Antipicornaviral compounds, compositions containing them,...

Details Antipicornaviral compounds, compositions containing them,... Antipicornaviral compounds, compositions containing them,...

1999-10-20

2001-12-18

Padmanabhan, Sreeni (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S378000, C514S415000, C514S423000, C514S436000, C514S440000, C514S553000, C514S539000, C546S280700, C546S335000, C548S245000, C548S491000, C548S550000, C549S039000, C560S009000, C560S015000, C560S017000, C560S029000, C560S039000, C560S042000

Reexamination Certificate

active

06331554

ABSTRACT:

BACKGROUND OF THE INVENTION
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.
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, 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.
SUMMARY OF THE INVENTION
The present invention is directed to compounds that function as picornaviral 3C protease inhibitors, particularly those that have antiviral activity. It is further directed to the 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:
M is O or S;
R
1
is H, F, an alkyl group, OH, SH, or an O-alkyl group;
R
2
and R
5
are independently selected from H,
 or an alkyl group, wherein the 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;
A, 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;
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;
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 further 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(O)—, —C(R′
13
)(R′
14
)—, —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;
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;
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;
and further 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;
R
3
and R
6
are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, op aryl group, a heteroaryl group, —C(O)R
17
, —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, R
3
and R
6
together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
R
7
is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR
7
, —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 R
7
, together with R
3
or R
6
and the atoms to which they are attached, form a heterocycloalkyl group;
R
20
is H, OH, or any suitable organic moiety; and
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

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