WO1995003288A1 - Derives heteroaromatiques et leur utilisation therapeutique - Google Patents

Derives heteroaromatiques et leur utilisation therapeutique Download PDF

Info

Publication number
WO1995003288A1
WO1995003288A1 PCT/EP1994/002029 EP9402029W WO9503288A1 WO 1995003288 A1 WO1995003288 A1 WO 1995003288A1 EP 9402029 W EP9402029 W EP 9402029W WO 9503288 A1 WO9503288 A1 WO 9503288A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
pharmaceutically acceptable
alkyl
group
Prior art date
Application number
PCT/EP1994/002029
Other languages
English (en)
Inventor
Harshad Kantilal Rami
Original Assignee
Smithkline Beecham Plc
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 Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1995003288A1 publication Critical patent/WO1995003288A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • This invention relates to certain novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
  • WO91/19702 discloses certain 3-aryl-2-hydroxypropionic acid derivatives which are stated to have useful hypoglycaemic and hypocholesterolaemic activity.
  • WO92/03425 disclose certain hydroxyurea derivatives which are also stated to be useful as hypoglycaemic and hypocholesterolaemic agents.
  • these compounds are considered to be useful for treating certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over ⁇ eating, such as obesity and anorexia bulimia.
  • A* represents a substituted or unsubstituted aromatic heterocyclyl group
  • a ⁇ represents a benzene ring having three optional substituents
  • R! represents a moiety CH2-R ⁇ wherein R ⁇ represents hydrogen, optionally substituted alkyl wherein optional substituents are selected from the list consisting of: alkox) .
  • R ⁇ represents hydrogen, optionally substituted alkyl wherein optional substituents are selected from the list consisting of: alkox) .
  • R represents OR ⁇ wherein R ⁇ represents hydrogen, alkyl, aryl or aralkyl, or R ⁇ represents-NR5R5a wherein R ⁇ and R ⁇ a each independently represent hydrogen or alkyl or R ⁇ and R ⁇ a together with the nitrogen atom to which they are attached form a heterocyclic ring;
  • X represents O, S or NR wherein R represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; m represents an integer in the range of from 1 to 6 and n represents an integer in the range of from 2 to 6.
  • A* represents a substituted or unsubstituted, single or fused ring aromatic heterocyclyl group comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
  • A* represents a substituted or unsubstituted single ring aromatic heterocyclyl groups having 4 to 7 ring atoms, preferably 5 or 6 ring atoms.
  • the A* aromatic heterocyclyl group comprises 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen.
  • Suitable values for A when it represents a 5- membered aromatic heterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl.
  • Suitable values for A* when it represents a 6- membered aromatic heterocyclyl group include pyridyl or pyrimidinyl, especially pyridyl.
  • a particular pyridyl group is a 2-pyridyl group.
  • A* represents a moiety of formula (a), (b) or (c):
  • R6 and R ⁇ each independently represents a hydrogen or halogen atom, an alkyl or alkoxy group or a substituted or unsubstituted aryl group or when R*> and R? are each attached to adjacent carbon atoms, then R" and R ⁇ together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R" and R ⁇ together may be substituted or unsubstituted; and in the moiety of formula (a) X* represents oxygen or sulphur.
  • a 1 represents a moiety of the abovedefined formula (a).
  • A* represents a moiety of the abovedefined formula (b).
  • A* represents a moiety of the above defined formula (c).
  • One favoured moiety (c) is that wherein the linking bond is attached to a ring carbon adjacent to the ring nitrogen atom.
  • R ⁇ and R ⁇ together represent a moiety of formula (d):
  • R ⁇ and R ⁇ each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R ⁇ and R ⁇ each independently represent hydrogen, halogen, alkyl or alkoxy.
  • R represents hydrogen.
  • R ⁇ represents hydrogen.
  • R ⁇ and R ⁇ both represent hydrogen.
  • R*> and R? each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, R" and R each independently represent hydrogen, alkyl or phenyl.
  • R ⁇ and R together represent the moiety of formula (d).
  • R*> and R? both represent hydrogen.
  • Favoured optional substituents for A ⁇ are selected from the group consisting of halogen, substituted or unsubstituted alkyl and alkoxy.
  • a ⁇ represents a moiety of formula (e):
  • R 0 and R* 1 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R 0 and R ⁇ each independently represent hydrogen, halogen, alkyl or alkoxy.
  • R*0 and R * each represent hydrogen.
  • X represents O. In a further aspect, X represents S. In yet a further aspect, and preferably, X represents NR.
  • R3 represents alkyl it is suitably C j .g alkyl including methyl, ethyl, n- and iso propyl, n- and iso butyl and pentyl, especially n-pentyl.
  • Suitable optional substituents for any alkyl group represented by R ⁇ include 1 to 3 substituents selected from the list consisting of: alkoxy, phenyl, phenoxy, aminoalkyl, alkylaminoalkyl and bisalkylaminoalkyl.
  • R3 represents substituted alkyl
  • a favoured optional substituent is a phenyl group, generally substituted at the terminal position on the respective alkyl group.
  • substituted alkyl groups represented by R ⁇ include benzyl, 2-phenylethyl, 3-phenylpropyl and 4-phenylbutyl, especially 2-phenylethyl and 4- phenylbutyl.
