GB2174087A

GB2174087A - Heterocyclic amino compounds

Info

Publication number: GB2174087A
Application number: GB08510294A
Authority: GB
Inventors: John Kitchin; Peter Clive Cherry; Alan David Borthwick; Adrian John Pipe; Andrew James Crame
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1985-04-23
Filing date: 1985-04-23
Publication date: 1986-10-29
Also published as: GB8510294D0

Abstract

Compounds are disclosed of formula (I): <IMAGE> wherein R is hydrogen, C1-6 alkyl; C1-6 alkyl substituted by C3-7 cycloalkyl; C3-6 alkenyl; C3-6 alkynyl; C3-7 cycloalkyl, aralkyl or -CHO; R<1> is C1-4 alkyl, C1-4 alkyl substituted by phenyl or C3-7 cycloalkyl; phenyl or C3-7 cycloalkyl; R<2> is hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or hydroxyl; and R<3> is hydrogen, fluorine or chlorine, and the physiologically acceptable salts thereof. The compounds have selective alpha 2-adrenoreceptor antagonist action and have a potential therapeutic use as an antidepressant or for treating migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic illness or senile dementia. The compounds may be formulated as pharmaceutical compositions in conventional manner optionally with other active ingredients such as an established antidepressant.

Description

SPECIFICATION Chemical compounds This invention relates to novel benzodioxinopyrrole derivatives, to processes for the preparation thereof, to pharmaceutical preparations containing them, and to their use in medicine.

The alpha (a)-adrenoreceptors of the sympathetic nervous system are classified pharmacologically into two sub-groups, namely ai and a2. The a2- type are situated predominantly on the presynaptic terminals of noradrenergic neurones and are activated by the released neurotransmitter. Such activation results in a diminished release of noradrenaline on subsequent stimulation of the neurones, the t2- adrenoreceptors thus forming part of an autoinhibitory feedback mechanism for regulating the synaptic concentration of the neurotransmitter.A selective a2- adrenoreceptor antagonist would be expected to produce an increase in the synaptic concentrations of noradrenaline by blocking the autoinhibitoryfeedback mechanism and would thus be of potential value in human medicine for the treatment of disorders such as depression which are associated with a deficiency of noradrenaline at postsynaptic adrenoreceptors.

a2-Adrenoreceptors also occur at non-neuronal sites such as on blood-platelets, in pancreatic islet cells, on adipocytes and in the proximal tubules of the kidney. Activation of a2-adrenoreceptors at these sites leads to platelet aggregation, inhibition of insulin release, inhibition of lipolysis and retention of sodium respectively.

A selective a2-adrenoreceptor antagonist thus has a potential therapeutic use as an antidepressant either alone or in a complimentary combination with an established antidepressant, and in either treating or preventing conditions such as migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic ileus and senile dementia.

We have now found that the compounds of formula (I) below and their physiologically acceptable salts have a selective oc2-adrenoreceptor antagonist action.

The invention thus provides compounds of general formula (I)

wherein R is a hydrogen atom or a group selected from C, 6 alkyl (optionally substituted by C3 7 cycloalkyl), C3 6 alkenyl, C3 6 alkynyl, C3 7 cycloalkyl, aralkyl (in which the alkyl moiety contains 1-5 carbon atoms(, or -CHO; R1 is a group selected from C1-4 alkyl (optionally substituted by phenyl or C3 7 cycloalkyl), phenyl or C3 7 cycloalkyl; R2 is a hydrogen atom or a fluorine or chlorine atom or a group selected from methyl, trifluoromethyl, methoxy and hydroxyl; and R3 is a hydrogen atom or a fluorine or chlorine atom; and the physiologically acceptable salts thereof.

In the above definition of general formula (I), the alkyl, alkenyl and alkynyl groups may be straight or branched chains.

When R contains a -C=C- or -0=-C- linkage this is not directly attached to the nitrogen atom. When R is alkyl it may be, for example, methyl, ethyl or propyl, methyl being preferred. When R is an alkyl group substituted by a C3 7 cycloalkyl group it may be, for example, cyclopropyl C1-3 alkyl such as cyclopropy Imethyl. When R is alkenyl it may be, for example, allyl and when R is alkynyl it may be, for example, propynyl. When R is cycloalkyl it may be, for example, cyclopropyl. When R is an aralkyl group it may be, for example, phenC1.5alkyl, such as benzyl.

