Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-22
2003-09-23
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S220000, C514S220000, C514S229200, C514S230200, C514S233200, C514S243000, C514S248000, C514S250000, C514S267000, C514S292000, C514S294000, C540S496000, C540S547000, C544S009000, C544S032000, C544S066000, C544S089000, C544S101000, C544S111000, C544S115000, C544S126000, C544S183000, C544S234000, C544S252000, C544S344000, C544S346000, C546S084000, C546S094000
Reexamination Certificate
active
06624159
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention provides heterocycle carboxamide derivatives. These compounds are useful as antiviral agents, in particular, 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 infectious 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. 5,792,774 discloses specific quinoline derivatives that are alleged to have therapeutic utility via inhibition of Phosphodiesterase IV esterase and/or Tumor Necrosis factor activity.
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 specific heterocycle carboxamide derivatives which are useful as antiviral agents, particularly against herpes viruses.
Even more specifically, the present invention provides a compound of formula I,
wherein,
X is Cl, Br, F, CN or NO
2
;
G is
(a) C
1-4
alkyl which is fully saturated or partially unsaturated and is substituted by hydroxy, or
(b) C
1-4
alkyl substituted by NR
1
R
2
or 4-tetrahydropyran;
R
1
is C
2-7
alkyl substituted by hydroxy, C
1-4
alkoxy, aryl, or heteroaryl;
R
2
is hydrogen or C
1-7
alkyl;
or R
1
and R
2
together with the nitrogen to which they are attached form (a) a morpholine which may be optionally substituted by aryl or C
1-7
alkyl; or (b) a pyrrolidine ring substituted by hydroxy;
W is a heterocycle of formula W1, W2, W3, W4, W5, W6, W7 or W8
A is CR
4
or nitrogen;
B is CR
5
or nitrogen;
D is
(a) —(CR
13
R
14
)
a
—, where a is 2 or 3
(b) —(CR
15
R
16
)
4
—,
(c) —Y—CR
13
R
14
—CR
13
R
14
—,
(d) —CR
13
R
14
—Y—CR
13
R
14
—,
(e) —Y—CR
13
R
14
—Y—,
(f) —CR
13
R
14
—CR
13
R
14
—Y—,
(g) —Y—(CR
15
R
16
)
n
—,
(h) —Y—CR
15
═CR
15
—,
(i) —Y—CR
15
═N—,
(j) —CR
15
═CR
15
—Y—,
(k) —N═CR
15
—Y—,
(l) —(CR
15
R
16
)
b
—N═CR
15
—, where b is 0 or 1
(m) —CR
15
═N—(CR
15
R
16
)
b
—, where b is 0 or 1
(n) —N═N—,
(o) —N═CR
15
—(CR
15
R
16
)
b
—, where b is 0 or 1
(p) —CR
15
═CR
15
—,
(q) —N═N—Y—,
(r) —Y—N═N—,
(s) —Y—N═CR
15
—, or
(t) —CR
5
R
16
—Y—CR
15
R
16
—CR
15
R
16
—;
E is CR
8
or nitrogen;
J is CR
15
or nitrogen;
K is
(a) —(CR
15
R
16
)
a
—, where a is 2 or 3, or
(b) —CR
15
═CR
15
—,
L is
(a) —(CR
15
R
16
)
a
—, where a is 2 or 3, or
(b) —Y—(CR
15
R
16
)—(CR
15
R
16
)—;
Y is oxygen, S(O)
m
, or NR
7
;
with the provisos that:
when W is of formula W1; G is C
1-4
alkyl which is fully saturated and is substituted by hydroxy or morpholinyl, in which morpholinyl is attached through nitrogen; A is CR
4
; B is CR
5
; and R
8
is hydrogen then at least one of R
13
, R
14
, or R
7
is not hydrogen or C
1-7
alkyl;
when W is of formula W1, A is CR
4
, B is CR
5
, D is —Y—CR
13
R
14
—CR
13
R
14
—, and R
8
is hydrogen then Y is not oxygen;
when W is of formula W1, A is CR
4
, and B is CR
5
then D is not —CR
15
═CR
15
—;
R
4
is H, halogen, or C
1-4
alkyl optionally substituted by one to three halogens;
R
5
is
(a) H,
(b) halo,
(c) OR
12
,
(d) SR
12
,
(e) C
1-7
alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR
12
, SR
12
, NR
10
R
11
, or halo,
(f) C
3-8
cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR
12
, SR
12
, or NR
10
R
11
,
(g) (C═O)R
9
,
(h) S(O)
m
R
9
,
(i) (C═O)OR
2
,
(j) NHSO
2
R
9
,
(k) nitro, or
(l) cyano;
R
7
is
(a) H,
(b) C
1-7
alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR
12
, SR
12
, NR
10
R
11
, or halo,
(c) C
3-8
cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR
12
, SR
12
, or NR
10
R
11
,
(d) aryl,
(e) het,
(f) (C═O)R
9
, or
(g) S(O)
m
R
9
;
R
8
is
(a) H,
(b) C
1-7
alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR
12
, SR
12
, NR
10
R
11
, or halo,
(c) OR
12
, or
(d) SR
12
;
R
9
is
(a) C
1-7
alkyl optionally substituted by OR
12
or NR
2
R
2
,
(b) C
3-8
cycloalkyl optionally substituted by OR
12
or NR
2
R
2
,
(c) NR
10
R
11
,
(d) aryl, or
(e) het, wherein said het is bound through a carbon atom;
R
10
and R
11
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 CONR
2
R
2
, CO
2
R
2
, het, aryl, cyano, or halo,
(d) C
2-7
alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR
2
R
2
, OR
2
, or SR
2
,
(e) C
3-8
cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR
2
, SR
2
, or NR
2
R
2
, or
(f) R
10
and R
11
together with the nitrogen to which they are attached form a het;
R
12
is
(a) H,
(b) aryl,
(c) het
(d) C
1-7
alkyl optionally substituted by aryl, or halogen,
(e) C
2-7
alkyl substituted by OR
2
, SR
2
, or NR
2
R
2
, or
(f) C
3-8
cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR
2
, SR
2
, or NR
2
R
2
;
R
13
, R
14
, R
15
, and R
16
are independently
(a) H
(b) C
1-7
alkyl which may be partially unsaturated and optionally substituted by one or more OR
12
, SR
12
, NR
10
R
11
, or halo groups,
(c) C
3-8
cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR
12
, SR
12
, or NR
10
R
11
,
(d) aryl,
(e) het, wherein said het is bound through a carbon atom,
(f) OR
12
,
(g) SR
12
,
(h) NR
10
R
11
;
(i) (C═O)OR
2
, or
(j) R
13
and R
14
or R
15
and R
16
together with the carbon to which they are attached form (C═O);
each m is independently 0, 1 or 2;
each n is independently 1 or 3;
aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl may be optionally substituted with one or more substituents selected from halo, OH, cyano, NR
2
R
2
, CO
2
R
2
, CF
3
, C
1-6
alkoxy, and C
1-6
alkyl which maybe further substituted by one to three SR
2
, NR
2
R
2
, OR
2
, or CO
2
R
2
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 oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO
2
R
2
, CF
3
, C
1-6
alkoxy, oxo, oxime, and C
1-6
alkyl which may be further substituted by one to three SR
2
, NR
2
R
2
Anderson David John
Bundy Gordon L.
Ciske Fred L.
Genin Michael J.
Graber David R.
Pharmacia & Upjohn Company
Rao Deepak
Yang Lucy X.
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