EP0691973A1

EP0691973A1 - THIENO-INDOLE DERIVATIVES AS 5HT2c AND 5HT2b ANTAGONISTS

Info

Publication number: EP0691973A1
Application number: EP94912514A
Authority: EP
Inventors: Ian Thomson Forbes; Roger Thomas Martin; Graham Elgin Jones
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 1993-03-29
Filing date: 1994-03-22
Publication date: 1996-01-17
Also published as: WO1994022871A1; JPH08508275A; GB9306460D0

Abstract

Novel thieno-indole compounds being 5HT2c and 5HT2b antagonists, processes for their preparation, compositions containing them and their use in the treatment of mammals.

Description

TH^* NO-IND'TLE DERIVATIVES AS 5HT2c AND 5HT2b ANTAGONISTS

This invention relates to novel compounds having pharmacological activity, to processes for their preparation, to compositions containing them and to their use in the treatment of mammals.

P. Fludzinski et. al., J. Med. Chem. 1986292415-2418 describes N-(l,2-dimethyl-3-ethyl-lH-indol-5-yl)-N'- (3-trifluoromethylphenyl)urea which shows selectivity for the rat stomach fundus serotonin receptor.

WO 92/05170 describes certain urea derivatives which are described as possessing 5HTJC receptor antagonist activity. The 5-HTjc receptor has recently been reclassified as the 5HT2C receptor [P. Hartig et al., Trends in Pharmacological Sciences (TIPS) 1993].

A structurally distinct class of compounds has now been discovered which have been found to have 5HT2C receptor antagonist activity. Certain compounds of the invention also exhibit 5HT2B antagonist activity. 5HT2 /2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, obsessive compulsive disorders, migraine, anorexia, Alzheimers disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.

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

wherein:

P represents a quinoline or isoquinoline residue or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur,

R\ is hydrogen, Ci .g alkyl, halogen, OR7 or NRgR where R7, Rg and R9 are independently hydrogen or Cj_6 alkyl; R2 is hydrogen or Cj_6 alkyl; R3 is hydrogen, Cι_6 alkyl, Cj.β alkoxy, or halogen; R4 is hydrogen or Cj.g alky R5 and Rg are each independently hydrogen or Cj.g alkyl; and n is 2 or 3.

Cι_6alkyl groups, whether alone or as part of another group, may be straight chained or branched and are preferably C1-.3 alkyl, such as methyl, ethyl, n- and iso- propyl, most preferably methyl.

Preferably Rj is hydrogen, Cj.6alkyl or halogen. Most preferably Rj is hydrogen, methyl or bromo.

Preferably R2 and R3 are hydrogen.

Preferably R5 and Rg are both hydrogen and n is 2, that is to say, the group -(CR5R^)_n- forms an ethylene linkage. The group -(CR5R6)_n- can be attached to the 4- or 6-position of the benzothiophene ring.

The urea moiety can be attached to a carbon or, when available, a nitrogen atom of the ring P, preferably it is attached to a carbon atom.

Suitable moieties when the ring P is a 5- or 6-membered aromatic heterocyclic ring include pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl. When P is a quinoline or isoquinoline residue, the urea moiety can be attached at any position of the ring, preferably to the 4-position.

Preferably P is pyridyl, quinolyl or isothiazolyl.

The substituent R3 can be attached to any vacant position in the phenyl part of the benzothiophene ring, that is to say, the 4-, 6- or 7-positions of the benzene ring. The substituent R4 can be attached to the 2- or 3-positions of the thiophene ring.

Preferred compounds of formula (I) include;

7,8-Dihydro-6-(3-pyridylcarbamoyl)-thieno[3,2-e]-indole, 6,7-Dihydro-5-(3-pyridylcarbamoyl)-5H-thieno[2,3-f]indole, 7,8-Dihydro-6-(5-quinolylcarbamoyl)-6H-thieno[3,2-e]indole, 7,8-Dihydro-6-(3-Methyl-5-isothiazolylcarbamoyl)-6H-thieno[3,2-e]indole, 6,7-Dihydro-5-(5-Bromo-3-pyridylcarbamoyl)-5H-thieno[2,3-f]indole, 7,8-Dihydro-6-(2-methyl-4-quinolylcarbamoyl)-6H-thieno[3,2-e]indole, 6,7-Dihydro-5-(2-methyl-4-quinolylcarbamoyl)-5H-thieno[2,3-f]indole, 6,7-Dihydro-5-(4-pyridylcarbamoyl)-5H-thieno[2,3-fJindole, and pharmaceutically acceptable salts thereof.

The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.

Compounds of formula (I) may also form N-oxides, S-oxides or solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term 'compound of formula (I)' also includes these forms.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. When R2 is hydrogen or when Rj is hydroxy or NR Rg and at least one of R7 and Rg are hydrogen, the compounds of formula (I) may exist tautomerically in more than one form. The invention extends to all tautomeric foπns of compounds of formula (I) and mixtures thereof.

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

(a) the coupling of a compound of formula (II);

_' " _* _Rι :_p _; _{A (||)}

with a compound of formula (HI); (CrVFV)_n

wherein A and B contain the appropriate functional group(s) necessary to form the moiety -NR2'CO when coupled, wherein R^ is R2 as defined in formula (I) or a group convertible thereto, and the variables Rj', R3', R4', R5' and Rg' arc R , R3, R4, R5 and R , respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary in any appropriate order, converting any R\ R2^*, R3', R4^*, R5' and R(.' when other than Ri, R2, R3. R4, 5 and Rg to R\, R2, R3, R4, R5 and R6, interconverting R\, R2, R3, R4, R5 and R6, and forming a pharmaceutically acceptable salt, or

(b) cyclising a compound of formula (TV):

wherein R R2', R3', R5 , and R ' are as defined in formulae (II) and (HI) and C and D contain the appropriate functional group(s) necessary to form the thiophene ring substituted by R3¹ and R4' as defined in formula (HI), and thereafter optionally and as necessary in any appropriate order, converting any R\ R2', R3', R4¹, R5' and R6^* when other than Rj, R2, R3, R4, R5 and Rg to Rj, R2, R3, R4, R5 and Rg, interconverting R\, R2, R3, R4, R5 and R , and forming a pharmaceutically acceptable salt.

