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WO1996004260A1 - Benzoxazoles et derives de pyridine utiles dans le traitement du diabete de type ii - Google Patents

Benzoxazoles et derives de pyridine utiles dans le traitement du diabete de type ii Download PDF

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Publication number
WO1996004260A1
WO1996004260A1 PCT/EP1995/003038 EP9503038W WO9604260A1 WO 1996004260 A1 WO1996004260 A1 WO 1996004260A1 EP 9503038 W EP9503038 W EP 9503038W WO 9604260 A1 WO9604260 A1 WO 9604260A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
formula
compound
acceptable salt
treatment
Prior art date
Application number
PCT/EP1995/003038
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English (en)
Inventor
David Haigh
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
Priority claimed from GB9415330A external-priority patent/GB9415330D0/en
Priority claimed from GBGB9425599.9A external-priority patent/GB9425599D0/en
Priority claimed from GBGB9509923.0A external-priority patent/GB9509923D0/en
Priority to BR9508468A priority Critical patent/BR9508468A/pt
Priority to MX9700763A priority patent/MX9700763A/es
Priority to SK122-97A priority patent/SK12297A3/sk
Priority to NZ292125A priority patent/NZ292125A/en
Priority to FI970357A priority patent/FI970357L/fi
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to CZ97254A priority patent/CZ25497A3/cs
Priority to JP8506194A priority patent/JPH10503508A/ja
Priority to EP95930436A priority patent/EP0772605A1/fr
Priority to AU33826/95A priority patent/AU697545B2/en
Publication of WO1996004260A1 publication Critical patent/WO1996004260A1/fr
Priority to NO970373A priority patent/NO307827B1/no
Priority to BG101180A priority patent/BG101180A/xx

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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 5 the use of such compounds and compositions in medicine.
  • A represents a substituted or unsubstituted aromatic heterocyclyl group
  • A** ' represents a benzene ring having three optional substituents
  • R ⁇ ' and R*5' each independently represent hydrogen, alkyl or alkylcarbonyl or R 4' and R-5' together with the nitrogen atom to which they are attached form a heterocyclic ring, providing that R* represents an aromatic heterocyclyl group only when Y' as defined below represents a bond ;
  • X' represents 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;
  • n' represents an integer in the range of from 2 to 6.
  • the compounds of formula (A) have particularly good blood- glucose lowering activity combined with freedom from adverse haematological and cardiac effects. These compounds are therefore considered to hold potential to be of particular use in the treatment and/or prophylaxis of hyperglycaemia and to be of particular use in the treatment of Type II diabetes. These compounds are also indicated to be of potential use for the treatment and/or prophylaxis of other diseases including hyperlipidaemia and hypertension. They are also indicated to be of use in the treatment and/or prophylaxis of cardiovascular disease, especially atherosclerosis.
  • 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.
  • These compounds are also indicated to be of of potential use in the treatment and/or prophylaxis of renal disease, especially renal disease associated with the development of Type II diabetes including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.
  • the prophylactic action of an insulin sensitiser upon nephropathy is also indicative that an insulin sensitising agent can be expected to prevent, reverse, stabilise or retard the progression of microalbuminuria to albuminuria. This is because microalbuminuria is considered to be a predictor of future nephropathy, especially in patients with clinical evidence of pre-diabetic insulin resistance syndrome, alternatively referred to as Syndrome X.
  • R° represents 2-benzoxazolyl or 2-pyridyl and R-- represents CH 2 OCH 3 or CF 3 .
  • R° represents 2-benzoxazolyl.
  • R 1 represents CH2OCH3.
  • R 1 represents CF3
  • 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.
  • 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 bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietyiamine, 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, where feasible, pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate, ⁇ -keto glutarate and ⁇ -glycerophosphate.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • the salts and/or solvates of the compounds of formula (I) may be prepared and isolated according to conventional procedures, for example sodium salts may be prepared by using sodium methoxide in methanol.
