Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-07
2001-05-29
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S233800, C546S114000, C546S127000
Reexamination Certificate
active
06239142
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides 4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide derivatives, more specifically, 5-benzylaminocarbonyl-4-oxo-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 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 Kaposi's sarcoma, body cavity based lymphomas, and multiple myeloma.
SUMMARY OF THE INVENTION
Applicant has discovered compounds that are useful as antiviral agents for treating herpesviral infections. Accordingly, the 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, and 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
, and 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, 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
, and 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 or preventing 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; and
a method for inhibiting a viral DNA polymerase, comprising contacting (in vitro or in vivo) the polymerase with an effective inhibitory amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
Compounds of formula I have a 4-substituted benzylaminocarbonyl substituent at the 5-position of the thieno[2,3-b]pyridine ring system. This substitution pattern has been found to provide compounds with significantly improved antiviral activity compared to thienopyridines lacking this substitution.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are used, unless otherwise described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to. When alkyl can be partially unsaturated, the alkyl chain may comprise one or more (e.g. 1, 2, 3, or 4) double or triple bonds in the chain.
Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. Het is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, 3, or 4 heteroatoms selected from the group consisting of oxy, thio, sulfinyl, sulfonyl, and nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group. Het includes “heteroaryl,” which encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxy, thio, and N(X) wherein X is absent or is H, O, C
1-4
alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
When R
4
together with R
3
form a carbocyclic, R
4
and R
3
together can be a 3, 4, 5,
Cudahy Michele M.
Schnute Mark E.
Scott Allen
Dentz Bernard
Pharmacia & Upjohn Company
Schwegman Lundberg Woessner & Kluth P.A.
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