  • R3 represents alkenyl it is suitably C2-6 alkenyl, a particular example is ethenyl.
  • Suitable optional substituents for any alkenyl group represented by R ⁇ include 1 to 3 substituents selected from the list consisting of: alkyl, phenyl and phenyl substituted with halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy and alkylcarbonyl.
  • R represents substituted alkenyl
  • favoured optional substituents include one or more C ⁇ _ alkyl groups, such as methyl, and phenyl: generally the substituents are at the terminal position on the respective alkenyl group.
  • substituted alkenyl groups represented by R ⁇ include 2-phenylethenyl and 2,2-dimethylethenyl.
  • R3 represents C _ ⁇ alkoxy
  • a particular example is methoxy
  • R ⁇ represents alkyl or optionally substituted alkyl.
  • R 2 represents OR 4 .
  • R 4 represents hydrogen, alkyl or aryl, in particular hydrogen or alkyl.
  • R 4 represents hydrogen or Cj.g alkyl such as methyl.
  • R represents hydrogen or alkyl.
  • suitable acyl groups include acetyl.
  • n 1
  • n 2
  • a compound of formula (I), and the pharmaceutically acceptable salts thereof may exist in one of several tautomeric forms, all of which arc encompassed by the present invention as individual tautomeric forms or as mixtures thereof.
  • the compounds of formula (I) may contain at least one chiral carbon, and hence they may exist in one or more stereoisomeric forms.
  • the present invention encompasses all of the stereoisomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof, whether as individual stereoisomers or as mixtures of isomers, including racemates.
  • the term 'aryl' includes phenyl and naphthyl; any aryl group mentioned herein may be optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxyca-rbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
  • alkyl groups are alkyl groups having straight or branched carbon chains containing up to 12 carbon atoms.
  • suitable alkyl groups are Cj-12 alkyl groups, especially C ⁇ _6 alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.
  • alkenyl groups are C2-12 alkenyl groups, especially C2-6 alkenyl groups
  • Suitable substituents for any alkyl group include those indicated above in relation to the term "aryl”.
  • Suitable acyl groups include alkylcarbonyl groups
  • Suitable pharmaceutically acceptable salts include salts of carboxy groups and acid addition salts.
  • Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example alumir :um, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alky ' Ines such as triethylamine, hydroxyalkylamines 1 -h as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇
  • -phenethylamine dehydroabietylamine, N,N , -bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
  • Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinr benzoate, ascorbate, methane-sulphonate, ⁇ -keto glutarate and ⁇ -glycerophospha
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • a compound of formula (I) may be prepared from a compound of formula (II) activated so as to react at the *CH2 carbon atom:
  • L.1 represents a halogen atom such as chlorine or bromine.
  • a suitably activated form of a compound of formula (II) is an anionic form or a masked anionic form.
  • Suitable reaction conditions are the appropriate conventional conditions depending upon the nature of the compounds of formula (II) and (III).
  • the reaction between the activated form of a compound of formula (II) and the compound of formula (III) may be carried out in an aprotic solvent, such as tetrahydrofuran, under anhydrous conditions, at a temperature which provides a suitable rate of formation of the required product, being generally a low to medium temperature, such as in the range of from -90°C to 40°C, conveniently at ambient temperature; preferably the reaction is carried out in an inert atmosphere, for example under nitrogen or argon.
  • an aprotic solvent such as tetrahydrofuran
  • the activated form of the compound of formula (II) may be prepared by any appropriate conventional procedure, for example the anionic form of the compound of formula (II) may be prepared by treating the compound of formula (II) with a base, such as a metal hydride base for example sodium hydride, or a metal amide base, such as a lithium amide.
  • a base such as a metal hydride base for example sodium hydride, or a metal amide base, such as a lithium amide.
  • a base such as a metal hydride base for example sodium hydride
  • a metal amide base such as a lithium amide.
  • One preferred base is the lithium amide, lithium diisopropylamide.
  • the masked anionic form of a compound of formula (II) may also be made by conventional procedures, for example, by treatment with a base in the presence of a chlorosilane such as chlorotrimetiiylsilane.
  • a compound of formula (II) may be prepared by reacting a compound of formula (IN):
  • R a represents HX-(CH.2) n -O- wherein X and n are as defined in relation to formula (I), or R a represents OH.
  • R a represents OH.
  • R a is HX-(CH2) n -O-.
  • an appropriate reagent capable of converting R a to a moiety (f) is a compound of formula (N):
  • A is as defined in relation to formula (I) and L 2 represents a leaving grc or atom.
  • a suitable leaving group L 2 is a halogen atom, preferably chlorine or bromine atom, or a thioalkyl group for example a thiomethyl group.
  • an appropriate reagent is a compound of formula (VI):
