Synthesis and physicochemical and biological properties of heteroannelated 3-methylxanthine derivatives

Article abstract of DOI:10.1007/s10600-013-0771-1

A method for preparing previously undescribed derivatives of imidazo[1,2-f]-, 1,3-oxazolo[2,3-f]-, and 1,2,4-triazino[3,4-f]xanthine, potential biologically active compounds, was developed. Their physicochemical properties and biological activity were studied.

Full text of DOI:10.1007/s10600-013-0771-1

Chemistry of Natural Compounds, Vol. 49, No. 5, November, 2013 [Russian original No. 5, September–October, 2013]
SYNTHESIS AND PHYSICOCHEMICAL AND BIOLOGICAL
PROPERTIES OF HETEROANNELATED
3-METHYLXANTHINE DERIVATIVES
1*
2
3
N. I. Romanenko, M. V. Nazarenko, V. I. Kornienko,
UDC 574.857.4211.024.03/04.057-026.8
2
3
1
T. N. Rak, B. A. Samura, and D. G. Ivanchenko
A method for preparing previously undescribed derivatives of imidazo[1,2-f]-, 1,3-oxazolo[2,3-f]-, and
1,2,4-triazino[3,4-f]xanthine, potential biologically active compounds, was developed. Their physicochemical
properties and biological activity were studied.
Keywords: synthesis, xanthine derivatives, diuretic activity, analgesic activity, anti-inflammatory activity.
Natural xanthine alkaloids (caffeine, theophylline, theobromine) and several of their synthetic derivatives (trental,
diprophylline, etofylline, nihexine, complamine, theofibrate, etc.) are widely used in medical practice as cardiovascular,
broncholytic, diuretic, analeptic, and hypolipidemic agents [1, 2]. Recently, interest in xanthine derivatives has risen considerably
because of their unique chemical and biological properties [3–5].
The goal of the present work was to continue our research [6–8] on the search for biologically active compounds in
the series of condensed xanthine derivatives. For this, several previously undescribed derivatives of imidazo[1,2-f]xanthine 4,
6–13 (Scheme 1) were synthesized via the reaction of 8-bromo-3-methyl-7-phenacylmethylxanthines 1–3 [9] with primary
amines in MeOH at 200°C. 1-Methyl-7-phenyl-8-ꢀ-hydroxyethylimidazo[1,2-f]xanthine (5) was prepared by brief refluxing
of 8-bromo-3-methyl-7-phenacylmethylxanthine (1) in an excess of monoethanolamine.
15
R
1
O
O
11
13
3
HN
1
HN
7
N
5
17
5
N
7
9
9
N
8
1
N
3
N
O
13
O
N
N
O
Br
11
CH
CH
R
2
3
3
R
1
10
10
15
1 - 3
4 - 13
17
15
O
19
O
11
1
N
7
N
13
O
O
5
5
N
N
H C
3
H C
3
3
21
15
9
N
9
N
1
O
3
N
O
O
O
O
Br
O
N
7
19
CH
10CH
3
17
3
10
15
14
17
19
O
17
15
O
11
7
N
13
7
N
5
N
O
O
3
19
13
H C
3
5
1
14
H C
3
N
15
21
1
9
N
9
N
11CH
3
3
N
CH
O
NH
O
O
N
O
O
N
N
H
3
22
23
16
OH
17
1: R = H; 2: R = CH ; 3: R = OCH ; 4: R = H; R = n-C H ; 5: R = H, R = (CH ) OH; 6: R = CH , R = n-C H
1
1
3
1
3
1
2
6
13
1
2
2 2
1
3
2
3
7
7: R = CH , R = (CH ) N(C H ) ; 8: R = CH , R = CH CH(OH)CH ; 9: R = CH , R = (CH ) OCH
1
3
2
2 2
2
5 2
1
3
2
2
3
1
3
2
2 3
3
10: R = OCH , R = C H ; 11: R = OCH , R = n-C H ; 12: R = OCH , R = n-C H ; 13: R = OCH , R = (CH ) N(CH )
1
3
2
2
5
1
3
2
3
1
3
2
4
9
1
3
2
2 2
3 2
7Scheme 1
1) Zaporozhe State Medical University, Ukraine, 69035, Zaporozhe, Prosp. Mayakovskogo, 26, e-mail:
ivanchenkodima@yandex.ru. 2) S. I. Georgievskii Crimea State Medical University, Ukraine, 95006, Simferopol, Lenin
Blvd., 5/7; 3) National Pharmaceutical University, Ukraine, 61002, Kharkov, Ul. Pushkinskaya, 53. Translated from Khimiya
Prirodnykh Soedinenii, No. 5, September–October, 2013, pp. 766–770. Original article submitted June 27, 2013.
