analogues 8-chloro-6-(4’-
methyl-l-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine
(
VIII
)
and 8-methyl-6-(4’-methyl-1-piperaziny1)-11H-pyrido
apafant,
a platelet activating inhibitor, are prominent
[2,3-b][1,4]benzodiazepine (IX) were reported as effective
neuroleptics.11 Besides, pyridobenzodiazepines are potential
examples in this context.4 Practice of isosterism in the
synthesis also worked well and effectively in this area. The
modulators of central nervous system and vasopressin V
2
thieno-fused-benzodiazepine flumezapine (I), which holds a
receptor.12 P. Liu, and others13 reported pyridobenzodiazepine
thiophene as an isosteric form of the benzene unit, revealed
more activity than the similar framework clozapine (II), due to
the electronegative methyl group at the thiophene
heterocycle.5
as sulfonamide–based bombesin receptor subtype 3 agonists.
MK–7725 is
a potent and selective bombesin receptor
subtype–3 agonist, used in the treatment of obesity.14 M. V.
Petrova, et al.15 reported a two-step synthetic procedure for
this compound, in which enaminone intermediate generated
in the first step underwent cyclization with an aldehyde. Thus,
in view of this, the synthetic effort aimed at the incorporation
of a pyridine unit with the diazepine framework represents a
vital explorative push towards the development of libraries of
bioactive scaffolds with pyridine-fused diazepine containing
heterocycles.
Among the combinations of fused heterocycles discovered
so far, those involving a pyridodiazepine fusion led to the
generation of many new potential candidates of medicinal
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Scheme 1. Reagents and conditions: (i) Phenol, K2CO3, DMF, reflux, 3.5 h; (ii)
NaN3, TBA–HS, DMSO, 45–50 °C; (iii) 70% acetic acid, reflux (iv) Allyl bromide,
K2CO3, DMF, rt, 12 h.
Next, MCR was performed in solvent-free environment
taking 2,3-diaminopyridine
quinoline-carbaldehyde
temperature reported earlier17 (Scheme 2). The resulting
pyrido[2,3-b][1,4]benzodiazepinones 7a were obtained in 76–
89 % yield, and with excellent purity (Table 1).
5, 1,3-cyclohexadione 6a
-b and
2
-4
in equimolar amounts, at 120 °C, a
-j
Fig. 1. Pharmacologically relevant benzodiazepine derivatives.
Among various synthetic routes, the cyclization of an
enaminone derived from a diketone and O-phenylenediamine
with an aldehyde is considered to be a widely studied
multicomponent domino procedure to achieve diazepine
heterocycles. McGowan et. al. and Eduardo et al. reported a
two-step method, combining enaminones generated in situ
with an aldehyde via cyclization reaction, catalyzed by acetic
acid in refluxing ethanol.16a-b Orlov et al.16c assembled a
Michael adduct generated in situ from an aldehyde and a
diketone with diamines via a multicomponent reaction (MCR)
method. The MCR approach has often provided synthetic
chemists with many green and ecological advantages, to
achieve synthetic targets. We have reported earlier synthesis
of quinolyldibenzo[b,e][1,4]diazepinones using MCR strategy.17
Inspired by the results, we report in the present work the Scheme 2. Reagents and conditions: (i) 120 °C, 2.5-3.5 h.
synthesis of new quinolylpyrido[2,3-b][1,4]benzodiazepinones
via MCR, using pyridine fusion with
a diazepine unit Table 1. Synthesis of quinolylpyrido[2, 3-b][1,4]benzodiazepin-7-ones 7a–j.
successfully. The obtained heterocycles were screened for
their antiproliferative activities. Docking studies were
performed to predict binding affinity for the MDM2 protein.
Product
R
Me
H
R1
H
R2
Me
Me
H
Time (h) Yield (%) M.P. °C a
7a
2.8
3.1
3.0
3.2
2.9
2.6
3.2
3.5
2.7
3.0
88
85
86
83
89
88
83
76
80
78
296―298
268―270
252―254
247―248
288―290
272―274
231―232
236―237
242―243
278―280
7b
H
Results and discussion
7c
Me
H
Cl
Cl
H
7d
H
Chemistry
7e
Me
H
Me
Me
H
As shown in Scheme 1, all requisite quinoline aldehydes 2-3
7f
H
employed in the present work were prepared according to the
reaction between the respective 2-chloroquinoline-3-
7g
Me
H
Cl
Cl
H
7h
H
carbaldehyde 1a
K2CO3 in DMF at reflux (to afford 2a
presence of TBA-HS in DMSO at 45-50 °C (to afford 3a
-
b
and phenol in the presence of anhydrous
), or sodium azide in the
). For
, compound 1a was heated with
7i
7j
Me
H
Me
Me
-b
H
aUncorrected
-b
the synthesis of aldehyde
4
70% AcOH18 prior to allylation19 (Scheme 1).
The allylation of heterocycles 7a
presence of anhydrous K2CO3 in DMF, yielded the
corresponding N5-allylated products 8a , after 12 h of stirring
of the reaction mass (Scheme 3, Table 2). Spectroscopic data
of all allylated compounds 8a confirmed the regioselectivity
-j, performed in situ in the
-j
-j
allylation at nitrogen N-5 of the diazepine ring (and not at
nitrogen N-10), supported further by the literature.20
2 | J. Name., 2012, 00, 1-3
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cell lines; A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573
(lung), T-47D (breast) and WiDr (colon), employing the SRB
assay.21 The experimental GI50 values are summarized in Table
3, and compared with those of the standard drugs (cisplatin,
etoposide and camptothecin) after 48 h of treatment. It was
observed that each cell line remained a target of minimum one
compound considering 50 µM a GI50 value. Compounds 7b
, 7d,
7e, 7g, 8a, 8c, 8e, 8g and 8i, were found active against HeLa
cell line (cervix), with GI50 values in the 3.8—43 µM range,
fitting into this analogy. Compound 8c, on the other hand,
having the lowest GI50 value of 3.8 µM resembled the standard
drug etoposide (3.3 µM) in activity, against the same cell line.
With GI50 values in the same range as those of 8c, compounds
8g and 8i produced similar effect against HeLa cells. T-47D
(breast) and WiDr (colon) are other cell lines against which
maximum three compounds; 8c, 8g and 8i, registered a
notable resistance. While 8g and 8i with GI50 values of 24 µM
and 26 µM against T-47D cells, respectively, were found very
near to standard etoposide, 8c with GI50 value of 5.8 µM was
comparable to the standard camptothecin in the activity.
