Synthesis and anti-hepatitis B virus activity of some 2,3-dihydroxyprop- 1-yl unnatural hetaryls

Article abstract of DOI:10.1002/(SICI)1521-4184(19999)332:9<327::AID-ARDP327>3.0.CO;2-N

The sodium salts of some hetaryls of the quinoxalin-2-ones 2-4, phthalazine-1,4-dione 5, phthalazin-1-one 6, and pyridazin-6-ones 7 and 8 were alkylated with (±) 2,3-0-isopropylidene-1-O-(4-toluenesulfonyl)glycerol (1) to give the respective tetraseco-nuc

Full text of DOI:10.1002/(SICI)1521-4184(19999)332:9<327::AID-ARDP327>3.0.CO;2-N

2,3-Dihydroxyprop-1-yl Unnatural Hetaryls
327
Synthesis and Anti-Hepatitis B Virus Activity of Some
2,3-Dihydroxyprop-1-yl Unnatural Hetaryls
a)
b)
a)
a)
El Sayed H. El Ashry *, Adel A.-H. Abdel-Rahman , Nagwa Rashed , and Hanaa A. Rasheed
a) Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
b) Chemistry Department, Faculty of Science, Menoufia University, Shebin El Koum, Egypt
Key Words: Tetraseco-nucleosides; inhibition; cytotoxicity; hepatitis B virus
the development of novel componds with anti-HBV activity
and minimal adverse effects on the host, the present work
deals with the synthesis and biological activity of the 2,3-di-
hydroxypropyl derivatives of some hetaryls.
Summary
The sodium salts of some hetaryls of the quinoxalin-2-ones 2–4,
phthalazine-1,4-dione 5, phthalazin-1-one 6, and pyridazin-6-ones
7 and 8 were alkylated with (±) 2,3-O-isopropylidene-1-O-(4-tolu-
enesulfonyl)glycerol (1) to give the respective tetraseco-nucleo-
sides 9–15. Their deisopropylidenation with 70% acetic acid in
water gave the corresponding 2,3-dihydroxyprop-1-yl hetaryls
16–22. Compounds 16–22 showed varying inhibition activity
against Hepatitis B virus (HBV) with low to moderate cytotoxicity,
where 18 and 21 showed the highest replication inhibition and low
cytotoxicity.
Introduction
Hepatitis B virus (HBV) infection has a great degree of
prominence due to the wide prevalence of the disease and the
lack of an ideal drug to combat the virus, especially in chronic
infections which can lead to cirrhosis of the liver and/or
hepatocellular carcinoma. In such carriers vaccination is not
an effective therapy and alpha interferon has demonstrated
[1–6]
some promise
. Nucleoside analogues and particularly the
unnatural L-configuration have emerged as potential anti-
HBV agents with more promising pharmacological and toxi-
[3,7–13]
cological profiles
than their D-counterparts. Thus,
2′-fluoro-5-methyl-β-L-arabino furanosyluracil (B-L-
FMAU) is considered as a clinical candidate for treatment of
[3,6,14]
chronic HBV infections
, and is undergoing preclinical
[15]
Figure 1
toxicology studies . The 2′,3′-dideoxy-β-L-cytidine (β-L-
ddc) and its 5-fluoro analogue (β-L-FddC) demonstrated
equally potent activity against HBV in vitro, having the same
Chemistry
ED value of 0.01 µM. The unusual group of nucleosides
50
such as L-SddC[(–)-BCH-189] in which the3′-CH group has
Synthesis of the target nucleosides has been achieved by the
2
[7,16–22]
been replaced by a hetero-atom
HBV and HIV activity in vitro. The compounds are undergo- protected derivative of the propanediol by a suitable hetaryl.
ing clinical trials in patients with AIDS and AIDS related
complex. The L-like BCH-189 is more potent than the D-like glycerol (1) was selected as the precursor for their synthesis.
exhibits potent anti- nucleophilic displacement of a leaving group on a suitably
Thus, (±)-2,3-O-isopropylidene-1-O-(4-toluenesulfonyl)
[7,10,12]
counterpart
Considerable effort has been devoted to the synthesis of propylidene glycerol
acyclo-nucleoside analogues which possess potent selective
The selected bases for this study were of the pyrazine or the
. The S-enantiomer of 9-(2,3-dihy- pyridazine type and their benzo analogues, which are frag-
.
