WO1998039295A1 - (r)n-(1-cyclopropylmethylpyrrolidine-2-ylmethyl)benzamide et son utilisation comme antidiarrheique - Google Patents

(r)n-(1-cyclopropylmethylpyrrolidine-2-ylmethyl)benzamide et son utilisation comme antidiarrheique Download PDF

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Publication number
WO1998039295A1
WO1998039295A1 PCT/EP1998/001562 EP9801562W WO9839295A1 WO 1998039295 A1 WO1998039295 A1 WO 1998039295A1 EP 9801562 W EP9801562 W EP 9801562W WO 9839295 A1 WO9839295 A1 WO 9839295A1
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WO
WIPO (PCT)
Prior art keywords
benzamide
ylmethyl
cyclopropylmethylpyrrolidin
formula
compounds
Prior art date
Application number
PCT/EP1998/001562
Other languages
English (en)
Inventor
Alain Calvet
Maria Chovet
Svein G. Dahl
Henry Jacobelli
Jean-Louis Junien
Pierre Riviere
Vassilia Theodorou
Original Assignee
Jouveinal
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jouveinal filed Critical Jouveinal
Priority to AU67302/98A priority Critical patent/AU6730298A/en
Publication of WO1998039295A1 publication Critical patent/WO1998039295A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • the invention relates to (R) N- (1-cyclopropyl- methylpyrrolidin-2-ylmethyl) benzamide and the (R,S) racemate corresponding to it, their 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 for 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-
  • thermolabile or thermostable cytotoxins and enterotoxins which are responsible for secretory diarrhoeas with a hydroelectrolytic component whose representative physiopathological model is that of cholera.
  • Other infectious agents are known to cause diarrhoeas of this type, such as Salmonella , Escherichia coll and Clostridium difficile strains.
  • adsorbent compounds Fluler'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.
  • 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.
  • acetorphan 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.
  • Patent FR 2 294 698 describes 2-methoxy-benzamide derivatives useful in the treatment of nervous and psychosomatic conditions and of formula: in which more particularly:
  • - n is an integer equal to 1
  • Certificate of addition FR 2 327 771 is directed at enantiomers corresponding to the compounds of the main Patent FR 2 294 698. • A second Certificate of addition FR 2 394 529 is directed at compounds, in their racemic and enantiomeric forms, which can be used in the treatment of conditions of the central nervous system region and of formula:
  • Patent FR 2 418 226 is directed at 2-methoxy-5- alkylthiobenzamides, which are racemic or enantiomeric, active in the central nervous system region and of formula:
  • n is equal to 1, 2, 3 or 4.
  • m is equal to 2 , 3 or 4
  • n is equal to 1, 2, 3 or 4
  • the Application EP 207 913 is directed at racemic catechol benzamides or optical isomers of formula:
  • R 3 is a cycloalkyl group, which are compounds useful in the treatment of emesis, of anxiety states, of psychosomatic illnesses such as schizophrenia and depression, illnesses relative to alcoholism, states of confusion and sleep disorders in elderly people.
  • the Applicant indicates that it prefers for the enantiomers the compounds of (S) configuration when R 3 is alkyl or alkenyl and those of (R) configuration when R 3 is phenyl or substituted phenyl.
  • the Patent FR 2 593 504 is directed at dihydrobenzofuran and chromancarboxamide derivatives, which are racemic or enantiomeric, of neuroleptic activity and of formula:
  • R 3 is cycloalkylalkyl
  • the Application FR 2 678 266 is directed at racemic and optical isomer derivatives of 2-hydroxy-4-amino-5- ethylsulfonylbenzamides, useful as anxiolytics and of formula:
  • This oxygen radical turns out to be essential for activity on the central nervous system, which activity, for the enantiomers is preferential of the (S) configuration when the substituent in position 1 of the pyrrolidine is lower alkyl or cycloalkylalkyl, and is preferential for the
  • the present invention differs radically from this prior art in proposing, as useful medicament for the treatment of secretory diarrhoeas, a novel benzamide which is not substituted in the ortho position by an oxygen atom, and for which in contrast to what is taught, the activity is preferential for the enantiomer of (R) configuration although the substituent radical in position 1 of the pyrrolidine is cyclopropylmethyl.
