Urinary incontinence is a common problem. It is estimated that the incidence of urinary incontinence ranges from between 1.642% in the elderly, with an incidence of between 15-30% in the community dwelling elderly. Whilst the prevalence of urinary incontinence is twice as high in women compared to men, it afflicts significant numbers of both sexes.

Besides the elderly, children frequently have nocturnal incontinence and some studies have shown incontinence in as many as 17% of young women who show no other signs of ill health.

There are three main types of urinary incontinence: 1) Stress, 2) Urge and 3) Mixed urinary incontinence. Stress urinary incontinence is the involuntary loss of urine during activities that increase the abdominal pressure, such as sneezing, coughing and laughing. Urge incontinence is due to the involuntary contraction of the bladder or to irritability and urge voiding even if the bladder is not full. Mixed incontinence is a combination of the previous two. In addition, there is also overfiow incontinence which refers to a condition where there is constant dribbiing, hesitancy, poor stream and impaired bladder sensation.

Urinary incontinence can be attributed to a number of different causes, including infections of the bladder, urethral hypermobility, intrinsic urethral sphincter incompetence, urethral or detrusor instability.

There are a number of different approaches to treating incontinence. These include physiotherapy, pelvic floor electrical stimulation, different surgical techniques, treatment with papaverine, the use of anticholinergics, for example propantheline, antispasmolitics such as oxybutynin, flavoxate and dicyciomine, and alpha-adrenergic agonists, for example, pseudoephedrine, ephedrine and phenylpropanolamine. However, these treatments have met with only limited success and many of the treatments are invasive or result in unwanted side effects. For example, ephedrine and phenylpropanolamine can increase blood pressure, anxiety, insomnia, headaches and cardiac arrhythmias. Papaverine treated patients reported anticholinergic symptoms including dry mouth, constipation and blurred vision.

There is, therefore, a continuing need for new agents which are effective in the treatment or prophylaxis of urinary incontinence.

As described in Steers and De Groat (Am. J Physiol Vol 257 pp R1441- R1449 ) meta-chlorophenyl-piperazine was investigated on bladder function in experiments with male anaesthetized rats. Results revealed a reciprocal action of this drug on penile and bladder activity. US patent No.4,971,969 and European patent No. 0 370 560 describe certain 1-[mono- or bis- (trifluoromethyl) 2-pyridinyl]piperazines and their pharmaceutically acceptable acid addition salts for use in the treatment of disorders of the central nervous system. It has now been found that one of these compounds, namely 1-[6- chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine and its pharmaceutically

acceptable acid addition salts is useful for the treatment of urinary incontinence in both sexes.

Accordingly, the present invention provides the use of a compound of formula (A): which is 1 [6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine and its pharmaceutically acceptable acid addition salts, for the manufacture of a medicament for the treatment or prophylaxis of urinary incontinence.

The compound of formula (A) and its pharmaceutically acceptable acid addition salts will be referred to collectively as compounds according to the present invention.

The present invention further includes the use of a compound according to the present invention for the manufacture of a medicament for the treatment or prophylaxis of urinary incontinence in an animal, for example, mammal including a human.

According to a further aspect, the present invention provides a method of treating urinary incontinence in an animal, including a human, which comprises treating said animal with a therapeutically effective amount of 1-[6-

chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine, or a pharmaceutically acceptable acid addition salt thereof.

The compounds according to the present invention have utility in treating any of the aforementioned types of urinary incontinence. These compounds are particularly useful in treating urinary incontinence in the elderly.

Suitable acid addition salts include hydrochloric, fumaric, maleic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation. Preferred salts include the hydrochloric and fumaric acid salt.

The amount of a compound of formula (A) or a pharmaceutically acceptable acid addition salt, also referred to herein as the active ingredient, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder being treated.