Suitable examples of groups A and B include: (i) A is -N=C=O and B is -H, (ϋ) A is -NR2'COL and B is -H, (iii) A is -NHR2' and B is COL, or (iv) A is halogen and B is -CONHR^, wherein R2' is as defined above and L is a leaving group. Examples of suitable leaving groups L include imidazole, halogen such as chloro or bromo or phenoxy or phenylthio optionally substituted, for example with halogen.

When A is -N=C=O and B is H the reaction is suitably caπied out in an inert solvent for example dichloromethane or toluene at ambient temperature.

When A is -NR^COL and B is H or when A is -NHR2' and B is COL, the reaction is suitably carried out in an inert solvent such as dichloromethane at ambient temperature optionally in the presence of a base, such as triethylamine or in dimethylformamide at ambient or elevated temperature.

When A is halogen and B is CONHR2', the reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of a base.

Examples of compounds of formula (IV) which can be used in the preparation of benzothiophenes include those where C is SCH2CO2R5 where R5 is Cι_6 alkyl and D is CHO, or C is SCH2CH(OR5)2 and D is hydrogen.

Suitable examples of groups Rj', R3' and R4¹ groups which are convertible to Rj, R3 and R4 alkyl groups respectively, include acyl groups which are introduced conventionally and may be converted to the corresponding alkyl group by conventional reduction, such as using sodium borohydride in an inert solvent followed by hydrogenolysis in an inert solvent. Hydrogen substituents may be obtained from alkoxycarbonyl groups which may be converted to hydrogen by hydrolysis and decarboxylation. When R\ is hydroxy it is preferably protected in the compound of formula (II) as, for example, benzyloxy which is cleaved by hydrogenation. Suitable examples of a group R^ which is convertible to R2 include alkoxycarbonyl and benzyl or para-methoxybenzyl which are converted to R2 is hydrogen using conventional conditions.

Interconversions of R\, R2, R3 and R4 are carried out by conventional procedures. For example, in the case where R2 is hydrogen it is possible to introduce a Cj_6 alkyl group at the R2 position by conventional alkylation using 1 molar equivalent of a Cj.g alkyl halide and 1 molar equivalent of a suitable base in an inert solvent.

It should be appreciated that it may be necessary to protect any R to R4 hydrogen variables which are not required to be interconverted. Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981). It is preferable, however, to introduce and interconvert the groups R\ to R4 before coupling compounds of formulae (II) and (UI) together, or cyclising the compound of formula (IV).

Compounds of formula (II) in which A is NHR2' are known compounds or can be prepared analogously to known compounds, see, for example, WO 92/05170.

Compounds of formula (II) in which A is -N=C=O may be prepared by treating a compound of formula (II) in which :

i) A is amino, with phosgene or a phosgene equivalent, in the presence of excess base in an inert solvent. ii) A is acylazide (i.e. CON3), via the nitrene, by thermal rearrangement using conventional conditions (ref L.S. Trifonov et al, Helv. Chim. Acta 1987 70262). iii) A is CONH2, via the nitrene intermediate using conventional conditions.

Examples of phosgene equivalents include carbonyldiimidazole and phenyl chloroformate.

Compounds of formula (II) in which A is -NR2'COL may be prepared by reacting a compound of formula (II) in which A is -NHR2' with phosgene or a phosgene equivalent, in an inert solvent, at low temperature, if necessary in the presence of one equivalent of a base such as triethylamine.

Compounds of formula (111) may be prepared:

(a) by cyclisation of compounds of formula (V), followed by reduction to the amine if necessary

CHCRs'F

wherein Q is CR^R^ , CR⁵O or CO2R where L is a leaving group and R^ and R*> are as defined in formula (I), m is 1 or 2, R^', R4', R5', Rg' and B are as defined in relation to formula (HI) above and R is aryl or alkyl group,

or (b) cyclisation of compounds of formula (VI)

wherein R3', R5', Rg' and B are as defined in relation to formula (HI) above and C and D are as defined in relation to formula (TV) above.

The cyclisation of a compound of formula (V) may be suitably carried out in an inert solvent at ambient or elevated temperatures, optionally in the presence of a base. Reduction, if necessary, may be carried out using conventional reduction techniques. The cyclisation of a compound of formula (VI) may be suitably carried out using the procedures outlined for the cyclisation of a compound of formula (TV), above.

Compounds of formula (II) in which A is halogen and B is hydrogen are commercially available. Hovel intermediates of formulae (HI) and (TV) also form part of the invention.

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative. N-oxides may be formed conventionally by reaction with hydrogen peroxide or percarboxylic acids.

Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT2Q/2B receptor antagonist activity and are believed to be of potential use in the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.

Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxisjTof anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.

The invention further provides a method of treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.

The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.

The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.01 to 100 mg kg; and such therapy may extend for a number of weeks or months.

