Anti-enterovirus compounds

Details Anti-enterovirus compounds Anti-enterovirus compounds

2003-05-23

2004-11-09

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S262000

Reexamination Certificate

active

06815444

ABSTRACT:

BACKGROUND
Enteroviruses belong to the family Picornaviridae. They include about 70 human serotypes, e.g., polioviruses, coxsackieviruses A (COX A1-24), coxsackieviruses B (COX B1-6), echoviruses 1-31, enteroviruses (EV68-71), and enterovirus 72 (hepatitis A).
Genomic sequences among various enteroviruses are well conserved. The virion of an enterovirus consists of a simple virus capsid and a single strand of RNA. The viral genome encodes a polyprotein that is proteolytically processed by host and viral proteases into 11 different mature proteins which are encoded in the following order: NH
2
-VP4-VP2-VP3-VP1-2A-2B-2C-3A-3B-3C-3D-CO
2
H.
Virology
Ed. Field, B. N. 1985. The single-stranded RNA is replicated by viral RNA polymerase. See, e.g., Holland et al. (1982)
Science
215: 1576-1585; Ward et al. (1988)
J. Virol
. 62: 558-562; and La Torre et al. (1990)
J. Virol
. 64: 664-671.
Enteroviruses primarily enter the body through the alimentary canal. They replicate in the cell lining of the alimentary canal before spreading throughout the body via the blood circulation. Clinical syndromes of enteroviral infections are generally mild. Occasionally, enteroviruses cause serious diseases such as paralytic poliomyelitis, meningitis, or myocarditis.
There is a need to develop compounds which are effective in treating infection by enteroviruses.
SUMMARY
The present invention is based on the identification of new compounds for use as a therapeutic agent to treat enteroviral infection.
In one aspect, this invention encompasses pyrazolopyrimidine compounds of formula (A):
A is (CH
2
)
q
—CHR
a
R
b
; each of R
1
and R
2
, independently, is hydrogen, halogen, cyano, nitro, or alkyl; or R
1
and R
2
taken together is (CH
2
)
r
; each of R
3
and R
4
, independently, is hydrogen, halogen, cyano, nitro, or alkyl; each of R
5
, R
a
, and R
b
, independently, is aryl, aralkyl, or heteroaryl, optionally substituted with halogen, cyano, nitro, alkyl, aryl, aralkyl, heteroaryl, OR, O(O)CR, C(O)R, C(O)OR, C(O)NRR′, SR, S(O)R, S(O)OR, NRR′, NR(O)CR′, NRC(O)OR′, or NRC(O)NR′R″; each of m, n, o, p, and r, independently, is 0 or 1, and q is 0, 1, or 2; in which each of R, R′, and R″, independently, is hydrogen or alkyl, provided that the sum of m, n, o, and p is 1, 2, 3, or 4. Note that the left atom shown in any substituted group described above is closest to the pyrazolopyrimidine ring. Also note that if there are more than one R-containing substituted groups in a pyrazolopyrimidine compound of this invention, the Rs can be the same or different. The same rule applies to other similar situation.
Referring to formula (A), a subset of the pyrazolopyrimidine compounds of this invention are those in which each of R
1
and R
2
is hydrogen. In some embodiments, the sum of m and p is 1 and the sum of n and o is also 1. In other embodiments, the sum of m and p is 1, and the sum of n and o is 2. In this subset of pyrazolopyrimidine compounds, q can be 0; each of R
a
and R
b
, independently, can be aryl or heteroaryl; R
5
can be phenyl, and each of R
3
and R
4
can be hydrogen.
Another subset of the pyrazolopyrimidine compounds of this invention are those in which R
1
and R
2
taken together is (CH
2
)
r
, and r is 1. In these embodiments, the sum of m and p can be 1 and the sum of n and o can also be 1; q can be 0; each of R
a
and R
b
, independently, can be aryl; R
5
can be aryl (e.g., phenyl); and each of R
3
and R
4
can be hydrogen.
In another aspect, this invention encompasses pyrazolopyrimidine compounds of formula (A), wherein A is (CH
2
)
q
—R
a
; each of R
1
and R
2
, independently is hydrogen, halogen, cyano, nitro, or alkyl; or R
1
and R
2
taken together is (CH
2
)
r
; each of R
3
and R
4
, independently, is hydrogen, halogen, cyano, nitro, or alkyl; R
5
is aryl, aralkyl, or heteroaryl, optionally substituted with halogen, cyano, nitro, alkyl, aryl, aralkyl, heteroaryl, OR, O(O)CR, C(O)R, C(O)OR, C(O)NRR′, SR, S(O)R, S(O)OR, NRR′, NR(O)CR′, NRC(O)OR′, or NRC(O)NR′R″; R