R1 may be, for example, methyl, ethyl, propyl, isopropyl, butyl, sec butyl, t-butyl, phenC1.3alkyl (e.g. benzyl, phenethyl), cyclopropylC1.3alkyl (e.g. cyclopropylmethyl), phenyl, or cyclopropyl.

Suitable physiologically acceptable salts are the acid addition salts formed with inorganic acids, for example hydrochlorides, hydrobromides, phosphates and sulphates, and with organic acids, for example citrates, tartrates, acetates, maleates and succinates. The hydrochlorides are particularly useful.

It will be appreciated that each compound of general formula (I) has more than one asymmetric centre.

The structural formulae herein are thus to be understood to depict all diastereoisomers and enantiomers of each of the compounds concerned as well as mixtures of diastereoisomers and enantiomers, including racemates.

A preferred group of compounds of general formula (I) is that wherein R is a hydrogen atom. Another preferred group of compounds of general formula (I) is that wherein R2 is a hydrogen or fluorine atom and R3 is a hydrogen atom, or (when R2 is a fluorine atom) is also a fluorine atom.

Afurther preferred group of compounds of formula (I) is that in which R1 is a C1.4 alkyl group, in particular a methyl group.

Important compounds are (1 a, 3aa, 9a)-(i)-2,3,3a,9a-tetrahydrn-1 -methyl-1 H- [1,4] benzodioxino [2,3-c] pyrrole; and (Ia, 3a(3, 9aa)-()-2 3 3a,9a4etrahydro-1-methyl-1H-[1,4] benzodioxino [2,3-c] pyrrole; and their physiologically acceptable salts, particularly the hydrochlorides.

The compounds of the invention have selective a2-adrenoreceptor antagonist action. The test for determining the a2-adrenoreceptor antagonist action is based on the ability to prevent the action of a selective a2-adrenoreceptor agonist such as clonidine or 5-bromo-N-(4,5-dihydro-1 H-imidazol-2-yl)-6quinoxalinamine, [R-(R*R*)]-2,3-dihydroxybutanedioate (UK 14304-18) on the rat field stimulated vas deferens preparation.

Clonidine and UK 14304-18 inhibit the twitch response of the rat isolated vas deferens to low frequency motor nerve stimulation. This inhibition is a consequence of activation of presynaptic adrenoreceptors of the ar type Antagonism of the effect of clonidine or UK 14304-18 is quantified by measuring the parallel shift to the right of the inhibitory a2-adrenoreceptor agonist loglO (concentration)/response curve in the presence of increasing concentrations of the antagonist. Potency and competitiveness of antagonism are determined by the method of Arunlakshana & Schild (Br. J.Pharmac. 1959, 48-58).

The compounds of the invention are thus of interest in the treatment or prevention of migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic ileus and senile dementia, and in particu iar for the treatment of depression.

According to a further aspect, the invention provides compounds of general formula (I) and their physiologically acceptable salts for use in the therapy or prophylaxis of migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic ileus and senile dementia and in particular depression. The compounds of the invention may be used either alone or with an additional active ingredient. Thus, for example, in the treatment of depression, the compound ofthe invention may be used alone, or may be co-administered with an established antidepressant (e.g. desmethylimipramine, imipramine or amitriptyline) either in a single formuiation or in separate formulations. The established antidepressant can be used in accordance with conventional practice.

The compounds according to the invention may be formulated in a conventional manner, optionally together with one or more other active ingredients, for administration by any convenient route for example for oral, rectal, intravenous or intramuscular administration. Orai administration is preferred.

Thus according to another aspect, the invention provides a pharmaceutical composition comprising a compound of general formula (I) and/or a physiologically acceptable salt thereof together with a physiologically acceptable carrier or excipient. The composition may optionally contain an additional active ingredient, for example an antidepressant such as desmethylimipramine, imipramine or amitriptyline.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with physiologically acceptable excipients.

Compositions for rectal administration may be in the form of suppositories using a conventional suppository excipient.

The compounds may be formulated for intravenous or intramuscular administration in dry form for reconstitution before use, or as a sterile solution or suspension.

A proposed daily dose for administration to man is 0.01 to 1 Omg/kg, for example 0.05 to 3mglkg, which may be conveniently administered in 1 to 3 doses per day. The precise dose administered will of course depend on the age and condition of the patient. The daily dosage may conveniently be administered in the form of dosage units, each unit containing for example 0.1 to 3 mg/kg of active ingredient.

