Synthesis of some 6-alkylureido-4-aryl- 2(1H)-pyridones: Fürther transformations and pharmacological activity

Article abstract of DOI:10.1515/znb-2015-0066

The Michael addition of enaminoesters to coumarins (1) does not lead to the formation of simple adducts 3 but to the rearranged 4-aryl-2-pyridone 4a. Now, N-carbamoylation of the 6-amino-2-pyridone 4a with alkyl isocyanates and further transformation of t

Full text of DOI:10.1515/znb-2015-0066

Z. Naturforsch. 2015; 70(11)b: 797–807
Lyubomir Dimitrov Raev, Ivo Christov Ivanov*, Henri Angel Astroug, Wolfgang Frey
and Silviya Georgieva Agontseva
Synthesis of some 6-alkylureido-4-aryl-
2
(1H)-pyridones: further transformations
and pharmacological activity
DOI 10.1515/znb-2015-0066
Received April 4, 2015; accepted June 7, 2015
1
Introduction
Abstract: The Michael addition of enaminoesters to In a series of earlier papers, we described the Michael
coumarins (1) does not lead to the formation of simple addition of some enaminoesters to coumarin (1a,
adducts 3 but to the rearranged 4-aryl-2-pyridone 4a. Scheme 1) and some of its 3-substituted (e.g. the cou-
Now, N-carbamoylation of the 6-amino-2-pyridone 4a marin-3-carboxylic acid 1b) and 3,6-disubstituted deriva-
with alkyl isocyanates and further transformation of the tives [1–5]. The initially formed adduct 3 spontaneously
corresponding novel ureido-2-pyridone derivatives 6a–g undergoes further intramolecular rearrangement to
into chromeno[3,4-c]pyridines 5d,g and O-acetyl deriva- give the simplest of the resulting stable adducts, ethyl
tives 7a–g are reported. All newly synthesized compounds 2-amino-4-(2-hydroxyphenyl)-6-oxo-1,4,5,6-tetrahydro-
1
13
were characterized by means of H/ C NMR, MS, IR spectra 3-pyridinecarboxylate (4a). Compound 4a could also be
and elemental analysis. The structure of the ureide 6f and obtained from coumarin-3-carboxylic acid (1b) and ethyl
of the N-cyclohexyl-O-acetyl derivative 7g were addition- 3,3-diaminoacrylate (2) accompanied by decarboxylation.
ally confirmed by crystal structure determinations. Acute
Carbamoylation of enamines with heterocumulenes,
toxicity after intraperitoneal administration, blood clot- leading to either C- or N-adducts, has been widely used
ting time, analgesic activity and the effects on the hexo- as the initial step in the synthesis of various heterocyclic
barbital sleeping time were tested on laboratory animals compounds, mainly derivatives of uracil [6]. Thus, 3-ami-
(
compounds 4a, 6a, 6c, 6d and 6g).
nopropenoic esters were added to organic isocyanates or
isothiocyanates yielding N-adducts which readily cyclized
Keywords: acute toxicity; analgesic activity; blood to 6-substituted uracils [7] in the presence of a base. In
clotting time; chromeno[3,4-c]pyridines; crystal structure; a similar way, we previously developed the first general
enaminoesters; hexobarbital sleeping time; isocyanates; method for direct preparation of 3-monosubstituted 6-ami-
2
-pyridones; ureides.
nouracils [8] by the addition of the ene-diamine (ketene
aminal) 2 to alkyl isocyanates. It seemed reasonable to
try an analogous approach by carbamoylating the cou-
marin–enaminoester adduct, the 2-pyridone 4a, which
contains the same ketene aminal moiety (Scheme 1). As
we reported earlier [3], the adduct 4a, on the other hand,
readily underwent simple recyclization on heating to give
the substituted chromeno[3,4-c]pyridine 5a. Conditions
have also been reported [1] for consecutive acetylation of
the primary amino and the phenolic group to yield the
corresponding acetyl derivatives 4b, c, d.
Dedicated to Professor Gerhard Maas on the occasion of his 65th
birthday.
*
Corresponding author: Ivo Christov Ivanov, Faculty of Pharmacy,
Medical University of Sofia, Dunav 2, BG-1000 Sofia, Bulgaria,
Fax: +35-929879874, E-mail: ivanov43@gmail.com
In the present paper, we wish to report N-carbamoyla-
tion of 4a with alkyl isocyanates and the results of some
trials on further transformation of the 3-alkyl ureides
Lyubomir Dimitrov Raev, Henri Angel Astroug and Silviya Georgieva
Agontseva: Faculty of Pharmacy, Medical University of Sofia, Dunav
6
a–g (Scheme 2) thus obtained. We also had to examine
if new synthesis of 3-alkyl-5-arylpyrido[2,3-d]pyrimidine-
,4,7(1H,3H,8H)-triones of type 8 with promising phar-
macological properties [9] was possible to be developed
2
, BG-1000 Sofia, Bulgaria
Wolfgang Frey: Institut für Organische Chemie und Biochemie,
Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart,
Germany
2
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7
98ꢀꢀꢀꢀꢁꢀL. D. Raev et al.: Synthesis of 6-alkylureido-4-aryl-2(1H)-pyridones
O-carbamoylation at the phenolic hydroxyl group
O
(Scheme 2). The reaction was successfully performed in
anhydrous acetonitrile at reflux to give the ureides 6a–g
with good yields (76–97 %). The expected IR spectral
bands could be observed for NH/OH-associated groups
as well as for all three different carbonyl groups (ester,
COOC2H5
NH2
O
+
O
COOC2H5
NH2
(
–CO2 from 1b)
O
X
H2N
2
1
a
b
X=H
X=COOH
2
H N
3
(
not isolable)
−
1
lactam, and urea) at about 1700, 1670 and 1620 cm ,
respectively. All relevant proton groups show the
1
OR1
R O
O
1
13
expected signals in the H NMR spectra. The C NMR
data of two selected representatives 6a,d are schemati-
cally presented in Fig. 1. In addition, the structure of the
ureides 6a–g was unambiguously confirmed by means of
X-ray crystallographic analysis of 6f (Fig. 2). An attempt
to bring 4a to reaction with methylisothiocyanate in ace-
tonitrile failed, even after 40-h reflux, i.e. no product
could be detected by means of thin-layer chromatogra-
phy (TLC).
COOC2H5
NHCOCH3
COOC2H5
(
CH3CO)2O
Heat
O
CH3COOH
–C H OH
2
5
O
N
H
O
N
NH2
O
N
NH2
H
H
1
4a: R1=H
5a
4
4
b: R =H
(
CH3CO)2O
pyridine
(CH3CO)2O
pyridine
1
4d: R1=COCH3
c: R =COCH3
Scheme 1:ꢀSynthetic route to the coumarin–enaminoester adduct 4a,
its N-acetyl (4b), N,O-diacetyl (4c) and O-acetyl (4d) derivatives, cf. [1].
C2H5ONa
10a
O
5
OH
in C2H5OH
10b
126.5
126.7
R2-N=C=O
4
3
o
COOCH2CH3
20–25
C
1
O
115.4
127.6
115.8
127.9
4a
118.9
154.7
119.1
155.0
CH3CN, reflux
1
NHCONHR2
NHCONHR2
O
N
O
N
H
HO
128.3
HO
128.4
30.0
H
6
a–g
168.3 59.4 14.6
169.0 59.5 14.6
2
29.8
5
d, g
COOCH CH
COOCH CH
2
3
3
36.2
36.5
81.4
81.5
(
CH3CO)2O
pyridine
169.3
155.1 150.0
169.5
155.5
1
4.2
150.3
40.0
19.8
O
N
H
NHCONHCH2CH3
O
N
H
NHCONHCH2CH2CH2CH3
13.9
34.3
31.4
6a
6d
OCOCH3
HO
O
1
35.2
R2
N
C4H9N=C=O
COOCH2CH3
1
23.2
127.1
126.2
4d
7d
147.9
NHCONHR2
20.7
O
N
H
O
N
N
O
H
H
CH3COO
127.8
1
68.0
168.4 59.4 13.9
COOCH2CH3
2
9.8
8
7
a–g
36.7
8
1.2
169.1
155.2 150.0
3
8.0
19.5
O
N
H
NHCONHCH2CH2CH2CH3
31.1
13.6
5
–7
a
b
c
d
e
f
g
R2
C2H5 C3H7 i-C3H7 n-C4H9 t-C4H9 n-C6H13 c-C6H11
7
d
Scheme 2:ꢀN-Carbamoylation of 4a (→ 6a–g) and consequent
1
3
Fig. 1:ꢀ C NMR chemical shifts (δ in ppm) of compounds 6a, d and
d (in [D ]DMSO).
acetylation (→ 7a–g). The structures 6f and 7g are confirmed by
7
6
crystal structure determinations.
by cyclization of the resulting 3-alkylureides 6a–g (cf.
