# Patent

## Title
Quaternary antimuscarinic compounds for the treatment of bladder diseases

## Abstract

The present invention relates to a method for treating bladder disease, including urinary incontinence, which involves intravesical administration of quaternary antimuscarinic compounds having longer duration of effect and fewer side effects than standard treatments.

## Background
This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/441,391, filed Jan. 16, 2003.


FIELD OF THE INVENTION
This invention relates to methods of treating bladder disease, particularly urinary incontinence.
BACKGROUND OF THE INVENTION
Urinary incontinence afflicts a large and diverse patient population. The United States Department of Health and Human Services Agency for Health Care Policy and Research (AHCPR) reviewed the literature on the incidence of urinary incontinence, including the clinical, psychological, and social impact of the disorder, as well as monetary costs to society. (Overview: Urinary Incontinence in Adults, Clinical Practice Guideline Update; Agency for Health Care Policy and Research, Rockville, Md. (1996) (AHCPR study)). The 1996 AHCPR study estimated that 13 million Americans are incontinent; of these, 11 million are women. One in four women ages 30-59 has experienced an episode of urinary incontinence, and 50% or more of the elderly persons living at home or in long-term care facilities are incontinent. $16.4 billion is spent every year on incontinence-related care: $11.2 billion for community-based programs and at home, and $5.2 billion in long-term care facilities. $1.1 billion is spent every year on disposable products for adults.
Twenty-nine investigators from 10 countries gathered in San Francisco in June, 2003, at an international symposium sponsored by The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to discuss the current understanding of risk factors and treatment outcomes for incontinence in women. (Brown et al., “Proceedings of the National Institute of Diabetes and Digestive and Kidney Diseases International Symposium on Epidemiologic Issues in Urinary Incontinence in Women,” Suppl to American J Obstetrics and Gynecology 2A (2003) (NIDDK Symposium). The NIDDK Symposium participants revealed the following facts. The estimated cost of incontinence increased by 250% over 10 years, an amount greater than can be accounted for by medical inflation. Other countries are experiencing this phenomenon as well. In Sweden, for example, the cost of incontinence was estimated as 1.8 billion Swedish crowns (1990 SEK, equivalent to $400 million 1995 U.S. dollars). The elderly account for more than two thirds of the cost of incontinence in the U.S., and costs are expected to increase with the increasing proportion of elderly in society.
A multitude of recent publications further highlight the rising cost to society associated with the management of incontinence and other bladder disorders (Hu et al., “Estimated Economic Costs of Overactive Bladder in the United States,” Urology 61(6):1123-1128 (2003); Shih et al., “Labor Costs Associated with Incontinence in Long-term Care Facilities,” Urology 62(3) 442-446 (2003); Green et al., “Urinary Incontinence in Subacute Care—A Retrospective Analysis of Clinical Outcomes and Costs,” MJA 178:550-553 (2003); Franstz et al., “Implementing an Incontinence Management Protocol in Long-Term Care,” J Gerontological Nursing 29(8):46-53 (2003)).
Contraction of the bladder detrusor muscle is mediated by cholinergic muscarinic receptors. Muscarinic receptors are divisible into several subtypes (M1-M5 for humans, m1-m5 for animals and other cells) that are distinguishable based on binding of selective ligands. These muscarinic receptor subtypes exist in differing concentrations in different tissues (for a detailed description of anticholinergic agents and their use in treating various diseases, see: Foye, W. O., Principles Of Medicinal Chemistry, Lea and Febiger, Philadelphia, Pa., pp. 328-348 (1989); Gilman and Goodman, The Pharmacological Basis of Therapeutics, 10th edition, Hardman et al., eds., McGraw-Hill, Chapter 7, pp. 162-173 (2000)).
The present invention targets muscarinic receptors by administration of novel antimuscarinic agents via a catheter to the bladder to attain prolonged maintenance of bladder control in otherwise incontinent patients while minimizing systemic side effects of the medication.
The drug oxybutinin chloride(4-diethylamino)2-butynyl-cc-cyclohexyl-a-hydroxybenzeneacetate HCl; trade name Ditropan®) is a standard antimuscarinic therapeutic agent for urinary incontinence. Relief of symptoms in neurogenic bladder disorders is thought to result from its combined antimuscarinic, antispasmodic, and local anesthetic activities. However, antimuscarinic medications are associated with side effects, including dry mouth and cognitive impairment, limiting its acceptability to many patients. These side effects are, at least, unpleasant, and may be intolerable when taken in combination with other medications commonly used by the elderly (Hogan D. B., “Revisiting the O Complex: Urinary Incontinence, Delirium and Polypharmacy in Elderly Patients,” Can Med Assoc J. 157:1071-7 (1997)). In fact, use of oral oxybutynin is frequently discontinued because of the unpleasantness of the side effects (Thuroff et al., “Randomized, Double-Blind, Multicenter Trial on Treatment of Frequency, Urgency and Incontinence Related to Detrusor Hyperactivity: Oxybutynin Versus Propantheline Versus Placebo,” J. Urol. 145:813-817 (1991)).
