1-Amino-3-(1H-1,2,3-triazol-1-yl)propylphosphonates as acyclic analogs of nucleotides

Article abstract of DOI:10.1002/ardp.201300471

A new series of 1-amino-3-(1H-1,2,3-triazol-1-yl)propylphosphonates (R)- and (S)-16 were obtained from enantiomerically pure (R)- and (S)-1-tert-butoxycarbonyl (Boc)-amino-3-azidopropylphosphonates and N-propargylated nucleobases in good yields. All 1,2,3-triazolylphosphonates (R)- and (S)-16 were evaluated for their activities against a broad range of DNA and RNA viruses. Compound (R)-16g (B = 3-acetylindole) was moderately active against vesicular stomatitis virus in HeLa cell cultures (EC₅₀ = 45 μM). In addition, (S)-16c (B = adenine), (R)-16f (B = N³-Bz- benzuracil), (R)-16g (B = 3-acetylindole), and (R)-16h (B = 5,6- dimethylbenzimidazole) were cytotoxic toward Crandell-Rees feline kidney (CRFK) cells (CC₅₀ = 2.9, 45, 72, and 96 μM, respectively). Compounds (R)-16g, (S)-16g, and (S)-16h were slightly cytostatic to different tumor cell lines. Among a new series of 1-amino-3-(1H-1,2,3-triazol-1-yl)- propylphosphonates, compound (R)-16g (B = 3-acetylindole) was found to be active against vesicular stomatitis virus in HeLa cell cultures. In addition, (S)-16c (B = adenine), (R)-16f (B = N³-Bz-benzuracil), (R)-16g (B = 3-acetylindole), and (R)-16h (B = 5,6-dimethylbenzimidazole) displayed cytotoxicity toward Crandell-Rees feline kidney cells and compounds (R)-16g, (S)-16g, and (S)-16h were slightly cytostatic to different tumor cell lines.

Full text of DOI:10.1002/ardp.201300471

Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
1
Full Paper
1-Amino-3-(1H-1,2,3-triazol-1-yl)propylphosphonates as
Acyclic Analogs of Nucleotides
Iwona E. Głowacka1, Jan Balzarini2, and Dorota G. Piotrowska1
1
ꢀ
ꢀ
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódz, Łódz, Poland
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
2
A new series of 1-amino-3-(1H-1,2,3-triazol-1-yl)propylphosphonates (R)- and (S)-16 were obtained from
enantiomerically pure (R)- and (S)-1-tert-butoxycarbonyl (Boc)-amino-3-azidopropylphosphonates and
N-propargylated nucleobases in good yields. All 1,2,3-triazolylphosphonates (R)- and (S)-16 were evaluated
for their activities against a broad range of DNA and RNA viruses. Compound (R)-16g (B ¼ 3-acetylindole)
was moderately active against vesicular stomatitis virus in HeLa cell cultures (EC50 ¼ 45 mM). In addition,
(S)-16c (B ¼ adenine), (R)-16f (B ¼ N3-Bz-benzuracil), (R)-16g (B ¼ 3-acetylindole), and (R)-16h (B ¼ 5,6-
dimethylbenzimidazole) were cytotoxic toward Crandell-Rees feline kidney (CRFK) cells (CC50 ¼ 2.9, 45,
72, and 96 mM, respectively). Compounds (R)-16g, (S)-16g, and (S)-16h were slightly cytostatic to different
tumor cell lines.
Keywords: Antiproliferative agents / Antiviral activity / Cycloaddition / Cytotoxic activity / Triazoles
Received: December 19, 2013; Revised: February 21, 2014; Accepted: February 21, 2014
DOI 10.1002/ardp.201300471
Introduction
low selectivity, drug resistance, and long-term toxicity of
approved drugs still impose serious limitations on their
application [9].
Acyclic analogs of nucleosides and nucleotides are the most
important and widely explored groups of potential antiviral
compounds [1, 2].
Over decades, several antiviral agents have been discovered
and some of them found application in clinical practice.
Among them, nucleoside analogs such as acyclovir, ganciclo-
vir, and penciclovir as well as phosphonylated nucleosides
such as adefovir, tenofovir, and cidofovir belong to the
clinically approved drugs with a broad spectrum and high
level of antiviral potency (Fig. 1) [3–8].
In case of treatment of viral infections, the primary
advantage of acyclic nucleoside and nucleotide analogs relies
on their stability to enzymatic degradation because of absence
of a glycosidic bond as well as on conformational flexibility of
the acyclic side-chain, which facilitates binding to enzymes
involved in the synthesis of nucleic acids, including inhibition
of reverse transcriptase and DNA polymerases. Problems of
In search of novel analogs with improved pharmacological
properties, various modified nucleosides have been obtained.
It has been well recognized that the physiological properties
of nucleosides/nucleotides may change dramatically if
additional heteroatoms or selected functional groups are
incorporated into the structure of the known compounds.
Thus, acyclic nucleosides in which a nitrogen atom was
included into an alkyl chain or placed as an additional amino
group were synthesized and some of them showed antiviral
and anticancer activity as well as anti-parasitic properties
(Fig. 2) [10–17].
AHPBU 1 exhibits inhibitory activity against uridine
phosphorylases isolated from Sarcoma 180 neoplastic cells
while showing low cytotoxicity [10]. Its close structural analog
2 was evaluated as an inhibitor in the treatment of parasite
infections [11]. Both adenine 3 and 4 [12] as well as guanine 5
and 6 [13] nucleoside analogs did not show any pronounced
activity against HSV-1 and HSV-2. On the other hand,
formamide derivative 7 appeared to be active toward both
HSV-1 and HSV-2 in MRC-5 cells [14]. Among various nitrogen-
containing nucleotides 8–10 obtained by Zhou, only analog 10
(B ¼ Gua) showed slight inhibitory activity against HSV-1,
Correspondence: Dr. Iwona E. Głowacka, Bioorganic Chemistry
Laboratory, Faculty of Pharmacy, Medical University of Łódz, Muszyn-
skiego 1, 90-151 Łódz, Poland.
E-mail: iwona.glowacka@umed.lodz.pl
Fax: þ48 42 6788398
ꢀ
ꢀ
ꢀ
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I. E. Głowacka et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
O
O
N
O
N
N
N
N
N
N
NH
NH
NH2
NH
NH2
N
HO
HO
HO
N
NH2
O
O
OH
Ganciclovir
OH
Penciclovir
Acyclovir
NH2
N
NH2
N
NH2
N
N
N
N
N
N
N
O
N
(HO)2(O)P
O
(HO)2(O)P
O
(HO)2(O)P
O
OH
Adefovir
Tenofovir
Cidofovir
Figure 1. Examples of clinically applied acyclic nucleoside/nucleotide analogs.