Scheme 2).
2
Results and discussion
2.1 Chemistry
Pursuing our interest in biologically active 2-pyridones
10–13], structurally related to 1,4-dihydropyridine
calcium antagonists, we first studied the reaction of
[
Fig. 2:ꢀMolecular structure of 6f in the crystal (displacement ellip-
soids are drawn at the 50 % probability level; hydrogen atoms are
omitted for clarity; only one alternative of the disordered atom C17
4
a with alkyl isocyanates in order to achieve selec-
tive C(2)-N-carbamoylation and to avoid competitive is shown).
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L. D. Raev et al.: Synthesis of 6-alkylureido-4-aryl-2(1H)-pyridonesꢂꢁꢀꢀꢀꢂ799
The successive acetylation of the phenolic hydroxyl NMR spectrum showed a typical ABX spin system for the
A
B
X
group was carried out in pyridine to selectively afford protons 5-H H and 4-H at δ ꢀ=ꢀ 2.61, 3.21 and 4.23 ppm,
the corresponding O-acetyl derivatives 7a–g (cf. [1]) respectively, in addition to the expected D O-exchange-
2
in quantitative yield. The molecular structure of the able signals due to the three NH groups at δ ꢀ=ꢀ 8.53, 11.01,
N-cyclohexyl-O-acetyl derivative 7g was confirmed by and 11.73 ppm. In the positive ion CI-MS spectra, the base
+
X-ray crystallographic analysis (Fig. 3).
peaks matched the [M+1] ions and the corresponding
In order to prove the structure of the products 7a–g isotope distribution confirmed the molecular formulae
chemically, we also used an alternative synthetic route for of 5d, g.
7
d, starting from the O-acetyl derivative 4d and n-butyliso-
Many known approaches for the synthesis of [1]
cyanate. We obtained a product (7d) which was identical benzopyrano[3,4-c]pyridines or [1]benzopyrano[4,3-b]
with that of the reaction of 6d with acetic anhydride–pyri- pyridines include coumarin derivatives as starting com-
dine (Scheme 2).
pounds or intermediates [14–19]; for a review see [20].
On the analogy with the published heterocycliza- Evidently, the preparation of the 4-ureido-1,10b-dihydro-
tion of other structurally similar ureide esters [6–8], 5H-[1]benzopyrano[3,4-c]pyridines 5d, g, as discussed
we tried to perform the cyclization of 6a–g under the above, is a new contribution to the synthesis of this
reported conditions, i.e. in the presence of sodium eth- heterocyclic class of compounds.
oxide at ambient temperature [7, 8]. However, instead of
the expected pyrido[2,3-d]pyrimidine 8, we isolated the
2
H-chromeno[3,4-c]pyridines 5d, g as products which are
2
.2 Pharmacology
actually coumarin derivatives again (Scheme 2). Their
structure was confirmed by means of spectral methods
The estimated acute toxicity LD of the tested compounds
50
(
IR, NMR and MS) and elemental analyses. Thus, three
after intraperitoneal administration to male line H mice
different carbonyl frequencies were observed at 1726,
−
1
is 4500 mg kg b.w. for compound 4a and more than
−
1
1
1
651 and 1622 cm in the IR spectrum of 5d, while its H
−
1
5
000 mg kg b.w. for compounds 6a, 6c, 6d and 6g. The
tested substances are practically non-toxic.
The results of the investigation of the effect of com-
pound 4a on the blood clotting time compared to warfarin
2
4 h after administration are presented in Table 1. It was
shown that 4a prolongs the clotting time of the control at
a dose 1/10 of LD .
50
The results of the investigation of the analgesic activity
(
hot-plate test in mice) of different doses of compound 4a
3
0 min after intraperitoneal administration are presented
in Table 2. At doses 1/10, 1/50, and 1/100 of LD , the cou-
50
marin–enaminoester 4a exhibits analgesic activity.
The results of the investigation of the analgesic activ-
ity (acetic acid writhing test in mice) of different doses
of compound 4a, administered intraperitoneally 60 min
before the acetic acid injection, are presented in Table 3.
The number of writhing was recorded during 30 min com-
mencing 5 min after the acetic acid injection, as presented
Fig. 3:ꢀMolecular structure of 7g in the crystal (displacement ellip-
soids are drawn at the 50 % probability level; hydrogen atoms are
omitted for clarity).
Table 1:ꢀBlood clotting time.
ꢁ
Control (saline)ꢁ
Warfarinꢁ
Compound ꢂa
Dose, mg kg ꢃ
−
ꢄ
–ꢄ
ꢃꢅꢉꢄ
±ꢃꢌ.ꢉꢄ
ꢃꢅꢆꢄ
ꢇꢅꢆ (ꢃ/ꢃꢆ LD )ꢄ
ꢈꢆ (ꢃ/ꢅꢆ LDꢅꢆ)ꢄ
ꢃꢋꢌ.ꢋꢄ
ꢇꢅ (ꢃ/ꢃꢆꢆ LDꢅꢆ)
ꢊꢃꢃ
ꢅꢆ
ꢇꢋꢈ ꢄ
a
a
Clotting time, sꢄ
ꢊꢇꢆ ꢄ
SD
ꢄ
±ꢍꢅ.ꢈꢄ
±ꢌꢌ.ꢌꢄ
±ꢅꢉ.ꢋꢄ
±ꢃꢆꢍ.ꢉ
ap ꢄ<ꢄ 0.001: level of significance compared to the controls.
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8
00ꢀꢀꢀꢀꢁꢀL. D. Raev et al.: Synthesis of 6-alkylureido-4-aryl-2(1H)-pyridones
Table 2:ꢀAnalgesic activity (hot-plate test).
ꢁ
Control (saline)ꢁ
Compound ꢂa
−ꢃ
Dose, mg kg ꢄ
–ꢄ
ꢃꢇ.ꢊꢄ
±ꢃ.ꢅꢄ
ꢇꢅꢆ (ꢃ/ꢃꢆ LD )ꢄ
ꢈꢆ (ꢃ/ꢅꢆ LD )ꢄ
ꢇꢅ (ꢃ/ꢃꢆꢆ LD5ꢄ)
ꢊꢉ.ꢉb
5
ꢄ
5ꢄ
ꢊꢌ.ꢍ ꢄ
a
a
Time, s
SD
ꢄ
ꢄ
ꢊꢃ.ꢋ ꢄ
±ꢍ.ꢉꢄ
±ꢌ.ꢆꢄ
±ꢃ.ꢈ
a
b
p ꢄ<ꢄ 0.001; p ꢄ<ꢄ 0.05: level of significance compared to the controls.
Table 3:ꢀAnalgesic activity of 4a (acetic acid writhing test).
ꢁ
Control (saline)ꢁ
Metamizoleꢁ
Compound ꢂa
Dose, mg kg ꢃ
−
ꢄ
–ꢄ
ꢋꢋ.ꢊꢄ
±ꢃꢇ.ꢃꢄ
ꢊꢅ (ꢃ/ꢃꢆ LDꢅꢆ)ꢄ
ꢃꢌ.ꢊꢄ
ꢇꢅꢆ (ꢃ/ꢃꢆ LD )ꢄ
ꢈꢆ (ꢃ/ꢅꢆ LD )ꢄ
ꢇꢅ (ꢃ/ꢃꢆꢆ LD )
ꢅꢆ
ꢊꢊ.ꢉ ꢄ
ꢅꢆ
ꢍꢈ.ꢉ ꢄ
ꢅꢆ
ꢌꢋ.ꢅ
a
a
b
Number of writhingꢄ
SD
ꢄ
±ꢃꢃ.ꢅꢄ
±ꢊ.ꢃꢄ
±ꢉ.ꢅꢄ
±ꢅ.ꢇ
a
b
p ꢄ<ꢄ 0.001; p ꢄ<ꢄ 0.05: level of significance compared to the controls.
−
1
in Table 3. Metamizole (dose 25 mg kg equal to 1/10 of
3
Conclusion
LD ) was used as a positive control. The action of 4a is
50
dose-dependent.
