Synthesis and reactions of new chiral linear carboxamides with an incorporated peptide linkage using nalidixic acid and amino acids as starting materials

Article abstract of DOI:10.5560/ZNB.2014-3282

A series of chiral linear carboxamide derivatives (2 - 15) with an incorporated peptide linkage have been prepared via the coupling of 1-ethyl-1,4-dihydro-7-methyl-4-oxo-quinoline-3-carboxylic acid (nalidixic acid, 1) with appropriate amino acid methyl esters. Coupling of 1 with amino acid methyl esters gave the corresponding peptide methyl esters 2, which were hydrolyzed with methanolic sodium hydroxide to the corresponding acids 3. Hydrazinolysis of esters 2 with hydrazine hydrate afforded the corresponding acid hydrazide derivatives 4. The latter compounds were coupled with appropriate aldehydes or acetophenone derivatives to afford the corresponding Schiff base derivatives 5 and 6, respectively. The hydrazide derivative 4b was reacted with phenyl isothiocyanate or carbonyl derivatives to give the corresponding thiosemicarbazide 7 and compounds 8 - 10, respectively. Also, 4b was treated with acid monoanhydrides to give the corresponding imide derivatives 11 - 13. Finally, 4b was reacted with tetracarboxylic acid dianhydride derivatives to afford the corresponding diimido carboxamide derivatives 14 and 15.

Full text of DOI:10.5560/ZNB.2014-3282

Synthesis and Reactions of New Chiral Linear Carboxamides with an
Incorporated Peptide Linkage Using Nalidixic Acid and Amino Acids as
Starting Materials
Nagy M. Khalifaa,b, Ahmed M. Naglaha,c, Mohamed A. Al-Omara,
Mohamed H. Abo-Ghaliac, and Abd El-Galil E. Amra,d
a
Pharmaceutical Chemistry Department, Drug Exploration & Development Chair (DEDC),
College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
Department of Therapeutical Chemistry, Pharmaceutical and Drug Industries Division,
b
National Research Centre, Dokki 12622, Cairo, Egypt
Peptide Chemistry Department, National Research Center, Cairo, Dokki, Egypt
Applied Organic Chemistry Department, National Research Center, Cairo, Dokki, Egypt
c
d
Reprint requests to Prof. Dr. Abd El-Galil E. Amr. E-mail: aeamr1963@yahoo.com
Z. Naturforsch. 2014, 69b, 351 – 361 / DOI: 10.5560/ZNB.2014-3282
Received October 5, 2013
A series of chiral linear carboxamide derivatives (2 – 15) with an incorporated peptide linkage
have been prepared via the coupling of 1-ethyl-1,4-dihydro-7-methyl-4-oxo-quinoline-3-carboxylic
acid (nalidixic acid, 1) with appropriate amino acid methyl esters. Coupling of 1 with amino acid
methyl esters gave the corresponding peptide methyl esters 2, which were hydrolyzed with methano-
lic sodium hydroxide to the corresponding acids 3. Hydrazinolysis of esters 2 with hydrazine hydrate
afforded the corresponding acid hydrazide derivatives 4. The latter compounds were coupled with
appropriate aldehydes or acetophenone derivatives to afford the corresponding Schiff base derivatives
5 and 6, respectively. The hydrazide derivative 4b was reacted with phenyl isothiocyanate or carbonyl
derivatives to give the corresponding thiosemicarbazide 7 and compounds 8 – 10, respectively. Also,
4b was treated with acid monoanhydrides to give the corresponding imide derivatives 11 – 13. Finally,
4b was reacted with tetracarboxylic acid dianhydride derivatives to afford the corresponding diimido
carboxamide derivatives 14 and 15.
Key words: 1-Ethyl-1,4-dihydro-7-methyl-4-oxoquinoline-3-carboxylic Acid, Amino Acids, Chiral
Derivatives, Schiff Base, Imides
Introduction
acids and the screening of their biological activ-
ity [11 – 16]. The peptide derivatives have antimicro-
In different areas of supramolecular and macro- bial and anti-inflammatory activities [17 – 20] and an-
cyclic chemistry, the synthesis and complexing prop- titumor properties [21 – 24]. We also demonstrated that
erties of azacrown compounds have been a subject some peptido-heterocyclic derivatives exhibit a gen-
of intensive exploration [1 – 7]. Synthesis and chem- eral ionophoric potency for divalent cations [25] and
ical modifications of existing antibacterial agents in are useful for assembling novel thiocyanate-selective
order to generate novel macromolecules with better membrane sensors [26]. Recently, some new hete-
therapeutic properties are necessary because of the rocyclic derivatives were synthesized which exhibit
emergence of multidrug-resistant bacteria [8]. Pep- analgetic, anti-parkinsonian, androgenic anabolic, and
tides rarely function well as drugs due to their low anti-inflammatory activities [27 – 32]. On the other
bioavailability and rapid degradation within cells [9]. hand, semicarbazide, thiosemicarbazide, and imide
The conversion of these active peptides into pep- derivatives show promising biological and pharma-
tidomimetics has been a successful approach for mak- cological activities [33]. Recently, some new hetero-
ing new biologically active compounds [10]. In ad- cyclic and macrocyclic pentapeptide derivatives have
dition, we reported the synthesis of some macro- been studied with respect to anti-HIV [34, 35], anti-
cyclic candidates from dipicolinic acid with amino inflammatory [36], anticoagulant [37], analgesic and
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352
N. M. Khalifa et al. · Chiral Linear Carboxamides with an Incorporated Peptide Linkage
Scheme 1. Synthetic routes for compounds 2 – 6.
anticonvulsant [38], anticancer [39], and antimicrobial esters 2, which were hydrolyzed with methanolic
activities [40 – 42]. In view of these observations and sodium hydroxide to the corresponding acids 3. Hy-
as a continuation of our previous works in heterocyclic drazinolysis of esters 2 with hydrazine hydrate af-
chemistry, we have carried out the study presented in forded the corresponding acid hydrazide derivatives
this report.
4. The latter compounds were coupled with appropri-
ate aldehyde and acetophenone derivatives to afford
the corresponding Schiff bases 5 and 6, respectively
(Scheme 1).
Results and Discussion
Coupling of 1 (nalidixic acid) with amino acid
The hydrazide derivative 4b was reacted with
methyl esters gave the corresponding peptide methyl phenyl isothiocyanate to give the corresponding
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N. M. Khalifa et al. · Chiral Linear Carboxamides with an Incorporated Peptide Linkage
353
Scheme 2. Synthetic routes for compounds 7 – 10.
thiosemicarbazide derivative 7. In addition, 4b was Experimental
condensed with carbonyl derivatives, namely, hex-
Melting points were determined in open glass capillary
tubes with an Electro Thermal Digital apparatus, (model:
IA9100) and are uncorrected. Elemental microanalyses for
carbon, hydrogen and nitrogen (Microanalytical Unit, NRC)
were found within the acceptable limits of the calculated val-
ues. Infrared spectra (KBr) were recorded on a Nexus 670
FTIR Nicolet Fourier transform infrared spectrometer. Pro-
ton nuclear magnetic resonance ( 1H NMR) spectra were
run in ([D6]DMSO) on a Jeol 500 MHz instrument. Mass
spectra were obtained on a MAT Finnigan SSQ 7000 spec-
trometer, using the electron impact technique (EI). Analyti-
cal thin layer chromatography (TLC) was performed on sil-
ica gel aluminum sheets, 60 F254 (E. Merck). Specific op-
oses, cyclohexanone or indoline-2,3-dione, in reflux-
ing glacial acetic acid to give the corresponding con-
densed products 8 – 10, respectively (Scheme 2).
