WO1996005817A1

WO1996005817A1 - Medicament for treatment or prophylaxis of incontinence

Info

Publication number: WO1996005817A1
Application number: PCT/GB1995/001995
Authority: WO
Inventors: Ulrik Fredrik Malt; Svein Blomhoff
Original assignee: Medinnova Sf; Dzieglewska, Hanna, Eva
Priority date: 1994-08-23
Filing date: 1995-08-22
Publication date: 1996-02-29
Also published as: GB9417135D0; AU3263795A

Abstract

The present invention relates to the use of compounds which interact with 5-HT1A receptors, especially azapirones or pharmaceutically acceptable salts thereof, for the preparation of medicaments for use in the treatment or prophylaxis of incontinence disorders, methods of treatment using these compounds and pharmaceutical compositions containing these compounds.

Description

MEDICAMENT FOR TREATMENT OR PROPHYLAXIS OF INCONTINENCE

The present invention relates to the treatment of incontinence disorders, and in particular to a new medical use for azapirones, and other compounds which interact with 5-HT1A receptors, in the treatment of urinary and fecal incontinence and related conditions.

The condition of incontinence is typified by the inappropriate flow of fluids in passages and from natural orifices of the body and includes both the flow of material from the body, for example in urinary and fecal inconvenience, and the retention of material in the body, for example in urinary retention.

Urinary incontinence may occur as the result of a number of medical conditions including the failure of voluntary control of vesical and urethral sphincters with constant or frequent involuntary passage of urine. Urinary incontinence conditions include active

incontinence, intermittent incontinence, overflow incontinence, paradoxical incontinence, paralytic incontinence, stress incontinence and passive

incontinence.

Treatment of urinary incontinence is in essence dependent on its type and severity. Generally speaking, there are three approaches, namely the use of

pharmacologic agents, electrical stimulation, or

surgery, the latter two being directed almost

exclusively to the treatment of sphincters of the urogenital tract.

The pharmocological approach is directed primarily to increasing the capacity of incontinent patients to store urine. Pharmacologic drugs in use include those directed towards improving stability of the detrusor muscle in the bladder wall (and thus bladder capacity) by blocking cholinergic transmission and those having a direct inhibitory effect on the smooth muscle of the bladder wall. Examples include anticholinergics (which suppress urgency and urgency incontinence as well as being useful in the treatment of neurogenic

incontinence) such as belladonna, propantheline bromide, methantheline bromide, baclophene, prazocine and

terodiline and the antimuscarinic agents oxybutynin, flavoxate hydrochloride and the antidepressant

imipramine hydrochloride. The side-effects for all anticholinergics include dry mouth, visual blurring and decreased gastrointestinal motility with resulting constipation.

Urethral resistance may be improved by alpha agonists. Examples include phenylpropanolamine,

ephedrine, and imipramine. Parasymphathomimetics (e.g. Urecholine) have been used with limited success in improving detrusor function. Most clinicians find, however, that significant improvement in bladder

contractility requires such high doses of Urecholine that the side effects (gastrointestinal disturbance) become prohibitive.

The sympathetic nervous system exercises important control over the bladder and urethra. Since the bladder neck and proximal urethra contain mainly alpha- adrenergic receptors, alpha-adrenergic stimulation of the smooth muscle in these areas increases urethral resistance. Sympathomimetic agents that stimulate alpha-adrenergic receptors have been used to treat stress urinary incontinence (SUI) and include ephedrine, pseudoephedrine hydrochloride and phenylpropanolamine hydrochloride. Although these agents may be useful in patients with mild SUI, surgical correction is often preferable to chronic medication with its associated side-effects such as increased irritability, cardiac palpitations, anxiety and drowsiness. Moreover, none of these drugs cure severe SUI. Nerve stimulation may be used as an alternative treatment. Finally the operative approach may be employed.

As with urinary incontinence, fecal incontinence may result from failure of voluntary control of rectal sphincters with involuntary passage of feces and flatus which may be due to anatomic disruption of the

sphincters resulting from previous surgery, obstetric trauma, or other injuries. Neurologic problems are primary in other patients with anatomically intact sphincters. Procidentia is often associated with incontinence if it remains untreated for long periods. In patients whose sphincters are anatomically intact, operant conditioning is used to overcome incontinence. Various operations have been proposed for improving the function of intact sphincters, but the results are mixed. Elderly patients generally are prone to failure of the repair or prompt recurrence of incontinence.