For treatment of detrusor overactivity, AHCPR 1992 (since reissued with revisions) recommended oxybutynin at oral doses of 2.5-5 mg/kg, to be taken 3-4 times per day. At the time of agency review, 5 of 6 randomized controlled studies reported superiority of oxybutinin to placebo. One exception was a study of elderly nursing home residents that used less frequent administration of the drug.
The dose-related antimuscarinic side effects of oral oxybutynin include marked xerostomia, dry skin, blurred vision, nausea, and constipation. Severe mouth dryness occurred in 84% of subjects receiving 5 mg/kg four times/day (AHCPR, 1992). Side effects could be minimized by administration of this compound via clean intermittent self-catheterization directly into the bladder (intravesical administration). However, this required at least daily self-catheterization. Better restoration of bladder control required multiple catheter insertions each day. A series of papers reported beneficial effects in different patient groups. The following are representative: Brendler et al., “Topical Oxybutynin Chloride For Relaxation of Dysfunctional Bladders,” J Urol. 141:1350-1352 (1989); Weese et al., “Intravesical Oxybutynin Chloride: Experience With 42 Patients,” Urology 41:527-530 (1993); Greenfield et al., “The Use of Intravesical Oxybutynin Chloride in Children with Neurogenic Bladder,” J. Urol. 146:532-534 (1991); Madersbacher et al., “Control of Detrusor Hyperreflexia by the Intravesical Instillation of Oxybutynine Hydrochloride,” Paraplegia 29:84-90 (1991).
A double-blind, randomized, placebo-controlled parallel group study of intravesical oxybutynin was reported in which there was some systemic absorption of the drug following intravesical administration, but the incidence of adverse side effects was low (Krishnan, K. R., “A Double-blind, Randomized, Placebo-Controlled Parallel Group, Multicentre Study of Intravesical Oxybutynin,” Neurourol. and Urodyn. 15:307-308 (1996)). However, the difficulty in patients being able to continue a typical intravesical instillation protocol is illustrated by Weese et al., “Intravesical Oxybutynin Chloride: Experience With 42 Patients,” Urology 41:527-530 (1993), which reported that instillation of the drug two to three times daily via clean self intermittent catheterization resulted in 21% of the patients dropping out due to inability to tolerate the catheterization or difficulty in retaining the drug solution in the bladder.
U.S. Pat. No. 5,001,160 to McPherson et al. describes antimuscarinic agents for the treatment of neurogenic bladder disease. The compounds disclosed were said to have longer durations of action than older anticholinergic agents such as methantheline and propantheline. The majority of neurogenic bladder patients have spastic or hypertonic conditions. Clinicians generally aim to convert this condition to hypotonia as a way to treat the primary problem of incontinence. Thus, when the condition has been “converted” to hypotonia, it can be managed in a straightforward way by intermittent catheterization. For those patients who cannot be converted from the hypertonic to the hypotonic state and who still need to urinate every hour, longer term treatment with muscarinic receptor antagonists (loosely called anticholinergics) was said to be necessary. As noted above, the current drug of choice for this treatment modality is oxybutynin, which is considered to be better than the older anticholinergics. McPherson et al. disclosed 1-aryl-1-hydroxy-1-R,-3-(4-R,-I-piperazinyl)-2-propanones for treatment of bladder disease (U.S. Pat. No. 5,001,160). In preferred compounds, R1 was a cycloalkyl of 3-6 carbons, most preferably cyclohexyl or cyclobutyl. R2 was lower alkyl, benzyl, para-substituted benzyl or cinnamyl. The most preferred compound was 1-cyclobutyl-1-hydroxy-1-phenyl-3-(4-benzyl-1-piperazinyl)-2-propanone. For parenteral administration, the compounds were prepared in conventional aqueous injection solutions. U.S. Pat. No. 5,001,160 also disclosed that extemporaneous injection solutions could be prepared from sterile pills, granules or tablets, and contained diluents, dispersing and surface active agents, binders, and lubricants, as well as the anticholinergic compound. Tolterodine is a new antimuscarinic of comparable duration of action which is reported to cause a lower incidence of dry mouth ( ̃9%). The following dose-related side effects were observed with tolterodine: diminished stimulated salivation after 3.2 mg, increased heart rate after 6.4 mg, and altered the nearpoint of vision after 12.8 mg. Six of 8 subjects reported micturition difficulties after a dose of 12.8 mg.
Other Drugs in the Treatment of Urinary Incontinence
Terodiline has both anticholinergic and calcium antagonist properties, and effectively reduces abnormal bladder contractions caused by detrusor instability (Langtry et al., “Terodiline. A Review of its Pharmacological Properties, and Therapeutic Use in the Treatment of Urinary Incontinence,” Drugs 40:748-761(1990)). When administered to adult patients with urge incontinence (generally as a 25 mg dose twice daily), terodiline reduced micturition frequency and incontinence episodes. Bladder volume at first urge and bladder capacity were increased. Children with diurnal enuresis respond similarly to a daily 25 mg dose. Terodiline at 50 mg/day was said to be preferred by patients when compared with emepronium 600 mg/day or flavoxate 600 mg/day, and tended to reduce voluntary micturition frequency and episodes of incontinence more effectively than these other drugs. Anticholinergic side effects were the most common ones reported.
Anhydroecgonine Derivatives as Anticholinergic Agents