Treatment of 4b with acid mono acid anhydrides,
namely, phthalic, tetrachlorophthalic-, 2,3-pyridine- or
1,8-naphthalenedicarboxylic acid anhydride, gave the
corresponding imide derivatives 11 – 13, respectively.
4b was also reacted with tetracarboxylic acid dianhy-
dride derivatives, namely, benzene- or naphthalenete-
tracarboxylic acid dianhydride, to afford the corre-
sponding diimido carboxamide derivatives 14 and 15,
respectively (Scheme 3).
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N. M. Khalifa et al. · Chiral Linear Carboxamides with an Incorporated Peptide Linkage
N
O
N
N
N
O
O
O
O
O
H
N
H
N
*
*
N
H
N
N
N
H
O
O
O
O
14
O
O
O
H
N
R
N
H
N
O
O
O
O
O
O
*
O
N
N
R
O
O
O
O
11a b
,
R
R
a
=
=
R
R
R
H
Cl
,
,
b R
R
R
O
O
O
O
O
H
N
N
O
N
O
O
N
NH2
*
H
H
N
O
N
N
O
*
N
N
H
O
4b
N
O
N
12
O
O
O
O
O
O
O
O
O
O
O
H
N
N
H
N
*
O
N
N
O
13
N
N
N
N
O
O
N
O
O
N
O
O
O
H
H
N
N
*
*
N
H
N
H
O
O
O
15
Scheme 3. Synthetic routes for compounds 11 – 15.
tical rotations were measured with a A. Krawss, Optronic, Synthesis of carboxamides 2a – c
P8000 polarimeter, in a 1 dm length observation tube, at the
To a cold and stirred dry dichloromethane solution
(25 mL, −20 ◦C) of nalidixic acid 1 (1 mmol), ethyl chlo-
roformate (1 mmol) and triethylamine (1 mmol) were suc-
cessively added. Ten minutes later, a cold methylene chlo-
ride solution (10 mL, −20 ◦C) of an amino acid methyl es-
indicated conditions, and evaluated according to the equa-
tion: [α]TD = 100α/(cl), where: α = observed rotation an-
gle, D = sodium line (λ = 589 nm), c = concentration (g
per 100 mL), l = path length in dm and T = experimental
temperature (◦C).
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N. M. Khalifa et al. · Chiral Linear Carboxamides with an Incorporated Peptide Linkage
355
ter, namely glycine methyl ester, L-valine methyl ester and CH), 6.72 (d, 1H, Ar-H), 7.86 (d, 1H, Ar-H), 8.05 (s, 1H,
isoleucine methyl ester (1 mmol), was added. Stirring of the Ar-H), 10.12 (s, 1H, NH, exchangeable with D2O) ppm. –
cold reaction mixture (−20 ◦C) was continued for 3 h and at 13C NMR (125 MHz, [D6]DMSO): δ = 11.71, 12.96, 14.87,
room temperature overnight. The solution was then washed 24.57, 25.43, 37.25, 49.81, 52.38, 54.02, 113.51, 114.32,
with water, 1 N hydrochloric acid, 1 N sodium bicarbonate, 118.84, 138.38, 148.34, 155.78, 160.20, 162.80, 172.18,
and finally with water (250 mL). The dried solution (anhy- 178.35 ppm. – MS (EI, 70 eV): m/z(%) = 359 (22) [M]+.
drous CaCl2) was evaporated, and the obtained oily residue – C19H25N3O4 (359.42): calcd. C 63.49, H 7.01, N 11.69;
was solidified by trituration with dry ether, filtered off, dried found C 63.44, H 6.95, N 11.64.
under vacuum, and recrystallized to afford the esters 2a – c.
Synthesis of acid derivatives 3a – c
Methyl {[(1-ethyl-7-methyl-4-oxo-1,4-dihydro-
Sodium hydroxide (1 N, 25 mL) was added dropwise to
a cold and stirred ethanolic solution (1 mmol, −5 ◦C) of an
ester 2a – c. Stirring was continued at that temperature for 2 h
and then for 12 h at room temperature followed by evapora-
tion of the solvent. The cold reaction mixture was acidified
with 1 N hydrochloric acid to pH ≈ 3, and the obtained solid
was filtered off, washed with cold water, dried, and recrystal-
lized to afford the title acid derivatives 3a – c, respectively.
1,8-naphthyridin-3-yl)carbonyl]amino}acetate (2a)
Yield 73%; m. p. 134 – 135 ◦C (MeOH). – IR (KBr):
ν = 3391 (NH), 1745 (C=O, ester), 1719 (C=O), 1665,
1534, 1255 (C=O, amide I, II and III) cm−1. – 1H NMR
(500 MHz, [D6]DMSO): δ = 0.99 (t, 3H, CH3), 2.48 (s,
3H, CH3), 3.12 (q, 2H, CH2), 3.86 (s, 3H, OCH3), 4.09 (s,
2H, CH2), 6.90 (d, 1H, Ar-H), 7.81 (d, 1H, Ar-H), 7.99 (s,
1H, Ar-H), 9.85 (s, 1H, NH, exchangeable with D2O) ppm.
–
13C NMR (125 MHz, [D6]DMSO): δ = 13.23, 24.94,
{[(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridin-
41.25, 50.12, 52.31, 113.28, 114.56, 118.87, 138.12, 149.11,
155.62, 160.35, 163.10, 170.02, 177.81 ppm. – MS (EI,
70 eV): m/z(%) = 303 (22) [M]+. – C15H17N3O4 (303.31):
calcd. C 59.40, H 5.65, N 13.85; found C 59.35, H 5.60, N
13.80.
3-yl)carbonyl]amino}acetic acid (3a)
Yield 61%; m. p. 201 – 202 ◦C (EtOH-ether). – IR (KBr):
ν = 3473, 3375 (NH, OH), 1724 (C=O, acid), 1718 (C=O),
1666, 1537, 1256 (C=O, amide I, II and III) cm−1. – 1H
NMR (500 MHz, [D6]DMSO): δ = 0.98 (t, 3H, CH3), 2.43
(s, 3H, CH3), 3.16 (q, 2H, CH2), 4.12 (s, 2H, CH2), 6.60
(d, 1H, Ar-H), 7.74 (d, 1H, Ar-H), 8.05 (s, 1H, Ar-H),
9.31, 10.61 (2s, 2H, NH, OH, exchangeable with D2O)
ppm. – 13C NMR (125 MHz, [D6]DMSO): δ = 14.16,
23.89, 44.13, 50.32, 113.64, 114.78, 118.41, 137.95, 149.11,
154.83, 160.14, 163.25, 173.50, 179.21 ppm. – MS (EI,
70 eV): m/z(%) = 289 [M+, 26]. C14H15N3O4 (289.29):
calcd. C 58.13; H 5.23; N 14.53; found C 58.07; H 5.18; N
14.47.
