Dinucleotides useful for the treatment of lung disease

Details Dinucleotides useful for the treatment of lung disease Dinucleotides useful for the treatment of lung disease

1999-04-30

2001-05-22

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Effervescent or pressurized fluid containing

Organic pressurized fluid

C424S489000

Reexamination Certificate

active

06235266

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to certain dinucleotides, pharmaceutical formulations containing the same, and methods of hydrating retained mucous secretions in the lungs of a subject by administering dinucleotides to the subject.
BACKGROUND OF THE INVENTION
In cystic fibrosis several functions of airway epithelia are abnormal, and deficiencies in both Cl
−
transport and Na
+
absorption are well documented. See, e.g. Knowles et al.,
Science
221, 1067 (1983); Knowles et al.,
J. Clin. Invest.
71, 1410 (1983). Regulation of Lon transport might have potential therapeutic benefit in lung diseases characterized by abnormalities in epithelial ion transport, e.g., cystic fibrosis.
One therapeutic goal in cystic fibrosis and other pulmonary diseases in which the water content of the mucous is altered is to hydrate the lung mucous secretions, so that the secretions may be thereafter more easily removed from the lungs by mucociliary action or simple coughing. The use of aerosolized amiloride to hydrate mucous secretions is described in U.S. Pat. No. 4,501,729. Amiloride appears to block Na
+
reabsorption by airway epithelial cells, and therefore inhibits water absorption from the mucous.
A different therapeutic approach for hydrating lung mucous secretions is exemplified by techniques that involve the administration of ATP or UTP, which appear to stimulate chloride secretion from respiratory epithelial cells. See, e.g., U.S. Pat. No. 5,292,498 to Boucher.
In view of the large numbers of people afflicted with cystic fibrosis, there is an ongoing need for new methods for providing methods of hydrating lung mucous secretions and thereby facilitating lung mucous clearance.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a pharmaceutical formulation comprising, in a pharmaceutically acceptable carrier (e.g., a solid or liquid carrier), a compound of Formula (I)
or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate lung mucous secretions. In a compound of Formula I:
n is from 1 to 6. n is preferably from 2 to 4, and is most preferably 4.
X is —OH or —SH, and is preferably —OH.
A and B are each independently selected from the group consisting of:
wherein R is H or Br. Optionally, the pharmaceutical formulation may further comprise a compound selected from the group consisting of amiloride, benzamil and phenamil in an amount effective to inhibit the reabsorption of water from lung mucous secretions.
A second aspect of the present invention is a method of hydrating mucous secretions in the lungs of a subject in need of such treatment, comprising administering to the lungs of the subject a compound of Formula I as given above, or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate lung mucous secretions.
A third aspect of the present invention is a method of treating cystic fibrosis in a subject in need of such treatment, comprising administering to the lungs of the subject a compound of Formula I as given above, or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate lung mucous secretions.
A fourth aspect of the present invention is the use of a compound of Formula I as given above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for hydrating mucous secretions in the lungs of a subject in need of such treatment.
The foregoing and other objects and aspects of the present invention are explained in detail in the specification set forth below.


REFERENCES:
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patent: 4501729 (1985-02-01), Boucher et al.
patent: 5292498 (1994-03-01), Boucher et al.
patent: 5304125 (1994-04-01), Leith
patent: 5512269 (1996-04-01), Molina y Vedia et al.
patent: 5628984 (1997-05-01), Boucher et al.
patent: 5635160 (1997-06-01), Stutts, III et al.
patent: 5656256 (1997-08-01), Boucher et al.
patent: 5683675 (1997-11-01), Molina y Vedia et al.
patent: 5725842 (1998-03-01), Boucher et al.
M. Knowles et al.; Activation by Extracellular Nucleotides of Chloride Secretion in the Airway Epithelia of Patients with Cystic Fibrosis;N. Engl. J. Med.325 533-538 (1991).
M. Knowles et al.; Extracellular ATP and UTP Induce Chloride Secretion in Nasal Epithelia of Cystic Fibrosis Patients and Normal Subject in vivo,Chest101:60S-63S (1992).
S. Mason et al.; Regulation of transepithelial ion transport and intracellular calcium by extracellular ATP in human normal and cystic fibrosis airway epithelium,Br. J. Pharmacol103:1649-1656 (1991).
K. Ng et aL.; The action of a water-soluble carbodiimide on adenosine 5′-polyphosphates,Nucl. Acids Res.15:3573-3580 (1987).
M. Stutts et aL.; Multiple modes of regulation of airway epithelial chloride secretion by extracellular ATP,Am J. Physiol.267:C1442-1451 (1994).

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