©
892
0009-3130/13/4905-0892 2013 Springer Science+Business Media New York

TABLE 1. PMR Spectra of Synthesized Compounds 4–17 (ꢁ, ppm)
Compound
4
NH (1H, s)
10.82
Harom.
NCH2 (2H, t)
4.12 (H-17)
H3-10 (3H, s)
3.44
Other resonances
7.56 (1H, s, H-6);
7.51 (5H, m, H-12-16)
1.67 (2H, m, H-18);
1.94 (6H, m, H-19-21);
0.81 (3H, t, ÑH3-22)
5.03 (1H, t, ÎH);
3.73 (2H, q, ÎÑH2-18)
2.38 (3H, s, CH3-17);
1.65 (2H, m, ÑH2-19);
0.71 (3H, t, ÑH3-20)
2.58 (2H, t, CH2-19);
2.38 (3H, s, CH3-17);
2.29 (4H, q, CH2-20, 21);
0.69 (6H, t, ÑH3-22, 23)
2.38 (3H, s, CH3-17);
0.98 (3H, d, ÑH3-20)
10.96
10.94
7.68 (3H, m, H-6, 12, 16);
7.51 (3H, m, H-13, 15)
7.64 (1H, s, H-6);
7.45 (2H, d, H-12, 16);
7.33 (2H, d, H-13, 15)
7.64 (1H, s, H-6);
4.13 (H-17)
4.04 (H-18)
3.40
3.39
5
6
10.95
4.13 (H-18)
3.40
7
7.51 (2H, d, H-12, 16);
7.33 (2H, d, H-13, 15)
10.95
10.94
7.63 (1H, s, H-6);
4.13–3.90
(3H, m, 2H-18, 19)
3.40
3.40
8
9
7.54 (2H, d, H-12, 16);
7.33 (2H, d, H-13, 15)
7.64 (1H, s, H-6);
7.46 (2H, d, H-12, 16);
7.33 (2H, d, H-13, 15)
4.14 (H-18)
3.19 (2H, t, ÎÑH2-20);
3.08 (3H, s, ÎÑH3-21);
2.38 (3H, s, CH3-17);
1.91 (2H, m, ÑH2-19)
3.84 (3H, s, ÎÑH3-17);
1.30 (3H, t, CH3-19)
10.84
10.71
10.86
7.51 (1H, s, H-6);
4.10 (2H, q, H-18)
4.03 (H-18)
3.42
3.42
3.42
10
11
12
7.46 (2H, d, H-13, 15);
7.06 (2H, d, H-12, 16)
7.47 (1H, s, H-6);
7.45 (2H, d, H-13, 15);
7.06 (2H, d, H-12, 16)
7.51 (1H, s, H-6);
3.85 (3H, s, ÎÑH3-17);
1.71 (2H, m, CH2-19);
0.78 (3H, t, ÑH3-20)
3.84 (3H, s, ÎÑH3-17);
1.65 (2H, m, ÑH2-19);
1.17 (2H, m, ÑH2-20);
0.78 (3H, t, ÑH3-21)
3.82 (3H, s, ÎÑH3-17);
2.48 (2H, t, CH2-19);
1.99 (6H, s, CH3-20, 21)
3.63 (3H, s, ÎÑH3-13)
4.07 (H-18)
7.46 (2H, d, H-13, 15);
7.06 (2H, d, H-12, 16)
10.95
7.59 (1H, s, H-6);
4.13 (H-18)
3.40
3.45
3.43
3.41
13
14
15
16
7.53 (2H, d, H-13, 15);
7.08 (2H, d, H-12, 16)
8.10 (2H, d, H-16, 21);
7.75 (1H, t, H-19);
7.63 (2H, t, H-19, 20)
8.83 (1H, s, H-3);
7.77 (2H, d, H-15, 19);
7.45 (3H, m, H-16-18)
8.04 (2H, d, H-17, 21);
7.73 (1H, t, H-19);
–
5.96 (2H, s, H-14)
4.54 (2H, s, H-11)
–
4.64 (2H, s, H-11)
3.67 (3H, s, ÎÑH3-13)
7.30 (1H, t) – Ñ8NH
5.66 (2H, s, H-14)
4.48 (2H, s, H-11)
4.76 (1H, t, ÎH);
3.62 (3H, s, ÎÑH3-13);
3.53 (2H, q, NHCH2-22);
3.33 (2H, q, ÎÑH2-23)
7.58 (2H, t, H-18, 20)
11.83
