Synthesis and Anti-HIV Activity of 5-Alkoxymethyl-3 В╨Ж-azido-2 В╨Ж3 В╨Ж-dideoxyuridines.

377
5-Alkoxymethyl-3 ’-azido-2’,3’-dideoxyuridines
Synthesis and Anti-HIV Activity of 5-Alkoxymethyl-3’-azido-2’,3’dideoxyuridines
Ahmed E.-S. Abdel-Megieda),Poul Hansena),Erik B. Pedersena)*,Claus Nielsenb),and Carsten M. Nielsenh)
Department of Chemistry, Odense University, 5230 Odense M, Denmark
h,
Retrovirus Laboratory, Department of Virology, Statens Seruminstitut, Artillerivej 5 , DK-2300 Copenhagen, Denmark
Received May 18, 1992
Synthese und Anti-HIV-Aktivitat von 5-Alkoxymethyl-3’-azido-2’,3’Methyl 3-azido-5-O-terr-butyldiphenyIsilyl-2,3-dideoxy-~-eryfhro-furanodidesoxyuridinen
side (3) was coupled with silylated 5-hydroxymethyluracil (la) and its C,C6 alkyl ethers lb-g to give the corresponding protected nucleosides 4a-g
0-Methyl-3 -azido-5-O-fer~-butylphenylsilyl-2,3-didesoxy-~-er~~rhr~-furawhich were deprotected with Bu,NF to afford 3-azido nucleosides 5a-g
nosid (3) wurde mit silyliertem 5-Hydroxymethyluracil (la) und dessen
and 6a-g. The a-anomers 6f,g show moderate activity against HIV. No
CI-C6-Alkylethernlb-g zu den entspr. geschutzten Nucleosiden 4a-g
significant activity against HSV-I was found for the compounds 5 and 6.
umgesetzt. Diese wurden mit Bu4NF in die 3-Azido-nucleoside 5a-g und
6a-g ubergefiihrt. Die a-Anomeren 6f,g zeigen nur geringe, 5-6 keine
Aktivitat gegen HIV.
Recently, a number of nucleosides have been identified as potential drugs
against human immunodeficiency virus (HIV)’). These include 3’-azido3’-deoxythymidine (AZT)2)which represents the first step in the development of practical chemotherapy against pathogenic human retrovirus. The
application of this compound implicates some difficulties due to the side
effects3), the key toxicity being suppression of bone marrow. Synthesis of
new nucleoside analogues offers a chance of finding compounds with less
prominent side effects than those observed for AZP).
5-Alkoxymethyluracils lb-g were prepared by acid catalyzed reaction of 5-hydroxyrnethyluracil5) (la) with methanol, ethanol, n-propanol, n-butanol, n-pentanol, and n-hexano1 according to described procedures. Silylation of 5hydroxymethyluracil (la) and its ether derivatives lb-g
with hexamethyldisilazane (HMDS) was performed according to Wittenburg6)prior to their coupling as silylated derivatives 2 with methyl 3-azido-5-0-tert-butyldiphenylsilyl2,3-dideoxy-~-erythro-pentofuranoside
(3)7)using the trimethylsilyl trifluoromethanesulfonate (TMS triflate) method of Vorbriiggen’) in anhydrous acetonitrile to give anomeric mixtures of the nucleosides 4a-g in 36-83% yield.
Treatment of these protected nucleosides with tetrabutylammonium fluoride in tetrahydrofuran (THF) at 0°C for 0.5 h
resulted in complete deprotection of the hydroxy group.
The anomeric mixtures were separated by silica gel chromatography to give the p-anomers 5a-g (27-38%) and the a anomers 6a-g (31-37%).
p- and a-anomers 5a-g and 6a-g, respectively, were identified by comparison with the ‘H-NMR data of Fleet9) for
a - and j3-anomers of AZT. Especially, the deshielding
effect of the nucleobase generates downfield shift of 5’-H
when the nucleobase is changed from the a-to the p-face of
the furanose ring, and more significantly by the same transformation, 4’-H is changed upfield”).
Arch. Pharm. (Weinheim)326,377-381 (1993)
2
0
N3
N3
3
4
0
4 +
ByNF
THF
N3
5
[Sil- terf-BuPh2Si
0
6
Scheme 1
0VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1993 0365-6233/93/0707-0377 $5.00 t ,2510
378
Pedersen et al.
Table 1: "C-NMR (6 values, TMS) of 5 and 6 in CD@D.