It was prepared by 4-toluenesulfonylation of 2,3-O-iso-
[27]
.
[23,24]
antiherpes activity
[25]
droxypropyl)adenine (S-DHPA) was found to haveinhibi- ments frequently reported in a wide variety of biologically
tory activity towards a number of DNA and RNA viruses. active compounds. Thus, the conversion of the bases quinox-
More recently, the phosphonate derivative 9-(3-hydroxy- alinones, phthalazinedione, phthalazinone, and the pyridazi-
2(S)-phosphonylmethoxypropyl)adenine (S-HPMPA) and its none 2–8 into the respective sodium salts was carried out by
analogues have been found to exhibit potent antiviral ef- heating their solutions in N,N-dimethylformamide with so-
[26]
fects . Since the trend for anti-HBV activity was similar to dium hydride. Treatment of the aforementioned salts with
[12]
that for anti-HIV activity , and there is a great demand for
(±)-2,3-O-isopropylidene-1-O-(4-toluenesulfonyl)glycerol
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0365-6233/99/0909/0327 $17.50 +.50/0

328
El Ashry, Abdel-Rahman, Rashed, and Rasheed
Table 1. Inhibition of HBV replication by 10 µM of selected compounds.
(1) gave the (±)2,3-isopropylidene-dihydroxypropyl deriva-
tives of the quinoxalinones 9–11, phthalazinedione 12,
phthalazinone 13, and the pyridazinones 14 and 15
(Scheme 1). Deprotection of the isopropylidene groups was
effected with 70% acetic acid in water to give the correspond-
ing (±)-2,3-dihydroxypropyl hetaryls 16–22, respectively.
The isopropylidene derivatives of phthalazinone and some
quinoxalinone analogues were not isolated, but converted
immediately to the respective 2,3-dihydroxypropyl nucleo-
sides. The structures of the isopropylidene derivatives have
——————————————————————————————
Compd.
% Inhibition
Cytotoxicity
1 Week 2 Weeks 3 Weeks
——————————————————————————————
16
17
18
19
20
21
22
30.9
80.9
87.1
81.3
33.2
81.8
78.6
30.3
80.3
83.9
80.0
31.1
79.8
77.7
30.1
71.3
80.5
72.1
28.9
78.3
70.5
7.7
13.5
5.5
14.3
8.1
1
been confirmed by analyzing their H-NMR spectral data.
They showed the presence of two singlets appearing at the
high magnetic field in the range 1.26–1.40 and 1.34–
1.49 ppm, respectively, corresponding to the two methyl
groups of the isopropylidene residue. The difference in their
chemical shifts (∆δ) lies in the range 0.08–0.14 ppm, which
is in agreement with that required (∆δ > 0.05) for α-terminal
5.3
16.7
——————————————————————————————
Acknowledgments
[28]
isopropylidene derivatives . The higher value of ∆δ in such
The authors thank the DANIDA establishment for support of the biological
testing and Professor Dr. R. R. Schmidt for making available some spectral
measurements performed at Konstanz University.
terminal derivatives is due to the interaction of the bulky
substituent on the dioxolane ring with only one of the two
methyl groups. The deprotected derivatives showed the ab-
sence of the signals corresponding to the isopropylidene
residue. The presence of signals due to the propyl residue and
the hetaryl groups confirmed the successful nucleophilic
displacement of the tosyloxy group in 1.
