WO1996033186A1 - Derives de dihydrobenzofurane substitues utilises en tant qu'agonistes de 5-ht¿4? - Google Patents

Derives de dihydrobenzofurane substitues utilises en tant qu'agonistes de 5-ht¿4? Download PDF

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Publication number
WO1996033186A1
WO1996033186A1 PCT/EP1996/001482 EP9601482W WO9633186A1 WO 1996033186 A1 WO1996033186 A1 WO 1996033186A1 EP 9601482 W EP9601482 W EP 9601482W WO 9633186 A1 WO9633186 A1 WO 9633186A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
amino
alkyl
furan
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Application number
PCT/EP1996/001482
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English (en)
Inventor
Daniele Fancelli
Carla Caccia
Dino Severino
Fabrizio Vaghi
Mario Varasi
Original Assignee
Pharmacia & Upjohn S.P.A.
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 Pharmacia & Upjohn S.P.A. filed Critical Pharmacia & Upjohn S.P.A.
Priority to JP8531446A priority Critical patent/JPH10502095A/ja
Priority to EP96912004A priority patent/EP0766680A1/fr
Publication of WO1996033186A1 publication Critical patent/WO1996033186A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to the use of substituted dihydrobenzofuran derivatives which act as 5-HT 4 receptor agonists in the treatment of gastrointestinal disorders and CNS disorders, to certain novel compounds having 5-HT 4 receptor agonist activity, to a process for their preparation and to pharmaceutical compositions containing them.
  • a non classical 5-hydroxytriptamine receptor has been designed (Trends Pharmacol. Sci. (1992) 13, 141-5) as the 5-HT 4 receptor.
  • 5-HT 4 receptor agonists resulted active in appropriate animal behavioural tests for memory dysfunctions (Ghelardini et al. 19 th C.I.N.P. Congress, Whashington, June 1994 ; Ghelardini et al. 10 th European Society for Neurochemistry, Jerusalem, August 1994).
  • the compounds of the invention can be useful in all the pathologies wherein a stimulation of the 5-HT 4 receptors is needed and therefore, the compounds of the invention can be useful, for example, as therapeutic prokinetic agents in the treatment of gastrointestinal disorders such as, e.g., dyspepsia, gastro-oesophageal reflux disease (GORD) and gastroparesis, and/or also in the treatment of CNS disorders characterized by learning and/or memory dysfunctions.
  • GORD gastro-oesophageal reflux disease
  • the present invention relates to dihyrobenzofuran derivatives of formula (I)
  • R 1 , R 2 and R 3 are, each independently, hydrogen, C 1 -C 6 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, amino, C 1 -C 4 alkylamino or C 1 -C 4 di-alkylamino;
  • X is O, NH or CH 2 ;
  • Z is a group (a), (b), (c) or (d)
  • n 1, 2, 3 or 4;
  • n zero or 1;
  • q is zero, 1 or 2;
  • R 4 is hydrogen , C 1 -C 6 alkyl, benzyl, cyclohexylmethyl or -CH 2 -CH 2 -SO 2 NH-R 6 in which R 6 is C 1 -C 6 alkyl or benzyl;
  • R 5 is C 1 -C 6 alkyl
  • T is halogen
  • the compounds of formula (I) can therefore be useful in the treatment of all the pathologies wherein a stimulation of the 5-HT 4 receptor is needed.
  • the compounds of formula (I) may be useful as therapeutic prokinetic agents in the treatment of gastrointestinal disorders such as, for example, dyspepsia, gastro-oesophageal reflux disease (GORD) or gastroparesis.
  • GORD gastro-oesophageal reflux disease
  • the compounds of formula (I) may also be useful, by virtue of their 5-HT 4 agonist properties, as cognition activators, in the treatment of CNS disorders characterized by learning and/or memory dysfunctions.
  • the alkyl, alkoxy and alkylamino groups may be branched or straight groups.
  • C 1 -C 6 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert- butyl.
  • C 1 -C 4 alkoxy groups include methoxy and ethoxy.
  • a C 1 -C 4 alkylamino group is, in particular, methylamino or ethylamino.
  • a C 1 -C 4 di-alkylamino group is, in particular, dimethylamino or diethylamino.
  • Halogen includes fluorine, bromine, chlorine or iodine, in particular, chlorine or bromine.
  • the pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic, e.g. hydrochloric, hydrobromic, sulphuric, and phosphoric acids, or organic, e.g. acetic, propionic, lactic, oxalic, malic, maieic, tartaric, citric, benzoic, mandelic, salicylic and fumaric acids.
  • inorganic e.g. hydrochloric, hydrobromic, sulphuric, and phosphoric acids
  • organic e.g. acetic, propionic, lactic, oxalic, malic, maieic, tartaric, citric, benzoic, mandelic, salicylic and fumaric acids.