7.70 (2H, m, H-16, 20);
7.47 (3H, m, H-17-19)
5.29 (2H, s, H-4); 3.39* (ÑH3-11) 3.67 (3H, s, ÎÑH3-14)
4.58 (2H, s, H-12)
17
NMR spectra of the synthesized imidazoxanthines 4-13 proved unambiguously their structures (Table 1). Singlets at
10.96–10.71 and 3.45–3.39 ppm that were due to resonances of N H- and N CH - protons, respectively, confirmed the uracil
3
1
3
part of the molecule. A singlet in the range 7.68–7.41 ppm that was due to absorption of an aromatic proton in the 6-position
confirmed the presence of an imidazole ring annelated on the f-edge. Aromatic protons of substituents in the 7-position of the
imidazoxanthines were observed in the range 7.54–7.06 ppm as multiplets or a doublet of doublets of the corresponding
intensity. Protons of methylene substituents in the 8-position were found as triplets in the range 4.13–4.03 ppm. The exception
was the 8-ꢀ-hydroxypropyl derivative 8, the resonance of the methylene protons in the PMR spectrum of which was overlapped
by the resonance of the methine proton and was recorded as a multiplet at 4.13–3.9 ppm. Methylene protons in the spectrum
of N -ethyl derivative 10 appeared as a classical quartet at 4.10 ppm. Resonances of other protons of the substituents in the
8
8-position corresponded completely to their structures.
893

TABLE 2. Biological Activity of Synthesized Compounds
Diuretic, mL
Analgesic
Anti-inflammatory
Compound
Number of writhings
Paw volume (M ꢂ m), mm
after 4 h
%
%
%
ꢂ
(M m)
after 4 h
76.5
–
28.0
–
47.7
36.8
2.6
17.0
57.4
36.4
2.6
34.4
–
47.1
1.4
44.3
20.7
5.7
11.4
56.4
49.3
12.1
40.0
–
4
ꢂ
ꢂ
ꢂ
5.47 0.18
33.5 2.12
0.74 0.11
5
2.68 ꢂ 0.24
6.48 ꢂ 0.21
5.49 ꢂ 0.15
3.98 ꢂ 0.11
5.31 ꢂ 0.12
54.8 ꢂ 1.76
24.3 ꢂ 2.44
29.4 ꢂ 1.53
45.3 ꢂ 2.11
38.6 ꢂ 1.23
1.38 ꢂ 0.18
0.78 ꢂ 0.11
1.11 ꢂ 0.13
1.32 ꢂ 0.21
1.24 ꢂ 0.18
109.0
77.1
28.4
71.3
141.3
83.2
34.2
70.0
–
6
7
8
9
10
11
12
13
ꢂ
ꢂ
ꢂ
7.48 0.31
19.8 1.86
0.61 0.15
5.68 ꢂ 0.24
4.16 ꢂ 0.18
5.27 ꢂ 0.17
3.10 ꢂ 0.12
5.24 ꢂ 0.17*
–
29.6 ꢂ 2.14
45.3 ꢂ 1.46
30.5 ꢂ 2.11
46.5 ꢂ 1.47
–
0.71 ꢂ 0.18
1.23 ꢂ 0.24
0.84 ꢂ 0.21
1.40 ꢂ 0.07
–
0.71 ꢂ 0.06*
ꢂ
0.76 0.05*
Control
Hypothiazid
Diclofenac
Analgin
69.0
–
–
–
41.5
33.8
–
49.3
45.7
27.2 ꢂ 1.32*
–
ꢂ
30.8 1.18*
______
*Differences statistically significant from control, p < 0.05.
