WO1997035862A1

WO1997035862A1 - Azaspiroderivatives

Info

Publication number: WO1997035862A1
Application number: PCT/EP1997/001406
Authority: WO
Inventors: Laramie Mary Gaster; Paul Adrian Wyman
Original assignee: Smithkline Beecham Plc
Priority date: 1996-03-27
Filing date: 1997-03-19
Publication date: 1997-10-02
Also published as: JP2000507254A; GB9606396D0; EP0889893A1

Abstract

Compounds of formula (I) where B is oxygen or sulphur, D is carbon or nitrogen, E is oxygen, CR?18R19 or NR20¿, with 5HT1B receptor antagonist activity.

Description

AZASPIRODERIVATIVES

The present invention relates to novel piperidine derivatives, processes for their preparation, and pharmaceutical compositions containing them.

EPA 0 533 266/7/8 disclose a series of benzanilide derivatives which are said to possess 5HT_{1 D} receptor antagonist activity. These compounds are said to be of use in the treatment of various CNS disorders. The 5HT_{1 D β} receptor has now been reclassifϊed as the 5HT_{1 B} receptor (P.R Hartig et al Trends in Pharmacological Science, 1996, 17, 103 - 105.

A structurally distinct class of compounds have now been discovered and have been found to exhibit 5HT_1B receptor antagonist activity. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt or N-oxide thereof:

in which

R¹ is hydrogen, halogen, C_{1 -6}alkyl, C_3-6cycloalkyl, COC_1-6alkyl, C_{1 -6}alkoxy, hydroxy, hydroxy C_{1 -6}alkyl, hydroxyC_1-6alkoxy, C_{1 -6}alkoxy C_{1 -6}alkoxy, acyl, nitro,

trifluoromethyl, cyano, SR⁹, SOR⁹, SO₂R⁹, SO₂NR¹⁰R¹¹, CO₂R¹⁰, NR¹⁰SO₂R ¹¹, CONR¹⁰R¹¹, CO₂NR¹⁰R¹¹, CONR¹⁰(CH₂)_pCO₂R¹¹ , (CH₂)_pNR¹⁰R¹¹,

(CH₂)_pCONR¹⁰R¹¹, (CH₂)_pNR¹⁰COR¹¹, (CH₂)_pCO₂C_1-6alkyl, CO₂(CH₂)_pOR¹⁰, CONHNR ¹⁰R^{1 1}, NR¹⁰R¹¹, N=CNR⁹NR¹⁰R^{1 1}, NR¹⁰CO₂R ^{1 1},

NR¹⁰CO(CH₂)_pNR¹⁰R^{1 1}, NR¹⁰CONR¹⁰R^{1 1}, CR¹⁰=NOR^{1 1}, CNR¹⁰=NOR¹¹, where R⁹, R¹⁰ and R¹¹ are independently hydrogen or C_1-6alkyl and p is 1 to 4; or R¹ is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;

R² and R³ are independently hydrogen, halogen, C_1-6alkyl, C_3-6cycloalkyl,

C_3-6cycloalkenyl, C_{1 -6}alkoxy, hydroxyC _1-6alkyl, C_{1 -6}alkylOC_1-6alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R¹⁰, CONR ¹⁰R¹¹, NR ¹⁰R¹¹ where R¹⁰ and R^{1 1} are independently hydrogen or C_1-6 alkyl, or R² and R³ together form a group -(CH₂)_r-R¹⁴-(CH₂)_s- where R¹⁴ is O, S, CH₂ or NR¹⁵ where R¹⁵ is hydrogen or C_{1 -6}alkyl and r and s are independently 0, 1 or 2;

B is oxygen or sulphur; D is nitrogen, carbon or a CH group;

R⁶ is hydrogen or C^{1 -6}alkyl and R⁷ is hydrogen, C^1-6alkyl, C^1-6alkoxy or halogen or R⁶ together with R⁷ forms a group -A- where A is (CR¹⁶R¹⁷)_t where t is 2, 3 or 4 and R¹⁶ and R¹⁷ are independently hydrogen or C_1-6alkyl or A is (CR¹⁶R ¹⁷)_u-J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR¹⁶=CR¹⁷, CR¹⁶=N, =CR¹⁶O, =CR¹⁶S or

