Bumetanide Derivatives for the Therapy of Stroke and Other Neurological Diseases/Disorders Involving NKCCs

A method of treating or preventing a neurological disease or disorder involving a Na+—K+-2Cl−—cotransporter (NKCC), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I):

• wherein:
• R1 is selected from —(C1-4 alkylene)-NH—(C1-4 alkylene)-R11, —COO—(C1-4 alkylene)-R11, —O—CO—(C1-4 alkylene)-R11, —CO—(C1-4 alkylene)-R11, —CO—NH—(C1-4 alkylene)-R11, —CO—N(C1-4 alkyl)—(C1-4 alkylene)-R11, —NH—CO—(C1-4 alkylene)-R11 and —N(C1-4 alkyl)-CO—(C1-4 alkylene)-R11;
• R11 is independently selected from —CF3, —CN and halogen;
• R2 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —OH, —O(C1-6 alkyl), —O(C1-6 alkylene)-OH, —O(C1-6 alkylene)-O(C1-6 alkyl), —S H, —S(C1-6 alkyl), —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), C1-6 haloalkyl, —O—(C1-6 haloalkyl), —CN, —NO2, —CHO, —CO—(C1-6 alkyl), —COOH, —COO—(C1-6 alkyl), —O—CO—(C1-6 alkyl), —CO—NH2, —CO—NH(C1-6 alkyl), —CO—N(C1-6 alkyl)(C1-6 alkyl), —NH—CO—(C1-6 alkyl), —N(C1-6 alkyl)-CO—(C1-6 alkyl), —SO2—NH2, —SO2—NH(C1-6 alkyl), —SO2—N(C1-6 alkyl)(C1-6 alkyl), —NH—SO2—(C1-6 alkyl) and —N(C1-6 alkyl)—SO2—(C1-6 alkyl);
• R3 is selected from —SO2—NH2, —SO2—NH(C1-6 alkyl), —SO2—N(C1-6 alkyl)(C1-6 alkyl), —SO2—N═(C1-6 alkylidene) and —SO2-halogen, wherein the alkyl moiety of said —SO2—NH(C1-6 alkyl), one or both of the alkyl moieties of said —SO2—N(C1-6 alkyl)(C1-6 alkyl), and the alkylidene moiety of said —SO2—N═(C1-6 alkylidene) are each optionally substituted with one or more groups independently selected from halogen, —CF3, —CN, —NO2, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), —OH, —O(C1-6 alkyl), —SH and —S(C1-6 alkyl);
• R4 is selected from —O—R41, —S—R41, —NH—R41, —N(C1-6 alkyl)-R41, halogen, hydrogen, carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R42;
• R41 is selected from —(C0-4 alkylene)-carbocyclyl, —(C0-4 alkylene)-heterocyclyl, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, wherein the carbocyclyl moiety of said —(C0-4 alkylene)-carbocyclyl and the heterocyclyl moiety of said —(C0-4 alkylene)-heterocyclyl are each optionally substituted with one or more groups R42, and wherein said C1-6 alkyl, said C2-6 alkenyl, said C2-6 alkynyl, the alkylene moiety of said —(C0-4 alkylene)-carbocyclyl, and the alkylene moiety of said —(C0-4 alkylene)-heterocyclyl are each optionally substituted with one or more groups R43;
• each R42 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —OH, —O(C1-6 alkyl), —O(C1-6 alkylene)-OH, —O(C1-6 alkylene)-O(C1-6 alkyl), —SH, —S(C1-6 alkyl), —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), halogen, C1-6 haloalkyl, —O—(C1-6 haloalkyl), —CN, —NO2, —CHO, —CO—(C1-6 alkyl), —COOH, —COO—(C1-6 alkyl), —O—CO—(C1-6 alkyl), —CO—NH2, —CO—NH(C1-6 alkyl), —CO—N(C1-6 alkyl)(C1-6 alkyl), —NH—CO—(C1-6 alkyl), —N(C1-6 alkyl)-CO—(C1-6 alkyl), —SO2—NH2, —SO2—NH(C1-6 alkyl), —SO2—N(C1-6 alkyl)(C1-6 alkyl), —NH—SO2—(C1-6 alkyl) and —N(C1-6 alkyl)—SO2—(C1-6 alkyl);
• each R43 is independently selected from —OH, —O(C1-6 alkyl), —SH, —S(C1-6 alkyl), —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), halogen, —CF3, —CN, —NO2, —CHO, —CO—(C1-6 alkyl), —COOH, —COO—(C1-6 alkyl), —O—CO—(C1-6 alkyl), —CO—NH2, —CO—NH(C1-6alkyl), —CO—N(C1-6 alkyl)(C1-6 alkyl), —NH—CO—(C1-6 alkyl) and —N(C1-6 alkyl)-CO—(C1-6 alkyl);
• R5 is selected from —NH2, —NH(C1-6 alkyl), —NO2 and hydrogen, wherein the alkyl moiety of said —NH(C1-6 alkyl) is optionally substituted with one or more groups independently selected from halogen, —CF3, —CN, —NO2, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), —OH, —O(C1-6 alkyl), —SH, —S(C1-6 alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R51;
• each R51 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —OH, —O(C1-6 alkyl), —O(C1-6 alkylene)-OH, —O(C1-6 alkylene)-O(C1-6 alkyl), —SH, —S(C1-6 alkyl), —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), halogen, C1-6 haloalkyl, —O—(C1-6 haloalkyl), —CN, —NO2, —CHO, —CO—(C1-6 alkyl), —COOH, —COO—(C1-6 alkyl), —O—CO—(C1-6 alkyl), —CO—NH2, —CO—NH(C1-6 alkyl), —CO—N(C1-6 alkyl)(C1-6 alkyl), —NH—CO—(C1-6 alkyl), —N(C1-6 alkyl)-CO—(C1-6 alkyl), —SO2—NH2, —SO2—NH(C1-6 alkyl), —SO2—N(C1-6 alkyl)(C1-6 alkyl), —NH—SO2—(C1-6 alkyl) and —N(C1-6 alkyl)—SO2—(C1-6 alkyl);
• and
• R6 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —OH, —O(C1-6 alkyl), —O(C1-6 alkylene)-OH, —O(C1-6 alkylene)-O(C1-6 alkyl), —SH, —S(C1-6 alkyl), —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)(C1-6 alkyl), halogen, C1-6 haloalkyl, —O—(C1-6 haloalkyl), —CN, —NO2, —CHO, —CO—(C1-6 alkyl), —COOH, —COO—(C1-6 alkyl), —O—CO—(C1-6 alkyl), —CO—NH2, —CO—NH(C1-6 alkyl), —CO—N(C1-6 alkyl)(C1-6 alkyl), —NH—CO—(C1-6 alkyl), —N(C1-6 alkyl)-CO—(C1-6 alkyl), —SO2—NH2, —SO2—NH(C1-6 alkyl), —SO2—N(C1-6 alkyl)(C1-6 alkyl), —NH—SO2—(C1-6 alkyl) and —N(C1-6 alkyl)—SO2—(C1-6 alkyl);
• or a pharmaceutically acceptable salt or solvate thereof.