  • a subject of the invention is (R) N- (l-cyclopropylmethylpyrrolidin-2- ylmethyl) benzamide of formula (I),
  • the invention is directed by way of novel products at (R) N- (l-cyclopropyl-methylpyrrolidin-2- yl ethyl) benzamide of formula (I), the (R,S) racemic compound (I 1 ) which corresponds to it, and their addition salts with pharmaceutically acceptable acids.
  • an optically pure quality is preferred for the (R) eutomer, that is to say that the product is virtually free of its (S) antipode and is at least of an optical purity of 95% and preferably equal f to or greater than 98% of (R) eutomer, this being determined by appropriate analytical means.
  • Racemate is conventionally understood as meaning the compound comprising the (R) and (S) enantiomers in equal parts. However, the compounds comprising a mixture in which the (R) eutomer is in a quantity greater than 50% are considered an integral part of the invention.
  • addition salts are understood as meaning those mineral or organic salts, including their possible iso ers, shown to be non-toxic in the customary therapeutic doses of which, for example, a list is presented in J. Phar . Sci., 1977, vol. 66, pp. 1- 19.
  • acetic, benzenesulphonic, camphorsulphonic , citric, ethanesulphonic, hydrobromic, lactic, maleic, malic, methanesulphonic, mucic, nitric, pamoic, phosphoric, salicylic, stearic, succinic, sulphuric or tartaric acid are used, and hydrochloric acid, which is preferred.
  • Another aspect of the invention relates to a process for the preparation of (R) N- (1-cyclopropylmethylpyrrolidin- 2-ylmethyl) benzamide of formula (I) and its (R,S) racemate (I 1 ) which consists in carrying out an N-substitution of the pyrrolidine radical of the (R) eutomer or of the (R,S) racemate of N- pyrrolidin-2-ylmethylbenzamide (II) , either by alkylation with a halomethyl-cyclopropane, preferably bromomethylcyclo-propane , or by reductive alkylation with cyclopropanecarboxaldehyde in the presence of a reducing agent, or alternatively in carrying out an acylation by the chloride, an anhydride or a cyclopropanecarboxylic acid ester and then in reducing the cyclopropanecarboxamide intermediate with an appropriate reducing agent or, - in carrying out the benzoylation of
  • the preferred processes employed consist in carrying out the N-substitution of the pyrrolidine radical of the (R) eutomer or of the (R,S) racemate of N-pyrrolidin- 2-ylmethylbenzamide (II) by alkylation with bromomethylcyclopropane and, particularly preferably, in carrying out the benzoylation of the (R) eutomer or of the (R,S) racemate of 2-aminomethyl-l-cyclopropylmethyl- pyrrolidine (III) by benzoyl chloride as described in scheme
  • the N-substitution reaction of the intermediates (II) by alkylation with bromomethylcylopropane consists in treating the reagents in equimolar ratio at a temperature from 20°C to the reflux temperature of the reaction solvent which is chosen from acetone, alcohols of low molecular weight, dimethylformamide (DMF) , dimethylsulphoxide (DMSO) or acetonitrile, which is preferred, optionally in the presence of an inorganic base, such as an alkali metal carbonate, or alternatively an organic base such as triethylamine.
  • the reaction solvent which is chosen from acetone, alcohols of low molecular weight, dimethylformamide (DMF) , dimethylsulphoxide (DMSO) or acetonitrile, which is preferred, optionally in the presence of an inorganic base, such as an alkali metal carbonate, or alternatively an organic base such as triethylamine.
  • the benzoylation of an intermediate (III) consists in reacting it with 1.0 to 1.25 mol of benzoyl chloride at a temperature of between 20 °C and the reflux temperature of the reaction solvent which is chosen from diethyl ether, tetrahydrofuran (THF) , dichloromethane, chloroform, toluene and, preferably, in the presence of an organic base such as triethylamine in equimolar quantity to the benzoyl chloride.
