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WO1993021166A1 - Composes heterocycliques et leur utilisation pour le traitement du diabete du type ii - Google Patents

Composes heterocycliques et leur utilisation pour le traitement du diabete du type ii Download PDF

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Publication number
WO1993021166A1
WO1993021166A1 PCT/GB1993/000735 GB9300735W WO9321166A1 WO 1993021166 A1 WO1993021166 A1 WO 1993021166A1 GB 9300735 W GB9300735 W GB 9300735W WO 9321166 A1 WO9321166 A1 WO 9321166A1
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Prior art keywords
formula
compound
phenyl
ethoxy
methylamino
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PCT/GB1993/000735
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English (en)
Inventor
David Haigh
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Smithkline Beecham Plc
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Priority claimed from GB929208016A external-priority patent/GB9208016D0/en
Priority claimed from GB929208451A external-priority patent/GB9208451D0/en
Priority claimed from GB929227046A external-priority patent/GB9227046D0/en
Priority claimed from GB929227047A external-priority patent/GB9227047D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to US08/318,615 priority Critical patent/US5589492A/en
Priority to JP5518096A priority patent/JPH07505647A/ja
Priority to EP93909044A priority patent/EP0635007A1/fr
Publication of WO1993021166A1 publication Critical patent/WO1993021166A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to certain novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to 5 the use of such compounds and compositions in medicine.
  • European Patent Applications, Publication Numbers 0008203, 0139421, 0155845, 0177353, 0193256, 0207581, 0208420, 0306228 and International Patent Application Publication No. WO 9101337 relate to thiazolidinedione derivatives which are disclosed as having hypoglycaemic and hypolipidaemic activity.
  • Chem. 0 Pharm. Bull 1982, 30 (10) 3580-3600 relates to certain thiazolidinedione derivatives having hypoglycaemic and hypolipidaemic activities.
  • Chem. Pharm. Bull 1982, 30 (10) 3563 also relates to certain ethyl 2-chloro propionate derivatives having hypoglycaemic and hypolipidaemic activities.
  • A*-- represents a substituted or unsubstituted aromatic heterocyclyl group
  • A* represents a benzene ring having three optional substituents
  • R2 represents OR wherein R*** 1 represents hydrogen, alkyl, aryl or aralkyl, or R2 represents-NR ⁇ R ⁇ wherein R ⁇ and R-- each independently represent hydrogen or alkyl or R ⁇ and R-5 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; and n represents an integer in the range of from 2 to 6.
  • Suitable aromatic heterocyclyl groups include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
  • Favoured aromatic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 4 to 7 ring atoms, preferably 5 or 6 ring atoms.
  • the aromatic heterocyclyl group comprises 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen.
  • Suitable values for A 1 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 haloge 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 ⁇ together may be substituted or unsubstituted; and in the moiety of formula (a) X* represents oxygen or sulphur.
  • a * * * represents a moiety of the abovedefined formula (a).
  • A- ⁇ represents a moiety of the abovedefined formula (b).
  • a 1 represents a moiety of the abovedefined formula (c).
  • R" and R ⁇ together represent a moiety of formula (d):
  • R-- and R ⁇ each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R8 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, R6 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 " 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 ••• 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.
  • A*** represents -(CH 2 ) m -CHRl.
  • R* represents halogen examples include fluorine, chlorine, bromine and iodine, preferably chlorine.
  • R-- * represents a moiety S(O) p A ⁇ .
  • suitable alkyl groups are C ⁇ .g alkyl groups such as methyl and propyl; an example is methyl; an example is iso propyl.
  • substitutuents for the alkyl group include OH, alkoxy or a moiety -NR S R* , wherein R s and R l each independently represents hydrogen or alkyl or R s and R r together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclic ring, or a moiety of formula -CO ⁇ 2 wherein X- ⁇ represents OH, alkoxy or a moiety of the above defined formula -NRSRt .
  • An example of a substituted alkyl group represented by A 4 includes (CH2) NR s R t wherein w is an integer in the range from 2 to 6, preferably 2, and R s and R* are as defined above.
  • a 4 When A 4 represents aryl, it is generally phenyl.
  • substituents for aryl groups represented by A 4 include alkyl, alkoxy and halogen, for example methyl, methoxy and chloride; phenyl substituents are usually substituted at the 4 - position on the phenyl ring.
