Compositions and methods for treating heart failure
OwnerFady Malik, Adam Lewis Tomasi +8inventors
InventorsFady Malik, Adam Lewis Tomasi, Bainian Feng, Bradley Paul Morgan, Han-Jie Zhou, Kathleen A. Elias, Pu-Ping Lu, Whitney Walter Smith, Xiangping Qian, David J. Morgans, JR.
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Abstract
Certain substituted benzamide derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
Claims40
A compound represented by Formula I:
- 9
- wherein:
- X is C(H)—, C(Z)—, C(H)—CH2—, N—, or S═;
- m is 1,2, or 3;
- n is 0, 1 or 2;
- p is 0, 1, 2 or 3;
- Z is alkyl, substituted alkyl or hydroxy;
- R1 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
- R2 is alkyl, substituted alkyl, alkoxycarbonyl, halo or hydroxy, substituting for a hydrogen of (CH2)m and/or (CH2)n;
- R3 is alkyl, hydrogen, or a valence bond of S═ when X is S═;
- and
- R4 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
- or a single stereoisomer, or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, provided that the compound is not 4-chloro-N-[4-(4-chloro-benzenesulfonyl)-1λ4-thiomorpholin-1-ylidene]-benzenesulfonamide or N-[4-(4-chloro-benzenesulfonyl)-1λ4-thiomorpholin-1-ylidene]-4-methoxy-benzenesulfonamide.
A method of treatment for heart failure, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound represented by Formula I:
- 10
- wherein:
- X is C(H)—, C(Z)—, C(H)—CH2—, N—, or S═;
- m is 1,2, or 3;
- n is 0, 1 or 2;
- p is O, 1, 2 or 3;
- Z is alkyl, substituted alkyl or hydroxy;
- R1 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
- R2 is alkyl, substituted alkyl, alkoxycarbonyl, halo or hydroxy, substituting for a hydrogen of (CH2)m and/or (CH2)n;
- R3 is alkyl, hydrogen, or a valence bond of S═ when X is S═;
- and
- R4 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
- or a single stereoisomer, or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
A pharmaceutical formulation comprising a pharmaceutically accepted excipient and a therapeutically effective amount of a compound represented by Formula I:
- 11
- wherein:
- X is C(H)—, C(Z)—, C(H)—CH2—, N—, or S═;
- m is 1, 2, or 3;
- n is 0, 1 or 2;
- p is 0, 1, 2 or 3;
- Z is alkyl, substituted alkyl or hydroxy;
- R1 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
- R2 is alkyl, substituted alkyl, alkoxycarbonyl, halo or hydroxy, substituting for a hydrogen of (CH2)m and/or (CH2)n;
- R3 is alkyl, hydrogen, or a valence bond of S═ when X is S═;
- and
- R4 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
- or a single stereoisomer, or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.