Experimental Part
Melting points were determined with a Meltemp apparatus 76-mm immer-
sion thermometer and are uncorrected. TLC was performed on Baker flex
silica gel 60 F-254 precoated plates. Column chromatography was performed
on Merck silica gel (0.040–0.063). 1H-NMR spectra were recordedon Bruker
AC 250 and 200 MHz spectrometers, in CDCl3 using tetramethylsilane
(TMS) as an internal standard. Chemical shifts (δ) are reported in ppm
relative to TMS and described as s (singlet), d (doublet), t(triplet), q (quartet),
m (multiplet), or bs (broad singlet). Microanalyses were performed by the
unit of Microanalysis, Faculty of Science, Cairo University.
2,3-O-Isopropylidene-1-O-(4-toluenesulfonyl)glycerol (1)
To a stirred ice-cooled solution of glycerol-1,2-acetonide (7.2 g, 0.05 mol)
in pyridine (30 ml), 4-toluenesulfonyl chloride (10.4 g, 0.06 mol) was added
portionwise. After standing for 16 h, the solution was diluted with ether
(30 ml). The resulting mixture was washed successively with 1 N HCl, water
and then saturated aqueous NaHCO3. The ether layer was dried over anhy-
drous Na2SO4 and concentrated to give 1 (13.1 g, 84% yield), ref.[22]
mp 40 °C, mp 41 °C.
General Procedure
(±)-2,3-O-Isopropylidene-2,3-dihydroxyprop-1-yl Hetaryls (9–15)
To a stirred solution of the hetaryls (5.0 mmol) in anhydrous DMF (10 ml)
was added NaH (60% dispersed in mineral oil, 0.20 g, 5.0 mmol). After
complete evolution of hydrogen, the mixture was heated at 100 °C for 1 h,
then 1 (1.43 g, 5.0 mmol) was added. The reaction mixture was stirred for
12 h at 100 °C, cooled to room temperature, and filtered. The solvent was
evaporated to dryness under reduced pressure and 10 ml of water was added
to the residue and the product was extracted with ether (3 × 20 ml). The ether
layer was dried and evaporated under reduced pressure to give a dark brown
gum which was purified by column chromatography using 1%
MeOH/CHCl3.
Scheme 1
Biological Activities
Compounds 16–22 were tested for their activity against
Hepatitis B virus (HBV) in Hep G 2.2.15 cell. The concen-
2
(±)-1-(2,3-O-Isopropylidene-2,3-dihydroxyprop-1-y1) (1H)-Quinoxalin-
2-one (9)
trations for the tested compounds were 10 M. Compounds 18
and 21 showed high inhibition activity (Table 1) and low
cytotoxicity. Compounds 17, 19, and 22 showed high inhibi-
tion activity with moderate cytotoxicity, while compounds 16
and 20 showed moderate viral replication inhibition and low
cytotoxicity.
Syrup (40% yield). 1H-NMR (CDCl3): δ = 1.26 (s, 3 H, CH3), 1.34 (s, H,
CH3), 3.84, 4.10 (2 m, 2H, CH2), 4.27 (m, 1 H, CH), 4.51 (m, 2 H, CH2),
7.29 (m, 1 H, Ar-H), 7.55 (m, 2 H, Ar-H), 7.85 (d, 1 H, J = 9.6 Hz, Ar-H),
8.24 (s, 1 H, Ar-H).
Arch. Pharm. Pharm. Med. Chem. 332, 327–330 (1999)

2,3-Dihydroxyprop-1-yl Unnatural Hetaryls
329
(±)-1-(2,3-O-Isopropylidene-2,3-dihydroxyprop-1-yl)-3-methyl-(1H)-quin-
oxalin-2-one (10)
Syrup (25% yield). 1H-NMR (CDCl3): δ = 3.46 (m, 3 H, OH, CH2), 4.03
(m, 3 H, CH, CH2), 4.51 (brs, 1 H, OH), 7.26 (m, 1 H, Ar-H), 7.73 (m, 3 H,
Ar-H), 8.34 (m, 1 H, Ar-H).– C11H12N2O3 (220.22) Anal. C,H,N. .