  • A*, X and n are as defined in relation to formula (I) and l represents hydrogen or a leaving group, such as a tosyiate or mesylate group.
  • reaction between the compound of formula (IV) and the appropriate reagent may be carried out under conditions Jictated by the particular compound of formula (IV) and the reagent chosen:
  • reaction between a compound of formula (IV) wherein R a represents HX-(CH2)n-O- and the compound of formula (V) may be carried out in any suitable solvent, for example dimethylformamide, at a temperature which provides a suitable rate of formation of the compound of formula (II), for example at an elevated temperature in the range from 50°C to 120°C, preferably in the presence of a base such as sodium hydride.
  • suitable solvent for example dimethylformamide
  • reaction conditions for the reaction between a compound of formula (IV) wherein R a is OH and the compound of formula (VI) tend to vary with the nature of (VI):
  • L 3 in the reagent of formula (VI) represents a leaving group, such as a tosylate or mesylate group
  • the reaction between the compound of formula (VI) and the compound of formula (II) wherein R a is OH may be carried out in an aprotic solvent, such as dimethylformamide, at a low to an elevated temperature, for example in the range from 50°C to 120°C, for example at 80°C, and preferably in the presence of a base, such as sodium hydride.
  • aprotic solvent such as dimethylformamide
  • the reaction between the compound of formula (VI) and the compound of formula (IN) wherein R a is OH is conveniently carried out in the presence of a suitable coupling agent; a suitable coupling agent being provided by diethylazodicarboxylate and triphenylphosphine.
  • the coupling reaction may be carried out in any suitable solvent at a low to medium temperature, for example in tetrahydrofuran at a temperature in the range of between 0 and 60°C, conveniently at ambient temperature.
  • R a represents a hydroxyl group and a particularly appropriate reagent is a compound of formula (VI).
  • a compound of formula (IV) may be prepared by reducing a compound of formula (VII):
  • a 2 and RP are as defined in relation to formula (IV), q is zero or an integer 1, 2, 3, 4 or 5 and R ⁇ represents R a or a protected form thereof; and thereafter, if required, removing any protecting group.
  • the reduction of a compound of formula (VII) may be effected by standard reduction methods, for example by catalytic reduction using platinum (IV) oxide catalyst and hydrogen.
  • a compound of formula (VII) may be prepared by reacting a compound of formula (VIII): b 2
  • R* 5 represents a protected OH group, such as a benzylated OH group.
  • RP and q are as defined in relation to the compound of formula (VII) and M" is a counter-ion, suitably a halogen, for example chloride or bromide.
  • reaction between the compound of formula (VIII) and the said reagent may be carried out under conventional conditions depending upon the particular nature of the reagent used: for example the reaction between a compound of formula (VIII) and the Wittig reagent of formula (IX) may be carried out under conventional Wittig reaction conditions in an aprotic solvent, such as tetrahydrofuran or, preferably dimethyl sulphoxide, at low to ambient temperature, such as in the range of fror-u - 10° to 25°C, generally at 0 - 10°C.
  • the reaction is most effectively carried out under an inert atmosphere and under anhydrous conditions.
  • the Wittig reagent is activated prior to addition of the compound of formula (VIH) by addition of a base such as sodium hydride.
  • the reagent is preferably a
  • RP is as defined in relation to formula (VI) and R*2 represents a Cj.g alkyl group, preferably a methyl or ethyl group, for example for compounds of formula (IV) wherein R*2 i s methoxy, the Wadsworth Emmons reagent of formula (X) is trimethyl phosphonoacetate.
  • the reaction between a compound of formula (VIII) and the Wadsworth Emmons reagent of formula (X) may be carried out under conventional Wadsworth Emmons reaction conditions, for example in an aprotic solvent, such as tetrahydrofuran, at low to ambient temperature, such as in the range of from -10° to 25°C generally at 0 - 10°C, and preferably in the presence of a base such as sodium hydride.
  • a base such as sodium hydride.
  • the reaction is most effectively carried out under an inert atmosphere and under anhydrous conditions.
  • the trimethyl phosphonoacetate is activated prior to addition of the compound of formula (VIII) by addition of a base such as sodium hydride.
  • a compound of formula (I) wherein m is 1 may be prepared by dehydroxylating a compound of formula (XI):
  • A*, A 2 , X, Rl, R 2 and n are as defined in relation to the compound of formula (I); and thereafter if required carrying out one or more of the following optional steps:
  • the dehydroxylation of the compounds of formula (XI) may be carried out using any appropriate dehydroxylation procedure, in particular we have found that the dehydroxylation is conveniently carried out by using a trialkylsilane, for example triethylsilane, in the presence of an acid such as trifluoroacetic acid.
  • the dehydroxylation reaction using the trialkylsilane is conveniently carried out in an inert solvent such as dichloromethane at any convenient temperature which provides a suitable rate of formation of the required product, for example at ambient temperature.
  • a compound of formula (XI) may be prepared by reacting a compound of formula (XII):