Next, we attempted to alkylate 7-phenacylmethylxanthines at the N H-group of the uracil fragment with subsequent
1
cyclization of the 1,7-disubstituted 8-bromo-3-methylxanthines into imidazo[1,2-f]xanthine derivatives.
Heating 7-benzoylmethyl-8-bromo-3-methylxanthine (1) with methylchloroacetate in DMF in the presence of K CO
2
3
on a boiling-water bath led unexpectedly to the formation of methyl(8-methyl-2-phenyl-1,3-oxazolo[2,3-f]xanthinyl-7-)acetate
(15). The expected methyl(7-benzoylmethyl-8-bromo-3-methylxanthinyl-1-)acetate (14) was formed as a side product in
25.7% yield. Two singlets of the appropriate intensity at 4.54 (2H, N CH ) and 3.63 ppm (3H, OCH ) in the NMR spectrum
1
2
3
of 14 (Table 1) confirmed that a methylacetate substituent was present in the 1-position. Methylene and methyl protons of the
methylacetate group of oxazoloxanthine 15 were recorded in the NMR spectrum as strong singlets at 4.64 and 3.67 ppm,
respectively, in addition to a strong resonance at 8.82 ppm (1H, H-3). A resonance for methylene protons at 5.96 ppm (2H)
was missing, which was characteristic for the spectrum of 14. The mass spectrum of 14 showed a peak for the molecular ion
+
with m/z 434:436 with intensity distribution 1:1. This indicated that the molecule contained one Br atom. A peak for M at
m/z 354 (99.9%) in the mass spectrum of 15 corresponded to the calculated molecular weight.
It seemed interesting to study the reaction of 15 with N-containing nucleophiles. Scheme 1 shows that the reaction of
15 with monoethanolamine in aqueous dioxane occurred with decyclization and led to the formation of methyl(7-benzoylmethyl-
8-ꢀ-hydroxyethylamino-3-methylxanthinyl-1-)acetate (16). Heating 15 with the stronger nucleophile hydrazine hydrate led
to recyclization of the oxazoloxanthine into methyl(9-methyl-3-phenyl-1,4-dihydro-1,2,4-triazino[3,4-f]xanthinyl-7-)acetate
+
(17). The NMR spectra of 16 and 17 agreed fully with their structures. The mass spectrum of ester 16 exhibited a peak for M
with m/z 415. This corresponded to the calculated molecular weight and indicated that the molecule contained an uneven
+
number of N atoms. The mass spectrum of 17 also exhibited a peak for M with m/z 368, which corresponded to the calculated
molecular weight.
Thus, the structures of the synthesized compounds were undoubtedly correct.
The diuretic, analgesic, and anti-inflammatory activities were studied in in vivo tests. Table 2 presents the experimental
results.
Diuretic activity of 1-methyl-7-phenyl-8-hexylimidazo[1,2-f]xanthine (4) was 7.5% greater than that of hypothiazid.
The anti-inflammatory activity of this compound was comparable to that of analgin and diclofenac sodium. Replacing the
hexyl radical in the 8-position of 1-methyl-7-phenylimidazo[1,2-f]xanthine by a ꢀ-hydroxyethyl (5) caused a sharp drop in
these activity parameters.
Introducing a p-methylphenyl substituent in the 7-position and shortening the hydrocarbon radical to three C atoms
caused a sharp increase of the diuretic and analgesic activity parameters compared with those of 4. Thus, 1-methyl-
7-p-methylphenyl-8-propylimidazo[1,2-f]xanthine (6) had diuretic activity that exceeded that of the standard drug by 40%.
Its anti-inflammatory and analgesic activities were comparable with those of diclofenac sodium.