  • a 4 is an aromatic heterocyclic group
  • suitable groups include those described herein for A---, especially moiety (c), for example 2-pyridyl.
  • alkylcarbonyl groups represented by A 4 include methylcarbonyl.
  • Favoured values of A 4 include methyl, propyl, an example being iso propyl, phenyl and -CH2CH2NH2.
  • Prefered values of A 4 are iso propyl and phenyl.
  • R ⁇ represents OR**- 1 .
  • R** ⁇ represents -NR ⁇ R*** 5 wherein R 4 and R$ are as defined above.
  • R**** represents hydrogen or alkyl.
  • s is alkyl it is suitably C- g alkyl, for example methyl or ethyl.
  • heterocyclic rings When -NR R5 or -NR ⁇ represents a heterocyclic ring, favoured heterocyclic rings are saturated or unsaturated, fused or monocyclic heterocyclic rings comprising 5, 6 or 7 ring atoms and optionally comprising 1 or 2 additional hetero- atoms, selected from O,S or N, in each ring.
  • Favoured rings are saturated rings.
  • Favoured rings are monocyclic rings.
  • Favoured, additional hetero-atoms are N or O. Examples of such heterocyclic rings include N- pyrrolidinyl, N-piperidinyl and N- morpholinyl.
  • NR 4 R 5 include NH2 and N(CH3) 2 ..
  • R represents hydrogen or alkyl.
  • suitable acyl groups include acetyl.
  • m represents 1.
  • n represents 2.
  • p represents zero or 2.
  • p represents zero.
  • a compound of formula (I), and the pharmaceutically acceptable salts thereof may exist in one of several tautomeric forms, all of which are 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 CHR - carbon atom is a chiral carbon.
  • 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.
  • Suitable substituents for any heterocyclyl group include up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a phenylene group, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
  • 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, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
  • 'halogen' refers to fluorine, chlorine, bromine and iodine; preferably chlorine.
  • alkyl groups are alkyl groups having straight or branched carbon chains, containing up to 12 carbon atoms.
  • suitable alkyl groups are C ⁇ -j2 alkyl groups, especially C ⁇ threadi alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl 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 aluminium, 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 alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as b ⁇ cyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroab ⁇ etylamine, N,N-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or
  • 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, succinate, benzoate, ascorbate, methane-sulphonate, ⁇ -keto glutarate and ⁇ -glycerophosphate.
  • pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide
  • pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, ⁇ -keto glutarate and ⁇ -glycerophosphate.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • the present invention also provides a process for the preparation of a compound of formula (I), or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable hydrate thereof, which process comprises reacting a compound of formula (II):
  • Rl, R2, A** and A*** 5 are as defined in relation to formula (I) and R a is a moiety convertible to a moiety of formula (f):
  • R a represents HX-(CH2) n -0- wherein X and n are as defined in relation to formula (I), or R a represents OH.
  • Ra represents OH.
  • R a is HX-(CH2) n -C
  • an appropriate reagent capable of converting R a to a moiety (f) is a compound of formula (III):
  • R x represents a leaving group.
  • a suitable leaving group R x includes a halogen atom, preferably a chlorine or bromine atom, or a thioalkyl group for example a thiomethyl group.
  • reaction between the compound of formula (II) and the appropriate reagent may be carried out under conditions suitable to the particular compound of formula (II) and the reagent chosen:
  • the abovementioned reaction between a compound of formula (II) wherein R a represents HX-(CH2) n -C»- and the compound of formula (III) 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 (I), 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.
  • R in the reagent of formula (IIIA) represents a leaving group, such as a tosylate or mesylate group
  • the reaction between the compound of formula (IIIA) 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.
  • an aprotic solvent such as dimethylformamide
  • R v in the reagent of formula (IIIA) represents a hydrogen atom
  • the reaction between the compound of formula (IIIA) and the compound of formula (II) 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.
  • a compound of formula (II), wherein A-*- * represents a moiety of formula - (CH2)m"CHR-l- wherein R! represents the above defined moiety S(O)pA 4 and m is as defined in relation to formula (I), may be prepared by reacting a compound of formula (IV):
  • R D is a moiety R a or a moiety convertible to a moiety R a
  • R-2- is R 2 or a protected form thereof
  • l ⁇ is a halogen atom, with an activated form of a compound of formula (V):
  • R-- and p are as defined in relation to formula (I); and thereafter, if required, converting a moiety R- 3 into a moiety R a and removing any protecting group.