Incontinence is a distressing condition which may severely incapacitate or stigmatize the sufferer. As can be seen from the above, present treatments are not entirely satisfactory since they may either not be effective on all types of incontinence, or they may involve invasive or unpleasant procedures such as surgery or nerve stimulation. Clearly, any new

treatment which helps to relieve or improve symptoms in such patients in a simple and non-invasive manner would be of benefit.

Surprisingly, it has now been found that the azapirone class of psychotropic drugs compounds is particularly effective in relieving the symptoms of urinary and fecal incontinence and, accordingly are of benefit in the treatment or prophylaxis of urinary and fecal incontinence and other related disorders.

Thus, according to one aspect, the present

invention provides the use of an azapirone or a

pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of incontinence disorders. Azapirones are a novel class of drugs, known primarily for their neurological properties and

demonstrate dopaminergic, noradrenergic and serotonin (5-hydroxy-tryptamine, 5-HT)-modulating effects without untoward side effects (see for example "Symposium on azapirones: a novel class of broad spectrum psychotropic agents 9.12.1989, USA; J. Clin. Psychopharm. 1990, 10(3) suppl.) Their primary use has been in the treatment of anxiety and depression, but more recently other uses have been proposed, for example in the treatment of sexual dysfunction (US-A-4, 640, 921), alcoholism (EP-A- 0303951), motion sickness and chemically-induced emesis (US-A-4, 943,428), cognitive disorders (WO 93/04681) and drug abuse (EP-A-0356997).

Generally speaking, azapirones may be defined as a class of compounds containing a 1,3-bisoxacyclo-2- azaalkane ring optionally containing other ring

heteroatoms eg. sulphur.

The most notable members of the class include buspirone, ipsapirone, gepirone and tandospirone, although a range of other azapirone compounds and derivatives have also been described (see for example EP-A-0356997, EP-A-0442424, EP-A-303951, EP-A-455510, US-A-4, 818, 756, EP-A-0129128 and EP-A-082402). All such compounds and derivatives are included within the scope of this invention, as are all their pharmaceutically acceptable salts, including both organic and inorganic salts (eg. with alkali and alkaline earth metal, ammonium, ethanolamine, diethanolamine and meglumine, chloride, hydrogen carbonate, phosphate, sulphate and acetate counterions). Appropriate pharmaceutically acceptable salts are well described in the

pharmaceutical literature. In addition, some of these salts may form solvates with water or organic solvents such as ethanol. Such solvates are also included within the scope of this invention .

Azapirones are partial agonists at 5-HT1A receptors. Over the last few years it has become apparent that the ligand for these receptors, namely serotonin (5-HT) is associated directly or indirectly with a number of physiological phenomena, including appetite, memory, thermoregulation, sleep, sexual behaviour, anxiety, depression, and hallucinogenic behaviour (see Glennon, J. Med. Chem. 30 , 1 (1987)).

5-HT receptors have been identified in the central nervous system (CNS; brain and spinal cord) and in peripheral tissues including the gastrointestinal tract, lung, heart, blood vessels, and various other smooth muscle tissues. Multiple types of 5-HT receptors have been recognized. These receptors have been classified as 5-HT1, 5-HT2, and 5-HT3 with at least the 5-HT1 receptor being further divided into sub-classes 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT1D.

The primary focus of research efforts surrounding the biochemistry and physiology of serotonin and

serotonin agonists has been directed toward the CNS, and in particular to the brain. It has also been identified that 5-HT receptors in smooth muscle of the

gastrointestinal tract mediate contraction of this tissue. In EP-455510 it has been disclosed that 5-HT1A agonists inhibit the secretion of gastric acid.

While not wishing to be limited by theory, it appears that the therapeutic effect on incontinence disorders may involve the activity of azapirones

directly on 5-HT1A receptors of the target organs, or possibly the small number of 5-HT1A receptors found in nerve fibres connecting these organs to the autonomic nerve system.

Viewed from a further aspect therefore, the present invention can be seen to provide use of a compound which interacts with 5-HT1A receptors, or a pharmaceutically acceptable salt thereof for the preparation of a

medicament for use in the treatment or prophylaxis of incontinence disorders. Compounds interacting with 5-HT1A receptors which may be used according to the invention include agonists, partial agonists and antagonists. Receptor agonists are defined as those compounds capable of binding to the receptor and directly activating its activity. Receptor antagonists bind to the receptor and block or inhibit its biological activity. Partial agonists both up- regulate and down-regulate the receptor and may exhibit both pre-synaptic and post-synaptic effects. Generally speaking, partial agonists directly activate the

receptor, but produce a smaller maximal effect. A wide range of such compounds are well known and widely described in the literature.