Furthermore, these compounds registered 26, 15 and 5.5 µM
respectively, as the GI50 values against WiDr (colon) cell line,
which resembled the standard drugs cisplatin, etoposide, and
camptothecin, respectively. Furthermore, TGI and LC50 values
Scheme 3: Reagents and condition (i) K2CO3, DMF, rt, 10-12 h.
Table 2: Synthesis of 5-allylquinolylpyrido[2,3-b][1,4] benzodiazepin-7-ones 8a-j.
Product
8a
R
Me
H
R1
H
R2
Yield (%)
93
M.P. °C a
Me
227―228
8b
8c
8d
8e
8f
H
Me
H
89
90
91
94
87
92
90
93
91
238―240
199―200
218―219
207―208
200―201
189―190
232―234
177―178
248―249
for all the tested compounds 7-8 are >100 µM, denoting the
Me Cl
absence of cell killing ability of the compounds.
H
Me
H
Cl
H
H
H
From the results on antiproliferative activity some
structure-activity relationships have been formed (Fig. 2).
Briefly, the biological activity could be enhanced by replacing
Me
Me
H
8g
8h
8i
Me Cl
H
Me
H
Cl
H
H
H
the H on N-5 with an allyl group (8 > 7). The derivatives with
Me
Me
two methyl groups at position 9 of the tricycle are more
potent than their corresponding analogues bearing only
8j
aUncorrected
hydrogens (8e
fragment, either a phenoxy group at position 2 (8c
chloro substituent at position 7 (8c 8a 8g 8e) exhibit higher
>
8f
,
8g
>
8h). Considering the quinolone
>
8g) or a
All of the newly synthesized compounds, 7a-j and 8a-j,
1
>
,
>
were characterized by elemental, mass spectrometry, and H
NMR, 13C NMR, DEPT-135 and IR spectroscopic data, which are
summarized in the experimental section. Two 1H NMR singlets;
one at δ 1.12–1.21 ppm and second at δ 1.15–1.25 ppm can be
attributed to six protons of two methyl groups, three each
attached to C–9. Two doublets; one at δ 5.57–5.98 ppm with
activity. The lead compound 8c holds all the aforementioned
substitutions.
coupling constant J = 5.2–5.4 Hz, and second in the
6.95 ppm range with J = 4.4–5.2 Hz, can be assigned to NH–5
and methine CH–6 protons respectively, in 7a . The NH–5
proton found in 7a did not appear in allylated products 8a
confirming that NH-5 took part in the allylation. On the other
hand, NH 11 proton showed a singlet in the δ 8.86–9.92 ppm
range, in all the compounds 8a . IR bands; one in the
2850―3020cm-1 range and second in the 3210–3510 cm-1
range, can be assigned to C–H and N–H vibrations,
respectively. A band in the 1631–1660 cm-1 range confirms
C=O carbonyl group in all the heterocycles. Two bands; one in
the 1080–1185 cm-1 range and second in the 1310–1395 cm-1
range confirmed the C–O and C–N bonds respectively.
ꢀ 5.78–
-
j
-j
-j,
–
-
j
Fig. 2. Structure–activity relationship parameters defined during this study.
Functional groups that enhance the antiproliferative activity are depicted
with dashed lines.
ν
ν
About 50% of all human tumours express wild-type p53,
which is one of the most potent tumour suppressor proteins in
human cancers. The ability of p53 to bind to
The antiproliferative activity of all the heterocycles was
evaluated using a panel of six representative human tumour
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Table 3. Antiproliferative activity (GI50) against human solid tumour cells.
Cell line (origin)a
Compound
A549
(lung)
—
HBL-100
(breast)
—
HeLa
(cervix)
—
SW1573
T-47D
(breast)
—
WiDr
(colon)
—
(lung)
—
7a
7b
7c
7d
7e
7f
97 (±4.5)
>100
93 (±10)
82 (±25)
—
84 (±22)
>100
27 (±3.7)
>100
>100
>100
>100
>100
—
>100
>100
96 (±7.7)
89 (±16)
—
>100
>100
96 (±5.9)
93 (±10)
—
62 (±7.4)
65 (±20)
—
43 (±11)
25 (±0.2)
—
7g
7h
7i
31 (±14)
—
48 (±17)
—
26 (±6.4)
—
77 (±3.2)
—
38 (±5.3)
—
41 (±0.9)
—
—
—
—
—
—
—
7j
>100
37 (±6.6)
—
>100
>100
>100
>100
—
>100
36 (±0.6)
—
>100
69 (±15)
—
8a
8b
8c
8d
8e
8f
62 (±24)
—
25 (±4.5)
—
5.3 (±2.4)
>100
34 (±15)
>100
19 (±7.5)
>100
22 (±9.0)
—
21 (±0.8)
>100
3.8 (±0.3)
>100
29 (±2.1)
>100
>100
>100
52 (±4.5)
>100
61 (±3.3)
—
5.8 (±0.6) 5.5 (±1.0)
>100
56 (±18)
>100
>100
83 (±20)
>100
52 (±5.5)
>100
33 (±5.7)
>100
8g
8h
8i
23 (±8.4)
>100
8.4 (±3.4)
>100
24 (±0.2)
>100
26 (±1.4)
>100
28 (±4.9)
—
5.6 (±0.5)
—
26 (±1.2)
—
15 (±7.9)
—
8j
[A]
[B]
[C]
—
1.9 (±0.2)
1.4 (±0.1)
2.0 (±0.3)
3.3 (±1.6)
3.0 (±0.4)
14 (±1.5)
15 (±2.3)
22 (±5.5)
26 (±5.3)
23 (±3.1)
—
—
0.23 (±0.05) 0.6 (±0.4) 0.25 (±0.12) 2.0 ±(0.5) 1.8 (±0.7)
[A]: Cisplatin, [B]: Etoposide, [C]: Camptothecin. a Values are given in μM and are means of two to four experiments; standard deviation is given in parentheses.