  • a suitable halogen atom 1.1 is a chlorine atom.
  • R 12 is R 2 .
  • a suitable activated form of a compound of formula (V) is an anionic form such as a salted form and especially an alkali metal salted form, for example a sodium salt.
  • Rb is a protecting group
  • the activated form of the compound of formula (V) may be prepared by any appropriate conventional procedure.
  • the anionic form of the compound of formula (V) may be prepared by treating the compound of formula (V) with a base, such as a metal hydride base, for example sodium hydride.
  • a compound of formula (II), wherein A*-* represents a moiety of formula - (CH2) m -CHRl- wherein R ⁇ represents a halogen atom and m is as defined in relation to formula (I), may be prepared from a compound of formula (IV) by converting R* 5 into R a and R* ⁇ 2 into R 2 , as necessary.
  • a compound of formula (IV) may be prepared by halogenating a compound of formula (VI):
  • R b A 2 (Cf-y m — CH, —CO — R 12 (VI) wherein A 2 , R- -* m and R- 3 are as defined in relation to the compound of formula (IV), with an appropriate halogenating agent; and thereafter, if required, converting a moiety R D into a moiety R a and removing any protecting group.
  • the compound of formula (VI) is in an activated form, in particular it is preferred if the - CH2" carbon atom is an activated carbon atom.
  • a suitable activated form of a compound of formula (VI) is an ionic form, in particular an anionic form.
  • the activated form of the compound of formula (VI) may be prepared by any appropriate conventional procedure.
  • the anionic form of the compound of formula (VI) may be prepared by treating the compound of formula (VI) with a base such as a metal hydride base, for example sodium hydride, or a metal amide base, for example a lithium amide base.
  • a base such as a metal hydride base, for example sodium hydride, or a metal amide base, for example a lithium amide base.
  • a base is the lithium amide, lithium diisopropylamide
  • the lithium amide base is preferably used in the presence of a chlorosilane such as chlorotrimethylsilane.
  • the reaction conditions for the halogenation of the compound of formula (VI) and the nature of the halogenating agent used are analogous to the conditions used and the reagent used for halogenation reactions discussed hereinafter.
  • any moiety R D may be converted into a moiety R a by the appropriate conventional means, for example when R- 3 represents -OH and R a represents HX-(CH2) n -0- the appropriate conversion may be carried out by coupling a compound wherein R-- is OH with a compound of formula (g):
  • the last abovementioned reaction is generally carried out in the presence of a suitable coupling agent; a suitable coupling agent being diethylazodicarboxylate and triphenylphosphine.
  • a suitable coupling agent being 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.
  • R D is either OH or a protected OH, such as a benzylated OH.
  • the compounds of formulae (V) and (VI) are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, in particular the compounds wherein R* 3 is OH, m is 1 and R* 2 is OH are commercially available compounds.
  • the compounds wherein R* 2 is protected OH may of course be prepared by appropriate protection procedures.
  • the compounds of formula (g), are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example those disclosed in EP0356214.
  • a compound of formula (I), wherein A represents a moiety of formula - (CH2)m-CHR- - wherein R! represents the above defined moiety S(0) «A 4 and m is as defined in relation to formula (I), or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be prepared by reacting a compound of formula (VII):
  • A*--, A 2 , X, m and n are as defined in relation to formula (I), R--- 2 is as defined in relation to formula (IV) and L 2 represents a leaving group, with a compound of the above defined formula (V); and thereafter if required carrying out one or more of the following optional steps:
  • L 2 represents a halogen atom, generally a chlorine atom.
  • a , A 2 , R* 2 , X, m and n are as defined in relation to formula (VII), with an appropriate halogenating agent, and thereafter if required carrying out one or more of the following optional steps:
  • the compound of formula (VIII) is in an activated form, in particular it is preferred if the -*CH2- carbon atom is an activated carbon atom.
  • a suitable activated form of a compound of formula (VIII) is an ionic form, in particular an anionic form.
  • the activated form of the compound of formula (VIII) may be prepared by any appropriate conventional procedure.
