Classifications

• • 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, hashington, June 1994 ; Ghelardini et al . 10 th European Society for Neurochemistry, Jerusalem, August 1994) .
• International patent application WO 93/16072 describes 5- HT 4 receptor antagonists derived from the benzopyran, benzothiopyran or benzofuran nucleus.
• 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 lf R 2 and R 3 are, each independently, hydrogen, C ⁇ Cg alkyl, halogen, hydroxy, C j - ⁇ alkoxy, amino, C 1 -C 4 alkylamino or C ⁇ di-alkylamino;
• X is 0, NH or CH 2 ;
• Z is a group (a) , (b) , (c) or (d)
• R 4 is hydrogen , C ⁇ Cg alkyl, benzyl, cyclohexylmethyl or - CH 2 -C-_ 2 -S0 2 N__-R 6 in which R 6 is C ⁇ Cg alkyl or benzyl ;
• R 5 is Ci-Cg alkyl
• T is halogen ; provided that, when Z is defined under (c) , then X is O or CH 2 , and their pharmaceutically acceptable salts, for use as 5-HT 4 agonists.
• 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.
• alkyl groups include methyl, ethyl, n- and iso-propyl, n - , iso- , sec- and tert- butyl.
• C -C. alkoxy groups include methoxy and ethoxy.
• a C x -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.
• 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 * -W wherein R- is C x - C 6 alkyl or phenyl-Ci-Cgalkyl and W is a radical corresponding to an anion of an acid.
• R x is C--C 4 alkyl or phenyl-C 1 -C 4 alkyl, in particular it is methyl, ethyl, n-propyl, ⁇ _-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. These compounds, which form a further object of the invention, are compounds of formula (I)
• R x is hydrogen
• R 2 is chlorine or bromine; R 3 is amino; X is 0 or NH; Z is a group (a) , (b) , (c) or (d) :
• R 4 is C 3 -C 5 alkyl or -CH 2 -CH 2 -S0 2 NH-CH 3 ;
• R 5 is C 3 -C 3 alkyl;and T is chlorine or bromine; provided that, when Z is defined under (c) , then X is O; and their pharmaceutically acceptable salts.
• preferred compounds according to the invention are the following: N- tl-butyl-1-azabicyclo [2, 2,2] oct-3-yl] -4-amino-5-chloro- 2 , 3 -dihydrobenzo [b] furan-7-carboxamide bromide; (1-azabicyclo [2,2,2] oct-3-yl) -4-amino-5-chloro-2, 3 -dihydro ⁇ benzo [b] furan- 7 -carboxylate; (i-butyl-piperid-4-yl)methyl-4-amino-5-chloro-2, 3-dihydro- benzo [b] furan-7-carboxylate;
• the compounds of formula (I) can be obtained by a process comprising : A) reacting a compound of formula (II)
• E is OH, Cl, Br or 1-imidazolyl
• R x , R 2 and R 3 are, each independently, hydrogen, C ⁇ Cg alkyl, halogen, hydroxy, ⁇ C- . -C 4 alkoxy, amino, C- . - ⁇ alkylamino or C- . -C 4 di-alkylamino, with an amine or an alcohol of formula (III) , (IV) or (V)
• Q is OH or NH 2 ; n is 1,2,3 or 4; m is 0 or 1; q is 0,1 or 2; and
• R 4 is hydrogen, Ci-Cg alkyl, benzyl, cyclohexylmethyl or
• R 6 is C ⁇ Cg alkyl or benzyl so obtaining a compound of formula (I) wherein R l t 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
• R-, R 2 and R 3 are are as defined above, with an organometallic derivative of formula (VII) , (VIII) or (IX)
• M is MgBr, MgCl or Li
• n, m, q, R 4 and R 5 are as defined above, so obtaining a compound of formula (I) wherein R x , R 2 and R 3 are as defined above, X is CH 2 and Z is a group (a) , (b) or (c) ; or C) reacting a compound of formula (X)
• R x , R 2 , R 3 and X are as defined above, and X is NH, 0 or CH 2 , with an alkyl halide of formula R 5 T wherein R 5 is 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,
• (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 S 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 .
• IC 50 concentration of the tested compound which forces the displacements of 50% of the bound radioligand concentration, obtained in the absence of inhibitor.
• [L] radioligand concentration
• 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.
• the pharmaceutical 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: N- (1-piperidyl)ethyl-4-amino-5-chloro-2, 3- dihydrobenzo [b] furan-7-carboxamide hydrochloride ' hydrate 50mg talc 2mg starch 2mg microcristalline cellulose 6mg magnesium stearate lmg

Applications Claiming Priority (3)

Publications (1)

Family

ID=10773159

Family Applications (1)

Country Status (4)

Families Citing this family (16)

Family Cites Families (5)

• 1995
  • 1995-04-18 GB GBGB9507882.0A patent/GB9507882D0/en active Pending
• 1996
  • 1996-04-04 JP JP8531446A patent/JPH10502095A/ja active Pending
  • 1996-04-04 WO PCT/EP1996/001482 patent/WO1996033186A1/en not_active Application Discontinuation
  • 1996-04-04 EP EP96912004A patent/EP0766680A1/de not_active Withdrawn

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events