WO1995029177A1

WO1995029177A1 - Tricyclic derivatives as 5ht2c and 5ht2b antagonists

Info

Publication number: WO1995029177A1
Application number: PCT/EP1995/000901
Authority: WO
Inventors: Francis David King; Peter Ham; Ian Thomson Forbes; Graham Elgin Jones
Original assignee: Smithkline Beecham P.L.C.
Priority date: 1994-04-23
Filing date: 1995-03-09
Publication date: 1995-11-02
Also published as: EP0757687A1; JPH09512025A

Abstract

Compounds of formula (I), processes for their preparation and their use as CNS agents are disclosed. In said formula P represents phenyl, 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; J represents a bicyclic aromatic or partially saturated ring system; R?1 and R2¿ are independently hydrogen, halogen, hydroxy, oxygen or C¿1-6?alkyl optionally substituted by one or more halogen atoms; R?4¿ is hydrogen, C¿1-6?alkyl, C1-6alkylthio, halogen, nitro, cyano, CF3, NR?8R9, CO¿2R?12, CONR12 or OR12¿, where R?8, R9 and R12¿ are independently hydrogen, C¿1-6?alkyl or arylC1-6alkyl; R?5¿ is hydrogen or C¿1-6?alkyl; n is 2 or 3; and the groups R?13 and R14¿ are independently hydrogen or C¿1-6?alkyl, provided that: P is not a heterocyclic group when J forms a benzothiophene ring.

Description

TRICYCLIC DERIVATIVES AS 5HT2C AND 5HT2B ANTAGONISTS

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

WO 94/04533 (SmithKline Beecham pic) describes indole and indoline derivatives which are described as possessing 5HT2C receptor antagonist activity. A structurally distinct class of compounds has now been discovered, which have been found to have 5HT2C receptor antagonist activity. Some or all of the compounds of the . invention also exhibit 5HT2B antagonist activity. 5HT2C/2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and 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.

Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.

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

wherein: P represents phenyl, 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;

J represents a bicyclic aromatic or partially saturated aromatic ring system;

R! and R² are independently hydrogen, halogen, hydroxy, oxygen, or C\. alkyl optionally substituted by one or more halogen atoms;

R is hydrogen, Ci _g alkyl, C\ _ alkylthio, halogen, nitro, cyano, CF3, NR8R9, ( ^R* ,

CONR¹² or OR¹², where R^, R9 and R¹² are independently hydrogen, C\. alkyl or arylCι_6alkyl; R5 is hydrogen or Ci _g alkyl; n is 2 or 3; and the groups R^ and R*⁴ are independendy hydrogen or Ci.g alkyl, provided that: P is not a heterocyclic group when J forms a benzothiophene ring.

< . alkyl groups, whether alone or as part of another group, can be straight chain or branched and are preferably C1.3 alkyl, such as methyl, ethyl, n- and iso- propyl. SuitablyRl and R² are independently hydrogen, halogen, hydroxy, oxygen, or

Ci .g alkyl optionally substituted by one or more halogen atoms. Preferably R and R² are both hydrogen.

Suitably R⁴ is hydrogen, C\. alkyl, C_j.g alkylthio, halogen, CF3, NR^R9 ₀r

OR*², where R^, R9 and R*² are independently hydrogen, C1.5 alkyl or arylCi .^alkyl.

Preferably R⁴ is hydrogen.

Suitably R^ is hydrogen or Cj.g alkyl. Preferably R^ is hydrogen. Suitably P represents phenyl, 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. Suitable moieties when the ring P is a 5-membered aromatic heterocyclic ring include, for example, isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl.

Suitable moieties when the ring P is a 6-membered aromatic heterocyclic ring include, for example, pyridyl, pyrimidyl or pyrazinyl. 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 a 6-membered heterocyclic ring, most preferably a 3-pyridyl group.

The urea moiety can be attached to a carbon or any available nitrogen atom of the ring P, preferably it is attached to a carbon atom. Suitably J represents a bicyclic aromatic or partially saturated ring system.

Preferably J represents a quinoline, tetrahydroquinoline, indazole, benzothiophene, dihydrobenzothiophene, indene, indane, benzothiazole, benzofuran or dihydrobenzofuran ring. Preferably J is quinoline, tetrahydroquinoline, benzothiophene, benzofuran or indane. Suitably the group -(CR13 14)_Π_ f_orms an ethylene or propylene group each of which can be substituted by C^galkyl. When J is quinoline or tetrahydroquinoline the group -(CRl3Rl )_n_ can be attached to the 5- or 7-positions of the ring J, with the urea linkage attached to the 6-position. When J is quinoline the group -(CR13R14)_Π_ _can i_so be attached to the 2- or 4-positions of the ring J, with the urea linkage attached to the 3-position. When J is a 6,5 ring system, for example a benzofuran ring, the group -(CRl3Rl4)_n_ _Can be attached to the 4- or 6-positions, with the urea linkage attached to the 5-position, or -(CR^ι:3R¹⁴)_n- can be attached to the 5- or 7-positions, with the urea linkage attached to the 6-position. Preferably the group -(CR^Rl4)_n_ j_s ethylene. Particularly preferred compounds of formula (I) include: l-(3-Pyridylcarbamoyl)-2,3-dihydro-lH-pyrrolo [2,3-g] quinoline, 2-Methyl-6,7-dihydro-5-(3-pyridylcarbamoyl)-furo[2,3-f]indole, l-(3-Pyridylcarbamoyl)-2,3-dihydropyrrolo-[2,3-f]-indene, 2,3-Dihydro- 1 -(3-pyridylcarbamoyl)-pyrrolo[3,2-b]quinoline, 5,6-Dihydro-3-methyl-N-(3-pyridyl)-furo[3,2-f]indole-7-carboxamide, 2,2-Dimethyl-2,3,6,7-tetrahydro-N-(3-pyridyl)furo[2,3-f]indole-5-carboxamide, 2,3,6,7-Tetrahydro-5-(3-pyridylcarbamoyl)-5H-thienq[2,3-f]indole, 5-Methyl-N-(3-pyridyl)-2,3,5,6,7,8-hexahydro-lH-pyrrolo[2,3-g]quinoline-l-carboxamide, 2,3-Dihydro-7-hydroxy-l-(3-pyridylcarbamoyl)pyrrolo-[2,3-f]indane, 2,3-Dihydro-7-oxo-l-(3-pyridylcarbamoyl)pyrrolo-[2,3-f] indane, 2-Bromo-5,6-dihydro-N-(3-pyridyl)-thieno-[3,2-f]indole-7-carboxamide, 5,6-Dihydro-N-(3-pyridyl)-thieno[3,2-f]-indole-7-carboxamide, or a pharmaceutically acceptable salt 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.

Certain compounds of formula (I) may also form N-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), for example those where P is pyridyl and R⁴ is hydroxy or NR^R9 and at least one of R^ and R^ are hydrogen, may exist tautomerically in more than one form. The invention extends to these and any other tautomeric forms and mixtures thereof.