  • the anionic form of the compound of formula (VIII) may be prepared by treating the compound of formula (V ⁇ i) with a base such as a metal hydride base such as sodium hydride, or a metal amide base, such as a lithium amide.
  • a base such as a metal hydride base such as sodium hydride, or a metal amide base, such as a lithium amide.
  • a base such as a metal hydride base such as sodium hydride, or a metal amide base, such as a lithium amide.
  • a base such as a metal hydride base such as sodium hydride, or a metal amide base, such as a lithium amide.
  • a base such as a metal hydride base such as sodium hydride, or a metal
  • halogenating agents are conventional halogenating agents capable of halogenating the -*CH2- carbon atom without disrupting the rest of the substrate molecule, one particular agent is an N-halosuccinimide such as N- chlorosuccinimide.
  • the reaction between the activated form of a compound of formula (VIII) and the halogenating agent may be carried out under the conditions necessitated by the particular nature of the compound of formula (VIII) and the halogenating agent used: for example, when an N-halosuccinimide is used as the halogenating agent, the reaction may be carried out in an aprotic solvent, such as tetrahydrofuran, preferably dry tetrahydrofuran, at a temperature which provides a suitable rate of formation of the required product, being generally a low temperature, for example in the range of from -90 tolO°C; and preferably the reaction is carried out under an inert atmosphere.
  • an aprotic solvent such as tetrahydrofuran, preferably dry tetrahydrofuran
  • a compound of formula (VH) may also be prepared from a compound of the above formula (VIII) by reacting with a reagent capable of forming the group L 2 , for example when L 2 is a halogen atom, by reaction with an appropriate halogenating agent, and thereafter, if required, removing any protecting group.
  • a reagent capable of forming the group L 2 for example when L 2 is a halogen atom
  • reaction with an appropriate halogenating agent e.g., Suitable reagents and reaction conditons are the appropriate conventional reagents such as the halogenating agents/conditons mentioned above.
  • a compound of formula (VUJ) may be prepared by reacting a compound of formula (IX):
  • R a , R- ⁇ 2 , A 2 and m are as defined above, with an appropriate reagent capable of converting R a into a moiety of the above defined formula (f).
  • the reagent capable of converting R a to a moiety of formula (f) is as defined above in relation to the formation of a compound of formula (I) from a compound of formula (II).
  • Suitable values for R a include those described hereinbefore.
  • Suitable reaction conditions for the reaction of the compound of formula (IX) and the appropriate reagent include those described above in relation to the preparation of compound (H) with the said appropriate reagent.
  • R a represents a hydroxyl group and a particularly appropriate reagent is the above defined compound of formula (IIIA).
  • the reaction between the compound of formula (IX), wherein R a is an hydroxyl group, and the reagent of the abovedefined formula (IDA) may be carried out in an aprotic solvent, such as dimethylformamide, at a low to an elevated temperature, for example in the range of from 50°C to 120°C, for example at 80°C, and preferably in the presence of a base, such as sodium hydride.
  • a compound of formula (VOT), wherein m is other than zeroj may also be prepared by reducing a compound of formula (X):
  • a , A 2 , R*** 2 , X and n are as defined in relation to formula (VII), and q is zero or an integer 1, 2, 3, or 4 and thereafter, if required, removing any protecting group.
  • the reduction of a compound of formula (X) may be effected by standard reduction methods, for example by catalytic reduction using platinum (IV) oxide catalyst and hydrogen.
  • a compound of formula (X) may be prepared by reacting a compound of formula (XI):
  • R 2 and q are as defined in relation to the compound of formula (X) and M" is a counter-ion, suitably a halogen, for example chloride or bromide.
  • the abovementioned reaction between the compound of formula (XI) 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 (XI) and the Wittig reagent of formula (XII) may be carried out under conventional Wittig reaction conditions, for example in an aprotic solvent, such as tetrahydrofuran or, preferably, dimethyl sulphoxide, at low to ambient temperature, such as in the range of from -10° to 25°C generally at 0 - 1Q°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 (XI) by addition of a base such as sodium hydride.
  • the reagent is preferably a Wadsworth Emmons reagent of formula (XIIA):
  • Emmons reagent of formula (XIIA) 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.
