Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-22
2004-05-04
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S264110, C544S279000
Reexamination Certificate
active
06730682
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. Nos. 5,753,666 and 5,891,878 and WO 97/04775 disclose specific 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.
Commonly assigned WO 00/40561 discloses quinolinecarboxamides as antiviral agents.
Commonly assigned WO 00/40563 discloses specific quinolinecarboxamides as antiviral agents.
Commonly assigned WO 00/53610 discloses 4-Oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides as antiviral agents.
Commonly assigned WO99/32450, discloses specific 4-hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents.
U.S. Pat. No. 5,945,431 discloses specific naphthyridine heterocyclic compounds having antiviral activity that are useful in the therapy and prophylaxis of cytomegalovirus (CMV) infection in mammals.
WO99/10347 discloses specific substituted 4-oxo-naphthyridine-3-carboxamides as brain receptor ligands having potential use in the treatment of central nervous system diseases and/or disorders.
WO98/19673 discloses specific heterocyclic agents for the treatment of diseases caused by viruses.
JP08301849 discloses specific heterocyclic agents useful as tachykinin receptor antagonists.
JP07033729 discloses specific N-cyano-N′-substituted-arylcarboxyimidamide compounds exhibiting K+ channel opening effects and having hypotensive action and coronary vasodilating action.
WO 00/40562 discloses novel 2-oxoquinolines as selective peripheral cannabinoid receptor modulators).
WO 97/34894 dosloses Naphthyridine derivatives and their analogues inhibiting cytomegalovirus.
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
1-7
alkyl which is partially unsaturated and is substituted by hydroxy, or
(b) C
1-4
alkyl substituted by NR
1
R
2
or 4tetrahydropyran;
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 morpholine which may be optionally substituted by aryl or C
1-7
alkyl;
W is a heterocycle of formula W1, W3, or W4;
A is CR
4
or nitrogen;
B is CR
5
or nitrogen;
C is CR
6
or nitrogen;
E and F are such that
(a) one is oxygen and the other is C(═O); or
(b) E is C(═O) and F is NR
7
;
J and K are such that
(a) J is nitrogen and K is CR
8
; or
(b) J is CR
6
and K is nitrogen;
with the provisos that when W is of formula W3 and J is nitrogen, then at least one of A and B is nitrogen;
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
6
is
(a) H,
(b) halo,
(c) aryl,
(d) het,
(e) OR
12
,
(f) SR
12
,
(g) 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
, aryl, halo, C
3-8
cycloalkyl optionally substituted by OR
12
, or het attached through a carbon atom,
(h) NR
10
R
11
,
(i) 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
,
(j) (C═O)R
9
,
(k) S(O)
m
R
9
,
(l) (C═O)OR
2
,
(m) NHSO
2
R
9
,
(n) nitro, or
(o) 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, or
(e) het;
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,
(b) NR
10
R
11
,
(c) aryl, or
(d) 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, het, 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
;
each m is independently 1 or 2;
aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl maybe 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
Schnute Mark E.
Vaillancourt Valerie A.
Coleman Brenda
Yang Lucy X.
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