Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-05
2003-11-25
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S080000, C544S128000, C544S171000, C544S156000
Reexamination Certificate
active
06653307
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention provides 1-aryl-4-oxo-1,4-dihydro-3-quinolinecarboxamide 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.
Commonly assigned PCT/US99/27959 discloses specific 4-oxo-1,4-dihydro-3-quinolinecarboxamide as antiviral agents.
Commonly assigned PCT/US99/27960 discloses specific quinolinecarboxamide as antiviral agents.
Commonly assigned W099/32450 discloses specific 4-hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents.
U.S. Pat. No. 4,959,363 discloses specific quinolonecarboxamide compounds, their preparation and use as antivirals.
U.S. Pat. No 5,622,967 discloses specific quinolonecarboxamide calpain inhibitors useful in the treatment of neurodegenerative diseases.
MPWentland et. al. has disclosed on a number of occasions specific 3-quinolinecarboxamides and their effect on antiherpetic activity. Relevant references include Des. Discovery 1997, 15, 25-38 (Antiviral properties of 3-quinolinecarboxamides: a series of novel non-nucleoside antiherpetic agents); J. Med.
Chem. 1993, 36, 1580-1596 (3-Quinolinecarboxamides. A series of novel orally-active antiherpetic agents); and
J. Med. Chem.
1995, 38, 2541-2545 (Cyclic variations of 3-quinolinecarboxamides and effects on antiherpetic activity).
GB 1,191,433 discloses specific quinolone derivatives as antiviral agents.
EP 612731 discloses specific quinolone and naphthyridinonecarboxylic acids compounds as antiviral agents.
U.S. Pat. No. 5,328,887 discloses specific quinolin-2-one and quinolin-4-one compounds and derivatives thereof for use as fluorescent donor elements in thermal transfer processes.
U.S. Pat. No. 5,175,151 discloses specific quinolone derivatives as antiviral and antihypertensive agents.
U.S. Pat. No. 5,753,666 and 5,891,878 and WO 97/04775 disclose specific I-alkyl-substituted-quinolone-3-carboxamides that are alleged to have therapeutic utility via inhibition of Phosphodiesterase IV esterase and/or Tumor Necrosis factor activity.
U.S. Pat No. 6,015,789 discloses specific thienopyridinones as GnRH agonists and antagonists for use in treating sex-hormone dependent diseases.
EP 945435 discloses specific novel pyridonecarboxylic acid derivatives as bactericides.
GB 2236751 discloses specific 4-oxoquinolines and analogs as 5-HT3 antagonists for use in the treatment of neuro-psychiatric disorders.
U.S. Pat. No. 4,876,644 discloses specific 1-aryl-3-quinolinecarboxarnides useful for the treatment of pain.
JP 02124871 discloses specific quinolonecarboxamides and analogs as 5-lipoxygenase inhibitors.
W096/16046 discloses specific benzyl pyrimidines useful as antibiotics.
JP 44012143 discloses specific 3-quinolinecarboxylic acid compounds with anti-inflammatory properties.
W098/23608 discloses specific compounds which are fused heterocycles useful as antagonists for the &agr;
v
&bgr;
3
and related integrin receptors.
U.S. Pat. No. 4,956,465 discloses specific quinoline and 1,8-naphthyridin-4-onecarboxylic acid which are C-bonded in the 7-position useful as antibacterials.
EP 370686 discloses a process for preparing specific quinoline carboxylic acid derivatives.
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 1-aryl-4-oxo-1,4-dihydro-3-quinolinecarboxamide 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, F, Br, CN, or NO
2
;
R
1
is H, halo, or Cl
4
alkyl optionally substituted by one to three halo;
R
2
is
(a) H,
(b) halo,
(c) aryl,
(d) het, wherein said het is bound via a carbon atom,
(e) C
1-7
alkyl which may be partially unsaturated and optionally substituted by one or more substituents of the group R
10
, NR
7
R
1
, halo, (C═O)R, or S(O)
m
R
6
,
(f) NR
7
R
8
,
(g) OR
11
,
(h) SR
11
,
(i) NHSO
2
R
6
,
(j) S(O)
m
R
6
,
(k) (C═O)R
1
,
(l) (C═O)OR
1
,
(m) CHO,
(n) cyano, or
(o) C
3-8
cycloalkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from halo, oxo, R
10
, C
1-7
alkyl, or NR
7
R
8
;
R
3
is
(a) H,
(b) halo,
(c) OR
11
, or
(d) C
1-7
alkyl which may be partially unsaturated and optionally substituted by one or more substituents of the group OR
11
, SR
11
, NR
7
R
8
, or halo, or
R
2
together with R
3
form a carbocyclic or saturated 5 or 6 membered het which may be optionally substituted by NR
7
R
8
, het attached through a carbon atom, or C
1-7
alkyl which may be optionally substituted by OR
12
;
R
4
is
(a) H,
(b) halo,
(c) OR
11
,
(d) C
1-7
alkyl which may be partially unsaturated and optionally substituted by one or more substituents of the group OR
11
, SR
11
, NR
7
R
8
, aryl, halo, C
3-8
cycloalkyl optionally substituted by OR
12
, or het attached through a carbon atom, or
(e) NR
7
R
8
;
R
5
is
(a) H,
(b) halo,
(c) OR
11
,
(d) O(CH
2
CH
2
O)
n
R
12
,
(e) C
3-8
cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halo, OR
12
, SR
12
oxo, C
1-7
alkyl, or NR
12
R
12
,
(f) het,
(g) aryl,
(h) NHSO
2
R
6
,
(i) S(O)
m
R,
(j) (C═O)R
6
,
(k) (C═O)OR
11
,
(l) nitro,
(m) cyano,
(n) SR
11
,
(o) NR
7
R
8
,
(p) C
1-7
alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from NR
7
R
8
, R
10
, S(O)
m
R
6
, (P═O)(OR
12
)
2
, (C═O)R
6
, or halo,
(q) CHO,
(r) SCN,
(s) any two adjacent R
5
substituents taken with the bond connecting them to form an aryl, or het, or
(t) any two adjacent R
5
substituents taken together constitute a C
3-6
alkyl chain which may be optionally substituted by R
9
, NR
7
R
8
, cyano, CO
2
R
12
, OR
11
, SR
11
, or (═O);
R
6
is
(a) C
1-7
alkyl,
(b) NR
11
R
11
,
(c) aryl, or
(d) het;
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 S(O)
m
R
6
, CONR
12
R
12
, CO
2
R
12
, (C═O)R
9
, 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
12
R
12
, OR
11
, or SR
11
,
(e) C
3-8
cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halo, OR
12
, SR
12
, oxo, or NR
12
R
12
,
(f) (C═O)R
9
, or
(g) R
7
and R
8
together with the nitrogen to which they are attached for a het;
R
9
is
(a
Pharmacia & Upjohn Company
Ramsuer Robert W.
Yang Lucy X.
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