Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-17
2001-06-19
Raymond, Richard L. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S228200, C514S231500, C514S312000, C514S314000, C544S055000, C544S062000, C544S096000, C544S111000, C546S153000
Reexamination Certificate
active
06248736
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides 4-oxo-1,4-dihydro-3-quinolinecarboxamide derivatives, more specifically, provides (4-chlorobenzyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide of formula I. These compounds are useful as antiviral agents, in particular, 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 the 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 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.
Compounds of the present invention are distinct from all other hydroxyquinoline pharmaceutical agents in that the unique position of chloro substitutent on the N-phenylmethyl of formula I is critical for having useful antiviral activities. These compounds are useful to treat or prevent the above referenced herpesviral infections, particularly, human cytomegaloviral infection.
INFORMATION DISCLOSURE
U.S. Pat. No. 5,891,878 discloses the use of compounds of structure 1 for the treatment of a disease state capable of being modulated by inhibition of production of phosphodiesterase IV or tumor necrosis factor,
wherein R
1
may be alkyl(1-6), alkyl(1-6)cycloalkyl, alkyl(1-6)heterocycle, alkyl(1-6)aryl or alkyl(1-6)heteroaryl each optionally substituted by halogen, alkoxy, hydroxy, CN, CO
2
H or corresponding ester or amide, alkyl(1-6), NR
9
R
10
, SO
2
NR
2
; R
3
may be phenyl, pyridyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, or cycloalkyl(3-10) which may be optionally substituted by halogen, alkoxy(1-6), OH, CN, CO
2
H and corresponding esters or amides, alkyl(1-6), haloalkyl(1-6), NR
9
R
10
, SO
2
NR
2
, aryl, heteroaryl, cycloalkyl heterocyclo, or may be fused to a second carbocyclic or heterocyclic ring; R
4-7
may be hydrogen, halogen, alkoxy(1-6), hydroxy, CN, CO
2
H, CO
2
alkyl(1-6), CONHalkyl(1-6), CONdialkyl(1-6), NR
9
R
10
, or alkyl(1-6) in which alkyl may be substituted by halogen, alkoxy(1-6), hydroxy, CN, CO
2
alkyl(1-6), CONHalkyl(1-6), CONdialkyl(1-6), NR
9
R
10
, SO
2
NR
2
; any two adjacent substituent R
4-7
may form a 5-7 membered ring containing 0, 1, or 2 heteroatoms; R
9-10
may be hydrogen, alkyl(1-6), aryl, heteroaryl, COCF
3
, SO
2
CF
3
, cycloalkyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, arylsulfonyl, alkylsulfonyl; or NR
9
R
10
may form a 5 or 6 membered ring such as a pyrrolidine, piperidine, morpholine, or piperazine ring; n may be 0-3.
U.S. Pat. No. 5,175,151 discloses compounds of structure 2 as antiviral and antihypertensive agents,
wherein R
1
may be alkyl, alkenylhalide, (CH
2
)
n
CO
2
R, or (CH
2
)
n
NR
6
R
7
where R
6
and R
7
may be hydrogen or alkyl; R
2
may include alkyl, alkoxy, aryloxy, aryl, aralkyl, halogen, acyloxy, amino optionally substituted, hydroxy, CH
2
OH, CO
2
H, alkylesters, CF
3
; R
3
may be alkyl, aralkyl, optionally substituted aryl, alkylheteroaryl, (CH
2
)
n
CO
2
R, or (CH
2
)
n
OH; R
5
may be hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, or alkoxy. The patent actually claims a significantly narrower scope which does not include 3-carboxamides.
PCT publication WO 97/14682 describes compounds useful as gronadotropin-releasing hormone antagonists according to the generic structure 3
wherein, R
1
is a substituent according to the formula XNR
5
R
6
where X is an alkylene or alkyl group optionally substituted by halogen, R
5
is an aralkyl substituent, and R
6
is an alkyl substituent; R
2
is an acylaminoaryl substituent; R
3
is a halogenaralkyl substituent; and R
4
is a carbonyl group optionally esterified or amidated for which NHCH
2
Ph is specified in the disclosure.
U.S. Pat. No. 5,328,887 discloses compounds for the use in a thermal transfer process which would include substructure 4 wherein R may be an optionally substituted hydrocarbon group; R′ may be an optionally substituted carboxamide; and the quinoline ring may be optionally substituted.
PCT publication, WO 98/23608 discloses compounds of structure 5
wherein, among the others, U may include —(CH
2
)
n
—, —(CH
2
)
n
—[O,S,N]—(CH
2
)
n
—, or linker groups attached through nitrogen; R may be a nitrogen containing heteroaryl substituent or guanidine substituent; R′ may be hydrogen, alkyl(1-4), or phenylalkyl(1-4); W is a C
1-3
alkyl in which the alkyl group is substituted by either one or two non-hydrogen substituents which may include a halogen substituted phenyl; and Y may be various carboxylate derivatives, sulfonate derivatives, phosphate derivatives and heterocycles, however, may not be hydrogen.
PCT publication, W099/32450 discloses compounds of structure 6
which are useful as antivial agents.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I
Wherein R
1
is C
1-7
alkyl, optionally substituted by hydroxy or NR
4
R
5
; R
2
is C
1-7
alkyl substituted by hydroxy or NR
4
R
5
; R
3
is H, F or C
1-7
alkoxy; R
4
and R
5
together with N are a 5- or 6-membered heterocyclic moiety having 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in which sulfur may be substituted by one (1) or two (2) oxygen atoms; and pharmaceutically acceptable salts thereof.
In another aspect, the present invention also provides:
A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I,
a method of treating and preventing herpesviral infections in a mammal, including human, and
a use of a compound of formula I to prepare a medicament for treating and preventing herpesviral infections in a mammal, including human.
DETAILED DESCRIPTION OF THE INVENTION
For the purpose of the present invention, the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C
i-j
indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive. Thus, for example, (C
1-3
)alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, straight and branched forms thereof.
The compounds of the present invention are named according to the IUPAC or CAS nomenclature system.
The term “C
1-7
”, “C
1-5
” and “C
1-4
” alkyl refer to an alkyl group having one to seven, one to five and one to four carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and their isomeric forms thereof.
A 5- or 6-membered heterocyclic moiety includes thiadiazolyl, thiazolyl, 1,1 -dioxo-thiazolyl, 1 -oxo-thiazolyl, benzothiazolyl, pyridinyl, imidazolyl, indolyl, pyrrolyl, morpholinyl, thiophenyl and 2-oxo-oxazolyl.
Compounds of the present invention may be in a form of pharmaceutically acceptable salts.
“Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. Mammal refers to human and animals.
The followin
Schnute Mark E.
Scott Allen
Strohbach Joseph Walter
Thaisrivongs Suvit
Turner Steven Ronald
Pharmacia & Upjohn Company
Raymond Richard L.
Truong Tamthom N.
Yang Lucy X.
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