Therapeutic dinucleotide and derivatives

Details Therapeutic dinucleotide and derivatives Therapeutic dinucleotide and derivatives

1999-05-21

2001-11-27

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S042000, C514S043000, C514S04400A, C514S049000, C514S052000, C536S026230, C536S025600

Reexamination Certificate

active

06323187

ABSTRACT:

TECHNICAL FIELD
This invention relates to a method of enhancing clearance of secretions by increasing the hydration of retained mucus secretions, stimulating the production of mucins, and increasing ciliary beat frequency by administering P
1
-(cytidine 5′-)-P
4
-(uridine 5′-)-tetraphosphate (CP
4
U) or pharmaceutically acceptable esters, amides or salts thereof.
BACKGROUND OF THE INVENTION
Chronic obstructive pulmonary disease (COPD) affects 15 million patients in the U.S. and is the sixth leading cause of death. It is characterized by the retention of mucus secretions in the lungs which results in progressive lung dysfunction over time. Many patients diagnosed with COPD have a disorder called chronic bronchitis (CB), and 600,000 patients are hospitalized each year due to an acute exacerbation of CB. Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are other examples of lung disorders which assume a clinical profile similar to COPD. Ciliary dyskinesia, whether primary or secondary, results in retained secretions that can only be cleared by coughing. Most patients with COPD utilize coughing to help clear retained secretions because of impaired mucociliary clearance.
Another disease state characterized by the accumulation of retained mucous secretions is sinusitis. Sinusitis is an inflammation of the paranasal sinuses typically associated with an upper respiratory infection. It can occur as either an acute or chronic condition. It is this country's most common health-care complaint, affecting an estimated 31 million people. (A. Moss and V. Parsons, National Center for Health Statistics, 1986: 66-7, DHHS Publication No. (PHS)86-1588 (1985)).
Otitis media (OM) is a viral or bacterial infection of the middle ear which primarily afflicts children under the age of three. It is usually precipitated by an upper respiratory infection which spreads into the middle ear via the nasopharynx and eustachian tube. Approximately 25-50 million office visits are made each year for diagnosis and treatment of OM. By age three, about 75% of children will have had at least one episode of acute OM (J. Klein,
Clin. Infect. Dis.
19, 823-33 (1994)). Following appropriate treatment with antibiotics, accumulated fluid in the middle ear remains, causing hearing impairment and potential language and cognitive development delays. Enhanced ability to clear secretions in the middle ear would reduce or eliminate significant sequelae of otitis media.
An additional disorder characterized by retained secretions is pneumonia. Patients who are immobilized for a variety of reasons are at high risk for developing pneumonia. Despite extra vigilance and numerous interventions, pneumonia develops in over 400,000 patients per year, with significant morbidity and mortality. Patients who require intubation and mechanical ventilation are at additional risk for ventilator associated pneumonia (VAP) due to immobility and the decrease in mucociliary clearance. The mortality rate for VAP can exceed 50% in more than 100,000 who develop VAP each year.
There are also situations where it is therapeutically desirable to increase drainage of the lacrimal system. When the lacrimal drainage system is not functioning properly the result can be excessive tearing (epiphora), mucopurulent discharge, and recurrent dacryocystitis. Current treatments for nasolacrimal duct obstruction are mostly invasive surgical procedures, and researchers have sought to discover noninvasive pharmaceutical treatments.
Tear secretion can be stimulated from lacrimal accessory tissues via P2Y
2
and/or P2Y
4
purinergic receptor-mediated mechanisms similar to those which hydrate airway epithelia. Dry eye disease is the general term for indications produced by abnormalities of the precorneal tear film characterized by a decrease in tear production or an increase in tear film evaporation, together with the ocular surface disease that results. Currently, the pharmaceutical treatment of dry eye disease is mostly limited to administration of artificial tears (saline solution) to temporarily rehydrate the eyes. However, relief is short lived and frequent dosing is necessary.
Normally, mucous secretions are removed via the mucociliary clearance (MCC) system. MCC relies on the integrated action of three components: 1) mucus secretion by goblet cells and submucosal glands; 2) the movement of cilia on epithelial cells which propels the mucus across the luminal surface; and 3) ion transport into and out of luminal epithelial cells which concomitantly controls the flow of water into the mucus.
It is now known that nucleoside phosphates such as uridine 5′-triphosphate (UTP) modulate all of the components of the MCC system. First, UTP has been shown to increase both the rate and total amount of mucin secretion by goblet cells in vitro (M. Lethem, et al.,
Am J. Respir. Cell Mol. Biol.
9, 315-22 (1993)). Second, UTP has been shown to increase cilia beat frequency in human airway epithelial cells in vitro (D. Drutz, et al.,
Drug Dev. Res.
37(3), 185 (1996)). And third, UTP has been shown to increase Cl
−
secretion, and hence, water secretion from airway epithelial cells in vitro (S. Mason, et al.,
Br. J. Pharmacol.
103, 1649-56 (1991)). In addition, it is thought that the release of surfactant from Type II alveolar cells in response to UTP (Gobran,
Am. J. Physiol.
267, L625-L633 (1994)) contributes to optimal functioning of the lungs and may assist in maximizing MCC. UTP has been shown to increase intracellular Ca
++
due to stimulation of phospholipase C by the P2Y
2
receptor (H. Brown, et al.,
Mol. Pharmocol.
40, 648-55 (1991)).
UTP's modulation of all components of the mucociliary escalator system results in improvement in lung mucociliary clearance in normal volunteers without any significant side-effects (K. Olivier, et al.,
Am J. Respir. Crit. Care Med.
154, 217-23 (1996)). In addition, UTP significantly enhances cough clearance (clearance of retained secretions by coughing) in patients with PCD (P. Noone, et al.,
Am. J. Respir. Crit. Care Med.
153, A530 (1996)). The dinucleotide, P
1
,P
4
-di(uridine-5′-)tetraphosphate, has also been shown to increase sputum production in normal healthy volunteers, indicating an enhancement of MCC.
Because of UTP's demonstrated ability to increase the clearance of retained mucous secretions, applicants were motivated to investigate other nucleoside phosphates in order to maintain or improve therapeutic efficacy while increasing stability. During the course of this investigation, it was found that CP
4
U, unlike the other cytidine-containing dinucleoside tetraphosphate C
2
P
4
, possessed surprising potency at the P2Y
2
and P2Y
4
receptors. Additionally, it was observed that CP
4
U had unexpectedly considerably enhanced resistance toward biological degradation, as evidenced by its stability in biological preparations. The present invention is based upon the potency and increased duration of action of CP
4
U in respiratory therapies due to its increased biological stability.
SUMMARY OF THE INVENTION
A method of enhancing secretion clearance by hydrating mucous and increasing ciliary beat frequency in a subject in need of such treatment is disclosed. The method comprises administering to the patient a compound of Formula I:
or pharmaceutically acceptable salts, esters or amides thereof.
Novel esters and amides of the compound of Formula I are also disclosed.
The compounds of Formula I are highly stable and selective agonists of the P2Y
2
and/or P2Y
4
purinergic receptor; thus, they are useful in the treatment of chronic obstructive pulmonary diseases such as chronic bronchitis, PCD, and cystic fibrosis; they are also useful in the treatment of immobilized patients who are at risk for developing pneumonia. Furthermore, because of their general ability to clear retained mucus secretions and stimulate ciliary beat frequency, the compounds of the present invention are useful in the treatment of sinusitis and otitis media. The compounds of Formula I are also us

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