=CR¹⁶-NR¹⁷;

R⁸ is hydrogen, C _1-6alkyl, C_3-6cycloalkyl, C_2-6alkenyl or C_{1 -6}alkylC_3-6cycloalkyl; R⁹ and R¹⁰ are independently hydrogen or C_1-6a lkyl;

E is oxygen, CR¹⁸R¹⁹ or NR²⁰ where R¹⁸, R¹⁹ and R²⁰ are independently hydrogen or C_{1 -6}alkyl or E is S(O)_v where v is 0, 1 or 2;

G is C=O or CR²¹R²² where R²¹ and R²² are independently hydrogen or C _1-6alkyl; X and Y are independently CR⁹R¹⁰ where R⁹ and R¹⁰ are as defined above; and m is 1, 2 or 3; provided that the group B is not oxygen when

• D is nitrogen, R⁶ and R⁷ form a group (CR¹⁶R¹⁷)_t or (CR¹⁶R¹⁷)_u-J where J is oxygen, sulphur or CR¹⁶=CR¹⁷, and G, X, Y and CR⁹R¹⁰ are all CH₂ groups; or

• D is nitrogen, R⁶ is hydrogen, R¹ is other than N=CNR⁹NR¹⁰R^{1 1} , and G, X, Y and CR⁹R¹⁰ are all CH₂ groups.

C_{1 -6}alkyl groups, whether alone or as part of another group, may be straight chain or branched. As used herein the term aryl includes phenyl and naphthyl. Heteroaryl groups include thienyl, furyl, pyridyl, pyrimidyl and pyrazinyl groups. Optional substituents for aryl and heteroaryl groups include those groups listed above for R²/R³.

Suitably R¹ is hydrogen, halogen, C_{1 -6}alkyl, C_3-6cycloalkyl, COC_1-6alkyl, C^alkoxy, hydroxy, hydroxyC_1-6alkyl, hydroxyC_1-6alkoxy, C_{1 -6}alkoxyC_{1 -6}alkoxy, acyl, nitro, trifluoromethyl, cyano, SR⁹, SOR⁹, SO₂R⁹, SO₂NR¹⁰R^H, CO₂R¹⁰, NR¹⁰SO₂R^{1 1}, CONR¹⁰R¹¹, CO₂NR¹⁰R^{1 1}, CONR¹⁰(CH₂)_pCO₂R¹¹,

(CH ₂)pNR¹⁰R^{1 1}, (CH₂)_pCONR¹⁰R^{1 1}, (CH ₂) _pNR¹⁰COR¹¹ , (CH₂)_pCO₂C_1-6alkyl, CO₂(CH₂)_pOR¹⁰, CONHNR ¹⁰R¹¹, NR¹⁰R^{1 1}, N=CNR⁹NR¹⁰R¹¹, NR¹⁰CO₂R¹¹ , NR¹⁰CO(CH₂)pNR¹⁰R¹¹, NR¹⁰CONR¹⁰R¹¹ , CR¹⁰=NOR¹¹ , CNR¹⁰=NOR¹¹ , where R⁹, R¹⁰ and R¹¹ are independently hydrogen or C_1-6alkyl and p is 1 to 4.

When R¹ is a 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur, suitable heterocyclic rings include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl. The heterocyclic rings can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom. Suitable substituents for these rings include R² and R³ groups as defined above. Preferably R¹ is optionally substituted triazolyl, thiazolyl, isoxazolyl, pyrazinyl or oxadiazolyl. Most preferably R¹ is optionally substituted oxadiazolyl. Preferred substituents include C_1-6alkyl such as methyl. Most preferably R¹ is a 5-methyl-1,2,4-oxadiazol-3-yl group.

