Amino-acid and dipeptide derivatives of 2-(6-ethyl-4-oxo-3-(4-phenyl-4H-1, 2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetic acid

Article abstract of DOI:10.1007/s10600-005-0199-3

Chromones modified by triazole, amino acids, and dipeptides were prepared by condensation of the N-hydroxysuccinimide ester of 2-(6-ethyl-4-oxo-3-(4- phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetic acid with salts of amino acids or dipeptides. The

Full text of DOI:10.1007/s10600-005-0199-3

Chemistry of Natural Compounds, Vol. 41, No. 5, 2005
AMINO-ACID AND DIPEPTIDE DERIVATIVES OF
2-(6-ETHYL-4-OXO-3-(4-PHENYL-4H-1,2,4-TRIAZOL-3-YL)-
4H-CHROMEN-7-YLOXY)ACETIC ACID
T. V. Shokol,1 V. V. Semenyuchenko,1 S. V. Shilin,1
A. V. Turov,1 A. S. Ogorodniichuk,2 and V. P. Khilya1
UDC 547.814.5
Chromones modified by triazole, amino acids, and dipeptides were prepared by condensation of the
N-hydroxysuccinimide ester of 2-(6-ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-
yloxy)acetic acid with salts of amino acids or dipeptides. The dipeptide derivatives were also synthesized by
extending the chain of amino acids.
Key words: chromones, isoflavones, triazoles, amino-acid derivatives, dipeptides, activated esters, synthesis.
Natural and synthetic isoflavonoids possess a broad spectrum of biological activity, for example, growth inhibition
of pathogenic microbes and fungi, inhibition of certain enzymes, anti-inflammatory activity, etc. [1, 2]. At present
3-hetarylchromones are widely used because introduction of a heteroaromatic core can impart valuable biological properties to
these compounds.
Introducing an amino acid or peptide into a hetaryl-substituted isoflavone can increase the hydrophilicity or
lipophilicity, increase or decrease the toxicity, and prolong its action. Furthermore, such modification can change the selectivity
of its action.
Methods for modifying chromones include those in which the 7-hydroxychromone is bound to an amino acid at the
C-terminus by aminoacylation of N-substituted amino acids [3-8] and at the N-terminus by Mannich aminomethylation [9,
10]. Activated esters are also used [7, 11, 12]. There is only a single report [4] on the synthesis of amino-acid derivatives
of 3-hetarylchromones, namely 7-O-aminoacyl-3-(1-methyl-2-benzimidazolyl)chromones.
Triazoles themselves [13] and 2,3-dihydro-3-(1 -1,2,4-triazol-1-yl)chromones [14] have alreadyexhibited biological
H
activities. Therefore, our goal was to synthesize amino-acid derivatives of triazole analogs of isoflavone.
Alkylation of starting 7-hydroxy-3-(4-phenyl-4 -1,2,4-triazol-3-yl)-6-ethyl-4 -chromen-4-one (1) with
H
H
ethylchloroacetate and subsequent acid hydrolysis of the resulting ester 2 produced 3, which then was used to acylate natural
and synthetic amino acids.
We used activated N-hydroxysuccinimide esters to activate the carboxylic group. The esters were prepared in high
yields, are active acylating agents, and do not racemize the chiral amino acids [15, 16]. This method was not used previously
to modify 3-hetarylchromones. N-Hydroxysuccimide ester 4 was prepared by reacting 3 with N-hydroxysuccinimide in
DMF:dioxane. The condensing agent was diisopropylcarbodiimide because diisopropylurea is soluble in water. This enabled
the reaction products to be easily purified and the reactions to be carried out in a single flask.
Activated ester 4 was reacted without purification with amino-acid salts in DMF:dioxane:water at room temperature.
After the reaction was finished, the desired compounds were isolated by acidolysis.
Thus, 5-18 were synthesized with glycine (5), β-alanine (6), γ-aminobutyric acid (GABA) (7), ε-aminocaproic acid (8),
L-valine (9), L-methionine (10), L-phenylalanine (11), L-leucine (12), L-isoleucine (13), L-aspargic acid (14), DL-norvaline
(15), DL-norleucine (16), DL-α-aminobutyric acid (17), and L-tryptophan (18).