  • Rl is as defined in relation to formula (I) and R 2 P is R 2 as defined in relation to formula (I), or a protected form thereof.
  • the compound of formula (XIII) is in an activated form, activated so as to react at the *CH2 carbon atom.
  • R P is usually R 2 .
  • R 2 P is usually a protected form of the required group R 2 , such as a benzylated or silylated form.
  • a suitable activated form of a compound of formula (XIII) is provided by forming an ionic form [R -CH-COR 2 ]- M + wherein R* and R 2 are as defined above and Mtas a salting ion such as an alkaline metal ion for example a lithium ion.
  • the activated form of a compound of formula (XIII) may be prepared by any appropiate method, for example by treating the compound of formula (XIII) with a base, such as a metal hydride base for example sodium hydride, or a metal amide base, such as a lithium amide.
  • a base such as a metal hydride base for example sodium hydride, or a metal amide base, such as a lithium amide.
  • a base such as a metal hydride base for example sodium hydride
  • a metal amide base such as a lithium amide.
  • One preferred base is the lithium amide, lithium diisopropylamide.
  • the reaction is conveniently carried out in an aprotic solvent, such as tetrahydrofuran, at any temperature which provides a suitable rate of formation of the required product, generally at a low to ambient temperature, such as a temperature in the range of from -80° to 25°C generally at -70°C.
  • aprotic solvent such as tetrahydrofuran
  • the reaction is most effectively carried out under an inert atmosphere, such as argon, and under anhydrous conditions.
  • a compound of formula (I) wherein m is 1 may also be prepared by reducing a compound of formula (XIV):
  • A*, A 2 , X, R , R 2 and n are as defined in relation to the compound of formula (I); and thereafter if required carrying out one or more of the following optional steps:
  • a pharmaceutically acceptable salt of a compound of formula (I) and/or a pharmaceutically acceptable solvate thereof may be carried out using conventional reduction procedures, in particular catalytic hydrogenation using for example a 10% palladium on charcoal catalyst and hydrogen in an alkanol solvent such as methanol, at a temperature and pressure which provides a suitable rate of formation of the required product, for example at ambient temperature and conveniently using hydrogen at atmospheric pressure.
  • a compound of formula (XIV) may be prepared by dehydrating a compound of the above defined formula (XI).
  • the dehydration of the compound of formula (XI) is suitably carried out under conventional dehydration reaction conditions, for example by treating the compound of formula (XI) with p ⁇ r ⁇ -toluenesulphonic acid in an inert, preferably water immisible solvent, such as toluene.
  • the reaction is conveniently carried out at any temperature which provides a suitable rate of formation of the required product generally being an elevated temperature, conveniently at the reflux temperature of the solvent, preferably removing the water produced form the reaction, using for example a Dean and Stark apparatus.
  • the compounds of formula (IV), wherein R a is OH and m is 1, are known commercially available compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in Dictionary of Organic Compounds 5th Edition, Vol. 3, p.3222, Chapman & Hall, or D.H. Williams et. al. J.Chem.Soc., Section B, 1969, 439, or J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.
  • the compounds of formulae (IX), (X) and (XIII) are known compounds or they may be prepared according to methods used to prepare known compounds, for example those disclosed in J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.
  • the compounds of formula (V), (VI), (VIII) and (XII) are known compounds or they are prepared according to methods used to prepare known compounds, for example those methods disclosed in EP 0306228.
  • the abovementioned conversion of a compound of formula (I) into a further compound of formula (I) includes: a) converting one group R into another group R; b) converting one group CO.R 2 into another group CO.R 2 .
  • Suitable conversions of one group R into another group R include converting a group R which represents hydrogen into a group R which represents an acyl group; such conversion may be carried out using an appropriate conventional acylation procedure, for example treating an appropriately protected compound of formula (I) with an acylating agent.
  • acetic anhydride may be used to prepare the compound of formula (I) wherein R is acetyl.
  • Suitable conversions of one group CO.R 2 into another group CO.R 2 include: (i) hydrolysing one group CCR 3 wherein R ⁇ is alkyl, aryl or aralkyl into a group CO.OH; and
  • protecting groups will be used when and ss necessary in accordance with conventional procedures.
  • Suitable protecting groups in any of the abovementioned reactions are those used conventionally in the art.
  • a suitable hydroxyl protecting group is a benzyl group.
  • a suitable amino protecting group is a benzyl group or a silyl group.
  • benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catab r hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
  • a benzyl halide such as benzyl bromide
  • N-benzyl group may be inserted and removed by similar treatment of an appropriate amine compound and an N-silyl group may be prepared by treating the appropriate amine compound with a chloroalkyl silane, such as tert-butyl dimethylsilylchloride, in the presence of a base such as sodiur- hydride.
