9-(2-Aryloxyethyl) derivatives of adenine - A new class of non-nucleosidic antiviral agents

Article abstract of DOI:10.1023/B:COHC.0000008270.32235.2b

New 9-(aryloxyalkyl) derivatives of adenine have been prepared by alkylation of adenine with tosylates, bromides, and α-chloro ethers containing terminal aromatic fragments in anhydrous DMF in the presence of potassium carbonate. The compounds of the 9-(2-phenoxyethyl)adenine series appear to be highly reactive against cytomegaloviruses of mankind in vitro, while derivatives of 9-(2-benzyloxyethyl)adenine demonstrate anti-HIV-1 activity. Compounds with shorter or longer chains, and also compounds which do not have aromatic fragments at the ends of the chains, do not possess antiviral activity.

Full text of DOI:10.1023/B:COHC.0000008270.32235.2b

Chemistry of Heterocyclic Compounds, Vol. 39, No. 9, 2003
9-(2-ARYLOXYETHYL) DERIVATIVES
OF ADENINE – A NEW CLASS OF NON-
NUCLEOSIDIC ANTIVIRAL AGENTS
V. I. Petrov1, A. A. Ozerov1, M. S. Novikov1, C. Pannecouque2, J. Balzarini2,
and E. De Clercq2
New 9-(aryloxyalkyl) derivatives of adenine have been prepared by alkylation of adenine with tosylates,
bromides, and α-chloro ethers containing terminal aromatic fragments in anhydrous DMF in the
presence of potassium carbonate. The compounds of the 9-(2-phenoxyethyl)adenine series appear to be
highly reactive against cytomegaloviruses of mankind in vitro, while derivatives of
9-(2-benzyloxyethyl)adenine demonstrate anti-HIV-1 activity. Compounds with shorter or longer
chains, and also compounds which do not have aromatic fragments at the ends of the chains, do not
possess antiviral activity.
Keywords: adenine, N(9)-alkylation, antiviral activity.
The problem of searching for effective media for the pharmacotherapy of virus infections has become
all the greater in connection with the AIDS pandemic and the wide distribution of opportunistic herpes virus
infections. At the present time the main direction remains the search for new antiviral agents among non-
nucleosidic compounds, which, in contrast to their nucleoside analogs, do not require metabolic activation in
vivo and are capable of direct interaction with the virus specific enzyme targets. Among adenine derivatives
which show antiviral activity and are not nucleosides are the known 9-(S)-(2,3-dihydroxypropyl)adenine (1),
which shows a wide range of antiviral activity [1], adenallene (2) which shows anti-HIV-1 activity in vitro, and
9-(allyloxymethyl)adenine (3), which we synthesized previously, and which inhibits the cytotoxic effect of
HIV-1 in MT-4 lymphocycte culture in the concentration range 50-500 µg/ml [3].
NH2
NH2
N
NH2
N
N
N
N
N
N
N
N
N
N
N
O
OH
OH
OH
1
3
2
__________________________________________________________________________________________
1
Scientific Research Institute for Pharmacology, Volgograd State Medical University, Volgograd
2
400131, Russia; e-mail: ozerov@vlink.ru. Rega Institute for Medical Research, Catholic University, Leuvain,
Belgium. Translated from Khimii Geterotsiklicheskikh Soedinenii, No. 9, 1389-1397, September, 2003. Original
article submitted March 19, 2003.
1218
0009-3122/03/3909-1218$25.00©2003 Plenum Publishing Corporation

Analysis of the chemical structures of non-nucleoside anti-HIV agents of various classes, including a
number of analogues of emivirin (6-benzyl-1-ethoxymethyl-5-isopropyluracil) [4] and derivatives of S-alkyl-6-
arylmethyl-2-thiouracil (S-DABO) [5], coupled with known information about the antiviral properties of other
adenine compounds [6], permitted the prediction that 9-substituted derivatives of adenine containing an
aromatic group at the end of an acyclic chain might be of considerable interest as potential antiviral substances.