  • THF tetrahydrofuran
  • dichloromethane dichloromethane
  • chloroform chloroform
  • toluene preferably, in the presence of an organic base
  • organic base such as triethylamine in equimolar quantity to the benzoyl chloride.
  • the compounds (I) , (!') / an ⁇ the mixtures of enantiomers included in the invention in which the (I) eutomer is in a proportion greater than 50%, and their salts have outstanding pharmacological properties, indicative of their utility, in the form of medicaments, for the treatment of diarrhoea, especially secretory diarrhoeas in man.
  • the eutomer (I) appears to be at least three times more active than its antipode of (S) configuration orally in mice, in the model of secretory diarrhoea caused by Salmonella lipopolysaccharide (LPS) , a model in which the (S) antipode has a limited maximum inhibitory effect, whatever the dose, at approximately 30%.
  • LPS Salmonella lipopolysaccharide
  • thermostable toxin of E . coli and the toxins A and B of C . difficile when compared to the compounds declared capable or potentially capable of treating secretory diarrhoeas, the (I) eutomer which is the subject of the invention turns out, without thereby acting on transit:
  • the compound (I) shows a remarkable inhibitory activity on intestinal secretion induced in rats by the cholera toxin.
  • compositions according to the invention which contain a therapeutically efficacious quantity of the eutomer (I), of the racemate (I') or of one of their salts, are appropriate for the treatment of diarrhoeas which may be commonplace, such as those of infants or of travellers, and which may be acute and/or persistent and of varying etiology in which the secretory component can just as well result from a decrease in absorption as from intestinal hypersecretion.
  • the compounds according to the invention are indicated for the treatment of diarrhoeas of inflammatory origin (Crohn's disease, post-radiotherapy enterites) , of obstructions by lymphoid hyperplasia or alternatively of anti-cancer chemotherapy.
  • compositions are appropriate for the symptomatic treatment of hypersecretory diarrhoeas such as those following neuroendocrinal tumour conditions (Zollinger-Ellison syndrome, VIPoma, somatostatinoma, carcinoid syndrome) , of HIV, viral or bacterial infections, or even of congenital dysfunctions or those caused by cathartic drugs, and during hypersecretions of intestinal inflammatory syndromes.
  • hypersecretory diarrhoeas such as those following neuroendocrinal tumour conditions (Zollinger-Ellison syndrome, VIPoma, somatostatinoma, carcinoid syndrome)
  • HIV HIV
  • viral or bacterial infections or even of congenital dysfunctions or those caused by cathartic drugs
  • the product is administered in various pharmaceutical forms containing in unit form from 2.5 to 50 mg of the eutomer (I) or of its racemate (I 1 ) or of one of their salts, especially of the hydrochloride, it being possible for the latter to be present in crystallized or amorphous form or alternatively to be prepared for immediate use during the production of the pharmaceutical forms, which can be, for non-limiting examples, tablets, coated tablets, capsules, powders, solutions, suspensions or gels.
  • the compound (I) or a congener, in salt form or not in salt form can represent from 1 to 90% by weight of the finished form, the pharmaceutically acceptable excipients representing from 99 to 10%.
  • the active principle can represent from 0.1 to 10% by weight, of the finished form for a liquid phase representing from 99.9 to 90% by weight.
  • the mixture is stirred at 20-25 °C for 1 hour and then extracted successively with 100 ml of 10% ammonia, 100 ml of water, 100 ml of 10% HC1, 100 ml of water, 100 ml of saturated sodium bicarbonate solution and finally 100 ml of water .
  • IR (KBr) 3300, 2750, 1640, 1540, 1310, 1290, 1180, 1140, 1020, 920, 830, 700, 680, 540cm ""1 .
  • the solution is stirred for 30 minutes at 20-25°C and then warmed and held at reflux for 40 minutes.
  • the mixture is concentrated in vacuo.
