−E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperid...

Details −E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperid... −E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperid...

1999-11-10

2002-08-27

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S192000

Reexamination Certificate

active

06440997

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to (−)E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine, its salts, and their use as antidiarrhoeal medicaments in man.
PRIOR ART
The secretory anomalies of the gastro-intestinal tract are responsible, with motor disorders, for the majority of chronic or acute diarrhoeas which, in 1990, were estimated to be the second cause of global mortality, especially in child populations of developing countries.
Chronic diarrhoeas are defined by their generally persistent duration of over two weeks. Their known mechanisms and the diagnostic strategy to be adopted in view of these cases has been documented by M. CERF —Gastroenterol. Clin. Biol, 1992, 16, T 12-T 21. and more recently by M. J. G. FARTHING—Eur. J. of Gastroenterol. & Hepatol. 1996, 8:157-167. The acute diarrhoeas, a great majority of which are of infectious origin, have likewise been documented by M. CERF and M. HAGIAGE: Diarrhées aiguës d'origine infectieuse (Acute diarrhoeas of infectious origin),—Editions Techniques—Encycl. Méd. Chir. (Paris-France), Gastro-entérologie, 9061 A
10
, 1992, 20pp.; and H. L. DuPONT—Review article: infectious diarrhoea—Aliment. Pharmacol. Ther. 1994; 8: pp.3-13. Among other causes, the important role of toxinogenesis during bacterial infection is discussed, and, especially, the expression of the pathogenic capacity by the synthesis of thermolabile or thermostable cytotoxins and enterotoxins, which are responsible for secretory diarrhoeas with a hydroelectrolytic component, and whose representative physiopathological model is that of cholera. Other infectious agents are known to cause diarrhoeas of this type, such as
Salmonella, Escherichia Coli
(
E. coli
) and
Clostridium difficile
(
C. difficile
) strains.
These latter agents, and more particularly
C. difficile
, are responsible for chronic and abundant secretory diarrhoeas, often of nosocomial origin, in subjects submitted to an intensive antibiotic therapy such as HIV positive patients. In the latter, the particularly incapacitating diarrhoeas are often associated with malabsorption, and contribute to the rapid development of an alarming state of denutrition.
For the treatment of secretory diarrhoeas, rehydration of the patients is recommended and sometimes turns out to be essential. Some compounds have been shown to be active (phenothiazine, chlonidine, bismuth salts) but their sensitive employment because of their secondary effects has led to their generalization being abandoned. The usual symptomatic treatments call for adsorbent compounds (Fuller's earth), modulators of the intestinal flora and, very widely, compounds called retardants, which are morphinomimetic antidiarrhoeals: loperamide (INN) and diphenoxylate (INN), known inhibitors of the motility of the GI tract: and, in fact, of controversial if not inadvisable utility for certain ailments, among other reasons through the delay which they contribute to the natural evacuation of pathogenic bacteria.
More recently, it has been proposed to treat these diarrhoeas with acetorphan (INN), a synthetic enkephalinase inhibitor dipeptide with antisecretory effect, which maintains the effect of enkephalins, antisecretory endogenous neuropeptides of the intestinal wall, which are normally rapidly hydrolysed in vivo by the enkephalinases which makes their effect fleeting.
As far as the therapy of diarrhoeas of patients infected with HIV is concerned, it is frequently necessary to resort to serious methods, which can only be carried out in an inpatient environment, such as rehydration and renutrition by the enteral or parenteral routes, which are combined with the symptomatic antidiarrhoeal treatment and an antibiotic therapy directed against the possible pathogenic agent. The usual antidiarrhoeal agents only have, most often, a relative and episodic efficacy. Recently, for these ciiarrhoeas and, more generally, cases resistant to conventional therapy, peptides inhibiting motility and gastrointestinal secretion related to somatostatin have been proposed (M. CAMILLERI—Digestion 1996;57 (suppl 1): 90-92 and M. J. G. FARTHING—Digestion 1996;57 (suppl 1): 107-113). Substitute synthetic compounds for this endogenous mediator are octreotide (INN) and valtreotide (INN), both octapeptides proposed with some success for the treatment of secretory diarrhoeas of AIDS. Although their duration of action is considerably longer than that of somatostatin, these expensive compounds are only active by repeated administration parenterally which leads to prohibitive treatment costs and, because of their mode of administration, makes their use virtually impossible in an outpatient environment. In addition, their lack of specificity, which has been pointed out, can involve secondary effects which dramatically aggravate the state of denutrition of the patients (disorders of the regulation of hydrocarbon metabolism and increase in steatorrhoea).
In addition, certain compounds defined as specific ligands for sigma receptors have shown antisecretory properties suggesting their use in the treatment of diarrhoeas. Thus (+)-N-cyclopropylmethyl-N-methyldiphenyl-1,4-ethyl-1-buten-3-yl-1-amine, or igmesine (INN), and its hydrochloride are disclosed among other compounds in European Patent 0 362 001. The compounds of this patent are defined in vitro as specific ligands for sigma receptors and shown, in vivo, in rats, to be inhibitors of amnesic phenomena caused by scopolamine, and inhibitors of gastroduodenal ulcers caused by the administration of cysteamine, this last activity being connected with their capacity to increase the alkaline duodenal secretion in anaesth,etized animals. In the broad sense, the compounds of this patent are indicated as useful for the treatment of dysfunctions of the gastrointestinal tract such as disorders of peristalsis, of motility, the phenomena of gastro-oesophageal and gastroduodenal reflux as well as for gastric and gastroduodenal ulceration.
Subsequently to these studies, the sigma receptors, whose localization was known in the central nervous system and the immune system, have been demonstrated by F. ROMAN et al. in the gastrointestinal tract of the guinea-pig (Life Sciences 1988, 42, 2217-2222) and then of man (Gastroenterology 1991, 100, A662).
In connection with these localizations, various experiments, among others by J. L. JUNIEN et al. (Neuropharmacology, Volume 30, No. 10, October 1991, pp. 1119-1124) have demonstrated the inhibitory action of igmesine on colonic hypermotility induced by stress via the corticotropin releasing hormone (CRH or CRF) in man. In addition,, P. RIVIERE et al. (Gastroenterol. Clin. Biol. 1991, 15 (2B), A70) show in vitro that igmesine modifies the transmembrane ionic transport through portions of mouse jejunum. This effect, antagonized by haloperidol, involves the participation of sigma receptors. V. J. CARLISI et al. (FASEB J. 1992, 6 (4), A1287) studied the effect of igmesine in vivo in mice, in a model of inflammatory diarrhoea caused by PGE
2
: at a dose of 30 mg/kg, igmesine, co-administered by the i.p. route with PGE
2
, delayed by approximately 15 min the appearance of the diarrhoea, an inhibitory effect antagonized by haloperidol, and which, tested for by the oral route, turned out to be zero at a dose of 60 mg/kg. More recently, G. SHI et al. (UEGW 1996—Paris—abstract No. 0786) showed the effect of igmesine at a dose of 200 mg p.o. in man on intestinal hypersecretion induced by PGE
2
.
On the other hand, the application WO 95/15948 discloses derivatives of 2-arylalkenylazacycloalkanes as ligands for sigma receptors, a process for their preparation and their application in therapeutics. The compounds, their isomers and their addition salts are proposed for the preparation of antipsychotic medicaments and are useful in gastroenterology. The experimental section describes in Example 2E racemic E-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine and its hydrochloride and, in addition, mentions without specific experimental results that the compounds of the application are

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