894

TABLE 3. Physicochemical Properties of Synthesized Compounds 4–13
Compound
Empirical formula
Yield, %
Compound
Empirical formula
Yield, %
mp, ꢃÑ
mp, ꢃÑ
211–212
296–297
255–256
184–185
287–288
C20H23N5O2
C16H15N5O3
C18H19N5O2
C21H26N6O2
C18H19N5O3
32.9
36.9
41.5
67.3
53.8
240–241
288–289
250–251
260–261
238–239
C19H21N5O3
C17H17N5O3
C18H19N5O3
C19H21N5O3
C19H22N6O3
60.0
47.2
53.8
62.7
41.9
4
5
6
7
8
9
10
11
12
13
Replacing the methyl by methoxy in the para-position of the phenyl radical in the 7-position and shortening further
the hydrocarbon radical in the 8-position continued to increase the studied activity parameters. The diuretic activity of
1-methyl-7-p-methoxyphenyl-8-ethylimidazo[1,2-f]xanthine (10) was 72.3% greater than that of hypothiazid. The analgesic
and anti-inflammatory activities were 15.9 and 7.1%, respectively, greater than that of diclofenac sodium. A distinct trend was
also found among the 7-p-methoxyphenyl derivatives (10, 11, 12). The diuretic, analgesic, and anti-inflammatory activity
decreased as the hydrocarbon radical was lengthened. Acomparison of the biological activity of 1-methyl-7-p-methylphenyl-
8-propylimidazo[1,2-f]xanthine (6) and 1-methyl-7-p-methoxyphenyl-8-propylimidazo[1,2-f]xanthine (11) showed that the
diuretic and analgesic activity parameters decreased if the methyl was replaced by methoxy.
Thus, a lead compound (10) was identified. Its diuretic, analgesic, and anti-inflammatory activity parameters were
greater than those of the standard drugs. Also, it was demonstrated that the search for compounds with diuretic, analgesic, and
anti-inflammatory activities among 7,8-disubstituted 1-methylimidazo[1,2-f]xanthines was promising.
EXPERIMENTAL
Melting points were determined in open capillaries on a PTP (M) instrument. Elemental analysis was carried out on
an Elementar vario L cube instrument. NMR spectra were recorded in DMSO-d or DMSO-d + CDCl with TMS internal
6
6
3
standard on a Bruker SF-400 spectrometer (operating frequency 400 MHz). Mass spectra were recorded on a Varian 1200L
instrument with electron-impact ionization (70 eV) and direct sample introduction. Analytical data for all compounds agreed
with those calculated. Tables 1 and 3 present the physicochemical properties of the synthesized compounds.
Synthesis of 8-n-Hexyl-1-methyl-7-phenylimidazo[1,2-f]xanthine (4). A mixture of 7-benzylmethyl-8-bromo-3-
methylxanthine (1, 3.63 g, 0.01 mol), n-hexylamine (3.96 mL, 0.03 mol), and MeOH (50 mL) was heated in a steel autoclave
for 6 h at 190–200°C, cooled and treated with H O (50 mL). The precipitate was filtered off and crystallized from aqueous
2
dioxane. Compounds 6–13 were prepared analogously.
Synthesis of 8-ꢀ-Hydroxyethyl-3-methyl-7-phenylimidazo[1,2-f]xanthine (5). A solution of bromoketone 1
(3.63 g, 0.01 mol) in monoethanolamine (10 mL) was refluxed for 3 h, cooled to 60°C, and treated with H O (50 mL). The
2
precipitate was filtered off, washed with H O, and crystallized from aqueous dioxane.
2
Synthesis of Methyl Esters 14 and 15. A suspension of 1 (18 g, 0.05 mol), methylchloroacetate (6.6 mL,
0.076 mol), and K CO (13.8 g, 0.1 mol) in DMF (150 mL) was refluxed on a boiling-water bath for 3 h with vigorous stirring
2
3
and then another 3 h before cooling. Oxazoloxanthine 15 was filtered off after 24 h, washed with H O, and crystallized from
2
aqueous dioxane. A precipitate of bromoketone 14 formed in the filtrate after removal of 15. It was filtered off, washed with
H O, and crystallized from aqueous EtOH.
2
Mass spectrum of methyl(7-benzoylmethyl-8-bromo-3-methylxanthinyl-7-)acetate (14) (EI, 70 eV), m/z (I , %):
rel.