We had previously prepared 3-O-aryl ethers of 9-(R,S)-(2,3-dihydroxypropyl)adenine and its pyrimidine analogs
as probable inhibitors of S-adenosyl-L-homocysteinylhydrolases [7,8], some of which (derivatives of adenine
and cytosine) were active against HIV-1, HIV-2, herpes virus type 1, and Koksaki virus in vitro [9]. In a
continuation of this study we have synthesized new 9-substituted derivatives of adenine containing aromatic
nuclei (phenyl, naphthyl) groups at the end of an acyclic chain containing 1-5 carbon atoms and including an
ether oxygen at various positions.
The synthesis of alkylating agents for the introduction of the aryl(oxy)alkyl substituents at N(9) adenine
was carried out by three basic schemes.
Commercial aliphatic-aromatic alcohols (benzyl, 2-phenylethyl, or 3-phenylpropyl) and also
butylcellosolve, 2-benzoyloxyethanol, and 2-(1-adamantyloxy)ethanol , obtained by the addition of ethylene
glycol to 1,3-dehydroadamantane[10] were converted into the α-chloro ethers by the Anry reaction [11] or the
tosylates which were used directly for the synthesis of the required compounds 6-11, 13, and 14.
Reactive halides of the benzyl (benzyl chloride, α-chloromethylnaphthalene, 1-bromo-1-phenylethane,
and diphenylbromomethane) of allyl types (allyl bromide) in an anhydrous glycol (ethylene glycol,
1,3-propylene glycol or 1,4-butylene glycol) at a temperature of about 80°C in the presence of potassium
hydroxide and dibenzo-18-crown-6 (molar ratio halide–glycol–alkali–coronand 1:5-10:1;0.05) readily formed
the corresponding ω-aryl(allyl)oxyalkanols, which were then converted into the tosylates used in the synthesis
of compounds 12, 18-21, 24, and 26.
Finally, compounds of the phenol type (phenol, α- and β-naphthol) were alkylated with an excess of
1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, or 1,5-dibromopentane by refluxing in the
presence of 30% aqueous potassium hydroxide and dibenzo-18-crown-6 (molar ratio of phenol–dibromoalkane–
alkali–coronand 1:3-5:1:0.05) which gave ω-aryloxyalkyl bromides – the synthons for obtaining the final
compounds 15-17, 23, 25, and 27.
Alkylated adenine bases were synthesized via the ω-aryl(oxy)alkyl bromides (method A) or the tosylates
of the ω-aryl(oxy)alkanols (method B) in anhydrous DMF in the presence of potassium carbonate at 110-120°C
by the method which we developed for the alkylation of adenine with arylglycidyl ethers [7, 8]. Alkylation of
adenine with benzyl chloride and α-chloromethylnaphthalene was carried out analogously, but the reaction
mixture was refluxed for 1 h more (method C) which allowed the preparation of the previously described [12]
9-benzyladenine (4) and also 9-(α-naphthylmethyl)adenine (5). The reaction of adenine with α-chloro ethers to
give compounds 8-10 was carried out in DMF in the presence of potassium carbonate at room temperature
(method D). For the synthesis of 9-(2-hydroxyethyl)adenine (11), removal of the benzoyl group from the
product of alkyation of adenine with the tosylate of 2-benzyloxyethanol was carried out at room temperature
with a methanolic ammonia solution without isolation of the 9-(2-benzoyloxyethyl)adenine.