The addition reaction of the aminopyridone 4a to alkyl
In the same way, the analgesic effects of compounds isocyanates was studied, and the conditions were speci-
4
a, 6a, 6c, 6d and 6g (all doses 1/10 of LD ) are measured fied under which the corresponding N-monocarbamoyl
5
0
as given in Table 4. Compound 6g displays the highest derivatives 6a–g could be obtained in good yields. Het-
analgesic effect at a dose 1/10 of LD .
erocyclization of some of the newly synthesized deriva-
5
0
The effects of compounds 4a, 6a, 6c, 6d and 6g tives 6 by heating in inert solvents was also examined.
all doses 1/50 of LD ) on the duration of sleep induced Only the base-catalyzed re-lactonization leading to
by hexobarbital (dose 80 mg kg b.w.) are presented in 4-ureidobenzopyrano[3,4-c]pyridines (5d, g) was possible
Table 5. All tested compounds were administered intra- but not the alternative heterocyclization to 5-arylpyrido[2,3-
peritoneally 30 min before hexobarbital. It was found d]pyrimidine derivatives of type 8. It was found further that
that all the substances (except 6g) administered at a the N-carbamoyl derivatives 6a–g could be converted into
dose 1/50 of LD significantly prolong the hexobarbital the corresponding N,O-diacetyl derivatives 7a–g by treat-
(
5
0
−
1
5
0
sleep.
ment with acetic anhydride in anhydrous pyridine.
Table 4:ꢀAnalgesic activity of 4a, 6a, 6c, 6d and 6g (acetic acid writhing test).
Compound
ꢁ
Control (saline)ꢁ
Metamizoleꢁ
ꢂaꢁ
ꢅaꢁ
ꢅcꢁ
ꢅdꢁ
ꢅg
Dose, mg kg ꢃ
−
ꢄ
–ꢄ
ꢋꢋ.ꢊꢄ
±ꢃꢇ.ꢃꢄ
ꢊꢅꢄ
ꢃꢌ.ꢊꢄ
±ꢃꢃ.ꢅꢄ
ꢇꢅꢆꢄ
ꢅꢆꢆꢄ
ꢅꢆꢆꢄ
ꢍꢇ.ꢆꢄ
±ꢃꢅ.ꢅꢄ
ꢅꢆꢆꢄ
ꢅꢆꢆa
ꢍ.ꢊ
±ꢆ.ꢍ
a
b
a
Number of writhingꢄ
ꢊꢊ.ꢉ ꢄ
ꢅꢉ.ꢅ ꢄ
ꢍꢆ.ꢍ ꢄ
SD
ꢄ
±ꢊ.ꢃꢄ
±ꢌ.ꢆꢄ
±ꢃꢇ.ꢇꢄ
a
b
p ꢄ<ꢄ 0.001; p ꢄ<ꢄ 0.05: level of significance compared to the controls.
Table ꢆ:ꢀEffects on hexobarbital sleeping time.
Compound
ꢁ
Hexobarbital (control)ꢁ
ꢂaꢁ
ꢅaꢁ
ꢅcꢁ
ꢅdꢁ
ꢅg
Dose, mg kg ꢃ
−
ꢄ
ꢉꢆꢄ
ꢊꢇ.ꢋꢄ
±ꢇ.ꢋꢃꢄ
ꢇꢅꢆꢄ
ꢅꢆꢆꢄ
ꢅꢆꢆꢄ
ꢅꢆꢆꢄ
ꢅꢆꢆ
ꢊꢆ.ꢌꢋ
±ꢍ.ꢇꢇ
a
b
a
a
Sleeping time (min)ꢄ
ꢃꢆꢌ.ꢆ ꢄ
ꢍꢌ.ꢅ ꢄ
ꢇꢉ.ꢆ ꢄ
ꢇꢉ.ꢉ ꢄ
SD
ꢄ
±ꢋ.ꢌꢋꢄ
±ꢌ.ꢆꢉꢄ
±ꢌ.ꢌꢍꢄ
±ꢇ.ꢍꢊꢄ
a
b
p ꢄ<ꢄ 0.001; p ꢄ<ꢄ 0.05: level of significance compared to the controls.
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L. D. Raev et al.: Synthesis of 6-alkylureido-4-aryl-2(1H)-pyridonesꢂꢁꢀꢀꢀꢂ801
The starting aminopyridone 4a and some of the result-
ing N-carbamoyl derivatives (6a, c, d, g) were submitted
to initial pharmacological screening. The found toxic dose
4
.3 General procedure for the reaction
of ethyl 2-amino-6-oxo-4-(2-
hydroxyphenyl)-1,4,ꢆ,6-tetrahydro-
pyridine-3-carboxylate (4a) with alkyl
isocyanates. Preparation of ethyl
4-(2-hydroxyphenyl)-2-(3-alkylureido)-
6-oxo-1,4,ꢆ,6-tetrahydropyridine-
−
1
LD of the tested compounds is more than 5000 mg kg ,
5
0
i.e. they are practically non-toxic. Studies have shown that
if applied in doses 1/10 of LD50 they extend significantly
the hexobarbital sleep and exhibit an analgesic effect,
which is most pronounced by the ureide 6g.
3-carboxylates (6a–g)
A solution of 10.0 mmol of the corresponding alkyl iso-
cyanate dissolved in 5 mL of anhydrous acetonitrile was
added dropwise under stirring to a solution of 1.38 g
(5.0 mmol) of 4a in 100 mL of hot anhydrous acetonitrile
for a period of 20 min. After reflux for several hours (TLC
4
Experimental section
4
.1 General information
Melting points were determined on a Büchi B-510 (Swit- monitoring), the reaction mixture was cooled down to
zerland) apparatus and were uncorrected. The IR spectra 0–5 °C and the separated crystals of 6a–g were filtered
were recorded in nujol on a Shimadzu 8001 FTIR spec- and washed with cold anhydrous acetonitrile. Recrys-
1
13
trometer (Shimadzu Corporation, Kyoto, Japan). H and C tallization from ethanol yielded the corresponding pure
NMR spectra were registered on a Bruker WP 100 MHz or product 6a–g.
a Bruker AMX 300/400 MHz spectrometer (Bruker Corpo-
ration, Billerica, MA, USA). Chemical shifts are expressed
in δ (ppm) downfield from tetramethylsilane (TMS) as an 4.3.1 Ethyl 4-(2-hydroxyphenyl)-2-(3-ethylureido)-
internal reference. The signals at 400 MHz were assigned
with the help of 2D correlation NMR spectra. Signals close
6-oxo-1,4,ꢆ,6-tetrahydropyridine-3-carboxylate (6a)
to δ ≈ 2.5 ppm in [D ]DMSO were partially overlapped by Reflux: 4 h. This product was obtained in 97 % yield as
6
the solvent. Mass spectra were measured on a Varian MAT a colorless solid with m.p. 200–202.5 °C, R ꢀ=ꢀ 0.28. – IR
f
−
1
1
7
11 spectrometer (Varian Inc., USA) at 70 eV (direct inlet). (nujol): ν ꢀ=ꢀ 3333, 3221, 1701, 1669, 1622, 1600 cm . – H
TLC monitoring was carried out on silica gel Merck GF254 NMR (100 MHz, [D ]DMSO): δ ꢀ=ꢀ 11.38 (s, 1H, NH), 10.93
6
pre-coated aluminum sheets (Merck KGaA, Darmstadt, (s, 1H, NH), 9.56 (s, 1H, OH), 8.30 (br.t, NH), 6.67–7.01 (m,
X
Germany), eluted with hexane–acetone 2:1 (v/v). Spots 4Harom.), 4.39 (d, 1H, J ꢀ=ꢀ 3 Hz, 4-H ), 3.98 (q, 2H, J ꢀ=ꢀ 7 Hz,
B
were visualized by treatment with I (vapor) and under UV OCH ), 3.10 (q, 2H, J ꢀ=ꢀ 7 Hz, NCH ), 2.82–3.05 (m, 1H, 5-H ),
2
2
2
irradiation (λ ꢀ=ꢀ 254 nm).
~2.56 (m, 1H, 5-HA), 1.05 (t, 3H, J ꢀ=ꢀ 7 Hz, CH ), 1.03 (t, 3H,
3
1
3
J ꢀ=ꢀ 7 Hz, CH ). – C NMR spectrum, see Fig. 1. – C H N O
3
17 21
3
5
(
347.37): calcd. C 58.78 H 6.09 N 12.10; found C 58.74, H
.09, N 12.10.