  • a chloroalkyl silane such as tert-butyl dimethylsilylchloride
  • the present invention accordingly provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use -s an active therapeutic substance.
  • the present invention provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia.
  • the present invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia.
  • the present invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperg
  • the present invention also provides a compound of formula (I) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof for use in the treatment of hypertension, cardiovascular disease and certain eating disorders.
  • Cardiovascular disease includes in particular atherosclerosis.
  • Certain eating disorders include in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating , such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia.
  • a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the general formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
  • the term 'pharmaceutically acceptable embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.
  • composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
  • compositions for oral administration are unit dosage forms such as tablets and capsules.
  • Other fixed unit dosage forms such as powders presented in sachets, may also be used.
  • the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
  • Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
  • composition will be formulated in unit dose form.
  • unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.
  • the present invention further provides a method fo* the treatment and/or prophylaxis of hyperglycaemia in a human or non-human » ammal which comprises administering an effective, non-toxic, amount of a compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a hyperglycaemic human or non-human mammal in need thereof.
  • the present invention further provides a method for the treatment of hyperlipidaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a hyperlipidaemic human or non-human mammal in need thereof.
  • the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
  • the compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.
  • the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg.
  • Similar dosage regimens are suitable for the treatment and/or prophylaxis of hyperlipidaemia in non-human mammals.
  • the dosages regimens for the treatment of hypertension, cardiovascular disease and eating disorders will generally be those mentioned above in relation to hyperglycaemia.
  • the present invention provides the use of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia.
  • the present invention also provides the use of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperlipidaemia, hypertension, cardiovascular disease or certain eating disorders.
  • the title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)propanoate and cinnamyl bromide as described in Example 1.
  • the crude product was chromatographed on silica gel eluting with 10 to 30% (gradient elution) ethyl acetate in hexane to afford the product as an oil.
  • the title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)propanoate and bromomethyl methyl ether by a procedure similar to that described in Example 1.
  • the crude product was chromatographed on a silica gel eluting with 10 to 30% (gradient) ethyl acetate in hexane to afford the product as an oil.
  • the title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)propanoate and 4-bromo-2-methyl-2-butene as described in Example 1.
  • the crude product was chromatographed on silica gel eluting with 5 to 20% (gradient elution) in hexane to afford the product as an oil.
  • the title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)propanoate and phenethylbromide by a similar method to that described in Example 1.
  • the crude product was chromatographed on silica gel eluting with 10 to 30% (gradient elution) ethyl acetate in hexane to afford the product as an oil.
  • lH NMR ⁇ (CDCI3) 1.80 (lH,m), 1.97 (lH,m), 2.50-2.72 (4H,m), 2.90 (lH,m), 3.34
  • the title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl propanoate and 1-iodohexane by a similar method to that described in Example 1.
  • the crude product was chromatographed on silica gel eluting with 5 to 30% (gradient elution) ethyl acetate in hexane to afford the product as an oil.
  • the title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)propanoate and iodoethane by a similar method to that described in Example 1.
  • the crude product was chromatographed on silica gel eluting with 5 to 30% (gradient elution)ethyl acetate in hexane to afford the product as an oil.
  • mice C57bll 6 obese (ob/ob) mice were fed on powdered oxoid diet. After at least one week, the mice rontinued on a powdered oxoid diet or were fed powered oxoid diet containing the test compound. After 8 days on the supplemented diet all of the mice were fasted for 5 hours prior to receiving an oral load of glucose (3g/kg). Blood samples for glucose analysis were taken 0, 45, 90 and 135 minutes after glucose administration and the results appear below as the percentage reduction in area under the blood glucose curve where test compound treated groups are compared with the control group. 8 mice were used for each treatment.