NH2
NH2
N
N
(Cl, Br, TsO)–(CH2)n–X–(CH2)m–R
DMF, K2CO3
N
N
N
N
N
H
N
(CH2)n–X–(CH2)m–R
4–27
1219

TABLE 1. Characteristics of Compounds 4-27
Found, %
——————
Com-
Empirical
formula
X
R
Calculated, %
mp, °C
Rf
Yield, %
n
m
pound
С
7
H
8
N
9
1
2
0
0
1
2
1
1
1
2
2
2
2
3
0
0
0
0
1
2
3
0
0
0
0
4
CH2
CH2
CH2
CH2
O
5
6
10
11
12
Ph
C12H11N5
C16H13N5
C13H13N5
C14H15N5
C13H13N5O
C14H15N5O
C15H17N5O
C7H9N5O
C10H13N5O
C11H17N5O
C17H23N5O
63.90
63.99
4.87
4.92
31.12
31.09
226-228
273-275
177-179
184-187
224-227
195-198
173-176
241-243
145-148
112–114
254-256
0.22
0.23
0.20
0.40
0.23
0.24
0.27
0.05
0.29
0.33
0.24
68 (C)
70 (C)
64 (B)
53 (B)
48 (D)
54 (D)
48 (D)
67 (B)
57 (B)
41 (B)
53 (B)
4
5
α-Naphthyl
70.01
4.83
25.10
69.80
4.76
25.44
Ph
65.31
65.25
5.40
5.48
29.43
29.27
6
Ph
66.43
6.08
27.50
7
66.38
5.97
27.65
Ph
61.30
61.16
5.05
5.13
27.24
27.43
8
O
Ph
62.40
5.72
25.80
9
62.44
5.61
26.01
O
Ph
H
63.72
63.59
6.13
6.05
24.58
24.72
10
11
12
13
14
O
47.12
5.16
38.88
46.92
5.06
39.09
O
CH2CH=CH2
Bu
54.85
54.78
5.90
5.98
32.14
31.94
O
56.03
7.31
29.63
56.15
7.28
29.77
O
1-Adamantyl
65.30
65.14
7.51
7.40
22.14
22.35

TABLE 1 (continued)
1
2
2
2
2
2
2
2
2
2
3
3
4
4
5
3
0
0
0
1
1
0
0
3
0
1
0
1
0
4
5
6
7
8
9
10
11
12
O
O
O
O
O
O
O
O
O
O
O
O
O
Ph
C13H13N5O
C17H15N5O
C17H15N5O
C14H15N5O
C18H17N5O
C15H17N5O
C20H19N5O
C16H19N5O
C14H15N5O
C15H17N5O
C15H17N5O
C16H19N5O
C16H19N5O
61.31
61.16
5.20
5.13
27.29
27.43
216-218
237-239
252-255
162-163
212-214
145-147
187-189
166-168
175-177
124-126
197-200
143-145
169-171
0.33
0.29
0.20
0.35
0.37
0.35
0.37
0.54
0.26
0.51
0.49
0.60
0.56
58 (A)
66 (A)
72 (A)
48 (B)
49 (B)
35 (B)
46 (B)
49 (B)
59 (A)
45 (B)
79 (A)
51 (B)
55 (A)
15
α-Naphthyl
66.93
4.80
23.12
16
17
18
19
20
21
22
23
24
25
26
27
66.87
4.95
22.94
β-Naphthyl
66.99
66.87
4.82
4.95
22.77
22.94
Ph
62.51
5.80
25.79
62.44
5.61
26.01
α-Naphthyl
67.91
67.70
5.43
5.37
21.80
21.93
CH(Me)Ph
63.70
6.11
24.55
63.59
6.05
24.72
CHPh2
Ph
69.40
69.55
5.63
5.54
20.14
20.28
64.53
6.40
23.68
64.63
6.44
23.55
Ph
62.56
62.44
5.43
5.61
25.92
26.01
Ph
63.70
6.12
24.60
63.59
6.05
24.72
Ph
63.77
63.59
6.09
6.05
24.55
24.72
Ph
64.50
6.58
23.60
64.63
6.44
23.55
Ph
64.78
64.63
6.50
6.44
23.47
23.55

The N(9)-substituted derivatives of adenine (Table 1) were readily obtained with equimolar ratios of
adenine and the alkylating agents in the conditions described (Table 1).
The antiviral properties of compounds 4-27 in vitro with respect to a wide range of DNA and RNA
containing viruses were studied at the Rega Institute for Medical Research (Catholic University, Louvain,
Belgium). The greatest effects of the new 9-(aryloxyalkyl) derivatives of adenine were demonstrated against the
human cytomegaloviruses (CMV) and HIV-1 (Table 2). Structure-activity analysis indicated that the most
powerful effects were shown by adenine derivatives in which the heterocyclic base and the aromatic unit were
separated by 3 or 4 atoms. Compounds with longer or shorter chains were less active.