6
4
.2 Ethyl 2-amino-4-(2-hydroxyphenyl)-
-oxo-1,4,ꢆ,6-tetrahydro-
-pyridinecarboxylate (4a)
improved procedure; cf. [1–ꢆ])
6
3
4
.3.2 Ethyl 4-(2-hydroxyphenyl)-2-[3-(1-propyl)ureido]-
(
6-oxo-1,4,ꢆ,6-tetrahydropyridine-3-carboxylate (6b)
A mixture of 31.7 g (0.16 mol) of coumarin-3-carboxylic acid Reflux: 6 h. This product was obtained in 90 % yield as a
(
(
1b) and 28.6 g (0.22 mol) of ethyl 3,3-diaminopropenoate colorless solid with m.p. 206–209 °C, R ꢀ=ꢀ 0.30. – IR (nujol):
f
−1
1
2) in 300 mL of anhydrous ethanol was refluxed under ν ꢀ=ꢀ 3335, 3218, 1700, 1669, 1620, 1600 cm . – H NMR
stirring for 5 h. The reaction mixture was concentrated in (100 MHz, [D ]DMSO): δ ꢀ=ꢀ 11.38 (s, 1H, NH), 10.91 (s, 1H,
6
vacuum to one-third of the initial volume and was allowed NH), 9.52 (s, 1H, OH), 8.29 (br.t, NH), 6.66–7.00 (m, 4Harom.),
X
to stay several hours at 5–10 °C. The separated crystals 4.39 (d, 1H, J ꢀ=ꢀ 3 Hz, 4-H ), 3.99 (q, 2H, J ꢀ=ꢀ 6.4 Hz, OCH2),
B
were filtered, washed with ethanol and recrystallized from 3.00 (q, 2H, J ꢀ=ꢀ 5.6 Hz, NCH ), 2.78–2.94 (m, 1H, 5-H ), ~2.48
2
A
ethanol. Yield: 27.6 g (66 %) of colorless platelets of 4a: (m, 1H, 5-H ), 1.34–1.48 (m, 2H, CH ), 1.03 (t, 3H, J ꢀ=ꢀ 7 Hz,
2
m.p. 187–189 °C (dec.) ([3]: yield 44–57 %, m.p. 192–195 °C). CH ), 0.86 (t, 3H, J ꢀ=ꢀ 7 Hz, CH ). – C H N O (361.40): calcd.
3
3
18 23
3
5
1
13
H NMR and C NMR spectral data are reported in [1].
C 59.82, H 6.41, N 11.63; found C 59.82, H 6.43, N 11.60.
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02ꢀꢀꢀꢀꢁꢀL. D. Raev et al.: Synthesis of 6-alkylureido-4-aryl-2(1H)-pyridones
−
1
1
4
.3.3 Ethyl 4-(2-hydroxyphenyl)-2-[3-(2-propyl)ureido]-
(nujol): ν ꢀ=ꢀ 3303, 3231, 1701, 1667, 1620, 1601 cm . – H
6
-oxo-1,4,ꢆ,6-tetrahydropyridine-3-carboxylate (6c) NMR (100 MHz, [D ]DMSO): δ ꢀ=ꢀ 11.41 (s, 1H, NH), 10.92 (s,
6
1
H, NH), 9.57 (s, 1H, OH), 8.3 (br.t, 1H, NH), 6.65–7.05 (m,
X
Reflux: 6 h. This product was obtained in 86 % yield as a 4Harom.), 4.41 (d, 1H, J ꢀ=ꢀ 7 Hz, 4-H ), 4.00 (m, 2H, OCH2),
B
colorless solid with m.p. 190–192 °C, R ꢀ=ꢀ 0.31. – IR (nujol): 3.9–4.1 (m, 2H, NCH ), 2.82 (d, 1H, J ꢀ=ꢀ 7 Hz, 5-H ), ~2.4 (m,
f
2
−
1
1
A
ν ꢀ=ꢀ 3328, 3227, 1700, 1663, 1620, 1603 cm . – H NMR overlapped by DMSO, 1H, 5-H ), 1.12–1.60 (m, 8H, 4 ꢀ×ꢀ CH ,
2
(
100 MHz, [D ]DMSO): δ ꢀ=ꢀ 11.40 (s, 1H, NH), 10.85 (s, 1H, hexyl), 1.03 (t, 3H, J ꢀ=ꢀ 7 Hz, CH ), 0.88 (br.t, 3H, CH ). –
6
3
3
NH), 9.52 (s, 1H, OH), 8.27 (d, 1H, J ꢀ=ꢀ 2.5 Hz, NH), 6.66–7.00 C H N O (403.48): calcd. C 62.51, H 7.24, N 10.41; found C
2
1
29
3
5
X
(
m, 4Harom.), 4.38 (d, 1H, J ꢀ=ꢀ 3 Hz, 4-H ), 3.99 (q, 2H, J ꢀ=ꢀ 6.2, 62.50, H 7.24, N 10.39.
B
OCH ), 3.71–3.85 (m, 1H, CHMe ), 2.79–3.04 (m, 1H, 5-H ),
2
2
A
~
2.48 (m, 1H, 5-H ), 1.09 (d, 6H, J ꢀ=ꢀ 3.2 Hz, 2 ꢀ×ꢀ CH , isopro-
3
pyl), 1.02 (t, 3H, J ꢀ=ꢀ 7 Hz, CH ). – C H N O (361.40): calcd. 4.3.7 Ethyl 4-(2-hydroxyphenyl)-2-(3-cyclohexylureido)-
3
18 23
3
5
C 59.82, H 6.41, N 11.63; found C 59.88, H 6.42, N 11.79.
6-oxo-1,4,ꢆ,6-tetrahydropyridine-3-carboxylate (6g)
Reflux: 4.5 h. This product was obtained in 82 % yield as
4
.3.4 Ethyl 4-(2-hydroxyphenyl)-2-[3-(1-butyl)ureido]-
a colorless solid with m.p. 218–218.5 °C, R ꢀ=ꢀ 0.36. – IR
f
6
-oxo-1,4,ꢆ,6-tetrahydropyridine-3-carboxylate (6d)
−1
1
(
nujol): ν ꢀ=ꢀ 3302, 3235, 1700, 1669, 1620, 1603 cm . – H
NMR (100 MHz, [D ]DMSO): δ ꢀ=ꢀ 11.41 (s, 1H, NH), 10.86 (s,
6
Reflux: 3 h. This product was obtained in 76 % yield as
a colorless solid with m.p. 195.5–197 °C, R ꢀ=ꢀ 0. 32. – IR
1
H, NH), 9.53 (s, 1H, OH), 8.26 (d, 1H, J ꢀ=ꢀ 4 Hz, NH), 6.66–
f
X
7
.00 (m, 4Harom.), 4.42 (d, 1H, J ꢀ=ꢀ 7 Hz, 4-H ), 3.9–4.1 (m,
−
1
1
(
nujol): ν ꢀ=ꢀ 3305, 3250, 1705, 1668, 1622, 1600 cm . – H
1
H, NCH), 3.99 (q, 2H, J ꢀ=ꢀ 7 Hz, OCH ), 2.80–3.05 (m, 1H,
2
NMR (400 MHz, [D ]DMSO): δ ꢀ=ꢀ 11.41 (s, 1H, NH), 10.92 (s,
6
B
A
5
-H ), ~2.48 (m, overlapped by DMSO, 1H, 5-H ), 1.7 and
1
H, NH), 9.57 (s, 1H, OH), 8.31 (t, 1H, J ꢀ=ꢀ 5 Hz, NH), 6.69,
1
.2 (2 ꢀ×ꢀ m , 10H, 5 ꢀ×ꢀ CH , cyclohexyl), 1.03 (t, 3H, J ꢀ=ꢀ 7 Hz,
c
2
6
.80, 6.86, and 7.02 (4 ꢀ×ꢀ m, 4 ꢀ×ꢀ 1H, 4Harom.), 4.40 (d, 1H, J ꢀ=ꢀ
CH ). – C H N O (401.46): calcd. C 62.83, H 6.78, N 10.47;
X
3
21 27
3
5
3
.5 Hz, 4-H ), 4.06 (m, 1H, OCH), 3.94 (m, 1H, OCH), 3.08
found C 63.04, H 6.86, N 10.52.
B
(
(
1
dt, 2H, J ꢀ=ꢀ 5 Hz, J ꢀ=ꢀ 7 Hz, NCH ), 2.90 (m, 1H, 5-H ), 2.49
2
A
m, 1H, 5-H ), 1.42–1.43 (m, 2H, CH ), 1.31–1.33 (m, 2H, CH ),
2
2
1
3
.05 (t, 3H, J ꢀ=ꢀ 7 Hz, CH ), 0.89 (t, J ꢀ=ꢀ 7.3 Hz, CH ). – C NMR
3
3
4
.4 Heterocyclization of the N-monoureides
d,g to pyridocoumarins ꢆd, g
spectrum, see Fig. 1. – C H N O (375.42): calcd. C 60.79, H
6
19
25
3
5
6
.71, N 11.19; found C 60.78, H 6.61, N 11.18.
