Antipicornaviral compounds and compositions, their...

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

1999-04-29

2003-03-11

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S351000, C514S378000, C514S423000, C546S329000, C548S248000

Reexamination Certificate

active

06531452

ABSTRACT:

FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION
The invention pertains to peptide-like and 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 such compounds in pharmaceutical compositions and therapeutic treatments for rhinoviral infections. The invention further relates to processes for synthesizing such compounds and compounds useful in such syntheses.
BACKGROUND OF THE INVENTION
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 on the market 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 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. patent application Ser. No. 08/850,398, filed May 2, 1997, now U.S. Pat. No. 5,856,530 by Webber et al.; U.S. patent application Ser. No. 08/991,282, filed Dec. 16, 1997, U.S. Pat. No. 6,020,371 by Dragovich et al.; and U.S. patent application Ser. No. 08/991,739, filed Dec. 16, 1997, U.S. Pat. No. 5,962,487 by Webber et al. These U.S. patent applications, the disclosures of which are incorporated herein by reference, describe certain antipicornaviral compounds. There is still a desire to discover small-molecule compounds that are especially potent antipicornaviral agents.
SUMMARY OF THE INVENTION
Thus, an object of this invention is to discover small-molecule compounds that are especially potent antipicornaviral agents. A further object of the invention is to provide intermediates useful for the synthesis of said protease-inhibiting compounds and synthetic methods useful for such syntheses. A yet further object of the invention is to achieve pharmaceutical compositions that are highly effective for treating maladies mediated by inhibition of picornaviral 3C proteases, such as the common cold.
Such objects have been attained through the discovery of compounds of the invention, which are picornaviral 3C protease inhibitors displaying particularly strong antiviral activity. It has surprisingly been discovered that peptido and peptidomimetic compounds containing a five-membered heterocyclic group have high rhinoviral-protease-inhibiting activity. It has further been surprisingly found that the rhinoviral-protease-inhibiting activity of peptido and peptidomimetic compounds may be significantly enhanced by replacing a glutamine-like moiety found in some known rhinoviral-protease-inhibiting compounds with a side-chain comprising a gamma- or delta-lactam.
The inhibitors of the present invention are of the following general formula (I):
wherein:
Y is —N(R
y
)—, —C(R
y
)(R
y
)—, or —O—, where each R
y
is independently —H or lower alkyl;
R
1
is —H, —F, -alkyl, —OH, —SH, or an O-alkyl group;
R
2
and R
3
are each independently H;
 or
 where n is an integer from 0 to 5, A
1
is CH or N, A
2
and each A
3
are independently selected from C(R
41
)(R
41
), NR
41
), S, S(O), S(O)
2
, and O, and A
4
is NH or NR
41
, where each R
41
is independently H or lower alkyl, provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A
1
, A
2
, (A
3
)
n
, A
4
and C═O, and at least one of R
2
and R
3
is
R
5
and R
6
are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
R
7
and R
8
are each independently H, 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
, where R
17
, R
18
, and R
19
are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group, provided that at least one of R
7
and R
8
is 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
;
R
9
is a suitable organic moiety; and
Z and Z
1
are each 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
, where R
21
, R
22
, R
23
, and R
24
are each 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 where 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, provided that Z and Z
1
are not both H;
or Z
1
and R
1
, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z
1
and R
1
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.
The invention also pertains to prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable solvates of compounds of the formula I.
In preferred embodiments of the compounds of the formula I, R
2
and R
3
are each independently H;
where n is an integer from 0 to 5, each R
41
is independently H or lower alkyl, and the stereochemistry at the carbon denoted with an asterisk may be R or S; provided that at least one of R
2
and R
3
is
Preferably, R
9
is a five-membered heterocycle having one to three heteroatoms selected from O, N, and S. Alternatively, R
9
is
where R
2
is
In other preferred embodiments, the variables of formula I are as follows. Z and Z
1
are each independently selected from H, F, lower alkyl, —CO
2
R
21
, and —C(O)NR
21
R
22
, provided that Z and Z
1
are not both H, where R
21
and R
22
are each 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 R
21
and R
22
, together with the atom(s) to which they are bonded, form a heterocycloalkyl group. At least one of R
2
or R
3
is
and the other is H. R
5
and R
6
are each independently selected from H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group, more prefer

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-3004396