Nucleosides with antiviral and anticancer activity

Details Nucleosides with antiviral and anticancer activity Nucleosides with antiviral and anticancer activity

2000-09-27

2002-11-05

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S008100, C514S047000, C514S048000, C514S051000, C514S052000, C530S322000, C536S026100, C536S026700, C536S026740, C536S026800, C536S026900, C536S029200

Reexamination Certificate

active

06475985

ABSTRACT:

BACKGROUND OF THE INVENTION
Chemotherapeutic nucleosides that function as inhibitors of polymerases must be phosphorylated intracellularly by endogenous nucleoside kinases to their respective mono-, di- and tri-phosphate derivatives. Unfortunately, biological targets, such as the herpes-virus or tumor cells, can readily become resistant to these nucleosides by either altering or removing the nucleoside kinase responsible for mono-phosphorylation. For example, the efficacy of antiviral nucleosides against HIV is reduced in monocytes and macrophages, since they contain only low levels of nucleoside kinases. In addition, in quiescent lymphocytes, thymidine analogs, such as AZT, are poorly phosphorylated. Because of these concerns, a number of approaches have been developed for the delivery of mono- and diphosphorylated nucleosides.
Recently, several attempts have been made to increase the therapeutic index of AZT by delivering the phosphorylated compound in the form of a phosphate or phosphoramidate prodrug. In particular, due largely to their reduced cytotoxicity, hydrophobic alkyl and aryl triesters of glycine, alanine, leucine, and phenylalanine phosphoramidates of AZT are highly effective and selective inhibitors of HIV viral replication.
In spite of these efforts, a continuing need exists for chemotherapeutic agents with antiviral and or anticancer properties.
SUMMARY OF THE INVENTION
The present invention provides compounds that act as antiviral and or anticancer agents. Accordingly there is provided a compound of the invention which is a compound of formula I:
wherein
R
1
is hydrogen, halo, hydroxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyloxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, trifluoromethyl, or NR
a
R
b
;
R
2
and R
3
are each independently hydrogen, halo, hydroxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyloxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, trifluoromethyl, azido, cyano, or NR
c
R
d
;
R
4
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, aryl(C
1
-C
6
)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted with 1, 2, or 3 halo, hydroxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyloxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
R
5
is an amino acid or a peptide;
X is oxy (—O—) thio (—S—) or methylene (—CH
2
—);
R
a
and R
b
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, phenyl, benzyl, phenethyl, or (C
1
-C
6
)alkanoyl; or R
a
and R
b
together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
R
c
and R
d
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, phenyl, benzyl, phenethyl, (C
1
-C
6
)alkanoyl, —C(═O)N(R
e
)(R
f
), or —C(═O)OR
g
; or R
c
and R
d
together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
R
e
and R
f
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, phenyl, benzyl, or phenethyl; or R
e
and R
f
together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino; and
R
g
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, phenyl, benzyl, or phenethyl;
or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula I wherein R
1
-R
4
have any of the values described herein, and wherein R
5
is a nitrogen linked radical of formula III:
wherein R
h
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-S—)C
1
-C
6
)alkyl-, aryl, heteroaryl, aryl(C
1
-C
6
)alkyl, or heteroaryl(C
1
-C
6
)alkyl; wherein any aryl or heteroaryl may optionally be substituted with 1, 2, or 3 Z; R
j
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, phenyl, benzyl, or phenethyl; and wherein each Z is independently halo, hydroxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyloxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino. Preferably, the carbon bearing R
h
has the (S) configuration.
The invention also provides a compound of formula I wherein R
1
-R
4
have any of the values described herein, and wherein R
5
is a nitrogen-linked radical of formula VI:
wherein R
ah
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-S—(C
1
-C
6
)alkyl-, aryl, heteroaryl, aryl(C
1
-C
6
)alkyl, or heteroaryl(C
1
-C
6
)alkyl; wherein any aryl or heteroaryl may optionally be substituted with 1, 2, or 3 Z; R
ai
and R
aj
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, phenyl, benzyl, or phenethyl; and each Z is independently halo, hydroxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyloxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino. Preferably, the carbon bearing R
ah
has the (S) configuration.
The invention also provides a compound of formula II:
wherein
R
6
is adenine, guanine, cytosine, thymine, or uracil, optionally substituted by 1, 2, or 3 Y; wherein each Y is independently halo, hydroxy (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyloxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, trifluoromethyl, hydroxy(C
1
-C
6
)alkyl, —(CH
2
)
1-4
P(═O)(OR
k
)
2
aryl, aryl(C
1
-C
6
)alkyl, or NR
m
R
n
, and wherein any aryl ring may optionally be substituted with 1, 2, or 3 halo, hydroxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyloxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
one of R
7
and R
8
is —NR(R
o
)C(═O)N(R
q
), or —N(R
o
)C(═O)OR
r
, and the other is hydrogen, halo, hydroxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyloxy, (C
1
-C
6
)alkanoyloxy, trifluoromethyl, azido, cyano, or RN
s
R
t
;
R
9
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, aryl(C
1
-C
6
)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted by 1, 2, or 3 halo, hydroxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyloxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
R
10
is an amino acid or a peptide;
X is oxy, thio, or methylene;
each R
k
is independently hydrogen or (C
1
-C
6
)alkyl;
R
m
and R
n
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, phenyl, benzyl, phenethyl, or (C
1
-C
6
)alkanoyl; or R
m
and R
n
together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
R
o
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, phenyl, benzyl, or phenethyl;
R
p
and R
q
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, phenyl, benzyl, or phenethyl; or R
p
and R
q
together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino; and
R
r
is hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, phenyl, benzyl, or phenethyl; and
R
s
and R
t
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, phenyl, benzyl, phenethyl, or (C
1
-C
6
)alkanoyl; or R
s
and R
t
together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula V:
wherein
R
11
is adenine, guanine, cytosine, thymine, or uracil, optionally substituted by 1, 2, or 3 U; wherein each U is independently halo, hydroxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyloxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, trifluoromethyl, hydroxy(C
1
-C
6
)alkyl, —(CH
2
)
1-4
P(═O)(OR
w
)
2
aryl, a

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