Landscapes

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

Abstract

L'invention concerne un composé de la formule (I) ou une forme tautomère de celui-ci et/ou un sel pharmaceutiquement acceptable de celui-ci, et/ou un solvate pharmaceutiquement acceptable de celui-ci. Dans cette formule A1 représente un groupe aromatique hétérocyclique substitué ou non; A2 représente un cycle benzène ayant trois substituants optionnels; R1 représente une fraction CH¿2?-R?3 où R3¿ représente hydrogène, alkyle éventuellement substitué où les substituants optionnels sont choisis dans la liste suivante: alcoxy, phényle, phénoxy, aminoalkyle, alkylaminoalkyle et bisalkylaminoalkyle. R3 peut également représenter un alcényle éventuellement substitué, les substituants optionnels étant choisis dans la liste suivante: alkyle, phényle et phényle substitué par des groupes halogène, alkyle, phényle, alcoxy, haloalkyle, hydroxy, amino, nitro, carboxy, alcoxycarbonyle, alcoxycarbonylalkyle, alkylcarbonyloxy ou alkylcarbonyle; ou R3 représente un groupe alcoxy; R2 représente OR4 où R4 représente hydrogène, alkyle, aryle ou un aralkyle, ou R2 représente -NR?5R5a où R5 et R5a¿ représentent chacun indépendamment hydrogène ou alkyle, ou R?5 et R5a¿ forment avec l'atome d'azote auquel ils sont fixés un cycle hétérocyclique; X représente O, S ou NR où R représente un atome d'hydrogène, un groupe alkyle, un groupe acyle, un groupe aralkyle où la fraction aryle peut être substituée ou non, ou un groupe aryle substitué ou non, m représente un nombre entier de 1 à 6 et n représente un nombre entier de 2 à 6. L'invention concerne aussi un procédé de préparation d'un tel composé, une composition le contenant et l'utilisation du composé et de la composition en médecine.
PCT/EP1994/002029 1993-07-22 1994-06-20 Derives heteroaromatiques et leur utilisation therapeutique WO1995003288A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939315148A GB9315148D0 (en) 1993-07-22 1993-07-22 Novel compounds
GB9315148.8 1993-07-22

Publications (1)

Publication Number Publication Date
WO1995003288A1 true WO1995003288A1 (fr) 1995-02-02

Family

ID=10739217

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/002029 WO1995003288A1 (fr) 1993-07-22 1994-06-20 Derives heteroaromatiques et leur utilisation therapeutique

Country Status (2)

