Antipicornaviral compounds and methods for their use and...

Details Antipicornaviral compounds and methods for their use and... Antipicornaviral compounds and methods for their use and...

2000-10-13

2002-03-26

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C548S230000, C548S235000, C548S247000, C549S478000, C549S483000, C549S488000, C560S027000, C560S122000, C560S128000

Reexamination Certificate

active

06362166

ABSTRACT:

The invention pertains to the discovery and use of new compounds that inhibit the enzymatic activity of picornaviral 3C proteases, specifically rhinovirus proteases (RVPs), as well as retard viral growth in cell culture.
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, menigovirus, 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 to cure the common cold, only treatments that relieve the symptoms.
One strategy that may be useful to treat picornaviral infections is 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. In theory, inhibition of 3C proteases can 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, small molecules that are specifically recognized, may represent an important and useful approach to treat and cure viral infections of this nature and, in particular, the common cold.
SUMMARY OF THE INVENTION
The present invention is directed to compounds that functions as picornaviral 3C protease inhibitors, particularly those that have antiviral activity. It is further directed to the preparation and use of such 3C protease inhibitors. The Inventors demonstrate that the compounds of the present invention bind to rhinovirus 3C proteases and preferably have antiviral cell culture activity. The enzymatic inhibition assays used reveal that these compounds can bind irreversibly, and the cell culture assays demonstrate that these compounds can possess antiviral activity.
The present invention is directed to compounds of the formula (I):
wherein
R
1
is H, F, an alkyl group, OH, SH, an O-alkyl group, or an S-alkyl group;
R
2
and R
5
are independently selected from H,
 or an alkyl group, wherein said alkyl group is different from
 with the proviso that at least one of R
2
or R
5
must be
 and wherein, when R
2
or R
5
is
X is ═CH or ═CF and Y
1
is ═CH or ═CF
or X and Y
1
together with Q′ form a three-membered ring
in which Q′ is —C(R
10
)(R
11
)— or —O—, X is —CH— or —CF—, and Y
1
is —CH—, —CF—, or —C(alkyl)—, where R
10
and R
11
independently are H, a halogen, or an alkyl group, or, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
or X is —CH
2
—, —CF
2
—, —CHF—, or —S—, and
Y
1
is —O—, —S—, —NR
12
—, —C(R
13
)(R
14
)—, —C(O)—, —C(S)—, or —C(CR
13
R
14
)—
wherein R
12
is H or alkyl, and R
13
and R
14
independently are H, F, or an alkyl group, or, together with the atoms to which they are bonded, form a cycloalkyl group or a heterocycloalkyl group;
and A
1
is C, CH, CF, S, P, Se, N, NR
15
, S(O), Se(O), P—OR
15
, or P—NR
15
R
16
wherein R
15
and R
16
independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the atom to which they are bonded, form a heterocycloalkyl group;
and D
1
is a moiety with a lone pair of electrons capable of forming a hydrogen bond;
and B
1
is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR
17
, —SR
17
, —NR
17
R
18
, —NR
19
NR
17
R
18
, or —NR
17
OR
18
wherein R
17
, R
18
, and R
19
independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group, or, wherein any two of R
17
, R
18
, and R
19
, together with the atom(s) to which they are bonded, form a heterocycloalkyl group;
and with the provisos that when D
1
is the moiety ≡N with a lone pair of electrons capable of forming a hydrogen bond, B
1
does not exist; and when A
1
is an sp
3
carbon, B
1
is not —NR
17
R
18
when D
1
is the moiety —NR
25
R
26
with a lone pair of electrons capable of forming a hydrogen bond, wherein R
25
and R
26
are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
and wherein D
1
—A
1
—B
1
optionally forms a nitro group where A
1
is N;
and wherein, when R
2
or R
5
is
X is ═CH or ═CF and Y
2
is ═C, ═CH or ═CF,
or X and Y
2
together with Q′ form a three-membered ring
in which Q′ is —C(R
10
)(R
11
)— or —O—, X is —CH— or —CF—, and Y
2
is —CH—, —CF—, or —C(alkyl)—, where R
10
and R
11
independently are H, a halogen, or an alkyl group, or, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
or X is —CH
2
—, —CF
2
—, —CHF—, or —S—, and
Y
2
is —O—, —S—, —N(R′
12
)—, —C(R′
13
)(R′
14
)—, —C(O)—, —C(S)—, or —C(CR′
13
R′
14
)—
wherein R′
12
is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR′
13
, —NR′
13
R′
14
, —C(O)—R′
13
, —SO
2
R′
13
, or —C(S)R′
13
, and R′
13
and R′
14
, independently are H, F, or an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group or, together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
and wherein any combination of Y
2
, A
2
, B
2
, and D
2
forms a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
and A
2
is C, CH, CF, S, P, Se, N, NR
15
, S(O), Se(O), P—OR
15
, or P—NR
15
R
16
wherein R
15
and R
16
independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group or, together with the atom to which they are bonded, form a heterocycloalkyl group;
and D
2
is a moiety with a lone pair of electrons capable of forming a hydrogen bond;
and B
2
is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR
17
, —SR
17
, —NR
17
R
18
, —NR
19
NR
17
R
18
, or —NR
17
OR
18
wherein R
17
, R
18
, and R
19
independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group, or, wherein any two of R
17
, R
18
, and R
19
, together with the atom(s) to which they are bonded, form a heterocycloalkyl group;
R
3
and R
6
are independently H, F, or an alkyl group;
R
4
is H, OH, or a suitable organic moiety;
Z and Z
1
are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R
21
, —CO
2
R
21
, —CN, —C(O)NR
21
R
22
, —C(O)NR
21
OR
22
, —C(S)R
21
, —C(S)NR
21
R
22
, —NO
2
, —SOR
21
, —SO
2
R
21
, —SO
2
NR
21
R
22
, —SO(NR
21
)(OR
22
), —SONR
21
, —SO
3
R
21
, —PO(OR
21
)
2
, —PO(R
21
)(R
22
), —PO(NR
21
R
22
)(OR
23
), —PO(NR
21
R
22
)(NR
23
R
24
), —C(O)NR
21
NR
22
R
23
, or —C(S)NR
21
NR
22
R
23
,
wherein R
21
, R
22
, R
23
, and R
24
are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or wherein any two of R
21
, R
22
, R
23
, and R
24
, together with the atom(s) to which they are bonded, form a heterocycloalkyl group;
or Z
1
, as defined above, together with R
1
, as defined above, and the atoms to which Z and R
1
are bonded, form a cycloalkyl or heterocycloalkyl group,
or Z and Z
1
, both as defined above, together with the atoms to which they are bonded, form a cycloalkyl or heterocycl

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