Syrup (45% yield). 1H-NMR (CDCl3): δ = 1.31 (s, 3 H, CH3), 1.39 (s, 3
H, CH3), 2.59 (s, 3 H, CH3), 3.86, 4.13 (2 m, 2 H, CH2) 4.24 (m, 1 H, CH),
4.54 (m, 2 H, CH2), 7.33 (m, 1 H, Ar-H), 7.52 (dd, 2H, Ar-H), 7.80 (d, 1 H,
J = 7.6 Hz, Ar-H).
(±)-5-Cyano-3,4-diphenyl-1-(2,3-dihydroxyprop-1-yl)(1H)-pyridazin-6-one
(21)
Syrup (20% yield). 1H-NMR (CDCl3): δ = 3.68 (m, 4 H, CH2, 2 OH), 4.33
(m, 2H, CH2), 4.55 (m, 1 H, CH), 7.26 (m, 10 H, Ar-H).– C20H17N3O3
(347.36) Anal. C,H,N.
(±)-3-(2,3-O-Isopropylidene-2,3-dihydroxyprop-1-yl)-2-phenyl-
2,3-dihydrophthalazine-1,4-dione (12)
Syrup (40% yield). 1H-NMR (CDCl3): δ = 1.40 (s, 3 H, CH3), 1.48 (s, 3
H, CH3), 3.92 (t, 1 H, J = 6.0 Hz, CH2), 4.16 (t, 1 H, J = 6.4 Hz, CH2), 4.38
(m, 2 H, CH2), 4.55 (m, 1 H, CH), 7.31 (m, 1 H, Ar-H), 7.45 (m, 2 H, Ar-H),
7.75 (m, 4H, Ar-H), 8.00 (m, 1 H, Ar-H), 8.44 (m, 1 H, Ar-H). 13C-NMR
(CDCl3): δ = 25.22 (CH3), 26.61 (CH3), 66.28 (CH2), 67.15 (CH2), 73.54
(CH), 109.61 (CMe2), 123.28, 124.19, 125.03, 126.86, 127.40, 128.33,
129.38, 131.97, 132.89, 141.72 (Ar-C), 149.54 (C=O), 158.10 (C=O).
(±)-5-Carbethoxy-3,4-diphenyl-1-(2,3-dihydroxyprop-1-yl)(1H)-pyridazin-
6-one (22)
Syrup (23% yield). 1H-NMR (CDCl3): δ = 0.94 (t, 3 H, J = 8.0 Hz, CH3),
3.69 (m, 2 H, CH2), 4.07 (m, 4H, CH2, 2 OH), 4.22 (m, 1 H, CH), 4.45 (m,
2 H, CH2), 7.11 (m, 5 H, Ar-H), 7.25 (m, 5 H, Ar-H).– C22H22N2O5 (394.41)
Anal. C,H,N.
Biological Activity Studies
(±)-5-Cyano-3,4-diphenyl-1-(2,3-O-isopropylidene-2,3-dihydroxy-
prop-1-yl)(1H)-pyridazin-6-one (14)
Maintenance media (RPMI/Glutamax, 93%; Pencilin + Streptomycin, 1%;
Gentamycin, 1%; Fetal/Calf serum, 5% and Geneticin 4 ml/100 ml media)
were added to the cell culture (Hep) G2 2.2.15 together with the tested
compounds (concentration = 10 µM). The supernatant media were collected
after one, two, and three weeks for the tested compounds and the controls
(Hep G2 2.2.15 cells without added compds). The DNA replication was
estimated by PCR (polymerase chain reduction) technique which was carried
out inthree steps: extraction ofDNAfromsupernatant, amplificationofDNA
by using thermal cycler and finally detection by DIG-ELISA technique. The
percent inhibition was calculated by the relation
Syrup (30% yield). 1H-NMR (CDCl3): δ = 1.35 (s, 3 H, CH3), 1.49 (s, 3
H, CH3), 3.95, 4.16 (2 m, 2 H, CH2), 4.31 (m, 1 H, CH), 4.54 (m, 1 H, CH2),
7.22 (m, 10 H, Ar-H).
