Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-12-13
2004-09-07
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S579000
Reexamination Certificate
active
06787563
ABSTRACT:
This application claims priority from French patent application number 0116785 of Dec. 21, 2001.
The invention relates to novel substituted N-(cyclopropylmethyl)azacycloalkanes, their salts, the pharmaceutical compositions containing them, their use as antidiarrhoeal medicaments and methods for their preparation.
The secretory abnormalities of the digestive apparatus are, with motility disorders, responsible for the majority of chronic or acute diarrhoeas which, in 1990, were estimated to be the second cause of mortality worldwide, in particular in infant populations of developing countries.
Chronic diarrhoeas are defined by their persistent duration generally of over two weeks. Their various aetiologies and the action to be taken in this group of pathologies have been documented in particular by M. Cerf,
Gastroenterol. Clin. Biol,
1992, 16: T 12-T 21. and by M. J. G. Farthing,
Eur. J. of Gastroenterol
. &
Hepatol.
1996, 8:157-167.
Acute diarrhoeas, which are, in the great majority, of infectious origin, have also been documented by M. Cerf and M. Hagiage: Diarrhées aiguës d'origine infectieuse [Acute diarrhoeas of infectious origin].
Éditions Techniques—Encycl. Méd. Chir
. (Paris, France), Gastro-entérologie, 9061 A10, 1992, 20p.; and H. L. Dupont, Review article: Infectious diarrhoea—
Aliment. Pharmacol. Ther.
1994; 8: 3-13. Among other causes, the important role of toxinogenesis during bacterial infection is acknowledged, and, in particular, the expression of the pathogenicity by the synthesis of cytotoxins and of enterotoxins, which are responsible for secretory diarrhoea with a water-electrolyte component; the representative physiopathological model is that of cholera diarrhoea.
Other infectious agents are known to cause such diarrhoeas, such as Salmonella,
Escherichia coli
and
Clostridium difficile
strains. The latter agents, and more particularly
C. difficile
, are responsible for chronic and abundant secretory diarrhoeas, often of nosocomial origin, in subjects subjected to an intensive antibiotic therapy such as patients who are seropositive for HIV. In the latter, the particularly incapacitating diarrhoeas are often associated with malabsorption, and contribute towards rapidly establishing an alarming state of undernourishment. They can also represent an undesirable effect of the antiviral treatments to which these patients are subjected. In the symptomatic treatment of secretory diarrhoeas, rehydration of the patients is recommended and sometimes proves essential.
Certain compounds (phenothiazine, clonidine, bismuth salts) have proved active in the treatment of secretory diarrhoeas, but their delicate use because of their side effects has led to their widespread use being abandoned.
The usual treatments involve adsorbent compounds (smectite), modulators of the intestinal flora and, very widely, so-called slowing compounds, which are morphinomimetic antidiarrhoeals: loperamide and diphenoxylate; the latter products are agents for slowing digestive tube transit and, for this reason, of disputed if not inadvisable usefulness for certain conditions because of the delay which they bring about in the natural evacuation of pathogenic microorganisms and their toxins.
More recently, it has been proposed to treat these diarrhoeas with acetorphan, a synthetic dipeptide, with antisecretory effect, an enkephalinase inhibitor, and therefore which maintains the effect of enkephalins; the enkephalins, antisecretory endogenous neuropeptides of the intestinal wall, are normally rapidly hydrolysed in vivo by enkephalinases, which makes their effect transient.
As regards the therapy of diarrhoeas in patients infected with HIV, it is frequently necessary to have recourse to cumbersome methods, which can only be performed in a hospital setting, such as rehydration and renourishment by the enteral or parenteral routes, with which a symptomatic antidiarrhoeal treatment and an antibiotic therapy directed against the possible pathogenic agent are combined. The usual antidiarrhoeals most often have only a relative and episodic efficacy. Recently, for these diarrhoeas and more generally for the cases refractory to conventional therapies, peptides inhibiting gastrointestinal motility and 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). Synthetic compounds which are substitutes for this endogenous mediator are octreotide and valtreotide, 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 through repeated administration by the parenteral route, which leads to prohibitive treatment costs and makes their use practically impossible in an outpatient department. Furthermore, their lack of specificity can cause side effects which dramatically aggravate the state of undernourishment of the patients (disorders in the regulation of the metabolism of carbohydrates and an increase in steatorrhoea).
International Application WO 95/15948 describes 2-(arylalkenyl)azacycloalkane derivatives, their method of preparation and their therapeutic application. These compounds are proposed for the preparation of antipsychotic medicaments and are useful in gastroenterology. Racemic (E)-2-(3,4-dichlorocinnamyl)-1-cyclopropylmethylpiperidine and its hydrochloride are described in Example 2E and, moreover, it is stated therein that the compounds of the application are active on secretory diarrhoeas induced in mice by the salmonella lipopolysaccharide (LPS), which suggests their usefulness in the treatment of secretory diarrhoeas of diverse aetiologies.
In International Application WO 98/39296 (S)-1-cyclopropylmethyl-2-[(E)-3-(3,4-dichlorophenyl)allyl]piperidine, its addition salts and their use in the preparation of pharmaceutical compositions intended for the treatment of diarrhoeas are described.
The present invention now provides novel compounds for the treatment of gastrointestinal disorders, in particular diarrhoeas. The invention thus relates to N-(cyclopropylmethyl)azacycloalkanes of the following general formula I:
in which R
1
is hydrogen or halogen, R
2
is hydrogen or halogen and X is methylene or ethylene.
In the present description the expression halogen is understood to mean fluorine, chlorine, bromine and iodine.
The present invention includes the individual enantiomers of the compounds having formula I and mixtures thereof. Separation of the racemate into the enantiomers can be carried out by methods known in the art.
Among the particularly preferred compounds of the present invention are the following compounds:
1-cyclopropylmethyl-2-(3-phenylpropyl)pyrrolidine;
(2R)-1-cyclopropylmethyl-2-(3-phenylpropyl)pyrrolidine;
1-cyclopropylmethyl-2-(3-phenylpropyl)piperidine, and
(2R)-1-cyclopropylmethyl-2-[3-(3,4-dichlorophenyl)propyl]piperidine.
The invention also relates to a pharmaceutical composition comprising at least one compound of general formula (I) as defined above, in combination with a pharmaceutically acceptable carrier.
The invention also relates to the use of an N-(cyclopropylmethyl)azacycloalkane of general formula (I) as a medicament.
The invention also relates to the use of an N-(cyclopropylmethyl)azacycloalkane of general formula (I) for the preparation of a medicament intended for the prevention and treatment of gastrointestinal conditions, particularly diarrhoeas in mammals, in particularly humans.
The invention thus provides a method for treating a patient suffering from a gastrointestinal condition, in particular diarrhoea, by administering a therapeutically effective amount of an N-(cyclopropylmethyl)azacycloalkane of general formula (I).
Among the diarrhoeas requiring a treatment according to the invention are those observed during irritable bowel syndrome (IBS), a particularly frequent digestive functional disorder.
The compounds used in the invention in
Benson Gregg C.
Lee Christine S.
Morris Patricia L.
Pfizer Inc.
Richardson Peter C.
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