The compounds according to the invention may be prepared by a number of processes. In the following description the groups R, R1, R2, and R3 are as previously defined for general formula (I) except where otherwise indicated.

According to a first example (A), a compound of general formula (I) may be prepared by amination of a compound of formula (II)

where Xis a leaving group such as a halogen atom, (e.g. chlorine, bromine or iodine), or a hydrocarbylsulphonyloxy group e.g. methylsulphonyloxy, with ammonia, aqueous ammonia or an amine of formula RNH2 where R is as previously defined except that R is not a hydrogen atom or the group -CHO.

In a particular embodiment of this process, following the amination reaction the resulting compound of general formula (I) or a salt thereof may be converted into another compound of general formula (i). Thus, for example, when R is arylmethyl, the amination reaction may optionally be followed by removal of the arylmethyl group to yield a compound of formula (I) where R is a hydrogen atom.

The amination reaction is conveniently effected at an elevated temperature e.g. reflux or sealed tube at e.g.

110"C, preferably in the presence of a suitable base e.g. an excess of the amine RNH2, sodium hydride or an alkali metal hydroxide such as sodium hydroxide or in the presence of an excess of the amine RNH2, optionally in the presence of a solvent such as an ether e.g. dioxan, chlorinated hydrocarbon e.g. chloroform or an alcohol e.g. ethanol. Optional removal of an arylmethyl group may be carried out for example by hydrogenolysis or, where appropriate, under acidic conditions, as described below.

According to another example (B), a compound of general formula (I) where R represents a hydrogen atom may be prepared by deprotection of a corresponding compound where R represents a protecting group.

Suitable protecting groups include, for example, arylmethyl and acyl groups. Conventional deprotection procedures may be used. For example, where appropriate an arylmethyl group (e.g. benzyl) may be removed by hydrogenolysis using, for example, hydrogen in the presence of a catalyst, such as platinum or palladium on a support (e.g. charcoal), in a solvent such as an alcohol e.g. methanol. Alternatively, where appropriate, an arylmethyl group (e.g. trityl) may be removed under acidic conditions, using for example an acid such as trifluoroacetic acid, formic acid or hydrobromic acid. Acyl groups may be removed by hydrolysis using an acid such as a mineral acid or a base such as an alkali metal hydroxide as appropriate.

The protected starting materials for this process may be prepared using standard methods for the protection of amines, for example as described by J.F.W. McOmie in "Protective Groups in Organic Chemistry" (Plenum Press,1973).

According to a further example (C), a compound of general formula (I) where R represents an alkyl group may be prepared by reduction of the corresponding compound in which R is an acyl group using a reducing agent such as lithium aluminium hydride or diborane in a suitable solvent such as ether ortetrahydrofuran at an elevated temperature e.g. reflux. Suitable acyl groups are, for example, formyl, acetyl, or carbonyloxyalkyl e.g. carbonyloxymethyl. The intermediate starting materials for this reaction may be prepared by acylation using conventional methods, for example by reaction of the compound of formula (I) in which R represents a hydrogen atom, with an acid chloride, acid an hydride, or ester.

The product of any of the processes (A), (B), and (C), described above may be subjected to one or two further reactions comprising: (D)(ii) converting the resulting compound of general formula (I) or a salt thereof into another compound of general formula (I); and/or (D)(i) converting a compound of general formula (I) or a salt thereof into a physiologically acceptable salt thereof.

Thus, it is also possible to prepare a compound of general formula (I) by a process comprising interconversion of another compound of general formula (I).

For example, a compound of general formula (I) in which R is a hydrogen atom may be converted by alkylation to a compound of general formula (i) in which R is an alkyl, substituted alkyl, alkenyl, alkynyl or aralkyl group. Conventional alkylation procedures may be used, for example reductive alkylation using an appropriate aldehyde with a complex metal hydride such as sodium or potassium borohydride or sodium cyanoborohydride in a suitable solvent such as an alcohol e.g. methanol.Alternatively, the alkylation may be performed with an alkylating agent RX (where R is an alkyl, substituted alkyl, alkenyl, alkynyl or aralkyl group and X is a leaving group such as a halogen atom e.g. chlorine or bromine, or a hydrocarbylsulphonyloxy group e.g.p-toluene sulphonyloxy) preferably in the presence of a base, such as potassium carbonate, optionally in a solvent such as an alcohol, e.g. methanol.