Suitably R² and R³ are independently hydrogen, halogen, C_{1 -6}alkyl,

C_3-6cycloalkyl, C_3-6cycloalkenyl, C_1-6alkoxy, hydroxyC_1-6alkyl, C _1-6alkylOC _1-6alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R ¹⁰, CONR ¹⁰R ¹¹ , NR¹⁰R¹¹ where R¹⁰ and R^{1 1} are independently hydrogen or C_1-6alkyl, or R² and R³ together form a group -(CH₂)_rR¹⁴-(CH₂)_s- where R¹⁴ is O, S, CH₂ or NR¹⁵ where R¹⁵ is hydrogen or C_1-6alkyl and r and s are independently 0, 1 or 2. Preferably the R² group is ortho with respect to the biphenyl linkage. Preferably R² is hydrogen or C_1-6alkyl, in particular methyl. Preferably R³ is hydrogen.

Suitably B is oxygen or sulphur. Preferably B is oxygen.

Suitably D is nitrogen, carbon or a CH group. Preferably D is nitrogen.

Suitably R⁶ is hydrogen or C_{1 -6}alkyl and R⁷ is hydrogen, C_1-6alkyl, C_1-6alkoxy or halogen or R⁶ together with R⁷ forms a group -A- where A is (CR ¹⁶R¹⁷)_t where t is 2, 3 or 4 and R¹⁶ and R¹⁷ are independently hydrogen or C_{1 -6}alkyl or A is (CR¹⁶R¹⁷)_U-J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR¹⁶=CR¹⁷, CR¹⁶=N, =CR¹⁶O, =CR¹⁶S or =CR¹⁶-NR¹⁷. Preferably R⁶ together with R⁷ forms a group -A- where A is (CR¹⁶R¹⁷)_t where t is 2 or 3 and R¹⁶ and R¹⁷ are both hydrogen.

Suitably R⁸ is hydrogen, C_{1 -6} alkyl, C_3-6cycloalkyl, C_2-6alkenyl or

C_1-6alkylC_3-6cycloalkyl. Preferably R⁸ is C_1-6alkyl, most preferably R⁸ is methyl.

Suitably R⁹ and R ¹⁰ are independently hydrogen or C_1-6alkyl. Preferably R⁹ and RIO are both hydrogen. Preferably m is 2 forming part of a spiro-piperidine ring.

Suitably E is oxygen, CR¹⁸R¹⁹ or NR²⁰ where R¹⁸, R¹⁹ and R²⁰ are independently hydrogen or C_{1 -6}alkyl or E is S(O)_v where v is 0, 1 or 2. Preferably E is oxygen.

Suitably G is C=O or CR²¹R²² where R²¹ and R²² are independently hydrogen or C_{1 -6}alkyl. Preferably G is CH₂.

Suitably X and Y are independently CR⁹R ¹⁰ where R⁹ and R¹⁰ are as defined above. Preferably X and Y are both CH₂.

Particularly preferred compounds of the invention include:

1'-Methyl-5-[2'-methyl-4^,-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-thiocarbonyl]- 2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine],

2,3-Dihydro-1^,-methyl-5-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4- carbonyl]spiro[furo[3,2-f]indole-3,4'-piperidine],

or pharmaceutically acceptable salts or N-oxides thereof.

Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalatcs, methanesulphonates and p-toluenesulphonates.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and the mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the invention.

In a further aspect the present invention provides a process for the preparation of a compound of formula (I) which comprises.

(a) for compounds of formula (I) where D is nitrogen and B is oxygen, reaction of a compound of formula (II):

in which R¹, R² and R³ are groups as defined in formula (I) or protected derivatives thereof and L is a leaving group,

with a compound of formula (III):

wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, E, G, X, Y, and m are groups as defined in formula (I) or protected derivatives thereof and optionally thereafter in any order:

• removing any protecting groups,

• converting a compound of formula (I) into another compound of formula (I),

• forming a pharmaceutically acceptable salt.

Suitable activated carboxylic acid derivatives of formula (II) include acyl halides and acid anhydrides. Activated compounds of formula (II) can also be prepared by reaction of the corresponding carboxylic acid with a coupling reagent such as

carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazide Preferably the group L is halo, particularly chloro. A compound of formulae (II) and (III) are typically reacted together in an inert organic solvent such as DMF, THF or dichloromethane at ambient or elevated temperature in the presence of a base such as an alkali metal hydroxide, triethylamine or pyridine.