  • the present invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and or a pharmaceutically acceptable hydrate thereof, which process comprises hydrolysing a compound of formula (II):
  • R° and R* are as defined in relation to formula (I) and L represents a hydrolysable group; and thereafter, if required, preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
  • a suitable hydrolysable group L* is a group of formula (a) or an epimer thereof:
  • a suitable hydrolysable group L* is an Evans chiral auxiliary, for example a group of formula (b) or an epimer thereof: O
  • a suitable hydrolysable group L ⁇ is a C . alkoxy group.
  • the hydrolysis of the compound of formula (II) is carried out using conditions appropriate for hydrolysing the particular group L* chosen, for example when LMs a group of formula (a) or a C g alkoxy group, the hydrolysis is suitably carried out under acidic conditions, for example using dilute sulphuric acid, conveniently in a water/dioxan mixture, for example a 1:1 mixture, at any temperature which provides a suitable rate of formation of the required product, generally at an elevated temperature, such as in the range of from 50°C to 120°C, for example 90°C; or when L* is a group of formula (b) the hydrolysis is generally carried out using lithium hydroperoxide in an aqueous solvent, such as aqueous tetrahydrofuran, at any temperature which provides a suitable rate of formation of the required product, generally at a reduced temperature, such as in the range of from - 10°C to 0°C
  • L s a group of formula (b)
  • the hydrolysis may be effected under basic conditions, using for example aqueous sodium hydroxide, in an appropriate solvent such as aqueous tetrahydrofuran usually at ambient temperature.
  • a compound of formula (II), wherein L * is a moiety of the above defined formula (a) or (b) may be prepared from a compound of formula (III) :
  • R° and R are as defined in relation to formula (I) and L*-- represents a leaving group; (i) for compounds of formula (II) wherein L ⁇ is a moiety of the above defined formula (a), by reaction with (S)-phenylglycinol; or (ii) for compounds of formula (II) wherein L* is a moiety of the above defined formula (b), by reaction with (5)-4-benzyloxazolidin-2-one, preferably an activated form thereof; and thereafter separating the required isomer from the mixture of diastereoisomers produced.
  • a suitable leaving group L**- is a halogen atom, for example a chlorine atom.
  • the reaction between the compounds of formula (III) and (S)-phenylglycinol may be carried out under conventional amidation conditions, for example in an inert solvent such as dichloromethane at a temperature which provides a suitable rate of foimation of the required product, suitably at ambient temperature and preferably in the presence of a base such as triethylamine.
  • a suitable activated form of S -4-benzyloxazolidin-2-one is a salted form, for example an alkali metal salted form, preferably a lithium salt.
  • the activated form of CS > )-4-benzyloxazolidin-2-one may be prepared by any appropiate conventional method.
  • the activated form is a lithium salt
  • it may be prepared by treating (S,)-4-benzyloxazolidin-2-one with a source of lithium ions in the presence of a base, suitably provided by n-butyllithium, in an aprotic solvent such as tetrahydrofuran, usually at a low temperature, for example in the range of from -78° to 0°C.
  • reaction between the compound of formula (III) and the activated form of (S -4-benzyloxazolidin-2-one may be carried out in an aprotic solvent, such as tetrahydrofuran, at a temperature which provides a suitable rate of formation of the required product, conveniently by allowing the reaction mixture to slowly warm from -78° to 0°C.
  • an aprotic solvent such as tetrahydrofuran
  • the activated form of (S ; )-4-benxyloxazolidin-2-one is prepared and then reacted in-situ with the compound of formula (III).
  • a compound of formula (III) may be prepared by hydrolysing the carboxylic ester COOR-2 of a compound of formula (IV):
  • R° and R are as defined in relation to formula (I) and R ⁇ represents an alkyl group, and thereafter converting the carboxylic acid group so formed into a moiety CO.lA
  • a suitable alkyl group R* ⁇ is a Cj.g alkyl group, especially a methyl group.
  • the hydrolysis of the carboxylic ester may be effected by use of any conventional hydrolysing agent, such as an alkaline metal hydroxide, for example sodium hydroxide.
