OA11683A - Use of thiahzolidinediones for the treatment of hyperglycaemia. - Google Patents

Abstract

A method for the treatment of hyperglycaemia wherein plasma glucose levels are in the range of elevated normal to </=126mg/dl, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.

Description

1 •116 8 3

Novel Heterocyclic Ethanolamine Dérivatives with Beta-AdrenoreceptorAgonistic Activity

This invention relates to novel compounds, to a process for preparing suchcompounds, to pharmaceutical compositions containing such compounds and to theuse of such compounds and compositions in medicine and agriculture.

It has been discovered that a sériés of novel heterocyclic ethanolaminedérivatives hâve good b-adrenoreceptor agonist activity and in particular show goodselectivity for bg-adrenoreceptors versus bj- or b2-adrenoreceptors. Thesecompounds are therefore indicated to hâve good anti-hyperglycaemic and/or anti-obesity activity coupled with especially good selectivity ffom cardiac andtremorigenic side effects.

These compounds are also indicated to hâve potential in the treatment ofgastrointestinal disorders such as peptic ulcération, oesophagitis, gastritis andduodenitis, intestinal ulcérations, including inflammatory bowel disease, and irritablebowel syndrome and also for the treatment of gastrointestinal ulcérations, especiallywhen induced by non-steroidal anti-inflammatory drugs or corticosteroids.

These compounds also hâve potential as growth promoters for livestock andfor decreasing birth mortality rate and increasing the post-natal survival rate inlivestock. These compounds may also be of use in increasing the high-density-lipoprotein (HDL) cholestérol concentration and decreasing the triglycérideconcentration in human blood sérum and are therefore of potential use in the treatmentand/or prophylaxis of atherosclerosis. They are also indicated to be useful for thetreatment of hyperinsulinaemia. They are also indicated to be useful for the treatmentof dépréssion.

Accordingly the présent invention provides a compound of formula (I):

R

OH

(I) or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté thereof, wherein, X represents a moiety of formula (a): 116 8 3

in which represents -CH=CH=, NH, S or O; represents an oxo or a thioxogroup; A^ represents H or an alkylcarbonyl group; and A^ represents hydroxy orNRSRt wherein Rs and R1· each independently represents H or alkyl; R° and Ri each independently represents hydrogen or an alkyl group; R^ represents OCH2CO2H, or an ester or amide thereof, or R^ represents a moiety offormula (b): il -O-CI-L-P-OR4 (b) wherein R^ and R$ each independently represent hydrogen, alkyl, hydroxyalkyl,cycloalkyl or R^ together with R$ represents (CH2)n wherein n is 2, 3 or 4; and R^ represents hydrogen, halogen, alkyl or alkoxy or R^ together with R^ represents amoiety of formula (c): O. (c) or an ester or amide thereof, wherein R represents hydrogen, alkyl, hydroxymethyl ora moiety of formula (CH2)nCO2H, wherein n is zéro or an integer 1,2 or 3, or anester or amide thereof.

Suitably, A1 is -CH=GH-.

Suitably, A^ is oxo.

Suitably, A^ is H.

Suitably, A4 is OH, favourably substituted at the 4-position relative to thebond linking X to the CHOH carbon atom.

Suitably R° is hydrogen.

Suitably, Ri is an alkyl group.

When Ri is alkyl, it is favourably a Cj.g alkyl group, especially a methyl group. 3 11 6 8 3

Suitably, R^ together with R^ represents a moiety of formula (c).

The compounds of formula (I) hâve two or more asymmetric carbon atoms, forexample those marked with asterisks in the formula. These compounds may thereforeexist in different stereoisomeric forms. The présent invention encompasses ailstereoisomers of the compounds of the general formula (I) whether free from otherisomers, or admixed with other isomers in any proportion, such as mixtures ofdiastereoisomers and racemic mixtures of enantiomers.

Of particular interest are those carbon atoms marked with one (*) or two (**)asterisks in the formula.

Preferably, the asymmetric carbon atom indicated by a single asterisk (*) is inthe R-configuration.

Preferably, the asymmetric carbon atom indicated by two asterisks (**) is inthe R-configuration.

It should also be mentioned that the carbon atom in moiety (c) marked withthree asterisks (***) may also be chiral when R is different from the other attachedsubstituent (as selected from CO2H or an ester or amide thereof).

When the (***) carbon is non-chiral, a suitable form of a compound offormula (I) is a mixture of the R(*)R(**) and S(*)S(**) enantiomers

When the (***) carbon is non-chiral, a preferred form of a compound offormula (I) is the R(*)R(* *) enantiomer.

The term 'alkyl' when used alone or when forming part of other groups (suchas the 'alkoxy' group) includes straight- or branched-chain alkyl groups containing 1to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.

The term 'cycloalkyl' includes C3.8 cycloalkyl groups, especially C5 or Cgcycloalkyl groups.

When used herein the term "halogen" refers to fluorine, chlorine, bromine andiodine, preferably chlorine.

Suitable esters are pharmaceutically acceptable esters.

Suitable pharmaceutically acceptable esters of carboxyl groups include alkylesters, especially Cj.g alkyl esters such as methyl.

Suitable amides are pharmaceutically acceptable amides.

Suitable pharmaceutically acceptable amides are those of formula -CONRIR^wherein RÎ and R^ each independently represent hydrogen, alkyl or alkoxyalkyl.

Suitable salts are pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts include acid addition salts, salts ofcarboxy groups and salts of phosphonic acid groups.

