Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-23
2002-12-03
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S118000
Reexamination Certificate
active
06489338
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns antiviral compounds, their methods of preparation and their compositions, and use in the treatment of viral infections. More particularly, the invention provides imidazopyridine and imidazopyrimidine derivatives (Formula I) for the treatment of respiratory syncytial virus infection.
2. Background Art
Respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory tract infection in infants, children, elderly and immunocompromised persons. Severe infection of the virus may result in bronchiolitis or pneumonia which may require hospitalization or result in death. (
JAMA,
1997, 277, 12). Currently only Ribavirin is approved for the treatment of this viral infection. Ribavirin is a nucleoside analogue which is administered intranasally as an aerosol. The agent is quite toxic, and its efficacy has remained controversial. Other than Ribavirin, RespiGam and Synagis are an immunoglobulin and monoclonal antibody, respectively, that neutralize RSV. They are the only two biologics that have been approved for prophylactic use in high risk pediatric patients for RSV infection. Both RespiGam and Synagis are very expensive and require parental administration.
Many agents are known to inhibit respiratory syncytial virus (De Clercq,
Int. J. Antiviral Agents,
1996, 7, 193). Y. Tao et al. (EP 0 058 146 A1, 1998) disclosed that Cetirizine, a known antihistamine, exhibited anti-RSV activity. Tidwell et al.,
J. Med. Chem.
1983, 26, 294 (U.S. Pat. No. 4,324,794, 1982), and Dubovi et al.,
Antimicrobial Agents and Chemotherapy,
1981, 19, 649, reported a series of amidino compounds with the formula shown below as inhibitors of RSV.
Hsu et al., U.S. Pat. No. 5,256,668 (1993) also disclosed a series of 6-aminopyrimidones that possess anti-viral activity against RSV.
In addition, Y. Gluzman, et al., (AU Patent, Au-A-14,704, 1997) and P. R. Wyde et al. (
Antiviral Res.
1998, 38, 31) disclosed a series of triazine containing compounds that were useful for the treatment and/or prevention of RSV infection.
Another series of compounds structurally related to this invention are pyrido[1,2-a]benzoazoles and pyrimidio[1,2a]benzimidazoles disclosed by S. Shigeta et al in
Antiviral Chem.
&
Chemother.
1992, 3, 171. These compounds have demonstrated inhibition of orthomyxovirus and paramyxovirus replication in HeLa cells. The structures of these compounds are shown in formulas Id and Ie, in which F═NH, S, or O; Q═—NHCOPh, —COOH, COOEt, or CN; T═COMe, CN, or COOEt; G═O or NH.
A bis-benzimidazole with an ethylenediol linker shown below has also been reported as a potent inhibitor of rhinoviruses (Roderick, et al.
J. Med. Chem.
1972, 15, 655).
Other structurally related compounds are bis-benzimidazoles which possess antifungal activity (B. Cakir, et al.
Eczacilik Fak. Derg.
1988, 5, 71).
Most recently Yu et al. have discovered a series of benzimidazoles (Formula II) for the treatment and prevention of RSV infection (WO 00/04900). In addition, Theodore Nitz has also found a series of compounds with Formula III that inhibit RSV in Hep-2 cell tissue culture assay (WO 99/38508). Although many other agents are known to inhibit respiratory syncytial virus (De Clercq,
Int. J. Antiviral Agents,
1996, 7, 193) none of them have been used in human clinical trials. Thus, there is a medical need for a convenient and less expensive anti-viral agent for the treatment and prevention of RSV infection.