DNA can be inhibited by the human murine double minute 2
(MDM2) oncoprotein which activates transcription and and our benzodiazepinones, it was thought reasonable to
promotes rapid degradation of p53. Benzodiazepine-like predict the interactions of the synthesized compounds 7a
compounds, such as TDP222669 (Fig. 3), have been reported in and 8a with the p53-binding domain of MDM2. Thus, all the
Based on the structure similarities between TDP222669
-j
-j
the literature having the ability to inhibit p53-MDM2 compounds were docked in the active site of human MDM2
interactions.22 The study of the antiproliferative activity of (PDB ID: 1T4E). To validate the docking protocol, reference
TDP222669 gave IC50 (72 h) values of 33-58 µM and >132 µM compound TDP222669 was also docked in the active site and
in human tumour cell lines expressing wt p53 and mutant/null its orientation was studied. The docking scores of the
p53, respectively.22d
compounds are shown in Table 4. The lead compound 8c
showed a glide score of -6.90 which was found to be
comparable to that of the reference compound TDP222669 (-
6.92). From the series of benzodiazepinones, two compounds
Cl
8a and 8g displayed better glide scores than the lead 8c
However, they showed reduced antiproliferative activity than
8c
.
HO2C
O
I
N
.
Cl
The binding interactions of p53-MDM2 are mediated by
N
hydrophobic surface pockets, namely F19, W23 and L26 (p53
numbering). These pockets are surrounded by various
hydrophobic residues i.e. M50, L54, L57, G58, I61, M62, Y67,
H73, V75, F91, V93, H96, I99 and Y100. The iodophenyl group
of TDP222669 fitted well into the F19 pocket (Fig. 4A),
O
H
TDP222669
Fig. 3. Structure of MDM2 inhibitor TDP222669.
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whereas the 4-chlorobenzyl group attached to the nitrogen
occupied the W23 pocket and the 4-chlorophenyl ring fitted
into the L26 pocket. The hydroxyl part of the carboxylic acid
formed a hydrogen bond with the residue V93 indicating that
TDP222669 is well fitted into the defined hydrophobic pockets.
Good contacts of TDP222669 were observed with L54, L57,
I61, M62, Y67, V93 and I99 residues. The chlorophenyl group
of the quinoline ring of compound 8c was oriented towards
the F19 pocket, the cyclohexanone group attached to
diazepine fitted into the W23 pocket and the propenyl group
attached to the nitrogen of diazepine scaffold fitted well into
the L26 pocket indicating that compound 8c was
accommodated nicely into the active site of MDM2 (Fig 4B).
The NH part of the diazepine ring formed a hydrogen bond
with residue L54. Good contacts of compound 8c with L54,
F55, I61, M62, F91, V93, H96 and I99 residues might explain in
part of its antiproliferative activity. The orientation of
compound 7j was different from compound 8c
. The
pyridobenzodiazepine scaffold of compound 7j was oriented
outside the active site of MDM2 as shown in Fig. 4C. It does
not form any hydrogen bond with the active site residues and
this might be one of the reasons for its lack of activity.
Table 4. Docking scores of compounds 7-8 and TDP222669.
Fig. 4. Binding modes of compounds A) TDP222669, B) 8c and C) 7j into the
active site of MDM2 (PDB ID: 1T4E). Left: docked pose; right: electrostatic
surface.
Compound ID
G-score
-5.98
-5.55
-5.80
-6.54
-5.07
-4.82
-5.71
-4.71
-4.69
-4.20
Compound ID
G-score
-7.50
-5.29
-6.90
-5.54
-5.61
-5.72
-7.00
-6.40
-6.21
-4.45
-6.92
7a
7b
7c
7d
7e
7f
8a
8b
Experimental
8c
8d
Materials and methods
8e
All solvents and reagents were used as supplied from the
commercial sources. Recorded all melting points are
uncorrected. IR spectra were recorded on Shimadzu FT-IR 8401
spectrometer using KBr discs, and are expressed as wave
8f
7g
7h
7i
8g
8h
8i
8j
1
numbers (cm-1). H NMR and 13C NMR spectra were recorded
7j
TDP222669
on a Bruker Avance 400 spectrometer operating at 400 MHz
1
for H NMR and 100 MHz for 13C NMR as solutions in DMSO,
unless and otherwise indicated. Chemical shifts are expressed
in parts per million (ppm, δ) and referenced to the residual
protic solvent. Coupling constants are expressed in Hertz (Hz).
Splitting patterns are designated as s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet. The degree of substitution (C,
CH, CH2, and CH3) was determined by the APT method. The ESI
mass spectra were measured on Shimadzu LCMS-2010
spectrometer. TLC was performed on Merck 60 F254 pre-
coated silica plates, and spots were detected either by means
of UV (254 nm, 366 nm) or permanganate solution [KMnO4 (3
g), K2CO3 (20 g), NaOH (5 mL, 5% in H2O), H2O (300 mL)] or 2,4
dinitrophenylhydrazoine solution [2,4-DNP (12 g), Conc. H2SO4
(6 mL), Water (8 mL), EtOH (20 mL)].
Conclusions
In conclusion, we have demonstrated the multicomponent
synthesis of 20 new quinolylpyrido[2,3-b][1,4]benzodiazepine-
7-ones
by
heating
quinoline-carbaldehyde,
2,3-
diaminopyridine and 1,3-cyclohexadione under solvent-free
conditions and in the absence of catalyst at 120 °C. Many of
these newer diazepine-heterocycles displayed noticeable
biological activities against human solid tumour cell lines HeLa
(cervix), T-47D (breast) and WiDr (colon). Compound 8c
registered excellent resistivity against HeLa (cervix) cell line
comparable that of the standard drug etoposide, and against
T-47D (breast) and WiDr (colon) cell lines comparable to that
of the standard drug camptothecin. Compounds having
etoposide−equivalent potential include 8g and 8i against the
same cell lines. Docking studies helped us to predict the
binding pattern of the compounds in the active site of MDM2
and could explain their observed antiproliferative activity.
Further experiments will be necessary in order to confirm
All the computational studies were performed using
Maestro 9.0 molecular modelling software.23 Structures of the
compounds were sketched and cleaned using ‘building tools’
option in Maestro 9.0 software. Energy minimization was
carried out using OPLS 2005 force field in standard option
“Ligprep 2.3”. TDP222669 (benzodiazepinedione MDM2
MDM2 as the cellular target of the lead compound 8c
.
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Journal Name
IR (KBr): νmax = 790, 1012, 1145, 1358, 1438, 1580, 1645, 2975,
3202cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 2.10 (m, 2H, 3–H),
2.21 (m, 2H, 8–H), 2.37 (s, 3H, 15–CH3),2.69 (m, 2H, 10–H), 5.80 (d,
1H, J = 5.2 Hz, 5–H), 6.21 (d, 1H, J = 4.8 Hz, 6–H), 6.70–7.64 (m, 12H,
antagonists) was used as reference compound which was also
minimized as per the same protocol mentioned above.
