Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-22
2003-05-06
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S300000, C544S127000, C546S123000
Reexamination Certificate
active
06559145
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 herpesviruses, 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 Hodgkin's 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.
WO098/19673 discloses specific heterocyclic agents for the treatment of diseases caused by viruses.
JP08301849 discloses specific heterocyclic agents useful as tachykinin receptor antagonists. They are suggested for use in treatment of the following diseases: inflammation, allergic diseases, CNS disorders, digestive system disorders, urinary tract disorders, cardiovascular diseases immunopathy. The reference suggests that the inventive compounds can be used to treat herpes, but classifies herpes as either an inflammation or allergic reaction disease. The reference does not suggest that the compounds can be used to treat infectious diseases.
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 discloses 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 herpesviruses.
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, heteroaryl, or aryl;
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; or pyrrolidine substituted by hydroxy;
W is a heterocycle of formula W1, W2, W3, W4, W5, W6, W7, W8, W9, W10, W11, W12, W13, W14, W15, W16, W17, W18, W19, W20, W21 or W22
A is CR
4
or nitrogen;
B is CR
5
or nitrogen;
C is CR
6
or nitrogen;
D is CR
8
or nitrogen;
E and F are such that one is oxygen and the other is C(═O);
J is NR
7
or oxygen;
K and L are defined such that
(a) K is CR
5
and L is CR
6
, or
(b) K is absent and L is sulfur;
M is oxygen, sulfur, or S(O)
m
;
Y is oxygen or sulfur;
with the provisos that:
when W is of formula W3 then at least one of A, B, or C is nitrogen and R
7
is other than H, and if C is nitrogen then A, B or A and B are nitrogen;
when W is of formula W4 then at least one of A, B, or C is nitrogen;
when W is of formula W9 then at least two of A, B, or C is nitrogen;
when W is of formula W16 and J is oxygen then R
7
is other than H;
when W is of formula W16 then J is other than NH;
when W is of formula W19, A is nitrogen, G is morpholinylmethyl, and X is chloro then R
8
is other than H;
when W is of formula W20 then at least one of A or D 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
Ciske Fred L.
Genin Michael J.
Lee Byung Hyun
Schnute Mark E.
Vaillancourt Valerie A.
McKane Joseph K.
Pharmacia & Upjohn Company
Small Andrea D.
Solomon Andrew M.
Yang Lucy X.
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