GB2129795A - Benzodioxinopyrroles - Google Patents

Description

1 v 1 GB 2 129 795 A 1 1

SPECIFICATION

Heterocyclic amino compounds and processes for their preparation 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 al and 02. The Ot2-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 OL2-adrenoreceptors 10 thus forming part of an autoinhibitory feedback mechanism for regulating the synaptic concentration of the neurotransmitter. A selective 0-2adrenoreceptor antagonist would be expected to produce an increase in the synaptic concentrations of noradrenaline by blocking the autoinhibitory feedback 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.

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

A selective 02-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 (1) below and their physiologically acceptable salts have a selective (y2-adrenoreceptor antagonist action. 25 Certain benzodioxinopyrrole derivatives are described as having been prepared in C.r Seances hebd. Ac. 25 Sci. 1961253,1172 by A. Funke and A. Paulsen. Funke etal describe a process starting from a meso-dibromosuccinate which is presumed by Funke eta/to yield a cis-benzodioxan clicarboxylate following the process described by Kao etal (Hua Hsueh Hsueh Pao 1957 23 480; Chem. Abs. 1958 52 16356h). Kao etal reported the preparation of cis- and trans-dl-benzodioxan clicarboxylates by reaction of catechol with meso- and d/-dibromosuccinates.

Funke eta/then converted their intermediate product into what are described as tetrahydrobenzodioxino pyrroles. The stereochernistry of these compounds was not specified butwould have been expected to be cis, as in the starting dicarboxylate.

Subsequently, Berthold etal (HeIv. Chim. Acta 1972 552461) have demonstrated that the reaction of catechol with the meso-dibromosuccinate affords a benzodioxole rather than a benzodioxan. In addition 35 Berthold etal demonstrated that this product is converted into a tetrahydrospirobenzodioxolopyrrole rather than a tetrahydrobenzodioxinopyrrole as believed by Funke etal.

We have repeated the process described by Funke and, as a result, we are able to confirm and extend the observations of Berthold etal. Thus, we have demonstrated that the reaction of catechol with either the meso- or the d/-dibromosuccinates results in the same compound to which we assign unambiguously the 40 benzodioxole structure. This compound is further converted to provide compounds to which we assign the tetra hydrospi robenzod ioxolopyrrol e ring system ratherthan the tetra hydrobenzodioxi nopyrrole system.

To summarise, the prior art literature contains reference only to the preparation of compounds which can be construed as cis-compounds. Furthermore, although the compounds are described as tetra hyd robenzo dioxinopyrroles this has been shown by Berthold and ourselves to be erroneous due to a previous misassignment of the structure of the starting material.

Furthermore, the prior art references are limited to a purely chemical discussion and there is no mention that any of the compounds prepared or said to be prepared have any biological activity.

The invention thus provides compounds of general formula (1) H 1,1 _ ob-R (D R wherein R is a hydrogen atom or a C1-6 alkyl (optionally substituted by C3-7 cycloalkyl), C3-6 alkenyl, C3-6 alkynyl, C3-7 cycloalky], aralkyl (in which the alkyl moiety contains 1-5 carbon atoms), or -CHO group, and the physiologically acceptable salts thereof.

In the above definitions of general formula (1), the alkyl, alkenyl and alkynyl groups may be straight or branched chains. When R contains a -C=Cor -C=-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 1 2 GB 2 129 795 A 2 cyclo propyl m ethyl. 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, phenC,-5alkyl, such as benzyl.

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 (1) is a trans isomer and exists as two enantiomers. The structural formulae herein are to be understood to depict either or both enantiomers of each of the compounds concerned as well as mixtures of the enantiomers, including racernates, even though the precise structure asset out only relates to one enantiomer.

A preferred group of compounds of general formula (1) is that wherein R is a hydrogen atom. Another preferred group of compounds of general formula (1) is that wherein R is a C1-3 alkyl group, particularly a methyl or ethyl group.

Particularly important compounds are (-f:) trans-2,3,3a,9a-tetrahydro-2methyl-1 H-[1,4]-benzodioxino-[2,3- c1pyrrole; (-) trans-2,3,3a,9a-tetrahydro-lH-[1,41-benzodioxino[2,3- c]pyrrole; (3aR-trans)-(+)-2,3,3a,9a- 15 tetrahydro-1 H-[1,41-benzodioxino[2,3-clpyrrole; (3aS-trans)-(-)-2,3,3a, 9a-tetrahydro-1 H-[1,4] benzodioxino[2,3-c]pyrrole; and their physiologically acceptable salts, particularly the hydrochlorides.

A compound of particular interest is H:) trans-2,3,3a,9a -tetra hyd ro- 1 H-[1,4]-benzodioxino[2,3-c]pyrrole, hydrochloride.

The compounds of the invention have selective a2-adrenoreceptor antagonist action. The test for 20 determining the OL2-a d ren o receptor antagonist action is based on the ability to prevent the action of the selective OL2-a d ren o receptor agonist clonidine on the rat field stimulated vas deferens preparation.

Clonidine inhibits 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 O2-tYpe.

Antagonism of the effect of clonidine is quantified by measuring the parallel shift to the right of the inhibitory 25 clonidine 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, 1448-58).

The a.-adrenoreceptor-type selectivity of the compounds of general formula (1) is similarly assessed by measuring the ability to produce a parallel shift to the right of the logio (con centratio n)/respo nse curve for the a,-adrenoreceptor agonist phenylephrine. The a,-adrenoreceptor- mediated responses of phenylephrine measured were contractions of the rat isolated anococcygeus muscle (Leighton, Butz & Parmeter, Eur. J.

Pharmac., 1979,5827-38).

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 35 particular for the treatment of depression.

