Conjugates of sodium channel blockers and methods of using...

Details Conjugates of sodium channel blockers and methods of using... Conjugates of sodium channel blockers and methods of using...

2002-04-12

2003-09-02

Riley, Jezia (Department: 1637)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C514S046000, C514S255030

Reexamination Certificate

active

06613345

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to conjugates of sodium channel blockers, and particularly covalent conjugates comprising a pyrazinoylguanidine sodium channel blocker and another compound such as another pyrazinoylguanidine sodium channel blocker or a P2Y
2
receptor agonist.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,501,729 to Boucher describes the use of respirable or non-respirable amiloride to hydrate airway mucous secretions, and U.S. Pat. No. 5,656,256 to Boucher and Stutts describes the use of respirable or non-respirable benzamil and phenamil to hydrate lung mucus secretions. U.S. Pat. No. 5,789,391 to Jacobus describes methods of treating sinusitis by administering uridine triphosphates (UTP) and related compounds such as P
1
,P
4
-di(uridine-5′ tetraphosphate (U
2
P
4
) in order to promote drainage of congested fluid in the sinuses.
U.S. Pat. No. 5,292,498 to Boucher describes nucleotides, particularly P2Y
2
receptor agonists, that can be used to hydrate airway mucus secretions. Dinucleotides that can be used to hydrate airway mucus secretions are described in U.S. Pat. No. 5,635,160 to Stutts et al.. Additional compounds that are P2Y
2
receptor ligands and can be used to hydrate airway mucus secretions are disclosed in W. Pendergast et al., U.S. Pat. No. 5,837,861, along with U.S. Pat. Nos. 5,763,447 to Jacobus and Leighton, and 5,789,391 to Jacobus et al.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a compound (hereinafter also referred to as an “active compound” or “active agent”) of the general formula P
1
-L-P
2
; wherein “P
1
” is a pyrazinoylguanidine sodium channel blocker, “L” is a linking group, and “P
2
” is either (i) a pyrazinoylguanidine sodium channel blocker or (ii) a P2Y
2
receptor agonist. An advantage of compounds of the present invention is that they are substantially non-absorbable, or absorption-retardant or exhibit delayed absorption on mucosal (e.g., airway, gastrointestinal) surfaces, thereby contributing to a prolonged mode of action and fewer systemic side effects.
A second aspect of the present invention is a composition comprising an active compound as defined above in an effective therapeutic amount, in a pharmaceutically acceptable carrier.
A third aspect of the present invention is a method of treating a mucosal surface in a subject in need thereof, comprising administering an active compound as described herein in an amount effective to treat the subject. In general, treatment of the subject will mean that the mucosal surface being treated with a compound or composition of the present invention will be hydrated, or that the compound or composition being used will block or otherwise retard the absorption of liquid onto or onto the mucosal surface, or that the mucosal surface will otherwise exhibit an increased volume of liquid on the mucosal surface.
A fourth aspect of the present invention is the use of an active compound as described above for the preparation of a medicament for treating a mucosal surface in a subject in need thereof, as described herein.
The foregoing and other objects and aspects of the present invention are explained in detail in the specification set forth below.


REFERENCES:
patent: 3313813 (1967-04-01), Cragoe, Jr.
patent: 5837861 (1998-11-01), Pendergast et al.
patent: 6264975 (2001-07-01), Boucher, Jr.
patent: WO 94/08593 (1994-04-01), None
patent: WO 96/18385 (1996-06-01), None
patent: WO 96/40059 (1996-12-01), None
patent: WO 00/23023 (2000-04-01), None
International Search Report, Nov. 20, 2000, Application No. PCT/US00/19775.

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