1)TarasShevchenkoKievNationalUniversity, 01033, Kiev,ul.Vladimirskaya, 64, e-mail: vkhilya@mail.univ.kiev.ua;
2) Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 02094, Kiev, ul.
Murmanskaya, 1. Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 435-439, September-October, 2005. Original
article submitted November 17, 2004.
0009-3130/05/4105-0533 ©2005 Springer Science+Business Media, Inc.
533

CO Et
2
COOH
O
O
HO
Et
O
O
O
O
O
O
Ph
N
Ph
N
Ph
N
ClCH CO Et
H SO
2 4
2
2
K CO
AcOH
2
3
Et
Et
N
N
N
N
N
N
1
2
3
SuOH, DIC
O
O
R
O
O
N
NH
COOH
NH(CH ) COOH
2 n
O
1. H N(CH ) COONa
1. H NCHRCOONa
2
2
2 n
O
O
O
O
O
O
Ph
N
Ph
Ph
N
+
+
2. H
2. H
N
Et
Et
Et
N
O
N
N
N
O
O
N
N
5: n = 1; 6: n = 2; 7: n = 3; 8: n = 5
9 - 18
4
9: R = i-Pr; 10: R = (CH ) SCH
2 2
11: R = Bn; 12: R = -Bu
3
1. H-Gly-Gly-ONa
+
i
1. SuOH, DIC
13: R = s-Bu; 14: R = CH COOH
2
2. amino acid, Na CO
2
3
2. H
15: R = n-Pr; 16: R = n-Bu
17: R = Et; 18: R =
+
3. H
N
H
O
O
O
O
COOH
H
N
H
H
N
H
N
H
N
COOH
COOH
Ph
N
O
N
H
O
O
O
O
O
O
O
O
Ph
N
Ph
N
Ph
N
Et
Et
Et
N
N
O
O
N
N
N
N
21
19
20
19 21
Dipeptidederivativesof2-(6-ethyl-4-oxo-3-(4-phenyl-4 -1,2,4-triazol-3-yl)-4 -chromen-7-yloxy)aceticacids(
-
)
H
H
19
3
was prepared from and glycylglycine analogously to amino-acid derivatives
were synthesized by two methods. Product
5 18 20
21
5
6
-
;
and , from amino-acid derivatives and , respectively, by stepwise extension of the amino-acid chain.
5 21
The formation of - was confirmed as follows. Their PMR spectra contain characteristic signals for the triazole ring
(1H singlet at 8.75-8.79 ppm for H-5), the chromone system (1H singlets at 6.88-7.10 ppm for H-8, 7.60-7.64 ppm for H-5, and
9 18
5 8
8.59-8.63 ppm for H-2), the amino-acid (see Experimental section), and the amide N–H ( - , 1H doublet at 8.02-8.29; - ,
1H triplet at 7.91-8.23 ppm). Signals for free carboxylic groups appeared at 11.81-12.81 ppm. Signals for OCH CO groups
2
11
12
of all compounds were 2H singlets at 4.62-4.76 ppm with the exception of and , where theyappeared as two doublets with
10 11 13
15 18
-
SSCC 14-15 Hz, i.e., these protons became nonequivalent. For
,
,
, and , the methylene protons of the amino-acid
9
12
moieties became nonequivalent. The differences in their chemical shifts were 0.1-0.2 ppm, SSCC 7-9 Hz. For and , the
methyls of the amino acids (CMe ) were also nonequivalent with differences in their chemical shifts of 0.2-0.3 ppm.
2
18
The COSY spectrum of was recorded in order to assign accurately the aromatic signals. As it turned out, the field
strength of the indole system increased the same as in tryptophan. The assignments for the signals are given in the
Experimental section.