  • Examples of pharmaceutically acceptable salts of the compounds of formula (I) wherein Z is a group (a) or (b) include quaternary derivatives such as, e.g., the compounds quaternised by compounds of formula R x -W wherein R x is C 1 - C 6 alkyl or phenyl-Ci-Cgalkyl and W is a radical corresponding to an anion of an acid.
  • R x is C 1 -C 4 alkyl or phenyl-C 1 -C 4 alkyl, in particular it is methyl, ethyl, n-propyl, n -butyl, benzyl or phenylethyl.
  • W is a halide such as, e.g., chloride, bromide or iodide.
  • Examples of pharmaceutically acceptable salts of the compounds of formula (I) wherein Z is a group (a), (b) or (c) also include internal salts, such as, e.g. N-oxides.
  • the compounds of formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N- oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are also object of the present invention.
  • Compounds of formula (I) wherein Z is a group (c) contain an asymmetric carbon atom and, for this reason, they can exist either as a mixture of optical isomers (racemic mixture) or as a single optical isomers (enantiomers) .
  • the enantiomers can be separately synthesised from optically pure starting material or separated from the racemic mixture in a conventional manner.
  • the present invention also include within its scope both the metabolites and the pharmaceutically acceptable bio- precursors (otherwise known as pro-drugs) of the compounds of formula (I).
  • This invention also refers to a preferred class of compounds within formula (I), as novel compounds.
  • R 1 is hydrogen
  • X is O or NH
  • Z is a group (a), (b), (c) or (d):
  • n 2 or 3;
  • n zero or 1;
  • q 1 or 2;
  • R 4 is C 3 -C 5 alkyl or -CH 2 -CH 2 -SO 2 NH-CH 3 ;
  • R 5 is C 3 -C 5 alkyl
  • T is chlorine or bromine
  • Examples of preferred compounds according to the invention are the following: N-[1-butyl-1-azabicyclo[2,2,2]oct-3-yl]-4-amino-5-chloro- 2,3-dihydrobenzo[b]furan-7-carboxamide bromide;
  • the compounds of formula (I) can be obtained by a process comprising:
  • E is OH, Cl, Br or 1-imidazolyl
  • R 1 , R 2 and R 3 are, each independently, hydrogen, C 1 -C 6 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, amino, C 1 -C 4 alkylamino or C 1 -C 4 di-alkylamino,
  • Q is OH or NH 2 ;
  • n 1,2,3 or 4;
  • n 0 or 1
  • q 0,1 or 2;
  • R 4 is hydrogen, C 1 -C 6 alkyl, benzyl, cyclohexylmethyl or
  • R 6 is C 1 -C 6 alkyl or benzyl so obtaining a compound of formula (I) wherein R 1 , R 2 , R 3 and R 6 are as defined above, X is NH or O and Z is a group
  • Y is OH, Cl, Br or CH 3 -NH-OCH 3 , and
  • R 1 , R 2 and R 3 are as defined above,
  • M is MgBr, MgCl or Li
  • n, m, q, R 4 and R 5 are as defined above,
  • R 1 , R 2 , R 3 and X are as defined above, and
  • X is NH, O or CH 2 , with an alkyl halide of formula R 5 T wherein R 5 is C 1 -C 6 alkyl and T is halogen, so obtaining a compound of formula
  • CH 2 and Z is a group (d) ; and, if desired, when a compound of formula (I) contains an asymmetric carbon atom,
  • reaction of a compound of formula (II) with a compound of formula (III), (IV) or (V) under step A) is an analogy process and can be carried out according to well known methods in the art.
  • (II) can be reacted with an alcohol or an amine of formula (III), (IV) or (V) in a suitable organic solvent such as, for instance, dichloromethane, tetrahydrofurane or acetonitrile, at a temperature ranging from about 0°C to about the reflux temperature of the mixture, in the presence of a proton scavenger such as, for instance, t-riethylamine, sodium hydrogen carbonate or potassium carbonate.
  • a suitable organic solvent such as, for instance, dichloromethane, tetrahydrofurane or acetonitrile
  • reaction of a compound of formula (VI) with a compound of formula (VII), (VIII) or (IX) under step B) can also be carried out according to well known methods in the art.
  • an acyl halide of formula (VI) can be reacted with a Grignard reactive of formula (VII), (VIII) or (IX) in a suitable organic solvent such as, e.g., tetrahydrofuran or diethyl ether in the presence of, e.g., Fe (acetylacetonate) 3 or Cul, at a temperature ranging from about -78°C to about 30°C.
  • reaction of a compound of formula (X) with an alkyl halide R 5 T under step C) can be carried out according to standard methodologies.
  • a compound of formula (X) can be reacted with a compound R 5 T as defined above, in the presence of a suitable organic solvent such as, e.g., methanol or ethanol, at a temperature ranging from about 30°C to about the reflux temperature of the mixture.
  • a suitable organic solvent such as, e.g., methanol or ethanol