The following examples illustrate the invention. Description 1 5-Nitrobenzo[b]thiophene (DI)

Ethyl 5-nitrobenzo[b]thiophenecarboxylate was prepared and hydrolysed to the corresponding acid as described by S. Rossi and R. Trave (II Farmaco - Ed. Sci., 1960, 15, 396). 5-Nitrobenzo[b]thiophenecarboxylic acid (4.32 g, 19.4 mmol) was heated with copper powder (1.2 g, activated by heating for several hours at 160°C in vacuo) in quinoline (25 ml) at 180-190°C for 2h. After cooling, the mixture was diluted with ether and washed thoroughly with 5N hydrochloric acid. The organic phase was dried and evaporated, and the crude product was recrystallised from ether to give the title compound (3.24 g, 77%), m.p. 142-145°C.

NMR (CDC1₃) δ: 7.52 (1H, d, J 6), 7.68 (1H, d, J 6), 8.00 (1H, d, J 8), 8.22 (1H, dd, J 8, 2), 8.74 (1H, d, J 2).

Description 2 4-Methyl-5-nitrobenzo[b]thiophene(D2)

To a solution of 5-nitrobenzo[b]thiophene(D 1) (1.79g, 10 mmol) in dry THF (100 ml), cooled to -20° C, was added methylmagnesium bromide (3M in ether, 6.66 ml, 20 mmol), such that internal temperature remained below -15° C. The mixture was then stirred at this temperature for 30 min. 2, 3-Dichloro-5,6-dicyanobenzoquinone (2.72 g, 12 mmol) was added and the mixture was stirred for 15 min. at room temperature. The mixture was then poured into dilute acetic acid (aqueous) and extracted three times with dichloromethane. Extracts were combined, washed with sodium bicarbonate (twice) and water, dried and evaporated. The residue was chromatographed on silica gel (120g) eluted with 1:1 petrol/dichloromethane to give the title compound (1.35 g; 47% combined yield from two preparations), m.p. 104-105° C (ether/petrol).

NMR (CDCl3)δ: 2.88 (3H, s), 7.60 (1H, d, J=6), 7.64 (1H, d, J=6), 7.81 (1H, d,

J=10), 7.92 (1H, d, J=10)

Description 3 4-(2-HydroxyethyI)-5-nitrobenzo[b]thiophene (D3) A mixture of 4-methyl-5-nitrobenzothiophene (D2) (1.045 g, 5.5 mmol), paraformaldehyde (0.18 g, 6 mmol) and potassium hydroxide (0.5 M in ethanol, 1.2 ml, 0.6 mmol) in DMSO (10 ml) was stirred at room temperature for 4 h. The mixture was then diluted with ethyl acetate and washed thoroughly with water. The organic phase was dried and evaporated, and the residue was chromatographed on silica gel (60g) eluted with 0-1.5% methanol/dichloromethane, to give the title compound (0.92 g, 75%), m.p. 83-85°

NMR (CDCl₃)δ: 1.82 (1H, t, J=6), 3.51 (2H, t, J=6), 4.08 (2H, q, J=6), 7.66 (2H, s),

7.84 (1H, d, J=10). 7.91 (1H, d, J=10)

Description 4 4-(2-Methylsulphonyloxyethyl)-5-nitrobenzo[b]thiophene(D4)

A mixture of hydroxyethyl compound (D3) (1.03g, 4.6 mmol), methylsulphonyl chloride (0.4 ml, 5.2 mmol) and triethylamine (0.7 ml, 5 mmol) in dichloromethane (20 ml) was stirred for 1 h at room temperature. A further portion of triethylamine (0.2 ml) was added and stirring was continued for 30 min. Water (10 ml) was then added and the mixture was stirred for approx. 10 min before acidification with 5M hydrochloric acid and separation of phases. The organic phase was washed with dilute hydrochloric acid, dried and evaporated. The residue was recrystallised from ether to give the title compound (1.0 g, 72%), m.p. 108-110° C.

NMR (CDCl₃)δ: 2.97 (3H, s), 3.72 (2H, t, J=6), 4.67 (2H, t, J=6), 7.71 (1H, d, J=6),

7.74 (1H, d, J=6), 7.92 (1H, d, J=10), 7.99 (1H, d, J=10)

Description 5 7,8-Dihydrothieno[3,2-e]indole (D5)

A mixture of the methanesulphonate (D4) (l.Og, 3.3mmol) and 10% palladium on charcoal (0.1 g) in ethanol (50 ml) was stirred under hydrogen at 47 psi for 6.5 h. A further 50 mg of palladium/charcoal was added and hydrogenation continued for 7 h. The mixture was filtered through kieselguhr and evaporated. The residue was partitioned between dichloromethane and water and the organic phase was extracted with dilute hydrochloric acid. The combined aqueous extracts were basified with 10% sodium hydroxide and extracted with DCM. The organic extract was dried and evaporated to give the tide compound (0.18 g, 31%) as a greenish oil. NMR (CDCl3)δ: 3.31 (2H, t, J=8), 3.78 (2H, t, J=8), 4.75 (broad s), 6.96 (1H, d,

J=10), 7.18 (1H, d, J=6), 7.48 (1H, d, J=6), 7.60 (1H, d, J=10)

Description 6

*2-Bromo-4-methylbenzenecarboxaIdehyde (D6)

Sodium nitrite (45.Og, 650 mmoles) in water (80 ml) was added drop wise to a mixture of 2-bromo-4-methylaniline (lOO.Og, 530 mmoles), concentrated hydrochloric acid (125 ml) and ice/water (400 ml) over 30 mins keeping the temperature <5° C. The mixture was stirred for a further 30 mins at 0° C and sodium acetate trihydrate (50.0g, 360 mmoles) was added.