a
is aryl, aralkyl, or heteroaryl, optionally substituted with halogen, cyano, nitro, alkyl, aryl, aralkyl, heteroaryl, OR, O(O)CR, C(O)R, C(O)OR, C(O)NRR′, SR, S(O)R, S(O)OR, NRR′, NR(O)CR′, NRC(O)OR′, or NRC(O)NR′R″; each of m, n, o, p, and r, independently, is 0 or 1; and q is 1; in which each of R, R′, and R″, independently, is hydrogen or alkyl, provided that the sum of m, n, o, and p is 1, 2, 3, or 4.
In these compounds, R
a
can be heteroaryl (e.g., thienyl), R
5
can be aryl (e.g., phenyl), and each of R
1
and R
2
can be hydrogen. In some embodiments, the sum of m and p is 1 and the sum of n and o is also 1, R
5
is phenyl, and each of R
3
and R
4
is hydrogen.
In a further aspect, this invention encompasses pyrazolopyrimidine compounds of formula (A), wherein A is (CH
2
)
q
—R
a
; each of R
1
and R
2
, independently, is hydrogen, halogen, cyano, nitro, or alkyl; or R
1
and R
2
taken together is (CH
2
)
r
; each of R
3
and R
4
, independently, is hydrogen, halogen, cyano, nitro, or alkyl; each of R
5
and R
a
, independently, is aryl, aralkyl, or heteroaryl, optionally substituted with halogen, cyano, nitro, alkyl, aryl, aralkyl, heteroaryl, OR, O(O)CR, C(O)R, C(O)OR, C(O)NRR′, SR, S(O)R, S(O)OR, NRR′, NR(O)CR′, NRC(O)OR′, or NRC(O)NR′R″; each of m, n, o, p, and r, independently, is 0 or 1; and q is 0 and 2; in which each of R, R′, and R″, independently, is hydrogen or alkyl, provided that the sum of m, n, o, and p is 1, 2, 3, or 4.
In these compounds, q can be 0, R
a
can be aralkyl (e.g., fluorenyl), R
5
can be aryl (e.g., phenyl), and each of R
1
and R
2
can be hydrogen. In some embodiments, the sum of m and p is 1 and the sum of n and o is also 1, R
5
is phenyl, and each of R
3
and R
4
is hydrogen.
This invention also features a method for treating infection by enteroviruses. The method includes administering to a subject in need thereof an effective amount of a compound of formula (A), wherein A is (CH
2
)
q
—CHR
a
R
b
or (CH
2
)
q
—R
a
; each of R
1
and R
2
, independently, is hydrogen, halogen, cyano, nitro, or alkyl; or R
1
and R
2
taken together is (CH
2
)
r
; each of R
3
and R
4
, independently, is hydrogen, halogen, cyano, nitro, or alkyl; each of R
5
, R
a
, and R
b
, independently, is aryl, aralkyl, or heteroaryl, optionally substituted with halogen, cyano, nitro, alkyl, aryl, aralkyl, heteroaryl, OR, O(O)CR, C(O)R, C(O)OR, C(O)NRR′, SR, S(O)R, S(O)OR, NRR′, NR(O)CR′, NRC(O)OR′, or NRC(O)NR′R″; each of m, n, o, p, and r, independently, is 0 or 1; and q is 0, 1, or 2; in which each of R, R′, and R″, independently, is hydrogen or alkyl, provided that the sum of m, n, o, and p is 1, 2, 3, or 4.
Alkyl, aralkyl, aryl, or heteroaryl herein refers to both substituted and unsubstituted moieties. The term “substituted,” in turn, refers to one or more substituents (which may be the same or different), each replacing a hydrogen atom. The substitutents may be the same or different from those described above. Examples of substituents include, but are not limited to, halogen, hydroxyl, amino, alkylamino, arylamino, dialkylamino, diarylamino, cyano, nitro, mercapto, carbonyl, carbamido, carbamoyl, carboxyl, thioureido, thiocyanato, sulfonamido, alkyl, alkenyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein alkyl, alkenyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, are optionally substituted with alkyl, aryl, heteroaryl, halogen, hydroxyl, amino, mercapto, cyano, or nitro. The term “alkyl” refers to a linear or branched, saturated or unsaturated C
1
-C
6
hydrocarbon moiety. The term “alkoxy” refers to a linear or branched, saturated or unsaturated, non-aromatic C
1
-C
10
moiety containing an oxygen radical, such as —OCH
3
or —OCH═C
2
H
5
. The term “cycloalkyl” refers to a saturated or unsaturated, non-aromatic C
3
-C
10

Affiliated with

Also associated with

Rating

Anti-enterovirus compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Anti-enterovirus compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Anti-enterovirus compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3353704