Methyl 2-{[(1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naph-
thyridin-3-yl)carbonyl]amino}-3-methylbutanoate (2b)
Yield 67%; m. p. 122 – 123 ◦C (MeOH). – [α]D25
=
−105.3 (c = 0.5, MeOH). – IR (KBr): ν = 3375 (NH), 1741
(C=O, ester), 1722 (C=O), 1662, 1530, 1252 (C=O, amide
I, II and III) cm−1. – 1H NMR (500 MHz, [D6]DMSO):
δ = 1.01 (t, 3H, CH3), 1.03 (d, 6H, 2 CH3), 2.40 (s, 3H,
CH3), 3.04 (q, 2H, CH2), 2.86 (m, 1H, CH), 3.89 (s, 3H,
OCH3), 4.58 (d, 1H, CH), 6.68 (d, 1H, Ar-H), 7.65 (d,
1H, Ar-H), 8.01 (s, 1H, Ar-H), 9.54 (s, 1H, NH, exchange-
able with D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO):
δ = 13.08, 17.62, 24.78, 33.37, 49.80, 52.26, 56.74, 113.93,
114.29, 118.66, 138.13, 148.42, 155.68, 160.18, 163.12,
172.03, 178.24 ppm. – MS (EI, 70 eV): m/z(%) = 345 (34)
[M]+. – C18H23N3O4 (345.39): calcd. C 62.59, H 6.71, N
12.17; found C 62.54, H 6.65, N 12.12.
2-{[(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridin-
3-yl)carbonyl]amino}-3-methyl-butanoic acid (3b)
Yield 67%; m. p. 180 – 182 ◦C (EtOH-ether). – [α]2D5
=
−112.1 (c = 0.5, MeOH). – IR (KBr): ν = 3482, 3370 (NH,
OH), 1723 (C=O, acid), 1716 (C=O), 1662, 1535, 1254
(C=O, amide I, II and III) cm−1. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.00 (t, 3H, CH3), 1.04 (d, 6H, 2 CH3),
2.49 (s, 3H, CH3), 2.81 (m, 1H, CH), 3.16 (q, 2H, CH2),
4.47 (d, 1H, CH), 6.65 (d, 1H, Ar-H), 7.78 (d, 1H, Ar-H),
8.01 (s, 1H, Ar-H), 9.54, 10.52 (2s, 2H, NH, OH, exchange-
Methyl 2-{[(1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naph-
thyridin-3-yl)carbonyl]amino}-3-ethylbutanoate (2c)
Yield 70%; m. p. 140 – 141 ◦C (MeOH). – [α]D25
=
−76.45 (c = 0.5, MeOH). – IR (KBr): ν = 3371 (NH), 1735 able with D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO):
(C=O, ester), 1715 (C=O), 1662, 1536, 1254 (C=O, amide δ = 13.45, 18.53, 23.94, 31.86, 49.26, 59.12, 114.33, 115.49,
I, II and III) cm−1. – 1H NMR (500 MHz, [D6]DMSO): 118.24, 138.65, 149.06, 156.11, 160.22, 163.18, 175.25,
δ = 0.98 (t, 3H, CH3), 1.05 (t, 3H, CH3), 1.14 (d, 3H, 178.98 ppm. – MS (EI, 70 eV): m/z(%) = 331 (18) [M]+.
CH3), 1.35 (m, 2H, CH2), 2.45 (s, 3H, CH3), 2.89 (m, 1H, – C17H21N3O4 (331.37): calcd. C 61.62, H 6.39, N 12.68;
CH), 3.14 (q, 2H, CH2), 3.80 (s, 3H, OCH3), 4.59 (s, 1H, found C 61.56, H 6.33, N 12.63.
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N. M. Khalifa et al. · Chiral Linear Carboxamides with an Incorporated Peptide Linkage
2-{[(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridin-
3-yl)carbonyl]amino}-3-ethyl-butanoic acid (3c)
1H, Ar-H), 7.84 (d, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 8.17,
9.71 (2s, 2H, 2 NH, exchangeable with D2O) ppm. – 13C
NMR (125 MHz, [D6]DMSO): δ = 13.34, 18.42, 24.06,
31.53, 49.18, 59.73, 113.92, 114.85, 118.79, 138.44, 148.90,
155.81, 159.78, 163.20, 170.65, 178.01 ppm. – MS (EI,
70 eV): m/z(%) = 345 (44) [M]+. – C17H23N5O3 (345.40):
calcd. C 59.12, H 6.71, N 20.28; found C 59.06, H 6.65, N
20.22.
Yield 63%; m. p. 192 – 194 ◦C (EtOH-ether). – [α]2D5
−96.5 (c = 0.5, MeOH). – IR (KBr): ν = 3486, 3378 (NH,
OH), 1728 (C=O, acid), 1722 (C=O), 1664, 1532, 1251
(C=O, amide I, II and III) cm−1. – 1H NMR (500 MHz,
[D6]DMSO): δ = 0.98 (t, 3H, CH3), 1.06 (t, 3H, CH3), 1.12
(d, 3H, CH3), 1.34 (m, 2H, CH2), 2.48 (s, 3H, CH3), 2.76
(m, 1H, CH), 3.17 (q, 2H, CH2), 4.31 (s, 1H, CH), 6.79 (d,
1H, Ar-H), 7.86 (d, 1H, Ar-H), 7.99 (s, 1H, Ar-H), 9.62,
10.49 (2s, 2H, NH, OH, exchangeable with D2O) ppm. –
13C NMR (125 MHz, [D6]DMSO): δ = 11.75, 13.29, 15.36,
25.16, 25.64, 36.57, 49.55, 56.19, 113.79, 114.69, 118.85,
138.74, 148.96, 155.81, 160.38, 162.78, 175.49, 177.61 ppm.
– MS (EI, 70 eV): m/z(%) = 345 (15) [M]+. – C18H23N3O4
(345.39): calcd. C 62.59, H 6.71, N 12.17; found C 62.54, H
6.65, N 12.12.