The diazonium solution/suspension was then added portionwise via a transfer tube to a solution of formaldoxime [formaldoxime prepared from paraformaldehyde (32.5g, 1000 mmoles) and hydroxylamine hydrochloride (74.0g, 1050 mmoles) by heating under reflux in water (400 ml) with sodium acetate trihydrate (150.0g, 1080 mmoles), copper sulphate pentahydrate (16.3g), sodium sulphite (2.2g) and anhydrous sodium acetate (210g, 2560 mmoles) for 20 mins] with vigorous stirring keeping the temperature <15° C (Care! reaction froths greatly). The mixture was stirred at ambient temperature for 1 hr and concentrated hydrochloric acid (470ml) was added. The mixture was then heated under reflux for 1 hr.

The product was steam distilled from the reaction for 3 hr and then extracted into diethyl ether (2x1000 ml), washed with saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and evaporated to dryness. Vacuum distillation at 5 mm Hg gave the title compound (57g, 53%) b.p. 102-108° C

NMR (CDC1₃) δ : 2.41 (3H, s), 7.22 (1H, d, J 8), 7.48 (1H, s), 7.81 (1H, d, J 8), 10.30 (1H, s).

* S-D. Jolad, S. Rajagopal, Org Synth Coll Vol. V, P.139, (1973)

Description 7 2-Bromo-4-methyl-5-nitrobenzenecarboxaldehyde (D7) Concentrated πiiric acid (36ml, 570 mmoles) wa' 'dded dropwise to 2-bromo-4- methylbenzene-carboxaldehyde (D6) (57g, 285 i >les) in concentrated sulphuric acid (300 ml) with stirring keeping the temperature <15° C. The mixture was stirred for a further 20 mins then poured onto ice/water (250 ml) with vigorous stirring. The mixture was extracted with 5% methanol/chloroform (3 x 1000 ml), washed with saturated sodium bicarbonate solution, filtered and evaporated to dryness. The residue was recrystallised from ethyl acetate/60-80 petrol to give the title compound (44.2g, 63%).

NMR (CDC1₃) δ : 2.63 (3H, s), 7.68 (1H, s), 8.49 (1H, s), 10.30 (1H, s).

Description 8 EthyI-5-nitro-6-methylbenzo[b]thiophene-2-carboxylate (D8)

Ethyl-2-mercaptoacetate (20 ml, 182 mmoles) was added to a solution of sodium ethoxide [prepared by treating ethanol (150 ml) with sodium metal (4.3 g, 180 mmoles)] keeping the temperature <5° C. After 20 mins ethanol (300 ml) was added followed by 2-bromo-4- methyl-5-nitrobenzene-carboxaldehyde (D7) (44.2g, 180 mmoles) portionwise over 10 mins resulting in a dense yellow precipitate. More ethanol (200 ml) was added and the mixture heated under reflux for 3 hr. The mixture was allowed to cool and the ethanol was removed in vacua. The residue was partitioned between dichloromethane and water, separated, dried (Na2SO4) and evaporated to dryness to give the title compound (46.0g, 96%).

NMR (CDCI3) δ : 1.42 (3H, t, J 6), 2.72 (3H, s), 4.42 (2H, q, J 6), 7.80 (1H, s), 8.10 (1H, s), 8.53 (1H, s).

Description 9 5-Nitro-6-methylbenzo[b]thiophene (D9)

Ethyl-5-nitro-6-methylbenzo[b]thiophene-2-carboxylate (D8) (46.0g, 170 mmoles) in ethanol (500 ml) and water (300 ml) was heated under reflux with sodium hydroxide (27.0 g, 680 mmoles) for 3 hours. The mixture was then allowed to cool and most of me ethanol was removed in vacua. The aqueous was then poured into a mixture of dilute hydrochloric acid (250 ml) and ice/water (100 ml) with vigorous stirring. The resulting fine precipitate was filtered off and dried. The dry solid was then heated in quinoline (300 ml) with copper powder (25 g, 3% mmoles) to 190° C for 3 hrs with stirring. The mixture was then cooled and diluted wid diethyl ether (100 ml), filtered through kieselguhr. The filtrate was washed with dilute hydrochloric acid (3 x 500 ml), water (500 ml) and saturated sodium chloride (500 ml), separated, dried (Na2SO4), filtered and evaporated to dryness to give the title compound (29.6g, 88%)

NMR (CDCI3) δ : 2.70 (3H, s), 7.40 (1H, d, J 6), 7.55 (1H, d, J 6), 7.80 (1H, s), 8.49 (1H, s).

Description 10 2-(5-Nitro-6-benzo[b]thienyl)acetaIdehyde (D10)

5-Nitro-6-methylbenzo[b]thiophene (D9) (29.6g, 153 mmoles) in dimethyl formamide (300 ml) was treated with dimethylformamide dimethyl acetal (61 ml, 460 mmoles) and pyrrolidine (25.7 ml, 300 mmoles) and heated to 150° C for 3 hrs under argon. The mixture was then cooled and evaporated to dryness. Toluene (600 ml), water (800 ml) and dilute hydrochloric acid (300 ml) were added to the residue and die mixture heated under reflux for 30 mins. The mixture was cooled and extracted with ethyl acetate (2 x 600 ml). The organic layer was washed widi water (500 ml), dried (Na2SO4) and evaporated to dryness. Flash chromatography on TLC silica gel eluting with dichloromethane gave the title compound (26.4g, 78%)

NMR (CDCI3) δ : 4.21 (2H, s), 7.48 (1H, d, J 6), 7.63 (1H, d, J 6), 7.79 (1H, s), 8.63 (1H, s), 9.90 (1H, s)

Description 11

2-(5-Nitro-6-benzo[b]thienyl)ethanol (Dll)

