WO1993009113A1

WO1993009113A1 - 2-((imidazol-2-yl)methyl)-isoindole derivatives as alpha-2-adrenoceptor antagonists

Info

Publication number: WO1993009113A1
Application number: PCT/GB1992/002047
Authority: WO
Inventors: John Michael Berge; Lee James Beeley; Michael Anthony Cawthorne
Original assignee: Smithkline Beecham Plc
Priority date: 1991-11-09
Filing date: 1992-11-05
Publication date: 1993-05-13
Also published as: PT101041A; GB9123857D0; AU2876292A; PT101041B

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein R?1 and R2¿ may each represent hydrogen or C¿1-6?alkyl, providing that at least one of R?1 or R2¿ represents C¿1-6?alkyl; and R?3 and R4¿ each represent hydrogen or R3 together with R4 represents a bond; a process for the preparation of such a compound, a pharmaceutical composition comprising such a compound, and the use of such a composition and compound in medicine.

Description

2-( (__MTOAZ01 2-YL) E^,mY )-ISOINDOLE DERIVATIVES AS A PHA-2-ADRENOCEPTOR A TAGC1NISTS

This invention relates to a certain class of heterocyclic compounds having activity as 0.2-adrenoceptor antagonists, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.

European Patent Applications, Publication Nos. 0238753 and 0313288 discloses certain heterocyclic compounds of the general formula (A):

(A) or a pharmaceutically acceptable salt, ester or amide thereof, wherein:

Z represents a residue of a substituted or unsubstituted aryl group,

X' represents O or NR° wherein R° represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, an alkanoyl group substituted or unsubstituted in the alkyl moiety, or an arylalkyl moiety substituted or unsubstituted in the aryl moiety,

n' represents an integer 1 or 2, m' represents an integer 1 or 2, p represents an integer 2 or 3, and q represents an integer in the range of from 1 to 12.

The compounds of formula (A) are disclosed as having good α2- adrenoceptor antagonist activity and to be of potential use for the treatment and or prophylaxis of hyperglycaemia and/or glaucoma and/or the treatment of hypertension and/or depression and/or for inhibiting blood platelet aggregation. EP 0313288 also discloses heterocyclic compounds of formula (B):

(B)

or a pharmaceutically acceptable salt thereof, wherein:

R^a and R^ may each represent hydrogen or alkyl providing that at least one of R^a or R" represents alkyl;

R^c and R^ each represent hydrogen or R^c and R^α together represent a bond; n" represents an integer 1 or 2; and " represents an integer 1 or 2.

The compounds of formula (B) are disclosed as having very good selectivity for the post-junctional 0C2-receptor and therefore show good selectivity from side effects. The compounds of formula (B) described as being of particular value in the treatment and/or prophylaxis of hyperglycaemia and/or the treatment of hypertension and/or for inhibiting blood platelet aggregation.

European Patent Application, Publication No 0120165 also discloses the use of certain cc2 adrenergic inhibitors to control weight loss via reduction of regional fat deposits.

It has now been discovered that a small class of compounds, falling within the general formula (A) but structurally distinct from the compounds of formula (B) and from the compounds of EP 0120165, shows oc2- adrenoceptor antagonist activity and surprisingly has good selectivity for the post-junctional αg-receptor and in addition is essentially free from α_j- adrenoceptor agonist activity and therefore shows good selectivity from side effects, such as those associated with -adrenoceptor agonist activity.

These compounds are potentially of particular value in the treatment and/or prophylaxis of hyperglycaemia and/or glaucoma and/or the treatment of hypertension and/or depression and/or for inhibiting blood platelet aggregation. They may also be useful for the treatment of benign prostatic hypertrophy.

In addition these compounds are indicated to be especially useful for the selective reduction of regional body fat deposits, especially via topical application.

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

(I)

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein R-~ and R^ may each represent hydrogen or Cι_6 alkyl, providing that at least one of Rl or R-2 represents

Cι_β alkyl; and

R3 and R^* each represent hydrogen or R^ together with R^ represents a bond.

Preferably, R* and R^ each represent methyl.

Preferably, Bβ and R^ together represent a bond.

Examples of the present invention include compounds selected from the group consisting of:

2-[4,5-dihydro-lH-imidazol-2-yl)methyl]-2,3-dihydro-4- (3-methylbut-2-enyIoxy)-6-methyl-lH-isoindole; and

2-[(4,5-d ydro-lH-imidazol-2-yl)methyl]-2,3-dihydro-4- 6(3-methylbutyloxy)-6-methyl-lH-isoindole;

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof

Suitable pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts.

Suitable pharmaceutically acceptable acid addition salts of compound (I) include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, sucάnate, benzoate, ascorbate, methanesulphonate, α-ketoglutarate, α-glycerophosphate, and glucose- 1-phosphate. Preferably the acid addition salt is a hemisuccinate, α-ketoglutarate, α-glycerophosphate, glucose-1-phosphate or maleate, in particular a maleate salt especially the 1:1 maleate salt.

^"When used herein the term 'alkyl' includes straight and branched chain alkyl groups containing from 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms.

When used herein the term 'Cτ_g alkyl' includes straight and branched chain alkyl groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl and butyl groups.

Pharmaceutically acceptable solvates include conventional, pharmaceutically acceptable solvates such as water.

The present invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, which process comprises cyclising a compound of formula (ID:

(II)

wherein ^~R-~, R^, R3 and R^* are as defined in relation to formula (I) and X is O or N; and thereafter, if required, converting a compound of formula (I) into a further compound of formula (I) and/or forming a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

A compound of formula (II) may be prepared by reacting a compound of formula (HD:

(III)

wherein R-~, R-^, R3 and R^ are as defined in relation to formula (I) and A represents -CN or CO2R wherein R represents C^.g alkyl, with 1,2-diaminoethane or an activated form thereof.

A suitable activated form of 1,2-diaminoethane is the trimethylaluminium adduct of 1,2-diaminoethane. The activated form of 1 ,2-dia i noethane is generally the preferred reagent when A represents -C0₂R.

Suitably, A is -C0₂R.

Suitably, R represents methyl. A compound of formula (I I) maybe prepared by reacting a compound of formula (IV):

(IV)

wherein A is as defined in relation to formula (III), with a compound of formula (V):

(V)

wherein R-*-, *^, R^ and ^ are as defined in relation to formula (I) and L*- represents a leaving group, preferably a bromine atom.

The compounds of formula (V) are generally known commercially available compounds or they may be prepared using methods analogous to those used to prepare known compounds for example the methods disclosed in Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 3rd Ed., New York, Wiley 1985.

A compound of formula (TV) may be prepared by reacting a compound of formula (VT):

wherein R represents a protecting group and i represents a leaving group, with a compound of formula (VII):

H₂N-CH₂-A (VII)

wherein A is as defined in relation to formula (III); and thereafter, if required, converting one compound of formula (IV) into another compound of formula (IV).

Suitably, ϊ represents a halogen atom, especially a chlorine or bromine atom, a methanesulphonate group or a p-toluenesulphonate group.

Preferably ϊβ represents a bromine atom.

Suitable conversions of one compound of formula (IV) into another compound of formula (IV) include those wherein A, in formula (IV), is converted from one value into another value: for example a compound of formula (IV) wherein A represents nitrile may be converted into a compound of formula (IV) wherein A represents -CO2 , wherein R is as defined in relation to formula (III), by any conventional procedure, for example by hydrolysis to give the corresponding carboxyUc acid followed by esterification.

Suitable conditions for hydrolysing, the nitrile group include acid conditions, for example using aqueous hydrobromic acid.

Suitable conditions for esterification are well known in the art and include treatment with the appropriate alcohol under acidic conditions.

A compound of formula (VI) may be prepared by reaction of a compound of formula (Vπi):

(VIII) wherein F is as defined in relation to formula (VI), with a reagent capable of converting a moiety -CH2-OH into a moiety -CH2- 2.

When ϊβ represents a halogen atom, especially a chlorine or bromine atom, a suitable reagent is a halogenating agent such as a phosphorous trihalide.

When lβ is chlorine a preferred reagent is phosphorous trichloride.

When iβ is bromine a preferred reagent is phosphorous tribromide.

When ∑β represents a methanesulphonate group, a suitable reagent is a methanesulphonyl halide especially methanesulphonyl chloride.

When iβ represents a p-toluenesulphonate group, a suitable reagent is a p-toluenesulphonyl halide especially p-toluenesulphonyl chloride.

A compound of formula (VIII) may be prepared by reducing a compound of formula (IX):

(IX)

wherein Ry is as defined in relation to formula (VI) and R^ is a Cι_galkyl group.

