WO1995019164A1

WO1995019164A1 - Use of m3 muscarinic antagonists for the treatment of motion sickness

Info

Publication number: WO1995019164A1
Application number: PCT/EP1995/000044
Authority: WO
Inventors: William Garth Rapeport; Robert Michael Wallis
Original assignee: Pfizer Limited; Pfizer Research And Development Company, N.V./S.A.; Pfizer Inc.
Priority date: 1994-01-14
Filing date: 1995-01-04
Publication date: 1995-07-20
Also published as: ZA95244B; AU1455395A; IL112257A0; TW276995B; GB9400600D0

Abstract

Motion sickness is treated or prevented by administration of M3-selective muscarinic receptor antagonists such as Darifenacin.

Description

se of M3 muscarinic antagonists for the treatment of motion sickness.

This invention relates to treatment of motion sickness, a condition characterised by nausea and vomiting caused by body motion. Seasickness and airsickness and spacesickness are instances of this condition. Motion sickness is commonly prevented by oral or transdermal administration of the alkaloid scopolamine (hyoscine) which is a known antimuscarinic agent, that is an agent which is a competitive inhibitor of acetylcholine at muscarinic receptor sites. However scopolamine is not selective between the three types of muscarinic receptor sites, known respectively as the M_lf M₂ and M₃ sites and therefore the receptor subtype involved in the control of motion sickness is unknown. In addition because of its non-selective action scopolamine, has undesirable side effects such as dry mouth, adverse effects on cognition and certain cardiac effects.

There are known muscarinic receptor antagonists which are selective for M₃ muscarinic sites over the Mi and M₂ sites, that is they are selective for smooth muscle muscarinic sites over cardiac muscle sites. They are gut-selective, generally have little or no antihistamine activity and include compounds which 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 dysmotility and chronic obstructive airways disease. Selective M₃ muscarinic receptor antagonists are described in patent documents EP-A-350309, WO 90/04583, EP-A-364123, EP-A-388054, WO 91/10650, WO 91/09014, WO 91/09015, WO 91/10651 and WO 91/10647. Particular compounds mentioned in these documents are 3R and 3R,S- diphenylmethoxy-1-(3,4-methylenedioxyphenethyl)- piperidine (mentioned in EP-A-350309) , the 3R- form of which is known as compound UK-76654, and (S)-2-(l-[2- (2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl)-2,2- diphenylacetamide (mentioned in EP-A-388054) , known as compound UK-88525 and their pharmaceutically acceptable salts. The latter compound, in the form of its hydrobromide, is known by the non-proprietary name Darifenacin.

It has now been discovered that the M₃ selective muscarinic receptor antagonists are effective in preventing or alleviating motion sickness without at least some of the side effects associated with known motion sickness remedies such as scopolamine. One aspect of the invention comprises a M₃ selective muscarinic receptor antagonist for use in the treatment or prevention of motion sickness. The invention also relates to a method of treating or preventing motion sickness which comprises administering to a patient an effective amount of a M₃ selective muscarinic receptor antagonist.

The invention also relates to use of an M₃-selective muscarinic receptor antagonist for the manufacture of a medicament for treatment or prevention of motion sickness.

It is believed that the compounds act via the brain and to achieve good efficacy they should be capable of penetrating the blood brain barrier. The compounds preferred for this purpose are those having lipophilic rather than polar physicochemical characteristics. Particularly preferred compounds are UK-88525 mentioned above, and its pharmaceutically acceptable salts. Preparation of UK-88525 is described in European Patent 388054. The pharmaceutically acceptable salts of this compound include acid addition salts such as the hydrochloride, hydrobromide, sulphate and bisulphate, phosphate or hydrogen phosphate, acetate, besylate, citrate, fumarate, gluconate, lactate, maleate, mesylate, succinate and tartrate salts. These salts may be prepared by conventional methods. The M₃ selective muscarinic receptor antagonist compound may generally be administered to a patient by conventional methods, for example orally or by injection, as described in the above-mentioned patent publications. The compounds may be made up into the appropriate formulations for administration by conventional methods. 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 admixture 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. The dose of active compound and frequency of administration required will generally depend not only on the identity of the compound but on the physiology of the patient. The dose administered will generally be determined by a physician bearing in mind the age, weight, anticipated response and medical history of the patient. For at least some of the M₃-selective muscarinic receptor antagonists, for an average adult weighing 70Kg the dose administered is likely to be from 1 to lOOmg. The action of the M₃-selective muscarinic receptor antagonists in preventing or alleviating motion sickness may be demonstrated as follows. In a double-blind trial, male adult volunteers are given, by conventional administration methods appropriate to the compound to be tested (preferably by oral dosing), varying doses of the compound or scopolamine, or placebo. 90 minutes later they are subjected to nauseagenic motion comprising cross coupled head movements whilst the subjects are blindfolded and subjected to increasing rotational velocity on a turntable according to a standard schedule comprising increasing the rotational velocity every 30 seconds by 2 degrees/second and having the subject complete a sequence of head movements of 45 degrees every 30 seconds. Tolerance of motion is assessed by the number of sequences of head movement required to produce maximum tolerated symptoms of nausea. The heart rate is measured, after 3 minutes sitting at rest, immediately before admistration of the compound and at intervals of 1 and 2 hours after administration.

In trials following the above procedure it was found that tolerance of nauseagenic motion is increased by both scopolamine, UK-76654 and UK-88,525. However the heart rate was significantly reduced at 1 and 2 hours post- administration of scopolamine whereas no heart rate reduction occurred with UK-76654 and UK-88,525.

Claims

CLAIMS 1. An. M₃-selective muscarinic receptor antagonist for use in the treatment or prevention of motion sickness. 2. (S)-2-(l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3- pyrrolidinyl)-2,

2-diphenylacetamide or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of motion sickness.

3. Use of an M₃-selective muscarinic receptor antagonist for manufacture of a medicament for treatment or prevention of motion sickness.

4. Use according to claim 3, in which said antagonist is (S)-2-(1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3- pyrrolidinyl)-2,2-diphenylacetamide or a pharmaceutically acceptable salt thereof.

5. A method of treating or preventing motion sickness, • which comprises administering to a patient an effective amount of an M₃-selective muscarinic receptor antagonist.

6. A method according to claim 5, in which said antagonist is (S)-2-(l-[2-(2,3-dihydrobenzofuran-5- yl)ethyl]-3-pyrrolidinyl)-2,2-diphenylacetamide.