Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-09
2004-03-16
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S392000, C546S274100, C548S311100, C548S323500
Reexamination Certificate
active
06706739
ABSTRACT:
BACKGROUND
The Picornaviridae family includes nearly 70 distinct serotypes of enteroviruses (EVs). Clinical manifestations of enterovirus infection range from mild “summer cold” to neurological and cardiovascular disorders.
An enterovirus consists of a simple virus capsid and a single strand of positive sense RNA. The capsid contains four proteins, VP1 to VP4. Variations within capsid proteins VP1 to VP3 are responsible for antigenic diversity among the enteroviruses, with neutralization sites most densely clustered on VP1 (Rueckert,
Virology
, Lippincott-Raven, New York, 1990, 507). Replication of RNA viruses is directed by viral RNA polymerase of relatively low fidelity that have an error frequency of 10
−3
to 10
−4
misincorporated nucleotides per round of replication (Holland et al.,
Science
, 1982, 215:1576-1585; Ward et al.,
J. Virol
., 1988, 62:558-562; and La Torre et al.,
J. Virol
., 1990, 64:664-671). In other words, replication of an enteroviruses genome consisting of about 7500 nucleotides results in a population molecules having on average at least one mutation. Moreover, recombination occurs at a very high frequency in the picornaviruse family (McCahon,
Arch. Virol
., 1981, 69:1-23).
There is a need to develop compounds which are effective in treating infection by genetically heterogeneous enteroviruses.
SUMMARY
One aspect of the present invention relates to a compound having the generic formula:
Referring to the formula, each of R
1
and R
3
, independently, is C
6-12
aryl, C
6-12
aralkyl, or heteroaryl, optionally substituted with one or more halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —C(O)R
4
, —SR
4
, —S(O)R
4
, —S(O)
2
R
4
, —NR
4
R
5
, —C(O)OR
4
, —C(O)NR
4
R
5
, —NO
2
, —O(O)CR
4
, —NR
4
(O)CR
5
, —NR
4
C(O)OR
5
, —NR
4
C(O)NR
5
R
6
, or R
7
, provided that if R
1
is heteroaryl, the heteroaryl forms a C—N bond with the imidazolidinone ring. R
2
is H, C
1-5
alkyl, C
1-5
haloalkyl, C
6-12
aryl, C
6-12
aralkyl, or heteroaryl, optionally substituted (e.g., mono- or di-substituted) with halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —C(O)R
4
, —SR
4
, —S(O)R
4
, —S(O)
2
R
4
, —NR
4
R
5
, —C(O)OR
4
, —C(O)NR
4
R
5
, —NO
2
, —O(O)CR
4
, —NR
4
(O)CR
5
, —NR
4
C(O)OR
5
, or —NR
4
C(O)NR
5
R
6
. Each of R
4
, R
5
, and R
6
, independently, is H or C
1-4
alkyl. R
7
is C
6-12
aryl, C
6-12
aralkyl, or heteroaryl, optionally substituted with halogen, C
1-4
alkyl, C
1-4
haloalkyl, —OR
4
, —NO
2
, —C(O)OR
4
, —CN, —NR
4
R
5
, or NR
4
C(O)OR
5
. T is NH or O; W is —CH
2
—O—, —(CH
2
)
2
—O—, —(CH
2
)
3
—O—, or —(CH
2
)
4
—O—; m is 4, 5, 6, 7 or 8; and each of x and y, independently, is 0 or 1, provided that at least one of x and y is 1.
The term “halogen” refers to fluorine, chlorine, bromine or iodine. The term “alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, a C
4
alkyl has 4 carbon atoms. The term “haloalkyl” refers to a straight-chain or branched hydrocarbon chain in which at least one hydrogen is replaced with halogen (e.g., —C(CH
3
)
2
CH
2
Cl or —CF
3
). The term “aryl” refers to a 6 to 12-carbon monocyclic or multicyclic aromatic system wherein up to 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include but are not limited to phenyl and naphthyl. The term “aralkyl” refers to alkyl substituted with aryl. The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic (each heteroatom being O, N, or S). Examples of heteroaryl groups include but are not limited to pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, quinolinyl, indolyl, and thiazolyl. The aryl or heteroaryl group can be connected to other moieties at one of more ring atoms that are available. For instance, a pyridyl can be connected at its 2-, 3- or 4-position with the 1-N atom of the imidazolidinonyl group.