Another example of this embodiment is the preparation of a compound of general formula (I) where R is a group -CHO, which may be prepared by formylation of a corresponding compound of formula (I) in which R is a hydrogen atom using an appropriate formylating agent such as a formyl ester, e.g. an alkyl formate such as methyl formate.

Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting the free base of formula (I) or a salt thereof with an appropriate acid, such as hydrogen chloride in the presence of a suitable solvent e.g. ethyl acetate, ether or CH2Cl2 to obtain the desired physiologically acceptable salt.

It may be desirable to protect various reactive substituents inthe starting materials for a particular reaction or sequence of reactions and subsequently to remove the protecting group after completion of the reaction or sequence. Such protection and subsequent deprotection may be particularly pertinent when R1 is a hydroxy substituent. Conventional protection and deprotection procedures can be employed cf. "Protective Groups in Organic Chemistry" Ed. by J F W McOmie (Plenum Press, 1973). Thus, for example, a phenolic hydroxyl group may be protected as an ether e.g. a 2-tetrahydropyranyl or methyl ether, which may subsequently be cleaved by a Lewis acid such as boron tribromide or aqueous hydrogen bromide.

The intermediate compounds of general formula (II) may be prepared by reaction of a corresponding diol of formula (III):

with a halide of formula X1A (where X1 is a hydrocarbyl-sulphonyl group e.g. methylsulphonyl and A is a halogen atom e.g. a chlorine atom) in the presence of a base e.g. triethylamine in a solvent such as dichloromethane; or with a halogenating agent such as thionyl chloride, phosphorous tribromide or hydrogen iodide.

A diol (III) may be prepared from a compound of formula (IV)

using hydrochloric acid in a solvent such as methanol.

A compound of formula (IV) may be obtained using the following sequence of reactions:

Reaction of the acid (IX) (cf Lalloz metal. J.Med.Chem.(1981 ),24, 994) with lithium diisopropylamide, followed by an aldehyde ECHO, in tetrahydrofuran yields an acid (VIII) which is converted to the corresponding ethyl ester (VII) using for example ethyl bromide and potassium carbonate in dimethyl-formamide.The ethyl ester (VII) is then reacted with (CH3O)2CH2 in the presence of phosphorous pentoxide in chloroform to yield a compound (VI), which is subjected to catalytic hydrogenation using for example hydrogen in the presence of palladium on charcoal and potassium carbonate in a solvent such as ethanol at room temperature, to give a mixture of diastereoisomers of formula (V) which are separated by chromatography, (e.g. on silica gel). Base catalysed equilibration of the individual diastereoisomers of the cis benzodioxin of formula (V), using for example sodium carbonate in a solvent such as ethanol at room temperature followed by reduction (using for example lithium aluminium hydride in diethyl ether) and chromatography (e.g. on silica gel) yields the trans isomers of formula (IV).

If desired, the above series of reactions may be performed without the intervening chromatography steps.

The mixture of isomers of formula (IV) thus obtained may be converted to a mixture of isomers of general formula (I) using the processes previously described. The mixture of isomers of formula (I) may be separated, using conventional techniques e.g. by chromatography on silica gel.

A specific enantiomer of general formula (I) may be prepared by resolution of a mixture of enantiomers of individual diastereoisomers of formula (I) by conventional methods e.g. by salt formation with an optically active acid followed by separation of the resulting diastereoisomericsalts, e.g. by fractional crystallisation.

Alternatively, resolution may be effected at any suitable intermediate stage.

The following Examples illustrate the invention. All temperatures are in "C. The following abbreviations are used: DMF - dimethylformamide; EA - ethyl acetate.

'Dried' refers to drying with MgSO4.

Intermediate 1 t 3-(1-Hydroxyethyl)- 1, 4-benzodioxin-2-carboxylic acid, ethyl ester A mixture of (+)-3-(1 -hydroxyethyl)-l, 4-benzodioxin-2-carboxylic acid (0.3g), bromoethane (0.11 ml) and K2CO3 (0.1g) in DMF (8ml) was stirred for 12h. A further quantity of K2CO3 (0.1g) was added and stirring was continued for 24h. EA was added and the suspension was washed successively with NaHCO3 solution and 2M hydrochloric acid. The solution was dried, the solvent was evaporated and the residue azeotroped with toluene. The residual solid was recrystallised from isopropyl ether to yield the title ester as white needles (0.299) m.p.107-109 .

