WO1993020819A1

WO1993020819A1 - Treatment of delayed gastric emptying

Info

Publication number: WO1993020819A1
Application number: PCT/EP1993/000781
Authority: WO
Inventors: Robert Michael Wallis; Stephen Alaric Williams
Original assignee: Pfizer Limited; Pfizer Research And Development Company, N.V./S.A.; Pfizer, Inc.
Priority date: 1992-04-14
Filing date: 1993-03-29
Publication date: 1993-10-28
Also published as: IL105313A0; GB9208230D0; ZA932583B; TW219331B; MX9302142A; AU3891093A

Abstract

Use of 3R-and 3R,S-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)-piperidine for treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.

Description

-4- TREATMENT OF DELAYED GASTRIC EMPTYING

This invention relates to treatment of medical conditions associated with delayed gastric emptying using 3R- or 3R,S-diphenylmethoxy-l-(3,4- - methylenedioxyphenethyl)piperidine, a compound disclosed in European Patent Application EP-A-0350309.

Diphenylmethoxy-1-(3 ,4-methylenedioxyphenethyl)- piperidine is of formula (I) :

Being an optically active compound, it exists as different stereoisomers and, as stated in EP-A-0350309, its 3R- form (known as compound UK-76,654) and its 3R,S- (racemic form) are gut-selective muscarinic receptor antagonists. They are useful in the treatment of diseases associated with altered motility and/or tone of smooth muscle, including irritable bowel syndrome, diverticular disease, urinary incontinence, oesophageal achalasia and chronic obstructive airways disease. Compound UK 76,654 and the corresponding racemate form acid addition salts and may be administered by conventional methods orally or by injection. The dose required for treating the above-mentioned diseases is typically 3.5 to 350 mg daily for an average human adult weighing 70 kg. It is known that muscarinic receptor antagonists, besides inhibiting small and large bowel motility, also tend to inhibit gastric emptying. Antagonists for which this effect has been discussed in the literature include propantheline (Hurwitz, Robinson and Herrin, 1977, Clin. Pharmacol. Therap. 2.206-210) , pirenzepine (Soffer, Kumar _r Mridha, Das-Gupta _r Britto and Wingate, 1988, Gastroenterol. 23.146-150) , atropine (Rashid and Bateman, 1990, Br. J. Clin. Pharmacol. 3C).25-34) and cyclotropium bromide (Stacher, Bergmann, Gaupmann, Schneider, Kugi, Hobart, Binder and Mittelbach-Steiner 1990, Br. J. Clin. Pharmacol. ,3£ 839-845) . However, such inhibition is often undesirable for patients who otherwise benefit from treatment with muscarinic receptor antagonists, including those affected by irritable bowel syndrome.

It has now been found, unexpectedly, that 3R and 3R,S-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine are capable of increasing gastric emptying rates when administered to patients at doses within the range which are likely to be used for treatment as muscarinic receptor antagonists. This effect, which is quite contrary to what might have been expected from existing knowledge , renders this compound suitable for the treatment of a number of conditions in patients for whom inhibition of gastric emptying is undesirable. These conditions include non-ulcer dyspepsia, neurogenic and non-neurogenic gastroparesis, idiopathic delayed gastric emptying, gastro-oesophageal reflux, nausea and vomiting.

The preparation of compound UK 76,654 or its racemate and the manner in which it may be administered to a patient, generally orally or by injection, are described in European Patent Application 0350309. The effect of the compound on gastric emptying may be demonstrated as follows, using the radiolabelled meal method described by Gustavsson (1982) _r Acta Radiologica Diagnosis 21 639-643. Healthy volunteers are given placebo or compound UK- 76654 or its 3R,S-racemic form orally in random order at varying doses followed 1 hour later by a meal typically consisting of two sausages, 120 g baked beans and mashed potato radioactively labelled with 2MBqTc^99m. Gastric emptying is measured over the next 2 to 3 hours, gastric emptying curves calculated and the time (t%) to emptying half of the meal deduced.

It is found that UK-76,654 has a significant effect in increasing gastric emptying rate of doses within or less than the range of 3.5-350 mg, particularly at doses around the 10 mg level. The dose administered for treatment of non-ulcer dyspepsia, gastroparesis, ideopathic delayed gastric emptying, gastro-oesophageal reflux, nausea and vomiting will be determined by a physician bearing in mind the age, weight, response and medical history of the patient but for average adults (70 kg) it is likely to be in the range of 1 to 100 mg.

For human use, 3R- or 3R,S-diphenylmethoxy-l-(3,4- methylenedioxyphenethyl)piperidine or its acid addition salts may be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example they may be administered orally in the form of tablets containing excipients such as starch or lactose or in capsules or ovules either alone or in combination with excipients or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example salts or glucose to make the solution isotonic with blood. Thus, one aspect of the invention comprises 3R- or 3R_rS-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine, or a pharmaceutically acceptable acid addition salt thereof, for use in the treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.

The invention also provides use of 3R- or 3R,S- diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine, or a pharmaceutically acceptable acid addition salt thereof, for_tιtmaking a medicament for treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.

The invention also provides a method of treating conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying, which comprises adminstering to the patient an effective amount of 3R- or 3R,S-diphenylmethoxy-l-(3,4- methylenedioxyphenethyl)piperidine or a pharmaceutically acceptable salt thereof.

The above-mentioned conditions include non-ulcer dyspepsia, gastroparesis, idiopathic delayed gastric emptying, gastro-oesophageal reflux_r nausea and vomiting.

Claims

1. Use of 3R- or 3R,S-diphenylmethoxy-l-(3,4- methylenedioxyphenethyl)-piperidine, or a pharmaceutically acceptable acid addition salt thereof> for making a medicament for treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.

2. 3R- or 3R,S-diphenylmethoxy-l-(3,4-methylene- dioxyphenethyl)-piperidine, or a pharmaceutically acceptable acid addition salt thereof, for use in treatment of conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying.

3. A method of treating conditions requiring antagonism of muscarinic receptors and increase, or prevention of reduction, in gastric emptying which comprises administering to a patient an effective amount of 3R- or 3R,S-diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine or a pharmaceutically acceptable salt thereof.

4. Use according to claim 1, or a method according to claim 3, in which said condition is non-ulcer dyspepsia, neurogenic or non-neurogenic gastroparesis, idiopathic delayed gastric emptying, gastro-oesophageal reflux, nausea or vomiting.