Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-08-27
2004-12-14
Owens, Amelia A. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S232200, C514S256000, C514S269000, C514S301000, C546S114000, C544S127000, C544S298000, C544S318000
Reexamination Certificate
active
06831081
ABSTRACT:
FIELD OF THE INVENTION
The present invention discloses 4-oxo-4,7-dihydrothieno[2,3-b)pyridine-5-carboxamides derivatives, and more specifically, provides compounds of formula (I) described herein below. These compounds are useful as antiviral agents, in particular, as age nts against viruses of the herpes family.
BACKGROUND OF THE INVENTION
The herpes viruses comprise a large family of double stranded DNA vies. 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. HCMV infection is also associated with cardiovascular disease and conditions including restenosis and atherosclerosis. 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 associate 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 herpesviruses is associated with several cardiovascular diseases or conditions in the host such as atherosclerosis and restenosis resulting in inflation 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 herpesviruses such as HSV, CMV, and EBV.
Infection in the animal population (livestock and companion) by strains of herpesviruses is endemic including cattle (Bovine herpesvirus 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.
Compounds of the present invention demonstrate unexpected activity against the above reference herpesviral infections, particularly, human cytomegaloviral infection.
INFORMATION DISCLOSURE
U.S. Pat. No. 6,239,142 discloses compounds and their use to treat herpesvirus infections.
EP 443568 discloses compounds having angiotensin II antagonist activity and antihypertensive activity. WO95/28405 discloses compounds potentially useful for the treatment of sex-hormone dependent cancers and as contraceptives.
JP 08301849 discloses compounds useful as tachykinin receptor antagonists.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I:
its enantiomeric, diastereomeric, or tautomeric isomer thereof, or a pharmaceutically acceptable salt thereof wherein,
G is phenyl substituted with from one (1) to five (5) R
1
substituents;
each R
1
is independently
(a) Cl,
(b) Br,
(c) F,
(d) CN,
(e) C
1-7
alkyl, or
(f) NO
2
;
R
1
is
(a) H,
(b) R
5
,
(c) NR
7
R
8
,
(d) SO
2
R
10
, or
(e) OR
9
;
A is C
1-7
alkyl;
W is a five- (5) or six- (6) membered heterocyclic ring having one (1), two (2) or three (3) heteroatoms selected from the group consisting of O, S(O), and N wherein W is optionally substituted with one or more OH, oxo (═O), or C
1-7
alkyl;
B is
(a) C
1-7
alkyl optionally substituted by OH or NR
7
R
8
,
(b) O, or
(c) NR
11
;
R
3
is
(a) phenyl, optionally fused to a benzene or pyridine ring, and optionally substituted by R
12
, wherein optionally any two adjacent R
12
substituents taken together constitute a group of the formula —O(CH
2
)O—, —(WC(═O)(CH
2
)
j
O—, or CH
2
)
i
—, or
(b) a five- (5) or six- (6) membered heteroaryl bonded via a carbon atom having one (1), two (2), or three (3) heteroatoms selected from the group consisting of O, S, and N—Z, wherein R
3
is optionally fused to a benzene or pyridine ring, and optionally substituted with one or more R
12
, wherein Z is absence, H, or C
1-4
alkyl;
R
4
is
(a) H,
(b) halo, or
(c) C
1-4
alkyl optionally substituted by halo;
R
5
is
(a) (CH
2
)
m
OCH
2
CH
2
OR
11
,
(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 R
6
substituents, or
(e) C
3-8
cycloalkyl which may be partially unsaturated and optionally substituted by one or more R
6
or C
1-7
alkyl optionally substituted by R
6
;
R
6
is
(a) OR
9
,
(b) SR
9
,
(c) NR
7
R
8
,
(d) halo,
(e) CONR
7
R
8
,
(f) CO
2
R
9
,
(g) het,
(h) phenyl, optionally substituted by R
12
,
(i) CN,
(j) oxo,
(k) SO
2
NR
9
R
11
,
(l) SO
m
R
10
, or
(m) P(═O)(OR
11
)(R
11
;
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 NR
11
R
11
, OR
11
, SR
11
, SO
m
R
10
, CONR
11
R
ll
, CO
2
R
11
, het, aryl, cyano, or halo,
(d) C
3-8
cycloalkyl,
(e) (C═O)R
10
, or
(f) R
7
and R
8
together with the nitrogen to which they are attached form a het;
R
9
is
(a) H,
(b) aryl,
(c) het, wherein the het is bound through a carbon atom,
(d) C
1-7
alkyl which is optionally partially unsaturated and is optionally substituted by one or more aryl het, OR
11
, SR
11
NR
11
R
11
, halo, or C
3-8
cycloalkyl substituents and which C
3-8
cycloalkyl is optionally substituted by OR
11
, or
(e) C
3-8
cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more halo, OR
11
, SR
11
, or NR
11
R
11
substituents;
R
10
is
(a) aryl,
(b) bet,
(c) C
1-7
alkyl which is optionally partially unsaturated and is optional substituted by one or more aryl, bet, OR
11
, SR
11
, NR
11
R
11
, halo, or C
3-8
cycloalkyl substituents and which C
3-8
cycloalkyl is optionally substituted by OR
11
, or
(d) C
3-8
cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more halo, OR
11
, SR
11
, or NR
11
R
11
substituents;
R
11
is
(a) H, or
(b) C
1-7
alkyl;
R
12
is
(a) halo,
(b) OR
14
,
(c) SR
11
,
(d) NR
7
R
8
,
(e) phenyl, optionally substituted by halo, C
1-7
alkyl, or C
1-7
alkoxy,
(f) C
1-7
alkyl which is optionally partially unsaturated and optionally substituted by R
13
,
(g) cyano,
(h) nitro,
(i) CONR
7
R
8
,
(j) SO
2
NR
7
R
8
,
(k) CO
2
R
11
, or
(l) NHC(═O)R
11
;
R
13
is
(a) phenyl, optionally substituted by halo, C
1-7
alkyl, or C
1-7
alkoxy,
(b) OR
11
,
(c) O(CH
2
CH
2
O)
n
R
11
,
(d) NR
7
R
8
, or
(e) halo;
R
14
is
(a) H
(b) alkyl, optionally substituted by halo,
(c) phenyl, optionally substituted by halo, C
1-7
alkyl, or C
1-7
alkoxy, or
(d) —(CH
2
CH
2
O)
n
OR
11
;
i is 3 or 4;
j is 0 or 1;
k is 0, 1, or 2;
each n is independently 1, 2, 3, 4 or 5;
each m is independently 1 or 2;
wherein any aryl is optionally substituted with one or more substitue
Ciske Fred L.
Genin Michael J.
Schnute Mark E.
Strohbach Joseph Walter
Thaisrivongs Suvit
Neidert Karl
Owens Amelia A.
Pharmacia & Upjohn
Richardson Peter
Zielinski Bryan C.
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