=
1-Ethyl-N-(1-hydrazinyl-3-ethyl-1-oxobutan-2-yl)-7-methyl-
4-oxo-1,4-dihydro-1,8-naphth-yridine-3-carboxamide (4c)
Yield 64%; m. p. 221 – 223 ◦C (MeOH). – [α]D25 = −89.5
(c = 0.5, MeOH). – IR (KBr): ν = 3594 – 3349 (NH, NH2),
1721 (C=O), 1668, 1537, 1255 (C=O, amide I, II and
III) cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 0.95
(t, 3H, CH3), 1.02 (t, 3H, CH3), 1.14 (d, 3H, CH3),
1.32 (m, 2H, CH2), 2.43 (s, 3H, CH3), 2.86 (m, 1H,
CH), 3.19 (q, 2H, CH2), 4.30 (s, 2H, NH2, exchange-
able with D2O), 4.49 (s, 1H, CH), 6.60 (d, 1H, Ar-H),
7.79 (d, 1H, Ar-H), 7.99 (s, 1H, Ar-H), 8.28, 9.64 (2s,
2H, 2 NH, exchangeable with D2O) ppm. – 13C NMR
(125 MHz, [D6]DMSO): δ = 11.64, 13.22, 15.29, 25.11,
25.54, 36.74, 49.68, 56.21, 113.60, 114.72, 118.93, 138.68,
149.03, 155.75, 160.43, 162.82, 170.66, 177.65 ppm. –
MS (EI, 70 eV): m/z(%) = 359 (8) [M]+. – C18H25N5O3
(359.42): calcd. C 60.15, H 7.01, N 19.48; found C 60.10, H
6.95, N 19.43.
Synthesis of hydrazide derivatives 4a – c
Hydrazine hydrate (0.8 mL, 16 mmol) was added to
a methanolic solution (10 mL) of 3 (1 mmol). The reaction
mixture was refluxed for 10 h, after which the solvent was
evaporated under reduced pressure. The obtained residue was
triturated with ether, filtered off, and recrystallized to afford
the corresponding hydrazides 4a – c.
1-Ethyl-N-(2-hydrazinyl-2-oxoethyl)-7-methyl-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carboxamide (4a)
Synthesis of hydrazone derivatives 5a – d and 6a, b
Yield 68%; m. p. 243 – 245 ◦C (MeOH). – IR (KBr): ν =
3510 – 3376 (NH, NH2), 1718 (C=O), 1665, 1535, 1252
(C=O, amide I, II and III) cm−1. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.00 (t, 3H, CH3), 2.40 (s, 3H, CH3),
3.11 (q, 2H, CH2), 4.05 (s, 2H, CH2), 4.28 (s, 2H, NH2, ex-
changeable with D2O), 6.58 (d, 1H, Ar-H), 7.80 (d, 1H, Ar-
H), 7.91 (s, 1H, Ar-H), 8.34, 9.67 (2s, 2H, 2 NH, exchange-
able with D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO):
δ = 13.24, 24.61, 44.93, 50.45, 113.49, 114.71, 118.56,
138.04, 149.26, 155.10, 169.97, 162.85, 170.43, 178.50 ppm.
– MS (EI, 70 eV): m/z(%) = 303 (12) [M]+. – C14H17N5O3
(303.32): calcd. C 55.44, H 5.65, N 23.09; found C 55.40, H
5.60, N 23.00.
A stirred solution of hydrazide
4 (1 mmol) and
active carbonyl derivatives, namely 4-isopropyl-
benzaldehyde, benzaldehyde, 4-methoxybenzaldehyde,
4-methoxyacetophenone, or 4-nitroacetophenone (1 mmol),
in acetic acid (30 mL) was refluxed for 2 – 4 h. The re-
action mixture was allowed to cool and the obtained
solid product was filtered off, dried, and recrystallized
to give the corresponding hydrazones 5a – d, respec-
tively.
N-{2-[2-(4-Isopropylbenzylidene)hydrazinyl]-2-oxoethyl}-
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-
3-carboxamide (5a)
Yield 68%; m. p. 201 – 203 ◦C (AcOH). – IR (KBr):
ν = 3370, 3229 (2 NH), 1715 (C=O), 1662, 1534, 1250
(C=O, amide I, II and III) cm−1. – 1H NMR (500 MHz,
[D6]DMSO): δ = 1.00 (t, 3H, CH3), 1.32 (d, 6H, 2 CH3),
1-Ethyl-N-(1-hydrazinyl-3-methyl-1-oxobutan-2-yl)-7-meth-
yl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (4b)
Yield 60%; m. p. 258 – 260 ◦C (MeOH). – [α]D25
=
−146.6 (c = 0.5, MeOH). – IR (KBr): ν = 3486 – 3319 2.45 (s, 3H, CH3), 3.16 (q, 2H, CH2), 3.27 (m, 1H, CH),
(NH, NH2), 1716 (C=O), 1660, 1534, 1256 (C=O, amide 4.10 (s, 2H, CH2), 6.76 –8.11 (m, 8H, Ar-H + CH=N),
I, II and III) cm−1. – 1H NMR (500 MHz, [D6]DMSO): 8.42, 9.71 (2s, 2H, 2 NH, exchangeable with D2O) ppm. –
δ = 1.00 (t, 3H, CH3), 1.06 (d, 6H, 2 CH3), 2.47 (s, 3H, 13C NMR (125 MHz, [D6]DMSO): δ = 13.19, 23.86, 24.74,
CH3), 2.84 (m, 1H, CH), 3.13 (q, 2H, CH2), 4.36 (s, 2H, 36.49, 45.70, 49.23, 113.43, 114.55, 118.48, 126.56, 129.24,
NH2, exchangeable with D2O), 4.45 (d, 1H, CH), 6.70 (d, 131.19, 138.15, 142.94, 149.09, 151.14, 155.57, 160.00,
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N. M. Khalifa et al. · Chiral Linear Carboxamides with an Incorporated Peptide Linkage
357
162.79, 173.50, 177.63 ppm. – MS (EI, 70 eV): m/z(%) = 24.83, 31.51, 36.49, 49.15, 60.92, 113.70, 114.42, 118.71,
433 (32) [M]+. – C24H27N5O3 (433.50): calcd. C 66.49, H 126.42, 129.35, 131.26, 138.37, 143.59, 148.86, 151.14,
6.28, N 16.16; found C 66.44, H 6.23, N 16.11.
155.81, 160.11, 163.26, 177.19, 177.89 ppm. – MS (EI,
70 eV): m/z(%) = 476 (24) [M]+. – C27H33N5O3 (475.58):
calcd. C 68.19, H 6.99, N 14.73; found C 68.14, H 6.93, N
14.68.
N-{2-[2-Benzylidenehydrazinyl]-1-isopropyl-2-oxoethyl}-
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-
3-carboxamide (5b)
N-(2-{2-[1-(4-Methoxyphenyl)ethylidene]hydrazinyl}-
1-isopropyl-2-oxoethyl)-4-oxo-1-ethyl-7-methyl-1,4-di-
hydro-1,8-naphthyridine-3-carboxamide (6a)
Yield 70%; m. p. 213 – 215 ◦C (AcOH). – [α]D25 = −58.7
(c = 0.5, MeOH). – IR (KBr): ν = 3364, 3210 (2 NH), 1721
(C=O), 1656, 1538, 1254 (C=O, amide I, II and III) cm−1
.