  • the hydrolysis of the compound of formula (IV) may be ca ⁇ ied out in any suitable solvent such as a methanol/water mixture, conveniently a 1:1 mixture, at a temperature which provides a suitable rate of formation of the required product, suitably at an elevated temperature and conveniently at the reflux temperature of the solvent.
  • a suitable solvent such as a methanol/water mixture, conveniently a 1:1 mixture
  • the conversion of the carboxylic acid group into the moiety CO.L*** may be carried out using any appropiate conventional procedure, depending upon the particular nature of the group L-2 chosen, thus when L ⁇ is a halogen a suitable procedure involves treatment of the carboxylic acid with an oxalyl halide, for example oxalyl chloride when L**- is chlorine.
  • reaction conditions for the conversion of the carboxylic acid group into the moiety CO.L**- will be dictated by the particular nature of L ⁇ and the source of L ⁇ chosen, for example when I?- is halogen and the source of ⁇ ?- is oxalyl chloride then the reaction may be carried out in an inert solvent such as dichloromethane or benzene at a temperature which provides a suitable rate of formation of the required product, suitably at ambient temperature or at an elevated temperature such as the reflux temperature of the solvent.
  • an inert solvent such as dichloromethane or benzene
  • a compound of formula (II) wherein I-.* is a moiety of formula (b) may also be prepared by dehydroxylation of a compound of formula (V):
  • the dehydroxylation of the compound of formula (V) is conveniently carried out by treatment with a trialkylsilane, for example triethylsilane, preferably in the presence of trifluoroacetic acid and conveniently using trifluoroacetic acid as solvent, at any temperature providing a suitable rate of formulation of the product, for example at a temperature in the range from 0°C to room temperature.
  • a trialkylsilane for example triethylsilane
  • a compound of formula (V) may be prepared by reacting a compound of formula (VIA): wherein R° is as defined in relation to formula (I), with a compound of formula (VIB):
  • R 1 is as defined in relation to formula (I); and thereafter separating the required isomer from the mixture of diastereoisomers produced.
  • the compound of formula (VIB) is in an activated form, which is preferably provided by treating the compound of formula (VIB) with an alkylboron triflate, for example dibutylboron triflate, preferably in the presence of an amine base such as triethylamine.
  • the activated form of the compound of formula (VIB) may be prepared by the appropriate conventional method depending upon the specific nature of the activated form chosen, for example the compound of formula (VIB) is reacted with dibutylboron triflate and triethylamine in an inert solvent such as dichloromethane at a temperature in the range of from -78° to 0°C.
  • reaction between the compounds of formulae (VIA) and (VIB) may be carried out in an in an inert solvent such as dichloromethane, at a temperature which provides a suitable rate of formation of the required product, conveniently by allowing the reaction mixture to slowly warm from -78° to 0°C.
  • an inert solvent such as dichloromethane
  • the activated form of the compound of formula (VIB) is prepared and then reacted in-situ with the compound of formula (VIA).
  • a suitable compound of formula (VIA) is 4-[2-[N-(2-benzoxazolyl)-N- methylamino]ethoxy]benzaldehyde.
  • a suitable means for separating any required single isomer from a mixture of diastereoisomers is chromatography, such as preparative high pressure liquid chromatography or silica gel column chromatography.
  • chromatography such as preparative high pressure liquid chromatography or silica gel column chromatography.
  • One convenient method for preparing a compound of formula (II) wherein L* is a C ⁇ _6 alkoxy group is the basic alcoholysis of a compound of formula (II) wherein L-,1 is a moiety of formula (b).
  • a suitable base is an alkali metal alkoxide, for example when i is methoxy the compound of formula (II) wherein L* is moiety (b) is treated with sodium methoxide in methanol.
  • a compound of formula (I) may also be prepared by resolving a racemic compound of formula (VII):
  • R° and R-- are as defined in relation to formula (I); and thereafter, if required, preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
  • the resolution of a compound of formula (VII) may be carried out using known resolution procedures, for example by reacting the compound of formula (VII) with a resolving agent, such as an optically active acid or base, to provide a mixture of diastereoisomeric salts which may then be separated by fractional crystallisation and thereafter the compound of formula (I) may be regenerated from the separated diastereoisomer salt by conventional means, such as hydrolysis.