Minimized structures were used for performing molecular
docking using “Glide 5.5”. The crystal structures of MDM2
(PDB ID 1T4E) was downloaded from RCSB.24 The crystal
structure was refined by removing water molecules and
heteroatoms in standard option “protein preparation wizard”
25. Receptor grid was prepared by using default setting in
standard option “Receptor Grid Generation” in Maestro 9.0.
The van der Waals radii of the ligands were scaled to 0.8 with
partial charge cut off 0.25. All the minimized structures were
docked with a flexible docking option by extra precision
method26.
Ar–H), 8.92 (s, 1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-d6): δC
=
21.15, 32.40, 44.78, 50.02, 52.22, 108.82, 120.91, 121.13,122.88,
123.57, 125.26, 125.53, 126.61, 126.88, 127.86,129.69, 129.89,
130.06, 131.62, 131.99, 134.53, 138.80,143.25, 153.99, 156.44,
160.22, 193.08ppm; Anal. Calcd for C28H24N4O2: C, 74.98; H, 5.39; N,
12.49; Found: C, 74.91; H, 6.36; N, 12.52
6-(7-Chloro-2-phenoxyquinolin-3-yl)-9,9-dimethyl-8,9,10,11-
tetrahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-one (7c):
IR (KBr): νmax = 756, 1140, 1336, 1392, 1523, 1631, 2940, 3239,
3315, 3439cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 1.17 (s, 3H, 9–
CH3), 1.19 (s, 3H, 9–CH3), 2.22 (s, 2H, 8–CH2), 2.70 (d, 1H, J = 16.0
Hz, 10–Ha), 2.82 (d, 1H, J = 16.8Hz, 10–Hb), 5.84 (d, 1H, J = 5.2 Hz,
5–H), 6.07 (d, 1H, J =4.8 Hz, 6–H), 6.62–7.80 (m, 12H, Ar–H), 8.86 (s,
1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-d6): δC = 28.85, 32.32,
44.71, 50.16, 52.85, 108.63, 120.87, 121.25, 122.86, 123.43, 125.34,
125.57, 126.57, 126.67, 127.84,129.78, 129.98, 130.75, 131.64,
132.21, 134.53, 138.53,143.02, 153.89, 156.87, 159.54, 193.18ppm;
Anal. Calcd for C29H25ClN4O2: C, 70.08; H, 5.07; N, 11.27; Found: C,
69.00; H, 5.03; N, 11.31
General procedure for synthesis of quinolylpyrido [2, 3-
b][1,4]
benzodiazepin-7-ones, 7a-j.
A
mixture containing 2,3-diaminopyridine
5,
1,3-
cyclohexadione 6a-b and quinolone-carbaldehyde 2-4 in
equimolar amount (2 mmol) was heated at 120 ˚C under
solvent-free conditions. The progress of the reactions was
monitored by the TLC and it was found out that the reaction
got finished entirely in 2.5-3.5 h. The solid products separated
out of the reactions were washed with ethanol and dried at
room temperature. The entire products 7a-j were received
quantitatively with an excellent purity.
6-(7-Chloro-2-phenoxyquinolin-3-yl)-5,6,8,9,10,11-hexahydro-
7Hpyrido[2,3-b][1,4] benzodiazepin-7-one (7d):
IR (KBr): νmax = 790, 1012, 1145, 1358, 1438, 1580, 1645, 2975,
1
3202cm-1; H NMR (400 MHz, DMSO-d6): δH = 1.90 (m, 2H, 9–CH2),
2.20 (s, 2H, 8–CH2), 2.78 (m, 2H, 10– CH2), 5.75 (d, 1H, J = 5.2 Hz, 5–
H), 5.95 (d, 1H, J = 4.8 Hz, 6–H), 6.71–7.75 (m, 12H, Ar–H), 8.90 (s,
1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-d6): δC = 32.40, 44.61,
50.12, 52.77, 108.23, 120.22, 121.55, 122.95, 123.50, 125.02,
125.78, 126.22, 126.85, 127.82, 129.78, 130.18, 130.75, 131.64,
General Procedure for synthesis of 5-allylquinolylpyrido[2,3-
b][1,4] benzodiazepin-7-ones, 8a-j
Respective quinolylpyrido[2,3-b][1,4]benzodiazepine-7-one 7a- 134.22, 134.53, 138.53, 143.02, 153.89, 156.87, 159.68,
193.25ppm; Anal. Calcd for C27H21N4O2: C, 69.15; H, 4.51; N, 11.95;
Found: C, 69.22; H, 4.48; N, 11.91.
j
crude products were mixed thoroughly with 15 mL K2CO3 (3
mmol) suspended in DMF, and added drop-wise 5 mL of allyl
bromide (2 mmol) solution in DMF. The resulting mass was
then stirred at room temperature to complete the reaction as
6-(7-Methyltetrazolo[1,5-a]quinolin-4-yl)-9,9-dimethyl-
5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-
confirmed by the TLC (10–12 h). The reaction mixture was one (7e):
IR (KBr): νmax = 761, 980, 1175, 1310, 1385, 1580, 1645, 3220, 3340,
poured into crushed ice with constant stirring. The solid so
separated out was filtered, washed with three 10 mL cold
water portions and dried. Further, purification by aqueous
ethanol as re-crystallizing solvent, gave pure product. All
3510cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 1.21 (s, 3H, 9–CH3),
1.25 (s, 3H, 9–CH3), 2.32 (s, 2H, 8– CH2), 2.45 (s, 3H, 15–CH3), 2.79
(d, 1H, J = 16.0 Hz, 10–Ha), 2.85 (d, 1H, J = 16.8 Hz, 10–Hb), 5.98 (d,
1H, J = 5.0 Hz, 5–H), 6.33 (d, 1H, J = 4.4 Hz, 10–H), 6.34–8.36 (m, 7H,
products 8a–j were obtained quantitatively with an excellent Ar–H), 8.88 (s, 1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-d6): δC
=
26.53, 28.88, 32.33, 42.92, 44.61, 54.08, 107.58, 115.02, 116.37,
118.60, 120.70, 121.10, 122.73, 123.30, 130.84, 131.59, 133.55,
134.46, 135.04, 138.45, 139.13, 156.27, 161.14, 192.76ppm; Anal.
Calcd for C24H23N7O: C, 67.75; H, 5.45; N, 23.04; Found: C, 67.70; H,
5.48; N, 23.00.
purity.