2-(5-Nitro-6-benzo[b]thienyl)acetaldehyde (D10) (25.3g, 114 mmoles) in ethanol was treated widi sodium borohydride (8.7g, 228 mmoles) with stirring at ambient temperature. Stirring was continued for 1 hr then most of the ethanol was removed in vacua. Water (500 ml) was added. The mixture was then acidified by careful addition of dilute hydrochloric acid (gas evolution) and then extracted with ethyl acetate (2 x 400 ml). The combined organics were washed widi water (500 ml) and saturated sodium chloride solution (500 ml), separated, dried (Na2SO4) and evaporated to dryness. This gave the title compound (25.0g, 98%). NMR (CDCI3) δ : 3.28 (2H, t, J 8), 3.95 (2H, t, J 8), 7.40 (IH, d, J 6), 7.58 (IH, d, J 6), 7.89 (IH, s), 8.45 (IH, s).

Description 12 2-(5-Nitro-6-benzo[b]thienyl)ethyl methane sulphonate (D12)

2-(5-Nitro-6-benzo[b]thienyl)ethanol (Dll) (25.0 g, 112 mmoles) in dichloromethane (500 ml) was treated widi triethylamine (16.4 ml, 118 mmoles). Methanesulphonyl chloride (9.2 ml, 118 mmoles) was then added dropwise with stirring over 15 mins. The mixture was stirred for a further 1 hr then washed wid saturated aqueous sodium bicarbonate (2 x 500 ml), dried (Na2, SO4) and evaporated to dryness to give the tide compound (19.6g, 88%).

NMR (CDCI3) δ : 2.98 (3H, s), 3.45 (2H, d, J 8), 4.60 (2H, d, J 8), 7.45 (IH, d, J 6), 7.63 (IH, d, J 6), 7.89 (IH, s), 8.51 (IH, s)

Description 13 6,7-Dihydro-5H-thieno[2 -f]indole (D13)

The methanesulphonate (D12) (24.0g, 80 mmoles) was hydrogenated at atmospheric pressure and at 50° C for 3 hrs in ethyl acetate (600 ml) with triethylamine (40 ml) over a 10% palladium on charcoal catalyst. The catalyst was then filtered off and d e filtrate washed wid saturated aqueous sodium bicarbonate, dried (Na2SO4) and evaporated to dryness to give the tide compound as an off-white solid (12.7g, 91%)

NMR (CDCI3) δ : 3.12 (2H, t, J 8), 3.40-3.60 (IH, br s), 3.65 (2H, t, J 8), 7.01 (IH, s), 7.11 (IH, d, J 6), 7.25 (IH, d, J 6), 7.53 (IH, s)

Example 1 73-Dihydro-6-(3-pyridylcarbamoyl)-thieno[3,2-e]-indole (El)

A solution of nicotinic acid azide (0.16 g, 1.1 mmol) in toluene (7 ml) was heated under reflux for 1.5 h. The solution was cooled and tiiienoindole (D5) (0.18g, 1.03 mmol) was added in dichloromethane (7 ml) containing a litde dimethylformamide. The mixture was stirred at room temperature for 2.5 h. The mixture was then washed widi water, and die aqueous phase was extracted with dichloromethane/methanol. The toluene phase and d e dichloromethane extract were combined, dried and evaporated. The residue was recrystallised from emanol water to give the tide compound (0.18 g, 59%) m.p. 192-197° C.

Found: C, 64.97; H, 4.63; N, 14.05% C₁₆H₁₃N3OS requires: C, 65.06; H, 4.44; N, 14.23%

NMR(D6"^DMSO)δ: 3.45(2H, t, J=8), 4.30 (2H, t, J=8), 7.33 (IH, d, J=6), 7.36 (IH, d,

J=6), 7.78 (IH, d, J=6), 7.80 (IH, d, J=6), 8.01 (IH, m, J=7), 8.07 (IH, d, J=7), 8.24 (IH, d, J=4), 8.74 (IH, s), 8.78 (IH, s)

Example 2

6,7-Dihydro-5-(3-pyridylcarbamoyl)-5H-thieno[2 -f]indole (E2)

Nicotinyl azide (0.06g, 0.4 mmol) in toluene (3ml) was heated under reflux for 1 h, dien cooled. 6,7-Dihydro-5H-thieno[2,3-fjindole (0.07g, 0.4 mmol) in dichloro- methane was added and die mixture was stirred for 1 h at room temperature. A litde petrol was added and die solid product was filtered off, washed widi petrol and dried in vacua to give the tide compound (0.085g, 72%), m.p. 183-185° C.

Found: C, 64.94; H, 4.73; N, 14.26 %

Ci6H₁₃N3OS requires C, 65.06; H, 4.44; N, 14.23%

NMR (D₆-DMSO) d: 3.28 (2H, t, J=9), 4.22 (2H, t, J=9), 7.34 (IH, m), 7.37 (IH, d,

J=5), 7.63 (IH, d, J=5), 7.77 (IH, s), 8.01 (IH, d, J=8), 8.23 (IH, d, J=5), 8.33 (IH, s), 8.75 (2H, m).