Country Link
GB (1) GB9315148D0 (fr)
WO (1) WO1995003288A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037970A1 (fr) * 1996-04-04 1997-10-16 Sankyo Company, Limited Derives d'acide phenylalkylcarboxylique
US5847008A (en) * 1996-02-02 1998-12-08 Merck & Co., Inc. Method of treating diabetes and related disease states
US5859051A (en) * 1996-02-02 1999-01-12 Merck & Co., Inc. Antidiabetic agents
US6020382A (en) * 1996-02-02 2000-02-01 Merck & Co., Inc. Method of treating diabetes and related disease states
US6090836A (en) * 1996-02-02 2000-07-18 Merck & Co., Inc. Benzisoxazole-derived antidiabetic compounds
US6090839A (en) * 1996-12-23 2000-07-18 Merck & Co., Inc. Antidiabetic agents
US6160000A (en) * 1996-12-23 2000-12-12 Merck & Co., Inc. Antidiabetic agents based on aryl and heteroarylacetic acids
US6294580B1 (en) 1996-02-28 2001-09-25 Glaxo Wellcome Inc. Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma
WO2002100812A1 (fr) * 2001-04-20 2002-12-19 Eisai Co., Ltd. Dérivé de l'acide carboxylique et son sel
US6528525B1 (en) 1997-10-02 2003-03-04 Sankyo Company, Limited Amidocarboxylic acid derivatives
JP2003527303A (ja) * 1998-06-19 2003-09-16 カイロン コーポレイション グリコーゲンシンターゼキナーゼ３のインヒビター
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
US6900232B2 (en) 2000-06-15 2005-05-31 Pharmacia Corporation Cycloalkyl alkanoic acids as integrin receptor antagonists
US7371777B2 (en) 2001-08-17 2008-05-13 Eisai Co., Ltd. Cyclic compound and PPAR agonist
EP2154131A1 (fr) * 2007-04-26 2010-02-17 Pharmafrontier, Co., Ltd. Inhibiteur du récepteur couplé à protéine g et produit pharmaceutique
US20210253513A1 (en) * 2018-06-15 2021-08-19 Pharmathen S.A. A novel process for the preparation of tapentadol

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées
WO1991019702A1 (fr) * 1990-06-14 1991-12-26 Pfizer Inc. Derives d'acide 3-aryl-2-hydroxypropionique et leurs analogues utilises comme agents hypoglycemiques
WO1992002520A1 (fr) * 1990-08-06 1992-02-20 Beecham Group P.L.C. Derives d'oxazolidine dione
WO1994001420A1 (fr) * 1992-07-03 1994-01-20 Smithkline Beecham Plc Composes heterocycliques comme produits pharmaceutiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées
WO1991019702A1 (fr) * 1990-06-14 1991-12-26 Pfizer Inc. Derives d'acide 3-aryl-2-hydroxypropionique et leurs analogues utilises comme agents hypoglycemiques
WO1992002520A1 (fr) * 1990-08-06 1992-02-20 Beecham Group P.L.C. Derives d'oxazolidine dione
WO1994001420A1 (fr) * 1992-07-03 1994-01-20 Smithkline Beecham Plc Composes heterocycliques comme produits pharmaceutiques