Suitable pharmaceutically acceptable acid addition salts include salts withinorganic acids such, for example, as hydrochloric acid, hydrobromic acid, ‘116 8 3 orthophosphoric acid or sulphuric acid, or with organic acids such, for example asmethanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid,citric acid, fiimaric acid, malic acid, succinic acid, salicylic acid, maleic acid oracetylsalicylic acid.

Suitable pharmaceutically acceptable salts of carboxy groups or phosphonicacid groups include métal salts, such as for example aluminium, alkali métal saltssuch as lithium, sodium or potassium, alkaline earth métal salts such as calcium ormagnésium and ammonium or substituted ammonium salts, for example those withCj_6 alkylamines such as triethylamine, hydroxy-Cj.g alkylamines such as2-hydroxyethylamine, bis-(2- hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine,cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine,N-benzyl-b-phenethylamine, dehydroabietylamine, Ν,Ν'-bisdehydroabietylamine,glucamine, N-methylglucamine or bases of the pyridine type such as pyridine,collidine or quinoline.

Suitable solvatés are pharmaceutically acceptable solvatés.

Suitable pharmaceutically acceptable solvatés are conventional solvatés,preferably hydrates.

The invention also provides a process for the préparation of a compound offormula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceuticallyacceptable solvaté thereof, which process comprises reacting a compound of formula(Π): X1—CH—CH2 /

O (II) wherein χΐ represents X as defined in relation to formula (I) or a protected formthereof, with a compound of formula (III): _3a Λ Λ 1 Η,Ν- CH-CH, 2a k° σπ) wherein R°, RJare as defined in relation to formula (I), R^a represents R^ as definedin relation to formula (I) or a protected form thereof and R^a represents R3 as defined 5 116 8 3 in relation to formula (I) or a protected form thereof; and thereafter, if necessary,carrying out one or more of the following optional steps: (i) converting one compound of formula (I) into another compound of formula (i); (ii) removing any protecting group; and (ii) preparing a pharmaceutically acceptable acid addition sait of a compound offormula (I) or a pharmaceutically acceptable solvaté thereof.

The reaction between the compounds of formulae (II) and (III) may be carried out in any suitable solvent, generally being an alkanol such as éthanol, at anytempérature providing a suitable rate of formation of the required product, suitably atan elevated température, such as the reflux température of the solvent and preferablyunder an inert atmosphère such as argon or nitrogen.

The compounds of formulae (II) are known compounds or they may beprepared using processes analogous to those used to préparé such compounds, forexample by use of the methods or analogous methods to those disclosed in Journal ofMedical Chemistry 1987,30,1563-1566. A chiral compound of formula (II) wherein the C* carbon atom is chiral maybe prepared from an activated form of a compound of formula (IV):

OH

L X1—CH—CH2—L1 (IV) wherein is as defined in relation to formula (II), C* is a chiral carbon andLHs a leaving group or atom, usually a halogen atom such as a chlorine atom, by anintramolecular displacement reaction. A suitable activated form of a compound of formula (IV) is a salted form suchas an alkali métal salted form, suitably a potassium salted form.

The activated form of a compound of formula (IV) may be prepared by theappropriate conventional process depending upon the particular nature of the activatedform, for example when the activated form is a salted form the compound of formula(IV) is treated with an appropriate source of salting ion such as an alkali métal sait; forexample potassium carbonate, in any suitable aprotic solvent such as acetone.

The intramolecular displacement reaction of the activated form of thecompound of formula (IV) may be carried out in any suitable aprotic solvent, such asacetone, at any température which pro vides a suitable rate of formation of the requiredproduct, usually at an elevated température such as the reflux température of thesolvent. 6 116 8 3

Conveniently the activated form of the compound of formula (IV) is preparedin situ with respect to the intramolecular displacement reaction for formation of therequired compounds of formula (II). A compound of formula (IV) may be prepared by the chiral réduction of acompound of formula (V):

O

II 1 —c—ch2l1 (V) wherein χΐ and iJ are as defined in relation to formula (IV).

The chiral réduction of the compound of formula (V) may conveniently becarried out using borane, suitably as a tetrahydrofuran complex, in the presence of achiral réduction catalyst such as those disclosed in Journal of American ChemicalSociety 1987,109,5551-5553.

Suitable conditions for the réduction of the compound of formula (V) are theappropriate conventional conditions for example the borane réduction may be carriedout using the conditions described in Journal of American Chemical Society, ibid. A compound of formlula (V) may be prepared by halogenating a compound offormula (VI):

O

II 1 —c—ch3 (VI) when χΐ is as defined above.

The halogénation of the compound of formula (VI) is conveniently carried outusing a benzyltrimethylammonium dihaloiodate as a halogenating agent (for examplebenzyltrimethylammonium dichloroiodate is used for chlorination) under conditionsdisclosed in the Synthesis, 1988^ 545-546. i

The compounds of formula (VI) are known compounds or they may beprepared using methods analogous to those used to préparé such compounds, forexample by use of the methods or analogous methods to those disclosed in theEuropean Journal of Médicinal Chemistry, 1984,19,341-346

The compounds of formula (III) are known compounds or they may beprepared according to methods used to préparé known compounds, for example by useof the methods or analogous methods to those disclosed in European PatentApplication Number 0023385 (especially for compounds of formula (III) whereinis OCH2CO2H or an ester or amide thereof) or International Application, Publication 7 H 6 8 3

Number WO 94/02493 (especially for compounds wherein R^ is a moiety ofhereinbefore defined formula (b)). A compound of formula (III) wherein R^ and R^ together represent a moietyof the above defined formula (c), may be prepared by reacting an activated form of a 5 compound of formula (VII):

(VII) io when R° and R1 are as defined in relation to formula (I) and is hydrogen or a nitrogen protecting group, with a compound of formula (VIII):

(VIII) 15 wherein represents a leaving group or atom, suitably a halogen group such as abromine atom, Ra represents R as defined in relation to formula (I) or a protectedform thereof and represents hydrogen or a carboxyl protecting group; andthereafter as required, removing any protecting group. 20 Suitably is a nitrogen protecting group, such as a teri-butyloxycarbonyl group.