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 stereospecif c or asymmetric synthesis.

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 the coupling of a compound of formula (II);

(ID with a compound of formula (HI);

^■B H

(CR R )_n

R (III)

wherein A and R" contain the appropriate functional group(s) necessary to form the moiety, -NR^ CO when coupled, wherein R^' is R^ as defined in formula (I) or a group convertible thereto, n, J and P as defined in formula (I), and the variables R , R² , R⁴ R¹³ and R¹⁴' are R¹, R², R⁴, R¹³ and R¹⁴ respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R*', R²', R⁴', R^', R ³' nd R14' _an(j _{wnen otner man} R¹, R², R⁴, R5, Rl3 and R1⁴ respectively to R¹, R², R⁴, R⁵, R¹³ and R¹⁴, interconverting Rl, R², R⁴, R^, R1 and R*⁴, and forming a pharmaceutically acceptable salt thereof.

Suitable examples of groups A and R^ include:

(i) A is -N=C=O and R⁶ is -H,

(ii) A is -NR5'C0L and R⁶ is -H,

(iii) A is -NHR⁵' and R⁶ is COL, or

(iv) A is halogen and R⁶ is -CONHR⁵', wherein R^' 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 R > is H the reaction is suitably carried out in an inert solvent for example dichloromethane or toluene at ambient temperature.

When A is -NR⁵'COL and R⁶ is H or when A is -NHR⁵' and R⁶ 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 R^ is CONHR^', the reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of a base. Suitable examples of groups R⁴' which are convertible to R⁴ alkyl groups 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 R⁴ is hydroxy it is preferably protected in the compound of formula (II) as, for example, benzyl which is removed by hydrogenation.

Suitable examples of a group R^' which is convertible to R^ include alkoxycarbonyl and benzyl or para-methoxybenzyl which are converted to R^ is hydrogen using conventional conditions. R⁴ halo and R /R² halo groups may be introduced by selective halogenation of the rings P or J respectively using conventional conditions.

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.

Compounds of formula (II) in which A is NR^ CQL can be prepared from the corresponding amine where A is NR^ H by treatment with a phosgene equivalent, for example phenyl chloroformate. Compounds of formula (II) in which A is halogen and R⁴' is hydrogen are commercially available.

Compounds of formula (III) may be prepared using methods analogous to those well known in the art, for example as disclosed in WO 94/04533. Novel intermediates of formulae (III) 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 5HT2C receptor antagonist activity, and certain compounds show 5HT2B antagonist activity. Compounds of formula (I) are therefore believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and 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. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS. 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 prophylaxis of the above disorders.

The invention further provides a method of treatment or prophylaxis of the above disorders, 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 the above disorders. 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 70.0 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; and such therapy may extend for a number of weeks or months.

When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.

The following Examples illustrate the preparation of pharmacologically active compounds of the invention.

Description 1 6-Nitro-l-trifluoroacetyIindoline (Dl)

6-Nitroindoline (6.50g, 40 mmol) and triethylamine (6.6 ml, 47 mmol) were stirred in i dichloromethane (65 ml) as trifluoroacetic anhydride (6.6 ml, 47 mmol) was added dropwise. This mixture was stirred for 0.75h, and water (100 ml) was added. After stirring for 10 min, the mixture was acidified with 5M HC1, and separated. The organic portion was washed with brine, dried (Na2SO4) and evaporated to give the title compound (9.64g, 93%) as a yellow-brown solid.

NMR (CDCI3) 6 : 3.4 (2H, t, J 8), 4.4 (2H, t, J 8), 7.4 (IH, d, J 8), 8.1 (IH, dd, J 8, 2), 9.05 (lH, d, J 2).

Description 2 6-Amino-l-trifluoroacetylindoline (D2)

6-Nitro-l-trifluoroacetylindoline (Dl) (4.10g, 16 mmol) was hydrogenated over 5% palladium on charcoal (60% aqueous paste, l.Og) in ethanol (200 ml) for 4 h. The catalyst was filtered off, and the filtrate was evaporated to give the title compound (3.60g, 99%) as a light brown solid.

NMR (CDCI3) δ : 3.15 (2H, t, J 8), 3.35 (2H, b), 4.25 (2H, t, J 8), 6.5 (IH, dd, J 8, 2), 7.0 (IH, d, J 8), 7.65 (IH, d, J 2).

Description 3

6-Hydroxy-l-trifluoroacetylindoline (D3)

6-Amino-l-trifluoroacetylindoline (D2) (2.98g, 13 mmol) was stirred in water (30 ml) as c H2SO4 (3 ml) was added dropwise. The solution was cooled to 0° C, and NaNO2 (0.98g, 14 mmol) in water (10 ml) was added dropwise, maintaining the temperature < 0° C. The mixture was stirred for 5 min, and then transferred to a boiling solution of CUSO4.5H2O (13.0g, 52 mmol) in water (50 ml). The mixture was boiled for 5 min and cooled, and the black solid was filtered off and air-dried. Chromatography on silica gel, eluting with 0- 5% methanol in chloroform, gave the title compound (l.Olg, 67%) as a dark brown solid.

NMR (DMSO-d₆) δ : 3.1 (2H, t, J 8), 4.25 (2H, t, J 8), 6.6 (IH, dd, J 8, 2), 7.1 (IH, d, J 8), 7.6 (IH, d, 2), 9.05 (IH, s). Description 4 6-(2-Oxopropoxy)-l-trifluoroacetyIindoIine (D4)

6-Hydroxy-l-trifluoroacetylindoline (D3) (2.00g, 8.7 mmol), anhydrous K2CO3 (1.79g, 13.0 mmol) and chloroacetone (0.84 ml, 10.4 mmol) were stirred in dry DMF (20 ml) for 64 h. The mixture was diluted with ethyl acetate (200 ml), washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (2.42g, 97%) as a brown oil.

Purification of a small portion by chromatography on silica gel, eluting with 0-10% ethyl acetate in chloroform, gave the compound as an off-white solid.

NMR (CDCI3) δ : 2.3 (3H, s), 3.2 (2H, t, J 8), 4.3 (2H, t, J 8), 4.6 (2H, s), 6.75 (IH, dd, J 8, 2), 7.15 (lh, d, J 8), 7.85 (IH, d, J 2).

Description 5 5,6-Dihydro-3-methyl-7-trifluoroacetylfuro[3,2-fjindole (D5)

c. H2SO4 (25 ml) was added at 0° C to 6-(2-oxopropoxy)-l-trifluoroacetylindoline (D4) (2.42g, 8.4 mmol). The dark mixture was then stirred at ambient temperature for 15 min, and poured onto ice. The crude product was extracted into ethyl acetate, and the extract was washed with water and brine, dried (Na2SO4) and evaporated to a brown gum.

Chromatography on silica gel, eluting with chloroform, gave the title compound (0.47g,

21%) as a yellow solid.

NMR (CDCI3) δ : 2.25 (3H, s), 3.35 (2H, t, J 8), 4.35 (2H, t, J 8), 7.35 (IH, s), 7.45 (IH, s), 8.35 (IH, s).