4
.4.1 1-Butyl-3-(2,ꢆ-dioxo-1,3,ꢆ,10b-tetrahydro-
4
.3.ꢆ Ethyl 4-(2-hydroxyphenyl)-2-[3-(t-butyl)ureido]-
2H-chromeno[3,4-c]pyridin-4-yl)urea (ꢆd)
6
-oxo-1,4,ꢆ,6-tetrahydropyridine-3-carboxylate (6e)
A solution of sodium ethoxide, prepared from 0.12 g
Reflux: 10 h. This product was obtained in 81 % yield as a (5.0 mmol) of sodium and 5 mL of ethanol, was added drop-
colorless solid with m.p. 179–182 °C, R ꢀ=ꢀ 0.35. – IR (nujol): wise under stirring to a suspension of 1.88 g (5.0 mmol) of
f
−
1
1
ν ꢀ=ꢀ 3314, 3256, 1703, 1671, 1624, 1602 cm . – H NMR (100 6d in 20 mL of anhydrous ethanol. The reaction mixture
MHz, [D ]DMSO): δ ꢀ=ꢀ 11.44 (s, 1H, NH), 10.73 (s, 1H, NH), was allowed to stay at room temperature for 7 days and
6
9
.52 (s, 1H, OH), 8.09 (s, 1H, NH), 6.66–7.08 (m, 4Harom.), the separated sodium salt was collected by filtration. It
X
4
.40 (d, 1H, J ꢀ=ꢀ 7 Hz, 4-H ), 3.99 (q, 2H, J ≈ 7 Hz, OCH2), was then mixed with some water and acidified with acetic
B
2
.83 (dd, 1H, J ꢀ=ꢀ 7 Hz, J ꢀ=ꢀ 16 Hz, 5-H ), 2.29 (d, 1H, J ꢀ=ꢀ 16 acid to pH ≈ 5. The crystals formed were filtered, washed
A
Hz, 5-H ), 1.28 (s, 9H, 3 ꢀ×ꢀ CH ), 1.02 (t, 3H, J ꢀ=ꢀ 7 Hz, CH ). with water and recrystallized from ethanol to give pure
3
3
–
C H N O (375.42): calcd. C 60.79, H 6.71, N 11.19; found 5d. Yield: 0.33 g (20 %) of colorless crystals with m.p.
19
25
3
5
C 60.80, H 6.66, N 11.16.
258–260 °C. IR: ν ꢀ=ꢀ 2350–3350 (3287 br., NH assoc.), 1726
−
1
1
(
Cꢀ=ꢀO, lactone), 1651, 1622 (Cꢀ=ꢀO) cm . – H NMR (400 MHz,
[
D ]DMSO): δ ꢀ=ꢀ 11.73 (s, 1H, NH, D O-exchangeable), 11.01
6
2
4.3.6 Ethyl 4-(2-hydroxyphenyl)-2-[3-(1-hexyl)ureido]-
(s, 1H, NH, D O-exchangeable), 8.53 (s, 1H, NH, D O-
2 2
6
-oxo-1,4,ꢆ,6-tetrahydropyridine-3-carboxylate (6f) exchangeable), 7.04, 7.15, 7.28, 7.41 (4 ꢀ×ꢀ m , 4 ꢀ×ꢀ 1H, 4Harom.),
c
X
4.23 (d, 1H, J ꢀ=ꢀ 14.3 Hz, 10b-H ), 3.21 (d, 1H, J ꢀ=ꢀ 15.6 Hz,
B
Reflux: 3.5 h. This product was obtained in 89 % yield 1-H ), 3.09 (s, 2H, N-CH ), 2.61 (dd, 1H, J ꢀ=ꢀ 14.3 Hz, J ꢀ=ꢀ 14.5
2
1
2
A
as a colorless solid with m.p. 191–193 °C, R ꢀ=ꢀ 0.35. – IR Hz, 1-H ), 1.42 (m, 2H, CH ), 1.31 (m, 2H, CH ), 0.89 (t, J ꢀ=ꢀ 3
f
2
2
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L. D. Raev et al.: Synthesis of 6-alkylureido-4-aryl-2(1H)-pyridonesꢂꢁꢀꢀꢀꢂ803
1
3
Hz, 3H, CH ). – C NMR (100 MHz, [D ]DMSO): δ ꢀ=ꢀ 169.9 4.ꢆ.1 Ethyl 4-(2-acetoxyphenyl)-2-(3-ethylureido)-
3
6
(
Cꢀ=ꢀO, lactam), 163.5 (C-4), 155.1 (Cꢀ=ꢀO, lactone), 152.7 (Cꢀ=ꢀO,
urea), 150.2 (C-6a), 128.8 (C-8), 127.0 (C-10), 125.9 (C-9), 125.0
C-10a), 116.5 (C-7), 75.3 (C-4a), 40.0 (NCH ), 35.9 (C-1), 31.2 Stirring for 4 days. The recrystallized product was
6-oxo-1,4,ꢆ,6-tetrahydropyridine-3-carboxylate (7a)
(
(
2
CH ), 29.2 (C-10b), 19.7 (CH ), 13.9 (CH ). – CI-MS (NH , 100 obtained in 92 % yield as colorless crystals with m.p.
2
2
3
3
eV; positive): m/z (%) ꢀ=ꢀ 117 (15), 134 (6), 229 (14), 233 (3), 199–201.5 °C, R ꢀ=ꢀ 0.36. – IR (nujol): ν ꢀ=ꢀ 3333, 3113, 1763,
f
+
−1
1
2
88 (1), 330 (100) [M+1] ; isotope distribution corresponds 1707, 1667, 1626 cm . – H NMR (100 MHz; [D ]DMSO): δ ꢀ=ꢀ
6
+
to [C H N O ] , 347 (13). – C H N O (329.35): C 62.00, H 11.50 (s, 1H, NH, D O-exchangeable), 10.84 (s, 1H, NH, D O-
17
20
3
4
17 19
3
4
2
2
5
.81, N 12.76; found C 61.79, H 5.74, N 12.55.
exchangeable), 8.30 (broad t, 1H, NH, D O-exchangeable),
2
X
7
.03–7.20 (m, 4Harom.), 4.28 (d, J ꢀ=ꢀ 7.3 Hz, 1H, 4-H ), 3.95 (m,
B
2
H, OCH ), 2.87–3.16 (m, 3H, N-CH and 5-H ), 2.49 (m, 1H,
2
2
A
5
-H ), 2.3 (s, 3H, COCH ), 1.05 (t, J ꢀ=ꢀ 7 Hz, 3H, COCH CH ),
3
2
3
4
.4.2 1-(2,ꢆ-Dioxo-1,3,ꢆ,10b-tetrahydro-
H-chromeno[3,4-c]pyridin-4-yl)-
-cyclohexylurea (ꢆg)
1
.00 (t, J ꢀ=ꢀ 7 Hz, 3H, CH ). – EI-MS (70 eV): m/z (%) ꢀ=ꢀ 389
3
+ +
2
3
(
13) [M] : isotope distribution corresponds to [C H N O ] ,
1
9
23
3
6
+
+
3
47 (8) [M–CH CO] , 318 (4) [M–C H NCO] , 316 (6)
2 2 5
+ +
[
M–COOC H ] , 301 (8) [M–CH CO–C H OH] , 300 (15),
2 5 2 2 5
+ +
A solution of sodium ethoxide, prepared from 0.12 g
5 mmol) of sodium and 5 mL of anhydrous ethanol, was
added dropwise under stirring to a suspension of 2.0 g
5 mmol) of 6g in 10 mL of anhydrous ethanol. The reac-
2
2
75 (9) [M–C H NCO–COCH ] , 254 (6) [M– C H OCOCH ] ,
2 5 3 6 4 3
+
(
45 (10) [M–C H NCO–COOC H ] , 230 (41) [M–C H NCO–
2
5
2
5
2
5
+
COCH –OC H ] , 229 (100), 203 (19), 183 (15). – C H N O
3
2
5
19 23
3
6
(
(
389.41): calcd. C 58.60, H 5.95, N 10.79; found C 58.46, H
.03, N 10.60.
tion mixture was allowed to stay at 20–25 °C for 4 d. Then
the solvent was removed in vacuo; the residue was mixed
with some water and neutralized with acetic acid to pH ≈ 5.