R Anomex
a)
C-l'b)
C-2'
C--3'
C-l'b)
C-5'
C-2
C-4
C-5
C-6
Other C
86.32
38.33
61 73
86.14
62.44
152.12
165.08
115.30
139.35
57.95 (CHz0)
86.41
38.48
61.46
86.20
62.25
152.05
165.13
112.06
141.01
58.41 (OCH3), 67.83 (CHzO),
86.45
38.49
61.57
86.25
62.33
152.05
165.08
112.47
140.81
15.36 (CH3), 65.86, 67.05 (CHz0)
84.12
36.39
59.64
83.87
60.14
150.14
162.55
110.74
138.62
10.43 (CHs), 22.30 (CHz), 64.35, 71.19 (CHzO)
86.46
38.46
61.65
86.25
62.38
152.05
165.06
112.55
140.73
14.22 (CHs), 20.31, 32.77 (CHz), 66.06,71.51
(CHz0)
84.16
36.43
60.17
83.90
60.74
150.17
162.58
110.76
138.66
13.84 CH3), 21.90, 27.81, 28.77 (CHz), 64.41,
69.57 [CHzO)
86.46
38.48
61.63
86.27
62.37
152.06
165.09
112.53
140.78
14.37 (CH3), 23.66, 26.88, 30.64, 32.81 (CHz),
66.07, 71.81 (CHz0)
88.14
38.83
62.40
87.93
63.17
152.11
165.19
114.88
138.78
57.86 (CHz0)
88.42
38.87
62.46
88.18
63.25
152.04
165.24
111.53
140.42
58.36 (OCHs), 67.83 (CHzO)
88.31
38.85
62.55
88.17
63.29
152.06
165.17
112.01
140.09
15.40 (CH3), 65.83, 66.96 (CHz0)
85.82
36.87
6P.14
85.56
60.70
150.11
162.59
110.34
137.96
10.37 (CH3), 22.37 (CHz), 64.28, 71.09 (CHz0)
85.83
36.89
6C.88
85.53
61.47
150.13
162.59
110.37
137.95
13.67 (CH3), 18.79, 31.24 (CHz), 64.34, 69.17
(CHz0)
88.27
38.89
6f.61
88.27
63.29
152.05
165.15
112.06
139.92
14.39 CH3), 23.57, 29.48, 30.46 (CH2), 66.02,
71.69 [CHzO)
88.28
38.90
62.62
88.28
63.31
152.06
165.15
112.09
139.89
14.38 (CH3), 23.67, 26.94, 30.74, 32.83 (CHz),
66.03, 71.70 (CHz0)
'C-NMR in DMSO-d6. b, C-I' and C-4' may be interchanged.
In antiviral studies Tourigny") reported compound 5b to
be inactive against Herpes Simplex Virus, type 1 (HSV-1)
and in antitumor investigations MeEnikI2) also found the
compound inactive. In conformity with the former observation all the nucleosides 5a,c-g and 6a-g did not show any
significant activity at 100 yM against HSV-1, strain Mclntyi'e, when tested in a continous cell line from rabbit cornea
(SIRC) which was maintained in Eagle's MEM containing
1% fetal calf serum (FCS) and the test compound. The hexyloxymethyl derivative 5g showed cytotoxicity at 100 yM but
no activity against HSV- 1 at subtoxic concentrations.
For evaluation of activity against HIV-1 (strain HTLVIIIB) MT-4 cells were incubated with virus, washed and
added in a proportion of 1: 10 to uninfected MT-4 cells
Table 2: Activity against HIV-I for compounds 5 and 6.
Cpd
5Substituent
H
a anomer (6)
B anomer (5)
'Jm
r
0.00
0.00
0.36141
0.56
0.04
AZT
CH3
-0.07
CH2CH3
-0.07
a
CHzOH
0.00
-1.03
b
CHzOCH3
0.02
-0.78
C
CH~OC~HS
0.02
-0.24
>loo
>loo
d
CHzOCsH7
0.02
0.30
>loo
>loo
e
CHzOC4Hg
0.02
0.84
>I00
>loo
f
CHzOCsHii
0.02
1.38
73
>loo
g
CHzOCsHi3
0.02
1.92
33
>loo
1.02
6414)
>loo
>500
,100
a) Effective dose of compound, achieving 50% reduction of HIV anti-gene production in
cultures of MT-4 cells.
Arch. Pharm. (Weinheirn)326,378-3Kf(1993)
5-Alkoxymethyl-3’-azido-2’,3’-dideoxyuridines
which had been preincubated in test compound containing
culture medium (RPM 1640 containing 10% FCS) for 2 h.
The MT-4 cells were maintained in culture medium likewise containing the test compound. Expression of HIV in
culture medium was quantitated by HIV antigen detection
ELISA13).
Although substructure searching, retrieval and sorting of
in vitro anti-HIV data have been acc~mplished’~),
no quantitative correlations have been found between structure and
anti-HIV activity. As expressed by Hammett CT,, the 5alkoxymethyl substituents selected in this investigation
have electronic properties similar to those of hydrogen,
methyl (AZT), and ethyl15)- all affecting activity against
HIV-1 when used as 5-substituents in 3’-azido-2’,3’-dideoxyuridine16). The 5-alkoxymethyl substituents have the
advantage that the Hansch hydrophobic parameter d5)
can
be adjusted easily by changing the size of the alkyl group.