  • the compounds of formula (VII) comprise the compounds of formula (I) admixed with other optical isomers.
  • a compound of formula (VII) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof forms a further aspect of the present invention.
  • the separated isomers of the compounds of formula (VII), in addition to the compounds of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof also comprise the present invention.
  • Suitable acids or bases for resolving the compounds of formula (VII) are as described in Enantiomers, Racemates and Resolution, J Jaques et al. 1981, Wiley Interscience, especially at pages 255 and 256. Suitable methods for effecting the resolution are also disclosed by Jaques et al.
  • the compounds of formula (IV) and (VIA), for example 4-[2-[N-(2- benzoxazolyl)-N-methylamino]ethoxy]benzaldehyde, are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example those disclosed in International Patent Application, Publication Number WO94/01420.
  • the compounds of formula (VIB) are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example those disclosed in Organic Synthesis Vol. 68, p83, 1990 Ed. J.D. White or methods analogous thereto, in combination with conventional methodology for the preparation of acid chlorides.
  • 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 an.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the above mentioned preparation of the compounds of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is a stereoselective procedure and that the compound of formula (I) is a single stereoisomer.
  • the present invention also includes a compound of formula (I) when present in admixture with less than 50% w/w of its racemic isomer, that is when it is greater than 50% optically pure, suitably 80-100% and preferably 90-100% pure, such as 90-95%, most preferably 95-100%, for example 95%, 96%, 97%, 98%, 99% or 99.9% optically pure.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof in optically pure form.
  • the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography.
  • the compounds of the invention are indicated as having useful therapeutic properties:
  • the present invention accordingly provides a compound of formula (I), 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 (I), 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 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 pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof for use in the treatment of hypertension, cardiovascular disease, certain eating disorders and/or the treatment and/or prophylaxis of renal disease.
  • the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the prevention, reversal, stabilisation or retardation of the progression of microalbuminuria to albuminuria.
  • 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.
  • Renal disease includes renal disease associated with the development of Type
  • diabetes including diabetic nephropathy, glomerulonephriris, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be administered ES ⁇ ££ 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 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.
  • the composition will be formulated in unit dose form. Such 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 hyperglycaemia 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 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, hypertension, cardiovascular disease, certain eating disorders, the treatment and/or prophylaxis of renal disease and/or the prevention, reversal, stabilisation or retardation of the progression of microalbuminuria to albuminuria in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a 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 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 hypertension, cardiovascular disease, certain eating disorders, the treatment and/or prophylaxis of renal disease and/or the prevention, reversal, stabilisation or retardation of the progression of microalbuminuria to albuminuria will generally be those mentioned above in relation to hyperglycaemia.
  • the present invention provides the use of a compound of formula (I), 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 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 and/or the prophylaxis of renal disease and/or in the prevention, reversal, stabilisation or retardation of the progression of microalbuminuria to albuminuria.
  • Example 2 5>3-[4-[2-[N-(2-BenzoxazolyI)-N-methylamino]ethoxy]phenyI]-2-(2 ⁇ - trifluoroethoxy)propanoic acid by hydrolysis of amide
  • Aqueous sodium hydroxide solution (2.5M, 65 mL, 0.163 mol, 2.3 eq) was added to a stirred solution of [3(2S), 4S]-3-[3-[4-[2-[N-(2-benzoxazolyl)-N- methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoyl]-4- benzyloxazolidin-2-one (from Procedure 10)(42.5 g, 0.071 mol) in THF (500 mL) and water (125 mL). The mixture was sti ⁇ ed for 20 minutes, the reaction was diluted with water (1 L) and extracted with dichloromethane (3 x 700 mL).