Alternatively L is an ester forming group such that the resulting esters of formula (II) can be reacted with compounds of formula (III) in the presence of an organo- aluminium reagent such as trimethylaluminium. Such a reaction is typically carried out in the presence of an inert solvant such as toluene.

Intermediate compounds of formulae (II) and (I II) can be prepared using standard procedures known in the art. Certain intermediate compounds of formula (III) are novel and form a further aspect of the invention.

It will be appreciated to those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques can be used such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981). For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives.

Carboxylic acid groups can be protected as esters. Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions.

5HT_{1 B} receptor antagonists, and in particular the compounds of the present invention, are expected to be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal affective disorder and dysthymia, anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; and disorders of eating behaviours, including anorexia nervosa and bulimia nervosa. Other CNS disorders include motor disorders such as Parkinson's disease, dementia in

Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.

5HT_{1 B} receptor antagonists, and in particular compounds of the present invention, may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, in the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and

hypothermia.

Therefore, the present invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy. The present invention also provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the

aforementioned disorders.

In another aspect the invention provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of the aforementioned disorders.

In a further aspect the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In particular the invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.

It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents.

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, reconstitu table powders, injectable or infusible 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 colorants.

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 sterilisation 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 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.

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

Description 1

1-Acetyl-6-aminoindoline

6-Nitroindoline (15.63g, 0.095 mol) was refluxed for 0.25 h in acetic anhydride (100 ml), cooled, and the precipitate filtered and washed with water, before drying in vacuo. This material (16.6g, 0.08 mol) was hydrogenated in ethanol (500 ml) over 10% palladium on charcoal (3.4g of 50% paste in water). The catalyst was removed by filtration and the filtrate was evaporated to leave the title compound as an off-white/cream powder (12.59g; 89%).

¹H NMR (250 MHz, CDCI₃) δ (ppm): 7.66 (s, 1H), 6.92 (d, 1H), 6.35 (d, 1H), 4.01 (t, 2H), 3.65 (br s, 2H), 3.05 (t, 2H), 2.2 (s, 3H)

Description 2

1-AceryI-6-hydroxyindoline

A solution of 1-acetyl-6-aminoindoline (D1, 12g, 0.068 mol) in concentrated sulfuric acid (9 ml) and water (137 ml) was cooled to 0°C and diazotised by the dropwise addition of sodium nitrite (4.8g) in water (34 ml), maintaining the temperature at below 5°C. After 0.5 h, the reaction mixture was added to a boiling stirred solution of copper (II) sulfate (69g) in water (120 ml). After evolution of nitrogen had ceased, the mixture was cooled, and the precipitate collected by filtration, washed with water, then dried. The compound was purified by column chromatography of its 0-acetyl derivative, then hydrolysed with aqueous NaOH at 20ºC over 18 hrs to afford the title compound as a grey solid (2.6g, 22%).

¹H NMR (250 MHz, d⁶DMSO) δ (ppm): 9.20 (s, 1H), 7.58 (d, 1H), 6.96 (d, 1H), 6.35 (dd, 1H), 4.04 (t, 2H), 2.98 (t, 2H), 2.12 (s, 3H). Description 3

1-Acetyl-5-bromo-6-hydroxyindoline

A stirred suspension of finely powdered 1-acetyl-6-hydroxyindoline (D2, 2.4g, 0.013 mole) in a mixture of DMF (25 ml) and glacial acetic acid (125 ml) at 15°C was treated portionwise over 5 minutes with N-bromosuccinimide (2.65g, 0.015 mole). The reaction mixture changed from yellow to grey-green in colour. The mixture was stirred at 15-20°C for 45 minutes, then cooled to 5°C and the solid filtered off, washed with acetic acid and dried to give the title compound as a grey solid (2.45g, 71%).

¹H NMR (250 MHz, d⁶DMSO) δ (ppm): 7.82 (s, 1H), 7.26 (s, 1H), 4.05 (t, 2H), 3.00 (t, 2H), 2.12 (s, 3H).

