Cyclopentane and cyclopentene compounds and use for...

Details Cyclopentane and cyclopentene compounds and use for... Cyclopentane and cyclopentene compounds and use for...

2001-05-07

2003-01-07

Wilson, James O. (Department: 1623)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Hydrolase

C548S303700, C560S122000, C562S504000

Reexamination Certificate

active

06503745

ABSTRACT:

TECHNICAL FIELD
The present invention is concerned with a new group of cyclopentane and cyclopentene compounds and their use as diagnostic agents for detecting influenza A and B. The compounds of the present invention bind to influenza A and B neuraminidase. Moreover, these compounds possess functionality which allows them to be bound to a surface or to a detectable label.
The diagnostic method of the present invention depends upon the ability of the disclosed compounds to bind specifically to the active site of influenza virus neuraminidase, or functionalized derivatives of such compounds, as binding and/or detecting agents to identify influenza virus in clinical specimens. The term “neuraminidase binders” is used hereinafter to refer to these compounds and their functionalized derivatives. The method and compounds of the present invention can function either in the presence or the absence of compounds binding non-specifically to influenza virus neuraminidase.
BACKGROUND OF INVENTION
Influenza A and B viruses are major causes of acute respiratory disease, with an estimated 30-50 million infections annually in the United States alone. Influenza A has been responsible for major epidemics, such as the “Spanish flu” of 1919 which killed millions of people. Many viral and bacterial infections may exhibit symptoms similar to those of influenza. The rapid identification of respiratory viruses would enable physicians to use the most appropriate therapy early in the illness. For example, an early and accurate diagnosis would allow decisions regarding the use of antibacterial therapy and hospitalization of children and the elderly.
Laboratory tests for the identification of viruses in clinical material are widely used, and a variety of different detection methodology is available. The textbook,
Laboratory Diagnosis of Viral Infections,
Marcel Dekker, 1992, Ed. E. H. Lennette, generally discusses methods which are used for a wide range of viruses, including influenza virus.
A number of tests are available for the diagnosis of influenza A and B. The traditional method of identifying influenza viruses has been the use of cell culture, which is highly sensitive and specific. Unfortunately, the time required for culture, isolation and identification of influenza virus can range between 2 and 10 days, thus making it virtually useless in guiding the physician to an appropriate therapy. Since influenza virus infection is normally self-limited, diagnosis must be rapid if therapy is to be effective. In other words, such cell culture methods are normally only of value in providing retrospective epidemiological information.
In addition to the cell culture methods for detecting influenza, there have recently become available a few rapid direct tests, which are specific for influenza A. Thus, a monoclonal immunofluorescence assay (IFA) has been reported (Spada, B. et al.,
J. Virol. Methods,
1991, 33: 305) and at least one enzyme immunoassay (EIA) is available (Ryan-Poirier, K. A. et al.,
J. Clin. Microbiol.,
1992, 30: 1072). A number of comparisons of these rapid detection methods for influenza A have been reported; see for example Leonardi, G. P. et al.,
J. Clin. Microbiol.,
1994, 32: 70, who recommended that direct specimen testing be used together with culture isolation, so as to permit both identification of the virus in time to institute therapy and infection control measures, and to monitor the antigenic constitution of influenza strains prevalent in the community for epidemiological purposes. The IFA method is reported to be labor-intensive, and requires considerable technical expertise, with the results often being difficult to interpret. On the other hand, the EIA method (Directigen FLU-A; Becton Dickinson Microbiology Systems) give a high level of false-positive results, and it has been recommended that this assay be used in laboratories only in addition to or as a substitute for direct immunofluorescence tests (Waner, J. L. et al.,
J. Clin. Microbiol.,
1991, 29: 479) .
As well as the problems mentioned above with the available rapid assays for influenza, there are other fundamental deficiencies in some of these methods. Firstly, none of the available assays can detect influenza B, which means that even a negative test result would leave the physician uncertain about the type of therapy that should be used. Secondly, if a rapid immunoassay method depends on the use of antibodies to one of the influenza A proteins, there may be a serious problem in detecting new strains of the virus which have undergone a drift or shift in the structure of the antigenic proteins. Influenza A is notorious for its propensity to undergo such changes.
Neuraminidase is one of the key proteins present on the surface of the influenza virus, and it plays an important role in the ability of the virus to infect human cells. It has long been thought that agents which bind to the neuraminidase enzyme might prevent invention by influenza, and much effort has gone into seeking such binders. While many compounds have shown in vitro activity against influenza neuraminidase, only recently has it been established that it is possible to achieve protection from influenza infection in vivo by the use of a powerful neuraminidase binder which binds to the active site of the enzyme (see von Itzstein, M. et al.,
Nature,
1993, 363: 418 and International Patent Applications No. WO 92/06691 and WO 91/16320). In particular, it has been found that 2,3-didehydro-2,4-dideoxy-4-guanidinyl-N-acetylneuraminic acid (Compound I, designated GG167) is a potent binder of influenza neuraminidase, and also shows potent in vivo antiviral activity in animals (Ryan, D. M. et al.,
Antimicrobiol Agents and Chemotherapy,
1994, 38: 2270) and in human volunteers (Hayden, F. G. et al.,
J. American Medical Assoc.,
1996, 275: 295).
More recently, it has been found that certain substituted cyclohexene derivatives of sialic acid are also potent binders of influenza virus neuraminidase (Kim, C. U. et al.,
J. Amer. Chem. Soc.,
1997, 119: 681), and specifically the compound (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (GS 4071).
It is the purpose of the present invention to provide a simple and sensitive means for detecting influenza viruses.
SUMMARY OF INVENTION
The present invention is concerned with cyclopentane and cyclopentene compounds represented by the following formulae:
wherein:
U is CH, O or S;
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
, (CH
2
)nSR
11
, or (CH
2
)n halogen;
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
11
)CH
2
NHR
10
, CH(OR
10
)CH(OR
10
)CH
2
NHR
10
, C(═NR
10
)N(R
10
)m, NHR
10
, NHC(═NR
10
)N(R
10
)m, (CH
2
)m-X—W—Y, CH
2
CH(X—W—Y)CH
2
OR
10
, CH(X—W—Y)CH(OR
10
)CH
2
OR
10
, CH(X—W—Y)CH
2
(OR
10
), CH(OR
10
)CH(X—W—Y)CH
2
OR
11
, CH(OR
10
)CH
2
(X—W—Y), CH
2
CH(X—W—Y)CH
2
NHR
10
, CH(X—W—Y)CH(OR
11
)CH
2
NHR
10
, CH(X—W—Y)CH
2
(NHR
10
), CH(OR
10
)CH(X—W—Y)CH
2
NHR
11
, or CH(NHR
10
)CH
2
(X—W—Y);
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
)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, 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, branched alkyl, cyclic alkyl, (CH
2
)n aromatic, (CH
2
)n substituted aromatic, or when m is 2 both R
10
groups

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