Anhydroecgonine methyl ester (AEME), the primary pyrolysis product of cocaine (Martin et al., “Pyrolysis and Volatilization of Cocaine,” J. Anal Toxicol 13:158-162 (1989)), is structurally similar to arecoline and anatoxin A. While investigating the effects of crack smoking, it was noted that experimental animals frequently showed bronchoconstriction (Wood et al., “Generation of Stable Test Atmospheres of Cocaine Base and Its Pyrolyzate, Methylecgonidine, and Demonstration of Their Biological Activity,” Pharmacology, Biochemistry & Behavior 55(2):237-48 (1996); Chen et al., “Pulmonary Effects of the Cocaine Pyrolysis Product, Methylecgonidine, in Guinea Pigs,” Life Sciences 56(1):7-12 (1995)).
This observation led to a focus on AEME and other anhydroecgonine esters (AEE) as bronchoconstrictors when given by inhalation. When this agent was studied in isolated guinea pig tracheal rings, it was found unexpectedly (in view of the bronchoconstricting action of cocaine), that AEME lacked cholinergic agonist activity in this tissue and in detrusor muscle in vitro. Subsequently, some agonistic effects were demonstrated at high doses in sheep consistent with action at the M2 muscarinic receptors.
Even more surprisingly, AEME turned out to be a potent non-competitive muscarinic antagonist in vitro (El-Fawal et al., “Airway Smooth Muscle Relaxant Effects of the Cocaine Pyrolysis Product, Methylecgonidine,” J Pharm Exp Ther 272:991-996 (1995)).
The antagonistic effects were insurmountable even with the addition of increasing amounts of acetylcholine (ACh). Furthermore, the anticholinergic effects were irreversible, so that tissue exposed to AEME could not later attain its original magnitude of contraction. These in vitro findings were unexpected because AEME, resembling arecoline and anatoxin in structure, was expected to behave as a cholinergic agonist. AEE compositions, derivatives or analogues thereof having anticholinergic activity, methods of preventing or inhibiting cholinergic responses, and methods of using the compositions to prevent or treat diseases associated with bronchoconstriction have been described (U.S. Pat. Nos. 5,552,407 and 5,821,249 to Wood et al.).
Note that some effects were subsequently demonstrated at high doses of this interesting compound that are consistent with agonist activity at the m2 muscarinic receptor in sheep (Scheidweiler et al., “Pharmacokinetics and Pharmacodynamics of Methylecgonidine, a Crack Cocaine Pyrolyzate,” J Pharm Exp Ther 307:1179-1187 (2003)), as well as effects in guinea pigs (Willetts et al., “Effects of Methylecgonidine on Acetylcholine-Induced Bronchoconstriction and Indicators of Lung Injury in Guinea Pigs,” Life Sciences 57(15):225-30 (1995)).
Other Bladder Diseases
Interstitial cystitis (IC), a syndrome occurring primarily in women, is characterized by urinary urgency and frequency, suprapubic pain, and petechial bladder mucosal hemorrhages upon distention under general anesthesia. Almost 50% of IC patients also suffer from allergies and irritable bowel syndrome, all of which are exacerbated by stress. One of the prevailing theories to explain IC pathophysiology is the increased number of activated mast cells in the bladder. Mast cells mediate hypersensitivity reactions wherein they are triggered by immunoglobulin E (IgE) and antigen (allergen) to release numerous vasoactive anproinflammatory substances. Mast cells are found in juxtaposition to neurons and are also activated by direct nerve stimulation, as well as by ACh, neurotensin, and Substance P. Barbalias, G A, “Interstitial Cystitis: Bladder Training with Intravesical Oxybutynin,” J. Urol. 163:1818-1822 (2000), demonstrated that intravesical administration of oxybutynin to women with interstitial cystitis resulted in an improvement in their signs and symptoms that was better than the improvement produced by simple expansion of the bladder with saline.
Targeting Parasympathetic Control of Organ Function
In addition to its role in bladder control, the parasympathetic nervous system plays a major role in regulating bronchomotor tone. One drug used to treat respiratory disease, such as asthma, is the quaternary anticholinergic agent isopropylatropine bromide, also called ipratropium bromide (Atrovent®) (Gross, H. J., “Ipratropium Bromide,” New Eng. J. Med. 319:486-494 (1988); “Anticholinergic Therapy: The State of the Art. Proceedings of a Symposium Held in Stratford-Upon Avon 8-9 Sep. 1986,” Higgenbottam et al, eds., Postgrad. Med. J. 63 (Suppl 1): 1-93 (1987)). This agent, administered by inhalation, is poorly absorbed so that it exerts its effects primarily, and in a limited manner, on the internal surfaces of the lungs. Thus, a major advantage of ipratropium for respiratory therapy is the possibility of reaching elevated regional tissue (e.g., lung) concentrations with few systemic anticholinergic effects. Another advantage of ipratropium compared to other anti-asthmatic drugs is its duration of action. Its pharmacologic effect becomes maximal in about an hour, and persists for several hours. A compound with these features may also be useful for long duration therapy of bladder disease.
Thus, antimuscarinic therapies are widely used for treatment of bladder diseases, but they are fraught with side effects, which not only limit their acceptance by patients, but also complicate medical management. What are needed are effective methods of treating bladder disease without the unpleasant side effects associated with the current standard therapeutics.
SUMMARY OF THE INVENTION
The present invention relates to a method for treating bladder disease in a subject. This method involves administering to a subject a pharmaceutical composition having a therapeutic amount of a compound selected from the group consisting of: (1) a compound having the formula




