Certain dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency

1. A compound of Formula IIIA:

X is oxygen, methylene, difluoromethylene, imido;

n=0, 1, or 2;

m=0, 1, or 2;

n+m 0, 1, 2, 3, or 4;

B is a purine or a pyrimidine residue linked through the 9- or 1-position, respectively;

Z=OH or N 3 ;

Z′=OH or N 3 ;

Y=H or OH;

Y′=H or OH;

provided that when Z is N 3 , Y is H or when Z′ is N 3 , Y′ is H;

R 4 is oxo, hydroxy, amino, cyano, aralkoxy, C 1-6 alkoxy, C 1-6 alkylamino, or dialkylamino;

R 5 is hydrogen, acyl, C 1-6 alkyl, phenyloxy, C 1-5 alkanoyl or absent;

R 6 is oxo, hydroxy, mercapto, C 1-4 alkoxy, C 7-12 arylalkoxy, C 1-6 alkylthio, amino, C 1-5 disubstituted amino, triazolyl, C 1-6 alkylamino or di-C 1-4 alkylamino, where the alkyl groups is optionally linked to form a heterocycle or link to N 3 to form a substituted ring; or

R 5 and R 6 taken together form a 5-membered fused imidazole ring between positions 3 and 4 of the pyrimidine ring, which is optionally substituted on the 4- or 5-positions of the etheno moiety with C 1-4 alkyl, phenyl, or phenyloxy, which themselves are optionally substituted;

R 7 is hydrogen, hydroxy, cyano, nitro, substituted and unsubstituted C 2-8 alkenyl, phenyl, substituted and unsubstituted C 2-8 alkynyl, halogen, CF 3 , substituted and unsubstituted C 1-8 alkyl, allylamino, bromovinyl, ethyl propenoate, propenoic acid; or

R 6 and R 7 taken together form a 5 or 6-membered saturated or unsaturated ring bonded through N or O at R 6 , such ring optionally contain substituents that themselves contain functionalities;

R 8 is hydrogen, amino or di-C 1-4 alkylamino, C 1-4 alkoxy, C 7-12 arylalkoxy, C 1-4 alkylthio, C 7-12 arylalkylthio, carboxamidomethyl, carboxymethyl, methoxy, methylthio, phenoxy or phenylthio; provided that when R 8 is amino or substituted amino, R 7 is hydrogen;

provided that when B=adenine, adenine 1-oxide, or 1,N 6 -ethenoadenine, then:

(a) R 6 ≠oxo when R 4 =oxo, Y=Z=OH and R 5 ═R 7 ═R 8 =H;

(b) R 7 ≠Br when R 4 ═R 6 =oxo, Y=Z=OH, and R 5 ═R 8 =H;

provided that when B=adenine, then:

(a) R 6 ≠amino when R 4 =oxo, Y=Z=OH, R 5 is absent, R 7 ═R 8 =H, and n+m=0, 1, or 2;

(b) R 7 ≠CH 3 when R 4 ═R 6 =oxo, Y=H, Z=OH, and R 5 ═R 8 =H;

(c) R 7 ≠F when R 4 ═R 6 =oxo, Y=H, Z=OH, R 5 ═R 8 ═H and n+m=2;

provided that when B=thymine, Y′=H and Z′=N 3 ; then R 7 ≠F, when R 4 ═R 6 =oxo, Y=OH, Z=OH, R 5 ═R 8 =H, and n+m=0;

provided that when B=thymine, Y′=H and Z′=N 3 ; then R 7 ≠CH 3 when R 4 ═R 6 =oxo, Y=H, Z=N 3 , R 5 ═R 8 =H, and n+m=0;

provided that when B=guanine, then:

(a) R 6 ≠oxo when R 4 =oxo, Y═Z=OH, R 5 ═R 7 ═R 8 =H and n+m=1 or 2;

(b) R 6 ≠amino when R 4 =oxo, Y=Z=OH, R 5 is absent, R 7 ═R 8 =H, n+m=1 or 2;

provided that when B is uridine, or 5-Br-uridine, then

(a) R 6 ≠oxo when R 4 =oxo, Y=Z=OH and R 6 ═R 7 ═R 8 =H;

(b) R 7 ≠Br when R 4 ═R 6 =oxo, Y=Z=OH, and R 5 ═R 8 =H;

provided that when B is 5-FU, then R 7 ≠F, when R 4 ═R 6 =oxo, Y=H, Z=OH, R 5 ═R 8 =H,

provided that when B is cytosine, then R 6 ≠amino, when R 4 =oxo, Y=Z=OH, R 5 is absent, R 7 ═R 8 =H, and n+m=1, or 2; and

provided that when B is cytosine, then R 6 ≠oxo, when R 4 =oxo, Y=Z=OH and R 5 ═R 7 ═R 8 =H, and n+m=2.