19 21
were recorded in order to identifysignals of the dipeptides. The signal ofone ofthe methylenes
COSY spectra of
-
20
in fell in the water-absorption region. Signals of the amides and methylenes were accurately assigned from the appearance
of cross peaks between signals at 7.90 and 3.1 and between those at 8.10 and 3.76 ppm. The signal of one methylene of
21
β-alanine in fell in the DMSO-absorption region; the signal of another at 2.31 ppm was a multiplet. The COSY spectrum
exhibited a cross peak between signals of the amide proton and a signal at 3.33 ppm. We note that the signal of the methylene
6
bound to the amide N in was also found at weaker field than the methylene bound to the carboxylate.
Thus, activated esters were used to prepare a series of amino-acid and dipeptide derivatives of 2-(6-ethyl-4-oxo-3-(4-
phenyl-4 -1,2,4-triazol-3-yl)-4 -chromen-7-yloxy)acetic acid.
H
H
534

EXPERIMENTAL
The course of reactions and purityof products were monitored by TLC on Silufol UV-254 plates using CHCl :CH OH
3
3
(9:1 and 4:1). PMR spectra were recorded in DMSO-d on a Varian Mercury 400 spectrometer relative to TMS internal
6
standard. Elemental analyses of all compounds agreed with those calculated.
Ethyl 2-(6-ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetate (2). A solution of 1
(15.4 g, 46 mmol) in DMF (40 mL) was treated with freshly calcined potash (12.7 g, 92 mmol), stirred, and treated dropwise
with ethylchloroacetate (15 mL, 92 mmol). The mixture was stirred for 2 h at 60-70°C and for 18 h without heating. The
reaction mixture was poured into water. The resulting precipitate was filtered off and recrystallized from CCl . Yield
4
15.44 g (80%), mp 171-172°C, C H N O .
23 21
3 5
PMR spectrum (δ, ppm, J/Hz): 1.21 (3H, t, J = 7.5, CH CH -6), 1.29 (3H, t, J = 7.5, CH CH CO ), 2.67 (2H, q,
3
2
2
2
2
J = 7.5, CH CH -6), 4.20 (2H, q, J = 7.5, CH CH CO ), 4.91 (2H, s, OCH CO ), 7.09 (1H, s, H-8), 7.40 (5H, s, Ph), 7.65 (1H,
3
2
3
2
2
2
2
s, H-5), 8.63 (1H, s, H-2), 8.77 (1H, s, H-5″
).
triazole
2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetic Acid (3). Compound 2 (15.44 g,
37 mmol) was dissolved in acetic acid (73.5 mL, 780 mmol) and H SO (18.4 mL, 380 mmol) and boiled for 10 min. On the
2
4
next day,it was poured into water (1.5 L). The resulting solid was filtered off and recrystallized from DMF. Yield 11.87 g
(82%), mp 266-267°C, C H N O .
21 17
3 5
PMR spectrum (δ, ppm, J/Hz): 1.21 (3H, t, J = 7.5, CH CH -6), 2.68 (2H, t, J = 7.5, CH CH -6), 4.82 (2H, s,
3
2
3
2
OCH COOH), 7.05 (1H, s, H-8), 7.41 (5H, s, Ph), 7.64 (1H, s, H-5), 8.62 (1H, s, H-2), 8.78 (1H, s, H-5′
), 13.06 (1H, br.s,
2
triazole
COOH).
GeneralMethodforSynthesizingAmino-acidDerivativesof2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-
4H-chromen-7-yloxy)acetic Acid 5-18. A solution of 3 (1.17 g, 3 mmol) and N-hydroxysuccinimide (0.46 g, 3.9 mmol) in
dioxane (absolute, 15 mL) and DMF (absolute, 7 mL) was stirred and treated with diisopropylcarbodiimide (0.6 mL, 3.9 mmol)
and stirred vigorously for 2 h (TLC monitoring). The resulting ester (4) was treated with a solution of amino acid (3.6 mmol)
and Na CO (0.19 g, 1.8 mmol) in water (22 mL) (0.38 g, 3.6 mmol of Na CO for aspartic acid). The reaction mixture was
2
3
2
3
stirred for 2-4 h (TLC monitoring). After the reaction was finished, the mixture was poured into water (200 mL) and acidified
with HCl until the pH was 2-3. The solid was filtered off on the following day and dried. It was crystallized from aqueous
alcohol if necessary.