Suitably T? is a carboxyl protecting group, such as an alkyl group.

Ra represents a protected form of R when required by the particular nature of R, for example when R is carboxyl then Ra is a protected carboxyl group such as a 25 group CO2T2 defined above. A suitable activated form of a compound of formula (VII). is an ionic form,such as a salted form, for example an alkali métal salted form.

The activated form of a compound of formula (IV) may be prepared by theappropriate conventional process depending upon the particular nature of the activated 30 form, for example when the activated form is a salted form the compound of formula(VII) is treated with an appropriate source of salting ion such as an alkali métal sait;for example potassium carbonate, in any suitable aprotic solvent such as acetone. 8 116 8 3

The reaction between the compounds of formulae (VII) and (VIII) may becarried out in any suitable aprotic solvent, such as acetone, at any température whichprovides a suitable rate of formation of the required product, usually at an elevatedtempérature such as the reflux température of the solvent.

Conveniently the activated form of the compound of formula (VII) is preparedin situ with respect to the reaction between the compounds of formulae (VII) and(VIII) which then form the required compounds of formula (III). A compound of formula (VII) is conveniently prepared according to thereaction scheme set out below: R1

L H2N- C— CH2- R°

Protectamino group eg by use of(t BuOCO)2Oand

EtjN in DMF (VII) *

The conditions of reaction for the above reaction scheme are those usedconventionally in the art such as the conditions described in the accompanyingexamples. «l|y

Suitably the C and C** carbon atom are chiral carbon atoms.

The compounds of formulae (VIII) are either known commercially availablécompounds (for example, the compounds wherein R is CO2H) or an ester or amidethereof or they may be prepared &amp;om such compounds using routine procedures orthey may be prepared using methods or analogous methods to those used to préparéknown compounds, for example those disclosed in Bull. Korean Chem. Soc. 1992,13,226-227. f

The compounds of formulae (A) are known compounds or they may beprepared by processes analogous to those used to préparé known compounds, forexample by use of the methods or analogous methods disclosed in the Journal ofMédicinal Chemistry 1973, 16,480-483.

Suitable conversions of one compound of formula (I) into another compoundof formula (I) include converting one group OR4 into another group OR4 and/orconverting one group OR^ into another group OR\

Suitable conversions of one group OR4 into another group OR4 include: (i) converting OR4 as hydroxy into OR4 as alkoxy; (ii) converting OR4 as alkoxy into OR4 as hydroxy; 9 ‘116 8 3 (iii) converting OR^ as alkoxy into OR^ as another alkoxy group.

The abovementioned conversion (i) may be carried out under conventionalphosphonate alkylation methods, using for example the appropriate alcohol (R^OH)in the presence of hydrogen chloride.

The abovementioned conversion (ii) may be carried out using conventionalphosphonate hydrolysis methods, for example by treating the appropriate compoundof formula (I) with an alkaline métal hydroxide, such as sodium hydroxide.

The abovementioned conversion (iii) may be carried out by first convertingOR4 as alkoxy into OR^ as hydroxy using the conditions set out in respect of theabovementioned conversion (ii), followed by converting the hydroxy group so formedinto another alkoxy group, using the conditions set out in respect of theabovementioned conversion (i).

The abovementioned conversion (iii) is of particular use for preparingcompounds of formula (I) wherein OR^ represents methoxy: such compounds aregenerally prepared ffom compounds of formula (I) wherein OR^ represents analkyloxy group other than methoxy (suitably ethoxy) by first hydrolysing the relevantOR^ group (via conversion (ii)) to préparé a compound of formula (I) wherein OR^represents hydroxy and thereafter methylating (via conversion (i)) to provide therequired compound wherein OR^ represents methoxy.

Suitable conversions of one group OR^ into another group OR$ includeanalogous conversions to those mentioned above in regard to converting one groupOR^ into another group OR^.

The protection of any reactive group or atom, may be carried out at anyappropriate stage in the aforementioned processes. Suitable protecting groups includethose used conventionally in the art for the particular group or atom being protected.Protecting groups may be prepared and removed using the appropriate conventionalprocedure. For example when T^ represents a ieri-butyloxycarbonyl nitrogenprotecting group it may be removed by acidic hydrolysis, using hydrogen chloride inether/ethyl acetate, or when T? represents an alkyl group as a carboxyl protectinggroup it may be removed by catalytic hydrogénation, using a palladium on carboncatalyst. A leaving group or atom is any group or atom that will, under the reactionconditions, cleave ffom the starting material, thus promoting reaction at a specifiedsite. Suitable examples of such groups unless othewise specified are halogen atoms,mesyloxy groups and tosyloxy groups.

The salts, esters, amides and solvatés of the compounds mentioned herein maybe produced by methods conventional in the art: For example, acid addition salts maybe prepared by treating a compound of formula (I) with the appropriate acid. 10 116 8 3

Esters of carboxylic acids may be prepared by conventional estérificationprocedures, for example alkyl esters may be prepared by treating the requiredcarboxylic acid with the appropriate alkanol, generally under acidic conditions.

Amides may be prepared using conventional amidation procedures, forexample amides of formula CONRJR^ may be prepared by treating the relevantcarboxylic acid with an amine of formula HNRÎrX wherein RJ and R^ are as definedabove. Altematively, a Cj.g alkyl ester such as a methyl ester of the acid may betreated with an amine of the above defined formula HNRJR^ to provide the requiredamide.