–
1H NMR (500 MHz, [D6]DMSO): δ = 1.02 (t, 3H, CH3),
Yield 51%; m. p. 154 – 156 ◦C (AcOH). – [α]D25 = −27.4
1.10 (d, 6H, 2 CH3), 2.40 (s, 3H, CH3), 2.80 (m, 1H, CH), (c = 0.5, MeOH). – IR (KBr): ν = 3393, 3212 (2 NH),
3.16 (q, 2H, CH2), 4.47 (d, 1H, CH), 6.75 −8.13 (m, 9H, 1718 (C=O), 1658, 1536, 1251 (C=O, amide I, II and III)
Ar-H + CH=N), 8.37, 9.68 (2s, 2H, 2 NH, exchangeable with cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 0.99 (t,
D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO): δ = 13.25, 3H, CH3), 1.15 (d, 6H, 2 CH3), 2.23 (s, 3H, CH3), 2.44 (s,
17.98, 24.86, 31.42, 49.23, 60.81, 113.75, 114.46, 118.69, 3H, CH3), 2.76 (m, 1H, CH), 3.11 (q, 2H, CH2), 3.81 (s,
129.19, 129.57, 131.28, 134.15, 138.39, 143.50, 148.86, 3H, OCH3), 4.46 (d, 1H, CH), 6.72 – 7.90 (m, 7H, Ar-H),
155.92, 160.01, 163.35, 176.95, 177.91 ppm. – MS (EI, 8.35, 9.64 (2s, 2H, 2 NH, exchangeable with D2O) ppm. –
70 eV): m/z(%) = 433 (12) [M]+. – C24H27N5O3 (433.50): 13C NMR (125 MHz, [D6]DMSO): δ = 13.17, 18.22, 23.11,
calcd. C 66.49, H 6.28, N 16.16; found C 66.43, H 6.22, N 24.95, 31.43, 49.50, 56.23, 61.14, 113.64, 114.20, 114.57,
16.12.
118.71, 126.39, 130.31, 138.29, 148.81, 155.74, 159.83,
162.79, 163.19, 169.05, 177.14, 177.80 ppm. – MS (EI,
70 eV): m/z(%) = 478 (6) [M]+. – C26H31N5O4 (477.56):
calcd. C 65.39, H 6.54, N 14.66; found C 65.34, H 6.50, N
14.60.
N-{2-[2-(4-Methoxybenzylidene)hydrazinyl]-1-isopropyl-
2-oxoethyl}-1-ethyl-7-methyl-4-oxo-1,4-dihydro-
1,8-naphthyridine-3-carboxamide (5c)
Yield 72%; m. p. 278 – 280 ◦C (AcOH). – [α]D25 = −38.3
(c = 0.5, MeOH). – IR (KBr): ν = 3469, 3219 (2 NH),
1718 (C=O), 1664, 1537, 1248 (C=O, amide I, II and III)
cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.00 (t,
3H, CH3), 1.08 (d, 6H, 2 CH3), 2.45 (s, 3H, CH3), 2.83
N-(2-{2-[1-(4-Nitrophenyl)ethylidene]hydrazinyl}-
1-isopropyl-2-oxoethyl)-4-oxo-1-ethyl-7-methyl-1,4-di-
hydro-1,8-naphthyridine-3-carboxamide (6b)
Yield 53%; m. p. 196 – 198 ◦C (AcOH). – [α]D25 = −66.2
(m, 1H, CH), 3.12 (q, 2H, CH2), 3.86 (s, 3H, OCH3), 4.55 (c = 0.5, MeOH). – IR (KBr): ν = 3380, 3329 (2 NH),
(d, 1H, CH), 6.68 – 8.09 (m, 8H, Ar-H + CH=N), 8.22, 9.78 1720 (C=O), 1654, 1532, 1250 (C=O, amide I, II and
(2s, 2H, 2 NH, exchangeable with D2O) ppm. – 13C NMR III) cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.00
(125 MHz, [D6]DMSO): δ = 13.21, 18.10, 24.71, 31.56, (t, 3H, CH3), 1.10 (d, 6H, 2 CH3), 2.41 (s, 3H, CH3),
49.41, 56.14, 61.23, 113.83, 114.26, 114.52, 118.64, 126.27, 2.46 (s, 3H, CH3), 2.99 (m, 1H, CH), 3.16 (q, 2H, CH2),
130.34, 138.32, 143.56, 148.89, 155.71, 159.87, 162.77, 4.56 (d, 1H, CH), 6.70 – 8.0 (m, 7H, Ar-H), 8.41, 9.76
163.25, 177.06, 177.84 ppm. – MS (EI, 70 eV): m/z(%) = (2s, 2H, 2 NH, exchangeable with D2O) ppm. – 13C
463 (10) [M]+. – C25H29N5O4 (463.53): calcd. C 64.78, H NMR (125 MHz, [D6]DMSO): δ = 13.22, 18.20, 23.24,
6.31, N 15.11; found C 64.72, H 6.25, N 15.05.
24.89, 31.47, 49.58, 60.91, 113.59, 114.26, 118.69, 121.42,
130.38, 138.31, 141.12, 148.78, 151.03, 155.79, 159.66,
162.75, 168.90, 177.24, 177.63 ppm. – MS (EI, 70 eV):
m/z(%) = 492 (10) [M]+. – C25H28N6O5 (492.53): calcd.
C 60.96, H 5.73, N 17.06; found C 60.90, H 5.65, N
17.00.