2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)acetic Acid(5). Yield88%,
mp 139-140°C, C H N O .
23 20
4 6
PMR spectrum (δ, ppm, J/Hz): 1.21 (3H, t, J = 7.5, CH CH -6), 2.72 (2H, q, J = 7.5, CH CH -6), 3.83 (2H, d, J = 5.6,
3
2
3
2
NHCH COOH), 4.72 (2H, s, OCH CO), 7.06 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s, H-5), 8.23 (1H, t, J = 5.6, NH), 8.63
2
2
(1H, s, H-2), 8.79 (1H, s, H-5′
), 12.57 (1H, br.s, COOH).
triazole
3-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)propanoic Acid(6). Yield
83%, mp 121-122°C, C H N O .
24 22
4 6
PMR spectrum (δ, ppm, J/Hz): 1.21 (3H, t, J = 7.5, CH CH -6), 2.43 (2H, t, J = 6.4, CH COOH), 2.71 (2H, q, J = 7.5,
3
2
2
CH CH -6), 3.39 (2H, m, NHCH CH COOH), 4.63 (2H, s, OCH CO), 7.02 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s, H-5),
3
2
2
2
2
7.98 (1H, t, J = 5.6, NH), 8.62 (1H, s, H-2), 8.78 (1H, s, H-5′
), 12.18 (1H, br.s, COOH).
triazole
4-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)butanoic Acid(7). Yield
86%, mp 109-110°C, C H N O .
25 24
4 6
PMRspectrum (δ, ppm, J/Hz): 1.21 (3H, t, J = 7.5, CH CH -6), 1.17 (2H, m, CH CH CH ), 2.23(2H, m, NHCH CH ),
3
2
2
2
2
2
2
2.72 (2H, q, J = 7.5, CH CH -6), 3.18 (2H, m, CH CH COOH), 4.63 (2H, s, OCH CO), 7.00 (1H, s, H-8), 7.40 (5H, s, Ph),
3
2
2
2
2
7.63 (1H, s, H-5), 7.99 (1H, t, J = 5.6, NH), 8.61 (1H, s, H-2), 8.78 (1H, s, H-5′
), 11.91 (1H, br.s, COOH).
triazole
6-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)hexanoic Acid(8). Yield
80%, mp 103-104°C, C H N O .
27 28
4 6
PMR spectrum (δ, ppm, J/Hz): 1.21 (3H, t, J = 7.5, CH CH -6), 1.32 (2H, m, NHCH CH CH CH CH ), 1.54 (4H,
3
2
2
2
2
2
2
m, NHCH CH CH CH CH ), 2.17 (2H, m, NHCH CH ), 2.71 (2H, q, J = 7.5, CH CH -6), 3.14 (2H, m, CH COOH), 4.62 (2H,
2
2
2
2
2
2
2
3
2
2
s, OCH CO), 6.99 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s, H-5), 7.91 (1H, t, J = 5.6, NH), 8.61 (1H, s, H-2), 8.78 (1H, s,
2
H-5′
), 11.81 (1H, br.s, COOH).
triazole
535

2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)-3-methylbutanoic Acid
(9). Yield 58%, mp 135-136°C, C H N O .
26 26
4 6
PMR spectrum (δ, ppm, J/Hz): 0.94 and 0.95 [6H, t, J = 6.8, CH(CH ) ], 1.22 (3H, t, J = 7.5, CH CH -6), 2.16 [1H,
3 2
3
2
m, CH(CH ) ], 2.70 (2H, q, J = 7.5, CH CH -6), 4.28 [1H, dd, J
= 5.6, J
= 8.8, NHCH(COOH)CH], 4.76 (2H, s,
3 2
3
2
CH,CH
CH,NH
OCH CO), 7.02 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s, H-5), 8.02 (1H, d, J = 8.8, NH), 8.61 (1H, s, H-2), 8.77 (1H, s,
2
H-5′
), COOH exchanged with D O.