However, no activity against HIV-1 was observed for the panomers 5a-g, not even for the substituents in the series of
ethoxymethyi to pentyloxymethyl, all having x-values comparable to those of hydrogen, methyl, and ethyl. From the
above findings we conclude the bulkiness of the 5-substituent to be crucial. A similar result has been found when 5alkoxymethyl was used as a substituent on 2’,3’-dideoxycytidine (DDC)l7).Also the a-anomers 6a,c-e with smaller,
alkoxymethyl groups were devoid of any activity against
HIV- 1. Interestingly, the a-anomers 6f,g with highly lipophilic 5-pentyloxymethyl and 5-hexyloxymethyl substituents show low activity against HIV-1 (Table 2). For these
two compounds we found CD50> 100 yM - cytotoxic dose,
required to reduce the viability of normal uninfected cells
by 50%. Although we have no explanation of this activity
against HIV-1, we propose that 3’-azido nucleosides, sufficiently lipophilic to enter the MT-4 cells, can undergo an
enzymatic trans glycosidation reaction to form AZT.
379
I -(3-Azido-5-O-tert-hutyldiphenylsilyl-2,3-dideoxya,P-o-erythro-pentofuranosyl)-5-hydroxymethyluru~il
(4a)
Yield 1.93 g (74%).- IH-NMR (CDC13): 6 (ppm) = 1.09 (s; 9H, tertbutyl), 2.2-2.9 (m; 2H, 2’-H), 3.7-4.5 (m; 6H, CH20, 3’-H, 4’-H, 5’-H),
6.20 (m; IH, I’-H), 7.3-7.7 (m; 11 H aromat., 6-H), 10.0 (br; IH, NH).”C-NMR (CDC13): 6 (ppm) = 19.16 and 19.33 (Me&), 26.85 and 27.00
(&3C), 37.89 and 38.49 (C-2’), 58.29 and 58.58 (CH,O), 60.48 and 61.48
(C-3’), 63.48 and 64.07 (C-57, 84.42, 84.78, 86.65, and 87.01 (C-I’ and
C-4’), 113.60 and 114.32 (C-5), 127.95, 128.03, 130.08, 130.20, 130.26,
132.30, 132.44, 132.61, 132.72, 135.36, 135.54 (C-arom.), 136.75 and
137.15 (C-6), 150.17 and 150.29 (C-2), 163.87 and 164.05 (C-4).
I -(3-Azido-5-O-tert-hutyldiphenylsilyl-2,3-dideoxya$-o-erythro-pentofuranosyl)-5-methoxymethyluracil(4b)
Yield 1.50 g (56%).- ‘H-NMR (CDCI,): 6 (ppm) = 1.08 (s; 9H, fertbutyl), 2.1-2.9 (m; 2H, 2’-H), 3.21 and 3.41 (2 x s; 3H, OCH,), 3.7-4.4 (m;
6H, 5’-H, 3’-H, CH,O, 4’-H), 6.20 (m; IH, I’-H), 7.3-7.7 (m; 11 H aromat., 6-H), 9.60 (br s; IH, NH).-13C-NMR (CDCI,): 6 (ppm) = 19.16 and
19.27 (Me,C), 26.84 and 26.97 (W&C), 37.75 and 38.48 (C-2’), 58.48
(OCH,), 60.48 and 61.40 (C-3’), 63.40 and 64.08 (C-5’), 66.40 and 66.74
(CH20), 84.32, 84.71, 86.61, and 86.99 (C-1’ and C-4’), 111.22 and
112.19 (C-5), 127.95, 130.08, 130.19, 132.40, 132.60, 132.70, 135.42,
135.54 (C-arom.), 137.39 (C-6), 150.13 and 150.24 (C-2), 162.61 and
162.90 ((2-4).
I -(3-Azido-5-O-tert-hutyldiphenylsilyl-2,3-dideoxy-a,P-~-erythro-pentofuranosyfi-5-ethoxymethyluracil(4c)
Yield 2.28 g (83%).- ‘H-NMR (CDCI?): 6 (ppm) = 1.1-1.3 (m; 12 H,
tert-butyl, CH,), 2.1-2.9 (m; 2H, 2’-H), 3.4-4.4 (rn;8H, CH,, 5’-H, 3’-H,
CH20, 4’-H), 6.20 (m; lH, 1’-H), 7.3-7.7 (m; 11 H aromat., 6-H), 9.60 (br
s; lH, NH).- I3C-NMR (CDCI,): 6 (ppm) = 14.86 and 14.98 (CH,), 19.00
and 19.10 (Me&), 26.68 and 26.81 (&C), 37.46 and 38.24 (C-27, 60.47
and 61.31 (C-3’), 63.31 and 64.22 (C-5’), 63.96 and 64.51 (CH,O), 66.58
(OCH,), 84.17, 84.78, 86.40, and 86.73 (C-1’ and C-4’), 127.79, 129.92,
130.01, 132.25, 132.44, 132.55, 135.26, 135.38 (C-arom.), 137.13 and
137.30 (C-2), 162.53 and 162.75 (C-4).