HSV-2, and CMV [15]. Aza-nucleotide 11 with nitrogen
incorporated into the phosphonoalkyl residue [16] and its
N-branched derivative 12 [17] appeared to be selective
inhibitors of phosphoribosyltransferase PfHGXPRT, a key
enzyme for the growth of Plasmodium falciparum, and at the
same time did not show detectable inhibitory activity against
human HGPRT. Moreover, it was shown that the protection
of the amino functionalities in 13 with bulky groups such as
O
N
O
N
NH2
O
N
O
Bn
N
N
N
N
N
NH
NH
N
HN
H2N
HO
HN
O
O
N
N
O
H2N
N
HO
HO
R
HOOC
O
X
NH2
NH2
NH2
NH2
X=O
NHC(O)H
1
R=OH
NH2
3
4
5
7
2
CH2
6
B
B
B
H
N
(HO)2(O)P
(HO)2(O)P
O
(HO)2(O)P
N
H
NH2
OH
OH
9
10
8
B = Ade, Gua, Cyt, Ura
O
B
N
N
NH
H
N
N
O
H
O
N
H
N
N
N
(HO)2(O)P
(HO)2(O)P
R'
NH
H
R
N
11
12
13
COOMe
B = uracil, thymine, 5-fluorouracil
R = alkyl
R' = H, Boc, Bz
Figure 2. Examples of nitrogen-containing nucleoside/nucleotide analogs.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
1-Amino-3-(1H-1,2,3-triazol-1-yl)propylphosphonates
3
tert-butoxycarbonyl (Boc) or benzoyl (Bz) leads to the
enhancement of antiviral activities of the protected
compounds [18].
Recently, we succeeded in the synthesis of several series of
acyclic nucleotide analogs equipped with a 1,2,3-triazolyl
linker between nucleobases and diethoxyphosphonoalkyl
units [19]. Among them, nucleotide analog 14 with a
trimethylene chain appeared to be active against both herpes
simplex viruses (HSV-1 and HSV-2) and feline herpes virus
(FHV) [19]. Moreover, several other compounds, namely 15a–f,
have been found to inhibit proliferation of CEM as well as
HeLa cells (Fig. 3) [19, 20].
In continuation of our ongoing program directed toward
synthesis of biologically active acyclic 1,2,3-triazolyl nucleo-
tides, a new series of 1-amino-(1,2,3-triazol-1-yl)propylphos-
phonates (R)- and (S)-16a–h were designed (Scheme 1) and their
antiviral and cytostatic properties were evaluated. N-Boc-
protection of the amino groups was deliberately left to be in
line with previous observations made by Lee and Kim [18].
Although biological activity of phosphonate nucleoside
O
O
O
N
N
Ph
Ac
Ac
Ac
N
N
N
N
N
N
N
(EtO)2(O)P
N
(EtO)2(O)P
15a
N
N
(EtO)2(O)P
N
N
N
N
N
(EtO)2(O)P
14
15c
15b
IC50 = 4.54 1.28 µM (CEM)
IC50 = 19 13 µM (HeLa)
IC50 = 11.4 2.2 µM (CEM)
IC50 = 18 3.5 µM (HeLa)
IC50 = 2.78 1.4 µM (CEM)
IC50 = 11 7.8 µM (HeLa)
EC50 = 17 µM (HSV-1, HSV-2)
EC50 = 24 µM (FHV)
Ac
Ac
Ac
N
N
N
OH
N
N
N
N
N
N
N
N
N
(EtO)2(O)P
(EtO)2(O)P
O
(EtO)2(O)P
15d
15f
15e
IC50 = 12 3.5 µM (CEM)
IC50 = 64 13 µM (CEM)
IC50 = 148 7 µM (HeLa)
IC50 = 21 0.14 µM (CEM)
Figure 3. Biologically active acyclic 1,2,3-triazolyl analogs of nucleotides, recently obtained in our group.
B
B
N
+
(EtO)2(O)P
N
(EtO)2(O)P
N3
N
NHBoc
NHBoc
(R)-16a−h
(S)-16a−h
(R)-17
(S)-17
18a−h
O
O
NHAc
N
O
NH2
O
Ac
H3C
CH3
CH3
N
N
N
N
NH
NH
NBz
N
NBz
B =
N
O
N
O
N
O
N
O
N
N
N
O
d
a
c
f
g
h
b
e
Scheme 1. Retrosynthesis of the designed 1,2,3-triazolyl analogs of nucleotides (R)- and (S)-16.
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I. E. Głowacka et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
analogs is usually discussed for the free acids, in order to
improve their bioavailability, they are administered as
prodrugs as diesters or diamides [4, 5, 7, 8, 21, 22]. For these
reasons and encouraged by our recent observations [19, 23, 24]
in current studies, diethyl esters 16 are subjected to biological
evaluation to improve low membrane permeability of diacids
[P(O)(OH)2].
Antiviral activity and cytostatic/cytotoxic evaluation
All enantiomerically pure (1,2,3-triazolyl)acyclonucleotide
analogs (R)- and (S)-16a–16h were evaluated for their antiviral
activities against a wide variety of DNA and RNA viruses, using
the following cell-based assays: (a) human embryonic lung
(HEL) cell cultures: herpes simplex virus-1 (KOS), herpes
simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus,
and herpes simplex virus-1 (TKꢀ KOS ACVr); (b) HeLa cell
cultures: vesicular stomatitis virus, Coxsackie virus B4, and
respiratory syncytial virus; (c) Vero cell cultures: para-
influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus
B4, and Punta Toro virus; (d) Crandell-Rees feline kidney
(CRFK) cell cultures: feline corona virus (FIPV), and FHV; (e)
Madin Darby canine kidney (MDCK) cell cultures: influenza A
virus H1N1 subtype (A/PR/8), influenza A virus H3N2 subtype
(A/HK/7/87) and influenza B virus (B/HK/5/72), and (f) CEM cell
cultures: human immunodeficiency virus [HIV-1 and HIV-2].
Ganciclovir, cidofovir, acyclovir, brivudin, (S)-9-(2,3-dihydroxy-
propyl)adenine [(S)-DHPA], Hippeastrum hybrid agglutinin
(HHA), Urtica dioica agglutinin (UDA), dextran sulfate (molecu-
lar weight 5000, DS-5000), ribavirin, oseltamivir carboxylate,
amantadine, and rimantadine were used as the reference
Results and discussion
Chemistry
Enantiomerically pure diethyl 1-(Boc-amino)-3-azidopropyl-
phosphonates (R)- and (S)-17 were obtained in good overall
yields from the N-Boc-protected 1-amino-3-hydroxyphospho-
nates (R)-19 [25] and (S)-19 [25, 26] by tosylation followed by
a nucleophilic substitution with sodium azide in dimethyl-
formamide (DMF) (Scheme 2) [27].
All propargylated nucleobases 18a–d (N1-propargyluracil
18a, N1-propargylthymine 18b, N9-propargyladenine 18c,
N4-acetyl-N1-propargylcytosine 18d), and propargylated
nucleobase analogs 18e–18h (N3-benzoyl-N1-propargyluracil
18e, N3-benzoyl-N1-propargylbenzuracil 18f, 3-acetyl-N-
propargylindole 18g, and 5,6-dimethyl-N1-propargyl-
benzimidazole 18h) have already been described in the
literature and were prepared according to the known
procedures [19, 28–31].