  • the residue is dissolved in 200 ml of chloroform.
  • the addition of 350 ml of ether causes the precipitation of the hydrochloride, which is filtered and dried.
  • the solution is stirred for 1 h 30 at 20-25°C and then extracted by successive fractions of 350 ml of 10% ammonia, water, 10% HCl, and then water.
  • the hydrochloric phase and the last aqueous phase are combined, alkalinized by NaOH and extracted with ether.
  • the combined ether phases are dried and the ether is removed by distillation.
  • the residue (31.0 g) is purified by rapid chromatography on a silica column. Elution with dichloromethane progressively concentrated in methanol allows 14.0 g of purified product to be obtained, which are recrystallized in 400 ml of boiling hexane.
  • IR(KBr) 3300, 2750, 1640, 1540, 1310, 1290, 1180, 1140, 1020, 920, 830, 700, 680, 540cm "1 .
  • mice In animals, the toxicity study was carried out in mice by the oral route. No mortality was noted up to the strongest dose studied, namely 300 mg/kg.
  • Example 3 In vitro pharmacological studies i) - affinity for sigma receptors The study of the capacity for interaction with the sigma receptors of the eutomer, which is the subject of the invention, and of its antipode was carried out by the determination of their binding to a rat brain membrane preparation, previously loaded with a labelled ligand specific for sigma receptors, in this case (+)[3H]-SKF 10,047. The technique used is that described by Largent, B.L. et al. in J. Pharmacol. Exp. Ther. , 1986, vol. 238, pp. 739-748.
  • the eutomer (I) of the invention does not show any affinity, the IC 50 in each test being greater than 10,000 nM.
  • Example 4 In vivo pharmacological studies 4-1) - inhibition of experimental toxigenic diarrhoeas Protocols a) diarrhoea induced by Salmonella lipopolysaccharides : The test is carried on mice according to a working procedure, instigated by M.J. CANCIO et al., Gastroenterology Nov. 1992, 103 (5), 1437-43, which in the rat induces, by an endotoxin, alterations in the transport of water and of electrolytes at the colon level.
  • dBA 2 male mice (Iffa-credo, les Oncins, France) weighing between 20 and 25 g are placed in individual cages.
  • the test product is administered by the oral route in solution or in aqueous suspension and then after one hour (t 0 of the test) an injection of lipopolysaccharides (LPS) of Salmonella enteriditis (Sigma 73. product - ref. L6761) is carried out in the tail vein at a rate of 15 mg/kg.
  • LPS lipopolysaccharides
  • Salmonella enteriditis Sigma 73. product - ref. L6761
  • a preweighed filter paper is then placed under each cage and the weight of faeces eliminated by the animals over two hours (t 120 ) is determined.
  • the effect of the test product is determined and is expressed as a percentage of inhibition of the weight of faeces at the dose considered with respect to the weight of faeces of a * batch of control animals only having received LPS under the same conditions.
  • the faeces are recovered as soon as voided and are brought together by periods of 30 min, for 120 min.
  • the faeces thus brought together are weighed before (fresh weight) and after (dry weight) drying at 120 °C for 24 h.
  • the quantity of water present in the faeces is calculated as the difference (fresh weight - dry weight) .
  • thermostable toxin of Escherichia coli (Sigma, E5763) is administered by the oral route at time zero in a dose of 600 U/mouse.
  • the animals of the control batch receive, at time zero, an oral administration of physiological serum.
  • the administration of the test products is carried out by the oral route one hour before the administration of the toxins.
  • the results are expressed as the quantity of faecal water amassed at the time 120 min and allow the ED 50 of the compounds to be calculated, which is the effective dose allowing 50% of weight of water of the faeces to be inhibited under the action of the test product.
  • the experimental protocol, the calculation and the expression of the results are identical to those described above.
  • the A and B toxins of Clostridium difficile are administered by the oral route at time zero at a dose of 6 ng/mouse.