1-(3-Azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-a,~-o-euythro-pentofuranosyl)-5-propyloxymethyluracil(4d)
Experimental Part
5-Hexyloxymethyluracil (lg)
5-HydroxymethyluraciI (3.55 g, 25 mmol), hexanol (200 ml) and conc.
HCI (2 ml) were refluxed for 5 h. After cooling to room temp., l g was filtered off as white crystals and recrystallized from ethanol. Yield 3.25 g
(58%); m.p. 215°C.
5-Hydroxymethyl- and 5-Alkoxymethyl-l-(3-azido-5-O-tert-butyIdiphenylsilyl-2,3-dideoxy-a,~~-erythro-pentofuranosyl)uracils
(4a-g). General
procedure
The 5-hydroxymethyl- and 5-alkoxymethyluracils la-g were silylated to
give 2a-g according to the standard procedure6). TMS triflate (1.25 ml, 6.5
mmol) in anhydrous CH,CN (5 ml) was added dropwise to a solution of
the silylated uracil (2, 6.5 mmol) in anhydrous CH,CN (50 ml) at -10°C.
The azido sugar 3 (5 mmol, 2.18 g) dissolved in CH,CN (10 ml) was
added dropwise during 15 min at -10°C. The temp. was raised slowly (1 h)
to 5°C. After stirring at 5°C for 3 h, the mixture was diluted with CH2Cl2
(50 ml) and washed with ice-cold aqueous NaHCO,. The org. phase was
separated, dried with Na,S04, concentrated in vucuo and purified on a silica gel column with CH2C12/MeOH(97:3) to give 4 as a glass or as a foam.
Arch. Pharm. (Weinheim) 326,378-381(1993)
Yield 2.23 g (79%).- ’H-NMR (CDCI,): 6 (ppm) = 0.83 and 0.94 (2 x t;
J = 7.5 Hz, 3H, CH,), 1.09 (s; 9H, tert-butyl), 1.60 (m; 2H, CH,), 2.1-2.9
(m; 2H, 2’-H), 3.32 and 3.48 (2 x t; J = 6.8 Hz, 2H, OCH,), 3.7-4.4 (m;
6H, 5’-H, 3’-H, CH20, 4’-H), 6.20 (m; IH, 1’-H), 7.3-7.8 (m; 11 H aromat., 6-H), 9.60 (s; lH, NH): I3C-NMR (CDCI,): 6 (ppm) = 10.49 (CH,),
19.17 and 19.26 (Me$), 22.73 and 22.91 (CH,), 26.86 and 26.97 (Me$),
37.57 and 38.41 (C-27, 60.73 and 61.52 (C-3’), 63.52 and 64.15 (C-5’),
64.58 and 64.85 (CH20), 72.67 and 72.74 (OCH,), 84.35, 84.03, 86.61,
86.90 (C-1’ and C-4’), 111.84 and 112.52 (C-5), 127.96, 130.08, 130.16,
132.46, 132.63, 132.74, 135.44, 135.55 (C-arom.), 137.1 I and 137.27 (C6). 150.15 and 150.31 (C-2), 162.60 and 162.82 (C-4).
I -(3-Azido-5-O-tert-butyldiphenylsilyl-2.3-dideoxy-a,~-~-erythro-pentofuranosyl)-5-butyloxymethyluracil
(4e)
Yield 1.99 g (69%).- ‘H-NMR (CDCI,): 6 (ppm) = 0.8-1.6 (m; 16 H,
CH,, tert-butyl, 2 x CH,), 2.1-2.9 (m; 2H, 2’-H), 3.36 and 3.52 (2 x t; J =
6.5 Hz, 2H, OCH2), 3.7-4.4 (m; 6H, 5’-H, 3’-H, CH,O, 4’-H), 6.20 (m;
lH, 1’-H), 7.3-7.7 (m; 11 H aromat., 6-H), 9.7 (s; lH, NH).- I3C-NMR
(CDCI,): 6 (pprn) = 13.88 (CH,), 19.16 and 19.25 (Me&), 19.23 and
19.33 (CH,), 26.85 and 26.97 (Me,C), 31.56 and 31.76 (CHZ), 37.58 and
38.39 (C-2’), 60.68 and 61.52 (C-3’), 63.50 and 64.13 (‘2-53, 64.60 and
Pedersen et al.
64.87 (CH,O). 70.82 and 70.89 (OCH,), 84.33, 85.01, 86.59, 86.87 (C-I’
and C-4’). 111.84 and 112.51 (C-5). 127.95, 127.99, 130.07, 130.16,
132.45, 132.62, 132.73, 135.43, 135.55 (C-mom.), 137.09 and 137.36 (C6), 150.20and 150.35 (C-2), 162.69 and 162.91 (C-4).