The invention accordingly further provides compounds of general formula (1) and their physiologically acceptable salts for use in the therapy or prophylaxis of migraine, thrombosis, diambetes, obesity, hypertension, constipation, paralytic ileus and senile dementia and, in particular depression. The compounds of the invention may be used either alone orwith an additional active ingredient. Thus, for example, in the treatment of depression, the compound of the invention may be used alone, or may be co-administered with an established antidepressant (e.g. desmethylimipramine, imipramine or amitripty line) either in a single formulation or, preferably, 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 ingredient, for administration by any convenient route for example for oral, rectal, intravenous or intramuscular administration.

Thus according to another aspect, the invention provides a pharmaceutical composition comprising a compound of general formula (1) 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 10 mg/kg, for example 0.05 to 3 mg/kg, which may be conveniently administered in 1 to 3 doses per day. The precise dose administered will of course 60 depend on the age and condition of the patient.

The compounds according to the invention may be prepared by a number of processes. In the following description the group R is as previously defined for general formula (1) except where otherwise indicated.

According to a first example, a compound of general formula (1) may be prepared by amination of a compound of formula (11) 11 1 GB 2 129 795 A 3 3 H 0: H2X ao E H2X 5 H (11) where X is a leaving group such as a halogen atom, (e.g. chlorine, bromide or iodine), or a hydrocarbylsulphonyloxy group e.g. methyisulphonyloxy, 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 -COH. 10 In a particular embodiment of this process, following the amination reaction the resulting compound of general formula (1) or a salt thereof may be converted into another compound of general formula (1). Thus, for example, when R is aryimethyi, the amination reaction may optionally be followed by removal of the aryimethyl group to yield a compound of formula (1) 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. 15 11WC, preferably in the presence of a suitable base e.g. an excess of the amine RNI-12, sodium hydride oran alkali metal hydroxide such as sodium hydroxide, 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 aryimethyl group may be carried out for example by hydrogenoiysis or, where appropriate, under acidic conditions, as described below.

According to another example, a compound of general formula (1) 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, aryimethyl and acyl groups. Conventional deprotection procedures may be used. For example, where appropriate an aryimethyl group (e.g. benzyl) may be removed by hydrogenolysis using, for example, hydrogen in the presence of a catalyst, such as platinum or 25 palladium on a support (e.g. charcoal), in a solvent such as an alcohol e. g. methanol. Alternatively, where appropriate, an aryimethyl group (e.g. trityl) may be removed under acidic conditions, using for example an acid such as trifluoroacetic acid, formic acid or HBr. 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, a compound of general formula (1) 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, formyi, acetyl, or carbonyloxyalkyl 35 e.g. ca rbo nyl oxym ethyl. The intermediate starting materials for this reaction may be prepared by acylation using conventional methods of a compound of formula (1) in which R represents a hydrogen atom, for example by reaction of the compound of formula (1) with an acid chloride, acid anhydride, or ester.

It is also possible to prepare a compound of general formula (1) by a process comprising interconversion of another compound of general formula (1).

For example, a compound of general formula (1) in which R is a hydrogen atom may be converted by alkylation to a compound of general formula (1) in which R is an alkyl, substituted alky], 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 maybe 45 performed with an alkylating agent R2X (where R2 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 hydrocarbyisulphonoxy group e.g. p-toluenesulphonyloxy) preferably in the presence of a base, such as potassium carbonate, optionally in a solvent such as an alcohol, e.g. ethanol.

Another example of this embodiment is the preparation of a compound of general formula (1) where R is a 50 - group -CHO, which may be prepared by acylation of a corresponding compound of formula (1) in which R is a hydrogen atom using an appropriate acylating agent such as an ester, e. g. an alkyl formate such as methyl formate.

Physiologically acceptable salts of the compounds of general formula (1) may be prepared by reacting the free base of formula (1) or a salt thereof with an appropriate acid, such as hydrogen chloride in the presence 55 of a suitable solvent e.g. ethyl acetate, ether or CHP2 to obtain the desired physiologically acceptable salt.

The intermediate compounds of general formula (11) may be prepared by reaction of the corresponding diol of formula (111) H CH20H a00 ISCH2 OH (1) H 4 GB 2 129 795 A 4 with a halide of formula XIA (where X, is a hydrocarbylsulphonyloxy group e.g. methylsulphonyloxy and A is a halogen atom e.g. chlorine) in the presence of a base e.g. triethylamine in a solvent such as clichloromethane; or with a halogenating agent such as thionyl chloride, phosphorous tribromicle or hydrogen iodide.

The trans diol of formula (111) is a novel compound and forms a further aspect of the invention. The diol (111) may be prepared by reduction of the corresponding diethyl ester of formula (IV):

0 -1 COOCH2CH3 j aO C00CH2CH3 OW using for example lithium aluminiurn hydride in tetrahydrofuran at O'C.

The diethyl ester (IV) may be prepared from the cis-isomer of formula M H ou,- GOOCH2CH3 20 ao", COCCH2CH3 (M) by base catalysed equilibration using for example sodium carbonate in a solvent such as ethanol at room temperature. The mixture of cis and trans isomers so obtained may be separated by conventional means for example by chromatography on silica gel using an eluant such as a mixture of petroleum ether and ethyl acetate.

The cis-isomer of formula (V) may be prepared by catalytic hydrogenation of the diester of formula (V]) 0 COOCH2CH3 :(COOCH2CH3 (M) 35 using for example hydrogen in the presence of palladium on charcoal in a solvent such as ethanol at room temperature.

The diester of formula (VI) may be obtained from a diacid of formula (VII):

0 COOH -O)COOH (M1D by esterifying the diacid (VII), for example, by refluxing with ethanolic hydrogen chloride. The diacid (VII) may be obtained from benzodioxin-2- carboxylic acid of formula (Vill) 0 - COOH (M9) 55 Reaction of the compound (111) (Lalloz et a1J. Med. Chem. 0 981),24 994) with lithium diisopropylamide followed by carbon dioxide provides the diacid of formula (11).