  • Oxalyl chloride (1.1 mL) was added to a solution of ( ⁇ )-3-[4-[2-[N-(2-benzoxazolyl)- N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid (1.72 g) in dry benzene (30 mL). The mixture was heated at reflux for 2 hours, cooled and evaporated to dryness to give the title compound as a gum which was used without further purification.
  • the resulting mixture was stirred at -78°C for 30 minutes, then warmed from -78°C to 0°C over 60 minutes along a linear gradient (warming rate - 1.3°C.min _1 ) and stirred at 0°C for a further 75 minutes.
  • the reaction mixture was poured into a quenching solution of methanol (500 mL), pH 7 phosphate buffer (250 mL) and hydrogen peroxide (27.5% w/v, 110 mL) and stirred vigourously for 30 minutes. Water (4 L) was added, the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 1 L).
  • Triediylsilane 120 mL, 0.75 mol was added over 5 minutes to a stirred, ice cooled solution of [3(2S, 3R), 4S]-3-[3-[4-[2-[N-(2-benzoxazolyl)-N- methylamino]ethoxy]phenyl]-3-hydroxy-2-(2,2,2-trifluoroethoxy)propanoyl]-4- benzyloxazolidin-2-one (46.23 g, 7.5 x 10 -2 mol) in trifluoroacetic acid (650 mL). The mixture was stirred at 0°C for 1 hour, then at room temperature for a further 60 hours.
  • the tide compound was prepared from (4S)-4-benzyI-3-[2-(2- methoxyethoxy)ethanoyl]oxazolidin-2-one by a method analogous to that described in Procedure 9.
  • the crude reaction mixture was chromatographed on silica gel using a gradient of 15-40% ethyl acetate in dichloromethane to afford the product as a gum (comprising 2 diastereoisomers, ratio >99:1 by -H NMR).
  • mice C57bll/6 obese (ob/ob) mice were fed on powdered oxoid diet. After at least one week, die mice continued 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 die blood glucose curve where test compound treated groups are compared with the control group. 8 mice were used for each treatment.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Composé de formule (I) ou sel et/ou solvat pharmaceutiquement acceptables dudit composés, dans laquelle Ro représente 2-benzoxazolyle ou 2-pyridyle et R1 représente CH¿2?OCH3 ou CF3, procédé de préparation desdits composés, composition pharmaceutique contenant lesdits composés et utilisation desdits composés et compositions en médecine.
PCT/EP1995/003038 1994-07-29 1995-07-28 Benzoxazoles et derives de pyridine utiles dans le traitement du diabete de type ii WO1996004260A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
BR9508468A BR9508468A (pt) 1994-07-29 1995-06-07 Composto processo para a preparação do mesmo composição farmacéutica processos para o tratamento e/ou profilaxia de hiperglicemia em um mamifero humano ou não humano e para o tratamento de hiperlípidemia hipertensão doença cardiovascular alguns distúrbios de alimentação o tratamento e/ou profilaxia de doença renal a prevenção revers o estabilização ou retardo da progressão de microalbuminuria em um mamifero humano ou não humano uso do composto e composto intermediário
AU33826/95A AU697545B2 (en) 1994-07-29 1995-07-28 Benzoxazoles and pyridine derivatives useful in the treatment of the ty pe II diabetes
EP95930436A EP0772605A1 (fr) 1994-07-29 1995-07-28 Benzoxazoles et derives de pyridine utiles dans le traitement du diabete de type ii
JP8506194A JPH10503508A (ja) 1994-07-29 1995-07-28 Ｉｉ型糖尿病の治療において有用なベンゾオキサゾールおよびピリジン誘導体
SK122-97A SK12297A3 (en) 1994-07-29 1995-07-28 Benzoxazoles, pyridine derivatives, process for producing same pharmaceutical composition containing them, their use and intermediate product
NZ292125A NZ292125A (en) 1994-07-29 1995-07-28 Benzoxazole and pyridine substituted phenyl carboxylic acid derivatives; medicaments
FI970357A FI970357L (fi) 1994-07-29 1995-07-28 Tyypin II diabeteksen hoitoon käyttökelpoisia bensoksatsoli- ja pyridiinijohdannaisia
MX9700763A MX9700763A (es) 1994-07-29 1995-07-28 Procedimiento para la preparacion de benzoxazoles y derivados de piridinas utiles en el tratamiento de la diabetes del tipo ii, los benzoxazoles y derivados de piridina obtenidos, composiciones de los mismos y su uso.