+
+
436 (Ì + 2, 6.4), 434 (Ì , 6.4), 354 (9.0), 109 (6.8), 106 (16.4), 105 (99.9), 104 (22.6), 91 (7.0), 81 (6.6); 77 (26.8).
Mass spectrum of methyl(8-methyl-2-phenyl-1,3-oxazolo[2,3-f]xanthinyl-6-)acetate (15) (EI, 70 eV), m/z (I , %):
354 (Ì , 99.9), 353 (Ì – Í, 34.4), 295 (18.4), 294 (21.2), 293 (5.9), 281 (9.8), 266 (22.4), 238 (11.0), 211 (7.4), 210 (33.2),
209 (9.5), 142 (7.2), 131 (5.3), 116 (10.1), 102 (11.9), 83 (13.9).
rel.
+
+
Synthesis of Aminoester 16. A solution of 15 (2.5 g, 6 mmol), monoethanolamine (3 mL, 50 mmol) in a mixture of
H O (10 mL) and dioxane (35 mL) was refluxed for 10 min, filtered hot, and adjusted with H O to 100 mL. The precipitate
2
2
was filtered off after 1 d, washed with H O, and crystallized from aqueous EtOH.
2
Mass spectrum of methyl(7-benzoylmethyl-8-ꢀ-hydroxyethylamino-3-methylxanthinyl-1-)acetate (16) (EI, 70 eV),
+
+
m/z (I , %): 416 (Ì + 1, 18.3), 415 (Ì , 81.1), 384 (17.0), 356 (7.5), 352 (6.5), 324 (43.5), 310 (9.1), 296 (8.3), 292 (5.7),
rel.
895

278 (5.8), 267 (5.3), 266 (19.9), 251 (10.0), 250 (77.4), 236 (9.4), 234 (7.2), 221 (5.2), 206 (8.2), 126 (7.0), 106 (7.6), 105
(99.9), 91 (10.3), 83 (6.3), 82 (18.4), 81 (11.1), 77 (43.2), 69 (5.8), 67 (8.5), 59 (7.7), 56 (6.5), 51 (5.9).
Synthesis of Triazinoxanthine 17. A suspension of 15 (3.54 g, 0.01 mol), hydrazine hydrate (5 mL, 0.1 mol), H O
2
(20 mL), and dioxane (30 mL) was refluxed for 30 min and cooled. The precipitate was filtered off and washed with H O,
2
EtOH, and Et O.
2
Mass spectrum of methyl(9-methyl-3-phenyl-1,4-dihydro-1,2,4-triazino[3,4-f]xanthinyl-7-)acetate (17) (EI, 70 eV),
+
+
m/z (I , %): 369 (Ì + 1, 13.3), 368 (Ì , 56.9), 337 (7.4), 336 (11.3), 310 (5.1), 309 (30.1), 308 (99.9), 280 (6.2), 279 (7.0), 252
rel.
(5.4), 225 (8.3), 224 (6.0), 205 (18.5), 204 (7.1), 121 (5.2), 104 (5.6), 103 (11.1), 102 (6.6), 95 (5.4), 94 (6.8), 83 (8.1), 82 (49.9),
81 (7.5), 77 (16.0), 68 (6.9), 67 (11.0), 59 (23.4), 56 (14.3), 55 (6.3).
The diuretic activity of the synthesized compounds was studied by the Berkhin method [10]. The compounds were
injected i.p. at a dose of 20 mg/kg as a 3–5% thin aqueous suspensions stabilized with Tween-80 30 min before aqueous
loading. The standard reference was hypothiazid at a dose of 25 mg/kg.
The analgesic activity of the synthesized xanthines was studied using white rats (160–210 g) and the acetic-acid
writhing model caused by i.p. injection of acetic-acid solution (0.75%) at a dose of 20 mg/kg. The anti-inflammatory activity
was studied using white rats and the acute aseptic edema model caused by subplantar injection into the hind paw of carrageenan
solution (0.1 mL, 1%) [11]. The standard drugs were diclofenac sodium and analgin at doses of 8 and 25 mg/kg, respectively.
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