Description 6 5,6-Dihydro-3-methyIfuro[3,2-f]indoIe (D6)

5,6-Dihydro-3-methyl-7-trifluoroacetylfuro[3,2-f]indole (D5) (0.49g, 1.8 mmol) was stirred in ethanol (10 ml) as 2.5M sodium hydroxide (1 ml) was added. The mixture was stirred for 15 min, diluted with water, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4) and evaporated to give the title compound (0.29g, 96%) as a brown oil. NMR (CDCI3) δ : 2.2 (3H, s), 3.1 (2H, t, J 8), 3.3 (IH, v b), 3.6 (2H, t, J 8), 6.7 (IH, s), 7.2 (2H, m).

Description 7 5-BenzyIoxyindoIine (D7)

5-Benzyloxyindole (14.0g, 63 mmol) was stirred in glacial acetic acid at 15°C as sodium cyanoborohydride (11.9g, 189 mmol) was added portionwise over lh. The mixture was stirred for a further lh, poured into water (500 ml) and basified by addition of potassium hydroxide. This mixture was extracted with ethyl acetate, and the extract was dried (Na2SO4) and evaporated to give the title compound (14.09g, 100%) as a cloudy oil.

1H NMR (250MHz, CDCI3) δ: 2.99 (2H, t, J8), 3.0 (IH, b), 3.54 (2H, t, J8), 4.98 (2H, s), 6.55 - 6.7 (2H, m), 6.85 (IH, m), 7.3 - 7.5 (5H, m).

Description 8 5-BenzyIoxy-l-trifluoroacetylindoline (D8)

5-Benzyloxyindoline (Dl, 14.09g, 63 mmol) and triethylamine (10.5ml, 75 mmol) were stirred in dichloromethane (250ml) as trifluoroacetic anhydride (10.5 ml, 75 mmol) was cautiously added. After stirring for lh, water (200ml) was added, and the mixture stirred vigorously for 15min, acidified (5M HC1) and separated. The aqueous portion was extracted with dichloromethane, and the combined organics were washed with brine, dried (Na2SO4) and evaporated to give the title compound (22.5g) as a brown solid.

*H NMR (250MHz, CDCI3) δ: 3.22 (2H, t, J8), 4.29 (2H, t, J8), 5.07 (2H, s), 6.8 - 6.95 (2H, m), 7.3 - 7.5 (5H, m), 8.12 (IH, d, J8)

Description 9 5-Hydroxy-l-trifluoroacetylindoline (D9)

5-Benzyloxy-l-trifluoroacetylindoline (D8, 22.5g, notionally 70 mmol) and 5% palladium on charcoal (60% aqueous paste, 5.0g) were hydrogenated in ethanol (400ml) for 18h. A further portion of catalyst was added, and hydrogenation continued for a further 18h. Catalyst was then filtered off onto kieselguhr, and the filtrate was evaporated to a gummy solid. This was dissolved in ethyl acetate, washed successively with dilute HC1, water, saturated NaHCO3 solution and brine, dried (Na2SO4) and evaporated to give the title compound (14.37g, 88%) as a light yellow solid.

1H NMR (200MHz, CDCi dsDMSO) δ: 2.97 (2H, t, J8), 4.01 (2H, t, J8), 6.4 - 6.6 (2H, m), 7.74 (IH, d, J8), 8.8 (IH, b)

Description 10 5-(2-Methyl-l-propen-3-yloxy)-l-trifIuoroacetyKndoline (D10)

5-Hydroxy- l-trifluoroacetylindoline (D9, 4.56g, 20 mmol), anhydrous potassium carbonate (4.1g, 30 mmol) and methallyl chloride (3.9ml, 40 mmol) were stirred in dry DMF at 60° C for 16 h. Further aliquots of potassium carbonate and methallyl chloride were then added, and reaction continued for a further 24h. The mixture was then partitioned between ethyl acetate and water, and separated. The organic portion was washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (5.00g, 89%) as a brown oil.

*H NMR (250MHz, CDC1₃) δ: 1.73 (3H, s), 3.32 (2H, t, J8), 4.26 (2H, t, J8), 4.43 (2H, s), 5.00 (IH, s), 5.09 (IH, s), 6.8 (2H, m), 8.10 (IH, d, J8).

Description 11

2^-DimethyI-2,3,6,7-tetrahydro-5-trifluoroacetylfuro[2^-fJindoIe (Dll)

5-(2-Methyl-l-propen-3-yloxy)- l-trifluoroacetylindoline (D10, 5.00g, 18 mmol) was stiιτed under Ar at 215°C in N,N-diethylaniline (25ml) for 5.5h. The mixture was then cooled, diluted with ethyl acetate, washed with 5M HCl and brine, dried (Na2SO4) and evaporated to give a brown- gum. Chromatography on silica (O-→l 00% CH2Q2/CHCI3, gradient) gave the title compound (2.1g, 42%) as a light yellow waxy solid.

*H NMR (250MHz, CDCI3) δ: 1.48 (6H, s), 3.00 (2H, s), 3.19 (2H, t, J8), 4.25 (2H, t, J8), 6.63 (IH, s), 8.03 (IH, s).

Description 12 2 -DimethyI-2,3,6,7-tetrahydrofuro[2,3-f]indole (D12)

2,2-Dimethyl-2,3,6,7-tetrahydro-l-trifluoroacetylfuro[2,3-f]indole (Dl 1, 0.26g, 0.91 mmol) was stirred in ethanol (10ml) containing 10% sodium hydroxide solution (1ml) for 2h. The mixture was then partitioned between ethyl acetate and water, and separated. The organic portion was washed with brine, dried (Na2SO4) and evaporated to give the title compound (0.15g, 85%) as a yellow green oil.

1H NMR (250MHz, CDC1₃) δ: 1.46 (6H, s), 2.92 (2H, s), 2.95 (2H, t, J8), 3.4 (IH, b), 3.50 (2H, t, J8), 6.49 (IH, s), 6.56 (IH, s)

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

Trifluoroacetic acid (4ml) was added to a mixture of 6,7-dihydro-5-(3-pyridylcarbamoyl)- 5H-thieno[2,3-f]indole (Reference WO 94/22871) (l.Og) and triethylsilane (1.63ml), with heating at 50°C. After 140h, the cooled mixture was neutralised with aqueous sodium carbonate solution and the aqueous layer extracted with diethyl ether. The organic phase was dried (Na2SO4), and concentrated under reduced pressure. The residue was chromatographed on silica eluting with 1% ethanol and chloroform to afford title compound (340mg).

1H NMR (CDCI3, 250MHz) δ: 2.95 (t, 2H), 3.12 (t, 2H), 3.33 (t, 2H), 3.55 (t, 2H), 6.58 (s, IH), 6.96 (s, IH)

Description 14 2 -Dihydro-lH-pyrrolo[3,2-b]quinoIine (D14)

A solution of ethyl 3-oxopyrrolidine-l-carboxylate (l.Og), 2-amino benzaldehyde (l.Og) and 85% aq sodium hydroxide (2.8ml) in ethanol (20ml) was stirred under an inert atmosphere for 20h. The ethanol was concentrated in vacuo and the residue partitioned between chloroform and water. The aqueous layer was acidified to pH8 and extracted with chloroform. The organic phase was dried (Na2SO4) and concentrated to afford product (950mg).