Intermediate 2 (#)-3-[1-(Methoxymethoxy)ethyl]- 1, 4-benzodioxin-2-carboxylic acid ethyl ester Phosphorus pentoxide (2g) was added in portions to a stirred solution of Intermediate 1 (4.69) and dimethoxymethane (10ml) in dry CHCl3 (20ml), and the mixture was stirred overnight. Further quantities of dimethoxymethane (5ml) and phosphorous pentoxide (1g) were added, and the mixture was stirred until the reaction was complete. The mixture was poured into ice-cooled Na2CO3 solution and the product was extracted with CHCl3. The organic solution was washed with brine, dried and the solvent evaporated. The product was triturated with isopropyl ether, the solid was filtered out and the solution evaporated to dryness.

Crystallisation of the resulting solid from isopropyl ether gave the title ester (4.49) m.p.63-65 .

Intermediate 3 [201, 3α (R*)]-(#)-2,3-Dihydro-3-[1-(methoxymethoxy)ethyl]- 7,4-benzodioxin-2-carboxylic acid, ethyl ester and Intermediate 4 [2Of, 3α (S*)]-(#)-2,3-Dihydro-3-[1-(methoxymethoxy)ethyl]- 1, 4-benzodioxin-2-carboxylic acid, ethyl ester.

A solution of Intermediate 2 (4g) in ethanol (50m1)was hydrogenated over 10% palladium on carbon (0.4g) and K2CO3 (0.59). When the reaction was complete the solids were filtered off and the solvent was evaporated. The crude product was purified by column chromatography on silica gel (230-400 mesh), eluting with a 3:1 mixture of 60-80 petrol and ether.The first comppnent (1.2g) obtained as an oil was f2a, 3a, -(RJ-()-2 3-dihydro-3-[1-(methoxymethoxy) ethyl 1, 4-benzodioxin-2-carboxylic acid, ethyl ester N MR (T CDCl3) 2.8-3.2 (4H,m, aromatic), 5.2 (1 H,d,J 2Hz,2-H), 5.32, 5.45 (2H,ABq, J 7Hz, OCH2O),5.76(2H,q, J 7Hz,CH2 CH3) 5.5-6.3 (2H,m,3-H, CHCH3),6.64(3H,s,OCH3),8.63(3H,3, J 6Hz, CH3), 8.71 (3H,t, J 7Hz, CH2CH3). The second component, obtained as an oil (1.7g) was[2ce, 3α (S*)]-(#)-2,3-dihydro-3-[1-(methoxymethoxy) ethyl]-1, 4-benzodioxin-2-carboxylicacid, ethyl ester.NMR (T CDCI3) 2.9-3.2 (4H,m, aromatic), 5.19 (1H,d,J 3Hz. 2-H), 5.25 (2H,s,OCH2O), 5.78(2H,q,J 7Hz, CH2CH3), 5.5-6.2 (2H,m,3-H, CHCH3), 6.6(3H,s, OCH3), 8.64(3H,d,J 7Hz, CH3), 8.78(3H,t,J 7Hz, CH2CH3).

Intermediate 5 3α (S*)-(#)-2,3-Dihydro-3-[1-(methoxymethoxy)ethyl]-1,4-benzodioxin-2- carboxylic acid, ethyl ester.

A mixture of [2a, 3α, (S*)]-(#)-2, 3-dihydro-3-[1 -(methoxymethoxy)ethyl]-l , 4-benzodioxin-2-carboxylic acid, ethyl ester (8) (1.6 g) and sodium carbonate (0.57 g) in ethanol (20 mis) was stirred for 47 h. Water was added and the product was extracted into ethyl acetate. The solution was dried over magnesium sulphate and the solvent evaporated giving a mixture of the cis and trans esters as clear oil (1.5 g) NMR (T,CDCI3) 2.8-3.2 (4H,m, aromatic), 5.0-5.5 (3H, m, 2-H, OCH2O), 5.5-6.1 (4H,m,3-H, CHCH3, CH2 CH3), 6.55,6.62 (3H,s,s, OCH3), 8.62(3H,d, J 6Hz, CHCH3), 8.7 8.75(3H, triplets, J 7Hz, CH2CH3).

The following intermediate was prepared in a similar manner to intermediate 5.

Intermediate 6 3α (R*)-(#)-2,3-Dihydro-3-[1-(methoxymethoxy)ethyl]-1,4-benzodioxin-2-carboxylic acid, ethyl ester.