The oxygen atom played a very important role in the composition of the chain: its presence was
responsible for the antiviral properties with respect to both viruses. Shift of the oxygen atom from the γ-position
in the acyclic relative to atom N(9) of adenine to the β- or δ-position led to practically complete loss in activity
(cf. compounds 7,8, and 15; 9, 18, and 23). Replacement of the aromatic phenyl nucleus in the active compound
15 by the unsaturated allyl group in compound 12, or the saturated butyl group (compound 13), or the bulky
non-aromatic 1-adamantyl group (compound 14), like the complete separation of the substituent with an oxygen
atom (compound 11) led to considerable weakening (by 6 to 150 times) or complete extinction of anti-
cytomegalovirus (CMV) activity. In contrast, substitution of the phenyl group in compound 15 by the
α-naphthyl (compound 16) or β-naphthyl groups (compound 17) increased the anti-viral effect against CMV by
TABLE 2. Anti-virus Activity of the Synthesized Compounds in vitro*
Anti-CMV activity (AD-169 strain)
Anti-HIV-1 activity (IIIB strain)
Com-
pound
EC50, µmol / l
CC50, µmol / l
EC50, µg/ml
CC50, µg/ml
>200
50
>200
>200
140
167
>50
>250
>50
65.0
43.8
25.0
>250
>250
>250
>50
>50
>10
>50
18.3
3.33
0.50
1.07
>20
>250
~250
>250
89.3
>250
104
4
5
>50
>50
>200
>200
>20
20
>50
2
50
0.32
0.005
0.05
0.2
0.8
>20
>20
2
6
200
7
>200
>200
>20
>200
>200
>200
200
48
9
>200
>200
>200
>20
8
9
127
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
>250
>250
~250
71.6
156
27.6
~250
~250
~250
~100
191
25.1
131
212
95.5
79.1
22.5
165
>20
5
>50
20
2
2
>200
>200
>200
121
65.0
>50
>50
~35
>10
>200
_______
* EC50 is the effective concentration which produces a 50% reduction in the
cytopathic effect of the virus on the cells; CC50 is the cytotoxic
concentration which decreases the survival rate of non-infected cells by
50%.
1222

TABLE 3. Effectiveness of the Anti-CMV Effect of the Synthesized
Compounds in vitro
Antivirus activity,
Selectivity index,
Cytotoxicity,
CC50, µmol/l
SI = CC50 / EC50
EC50, µmol/l
Compound
AD-169
AD-169
Davis strain
Davis strain
strain
strain
0.32
0.005
0.05
0.2
0.37
0.005
0.04
0.4
48
150
1800
>4000
>1000
>250
>24
130
1800
>5000
>500
>75
>25
>300
15
16
17
18
19
9
>200
>200
>200
>150
>150
0.8
2.7
Gantsiklovir
Cilofovir
6.3
0.5
5.9
0.5
>300
65 and 6 times respectively. In summary the antiviral effects in vitro of the analogues of
9-(2-phenoxyethyl)adenine 15-17 and 9-(2-benzyloxyethyl)adenine 18 and 19 considerably exceed the activity
of ganciklovir [13] and cidofovir [14] which are currently in clinical use as anti-CMV agents (Table 3).
In contrast to the derivatives of 9-(2-phenoxyethyl)adenine 15-17, the derivatives of
9-(2-benzyloxyethyl)adenine 18-21 show antiviral activity against HIV-1 as well as CMV virus. An increase in
the size of the aromatic substituent and branching in the chain at the α-position of the benzyl radical also
considerably increase the antiviral activity of the substance, which reaches its maximum with compound 20
(inhibitory concentration EC50 = 0.50 µg/ml, selectivity index SI > 200).
We have therefore a new class of non-nucleosidic inhibitors of virus reproduction which have high
activity against human CMV and at the same time show anti-HIV-1 activity in vitro. On the basis of the
structure-activity ratios in the compounds obtained, further deliberately directed search for new highly active
compounds for the complex medical treatment of AIDS and opportunistic CMV infection.
EXPERIMENTAL
1H NMR spectra of 1:1 DMSO-d6–acetone-d6 solutions with MDS as internal standard were recorded
with a Tesla BS-567A (100 MHz). Interpretation of the spectra was carried out using the decision programme
ACD/HNMR Pro 3.0 (Advanced Chemistry Development, Canada). Electron impact mass spectra were recorded
with a Varian MAT-111 machine with direct inlet of the sample into the ion source, energy of ionizing electrons
70 eV). TLC was carried out Silufol UV-254 strips with 10:1 chloroform–methanol as eluent, and development
with iodine vapor. Melting points were measured in glass capillaries with a Mel-Temp 3.0 apparatus
(Laboratory Devices,Inc, U.S.A.).
