Substituted pyrrolidine compounds useful as neuraminidase...

Details Substituted pyrrolidine compounds useful as neuraminidase... Substituted pyrrolidine compounds useful as neuraminidase...

2000-10-20

2003-02-11

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S531000

Reexamination Certificate

active

06518299

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel substituted pyrrolidine compounds and derivatives thereof useful as neuraminidase inhibitors, to pharmaceutical compositions containing said compounds useful for the prevention, treatment or amelioration of viral, bacterial and other infections, and to methods of using said compounds. The present invention is also concerned with novel intermediates or precursors for producing the novel substituted pyrrolidine compounds of the present invention.
BACKGROUND OF THE INVENTION
Despite the wealth of information available, influenza go 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 is 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 protein 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 glycoproteins have been determined.
Influenza viruses continually undergo antigenic variation in the two surface antigens, 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 progeny 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 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 NA 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 PS 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
NO
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. Pat. No. 5,602,277. Yamamoto et al. describe various sialic acid isomers as having inhibitory activity against neuraminidase in Synthesis of Sialic Acid Isomers With Inhibitory Activity Against Neuramninidase, TETRAHEDRON LETTERS, Vol. 33, No. 39, pp. 5791-5794, 1992.
WO 96/26933 to Gilead Sciences, Inc. describes certain 6-membered ring compounds as possible inhibitors of neuraminidase.
WO 98/17647 to Gilead Sciences, Inc. describes certain 6-membered piperidine compounds as possible inhibitors of neuraminidase.
Hoff et al suggest that certain N-aryl &agr;-pyrrolidinones are useful as intermediates for dyes and pharmaceuticals, as reported in
Chemical Abstracts
, Vol. 52, Item 11124g, 1958.
However, none of these references disclose the pyrrolidine derivatives of the present invention.
SUMMARY OF INVENTION
The present invention relates to certain substituted pyrrolidine compounds. More particularly, the compounds of the present invention are selected from the group consisting of the following formulae:
wherein
wherein
Z is —C(R
2
)(R
3
), —CH—N(R
2
)(R
3
), C(R
3
)[(CH
2
)nR
2
], or CH—C(R
3
)(CH
2
)nR
2
;
R
1
is H, (CH
2
)nOH, (CH
2
)nNH
2
, (CH
2
)nNR
10
R
11
, (CH
2
)nOR
11
, or (CH
2
)nF;
R
9
is (CH
2
)nCO
2
H, (CH
2
)nSO
3
H, (CH
2
)nPO
3
H
2
, (CH
2
)nNO
2
, esters thereof, or salts thereof;
R
2
is H, NHC(O)R
5
, NHC(S)R
5
, NHSO
2
R
5
, C(O)NHR
5
, SO
2
NHR
5
, CH
2
S(O)R
5
, or CH
2
SO
2
R
5
;
R
3
is H, (CH
2
)nCO
2
R
10
, (CH
2
)mOR
10
, C(O)N(R
10
)m, (CH
2
)nN(R
10
)m, CH(R
10
)m, (CH
2
)n(R
10
)m, CH
2
CH(OR
10
)CH
2
OR
10
, CH(OR
10
)CH(OR
10
)CH
2
OR
10
, CH
2
OR
10
, CH(OR
10
)CH
2
NHR
10
, CH
2
CH(OR
10
)CH
2
NHR
10
, CH(OR
10
)CH(OR
10
)CH
2
NHR
10
, C(═NR
10
)N(R
10
)m, NHR
10
, or NHC(═NR
10
)N(R
10
)m;
R
4
is H, (CH
2
)nOH, (CH
2
)nNR
10
R
11
, (CH
2
)nNH
2
, (CH
2
)nC(═NH)(NH
2
), (CH
2
)nR
10
R
11
, (CH
2
)nNHC(═NR
11
)NH
2
, (CH
2
)nNHC(═NR
7
)NH
2
, (CH
2
)nCN, (CH
2
)nN
3
, C(═NH)NH
2
, C(NR
7
)NH
2
, or C(NR
11
)NH
2
;
R
5
is H, lower alkyl, lower branched chain alkyl, cyclic alkyl, halogen substituted alkyl, aryl, substituted aryl, or CF
3
;
R
7
is H, (CH
2
)nOH, (CH
2
)nCN, (CH
2
)nNH
2
, or (CH
2
)nNO
2
;
R
10
is H, lower alkyl, lower alkylene, lower branched alkyl, cyclic alkyl, (CH
2
)n aromatic, (CH
2
)n substituted aromatic, or when m is 2 both R
10
groups can also be interconnected to form an N substituted heterocyclic ring, or other 5 or 6 membered heterocyclic ring;
R
11
is lower alkyl, lower branched alkyl, or (CH
2
)m aromatic;
R
13
is H, (CH
2
)nOH, (CH
2
)nNH
2
, (CH
2
)nNR
10
R
11
, (CH
2
)nOR
11
, (CH
2
)nF, (CH
2
)nOC(O)R
11
, or (CH
2
)nNHC(O)R
11
;
m is 1 or 2;
n is 0-4;
and pharmaceutically acceptable salts thereof.
The present invention is also concerned with compositions for in

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