where Q is a group of the formula





R and R1 are each independently C1-C4-alkyl, R1 is thienyl, phenyl, cyclopentyl or cyclohexyl, and X− is a physiologically acceptable anion; (2) a compound having the formula





where X− is a physiologically acceptable ion; (3) a compound having the formula





where X− is a physiologically acceptable ion; (4) a compound having the formula





where R1 is 2-thienyl or cyclopentyl, and A is 3α-(6,7-dehydro)-tropanyl methobromide, 3β-tropanyl methobromide, or 3α-(N-isopropyl)-nortropanyl methobromide; (5) a compound having the formula





where R is an optionally halo- or hydroxyl-substituted C1-4 alkyl group, R1 is a C1-4-alkyl group, or R and R1 together form a C4-6-alkylene group, X− is a physiologically acceptable anion, and R1 is H, OH, CH3, CH2OH, C1-4 alkyl or C1-4-alkoxy; (6) a compound having the formula





where R is an optionally halo- or hydroxy-substituted C1-4-alkyl group, R1 is a C1-4-alkyl group, or R and R1 together form a C4-6-alkylene group, X− is a physiologically acceptable anion and R1 is H, OH, CH3, CH2OH, C1-4-alkyl or C1-4-alkoxy; (7) a compound having the formula





(8) a compound having the formula





and (9) a compound having the formula





where X− is a physiologically acceptable anion.

The administration of antimuscarinic agents, often called anticholinergics in clinical medicine, with prolonged duration of action via a catheter to the bladder, results in prolonged maintenance of bladder control in otherwise incontinent patients. Agents with durations of action between a week and a month could be useful for a significant number of patients and perhaps reach distinct groups for whom no satisfactory treatment is currently available. In addition, a goal of drug research in the field of urinary incontinence has been to develop or identify long-acting antimuscarinic agents for the control of overactive bladder, detrusor instability, and urge incontinence that are free of side effects such as dry mouth and cognitive impairment. Standard antimuscarinic medications for the treatment of detrusor instability or urge incontinence produce side effects that may be intolerable, particularly when taken in combination with other medications commonly used by the elderly. The present invention is directed to overcoming these and other deficiencies in the art.


DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for treating bladder disease in a subject. This method involves administering to a subject a pharmaceutical composition having a therapeutic amount of a compound selected from the group consisting of: a compound having the formula




where Q is a group of the formula





R and R1 are each independently C1-C4-alkyl, R1 is thienyl, phenyl, cyclopentyl or cyclohexyl, and X− is a physiologically acceptable anion. In this aspect and all aspects of the present invention, R may be, without limitation, CH3, C2H5, n-C3H7, or i-C3H7; R1 may be, without limitation, CH3, and X− is meant to include, without limitation, bromide (Br−) and CH3SO3.