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6020382A (en) * 1996-02-02 2000-02-01 Merck & Co., Inc. Method of treating diabetes and related disease states
US5847008A (en) * 1996-02-02 1998-12-08 Merck & Co., Inc. Method of treating diabetes and related disease states
US5859051A (en) * 1996-02-02 1999-01-12 Merck & Co., Inc. Antidiabetic agents
US6090836A (en) * 1996-02-02 2000-07-18 Merck & Co., Inc. Benzisoxazole-derived antidiabetic compounds
US6294580B1 (en) 1996-02-28 2001-09-25 Glaxo Wellcome Inc. Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma
US6103907A (en) * 1996-04-04 2000-08-15 Sankyo Company, Limited Phenylalkylcarboxylic acid compounds and compositions for treating hyperglycemia
EP0916651A4 (fr) * 1996-04-04 2001-09-12 Sankyo Co Derives d'acide phenylalkylcarboxylique
WO1997037970A1 (fr) * 1996-04-04 1997-10-16 Sankyo Company, Limited Derives d'acide phenylalkylcarboxylique
EP0916651A1 (fr) * 1996-04-04 1999-05-19 Sankyo Company, Limited Derives d'acide phenylalkylcarboxylique
US6090839A (en) * 1996-12-23 2000-07-18 Merck & Co., Inc. Antidiabetic agents
US6160000A (en) * 1996-12-23 2000-12-12 Merck & Co., Inc. Antidiabetic agents based on aryl and heteroarylacetic acids
US6528525B1 (en) 1997-10-02 2003-03-04 Sankyo Company, Limited Amidocarboxylic acid derivatives
JP2003527303A (ja) * 1998-06-19 2003-09-16 カイロン コーポレイション グリコーゲンシンターゼキナーゼ３のインヒビター
US6900232B2 (en) 2000-06-15 2005-05-31 Pharmacia Corporation Cycloalkyl alkanoic acids as integrin receptor antagonists
WO2002100812A1 (fr) * 2001-04-20 2002-12-19 Eisai Co., Ltd. Dérivé de l'acide carboxylique et son sel
US7544835B2 (en) 2001-04-20 2009-06-09 Eisai R&D Management Co., Ltd. Carboxylic acid derivative and salt thereof
SG161743A1 (en) * 2001-04-20 2010-06-29 Eisai R&D Man Co Ltd Carboxylic acid derivative and salt thereof
US7371777B2 (en) 2001-08-17 2008-05-13 Eisai Co., Ltd. Cyclic compound and PPAR agonist
US6716842B2 (en) 2002-04-05 2004-04-06 Warner-Lambert Company, Llc Antidiabetic agents
EP2154131A1 (fr) * 2007-04-26 2010-02-17 Pharmafrontier, Co., Ltd. Inhibiteur du récepteur couplé à protéine g et produit pharmaceutique
EP2154131A4 (fr) * 2007-04-26 2011-09-21 Pharmafrontier Co Ltd Inhibiteur du récepteur couplé à protéine g et produit pharmaceutique
US20210253513A1 (en) * 2018-06-15 2021-08-19 Pharmathen S.A. A novel process for the preparation of tapentadol

Also Published As

Publication number Publication date
GB9315148D0 (en) 1993-09-08

Similar Documents

Publication Publication Date Title
AP776A (en) Benzoxazoles and pyridine derivatives useful in the treatment of the type Ii diabetes.
US5132317A (en) Compounds
WO1994013650A1 (fr) Derives heterocycliques et leur utilisation comme produits pharmaceutiques
EP0658161B1 (fr) Derives substitues de la thiazolidinedione
WO1995003288A1 (fr) Derives heteroaromatiques et leur utilisation therapeutique
US5741803A (en) Substituted thiazolidinedionle derivatives
US5478851A (en) Dioxothiazolidine compounds
US5075300A (en) Novel compounds
US5391565A (en) Oxazolidine dione derivatives
NZ502966A (en) Agonist of PPAR-alpha and PPAR-gamma for the manufacture of medicaments for treating Syndrome X
EP0193256A1 (fr) Dérivés de thiazolidinediones, leur préparation et utilisation
WO1992007838A1 (fr) Derives de thiazolidine-dione
JP3067809B2 (ja) 新規置換２，４―チアゾリジンジオン誘導体、その製造方法およびそれを含む薬剤組成物
WO1995017394A1 (fr) Derives heterocycliques et leur utilisation dans des produits pharmaceutiques
JPH0819128B2 (ja) イソキサゾ−ルおよびフラン誘導体、その製法並びに抗ウイルス剤としての用途
NO300735B1 (no) Tiazolidindionderivater samt farmasöytiske preparater inneholdende dem
EP0635007A1 (fr) Composes heterocycliques et leur utilisation pour le traitement du diabete du type ii
US5478850A (en) Thiazolidinedione derivatives
US5063240A (en) Novel compounds
US6686475B2 (en) Compounds
US4220648A (en) Antidiabetic 1,2-dihydro-2-oxo-6-neopentyl-nicotinic acids
JP3527514B2 (ja) ２−スルファモイル安息香酸誘導体
WO1994029302A1 (fr) Derives heterocycliques et leur utilisation dans les produits pharmaceutiques
US5589492A (en) Heterocyclic compounds and their use in the treatment of Type-II diabetes
EP0101380A2 (fr) Nicotinamide 1-oxyde N-substitué, ses sels, procédé pour leur préparation et compositions pharmaceutiques en contenant

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase