WO1995017394A1 - Derives heterocycliques et leur utilisation dans des produits pharmaceutiques - Google Patents

Derives heterocycliques et leur utilisation dans des produits pharmaceutiques Download PDF

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WO1995017394A1
WO1995017394A1 PCT/EP1994/004112 EP9404112W WO9517394A1 WO 1995017394 A1 WO1995017394 A1 WO 1995017394A1 EP 9404112 W EP9404112 W EP 9404112W WO 9517394 A1 WO9517394 A1 WO 9517394A1
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formula
compound
group
pharmaceutically acceptable
moiety
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PCT/EP1994/004112
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Barrie Christian Charles Cantello
David Haigh
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Smithkline Beecham Plc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • This invention relates to certain novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
  • certain novel compounds show particularly good blood-glucose lowering activity and are therefore of potential use in the treatment and/or prophylaxis of hyperglycaemia and are 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.
  • Al represents a substituted or unsubstituted aromatic heterocyclyl group;
  • a ⁇ represents a benzene ring having three optional substituents;
  • a ⁇ represents a moiety of formula -(CH2) m -CH(OR 1 )- wherein m represents an integer in the range of from 1 to 5 and
  • R.1 represents a moiety -(CH2) x -Y 1 -(CH2)y-T wherein Y 1 represents O, NR° wherein R° is H, alkyl or alkylcarbonyl or Y 1 is S, T represents a phenyl group optionally substituted with up to 3 substituents selected from halo, alkyl and alkoxy, x represents an integer in the range of from 2 to 5 and y represents zero or an integer in the range of from 1 to 5; or
  • R2 represents OR 3 wherein R ⁇ represents hydrogen, alkyl, aryl or aralkyl or R ⁇ represents an aromatic heterocyclyl group or -NR4R5 wherein R ⁇ and R ⁇ each independently represent hydrogen, alkyl or alkylcarbonyl or R ⁇ and R ⁇ 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;
  • 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 5 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 ⁇ 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* represents a moiety of formula (a), (b) or (c):
  • R6 and R ⁇ each independently represents a hydrogen or halogen atom, an alkyl or alkoxy group or a substituted or unsubstituted aryl group or when R6 and R ⁇ are each attached to adjacent carbon atoms, then R6 and R ⁇ together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R ⁇ and R ⁇ together is substituted or unsubstituted; and in the moiety of formula (a) ⁇ l represents oxygen or sulphur.
  • Al represents a moiety of the abovedefined formula (a).
  • Al represents a moiety of the abovedefined formula (b).
  • A* represents a moiety of the abovedefined formula (c).
  • a particular form of moiety (c) is a moiety (c 1 ):
  • R ⁇ and R ⁇ are as defined in relation to formula (c).
  • R ⁇ and R ⁇ together represent a moiety of formula ( ):
  • R ⁇ a and R ⁇ D each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R ⁇ a and R ⁇ D each independently represent hydrogen, halogen, alkyl or alkoxy.
  • R ⁇ a represents hydrogen.
  • R ⁇ D represents hydrogen.
  • R ⁇ a and R ⁇ b both represent hydrogen.
  • R ⁇ and R 7 each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, R ⁇ and R 7 each independently represent hydrogen, alkyl or phenyl.
  • R ⁇ and R 7 together represent the moiety of formula (d).
  • R 6 and R 7 both represent hydrogen.
  • a ⁇ represents a moiety of formula (e):
  • RlO and R ⁇ each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R ⁇ and RU each independently represent hydrogen, halogen, alkyl or alkoxy.
  • R 0 or R 1 represent alkoxy
  • a suitable alkoxy group is a methoxy group.
  • R ⁇ and R 1 1 each represent hydrogen.
  • A3 represents a moiety of formula -(CH2) m -CH(OR 1 )-.
  • x represents 2.
  • y represents zero.
  • Y* represents O.
  • T represents phenyl.
  • R 1 represents a moiety of formula -CH2-CH2-O-phenyl.
  • R ⁇ represents hydrogen or alkyl.
  • R3 is alkyl
  • examples of R ⁇ include methyl and ethyl.