1,3-Dipolar cycloadditions of azides (R)- and (S)-17 with N-
propargyl nucleobases 18a–18d and propargylated nucleo-
base analogs 18e–18h were carried out in a microwave oven
leading to the formation of 1,2,3-triazole derivatives (R)- and
(S)-16a–h, respectively. The crude reaction mixtures were
subjected to column chromatography, and in all cases, good
to excellent overall yields of final products were obtained
(Scheme 2). Structure and purity of all (1,2,3-triazolyl)-
acyclonucleotides (R)- and (S)-16a–h were established by 1H,
13C, and 31P NMR and IR techniques as well as by elemental
analysis.
compounds. The antiviral activity was expressed as the EC50
:
the compound concentration required to reduce virus-
induced cytopathogenicity by 50% (other viruses).
The cytotoxicity of the tested compounds toward the
uninfected host cells was defined as the minimum cytotoxic
concentration (MCC) that causes a microscopically detectable
alteration of normal cell morphology. The 50% cytotoxic
concentration (CC50), causing a 50% decrease in cell viability
was determined using a colorimetric 3-(4,5-dimethylthiazol-2-
yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
(MTS) assay system.
All synthesized compounds were tested against a broad
variety of viruses but only analog (R)-16g (B ¼ 3-acetylindole)
showed moderate activity against vesicular stomatitis virus in
HeLa cell cultures (EC50 ¼ 45 mM). When compared with our
B
N
(EtO)2(O)P
OH
(EtO)2(O)P
OTs
(EtO)2(O)P
N3
(EtO)2(O)P
N
a
b
c
N
NHBoc
NHBoc
NHBoc
NHBoc
(R)-19
(S)-19
(R)-20
(S)-20
(R)-17
(S)-17
(R)-16a−h
(S)-16a−h
B = a. uracil; b. thymine; c. adenine; d. N4-acetylcytosine;
e. N3-benzoyluracil; f. N3-benzoylbenzuracil;
g. 3-acetyloindole; h. 5,6-dimethylbenzimidazole
Scheme 2. Reactions and conditions: (a) TsCl, NEt3, CH2Cl2; (b) NaN3, DMF; and (c) N-propargylated nucleobases 18a–18d and
propargylated nucleobase analogs 18e–18h, CuSO4 · 5H2O (0.05 equiv.), sodium ascorbate (0.1 equiv.), H2O–EtOH (1:1), MW, 40–45°C,
15 min.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
1-Amino-3-(1H-1,2,3-triazol-1-yl)propylphosphonates
5
entire collection of phosphonate nucleoside analogs having 3-
acetylindole as a nucleobase mimetic, compound (R)-16g is the
very first antiviral hit. Since its enantiomer (S)-16g was not
active one may conclude that the spatial orientations of the N-
Boc-amino and diethoxyphosphoryl groups are discriminative
to exert antiviral response (Table 1).
On the other hand, although none of the phosphonate
analogs 16 was active against feline corona and feline herpes
viruses, several compounds from the (R)-16 series, namely (R)-
16f (B ¼ N3-Bz-benzuracil), (R)-16g (B ¼ 3-acetylindole), and (R)-
16h (B ¼ 5,6-dimethylbenzimidazole) appeared slightly cyto-
toxic to CRFK cells (CC50 ¼ 45, 72, and 96 mM, respectively),
while compound (S)-16c (B ¼ adenine) exhibited significant
cytotoxicity (CC50 ¼ 2.9 mM) to these cell cultures (Table 2).
The cytostatic activity of the tested compounds was defined
as the 50% cytostatic inhibitory concentration (IC50), causing a
50% decrease in cell proliferation and was determined against
murine leukemia L1210, human lymphocyte CEM and human
cervix carcinoma HeLa cells.
Table 2. Cytotoxicity and antiviral activity of enantiomerically pure
(R)- and (S)-1-Boc-amino-3-(1H-1,2,3-triazol-1-yl)propylphospho-
nates 16 in CRFK cell cultures.
EC50 (mM)
Feline
corona
virus
Feline
herpes
virus
Base
(B)
CC50
(mM)
Compound
(R)-16c
(S)-16c
>100
>100
>0.8
>100
>0.8
2.9
(R)-16f
(S)-16f
45.5
100
>20
>100
>20
>100
(R)-16g
(S)-16g
71.6
>100
>20
>100
>20
>100
(R)-16h
(S)-16h
96.3
>100
>20
>100
>20
>100
Compound (R)-16g and (B ¼ 3-acetylindole) appeared slight-
ly cytostatic against murine leukemia L1210, human CEM
and HeLa cells at an IC50 of 172 ꢁ 6, 193 ꢁ 81, and 122 ꢁ 3 mM,
respectively, whereas its enantiomer (S)-16g affected human
CEM cell proliferation only at an IC50 of 172 ꢁ 26 (Table 3).
However, phosphonate nucleoside analogs having 3-acetylin-
dole as a nucleobase mimetic 21a–21g (Fig. 4) [19] appeared
cytostatic against human CEM line at IC50 of 2.78 ꢁ 1.4 to
100 ꢁ 2.8 mM for the entire series depending on the length
(CH2, CH2CH2, CH2CH2CH2, and CH2CH2CH2CH2) and substi-
tution [CH(OH)CH2, CH(OH)CH2CH2, and CH2CH(OH)CH2] of
the linker between the phosphorus atom and an 1,2,3-triazole
ring [19]. The same series of phosphonate analogs was found
at least an order of magnitude less active against HeLa cells,
and the most active were phosphonates with CH2, CH2CH2
and CH2CH2CH2 linkers (IC50 of 11.76 ꢁ 7.6, 18 ꢁ 3.5, and
19 ꢁ 13 mM, respectively) [19]. Cytostatic activity of the
UDH (mg/mL)
Ganciclovir
>100
>100
0.8
>100
0.4
4.0
Table 3. Inhibitory effect of enantiomerically pure (R)- and
(S)-1-Boc-amino-3-(1H-1,2,3-triazol-1-yl)propylphosphonates 16
against the proliferation of murine leukemia (L1210), human
T-lymphocyte (CEM), and human cervix cells (HeLa).
IC50 (mM)
Base
(B)
Compound
L1210
CEM
HeLa
(R)-16g
(S)-16g
172 ꢁ 6
>250
193 ꢁ 81
172 ꢁ 26
122 ꢁ 3
ꢂ250
(R)-16h
(S)-16h
>250
>250
>250
>250
>250
189 ꢁ 34
Table 1. Cytotoxicity and antiviral activity of enantiomerically pure
(R)- and (S)-1-Boc-amino-3-(1H-1,2,3-triazol-1-yl)propylphospho-
nates 16 in HeLa cell cultures.
5-Fluorouracil
0.33 ꢁ 0.17
18 ꢁ 5
0.54 ꢁ 0.12
EC50 (mM)
Vescicular
Respiratory
phosphonates 21a–g against murine leukemia L1210 cells
was even lower [19] and in general comparable with that of
(R)-16g.