I -(3-Azido-2,3-dideox.~-~-~-rrythr.o-/,entofuruno,~yl)-S-methoxymethy/~rruc,il (5b)
Yield 1.98 g (67’%).- ‘H-NMR (CDCI,): 6 (ppm) = 0.8-1.7 (m: 18 H,
CH,, 3 x CH,, terl-butyl), 2.2-2.9 (m: 2H, 2’-H), 3.34 and 3.51 (2 x t; J =
6.6 Hz, 2H, OCH2). 3.7-4.4 (m; 6H, 5’-H, 3’-H, CH20, 4’-H), 6.20 (m:
IH, l’-H), 7.2-7.7 (m: I I H aromat., 6-H), 9.4 (br s: lH, NH): I3C-NMR
(CDCI,): 6 (ppin) = 14.02 (CH,), 19.18 and 19.27 (Me&), 22.46 and
22.53 (CH2). 26.86 and 26.98 (&C), 28.20 and 28.32 (CH,), 29.19 and
29.38 (CH2), 37.51 and 38.42 (C-27, 60.68 and 61.53 (C-3’), 63.52 and
64.15 (C-S’), 64.62 and 6429 (CH,O), 71.17 and 71.24 (OCH,), 84.36,
85.09, 86.62. 86.90 (C-I’ and C-4’), 11 1.85 and I12.51 (C-5). 127.96,
130.09, 130.17, 132.46. 132.75, 135.45, 13536 (C-arom.), 137.08 and
137.49 (C-61, 150.09 and 150.25 (C-2), 162.52 and 162.73 (C-4).
I -(3-Azido-2,3-dideoxy-~-~-er~thrr~-pentofurutiosylj-S-metho,uymethylurucil (6bj
’
Yield 0.161 g (27%), colorless oil.- IR (Film): 2109 cm (N3).- ‘HNMR (CD,OD): 6 (pprn) = 2.46 (m; 2H, 2’-H), 3.39 (s; 3H, CH,), 3.78
(dd; J = 12.0 Hz and 3.1 Hz, IH, S’-H,), 3.89 (dd: J = 12.0 Hz and 3.2 Hz,
I -(3-Azid~~-5-O-terr-butyldip~i~~nyls~/yl-Z
.S-dideoxy- a,P-u-er.?~thro-()ent~~(-IH, 5‘-Hb),3.97 (m; IH, 4’-H), 4.19 (s; 2H, CH,O), 4.39 (m; lH, 3’-H),
6.20 (t; J = 6.2 Hz, IH, 1 ’-H), 8.09 (s: 1 H, 6-H).
runosyl)-S-(priityloxq.methyl~urueil(4fJ
Yield 0.190 g (32%), colorless semicrystalline compound.- 1R (KBr):
2109 cm-‘ (N&- ’H-NMR (CD30D): 6 (ppm) = 2.28 (m; 1H. 2’-H,), 2.85
(m: lH, 2’-H,), 3.41 (s; 3H, CHI), 3.69 (m; 2H. 5’-H), 4.23 (m; 3H, 4’-H,
CH,O), 4.37 (m: 1H. 3’-H), 6.18 (dd; J = 6.8 Hz and 3.2 Hz, IH, I’-H),
7.79 (s; IH, 6-H).
I -(3-A;ido-2,.~-dideoxy-P-o-c~rythro-pe~~t~~uruno.~yl)-S-ethoxymethy/urucil
(5cj
Yield 0.218 g (35%), colorless thick oil.. IR (Film): 2109 cm-l (N&
‘H-NMR (CD,OD): 6 (ppm) = 1.24 (t: J = 7.0 Hz, 3H, CH,), 2.47 (m; 2H,
I -~3-A~i~Io-.5-0-tert-hut?.ldi~~hen~lsilyl-2,3-didro~,ty-a.~-1~-rrythro-pentofir2’-H), 3.59 (9; J = 7 Hz, 2H, CH,), 3.78 (dd: J = 12.1 Hz and 3.3 Hz, IH,
i.unnsvl)-S-(h~~x~Iox~~ieth~lJL~rucil
(4gJ
S’-H,), 3.90 (dd; J = 12.1 Hz and 3.3 Hz, IH, 5’-Hh), 3.97 (m; IH, 4’-H),
Yield 1.09 g (36%): ‘H-NMR (CDCI,): 6 (ppm) = 0.8-1.7 (m; 20 H,
4.25 (s; 2H, CH,O), 4.40 (m; IH, 3’-H), 6.21 (t: J = 6.3 Hz, IH, l‘-H),
CHI. tert-butyl, 4 x CH,), 2.1-2.9 (m; 2H, 2’-H), 3.34 and 3.51 (2 x t; J =
8.08 (s: IH, 6-H).