Description 4

1-Acetyl-5-bromo-6-[(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)methoxy]indoline The title compound was prepared from 1-acetyl-5-bromo-6-hydroxyindoline (D3) and 1- methyl-1,2,5,6-tetrahydropyridine-4-methanol (J. Med. Chem., 1988, 31, 545) using the procedure of Description 8a in W096/19477. The product was purified by acid/base extraction, then used in the next step. ¹H NMR (250 MHz, CDCI₃) δ (ppm): 7.96 (s, 1H), 7.27 (s, 1H), 5.84 (m, 1H), 4.50 (s, 2H), 4.05 (t, 2H), 3.10 (t, 2H), 3.03-2.95 (m, 2H), 2.58 (t, 2H), 2.35 (s, 3H), 2.35-2.25 (m, 2H), 2.20 (s, 3H).

Description 5

7-Acetyl-1'-methyl-2,3,5,6-tetrahydrospiro[furo[3,2-f]indole-3,4'-piperidine]

The title compound was prepared from 1-acetyl-5-bromo-6-[(1-methyl-1,2,5,6- tetrahydropyridin-4-yl)methoxy]indoline (D4) using a similar procedure to Description 8b in WO96/ 19477, but with toluene at 80°C in place of refluxing benzene. The product was obtained from the acid/base purification as a beige solid (94%).

¹H NMR (250 MHz, CDCI₃) δ (ppm): 7.75 (s, 1H), 6.85 (s, 1H), 4.37 (s, 2H), 4.05 (t, 2H), 3.10 (t, 2H), 2.95-2.75 (m, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.05-1.85 (m, 4H), 1.80- 1.65 (m, 2H).

Description 6

1'-MethyI-2,3,5,6-tetrahydrospiro[furo[3,2 -f]indole-3,4'-piperidine]

The title compound was prepared from 7-acetyl-1'-methyl-2,3,5,6- tetrahydrospiro[furo[3,2-f]indole-3,4'-piperidine] (D5) using the procedure of Description 8c in W096/19477. The product was recry stall ised from ethyl acetate/60-80 petrol (44%). ¹H NMR (250 MHz, CDCI₃) δ (ppm): 6.83 (s, 1H), 6.05 (s, 1H), 4.32 (s, 2H), 3.7 (br s, 1H), 3.55 (t, 2H), 2.93 (t, 2H), 2.90-2.75 (m, 2H), 2.30 (s, 3H), 2.05-1.85 (m, 4H), 1.80- 1.65 (m, 2H). Description 7

2,3-Dihydro-1'-methylspiro[furo[3,2-f]indole-3,4'-piperidine]

A stirred solution of 1' -methyl-2,3,5,6-tetrahydrospiro[furo[3,2-f]indole-3,4'-piperidine] (D6, 1.0g, 4.1 mmole) in dichloromethane (70 ml) at room temp, under argon was treated with manganese dioxide (0.68g, 8.2 mmole). The mixture was stirred for 18 hours, then additional manganese dioxide was added (0.30g, 2.4 mmole). The mixture was stirred for an additional 24 hours, then filtered through a pad of kieselguhr and the filtrate

concentrated under vacuum. The two components present were separated by

chromatography on neutral alumina. Elution with ether gave the title compound as a white solid (0.41g, 41%), further elution with ethyl acetate gave the second component.

¹H NMR (200 MHz, CDCI₃) δ (ppm): 8.10 (br s, 1H), 7.32 (s, 1H), 7.10-7.04 (m, 1H), 6.78 (s, 1H), 6.50-6.43 (m, 1H), 4.40 (s, 2H), 2.90-2.80 (m, 2H), 2.35 (s, 3H), 2.20-1.95 (m, 4H), 1.90-1.70 (m, 2H).

