PT101041B - IMIDAZOLYLMETHYL-INDOLE DERIVATIVES CONTAINING ANTAGONIST ACTIVITY OF ADRENOCEPTORS ALPHA 2, PROCESS FOR PREPARING AND USING THEM - Google Patents

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein R<1> and R<2> may each represent hydrogen or C1-6alkyl, providing that at least one of R<1> or R<2> represents C1-6alkyl; and R<3> and R<4> each represent hydrogen or R<3> together with R<4> 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

IMIDAZOLYLMETHYL-INDOLE DERIVATIVES THAT HAVE ANTAGONIST ACTIVITY OF ADRENOCEPTORS ₂ , PROCESS FOR THEIR PREPARATION AND USE

DESCRIPTIVE MEMORY

resume

The present invention says la (I):

respect to compounds of formulas

or a pharmaceutically acceptable salt thereof, or a salt thereof. 1 2 pharmaceutically acceptable solvate, wherein R and R can each represent hydrogen or C alkyl with the proviso that at least one of R or R represents C _nc alkyl; and R and R. . 3 '. ⁶ 4 each represent hydrogen or R together with R

represents a connection; as well as the process for the preparation of these compounds.

The invention also concerns a pharmaceutical composition comprising one of these compounds and the use of that composition and compounds in medicine.

This invention relates to some classes of heterocyclic compounds that have activity as ₂ -adenoaceous antagonists, with a process for the preparation of these compounds, with pharmaceutical compositions of these compounds and with the use of these compounds and compositions in medicine.

European Patent Applications, Publication Nos. 0238753 and 0313288 describe some heterocyclic compounds of general formula (A):

or a pharmaceutically acceptable salt thereof, an ester or amide, in which:

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

X 'represents 0 or RN °, where R ° represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkanoyl group in the alkyl portion, or a substituted or unsubstituted arylalkyl portion in the aryl portion, 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 from 1 to 12.

The compounds of formula (A) are described as having a good ₂ -adrenoceptor antagonist activity and as being of potential use for the treatment and / or prophylaxis of hyperglycemia and / or glaucoma and / or the treatment of hypertension and / or depression and / or to inhibit blood platelet aggregation.

EP 0313288 also describes heterocyclic compounds of formula (B):

or a pharmaceutically acceptable salt thereof, where:

R ^a and R ^b can each represent hydrogen or alkyl, with the proviso that at least one of R ^a and R ^D represents alkyl;

R ^c and R 4 each represent hydrogen, or R ^c and together represent a bond;

n '' represents an integer 1 or 2;

and m represents an integer 1 or 2.

The compounds of formula (B) are described as having very good selectivity for post-junction of the α-receptor and therefore show good selectivity for side effects. The compounds of formula (B) are described as being of particular value in the treatment and / or prophylaxis of hyperglycemia and / or in the treatment of hypertension and / or for the inhibition of blood platelet aggregation.

The European Patent application, Publication No. 0120165 also describes the use of some Î ± -adrenergic inhibitors to control weight loss by reducing regional fat deposits.

It has now been discovered that a small class of compounds, included in formula (A) but structurally distinct from the compounds of formula (B) and the compounds of EP 0120165, which shows ₂ -adenoaccepting antagonist activity and surprisingly has a good selectivity for powders the α- ₂ -receptor junction and in addition is essentially free of β-adrenoceptor agonist activity and therefore shows good selectivity for side effects, such as those associated with β-adrenoceptor agonist activity.

These compounds are potentially of particular value in the treatment and / or prophylaxis of hyperglycemia and / or glaucoma and / or the treatment of hypertension and / or depression and / or for

inhibition of blood platelet aggregation. They can 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 fat deposits in body regions, especially via topical application.

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

or a pharmaceutically acceptable salt thereof, or a solvate thereof 1 2 pharmaceutically acceptable carrier, wherein R and R may each represent hydrogen or alkyl ^C ₁ _ ₆ with the proviso that at least one of R ¹ or R ² represents alkyl ; and

4. .3

R and R each represent hydrogen or R together. - to R represents a connection.