1H NMR (CDCI3 250MHz) δ: 3.50 (t, 2H), 3.95 (t, 2H), 7.15 (s, IH), 7.51 - 7.60 (m, 2H), 7.71 - 7.78 (m, IH), 8.04 - 8.10 (m, IH) Description 15 6-Trifluoroacetamido-l,2,3,4-tetrahydroquinoIine (D15)

6-Trifluoroacetamidoquinoline (16.5g, 69 mmoles) in methanol (250ml) was treated with nickel chloride hexahydrate (3.3g, 14 mmoles) and sodium borohydride (13.4g, 350 mmoles) -portion wise. After A hrs the mixture was concentrated in vacuo and the residue treated with dilute hydrochloric acid (500ml). Basification followed by extraction with dichloromethane and chromatography on silica gel gave the title compound (D15) (6.5g, 39%)

NMR (CDCI3) δ: 1.85 - 2.02 (2H, m), 2.71 - 2.85 (2H, m), 3.25 - 3.39 (2H, m), 3.80 - 4.02 (IH, brs), 6.45 (IH, d, J=l lHz), 7.03 - 7.12 (IH, m), 7.15 (IH, s), 7.55 - 7.85 (IH, brs).

Description 16 l-Ethoxycarbonyl-6-trifluoroacetamido-l,2,3,4-tetrahydroquinoline (D16)

6-Trifluoroacetamido- 1,2,3,4- tetrahydroquinoline (D15) (5.2g, 21 m moles) was treated with ethyl chloroformate and triethylamine in the usual way to give the title compound (D16) (6.5g, 96%).

NMR (CDCI3) δ: 1.33 (3H, t, J=9Hz), 1.95 (2H, t, J=7H), 2.78 (2H, t, J=7Hz), 3.75 (2H, t, J=7Hz), 4.25 (2H, q, J=7Hz), 7.15 - 7.22 (IH, m), 7.45 (IH, s), 7.75 (IH, d, J=12Hz), 7.80 - 8.00 (IH, brs)

Description 17- 6-Amino-l-ethoxycarbonyI-l,2,3_>4,-tetrahydroquinoline (D17)

Hydrolysis of l-ethoxycarbonyl-6-trifluoroacetamido-l,2,3,4-tetrahydroquinoline (D16) (6.5g, 20 m moles) with 1.2 equivalents of sodium hydroxide in ethanol gives the title compound (D17) (3.6g, 80%)

NMR (CDCI3) δ: 1.30 (3H, t, J=7Hz), 1.83 - 1.99 (2H, m), 2.70 (2H, t, J=7Hz),

3.40 - 3.60 (2H, brs), 3.71 (2H, t, J=7Hz), 4.21 (2H, q, J=7Hz), 6.38 - 6.57 (2H, m), 7.45 (IH, d, J=10Hz) Description 18 6-(2,2-Dimethoxyethyl)amino-l-ethoxycarbonyI-l,2 ,4-tetrahydroquinoline (D18)

6-Amino-l-ethoxycarbonyl-l,2,3,4-tetrahydroquinoline (D17) (3.6g, 16m moles) was > hydrogenated over 10% palladium on charcoal catalyst (0.5g) in the presence of dimethoxy ethanal - 41% solution in methyl-t-butyl ether (6.7g, 27m moles) for 4hrs. The catalyst was then filtered off and the filtrate evaporated to dryness. Chromatography on silica gel eluting with 0-2% methanol/dichloromethane gave the title compound (D18) (4.5g, 90%).

NMR (CDC1 ) δ: 1.30 (3H, t, J=8Hz), 1.83 - 1.99 (2H, m), 2.70 (2H, t, J=7Hz, 3.20 (2H, d, J=7Hz), 3.39 (6H, s), 3.72 (2H, t, J=7Hz), 4.21 (2H, q, J=8Hz), 4.55 (IH, t, J=6Hz), 6.33 - 6.51 (2H, m), 7.42 (IH, d, J=8Hz).

Description 19 5-Ethoxycarbonyl-l-trifluoroacetyl-5,6,7,8-tetrahydro-lH-pyrroIo[2 -g]quinoline (D19)

6(2,2-Dimethoxyethyl)amino-l-ethoxycarbony 1-1, 2,3, 4- tetrahydroquinoline (D18) (4.5g, 15 mmoles) was heated under reflux in a mixture of trifluoroacetic acid (50ml) and trifluroacetic anhydride (20ml) for 60 hrs. The mixture was then evaporated to dryness. Column chromatography on silica gel eluting with 0 - 1% methanol dichloromethane gave the tide compound (D19) (1.65g, 33%)

NMR (CDCI3) δ: 1.32 (3H, t, J=8), 1.92 - 2.12 (2H, m), 2.92 (2H, t, J=7Hz), 3.79 (2H, t, J=7Hz), 4.25 (2H, q, J=8Hz), 6.70 (IH, d, J=5Hz), 7.35-7.42 (IH, m), 7.92 (IH, s), 8.13 (IH, s).

Description 20 5-Ethoxycarbonyl-5,6,7,8-tetrahydro-lH-pyrroIo[2,3-g]quinoline (D20)

5-Ethoxycarbonyl-l-trifluoroacetyl-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-g]quinoline (D19) (1.65g, 5m moles) in methanol (50ml) was treated with potassium carbonate (0.9g, 7 m moles) at ambient temperature for 2hrs. The mixture was evaporated to dryness and the residue partitioned between 2% methanol/dichloromethane and water. The organics were dried (Na2SO4) and evaporated to dryness to give the title compound (D20) (1.05g, 88%). NMR (CDCI3) δ:1.35 (3H, t, J=8Hz), 1.91 - 2.12 (2H, m), 2.81 (2H, t, J=7Hz), 3.80 (2H, t, J=7Hz), 4.25 (2H, q, J=8Hz), 6.45 - 6.50 (IH, m), 7.05 - 7.15 (2H, m), 7.80 (IH, s), 8.01 - 8.15 (IH, brs)

Description 21

5-EthoxycarbonyI-2 ^,6,7,8-hexahydro-lH-pyrroIo[2,3-g]quinoline (D21)

5-Ethoxycarbonyl-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-g]quinoline (D20) (1.05g, 4 mmoles) in glacial acetic acid (25ml) was treated with sodium cyanoborohydride (1.25g, 20m moles) at ambient temperature for Ihr. The mixture was diluted witi water, basified with sodium hydroxide and extracted with dichloromethane. The organics were dried (Na2SO4) and evaporated to dryness. Chromatography on silica gel eluting with 0 - 2% methanol/dichloromethane gave the title compound (D21) (0.84g, 79%).

