Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-18
2002-12-17
Gerstl, Robert (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S378000, C514S381000, C514S383000, C514S348000, C548S203000, C548S247000, C548S251000, C548S252000, C548S265200, C548S336100
Reexamination Certificate
active
06495580
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds, compositions and methods for preventing and treating viral infections, and the diseases associated therewith, particularly those viral infections and associated diseases caused by viruses of the Pneumovirinae subfamily of the Paramyxoviridae.
BACKGROUND OF THE INVENTION
The Pneumovirinae subfamily of the Paramyxoviridae family consists of pneumoviruses that cause significant disease in humans and a number of animal species including cattle, goats, sheep, mice and in avian species.
Human respiratory syncytial virus (RSV), the prototypic member of the pneumovirus group, is the major pediatric viral respiratory tract pathogen, causing pneumonia and bronchiolitis in infants and young children. RSV disease is seasonal, with outbreaks in the U.S. typically beginning in November and continuing through April. During these yearly epidemics, approximately 250,000 infants contract RSV pneumonia, and up to 35% are hospitalized. Of those hospitalized, mortality rates of up to 5% have been reported. Children with underlying conditions such as prematurity, congenital heart disease, bronchopulmonary dysplasia and various congenital or acquired immunodeficiency syndromes are at greatest risk of serious RSV morbidity and mortality. In adults, RSV usually causes upper respiratory tract manifestations but can also cause lower respiratory tract disease, especially in the elderly and in immunocompromised persons. Infection in elderly and immunocompromised persons can be associated with high death rates. Natural infection with RSV fails to provide full protective immunity. Consequently, RSV causes repeated symptomatic infections throughout life.
The pneumoviruses of animals and avian species are similar to the human virus antigenically, in polypeptide composition and in disease causation.
Attempts to develop vaccines for RSV are ongoing, but none have yet been demonstrated to be safe and efficacious. Vaccine development has been shadowed by adverse reactions exhibited by the initial formalin-inactivated RSV vaccine introduced in the late 1960s. Immunized children showed an increased incidence of RSV lower respiratory tract disease and developed abnormally severe illnesses, including death.
Chemotherapy with ribavirin [1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide], an antiviral nucleoside which is the only pharmaceutical approved by the U.S. Food and Drug Administration (FDA) for treatment of RSV disease, is considered only for certain RSV patients (e.g., those at high risk for severe complications or who are seriously ill with this infection). However, its efficacy and value are controversial. Recent studies have reported a failure to demonstrate either clinical or economic benefit to patients of ribavirin treatment. Moreover, ribavirin has certain toxic side-effects and, in order to minimize these, must be administred by inhalation as an aerosol in an enclosed environment.
A human intravenous immune globulin (IVIG) preparation is licensed for prophylactic use in certain patients at high-risk for RSV disease. Administration of this drug requires intravenous infusion of a large volume over a 2 to 4 hour period in children who have limited venous access due to prior intensive therapy, as well as compromised cardiopulmonary function. Moreover, intravenous infusion necessitates monthly hospital visits during the RSV season, which in turn places children at risk of nosocomial infections.
Thus, a need exists for new anti-viral agents and treatments for RSV infection that overcome the shortcomings of existing pharmaceutical preparations.