Procedures for performing binding assays to

determine 5-HT1A agonist activity are known to those skilled in the art and include, for example, the

techniques described in Wong et al., Life Sciences, 46, 231-235 (1990) and the references cited therein. The relationship between apparent binding affinity (K₁) as a function of inhibitor IC₅₀ values, radioligand

concentration and dissociation of the ligand-receptor complex is also known to those skilled in the art. For example, see Cheng et al., Biochemical Pharmacology, 22, 3099-3108 (1973); and Taylor et al., Life Sciences, 41, 1961-1969 (1987). Likewise 5-HT1A antagonist activity may also be easily determined and assayed (see for example J. Pharmacol. Exp. Ther. 238. 248-253 (1986) and J. Pharmacol. Exp. Ther. 258, 58-65 (1991).

In addition to the azapirones, 5-HT1A agonists and partial agonists include the following classes of compounds which may be used according to the present invention:

1) 2-amino-1,2,3,3,4-tetrahydronaphthalenes and 3- amino chromanes;

2) 4-amino-1,3,4,5-tetrahydrobenz-[c,d]indoles;

3) non-endogenous indoles; 4) aryloxy propanolamines;

5) benzodioxanes;

6) phenylcyclopropylamines;

7) piperidinylmethyl tetrahydroisoquinolines; and

8) N-arylpiperazines (including, inter alia, those

which are azapirones).

Such compounds are described in more detail in EP- A-0455510 and the references cited therein.

WO93/04681 describes a range of suitable partial agonists and antagonists, which, in addition to the azapirones, include:

1) piperazine derivatives such as 1-[10,11-dihydro-8- (methylthio)-dibenzo [b, f] thiepin-10-yl]-4- methylpiperazine (Methiothepin);

2) 1,1-diethyl-3- (8a-ergolinyl) urea derivatives such as Lisuride (die Vivo and Maayani, J. Pharmacol, Exp. Ther. 238, 248-253) und Terguride (for example Kehr, Eur. J. Pharmacol. 97, 111-119 (1984));

3) 2-amino-tetralines such as 5-fluoro-8-hydroxy-2- (dipropylamino)-tetraline (J. Med. Chem. 33, 1541- 1544 (1990)) and Spiperon (8-[3-(p- fluobenzoyl) propyl]-1-phenyl-1,3,8- triazaspiro [4, 5] decan-4-one).

As mentioned above, pharmaceutically acceptable salts and solvates of such compounds may readily be prepared using counterions and techniques well known in the art. All such salts and solvates as well as any isomers (eg. stereoisomers and/or enantiomers) and their mixtures are all included according to the invention.

Incontinence disorders which may be treated

according to the present invention, include all those in which inappropriate flux of fluid occurs in passages or from natural orifices of the animal body. Typically, incontinence disorders may be associated with conditions of the gastrointestinal and urogenital tracts which include for example urinary and fecal incontinence and urinary retention.

Other aspects of the invention accordingly provide a method of treatment of the human or non-human animal body to combat incontinence disorders, said method comprising administering to said body a compound

interacting with 5-HT1A receptors, or a pharmaceutically acceptable salt thereof.

More particularly, the invention provides a method of treatment of the human or non-human animal body to combat incontinence disorders, said method comprising administering to said body an azapirone or a

pharmaceutically acceptable salt thereof.

As used herein, the term "combat" includes both therapy and prophylaxis, in particular of individuals with a history of, or at risk from, incontinence

disorders.

The compounds useful in practising the invention are preferably formulated prior to administration. The present invention therefore also provides a

pharmaceutical composition for use in the treatment or prophylaxis of incontinence disorders, said composition comprising a compound interacting with 5-HT1A receptors or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient.

In one preferred embodiment, such compositions may comprise an azapirone or a pharmaceutically acceptable salt thereof.

The active ingredient in such compositions may comprise from about 0.1% to about 99% by weight of the formulation. By "pharmaceutically acceptable" is meant that the ingredient must be compatible with other ingredients of the compositions as well as

physiologically acceptable to the recipient.

Pharmaceutical compositions for use according to the present invention may be formulated in conventional manner using readily available ingredients, for example as described in any of the afore-mentioned patent specifications. Thus, the active ingredient may be incorporated, optionally together with other active substances, with one or more conventional carriers, diluents and/or excipients, to produce conventional galenic preparations such as tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions sterile packaged powders, and the like.

