Dimeric inhibitors of influenza neuraminidase

Details Dimeric inhibitors of influenza neuraminidase Dimeric inhibitors of influenza neuraminidase

2000-09-08

2003-04-15

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C435S005000, C514S062000, C530S322000, C536S004100, C536S055100

Reexamination Certificate

active

06548476

ABSTRACT:

This invention relates to a new class of chemical compounds and their use in medicine. In particular the invention concerns novel dimeric compounds, methods for their preparation, pharmaceutical formulations thereof and their use as antiviral agents.
BACKGROUND OF THE INVENTION
Enzymes with the ability to cleave N-acetyl neuraminic acid (NANA), also known as sialic acid, from other carbohydrates are present in many microorganisms. These include bacteria such as
Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae
and
Arthrobacter sialophilus,
and viruses such as influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus and Sendai virus. Most of these viruses are of the orthomyxovirus or paramyxovirus groups, and carry a neuraminidase activity on the surface of the virus particles. Many of these neuraminidase-possessing organisms are major pathogens of man and/or animals, and some, such as influenza virus and Newcastle disease virus, cause diseases of enormous importance.
It has long been thought that inhibitors of neuraminidase might prevent infection by neuraminidase-bearing viruses. Most of the known neuraminidase inhibitors are analogues of neuraminic acid, such as 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA) and some of its derivatives (Meindl et al, Virology, 1974 58 457). Our International Patent Publication No. WO 91/16320 describes a number of analogues of DANA which are active against viral neuraminidase, and it has been shown in particular that 4-guanidino-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Compound (A), code number GG167) is useful in the treatment of influenza A and B (N. Engl. J. Med., 1997 337 874-880). Other patent applications describe various closely-related sialic acid derivatives (eg. PCT Publications No. WO 95/18800, No. WO 95/20583 and No. WO 98/06712), and anti-viral macromolecular conjugates of GG167 have also been described (International Patent Application No. PCT/AU97/00771).
AC represents acetyl.
In addition to the sialic acid based inhibitors mentioned above, other types of highly active inhibitors of influenza virus neuraminidase have also been described, particularly those based on 5- and 6-membered carbocyclic ring systems (eg. International Patent Publications No. WO 96/26933 and No. 97/47194).
Recently, International Patent Publication No. WO 97/06157, No. WO 98/06712 and European Patent Application No. 0823428 have described certain derivatives of compound (A) in which the normal sialic acid 7-hydroxy group is replaced by various other functionalities, which inhibit multiplication of the influenza virus.
It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.
We have now found that, surprisingly, when two neuraminidase-binding compounds are suitably linked together, through a region of the molecule that is not involved in binding to the active site, the resultant dimers show outstanding anti-viral activity. In particular we have found that, although an extra substituent attached to compound (A) at the 7-position generally causes a slight decrease in the anti-influenza activity, when two such 7-substituted molecules of compound (A) are both attached to a suitable spacer moiety, the anti-influenza activity can be greatly enhanced. The compounds have a longer duration of action than compound (A) alone. Though not wishing to be bound or limited by any proposed mechanism for the observed effect, we believe that the dimeric compounds of the invention have improved anti-influenza activity because they are able to bind to two separate neuraminidase molecules, and thereby cause aggregation of the neuraminidase tetramers and/or the influenza virions, or that by having one copy of zanamivir bound to the active site of the neuramindase, and a second copy in close proximity then the binding kinetics may be more efficient, in that as one copy dissociates the second copy can bind more rapidly than a free molecule of zanamivir. We have now shown that dimeric compounds have enhanced properties, including long duration of action. Again not wishing to be bound by theory, the basis for the long residence time in the lungs is thought to be due to the size and molecular weight of the macromolecule preventing entry through tight junctions in the respiratory epithelium, and the polarity of the macromolecule being such that passage through the cell membranes occurs very inefficiently. An alternative theory is that the compounds themselves interact with the phospholipids in the cell membrane or other components of the respiratory epithelium, and increase the residency time in the lungs.
SUMMARY OF THE INVENTION
In a first aspect the invention provides a dimeric compound which comprises two neuraminidase-binding groups attached to a spacer or linking group. The neuraminidase-binding group may be any compound which binds to the active site of influenza virus neuraminidase, provided that it is not cleaved by the enzyme. The neuraminidase binding group should itself have a high binding affinity; preferably the IC
50
or Kd for the neuraminidase binding group will be of 10
−6
M or better. Preferably the dimeric compound comprises two neuraminidase-binding neuraminic acid (sialic acid) derivatives or cyclopentyl or cyclohexenyl carboxylic acid derivatives covalently attached to a common spacer group.
In a preferred embodiment, the invention provides a compound of General Formula I, and optical and geometric isomers thereof;
in which the neuraminidase binding group is a 2,3-dehydrosialic acid derivative which is attached to a spacer group Y via the 7-position;
R represents an azido group, a hydroxy group, an unsubstituted or substituted guanidino group, or an unsubstituted or substituted amino group;
R
2
represents COCH
3
, COCF
3
, SO
2
CH
3
or SO
2
CF
3
;
X represents O, O(C═O), NH, NHCO, O(C═O)NH, O(C═S)NH, NH(C═O)NH, or NH(C═S)NH;
and the spacer group Y is an optionally substituted straight or branched or cyclic group or a combination thereof of up to 100 backbone atoms in length, with the backbone atoms selected from the group consisting of carbon, nitrogen, oxygen and sulphur;
or a pharmaceutically acceptable derivative thereof.
Preferably the spacer group Y is 8 to 100, more preferably 10 to 50, even more preferably 12 to 30 atoms long.
Preferably R is a substituted or unsubstituted amino or guanidino group, more preferably an amino or guanidino group.
Preferably R
2
is acetyl or trifluoroacetyl.
Preferably X is O or O(C═O)NH.
Most preferably:
R is an amino or guanidino group;
R
2
is acetyl or trifluoroacetyl;
X is O(C═O)NH; and
Y is a group of between 10 and 50 atoms in length.
The molecular weight of the compounds of the invention is generally in the range of from 650 to 500,000, preferably from 650 to 20,000, and even more preferably 650 to 2,000.
The biological activity of the compounds of the invention is based on the use of ligands on the backbone which are able to bind specifically to the active site of influenza virus neuraminidase, or of functionalised derivatives of such compounds. The term “neuraminidase binders” is used herein to refer to these compounds and their functionalized derivatives. The method and compounds of the invention can function either in the presence or the absence of compounds binding non-specifically to influenza virus neuraminidase. The neuraminidase binder may be any agent which binds to the active site of influenza virus neuraminidase, provided that it is not cleaved by the enzyme. The binding need not be irreversible, but the binding group should have a high binding affinity, preferably the IC
50
or the Kd will be of 10
−6
M or less. The person skilled in the art will readily be able to optimize the spacer length by routine experimentation.
In general it is intended that when any variable occurs twice in formula (I

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