To obtain a specific enantiomer of general formyla (1), a diol of formula (111) having the required chirality 60 should be used in the above processes.

The enantiomeric diol starting material can be prepared from the appropriate dibenzyl threitol of formula Ma) or (lXb) a z 0 b GB 2 129 795 A 5 U HO CH2 OCH2 HO1 C1-120CH2Ph H (Eg:a) HO CH20CH2Ph HO CH20CH2Ph H CK b) using the following sequence (one enantiomer only shown); 10 H H TsO E C 20CH2Ph 1 CH20CH2Ph UX: a) - 1.1M 15 a00 t=:CH20CH2Ph T50 CH20CH2Ph H (X) (X0 H (where Ts represents CH3-0-SO2-).

Thus, reaction of the enantiomer (IXa) with 4-toluenesulphonyl chloride in pyridine yields the bis-tosylate (X) which on heating with catechol in acetonitrile containing cesium fluoride gives the benzodioxin (Xl) which may be converted to the enantiomer diol (111) using hydrogen and palladium on charcoal with an ethanol solvent. Use of the enantiomer (1Xb) in the same sequence yields the other required enantiomer of formula (111).

The S,S,-enantiorner of formula (iX) is a known compound; and the FI,Renantiorner may be prepared by methods analogous to those for preparing the S,S-enantiorner.

A specific enantiomer of general formula (1) may also be prepared by resolution of a mixture of enantiomers of formula (1) by conventional methods, e.g. by salt formation with optically active acid followed by separation of the resulting diastereoisomeric salts, e.g. by fractional crystallisation. Alternative ly, resoltuion may be effective at any suitable intermediate stage.

The following Examples illustrate the invention. Ail temperatures are in 'C. "Dried" refers to drying with 35 M9SC)4 unless otherwise stated. Chromatography was carried out on silica gel.

The following abbreviations are used:- THF Tetrahydrofuran EA Ethyl acetate 40 ER Ether PE Petroleum ether (bp 40-60') DIVISO Dimethyisulphoxide TFA Trifluoroacetic acid.

45 INTERMEDIATE 1 [2S-(RR)]-(-)1,4-Bis(phenylmethoxy)butane-2,3-diolbis(4- methylbenzenesulphonate) Toluene-4-sulphonyl chloride (6.0g) was added to an ice cooled solution of [2S-(R,R)]-(-)-1,4- bis(phenyimethoxy)butane-2,3-dioI (4.0g) in pyridine (50mi) and the mixture was stirred at ambient temperature for 4 days. The mixture was poured into EA and the solution was washed, successively, with 50 2Whydrochioric acid, saturated NaHC03 and water. The solution was dried, evaporated and the residue triturated under ER. The solid was collected, washed with ER and dried in vacuo to yield the title compound 23 5.6g as a white solid m.p. 125-127'. 10LID =-15.5'(cO.97,CHC13).

INTERMEDIATE 2 (2R-trans)-(+)-2,3-Bis[(phenylmethoxy)methyll-2,3-dihydro1,4- benzodioxin A mixture of catechol (0.54g) and Intermediate 1 (2g) in dry acetonitrile (40ml) was stirred under nitrogen and was warmed until a clear solution was obtained. Cesium fluoride (0. 95g) was added and the mixture was heated at reflux for 3 days, with additional batches of cesium fluoride being added after 3h (0.95g), 24h (1.9g) and 48h (1.9g). After the dark brown mixture had cooled, the solution was decanted and was evaporated to 60 dryness. The combined residues were suspended in EA and the mixture was washed with 2N NaOH solution. The washings were re-extracted with EA and the combined ethyl acetate solutions were filtered and washed with brine. The solution was dried and the solvent was evaporated. The residue was suspended in ER and filtered and the filtrate was chromatographed using a mixture of PE and ER as eluant. Fractions containing the product were combined and evaporated to give the title compound 0.37g as a clear oil [a]'2 = + 36.2' (c 65 D k 6 GB 2 129 795 A 1 6 0.91, CHC13). NIVIR (CDC[3),r3.0 to 3.3 (m, 4H, aromatic), 2.69 (S, 1 OH, Ph-CH2_),538 and 5.54 (ABq, J1 2,4H, PhCH2),622 (m, 4H, -CH20_),5.69 (m, 2H, ring protons).

INTERMEDIATE 3 5 (2Rtrans)-(+)-2,3-Dihydro-1,4-benzodioxin-2,3-dimethanol A solution of Intermediate 2 (5.50g) in ethanol (300mi), was hydrogenolised at ambient temperature and pressure, using 10% palladium on charcoal (0.5g) as catalyst, until hydrogen uptake ceased. The catalyst was filtered off, washed well with ethanol and the combined filtrate and washings evaporated. The residue was triturated with ER, the solid was collected, washed with ER and dried in vacuo to afford the title compound 1(1 1.819,mpl28-129.5'. [()j23 = +54.50 (c 1.01, CHC13). D INTERMEDIATE 4 (2R-trans)-(+)-2,3-Dihydro- 1,4-benzodioxin-2,3-dimethanol dimethanesulphonate A solution of methane sulphonyl chloride (1.90mi) in CH2C12 (50mi) was added, over 0.25h, to an ice cooled solution of Intermediate 3 (2.10g) and triethylamine (4.60mi) in CH2C12 (50mi). The resulting solution was 15 stirred for a further 0.25h then washed successively with water, 2Whydrochloric acid, saturated NaHC03 and brine. The solution was passed through phase-separating paper and the solvent evaporated. The residue was then triturated under ER, the solid was collected, washed with ER and dried in vacuo to give the title compound 3.5g as a white solid m.p. 90- 92o. [a]23 D = +23X (c 1.3, CHC13).

