Antipicornaviral compounds and compositions, their...

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

2000-12-01

2003-02-04

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S300000, C514S333000, C514S299000, C514S343000, C546S113000, C546S183000, C546S256000, C546S272100, C546S278400

Reexamination Certificate

active

06514997

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to pyridone-containing peptidomimetic 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 these compounds in pharmaceutical compositions, methods of treatment of rhinoviral infections using these compounds and compositions, and processes for the synthesis of these compounds and compounds useful in the syntheses thereof.
2. Related Background Art
The picomaviruses 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 on the market that cure the common cold, only treatments that relieve the symptoms.
Picornaviral infections may be treated by inhibiting the proteolytic picornaviral 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 viral 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 small 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 small-molecule inhibitors of the enzymatic activity of picornaviral 3C proteases (i.e., antipicornaviral compounds) have been recently discovered. See, for example: U.S. Pat. No. 5,856,530; U.S Pat. No. 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 Ireversible 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 small-molecule compounds that are especially potent antipicornaviral agents.
Inhibitors of other related cysteine proteases such as cathepsins have been described in, e.g., U.S. Pat. No. 5,374,623; U.S. Pat. No. 5,498,616; and WIPO International Publication Nos. WO 94/04172, WO 95/15749, WO 97/19231, and WO 97/49668. There yet remains a need for inhibitors targeting the picornaviral 3C cysteine protease with desirable pharmaceutical properties, such as high specificity.
SUMMARY OF THE INVENTION
This invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the general formula:
wherein:
R
a
is substituted or unsubstituted heterocycloalkyl or heterocycloalkylalkyl;
R
b
is a substituent having the formula:
wherein:
R
f
and R
g
are 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;
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
1
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
c
is H, halogen or a substituted or unsubstituted lower alkyl group;
R
d
is H, halogen, hydroxyl, a substituted or unsubstituted alkyl, alkoxy or alkylthio group;
R
e
is H or a substituted or unsubstituted alkylgroup; and
Z and Z
1
are 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)OR
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
, or —C(S)NR
n
NR
o
R
p
, wherein R
n
, R
o
, R
p
, and R
q
are independently H, a substituted or unsubstituted alkyl group, cycloalkyl group, aryl group, heterocycloalkyl group, acyl group or thioacyl group, or wherein 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 atom 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.
Preferably, when R
a
is substituted or unsubstituted heterocycloalkylalkyl, the alkyl moiety thereof is a substituted or unsubstituted saturated alkyl moiety.
Specifically, this invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the general Formula I:
wherein:
R
1
is H, a substituted or unsubstituted lower alkyl group or a suitable nitrogen protecting group;
R
2
is an alkylcarbonyl group, an arylcarbonyl group, a cycloalkylcarbonyl group, a heterocycloalkylcarbonyl group, a heteroarylcarbonyl group, or an alkyloxycarbonyl group, wherein each of the alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl moieties in the above groups may be substituted or unsubstituted, or a suitable nitrogen protecting group;
R
3
is H or a suitable substituent; or
R
1
together with R
2
form a suitable nitrogen protecting group; or
R
2
together with R
3
form a heterocycloalkyl ring or heteroaryl ring, which may be optionally substituted;
R
4
is H or a suitable substituent;
the dotted line represents an optional bond;
R
5
is H or a suitable substituent;
R
6
is H or a substituted or unsubstituted alkyl group; or
R
5
together with R
6
form a heterocycloalkyl ring, which may be optionally substituted;
R
7
and R
10
are independently H, halogen or a substituted or unsubstituted lower alkyl group;
R
8
is H or a substituted or unsubstituted lower alkyl group;
R
11
is H, halogen, hydroxyl, a substituted or unsubstituted alkyl, alkoxy or alkylthio group;
R
9
is a substituent having the formula:
wherein:
R
12
and R
13
are 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;
A
2
is C(R
14
)(R
15
), N(R
16
) S, S(O), S(O)
2
, or O; where each R
14
, R
15
, and R
16
is independently H or lower alkyl;
each A
3
present is independently C(R
14
)(R
15
), N(R
16
), S, S(O), S(O)
2
, or O; where each R
14
, R
15
, and R
16
is independently H or lower alkyl;

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