US2012178749A1PendingUtilityA1
Ns1 protein inhibitors
Est. expiryDec 7, 2027(~1.4 yrs left)· nominal 20-yr term from priority
A61P 31/12A61K 31/535A61P 31/16A61K 31/44A61K 31/165A61K 31/47A61P 31/14A61K 31/515A61K 31/425A61K 31/495Y02A50/30
39
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Claims
Abstract
The present invention generally relates to compounds to treat viral infections and methods of their use. In particular, compounds of the present invention inhibit the activity of NS1 protein, thereby mitigating viral infection and, in particular, influenza virus infection. Accordingly, NS1 protein inhibitors and methods of treatment that employ such inhibitors are contemplated by the present invention.
Claims
exact text as granted — not AI-modified1 . A method of treating or preventing a viral infection in a patient comprising administering to said patient an effective amount of an NS1 protein inhibitor.
2 . The method of claim 1 , wherein the NS1 protein inhibitor is further defined as a compound of formula (I), (II), or (XII):
wherein:
X 1 is O or S;
X 2 is either not present or is hydrogen, O, NO 2 , hydroxy, or COOH;
X 3 is hydrogen, lower alkyl, O, S, 4-propoxyphenyl, thienyl, or
Y 1 is —NH, —NCH 3 , or S;
Y 2 is C or N;
Y 3 is —CH, —CH 2 CH 3 , —CH 2 CH 2 C 6 H 5 , —C-thienyl, —CC(O)NHC 6 H 4 I, —CC(O)NHCH 2 furanyl, —N(CH 2 ) a COOH, —NHCH(pyridinyl)(CH 2 C(O)pyridinyl), —N—(CH 2 ) k C 6 H 5 CO 2 H, or O, wherein a is 1-5 and k is 0 or 1;
Y 4 is C or N;
A 1 is either not present or is —NH—, —CH 2 —, or —CH—;
A 2 is O, —NH—, —CO—, or —N—;
R 1 is
wherein R 13 is halogen; R 14 is lower alkyl, and wherein * indicates a point of attachment;
R 2 is hydrogen, lower alkyl, phenyl, or
R 3 is hydrogen or —SO 2 (CH 2 ) m C(O)CH 3 , wherein m is 1-4;
R 4 is hydrogen, —C(O)CH 3 , or —NO 2 ;
R 5 is hydrogen, lower alkyl, or halogen;
R 6 is hydrogen or hydroxy;
R 7 is hydrogen, halogen, cyano, lower alkyl, or together with R 8 forms a phenyl group;
R 8 is hydrogen, lower alkyl, —NO 2 , lower alkoxy, cyano, —CH 2 COOH, —SO 2 (CH 2 ) m C(O)CH 3 , wherein m is 1-4, or together with R 7 forms a phenyl group;
R 9 is hydrogen, halogen, or —NO 2 ;
R 10 is hydrogen, —NO 2 , N-piperidinyl, —C(O)NHCH 2 furanyl,
R 11 is hydrogen, hydroxy, or together with R 12 forms a phenyl group;
R 12 is either not present or is hydrogen, lower alkyl, or together with R 11 forms a phenyl group;
n is 0 or 1; and
each bond numbered 1-5 is each independently a single or double bond;
provided R 4 -R 8 are not all hydrogen.
3 . The method of claim 1 , wherein the compound of formula (XII) is further defined as a compound of formula (III):
wherein:
X 2 is either not present or is hydrogen, O, NO 2 , hydroxy, or COOH;
X 3 is hydrogen, lower alkyl, O, S, 4-propoxyphenyl, thienyl, or
Y 2 is C or N;
Y 3 is —CH, —C-thienyl, —CC(O)NHC 6 H 4 I, —CC(O)NHCH 2 furanyl, —N(CH 2 ) a COOH, —NHCH(pyridinyl)(CH 2 C(O)pyridinyl), or O, wherein a is 1-4;
Y 4 is C or N;
R 9 is hydrogen or halogen;
R 10 is hydrogen, —NO 2 , —C(O)NHCH 2 furanyl,
R 11 is hydrogen, hydroxy, or together with R 12 forms a phenyl group;
R 12 is either not present or is hydrogen, lower alkyl, or together with R 11 forms a phenyl group; and
each bond numbered 2-5 is each independently a single or double bond.
4 . The method of claim 1 , wherein the compound of formula (XII) is further defined as a compound of formula (XIII):
wherein:
R x and R y are each independently lower alkyl, or R x and R y are joined to form a piperidinyl, pyrrolidinyl, or pyridinyl ring; and
f is 1-5.
5 . The method of claim 4 , wherein R x and R y are joined to form a piperidinyl ring.
6 . The method of claim 1 , wherein the viral infection is influenza.
7 . The method of claim 1 , wherein the viral infection is caused by the influenza A virus, influenza B virus, a bunyavirus, an arenavirus, an encephalitis virus, rabies or a filovirus.
8 . The method of claim 2 , wherein the compound of formula (I), (II), or (XII) is further defined as a compound of formula (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI):
wherein:
A 3 is —C(O)— or —CH 2 —;
X 4 is O or S;
Y 5 is N or C;
R 15 is acetylphenyl, furanylmethyl, iodophenyl, or
R 16 is halogen, toluoylmethyl,
R 17 is halogen or
R 18 is hydrogen or
R 19 is lower alkyl;
R 20 is methylthieno,
wherein R 27 is halogen;
R 21 and R 22 are each independently hydrogen, lower alkyl, or phenyl;
R 23 is
R 24 is hydrogen or hydroxy;
R 25 hydrogen or lower alkyl;
R 26 is lower alkyl;
R 27 is hydrogen or hydroxy;
R 28 is hydrogen, lower alkyl, cyano, or together with R 29 forms a phenyl group;
R 29 is hydrogen, lower alkyl, cyano, lower alkoxy, —NO 2 , or together with R 28 forms a phenyl group;
a=1-5; and
m=1-4.
9 . The method of claim 2 , wherein the compound of formula (I), (II), or (XII) is further defined as any one of the following:
10 . The method of claim 1 , wherein the method of administration is selected from the group consisting of an inhaled aerosol, nasal spray, oral formulation and injection.
11 . The method of claim 1 , wherein the dose of NS1 protein inhibitor that is administered is about 1 mg/kg to about 50 mg/kg.
12 . A method of inhibiting NS1 protein comprising administering to a cell an effective amount of an NS1 protein inhibitor.
13 . The method of claim 12 , wherein the cell is in vitro.
14 . The method of claim 12 , wherein the cell is in vivo.
15 . A method of inhibiting influenza A virus cytopathic effect in a cell comprising administering to said cell an effective amount of an NS1 protein inhibitor.
16 . A method of reducing the severity or duration of a viral infection in a patient comprising administering to said patient an effective amount of an NS1 protein inhibitor.
17 . The method of claim 16 , wherein the viral infection is influenza.
18 . The method of claim 16 , wherein the viral infection is caused by the influenza A virus.
19 . A method of treating or preventing a viral infection in a patient comprising administering to said patient an effective amount of an NS1 protein inhibitor in combination with a neuraminidase inhibitor or an M2 proton channel inhibitor.
20 . A method of selecting for a compound that inhibits NS1 protein comprising:
a) infecting a cell with plasmids expressing luciferase and NS1 protein, b) contacting the cell with a target compound, and c) quantifying the luciferase signal; wherein a decrease in the luciferase signal relative to the signal obtained in the absence of target compound indicates that the target compound is an NS1 protein inhibitor.
21 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, and/or excipient and any one or more of the following:Cited by (0)
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