Anti-viral compounds

Details Anti-viral compounds Anti-viral compounds

2000-04-10

2001-01-30

Aulakh, Charanjit S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S019000, C560S051000

Reexamination Certificate

active

06180816

ABSTRACT:

Influenza viruses cause an infectious disease for which there is no adequate therapeutic agent. The disadvantages of existing treatments include the onset of clinical resistance within thirty six hours and the ineffectiveness of the agents against influenza B. Killed influenza virus vaccines have been available for over sixty years. However, these vaccines have not lessened the morbidity, mortality or severe financial loss caused by this disease. It follows that an agent which treats or prevents an influenza infection or is effective at preventing the clinical symptoms associated with an influenza infection will result in a significant benefit to society.
Currently, the only compounds approved for the therapeutic and prophylactic treatment of influenza infections are the adamantanes: amantadine and rimantadine. These compounds inhibit influenza A by inhibiting the function of the M2 ion channel activity of the virus. Amantadine is a potent in vitro inhibitor of influenza A virus as demonstrated by standard antiviral assays such as the plaque reduction assay. Amantadine is effective in reducing the duration of fever and other systemic complaints including but not limited to myalgia (muscular ache) and fatigue when administered to individuals infected with influenza A within forty-eight hours of the onset of clinical symptoms. It has also been observed that amantadine results in a one hundred-fold decrease of virus titer in the nasal washes of human volunteers infected with wild-type influenza virus which correlates with a dramatic decrease in fever score. Thus, in vitro influenza inhibition is predictive of useful in vivo effects, i.e. a reduction of the clinical symptoms associated with the influenza infection.
The present invention derives from the fact that influenza is an enveloped virus which dictates that the virus envelope must be fused with the endosomal membrane of the host cell in order to initiate the process of introducing its genetic information into the cell. Because this process is common to all enveloped viruses, it is an attractive target for antiviral chemotherapy. Examples of envelope viruses which are inhibited according to the present invention include influenza, bovine diarrheal, hepatitis C, tick borne encephalitis and the like. The fusion domain of the envelope glycoprotein of influenza, hemagglutinin (HA) has been well-characterized. See, White J. M., Annu. Rev. Physiol. vol. 52, pages 675-697 (1990) which is herein incorporated by reference.
Influenza virus HA provides at least two distinct functions: 1) recognition of the host cell receptor, i.e., sialic acid residues on glycoconjugates, and 2) fusion of the viral envelope with the endosomal membrane. Both functions are essential for the propagation of influenza virus in vitro and in vivo. During viral maturation, monomeric HA is inserted into a lipid bilayer, post-translationally modified and oligomerized into a trimer of identical subunits (trimeric HA). The infectivity of the progeny virus is contingent upon a site-specific cleavage of HA by host cell protease(s). This cleavage results in the formation of two polypeptide chains, HA1 and HA2, which remain associated by non-covalent interactions as well as by an intermolecular and intramolecular disulfide bonds.
It has been established that influenza HA has two functionally relevant conformations. One conformation (Form A) exists as a metastable structure at neutral pH and mediates receptor recognition. Following receptor mediated binding to the host cell, the virus is transported to the endosomal compartment where it encounters an acidic environment. The low pH triggers a dramatic structural rearrangement of HA (Form A) which results in the formation of the other, more stable conformation of HA (Form B).
