Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-07-08
1996-03-12
Chano, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546224, A61K 31445, C07D21156
Patent
active
054986184
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
In U.S. Pat. No. 4,962,115 there are described N-(3-hydroxy-4-piperidinyl)benzamide derivatives having gastro-intestinal motility stimulating activity. In JP-A-2-104572 there are also described benzamide derivatives having digestive tract hypergic action. EP-A-0,278,173 discloses the use of heterocyclic derivatives of among others which are benzoic acid, acting as 5HT.sub.3 -antagonists for treating depression. The present compounds differ structurally and show unexpectedly high affinity as ligands for the 5HT.sub.2 -receptor, yielding strong and specific 5HT.sub.2 -antagonism.
DESCRIPTION OF THE INVENTION
The present invention is concerned with compounds having the formula ##STR2## the pharmaceutically acceptable acid addition salts thereof and the stereoisomeric forms thereof, wherein or haloC.sub.1-4 alkyl;
In the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C.sub.1-4 alkyl defines straight and branch chained saturated hydrocarbon radicals having 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C.sub.2-4 alkanediyl defines bivalent straight or branch chained hydrocarbon radicals containing from 2 to 4 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the branched isomers thereof.
The term "stereochemically isomeric forms" as used hereinbefore and hereinafter defines all the possible stereoisomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration. The present invention clearly intends to embrace in its scope both the individual stereochemically isomeric forms as well as mixtures thereof. It has to be understood that, when mixtures of enantiomers are present, they may be separated according to classical resolution methods, e.g. by fractional crystallization of their acid addition salts with a suitable chiral acid or by the separation by chromatography using a chiral phase.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, hydroxyacetic, propanoic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form. The term acid addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
Interesting compounds are those compounds of formula (I) wherein R.sup.4 and R.sup.5 are hydrogen or wherein the group NR.sup.4 R.sup.5 represents azido.
Particular compounds within the invention are those compounds wherein R.sup.2 and R.sup.3 are positioned in the 2- and 4-position of the phenoxy moiety; such compounds having more in particular a R.sup.2 which is 4-fluoro; and/or wherein Alk is 1,3-propanediyl.
Particularly interesting compounds are those wherein R.sup.1 represents a halo.
Preferred compounds are: ethoxybenzamide; -methoxybenzamide; methoxybe
REFERENCES:
patent: 4962115 (1990-10-01), Van Daele
CA 108;49149t (1988) Moriarty et al., "Inhitition of the effect of serotonin on rat ileal transport by cisapride: evidence in favor of the 5-HT.sub.2 receptors".
Moriarty et al., "Inhibition of the effect of serotonin on rat ileal transport by cisapride: evidence in favor of the 5-HT.sub.2 receptors. " Gut, 1987, 28, 844-848.
CA 102: 56714c (1985) Arnt et al., "The Citalopram/5-HTP-induced Head Shade Syndrome is Correlated to 5-HT.sub.2 Recptor Affinity and also Influenced by other Transmitters".
Arnt et al., "The Citalopram/5-HTP-induced Head Shake Syndrome is Correlated to 5-HT.sub.2 Receptor Affinity and also Influenced by other Transmitters", Acta, Pharmacol. et Toxicol. 1984, 55, 363-372.
Leysen Josepha E. M. F.
Van Daele Georges H. P.
Chano Ceila
Janssen Pharmaceutica N.V.
Metz Charles J.
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