SUMMARY OF THE INVENTION
In one aspect, the invention provides a compound of the formula:
wherein Het represents an unsubstituted or substituted five to seven membered heterocyclic ring containing one to three heteroatoms selected from nitrogen, oxygen or sulfur, said heterocyclic ring substituents being at least one selected from those consisting of hydrogen, alkyl, amino, monoalkylamino or dialkylamino;
R
1
represents a radical selected from the group consisting of hydrogen; halogen; perfluoroalkyl; alkoxyalkyl; amino; alkylamino; dialkylamino; amido; alkylaminoalkyl; an unsubstituted or substituted, saturated or unsaturated, straight- or branched-chain alkyl radical, said alkyl chain substituent being at least one hydroxy group; carboxy; an unsubstituted or substituted phenyl radical (C
6
H
5
), said phenyl radical substituent being at least one selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, halogen, perfluoroalkyl, thio, nitro, carboxy, carboxyalkyl, carbalkoxy, carbalkoxyalkyl, carboxamide, carboxamidoalkyl, alkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamide, amidino, cyano, amino, amido, alkylamino, dialkylamino, alkylaminoalkyl, or alkoxy monosubstituted with a substituent selected from the group consisting of carboxy, amino, alkylamino or dialkylamino; a cycloalkyl radical; or a heterocyclic radical selected from the group consisting of pyridine, thiophene, oxazole, oxadiazole, thiadiazole, pyrazole, tetrazole, furan, pyrrole, isoxazole, imidazole, triazole and thiazole, including all positional isomers of said heterocyclic radicals;
R
2
represents a radical selected from the group consisting of hydrogen, hydroxy, thio, alkoxy, carboxy, carboxyalkyl, amino, alkylamino, dialkylamino, carboxamide, carboxamidoalkyl, sulfonamide acetamido;
X represents a valence bond or a divalent linking moiety selected from the group consisting of —N═CH—, —CH═N—, —(CH
2
)
n
—NH—, —NH—(CH
2
)
n
—, —(CH
2
)
n
—, —CH═CH—or —N═N—, n being an integer from 1 to 8;
Z represents a substituent selected from the group consisting of hydrogen, formyl, hydroxy or —X—Het, wherein X and Het are as previously defined; the isomeric forms of said compound and the pharmaceutically acceptable salts of said compound.
Particularly preferred are compounds having the formula:
wherein X is a divalent linking moiety selected from the group of —N═C— or —CH═CH—; R is a radical selected from the group of hydrogen, hydroxy, alkoxy, alkyl, halogen, nitro or alkoxy monosubstituted with a substituent selected from carboxy, amino, monoalkylamino, dialkylamino or acetamido; R
2
is hydroxy; and R
3
is a heterocylic radical selected from the group consisting of 1-pyrazolyl radicals, 1-triazolyl radicals (including the 1,2,3-;1,2,4-; or 1,3,4-isomers thereof), 4-triazolyl radicals, 1-tetrazolyl radicals or 2-tetrazolyl radicals (including the isomers thereof) and the amino- and alkyl-derivatives of such radicals, including, without limitation, 5-amino-1H-tetrazolyl, 3-amino-4H-1,2,4 triazolyl, 5-amino-1H-1,2,4 triazolyl, 5-amino-2H-tetrazolyl and 5-methyl-1H-tetrazolyl radicals.
In accordance with another aspect, the present invention provides a class of novel intermediates that are useful in preparing the anti-viral agents described herein. These intermediates have the general formula:
wherein Q represents a reactive group selected from those consisting of 5,5-dimethyl-1,3-dioxan and formyl; R
5
is a radical selected from those consisting of hydrogen and hydroxy; R
6
is a radical selected from those consisting of hydroxy, alkoxy, aryloxy and aralkoxy and R
7
is a radical selected from those consisting of hydrogen, hydroxy, alkoxy, alkoxyalkyl, halogen, perfluoroalkyl, thio, nitro, carboxy, carboxyalkyl, carbalkoxy, carbalkoxyalkyl, carboxamide, carboxamidoalkyl, alkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamide, amidino, cyano, amino, amido, alkylamino, dialkylamino, alkylaminoalkyl, or alkoxy monosubstituted with a substituent selected from the group consisting of carboxy, amino, alkylamino or dialkylamino.
The present invention also provides new synthetic methods for preparation of the compounds described herein. One method comprises causing a 3-halogen substituted-4-alkoxy-substituted benzaldehyde, in which the aldehyde moiety is protected with a protecting group, to undergo reaction with an alkylated alkali metal to effect a ha
Nitz Theodore J.
Pevear Daniel C.
Dann Dorfman Herrell and Skillman, P.C.
Gerstl Robert
ViroPharma Incorporated
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