Example 1

1'-Methyl-S-[2'-methyl-4'-(5-methyl-1,2 ,4-oxadiazol-3-yl)bipheny l-4-thiocarbonyl]-

2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]

A stirred solution of 1'-methyl-5-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4- carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (Example 1 in WO 96/19477) (300 mg, 0.577 mmol) in toluene (25 ml) under argon was treated with

Lawesson's reagent (117 mg, 0.288 mmol) and the suspension was heated under reflux for 3 hrs until a yellow solution resulted. The reaction mixture was allowed to cool to room temperature, then concentrated in vacuo and loaded onto a neutral alumina column and eluted with DCM, to remove excess Lawesson's reagent. Elution with 1%

methanol/dichloromethane afforded the crude product, which was concentrated in vacuo and the resulting bright yellow solid was chromatographed on silica gel eluting with 2% methanol/dichloromethane to afford the title compound as a bright yellow foam, which crystallised on standing (157 mg, 51%). This was converted to its hydrochloride salt, which precipitated from acetone. ¹H NMR (free base) (250 MHz, CDCI₃) δ (ppm): 8.01 (s, 1H), 7.94 (dd, 1H), 7.51 (d, 2H), 7.39 (dd, 3H), 6.68 (s, 1H), 4.67 (t, 2H), 4.30 (s, 2H), 3.17 (t, 2H), 2.69 (s, 3H), 2.64 (br s, 2H), 2.39 (s, 3H), 2.25 (s, 3H), 1.96-1.72 (m, 2H), 1.65-1.37 (m, 4H). 1-Aromatic signal not discernible from the spectrum.

Example 2

2,3-Dihydro-1^,-methyl-5-[2^,-methyl-4^,-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4- carbonyI]spiro[furo[3,2-f]-ndole-3,4'-piperidine]

A solution of 2,3-dihydro-1'-methylspiro[furo[3,2-f]indole-3,4'-piperidine] (D7, 187 mg, 0.77 mmole) in dry THF (3 ml) was added dropwise over 0.25 hours to a stirred solution of ethylmagnesium bromide (0.80 mmole) in dry THF (5 ml) at room temp, under argon and the resulting mixture heated at 40°C for 30 minutes. The dark green solution was then cooled to 0°C and treated dropwise over 5 minutes with a solution of 2'-methyl-4'-(5- methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl chloride (265 mg, 0.85 mmole, WO9619477-A1, Example 1) in dry THF (3 ml). The reaction mixture was stirred at room temp, for 0.5 h, then at 40°C for 0.75h, then concentrated under vacuum. The residue was treated with 10% Na₂CO₃ solution and extracted with dichloromethane. The extract was dried (Na₂SO₄), concentrated in vacuo and the residual brown solid chromatographed on silica gel eluting with 0-5% methanol/chloroform. This afforded the 1,3-diaroylated product (70 mg), which was treated with methanol (10 ml), 10% NaOH solution (10 ml) and dichloromethane (10 ml) and the two-phase system stirred at room temp, for 1 h. The mixture was extracted with dichloromethane (2 x 30 ml) and the combined extract dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by preparative plate TLC on silica gel eluting with 10% methanol/chloroform and the oil obtained was crystallised from ethyl acetate to afford the title compound as a beige solid (21 mg). ¹H NMR (200 MHz, CDCI₃) δ (ppm): 8.74 (br s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.75 (d, 1H), 7.68 (d, 2H), 7.40 (d, 1H), 7.24 (d, 2H), 7.17 (d, 1H), 6.60 (s, 1H), 4.25 (s, 2H), 2.80-2.60 (m, 2H), 2.48 (s, 3H), 2.17 (s, 6H), 2.05-1.75 (m, 4H), 1.70-1.52 (m, 2H).

Claims

CLAIMS:

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

in which

R¹ is hydrogen, halogen, C_1-6alkyl, C_3-6Cycloalkyl, COC_1-6alkyl, C_1-6alkoxy, hydroxy, hydroxyC_1-6alkyl, hydroxy C_1-6alkoxy, C_1-6alkoxy C_1-6alkoxy, acyl, nitro,

trifluoromethyl, cyano, SR⁹, SOR⁹, SO₂R⁹, SO₂NR¹⁰R¹¹, CO₂R¹⁰, NR¹⁰SO₂R¹¹, CONR¹⁰R¹¹, CO₂NR¹⁰R¹¹, CONR¹⁰(CH₂)pCO₂R¹¹, (CH₂)_pNR¹⁰R¹¹,