6.6 Hz, 2H, OCH?), 3.7-4.4 (m; 6H, 5’-H, 3’-H, CH?O. 4’-H), 6.20 (m;
lH, l’-H), 7.3-7.8 (m; 11 H aromat., 6-H), 9.68 (s; IH, NH).. I3C-NMR
1-(3-Azid~~-2,3-dideoxy-ff-~-erythro-pent~~furuno.~yl)-S-~tho,~ymethylur.uiil
(CDCI,): 6 (ppm) = 14.04 (CH,), 19.17 and 19.27 (Me3C), 22.58 and
(6c)
22.60 (CH?), 25.70 and 25.82 (CH2), 26.85 and 26.98 ( b I C ) , 29.47 and
Yield 0.355 g (57%), white CryStdk from ethyl acetate; m.p. 95-98°C.29.67 (CH,), 31.63 and 3 I .69 (CH,), 37.61 and 38.41 (C-23, 60.66 and
IR (KBr): 2109 cm“ (N+ ‘H-NMR (CD30D): 6 (ppm) = 1.25 (t: J = 7.0
61.50 (C-5’1, 63.51 and 64.13 (C-3’). 64.61 and 64.87 (CH,O), 71.16 and
Hz, 3H, CH?), 2.27 (m: IH, 2’-H,), 2.85 (m; IH, 2’-Hb), 3.60 (9: J = 7.0
71.24 (OCH,), 84.35, 85.04, 86.61, 86.89 ( C - I ’ and C-4’), 111.84 and
Ha, 2H, CH,), 3.69 (m: 2H, 5’-H), 4.29 (s; 2H, CH,O), 4.38 (m; 2H, 4’-H,
112.52 (C-S), 127.96, 128.00, 130.08, 130.17, 132.45, 132.62, 132.73.
3’-H), 6.20 (dd; J = 6.9 Hz and 3.1 Hz, IH, l’-H), 7.80 (s; IH, 6-H).
135.44, 135.55 (C-arom.), 137.06 and 137.39 (C-6). 150.20 and 150.35 (C2), 162.69 and 162.90 (C-4).
I -(3-A~ido-2.3-dideoxy-~-n-er~thro-pentofurunosylj-S-propylo~~methylurucil (5d)
5-Hyirosynieth.vl- und 5-Alko.rymethyl-l-(3-Azido-2,3-dideci,~y-y-r~-c~~ythroYield 0.221 g (34%), colorless thick oil.- IR (Film): 2109 cm-‘ (N3).pentofir~uno.syl~uru~~ils
5a-g und 6a-g. Generul procedure
‘H-NMR (DMSO-d,): 6 (ppm) = 0.86 (t: J = 7.3 Hz, 3H, CH,), 1.51 (m;
The protected nucleoside 4a-g (2 mmol) was dissolved in THF (20 ml)
2H, CH,), 2.35 (m; 2H, 2’-H), 3.35 (m: 2H, CH,), 3.62 (m; 2H, S’-H).
at 0°C and 2 ml of 1 M Bu,NF in THF were added slowly with stirring.
3.84 (m; IH, 4’-H). 4.08 (s: 2H, CH,O), 4.39 (m: lH, 3’-H), 6.09 (t; J =
After 30 rnin at 0°C THF was evaporated in i w u o and the crude product
6.3 Hz, IH, l’-H), 7.87(s; IH,h-H), 11.41 (s; IH,NH).
was purified on a silica gel column with ethyl acetate to give the pure panomers 5a-g and a-anomers 6a-g.
I -(.~-Azido-2,3-dide~.~y-tr-D-e,ythro-~~ent~furunosv1)-5-~~r~~p~~~o,~~m~~
urucil (6d)
I -(.~-A5do-2.3-clicleo.uv-~-n-c~r~thro-p~~nt~~urunos~I)-S-~tydroxymethyIuruYield 0.234 g (36%), white crystals from ethyl acetate; m.p. 103u I (5al
105°C.- IR (KBr): 2109 cm-l (N3).- ‘H-NMR (DMSO-d6):6 (ppm) = 0.87
(t; J = 7.3 Hz, 3H, CH3), 1.52 (m; 2H, CH,), 2.07 (m; IH, 2’-H,), 2.73 (m;
Yjeld 0.204 g (36%), colorless thick oil.. IR (KBr): 2109 cm-’ (N3).- ‘HIH, 2’-Hh), 3.36 (m; 4H, S’-H, OCH,), 4.14 (s; 2H, CH,O), 4.27 (m; IH,
NMR (CD30D):6 (ppm) = 2.46 (m; 2H, 2’-H), 3.78 (dd: J = 12.1 Hz and
4’-H), 4.39 (m; IH, 3’-H), 5.07 (t; J = 5.3 Hz, IH, OH), 6.10 (dd; J = 6.9
3.5 Hz, IH, S’-HA),3.88 (dd; J = 12.1 Hz and 3.4 Hz, lH, S’-H,). 3.97 (m;
Hz and 3.4 Hz, IH, I’-H), 7.69 (s; IH, 6-H), 11.40 (s; lH, NH).