(±)-5-Carbethoxy-3,4-diphenyl-1-(2,3-O-isopropylidene-2,3-dihydroxy-
prop-1-yl)-(1H)-pyridazin-6-one (15)
Syrup (38% yield). 1H-NMR (CDCl3): δ = 0.95 (t, 3 H, J = 7.1 Hz, CH3),
1.33 (s, 3 H, CH3), 1.46 (s, 3 H, CH3), 3.95 (m, 2 H, CH2), 4.11 (m, 2 H,
CH2), 4.28 (m, 1 H, CH), 4.48 (m, 1 H, CH2), 4.62 (m, 1 H, CH2), 7.23 (m,
10 H, Ar-H).
Inhibition of compd
% Inhibition = (
− 1 ) × 100
Inhibition of control
The percentage cytotoxicity could be estimated by the relation between the
number of the living and dead cells after three weeks counted by the
hemocytometer.
General Procedure:
(±)-2,3-Dihydroxyprop-1-yl Hetaryls (16–22)
The isopropylidenes 9–15 (5.0 mmol) were dissolved in 70% AcOH
(5.0 ml). The mixture was heated under reflux for 2 h. The solvent was
evaporated under reduced pressure and the residue was coevaporated with
H2O (2 × 3 ml) and ethanol (2 × 3 ml). The residual oil was purified by
column chromatography using 3% MeOH/CHCl3.
References
[1] S. B. Pai, S.-H. Liu, Y.-L. Zhu, C.K. Chu, Y. C. Cheng, Antimicrob.
Agents Chemother. 1996, 40, 380–386.
[2] J. M. Chirgwin, A. F. Przybla, R. J. Mac Donald, W. J. Rutter,
(±)-1-(2,3-Dihydroxyprop-1-y1)(1H)-quinoxalin-2-one (16)
Biochemistry 1979, 18, 5294.
Syrup (28% yield). 1H-NMR (CDCl3): δ = 3.68 (m, 3 H, CH2, OH), 4.19
(m, 3 H, CH, CH2), 4.45 (brs, 1 H, OH), 7.60 (m, 5 H, Ar-H).– C11H12N2O3
(220.22) Anal. C,H,N.
[3] C. K. Chu, T. W. Ma, K. Shanmuganathan, C. Wang, Y. Xiang, S. B.
Pai, G.-Q. Yao, J.-P. Sommadossi, Y.-C. Cheng, Antimicrob. Agents
Chemother. 1995, 39, 979–981.
[4] J. M. Colcacino, S. K. Malcolm, S. R. Jaskunas, Antimicrob. Agents
Chemother. 1994, 38, 1997–2002.
(±)-1-(2,3-Dihydroxyprop-1-y1)-3-methyl-(1H)-quinoxalin-2-one (17)
Syrup (35% yield). 1H-NMR (CDCl3): δ = 2.60 (s, 3 H, CH3), 3.54 (m, 4
H, CH2, CH, OH), 4.90 (brs, 1 H, OH), 4.43 (m, 2 H, CH2), 7.43 (m, 1 H,
Ar-H), 7.70 (m, 2 H, Ar-H), 7.80 (d, 1 H, J = 8.0 Hz, Ar-H).–
C12H14N2O3(234.25) Anal. C,H,N.
[5] B. A. Larder, B. Chesebro, D. D. Richman, Antimicrob. Agents
Chemother. 1990, 34, 436–441.
[6] W. B. Parker, Y.-C. Cheng, J. NIH Res. 1994, 6, 57–61.