Form B of HA is required for fusion of the virus envelope with the endosomal membrane. It is the structural rearrangement from Form A to Form B of HA that allows the fusion domain of HA to directly interact with the endosomal membrane enabling the release of viral genetic information into the host cell cytoplasm. These considerations lend themselves to the development of a strategy for antiviral intervention based on the abrogation of HA-mediated fusion of virus-host membranes.
The present invention relates to a compound of the formula:
wherein:
R
0
and R
1
are independently hydrogen, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy(C
1
-C
6
alkyl), sulfhydryl, sulfamyl, —SO
2
—Cl, —S—C(O)—N(CH
3
)
2
, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, C
1
-C
4
alkylsulfonylamino, di(C
1
-C
4
alkylsulfonyl)amino —X
0
—O—C(O)—C
l
-C
4
alkyl, —O—(X
1
)
i
—X
2
, —C(O)—X
3
, —N—C(O)—R
2
or —O—R
3
;
X
0
is a bond or divalent(C
1
-C
6
alkyl);
X
1
is an amino acid;
X
2
is hydrogen or an amino protecting group;
i is 1, 2 or 3;
X
3
is C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo(C
1
-C
6
alkyl), hydroxy(C
1
-C
6
alkyl) or phenyl;
R
2
is C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halo(C
1
-C
4
alkyl), hydroxy(C
1
-C
4
alkyl), phenyl, p-methoxy-phenyl, p-fluoro-phenyl, naphthyl, pyridyl, piperidinyl, thiazolyl, oxazolyl, thienyl, furyl, tetrahydrofuryl or cyclohexyl;
R
3
is C
1
-C
6
alkenyl, —CH
2
—R
3a
, —C(O)—R
3b
, —C(S)—R
3c
, —C(CH
3
)
2
C(O)NH
2
, phenyl or a group of the formula:
R
3a
is phenyl, p-fluorophenyl, pyridyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, N-(C
1
-C
4
alkoxycarbonyl)piperidinyl, N-(trifluoromethyl)-piperidinyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isooxazolyl, quinolyl, isoquinolyl, thienyl, furyl, tetrahydrothienyl, tetrahydrofuryl, cyclohexyl, cyclopentyl, cyclopropyl or naphthyl;
R
3b
is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, N—(C
1
-C
4
alkoxycarbonyl)piperidinyl, N-(trifluoromethyl)piperidinyl, benzyloxy, pyridylmethyloxy, C
1
-C
6
alkoxy, halo(C
1
-C
4
alkoxy), amino, C
1
-C
4
alkylamino or di(C
1
-C
4
alkyl)amino;
R
3c
is amino, C
1
-C
4
alkylamino or di(C
1
-C
4
alkyl)amino;
R
3d
is oxygen, hydroximino, hydrazino or ═CHZ;
Z is hydrogen, C
1
-C
4
alkyl, halogen, di(C
1
-C
4
alkyl)amino, C
1
-C
4
alkoxycarbonyl, carbamoyl(C
1
-C
4
alkyl), N—(C
1
-C
4
alkyl)carbamoyl or N,N-di(C
1
-C
4
alkyl)carbamoyl;
R
3e
is hydrogen, nitro or trifluoromethyl;
X is a bond or —(CH
2
)—;
R
4
is hydrogen, hydroxy, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, C
1
-C
4
alkoxy, ═O, —O—S(CH
3
)
2
C(CH
3
)
3
, C
2
-C
6
alkanoyloxy, N—(C
2
-C
6
alkanoyl)amino, ═N—R
5
or R
4
and R
6
combine to form a bond;
R
5
is hydroxy, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, C
1
-C
4
alkoxy, pyridylmethoxy, benzyloxy, piperazinyl, N-(methyl)piperazinyl or —O—CH
2
—C(O)—R
5a
;
R
5a
is hydroxy or C
1
-C
4
alkoxy;
R
6
is hydrogen, halo, C
1
-C
4
alkyl or ═O;
R
7
is hydrogen or C
1
-C
4
alkyl;
R
8
is hydroxy, halo, C
1
-C
6
alkoxy, pyrrolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, morpholinyl or —N(R
9
)—R
10
;
R
9
is hydrogen or methyl;
R
10
is -(divalent C
1
-C
6
alkyl)—R
10a
;
R
10a
is pyridyl,
with the proviso that
i) when R
4
is hydrogen or ═O, then R
0
and R
1
cannot both be hydrogen;
ii) when R
0
cannot be isopropyl; and R
4
is hydrogen; and R
1
cannot be hydrogen, hydroxy or methoxy;
iii) when R
0
is hydrogen; and R
4
is hydrogen; then R
1
cannot be hydrogen, hydroxy, methoxy, —C(O)CH
3
or —OC(O)CH
3
;
or a pharmaceutically acceptable salt thereof.
The present invention provides new compounds of formula as described above, that are useful for treating or preventing a viral infection where the virus is an envelope virus that undergoes hemagglutinin-mediated fusion with a host cell and/or the resultant symptoms. These compounds, their pharmaceutically acceptable salts and the corresponding pharmaceutical formulations can be used alone or in combination with other antivirals, immunomodulators, antibiotics or vaccines.
All temperatures stated herein are in degrees Celsius (°C.). All units of measurement employed herein are in weight units except for liquids which are in volume units.
The term “halo” repre

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