2
triazole
2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)-4-(methylthio)butanoic
Acid (10). Yield 69%, mp 115-116°C, C H N O S.
26 26
4 6
PMR spectrum (δ, ppm, J/Hz): 1.23 (3H, t, J = 7.5, CH CH -6), 1.95 (1H, m, SCH -β), 2.04 (4H, m, SCH and
3
2
2
3
SCH -α), 2.47 [2H, m, CH(COOH)CH CH S), 2.72 (2H, q, J = 7.5, CH CH -6), 4.41 [1H, m, NHCH(COOH)CH ], 4.73 (2H,
2
2
2
3
2
2
s, OCH CO), 7.03 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s, H-5), 8.29 (1H, d, J = 7.2, NH), 8.61 (1H, s, H-2), 8.78 (1H, s,
2
H-5′
), COOH exchanged with D O.
2
triazole
2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)-3-phenylpropanoic Acid
(11). Yield 79%, mp 150-151°C, C H N O .
30 26
4 6
PMR spectrum (δ, ppm, J/Hz): 1.16 (3H, t, J = 7.5, CH CH -6), 2.64 (2H, q, J = 7.5, CH CH -6), 2.99 and 3.13 (1H
3
2
3
2
each, m, CH Ph), 4.55 [1H, m, NHCH(COOH)CH ], 4.68 and 4.62 (1H each, 2d, J = 14.8, OCH CO), 6.88 (1H, s, H-8), 7.17
2
2
2
(5H, s, CH Ph), 7.41 (5H, s, Ph
), 7.62 (1H, s, H-5), 8.11 (1H, d, J = 7.2, NH), 8.63 (1H, s, H-2), 8.78 (1H, s, H-5′
),
triazole
2
triazole
12.81 (1H, br.s, COOH).
2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)-4-methylpentanoic Acid
(12). Yield 66%, mp 134-135°C, C H N O .
27 28
4 6
PMR spectrum (δ, ppm, J/Hz): 0.90 and 0.93 [3H each, d, J = 6.5, CH(CH ) ], 1.22 (3H, t, J = 7.5, CH CH -6), 1.60
3 2
3
2
[2H, pt, J
= J
= 6.6, CH(COOH)CH CH], 1.66 [1H, m, CH CH(CH ) ], 2.70 (2H, q, J = 7.5,
CH ,CH(COOH)
CH ,CHC(Me ) 2 2 3 2
2
CH CH -6),24.31 (1H, m, NHCH), 4.692and 4.75 (2H, 2d, J = 14.8, OCH CO), 7.00 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H,
3
2
2
s, H-5), 8.20 (1H, d, J = 8.0, NH), 8.61 (1H, s, H-2), 8.76 (1H, s, H-5′
), 12.60 (1H, br.s, COOH).
triazole
2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)-3-methylpentanoicAcid
(13). Yield 80%, mp 132-133°C, C H N O .
27 28
4 6
PMR spectrum (δ, ppm, J/Hz): 0.92 [6H, m, CH(CH )CH CH ], 1.22 [4H, t, J = 7.5, CH CH -6 and CH(CH )α-
3
2
3
3
2
3
CH CH ], 1.48 [1H, d, J = 7.0, CH(CH )β-CH CH ), 1.87 (1H, m, CH CHCH ), 2.70 (2H, q, J = 7.5, CH CH -6), 4.30 [1H,
2
3
3
2
3
3
2
3
2
dd, J
= 5.2, J
= 8.8, NHCH(COOH)CH], 4.74 (2H, s, OCH CO), 7.02 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s,
CH,CH
CH,NH 2
H-5), 8.01 (1H, d, J = 8.8, NH), 8.60 (1H, s, H-2), 8.75 (1H, s, H-5′
), COOH exchanged with D O.
2
triazole
2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)succinicAcid(14). Yield
57%, mp 137-138°C, C H N O .