Example 3 7,8-Dihydro-6-(5-quinolylcarbamoyI)-6H-thieno[3,2-e]indole (E3)

5-Aminoquinoline (0.27g, 1.9 mmol) and 1,1 '-carbonyldiimidazole (0.3 lg, 1.9 mmol) were stirred at reflux under Ar in dry dichloromethane (10 ml) for 2.5h. The mixture was evaporated to dryness, and die residue was dissolved in dry DMF (10 ml). 7,8-Dihydro- 6H-thieno[3,2-e]indole (D5) (0.30g, 1.7 mmol) was added, and this mixture was stirred at 115° C for lh, when it was poured into water (200 ml). The precipitate was filtered off and dried in vacua. Chromatography on silica gel, eluting with 0-1% methanol/ethyl acetate, gave the tide compound (0.3 lg, 52%) as a greenish-grey powder, m.p. 243-4° C. NMR (DMSOd6) (δ ): 3.49 (2H, t, J 8), 4.44 (2H, t, J 8), 7.36 (IH, d, J 5), 7.53 (IH, dd, J 8, 4), 7.64 (IH, d, J 7), 7.7-7.85 (3H, m), 7.92 (IH, d, J 8), 8.03 (IH, d, J 9), 8.48 (IH, d, J 8), 8.85 (IH, s), 8.92 (IH, m)

Found: C, 66.7; H, 4.4; N, 11.7%

C20H15N3OS 0.75H2O requires C, 66.9; H, 4.6; N, 11.7%

Example 4

7^-Dihydro-6-(3-Methyl-5-isothiazolylcarbamoyl)-6H-thieno[3,2-e]indole (E4)

This was prepared from 5-amino-3-methylisothiazole hydrochloride (0.26g, 1.7mmol) and 7,8-dihydro-6H-thieno[3,2-e]indole (D5), following the procedure of Example 3, but including 1 equivalent of triethylamine in the initial step. Recrystallisation from methanol/dichloromed ane gave the desired material.

NMR (DMSOd6) (δ ): 2.30 (3H, s), 3.47 (2H, t, J 8), 4.26 (2H, t, J 8), 6.77 (IH, s), 7.36 (IH, d, J 6), 7.8 (2H, m), 8.06 (IH, d, J 8), 10.55 (IH, b s).

Found: C, 57.1; H, 4.3; N, 13.4%. C₁₅H₁₃NOS₂ requires C, 57.1; H, 4.2; N, 13.3%

Example 5

6,7-Dihydro-5-(5-Bromo-3-pyridylcarbamoyl)-5H-thieno[2 -f]indole (E5)

This was prepared from 6,7-dihydro-5H-dιieno[2,3-fjindole (D ) (0.28g, 1.6 mmol) and 5-bromonicotinoyl azide (0.38g, 1.7 mmol), following the procedure of Example 2. Recrystallisation of the crude product from ethanoVpetroleum ether (b.p. 60-80°C) gave the tide compound (0.16g, 34%) as an off-white solid, m.p. 203-5° C decomp.

NMR (DMSOdg) (δ ): 3.34 (2H, t, J 8), 4.23 (2H, t, J 8), 7.39 (IH, d, J 4), 7.65 (IH, d, J 4), 7.80 (IH, s), 8.35 (3H, m), 8.78 (IH, d, J 2), 8.97 (IH, s)

Found: C, 51.2; H, 3.4; N, 11.0%. C₁₆H₁₂BrN₃OS requires: C, 51.4; H, 3.2; N, 11.2%

Example 6 7,8-Dihydro-6-(2-methyl-4-quinolylcarbamoyI)-6H-thieno[3,2-e]indole (E6)

To an ice-cooled solution of l,l'-carbonyl diimidazole (0.47g, 2.86 mmol) in dry dichloromethane (15 ml) was added 4-aminoquinaldine (0.4 lg, 2.6 mmol) in dichloromethane (30 ml). The mixture was stirred for 1.75 h while warming from 0°C to room temperature. Solvent was then evaporated and replaced by dry DMF (10 ml). A solution of 7,8-dihydro-6H-thieno[3,2-e]indole (D5, 0.45g, 2.57 mmol) in dry DMF (10 ml) was added, and die mixture was stirred for 1.25h at 100-120° C. The mixture was then cooled and poured into water. The solid product was filtered off, washed with water and dried, tiien recrystallised twice from dichloromethane/petrol to give the tide compound (0.35g, 38%), m.p. 229-231° C.

NMR (DMSOds) (δ ): 2.65 (3H, s), 3.49 (2H, t, J 8), 4.50 (2H, t, J 8), 7.38 (IH, d, J 6), 7.54 (IH, t, J 7), 7.72 (IH, t, J 7), 7.80 (3H, m), 7.92 (IH, d, J 7), 8.07 (IH, d, J 7), 8.18 (IH, d, J 7), 8.87 (IH, s)

Found: C, 70.04; H, 5.02; N, 11.66% C2iH₁₇N₃OS requires C, 70.17; H, 4.77; N, 11.69%

Example 7 6,7-Dihydro-5-(2-m€thyl-4-quinolylcarbamoyl)-5H-thieno[2 -πindole (E7)

The tide compound was prepared by die metiiod of Example 3 from 2-methyl-4- aminoquinoline (0.46g, 29 mmoles) and 6,7-dihydro-5H-tiιieno [2,3-f] indole (D13) (0.5g, 29 mmoles). Recrystallisation from methanol/dichloromethane gave the tide compound as white crystals (0.5 lg, 49%) m.p. 237-8° C.

NMR (DMSO-d ) δ : 2.60 (3H, s), 3.30 (2H, t, J 8), 4.40 (2H, t, J 8), 7.35 (IH, d, J 6), 7.45-7.55 (IH, m), 7.60-7.95 (5H, m), 8.10-8.21 (IH, m), 8.35 (IH, s), 8.30-8.45 (IH, brs).

