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1. (WO2007002945) AGONISTES DU RECEPTEUR DE P2Y6 DESTINES AU TRAITEMENT DE MALADIES PULMONAIRES
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

WHAT IS CLAIMED:
1. A method of enhancing or facilitating the clearance of the lung mucus secretions of a subject in need of such treatment, comprising administering to the lungs of the subject a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in an amount sufficient to clear mucus secretions;
Formula I


wherein: B is a purine or a pyrimidine residue according to general Formulae IV or

V;
n and p = 0 or 1 ; such that the sum of n + p is from 0 to 2, with the proviso that when A = M, the sum of n + p is 1 ;
X1 and X2 are independently O, NH, CH2, CHF, CHCl, CF2, or CCl2;
T1, V, and W are independently O or S;
M = H+, NH4+, Na+ or other pharmaceutically-acceptable inorganic or organic counter ion;
Y= OR1;
Z = OR2;
G7
A = M, or
A is a nucleoside residue which is defined as:


wherein: D = O or CH2;
Z' = H or OH Y' = H or OH;
B' is a purine or a pyrimidine residue according to general Formulae IV or V which is linked to the 1'- position of the furanose or carbocycle via the 9- or 1- position of the base, respectively.
R1 and R2 are residues that are linked directly to the 2'- and /or 3'-hydroxyls of the furanose via a carbon atom according to Formula II, or linked directly to two (2'- and

3'-) hydroxyls of the furanose via a common carbon atom according to Formula III;

Formula II


wherein O is the corresponding T- and/or V- oxygen of the furanose;
C is a carbon atom;
R5, R6, and R7 are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, such that the moiety defined according to Formula II is an ether; or
R5 and R6 are H, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, and R7 is alkoxy, cycloalkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy such that the moiety defined according to Formula II is an acyclic acetal or ketal; or
R5 and R6 are taken together as oxygen or sulfur doubly bonded to C, and R7 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, such that the moiety defined according to Formula II is an ester or thioester; or
R5 and R6 are taken together as oxygen or sulfur doubly bonded to C, and R7 is amino or mono- or disubstituted amino, where the substituents are alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, such that the moiety according to Formula II is a carbamate or thiocarbamate; or
R5 and R6 are taken together as oxygen or sulfur doubly bonded to C, and R7 is alkoxy, cycloalkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy, such that the moiety according to Formula II is a carbonate or thiocarbonate; or R7 is not present and R5 and R6 are taken together as oxygen or sulfur doubly bonded to C and both the T- and 3'- oxygens of the furanose are directly bound to C to form a cyclical carbonate or thiocarbonate;
Formula III


wherein the O atoms are the T- and 3'- oxygens of a furanose; and the T- and 3'-oxygens of the furanose are linked by a common carbon atom (C) to form a cyclical acetal, cyclical ketal, or cyclical orthoester;
for cyclical acetals and ketals, R8 and R9 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, substituted aralkyl, substituted aryl, or can be joined together to form a homocyclic or heterocyclic ring composed of 3 to 8 atoms, preferably 3 to 6 atoms;
for cyclical orthoesters, R8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, R9 is alkyloxy, cycloalkyloxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy;
B and B' are independently a purine residue, as in Formula IV, linked through the 9-position, or a pyrimidine residue, as in Formula V, linked through the 1- position.
Formula IV


Formula V



wherein:
R10 and R13 independently are hydroxy, oxo, amino, mercapto, alkylthio, alkyloxy, aryloxy, alkylamino, cycloalkylamino, aralkylamino, arylamino, diaralkylamino,
diarylamino, or dialkylamino, where the alkyl groups are optionally linked to form a heterocycle; or
R1O and Ri3 independently are acylamino according to Formula VI;
when R1O in a purine or R13 in a pyrimidine has as its first atom nitrogen, R1O and R11 or Ri3 and Ri4 can be taken together to form a 5-membered fused imidazole ring (to give an etheno compound), optionally substituted on the etheno ring with one or more alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl moieties, as described for R5-R9 above;
Rn is hydrogen, O or is absent;
Ri4 is hydrogen, or acyl;
R12 is hydrogen, chlorine, amino, monosubstituted amino, disubstituted amino, alkylthio, arylthio, or aralkylthio, where the substituent on sulfur contains up to a maximum of 20 carbon atoms, with or without unsaturation, and with or without substituents on the chain;
R15 is hydrogen, methyl, alkyl, halogen, alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;

Formula VI



wherein C is a carbon atom;
W1 is oxygen or sulfur;

R16 is amino or mono- or disubstituted amino, such that the moiety according to Formula VI is a urea or thiourea; or
R16 is alkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy, such that the moiety according to Formula VI is a carbamate or thiocarbamate; or
R16 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl, with or without substituents or heteroatoms, such that the moiety according to Formula VI is an amide.

2. A method of facilitating the hydration of lung mucus secretions of a subject in need of such treatment, comprising administering to the lungs of the subject a compound of

Formula I as described in Claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in an amount sufficient to hydrate lung secretions.

3. A method of preventing or treating a disease or condition associated with impaired or deficient airway function, comprising administering to the lungs of the subject a compound of Formula I as described in Claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in an amount effective to activate P2Y6 receptors on airway epithelia.

4. The method according to Claim 3, wherein said disease is chronic obstructive pulmonary disease, chronic bronchitis, emphysema, cystic fibrosis, primary ciliary dyskinesia, or alpha 1 antitrypsin deficiency.

5. The method according to Claim 4, wherein said disease is chronic bronchitis.

6. The method according to Claim 4, wherein said disease is chronic obstructive pulmonary disease.

7. The method according to Claim 4, wherein said disease is primary ciliary dyskinesia.

8. The method according to Claim 4, wherein said disease is cystic fibrosis.

9. The method according to any one of Claims 1-8, wherein said compound of Formula I is a compound of Formula Ia, Formula Ia



wherein B2 and B3 are independently uracil, N-methyluracil, 5-methyluracil, 5-bromouracil, 5-chlorouracil, 4-thiouracil, 4-thiomethyluracil, cytosine, 5-methylcytosine, 5-bromocytosine, N-methylcytosine, N-phenylcytosine, N-benzylcytosine, N5N-dimethylcytosine or guanosine; and
Q is phenyl, substituted phenyl, benzyl, substituted benzyl, phenylacetylene, substituted phenylacetylene, styryl, substituted styryl, phenethyl, or substituted phenethyl.

10. The method according to Claim 9, wherein said compound is selected from the group consisting of: P1 -(2',3'-benzylacetal uridine 5'-) P3-(uridine 5'-) triphosphate; P1 -(T, 3'-benzylacetal uridine 5'-) P3-(cytidine 5') triphosphate; P1 -(2',3'-benzylacetal guanosine 5'-) P3-(uridine 5'-) triphosphate; P1 -(2',3'-phenylacetal uridine 5'-) P3-(uridine 5'-)
triphosphate; P1 -[2',3'-(phenylacetylene)acetal uridine 5'-] P3-(uridine 5'-) triphosphate; and P1 ~(2',3'-phenylacetal cytidine 5'-) P3-(uridine 5'-) triphosphate.

11. The method according to Claim 10, wherein said compound is P1 -(2',3'-benzylacetal uridine 5'-) P3-(uridine 5'-) triphosphate.

12. The method according to any one of Claims 1 -4, wherein said compound is administered by inhalation.

13. The method according to any one of Claims 1 -4, wherein said compound is administered in a form of an aerosol suspension of respirable particles.

14. The method according to Claiml 3 , wherein said respirable particles have a size of 1-10 micron.