INTERMEDIATE 5 (4R-trans)-(+)-4,5-Bisl(phenylmethoxy)methyll-2,2-dimethyl1,3-dioxolane A solution of (4R-tra ns)-(-)-2,2-d i methyl -1,3-d ioxo ia ne-4,5-d im etha n ol (51 g) in THF (400mi) was added dropwise to a stirred suspension of sodium hydride (1 7.5g of 80% in oil) in TH F (200mi). After 0.75h, benzyl bromide (116.39) was added dropwise and the resulting mixture was stirred for 18h, and was then heated at 25 reflux for 2h. After stirring for a further 20h at 20', the mixture was cooled in ice, water (1 Omi) was added and the mixture was evaporated to dryness. The residue was extracted with ER, and the organic solution was dried and the solvent was evaporated giving a crude product (1 30g) which was used without further purification.

INTERMEDIATE 6 [2R-(R,R)]-(+)- 1,4-Bis(phenylmethoxy)butane-2,3-diol A solution of Intermediate 5 (130g) in 0.5N hydrochloric acid (40mi) and methanol (400mi) was heated gently, and the acetonelmethanol mixture was distilled out over 5h. The mixture was concentrated, neutralised with NaHC03 solution and was extracted with EA. The solution was dried and the solvent was 35 evaporated. The product was triturated with ER and PE to give the title compound 69g, m.pt. 44-45', [UJ21 D + 5.4' (c, 0.84, CHC13).

INTERMEDIATE 7 [2R-(RIR)]-(+)- 1,4-Bis(phenylmethoxy)butane-2,3-diol. bis (4- methylbenzenesulphonate) To a solution of Intermediate 6 (32.7g) in pyridine (400 mi), cooled in ice, was added toluene-4-sul phony] chloride (49g) and the mixture was stirred at 20'for 4 days. The mixture was cooled in ice, and 1 Omi of water was added dropwise, followed by a further 1 litre of water. The precipitate was collected, washed with water [U122 = and dried to give the title compound, 56.3g, m.pt. 123-125', D 14.7' (c 0. 89, CHC13).

INTERMEDIATE 8 (2S-Trans)-(-)-2,3-Bis[phenylmethoxy)methyll-2,3-dihydro-1,4-benzodioxin A mixture of catechol (8.1 g) and Intermediate 7 (30g) in dry acetonitrile (600ml) was stirred under nitrogen and was warmed until a clear solution was obtained. Cesium fluoride (1 6. 6g) was added and the mixture was heated at reflux for 3 days, with additional batches of cesium fluoride being added after 20h (7g), 28h (7.4g) 50 and 44h (7.2g) and 52h (7.5g). After the dark brown mixture had cooled, the solution was decanted and was evaporated to dryness. The combined residues were suspended in EA and the mixture was washed with 2N NaOH solution. The washes were re-extracted with EA and the combined EA solutions were filtered and washed with brine. The solution was dried and the solvent was evaporated. The crude product was purified by chromatography to give the title compound6g, 1Q1D'O = -38o (c 1.2; CHC13)- INTERMEDIATE 9 (2S-trans)-(-)-2,3-Dihydro1,4-benzodioxin-2,3-dimethanol A solution of Intermediate 8 (5.9g) in ethanol (250mi) was stirred with 10% palladium on charcoal and was hydrogenated at atmospheric pressure. The calculated amount of hydrogen had been taken up after 5 hours. 60 The mixture was filtered, and the solvent was evaporated giving a crude solid. Purification by trituration with ). [0121 = PE gave the title compoundas a white solid (2.1 g D -54.2' (c 0.81, EtOH), T(C13C13 + DMS0d6) 3.14 (s, 4H, aromatic), 5.50 (t, J6,2H, CH), 5.88 (m, 2H, CHCH2) and 6.07 (m, 4H, CH-CH2).

1 7 GB 2 129 795 A 7 INTERMEDIATE 10 (2S-trans)-(-)-2,3-Dihydro1,4-benzodioxin-2,3-dimethanol dimethanesulphonate A solution of methanesulphonyl chloride (1.8mi) in dichloromethane (50mi) was added, over 0.25h, to an ice cooled solution of intermediate 9 (2g) and triethylamine (4.3mi) in CH2C12 (50mi). The resulting solution was stirred for a further 0.25h and then washed successively with water, 2Whydrochloric acid, saturated NaHC03 and brine. The solution was passed through phase-separating paper and the solvent was evaporated. The residue was then triturated under ER, the solid was collected, washed with ER and dried in vacuo to give the title compound3.2g, m.p. 86-890, [0j24 = -26.6'(c 1.3, CHC13). D INTERMEDIATEll 1,4-Benzodioxin-2,3-dicarboxylic acid n-Butyl lithium (185 mi, of a 1.42 M solution in hexane) was added to a solution of diisopropylamine (37.0 ml), in dry THF (300 m[) at -7W and the the solution was stirred for 0.25 h. A solution of 1,4-benzodioxin2carboxylic acid (23.40 g) in dry THF (400 mi) was then added over 0.5h and the resulting solution was stirred at -780 for 1 h. The solution was then poured onto finely crushed C02 and the mixture left to stand overnight. The mixture was evaporated and 2N-hydrochloric acid (250m1) was added cautiously, followed by concentrated hydrochloric acid (40mi). EA (500mi) and THF (100mi) were added to the mixture, which was shaken and the organic layer separated. The aqueous phase was further extracted with EA and the combined extracts were dried. Evaporation of the solvent gave an orange solid which was triturated under ER for 0.5h.