The precipitated product was filtered, washed with water
and recrystallized from ethanol. Yield: 1.65 g (93 %) of
colorless sparkling needles of 5g with m.p. 240–243 °C. –
6
4
.ꢆ.2 Ethyl 4-(2-acetoxyphenyl)-2-[3-(1-propyl)ureido]-
6
-oxo-1,4,ꢆ,6-tetrahydropyridine-3-carboxylate (7b)
IR: ν ꢀ=ꢀ 2350–3350, 3339 (br., NH
), 1723 (Cꢀ=ꢀO, lactone),
assoc.
Stirring for 24 h. The recrystallized product was obtained
−
1
1
1
657, 1622 (Cꢀ=ꢀO) cm . – H NMR (100 MHz, [D ]DMSO):
6
in 82 % yield as colorless crystals with m.p. 175.5–177 °C,
δ ꢀ=ꢀ 11.75 (s, 1H, NH-lactam, D O-exchangeable), 10.92 (s,
2
R ꢀ=ꢀ 0.39. – IR (nujol): ν ꢀ=ꢀ 3341, 3127, 1763, 1705, 1667, 1626
f
1
4
H, 4-NH), 8.46 (d, J ꢀ=ꢀ 6.9 Hz, 1H, NH-C H ), 7.03–7.42 (m,
6 11
−1 1
cm .- H NMR (100 MHz, [D ]DMSO): δ ꢀ=ꢀ 11.51 (s, 1H, NH,
X
6
Harom.), 4.23 (dd, J ꢀ=ꢀ 15 Hz, J ≈ 6.7 Hz, 1H, 10b-H ), 3.11 (d,
1
2
D O-exchangeable), 10.85 (s, 1H, NH, D O-exchangeable),
B
A
2
2
J ≈ 5.3 Hz, 1H, 1-H ), 2.78 (s, 1H, NCH), 2.4–2.6 (m, 2H, 1-H ),
8
4
.32 (broad t, 1H, NH, D O-exchangeable), 7.03–7.24 (m,
2
1
.0–2.0 [broad m, 10H, CH(CH ) ]. – CI-MS (NH , 100 eV;
2 5 3
X
Harom.), 4.28 (d, 1H, J ꢀ=ꢀ 7.1 Hz, 4-H ), 3.85–3.99 (m, 2H,
positive): m/z (%) ꢀ=ꢀ 100 (4), 143 (18), 160 (2), 229 (17), 233
B
A
OCH ), 2.92–3.20 (m, 3H, NCH + 5-H ), 2.49 (m , 1H, 5-H ),
+
2
2
c
(
[
3), 356 (100) [M+1] ; isotope distribution corresponds to
2
.31 (s, 3H, COCH ), 1.34–1.55 (m, 2H, CH , propyl), 1.00 (t,
3 2
+
C H N O ] , 373 (9). – C H N O (355.39): calcd. C 64.21,
19
22
3
4
19 21
3
4
J ꢀ=ꢀ 7 Hz, 3H, CH , ester), 0.86 (t, J ꢀ=ꢀ 7 Hz, 3H, CH , propyl).
3
3
H 5.96, N 11.82; found C 63.98, H 5.94, N 11.86.
+
–
EI-MS (70 eV): m/z (%) ꢀ=ꢀ 403 (19) [M] : isotope distri-
+
+
bution corresponds to [C H N O ] ; 361 (9) [M–CH CO] ,
2
0
25
3
6
2
+
3
30 (5) [M–COOC H ] , 315 (9) [M–CH CO–C H OH], 314
2 5 2 2 5
+ +
4
.ꢆ General procedure for the preparation
(20) [M–COCH –C H OH] , 275 (12) [M–C H NCO–COCH ] ,
3 2 5 3 7 3
+
245 (10) [M–C H NCO–COOC H ] , 230 (46) [M–C H NCO–
3 7 2 5 3 7
+
of O-acetyl-3-monoalkylureides 7a–g
COCH –OC H ] , 229 (100), 203 (20), 183 (18). – C H N O
3
2
5
20 25
3
6
Acetic anhydride (0.56 g, 5.5 mmol) was added drop- (403.43): calcd. C 59.54, H 6.25, N 10.42; found C 59.43, H
wise at ambient temperature (20–25 °C) under stirring 6.18, N 10.30.
to a solution of the corresponding 3-alkylureide 6a–g
(
5.0 mmol) in anhydrous pyridine (10 mL). Stirring was
continued until exhaustion of the starting 3-alkylureide 4.ꢆ.3 Ethyl 4-(2-acetoxyphenyl)-2-[3-(2-propyl)ureido]-
a–g (several days; TLC monitoring), the volatile compo- 6-oxo-1,4,ꢆ,6-tetrahydropyridine-3-carboxylate (7c)
nents were removed in vacuo and the residue was recrys-
tallized from ethanol to give pure 7a–g. More details are Stirring for 24 h. The recrystallized product was obtained
given below. in 88.5 % yield as colorless crystals with m.p. 186–188
6
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8
04ꢀꢀꢀꢀꢁꢀL. D. Raev et al.: Synthesis of 6-alkylureido-4-aryl-2(1H)-pyridones
−
1
°
1
C, R ꢀ=ꢀ 0.41. – IR (nujol): ν ꢀ=ꢀ 3302, 3100, 1755, 1701, 1669, 0.43. – IR (nujol): ν ꢀ=ꢀ 3347, 3134, 1763, 1713, 1669, 1630 cm .
f
−
1
1
1
618 cm . – H NMR (100 MHz, [D ]DMSO): δ ꢀ=ꢀ 11.55 (s, 1H, – H NMR (100 MHz, [D ]DMSO): δ ꢀ=ꢀ 11.65 (s, 1H, NH, D O-
6 6 2
NH, D O-exchangeable), 10.80 (s, 1H, NH, D O-exchange- exchangeable), 10.71 (s, 1H, NH, D O-exchangeable), 8.17
2
2
2
able), 8.26 (d, 1H, J ꢀ=ꢀ 6.9 Hz, NH, D O-exchangeable), (s, 1H, NH, D O-exchangeable), 7.15–7.23 (m, 4Harom.), 4.32
2
2
X
X
7
.11–7.25 (m, 4Harom.), 4.29 (d, 1H, J ꢀ=ꢀ 7.4 Hz, 4-H ), 3.73–4.07 (d, J ꢀ=ꢀ 7.1 Hz, 1H, 4-H ), 3.83–4.01 (m, 2H, OCH ), 2.93–3.18
2
B
B
A
(
m, 3H, OCH + NCH), 2.92–3.17 (m, 1H, 5-H ), 2.48 (m , 1H, (m , 3H, N-CH + 5-H ), 2.49 (m , 1H, 5-H ), 2.31 (s, 3H,
2
c
c
2
c
A
5
-H ), 2.31 (s, 3H, COCH ), 1.10 (d, 6H, J ꢀ=ꢀ 6.3 Hz, 2 ꢀ×ꢀ CH , COCH ), 1.28 [s, 9H, C(CH ) ], 1.00 (t, 3H, J ꢀ=ꢀ 7 Hz, CH ).
3 3 3 3 3 3
+
isopropyl), 1.01 (t, 3H, J ꢀ=ꢀ 6,9 Hz, CH , ester). – EI-MS – EI-MS (70 eV): m/z (%) ꢀ=ꢀ 417 (21) [M] : isotope distribu-
3
+
+
+
(
70 eV): m/z (%) ꢀ=ꢀ 403 (21) [M] : isotope distribution tion corresponds to [C H N O ] ; 375 (4) [M–CH CO] , 344
2
1
27
3
6
2
+
+
+
+
corresponds to [C H N O ] , 330 (6) [M–COOC H ] , 315 (4) [M–COOC H ] , 328 (8) [M–COCH –C H OH] , 318 (10)
2
0
25
3
6
2
5
2
5
3
2
5
+
+
+
+
(
2
7) [M–CH CO–C H OH] , 314 (16) [M–COCH –C H OH] , [M–C H NCO] , 275 (13) [M– C H NCO–COCH ] , 245 (17)
2
2
5
3
2
5
4
9
4
9
3
+
+
75 (12) [M–C H NCO–COCH ] , 245 (13) [M–C H NCO– [M–C H NCO–COOC H ] , 230 (52) [M–C H NCO–COCH –
3 7 3 3 7 4 9 2 5 4 9 3
+ + +
COOC H ] , 230 (49) [M–C H NCO–COCH –OC H ] , 229 OC H ] , 229 (100), 203 (12), 183 (10). – C H N O (417.46):
2
5
3
7
3
2
5
2
5
21 27
3
6
(
100), 203 (17), 183 (14). – C H N O (403.43): calcd. C C 60.42, H 6.52, N 10.07; found C 60.30, H 6.52, N 10.01.
20 25 3 6
5
9.54, H 6.25, N 10.42; found C 59.35, H 6.28, N 10.31.