A suitable reducing agent is a complex metal hydride such as Hthium aluminium hydride-

Suitably, Εp is a methyl group.

The compounds of formula (IX) are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example methods disclosed in Synthesis, 1982, 223. Suitable conversions of one compound of formula (I) into another compound of formula (I) include those in which a compound wherein R3 and R together represent a bond is converted into a compound wherein

R3 and R^* each represent hydrogen; such a conversion may be carried out using any conventional procedure such as catalytic reduction.

The salts of the compounds of formula (i) may be prepared by the appropriate conventional procedure.

The cyclisation of compounds of formula (II) may be carried out under any appropriate conditions, using any suitable solvent system and temperature range appropriate to the particular compound of formula (II), but usually at an elevated temperature.

Favourably, for the preparation of a compound of formula (I), the compound of formula (II) is not isolated from the reaction between the appropriate compound of formula (III) and 1,2-diaminoethane or an activated form thereof, thus the compound of formula (II) is converted in-situ to a compound of formula (I).

Thus, in this favoured form of the process for the preparation of compounds of formula (I), the appropriate compound of formula (III) and 1,2-diaminoethane, or more favourably an activated form thereof, are reacted together at an elevated temperature, for example within the range 80°C to 130°C, preferably 110°C, in any suitable solvent such as toluene, preferably under an atmosphere of nitrogen, or alternatively when A represents -CN the reaction may be carried out in the absence of an additional solvent.

Favourably in the last abovementioned reaction, the compound of formula (III) wherein A is -CO2R is reacted with the activated form of 1,2-diaminoethane, suitably the trimethylaluminium adduct of 1,2-diaminoethane.

It will be understood that under the abovementioned conditions the compound of formula (II) initially formed in the reaction between the compound of formula (III) and 1,2-diaminoethane or an activated form thereof; subsequently undergoes cyclisation to give the required compound of formula (I).

Accordingly, in an alternative aspect the present invention provides a process for the preparation of a compound of formula (I) which process comprises reacting a compound of formula (III) with 1,2-diaminoethane and thereafter if required converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof.

The reaction between compounds of formulae (IV) and (V) may be carried out in any suitable solvent such as a lower alkyl ketone, for example butanone, at any convenient temperature, suitably at the reflux temperature of the solvent, in the presence of a base, preferably potassium carbonate.

A compound of formula (VI) may be prepared from a compound of formula (Vπi) by using conditions appropriate to the nature of the reagent capable of converting a moiety -CH2-OH into a moiety -CH2-L2, for example:

(i) when iβ represents halogen, especially a chlorine or bromine atom and the reagent is a phosphorus trihalide, the reaction may conveniently be carried out at low to ambient temperature, for example at 5°C, in any suitable solvent, such as diethyl ether;

(ϋ) when lβ represents a methanesulphonate group or a p-toluenesulphonate and the reagent is a methanesulphonyl halide or a toluenesulphonyl halide respectively, the reaction may be carried out in any suitable solvent, such as pyridine, at a low to ambient temperature, suitably at ambient temperature.

The reaction between the compounds of formulae (VI) and (VII) may conveniently be carried out in an aprotic solvent, such as dimethylformamide, preferably at a slightly elevated temperature, for example at a temperature in the range of between 20°C and 60°C.

The reduction of the compound of formula (IX) is carried out under conditions appropriate to the reducing agent used. Thus, when lithium aluminium hydride is the reducing agent, the reaction may conveniently be carried out in an aprotic solvent, such as diethyl ether or tetrahydrofuran, at low to elevated temperature, more usually at the reflux temperature of the solvent.

In the abovementioned processes any reactive groups may be present as protecting groups. Suitable protecting groups are those used conventionally in the art; for example a suitable hydroxyl protecting group y is a benzyl group or, conveniently in this work, a methyl group.

The conditions of preparation and removal of the relevant protecting group are those used conveniently in the art. Thus, when R is a benzyl group, the compound of formula (X) may conveniently be reacted with benzyl bromide in the presence of a base such as potassium carbonate, in a solvent such as dimethylformamide, conveniently at an elevated temperature, for example 80°C. Also, when R is a benzyl group the benzyl group may be removed by using a reagent such as boron trifluoride dimethylsulphide complex.

