Enterokinetic benzamide

Details Enterokinetic benzamide Enterokinetic benzamide

1999-06-04

2001-10-30

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S196000

Reexamination Certificate

active

06310077

ABSTRACT:

The present invention is concerned with a novel benzamide derivative and the pharmaceutically acceptable acid addition salts thereof, pharmaceutical compositions comprising said novel compound, processes for preparing said compounds and compositions, and the use thereof as a medicine, in particular in the treatment of conditions involving an impaired motility of the intestine, especially of the colon.
In our EP-0,389,037-A, published on Sep. 26, 1990, N-(3-hydroxy-4-piperidinyl) (dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide derivatives are disclosed as having gastrointestinal motility stimulating properties. In our EP-0,445,862-A, published on Sep. 11, 1991, N-(4-piperidinyl) (dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide derivatives are disclosed also having gastrointestinal motility stimulating properties.
The compound subject to the present application differs therefrom by showing superior enterokinetic properties.
The present invention concerns a compound of formula
and the pharmaceutically acceptable acid addition salts thereof.
The chemical name of the compound of formula (I) is 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids: or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butane-dioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, &rgr;-toluenesulfonic, cyclamic, salicylic, &rgr;-aminosalicylic, pamoic and the like acids. The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof are able to form. Such solvates are, for example, hydrates, alcoholates and the like. Conversely the salt form can be converted by treatment with alkali into the free base form. Hereinafter the term “compounds of formula (I)” means the compound of formula (I) as well as the pharmaceutically acceptable acid addition salts thereof, unless otherwise mentioned.
Interesting compounds of formula (I) are the acid addition salts which are formed by treating the base form of the compound of formula (I) with hydrohalic acids or butane-dioic acid.
Preferred compounds of formula (I) are 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrochloride and 4-amino-5-chloro-2,3dihydro-N-[l-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide butane-dioate (1:1).
The compounds of formula (I) may be prepared according to procedures which are disclosed in EP-0,389,037-A and EP-0,445,862-A. A number of preparation alternatives are shown hereinunder.
In the following preparations, the reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, distillation, crystallization, trituration and chromatography.
The compounds of formula (I) can be prepared by N-alkylating an intermediate of formula (II) with an alkylating reagent of formula (III), wherein W is an appropriate leaving group such as a halo, e.g. chloro; or a sulfonyloxy leaving group, e.g. methanesulfonyloxy (mesylate) or a p-toluenesulfonyloxy (tosylate) in a reaction inert solvent such as a dipolar aprotic solvent, e.g. dimethyl formamide, in the presence of an appropriate base such as, for instance, triethylamine. A suitable catalyst such as potassium iodide may also be added to enhance the reaction rate.
The compound of formula (I) may also be prepared by an N-acylation reaction of a carboxylic acid of formula (IV) or a reactive intermediate thereof and an amine of formula (V). Said N-acylation reaction may be performed by stifling the two reactants in a reaction-inert solvent, such as a chlorinated hydrocarbon, e.g. chloroform, or an aromatic hydrocarbon, e.g. toluene.
The above-mentioned intermediates are art-known or the preparation thereof is mentioned in EP-0,389,037-A and EP-0,445,862-A.
The compounds of formula (I) possess excellent intestinal motility stimulating properties. In particular the present compounds of formula (I) show significant motility enhancing effects on the small and large intestine. In other words the present compounds of formula (I) have enterokinetic properties. These properties are supported by the pharmacological examples described hereinunder. The present compounds of formula (I) enhance non-adrenergic non-cholinergic (NANC) excitation and the propulsion of faecal pellets through the large bowel. In addition, they accelerate gastric emptying and small intestinal contractile activity and have a facilitating effect on the cholinergic nerves. Said compounds are also devoid of 5-HT
2
or 5-HT
3
receptor antagonistic properties. Moreover, the present compounds also show in-vivo activity as is evidenced in the “Telemetric recording of colonic motility in conscious dogs” test.
In view of their useful enterokinetic enhancing properties the subject compounds may be formulated into various forms for administration purposes.
To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient

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