  • 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 (XI) by addition of a base such as sodium hydride.
  • a suitable reagent capable of converting the CHO carbon atom into a group of the above defined formula -A ⁇ -CO-R 2 is a Wittig reagent of formula (XDI):
  • R- ⁇ and m are as defined on relation to formula (I) and R ⁇ 2 and M are as defined in relation to formula (XII).
  • reaction between the compound of formula (XI) 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 (XI) and the Wittig reagent of formula (XIII) may be carried out under conventional Wittig reaction conditions, for example in an aprotic solvent, such as tetrahydrofuran or, preferably, dimethyl sulphoxide, 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.
  • 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 (XI) by addition of a base such as sodium hydride.
  • a base such as sodium hydride.
  • the reagent is a Wadsworth Emmons reagent of formula (XIIIA):
  • R is as defined in relation to formula (I) and and R * are R***-*-* are as defined in relation to formula (XIIA); for example, for compounds of formula (I), wherein R* is fluorine and R 2 is ethyl, a suitable Wadsworth Emmons reagent is triethyl 2- fiuorophosphonoacetate.
  • reaction between the compound of formula (XI) and the Wadsworth Emmons reagent may be carried as described herein before for the reacton between the compounds of formulae (XI) and XIIA).
  • the reduction (i) may be effected by standard reduction methods, for example by catalytic reduction using platinum (IV) oxide catalyst or a 10% palladium on carbon catalyst and hydrogen, in any suitable solvent such as an alkanolic solvent, for example ethanol.
  • A**- 5 represents a moiety of formula -CH2-CH2-.
  • the reaction conditions for the reaction between the compounds of formulae (XII) or (XIIA) and (XIV) are analogous to those used in the reaction between the compounds of formulae (XI) and (XII) or (XIIA).
  • the present invention also provides a process for preparing a compound of formula (I) wherein A-*-* represents a moiety of formula -(CH2) m -CHRl- wherein R! represents the above defined moiety S(O) p A 4 and m is as defined in relation to formula (I),or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, which process comprises hydrolysing a compound of formula (XV):
  • Suitable hydrolysis conditions are conventional conditions and include basic hydrolysis using , for example, an alkali metal base such as sodium hydroxide in any suitable solvent, generally an aqueous solvent, at a temperature providing a convenient rate of formation of the required product, generally at an elevated temperature such as the reflux temperature of the solvent,and preferably under an inert atmosphere.
  • Suitable conversions of R- as SH into another R-- and or R 2 as OH into another R 2 may be carried out under the appropriate conventional conditions such as those describred hereinafter.
  • the compounds of formula (IX), wherein R a is OH, are known 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 March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.
  • the compounds of formulae (XII), (XHA), (XIII) and (XIIIA) are known compounds or they may be prepared according to methods used to prepare known compounds, for example those disclosed in J. A er. Chem. Soc. 1961, 83, 1733, Synlett. 1991, 517 or J.Org. Chem. 1990, 55, 4639.
  • the compounds of formula (III), (IIIA), (XI), (XIV) and (XV) are known compounds or they are prepared according to methods used to prepare known compounds, for example those methods disclosed in EP 0306228.
  • 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 S(0)p.R* into another group S(0)p.Rl include converting a group S(0)p.Rl wherein p is zero into a group wherein p is 2, such conversion may be carried out using an appropriate conventional oxidation procedure, for example treating an appropriately protected compound of formula (I) with an oxidising agent such as monoperoxyphthalic acid, preferably salted as a magnesium salt.
  • an oxidising agent such as monoperoxyphthalic acid, preferably salted as a magnesium salt.
  • Suitable conversions of one group CO.R 2 into another group CO.R 2 include: (i) hydrolysing one group CO.R 2a wherein R 2a is alkyl, aryl or aralkyl into a group CO.OH; and
  • Suitable hydrolysis methods for use in conversion c (i) are conventional ester hydrolysis methods, for example using an alkali hydroxide in aqueous methanol.
  • Suitable amination methods for conversion c (ii) include conventional methods, for example treatment with aqueous ammonia in tetrahydrofuran/methanol or treatment with an appropriate dialkylamine in a solvent such as tetrahydrofuran/methanol .
  • any reactive group in the substrate molecule may be protected, according to conventional chemical practice.
  • 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.