The mixture of cis and trans esters was prepared form [2α, 3α (R*)] - . (+)- 2 3-dihydro-3-[1 (methoxymethoxy) ethyl]-1, 4-benzodioxin-2-carboxylic acid ethyl ester (0.8 g), NMR (T CDCI3). 2.9-3.4(4H,m, aromatic).5.02, 5.3(2H,d(J2) and d (J 3Hz), 2-H), 5.4, 5.48 (2H,s,s OCH2O), 5.5-6.5 (4H, 3-H, CHCH3, CH2CH3), 6.71 (3H,s,OCH3), 8.5-9.0 (6H,CH2CH3 CHCH3).

Intermediate 7 [2α, 3ss(S*)]-(#)-2,3-Dihydro-3-[1-(methoxymethoxy)ethyl]-1,4-benzodioxin-2-methanol.

Lithium aluminium hydride (0.2 g) was added to a stirred solution of the isomeric mixture 3α (S*)-(#)-2, 3-dihydro-3-[1-(methoxymethoxy)ethyl]-1,4-benzodioxin-2-carboxylic acid ethyl ester (1.5 g) in dry ether (40 mls) and the mixture was stirred for 2 h. Wet ether was added, followed by water and the layers were separated. The aqueous phase was extracted with dichloromethane, the extract was combined with the ether solution and dried over magnesium sulphate. Evaporation of the solvent gave a mixture of cis and trans isomers which was separated by column chromatography on silica gel eluting with a 1:2 mixture of petrol and ether to give the title compound as an oil 0.45 g. NMR (T CDCl3) 3.2(4H,s, aromatic), 5.29, 5.44 (2H, ABq, J 7Hz, OCH2O), 5.7-6.3 (5H, multiplets, 2-H, 3-H, CHCH3, CH2OH), 6.7 (3H,s, OCH3), 8.68(3H,d,J 6Hz CH3), 7.41(1 H,s, OH).

The following Intermediate was prepared in a similar manner to Intermediate 7.

Intermediate 8 [2α, 3ss(R*)]-(#)-2,3-Dihydro-3-[1-(methoxymethoxy)ethyl]-1,4-benzodioxin-2-methanol.

The title compound (0.26 g) was prepared from a mixture of cis and trans 3α (R*)-(#)-2, 3-dihydro-3-[1 (methoxymethoxy)ethyl]-1, 4-benzodioxin-2-carboxylic acid ethyl ester. N MR(T, CDCI3) 3.25(4H,s, aromatic).

5.4(2H,s,OCH2O), 5.7-6.4 (5H, multiplets, 2-H, 3-H, CH2OH, CHMe), 6.7(3H,s,OCH3), 8.75 (3H, d, J 6Hz, CH3), 7.43 (1H,s,OH).

Intermediate 9 [2α (S*), 3ss]-(#)-2,3-Dihydro-α-methyl-1,4-benzodioxin-2,3-dimethanol.

A solution of [2α, 3ss (S*)]-(#)-2,3-dihydro-3-[1-(methoxymethoxy)ethyl]-1,4-benzodioxin-2-methanol (0.4 g) in methanol (20 mls) with concentrated hydrochloric acid (0.4 mls) was heated at reflux for 15 minutes. The solvent was evaporated, chloroform was added and the solution was washed with brine, dried over magnesium sulphate and the solvent was evaporated giving the title diolas a white solid 0.31 g, m.pt.

96-98 , NMR(T CDCl3)3.19 (4H,s, aromatic), 5.6-6.3 (5H, multiplets, 2-H, 3-H, CHCH3, CH2OH), 7.6(2H,s, OH), 8.62(3H,d, J 6Hz, CH3).

The following Intermediate was prepared in a similar manner to Intermediate 9.

Intermediate 10 [2α (R*), 3ss]-(#)-2,3-dihydro-α-methyl-1,4-benzodioxin-2,3-dimethanol.

The diol (0.17 g) was prepared from [2α, 3ss (R*)]-(#)-2,3-dihydro-3-[1-(methoxymethoxy)ethyl]-1, 4-benzodioxin-2-methanol as a white solid. NMR(T, CDCl3)3.2 (4H,s, aromatic), 5.8-6.4 (5H, multiplets, 2-H, 3-H, CH2OH, CHCH3), 7.5-7.9 (2H, s, (OH)2).

Intermediate 17 [2α (R*), 3ss]-(#)-2,3-Dihydro-α-methyl-1,4-benzodioxin-2,3-dimethanol bis (methanesulphonate).