2. A compound according to Formula IIA:

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;

B is a purine residue linked through the 9-position;

Z=OH or N 3 ;

Z′=OH or N 3 ;

Y=H or OH;

Y′=H or OH;

provided that when Z is N 3 , Y is H or when Z′ is N 3 , Y′ is H;

R 1 is H, C 1-8 alkyl, phenyl or phenyloxy, optionally substituted with halogen, hydroxy, C 1-4 alkoxy, C 1-8 alkyl, C 6-10 aryl, carboxy, cyano, nitro, sulfonamido, sulfonate, phosphate, sulfonic acid, amino or substituted amino, wherein the amino is singly or doubly substituted by a C 1-4 alkyl and when doubly substituted, the alkyl groups are optionally linked to form a heterocycle; or A(C 1-6 alkyl)CONH(C 1-6 alkyl)B wherein A and B are amino, mercapto, hydroxy or carboxyl;

R 2 is O or is absent; or

R 1 and R 2 taken together forms a 5-membered fused imidazole ring, which is optionally substituted on the 4- or 5-positions of the etheno moiety with C 1-4 alkyl, phenyl or phenyloxy, optionally substituted with halogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 6-10 aryl, arylalkyl, carboxy, cyano, nitro, sulfonamido, sulfonate, phosphate, sulfonic acid, amino or substituted amino, wherein the amino is singly or doubly substituted by a C 1-4 alkyl and when doubly substituted, the alkyl groups is optionally linked to form a heterocycle; and

R 3 is H, C 1-8 alkyl, phenyl or phenyloxy, optionally substituted with halogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 6-10 aryl, carboxy, cyano, nitro, sulfonamido, sulfonate, phosphate, sulfonic acid, amino or substituted amino, wherein the amino is singly or doubly substituted by a C 1-4 alkyl and when doubly substituted, the alkyl groups is optionally linked to form a heterocycle; C 7-12 arylalkyl; C 1-4 alkylamino, phenylamino, C 7-12 arylalkylamino, C 1-4 alkoxy, or C 7-12 arylalkyloxy; C 1-4 alkylthio, phenylthio, C 7-12 arylalkylthio, or -A(C 1-6 alkyl)CONH(C 1-6 alkyl)B- wherein A and B are independently amino, mercapto, hydroxy or carboxyl;

provided that R 1 ≠H, when X is oxygen, methylene, or difluoromethylene, Y is OH, B is adenine, R 2 is absent, and R 3 is hydrogen;

provided that R 1 ≠H, when n+m=2, X is oxygen, Y is OH, B is adenine, R 2 is absent, and R 3 is bromo, or 6-aminohexyl;

provided that R 1 ≠H, when n+m=2, X is oxygen, Y is H, B is adenime, R 2 is absent, and R 3 is H;

provided that R 2 ≠O, when n+m=2, X is oxygen, Y is OH, R 1 ═R 3 =H, and B is adenine, adenine 1-oxide, or 1,N 6 -ethenoadenine;

provided that R 1 and R 2 do not form a 5-membered fused imidazole ring, when n+m=2, X is oxygen, Y is OH, R 3 is H, and B is adenine, adenine 1-oxide, or ethenoadenine.

3. The compound according to claim 1 or 2 , wherein the ribosyl moieties are in the D-configuration.

4. The compound according to claim 1 or 2 , wherein the ribosyl moieties are in the L-configuration.

5. A pharmaceutical composition comprising a compound of Formula IIIA or IIA as described in claim 1 or 2 , or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier therefor.

6. A method of treating chronic abstructive pulmonary diseases in a mammal by administering an effective chronic obstructive pulmonary disease treatment amount of a compound of Formula IIIA or IIA as described in claim 1 or 2 .

7. A method of treating sinusitis, otitis media or nasolacrimal duct obstruction in a mammal by administering an effective mucus secretion clearing amount of a compound of Formula IIIA or IIA as described in claim 1 or 2 .

8. A method of treating dry eye in a mammal by administering an effective dry eye treatment amount of a compound of Formula III A or IIA as described in claim 1 or 2 .

9. A method of treating retinal detachment in a mammal by administering an effective retinal detachment treatment amount of compound of Formula IIIA or IIA as described in claim 1 or 2 .

10. A method of facilitating sputum induction in a mammal by administering an effective amount of a compound of Formula IIIA or IIA as described in claim 1 or 2 , to facilitate sputum induction.

11. A method of facilitating expectoration in mammal by administering an effective amount of a compound of Formula IIIA or IIA as described in claim 1 or 2 , to facilitating expectoration.

12. A method of treating cystic fibrosis in a mammal by administering an effective amount of a compound of Formula IIIA or IIA as described in claim 1 or 2 to treat cystic fibrosis.

13. A method of treating cystic fibrosis in a mammal by admininstering an effective amount of P 1 -(2′-deoxycytidine 5′-)-P 4 -(uridine 5′-)tetraphosphate.