As stated above, the compounds of formula (I), the pharmaceutically acceptable salts thereof and the pharmaceutically acceptable solvates thereof are indicated to have useful pharmaceutical properties.

The present invention therefore provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

In a particular aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment and/or prophylaxis of hyperglycaemia.

In a further aspect the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment and or prophylaxis of glaucoma and/or the treatment of hypertension and/or depression and/or for inhibiting blood platelet aggregation and/or for the treatment of benign prostatic hypertrophy. In a further aspect, the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, for use in the reductuion of regional body fat deposits.

A compound of the formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, may be administered perse or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefor.

As used herein 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.

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

Usually unless indicated to the contrary the pharmaceutical compositions of the invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption, are also envisaged.

Particularly suitable 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.

In accordance with conventional pharmaceutical practice 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, such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the

British and US Pharmacopoeias.

For the selective reduction of regional body fat deposits the compounds of the invention may be administered systemically or, preferably, topically.

For the selective reduction of regional body fat specific delivery of the active ingredient may be accomplished by any means whereby a higher concentration is achieved in a specific region of the body to achieve the desired effect. Examples of acceptable delivery systems includes injection, surgical implantation and topical application ,of such as by ointments and creams, to the surface of the skin over the regional fat deposit.After delivery, diffusion of the active ingredient throughout the regional fat deposit may be aided by heating or massaging of the deposit, or similar procedures.

For the selective reduction of regional body fat deposits the compounds of the invention may be administered as compounds per se or as pharmaceutical compositions.

Thus, in one particular aspect, the invention provides a composition for application to a selected part of the human or non human mammalian body for the selective reduction of regional body fat deposits, which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

Suitable compositions for administration comprise sterile solutions of the active chemical in aqueous solvents such as saline.

Favoured compositions are topical compositions, such as ointments or creams containing active ingredient.

Suitable carriers are conventional carriers including those described in EP 0120165.

Generally, the type of composition suitable any of the compositions of the invention and methods for preparing such compositions are those used conventionally and include for example those disclosed in standard reference texts, such as those mentioned above or those disclosed in the above mentioned European patent applications.

Most suitably the composition will be formulated in unit dose form.

For the treatment and/or prophylaxis of hyperglycaemia such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.: Such unit doses will also be suitable for the treatment and/or prophylaxis of glaucoma and/or the treatment of hypertension and/or depression and/or for inhibiting blood platelet aggregation.and/or the treatment of benign prostatic hypertrophy.

For the selective reduction of regional body fat deposits such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.

The present invention further provides a method for the treatment and/or prophylaxis of hyperglycaemia in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, 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 and/or prophylaxis of glaucoma and/or the treatment of hypertension and/or depression and/or for inhibiting blood platelet aggregation and/or for the treatment of benign prostatic hypertrophy in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof

In yet another aspect, the invention provides a method for achieving a selective reduction in body weight, which method comprises treating a portion of the body where weight reduction is required with an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

Suitably such method is a part of a general weight loss programme, whereby an acceleration of weight loss is achieved from the portion of the body to which the chemical was selectively delivered.

Preferably, the treatment includes topical treatment.

Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this as stated forms a particular aspect of the present invention.

In the treatment and/or prophylaxis of hyperglycaemic humans or the treatment of hypertensive humans the compound of the formula (I), or a pharmaceutically acceptable salt thereof, 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.

In the treatment and/or prophylaxis of hyperglycaemic non-human mammals, especially dogs, 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.

In the treatment and/or prophylaxis of glaucoma and/or the treatment of hypertension and/or depression and/or for inhibiting blood platelet aggregation and/or for the treatment of benign prostatic hypertrophy, in human or non-human mammals, dosage regimes are as indicated above for the treatment and/or prophylaxis of hyperglycaemic human or non-human mammals.

The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia.

The present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for use in the treatment and/or prophylaxis of glaucoma and/or the treatment of hypertension and/or depression and/or for inhibiting blood platelet aggregation and/or for the treatment of benign prostatic hypertrophy.

No toxicological effects are indicated when a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in any of the abovementioned dosage ranges.

The following Examples illustrate the invention but do not limit it in any way.

