Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-09-01
2001-08-07
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S240000
Reexamination Certificate
active
06271373
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds, compositions and methods for the treatment of influenza infection. In particular, the present invention relates to novel pyridazine derivatives, pharmaceutical compositions containing such derivatives and their use in treating influenza infection and other viral diseases.
BACKGROUND OF THE INVENTION
There are three known influenza-type viruses which affect human beings: Influenza A, B and C. Influenza A viruses have been isolated from many animal species in addition to humans, while the influenza B and C viruses infect mainly humans. The influenza viruses are enveloped viruses containing negative single-stranded RNA's which are segmented and encapsidated. The influenza virus envelope is characterized by the presence of two surface glycoproteins: hemagglutinin and neuraminidase. The influenza A and B virions are pleomorphic and are usually 80-120 nm in diameter. The influenza C virion has many distinctive properties and is thus distinguished from the closely related A and B virions. Infection with influenza A or B often can cause a highly contagious, acute respiratory illness.
Influenza viruses have a major impact on morbidity leading to increases in hospitalization and in visits to health care providers. High rates of hospitalization are observed for patients over 65 years of age and also for children less than 5 years of age. Influenza virus is also unique among respiratory viruses in being a cause of excess mortality. Furthermore, the spread of influenza virus through a population can result in epidemics which have considerable economic impact. For example, high rates of mortality were observed due to influenza infection during the influenza epidemics of 1957, 1968 and 1977.
Fields Virology
, Second Edition, Volume 1, pp. 1075-1152 (1990).
There are relatively few known compounds that have significant anti-viral activity against influenza viruses. Two of these, amantadine and rimantadine are approved in the United States for the treatment of influenza virus disease. Both compounds are most effective when used prophylactically and influenza viruses develop resistance to both compounds rapidly. See U.S. Pat. No. 3,152,180 and 3,352,912. Other compounds reported to have activity against influenza viruses are disclosed in U.S. Pat. Nos. 3,483,254, 3,496,228, 3,538,160, 3,534,084 and 3,592,934.
Insofar as is known, pyridazine derivatives have not been previously reported as being useful for the treatment of influenza infection.
SUMMARY OF THE INVENTION
In accordance with one aspect, the present invention provides compounds, including isomeric forms, of the following structure:
wherein R
1
represents a lower alkyl (C
1
-C
6
) substituent which may be straight or branched; R
2
represents an aryl substituent of the formula:
V represents a substituent selected from the group consisting of COOR
3
, CONR
4
R
5
, SO
2
NR
6
R
7
and
W, X, Y and Z represent the same or different substituents selected from the group consisting of H, alkyl, halogen, CF
3
, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl COOR′ and CONR″R′″; Q and the carbon atoms to which it is attached represent a heterocyclic ring selected from the group consisting of
wherein the bond between positions a, b of said heterocyclic ring forms a common bond with aromatic ring (Ar); R
3
and R′ are the same or different and represent H or an alkyl (C
1
-C
6
) substituent; R
4
, R
5
, R
6
, R
7
, R″ and R′″ are the same or different and represent H, an alkyl substituent, an aryl substituent, an aralkyl substituent, a heterocyclic substituent, a heterocyclicalkyl substituent, or a carboxyalkyl substituent, said aryl substituent and the aryl moiety of said aralkyl substituent having the formula:
wherein Q, V, W, X, Y and Z are as previously defined, said heterocylic substituent or the heterocylic moiety of said heterocyclicalkyl substituent having the formula
wherein A is selected from the group consisting of carbon, nitrogen, sulfur or oxygen, and R
8
, R
9
, R
10
, R
11
are the same or different and represent H, alkyl, halogen, CF
3
, alkoxy, alkylthio, OH, alkylamino, dialkylamino, COOH, CONH
2
and SO
2
NH
2
, and the isomers and pharmaceutically acceptable salts of said compound.
Included within the invention also are the pharmaceutically acceptable salts of the above compounds.
According to still another aspect, the present invention provides pharmaceutical compositions comprising one or more of the above-described pyridazine derivatives in combination with a pharmaceutically acceptable carrier medium.
In accordance with yet another aspect, the present invention provides a method for treating viral influenza infections in mammalian hosts by administering an effective amount of the compounds of the invention to a patient susceptible to influenza infection or suffering from such an infection.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention can be conveniently prepared from known starting materials and specific embodiments of anti-influenza compounds within the scope of the invention are exemplified below.
In vitro studies demonstrating the usefulness of the compounds of the invention as anti-viral agents against the influenza virus have been performed. Anti-viral activity was measured on the basis of inhibition of influenza virus transcriptase, reduction in plaque formation by the influenza virus and reduction in cleavage of cap 1 RNA by the influenza virus. In addition, the effect of the anti-influenza compounds on cell growth was measured using a tetrazolium salt (MTT) method. Finally, drug acute tolerance was measured using studies on mice. These biological studies of the anti-viral activity of the compounds of the invention are described in the examples that follow.
Among the particularly preferred embodiments of the invention are compounds, including isomeric forms, having the formula:
wherein R
1
represents CH
3
; R
2
represents
V represents a substituent selected from the group consisting of COOH
3
, SO
2
NR
4
R
5
and
R
4
and R
5
are the same or different and represent H, acetyl, methyl, substituted or unsubstituted phenyl, or substituted or unsubstituted pyridyl, said phenyl and said pyridyl substituents being selected from those consisting of alkyl, alkoxy, hydroxy, carboxy and halogen groups; W represents a substituent selected from the group consisting of H, CH
3
or Cl; X, Y and Z represent H; and the pharmaceutically acceptable salts of said compounds.
Also preferred are compounds, including isomeric forms, having the formula:
wherein R
1
represents CH
3
; R
2
repesents
Q and the carbon atoms to which it is attached represent a heterocyclic ring selected from the group consisting of
wherein the bond between positions a, b of said heterocyclic ring forms a common bond with aromatic ring (Ar); and the isomers and pharmaceutically acceptable salts of said compound.
The term “alkyl” as used herein refers to aliphatic hydrocarbon radicals of one to six carbon atoms in length. Similarly, the term “alkyl”, or any variation thereof, used in combination form to name substituents, such as alkoxy (—O-alkyl), alkylthio (—S-alkyl), alkylamino (—NH-alkyl), alkylsulfonyl (—S(O)
2
-alkyl), carboxyalkyl (-alkyl-COOH), or the like, also refers to aliphatic hydrocarbon radicals of one to six carbon atoms in length, and preferably of one to four carbon atoms in length.
Isomers of the compound of Formula I, above, that are within the scope of the invention include, without limitation, tautomeric forms of such compound.
As previously noted, the compounds of Formula I, above, including their pharmaceutically acceptable salts, exhibit antiviral activity against influenza virus.
The compounds of the invention can form salts with inorganic and organic bases, including, for example, alkali metal salts, such as Na or K salts, alkaline earth metal salts, such as Ca or Mg salts, ammonium, substituted ammonium and other amine salts such as morpholine, piperidine or pyridine salts.
Th
Bailey Thomas R.
Diana Guy D.
Gorczyca William P.
Nitz Theodore J.
Young Dorothy C.
Dann Dorfman Herrell and Skillman, P.C.
Kifle Bruck
ViroPharma Incorporated
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