WO1996028158A1

WO1996028158A1 - Benzamide derivative for treating incontinence

Info

Publication number: WO1996028158A1
Application number: PCT/EP1996/001014
Authority: WO
Inventors: Mark Bushfield
Original assignee: Pfizer Limited; Pfizer Research And Development Company, N.V./S.A.; Pfizer Inc.
Priority date: 1995-03-14
Filing date: 1996-03-06
Publication date: 1996-09-19
Also published as: GB9505084D0

Abstract

The use of a benzamide derivative of formula (I) for the manufacture of a medicament for the treatment of urinary urge incontinence.

Description

BENZAMIDE DERIVATIVE FOR TREATING INCONTINENCE

This invention relates to the use of (S)-(-)-N-[2-(3,4-dichlorophenyl)- 4-(4-phenyl-4-acetamidopiperidino)butyl]-N-methylbenzamide and its pharmaceutically acceptable salts in treating urinary urge incontinence.

This compound has the structural formula:-

This compound and its preparation are described in EP-A-0474561 , specifically, in Example 72. The utilities described in EP-A-0474561 are the treatment of neurokinin A-dependent pathology, especially the treatment of neurogenic inflammations of the respiratory tract, such as, for example, asthma or bronchoconstriction. There is no suggestion of utility in the treatment of urinary urge incontinence.

Thus the present invention relates to the use of the compound (I) and its pharmaceutically acceptable salts in treating urinary urge incontinence.

Suitable pharmaceutically acceptable salts of the compound (I) include, for example, the hydrochloride, hydrobromide, hydroiodide, sulphate, bisuiphate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, benzenesulfonate and p-toluenesulfonate salts. For a comprehensive review of suitable salts see e.g. Berge et. al., J.Pharm.Sc , 66, 1-19 (1977). For human use in the treatment of urinary urge incontinence, the compound of the formula (I) and its salts can be administered alone, but will generally be administered in admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, it can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. It can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, it is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.

For oral and parenteral administration to human patients, the daily dosage level of the compound of the formula (I) and its salts will be from 0.5 to 5mg/kg (in single or divided doses) and preferably will be from 1 to 2 mg/kg. Thus tablets or capsules of the compound will contain from 50 to 200mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Alternatively, the compound of the formula (I) and its salts can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, it can be incorporated into a cream consisting of an aqueous emulsion of polythylene glycols or liquid paraffin; or it can be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.

It is to be appreciated that reference to treatment includes prophylaxis as well as the alleviation of established symptoms of the disease.

We have found that the compound (I) inhibits the micturition reflex in the anaesthetised guinea pig, as described by Metcalfe et al, Br. J. Pharmacol., 112, 563P (1994). Animals were anaesthetised with urethane (1.2g/kg, i.p.) and, after tying off the external urethra, a catheter was inserted via the dome into the bladder for intraluminal pressure recording. The effects of compound (I) on [βAla8]NKA4-10-induced increases in bladder pressure were determined. Administration of [βAla8]NKA4-10 (5 μg/kg, i.v.) resulted in activation of the afferent arm of the micturition reflex leading to bladder contractions. Such bladder contractions were shown to be reflex-mediated since they could be inhibited by atropine or ganglion blockers such as hexamethonium which interfere with the efferent arm of the micturition reflex. Therefore, these studies measured the ability of compound (I) to ihhibit bladder neuronal NK2 receptors.

Results and conclusions

We found that compound (I) blocked agonist-induced reflex bladder contractions at doses of 30μg/kg i.v. and above (n = 4 animals). This data indicated that compound (I) is a potent antagonist of the bladder neuronal NK2 receptors controlling micturition. Therefore, compound (I), by inhibiting sensitisation of bladder sensory nerves, provides an effective therapy for urinary urge incontinence.

Claims

1. The use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the treatment of urinary urge incontinence:-

2. A method of treating urinary urge incontinence in a patient which comprises administering a therapeutically effective amount of the compound of the formula (I) as defined in claim I or a pharmaceutically acceptable salt thereof to said patient.