Pyridoquinoxaline antivirals

Details Pyridoquinoxaline antivirals Pyridoquinoxaline antivirals

2002-12-19

2004-02-03

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S115000

Reexamination Certificate

active

06686356

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides pyridoquinoxalines that are useful as antiviral agents. More specifically, it provides compounds of formula I described herein below against herpesviruses.
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 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 herpesviruses 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.
The compounds of the present invention may also be useful for the treatment of herpesvirus infections in animals, for example illnesses caused by bovine herpesvirus 1-5 (BHV), ovine herpesvirus 1 and 2, Canine herpesvirus 1, equine herpesvirus 1-8 (EHV), feline herpesvirus 1 (FHV), and pseudorabies virus (PRV) viral infections.
It has been surprisingly discovered that when a C
1-6
alkyl is placed on the nitrogen of the pyridoquinoxaline moiety of formula I, compounds of the present invention demonstrate greatly enhanced oral bioavailability and improved selectivity for the viral targets.
INFORMATION DISCLOSURE
U.S. Pat. No. 5,792,774 discloses specific quinoline derivatives that arc alleged to have therapeutic utility via inhibition of Phosphodiesterase IV esterase and/or Tumor Necrosis factor activity.
PCT/US01/16494 discloses heterocycle carboxamides as antiviral agents.
Despite the above teachings, there still exists a need in the art for compounds that have enhanced oral bioavailability and improved selectivity for the viral targets.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I,
or a pharmaceutically acceptable salt thereof wherein:
R
1
is F, Cl, Br, CN or NO
2
;
R
2
is C
1-6
alkyl, optionally substituted by one to three OR
3
, NR
3
R
3
, aryl or het;
R
3
is hydrogen or C
1-4
alkyl;
het is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyridyl, imidazolyl, azetidyl, tetrahydrofuranyl or imidazolidinyl; and aryl is a phenyl or pyridyl radical, attached via a carbon atom, optionally substituted by one to three halogen, OR
3
or NR
3
R
3
.
The present invention further provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (the composition preferably comprises an effective antiviral amount of the compound or salt).
The present invention further provides a method of treating or preventing a herpesviral infection, comprising administering to a mammal in need of such treatment, a compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of treating or preventing a herpesviral infection comprising administering orally, parenterally, topically, rectally, nasally, sublingually or transdermally an effective amount of a compound of formula I.
The present invention further provides a composition and method for the treatment of herpesviral infections comprising the step of administering a composition comprising a pharmaceutically effective amount of the compound of formula I and at least one other antiviral agent.
The present invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical treatment.
The present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing a herpesviral infection in a mammal.
The present invention further provides 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.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are used, unless otherwise described. Alkyl denotes 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.
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
1-4
)alkyl refers to alkyl of one to four carbon atoms, inclusive, or methyl, ethyl, propyl, isopropyl and butyl, straight and branched forms thereof.
Mammal denotes human and animals. Animals specifically refers to food animals or companion animals.
Compounds of the invention may have one or more chiral centers 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. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. “Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hours and “rt” for room temperature).
Specifically, R
1
is chloro.
Specifically, R
2
is methyl.
Specifically, R
2
is C
1-4
alkyl, optionally substituted by OH or NH
2
.
Specifically, R
2
is C
1-4
alkyl optionally substituted by OC
1-3
alkyl Specifically, R
2
is C
1-4
alkyl, optionally substituted by morpholinyl, piperidinyl, piperazinyl, or pyrrolidinyl.
Examples of the compounds of the present invention are:
a). N-(4-chlorobenzyl)-1-methyl-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,
b). N-(4-chlorobenzyl)-1-ethyl-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,
c). N-(4-chlorobenzyl)-1-(2-hydroxyethyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,
d). N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-1-(2-phenylethyl)-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,
e). N-(4-chlorobenzyl)-1-(2-hydroxy-2-phenylethyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide,
f). N-(4-chlorobenzyl)-1-(2,3-dihydroxypropyl)-9-(morpholin-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1

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