Found: C, 69.87; H, 4.89; N, 11.70% C2iH₁₇N₃OS requires: C, 70.17; H, 4.77; N, 11.69% Found M⁺, C21H17N3OS requires 359

Example 8 6,7-Dihydro-5-(4-pyridylcarbamoyI)-5H-thieno[23-f]indole (E8)

The tide compound was prepared by d e metiiod of Example 3 from 4-aminopyridine (0.27 g, 29 mmoles) and 6,7-dihydro-5H-thieno[2,3-f]indole (0.5g, 29 mmoles). Recrystallisation from methanol/dichloromethane gave d e tide compound as light green crystals (0.45g, 53%) m.p. >240° C.

NMR (DMSO-d6) δ : 3.30 (2H, t, J 8), 4.22 (2H, t, J 8), 7.39 (IH, d, J 6), 7.59-7.68 (3H, m), 7.80 (IH, s), 8.30-8.44 (3H, m), 8.95 (IH, s).

Found: C, 63.91; H, 4.63; N, 14.10% requires: C, 63.79; H, 4.54; N, 13.95% Found M+ 295, Ci6H₁₃N OS requires 295

Pharmacological Data

Reversal of MCPP-induced Hypolocomotion

Administration of m-(chlorophenyl)piperazine (mCPP) to rats induces hypolocomotion (Kennett and Curzon 1988, Luckie et al. 1989) as seen with die related drug l-(m- trifluoromethylphenyl)piperazine (TFMPP) (Lucki and Frazer 1982, Kennett and Curzon 1988). This effect was blocked by die non specific 5-HT2C 5-HT2A receptor antagonists mianserin, cyproheptadine and metergoline and perhaps by mesulergine. It was not blocked by die 5-HT2A receptor antagonists ketanserin and ritanserin at relevant doses (Kennett and Curzon 1991) nor by antagonists of 5-HTIA_> 5-HTJB, 5-HT3, α2 adrenoceptors or dopamine D2 receptors. The effect of mCPP is therefore considered to be mediated by 5-HT2C receptors (Kennett and Curzon 1988) as confirmed by subsequent studies (Lucki et al., 1989). Since mCPP causes hypolocomotion when infused into the cerebral ventricles this effect is probably centrally mediated (Kennett and Curzon 1988).

mCPP-induced hypolocomotion was measured in automated locomotion cages of dimensions 56 cm long x 16Vi cm wide x 25 cm high and made of black perspex. Two photobeams traversed die widtii of the cages at either end at ground level. Sequential breaking of these beams allowed d e measurement of cage transits.

Male Sprague Dawley rats (200-250g) (Charles River) were housed in groups of six. They were given drugs orally lh pretest and 40 mins later mCPP (7 mg/kg i.p.). After a further 20 min they were placed in individual automated cages in groups of four under red light in an adjacent room. After 10 min the test was terminated. Reversal of mCPP-induced hypolocomotion was considered as evidence of in vivo central 5-HT2C receptor antagonist properties.

Kennett, G.A., Curzon, G., (1988). Brit. J. Pharmacol. 94, 137-147. Kennet G.A., Curzon, G., (1991). BritJ. Pharmacol. 103, 2016-2020. Lucki, I., Frazer, A., (1982) Am. Soc. Neurosci. 8(abstr.), 101. Lucki, I., Ward, M.R., Frazer, A., (1989). J.Pharmacol. Exp. Therap. 249, 155-164.

The compounds of examples 1, 2 and 5 had ID50 values of 1.4 to 9.6 mg/kg p.o. [3H]-mesulergine binding to rat or human 5-HT2C clones expressed in 293 cells in vitro

Evidence from the literature suggests that 5-HT2C antagonists may have a number of merapeutic indications including die treatment of anxiety, migraine, depression, feeding disorders and obsessive compulsion disorders. (Curzon and Kennett, 1990; Fozard and Gray, 1989) and Alzheimer's Disease (Lawlor, 1989, J. Arch. Gen. Psychiat. Vol. 46 p.542).

The affinity of test drugs for the 5-HT2C binding site can be determined by assessing their ability to displace [^HJ-mesulergine from 5-HT2C clones expressed in 293 cells (Julius et al., 1988). The method employed was similar to that of Pazos et al, 1984.

The cells suspension (50ml) was incubated widi [^HJ-mesulergine (0.5nM) in Tris HCl buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the presence of mianserin (10""M). Ten concentrations of test drug (3 x 10^~9 to 10^" M final concentration) were added in a volume of 50ml. The total assay volume was 500ml. Incubation was stopped by rapid filtration using a Brandel cell harvester and radioactivity measured by scintillation counting. The IC50 values were determined using a four parameter logistic program (DeLean 1978) and die pKj (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where:

i = IC50

1+ C

Kd

Kj = inhibition constant.

C = concentration of [^Hj-mesulergine

Kd = Affinity of mesulergine for 5-HT2C binding sites.

Curzon, G.A. and Kennett, G.A. (1990). TIPS, Vol. 11, 181-182. Fozard, J.R. and Gray, J.A. (1989). TIPS, Vol. 10, 307-309. Pazos, A. et al. (1984). Eur. J. Pharmacol., 106, 531-538. Julius et al. (1988) Science 241, 558-564

DeLean A, Munson P.J., Rodbaud D (1978) Am. J. Physiol 235, E97-E102.

The compounds of examples 1 to 8 had pKj values from 5 1 to 8-4.

Geller-Seifter Procedure

Potential anxiolytic properties are evaluated using the Geller-Seifter procedure based on that originally described by Geller and Seifter, (1960) Psychopharmacologia, 1, 482-492. This procedure has been shown to be selective for drugs with anxiolytic properties (Cook and Sepinwall, (1975) "Mechanism of Action of Benzodiazepines" ed. Costa, E. and Greengard, P., Raven Press, New York, pp. 1-28).

