Inhibitors of the influenza A virus M2 proton channel

Patent metadata

Field	Value
Publication number	US-9403777-B2
Application number	US-201314036813-A
Country	US
Kind code	B2
Filing date	Sep 25, 2013
Priority date	Aug 1, 2010
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

Provided are compounds that are capable of modulating the activity of the influenza A virus via interaction with the M2 transmembrane protein. Also provided are methods for treating an influenza A-affected disease state or infection comprising administering a composition comprising one or more compounds that have been identified as being capable of interaction with the M2 protein.

First claim

What is claimed:

1. A compound of formula (I):

wherein
(a)
X and Y are independently a bond, alkylene, or amine;
R 1 is alkyl, hydroxyl, carbonyl, carboxyl, cyano, amino, —CH(R 5 )(R 6 ), or forms an oxo group together with R 2 ;
R 2 is alkyl, hydroxyl, carbonyl, carboxyl, cyano, amino, or —CH(R 5 )(R 6 );
R 3 and R 4 are independently hydrogen or —CH(R 7 )(R 8 );
R 5 and R 6 are independently hydrogen, alkyl, hydroxyl, carbonyl, or amino;
R 7 and R 8 are independently hydrogen, alkyl, alkoxy, hydroxyl, carbonyl, or amino;
dashed lines a and b are optional bonds; and,
n is 0-3, or,

(b)
X and Y are independently a bond, alkylene, or amine;
R 1 is hydrogen, alkyl, hydroxyl, carbonyl, carboxyl, cyano, —CH(R 5 )(R 6 ), or forms an oxo group together with R 2 ;
R 2 is hydrogen, alkyl, hydroxyl, carbonyl, carboxyl, cyano, or —CH(R 5 )(R 6 );
R 3 and R 4 are independently hydrogen or —CH(R 7 )(R 8 );
R 5 and R 6 are independently hydrogen, alkyl, hydroxyl, or carbonyl;
R 7 and R 8 are independently hydrogen, alkyl, alkoxy, hydroxyl, or carbonyl;
dashed lines a and b are optional bonds; and,
n is 0-3,

or,
(c)
X and Y are independently a bond, alkylene, or amine;
R 1 is amino, —CH(R 5 )(R 6 ), or forms an oxo group together with R 2 ;
R 2 is hydrogen, alkyl, hydroxyl, carbonyl, carboxyl, cyano, amino, or —CH(R 5 )(R 6 );
R 3 is hydrogen or —CH(R 7 )(R 8 );
R 4 is —CH(R 7 )(R 8 );
R 5 and R 6 are independently hydrogen, alkyl, hydroxyl, carbonyl, or amino;
R 7 and R 8 are independently hydrogen, alkyl, alkoxy, hydroxyl, carbonyl, or amino;
dashed lines a and b are optional bonds; and,
n is 0-3,

or,
(d)
X and Y are independently a bond, alkylene, or amine;
R 1 is hydrogen, alkyl, hydroxyl, carbonyl, carboxyl, cyano, amino, —CH(R 5 )(R 6 ), or forms an oxo group together with R 2 ;
R 2 is hydrogen, alkyl, hydroxyl, carbonyl, carboxyl, cyano, amino, or —CH(R 5 )(R 6 );
R 3 and R 4 are independently hydrogen or —CH(R 7 )(R 8 );
R 5 and R 6 are independently hydrogen, alkyl, hydroxyl, carbonyl, or amino;
R 7 and R 8 are independently hydrogen, alkyl, alkoxy, hydroxyl, carbonyl, or amino;
at least one of lines a and b represents a bond; and,
n is 0-3,

or,
(e)
X is a bond or alkylene;
Y is methylene;
R 1 is amino, —CH(R 5 )(R 6 ), or forms an oxo group together with R 2 ;
R 2 is hydrogen, alkyl, hydroxyl, carbonyl, carboxyl, cyano, amino, or —CH(R 5 )(R 6 );
R 3 is hydrogen or —CH(R 7 )(R 8 );
R 4 is —CH(R 7 )(R 8 );
R 5 and R 6 are independently hydrogen, alkyl, hydroxyl, carbonyl, or amino;
R 7 and R 8 are independently hydrogen, alkyl, alkoxy, hydroxyl, carbonyl, or amino;
dashed lines a and b are optional bonds; and,
n is 0-3,
or a stereoisomer, partial stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid hydrate, or N-oxide thereof.

2. The compound according to claim 1 wherein X and Y are each independently methylene or ethylene.

3. The compound according to claim 2 wherein X is methylene and Y is ethylene.

4. The compound according to claim 2 wherein at least one of R 1 and R 2 is hydrogen.

5. The compound according to claim 4 wherein one of R 1 and R 2 is carbonyl, amino, carboxyl, cyano, or —CH(R 5 )(R 6 ).

6. The compound according to claim 5 wherein n is 1 or 2, except that if n is 1, both X and Y are methylene, and both R 3 and R 4 are hydrogen, then one of R 1 and R 2 is not carbonyl.

7. The compound according to claim 5 wherein one of R 1 and R 2 is —CH(R 5 )(R 6 ).

8. The compound according to claim 7 wherein one of R 5 and R 6 is amino.

9. The compound according to claim 1 wherein said compound is:

 wherein n is 0, 2 or 3;

10. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

Assignees

• Univ Pennsylvania

Inventors

• Degrado William F
• Wang Jun

Classifications

• A61K31/19

  Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60) · CPC title

• C07C61/13

  having two rings · CPC title

• C07C49/323

  having keto groups bound to condensed ring systems · CPC title

• C07D223/32 Primary

  containing carbocyclic rings other than six-membered · CPC title

• C07C2602/50

  Spiro compounds · CPC title