Spectroscopy data of compounds:
6-(6-Methyl-2-phenoxyquinolin-3-yl)-9,9-dimethyl-5,6,8,9,10,11-
hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-one (7a):
6-(7-Methyltetrazolo[1,5-a]quinolin-4-yl)-5,6,8,9,10,11-hexahydro-
7H-pyrido[2,3-b][1,4]benzodiazepin-7-one (7f):
IR (KBr): νmax = 817, 1002, 1138, 1360, 1422, 1572, 1656, 2958,
3155, 3310 cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 1.14 (s, 3H, 9–
CH3), 1.16 (s, 3H, 9–CH3), 2.17 (s, 2H, 8–H), 2.35 (s, 3H, 15–CH3),
2.66 (d, 1H, J = 16.0 Hz, 10–Ha), 2.79 (d, 1H, J = 16.8 Hz, 10–Hb),
5.89 (d, 1H, J = 5.2 Hz, 5–H), 6.15 (d, 1H, J = 4.8 Hz, 6–H), 6.57–7.54
(m, 12H, Ar–H), 9.01 (s, 1H, 11–H) ppm; 13C NMR (100 MHz, DMSO-
d6): δC = 21.15, 28.54, 32.39, 44.61, 49.96, 52.63, 108.82, 120.91,
121.13, 122.75, 123.47, 125.16, 125.53, 126.61, 126.88, 127.86,
129.69, 129.89, 130.06, 131.62, 131.99, 134.53, 138.53, 143.02,
153.99, 156.44, 159.62, 192.61 ppm; Anal. Calcd for C30H28N4O2: C,
75.61; H, 5.92; N, 11.76; Found: C, 75.68; H, 5.95; N, 11.72
IR (KBr): νmax = 770, 968, 1160, 1330, 1390, 1595, 1660, 2910, 3225,
3380, 3490 cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 1.98 (m, 2H, 9–
H), 2.28 (m, 2H, 8–H), 2.35 (S, 3–H, 15–CH3), 2.72 (m, 2H, 10–H),
5.64 (d, 1H, J = 5.2 Hz, 5–H), 5.76 (d, 1H, J = 5.0 Hz, 6–H), 6.52–7.34
(m, 7H, Ar–H), 8.94 (s, 1H, 11–H) ppm; 13C NMR (100 MHz, DMSO-
d6): δC = 21.02, 22.11, 31.33, 36.62, 58.19, 117.92, 120.65, 122.25,
123.15, 123.63, 123.99, 127.50, 128.05, 129.28, 136.55, 136.48,
138.82, 147.79, 158.91, 193.22 ppm; Anal. Calcd for C22H19N7O: C,
66.49; H, 4.82; N, 24.67; Found: C, 66.55; H, 4.85; N, 24.63.
6-(6-Methyl-2-phenoxyquinolin-3-yl)-5,6,8,9,10,11-hexahydro-
7Hpyrido[2,3-b][1,4]benzodiazepin-7-one (7b):
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5NJ03280F
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ARTICLE
6-(8-Chlorotetrazolo[1,5-a]quinolin-4-yl)-9,9-dimethyl-
5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-
one (7g):
126.74, 127.62, 130.18, 131.70, 134.54, 136.68, 136.81, 136.87,
140.94, 143.22, 154.38, 156.31, 159.87, 192.50ppm; Anal. Calcd for
C33H32N4O2: C, 76.72; H, 6.24; N, 10.84; Found: C, 76.65; H, 6.28; N,
IR (KBr): νmax = 761, 980, 1175, 1310, 1385, 1580, 1645, 2917, 3220, 10.87.
1
3340, 3510cm-1; H NMR (400 MHz, DMSO-d6): δH = 1.15 (s, 3H, 9–
CH3), 1.18 (s, 3H, 9–CH3), 2.18 (s, 2H, 8–CH2), 2.63 (d, 1H, J = 16.0 5-Allyl-6-(6-methyl-2-phenoxyquinolin-3-yl)-5,6,8,9,10,11-
Hz, 10–Ha), 2.92 (d, 1H, J = 16.4 Hz, 10– Hb), 5.98 (d, 1H, J = 5.0 Hz, hexahydro- 7H-pyrido[2,3-b][1,4]benzodiazepin-7-one (8b):
5–H), 6.02 (d, 1H, J = 5.2 Hz, 6–H), 6.81–7.57 (m, 7H, Ar–H), 9.82 (s, IR (KBr): max = 748, 921, 1196, 1329, 1390, 1501, 1530, 1582, 1614,
ν
1
1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-d6): δC = 28.85, 32.32, 2923, 3147, 3311cm-1; H NMR (400 MHz, DMSO-d6): δH = 1.74 (m,
44.71, 44.88, 50.16, 52.85, 106.08, 120.87, 121.25, 122.86, 125.57, 2H, 9–H), 2.10 (m, 2H, 8–H), 2.34 (s, 3H, 15–CH3), 2.62 (m, 2H, 10–
127.84, 128.22, 129.78, 129.98, 130.70, 131.64, 134.53, 138.53, H), 3.97 (m, 2H, 22–H), 5.06 (d, 1H, J = 10 Hz, 20–Ha), 5.19 (d, 1H, J
139.58, 153.89, 159.54, 193.18ppm; Anal. Calcd for C23H20ClN7O: C, = 16.8 Hz, 20–Hb), 5.80 (m, 1H, 21– H), 6.20 (s, 1H, 6–H), 6.67–7.52
61.95; H, 4.52; N, 21.99; Found: C, 61.99; H, 4.49; N, 22.03.
(m, 12H, Ar–H), 9.00 (s, 1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-
d6): δC = 22.15, 32.47, 44.40, 50.04, 56.51, 56.54, 109.49, 117.36,
120.68, 122.16, 123.01, 123.72, 124.91, 125.52, 126.56, 126.74,
127.59, 130.05, 131.70, 134.43, 136.68, 136.81, 136.87, 139.94,
6-(8-Chlorotetrazolo[1,5-a]quinolin-4-yl)-5,6,8,9,10,11-hexahydro-
7Hpyrido[2,3-b][1,4] benzodiazepin-7-one (7h):
IR (KBr): νmax = 780, 915, 1181, 1330, 1393, 1588, 1638, 2830, 3240, 142.96, 154.38, 156.11, 159.76, 192.68ppm; Anal. Calcd for
3340cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 1.18 (s, 2H, 9–H), 2.22
C
31H28N4O2: C, 76.21; H, 5.78; N, 11.47; Found: C, 76.15; H, 5.82; N,
(m, 2H, 8–CH2), 2.80 (m, 2H, 10–H), 5.62 (d, 1H, J = 5.4 Hz, 5–H), 11.50.