  • mice Female Wistar rats (160-180 g) are made to fast from solid food 24 h before the test. At time zero, the animals receive 0.1 mg/kg p.o. of cholera toxin (Sigma, C3012). Three hours later, the animals are sacrificed. After median laparotomy, the intestine is ligated at the level of the pylorus and the ileocaecal junction, removed (from the duodenum to the caecum) , and weighed full and then empty. The test products are given orally 1 h before administration of the cholera toxin.
  • the results are expressed as weight of intestinal contents, the ED 5 o' being the dose allowing the weight of the intestinal contents to be inhibited by 50% under the action of the test product.
  • the eutomer (I) shows an ED 5 o of 0.017 mg/kg.
  • the active principle is mixed into the lactose and then granulated with the HPMC in solution.
  • the grains are dried and screened on a grid of 1 mm mesh.
  • the CMC and the silica are mixed and then added to the granules.
  • the mixture is then mixed intimately with the magnesium stearate and then compressed at a rate of 120 mg per scored tablet.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le (R)N-(1-cyclopropylméthylpyrrolidine-2-ylméthyl)benzamide selon la formule (I), son mélange racémique (R,S) et leurs sels d'addition avec des acides pharmaceutiquement acceptables. L'invention concerne leur utilisation comme antidiarrhéiques chez le mammifère.
PCT/EP1998/001562 1997-03-05 1998-03-04 (r)n-(1-cyclopropylmethylpyrrolidine-2-ylmethyl)benzamide et son utilisation comme antidiarrheique WO1998039295A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU67302/98A AU6730298A (en) 1997-03-05 1998-03-04 (r)n-(1-cyclopropylmethylpyrrolidin-2-ylmethyl)benzamide and its use as an antidiarrhoeal

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR97/02714 1997-03-05
FR9702714A FR2760454B1 (fr) 1997-03-05 1997-03-05 (r) n-(1-cyclopropylmethyl-pyrrolidine-2ylmethyl)-benzamide et son utilite comme antidiarrheique

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WO1998039295A1 true WO1998039295A1 (fr) 1998-09-11

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AU (1) AU6730298A (fr)
FR (1) FR2760454B1 (fr)
WO (1) WO1998039295A1 (fr)
ZA (1) ZA981850B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6787563B2 (en) 2001-12-21 2004-09-07 Pfizer Inc. Crystalline 3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2447910A2 (fr) * 1979-02-05 1980-08-29 Synthelabo Methoxy-2 alkylthio-5 benzamides et leur application en therapeutique
FR2447911A1 (fr) * 1979-02-05 1980-08-29 Synthelabo Benzamides et leur application en therapeutique
FR2578539A1 (fr) * 1985-03-08 1986-09-12 Therapeutiques Ste Monega Et Nouveaux benzamides de l'acide 2,4,6-trimethoxybenzoique, leur procede de preparation et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2447910A2 (fr) * 1979-02-05 1980-08-29 Synthelabo Methoxy-2 alkylthio-5 benzamides et leur application en therapeutique
FR2447911A1 (fr) * 1979-02-05 1980-08-29 Synthelabo Benzamides et leur application en therapeutique
FR2578539A1 (fr) * 1985-03-08 1986-09-12 Therapeutiques Ste Monega Et Nouveaux benzamides de l'acide 2,4,6-trimethoxybenzoique, leur procede de preparation et leur utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
T. HÖGBERG ET AL.: "Potential antipsychotic agents. Synthesis and stereoselective dopamine D-2 receptor blockade of a potent class 0f substituted (R)-N-[(1-benzyl-2-pyrrolidinyl)methyl]benzamides. Relations to other side chain congeners.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 34, no. 3, 1991, WASHINGTON US, pages 948 - 955, XP002047331 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6787563B2 (en) 2001-12-21 2004-09-07 Pfizer Inc. Crystalline 3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate

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AU6730298A (en) 1998-09-22
ZA981850B (en) 1998-09-07
FR2760454A1 (fr) 1998-09-11
FR2760454B1 (fr) 1999-04-30

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