The solid was to afford the title compound (25.0 g) m.p. 215-218'.

INTERMEDIATE 12 1,4-Benzodioxin-2,3-dicarboxylic acid, diethyl ester Intermediate 11 (24.00g) was suspended in ethanol (300ml) and dry HCI was passed through the mixture for about 0.2h. The resulting solution was heated under ref lux for 3h, cooled and evaporated. The residual oil 25 was dissolved in EA, washed with saturated NaHC03 solution, dried and evaporated to give the title compound (26.1g) as a brown crystalline solid M.P. 35-370. INTERMEDIATE 13 Cis 2,3-Dihydro- 1,4-benzodioxin-2,3-dicarboxylic acid,

diethyl ester A solution of Intermediate 12 (5.00g) in ethanol (50mi), was hydrogenated at ambient temperature and pressure, using 10% palladium on charcoal (0.5g) as catalyst, until hydrogen uptake ceased. The catalyst was filtered off, washed well with ethanol and the combined filtrate and washings were evaporated to give a colourless oil. This solidified on standing to afford the title compound (5.0g) as a crystalline solid m.p. 52-550.

INTERMEDIATE 14 Trans-( )-2,3-Dihydro-1,4-benzodioxin-2,3-dicarboxylic acid, diethyl ester Anhydrous Na2CO3 (21.50g) was added to a solution of Intermediate 13 (18. 80g) in ethanol (500ml) and the mixture was stirred at ambient temperature for 24h. The mixture was cautiously acidified with concentrated HCI and evaporated. The residue was then shaken with EA and water, the organic phase was separated and 40 the aqueous layer was further extracted with EA. The combined extracts were dried and evaporated to give a brown oil (19.6g) containing a 40:60 mixture of cis and trans-diesters. The oil was chromatographed using medium pressure chromatography with a mixture of petroleum ether (b.p. 60- 80') EA (8:1) as eluant.

Fractions containing the less polar trans isomer were combined and evaporated to yield the title compound (9.3g) as a pale yellow crystalline solid M.P. 54-56'.

INTERMEDIATE 15 Trans-( )-2,3-Dihydro-1,4-benzodioxin-2,3-dimethanol Asolution of Intermediate 14 (8.56g) in dryTHF (150mi) was added, over 0. 3h, to an ice-cooled suspension of LiA[H4 (4.40g) in dry THF (100mi). The mixture was stirred fora further 0.5h at 0'then saturated ammonium chloride solution was added dropwise. The mixture was filtered, and the solid was washed well with THF. The combined filtrate and washings were evaporated and the residue partitioned between EA and water. The organic layer was separated and the aqueous layer further extracted with EA. The combined extracts were dried, evaporated and the residue triturated under ER. The solid was collected, washed with ER and dried in vacuo to give the title compound (4.5g) as a white solid m.p. 119120'.

INTERMEDIATE 16 Trans-(-:)2,3-Dihydro 1,4-benzodioxin-2,3-dimethanol dimethanesulphonate A sol ution of methanesu 1 phonyl chloride (3.60m 1) in CH2C12 (1 00mi) was added, over 0.25h, to an ice cooled solution of Intermediate 15 (4.009) and triethylamine (8.70 mi) in CH2C12 (100mi). The resulting 60 solution was stirred for a further 0.25h then washed successively with water, 2Whydrochloric acid, saturated Nal-IC03 and brine. The solution was passed through phase-separating paper and the solvent evaporated.

The residue was then triturated under ER, the solid was collected, washed with ER and dried in vacuo to give the title compound (6.79) as a white solid m.p. 83-84'.

1 8 GB 2 129 795 A 1 EXAMPLE 1 (3aR-trans)-(+)-2-Phenylmethyl-2,3,3a,9a-tetrahydro-1H-[1,4jbenzodioxino[2, 3-clpyrrole, hydrochloride A mixture of Intermediate 4 (3.20g) and benzylamine (25mi) was heated at 120'for 0.5h and the cooled solution poured into EA. The mixture was basified with 2N NaOH and the organic layer was separated. The aqueous layer was further extracted with EA and the combined extracts were dried. Evaporation gave an oil which was dissolved in EA (30mi) and ER (30mi) and the solution was acidified with ER and dried in vacuo to afford the title compound 2.3g as a white powder m.p. 236-2380 (dec) [0t123 = + 102.5' (c 0.45, H20). N M R D (TFA) T 2.42 (s, 5H, CH2Ph), 2. 97 (s, 4H, aromatic), 5.32 (d, J6,2H, CH2Ph), 5.2-6.2 (multiplets, 6H, C]- H2, C3-1-12, C3a-H and C9a-H).

EXAMPLE 2 (3aR-trans)(+)-2,3,3a,9a- Tetrahydro- 1H-[1,41-benzodioxino[2,3clpyrrole, hydrochloride A suspension of the compound of Example 1 (2.009) in methanol (100mi) was hydrogenolised at ambient temperature and pressure, using 10% palladium on charcoal (0.2g) as catalyst, until hydrogen uptake ceased.

The catalyst was filtered off, washed with methanol and the combined filtrate and washings were evaporated. Crystallisation of the residue from methanol gave the title compound 0.71g as off white prisms m. p 271- 274'. [(X123 = +1543'(c 0.73, dmso). NMR (dmso-d6) T 2.99 (s, 4H, aromatic), 5.59 (m, 2H, C3a-H and D C9a-H), 6.19 and 6.71 (2m, 4H, C,-1-12 and C3-H2).