  • R2 is an aromatic heterocyclyl group it is suitably a single ring aromatic heterocyclyl group having 5 ring atoms, which ring atoms comprise nitrogen and optionally 1, 2 or 3 additional hetero atoms; examples include 1, 2, 4-triazole; 1, 2, 4- oxadiazole and tetrazolyl; generally the aromatic heterocyclyl group is C-linked.
  • Suitable substituents on the aromatic heterocyclyl group include alkyl, aryl, alkoxy and halo, an example of a substituent is methyl.
  • heterocyclic rings When -NR 4 R 5 or -NR s R l 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.
  • a further example of NR R 5 is NH2-
  • R 2 represents NR 4 R 5 .
  • R 2 is OR 3 .
  • R 2 represents OR 3 wherein R 3 represents hydrogen, alkyl, aryl or aralkyl or R 2 represents -NR 4 R 5 , Y is CO or CS; preferably, Y is CO.
  • R 2 is an aromatic heterocyclyl group, Y is a bond.
  • R represents hydrogen or alkyl.
  • suitable acyl groups include alkylcarbonyl groups, such as acetyl.
  • n 1 or 2.
  • m 1 or 2.
  • n 2
  • 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.
  • a 3 represents a moiety of formula -(CH2) m -CH(ORl)- the CH(ORl)-carbon atom is a chiral carbon.
  • the present invention encompasses all of the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof, whether as individual isomers 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 Cj-12 ⁇ c yl groups, especially C g 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”.
  • Favoured aralkyl groups are phenylalkyl groups, optionally substituted on the aryl or alkyl moieties as defined herein.
  • 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 bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such
  • 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, malear ⁇ citrate, succinate, benzoate, ascorbate, methane- sulphonate, ⁇ -keto glu.-.rate and ⁇ -glycerophosphate.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • 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 tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, which process comprises reacting a compound of formula (II):
  • a 2 and Y are as defined in relation to formula (I);
  • a 3 ' represents a moiety of formula -(CH2) m -CH(OR 1 )- wherein R*' represents R! as defined in relation to formula (I) or a protected form thereof, and m is as defined in relation to formula (I), or
  • R 2' represents R 2 as defined in relation to formula (1) or a protected form thereof and
  • R a is a moiety convertible to a moiety of formula (f):
  • A*, X and n are as defined in relation to formula (I); with an appropriate reagent capable of converting R a to the said moiety (f) and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) to a further compound of formula
  • R a represents HX-(CH2) n -O- wherein X and n are as defined in relation to formula (I), or R a represents OH.
  • R a represents OH.
  • an appropriate reagent capable of converting R a to a moiety (f) is a compound of formula (HI):
  • 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.
  • R 1' is R 1 .
  • R 2 ' represents OR 3 ' wherein R 3 ' represents hydrogen, alkyl, aryl, aralkyl or R 2 ' represents the above defined moiety -NR 4 R 5 .
  • an appropriate reagent is a compound of formula (IIIA):
  • reaction between the compound of formula (II) and the appropriate reagent may be carried out under conditions suitable to the particular compound of formula (TJ) and the reagent chosen:
  • the abovementioned reaction between a compound of formula (II) wherein R a represents HX-(CH2) n -O- 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 triethylamine.
  • reaction between the compound of formula (II) wherein R a is OH and the reagent of the abovedefined formula (IIIA) 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
  • a compound of formula (II), wherein A 3 ' represents a moiety of formula -(CH2) m -CH(OR * ')-, may be prepared by reacting a source of a carbene of formula (IV):
  • R D is a moiety R a or a ⁇ -oiety convertible to a moiety R a and R ⁇ is the above defined R 2 ' or a protecting group, with a compound of formula (V):
  • R*' is defined in relation to formula (II); and thereafter, if required, converting a moiety R D into a moiety R a and removing any protecting group.
  • Y is CO.
  • R 9 is OR 3 ' or - ⁇ R 4 R5.
  • a suitable source of the carbene of formula (IV) is provided by reacting a compound of formula (IVA):
  • a 2 , R 9 , Rb, Y and m are as defined in relation to formula (IV), with a suitable catalyst such as a rhodium (II) salt, for example rhodium (II) acetate, or a copper(II) salt, such as Cu(Cl)2, or copper powder.
  • a suitable catalyst such as a rhodium (II) salt, for example rhodium (II) acetate, or a copper(II) salt, such as Cu(Cl)2, or copper powder.
  • the reaction between the carbene of formula (IV) and the compound of formula (V) may be carried out under conventional conditions, generally in an inert solvent, such as benzene, or when practicable in compound (V) as solvent, at any temperature providing a convenient rate of formation of the required product, generally at an elevated temperature, such as the reflux temperature of the solvent:
  • an inert solvent such as benzene
  • compound (V) as solvent at any temperature providing a convenient rate of formation of the required product, generally at an elevated temperature, such as the reflux temperature of the solvent:
  • the conditions used are analogous to those disclosed in Tetrahedron Lett., 1973, 2233.
  • the compound of formula (IVA) may be prepared by diazotizing a compound of formula (VI):
  • a 2 , R 9 , R D , y and m are as defined in relation to the compound of formula (IV), with an appropriate diazotizing agent; and thereafter, if required, converting a moiety R D into a moiety R a and removing any protecting group.
  • a suitable diazotizing agent is an alkyl nitrite, such as iso-amyl nitrite.
  • Suitable diazotising conditions for preparing the compound of formula (IVA) are conventional conditions, for example those disclosed in Tetrahedron Lett., 1971, 4495.
  • Any moiety R D may be converted into a moiety R a by the appropriate conventional means, for example when Rb represents -OH and R a represents HX-(CH2) n -O- the appropriate conversion may be carried out by coupling a compound of formula (VI) wherein R D 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 in (IV) is either OH or a suitably protected OH, such as a silylated OH.
  • the compounds of formula (V) are known commercially available compounds or they may be prepared using methods analogous to those used to prepare such compounds.
  • the compounds of formula (VI) are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example those disclosed in Tetrahedron Lett., 1971, 4495, in particular the compound wherein R 9 is OCH3, m is 1, A 2 is 1,4-phenylene and R D is OH is a commercially available compound.
  • 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 3 represents a moiety of formula - (CH2) m -CH(OR 1 )-. 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 an activated form of a compound of formula (VII): A— X— (CH 2 ) n o— A— (CH 2 ) m — CH — Y -R*
  • R is as defined in relation to formula (I) and L represents a leaving group or atom; and thereafter if required carrying out one or more of the following optional steps:
  • L* is a halogen atom, for example a bromine atom.
  • a suitable activated form of a compound of formula (VII) is an anionic form such as a salted form and especially an alkali metal salted form, for example a sodium salt.
  • the activated form of the compound of formula (VII) may be prepared by any appropriate conventional procedure.
  • the anionic form of the compound of formula (VII) may be prepared by treating the compound of formula (VII) with a base, such as a metal hydride base, for example sodium hydride.
  • the reaction conditions for the reaction between the compounds of formulae (VII) and (VIII) are generally conventional alkylation conditions.
  • reaction between the salted form of a compound of formula (VII) and a compound of formula (VIII) may be carried out in an aprotic solvent, such as dimethylformamide, at any temperature providing a suitable rate of formation of the required product, generally an elevated temperature such as in the range of 40°C to 100°C, for example 80°C.
  • an aprotic solvent such as dimethylformamide
  • the formation of the activated form of (VII) from (VII) - for example the formation of a salted form of (VII) - may be carried out in-situ prior to the reaction of the activated form of (VII) with the above defined compound of formula (VIII).
  • a compound of formula (VII) may be prepared by reacting a compound of formula (IX):
  • R a , R 9 , A 2 , Y and m are as defined above and T is hydrogen or a hydroxyl protecting group, with an appropriate reagent capable of converting R a to 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 (II) 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 (IIIA) 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.
  • aprotic solvent such as dimethylformamide
  • 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 J. March, Advanced
  • a compound of formula (I), wherein A 3 represents a moiety of formula - (CH2) m -CH(OR )-, 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 source of a carbene of formula (X):
  • a suitable source of a carbene of formula (X) is provided be reacting a compound of formula (XI):
  • the carbene of formula (X) may be prepared from the compound of formula (XI) by using an analogous procedure to that used for the preparation of the carbene of formula (IV) from the compound of formula (IVA).