NMR (CDCI3) δ: 1.32 (3H, t, J=8Hz), 1.85 - 1.98 (2H, m), 2.68 (2H, t, J=7Hz), 2.99 (2H, t, J=9Hz), 3.51 (2H, t, J=9Hz), 3.68 (2H, t, J=7Hz), 4.20 (2H, q, J=8Hz), 6.33 (IH, s), 7.21 (IH, s), 7.30 - 7.42 (IH, brs).

Description 22 5-Methyl-2,3,5,6,7,8-hexahydro- lH-pyrroIo[2,3-g]quinoline (D22)

5-Ethoxycarbonyl-2,3,5,6,7,8-hexahydro-lH-pyrrolo[2,3-g]quinoline (D21) (0.84g, 3 m moles) in dry tetrahydrofuran (50ml) was treated with lithium aluminum hydride (0.27 g, 7 m moles) at ambient temperature for Ihr. The usual work up gave the tide compound (D22) (0.64g, 100%).

NMR (CDCI3) δ: 1.95 - 2.05 (2H, m), 2.71 (2H, t, J=7Hz), 2.80 (3H, s), 2.95 (2H, t, J=9Hz), 3.15 (2H, t, J=7Hz), 3.45 (2H, t, J=9Hz), 6.40 (2H, s), 6.55 (IH, s).

Description 23 l-AcetyI-6-nitroindoline (D23)

To a stirred solution of 6-nitroindoline (25g, 0.15mmol) in dichloromethane (200ml) and pyridine (14.7ml, 0.18mol) at 0°C was added dropwise acetyl chloride (13ml, 0.18mol). The mixture was stiιτed for Ihr at 0°C treated with water (100ml) and stirred for a further ^lAbι. The phases were separated and the organics washed (5N HCl, H2O, brine), dried and concentrated to afford the title compound (31.5g, 100%) as a pale green solid. 1H NMR (250MHz CDCI3) δ: 2.28 (s, 3H), 3.30 (t, 2H), 4.2 (t, 2H), 7.26 (m, IH), 7.89 (m, IH), 8.95 (s, IH).

Description 24 l-Acetyl-6-aminoindoIine (D24)

A suspension of D23 (31g, 150mmol) and 10% Pd/C (2g) in ethanol (700ml) was hydrogentated (50psi, 45°C) for Ihr. The catalyst was filtered and washed (50% CH2Cl2 ^MeOH)- Th filtrate was concentrated to afford the title compound (26.3g, 99%) as brown oil.

1H NMR (250MHz CDCI3) δ: 2.20 (s, 3H), 3.05 (t, 2H), 3.66 (br, 2H), 4.00 (t, 2H), 6.35 (m, IH), 6.92 (m, IH), 7.68 (s, IH)

Description 25 l-Acetyl-6-iodoindoline (D25)

The title compound was prepared from D24 in 76% yield using modified Sandmeyer conditions.

1H NMR (250MHz) δ: 2.20 (s, 3H), 3.14 (t, 2H), 4.04 (t, 2H) 6.90 (d, IH), 7.82 (dd, IH), 8.59 (s, IH).

Description 26

(l-Acetyl-5-indoIinyl)propenoic acid, benzyl ester (D26)

The title compound was prepared from D25 and benzyl acrylate using Heck conditions * in 70% yield.

1H NMR (250MHz CDCI3) δ: 2.22 (s, 3H), 3.20 (t, 2H), 4.10 (t, 2H), 5.24 (s, 2H), 6.39 (d, IH), 7.37 (m, 7H), 7.68 (d, IH), 8.20 (d, IH). ¹ Organic reactions, Vol. 27, pg 345-390. Description 27 (l-Acetyl-5-indolinyl)propionic acid (D27)

The tide compound was prepared from D26 using standard hydrogenation conditions in 92% yield as a white solid.

Description 28 l-Acety!-2,3-dihydro-7-oxo pyrrolo [2,3-f]indane (D28)

A solution of D27 (6.2g, 26.6 mmol) in dichloromethane (100ml) was treated with oxalyl chloride (2.48ml, 29mmol) and dimediylformamide (2ml, dropwise) and stirred for 20 minutes. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane (100ml) and cooled to 0°C. To this solution was added portionwise aluminium chloride (10.6g, 79mmol) and the mixture allowed to warm to room temperature and stirred for 12 hours. The mixture was poured onto ice and 5N HCl (50ml) added. The aqueous was extracted (dichloromethane) and me organics dried and concentrated. Flash chromatography on the residue eluting widi 50% ethyl acetate/60°C-80°C petroleum ether afforded the tide compound (4.1g, 72%) as a white solid.

1H NMR (250MHz CDCI3) δ: 2.24 (s, 3H), 2.70 (m, 2H), 3.07 (m, 2H), 3.25 (t, 2H),4.12 (t, 2H), 7.24 (s, IH), 8.49 (s, IH).

Description 29 AcetyI-2,3-dihydro-7-hydroxy-pyrrolo-[2,3-f]indane (D29)

To a stirred suspension of D28 (2.9g, 13mmol) in ethanol (100ml) was added portionwise sodium borohydride (0.6g, 15mmol) under argon. The suspension was stirred at room temperature for 4 days and the solvent removed in vacuo. The residue was triturated with water. Filtration and drying of the solid afforded the tide compound (2.6g, 92%) as a white solid.

1H NMR (250MHz, CDCI3) δ: 1.9 (m, IH), 2.48 (m, IH), 2.71 (m, IH), 2.95 (m, 3H), 3.52 (t, 2H), 4.82 (br, IH), 5.10 (t, IH), 6.68 (s, IH), 6.99 (s, IH). Description 30 2,3-Dihydro-7-hydroxy-pyrrolo-[2,3-f)-indane (D30)

A suspension of D29 (lg, 4.6mmol) in ethanol (30ml) was treated witii 10% N sodium hydroxide solution (20ml) and sodium hydroxide pellets (l.lg, 27.5mmol). The mixture was refluxed for 12 hours under argon, cooled and partitioned between dichloromethane and water. The organic phase was dried and concentrated to give the title compound (0.29g, 37%) as a yellow solid.

1H NMR (250MHz CDC1₃) δ: 1.9 (m, IH), 2.45 (m, IH), 2.70 (m, IH), 2.94 (m, 3H) 3.53 (t, 2H), 5.11 (t, IH), 6.68 (s, IH), 7.0 (s, IH)

Description 31 l,l'-Diacetyl-(6-indoly])-disulphide (D31)

N-methyl-6-(chlorosulphonyl)indolinel was converted to the title compound in 50% yield using the method of Olah et α/².

References

1. Carlier, P.R., Lockshin, M.P., Filosa, M.P., J. Org. Chem., 1994, 5j>, 3232. 2. Olah, G.A., Navang, S.C., Field, L.A., Salem, G.F., J. Org. Chem., 1980, 45_, 4792.

Description 32 l-Acetyl-6-mercaptoindoline (D32)

A mixture of (l,r-diacetyl-(6-indolyl)-disulphide) (2.76g, 7.2 mmol) triphenyl phosphine (2.8g, 10.8 mmol) and concentrated hydrochloric acid (20 drops) in dioxane/water (100ml/ 10ml) was heated to reflux under argon for 2 h. The mixture was evaporated to dryness, redissolved in ethyl acetate and extracted (2x) with 1% aqueous sodium hydroxide. The aqueous extract was washed with ethyl acetate, tiien acidified with 1M aqueous hydrochloric acid and extracted (2x) with ethyl acetate. Drying (sodium sulphate) and evaporation afforded the product as a white solid (1.36g, 49%).

NMR (CDCI3): 2.20 (3H, s), 3.15 (2H, t, J 8Hz), 3.50 (IH, s), 4.05 (2H, t, J 8Hz), 6.90 (IH, dd, J 6Hz), 7.05 (IH, d, J 6Hz) and 8.15 (IH, d, J 1Hz) Description 33 l-Acetyl-6-(2,2-diethoxyethylthio)-indoline (D33)

A solution of l-acetyl-6-mercaptoindoline (4.25g, 22 mmol) in DMF (30 ml) at 0° C under argon was treated widi sodium hydride (0.7g, 80% dispersion, 0.55g of NaH, 23 mmol) tiien after 0.75h with the bromoacetaldehyde dietiiyl acetal (4ml, 5.1g, 26.4 mmol). The mixture was heated to 50° C for 1 h, then aqueous ammonium chloride (10 ml) was added and the mixture evaporated to dryness. The residue was dissolved in ethyl acetate and washed with dilute brine (3x), brine (lx), then dried (Na2SO4) and evaporated. Chromatography on silica, eluting with a 0-2% methanol in dichloromethane gradient afforded the product as a colourless oil (4.4g, 65%).

Description 34

7-Acetyl-5,6-dihydro-7H-thieno[3,2-f]indole (D34)

A solution of l-acetyl-6-(2,2-died oxyethyldιio)indoline (0.42g, 1.35 mmol) in toluene (8 ml) was treated with a solution of titanium tetrachloride in toluene (1M; 1.6 ml, 1.6 mmol) and heated to 50° C for 10 minutes. The cooled reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic extract was dried (Na2SO4) and evaporated affording a brown oil (0.24g). Chromatography, eluting with 50%, 70%, then 100% etiiyl acetate in 60/80 petroleum ether afforded the title compound as a white solid (100 mg, 33%).

NMR (CDC1₃) δ:2.25 (3H, s), 3.30 (2H, t, J8Hz), 4.10 (2H, t, J8Hz), 7.30 (IH, d, J5Hz), 7.45 (IH, d, J5Hz), 7.60 (IH, s), 8.65 (IH, s).

Description 35 7-Acetyl-2-bromo-5,6-dihydro-7H-thieno[3,2-f]indole (D35)

A solution of the 7-acetyl-5,6-dihydro-7H-thieno[3,2-f]indole (90 mg, 0.41 mmol) in chloroform (6 ml) was treated with a solution of bromine (100 mg, 0.62 mmol) in chloroform (1 ml). After 0.75h the reaction mixture was diluted with chloroform (20 ml), and washed with dilute aqueous sodium sulphite, dien half-saturated brine. Drying (Na2SO4) and evaporation afforded a white solid (130 mg). Chromatography, on silica, eluting with 0-100% ethyl acetate in 60/80 petroleum ether afforded the product as a white crystalline solid (108 mg, 83%). NMR (CDCI3) δ:2.25 (3H, s), 3.25 (2H, q, J 8Hz), 4.10 (2H, q, J 8Hz), 7.15 (IH, s), 7.40 (IH, s), 8.60 (IH, s).

Description 36 2-Bromo-5,6-dihydro-7H-thieno[3,2-flindoIe (D36)

This was prepared from D35 using a similar method to D12 affording die tide compound as a white solid (125mg, 67%).

NMR (CDCI3) δ:3.10 (2H, t, J 8Hz), 3.60 (2H, t, J 8Hz), 3.90 (IH, bs), 6.85 (IH, s), 7.10 (IH, s), 7.45 (IH, s).

Description 37 5,6-Dihydro-7H-thieno[3,2-f]indole (D37)

This was prepared from D34 using a similar method to D12 affording the tide compound as a white solid (40 mg, 60%).

NMR (CDCI3) δ:3.10 (2H, t, J 8Hz), 3.60 (2H, t, J 8Hz), 3.90 (H, bs), 7.05 (IH, s), 7.10 (d, J5Hz), 7.15 (d, J5Hz), 7.50 (IH, s).

Example 1 l-(3-Pyridylcarbamoyl)-2,3-dihydro-lH-pyrrolo [2,3-g] quinoline (El)

A solution of nicotinoyl azide (90 mg, 0.6 mmol) in toluene (4 ml) was heated under reflux for 1.75 h. After cooling, a solution of 2,3-dihydro-lH-pyrrolo [2,3-g] quinoline (O.lg, 0.59 mmol) in dichloromethane was added and the mixture was stirred overnight. The precipitate was filtered off and washed with petrol. Recrystallisation from dichloromethane/petrol gave the title compound (0.09g, 53%), m.p. 215-216° C.

NMR (d₆-DMSO) δ : 3.43 (2H, t, J = 7), 4.27 (2H, t, J = 7), 7.39 (2H, m), 7.80 (IH, s), 8.04 (IH, d, J = 8), 8.23 (IH, d, J = 8), 8.28 (2H, s), 8.69 (IH, m), 8.81 (IH, s), 8.92 (IH, s). Example 2 2-Methyl-6,7-dihydro-5-(3-pyridylcarbamoyI)-furo[2,3-f]indoIe (E2)

This was prepared from 2-methyl-6,7-dihydrofuro[2,3-f]indole (0.18g, 1.0 mmol) and nicotinoyl azide (0.17g, 1.1 mmol), following the procedure of Example 1. The reaction mixture was evaporated to dryness, and chromatographed on silica gel, using 0-4% methanol/chloroform. The product was triturated with toluene and dried in vacuo to give the title compound (0.18g, 59%) as a white powder, m.p. 230-230.5° C.

NMR (DMSO-d₆) δ : 2.4 (3H, s), 3.25 (2H, t, J = 8), 4.2 (2H, t, J = 8), 6.5 (IH, s), 7.3

(2H, m), 8.0 (2H, m), 8.2 (IH, d, J = 4), 8.7 (IH, s), 8.75 (IH, s). m.s. (m/z): Found, M+l = 294. C17H15N3O2 requires M + 1 = 294

Analysis: Found: C, 69.5; H, 5.3; N, 14.3%. 17^H15^N3°2 requires C, 69.6; H, 5.2; N, 14.3%.

Example 3 l-(3-Pyridylcarbamoyl)-2,3-dihydropyrrolo-[2,3-f]-indene (E3)

A solution of 3-pyridylisocyanate (prepared by heating nicotinoyl azide 0.32g, 2.1 mmol) in toluene was added to a stirred solution of 2,3-dihydropyrrolo-[2,3-f]indene (0.3 lg, 1.9 mmol) in dichloromethane. After 24 hr stirring, the solid was filtered and chromatographed to yield die tide compound 0.42g, 80% as a tan powder.

