Antiviral compounds

Details Antiviral compounds Antiviral compounds

2002-06-25

2004-11-30

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S277000

Reexamination Certificate

active

06825348

ABSTRACT:

BACKGROUND
The DNA genome in the particle of a DNA virus can be double-stranded, single-stranded, or partially double-stranded DNA.
Papovaviridae
(e.g., papillomaviruses),
herpesviridae
(e.g., herpes simplex viruses), and
adenoviridae
(e.g., adenoviruses) contain double-stranded DNA genomes. Some viruses from
parvoviridae
(e.g., parvoviruses) contain single-stranded DNA as their genomes. Some viruses from
hepadnaviridae
(e.g., hepatitis B virus) contain partially double-stranded DNA as their genomes, and replicate their genomes through RNA intermediates. In contrast, retroviruses are a family of RNA viruses that replicate through a DNA intermediate. Examples of retroviruses include Moloney murine sarcoma viruses, human T-cell lymphotrophic viruses, human immunodeficiency viruses, and human foamy viruses.
Viruses described above cause a variety of diseases, such as the flu, common cold, herpes, measles, small pox, and encephalitis. Vaccination only offers protection for uninfected individuals for a few viral diseases. Thus, there is a need for identifying therapeutic agents useful for preventing or treating viral infection.
SUMMARY
The present invention is based, in part, on the discovery of nucleotide analogs that possess anti-viral activity.
In one aspect, this invention relates purine compounds of formula (I):
R
1
is NH
2
or OH; R
2
is H or NH
2
; R
3
is H or alkyl; each of m and n, independently, is 1, 2, 3, or 4; X is O, S, or NH; and Y is H, halogen, OR
a
, P(O)(OR
a
)
2
, or P(O)(OR
a
)(OR
b
), in which R
a
is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, and R
b
is
(referred to as “sugar-A(R
c
)—OP(O)(OR
d
)(OR
e
)” hereinafter), wherein A is adenine, guanine, cytosine, uracil, or thymine; R
c
is H or OH; R
d
is H or alkyl; R
e
is H, alkyl, or 5-ethylidene-(3,4-dialkoxyl)-furan-2-one; provided that if R
1
is NH
2
, R
2
is H; and if R
1
is OH, R
2
is NH
2
. Note that the left atom shown in any of the substituted groups set forth above is closest to the purine ring.
Referring to formula (I), a subset of the purine compounds are those in which each of R
1
is NH
2
and R
2
is H. In these compounds, R
3
can be H; X can be O; and each of m and n, independently, is 1 or 2. In some embodiments, m is 1, X is O, n is 2, and Y is OR
a
, in which R
a
can be H. In other embodiments, m is 2, X is O, n is 1, and Y is P(O)(OR
a
)
2
, in which R
a
can be H. In still other embodiments, m is 2, X is O, n is 1, and Y is P(O)(OR
a
)(OR
b
), in which R
a
can be H, and R
b
can be sugar-A(R
c
)—OP(O)(OR
d
)(OR
e
).
Another subset of the purine compounds of formula (I) are those in which R
1
is OH and R
2
is NH
2
. In these compounds, R
3
can be H; X can be O; and each of m and n, independently, is 1 or 2. In some embodiments, m is 1, X is O, n is 2, and Y is OR
a
, in which R
a
can be H. In other embodiments, m is 2, X is O, n is 1, and Y is P(O)(OR
a
)
2
, in which R
a
can be H. In still other embodiments, m is 2, X is O, n is 1, and Y is P(O)(OR
a
)(OR
b
), in which R
a
can be H, and R
b
can be sugar-A(R
c
)-OP(O)(OR
d
)(OR
e
).
In another aspect, this invention encompasses purine compounds of formula (II):
R
1
is NH
2
or OH; R
2
is H or NH
2
; R
3
is H or alkyl; each of m and n, independently, is 1, 2, 3, or 4; X is O, S, or NH; and Y is P(O)(OR
a
)(OR
b
), in which R
a
is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl; and R
b
is 5-ethylidene-(3,4-dialkoxy)-furan-2-one or sugar-A(R
c
)—OP(O)(OR
d
)(OR
e
); wherein A is adenine, guanine, cytosine, uracil, or thymine; R
c
is H or OH; R
d
is H or alkyl; R
e