9-(1-Naphthylmethyl)adenine (5). A mixture of adenine (2.0 g, 14.8 mmol) and anhydrous potassium
carbonate (3.0 g, 21.7 mmol) in DMF (50 ml) was stirred for 30 min at 105-110°C, α-chloromethylnaphthalene
(2.7 g, 15.2 mmol) was added, stirring was continues at the same temperature for 2 h, and the mixture was
refluxed for 1 h. The hot reaction mixture was filtered, the filtrate was evaporated in vacuum, cooled, and the
solid residue was washed with water (25 ml), dried in air, and recrystallized from glacial acetic acid (25 ml) to
1
give compound 5 (2.85 g) as a white crystalline substance. H NMR spectrum, δ, ppm: 5.75 (2H, s, CH2);
6.97-7.90 (7H, m, naphthyl); 7.07 (2H, br. s, NH2); 7.99 (1H, s, 8-H); 8.11 (1H, s, 2-H). Mass spectrum, m/z 275
[M+].
1223

9-(2-Hydroxyethyl)adenine (11). A mixture of adenine (2.0 g, 14.8 mmol) and anhydrous potassium
carbonate (3.0 g, 21.7 mmol) in DMF (50 ml) was stirred for 30 min at 105-110°C, a solution of 2-benzoylethyl
tosylate (4.6 g, 15.0 mmol) in DMF (10 ml) was added, and the mixture was stirred at the same temperature for
2 h. The hot reaction mixture was filtered, the filtrate was evaporated in vacuum, cooled, dissolved in methanol
(50 ml), saturated with gaseous ammonia, and stirred for 1 d at room temperature in a sealed vessel. The
reaction mixture was evaporated to dryness in vacuum (~100°C), cooled, washed with ether (3 × 10 ml), and
1
recrystallized from DMF (20 ml) to give compound 11 (1.75 g) as light-yellow crystals. H NMR spectrum,
δ, ppm: 3.58-3.81 (2H, m, CH2O); 4.01-4.25 (2H, m, NCH2); 4.96 (1H, br. s, OH); 7.19 (2H, br. s, NH2); 7.99
(1H, s, 8-H); 8.04 (1H, s, 2-H). Mass spectrum: m/z 179 [M+].
9-[2-(Phenoxy)ethyl]adenine (15). A mixture of adenine (2.0 g, 14.8 mmol) and anhydrous potassium
carbonate (3.0 g, 21.7 mmol) in DMF (50 ml) was stirred for 30 min at 105-110°C, a solution of 1-bromo-2-
phenoxyethane (3.0 g, 14.9 mmol) in DMF (10 ml) was added and the mixture was stirred at the same
temperature for 2 h. The hot solution was filtered, the filtrate evaporated in vacuum, cooled, and the solid
residue was washed with water (25 ml), dried in the air, and recrystallized from 95% ethanol to give compound
15 (2.20 g) as white crystals. 1H NMR spectrum, δ, ppm: 4.20-4.57 (4H, m, CH2CH2); 6.67-7.23 (7H, m, phenyl,
NH2); 8.03 (1H, s, 8-H); 8.09 (1H, s, 2-H). Mass spectrum, m/z 255 [M+].
Compounds 4, 6-10, 12-14, and 16-27 were made analogously.
1
9-Benzyladenine (4). H NMR spectrum, δ, ppm: 5.43 (2H, s, CH2); 6.95-7.25 (7H, m, phenyl, NH2);
8.12 (1H, s, 8-H); 8.28 (1H, s, 2-H). Mass spectrum, m/z 225 [M+].
9-(2-Phenylethyl)adenine (6). 1H NMR spectrum, δ, ppm: 3.39 (4H, m, CH2CH2); 7.0 (2H, br. s, NH2);
7.12 (5H, m, phenyl); 8.02, 1H, s, 8-H); 8.11 (1H, s, 2-H). Mass spectrum, m/z 239 [M+].
1
9-(3-Phenylpropyl)adenine (7). H NMR spectrum, δ, ppm, (J, Hz): 1.91-2.66 (4H, m, CH2CH2); 4.12
(2H, t, J = 7, NCH2); 7.04 (2H, br. s, NH2); 7.08 (5H, s, phenyl); 8.00 (1H, s, 8-H); 8.04 (1H, s, 2-H). Mass
spectrum, m/z 253 [M+].