IH, 4’-H), 4.40 (m: 3H, 3’-H, CH20),6.23 (t; J = 6.4 Hz, lH, I’-H), 7.99
(s; IH, 6-Hi.
I -(3-Azid0-2,3-dideox~-~-~-er~~th~o-pento~u~unos~~1J-5-bu~1oxymeth~~l
cil (5ej
I -(.~-A~ido-2,3-iliileo.~y-a-r~-e~ythro-pentr~~t~uno~ylj~5-(hvdrox~~mcYield 0.210 g (3l%), colorless thick oil.- IR (Film): 2109 cm-’ (N2):
th~lJurucrI(6aJ
‘H-NMR (CD,OD): 6 (ppm) = 0.97 (t; J = 7.3 Hz, 3H, CH,), 1.44 (m; 2H,
Yield 0.232 g (410/0),colorless semicrystalline compound.- IR (KBr):
CH2), 1.61 (in;2H, CH,), 2.46 (m; 2H, 2’-H), 3.54 (t; J = 6.5 Hz. 2H,
2109 cm.’ (N3).- ‘H-NMR (CD,OD): 6 (ppm) = 2.26 (m; IH, 2’-H,), 2.87
CH,), 3.78 (dd; J = 12.1 Hz and 3.4 Hz, IH, S’-H,), 3.88 (dd: J = 12.1 Hz
and 3.3 Hz, IH, 5’-Hh),3.97 (m; IH, 4’-H), 4.24 (s; 2H, CH,O), 4.39 (m;
(nil IH. 2’-H,), 3.70 (m: 2H, 5’-H), 4.39 (m; 4H, 4’-H. 3’-H, CHzO), 6.21
IH, 3’-H), 6.21 (t; J = 6.3 Hz, IH, I’-H), 8.06 (s: IH, 6-H).
(dd; J = 6.9 Hz and 3.6 Hz, IH, l’-H), 7.79 (s; IH, 6-H).
Arch. Phurm (Weinherm)326,378-381 (1993)
S-Alkoxymethyl-3’-azido-2’,3
’-dideoxyuridines
381
143-Azido-2,.~-dideo.~~-a-o-er7;thro-perztojirr.anosyl~-S-but~~l~~xymethylura1.63 (m: 2H, CH,), 2.26 (m; IH, 2’-H,), 2.86 (m; IH, 2’-H,), 3.54 (m; 2H,
cil (6e)
OCH,), 3.68 (m; 2H, 5’-H), 4.34 (m; 4H, 3’-H, 4’-H, CH,O), 6.21 (dd; J =
7.0and3.2Hz, IH, I’-H),7.79(~:1H,6-H).
Yield 0.278 g (41%), white crystals from ethyl acetate; m.p. 132135°C.- IR (KBr): 2109 cm-‘ (N,).- ‘H-NMR (DMSO-d,): 6 (ppm) = 0.87
(t; J = 7.2 Hz, 3H, CH,), 1.35 (m; 2H, CH,), 1.49 (m; 2H, CH,), 2.09 (m;
lH, 2’-H,), 2.75 (m; IH, 2’-Hb), 3.45 (m; 4H, 5’-H, OCH2), 4.13 (s; 2H,
References
CH,O), 4.27 (m; IH, 4’-H), 4.40 (m; lH, 3’-H), 6.10 (dd; J = 6.9 Hz and
3.4 Hz, l’-H), 7.76 (s; IH, 6-H).
1 E. De Clercq, A. Van Aerschot, P. Herdewijn, M. Baba, R. Pauwels,
and J. Balzarini, Nucleosides & Nucleotides 8, 659 (1989), and references cited therein.
I -(3-Azido-2,3-dideox?-~-o-er~thro-pentofuranosyl)-5-(pentylo.uyme2 H. Mitsuya, K.J. Weinhold, P.A. Furman, M.H. St.Clair, S.N. Lehrthyljurmil (Sf)
man, R.C. Gallo, D. Bolognesi, D.W. Barry, and S. Broder, Proc.
Yield 0.226 g (32%). colorless thick oil.- IR (Film): 2109 cm-’ (N3).Narl. Acad. Sci.U.S.A. 82,7096 (1985).
3 S. Broder, Pharm. Technology 12.24 (1988).
‘H-NMR (DMSO-d,): 6 (ppm) = 0.86 (t; J = 6.5 Hz, 3H, CH,), 1.28 (m;
4 D.D. Richman, M.A. Fischl, M.H. Grieco, M.S. Gottlieb, P.A. Vol4H, 2 x CH,), 1.50 (m; 2H, CH,), 2.39 (m; 2H, 2’-H), 3.38 (m; 2H,
berding, O.L. Laskin, J.M. Leedom, J.E. Groopman, D. Mildvan, M.S.