5.95 (d, 1H, J = 5.2 Hz, 6–H), 6.75–7.82 (m, 7H, Ar–H), 9.62 (s, 1H,
11–H)ppm; 13C NMR (100 MHz, DMSO-d6):
δ
C = 44.88, 45.08, 50.25, 5-Allyl-6-(7-chloro-2-phenoxyquinolin-3-yl)-9,9-dimethyl-5,6,8,9,
52.90, 106.18, 120.77, 121.35, 123.02. 125.57, 127.72, 128.28, 10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-one (8c):
129.83, 130.10, 130.65, 131.78, 134.45, 138.85, 139.58, 153.95, IR (KBr): max = 770, 890, 1080, 1140, 1345, 1480, 1545, 1650, 2890,
159.22, 193.45ppm; Anal. Calcd for C21H16ClN7O: C, 60.36; H, 3.86; 3080, 3250, 3340cm-1; H NMR (400 MHz, DMSO-d6): δH = 1.21 (s,
ν
1
N, 23.46; Found: C, 60.40; H, 3.83; N, 23.40.
3H, 9–CH3), 1.28 (s, 3H, 9–CH3), 2.32 (s, 2H, 8–H), 2.75 (d, 1H, J =
16.0 Hz, 10–Ha), 2.85 (d, 1H, J = 16.0 Hz, 10– Hb), 3.50 (m, 2H, 22–
H), 5.18 (d, 1H, J = 10 Hz, 20–Ha), 5.31 (d, 1H, J = 16.4 Hz, 20–Hb),
5.75 (m, 1H, 21–H), 6.10 (s, 1H, 6–H), 6.75–7.71 (m, 12H, Ar–H),
6-(1-Allyl-6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-9,9-dimethyl-
5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-
one (7i):
8.98 (s, 1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-d6):
C = 27.99,
δ
IR (KBr): νmax = 787, 933, 1116, 1285, 1392, 1444, 1519, 1572, 1607, 28.83, 32.70, 44.52, 51.16, 56.51, 57.14, 109.57, 114.45, 120.73,
1653, 2917, 2975, 3051, 3215, 3368cm-1; 1H NMR (400 MHz, DMSO- 122.25, 123.11, 123.72, 125.22, 125.45, 126.43, 126.74, 127.56,
d6): δH = 1.12 (s, 3H, 9–CH3), 1.15 (s, 3H, 9–CH3), 2.120 (s, 2H, 8–H), 130.18, 131.70, 134.54, 136.68, 136.81, 136.87, 141.04, 143.22,
2.26 (s, 3H, 15–CH3), 2.61 (d, 1H, J = 16.0 Hz, 10–Ha), 2.75 (d, 1H, J = 154.38, 156.31, 159.68, 192.74ppm; Anal. Calcd for C32H29ClN4O2: C,
16.0 Hz, 10–Hb), 4.71 (m, 2H, 22–H), 5.02 (m, 2H, 20–H), 5.57 (d, 71.57; H, 5.44; N, 10.43; Found: C, 71.52; H, 5.47; N, 10.39.
1H, J = 5.2 Hz, 5–H), 5.78 (d, 1H, J = 5.2 Hz, 6–H), 5.88 (s, 1H, 21–H),
6.43–7.84 (m, 7H, Ar–H), 8.92 (s, 1H, 11–H)ppm; 13C NMR (100 MHz, 5-Allyl-6-(7-chloro-2-phenoxyquinolin-3-yl)-5,6,8,9,10,11-
DMSO-d6): δC = 20.34, 20.38, 28.24, 28.68, 28.84, 32.31, 44.15, hexahydro- 7H-pyrido[2,3-b][1,4]benzodiazepin-7-one (8d):
44.61, 49.97, 54.17, 107.80, 115.18, 119.72, 120.48, 120.99, 123.24, IR (KBr): max = 780, 960, 1055, 1178, 1350, 1410, 1560, 1640, 2896,
ν
128.73, 131.51, 131.61, 132.73, 133.72, 133.95, 136.26, 138.52, 3250, 3455cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 1.362.59 (m,
156.16, 161.14, 192.74ppm; Anal. Calcd for C27H28N4O2: C, 73.61; H, 6H, 8, 9 & 10–H), 3.88 (m, 2H, 22–H), 5.15 (d, 1H, J = 10 Hz, 20–Ha),
6.41; N, 12.72; Found: C, 73.50; H, 6.45; N, 12.69.
5.22 (d, 1H, J = 16.8 Hz, 20–Hb), 5.98 (m, 1H, 21–H), 6.15 (s, 1H, 6–
H), 6.62–7.45 (m, 12H, Ar–H), 9.05 (s, 1H, 11–H)ppm; 13C NMR (100
MHz, DMSO-d6): δC = 32.58, 44.38, 51.26, 56.65, 57.04, 109.70,
117.34, 120.83, 122.21, 123.31, 123.72, 125.22, 125.45, 126.56,
6-(1-Allyl-6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-5,6,8,9,10,11-
hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-one (7j):
IR (KBr): νmax = 782, 940, 1126, 1278, 1395, 1444, 1580, 1653, 2895, 126.74, 127.43, 130.08, 131.81, 134.40, 136.54, 136.68, 136.87,
2975, 3051, 3210cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 2.18 (m, 141.22, 143.31, 154.38, 156.26, 159.68, 193.68ppm; Anal. Calcd for
2H, 9–H), 2.21 (m, 2H, 8–H), 2.30 (s, 3H, 15–CH3), 2.68 (m, 2H, 10– C30H25ClN4O2: C, 70.79; H, 4.95; N, 11.01; Found: C, 70.82; H, 4.98;
H), 4.75 (m, 2H, 22–H), 5.52 (m, 2H, 20–H), 5.52 (d, 1H, J = 5.2 Hz, N, 11.05.