NMR (250 MHz, DMSO) δ = 8.85 (m, IH Ar): 8.77 (s, IH, Ar), 8.31 (d, IH, J = 5, Ar), 8.10 (m, 2H, Ar), 7.38 (m, 2H, Ar), 6.95 (dd, IH, J = 5, alkene), 6.61 (dd, IH, J = 5, alkene), 4.28 (t,- 2H, J = 7, indoline), 3.3 (t, 2H, J = 7.5, indoline) Mpt. = 180° -182° C (dec.)

Example 4 2,3-Dihydro-l-(3-pyridylcarbamoyI)-pyrrolo[3,2-b]quinoline (E4)

A solution of nicotinoyl azide (218 mg) in dry toluene (5 ml) was heated at reflux for 5 min, cooled to r.t. and poured into a solution of 2,3-dihydro-pyrrolo[3,2-b]quinoline (250 mg) in dichloromethane (5 ml). The mixture was cooled for 2h and the product removed by filtration. Column chromatography on silica using chloroform and increasing volumes of ethanol (up to 20%) as eluant and subsequent crystallisation from ethanol-diethyl ether gave the title compound as a beige solid (50 mg). 1H NMR (d₆-DMSO, 270 MHz) δ : 3.44 (t, 2H), 4.28 (t, 2H), 7.38 (dd, IH), 7.41-7.59 (m, 2H), 7.85 (d, 2H), 7.99-8.08 (m, IH), 8.27 (dd, IH), 8.41 (s, IH), 8.81 (d, IH), 8.99 (b s, IH). m.p. 205-208° C M+ (El) 290

Example 5 5,6-Dihydro-3-methyl-N-(3-pyridyl)-furo[3^-f]indoIe-7-carboxamide (E5)

Nicotinoyl azide (0.14g, 0.94 mmol) was stirred at reflux under Ar in dry toluene (5 ml) for 0.75h, and cooled to ambient temperature. This was then filtered dirough cotton wool into a stirred solution of 5,6-dihydro-3-methylfuro[3,2-f]indole (D6) (0.15g, 0.86 mmol) in dichloromethane (5 ml). After stirring for 15 min, the suspension was cooled in ice, and the precipitate was filtered off and dried. This gave the title compound (0.15g, 59%) as a tan powder.

NMR (DMSO-d₆) δ : 2.17 (3H, s), 3.27 (2H, t, J 8), 4.24 (2H, t, J 8), 7.35 (2H, m), 7.62 (IH, d, J 2), 8.01 (2H, m), 8.24 (IH, m), 8.76 (2H, s). M.S. (C.I.) (m/z) [M + H]+ = 294. C₁₇H₁₅N₃O2 requires [M + H]+ = 294

Example 6 2^-Dimethyl-2,3,6,7-tetrahydro-N-(3-pyridyl)furo[2,3-f]indoIe-5-carboxamide (E6)

This material was prepared from 2,2-dimemyl-2,3,6,7-tetrahydrofuro[2,3-f]indole (D12, 0.147g, 0.77mmol), following the procedure of Example 1. This gave the title compound (0.147g, 61%) as a white powder.

1H NMR (250MHz, CDC1₃) δ: 1.48 (6H, s), 2.99 (2H, s), 3.18 (2H, t, J8), 4.11 (2H, t, J8), 6.60 (2H, s), 7.15 - 7.30 (2H, m), 7,76 (IH, s), 8.08 (IH, m), 8.30 (lH,d, J4), 8.50 (lH, d, J2).

Example 7 2^,6,7-Tetrahydro-5-(3-pyridylcarbamoyl)-5H-thieno[2 -f]indoIe (E7)

A solution of nicotinoyl azide (309mg) in toluene (5ml) was heated to reflux for 5 min and cooled to room temperature and poured into a solution of 2,3,6,7-tefrahydro-5H- thieno[2,3-f]indole D13 (340mg) in CR2O2 (20ml). After 2h at 0°C, the product was collected by suction filtration and recrystallised from ethanol/CH2Cl2 to give the title compound as a white powder (280mg). m.p. 185-189°C

H NMR (CDC1₃, 250MHz)δ: 3.16 - 3.30 (4H, m), 3.40 (t, 2H), 4.12 (t, 2H), 6.44 (s,

IH), 7.02 (s, IH), 7.23 - 7.30 (m, IH), 7.82 (s, IH), 8.10 (dd, IH), 8.35 (d, IH), 8.50 (d, IH)

Example 8

5-Methyl-N-(3-pyridyl)-2,3^,6,7 -hexahydro-lH-pyrrolo[2,3-g]quinoIine-l- carboxamide hydrogen oxalate salt (E8)

The tide compound was prepared in die usual manner from 5-methyl-2,3,5,6,7,8- hexahydro-lH-pyrrolo-[2,3-g]quinoline (D22) (0.64g, 3m moles) and 3-pyridylisocyanate (0.4g, 3 mmoles) followed by treatment with oxalic acid and recrystallisation from methanol/diethylether. This gave (E8) (0.42g, 31%) m.p.l93-194°C

NMR (DMSO-d₆) δ: 1.80 - 1.95 (2H, m), 2.68 (2H, t, J=7Hz), 2.79 (3H, s), 3.05 - 3.19 (4H, m), 4.05 (2H, t, J=9Hz), 6.52 (IH, s), 7.30-7.38 (IH, ), 7.49 (IH, s), 7.97 - 8.03 (IH, s), 8.15 - 8.25 (IH, brs), 8.59 (IH, s), 8.71 - 8.83 (IH, brs).

Example 9 2^3-Dihydro-7-hydroxy-l-(3-pyridylcarbamoyl)pyrrolo-[2^-f|indane (E9)

A solution of 3-pyridyl acyl azide (0.25g, l.όmmol) in toluene (10ml) was refluxed under argon for ~V£hr and cooled. To a solution of D30 (0.27 g, l.όmmol) in dichloromethane (10ml) was added the freshly formed 3-pyridylisocyanate solution. The solid which precipitated was filtered and dried. Recrystallisation from dichloromethane/ethanol afforded the tide compound (0.33g, 70%) as a white solid.

