Synthesis of new and potent analogues of anti-tuberculosis agent 5-nitro-furan-2-carboxylic acid 4-(4-benzyl-piperazin-1-yl)-benzylamide with improved bioavailability

Article abstract of DOI:10.1016/j.bmcl.2006.02.048

Previously, the lead compound 5-nitro-furan-2-carboxylic acid 4-(4-benzyl-piperazin-1-yl)-benzylamide was identified in our anti-tuberculosis drug discovery program. Although this compound demonstrated excellent in vitro activity, it did not meet the expe

Full text of DOI:10.1016/j.bmcl.2006.02.048

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2584–2589
Synthesis of new and potent analogues of anti-tuberculosis agent
5-nitro-furan-2-carboxylic acid 4-(4-benzyl-piperazin-1-yl)-
benzylamide with improved bioavailability
Rajendra P. Tangallapally,a Robin E. B. Lee,a Anne J. M. Lenaertsb and Richard E. Leea,*
aDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center,
847 Monroe Ave., Rm 327, Memphis, TN 38163, USA
bDepartment of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA
Received 23 December 2005; revised 16 February 2006; accepted 16 February 2006
Available online 10 March 2006
Abstract—Previously, the lead compound 5-nitro-furan-2-carboxylic acid 4-(4-benzyl-piperazin-1-yl)-benzylamide was identified in
our anti-tuberculosis drug discovery program. Although this compound demonstrated excellent in vitro activity, it did not meet the
expected in vivo profiles due to structural features that resulted in rapid metabolic cleavage and poor absorption, which therefore
limited its bioavailability. In efforts to increase the bioavailability, a new series of analogues was successfully synthesized using three
modification schemes: replacement of the benzyl group on the piperazine C-ring with carbamate and urea functional groups; intro-
duction of a nitrogen atom into the aromatic ring-B; and expansion of the ring-B to a bicyclic tetrahydroisoquinoline moiety. These
modifications retained strong activity and in some case gained superior anti-tuberculosis activity, increased absorption, and serum
half life.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Mycobacterium tuberculosis is a deadly obligate human
pathogen. The global effect of tuberculosis is immense.
According to the World Health Organization, in 2003
there were 8.8 million new cases reported, killing 1.7 mil-
lion people.1 Based on the trend over the past few years,
a total of 225 million new cases and 79 million deaths
are expected from tuberculosis between 1998 and
2030.2 According to the Global Burden of Disease
Study, TB is the seventh leading cause of global prema-
ture mortality and disability, and this figure is estimated
to remain the same even in the year 2020.3 Further com-
plicating this already adverse situation is the increase in
multi-drug resistant tuberculosis strains,4 and the syner-
gistic pathological effects of tuberculosis and HIV
co-infection. Hence, there is an urgent need to develop
new, potent, and fast acting anti-tuberculosis drugs with
low toxicity profiles.
amide compounds with inhibitory activity against
M. tuberculosis.5,6 Among them, 5-nitro-furan-2-carbo-
xylic acid 4-(4-benzyl-piperazin-1-yl)-benzylamide [I]
was identified with good in vitro activity (MIC90
0.0125 lg/mL) (Fig. 1).6 However, this compound did
not perform well during in vivo studies due to a short
biological half life and rapid elimination. Analysis of
the structure I led us to attribute this behavior to two
sites that are likely candidates for rapid metabolic cleav-
age: the furanyl amide bond and the benzyl-piperazine
bond. Hence, in this study these features were modified
in an attempt to achieve increased bioavailability. Ring-
A has been retained intact, as previous attempts to
change this part of the molecule to nitrothiophene and
nitroimidazole resulted in loss of activity against
O
-O
O
O
In our ongoing efforts to develop new anti-tuberculosis
agents, we previously discovered a series of nitrofuranyl
O
N
n
N
N+
Ring A
N
NH
N
X
O
N
R
Ring B
O2N
I
Ring C
II; R = Alkyl, NCOOR, NCONHR;
X = C, N; n = 1, 2
Keywords: Tuberculosis; Antibiotic; Bioavailability; Nitrofuran.
*
Figure 1. Lead compound from the previous library and general
structures of the target compounds.