1
9-(Benzyloxymethyl)adenine (8). H NMR spectrum, δ, ppm: 4.51 (2H, s, CH2); 5.57 (2H, s, NCH2);
6.98 (2H, br. s, NH2); 7.19 (5H, s, phenyl); 8.07 (1H, s, 8-H); 8.12 (1H, s, 2-H). Mass spectrum, m/z 255 [M+].
9-(2-Phenylethoxymethyl)adenine (9). 1H NMR spectrum, δ, ppm (J, Hz): 2.47 (2H, t, J = 6, CH2);
4.12 (2H, t, J = 6, OCH2); 5.52 (2H, s, NCH2O); 7.01 (2H, br. s, NH2); 7.08 (5H, s, phenyl); 7.98, 1H, s, 8-H);
8.11 (1H, s, 2-H). Mass spectrum, m/z 269 [M+].
1
9-(3-Phenylpropoxymethyl)adenine (10). H NMR spectrum, δ, ppm (J, Hz): 1.39-1.83 (2H, m, CH2);
2.57 (2H, J = 6, CH2); 3.48 (2H, J = 6, OCH2); 5.45 (2H, s, NCH2O); 7.02 (2H, br. s, NCH2); 7.14 (5H, s,
phenyl); 8.01 (1H, s, 8-H); 8.08 (1H, s, 2-H). Mass spectrum, m/z 283 [M+].
1
9-(2-Allyloxyethyl)adenine (12). H NMR spectrum, δ, ppm (J, Hz): 3.68 (2H, t, J = 6, CH2O); 3.84
(2H, dd, J = 5, J = 1, OCH2); 4.26 (2H, t, J = 6, NCH2); 4.85-5.17 (2H, m, =CH2); 5.44-5.90 (1H, m, -CH=);
6.88 (2H, br. s, NH2); 7.92 (1H, s, 8-H); 8.05 (1H, s, 2-H). Mass spectrum, m/z 210 [M+].
9-(2-Butoxyethyl)adenine, (13). 1H NMR spectrum, δ, ppm (J, Hz): 0.75 (3H, t, J = 6, CH3);
1.02-1.65 (4H, m, CH2CH2); 3.29 (2H, t, J = 5, OCH2); 3.63 (2H, t, J = 5, OCH2); 4.26 (2H, t, J = 5, NCH2);
6.90 (2H, br. s, NH2); 7.98 (1H, s, 8-H); 8.12 (1H, s, 2-H). Mass spectrum, m/z 235 [M+].
1
9-[2-(1-Adamantyloxy)ethyl]adenine (14). H NMR spectrum, δ, ppm (J, Hz): 1.44-2.10 (15H, m,
adamantyl); 3.61 (2H, t, J = 6, OCH2); 4.24 (2H, t, J = 6, NCH2); 6.90 (2H, br. s, NH2); 7.94 (1H, s, 8-H); 8.08
(1H, s, 2-H) Mass spectrum, m/z 313 [M+].
1
9-[2-(1-Naphthyloxy)ethyl]adenine (16). H NMR spectrum, δ, ppm: 4.34-4.71 (4H, m, NCH2CH2O);
6.76-7.97 (9H, m, naphthyl, NH2); 7.94 (1H, s, 8-H); 8.17 (1H, s, 2-H). Mass spectrum, m/z 305 [M+].
1
9-[2-(2-Naphthyloxy)ethyl]adenine (17). H NMR spectrum, δ, ppm: 4.27-4.63 (4H, m, NCH2CH2O);
6.89-7.85 (9H, m, naphthyl, NH2); 8.04 (1H, s, 8-H); 8.11 (1H, s, 2-H). Mass spectrum, m/z 305 [M+].
1224

9-(2-Benzyloxyethyl)adenine (18). 1H NMR spectrum, δ, ppm (J, Hz): 3.43 (2H, t, J = 6, OCH2); 4.31
(2H, t, J = 6, NCH2); 6.97 (2H, br. s, NH2); 7.10 (5H, s, phenyl); 8.03 (1H, s, 8-H); 8.10 (1H, s, 2-H). Mass
spectrum: m/z 269 [M+].