  • the reaction conditions for the reaction between the compounds of formulae (X) and (V) are equivalent to those used in the reaction between the compounds of formulae (IV) and (V).
  • the compound of formula (XI) may be prepared by reaction between the compounds of formulae (IIIA) and (VI) using an analogous procedure to that used for the preparation of the compound of formula (I) from the compounds of formulae (II) and (IIIA) and thereafter diazotized as described above for the conversion of (VI) to (IVA).
  • R*', R 2' and Y are as defined in relation to formula (II) and R*0 represents a Cj.g alkyl group, preferably a methyl or ethyl group.
  • the reaction between the compounds of formulae (XII) and (XM) 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 0° to 25°C, conveniently at ambient temperature, preferably in an inert atmosphere and under anhydrous conditions.
  • an aprotic solvent such as tetrahydrofuran
  • ambient temperature such as in the range of from 0° to 25°C
  • ambient temperature such as in the range of from 0° to 25°C
  • the compound of formula (XIII) is suitably activated, for example by the addition of a base such as sodium hydride or n-butyl lithium, prior to the addition of the compound of formula (XII).
  • the reduction of a compound wherein A 3 represents a moiety of formula to provide a compound wherein A 3 represents a moiety of formula -(CH2)m" H(OR )- may be carried out using conventional reduction methods, such as catalytic reduction using for example a 10% palladium-on- carbon catalyst in an alkanolic solvent such as ethanol, or by use of a metal/solvent system such as magnesium metal/methanol as described in Tet. Lett. 1986, 21, 2409.
  • a compound of formula (XII) may be prepared from a compound of formula (X ⁇ A):
  • a compound of formula (XIIA) may be prepared from a compound of formula (XIIB):
  • reaction conditions for the reaction between the compounds of formulae (IIIA) and (XIIB) are those described above for the reaction between the compounds of formulae (II) and (IIIA).
  • a compound of formula (II) wherein A 3 ' represents a moiety of formula -CH- ⁇ C OR 1 ')- or -CH2-CH(OR l ')-, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be prepared by reacting a compound of formula (XIV):
  • R D is a protected OH group.
  • the compounds of formula (XIIB) are known commercially available compounds or they are compounds prepared by analogous methods used to prepare such compounds or they may be prepared from such compounds, for example by converting a commercially available carboxylic acid into an alkyl ester.
  • the compounds of formula (XIII), are known compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in Annalen Chemie 1966, 699, 53 or J. Org. Chem. 1983, 48, 3408 and Tetrahedron 1992, 48, 3991.
  • the compounds of formulae (XIV) are known compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in EP 0306228.
  • a compound of formula (I), wherein A 3 represents a moiety of formula -CH2 - CH ⁇ R 1 )- wherein R 1 represents alkyl, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be prepared by hydrolysing a compound of formula (XV):
  • a 1 , A 2 , R 1 , X and n are as defined in relation to formula (I) to provide a compound of formula (I) wherein R 2 represents OH; and thereafter, if required, converting R 2 as OH into another R 2 ; and thereafter, if required,carrying out one or more of the following optional steps: (i) converting a compound of formula (I) into a further compound of formula
  • the hydrolysis of the compound of formula (XV) may be carried out using conventional conditions and reagents for nitrile hydrolysis, for example basic hydrolysis using 10% sodium hydroxide in methanol.
  • R 2 as OH into another R 2 may be effected by using any convenient method, such as those methods described hereinafter.
  • a compound of formula (XV) may be prepared from a compound of formula (XVI):
  • the reaction between the compounds of formulae (XVI) and trimethylsilylcyanide may be carried out in an inert solvent, such as dichloromethane, at low to ambient temperature, conveniently at ambient temperature and preferably in the presence of a Lewis acid catalyst, such as boron trifluoride etherate.
  • a compound of formula (XVI) may be prepared from a compound of formula (XVII):
  • R la -OH (XVIII) wherein R* a is as defined above.
  • the reaction between the compounds of formulae (XVII) and (XVIII) is suitably carried out using the compound of formula (XVIII) as solvent, generally at an elevated temperature such as the reflux temperature of the solvent and preferably in the presence of p-toluenesulphonic acid.