In another aspect of the present invention, treatment of a bladder disease involves administering to a subject a compound having the formula




where X− is a physiologically acceptable ion as described herein above.

In another aspect of the present invention, treatment of a bladder disease involves administering to a subject a compound having the formula




where X— is a physiologically acceptable ion as described above.

In another aspect of the present invention, treatment of a bladder disease involves administering to a subject a compound having the formula




where R1 is 2-thienyl or cyclopentyl, and A is 3α-(6,7-dehydro)-tropanyl methobromide, 3β-tropanyl methobromide, or 3α-(N-isopropyl)-nortropanyl methobromide.

In another aspect of the present invention, treatment of a bladder disease involves administering to a subject a compound having the formula




where R is an optionally halo- or hydroxyl-substituted C1-4 alkyl group, R1 is a C1-4 alkyl group, or R and R1 together form a C4-6-alkylene group, X− is a physiologically acceptable ion as described herein above, and R1 is H, OH, CH2OH, C1-4 alkyl or C1-4 alkoxy.

In another aspect of the present invention, treatment of a bladder disease involves administering to a subject a compound having the formula




where R is an optionally halo- or hydroxyl-substituted C1-4 alkyl group, R1 is a C1-4 alkyl group, or R and R1 together form a C4-6-alkylene group, X− is a physiologically acceptable ion as described herein above, and R1 is H, OH, CH2OH, C1-4 alkyl or C1-4 alkoxy.

In another aspect of the present invention, treatment of a bladder disease involves administering to a subject a compound having the formula:




In another aspect of the present invention, treatment of a bladder disease involves administering to a subject a compound having the formula




In another aspect of the present invention, treatment of a bladder disease involves administering to a subject a compound having the formula




where X− is a physiologically acceptable ion as described herein above.