1
9-[2-(1-Naphthylmethoxy)ethyl]adenine (19): H NMR spectrum, δ, ppm: 3.73-3.98 (2H, m, OCH2);
4.23-4.42 (2H, m, NCH2); 4.86 (2H, s, OCH2); 6.98 (2H, br. s, NH2); 7.18-7.88 (7H, m, naphthyl); 7.93 (1H, s,
8-H); 8.02 (1H, s, 2-H). Mass spectrum, m/z 319 [M+].
1
9-[2-(1-Phenylethoxy)ethyl]adenine (20). H NMR spectrum, δ, ppm (J, Hz): 1.58 (3H, s, CH3); 3.73
(2H, t, J = 6, OCH2); 4.21-4.40 (3H, m, NCH2, CH); 7.00 (2H, br. s, NH2); 7.09 (5H, s , phenyl); 8.03 (1H, s,
8-H); 8.12 (1H, s, 2-H). Mass spectrum, m/z 283 [M+].
1
9-[2-(Diphenylmethoxy)ethyl]adenine (21). H NMR spectrum, δ, ppm (J, Hz): 3.69 (2H, t, J = 6,
OCH2); 4.36 (2H, t, J = 6, NCH2); 5.37 (1H, s, CH); 7.01 (2H, br. s,NH2); 7.11 (10H, s, phenyl); 8.03 (1H, s,
8-H); 8.13 (1H, s, 2-H). Mass spectrum, m/z 318 [M - HCN]+.
1
9-[2-(3-Phenylpropoxy)ethyl]adenine (22). H NMR spectrum, δ, ppm (J, Hz): 1.47-1.82 (2H, m ,
CH2); 2.52 (2H, J = 6 , CH2); 3.19-3.70 (4H, m, CH2OCH2); 4.23 (2H, t, J = 6, NCH2); 6.95 (2H, br. s, NH2);
7.12 (5H, s, phenyl); 8.02 (1H, s, 8-H); 8.08 (1H, s, 2-H). Mass spectrum, m/z 297 [M+].
1
9-(3-Phenoxypropyl)adenine (23). H NMR spectrum, δ, ppm): 1.70-1.95 (2H, m, CH2); 3.45-3.80
(4H, m, NCH2CH2O); 6.62-7.30 (7H, m, phenyl, NH2); 7.95 (1H, s, 8-H); 8.04 (1H, s, 2-H). Mass spectrum, m/z
269 [M+].
1
9-(3-Benzyloxypropyl)adenine (24). H NMR spectrum, δ, ppm : 1.68-1.95 (2H, m, CH2); 3.44-3.76
(4H, m, NCH2CH2O); 4.42 (2H, s, OCH2); 6.90 (2H, br.s, NH2); 7.12 (5H, s, phenyl); 7.93 (1H, s, 8-H); 8.04
(1H, s, 2-H). Mass spectrum, m/z 283 [M+].
9-(4-Phenoxybutyl)adenine (25). 1H NMR spectrum, δ, ppm (J, Hz): 1.52-2.06 (4H, m, CH2CH2); 3.89
(2H, t, J = 6, OCH3); 4.14 (2H, t, J = 6, NCH2); 6.65-7.22 (7H, m, phenyl, NH2); 7.98 (1H, s, 8-H); 8.04 (1H, s,
2-H). Mass spectrum, m/z 283 [M+].
1
9-(4-Benzyloxybutyl)adenine (26). H NMR spectrum, δ, ppm (J, Hz): 1.38-2.06 (4H, m, CH2CH2);
3.37 (2H, t, J = 6, OCH2); 4.08 (2H, t, NCH2); 4.32 (2H, s, OCH2); 6.82 (2H, br.s, NH2); 7.14 (5H, s, phenyl);
7.91 (1H, s, 8-H); 8.04 (1H, s, 2-H). Mass spectrum, m/z 297 [M+].
9-(5-Phenoxypentyl)adenine (27). 1H NMR spectrum, δ, ppm (J, Hz): 1.10-2.03 (6H, m, CH2CH2CH2);
3.82 (2H, t, J = 6, OCH2); 4.08 (2H, t, J = 6, NCH2); 6.62-7.20 (7H, m, phenyl, NH2); 7.91 (1H, s, 8-H); 8.02
(1H, s, 2-H). Mass spectrum, m/z 297 [M+].
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