8 EXAMPLE 3 (3aS-Trans)-(-)-2-Phenylmethyl2,3,3a.9a, tetrahydro-1H-[1,41benzodioxino[2,3-clpyrrole, hydrochloride A mixture of Intermediate 10 (3. 0g) and benzylamine (1 5mi) was heated at 1200 for 0.5h and the cooled solution poured into EA. The mixture was basified with 2N NaOH and the organic layer was separated. The aqueous layer was further extracted with EA and the combined extracts were passed through a phase separation paper. Evaporation gave an oil which was dissolved in EA (20mi) and ER (20mi) and the solution 25 was acidified with 2N-hydrochloric acid. The precipitate was collected, washed with ER and dried in vacuo to afford the title compound 2.52g as white plates m.p. 238-240', [0j21 = - 98.18' (c 0.34, H20) N MR (TFA),r 2.38 D (s, 5H, CH2Ph) 2.95 (s, 4H, aromatic), 5.3 (d, J6,2H, CH2Ph), 5.2 - 6.2 (multiplets, 6H, Cl -1-12, C3-1-12, C3a-H and C9a-H).

EXAMPLE 4 (3aS-Trans)-(-)-2,3,3a,9a, Tetrahydro1H-[1,4-benzodioxino[2,3-clpyrrole, hydrochloride Asolution of the compound of Example 3 (2.4g) in methanol (120mi) was hydrogenated at ambient temperature and pressure, using 10% palladium on charcoal (0.24g) as catalyst, until hydrogen uptake ceased. The catalyst was filtered off, washed well with methanol and the combined filtrate and washings 35 were evaporated. Crystallisation of the residue from methanol afforded the title compound 1.Og as white prisms m.p. 272-276', lOdD = -1 51.4'(c, 0.74, DIVISO), NMR (dmso-d6),r 2. 9 to 3.1 (m, 4H, aromatic), 5.63 (m, 2H, C3.-H and Cga-H), and 6.22 and 6.72 (two multiplets, each 2H, Cl -112 and C3-H2).

W EXAMPLE 5 a) ( )trans-2-Methyl-2,3,3a,9a-tetrahydro-1H-[1,41-benzodioxino[2,3clpyrrole, hydrochloride Intermediate 16 (2.00g) and methylamine (10mi) were placed in a sealed glass tube and the mixture was heated at 1100 for 3h. After opening, the tube was left at room temperature overnight to remove excess methylamine. The residue was dissolved in methanol and the solution evaporated. The solid obtained was partitioned between a mixture of 2N-NaOH (10mi), water (5mi) and EA (20mi) and the organic phase was 45 separated. The aqueous layer was further extracted with EA and the combined extracts were dried and evaporated to give a pale brown crystalline solid. This was dissolved in a mixture of ER (10mi) and EA (3mi) and the solution filtered. The filtrate was then acidified with ethereal hydrogen chloride and the precipitate was collected, washed well with ER and dried in vacuo. Crystallisation from EA-methanol yielded the title compound (0.44g) as needles. NMR (dmso-d6),r 2.9-3.1 (m, 4H, aromatic), 5. 3 - 5.6 (m, 2H, C3a-H and 50 C9a-H), 6.05 and 6.42 (m,4H, Cl-H2 and C3-1-12),6.98 (s, 3H, N-Me).

The following compounds were prepared using a similar procedure:

b) ( )trans-2-Ethyl-2,3,3a,9atetrahydro-1H-[1,41-benzodioxino[2,3clpyrrole, hydrochloride From Intermediate 16 and ethylamine. The product was obtained as pink prisms 0.84g m.p. 249-245o 55 (isopropyl alcohol), NMR (dmso-d6) r 2.97 (s, 4H, aromatic), 5.0 to 5.8 and 5.8-6.8 (multiplets, 7H,NH, Cl-2H, C3-2H, C3a-H and C9a-H), 6.63 (q, 7Hz, 2H, NCH2CH3),8.68 (t, 7Hz, 3H, NCH2CH3).

c) (:t) trans-2Cyclopropyl-2,3,3a,9a-tetrahydro-1H-[1,4]benzodioxino[2, 3clpyrrole, hydrochloride From Intermediate 16 and cyclopropylamine. The crude free base was dissolved in a mixture of EA (20mi) 60 and ER (20m1) and the solution was acidified with 2N-hydrochloric acid. The precipitate was collected, washed with ER, then EA and dried in vacuo to yield the title compoundO. 999 as white microcrystals m.p.

204-205'. NMR (TFA) T 2.98 (s, 4H, aromatic) 5.0-6.6 (multiplets, 6H, Cl 2H, C3-2H, C3a-H and Cg,-H), 6.80 (m, 1 H, cyclopropyl CH), 8.4-9.1 (m, 4-H, cyclopropyl CH2).

il 9 1 GB 2 129 795 A 9 d) ( )trans-2-(Cyclopropylmethyl)-2,3,3a.9atetrahydro-1H-[1,41benzodioxino[2,3-c jpyrrolehydrochloride From Intermediate 16 and aminomethylcyclopropane. The crude free base was dissolved in EA (40m1) and the solution acidified with 2N-hydrochloric acid. The precipitate was collected, washed with EA and dried in vacuo to afford the title compound 1.16g, as white microcrystals m.p. 243t.246'. NMR (TFA) T 2.97 (s, 4H, aromatic), 5.1-6.7 (multiplets, 8H, Cl-2H, C3-2H, C3a-H, C9a-1-1 and NCH2 8.70 (m, 1H, cyclopropyl CH), 8.9-9.6 (m, 4H, cyclopropyi CH2).

e) ( )trans-2,3,3a,9a-Tetrahydro-2-(2-propenyl)-IH-[1,41-benzodioxino[2,3clpyrr ole, hydrochloride From Intermediate 16 and allylamine. After trituration with isopropyl alcohol the product was obtainedas 10 a buff powder 1.2 9. m.p. 234-236'. NMR (dmso-d6) T 2.97 (s, 4H, aromatic), 3.74.2 (m, 1 H, NCH2CH=CH2), 4.24. 6 (m, 2H, NCH2CH=CH2), 5.5 (m, (broad), 2H, C3a-H and C9a-H), 5.8-7.2 (multiplets, 6H, Cl -2H, C3-21-1 and N-CH2CH=CH2).