N-{2-[2-(4-Isopropylbenzylidene)hydrazinyl]-1-isopropyl-
2-oxoethyl}-1-ethyl-7-methyl-4-oxo-1,4-dihydro-
1,8-naphthyridine-3-carboxamide (5d)
Yield 53%; m. p. 238 – 240 ◦C (AcOH). – [α]D25 = −140.8
(c = 0.5, MeOH). – IR (KBr): ν = 3369, 3225 (2 NH),
1716 (C=O), 1660, 1540, 1249 (C=O, amide I, II and III)
cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 0.99 (t, 3H,
CH3), 1.04 (d, 6H, 2 CH3), 1.23 (d, 6H, 2 CH3), 2.44 (s, 3H,
CH3), 2.95 (m, 1H, CH), 3.12 (q, 2H, CH2), 3.21 (m, 1H,
N-{2-Oxo-1-isopropyl-2-[2-(phenylcarbamothioyl)hydra-
zinyl]ethyl}-1,4-dihydro-1-ethyl-7-methyl-4-oxo-
1,8-naphthyridine-3-carboxamide (7)
Equimolar quantities of the acid hydrazide 4 (20 mmol)
CH), 4.43 (d, 1H, CH), 6.72 – 8.10 (m, 8H, Ar-H + CH=N), and phenyl isothiocyanate (20 mmol) were dissolved in ab-
8.41, 9.73 (2s, 2H, 2 NH, exchangeable with D2O) ppm. – solute ethanol (50 mL) and the solution refluxed for 3 h and
13C NMR (125 MHz, [D6]DMSO): δ = 13.20, 18.14, 23.55, then allowed to cool to room temperature. Fine crystals of
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358
N. M. Khalifa et al. · Chiral Linear Carboxamides with an Incorporated Peptide Linkage
the thiosemicarbazide 8 were separated out, filtered off, and 1715 (C=O), 1660, 1540, 1247 (C=O, amide I, II and III)
recrystallized from methanol to afford the compound in 81% cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.01 (t, 3H,
yield; m. p. 131 – 133 ◦C. – [α]D25 = −64.6 (c = 0.5, MeOH). CH3), 1.11 (d, 6H, 2 CH3), 2.43 (s, 3H, CH3), 2.78 (m, 1H,
– IR (KBr): ν = 3375 – 3211 (2 NH), 1719 (C=O), 1656, CH), 3.16 (q, 2H, CH2), 3.24 – 3.38 (m, 2H, 60-H, 600-H),
1535, 1251 (C=O, amide I, II and III), 1198 (C=S) cm−1. – 3.54 (m, 2H, 50-H, 40-H), 3.81 (t, 1H, 60-OH, exchangeable
1H NMR (500 MHz, [D6]DMSO): δ = 1.01 (t, 3H, CH3), with D2O), 4.16 (m, 2H, 50-OH, 40-OH, exchangeable with
1.10 (d, 6H, 2 CH3), 2.51 (s, 3H, CH3), 2.85 (m, 1H, CH), D2O), 4.45 (m, 3H, 20-H, 30-H, 30-OH, exchangeable with
3.17 (q, 2H, CH2), 4.41 (d, 1H, CH), 6.53 – 7.96 (m, 8H, D2O), 4.55 (d, 1H, CH), 4.76 (d, 1H, 20-OH, exchangeable
Ar-H), 8.53, 9.74, 10.34 (br s, 3H, 3 NH, exchangeable with with D2O), 6.95 (t, 1H, Ar-H), 7.23 (d, 1H, 10-H), 7.90 (t,
D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO): δ = 13.28, 1H, Ar-H), 8.02 (s, 1H, Ar-H), 8.42, 9.75 (2s, 2H, 2 NH,
18.23, 24.86, 31.47, 49.25, 61.17, 113.89, 114.36, 118.82, exchangeable with D2O) ppm. – 13C NMR (125 MHz,
125.12, 126.78, 128.94, 137.21, 138.34, 148.86, 155.79, [D6]DMSO): δ = 13.12, 18.32, 24.74, 31.62, 49.40, 60.93,
160.14, 162.72, 170.55, 177.68, 181.60 ppm. – MS (EI, 63.01, 68.16, 72.28, 73.24, 74.55, 113.63, 114.45, 118.49,
70 eV): m/z(%) = 480 (7) [M]+. – C24H28N6O3S (480.58): 138.41, 148.78, 153.72, 155.69, 159.56, 162.80, 177.21,
calcd. C 59.98, H 5.87, N 17.49, S 6.67; found C 59.92, H 177.65 ppm. – MS (EI, 70 eV): m/z(%) = 507 (30) [M]+.
5.81, N 17.44, S 6.62.
– C23H33N5O8 (507.54): calcd. C 54.43, H 6.55, N 13.80;
found C 54.35, H 6.50, N 13.75.
Synthesis of N’-(glycosyl)acetohydrazide derivatives 8a – c
N-{2-[2-(D-Mannomethylene)hydrazinyl]-1-isopropyl-
2-oxoethyl}-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naph-
thy-ridine-3-carboxamide (8c)
A mixture of 4 (10 mmol), D-glucose, D-galactose or D-
mannose (10 mmol), and a catalytic amount of acetic acid
was heated at reflux in ethanol (50 mL) for 2 – 4 h, the re-
action mixture was allowed to cool to room temperature, the
precipitate was filtered off, washed with ethanol, dried and
recrystallized from methanol to afford compounds 8a – c.
Yield 50%; m. p. 191 – 193 ◦C (MeOH). – [α]D25 = −46.3
(c = 0.5, MeOH). – IR (KBr): ν = 3560 – 3347 (OH, NH),
1722 (C=O), 1660, 1536, 1254 (C=O, amide I, II and III)
cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 0.98 (t,
3H, CH3), 1.10 (d, 6H, 2 CH3), 2.52 (s, 3H, CH3), 2.72
(m, 1H, CH), 3.16 (q, 2H, CH2), 3.21 – 3.38 (m, 2H, 60-
H, 600-H), 3.46 – 3.57 (m, 3H, 50-H, 40-H, 60-OH, exchange-
able with D2O), 4.19 (d, 1H, 50-OH, exchangeable with
D2O), 4.29 (d, 1H, 40-OH, exchangeable with D2O), 4.45
(m, 3H, 20-H, 30-H, 30-OH, exchangeable with D2O), 4.53
(d, 1H, CH), 4.78 (d, 1H, 20-OH, exchangeable with D2O),
6.90 (d, 1H, Ar-H), 7.70 (d, 1H, 10-H), 7.86 (d, 1H, Ar-
H), 7.99 (s, 1H, Ar-H), 8.39, 9.76 (2s, 2H, 2 NH, exchange-
able with D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO):
δ = 13.15, 18.19, 24.71, 31.47, 49.51, 60.93, 63.89, 67.23,
71.27, 72.31, 73.63, 113.49, 114.33, 118.59, 138.33, 148.89,
153.75, 155.83, 159.77, 162.85, 177.23, 177.61 ppm. – MS
(EI, 70 eV): m/z(%) = 507 (18) [M]+. – C23H33N5O8
(507.54): calcd. C 54.43, H 6.55, N 13.80; found C 54.36,
H 6.50, N 13.74.
N-{2-(D-Glucomethylene)hydrazinyl]-1-isopropyl-2-oxo-
ethyl}-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (8a)
Yield 45%; m. p. 223 – 225 ◦C (MeOH). – [α]D25 = −18.4
(c = 0.5, MeOH). – IR (KBr): ν = 3546 – 3319 (OH, NH),
1719 (C=O), 1660, 1538, 1258 (C=O, amide I, II and III)
cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.00 (t, 3H,
CH3), 1.14 (d, 6H, 2 CH3), 2.40 (s, 3H, CH3), 2.84 (m, 1H,
CH), 3.18(q, 2H, CH2), 3.25 – 3.61 (m, 4H, 60H, 600H, 50H,
40H), 3.96 (t, 1H, 60OH), 4.37 (m, 2H, 50OH, 40OH), 4.53
(d, 1H, CH), 5.26 (m, 3H, 20H, 30H, 30OH), 5.57 (d, 1H,
20OH), 6.90 (d, 1H, Ar-H), 7.13 (d, 1H, 10H), 7.81 (d, 1H, Ar-
H), 7.99 (s, 1H, Ar-H), 8.31, 9.84 (2s, 2H, 2 NH, exchange-
able with D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO):
δ = 13.18, 18.24, 24.68, 31.52, 49.45, 60.89, 63.96, 67.11,
71.32, 72.15, 73.50, 113.52, 114.33, 118.54, 138.36, 148.82,
153.64, 155.75, 159.60, 162.78, 177.17, 177.59 ppm. – MS
(EI, 70 eV): m/z(%) = 507 (22) [M]+. – C23H33N5O8
(507.54): calcd. C 54.43, H 6.55, N 13.80; found C 54.38,
H 6.50, N 13.75.
