Antipicornaviral compounds and compositions, their...

Details Antipicornaviral compounds and compositions, their... Antipicornaviral compounds and compositions, their...

2001-06-13

2003-10-14

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S343000, C514S367000, C514S387000, C514S414000, C514S422000, C546S278400, C546S138000, C548S162000, C548S306100, C548S525000, C548S535000, C548S492000

Reexamination Certificate

active

06632825

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to compounds that advantageously inhibit the enzymatic activity of picornaviral 3C proteases, especially rhinovirus 3C proteases (RVPs), and that retard viral growth in cell culture. The invention also relates to the use of such compounds in pharmaceutical compositions and therapeutic treatments for rhinoviral infections. The invention further relates to processes for synthesizing such compounds and intermediate compounds useful in such syntheses.
2. Related Background Art
The picornaviruses are a family of tiny non-enveloped positive-stranded RNA-containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis virus, foot and mouth viruses, hepatitis A virus, and others. The human rhinoviruses are a major cause of the common cold. To date, there are no effective therapies that cure the common cold, only treatments that relieve the symptoms.
Picornaviral infections may be treated by inhibiting the proteolytic 3C enzymes. These enzymes are required for the natural maturation of the picornaviruses. They are responsible for the autocatalytic cleavage of the genomic, large polyprotein into the essential viral proteins. Members of the 3C protease family are cysteine proteases, where the sulfhydryl group most often cleaves the glutamine-glycine amide bond. Inhibition of 3C proteases is believed to block proteolytic cleavage of the polyprotein, which in turn can retard the maturation and replication of the viruses by interfering with viral particle production. Therefore, inhibiting the processing of this cysteine protease with selective molecules that are specifically recognized should represent an important and useful approach to treat and cure viral infections of this nature and, in particular, the common cold.
Some inhibitors of the enzymatic activity of picornaviral 3C proteases (i.e., antipicornaviral compounds) have been recently discovered. See, for example: U.S. Pat. Nos. 5,856,530; 5,962,487; U.S. patent application Ser. No. 08/991,282, filed Dec. 16, 1997, by Dragovich et al.; and U.S. patent application Ser. No. 09/301,977, filed Apr. 29, 1999, by Dragovich et al. See also: Dragovich et al., “Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors . . . , ”
J. Med. Chem.
(1999), Vol. 42, No. 7, 1203-1212, 1213-1224; and Dragovich et al., “Solid-phase Synthesis of Irreversible Human Rhinovirus 3C Protease Inhibitors . . . ,”
Bioorg. & Med. Chem.
(1999), Vol. 7, 589-598. There is still a desire, however, to discover compounds that are especially potent antipicornaviral agents.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the general formula I:
wherein:
R
a
may be selected from an aryl, heteroaryl, alkyl, alkenyl, amino, cycloalkyl or heterocycloalkyl group, provided that R
a
is not pyrrolidinyl, where the aryl, heteroaryl, alkyl, alkenyl, amino, cycloalkyl or heterocycloalkyl group is unsubstituted or substituted with one or more suitable substituents;
R
c
is a substituent having the formula:
wherein:
R
f
and R
g
are each independently H or lower alkyl;
m is 0 or 1;
p is an integer of from 0 to 5;
A
1
is CH or N;
when p is 1, 2, 3, 4, or 5, A
2
is C(R
h
)(R
i
), N(R
j
), S, S(O), S(O)
2
, or O, and when p is 0, A