Corresponding author. Tel.: +1 9014486018; e-mail: relee@
utmem.edu
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.02.048

R. P. Tangallapally et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2584–2589
2585
M. tuberculosis. However, previous modifications at
ring-B and ring-C were well tolerated lending hope that
the proposed modifications would not significantly
diminish the anti-tuberculosis activity while increasing
the potential bioavailability.6
corresponding carbamate derivatives 1b–f, or with alkyl
isocyanates9 to afford the corresponding urea derivatives
1g and 1h. The same approach was employed to make
the diazepane (seven-membered ring) analogues, start-
ing with 1-boc-(1,4) diazepane [6b] instead of 6a.
In this study, ring-C analogues were explored by
replacement of the benzyl group with more metabolical-
ly stable functional groups. During synthesis of interme-
diate 9a, it was discovered that the biological activity of
the boc-protected 1a was several fold more active than
the lead compound I. Therefore, the functionalization
of the terminal nitrogen on the piperazine ring was fo-
cused using carbamate and urea groups. Two modifica-
tions to ring-B were explored. The first modification was
the introduction of a nitrogen atom into the ring to
make the molecule more polar, in order to facilitate
solubility and increase absorption. In the second modi-
fication, the ring was expanded to a bicyclic, tetrahy-
droisoquinoline moiety to make a more rigid tertiary
amide, which was expected to be more resistant to pro-
teolysis. The synthesis of the target molecules in these
three schemes, their in vitro activities against M. tuber-
culosis, and bioactivities are discussed in this paper.
For the synthesis of analogues with a nitrogen atom
incorporated in ring-B, commercially available 6-pipe-
razinonicotinonitrile [10] was used as the starting mate-
rial (Scheme 2). The piperazinyl amine 10 was protected
with a boc functional group, followed by the reduction
of the nitrile functional group by catalytic hydrogena-
tion using Raney-Ni in the presence of palladium carbon
and lithium hydroxide to give the corresponding benzyl
amine 11 in 93% yield. Amine 11 was then treated with
5-nitro-furan-2-carbonyl chloride [8] to give amide 3a in
86% yield. The boc-deprotection of 3a was achieved
using trifluoroacetic acid leaving the secondary amine
functional group open for a variety of functionalization.
Compound 12 was first treated with benzyl bromide in
the presence of K2CO3 to give 3b (71% yield), a close
analogue of I. Analogous compounds to 1b and 1h were
also synthesized from 12 by treatment with ethyl chloro-
formate in the presence of triethyl amine to afford the
carbamate 3c in 79% yield. Similarly, compound 12
was treated with 2-isocyanato-propane in the presence
of triethyl amine to afford the urea derivative 3d in
82% yield.
The synthesis of 9a (Scheme 1) started from 4-fluoro
benzonitrile [5], which was subjected to aromatic nucle-
ophilic substitution with 1-boc-piperazine [6a] in the
presence of K2CO3 at 90 ꢁC to give the corresponding
nitrile 7a in 89% yield.7 7a was subjected to reduction
with catalytic hydrogenation using Raney-Ni in the
presence of palladium on carbon and lithium hydroxide
to give the corresponding benzyl amine,8 which was
immediately subjected to acylation using 5-nitro-furan-
2-carbonyl chloride [8] to afford amide 1a in 94% yield.
The boc-protection group on 1a was removed using
trifluoroacetic acid to give the piperazinyl amine 9a.
Compound 9a was then treated with alkyl chlorofor-
mates in the presence of triethyl amine to afford the
For the synthesis of bicyclic tetrahydroisoquinoline ana-
logues in the ring-B, an efficient and facile strategy was
developed by employing Schmidt rearrangement10 on
commercially available 5-fluoroindanone [13]. Com-
pound 13 was treated with sodium azide in an acidic
solution to afford lactam 14 in 55% yield11 (Scheme 3).
The amide functionality was then exploited as an elec-
tron-withdrawing group to activate the fluorine on inter-
mediate 14 for nucleophilic aromatic substitution.