Example 1

2-[4,5-Dihydro-lH-imidazol-2.yl)methyl]-2,3-dihydro-4.(3- methylbut-2-enyloxy)-6-methyl-lH-isoindole, maleate (1:1)

To a solution of trimethylaluminium (5ml of a 2M toluene solution) in toluene (30ml) at 5°C under a nitrogen atmosphere was added 1,2-diaminoethane (0.53ml,7.1mmol). After 0.25h at room temperature methyl ( l,3-dihydro-4-(3-methylbut-2-enyloxy)-6-methyl-2H- isoindolyl)]-2-acetate (lg, 3.5mmol) in dry toluene (10ml) was added, and the resultant mixture stirred under reflux for 3h. After cooling to 5°C a mixture of dichloromethane (5ml), methanol (1ml) and water (1ml) was added. The mixture was warmed on a steam bath for O.lh, cooled, dried and evaporated to yield the crude product. This was dissolved in ethyl acetate (15ml) and treated with maleic acid (0.348g) in acetone (3ml), the solution was heated on a steam bath then allowed to cool to room temperature. Further cooling to -15°C resulted in crystallisation, the mixture was filtered and the solid dried under vacuum at 40°C to yield the title compound as a light brown solid.

iH-nmr δ (D₆-DMSO)

10.5-9.8 (2H, brd s, exchanges with D₂0); 6.69 (lH,s); 6.65 (lH,s); 6.02 (2H,s); 5.4-5.3 (lH,m); 4.51 (2H,d); 3.9-3.8 (10H,m); 3.5-3.3QH, brd s, exchanges with D₂0), 2.28 (3H,s); 1.74 (3H,s); 1.70 (3H,s). Example 2

2-[(4,5-D ydro-lH-imidazol-2-yl)methyl]-2,3-dihydro-4-(3-methyl- butyIoxy)-6-methyl-lH-isoindole, maleate (1:1)

The title compound was obtained from methyl (l,3-dihydro-4-(3-methyl- butyloxy)-6-methyl-2H-isoindole)-2-acetate (1.5g, 5.3mmol) by an analogous procedure to that described in Example 1.

iH-nmr δ (D6"^DMSO)

10.0-9.8 (2H, brd s, exchanges withD₂0); 6.68 (lH,s); 6.49 (lH,s); 6.02 (2H,s); 4.0-3.9 (12H,m); 3.85 (3H,s); 3.3-3.2 (IH, brd s, exchanges with D₂0); 1.76 (lH,m); 1.58 (2H,dxd); 0.93 (3H,s); 0.91 (3H,s).

Procedure 1

2,3-Bis(hydroxymethyl)-l-methoxy-5-methylbenzene.

To a suspension of lithium aluminium hydride (8g,0.22mol) in dry diethyl ether (250ml) was added dropwise dimethyl 3-methoxy-5-methylphthalate (24g, 0.1 mol) in dry tetrahydrofuran (100ml). The resultant mixture was heated under reflux for 1.5h, then cooled in ice water to 5°C. The excess hydride reducing agent and aluminium complexes were destroyed by the sequential addition of water (8ml), 10% sodium hydroxide (8ml) and water (16ml). After stirring for 0.5h the mixture was filtered under vacuum and the inorganic salts washed with dichloromethane (3x100ml aliquots). The combined organic phases were dried and evaporated to yield the title compound as a white crystalline solid.

lH-nmr δ (CDCl3/D₆-DMSO)

6.85 (IH, brd s); 6.72 (IH, brd s); 4.74 (2H,s); 4.65 (2H,s); 4.40 (2H, brd s exchanges with D₂0); 3.82 (3H,s); 2.32 (3H,s).

Procedure 2

2,3-Bis(bromometb.yl)-l-methoxy-5-methylbenzene

To a suspension of 2,3-bis(hydroxymethyl)-l-methoxy-5-methylbenzene

(15.8g, 87mmol) in dry diethyl ether (250ml) was added phosphorus tribromide (25ml, 0.26mol) in dry diethyl ether (25ml). After 4h the mixture was poured onto crushed ice and stirred vigorously. The aqueous layer was saturated with sodium chloride and the organic layer separated.

The aqueous phase was extracted with ethyl acetate (2x100ml aliquots).