2

Preferably, R and R each represent methyl.

Preferably, R and R together represent a bond.

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

2 - ((4,5-dihydro-1H-imidazol-2-yl) methyl] -2,3-dihydro-4- (3-methylbut-2-enyloxy) -6-methyl-1H-isoindole ; and

2 - ((4,5-dihydro-1H-imidazol-2-yl) methyl] -2,3-dihydro-4- (3-methylbutyloxy) -6-methyl-1H-isoindole;

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof.

Pharmaceutically acceptable salts of the compounds of formula (I) include salts of the addition of acids.

Suitable pharmaceutically acceptable acid addition salts of compound (I) include pharmaceutically acceptable inorganic salts such as sulfate, nitrate, phosphate, borate, hydrochloride, and hydrobromide and organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate , ascorbate, methanesulfonate, 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 or branched chain alkyl groups, which contain from 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms.

When used herein, the term C_alkyl includes branched or straight chain alkyl groups, which contain 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, the process of which comprises cyclizing a compound of formula (II):

to

2 3 4. .

where R, R, R and R are defined as with respect to formula (I) and X is O or N; and then, if desired, converting a compound of formula (I) to another compound of formula (I) and / or forming a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

A compound of formula (II) can be prepared by reacting a compound of formula (III):

(IH)

2 3 4. .

where R, R, R · and R are defined as with respect to formula (I) and A represents -CN or CO ₂ R, where R represents C ₁ _ _g alkyl, with 1,2-diaminoethane or a form thereof activated.

An activated form of 1,2-diaminoethane is the adduct of trimethylaluminum and 1,2-diaminoethane. The activated form of 1,2-diaminoethane is generally the preferred reagent, when A represents -C0 R.

Suitably, A is -C0 R.

Suitably, R represents methyl.

A compound of formula (III) can be prepared by reacting a compound of formula (IV):

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

R ¹ /

L ¹ - CH ₂ - CH - C - R ² \

R ³ (V)

2 3 4. .

where R, R, R and R are defined as in relation to formula 1. .

(I) and L represents an easily releasable group, preferably a bromine atom.

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

A compound of formula (IV) can be prepared by reacting a compound of formula (VI):

(SAW)

V 2 where R ^J represents a protecting group and L represents an easily releasable group, with a compound of formula (VII):

H ₂ N-CH ₂ -A (VII) where A is defined as in relation to formula (III); and then, if desired, converting a compound of formula (IV) to another compound of formula (IV).

Suitably, L represents a halogen atom, especially a chlorine or bromine atom, a methanesulfonate group or a p-toluenesulfonate group.

. 2

Preferably L represents a bromine atom.

Suitable conversions of a compound of formula (IV) to another compound of formula (IV) include those in which A, in formula (IV), is converted from one value to another value: for example a compound of formula (IV), into whereas A represents nitrile, can be converted into a compound of formula (IV), where A represents -CO ₂ R, where R is defined as in relation to formula (III), by any conventional procedure, for example by hydrolysis to give the corresponding carboxylic acid, followed by esterification.

Γ2

Suitable conditions for the hydrolysis of the nitrile group include acidic conditions, for example using aqueous boric 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) can be prepared by reacting a compound of formula (VIII):

OR ^Y h 1 ^ ch ₂ —oh II ^ CH ₂ —OH H ₃ C ^Z (VUD where R ^ is defined as in relation to formula (VI), common reagent capable of converting a portion -CH ^ -OH in a portion

- ^CH 2- ^L 2 ·

When L represents a halogen atom, special &

a chlorine or bromine atom, a suitable reagent is a halogenating agent, such as a phosphorus trihalide.

When L is chlorine, a preferred reagent is phosphorus trichloride.

When L is bromine, a preferred reagent is phosphorous tribromide.

When L represents a methanesulfonate group, a suitable reagent is a methanesulfonyl halide, especially methanesulfonyl chloride.

When L represents a p-toluenesulfonate group, a suitable reagent is a p-toluenesulfonyl halide, especially p-toluenesulfonyl chloride.