  • R 1 a is methyl.
  • the compounds of formula (XVIII) and (XIX) are known compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.
  • a compound of formula (I), wherein A 3 is (CH2) m -CH(OR 1 )- and R 2 is a C- linked aromatic heterocyclyl group, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, may be prepared by reacting a compound of the above defined formula (XII) with an activated form of a compound of formula (XX)
  • het-CH is an aromatic heterocyclic group represented by R 2 which contains at least 1 carbon atom and thereafter converting the compound wherein R is hydrogen into another R ; and thereafter if required: (i) converting a compound of formula (I) to a further compound of formula
  • a suitable activated form of a compound of formula (XX) is a salted form such as a lithium salted form.
  • the activated form of a compound of formula (XX) may be prepared by reacting an aromatic heterocyclic group Het-CH or Het-CL, wherein L is a leaving group such as halogen, with an appropriate, conventional activating agent such as a salting agent, for example an alkyl lithium, in an aprotic solvent such as tetrahydrofuran according to known methods and procedures for example those disclosed in Adv. Heterocyclic chem., 1993, 56, 155.
  • an appropriate, conventional activating agent such as a salting agent, for example an alkyl lithium
  • A*, A 2 , R , X, m and n are as defined in relation to formula (I), with a source of azide ions such as an azide salt, suitably an alkali metal azide, for example sodium azide.
  • the compound of formula (XXI) may be prepared by dehydrating a compound of formula (I) wherein A 3 is (CH2) m -CH(OR 1 ) and YR 2 is CONH2 using for example POCI3.
  • reaction between the compound of formula (XXI) and the source of azide ions may be carried out under conventional conditions for example when sodium azide is the source of azide ions the reaction may be effected in an aprotic solvent such as dimethylformamide generally at an elevated temperature, for example the reflux temperature of the solvent; preferably in the presence of trimethylsilyl chloride.
  • an aprotic solvent such as dimethylformamide generally at an elevated temperature, for example the reflux temperature of the solvent; preferably in the presence of trimethylsilyl chloride.
  • the conversion of a compound of formula (I) to a further compound of formula (I) may be carried out by using any appropriate conventional procedure.
  • 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 Y.R 2 wherein Y is CO into another group Y.R 2 include:
  • 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) or c(iii) include conventional methods, for example treatment with aqueous ammonia in tetrahydrofuran/methanol.
  • Suitable halogenation methods for conversion c(iii) include conventional methods, for example treatment with oxalyl chloride.
  • alkyl esters may be prepared by using the appropriate alkanol, for example methanol, in the presence of an acid and aralkyl esters may be prepared by treatment of a salted YOH group, such as a sodium salt, with an appropriate aralkyl halide, for example benzyl bromide.
  • a salted YOH group such as a sodium salt
  • Suitable conversion of a group Y.NH2 wherein Y is CO into a group Y- C-Het wherein Y is a bond and C-Het is a C-linked aromatic heterocyclyl group includes: a) reaction with a hydrazine, for example hydrazine hydrate, and an amide acetal, such as dimethylformamide dimethyl acetal, to provide a 1,2,4-triazole; or b) reaction with a hydroxylamine, for example hydroxylamine hydrochloride, and an amide acetal, such as dimethylformamide dimethyl acetal, to provide a 1,2,4-oxadiazole.
  • a hydrazine for example hydrazine hydrate
  • an amide acetal such as dimethylformamide dimethyl acetal
  • Suitable conversions of one group CO.R 2 into another group CS.R 2 may be effected using conventional methods.for example by using Lawesson's reagent in a solvent such as toluene, at any temperature providing an acceptable rate of formation of the required product, conveniently at the reflux temperature of the solvent.
  • 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.
  • suitable hydroxyl protecting groups include benzyl or trialkylsilyl groups.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • a 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.
  • 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.
  • certain compounds of formula (I) there is provided a novel process for separating optical isomers of such compounds. Indeed the newly discovered process is considered to be capable of separating optical isomers of any compound providing the chiral carbon of such compound is attached to a carboxy ester group and a group OZ 1 wherein Z ⁇ is alkyl, aryl or aralkyl.