EXAMPLE 6 ( ) trans-2,3,3a,9a, Tetrahydro-2-phenyImethyl 1H-[1,41-benzodioxino[2,3- clpyrrole, hydrochloride A mixture of Intermediate 16 (2.00g) and benzylamine (1 Omi) was heated at 1200 for 0.5h and the cooled solution poured into EA. The mixture was basified with 2N NaOH and the organic layer was separated. The aqueous layer was further extracted with EA and the combined extracts were dried. Evaporation gave an oil which was dissolved in EA (20mi) and ER (20mi) and the solution was acidified with 2Whydrochloric acid. 20 The precipitate was collected, washed with ER and dried in vacuo to afford the title compound (1.39) as white plates. NMR (TFA) T 2.47 (s, 5H, CH2Ph), 3.03 (s, 4H, aromatic), 5.38 (d, 2H, CH2Ph), 5.2 - 6.2 and 6.48 (multiplets, 6H, Cl-H2, C3-H2, C3a-H and c9a-H).

EXAMPLE 7 (::) trans-2,3,3a,9a-Tetrahydro-1H-[1,41-benzodioxino [2,3-clpyrrole, hydrochloride A solution of the compound of Example 6 (1.00g) in methanol (50mi) was hydrogenated at ambient temperature and pressure, using 10% palladium on charcoal (0,10g) as catalyst, until hydrogen uptake ceased. The catalyst was filtered off, washed well with methanol and the combined filtrate and washings were evaporated. Crystallisation of the residue from methanol afforded the title compound (0.43g) as white 30 prisms m.p. 271-274'. NMR (dmso-d6) T 2.99 (s, 4H, aromatic), 5.59 (m, 2H, C3a-H and C9a-H), 5.9 - 6.4 and 6.5 - 6.9 (2m, 4H, Cl-1-12 and C3-H2).

EXAMPLE 8 ( ) trans2,3,3a,9a,-Tetrahydro-2-propyl-1H-[1,41-benzodioxino[2,3- clpyrrole, hydrochloride A solution of the compound of Example 5 e) (0.60g) in methanol (50mi) was hydrogenated at ambient temperature and pressure, using 10% palladium on charcoal (0.06g) as catalyst until hydrogen uptake ceased. The catalyst was filtered off, washed well with methanol and the combined filtrate and washings were evaporated. The residue was triturated under isopropyl alcohol, the solid was collected, washed with isopropyl alcohol and dried in vacuo to yield the title compound 0.35 gas an off-white crystalline solid m.p. 40 243-245' NMR (dmso-d6)T3.02 (s,4H, aromatic), 5.56 (m, 2H,C3, and C9a-H), 5.9-6.9 (multiplets, 6H, Cl-2H, C3-21-1 and N-CH2CH2CH3),8.26 (m, 2H, NCH2CH2CH3), and 9.06 (t, 3H, NCH2CH,CH3).

EXAMPLE 9 ( ) trans-2,3,3a,9a-Tetrahydro-2-(2-propynyl)-1H-[1,41-benzodioxino[2,3clpyrrol e. hydrochloride A solution of propa rgyl bromide (0.7 mi of an 80% '1w solution in toluene) in ethanol (5mi) was added to a mixture of the compound of Example 7, free base (1.1 g) and potassium carbonate (1.1 g) in ethanol (1 5ml), over 0.3h. The mixture was stirred at ambient temperature for 3h, then heated at 90'for 1 h and the cooled mixture was evaporated. The residue was partitioned between EA and water, and the aqueous phase separated. This was further extracted with EA and the combined extracts evaporated. The residue was 50 dissolved in EA and the solution was washed with 2Whydrochloric acid. The acid washings were made basic with 1 ON-NaOH and the resulting mixture was extracted with EA. Evaporation of the organic extracts gave a residue which was dissolved in a mixture of EA (25mi) and ER (1 OmO and the solution was acidified with ethereal hydrogen chloride. The precipitate was collected, washed first with ER, then isopropyl alcohol and then dried in vacuo. Crystallisation from ethanol gave the title compound 0.44 gas pale brown plates m.p. 55 211-213'. NMR (dmso-d6),r 2.98 (s, -4H, aromatic), 53-5.8 (m, 4H, C3a-H, Q9,,-1-1 and NCH2C=-CH), 5.8 to 6.6 (multiplets, 4H, Cl and C3-CH2), and 6.20 (t, 2Hz, 1 H, C=-CH).

EXAMPLE 10 ( )trans-2,3,3a,9a-Tetrahydro-1H-[1,41benzodioxino[2,3-clpyrrole-2carboxald ehyde A solution of the compound of Example 7, free base (2.09) in methyl formate (15mi) was stirred at ambient temperature for 2h and the resulting mixture was evaporated. The residue was triturated under ER, and the solid was collected, washed with ER and dried in vacuo to afford the title compound2.2g as white microcrystals m.p. 207-208o. NMR (TFA) T 1.53 (s, 1 H, NCHO), 3.00 (s, 4H, aromatic), 53-5.8 and 5.9-6.6 (multiplets, 6H, Cl-2H, C3-2H, C3,-H and C9,,-1-1).