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

(IX)

V. . - 5 where R ^{J is} defined as in relation to formula (VI) and R is an alkyl group

A suitable reducing agent is a metal hydride complex, such as aluminum and lithium hydride.

Suitably, R is a methyl group.

The compounds of formula (IX) are known compounds or they can be prepared using methods analogous to those used for the preparation of known compounds, for example by the methods described in Synthesis, 1982, 223.

Suitable conversions of a compound of formula (I) to another compound of formula (I) include those in which a compound 4 where R and R together represent a bond, is converted to a compound in which R and R each represents hydrogen; this conversion can be performed using any conventional procedure, such as catalytic reduction.

The salts of the compounds of formula (I) can be prepared by the appropriate conventional procedure.

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

Favorably, 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, so compound of formula (II) is converted in situ to a compound of formula (I).

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

X '

Favorably in the last reaction mentioned above, the compound of formula (III), in which A is -CO ₂ R, is reacted with the activated form of 1,2-diaminoethane, suitably the adduct of trimethylaluminum and 1,2-diaminoethane.

It is to be understood that under the conditions mentioned above 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 cyclization to give the desired compound from formula (I).

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

The reaction between compounds of formulas (IV) and (V) can be carried out in any solvent, such as an alkyl ketone below the reflux temperature, 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) can be prepared from a compound of formula (VIII) using the conditions appropriate to the nature of the reagent, capable of converting a -CH ^ -OH portion to a -CH ₂ “L, for example:

. 2 (1) when L represents halogen, especially a chlorine or bromine atom and the reagent is phosphorous trihalide, the reaction can conveniently be carried out at a

temperature below room temperature, for example at 5 ° C, in any suitable solvent, such as diethyl ether;

(ii) when L represents a methanesulfonate group or a p-toluenesulfonate and the reagent is a methanesulfonyl halide or a toluenesulfonyl halide respectively, the reaction can be carried out in any suitable solvent, such as pyridine, at a temperature below room temperature, properly at room temperature.

The reaction between the compounds of formulas (VI) and (VII) can be conveniently carried out in an aprotic solvent, such as dimethylformamide, preferably at a slightly elevated temperature, for example at a temperature in the range 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 aluminum hydride is the reducing agent, the reaction can conveniently be carried out in an aprotic solvent, such as diethyl ether or tetrahydrofuran, from low to high temperatures, more usually at the reflux temperature of the solvent.

In the aforementioned processes any of the reactive groups can be present as protecting groups. Suitable protecting groups used conventionally in the art, for example a suitable hydroxyl protecting group 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 field. Thus, when R ^y is a benzyl group, the compound of formula (X)

it can 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 it is a benzyl group, it can be removed by using a reagent like the boron trifluoride and dimethyl sulfide complex.

As indicated above, the compounds of formula (I), their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates 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, to be used 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 hyperglycemia.

In another 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 inhibiting blood platelet aggregation and / or treating benign prostatic hypertrophy.

In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically salt thereof

acceptable or a pharmaceutically acceptable solvate thereof, for use in reducing fat deposits in body regions.

A compound of formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, can be administered per se or, preferably, in the form of a pharmaceutical composition also comprising a pharmaceutically acceptable support.

Accordingly, the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate and therefore a pharmaceutically acceptable support.

As used herein the term pharmaceutically acceptable encompasses compounds, compositions and ingredients for both human and veterinary use: for example the term pharmaceutically acceptable salt encompasses a veterinarily acceptable salt.

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

Usually, unless otherwise indicated, 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 in view.

Particularly, compositions suitable for oral administration are in unit dosage forms, such as tablets or capsules. Other fixed dosage forms, such as powders presented in pouches, can also be used.

According to conventional practice, the support can comprise a diluent, filler, disintegrating agent, weight agent, lubricant, colorant, taste agent or other conventional adjuvants.

Typical supports include, for example, microcrystalline cellulose, starch, sodium starch glycolate, such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and Bristish and US Pharmacopoeias.

For the selective reduction of fat deposits in body regions, the compounds of the invention can be administered systematically or, preferably, topically.