Synthesis of acetohydrazone derivatives 9 and 10
A stirred glacial acetic acid suspension (20 mL) of hy-
drazide 4 (10 mmol) and ketonic derivatives, namely cyclo-
hexanone or isatin (10 mmol), was refluxed for 3 h and then
allowed to cool to room temperature. The separated solid was
collected by filtration, dried, and recrystallized to yield the
N-{2-[2-(D-Galactomethylene)hydrazinyl]-1-isopropyl-
2-oxoethyl}-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naph-
thy-ridine-3-carboxamide (8b)
Yield 43%; m. p. 202 – 204 ◦C (MeOH). – [α]2D5 = −38.5 corresponding acetohydrazide derivatives 9 and 10, respec-
(c = 0.5, MeOH). – IR (KBr): ν = 3540 – 3328 (OH, NH), tively.
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359
N-[2-(2-Cyclohexylidenehydrazinyl)-1-isopropyl-2-oxo-
ethyl]-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthy-
ridine-3-carboxamide (9)
1719 (C=O), 1654, 1534, 1250 (C=O, amide I, II and III)
cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.01 (t,
3H, CH3), 1.06 (d, 6H, 2 CH3), 2.48 (s, 3H, CH3), 2.74 (m,
1H, CH), 3.14 (q, 2H, CH2), 4.41 (d, 1H, CH), 6.65 – 8.15
(m, 7H, Ar-H), 8.79, 9.34 (2s, 2H, 2 NH, exchangeable
with D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO): δ =
13.16, 18.25, 24.81, 31.40, 49.27, 60.73, 113.62, 114.34,
118.78, 127.66, 131.94, 132.46, 138.37, 148.75, 155.68,
159.70, 162.69, 165.09, 172.55, 177.62 ppm. – MS (EI,
70 eV): m/z(%) = 475 (15) [M]+. – C25H25N5O5 (475.50):
calcd. C 63.15, H 5.30, N 14.73; found C 63.10, H 5.25, N
14.67.
Yield 66%; m. p. 131 – 133 ◦C (AcOH). – [α]D25 = −78.2
(c = 0.5, MeOH). – IR (KBr): ν = 3347, 3319 (2 NH), 1718
(C=O), 1658, 1540, 1254 (C=O, amide I, II and III) cm−1
.
–
1H NMR (500 MHz, [D6]DMSO): δ = 0.99 (t, 3H, CH3),
1.08 (d, 6H, 2 CH3), 1.25 – 1.37 (m, 10H, CH2), 2.45 (s,
3H, CH3), 2.85 (m, 1H, CH), 3.12 (q, 2H, CH2), 4.56 (d,
1H, CH), 6.73 (d, 1H, Ar-H), 7.79 (d, 1H, Ar-H), 8.02 (s,
1H, Ar-H), 8.43, 9.84 (2s, 2H, 2 NH, exchangeable with
D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO): δ = 13.22,
18.20, 24.78, 24.96, 27.13, 28.36, 31.44, 34.25, 49.31, 60.98,
113.75, 114.29, 118.71, 138.28, 148.80, 155.72, 159.67,
161.85, 162.78, 177.15, 179.59 ppm. – MS (EI, 70 eV):
m/z(%) = 425 (14) [M]+. – C23H31N5O3 (425.52): calcd.
C 64.92, H 7.34, N 16.46; found C 64.85, H 7.30, N 16.40.
N-{2-[(4,5,6,7-Tetrachloro-1,3-dioxo-1,3-dihydro-2H-iso-
indol-2-yl)amino]-1-isopropyl-2-oxo-ethyl}-1-ethyl-7-me-
thyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide (11b)
Yield 86%; m. p. 166 – 168 ◦C (AcOH-ether). – [α]2D5
=
4-Oxo-N-{2-oxo-1-isopropyl-2-[(2E)-2-(2-oxo-1,2-dihydro-
3H-indol-3-ylidene)hydrazinyl]-ethyl}-1-ethyl-7-methyl-
1,4-dihydro-1,8-naphthyridine-3-carboxamide (10)
−102.6 (c = 0.5, DMF). – IR (KBr): ν = 3394, 3370 (2 NH),
1728 (C=O), 1650, 1536, 1252 (C=O, amide I, II and III)
cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 1.00 (t,
3H, CH3), 1.04 (d, 6H, 2 CH3), 2.40 (s, 3H, CH3), 2.65
(m, 1H, CH), 3.12 (q, 2H, CH2), 4.46 (d, 1H, CH), 6.62
(d, 1H, Ar-H), 7.83 (d, 1H, Ar-H), 8.05 (s, 1H, Ar-H),
8.89, 9.17 (2s, 2H, 2 NH, exchangeable with D2O) ppm. –
13C NMR (125 MHz, [D6]DMSO): δ = 13.21, 18.20, 24.79,
31.46, 49.30, 60.82, 113.58, 114.39, 118.83, 128.89, 133.64,
138.28, 138.45, 148.67, 155.70, 159.76, 162.78, 165.12,
172.49, 177.56 ppm. – MS (EI, 70 eV): m/z(%) = 613 (7)
[M]+. – C25H21Cl4N5O5 (613.28): calcd. C 48.96, H 3.45,
Cl 23.12, N 11.42; found C 48.90, H 3.40, Cl 23.08, N
11.35.
Yield 77%; m. p. 160 – 162 ◦C (AcOH). – [α]D25 = −86.4
(c = 0.5, MeOH). – IR (KBr): ν = 3429 – 3365 (3NH), 1720
(C=O), 1655, 1542, 1254 (C=O, amide I, II and III) cm−1
.
–
1H NMR (500 MHz, [D6]DMSO): δ = 1.02 (t, 3H, CH3),
1.12 (d, 6H, 2 CH3), 2.40 (s, 3H, CH3), 2.69 (m, 1H, CH),
3.16 (q, 2H, CH2), 4.43 (d, 1H, CH), 6.67 – 8.11 (m, 7H,
Ar-H), 8.38, 9.79, 10.57 (3s, 3H, 3 NH, exchangeable with
D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO): δ = 13.19,
17.95, 24.73, 31.51, 49.26, 60.90, 113.82, 114.17, 117.92,
118.65, 121.83, 124.55, 129.63, 131.56, 133.05, 138.21,
146.74, 148.65, 155.79, 159.77, 162.70, 167.60, 177.10,
177.55 ppm. – MS (EI, 70 eV): m/z(%) = 474 (16) [M]+.
– C25H26N6O4 (474.51): calcd. C 63.28, H 5.52, N 17.71;
found C 63.22, H 5.46, N 17.65.
N-{2-[(5,7-Dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-
yl)amino]-1-isopropyl-2-oxoethyl}-1-ethyl-7-methyl-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carboxamide (12)
Synthesis of imide derivatives 11 – 13
A stirred glacial acetic acid suspension (30 mL) of hy-
drazide 4 (1 mmol) and an acid anhydride derivative, namely
phthalic anhydride, 1,2,4,5-tetrachlorophthalic anhydride,
naphthalene-1,8-dicarboxylic acid anhydride or quinolinic
anhydride (1 mmol), was heated (80 ◦C) for 1 – 3 h. The re-
action mixture was concentrated under reduced pressure,
cooled, and the separated solid was collected by filtration,
dried, and recrystallized to yield the corresponding imide
derivatives 11a, b, 12 and 13, respectively.