5–H), 5.92 (d, 1H, J = 4.8 Hz, 6–H), 6.03 (s, 1H, 21–H), 6.82–7.75 (m,
7H, Ar–H), 9.52 (s, 1H, 11– H)ppm; 13C NMR (100 MHz, DMSO-d6): 5-Allyl-6-(7-methyltetrazolo[1,5-a]quinolin-4-yl)-9,9-dimethyl-
δ
C = 20.34, 28.75, 28.95, 32.22, 44.88, 44.98, 50.07, 54.53, 107.65, 5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-
115.25, 119.85, 120.77, 121.10, 123.35, 128.73, 131.51, 131.61, one (8e):
132.73, 133.72, 133.90, 136.53, 138.22, 156.88, 161.22, IR (KBr): νmax = 766, 1046, 1393, 1469, 1576, 1660, 2890, 2956,
192.80ppm; Anal. Calcd for C25H24N4O2: C, 72.60; H, 5.86; N, 13.55; 3217, 3480cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 11.07 (s, 3H, 9–
Found: C, 72.80; H, 5.86; N, 13.58.
CH3), 1.12 (s, 3H, 9–CH3), 2.07 (m, 2H, 8–H), 2.34 (s, 3H, 15–CH3),
2.56 (d, 1H, J = 16.0 Hz, 10–Ha), 2.70 (d, 1H, J = 16.0 Hz, 10–Hb),
4.02 (m, 2H, 24–H), 5.08 (d, 1H, J = 10 Hz, 22–Ha), 5.28 (d, 1H, J =
16.4 Hz, 22–Hb), 5.78 (m, 1H, 23–H), 6.06 (s, 1H, 6–H), 6.53–7.38
(m, 7H, Ar–H), 8.86 (s, 1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-
5-Allyl-6-(6-methyl-2-phenoxyquinolin-3-yl)-9,9-dimethyl-
5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-
one (8a):
IR (KBr):
νmax = 780, 850, 980, 1085, 1368, 1450, 1588, 1645, 2940, d6): δC = 21.15, 27.81, 28.93, 32.45, 44.85, 50.40, 56.77, 58.14,
1
3210cm-1; H NMR (400 MHz, DMSO-d6): δH = 1.12 (s, 3H, 9–CH3), 108.96, 116.14, 117.82, 120.77, 122.09, 122.99, 123.63, 123.83,
1.15 (s, 3H, 9–CH3), 2.25 (s, 2H, 8–H), 2.45 (s, 3H, 15–CH3), 2.65 (d, 127.40, 127.97, 129.12, 129.25, 129.83, 136.24, 136.48, 138.41,
1H, J = 16.0 Hz, 10–Ha), 2.72 (d, 1H, J = 16.0 Hz, 10–Hb), 3.89 (m, 139.57, 158.73, 193.01ppm; Anal. Calcd for C27H27N7O: C, 69.66; H,
2H, 22–H), 5.13 (d, 1H, J = 10 Hz, 20–Ha), 5.29 (d, 1H, J = 16.4 Hz, 5.85; N, 21.06; Found: C, 69.60; H, 5.88; N, 21.02.
20–Hb), 5.78 (m, 1H, 21–H), 6.05 (s, 1H, 6–H), 6.70–7.82 (m, 12H,
Ar–H), 8.89 (s, 1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-d6): δC
=
5-Allyl-6-(7-methyltetrazolo[1,5-a]quinolin-4-yl)-5,6,8,9,10,11-
20.35, 28.56, 28.74, 32.68, 44.52, 51.04, 56.51, 56.54, 109.49, hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-one (8f):
117.36, 120.70, 122.16, 123.01, 123.72, 125.12, 125.45, 126.54,
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ARTICLE
IR (KBr):
Journal Name
ν
max = 750, 990, 1080, 1355, 1425, 1588, 1655, 2890, 3150, 132.98, 133.64, 134.71, 134.88, 135.77, 136.26, 137.14, 140.36,
3250, 3388cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 1.25 (m, 2H, 9– 158.37, 161.28, 192.53 ppm; Anal. Calcd for C28H28N4O2: C, 74.31;
H), 2.21 (m, 2H, 8–H), 2.44 (s, 3H, 15–CH3), 2.66 (m, 2H, 10–H), 4.18 H, 6.24; N, 12.38; Found: C, 74.39; H, 6.28; N, 12.42
(m, 2H, 24–H), 5.22 (d, 1H, J = 10 Hz, 22–Ha), 5.30 (d, 1H, J = 16.4
Hz, 22–Hb), 5.80 (m, 1H, 23–H), 6.02 (s, 1H, 6–H), 6.62–7.75 (m, 7H,
Acknowledgements
Ar–H), 8.98 (s, 1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-d6): δC
=
21.25, 32.21, 44.85, 50.48, 56.87, 58.14, 108.82, 116.22, 117.96,
120.63, 122.09, 122.83, 123.77, 124.12, 127.40, 127.97, 129.09,
129.25, 129.83, 136.24, 136.48, 138.57, 139.41, 158.73,
192.91ppm; Anal. Calcd for C25H23N7O: C, 68.63; H, 5.30; N, 22.41;
Found: C, 68.70; H, 5.35; N, 22.45.
We express our thanks to the Head, Department of Chemistry,
S. P. University for providing required research facilities. We
(HAB, TRS & GCB) are grateful to the UGC, New Delhi for
financial support under the UGC schemes; RFSMS and the
UGC-CAS program.
5-Allyl-6-(8-chlorotetrazolo[1,5-a]quinolin-4-yl)-9,9-dimethyl-
5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-
one (8g):
Notes and references
1
H. Tucker and D. J. Le Count, In Comprehensive Heterocyclic
Chemistry II; A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Eds.;
Pergamon Press, 1996; pp 151−182.
IR (KBr): max = 810, 978, 1090, 1158, 1345, 1396, 1568, 1660, 2840,
ν
1
3025, 3180, 3355cm-1; H NMR (400 MHz, DMSO-d6): δH = 1.12 (s,
3H, 9–CH3), 1.18 (s, 3H, 9–CH3), 2.21 (m, 2H, 8–H), 2.65 (d, 1H, J =
16.0 Hz, 10–Ha), 2.78 (d, 1H, J = 16.0 Hz, 10– Hb), 4.12 (m, 2H, 24–
H), 5.18 (d, 1H, J = 10 Hz, 22–Ha), 5.32 (d, 1H, J = 16.4 Hz, 22–Hb),
5.80 (m, 1H, 23–H), 6.12 (s, 1H, 6–H), 6.65–7.49 (m, 7H, Ar–H), 9.02
2
a) A. Kondaskar, S. Kondaskar, J. C. Fishbein, B. A. Carter-
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(s, 1H, 11–H)ppm; 13C NMR (100 MHz, DMSO-d6):
C = 27.45, 28.32,
δ
32.28, 44.77, 50.56, 56.83, 58.04, 109.06, 116.22, 117.72, 120.97,
122.19, 122.83, 123.63, 123.97, 127.40, 127.58, 129.12, 129.25,
129.83, 136.29, 136.48, 138.57, 139.48, 158.29, 192.71ppm; Anal.
