Quaternary ammonium salts and use thereof as medicine

Details Quaternary ammonium salts and use thereof as medicine Quaternary ammonium salts and use thereof as medicine

1995-01-12

1996-11-12

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548205, 549495, 549 75, 564288, 564237, 564 45, 564 47, 564 23, 564 27, 514438, 514471, 514580, 514595, 514643, C07D27728, C07D30752, C07D33322, C07C21163

Patent

active

055740545

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP93/00607 filed May 10, 1993 and published as WO93/23360 Nov. 25, 1993.
1. Technical Field
The present invention relates to novel quaternary ammonium salts and use of the salts as medicines.
2. Background Art
Conventionally, trimebutine maleate has been primarily used as a gastroprokinetic agent.
Trimebutine maleate has wide utility due to its dual activities of promoting and suppressing the gastric contractions. However, it is not necessarily satisfactory in that relatively high dose, i.e., 300 mg per day is required, and that adverse side effects are involved.
Therefore, studies have been conducted in search for gastroprokinetic agents which can replace trimebutine maleate (Japanese Patent Application Laid-open (kokai) No. 163074/1991).
However, the results have not necessarily been successful in providing gastroprokinetics. Accordingly, development of drugs which possess much stronger activity in enhancement of gastrointestinal motility has still been desired.


DISCLOSURE OF THE INVENTION

Accordingly, the present invention provides novel quaternary ammonium salts represented by the following formula (I): ##STR1## [wherein R.sup.1 and R.sup.2 represent lower alkyl groups which may be the same or different from each other; R.sup.3 represents hydrogen, lower alkyl, phenyl, benzyl, or --COOR.sup.4 (wherein R.sup.4 represents lower alkyl); A represents lower alkyl, lower alkenyl, lower alkynyl, --(CH.sub.2).sub.p --COOR.sup.5 (wherein R.sup.5 represents hydrogen or lower alkyl, and p represents an integer of from 1 to 5) ##STR2## wherein R.sup.6 represents hydrogen, hydroxyl, nitro, lower alkyl, --COOR.sup.5, or --SO.sub.3 R.sup.5); Q.sup.31 represents a counter anion of quaternary ammonium salt; X represents ##STR3## Y represents methylene, oxygen or sulfur; Z represents ##STR4## (wherein R.sup.7 and R.sup.8 are the same or different from each other and independently represent hydrogen, halogen, nitro, lower alkyl or lower alkoxyl, and R.sup.9 represents lower alkyl or phenyl); 1 and m represent each an integer of 1 or 2; and n represents an integer of from 1 to 3], and use of the salts as medicines.
Since the compounds according to the present invention have an activity of accelerating the gastrointestinal contractions, i.e., they improve the gastrointestinal motility remarkably, as well as high safety, they have utility in the medical field of treating the gastrointestinal disorders and the like.


BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the term "lower alkyl" encompasses alkyl groups having 1 to 5 carbon atoms, examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl and the like.
The term "lower alkenyl" encompasses alkenyl groups having 2 to 5 carbon atoms, which include vinyl, allyl, butenyl, 3-methyl-2-butenyl and the like.
The term "lower alkynyl" encompasses alkynyl groups having 2 to 5 carbon atoms, which include ethynyl, propargyl and the like.
Examples of the counter anion of quaternary ammonium salt include fluorine ion, chlorine ion, bromine ion, iodine ion, HSO.sub.4.sup.-, ClO.sub.3.sup.-, NO.sub.3.sup.-, cyanide ion, HSO.sub.3.sup.- ion, IO.sub.3.sup.- ion, HCO.sub.2.sup.-, CH.sub.3 CO.sub.2.sup.-, OH.sup.-, phenolate ion, methanesulfonate ion, toluenesulfonate ion and the like.
The compound (I) of the present invention is prepared, for example, by the following reaction scheme: ##STR5## (wherein R.sup.1, R.sup.2, R.sup.3, A, Q, X, Y, Z, l, m and n have the same meaning as defined hereinbefore).
That is, compound (I) is obtained by reacting compound (II) which is obtainable by applying a known method (Japanese Patent Application Laid-open (kokai) No. 40956/1983; Japanese Patent Application Laid-open (kokai) No. 91980/1982; R. Soc. Chem., 42, Regul. Biol. Mech., 45-47, 1982) with compound (III).
The above reaction is preferably carried out in an inert solvent such as methanol, ethanol, dichloromethane, chloroform, ethyl acetate, dimethylformamid

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