SUMMARY OF THE INVENTION
This invention relates to compounds having the Formula I, and pharmaceutically acceptable salts thereof
wherein:
W is O or S;
R
1
is —(CR′R″)
n
—X;
X is H, C
1-12
alkyl, C
2-12
alkenyl, C
2-12
alkynyl, C
3-7
cycloalkyl, C
4-7
cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionally substituted with one to six of the same or different halogen atoms; halogen, CN, OR′, OCOR″″, NR′R″, NR′COR″, NR′CONR″R′″, NR′SO
2
R″, NR′COOR″, COR′, CR′″NNR′R″, CR′NOR″, COOR′, CONR′R″, SO
m
R′, PO(OR′)
2
, aryl, heteroaryl or non-aromatic heterocycle;
m is 0-2; n is 2-6;
R
2
is
(i) H, C
1-12
alkyl, C
2-12
alkenyl, C
2-12
alkynyl, C
3-7
cycloalkyl, C
4-7
cycloalkenyl, —(CH
2
)
t
, C
3-7
cycloalkyl, —(CH
2
)
t
, C
4-7
cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionally substituted with one to six of the same or different halogen atoms; SO
2
R″, SO
2
NR′R″ or CN; wherein t is 1-6;
(ii) —(CR′R″)
n′
—Y, wherein Y is CN, OR′, OCONR′R″, NR′R″, NCOR′, NR′SO
2
R″, NR′COOR″, NR′CONR″R′″, COR′, CR′″NNR′R″, CR′NOR″, COOR′, CONR′R″, SO
m
R′, SO
2
NR′R″ or PO(OR′)
2
; wherein
m is 0-2 and n′ is 1-6;
(iii) —(CR′R″)
n″
—C
6
H
4
—Z, wherein the Z group may be in the ortho, meta or para position relative to the —(CH
2
)
n″
group; Z is CN, OR′, OCONR′R″, NO
2
, NR′R″, NCOR′, NR′SO
2
R″, NR′COOR″, NR′CONR″R′″, COR′, CR′″NNR′R″, CR′NOR″, COOR′, CONR′R″, SO
m
R′, SO
2
NR′R″ or PO(OR′)
2
;
m is 0-2; n″ is 0-6; or
(iv) —(CR′R″)n′″-heteroaryl, wherein n′″ is 0-6;
(v) —(CR′R″)n′″-non-aromatic heterocycle, wherein n′″ is 0-6;
R
3
, R
4
, R
5
and R
6
are each independently hydrogen, halogen, C
1 6
alkyl, C
1-6
alkyl substituted with one to six of the same or different halogen atoms, OR′, CN, COR′, COOR′, CONR′R″, or NO
2
;
A, B, E, D are each independently C—H, C—Q—, N, or N—O; provided at least one of A, B, E or D is not C—H or C—Q; wherein Q is halogen, C
1-3
alkyl or C
1-3
alkyl substituted with one to three of the same or different halogen atoms; and
R′, R″, R′″ are each independently H, C
1-6
alkyl, C
2
6
alkenyl, C
2-6
alkynyl, C
3-7
cycloalkyl, C
4-7
cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl being optionally substituted with one to six of the same or different halogen atoms; or R′ and R″ taken together form a cyclic alkyl group having 3 to 7 carbon atoms; benzyl or aryl;
R″″ is C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-7
cycloalkyl, C
4-7
cycloalkenyl, NR′R″, CR′NR″R′″, aryl, heteroaryl, non-aromatic heterocycle; and
Non-aromatic heterocycle is a 3-7 membered non-aromatic ring containing at least one and up to 4 non-carbon atoms selected from the group consisting of O, S, N, and NR′;
Aryl is phenyl, naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl;
Heteroaryl is a 4-7 membered aromatic ring which contains one to five heteroatoms independently selected from the group consisting of O, S, N or NR′, wherein said aromatic ring is optionally fused to group B′;
B′ is an aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl;
Aryl, B′, said 4-7 membered aromatic ring, and said 3-7 membered non-aromatic ring may each independently contain one to five substituents which are each independently selected from R
7
, R
8
, R
9
, R
10
or R
11
; and R
7
, R
8
, R
9
, R
10
and R
11
are each independently
(i) H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-7
cycloalkyl, C
4-7
cycloalkenyl, each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl being optionally substituted with one to six of the same or different halogen atoms; and
(ii) halogen, CN, NO
2
, OR′, NR
Civiello Rita L.
Combrink Keith D.
Gulgeze Hatice Belgin
Meanwell Nicholas A.
Sin Ny
Bristol--Myers Squibb Company
DuBoff Samuel J.
Raymond Richard L.
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