CN
H
CN
N
O
N
H
O
b, c
n
a
+
N
N
N
N
O2N
O
N
n
O
O
F
n
1a, n = 1
2a, n = 2
O
5
O
O
6a, n = 1
6b, n = 2
d
7a, n = 1
7b, n = 2
O
N
H
9a, n = 1
9b, n = 2
O
N
-O
NH
N+
n
O
e
f
O
O
N
H
H
N
N
O
N
O
N
-O
N
H
O
-O
R
R
N
N+
N+
n
n
O
O
O
Urea derivatives
O
Carbamate derivatives
1g,h, n = 1
2d, n = 2
1b-f, n = 1
2c, n = 2
Scheme 1. Reagents and conditions: (a) K2CO3, DMSO, 90 ꢁC, 8 h; (b) Raney-Ni, H2, Pd/C, EtOAc, LiOH; (c) 8, CH2Cl2, Et3N, rt, 6 h; (d) dil aq
HCl, THF, 0 ꢁC to rt, 1 h; (e) ROCOCl, Et3N, THF, rt, 6 h; (f) RNCO, Et3N, THF, rt, 6 h.

2586
R. P. Tangallapally et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2584–2589
O-
N+
O2N
O-
N+
H2N
O
O
O
CN
O
O
O
O
O
N
O
HN
N
c
d
e
HN
a,b
HN
N
N
N
N
O
N
N
N
H
N
N
O
12
N
N
N
10
11
N
H
O
3a
3b
g
f
O
O
N
N
N
H
N
O
N
O
N
H
O
-O
H
N
-O
N
N
N+
N+
3d
3c
O
O
O
O
Scheme 2. Reagents and conditions: (a) K2CO3, DMSO, 90 ꢁC, 8 h; (b) Raney-Ni, H2, Pd/C, EtOAc, LiOH; (c) 8, CH2Cl2, Et3N, rt; (d) CF3COOH–
H2O, THF; (e) BnBr, K2CO3, DMF, rt, 6 h; (f) EtOCOCl, Et3N, THF, rt, 6 h; (g) PrNCO, Et3N, THF, rt, 6 h.
i
substitutions 3b and 4a demonstrated the most potent
MIC activity. Ethyl carbonate 1c had the best activity
O
O
O
of the carbonate/urea series with carbonates 1a–f and
3c having generally better MIC activity than the ureas
1g, 1h, and 3d. The introduction of a diazepane C-ring
2a–d reduced MIC activity compared with the corre-
sponding piperazines I, 1c, and 1h. The introduction
of pyridyl 3a–d or tetrahydroisoquinoline 4a–c B-ring
had little effect on the MIC activity of the series and
was well tolerated.
b
a
HN
HN
F
F
N
13
14
X
15a: X = N-Bn
15b: X = N-Me
15c: X = S
c
O
d
O
HN
N
O2N
N
N
X
X
4a: X = N-Bn,
4b: X = N-Me
4c: X = S
Preliminary bioavailability of a selected set of com-
pounds was assessed using a bioactivity assay. Briefly,
mice were dosed via oral gavage at 300 mg/kg in 0.5%
methylcellulose. Mice were subsequently bled at set
intervals (at 0.5, 2.5, 4 and 8 h after dosing) with three
mice per time point. The serum collected from these
mice was then serially diluted and tested for anti-tuber-
culosis activity in a bioassay using M. tuberculosis.12,13
The results from the bioassay reflect approximate con-
centrations of unbound bioactive product in the serum
rather than providing total drug levels (Table 1). The
bioactivity results indicate that compounds 1g, 2d, 3c,
and 3d had the best Cmax values. The longest T1/2 values
were obtained for 2a, 3a, 4a, and 4b. Within these data,
general trends were observed. The pyridinyl series 3a–d
achieved the best absorption, the benzyl B-ring series
resulted in short half lives, and the tetrahydroisoquino-
lines 4a and 4b had longer half lives. The diazepane C-
ring compounds 2a and 2d also had better half lives.
16a: X = N-Bn
16b: X = N-Me
16c: X = S
Scheme 3. Reagents and conditions: (a) NaN3, MeSO3H–CH2Cl2; (b)
sec-amine, K2CO3, DMSO, 140 ꢁC; (c) BH3–THF, rt; (d) 8, CH2Cl2,
Et3N, rt.
Compound 14 upon reaction with benzyl-piperazine in
the presence of K2CO3 at 140 ꢁC for 24 hours afforded
the substituted lactam 15a in 75% yield. Compound
15a was reduced to the tetrahydroisoquinoline deriva-
tive 16a (81% yield) using borane–THF. Compound
16a was then treated with 5-nitro-furan-2-carbonyl chlo-
ride [8] to give the desired target compound 4a in 91%
yield. Similarly, the fluoro group on lactam 14 was
substituted with N-methyl-piperazine and thiomorpho-
line separately to give the corresponding intermediates
15b (83% yield) and 15c (69% yield), respectively. The
subsequent reduction of the lactam to tetrahydroiso-
quinoline derivative 16b and 16c followed by acylation
with 5-nitro-furan-2-carbonyl chloride [8] afforded com-
pound 4b (82% yield) and 4c (79% yield).