Base MCC stomatitis Coxsackie syncytial
Compound
(B)
(mM)
>100
virus
virus B4
virus
(R)-16g
45
>100
>100
Conclusions
(S)-16g
(S)-DHPA
Ribavirin
>100
>250
>250
>100
126
7
>100
>250
112
>100
>250
6
Enantiomerically pure 1-Boc-amino-3-azidopropylphospho-
nates (R)- and (S)-17 were obtained from the N-Boc-protected
1-aminohydroxyphosphonates (R)- and (S)-19 and applied to
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I. E. Głowacka et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
literature. Microwave irradiation experiments were carried out in
50 mL glass vials in a microwave reactor Plazmatronika RM 800.
Ac
Starting materials
N
Diethyl 1-Boc-amino-3-hydroxypropylphosphonates (R)- and (S)-19
were prepared as previously reported [25]. All propargylated
nucleobases 18a–18d and propargylated nucleobase analogs 18e–
18h were obtained according to the procedures described in the
literature [19, 28–31].
(EtO)2(O)P
X
N
N
N
21a−g
a. X = CH2
b. X = (CH2)2
Preparation of tosylates (R)- and (S)-20
c. X = (CH2)3
To a solution of N-Boc-aminohydroxypropylphosphonates (R)- or
(S)-19 (1.00 mmol) in methylene chloride (3 mL), triethylamine
(2.00 mmol) was added followed by tosyl chloride (2.00 mmol).
The reaction mixture was stirred at room temperature for 16 h;
the solution was washed with water (2 ꢃ 2 mL), dried (MgSO4),
d. X = (CH2)4
e. X = CH(OH)CH2
f. X = CH2CH(OH)CH2
g. X = CH(OH)CH2CH2
filtered, and concentrated in vacuo.
A crude product was
Figure 4. Acyclic phosphonate nucleoside analogs having 3-acetyl-
indole as a nucleobase mimetic 21a–21g [19].
chromatographed on a silica gel column (chloroform–methanol,
200:1, v/v) to give pure tosylates (R)- or (S)-20.
tert-Butyl (R)-1-(O,O-diethylphosphono)-3-(p-toluene-
cycloaddition with N-propargylated nucleobases 18a–18d and
N-propargylated nucleobase analogs 18e–18h to provide a
series of 1-amino-3-(1H-1,2,3-triazol-1-yl)propylphosphonates
(R)- and (S)-16a–h as acyclic analogs of nucleotides.
sulfonyloxy)propylcarbamate (R)-20
20
Yield: 86%; colorless oil; ½aꢄD ¼ ꢀ25.4 (c 1.33, CHCl3). IR (film):
n ¼ 3288, 3028, 2992, 2969, 1683, 1230, 1026, 779, 696 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d ¼ 7.80 (d, J ¼ 8.1 Hz, 1H), 7.33
(d, J ¼ 8.1 Hz, 1H), 4.70 (brd, J ¼ 9.3 Hz, 1H, NH), 4.17–4.04 (m,
7H, 2 ꢃ POCH2CH3, PCH, PCCCH2), 2.44 (s, 3H, CH3), 2.39–2.18 (m,
1H, PCCHaHb), 1.99–1.76 (m, 1H, PCCHaHb), 1.45 (s, 9H, 3 ꢃ CH3),
1.31 (t, J ¼ 7.0 Hz, 6H, 2 ꢃ POCH2CH3); 13C NMR (75.5 MHz, CDCl3):
d ¼ 155.0 (d, J ¼ 5.4 Hz, C–O), 144.7, 132.8, 129.8, 127.9, 80.1, 66.7
(d, J ¼ 14.9 Hz, PCCC), 62.9 (d, J ¼ 7.1 Hz, POC), 62.7 (d, J ¼ 7.1 Hz,
POC), 43.9 (d, J ¼ 158.3 Hz, PC), 29.7 (d, J ¼ 4.3 Hz, PCC), 28.3, 21.7,
16.6 (d, J ¼ 6.0 Hz, POCC), 16.4 (d, J ¼ 6.0 Hz, POCC); 31P NMR
(121.5 MHz, CDCl3): d ¼ 24.11 ppm. Anal. calcd. for C19H32NO8PS:
C, 49.02; H, 6.93; N, 3.01. Found: C, 49.06; H, 6.96; N, 3.17.
All synthesized 1,2,3-triazolylphosphonates (R)- and (S)-16a–h
were evaluated for activity against a variety of DNA and RNA
viruses, and compound (R)-16g (B ¼ 3-acetylindole) was found
moderately active against vesicular stomatitis virus in HeLa cell
cultures (EC50 ¼ 45mM). Moreover, compounds (S)-16c (B ¼
adenine), (R)-16f (B ¼ N3-Bz-benzuracil), (R)-16g (B ¼ 3-acetylin-
dole), and (R)-16h (B ¼ 5,6-dimethylbenzimidazole) appeared
cytotoxic to CRFK cell cultures (CC50 ¼ 2.9, 45, 72, and 96mM,
respectively). Furthermore, (R)-16g exhibited slight inhibitory
activity on proliferation of L1210, CEM, and HeLa cells, whereas
(S)-16g and (S)-16h were cytostatic to CEM cell cultures only.
tert-Butyl (S)-1-(O,O-diethylphosphono)-3-(p-toluene-
sulfonyloxy)propylcarbamate (S)-20
20
Yield: 90%; colorless oil; ½aꢄD ¼ þ24.9 (c 1.11, CHCl3). Anal. calcd.
for C19H32NO8PS: C, 49.02; H, 6.93; N, 3.01. Found: C, 49.27;
H, 6.85; N, 3.24.
Experimental
Chemistry
Preparation of azides (R)- and (S)-17
1H NMR were taken in CDCl3 or CD3OD on the following
spectrometers: Varian Mercury-300 and Bruker Avance III
(600 MHz) with TMS as an internal standard, chemical shifts d in
ppm with respect to TMS, coupling constants J in Hz. 13C NMR
spectra were recorded for CDCl3, CD3OD, or DMSO-d6 solutions on a
Varian Mercury-300 and Bruker Avance III (600 MHz) spectrometer at
75.5 and 151 MHz, respectively. 31P NMR spectra were taken in CDCl3
or CD3OD on Varian Mercury-300 at 121.5 MHz. IR spectral data were
measured on an Infinity MI-60 FT-IR spectrometer. Melting points
were determined on a Boetius apparatus and are uncorrected.