[7] J. W. Beach, L. S. Jeong, A. J. Alves, D. Pohl, H. O. Kim, C.-N. Chang,
S.-L. Doong, R. F. Schinazi, Y.-C. Cheng, C. K. Chu, J. Org. Chem.
1992, 57, 2217–2219.
(±)-3-Benzyl-1-(2,3-dihydroxyprop-1-yl)(1H)-quinoxalin-2-one (18)
Syrup (20% yield). 1H-NMR (CDCl3): δ = 2.42 (s, 2 H, CH2), 3.62 (m, 3
H, CH2, OH) 3.94 (m, 2 H, CH2), 4.32 (brs, 1 H, OH), 4.53 (m, 1 H, CH),
7.28 (m, 5 H, Ar-H), 7.55 (m, 1 H, Ar-H), 7.76 (m, 2 H, Ar-H), 8.02 (m, 1
H, Ar-H).– C18H18N2O3 (310.34) Anal. C,H,N.
[8] L. D. Condreay, R. W. Jansen, T. F. Powdrill, L. C. Johnson, D. W.
Selleseth, M. T. Paff, S. M, Daluge, G. R. Painter, P. A. Furman, M. N.
Ellis, D. R. Averett, Antimicrob. Agents Chemother. 1994, 38, 616–619.
[9] S.-L. Doong, C.-H. Tsai, R. F. Shinazi, D. C. Liotta, Y.-C. Cheng, Proc.
Natl. Acad. Sci. USA 1991, 88, 8495–8499.
(±)-3-(2,3-Dihydroxyprop-1-yl)-2-phenyl-2,3-dihydrophthalazine-
1,4-dione (19)
[10] P. A. Furman, M. Davis, D. C. Liotta, M. Paff, L. W. Frick, D. J. Nelson,
R. E. Dornsife, J. A. Warster, L. J. wilson, J. A. Fyfe, J. V. Tuttle, W.
H. Miller, L. Condreay, D. R. Averett, R. F. Shinazi, G. R. Painter,
Antimicrob. Agents Chemother. 1992, 36, 2686–2692.
Syrup (30% yield). 1H-NMR (CDCl3): δ = 3.71 (m, 4 H, CH2, 2 OH), 4.11
(m, 1 H, CH), 4.32 (d, 2 H, J = 4.0 Hz, CH2), 7.27 (m, 1 H, Ar-H), 7.39 (t, 2
H, J = 8 Hz, Ar-H), 7.66 (m, 4 H, Ar-H), 7.91 (m, 1 H, Ar-H), 8.37 (m, 1 H,
Ar-H).– C17H16N2O4(312.31) Anal. C,H,N.
[11] G. Gosselin, R. F. Schinazi, J.-P. Sommadossi, C. Mathe, M.-C. Ber-
gogne, A.-M. Aubertin, A. Kirn and J.-L. Imbach, Antimicrob. Agents
Chemother. 1994, 38, 1292.
(±)-2-(2,3-Dihydroxyprop-1-yl)(2H)-phthalazin-1-one (20)
Arch. Pharm. Pharm. Med. Chem. 332, 327–330 (1999)

330
El Ashry, Abdel-Rahman, Rashed, and Rasheed
[12] H. O. Kim, K. Shanmuganathan, A. J. Alves, L. S. Jeong, J. W. Beach,
R. F. Shinazi, C.-N. Chang, Y.-C. Cheng, C. K. Chu, Tetrahedron Lett.
1992, 33, 6899–6902.
[23] E. S. H. El Ashry, Y. El kilany, Adv. Heterocycl. Chem. 1996, 67,
391–438; E. S. H. El Ashry, Y. El kilany, Adv. Heterocycl. Chem. 1997,
68, 1–88; E. S. H. El Ashry, Y. El kilany, Adv. Heterocycl. Chem. 1998,
69, 129–215; C. K. Chu, S. J. Cutler, J. Heterocycl. Chem. 1986, 23,
289–319; R. J. Remy, J. A. Secrist, III, Nucleosides Nucleotides 1985,
4, 411–427.