  • 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 catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
  • a benzyl halide such as benzyl bromide
  • R ⁇ represents " a substituted alkyl wherein the substituent is a moiety of the above defined formula ⁇ lNR s R t ' wherein X*** is a bond (and in particular when R ⁇ is (C ⁇ )2 ⁇ _2), R 2 is OH and p is zero, it is generally found convenient to protect the said moiety (h) as a thiazine-3-one and to remove such protection by treating with a base, such as aqueous sodium hydroxide.
  • the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof may be prepared as individual isomers using conventional chemical procedures.
  • the compounds of the invention are indicated as having useful therapeutic properties:
  • 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 as an active therapeutic substance.
  • the present invention provides a compound of formula ®, 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 and/or prophylaxis of hyperlipidaemia.
  • 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.
  • 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. Accordingly, the present invention also provides 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 for the treatment and/or prophylaxis of hyperglycaem ⁇ a in a human or non-human mammal 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.
  • j-Thiocresol (0.43 g) was added slowly to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in oil, 0.14 g) in dry N, N-dimethylformamide (23 mL) under N2- The mixture was allowed to warm to room temperature over 30 minutes prior to the addition of a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N- methylamino]ethoxy]phenyl]-2-chloropropanoate (1.31 g) in dry N, N- d ⁇ methylformamide (16 mL) and the mixture was then left stirring at room temperature for a further 12 hrs.
  • the title compound was prepared as a gum from methyl 3-[4-[2-[N-(2- benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-chloropropanoate and 4-chlorothiophenol by a procedure similar to that described in Example 23.
  • Triethylamine (0.4 mL) was added to an ice-cooled solution of 3-[4-[2-[N-(2- benzoxazolyl)-N-methylamino]ethoxy]phenyl]propanoic acid (1.00 g) in dry tetrahydrofuran (20 mL). The mixture was stirred at 0°C during the addition of freshly distilled methyl chloroformate (0.25 mL), and stirring continued at this temperature for 45 minutes prior to the addition of a solution of dimethylamine in industrial methylated spirit (30% w/v; 20 mL). The mixture was stirred at room temperature for 20 hrs then evaporated. The residue was suspended in water (100 mL).
  • mice C57bll/6 obese (ob/ob) mice were fed on powdered oxoid diet. After at least one week, the mice continued on a powdered oxoid diet or were fed powdered 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 (3 g/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 groups. 8 mice were used for each treatment.

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
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  • Obesity (AREA)
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Abstract

L'invention concerne un composé de la formule A1-X-(CH¿2?)n-O-A?2-A3-CO.R2¿ (I); ou une forme tautomère de celui-ci et/ou un sel de celui-ci acceptable sur le plan pharmaceutique et/ou un solvate de celui-ci acceptable sur le plan pharmaceutique, où A1 représente un groupe hétérocyclyle aromatique, substitué ou non; A2 représente un noyau benzénique ayant, le cas échéant, trois substituants; A3 représente un groupe de la formule -(CH¿2?)m-CHR?1- où R1¿ représente un atome d'halogène ou un groupe de la formule S(O)¿p?A?4, où A4¿ représente un hydrogène, un groupe alkyle, aryle, aralkyle, alkylcarbonyle, ou hétérocyclyle aromatique substitué ou non, p représente le zéro ou le nombre entier 1 ou 2 et m représente le zéro ou un nombre entier compris entre 1 et 5, ou A3 représente un groupe de la formule -CH=CR?1, où R1¿ est comme défini ci-dessus; R2 représente OR3 où R3 représente un hydrogène, un groupe alkyle, aryle ou aralkyle, ou R2 représente -NR?4R5 où R4 et R5¿ constituent ensemble avec un atome d'azote auquel ils sont liés un groupe hétérocyclique; X représente O, S, ou NR où R représente un atome d'hydrogène, un groupe alkyle, acyle, ou aralkyle où le groupe aryle peut être substitué ou non, ou un groupe aryle substitué ou non; et n représente un nombre entier compris entre 2 et 6. L'invention concerne également un procédé pour la préparation d'un tel composé, une composition pharmaceutique le contenant et l'utilisation d'un tel composé ou d'une telle composition en médecine.