2
is C(R
h
)(R
i
)(R
j
), N(R
i
)(R
j
), S(R
i
), S(O)(R
i
), S(O)
2
(R
i
), or O(R
i
), where each R
h
, R
i
and R
j
is independently H or a lower alkyl group;
each A
3
present is independently C(R
h
)(R
i
), N(R
j
), S, S(O), S(O)
2
, or O; where each R
h
, R
i
and R
j
is independently H or lower alkyl;
when p is 1, 2, 3, 4, or 5, A
4
is N(R
k
), C(R
h
)(R
i
), or O; and when p is 0 (i.e., A
3
is not present), A
4
is N(R
k
)(R
l
), C(R
h
)(R
i
)(R
j
), and O(R
l
), where each R
h
, R
i
and R
j
is independently H or lower alkyl, each R
k
is H, alkyl, aryl, or acyl, and each R
l
is H, alkyl, or aryl;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A
1
, (A
2
)
m
, (A
3
)
p
, A
4
, and C═O, where each dotted line in the ring depicts a single bond when A
2
is present (i.e., m=1) and a hydrogen atom when A
2
is absent (i.e., m=0);
R
d
is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
R
b
is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
Z and Z
1
are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, —C(O)R
n
—CO
2
R
n
—CN, —C(O)NR
n
R
o
, —C(O)NR
n
OR
o
, —C(S)R
n
, —C(S)OR
n
—C(S)NR
n
R
o
, —C(═NR
n
)R
o
, —C(═NR
n
)OR
o
, —NO
2
, —SOR
o
, —SO
2
R
n
, —SO
2
NR
n
R
o
, —SO
2
(NR
n
)(OR
o
), —SONR
n
, —SO
3
R
n
, —PO(OR
n
)
2
, —PO(OR
n
)(OR
o
), —PO(NR
n
R
o
)(OR
p
), —PO(NR
n
R
o
)(NR
p
R
q
), —C(O)NR
n
NR
o
R
p
, —C(S)NR
n
NR
o
R
p
, where R
n
, R
o
, R
p
and R
q
are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R
n
, R
o
, R
p
and R
q
, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted,
or Z and R
d
, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and R
d
are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group,
or Z and Z
1
, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z
1
are as defined above (except for moieties that cannot form the cycloalkyl or heterocycloalkyl group); and
In another embodiment of the compounds of the above Formula I,
A
1
is CH or N; A
2
is C(R
h
)(R
i
), N(R
j
), S, S(O), S(O)
2
, or O; where each R
h
, R
i
and R
j
is independently H or lower alkyl; each A
3
present is independently C(R
h
)(R
i
), N(R
j
), S, S(O), S(O)
2
, or O; where each R
h
, R
i
and R
j
is independently H or lower alkyl; when p is 1, 2, 3, 4, or 5, A
4
is N(R
k
), C(R
h
)(R
i
), or O; and when p is 0 (i.e., A
3
is not present), A
4
is N(R
k
)(R
l
), C(R
h
)(R
i
)(R
j
), and O(R
l
), where each R
h
, R
i
and R
j
is independently H or lower alkyl, each R
k
is H, alkyl, aryl, or acyl, and each R
l
is H, alkyl, or aryl; provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A
1
, (A
2
)
m
, (A
3
)
p
, A
4
, and C═O, where each dotted line in the ring depicts a single bond when A
2
is present (i.e., m=1) and a hydrogen atom when A
2
is absent (i.e., m=0); and Z and Z
1
are each independently H, F, a unsubstituted or substituted alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, —C(O)R
n
, —CO
2
R
n
, —CN, —C(O)NR
n
R
o
, —C(O)NR
n
OR
o
, —C(S)R
n
, —C(S)NR
n
R
o
, —NO
2
, —SOR
o
, —SO
2
R
n
, —SO
2
NR
n
R
o
, —SO
2
(NR
n
)(OR
o
), —SONR
n
, —SO
3
R
n
, —PO(OR
n
)
2
, —PO(OR
n
)(OR
o
), —PO(NR
n
R
o
)(OR
p
), —PO(NR
n
R
o
)(NR
p
R
q
), —C(O)NR
n
NR
o
R
p
, —C(S)NR
n
NR
o
R
p
, where each R
n
, R
o
, R
p
and R
q
are independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R
n
, R
o
, R
p
and R
q
, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted,

Affiliated with

Also associated with

Rating

Antipicornaviral compounds and compositions, their... does not yet have a rating. At this time, there are no reviews or comments for this patent.

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

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3118201