For the selective reduction of fat in body regions, specific deliveries of the active ingredient can be achieved by any means by which a high concentration is achieved in a specific region of the body, to achieve the desired effect. Examples of acceptable delivery systems include injections, surgical implantation and their topical application, such as ointments and creams, to the surface of the skin over the regional fat deposit. After delivery, the diffusion of the active ingredient through the entire regional fat deposit can be helped by heating or massaging the deposit, or similar procedures.

For the selective reduction of fat deposits in body regions, the compounds of the invention can be administered as compounds per se or as pharmaceutical compositions.

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

Compositions suitable for administration comprise sterile solutions of an active chemical in aqueous solvents, such as in a saline solution.

Favored compositions are topical compositions, such as ointments or creams that contain the active ingredient.

Suitable supports are conventional supports that include those described in EP 0120165.

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

More suitably, the composition is formulated in a unit dose form.

For the treatment and / or prophylaxis of hyperglycemia, as a unit dose normally, it will contain an amount of

active ingredient in the range from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially from 0.1 to 250 mg. These 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 the inhibition of blood platelet aggregation and / or the treatment of benign prostatic hypertrophy.

For the selective reduction of fat deposits in regions of the body, as a unit dose normally, it will contain an amount of the active ingredient in the range from 0.1 to 1000 mg, more usually from 0.1 to 500 mg, and more especially from 0, 1 to 250 mg.

The present invention further provides a method for the treatment and / or prophylaxis of hyperglycemia in a human or non-human mammal, which comprises administering a non-toxic, effective amount of a compound of formula (I), or a salt thereof pharmaceutically acceptable, or a pharmaceutically acceptable solvate thereof to a human or hyperglycemic non-human mammal, in need.

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 the inhibition of blood platelet aggregation and / or for the treatment of benign protein hypertrophy in a human or non-human mammal, comprising administering a non-toxic, effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or to a non-human mammal, in need.

In yet another aspect, the present invention provides a method for achieving a selective reduction in body weight, the

The method comprises treating a body portion where weight reduction is desired with a non-toxic, effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

Suitably, this method is a part of a general weight loss program, where an acceleration of weight loss is achieved from the body portion to which the chemist has been selectively delivered.

Preferably, treatment includes topical treatment.

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

In the treatment and / or prophylaxis of hyperglycemic humans and hypertensive humans, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be given in doses, as described above, one to six times in a day, so that the total daily dose for an adult of 70 kg is generally in the range of 0.1 to 6000 mg, and more usually from about 1 to 1500 mg.

In the treatment and / or prophylaxis of hyperglycaemic non-human mammals, especially dogs, the active ingredient can be administered via the mouth, usually once or twice a day and in an amount ranging from about 0.025 mg / kg to 25 mg / kg, for example. example from 0.1 mg / kg to 20 mg / kg.

For the treatment and / or prophylaxis of glaucoma and / or the treatment of hypertension and / or depression and / or for the inhibition of blood platelet aggregation and / or for the treatment of benign prostatic hypertrophy in a human or non-human mammal, dosage regimens are as indicated above for treatment and / or prophylaxis in humans or in hyperglycemic 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 drug for the treatment and / or prophylaxis of hyperglycemia.

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 for the treatment of hypertension and / or depression and / or for the inhibition of 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 dosage ranges indicated above.

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

Example 1

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

co ₂ h co ₂ h

To a solution of trimethyl aluminum (5 ml of a 2M toluene solution) in toluene (30 ml), at 5 ° C, under a nitrogen atmosphere, was added 1,2-diaminoethane (0.53 ml; 7, 1 mmol). After 0.25 h, at room temperature o [1,3-dihydro-4- (3-methylbut-2-enyloxy) -6-methyl-2H-isoindolyl)] - methyl 2-acetate (1 g ; 3.5 mmol) in dry toluene (10 ml) was added, and the resulting mixture was stirred at reflux for 3 hours. After cooling to 5 ° C, a mixture of dichloromethane (5 ml), methanol (1 ml) and water (1 ml) was added. The mixture was heated on a steam bath for 0.1 h, cooled, dried and evaporated to give the crude product. This was dissolved in ethyl acetate (15 ml) and treated with maleic acid (0.348 g) in acetone (3 ml). The solution was heated on a steam bath, then allowed to cool to room temperature. Further cooling to -15 ° C resulted in crystallization, the mixture was filtered and the solid was dried under vacuum at 40 ° C, to give the title compound as a light brown solid.