Examples of suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, aglinates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, water, water/ethanol, water/ glycol, water/polyethylene, glycol, propylene glycol, methyl cellulose, methylhydroxybenzoates, propyl

hydroxybenzoates, talc, magnesium stearate, mineral oil or fatty substances such as hard fat or suitable

mixtures thereof. The compositions may additionally include lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavouring agents, and the like. The

compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.

The compositions are preferably formulated in a unit dosage form, eg. with each dosage containing from about 0.1 to about 500 mg of the active ingredient.

The precise dosage of the active compound to be administered and the length of the cause of treatment will, of course, depend on a number of factors including for example, the age and weight of the patient, the specific condition requiring treatment and its severity, and the route of administration. Generally however, an effective dose may lie in the range of from about 0.01 mg/kg to about 20 mg/kg per day, eg from about 0.05 to about 10 mg/kg per day, preferably from about 0.2 to 1.0 mg/kg per day, administered one or more times per day. Thus for example, an appropriate daily dose for an adult, may be from 10 to 100 mg per day, eg 20 to 50 mg per day.

The administration may be by any suitable method known in the medicinal arts, including for example oral, parenteral (eg. intramuscular, subcutaneous,

intraperitoneal or intravenous) rectal or topical administration or administration by inhalation.

The invention will now be described in more detail by way of the following non-limiting Examples:

Formulation Example 1 - Hard gelatin capsules

Capsules are prepared using the following ingredients:

The active ingredient is selected from those shown in Table 1. The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

Formulation Example 2

A tablet is prepared using the ingredients below:

The active ingredient is selected from those shown in Table 1. The components are blended and compressed to form tablets each weighing 665 mg.

The active compounds, selected from Table 1, is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder- of the propellant. The valve units are then fitted to the container.

Formulation Example 4

Tablets, each containing 60 mg of active ingredient, are made as follows:

The active ingredient (selected from Table 1), starch and cellulose are sieved and mixed thoroughly. The aqueous solution containing polyvinyl pyrrolidone is mixed with the resultant powder, and the mixture then is passed again through a sieve. The granules so produced are dried at 50ºC and passed through a sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S.

sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Formulation Example 5

Suspensions, each containing 50 mg of active ingredient per ml dose, are made as follows:

The active ingredient (selected from Table 1), passed through a sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavour and colour are diluted with a portion of the water and added, with stirring.

Sufficient water is then added to produce the required volume.

Example 6

One female patient suffering from both fecal and urinary incontinence reported relief of the symptoms after treatment with buspirone.

The patient's fecal incontinence started immediately after a delivery in 1987, after which the patient no longer felt the urge to defecate. Two years later the urinary incontinence started. The fecal incontinence was diagnosed as the result of a sensory nerve damage at the Department of neurology at the National hospital. The etiology of the urinary incontinence has not been found.

As a result of buspirone (Buspar) treatment of 40 mg per day, the patient's urinary incontinence improved

immediately. The patient's fecal incontinence improved after a period of 3-4 weeks, with a return of the patient's urge to defecate.

Example 7

One 40 year old, female patient suffering from migraine and bladder incontinence for many years, subjected to surgical intervention three times (stoma), and also suffering from an anxiety disorder, reported relief of these symptoms after treatment with buspirone.

As a result of buspirone treatment of 25 mg a day from 4th August 1992, the patient's anxiety was markedly improved. After 2-3 weeks, the following additive effects were noted:

The frequency of the patient's migraine attacks reduced (2 attacks during the last 4 months in comparison to approximately twice monthly prior to medication).

The patient's urinary incontinence, persistent since 1975, disappeared.

After 2 months treatment with buspirone was stopped, whereafter the symptoms gradually relapsed. After 1 month the patient was once again treated with buspirone resulting in the same excellent effects.

Example 8

The patient is a 35 year old woman. In 1988 she was operated on for a prolaps of L5 in the columna. At the time of surgery she had urinary retention. Since then she has suffered continuously from low back pain, and irridiation pain from the L5/S1 area. She has been using a back cast, but with only temporary relief of her symptoms. A further operation is now being considered.

Since 1988 she has also had long periods with urinary problems. On occasion she has been incontinent, but mostly has suffered from urinary retention. She has been taught self-catherisation, and uses this when necessary. As a part of this routine she also measures her residual urine.

During a period in which the patient was experiencing urinary retention she was given buspirone at a dose of 30 mg a day. After two weeks of treatment she reported a reduction of residual urine, and soon no longer needed catherisation. Buspirone was administered for a total period of 4 months, without relapse of the patient's urinary symptoms.