Compounds of formula (I) and pharmaceutically acceptable acid addition saltsthereof; or a pharmaceutically acceptable solvaté thereof, produced by the aboveprocesses, may be recovered by conventional methods.

If required mixtures of isomers of the compounds of the invention may beseparated into individual stereoisomers by conventional means, for example by theuse of an optically active acid as a resolving agent. Suitable optically active acidswhich maybe used as resolving agents are described in 'Topics in Stereochemistry',Vol. 6, Wiley Interscience, 1971, Allinger, N.L. and Eliel, W.L. Eds.

Altematively, any enantiomer of a compound of the invention may be obtainedby stereospecific synthesis using optically pure starting materials of knownconfiguration.

The absolute configuration of compounds mây be determined by conventionalX-ray crystallographic techniques.

As previously indicated, the compounds of the présent invention hâve valuablepharmacological properties:

The présent invention accordingly provides a compound of formula (I) or apharmaceutically acceptable acid addition sait thereof, or a pharmaceutically -acceptable solvaté thereof, for use as an active therapeutic substance.

In one aspect, the présent invention provides a compound of formula (I), or apharmaceutically acceptable acid addition sait thereof, or a pharmaceuticallyacceptable solvaté thereof, for use in the treatment of hyperglycaemia in human ornon-human animais.

The présent invention further provides a compound of formula (I), orpharmaceutically acceptable acid addition sait thereof, or a pharmaceuticallyacceptable solvaté thereof, for use in the treatment of obesity in human or non-humananimais. A compound of formula (I), or a pharmaceutically acceptable acid addition saitthereof, or a pharmaceutically acceptable solvaté thereof, may be administered per seor, preferably', as a pharmaceutical composition also comprising a pharmaceuticallyacceptable carrier. 11 116 8 3

Accordingly, the présent invention also provides a pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceutically acceptableacid addition sait thereof, or a pharmaceutically acceptable solvaté thereof, and apharmaceutically acceptable carrier therefor.

As used herein the term "pharmaceutically acceptable" embraces compounds,compositions and ingrédients for both human and veterinary use: for example the term"pharmaceutically acceptable sait" embraces a veterinarily acceptable sait.

The composition may, if desired, be in the form of a pack accompanied bywritten or printed instructions for use.

Usually the pharmaceutical compositions of the présent invention will beadapted for oral administration, although compositions for administration by otherroutes, such as by injection, are also envisaged.

Particularly suitable compositions for oral administration are unit dosageforms such as tablets and capsules. Other fixed unit dosage forms, such as powderspresented in sachets, may also be used.

In accordance with conventional pharmaceutical practice the carrier maycomprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourantor other conventional adjuvant.

Typical carriers include, for example, microcrystalline cellulose, starch,sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone,magnésium stearàte or sodium lauryl sulphate.

Most suitably the composition will be formulated in unit dose form. Such unitdose will normally contain an amount of the active ingrédient in the range of from 0.1to 1000 mg, more usually 2-100 mg or 0.1 to 500 mg, and more especially 0.1 to 250mg.

The présent invention further provides a method for treating hyperglycaemiain a human or non-human mammal, which comprises administering an effective,non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptableacid addition sait thereof, or a pharmaceutically acceptable solvaté thereof, to ahyperglycaemic human or non-human mammal in need thereof.

The présent invention further provides a method for treating obesity or for thetreatment and/or prophylaxis of atherosclerosis in a human or non-human mammal,which comprises administering an effective, non-toxic, amount of a compound offormula (I), or a pharmaceutically acceptable acid addition sait thereof, or apharmaceutically acceptable solvaté thereof, to a human or non-human mammal inneed thereof.

Conveniently, the active ingrédient may be administered as a pharmaceuticalcomposition hereinbefore defined, and this forms a particular aspect of the présentinvention. 12 H 6 8 3

In treating hyperglycaemic or obese humans the compound of formula (I), or apharmaceutically acceptable sait, ester or amide thereof; or a pharmaceuticallyacceptable solvaté thereof, may be taken in doses, such as those described above, oneto six times a day in a manner such that the total daily dose for a 70 kg adult willgenerally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500mg.

The treatment regimens for atherosclerosis are generally as described forhyperglycaemia.

In treating non-human mammals, especially dogs, the active ingrédient may beadminstered by mouth, usually once or twice a day and in an amount in the range offfom about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg.

In a further aspect the présent invention also provides a method for increasingweight gain and/or improving the feed utilisation efficiency and/or increasing leanbody mass and/or decreasing birth mortality rate and increasing post/natal survivalrate; of livestock, which method comprises the administration to livestock of aneffective non-toxic amount of a compound of formula (I) or a veterinarily acceptableacid addition sait thereof, or a veterinarily acceptable solvaté thereof.

Whilst the compounds of formula (I) and the veterinarily acceptable acidaddition salts thereof or a veterinarily acceptable solvaté thereof, may be administeredto any livestock in the abovementioned method, they are particularly suitable forincreasing weight gain and/or feed utilisation efficiency and/or lean body mass and/ordecreasing birth mortality rate and increasing post-natal survival rate; in poultry,especially turkeys and chickens, cattle, pigs and sheep. -In the preceding method the compounds of formula (I) or veterinarilyacceptable acid addition salts thereof will normally be administered orally althoughnon-oral modes of administration, for example injection or implantation, are alsoenvisaged. Suitably the compounds are administered in the feed-stuff or drinkingwater provided for the livestock. Conveniently these are administered in thefeed-stuff at ffom 10-3 ppm _ 500ppm of total daily fed intake, more usually O.Olppmto 250ppm, suitably less than 10Oppm.