¹ H NMR δ (D -DMSO)

O

10.5 - 9.8 (2H, s broad, exchange with D ₂ 0); 6.69 (1H,

s); 6.65 (1H, s); 6.02 (2H, s); 5.4 - 5.3 (1H, m); 4.51 (2H, d);

3.9 - 3.8 (10H, m); 3.5 - 3.3 (1H, s broad, exchange with D ₂ O);

2.28 (3H, s); 1.74 (3H, s); 1.70 (3H, s).

Example 2

2 - [(4,5-Dihydro-1H-imidazol-2-yl) methyl] -2,3-dihydro-4- (3-methylbutyloxy) -6-methyl-1H-isoindole maleate (1 :1)

title compound was obtained from methyl [1,3-dihydro-4- (3-methylbutyloxy) -6-methyl-2H-isoindole) -2-acetate (1.5 g, 5.3 mmol) through a procedure analogous to that described in Example 1.

NMR ^_1 H 6 (D -DMSO) d

10.0 - 9.8 (2H, s broad, exchange with D ₂ O); 6.68 (1H,

s); 6.49 (1H, s); 6.02 (2H, s); 4.0 - 3.9 (12H, m); 3.85 (3H, S); 3.3 - 3.2 (1H, s broad, exchange with D ₂ 0); 1.76 (1H, m); 1.58 (2H, .dxd); 0.9-3 (3H, .s) 0.91 · (3H, s).

Procedure 1

2,3-Bis (hydroxymethyl) -1-methoxy-5-methylbenzene

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

1001-¼ 5 (CDC1- / D -DMSO) v

6.85 (1H, s broad); 6.72 (1H, broad s); 4.74 (2H, s); 4.65 (2H, s); 4.40 (2H, s broad, exchange with D2O); 3.82 (3H, s); 2.32 (3H, s).

Procedure 2

2,3-Bis (bromomethyl) -1-methoxy-5-methylbenzene

To a suspension of 2,3-bis (hydroxymethyl) -1-methoxy-5-methylbenzene (15.8 g; 87 mmol) in dry diethyl ether (250 ml) was added phosphorous tribromide (25 ml; 0.26 mol ) in dry diethyl ether (25 ml). After 4 h, the mixture was poured into crushed ice and stirred vigorously. The aqueous layer was saturated with sodium chloride and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (2 x 100 ml aliquots). The combined organic phases were washed with water (200

ml) and with solution of bicarbonate saturated sodium (200 ml), dry and evaporated to originate the compound in epigraph, in form of a solid White. ¹ H NMR δ (CDC1 ₃ ) 6.81 (1H, S) ; 6.78 (1H, S) ; 4.76 (2H, s); 4.57 (2H, s); 3.83 (3H, s); 2.31 (3H, s).

Procedure 3

1,3-Dihydro-4-methoxy-6methyl-2H-isoindole-2-acetonitrile

To a solution of aminoacetonitrile hydrochloride (70 g, 76 mmol) and triethylamine (26 ml; 0.192 mol) in dimethylformamide (200 ml) at 50 ° C, 2,3-bis (bromomethyl) -1 was added dropwise -methoxy-5-methylbenzene (19.7 g; 64 mmol) in dimethylformamide (50 ml). After 3 h, the mixture was cooled and poured into water (600 ml). The organic material was extracted in ethyl acetate (2 x 100 ml aliquots). The combined organic phases were washed with water (1 x 250 ml), dried and evaporated to give the title compound as a light red oil.

1 H NMR (CDC1)

6.80 (1H, s); 6.58 (1H, s); 4.08 (4H, s); 3.82 (3H, s);

3.78 (2H, S); 2.35 (3H, s).