OCH,), 3.67 (m; 2H, 5’-H), 3.86 (m; IH, 4’-H), 4.08 (s; 2H, CH,O), 4.38
G.G. Jackson, D.T. Durack, and S. Nusinoff-Lehman, Engl. J.
Hirsch,
(m; IH, 3‘-H), 5.21 (t; J = 5.2 Hz, IH, OH), 6.09 (t; J = 6.3 Hz, lH, 1’-H),
Med. 317, 192 (1987).
7.87 (s; IH, 6-H).
5 R.E Cline, R.M. Fink, and K. Fink, J. Am. Chem. SOC.81, 2521
(1959).
I -(3-Azido-2,3-dideoxy-a-o-erythro-pentofuranosylj-S-(penryloxyme
6 E. Wittenburg, 2. Chem. 4,303 (1964).
.thyl)uracil i6f)
7 P. Hansen and E.B. Pedersen, Acta Chem. Scand. 44,522 (1990).
8 H. Vorbriiggen, K. Krolikiewicz, and B. Bennua, Chem. Ber. 114,
Yield 0.262 g (37%), white crystals; m.p. 124-125°C.- ‘H-NMR
1234 (1981).
(CD2OD): 6 (ppm) = 0.95 (t; J = 7.0 Hz, 3H, CH,), 1.38 (m; 4H, 2 x CH,),
9 G.W.J. Fleet, J.C. Son, and A.E. Derome, Tetrahedron 44,625 (1988).
1.64 (m; 2H, CH,), 2.25 (m; IH, 2’-H,), 2.85 (m; lH, 2’-Hb), 3.54 (m; 2H,
10 M. Okabe, R.-C. Sun, S.Y.-K. Tam, L.J. Todaro, and D.L. Coffen, J.
OCH,), 3.68 (m; 2H, 5’-H), 4.34 (m; 4H, 3’-H, 4’-H, CH,O), 6.21 (dd; J =
Org. Chem. 53,4780 (1988).
I I G. Tourigny, A.L. Stuart, I. Ekiel, P.J. Aduma, and S.V. Gupta,
6.9 Hz and 3.0 Hzf, 7.79 (s; IH, 6-H).
Nucleosides & Nucleotides 8, 1189 (1989).
I -(3-Azido-?,3-dideoxy-~o-erythro-penrofuruno.~yl)-S-(he~lo~me- 12 S. Ya Mel’nik, A.A. Bakhmedova, I.V. Yartseva, O.S. Zhukova, and
N.P. Yavorskaya, Bioorg. Khim. 17, 1101 (1991); Chem. Ahsrr. 115,
thyljurucil i5gj
232742q (1991).
13 C.M. Nielsen, I.C. Bygbjerg, and B.F. Vestergaard, Lancet I, 556
Yield 0.280 g (38%), colorless thick oil.- IR (Film): 2109 cm-I (N,).(1 987).
‘H-NMR (CDIOD): 6 (ppm) = 0.94 (t; 6.3 Hz, 3H, CH,), 1.36 (m; 6H, 3 x
14 E. De Clercq, AIDS Res. Human Retrovir. 8, 119 (1Y92).
CH,), 1.60 (m; 2H, CH,), 2.46 (m; 2H, 2’-H), 3.53 (t; J = 5.5 Hz, 2H,
M. Nasr, J. Cradock, and M.I. Johnston, AIDS Res. Human Retrovir,
OCH,), 3.77 (dd; J = 12.1 HZ and 3.3 Hz, lH, 5’-H,), 3.87 (dd; J = 12.1 HZ
8, 135 (1992).
and 3.3 Hz, lH, 5’-Hb), 3.98 (m; IH, 4’-H), 4.24 (s; 2H, CH,O), 4.39 (m;
15 C. Hansch and A. Leo, Substitution Constants for Correlation AnalIH, 3’-H), 6.21 (t; J = 6.2 Hz, IH, 1’-H), 8.06 (s; IH, 6-H).
ysis in Chemistry and Biology, John Wiley & Sons, New York 1979.
16 J. Balzarini, M. Baba, R. Pauwels, P. Herdewijn, and E. De Clercq,
1-(3-Azido-2,3
-dideox~~-a-o-erythro-penf~~uranosyl)-S-(hexy/oxymeBiochem. Pharmacol. 37,2847 (1988).
17 A.E.-S. Abdel-Megied, E.B. Pedersen, and C.M. Nielsen, Monatsh.
thy1)urucil (6g)
Chem. 122,59 (1991).
Yield 0.238g (32%), colorless oil.. IR (KBr): 2109 cm-’ (N3).- ‘H-NMR
(CD,OD): 6 (ppm) = 0.94 (t; J = 6.7 Hz, 3H, CH,), 1.36 (m; 6H, 3 x CH,),
[Ph60]
Arch.Pharm. (Weinheimj 326,378-381(1993)