Antipicornaviral compounds and compositions, their...

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

2000-08-03

2003-03-18

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S367000, C548S180000, C548S200000

Reexamination Certificate

active

06534530

ABSTRACT:

FIELD OF THE INVENTION
The invention pertains to certain 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 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.
Picomaviral 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. Pat. No. 5,856,530, issued Jan. 5, 1999, to Webber et al.; U.S. patent application Ser. No. 08/991,282, filed Dec. 16, 1997, by Dragovich et al.; U.S. patent application Ser. No. 08/991,739, filed Dec. 16, 1997, by Webber 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 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, issued Dec. 20, 1994, to Zimmermnan et al.; U.S. Pat. No. 5,498,616, issued Mar. 12, 1996, to Mallamo et al.; 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
Thus, an object of this invention is to discover small-molecule compounds that inhibit picornaviral 3C proteases and are especially potent antipicornaviral agents. A further object of the invention is to provide intermediates useful for the synthesis of protease-inhibiting compounds and synthetic methods useful for such syntheses. A yet further object of the invention is to achieve pharmaceutical compositions that are 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 following general formula 1:
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 unsubstituted or substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or —C(O)R
16
, where R
16
is unsubstituted or substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, or amine;
R
2
and R
8
are each independently H, F, or unsubstituted or substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R
3
and R
9
are each independently H or unsubstituted or substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —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, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or acyl;
R
4
is a suitable organic moiety;
R
5
, R
6
and R
7
are each independently H, F, or lower alkyl;
m is 0 or 1;
p is an integer of from 0 to 5;
A
1
is CH or N;
each A
2
present is independently C(R
10
)(R
11
), N(R
12
), S, S(O), S(O)
2,
or O, where each R
10
, R
11
and R
12
is independently H or lower alkyl;
each A
3
present is independently C(R
10
)(R
11
), N(R
12
), S, S(O), S(O)
2
, or O, where each R
10
, R
11
and R
12
is independently H or lower alkyl;
when p is 1, 2, 3, or 4, A
4
is N(R
13
), C(R
10
)(R
11
), or O, and when p is 0 (i.e., A
3
is not present), A
4
is N(R
13
)(R
14
), C(R
10
)(R
11
)(R
12
), and O(R
14
), provided that when p is 0 and A
4
is O(R
14
), A
1
is not CH, where each R
10
, R
11
and R
12
is independently H or lower alkyl, each R
13
is H, alkyl, aryl, or acyl, and each R
14
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).
In addition to compounds of the formula I, antipicomaviral agents of the invention include prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates of such compounds.
In a preferred embodiment of formula I, R
2
and R
8
are not both hydrogen, and R
3
and R
9
are not both hydrogen. In another preferred embodiment of formula I: R
2
is benzyl optionally substituted with a halogen; R
3
is a lower alkyl; R
4
is Cbz; and R
7
, R
8
, and R
9
are each H.
In a preferred embodiment, R
1
is a substituted methylene group, for example, —CH
2
NR
20
R
21
, —CH
2
OR
20
, —CH
2
OC(O)R
20
, —CH
2
ONR
20
R
21
, or —CH
2
SR
20
, where R
20
and R
21
are each independently selected from H, optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and —C(O)R
22
, where R
22
is selected from optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, and amine, and optionally any two of R
20
, R
21
, and R
22
, together with the atoms to which they are bound, form a 4- to 7-membered ring. In an alternative preferred embodiment, R
1
is —CR
23
═CR
24
R
25
or —C≡CR
26
, where R
23
, R
24
, R
25
and R
26
are each independently selected from H and optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In yet another preferred embodiment, R
1
is a —C(O)R
16
group, where R
16
is —NR
27
R
28
, wherein R
27
and R
28
are each independently selected from H and optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or R
27
and R
28
together with the nitrogen to which they are bound form a 4- to 7-membered heterocyclic ring. In another preferred embodiment, R
1
is a mono- or bi-cyclic heteroaryl or aryl group.
Especially preferred compounds are depicted by formula I-a:
wherein R
1
through R
6
, A
1
through A
4
, m, p, and Y are as defined above.
In preferred embodiments of c

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