Procedure 4 (1,3-Dihydro-4-hydroxy-6-methyl-2H-isoindole) -2-methyl acetate

A mixture of (1,3-dihydro-4-methoxy-6-methyl-2H-isoindole) -2-acetonitrile (8.8 g; 44 mmol) and 48% aqueous hydrobromic acid (70 ml) was heated under reflux for 14 h under a nitrogen atmosphere. The solution was cooled and the solvent was evaporated. The residue was dissolved in methanol (200 ml) and the resulting mixture saturated with hydrogen chloride gas. After 18 h, the solvent was evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarboanate solution. The organic layer was dried and evaporated to give the crude product. Dry flash chromatography on silica gel, eluting with ethyl acetate, gave the title compound as a light brown oil.

11101-¼ δ (cdci ₃ )

7.3 - 7.0 (1H, s broad, exchange with D ₂ 0); 6.42 (1H, s);

6.21 (1H, s); 3.95 (4H, s); 3.57 (3H, s); 3.35 (2H, s); 2.05 (3H, s).

Procedure 5

Methyl (1,3-Dihydro-4- (3-methylbut-2-enyloxy) -6-methyl-2H-isoindole) -6-acetate

—CO ₂ CH ₃

To a mixture of methyl (1,3-dihydro-4-hydroxy-6-methyl-2H-isoindole) -2-acetate (1.5 g; 6.7 mmol), triphenylphosphine (1.8 g; 6.8 mmol) and 3-methylbut-2-enole (0.67 ml; 6.7 mmol) in dry tetrahydrofuran (40 ml), at 5 ° C, under a nitrogen atmosphere, sodium azodicarboxylate was added diethyl (1.2 ml; 7.6 mmol) in dry tetrahydrofuran (5 ml). After 1 h, at room temperature, the solvent was evaporated and the residue was partitioned between diethyl ether and water. The organic layer was dried and concentrated to about 20 ml. After cooling to -15 ° C, the solid was filtered and discharged. The filtrate was evaporated and purified by dry flash chromatography on silica gel, eluting with 0 - 30% ethyl acetate in hexane, to give the title compound as an oil.

NMR- ^ H δ (CDC1 ₃ )

6.61 (1H, s); 6.52 (1H, s); 5.5 - 5.4 (1H, 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

Methyl (1,3-Dihydro-4- (3-methylbutyloxy) -6-methyl-2H-isoindole) -2-acetate

title compound was obtained from methyl (1,3-dihydro-4-hydroxy-6-methyl-2H-isoindole) -2-acetate (2.0 g; 9.0 mmol) and 3- methylbutanol (1 ml; 9.2 mmol) using a method analogous to that described in Procedure 5.

^X- NMR H 6 (CDC1 ₃ )

6.61 (1H, s); 6.50 (1H, 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 Pharmacological Selectivity for Pre- and Post-junction of c ^ -Adrenaceptors

To determine the post-junction activity of a ₂ -adenoacceptors, ring segments of the lateral saphenous vein of rabbits were mounted in organ baths at 37 ° C, which contain Krebs medium. The contractions of these tissues in response to

norepinephrine are induced via the post-junction of ₂ -adenoacceptors (Alabaster et al, 1985) and therefore the ability of _2- adenoacceptor antagonists to pharmacologically antagonize these contractions gives rise to a quantitative measure of the activity of compounds for this receptor subtype .

Pre-junction activity is stimulated by the ability of Î ± -adrenoaccepted antagonists to reverse clonidine inhibition induced by [H] -noradrenaline from segments of rabbit aorta. Rabbit abdominal aorta rings were incubated at 37 ° C in Krebs' medium, which contains 40 / xCi of 3 ...

[π] -noradrenaline (specific activity 10 - 30 Ci / mmol), for 1 hour. The tissues were then mounted vertically between parallel platinum electrodes and superfused with tritium-free Krebs medium. Electrical stimulation was performed using square wave pulses of 0.5 msec and 100 V duration that were delivered to tissues at a frequency of 2 Hz. The superfusate was collected in fractions of 3 minutes. Six stimuli (S ₁ ~ Sg) were applied to each tissue. Clonidine was added to the superfusion stream after S ₂ at a concentration of 0.01 μΜ and again after at a concentration of 0.1 μΜ. Each antagonist was added after and another clonidine concentration (1 μΜ) after s ₅ · At the end of each experiment each aortic segment was solubilized in 150 μΐ of Fisosolve tissue solubilizer and the radioactivity of both superfusate samples and of the aortic rings was determined by liquid scintillation spectroscopy.