4
.ꢆ.6 Ethyl 4-(2-acetoxyphenyl)-2-[3-(1-hexyl)ureido]-
4
.ꢆ.4 Ethyl 4-(2-acetoxyphenyl)-2-[3-(1-butyl)ureido]-
6
-oxo-1,4,ꢆ,6-tetrahydro-3-pyridinecarboxylate (7f)
6
-oxo-1,4,ꢆ,6-tetrahydro-3-pyridinecarboxylate (7d)
Stirring for 4 days. The recrystallized product was obtained
Stirring for 4 days. This product was obtained from 6d
in 93 % yield after recrystallization as colorless crystals
with m.p. 168–170 °C. Alternative preparation from 4d (cf.
Scheme 2): To a suspension of 159 mg (0.5 mmol) of 4d
in 6 mL of anhydrous acetonitrile, a solution of 0.11 mL
in 89 % yield as a colorless solid with m.p. 163–166 °C, R ꢀ=ꢀ
f
−1
0
.41. – IR (nujol): ν ꢀ=ꢀ 3292, 3094, 1755, 1684, 1667, 1618 cm .
1
–
H NMR (300 MHz, [D ]DMSO): δ ꢀ=ꢀ 11.54 (s, 1H, NH, D O-
6
2
exchangeable), 10.85 (s, 1H, NH, D O-exchangeable), 8.32
2
(
broad t, 1H, NH, D O-exchangeable), 7.09–7.29 (m, 4Harom.),
2
(1.0 mmol) of butylisocyanate in 1.0 mL of anhydrous ace-
X
4
.30 (d, 1H, J ꢀ=ꢀ 7.5 Hz, 4-H ), 3.85–4.07 (m, 2H, OCH ), 3.01–
2
tonitrile was added dropwise under stirring. The mixture
was allowed to stay for 12 days at 20–25 °C, and the sepa-
rated crystals of 7d were filtered and washed with ace-
tonitrile. Yield: 170 mg (81 %) of 7d, colorless crystals
B
A
3
.15 (m , 3H, N-CH + 5-H ), 2.49 (d, J ꢀ=ꢀ 7.5 Hz, 1H, 5-H ),
.33 (s, 3H, COCH ), 1.24–1.50 [m, 8H, (CH ) ], 1.03 (t, 3H,
c
2
2
3
2
4
J ꢀ=ꢀ 7 Hz, CH , ester), 0.88 (t, J ꢀ=ꢀ 7 Hz, 3H, CH , hexyl). –
3
3
+
EI-MS (70 eV): m/z (%) ꢀ=ꢀ 445 (10) [M] : isotope distribu-
tion corresponds to [C H N O ] , 403 (5) [M–CH CO] , 372
with m.p. 168–170 °C, R ꢀ=ꢀ 0.42. – IR (nujol): ν ꢀ=ꢀ 3364,
f
+
+
−
1
1
23 31
3
6
2
3
134, 1754, 1673, 1655, 1615 cm . – H NMR (300 MHz, [D ]
6
+
+
(
4) [M–COOC H ] , 356 (12) [M–COCH –C H OH] , 318 (6)
2
5
3
2
5
DMSO): δ ꢀ=ꢀ 11.54 (s, 1H, NH), 10.86 (s, 1H, NH), 8.33 (br.s,
+
+
[
M–C H NCO] , 245 (12) [M–C H NCO–COOC H ] , 230
X
6
13
6
13
2
5
1
H, NH), 7.07–7.30 (m, 4Harom.), 4.31 (d, J ꢀ=ꢀ 7.4 Hz, 1H, 4-H ),
+
(
1
46) [M–C H NCO–COCH –OC H ] , 229 (100), 203 (17),
83 (13). – C H N O (445.51): calcd. C 62.01, H 7.01, N 9.43;
B
6
13
3
2
5
3
.85–4.08 (m, 2H, OCH ), 2.98–3.18 (m, 3H, NCH + 5-H ),
2
2
A
23 31
3
6
2
.33 (s, 3H, COCH ), 2.24 (d, J ꢀ=ꢀ 16.2 Hz, 1H, 5-H ), 1.21–1.55
3
found C 61.89, H 7.01, N 9.35.
(
m, 4H, two CH ), 1.03 (t, J ꢀ=ꢀ 7.0 Hz, 3H, CH , ester), 0.90 (t,
2
3
J ꢀ=ꢀ 7.3 Hz, 3H, CH , butyl). – EI-MS (70 eV): m/z (%) ꢀ=ꢀ 417
3
+
+
+
(
(
29), [M] , 375 (8) [M–CH CO] , 344 (7) [M–COOC H ] , 328
2
2
5
4
.ꢆ.7 Ethyl 4-(2-acetoxyphenyl)-2-(3-cyclohexylureido)-
+
+
19) [M–COCH –C H OH] , 318 (8) [M–C H NCO] , 275 (12)
3
2
5
4
9
6
-oxo-1,4,ꢆ,6-tetrahydro-3-pyridinecarboxylate (7g)
+
+
[
M–C H NCO–COCH ] , 245 (13) [M–C H NCO–COOC H ] ,
4
9
3
4
9
2
5
+
2
30 (48) [M–C H NCO–COCH –OC H ] , 229 (100), 203 (15),
4 9 3 2 5
Stirring for 4 days. The recrystallized product was obtained
13
1
83 (14). – C NMR spectrum of 7d, see Fig. 1. – C H N O
2
1
27
3
6
in 88 % yield as a colorless solid with m.p. 197–199 °C, R ꢀ=ꢀ
f
(
417.46): calcd. C 60.42, H 6.52, N 10.07; found C 60.21, H
0
.44. The Oak Ridge Thermal Ellipsoid Plot (ORTEP) view
6
.51, N 10.01.
of the molecule 7g with the atomic numbering is shown
in Fig. 2. – IR (nujol): ν ꢀ=ꢀ 3335, 3141, 1769, 1707, 1672, 1628
−
1
1
4
.ꢆ.ꢆ Ethyl 4-(2-acetoxyphenyl)-2-(3-tert-butylureido)-
cm . – H NMR (100 MHz; [D ]DMSO): δ ꢀ=ꢀ 11.54 (s, 1H, NH,
6
6
-oxo-1,4,ꢆ,6-tetrahydro-3-pyridinecarboxylate (7e) D O-exchangeable), 10.78 (s, 1H, NH, D O-exchangeable),
2
2
8
.20 (d, J ꢀ=ꢀ 7 Hz, 1H, NH, D O-exchangeable), 7.08–7.22 (m,
2
X
Stirring for 4 days. The recrystallized product was obtained 4Harom.), 4.28 (d, 1H, J ꢀ=ꢀ 7.3 Hz, 4-H ), 3.93 (q, 2H, J ꢀ=ꢀ J ꢀ=ꢀ
1
2
B
in 87 % yield as a colorless solid with m.p. 166–168 °C, R ꢀ=ꢀ 3.9 Hz, OCH ), 2.83–3.18 (m, 2H, N-CH + 5-H ), ~2.45 (m, 1H,
f
2
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L. D. Raev et al.: Synthesis of 6-alkylureido-4-aryl-2(1H)-pyridonesꢂꢁꢀꢀꢀꢂ80ꢆ
A
5
-H , overlapped by DMSO), 2.31 (s, 3H, COCH ), 1.10–1.33 (deg), anisotropic displacement parameters, hydrogen
3
and 1.63–1.89 (m, 10H, five CH ), 1.00 (t, J ꢀ=ꢀ 7 Hz, 3H, CH ). coordinates, torsion angles (deg) have been deposited at
2
3
+
–
EI-MS (70 eV): m/z (%) ꢀ=ꢀ 443 (10) [M] : isotope distri- Cambridge Crystallographic Data Centre.
+
+
bution corresponds to [C H N O ] , 401 (4) [M–CH CO] ,
CCDC 908171 (6f) and CCDC 908172 (7g) contain the
2
3
29
3
6
2
+
+
3
70 (3) [M–COOC H ] , 354 (10) [M–COCH –C H OH] , 318 supplementary crystallographic data for this paper. These
2
5
3
2
5
+
+
(
[
6) [M–C H NCO] , 275 (11) [M–C H NCO–COCH ] , 245 (13) data can be obtained free of charge via www.ccdc.cam.
6
11
6
11
3
+
M–C H NCO–COOC H ] , 230 (45) [M– C H NCO–COCH – ac.uk/data_request/cif.
6 11 2 5 6 11 3
+
OC H ] , 229 (100), 203 (15), 183 (12). – C H N O (443.50):
2
5
23 29
3
6
C 62.29 H 6.59 N 9.47; found C 62.13, H 6.59, N 9.30.
