Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-01-23
2004-04-27
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S128000
Reexamination Certificate
active
06727248
ABSTRACT:
FIELD OF THE INVENTION
The present invention discloses disubstiuted 4-oxo-1,4-dihydro-3-quinolinecarboxamide derivatives, and more specifically, provides compounds of formula (I) described herein below. 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 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 causitive 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.
Due to the selective substitutents, Y and Z, on the quinoline ring, and the unique position of the X substitutent on the N-phenylmethyl of formula I described herein below, compounds of the present invention demonstrate unexpected activity against the above reference herpesviral infections, particularly, human cytomegaloviral infection.
INFORMATION DISCLOSURE
U.S. Pat. No. 5,891,878 discloses the use of compounds of the following structure for the treatment of a disease state capable of being modulated by inhibition of production of phosphodiesterase IV or tumor necrosis factor,
PCT publication, WO99/32450 discloses compounds of the structure below
which are useful as antiviral agents.
PCT publication, WO00/40561 discloses the quinolinecarboxamide structure below as antiviral agents:
PCT publication, WO00/40563 discloses the 4-oxo-1,4-dihydro-3-uqinolinecarboxamide structure below as antiviral agents:
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I
or a pharmaceutically acceptable salt thereof wherein
X is Cl, Br, CN, NO
2
, or F;
Y is morpholinylmethyl, tetrahydro-2H-pyranylmethyl, hydroxypropynyl, or hydroxypropyl;
Z is het
1
, or C
1-7
alkyl optionally substituted with at least one halo, NR
1
R
2
, OR
3
, or het
2
;
R
1
and R
2
are independently H, C
1-7
alkyl, or C
2-7
alkyl substituted with at least one OH;
R
3
is H, or C
1-7
alkyl;
het
1
is a five-(5), or six-(6) membered saturated or unsaturated heterocyclic ring bonded via a carbon atom having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, wherein the het is optionally fused to a benzene ring, and optionally substituted with one or more substituents selected from the group consisting of halo, OR
3
, CN, phenyl, C
2
R
3
, CF
3
, or C
1-6
alkyl which may be further substituted by one to three SR
3
, NR
3
R
3
, OR
3
, or CO
2
R
3
groups; and het
2
is a five-(5), or six-(6) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, wherein het is optionally fused to a benzene ring, and optionally substituted with one or more substituents selected from the group consisting of halo, OR
3
, CN, phenyl, CO
2
R
3
, CF
3
, oxo, oxime, or C
1-6
alkyl which may be further substituted by one to three SR
3
, NR
3
R
3
, OR
3
, or CO
2
R
3
groups.
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 method for inhibiting a viral DNA polymerase, comprising contacting the polymerase with an effective inhibitory amount of a compound of claim
1
, or a pharmaceutically acceptable salt thereof,
a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical treatment or prevention of a herpesviral infection in a mammal.
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
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
1-7
)alkyl refers to alkyl of one to seven carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl, straight and branched forms thereof.
The term “het
1
” is a five-(5), or six-(6) membered saturated or unsaturated heterocyclic ring bonded via a carbon atom having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, wherein the het is optionally fused to a benzene ring, and optionally substituted with one or more substituents selected from the group consisting of halo, OH, CN, phenyl, CO
2
R
3
, CF
3
, OC
1-6
alkyl, or C
1-6
alkyl which may be further substituted by one to three SR
3
, NR
3
R
3
, OR
3
, or CO
2
R
3
groups.
The term “het
2
” is a five-(5), or six-(6) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, or nitrogen, wherein het is optionally fused to a benzene ring, and optionally substituted with one or more substituents selected from the group consisting of halo, OH, CN, phenyl, CO
2
R
3
, CF
3
, OC
1-6
alkyl, oxo, oxime, or C
1-6
alkyl which may be further substituted by one to three SR
3
, NR
3
R
3
, OR
3
, or CO
2
R
3
groups. The preferred substitutent is oxo or hydroxy.
When a het contains a sulfur atom, the sulfur atom may be mono- or di-oxidized.
Examples of“het
1
” include, but not limit to, pyridine, imidazole, thiazole, oxazole, thiadiazole, oxadiazole, imidazoline, pyrimidine, pyrazine, or indole.
Examples “het
2
” include, but not limit to, imidazolidine, imidazoline, pyrazolidine, pyrazoline, dioxolane, imidazole, oxathiolane, oxazolidine, pyrrolidine, pyrroline, piperidine, piperazine, morpholine, thiomorpholine, isochroman, chroman, indoline, or isoindoline.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine antiviral activity using the standard tests described herein, or using other similar tests which are well known in the art.
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. “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 undesira
Huang Audris
Vaillancourt Valerie A.
McKane Joseph K.
Pharmacia & Upjohn Company
Shiao Robert
Yang Lucy X.
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