  • the present invention provides a process for separating optical isomers of a compound (the substrate ester) which comprises a moiety of formula (H):
  • C* is a chiral carbon
  • Z is a C ⁇ j2 alk y* ⁇ rou P ⁇ md
  • Z* is a C . _ ⁇ alkyl, aryl or an aryl alkyl group, which process comprises enantioselectively hydrolysing the ester group CO2Z of one enantiomer into a carboxyl group with a lipase from Rhizopus delemar, Rhizopus arrhizus, Rhizopus LIP F4 or a lipase from Mucor miehei; and thereafter, as necessary, isolating either the enantiomerically enriched product carboxylic acid or the enanatiomerically enriched substrate ester.
  • the enantiomerically enriched product carboxylic acid and/or the enanatiomerically enriched substrate ester may be isolated using conventional extraction methods, such as phase separation and/or extraction into a suitable solvent, and thereafter, if required it may be chromatographed.
  • the enantiomerically enriched substrate ester may be converted by hydrolysis into the respective carboxylic acid which may then be isolated in the usual way.
  • the enantiomerically enriched substrate ester may be hydrolysed by treatment with the abovementioned lipases to give the respective carboxylic acid.
  • the compounds of formula (I) which fall within formula (H) are those compounds wherein Z represents R 3 and represents Rl;
  • the novel process may be used to prepare enantiomerically enriched compounds of formula (I) wherein A 3 represents (CH2) m -CH(OR 1 )-, Y represents CO, R 2 is OR 3 and A*, A 2 , Rl, R 3 X, m and n are as defined in relation to formula (I)- (hereinafter referred to as compounds of formula (IA)).
  • the microbial lipase enzymes may be obtained by conventional culturing techniques such as those disclosed in J. Bacteriol., 1982, Vol.150498-505. H. Gilbert at-d M. Tully, European Patent Application No. 0198440 and British Patent No. 1,474,519.
  • the lipase may be isolated as a pure enzyme or, in the alternative a suitable source of the lipase may be incorporated into the reaction.
  • the microbial lipase enzymes are obtained commercially as purified or partially purified enzyme preparations.
  • the hydrolysis of the compound of formula (H) may be carried out in any suitable aqueous solvent having controlled pH, for example in an aqueous buffer or in a solvent wherein the pH is controlled by the addition of aqueous sodium hydroxide, at a pH which provides a suitable rate of formation of the required product, which is generally a pH in the range of from 5 to 9, such as in the range of from 6 to 8, for example at pH7.
  • the hydrolysis may be carried out at any temperature which provides a suitable rate of formation of the required product, being generally at a low to ambient temperature, such as a temperature in the range of from 5°C to 40°C, such as in the range of from 20°C to 40°C and preferably in the range of from 20°C to 30°C, for example 23°C.
  • the substrate mixture is introduced into the reaction system as a solution in an organic solvent which may be a water miscible solvent such as acetone, tetrahydrofuran, dimethylsulphoxide, dimethylformamide or acetonitrile.
  • organic solvent which may be a water miscible solvent such as acetone, tetrahydrofuran, dimethylsulphoxide, dimethylformamide or acetonitrile.
  • the stereoselective process selectively hydrolyses the compound (IA) having the same stereochemistry at the asterisked carbon atom as the equivalent carbon atom in (-) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]- 2-methoxypropanoic acid.
  • reaction conditions such as the particular acidic pH and the reaction temperature which provide optimum enrichment for any particular enantiomerically enriched compound (H) may be determined by routine experimentation.
  • the stereoselective reaction provides enantiomerically enriched compound (IA) in the form wherein the required enantiomer is present in greater than 70% w/w; and favourably greater than 80% w/w.
  • the product from the stereoselective process provides enantiomerically enriched compound (IA) in the form wherein the required enantiomer is present as 80- 100% w/w, preferably 90-100%, such as 90-95%, and most preferably 95-100%, for example 95%, 96%, 97%, 98%, 99% or 100% w/w.
  • the above mentioned enantiomerically enriched compound (IA) is considered to form a further aspect of the present invention. Accordingly the present invention provides enantiomerically enriched compound (IA) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.