PCT/GB1993/000735 1992-04-10 1993-04-07 Composes heterocycliques et leur utilisation pour le traitement du diabete du type ii WO1993021166A1 (fr)

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US08/318,615 US5589492A (en) 1992-04-10 1993-04-07 Heterocyclic compounds and their use in the treatment of Type-II diabetes
JP5518096A JPH07505647A (ja) 1992-04-10 1993-04-07 複素環化合物および２型糖尿病の治療におけるそれらの使用
EP93909044A EP0635007A1 (fr) 1992-04-10 1993-04-07 Composes heterocycliques et leur utilisation pour le traitement du diabete du type ii

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GB9227046.1 1992-12-29
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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP0948327A1 (fr) * 1996-12-23 1999-10-13 Merck & Co., Inc. Agents antidiabetiques
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
US6417212B1 (en) * 1999-08-27 2002-07-09 Eli Lilly & Company Modulators of peroxisome proliferator activated receptors
US6531494B1 (en) 2001-08-29 2003-03-11 Pharmacia Corporation Gem-substituted αvβ3 antagonists
WO2003024943A2 (fr) * 2000-04-24 2003-03-27 Aryx Therapeutics Matieres et procedes pour le traitement de diabetes, de l'hyperlipidemie, de l'hypercholesterolemie, et de l'atherosclerose
US6784199B2 (en) 2000-09-21 2004-08-31 Aryx Therapeutics Isoxazolidine compounds useful in the treatment of diabetes, hyperlipidemia, and atherosclerosis in mammals
US6900232B2 (en) 2000-06-15 2005-05-31 Pharmacia Corporation Cycloalkyl alkanoic acids as integrin receptor antagonists
US6958355B2 (en) 2000-04-24 2005-10-25 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US7022722B2 (en) 2000-04-24 2006-04-04 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
WO2006077206A1 (fr) 2005-01-19 2006-07-27 Adamed Sp. Z O.O. Nouveaux derives d'acide 3-phenylpropionique et leurs utilisations en tant que ligands du recepteur ppar-gamma
EP1917962A1 (fr) 1998-11-12 2008-05-07 Smithkline Beecham Plc Composition pharmaceutique pour libération modifiée d'un agent sensibilisateur à l'insuline
EP1992337A1 (fr) 1998-11-12 2008-11-19 Smithkline Beecham Plc Nouvelle composition à libération modifiée
EP2036554A1 (fr) 2000-06-19 2009-03-18 SmithKline Beecham plc Combinaisons d'inhibiteurs de dipeptidylpeptidase iv et d'autres agents antidiabetiques pour traiter le diabete sucre
US7585880B2 (en) 2003-12-26 2009-09-08 Takeda Pharmaceutical Company Limited Phenylpropanoic acid derivatives
EP2154131A1 (fr) * 2007-04-26 2010-02-17 Pharmafrontier, Co., Ltd. Inhibiteur du récepteur couplé à protéine g et produit pharmaceutique
EP2266576A1 (fr) 1997-06-18 2010-12-29 SmithKline Beecham Limited Traitement du diabete avec du thiazolidinedione et de la sulfonyluree

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EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées
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WO1992002520A1 (fr) * 1990-08-06 1992-02-20 Beecham Group P.L.C. Derives d'oxazolidine dione

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CHEMICAL AND PHARMACEUTICAL BULLETIN. vol. 30, no. 10, October 1982, TOKYO JP pages 3580 - 3600 TAKASHI SOHDA ET AL 'Studies on antidiabetic agents.II.Synthesis of 5-(4-( 1-methylcyclohexylmethoxy)-benzyl)thiazoli dine-2,4-dione(ADD-3878) and its derivatives' cited in the application *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859051A (en) * 1996-02-02 1999-01-12 Merck & Co., Inc. Antidiabetic agents
US5847008A (en) * 1996-02-02 1998-12-08 Merck & Co., Inc. Method of treating diabetes and related disease states
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
US6294580B1 (en) 1996-02-28 2001-09-25 Glaxo Wellcome Inc. Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma
US6160000A (en) * 1996-12-23 2000-12-12 Merck & Co., Inc. Antidiabetic agents based on aryl and heteroarylacetic acids
US6090839A (en) * 1996-12-23 2000-07-18 Merck & Co., Inc. Antidiabetic agents
EP0948327A1 (fr) * 1996-12-23 1999-10-13 Merck & Co., Inc. Agents antidiabetiques
EP0948327A4 (fr) * 1996-12-23 2003-04-02 Merck & Co Inc Agents antidiabetiques
EP2266576A1 (fr) 1997-06-18 2010-12-29 SmithKline Beecham Limited Traitement du diabete avec du thiazolidinedione et de la sulfonyluree
US7045519B2 (en) 1998-06-19 2006-05-16 Chiron Corporation Inhibitors of glycogen synthase kinase 3
US7425557B2 (en) 1998-06-19 2008-09-16 Novartis Vaccines And Diagnostics, Inc. Inhibitors of glycogen synthase kinase 3
EP1992337A1 (fr) 1998-11-12 2008-11-19 Smithkline Beecham Plc Nouvelle composition à libération modifiée
EP1917962A1 (fr) 1998-11-12 2008-05-07 Smithkline Beecham Plc Composition pharmaceutique pour libération modifiée d'un agent sensibilisateur à l'insuline
US6417212B1 (en) * 1999-08-27 2002-07-09 Eli Lilly & Company Modulators of peroxisome proliferator activated receptors
US6610696B2 (en) 1999-08-27 2003-08-26 Eli Lilly And Company Modulators of peroxisome proliferator activated receptors
US6825222B2 (en) 1999-08-27 2004-11-30 Eli Lilly And Company Modulators of peroxisome proliferator activated receptors
WO2003024943A2 (fr) * 2000-04-24 2003-03-27 Aryx Therapeutics Matieres et procedes pour le traitement de diabetes, de l'hyperlipidemie, de l'hypercholesterolemie, et de l'atherosclerose
US7022722B2 (en) 2000-04-24 2006-04-04 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US6768008B2 (en) 2000-04-24 2004-07-27 Aryx Therapeutics Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
US6958355B2 (en) 2000-04-24 2005-10-25 Aryx Therapeutics, Inc. Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
WO2003024943A3 (fr) * 2000-04-24 2003-05-22 Aryx Therapeutics Matieres et procedes pour le traitement de diabetes, de l'hyperlipidemie, de l'hypercholesterolemie, et de l'atherosclerose
US6900232B2 (en) 2000-06-15 2005-05-31 Pharmacia Corporation Cycloalkyl alkanoic acids as integrin receptor antagonists
EP2036554A1 (fr) 2000-06-19 2009-03-18 SmithKline Beecham plc Combinaisons d'inhibiteurs de dipeptidylpeptidase iv et d'autres agents antidiabetiques pour traiter le diabete sucre
US6784199B2 (en) 2000-09-21 2004-08-31 Aryx Therapeutics Isoxazolidine compounds useful in the treatment of diabetes, hyperlipidemia, and atherosclerosis in mammals
US6531494B1 (en) 2001-08-29 2003-03-11 Pharmacia Corporation Gem-substituted αvβ3 antagonists
US7585880B2 (en) 2003-12-26 2009-09-08 Takeda Pharmaceutical Company Limited Phenylpropanoic acid derivatives
US7309791B2 (en) 2005-01-19 2007-12-18 Adamed Sp. Z.O.O 3-phenylpropionic acid derivatives
KR100889447B1 (ko) * 2005-01-19 2009-03-24 아다메드 에스피. 제트 오.오. 신규한 3-페닐프로피온산 유도체 및 ｐｐａｒ-감마 수용체리간드로서의 그의 용도
AU2006207492B8 (en) * 2005-01-19 2009-03-26 Adamed Sp. Z O.O. New 3-phenylpropionic acid derivatives and their use as PPAR- gamma receptor ligands
AU2006207492B2 (en) * 2005-01-19 2009-03-05 Adamed Sp. Z O.O. New 3-phenylpropionic acid derivatives and their use as PPAR- gamma receptor ligands
US7629370B2 (en) 2005-01-19 2009-12-08 Adamed Sp. Z O.O. 3-phenylpropionic acid derivatives
WO2006077206A1 (fr) 2005-01-19 2006-07-27 Adamed Sp. Z O.O. Nouveaux derives d'acide 3-phenylpropionique et leurs utilisations en tant que ligands du recepteur ppar-gamma
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

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MX9302088A (es) 1994-07-29

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