The results were calculated by the method of Docherty et al, 1982, with the stimulation evoked a flood of tritium expressed as a percentage of the tritium content of the tissue in the attack during the respective stimulation period.

Example Number Post-synaptic pa ₂ Pre-synaptic pa ₂ 1 7.1 <5.0 2 6.7 <5.0

Alabaster V. A., Keir R. F. and Peters C. J. (1985) Naunun-Schmiedeber's Arch Pharmacol 330, 33 - 36.

Docherty J. R., Gothert M., Dieckhoffer C. and Starke K. (1982).

Arzneim-Forsch, Drug Res., 32, 1534 - 1540.

Post-junction agonism of aladrenoacceptor

Post-junction activity was determined using a method similar to that described for post-junction activity at ₂ , but using rabbit aorta rings. Contractions of this tissue are induced by post-junction of β-adrenoceptors (Docherty et al. 1981), and so the pD2 of β-adrenoceptor agonists was calculated from their ability to contract aortic rings compared to noradrenaline.

Number of

Postsynaptic

Example

P ° ₂ <5.0

Docherty J. R., Constantine J. W. and Starke K. 1981.

Arch Pharmocol. 317.

Lisbon, November 6, 1992

VICTOR COROON STREET, 10-A 3, “

1200 LISBON

Claims (7)

CLAIMS ia. - Compound, characterized by presenting the formula (I): (D or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate 12 thereof, wherein R and R can each represent hydrogen or C C _ alkyl, with ^the proviso that at least one of R ¹ or R ² represents C ₁ _ ₆ alkyl; ® 3 4. . 3 R and R each represent hydrogen or R together with R represents a bond. 2-. A compound according to claim 1, characterized in that R and R each represent methyl. 38. The compound according to claim 1 or a. . . 3 Claim 2, characterized in that R and R together represent a bond. 48. A compound according to claim 1, characterized in that it is selected from the group consisting of: 2 - [(4,5-dihydro-1H-imidazol-2-yl) methyl] -2,3-dihydro-4- (3-methylbut-2-enyloxy) -6-methyl-1H-isoindole ; and 2- [(4,5-dihydro-1H-imidazol-2-yl) methyl] -2,3-dihydro-4- (3-methylbutyloxy) -6-methyl-1H-isoindole; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof. 5 ^. - Process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, characterized by comprising: a) the cyclization of a compound of formula (II): 1 2 3 4. . where R, R, R and R are defined as in relation to formula (I) and X is 0 or N; or b) the reaction of a compound of formula (III): (III) 12 3 4. . where R, R, R and R are defined as with respect to formula (I) and A represents -CN or CO_Rem where R represents C alkyl. Z _L “O with 1,2-diaminoethane or with an activated form thereof, and then the cyclization of the compound defined above of formula (III) thus formed; and then, if desired, converting a compound of formula (I) to another compound of formula (I) and / or forming a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. 63. - Pharmaceutical composition, characterized in that it comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate, and a pharmaceutically acceptable support for that purpose. 7®. - A compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, characterized in that it is intended for use as an active therapeutic substance. 8®. - A compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, characterized in that it is intended for use in the treatment and / or prophylaxis of hyperglycemia, glaucoma, hypertension, depression, for the inhibition of platelet aggregation blood and / or for the treatment of benign prostatic hypertrophy and / or for the selective reduction of fat deposits in body regions. 92. - Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, characterized in that said compound is used for the preparation of a medicament for the treatment and / or prophylaxis of hyperglycemia, hypertension and / or for the inhibition of blood platelet aggregation and / or for the treatment of benign prostatic hypertrophy and / or for the selective reduction of fat deposits in body regions.