Rats are trained on a variable interval 30 sec schedule (VI30) to press a lever in order to obtain food reward. The 5 min sessions of the VI30 schedule alternate with 2-5 min of a schedule (FR5) in which every 5th lever press is followed by presentation of a food pellet paired wid a 0.5 sec mild footshock. The total study lasts approximately 30 mins. Rats typically respond widi high rates of lever pressing under die VB0 schedule and low response rates under die FR5 'conflict' session. Anxiolytic drugs increase the suppressed response rates of rats in a 'conflict' session.

Drugs are administered intraperitoneally or orally to groups of 3-8 rats 30 min before testing. The results arc expressed as die percentage increase in the square root of the total number of lever presses in the FR5 'conflict' session. Square root transformation is necessary to normalise the data for statistical analysis using parametric methods.

The compounds of Examples 1 and 2 showed a significant increase in responding in the 'conflict' session at dose levels in the range 1 to 2 mg kg p.o.

Rat Fundus: 5-HT2B Receptors

The 5-HT receptor in the rat fundic strip (RFS) has been characterised as 5-HT2B- Hence this tissue may be used to assess the 5-HT2B antagonist properties of compounds.

Whole stomachs were obtained from male CD Rats (Charles River, 250-350g). Strips of fundus (2cm x 0.5 cm) were cut from the greater curvature and d e mucosae carefully removed. Tissues were tiien further dissected into smaller strips (2mm x 20mm) which were mounted in organ baths containing oxygenated Tyrodes solution at 37° C containing indomed acin (3 μM). Preparations were maintained under a resting tension of 0.5g and exposed to die irreversible MAO inhibitor pargyline (100 μM for 30 minutes followed by washout). Over a lh equilibration period, rat f indic strips were challenged widi 1 x 10"^ M 5-HT at 15 minute intervals until cumulative concentration-effect curve to the standard agonist 5-HT (1 x 10"^ upwards) was constructed to determine die individual sensitivity of each preparation. A further concentration-effect curve to either 5-HT, or other agonists was constructed no sooner than lh after completion of die previous curve. When necessary tissues were equilibrated widi die antagonists over this one hour period. Antagonists affinities arc expressed as pA2 estimates.

The compound of Example 2 has a pA2 value of 7.97.

Claims

Claims:

1. A compound of formula (I) or a salt thereof:

wherein:

Rj is hydrogen, Cj.g alkyl, halogen, OR7 or NR R9 where R7, Rg and R9 are independendy hydrogen or C\. alkyl;

R2 is hydrogen or Cj.6 alkyl;

R3 is hydrogen, C . alkyl, C\. alkoxy, or halogen;

R4 is hydrogen or Cj.g alkyl;

R5 and Rg are each independendy hydrogen or C g alkyl; and n is 2 or 3.

2. A compound according to claim 1 in which R\ is hydrogen, Cj.galkyl or halogen.

3. A compound according to claim 1 or 2 in which R2 and R3 are hydrogen.

4. A compound according to any one of claims 1 to 3 in which R5 and Rg are both hydrogen and n is 2.

5. A compound according to any one of claims 1 to 4 in which P is pyridyl, quinolyl or isothiazolyl.

6. A compound according to claim 1 which is: 7,8-Dihydro-6-(3-pyridylcarbamoyl)-thieno[3,2-e]-indole,

6,7-Dihydro-5-(3-pyridylcarbamoyl)-5H-thieno[2,3-f]indole,

7,8-Dihydro-6-(5-quinolylcarbamoyl)-6Η-thieno[3,2-e]indole,

7,8-Dihydro-6-(3-Methyl-5-isothiazolylcarbamoyl)-6H-thieno[3,2-e]indole,

6,7-Dihydro-5-(5-Bromo-3-pyridylcarbamoyl)-5H-thieno[2,3-f]indole,

7,8-Dihydro-6-(2-medιyl-4-quinolylcarbamoyl)-6H-thieno[3,2-e]indole,

6,7-Dihydro-5-(2-methyl-4-quinolylcarbamoyl)-5H-thieno[2,3-fJindole,

6,7-Dihydro-5-(4-pyridylcarbamoyl)-5H-thieno[2,3-f]indole, and pharmaceutically acceptable salts thereof.

7. A compound according to any one of claims 1 to 6 for use in therapy.

8. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or excipient.

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

(a) the coupling of a compound of formula (II);

Rf A (10

with a compound of formula (III);

wherein A and B contain the appropriate functional group(s) necessary to form the moiety -NR2'CO when coupled, wherein R2¹ is R2 as defined in formula (I) or a group convertible tiiereto, and die variables Rj', R3', R4', R5' and Rg' are R\, R3, R4, R5 and Rg, respectively, as defined in formula (I), or groups convertible tiiereto, and tiiereafter optionally and as necessary in any appropriate order, converting any Rj', R^, R3', R4', R5' and Rg' when otiier than Rj, R2, R3, R4, R5 and Rg to R , R2, R3, R4, R5 and Rg, interconverting Rj, R2, R3, R4, R5 and Rg, and forming a pharmaceutically acceptable salt, or

(b) cyclising a compound of formula (IV):

wherein R\ R ', R3', R5', and Rg' are as defined in formulae (II) and (HI) and C and D contain the appropriate functional group(s) necessary to form the thiophene ring substituted by R3' and R4' as defined in formula (UI), and diereafter optionally and as necessary in any appropriate order, converting any R R2', R3¹, R4', Rs' and Rg' when odier than Rj, R2, R3, R4, R5 and Rg to Rj, R2, R3, R4, R5 and Rg, interconverting R\, R2- R3, R4, R5 and Rg, and forming a pharmaceutically acceptable salt.