Yield 69%; m. p. 129 – 131 ◦C (AcOH-ether). – [α]2D5
=
−103.5 (c = 0.5, DMF). – IR (KBr): ν = 3412, 3351 (2 NH),
1722 (C=O), 1648, 1532, 1250 (C=O, amide I, II and III)
cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 0.99 (t,
3H, CH3), 1.03(d, 6H, 2 CH3), 2.47 (s, 3H, CH3), 2.78 (m,
1H, CH), 3.14 (q, 2H, CH2), 4.45 (d, 1H, CH), 6.65 – 8.97
(m, 6H, Ar-H), 8.90, 9.36 (2s, 2H, 2 NH, exchangeable with
D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO): δ = 13.18,
18.35, 24.85, 31.43, 49.25, 60.84, 113.48, 114.49, 118.83,
127.96, 128.51, 138.31, 138.55, 146.28, 148.68, 152.72,
155.67, 159.60, 162.71, 164.93, 165.41, 171.59, 177.61 ppm.
– MS (EI, 70 eV): m/z(%) = 476 (6) [M]+. – C24H24N6O5
(476.48): calcd. C 60.50, H 5.08, N 17.64; found C 60.44, H
N-{2-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)amino]-
1-isopropyl-2-oxoethyl}-1-ethyl-7-methyl-4-oxo-1,4-di-
hydro-1,8-naphthyridine-3-carboxamide (11a)
Yield 78%; m. p. 126 – 128 ◦C (AcOH-ether). – [α]2D5
=
−106.4 (c = 0.5, DMF). – IR (KBr): ν = 3371, 3324 (2 NH), 5.02, N 17.60.
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N. M. Khalifa et al. · Chiral Linear Carboxamides with an Incorporated Peptide Linkage
N-{2-[(1,3-Dioxo-3a,6-dihydro-1H-benzo[de]isoquinolin-
2(3H)-yl)amino]-1-isopropyl-2-oxoethyl}-1-ethyl-7-methyl-
4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxamide (13)
2.45 (s, 6H, 2 CH3), 2.68 (m, 2H, 2CH), 3.14 (q, 4H,
2 CH2), 4.41 (d, 2H, 2CH), 6.60 – 8.99 (m, 8H, Ar-H), 8.86,
9.43 (2s, 4H, 4NH, exchangeable with D2O) ppm. – 13C
NMR (125 MHz, [D6]DMSO): δ = 13.12, 18.27, 24.62,
31.38, 49.31, 60.79, 113.68, 114.23, 118.69, 125.35, 135.66,
138.27, 148.57, 155.72, 159.56, 162.69, 164.77, 172.53,
177.67 ppm. – MS (EI, 70 eV): m/z(%) = 872 (8) [M]+. –
C44H44N10O10 (872.88): calcd. C 60.54, H 5.08, N 16.05;
found C 60.50, H 5.00, N 16.00.
Yield 74%; m. p. 147 – 149 ◦C (AcOH-ether). – [α]2D5
−98.8 (c = 0.5, DMF). – IR (KBr): ν = 3389, 3341 (2 NH),
1726 (C=O), 1652, 1536, 1249 (C=O, amide I, II and III)
cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 0.99 (t, 3H,
CH3), 1.02 (d, 6H, 2 CH3), 2.43 (s, 3H, CH3), 2.76 (m,
1H, CH), 3.12(q, 2H, CH2), 4.42 (d, 1H, CH), 6.60 – 8.11
(m, 9H, Ar-H), 8.95, 9.22 (2s, 2H, 2 NH, exchangeable with
D2O) ppm. – 13C NMR (125 MHz, [D6]DMSO): δ = 13.23,
18.29, 24.75, 31.41, 49.33, 60.80, 113.61, 114.42, 118.78,
123.81, 125.76, 128.53, 130.79, 137.84, 138.19, 138.36,
148.64, 155.76, 159.14, 159.82, 162.73, 172.68, 177.50 ppm.
– MS (EI, 70 eV): m/z(%) = 525 (26) [M]+. – C29H27N5O5
(525.56): calcd. C 66.27, H 5.18, N 13.33; found C 66.20, H
5.12, N 13.28.
=
2,8-Bis{1-ethyl-7-methyl-N-[3-methyl-1-(methylamino)-
1-oxobutan-2-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-
3-carboxamido}benzo[de]isoquinolin-1,3,6,8(2H,7H)-yl)
tetraone (15)
Yield 52%; m. p. 251 – 253 ◦C (AcOH-ether). – [α]2D5
=
−158.1 (c = 0.5, DMF). – IR (KBr): ν = 3534 – 3315
(4 NH), 1726 – 1665 (10 C=O), 1649, 1540, 1248 (C=O,
amide I, II and III) cm−1. – 1H NMR (500 MHz,
[D6]DMSO): δ = 0.99 (t, 6H, 2 CH3), 1.05(d, 12H, 4 CH3),
2.49 (s, 6H, 2 CH3), 2.77 (m, 2H, 2CH), 3.12 (q, 4H,
2 CH2), 4.43 (d, 2H, 2CH), 6.65 – 8.31 (m, 10 H, Ar-H),
8.79, 9.34 (2s, 4H, 4NH, exchangeable with D2O) ppm. –
13C NMR (125 MHz, [D6]DMSO): δ = 13.15, 18.24, 24.53,
31.42, 49.25, 60.62, 113.74, 114.18, 118.65, 120.78, 135.27,
138.19, 140.02, 148.68, 155.69, 158.95, 159.51, 162.73,
172.47, 177.55 ppm. – MS (EI, 70 eV): m/z(%) = 923 (4)
[M]+. – C48H46N10O10 (922.94): calcd. C 62.46, H 5.02, N
15.18; found C 62.40, H 4.96, N 15.13.
Synthesis of bis-imide derivatives 14 and 15
The same procedure as for compounds 11 – 13 was em-
ployed except for using 1,2,4,5-benzenetetracarboxylic di-
anhydride or 1,4,5,8-naphthylenetracarboxylic dianhydride
(2 mmol) in refluxing glacial acetic acid.
2,6-Bis{1-ethyl-7-methyl-N-[3-methyl-1-(methylamino)-
1-oxobutan-2-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-
3-carboxamido}pyrrolo[3,4-f]isoindole-1,3,5,7(2H,6H)-
tetrone (14)
Yield 69%; m. p. 124 – 126 ◦C (AcOH-ether). – [α]2D5
=
Acknowledgement
−165.2 (c = 0.5, DMF). – IR (KBr): ν = 3510 – 3325
(4 NH), 1722 – 1680 (10 C=O), 1645, 1538, 1256 (C=O,
The authors extend their appreciation to the Deanship of
amide I, II and III) cm−1. – 1H NMR (500 MHz, Scientific Research at King Saud University for funding the
[D6]DMSO): δ = 1.00 (t, 6H, 2 CH3), 1.06 (d, 12H, 4 CH3), work through the research group project no. RGP-VPP-099.
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