The combined organic phases were washed with water (200ml) and saturated sodium bicarbonate solution (200ml), drying and evaporation gave the title compound, as a white solid.

iH-nnir δ (CDC1₃)

6.81(lH,s); 6.78(lH,s); 4.76(2H,s); 4.57(2H,s); 3.83 (3H,s); 2.31(3H,s). Procedure 3

l,3-I iIιydι»-4-ιιιefhoxy-β-ιnethyl-2H-isoindole-2-acetoιιitrile

To a solution of aminoacetonitrile hydrochloride (70g,76mmol) and triethylamine (26ml, 0.192mol) in dimethylformamide (200ml) at 50°C was added dropwise 2,3-bis(bromomethyl)-l-methoxy-5-methylbenzene (19.7g, 64mmol) in dimethylformamide (50ml). After 3h the mixture was cooled and poured into water (600ml). The organic material was extracted into ethyl acetate (2x100ml aliquots). The combined organic phases were washed with water (1x250ml), dried and evaporated to yield the title compound as a pale red oil.

6.80(lHs); 6.58(lH,s); 4.08(4H,s); 3.82(3H,s); 3.78(2H,s); 2.35(3H,s).

Procedure 4

Methyl (l,3-dihydκ>-4-hydroxy-6-ιnethyl-2H-isoindole)-2-acetate

— CH,— COpCH,

A mixture of (l,3-dihydro-4-methoxy-6-methyl-2H- isoindole)-2-acetonitrile (8.8g 44mmol) and 48% aqueous hydrobromic acid (70ml) was heated under reflux for 14h under an atmosphere of nitrogen. The solution was cooled and the solvent evaporated. The residue was dissolved in methanol (200ml) and the resultant mixture saturated with gaseous hydrogen chloride. After 18h the solvent was evaporated and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried and evaporated to yield the crude product. Dry flash chromatography over silica eluting with ethyl acetate gave of the title compound as a light brown oil.

iH-nmr δ (CDCI3)

7.3-7.0(lH,brd s exchanges with D₂0); 6.42(lH,s); 6.21(lH,s); 3.95(4H,s), 3.57(3H,s); 3.35(2H,s); 2.05(3H,s)

Procedure 5

Methyl (l,3-dihydro-4-(3-methylbut-2-enyloxy)-6-methyl- 2H-isoindole)-6 -acetate

To a mixture of methyl(l,3-dihydro-4-hydroxy-6-methyl-2H-isoindole)-2- acetate (1.5g, 6.7mmol), triphenylphosphine (1.8g, 6.8mmol) and 3- methylbut-2-enol (0.67ml, 6.7mmol) in dry tetrahydrofuran (40ml) at 5°C under an atmosphere of nitrogen was added diethyl azodicarboxylate (1.2ml, 7.6mmol) in dry tetrahydrofuran (5ml). After lh at room temperature the solvent was evaporated and the residue partitioned between diethyl ether and water. The organic layer was dried and concentrated to about 20ml. After cooling to -15°C the solid was filtered off and discarded. The filtrate was evaporated and purified by dry flash chromatography over silica eluting with 0-30% ethyl acetate in hexane to yield the title compound as oil.

iH-nmr δ (CDCI3) 6.61(lH,s), 6.52(lH,s); 5.5-5.4(lH,m); 4.94(2H,d); 4.07 (4H,s); 3.74(3H,s);

3.59(2H,s); 2.32(3H,s); 1.77(3H,s); 1.71(3H,s).

Procedure 6

Meihyl(l-3-d ydι >-4 3-meaιylbutyloxy)-6-methyl-2H isoindole)-2- acetate.

The title compound was obtained from methyl (l,3-dihydro-4-hydroxy-6- methyl-2H-isoindoIe)-2-acetate (2.0g, 9.0mmol) and 3-methylbutanol (lml, 9.2mmol) by an analogous method to that described in Procedure 5.

lH-nmr δ (CDCI3)

6.61(lH,s); 6.50(lH,s); 4.08 (4H,s); 3.97(2H,d);

3.71(3H,s), 3.58(2H,s); 2.27(3H,s); 1.9-1.6(3H,m); 0.96(3H,s); 0.85(3H,s).

Pharmacological Data

Demonstration of the Pharmacological Selectivity for Pre- and Post-junctional α2-Adrenoceptors.

To determine post-junctional α2-adrenoceptor activity, ring segments of rabbit lateral saphenous vein were mounted in organ baths at 37°C containing Krebs medium. Contractions of this tissue in response to noradrenaline are mediated via post-junctional α2-adrenoceptors (Alabaster et al, 1985) and therefore the ability of α2-adrenoceptor antagonists to pharmacologically antagonise such contractions gives a quantitive measure of the activity of compounds for this receptor subtype.