  • the present invention also provides enantiomerically enriched compound (IA) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein the required isomer is present in greater than 50% w/w; suitably greater than 70% w/w and favourably greater than 80% w/w.
  • the enantiomerically enriched compound (IA) is in a form wherein 80-100% w/w , preferably 90- 100%, such as 90-95%, and most preferably 95-100%, for example 95%, 96%, 97%, 98%, 99% or 100% w/w is in the form of the required isomer of a compound of formula (IA).
  • a compound of formula (IA) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, preferably in optically pure form preferably in optically pure form.
  • the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography.
  • 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 (I), or a tautomeric form thereof and or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia.
  • the present invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment 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.
  • Cardiovascular disease includes in particular atherosclerosis.
  • Certain eating disorders include in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating ,such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia.
  • a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be administered rjei se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the general formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
  • the term 'pharmaceutically acceptable embraces compounds, compositions and ingredients for both human and veterinary use: for example the term 'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.
  • composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
  • compositions for oral administration are unit dosage forms such as tablets and capsules.
  • Other fixed unit dosage forms such as powders presented in sachets, may also be used.
  • the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
  • Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
  • composition will be formulated in unit dose form.
  • unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.
  • the present invention further provides a method 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 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.
  • mice C57W1/6 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 powered oxoid diet containing the test compound. After 8 days on the supplemented diet all of the mice were fasted for 5 hours prior to receiving an oral load of glucose (3g/kg). Blood samples for glucose analysis were taken 0,45,90 and 135 minutes after glucose administration and the results appear below as the percentage reduction in area under the blood glucose curve where test compound treated groups are compared with the control group. 8 mice were used for each treatment.

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Abstract

L'invention concerne un composé de la formule (I) A1—X—(CH¿2?)n—O—A?2—A3—YR2¿, ou une forme tautomère de celui-ci, et/ou un sel de celui-ci pharmaceutiquement acceptable et/ou un solvate de celui-ci pharmaceutiquement acceptable. Dans cette formule: A1 représente un groupe hétérocyclyle aromatique substitué ou non substitué; A2 représente un cycle benzène comprenant trois éventuels substituants; A3 représente une fraction de formule (CH¿2?)m-CH(OR?1¿)- où m représente un nombre entier de 1 à 5 et, R1 représente une fraction -(CH¿2?)x-Y?1-(CH¿2)y-T où Y1 représente O, NRo où Ro représente H, alkyle ou alkylcarbonyle, ou bien Y1 représente S, T représente un groupe phényle éventuellement substitué par trois substituants au maximum, choisis parmi halo, alkyle et alcoxy, x représente un nombre entier de 2 à 5 et y représente zéro ou un nombre entier de 1 à 5; ou bien A3 représente une fraction de formule -(CH¿2?)m-1-CH=C(OR?1¿)- dans laquelle R1 et m sont tels que définis ci-dessus; R2 représente OR3 où R3 représente hydrogène, alkyle, aryle ou aralkyle, ou bien R2 représente un groupe hétérocyclyle aromatique ou -NR?4R5, R?4 et R5¿ représentant chacun indépendamment hydrogène, alkyle ou alkylcarbonyle, ou R4 et R5 ensemble avec l'atome d'azote auquel ils sont attachés formant un cycle hétérocyclique, à la condition que R2 représente un groupe hétérocyclyle aromatique seulement lorsque Y tel que défini ci-dessous représente une liaison; X représente NR où R représente un atome d'hydrogène, un groupe alkyle, un groupe acyle, un groupe aralkyle dans lequel la fraction aryle peut être substituée ou non substituée, ou un groupe aryle substitué ou non substitué; Y représente C=O ou C=S ou une liaison, à condition que Y représente une liaison seulement lorsque R2 représente le groupe hétérocyclyle aromatique mentionné ci-dessus; et n représente un nombre entier compris de 2 à 6. L'invention concerne également un procédé de préparation d'un tel composé, une composition contenant celui-ci, ainsi que l'utilisation dudit composé et de ladite composition en médecine.
PCT/EP1994/004112 1993-12-22 1994-12-10 Derives heterocycliques et leur utilisation dans des produits pharmaceutiques WO1995017394A1 (fr)

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