4
.7 Pharmacology
4
.6 Crystal structure determinations
4.7.1 Laboratory animals
Suitable single crystals of 6f and 7g were obtained by Male mice line H (body weight 20–25 g) were used. The
simple recrystallization from anhydrous ethanol with mice were housed in plexiglass cages (six per cage) in a
charcoal decolorization and slowly cooling the hot solu- 12/12 light/dark cycle, under standard laboratory condi-
tion. Data collection and data reduction were performed tions (ambient temperature 20 ± 2 °C and humidity 72 ±
with Xꢁꢂꢃꢄꢁ, release 2.32 (Siemens, 1999). The structures 4 %) with free access to water and standard pelleted rat
were solved by Direct Methods (Sꢅꢆꢇꢈꢁ-97 [21]) and refined food 53-3, produced according to ISO 9001:2008. Animals
with Sꢅꢆꢇꢈꢇ-97 [22]. Molecular graphics were made with were purchased from the National Breeding Center,
Xꢉ (Sꢅꢆꢇꢈꢊꢇ-Pꢇꢋꢁ [23]).
Sofia, Bulgaria. A minimum of 7 days of acclimatization
Important crystal structure data are summarized in was allowed before the commencement of the study and
Table 6. Atomic coordinates, bond lengths (Å) and angles their health was monitored regularly by a veterinary
Table 6:ꢀCrystal data, data collection and structure refinement details for 6f and 7g.
ꢁ
ꢅf
ꢁ
ꢇg
Chemical formula
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
C H N O
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
C H N O
ꢌ
ꢊꢃ ꢊꢈ
ꢇꢆꢍ.ꢇꢋ
ꢍ
ꢅ
ꢊꢍ ꢊꢈ
ꢇꢇꢍ.ꢇꢈ
ꢍ
Mr
Temperature, K
Crystal system
Space group
a, Å
ꢊꢈꢍ
ꢊꢈꢍ
Triclinic
Triclinic
Pꢃ
̅
Pꢃ
̅
ꢉ.ꢆꢋꢋꢈ (ꢋ)
ꢈ.ꢉꢅꢇꢃ (ꢈ)
ꢃꢇ.ꢇꢉꢍꢋ (ꢃꢌ)
ꢉꢋ.ꢇꢉꢋ (ꢉ)
ꢉꢈ.ꢌꢋꢉ (ꢈ)
ꢌꢉ.ꢌꢅꢇ (ꢋ)
ꢃꢆꢋꢊ.ꢋꢊ (ꢃꢉ)
ꢊ
ꢉ.ꢍꢆꢈꢋ (ꢇ)
ꢃꢆ.ꢍꢉꢋꢌ (ꢋ)
ꢃꢇ.ꢇꢌꢃꢍ (ꢉ)
ꢋꢍ.ꢍꢊꢉ (ꢌ)
ꢉꢌ.ꢃꢈꢃ (ꢅ)
ꢋꢌ.ꢋꢃꢉ (ꢌ)
ꢃꢃꢌꢍ.ꢉꢃ (ꢃꢊ)
ꢊ
b, Å
c, Å
α, deg
β, deg
γ, deg
V, Åꢍ
Z
Radiation; λ, Å; monochromatorꢄ
CuK ; ꢃ.ꢅꢇꢃꢋꢉ; graphite
α
−
ꢃ
μ(CuK ), mm
ꢄ
ꢄ
ꢆ.ꢋꢇ
ꢄ
ꢄ
ꢆ.ꢋꢌ
α
Crystal size, mmꢍ
Data collection
ꢆ.ꢍꢆ ꢄ×ꢄ ꢆ.ꢆꢋ ꢄ×ꢄ ꢆ.ꢆꢋ
ꢆ.ꢅꢆ ꢄ×ꢄ ꢆ.ꢊꢆ ꢄ×ꢄ ꢆ.ꢃꢆ
ꢂDiffractometer
ꢄ
ꢄ
ꢄ
ꢄ
Siemens Pꢇ
None
ꢆ.ꢅꢈꢈ
ꢇꢌꢍꢃ/ꢍꢋꢍꢋ/ꢆ.ꢆꢊꢅ
ꢂAbsorption correction
−
ꢃ
ꢂ(sin θλ)max, Å
ꢄ
ꢄ
ꢆ.ꢌꢆꢃ
ꢇꢌꢉꢈ/ꢍꢉꢉꢈ/ꢆ.ꢆꢊꢊ
ꢂRefl. total/unique/Rint
Refinement
ꢂH atom treatment
ꢂRef. param./restraints
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
H atoms located by a difference fourier map and refined constrained using standard riding models
ꢊꢋꢇ/ꢆ
ꢆ.ꢃꢊꢊꢉ/ꢆ.ꢊꢉꢅꢃ
ꢃ.ꢆꢌꢌ
ꢆ.ꢍꢈ/−ꢆ.ꢊꢋ
ꢄ
ꢄ
ꢄ
ꢄ
ꢊꢈꢆ/ꢆ
ꢊ
ꢂR (F)/wR(F ) (all data)
ꢆ.ꢃꢃꢋꢉ/ꢆ.ꢍꢆꢅꢉ
ꢃ.ꢆꢌꢅ
ꢊ
ꢂGoF (F )
ꢂΔρmax/min, e Å ꢍ
−
ꢆ.ꢍꢅ/−ꢆ.ꢇꢃ
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8
06ꢀꢀꢀꢀꢁꢀL. D. Raev et al.: Synthesis of 6-alkylureido-4-aryl-2(1H)-pyridones
physician. Vivarium (certificate of registration of farm the same route, as a reference drug. The remaining groups
No. 0072/01.08.2007) was inspected by the Bulgarian were treated with the respective compounds. All animals
−
1
Drug Agency in order to check the husbandry conditions received 0.1 mL kg (i.p.) of 3 % acetic acid 30 min after
No. A-11-1081/03.11.2011). All performed procedures were treatment. The number of writhing was recorded during
approved by the Institutional Animal Care Committee 30 min commencing 5 min after the acetic acid injection.
KENIMUS) and the principles stated in the European A writhe is indicated by abdominal constriction and
(
(
Convention for the Protection of Vertebrate Animals used stretching of at least one hind limb [29].
for Experimental and other Scientific Purposes (ETS 123)
(
Council of Europe, 1991) were strictly followed through-
out the experiment [24].
4.7.ꢆ Hexobarbital-induced sleeping time
The effects of the compounds administered intraperito-
neally on the duration of sleep induced by hexobarbital
4.7.2 Acute toxicity
−
1
(
dose 80 mg kg b.w.). Compounds were administered
The acute toxicity was established after intraperitoneal intraperitoneally 30 min before hexobarbital in doses
administration (i.p. LD ) of the studied compounds. Com- equal to 1/50 of LD50.
5
0
pounds were dissolved in saline (0.9 % NaCl) with one
drop of Tween 80. LD50 was evaluated for five different
doses (1000, 1500, 2000, 4000 and 5000 mg kg ), each
on six animals, and calculated by the Litchfield–Wilcoxon
method, using a personal computer.
4
.7.6 Statistical analysis
−
1
Data are presented as the mean ± standard deviation (SD).
Statistical analysis was performed using Student’s t-test.
The significance of difference was considered to include
values of p ꢀ<ꢀ 0.05 or p ꢀ<ꢀ 0.001.
4
.7.3 Blood clotting time
Acknowledgments: This project was funded by the State
Research Funds of the Medical University of Sofia. We wish
to thank the Management of the Faculty of Pharmacy for
providing the research facilities. We gratefully acknowl-
edge the Microanalytical Laboratory and the Laboratory of
Mass Spectrometry of the Institute of Organic Chemistry,
University of Stuttgart (Head Dr. Joachim Opitz).
The influence of the investigated compounds on blood
clotting time was determined by the method of Morawitz.
The investigation was performed on 30 male white mice
(
six animals in a group). The compounds were adminis-
tered intraperitoneally in doses of 1/10, 1/50 and 1/100 of
LD . Twenty-four hours after the compound administra-
50
tion the clotting time was assessed after small incision
of sublingual vein and measuring the clotting time of the
second drop blood on clean glass [25].
References
[
[
[
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[
10] E. V. Stoyanov, I. C. Ivanov, Molecules 2004, 9, 627.
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12] M. Torres, S. Gil, M. Parra, Curr. Org. Chem. 200ꢆ, 9, 1757; and
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50
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L. D. Raev et al.: Synthesis of 6-alkylureido-4-aryl-2(1H)-pyridonesꢂꢁꢀꢀꢀꢂ807
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