This series of compounds has been designed to increase
the bioavailability of lead compound 5-nitro-furan-2-car-
boxylic acid 4-(4-benzyl-piperazin-1-yl)-benzylamide [I]
by addressing the metabolic instability of the molecule
and increasing absorption. Three modification schemes
were explored, 20 compounds were synthesized,14 tested
in vitro for MIC activity, and the bioactivity of nine com-
pounds was tested in mice (Table 1). Modifications in
each of these schemes affected the anti-tuberculosis activ-
ity, presenting the challenge of selecting compounds from
Determination of the anti-tuberculosis activity was car-
ried out using microbroth dilution and visual inspection
as described previously.6 The MIC values of compounds
in this study range from 0.0062 to 1.56 lg/mL and are
therefore commensurate with current therapeutic anti-
tuberculosis agents (Table 1). Benzyl-piperazine C-ring

R. P. Tangallapally et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2584–2589
Table 1. Structures of advanced hit analogues and their anti-tuberculosis activity
2587
b
c
T1/2 (h)
Compound
MIC90 (lg/ml)
Cmax (lg/ml)
Tmax (h)
O
O
O2N
R =
Structure
2.24a
0.5a
1.1a
R
N
H
I
0.0125
0.025
0.1
N
N
N
O
R
NH
N
1a
1b
1c
O
O
R
R
NH
NH
N
N
O
O
0.0062
N
N
O
O
NH
R
1d
0.05
N
N
O
R
NH
O
1e
1f
0.05
0.5
N
N
O
O
R
R
R
NH
NH
NH
N
N
O
O
1g
1h
2a
2b
2c
2d
3a
3b
0.2
4.8
2.5
0.5
1.5
7.5
N
N
HN
O
N
N
0.8
HN
R
R
NH
N
O
0.1
0.28
N
O
NH
0.8
N
N
NH
NH
R
R
O
N
N
N
0.1
O
H
N
N
0.8
7.4
0.5
0.5
0.5
2
O
NH
NH
R
O
N
N
0.05
0.0062
1.23
1.47
2.3
1.3
N
N
O
R
N
N
R
R
NH
NH
O
3c
3d
4a
0.05
6.56
22
2.5
2.5
0.5a
0.7
0.5
3.5a
N
N
N
O
O
N
N
0.56
HN
N
R
0.0062
0.736a
N
N
N
(continued on next page)

2588
R. P. Tangallapally et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2584–2589
Table 1 (continued)
b
c
T1/2 (h)
Compound
MIC90 (lg/ml)
Cmax (lg/ml)
Tmax (h)
O
O
O2N
R =
Structure
0.28a
0.5a
2a
R
N
N
4b
4c
0.2
0.4
N
N
R
N
S
a Determined using the HCl salt of the compound.
b Drug levels in the mouse serum are estimated by multiplying the dilution factor by the MIC value of the drug in the presence of 10% serum.
c Estimated based on graph of concentration versus time curve.
the series that have significant anti-tuberculosis activity,
but are also likely to be well absorbed with a long half life
in serum. Compounds selected under these criteria can
then enter lengthy testing in animal models of tuberculo-
sis infection with an increased chance of success. The first
modification explored was the replacement of the benzyl-
piperazine C-ring substituent of I with carbamates and
ureas. Compounds in this series showed good MIC activ-
ity, increased absorption, and lower serum binding but
were just as rapidly eliminated as I. The second modifica-
tion explored was the introduction of the pyridinyl B-
ring, which had little affect on MIC activity or serum half
life, but significantly boosted absorption, most likely due
to increased solubility. The final modification evaluated
was introduction of tetrahydroisoquinoline B-ring which
significantly increased the serum half life while maintain-
ing or improving MIC activity. This suggests that rapid
metabolism of the furanyl amide bond is the limiting fac-
tor for bioavailability of this series and that bioisosteric
replacement may be a fruitful future strategy for the
development of this series. In the course of this study it
emerged that serum binding and tissue distribution may
also be important factors that need to be addressed as this
series progresses. As it was noted during the bioavailabil-
ity assay the MIC activity of most of the compounds in
this series decreased in the presence of serum, for example
the MIC value for 4a was tenfold worse in the presence of
10% mouse serum. The best compounds in this series are
currently undergoing a detailed microbiological assess-
ment and are being tested in in vivo infection models.