A suitable daily dose for any of the above mentioned disorders will be in the range of 0.01 to 5 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.1 to 2 mg per kilogram body weight per day and most preferably in the range 0.3 to 1.0 mg per kilogram body weight per day. In the case of tolerance development, treatments can be further optimalised by increasing the dose upto 2-10 times in the course of a chronic treatment in humans. The desired dose may be presented as one, two, three, four, five or more sub-doses administered at appropriate intervals throughout the day.

While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. Accordingly, the present invention further provides a pharmaceutical formulation for use in the treatment of urinary incontinence comprising a compound of formula (A) or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier thereof and optionally other therapeutic agents. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipients thereof. The invention further includes a pharmaceutical formulation, as hereinbefore described, in combination with packaging material suitable for the pharmaceutical formulation, said packaging material including instructions for the use of the pharmaceutical formulation in the treatment of urinary incontinence.

Formulations include those adapted for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and epidural) administration. The formulations may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al.,Remington's Pharmaceutical Sciences (18th ed., Mack Publishing company, 1990, see especially Part 8 : Pharmaceutical Preparations and their Manufacture). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Such accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents and wetting agents.

Formulations adapted for oral administration may be presented as discrete units such as tablets or capsules each containing a predetermined amount of active ingredient; as a powder or granulates; as a solution or suspension. The

active ingredient may also be presented as a bolus or paste, or may be contained within liposomes or microparticles.

Formulations for rectal administration may be presented as a suppository or enema.

Formulations adapted for parenteral administration include aqueous and non- aqueous sterile injection. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.

Formulations adapted for administration by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurised aerosols, nebulisers or insufflators.

Formulations may, for example, be presented in a suitable sustained release form, for example, in a device such as the Minipump.

The compounds according to the invention may be presented for use in the form of a veterinary formulation, such formulations may be prepared by methods conventional in the art.

The compounds according to the present invention are non-toxic.

The compound of formula (A) and its pharmaceutically acceptable acid addition salts may be prepared by any method known in the art for the preparation of a compound of similar structure. Typically the compounds are

prepared by the methods described in US patent No.4,971,969 the contents of which are incorporated herein by reference.

The following examples are for illustration and should not be considered to be limiting in anyway:- Example 1 1 -[6-chlorn-5-(trifluoromethyl2-pyridinypiperazine The title compound was prepared in accordance with the procedure described in US patent No.4,971,969.

Example 2 Urination Assay Method Female mice (Swiss CO-1, Charles River, Paderhorn), weighing 24-31 grams were housed in groups of 8 or 10 per cage of 40 x 24 x 14 cm (Marcrolont, type Ill).

On the day of the experiment the mice were injected subcutaneously with either saline or test compound in different concentrations. The volume of injection was 0.2 mit10 grams body weight. This is a two times larger injection volume than the usual 0.1 ml/10 grams in order to stimulate urine production.

After injection there was no food and water available. Immediately or 15 min.

after injection (experiment with Compound A) the mice were placed individually without food and water in clean cages of 40 x 24 x 14 cm (Marcrolont, type Ill) with filter paper on the floor.

Separate bouts of urination were quantified after allowing 5 minutes of spreading on the filter paper and measuring the diameter of the wet spot on the filter paper. The size of the urine-spots was calculated by the formula 14 TC D2, where D is the diameter of the spot in cm. assuming that the spots circular in shape.

The filter paper was renewed when several urine spots were made. Also, faecal droppings were counted. Cumulative measures of urine and faecal pellet production were obtained by observing continuously for 2 or 5 hours after injection. For the experiments with single treatment with Compound A we report here only the urine production results during the first hour after injection.

Route of administration: subcutaneously (s.c.) Vehicle: 0.9% (m/v) NaCI in water for all compounds.

Results Compound A Dose in No. of animals Urine wet spot size per mouse cumulated mglkg during 15-60 min post-injection 0.0 10 22.9+4.3 0.3 10 21.4j5.4 1.0 10 14.0 ' 4.6 3.0 10 8.7#4.1 * * P < 0.05 with Mann-Whitney U-test