Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-17
2003-01-21
Chang, Ceila (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S210020, C514S211030, C514S423000, C514S424000, C514S428000, C540S200000, C540S531000, C546S024000, C546S221000, C546S243000, C548S413000, C548S541000, C548S543000, C548S551000
Reexamination Certificate
active
06509359
ABSTRACT:
DESCRIPTION
1. Technical Field
This invention relates to novel pyrrolidin-2-one derivatives, their use as neuraminidase inhibitors, to pharmaceutical compositions containing these novel compounds useful for the prevention, treatment or amelioration of viral, bacterial and other infections, and to methods of using the compounds. The present invention is also concerned with novel intermediates or precursors for producing the novel pyrrolidin-2-one compounds of the present invention.
2. Background of the Invention
Despite the wealth of the information available, influenza remains a potentially devastating disease of man, lower mammals, and birds. No effective vaccine exists and no cure is available once the infection has been initiated.
Influenza viruses consist of eight pieces of single stranded RNA, packaged in orderly fashion within the virion. Each piece codes for one of the major viral proteins. The replication complex is enclosed with a membrane composed of matrix proteins associated with a lipid bilayer. Embedded in the lipid bilayer are two surface glycoprotein spikes, hemagglutinin (HA) and the enzyme neuraminidase (NA). All of the viral genes have been cloned and the three-dimensional structures of the surface glycoproetins have been determined.
Influenza viruses continually undergo variation in the two surface antigen, HA and NA, toward which neutralizing antibodies are directed. For this reason, vaccines and a subject's natural immune system have not been very effective. Attention is now being directed to finding other potential antiviral agents acting at other sites of the virion. This invention is directed to novel compounds which are useful in inhibiting the viral surface enzyme NA.
Furthermore, many other organisms carry NA. Many of these NA-possessing organisms are also major pathogens of man and/or mammals, including
Vibraeo cholerae, Clostridium perfringes, Streptococcus pneumonia, Arthrobacter sialophilas
, and other viruses, such as parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, and Sendai virus. Compounds of this invention are also directed to inhibiting NA of these organisms.
In viruses, NA exists as a tetramer made of four roughly spherical subunits and a centrally-attached stalk containing a hydrophobic region by which it is embedded in the organism's membrane. Several roles have been suggested for NA. The enzyme catalyzes cleavage of the &agr;-ketosidic linkage between terminal sialic acid and an adjacent sugar residue. Removal of the sialic acid lowers the viscosity and permits access of the virus to the epithelial cells. NA also destroys the HA receptor on the host cell, thus allowing elution of progency virus particles from infected cells. Research indicates that the active site for influenza neuraminidase remains substantially unchanged for the major strains of influenza. For example, a comparison of sequences from influenza A subtypes and influenza B shows conserved residues with crucial structural and functional roles. Even though the sequence homology is only about 30%, many of the catalytic residues are conserved. Furthermore, the three-dimensional structures of influenza A and B neuraminidases have been determined. Superposition of the various structures shows remarkable structural similarity of the active site. Since the active site amino acid residues are conserved in all known influenza. A neuraminidases that have been sequenced so far, an inhibitor that is effective against different strains of influenza A and/or B neuraminidase can be designed based on the three-dimensional structure of a neuraminidase.
In general, the role of NA is thought to be for the mobility of the virus both to and from the site of infections. Compounds that inhibit neuraminidase's activity may protect a subject from infection and/or cure a subject once infection has set in. It is a further object of this invention to provide a method of using compounds of this invention for preventing, treating and/or curing a viral infection.
Analogs of neuraminic acid, such as 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and its derivatives are known to inhibit HA in vitro; however, these compounds are inactive in vivo. Palese and Schulman, in CHEMOPROPHYLAXIS AND VIRUS INFECTION OF THE UPPER RESPIRATORY TRACT, Vol. 1 (J. S. Oxford, Ed.), CRC Press, 1977, at pp. 189-205.
