Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders

摘要

The present disclosure is directed to compounds of the structure (X):;
wherein:
n is 2 or 3;NHE has the structure;
wherein:
R1 is H or —SO2—NR7R8—;R2 is selected from H, —NR7(CO)R8, —SO2—NR7R8— and —NR7R8;R3 is hydrogen;R7 is hydrogen;R8 is a bond linking to L;L is a polyalkylene glycol linker; andCore has the following structure:;
wherein:
X is selected from the group consisting of a bond, —O—, —NH—, NHC(═O)—, —NHC(═O)NH— and —NHSO2—; andY is selected from the group consisting of a bond, optionally substituted C1-6 alkylene, optionally substituted benzene, pyridinyl, a polyethylene glycol linker and —(CH2)1-6O(CH2)1-6—, and methods of using such compounds for the treatment of irritable bowel syndrome, chronic kidney disease and end-stage renal disease.

主权项

1. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure (X):wherein:
n is 2; NHE has the structurewherein:
R1 is H or —SO2—NR7R8—; R2 is selected from H, —NR7(CO)R8, —SO2—NR7R8— and —NR7R8; R3 is hydrogen; R7 is hydrogen; R8 is a bond linking to L; L is a polyalkylene glycol linker; and Core has the following structure:wherein:
X is selected from the group consisting of a bond, —O—, —NH—, NHC(═O)—, —NHC(═O)NH— and —NHSO2—; and Y is selected from the group consisting of a bond, optionally substituted C1-6 alkylene, optionally substituted benzene, pyridinyl, a polyethylene glycol linker and —(CH2)1-6O(CH2)1-6.