Methanesulphonyl chioride (0.3 mls) was added to a stirred solution of [2α(s*)3ss]-(#)-2,3-dihydro-α- methyl-1, 4-benzodioxin-2, 3-dimethanol (0.31 g) and triethylamine (0.7 mls in dichloromethane (15 mis) at 00. After 2 hours the solution was washed with 2M hydrochloric acid followed by sodium bicarbonate solution, was dried over magnesium sulphate and the solvent evaporated leaving the bis(methanesulphonate) as a gum 0.54 g NMR(T, CDCI3) 3.2 (4H,s,aromatic), 4.7-5.2 (1 H, multiplet, CHCH3), 5.4-6.1 (4H, multiplets, 2-H, 3-H, CH2O), 7.01,7.05 (6H, s,s,(SO2CH3)2),8.45(3H,d,J 6Hz, CH3).

The following Intermediate was prepared in a similar manner to Intermediate 11.

Intermediate 12 [2α (S*), 3ss]-(#)-2,3-Dihydro-α-methyl-1,4-benzodioxin-2,3-dimethanol bis (methanesulphonate).

The title compound was obtained as a gum (0.29 g) from [2α (R*), 3ss]-(#)-2,3-dihydro-α-methyl-1, 4-benzodioxin-2, 3-dimethanol. NMR(T CDCl3), 3.1 (4H,s, aromatic), 4.9-5.9(5H, multiplets, 2-H, 3-H, CH2O, CHCH3), 6.93 (6H,s,(OSO2CH3)2), 8.43(3H,d, J 6Hz, CH3).

Example 1 (1α, 3ass, 9aα)-(#)-2,3,3a,9a - Tetrahydro-1-methyl-2-(phenylmethyl)-1H-[1,4]benzodioxino[2,3-c]pyrrole.

A solution of [2α (R*), 3ss]-(#)-2,3-dihydro-α-methyl-1,4-benzodioxin-2,3-dimethanol bis (methanesulphonate) (0.54 g) in benzylamine (3 mls) was heated at 120-135 for 3.5 h. Ethyl acetate was added and the solution was washed with 2M sodium hydroxide solution, dried over magnesium sulphate and the solvent was evaporated. The crude product was purified by chromatography to give the title compound 0.2 g, NMR(T CDCl3)2.77 (5H, s,Ph), 3.2(4H,s, aromatic), 5.99, 6.5(2H,ABq,J 14Hz, PhCH2), 5.6-6.3 (2H,m, 3a-H, 9a-H), 6.7-7.3 (3H, 1 H, 3 H2), 8.65 (3H, d, J 6Hz, CH3).

The following compound was prepared in a similar manner to the compound of Example 1.

Example 2 (1α 3aα, 9ass)-(#)-2,3,3a,9a-Tetrahydro-1-methyl-2-(phenylmethyl)-1H-[1,4]benzodioxino[2,3-c]pyrrole.

The title compound (0.17 g) was prepared from [2α(S*), 3ss]-(#)-2,3-dihydro-α-methyl-1,4-benzodioxin-2, 3-dimethanol bis (methanesulphonate). NMR(T, CDC13)2.79(5H,s,Ph), 3.2(4H,s,aromatic), 5.5-6.15(2H,m,3a H,9a-H), 6.21 (2H,s,PhCH2),6.4-7.0, 7.2-7.6 (3H,m,l-H,3-H2), 8.96(3H,d,J 6Hz,CH3).

Example 3 (1α, 3ass, 9aα)-(#)-2,3,3a,9a - Tetrahydro-1-methyl-1H-[1,4]-benzodioxino[2,3-c]pyrrole hydrochloride A solution of (1α, 3ass, 9aα)-(#)-2,3a, 9a-tetrahydro-1-methyl-2-(phenylmethyl)-1H-[1,4]benzodioxino[2,3 cipyrrole(0.2 g) in methanol (2 mls) was treated with excess of a solution of hydrogen chloride in ether and the solution was evaporated to dryness. The hydrochloride salt in methanol (20 mls) was hydrogenated over 10% palladium on charcoal (25 mgs). The catalyst was filtered off, the solvent was evaporated and the residual solid was triturated with isopropyl alcohol to give the title compound as a white solid (0.1 g). M.pt.

