Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-29
2003-09-16
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S127000, C544S058600, C546S114000
Reexamination Certificate
active
06620810
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides 4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide derivatives, more specifically, 5-benzylaminocarbonyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine derivatives of formula (I), which are useful as antiviral agents (e.g. as agents against viruses of the herpes family).
BACKGROUND OF THE INVENTION
The herpes viruses 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.
Infection by or reactivation of herpes viruses is also associated with several cardiovascular diseases or conditions in the host such as atherosclerosis and restenosis resulting in inflammation of coronary vessel walls. It is thought that in many patients suffering from restenosis following coronary atherectomy, viral infection, particularly by CMV, plays an important role in the proliferation of the disease. Atherosclerosis is believed to be associated with the overall infectious disease burden in the host and particularly by the herpesvirus such as HSV, CMV, and EBV. Infection in the animal population (livestock and companion) by strains of herpesviruses is endemic including cattle (Bovine herspesvirus 1-5, BHV), sheep (Ovine herpesvirus 1 and 2), dog (Canine herpesvirus 1), horse (Equine herpesvirus 1-8, EHV), cat (Feline herpesvirus 1, FHV), swine (pseudorabies virus, PRV), and many species of fowl. In the case of bovine herpesvirus infection, animals may suffer from ocular, respiratory, or digestive disorders. Pseudorabies is an extremely contagious viral pathogen infecting several species such as cattle, horses, dogs, cats, sheep, and goats leading to rapid death. The virus is benign in adult swine, however, it remains contagious and leads to high mortality in pigs under three weeks. Infection of horses by equine herpesvirus may lead to neurological syndromes, respiratory disease, and neonatal disease. Herpesvirus infection in cats leads to the disease known as feline viral rhinotracheitis (FVR) which is characterized by rhinitis, tracheitis, laryngitis, and conjunctivitis.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is
(a) Cl,
(b) Br,
(c) CN,
(d) NO
2
, or
(e) F;
R
2
is
(a) H,
(b) R
5
,
(c) NR
7
R
8
,
(d) SO
2
R
9
, or
(e) OR
9
;
R
3
is
(a) H,
(b) halo,
(c) aryl,
(d) S(O)mR
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
;
R
4
is
(a) H,
(b) halo,
(c) C
1-4
alkyl, or
(d) R
4
together with R
3
form a carbocyclic or het, either of which may be optionally substituted by NR
7
R
8
, by C
1-7
alkyl which may be optionally substituted by OR
14
, or by het, wherein said het is bound via a carbon atom;
R
5
is
(a) (CH
2
CH
2
O)
i
R
10
,
(b) het, wherein said het is bound via a carbon atom,
(c) aryl,
(d) C
1-7
alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR
7
R
8
, R
11
, SO
m
R
9
, and OC
2-4
alkyl which may be further substituted by het, OR
10
, or NR
7
R
8
, or
(e) C
3-8
cycloalkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from a group consisting of R
11
, NR
7
R
8
, SO
m
R
9
, and C
1-7
alkyl optionally substituted by R
11
, NR
7
R
8
, or SO
m
R
9
;
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 a group consisting of NR
10
R
10
, R
11
, SO
m
R
9
, CONR
10
R
10
, or halo, or,
(d) R
7
and R
8
together with the nitrogen to which they are attached form ahet;
R
9
is
(a) aryl,
(b) het,
(c) C
3-8
cycloalkyl, or
(d) C
1-7
alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR
10
R
10
, R
11
, SH, CONR
10
R
10
, or halo;
R
10
is
(a) H, or
(b) C
1-7
alkyl optionally substituted by OH;
R
11
is
(a) OR
10
,
(b) Ohet,
(c) Oaryl,
(d) CO
2
R
10
,
(e) het,
(f) aryl, or
(g) CN;
R
12
is
(a) H,
(b) het,
(c) aryl,
(d) C
3-8
cycloalkyl, or
(e) C
1-7
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 i is independently 2, 3, or 4;
each n is independently 1, 2, 3, 4 or 5;
each m is independently 0, 1, or 2;
M is sodium, potassium, or lithium;
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 maybe further substituted by one to three SR
14
, NR
14
R
14
, OR
14
, het, or CO
2
R
14
; and
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 maybe further substituted by one to three SR
14
, NR
14
R
14
, OR
14
, or CO
2
R
14
.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises an effective antiviral amount of the compound or salt);
a method of treating a herpesviral infection, comprising administering to a mammal (e.g. a human) in need of such treatment, a compound of formula (I) or a pharmaceutically acceptable salt thereof;
a method for treating atherosclerosis or restenosis, comprising administering to a mammal in need of such treatment, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof;
a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical treatment (e.g. the treatment of a herpesviral infection, atherosclerosis or restenosis);
the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a herpesviral infection in a mammal (e.g. a human);
the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating atherosclerosis or restenosis in a mammal (e.g. a human); and
a method for inhibiting a viral DNA polymerase, comprising co
Pharmacia & Upjohn Company
Ramsuer Robert W.
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