These compounds are described in further detail in U.S. Pat. Nos. 5,610,163, 5,654,314, and 5,770,738 to Banholzer et al., which are hereby incorporated by reference in their entirety.
An exemplary compound for use in the method of the present invention is tiotropium bromide (6β,7β,Epoxy-3α-[2-hydroxy-2,2-di(2-thienyl)acetoxy]-8,8-dimethyl-1αH,5αH-tropanium bromide) (Norman et al., “Tiotropium Bromide, Treatment of COPD Bronchodilator Muscarinic Antagonist,” Drugs of the Future 25(7):693-699 (2000), which is hereby incorporated by reference in its entirety). This new generation compound has been shown to have unique pharma, exhibiting a specific highly potent antagonism at all subtypes of human muscarinic receptors in the 10-11 M range in vitro (KD-value from kinetic measurements at M3: 14 pM) (Disse et al., “Ba 679 BR, A Novel Long-Acting Anticholinergic Bronchodilator,” Life Sci 52(5-6):537-44 (1993); Disse et al., “Tiotropium (Spiriva): Mechanistical Considerations and Clinical Profile in Obstructive Lung Disease,” Life Sci 4(6-7):457-64 (1999), which are hereby incorporated by reference in their entirety), but its special characteristic is its slow dissociation from M3-receptors (half-life of 35 hours) as compared to 16 minutes for ipratropium. This is indicative of a long duration of action effected by prolonged receptor binding and not by long residence time in plasma or tissue compartments. Tiotropium, similar to ipratropium, is in the classical view not subtype-selective (based on similar KD values at muscarinic receptor subtypes). However, tiotropium dissociation from M2 (3.6 hours) is faster than from M3-receptors (35 hours) which, in functional experiments, is manifest as a “kinetic type” of receptor subtype selectivity of M3 (and M1) over M2 receptors (Takahashi et al., “Effect of Ba 679 BR, A Novel Long-Acting Anticholinergic Agent, On Cholinergic Neurotransmission in Guinea Pigs and Human Airways,” Am J Resp Crit Care Med 150:1640-1645 (1994), which is hereby incorporated by reference in its entirety).
Both enantiomers of the compounds and racemic mixtures are understood to be suitable for use in the present invention.
The preferred route of administration for treatment is intravesical, although oral or systemic routes might be effective if controlled release within the bladder could be achieved with further pharmaceutical development effort.
Methods for intravesical administration of medications to the bladder are well-known, as are methods for testing the efficacy of compounds for the treatment of disease. For example, publications are available that teach intravesical delivery and testing methods (Wood et al., “Automated Noninvasive Measurement of Cyclophosphamide-Induced Changes in Murine Voiding Frequency and Volume,” J Urol. 165:653-659 (2001); Eichel et al., “Assessment of Murine Bladder Permeability with Fluorescein: Validation With Cyclophosphamide and Protamine,” Urology 58(1):113-118 (2001); Sessions et al., “Continuous Bladder Infusion Methods for Voiding Function in the Ambulatory Mouse,” Urology 60(4):707-713 (2002); which are hereby incorporated by reference in their entirety); uroflow measurement methodologies (Wood et al., “Uroflow in Murine Urethritis,” Abstract, Research Insights into Interstitial Cystitis: A Basic and Clinical Science Symposium, Oct. 30-Nov. 1, 2003, Alexandria Va.; co-presented by the National Institute of Diabetes and Digestive and Kidney Diseases and the Interstitial Cystitis Association, which is hereby incorporated by reference in its entirety); and the assessment of the efficacy and location of the peripheral (i.e., non-CNS) effect of a test compound (U.S. Pat. No. 6,573,282 to Yaksh et al., which is hereby incorporated by reference in its entirety).
A wide variety of patient populations may benefit from these medications, especially those with urge and frequency incontinence, detrusor instability, and detrusor-external sphincter dyssynergia. A non-exclusive list of exemplary conditions to which the present invention is suitable include: urge incontinence, cystitis (including interstitial cystitis), bladder dysfunction of multiple sclerosis, benign prostatic hyperplasia, myelomeningocele (spina bifida), spinal cord injury, patients with dementias for whom antimuscarinic medications are contraindicated, parkinsonism, and patients who cannot tolerate systemic effects of antimuscarinic medications because of concurrent medication with other agents or because of blurred vision, dry mouth, constipation, cognitive impairment or other sequelae of antimuscarinic medications.
The present invention relates to a method for treating bladder disease comprising administering an antimuscarinic agent or a derivative or analogue thereof as described above in a pharmaceutically acceptable carrier or excipient for intravesical instillation. Preferred additions to such compositions are materials which enhance viscosity or promote the entry of the active agent into the bladder wall, including carboxymethyl celluloses, glycosaminoglycans (GAGs), pentosan polysulfate, heparin, or heparin-like compounds. In one aspect of the present invention, the treatment includes the physical or pharmacological creation of a depot/slow release compartment for the composition. This can be achieved, for example, by delivery of the agent using liposomes or other known delivery agents having the noted action on release. Another approach involves the use of protamine (or a protamine-like compound) to alter the surface of the bladder, thereby fostering access or to enhance access. The subject is first treated with protamine or a protamine-like agent, followed by administration of the active antimuscarinic agent in combination with a glycosoaminoglycans.
In another aspect of the present invention, the endogenous intravesical GAG compartment is exchanged with, or replaced by, an exogenously applied mixture that incorporates the antimuscarinic composition of this invention. Suitable additions would also include those which would provide the formulation with a longer mechanical presence in the bladder, allowing the compound of the present invention to diffuse from the bladder tissue, find a site on the bladder wall, or enhance the ability of the compound to infiltrate the tissue, and/or provide a slow release of existing pools of drug from the tissue.
Considering the spectrum of potential side effects of agents with irreversible or very long duration activities, the prevention of central nervous system (CNS) effects emerges as a significant priority, as one would not want a chronic impairment of memory or cognition in an elderly population. Thus, quaternary amino compounds emerge as the most preferred in this regard. Quaternary antimuscarinic compounds have achieved clinical use. Quaternary compounds have long been used in experimental pharmacology to distinguish central from peripheral mechanisms of actions. For example, methylatropine and methylscopolamine retain their peripheral anticholinergic activities, but do not affect conditioned behaviors as effectively as do atropine or scopolamine molecules.
For use in accordance with this invention, the preferred antimuscarinic agent has (1) receptor-selective activity, and (2) the activity is of long duration in the target organ following local administration to an internal surface of that organ. An example from the art of treating asthma is the local application of isopropylatropine to the inner surface of the lung. If the agent is not given in excess dosage, long duration side effects should not occur. Quaternization does not eliminate peripheral activity; one of the primary purposes of this chemical change is to prevent passage of the agent across the blood-brain barrier. There are no known publications describing the effect of quaternization of a compound administered intravesically on subsequent blood levels of the quaternary compound. There is an expectation of some systemic absorption. The main consequence of overdose via the intravesical route is most likely to be hypotonicity of the bladder detrusor muscle. This side effect would be counteracted by clean intermittent or subchronic catheterization until the effect diminishes. No significant peripheral side effects in the presence of drug-induced detrusor hypotonicity are expected. Nonetheless, chemical modifications of the antimuscarinic agent to exclude it from the central nervous system is desirable in the context of chronic use; if the usual anticholinergic peripheral side effects did occur, they might be unpleasant but would not result in subtle or serious central nervous system impairment.
An agent may achieve long duration of action by having high affinity for, or slow off-rates from, the receptor responsible for its clinically useful effect. Alternatively, the agent may be retained in the body for a prolonged period of time, or differentially partition into or be retained within a compartment of the body in which the agent exerts its desirable effects. The urothelium is lined with glycoprotein and glycosaminoglycan structures that present a negative charge to the lumen of the bladder; one consequence is the ordering of water molecules into layers at the bladder surface, a phenomenon that may play a role in urothelial barrier function. Since intravesically administered quaternary agents have a positive charge, they may be electrostatically attracted to this surface where they may bind. In so doing they may be held in proximity to the site of action of the compound, resulting in a prolongation of their duration of action.
As used in the present invention, “antimuscarinic” is interchangeable with “anticholinergic.” Acetylcholine is a flexible compound that changes in length and therefore the same compound (in different conformations) fits nicotinic and muscarinic acetylcholine receptors. As used in the art, in particular when describing atropine-like drugs such as ipratropium, both anticholinergic and antimuscarinic are correct, the latter being preferred by the pharmacologic purist (Witek, T. J. Jr., “Anticholinergic Bronchodilators,” Respiratory Clinica of North America 5:521-536 (1999), which is hereby incorporated by reference in its entirety).
According to the present invention, a composition used to treat bladder disease is preferably substantially irreversible, meaning that it has a prolonged duration of action compared to a conventional muscarinic antagonist. This may be a result of covalent bonding to a receptor or another site of the cell, or because of a slow “off rate”. This term is not intended to imply that one cannot measure an “off rate” (as in the case of hydrolysis of a xenobiotic where the receptor is left in a free state). To be substantially irreversible as intended herein, a compound preferably has a duration of pharmacologic effect of at least 12 hours, more preferably at least 24 hours, more preferably at least 7 days, even more preferably at least about 3 weeks. The desired pharmacologic effect is that of increased residual bladder volume and/or reduced peak intravesical pressure, leading to the prevention of unwanted episodes of micturition. As is well-known in the pharmacologic arts, termination of an agent's action may result from a number of processes including tolerance of the subject, dissociation from the receptor, receptor upregulation, breakdown of the agent in situ, and the associated return of the receptor to the functional population.
The criteria for the inclusion of a compound in the present invention are its ability to mimic the actions of an anticholinergic drug, such as oxybutynin, but with a longer duration of action. The compounds of this invention must have an action that results in one or, preferably, a combination, of the following outcomes: (1) decreased peak intravesical pressure during voiding; (2) increased bladder capacity; (3) increased interval between voids. Furthermore, the compound should have few side effects and be well-tolerated by patients. Side effects are minimized in several ways, compared to drugs in the prior art. First, intravesical administration, the preferred route, itself results in fewer systemic effects than systemic administration of the drug.
The presence of a quaternary nitrogen atom, a high degree of lipophilicity, a bulky side chain or other means for increasing the overall size and molecular mass of the pharmacologically active moiety, or a combination of these properties, minimizes entry into the CNS, thereby avoiding a significant number of known side effects.
As used herein, “alkyl” or “alkylene” is intended to include both branched and straight-chain aliphatic hydrocarbon groups having a specified number of carbon atoms. Examples of alky groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
“Alkoxy” or “alkyloxy” as used herein represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly, “alkylthio” or “thioalkoxy” as used herein represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
As used herein, “pharmaceutically acceptable ions” refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, without limitation, those derived from inorganic acids including hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids including, without limitation, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmist, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., p. 1418, Mack Publishing Company, Easton, Pa. (1985), which is hereby incorporated by reference in its entirety.
Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.