The results from these studies will be reported in due
course. In conclusion, we have successfully further elabo-
rated this series of anti-tuberculosis compounds, devel-
oped compounds with highly potent anti-tuberculosis
activities, and improved bioactivity.
References and notes
1. World Health Organization Global Tuberculosis Pro-
gramme (2005) WHO Report on the Tuberculosis Epi-
demic 2005 (WHO, Geneva).
2. Murray, C. J. L.; Salomon, J. A. Proc. Natl. Acad. Sci.
U.S.A. 1998, 13881.
3. Murray, C. J. L.; Lopez, A. D. Science 1996, 274, 740.
´
4. Pablos-Mendez, A.; Raviglione, M. C.; Laszlo, A.; Binkin,
N.; Rieder, H. L.; Bustreo, F.; Cohn, D. L.; Lambregts-
van Weezenbeek, C. S. B.; Kim, S. J.; Chaulet, P.; Nunn,
P. N. Eng. J. Med. 1998, 338, 1641.
5. Tangallapally, R. P.; Lee, R. E.; Yendapally, R.; Hevener,
K.; Jones, V. C.; Lenaerts, A. J. M.; McNeil, M. R.;
Wang, Y.; Franzblau, S.; Lee, R. E. J. Med. Chem. 2004,
47, 5276.
6. Tangallapally, R. P.; Yendapally, R.; Lee, R. E.; Lenaerts,
A. J. M.; Lee, R. E. J. Med. Chem. 2005, 48, 8261.
7. Brown, G. R.; Foubister, A. J.; Ratcliffe, P. D. Tetrahe-
dron Lett. 1999, 40, 1219.
8. Klenke, B.; Gilbert, I. H. J. Org. Chem. 2001, 66, 2480.
9. Boswell, R. F., Jr.; Helsley, G. C.; Duncan, R. L., Jr.;
Funderburk, W. H.; Johnson, D. N. J. Med. Chem. 1974,
17, 1000.
10. Yoshinori, M.; Hiroshi, S.; Naoto, H.; Yoshio, I.; Masa-
hiko, S.; Tsunehiko, N. J. Labelled Compd. Radiopharm.
2000, 43, 983.
11. Prepartion of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one
[14]: sodium azide (865 mg, 13.32 mmol) was added
portionwise to a stirred solution of 5-fluoroindanone [13]
(1.0 g, 6.66 mmol) in 1:1 methanesulfonic acid/dichloro-
methane (10 mL), while the temperature was maintained
between 22 ꢁC and 29 ꢁC. Once addition was complete, the
mixture was stirred at room temperature for 16 h. The
mixture was cooled to 0 ꢁC and neutralized by the
addition of 5 N NaOH solution and the organic layer
separated. The aqueous layer was extracted with dichlo-
romethane (3· 25 mL) and the combined organic fractions
were washed with water (50 mL), brine (50 mL) and dried
over anhydrous sodium sulfate. Filtration and concentra-
tion followed by flash silica gel chromatography (pet.
ether/ethyl acetate) gave 605 mg of lactam 14 (55% yield).
TLC 0.6 Rf in 100% ethyl acetate; 1H NMR (500 MHz,
CDCl3): d 3.02 (t, J = 6.59 Hz, 2H), 3.60 (dt, J = 2.29,
6.83 Hz, 2H), 6.08–6.15 (br s, 1H), 6.93 (dd, J = 2.68,
9.03 Hz, 1H), 7.04 (dt, J = 2.68, 8.54 Hz, 1H), 8.1 (dd,
J = 5.85, 8.54 Hz, 1H); ESI-MASS: 188.3 (M+23).
Acknowledgment
We thank Veronica Gruppo, Karen Marietta, and
Christine Johnson for their excellent technical
assistance. This work was supported by Grant
AI062415 from the National Institutes of Health.

R. P. Tangallapally et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2584–2589
2589
12. Lee, R. E.; Protopopova, M.; Crooks, E.; Slayden, R. A.;
Terrot, M.; Barry, C. E., III J. Comb. Chem. 2003, 5, 172.