250-260 (dec.) NMR(T DMSO-d6)-0.19 (2H, broad singlet, NH+2), 2.9-3.1 (4H,m, Aromatic), 5.54(1H,m,3a-H), 5.91(1 H,m,9a-H), 6.2,6.64 (2H,m,3- H2), approx. 6.2(1 H,m,l- H),8.42(3H,d,J 7Hz,1 - Me).

The following compound was prepared in a similar manner to the compound of Example 3.

Example 4 (1α, 3aα 9ass)-(#)-2,3,3a,9a-Tetrahydro-1-methyl-1H-[1,4]benzodioxino[2,3-c]pyrrole hydrochloride.

Obtained from 1α, 3aα, 9aB)-(#)-2,3,3a,9a,tetrahydro-1-methyl-2-(phenylmethyl)-1H-[1,4] benzodioxino [2, 3-c]pyrrole (0.11 g) m.pt. 258-259 (dec.), NMR (# DMSO-d6), 0.0(2H, broad S, NH+2), 2.9-3.1 (4H,m,aromaties), 5.42 (1H,d,d,J 11,8,8 Hz, 3a-H), 5.67 (1H,t,J 8Hz,9a-H),5.71 (1H,dq, J 8,8 Hz, 1-H0, 6.20, (1H,dd,J 11.5,8, 3-H) and 6.73 (1H,t,J 11 hz 3-H), 8.63 (3H,s,1-Me).

Claims

1. Compounds of general formula (I)

wherein R is a hydrogen atom or a group selected from unsubstituted C1-6alkyl, C1-6 alkyl substituted by C3-7 cycloalkyl, C3-6 alkenyl, C3-6 alkynyl, C3-7 cycloalkyl, aralkyl (in which the alkyl moiety contains 1-5 carbon atoms), and-CHO ; R Is a group selected from unsubstituted C1-4 alkyl, C1-4 alkyl substituted by C3-7 cycloalkyl, phenyl and C3-7 cycloalkyl ; R2 is a hydrogen atom or a fluorine or chlorine atom or a group selected from methyl, trifluoromethyl, methoxy and hydroxyl; and R3 is a hydrogen atom or a fluorine or chlorine atom and the physiologically acceptable salts thereof.

2. Compounds according to claim 1, wherein R is a hydrogen atom.

3. Compounds according to claim 1 or 2, wherein R2 is a hydrogen orflurorine atom and R3 is a hydrogen atom or R2 and R3 both represent fluorine atoms.

4. Compounds according to any of claims 1 to 3, wherein R1 is a C1-4 alkyl group.

5. Compounds according to claim 4, wherein Ri is a methyl group.

6. Compounds selected from (1α, 3aα, 9ass)-(#)-2,3,3a,9a-tetrahydro-1-methyl-1H-[1,4]benzodioxino [2,3-c]pyrrole ; and (1α, 3ass, 9aα) - (#) - 2,3,3a,9a-tetrahydro-1-methyl-1H-[1,4] benzodioxino [2,3-c]pyrrole ; and their physiologically acceptable salts.

7. Compounds according to any of claims 1 to 6, wherein the physiologically acceptable salts are selected from hydrochlorides, hydrobromides, phosphates, sulphates, citrates, tartrates, acetates, maleates and succinates.

8. Compounds according to claim 7, wherein the physiologically acceptable salts are the hydrochlorides.

9. A pharmaceutical composition comprising an effective amount of at least one compound selected from compounds of general formula (I) as defined in claim 1 and physiologically acceptable salts thereof together with a physiologically acceptable carrier or excipient.

10. A pharmaceutical composition according to claim 9, which comprises an additional active ingredient which is an antidepressant.

11. A process for preparing a compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt thereof which comprises: (A) aminating a compound of general formula (II) :

where R1, R2 and R3 are as defined in claim 1 and X is a leaving group with ammonia, aqueous ammonia or an amine of formula RNH2 where R is as defined in claim 1 except that R is not a hydrogen atom or the group -CHO; or (B) in order to prepare a compound of general formula (I) where R represents a hydrogen atom, deprotecting a corresponding compound where R represents a protecting group; or (C) in order to prepare a compound of general formula (I) where R represents an alkyl group, reducing the corresponding compound in which R is an acyl group; and if necessary and/or desired subjecting the resulting compound to one or two further reactions comprising D(i) converting the resulting compound of general formula (I) or a salt thereof into another compound of general formula (I); and/or D(ii) converting a compound of general formula (I) o; a salt thereof into a physiologically acceptable salt thereof.