25 22
4 8
PMR spectrum (δ, ppm, J/Hz): 1.21 (3H, t, J = 7.5, CH CH -6), 2.70 [4H, m, CH CH -6 and CH(COOH)CH COOH],
3
2
3
2
2
4.64 [1H, m, NHCH(COOH)CH ], 4.72 (2H, s, OCH CO), 7.05 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s, H-5), 8.21 (1H, d,
2
2
J = 8.4, NH), 8.61 (1H, s, H-2), 8.76 (1H, s, H-5′
), 12.57 (0.5H, br.s, COOH), the other COOH exchanged with D O.
2
triazole
2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)pentanoicAcid(15). Yield
85%, mp 181-182°C, C H N O .
26 26
4 6
PMR spectrum (δ, ppm, J/Hz): 0.92 (3H, t, J = 7.5, CH CH ), 1.21 (3H, t, J = 7.5, CH CH -6), 1.36 (2H, m,
2
3
3
2
CH CH CH ), 1.67 and 1.75 [1H each, 2d, J = 8.8, CH(COOH)CH CH ], 2.70 (2H, q, J = 7.5, CH CH -6), 4.30 [1H, m,
2
2
3
2
2
3
2
NHCH(COOH)CH], 4.71 (2H, s, OCH CO), 7.02 (1H, s, H-8), 7.40 (5H, s, Ph), 7.63 (1H, s, H-5), 8.17 (1H, d, J = 7.2, NH),
2
8.61 (1H, s, H-2), 8.78 (1H, s, H-5′
), 12.53 (1H, br.s, COOH).
triazole
2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)hexanoic Acid(16). Yield
86%, mp 112-113°C, C H N O .
27 28
4 6
PMR spectrum (δ, ppm, J/Hz): 0.89 (3H, t, J = 7.5, CH CH CH ), 1.22 (3H, t, J = 7.5, CH CH -6), 1.31 (4H, m,
2
2
3
3
2
CH CH CH CH ), 1.68 and 1.80 [1H each, m, CH(COOH)CH CH ], 2.71 (2H, q, J = 7.5, CH CH -6), 4.28 [1H, m,
2
2
2
3
2
2
3
2
NHCH(COOH)CH], 4.71 (2H, m, OCH CO), 7.01 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s, H-5), 8.14 (1H, d, J = 8.0, NH),
2
8.59 (1H, s, H-2), 8.74 (1H, s, H-5′
), 12.60 (1H, br.s, COOH).
triazole
2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)butanoic Acid(17). Yield
85%, mp 133-134°C, C H N O .
25 24
4 6
536

PMR spectrum (δ, ppm, J/Hz): 0.94 [3H, t, J = 7.5, CH(COOH)CH CH ], 1.22 (3H, t, J = 7.5, CH CH -6), 1.74 and
2
3
3
2
1.85 [1H each, m, CH(COOH)CH CH ], 2.70 (2H, q, J = 7.5, CH CH -6), 4.25 [1H, m, NHCH(COOH)CH], 4.73 (2H, s,
2
3
3
2
OCH CO), 7.03 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s, H-5), 8.17 (1H, d, J = 8.0, NH), 8.62 (1H, s, H-2), 8.79 (1H, s,
2
H-5′
), 12.68 (1H, br.s, COOH).
triazole
2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)-3-(1H-indol-3-
yl)propanoic Acid (18). Yield 86%, mp 161-162°C, C H N O .
32 27
5 7
PMR spectrum (δ, ppm, J/Hz): 1.12 (3H, t, J = 7.5, CH CH -6), 2.58 (2H, q, J = 7.5, CH CH -6), 3.20 and 3.26 [1H
3
2
3
2
each, m, CH(COOH)CH2indole], 4.62 [1H, m, NHCH(COOH)CH ], 4.67 (2H, s, OCH CO), 6.92 (1H, m, H-5′), 6.94 (1H, m,
2
2
H-6′), 7.01 (1H, m, H-2′), 7.10 (1H, s, H-8), 7.30 (1H, d, J = 8.0, H-7′), 7.40 (5H, s, Ph), 7.51 (1H, d, J = 8.8, H-4′), 7.60 (1H,
s, H-5), 8.03 (1H, d, J = 8.8, NH), 8.62 (1H, s, H-2), 8.77 (1H, s, H-5″
), 10.74 (1H, br.s, NH
), COOH exchanged with
triazole
indole
D O.