Pre-junctional activity is estimated by the ability of α2-adrenoceptor antagonists to reverse a clonidine-induced inhibition of

[3H]-noradrenaline release from segments of rabbit aorta. Rings of rabbit abdominal aorta were incubated at 37°C in Krebs medium containing 40 μCi of [3H]-noradrenaline (specific activity 10-30Ci/mmol) for 1 hour. Tissues were then mounted vertically between parallel platinum electrodes and superfused with tritium-free Krebs medium. Electrical stimulation was carried out using square wave pulses of 0.5 msec duration and 100V were delivered to the tissues at a frequency of 2Hz. The superfusate was collected in 3 minute fractions. Six stimuli (Si-Sβ) were applied to each tissue. Clonidine was added to the superfusion stream after S2 at a concentration of O.OlμM and again after S3 at a concentration of O.lμM. Each antagonist added after S4 and a further concentration of clonidine (lμM) infused after S5. At the end of each experiment each aortic segment solubilised in 150μl of Fisosolve-^ tissue solubiliser and the radioactivity of both superfusate samples and aortic rings determined by liquid scintillation spectroscopy.

Results are calculated by the method of Docherty et al, 1982, with stimulation evoked overflow of tritium expressed as a percentage of the tritium content of the tissue at the onset of the respective stimulation period.

Alabaster V.A., Keir R.F. and Peters C.J. (1985) Naunun-Schmiedeberg's Arch Pharmacol 330, 33-36. Docherty J.R., Gothert M., Dieckhoffer C. and Starke (1982) Arzneim-Forsch, Drug Res., 32, 1534-1540.

Post-junctional αχ-adrenoceptor agonism

Post-junctional α activity was determined using a method similar to that for post-junctional α activity, but using rings of rabbit aorta. Contractions of this tissue are mediated by post-junctional αχ-adrenoceptors (Docherty et al. 1981), and so the pD2 of αj-adrenoceptor agonists was calculated from their ability to contract the rings of aorta in comparison with noradrenaline.

Example Post-synaptic

Number pD₂

1 <5.0

Docherty J.R., Constantine J.W. and Starke K 1981. Arch. Pharmocol. 317.

Claims

A compound of formula (I):

(I)

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein ^~R~- and R***** may each represent hydrogen or C _g alkyl, providing that at least one of R-- or R-^ represents Cχ_g alkyl; and

R and R^* each represent hydrogen or R together with R4 represents a bond.

2. A compound according to claim 1, wherein R--- and R^ each represent methyl.

3. A compound according to claim 1 or claim 2, wherein R and R^ together represent a bond.

4. A compound according to claim 1, selected from the group consisting of:

2-[4,5-dihydro-lH-imidazol-2-yl)methyl]-2,3-dihydro-4- (3-methylbut-2-enyloxy)-6-methyl-lH-isoindole; and

2-[(4,5-dihydro-lH-imidazol-2-yl)methyl]-2,3-dihydro-4- (3-methylbutyloxy)-6-methyl-lH-isoindole; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof.

5. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, which process comprises: a) cyclising a compound of formula (II):

(ID

wherein R-**-, Rβ, R^ and ^ are as defined in relation to formula (I) and X is O or N; or b) reacting a compound of formula (DI):

(IH)

wherein B. B , Bβ and R4* are as defined in relation to formula (I) and A represents -CN or CO2R wherein R represents Cχ.g alkyl, with 1,2-diaminoethane or an activated form thereof, and thereafter cyclising the above defined compound of formula (ID) so formed; and thereafter, if required, converting a compound of formula (I) into a further compound of formula (I) and/or forming a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

6. A pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.

7. A compound of formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

8. A compound of formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, for use in the treatment and/or prophylaxis of hyperglycaemia, glaucoma, hypertension, depression, for inhibiting blood platelet aggregation and/or for the treatment of benign prostatic hypertrophy and/or for the selective reduction of regional body fat deposits.

9. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia, glaucoma, hypertension, depression and/or for inhibiting blood platelet aggregation and/or for the treatment of benign prostatic hypertrophy and/or for the selective reduction of regional body fat deposits.

10. A method for the treatment and/or prophylaxis of hyperglycaemia, glaucoma, hypertension, depression and/or for inhibiting blood platelet aggregation and/or for the treatment of benign prostatic hypertrophy and/or for the selective reduction of regional body fat deposits.in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.