Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-07
1998-09-08
Jarvis, William R. A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514327, 514317, A61K 31445
Patent
active
058045899
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR96/00976, filed Jun. 21, 1996.
The present invention relates to new therapeutical applications of N-cyclohexylbenzamides.
Irritable bowel syndrome (IBS) is defined by the presence of abdominal pain, of irregular defecation, which may or may not be associated with the abdominal pain, and generally of abdominal distensions.
The multiplicity of these symptoms has led to the proposal of a classification of this pathology as a function of the existence of constipation or of diarrhoea.
The constipation observed in certain forms of IBS can be treated by agents which stimulate intestinal motoricity and more particularly colic motoricity.
The N-cyclohexylbenzamides described in EP 0,507,672 are known to stimulate digestive motoricity and can therefore be proposed for restoring colic transit in patients affected by IBS where constipation is predominant.
It has been shown that, in this pathology, patients complaining of abdominal pain exhibit a lowered visceral sensitivity threshold (Medecine/Sciences (1994), 10, 1107-15).
This threshold can be raised by various pharmacological agents such as kappa agonists or certain 5-HT.sub.3 antagonists, such as granisetron (WO 94/01095). The latter compound is, moreover, known to decrease rectal motoricity (Aliment. Pharmacol. Ther. (1993), 7, 175-80) and other 5-HT.sub.3 antagonists, such as ondansetron (Dig. Dis. Sci. (1990), 35, 477-80), are known to slow down colic transit.
The N-cyclohexylbenzamides described in EP 0,507,672, in contrast to compounds such as granisetron, do not possess an effect with respect to 5-HT.sub.3 receptors.
The Applicant Company has now discovered that certain compounds described in EP 0,507,672 have the property of increasing the threshold for perception of pain of visceral origin.
The Applicant Company has also discovered that these same compounds possess an anti-inflammatory effect with respect to a model for ulcerative colitis.
These compounds correspond to the general formula ##STR2## in which R.sub.1 is a linear, branched or cyclized C.sub.1 -C.sub.5 alkyl radical and alkyl radical, a hydroxyl radical, a C.sub.1 -C.sub.5 alkoxy radical
The presence of two asymmetric centres means that the formula I encompasses four stereoisomers. The compounds used in the invention have the 2R absolute configuration, the preferred compounds having the 1R, 2R absolute configuration. The racemic compounds with the cis relative configuration (which are equimolar mixtures of the 1R, 2R and 1S, 2S enantiomers) contain the active isomer and can therefore be used in the invention. Likewise, the racemic compounds with the trans relative configuration (which are equimolar mixtures of the 1S, 2R and 1R, 2S enantiomers) can also be used in the invention.
The particularly preferred compounds are those corresponding to the formula I where R.sub.1 is a methyl or cyclopropylmethyl radical, R.sub.2 is a methyl radical and R.sub.3 is a hydrogen atom.
The compounds of formula I can be prepared by synthetic methods described in EP 0,507,672, by condensing the benzoic acids of the general formula II with the diamines of general formula III exhibiting the desired stereochemistry ##STR3##
The racemic diamines III with the cis relative configuration are prepared, according to the synthetic route described in EP 0,507,672, from (cis)-2-(trifluoroacetamido)cyclohexanecarboxylic acid.
The diamine III where R.sub.2 .dbd.H and R.sub.3 .dbd.CH.sub.3, with 1R, 2R absolute configuration, has also been described in EP 0,507,672.
The diamine III where R.sub.2 .dbd.H and R.sub.3 .dbd.CH.sub.3, with 1S, 2R absolute configuration, has been prepared from the amino ester IV (itself obtained according to the method described in Tetrahedron Letters (1984), 25, 2557-2560) according to the following series of reactions: ##STR4##
The subject of the present invention is therefore the use of the compounds of formula I or of their pharmaceutically acceptable salts for the manufacture of a medicament intended for the treatment of pain of visceral origin, in particular pr
REFERENCES:
patent: 5273973 (1993-12-01), Christinaki et al.
by N.W. Read et al., "The Importance of 5-Hydroxytryptamine Receptors in the Gut", Pharmac. Ther., vol. 62, No. 1-2, 1994, pp. 159-173.
by N.J. Talley, "5-Hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications", Aliment. Pharmacol. Ther., vol. 6, No. 3, 1992, pp. 273-279 .
Bouyssou Thierry
Christinaki Helene
Renaud Alain
Jarvis William R. A.
Laboratoires Jacques Logeais
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