1H NMR (250MHz d₆ DMSO) δ: 1.78 (m, IH), 2.31 (m, IH), 2.61 (m, IH) 2.82 (m, IH), 3.14 (t, 2H), 4.12 (t, 2H), 4.95 (t, IH), 5.2 (d, IH), 7.01 (s, 1H),7.32 (m, IH), 7.89 (s, IH), 7.98 (dd, 1H),8.20 (m, IH), 8.66 (s, IH), 8.75 (m, IH) m.p. 200-201 °C

C17H17N3O2 requires C, 69.14; H, 5.80; N, 14.23 Found C, 68.85; H, 5.94; N, 14.34 Example 10 2^-Dihydro-7-oxo-l-(3-pyridylcarbamoyl)pyrrolo-[2,3-f]indane (E10)

To a stirred suspension of E9 (0.5g, 1.7mmol) in dichloromethane (20ml) was added manganese dioxide (1.03g, 11.9mmol) and die mixture refluxed for 36 hours under argon. The mixture was filtered dirough kieselguhr, the pad washed (5% methanol/dichloromediane) and die filtrate concentrated. Rash chromatography eluting with 2% methanol/dichloromethane afforded the title compound (0.23g, 46%) as a white solid.

m.p. >250°C

*H NMR (250MHz d₆-DMSO) δ: 2.63 (m, 2H), 3.01 (m, 2H, m), 3.28 (t, 2H), 4.21 (t, 2H), 7.35 (m, 2H), 8.00 (m, 2H), 8.24 (m, IH), 8.74 (d, IH), 8.80 (s, IH) M.S. ^m/z=293 (28%)

C₁₇H₁₅N3θ2.H2θ requires C, 65.56; H, 5.50; N, 13.96 Found C, 65.55; H, 5.01; N, 13.59

Example 11 2-Bromo-5,6-dihydro-N-(3-pyridyI)-thieno-[3,2-f]indole-7-carboxamide (Ell)

This was prepared from D36 according to die general mediod as for Example 1 affording the tide compound as a white solid (158 mg, 86%) m.p. >200° C.

δ(DMSO): 3.30 (2H, t, J 8Hz), 4.20 (2H, , J 8Hz), 7.35 (IH, m), 7.45 (IH, s), 7.60

(IH, s), 8.00 (IH, m), 8.25 (IH, m), 8.35 (IH, s), 8.75 (IH, m), 8.80 (IH, s). m/e 375 M⁺ Ci6Hi2N3Br O S requires 375

Example 12 5,6-Dihydro-N-(3-pyridyl)-thieno[3,2-f]-indoIe-7-carboxamide (E12)

This was prepared from D37 by the general mediod of Example 1 affording the title compound as a white solid (15 mg, 44%), mp 218-22° C. NMR (DMSO) δ: 3.30 (2H, t, J 8Hz), 4.25 (2H, t, J 8Hz), 7.30 (IH, d, J 5Hz),

7.35 (IH, m), 7.55 (IH, d, J 5Hz), 7.70 (IH, s), 8.00 (IH, m), 8.25 (IH, m), 8.40 (IH, s), 8.80 (2H, m). m/e 295 M+ C₁6H₁3N3θ S requires 295

Pharmacological Data

[^•Η]-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 therapeutic indications including the 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 dieir ability to displace [ H]-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 (400ml) was incubated widi [³H]-mesulergine (0.5nM) in Tris HCl buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in d e presence of mianserin (10^"^M). Ten concentrations of test drug (3 x 10^~9 to 10^"4M 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 the pK_j (the negative logaritiim of the inhibition constant) calculated from the Cheng Prusoff equation where: Ki = IC₅₀

l+_£ Kd Kj = inhibition constant. C = concentration of [³H]-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 12 had pKi values in the range 6.43 - 8.58

Claims

Claims:

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

(I) wherein: P represents phenyl, 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;

J represents a bicyclic aromatic or partially saturated ring system;

R! and R² are independently hydrogen, halogen, hydroxy, oxygen, or C^.g alkyl optionally substituted by one or more halogen atoms;

R⁴ is hydrogen, C . alkyl, C\. alkyldiio, halogen, nitro, cyano, CF3, NR^R⁹, CO2R¹²,

CONR ² or OR ^², where R^, R⁹ and R*² are independendy hydrogen, C\.(, alkyl or arylCι_6alkyl;

R5 is hydrogen or Cj_6 alkyl; n is 2 or 3; and the groups R*³ and R ⁴ are independently hydrogen or C\. alkyl, provided tiiat:

P is not a heterocyclic group when J forms a benzothiophene ring.

2. A compound according to claim 1 in which P is pyridyl.

3. A compound according to claim 2 or 3 in which J is quinoline, tetrahydroquinoline, benzofuran, benzothiophene, or indane.

4. A compound according to any one of claims 1 to 3 in which R! and R² are both hydrogen.

5. A compound according to any one of claims 1 to 4 in which R⁴ and R^ are both hydrogen.

6. A compound according to any one of claims 1 to 5 in which (CHR^l )_n is an ethylene group.

7. A compound according to claim 1 which is selected from: l-(3-Pyridylcarbamoyl)-2,3-dihydro-lH-pyrrolo [2,3-g] quinoline,

2-Methyl-6,7-dihydro-5-(3-pyridylcarbamoyl)-furo[2,3-f]indole, l-(3-Pyridylcarbamoyl)-2,3-dihydropyrrolo-[2,3-f]-indene,

2,3-Dihydro-l-(3-pyridylcarbamoyl)-pyrrolo[3,2-b]quinoline,

5,6-Dihydro-3-medιyl-N-(3-pyridyl)-furo[3,2-f]indole-7-carboxamide,

2,2-DimeΛyl-2,3,6,7-tetrahydro-N-(3-pyridyl)furo[2,3-fjindole-5-carboxamide,

2,3,6,7-Tetrahydro-5-(3-pyridylcarbamoyl)-5H-thieno[2,3-f]indole, 5-Methyl-N-(3-pyridyl)-2,3,5,6,7,8-hexahydro- lH-pyrrolo[2,3-g]quinoline- 1-carboxamide,

2,3-Dihydro-7-hydroxy-l-(3-pyridylcarbamoyl)pyrrolo-[2,3-fJindane,

2,3-Dihydro-7-oxo-l-(3-pyridylcarbamoyl)pyrrolo-[2,3-f| indane,

2-Bromo-5,6-dihydro-N-(3-pyridyl)-diieno-[3,2-f]indole-7-carboxamide,

5,6-Dihydro-N-(3-pyridyl)-dιieno[3,2-f]-indole-7-carboxamide, or a pharmaceutically acceptable salt tiiereof.

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

9. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier or excipient.

10. A process for the preparation of a compound of formula (I) or a salt thereof, which process comprises: the coupling of a compound of formula (II)

(ID with a compound of formula (III);

(IH)

wherein A and R^ contain the appropriate functional group(s) necessary to form the moiety, -NR^ CO when coupled, wherein R^' is R^ as defined in formula (I) or a group convertible tiiereto, n, J and P as defined in formula (I), and the variables R*', R²', R⁴' R¹³'and R¹⁴' are R¹, R², R⁴, R¹³ and R¹⁴ respectively, as defined in formula (I), or groups convertible diereto, and thereafter optionally and as necessary and in any appropriate order, converting any R¹', R²', R⁴', R5¹, R ³' and R ⁴' and when otiier than R¹, R² R⁴, R⁵, R¹³ and R¹⁴ respectively to Rl, R², R⁴ R5, R1³ and R¹⁴, interconverting R*, R², R⁴, R^, R^³ and R^⁴, and forming a pharmaceutically acceptable salt thereof.