Elemental analyses were performed by the Microanalytical Labora-
tory of this Faculty on a Perkin Elmer PE 2400 CHNS analyzer. The
following adsorbents were used: column chromatography, Merck
silica gel 60 (70–230 mesh); analytical TLC, Merck TLC plastic sheets
silica gel 60 F254. TLC plates were developed in chloroform–methanol
solvent systems. Visualization of spots was effected with iodine
vapors. All solvents were purified by methods described in the
To a solution of tosylate (R)- or (S)-20 (1.00 mmol) in DMF (4 mL) NaN3
(2.00mmol) was added and the suspension was stirred at room
temperature for 24h. A crude reaction mixture was co-evaporated
in vacuo with toluene (3 ꢃ 5mL) and the residue was dissolved in
methylene chloride (5mL), washed with water (2ꢃ 2 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The products (R)- or
(S)-17 were used in the next step without further purification.
tert-Butyl (R)-3-azido-1-(O,O-diethylphosphono)-
propylcarbamate (R)-17
20
Yield: 94%; colorless oil; ½aꢄD ¼ ꢀ23.4 (c 0.87, CHCl3). IR (film):
n ¼ 3301, 2994, 2984, 2899, 2190, 1678, 1225, 1024 cmꢀ1; 1H NMR
(300 MHz, CDCl3): d ¼ 4.75 (brd, J ¼ 9.9 Hz, 1H, NH), 4.20–4.10 (m,
4H, 2 ꢃ POCH2CH3), 3.48–3.37 (m, 3H, PCH and PCCCH2), 2.36–2.18
(m, 1H, PCCHaHb), 1.81–1.78 (m, 1H, PCCHaHb), 1.45 (s, 9H, 3 ꢃ CH3),
1.31 (t, J¼ 6.9 Hz, 6H, 2 ꢃ POCH2CH3); 13C NMR (75.5 MHz, CDCl3):
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
1-Amino-3-(1H-1,2,3-triazol-1-yl)propylphosphonates
7
–
d ¼ 155.2 (d, J ¼ 5.7Hz, C O), 80.1, 62.9 (d, J ¼ 7.1Hz, POC), 62.5 (d,
1025 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d ¼ 9.09 (s, 1H, NH), 7.82
–
0
–
–
J ¼ 7.1Hz, POC), 48.1 (d, J¼ 14.3 Hz, PCCC), 44.6 (d, J ¼ 157.7Hz, PC),
29.6 (d, J ¼ 4.3 Hz, PCC), 28.3, 16.5 (d, J ¼ 6.3Hz, POCC), 16.4 (d,
J ¼ 6.3Hz, POCC); 31P NMR (121.5MHz, CDCl3): d ¼ 25.20ppm. Anal.
calcd. for C12H25N4O5P: C, 42.85; H, 7.49; N, 16.66. Found: C, 42.72;
H, 7.35; N, 16.42.
(s, 1H, HC5 ), 7.35 (d, J ¼ 1.2 Hz, 1H, HC CCH ), 5.11 (dd,
3
J ¼ 10.3 Hz, J ¼ 3.0 Hz, 1H, NH), 5.00 (AB, JAB ¼ 15.1 Hz, 1H, CHaHb),
4.94 (AB, JAB ¼ 15.1 Hz, 1H, CHaHb), 4.53–4.42 (m, 2H, PCCCHaHb),
4.19–3.93 (m, 5H, 2 ꢃ POCH2CH3, PCH), 2.60–2.38 (m, 1H,
PCCHaHb), 2.28–2.04 (m, 1H, PCCHaHb), 1.91 (d, J ¼ 1.2 Hz, 3H,
–
HC CCH ), 1.45 (s, 9H, 3 ꢃ CH ), 1.32 (t, J ¼ 6.9 Hz, 6H, 2 ꢃ
–
3
3
13
–
–
POCH2CH3); C NMR (151 MHz, CDCl ): d ¼ 165.3 (s, C O); 156.1
3
tert-Butyl (S)-3-azido-1-(O,O-diethylphosphono)-
–
–
(d, J ¼ 4.1 Hz, C O), 151.3, 142.5, 141.2, 124.2, 110.2, 79.6, 63.0 (d,
propylcarbamate (S)-17
J ¼ 7.4 Hz, POC), 62.8 (d, J ¼ 7.4 Hz, POC), 46.5 (d, J ¼ 15.5 Hz,
PCCC), 44.3 (d, J ¼ 160.6 Hz, PC), 42.3, 29.4 (d, J ¼ 4.5 Hz, PCC), 27.3,
15.4 (d, J ¼ 5.3 Hz, POCC), 15.3 (d, J ¼ 5.3 Hz, POCC), 12.2; 31P NMR
(121.5 MHz, CDCl3): d ¼ 24.47 ppm. Anal. calcd. for C20H33N6O7P ·
H2O: C, 46.33; H, 6.80; N, 16.21. Found: C, 46.09; H, 6.92; N, 16.40.
20
Yield: 98%; colorless oil; ½aꢄD ¼ þ21.2 (c 0.82, CHCl3). Anal. calcd.
for C12H25N4O5P: C, 42.85; H, 7.49; N, 16.66. Found: C, 42.69;
H, 7.56; N, 16.58.
General procedure for the preparation of 1,2,3-triazoles
(R)- and (S)-16a–h
tert-Butyl (S)-1-(O,O-diethylphosphono)-3-{4-[(3,4-
dihydro-5-methyl-2,4-dioxopyrimidin-1-yl)methyl]-1H-
1,2,3-triazol-1-yl}propylcarbamate (S)-16b
To a solution of azidoalkylphosphonates (R)- or (S)-17 (1.00 mmol)
in EtOH (1 mL) and H2O (1 mL) CuSO4 · 5H2O (0.05 mmol), sodium
ascorbate (0.10 mmol), and alkynes (1.00 mmol) were added. The
reaction mixture was irradiated in a microwave reactor at 40–
45°C for 15 min. The solvent was removed by vacuum evapora-
tion and the residue was suspended in chloroform (5 mL) and
filtered through a layer of celite. The solution was concentrated
in vacuo and the crude product was purified on a silica gel column
with chloroform–methanol mixtures (50:1, 20:1, or 10:1 v/v) to
give the respective 1,2,3-triazoles (R)- or (S)-16.
20
Yield: 72%; white powder, m.p. 78–80°C; ½aꢄD ¼ þ13.8 (c 0.98,
CHCl3). Anal. calcd. for C20H33N6O7P · H2O: C, 46.33; H, 6.80;
N, 16.21. Found: C, 46.13; H, 7.10; N, 16.35.