CZ97254A CZ25497A3 (en) 1994-07-29 1995-07-28 Benzoxazoles and pyridine derivatives usable for treating type ii diabetes
NO970373A NO307827B1 (no) 1994-07-29 1997-01-28 Benzoksazol- og pyridinderivater, anvendelse av dem og farmasøytisk preparat inneholdende dem
BG101180A BG101180A (en) 1994-07-29 1997-01-29 Benzoxazoles and pyridine derivatives useful in the treatment of the type ii diabetes

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GB9415330.1 1994-07-29
GB9415330A GB9415330D0 (en) 1994-07-29 1994-07-29 Novel compounds
GB9425599.9 1994-12-19
GBGB9425599.9A GB9425599D0 (en) 1994-12-19 1994-12-19 Novel compounds
GBGB9509923.0A GB9509923D0 (en) 1995-05-17 1995-05-17 Novel compounds
GB9509923.0 1995-05-17
GBPCT/GB95/01323 1995-06-07
PCT/GB1995/001323 WO1996004261A1 (fr) 1994-07-29 1995-06-07 Benzoxoazoles et derives de pryridine destines a etre utilises pour le traitement du diabete tardif

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AP (1) AP776A (fr)
BR (1) BR9508468A (fr)
CA (1) CA2196079A1 (fr)
CZ (1) CZ25497A3 (fr)
DZ (1) DZ1916A1 (fr)
FI (1) FI970357L (fr)
HU (1) HUT76637A (fr)
IL (3) IL114759A (fr)
MA (1) MA23632A1 (fr)
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WO1997025042A1 (fr) * 1996-01-09 1997-07-17 Smithkline Beecham P.L.C. Utilisation d'un agoniste de ppar-alpha et de ppar-gamma dans le traitement du syndrome x
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WO2000026200A1 (fr) * 1998-10-29 2000-05-11 Dr. Reddy's Research Foundation Technique amelioree de preparation de nouveaux agents antidiabetiques
US6531596B1 (en) 1998-10-29 2003-03-11 Dr. Reddy's Laboratories Ltd. Process for the preparation of new antidiabetic agents
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US7348426B1 (en) 1999-04-28 2008-03-25 Dr. Reddy's Laboraties Limited Substituted bicyclic heterocycles, process for their preparation and their use as antiobesity and hypocholesterolemic agents
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US7202213B2 (en) 2000-01-28 2007-04-10 Novo Nordisk A/S Combination therapy using a dual PPAR-α/PPAR-γ activator and a GLP-1 derivative for the treatment of metabolic syndrome and related diseases and disorders
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MX9700763A (es) 1997-05-31
OA10470A (en) 2002-04-08
NO970373D0 (no) 1997-01-28
DZ1916A1 (fr) 2002-02-17
BR9508468A (pt) 1997-11-25
AP776A (en) 1999-10-28
FI970357A7 (fi) 1997-03-26
AP9700918A0 (en) 1997-01-31
IL125525A (en) 2000-02-29
NO307827B1 (no) 2000-06-05
EP0772605A1 (fr) 1997-05-14
PL318766A1 (en) 1997-07-07
IL114759A0 (en) 1995-12-31
IL125525A0 (en) 1999-03-12
FI970357L (fi) 1997-03-26
SK12297A3 (en) 1997-08-06
FI970357A0 (fi) 1997-01-28
CA2196079A1 (fr) 1996-02-15
CZ25497A3 (en) 1997-09-17
MA23632A1 (fr) 1996-04-01
WO1996004261A1 (fr) 1996-02-15
NO970373L (no) 1997-03-18
HUT76637A (en) 1997-10-28
IL114759A (en) 1999-10-28

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