  • the acid derivatives (II) and (VI) are either known products (EP 0 234 872 Al Adria Laboratories Inc. ) or may be prepared from the corresponding acids by methods well known in the art.
  • the alcohols and amines of formulae (III), (IV) and (V) are either commercially available or known products.
  • the organometallic derivatives of formulae (VII), (VIII) and (IX) can be prepared by standard methodologies from the corresponding alkyl halides which are either commercially available products or can be easily prepared from the corresponding alcohols of formulae (III), (IV) and (V).
  • the compounds of formula (X) wherein X is NH are known compounds (EP 0 234 872 Al Adria Laboratories Inc.).
  • the alkyl halides of formula R 5 T are commercially available products.
  • the compounds of the present invention are potent agonists of 5-HT (serotonin) on 5-HT 4 receptors and can therefore be used in the treatment of the pathologies wherein a stimulation of the 5-HT 4 receptor is needed.
  • 5-HT 4 agonists are known being stimulant of gastrointestinal motility
  • the compounds of the present invention can be useful as therapeutic prokinetic agents, for example, in the treatment of gastrointestinal disease such as, for instance, dyspepsia, gastro-oesophageal reflux disease (GORD) or gastroparesis.
  • GORD gastro-oesophageal reflux disease
  • 5-HT 4 receptor affinity of the compounds of the present invention was determined by the inhibition of the binding of the 5-HT 4 receptor radioligand [ 3 H] -GR-113808 in rat striatum, according to the method of Grossman et al. (Br. J. Pharmacol., 1993, 109,618-624).
  • the activity of the compounds of the present invention as 5-HT 4 agonists was evaluated "in vitro" by the receptor- mediated relaxation responses of rat, carbachol precontracted oesophageal muscolaris mucosae, following the method of Baxter et al., (Naunhyn Schmiedeberg' s Arch. Pharmacol., 1991, 343, 439-446).
  • IC 50 concentration of the tested compound which forces the displacements of 50% of the bound radioligand concentration, obtained in the absence of inhibitor.
  • Kd dissociation constant of the radioligand-receptor complex.
  • EC 50 efficacy concentration: concentration of the tested compound which induces 50% of the max. response (in this case 50% of the max. relaxation).
  • i.a. intrinsic activity: max. response/max response of the natural agonist (in this case max. relaxation/5-HT max. relaxation).
  • the compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscolarly, or by intravenous injection or infusion.
  • dosage forms e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscolarly, or by intravenous injection or infusion.
  • the dosage depends on the age, weight,, conditions of the patient and on the administration route; for example, the dosage adopted for oral administration to adult humans e.g. for the representative compound of the invention FCE 29034A may range from about 1 to about 500 mg pro dose, from 1 to 5 times daily.
  • the invention includes pharmaceutical compositions comprising a compound of the invention as an active principle in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent) .
  • a pharmaceutically acceptable excipient which can be a carrier or a diluent
  • compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, destrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, destrose, saccharose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidon
  • a starch alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersion for oral administration may be e.g. syrups, emulsions and suspension.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspensions or solutions for intramuscolar injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride.
  • the solutions for intravenous injections or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, acqueous, isotonic saline solutions.
  • the suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • Volatilies were evaporated under reduced pressure and the residue was taken up with water and ethyl acetate; the layers were separated, the organic layer was dried over anhydrous sodium sulphate and evaporated to give 1.0 of raw material, which was partially purified by column chromatography over silica gel (eluant chloroform/methyl alcohol/ammonia solution 30% 46:4:0.1).
  • the carboxamide was conveniently isolated as its hydrochloride by adding to the free base in aceton/isopropyl alcohol 1 equivalent of hydrochloric acid in isopropyl alcohol.
  • preparation can be made of capsules having the following composition:

Abstract

La présente invention se rapporte à l'utilisation de dérivés de dihydrobenzofurane substitués comportant une activité d'agoniste de récepteurs 5HT4, agissant en tant qu'agents pro-cinétiques thérapeutiques dans le traitement de troubles gastro-intestinaux tels que, par exemple, la dyspepsie, la maladie du reflux gasto-÷sophagique (GORD) ou la gastro-parèsie. Les composés de l'invention peuvent être également utilisés dans le traitement des troubles SNC, caractérisés par des dysfonctionnements d'apprentissage et/ou de mémoire. Plusieurs de ces dérivés de dihydrobenzofurane sont des nouveaux composés et, en tant que tels, constituent un autre objet de l'invention ainsi que leur procédé de préparation et les compositions pharmaceutiques les contenant.
PCT/EP1996/001482 1995-04-18 1996-04-04 Derives de dihydrobenzofurane substitues utilises en tant qu'agonistes de 5-ht¿4? WO1996033186A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP8531446A JPH10502095A (ja) 1995-04-18 1996-04-04 ５−ｈｔ▲下４▼アゴニストとしての置換ジヒドロベンゾフラン誘導体
EP96912004A EP0766680A1 (fr) 1995-04-18 1996-04-04 Derives de dihydrobenzofurane substitues utilises en tant qu'agonistes de 5-ht 4

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9507882.0A GB9507882D0 (en) 1995-04-18 1995-04-18 Substituted dihydrobenzofuran derivatives as 5-ht4 agonists
GB9507882.0 1995-04-18

Publications (1)

Publication Number Publication Date
WO1996033186A1 true WO1996033186A1 (fr) 1996-10-24

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EP (1) EP0766680A1 (fr)
JP (1) JPH10502095A (fr)
GB (1) GB9507882D0 (fr)
WO (1) WO1996033186A1 (fr)

Cited By (16)

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WO1999058527A2 (fr) * 1998-05-14 1999-11-18 EGIS Gyógyszergyár Rt. Derives de benzofuranne, composition pharmaceutique renfermant ces derives et procede de preparation du principe actif
WO2002062324A2 (fr) * 2001-02-05 2002-08-15 Michael Albert Kamm Traitement des troubles de la motilite oesophagienne et du reflux gastro-oesophagien
WO2003055878A1 (fr) * 2001-12-27 2003-07-10 Bayer Healthcare Ag Amides d'acide 2-heteroarylcarboxylique
US6635643B2 (en) 1997-07-11 2003-10-21 Janssen Pharmaceutica, N.V. Bicyclic benzamides of 3- or 4-substituted 4-(aminomethyl)-piperidine derivatives
US6828330B2 (en) 2001-06-12 2004-12-07 Pharmacia & Upjohn Company Quinuclidine-substituted hetero-bicyclic aromatic compounds for the treatment of disease
US6849620B2 (en) 2001-10-26 2005-02-01 Pfizer Inc N-(azabicyclo moieties)-substituted hetero-bicyclic aromatic compounds for the treatment of disease
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WO2005092882A1 (fr) * 2004-03-01 2005-10-06 Pfizer Japan, Inc. Derives de 4-amino-5-halogeno-benzamide utiles comme agonistes du recepteur 5-ht4 dans le traitement des troubles gastro-intestinaux, du systeme nerveux central, neurologiques et cardio-vasculaires
US7067515B2 (en) 2001-06-12 2006-06-27 Pfizer Inc. Quinuclidines-substituted-multi-cyclic-heteroaryls for the treatment of disease
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Cited By (31)

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US6509339B2 (en) * 1996-02-29 2003-01-21 Janssen Pharmaceutica N.V. N-substituted 4-((4′-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties
US6800628B2 (en) 1996-02-29 2004-10-05 Janssen Pharmaceutica N.V. N-substituted 4-((-4′-aminobenzoyl)-oxymethyl)-piperidines having gastric prokinetic properties
WO1997031897A1 (fr) * 1996-02-29 1997-09-04 Janssen Pharmaceutica N.V. Nouvelles 4-((4'-aminobenzoyl)-oxymethyl)-piperidines n-substituees ayant des proprietes gastrocinetiques
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GB9507882D0 (en) 1995-05-31
EP0766680A1 (fr) 1997-04-09

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