13. Gruppo, V.; Johnson, C. M.; Marietta, K. S.; Scherman,
H.; Zink, E. E.; Crick, D. C.; Adams, L. B.; Orme, I. M.;
Lenaerts, A. J. Antimicrob. Agents Chemother., in press.;
14. Selected spectral data for target compounds. Compound
1c: 1H NMR (300 MHz, CDCl3): d 1.35 (t, J = 7.1 Hz,
3H), 3.17 (t, J = 4.9, 5.2 Hz, 4H), 3.65 (t, J = 5.3, 4.9 Hz,
4H), 4.2 (q, J = 7.1 Hz, 2H), 4.57 (d, J = 5.7 Hz, 2H),
6.76–6.84 (br s, 1H), 6.94 (d, J = 8.7 Hz, 2H), 7.26–7.36
(m, 3H), 7.37 (d, J = 3.7 Hz, 1H); 13C NMR (300 MHz,
CDCl3): ppm 14.11, 42.56, 43.0, 48.66, 60.95, 111.85,
115.42, 116.2, 127.96, 128.68, 147.58, 150.42, 154.93,
155.51; ESI-MS: 401.8 (MÀ1); Anal. Calcd for
C19H22N4O6: C, 56.71; H, 5.51; N, 13.92. Found: C,
56.27; H, 5.51; N, 13.56.
11.3, 22.92, 41.85, 43.2, 48.44, 113.35, 115.43, 115.69,
128.38, 129.25, 148.29, 150.18, 155.88, 157.37; ESI-MS:
438.1 (M+23); Anal. Calcd for C20H25N5O5: C, 57.82; H,
6.07; N, 16.86. Found: C, 57.72; H, 6.36; N, 16.73.
Compound 3b: 1H NMR (300 MHz, CDCl3): d 2.57 (t,
J = 5.0 Hz, 4H), 3.57 (t, J = 4.7, 5.32 Hz, 4H), 4.51 (d,
J = 5.8 Hz, 2H), 6.62 (d, J = 8.7 Hz, 2H), 6.7–6.8 (br s,
1H), 7.27–7.42 (m, 7H), 7.51 (dd, J = 2.4, 8.7 Hz, 1H), 8.18
(d, J = 2.2 Hz, 1H); 13C NMR (300 MHz, DMSO-d6): ppm
39.62, 44.81, 52.25, 62.04, 106.74, 113.34, 115.5, 122.9,
126.88, 128.1, 128.8, 137.5, 137.96, 147.04, 148.18, 151.35,
155.92, 158.4; Anal. Calcd for C22H23N5O4: C, 62.70; H,
5.50; N, 16.62. Found: C, 61.57; H, 5.56; N, 16.07.
Compound 4b: 1H NMR (500 MHz, CDCl3): d 2.35 (s,
3H), 2.52–2.62 (br s, 4H), 2.88–3.06 (m, 2H), 3.16–3.24 (m,
4H), 3.9–4.05 (m, 2H), 4.75–4.95 (m, 2H), 6.71–6.75 (m,
1H), 6.79–6.87 (m, 1H), 7.0–7.11 (m, 1H), 7.18–7.23 (m,
1H), 7.36 (d, J = 3.9 Hz, 1H); 13C NMR (300 MHz,
DMSO-d6): ppm 27.87, 29.19, 44.29, 45.65, 47.23, 48.14,
54.49, 112.8,113.94, 114.77, 116.82, 122.88, 126.92, 134.84,
147.84, 149.82, 151.18, 157.03; ESI-MS: 393.5 (M+23);
Anal. Calcd for C19H22N4O4: C, 61.61; H, 5.99; N, 15.13.
Found: C, 61.47; H, 5.99; N, 15.03.
Compound 1g: 1H NMR (500 MHz, DMSO-d6): d 0.86 (t,
J = 7.3 Hz, 3H), 1.45 (sextet, J = 7.3 Hz, 2H), 3.01 (q,
J = 6.1 Hz, 2H), 3.07 (t, J = 5.1 Hz, 4H), 3.45 (t, J = 4.8,
5.3 Hz, 4H), 4.39 (d, J = 6.1 Hz, 2H), 6.6 (t, J = Hz, 1H),
6.96 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 7.46 (d,
J = 3.9 Hz, 1H), 7.79 (d, J = 3.9 Hz, 1H), 9.36 (t,
J = 6.1 Hz, 1H); 13C NMR (300 MHz, DMSO-d6): ppm