(CH₂)_pCONR₁₀R¹¹, (CH₂)pNR¹⁰COR¹¹, (CH₂)pCO₂C_1-6alkyl, CO₂(CH₂)_pOR¹⁰,

CONHNR¹⁰R¹¹, NR¹⁰R¹¹, N=CNR⁹NR¹⁰R¹¹, NR¹⁰CO₂R¹¹,

NR¹⁰CC(CH₂)_pNR¹⁰R¹¹, NR¹⁰CONR¹⁰R¹¹, CR¹⁰=NOR¹¹, CNR¹⁰= NOR¹¹, where R⁹, R¹⁰ and R¹¹ are independently hydrogen or C_1-6alkyl and p is 1 to 4; or R¹ is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;

R² and R³ are independently hydrogen, halogen, C_1-6alkyl, C_3-6cycloalkyl,

C_3-6Cycloalkenyl, C_1-6alkoxy, hydroxyC_1-6alkyl, C_1-6alkylOC_1-6alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R¹⁰, CONR¹⁰R¹¹, NR¹⁰R¹¹ where R¹⁰ and R¹¹ are independently hydrogen or C_1-6alkyl, or R² and R³ together form a group -(CH₂)_r-R¹⁴-(CH₂)_s- where R¹⁴ is O, S, CH₂ or NR¹⁵ where R¹⁵ is hydrogen or C_1-6alkyl and r and s are independently 0, 1 or 2;

B is oxygen or sulphur;

D is nitrogen, carbon or a CH group;

R6 is hydrogen or C_1-6alkyl and R⁷ is hydrogen, C_1-6alkyl, C_1-6alkoxy or halogen or R⁶ together with R⁷ forms a group -A- where A is (CR¹⁶R¹⁷)_t where t is 2, 3 or 4 and R¹⁶ and R¹⁷ are independently hydrogen or C_1-6alkyl or A is (CR¹⁶R¹⁷)_U-J where u is 0, 1, 2 or 3 and J is oxygen, sulphur, CR¹⁶=CR¹⁷, CR¹⁶=N, =CR¹⁶O, =CR¹⁶S or

=CR¹⁶-NR¹⁷;

R⁸ is hydrogen, C_1-6alkyl, C_3-6cycloalkyl, C_2-6alkenyl or C_1-6alkylC_3-6cycloalkyl; R⁹ and R¹⁰ are independently hydrogen or C_1-6alkyl; E is oxygen, CR¹⁸R¹⁹ or NR²⁰ where R¹⁸, R¹⁹ and R²⁰ are independently hydrogen or C_{1 -6}alkyl or E is S(O)_v where v is 0, 1 or 2;

G is C=O or CR²¹R²² where R²¹ and R²² are independently hydrogen or C _1-6 alkyl; X and Y are independently CR⁹R¹⁰ where R⁹ and R¹⁰ are as defined above; and m is 1, 2 or 3; provided that the group B is not oxygen when

• D is nitrogen, R⁶ is hydrogen, R¹ is other than N=CNR⁹NR¹⁰R^{1 1}, and G, X, Y and CR⁹R¹⁰ are all CH₂ groups.

2. A compound according to claim 1 in which R¹ is optionally substituted oxadiazole.

3. A compound according to claim 1 or 2 in which R² is C_1-6alkyl.

4. A compound according to any one of claims 1 to 3 in which m is 2.

5. A compound according to any one of claims 1 to 4 in which R⁸ is C_{1 -6}alkyl.

6. A compound according to any one of claims 1 to 5 in which E is oxygen.

7. A compound according to claim 1 which is:

1'-Methyl-5-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-thiocarbonyl]- 2,3,6,7-tetrahydrospiro[furot2,3-f]indole-3,4'-piperidine],

2,3-Dihydro-1'-methyl-5-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4- carbonyl]spiro[furo[3,2-f]indole-3 ,4'-piperidine],

or pharmaceutically acceptable salts or N-oxides thereof.

8. A process for the preparation of a compound of formula (I) which comprises:

with a compound of formula (III):

• removing any protecting groups,

• converting a compound of formula (I) into another compound of formula (I),

• forming a pharmaceutically acceptable salt..

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

10. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 in association with a pharmaceutically acceptable carrier or excipient.