The particular formulations used will of course dépend upon the mode ofadministration but will be those used conventionally in the mode of administrationchosen. For administration in feed-stuff the drugs are conveniently formulated as apremix in association with a suitable carrier.

Accordingly, the présent invention also provides a veterinarily acceptablepremix formulation comprising a compound of formula (I), or a veterinarilyacceptable acid addition sait thereof; or a veterinarily acceptable solvaté thereof, inassociation with a veterinarily acceptable carrier therefore. 13 î I S 8 3

Suitable carriers are inert conventional agents such as powdered starch. Otherconventional feed-stuff premix carriers may also be employed.

No unacceptable toxicological effects are expected when compounds of theinvention are administered in accordance with the présent invention.

The following Examples illustrate the invention but do not limit it in any way. 5 14 116 8 3

Procedure 1 8-Benzyloxy-5-chloroacetylcarbostyril

A solution of 5-acetyl-8-benzyloxycarbostyril (1.75g, 6mMol) in 1,2-dichloroethane (60 ml)/methanol (40 ml) and benzyltrimethylammoniumdichloroiodate (4.2g, 12 mMol) was heated at 60°C under an argon atmosphère for 2 io hours.

After cooling, the solvent was evaporated and the residue taken up intochloroform (200 ml) washed with sodium metabisulphite solution (100 ml), water (2 x75 ml), brine (75 ml), dried and evaporated. Purification by trituration withdichloromethane/ diethyl ether gave the title compound as an orange solid; m.p. 201- 15 203°C. !h NMR ô(CDC13) 9.35 - 9.25 (1H, b, exchanges with D2O), 8.82 (1H, d, J = 10 Hz), 7.66 (1H, d, J = 8.5 Hz), 7.40 (5H, b), 7.07 (1H, d, J = 8.5 Hz), 20 6.80 (1H, d, J = 10 Hz), 5.28 (2H, s) and 4.68 (2H, s) ppm.

Procedure 2 (R)-8-Benzyloxy-5-(2-chIoro-l-hydroxyethyI)carbostyril

Borane-tetrahydrofuran complex (IM in tetrahydrofuran, 1 ml, ImMol) wasadded dropwise to a solution of (R)-tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo 30 [1,2-c][l,3,2] oxazaborole (0.1 equiv, 30 mg, 0.1 mMol) in tetrahydrofuran (6 ml) at ambient température under an argon atmosphère. Afiter 5 minutes, 8-benzyloxy-5- 15 116 8 3 chloroacetylcarbostyril (328 mg, 1 mMol) was added and the reaction mixture wasstirred for a further 15 minutes. The reaction mixture was cooled to 5°C andquenched by the dropwise addition of methanol (2 ml). The quenched reactionmixture was stirred for 15 minutes at 5°C and for 30 minutes at ambient température.The solvent was evaporated and the residue was purified by chromatography on silicagel eluting with 10% methanol in ethyl acetate to afford the title compound as a paleyellowsolid; m.p. 148-149°C; [a]jy25 -9.0°(c=l, methanol). lH NMR Ô(d6-DMSO) 10.8- 10.5 (1H, b, exchanges with D2O), 8.18 (1H, d, J = 9.9 Hz), 7.6-7.55(2H, m), 7.4-7.3 (3H,m) 7.19 (2H, b), 6.54 (1H, d, J = 9.9 Hz), 5.90 (1H, d, J = 4.9 Hz, exchanges with D2O), 5.30 (2H, s), 5.23 - 5.15 (1H, m) and 3.8- 3.6 (2H, m) ppm.

Procedure 3 (R)-8-Benzyloxy-5-oxiranylcarbostyril

A suspension of (R)-8-benzyloxy-5-(2-chloro-l-hydroxyethyl)carbostyril (130mg, 0.4 mMol) in acetone (10 ml) containing potassium carbonate (276 mg, 2 mMol)was stirred at 60°C under an argon atmosphère for 18 hours. After cooling, thesuspension was filtered and the filter pad was washed with acetone. The filtrâtes werecombined and evaporated. Purification of the residue by chromatography on silica geleluting with ethyl acetate gave the title compound as a pale yellow solid; m.p. 146-150°C; [α]β25 -30° (c = 0.91, chloroform). !h NMR ô(CDC13) 9.2 (1H, b, exchanges with D2O), 8.10 (1H, d, J = 9.9 Hz), 7.42 (5H, b), 7.07 (1H, d, J = 8.2 Hz), 7.00 (1H, d, J = 8.2 Hz), 6.74 (1H, d, J = 9.9 Hz), 5.18 (2H, s), 4.22 (1H, dd, J = 3.9,2.4 Hz), 3.21 (1H, dd, J = 5.5, 3.9 Hz) and2.79 (1H, dd, J = 5.5,2.4 Hz) ppm. 16 116 8 3

Procedure 4 (R)-3-(3,4-Dihydroxyphenyl)-2-propylamine hydrobromide

A solution of (R)-3-(3,4-dimethoxyphenyl)-2-propylamine hydrochloride (500mg, 2.15 mMol) in hydrogen bromide (48%, 5 ml) was stirred at 100°C under anargon atmosphère for 20 hours. After cooling, the solvent was evaporated and the io residue was dried giving the title compound. !hNMR ô(d6-DMSO/D2O) 6.9 - 6.4 (3H, m), 3.5 - 2.4 (3H, m) and 1.3 (3H, d, J = 7 Hz) ppm. 15 Procedure 5 (R)-N-(t-Butyloxycarbonyl)-3-(3,4-dihydroxyphenyl)-2-propyIamine