## Claims

1. A method for treating urge incontinence in a subject, said method comprising:
administering intravesically to the subject a pharmaceutical composition comprising:
a therapeutic amount of a compound selected from the group consisting of: (1) a compound having the formula





wherein Q is a group of the formula




R and R1 are each independently C1-C4-alkyl, R1 is thienyl, phenyl, cyclopentyl or cyclohexyl and X− is a physiologically acceptable anion; (2) a compound having the formula




wherein X− is a physiologically acceptable ion; (3) a compound having the formula




wherein X− is a physiologically acceptable ion; (4) a compound having the formula




wherein R1 is 2-thienyl or cyclopentyl, and A is 3α-(6,7-dehydro)-tropanyl methobromide, 3β-tropanyl methobromide, or 3α-(N-isopropyl)-nortropanyl methobromide; (5) a compound having the formula




wherein R is an optionally halo- or hydroxyl-substituted C1-4 alkyl group, R1 is a C1-4 alkyl group, or R and R1 together form a C4-6 alkylene group; X− is a physiologically acceptable anion, and R1 is H, OH, CH2OH, C1-4 alkyl or C1-4 alkoxy; (6) a compound having the formula




wherein R is an optionally halo- or hydroxy-substituted C1-4-alkyl group, R1 is a C1-4-alkyl group, or R and R1 together form a C4-6-alkylene group, X− is a physiologically acceptable anion and R1 is H, OH, CH3, CH2OH, C1-4-alkyl, or C1-4-alkoxy; (7) a compound having the formula



