Benzimidazolone antiviral agents

Details Benzimidazolone antiviral agents Benzimidazolone antiviral agents

2001-09-14

2003-01-14

Rao, Deepak R. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S254060, C514S269000, C514S322000, C514S363000, C514S364000, C514S370000, C514S381000, C514S387000, C544S139000, C544S310000, C544S370000, C546S199000, C546S273700, C548S113000, C548S139000, C548S132000, C548S181000, C548S250000, C548S350100

Reexamination Certificate

active

06506738

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 benzimidazolone derivatives 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. RespiGam, approved for prophylaxis in high risk pediatric patients, is an intravenous immunoglobulin which effectively neutralizes the virus. Recently, Synagis, a monoclonal antibody administered through intramuscular injection has also been approved for use in high risk pediatric patients. However, both drugs are very expensive. Accordingly, inexpensive, safe and effective antiviral agents against respiratory syncytial virus will be beneficial for patients.
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 Ceterizine, 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.
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.
In addition, T. Nitz, et al., (WO Patent, WO 00/38508, 1999) disclosed a series of triaryl containing compounds that were useful for the treatment and/or prevention of RSV and related pneumoviral infections.
A related series of compounds were first disclosed by F. Pagani and F. Sparatore in
Boll Chim Farm.
1965, 104, 427 and by G. Paglietti, et al. in
Il Farmaco, Ed. Sci.
1975, 30, 505, and found to possess analgesic and anti-arrhythmic activity. The structural formula for these compounds are depicted in Formula Ia and Ib.
In Formula Ia and Ib, A is —(CH
2
)n-N(R)
2
, n=2 or 3, R═Me or Et,
Another series of closely related compounds that Sparatore had disclosed were in
Il Farmaco Ed. Sci.
1967, 23, 344 (U.S. Pat. No 3,394, 141, 1968). Some of the compounds were reported to have analgesic, anti-inflammatory or anti-pyretic activities. The structure of these compounds is depicted in formula Ic. In Formula Ic, C═H, CF
3
, or N
2
. D is —(CH
2
)n-NR
2
, n=2 or 3, R═Me or Et, or
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 R═NH, S, or O; Q═—NHCOPh, —COOH, COOEt, or CN; T═COMe, CN, or COOEt; G=O or NH.
Another series of 2-aminobenzimidazoles have been reported by E. Janssens, et al. as inhibitors of RSV in a series of recent publications and representative examples formula 1f-1h are shown below from PCT WO 01/0061 1 A1; PCT WO 01/00612 and PCT WO 01/00615, respectively all published on Jan. 4, 2001.
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.
Also, H. R. Howard et al. reported a series of benzimidazolone-1-acetic acids that possessed aldolase reductase inhibitory activity (
Eur. J. Med. Chem.
1992, 27, 779-789).
Other prior art related to the chemical structure of the present invention:
(1) F. Sparatore, et al, “Derivati Benzotriazolici Attivi Sull′accrescimento Delle Piante,”
Il Farmaco Ed. Sci.
1978, 33, 901.
(2) Katritzky, A. R. et al, “Synthesis and Transformations Of Substituted Benzazolyl- and Tetrazolyl(benzotriazol-1-yl)methanes,”
J. Heterocyclic Chem.
1996,33,1107.
(3) Terri A. Fairley, et al. “Structure, DNA Minor Groove Binding, And Base Pair Specificity of Alkyl and Aryl-Linked Bis(amidinobenzimidazoles) and Bis(amidinoindoles),
J. Med Chem.
1993, 36, 1746.
(4) R. K. Upadhyay et al, “New Synthesis and Biological Evaluation,”
Indian J Heterocyclic Chem.
1994, 4, 121.
(5) A. R. Katritzky, et al, “A New Route to N-substituted Heterocycles,”
Tetrahedron,
1993, 49, 2829.
(6) K. Yu et al. in Substituted Benzimidazole Anti-viral Agents, PCT WO 00/04900 published February 3, 2000.
SUMMARY OF THE INVENTION
This invention relates to the antiviral activity against RSV found in a series of 1-substituted 2-(3′-N-substituted 2-oxo-benzimidazolylmethyl)-benzimidazoles. The structural formula for these compounds are depicted in Formula 1, and includes pharmaceutically acceptable salts thereof.
wherein:
R
1
is —(CR
v
R
w
)
n
—X;
R
v
and R
w
are independently selected from the group consisting of H, C
1-6
alkyl, and C
2-6
alkenyl; optionally substituted with 1-6 of the same or different halogen;
X is H, C
1-6
alkyl, C
2-6
alkenyl; each of said C
1-6
alkyl, C
2-6
alkenyl being optionally substituted with (1) one to six same or different halogen or hydroxy; (2) a member selected from the group consisting of phenyl, —C(═NOH)NH
2
, —CH(OH)-Ph, -Ph-S(O)
2
C
1-6
alkyl,
(3) a member from Group A1;
Group A1 is CN, OR′, NR′R″, R′NCOR″, NR′CONR″R′″, NR′SO
2
R″, NR′COOR″, COR′, COOR′, OS(O)
2
R′, S(O)
t
R′ or PO(OR′)
2
;
n is 1-6;
tis0-2;
R
2
is
(i) H, C
1
alkyl, C
2-6
alkenyl, phenyl, or a functionality selected from Group A2 or Group B; each of said C
1-6
alkyl, C
2-6
alkenyl, and phenyl being optionally substituted with (1) one to six same or different halogen or hydroxy or (2) one to two same or different members of Group A or Group B;
(ii) —(CR
x
R
Y
)
n′
, —(CO)
p
—C
6
H
4
-(Z
1
)(Z
2
), wherein Z
1
and Z
2
are each independently selected from the group consisting of Group A, Group B, and —(CH
2
)
n′
—Z′; wherein said Z′ is heterocycle or —(NR
d
R
e
R
f
)+(halogen)-; and the Z
1
and Z
2
groups may each be in the ortho, meta or para position relative to the —(CR
x
R
Y
)
n′
—(CO)
p
-group; wherein R
d
, R
e
and R
f
are independently C
1-6
alkyl, C
2-6
alkenyl, OH or C
1-6
alkyl COOH;
p is 0 or 1;
n′ is 1-6; or
(iii) —(CR
x
R
y
)
n″
—heterocycle;
n″ is 0-6;
R
3
, R
6,
R
7
and R
10
are each independently H;
R
5
, R
8
and R
9
are each independently H, halogen or CF
3
;
R
4
is selected from the group consisting of H, halogen, CN, —C(O)C
1-6
alkyl and
 R
11
, R
12
are each independently H;
R
x
, R
y
are each independently H or C
1-6
alkyl;
Group A2 is COR′, COOR′, CONRR″″ or CONR′SO
2
R″;
Group A3 is CN, N
2
, OR′, OCONR′R″, NR′R″, N(R′) COR″, N(R′)CONR″R″′,
NR′SO
2
R″, NR′COOR″, SO
m
R′, SO
2
NR′R″, SO
2
NR′COR″ or PO(OR′)
2
;
Group A is a member selected from Group A2 and

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