tert-Butyl (R)-1-(O,O-diethylphosphono)-3-{4-[(6-amino-
9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}-
propylcarbamate (R)-16c
20
Yield: 99%; colorless oil; ½aꢄD ¼ ꢀ13.8 (c 1.28, CHCl3). IR (film):
n ¼ 3329, 3210, 2982, 1704, 1644, 1601, 1242, 1165, 1027 cmꢀ1
;
tert-Butyl (R)-1-(O,O-diethylphosphono)-3-{4-[(3,4-
dihydro-2,4-dioxopyrimidin-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}propylcarbamate (R)-16a
1H NMR (300 MHz, CDCl3): d ¼ 8.37 (s, 1H), 8.00 (s, 1H), 7.79 (s, 1H),
5.82 (brs, 2H), 5.52 (AB, JAB ¼ 15.5 Hz, 1H, CHaHb), 5.49 (AB,
JAB ¼ 15.5 Hz, 1H, CHaHb), 5.20 (dd, J ¼ 10.5 Hz, J ¼ 3.2 Hz, 1H, NH),
4.57–4.47 (m, 1H, PCCCHaHb), 4.38–4.17 (m, 1H, PCCCHaHb), 4.09–
3.93 (m, 5H, 2 ꢃ POCH2CH3, PCH), 2.49–2.39 (m, 1H, PCCHaHb),
2.20–2.04 (m, 1H, PCCHaHb), 1.44 (s, 9H, 3 ꢃ CH3), 1.31
20
Yield: 88%; amorphous solid, m.p. 76–79°C; ½aꢄD ¼ –12.1 (c 1.13,
CHCl3). IR (KBr): n ¼ 3223, 3143, 3038, 2933, 2812, 1694, 1235,
1028 cmꢀ1; 1H NMR (300 MHz, CDCl3): d ¼ 9.12 (brs, 1H, NH), 7.83
0
–
–
(s, 1H, HC5 ), 7.52 (d, J ¼ 8.0 Hz, 1H, HC CH), 5.71 (d, J ¼ 8.0 Hz, 1H,
(t, J ¼ 6.9 Hz, 3H, POCH2CH3), 1.28 (t, J ¼ 6.9 Hz, 3H, POCH2CH3);
–
HC CH), 5.14 (dd, J ¼ 9.8 Hz, J ¼ 2.6 Hz, 1H, NH), 5.00 (AB,
–
13
–
C NMR (151 MHz, CDCl ): d ¼ 155.6 (d, J ¼ 5.5 Hz, C O), 153.0,
–
3
JAB ¼ 15.1 Hz, 1H, CHaHb), 4.98 (AB, JAB ¼ 15.1 Hz, 1H, CHaHb), 4.53–
4.45 (m, 2H, PCCCHaHb), 4.17–3.98 (m, 5H, 2 ꢃ POCH2CH3, PCH),
2.58–2.47 (m, 1H, PCCHaHb), 2.30–2.06 (m, 1H, PCCHaHb), 1.46
(s, 9H, 3 ꢃ CH3), 1.32 (t, J ¼ 6.9Hz, 6H, 2 ꢃ POCH2CH3); 13C NMR
149.6, 142.2, 140.4, 123.7, 119.3, 80.5, 63.2 (d, J ¼ 6.8 Hz, POC),
62.8 (d, J ¼ 6.8 Hz, POC), 47.0 (d, J ¼ 15.1 Hz, PCCC), 44.6
(d, J ¼ 158.8 Hz, PC), 38.6, 30.9 (d, J ¼ 4.2 Hz, PCC), 28.2, 16.4
(d, J ¼ 5.4 Hz, POCC), 16.3 (d, J ¼ 5.4 Hz, POCC); 31P NMR
(121.5 MHz, CDCl3): d ¼ 23.76 ppm. Anal. calcd. for C20H32N9O5P:
C, 47.15; H, 6.33; N, 24.74. Found: C, 46.88; H, 6.14; N, 24.86.
–
–
–
–
(151 MHz, CDCl ): d ¼ 165.1 (s, C O); 156.1 (d, J ¼ 4.1 Hz, C O),
3
151.2, 145.4, 142.3, 124.3, 101.4, 79.6, 63.1 (d, J ¼ 7.2 Hz, POC),
62.9 (d, J ¼ 7.2 Hz, POC), 46.6 (d, J ¼ 15.6 Hz, PCCC), 44.3
(d, J ¼ 160.5 Hz, PC), 42.6, 29.5 (d, J ¼ 4.8Hz, PCC), 27.4, 15.4
(d, J ¼ 5.4 Hz, POCC), 15.3 (d, J ¼ 5.4 Hz, POCC); 31P NMR (121.5 MHz,
CDCl3): d ¼ 24.49 ppm. Anal. calcd. for C19H31N6O7P: C, 46.91;
H, 6.42; N, 17.28. Found: C, 47.06; H, 6.64; N, 17.40.
tert-Butyl (S)-1-(O,O-diethylphosphono)-3-{4-[(6-amino-
9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}-
propylcarbamate (S)-16c
20
Yield: 81%; colorless oil; ½aꢄD ¼ þ13.1 (c 0.94, CHCl3). Anal. calcd.
tert-Butyl (S)-1-(O,O-diethylphosphono)-3-{4-[(3,4-
dihydro-2,4-dioxopyrimidin-1-yl)methyl]-1H-1,2,3-triazol-1-
yl}propylcarbamate (S)-16a
for C20H32N9O5P: C, 47.15; H, 6.33; N, 24.74. Found: C, 47.42;
H, 6.47; N, 24.96.
20
Yield: 80%; amorphous solid, m.p. 79–81°C; ½aꢄD ¼ þ11.9 (c 1.72,
tert-Butyl (R)-1-(O,O-diethylphosphono)-3-{4-[(4-
acetylamino-2-oxopyrimidin-1-yl)methyl]-1H-1,2,3-triazol-
1-yl}propylcarbamate (R)-16d
CHCl3). Anal. calcd. for C19H31N6O7P: C, 46.91; H, 6.42; N, 17.28.
Found: C, 46.80; H, 6.52; N, 17.24.
20
Yield: 72%; white powder, m.p. 197–199°C; ½aꢄD ¼ ꢀ40.9 (c 1.55,
tert-Butyl (R)-1-(O,O-diethylphosphono)-3-{4-[(3,4-
dihydro-5-methyl-2,4-dioxopyrimidin-1-yl)methyl]-1H-
1,2,3-triazol-1-yl}propylcarbamate (R)-16b
CHCl3). IR (KBr): n ¼ 3221, 3046, 2982, 2932, 1676, 1623, 1224,
1048 cmꢀ1; 1H NMR (300 MHz, CDCl3): d ¼ 10.05 (brs, 1H, NH), 7.96
0
–
(d, J ¼ 7.4 Hz, 1H, HC CH), 7.93 (s, 1H, HC5 ), 7.42 (d, J ¼ 7.4 Hz, 1H,
–
20
–
–
Yield: 73%; white powder, m.p. 86–89°C; ½aꢄD ¼ ꢀ14.3 (c 1.13,
HC CH), 5.94 (brd, J ¼ 10.1 Hz, 1H, NH), 5.10 (AB, J ¼ 14.4 Hz, 1H,
AB
CHCl3). IR (KBr): n ¼ 3287, 2982, 2932, 2820, 1696, 1122,
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
CHaHb), 5.08 (AB, JAB ¼ 14.4 Hz, 1H, CHaHb), 4.54–4.40 (m, 2H,
www.archpharm.com

8
I. E. Głowacka et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
PCCCHaHb), 4.17–3.85 (m, 5H, 2 ꢃ POCH2CH3, PCH), 2.46–2.40 (m,
1H, PCCHaHb), 2.32–2.06 (m, 1H, PCCHaHb), 2.20 (s, 3H, CH3), 1.45
(s, 9H, 3 ꢃ CH3), 1.32 (t, J ¼ 6.9 Hz, 6H, 2 ꢃ POCH2CH3); 13C NMR
PCCCHaHb), 4.14–4.07 (m, 4H, 2 ꢃ POCH2CH3), 4.04–3.96 (m, 1H,
PCH), 2.47–2.40 (m, 1H, PCCHaHb), 2.16–2.08 (m, 1H, PCCHaHb),
1.41 (s, 9H, 3 ꢃ CH3), 1.29 (t, J ¼ 7.1 Hz, 3H, POCH2CH3), 1.28 (t,
J ¼ 7.1 Hz, 3H, POCH2CH3); 13C NMR (151 MHz, CDCl3): d ¼ 168.6 (s,
–
–
–
(151 MHz, CDCl ): d ¼ 171.2 (s, C O); 163.0 (s, C O); 155.8 (d,
–
3
–
–
–
–
–
J ¼ 6.0 Hz, C O), 155.7, 148.7, 145.4, 141.5, 125.1, 97.0, 79.7, 63.3
C O), 161.1 (s, C O); 155.4 (d, J ¼ 5.7 Hz, C O), 149.5, 142.3, 140.3,
–
–
–
(d, J ¼ 6.9 Hz, POC), 62.7 (d, J ¼ 6.9 Hz, POC), 47.1 (d, J ¼ 17.4 Hz,
PCCC), 44.9 (d, J ¼ 159.8 Hz, PC), 44.7, 30.8 (d, J ¼ 4.3 Hz, PCC), 28.3,
24.6, 16.3 (d, J ¼ 5.5 Hz, POCC); 31P NMR (121.5 MHz, CDCl3):