(8) a compound having the formula




and (9) a compound having the formula





wherein X− is a physiologically acceptable anion and
an additive which enhances adherence of said compound to the subject's bladder-wall and prolongs duration of action compared to when the compound is not in a composition containing the additive.

2. The method according to claim 1, wherein the compound has the formula




wherein Q is a group of the formula




R and R1 are each independently C1-4-alkyl, R1 is thienyl, phenyl, cyclopentyl or cyclohexyl, and X− is a physiologically acceptable anion.

3. The method according to claim 2, wherein R is CH3, C2H5, n-C3H7, or i-C3H7 and R1 is CH3.

4. The method according to claim 3, wherein R1 is thienyl.

5. The method according to claim 2, wherein X− is Br− or CH3SO3.

6. The method according to claim 1, wherein the compound has the formula




wherein X− is a physiologically acceptable ion.

7. The method according to claim 1, wherein the compound has the formula




wherein X− is a physiologically acceptable ion.

8. The method according to claim 1, wherein the compound has the formula




R1 is 2-thienyl or cyclopentyl, and A is 3α-(6,7-dehydro)-tropanyl methobromide, 3β-tropanyl methobromide, or 3α-(N-isopropyl)-nortropanyl methobromide.

9. The method according to claim 8, wherein R1 is 2-thienyl and A is 3α-(6,7-dehydro)-tropanyl methobromide.

10. The method according to claim 8, wherein R1 is 2-thienyl and A is 3β-tropanyl methobromide.

11. The method according to claim 8, wherein R1 is cyclopentyl and A is 3α-(N-isopropyl)-nortropanyl methobromide.

12. The method according to claim 1, wherein the compound has the formula




wherein R is an optionally halo- or hydroxyl-substituted C1-4 alkyl group, R1 is a C1-4 alkyl group, or R and R1 together form a C4-6 alkylene group; X− is a physiologically acceptable anion, and R1 is H, OH, CH3, CH2OH, C1-4 alkyl or C1-4 alkoxy.

13. The method according to claim 12, wherein X− is bromide.

14. The method according to claim 12, wherein R1 is OH, CH3, or CH2OH.

15. The method according to claim 12, wherein R is methyl and R1 is methyl, ethyl, n-propyl or i-propyl.

16. The method according to claim 1, wherein the compound has the formula




wherein R is an optionally halo- or hydroxy-substituted C1-4-alkyl group, R1 is a C1-4-alkyl group, or R and R1 together form a C4-6-alkylene group, X− is a physiologically acceptable anion and R1 is H, OH, CH2OH, C1-4-alkyl, or C1-4-alkoxy.

17. The method according to claim 16, wherein X− is bromide.

18. The method according to claim 16, wherein R1 is OH, CH3, or CH2OH.

19. The method according to claim 16, wherein R is methyl and R1 is methyl, ethyl, n-propyl or i-propyl.

20. The method according to claim 1, wherein the compound has the formula

21. The method according to claim 1, wherein the compound has the formula

22. The method according to claim 1, wherein the compound has the formula




wherein X− is a physiologically acceptable anion.

23. The method according to claim 22, wherein X− is a bromide.

24. The method according to claim 1, wherein the prolonged duration of action is at least about three weeks.

25. The method according to claim 1, wherein the additive is selected from the group consisting of carboxymethyl celluloses, glycosaminoglycans, pentosan polysulfate, and heparin.

26. The method according to claim 1, wherein the additive enhances viscosity or promotes entry into or adherence of the compound to the bladder wall.

27. The method according to claim 1, wherein the additive is a liposome in which the compound is contained.

28. The method according to claim 1, wherein the additive alters the surface of the bladder to foster and/or enhance access of the compound to the bladder.

29. The method according to claim 1, wherein the additive is a protamine.

30. The method according to claim 26, wherein the additive enhances viscosity of the compound.

31. The method according to claim 26, wherein the additive promotes entry of the compound into the bladder wall.

32. The method according to claim 26, wherein the additive promotes adherence of the compound to the bladder wall.