[13] T. S. Lin, M. Z. Luo, S. B. Pai, G. E. Dutschuman, Y.-C. Cheng, J. Med.
Chem. 1994, 37, 798–803.
[14] T. W. Ma, S. B. Pai, Y. L. Zhu, J. S. Lin, K. Shanmuganathan, J. Du,
C. G. Wang, H. Kim, M. G. Newton, Y.-C. Cheng, C. K. Chu, J.Med.
Chem. 1996, 39, 2835–2843.
[24] M. MacCoss, R. L. Tolman, W. T. Ashton, A. F. Wagner, J. Hannah,
A. K. Field, J. D. Karkas, J. I. Germershausen, Chem. Scr. 1986, 26,
113–121; M. Yokoyama, S. Watanabe, Yuki Gosei Kagaku Kyokaishi
1989, 47, 694–706 [CA 1990, 11, 98984C]; J. Balzarini, E. De Clercq,
Pharmacochem. Libr. 1990, 14, 175–194; C. K. Chu, D. C. Baker,
Nucleosides and Nucleotides as Antitumor and Antiviral Agents, Ple-
num Press, New York, 1993; E. De Clercq, 1nt. J. Immunopharmacol.
1991, 13, 91–98.
[15] T. W. Ma, J. S. Lin, M. G. Newton, Y.-C. Cheng, C. K. Chu, J. Med.
Chem. 1997, 40, 2750–2754.
[16] C. K. Chu, J. W. Beach, L. S. Jeong, B. G. Choi, F. L. Comer, A. J.
Alves, R. F. Schinazi, J. Org. Chem., 1991, 56, 6503–6505.
[25] E. De Clercq, P. F. Torrence, J. Carbohydr. Nucleosides Nucleotides
1978, 5, 187–224; A. Holy, Collect. Czech. Chem. Commun. 1975, 40,
187–214; E. De Clercq, A. Holy, J. Med. Chem. 1979, 22, 510–513.
[17] L. S. Jeong, A. J. Alves, S. W. Carrigan, H. O. Kim, J. W. Beach, C.
K. Chu, Tetrahedron Lett. 1992, 33, 595–598.
[18] J. A. V. Coates, N. S. Cammack, H. J. Jenkinson, I. M. Mutton, B. A.
Pearson, R. Storer, J. M. Cameron, C. R. Penn, Antimicrob. Agents
Chemother. 1992, 36, 202–205.
[26] E. De Clercq, A. Holy, I. Rosenberg, T. Sakuma, J. Balzarini, P. C.
Maudgal, Nature (London) 1986, 323, 464–468; A. Holy, I. Rosenberg,
Collect. Czech. Chem. Commun. 1987, 52, 2775–2791; R. R. Webb II,
J. C. Martin, Tetrahedron Lett. 1987, 28, 4963–4964; L. Naesens, J.
Balzarini, E. De Clercq, Rev. Med. Virol., 1994, 4, 147–159; E. De
Clercq, T. Sakuma, M. Baba, R. Pauwels, J. Balzarini, I. Rosenberg, A.
Holy, Antiviral Res. 1987, 8, 261–272.
[19] D. W. Norbeck, S. Spanton, S. Broder, H. Mitsuya, Tetrahedron Lett.
1989, 30, 6263–6266.
[20] C. K. Chu, S. K. Ahn, H. O. Kim, J. W. Beach, A. J. Alves, L. S. Jeong,
Q. Islam, P. Van Roey, R. F. Schinazi, Tetrabedron Lett. 1991, 32,
3791–3794.
[27] J. J. Baldwin, A. W. Raab, K. Mensler, B. H. Arison, D. E. Mc Clure,
J. Org. Chem. 1978, 43, 4876–4878.
[21] H. O. Kim, S. K. Ahn, A. J. Alves, J. W. Beach, L. S. Jeong, B. G. Choi,
P. Van Roey, R. F. Shinazi, C. K. Chu, J. Med. Chem. 1992, 35,
1987–1995.