About 6 months after the end of the 4 months buspirone administration period, she once again developed urinary retention and hence started self-c therisation. On administration of buspirone at the same dose as used previously, the patient once again experienced the same significant relief of her symptoms.

Claims

1. The use of a compound which interacts with 5-HT1A receptors, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for use in the treatment or prophylaxis of incontinence disorders.

2. The use as claimed in claim 1 wherein the compound is a 5-HT1A agonist, partial agonist or antagonist.

3. The use as claimed in claim 1 or 2 wherein the compound is selected from the list:

1) 2 -amino-1,2,3,3,4-tetrahydronaphthalenes and 3- amino chromanes;

2) 4 -amino-1,3,4,5-tetrahydrobenz- [c, d] indoles;

3) non-endogenous indoles;

4) aryloxy propanolamines;

5) benzodioxanes;

6) phenylcyclopropylamines;

7) piperidinylmethyl tetrahydroisoquinolines;

8) N-arylpiperazines;

9) piperazine derivatives,-

10) 1,1-diethyl-3-(8a-ergolinyl) urea derivatives; and

11) 2-amino-tetralines.

4. The use as claimed in any one of claims 1 to 3 wherein the compound is an azapirone, derivative or pharmaceutically acceptable salt thereof.

5. The use as claimed in claim 4 wherein the azapirone is buspirone or a pharmaceutically acceptable salt thereof.

6. The use as claimed in any one of claims 1 to 5 wherein the incontinence disorders are associated with conditions of the gastrointestinal or urogenital tracts.

7. The use as claimed in claim 6 wherein the

incontinence disorder is urinary incontinence, fecal incontinence or urinary retention.

8. The use as claimed in any one of claims 1 to 7 wherein the medicament contains the compound in an amount sufficient to administer an effective dose from about O.lmg/kg to about 20mg/kg.

9. The use as claimed in claim 8 wherein the effective dose is from about 0.05 to 10mg/kg.

10. A method of treatment of the human or non-human animal body to combat incontinence disorders, said method comprising administering to said body a compound interacting with 5-HT1A receptors, or a pharmaceutically acceptable salt thereof.

11. A method as claimed in claim 10 wherein the

compound is a 5-HT1A agonist, partial agonist or antagonist.

12. A method as claimed in claim 10 or 11 wherein the compound is selected from the list:

1) 2-amino-1,2,3,3,4-tetrahydronaphthalenes and 3- amino chromanes;

2) 4-amino-1,3,4,5-tetrahydrobenz- [c, d] indoles;

3) non-endogenous indoles;

4) aryloxy propanolamines;

5 ) benzodioxanes;

6) phenylcyclopropylamines;

7) piperidinylmethyl tetrahydroisoquinolines;

8) N-arylpiperazines;

9) piperazine derivatives;

10) 1,1-diethyl-3- (8a-ergolinyl) urea derivatives; and

11) 2-amino-tetralines.

13. A method as claimed in any one of claims 10 to 12 wherein the compound is an azapirone, derivative or pharmaceutically acceptable salt thereof.

14. A method as claimed in claim 13 wherein the

azapirone is buspirone or a pharmaceutically acceptable salt thereof.

15. A method as claimed in any one of claims 10 to 14 wherein the incontinence disorders are associated with conditions of the gastrointestinal or urogenital tracts.

16. A method as claimed in claim 15 wherein the

17. A method as claimed in any one of claims 10 to 16 wherein said compound is administered at a dose of from about 0. lmg/kg to about 20mg/kg.

18. A method as claimed in claim 17 wherein the dose is from about 0.05 to 10mg/kg.

19. A pharmaceutical composition for use in the

treatment or prophylaxis of incontinence disorders, said composition comprising a compound interacting with 5- HT1A receptors or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 5, together with at least one pharmaceutically acceptable carrier, diluent or excipient.

20. A pharmaceutical composition as claimed in claim 19 wherein the incontinence disorders are associated with conditions of the gastrointestinal or urogenital tracts.

21. A pharmaceutical composition as claimed in claim 20 wherein the incontinence disorder is urinary incontinence, fecal incontinence or urinary retention.

22. A pharmaceutical composition as claimed in any one of claims 19 to 21 wherein the composition contains the compound in an amount sufficient to administer an effective dose from about 0.1mg/kg to about 20mg/kg.

23. A pharmaceutical composition as claimed in claim 22 wherein the effective dose is from about 0.05 to

10mg/kg.