GB 2 129 795 A 1 EXAMPLE 11 (-!:) trans-2,3,3a,9a-Tetrahydro-2-methyl-1H-[1,41-benzodioxino[2,3- clpyrrole, hydrochloride The compound of Example 10 (1.50g) was added, in portions, to an ice cooled suspension of LiAM4 (0.64g) in THF (50mi) and the resulting mixture was stirred at ambient temperature for 3.5h then heated under reflux for 2h. The mixture was cooled in ice and excess LiAM4 was destroyed by the addition of water. The mixture 5 was filtered and the solid washed with THE The combined filtrate and washings were evaporated and the residue partitioned between EA and 2N- NaOH. The aqueous phase was separated and further extracted with EA. The combined extracts were dried and evaporated to give a white, crystalline solid (1.289). A portion (0.88g) of the solid was dissolved in ER (1 Orril) and the solution was acidified with ethereal hydrogen chloride. The solid was collected and crystallised twice (methanol/ethyl acetate) to give the title compound 10 0.519 as a white crystalline solid. NIVIR (dmso-d6),r 2.9-3.1 (m, 4H, aromatic), 53-5.6 (m, 2H, C3a-H and Cg,,-H), 6.05 and 6.42 (m, 4H, Cl -H2 and C3-H2),6.98 (s, 3H, N-Me).

Pharmaceutical Examples Pharmaceutical compositions according to the invention may be formulated in accordance with the 15 following instructions.

In these Examples, "Active Ingredient" refers to ( ) trans 2,3,3a,9atetrahydro-1 H-[1,41-benzodioxino[2,3 c1pyrrole hydrochloride. Othercompounds of the invention may beformulated in similarfashion.

1. Oral Capsule per capsule Active Ingredient 50 mg Magnesium stearate 0.5 mg Anhydrous lactose 50 mg 25 Blend the active ingredient with the lactose and magnesium stearate. Fill the blend into appropriate size hard gelatin capsules (lock fitting type) on an automatic capsule filling machine.

2. Oral Syrup 30 per 5 mI dose Active Ingredient 50 mg Sodium citrate 25 mg Citric acid to pH 4.5 35 Sunset yellow FCF (Dye) 0.25 mg Methyl hydroxybenzoate sodium 5.0 mg Propyl hydroxybenzoate sodium 2.0 mg Liquid orange flavour qS Sucrose 3.25 g 40 Purified water to 5.0 mi Dissolve the sucrose in a minimum quantity of water. Add a concentrated solution of sodium citrate with stirring and adjust the pH to 4.5 with citric acid. With continued stirring, add a 10% aqueous solution of the active ingredient, followed by a solution of the dye, a solution of the hydroxybenzoates and lastly the flavour. 45 Adjust almost to volume with water and stir. Check the pH and adjust to 4.5 with citric acid if necessary. Make up to volume with water.

3. Oral Tablet k i p per tablet 50

Active ingredient 50 mg Polyvinyl pyrrolidone 4.0 mg Sodium starch glycollate 10.0 mg Magnesium stearate 2.0 mg 55 Lactose to tablet core weight of 200 mg Blend the active ingredientwith the lactose. Add a sufficient quantity of polyvinyl pyrrolidone solution to produce a damp mass suitable for granulation. Prepare the granules and dry using a tray of fluid bed dryer.

Pass through a sieve, blend with the remaining ingredients and compress into 8mm diametertablets on a 60 tablet machine.

Film coat the tablet cores with hydroxypropyl methyl cellulose or similar film forming material, using either an aqueous or non-aqueous solvent system. A plasticizer and suitable colour may be included in the film coating solution.

z 1 11 1 GB 2 129 795 A 11

Claims (12)

1. A compound of general formula M:

H 5 ub-R l- 0 = (1) R 10 wherein R is a hydrogen atom or a C1-6 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 group, and physiologically acceptable salts thereof.

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

3. A compound according to claim 1, wherein R is a methyl group, an ethyl group or a cyclopropyl group.

4. ( ) trans-2,3,3a,9a-Tetrahydro-2-methyl-lH-[1,4]-benzodioxino [2,3clpyrrole and its physiologically acceptable salts.

5. W trans-2,3,3a,9a-Tetrahydro-lH-[1,41-benzodioxino[2,3-c]pyrrole and its physiologically acceptable 20 salts.

6. (3aR-trans-(+)-2,3,3a-9a-Tetrahydro-lH-[1,41-benzodioxino[2,3clpyrrole; (3aS-trans)-(+)-2,3,3a,9a tetrahydro-1 H-[1,4]-benzodioxino[2,3-clpyrrole; and their physiologically acceptable salts.

7. A compound according to any of claims 1 to 6 wherein the physiologically acceptable salts is a hydrochloride, hydrobromide, phosphate, sulphate, citrate, tartrate, acetate, maleate or succinate. 25

8. Gt) trans-2,3,3a,9a-Tetrahydro-1.H-[1,41-benzodioxino[2,3-clpyrrole, hydrochloride.

9. A pharmaceutical composition comprising a compound of general formulaffi and/or a physiologically acceptable salt thereof together with a physiologically acceptable carrier or excipient.

10. A pharmaceutical composition according to claim 9, which also comprises an established antidepressant.

11. A compound of general formula (1) as defined in claim 1 or a physiologically acceptable salt thereof for use in the therapy or prophylaxis of migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic ileus, senile dementia, analepsis, appetite supression or depression.

12. A process for the preparation of a compound of general formula (1) as defined in claim 1 or a physiologically acceptable salt thereof which comprises A. aminating a compound of general formula (ii):

-4 0 CH2X 40 H2X 0D where 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 (1) 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 (1) where R represents an alkyl group, reducing the 50 corresponding compound where R represents an acyl group; and, if desired, subjecting the compound thus obtained to one or two further reactions comprising D. (i) converting the resulting compound of general formula (1) or a salt thereof into another compound of _general formula (1) and/or 00 converting a compound of general formula (1) or a saitthereof into a physiologically acceptable salt 55 thereof.

1 Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1984.

Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.