d ¼ 24.24 ppm. Anal. calcd. for C21H34N7O7P: C, 47.81; H, 6.50; N,
18.59. Found: C, 48.10; H, 6.62; N, 18.31.
136.2, 135.0, 129.2, 128.9, 124.1, 123.7, 115.6, 115.4, 80.5, 62.9 (d,
J ¼ 6.7 Hz, POC), 62.7 (d, J ¼ 6.7 Hz, POC), 47.0 (d, J ¼ 14.6 Hz,
PCCC), 44.7 (d, J ¼ 158.4 Hz, PC), 38.9, 31.1 (d, J ¼ 3.7 Hz, PCC), 28.2,
16.4 (d, J ¼ 5.5 Hz, POCC), 16.3 (d, J ¼ 5.5 Hz, POCC); 31P NMR
(243 MHz, CDCl3): d ¼ 23.31 ppm. Anal. calcd. for C30H37N6O8P ꢃ
H2O: C, 54.71; H, 5.97; N, 12.76. Found: C, 54.89; H, 6.12; N, 12.56.
tert-Butyl (S)-1-(O,O-diethylphosphono)-3-{4-[(4-
acetylamino-2-oxopyrimidin-1-yl)methyl]-1H-1,2,3-triazol-
1-yl}propylcarbamate (S)-16d
tert-Butyl (S)-1-(O,O-diethylphosphono)-3-{4-[(3,4-
dihydro-3-benzoyl-2,4-dioxoquinazolin-1-yl)methyl]-1H-
1,2,3-triazol-1-yl}propylcarbamate (S)-16f
20
Yield: 74%; white powder, m.p. 221–223°C; ½aꢄD ¼ þ40.5 (c 2.13,
20
CHCl3). Anal. calcd. for C21H34N7O7P: C, 47.81; H, 6.50; N, 18.59.
Found: C, 47.63; H, 6.40; N, 18.81.
Yield: 75%; white powder, m.p. 90–93°C; ½aꢄD ¼ þ4.5 (c 1.08,
CHCl3). Anal. calcd. for C30H37N6O8P · H2O: C, 54.71; H, 5.97;
N, 12.76. Found: C, 54.82; H, 5.73; N, 12.86.
tert-Butyl (R)-1-(O,O-diethylphosphono)-3-{4-[(3,4-
dihydro-3-benzoyl-2,4-dioxopyrimidin-1-yl)methyl]-1H-
1,2,3-triazol-1-yl}propylcarbamate (R)-16e
tert-Butyl (R)-1-(O,O-diethylphosphono)-3-{4-[(3-
acetylindol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}-
propylcarbamate (R)-16g
20
Yield: 72%; white powder, m.p. 131–133°C; ½aꢄD ¼ ꢀ14.0 (c 1.17,
20
CHCl3). IR (KBr): n ¼ 3263, 2982, 2932, 1748, 1704, 1662, 1235,
1026, 975, 754 cmꢀ1, 1H NMR (600 MHz, CDCl3): d ¼ 7.91–7.89 (m,
2H, Haromat.), 7.75 (s, 1H, HC50), 7.65–7.63 (m, 1H, Haromat.), 7.63 (d,
Yield: 81%; white powder, m.p. 160–163°C; ½aꢄD ¼ ꢀ20.8 (c 1.14,
CHCl3). IR (KBr): n ¼ 3271, 3112, 2982, 2931, 1722, 1630, 1025,
746 cmꢀ1; 1H NMR (600 MHz, CDCl3): d ¼ 8.38–8.35 (m, 1H), 7.87 (s,
1H), 7.57 (s, 1H), 7.44–7.42 (m, 1H), 7.28–7.25 (m, 2H), 5.43 (s, 2H),
5.10 (brd, J ¼ 10.5 Hz, 1H, NH), 4.52–4.48 (m, 1H, PCCCHaHb), 4.34–
4.29 (m, 1H, PCCCHaHb), 4.11–4.06 (m, 4H, 2 ꢃ POCH2CH3), 3.95–
3.86 (m, 1H, PCH), 2.49 (s, 3H, CH3), 2.47–2.37 (m, 1H, PCCHaHb),
2.14–2.04 (m, 1H, PCCHaHb), 1.43 (s, 9H, 3 ꢃ CH3), 1.28 (t,
–
J ¼ 8.1 Hz, 1H, HC CH), 7.49–7.46 (m, 2H, Haromat.), 5.79 (d,
–
–
J ¼ 8.0 Hz, 1H, HC CH), 5.16 (brd, J ¼ 9.5 Hz, 1H, NH), 5.04 (AB,
–
JAB ¼ 15.1 Hz, 1H, CHaHb), 4.97 (AB, JAB ¼ 15.1 Hz, 1H, CHaHb), 4.53–
4.48 (m, 1H, PCCCHaHb), 4.43–4.37 (m, 1H, PCCCHaHb), 4.14–4.07
(m, 4H, 2 ꢃ POCH2CH3), 4.03–3.96 (m, 1H, PCH), 2.48–2.42 (m, 1H,
PCCHaHb), 2.18–2.10 (m, 1H, PCCHaHb), 1.43 (s, 9H, 3 ꢃ CH3), 1.29
(t, J ¼ 6.9 Hz, 6H, 2 ꢃ POCH2CH3); 13C NMR (151 MHz, CDCl3):
J ¼ 7.1 Hz, 3H, POCH2CH3), 1.25 (t, J ¼ 7.1 Hz, 3H, POCH2CH3);
13
–
C NMR (151 MHz, CDCl ): d ¼ 193.3 (s, C O), 155.5 (d, J ¼ 5.0 Hz,
–
3
–
–
–
d ¼ 168.7, 162.3 (s, C O); 155.5 (d, J ¼ 5.8 Hz, C O), 149.8, 144.2,
C O), 142.7, 136.6, 134.7, 126.5, 123.5, 123.2, 122.7, 122.6, 117.6,
–
–
–
141.3, 135.1, 130.4, 129.2, 124.3, 102.4, 80.6, 63.0 (d, J ¼ 6.7 Hz,
POC), 62.8 (d, J ¼ 6.7 Hz, POC), 47.0 (d, J ¼ 14.9 Hz, PCCC), 44.6 (d,
J ¼ 157.9 Hz, PC), 43.3, 31.0 (d, J ¼ 3.7 Hz, PCC), 28.2, 16.4 (d,
J ¼ 5.5 Hz, POCC), 16.3 (d, J ¼ 5.5 Hz, POCC); 31P NMR (243 MHz,
CDCl3): d ¼ 23.32 ppm. Anal. calcd. for C26H35N6O8P: C, 52.88; H,
5.97; N, 14.23. Found: C, 52.61; H, 5.72; N, 13.98.
