Method of treating ciliary dyskinesia with dinucleoside polyphosphate compounds or UTP analogues

A method of treating primary ciliary dyskinesia in a subject in need of such treatment, said method comprising:

• administering to a subject a pharmaceutical composition comprising a compound of Formula I or IV, or pharmaceutically acceptable salt thereof, in an amount effective to increase ciliary beat frequency in an affected part of the body selected from the group consisting of the lungs, upper airways, eyes, genito-urinary tract, spermatozoa, ovaries, fallopian tubes, neutrophils, and macrophages:
• wherein:
• X1, X2, and X3 are each independently selected from the group consisting of OH and SH;
• R1 is selected from the group consisting of O, imido, methylene, and dihalomethylene;
• and wherein Formula I is not uridine triphosphate (UTP);
• and
• R2 is selected from the group consisting of H and Br;
• wherein:
• X is oxygen, methylene, difluoromethylene, imido;
• n=0, 1 or 2;
• m=0, 1 or 2;
• n+m=0, 1, 2, 3 or 4;
• Z=OH or N3;
• Z′=OH or N3;
• Y=H or OH;
• Y′=H or OH;
• B and B′ are each independently a pyrimidine residue as in Formula IVb linked through the 1-position,
• wherein:
• R4 is hydrogen, hydroxy, mercapto, amino, cyano, aralkoxy, C1-6 alkylthio, C1-6 alkoxy, C1-6 alkylamino or dialkylamino, the alkyl groups optionally linked to form a heterocycle;
• R5 is hydrogen, acyl, C1-6 alkyl, aroyl, optionally functionalized as defined below, C1-5 alkanoyl, benzoyl, or sulphonate;
• R6 is hydroxy, mercapto, alkoxy, aralkoxy, C1-6alkylthio, amino, C1-5 disubstituted amino, triazolyl, alkylamino or dialkylamino, where the alkyl groups are optionally linked to form a heterocycle or link to N3 to form an optionally substituted ring;
• or
• R5 and R6 taken together form a 5-membered fused imidazole ring between positions 3 and 4 of the pyrimidine ring optionally substituted on the 4- or 5-positions of the etheno moiety with alkyl, aryl or aralkyl moieties as defined below;
• R7 is hydrogen, hydroxy, cyano, nitro, alkenyl with the alkenyl moiety optionally linked through oxygen to form a ring optionally substituted on the carbon adjacent to the oxygen with alkyl or aryl groups, substituted alkynyl, halogen, substituted alkyl, perhalomethyl, C2-6 alkyl, C2-3 alkenyl, or substituted ethenyl, C2-3 alkynyl or substituted alkynyl;
• or together R6-R7 may form a 5 or 6-membered saturated or unsaturated ring bonded through N or O at R6, such a ring may contain substituents that themselves contain functionalities;
• provided that when R8 is amino or substituted amino, R7 is hydrogen;
• and
• R8 is hydrogen, amino or substituted amino, alkoxy, arylalkoxy, alkylthio, arylalkylthio, carboxamidomethyl, carboxymethyl, methoxy, methylthio, phenoxy or phenylthio;
• or
• pharmaceutically acceptable esters, amides or salts thereof.