Von Itzstein et al. Describes cyclohexane analogs of &agr;-D-neuraminic acid of the formula
wherein:
A is O, C or S in Formula (a), and N or C in Formula (b);
R
1
is CO
2
H PO
3
H
2
, NO
2
, SO
2
H, SO
3
H, tetrazolyl-, CH
2
CHO, CHO, or CH(CHO)
2
; R
2
is H, OR
6
, F, Cl, Br, CN, NHR
6
, SR
6
or CH
2
X, where X is NHR
6
halogen, or OR
6
;
R
3
and R
3
′ are H, CN, NHR
6
, SR
6
, ═NOR
6
, OR
6
, guanidino, NR
6
;
R
4
is NHR
6
, SR
6
, OR
6
, CO
2
R
6
, NO
2
, C(R
6
)
3
, CH
2
CO
2
R
6
, CH
2
or CH
2
NHR
6
;
R
5
is CH
2
YR
6
, CHYR
6
CH
2
YR
6
or CHYR
6
CHYR
6
CH
2
YR
6
;
R
6
is H, acyl, alkyl, allyl, or aryl;
Y is O, S, NH, or H;
and pharmaceutical salts thereof, useful as antiviral agents.
In addition, certain benzene derivatives are suggested in U.S. Pat. No. 5,453,533 as being inhibitors of influenza virus neuraminidase and various others are disclosed in U.S. patent application ser. No. 08/413,886. Yamamoto et al. Describe various sialic acid isomers as having inhibitory activity against neuraminidase in Synthesis of Sialic Acid Isomers Inhibitory Activity Against Neuraminidase, TETRAHEDRON LETTERS, Vol. 33, No. 39, pp. 5791-5794, 1992.
U.S. Pat. No. 5,512,596 and WO 96/26933 to Gilead Sciences, Inc. describes certain 6-membered ring compounds as possible inhibitors of neuraminidase.
Hoff, et al. Suggests that certain N-aryl &agr;-pyrrolidinones are useful as intermediates for dyes and pharmaceuticals, as reported in
Chemical Abstracts
, Vol. 52, Item 11124 g, 1958.
However, none of these references disclose the novel pyrrolidin-2-one derivatives of the present invention.
SUMMARY OF THE INVENTION
An aspect of the present invention is directed to compounds represented by the formula:
wherein
Q is CO
2
H, SO
3
H, PO
3
H
2
, NO
2
or esters thereof;
T is H, OH or OH
2
n is 0-3;
X is (CH
2
)n, (CH
2
)nNH, (CH
2
)nO or (CH
2
)nS;
Each of R
1
and R
2
individually is H, (CH
2
)mA, or (CH
2
)mZ, and R
1
and R
2
can be the same or different;
Each of R
6
and R
7
individually is H, (CH
2
)mA, or (CH
2
)mZ, and R
6
and R
7
can be the same or different;
m is 1-3;
each of R
3
, R
4
R
5
individually is H, lower alkyl, branched alkyl, cycloalkyl, aryl or alkaryl, and R
3
, R
4
and R
5
can be the same as or can differ from each other; and pharmaceutically acceptable salts thereof.
The present invention is also concerned with compositions for inhibiting influenza virus neuraminidase comprising a pharmaceutically acceptable carrier and an amount effective for inhibiting influenza virus neuraminidase of a compound as defined above.
A further aspect of the present invention involves a method for inhibiting influenza virus that comprises administering to a patient in need thereof a compound as defined above in an amount effective for inhibiting influenza virus neuraminidase.
A still further aspect of the present invention is concerned with preventing and treating influenza virus infection comprising administering to a patient in need thereof a compound as defined above in an amount effective for inhibiting influenza virus neuraminidase.
The present invention is also concerned with methods for producing the compounds defined above.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from
Atigadda Venkatram Reddy
Babu Yarlagadda S.
Brouillette Wayne J.
Luo Ming
Chang Ceila
Connolly Bove & Lodge & Hutz LLP
Wright Sonya
LandOfFree
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