Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-15
2002-10-01
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S058200, C544S113000, C544S116000, C544S235000
Reexamination Certificate
active
06458788
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention provides novel cinnolines, which are useful as antiviral agents (e.g. as agents against viruses of the herpes family).
2. Technology Description
The herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans.
HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease. VZV is the causative agent of chicken pox and shingles. EBV causes infections mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the causative agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi's sarcoma, body cavity based lymphomas, and multiple myeloma.
U.S. Pat. No. 4,826,837 discloses 4-hydroxycinnoline-3-carboxamides and their use for the treatment of neoplastic diseases and acute and chronic infections of both bacterial and viral origin in mammals.
U.S. Pat. No. 4,886,800 discloses 4-substituted-cinnoline-3-carboxylic acids and 3-acyl-4-substituted-cinnoline derivatives and their use as central nervous system depressants.
U.S. Pat. Nos. 5,753,666 and 5,891,878 and WO 97/04775 disclose 1-alkyl-substituted-quinolone-3-carboxamides that are alleged to have therapeutic utility via inhibition of Phosphodiesterase IV esterase and/or Tumor Necrosis factor activity.
WO 99/38867 discloses 1-cycloalkyl-1,8-naphthyridin-4-one derivatives; pharmacologically acceptable salts or solvates thereof; and a phosphodiesterase IV inhibitor containing any of the above as an active ingredient.
Commonly assigned PCT/U.S. 98/25192 discloses 4-hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents.
Despite the above teachings, there still exists a need in the art for novel compounds that demonstrate desirable antiviral activity.
BRIEF SUMMARY OF THE INVENTION
In accordance with the present invention, novel compounds which demonstrate antiviral activity are provided. More specifically, the compounds are 4-hydroxy-3-cinnolinecarboxamides which are useful as antiviral agents, particularly against herpes viruses.
Even more specifically, the compounds are of formula (II)
or a pharmaceutically acceptable salt thereof wherein,
A is
(a) Cl,
(b) Br,
(c) CN,
(d) NO
2
, or
(e) F;
R
1
is
(a) aryl,
(b) S(O)
m
R
6
,
(c) (C═O)R , with the proviso that if R
6
is NR
7
R
8
, then R
7
and R
8
do not both equal H
(d) (C═O)OR
9
,
(e) cyano,
(f) het, wherein said het is bound via a carbon atom,
(g) Ohet,
(h) NR
7
R
8
with the proviso that R
7
and R
8
do not both equal H
(i) SR
10
,
(j) Shet,
(k) NHCOR
12
,
(l) NHSO
2
R
12
,
(m) C
1-7
alkyl which is partially unsaturated and optionally substituted by one or more substituents of the group R
11
, OR
13
, SR
10
, SR
13
, NR
7
R
8
, halo, (C═O)C
1-7
alkyl, or SO
m
R
9
, or
(n) C
1-7
alkyl which is substituted by one or more substituents of the group R
11
, OR
13
, SR
10
, SR
13
, NR
7
R
8
, halo, (C═O)C
1-7
alkyl, or SO
m
R
9
;
R
2
is
(a) H,
(b) halo,
(c) aryl,
(d) S(O)
m
R
6
,
(e) (C═O)R
6
,
(f) (C═O)OR
9
,
(g) cyano,
(h) het, wherein said het is bound via a carbon atom,
(i) OR
10
,
(j) Ohet,
(k) NR
7
R
8
,
(l) SR
10
,
(m) Shet,
(n) NHCOR
12
,
(o) NHSO
2
R
12
, or
(p) C
1-7
alkyl which may be partially unsaturated and optionally substituted by one or more substituents of the group R
11
, OR
13
, SR
10
, SR
13
, NR
7
R
8
, halo, (C═O)C
1-7
alkyl, or SO
m
R
9
, or
(q) R
1
together with R
2
form a carbocyclic or het which may be optionally substituted by NR
7
R
8
, or C
1-7
alkyl which may be optionally substituted by OR
14
;
R
6
is
(a) C
1-7
alkyl,
(b) NR
7
R
8
(c) aryl, or
(d) het, wherein said het is bound via a carbon atom;
R
7
and R
8
are independently
(a) H,
(b) aryl,
(c) C
1-7
alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from NR
10
R
10
, R
11
, SO
m
R
9
, CONR
10
OR
10
O, or halo, or,
(d) R
7
and R
8
together with the nitrogen to which they are attached form a het;
R
9
is
(a) aryl,
(b) het,
(c) C
3-8
cycloalkyl,
(d) methyl, or
(e) C
2
7
alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from NR
10
R
10
, R
11
, SH, CONR
10
R
10
, or halo;
R
10
is
(a) H,
(b) methyl, or
(c) C
2-7
alkyl optionally substituted by OH;
R
11
is
(a) OR
10
,
(b) Ohet,
(c) Oaryl,
(d) CO
2
R
10
,
(e) het,
(f) aryl,
(g) CN, or
(h) C
3-8
cycloalkyl which may be partially unsaturated and optionally substituted by one or more substituents seleted from a group consisting of R
11
, NR
7
R
8
, SO
m
R
9
, or C
1-7
alkyl optionally substituted by R
11
, NR
7
R8, or SO
m
R
9
;
R
12
is
(a) H,
(b) het,
(c) aryl,
(d) C
3-8
cycloalkyl,
(e) methyl, or
(f) C
2
7
alkyl optionally substituted by NR
7
R
8
or R
11
;
R
13
is
(a) (P═O)(OR
14
)
2
,
(b) CO(CH
2
)
n
CON(CH
3
)—(CH
2
)
n
SO
3
−
M
+
,
(c) an amino acid,
(d) C(═O)aryl, or
(e) C(═O)C
1-7
alkyl optionally substituted by NR
7
R
8
, aryl, het, CO
2
H, or O(CH
2
)
n
CO
2
R
14
;
R
14
is
(a) H, or
(b) C
1-7
alkyl;
each n is independently 1, 2, 3, 4 or 5;
each m is independently 0, 1, or 2;
M is sodium, potassium, or lithium;
aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic;
wherein any aryl is optionally substituted with one or more substituents selected from the group consisting of halo, OH, cyano, CO
2
R
14
, CF
3
, C
1-6
alkoxy, and C
1-6
alkyl which may be further substituted by one to three SR
14
, NR
14
R
14
, OR
14
, or CO
2
R
14
groups;
het is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group;
wherein any het is optionally substituted with one or more substituents selected from the group consisting of halo, OH, cyano, phenyl, CO
2
R
14
, CF
3
, C
1-6
alkoxy, oxo, oxime, and C
1-6
alkyl which may be further substituted by one to three SR
14
, NR
14
R
14
, OR
14
, or CO
2
R
14
groups.
In particularly preferred embodiments, R
1
is either CH
2
-morpholine, CH
2
-(tetrahydro-2H-pyran-4-yl), alkynl-CH
2
OH or (CH
2
)
3
OH.
Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of formula (II) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In preferred embodiments, the composition preferably comprises a therapeutically effective amount of the compound or salt.
Still another embodiment of the present invention provides a method for treating a disease or condition in a mammal caused by a viral infection, particularly a herpes viral infection, comprising administering to the mammal a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.
A further embodiment of the present invention comprises the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing diseases or disorders caused by a viral infection, and particularly a herpes viral infection.
A final embodiment of the present invention comprises a method for inhibi
Larsen Scott D.
Nair Sajiv K.
Vaillancourt Valerie A.
Pharmacia & Upjohn Company
Ramsuer Robert W.
Solomon Andrew M.
Yang Lucy X.
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