109.8, 80.6, 62.9 (d, J ¼ 7.0 Hz, POC), 62.7 (d, J ¼ 7.0 Hz, POC), 46.8
(d, J ¼ 14.6 Hz, PCCC), 44.4 (d, J ¼ 157.7 Hz, PC), 42.3, 31.0 (d,
J ¼ 4.3 Hz, PCC), 28.2, 27.5, 16.3 (d, J ¼ 5.7 Hz, POCC), 16.2 (d,
J ¼ 5.5 Hz, POCC); 31P NMR (243 MHz, CDCl3): d ¼ 23.24 ppm. Anal.
calcd. for C25H36N5O6P · H2O: C, 54.44; H, 6.94; N, 12.70. Found: C,
54.63; H, 6.98; N, 12.48.
tert-Butyl (S)-1-(O,O-diethylphosphono)-3-{4-[(3,4-
dihydro-3-benzoyl-2,4-dioxopyrimidin-1-yl)methyl]-1H-
1,2,3-triazol-1-yl}propylcarbamate (S)-16e
tert-Butyl (S)-1-(O,O-diethylphosphono)-3-{4-[(3-
acetylindol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}-
propylcarbamate (S)-16g
20
20
Yield: 75%; colorless oil; ½aꢄD ¼ þ14.1 (c 1.72, CHCl3). Anal. calcd.
Yield: 87%; white powder, m.p. 164–165°C; ½aꢄD ¼ þ20.3 (c 1.63,
for C26H35N6O8P: C, 52.88; H, 5.97; N, 14.23. Found: C, 53.10; H,
5.79; N, 14.00.
CHCl3). Anal. calcd. for C25H36N5O6P · H2O: C, 54.44; H, 6.94; N,
12.70. Found: C, 54.40; H, 7.00; N, 12.90.
tert-Butyl (R)-1-(O,O-diethylphosphono)-3-{4-[(3,4-
dihydro-3-benzoyl-2,4-dioxoquinazolin-1-yl)methyl]-1H-
1,2,3-triazol-1-yl}propylcarbamate (R)-16f
tert-Butyl (R)-1-(O,O-diethylphosphono)-3-{4-[(5,6-
dimethylbenzimidazol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}-
propylcarbamate (R)-16h
20
20
Yield: 85%; colorless oil; ½aꢄD ¼ ꢀ4.6 (c 0.95, CHCl3). IR (film):
Yield: 94%; colorless very thick oil; ½aꢄD ¼ ꢀ12.9 (c 1.31, CHCl3). IR
n ¼ 3267, 3034, 2990, 1748, 1710, 1665, 1230, 1027, 754,
(film): n ¼ 3268, 3122, 2977, 2932, 1715, 1224, 1021, 973,
688 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d ¼ 8.18 (dd, J ¼ 7.8 Hz,
840 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d ¼ 7.90 (s, 1H), 7.55
J ¼ 1.5 Hz, 1H), 7.97–7.95 (m, 2H, Haromat.), 7.74–7.24 (m, 1H,
Haromat.), 7.73 (s, 1H, HC50), 7.65–7.63 (m, 2H, Haromat.), 7.28 (dt,
J ¼ 7.8 Hz, J ¼ 0.5 Hz, 1H, Haromat.), 5.41 (AB, JAB ¼ 15.9 Hz, 1H,
CHaHb), 5.37 (AB, JAB ¼ 15.9 Hz, 1H, CHaHb), 5.06 (brd, J ¼ 8.8 Hz,
1H, NH), 4.49–4.44 (m, 1H, PCCCHaHb), 4.40–4.35 (m, 1H,
(s, 1H), 7.50 (s, 1H), 7.22 (s, 1H), 5.43 (s, 2H), 4.91 (dd, J ¼ 10.5 Hz,
J ¼ 3.6 Hz, 1H, NH), 4.54–4.45 (m, 1H, PCCCHaHb), 4.35–4.25
(m, 1H, PCCCHaHb), 4.14–4.05 (m, 4H, 2 ꢃ POCH2CH3), 4.04–3.86
(m, 1H, PCH), 2.47–2.33 (m, 1H, PCCHaHb), 2.37 (s, 3H, CH3), 2.35
(s, 3H, CH3), 2.16–2.00 (m, 1H, PCCHaHb), 1.43 (s, 9H, 3 ꢃ CH3), 1.29
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
1-Amino-3-(1H-1,2,3-triazol-1-yl)propylphosphonates
9
(t, J ¼ 7.1 Hz, 3H, POCH2CH3), 1.26 (t, J ¼ 7.1 Hz, 3H, POCH2CH3); References
13
–
C NMR (151 MHz, CDCl ): d ¼ 155.5 (d, J ¼ 6.0 Hz, C O), 143.1,
–
3
132.5, 131.3, 123.0, 120.5, 110.1, 80.8, 63.3 (d, J ¼ 7.0 Hz, POC),
63.0 (d, J ¼ 7.0 Hz, POC), 47.1 (d, J ¼ 15.1 Hz, PCCC), 44.7 (d,
J ¼ 157.7 Hz, PC), 40.8, 31.4 (d, J ¼ 4.6 Hz, PCC), 28.5, 20.8, 20.5,
16.7 (d, J ¼ 5.7 Hz, POCC), 16.6 (d, J ¼ 5.5 Hz, POCC); 31P NMR
(121.5 MHz, CDCl3): d ¼ 23.67 ppm. Anal. calcd. for C24H37N6O5P:
C, 55.37; H, 7.16; N, 16.14. Found: C, 55.44; H, 7.18; N, 16.43.
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20
Yield: 88%; colorless very thick oil; ½aꢄD ¼ þ13.0 (c 1.31, CHCl3).
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ꢀ
this work was supported by the Medical University of Łódz internal
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The authors have declared no conflict of interest.
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

10
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ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com