A solution of (R)-3-(3l4-dihydroxyphenyl)-2-propylamine hydrobromide (480mg, 1.9 mMol) in dimethylformamide (5 ml) containing triethylamine (3 equiv, 586mg, 5.7 mMol) was stirred at 5°C under an argon atmosphère for 15 minutes.Di-Zeri-butyl dicarbonate (414 mg, 1.9 mMol) was added and the reaction mixture was 25 stirred at 5°C for 1 hour and then at ambient température for 1 hour. The solvent wasevaporated. Ethyl acetate (100 ml) and water (50 ml) were added and the organiclayer was separated, washed with water (50 ml) and brine (50 ml), dried (MgSC>4) andevaporated. Purification of the residue by chromatography on silica gel eluting with25% ethyl acetate in «-hexane gave the title compound, m.p. 116-118°C; 116 8 3 [α]ρ25 +2° (c = 1, chloroform).iH NMR ô(CDC13) 6.76 (1H, d, J = 7.9 Hz), 6.70 (1H, d, J = 2 Hz), 6.55 (1H, dd, J = 7.9, 2 Hz)s 6.25-5.90 (2H, b, exchanges with D2O), 4.45 (1H, b, exchanges with D2O), 3.8 (1H, b), 2.75 - 2.5 (2H, m), 1.43 (9H, s) and 1.07 (3H, d, J = 6.6 Hz) ppm.

Procedure 6 10 (R)-Diethyl-5-[N-(t-butyloxycarbonyl)-2-aminopropyl]-l,3-benzodioxoIe-2,2-dicarboxylate

15 A solution of (R)- N-(t-butyloxycarbonyl)-3 -(3,4-dihydroxyphenyl)-2- propylamine (1.07g, 4 mMol) in acetone (25 ml) containing potassium carbonate (3equiv, 1.66 g, 12 mMol) was stirred at 60°C under an argon atmosphère for 1 hour.After cooling to ambient température, a solution of diethyl dibromomalonate (1.27 g, 4 mMol) in acetone (7 ml) was added and the reaction was stirred at ambient 20 température for 18 hours. The suspension was filtered and the residue was washedwith ethyl acetate. The filtrâtes were combined and evaporated. The residue waspartitioned between ethyl acetate (200 ml) and dilute hydrochloric acid (100 ml, pH5).The organic layer was separated, washed with water (2 x 100 ml) and brine (100 ml),dried (MgSOzj.) and evaporated. The residue was purified by column chromatography 25 on silica gel eluting with 25% ethyl acetate in «-hexane giving the title compound asan oil; [a]j)25 -3° (c = 0.68, chloroform). !h NMR ô(CDC13) 30 6.86 (1H, d, J = 8 Hz), 6.78 (1H, d, J = 1-.3 Hz), 6.71 (1H, dd, J = 8,1.3 Hz), 4.41-4.32 (5H, m), 3.8 (1H, b, exchanges with D2Û),2.76 (1H, dd, J = 13.5, 5.6 H3),2.60 (1H, dd, J= 13.5, 7.2 Hz),1.43 (9H, s), 1.36 -1.31 (6H,m) and 1.07 (3 H, d, J = 6.6 Hz) ppm. 18 116 8 3

Procedure 7 (R)-Diethyl-5-(2-aminopropyl)-l,3-benzodioxole-2,2-dicarboxylate hydrochloride

A solution of (R)-diethyl-5-[N-(t-butyloxycarbonyl)-2-aminopropyl]-l,3-benzodioxole-2,2-dicarboxylate (3.0 g, 7 mMol) in ethyl acetate (40 ml) and hydrogen io chloride (IM in diethyl ether, 56 ml, 56 mMol) was stirred at ambient températureunder an argon atmosphère for 48 hours. The solvent was evaporated and the residuewas dried giving the title compound as a glass. hïNMR Ô(d6-DMSO) 15 8.07 (3H, b, exchanges with D2O), 7.10 - 7.06 (2H, m), 6.85 (1H, dd, J = 8, 1.4 Hz), 4.33 (4H, q, J = 7.1 Hz), 3.5 - 3.4 (1H, m), 2.93 (1H, dd, J = 13.4, 5.8 Hz), 2.66 (1H, d, J = 13.5, 8.2 Hz), 1.24 (6H, t, J = 7.1 Hz) and 1.12 (3H, d, J = 6.3 Hz) ppm. 19 116 8 3

Procedure 8 (R)-Diethyl-5-(2-aminopropyl)-l,3-benzodioxole-2,2-dicarboxylate

Me

H2N

CO2Et CO2Et A solution of (R)-diethyl-5-(2-aminopropyl)-l,3-benzodioxole-2,2-dicarboxylate hydrochloride (646 mg, 2 mMol) in dichloromethane (80ml) wasshaken with a saturated solution of sodium hydrogen carbonate (20 ml) for 30seconds. The organic layer was separated and the aqueous layer was extracted withdichloromethane (2 x 50 ml). The combined organic extracts were washed with water (50 ml) andbrine (50 ml), dried (MgSC>4). The solvent was evaporated giving the title compoundwhich was used immediately in Procedure 9.