is H, alkyl, or 5-ethylidene-(3,4-dialkoxyl)-faran-2-one; provided that if R
1
is NH
2
, R
2
is H; and if R
1
is OH, R
2
is NH
2
.
Referring to formula (II), a subset of the purine compounds are those in which each of R
1
is NH
2
and R
2
is H. In these compounds, R
3
can be H; X can be O; and each of m and n, independently, is 1 or 2. In some embodiments, m is 2, X is O, n is 1, and Y is P(O)(OR
a
)(OR
b
), in which R
a
can be H, and R
b
can be 5-ethylidene-(3,4-dialkoxy)-furan-2-one.
Another subset of the purine compounds of formula (II) are those in which R
1
is OH and R
2
is NH
2
. In these compounds, R
3
can be H; X can be O; and each of m and n, independently, is 1 or 2. In some embodiments, m is 2, X is O, n is 1, and Y is P(O)(OR
a
)(OR
b
), in which R
a
can be H, and R
b
can be 5-ethylidene-(3,4-dialkoxy)-furan-2-one.
Also within the scope of this invention is a method of preparing certain purine compounds of formula (I). The method includes reacting a compound of formula (III):
with an alkyl-X—(CH
2
) halide to obtain a compound of formula (IV):
In formulae (III) and (IV), R
1
is NH
2
or OH; R
2
is H or NH
2
; R
3
is H or alkyl; and X is O, S, or NH; provided that if R
1
is NH
2
, R
2
is H; and if R
1
is OH, R
2
is NH
2
.
Unless specifically pointed out, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, adenine, guanine, cytosine, uracil, and thymine mentioned above include both substituted and unsubstituted moieties. The term “substituted” refers to one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of substituents include, but are not limited to, halogen, cyano, nitro, hydroxyl, amino, mercapto, C
1
~C
6
alkyl, C
1
~C
6
alkenyl, C
1
~C
6
alkynyl, aryl, heteroaryl, C
4
~C
8
cyclyl, C
4
~C
8
heterocyclyl, alkyloxy, aryloxy, alksulfanyl, arylsulfanyl, alkylamino, arylamino, dialkylamino, diarylamino, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylcarboxyl, arylcarboxyl, heteroarylcarboxyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbamido, arylcarbamido, heterocarbamido, alkylcarbamyl, arylcarbamyl, heterocarbamyl, wherein each of alkyl (including alk), alkenyl, aryl, heteroaryl, cyclyl, and heterocyclyl is optionally substituted with halogen, cyano, nitro, hydroxyl, amino, mercapto, C
1
~C
6
alkyl, aryl, heteroaryl, alkyloxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkylcarboxyl, arylcarboxyl, alkyloxycarbonyl, or aryloxycarbonyl.
The term “alkyl” refers to both linear and branched alkyl. The term “cyclyl” refers to a hydrocarbon ring containing 4 to 8 carbons. The term “heterocyclyl” refers to a ring containing 4 to 8 ring members that have at least one heteroatom (e.g., S, N, or O) as part of the ring. The term “aryl” refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and pyrenyl. The term “heteroaryl” refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl moieties include, but are not limited to, furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl.
All of the purine compounds described above include the compounds themselves, as well as their salts. The salts, for example, can be formed between a positively charged substituent (e.g., amino) on a compound and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a negatively charged substituent (e.g., carboxylate) on a compound can form a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion.
In addition, some of the just-described purine compounds have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double bond isomeric forms.
Exemplary purine compounds of formula (I) and (II) include:
This invention also features a method of treating infection by virus. The method includes administering to a subject in need thereof an effective amount of a purine compound of formula (I) or formula (II) as described

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