2
2-(2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)acetamido)aceticAcid
(19) was synthesized from 3 and glycylglycine by the method used for 5-18. Yield 64%, mp 146-147°C, C H N O .
25 23
5 7
PMR spectrum (δ, ppm, J/Hz): 1.22 (3H, t, J = 7.5, CH CH -6), 2.73 (2H, q, J = 7.5, CH CH -6), 3.78 and 3.84 (2H
3
2
3
2
each, d, J = 5.6, NHCH ), 4.73 (2H, s, OCH CO), 7.07 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s, H-5), 8.20 and 8.23 (1H each,
2
2
t, J = 5.6, NH), 8.63 (1H, s, H-2), 8.78 (1H, s, H-5′
), 12.45 (1H, br.s, COOH).
triazole
4-(2-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)acetamido)butanoic
Acid (20). A solution of 5 (1.3 g, 2.9 mmol) and N-hydroxysuccinimide (0.46 g, 3.9 mmol) in dioxxane (20 mL) and DMF
(5 mL) was treated with diisopropylcarbodiimide (0.6 mL, 3.9 mmol). The mixture was stirred vigorously for 2 h (TLC
monitoring). The resulting activated ester was treated with a solution of GABA (0.37 g, 3.6 mmol) and Na CO (0.19 g,
2
3
1.8 mmol) in water (25 mL). The reaction mixture was stirred for 2.5 h and poured into water (200 mL) after the reaction was
finished. On the following day the oil that appeared in the water was ground. The water was decanted. The oil was filtered
and ground in ethylacetate. White crystals were filtered off.
Yield 77%, mp 115-116°C, C H N O .
27 27
5 7
PMR spectrum (δ, ppm, J/Hz): 1.23 (3H, t, J = 7.5, CH CH -6), 1.69 (2H, m, CH CH NH), 2.22 (2H, t, J = 7.2,
3
2
2
2
CH CH COOH), 2.72 (2H, q, J = 7.5, CH CH -6), 3.1 (s, NHCH CH ), 3.76 (2H, d, J = 5.2, NHCH CO), 4.72 (2H, s,
2
2
3
2
2
2
2
OCH CO), 7.07 (1H, s, H-8), 7.40 (5H, s, Ph), 7.64 (1H, s, H-5), 7.90 (1H, t, J = 5.6, CONHCH CH ), 8.10 (1H, t, J = 5.2,
2
2
2
CONHCH CO), 8.61 (1H, s, H-2), 8.75 (1H, s, H-5′
), 11.90 (1H, br.s, COOH).
triazole
2
2-(3-(2-(6-Ethyl-4-oxo-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-4H-chromen-7-yloxy)acetamido)propanamido)-3-
phenylpropanoic Acid (21) was synthesized from 6 and L-phenylalanine by the method used for 20.
Yield 42%, mp 123-124°C, C H N O .
33 31
5 7
PMR spectrum (δ, ppm, J/Hz): 1.20 (3H, t, J = 7.5, CH CH -6), 2.31 (2H, br.m, CH CH CO), 2.71 (2H, q, J = 7.5,
3
2
2
2
CH CH -6), 2.88 and 3.05 (1Heach, m, CH Ph), 3.33 (2H, br.m, NHCH CH ), 4.48 [1H, m, NH(COOH)CHCH Ph], 4.59 (2H,
3
2
2
2
2
2
s, OCH CO), 7.01 (1H, s, H-8), 7.14 (2H, m, H -2′,6′), 7.21 (3H, s, H -3′,4′,5′), 7.41 (5H, s, Ph ), 7.64 (1H, s, H-5), 7.93
triazole
2
Ph
Ph
(1H, t, J = 5.2, CONHCH CH ), 8.17 [1H, d, J = 8.4, CONHCH(COOH)CH ], 8.61 (1H, s, H-2), 8.79 (1H, s, H-5′ ), COOH
triazole
2
2
2
exchanged with D O.
2
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