Calcd for C26H24ClN7O: C, 64.26; H, 4.98; N, 20.18; Found: C, 64.23;
H, 5.01; N, 20.13.
5-Allyl-6-(8-chlorotetrazolo[1,5-a]quinolin-4-yl)-5,6,8,9,10,11-
hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-7-one (8h):
IR (KBr): max = 750, 935, 1150, 1345, 1408, 1590, 1658, 2912, 3150,
ν
3330cm-1; 1H NMR (400 MHz, DMSO-d6): δH = 1.21 (m, 2H, 9–H),
2.05 (m, 2H, 8–H), 2.65 (m, 2H, 10–H), 4.25 (m, 2H, 24–H), 5.28 (d,
1H, J = 10 Hz, 22–Ha), 5.36 (d, 1H, J = 16.4 Hz, 22–Hb), 5.89 (m, 1H,
23–H), 6.07 (s, 1H, 6– H), 6.65–7.82 (m, 7H, Ar–H), 8.89 (s, 1H, 11–
H)ppm; 13C NMR (100 MHz, DMSO-d6): δC = 30.54, 42.85, 44.65,
54.28, 107.69, 115.42, 116.81, 118.78, 120.85, 121.67, 122.69,
123.72, 130.35, 131.65, 133.88, 134.66, 135.25, 139.15, 139.65,
156.84, 161.73, 192.59ppm; Anal. Calcd for C24H20ClN7O: C, 62.95;
H, 4.40; N, 21.41; Found: C, 62.89; H, 4.42; N, 21.39.
3
4
5-Allyl-6-(1-allyl-6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-9,9-
dimethyl-5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]
benzodiazepin-7-one (8i):
5
6
IR (KBr): νmax = 772, 950, 1090, 1278, 1389, 1450, 1526, 1580, 1653,
1
2918, 3055, 3240cm-1; H NMR (400 MHz, DMSO-d6): δH = 1.11 (s,
Future, 1983, 8, 110.
3H, 9–CH3), 1.31 (s, 3H, 9–CH3), 2.12 (s, 2H, 8–H), 2.29 (s, 3H, 15–
CH3), 2.55 (d, 1H, J = 16.0 Hz, 10a–H), 2.72 (d, 1H, J = 15.6 Hz, 10b–
H),4.03 (m, 2H, 22–H), 4.67 (m, 2H, 25–H), 4.96 (m, 4H, 20 & 23–H),
5.73 (m, 2H, 21 & 24–H), 5.93 (s, 1H, 6–H), 6.52–7.24 (m, 7H, Ar–H),
a) F. Savelli, A. Boido, I. Vazzana and F. Sparatore, J. Heterocycl.
Chem., 1987, 24, 1709; b) F. Savelli, A. Boido, M. Satta, A. Peana
and C. Marzano, Farmaco, 1994, 49, 259; c) F. Savelli, A. Boido
and G. Damonte, J. Heterocycl. Chem., 1996, 33, 1737.
D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev. 2003,
103, 893.
8.89 (s, 1H, 11– H)ppm; 13C NMR (100 MHz, DMSO-d6):
C = 20.34,
δ
7
8
9
27.93, 28.94, 32.44, 44.15, 44.35, 50.02, 56.40, 57.23, 109.66,
114.93, 116.05, 116.75, 119.77, 120.40, 121.25, 122.16, 123.48,
131.22, 131.37, 132.98, 133.85, 134.72, 135.95, 136.28, 137.13,
140.48, 156.36, 161.22, 192.17ppm; Anal. Calcd for C30H32N4O2:
C,74.97; H, 6.71; N, 11.66; Found: C, 75.05; H, 6. 68; N, 11.62.
B. H. Jaup and G. Dotevall, Scand. J. Gastroenterol., 1981, 16
,
769.
a) N. F. Muller and R. P. Dessing, European Society of Clinical
Pharmacy. European Drug Index, 1997, Volume 33; b) D. J.
Triggle, Dictionary of Pharmacological Agents. Boca Raton:
Chapman & Hall/CRC. 1996, p. 1680; c) W. J. Kinnier, R. D. Tabor
and L. Y. Norrell, Biochem. Pharmacol., 1984, 33, 3001.
5-Allyl-6-(1-allyl-6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-
5,6,8,9,10,11-hexahydro-7H-pyrido[2,3-b][1,4]benzodiazepin-
7-one (8j):
10 a) W. E. Eberlein, W. W. Engel, G. Trummlitz, G. Schmidt and R.
Hammer, J. Med. Chem. 1988, 31, 1169; b) W. G. Eberlein, G.
Trummlitz, W. W. Engel, G. Schmidt, H. Pelzer and N. Mayer, J.
Med. Chem., 1987, 30, 1378; c) W. W. Engel, W. G. Eberlein, G.
IR (KBr): νmax = 755, 921, 1027, 1147, 1222, 1362, 1466, 1530, 1576,
1
1642, 1959, 3186, 323, 3373cm-1; H NMR (400 MHz, DMSO-d6): δH
= 1.99–2.25 (m, 4H, 8 & 9–CH2), 2.29 (s, 3H, 15–CH3), 2.68 (m, 2H,
10–CH2), 4.03 (m, 2H, 22–H), 4.67 (m, 2H, 25–H), 4.96 (m, 4H, 20 &
23–H), 5.73 (m, 2H, 21 & 24–H), 5.93 (s, 1H, 6–H), 6.52–7.24 (m, 7H,
Mihm, R. Hammer and G. Trummlitz, J. Med. Chem., 1989, 32
,
Ar–H), 8.89 (s, 1H, 5–H) ppm; 13C NMR (100 MHz, DMSO-d6): δC
=
1718.
11 a) J. F. LiBgeois, J. Bruhwyler, J. Damas, T. P. Nguyea, M. G. Eric,
20.35, 22.02, 31.08, 36.57, 44.11, 57.72, 110.73, 115.96, 116.88,
119.82, 120.39, 121.01, 122.07, 123.37, 128.65, 131.08, 131.32,
C. M. Mercier, F. A. Register and J. E. Delarget, J. Med. Chem.,
8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5NJ03280F
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A series of 20 benzodiazepinones resembling MDM2 inhibitors was synthesized. The antiproliferative activity of
these compounds was studied.