[28] E. S. H. El Ashry, Eur. Carbohydr. Symp. Darmstadt Germany 1987,
C-35; E. S. H. El Ashry, J. Chem. Soc. Chem. Commun. 1986, 1024–
1026.
[22] K. L. Grove, X. Guo, S.-H. Liu, Z. Gao, C. K. Chu, Y.-C. Cheng,
Cancer Res. 1995, 55, 3008–3011.
Received: April 15, 1999 [FP385]
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999 – Printed in the Federal Republic of Germany
Alle Rechte, insbesondere die der Übersetzung in fremde Sprachen, vorbehalten. Kein Teil dieser Zeitschrift darf ohne schriftliche Genehmigung des Verlages in irgendeiner Form
– durch Fotokopie, Mikrofilm oder irgendein anderes Verfahren – reproduziert oder in eine von Maschinen, insbesondere von Datenverarbeitungsmaschinen verwendbare Sprache
übertragen oder übersetzt werden.– All rights reserved (including those of translation into foreign languages). No part of this issue may be reproduced in any form – photoprint,
microfilm, or any other means – nor transmitted or translated into a machine language without the permission in writing of the publishers.– Von einzelnen Beiträgen oder Teilen
von ihnen dürfen nur einzelne Vervielfältigungsstücke für den persönlichen und sonstigen eigenen Gebrauch hergestellt werden. Die Weitergabe von Vervielfältigungen, gleichgültig
zu welchem Zweck sie hergestellt werden, ist eine Urheberrechtsverletzung. Der Inhalt dieses Heftes wurde sorgfältig erarbeitet. Dennoch übernehmen Autoren, Herausgeber,
Redaktion und Verlag für die Richtigkeit von Angaben, Hinweisen und Ratschlägen sowie für eventuelle Druckfehler keine Haftung. This journal was carefully produced in all its
parts. Nevertheless, authors, editors and publishers do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data,
illustrations, procedural details or other items may inadvertently be inaccurate.– Die Wiedergabe von Gerbrauchsnamen, Handelsnamen,Warenbezeichnungen u. dgl. in dieser
Zeitschrift berechtigt nicht zu der Annahme, daß solcheNamen ohne weiteres vonjedermann benutzt werden dürfen. Es handelt sich häufig um gesetzlich eingetragene Warenzeichen,
auch wenn sie in dieser Zeitschrift nicht als solche gekennzeichnet sind. Druck und Buchbinder: Druck Partner Rübelmann GmbH, D-69502 Hemsbach.– Unverlangt zur Rezension
eingehende Bücher werden nicht zurückgesandt.
For USA and Canada: Archiv der Pharmazie (ISSN 0365-6233) is published monthly.– Printed in the Federal Republic of Germany.
US Postmaster: Periodicals postage paid at Jamaica, NY 11431. Air freight and mailing in the USA by Publications Expediting Services Inc., 200 Meacham Ave., Elmont NY 11003.
Send address changes to: “Archiv der Pharmazie”, c/o Publications Expediting Services Inc., 200 Meacham Ave., Elmont NY 11003
Valid for users in the USA: The appearance of the code at the bottom of the first page of an article in this journal (serial) indicates the copyright owner’s consent that copies of the
article may be made for personal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition, however, that copier pay the stated per
copy fee throught the Copyright Clearance Center, Inc., for copying beyond that permitted by Sections 107 for 108 of the U.S. Copyright Law. This consent does not extend to
other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective work, or for resale. For copying from back
volumes of this journal see »Permissions to Photo-Copy: Publisher’s Fee List« of the CCC.
Printed on chlorine- and acid-free paper/Gedruckt auf säurefreiem und chlorfrei gebleichtem Papier
Arch. Pharm. Pharm. Med. Chem. 332, 327–330 (1999)