Procedure 9 (RR)-Diethy 1-5- [2- [2- [5-(8-benzyloxy carbostyryl)] -2-hy droxyethylamino] propy 1] -l,3-benzodioxole-2,2-dicarboxylate

Me

HO CO2Et A suspension of (R)-diethyl-5-(2-aminopropy 1)-1,3 -benzodioxole-2,2-dicarboxylate (2 equiv, 417 mg, 1.3 mMol) and (R)-8-benzyloxy-5-oxiranylcarbostyril (190 mg, 0.65 mMol) in éthanol (10 ml) was heated under reflux 20 *116 8 3 under an argon atmosphère for 24 hours. After cooling, the solvent was evaporated.Purification of the residue by chromatography on silica gel eluting with 0-20%methanol in ethyl acetate gave the title compound as a pale orange solid; m.p. 65-67°C; [a]p)25_i8° (C= 0.31, chloroform). 5 !h NMR Ô(CDC13) 9.5-9.0 (1H, b, exchanges with D2O), 8.10 (1H, d, J = 9.9 Hz), 7.41 (5H, b), 7.23 (1H, d, J = 8.4 Hz), 7.02 (1H, d, J = 8.4 Hz), 6.87 (1H, d, J = 8 Hz), 6.79 (1H, d, J = 1.2 Hz), io 6.71 (1H, dd, J = 8, 1.2 Hz), 6.67 (1H, d, J = 9.9 Hz), 5.18 (2H, s), 5.06 (1H, dd, J = 6.3,2 Hz), 4.40 - 4.32 (4H, 2 x q, J = 7.1 Hz), 3.0 - 2.93 (2H, m), 2.8 - 2.6 (3H, m), 2.6 - 2.4 (2H, b, exchanges with D2O),1.37-1.31 (6H, 2 x t, J = 7.1 Hz) and 1.10 (3H, d, J = 6.3 Hz) ppm. 15 Example 1 (RR)-5-[2-[2-[5-(8-Hydroxycarbostyryl)]-2-hydroxyethylamino]propyl]-l,3-benzodioxole-2,2-dicarboxylic acid

A solution of (RR) diethyl-5-[2-[2-[5-(8-benzyloxycarbostyryl)]-2-hydroxyethylamino] propyl]-l,3rbenzodioxole-2,2-dicarboxylate (269 mg, 0.43 mMol) in dioxan (6 ml)/water (2 ml) and lithium hydroxide (IM, 8 equiv, 3.5 ml, 25 3.5 mMol) was stirred at ambient température under an argon atmosphère for 2 hours.

The pH of the solution was adjusted to pH7 with 2N hydrochloric acid and the solventwas evaporated.

The residue was dissolved in methanol (25 ml)/water (5 ml), palladium oncharcoal (10%, 30 mg) was added and the mixture was hydrogenated at ambient 3o température and pressure for 24 hours. The suspension was filtered through a pad offilter aid and the filter pad was washed with methanol (150 ml) and water (20 ml).

The filtrâtes were combined and evaporated giving a dark residue. Purification by 21 1 1 6 8 3 chromatography on reverse phase silica eluting with water afforded the titlecompound as a yellow solid; m.p. > 250 °C; [ct]£)25 -31° (C = 0.51, water). *H NMR 5(D2O) 8.32 (1H, d, J = 9.8 Hz), 7.11 (1H, d, J = 8.3 Hz), 6.84-6.76 (3H, m), 6.73 (1H, d, J = 9.8 Hz), 6.61 (1H, dd, J = 8.3, 1.2 Hz), 5.35 (1H, dd, J = 8, 5 Hz), 3.4-3.3 (2H, m), 3.16 (1H, dd, J = 12.4, 5 Hz), 3.0 - 2.77 (2H, m) and 1.23 (3H, d, J = 6.3 Hz) ppm.

Pharmacological Data: The activity of the présent compounds may be tested by useof the foliowing procedures:

Agonist Activity at Rat bj and b2 Adrenoceptors In Vitro bj-Adrenoceptor Agonism: Female Sprague-Dawley rats (150-250g) are killed by ablow to the head and exsanguinated. Spontaneously beating right atria are removedby the method of Broadley and Lumleyl and mounted on a glass tissue holder. Eachtissue is placed in 30 ml organ baths at 37°C containing Kreb's-Henseleit solution.Each atrium is attached to an isométrie transducer by cotton and placed under aninitial resting tension of lg. Rate recordings from the spontaneous beating atria areobtained from the tension signal using a Lectromed Type 4522 ratemeter. Ail tracesare recorded on a Lectromed M4 chart recorder, b-adrenoceptor agonists are thenadded to the Krebs medium in a cumulative fashion and the results expressed as apercentage increase in atrial rate. b2-Adrenoceptor Agonism: Rat uterine homs are removed and bisectedlongitudinally. Each tissue is tied to a glass tissue holder and placed in Krebs-Henseleit solution in a 30 ml organ bath as before. Tissues are placed under a restingtension of lg and allowed to equilibrate. Each uterine strip is pre-contracted by theaddition of 40mM K+ to the bath to produced a steady tonie contraction, b-agonistsare then added to the bath in a cumulative manner and results expressed as percentageinhibition of contraction.

Agonist EC50 (atria) and IC5Q (uteri) are calculated as the concentration ofagonist producing 50% of their maximum increase in atrial rate or uterine relaxation.Relative intrinsic activity expressed as the maximal responses to test agonists relativeto isoprénaline (=1.0) in both atria and uteri. b 3-Adrenoceptor- Mediated Adenylyl Cyclase Activity: Adenylyl cyclase activitywas assayed by the method of Kirkham et. al.2 by the addition of 40 ml (70 -80 mg 22 116 8 3 protein) to the incubation medium of the above CHO cell plasma membranestransfected with the human bj-adrenoceptor. cAMP produced over 20 minutes wasseparated from ATP by the method of Salomon et al.3. Agonist EC50 values andintrinsic activities were expressed as the concentration of agonist producing 50 % 5 activation of adenylyl cyclase and the maximum response produced by each agonistrelative to that produced by (-) isoprénaline respectively.