Referring to the above formula, one subset of the compounds are featured by that each of R
1
and R
3
, independently, is C
6-12
aryl, C
6-12
aralkyl, or heteroaryl, optionally substituted with halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —SR
4
, —NR
4
R
5
, —NR
4
C(O)NR
5
R
6
, or R
7
; and R
7
is C
6-12
aryl or heteroaryl, optionally substituted with C
1-4
haloalkyl, halogen, —OR
4
, or —NO
2
. These compounds include those in which each of R
1
and R
3
, independently, can be pyridinyl, phenyl, or thiazolyl, optionally substituted with halogen, —OR
4
, C
1-4
alkyl, C
1-4
alkyl-OR
4
, —CN, —SR
4
, —NR
4
R
5
, —NR
4
C(O)NR
5
R
6
, or R
7
, wherein R
7
is C
6-12
aryl or heteroaryl, optionally substituted with C
1-4
haloalkyl, halogen, —OR
4
, or —NO
2
; those in which R
2
can be H, C
1-5
alkyl, C
1-5
haloalkyl, C
6-12
aryl, C
6-12
aralkyl, or heteroaryl, optionally substituted with halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —SR
4
, —NR
4
R
5
, or —C(O)NR
4
R
5
; and those in which x is 1 and T is O.
Another subset of the compounds are featured by that R
2
is H, C
1-5
alkyl, C
6-12
aryl, C
6-12
aralkyl, or heteroaryl, optionally substituted with halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —SR
4
, —NR
4
R
5
, or —C(O)NR
4
R
5
. In these compounds, x can be 1 and T can be O.
A further subset of the compounds are featured by that x is 1 and T is O.
Yet still another subset of the compounds are featured by that y is 1, and W is —(CH
2
)
2
—O— or —(CH
2
)
3
—O—. These compounds include those in which x is 1 and T is O; those in which each of R
1
and R
3
, independently, is C
6-12
aryl, C
6-12
aralkyl, or heteroaryl, optionally substituted with halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —SR
4
, —NR
4
R
5
, —NR
4
C(O)NR
5
R
6
, or R
7
, R
7
being C
6-12
aryl or heteroaryl, optionally substituted with C
1-4
haloalkyl, halogen, —OR
4
, or —NO
2
; and those in which R
2
is H, C
1-5
alkyl, C
1-5
haloalkyl, C
6-12
aryl, C
6-12
aralkyl, or heteroaryl, optionally substituted with halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —SR
4
, —NR
4
R
5
, or —C(O)NR
4
R
5
. They further include compounds in which each of R
1
and R
3
, independently, is pyridinyl, phenyl, or thiazolyl, optionally substituted with halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —SR
4
, —NR
4
R
5
, —NR
4
C(O)NR
5
R
6
, or R
7
, wherein R
7
is C
6-12
aryl or heteroaryl, optionally substituted with C
1-4
haloalkyl, halogen, —OR
4
, or —NO
2
. Examples of such compounds include:
Still a further subset of the compounds are featured by that y is 0. These compounds include those in which each of R
1
and R
3
, independently, is C
6-12
aryl, C
6-12
aralkyl, or heteroaryl, optionally substituted with halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —SR
4
, —NR
4
R
5
, —NR
4
C(O)NR
5
R
6
, or R
7
, wherein R
7
is C
6-12
aryl or heteroaryl, optionally substituted with C
1-4
haloalkyl, halogen, —OR
4
, or —NO
2
; those in which R
2
is H, C
1-5
alkyl, C
1-5
haloalkyl, C
6-12
aryl, C
6-12
aralkyl, or heteroaryl, optionally substituted with halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —SR
4
, —NR
4
R
5
, or —C(O)NR
4
R
5
; those in which x is 1, and T is O. They also include compounds in which each of R
1
and R
3
, independently, is pyridinyl, phenyl, or thiazolyl, optionally substituted with halogen, —OR
4
, C
1-4
alkyl, C
1-4
haloalkyl, C
1-4
alkyl-OR
4
, —CN, —SR
4
, —NR
4
R
5
, —NR
4
C(O)NR
5
R
6
, or R
7
, and R
7
is C
6-12
aryl or heteroaryl, optionally substituted with C
1-4
haloalkyl, halogen, —OR
4
, or —NO
2
. Examples of such compounds include:
The compounds described above include their pharmaceutically acceptable salts and prodrugs, if applicable. Such a salt can be forme
Chang Chung-Ming
Chen Shu-Jen
Chern Jyh-Haur
Hsu Ming-Chu
Li Wen-Tai
National Health Research Institute
Seaman D. Margaret
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