References 10 1. K. J. Broadley &amp; P. Lumley (1977) Br. J. Pharmacol. 59. 51 2. D. Kirkham et. al., Biochem. J., 1992,284, 301. 3. Y. Salomon et al., Anal. Biochem., 1974,58, 541.

Claims (18)

23 10 Claims

1. A compound of formula (I): OH R* 116 8 3 X—CH- CHrNH-*C— CH2“\__/ R2R° (I) or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté thereof, wherein, X represents a moiety of formula (a): .AÎ. (a) in which represents -CH=CH=, NH, S or O; A^ represents an oxo or a thioxo15 group; A^ represents H or an alkylcarbonyl group; and A4 represents hydroxy or NRsRt wherein Rs and R1 each independently represents H or alkyl; R° and R^ each independently represents hydrogen or an alkyl group; R^ represents OCH2CO2H, or an ester or amide thereof, or R^ represents a moiety offormula (b): 20 -o-ch2-p-or OR (b) wherein R4 and R5 each independently represent hydrogen, alkyl, hydroxyalkyl,25 cycloalkyl or R4 together with R5 represents (CH2)n wherein n is 2, 3 or 4; and 24 116 8 3 R.3 represents hydrogen, halogen, alkyl or alkoxy or R^ together with R^ représente amoiety of formula (c):

XCO2H 5 (c) or an ester or amide thereof, wherein R represents hydrogen, alkyl, hydroxymethyl ora moiety of formula (CH2)nCO2H, wherein n is zéro or an integer 1, 2 or 3, or anester or amide thereof. io

2. A compound according to claim 1, wherein is -CH=CH-.

3. A compound according to claim 1 or claim 2, wherein A^ is oxo.

4. A compound according to any one of daims 1 to 3, wherein A^ is H. 15

5. A compound according to any one of daims 1 to 3, wherein A^ is OH,substituted at the 4-position relative to the bond linking X to the CHOH carbon atom.

• 6. A compound according to claim 5, wherein R° is hydrogen. 20

7. A compound according to claim 5 or claim 6, wherein Rlis an alkyl group.

8. A compound according to any one of daims 1 to 7, wherein, R^ together withR^ represents a moiety of formula (c). 25

9. A compound according to claim 1, being:(RR)-5-[2-[2-[5-(8-hydroxycarbpstyryl)]-2-hydroxyethylamino]propyl]-l,3-benzodioxole-2,2-dicarboxylic acid or a pharmaceutically acceptable sait thereof, or apharmaceutically acceptable solvaté thereof. 30

10. A compound according to any one of daims 1 to 7, wherein with référencé toformula (I), the asymmetric carbon atom corresponding to that indicated by a single 25 116 8 3 asterisk (*) is in the S-configuration and fhe asymmetric carbon atom correspondingto that indicated by two asterisks (**) is in the R-configuration.

11. A process for the préparation of a compound of formula (I), or a sait thereof or5 a solvaté thereof, which process comprises reacting a compound of formula (II): X1—CH—CH2O (Π) io wherein χΐ represents X as defined in relation to formula (I) or a protected formthereof, with a compound of formula (III):

(III) 15 wherein R°, Rlare as defined in relation to formula (I), R^a represents R^ as definedin relation to formula (I) or a protected form thereof and R^a represents R^ as definedin relation to formula (Ί) or a protected form thereof; and thereafter, if necessary,carrying out one or more of the following optional steps: 20 (i) converting one compound of formula (I) to another compound of formula (I); and (ii) removing any protecting group; and (iii) preparing a pharmaceutically acceptable sait thereof of a compound of formula(I) or a pharmaceutically acceptable solvaté thereof. 25

12. A pharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable sait thereof; or a pharmaceutically acceptable solvatéthereof, and a pharmaceutically acceptable carrier therefor. 26 11683

13. A compound of formula (I), or a pharmaceutically acceptable sait thereof; or apharmaceutically acceptable solvaté thereof, for use as an active therapeuticsubstance. 5

14. A compound of formula (I), or a pharmaceutically acceptable sait thereof; or a pharmaceutically acceptable solvaté thereof, for use in the treatment ofhyperglycaemia, obesity, atherosclerosis, hyperinsulinaemia, gastrointestinal disordersor the treatment of gastrointestinal ulcérations. io

15. The use of a compound of formula (I), or a pharmaceutically acceptable saitthereof; or a pharmaceutically acceptable solvaté thereof, for the manufacture of amédicament for the treatment of hyperglycaemia, obesity, atherosclerosis,hyperinsulinaemia, gastrointestinal disorders or the treatment of gastrointestinalulcérations. 15

16. A method for treating hyperglycaemia, obesity, atherosclerosis,hyperinsulinaemia, gastrointestinal disorders or the treatment of gastrointestinalulcérations in a human or non-human mammal, which comprises administering aneffective, non-toxic, amount of a compound of formula (I), or a pharmaceutically 20 acceptable sait thereof; or a pharmaceutically acceptable solvaté thereof, to the humanor non-human mammal in need thereof.

17. A method for increasing weight gain and/or improving the feed utilisationefficiency and/or increasing lean body mass and/or decreasing birth mortality rate and 25 increasing post/natal survival rate; of livestock, which method comprises theadministration to livestock of an effective non-toxic amount of a compound of ·formula (I) or a veterinarily acceptable sait thereof; or a veterinarily acceptable solvatéthereof. 30

18. A veterinarily acceptable premix formulation comprising a compound of formula (I), or a veterinarily acceptable sait thereof; or a veterinarily acceptablesolvaté thereof, in association with a veterinarily acceptable carrier therefore.